U.S. patent application number 13/581179 was filed with the patent office on 2012-12-27 for process for the preparation of substituted prolyl peptides and similar peptidomimetics.
This patent application is currently assigned to Vereniging voor Christelijk hoger onderwijs wetenschappelijk onderzoek en patieentenzorg. Invention is credited to Romano Orru, Marloes Polak, Eelco Ruijter, Nicholas Turner, Anass Znabet.
Application Number | 20120329704 13/581179 |
Document ID | / |
Family ID | 43088069 |
Filed Date | 2012-12-27 |
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United States Patent
Application |
20120329704 |
Kind Code |
A1 |
Ruijter; Eelco ; et
al. |
December 27, 2012 |
PROCESS FOR THE PREPARATION OF SUBSTITUTED PROLYL PEPTIDES AND
SIMILAR PEPTIDOMIMETICS
Abstract
The present invention relates to a process for the
stereoselective preparation of a compound having the general
formula (I) or its respective diastereomers: comprising reacting a
compound having the general formula (II) or its diastereomers: with
a compound of the general formula III: R.sup.3--COOH and a compound
of the general formula IV: R.sup.4--NC wherein R.sup.1 represents
each independently, or jointly a substituted or unsubstituted
alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or
tricyclic, or heterocyclic structure, and R.sup.2 represents a
hydrogen atom, a substituted or unsubstituted alkyl, alkenyl,
alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or
heterocyclic structure, and R.sup.3 represents a substituted or
unsubstituted alkyl, alkenyl, or alkynyl, or an aromatic or
non-aromatic aromatic or non-aromatic, mono-, di- or tricyclic, or
heterocyclic structure. ##STR00001## R.sup.3--COOH (III)
R.sup.4--NC (IV)
Inventors: |
Ruijter; Eelco; (Woerden,
NL) ; Orru; Romano; (Haarlem, NL) ; Znabet;
Anass; (Amsterdam, NL) ; Polak; Marloes;
(Voorhout, NL) ; Turner; Nicholas; (Manchester,
GB) |
Assignee: |
Vereniging voor Christelijk hoger
onderwijs wetenschappelijk onderzoek en patieentenzorg
Amsterdam
NL
|
Family ID: |
43088069 |
Appl. No.: |
13/581179 |
Filed: |
September 16, 2010 |
PCT Filed: |
September 16, 2010 |
PCT NO: |
PCT/EP10/63656 |
371 Date: |
September 13, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61307873 |
Feb 25, 2010 |
|
|
|
Current U.S.
Class: |
514/3.7 ;
435/68.1; 514/21.9; 530/330 |
Current CPC
Class: |
C07D 209/58 20130101;
C07D 403/06 20130101; C07D 209/94 20130101; C07C 291/10 20130101;
C07C 2601/04 20170501; C07D 241/24 20130101; C07C 231/06 20130101;
C07C 2601/02 20170501; A61P 31/12 20180101; C07D 209/52 20130101;
C07C 237/14 20130101; C07D 403/12 20130101 |
Class at
Publication: |
514/3.7 ;
435/68.1; 530/330; 514/21.9 |
International
Class: |
A61K 38/06 20060101
A61K038/06; C07K 5/00 20060101 C07K005/00; A61P 31/12 20060101
A61P031/12; C12P 21/02 20060101 C12P021/02 |
Claims
1. A process for stereo-selectively preparing a compound of formula
I or diastereomer thereof: ##STR00054## comprising reacting a
compound of formula II or a diastereomer thereof: ##STR00055## with
a compound of formula III: R.sup.3--COOH (III) and a compound of
formula IV: R.sup.4--NC (IV) wherein R.sup.1 represents each
independently, or jointly a substituted or unsubstituted alkyl,
alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or
tricyclic, or heterocyclic group, R.sup.2 represents a hydrogen
atom, a substituted or unsubstituted alkyl, alkenyl, alkynyl,
aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic
group, and R.sup.3 represents a substituted or unsubstituted alkyl,
alkenyl, or alkynyl, or an aromatic or non-aromatic aromatic or
non-aromatic, mono-, di- or tricyclic, or heterocyclic group.
2. The process according to claim 1, wherein both substituents
R.sup.1 jointly form a substituted or unsubstituted 3-, 4-, 5-, 6-,
7- or 8-membered ring structure.
3. The process according to claim 2, wherein R.sup.1 is chosen such
that the compound of formula I has a structure of formula V:
##STR00056##
4. The process according to claim 2, wherein R.sup.1 is chosen such
that the compound of formula I has a structure of formula VI:
##STR00057##
5. The process according to claim 2, wherein R.sup.1 is chosen such
that the compound of formula I has a structure of formula VII:
##STR00058##
6. The process according to claim 1, wherein R.sup.2 represents a
dipeptide of formula VIII: ##STR00059## wherein R.sup.a and R.sup.b
each independently represents a hydrogen atom, a halogen atom,
C.sub.1-14 alkyl optionally substituted by halogen, a cycloalkyl
group, an aryl group, a lower alkoxy group, a lower thioalkyl
group, a cycloalkyloxy group, an aralkyloxy group or an alkanoyl
group; a hydroxyl group, a nitro group, a formyl group, an amino
group which may be protected or substituted, a cycloalkyloxy,
aralkyloxy, alkanoyl, ureido or mono-, di- or tricyclic
heterocyclic group, all of which groups may optionally be
substituted.
7. The process according to claim 1, wherein the compound of
formula IV has a structure of formula IX: ##STR00060## wherein
R.sup.d, R.sup.e and R.sup.f each independently represents a
hydrogen atom, a halogen atom, a substituted or unsubstituted
alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or
tricyclic and/or a heterocyclic group.
8. The process according to claim 1, further comprising: preparing
the compound of formula IIa or IIb by desymmetrization of
3,4-substituted meso-pyrrolidine.
9. The process according to claim 8, wherein the desymmetrization
comprises treating the meso-pyrrolidine with an enzyme capable of
catalysing oxidation of an amine in an enantio selective
manner.
10. The method according to claim 9, wherein the enzyme is a
monoamine oxidase N derived from Aspergillus niger.
11. The process according to claim 1, wherein R.sup.2 is chosen
such that the compound of formula III has a structure of formula
XV: ##STR00061##
12. The process according to claim 1, wherein R.sup.3 is chosen
such that the compound of formula IV has a structure of formula
XVI: ##STR00062##
13. The process according to claim 12, further comprising:
isolating from a reaction product a compound of formula XVII:
##STR00063##
14. The process according to claim 13, further comprising:
subjecting the compound of formula XVII to a saponification,
followed by a selective oxidation to form a compound of formula
XVIII: ##STR00064##
15. The process according to claim 14, wherein the saponification
is carried out by contacting the compound of formula XVII with an
alkaline metal carbonate in a suitable solvent, to obtain a
saponified alcohol product.
16. The process according to claim 15, wherein the selective
oxidation is carried out by contacting the saponified alcohol
product with a suitable oxidant in a suitable solvent.
17. A compound obtained by the process according to claim 1, or an
enantiomer, stereoisomer, rotamer, tautomer, racemate,
pharmaceutically acceptable salt or solvate thereof.
18-24. (canceled)
25. A method for catalyzing an organochemical reaction, comprising
adding a compound obtained from the process of claim 1 to the
organochemical reaction.
26. (canceled)
27. A composition comprising a compound of formula I obtained from
the process of claim 1 and a pharmaceutically acceptable carrier,
diluent or excipient.
28. The process according to claim 1, further comprising:
formulating a compound of formula (I) and optionally a utilizable
carrier to a pharmaceutical composition.
29. A method for treating a condition associated with viral
infections in a subject, comprising: administering to a subject in
need thereof at least one compound of formula (I) obtained from the
process of claim 1 or a pharmaceutically acceptable salt or N-oxide
thereof.
30-31. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to substituted prolyl peptides
and similar peptidomimetics, methods for their preparation, and a
variety of uses including as inhibitors of disease-associated
targets as well as an organocatalyst component.
BACKGROUND TO THE INVENTION
[0002] Optically pure 3,4-substituted prolyl peptides and related
peptidomimetic compounds are of considerable interest in
organocatalysis and medicinal chemistry, specifically since they
form key structural elements of the hepatitis C virus NS3 protease
inhibitors telaprevir and boceprevir as disclosed in for instance
WO2003/062265.
[0003] Multicomponent reactions (MCRs) offer the ability to rapidly
and efficiently generate collections of structurally and
functionally diverse organic compounds. Although MCRs are very
efficient by their nature, the stereocontrol in these reactions is
mostly not trivial.
[0004] The Ugi reaction is undoubtedly one of the most widely
applied MCRs. It is of considerable interest owing to its
exceptional synthetic efficiency and is widely used in the field of
modern combinatorial and medicinal chemistry. The Ugi reaction
involves a one-pot condensation of an aldehyde, an amine, a
carboxylic acid and an isocyanide to produce chiral
.alpha.-acylaminoamides. In 1982, Nutt and Joullie reported a
variation on the Ugi reaction (further referred to herein as
Joullie-Ugi reaction, or JU-3CR), which employed substituted
1-pyrrolines to produce substituted prolyl peptides. However, as in
most MCRs, controlling the newly formed stereocenter proves highly
complex, and therefore the reaction suffers from poor and/or
unpredictable (dia)stereoselectivity, as illustrated for instance
by WO2006/061585. This document discloses a JU-3CR employing
dihydroxypyrolline compounds to form peptidomimetic compounds
comprising dihydroxyproline structures. The reported products are
formed in only limited yields and mostly unpredictable
diastereoselectivity, while requiring the use of protecting groups
that are often difficult to remove, such as benzyl groups.
[0005] Accordingly, the known multicomponent reactions for the
preparation of proline derivative comprising peptides and
peptidomimetics suffer from poor and/or unpredictable
(dia)stereoselectivity. Alternative process schemes are tedious,
require numerous steps and hence suffer from low yields.
[0006] Notwithstanding the state of the art it would be desirable
to provide an enantioselective Joullie-Ugi reaction, or JU-3CR for
preparing substituted prolyl peptide structures.
SUMMARY OF THE INVENTION
[0007] The present invention relates to a stereoselective process
for the preparation of a compound having the general formula Ia or
Ib:
##STR00002##
comprising reacting a compound having the general formula II or its
diastereomers:
##STR00003##
with a compound of the general formula III:
R.sup.3--COOH (III)
and a compound of the general formula IV:
R.sup.4---NC (IV)
[0008] wherein R.sup.1 represents each independently, or jointly a
substituted or unsubstituted lower alkyl, alkenyl, alkynyl,
aromatic or non-aromatic, or heterocyclic structure, and
[0009] wherein R.sup.2 represents each independently a hydrogen, or
each independently or jointly a substituted or unsubstituted alkyl,
alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or
tricyclic, or heterocyclic structure, and
[0010] R.sup.3 represents a substituted or unsubstituted alkyl,
alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or
tricyclic, heterocyclic, alkyloxy, alkanoyl, amino, ureido or a
peptide structure, and
[0011] R.sup.4 represents a substituted or unsubstituted alkyl,
alkenyl, or alkynyl, or an aromatic or non-aromatic aromatic or
non-aromatic, mono-, di- or tricyclic, or heterocyclic alkyl,
alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or
tricyclic, heterocyclic, alkyloxy, alkanoyl, amino, ureido or a
peptide structure.
[0012] In the subject process, stereoselectivity refers to
enantioselectivity or diastereoselectivity, depending on the
substrates.
[0013] As used herein, the term "alkyl" denotes a saturated
straight or branched hydrocarbon chain comprising carbon and
hydrogen atoms, for example, methyl, ethyl, propyl, isopropyl,
n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred alkyl
groups are groups with 1-10 carbon atoms.
[0014] The term "alkyloxy" denotes an alkyl group as defined above,
which is attached via an oxygen atom.
[0015] The term "alkyl substituted by halogen" denotes an alkyl
group as defined above, wherein at least one hydrogen atom is
replaced by halogen, for example CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CF.sub.3,
CH.sub.2CF.sub.2CF.sub.3 and the like. The term "halogen" denotes
chlorine, iodine, fluorine and bromine.
[0016] The term "cycloalkyl" denotes a saturated carbocyclic ring,
preferably containing from 3 to 10 carbon atoms, more preferably 3
to 8 carbon atoms, yet more preferably from 3 to 6 carbon atoms,
for example, cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl.
[0017] The term "cycloalkenyl" denotes a saturated carbocyclic
ring, preferably containing from 3 to 10 carbon atoms, more
preferably 3 to 8 carbon atoms, yet more preferably from 3 to 6
carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl.
[0018] The term cyclocalkyl preferably comprises (C.sub.1-C.sub.10)
alkyl. The term "(C.sub.1-C.sub.10) alkyl" means a straight chain
or branched non cyclic hydrocarbon having from 1 to 10 carbon
atoms. Representative straight chain --(C.sub.1-C.sub.10) alkyls
include (C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9 and C.sub.10 alyls, such as -methyl,
-ethyl, -n propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl,
-n-octyl, -n-nonyl, and -n-decyl.
[0019] A branched alkyl means that one or more straight chain
--(C.sub.1-C.sub.8) alkyl groups, such as -methyl, -ethyl or
-propyl, replace one or both hydrogens in a --CH.sub.2-- group of a
straight chain alkyl. A branched non cyclic hydrocarbon means that
one or more straight chain (C.sub.1-C.sub.10) alkyl groups, such as
-methyl, -ethyl or -propyl, replace one or both hydrogens in a
--CH.sub.2-- group of a straight chain non cyclic hydrocarbon.
[0020] The term "--(C.sub.1-C.sub.2)alkyl" means a straight chain
non cyclic hydrocarbon having 1 or 2 carbon atoms. Representative
straight chain "--(C.sub.1-C.sub.2)alkyl groups include -methyl and
-ethyl.
[0021] The term "(C.sub.1-C.sub.3)alkyl" means a straight chain or
branched non cyclic hydrocarbon having from 1 to 3 carbon atoms.
Representative straight chain (C.sub.1-C.sub.3)alkyl groups include
-methyl, -ethyl, and -n-propyl. Representative branched
--(C.sub.1-C.sub.3)alkyl groups include -iso-propyl.
[0022] The term "(C.sub.1-C.sub.4)alkyl" means a straight chain or
branched non cyclic hydrocarbon having from 1 to 4 carbon atoms.
Representative straight chain --(C.sub.1-C.sub.4)alkyl groups
include -methyl, -ethyl, -n-propyl, and -n-butyl. Representative
branched --(C.sub.1-C.sub.4)alkyls include -iso-propyl, -sec-butyl,
-iso-butyl, and -tert-butyl. The term "(C.sub.1-C.sub.6)alkyl"
means a straight chain or branched non cyclic hydrocarbon having
from 1 to 6 carbon atoms. Representative straight chain
--(C.sub.1-C.sub.6)alkyls include -methyl, -ethyl, -n-propyl,
-n-butyl, -n-pentyl, and -n-hexyl. Representative branched
(C.sub.1-C.sub.6)alkyls include iso-propyl, -sec-butyl, -iso-butyl,
-tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl,
3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,
2,3-dimethylbutyl, and 3,3-dimethylbutyl.
[0023] Representative branched --(C.sub.1-C.sub.10) alkyl groups
include iso-propyl, sec-butyl, iso-butyl, tert-butyl, iso-pentyl,
neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,
2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl,
4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl,
1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl,
3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and
3,3-dimethylheptyl.
[0024] The term "(C.sub.2-C.sub.10)alkenyl" means a straight chain
or branched non cyclic hydrocarbon having from 2 to 10 carbon atoms
and including at least one carbon-carbon double bond. A branched
alkenyl means that one or more straight chain
--(C.sub.1-C.sub.8)alkyl groups, such as -methyl, -ethyl or
-propyl, replace one or both hydrogens in a --CH.sub.2-- or
--CH.dbd. group of a straight chain alkenyl. Representative
straight chain and branched (C.sub.2-C.sub.10)alkenyl groups
include -vinyl, -allyl, 1-butenyl, -2-butenyl, -iso-butylenyl,
-1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, 2-methyl-2-butenyl,
-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,
-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,
-3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,
-2-decenyl, -3-decenyl, and the like.
[0025] The term "C.sub.1-C.sub.6)alkoxy" represents a straight
chain or branched non cyclic hydrocarbon having one or more ether
groups and from 1 to 6 carbon atoms. Representative straight chain
and branched C.sub.1-C.sub.6)alkoxy groups include -methoxy,
-ethoxy, -methoxymethyl, -2-methoxyethyl, -5-methoxypentyl,
-3-ethoxybutyl and the like.
[0026] The term "C.sub.3-C.sub.12 cycloalkyl" groups refers to a
saturated monocyclic hydrocarbon having from 3 to 12 carbon atoms.
Representative C.sub.3-C.sub.12 cycloalkyl groups are -cyclopropyl,
-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,
-cyclononyl, -cyclodecyl, and -cyclododecyl.
[0027] "C.sub.4-C.sub.8 cycloalkyl" groups refers to "4- to
8-member cycloalkyl rings", meaning a saturated monocyclic
hydrocarbon having from 4 to 8 carbon atoms. Representative
--C.sub.4-C.sub.8 cycloalkyl groups are -cyclobutyl, -cyclopentyl,
-cyclohexyl, -cycloheptyl, and -cyclooctyl.
[0028] C.sub.3-C.sub.8 cycloalkyl groups mean a saturated
monocyclic hydrocarbon having from 3 to 8 carbon atoms.
Representative C.sub.3-C.sub.8 cycloalkyl groups include
-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl,
and -cyclooctyl.
[0029] C.sub.3-C.sub.7 cycloalkyl groups means a saturated
monocyclic hydrocarbon having from 3 to 7 carbon atoms.
Representative C.sub.3-C.sub.7 cycloalkyl groups include
-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, and
-cycloheptyl.
[0030] "-(6- to 10-membered) heterobicyclic" or "-(6- to
10-membered) bicycloheterocyclo" group refers to a 6 to 10 membered
bicyclic, heterocyclic ring which is either saturated, unsaturated
non-aromatic, or aromatic. A -(6- to 10-membered)heterobicyclic
group contains from 1 to 4 heteroatoms independently selected from
nitrogen, which can be quaternized; oxygen; and sulfur, including
sulfoxide and sulfone. The -(6- to 10-membered)heterobicyclic group
can be attached via a nitrogen or carbon atom. Representative -(6-
to 10-membered)heterobicyclic groups
include-3-azabicyclo[3.1.0]hexane, -quinolinyl, -isoquinolinyl,
-chromonyl, -coumarinyl, -indolyl, -indolizinyl, benzo[b]furanyl,
benzo[b]thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl,
isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl,
-carbazolyl, -[beta]-carbolinyl, -indolinyl, -isoindolinyl,
-1,2,3,4-tetrahydroquinolinyl, -1,2,3,4-tetrahydroisoquinolinyl,
pyrrolopyrrolyl and the like.
[0031] The term "CH.sub.2(halo)" group means a methyl group where
one of the hydrogens of the methyl group has been replaced with a
halogen. Representative --CH.sub.2(halo) groups include
--CH.sub.2F, --CH.sub.2Cl, --CH.sub.2Br, and --CH.sub.2I.
[0032] The term "--CH(halo).sub.2" means a methyl group where two
of the hydrogens of the methyl group have been replaced with a
halogen. Representative --CH(halo).sub.2 groups include
--CHF.sub.2, --CHCl.sub.2, --CHBr.sub.2, --CHBrCl, --CHClI, and
--CHI.sub.2.
[0033] The term "--C(halo).sub.3" means a methyl group where each
of the hydrogens of the methyl group has been replaced with a
halogen. Representative --C(halo).sub.3 groups include --CF.sub.3,
--CCl.sub.3, --CBr.sub.3, and --Cl.sub.3.
[0034] "-Halogen" or "-halo" means --F, --Cl, --Br, or --I.
[0035] "Oxo", ".dbd.O", and the like as used herein mean an oxygen
atom doubly bonded to carbon or another element.
[0036] When a first group is "substituted with one or more" second
groups, one or more hydrogen atoms of the first group are replaced
with a corresponding number of second groups. When the number of
second groups is two or greater, each second group can be the same
or different.
[0037] The term "aryl" as used herein is a carbocyclic ring system,
containing from 6 to 10 carbon atoms forming one or more rings, and
wherein at least one ring is aromatic in nature, for example
phenyl, naphthyl or 5,6,7,8-tetrahydronaphthalen-1-yl. The most
preferred aryl group is phenyl.
[0038] The term "enantiomeric excess" refers to a difference
between the amount of one enantiomer and the amount of the other
enantiomer that is present in the product mixture. Thus for
example, enantiomeric excess of 96% refers to a product mixture
having 98% of one enantiomer and 2% of the other enantiomer.
[0039] The terms "enantiomeric excess" and "diastereomeric excess"
are used interchangeably herein. Compounds with a single
stereocenter are referred to as being present in "enantiomeric
excess," those with at least two stereocenters are referred to as
being present in "diastereomeric excess." In the graphic
representations of racemic or enantiomerically pure compounds used
herein, solid and broken wedges are used to denote the absolute
configuration of a chiral element; wavy lines indicate disavowal of
any stereochemical implication which the bond it represents could
generate; solid and broken bold lines are geometric descriptors
indicating the relative configuration shown but not implying any
absolute stereochemistry; and wedge outlines and dotted or broken
lines denote enantiomerically pure compounds of indeterminate
absolute configuration.
[0040] The term "heterocyclic" embraces both "heteroaryl" and
"heterocycloalkyl" groups. The term "heteroaryl" as used herein is
an aromatic ring system, containing from 5 to 10 ring atoms forming
one or more rings, wherein at least one ring atom is a heteroatom
selected from the group consisting of O, N and S, and wherein at
least one ring is aromatic in nature, for example oxazolyl,
pyridyl, thiophenyl, quinolinyl, pyrrolyl, furyl, benzoimidazolyl,
imidazolyl and the like. The most preferred group is pyridyl.
[0041] The term "heterocycloalkyl" denotes a fully saturated ring
system, wherein one or two ring atoms are N, O or S, for example
piperazinyl, pyrrolidinyl, morpholinyl or piperidinyl.
[0042] The term "monoamine oxidase" refers to a polypeptide having
an enzymatic capability of oxidizing a compound of structural
Formula I, supra to the corresponding product of structural Formula
II, supra. The polypeptide typically utilizes an oxidized cofactor,
such as but not limited to flavin adenine dinucleotide (FAD),
flavin adenine mononucleotide (FMN), nicotinamide adenine
dinucleotide (NAD), or nicotinamide adenine dinucleotide phosphate
(NADP). In a particular embodiment, the oxidized cofactor is FAD.
Monoamine oxidases as preferably used herein include naturally
occurring (wild type) monoamine oxidases as well as non-naturally
occurring engineered polypeptides generated by human
manipulation.
[0043] The term "naturally occurring" or "wild type" refers to a
polypeptide occurring in nature. For example, a naturally occurring
or wild type polypeptide or polynucleotide sequence is a sequence
present in an organism that can be isolated from a source in nature
and which has not been intentionally modified by human
manipulation.
[0044] The term "peptide" denotes polymers of amino acids linked by
peptide bonds.
[0045] The term "peptidomimetics" denotes structures that resemble
polymers of amino acids linked by peptide bonds, either comprising
non-naturally occurring .alpha.-, .beta.- or similar amino acids,
or using structurally different building blocks.
[0046] "Pharmaceutically acceptable" such as pharmaceutically
acceptable salt, carrier, excipient, etc., means pharmacologically
acceptable and substantially non-toxic to the subject to which the
particular compound is administered.
[0047] The term "pharmaceutically acceptable salt" embraces salts
with inorganic and organic acids, such as hydrochloric acid, nitric
acid, sulfuric acid, phosphoric acid, citric acid, formic acid,
fumaric acid, maleic acid, acetic acid, succinic acid, tartaric
acid, methane-sulfonic acid, p-toluenesulfonic acid and the
like.
[0048] The term "Pharmaceutically acceptable N-oxide" refers to
N-oxides of tertiary nitrogen atoms in a molecule, which may be
more potent than their corresponding tertiary amine, or less.
N-oxides may or may not be reduced to their corresponding tertiary
amines after indigestion. When N-oxides are converted to their
corresponding tertiary amines, the conversion may be in mere trace
amounts or nearly quantitative. Further, once formed, N-oxides may
be more active than their corresponding tertiary amines, less
active or even completely inactive.
[0049] The term "prodrug" refers to a precursor form of the
compound that is metabolized to form the active ingredient.
[0050] The term "stereoselective" refers to the preferential
formation in a chemical or enzymatic reaction of one stereoisomer
over another. Stereoselectivity can be partial, where the formation
of one stereoisomer is favoured over the other, or it may be
complete where only one stereoisomer is formed. When the
stereoisomers are enantiomers, the stereoselectivity is referred to
as enantioselectivity, the fraction reported as a percentage of one
enantiomer in the sum of both. It is commonly alternatively
reported in the art (typically as a percentage) as the enantiomeric
excess (e.e.) calculated therefrom according to the formula [major
enantiomer-minor enantiomer]/[major enantiomer+minor enantiomer].
Where the stereoisomers are diastereoisomers, the stereoselectivity
is referred to as diastereoselectivity, the fraction (typically
reported as a percentage) of one diastereomer in a mixture of two
diasteromers, commonly alternatively reported as the diastereomeric
excess (d.e.). Enantiomeric excess and diastereomeric excess are
types of stereomeric excess. The present process allows a
stereoselective preparation of the desired compounds in a simple an
convergent manner, yielding the desired enantiomers--or
diastereomers based on easily available chiral information
preferably derived from 3R,4S- or 3S,4R-configured pyrrolidine
compounds.
[0051] The term "stereospecificity" refers to the preferential
conversion in a chemical or enzymatic reaction of one stereoisomer
over another. Stereospecificity can be partial, where the
conversion of one stereoisomer is favored over the other, or it may
be complete where only one stereoisomer is converted.
[0052] The term "chemoselectivity" refers to the preferential
formation in a chemical or enzymatic reaction of one product over
another.
[0053] "Therapeutically effective amount" means an amount that is
effective to prevent, alleviate or ameliorate symptoms of disease
or prolong the survival of the subject being treated.
[0054] As used herein, the terms "stereoisomer", "stereoisomeric
form" and the like are general terms for all isomers of individual
molecules that differ only in the orientation of their atoms in
space. It includes enantiomers and isomers of compounds with more
than one chiral center that are not mirror images of one another
("diastereomers").
[0055] The term "chiral centre" refers to a carbon atom to which
four different groups are attached.
[0056] The term "enantiomer" or "enantiomeric" refers to a molecule
that is non-superimposeable on its mirror image and hence optically
active where the enantiomer rotates the plane of polarized light in
one direction and its mirror image rotates the plane of polarized
light in the opposite direction.
[0057] The term "racemic" refers to a mixture of equal parts of
enantiomers which is optically inactive.
[0058] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule.
[0059] "Substantially enantiomerically pure" as used herein means
that the indicated enantiomer of a compound is present to a greater
extent or degree than another enantiomer of the same compound.
Accordingly, in particular embodiments, a substantially
enantiomerically pure compound is present in 80%, 85%, 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% enantiomeric excess over
another enantiomer of the same compound.
[0060] "Substantially stereomerically pure" as used herein means
that the indicated enantiomer or diastereomer of a compound is
present to a greater extent or degree than another enantiomer or
diastereomer of the same compound. As noted above with respect to
"stereoselectivity", enantiomeric excess and diastereomeric excess
are types of stereomeric excess. Accordingly, in particular
embodiments, a substantially stereomerically pure compound is
present in 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
or 99% stereomeric excess over another enantiomer or diastereomer
of the same compound.
[0061] Unlike prior art processes for the enantioselective
preparation of compounds according to formula (I), the process of
the present invention allows for the synthesis of either enantiomer
of according to formula (I) in excellent yield and enantiomeric
excess at mild conditions, and in a very small number of steps. In
addition, the inventive process of the present invention allows for
very effective use of readily available chiral starting
information. Insofar, the process of the present invention is
highly efficient as it does not produce 50% of the unwanted
enantiomer. These advantages combine to make the process of the
present invention very economic and amenable to industrial scale
up.
[0062] The process according to the invention advantageously allows
for the enantioselective formation of products, i.e., may produce
products having a high enantiomeric excess. An "enantioselective"
process according to the invention hence results in the formation
of a product with an enantiomeric excess and/or diastereomeric
excess of the desired respective enantiomer or diastereomers.
[0063] In an exemplary embodiment, the method produces the product
with an enantiomeric excess of a product from 80% ee (de) to
>99.9% ee (de), more preferably from 90% ee (de) to 99.9% ee
(de), yet more preferably from 95% ee (de) to >99.7% ee (de),
still more preferably from 98% ee (de) to >99.5% ee (de), still
more preferably from 99.0% ee (de) to more than 99.3% ee(de).
[0064] For analysis of yield, diastereomeric and/or enantiomeric
excess, the product may be analyzed by NMR (e.g., .sup.1H NMR,
.sup.13C NMR, etc.), HPLC, GLC, or the like. In some cases, more
than one analysis may be performed. For example, a product may be
analyzed by NMR, wherein the presence of different enantiomers may
be indicated by NMR peaks characteristic of a particular enantiomer
upon addition of a chiral shift reagent. In some embodiments, the
product may be analyzed using chromatography (e.g., HPLC or GLC),
where different enantiomers or diastereomers may exhibit distinct
retention times. Yet further, crystallographic evidence may be
employed where a product of intermediate can be crystallized to
such form that supports a sutibale analysis. A person skilled in
the art will be able to determine the appropriate method, or
combination of methods, to utilize based upon the product to be
analyzed.
DETAILED DESCRIPTION OF THE INVENTION
[0065] In the process according to the invention, the use of the
optically active 1-pyrroline compounds of formula II and the
diastereomers in a reaction with compounds of general formula (III)
and (IV) resulted in the formation of compounds (I) with an
unprecedentedly high (dia)stereoselectivity and yield. Without
wishing the bound to any particular theory, it is believed that the
steric bulk of the substituents at the 3 and 4 position of the
pyrroline compounds according to formula IIa or b directs the
addition of nucleophiles to the imine with high
diastereoselectivity.
[0066] The 1-pyrroline compound according to formula II may be
conveniently prepared by the desymmetrization of 3,4-substituted
meso-pyrrolidines. This may advantageously be performed in a
biocatalytic process, such as a process comprising treating the
meso-pyrrolidines with an enzyme capable of catalysing oxidation of
the amine in an enantioselective manner to form compound II.
[0067] In the case of R.sup.2 being different from hydrogen, the
diastereomers of compound II referred to above include the
following compounds of general formula IIa and IIb:
##STR00004##
[0068] which will result predominantly in the formation of the
respective stereoisomers of compound I according to general formula
Ia and Ib:
##STR00005##
[0069] The (3R,7S)-diastereomers IIc and IId, i.e. the
diastereomers having the opposite configuration of the substituents
R.sup.2 can also be employed, yielding the equivalent
(3R,7S)-configured proline derivatives Ic and Id.
[0070] Monoamine oxidase enzymes suitable for use in biocatalytic
process have been used to resolve and deracemize racemic chiral
amines via the stereospecific oxidation of one enantiomer to the
corresponding imine using oxygen. Derivatives of the flavin
dependent monoamine oxidase of Aspergillus niger (MAO N) (Shilling
et al. et al. (1995) Biochim. Biophys. Acta. 1243: 529 37) have
been reported as useful, in combination with non specific chemical
reducing agents, for the deracemization of (d/1)
.alpha.-methylbenzylamine to provide enantiomerically pure (93% ee)
(d/l) .alpha.-methylbenzylamine (Alexeeva et al. (2002), Angew.
Chem. Int. Ed. 41: 3177-3180). Derivatives of the flavin dependent
monoamine oxidase of Aspergillus niger were also used for
deracemization of (R/S)-2-phenypyrrolidine to provide
enantiomerically pure (98% ee) (R)-2-phenypyrrolidine (Carr et al.
(2005), ChemBioChem 6: 637 39; Gotor et al. "Enantioselective
Enzymatic Desymmetrization in Organic Synthesis," Chem. Rev. (2005)
105: 313.
[0071] Preferably the biocatalytic desymmetrization comprises
treating subsequently or simultaneously in situ the obtained
oxidised amine with a chemical reducing agent, more preferably a
non-enantioselective reducing agent, yet more preferably a reducing
agent selected from sodium borohydride, sodium cyanoborohydride, an
amine-borane complex or a transfer hydrogenation agent.
[0072] More preferably, the enzyme is a microbial monoamine
oxidase, preferably a monoamine oxidase N derived from naturally
occurring, selectively bred or genetically modified Aspergillus
species, preferably A. niger.
[0073] Most preferably, the biocatalytic desymmetrization is
performed using the monoamine oxidase N (MAO-N) from Aspergillus
niger according to the method disclosed in WO03080855, and in J.
Turner et al., Angew. Chem. Int. Ed. 2002, 41, 3177-3180; and
Turner et al., Angew. Chem. Int. Ed. 2003, 42, 4807-4810.
[0074] R.sup.1 according to the invention may each independently or
jointly be the same group, and preferably represents a hydrogen
atom, a halogen atom, a hydroxyl group, a nitro group, a formyl
group, an amino group which may be protected or substituted, a
lower alkyl, cycloalkyl, aryl, lower alkoxy, cycloalkyloxy,
aralkyloxy, alkanoyl, ureido or monocyclic heterocyclic group.
Suitable imino compounds according to formula II are those
disclosed in WO-A-2010/008828, more advantageously n paragraph [27]
and [29] of this publication.
[0075] More preferably, both substituents R.sup.1 jointly form an
optionally substituted 3-, 4-, 5-, 6-, 7- or 8 membered ring
structure. This ring structure jointly formed by the substituents
R.sup.1 may preferably be a saturated or unsaturated, mono-, bi- or
tricyclic, (C.sub.1-C.sub.10) alkyl, (C.sub.2-C.sub.10)alkenyl,
C.sub.1-C.sub.6)alkoxy C.sub.3-C.sub.12 cycloalkyl CH.sub.2(halo),
--CH(halo).sub.2 or --C(halo).sub.3, heterocyclic such as
heterocycloalkyl structure. The proline ring together with the ring
structure formed by the substituents R.sup.1 may advantageously be
bi- or tri-cyclic or of a higher annealed order.
[0076] Preferred embodiments of the process according to the
invention employ compounds according to formula II with the
structure according to general formula V, or the opposite
enantiomer:
##STR00006##
according to formula VI, or the opposite enantiomer:
##STR00007##
according to formula VII, or the opposite enantiomer:
##STR00008##
[0077] R.sup.2 preferably represents a hydrogen atom, a (lower)
alkyl group, preferably comprising from 1 to 4 carbon atoms, a
lower alkyl group substituted by halogen, a cycloalkyl group, a
(lower) alkoxy group, a (lower) thioalkyl group, a cycloalkyloxy
group, an aralkyloxy group or an alkanoyl group; a hydroxyl group
which may be protected or substituted, a nitro group, a formyl
group, an amino group which may be protected or substituted, a
cycloalkyloxy, aralkyloxy, alkanoyl, ureido or mono-, di- or
tricyclic heterocyclic group, all of which groups may optionally be
substituted.
[0078] R.sup.3 preferably represents a hydrogen atom, a lower alkyl
group comprising from 1 to 4 carbon atoms, a lower alkyl group
substituted by halogen, a cycloalkyl group, an aryl group, a lower
alkoxy group, a lower thioalkyl group, a cycloalkyloxy group, an
aralkyloxy group or an alkanoyl group; a hydroxyl group, a nitro
group, a formyl group, an amino group which may be protected or
substituted, a cycloalkyloxy, aralkyloxy, alkanoyl, ureido or
mono-, di- or tricyclic heterocyclic group, all of which groups may
optionally be substituted.
[0079] More preferably, R.sup.3 represents a compound according to
general formula VIII:
##STR00009##
wherein R.sup.a and R.sup.b each independently represents a
hydrogen atom, a (lower) alkyl group preferably comprising from 1
to 4 carbon atoms, a (lower) alkyl group substituted by halogen
such as a --CH.sub.2(halo), a --CH(halo).sub.2 or a --C(halo).sub.3
group, a cycloalkyl group, an aryl group, a lower alkoxy group, a
lower thioalkyl group, a cycloalkyloxy group, an aralkyloxy group
or an alkanoyl group; a hydroxyl group, a nitro group, a formyl
group, an amino group which may be protected or substituted, a
cycloalkyloxy, aralkyloxy, alkanoyl, ureido or mono-, di- or
tricyclic heterocyclic group, all of which groups may optionally be
substituted.
[0080] R.sup.a preferably represents a branched alkyl group, more
preferably a C.sub.3 or C.sub.4 alkyl group, and most preferably a
tertiary butyl group.
[0081] R.sup.b preferably represents a (C.sub.1-C.sub.10) alkyl,
(C.sub.2-C.sub.10)alkenyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.12)cycloalkyl, --CH.sub.2(halo), --CH(halo).sub.2
or --C(halo).sub.3, heterocyclic such as heterocycloalkyl group, or
more preferably a N-tert-butyl amino group or a
cyclohexyl-2-(pyrazine-2-carboxamido)acetamido) group, in
particular for the synthesis of
(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl-
butanoic acid.
[0082] R.sup.4 preferably represents a lower alkyl group comprising
from 1 to 4 carbon atoms, a lower alkyl group substituted by
halogen, a cycloalkyl group, an aryl group, a lower alkoxy group, a
lower thioalkyl group, a cycloalkyloxy group, an aralkyloxy group
or an alkanoyl group; a hydroxyl group, a nitro group, a formyl
group, an amino group which may be protected or substituted, a
cycloalkyloxy, aralkyloxy, alkanoyl, ureido or mono-, di- or
tricyclic heterocyclic group, all of which groups may optionally be
substituted.
[0083] In a preferred embodiment of the subject process, the
compound according to general formula IV preferably has a structure
according to general formula IX
##STR00010##
wherein R.sup.d, R.sup.e and R.sup.f each independently represents
a hydrogen atom, a halogen atom, a substituted or unsubstituted
alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or
tricyclic and/or a heterocyclic group.
[0084] Such compounds may advantageously be prepared from precursor
compounds of the general formula X by dehydration under suitable
conditions.
##STR00011##
Accordingly the present process further comprises:
[0085] A1) reacting a compound of the general formula XI:
##STR00012##
with a compound of the formula XII:
R.sup.e--COOH (XII),
and a compound of the general formula XIII
R.sup.f--NC (XIII)
under such conditions that compound X is formed,
[0086] wherein R.sup.d represents a hydrogen atom, a substituted or
unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic,
mono-, di-polycyclic or alkylcycloalkyl, or a heterocyclic
structure,
[0087] R.sup.e represents a substituted or unsubstituted alkyl,
alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or
tricyclic, or heterocyclic structure, and
[0088] R.sup.f represents a hydrogen atom, a substituted or
unsubstituted alkyl, alkenyl, or alkynyl structure.
[0089] Preferably, compound XIII thus obtained is subsequently
isolated from the reaction mixture.
[0090] R.sup.d preferably represents a hydrogen, a straight chain
alkyl, a branched chain alkyl, a cycloalkyl, an
alkylene-cycloalkyl, an aryl, alkylene-aryl, SO.sub.2-alkyl,
SO.sub.2-aryl, alkylene-SO.sub.2-aryl, -alkylene-SO.sub.2-alkyl,
heterocyclyl or alkylene-heterocyclyl; CH.sub.2CO--X--H,
--CH.sub.2CO--X-straight chain alkyl, --CH.sub.2CO--X-branched
chain alkyl, --CH.sub.2CO--X-cycloalkyl,
--CH.sub.2CO--X-alkylene-cycloalkyl, --CH.sub.2CO--X-aryl,
--CH.sub.2CO--X-alkylene-aryl, --CH.sub.2CO--X-heterocyclyl,
--CH.sub.2CO--X-alkylene-heterocyclyl or --CH.sub.2CO-aryl; wherein
X represents O or NH.
[0091] R.sup.e preferably represents hydrogen, a straight chain
alkyl, a branched chain alkyl, a cycloalkyl, an
alkylene-cycloalkyl, an aryl, and/or alkylene-aryl.
[0092] R.sup.f preferably represents hydrogen, a straight chain
alkyl, a branched chain alkyl, a cycloalkyl, an
alkylene-cycloalkyl, an aryl, and/or alkylene-aryl.
[0093] In the present invention, the substituents R.sup.d to
R.sup.f according to general formula (I) are defined as
follows:
[0094] In a preferred embodiment of the subject invention, R.sup.d
represents an alkyl group such as ethyl, or an alkylcycloalkyl
group, such as ethylcyclopropyl or ethlycyclobutyl.
[0095] R.sup.e preferably is an acetate group, and R.sup.f
preferably is a cyclopropyl group. The process according to the
present invention further advantageously comprises a step c) of
subjecting compound X to dehydrating conditions to obtain an
isocyanate compound according to general formula IX as set out
herein above.
[0096] This may advantageously be achieved for instance by
treatment of the formamido compound (X) with phosgene, diphosgene
(trichloromethylchloroformate) and/or triphosgene
[bis(trichloromethyl) carbonate], under suitable conditions as
known to a skilled person.
[0097] Preferably, the aldehyde according to formula XI is derived
from an optionally substantially enantiomerically pure
2-substituted 2-amino-1-ethanol according to general formula
XIV
##STR00013##
wherein R.sup.1 represents R.sup.d as defined herein above.
[0098] The aldehyde compound XI may advantageously be prepared from
an substituted 2-amino-1-ethanol according to general formula XIV
by A) N-formylation, and B) by a selective oxidation of the primary
alcohol of the obtained N-formylated alcohol intermediate to an
aldehyde.
[0099] This oxidation is advantageously performed by employing a
Dess-Martin oxidation. In this way, the stereogenic centre and
various substituents R.sup.d can be introduced from often
commercially or synthetically readily available 2-aminoethanols. A
so-called Dess-Martin oxidation employs the Dess-Martin Periodinane
(DMP), a hypervalent iodine compound for the selective and very
mild oxidation of alcohols to aldehydes or ketones, as disclosed
for instance in Y. Yip, F. Victor, J. Lamar, R. Johnson, Q. M.
Wang, J. I. Glass, N. Yumibe, M. Wakulchik, J. Munroe, S.-H Chen,
Bioorg. Med. Chem. Lett. 2004, 14, 5007-5011.
[0100] The oxidation preferably may be performed in dichloromethane
or chloroform at room temperature, and is usually complete within
0.5-2 hours. Products are easily separated from the iodo-compound
by-product after basic work-up.
[0101] Preferably, the Dess-Martin oxidation according to the
invention is performed in the presence of compound IV, in such a
way that the aldehyde II that is formed during the Dess-Martin
oxidation immediately reacts in a Passerini reaction with the
acetic acid that is formed as a by-product of the Dess-Martin
oxidation as carboxylic acid III and isocyanide IV. This has the
tremendous benefit that the atomic efficiency of the reaction is
increased, since the Dess-Martin Periodinane (DMP) also provides a
reactant for the second stage of the reaction, i.e., the Passerini
three-component reaction. In addition, the combination of two
reaction steps in one pot is advantageous in terms of both time and
resources (less solvent and manpower required, one workup and
chromatography less, etc.).
In a preferred embodiment of the subject process, the compound
according to formula V
##STR00014##
is reacted with a compound according to general formula XV:
##STR00015##
and a compound according to general formula XVI:
##STR00016##
Under conditions that allow formation of a compound according to
formula XVII:
##STR00017##
After the reaction, compound XVII could be advantageously isolated
from the reaction mixture.
[0102] The subject process further preferably comprises subjecting
the compound according to formula XVII to a saponification reaction
to remove the acetate from the secondary alcohol at the
.alpha.-hydroxy-.beta.-amino acid structure.
[0103] The saponification preferably is carried out by contacting
the compound according to formula XVII with a alkaline metal
carbonate, preferably K.sub.2CO.sub.3 in a suitable solvent, to
obtain a saponified alcohol product according to formula XIIa.
[0104] The released intermediate compound comprising the secondary
alcohol is the subjected to a selective oxidation of the secondary
alcohol to form compound XVIII,
##STR00018##
This compound, which also known as Telaprevir, could be prepared in
higher yields and with higher efficiency than any previously
disclosed processes. Furthermore, the chiral information used for
the preparation was derived from readily available simple building
blocks, making the process a highly effective approach to such
prolyl dipeptides and similar peptidomimetics.
[0105] In a further preferred embodiment of the subject process, a
compound according to general formula VII as defined herein above
is reacted with an acid compound according to general formula
XVII:
##STR00019##
and an isocyanide compound according to general formula XX:
##STR00020##
to obtain a compound according to general formula XXI
##STR00021##
which may advantageously be saponified to a secondary alcohol and
subsequently oxidized to a ketone, thereby yielding, after removal
under suitable conditions of the R.sup.2 group, a compound
according to formula XXII:
##STR00022##
also known as Boceprevir.
[0106] The process according to the present invention
advantageously permits to selectively produce the two diastereomers
according to the general formula XXIIa:
##STR00023##
[0107] and according to the general formula XXIIb,
respectively,
##STR00024##
The subject invention therefore also relates to a process wherein
XXIIa or XXIIb are selectively prepared, and to the thus obtained
compounds XXIIa or XXIIb.
[0108] Suitable solvents for the subject reaction are polar protic
and aprotic organic solvents, including methanol, ethanol,
2-propanol and other alcohol solvent, tetrahydrofuran, 1,4-dioxane,
acetonitrile, and/or mixtures of these solvents with water or less
polar organic solvents, such as dichloromethane or chloroform.
[0109] The saponification or removal of the ester group through
hydrolysis may be performed by any suitable method known to a
skilled person. Preferably, it is carried out by contacting the
obtained reaction product according to formula I with an alkaline
metal carbonate, more preferably K.sub.2CO.sub.3 in a suitable
solvent, to obtain a saponified alcohol product. The saponified
alcohol product may then advantageously be oxidised selectively at
the secondary alcohol function, preferably without affecting the
other structures on the compound, to yield a ketone compound.
The selective oxidation is preferably carried out by contacting the
saponified alcohol product with a suitable oxidant in a suitable
solvent. Suitable solvents include dichloromethane, THF, ethyl
acetate, DMSO. Suitable oxidants include hypervalent iodine
reagents such as IBX, Dess-Martin periodinane, etc., or a
combination of TEMPO and PhI(OAc).sub.2 or related reagents.
[0110] The compounds obtainable by the subject process may further
advantageously be used as (asymmetric) organocatalysts for the
addition of enolizable aldehydes to electrophiles such as (among
others) nitroalkenes, .alpha.,.beta.-unsaturated carbonyl compounds
(aldehydes, esters, amides), vinyl sulfones, and the like. The
subject invention also advantageously relates to compounds XVII,
XVIIa, XXIIa and XXIIb, asc curucal building blocks for prolyl
dipeptides.
EXPERIMENTAL SECTION
[0111] The following non-limiting experiments illustrate the
process according to the subject invention.
[0112] General Information
Starting materials and solvents were purchased from ABCR and
Sigma-Aldrich and were used without treatment.
3-Azabicylo[3,3,0]octane hydrochloride was purchased from AK
Scientific.
(1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene was
prepared according to literature procedure..sup.1 Column
chromatography was performed on silica gel. .sup.1H and .sup.13C
NMR spectra were recorded on a Bruker Avance 400 (400.13 MHz for
.sup.1H and 100.61 MHz for .sup.13C) or Bruker Avance 500 (500.23
MHz for .sup.1H and 125.78 MHz for .sup.13C) in CDCl.sub.3 and
DMSO-d.sub.6. Chemical shifts are reported in 6 values (ppm)
downfield from tetramethylsilane.
[0113] Electrospray Ionization (ESI) mass spectrometry was carried
out using a Bruker micrOTOF-Q instrument in positive ion mode
(capillary potential of 4500 V). GC-MS spectra were recorded on a
Hewlett Packard HP 6890 equipped with a J & W Scientific;
HP-1MS; 30 m.times.0.32 mm.times.0.25 .mu.m column (injector temp.
300.degree. C., oven temp. 100.degree. C. to 280.degree. C. at
5.degree. C./min, hold for 10 min., He 1.6 ml/min. and detector
temp. 275.degree. C.) and a HP 5973 Mass Selective Detector. GC-FID
analyses were performed on Agilent 6850 GC with a J & W
Scientific; HP-1; 30 m.times.0.32 mm.times.0.25 .mu.m (injector
temp. 300.degree. C., oven temp. 100.degree. C. to 280.degree. C.
at 5.degree. C./min, hold for 10 min., He 1.6 ml/min. and detector
temp. 275.degree. C.) and a Varian Chirasil-Dex CB; 25 m.times.0.25
mm.times.0.26 .mu.m column (inj. 250.degree. C., oven temp.
100.degree. C. to 180.degree. C. at 5.degree. C./min, hold for 10
min., He 1.6 ml/min. and detector temp. 275.degree. C.) equipped
with a Gerstel Multipurpose sampler MPS2L. Normal phase HPLC was
performed on Agilent systems. Normal phase HPLC system was equipped
with a G1322A degasser, a G1311A quaternary pump, a G1329
autosampler unit, a G1315B diode array detector and a G1316A
temperature controlled column compartment. Infrared (IR) spectra
were recorded neat, and wavelengths are reported in cm.sup.-1.
Optical rotations were measured with a sodium lamp and are reported
as follows: [.alpha.].sub.D.sup.20 (c=g/100 mL, solvent). Methyl
3-isocyanopropionate was synthesized as reported
previously..sup.3
[0114] General Procedure 1: Preparation of Optically Active Imines
(3S,7R)-4 and 6.
Unless stated otherwise: imines were synthesised according to
literature procedure.sup.2 with minor adjustments. 2.5 g of
freeze-dried MAO-N D5 E. Coli were rehydrated for 30 min. in 20 ml
of KPO.sub.4 buffer (100 mM, pH=8.0) at 37.degree. C. Subsequently
1 mmol amine ((3S,7R)-4 or 6) in 30 ml of KPO.sub.4 buffer (100 mM,
pH=8.0) was prepared.
[0115] The pH of the solution was adjusted to 8.0 by addition of
NaOH and then added to the rehydrated cells. After 16-17 h The
reaction was stopped (conversions were >95%) and worked up. For
workup the reaction mixture was centrifuged at 4000 rpm and
4.degree. C. until the supernatant had clarified (40-60 min.). The
pH of the supernatant was then adjusted to 10-11 by addition of aq.
NaOH and the supernatant was subsequently extracted with t-butyl
methyl ether or dichloromethane (4.times.70 mL). The combined
organic phases were dried with Na.sub.2SO.sub.4 and concentrated at
the rotary evaporator.
[0116] General Procedure 2: Preparation of Optically Active
Ugi-Type Products 5a-g & 7a-g
Unless stated otherwise: Imine (0.70 mmol) was dissolved in 2 ml of
CH.sub.2Cl.sub.2 followed by the addition of carboxylic acid (0.93
mmol) and isocyanide (0.93 mmol). The reaction mixture was stirred
for 24 h at RT. CH.sub.2Cl.sub.2 (8 mL) was added and the resulting
mixture was washed with Na.sub.2CO.sub.3 (2.times.10 mL), dried
(MgSO.sub.4), filtered, and concentrated. Note: rotamers could be
observed in the NMR data.
General Procedure 3: Determination of Enantiomeric Excess (ee) and
Diastereomeric Ratio (d.r.)
[0117] Racemic imines were synthesised according to literature
procedure.sup.2. Racemic Ugi-type products were prepared according
to general procedure 3. Diastereomers could be separated by GC-MS
and GC-FID. Enantiomers could be separated by normal phase HPLC and
GC-FID.
Example 1
##STR00025##
[0118] Compound 5a:
[0119] General procedure 2 was followed using
3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol), acetic
acid (55 mg, 52 .mu.l, 0.91 mmol) and t-butyl isocyanide (76 mg,
103 .mu.l, 0.91 mmol) giving 5a as a white solid, yield 73%.
[0120] 93:7 d.r. [HP-1, t (major)=14.852 min, t (minor)=16.773
min]; 95% ee [CP Chirasil-DEX CB, t (minor)=20.449 min, t
(major)=20.860 min]; [.alpha.].sub.D.sup.20=-47.8.degree. (c=0.34,
MeCN). .sup.1H NMR (400.1 MHz, CDCl.sub.3): .delta. 6.58 (bs, 1H),
4.28 (d, J=2.1 Hz, 1H), 3.70 (dd, J=8.3, 10.6 Hz, 1H), 3.24 (dd,
J=4.5, 10.6 Hz, 1H), 2.96-2.93 (m, 1H), 2.91-2.82 (m, 1H), 2.01 (s,
3H), 1.93-1.78 (m, 2H), 1.71-1.42 (m, 2H), 1.41-1.31 (m, 2H), 1.25
(s, 9H); .sup.13C NMR (100.6 MHz, CDCl.sub.3) .delta. 170.5, 170.0,
66.8, 54.4, 51.0, 45.0, 42.7, 32.5, 32.3, 28.7, 25.7, 22.6; IR
(neat): .nu..sub.max (cm.sup.-1)=3277 (m), 2957 (m), 1668 (s), 1630
(s), 1549 (s), 1447 (s), 1420 (s), 1223 (s), 667 (m), 606 (m); HRMS
(ESI+) calcd for C.sub.14H.sub.24N.sub.2O.sub.2 ([M+H].sup.+)
253.1916. found 253.1925.
Example 2
##STR00026##
[0121] Compound 5b:
[0122] General procedure 2 was followed using
3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol), benzoic
acid (111 mg, 0.91 mmol) and t-butyl isocyanide (76 mg, 103 .mu.l,
0.91 mmol) giving 5b as a white solid, yield 73%.
[0123] 93:7 d.r. [HP-1, t (major)=23.672 min, t (minor)=25.601
min]; 95% ee [Daicel Chiralpak AD-H, hexane/2-propanol=96/4, v=1.0
mL/min.sup.1, .lamda.=254 nm, t (minor)=10.698 min, t
(major)=11.620 min]; [.alpha.].sub.D.sup.20=-53.7.degree. (c=0.34,
MeCN). .sup.1H NMR (400.1 MHz, CDCl.sub.3): .delta. 7.49-7.38 (m,
5H), 6.66 (bs, 1H), 4.54 (d, J=2.8 Hz), 3.72 (dd, J=11.4, 7.8 Hz,
1H), 3.23 (d, J=11.0, 1H), 3.15-3.10 (m, 1H), 2.73-2.58 (m, 1H),
1.96-1.82 (m, 1H), 1.82-1.69 (m, 1H), 1.68-1.41 (m, 3H), 3.15-3.10
(m, 1H), 1.28 (s, 9H), 1.24-1.06 (m, 1H); .sup.13C NMR (100.6 MHz,
CDCl.sub.3) .delta.170.3, 170.1, 136.3, 130.1, 128.4, 126.9, 67.1,
60.4, 55.9, 51.1, 44.2, 43.3, 33.0, 32.7, 28.7, 26.2; IR (neat):
.nu..sub.max (cm.sup.-1)=3310 (m), 2961 (m), 1674 (s), 1618 (s),
1416 (s), 1223 (s), 698 (s); HRMS (ESI+) calcd for
C.sub.19H.sub.26N.sub.2O.sub.2 ([M+H].sup.+) 315.2073. found
315.2077.
Example 3
##STR00027##
[0124] Compound 5c:
[0125] General procedure 2 was followed using
3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol),
3-furoic acid (102 mg, 0.91 mmol) and isopropyl isocyanide (63 mg,
86 .mu.l, 0.91 mmol) giving 5c as a white solid, yield 75%.
[0126] 92:8 d.r. [HP-1, t (major)=21.290 min, t (minor)=23.012 min]
94% ee [Daicel Chiralpak AD-H, hexane/2-propanol=90/10, v=1.0
mLmin.sup.1, .lamda.=254 nm, t (minor)=7.417 min, t (major)=12.039
min]; [.alpha.].sub.D.sup.20=-33.3.degree. (c=0.30, MeCN). .sup.1H
NMR (400.1 MHz, CDCl.sub.3): .delta. 7.80 (bs, 1H), 7.43 (bs, 1H),
6.72 (bs, 1H), 6.51 (d, J=6.3 Hz, 1H), 4.56 (d, J=2.3 Hz, 1H), 4.03
(oct, J=7.1 1H), 3.88 (dd, J=10.4, 8.3 Hz, 1H), 3.53 (dd, J=10.4,
3.8 Hz, 1H), 3.09-3.01 (m, 1H), 2.95-2.84 (m, 1H), 2.00-1.84 (m,
2H), 1.74-1.65 (m, 1H), 1.64-1.54 (m, 1H), 1.53-1.43 (m, 1H),
1.43-1.33 (m, 1H), 1.17 (d, J=6.3 Hz, 3H) 1.13 (d, J=6.3 Hz, 3H);
.sup.13C NMR (100.6 MHz, CDCl.sub.3) .delta. 170.1, 163.2, 144.3,
142.8, 121.8, 110.4, 66.8, 54.8, 44.4, 43.3, 41.3, 32.4, 32.2,
25.6, 22.5, 22.4; IR (neat): .nu..sub.max(cm.sup.-1)=3281 (w), 2949
(w), 1647 (m), 1609 (s), 1547 (s), 1427 (s), 1159 (s), 737 (s), 598
(s); HRMS (ESI+) calcd for C.sub.16H.sub.22N.sub.2O.sub.3
([M+H].sup.+) 291.1709. found 291.1721.
Example 4
##STR00028##
[0127] Compound 5d:
[0128] General procedure 2 was followed using
3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol), benzoic
acid (111 mg, 0.91 mmol) and isopropyl isocyanide (63 mg, 86 .mu.l,
0.91 mmol) giving 5d as a white solid, yield 78%.
[0129] 92:8 d.r. [HP-1, t (major)=23.809 min, t (minor)=25.563
min]; 94% ee [Daicel Chiralpak AD-H, hexane/2-propanol=96/4, v=1.0
mL/min.sup.1, .lamda.=254 nm, t (minor)=16.613 min, t
(major)=21.363 min]; [.alpha.].sub.D.sup.20=-52.4.degree. (c=0.42,
MeCN). .sup.1H NMR (400.1 MHz, CDCl.sub.3): .delta. 7.46-7.36 (m,
1H), 6.63 (bs, 1H), 4.59 (d, J=2.0 Hz, 1H), 4.10-4.01 (m, 1H), 3.73
(dd, J=11.4, 7.8 Hz, 1H), 3.73 (dd, J=11.4, 7.8 Hz, 1H), 3.32-3.29
(m, 1H), 3.23-3.17 (m, 1H), 2.76-2.71 (m, 1H), 2.02-1.94 (m, 1H),
1.88-1.78 (m, 1H), 1.75-1.63 (m, 1H), 1.63-1.50 (m, 1H), 1.16 (d,
J=6.6 Hz, 3H) 1.13 (d, J=6.6 Hz, 3H); .sup.13C NMR (100.6 MHz,
CDCl.sub.3) .delta. 170.4, 170.0, 136.2, 130.1, 128.4, 126.9,
126.6, 66.5, 55.9, 44.3, 43.3, 41.5, 32.9, 32.6, 26.1, 22.7, 22.6;
IR (neat): .nu..sub.max(cm.sup.-1)=3300 (m), 2959 (m), 1615 (s),
1545 (s), 1416 (s), 1229 (m), 700 (m); HRMS (ESI+) calcd for
C.sub.18H.sub.24N.sub.2O.sub.2 ([M+H].sup.+) 301.1916. found
301.1914.
Example 6
##STR00029##
[0130] Compound 5e:
[0131] General procedure 2 was followed using
3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol), acetic
acid (55 mg, 52 .mu.l, 0.91 mmol) and benzyl isocyanide (107 mg,
111 .mu.l, 0.91 mmol) giving 5e as a white solid, yield 71%.
[0132] 92:8 d.r. [HP-1, t (major)=25.098 min, t (minor)=26.457
min]; 94% ee [Daicel Chiralpak OJ-H, hexane/2-propanol=93/7, v=1.0
mLmin.sup.1, .lamda.=254 nm, t (minor)=9.948 min, t (major)=10.718
min]; [.alpha.].sub.D.sup.20=-18.8.degree. (c=0.32, MeCN). .sup.1H
NMR (400.1 MHz, CDCl.sub.3): .delta. 7.36-7.25 (m, 5H), 7.16 (bs,
1H), 4.47 (d, J=2.0 Hz, 1H), 4.25 (dd, J=15.2, 5.8 Hz, 2H), 3.73
(dd, J=10.6, 8.3 Hz, 1H), 3.28 (dd, J=10.5, 4.5 Hz, 1H), 3.10-3.03
(m, 1H), 2.96-2.88 (m, 1H), 2.10 (s, 3H), 2.01-1.85 (m, 1H),
1.82-1.55 (m, 2H), 1.52-1.39 (m, 2H); .sup.13C NMR (100.6 MHz,
CDCl.sub.3) .delta. 171.3, 170.1, 138.3, 128.5, 128.4, 127.9,
127.4, 127.0, 65.9, 54.3, 45.4, 43.2, 42.7, 32.6, 32.2, 25.5, 22.1;
IR (neat): .nu..sub.max(cm.sup.-1)=3267 (m), 2951 (w), 1626 (s),
1537 (m), 1418 (s), 1231 (s), 1030 (w), 748 (s); HRMS (ESI+) calcd
for C.sub.17H.sub.22N.sub.2O.sub.2 ([M+H].sup.+) 287.1760. found
281.1765.
Example 7
##STR00030##
[0133] Compound 5f:
[0134] General procedure 2 was followed using
3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol), benzoic
acid (111 mg, 0.91 mmol) and benzyl isocyanide (107 mg, 111 .mu.l,
0.91 mmol) giving 5f as a white solid, yield 81%.
[0135] 92:8 d.r. [HP-1, t (major)=33.333 min, t (minor)=35.085
min]; 97% ee [Daicel Chiralpak AD-H, hexane/2-propanol=96/4, v=1.0
mL/min.sup.1, .lamda.=254 nm, t (minor)=18.134 min, t
(major)=23.440 min]; [.alpha.].sub.D.sup.20=-52.6.degree. (c=0.38,
MeCN). .sup.1H NMR (400.1 MHz, CDCl.sub.3): .delta. 7.34-7.11 (m,
10H), 6.73 (bs, 1H), 4.61 (d, J=2.8 Hz, 1H). 4.37 (dd, J=5.3, 2.8
Hz, 2H), 3.66 (dd, J=11.1, 7.6 Hz, 1H), 3.24 (dd, J=10.9, 1.8 Hz,
1H), 3.18-3.11 (m, 1H), 2.72-2.64 (m, 1H), 1.92-1.82 (m, 1H),
1.82-1.62 (m, 1H), 1.25-1.13 (m, 1H); .sup.13C NMR (100.6 MHz,
CDCl.sub.3) .delta.171.1, 170.3, 138.3, 135.9, 132.6, 130.0, 129.7,
128.4, 128.21, 128.0, 127.7, 127.3, 127.0, 126.9, 126.4, 66.3,
55.8, 44.9, 43.2, 43.1, 32.8, 32.4, 25.9; IR (neat):
.nu..sub.max(cm.sup.-1)=3262 (m), 2928 (m), 1674 (s), 1613 (s),
1545 (s), 1423 (s), 1223 (m), 698 (s), 669 (s); HRMS (ESI+) calcd
for C.sub.22H.sub.24N.sub.2O.sub.2 ([M+H].sup.+) 349.1916. found
349.1924.
Example 8
##STR00031##
[0136] Compound 5g:
[0137] General procedure 2 was followed using
3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol),
isobutyric acid (80 mg, 84 .mu.l, 0.91 mmol) and t-butyl isocyanide
(76 mg, 103 .mu.l, 0.91 mmol) giving 5g as a white solid, yield
83%.
[0138] 93:7 d.r. [HP-1, t (major)=17.165 min, t (minor)=18.750
min]; 97% ee [CP Chirasil-DEX CB, t (minor)=21.439 min, t
(major)=21.846 min]; [.alpha.].sub.D.sup.20=-47.8.degree. (c=0.34,
MeCN). .sup.1H NMR (400.1 MHz, CDCl.sub.3): .delta. 6.71 (bs, 1H),
4.37 (d, J=1.8 Hz, 1H), 3.65 (dd, J=10.6, 8.3 Hz, 1H), 3.34 (dd,
J=4.3, 10.9 Hz, 1H), 3.04-2.98 (m, 1H), 2.89-2.81 (m, 1H), 2.65
(sep, J=6.8 Hz, 1H), 2.01-1.83 (m, 2H), 1.70-1.48 (m, 2H),
1.45-1.35 (m, 2H), 1.29 (s, 9H), 1.13 (d, J=6.6 Hz, 3H), 1.10 (d,
J=6.8 Hz, 3H); .sup.13C NMR (100.6 MHz, CDCl.sub.3) .delta.176.5,
170.4, 66.5, 53.0, 43.7, 42.7, 32.8, 32.3, 32.0, 30.8, 24.9, 18.9,
18.5; IR (neat): .nu..sub.max (cm.sup.-1)=3291 (m), 2963 (m), 2870
(w), 1684 (s), 1618 (s), 1551 (s), 1433 (s), 1225 (s), 1090 (m),
658 (m); HRMS (ESI+) calcd for C.sub.14H.sub.24N.sub.2O.sub.2
([M+H].sup.+) 281.2229. found 281.2235.
Example 9
##STR00032##
[0139] Compound 7a:
[0140] General procedure 2 was followed using
(1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), acetic acid (55 mg, 52 .mu.l, 0.91 mmol) and
t-butyl isocyanide (76 mg, 103 .mu.l, 0.91 mmol) giving 7a as a
white solid, yield 83%.
[0141] >99:1 d.r. (t (major)=18.179 min); >99% ee [Daicel
Chiralpak AD-H, hexane/2-propanol=92/8, v=1.0 mLmin.sup.1,
.lamda.=220 nm, t (major)=5.319 min, t (minor)=6.587 min];
[.alpha.].sub.D.sup.20=-24.0.degree. (c=0.25, MeCN). .sup.1H NMR
(400.1 MHz, CDCl.sub.3): .delta. 6.65 (bs, 1H), 6.14-6.13 (m, 2H),
4.09 (d, J=2.0 Hz, 1H), 3.47 (dd, J=11.4, 8.6 Hz, 1H), 3.36-3.32
(m, 1H), 3.15 (dd, J=11.4, 2.0 Hz, 1H), 2.98-2.92 (m, 3H), 1.95 (s,
3H), 1.51-1.41 (m, 2H), 1.30 (s, 9H); .sup.13C NMR (100.6 MHz,
CDCl.sub.3) .delta.170.6, 169.0, 135.4, 134.0, 62.9, 51.7, 51.0,
50.3, 47.0, 46.6, 46.0, 45.1, 28.7, 22.8; IR (neat):
.nu..sub.max(cm.sup.-1)=3283 (w), 2970 (w), 2942 (w), 1647 (s),
1634 (s), 1553 (s), 1414 (s), 1223 (s), 733 (s); HRMS (ESI+) calcd
for C.sub.16H.sub.24N.sub.2O.sub.2 ([M+H].sup.+) 277.1916. found
277.1922.
Example 10
##STR00033##
[0142] Compound 7b:
[0143] General procedure 2 was followed using
3-azabicyclo[3,3,0]oct-2-ene (6, 76 mg, 0.70 mmol), benzoic acid
(111 mg, 0.91 mmol) and t-butyl isocyanide (76 mg, 103 .mu.l, 0.91
mmol) giving 7b as a white solid, yield 82%.
[0144] >99:1 d.r. (t (major)=26.830 min); HP-1, >99% ee
[Daicel Chiralpak AD-H, hexane/2-propanol=96/4, v=1.0 mLmin.sup.1,
.lamda.=220 nm, t (minor)=9.712 min, t (major)=11.741 min];
[.alpha.].sub.D.sup.20=-43.1.degree. (c=0.33, MeCN). .sup.1H NMR
(400.1 MHz, CDCl.sub.3): .delta. 7.43-7.34 (m, 1H), 6.63 (bs, 1H),
6.20 (dd, J=5.8, 3.0 Hz, 1H), 5.91 (dd, J=5.6, 2.6 Hz, 1H), 4.43
(d, J=2.0 Hz, 1H), 3.52 (dd, J=11.9, 8.6 Hz, 1H), 3.44-3.39 (m,
1H), 3.05-3.00 (m, 2H), 2.91-2.85 (m, 1H), 2.78-2.76 (m, 1H),
1.48-1.45 (m, 1H), 1.40-1.37 (m, 1H), 1.32 (s, 9H); .sup.13C NMR
(100.6 MHz, CDCl.sub.3) .delta.168.6, 168.0, 135.0, 133.2, 132.7,
128.4, 126.8, 124.9, 61.3, 50.4, 49.9, 49.5, 45.4, 44.9, 43.9,
43.3, 27.1; IR (neat): .nu..sub.max(cm.sup.-1)=3283 (m), 2970 (m),
2942 (m0, 1647 (s), 1634 (s), 1553 (s), 1414 (s), 1223 (s), 733
(s); HRMS (ESI+) calcd for C.sub.21H.sub.26N.sub.2O.sub.2
([M+H].sup.+) 339.2073. found 339.2082.
Example 11
##STR00034##
[0145] Compound 7c:
[0146] General procedure 2 was followed using
1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), 3-furoic acid (102 mg, 0.91 mmol) and isopropyl
isocyanide (63 mg, 86 .mu.l, 0.91 mmol) giving 7c as a white solid,
yield 75%.
[0147] >99:1 d.r. (t (major)=24.364 min); >99% ee [Daicel
Chiralpak AD-H, hexane/2-propanol=90/10, v=1.0 mLmin.sup.1,
.lamda.=220 nm, t (minor)=8.404 min, t (major)=9.968 min];
[.alpha.].sub.D.sup.20=-35.7.degree. (c=0.28, MeCN). .sup.1H NMR
(400.1 MHz, CDCl.sub.3): .delta. 7.71 (dd, J=1.5, 0.8 Hz, 1H), 7.42
(dd, J=2.0, 1.5 Hz, 1H), 6.65 (dd, J=1.8, 0.8 Hz, 1H), 6.50 (d,
J=6.6 Hz, 1H), 6.19-6.17 (m, 1H), 5.98-5.96 (m, 1H), 4.42 (d, J=2.0
Hz, 1H), 4.06-3.94 (m, 1H), 3.63 (dd, J=11.4, 8.8 Hz, 1H),
3.43-3.39 (m, 2H), 3-06-3.02 (m, 2H), 2.90-2.88 (m, 1H), 1.51-1.43
(m, 2H), 1.13 (d, J=6.6 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H); .sup.13C
NMR (100.6 MHz, CDCl.sub.3) .delta. 170.2, 162.7, 144.1, 142.9,
135.1, 134.4, 121.9, 110.4, 62.8, 51.6, 51.2, 47.1, 46.5, 45.8,
45.2, 41.5, 22.6, 22.7, 22.6; IR (neat):
.nu..sub.max(cm.sup.-1)=3275 (m), 2970 (m), 2934 (m), 1678 (s),
1594 (s), 1545 (s), 1437 (s), 1219 (s), 1153 (m), 1018 (m) 874 (m0,
754 (s); HRMS (ESI+) calcd for C.sub.18H.sub.22N.sub.2O.sub.2
([M+H].sup.+) 315.1709. found 315.1725.
Example 12
##STR00035##
[0148] Compound 7d:
[0149] General procedure 2 was followed using
1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), benzoic acid (111 mg, 0.91 mmol) and isopropyl
isocyanide (63 mg, 86 .mu.l, 0.91 mmol) giving 7d as a white solid,
yield 78%.
[0150] >99:1 d.r. (t (major)=27.054 min); >99% ee [Daicel
Chiralpak AD-H, hexane/2-propanol=96/4, v=1.0 mLmin.sup.1,
.lamda.=220 nm, t (minor)=17.354 min, t (major)=29.404 min];
[.alpha.].sub.D.sup.20=-38.7.degree. (c=0.31, MeCN). .sup.1H NMR
(400.1 MHz, CDCl.sub.3): .delta. 7.43-7.35 (m, 5H), 6.59 (d, J=7.6
Hz, 1H), 6.23-6.21 (m, 1H), 5.93-5.91 (m, 1H), 4.48 (d, J=1.7 Hz,
1H), 4.11-3.98 (m, 1H), 3.55 (dd, J=11.9, 8.8 Hz, 1H), 3.48-3.45
(m, 1H), 3.07-3.00 (m, 2H), 2.92-2.87 (m, 1H), 2.81-2.77 (m, 1H),
1.48-1.39 (m, 2H), 1.14 (d, J=6.6 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H);
.sup.13C NMR (100.6 MHz, CDCl.sub.3) .delta. 170.1, 169.8, 136.5,
134.8, 134.4, 130.1, 128.4, 126.6, 62.3, 52.0, 51.5, 47.0, 46.5,
45.6, 44.9, 41.5, 22.7, 22.6; IR (neat):
.nu..sub.max(cm.sup.-1)=3287 (m), 2967 (m), 2940 (m), 1682 (s),
1601 (s), 1539 (s), 1424 (s), 1217 (s), 739 (s), 664 (m); HRMS
(ESI+) calcd for C.sub.20H.sub.24N.sub.2O.sub.2 ([M+H].sup.+)
325.1916. found 325.1919.
Example 13
##STR00036##
[0151] Compound 7e:
[0152] General procedure 2 was followed using
1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), acetic acid (55 mg, 52 .mu.l, 0.91 mmol) and
benzyl isocyanide (107 mg, 111 .mu.l, 0.91 mmol) giving 7e as a
white solid, yield 78%.
[0153] >99:1 d.r. (t (major)=28.213 min); >99% ee [Daicel
Chiralpak OJ-H, hexane/2-propanol=92/8, v=1.0 mLmin.sup.1,
.lamda.=220 nm, t (minor)=9.100 min, t (major)=10.760 min];
[.alpha.].sub.D.sup.20=-21.4.degree. (c=0.28, MeCN). .sup.1H NMR
(400.1 MHz, CDCl.sub.3): .delta. 7.31-7.21 (m, 5H), 6.13-6.08 (m,
2H), 4.46 (dd, J=14.9, 6.1 Hz, 1H), 4.32 (dd, J=15.2, 5.8 Hz, 1H),
4.25 (d. J=2.0 Hz, 1H), 3.47-3.43 (m, 2H), 3.18 (dd, J=11.4, 2.0
Hz, 1H), 3.01-2.95 (m, 3H), 2.0 (s, 3H), 1.54-1.43 (m, 2H);
.sup.13C NMR (100.6 MHz, CDCl.sub.3) 171.3, 169.3, 138.3, 135.4,
134.1, 128.6, 127.4, 127.3, 62.2, 51.7, 50.3, 47.1, 46.7, 46.0,
45.1, 43.4, 22.7; IR (neat): .nu..sub.max(cm.sup.-1)=3314 (w), 3082
(w), 2970 (w), 2932 (w), 1553 (s), 1433 (s), 1360 (m), 1317 (m),
1233 (m), 745 (s), 696 (s); HRMS (ESI+) calcd for
C.sub.19H.sub.22N.sub.2O.sub.2 ([M+H].sup.+) 311.1760. found
311.1745.
Example 14
##STR00037##
[0154] Compound 7f:
[0155] General procedure 2 was followed using
31R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), benzoic acid (111 mg, 0.91 mmol) and benzyl
isocyanide (107 mg, 111 .mu.l, 0.91 mmol) giving 7f as a white
solid, yield 80%.
[0156] >99:1 d.r. (t (major)=36.331 min); >99% ee [Daicel
Chiralpak OD-H, hexane/2-propanol=92/8, v=1.0 mLmin.sup.1,
.lamda.=220 nm, t (major)=11.489 min, t (minor)=13.626 min];
[.alpha.].sub.D.sup.20=-35.1.degree. (c=0.29, MeCN). .sup.1H NMR
(400.1 MHz, CDCl.sub.3): .delta. 7.44-7.17 (m, 10H), 6.24-6.18 (m,
1H), 5.95-5.93 (m, 1H), 4.60 (d, J=1.8 Hz, 1H), 4.45 (d, J=5.8 Hz,
2H), 3.58-3.50 (m, 2H), 3.10-3.04 (m, 2H), 2.95-2.89 (m, 1H),
2.83-2.79 (m, 1H), 1.50-1.41 (m, 2H); .sup.13C NMR (100.6 MHz,
CDCl.sub.3) .delta. 171.1, 169.9, 138.4, 136.4, 134.4, 130.1,
128.6, 128.4, 127.4, 127.3, 126.4, 62.2, 52.1, 51.6, 47.0, 46.6,
45.6, 45.0, 43.5; IR (neat): .nu..sub.max (cm.sup.-1)=3268 (m),
3077 (w), 2972 (w), 2872 (w), 1684 (s), 1597 (s), 1560 (s), 1495
(m), 1431 (s), 1221 (s), 731 (s), 696 (s); HRMS (ESI+) calcd for
C.sub.24H.sub.24N.sub.2O.sub.2 ([M+H].sup.+) 373.1916. found
373.1901.
Example 15
##STR00038##
[0157] Compound 7g:
[0158] General procedure 2 was followed using
1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), isobutyric acid (80 mg, 84 .mu.l, 0.91 mmol) and
t-butyl isocyanide (76 mg, 103 .mu.l, 0.91 mmol) giving 7g as a
white solid, yield 81%.
[0159] >99:1 d.r. (t (major)=19.912 min); >99% ee [Daicel
Chiralpak AD-H, hexane/2-propanol=95/5, v=1.0 mLmin.sup.1,
.lamda.=220 nm, t (minor)=5.037 min, t (major)=6.877 min];
[.alpha.].sub.D.sup.20=-35.3.degree. (c=0.34, MeCN). .sup.1H NMR
(400.1 MHz, CDCl.sub.3): .delta. 6.13-6.08 (m, 2H), 4.15 (d, J=1.8
Hz, 1H), 3.43 (dd, J=11.4, 8.6 Hz, 1H), 3.37-3.33 (m, 1H), 3.26
(dd, J=11.4, 2.0 Hz, 1H), 2.99-2.91 (m, 3H), 2.50 (sep, J=6.8 Hz,
1H), 1.54-1.38 (m, 2H), 1.27 (s, 9H), 1.06 (d, J=6.8 Hz, 3H), 1.03
(d, J=6.8 Hz, 3H); .sup.13C NMR (100.6 MHz, CDCl.sub.3) .delta.
175.6, 170.7, 135.3, 134.2, 62.7, 51.8, 50.8, 49.1, 47.01, 46.5,
45.2, 32.2, 28.7, 19.2, 18.3; IR (neat): .nu..sub.max
(cm.sup.-1)=3325 (m), 2966 (m), 1678 (m), 1624 (s), 1553 (s), 1435
(s), 1315 (w), 1231 (m), 1088 (w); HRMS (ESI+) calcd for
C.sub.18H.sub.28N.sub.2O.sub.2 ([M+H].sup.+) 305.2229. found
305.2224.
Example 16
##STR00039##
[0160] Compound 8a:
[0161] General procedure 2 was followed using
1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), Fmoc-D-Pro-OH (307 mg, 0.91 mmol) and t-butyl
isocyanide (76 mg, 103 .mu.l, 0.91 mmol). The crude product 8 was
subjected using column chromatography (SiO.sub.2, EtOAc (1):
cyclohexane (2)). Fmoc deprotection using 25% piperidine in DMF
followed by column chromatography (CH.sub.2Cl.sub.2/MeOH 9:1) gave
8a as a white solid in 66% yield over two steps.
[.alpha.].sub.D.sup.20=-75.0.degree. (c=0.16, MeCN). .sup.1H NMR
(500.2 MHz, CDCl.sub.3): .delta. 6.75 (bs, 1H), 6.11 (d, J=5.7 Hz,
2H), 5.01 (bs, 1H), 4.20 (bs, 1H), 3.92-3.83 (m, 1H), 3.45-3.41 (m,
1H), 3.24-3.22 (m, 1H), 3.20-3.10 (m, 2H), 3.03-2.98 (m, 2H),
2.95-2.89 (m, 1H), 2.19-2.09 (m, 1H), 1.94-1.57 (m, 3H), 1.57-1.39
(m, 2H), 1.28 (s, 9H); .sup.13C NMR (125.8 MHz, CDCl.sub.3) .delta.
170.5, 135.4, 134.4, 63.7, 61.4, 51.6, 51.0, 49.01, 47.2, 46.9,
46.5, 46.3, 45.4, 30.0, 28.7, 25.9; IR (neat): .nu..sub.max
(cm.sup.-1)=2960 (w), 1668 (s), 1622 (s), 1566 (m), 1414 (s), 1234
(m), 1094 (w), 853 (s); HRMS (ESI+) calcd for
C.sub.19H.sub.29N.sub.3O.sub.2 ([M+H].sup.+) 332.2338. found
332.2342.
Example 18
##STR00040##
[0162] Compound 9:
[0163] General procedure 2 was followed using
1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), Fmoc-L-Pro-OH (307 mg, 0.91 mmol) and t-butyl
isocyanide (76 mg, 103 .mu.l, 0.91 mmol) giving 9 as a white solid,
yield 76%.
[0164] [.alpha.].sub.D.sup.20=-6.7.degree. (c=0.60, MeCN). .sup.1H
NMR (500.2 MHz, CDCl.sub.3): .delta. 7.76 (d, J=7.6 Hz, 2H),
.delta. 7.59 (d, J=7.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.40 (d,
J=7.4 Hz, 2H), 7.40 (d, J=7.4 Hz, 2H), 7.31 (d, J=7.4 Hz, 2H),),
6.62 (bs, 1H), 6.19 (dd, J=5.6, 2.9 Hz, 1H), 6.11 (dd, J=5.6, 2.5
Hz, 1H), 4.35-4.33 (m, 1H), 4.30-4.28 (m, 2H), 4.24-4.22 (m, 1H),
4.20 (d, J=1.9 Hz, 1H), 3.72-3.58 (m, 2H), 3.35-3.32 (m, 1H),
3.25-3.22 (m, 2H), 2.93-2.90 (m, 2H), 2.18-2.13 (m, 2H), 1.95-1.91
(m, 2H), 1.52-1.40 (m, 2H), 1.29 (s, 9H);); .sup.13C NMR (125.8
MHz, CDCl.sub.3) .delta. 170.6, 170.4, 154.8, 143.9, 141.3, 135.9,
134.2, 127.8, 127.7, 127.1, 127.0, 125.1, 125.0, 120.0, 67.5, 63.3,
58.3, 51.8, 51.2, 49.4, 47.7, 47.4, 47.2, 47.1, 46.9, 44.4, 28.7,
28.6, 25.0; IR (neat): .nu..sub.max(cm.sup.-1)=2965 (w), 1643 (s),
1520 (w), 1449 (s), 1418 (s), 1358 (m), 1123 (m), 758 (m), 739 (s);
HRMS (ESI+) calcd for C.sub.34H.sub.39N.sub.3O.sub.4 ([M+H].sup.+)
554.3019. found 554.3019.
Example 19
##STR00041##
[0165] Compound 10:
[0166] General procedure 2 was followed using
31R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), benzoic acid (111 mg, 0.91 mmol) and
(R)-(+)-methylbenzyl isocyanide (119 mg, 123 .mu.l, 0.91 mmol)
giving 10 as a white solid, yield 73%.
[0167] [.alpha.].sub.D.sup.20=-24.0.degree. (c=0.25, MeCN). .sup.1H
NMR (500.2 MHz, CDCl.sub.3): .delta. 7.45-7.19 (m, 11H), 6.24 dd,
J=5.7, 2.9 Hz, 1H), 5.93 dd, J=5.7, 2.9 Hz, 1H), 5.11-5.03 (m, 1H),
4.59 d, J=1.8 Hz, 1H), 3.53-3.49 (m, 1H), 3.40-3.35 (m, 1H),
3.02-2.97 (m, 2H), 2.88-2.81 (m, 1H), 2.77-2.75 (m, 1H), 1.48-1.39
(m, 2H), 1.45 (d, J=7.0 Hz, 2H); .sup.13C NMR (125.8 MHz,
CDCl.sub.3): .delta. 169.8, 169.8, 144.0, 136.4, 134.8, 134.3,
130.0, 128.5, 128.4, 126.9, 126.4, 125.7, 62.0, 51.8, 51.5, 49.0,
47.0, 46.4, 45.5, 44.4, 22.7; IR (neat): .nu..sub.max
(cm.sup.-1)=3302 (w), 3239 (w), 3059 (w), 2665 (w), 2929 (w), 1664
(s), 1559 (s), 1558 (s), 1427 (s), 1248 (m), 1020 (m), 698 (s), 667
(m); HRMS (ESI+) calcd for C.sub.25H.sub.26N.sub.2O.sub.2
([M+H].sup.+) 387.2073. found 387.2067.
Example 20
##STR00042##
[0168] Compound 11:
[0169] General procedure 2 was followed using
31R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), benzoic acid (111 mg, 0.91 mmol) and
(S)-(-)-methylbenzyl isocyanide (119 mg, 123 .mu.l, 0.91 mmol)
giving 11 as a white solid, yield 70%.
[0170] [.alpha.].sub.D.sup.20=-78.6.degree. (c=0.28, MeCN). .sup.1H
NMR (400.1 MHz, CDCl.sub.3): .delta. 7.43-7.16 (m, 11H), 6.24-6.19
(m, 1H), 5.97-5.90 (m, 1H), 5.10-5.01 (m, 1H), 4.52 (bs, 1H),
3.61-3.56 (m, 1H), 3.47-3.44 (m, 1H), 3.09-3.06 (m, 1H), 2.99 (bs,
1H), 2.93-2.87 (m, 1H), 2.80 (bs, 1H), 1.50-1.39 (m, 2H), 1.43 (d,
J=6.8 Hz, 3H); .sup.13C NMR (125.8 MHz, CDCl.sub.3) 170.1, 169.9,
143.3, 136.5, 134.8, 134.4, 130.1, 128.7, 128.5, 127.2, 126.5,
126.1, 62.4, 52.1, 51.6, 49.1, 47.0, 46.5, 45.6, 44.9, 22.4; IR
(neat): .nu..sub.max(cm.sup.-1)=3281 (m), 3281 (m), 2955 (m), 1638
(s), 1528 (s), 1397 (s), 1343 (m), 1227 (m), 1117 (m), 700 (s);
HRMS (ESI+) calcd for C.sub.25H.sub.26N.sub.2O.sub.2 ([M+H].sup.+)
387.2073. found 387.2067.
Example 21
##STR00043##
[0171] Compound 12:
[0172] General procedure 2 was followed using
1R,2S,6R,7S)-4-methyl-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene (6,
93 mg, 0.70 mmol), Fmoc-L-Pro-OH (307 mg, 0.91 mmol) and t-butyl
isocyanide (76 mg, 103 .mu.l, 0.91 mmol). The crude product was
purified by column chromatography (SiO.sub.2, EtOAc (1):
cyclohexane (2)). Simultaneous Fmoc deprotection and saponification
according to literature procedure.sup.4 followed by addition of 1.1
eq. TFA and purification using reversed phase chromatography
(C.sub.18, H.sub.2O (1): EtOH (1)) gave 12 as a colorless solid, in
62% yield over two steps.
[0173] [.alpha.].sub.D.sup.20=-6.8.degree. (c=0.30, MeCN). .sup.1H
NMR (500.2 MHz, DMSO): .delta. 12.43 (bs, 1H), 9.68-9.44 (m, 1H),
8.54 (bs, 1H), 8.19-8.14 (m, 1H), 6.29-6.25 (m, 1H), 6.13 (dd,
J=5.7, 2.9 Hz, 1H), 3.95 (bs, 1H), 3.66-3.59 (m, 1H), 3.37-3.18 (m,
5H), 2.96 (bs, 2H), 2.79-2.73 (m, 1H), 2.50-2.38 (m, 4H), 1.97-1.85
(m, 2H), 1.69-1.57 (m, 2H), 1.46-1.35 (m, 2H); .sup.13C NMR (125.8
MHz, CDCl.sub.3) .delta. 172.7, 171.2, 165.8, 158.1, 157.9, 135.6,
134.8, 117.9, 115.5, 62.9, 58.1, 50.9, 49.6, 49.0, 46.5, 46.4,
45.8, 44.1, 34.6, 33.8, 27.9, 23.6; IR (neat): .nu..sub.max
(cm.sup.-1)=2949 (w), 1640 (s), 1175 (s) 1130 (s), 833 (m), 719
(m); HRMS (ESI+) calcd for C.sub.20H.sub.26F.sub.3N.sub.3O.sub.3
([M+H].sup.+) 347.1845. found 348.1929.
##STR00044##
Example 22
(S)-Methyl 2-cyclohexyl-2-(pyrazine-2-carboxamido)acetate (9)
[0174] Pyrazinecarboxylic acid (2.72 g, 21.9 mmol) was added to a
solution of L-cyclohexylglycine methyl ester (4.13 g, 19.9 mmol) in
CH.sub.2Cl.sub.2 (100 ml) at room temperature under N.sub.2,
forming a white suspension. Triethylamine (6.33 ml, 4.62 g, 45.8
mmol) was added, followed by
benzotriazol-1-yloxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (BOP; 9.69 g, 21.9 mmol), which turned the
reaction mixture from purple to an orange solution. After two days
of stirring at room temperature the reaction mixture was washed two
times with 50 ml saturated Na.sub.2CO.sub.3, followed by the
washing of the aqueous layers with CH.sub.2Cl.sub.2 (2.times.50
ml). The organic layers were collected and dried with MgSO.sub.4,
followed by concentration in vacuo. Purification by silica gel
flash chromatography (c-Hex:EtOAc=2:1 with 0.5% triethylamine)
afforded 9 (5.28 g, 19.03 mmol, 96%) as a yellow oil that
solidified upon standing to give a white solid.
[0175] [.alpha.].sub.D.sup.20=+42.5 (c=1.13, CHCl.sub.3); .sup.1H
NMR (250.13 MHz, CDCl.sub.3) .delta.=9.39 (d, J=1.25 Hz, 1H), 8.76
(d, J=2.5 Hz, 1H), 8.57 (t, J=1.5 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H),
4.74 (dd, J=5.5, 9.3 Hz, 1H), 3.78 (s, 3H), 1.96 (m, 1H), 1.77 (m,
5H), 1.24 (m, 5H); .sup.13C NMR (62.90 MHz, CDCl.sub.3):
.delta.=172.0 (C), 162.8 (C), 147.4 (CH), 144.5 (CH), 144.1 (C),
142.7 (CH), 57.0 (CH), 52.3 (CH.sub.3), 41.2 (CH), 29.7 (CH.sub.2),
28.4 (CH.sub.2), 26.0 (CH.sub.2); IR (neat): .nu..sub.max
(cm.sup.-1)=3374 (m), 2920 (s), 2845 (w), 1740 (s), 1665 (s); HRMS
(ESI, 4500 V): m/z calcd. for
C.sub.14H.sub.19N.sub.3O.sub.3Na.sup.+ ([M+Na].sup.+) 300.1319.
found 300.1319.
Example 23
##STR00045##
[0176] (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid
(10)
[0177] A solution of 1 M NaOH (12 ml, 12 mmol) was added to a
solution of 9 (2.77 g, 10 mmol) in THF (25 ml) at 0.degree. C. MeOH
was added to the formed suspension, to give a clear, colorless
solution. The reaction mixture was stirred overnight at room
temperature, followed by concentration in vacuo. The pH of the
aqueous layer was set on 3.5 with a 1 M KHSO.sub.4 solution and was
extracted with EtOAc (2.times.25 ml). The mixture was dried with
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo, to give 10
(2.49 g, 9.45 mmol, 95%) as a white solid.
[0178] [.alpha.].sub.D.sup.20=+50.9 (c=1.06, CHCl.sub.3); .sup.1H
NMR (250.13 MHz, CDCl.sub.3): .delta.=9.38 (d, J=1.5 Hz, 1H), 8.78
(d, J=2.5 Hz, 1H), 8.58 (dd, J=1.5, 2.5 Hz, 1H), 8.27 (d, J=9.0,
1H), 4.77 (dd, J=4.3, 5.0 Hz, 1H), 2.00 (m, 1H), 1.76 (m, 5H), 1.37
(m, 5H); .sup.13C NMR (62.90 MHz, CDCl.sub.3): .delta.=175.7 (C),
163.0 (C), 147.2 (CH), 144.3 (CH), 144.2 (C), 142.0 (CH), 56.9
(CH), 40.9 (CH), 29.7 (CH.sub.2), 28.1 (CH.sub.2), 25.9 (CH.sub.2);
IR (neat): .nu..sub.max (cm.sup.-1)=3383 (m), 2928 (s), 2852 (w),
1713 (m), 1676 (s), 1518 (s); HRMS (ESI, 4500 V): m/z calcd. For
C.sub.13H.sub.17N.sub.3O.sub.3Na.sup.+ ([M+Na].sup.+) 286.1162.
found 286.1158.
Example 23
##STR00046##
[0179] (S)-methyl
2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)-acetamido)-3,3-dimethylbut-
anoate (11)
[0180] 10 (0.653 g, 4.5 mmol) was added to a solution of H-Tle-OMe
(0.653 g, 4.5 mmol) in DMF (40 ml).
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (EDC-HCl; 0.919
g, 6.75 mmol) was added to this colorless solution followed by
1-hydroxy-7-azabenzotriazole (HOAt; 1.035 g, 5.4 mmol) giving a
bright yellow solution. The reaction mixture was stirred for 3 days
and afterwards concentrated in vacuo. The formed yellow solid was
dissolved in EtOAc, washed with 40 ml saturated aqueous ammonium
chloride solution and 40 ml of saturated aqueous NaHCO.sub.3
solution. The organic layers were collected, dried with MgSO.sub.4
and concentrated in vacuo to give 11 (1.48 g, 3.78 mmol, 84%) as a
white solid.
[0181] [.alpha.].sub.D.sup.20=-2.0 (c=1.0, CHCl.sub.3); .sup.1H NMR
(250.13 MHz, CDCl.sub.3): .delta.=9.39 (d, J=1.5 Hz, 1H), 8.76 (d,
J=2.3 Hz, 1H), 8.55 (dd, J=2.4, 1.8 Hz, 1H), 8.29 (d, J=8.1, 1H),
6.40 (d, J=9.3 Hz, 1H), 4.46 (m, 2H), 3.74 (s, 3H), 1.81 (m, 1H),
1.76 (m, 4H), 1.24 (m, 6H), 0.96 (s, 12H); .sup.13C NMR (62.90 MHz,
CDCl.sub.3): .delta.=171.7 (C), 170.4 (C), 163.0 (C), 147.5 (CH),
144.5 (CH), 144.2 (C), 142.7 (CH), 60.2 (CH.sub.3), 58.4 (CH), 51.9
(CH), 40.5 (CH), 31.7 (C), 29.7 (CH.sub.2), 28.7 (CH.sub.2), 26.6
(CH.sub.3), 25.9 (CH.sub.2); IR (neat): .nu..sub.max
(cm.sup.-1)=3350 (m), 2928 (m), 2853 (w), 1738 (s), 1686 (s), 1640
(s), 1520 (s); HRMS (ESI, 4500 V): m/z calcd. for
C.sub.20H.sub.30N.sub.4O.sub.4Na.sup.+ ([M+Na].sup.+) 413.2159.
found 413.2169.
##STR00047##
Example 24
(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylb-
utanoic acid (2)
[0182] A solution of 1 M NaOH (0.94 ml, 0.94 mmol) was added to a
solution of 11 (0.31 g, 0.78 mmol) in THF (3 ml) at 0.degree. C.
MeOH was added to the formed suspension, to give a clear and
colourless solution. The reaction mixture was stirred overnight at
room temperature, followed by concentration in vacuo. The pH of
this aqueous layer was set to 3.5 with 1 M KHSO.sub.4 and
subsequently extracted with EtOAc (2.times.10 ml). The mixture was
dried with Na.sub.2SO.sub.4, filtered, and concentrated in vacuo,
to give 2 (0.28 g, 0.75 mmol, 95%) as a white solid.
[0183] [.alpha.].sub.D.sup.20=+21.7 (c=1.015, CHCl.sub.3); .sup.1H
NMR (250.13 MHz, CDCl.sub.3): .delta.=9.39 (d, J=1.3 Hz, 1H), 8.77
(d, J=2.5 Hz, 1H), 8.57 (dd, J=1.5, 2.5 Hz, 1H), 8.35 (d, J=9 Hz,
1H), 6.70 (d, J=9.0 Hz, 1H), 4.45 (t, J=8.8 Hz, 1H), 4.42 (d, J=9.2
Hz, 1H), 1.94 (m, 1H), 1.71 (m, 5H), 1.20 (m, 5H), 1.01 (s, 9H);
.sup.13C NMR (62.90 MHz, CDCl.sub.3): .delta.=173.4 (C), 170.5 (C),
163.3 (C), 147.4 (CH), 144.4 (CH), 144.2 (C), 142.8 (CH), 58.4
(CH), 51.9 (CH), 40.4 (CH), 34.7 (C), 29.8 (CH.sub.2), 28.6
(CH.sub.2), 26.6 (CH.sub.3), 25.8 (CH.sub.2); IR (neat):
.nu..sub.max (cm.sup.-1)=3335 (w), 2930 (m), 1726 (m), 1663 (s),
1514 (s); HRMS (ESI, 4500 V): m/z calc. for
C.sub.19H.sub.29N.sub.4O.sub.4Na.sup.+ ([M+Na].sup.+) 399.2003.
found 399.2013.
Example 25
##STR00048##
[0184] (S)-2-formamido-1-pentanol (12)
[0185] (S)-2-amino-1-pentanol (1.00 g, 9.7 mmol) was dissolved in
ethylformate (7.84 ml, 7.19 g, 97 mmol). This reaction mixture was
refluxed at 80.degree. C. for 4 hours, followed by stirring
overnight at room temperature. The colourless solution was
concentrated in vacuo and stirred for 1 hour in a 10 mol %
K.sub.2CO.sub.3 in MeOH (25 ml). Afterwards, the pH was set to 7
with DOWEX 50wx8, followed by filtration and concentration in vacuo
to give 12 (1.26 g, 9.61 mmol, 99%).
[0186] [.alpha.].sub.D.sup.20=-29.6 (c=1.15, CHCl.sub.3); .sup.1H
NMR (250.13 MHz, CDCl.sub.3): .delta.=8.20 (s, 1H), 5.81 (bs, 1H),
4.04 (m, 1H), 2.11 (b, 1H), 1.47 (m, 4H), 0.94 (t, J=7.0 Hz, 3H);
.sup.13C NMR (62.90 MHz, CDCl.sub.3): 161.8 (C), 65.1 (CH.sub.2),
50.6 (CH), 33.2 (CH.sub.2), 19.2 (CH.sub.2), 13.9 (CH.sub.3); IR
(neat): .nu..sub.max (cm.sup.-1)=3248 (s), 2957 (m), 1651 (s), 1528
(m), 1381 (m); HRMS (ESI, 4500 V): m/z calcd. for
C.sub.6H.sub.13NO.sub.2Na.sup.+ ([M+Na].sup.+) 154.0838. found
154.0835.
Example 26
##STR00049##
[0187] (S)-2-formamidopentanal
[0188] (7). Dess-Martin periodinane (5.514 g, 13 mmol) was added to
a solution of (S)-2-formamido-1-pentanol (12, 1.31 g, 10 mmol) in
CH.sub.2Cl.sub.2 (100 ml) at room temperature. The white suspension
was stirred for 2 days and subsequently 35 ml MeOH was added and
stirred for 30 minutes. The resulting suspension was filtrated and
the filtrate was concentrated in vacuo. The crude product was
purified by silica gel flash chromatography (cHex:EtOAc=1:4) to
give 7 (1.08 g, 8.29 mmol, 83%) as a white solid. NMR analysis
indicates that 7 is in equilibrium with its cyclic dimer.
[0189] [.alpha.].sub.D.sup.20=+37.6 (c=0.745, CHCl.sub.3); .sup.1H
NMR assigned to the monomer (250.13 MHz, CDCl.sub.3): .delta.=8.22
(s, 1H), 7.84 (s, 1H), 7.10 (m, 1H), 5.31 (m, 1H), 1.52 (m, 4H),
0.95 (m, 3H); .sup.13C NMR assigned to the monomer (100.61 MHz,
CDCl.sub.3): 198.8 (CH), 161.7 (CH), 57.4 (CH), 30.8 (CH.sub.2),
18.4 (CH.sub.2), 13.7 (CH.sub.3); .sup.1H NMR assigned to the dimer
(400.13 MHz, CDCl.sub.3) 8.22 (s, 2H), 5.26 (m, 2H), 3.72 (m, 2H)
1.52 (m, 8H), 0.95 (m, 6H;) .sup.13C NMR (100.61 MHz, CDCl.sub.3)
assigned to the dimer: 161.7 (CH), 89.8 (CH), 63.1 (CH), 30.8
(CH2), 18.4 (CH2), 13.7 (CH3); IR (neat): .nu..sub.max (cm.sup.-1):
3325 (s), 2959 (s), 1649 (s), 1530 (s), 1381 (m), 1123 (w); HRMS
(ESI, 4500 V): m/z calc. for C.sub.6H.sub.12NO.sub.2.sup.+
([M+H].sup.+) 130.0863. found 130.0858.
[0190] It was noted that the dimer exists as a mixture of
diastereomers.
Example 27
##STR00050##
[0191] (3S)-2-acetoxy-N-cyclopropyl-3-formamidohexanoyl amide
(13)
From 7:
[0192] Aldehyde 7 (0.892 g, 6.91 mmol) was added to a solution of
cyclopropyl isocyanide (0.410 g, 6.12 mmol) in CH.sub.2Cl.sub.2
(110 ml) and stirred for 5 minutes at room temperature. Acetic acid
(0.711 ml, 0.747 g, 12.44 mmol) was added and the yellow reaction
mixture was stirred for 3 days at room temperature. The reaction
mixture was washed twice with 100 ml saturated Na.sub.2CO.sub.3,
followed by drying with Na.sub.2SO.sub.4 and concentration in
vacuo. The crude was purified by silica gel flash chromatography
(5% MeOH in CH.sub.2Cl.sub.2, 1% triethylamine).
(3S)-2-acetoxy-N-cyclopropyl-3-formamidohexanoyl amide (0.99 g,
3.87 mmol, 56%) was obtained as a white solid as a 78:22 mixture of
diastereomers.
From 12:
[0193] Dess Martin periodinane (5.66 g, 12.3 mmol) was added to a
solution of (S)--N-(1 hydroxypentan-2-yl)formamide (1.15 g, 8.8
mmol) in CH.sub.2Cl.sub.2 (12 ml) at room temperature. The white
suspension was stirred for 60 minutes and subsequently cyclopropyl
isocyanide (0.74 g, 10.0 mmol) was added and stirred for 48 hours.
The resulting suspension was filtrated and washed twice with 10 ml
saturated Na.sub.2CO.sub.3, followed by drying with
Na.sub.2SO.sub.4 and concentration in vacuo. The crude product was
purified by silica gel flash chromatography (5% MeOH in
CH.sub.2Cl.sub.2, 1% triethylamine) to give 13 (1.34 g, 5.22 mmol,
60%) as a pale yellow solid as a 78:22 mixture of
diastereomers.
[0194] .sup.1H NMR (130.degree. C., 400.13 MHz, DMSO-d.sub.6):
.delta.=8.03 (s, 1H), 7.52 (m, 1H), 7.30 (m, 1H), 4.89 (d, J=4.4,
1H), 4.28 (m, 1H), 2.65 (m, 1H), 2.17 (s, 3H), 1.27-1.47 (m, 4H),
0.89 (t, J=7.2, 3H), 0.63 (m, 2H), 0.48 (m, 2H); .sup.13C NMR
(125.78 MHz, DMSO-d.sub.6): .delta.=169.8 (C), 168.5 (C), 160.6
(CH), 74.4 (CH), 47.5 (CH), 22.2 (CH), 18.4 (CH.sub.3), 13.6
(CH.sub.3), 5.7 (CH.sub.2); IR (neat): .nu..sub.max (cm.sup.-1)
3283 (s), 2961 (w), 1744 (m), 1661 (s), 1530 (s), 1238 (s); HRMS
(ESI, 4500 V): m/z calcd. for
C.sub.12H.sub.20N.sub.2O.sub.4Na.sup.+ ([M+Na].sup.+) 279.1315.
found 279.1325.
Example 28
##STR00051##
[0195] (3S)-2-acetoxy-N-cyclopropyl-3-isocyano-hexanoyl amide
(4)
[0196] N-methylmorpholine (0.57 ml, 0.562 g, 5.56 mmol) was added
to a solution of
(S)-1-(cyclopropylamino)-3-formamido-1-oxohexan-2-yl acetate (0.713
g, 2.78 mmol) in CH.sub.2Cl.sub.2 (40 ml) at room temperature. The
reaction mixture was cooled to -78.degree. C. and triphosgene
(0.289 g, 0.97 mmol) was quickly added and stirred for 5 minutes at
this temperature. The resulting yellow solution was warmed up to
-30.degree. C. and was stirred for another 3 h. Subsequently, the
reaction was quenched with water and extracted twice with
CH.sub.2Cl.sub.2 (40 ml). The organic layers were collected, dried
with Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product
was purified by silica gel flash chromatography (2% MeOH in
CH.sub.2Cl.sub.2) to give 4 (0.578 g, 2.42 mmol, 87%) as a white
solid.
[0197] .sup.1H NMR (250.13 MHz, CDCl.sub.3): .delta.=6.28 (s, 1H),
5.25 (d, J=2.5 Hz, 1H), 4.2 (m, 1H), 2.74 (m, 1H), 2.24 (s, 3H),
1.55 (m, 4H), 0.96 (m, 3H), 0.84 (m, 2H), 0.60 (m, 2H); .sup.13C
NMR (62.90 MHz, CDCl.sub.3): .delta.=169.7 (C), 168.3 (C), 74.4
(CH), 47.5 (CH), 22.0 (CH), 20.6 (CH.sub.3), 18.5 (CH.sub.2), 13.5
(CH.sub.3), 5.5 (CH.sub.2); IR (neat): .nu..sub.max (cm.sup.-1):
3267 (s), 2959 (m), 1745 (m), 1643 (s), 1512 (m), 1221 (s); HRMS
(ESI, 4500 V): m/z calcd. for
C.sub.12H.sub.18N.sub.2O.sub.3Na.sup.+ ([M+Na].sup.+) 261.1210.
found 261.1214.
Example 29
##STR00052##
[0198] Compound 14.
[0199] Isocyanide 4 (0.549 g, 2.3 mmol) was dropwise added to a
solution of imine 3 (0.252 g, 2.3 mmol) and carboxylic acid 2
(0.602 g, 1.60 mmol) in CH.sub.2Cl.sub.2 (5 ml) at room
temperature. This yellow solution was stirred for 72 hours and
afterwards diluted with 5 ml CH.sub.2Cl.sub.2. The reaction mixture
was washed twice with saturated Na.sub.2CO.sub.3 solution (10 ml)
and twice with saturated NH.sub.4Cl. The organic layers were
collected, dried with MgSO.sub.4 and concentrated in vacuo. The
crude product was purified by silica gel flash chromatography (5%
MeOH in CH.sub.2Cl.sub.2) to give 14 (0.876 g, 1.21 mmol, 76%) as a
mixture of diastereomers.
[0200] .sup.1H NMR (500.23 MHz, CDCl.sub.3): .delta.=9.50 (s, 1H),
8.75 (d, J=2.5, 1H), 8.59 (s, 1H), 8.35 (d, J=9.0, 1H), 6.84 (d,
J=9.0, 1H), 6.44 (s, 1H), 5.20 (d, J=3.0, 1H), 4.74 (d, J=9.5, 1H),
4.58 (t, J=7.5, 1H), 4.38 (m, 1H), 3.37 (d, J=6.0, 1H), 2.82 (m,
1H), 2.69 (m, 1H), 2.11 (s, 3H), 1.26 (s, 2H), 0.97 (s, 9H), 0.86
(m, 3H), 0.84-2.00 (m, 21H), 0.76 (m, 2H), 0.51 (m, 2H); .sup.13C
NMR (125.78 MHz, CDCl.sub.3): .delta.=170.5 (C), 169.3 (C), 162.9
(C), 147.4 (CH), 144.6 (CH), 144.2 (C), 142.8 (CH), 74.4 (CH), 66.6
(CH), 58.3 (CH), 56.6 (CH), 54.5 (CH.sub.2), 44.9 (CH), 43.0 (CH),
41.3 (CH), 35.5 (C), 26.4 (CH.sub.3), 20.8 (CH.sub.3), 19.1
(CH.sub.2), 13.8 (CH.sub.3), 6.6 (CH.sub.2); .nu..sub.max
(cm.sup.-1): 3306 (m), 2928 (m), 2931 (m), 1743 (w), 1655 (s), 1520
(m), 1219 (m); HRMS (ESI, 4500 V): m/z calcd. for
C.sub.38H.sub.57N.sub.7O.sub.7Na.sup.+ ([M+Na].sup.+) 746.4212.
found 746.4107.
Example 30
##STR00053##
[0201] Telaprevir (1).
[0202] 250 .mu.l of saturated K.sub.2CO.sub.3 was added to a
solution of 14 (0.514 g, 0.75 mmol) in MeOH (20 ml) at room
temperature. The reaction mixture was stirred for 30 minutes at
room temperature resulting in a pale yellow suspension. After full
conversion (as judged by TLC analysis), the reaction mixture was
washed with 20 ml brine, the aqueous layer was washed again with 10
ml CH.sub.2Cl.sub.2 (2.times.). The organic layers were collected,
dried with MgSO.sub.4 and concentrated in vacuo, to yield a pale
yellow solid. The yellow solid was dissolved in CH.sub.2Cl.sub.2
(10 ml) and Dess-Martin periodinane (0.650 g, 1.532 mmol) was added
at room temperature. The reaction mixture was stirred overnight
before adding saturated NaHCO.sub.3 solution (10 ml) and saturated
Na.sub.2S.sub.2O.sub.3 solution (10 ml). This mixture was stirred
for 10 minutes, separated and the aqueous layers were washed with
EtOAc (2.times.10 ml). The organic layers were collected, dried
with MgSO.sub.4 and concentrated in vacuo to give the crude product
as an 83:13:4 mixture of diastereomers. After silica gel flash
chromatography (1% MeOH in CH.sub.2Cl.sub.2), 1 (0.412 mg, 0.61
mmol, 80%) was obtained as a white solid.
[0203] .sup.1H NMR (500.23 MHz, DMSO-d.sub.6): .delta.=9.19 (d,
J=1.4 Hz, 1H), 8.91 (d, J=24.5 Hz, 1H), 8.76 (dd, J=1.5, 2.5 Hz,
1H), 8.71 (d, J=5.3 Hz, 1H), 8.49 (d, J=9.2 Hz, 1H), 8.25 (d, J=6.8
Hz, 1H), 8.21 (d, J=8.9 Hz, 1H), 4.94 (m, 1H), 4.68 (dd, J=6.5, 9.0
Hz, 1H), 4.53 (d, J=9.0 Hz, 1H), 4.27 (d, J=3.5 Hz, 1H), 3.74 (dd,
J=8.0, 10 Hz, 1H), 2.74 (m, 1H), 3.64 (d, J=3.5 Hz, 1H), 0.92 (s,
9H), 0.87 (t, 3H), 0.84-1.40 (m, 23H), 0.65 (m, 2H), 0.56 (m, 2H);
.sup.13C NMR (125.78 MHz, CDCl.sub.3): .delta.=197.0 (C), 171.8
(C), 170.4 (C), 169.0 (C), 162.1 (C), 161.9 (C), 147.9 (CH), 144.0
(C), 143.4 (CH), 56.4 (CH), 56.3 (CH), 54.2 (CH), 53.4 (CH), 42.3
(CH), 41.3 (CH), 32.1 (CH), 31.8 (CH), 31.6 (CH), 29.1 (CH), 28.0
(CH), 26.4 (CH.sub.3); .nu..sub.max (cm.sup.-1): 3302 (m), 2928
(m), 2858 (w), 1658 (s), 1620 (s), 1561 (s), 1442 (m); HRMS (ESI,
4500 V): m/z calcd. for C.sub.36H.sub.53N.sub.7O.sub.6Na.sup.+
([M+Na].sup.+) 702.3950. found 702.3941.
REFERENCES
[0204] 1. S. Michaelis, S. Blechert, Chem. Eur. J. 2007, 13,
2358-2368 [0205] 2. V. Kohler, K. R. Bailey, A. Znabet, J. Raftery,
M. Helliwell, N. J. Turner, Angew. Chem. Int. Ed. 2010, 49,
2182-2184. [0206] 3. N. Elders, E. Ruijter, F. J. J. de Kanter, E.
Janssen, M. Lutz, A. L. Spek, R. V. A. Orru Chem. Eur. J. 2009,
6096-6099. [0207] 4. V. Theodorou, K. Skobridis, A. G. Tzakos, V.
Ragoussis Tetrahedron Lett. 2007, 48, 8230-8233.
[0208] While the present invention has been described with
reference to specific preferred embodiments, it should be
appreciated that variations are possible without departing from the
scope of the invention. Therefore, the invention is not intended to
be limited by the description in the specification but only by the
language of the claims and equivalents thereof.
* * * * *