U.S. patent application number 10/420716 was filed with the patent office on 2003-11-27 for method for producing epothilone b and derivatives, and intermediate products for this method.
This patent application is currently assigned to Schering Aktiengesellschaft. Invention is credited to Mantoulidis, Andreas, Mulzer, Johann, Ohler, Elisabeth.
Application Number | 20030220503 10/420716 |
Document ID | / |
Family ID | 7885043 |
Filed Date | 2003-11-27 |
United States Patent
Application |
20030220503 |
Kind Code |
A1 |
Mulzer, Johann ; et
al. |
November 27, 2003 |
Method for producing epothilone B and derivatives, and intermediate
products for this method
Abstract
This invention relates to a process for the production of
epothilone B and derivatives as well as intermediate products for
this process. In the new process, epothilone B or the derivatives
are built up in high yields from the C1-C6, C7-C10 and C11-C20
fragments (2, 3 and 4) that can be obtained at a reasonable price
and free of diastereomers (the variable radicals have the meanings
that are indicated in the description).
Inventors: |
Mulzer, Johann; (Berlin,
DE) ; Mantoulidis, Andreas; (Wien, AT) ;
Ohler, Elisabeth; (Klosterneuburg, AT) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
Schering Aktiengesellschaft
Berlin
DE
|
Family ID: |
7885043 |
Appl. No.: |
10/420716 |
Filed: |
April 23, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10420716 |
Apr 23, 2003 |
|
|
|
09807370 |
Jun 1, 2001 |
|
|
|
6605726 |
|
|
|
|
09807370 |
Jun 1, 2001 |
|
|
|
PCT/EP99/07746 |
Oct 14, 1999 |
|
|
|
Current U.S.
Class: |
548/181 |
Current CPC
Class: |
C07D 277/24 20130101;
Y02P 20/55 20151101; C07D 493/04 20130101 |
Class at
Publication: |
548/181 |
International
Class: |
C07D 417/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 14, 1998 |
DE |
198 48 306.6 |
Claims
1. Process for the production of epothilone B and derivatives of
general formula 19in which R means a methyl group, and R.sup.6
means a straight-chain or branched-chain alkyl group with up to 6
carbon atoms, a cycloalkylalkyl group with up to 10 carbon atoms, a
phenyl group, 1- or 2-naphthyl group, heteroaryl group, benzyl
group or methylheteroaryl group, characterized in that a compound
of general formula 3 20in which PG.sub.3 means a hydroxy protective
group, and FG.sub.3 means a phenylsulfonyl group, is reacted with a
compound of general formula 4 21in which FG.sub.4 means an iodine
atom or another leaving group, and PG.sub.4 meats a hydroxy
protective group, to form a compound of general formula 34-I 22in
which PG.sub.3 and PG.sub.4 have the above-indicated meanings, the
compound of general formula 34-I is reacted with a compound of
general formula 2 23in which PG.sub.21 and PG.sub.22, independently
of one another, in each case mean a hydroxy protective group, and
R.sub.6 means a straight-chain or branched-chain alkyl group with
up to 6 carbon atoms, a cycloalkylalkyl group with up to 10 carbon
atoms, a phenyl group, 1- or 2-naphthyl group, heteroaryl group,
benzyl group or methylheteroaryl group, to form a compound of
general formula 234 24in which PG.sub.21, PG.sub.22, PG.sub.4 and
R.sup.6 have the already indicated meanings, and this compound of
general formula 234 is reacted over the stages 25to form epothilone
D or a derivative of epothilone D 26and the latter then is
optionally converted by epoxidation into epothilone B
(R.dbd.CH.sub.3) or a derivative of epothilone B. 27
2. Process for the production of compounds of general formula 2
according to claim 1 28in which PG.sub.21 and PG.sub.22,
independently of one another, in each case mean a hydroxy
protective group, and R.sup.6 means a straight-chain or
branched-chain alkyl group with up to 6 carbon atoms, a
cycloalkylalkyl group with up to 10 carbon atoms, a phenyl group,
1- or 2-naphthyl group, heteroaryl group, benzyl group or
methylheteroaryl group wherein a compound of general formula 2-I
29in which PG.sub.21 means a hydroxy protective group, is reacted
under chiral catalysis with a silylketenacetal of general formula
30(R.sup.2=methyl, ethyl, etc.) with mediation by
7-tosylvaline/diborane to form a compound of general formula 2-II
31in which PG.sub.21 and R.sub.2 have the above-indicated meanings,
then the 3-hydroxy group is protected while a compound of general
formula 2-III 32in which PG.sub.21 and PG.sub.22, independently of
one another, in each case mean a hydroxy protective group, and
R.sup.2 has the above-indicated meaning, is obtained, then a methyl
group is added to the carbonal group of compound 2-III while a
compound of general formula 2-IV 33in which PG.sub.21 and
PG.sub.22, independently of one another, in each case mean a
hydroxy protective group, is obtained, and then is converted with
an alkyl, cycloalkylalkyl, aryl, heteroaryl, methyl, aryl or
methylheteroaryl halide of general formula 2-X R.sup.6Hal (2-X) in
which R.sup.6 has the already indicated meaning, and Hal stands for
a halogen atom fluorine, chlorine or bromine, into a compound
of-general formula 2 34in which PG.sub.21, PG.sub.22 and R.sup.6
have the above-indicated meanings, or the compound 2-III is reduced
to alcohol, the latter is selectively oxidized to aldehyde, a
radical of formula --CH.sub.2--R.sup.6 is added to the latter with
an organometallic compound, and the alcohol that is produced is
oxidized to form the ketone of general formula 2.
3. Process for the production of compounds of general formula 3
according to claim 1 35in which PG.sub.3 means a hydroxy protective
group, and FG.sub.3 means a phenylsulfonyl group, wherein the free
hydroxyl group of the compound of general formula 3-I 36in which
PG.sub.3 means a hydroxy protective group, is converted into a
better leaving group FG.sub.31 (compound 3-II) 37and then with
disclacement of FG.sub.31, the group --CH.sub.2--SO.sub.2-phenyl
(FG.sub.3=--SO.sub.2-phenyl) is added while a compound of general
formula 3 38is obtained.
4. Compounds of general formula 234 39in which PG.sub.21,
PG.sub.22, and PG.sub.4, independently of one another, in each case
mean a hydroxy protective group, and R.sup.6 means a straight-chain
or branched-chain alkyl group with up to 6 carbon atoms, a
cycloalkylalkyl group with up to 10 carbon atoms, a phenyl group,
1- or 2-naphthyl group, heteroaryl group, benzyl group or
methylheteroaryl group.
Description
[0001] This invention relates to a process for the production of
epothilone B and derivatives as well as intermediate products for
this process.
[0002] It is known that the natural substances epothilone A
(R.dbd.H) and epothilone B (R=methyl) (compound I, DE 195 42 986
A1, DE 41 38 042 C2) 1
[0003] have a fungicidal and cytotoxic effect. According to
indications for in vitro activity against mammary and intestinal
tumor cell lines, this family of compounds appears especially
advantageous for the development of a pharmaceutical agent. Various
working groups have successfully endeavored to synthesize these
macrocyclic compounds. The working groups start from various
fragments of the macrocycle to synthesize the desired natural
substances.
[0004] In any case, diastereomer-pure fragments as starting
products and intermediate products are required for a successful
epothilone synthesis. Diastereomer purity is often decisive for the
action and reliability of a pharmaceutical agent and thus a
requirement for its production.
[0005] The total synthesis of epothilone A is described by Schinzer
et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew.
Chem. 1997, 109, No. 5, pp. 543-544).
[0006] Epothilone derivatives were already described by Hofle et
al. in WO 97/19086. These derivatives were produced starting from
natural epothilone A or B.
[0007] Another synthesis of epothilone and epothilone derivatives
was described by Nicolaou et al. in Angew. Chem. 1997, 109, No.
1/2, pp. 170-172. Nicolaou et al. also described the synthesis of
epothilone A and B and several epothilone analogs in Nature, Vol.
387, 1997, pp. 268-272, and the synthesis of epothilone A and its
derivatives in J. Am. Chem. Soc., Vol.,119, No. 34, 1997, pp.
7960-7973, as well as the synthesis of epothilone A and B and
several epothilone analogs in J. Am. Chem. Soc., Vol. 119, No. 34,
1997, pp. 7974-7991.
[0008] Nicolaou et al. also describe in Angew. Chem. 1997, 109, No.
19, pp. 2181-2187 the production of epothilone A analogs using
combinative solid-phase synthesis. Several epothilone B analogs are
also described there.
[0009] The object of this invention is to provide a process for the
production of epothilone B and derivatives, in which epothilone is
built up from fragments that can be obtained at a reasonable price
and enantioselectively as starting products.
[0010] Another object is the provision of epothilone B or its
derivatives in higher yields than according to the previously known
processes.
[0011] The production of epothilone B according to this invention
is based on the linkage of three partial fragments 2, 3, and 4
according to the diagram below: 2
[0012] 2 means a C1-C6 fragment (epothilone numbering system) of
general formula: 3
[0013] in which
[0014] PG.sub.21 and PG.sub.22, independently of one another, in
each case mean a hydroxy protective group and
[0015] R.sup.6 means a straight-chain or branched-chain alkyl group
with up to 6 carbon atoms, a cycloalkylalkyl group with up to 10
carbon atoms, or a phenyl group, 1- or 2-naphthyl group, heteroaryl
group, benzyl group or methylheteroaryl group.
[0016] 3 stands for a C7-C10 fragment (epothilone numbering system)
of general formula: 4
[0017] in which
[0018] PG.sub.3 means a hydroxy protective group, and
[0019] FG.sub.3 means a phenylsulfonyl group.
[0020] 4 stands for a C11-C20 fragment (epothilone numbering
system) of general formula: 5
[0021] in which
[0022] FG.sub.4 means an iodine atom or another leaving group,
and
[0023] PG.sub.4 means a hydroxy protective group.
[0024] Synthesis:
[0025] Production of 2:
[0026] According to this invention, partial fragment 2 is obtained
with use of the following synthesis route enantioselectively from
very reasonably-priced starting compounds in an efficient way with
high enantiomer excesses.
[0027] The substituents have--unless otherwise indicated--the
meanings that are already indicated above in the individual
fragments: 6
[0028] Steps a and b:
[0029] The protected 3-hydroxypropanal (2-I), which was produced
analogously to the literature (Kiyooka et al., J. Org. Chem., 1991,
56, 2276,-2278) from 1,3-propanediol by monoprotection and
oxidation, is reacted under chiral catalysis with a
silylketenacetal of general formula 7
[0030] (R.sup.2=methyl, ethyl, etc.) with mediation by
N-tosylvaline/diborane to form (2-II), with high enantiomeric
excess. In compound (2-II), the 3-hydroxy group is then protected
according to methods that are known to one skilled in the art for
the production of the compound of general formula (2-III).
[0031] As alkyl, silyl and acyl radicals for the protective groups
PG.sub.21, PG.sub.22, PG.sub.3 and PG.sub.4, the radicals that are
known to one skilled in the art are considered. Alkyl or silyl
radicals that can be easily cleaved from the corresponding alkyl
and silyl ethers, such as, for example, the methoxymethyl,
methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl,
trimethylsilyl, triethylsilyl, tert-butyl-dimethylsilyl,
tert-butyldiphenylsilyl, tribenzylsilyl, trilsopropylsilyl, benzyl,
para-nitrobenzyl, or para-methoxybenzyl radical, and alkylsulfonyl
and arylsulfonyl radicals, are preferred. As acyl radicals, e.g.,
formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or
benzoyl, which can be substituted with amino and/or hydroxy groups,
are suitable.
[0032] A survey on protective groups is found in, e.g., "Protective
Groups in Organic Synthesis," Theodora W. Green, John Wiley and
Sons.
[0033] In this case, those protective groups are preferred that can
be cleaved under the action of fluoride, such as, e.g.,
trimethylsilyl, tert-butyldimethylsilyl, triisopropyl,
triethylsilyl, tert-butyldiphenylsilyl radicals, and of the latter
especially the tert-butyldimethylsilyl radical, triisopropylsily
radical, and the tert-butyldiphenylsilyl radical. 8
[0034] Steps c and d:
[0035] Compound (2-III) is converted into methylketone (2-IV) by
reaction with trimethylsilylmethyllithium and is then reacted to
form the compound of general formula 2, according to the methods
known to one skilled in the art, with an alkyl, cycloalkylalkyl,
aryl, heteroaryl, methylaryl or methylheteroaryl halide of formula
(2-X), R.sup.6-Hal, in which R.sup.6 means a straight-chain or
branched-chain alkyl group with up to 6 carbon atoms, a
cycloalkylalkyl group with up to 10 carbon atoms, a phenyl group,
1- or 2-naphthyl group, heteroaryl group, benzyl group or
methylheteroaryl group, and Hal means a halogen atom (chlorine,
bromine or iodine).
[0036] As an alternative, compound (2-III) can also be reduced to
alcohol, according to methods that are known to one skilled in the
art, selectively oxidized to aldehyde and then reacted with an
organometallic compound Me--CH.sub.2--R.sup.6 (Me stands for a
lithium atom or for a radical MgHal, Hal=Cl, Br: R.sup.6 has the
above-indicated meaning). Subsequent oxidation then also yields a
compound of general formula 2.
[0037] As C.sub.1-C.sub.6 alkyl groups for R.sup.6, for example, a
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
pentyl, isopentyl, neopentyl, or hexyl group is suitable.
[0038] For a cycloalkylalkyl group R.sup.6 with up to 10 carbon
atoms, for example, the cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl or cyclohexylmethyl group can be mentioned.
[0039] The heteroaryl radical, either as R.sup.6 or in
methylheteroaryl group R, can be, for example, a furyl, thienyl,
pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl,
quinolyl, or thiazolyl radical.
[0040] The radicals that are possible above for R.sup.6 can be
substituted in one or more places by halogen, OH, O-alkyl,
CO.sub.2H, CO.sub.2 -alkyl, --NH.sub.2, --NO.sub.2, --N.sub.3,
--CN, C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 acyl, or
C.sub.1-C.sub.20 acyloxy groups. Heteroatoms in the heteroaryl
radicals can be oxidized.
[0041] Production of 3:
[0042] The substituents have--if not otherwise indicated--the
meanings that are already indicated above in the individual
fragments.
[0043] Partial fragment 3 can be produced in high optical purity
from the hydroxyisobutyric acid methyl ester that can be obtained
inexpensively. 9
[0044] Steps a and b:
[0045] Compound (3-I) is available in a known way by monoprotection
and reduction from the commercially available hydroxyisobutyric
acid-methyl ester. Compound (3-I) is reacted with tosyl chloride to
form compound (3-II) (thus conversion of the hydroxy group into a
better leaving group; instead of the tosyl radical, other
conventional leaving groups, such as mesylate, triflate, etc., are
also possible); subsequent addition of a methylsulfone anion
(within the context of the examples of this invention this is
phenylsulfonylmethyl anion) yields a compound of general formula
3.
[0046] Production of 4:
[0047] The substituents have--if not otherwise indicated the
meanings that are already indicated above in the individual
fragments.
[0048] The partial fragments of formula 4 can be produced in an
efficient way with very high optical purity from inexpensive malic
acid that can be obtained at a reasonable price.
[0049] The synthesis is described below in the example of
L-(-)-malic acid.
[0050] Starting from D-(+)-malic acid, the corresponding
enantiomeric compounds are obtained, or starting from racemic malic
acid, the corresponding racemic compounds are obtained. 10
[0051] Steps a and b:
[0052] Compound (4-I) can be obtained commercially or according to
known processes from the conventional literature (Green et al.,
Tetrahedron, 199S, 51, 2865-2874). Compound (4-I) is protected
according to the methods that are known to one skilled in the art.
As protective groups, the protective groups that are already
indicated in more detail above under "Steps a and b" are suitable.
In the second step, compound (4-II) is reacted by the addition of
methyllithium to form the hemiacetal compound, which is in
equilibrium with the open-chain form (4-III). 11
[0053] Step c:
[0054] Compound (4-III) reacts in a highly (E)-stereoselective
manner, from the open form that is present in equilibrium, with
(2-methyl-thiazol-4-yl-methyl)-tributyl-phosphonium ylide, which
was obtained by deprotonation of the corresponding chloride or
bromide, to, form compound (4-IV). 12
[0055] Step d:
[0056] After selective oxidation of compound (4-IV) into aldehyde,
the latter is converted (Z)-stereospecifically into compound (4-V)
according to a method that is known to one skilled in the art with
a Still-Genari-Wittig reaction. 13 14
[0057] Steps e and f:
[0058] After compound (4-V) is reduced to form allyl alcohol
(4-VI), the terminal hydroxyl group is functionalized for the
linkage by conversion into a better leaving group, for example into
iodide, and yields the compound of general formula 4.
[0059] As other leaving groups, for example, the mesylate, tosylate
and triflate can be mentioned.
[0060] The production of compounds 4-V and 4-VI can also be
performed as described in International Patent Application
PCT/EP98/04462. Individual fragments 2, 3 and 4 are merged as shown
in International Patent Application PCT/EP 98/04462 and are
described more precisely below.
[0061] First, to this end, the synthesis of a coupling fragment
34-I from individual fragments 3 and 4 is to be performed. This
C7-C20 coupling fragment 34-I (epothilone numbering system) is
produced by anionic, sulfone-stabilized coupling and subsequent
reductive desulfonation. 15
[0062] Steps a and b:
[0063] After deprotonation of compound 3, it is anionically coupled
to compound 4. Subsequent reductive desulfonation according to the
methods that are known to one skilled in the art yields the C7-C20
coupling fragment (34-I). 16
[0064] Steps c, d and e
[0065] After protection of the 7-hydroxy group and protection
removal of the primary hydroxyl group (cleavage of PG.sub.3) in
compound 34-I and selective oxidation into aldehyde, C1-C20
coupling fragment (234) is shown with compound 2-in the form of an
aldol reaction
[0066] Epothilone B 1 or a derivative thereof is ultimately
produced in 8 additional synthetic stages from compound (234)
analogously to the existing literature (K. C. Nicolaou et al.,
Nature, Vol. 387, 1997, pp. 268-272 and J. Am. Chem. Soc. 1997,
119, pp. 7960-7973). 1718
[0067] The examples below are used for a more detailed explanation
of the invention, without intending that it be limited thereto:
EXAMPLES A-C
[0068] Production of the Compound of Formula 3
EXAMPLE A
[0069]
(3S)-4-((1,1-Dimethylethyl)diphenylsilyloxy]-3-methyl-1-phenylsulfo-
nylbutane
[0070] In 20 ml of absolute pyridine, 6.57 g (20 mmol) of
TBDPS-protected (2S)-methylpropane-1,3-diol is mixed with 6.94 g.
(40 mmol) of tosyl chloride at 0.degree. C., and it is stirred for
3.5 hours (Pyr-HCl salts precipitate out). For working-up, ice is
added, and it is stirred for 1 more hour. It is now extracted
several times with ether, washed with saturated NaHCO.sub.3
solution, dried on MgSO.sub.4, filtered and concentrated by
evaporation under vacuum in a rotary evaporator.
[0071] The crude product that still smells like pyridine is
flash-chromatographed on a 10:1-hex/EE-silica gel column. 8.67 g
(92.5%) of tosylated product, which was immediately further
processed, was obtained.
[0072] In 180 ml of absolute THF, 4.34 g (27.9 mmol, 1.5
equivalents) of methylphenylsulfone is mixed at -20.degree. C. with
16.77 ml (26.832 mmol, 1.45 equivalents) of a 1.6 M nBuLi solution
and slowly allowed to heat (30 minutes) to room temperature
(initially an orange, clear solution becomes cloudy). Now, the
tosylate, dissolved in about 20 ml of absolute THF, is added at
room temperature and stirred for about 12 more hours.
[0073] The violet solution is quenched with saturated NH.sub.4Cl
solution and then NaK-tartrate solution is added, until two clear
phases are produced. The phases are separated, the aqueous phases
are extracted twice more with ether, the combined organic phases
are dried on MgSO.sub.4 and filtered on a short silica gel frit,
rewashed with ether and concentrated by evaporation under vacuum in
a rotary evaporator.
[0074] After chromatography on a 5:1-hex/EE silica gel column,
7.689 g of the title compound was obtained as a viscous, colorless
oil, and also 630 mg of tosylated product, colorless, was obtained.
The title compound is thus-obtained in 89.1% yield or in 96.0%
yield keeping in mind the recovered educt (with the two chemical
reactions, thus 82.4% yield or 88.8% yield).
[0075] R.sub.f-value of tosylated product
(hex/EE=3:1).apprxeq.0.6
[0076] F II (blue),
[0077] F III (pale blue),
[0078] R.sub.f-value of the title compound
(hex/EE=3:1).apprxeq.0.39
[0079] F II (pale blue);
[0080] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0081] 0.84 (d, J=6.4 Hz, 3H, 3-CH.sub.3); 0.96 (s, 9H,
--SiC(CH.sub.3).sub.3); 1.60 (ddt, .sup.2J=12.8 Hz, J.sub.2a-H,
3-H=8.9 Hz, J.sub.2a-H, 1-H=7.4 Hz, 1H, 2a-H); 1.70 (mc, 1H, 3-H);
1.86 (dddd, .sup.2J=12.8 Hz, J.sub.2b-H, 3-H=8.9 Hz, J.sub.2b-H,
1-H=7.9 Hz, J.sub.2b-H, 1-H=5.9 Hz, 1H, 2b-H); 3.09 (mc, 2H, 1-H);
3.36 (dd, .sup.2J=9.8 Hz, J.sub.4a-H, 3-H=6.4 Hz, 1H, 4a-H); 3.44
(dd, .sup.2J=9.8 Hz, J.sub.4b-H, 3-H.ident.5.0 Hz, 1H, 4b-H); 7.37
(m, 6H, CH.sub.arom); 7.55 (m, 6H, CH.sub.arom); 7.63 (m, 1H,
(Ts)p-CH.sub.arom); 7.88 (mc, 2H, (Si)p-CH.sub.arom).
[0082] MS (El): m/e=
[0083] 468 [M+1]; 467 [M]; 460; 425; 414; 383; 382; 326; 267; 252;
213; 182; 136; 57.
[0084] Angle of rotation: [.alpha.].sub.D.sup.20=-5.8; (c=2.01;
CHCl.sub.3)
[0085] C.sub.27H.sub.34O.sub.3SSi:
(M=466.71 g.multidot.mol.sup.-1)
[0086] EA: Cld.: C: 69.5% H: 7.3%
[0087] Fnd.: C: 69.37% H: 7.50%
EXAMPLE B
[0088] (3S)-4-Hydroxy-3-methyl-1-phenylsulfonylbutane
[0089] In 140 ml of absolute THF, 7.5 g (16.07 mmol) of the sulfone
that is produced according to Example A is mixed with 22 ml (24.105
mmol) of a 1.1 M TBAF solution and stirred for 10 hours at room
temperature. The reaction is quenched with saturated NH.sub.4Cl
solution, the phases are separated, the aqueous phase is extracted
twice more with ether, the combined organic phases are dried on
MGSO.sub.4, filtered and concentrated by evaporation under vacuum
in a rotary evaporator.
[0090] After chromatography on a 1:1-hex/EE-silica gel column, 3.21
g (87.5) of the title compound was obtained as a colorless, viscous
oil.
[0091] R.sub.f-value (hex/EE=1:1).apprxeq.0.12 F III (pale
blue);
[0092] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0093] 0.87 (d, J=6.9 Hz, 3H, 3-CH.sub.3); 1.52 (t, J.sub.4-OH,
4-H=4.9 Hz, 1H, 4-OH); 1.60 (mc, 1H, 2a-H); 1.71 (mc, 1H, 3-H);
1.85 (ddt, .sup.2J=12.8 Hz, J.sub.2b-H, 3-H=9.4 Hz, J.sub.2b-H,
1-H=5.9 Hz, 1H, 2b-H); 3.15 (mc, 2H, 1-H); 3.40 (ddt, 2H, 4-H);
7.55 (mc, 2H, CH.sub.arom); 7.64 (mc, 1H, CH.sub.arom); 7.89 (mc,
2H, CH.sub.arom).
[0094] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0095] 16.3 (C-5); 26.1 (C-2); 34.6 (C-3); 54.3 (C-1); 67.4 (C-4);
128.0+129.3 (C-7 and C-8); 133.7 (C-9); 139.1
[0096] IR (Si film): .nu. in cm.sup.-1=
[0097] 3510br; 3063m; 2959s; 2934s; 2878s; 2668w; 1585w; 1447s;
1407m; 1302m; 1041m; 986m; 908m; 789s; 739s.
[0098] MS (El, 70 eV, 100.degree. C.): m/e=
[0099] 227 [M]; 210; 198 (58); 181 (8); 169 (13), 156 (17); 143
(100); 132 (26); 125 (37); 105 (30); 94 (15); 91 (27); 87 (83); 78
(85); 77 (97); 69 (93); 51 (30).
[0100] C.sub.23H.sub.29NO.sub.4S:
(M=228.30 g.multidot.mol.sup.-1)
EXAMPLE C
[0101]
(3S)-4-[(1,1-Dimethylethyl)dimethylsilyloxy]-3-methyl-1-phenylsulfo-
nyl-butane (Compound of Formula 3)
[0102] 5.548 g (24.3 mmol) of the compound that is produced
according to Example B with 3.31 g (2 equivalents, 48.6 mmol) of
imidazole are introduced into 30 ml of absolute DMF. 4.75 g (1.3
equivalents, 31.59 mmol) of TBSCl is now slowly added at 0.degree.
C. and stirred for 3 hours, whereby the temperature may slowly
increase to room temperature.
[0103] For working-up, 50 ml of saturated NH.sub.4Cl solution is
added at 0.degree. C. and diluted with ether. The phases are
separated, the aqueous phase is extracted three more times with
ether, the combined organic phases are washed with water, dried on
MGSO.sub.4, filtered on 3 cm of silica gel and concentrated by
evaporation in a vacuum.
[0104] Chromatographic purification on a 5:1-hex/EE-silica gel
column produced 8.216 g (98.7%) of the title compound.
[0105] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. in ppm=
[0106] -0.03 (s, 6H, --Si(CH.sub.3).sub.2); 0.81 (s, 9H),
--SiC(CH.sub.3).sub.3); 0.83 (d, J=6.5 Hz, 3H, 3-CH.sub.3); 1.55
(m, 1H, 2a-H); 1.65 (mc, 1H, 3-H); 1.79 (m, 1H, 2b-H); 3.14 (dd,
J=9.0 Hz, J=7.0 Hz, 2H, 1-H); 3.31 (dd, .sup.2J=10.0 Hz,
J.sub.4a-H,3-H=6.5 Hz, 1H, 4a-H); 3.42 (dd, .sup.2J=10.0 Hz,
J.sub.4b-H, 3H.congruent.5.0 Hz, 1H, 4b-H); 7.55 (m, 2H,
p-CH.sub.arom); 7.64 (m, 1H, m-CH.sub.arom); 7.90 (m, 2H,
o-CH.sub.arom).
[0107] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0108] -5.5 (Si(CH.sub.3).sub.2; 16.3 (3-CH.sub.3); 18.2
(SiC(CH.sub.3).sub.3); 25.8 (SiC(CH.sub.3).sub.3); 26.4 (C-2); 34.6
(C-3); 54.6 (C-1); 67.5 (C-4); 128.1 (o-CH.sub.arom); 129.2
(M-CH.sub.arom); 133.5 (p-CH.sub.arom); 139.1 (i-CH.sub.arom).
[0109] IR (Si-film): .nu. in cm.sup.-1=
[0110] 2957s; 1586w; 1447s; 1389m; 1306s; 1106vs; 740s; 689s;
562s.
[0111] MS (Fl, 7 kV, 3 mA, 40.degree. C.): m/e=
[0112] 343 ([M]); 310; 288; 287; 286; 285; 252; 224; 202; 182; 166;
125; 110; 78; 58; 57.
[0113] Angle of rotation: [.alpha.].sub.D.sup.20=-6.7; (c=2.64;
CHCl.sub.3)
[0114] C.sub.17H.sub.30O.sub.3SSi:
(M=342.56 g.multidot.mol.sup.-1)
[0115] EA: Cld.: C: 59.6% H 8.8%
[0116] Fnd.: C: 59.38% H 8.72%
EXAMPLES D-J
[0117] Production of Compound 4
EXAMPLE D
[0118]
(3S)-3-[(1,1-Dimethylethyl)dimethylsilyloxy]-oxolan-2-one
[0119] 3.92 g (38.4-mmol) of (S)-3-hydroxybutyrolactone with 5.23 g
(2 equivalents, 76.8 mmol) of imidazole are introduced at 0.degree.
C. into 50 ml of absolute DMF. 7.53 g (1.3 equivalents, 49.92
mmol), of TBSCl is now slowly added and stirred for 2.5 hours.
[0120] For working-up, it is diluted with 100 ml of ether, and the
reaction is quenched by adding 100 ml of saturated NH.sub.4Cl
solution. The phases are separated, the aqueous phase is extracted
three more times with ether, the combined organic phases are washed
with water, dried on MGSO.sub.4, filtered on 3 cm of silica gel and
concentrated by evaporation in a vacuum.
[0121] Chromatographic purification on a 15:1-hex/EE-silica gel
column produced 8.272 g (99.6%) of the title compound, as a
colorless oil (crystallized at <-20.degree. C.).
[0122] R.sub.f-value (hex/EE=1:1).apprxeq.0.70
[0123] R.sub.f-value (hex/EE=5:1).apprxeq.0.51 F I (blue);
[0124] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0125] 0.14 (s, 3H, --SiCH.sub.3); 0.17 (s, 3H, --SiCH.sub.3); 0.91
(s, 9H, --SiC(CH.sub.3).sub.3), 2.22 (dddd, J=12.8 Hz, J.sub.4-Ha,
3-H=9.0 Hz, J.sub.4-Ha, 5-Ha=9.0 Hz, J.sub.4-Ha, 5-Hb=8.6 Hz, 1H,
4-Ha); 2.45 (m, 1H, 4-Hb); 4.19 (td, J.sub.5-Ha, 4-Ha and 5-Hb=9.0
Hz, J.sub.5-Ha, 4-Hb=6.6 Hz, 1H, 5-Ha); 4.34-4.43 (m, 2H, 5-Hb and
3-H).
[0126] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0127] -5.3 (SiCH.sub.3); -4.2 (SiCH.sub.3); 18.2
(SiC(CH.sub.3).sub.3); 25.6 (SiC(CH.sub.3).sub.3); 32.3 (C-4); 64.7
(C-5); 68.2 (C-3); 175.8 (C-2).
[0128] IR (Si-Film): .nu. in cm.sup.-1=
[0129] 2956s; 2931s; 2887m; 2858s; 1788vs; 1473w; 1464w; 1362w;
1254m; 1220m; 1154vs; 1022s; 999s; 947m; 888m; 840s.
[0130] MS (Fl, 7 kV, 3 mA, 20.degree. C.): m/e=
[0131] 217 ([M+1], <1); 161 (4); 160 (11); 159 ([M-tBu], 100);
132 (<1).
[0132] Angle of rotation: [.alpha.].sub.D.sup.20=-30.5; (c=5.82;
CHCl.sub.3)
[0133] C.sub.10H.sub.20O.sub.3Si:
(M=216.35 g.multidot.mol.sup.-1)
EXAMPLE E
[0134]
(3S)-3-[(1,1-Dimethylethyl)dimethylsilyloxy]-2-methyl-oxolan-2-ol
or
(3S)-3-[(1,1-dimethylethyl)dimethylsilyloxy]-5-hydroxy-pentan-2-one
[0135] In 100 ml of absolute THF, 5.27 g (ex 24.34 mmol of
(S)-3-hydroxybutyrolactone) of the crude compound of Example D is
mixed drop by drop at -78.degree. C. with 18.26 ml (.gtoreq.1.2
equivalents, 29.216 mmol) of a 1.6 M MeLi solution (in ether,
Fluka) and stirred for 90 more minutes. The cooling bath is
removed, and the reaction is quenched by the quick but controlled
addition of saturated NH.sub.4Cl solution. The reaction solution is
allowed to heat to room temperature. It is now mixed with saturated
NaK-tartrate solution until two clear phases form. The solution is
diluted with ether, the phases are separated, the aqueous phase is
extracted twice more with ether, the combined organic phases are
dried on MGSO.sub.4, filtered and concentrated by evaporation in a
vacuum.
[0136] Chromatographic purification on a 10:1-5:1-hex/EE
gradient-silica gel column produced 4.958 g (87.7% over the two
stages) of the title compound(s) as a colorless, crystalline
compound.
[0137] Owing to this equilibrium and the diastereomer mixture, a
complete characterization of the product is not possible.
[0138] R.sub.f-value (hex/EE 5:1).apprxeq.0.22 F I (blue);
[0139] F III (green);
[0140] MS (Fl, 7 kV, 3 mA, 20.degree. C.): m/e=
[0141] 214 ([M-H.sub.2O]); 203; 189; 176; 175 ([M-tBu]); 157;
132.
[0142] C.sub.11H.sub.24O.sub.3Si:
(M=232.39 g.multidot.mol.sup.-1)
[0143] EA: Cld.: C: 56.9% H: 10.4%
[0144] Fnd. : C: 57.15% H: 10.34%
EXAMPLE F
[0145] 4-Chloromethyl-2-methyl thiazole
[0146] A solution of 1,3-dichloropropan-2-one (4.82 g, 38 mmol) and
thioacetamide (7.5 g, 0.1 mol) in anhydrous ethanol (70 ml) was
heated to boiling under argon for 5.5 hours and then concentrated
by evaporation in a vacuum. The dark-colored crystalline residue
was dissolved in water (about 250 ml), the aqueous solution was
washed several times with diethyl ether and brought to pH.apprxeq.8
by adding NaHCO.sub.3 and then shaken out with diethyl ether (four
times 100 ml). The dried, dark organic phase was filtered on a frit
coated with silica gel, rewashed with hex/ES (3:1) and concentrated
by evaporation.
[0147] The residue was purified by bulb tube distillation (bath
temperature: 90-95.degree. C., 10 Torr). 11.91 g (81%) of the title
compound was obtained as a light yellowish, skin-irritating
oil.
EXAMPLE G
[0148] (2-Methyl thiazol-4-yl)-methyl-tri-n-butyl-phosphonium
chloride
[0149] Tri-n-butylphosphane (38 ml, 0.156 mol) was added to a
solution of 4-chloromethyl-2-methylthiazole (23 g, 0.156 mol) in
anhydrous benzene-(200 ml) under argon, and the solution was heated
to boiling for 8 hours. Then, it was concentrated by evaporation in
a vacuum, the residue was dried for 30 more minutes at 0.01 Torr,
and the phosphonium salt was brought to crystallization by
trituration with dry diethyl ether. 53 g (97%) of the title
compound was obtained as colorless, hygroscopic crystals.
[0150] A sample under analysis was converted with aqueous KBr
solution into the corresponding bromide and purified by flash
chromatography on silica gel (EE/MeOH, 4:1) (melting point:
102-105.degree. C.).
[0151] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0152] 0.86 (t, J.sub.HH=7.0 Hz, 9H, CH.sub.2CH.sub.3) 1.35-1.50
(m, 12H, CH.sub.2); 2.35 (mc, 6H, P--CH.sub.2--R); 2.59 (s, 3H,
2-CH.sub.3); 4.28 (d, .sup.2J.sub.HP=14.6 Hz, 2H, P--CH.sub.2-TAr);
7.65 (d, .sup.4J.sub.HP=3.5 Hz, 1H, 5-H).
[0153] .sup.13C-NMR (100 MHz, CDCl.sub.3) .delta. in ppm=
[0154] 13.2 (--CH.sub.2H.sub.3); 19.0 (2-CH.sub.3); 19.0
(.sup.1J.sub.PC=46.8 Hz, P--CH.sub.2--R) 22.6 (.sup.1J.sub.PC=47.4
Hz, P--CH.sub.2-TAr); 23.4 (J.sub.PC=5.4 Hz, --CH.sub.2--); 23.8
(J.sub.PC=15.3 Hz, --CH.sub.2--); 119.8 (.sup.3J.sub.PC=9.2 Hz,
C-5); 142.9 (.sup.2J.sub.PC=9.9 Hz, C-4); 166.7 (.sup.4J.sub.PC=1.5
Hz, C-2).
EXAMPLE H
[0155]
(3S,4E)-3-[(1,1-Dimethylethyl)dimethylsilyloxy]-4-methyl-5-(2-methy-
lthiazol-4-yl)pent-4-enol
[0156] 16.8 g (48.0 mmol) of the compound that is produced
according to Example G is deprotonated in 200 ml of absolute THF at
-78.degree. C. with a solution of 1.1 equivalents, NaHMDS/KHMDS
(about 1:1), dissolved in 70 ml of absolute THF. After 40 minutes,
4.914 g (21.145 mmol) of the compound that is produced according to
Example E and that is dissolved in 20 ml of absolute THF is slowly
added.
[0157] After 1 hour at -78.degree. C. (virtually no conversion),
the cooling bath is removed, heated to about 40.degree. C. and
stirred for 20 more minutes.
[0158] For working-up, it is diluted with 100 ml of ether and
quenched by adding 250 ml of saturated NH.sub.4Cl solution. Then,
the phases are separated, the aqueous phase is extracted three more
times with ether, the combined organic phases are dried on
MgSO.sub.4, filtered and concentrated by evaporation.
[0159] 2.times. chromatographic purification on a3:1-hex/EE-silica
gel column produced a total of 559 mg (still slightly contaminated)
product and 4.9 g of the title compound (yield 78.8% at a 1:9
ratio) as viscous, colorless oils, which crystallizes in a
deep-freezing device (<-20.degree. C.). (In the case of the
compound, the nonpolar compound is not the expected DB-isomer, but
rather the C1-silylated compound based on a silyl shift under the
reaction conditions.)
[0160] R.sub.f-value (hex/EE=3:1) of nonpolar both F I (blue);
[0161] product.apprxeq.0.32
[0162] R.sub.f-value (hex/EE=3:1) of the title
[0163] compound.apprxeq.0.21
[0164] .sup.1H-NMR (400 MHz, CDCl.sub.3) of nonpolar product:
.delta. in ppm=
[0165] 0.068 (s, 3H, --SiCH.sub.3); 0.072 (s, 3H, --SiCH.sub.3);
0.90 (s, 9H, --SiC(CH.sub.3).sub.3); 1.82 (m, 2H, 2-H); 2.02 (s,
3H, 4-CH.sub.3); 2.69 (s, 3H, TAr--CH.sub.3); 3.46 (d, J=2.5 Hz,
1H, 3-OH); 3.79-3.90 (m, 2H, 1-H); 4.36 (t, J=6.0 Hz, 1H, 3-H);
6.59 (s, 1H, 5-H); 6.91 (s, 1H, TAr--CH.sub.arom).
[0166] .sup.13C-NMR (100 MHz, CDCl.sub.3) of nonpolar product:
.delta. in ppm=
[0167] -5.53 (SiCH.sub.3); -5.51 (SiCH.sub.3); 14.8 (4-CH.sub.3);
18.1 (SiC(CH.sub.3).sub.3); 19.2 (TAr--CH.sub.3); 25.9
(SiC(CH.sub.3).sub.3); 37.1 (C-2); 62.2 (C-1); 76.9 (C-3); 115.3
(C-7); 118.2 (C-5); 141.8 (C-4); 153.2 (C-6); 164.4 (C-8).
[0168] Angle of rotation: [.alpha.].sub.D.sup.20=-7.5; (c=2.3;
CHCl.sub.3)
[0169] C.sub.16H.sub.29NO.sub.2SSi:
(M=327.55 g.multidot.mol.sup.-1)
[0170] EA: Cld.: C: 58.75 H: 8.99% N: 4.3%
[0171] Fnd. : C: 58.48% H: 8.85% N: 4.41%
[0172] .sup.1H-NMR (400 MHz, CDCl.sub.3) of the title compound:
.delta. in ppm=
[0173] 0.01 (s, 3H, --SiCH.sub.3); 0.07 (s, 3E, --SiCH.sub.3); 0.88
(s, 9H, --SiC(CH.sub.3).sub.3); 1.73-1.90 (m, 2H, 2-H); 1.98 (.s,
3H, 4-CH.sub.3); 2.28 (t, J=5.0 Hz, 1H, 1-OH); 2.67 (s, 3H,
TAr--CH.sub.3); 3.71 (m, 2H, 1-H); 4.35 (dd, J.sub.3-H,2'-H=7.5 Hz,
J.sub.3-H,2-H=4.5 Hz, 1H, 3-H); 6.49 (s, 1H, 5-H); 6.89 (s, 1H,
TAr--CH.sub.arom).
[0174] .sup.13C-NMR (100 MHz, CDCl.sub.3) of the title compound:
.delta. in ppm=
[0175] -4.8 (SiCH.sub.3); -4.2 (SiCH.sub.3); 14.7 (4-CH.sub.3);
18.5 (SiC(CH.sub.3).sub.3); 19.6 (TAr--CH.sub.3); 26.2
(SiC(CH.sub.3).sub.3); 38.7 (C-2); 60.6 (C-1); 77.7 (C-3); 115.7
(C-7); 119.2 (C-5); 142.0 (C-4); 153.4 (C-6); 164.9 (C-8).
[0176] IR (Si film): .nu. in cm.sup.-1=
[0177] 3385br; 2954vs; 2928vs; 2885m; 2856s; 1655w; 1508w; 1472m;
1462m; 1440w; 1388w; 1360w; 1255m; 1184w; 1098vs; 1027s; 1005s;
978m; 939w; 884m; 837vs; 777vs; 738m.
[0178] MS (Fl, 7 kV, 3 mA, 20.degree. C.): m/e=
[0179] 327 ( [M]); 270; 269; 223, 222; 215; 197; 195; 175; 165;
133; 132; 113; 112.
[0180] Angle of rotation: [.alpha.].sub.D.sup.20=-31.5; (c=2.81;
CHCl.sub.3)
[0181] C.sub.16H.sub.29NO.sub.2SSi:
(M=327.55 g.multidot.mol.sup.-1)
EXAMPLE I
[0182]
(5S,2Z,6E)-2,6-Dimethyl-5-[(1,1-dimethylethyl)-dimethylsilyloxy]-7--
(2-methylthiazol-4-yl)hepta-2,6-dienoic acid ethyl ester
[0183] In 150 ml of absolute CH.sub.2Cl.sub.2, 1.57 ml (1.2
equivalents, 17.95 mmol) of oxalyl chloride is slowly mixed at
-78.degree. C. with 2.66 ml (2.5 equivalents, 37.4 mmol) of DMSO
and stirred for 10 more minutes. 4.9 g (14.96 mmol) of the compound
that is produced according to Example H and dissolved in 20 ml of
absolute CH.sub.2Cl.sub.2 is now slowly added in drops. After 45
minutes, 12.8 ml (5 equivalents, 74.8 mmol) of Hunig base is added,
the cooling bath is removed, and the temperature of the reaction
solution is allowed to increase to room temperature over a period
of 1 hour. It is now diluted with ether, quenched with saturated
NH.sub.4Cl solution, the phases are separated, the organic phase is
washed successively with water, saturated NaHCO.sub.3 solution,
water and brine, dried on MgSO.sub.4, filtered and concentrated by
evaporation in a vacuum.
[0184] After extensive drying under high vacuum (about 0.1 mbar),
the crude aldehyde is immediately used.
[0185] 6.73 g (>1.3 equivalents, 19.455 mmol) of
2-phosphonopropionic acid-(trifluoro)-triethylester and 11.87 g
(M=264.32 g.multidot.mol.sup.-1; .gtoreq.3 equivalents, 44.91 mmol)
of 18-crown 6 are introduced at -78.degree. C. into 200 ml of
absolute THF. It is now deprotonated by the slow addition of 3.614
g (M=199.49 g.multidot.mol.sup.-1; 1.15 equivalents, 17.21 mmol,
95% KHMDS) of KHMDS, dissolved in some absolute THF, and it is
stirred for 15 more minutes, whereby the cooling bath is removed
briefly. Then, the crude aldehyde, dissolved in about 45 ml of
absolute THF, is slowly added over a period of 70 minutes and
stirred for 30 more minutes. The cooling bath is removed, and the
reaction is quenched by adding saturated NH.sub.4Cl solution.
[0186] After phase separation, it is washed-with saturated
NaHCO.sub.3 solution, the aqueous phases are extracted twice more
with ether, and the combined organic phases are dried on magnesium
sulfate. After the organic phases are filtered on a short silica
gel frit, it is concentrated by evaporation in a vacuum.
Chromatographic purification on a 15:1-10:1-hex/EE-gradient silica
gel column produced 5.453 g (89%) of the title compound as a single
double-bond isomer.
[0187] R.sub.f-value (hex/EE=3:1).apprxeq.0.63 F III (very pale
blue);
[0188] R.sub.f-value (hex/EE=5:1).apprxeq.0.46 F II (blue);
[0189] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0190] 0.01 (s, 3H, --SiCH.sub.3); 0.04 (s, 3H, --SiCH.sub.3); 0.88
(s, 9H, --SiC(CH.sub.3).sub.3); 1.28 (t, J=7.0 Hz, 3H,
--CO.sub.2CH.sub.2CH.sub.3); 1.88 (s, 3H, 2-CH.sub.3); 2.00 (s, 3H,
6-CH.sub.3); 2.70 (s, 3H, TAr--CH.sub.3); 2.75 (m, 2H, 4-H); 4.18
(q, J=7.0 Hz, 2H, --CO.sub.2CH.sub.2CH.sub.3); 4.21 (t, J=5.5Hz,
1H, 5-H); 5.98 (td, J.sub.3-H,4-H=7.3 Hz, .sup.4J.sub.3-H,2-CH3=1.5
Hz, 1H, 3-H); 6.49 (s, 1H, 7-H); 6.91 (s, 1H,
TAr--CH.sub.arom).
[0191] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0192] -5.1 (SiCH.sub.3); -4.7 (SiCH.sub.3); 14.1 (12-CH.sub.3);
14.3 (CO.sub.2CH.sub.2CH.sub.3); 18.2 (SiC(CH.sub.3).sub.3); 19.2
(TAr--CH.sub.3); 20.7 (2-CH.sub.3); 25.8 (SiC(CH.sub.3).sub.3);
36.6 (C-4); 60.1 (CO.sub.2CH.sub.2CH.sub.3); 77.9 (C-5); 115.2
(C-9); 118.8 (C-7); 128.3 (C-2); 139.0 (C-3); 141.9 (C-6); 153.2
(C-8); 164.4 (C-10); 168.0 (CO.sub.2Et).
[0193] IR (Si film): .nu. in cm.sup.-1=
[0194] 2956vs; 2929vs; 2896m; 2856s; 1714vs; 1648w; 1506w; 1472m;
1462m; 1372m; 1252s; 1210s; 1185m;; 1132s; 1096vs; 1032m; 951w;
837vs; 808m; 777s; 737w.
[0195] MS (Fl, 7 kV, 3 mA, 40.degree. C.): m/e=
[0196] 410 ([M]); 352; 336; 297; 282,; 253; 224; 167; 132; 127; 58;
57.
[0197] C.sub.21H.sub.35NO.sub.3SSi:
(M=409.65 g.multidot.mol.sup.1)
[0198] EA: Cld.: C: 61.6% H: 8.6% N: 3.4%
[0199] Fnd.: C: 61.55% H: 8.53% N: 3.39%
EXAMPLE J
[0200]
(5S,2Z,6E)-2,6-Dimethyl-5-[(1,1-dimethylethyl)-dimethylsilyloxy]-7--
(2-methylthiazol-4-yl)hepta-2,6-dienol (Compound of Formula 4)
[0201] In 250 ml of absolute THF, 5.43 g (13.255 mmol) of the
compound, produced according to Example 1, is mixed at 0.degree. C.
drop by drop with 40 ml of a 1M DIBAH solution (in heptane). After
2.5 hours, quenching is done with 3 ml of MeOH at 0.degree. C. to
stop the reaction, and after dilution with diethyl ether, 200 ml of
semi-concentrated NaK-tartrate solution is added. After about 45
vigorous stirring at room temperature, the two clear phases are
separated, the aqueous phase is extracted twice more with ether,
and the combined organic phases are dried on magnesium sulfate,
filtered and concentrated by evaporation. Chromatographic
purification on a 5:1-hex/EE-silica gel column produced 4.752 g
(97.5%) of the title compound as a viscous, colorless oil, which
crystallizes in a deep-freezing device.
[0202] R.sub.f-value (hex/EE=3:1)=0.24 F III (intense violet);
[0203] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0204] 0.02 (s, 3H, --SiCH.sub.3); 0.04 (s, 3H, --SiCH.sub.3); 0.88
(s, 9H, --SiC(CH.sub.3).sub.3); 1.79 (s, 3H, 2-CH.sub.3); 2.00 (d,
.sup.4J=1.0 Hz, 3H, 6-CH.sub.3); 2.20 (t, J=6.0 Hz, 1H, 1-OH); 2.22
(m, 1H, 4-H); 2.46 (dt, J=14.1 Hz, J=8.0 Hz, 1H, 4-H); 2.69 (s, 3H,
TAr--CH.sub.3); 4.00 (dd, J=12.0 Hz, J=6.5 Hz, 1H, 1-H); 4.12 (dd,
J=12.0 Hz, J=5.0 Hz, 1H, 1-H); 4.13 (dd, J=11.0 Hz, J=5.0 Hz, 1H,
5-H); 5.30 (td, J=8.0 Hz, J=2.5 Hz, 1H, 3-H); 6.43 (s, 1H, 7-H);
6.91 (s, 1H, TAr--CH.sub.arom).
[0205] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0206] -4.9 (Si(CH.sub.3).sub.2); -4.7 (Si(CH.sub.3).sub.2); 14.2
(6-CH.sub.3); 18.3 (SiC(CH.sub.3).sub.3); 19.2 (TAr--CH.sub.3);
22.0 (2-CH.sub.3); 25.8 (SiC(CH.sub.3).sub.3); 35.4 (C-4); 61.9
(C-1); 78.2 (C-5); 115.2 (C-9); 118.8 (C-7); 124.3 (C-3); 137.6
(C-2); 142.2 (C-6); 152.9-(C-8); 164.6 (C-10).
[0207] IR (Si film): .nu. in cm.sup.-1=
[0208] 3333br; 2956s; 2927s; 2856s; 1657w; 1508w; 1472m; 1462m;
1441m; 1253s; 1185w; 1100vs; 1006s; 938m; 887m; 836s; 776s;
737m.
[0209] MS (Fl, 7 kV, 3 mA, 35.degree. C.): m/e=
[0210] 368 ([M+1]); 367 ([M]); 365; 309; 285; 282; 252; 237; 235;
224; 167; 132; 115; 85; 75; 58; 57.
[0211] Angle of rotation: [.alpha.].sub.D.sup.20=-6.8; (c=2.20;
CHCl.sub.3)
[0212] C.sub.19H.sub.33NO.sub.2SSi:
(M=367.62 g.multidot.mol.sup.-1)
EXAMPLES K-L
[0213] Production of Compound 34-I
EXAMPLE K
[0214]
(2S,4R,6Z,9S,10E)-1,9-Bis[(1,1-dimethylethyl)dimethylsilyloxy]-11-(-
2-methylthiazol-4-yl)-4-phenylsulfonyl-2,6,10-trimethyl-undeca-6,10-diene
[0215] In 100 ml of absolute CH.sub.3CN/ether (3:2), 4.66 g (12.676
mmol) of the compound, produced according to Example J, is
introduced in succession with 4.324 g (16.479 mmol, 1.3
equivalents) of Ph.sub.3P and 1.164 9 (17.113 mmol, 1.35
equivalents) of imidazole. 4.625 g (17.746 mmol, 1.4 equivalents)
of iodine is slowly added to this solution and stirred for 60 more
minutes at room temperature.
[0216] For working-up, 400 ml of cold ether is added (formation of
precipitate), filtered, and the filtrate is washed three times with
saturated Na.sub.2S.sub.2O.sub.3 solution. The organic phase is
then dried on MgSO.sub.4, filtered on silica gel and concentrated
by evaporation. The crude product is dried in a light-free
environment in an oil pump vacuum (about 0.1 mbar) and used in the
subsequent reaction.
[0217] 5.645 g (12.676 mmol, 1.3 equivalents) of the compound,
produced according to Example C, with 6.7 g (25.35 mmol, 2
equivalents) of 18-crown 6 are introduced at -78.degree. C. into
350 ml of absolute THF and slowly mixed with a solution of 3.59 g
(17.113 mmol, 1.35 equivalents, 95% KHMDS) of KHMDS, in some
absolute THF. After 60 minutes, the crude allyl iodide, dissolved
in 60 ml of absolute THF, is added drop by drop at -78.degree. C.
After 60 minutes, the cooling bath is removed, diluted with 250 ml
of ether, and the reaction is quenched by adding 250 ml of
saturated NH.sub.4Cl solution. The phases are separated, the
aqueous phase is extracted once more with ether, the combined
organic phases are washed twice more with saturated
Na.sub.2S.sub.2O.sub.3 solution, then dried on MgSO.sub.4, filtered
on 2 cm of silica gel and concentrated by evaporation.
[0218] 2.times. chromatographic purification on a
10:1-5:1-hex/EE-gradient silica gel column and a 10:1-hex/EE-silica
gel column produced 8.185 g of the title compound, as a
diastereoisomer mixture, also with some educt (Example C), which
can be separated on an MC-silica gel column.
[0219] R.sub.f-value (hex/EE=3:1).apprxeq.0.54 F III (intense
violet);
[0220] IR (Si film): .nu. in cm.sup.-1=
[0221] 2957vs; 2885vs; 2855vs; 1506m; 1472s; 1462s; 1447s; 1388m;
1361m; 1305s; 1256s; 1184m; 1145vs; 1102vs; 1027m; 1006m; 939s;
911s; 837vs; 775vs; 737vs; 691m; 668w.
[0222] MS (Fl, 7 kV, 3 mA, 150.degree. C.): m/e=
[0223] 694 ([M+2]); 693 ([M+1]); 692 ([M], 100); 636; 550; 431; 410
(<1); 282 (3); 267; 159(2); 142; 132; 115; 114.
[0224] C.sub.36H.sub.71NO.sub.4S.sub.2Si.sub.2:
(M=692.17 g.multidot.mol.sup.-1)
EXAMPLE L
[0225]
(2S,6Z,9S,10E)-1,9-Bis[(1,1-dimethylethyl)dimethylsilyloxy]-11-(2-m-
ethylthiazol-4-yl)-2,6,10-trimethyl-undeca-6,10-diene
[0226] (Compound of Formula 34-I)
[0227] 580 mg (0.838 mmol) of the compound, produced according to
Example K, is introduced at -15.degree. C. with 175 mg (1.232 mmol)
of Na.sub.2HPO.sub.4 into 12 ml of MeOH/THF (2:1). 1.466 g (3.189
mmol) of 5% sodium amalgam is now added, the cooling bath is
removed after 30 minutes, and the temperature of the reaction
solution increases to room temperature over a period of 90 minutes.
For working-up, it is filtered and rewashed with ether and water.
The filtered solution is washed with saturated NH.sub.4Cl solution,
dried on MgSO.sub.4, filtered on 1 cm of silica gel and
concentrated by evaporation in a vacuum.
[0228] Chromatographic purification on a 25:1-hex/EE-silica gel
column produced 300 mg (64.9%) of the title compound as a colorless
oil.
[0229] R.sub.f-value (hex/EE=5:1).apprxeq.0.74
[0230] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0231] 0.008 (s, 3H, --SiCH.sub.3); 0.02 (s, 6H,
--Si(CH.sub.3).sub.2); 0.04 (s, 3H, --SiCH.sub.3); 0.85 (d, J=6.5
Hz, 3H, 2-CH.sub.3); 0.88 (s, 18H, --SiC(CH.sub.3).sub.3's);
1.29-1.39 (m, 3H); 1.65 (s, 3H, 6-CH.sub.3); 1.97 (m, 2H); 1.99 (s,
3H, 10-CH.sub.3); 2.24 (m, 2H, 8-H); 2.70 (s, 3H, TAr--CH.sub.3);
3.33 (dd, J=9.5 Hz, J=6.5 Hz, 1H, 1-H); 3.43 (dd, J=9.5 Hz, J=5.5
Hz, 1H, 1-H); 4.07 (dd, J.sub.9-H,8-H.congruent.J.su-
b.9-H,8'-H=6.5 Hz, 1H, 9-H); 5.12 (dd,
J.sub.7-8,8-H.congruent.J.sub.7-H,8- '-H=6.5 Hz, 1H, 7-H); 6.44 (s,
1H, 11-H); 6.90 (s, 1H, TAr--CH.sub.arom).
[0232] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0233] -5.4 (SiCH.sub.3); -4.7 (SiCH.sub.3); 13.9 (10-CH3); 16.7
(2-CH.sub.3); 18.6 (2-SiC(CH.sub.3).sub.3); 19.2 (TAr--CH.sub.3);
223.5 (6-CH); 25.8 (C-8); 25.9 (SiC(CH.sub.3).sub.3); 26.0
(SiC(CH.sub.3).sub.3); 32.3 (C-4); 33.2 (C-3); 35.3 (C-5); 35.8
(C-2); 68.4 (C-1); 79.1 (C-9); 114.9 (C-13); 118.7 (C-11); 121.4
(C-7); 136.9 (C-6); 142.6 (C-10); 153.3 (C-12); 164.3 (C-14).
[0234] IR (Si film): .nu. in cm.sup.-1=
[0235] 2956s; 2928s; 2856s; 1472m; 1462m; 1388w; 1360w; 1255m;
1183w; 1097vs; .sup.1006w; 940m; 836s; 775s.
[0236] MS (Fl, 7 kV, 3 mA, 110.degree. C.): m/e=
[0237] 553 ([M+1]); 552 ([M], 100); 495 ([M-tBu]); 463; 417; 365;
283 (8); 282 (33); 269 (2); 224; 167; 159; 115 (<1).
[0238] Angle of rotation: [.alpha.].sub.D.sup.20=+8.4; (c=4.35;
CHCl.sub.3)
[0239] C.sub.30H.sub.57NO.sub.2SSi.sub.2:
(M=552.01 g.multidot.mol.sup.-1)
[0240] EA: Cld.: C: 65.3% H: 10.4% N: 2.5%
[0241] Fnd.: C: 65.51% H: 10.23% N 2.58%
EXAMPLES M-T
[0242] Production of Compound 2
EXAMPLE M
[0243] N-Tosyl-D-valine
[0244] A solution of tosyl chloride (20 g, 0.1 mol) in diethyl
ether (100 ml) was added in drops at room temperature to a solution
of D-valine (11.7 g, 0.1 mol) in 200 ml of 1N NaOH, and the
two-phase mixture was stirred vigorously for 4 hours. Then, the
diethyl ether phase was separated, the aqueous phase was washed
twice more with diethyl ether and acidified at 0.degree. C. by
adding concentrated HCl. After 30 minutes, it was suctioned off,
liberally rewashed with ice water and dried for several hours at
0.01 Torr. 18.1 g, (67%), of colorless crystals was obtained
(melting point: 147.degree. C.).
EXAMPLE N
[0245]
(3S)-5-[(1,1-Dimethylethyl)dimethylsilyloxy]-2,2-dimethyl-3-hydroxy-
-pentanoic acid-methyl ester
[0246] In 50 ml of absolute CH.sub.2Cl.sub.2, 1.355 g (5 mmol) of
the compound, produced according to Example M, under argon is mixed
slowly (30 minutes) at room temperature with 5 ml of a 1M
BH.sub.3-THF complex solution (in THF) and stirred for 20 more
minutes (cat. formation).
[0247] The solution is cooled to -78.degree. C., and mixed in
succession with 940 mg (5 mmol) of TBS-protected 3-hydroxypropanal
and 960 mg (5.5 mmol, 1.1 equivalents) of
1-methoxy-2-methyl-1-(trimethylsilyloxy)-prop-1- -ene, in each case
dissolved in 5 ml of absolute CH.sub.2Cl.sub.2.
[0248] After 4 hours, it is quenched with 35 ml of phosphate buffer
(pH=6.9), the phases are separated, the aqueous phase is shaken out
three more times with CH.sub.2Cl.sub.2 (20 ml each), the combined
organic phases are then dried on MgSO.sub.4, filtered and
concentrated by evaporation. The residue is taken up with cold
hexane for recovery of N-tosyl-D-valine, filtered (about 96% of
cat. recovered) and concentrated by evaporation.
[0249] Chromatographic purification on a 15:1-hex/EE-silica gel
column produced 1.248 g (88%) of the title compound as a colorless
oil.
[0250] R.sub.f-value (hex/EE=5:1).apprxeq.0.39 F I (blue)
[0251] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0252] 0.06 (s, 6H, --Si(CH.sub.3).sub.2); 0.88 (s, 9H,
--SiC(CH.sub.3).sub.3); 1.15 (s, 3H, 2-CH.sub.3); 1.19 (,s, 3H,
2-CH.sub.3); 1.57 (ddd, J=11.0 Hz, J=5.5 Hz, J=1.0 Hz, 2H, 4-H);
3.37 (d, J=3.5 Hz, 1H, 3-OH); 3.68 (s, 3H, --CO.sub.2CH.sub.3);
3.80 (m, 1H, 5-Ha); 3.87 (dd, J=10.0 Hz, J=5.0 Hz, 1H, 5-Hb); 3.92
(m, 1H, 3-H).
[0253] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0254] -5.5 (Si(CH.sub.3).sub.2); 18.2 (SiC(CH.sub.3).sub.3); 20.6
(2-CH.sub.3); 21.3 (2-CH.sub.3); 25.9 (SiC(CH.sub.3).sub.3); 33.7
(C-4); 47.1 (C-2); 51.8 (CO.sub.2CH.sub.3); 62.6 (C-.sub.5); 76.0
(C-3); 177.8 (C-1).
[0255] IR (Si film) .nu. in cm.sup.-1=
[0256] 3630br; 2955s; 2931s; 2884m; 2858s; 1733s; 1472m; 1435w;
1389w; 1257s; 1193m; 1138s; 1099vs; 1006w; 985w; 884w; 838vs.
[0257] MS (Fl, 7 kV, 3 mA, 20.degree. C.): m/e=
[0258] 291 ([M]); 261; 2,35 (4); 234 (15); 233 (,[M-tBu], 100);
189; 131; 102.
[0259] Angle of rotation: [.alpha.].sub.D.sup.20=+3.0; (c=1.88;
CHCl.sub.3)
[0260] C.sub.14H.sub.30O.sub.4Si:
(M=290.47 g.multidot.mol.sup.-1)
[0261] EA: Cld.: C: 57.9% H: 10.4%
[0262] Fnd.: C: 58.26% H 10.31%
EXAMPLE O
[0263]
(3S)-3,5-[(1,1-Dimethylethyl)dimethylsilyloxy]-2,2-dimethyl-pentano-
ic acid methyl ester
[0264] 5.32 g (18.315 mmol) of the compound, produced according to
Example N. is introduced at 0.degree. C. with 6.38 ml of
2,6-lutidine (3 equivalents) into 100 ml of absolute
CH.sub.2Cl.sub.2. 5.05 ml (1.2 equivalents) of TBS triflate is now
slowly added in drops. After 3 hours at 0.degree. C., the cooling
bath is removed, and the reaction is quenched by adding 25 ml of
saturated NH.sub.4Cl solution.
[0265] The phases are separated, the aqueous phase is extracted
twice more with CH.sub.2Cl.sub.2, the combined organic phases are
then dried on MgSO.sub.4, filtered on 5 cm of silica gel and
concentrated by evaporation.
[0266] After drying in an oil pump vacuum (about 0.1 mbar),
NMR-clean product was already obtained, which was purified
chromatographically for analysis on a 3%, and then later 5%, ether
on a hexane-silica gel column. 7.123 g (96.1%) of the title
compound was obtained as a colorless oil.
[0267] R.sub.f-value (hex/EE=10:1).apprxeq.0.33 F I (blue);
[0268] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0269] 0.02 (s, 3H, --SiCH.sub.3); 0.03 (s, 3H, --SiCH.sub.3);
0.033 (s, 3H, --SiCH.sub.3); 0.07 (s, 3H, --SiCH.sub.3); 0.86 (s,
9H, --SiC(CH.sub.3).sub.3); 0.89 (s, 9H, --SiC(CH.sub.3).sub.3);
1.08 (s, 3H, 2-CH.sub.3); 1.15 (s, 3H, 2-CH.sub.3); 1.59 (m, 2H,
4-H); 3.62 (m, 2H, 5-H); 3.64 (s, 3H, --CO.sub.2CH.sub.3); 4.05
(dd, J=7.5 Hz, J=3.0 Hz, 1H, 3-H).
[0270] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0271] -5.3 (Si(CH.sub.3).sub.2); -4.3 (SiCH.sub.3); -3.9
(SiCH.sub.3); 18.3 (SiC(CH.sub.3).sub.3); 20.4 (2-CH.sub.3); 21.7
(2-OH.sub.3); 25.9 (SiC(CH.sub.3).sub.3); 26.0
(SiC(CH.sub.3).sub.3); 36.9 (C-4) 48.3 (C-2); 51.6
(CO.sub.2CH.sub.3); 60.3 (C-5); 73.4 (C-3); 177.6 (C-1).
[0272] IR (Si film): .nu. in cm.sup.-1=
[0273] 2955s; 2930s; 2886m; 2858s; 1736s; 1472m; 1464m; 1434w;
1388w; 1257s; 1135m; 1039w; 1006w; 939w; 837vs.
[0274] MS (Fl, 7 kV, 3 mA, 20.degree. C.): m/e=
[0275] 405 ([MM], 1); 349 (9); 348 (23); 347 ([M-tBu], 100); 303;
267; 233 (1); 220; 199; 159; 132; 115 (2).
[0276] Angle of rotation: [.alpha.].sub.D.sup.20=-6.0; (c=3.91;
CHCl.sub.3)
[0277] C.sub.20H.sub.44O.sub.4Si.sub.2:
(M=404.73 g.multidot.mol.sup.-1)
[0278] EA: Cld.: C: 59.4% H: 11.0%
[0279] Fnd.: C: 59.50% H: 10.74%
EXAMPLE P
[0280]
(5S)-4,6-Bis-[(1,1-dimethylethyl)dimethylsilyloxy]-3,3-dimethyl-hex-
an-2-one
[0281] 5.5 ml of a 1M trimethylsilylmethyllithium solution in
pentane (2.2 equivalents) is added in a portion at, 0.degree. C. to
a solution of (1.013 g, 2.5 mmol) of the compound, produced
according to Example O, in absolute pentane (12 ml). After 4 hours
of stirring, 2.5 ml of MeOH is added to the colorless suspension,
and the resulting pale yellow emulsion is stirred vigorously for 1
hour at room temperature.
[0282] For working-up, it is diluted with diethyl ether/water, the
phases are then separated, and the aqueous phase is extracted three
more times with diethyl ether. The combined organic phases are
dried on NaSO.sub.4, filtered and concentrated by evaporation.
Flash chromatography on silica gel (75 g, hex/Et.sub.2O, 98:2)
produced 947 mg (97%.) of the title compound as a colorless
oil.
[0283] R.sub.f-value (hex/EE=96:4).apprxeq.0.4 F III
(yellow-brown);
[0284] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0285] -0.01 (s, 3H, --SiCH.sub.3); 0.00 (s, 3H, --SiCH.sub.3);
0.02 (s, 3H, --SiCH.sub.3); 0.06 (s, 3H, --SiCH.sub.3); 0.85 (s,
18H, --SiC(CH.sub.3).sub.3); 1.01 (s, 3H, 3-CH.sub.3); 1.06 (s, 3H,
3-CH.sub.3); 1.39-1.59 (m, 2H, 5-H); 2.10 (s, 3H, 1-H); 3.54-3.64
(m, 2H, 6-H); 4.00 (dd, J.sub.4-H,5a-H=3.0 Hz, J.sub.4-H,5b-H=8.0
Hz, 1H, 3-H).
[0286] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0287] -4.9 (SiCH.sub.3); -3.7 (SiCH.sub.3); -3.6 (SiCH.sub.3);
18.6 (SiC(CH.sub.3).sub.3); 18.7 (SiC(CH.sub.3).sub.3); 20.4
(3-CH.sub.3); 22.3 (3-CH.sub.3); 26.3 (SiC(CH.sub.3).sub.3); 26.4
(SiC(CH.sub.3).sub.3); 27.1 (C-1); 37.6 (C-5); 53.8 (C-3); 60.4
(C-1); 73.7 (C-6); 213.7 (C-2).
[0288] MS (Fl, 7 kV, 3 mA, .degree. C.): m/e=
[0289] 389 ([M+H], 1); 331 ([M-tBu], 100).
EXAMPLE Q
[0290]
(3S)-1,3-[(1,1-Dimethylethyl)dimethylsilyloxy]-4,4-dimethyl-pentan--
5-ol
[0291] In 100 ml of absolute toluene, 4.047 g (10 mmol) of the
compound, produced according to Example P, is mixed drop by drop at
-20.degree. C. with 30 ml (3 equivalents) of a 1M DIBAH solution
(in heptane) and stirred for 2 more hours.
[0292] It is now quenched at 0.degree. C. by adding 5 ml of MeOH,
diluted with 150 ml of ether and slowly mixed with 250 ml of
saturated NaK-tartrate solution, and vigorous stirring is continued
until two clear phases have formed. The phases are separated, the
aqueous phase is extracted three more times with ether, the
combined organic phases are then dried on MgSO.sub.4, filtered on 1
cm of silica gel and concentrated by evaporation.
[0293] Chromatographic purification on a 10:1-hex/EE-silica gel
column produced 3.527 g (93.6%) of the title compound as a
colorless oil.
[0294] R.sub.f-value (hex/EE=10:1).apprxeq.0.32
[0295] R.sub.f-value (hex/EE=5:1).apprxeq.0.53 F I (intense
blue);
[0296] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0297] 0.04 (s, 6H, --Si(CH.sub.3).sub.2); 0.078 (s, 3H,
--SiCH.sub.3); 0.084 (s, 3H, --SiCH.sub.3); 0.79 (s, 3H,
2-CH.sub.3); 0.878 (s, 9H, --SiC(CH.sub.3).sub.3); 0.883 (s, 9H,
--SiC(CH.sub.3).sub.3); 0.98 (s, 3H, 2-CH.sub.3); 1.62 (m, 1H,
4-H); 1.90 (m, 1H, 4-H); 2.87 (dd, J=7.0 Hz, J=4.0 Hz, 1H, 1-OH);
3.28 (dd, J=10.5 Hz, J=7.0 Hz, 1H, 3-H); 3.66 (m, 4H, 1-H and
5-H).
[0298] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0299] -5.33 (SiCH.sub.3); -5.30 (SiCH.sub.3); -4.3 (SiCH.sub.3);
-4.0 (SiCH.sub.3); 18.2 (SiC(CH.sub.3).sub.3); 18.3
(SiC(CH.sub.3).sub.3); 22.0 (2-CH.sub.3); 22.8 (2-CH.sub.3); 25.9
(SiC(CH.sub.3).sub.3); 26.0 (SiC(CH.sub.3).sub.3); 36.4 (C-2); 39.3
(C-4); 60.7 (C-5); 70.2 (C-1); 76.7 (C-3).
[0300] IR (Si film): .nu. in cm.sup.-1=
[0301] 3450br; 2958s; 2931s; 2885m; 2858s; 1473m; 1464m; 1407w;
1389m,; 1361m; 1256s; 1103vs; 1043s; 1006m; 939m; 836vs.
[0302] MS (El, eV, .degree. C.) m/e=
[0303] 377 ([M], 3); 350; 321 (10); 320 (25); 319 ([M-tBu], 100);
261; 187; 173 (1); 131; 115 (4); 114.
[0304] C.sub.19H.sub.44O.sub.3Si.sub.2:
(M=376.72 g.multidot.mol.sup.-1)
[0305] EA: Cld.: C: 60.6% H: 11.8%
[0306] Fnd.: C: 60.82% H: 11.70%
EXAMPLE R
[0307]
(3S)-3,5-[(1,1-Dimethylethyl)dimethylsilyloxy]-2,2-dimethyl-pentana-
l
[0308] In 100 ml of absolute CH.sub.2Cl.sub.2 and 2 ml of absolute
pyridine, 820 mg (2.177 mmol) of the compound, produced according
to Example Q, is mixed in portions at 0.degree. C. with 1.21 g (1.3
equivalents, 2.83 mmol) of Dess-Martin-periodinane and stirred for
2 more hours. It is now diluted with 100 ml of ether (formation of
precipitate), filtered, and the filtrate is washed twice with 50 ml
each of saturated NaHCO.sub.3/saturated Na.sub.2S.sub.2O.sub.3
solution (1:1). The phases are separated, the aqueous phase is
extracted twice more with CH.sub.2Cl.sub.2, the combined organic
phases are dried on MgSO.sub.4, filtered on 1 cm of silica gel and
concentrated by evaporation. The crude aldehyde is immediately used
after drying by the oil pump (about 0.1 mbar).
[0309] R.sub.f-value (hex/EE=10:1).apprxeq.0.67 F I (blue);
EXAMPLE S
[0310]
(3S,5RS)-1,3-Bis[(1,1-dimethylethyl)dimethylsilyloxy]-4,4-dimethyl--
heptan-5-ol
[0311] The compound that is produced according to Example R is
mixed in 10 ml of absolute diethyl ether at 0.degree. C. drop by
drop with 762 .mu.l (.gtoreq.1.05 equivalents, 2.286 mmol) of a 3M
EtMgBr solution (in ether). After 2 hours, it is diluted with ether
and quenched by adding 50 ml of saturated NH.sub.4Cl solution. The
phases are separated, the aqueous phase is extracted three more
times with ether, the combined organic phases are then dried on
MgSO.sub.4, filtered and concentrated by evaporation.
[0312] Chromatographic purification on a 25:1-hex/EE-silica gel
column produced 530 mg (60.2%) ofthe title compound and 316 mg
(38.5%),as a by-product (Example Q), resulting from the reduction
by the EtMgBr.
[0313] R.sub.f-value (hex/EE=10:1) of nonpolar
product.apprxeq.0.53
[0314] R.sub.f-value (hex/BE=10:1) of polar
product.apprxeq.0.44
[0315] R.sub.f-value (hex/ether=9:1) of nonpolar
product.apprxeq.0.32
[0316] R.sub.f-value (hex/ether=9:1) of polar
product.apprxeq.0.25
[0317] F I (blue);
[0318] .sup.1H-NMR (400 MHz, CDCl.sub.3) of nonpolar product:
.delta. in ppm=
[0319] 0.03 (s, 3H, --SiCH.sub.3); 0.04 (s, 3H, --SiCH.sub.3); 0.11
(s, 3H, --SiCH.sub.3); 0.112 (s, 3H, --SiCH.sub.3); 0.73 (s, 3H,
4-CH.sub.3); 0.88 (s, 9H, --SiC(CH.sub.3).sub.3); 0.90 (s, 9H,
--SiC(CH.sub.3).sub.3); 0.97 (s, 3H, 4-CH.sub.3); 1.00 (t, J=7.0
Hz, 3H, 7-H); 1.35 (m, 2H, 6-H); 1.70 (mc, 1H, 2-H); 1.92 (mc, 1H,
2-H); 3.63 (m, 2H, 1-H); 3.71 (m, 1H, 3-H); 4.29 (s, 1H, 5-OH).
[0320] .sup.13C-NMR (100 MHz, CDCl.sub.3) of nonpolar product:
.delta. in ppm=
[0321] -5.31 (SiCH.sub.3); -5.27 (SiCH.sub.3); -4.3 (SiCH.sub.3);
-3.9 (SiCH.sub.3); 11.3 (C-7); 18.20 (SiC(CH.sub.3).sub.3); 18.24
(SiC(CH.sub.3).sub.3); 20.5 (4-CH.sub.3); 23.5 (4-CH.sub.3); 24.5
(C-6); 25.9 (SiC(CH.sub.3).sub.3); 26.1 (SiC(CH.sub.3).sub.3); 36.0
(C-2); 40.7 (C-4); 60.1 (C-1); 77.4 (C-3); 80.5 (C-5).
[0322] IR (Si film): .nu. in cm.sup.-1=
[0323] 3500br; 2957vs; 2930s; 2884s; 2858s; 1472s; 1464m; 1409w;
1389m; 1362m; 1326w; 1256s; 1216w; 1101vs; 1048m; 1022m; 1004s;
976w; 955m; 940m; 925w; 836vs; 810m; 776s.
[0324] MS (Fl, 7 kV, 3 mA, 20.degree. C.) m/e=
[0325] 405 ([M], 4); 349 (7); 348 (27); 347 ([M-tBu], 100); 159
(3); 115 (7).
[0326] C.sub.21H.sub.48O.sub.3Si.sub.2:
(M=404.76 g.multidot.mol.sup.-1)
[0327] EA: Cld.: C: 62.3% H: 12.0%
[0328] Fnd.: C.: 62.57% H: 11.98%
[0329] .sup.1H-NMR (400 MHz, CDCl.sub.3) of polar product: .delta.
in ppm=
[0330] 0.05 (s, 3H, --SiCH.sub.3); 0.06 (s, 3H, --SiCH.sub.3); 0.07
(s, 6H, --Si(CH.sub.3).sub.2); 0.74 (s, 3H, 4-CH.sub.3); 0.85 (s,
3H, 4-CH.sub.3); 0.89 (s, 9H, --SiC(CH.sub.3).sub.3); 0.90 (s, 9H,
--SiC(CH.sub.3).sub.3); 0.98 (t, J=7.0 Hz, 3H, 7-H); 1.29 (mc, 1H,
6-H); 1.49 (m, 2H, 2-H); 2.00 (mc, 1H, 6-H); 2.74 (dd, J=4.5 Hz,
J=1.0 Hz, 1H, 5-OH); 3.33 (ddd, J=10.0 Hz, J=4.5 Hz, J=1.5 Hz, 1H,
3-H); 3.68 (td, J=9.5 Hz, J=4.5 Hz, 1H, 5-H); 3.75 (m, 2H,
1-H).
[0331] .sup.13C-NMR (100 MHz, CDCl.sub.3) of polar product: .delta.
in ppm=
[0332] -5.4 (2-SiCH.sub.3); -4.4 (SiCH.sub.3); -3.6 (SiCH3); 11.7
(C-7); 18.3 (SiC(CH.sub.3).sub.3); 18.4 (SiC(CH.sub.3).sub.3); 18.5
(4-CH.sub.3); 18.7 (4-CH.sub.3); 24.2 (C-6); 26.0
(SiC(CH.sub.3).sub.3); 26.1 (SiC(CH.sub.3).sub.3); 36.5 (C-2); 42.8
(C-4); 61.9 (C-1); 75.5 (C-3); 78.0 (C-5).
[0333] IR (Si film): .nu. in cm.sup.-1=
[0334] 3484br; 2957vs; 2931s; 2884m; 2858s; 1472m; 1464m; 1389w;
1361w; 1256s; 1094vs; 1034w; 1005w; 938m; 836vs; 775s.
[0335] MS (Fl, 7 kV, 3 mA, 20.degree. C.): m/e=
[0336] 405 ([M], 7); 365 (2); 364 (8); 349 (7); 348 (26); 347
([M-tBu], 100); 307 (6); 306 (17); 305 (78); 267 (3);h 115 (3).
[0337] C.sub.21H.sub.48O.sub.3Si.sub.2:
(M=404.76 g.multidot.mol.sup.-1)
EXAMPLE T
[0338]
(5S)-5,7-Bis((1,1-dimethylethyl)dimethylsilyloxy]-4,4-dimethyl-hept-
an-3-one (Compound of Formula 2)
[0339] 1.) Variant:
[0340] In 60 ml of absolute CH.sub.2Cl.sub.2 and 1 ml of absolute
pyridine, 495 mg (1.223 mmol) of the compound that is produced
according to Example S is mixed in portions at 0.degree. C. with
778 mg (1.5 equivalents, 1.834 mmol) of Dess-Martin-periodinane,
and it is stirred for 2 more hours. It is now diluted with 100 ml
of ether (formation of precipitate), filtered, and the filtrate is
washed twice with 60 ml each of saturated NaHCO.sub.3/saturated
Na.sub.2S.sub.2O.sub.3 solution (1:1). The phases are separated,
the aqueous phase is extracted twice more with CH.sub.2Cl.sub.2,
the combined organic phases are dried on MgSO.sub.4, filtered on 1
cm of silica gel and concentrated by evaporation. After drying by
the oil pump (about 0.1 mbar), 487 mg (99%) of the title compound
was obtained as (NMR-clean) colorless oil.
[0341] 2.) Variant:
[0342] n-BuLi (0.3 ml, 2.5 M solution in hexane, 0.75 mmol, 1.33
equivalents) is added in drops at -78.degree. C. to a solution of
DIPA (110 .mu.l, 0.78 mmol, 1.38 equivalents) in absolute THF (4
ml), and it is allowed to heat slowly (40 minutes) to room
temperature.
[0343] A solution of (220 mg, 0.566 mmol) of the compound, produced
according to Example P, in absolute THF is quickly added in drops
to the LDA solution that is again cooled to -78.degree. C. After 30
minutes of stirring, methyl iodide (0.5 ml, 9 mmol, 16 equivalents)
is added to the enolate solution, the cooling bath is removed, and
it is stirred for 1.5 more hours.
[0344] For working-up, it is quenched at 0.degree. C. with 10 ml of
saturated NH.sub.4Cl solution, the phases are separated, the
aqueous phase is shaken out three more times with 10 ml of
CH.sub.2Cl.sub.2 each. The combined organic phases are dried on
NaSO.sub.4, filtered and concentrated by evaporation. Flash
chromatography on silica gel (10 g, hex/Et.sub.2O, 97:3) produced
195 mg (85%) of the title compound as a colorless oil.
[0345] R.sub.f-value (MC/hex=1:1).apprxeq.0.44 F I (blue);
[0346] F III (intense violet-blue);
[0347] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0348] 0.02 (s, 3H, --SiCH.sub.3); 0.03 (s, 3H, --SiCH.sub.3); 0.04
(s, 3H, --SiCH.sub.3); 0.08 (s, 3H, --SiCH.sub.3); 0.87 (s, 9H,
--SiC(CH.sub.3).sub.3); 0.88 (s, 9H, --SiC(CH.sub.3).sub.3); 0.99
(t, J=7.3. Hz, 3H, 7-CH.sub.3); 1.04 (s, 3H, 4-CH.sub.3); 1.10 (s,
3H, 4-CH.sub.3); 1.50 (m, 2H, 2-H); 2.51 (dg, 2H, 6-H each); 3.62
(m, 2H, 1-H); 4.06 (dd, J=7.5 Hz, J=3.0 Hz, 1H, 3-H).
[0349] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0350] -5.3 (2-SiCH.sub.3); -4.1 (2-SiCH.sub.3); 7.7 (C-7); 18.3
(2-SiC(CH.sub.3).sub.3); 20.0 (4-CH.sub.3); 22.2 (4-CH.sub.3); 25.9
(SiC(CH.sub.3).sub.3); 26.1 (SiC(CH.sub.3).sub.3); 31.6 (C-6); 37.3
(C-2); 53.0 (C-4); 60.1 (C-1); 73.4 (C-3); 215.6 (C=0).
[0351] IR (Si film): .nu. in cm.sup.-1=
[0352] 2956s; 2928s; 2895m; 2856s; 1472m; 1462m; 1388w; 1360w;
1255m; 1183w; 1097vs; 1006w; 940m; 836vs; 775s.
[0353] MS (Fl, 7 kV, 3 mA, 20.degree. C.): m/e=
[0354] 403 ([M]); 347; 346 ([M-tBu]); 345 (100); 303; 57.
[0355] C.sub.21H.sub.46O.sub.3Si.sub.2:
(M=402.76 g.multidot.mol.sup.-1)
[0356] EA: Cld.: C: 62.6%. H: 11.55%
[0357] Fnd. : 0: 62.67. H: 11.29%
EXAMPLES U-V
[0358] Production of Compound 234
EXAMPLE U
[0359]
(2S,6Z,9S,10E)-9-[(1,1-Dimethylethyl)dimethylsilyloxy]-11-(2-methyl-
thiazol-4-yl)-2,6,10-trimethyl-undeca-6,10-dien-1-ol
[0360] In 80 ml of MeOH/CH.sub.2Cl.sub.2 (1:1), 1.385 g (2.509
mmol) of the compound that is produced according to Example L is
mixed in portions at 0.degree. C. with 583 mg (1 equivalent, 2.509
mmol) of CSA, and it is stirred for 5 more hours, whereby the
temperature may slowly rise to 10.degree. C.
[0361] The reaction is quenched by the addition of 150 ml of
saturated NaHCO.sub.3 solution and diluted with 150 ml of ether.
The phases are separated, the aqueous phase is extracted twice more
with 100 ml of ether each, the combined organic phases are then
dried on MgSO.sub.4, filtered on 2 cm of silica gel and
concentrated by evaporation in a vacuum.
[0362] Chromatographic purification on a 5:1-hex/EE-silica gel
column produced 1.094 g (99.6%) of the title compound as a
colorless, viscous oil.
[0363] R.sub.f-value (hex/EE=5:1).apprxeq.0.11
[0364] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0365] -0.01 (s, 3H, --SiCH.sub.3); 0.03 (s, 3H, --SiCH.sub.3);
0.88 (s, 9H, --SiC(CH.sub.3).sub.3 ); 0.90 (d, J=6.5 Hz, 3H,
2-CH.sub.3); 1.32-1.42 (m, 3H); 1.60 (m, 1H, 2-H); 1.66 (d,
.sup.4J=1.0 Hz, 3H, 6-CH.sub.3); 1.96 (m, 1-2H); 1.98 (d,
.sup.4J=1.0 Hz, 3H, 10-CH.sub.3); 2.24 (m, 2H, 8-H); 2.69 (s, 3H,
TAr--CH.sub.3); 3.39 (m, 1H, 1-H); 3.43 (m, 1H, 1-H); 4.08 (dd,
J.sub.9-H,8-H.congruent.J.sub.9-H,8'-H,=6.5 Hz, 1H, 9-H); 5.14 (dd,
J.sub.7-H,8-H.ident.J.sub.7-H,8'-H=7.0 Hz, 1H, 7-H); 6.44 (s, 1H,
11-H); 6.91 (s, 1H, TAr--CH.sub.arom).
[0366] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0367] -4.9 (SiCH.sub.3); -4.7 (SiCH.sub.3); 13.9 (10-CH.sub.3);
16.2 (2-CH.sub.3); 18.2 (SiC(CH.sub.3).sub.3); 19.1
(TAr--CH.sub.3); 23.4 (6-CH3); 25.3 (C-5); 25.8
(SiC(CH.sub.3).sub.3); 32.1 (C-4); 33.1 (C-3); 35.5 (C-8); 35.7
(C-2); 68.1 (C-1); 79.2 (C-9); 114.8 (C-13); 118.7 (C-11); 121.7
(C-7); 136.8 (C-6); 142.7 (C-10); 153.2 (C-12); 164.4 (C-14).
[0368] IR (Si film): .nu. in cm.sup.-1=
[0369] 3385br; 2956s; 2927s; 2856s; 1508w; 1461m; 1449m; 1406w;
1388w; 1376w; 1360w; 1253m; 11,84m; 1102vs; 1005m; 940s; 888s;
836vs; 776s; 737m.
[0370] MS (Fl, 7 kV, 3 mA, 150.degree. C.): m/e=
[0371] 439 ([M+H]); 438 ([M]); 396; 380; 284; 283; 282 (100); 183;
143; 115; 57.
[0372] Angle of rotation: [.alpha.].sub.D.sup.20=+9.5; (c=1.37;
CHCl.sub.3)
[0373] C.sub.24H.sub.43No.sub.2SSi:
(M=437.75 g.multidot.mol.sup.-1)
EXAMPLE V
[0374]
(3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-Hexamethyl-7-hydroxy-16-(2--
methylthiazol-4-yl)-1,3,15-tris[(1,1-dimethylethyl)dimethylsilyloxy]-hepta-
-dec-12,16-dien-5-one
[0375] (Compound of Formula 234, whereby R=methyl)
[0376] In 80 ml of absolute CH.sub.2Cl.sub.2 with 2 ml of absolute
pyridine, 983 mg (2.246 mmol) of the compound, produced according
to Example U, is mixed in portions at 0.degree. C. with 1.24 g (1.3
equivalents, 2.92 mmol) of Dess-Martin-periodinane and stirred for
4 more hours. For working-up, it is diluted with 200 ml of ether
(formation of precipitate), filtered on a 1 cm silica gel frit, and
then the filtrate is washed three times with 100 ml each of
saturated NaHCO.sub.3/saturated Na.sub.2S.sub.2O.sub.3 solution
(1:1). The organic phase is dried on MgSO.sub.4, filtered on 5 cm
of silica gel and concentrated by evaporation. The crude aldehyde
is then dried in an oil pump vacuum (about 0.1 mbar) and thus
immediately used in the subsequent reaction.
[0377] In 10 ml of absolute THF, 441 .mu.l (1.4 equivalents, 3.14
mmol) of DIPA is slowly mixed at -20.degree. C. with 1.258 ml (1.4
equivalents, 3.14,mmol) of a 2.5 M nBuLi solution (in hexane) and
stirred for 20 more minutes. The finished LDA solution is cooled to
-78.degree. C., mixed slowly with 1.266 g (1.4 equivalents, 3.14
mmol) of the compound that is produced according to Example T and
diluted in 10 ml of absolute THF, stirred for 15 more minutes and
allowed to heat to -35.degree. C. over a period of 45 minutes.
Then, it is cooled to -95.degree. C., added drop by drop to the
crude aldehyde, dissolved in some absolute THF, and stirred for 90
more minutes, whereby the temperature may rise slowly to
-80.degree. C. For working-up, the cooling bath is removed,
quenched with 50 ml of saturated NH.sub.4Cl solution and diluted
with ether. The phases are separated, the aqueous phase is
extracted twice more with ether, the combined organic phases are
dried on MgSO.sub.4, filtered and concentrated by evaporation.
[0378] Chromatographic precleaning on 25:1-hex/EE-silica gel
columns produced 1.305 g (69%, over two stages) of the title
compound as a mixed fraction of the two diastereomers. The
separation of the diastereomeric aldol products was carried out via
preparative HPLC in 9:1-hex/EE.
[0379] R.sub.f-value (MC) of aldehyde.apprxeq.0.26
[0380] R.sub.f-value (MC) of the title compound.apprxeq.0.14
[0381] .sup.1H-NMR (400 MHz, CDCl.sub.3) of aldehyde: .delta. in
ppm=
[0382] -0.01 (s, 3H, --SiCH.sub.3); 0.03 (s, 3H, --SiCH.sub.3);
0.88 (s, 9H, --SiC(CH.sub.3).sub.3); 1.07 (d, J=6.5 Hz, 3H,
2-CH.sub.3); 1.30-1.43 (m, 3H); 1.65 (d, .sup.4J=1.5 Hz, 3H,
6-CH.sub.3); 1.64-1.72 (m, 1H); 1.99 (d, .sup.4J=1.0 Hz, 3H,
10-CH3); 2.00-2.06 (m, 2H); 2.18-2.33 (m, 3H); 2.69 (s, 3H,
TAr--CH.sub.3); 4.07 (t, J.sub.9-H, 8-H.ident.J.sub.9-H,8'-H=6.5
Hz, 1H, 9-H); 5.15 (, J.sub.7-H,8-H.congruent.J.sub.7-H,8'-H=6.5
Hz, 1H, 7-H); 6.44 (s, 1H, 11-H); 6.91 (s, 1H, TAr--CH.sub.arom);
9.59 (d, J=1.5 Hz, 1H, 1-H).
[0383] .sup.13C-NMR (100 MHz, CDCl.sub.3) of aldehyde: .delta. in
ppm=
[0384] -5.0 (SiCH.sub.3); -4.7 (SiCH.sub.3); 13.3 (2-CH.sub.3);
14.0 (10-CH.sub.3); 18.2 (SiC(CH.sub.3).sub.3); 19.2
(TAr--CH.sub.3); 23.4 (6-CH.sub.3); 25.2 (C-5); 25.8
(SiC(CH.sub.3).sub.3); 30.4 (C-4); 31.8 (C-3); 35.4 (C-8); 46.3
(C-2); 78.9 (C-9); 115.0 (C-13); 118.7 (C-11); 122.1 (C-7); 136.0
(C-6); 142.4 (C-10); 153.2 (C-12); 164.3 (C-14); 205.1 (C-1).
[0385] .sup.1H-NMR (400 MHz, CDCl.sub.3) of the title compound:
.delta. in ppm=
[0386] -0.01 (s, 3H, --SiCH.sub.3); 0.02. (s, 6H,
--Si(CH.sub.3).sub.2); 0.03 (s, 3H, --SiCH.sub.3); 0.07 (s, 3H,
--SiCH.sub.3); 0.09 (s, 3H, --SiCH.sub.3); 0.81 (d, J=7.0 Hz, 3H,
8-CH.sub.3); 0.87 (s, 18H, --SiC(CH.sub.3).sub.3); 0.89 (s, 9H,
--SiC(CH.sub.3).sub.3); 1.01 (d, J=7.0 Hz, 3H, 6-CH.sub.3); 1.08
(s, 3H, 4-CH.sub.3); 1.20 (s, 3H, 4-CH.sub.3); 1.24-1.35 (m, 2H);
1.43-1.53 (m, 3H); 1.57-1.67 (m, 1H); 1.65 (s, 3H, 12-CH.sub.3);
1.69-1.77 (m, 1H); 1.90-2.02 (m, 2H, 11-H); 1.98 (s, 3H,
16-CH.sub.3); 2.23 (m, 2H, 14-H); 2.70 (s, 3H, TAr--CH.sub.3); 3.29
(m, 1H, 6-H); 3.59 (m, 1H); 3.66 (m, 1H, 7-H); 3.89 (dd, J=7.5 Hz,
J=3.0 Hz, 1H, 15-H); 4.08 (t, J=6.5 Hz, 1H, 3-H); 5.12 (t, J=7.6
Hz, 1H, 13-H); 6.44 (s, 1H, 17-H); 6.90 (s, 1H,
TAr--CH.sub.arom).
[0387] .sup.13C-NMR (100 MHz, CDCl.sub.3) of the title compound:
.delta. in ppm=
[0388] -5.3 (SiCH.sub.3); -4.9 (SiCH.sub.3); -4.7 (SiCH.sub.3);
-4.1 (SiCH.sub.3); -3.8 (SiCH.sub.3); 9.6 (6-CH.sub.3); 13.9
(16-CH.sub.3); 15.4 (8-CH3); 18.3 (SiC(CH.sub.3).sub.3); 19.2
(TAr--CH.sub.3); 20.5 (4-CH.sub.3); 22.9 (4-CH.sub.3); 23.5
(12-CH.sub.3); 25.2 (C-11); 25.9 (SiC(CH.sub.3).sub.3); 26.1
(SiC(CH.sub.3).sub.3); 32.4 (C-10); 33.0 (C-9); 35.3 (C-14); 35.5
(C-8); 37.9 (C-2); 41.4 (C-6); 54.0 (C-4); 60.5 (C-1); 74.2+74.9
(C-3 and C-7); 79.1 (C-15); 114.9 (C-19); 118.7 (C-17); 121.5
(C-13); 136.9 (C-12); 142.6 (C-16); 153.3 (C-18); 164.3 (C-20);
222.2 (C-5).
[0389] IR (Si film): .nu. in cm.sup.-1=
[0390] 2956s; 2932s; 2885s; 2858s; 1472s; 1463s; 1444m; 1389m;
1366m; 1257vs; 1198m; 1132m; 1075m; 1006m; 940w; 874m; 838s; 814m;
777vs.
[0391] .sup.1H-NMR (400 MHz, CDCl.sub.3) of polar product: .delta.
in ppm=
[0392] -0.01 (s, 3H, --SiCH.sub.3); 0.02. (s, 3H, --SiCH.sub.3);
0.03 (s, 3H, --SiCH.sub.3); 0.04 (s, 3H, --SiCH.sub.3); 0.015 (s,
3H, --SiCH.sub.3); 0.10 (s, 3H, --SiCH.sub.3); 0.87 (s, 9H,
--SiC(CH.sub.3).sub.3); 0.88 (s, 18H, --SiC(CH.sub.3).sub.3); 0.97
(d, J=6.5 Hz, 3H, 8-CH.sub.3); 1.05 (d, J=6.5 Hz, 3H, 6-CH3); 1.10
(s, 3H, 4-CH.sub.3); 1.14 (s, 3H, 4-CH3); 1.29-1.41 (m, 3H); 1.51
(m, 3H); 1.58 (m, 1H); 1.67 (s, 3H, 12-CH.sub.3); 1.90-2.00 (m, 2H,
11-H); 1.99 (d, .sup.4J=1.0 Hz, 3H, 16-CH.sub.3); 2.18-2.30 (m, 2H,
14-H); 2.70 (s, 3H, TAr--CH.sub.3); 3.22 (qd, J=7.0 Hz, J=2.0 Hz,
1H, 6-H); 3.40 (d, J=8.0 Hz, 1H, 7-OH); 3.47 (s, 1H); 3.58-3.69 (m,
2H); 4.03 (dd, J=7.0 Hz, J=3.5 Hz, 1H, 15-H); 4.08 (t, J=7.0 Hz,
1H, 3-H); 5.14 (t, J=7.0 Hz, 1H, 13-H); 6.45 (s, 1H, 17-H); 6.90
(s, 1H, TAr--CH.sub.arom).
[0393] .sup.13C-NMR (100 MHz, CDCl.sub.3) of polar product: .delta.
in ppm=
[0394] -5.3 (SiCH.sub.3); -4.9 (SiCH.sub.3); -4.7 (SiCH.sub.3);
-4.0 (SiCH.sub.3); -3.7 (SiCH.sub.3); 10.8 (C-6); 13.9
(16-CH.sub.3); 15.5 (8-CH.sub.3); 18.4 (SiC(CH.sub.3).sub.3); 19.2
(TAr--CH.sub.3); 19.6 (4-CH.sub.3); 22.8 (4-CH.sub.3); 23.6
(12-CH3); 25.2 (C-11); 25.8 (SiC(CH.sub.3).sub.3); 25.9
(SiC(CH.sub.3).sub.3); 26.2 (SiC(CH.sub.3).sub.3); 32.3 (C-10);
32.9 (C-9); 35.4 (C-14); 35.5 (C-8); 37.8 (C-2); 41.4 (C-6); 54.3
(C-4); 60.2 (C-1); 72.7+75.1 (C-3 and C-7); 79.0 (C-15); 114.9
(C-.sub.19); 118.7 (C-17); 121.7 (C-13); 136.6 (C-12); 142.5
(C-16); 153.2 (C-18); 164.3 (C-20); 221.8 (C-5).
[0395] IR (Si film): .nu. in cm.sup.-1=
[0396] 2956m; 2928m; 2856m; 1686w; 1619w; 1508w; 1472m; 1462m;
1407w; 1388m; 1361m; 1322w; 1255m; 1183m; 1104vs; 1032m; 97.7m;
939m; 836s; 775s; 738m.
EXAMPLE W
[0397]
(3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-Hexamethyl-16-(2-methylthia-
zol-4-yl)-1,3,7,15-tetrakis[(1,1-dimethylethyl)-dimethylsilyloxy]-heptadec-
-12,16-dien-5-one
[0398] 493 mg (0.588 mmol) of the compound that is produced
according to Example V is introduced at 0.degree. C. with 250 .mu.l
of 2,6-lutidine (3 equivalents, 1.764 mmol) into 15 ml of absolute
CH.sub.2Cl.sub.2. 203 .mu.l (1.5 equivalents, 0.882 mmol) of TES
triflate is now slowly added in drops.
[0399] After 3 hours at 0.degree. C., the cooling bath is removed,
and the reaction is quenched by adding saturated NH.sub.4Cl
solution. The phases are separated, the aqueous phase is extracted
twice more with CH.sub.2Cl.sub.2, the combined organic phases are
then dried on MgSO.sub.4, filtered on 5 cm of silica gel and
concentrated by evaporation.
[0400] Chromatographic purification on a 25:1-hex/EE-silica gel
column produced 560 mg (quant.) of the title compound as a
colorless oil.
[0401] R.sub.f-value (hex/EE=10:1).apprxeq.0.56 F IV (intense
blue);
[0402] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0403] -0.01 (s, 3H, --SiCH.sub.3); 0.017 (s, 3H, --SiCH.sub.3);
0.02 (s, 3H, --SiCH.sub.3); 0.03 (s, 3H, --SiCH.sub.3); 0. 047 (s,
6H, --SiCH.sub.3); 0.053 (s, 3H, --SiCH.sub.3); 0.08 (s, 3H,
--SiCH.sub.3); 0.871 (s, 9H, --SiC(CH.sub.3).sub.3); 0.876 (s, 9H,
--SiC(CH.sub.3).sub.3); 0.88 (s, 9H, --SiC(CH.sub.3).sub.3); 0.875
(v, 3H, 8-CH.sub.3); 0.89 (s, 9H, --SiC(CH.sub.3).sub.3); 1.01 (s,
3H, 4-CH.sub.3); 1.03 (d, J=7.0 Hz, 3H, 6-CH.sub.3); 1.21 (s, 3H,
4-CH.sub.3); 1.24-1.28 (m, 2H); 1.30-1.40 (m, 4H); 1.64 (s, 3H,
12-CH.sub.3); 1.90-1.97 (m, 2H, 11-H); 1.98 (d, .sup.4J=1.0 Hz, 3H,
16-CH.sub.3); 2.22 (m, 2H, 14-H); 2.70 (s, 3H, TAr--CH.sub.3); 3.13
(qd, J=? Hz, J=6.5 Hz, 1H, 6-H); 3.56 (ddd, J=? Hz, J=7.5 Hz, J=2.0
Hz, 1H, 1-H); 3.66 (td, J=9.6 Hz, J=9.0 Hz, J=5.0 Hz, 1H, 1-H);
3.75 (dd, J=7.0 Hz, J=1.5 Hz, 1H, 7-H); 3.87 (dd, J=7.5 Hz, J=2.5
Hz, 1H, 15-H); 4.07 (t, J=6.5 Hz, 1H, 3-H); 5.12 (t, J=7.0 Hz, 1H,
13-H); 6.44 (s, 1H, 17-H); 6.90 (s, 1H, TAr--CH.sub.arom).
[0404] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0405] -5.3 (SiCH.sub.3); -4.9 (SiCH.sub.3); -4.7 (SiCH.sub.13);
-4.0 (SiCH.sub.3); -3.8 (SiCH.sub.3); -3.7 (SiCH.sub.3); 13.9
(16-CH.sub.3); 15.4 (8-CH.sub.3); 17.5 (6-CH.sub.3); 18.2
(SiC(CH.sub.3).sub.3); 18.3 (SiC(CH.sub.3).sub.3); 18.5
(SiC(CH.sub.3).sub.3); 19.2 (TAr--CH.sub.3); 19.4 (4-CH.sub.3);
23.5 (12-CH.sub.3); 24.5 (4-CH.sub.3); 24.9 (C-11); 25.9
(SiC(CH.sub.3).sub.3); 26.0 (SiC(CH.sub.3).sub.3); 26.1
(SiC(CH.sub.3).sub.3); 26.2 (SiC(CH.sub.3).sub.3); 31.1 (CH.sub.2);
32.6 (CH.sub.2); 35.3 (C-14); 38.1 (C-2); 39.0 (CH); 45.0 (C-6);
53.7 (C-4); 61.0 (C-1); 74.1 (C-3); 77.5 (C-7); 79.0 (C-15); 114.9
(C-19); 118.7 (C-17); 121.6 (C-13); 136.8 (C-12); 142.5 (C-16);
153.3 (C-18); 218.2 (C-5).
EXAMPLE X
[0406]
(3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-Hexamethyl-16-(2-methylthia-
zol-4-yl)-3,7,15-tris[(1,1-dimethylethyl)-dimethylsilyloxy]-heptadec-12,16-
-dien-5-on-1-ol
[0407] In 20 ml of MeOH/CH.sub.2Cl.sub.2 (1:1), 540 mg
(.apprxeq.0.567 mmol) of the compound that is produced according to
Example W is slowly mixed at 0.degree. C. with 132 mg (1
equivalent, 0.567 mmol) of CSA and stirred for 4 more hours.
[0408] For working-up, it is diluted with CH.sub.2Cl.sub.2, and the
reaction is quenched by adding saturated NaHCO.sub.3 solution.
Then, the phases are separated, the aqueous phase is extracted
twice more with CH.sub.2Cl.sub.2, and the combined organic phases
are dried on MgSO.sub.4, filtered and spun in.
[0409] Flash chromatography on a 10:1-hex/EE-silica gel column
produced 412 mg (87%) of the title compound as a colorless oil.
[0410] R.sub.f-value (hex/EE=10:1).apprxeq.0.17 F III (intense
blue);
[0411] R.sub.f-value (hex/EE=5:1).apprxeq.0.32 F IV (intense
blue);
[0412] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0413] -0.01 (s, 3H, --SiCH.sub.3); 0.03 (s, 3H, --SiCH.sub.3);
0.06 (s, 9H, 3x --SiCH.sub.3); 0.10 (s, 3H, --SiCH.sub.3);
0.86-0.92 (m, 30H, 3x --SiC(CH.sub.3).sub.3 and 8-CH.sub.3); 1.048
(d, J=6.9 Hz, 3H, 6-CH.sub.3); 1.051 (s, 3H, 4-CH.sub.3); 1.09-1.20
(m, 2H); 1.21 (s, 3H, 4-CH.sub.3); 1.26-1.50 (m, 5H); 1.65 (s, 3H,
12-CH); 1.90-2.05 (m, 2H, 11-H); 1.98 (d, .sup.4J=0.9 Hz, 3H,
16-CH.sub.3); 2.22 (mc, 2H, 14-H); 2.70 (s, 3H, TAr--CH.sub.3);
3.12 (qd, J=7.1 Hz, J=6.7 Hz, 1H, 6-H); 3.63 (dd, J=6.0 Hz, J=5.6
Hz, 2H, 1-H); 3.79 (dd, J=7.1 Hz, J=1.3 Hz, 1H, 7-H), 4.03-4.10 (m,
2H, 3-H and 15-H); 5.13 (t, J=7.5 Hz, 1H, 13-H); 6.44 (s, 1H,
17-H); 6.90 (s, 1H, TAr--CH.sub.arom).
[0414] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0415] -4.9 (SiCH.sub.3); -4.7 (SiCH.sub.3); -3.93 (SiCH.sub.3);
-3.91 (SiCH.sub.3); -3.8 (SiCH.sub.3); -3.6 (SiCH.sub.3); 13.9
(16-CH.sub.3); 14.2 (6-CH.sub.3); 15.6 (8-CH.sub.3); 17.6
(4-CH.sub.3); 17.8 (4-CH.sub.3); 18.2 (SiC(CH.sub.3).sub.3); 18.3
(SiC(CH.sub.3).sub.3); 18.5 (SiC(CH.sub.3).sub.3); 19.2
(TAr--CH.sub.3); 23.5 (12-CH.sub.3); 24.9 (C-11); 25.9
(SiC(CH.sub.3).sub.3); 26.0 (SiC(CH.sub.3).sub.3); 26.2
(SiC(CH.sub.3).sub.3); 30.9 (C-10); 32.5 (C-9); 35.4 (C-14); 38.4
(C-2); 38.8 (CH); 45.1 (C-6); 53.8 (C-4); 60.2 (C-1); 73.1 (C-3);
77.5 (C-7); 79.0 (C-15); 114.9 (C-19); 118.7 (C-17); 121.6 (C-13);
136.7 (C-12); 142.5 (C-16); 153.3 (C-18); 164.3 (C-20); 218.2
(C-5).
[0416] IR (Si film): .nu. in cm.sup.-1=
[0417] 3320br; 2956s; 2928s; 1856s; 1686w; 1472m; 1462m; 1407w;
1388m; 1361w; 1255s; 1183w; 1104vs; 1032m; 977m; 939s; 836vs;
775vs; 738s.
[0418] MS (Fl, 7 kV, 3 mA, 195.degree. C.): m/e=
[0419] 840 ([M+H]); 839 ([M]); 781; 706; 649; 550; 283; 282 (100);
268; 189; 132; 115; 57.
EXAMPLE Y
(3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-Hexamethyl-16(2-methylth-
iazol-4-yl)-3,7,15-tris[(1,1-dimethylethyl)-dimethylsilyloxy]-heptadec-12,-
16-dien-5-onic acid
[0420] In 50 ml of absolute CH.sub.2Cl.sub.2 and 1 ml of absolute
pyridine, 389 mg (0.4639 mmol) of the compound that is produced
according to Example X is mixed with 258 mg (1.3 equivalents) of
Dess-Martin-periodinane and stirred for 2 more hours. It is now
diluted with 150 ml of ether, filtered, and the filtrate is washed
with 100 ml of saturated NaHCO.sub.3/saturated
Na.sub.2S.sub.2O.sub.3 solution (1:1). The phases are separated,
the aqueous phase is extracted twice more with CH.sub.2Cl.sub.2,
the combined organic phases are dried on MgSO.sub.4, filtered on 1
cm of silica gel, concentrated by evaporation and dried. The crude
aldehyde is equally further reacted without being purified, crude,
after drying in an oil pump vacuum.
[0421] The crude aldehyde is mixed in 10.3 ml of tert-butanol and
10.3 ml of 2,3-dimethyl-but-2-ene at room temperature with a
solution of 211 mg (5 equivalents) of NaClO.sub.2 and 211 mg of
NaH.sub.2PC.sub.4 in 2.11 ml of water, and it is stirred for 40
more minutes. For working-up, it is diluted with 150 ml (2:1) of
CH.sub.2Cl.sub.2/water, slightly acidified with 2 drops of TFA, the
phases are separated, the aqueous phase is extracted twice more
with CH.sub.2Cl.sub.2, the combined organic phases are dried on
MgSO.sub.4, filtered on 1 cm of silica gel and concentrated by
evaporation. Flash chromatography on a
10:1-5:1-3:1-hex/EE-gradient-si- lica gel column produced 380 mg
(96.1%) of the title compound as a very viscous, colorless oil.
[0422] R.sub.f-value (hex/EE=5:1) of the aldehyde.apprxeq.0.56
[0423] F III or F IV (intense blue);
[0424] R.sub.f-value (hex/EE=5:1) of the title
compound.apprxeq.0.30
[0425] F III or F IV (intense violet-blue);
[0426] .sup.1H-NMR (40.0 MHz, CDCl.sub.3): .delta. in ppm=
[0427] -0.02 (s, 3H), --SiCH.sub.3); 0.02 (s, 3H, --SiCH.sub.3);
0.03 (s, 3H, --SiCH.sub.3); 0.07 (s, 3H, --SiCH.sub.3); 0.08 (s,
3H, --SiCH.sub.3); 0.12 (s, 3H, --SiCH.sub.3); 0.88 (s, 18H;
--SiC(CH.sub.3).sub.3); 0.885 (v, 3H, 8-CH.sub.3); 0.89 (s, 9H,
--SiC(CH.sub.3).sub.3); 1.06 (d, J=7.0 Hz, 3H, 6-CH.sub.3); 1.15
(s, 6H, 4-CH.sub.3); 1.35-1.50 (m, 5H); 1.67 (s, 3H, 12-CH.sub.3);
1.86-1.94 (m, 2H, 11-H); 1.94 (d, .sup.4J=1.0 Hz, 3H, 16-CH.sub.3);
2.12-2.22 (m, 2 or 3H); 2.33 (dd, J=16.6 Hz, J=6.5 Hz, 1H, 2-H);
2.43 (dd, J=16.6 Hz, J=3.5 Hz, 1H, 2-H); 2.70 (s, 3H,
TAr--CH.sub.3); 3.13 (qd, J=7.0 Hz, J=6.0 Hz, 1H, 6-H); 3.74 (dd,
J=5.5 Hz, J=2.0 Hz, 1H, 7-H); 4.12 (m, 1H, 15-H); 4.40 (dd, J=7.0
Hz, J=3.5 Hz, 1H, 3-H); 5.17 (t, J=7.0 Hz, 1H, 13-H); 6.63 (s, 1H,
17-H); 6.92 (s, 1H, TAr--CH.sub.arom).
[0428] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0429] -5.0 (SiCH.sub.3); -4.7 (SiCH.sub.3); -4.5 (SiCH.sub.3);
-4.1 (SiCH.sub.3); -4.0 (SiCH.sub.3); -3.9 (SiCH.sub.3); 14.0
(16-CH.sub.3); 15.8 (8-CH.sub.3); 16.4 (6-CH.sub.3); 18.3
(SiC(CH.sub.3).sub.3); 18.5 (SiC(CH.sub.3).sub.3); 18.6
(4-CH.sub.3); 18.7 (4-CH.sub.3); 23.4; 23.5 (12-CH.sub.3); 24.9
(C-11); 25.6; 25.8 (SiC(CH.sub.3).sub.3); 26.1
(SiC(CH.sub.3).sub.3); 26.2 (SiC(CH.sub.3).sub.3); 31.7 (C-10);
32.5 (C-9); 33.9 (C-9); 35.4 (C-14); 39.5 (C-8 ?); 39.9; 44.2
(C-6); 54.0 (C-4); 63.7; 73.1 (C-3); 76.7 (C-7); 79.2 (C-15); 114.4
(C-19); 118.1 (C-17); 121.7 (C-13); 137.1 (C-12); 143.7 (C-16);
152.7 (C-18); 165.3 (C-20); 174.0 (C-1); 218.2 (C-5).
[0430] MS (Fl, 7 eV, 3 mA, 195.degree. C.) m/e=
[0431] 854 ([M+H]); 853 ([M]); 796; 795; 720; 684; 663; 649; 593;
541; 283; 282; 203; 168; 93; 57.
EXAMPLE Z
[0432]
(3S,6R,7S,8S,12Z,15S,16E)-3,7-Bis[(1,1-dimethylethyl)-dimethylsilyl-
oxy]-4,4,6,8,12,16-hexamethyl-15-hydroxy-16-(2-methylthiazol-4-yl)-heptade-
ca-12,16-dien-5-onic acid
[0433] In 10 ml of absolute THF, 365 mg (0.44576 mmol) of the
compound that is produced according to Example Y is mixed at room
temperature with 2.23 ml (5 equivalents) of a 1 M TBAF solution (in
THF) and stirred for 10 more hours.
[0434] For working-up, it is diluted with 100 ml of ether and
quenched by adding 70 ml of saturated NH.sub.4Cl solution. The
phases are separated, the aqueous phase is extracted twice more
with ether, the combined organic phases are dried on MgSO.sub.4,
filtered and concentrated by evaporation.
[0435] Flash chromatography on a
6:5:1-4:3:1-2:1:1-MC/hex/EE-gradient-sili- cagel-column produced
180 mg of the title compound as a colorless, viscous oil.
[0436] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0437] 0.04 (s, 3H, --SiCH.sub.3); 0.055 (s, 3H, --SiCH.sub.3);
0.07 (s, 3H, --SiCH.sub.3); 0.10 (s, 3H, --SiCH.sub.3); 0.865 (s,
9H, --(SiC(CH.sub.3).sub.3); 0.89 (S, 9H, --SiC(CH.sub.3).sub.3);
0.90 (d (hv), J.apprxeq.7.0 Hz, 3H, 8-CH.sub.3); 1.05 (d, J=6.5 Hz,
3H, 6-CH.sub.3); 1.10 (s, 3H, 4-CH.sub.3); 1.19 (s, 3H,
4-CH.sub.3); 1.34-1.50 (m, 2H); 1.48-1.56 (mc, 3H); 1.70 (s, 3H,
12-CH.sub.3); 1.92-2.01 (m, 1H, 14-H); 2.01 (d, .sup.4J=1.0 Hz, 3H,
16-CH.sub.3); 2.04-2.14 (m, 1H, 14-H); 2.26 (dd, J=16.6 Hz, J=6.0
Hz, 1H, 2-H); 2.33 (mc, 2H, 11-H); 2.435 (dd, J=16.6 Hz, J=4.0Hz,
1H, 2-H); 2.70 (s, 3H, TAr--CH.sub.3); 3.14 (qd, J=7.0 Hz, J=6.5
Hz, 1H, 6-H); 3.76 (dd, J=7.0 Hz, J=2.0 Hz, 1H, 7-H); 4.14 (t,
J=6.5 Hz, 1H, 15-H); 4.40 (dd, J=6.0 Hz, J=4.0 Hz, 1H, 3-H); 5.17
(t, J=7.0 Hz, 1H, 13-H); 6.63 (s, 1H, 17-H); 6.94 (s, 1H,
TAr--CH.sub.arom).
[0438] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0439] -4.7 (SiCH.sub.3); -4.1 (SiCH.sub.3); -3.9 (SiCH.sub.3);
-3.8 (SiCH.sub.3); 13.8 (16-CH.sub.3); 14.6 (8-CH.sub.3); 16.0
(6-CH.sub.3); 17.1; 18.2 (SiC(CH.sub.3).sub.3); 18.5
(SiC(CH.sub.3).sub.3); 18.9 (TAr--CH.sub.3); 19.9 (4-CH.sub.3);
23.1 (4-CH.sub.3); 23.6 (12-CH.sub.3); 26.1 (SiC(CH.sub.3).sub.3);
26.2 (SiC(CH.sub.3).sub.3); 26.3 (CH.sub.2); 26.4 (CH.sub.2); 31.3
(CH.sub.2); 32.5 (CH.sub.2); 34.2 (CH.sub.2); 39.2 (CH); 40.9
(CH?); 44.8 (CH); 51.9; 53.8 (C-4); 74.2 (C-3); 77.3 (C-7); 77.4
(C-15); 115.1 (C-19); 118.7 (C-17); 120.3 (C-13); 139.4 (C-12);
142.2 (C-16); 152.7 (C-18); 165.0 (C-20); 174.9 (C-1); 217.9
(C-5).
[0440] IR (Si film): .nu. in cm.sup.-1=
[0441] 3357br; 2958s; 2932s; 2856m; 1696m; 1508w; 1472m; 1387m;
1293m; 1255m; 1186m; 1106vs; 988s; 952m; 875s; 837vs; 815m; 776vs;
737s.
[0442] MS (Fl, 7 eV, 3 mA, 190.degree. C.): m/e=
[0443] 739 ([M+H]); 738 ([M]);; 722; 721; 720; 682; 662; 606; 427;
329; 295; 203; 129; 57.
EXAMPLE AA
[0444] Silylated Epothilone D
[0445] 65 mg (0.338 mmol, 2 equivalents) of
N'-(3-dimethylaminopropyl)-N-e- thylcarbodiimide-HCl (EDCl), 54 mg
(0.507 mmol, 3 equivalents) of DMAP and 54 mg (0.338 mmol, 2
equivalents) of DMAP-HCl in 100 ml of ethanol-free absolute
CHCl.sub.3 [filtered on bas. Alox B and distilled over CaH.sub.2]
are introduced into a 250 ml three-necked round-bottom flask with
an argon connection, pressure equalization and jacketed coil
condenser. The solution is heated to reflux temperature, and then a
solution of 125 mg (0.169 mmol) of the compound that is produced
according to Example Z in 8 ml of absolute CHCl.sub.3 is added drop
by drop via an injection device over a period of 17 hours and
stirred for 30 more minutes after the last addition.
[0446] The reaction solution is allowed to cool and quenched by
adding 100 ml of saturated NH.sub.4Cl solution and stirred
vigorously for 30 more minutes. Then, the phases are separated, the
aqueous phase is extracted twice with CH.sub.2Cl.sub.2, the
combined organic phases are dried on MgSO.sub.4, filtered on 0.5 cm
of silica gel and concentrated by evaporation.
[0447] Chromatography on a 25:1-hex/EE-gradient-silica-gel-column
produced 84 mg (69%) of the title compound as a flat yellowish
oil.
[0448] R.sub.f-value (hex/EE=10:1).apprxeq.0.37 F III and F IV
(violet blue);
[0449] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0450] -0.12 (s, 3H, --SiCH.sub.3); 0.07 (s, 3H, --SiCH.sub.3);
0.095 (s, 3H, --SiCH.sub.3); 0.10 (s, 3H, --SiCH.sub.3); 0.83 (s,
9H, --SiC(CH.sub.3).sub.3); 0.93 (s, 9H, --SiC(CH.sub.3).sub.3);
0.97 (d, J=7.0 Hz, 3H, 8-CH.sub.3); 1.09 (d, J=6.5 Hz, 3H,
6-CH.sub.3); 1.13 (s, 3H, 4-CH.sub.3); 1.18 (s, 3H, 4-CH.sub.3);
1.47-1.61 (m, 3H); 1.66 (s, 3H, 12-CH.sub.3); 1.66-1.77 (m, 2H);
2.02-2.08 (m, 1H or 2H); 2.09 (d, .sup.4J=1.0 Hz, 3H, 16-CH.sub.3);
2.41-2.49 (m, 1H); 2.62-2.71 (m, 2H); 2.69 (s, 3H, TAr--CH.sub.3);
2.79 (dd, J=16.6 Hz, J=1.5 Hz, 1H, 2-H); 3.01 (qd, J=7.0 Hz, J=6.5
Hz, 1H, 6-H); 3.88 (d, J=9.0 Hz, 1H, 7-H); 4.02 (d, J=8.5 Hz, 1H,
3-H); 4.96 (d, J=9.6 Hz, 1H, 15-H); 5.15 (t, J=8.0 Hz, 1H, 13-H);
6.55 (s, 1H, 17-H); 6.95 (s, 1H, TAr--CH.sub.arom).
[0451] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0452] -5.6 (SiCH.sub.3); -3.70 (SiCH.sub.3); -3.69 (SiCH.sub.3);
-3.3 (SiCH.sub.3); 15.3+17.8 (C-16 and C-6); 18.6
(SiC(CH.sub.3).sub.3); 18.7 (SiC(CH.sub.3).sub.3); 19.2
(TAr--CH.sub.3); 23.1 (4-CH.sub.3's); 24.3; 24.5; 25.7; 26.2
(SiC(CH.sub.3).sub.3); 26.4 (SiC(CH.sub.3).sub.3); 27.4; 29.7;
31.4; 31.9; 32.5; 39.2 (C-2); 53.4 (C-4); 76.3 (C-3 and/or C-7);
79.9 (C-15); 115.9 (C-19); 119.2 (C-17); 119.4 (C-13); 138.8
(C-12); 140.6 (C-16); 152.5 (C-18); 164.5 (C-20); 171.2 (C-1);
215.1 (C-5).
[0453] C.sub.39H.sub.69NO.sub.5SSi.sub.2:
(M=720.21 g.multidot.mol.sub.-1)
EXAMPLE AB
[0454] Epothilone D
[0455] 75 mg (0.104 mmol) of the compound that is produced
according to Example AA is introduced at 0.degree. C. with 1.5 ml
of absolute pyridine into 5 ml of absolute THF. 1.5 ml of
HF-pyridine is now added drop by drop and allowed to heat slowly to
room temperature. After 18 hours (almost only educt), another 1.5
ml of HF-pyridine is added drop by drop, again at 0.degree. C., and
stirred for 18 more hours.
[0456] For working-up, it is mixed drop by drop with saturated
NaHCO.sub.3 solution at 0.degree. C., then diluted with diethyl
ether and saturated NaHCO.sub.3 solution. Then, the phases are
separated, the aqueous phase is extracted three times with diethyl
ether, the combined organic phases are dried on MgSO.sub.4,
filtered and concentrated by evaporation.
[0457] Chromatography on a 3:1-hex/EE-silica gel column produced 44
mg (69.8%) (monodesilylated product) and 10 mg (19.6%) of the title
compound (epothilone D). The monodesilylated product is again
subjected to the above conditions. After chromatography on a
3:1-hex/EE-silica gel column, 39 mg (76.3%) of the title compound
was again obtained, thus a total of 49 mg (95.8%) of epothilone
D.
[0458] R.sub.f-value (hex/EE=1.1) monosilylated.apprxeq.0.67 F IV
(blue);
[0459] R.sub.f-value (hex/EE=3:1) monosilylated.apprxeq.0.19 F IV
(blue);
[0460] R.sub.f-value (hex/EE=1:1) of the title
compound.apprxeq.0.52
[0461] F IV (blue);
[0462] R.sub.f-value (hex/EE=3:1) of the title
compound.apprxeq.0.11
[0463] F IV (blue);
[0464] .sup.1H-NMR (400 Mz, CDCl.sub.3): .delta. in ppm=
[0465] 1.01 (d, J=7.0 Hz, 3H, 8-CH.sub.3); 1.06 (s, 3H,
4-CH.sub.3); 1.18 (d, J=7.0 Hz, 3H, 6-CH.sub.3); 1.24-1.31 (m, 4H);
1.33 (s, 3H, 4-CH.sub.3); 1.65 (s, 3H, 12-CH.sub.3); 1.68-1.78 (m,
1 or 2H, ?); 1.83-1.89 (m, 1H); 2.06 (d, .sup.4J=1.0 Hz, 3H,
16-CH.sub.3); 2.22 (ddd, J=15.6 Hz, J.sub.11-Ha, 10-Ha=3.5 Hz,
J.sub.11-Ha, 10-Hb=2.0 Hz, 1H, 11-Ha); 2.28 (dd, J=14.6 Hz,
J.sub.2-Ha ,3-H=3.0 Hz, 1H, 2-Ha); 2.29-2.35 (m, 1H); 2.45 (dd,
J.sub.2-Hb,3-H=14.6 Hz, J.sub.2-Hb,3-H=11.0 Hz, 1H, 2-Hb); 2.63
(dt, J=15.1 Hz, J.sub.14-Ha,15 and 13-H=10.0 Hz, 1H, 14-Ha); 2.68
(s, 3H, TAr--CH.sub.3); 3.02 (br, 1H, OH); 3.15 (qd,
J.sub.6-H,6-CH3=6.9 Hz, J.sub.6-H,7-H=2.5 Hz, 1H, 6-H); 3.45 (br,
1H, OH); 3.71 (dd, J.sub.7-H,8-H=4.0 Hz, J.sub.7-H,6-H=2.5 Hz, 1H,
7-H); 4.28 (dd, J.sub.3-H,2-Hb=11.0 Hz, J.sub.3-H,2-Ha=2.5 Hz, 1H,
3-H); 5.13 (dd, J.sub.13-H,14-Ha)=10.0 Hz, J.sub.13-H,14-Hb=5.0 Hz,
1H, 13-H); 5.21 (dd, J.sub.15-H,14-Ha=10.0 Hz, J.sub.15-H,14-Hb=1.5
Hz, 1H, 15-H); 6.57 (s, 1H, 17-H); 6.94 (s, 1H,
TAr--CH.sub.arom).
[0466] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. in ppm=
[0467] 13.4 (16-CH.sub.3); 15.7 (6-CH.sub.3); 18.0 (8-CH.sub.3);
19.0 (TAr--CH.sub.3); 22.9 (4-CH.sub.3's); 25.4 (C-11); 31.6+31.7
(C-9 and C-10); 32.5 (C-14); 38.4 (C-8); 39.6 (C-2); 41.7 (C-6);
53.5 (C-4); 72.3 (C-3); 74.1 (C-7); 78.9 (C-15); 115.6 (C-19);
119.2 (C-17); 120.9 (C-13); 138.4 (C-12); 139.2 (C-16); 152.0
(C-18); 165.0 (C-20); 170.4 (C-1); 220.7 (C-5).
[0468] C.sub.39H.sub.69NO.sub.5SSi.sub.2:
(M=720.21 g.multidot.mol.sup.-1)
EXAMPLE AC
[0469] Epothilone B
[0470] In 3.5 ml of absolute CHCl.sub.3 (put on a column on alox B
and distilled of CaH.sub.2), 43 mg (87.4 .mu.mol) of the compound
that is produced according to Example AB is mixed at -18.degree. C.
with 32.5 mg (.apprxeq.1.5 equivalents, 131.1 .mu.mol, about 70%)
of mCPBA and stirred for 5 hours at a temperature that is kept
constant.
[0471] For working-up, it is diluted with 14 ml of
CH.sub.2Cl.sub.2, and the reaction is quenched by adding 15 ml of
saturated NaHCO.sub.3 solution. The phases are separated, the
aqueous phase is extracted four more times with CH.sub.2Cl.sub.2,
the combined organic phases are then dried on MgSO.sub.4, filtered
and concentrated by evaporation.
[0472] Chromatographic precleaning on a 1:1-hex/EE-silica gel
column produced 36 mg (81.1%) of the title compound as a 4:1
mixture of epothilone B and its .alpha.-epoxidisomer. HPLC
separation of a small amount was performed on 20% iPrOH in
hexane.
[0473] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. in ppm=
[0474] 0.99 (d, J=7.0 Hz, 3H, 8-CH.sub.3); 1.07 (s, 3H,
4-CH.sub.3); 1.16 (d, J=7.0 Hz, 3H, 6-CH.sub.3); 1.27 (s, 3H,
4-CH.sub.3); 1.36 (s, 3H, 12-CH.sub.3); 1.35-1.45 (m, 3H);
1.46-1.54 (m, 2H); 1.65-1.77 (m, 3H); 1.91 (dd, J=15.6 Hz, J=8.0
Hz, 1H , 14-H); 2.08 (s, 3H, 16-CH.sub.3); 2.06-2.13 (m (v), 1H,
14-H); 2.35 (dd, J=13.5 Hz, J=2.5 Hz, 1H, 2-H); 2.53 (dd, J=14.1
Hz, J=10.0 Hz, 1H, 2-H); 2.65 (br, 1H, OH); 2.69 (s, 3H,
TAr--CH.sub.3); 2.80 (dd, J=7.5 Hz, J=4.5 Hz, 1H, 13-H); 3.29 (qd,
J=7.0 Hz, J=4.0 Hz, 1H, 6-H); 3.71 (t, J=4.0 Hz, 1H, 7-H); 4.22
(br, 2H, 3-H and OH); 5.41 (d, J=8.0 Hz, J=3.0 Hz, 1H, 15-H); 6.58
(s, 1H, 17-H); 6.96 (s, 1H, TAr--CH.sub.arom).
[0475] Preparative Methods:
[0476] All reactions of organometallic reagents and all reactions
in absolute solvents are performed in an air-free and moisture-free
environment. Before the beginning of the test, the glass devices
that are used are heated several times in a vacuum (about 0.01
mbar) and aerated with dried argon of the Linde Company. Unless
otherwise indicated, all reaction batches are stirred
magnetically.
[0477] Methylene chloride is predried on a basic aluminum oxide
column of the activity stage I (Woelm) and made absolute on calcium
hydride. After predrying on a basic aluminum oxide column over an
8:1 sodium/potassium alloy, diethyl ether is refluxed until stable
blue coloring of the benzophenone indicator is achieved and is
freshly distilled off before use. Tetrahydrofuran (THF) is predried
on KOH, filtered over a column that is coated with basic aluminum
oxide and then distilled on potassium with triphenylmethane as an
indicator.
[0478] After predrying on calcium chloride just like hexane (hex),
ethyl acetate (EE) is distilled off in a rotary evaporator before
use for column chromatography.
[0479] Chromatographic Process:
[0480] All reactions are tracked by thin-layer chromatography (TLC)
on silica gel-60-aluminum foils with UV-indicator F.sub.254 of the
Merck Company. As mobile solvent, in most cases solvent mixtures
that consist of hexane (hex) and ethyl acetate (EE) are used. For
visualization of non-UV-active substances, anisaldehyde/glacial
acetic acid/sulfuric acid (1:100:1) has been taken as a standard
immersion reagent in most cases.
[0481] The preoperative column chromatography is performed on
silica gel-60 of the Merck Company (0.04-0.063 mm, 230-400 mesh),
whereby as eluant, solvent mixtures that consist of hexane (hex)
and ethyl acetate (EE) or diisopropyl ether are used.
[0482] On an analytical scale as well as on a preoperative scale,
the high-pressure liquid chromatographic separations (HPLC) are
performed on the modular systems of the Knauer Company (pump 64, UV
and RI detectors, columns and-recorders), Waters/Millipore
(injection system U6K9) and Milton-Roy (integrator CI-10). For the
analytical HPLC, in most cases a Knauer column (4-250 mm) with 5
.mu.m of Nucleosil is used, and for the preoperative HPLC, a column
(16-250 mm, 32,250 mm or 64-300 mm) with 7 .mu.m or 5 .mu.m
Nucleosil 50 is used.
[0483] Dye Reagents
[0484] Dye reagent I (F I): In the case of most compounds that can
be reduced, 1 g of cerium(IV) sulfate in 10 ml of concentrated
sulfuric acid and 90 ml of water produce an intense blue color
reaction during drying.
[0485] Dye reagent II (F II): A 10% ethanolic solution of
molybdatophosphoric acid produces another immersion reagent for
detecting unsaturated compounds that can be reduced. In contrast to
dye reagent I, the molybdate dye reagent, especially pertaining to
several functionalities, shows a broader color spectrum with
virtually identical reliability.
[0486] Dye reagent III (F III): 1 ml of anisaldehyde in 100 ml of
ethanol and 2 ml of concentrated sulfuric acid produces an
extremely sensitive dye reagent that also likely shows the broadest
color spectrum.
[0487] Dye reagent IV (F IV): Like the anisaldehyde reagent, 1 g of
vanillin in 100 ethanol and 2 ml of concentrated sulfuric acid is a
very sensitive dye reagent with a broad color spectrum.
[0488] Dye reagent V (F V): 1 g of 2,4-dinitrophenylhydrazine in 25
ml of ethanol, 8 ml of water and 5 ml of concentrated sulfuric acid
is an excellent immersion reagent that is selective even without
heating on aldehyde and that responds somewhat more slowly to
ketones.
[0489] Dye reagent VI (F VI): A 0.5% aqueous solution of potassium
permanganate indicates oxidizable groups by decoloration, whereby
unsaturated, non-aromatic structural units react spontaneously
without heating.
[0490] Spectroscopic Process and General Analysis:
[0491] NMR Spectroscopy
[0492] The .sup.1H-NMR spectra are recorded with a DRX 250 DRX 400
spectrometer of the Bruker Company with the substances as a
solution in deuterated solvents and tetramethylsilane as an
internal standard. The evaluation of the spectra is carried out
according to rules of the first order. If a signal multiplicity
that occurs cannot be explained in this way, the indication of the
observed line assembly is done. To determine the stereochemistry,
the NOE-spectroscopy (Nuclear Overhauser Effect) is used.
[0493] To characterize the signals, the following abbreviations are
used: s (singlet), d (doublet), dd (double doublet), ddd (6-line
system with two identical coupling constants or an 8-line system
with three different coupling constants), t (triplet), q (quartet),
quint (quintet), sext (sextet), sept (septet), m (multiplet), mc
(centered multiplet), br (broad), hv (semi-masked signal) and v
(masked signal).
[0494] The .sup.13C-NMR spectra are measured with an AC 250 of the
Bruker Company with CDCl.sub.3-signal at 77.0 ppm as an internal
standard, whereby the proton resonances are
broadband-decoupled.
[0495] IR-Spectroscopy
[0496] The infrared spectra are recorded with devices of the
Perkin-Elmer Company (Model 257 or 580 B) and Nicolet Company (FTIR
Interferometer System 55XC). The oils are measured as films between
potassium bromide disks. The bands are indicated according to
decreasing wave number (cm.sup.-1). For characterization, the
following designations are selected: vs (very strong), s (strong),
m (medium), and w (weak).
[0497] Abbreviations:
[0498] abs.: absolute, Ar: aryl/aromatic compound, ber.:
calculated, brine: cold, saturated common salt solution, nBuLi:
nbutyllithium, c: concentration, COSY: correlated spectroscopy,
CSA: camphorsulfonic acid, DC: thin-layer chromatography, DCM:
dichloromethane; DDQ: dichloro-dicyano-quinone, d.e.:
diastereomeric excess, DIBAH: diusobutyl-aluminum hydride, DIPA:,
diisopropylamine, DMAP: dimethylaminopyridine, DMF:
N,N'-dimethylformamide, DMS: dimethyl sulfide, DMSO: dimethyl
sulfoxide, ds: diastereoselection, EA: elementary analysis, e.e.:
enantiomeric excess, EE: ethyl acetate, El: electron impact
ionization, eq: equivalent(s), eV: electron volt, FG: functional
group, Fl: field ionization, gef.: found, ges.: saturated, h:
hour(s), Hex: n-hexane, HMDS: hexamethyldisilazide, HPLC:
high-pressure liquid chromatography, Hunig base:
N-ethyl-diisopropylamine, HRMS: high resolution mass spectrometry,
HV: high vacuum, iPrOH: 2-propanol, IR: infrared
spectrometry/infrared spectrum, J: coupling constant, LDA: lithium
diisopropylamine, Lsg.: solution, Lsm.: solvent, MC: methylene
chloride, Me: methyl, MeLi: methyllithium, min: minute(s), MS: mass
spectrometry/mass spectra, NMR: Nuclear Magnetic Resonance, NOE:
Nuclear Overhauser Effect, PCC: pyridinium chlorochromate, PG:
protective group, Ph: phenyl, ppm: parts per million, Rkt.:
reaction, rt: retention time, RT: room temperature (20-30.degree.
C.), Std.: hour(s), TBAF: tetra-n-butylammonium fluoride, TBDPS:
tert-butyldiphenyl-silyl-, TBDPSCl: tert-butyldiphenyl-silyl
chloride, TBS: tert-butyldimethyl-silyl- -,TBSCl:
tert-butyldimethyl-silyl chloride, TSBTriflat:
tert-butyldimethyl-silyl-triflate, TEA: triethylamine, tert./t:
tertiary, TFA: trifluoroethanoic acid.
* * * * *