U.S. patent application number 14/628333 was filed with the patent office on 2015-08-27 for process for preparing morphine compounds.
This patent application is currently assigned to Brock University. The applicant listed for this patent is Tomas Hudlicky, Vimal Varghese. Invention is credited to Tomas Hudlicky, Vimal Varghese.
Application Number | 20150239860 14/628333 |
Document ID | / |
Family ID | 53881574 |
Filed Date | 2015-08-27 |
United States Patent
Application |
20150239860 |
Kind Code |
A1 |
Varghese; Vimal ; et
al. |
August 27, 2015 |
PROCESS FOR PREPARING MORPHINE COMPOUNDS
Abstract
The present application relates to processes for the preparation
of morphine compounds utilizing a novel intramolecular [4+2]
cycloaddition reaction.
Inventors: |
Varghese; Vimal; (St.
Catharines, CA) ; Hudlicky; Tomas; (St. Catharines,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Varghese; Vimal
Hudlicky; Tomas |
St. Catharines
St. Catharines |
|
CA
CA |
|
|
Assignee: |
Brock University
St. Catharines
CA
|
Family ID: |
53881574 |
Appl. No.: |
14/628333 |
Filed: |
February 23, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61943556 |
Feb 24, 2014 |
|
|
|
Current U.S.
Class: |
549/457 |
Current CPC
Class: |
C07D 307/77 20130101;
C07F 7/1804 20130101 |
International
Class: |
C07D 307/77 20060101
C07D307/77; C07F 7/18 20060101 C07F007/18 |
Claims
1. A process for the preparation of a compound of Formula I
comprising treating a compound of Formula II under [4+2]
intramolecular cycloaddition conditions: ##STR00032## wherein:
represents a single or double bond; Z is O when Z represents a
double bond and Z is OPG.sup.1 when Z represents a single bond; OR
represents a leaving group; at least one of Y and X is NMePG.sup.2
and the other is LG, or Y is H and X is NMePG.sup.2; PG.sup.1 and
PG.sup.2 are, independently, protecting groups; and LG is a leaving
group, and one or more available hydrogens in the compounds of
Formulae I and II is/are optionally replaced with F and/or one or
more of available atoms in the compounds of Formulae I and II
is/are optionally replaced with an isotopic label.
2. The process of claim 1, wherein the compound of Formula II is
prepared by converting a compound of Formula III into a compound of
Formula II by oxidative dearomatization: ##STR00033## wherein , X,
Y, Z and OR are as defined in claim 1.
3. The process of claim 2, wherein the compound of the Formula III
is prepared by reacting a compound of the Formula IV with a
compound of the Formula V under Mitsunobu reaction conditions to
provide a compound of the Formula VI followed by Wittig
homologation of the CHO group and removal of PG.sup.3: ##STR00034##
wherein , X, Y and Z are as defined in claim 1; and PG.sup.3 is a
protecting group.
4. The process of claim 3, wherein the Wittig homologation of the
CHO group is performed by reacting a compound of the Formula VI
with a Wittig reagent of the Formula VII: ##STR00035## wherein Y is
as defined in claim 1; and [A.sup.-] is a suitable counteranion
under Wittig reaction conditions.
5. The process of claim 2, wherein the compound of the Formula III
wherein Y is H is prepared by Wittig homologation of the CHO group
in a compound of Formula X to provide a compound of Formula XI,
followed by selective removal of PG.sup.5 to provide a compound of
Formula XII, then reacting the compound of Formula XII with a
compound of Formula V under Mitsunobu reaction conditions and
removal of PG.sup.4: ##STR00036## wherein: , X, Y and Z are as
defined in claim 1; and PG.sup.4 and PG.sup.5 are protecting groups
that are removable under different conditions.
6. The process of claim 5, wherein the Wittig homologation of the
CHO group is performed by reacting a compound of the Formula X with
a Wittig reagent of the Formula VII: ##STR00037## wherein Y is as
defined in claim 1; and [A.sup.-] is a suitable counteranion under
Wittig reaction conditions.
7. The process of claim 1, wherein Z and CC both represent single
bonds and Z is OPG.sup.1.
8. The process of claim 1, wherein Y is H and X is NMePG.sup.2.
9. The process of claim 3, wherein X is NMePG.sup.2 or LG, Z is O,
Z is a double bond and CC is a single bond and the compound of
Formula V is prepared by treating a compound of the Formula VIII
under Birch reduction conditions to provide a compound of the
Formula IX and treating the compound of the Formula IX under Davis
hydroxylation conditions to provide the compound of the Formula V,
wherein X is NMePG.sup.2 or LG, Z is O, Z is a double bond and CC
is a single bond: ##STR00038##
10. The process of claim 1, wherein X is LG and Y is
NMePG.sup.2.
11. The process of claim 1, wherein the stereochemistry of the
compound of Formula II is selected so that the compound of Formula
I has the same stereochemistry as that found in hydromorphone.
12. The process of claim 1, wherein the stereochemistry of the
compound of Formula II is selected so that the compound of Formula
I has the same stereochemistry as that found in ent-hydromorphone.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of priority from
co-pending U.S. provisional application No. 61/943,556 filed on
Feb. 24, 2014, the contents of which are incorporated herein by
reference in their entirety.
FIELD
[0002] The present application relates to processes for the
preparation of morphine compounds. In particular, the present
application relates to a novel process for forming the morphine
skeleton using a [4+2] intramolecular cycloaddition reaction.
BACKGROUND
[0003] A truly practical synthesis of morphine and congeners has
not yet appeared in spite of focused effort and many creative
approaches having been published..sup.1
SUMMARY
[0004] In one embodiment, the present application includes a
process for the preparation of a compound of Formula I comprising
treating a compound of Formula II under [4+2] intramolecular
cycloaddition conditions:
##STR00001##
wherein: represents a single or double bond; Z is O when Z
represents a double bond and Z is OPG.sup.1 when Z represents a
single bond; OR represents a leaving group; at least one of Y and X
is NMePG.sup.2 and the other is LG,
or Y is H and X is NMePG.sup.2;
[0005] PG.sup.1 and PG.sup.2 are, independently, protecting groups;
and LG is a leaving group, and one or more available hydrogens in
the compounds of Formulae I and II is/are optionally replaced with
F and/or one or more of available atoms in the compounds of
Formulae I and II is/are optionally replaced with an isotopic
label.
[0006] Processes for preparing compounds of Formula II, and
precursors thereof, are described and included in the present
application, as well as the conversion of the compounds of Formula
I into various morphine compounds.
[0007] It has been demonstrated that the process of the present
application is enantiodivergent. For example, an enantiomer of
hydromorphone (ent-hydromorphone) has been made and the other
enantiomer is readily available using the same process.
[0008] The present application also includes any of the novel
compounds disclosed herein. In particular, the present application
includes compounds 5, 6, 17, 18, 19a, 19b, 20, 21, 23, 24, 25 and
26 as shown in Schemes 1 and 4 hereinbelow.
[0009] Other features and advantages of the present application
will become apparent from the following detailed description. It
should be understood, however, that the detailed description and
the specific examples while indicating embodiments of the
application are given by way of illustration only and the scope of
the claims should not be limited by the embodiments set forth in
the examples, but should be given the broadest interpretation
consistent with the description as a whole.
DETAILED DESCRIPTION
I. Definitions
[0010] Unless otherwise indicated, the definitions and embodiments
described in this and other sections are intended to be applicable
to all embodiments and aspects of the present application herein
described for which they are suitable as would be understood by a
person skilled in the art.
[0011] In understanding the scope of the present application, the
term "comprising" and its derivatives, as used herein, are intended
to be open ended terms that specify the presence of the stated
features, elements, components, groups, integers, and/or steps, but
do not exclude the presence of other unstated features, elements,
components, groups, integers and/or steps. The foregoing also
applies to words having similar meanings such as the terms
"including", "having" and their derivatives. The term "consisting"
and its derivatives, as used herein, are intended to be closed
terms that specify the presence of the stated features, elements,
components, groups, integers, and/or steps, but exclude the
presence of other unstated features, elements, components, groups,
integers and/or steps. The term "consisting essentially of", as
used herein, is intended to specify the presence of the stated
features, elements, components, groups, integers, and/or steps as
well as those that do not materially affect the basic and novel
characteristic(s) of features, elements, components, groups,
integers, and/or steps.
[0012] The term "suitable" as used herein means that the selection
of the particular compound or conditions would depend on the
specific synthetic manipulation to be performed, and the identity
of the molecule(s) to be transformed, but the selection would be
well within the skill of a person trained in the art. All
process/method steps described herein are to be conducted under
conditions for the reaction to proceed to a sufficient extent to
provide the product shown. A person skilled in the art would
understand that all reaction conditions, including, for example,
reaction solvent, reaction time, reaction temperature, reaction
pressure, reactant ratio and whether or not the reaction should be
performed under an anhydrous or inert atmosphere, can be varied to
optimize the yield of the desired product and it is within their
skill to do so.
[0013] The expression "proceed to a sufficient extent" as used
herein with reference to the reactions or process/method steps
disclosed herein means that the reactions or process/method steps
proceed to an extent that conversion of the starting material or
substrate to product is maximized. Conversion may be maximized when
greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95 or 100% of the starting material or
substrate is converted to product.
[0014] Terms of degree such as "substantially", "about" and
"approximately" as used herein mean a reasonable amount of
deviation of the modified term such that the end result is not
significantly changed. These terms of degree should be construed as
including a deviation of at least .+-.5% of the modified term if
this deviation would not negate the meaning of the word it
modifies.
[0015] As used in this application, the singular forms "a", "an"
and "the" include plural references unless the content clearly
dictates otherwise. For example, an embodiment including "a
compound" should be understood to present certain aspects with one
compound or two or more additional compounds.
[0016] In embodiments comprising an "additional" or "second"
component, such as an additional or second compound, the second
component as used herein is chemically different from the other
components or first component. A "third" component is different
from the other, first, and second components, and further
enumerated or "additional" components are similarly different.
[0017] In embodiments of the present application, the compounds in
the processes/methods described herein have at least one asymmetric
center. Where compounds possess more than one asymmetric center,
they may exist as diastereomers. It is to be understood that all
such isomers and mixtures thereof in any proportion are encompassed
within the scope of the processes/methods of the present
application. It is to be further understood that while the
stereochemistry of the compounds in the processes/methods may be as
shown in any given compound listed herein, such compounds may also
contain certain amounts (e.g. less than 20%, suitably less than
10%, more suitably less than 5%) of compounds having alternate
stereochemistry.
[0018] The term "protecting" as used herein refers to using a
chemical moiety, i.e. a "protecting group" of "PG" which protects
or masks a reactive portion of a molecule to prevent side reactions
in that reactive portion of the molecule, while manipulating or
reacting a different portion of the molecule. After the
manipulation or reaction is complete, the protecting group is
removed under conditions that do not degrade or decompose the
remaining portions of the molecule; i.e. the protected reactive
portion of the molecule is "deprotected". The selection of a
suitable protecting group can be made by a person skilled in the
art. Many conventional protecting groups are known in the art, for
example as described in "Protective Groups in Organic Chemistry"
McOmie, J. F. W. Ed., Plenum Press, 1973, in Greene, T. W. and
Wuts, P. G. M., "Protective Groups in Organic Synthesis", John
Wiley & Sons, 3.sup.rd Edition, 1999 and in Kocienski, P.
Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The
Americas). Examples of suitable protecting groups include, but are
not limited to t-Boc, C.sub.1-6acyl, Ac, Ts, Ms, silyl ethers such
as TMS, TBDMS, TBDPS, Tf, Ns, Bn, Fmoc, dimethoxytrityl,
methoxyethoxymethyl ether, methoxymethyl ether, pivaloyl,
p-methyoxybenzyl ether, tetrahydropyranyl, trityl, ethoxyethyl
ethers, carbobenzyloxy, benzoyl and the like.
[0019] The term "leaving group" or "LG" as used herein refers to a
group that is readily displaceable by a nucleophile, for example,
under nucleophilic substitution reaction conditions. Examples of
suitable leaving groups include, but are not limited to, halo, OMs,
OTs, ONs, OTf, OC.sub.1-6acyl, and the like, including isotopically
labeled versions thereof
[0020] The term "acyl" as used herein, whether it is used alone or
as part of another group, means straight or branched chain,
saturated acyl groups. The number of carbon atoms that are possible
in the referenced acyl group are indicated by the numerical prefix
"C.sub.n1-n2". For example, the term C.sub.1-6acyl means an acyl
group having 1, 2, 3, 4, 5 or 6 carbon atoms.
[0021] The term "halo" as used herein refers to a halogen atom and
includes F, Cl, Br and I.
[0022] The term "oxidizing agent" as used herein means any compound
or combination of compounds that oxidizes a desired functional
group(s) but does not otherwise react with or degrade the substrate
comprising the functional group(s). An oxidizing agent results in
the overall loss of electrons, or in the case of organic chemistry,
hydrogen atoms from the functional group.
[0023] The term "reducing agent" as used herein means any compound
or combination of compounds that reduces a desired functional
group(s) but does not otherwise react with or degrade the substrate
comprising the functional group(s). A reducing agent results in the
overall gain of electrons, or in the case of organic chemistry,
hydrogen atoms to the functional group. It is an embodiment of the
application that the reducing agent is a metal hydride reducing
agent.
[0024] The term "inert solvent" as used herein means a solvent that
does not interfere with or otherwise inhibit a reaction.
Accordingly, the identity of the inert solvent will vary depending
on the reaction being performed. The selection of inert solvent is
within the skill of a person in the art. Examples of inert solvents
include, but are not limited to, benzene, toluene, tetrahydrofuran,
ethyl ether, ethyl acetate, dimethyl formamide (DMF), acetonitrile,
C.sub.1-6alkylOH (e.g. methanol, ethanol, n-propanol, 2-propanol,
n-butanol, butan-2-ol and 2-methyl-1-propanol), diethylcarbonate,
hexane and dimethylslfoxide (DMSO) including isotopically labeled
versions thereof. Further examples can include aqueous solutions,
such as water and dilute acids and bases, and ionic liquids,
provided that such solvents do not interfere with the reaction.
[0025] The term "alkyl" as used herein, whether it is used alone or
as part of another group, means straight or branched chain,
saturated alkyl groups. The number of carbon atoms that are
possible in the referenced alkyl group are indicated by the
numerical prefix "C.sub.n1-n2". For example, the term
C.sub.1-6alkyl means an alkyl group having 1, 2, 3, 4, 5 or 6
carbon atoms.
[0026] The term "solvent" includes both a single solvent and a
mixture comprising two or more solvents.
[0027] The term "available", as in "available hydrogen atoms" or
"available atoms" refers to atoms that would be known to a person
skilled in the art to be capable of replacement by either a
fluorine atom (in the case of hydrogen atoms) or isotopic labels
(in the case of all atoms) using methods known in the art.
[0028] The term "counteranion" as used herein refers to a
negatively charged species consisting of a single element, or a
negatively charged species consisting of a group of elements
connected by ionic and/or covalent bonds.
[0029] t-Boc as used herein refers to the group
t-butyloxycarbonyl.
[0030] Ac as used herein refers to the group acetyl.
[0031] Ts (tosyl) as used herein refers to the group
p-toluenesulfonyl.
[0032] Ms as used herein refers to the group methanesulfonyl.
[0033] TBDMS as used herein refers to the group
t-butyldimethylsilyl.
[0034] TBDPS as used herein refers to the group
t-butyldiphenylsilyl.
[0035] TMS as used herein refers to the group trimethylsilyl.
[0036] Tf as used herein refers to the group
trifluoromethanesulfonyl.
[0037] Ns as used herein refers to the group naphthalene
sulphonyl.
[0038] Bn as used herein refers to the group benzyl.
[0039] Fmoc as used herein refers to the group
fluorenylmethoxycarbonyl.
[0040] The term "morphine compound" as used herein refers to a
compound containing the 5 ring morphine skeleton as follows:
##STR00002##
with optional substituents on one or more of the ring atoms and
optional double bonds in ring C. In an embodiment, the morphine
compound is ent-hydromorphone or hydromorphone.
[0041] The term "oripavine" as used herein refers to a compound of
the following formula:
##STR00003##
[0042] The term "hydromorphone" as used herein refers to a compound
of the following formula:
##STR00004##
[0043] The term "ent-hydromorphone" as used herein refers to a
compound of the following formula:
##STR00005##
[0044] The term "thebaine" as used herein refers to a compound of
the following formula:
##STR00006##
[0045] The term "morphine" as used herein refers to a compound of
the following formula:
##STR00007##
II. Processes
[0046] In the present application a strategy to construct the
morphine skeleton by an intramolecular [4+2] cycloaddition reaction
is reported. A schematic of a representative example of the overall
strategy as it applies to the preparation of hydromorphine and
ent-hydromorphine is shown in Scheme 1:
##STR00008##
[0047] Therefore, in one embodiment, the present application
includes a process for the preparation of a compound of Formula I
comprising treating a compound of Formula II under [4+2]
intramolecular cycloaddition conditions:
##STR00009##
wherein: represents a single or double bond; Z is O when Z
represents a double bond and Z is OPG.sup.1 when Z represents a
single bond; OR represents a leaving group; at least one of Y and X
is NMePG.sup.2 and the other is LG,
or Y is H and X is NMePG.sup.2;
[0048] PG.sup.1 and PG.sup.2 are, independently, protecting groups;
and LG is a leaving group, and one or more available hydrogens in
the compounds of Formulae I and II is/are optionally replaced with
F and/or one or more of available atoms in the compounds of
Formulae I and II is/are optionally replaced with an isotopic
label.
[0049] In an embodiment, the compound of Formula II is derived from
the corresponding phenol by oxidative dearomatization using, for
example, lead tetraacetate (Pb(OAc).sub.4), diacetoxyiodobenzene
(DAIB), bis trifluoroacetoxyiodo benzene (PIFA) or Dess-Martin
periodinane. In another embodiment, the oxidative dearomatization
comprises electrochemical anodic oxidation. The selection of
suitable conditions for electrochemical anodic oxidation can be
made by a person skilled in the art.
[0050] Accordingly, in a further embodiment, the present
application includes a process of preparing a compound of Formula I
comprising converting a compound of Formula III into a compound of
Formula II by oxidative dearomatization followed by treating the
compound of Formula II under [4+2] intramolecular cycloaddition
conditions to provide the compound of Formula I:
##STR00010##
wherein: represents a single or double bond; Z is O when Z
represents a double bond and Z is OPG.sup.1 when Z represents a
single bond; OR represents a leaving group; at least one of Y and X
is NMePG.sup.2 and the other is LG,
or Y is H and X is NMePG.sup.2;
[0051] PG.sup.1 and PG.sup.2 are, independently, protecting groups;
and LG is a leaving group, and one or more available hydrogens in
the compounds of Formulae I-III is/are optionally replaced with F
and/or one or more of available atoms in the compounds of Formulae
I-III is/are optionally replaced with an isotopic label.
[0052] In an embodiment, the compound of Formula III is available
by reacting a compound of the Formula IV with a compound of the
Formula V under Mitsunobu reaction conditions to provide a compound
of the Formula VI followed by Wittig homologation of the CHO group
and removal of PG.sup.3:
##STR00011##
wherein: represents a single or double bond; Z is O when Z
represents a double bond and Z is OPG.sup.1 when Z represents a
single bond; at least one of Y and X is NMePG.sup.2 and the other
is LG,
or Y is H and X is NMePG.sup.2;
[0053] PG.sup.1, PG.sup.2 and PG.sup.3 are, independently,
protecting groups; and LG is a leaving group, and one or more
available hydrogens in the compounds of Formulae III-VI is/are
optionally replaced with F and/or one or more of available atoms in
the compounds of Formulae III-VI is/are optionally replaced with an
isotopic label.
[0054] In an embodiment, the Wittig homologation of CHO in the
compound of Formula VI is performed by reacting a compound of the
Formula VI with a Wittig reagent, for example, a compound of the
Formula VII:
##STR00012##
wherein A- is a suitable counteranion and Y is as defined above,
under Wittig reaction conditions.
[0055] In another embodiment, the compound of the Formula III
wherein Y is H is prepared by Wittig homologation of the CHO group
in a compound of Formula X to provide a compound of Formula XI,
followed by selective removal of PG.sup.5 to provide a compound of
Formula XII, then reacting the compound of Formula XII with a
compound of Formula V under Mitsunobu reaction conditions and
removal of PG.sup.4:
##STR00013##
wherein: represents a single or double bond; Z is O when Z
represents a double bond and Z is OPG.sup.1 when Z represents a
single bond; at least one of Y and X is NMePG.sup.2 and the other
is LG,
or Y is H and X is NMePG.sup.2; and
[0056] PG.sup.2, PG.sup.4 and PG.sup.5 are, independently,
protecting groups, wherein PG.sup.4 and PG.sup.5 are protecting
groups that are removable under different conditions.
[0057] In an embodiment, the Wittig homologation of CHO in the
compound of Formula X is performed by reacting a compound of the
Formula X with a Wittig reagent, for example, a compound of the
Formula VII:
##STR00014##
wherein A- is a suitable counteranion and Y is as defined above,
under Wittig reaction conditions.
[0058] Compounds of the Formula V, when X is NMePG.sup.2, Z is
OPG.sup.1 and Z and CC are both single bonds, are available, for
example, using methods known in the art, for example from
(2-bromoethyl)benzene as described in the literature.sup.4,5 and as
shown in Scheme 3 below. Alternatively, compounds of the Formula V,
when Z is O, Z is a double bond and CC is a single bond, are
prepared, for example, by the Birch reduction of a compound of the
Formula VIII to provide a compound of the Formula IX, wherein X is
as defined above. A Davis hydroxylation, which can be performed
asymmetrically to provide either enantiomer, is then used to
convert the compound of the Formula IX into the compound of the
Formula V. The present application therefore also includes a
process for preparing a compound of the Formula V, wherein X is
NMePG.sup.2 or LG, Z is O, Z is a double bond and CC is a single
bond comprising treating a compound of the Formula VIII under Birch
reduction conditions to provide a compound of the Formula IX and
treating the compound of the Formula IX under Davis hydroxylation
conditions to provide the compound of the Formula V, wherein X is
NMePG.sup.2 or LG, Z is O, Z is a double bond and CC is a single
bond:
##STR00015##
[0059] Compounds of the Formula IV, are known and are prepared, for
example, from 3,4-dihydroxylbenzaldyde as described in the
literature.sup.2 and as shown in Scheme 2 below.
[0060] Compounds of the Formula VII, VIII and X are either known in
the art or are prepared using methods known in the art.
[0061] In an embodiment, Z and CC both represent single bonds.
Therefore, in an embodiment, Z is OPG.sup.1.
[0062] In an embodiment, Y is H and X is NMePG.sup.2.
[0063] In another embodiment, X is LG and Y is NMePG.sup.2.
[0064] In an embodiment, OR is OAc.
[0065] In an embodiment, the stereochemistry of the compounds of
Formula II-XII is selected so that the compound of Formula I has
the same stereochemistry as that found in hydromorphone. In an
embodiment, the stereochemistry of the compounds of Formula II-XII
is selected so that the compound of Formula I has the same
stereochemistry as that found in ent-hydromorphone.
[0066] In an embodiment, the intramolecular cycloaddition
conditions comprise heating a substrate, i.e. a compound comprising
a diene and a dienophile such as a compound of Formula II, in an
inert organic solvent, optionally in the presence of a
catalyst.
[0067] In a further embodiment, oxidative dearomatization
conditions comprise treating an appropriate aromatic substrate with
a suitable oxidizing agent, such as Pb(OAc).sub.4,
diacetoxyiodobenzene (DAIB), bis trifluoroacetoxyiodo benzene
(PIFA) or Dess-Martin periodinane, in an inert organic solvent,
optionally with heating. In a further embodiment, the oxidative
dearomatization to provide the compounds of Formula II and
intramolecular cycloaddition are performed in a single step,
wherein the compound of Formula II is formed in situ and converted,
under the oxidative dearomatization conditions to a compound of the
Formula I. In an embodiment, the oxidizing agent is
Pb(OAc).sub.4.
[0068] In an embodiment, the Mitsunobu reaction conditions comprise
treating the substrates in the presence of a trialkylphosphine, or
a triarylphosphone, and an azodicarboxylate, such as
tetramethylazodicarboxamide (TMAD), diethylazodicarboxylate (DEAD)
or diisopropylazodicarboxylate (DIAD) in an inert organic solvent.
The reaction conditions optionally comprise heating or cooling
depending on the substrates as would be known to a person skilled
in the art.
[0069] In an embodiment, Wittig homologation refers to the
conversion of an aldehyde to the next higher homolog (i.e. addition
of one methylene unit) using Wittig reaction conditions.
[0070] In an embodiment, Wittig reaction conditions comprise
reaction of an aldehyde-containing substrate with a Wittig reagent,
for example a compound of the Formula VII as defined above at low
temperature (for example, -50.degree. C. to -100.degree. C.) in an
inert organic solvent, followed by warming to, for example room
temperature or above,
[0071] In an embodiment, Birch reduction conditions comprise
reaction of an aromatic substrate, such as a compound of Formula
VIII, with anhydrous ammonia, t-BuOH and metals such as Na, Li etc.
at low temperature (for example, -50.degree. C. to -100.degree. C.)
in an inert organic solvent, followed by warming to, for example
room temperature or above, and treating with a suitable acid to
provide, for example, the desired enone IX.
[0072] In an embodiment, Davis hydroxylation conditions comprise
reaction of an enone, for example a compound of Formula IX, with
metal bases at low temperature (for example, -50.degree. C. to
-100.degree. C.) in an inert organic solvent, followed by reacting
with Davis oxaziridine (or equivalent reagent) at low temperature
(for example, -50.degree. C. to -100.degree. C.), quenching the
reaction with a suitable acid to provide, for example, the desired
alcohol V.
[0073] Standard methods and reactions are used to convert the
compound of Formula I into morphine compounds. For example, when
one of X and Y is NMePG.sup.2 and the other is LG, removal of
PG.sup.2 followed by nucleophilic displacement of the LG leads to
the formation of the ring D of the morphine skeleton. In another
example, when Y is H and X is NMePG.sup.2, formation of ring D is
carried out using reductive cyclization, such as nitrogen centered
radical cyclization. Oxidation and/or reduction of the various
functional groups, such as the C6 OH group, as well as removal of
protecting groups are performed to provide the desired morphine
compound.
[0074] The following non-limiting examples are illustrative of the
present application:
EXAMPLES
[0075] The reactions and numbering referred to in Examples 1 and 2
are depicted in Scheme 2:
##STR00016##
Example 1
4-Formyl-2-hydroxyphenyl acetate (16)
##STR00017##
[0077] Aldehyde 15.sup.2 (3.9 g, 28 mmol) was dissolved in THF and
the solution was cooled to 0.degree. C. Then a 2 N solution of NaOH
in water (70 mmol) was added dropwise followed by the addition of
acetic anhydride (3.2 mL, 34 mmol). The reaction mixture was
stirred for 20 minutes, diluted with EtOAc, made acidic with 2.5 mL
of con. HCl and 20 mL of phosphate buffer (pH=2.5). Then it was
filtered through a pad of Celite.TM. and the organic phase was
separated. The aqueous phase was washed 3 times with EtOAc, organic
washes were combined, washed with brine, dried over
Na.sub.2SO.sub.4 and solvent was evaporated under reduced pressure
to obtain the crude product, which was purified by suction
filtration chromatography on silica gel with [CH.sub.2Cl.sub.2/MeOH
(98:2).fwdarw.CH.sub.2Cl.sub.2/MeOH (95:5)] as eluent to provide 16
as a light yellow solid (4.2 g, 23.3 mmol, 84%). It was
recrystallized from ether to provide colourless crystals.
[0078] m.p. 88-91.degree. C. (ether), [lit..sup.3 87-89.degree. C.
(ether-light petrol)]; R.sub.f=0.33 [CH.sub.2Cl.sub.2/MeOH (98:2)];
IR (CHCl.sub.3, cm.sup.-1) v 3564, 3374, 3028, 2838, 2737, 1773,
1696, 1607, 1509, 1441, 1371, 1296, 1277, 1172; .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 9.78 (s, 1H), 7.69 (dd, J=8.4 Hz, 1.8,
1H), 7.58 (d, J=2.1 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 4.95 (bs, 1H),
2.33 (s, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) .delta. 191.8,
169.3, 155.4, 139.1, 129.6, 129.1, 124.0, 116.7, 19.2; MS (EI) m/z
(%) 180 (11), 138 (65), 137 (55), 43 (100); HRMS (EI) calcd for
C.sub.9H.sub.8O.sub.4: 180.0423. Found 180.0427; Anal. Calcd for
C.sub.9H.sub.8O.sub.4: C, 60.00; H, 4.48. Found C, 60.24; H,
4.59.
Example 2
3-Hydroxy-4-(methoxymethoxy)benzaldehyde (18)
##STR00018##
[0080] To a suspension of K.sub.2CO.sub.3 (2.3 g, 16.8 mmol) in DMF
(30 mL) at 0.degree. C. was added MOMCl (0.84 mL, 2 mmol) dropwise.
Then a solution of 16 (1 g, 5.6 mmol) in DMF (30 mL) was added
dropwise through an addition funnel. The reaction mixture was
allowed to stir for another 30 minutes and was diluted with
H.sub.2O (100 mL). It was then extracted three times with Et.sub.2O
(75 mL), organic washes were combined, washed with brine solution,
dried over Na.sub.2SO.sub.4, and the solvent was evaporated under
reduced pressure to provide the crude acetate 17 which was taken to
next step without further purification.
[0081] A saturated solution of K.sub.2CO.sub.3 in MeOH (15 mL) was
added to a solution of acetate 17 in MeOH (10 mL) at room
temperature. The reaction mixture was stirred at room temperature
for 40 minutes, then the pH of the reaction mixture was adjusted to
7 using 1 N HCl and NH.sub.4Cl (saturated) solution. The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (3.times.100 mL), washed
with brine, dried over Na.sub.2SO.sub.4, and the volatiles were
removed in vacuo to provide crude product, which was filtered
through a plug of silica using EtOAc to yield 18 (0.72 g, 3.95
mmol, 71% over two steps) as a colourless liquid.
[0082] R.sub.f=0.15 [hexane/EtOAc (80:20)]; IR (CHCl.sub.3,
cm.sup.-1) v 3615, 3028, 3007, 2964, 2740, 1705, 1578, 1464;
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.79 (s, 1H), 7.42 (d,
J=1.8 Hz, 1H), 7.35 (dd, J=8.4, 1.8 Hz, 1H), 7.17 (d, J=8.4 Hz,
1H), 6.54 (s, 1H), 5.26 (s, 2H), 3.47 (s, 3H); .sup.13C NMR
(CDCl.sub.3, 75 MHz) .delta. 191.4, 149.8, 146.7, 131.4, 124.3,
114.9, 114.3, 95.2, 56.6; MS (EI) m/z (%) 182 (13), 45 (100);
HRMS-EI calcd for C.sub.9H.sub.10O.sub.4: 182.0579 found
182.0576.
[0083] The reactions and numbering referred to in Examples 3-4 are
depicted in Scheme 3:
##STR00019##
Example 4a
N-(2-((5S,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-hydroxycyclohex-1-en-1-yl-
)ethyl)-N,4-dimethylbenzenesulfonamide (13)
[0084] The synthesis of the homochiral subunit 13 was accomplished
as shown in Scheme 3 and as previously described..sup.4,5
Dihydroxylation of 8 by whole-cell fermentation with E. coli JM 109
(pDTG601A).sup.6 yielded 9, which was immediately subjected to a
selective reduction with potassium azodicarboxylate, followed by
protection of the diol to give 10. Displacement of bromine in 10
with methylamine produced 11 (the tosylation of this compound could
be used in the future to provide 14 and hence 19b, Scheme 4, in a
more direct way). Hydrolysis of the acetonide with HCl was followed
by protection of the secondary amine as a Boc carbamate to provide
12 in a one-pot operation; regioselective silylation of the distal
hydroxyl then provided alcohol 13.
Example 4b
N-(2-((5S,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-hydroxycyclohex-1-en-1-yl-
)ethyl)-N,4-dimethylbenzenesulfonamide (14)
##STR00020##
[0086] To a solution of 13 (1 g, 2.59 mmol) in CH.sub.2Cl.sub.2 at
0.degree. C. was added TFA (4 mL, 32 mmol) and was stirred for 20
minutes. Then the reaction mixture was diluted with
CH.sub.2Cl.sub.2 (60 mL), then saturated NaHCO.sub.3 solution was
added and pH was adjusted to -9. The organic layer was separated
and the aqueous layer was washed with CH.sub.2Cl.sub.2 (3.times.30
mL), the organic washes were combined and were washed with brine
solution, dried over Na.sub.2SO.sub.4 and solvent was evaporated
under reduced pressure to provide crude product (540 mg). Then the
aqueous phase was saturated with NaCl and was washed with
CHCl.sub.3:EtOH (3:1) (3.times.30 mL), dried over Na.sub.2SO.sub.4
and solvent was evaporated under reduced pressure to provide
another 200 mg of crude product. The crude material was taken to
the next step without further purification.
[0087] To a solution of crude product (740 mg, 2.6 mmol) in
CH.sub.2Cl.sub.2 at 0.degree. C. was added Et.sub.3N (0.47 mL, 3.37
mmol) followed by TsCl (593 mg, 3.1 mmol). The reaction mixture was
slowly warmed to room temperature and was stirred for 3 hours. Then
the solvent was evaporated under reduced pressure and column
chromatography on silica gel using [hexane/EtOAc
(90:10).fwdarw.hexane/EtOAc (70:30)] to provide 14 (979 mg, 2.2
mmol, 86%) as a clear liquid.
[0088] R.sub.f=0.12 [hexane/EtOAc (70:30)];
[.alpha.].sup.20.sub.D=-30.0 (c=1.15, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3550, 3028, 3008, 2954, 2930, 2885, 2859, 1690, 1598,
1462, 1373, 1339, 1160, 1088; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 7.64 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 5.58 (bs,
1H), 3.92 (d, J=3.6 Hz, 1H), 3.83-3.78 (m, 1H), 3.35-3.26 (m, 1H),
3.00-2.93 (m, 1H), 2.70 (s, 3H), 2.39 (s, 4H), 2.30-2.23 (m, 1H),
2.21-1.88 (m, 3H), 1.80-1.67 (m, 1H), 1.56-1.52 (m, 1H), 0.89 (s,
9H), 0.14-0.09 (m, 6H); .sup.13C NMR (CDCl.sub.3, 75 MHz) .delta.
143.1, 134.8, 134.0, 129.6, 127.3, 127.2, 70.7, 68.7, 49.1, 34.6,
33.1, 25.8, 25.5, 23.9, 21.4, 18.0, -4.5, -4.9; MS (EI) m/z (%) 382
(4), 324 (8), 200 (10), 199 (25), 198 (100), 197 (86), 155 (67),
140 (21), 105 (15), 91 (58), 77 (13), 75 (81), 73 (30), 57 (16), 44
(35); HRMS (EI) calcd for C.sub.22H.sub.37NO.sub.4SSi
(M.sup.+-C.sub.4H.sub.9): 382.1508. Found 382.1496; Anal. Calcd for
C.sub.22H.sub.37NO.sub.4SSi: C, 60.10; H, 8.48. Found C, 59.92; H,
8.28.
[0089] The reactions and numbering referred to in Examples 5-14 are
depicted in Scheme 4:
##STR00021##
Example 5
tert-Butyl(2-((5S,6S)-5-((tert-butyldimethylsilyl)oxy)-6-(5-formyl-2-(meth-
oxymethoxy)phenoxy)cyclohex-1-en-1-yl)ethyl)(methyl) carbamate
(19a)
##STR00022##
[0091] To a solution of alcohol 13 (3.19 g, 8.28 mmol) and phenol
18 (1.66 g, 9.11 mmol) in THF (30 mL) at -10.degree. C. was added
PBu.sub.3 (2.9 mL, 11.59 mmol) followed by
tetramethylazodicarboxamide (TMAD) (1.9 g, 10.76 mmol). The
reaction mixture was slowly warmed to room temperature and was
stirred for 18 hours. Solvent was evaporated under reduced pressure
and purified by flash column chromatography on silica gel using
[hexane/EtOAc (90:10)] as eluent to isolate product 19a (3.7 g, 6.7
mmol, 81%) as a clear oil.
[0092] R.sub.f=0.39 [hexane/EtOAc (70:30)];
[.alpha.].sup.20.sub.D=-27.6 (c=1.48, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3681, 3009, 2931, 1726, 1682, 1582, 1506, 1394, 1271,
1159; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.86 (s, 1H), 7.70
(s, 1H), 7.44 (dd, J=8.1, 1.5 Hz, 1H), 7.28-7.24 (m, 1H), 5.69 (s,
1H), 5.29 (s, 2H), 4.75 (s, 1H), 4.11-4.06 (m, 1H), 3.49 (s, 3H),
3.25-3.17 (m, 2H), 2.72 (s, 3H), 2.35-2.04 (m, 4H), 1.93-1.86 (m,
1H), 1.79-1.70 (m, 1H), 1.41 (s, 9H), 0.81 (s, 9H), 0.00 (s, 3H),
-0.09 (s, 3H); .sup.13C NMR (CDCl.sub.3, 75 MHz, rotameric) .delta.
190.8, 155.7, 152.7, 149.8, 132.4, 131.1, 128.6, 125.8, 125.2,
115.5, 94.8, 80.3, 79.3, 70.4, 60.5, 56.5, 48.5, 34.5, 32.3, 31.7,
28.5, 25.8, 22.8, 18.0, -4.7, -4.8; MS (EI) m/z (%) 312 (37), 268
(50), 237 (29), 136 (34), 57 (51), 44 (100)); HRMS-EI calcd for
C.sub.29H.sub.47NO.sub.7Si: 549.3122 found 549.3115; Anal. Calcd
for C.sub.29H.sub.47NO.sub.7Si: C, 63.36; H, 8.62. Found C, 63.02;
H, 8.61.
Example 6
N-(2-((5S,6S)-5-((Tert-butyldimethylsilyl)oxy)-6-(5-formyl-2-(methoxymetho-
xy)phenoxy)cyclohex-1-en-1-yl)ethyl)-N,4-dimethylbenzenesulfonamide
(19b)
##STR00023##
[0094] To a solution of alcohol 14 (190 mg, 0.43 mmol) and phenol
18 (102 mg, 0.56 mmol) in THF (6 mL) at -10.degree. C. was added
PBu.sub.3 (0.15 mL, 0.65 mmol) followed by
tetramethylazodicarboxamide (TMAD) (111 mg, 0.65 mmol). The
reaction mixture was slowly warmed to room temperature and was
stirred for 22 hours. Solvent was evaporated under reduced pressure
and purified by flash column chromatography on silica gel using
[hexane/EtOAc (80:20).fwdarw.hexane/EtOAc (50:50)] as eluent to
isolate product 19b (130 mg, 0.22 mmol, 50%) as a clear oil.
[0095] R.sub.f=0.34 [hexane/EtOAc (70:30)];
[.alpha.].sup.20.sub.D=-21.1 (c=1.5, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3028, 3009, 2954, 2930, 2857, 1688, 1596, 1584, 1505,
1463, 1339, 1264, 1160, 1126, 1084; .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.87 (s, 1H), 7.69 (d, J=1.2 Hz, 1H), 7.55-7.45 (m,
3H), 7.28-7.23 (m, 3H), 5.75 (s, 1H), 5.31-5.26 (m, 2H), 4.72 (d,
J=4.8 Hz, 1H), 4.14-4.05 (m, 1H), 3.48 (s, 3H), 3.05-3.01 (m, 1H),
2.94-2.88 (m, 1H), 2.62 (s, 3H), 2.50-2.40 (m, 4H), 2.36-2.26 (m,
1H), 2.19-2.13 (m, 2H), 1.89-1.87 (m, 1H), 1.85-1.83 (m, 1H), 0.80
(s, 9H), -0.00 (s, 3H), -0.11 (s, 3H); .sup.13C NMR (CDCl.sub.3, 75
MHz, rotameric) .delta. 190.9, 152.8, 150.1, 149.4, 143.1, 134.6,
131.8, 130.9, 129.6, 128.9, 127.3, 125.4, 115.4, 115.1, 94.8, 79.9,
70.2, 60.4, 56.5, 49.4, 34.9, 32.4, 28.0, 25.7, 22.7, 21.5, 17.9,
-4.9, -5.0; MS (EI) m/z (%) 546 (2), 199 (12), 198 (100), 155 (44),
91 (47), 75 (67), 45 (77); HRMS (EI) calcd for
C.sub.31H.sub.45NO.sub.7SSi (M.sup.+-C.sub.4H.sub.9): 546.1982.
Found 546.1976.
Example 7
tert-Butyl(2-((5S,6S)-5-((tert-butyldimethylsilyl)oxy)-6-(2-(methoxy-metho-
xy)-5-vinylphenoxy)cyclohex-1-en-1-yl)ethyl)(methyl)carbamate
(20)
##STR00024##
[0097] To a suspension of Wittig salt
CH.sub.3P.sup.+Ph.sub.3Br.sup.- (2.26 g, 6.3 mmol) in THF (20 mL)
at -78.degree. C., nBuLi (2.9 mL, 5.8 mmol) was added and the
resulting yellow solution was stirred for 15 minutes. It was then
warmed to 0.degree. C., and aldehyde 19a (1.58 g, 2.9 mmol) in THF
(20 mL) was cannulated into the reaction mixture, which was stirred
for another 10 minutes at 0.degree. C. The resulting yellow
suspension was heated to reflux for 4 hours whereupon the solvent
was evaporated under reduced pressure and column chromatography on
silica gel using hexane/EtOAc (80:20) provided 20 (1.3 g, 2.37
mmol, 82%) as a colourless liquid.
[0098] R.sub.f=0.57 [hexane/EtOAc (70:30)];
[.alpha.].sup.20.sub.D=-9.4 (c=0.17, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3009, 2954, 2930, 2898, 2857, 1683, 1601, 1577, 1506,
1261; .sup.1H NMR (CDCl.sub.3, 300 MHz, rotameric) .delta.
7.21-7.20 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.01-6.93 (m, 1H),
6.67-6.57 (m, 1H), 5.67-5.58 (m, 2H), 5.20-5.13 (m, 3H), 4.57 (bs,
1H), 4.08 (bs, 1H), 3.48 (s, 3H), 3.20-3.16 (m, 2H), 2.73 (bs, 3H),
2.36-2.04 (m, 4H), 1.89-1.86 (m, 1H), 1.74-1.67 (m, 1H), 1.42 (s,
9H), 0.83 (s, 9H), -0.01 (s, 3H), -0.08 (s, 3H); .sup.13C NMR
(CDCl.sub.3, 75 MHz, rotameric) .delta. 155.6, 149.2, 147.2, 136.3,
132.6, 132.3, 128.2, 127.8, 119.7, 114.2, 113.7, 116.9, 114.2,
113.7, 112.4, 95.3, 79.9, 79.0, 69.6, 60.3, 56.0, 48.4, 47.7, 34.4,
32.6, 31.8, 28.4, 27.6, 25.7, 22.4, 20.9, 17.9, -4.8, -4.9; MS (EI)
m/z (%) 312 (35), 268 (72), 237 (28), 225 (17), 180 (24), 136 (57),
109 (30), 75 (77), 57 (57), 45 (100); HRMS (EI) calcd for
C.sub.30H.sub.49NO.sub.6Si: 547.3329. Found 547.3323; Anal. Calcd
for C.sub.30H.sub.49NO.sub.6Si: C, 65.78; H, 9.02. Found C, 65.52;
H, 8.85.
Example 8
tert-Butyl(2-((5S,6S)-5-((tert-butyldimethylsilyl)oxy)-6-(2-hydroxy-5-viny-
lphenoxy)cyclohex-1-en-1-yl)ethyl)(methyl)carbamate (21)
##STR00025##
[0100] To a solution of 20 (1.3 g, 2.4 mmol) in CH.sub.2Cl.sub.2
(25 mL) at 0.degree. C. was added ZnBr.sub.2 (0.59 g, 2.6 mmol)
followed by 1-dodecane thiol (1.1 mL, 4.8 mmol). Then the reaction
mixture was stirred for 10 minutes, diluted with CH.sub.2Cl.sub.2
(60 mL), then NaHCO.sub.3 (sat) solution was added dropwise and the
mixture was filtered through a pad of celite. The aqueous layer was
separated and further extracted with CH.sub.2Cl.sub.2. The combined
organic solution was dried with Na.sub.2SO.sub.4, volatiles were
removed in vacuo to provide crude product and column chromatography
on silica gel using [hexane/EtOAc (90:10)] provided 21 (1.12 g,
2.22 mmol, 93%) as a clear liquid.
[0101] R.sub.f=0.27 [hexane/EtOAc (80:20)];
[.alpha.].sup.20.sub.D=+1.0 (c=3.15, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3535, 3297, 2955, 2930, 2858, 1684, 1605, 1508, 1396,
1268, 1161; .sup.1H NMR (CDCl.sub.3, 300 MHz, rotameric) .delta.
7.06 (s, 1H), 6.92-6.86 (m, 2H), 6.60 (dd, J=17.4, 10.8 Hz, 1H),
5.65 (s, 1H), 5.56 (d, J=17.7 Hz, 1H), 5.09 (d, J=10.8 Hz, 1H),
4.58 (s, 1H), 4.10-4.06 (m, 1H), 3.71 (bs, 0.6H), 3.15 (bs, 0.8H),
2.95-2.91 (m, 0.6H), 2.75 (s, 3H), 2.33-1.95 (m, 4H), 1.70-1.68 (m,
2H), 1.43 (s, 9H), 0.86 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H);
.sup.13C NMR (CDCl.sub.3, 75 MHz, rotameric) .delta. 155.7, 146.8,
145.7, 136.7, 130.5, 129.2, 119.7, 115.3, 111.0, 109.8, 79.2, 78.7,
69.6, 68.7, 48.6, 47.6, 44.1, 33.8, 33.1, 31.2, 31.4, 29.6, 29.5,
29.3, 29.0, 28.4, 27.5, 26.7, 25.7, 22.7, 21.9, 17.9, -4.8; MS (EI)
m/z (%) 312 (14), 268 (15), 237 (17), 228 (17), 136 (42), 109 (15),
105 (240), 83 (34), 75 (56), 57 (90), 44 (100); HRMS (EI) calcd for
C.sub.28H.sub.45NO.sub.5Si: 503.3067. Found 503.3073; Anal. Calcd
for C.sub.28H.sub.45NO.sub.5Si: C, 66.76; H, 9.00. Found C, 65.85;
H, 9.07.
Example 9
(4aS,4a1R,5S,7aR)-4a1-(2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)-5-((te-
rt-butyldimethylsilyl)oxy)-3-oxo-3,3a,3a1,4a,4a1,5,6,7,7a,8-decahydrophena-
nthro[4,5-bcd]furan-3a-yl acetate (6)
##STR00026##
[0103] A solution of lead tetraacetate (37.9 mg, 0.08 mmol) in DCE
(1 mL) was added dropwise to a refluxing solution of 21 (43 mg,
0.08 mmol) in DCE (1 mL). The reaction mixture was stirred for
another 4 hours, cooled to room temperature, and then passed
through a plug of celite and solvent was evaporated under reduced
pressure to obtain the crude product which was purified by column
chromatography on silica gel using [hexane/EtOAc
(90:10).fwdarw.hexane/EtOAc (70:30)] as eluent to provide 6 (24 mg,
0.04 mmol, 50%) as a colourless liquid.
[0104] R.sub.f=0.46 [hexane/EtOAc (70:30)];
[.alpha.].sup.20.sub.D=-22.0 (c=1.2, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3024, 3009, 2951, 2931, 2858, 1730, 1686, 1625, 1462,
1368, 1252, 1161; .sup.1H NMR (300 MHz, CDCl.sub.3, rotameric)
.delta. 7.06 (d, J=9.9 Hz, 1H), 6.47 (bt, J=3.6 Hz, 1H), 5.98 (d,
J=9.9 Hz, 1H), 4.15-4.05 (m, 1H), 3.42-3.10 (m, 4H), 2.87 (s, 3H),
2.27-2.22 (m, 2H), 2.16 (bs, 1H), 2.13 (s, 3H), 2.04-2.02 (m, 2H),
1.72 (bs, 1H), 1.53-1.51 (m, 1H), 1.47 (s, 9H), 1.14-1.05 (m, 2H),
0.84 (s, 9H), -0.01 (s, 3H), -0.05 (s, 3H); .sup.13C NMR (75 MHz,
CDCl.sub.3, rotameric) .delta.88.2, 170.9, 155.4, 144.5, 139.0,
134.2, 122.7, 103.9, 90.6, 79.7, 74.2, 73.5, 52.0, 48.6, 45.9,
45.4, 40.7, 39.8, 38.6, 37.3, 34.4, 30.8, 29.4, 28.5, 25.8, 21.3,
20.6, 18.1, -4.6, -5.1; MS (EI) m/z (%) 388 (10), 345 (10), 313
(12), 287 (25), 171 (15), 83 (12), 75 (23), 73 (45), 59 (34), 57
(87), 44 (100); HRMS (EI) calcd for C.sub.30H.sub.47NO.sub.7Si
(M.sup.+-C.sub.2H.sub.4O.sub.2): 501.2911. Found 501.2910; Anal.
Calcd for C.sub.30H.sub.47NO.sub.7Si: C, 64.14; H, 8.43. Found C,
64.03; H, 8.45.
Example 10
(4aS,4a1R,5S,7aR)-5-((tert-Butyldimethylsilyl)oxy)-4a1-(2-(N,4-dimethylphe-
nylsulfonamido)ethyl)-4a,4a1,5,6,7,7a-hexahydro phenanthro
[4,5-bcd]furan-3-yl 4-methylbenzenesulfonate (23)
##STR00027##
[0106] A solution of 6 (16 mg, 0.028 mmol) in CH.sub.2Cl.sub.2 (1.5
mL) was cooled in an ice bath and TFA (0.5 mL) was added dropwise.
The reaction mixture was stirred for 10 minutes, diluted with
CH.sub.2Cl.sub.2 (4.5 mL) and the pH of the reaction mixture was
adjusted to .about.7 using saturated Na.sub.2CO.sub.3 solution. The
organic layer was separated, washed with water, dried over
Na.sub.2SO.sub.4 and evaporated in vacuo to obtain the crude
product (22) which was immediately taken to next step without
further purification.
[0107] To a solution of 22 in CH.sub.2Cl.sub.2 cooled in an ice
bath, was added Et.sub.3N (6.3 .mu.L, 0.045 mmol) and TsCl (8.6 mg,
0.045 mmol) and the resulting reaction mixture was stirred for 10
hours. The solvent was evaporated under reduced pressure and the
crude product was purified by column chromatography on silica gel
using [hexane/EtOAc (90:10).fwdarw.hexane/EtOAc (80:20)] as eluent
to provide 23 (9 mg, 0.013 mmol, 46% over two steps) as a light
yellow oil.
[0108] R.sub.f=0.47 [hexane/EtOAc (70:30)];
[.alpha.].sup.20.sub.D=-106.5 (c=0.42, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3027, 2929, 2857, 1599, 1490, 1446, 1378, 1341, 1274,
1221, 1158; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.78 (d,
J=8.4 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.31-7.26 (m, 4H), 6.84 (d,
J=8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 6.35 (d, J=9.6 Hz, 1H), 5.92
(dd, J=9.6, 5.7 Hz, 1H), 4.36 (d, J=6.9 Hz, 1H), 3.31-3.23 (m, 1H),
3.05-2.95 (m, 1H), 2.82-2.72 (m, 1H), 2.59 (s, 3H), 2.44 (s, 3H),
2.40 (s, 3H), 2.36-2.34 (m, 1H), 1.77-1.68 (m, 2H), 1.63-1.55 (m,
3H), 1.25-1.17 (m, 1H), 0.88 (s, 9H), 0.08 (s, 3H), -0.01 (s, 3H);
.sup.13C NMR (150 MHz, CDCl.sub.3) .delta. 148.2, 145.3, 143.3,
134.6, 133.0, 132.8, 132.7, 129.7, 129.6, 129.2, 128.9, 128.8,
127.4, 124.1, 122.5, 117.7, 98.2, 73.9, 46.1, 44.7, 39.7, 35.8,
34.8, 29.8, 29.7, 26.6, 25.8, 21.7, 21.5, 18.1, -4.6, -5.0; MS (EI)
m/z (%) 653 (3), 198 (34), 155 (12), 149 (19), 124 (28), 123 (13),
100 (42), 92 (17), 91 (58), 83 (16), 57 (35), 43 (100); HRMS (EI)
calcd for C.sub.37H.sub.47NO.sub.7S.sub.2Si
(M.sup.+-C.sub.4H.sub.9): 652.1859. Found 652.1852; Anal. Calcd for
C.sub.37H.sub.47NO.sub.7S.sub.2Si: C, 62.59; H, 6.67. Found C,
62.52; H, 6.63.
Example 11
(4aS,4a1R,5S,7aR)-4a1-(2-(N,4-Dimethylphenylsulfonamido)ethyl)-5-hydroxy-4-
a,4a1,5,6,7,7a-hexahydrophenanthro[4,5-bcd]furan-3-yl
4-methylbenzenesulfonate (24)
##STR00028##
[0110] To a mixture of 23 (141 mg, 0.19 mmol) and THF (5 mL) at
room temperature was added tetrabutylammonium fluoride (TBAF)
solution in THF (0.34 mL, 0.34 mmol). The resulting mixture was
stirred for 6 hours and the solvent was evaporated under reduced
pressure to provide the crude product, which was purified by column
chromatography on silica gel using [hexane/EtOAc
(70:30).fwdarw.hexane/EtOAc (50:50)] as eluent to provide 24 (101
mg, 0.17 mmol, 86%) as a clear oil.
[0111] R.sub.f=0.29 [hexane/EtOAc (50:50)];
[.alpha.].sup.18.sub.D=-20.4 (c=0.55, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3518, 3033, 2926, 2861, 1597, 1489, 1445, 1335, 1191,
1177, 1088; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.76 (d, J=8.4
Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.33-7.26 (m, 4H), 6.78 (d, J=8.1
Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 6.35 (d, J=9.6 Hz, 1H), 5.93 (dd,
J=9.6, 5.7 Hz, 1H), 4.48 (d, J=7.2 Hz, 1H), 3.08-2.98 (m, 2H),
2.84-2.74 (m, 1H), 2.57 (s, 3H), 2.47-2.36 (m, 8H), 1.88-1.56 (m,
4H), 1.27-1.15 (m, 1H), 0.89-0.76 (m, 1H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.47.9, 145.6, 143.4, 134.3, 133.0, 132.6, 129.7,
129.3, 129.1, 128.7, 127.4, 123.8, 122.5, 117.9, 98.0, 76.7, 72.9,
46.1, 44.7, 39.3, 35.2, 34.8, 27.8, 26.9, 21.7, 21.5; MS (EI) m/z
(%) 595 (1), 440 (4), 384 (3), 229 (7), 198 (10), 155 (35), 139
(13), 124 (20), 97 (13), 92 (18), 91 (100), 69 (21), 57 (30); HRMS
(EI) calcd for C.sub.31H.sub.33NO.sub.7S.sub.2: 595. 1698. Found
595. 1693.
Example 12
(4S,4aS,7S,7aS,12bR)-7-((tert-Butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,-
6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol
(25)
##STR00029##
[0113] To a mixture of tBuOH (64 .mu.L, 0.62 mmol) and THF (2 mL)
at -78.degree. C. was added liquid NH.sub.3 (.about.15 mL) and Li
wire (37 mg, 5.3 mmol). The resulting blue color reaction mixture
was stirred for five minutes and 23 (35 mg, 0.05 mmol) in THF (2
mL) was added dropwise. The reaction mixture was stirred for
another 10 minutes while it remained blue in color. Then 2 g of
NH.sub.4Cl was added as a solid, followed by 10 mL of MeOH and 20
mL of saturated NH.sub.4Cl solution. This mixture was then washed
three times with CH.sub.2Cl.sub.2 (20 mL), the combined organic
layers were washed with saturated NaCl solution, and dried over
Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure
to provide the crude product, which was purified by column
chromatography on silica gel using [CH.sub.2Cl.sub.2/MeOH
(95:5).fwdarw.CH.sub.2Cl.sub.2/MeOH (90:10)] as eluent to provide
25 (16 mg, 0.04 mmol, 82%) as a colourless oil.
[0114] R.sub.f=0.24 [CH.sub.2Cl.sub.2/MeOH (90:10)];
[.alpha.].sup.20.sub.D=+70.5 (c=0.8, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) v 3688, 3586, 2953, 2931, 2858, 1624, 1604, 1505, 1455,
1220, 1119, 1098; .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.70
(d, J=8.4 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 4.91 (bs, 1H), 4.31 (d,
J=6.6 Hz, 1H), 3.39-3.35 (m, 1H), 3.25 (d, J=2.4 Hz, 1H), 2.98 (d,
J=18.6 Hz, 1H), 2.68 (dd, J=12, 4.2 Hz, 1H), 2.46 (s, 3H),
2.44-2.43 (m, 1H), 2.28-2.22 (m, 2H), 2.03 (s, 1H), 1.95-1.90 (m,
1H), 1.67-1.65 (m, 2H), 1.53-1.50 (m, 1H), 1.39-1.32 (m, 1H), 0.88
(s, 9H), 0.10 (s, 3H), 0.01 (s, 3H); .sup.13C NMR (150 MHz,
CDCl.sub.3) .delta. 143.0, 139.9, 129.9, 124.5, 119.2, 117.0, 97.3,
73.7, 59.5, 46.9, 42.9, 42.2, 41.7, 34.7, 31.6, 25.8, 23.4, 20.4,
18.1, -4.5, -4.8; MS (EI) m/z (%) 401 (3), 120 (29), 118 (32), 87
(92), 85 (80), 83 (76), 60 (30), 47 (100), 43 (44); HRMS (EI) calcd
for C.sub.23H.sub.35NO.sub.3Si: 401.2386. Found 401.2375.
Example 13
(4S,4aS,7S,7aS,12bR)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanob-
enzofuro[3,2-e]isoquinoline-7,9-diol (26)
##STR00030##
[0116] To a mixture of tBuOH (35 .mu.L, 0.34 mmol) and THF (2 mL)
at -78.degree. C. was added liquid NH.sub.3 (.about.15 mL) and Li
wire (20 mg, 2.85 mmol). The resulting blue colour reaction mixture
was stirred for five minutes and 24 (20 mg, 0.03 mmol) in THF (2
mL) was added dropwise. The reaction mixture was stirred for
another 10 minutes while the reaction mixture remained blue in
color. Then 2 g NH.sub.4Cl was added as a solid, followed by 10 mL
of MeOH and 20 mL of saturated NH.sub.4Cl solution. This mixture
was then washed three times with CH.sub.2Cl.sub.2 (20 mL), the
combined organic washes were washed with saturated NaCl solution
and was further dried over Na.sub.2SO.sub.4. The solvent was
evaporated under reduced pressure to provide the crude product,
which was purified by column chromatography on silica gel using
[CH.sub.2Cl.sub.2/MeOH (90:10).fwdarw.CH.sub.2Cl.sub.2/MeOH
(80:20).fwdarw.MeOH] as eluent to provide 26 (9.1 mg, 0.03 mmol,
93%) as a white solid.
[0117] m.p. >200.degree. C.; R.sub.f=0.15 [CH.sub.2Cl.sub.2/MeOH
(80:20)]; [.alpha.].sup.20.sub.D=+57.0 (c=0.35, MeOH); IR
(CHCl.sub.3, cm.sup.-1) v 3311, 2923, 1599, 1462, 1313, 1255, 1084;
.sup.1H NMR (600 MHz, MeOD) .delta. 6.71 (d, J=7.8 Hz, 1H), 6.66
(d, J=7.8 Hz, 1H), 4.33 (d, J=6.6 Hz, 1H), 3.66 (s, 1H), 3.16 (d,
J=19.2 Hz, 1H), 3.02 (d, J=11.4 Hz, 1H), 2.78 (s, 3H), 2.64-2.60
(m, 1H), 2.39 (d, J=9.6 Hz, 1H), 2.10-2.05 (m, 1H), 1.81 (d, J=10.6
Hz, 2H), 1.68-1.66 (m, 1H), 1.43-1.31 (m, 2H), 1.03-0.97 (m, 1H),
0.93-0.90 (m, 1H); .sup.13C NMR (150 MHz, MeOD) .delta. 142.9,
140.9, 128.5, 122.1, 119.3, 117.5, 95.5, 72.1, 60.9, 47.2, 42.1,
40.6, 40.4, 33.2, 30.1, 22.9, 20.8; MS (EI) m/z (%) 287 (92), 286
(23), 230 (22), 228 (10), 164 (17), 149 (15), 97 (17), 84 (26), 70
(32), 57 (53), 43 (100); HRMS (EI) calcd for
C.sub.17H.sub.21NO.sub.3: 287.1521. Found 287.1519.
Example 14
(4S,4aS,7aS,12bR)-9-Hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methan-
obenzofuro[3,2-e]isoquinolin-7(7aH)-one (4)
##STR00031##
[0119] To a suspension of 26 (8 mg, 0.028 mmol) and benzophenone
(10.2 mg, 0.056 mmol) in a mixture of toluene (1 mL) and DME (1 mL)
was added potassium tert-butoxide (18 mg, 0.16 mmol) at room
temperature. The resulting reaction mixture was heated at
85.degree. C. for 8 hours and then the solvent was evaporated under
reduced pressure to obtain the crude reaction mixture, which was
purified by column chromatography on silica gel using
[CH.sub.2Cl.sub.2/MeOH (95:5).fwdarw.CH.sub.2Cl.sub.2/MeOH (90:10)]
as eluent to provide 4 (3.5 mg, 0.012 mmol, 44%) as a white solid
along with unreacted starting material 26 (4 mg, 0.014 mmol, 53%).
The physical and spectral properties of 4 were matched with those
given in the literature..sup.7
[0120] m.p. >200.degree. C.; [lit..sup.[3]m.p. 266-267.degree.
C. (ethanol)]; R.sub.f=0.41 [CH.sub.2Cl.sub.2/MeOH (80:20)];
[.alpha.].sup.20.sub.D+190.0 (c=0.13, dioxane), [lit..sup.[3]
[.alpha.].sup.25.sub.D=-194 (c=0.98, dioxane); .sup.1H NMR (300
MHz, MeOD) .delta.6.70 (dd, J=14.1, 8.4 Hz, 2H), 4.61 (s, 1H), 3.56
(bs, 1H), 3.14 (d, J=19.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.77-2.72 (m,
4H), 2.60-2.52 (m, 1H), 2.36-2.32 (m, 1H), 2.00-1.87 (m, 1H), 1.80
(dd, J=13.2, 2.7 Hz, 1H), 1.68 (dd, J=13.2, 2.4 Hz, 1H), 1.45-1.40
(m, 1H), 1.14-1.05 (m, 1H), 0.92-0.89 (m, 1H).
[0121] All publications, patents and patent applications are herein
incorporated by reference in their entirety to the same extent as
if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated by
reference in its entirety. Where a term in the present application
is found to be defined differently in a document incorporated
herein by reference, the definition provided herein is to serve as
the definition for the term.
FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE SPECIFICATION
[0122] .sup.1 For reviews of morphine alkaloid syntheses and
discussion of strategies see: (a) U. Rinner, T. Hudlicky, Top.
Curr. Chem. 2012, 309, 33-66; (b) J. Zezula, T. Hudlicky, Synlett
2005, 388-405; (c) D. F. Taber, T. D. Neubert, M. F. Schlecht, in
Strategies and Tactics in Organic Synthesis, Vol. 5 (Ed.: H.
Michael), Elsevier, London, 2004, pp. 353-389; (d) T. Hudlicky, J.
Heterocyclic Chem. 2000, 37, 535-539; (e) B. H. Novak, T. Hudlicky,
J. W. Reed, J. Mulzer, D. Trauner, Curr. Org. Chem. 2000, 4,
343-362; (f) T. Hudlicky, G. Butora, S. P. Fearnley, A. G. Gum, M.
R. Stabile, in Studies in Natural Products Chemistry, Vol. 18, Part
K (Ed.: R. Atta-ur), Elsevier, Amsterdam, 1995, pp. 43-154; (g) M.
Maier, in Organic Synthesis Highlights II, (Ed.: H. Waldmann), VCH,
Weinheim, 1995, pp. 357-369. [0123] .sup.2 A. M. Sawayama, H.
Tanaka, T. J. Wandless, J. Org. Chem. 2004, 69, 8810-8820. [0124]
.sup.3 J. G. Buchanan, D. G. Hill, R. H. Wightman, I. K. Boddy, B.
D. Hewitt, Tetrahedron 1995, 51, 6033-6050. [0125] .sup.4 H.
Leisch, A. T. Omori, K. J. Finn, J. Gilmet, T. Bissett, D. Ilceski,
T. Hudlicky, Tetrahedron 2009, 65, 9862-9875. [0126] .sup.5 J.
Duchek, T. G. Piercy, J. Gilmet, T. Hudlicky, Can. J. Chem. 2011,
89, 709-729. [0127] .sup.6 G. J. Zylstra, D. T. Gibson, J. Biol.
Chem. 1989, 264, 14940-14946. [0128] .sup.7 H. Rapoport, R.
Naumann, E. R. Bissell, R. M. Bonner, J. Org. Chem. 1950, 15,
1103-1107.
* * * * *