U.S. patent application number 09/796606 was filed with the patent office on 2001-12-20 for anthracycline analogues bearing latent alkylating substituents.
This patent application is currently assigned to Board of Regents. Invention is credited to Cherif, Abdallah, Farquhar, David.
Application Number | 20010053845 09/796606 |
Document ID | / |
Family ID | 24435271 |
Filed Date | 2001-12-20 |
United States Patent
Application |
20010053845 |
Kind Code |
A1 |
Farquhar, David ; et
al. |
December 20, 2001 |
Anthracycline analogues bearing latent alkylating substituents
Abstract
Compound having the structure 1 where anthracycline, N, R.sup.a,
X, R.sup.b, n and m are as defined in the specification. The
compound of the invention is activatable in vivo by esterases and
spontaneous dehydration to form an aldehyde. The aldehyde may
couple to nucleophiles of intracellular macromolecules. The
compounds of the invention are cytotoxically effective in the
inhibition of human myeloma cells.
Inventors: |
Farquhar, David; (Houston,
TX) ; Cherif, Abdallah; (Houston, TX) |
Correspondence
Address: |
Nixon & Vanderhye P.C.
8th Floor
1100 N. Glebe Rd.
Arlington
VA
22201
US
|
Assignee: |
Board of Regents
|
Family ID: |
24435271 |
Appl. No.: |
09/796606 |
Filed: |
March 2, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09796606 |
Mar 2, 2001 |
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08441240 |
May 15, 1995 |
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6284737 |
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08441240 |
May 15, 1995 |
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08034904 |
Mar 22, 1993 |
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08034904 |
Mar 22, 1993 |
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07608149 |
Nov 1, 1990 |
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5196522 |
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Current U.S.
Class: |
536/6.4 |
Current CPC
Class: |
A61P 31/04 20180101;
C07H 15/252 20130101; A61P 35/00 20180101 |
Class at
Publication: |
536/6.4 ;
514/34 |
International
Class: |
C07H 015/24; A61K
031/704 |
Goverment Interests
[0001] Work relating to the development of the present invention
was supported by Grant CA 42708 from the National Institutes of
Health, DHHS. This support gives the United States Government
certain rights in the present invention.
Claims
What is claimed is:
1. A compound of the formula 4where: anthracycline is doxorubicin,
daunorubicin or a derivative thereof; N is the 3' nitrogen of
daunosamine; R.sup.a is H or alkyl; X is O, S, CR.sup.c.sub.2 or
NR.sup.c, where R.sup.c is H or alkyl; R.sup.b is alkyl or aryl; n
is 1 to 6; and m is 0 to 6.
2. The-compound of claim 1 wherein R.sup.c is H, methyl, ethyl,
propyl or butyl.
3. The compound of claim 1 wherein R.sup.a is H, R.sup.b is
CH.sub.3, X is CR.sup.c.sub.2, R.sup.c is H, n is 2'and m is 1.
4. The compound of claim 1 wherein R.sup.a is CH.sub.3 or H,
R.sup.b is CH.sub.3, X is 0, n is 2, and m is 1.
5. The compound of claim 1 wherein R.sup.a is H, R.sup.b is
CH.sub.3, X is CR.sup.c.sub.21 R.sup.c is H, n is 2 and m is 0.
6. The compound of claim 1 wherein R.sup.a is H, R.sup.b is
CH.sub.3, X is CR.sup.c.sub.2, R.sup.c is H, n is 2 and m is 2.
7. The compound of claim 1 wherein R.sup.a is H, R.sup.b is
CH.sub.3, X is CR.sup.c.sub.2, R.sup.c is H, n is 2 and m is 0.
8. The compound of claim 1 wherein R.sup.a is H, R.sup.b is
CH.sub.3'X is O, n is 2 and m is 2.
9. The compound of claim 1 wherein R.sup.a is H, R.sup.b is
CH.sub.3, X is CR.sup.c.sub.2, R.sup.c is H, n is 2 and m is 4.
10. The compound of claim 1 wherein R.sup.a is H, methyl, ethyl,
propyl or butyl.
11. The compound of claim 1 wherein R.sup.b is alkyl.
12. The compound of claim 1 wherein R.sup.b is the alkyl methyl,
ethyl, propyl or butyl.
13. The compound of claim 1 wherein R.sup.b is methyl.
14. The compound of claim 1 wherein X is CR.sup.c.sub.2, RC is H,
and m+n is from 1 to 9.
15. The compound of claim 1 wherein X is O, S or NRc, R.sup.c is
H.
16. The compound of claim 1 wherein anthracycline is doxorubic
in.
17. N-(5,5-Diacetoxypentyl) doxorubicin or a pharmaceutically
acceptable salt thereof.
18. N-(2,2-Diacetoxyethyloxyethyl) doxorubicin or a
pharmaceutically acceptable salt thereof.
19. N-(4,4-Diacetoxybutyl) doxorubicin or a pharmaceutically
acceptable salt thereof.
20. N-(6,6-Diacetoxyhexyl) doxorubicin or a pharmaceutically
acceptable salt thereof.
21. N-(4,4-Diacetoxy-3,3-dimethylbutyl) doxorubicin or a
pharmaceutically acceptable salt thereof.
22. N-(3,3-Diacetoxypropyloxy-1-ethyl) doxorubicin or a
pharmaceutically acceptable salt thereof.
23. N-(8,8-Diacetoxyoctyl) doxorubicin or a pharmaceutically
acceptable salt thereof.
Description
BACKGROUND OF THE INVENTION
[0002] This invention is in the field of anthracycline
chemistry.
[0003] More particularly it concerns derivatives of the
anthracyclines, doxorubicin and daunorubicin, that are useful as
antitumor agents.
[0004] Daunorubicin is used for the treatment of certain leukemias.
Doxorubicin (adriamycin) is one of the most useful anticancer drugs
in use at this time. Doxorubicin is a principle agent in the
treatment of an unusually wide number of solid tumors and
leukemias. Regrettably, many patients with these tumors fail to
respond and essentially no patients with certain serious tumor
types (colon cancer, melanoma) are successfully treated.
Additionally, in some patients chronic adriamycin treatment
produces irreversible heart damage that can be fatal if continued.
Thus, there is great need for analogues which give a better rate of
response, a wider spectrum of response, and/or reduced
cardiotoxicity. More effective and less toxic agents are widely
sought and are a fundamental object of this invention.
[0005] Much of the history and prior art of doxorubicin and its
anthracycline analogues is found in the article "Adriamycin" by
David W. Henry, ACS Symposium Series, No. 30, Cancer Chemotherapy,
American Chemical Society, pp. 15-57 (1976) and in the book
Doxorubicin by Frederico Arcamone, Academic Press, 1981. The
derivative AD32 is disclosed in U.S. Pat. No.. 4,035,566, dated
Jul. 12, 1977.
[0006] 5-Iminodaunorubicin is shown in U.S. Pat. No. 4,109,076
which issued on Aug. 22, 1978, to David W. Henry and George L.
Tong. The doxorubicin equivalent is shown in "Synthesis and
Preliminary Antitumor Evaluation of 5-Iminodoxorubicin", J. Med.
Chem. 24, 669 (1981) by Edward M. Acton and George L. Tong.
5-Iminodoxorubicin retained activity with reduced side effects with
5-Iminodoxorubicin showed enhanced activity but required higher
dosages.
[0007] 3'-Deamino-3-(4-morpholinyl)daunorubicin is described in
U.S. Pat. No. 4,301,277 issued on Nov. 17. 1981 to Acton et al. It
was active at one-fortieth the dose of doxorubicin but gave a
substantially identical T/C value (166% vs 160% against P388). This
compound and its preparation and properties are also disclosed in
"Enhanced Antitumor Properties of 3'-(4-Morpholinyl) and
3'-(4-Methoxy-1-piperidinyl) Derivatives of 3'Deaminodaunorubicin",
J. Med. Chem., 25, pp. 18-24 (1982) by Mosher et al.
[0008] A general reductive alkylation process for preparing certain
new semi-synthetic anthracycline derivatives is described in
"Adriamycin Analogues. 3. Synthesis of N-Alkylated Anthracyclines
With Enhanced Efficacy and Reduced Cardiotoxicity", J. Med. Chem.,
22 pp. 912-918 (1979) by Tong et al.
[0009] A group of daunorubicin and doxorubicin derivatives is
disclosed in U.S. Pat. No. 4,585,859, issued Apr. 29, 1986.
Included in this group are 3'-deamino-31-(31"-cyano-41"-morpholinyl
doxorubicin;
3'-deamino-3'(31"-cyano-4"-morpholinyl)-13-dihydrodoxorubicin;
(3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and
3'-deamino-3'-(4"-morpholinyl-5-iminodoxorubicin and derivatives
thereof which have activity as antitumor agents.
[0010] U.S. Pat. No. 4,841,085, Jun. 20, 1989, by one of the
present inventors, describes diacetatopropyl phosphoramidic mustard
derivatives activatable in vivo by endogenous esterases.
[0011] U.S. Pat. No. 4,826,964 issued May 2, 1989 to Acton et al.
describes cyanomorpholino doxorubicin which contains an esterified
hydroxyl group on the morpholino group. There appears to be little,
other than general classification, in common between this compound
and those of the present invention.
[0012] U.S. Pat. No. 4,755,619 issued Jul. 5, 1988 to Creighton et
al. discusses a multifunctional compound which is a derivatized
dicarbonylalkyl N-substituted drug which may be activated in vivo
by hydrolysis of an ester group. This is indirectly related to the
compound of the present invention but is chemically quite
different. It is suggested, see column 9, lines 20-30, that the
subject compounds and anthracyclines such as doxorubicin may be
advantageously used together to treat cancer synergistically while
avoiding the cardiotoxicity of the doxorubicin. While there was
some analogy in chemical structure and in vivo activation, this
reference does not seriously detract from the patentability of the
present invention.
[0013] The Tsuchiya et al. reference (J. Antibiotics, July 1988,
988-991) describe doxorubicin derivatives with excellent activities
against L1210 leukemia and lowered toxicities as compared to
doxorubicin. These derivatives, although having ester linkages, are
nonanalogous to those of the present invention.
[0014] The Acton et al. reference (J. Med. Chem. 1986, 29,
2120-2122) describes cyanomorpholinyl doxorubicin compounds and
their properties.
[0015] The Horton and Priebe reference (J. Antibiotics, XXXVI,
1211-1215, 1983) describes a range of esterified anthracycline
derivatives. None of these derivatives has the bis-acetal
substituents of the present invention.
[0016] The Tong et al. reference (J. Med. Chem. 8, 912-918, 1979)
describes various N-alkyl and N,N-dialkyl anthracyclines and their
13-dihydro derivatives.
[0017] The pertinent subject matter of the above references is
specifically incorporated herein by reference.
SUMMARY OF THE INVENTION
[0018] The present invention is a compound having the structure
2
[0019] where:
[0020] anthracycline is doxorubicin, daunorubicin or a derivative
thereof;
[0021] N is the 3' nitrogen of daunosamine;
[0022] R.sup.a is H or alkyl;
[0023] X is O or S, CR.sup.c.sub.2 or NR.sup.c, where R.sup.c is H
or alkyl;
[0024] R.sup.b is alkyl or aryl;
[0025] n is 1 to 6; and
[0026] m is 0 to 6.
[0027] R.sup.a and R.sup.c are preferably and independently H,
methyl, ethyl, propyl or butyl. R.sup.b when an alkyl is preferably
methyl, ethyl, propyl or butyl, although other alkyl substituents
are usable. The compound of the present invention as described
above is activatable in vivo by esterases and spontaneous
dehydration to form an aldehyde. The aldehyde may couple to
nucleophiles of intracellular macromolecules. The compounds of the
present invention are cytotoxically effective in the inhibition of
human leukemia myeloma cells.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 schematically describes potentially alkylating
derivatives of doxorubicin.
[0029] FIG. 2 schematically describes preferred compounds of the
present invention.
[0030] FIG. 3 schematically describes the activation mechanism for
the compounds of the present invention.
[0031] FIG. 4 generically describes a synthetic scheme for an
embodiment of the present invention.
DESCRIPTION OF PREFERRED EMBODIMENT
[0032] The anthracycline antibiotic doxorubicin is effective in the
palliative management of a wide variety of human malignancies
However, the clinical utility of doxorubicin is limited by a number
of problems, including intrinsic and acquired drug resistance and
dose-dependent cardiomyopathy. Numerous analogues have been
synthesized in an attempt to overcome these shortcomings..sup.2-4 A
series of derivatives in which the 3'-amino group of the
daunosamine sugar As replaced with a morpholino substituent has
been reported by Acton and coworkers. .sup.5-7 One of these
analogues, 3'-deamino-3'-(3-cyano-4-morpholinyl)-adriamycin
(MRA-CN) is 100 to 1000 times more cytotoxic than doxorubicin in
vitro.sup.7-10 and in vivo.sup.6,11 and retains its potency against
several tumor cell lines with acquired resistance to
doxorubicin..sup.9,12,13
[0033] The compounds of the present invention, bis(acyloxy) acetals
of an anthracycline such as doxorubicin (adriamycin), for example,
are designed to be relatively stable, non-toxic but subject to
activation by in vivo enzymes (esterases) to form an aldehyde
hydrate from the bis (acyloxy) acetal. This aldehyde hydrate is
labile and eliminates water to form an aldehyde. By varying the
composition of the anthracycline bisacyloxy-bearing side chain,
many different analogues are possible, all of which will be
activatable at various rates by endogenous esterases and
spontaneous decompositions to form active anthracycline aldehyde
derivatives. It is possible to vary the composition of the side
chain in both composition and length to prepare a series of such
analogues having desired specificities and/or non-toxicities toward
particular biological sites. The side chain connecting the
anthracycline and the bis acyloxy substituent will comprise at
least one methylene (CH.sub.2) group and may contain up to 9 such
groups. When more than one methylene group is present there may be
an additional spacer group such as O, S or NR.sup.a where R.sup.a
is H or alkyl with usually less than 5 carbon atoms, depending upon
the particular properties desired.
[0034] A series of analogues, 1, (FIG. 1) bearing alkylating or
latent alkylating substituents, R, on the 3'-position of the
daunosamine sugar were prepared. These compounds were designed on
the premise that alkylating anthracyclines should bind covalently
to critical intracellular macromolecules and overcome resistance to
doxorubicin arising from reduced cellular drug accumulation.
However, in growth inhibitory studies against mouse (L1210 and
P388) and human (uterine sarcoma, myelocytic) tumor cells in vitro,
these analogues were 5- to 100-fold less potent than the parent
compound (doxorubicin). These analogs nevertheless did retain their
cytotoxic activity against variants of these same cell lines which
were resistant to doxorubicin.
[0035] To identify new alkylating anthracyclines with increased
potency, a series of doxorubicin analogues was synthesized in which
the 3'-amino group is substituted with a latent alkanal or
heteroalkanal group. A rationale for the design of these compounds
was that: (a) the latent alkanal or heteroalkanal groups would be
converted to the corresponding free aldehydes when the drugs were
placed in a biological medium (such as cells or whole organisms),
and (b) the liberated free aldehydes would react with nucleophiles
(such as amino or sulfhydryl groups) proximate to the DNA
drug-binding site to form covalent adducts. As a consequence, drug
egress from the cell should be inhibited.
[0036] Because of the intrinsic chemical reactivity of free
aldehydes, the alkanal (or heteroalkanal) groups were introduced
into the doxorubicin molecule in latentiated form. Bis(acyloxy)
groups were selected for this purpose. The general structure of the
new doxorubicin analogues is shown in FIG. 2, where the
anthracycline is doxorubicin or daunorubicin.
[0037] Additionally, the acyloxy group may be varied. For example,
the acyloxy group may be acetate, propionate, butyrate (n or t) or
even benzoate or substituted benzoate. The acyloxy substituent may
also be varied to control the rate of drug activation resulting
from ester hydrolysis. For example, certain sterically hindered
ester groups may be hydrolyzed much less rapidly than a simpler
substituent such as acetoxy.
[0038] The mechanism for regeneration of the free aldehyde is
illustrated in FIG. 3 with respect to compound 2a (FIG. 2 n=2, m=1,
X=CR.sup.c.sub.2 where R.sup.c is H, R.sup.b=CH.sub.3 and
R.sup.a=H). In the presence of carboxylate esterases, enzymes that
are ubiquitous in tissue, and which show low substrate specificity,
compound 2a can be hydrolyzed to the corresponding aldehyde
hydrate, 3a. Elimination of water from 3a generates the free
aldehyde, 4a. The aldehyde group can then react with a nucleophile
such as one on a macromolecule proximate to, or within, a
DNA-binding site to form a potential covalent drug-DNA adduct,
5a.
[0039] Apart from recent studies by the inventors' laboratory with
cyclophosphamide metabolites (see U.S. Pat. No. 4,841,085 and
Aldophosphamide bis(acetoxy)acetal and Structural Analogues. J.
Med. Chem., In Press, 1990, for example) this approach to the
bioreversible latentiation of aldehydes has not been described
previously and has not at all been described before for
anthracycline derivatives.
[0040] An important aspect of this strategy is that by judicious
selection of the acyloxy groups, it should be possible to modify
the lipophilicity and aqueous solubility of these analogues.
Moreover, since these compounds are designed to be activated by
carboxylate esterases (enzymes present in all cells), the acyloxy
masking groups can be altered to control the rate at which the
active "alkylating" anthracyclines are formed.
[0041] A number of compounds having the general structure 2 have
been prepared. These were synthesized by condensing doxorubicin
with a dialdehyde monoacetal then reducing the intermediate imine
with NaBH.sub.3CN. The overall synthetic strategy can be
exemplified with respect to 2a as schematically illustrated in FIG.
4.
[0042] To the best of applicants' knowledge, dialdehyde monoacetals
such as 10 have not been reported previously. [These should be
versatile synthetons in organic synthesis since the acetal ester
groups can be cleaved under extremely mild conditions (weak base or
esterase activity)]. Condensation of 10 with doxorubicin, 11, in
the presence of NaCNBH.sub.3 generated 2a directly in >50%
yield. Evidence for the structure of 2a was obtained by .sup.1H and
COSY NMR, and by mass spectrometry. The compound is freely soluble
in aqueous media and is stable at neutral pH.
[0043] To investigate structure-activity relationships for this
class of compounds, the analogs (based upon structure 2 of FIG. 2)
shown in Table 1 have been prepared.
1TABLE 1 2a n = 2, m = 1, X = CH.sub.2, R.sup.b = CH.sub.3, R.sup.a
= H 2b n = 2, m = 1, X = O, R.sup.b = CH.sub.3, R.sup.a = CH.sub.3
2c n = 2, m = 0, X = CH.sub.2, R.sup.b = CH.sub.3, R.sup.a = H 2d n
= 2, m = 2, X = CH.sub.2, R.sup.b = CH.sub.3, R.sup.a = H 2e n = 2,
m = 0, X = C(CH.sub.3).sub.2, R.sup.b = CH.sub.3, R.sup.a = H 2f n
= 2, m = 2, X = O, R.sup.b = CH.sub.3, R.sup.a = H 2g n = 2, m = 4,
X = CH.sub.2, R.sup.b = CH.sub.3, R.sup.a = H
[0044] This strategy obviously may be readily extended to the
synthesis of a series of analogues where, e.g., X=O, S, NR.sup.c or
CR.sup.c.sub.2 where R.sup.c is H or alkyl; n=1-6; m=0-6;
R.sup.a=H, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7 or other
hydrocarbons (C.sub.xH.sub.2x+1); and R.sup.b=CH.sub.3,
C.sub.2H.sub.5, C.sub.xH.sub.7, or C(CH.sub.3).sub.3. While
hydrochloride salts have been prepared, it is well known to utilize
other pharmaceutically acceptable acids in place of hydrochloric
acid to make numerous pharmaceutically acceptable salts. 3
2 TABLE 2 IC.sub.50.sup.a (nM) Compound CEM (VLB).sup.c Resistance
index CEM.sup.b cells cells ([CEM(VLB)]/[CEM]) Doxorubicin 10 1340
134 Compound 2a 0.15 1 6 Compound 2b 3 15 5 .sup.aDetermined after
six days incubation with drug at 37.degree. C. .sup.bA human
T-lymphoblastic cell line .sup.cA human T-lymphoblastic cell line
resistant to Velban (vinblastine)
[0045] Compound 2a was 60 times more toxic to the parent CEM cells
than doxorubicin, and showed markedly reduced cross resistance agai
nst the velban resistant mutant.
[0046] In related studies compound 2a was shown to be 400 times
more potent (IC.sub.50=1.5 nM) to 8226R40 human myeloma cells than
doxorubicin (IC.sub.50=600 nM).
EXAMPLE 2
Synthetic and Related Methods
[0047] Experimental.
[0048] Nuclear magnetic resonance spectra (.sup.1H and .sup.13C)
were recorded at ambient temperature on an IBM-Bruker Model NR/200
AF spectrometer in the Fourier transform mode in CDCl.sub.3 with
tetramethylsilane as an internal reference. Chemical shifts (o) are
reported in parts per million (ppm) and coupling constants (J) in
hertz units. Specialist NMR techniques used for structural
assignment include: off-resonance decoupling plus single frequency,
selective heteronuclear decoupling, homonuclear-shift-correlated
2D-NMR (COSY), homonuclear shift-correlated 2D-NMR with a delay
period to emphasize long range or small coupling (COSYLR), and
heteronuclear shift-correlated 2D-NMR using polarization transfer
from .sup.1H to .sup.13C via Jcx (XH-CORR). Mass spectral analyses
were conducted at TexMS, 15701 West Hardy Road, Houston, Tex. using
an atmospheric pressure desorption technique. All chemical
reactions were carried out in dry glassware and were protected from
atmospheric moisture. Solvents were dried over freshly activated
(300.degree. C./1 h) molecular sieves (type 4 A). Evaporations were
carried out on a rotary evaporator under aspirator vacuum at a bath
temperature of <25.degree. C. The homogeneity of the products
was determined by ascending TLC on silica-coated glass plates
(silica gel 60 F 254, Merck) using mixtures of CHCl.sub.3-MeOH as
the eluting solvent. Preparative separations were performed on
thick layers (20 cm.times.20 cm.times.2 mm) of the same adsorbent
or by column chromatography on silica gel (Merck, 230-400 mesh)
using mixtures of CHCl.sub.3-MeOH as eluent.
[0049] Preparation of 5-Hexen-1-al (8)
[0050] Method A:
[0051] A solution of the Jones reagent.sup.16 in acetone (10 mL,
2.67 M) was added, dropwise, with stirring over 10 min to a
solution of 5-hexen-1-ol (6) (2 mL, 1.67 g, 17 mmol) in acetone (5
mL) at 0.degree. C. The reaction mixture was maintained at
5.degree. C. for 1 h. Saturated NaHCO.sub.3 solution was added to
bring the pH to 7.0 and the mixture was extracted with CHCl.sub.3
(3.times.20 mL). The combined extracts were washed with H.sub.2O
(3.times.20 mL), and dried over anhydrous Na.sub.2SO.sub.4. The
solvent was evaporated to give a crude product, which was then
purified by filtering-column chromatography on silica gel (98:2
CHCl.sub.3/MeOH) to give 0.98 g (10 mmol) of pure 5-hexen-1-al (8)
as a colorless oil. Yield 59%.
[0052] .sup.1H NMR [chemical shift (o), multiplicity, coupling
constant (Hz), number of protons, atom]: 9.71 (t, J=1 Hz, 1 H,
H-1), 5.75 (m, 1 H, H-5), 5.04 (m, 2 H, H-6), 2.45 (m, 2 H, H-2),
2.08 (m, 2 H, H-4), 1.72 (m, 2 H, H-3).
[0053] .sup.13C NMR (ppm, atom): 201.95 (C-1), 137.18 (C-5), 115.07
(C-6), 42.67 (C-2), 32.55 (C-4), 20.75 (C-3).
[0054] Method B:
[0055] A solution of 5-hexen-1-ol (6) (2 mL, 1.67 g, 17 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was added in one portion to a stirred
solution of pyridinium chlorochromate.sup.16 (5.5 g, 25.5 mmol) in
anhydrous CH.sub.2Cl.sub.2 (35 mL) contained in a 100 mL round
bottomed flask fitted with a reflux condenser. After 2.5 h at
ambient temperature, dry ether (40 mL) was added. The organic
supernatant was decanted and the residual black gum was triturated
with anhydrous ether (3.times.10 mL) until a black granular solid
remained. The organic extracts were combined, filtered through a
short pad of florisil, then concentrated under reduced pressure.
The residual liquid was passed through a short Vigreaux column to
give 1.37 g of pure 5-hexen-1-al (8) (14 mmol, 82%).
[0056] The spectral properties of the compound were identical with
that of the product obtained by Method A.
[0057] Method C:
[0058] 4A powdered molecular sieves (500 mg/mmol, 8.5 g) was added
to a solution of 5-hexen-1-ol (6) (2 mL, 1.67 g, 17 mmol) and
N-methylmorpholine N-oxide (1.5 eq., 25.6 mmol, 3.4 g) in
CH.sub.2Cl.sub.2 (35 mL). The mixture was stirred for 10 min at
room temperature under a nitrogen atmosphere then
tetrapropyl-ammonium perruthenate (TPAP).sup.17 (0.30 g, 0.85 mmol,
5 mol %) was added in one portion. The initially green mixture
progressively darkened.
[0059] The reaction was completed after 2 h at room temperature (as
evidenced by TLC), CH.sub.2Cl.sub.2 (35 mL) was added and the
mixture was passed first through a short pad of filter agent,
(Celite). The filtrate was evaporated and the residual crude was
purified by filtering-column chromatography on silica gel (98:2,
CHCl.sub.3/MeOH) to afford 1.47 g of pure 5-hexen-1-al (8) (15
mmol, 88%).
[0060] The spectral properties of the compound were identical with
that of the product obtained by Method A.
[0061] Since the TPAP oxidation procedure gave the best yields and
was the most convenient, it was used for all subsequent procedures
for the preparation of aldehydes from the corresponding
alcohols.
[0062] 4-Penten-1-al (13):
[0063] This product was prepared from:
[0064] a: 4-Penten-1-ol (12) (1.76 mL, 1.46 g, 17 mmol) as desribed
for 5-hexen-1-al (8), Method C. The total yield of the desired
aldehyde (13) was 91%, (15.58 mmol, 1.31 g).
[0065] .sup.1H NMR: 9.91 (t, J=1 Hz, 1 H, H-1), 5.80 (m, 1 H, H-4),
5.21 (m, 2 H, H-5), 2.12 (m, 2 H, H-2), 1.95 (m, 2 H, H-3).
[0066] .sup.13C NMR: 200.28 (C-i), 137.61 (C.sub.4), 114.96 (C-5),
32.80 (C-2), 32.21 (C-3).
[0067] b: 5-Hexen-1,2-diol (2.24 mL, 2.2 g, 18.9 mmol) was added
slowly, with stirring, over 10 min to a solution of NaIO.sub.4 (4.1
g) in water (45 mL) under ice cooling, and then left at room
temperature for 2 h. Ethanol (30 ml) was added and the mixture was
filtered to remove precipitated sodium salts, and concentrated.
Chloroform (50 ml) and H.sub.2O (20 ml) were added, and the organic
layer was separated, dried, filtered, and evaporated to dryness.
The residue was chromatographed on silica gel (96:4
CHCl.sub.3/MeOH) to give 4-penten-1-al (13) as a colorless liquid
(1.2 g, 14.2 mmol, 75%).
[0068] The spectral properties of the compound were identical with
that of the product obtained by method a.
[0069] 6-Repten-1-al (18):
[0070] This product was prepared from 6-hepten-1-ol (17) (1.9 g, 17
mmol), as described for 5-hexen-1-al (8), Method C. The total yield
of the desired (18) was 90%, (15.3 mmol, 1.72 g).
[0071] .sup.1H NMR: 9.62 (s, 1 H, H-1), 5.83 (m, 1 H, H-6), 4.92
(m, 2 H, H-7), 2.41 (t, 2 H, J=7.1 Hz, H-2), 1.74 (m, 2 H, H-3),
1.51 (m, 2 H, H-5), 1.35 (m, 6 H, H-4).
[0072] .sup.13C NMR: 202.51 (C-1), 138.04 (C-6), 114.67 (C-7),
43.44 (C-2), 33.43 (C-5), 28.13 (C-3), 24.81 (C-4).
[0073] 8-Nonen-1-al (22):
[0074] This product was prepared from 8-nonen-1-ol.sup.18 (21) (2.4
g, 17 mmol) as desribed for 5-hexen-1-al (8), Method C. The residue
was subjected to a column chromatography on silica gel (98:2
CHC13/MeOH), yielding 2.12 g as a syrup (15.13 mmol, 89%) of
(22).
[0075] .sup.1H NMR: 9.65 (s, 1 H, H-1), 5.72 (m, 1 H, H-8), 4.95
(m, 2 H, H-9), 2.43 (t, 2 H, J=5 Hz, H-2), 2.12 (m, 2 H, H-7), 1.54
(m, 2 H, H-3), 1.33 (m, 6 H, H-4, H-5, H-6).
[0076] .sup.13C NMR: 200.54 (C-1), 138.82 (C-8), 114.11 (C-9),
35.01 (C-2), 34.24 (C-7), 28.83 (C-3), 28.74 (C-6), 23.92 (C-4),
23.24 (C-5).
[0077] 3-(Allyloxy)propionaldehyde (25):
[0078] A solution of allyl alcohol (30 mL, 25.6 g, 0.44 mol),
monochloroacetic acid (3 g, 0.032 mol), and sodium hydroxide (1.27
g, 0.032 mol) in H.sub.2O (5 mL) was added dropwise, with stirring
over 10 min to acrolein (80 mL, 1.2 mol) contained in a 250 ml
flask. Acetic acid ( 12 mL, 0.21 mol) was added and the reaction
mixture was maintained at 40.degree. C. for 40 h. After cooling to
room temperature, the mixture was washed with H.sub.2O (50
mL.times.3), and the organic layer was dried over anhydrous
Na.sub.2SO.sub.4. The solution was concentrated under aspirator
vacuum at 40.degree. C. to remove volatile by-products. The
residual viscous oil was purified by column chromatography on
silica gel using CH.sub.2Cl.sub.2 as a eluent to give 34.2 g of
(25) (0.3 mol) as a colorless oil. Yield, 69%.
[0079] .sup.1H NMR: 9.82 (t, 1 H, J=1 Hz, H-1), 5.82 (m, 1 H,
H-2'), 5.21 (m, 2 H, H-3'), 3.93 (dt, 2 H, J=3,1 Hz, H-1'), 3.82
(t, 2 H, J=4 Hz, H-3), 2.61 (dt, 2 H, J=4, 1 Hz, H-2).
[0080] .sup.13C NMR: 202.12 (C-1), 134.24 (C-2'), 116.24 (C-3'),
71.43 (C-1'), 64.34 (C-3), 34.12 (C-2).
[0081] 5-Hexen-1,1-diacetate (9):
[0082] 5-Hexen-1-al (8) (5 g, 5.9 mL, 50.9 mmol) was added
dropwise, with stirring over 5 min at ambient temperature to a
solution of acetic anhydride (3 mL, 31 mmol) and BF.sub.3.Et.sub.2O
(0.5 mL) in anhydrous Et.sub.2O (10 mL). The reaction mixture was
stirred for 10 min, then washed successively with 25% NaOAc
solution (20 mL) and H.sub.2O (25 mL.times.2), and dried over
anhydrous Na.sub.2SO.sub.4. The ether was evaporated and the
residue was distilled to give the diacetoxy acetal (9) (9.6 g, 48
mmol, 94%). The product was used in subsequent reactions without
further purification.
[0083] .sup.1H NMR: 6.83 (t, 1 H, J=5 Hz, H-1), 5.58 (m, 1 H, H-5),
5.02 (m, 2 H, H-6), 2.12 (s, 6 H, CH.sub.3), 2.05 (m, 2 H, H-2),
1.85 (m, 2 H, H-4), 1.50 (m, 2 H, H-3).
[0084] .sup.13C NMR: 168.42 (COCH.sub.3), 137.43 (C-5), 114.81
(C-6), 89.92 (C-1), 32.82 (C-2), 32.14 (C-4), 22.23 (C-3), 20.32
(CH.sub.3).
[0085] 4-Penten-1,1-diacetate (14):
[0086] The compound was prepared from 4-penten-1-al (13) ( 6.7 g,
7.8 mL, 80 mmol), acetic anhydride (5.7 mL, 6.13 g, 60 mmol) and
BF.sub.3.Et.sub.2O (0.2 mL) in Et.sub.2O (6 mL) as described for
(9). After removing the excess of acetic anhydride by distillation,
the residue was subjected to a column chromatography on silica gel
(97:3 CHCl.sub.3/MeOH) to give the diacetoxy acetal (14) (14 g,
75.2 mmol, 94%)
[0087] .sup.1H NMR: 6.85 (t, 1 H, H-1, J=5 Hz), 5.74 (m, 1 H, H-4),
4.95 (m, 2 H, H-5), 2.05 (m, 2 H, H-2), 2.03 (s, 6 H, CH.sub.3ac.),
1.85 (m, 2 H, H-3).
[0088] .sup.13C NMR: 168.75 (COCH.sub.3), 137.64 (C-4), 115.01
(C-5), 89.85 (C-1), 32.96 (C-2), 32.17 (C-3), 20.24 (CH.sub.3).
[0089] 6-Hepten-1,1-diacetate (19):
[0090] The compound was prepared from 6-heptenal (18) (4 g, 4.7 mL,
35 mmol), acetic anhydride (2.8 mL, 3.1 g, 30 mmol) and
BF.sub.3.Et.sub.2O (0.2 mL) in Et.sub.2O (5 mL) as described for
(9). After removing the 25 excess of acetic anhydride by
distillation, the residue was subjected to a column chromatography
on silica gel (97:3 CHCl.sub.3/MeOH) to give the diacetoxy acetal
(19) (7.14g, 33.3 mmol, 95%)
[0091] .sup.1H NMR: 6.87 (t, J=5 Hz, 1 H, H-1), 5.83 (m, 1 H, H-6),
4.98 (m, 2 H, H-7), 2.15 (dt, J=5, 1 Hz, 3 H, H-2), 2.02 (s, 6 H,
CH.sub.3ac), 1.90 (m, 2 H, H-5), 1.64 (m, 4 H, H-3, H-4).
[0092] .sup.13C NMR: 168.54 (COCH.sub.3), 137.93 (C-6), 114.92
(C-7), 89.86 (C-1), 33.43 (C-2), 33.14 (C-5), 24.52 (C-3), 21.21
(C-4), 20.22 (CH.sub.3).
[0093] 2.2-Dimethyl-4-pentene-1.1-diacetate (29):
[0094] The compound was prepared from 2,2-dimethyl-4-penten-1-al
(28) (3 mL, 2.5 g, 22 mmol) acetic anhydride (1.4 mL, 1.56 g, 15
mmol) and BF.sub.3.Et.sub.2O (0.2 mL) in Et.sub.2O (5 mL) as
described for (9). After removing the excess of acetic anhydride by
distillation, the residue was subjected to a column chromatography
on silica gel (96:4 CHCl.sub.3/MeOH) to give the diacetoxy acetal
(29) (4.44 g, 20.7 mmol, 94%).
[0095] .sup.1H NMR: 6.52 (s, 1 H, H-1), 5.75 (m, 1 H, H-4), 4.95
(m, 2 H, H-5), 2.05 (s, 6 H, CH.sub.3ac), 2.02 (m, 2 H, H-3), 1.85
(s, 6 H, CH.sub.3) .sup.13CNR 168.63 (COCH.sub.3) 133.46 (C-4),
117.65 (C-5), 93.55 (C-1), 41.43 (C-3), 37.42 (C-2), 21.01
(CH.sub.3), 20.34 (CH.sub.3ac)
[0096] 8-Nonen-1,1-diacetate (23):
[0097] The compound was prepared from 8-nonen-1-al (22) (8.3 mL, 7
g, 50 mmol), acetic anhydride (3.8 mL, 4 g, 40 mmol) and
BF.sub.3.Et.sub.2O (0.2 mL) in Et.sub.2O (7 mL) as described for
(9). After removing the excess of acetic anhydride by distillation,
the residue was subjected to a column chromatography on silica gel
(97:3 CHCl.sub.3/MeOH) to give the diacetoxy acetal (23) (11.75 g,
48.5 mmol, 97%).
[0098] .sup.1H NMR: 6.82 (t, 1 H, J=5.6 Hz, H-1), 5.75 (m, 1 H,
H-8), 4.95 (m, 2 H, H-9), 2.02 (s, 6 H, CH.sub.3ac.), 1.98 (m, 2 H,
H-7), 1.75 (m, 2 H, H-2), 1.54 (m, 2 H, H-4), 1.35 (m, 6 H, H-6,
H-5, H-3).
[0099] .sup.13C NMR: 168.84 (COCH.sub.3), 138.83 (C-8), 114.12
(C-9), 90.43 (C-1), 34.92 (C-2), 34.15 (C-7), 28.84 (C-3), 28.71
(C-6), 23.84 (C-4), 23.21 (C-5), 20.64 (CH.sub.3).
[0100] 3-(Allyloxy)propane-1,-diacetate (26):
[0101] The compound was prepared from 3-(allyloxy)propionaldehyde
(25) (5.2 mL, 5 g, 44 mmol), acetic anhydride (2.4 mL, 25 mmol) and
BF.sub.3/Et.sub.2O (0.2 mL) in Et.sub.2O (5 mL) as described for
(9). After removing the excess of acetic anhydride by distillation,
the residue was subjected to a column chromatography on silica gel
(96:4 CHCl.sub.3/MeOH) to give the diacetoxy acetal(26) (8.94 g,
41.4 mmol, 94%).
[0102] .sup.1H NMR: 6.92 (t, 1 H, J=4 Hz, H-1), 5.85 (m, 1 H,
H-2'), 5.23 (m, 2 H, H-3'), 3.95 (dt, 2 H, J=3,1 Hz, H-1'), 3.44
(t, 2 H, J=4 Hz, H-3), 2.01 (s, 6 H, CH.sub.3ac), 1.95 (dt, 2 H,
J=4, 2 (1 Hz, H-2).
[0103] .sup.13C NMR: 168.02 (COCH3), 134.44 (C-2'), 116.43 (C-3'),
88.42 (C-1), 71.41 (C-1'), 64.76 (C-3), 33.25 (C-2), 20.26
(CH.sub.3).
[0104] 2-Propene-1,1-diacetate (31):
[0105] The compound was prepared from acrolein (6 mL, 5 g, 90
mmol), acetic anhydride (5.7 mL, 6.13 g, 60 mmol) and
BF.sub.3/Et.sub.2O (0.25 mL) in Et.sub.2O (5 mL) as described for
(9) After removing the excess of acetic anhydride by distillation,
the residue was subjected to a column chromatography on silica gel
(97:3 CHCl.sub.3/MeOH) to give the diacetoxy acetal (31) (13.7 g,
86.4 mmol, 96%).
[0106] .sup.1H NMR: 7.14 (d, J=7 Hz, 1 H, H-1), 5.85 (m, 1 H, H-2),
5.45 (m, 2 H. H-3), 2.05 (s, 6 H, CH.sub.3).
[0107] .sup.13C NMR: 168.15 (COCH.sub.3), 131.12 (C-2), 119.44
(C-3), 88.76 (C-1), 20.38 (CH.sub.3).
[0108] 5-Pentanal-1,1-diacetate (10):
[0109] A solution of 5-hexen-i,i-diacetate (9) (5 g, 3.5 ml,25
mmol) in CH.sub.2Cl.sub.2 (5 mL) was placed in a long cylindrical
gas absorption vessel with an inlet dispersion tube extending to
the base. The vessal was cooled to -70.degree. C. in a dry
ice/acetone mixture, and ozone was introduced. Ozonization was
continued until all of the compound had reacted (blue color due to
the formation of the ozonide), approximately 20 min. Methyl sulfide
(7.25 mL, 0.1 mol, 4 equivalents) was added to the blue solution of
ozonide and the mixture was stirred overnight to reduce the ozonide
to the corresponding aldehyde. The excess methyl sulfide was
evaporated, and the residue was subjected to a column
chromatography on silica gel (CH.sub.2Cl.sub.2) giving aldehyde
(10) (4.29 g, 21.25 mmol, 85%) as a syrup.
[0110] .sup.1H NMR: 9.83 (t, 1 H, J=1 Hz, H-5), 6.75 (t, 1 H, J=5
Hz, H-1), 2.66 (dt, 2 H, J=5.5, 1 Hz, H-4), 2.14 (s, 6 H,
CH.sub.3), 2.05 (m, 2 H, H-2), 1.85 (m, 2 H, H-3).
[0111] .sup.13C NMR: 201.43 (C-5), 168.72 (COCH.sub.3), 89.61
(C-1), 42.86 (C-4), 32.10 (C-2), 20.54 (CH.sub.3), 15.62 (C-3).
[0112] analysis: calc'd for C.sub.9H.sub.14O.sub.5- c, 53.46; H
6.98.
[0113] Found . . . c, 53.61; H 7.87.
[0114] 4-Butanal-1.1-diacetate (15):
[0115] The compound was prepared from 4-penten-1,1-diacetate (14)
(4.65 g, 3.45 mL, 25 mmol) in CH.sub.2Cl.sub.2 (5 mL) as described
for (10). After removing the excess of methyl sulfide by
distillation, the residue was subjected to a column chromatography
on silica gel (CH.sub.2Cl.sub.2) to give the desired aldehyde (15)
(4.04g, 21.5 mmol, 86%) as a colorless oil.
[0116] .sup.1H NMR: 9.83 (t, 1 H, J=1 Hz, H-4), 6.75 (t, 1 H, J=5
Hz, H-1), 2.66(dt, 2 H, J=5.5, 1Hz, H-3), 2.14 (s, 6 H, CH.sub.3),
2.05 (m, 2 H, H-2).
[0117] .sup.13C NMR: 201.43 (C-4), 168.72 (COCH.sub.3), 89.61
(C-1), 42.86 (C-3), 32.10 (C-2), 20.54 (CH.sub.3).
[0118] 6-Hexanal-1,1-diacetate (20):
[0119] The compound was prepared from 6-hepten-1,1-diacetate (19)
(5.35 g, 3.5 mL, 25 mmol) in CH.sub.2Cl.sub.2 (5 mL) as described
for (10).
[0120] After removing the excess of Methyl sulfide by distillation,
the residue was subjected to a column chromatography on silica gel
(CH.sub.2Cl.sub.2) to give the desired aldehyde (20) (4.71 g 21.8
mmol, 87%) as a colorless oil.
[0121] .sup.1H NMR: 9.83 (t, 1 H, J=1 Hz, H-6), 6.75 (t, 1 H, J=5
Hz, H-1), 2.66 (dt, 2 H, J=5.5, 1 Hz, H-5), 2.14 (s, 6 H,
CH.sub.3), 2.05 (m, 2 H, H-2), 1.85 (m, 2 H, H-3), 1.82 (m, 2H,
H-4).
[0122] .sup.13C NMR: 201.43 (C-6), 168.72 (COCH.sub.3), 89.61
(C-1), 42.86 (C-5), 32.10 (C-2), 20.54 (CH.sub.3), 15.62 (C-3),
15.60 (C-4).
[0123] 8-Octanal-1.1-diacetate (24):
[0124] The compound was prepared from 8-nonen-1,1-diacetate (23)
(6.05 g, 25 mmol) in CH.sub.2Cl.sub.2(5 mL) as described for (10).
After removing the excess of Methyl sulfide by distillation, the
residue was subjected to a column chromatography on silica gel
(CH.sub.2Cl.sub.2) to give the desired aldehyde (24) (5.12 g, 21
mmol, 84%) as a colorless oil.
[0125] .sup.1H NMR: 9.83 (t, 1 H, J=1 Hz, H-8), 6.75 (t, 1 H, J=5
Hz, H-1), 2.66(dt, 2 H, J=5.5, 1 Hz, H-7), 2.14 (s, 6 H, CH.sub.3),
2.05 (m, 2 H, H-2), 1.85 (m, 2 H, H-3), 1.82-1.75 (m, 6H, H-4, H-5,
H-6).
[0126] .sup.13C NMR: 201.50 (C-8), 168.70 (COCH.sub.3), 89.66
(C-1), 42.88 (C-7), 32.15 (C-2), 20.58 (CH.sub.3) , 15.62 (*C-3),
15.60 (*C-4), 15.46 (*C-5), 15.00 (*C-6). Assignments for C.sub.3,
C.sub.4, C.sub.5 and C.sub.6 may be interchanged.
[0127] O-(3,3-diacetoxylropyl)glycolaldehyde (27):
[0128] The compound was prepared from
3-(allyloxy)propane-1,1-diacetate (26) (5.4 g, 25 mmol) in
CH.sub.2Cl.sub.2 (5 mL) as described for (10). After removing the
excess of Methyl sulfide by distillation, the residue was subjected
to a column chromatography on silica gel (CH.sub.2Cl.sub.2) to give
the desired aldehyde (27) (4.58 g, 21 mmol, 84%) as a colorless
oil.
[0129] .sup.1H NMR: 9.63 (t, 1 H, J=1 Hz, H-1'), 6.74 (t, I H,
J=4.2 Hz, H-1), 4.27 (d, 2 H, J=1 Hz, H-2'), 3.45 (t, 2 H, J=4.2
Hz, H-3) , 2. 01 (s, 6 H, CH.sub.3ar) 1.95 (dt, 2 H, J=4, 2 Hz,
H-2).
[0130] .sup.13C NMR: 199.94 (C-1'), 168.35 (COCH.sub.3), 88.37
(C-1), 72.32 (C-2'), 64.66 (C-3), 33.35 (C-2), 20.36
(CH.sub.3).
[0131] Analysis Calc'd for C H.sub.14O.sub.6: C,49.54; H, 6.47.
[0132] Found: C,49.51; H, 6.58.
[0133] 2,2-Dimethyl-4-butanal-1 l-diacetate (30):
[0134] The compound was prepared from
2,2-dimethyl-4-pentene-1,1-diacetate (29) (5.32 g, 3.54 mL, 25
mmol) in CH.sub.2Cl.sub.2 (5 mL) as described for (10). After
removing the excess of Methyl sulfide by distillation, the residue
was subjected to a column chromatography on silica gel
(CH.sub.2Cl.sub.2) to give the desired aldehyde (30) (4.68 g, 21.8
mmol, 87%) as a colorless oil.
[0135] .sup.1H NMR: 9.85 (t, 1 H, J=1 Hz, H-4), 6.65 (t, 1 H, J=5
Hz, H-1), 2.08 (s, 6 H, CH.sub.3ac), 2.01 (m, 2 H, H-3), 1.85 (s, 6
H, CH.sub.3).
[0136] .sup.13C NMR: 201.05 (C-4), 168.72 (COCH.sub.3), 89.65
(C-1), 42.80 (C-3), 37.42 (C-2), 21.50 (CH.sub.3), 20.35
(CH.sub.3ac.)
[0137] Analysis Calc'd. for C.sub.10H .sub.6O.sub.5: C, 55.55; H,
7.46.
[0138] Found: C, 54.67; H, 7.55.
[0139] o-(2,2-diacetoxyethYl)lvcoQlaldehyde (35):
[0140] This compound was prepared in four steps from anhydrous
glycerol by monoalkylation, oxidation of the diol, acetylation and
ozonolysis
[0141] 3-Allyloxy-1,2-propandiol (32):
[0142] KOH (11.2 g, 200 mmol) was added cautiously to anhydrous
glycerol (60 mL, 821 mmol) in a 250 mL flask, and the mixture was
heated to 60.degree. C. under a nitrogen atmosphere until the KOH
had dissolved. After cooling to room temperature, allyl bromide
(17.3 mL, 20 mmol) was added over 15 min, dropwise with stirring
and the mixture was stirred at 90.degree. C. for 14 h. After
cooling to room temperature, the mixture was diluted with aqueous
50% K.sub.2CO.sub.3 (100 mL) then extracted with CH.sub.2Cl.sub.2
(3.times.100 mL). The combined extracts were dried, filtered and
evaporated. The residual diol, a colorless oil, 22.5 g (32) (170
mmol, 85%), was used for subsequent reaction without further
purification.
[0143] .sup.1H NMR: 5.92 (m, 1 H, H-2'), 5.21 (m, 2 H, H-3'), 4.14
(m, 1 H, H-2), 3.97 (m, 2 H, H-3), 3.79 (m, 2 H, H-1'), 3.71 (m, 2
H, H-1).
[0144] .sup.13C NMR: 134.19 (C-2'), 117.18 (C-3'), 72.09 (C-1'),
71.11 (C-1), 70.74 (C-2), 63.72 (C-3).
[0145] 2-Allyloxyethan-1-al (33):
[0146] This diol (32) (1.71 mL, 2.5 g, 18.9 mmol) was added slowly,
25 with stirring, over 10 min to a solution of NaIO.sub.4 (4.1 g)
in water (45 mL) under ice cooling and then left at room
temperature for 2 h. Ethanol (30 ml) was added and the mixture was
filtered to remove precipitated sodium salts, and concentrated.
Chloroform (50 ml) and H.sub.2O (20 ml) were added, and the organic
layer was separated, dried, filtered, and evaporated to dryness.
The residue was chromatographed on silica gel (96:4
CHCl.sub.3/MeOH) to give allyloxy glycol aldehyde (33) as a
colorless liquid (1.32 g, 13.2 mmol, 70%).
[0147] .sup.1H NMR: 9.73 (t, 1 H. J=1 Hz, H-1), 5.95 (m, 1 H,
H-2'), 5.37 (m, 2 H, H-3'), 4.05 (m, 4 H, H-1, H-2).
[0148] .sup.13C NMR: 199.86 (C-1), 133.32 (C-2'), 117.02 (C-3'),
74.65 (C-2), 71.64 (C-11).
[0149] 2-Allyloxyethane-1,1-diacetate (34):
[0150] The aldehyde (33) (1.32 g, 13.2 mmol) was added dropwise,
with stirring, over 5 min at ambient temperature to a solution of
acetic anhydride (1.5 mL, 16.5 mmol), Et20 (5 mL) and
BF.sub.3.Et.sub.2O (0.1 mL). The reaction mixture was stirred for
10 min then washed sucessively with 25% NaOAc solution (5 mL) and
H.sub.2O (10 mL .times.2), and dried over anhydrous
Na.sub.2SO.sub.4. After removing the excess of acetic anhydride by
distillation, the residue was subjected to a column chromatography
on silica gel (97:3 CHCl.sub.3/MeOH) to give the
diacetoxyacetal(34) (2.55 g, 12.6 mmol, 95%).
[0151] .sup.1H NMR: 6.82 (t, 1 H, J=5 Hz, H-1), 5.75 (m, 1 H,
H-2'), 5.15 (m, 2 H, H-3'), 3.98 (m, 2 H, H-1'), 3.55 (d, 2 H, J=5
Hz, H-2), 2.09 (s, 6 H, CH.sub.3).
[0152] .sup.3C NMR: 168.33 (COCH.sub.3) 133.74 (C-2'), 117.21
(C-3'), 87.34 (C-1), 72.04 (C-1'), 68.53 (C-2), 20.31
(CH.sub.3).
[0153] O-(2,2-diacetoxvethvl)glvcolaldehyde (35):
[0154] The diacetoxy acetal (34) (2.55 g, 12.6 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was ozonized as described for compound
(10). Methyl sulfide (3.7 mL, 50.5 mmol, 4 equiv.) was added to the
blue ozonide sulution and the mixture was stirred overnight.
Evaporation of solvent and unreacted methyl sulfide, and
chromatography on silica gel (CH.sub.2Cl.sub.2 eluent) gave the
corresponding aldehyde (35), (2.21 g, 10.84 mmol, 86%).
[0155] .sup.1H NMR: 9.62 (t, 1 H, J 1 Hz, H-1'), 6.84 (t, 1 H,
J=5.2 Hz, H-1), 4.23 (d, 2 H, J=1 Hz, H-2'), 3.86 (d, 2 H, J=5.2
Hz, H-2), 2.01 (s, 6 H, CH.sub.3).
[0156] .sup.13C NMR: 199.94 (C-1'), 168.35 (COCH.sub.3), 87.37
(C-1), 72.32 (C-2'), 68.51 (C-2), 20.35 (CH.sub.3).
[0157] Analysis calc'd. for C.sub.8H.sub.12O.sub.6: C, 47.06; H,
5.92.
[0158] Found: C, 46.84; H, 5.81.
[0159] Ethyl allyl-4-butyrate (16):
[0160] A solution of heptenoic acid (1.1 mL, 1 g, 7.8 mmol) in
ethanol (2 mL) was added to a stirred solution of p-toluene
sulfonic acid (0.19 g, 1 mmol) in ethanol (10 mL). The mixture was
stirred at 60.degree. C. for 2 h, then allowed to cool to room
temperature. Aqueous NaHCO.sub.3 (50%) was added (25 mL), and the
organic layer was extracted with CH.sub.2Cl.sub.2 (2.times.25 mL),
dried over Na.sub.2SO.sub.4, filtered and evaporated. The colorless
oil which remained was identified as the desired ester (16), (1.19
g, 7.64 mmol, 98%).
[0161] .sup.1H NMR: 5.83 (m, 1 H, H-6), 4.96 (m, 2 H, H-7), 4.15
(q, 2 H, q, J=7 Hz, OCH.sub.2CH.sub.3), 2.36 (t, J=7.2 Hz, 2 H,
H-2), 2.05 (q, J=8 Hz, 2 H, H-5), 1.61 (m, 2 H, H-3), 1.45 (m, 2 H,
H-4), 1.33 (t, 3 H, J=7 Hz, OCH.sub.2CH.sub.3).
[0162] .sup.13C NMR: 173.34 (C-1), 138.01 (C-6), 114.32 (C-7),
58.83 (OCH.sub.2CH.sub.3), 33.82 (C-2) , 33.01 (C-5), 28.02 (C-3),
24.14 (C-4), 13.72 (OCH2CH.sub.3).
[0163] 6-Hepten-1-ol (17):
[0164] A solution of the ester (16), (0.6 g, 3.85 mmol) in THF (5
mL) was cooled to 0.degree. C. in an ice/salt bath. A solution of
DIBAL (1 M in Hexane, 6 mL, 6 mmol) was added dropwise with
stirring over 10 min. The solution was then warmed to ambient
temperature and allowed to stir for an additional 2 h. The excess
DIBAL was carefully quenched by the addition of 10 mL of H.sub.2O.
The organic layer was extracted with CHCl.sub.3 (2.times.15 mL),
combined, and dried over Na.sub.2SO.sub.4. Evaporation of the
solvent, chromatography on silica gel (93:7 CHCl.sub.3/MeOH) gave
the alcohol (17) as a colorless oil (0.4 g, 3.54 mmol, 92%).
[0165] .sup.1H NMR: 5.85 (m, 1 H, H-6), 4.95 (m, 2 H, H-7), 3.62
(t, 2 H, J=6 Hz, H-1), 2.62 (bs, 1 H, OH), 2.02 (m, 2 H, H-2), 1.54
(m, 2 H, H-5), 1.55 (m, 4 H, H-3, H-4.
[0166] .sup.13C NMR: 138.76 (C-6) , 114.24 (C-7), 62.5 (C-1) ,
33.62 (C-2), 32.47 (C-5), 28.60 (*C-3), 25.11 (*C-4). Assignments
for C.sub.3 and C.sub.4 may be interchanged.
[0167] N-(5,5-Diacetox2entyl) doxorubicin hydrochloride (2a):
[0168] A stirred solution of doxorubicin hydrochloride (20 mg,
0.035 mmol) and 5-pentanal-1,1-diacetate (10) (14 mg, 2 eq, 0.07
mmol) in CH.sub.3CN--H.sub.2O (2:1) (5 mL) was treated with a
solution of NaBH.sub.3CN (1M in THF) (24 uL, 0.67 eq, 0.024 mmol).
The mixture 30 was stirred under a nitrogen atmosphere at room
temperature in the dark for 1 h. When reaction was complete (as
evidenced by TLC of a 5 uL aliquot) the solution was diluted with
H.sub.2O (8 ml) and then extracted repeatedly (10.times.10 mL) with
CHCl.sub.3-MeOH (5:1). The combined extracts were dried and
evaporated to give a red amorphous solid (16 mg). Preparative TLC
of this product (,CHCl.sub.3-MeOH, 10:1; R.sub.f=0.60) afforded
N-(pentan-5-al diacetoxy acetal) doxorubicin (10 mg, 0.0137 mmol).
The product was suspended in H.sub.2O (1 mL) and acidified to pH 5
by dropwise addition of 0.05 N HCl (approx. 0.5 mL). The solution
was lyophilized to afford the title compound (10.25 mg ,0.0134
mmol, 38%). It was then stored under a nitrogen atmosphere in a
tightly stoppered vessel at -78.degree. C. in the dark.
[0169] .sup.1H NMR (free base): 8.01 (dd, J=8.2, 0.9 Hz, 1 H, H-1),
7.82 (t, J=8.2 Hz, 1 H, H-2), 7.39 (dd, J=8.2, 0.9 Hz, 1 H, H-3),
6.73 (t, J=5.46, 1 H, H-5"), 5.52 (t, J=1 Hz, 1 H, H-1'), 5.3 (bs,
1 H, H-7), 4.75 (s, 2 H, H-14), 4.12 (s, 3 H, CH.sub.3ar.), 3.62
(bs, 1 H, H-5'), 3.62 (m, 1 H, H-4'), 3.25 (d, J=16 Hz, 1 H,
H-10a), 2.95 (d, J=16 Hz, 1 H, H-10b), 2.85 (m, 1 H, H-31), 2.65
(m, 2 H, H-1"), 2.35 (m, 1 H, H-8a), 2.25 (m, 1 H, H-8b), 2.01 (s,
6 H, CH.sub.3ac.), 1.82 (m, 2 H, H-2'a), 1.76 (m, 2 H, H-4"), 1.75
(m, 1 H, H-2'b), 1.40 (m, 2 H, H-3"), 1.35 (d, J=6 Hz, 3 H,
H-6').
[0170] MS (electrospray): 730 (M+H).sup.+.
[0171] N-(2,2-Diacetoxvethyloxvethyl) doxorubicin HCl (2b):
[0172] The compound was prepared from doxorubicin HCl (20 mg, 0.035
mmol, O-(2,2-diacetoxyethyl)glycolaldehyde (35) (14.3 mg, 2 eq.,
0.07 mmol), NaBH.sub.3CN (1 M in THF) (24 ul, 0.67 eq, 0.024 mmol)
in CH.sub.3CN--H.sub.2O (2:1) (5 mL), as desribed for (2a). When
reaction was complete (as evidenced by TLC of a 5 uL aliquot) the
solution was diluted with H.sub.2O (8 ml) and then extracted
repeatedly (10.times.10 mL) with CHCl.sub.3-MeOH (5:1). The
combined extracts were dried and evaporated to give a red amorphous
solid (17.5 mg). Preparative TLC of this product (CHCl.sub.3-MeOH,
10:1; R.sub.f=0.6) afforded N-(2,2-diacetoxyethyloxyethyl)
doxorubicin (9.1 mg, 0.012 mmol). The product was suspended in
H.sub.2O (1 mL) and acidified to pH 5 by dropwise addition of 0.05
N HCl (approx. 0.5 mL). The solution was lyophilized to afford the
title compound (9.4 mg, 0.012 mmol, 34%). It was then stored under
a nitrogen atmosphere in a tightly stoppered vessel at -78.degree.
C. in the dark.
[0173] MS-electrospray: 746 (M+Me+1).
[0174] .sup.1H NMR (free base) : 8.11 (dd, J=8.2, 0.8 Hz, 1 H,
H-1), 7.82 (t, J=8.2 Hz, 1 H, H-2), 7.35 (dd, J=8.2, 0.8 Hz, 1 H,
H-3), 6.75 (t, 1 H, J=5.5, H-lb") 5.50 (t, J=1 Hz, 1 H, H-1'), 5.35
(bs, 1 H, H-7), 4.75 (s, 2 H, H-14), 4.11 (s, 3 H, CH.sub.3ar.),
3.84 (bs, 1 H, H-5'), 3.77 (m, 1 H, H-4'), 3.65 (m, 2 H, H-2"a),
3.54 (m, 2 H, H-2b"), 3.25 (d, J=16 Hz, 1 H, H-10a), 3.21 (m, 1 H,
H-3'), 3.14 (m, 2 H, H-1"), 2.95 (d, J=16 Hz, 1 H, H-10b), 2.35 (m,
1 H, H-8a), 2.25 (m, 1 H, H-8b), 2.24 (m, 2 H, H-2'a), 2.12 (m, 1
H, H-2'b), 2.01 (s, 6 H, CH.sub.3ac.), 1.34 (d, J=6 Hz, 3 H,
H-6').
[0175] N-(4.4-Diacetoxybutyl) doxorubicin HCl (2c):
[0176] The compound was prepared from doxorubicin. HCl (20 mg,
0.035 mmol), 4-butanal-1,1-diacetate (15) (13.2 mg, 2 eq., 0.07
mmol) and NaBH.sub.3CN (1 M in THF) (24 ul, 0.67 eq., 0.024 mmol)
in CH.sub.3CN--H.sub.2O (2:1) (5 mL) as described for (2a). When
reaction was complete (as evidenced by TLC of a 5 uL aliquot) the
solution was diluted with H.sub.2O (8 ml) and then extracted
repeatedly (9.times.10 mL) with CHCl.sub.3-MeOH (5:1). The combined
extracts were dried and evaporated to give a red amorphous solid
(15 mg). Preparative TLC of this product (CHCl.sub.3-MeOH, 10:1;
R.sub.f=0.59) afforded (4,4-diacetoxybutyl) doxorubicin (10 mg,
0.014 mmol). The product was suspended in H.sub.2O (1 mL) and
acidified to pH 5 by dropwise addition of 0.05 N HCl (approx. 0.5
mL). The solution was lyophilized to afford the title compound
(10.17 mg ,0.0135 mmol, 39%). It was then stored under a nitrogen
atmosphere in a tightly stoppered vessel at -78.degree. C. in the
dark.
[0177] .sup.1H NMR (free base) : 8.05 (dd, J=8.1, 0.85 Hz, 1 H,
H-1), 7.90 (t, J=8.1 Hz, 1 H, H-2), 7.42 (dd, J=8.1, 0.85 Hz, 1 H,
H-3), 6.75 (t, J=5.45 Hz, 1 H, H-411), 5.52 (bs, 1 H, H-1'), 5.31
(bs, 1 H, H-7), 4.72 (s, 2 H, H-14), 4.05 (s, 3 H, CH.sub.3ar.),
3.65 (bs, 1 H, H-5'), 3.61 (m, 1 H, H-41), 3.32 (d, J=16.2 Hz, 1 H,
H-10a), 3.03 (d, J=16.2 Hz, 1 H, H-10b), 2.81 (m, 1 H, H-3'), 2.60
(m, 2 H, H-1"), 2.44 (m, 1 H, H-8a), 2.22 (m, 1 H, H-8b), 2.02 (s,
6 H, CH.sub.3ac.), 1.75 (m, 2 H, H-2'a), 1.75 (m, 2 H, H-3''), 1.71
(m, 1 H, H-2'b), 1.42 (m, 2 H, H-2"), 1.35 (d, J=6 Hz, 3 H,
H-6').
[0178] N-(6,6-Diacetoxyhexyl) doxorubicin hydrochloride (2d):
[0179] A stirred solution of doxorubicin hydrochloride (20 mg,
0.035 mmol) and 6-hexanal-1,l-diacetate (20) (15 mg, 2 eg, 0.07
mmol) in CH.sub.3CN--H.sub.2O (2:1) (5 mL) was treated with a
solution of NaBH.sub.3CN (1M in THF) (24 uL, 0.67 eg, 0.024 mmol).
The mixture was stirred under a nitrogen atomosphere at room
temperature in the dark for 1 hour. When reaction was complete (as
evidenced by TLC of a 5 uL aliquot) the solution was diluted with
H.sub.2O (8 ml) and then extracted repeatedly (10.times.10 mL) with
CHCl.sub.3-MeOH (5:1). The combined extracts were dried and
evaporated to give a red amorphous solid (18 mg). Preparative TLC
of this product (CHCL.sub.3-MeOH, 10:1; R.sub.f=0.60) afforded
N-(6,6-diacetoxyhexyl) doxorubicin (10.4 mg, 0.014 mmol). The
product was suspended in H.sub.2O (1 mL) and acidified to pH 5 by
dropwise additin of 0.05 N HCl. (approx. 0.5 mL). The solution was
lyophilized to afford the title compound (10.75 mg, 0.0138 mmol,
39%). It was then stored under a nitrogen atmosphere in a tightly
stoppered vessel at -78.degree. C. in the dark.
[0180] .sup.1H NMR (free base): 8.03 (dd, J=8.2, 0.9 Hz, 1 H, H-1),
7.84 (t, J=8.2 Hz, 1 H, H-2), 7.37 (dd, J=8.2, 0.9 Hz, 1 H, H-3),
6.76 (t, J=5.46, 1 H, H-6.sup.11), 5.52 (t, J=1 Hz, 1 H, H-1'), 5.4
(bs, 1 H, H-7), 4.75 (s, 2 H, H-14), 4.14 (s, 3 H, CH.sub.3ar.),
3.65 (bs, 1 H, H-5'), 3.63 (m, 1 H, H-4'), 3.25 (d, J=16 Hz, 1 H,
H-10a), 2.96 (d, J=16 Hz, 1 H, H-10b), 2.85 (m, 1 H, H-3'), 2.66
(m, 2 H, H-1"), 2.36 (m, 1 H, H-8a), 2.23 (m, 1 H, H-8b), 2.05 (s,
6 H, CH.sub.3ac.), 1.82 (m, 2 H, H-2'a), 1.78 (m, 2 H, H-5"), 1.75
(m, 1 H, H-2'b), 1.65 (m, 2 H, H-2"), 1.40 (m, 2 H, H-3"), 1.39 (m,
2 H, H-4"), 1.32 (-d, J=6 Hz, 3 H, H-6').
[0181] N-(4,4-Diacetoxy-3,3-dimethylbutyl) doxorubicin HCl
(2e):
[0182] The compound was prepared from doxorubicin HCl (20 mg, 0.035
mmol), dimethyl 2,2-dimethyl-4-butanal-1,l-diacetate (30) (15 mg, 2
eq., 0.07 mmol) and NaBH.sub.3CN (1 M in THF) (24 uL, 0.67 eq.,
0.024 mmol), in CH.sub.3CN--H.sub.2O (2:1) (5 mL), as described for
(2a). When reaction was complete (as evidenced by TLC of a 5 uL
aliquot) the solution was diluted with H.sub.2O (8 ml) and then
extracted repeatedly (9.times.10 mL) with CHCl.sub.3-MeOH (5:1).
The combined extracts were dried and evaporated to give a red
amorphous solid (17 mg). Preparative TLC of this product
(CHCL.sub.3-MeOH, 10:1; R.sub.f=0.54) afforded
N-(4,4-diacetoxy-3,3-dimethylbutyl) doxorubicin (11.2 mg, 0.015
mmol). The product was suspended in H.sub.2O (1 mL) and acidified
to pH 5 by dropwise addition of 0.05 N HCl (approx. 0.5 mL). The
solution was lyophilized to afford the title compound (10.8 mg,
0.0138 mmol, 39%). It was then stored under a nitrogen atmosphere
in a tightly stoppered vessel at -78.degree. C. in the dark.
[0183] .sup.1H NMR (free base): 8.02 (dd, J=8.15, 0.83 Hz, 1 H,
H-1), 7.91 (t, J=8.15 Hz, 1 H, H-2), 7.54 (dd, J=8.15, 0.83 Hz, 1
H, H-3), 6.65 (s, 1 H, H-4"), 5.52 (bs, 1 H, H-1'), 5.35 (bs, 1 H,
H-7),-4.72 (s, 2 H, H-14), 4.03 (s, 3 H, CH.sub.3ar.), 3.65 (bs, 1
H, H-5'), 3.60 (m, 1 H, H-4'), 3.35 (d, J=16.4 Hz, 1 H, H-10a),
3.05 (d, J=16.4 Hz, 1 H, H-10b), 2.95 (m, 1 H, H-3'), 2.61 (m, 2 H,
H-1"), 2.40 (m, 1 H, H-8a), 2.26 (m, 1 H. H-8b), 2.01 (s, 6 H,
CH.sub.3ac. ), 1.78 (m, 2 H, H-2'a), 1.73 (m, 1 H, H-2'b), 1.55 (s,
6 H, CH3), 1.52 (m, 2 H, H-2"), 1.35 (d, J=6 Hz, 3 H, H-6').
[0184] N-(3,3-Diacetoxypropyloxy-1-ethyl) doxorubicin HCl (2f):
[0185] The compound was prepared from doxorubicin HCl (20 mg, 0.035
mmol, 3,3-diacetatepropyloxy-1-ethanal (27) (15.2 mg, 2 eq., 0-.07
mmol), NaBH.sub.3CN (1 M in THF) (24 ul, 0.67 eq, 0.024 mmol) in
CH.sub.3CN--H.sub.2O (2:1) (5 mL), as desribed for (2a). When
reaction was complete (as evidenced by TLC of a 5 uL aliquot) the
solution was diluted with H20 (8 ml) and then extracted repeatedly
(10.times.10 mL) with CHCl.sub.3-MeOH (5:1). The combined extracts
were dried and evaporated to give a red amorphous solid (17.5 mg).
Preparative TLC of this product (CHCL.sub.3-MeOH, 10:1;
R.sub.f=0.6) afforded N-(3,3-diacetoxypropyloxyethyl) doxorubicin
(9.1 mg, 0.012 mmol). The product was suspended in H20 (1 mL) and
acidified to pH 5 by dropwise addition of 0.05 N HCl (approx. 0.5
mL). The solution was lyophilized to afford the title compound (9.4
mg, 0.012 mmol, 34%). It was then stored under a nitrogen
atmosphere in a tightly stoppered vessel at -78.degree. C. in the
dark.
[0186] 1H NMR (free base): 8.10 (dd, J=8.1, 0.8 Hz, 1 H, H-1), 7.82
(t, J=8.1Hz, 1 H, H-2), 7.34 (dd, J=8.1, 0.8 Hz, 1 H, H-3), 6.73
(t, J=5.4 Hz, 1 H, H-"c) 5.52 (t, J=1 Hz, 1 H, H-1'), 5.4 (bs, 1 H,
H-7), 4.73 (s, 2 H, H-14), 4.12 (s, 3 H, CH.sub.3ar.), 3.82 (bs, 1
H, H11-5'), 3.75 (m, 1 H, H-4'), 3.62 (m, 2 H, H-2"a), 3.53 (m, 2
H, H-2b"), 3.25 (d, J=16 Hz, 1 H, H-l0a), 3.20 (m, 1 H, H-31), 3.15
(m, 2 H, H-l"a), 2.95 (d, J=16 Hz, 1 H, H-10b), 2.38 (m, 1 H,
H-8a), 2.35 (m, 1 H, H-8b), 2.24 (m, 2 H, H-2'a), 2.15 (m, 1 H.
H-2'b), 2.02(s, 6 H. CH.sub.3ac.), 1.95 (dt, 2 H, J=5.4, 2 Hz,
H-2"b), 1.35 (d, J=6 Hz, 3 H, H-6').
[0187] N-(8,8-Diacetoxvoctyl) doxorubicin hydrochloride (2 g):
[0188] A stirred solution of doxorubicin hydrochloride (20 mg,
0.035 mmol) and 8-octanal-1,1-diacetate (24) (17.1 mg, 2 eg, 0.07
mmol) in CH.sub.3CN--H.sub.2O (2:1) (5 mL) was treated with a
solution of NaBH.sub.3CN (lM in THF) (24 uL, 0.67 eg, 0.024 mmol).
The mixture was stirred under a nitrogen atmosphere at room
termperature in the dark for 1 hour. When reaction was complete (as
evidenced by TLC of a 5 uL aliquot) the solution was diluted with
H.sub.2O (8 ml) and then extracted repeatedly (10.times.10 mL) with
CHCl.sub.3-MeOH (5:1). The combined extracts were dried and
evaporated to give a red amorphous solid (19 mg). Preparative TLC
of this product (CHCl.sub.3-MeOH, 10:1; R.sub.f=0.60) afforded
N-(8,8-diacetoxyoctyl) doxorubicin (11.6 mg, 0.015 mmol). The
product was suspended in H.sub.2O (1 mL) and acidified to pH 5 by
dropwise addition of 0.05 N HCl (approx. 0.5 mL). The solution was
lyophilized to afford the title compound (11.72 mg, 0.0145 mmol,
41%). It was then stored under a nitrogen atmosphere in a tightly
stoppered vessel at -78.degree. C. in the dark.
[0189] .sup.1h NMR (free base): 8.05 (dd, J=8.2, 0.9 Hz, 1 H, H-1),
7.85 (t, J=8.2 Hz, 1 H, H-2), 7.40 (dd, J=8.2, 0.9 Hz, 1 H, H-3),
6.72 (t, J=5.46, 1 H, H-8"), 5.55 (T, J=1 Hz, 1 H, H-1'), 5.35 (bs,
1 H, H-7), 4.71 (s, 2 H, H-14), 4.16 (s, 3 H, CH.sub.3ar.), 3.68
(bs, 1 H, H-5'), 3.65 (m, 1 H, H-4'), 3.28 (d, J=16 Hz, 1 H,
H-10a), 2.98 (d, J=16 Hz, 1 H, H-10b), 2.85 (m, 1 H, H-3'), 2.68
(m, 2 H, H-1"), 2.35 (m, 1 H, H-8a), 2.25 (m, 1 H, H-8b), 2.04 (s,
6 H, CH.sub.3ac.), 1.85 (m, 2 H, H-2'a), 1.75 (m, 2 H, H-7"), 1.76
(m, 1 H, H-2'b), 1.68 (m, 2 H, H-2"), 1.41 (m, 2 H, H-3"), 1.40 (m,
6 H, H-4.sup.11, H-5"), 1.39 (m, 2 H, H-6"), 1.35 (d, J=6 Hz, 3 H,
H-6').
[0190] By usage of analogous cogeners, those of skill in the art
may readily adopt the above synthetic methods to produce almost
innumerable varieties of the subject compounds.
[0191] The following references as well as those-listed in the body
of the specification are incorporated in pertinent part herein for
the reasons cited.
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