U.S. patent application number 13/014479 was filed with the patent office on 2011-12-29 for schweinfurthin analogues.
This patent application is currently assigned to Government of the United States of America, National Institute of Health. Invention is credited to John A. Beutler, Jeffrey D. Neighbors, David F. Wiemer.
Application Number | 20110319481 13/014479 |
Document ID | / |
Family ID | 35056782 |
Filed Date | 2011-12-29 |
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United States Patent
Application |
20110319481 |
Kind Code |
A1 |
Wiemer; David F. ; et
al. |
December 29, 2011 |
SCHWEINFURTHIN ANALOGUES
Abstract
Methods and intermediates for preparing enantiomerically
enriched Schweinfurthin analogs which are useful for the treatment
of cancer, as well as novel Schweinfurthin analogs having
anti-cancer activity, compositions comprising such analogs and
therapeutic methods comprising administering such analogs.
Inventors: |
Wiemer; David F.; (Iowa
City, IA) ; Neighbors; Jeffrey D.; (Iowa City,
IA) ; Beutler; John A.; (Braddock, MD) |
Assignee: |
Government of the United States of
America, National Institute of Health
Rockville
MD
University of Iowa Research Foundation
Iowa City
IA
|
Family ID: |
35056782 |
Appl. No.: |
13/014479 |
Filed: |
January 26, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12025617 |
Feb 4, 2008 |
7902228 |
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13014479 |
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11093270 |
Mar 29, 2005 |
7358377 |
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12025617 |
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60557243 |
Mar 29, 2004 |
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Current U.S.
Class: |
514/454 ;
549/388 |
Current CPC
Class: |
C07D 311/78 20130101;
C07D 311/80 20130101; A61P 35/00 20180101 |
Class at
Publication: |
514/454 ;
549/388 |
International
Class: |
A61K 31/352 20060101
A61K031/352; A61P 35/00 20060101 A61P035/00; C07D 311/82 20060101
C07D311/82 |
Goverment Interests
GOVERNMENT FUNDING
[0002] The invention described herein was made with government
support under Grant Numbers DAMD17-01-1-0276 and DAMD17-02-1-0423
awarded by the US Department of Defense, Breast Cancer Research
Program. The United States Government has certain rights in the
invention.
Claims
1. A compound of formula (XX): ##STR00067## wherein: R.sub.7 and
R.sub.8 are each independently H or (C.sub.1-C.sub.6)alkyl; R.sub.9
is H, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl,
(C.sub.2-C.sub.15)alkanoyloxy, aryl or heteroaryl, which aryl or
heteroaryl is optionally substituted with one or more halo,
hydroxy, cyano, CF.sub.3, OCF.sub.3, NR.sup.aR.sup.b,
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl,
(C.sub.1-C.sub.15)alkoxy(C.sub.1-C.sub.15)alkoxy,
--P(.dbd.O)(OH).sub.2, and (C.sub.2-C.sub.15)alkanoyloxy; R.sub.10
is H or (C.sub.1-C.sub.6)alkyl; and R.sup.a and R.sup.b are each
independently H or (C.sub.1-C.sub.6)alkyl wherein any
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, or
(C.sub.2-C.sub.15)alkanoyloxy of R.sub.7, R.sub.8, and R.sub.9 is
optionally substituted with one or more halo, hydroxy, cyano, or
oxo (.dbd.O). or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R.sub.7 is H.
3. The compound of claim 1 wherein R.sub.7 is
(C.sub.1-C.sub.6)alkyl.
4. (canceled)
5. The compound of claim 1 wherein R.sub.8 is H.
6. The compound of claim 1 wherein R.sub.8 is
(C.sub.1-C.sub.6)alkyl.
7. (canceled)
8. The compound of claim 1 wherein R.sub.9 is H.
9. The compound of claim 1 wherein R.sub.9 is
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl,
(C.sub.2-C.sub.15)alkanoyloxy.
10. (canceled)
11. The compound of claim 1 wherein R.sub.9 is aryl optionally
substituted with one or more halo, hydroxy, cyano, CF.sub.3,
OCF.sub.3, NR.sup.aR.sup.b, (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy.
12. The compound of claim 1 wherein R.sub.9 is aryl optionally
substituted with one or more halo, hydroxy, cyano, CF.sub.3,
OCF.sub.3, NR.sup.aR.sup.b, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy.
13. The compound of claim 1 wherein R.sub.9 is aryl optionally
substituted with one or more halo, hydroxy, cyano, CF.sub.3,
OCF.sub.3, NR.sup.aR.sup.b, (C.sub.2-C.sub.15)alkenyl,
(C.sub.1-C.sub.15)alkoxy.
14. The compound of claim 11 wherein aryl is phenyl or
naphthyl.
15. The compound of claim 1 wherein R.sub.9 is of the formula
##STR00068## wherein: R.sup.c and R.sup.e are each independently H,
halo, hydroxy, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
methoxymethoxy, and (C.sub.2-C.sub.15)alkanoyloxy; and R.sup.d is
H, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy; wherein any (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, or (C.sub.2-C.sub.15)alkanoyloxy
of R.sup.c, R.sup.e, and R.sup.d is optionally substituted with one
or more halo, hydroxy, cyano, or oxo (.dbd.O).
16. The compound of claim 1 wherein R.sub.9 is of the formula
##STR00069## wherein: R.sup.c and R.sup.e are each independently H,
halo, hydroxy, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
methoxymethoxy, and (C.sub.2-C.sub.15)alkanoyloxy; and R.sup.d is
H, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy; R.sup.g is H, cyano, fluoro, or
--P(.dbd.O)(OH).sub.2; and R.sup.h is H, cyano, fluoro, or or
--P(.dbd.O)(OH).sub.2; wherein any (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, or (C.sub.2-C.sub.15)alkanoyloxy
of R.sup.c, R.sup.e, and R.sup.d is optionally substituted with one
or more halo, hydroxy, cyano, or oxo (.dbd.O).
17. The compound of claim 6 wherein R.sup.c and R.sup.e are each
independently H, fluoro, chloro, bromo, hydroxy, or methoxy.
18. The compound of claim 6 wherein at least one of R.sup.c and
R.sup.e is hydroxy.
19. The compound claim 16 wherein R.sup.d is
(C.sub.2-C.sub.15)alkenyl optionally substituted with one or more
halo, hydroxy, or oxo (.dbd.O).
20. The compound of claim 16 wherein R.sup.d is hydrogen,
trans-3,7-dimethyl-2,6-octadien-1-yl, or
trans-3,7-dimethyl-8-hydroxy-2,6-octadien-1-yl.
21. The compound of claim 1 wherein R.sub.9 is isoxazolyl,
imadazolyl, pyridyl, indolyl, or benzo[b]furanyl.
22. (canceled)
23. A pharmaceutical composition comprising a compound as described
in claim 1 and a pharmaceutically acceptable carrier.
24. A method for treating cancer comprising administering a
therapeutically effective amount of a compound as described in
claim 1 to a mammal.
25. (canceled)
Description
PRIORITY OF INVENTION
[0001] This application is a continuation of U.S. Ser. No.
12/025,617 filed on Feb. 4, 2008, which is a continuation of U.S.
Ser. No. 11/093,270 filed on Mar. 29, 2005, which claims the
benefit of U.S. Provisional Patent Application No. 60/557,243,
filed 29 Mar. 2004, which applications are incorporated herein by
reference and made a part hereof.
BACKGROUND OF THE INVENTION
[0003] The family of natural products known as the schweinfurthins
includes four compounds (FIG. 1, 1-4) isolated from the African
plant Macaranga schweinfurthii Pax (see Beutler, J. A. et al., J.
Nat. Prod. 1998, 61, 1509-1512; and Beutler, J. A., et al., Nat.
Prod. Lett. 2000, 14, 349-404). Schweinfurthins A (1), B (2), and D
(4) display significant activity in the NCI's 60-cell line
anticancer assay with mean GI.sub.50's <1 .mu.M. Their
biological activity has attracted interest because some CNS, renal,
and breast cancer cell lines are among the types most sensitive to
these compounds. Inspection of the spectrum of activity shows no
correlation with any currently used agents and suggests that these
compounds may be acting at a previously unrecognized target or
through a novel mechanism.
[0004] Repeated attempts to isolate larger samples of the
schweinfurthins from natural sources have met with limited success;
the absolute stereochemistry of these compounds has yet to be
determined.
[0005] A cascade cyclization approach to the synthesis of racemic
Schweinfurthin B was reported by E. Treadwell, et al., Organic
Letters, 2002, 4, 3639-3642. The reported synthetic method,
however, could not be elaborated to provide enantiomerically
enriched mixtures of Schweinfurthin B.
[0006] Accordingly, there exists a need for synthetic methods that
are useful for preparing enantiomerically enriched Schweinfurthin
compounds. In addition to providing commercially useful quantities,
such methods would allow sufficient quantities of the
Schweinfurthin compounds to be prepared such that the absolute
stereochemistry of the biologically active natural products can be
determined.
[0007] Additionally, general synthetic methods for preparing the
Schweinfurthin ring structure would allow the preparation of
structurally related compounds that might also have useful
biological activity.
SUMMARY OF THE INVENTION
[0008] Applicant has discovered a process for preparing
enantiomerically enriched Schweinfurthin B and D analogs. In one
embodiment, the invention provides intermediate compounds useful
for preparing Schweinfurthin analogs.
[0009] The invention also provides a compound of formula (XX):
##STR00001##
wherein: [0010] R.sub.7 and R.sub.8 are each independently H or
(C.sub.1-C.sub.6) alkyl; [0011] R.sub.9 is H,
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl,
(C.sub.2-C.sub.15)alkanoyloxy, aryl or heteroaryl, which aryl or
heteroaryl is optionally substituted with one or more halo,
hydroxy, cyano, CF.sub.3, OCF.sub.3, NR.sup.aR.sup.b,
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.5)alkenyl,
(C.sub.2-C.sub.5)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl,
(C.sub.1-C.sub.5)alkoxy(C.sub.1-C.sub.15)alkoxy,
--P(.dbd.O)(OH).sub.2, and (C.sub.2-C.sub.15)alkanoyloxy; [0012]
R.sub.10 is H or (C.sub.1-C.sub.6) alkyl; and [0013] R.sup.a and
R.sup.b are each independently H or (C.sub.1-C.sub.6)alkyl [0014]
wherein any (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, or
(C.sub.2-C.sub.15)alkanoyloxy of R.sub.7, R.sub.8, and R.sub.9 is
optionally substituted with one or more halo, hydroxy, cyano, or
oxo (.dbd.O). [0015] or a pharmaceutically acceptable salt
thereof.
[0016] The invention also provides a pharmaceutical composition
comprising a compound of formula (XX), or a pharmaceutically
acceptable salt thereof, in combination with a pharmaceutically
acceptable diluent or carrier.
[0017] Additionally, the invention provides a therapeutic method
for treating cancer comprising administering to a mammal in need of
such therapy, an effective amount of a compound of formula (XX), or
a pharmaceutically acceptable salt thereof.
[0018] The invention provides a compound of formula (XX) for use in
medical therapy (e.g. for use in treating cancer), as well as the
use of a compound of formula (XX) for the manufacture of a
medicament useful for the treatment of cancer in a mammal, such as
a human.
[0019] The invention also provides processes and intermediates
disclosed herein that are useful for preparing compounds of formula
(XX) as well as other Schweinfurthin analogs.
BRIEF DESCRIPTION OF THE FIGURES
[0020] FIG. 1 shows the structure of Schweinfurthin analogs
A-D.
[0021] FIGS. 2-3 illustrates synthetic methods and intermediates
useful for preparing Schweinfurthin analogs.
DETAILED DESCRIPTION
[0022] The following definitions are used, unless otherwise
described: alkyl, alkoxy, alkenyl, alkynyl, etc. denote both
straight and branched groups; but reference to an individual
radical such as Apropyl@ embraces only the straight chain radical,
a branched chain isomer such as Aisopropyl@ being specifically
referred to. Alkenyl denotes a hydrocarbon chain with one or more
(1, 2, 3, or 4) double bonds. Likewise, alkynyl denotes a
hydrocarbon chain with one or more (1, 2, 3, or 4) triple bonds.
Aryl denotes a phenyl radical or an ortho-fused bicyclic
carbocyclic radical having about nine to ten ring atoms in which at
least one ring is aromatic; and heteroaryl encompasses a monocyclic
aromatic ring containing five or six ring atoms consisting of
carbon and one to four heteroatoms each selected from the group
consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is
absent or is H, O, (C.sub.1-C.sub.4)alkyl, phenyl or benzyl, as
well as a radical of an ortho-fused bicyclic heterocycle of about
eight to ten ring atoms derived therefrom, particularly a
benz-derivative or one derived by fusing a propylene, trimethylene,
or tetramethylene diradical thereto.
[0023] It will be appreciated by those skilled in the art that
compounds of the invention having a chiral center may exist in and
be isolated in optically active and racemic forms. Some compounds
may exhibit polymorphism. It is to be understood that the present
invention encompasses any racemic, optically-active, polymorphic,
or stereoisomeric form, or mixtures thereof, of a compound of the
invention, which possess the useful properties described herein, it
being well known in the art how to prepare optically active forms
(for example, by resolution of the racemic form by
recrystallization techniques, by synthesis from optically-active
starting materials, by chiral synthesis, or by chromatographic
separation using a chiral stationary phase). The term
"enantiomerically enriched" ("ee") as used herein refers to
mixtures that have one enantiomer present to a greater extent than
another. In one embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 2% ee; in another embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 5% ee; in another embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 20%; in another embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 50%; in another embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 80%; in another embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 90%; in another embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 95%; in another embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 98%; in another embodiment of the invention, the term
"enantiomerically enriched" refers to a mixture having at least
about 99%.
[0024] The term "enantiomerically enriched" includes
enantiomerically pure mixtures which are mixtures that are
substantially free of the species of the opposite optical activity
or one enantiomer is present in very low quantities, for example,
0.01%, 0.001% or 0.0001%.
[0025] The term "protecting group" or "blocking group" refers to
any group which, when bound to a hydroxy prevents undesired
reactions from occurring at this group and which can be removed by
conventional chemical or enzymatic steps to reestablish the
hydroxyl group. The particular removable blocking group employed is
not critical and preferred removable hydroxyl blocking groups
include conventional substituents such as allyl, benzyl, acetyl,
chloroacetyl, thiobenzyl, benzylidine, phenacyl, methyl methoxy,
silyl ethers (e.g., t-butyl-diphenylsilyl or t-butylsilyl ("TBS"))
and any other group that can be introduced chemically onto a
hydroxyl functionality and later selectively removed either by
chemical or enzymatic methods in mild conditions compatible with
the nature of the product. Suitable hydroxyl protecting groups are
known to those skilled in the art and disclosed in more detail in
T. W. Greene, Protecting Groups In Organic Synthesis; Wiley: New
York, 1981, and the references cited therein.
[0026] Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents.
[0027] Specifically, (C.sub.1-C.sub.15)alkyl can be methyl, ethyl,
propyl, isopropyl, butyl, iso-butyl, sec-butyl, t-butyl, pentyl,
3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, do-decyl, hexadecyl,
octadecyl, icosyl; (C.sub.1-C.sub.15)alkoxy can be methoxy, ethoxy,
propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy,
3-pentoxy, or hexyloxy; (C.sub.2-C.sub.15)alkenyl can be vinyl,
allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl,
2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl;
(C.sub.2-C.sub.15)alkynyl can be ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,
or 5-hexynyl; (C.sub.1-C.sub.15)alkanoyl can be acetyl, propanoyl
or butanoyl; (C.sub.1-C.sub.15)alkoxycarbonyl can be
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or
hexyloxycarbonyl; (C.sub.2-C.sub.15)alkanoyloxy can be acetoxy,
propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or
hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl.
[0028] In one specific embodiment of the invention R.sub.7 is
H.
[0029] In one specific embodiment of the invention R.sub.7 is
(C.sub.1-C.sub.6)alkyl.
[0030] In one specific embodiment of the invention R.sub.7 is
methyl.
[0031] In one specific embodiment of the invention R.sub.8 is
H.
[0032] In one specific embodiment of the invention R.sub.8 is
(C.sub.1-C.sub.6)alkyl.
[0033] In one specific embodiment of the invention R.sub.8 is
methyl.
[0034] In one specific embodiment of the invention R.sub.9 is
H.
[0035] In one specific embodiment of the invention R.sub.9 is
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl,
(C.sub.2-C.sub.15)alkanoyloxy.
[0036] In one specific embodiment of the invention R.sub.9 is
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl, or
(C.sub.2-C.sub.15)alkynyl.
[0037] In one specific embodiment of the invention R.sub.9 is aryl
optionally substituted with one or more halo, hydroxy, cyano,
CF.sub.3, OCF.sub.3, NR.sup.aR.sup.b, (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy.
[0038] In one specific embodiment of the invention R.sub.9 is aryl
optionally substituted with one or more halo, hydroxy, cyano,
CF.sub.3, OCF.sub.3, NR.sup.aR.sup.b, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy.
[0039] In one specific embodiment of the invention R.sub.9 is aryl
optionally substituted with one or more halo, hydroxy, cyano,
CF.sub.3, OCF.sub.3, NR.sup.aR.sup.b, (C.sub.2-C.sub.15)alkenyl,
(C.sub.1-C.sub.15)alkoxy.
[0040] In one specific embodiment of the invention aryl is phenyl
or naphthyl.
[0041] In one specific embodiment of the invention R.sub.9 is of
the formula
##STR00002##
wherein: [0042] R.sup.c and R.sup.e are each independently H, halo,
hydroxy, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
methoxymethoxy, and (C.sub.2-C.sub.15)alkanoyloxy; and [0043]
R.sup.d is H, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy; [0044] wherein any
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, or
(C.sub.2-C.sub.15)alkanoyloxy of R.sup.c, R.sup.e, and R.sup.d is
optionally substituted with one or more halo, hydroxy, cyano, or
oxo (.dbd.O).
[0045] In one specific embodiment of the invention R.sub.9 is of
the formula
##STR00003##
wherein: [0046] R.sup.c and R.sup.e are each independently H, halo,
hydroxy, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
methoxymethoxy, and (C.sub.2-C.sub.15)alkanoyloxy; and [0047]
R.sup.d is H, (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy; [0048] R.sup.g is H, cyano, fluoro,
or or --P(.dbd.O)(OH).sub.2; and [0049] R.sup.h is H, cyano,
fluoro, or --P(.dbd.O)(OH).sub.2; [0050] wherein any
(C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, or
(C.sub.2-C.sub.15)alkanoyloxy of R.sup.c, R.sup.e, and R.sup.d is
optionally substituted with one or more halo, hydroxy, cyano, or
oxo (.dbd.O).
[0051] In one specific embodiment of the invention R.sup.c and
R.sup.e are each independently H, fluoro, chloro, bromo, hydroxy,
or methoxy.
[0052] In one specific embodiment of the invention at least one of
R.sup.c and R.sup.e is hydroxy.
[0053] In one specific embodiment of the invention R.sup.d is
(C.sub.2-C.sub.15)alkenyl optionally substituted with one or more
halo, hydroxy, or oxo (.dbd.O).
[0054] In one specific embodiment of the invention R.sup.d is
hydrogen, trans-3,7-dimethyl-2,6-octadien-1-yl, or
trans-3,7-dimethyl-8-hydroxy-2,6-octadien-1-yl.
[0055] In one specific embodiment of the invention R.sub.9 is
isoxazolyl, imadazolyl, pyridyl, indolyl, or benzo[b]furanyl.
[0056] In one specific embodiment of the invention the compound of
the invention is isolated and purified.
[0057] In one specific embodiment the invention provides a diol of
formula (II)
##STR00004##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.3, R.sub.4, and R.sub.5 are each
independently a suitable hydroxy protecting group.
[0058] In one specific embodiment the invention provides an epoxide
of formula (III)
##STR00005##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.3, R.sub.4, and R.sub.5 are each
independently a suitable hydroxy protecting group.
[0059] In one specific embodiment the invention provides a compound
of formula (IV)
##STR00006##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6) alkyl; and R.sub.3 and R.sub.5 are each
independently a hydroxy protecting group.
[0060] In one specific embodiment the invention provides an alcohol
of formula (V)
##STR00007##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.5 is a hydroxy protecting
group.
[0061] In one specific embodiment the invention provides an
aldehyde of formula (VI)
##STR00008##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.5 is a hydroxy protecting
group.
[0062] In one specific embodiment the invention provides a stilbene
of formula (VII)
##STR00009##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; [0063] R.sub.5 is a hydroxy protecting
group; and [0064] R.sub.6 is aryl or heteroaryl optionally
substituted with one or more halo, hydroxy, cyano, CF.sub.3,
OCF.sub.3, NR.sup.aR.sup.b, (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.5)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy; wherein any (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, or (C.sub.2-C.sub.15)alkanoyloxy
of R.sub.6 is optionally substituted with one or more halo,
hydroxy, cyano, or oxo (--O);
[0065] In one specific embodiment the invention provides a compound
of formula (VIII)
##STR00010##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.6 is aryl or heteroaryl
optionally substituted with one or more halo, hydroxy, cyano,
CF.sub.3, OCF.sub.3, NR.sup.aR.sup.b, (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy; wherein any (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, or (C.sub.2-C.sub.15)alkanoyloxy
of R.sub.6 is optionally substituted with one or more halo,
hydroxy, cyano, or oxo (.dbd.O).
[0066] In one specific embodiment the invention provides a diol of
formula (IX)
##STR00011##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.6 is aryl or heteroaryl
optionally substituted with one or more halo, hydroxy, cyano,
CF.sub.3, OCF.sub.3, NR.sup.aR.sup.b, (C.sub.1-C.sub.15) alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, and
(C.sub.2-C.sub.15)alkanoyloxy; wherein any (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, or (C.sub.2-C.sub.15)alkanoyloxy
of R.sub.6 is optionally substituted with one or more halo,
hydroxy, cyano, or oxo (.dbd.O).
[0067] In one specific embodiment the invention provides a compound
which is enantiomerically enriched and has an enantiomeric excess
of at least about 90%.
[0068] In one specific embodiment the invention provides a compound
which is enantiomerically enriched and has an enantiomeric excess
of at least about 95%.
[0069] In one specific embodiment the invention provides a compound
which is enantiomerically enriched and has an enantiomeric excess
of at least about 98%.
[0070] In one specific embodiment the invention provides a compound
which is enantiomerically enriched and has an enantiomeric excess
of at least about 99%.
[0071] In one specific embodiment the invention provides a compound
which is enantiomerically pure.
[0072] In one specific embodiment the invention provides a compound
of formula (XX) which is the SSS enantiomer.
[0073] In one specific embodiment the invention provides a compound
of formula (XX) which is the RRR enantiomer.
[0074] In one specific embodiment the invention provides a
pharmaceutical composition comprising a compound of formula (XX),
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0075] In one specific embodiment the invention provides a method
for treating cancer comprising administering a therapeutically
effective amount of a compound of the invention to a mammal.
[0076] In one specific embodiment the invention provides a compound
of the invention for use in medical therapy.
[0077] In one specific embodiment the invention provides the use of
a compound as described in any one of claims 1-22 to prepare a
medicament useful for treating cancer (e.g. breast cancer or a
cancer of the CNS or renal system).
[0078] In one specific embodiment the invention provides method of
preparing a compound of formula (IIa):
##STR00012##
comprising oxidizing a diene of formula (Ia):
##STR00013##
to provide the diol of formula (IIa).
[0079] In one specific embodiment the invention provides a method
for preparing an epoxide of formula (IIIa)
##STR00014##
comprising treating a diol of formula (IIa):
##STR00015##
with a suitable base and mesyl chloride to provide the epoxide of
formula (IIIc).
[0080] In one specific embodiment the invention provides a method
of preparing a compound of formula (IVa)
##STR00016##
comprising treating epoxide of formula (IIIa):
##STR00017##
with tetrabutylammonium fluoride and trifluoroacetic acid to
provide a compound of formula (IVa).
[0081] In one specific embodiment the invention provides a method
of preparing an alcohol of formula (Va)
##STR00018##
comprising treating a compound of formula (IVa)
##STR00019##
with potassium carbonate and methanol to provide the compound of
formula (Va).
[0082] In one specific embodiment the invention provides a method
of preparing an aldehyde of formula (VIa)
##STR00020##
comprising oxidizing the alcohol of formula (Va)
##STR00021##
to provide the aldehyde of formula (VIa).
[0083] In one specific embodiment the invention provides a method
of preparing a stilbene of formula (VIIa):
##STR00022##
comprising reacting an aldehyde of formula (VIa):
##STR00023##
with a phosphonate of the following formula:
##STR00024##
to provide the stilbene of formula (VIIa)
[0084] In one specific embodiment the invention provides a method
for preparing a compound of formula (VIIIa):
##STR00025##
comprising deprotecting a corresponding compound of formula
(VIIa):
##STR00026##
by treatment with a suitable acid to provide the compound of
formula (VIIIa).
[0085] In one specific embodiment the invention provides a method
for preparing a diol compound of formula (IXa):
##STR00027##
comprising converting a corresponding compound of formula
(VIIIa)
##STR00028##
to the diol.
[0086] In one specific embodiment the invention provides a compound
of formula (IIa):
##STR00029##
[0087] In one specific embodiment the invention provides an
enantiomerically enriched compound of formula (IIIa):
##STR00030##
[0088] In one specific embodiment the invention provides an
enantiomerically enriched compound of the following formula:
##STR00031##
[0089] In one specific embodiment the invention provides a compound
of formula (IVa)
##STR00032##
[0090] In one specific embodiment the invention provides a compound
of formula (Va)
##STR00033##
[0091] In one specific embodiment the invention provides a compound
of formula (VIa)
##STR00034##
[0092] In one specific embodiment the invention provides a compound
of formula (VIIa):
##STR00035##
[0093] In one specific embodiment the invention provides a compound
of formula (VIIIa):
##STR00036##
[0094] In one specific embodiment the invention provides a compound
of formula (IXa):
##STR00037##
[0095] In one specific embodiment the invention provides a method
of preparing a diol of formula (II);
##STR00038##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.3, R.sub.4, and R.sub.5 are each
independently a suitable hydroxy protecting group; comprising:
oxidizing a corresponding diene of formula (I);
##STR00039##
to provide the diol of formula (II).
[0096] In one specific embodiment the invention provides a method
for preparing an epoxide of formula (III)
##STR00040##
comprising converting a corresponding diol of formula (II);
##STR00041##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.3, R.sub.4, and R.sub.5 are each
independently a hydroxy protecting group; to the epoxide of formula
(III).
[0097] In one specific embodiment the invention provides a method
of preparing a compound of formula (IV)
##STR00042##
comprising selectively removing R.sub.4 from a corresponding
epoxide of formula (III)
##STR00043##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.3, R.sub.4, and R.sub.5 are each
independently a hydroxy protecting group to provide an epoxy
alcohol, and treating the epoxy alcohol with a suitable acid to
provide a compound of formula (IV).
[0098] In one specific embodiment the invention provides a method
of preparing an alcohol of formula (V)
##STR00044##
comprising selectively removing R.sub.3 from a corresponding
compound of formula (IV)
##STR00045##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.3 and R.sub.5 are each
independently a hydroxy protecting group.
[0099] In one specific embodiment the invention provides a method
of preparing an aldehyde of formula (VI)
##STR00046##
comprising oxidizing a corresponding alcohol of formula (V)
##STR00047##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.5 is a hydroxy protecting group
to provide the aldehyde of formula (VI).
[0100] In one specific embodiment the invention provides a method
of preparing a stilbene of formula (VII):
##STR00048##
wherein R.sub.6 is aryl or heteroaryl optionally substituted with
one or more halo, hydroxy, cyano, CF.sub.3, OCF.sub.3,
NR.sup.aR.sup.b, (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, or (C.sub.2-C.sub.15)alkanoyloxy;
wherein any (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, or
(C.sub.2-C.sub.15)alkanoyloxy of R.sub.6 is optionally substituted
with one or more halo, hydroxy, cyano, or oxo (.dbd.O); comprising
reacting a corresponding aldehyde of formula (VI)
##STR00049##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.5 is a hydroxy protecting group
with a requisite alkene forming reagent.
[0101] In one specific embodiment the invention provides a method
for preparing a compound of formula (VIII):
##STR00050##
wherein R.sub.6 is aryl or heteroaryl optionally substituted with
one or more halo, hydroxy, cyano, CF.sub.3, OCF.sub.3,
NR.sup.aR.sup.b, (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, or (C.sub.2-C.sub.15)alkanoyloxy;
wherein any (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, or
(C.sub.2-C.sub.15)alkanoyloxy of R.sub.6 is optionally substituted
with one or more halo, hydroxy, cyano, or oxo (.dbd.O); comprising
removing the protecting group R.sub.5 from a corresponding compound
of formula (VII):
##STR00051##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.5 is a hydroxy protecting
group.
[0102] In one specific embodiment the invention provides a method
for preparing a diol of formula (IX):
##STR00052##
comprising converting a corresponding compound of formula
(VIII):
##STR00053##
wherein R.sub.1 and R.sub.2 are each independently H or
(C.sub.1-C.sub.6)alkyl; and R.sub.6 is aryl or heteroaryl
optionally substituted with one or more halo, hydroxy, cyano,
CF.sub.3, OCF.sub.3, NR.sup.aR.sup.b, (C.sub.1-C.sub.15)alkyl,
(C.sub.2-C.sub.15)alkenyl, (C.sub.2-C.sub.15)alkynyl,
(C.sub.1-C.sub.15)alkoxy, (C.sub.1-C.sub.15)alkanoyl,
(C.sub.1-C.sub.15)alkoxycarbonyl, or (C.sub.2-C.sub.15)alkanoyloxy;
wherein any (C.sub.1-C.sub.15)alkyl, (C.sub.2-C.sub.15)alkenyl,
(C.sub.2-C.sub.15)alkynyl, (C.sub.1-C.sub.15)alkoxy,
(C.sub.1-C.sub.15)alkanoyl, (C.sub.1-C.sub.15)alkoxycarbonyl, or
(C.sub.2-C.sub.15)alkanoyloxy of R.sub.6 is optionally substituted
with one or more halo, hydroxy, cyano, or oxo (.dbd.O); to the
diol.
[0103] In cases where compounds are sufficiently basic or acidic to
form stable nontoxic acid or base salts, administration of the
compounds as salts may be appropriate. Examples of pharmaceutically
acceptable salts are organic acid addition salts formed with acids
which form a physiological acceptable anion, for example, tosylate,
methanesulfonate, acetate, citrate, malonate, tartarate, succinate,
benzoate, ascorbate, .alpha.-ketoglutarate, and
.alpha.-glycerophosphate. Suitable inorganic salts may also be
formed, including hydrochloride, sulfate, nitrate, bicarbonate, and
carbonate salts.
[0104] Pharmaceutically acceptable salts may be obtained using
standard procedures well known in the art, for example by reacting
a sufficiently basic compound such as an amine with a suitable acid
affording a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium or lithium) or alkaline earth metal (for
example calcium) salts of carboxylic acids can also be made.
[0105] Suitable acids includes any organic acid suitable to
catalyze the reaction, such as, trifluoroacetic acid (TFA).
Suitable base includes any base suitable to catalyze the reaction,
such as, triethyl amine (TEA).
[0106] Alkene forming reagent, as used herein, includes any reagent
suitable to react with an aldehyde to form a double bond, such as,
an ylide or phosphonate reagent.
[0107] As used herein, the terms "isolated" and "purified" refer to
substances that are substantially free of other biological agents,
for example, at least about 95%, about 98%, or about 99% pure.
[0108] As used herein, the term "AD-mix-.alpha.," refers to an
asymmetric dihydroxylation chiral ligand system involving two
naturally derived dihydroquinine (DHQD) alkaloid units linked
together by a phthalazine (PHAL) linker. The enantiomeric alkaloid
does not occur in nature, so the naturally derived diasteromeric
dihydroquinidine (DHQ) based analogue is used, (DHQ).sub.2PHAL,
K.sub.3Fe(CN).sub.6--K.sub.2CO.sub.3 and K.sub.2OsO.sub.4-2H.sub.2O
(First reported by K. Barry Sharpless (cf. J. Org. Chem., 1992, 57,
2768)). It is commercially available from Aldrich (licensed from
Rhodia-Chirex Inc.) The term "AD-mix-.alpha.," includes the related
reagent "AD-mix-.beta.." Other suitable AD-mix-.alpha. reagents or
alternatives are known to those skilled in the art and disclosed in
more detail by Corey and Zhang in Organic Letters, 2001, 3,
3211-3214, and the references cited therein.
[0109] As used herein, the terms "treat," "treatment," and
"treating," extend to prophylaxis and include prevent, prevention,
preventing, lowering, stopping or reversing the progression or
severity of the condition or symptoms being treated. As such, the
term "treatment" includes both medical, therapeutic, and/or
prophylactic administration, as appropriate.
[0110] Compounds and pharmaceutical compositions suitable for use
in the present invention include those wherein the active compound
is administered in an effective amount to achieve its intended
purpose. More specifically, a "therapeutically effective amount"
means an amount effective to treat the disease, disorder, and/or
condition. Determination of a therapeutically effective amount is
well within the capacity of persons skilled in the art, especially
in light of the detailed disclosure provided herein.
[0111] The pharmaceutically active compounds of the invention can
be formulated as pharmaceutical compositions and administered to a
mammalian host, such as a human patient in a variety of forms
adapted to the chosen route of administration, i.e., orally or
parenterally, by intravenous, intramuscular, topical or
subcutaneous routes.
[0112] Thus, the present compounds may be systemically
administered, e.g., orally, in combination with a pharmaceutically
acceptable vehicle such as an inert diluent or an assimilable
edible carrier. They may be enclosed in hard or soft shell gelatin
capsules, may be compressed into tablets, or may be incorporated
directly with the food of the patient's diet. For oral therapeutic
administration, the active compound may be combined with one or
more excipients and used in the form of ingestible tablets, buccal
tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like. Such compositions and preparations should contain at
least 0.1% of active compound. The percentage of the compositions
and preparations may, of course, be varied and may conveniently be
between about 2 to about 60% of the weight of a given unit dosage
form. The amount of active compound in such therapeutically useful
compositions is such that an effective dosage level will be
obtained.
[0113] The tablets, troches, pills, capsules, and the like may also
contain the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, sucrose or fructose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and flavoring such as
cherry or orange flavor. Of course, any material used in preparing
any unit dosage form should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed. In addition, the
active compound may be incorporated into sustained-release
preparations and devices.
[0114] The active compound may also be administered intravenously
or intraperitoneally by infusion or injection. Solutions of the
active compound or its salts can be prepared in water, optionally
mixed with a nontoxic surfactant. Dispersions can also be prepared
in glycerol, liquid polyethylene glycols, triacetin, and mixtures
thereof and in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to prevent the growth of
microorganisms.
[0115] The pharmaceutical dosage forms suitable for injection or
infusion can include sterile aqueous solutions or dispersions or
sterile powders comprising the active ingredient which are adapted
for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions, optionally encapsulated in
liposomes. In all cases, the ultimate dosage form should be
sterile, fluid and stable under the conditions of manufacture and
storage. The liquid carrier or vehicle can be a solvent or liquid
dispersion medium comprising, for example, water, ethanol, a polyol
(for example, glycerol, propylene glycol, liquid polyethylene
glycols, and the like), vegetable oils, nontoxic glyceryl esters,
and suitable mixtures thereof. The proper fluidity can be
maintained, for example, by the formation of liposomes, by the
maintenance of the required particle size in the case of
dispersions or by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars, buffers or sodium chloride. Prolonged absorption
of the injectable compositions can be brought about by the use in
the compositions of agents delaying absorption, for example,
aluminum monostearate and gelatin.
[0116] Sterile injectable solutions are prepared by incorporating
the active compound in the required amount in the appropriate
solvent with various of the other ingredients enumerated above, as
required, followed by filter sterilization. In the case of sterile
powders for the preparation of sterile injectable solutions, the
preferred methods of preparation are vacuum drying and the freeze
drying techniques, which yield a powder of the active ingredient
plus any additional desired ingredient present in the previously
sterile-filtered solutions.
[0117] For topical administration, the present compounds may be
applied in pure form, i.e., when they are liquids. However, it will
generally be desirable to administer them to the skin as
compositions or formulations, in combination with a
dermatologically acceptable carrier, which may be a solid or a
liquid. Useful solid carriers include finely divided solids such as
talc, clay, microcrystalline cellulose, silica, alumina and the
like. Useful liquid carriers include water, alcohols or glycols or
water-alcohol/glycol blends, in which the present compounds can be
dissolved or dispersed at effective levels, optionally with the aid
of non-toxic surfactants. Adjuvants such as fragrances and
additional antimicrobial agents can be added to optimize the
properties for a given use. The resultant liquid compositions can
be applied from absorbent pads, used to impregnate bandages and
other dressings, or sprayed onto the affected area using pump-type
or aerosol sprayers.
[0118] Thickeners such as synthetic polymers, fatty acids, fatty
acid salts and esters, fatty alcohols, modified celluloses or
modified mineral materials can also be employed with liquid
carriers to form spreadable pastes, gels, ointments, soaps, and the
like, for application directly to the skin of the user.
[0119] Examples of useful dermatological compositions which can be
used to deliver the pharmaceutically active compounds of the
invention to the skin are known to the art; for example, see
Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No.
4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman
(U.S. Pat. No. 4,820,508).
[0120] Useful dosages of the pharmaceutically active compounds of
the invention can be determined by comparing their in vitro
activity, and in vivo activity in animal models. Methods for the
extrapolation of effective dosages in mice, and other animals, to
humans are known to the art; for example, see U.S. Pat. No.
4,938,949.
[0121] The amount of the compound, or an active salt or derivative
thereof, required for use in treatment will vary not only with the
particular salt selected but also with the route of administration,
the nature of the condition being treated and the age and condition
of the patient and will be ultimately at the discretion of the
attendant physician or clinician.
[0122] The compounds of the invention can also be administered in
combination with other therapeutic agents that are effective to
treat cancer.
[0123] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations; such as multiple
inhalations from an insufflator or by application of a plurality of
drops into the eye.
[0124] The anti-cancer activity of a compound of the invention may
be determined using pharmacological models which are well known to
the art, for example, NCI 60-cell line anticancer assay.
Representative compounds of formula (XX) were tested and were found
to have anti-cancer activity as illustrated in this assay.
[0125] The invention will now be illustrated by the following
non-limiting Examples.
EXAMPLES
Example 1
3-Deoxyschweinfurthin B (30, FIG. 3)
##STR00054##
[0127] To a solution of stilbene 29 (24 mg, 0.04 mmol) in MeOH (2
mL) was added camphorsulphonic acid (10 mg, 0.04 mmol). The
resulting solution was stirred at rt for 20 hr, and then heated to
60.degree. C. for an additional 5 hr. The reaction was quenched by
addition of sat. NaHCO.sub.3, extracted with ethyl acetate, and the
organic phase was washed with brine and dried over MgSO.sub.4.
Concentration in vacuo, followed by final purification by column
chromatography (1:1, hexanes:ethyl acetate) afforded
3-deoxyschweinfurthin B (30, 16 mg, 79%) as a clear oil: .sup.1H
NMR (CDCl.sub.3) .delta. 6.83 (m, 4H), 6.55 (s, 2H), 5.31 (s, 1H),
5.28 (t, J=6.9 Hz, 1H), 5.06 (m, 1H), 3.88 (s, 3H), 3.43 (m, 3H),
2.72 (d, J=9.1 Hz, 2H), 2.15-2.06 (m, 5H), 1.90-1.82 (m, 3H), 1.82
(s, 3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.25 (s, 3H), 1.10 (s, 3H),
0.88 (s, 3H); .sup.13C NMR (CDCl.sub.3) .delta. 155.2 (2C), 148.9,
142.7, 139.2, 137.1, 132.1, 128.8, 128.6, 125.7, 124.2, 122.6,
121.4, 120.6, 112.8, 107.0, 106.2 (2C), 78.0, 77.1, 55.0, 46.8,
39.7, 38.4, 37.6, 28.3, 27.3, 26.4, 25.7, 23.1, 22.5, 19.8, 17.7,
16.2, 14.3; HRMS (ESI) calcd for C.sub.35H.sub.46O.sub.5 (M.sup.+)
546.3345, found 546.3342.
[0128] The intermediate stilbene 29 was prepared as follows.
[0129] a.
3-(3',7'-Dimethyl-2-octen-6'S,7'-diol)-4-(tert-butyldimethyl-sil-
oxy)-5-methoxy-benzyloxy]-tert-butyldimethylsilane (21, FIG. 2). To
a solution of AD-mix-.alpha. (2.41 g) in water/t-BuOH (15 mL, 1:1)
was added methanesulfonamide (0.17 g) and the solution was cooled
to -7.degree. C. The geranylated arene 13 (0.89 g, 1.71 mmol) (As
reported by E. Treadwell, et al., Organic Letters, 2002, 4,
3639-3642) was added via syringe as a neat oil and the solution was
kept at 0.degree. C. for 20 hours, and then allowed to warm to rt
and stirred for an additional 5 days. Solid Na.sub.2SO.sub.3 was
added and the solution was stirred for 1 hour. The solution was
extracted with EtOAc, the resulting organic layer was washed with
2N NaOH and brine, and then dried (MgSO.sub.4) and concentrated in
vacuo to afford a clear oil. Final purification by column
chromatography (1:1 hexanes:ethyl acetate) gave the diol 21 (0.86
g, 92%) as a clear oil: .sup.1H NMR .delta. 6.72 (d, J=2.0 Hz, 1H),
6.65 (d, J=2.0 Hz, 1H), 5.38 (t, J=7.1 Hz, 1H), 4.64 (s, 2H), 3.77
(s, 3H), 3.35 (d, J=7.3 Hz, 2H), 3.35 (m, 1H), 2.33-2.23 (m, 2H),
2.17-2.00 (m, 2H), 1.70 (s, 3H), 1.66-1.56 (m, 1H), 1.50-1.36 (m,
1H), 1.19 (s, 3H), 1.15 (s, 3H), 1.00 (s, 9H), 0.93 (s, 9H), 0.17
(s, 6H), 0.08 (s, 6H); .sup.13C NMR .delta. 149.7, 141.3, 135.7,
133.7, 132.1, 123.3, 119.0, 107.3, 78.2, 73.0, 65.0, 54.7, 36.7,
29.7, 28.5, 26.4, 26.1 (3C), 25.9 (3C), 23.2, 21.0, 18.9, 16.2,
-3.9 (2C), -5.2 (2C). Anal. Calcd for
C.sub.30H.sub.56O.sub.5Si.sub.2: C, 65.17; H, 10.21. Found: C,
65.11, H, 10.22.
[0130] b.
4-(tert-Butyldimethylsilyloxy)-5-methoxy-3-(3',7'-dimethyl-6'-ep-
oxy-2'-octenyl)benzyloxy-tert-butyldimethylsilane (24, FIG. 3). To
a solution of diol 21 (2.03 g, 3.7 mmol), in CH.sub.2Cl.sub.2 (20
mL) at 0.degree. C., was added TEA (1.35 mL, 9.69 mmol) followed 30
minutes later by MSCl (0.43 mL, 5.58 mmol). After 35 minutes the
reaction was allowed to warm to rt, and after a total of 2 hrs a
second aliquot of TEA (0.80 mL, 5.74 mmol) was added and the
reaction was stirred for 30 min. A solution of K.sub.2CO.sub.3
(2.31 g, 16.7 mmol) in MeOH (70 mL) was poured into the vessel and
the solution was allowed to react for 20 hours. After filtration
and extraction of the of the resulting filtrate with ethyl acetate,
the combined organic phase was washed with brine, dried
(MgSO.sub.4), and concentrated under vacuum to afford a white oil.
Final purification by flash chromatography (12:1 hexanes:ethyl
acetate) yielded the target epoxide 24 as a viscous clear oil (1.48
g, 75%): .sup.1H NMR .delta. 6.72 (d, J=1.7 Hz, 1H), 6.65 (d, J=1.6
Hz, 1H), 5.36 (tm, J=7.2 Hz, 1H), 4.64 (s, 2H), 3.77 (s, 3H), 3.34
(d, J=7.1 Hz, 2H), 2.72 (t, J=6.3 Hz, 1H), 2.30-2.10 (m, 2H), 1.70
(s, 3H), 1.75-1.60 (m, 2H), 1.28 (s, 3H), 1.25 (s, 3H), 0.99 (s,
9H), 0.93 (s, 9H), 0.17 (s, 6H), 0.08 (s, 6H); .sup.13C NMR .delta.
149.7, 141.3, 135.0, 133.7, 132.1, 123.3, 119.0, 107.3, 65.0, 64.2,
58.3, 54.7, 36.3, 28.5, 27.4, 26.1 (3C), 26.0 (3C), 24.9, 18.9,
18.7, 18.4, 16.2, -3.9 (2C), -5.2 (2C). Anal. Calcd for
C.sub.30H.sub.54O.sub.4Si.sub.2: C, 67.36; H, 10.17. Found: C,
67.12; H, 10.28.
[0131] c.
(6'R)-4-Hydroxy-3-methoxy-5-(3',7'-dimethyl-6'-epoxy-2'-octenyl)-
-benzyl alcohol (26, FIG. 3). Silyl ether 24 (840 mg, 1.57 mmol)
was dissolved in THF (70 mL) and the solution was cooled to
0.degree. C. To this solution was added TBAF (4.6 mL, 1.00 M in
THF), the reaction was allowed to warm to rt and after 1.5 hrs was
quenched with sat. NH.sub.4Cl. After extraction with ethyl acetate,
the combined organic extract was washed with water and brine, dried
over MgSO.sub.4, and concentrated in vacuo to give a yellow oil.
Final purification by flash chromatography (4:1, hexanes:ethyl
acetate) gave the diol 26 (352 mg, 96%): .sup.1H NMR (CDCl.sub.3)
.delta. 6.77 (s, 1H), 6.74 (s, 1H), 5.70 (s, 1H), 5.37 (t, J=7.3
Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 3.89, (s, 3H), 3.36 (d, J=7.3 Hz,
2H), 2.71 (t, J=6.2 Hz, 1H), 2.24-2.12 (m, 2H), 1.74 (s, 3H),
1.68-1.62 (m, 3H), 1.27 (s, 3H), 1.25 (s, 3H); .sup.13C NMR
(CDCl.sub.3) .delta. 146.3, 142.8, 135.3, 132.1, 127.0, 122.7,
120.7, 107.5, 65.6, 64.3, 58.4, 56.0, 36.4, 27.8, 27.3, 24.8, 18.7,
16.1. Anal. Calcd for C.sub.18H.sub.26O.sub.4.0.5H.sub.2O: C,
68.55; H, 8.63. Found: C, 68.23; H, 8.53.
[0132] d. Diol (27, FIG. 3). To a solution of epoxyphenol 26 (352
mg, 1.2 mmol) in CH.sub.2Cl.sub.2 (40 mL) at 0.degree. C. was added
trifluoroacetic acid (0.26 mL, 3.4 mmol). The resulting solution
was allowed to stir 2 hours and Et.sub.3N (1.4 mL, 10.0 mmol) was
added. After an additional 30 minutes, water (75 mL) was added, the
phases were separated, and the aqueous phase was extracted with
ethyl acetate. The combined organic phase was washed with water,
and brine then dried (MgSO.sub.4), and concentrated. Final
purification by flash chromatography (2:1 to 1:1 hexanes:ethyl
acetate) afforded the tricyclic diol 27 (135 mg, 38%) as a light
yellow oil: .sup.1H NMR (CDCl.sub.3) .delta. 6.73 (s, 1H), 6.70 (s,
1H), 4.57 (s, 2H), 3.86 (s, 3H), 3.39 (dd, J=11.6, 3.8 Hz, 1H),
2.69 (d, J=8.9 Hz, 2H), 2.15-2.04 (m, 2H), 1.88-1.59 (m, 6H, 2H
exchange with D.sub.2O), 1.23 (s, 3H), 1.08 (s, 3H), 0.87 (s, 3H);
.sup.13C NMR (CDCl.sub.3) .delta. 148.9, 142.1, 132.0, 122.5,
120.4, 108.5, 78.0, 76.8, 65.5, 56.0, 46.7, 38.3, 37.6, 28.3, 27.3,
23.1, 19.7, 14.2; HRMS (ESI) calcd for C.sub.18H.sub.26O.sub.4
(M.sup.+) 306.1831, found 306.1823. Anal. Calcd for
C.sub.18H.sub.26O.sub.4.0.75H.sub.2O: C, 67.58; H, 8.66. Found: C,
67.96; H, 8.33.
[0133] e. Aldehyde (28, FIG. 3). To a solution of benzylic alcohol
27 (251 mg, 0.82 mmol) in CH.sub.2Cl.sub.2 (30 mL) was added
MnO.sub.2 (1.71 g, 19.6 mmol) as a single aliquot.
[0134] The resulting suspension was allowed to stir for 26 hours
then filtered through celite and the residue was concentrated in
vacuo to afford the aldehyde 28 as a white solid (249 mg, 100%):
[.alpha.].sup.25.0.sub.D=+97.8 (c 0.126, CHCl.sub.3); .sup.1H NMR
(CDCl.sub.3) .delta. 9.80 (s, 1H), 7.25 (s, 1H), 7.24 (s, 1H), 3.90
(s, 3H), 3.45 (dd, J=11.4, 3.8 Hz, 1H), 2.80-2.77 (m, 2H),
2.22-2.15 (m, 1H), 1.94-1.82 (m, 2H), 1.74-1.61 (m, 2H), 1.28 (s,
3H), 1.13 (s, 3H), 0.91 (s, 3H); .sup.13C NMR .delta. 191.1, 149.5,
148.7, 128.7, 127.3, 122.5, 107.3, 78.4, 77.8, 56.0, 46.5, 38.4,
37.5, 28.2, 27.3, 23.0, 20.0, 14.3. Anal. Calcd for
C.sub.18H.sub.24O.sub.4.1H.sub.2O: C, 67.06; H, 8.13. Found: C,
66.98; H, 8.17.
[0135] f. 3-Deoxy-dimethoxyschweinfurthin B (29, FIG. 3). A
suspension of NaH (29 mg, 1.2 mmol), and 15-crown-5 (4 .mu.L, 0.02
mmol) in THF (1.5 mL) was cooled to 5.degree. C. To this was added
aldehyde 28 (10 mg, 0.03 mmol) and phosphonate 5 (22 mg, 0.05 mmol)
in THF (2 mL). The mixture was allowed to warm to rt and stirred a
total of 18 hr. Water was added dropwise, and the solution was
extracted with ether. The resulting organic phase was washed with
brine, dried over MgSO.sub.4, and concentrated in vacuo. Final
purification by column chromatography (3.5:1 to 1:1, hexanes:ethyl
acetate) gave the stilbene 29 (15.2 mg, 80%) as a straw colored
oil: .sup.1H NMR (CDCl.sub.3) 6.95-6.85 (m, 6H), 5.24 (s, 4H), 5.24
(t, 1H), 5.07 (t, J=11.7 Hz, 1H), 3.89 (s, 3H), 3.50 (s, 6H), 3.40
(m, 3H), 2.72 (d, J=8.7 Hz, 2H), 2.16-1.85 (m, 7H), 1.79 (s, 3H),
1.70-1.65 (m, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.26 (s, 3H), 1.10
(s, 3H), 0.89 (s, 3H); .sup.13C NMR (CDCl.sub.3) .delta. 155.9
(2C), 148.9, 142.5, 136.7, 134.6, 131.2, 128.9, 128.2, 126.4,
124.3, 122.6, 122.5, 120.5, 119.5, 106.8, 105.9 (2C), 94.5 (2C),
78.1, 77.0, 55.9 (2C), 55.9, 46.7, 39.8, 38.4, 37.7, 28.3, 27.3,
26.7, 25.6, 23.1, 22.7, 19.8, 17.6, 16.0, 14.3; HRMS (ESI) calcd
for C.sub.39H.sub.54O.sub.7 (M.sup.+) 634.3870, found 634.3871.
This compound is also a compound of the invention.
[0136] As shown in FIG. 2, the intermediate diol 21 can be prepared
in enantiomerically pure form through formation of the S-mandelate
or R-mandelate ester, followed by separation of the resulting
diastereomers (e.g. by chromatography) and subsequent hydrolysis.
For example see Neighbors J. D. et al., J. Org. Chem., 2005, 70,
925-931. Details for the preparation of the mandelate esters is
provided below.
[0137] g. S-19-methyl mandelate (22, FIG. 2). To a solution of diol
21 (33 mg, 0.1 mmol), EDC (19 mg, 0.1 mmol), and DMAP (4 mg, 0.03
mmol), in CH.sub.2Cl.sub.2 (2 mL) was added S-(+)-O-methyl mandelic
acid (12 mg, 0.1 mmol). After 1 hour at rt, water was added and the
resulting solution was extracted with CH.sub.2Cl.sub.2. The
combined organic phase was dried (MgSO.sub.4) and concentrated.
Further purification by flash chromatography (5:1 to 2:1
hexanes:ethyl acetate) afforded the mandelate ester 22 (25 mg, 60%)
as a clear oil, along with a small amount of the diastereomeric
ester (not isolated): [.alpha.].sup.26.4.sub.D=+42.1 (c 0.28,
CHCl.sub.3); .sup.1H NMR (CDCl.sub.3) .delta. 7.46 (dd, J=7.9, 1.8
Hz, 2H), 7.40-7.32 (m, 3H), 6.72 (s, 1H), 6.64 (s, 1H), 5.27 (t,
J=8.0 Hz, 1H), 4.79 (s, 1H), 4.65 (s, 2H), 3.77 (s, 3H), 3.43 (s,
3H), 3.33 (d, J=7.9 Hz, 2H), 1.96 (t, J=8.0 Hz, 2H), 1.78-1.61 (m,
3H), 1.64 (s, 3H), 1.00 (s, 9H), 0.94 (s, 15H), 0.18 (s, 6H), 0.09
(s, 6H); .sup.13C NMR .delta. 170.4, 149.7, 141.3, 136.5, 135.0,
133.7, 132.1, 129.0, 128.7 (2C), 127.2 (2C), 123.1, 119.0, 107.3,
82.6, 80.7, 72.3, 65.0, 57.3, 54.7, 35.0, 28.5, 28.1, 26.1 (3C),
26.0 (3C), 25.9, 24.6, 18.9, 18.4, 16.3, -3.9 (2C), -5.1 (2C); HRMS
(ESI) calcd for C.sub.39H.sub.MO.sub.7Si.sub.2Na
(M+Na).sup.+723.4088, found 723.4090.
[0138] h. R--O-methyl mandelate (23, FIG. 2). In a manner identical
to that described above for preparation of ester 22, the diol 21
(38 mg, 0.07 mmol), EDC (20 mg, 0.1 mmol), and DMAP (10 mg, 0.08
mmol) were allowed to react with R-(-)-O-methyl mandelic acid (12
mg, 0.07 mmol). Standard workup and final purification by column
chromatography (5:1 hexanes:ethyl acetate) afforded the target
ester 23 (41.5 mg, 82%) as a clear oil along with the
R,R-diastereomer (total yield of 100%). A diastereomeric ratio of
84:16, corresponding to an initial ee of 68%, was determined by
integration of signals at 5.00 and 5.27 ppm in the .sup.1H NMR
spectrum of the initial mixture. For diastereomer 23: .sup.1H NMR
.delta. 7.46 (d, J=8.7 Hz, 2H), 7.36-7.28 (m, 3H), 6.73 (s, 1H),
6.57 (s, 1H), 5.00 (t, J=6.6 Hz, 1H), 4.80 (m, 2H), 4.65 (s, 2H),
3.78 (s, 3H), 3.43 (s, 3H), 3.24 (d, J=6.9 Hz, 2H), 1.60 (m, 5H, 1H
exchanges with D.sub.2O), 1.45 (s, 3H), 1.16 (s, 6H), 0.99 (s, 9H),
0.93 (s, 9H), 0.17 (s, 6H), 0.09 (s, 6H); .sup.13C NMR .delta.
170.9, 149.7, 141.3, 136.3, 134.9, 133.6, 132.1, 128.8, 128.6 (2C),
127.1 (2C), 123.0, 119.0, 107.3, 82.7, 80.7, 72.4, 65.1, 57.3,
54.7, 35.4, 28.3, 28.2, 26.6, 26.1 (3C), 26.0 (3C), 24.7, 18.9,
18.4, 16.1, -3.9 (2C), -5.1 (2C); HRFABMS calcd for
C.sub.39H.sub.64O.sub.7NaSi.sub.2 (M+Na).sup.+ 723.4088, found
723.4101.
Example 2
Dimethoxy-3-deoxyschweinfurthin B (34)
##STR00055##
[0140] A solution of phosphonate 33 (20 mg, 0.04 mmol) and aldehyde
28 (10 mg, 0.03 mmol) in THF (1.5 mL) was added to a suspension of
NaH (29 mg, 0.71 mmol, 60% suspension in oil) and 15C5 (4 .mu.L, 22
nmol) in THF (2.5 mL) at 0.degree. C. The resulting mixture was
allowed to come to rt and stir for 20 hours. The solution was
quenched with water, extracted (ether), and the combined organic
layers were washed with brine. The residual organic layer was dried
(MgSO.sub.4), and concentrated in vacuo to give a yellow oil. Final
purification by column chromatography (1:1 hexanes:EtOAc) afforded
the target schweinfurthin analog 34 (6.4 mg, 37%) as a clear oil:
.sup.1H NMR .delta. 6.95-6.88 (m, 4H), 6.67 (s, 2H), 5.19 (t, J=6.8
Hz, 1H), 5.07 (t, J=5.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 6H),
3.46-3.44 (m, 2H), 3.36-3.33 (m, 1H), 2.75-2.72 (m, 2H), 2.21-1.75
(m, 9H), 1.77 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H), 1.27 (s, 3H),
1.10 (s, 3H), 0.89 (s, 3H); HREIMS calcd for
C.sub.37H.sub.50O.sub.5 (M.sup.+) 574.3658, found 574.3651.
[0141] The intermediate phosphonate 33 was prepared as follows.
[0142] a.
[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dimethoxy-phenyl]-methanol
(32) nBuLi (0.87 mL, 2.15 M in hexanes) was added dropwise to a
solution of benzylic alcohol 31 (105 mg, 0.62 mmol) and TMEDA (0.28
mL, 1.9 mmol) in THF (10 mL) at -20.degree. C. After the solution
was stirred at -20.degree. C. for 1 h, CuBr as its DMS complex (255
mg, 1.24 mmol) was added in one portion and the solution was
stirred for 1 h at -20.degree. C. Geranyl bromide (0.15 mL, 0.76
mmol) in THF (5 mL) was added via syringe and the reaction mixture
was stirred for 2 h at -20.degree. C. The reaction was quenched by
addition of 1N NH.sub.4Cl, the aqueous layer was neutralized to pH
7 with 1N HCl, and this layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried (MgSO.sub.4),
and concentrated in vacuo. Final purification of the residue by
flash column chromatography (20% EtOAc in hexanes) afforded alcohol
32 (76 mg, 40%) as a clear oil. .sup.1H NMR .delta. 6.54 (s, 2H),
5.17-5.12 (tm, J=7.1 Hz, 1H), 5.07-5.02 (tm, J=6.9 Hz, 1H), 4.63
(s, 2H), 3.80 (s, 6H), 3.31 (d, J=7 Hz, 2H), 2.04-1.89 (m, 4H),
1.74 (s, 3H), 1.63 (s, 3H), 1.55 (s, 3H); .sup.13C NMR .delta.
160.3 (2C), 141.8, 136.8, 133.2, 126.6, 124.8, 119.9, 104.7 (2C),
68.0, 57.9 (2C), 41.9, 28.9, 27.8, 24.2, 19.8, 18.1. Anal. Calcd
for C.sub.19H.sub.28O.sub.3: C, 74.96; H, 9.27. Found: C, 74.82; H,
9.34.
[0143] b.
[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dimethoxy-benzyl]-phosphon-
ic acid diethyl ester (33) Methanesulfonyl chloride (0.15 mL, 1.94
mmol) was added dropwise to a solution of alcohol 32 (181 mg, 0.59
mmol) and Et.sub.3N (0.3 mL 1.9 mmol) in CH.sub.2Cl.sub.2 (5 mL)
and the solution was stirred for 2 h at 0.degree. C. The reaction
mixture was allowed to warm to rt over 5 h, quenched by addition of
H.sub.2O, and extracted with EtOAc. The combined organic layers
were washed with NH.sub.4Cl (sat), brine, dried (MgSO.sub.4), and
concentrated in vacuo. The resulting residue and NaI (310 mg, 2.06
mmol) were stirred in acetone (8 mL) for 24 h. The reaction mixture
was concentrated in vacuo to afford a red solid, which was
dissolved in EtOAc. After the resulting yellow solution was washed
once with NaHCO.sub.3 and then with Na.sub.2S.sub.2O.sub.3 until
the color faded, it was extracted with ether and the combined
organic layers were dried (MgSO.sub.4) and concentrated in vacuo.
The resulting yellow oil was added to triethyl phosphite (1.5 mL)
and the mixture was heated at 100.degree. C. for 20 h. After the
solution was allowed to cool to rt, it was poured into ether (5
mL). The mixture was extracted with ether, dried (MgSO.sub.4), and
concentrated in vacuo. The initial yellow oil was purified by flash
chromatography (50% EtOAc in hexanes) to afford phosphonate 33 (73
mg, 40%) as a light yellow oil: .sup.1H NMR .delta. 6.49 (d, J=2.4
Hz, 2H), 5.18-5.13 (tm, J=7.3 Hz, 1H), 5.07-5.02 (tm, J=6.8 Hz,
1H), 4.09-3.98 (m, 4H), 3.80 (s, 6H), 3.31 (d, J=7.0 Hz, 2H), 3.11
(d, J.sub.PH=21.5 Hz, 2H), 2.06-1.94 (m, 4H), 1.82 (s, 3H), 1.68
(s, 3H), 1.56 (s, 3H), 1.27 (tm, J=7.0 Hz, 6H); .sup.13C NMR 160.9
(d, J.sub.CP=3.1 Hz, 2C), 137.5, 134.1, 132.9 (d, J.sub.CP=9.0 Hz),
127.5, 125.7 (d, J.sub.CP=2.9 Hz), 120.1 (d, J.sub.CP=3.4 Hz),
108.6 (d, J.sub.CP=6.7 Hz, 2C), 65.1 (d, J.sub.CP=6.7 Hz, 2C), 58.7
(2C), 42.8, 37.1 (d, J.sub.CP=137.3 Hz), 29.7, 28.6, 24.9, 20.6,
19.4 (d, J.sub.CP=6.0 Hz, 2C), 18.9; .sup.31P NMR .delta. +26.4;
HRMS (EI) calcd for C.sub.23H.sub.37O.sub.5PNa [M.sup.++Na],
447.2276; found 447.2265.
Example 3
7-{2-[4-(3,7-Dimethyl-octa-6,7-dienyl)-phenyl]-vinyl}-5-methoxy-1,1,4a-tri-
methyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (56)
##STR00056##
[0145] To a suspension of NaH (64 mg, 1.6 mmol, 60% in mineral oil)
in THF (17 mL) at 0.degree. C. was added a mixture of phosphonate
43 (56 mg, 0.15 mmol) and aldehyde 28 (28 mg, 0.09 mmol) in THF (3
mL). After 5 min 15C5 (10 .mu.L) was added and the reaction was
allowed to warm to rt and stir for 19 hr. Water was added and the
mixture was extracted with ethyl acetate. The combined organic
phase was washed with brine and dried (MgSO.sub.4). Concentration
in vacuo afforded a yellow oil and final purification by column
chromatography (1:1 hexanes:EtOAc) gave the stilbene 56 (26 mg,
55%) as a clear oil: .sup.1H NMR .delta. 7.40 (m, 2H), 7.16 (m,
2H), 6.95-6.94 (m, 2H), 6.89-6.88 (m, 2H), 5.34 (td, J=7.3, 1.0 Hz,
1H), 5.11 (t, J=6.7 Hz, 1H), 3.89 (s, 3H), 3.43 (dd, J=11.7, 4.0
Hz, 1H), 3.35 (d, J=7.3 Hz, 2H), 2.74-2.71 (m, 2H), 2.16-2.04 (m,
5H), 1.90-1.81 (m, 2H), 1.80-1.70 (m, 2H), 1.71 (s, 3H), 1.69 (s,
3H), 1.61 (s, 3H), 1.25 (s, 3H), 1.10 (s, 3H), 0.90 (s, 3H);
.sup.13C NMR .delta. 148.9, 142.5, 140.9, 136.3, 135.2, 131.4,
129.1 (2C), 128.6, 127.8, 126.2, 126.2 (2C), 124.2, 122.8, 122.6,
120.4, 106.9, 78.0, 77.0, 56.0, 46.7, 39.7, 38.4, 37.6, 33.9, 28.3,
27.3, 26.6, 25.7, 23.1, 19.8, 17.7, 16.1, 14.3; HREIMS calcd for
C.sub.35H.sub.46O.sub.3 (M.sup.+) 514.3447, found 514.3447.
[0146] The intermediate phosphonate 43 was prepared as follows.
##STR00057##
[0147] a.
tert-Butyl-[4-(3,7-dimethyl-octa-2,6-dienyl)-benzyloxy]-dimethyl-
-silane (40) nBuLi (7.90 mL, 2.5 M in hexane, 19.8 mmol) was added
dropwise to a stirred solution of aryl bromide 39 (3.13 g, 10.4
mmol) in THF (15 mL) over 15 min at -78.degree. C. The reaction
mixture was allowed to stir for 2 h at -78.degree. C. Geranyl
bromide (2.5 mL, 12.6 mmol) was added dropwise and the reaction
mixture was stirred for 2 h at -78.degree. C. The reaction mixture
was allowed to warm to rt, was quenched by addition of H.sub.2O,
and then was extracted with ether. The combined organic layers were
washed with NH.sub.4Cl (sat), brine, dried (MgSO.sub.4), and
concentrated in vacuo. Final purification of the residue by flash
column chromatography (hexanes) afforded compound 40 (2.61 g, 70%)
as a light yellow oil: .sup.1H NMR .delta. 7.24-7.19 (m, 2H),
7.14-7.12 (m, 2H), 5.43-5.38 (tm, J=7.4 Hz, 1H), 5.20-5.15 (tm,
J=7.5 Hz, 1H), 4.77 (s, 2H), 3.41 (d, J=7.4 Hz, 2H), 2.19-2.09 (m,
4H), 1.77 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H), 1.01 (s, 9H), 0.16
(s, 6H); .sup.13C NMR .delta.. 140.6, 140.0, 136.3, 131.6, 128.4
(2C), 126.4 (2C), 124.5, 123.4, 65.1, 39.9, 34.1, 26.8, 26.2 (3C),
25.9, 18.6, 17.9, 16.3, -5.0 (2C). Anal. Calcd for
C.sub.23H.sub.38OSi: C, 77.01; H, 10.68. Found: C, 77.08; H,
10.69.
[0148] b. [4-(3,7-Dimethyl-octa-2,6-dienyl)-phenyl]-methanol (41)
TBAF (26.0 mL, 1.0 M in THF, 26.0 mmol) was added dropwise to a
stirred solution of protected alcohol 40 (2.56 g, 7.14 mmol) in THF
(20 mL). The solution was stirred for 2 h at 0.degree. C. and then
was allowed to warm to rt over 5 h. The reaction was quenched by
addition of NH.sub.4Cl (sat), and extracted with EtOAc. The
combined organic layers were washed with brine, dried (MgSO.sub.4),
and concentrated in vacuo. Final purification of the residue by
flash column chromatography (20% EtOAc in hexanes) afforded
compound 41 (1.35 g, 77%) as a light yellow oil: .sup.1H NMR
.delta. 7.28-7.24 (m, 2H), 7.18-7.15 (m, 2H), 5.35-5.30 (tm, J=7.2
Hz, 1H), 5.12-5.08 (tm, J=6.7 Hz, 1H), 4.63 (s, 2H), 3.35 (d, J=7.3
Hz, 2H), 2.12-2.02 (m, 4H), 1.70 (s, 1H exchanges with D.sub.2O),
1.70 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H); .sup.13C NMR .delta.
141.6, 138.5, 136.5, 131.7, 128.7 (2C), 127.4 (2C), 124.4, 123.1,
65.4, 39.9, 34.1, 26.8, 26.0, 17.9, 16.3; HRMS (EI) calcd for
C.sub.17H.sub.24O [M.sup.+], 244.1827; found 244.1832.
[0149] c. 1-(3,7-Dimethyl-octa-2,6-dienyl)-4-iodomethyl-benzene
(42) Methanesulfonyl chloride (1.8 mL, 23.3 mmol) was added
dropwise to a stirred solution of alcohol 41 (1.27 g, 5.22 mmol)
and Et.sub.3N (3 mL 21.5 mmol) in CH.sub.2Cl.sub.2 (20 mL) at
0.degree. C. over 2 h. The reaction mixture was allowed to warm to
rt over 5 h. After the reaction was quenched by addition of water,
it was extracted with EtOAc. The combined organic layers were
washed with NH.sub.4Cl (sat), brine, dried (MgSO.sub.4), and
concentrated in vacuo. The resulting yellow residue was treated
with NaI (3.51 g, 23.4 mmol) in acetone (20 mL) at rt for 24 h. The
reaction mixture was concentrated in vacuo to afford a red solid,
which was dissolved in EtOAc. After the resulting solution was
washed once with NaHCO.sub.3 and then with Na.sub.2S.sub.2O.sub.3
until the color faded, the aqueous layer was extracted with ether
and the combined organic layers were dried (MgSO.sub.4) and
concentrated in vacuo. Final purification of the residue by flash
column chromatography (20% EtOAc in hexanes) afforded compound 42
(1.44 g, 78%) as a yellow oil: .sup.1H NMR .delta. 7.30-7.24 (m,
2H), 7.11-7.08 (m, 2H), 5.35-5.30 (tm, J=7.2 Hz, 1H), 5.14-5.09
(tm, J=6.6 Hz, 1H), 4.47 (s, 2H), 3.33 (d, J=7.2 Hz, 2H), 2.14-2.03
(m, 4H), 1.71 (s, 6H), 1.61 (s, 3H); .sup.13C NMR .delta. 141.9
(2C), 136.8, 131.7, 129.0 (2C), 128.9 (2C), 124.4, 122.8, 39.9,
34.1, 26.8, 26.0, 17.9, 16.3, 6.4; HRMS (EI) calcd for
C.sub.17H.sub.23 [M.sup.+-I], 227.1800; found 227.1801.
[0150] d.
Diethyl[4-(3,7-dimethyl-octa-2,6-dienyl)-benzyl]phosphonate (43) A
stirred solution of iodide 42 (1.35 g, 3.82 mmol) in triethyl
phosphite (25 mL) was heated at reflux for 4 h, and then allowed to
cool to rt. Excess triethyl phosphite was removed by vacuum
distillation and the resulting yellow oil was purified by flash
chromatography (30% EtOAc in hexanes) to afford phosphonate 43
(1.34 g, 97%) as a light yellow oil: .sup.1H NMR .delta. 7.22-7.18
(m, 2H), 7.12-7.09 (m, 2H), 5.33-5.29 (tm, J=7.2 Hz, 1H), 5.11-5.08
(tm, J=6.6 Hz, 1H), 4.06-4.00 (m, 4H), 3.32 (d, J=7.2 Hz, 2H), 3.11
(d, J.sub.PH=21.3 Hz, 2H), 2.12-2.05 (m, 4H), 1.69 (s, 3H), 1.68
(s, 3H), 1.60 (s, 3H), 1.24 (t, J=7.2 Hz, 6H); .sup.13C NMR .delta.
140.6 (d, J.sub.CP)=3.8 Hz), 136.5, 131.7, 129.8 (d, J.sub.CP=6.5
Hz, 2C), 128.9 (d, J.sub.CP=9.3 Hz), 128.7 (d, J.sub.CP=3.1 Hz,
2C), 124.5, 123.1, 62.2 (d, J.sub.CP=6.8 Hz, 2C), 39.9, 34.4, 32.6
(d, J.sub.CP=138.2 Hz), 26.8, 26.0, 17.9, 16.6 (d, J.sub.CP=6.1 Hz,
2C), 16.3; .sup.31P NMR .delta. +26.6. Anal. Calcd for
C.sub.21H.sub.33O.sub.3P: C, 69.21; H, 9.13. Found: C, 69.09; H,
9.16.
Example 4
7-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-phenyl]-vinyl}-5-metho-
xy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol
(57)
##STR00058##
[0152] To a stirred suspension of NaH (30 mg, 1.3 mmol) and 15C5 (5
.mu.L, 3 mol %) in THF (5 mL) was added phosphonate 46 (71 mg,
0.177 mmol) and aldehyde 28 (20 mg, 0.066 mmol) at 0.degree. C. and
the solution was allowed to warm to rt over 10 h. The reaction was
quenched by addition of water and then was extracted with EtOAc.
The combined organic layers were washed with brine, dried
(MgSO.sub.4), and concentrated in vacuo. Final purification of the
residue by flash column chromatography (50% EtOAc in hexanes)
afforded compound 57 (30.9 mg, 85%) as a clear oil: .sup.1H NMR
6.99-6.79 (m, 6.79), 5.26-5.22 (tm, J=7.0 Hz, 1H), 5.09-5.04 (tm,
J=6.8 Hz, 1H), 3.9 (s, 3H), 3.47-3.42 (m, 1H), 3.37-3.35 (dm, J=7.2
Hz, 2H), 2.77-2.74 (m, 1H), 2.73-2.70 (m, 1H), 2.18-1.82 (m, 7H),
1.76 (s, 3H), 1.72-1.69 (m, 2H), 1.65 (s, 3H), 1.58 (s, 3H), 1.27
(s, 3H), 1.09 (s, 3H), 0.90 (s, 3H); .sup.13C NMR .delta.
163.4-160.0 (dd, J.sub.CF=241.8 Hz, J.sub.CF=9.8 Hz, 2C), 149.3,
143.4, 137.9, 136.8, 131.7, 130.5, 124.5 (t, J.sub.CF=9.5 Hz),
124.3, 123.0, 121.1, 120.8, 115.9 (t, J.sub.CF=23.4 Hz), 110.0,
108.7 (dd, J.sub.CF 26.6 Hz, J.sub.CF=8.6 Hz, 2C), 107.3, 78.2,
77.4, 56.3, 47.0, 39.8, 38.6, 37.9, 28.5, 27.6, 26.7, 25.8, 23.4,
21.6 (t, J.sub.CF=2.0 Hz), 20.1, 17.8, 16.2, 14.5; HRMS (EI) calcd
for C.sub.35H.sub.44O.sub.3F.sub.2[M.sup.+], 550.3259; found
550.3256.
[0153] The intermediate phosphonate 46 was prepared as follows.
##STR00059##
[0154] a.
[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-phenyl]-methanol
(45) A solution of benzylic alcohol 44 (67 mg, 0.46 mmol) and TMEDA
(0.21 mL, 1.4 mmol) in THF (10 mL) was cooled to -20.degree. C.
After nBuLi (0.64 mL, 2.15 M in hexanes) was added dropwise and the
solution was stirred at -20.degree. C. for 1 h, CuBr as its DMS
complex (192 mg, 0.93 mmol) was added in one portion and the
solution was stirred for 1 h at -20.degree. C. A solution of
geranyl bromide (0.11 mL, 0.55 mmol) in THF (5 mL) was added to the
reaction mixture via syringe at -20.degree. C. and the solution was
stirred for 2 h. The reaction was quenched by addition of 1N
NH.sub.4Cl, the aqueous layer was neutralized to pH 7 with 1N HCl,
and then was extracted with EtOAc. The combined organic layers were
washed with brine, dried (MgSO.sub.4), and concentrated in vacuo.
Purification by flash column chromatography (20% EtOAc in hexanes)
afforded alcohol 45 (68 mg, 53%) as a clear oil: .sup.1H NMR
.delta. 6.91-6.83 (dm, J.sub.HF=7.5 Hz, 2H), 5.23-5.19 (tm, J=7.3
Hz, 1H), 5.08-5.03 (tm, J=6.8 Hz, 1H), 4.65 (d, J=5.6 Hz, 2H,
becomes a singlet at D.sub.2O wash), 3.36 (d, J=7.2 Hz, 2H),
2.07-1.96 (m, 4H), 1.75 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H);
.sup.13C NMR .delta. 161.6 (dd, J.sub.CF=246.9, 9.6 Hz, 2C), 141.2
(t, J.sub.CF=9.0 Hz), 136.8, 131.7, 124.3, 120.7, 116.4 (t,
J.sub.CF=20.9 Hz), 109.4 (dd, J.sub.CF=26.6, 8.9 Hz, 2C), 54.4 (t,
J.sub.CP=2.1 Hz), 39.8, 26.7, 25.9, 21.5 (t, J.sub.CF=2.5 Hz),
17.9, 16.2; HRMS (EI) calcd for C.sub.17H.sub.22F.sub.2O [M.sup.+],
280.1639; found 280.1639.
[0155] b.
[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-benzyl]-phosphoni- c
acid diethyl ester (46) PBr.sub.3 (0.03 mL, 0.32 mmol) was added
dropwise to a solution of alcohol 45 (180 mg, 0.64 mmol) in ether
(10 mL) and the solution was stirred for 7 h at 0.degree. C. The
reaction mixture was poured into ice water, extracted with ether,
and washed with brine. The combined organic layer was dried
(MgSO.sub.4), and concentrated in vacuo. The resulting yellow oil
was added to triethyl phosphite (3 mL) and sodium iodide (62 mg,
0.41 mmol), and the mixture was heated at 100.degree. C. for 30 h.
After this solution was allowed to cool to rt, it was poured into
ether (10 mL) and washed with sodium thiosulfate. The mixture was
extracted with ether, dried (MgSO.sub.4), and concentrated in
vacuo. The initial yellow oil was purified by flash chromatography
(gradient, 30-80% EtOAc in hexanes) to afford phosphonate 46 (153
mg, 60%) as a light yellow oil: .sup.1H NMR .delta. 6.84-6.77 (m,
2H), 5.22-5.17 (tm, J=6.4 Hz, 1H), 5.08-5.03 (tm, J=6.9 Hz, 1H),
4.11-4.00 (m, 4H), 3.35-3.32 (dm, J=7.2 Hz, 2H), 3.11-3.04 (dm,
J.sub.CP=21.7 Hz, 2H), 2.07-1.92 (m, 4H), 1.74 (s, 3H), 1.65 (s,
3H), 1.58 (s, 3H), 1.31-1.24 (tm, J=7.1 Hz, 6H); .sup.13C NMR
.delta. 161.4 (ddd, J.sub.CF=245.7, 10.0 Hz, J.sub.CP=3.5 Hz, 2C),
136.8, 132.0-131.6 (m), 131.7, 124.3, 120.7, 116.0 (td,
J.sub.CF=20.3 Hz, J.sub.CP=3.5 Hz), 112.9-112.5 (m, 2C), 65.5 (d,
J.sub.CP=6.75 Hz, 2C), 39.8, 33.5 (dd, J.sub.CP=139.2 Hz,
J.sub.CF=1.9 Hz), 26.7, 25.9, 21.4 (t, J.sub.CF=1.7 Hz), 17.9, 16.6
(d, J.sub.CP=6.00 Hz, 2C), 16.1; .sup.31P NMR .delta.+24.8 (t,
J.sub.CP=2.3 Hz). Anal. Calcd for C.sub.21H.sub.31F.sub.2O.sub.3P:
C, 62.99; H, 7.80. Found: C, 63.22; H, 7.98.
Example 5
5-Methoxy-1,1,4a-trimethyl-7-styryl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-o-
l (59)
##STR00060##
[0157] To a suspension of NaH (26 mg, 1 mmol) and 15C5 (5 .mu.L, 3
mol %) in THF (5 mL) was added phosphonate 43 (25 mg, 0.12 mmol)
and aldehyde 28 (15.8 mg, 0.05 mmol) at 0.degree. C. and the
reaction mixture was stirred for 10 h at rt. The reaction was
quenched by addition of water and extracted with EtOAc. The
combined organic layers were washed with brine, dried (MgSO.sub.4),
and concentrated in vacuo. Final purification of the residue by
flash column chromatography (35% EtOAc in hexanes) afforded
compound 59 (17 mg, 90%) as a clear oil: .sup.1H NMR .delta.
7.50-7.47 (m, 2H), 7.37-7.34 (m, 2H), 7.26-7.20 (m, 1H), 6.98 (d,
J=8.5 Hz, 2H), 6.91-6.87 (m, 2H), 3.90 (s, 3H), 3.46-3.41 (m, 1H),
2.77-2.75 (m, 1H), 2.72-2.68 (m, 2H), 2.16-2.11 (m, 1H), 1.90-1.81
(m, 2H), 1.74-1.55 (m, 3H), 1.26 (s, 3H), 1.11 (s, 3H), 0.89 (s,
3H); .sup.13C NMR .delta. 149.2, 142.9, 137.9, 129.2, 128.9 (2C),
128.8, 127.4, 126.5, 126.4 (2C), 122.9, 120.8, 107.2, 78.2, 77.3,
56.3, 47.0, 38.6, 37.9, 28.5, 27.6, 23.4, 20.1, 14.5; HRMS (EI)
calcd for C.sub.25H.sub.30O.sub.3 [M.sup.+], 378.2195; found
378.2195.
Example 6
5-[2-(7-Hydroxy-4-methoxy-8,8,10a-trimethyl-5,7,8,8a,9,10a-hexahydro-6H-xa-
nthen-2-yl)-vinyl]-benzene-1,3-diol (60)
##STR00061##
[0159] To a stirred solution of stilbene 54 (30 mg, 0.06 mmol) in
methanol (5 mL) was added CSA (20 mg, 0.09 mmol) and the solution
was allowed to stir 10 h at 50.degree. C. The reaction mixture was
allowed to cool to rt, concentrated in vacuo, and the residue was
dissolved in EtOAc and water. The mixture was extracted with ether,
washed with brine, dried (MgSO.sub.4), and concentrated in vacuo.
Final purification of the residue by flash column chromatography
(60% EtOAc in hexanes) afforded compound 60 (23 mg, 93%) as a clear
oil: .sup.1H NMR (CDCl.sub.3/CD.sub.3OD) .delta. 7.06-6.88 (m, 4H),
6.58 (d, J=2.0 Hz, 2H), 6.31 (t, J=2.0 Hz, 1H), 3.97 (s, 3H),
3.75-3.68 (m, 1H), 2.96-2.81 (m, 2H), 2.20-1.68 (m, 5H), 1.33 (s,
3H), 1.16 (s, 3H), 0.97 (s, 3H); .sup.13C NMR
(CDCl.sub.3/CD.sub.3OD) .delta. 157.7 (2C), 148.3, 142.0, 139.4,
128.8, 128.0, 125.9, 122.3, 120.3, 106.6, 104.3 (2C), 101.2, 77.0,
76.7, 55.1, 46.9, 37.8, 37.2, 27.2, 26.2, 22.5, 18.9, 13.4; HRMS
(EI) calcd for C.sub.25H.sub.30O.sub.5 [M.sup.+], 410.2093; found
410.2093.
[0160] The intermediate stilbene 54 was prepared as follows.
##STR00062##
[0161] a. (3,5-bis-Methoxymethoxy-benzyl)-phosphonic acid diethyl
ester (37). Methanesulfonyl chloride (1.4 mL, 18.1 mmol) was added
dropwise to a stirred solution of alcohol 35 (881 mg, 3.9 mmol) and
Et.sub.3N (2.2 mL 15.76 mmol) in CH.sub.2Cl.sub.2 (150 mL). The
solution was stirred for 2 h at 0.degree. C. The reaction mixture
was allowed to warm to rt over 5 h, quenched by addition of water,
and extracted with EtOAc. The combined organic layers were washed
with NH.sub.4Cl (sat), brine, dried (MgSO.sub.4), and concentrated
in vacuo. The yellow residue was treated with NaI (2.33 g, 15.6
mmol) in acetone (20 mL) for 24 h at rt. The reaction mixture was
concentrated in vacuo to a red solid, which was dissolved in EtOAc.
After the resulting yellow solution was washed once with
NaHCO.sub.3 and then with Na.sub.2S.sub.2O.sub.3 until the color
faded, it was extracted with ether and the combined organic layers
were dried (MgSO.sub.4) and concentrated in vacuo. Final
purification of the residue by flash column chromatography (30%
EtOAc in hexanes) afforded compound iodide (1.12 g, 84%) as a
yellow oil: .sup.1H NMR .delta. 6.73 (d, J=2.2 Hz, 2H), 6.63 (t,
J=2.2 Hz, 1H), 5.2 (s, 4H), 4.4 (s, 2H), 3.5 (s, 6H); .sup.13C NMR
.delta. 158.5 (2C), 141.5, 110.3 (2C), 104.7, 94.7 (2C), 56.3 (2C),
5.5; HRMS (EI) calcd for C.sub.11H.sub.15O.sub.4I [M.sup.+],
338.0015; found 338.0016. A stirred solution of this iodide (1.11
g, 3.3 mmol) in triethyl phosphite (2.5 mL) was heated at reflux
for 9 h, then it was allowed to cool to rt and poured into ether (8
mL). The resulting mixture was extracted with ether, dried
(MgSO.sub.4) and concentrated in vacuo. Final purification of the
residue by flash chromatography (gradient, 30-80% EtOAc in hexanes)
afforded phosphonate 37 (734 mg, 64%) as a light yellow oil:
.sup.1H NMR .delta. 6.58-6.55 (m, 3H), 5.06 (s, 4H), 3.97 (m, 4H),
3.39 (s, 6H), 3.01 (d, J.sub.PH=21.6 Hz, 2H), 1.20 (tm, J=7.1 Hz,
6H); .sup.13C NMR .delta. 158.2 (d, J.sub.CP=3.2 Hz, 2C), 133.8 (d,
J.sub.CP=8.8 Hz), 111.2 (d, J.sub.CP=6.5 Hz, 2C), 103.5 (d,
J.sub.CP=3.4 Hz), 94.4 (2C), 62.1 (d, J.sub.CP=6.6 Hz, 2C), 55.9
(2C), 33.9 (d, J.sub.CP=138.1 Hz), 16.3 (d, J.sub.CP=6.1 Hz, 2C);
.sup.31P NMR .delta. +25.7. Anal. Calcd for
C.sub.15H.sub.25O.sub.7P: C, 51.72; H, 7.23. Found: C, 51.55; H,
7.27.
[0162] b.
7-[2-(3,5-bis-Methoxymethoxy-phenyl)-vinyl]-5-methoxy-1,1,4a-tri-
methyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (54) To a stirred
suspension of NaH (30 mg, 1.3 mmol) and 15C5 (5 .mu.L, 3 mol %) in
THF (5 mL) was added phosphonate 37 (25 mg, 0.12 mmol) and aldehyde
28 (20 mg, 0.066 mmol) at 0.degree. C. The reaction mixture was
allowed to warm to rt over 10 h. The reaction was quenched by
addition of water, and extracted with EtOAc. After the combined
organic layers were washed with brine, dried (MgSO.sub.4), and
concentrated in vacuo, final purification by flash column
chromatography (50% EtOAc in hexanes) afforded compound 54 (30 mg,
91%) as a clear oil: .sup.1H NMR .delta. 7.00 (d, J=17.1 Hz, 1H),
6.90-6.85 (m, 5H), 6.64 (t, J=2.1 Hz, 1H), 5.20 (s, 4H), 3.90 (s,
3H), 3.51 (s, 6H), 3.46-3.42 (m, 1H), 2.76-2.74 (m, 1H), 2.73-2.71
(m, 1H), 2.17-2.11 (m, 1H), 1.91-1.81 (m, 2H), 1.75-1.54 (m, 2H),
1.27 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); .sup.13C NMR .delta.
158.7 (2C), 149.2, 143.0, 140.1, 129.6, 128.9, 126.2, 122.8, 120.9,
107.8 (2C), 107.3, 104.1, 94.7 (2C), 78.2, 77.3, 55.3 (2C), 56.2,
46.9, 38.6, 37.9, 28.5, 27.6, 23.4, 20.1, 14.5; HRMS (EI) calcd for
C.sub.29H.sub.38O.sub.7 [M.sup.+], 498.2618; found 498.2608. This
compound is also a compound of the invention.
Example 7
2-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-5-[2-(7-hydroxy-4-methoxy-8,8,1-
0a-trimethyl-5,7,8,8a,9,10a-hexahydro-6H-xanthen-2-yl)-vinyl]-benzene-1,3--
diol (62)
##STR00063##
[0164] CSA (20 mg, 0.09 mmol) was added to a stirred solution of
stilbene 58 (17 mg, 0.026 mmol) in methanol (5 mL) and the reaction
mixture was allowed to stir for 15 h at 50.degree. C. The reaction
mixture was allowed to cool to rt, and concentrated in vacuo and
the residue was dissolved in EtOAc and water. The mixture was
extracted with ether, the organic layer was washed with brine,
dried (MgSO.sub.4), and concentrated in vacuo. Purification of the
residue by flash column chromatography (80% EtOAc in hexanes)
afforded compound 62 (6 mg, 42%) as a clear oil: .sup.1H NMR
.delta. 6.94-6.73 (m, 4H), 6.49 (s, 2H), 5.40 (s, 2H, exchangeable
with D.sub.2O), 5.31-5.29 (m, 2H), 4.01 (s, 2H), 3.89 (s, 3H),
3.45-3.43 (m, 3H), 2.74-2.72 (m, 1H), 2.72-2.70 (m, 1H), 2.37-2.12
(m, 5H), 1.91-1.57 (m, 10H), 1.46 (s, 1H, exchangeable with
D.sub.2O), 1.26 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); .sup.13C NMR
.delta. 155.2 (2C), 149.2, 142.9, 139.2, 137.6, 136.5, 129.0 (2C),
125.8, 125.0, 122.9, 122.7, 120.8, 112.6, 107.2, 106.4 (2C), 78.1,
69.1, 56.2, 47.0, 39.4, 38.6, 37.9, 28.4, 27.6 (2C), 25.1, 23.4,
22.7, 20.1, 15.8, 14.5, 13.9; HRMS (EI) calcd for
C.sub.35H.sub.46O.sub.6 [M.sup.+], 561.3216; found 561.3214.
[0165] The intermediate stilbene 58 was prepared as follows.
##STR00064##
[0166] a.
{4-[8-(tert-butyl-diphenyl-silanyloxy)-3,7-dimethyl-octa-2,6-die-
nyl]-3,5-bis-methoxymethoxy-phenyl}-methanol (49) PBr.sub.3 (0.7
mL, 7.4 mmol) was added dropwise to a solution of alcohol 47 (521
mg, 1.27 mmol) in ether (10 mL) and the solution was stirred for 7
h at 0.degree. C. The reaction mixture was poured into ice water,
extracted with ether, and washed with brine. The combined organic
layer was dried (MgSO.sub.4), and concentrated in vacuo to give a
yellow residue, bromide 48. A solution of benzylalcohol 35 (305 mg,
1.34 mmol) in THF (5 mL) was added to a stirred suspension of KH
(87 mg, 2.2 mmol) in THF (10 mL) and the reaction mixture was
stirred for 1 h at 0.degree. C. After TMEDA (0.4 mL, 2.7 mmol) was
added, the solution was cooled to -20.degree. C., then nBuLi (1.87
mL, 2.15 M in hexanes) was added dropwise and the solution was
stirred at -20.degree. C. for 1 h. CuBr as its DMS complex (556 mg,
2.7 mmol) was added in one portion and the solution was stirred for
1 h at -20.degree. C. Bromide 48 in THF (5 mL) was added to the
reaction mixture via syringe at -20.degree. C. After 2 h, the
reaction was quenched by addition of 1N NH.sub.4Cl, and the aqueous
layer was neutralized to pH 7 with 1N HCl, and extracted with
EtOAc. The combined organic layer was washed with brine, dried
(MgSO.sub.4), and concentrated in vacuo. Final purification by
flash column chromatography (20% EtOAc in hexanes) afforded
compound 49 (341 mg, 43% from alcohol 47) as a clear oil: .sup.1H
NMR .delta. 7.70-7.67 (m, 4H), 7.43-7.35 (m, 6H), 6.79 (s, 2H),
5.43-5.39 (tm, J=7.0 Hz, 1H), 5.26-5.19 (m, 5H), 4.62 (s, 2H), 4.03
(s, 2H), 3.47 (s, 6H), 3.40 (d, J=9 Hz, 2H), 2.19-1.96 (m, 4H),
1.81 (s, 3H), 1.59 (s, 3H), 1.06 (s, 9H); .sup.13C NMR .delta.
156.0 (2C), 140.2, 135.8 (4C), 134.8, 134.2 (2C), 134.1, 129.7
(2C), 127.8 (4C), 124.6, 122.9, 119.6, 106.7 (2C), 94.6 (2C), 69.3,
65.7, 56.2 (2C), 39.8, 27.1 (3C), 26.4, 22.8, 19.5, 16.3, 13.7.
Anal. Calcd for C.sub.37H.sub.50O.sub.6Si: C, 71.81; H, 8.14.
Found: C, 71.72; H, 7.98.
[0167] b.
tert-Butyl-[8-(4-iodomethyl-2,6-bis-methoxymethoxy-phenyl)-2,6-d-
imethyl-octa-2,6-dienyloxy]-diphenyl-silane (50) Methanesulfonyl
chloride (0.1 mL, 1.3 mmol) was added dropwise to a stirred
solution of alcohol 49 (364 mg, 0.62 mmol) and Et.sub.3N (0.2 mL
1.4 mmol) in CH.sub.2Cl.sub.2 (5 mL) and the solution was stirred
for 2 h at 0.degree. C. The reaction mixture was allowed to warm to
it over 5 h, quenched by addition of H.sub.2O, and extracted with
EtOAc. The combined organic layers were washed with NH.sub.4Cl
(sat) and brine, dried (MgSO.sub.4), and concentrated in vacuo. The
resulting yellow residue was allowed to react with NaI (132 mg,
0.886 mmol) in acetone (8 mL) for 24 h at it. The reaction mixture
was concentrated in vacuo to afford a red solid, which was
dissolved in EtOAc. After the resulting yellow solution was washed
once with NaHCO.sub.3 and then with Na.sub.2S.sub.2O.sub.3 until
the color faded, it was extracted with ether and the combined
organic layers were dried (MgSO.sub.4) and concentrated in vacuo.
Final purification by flash column chromatography (30% EtOAc in
hexanes) afforded the iodide 50 (347 mg, 77%) as a yellow oil:
.sup.1H NMR .delta. 7.77-7.72 (m, 4H), 7.49-7.38 (m, 6H), 6.84 (s,
2H), 5.48-5.44 (tm, J=6.6 Hz, 1H), 5.29-5.19 (tm, J=6.0 Hz, 1H),
5.20 (s, 4H), 4.43 (s, 2H), 4.08 (s, 2H), 3.50 (s, 6H), 3.41 (d,
J=7.1 Hz, 2H), 2.30-2.01 (m, 4H), 1.85 (s, 3H), 1.63 (s, 3H), 1.11
(s, 9H); .sup.13C NMR .delta. 155.8 (2C), 138.1, 135.7 (4C), 134.9,
134.1 (2C), 134.0, 129.7 (2C), 127.8 (4C), 124.5, 122.6, 120.2,
108.6 (2C), 94.6 (2C), 69.2, 56.2 (2C), 39.8, 27.0 (3C), 26.3,
22.9, 19.5, 16.3, 13.7, 6.7; HRMS (EI) calcd for
C.sub.37H.sub.49IO.sub.5Si [M.sup.+], 728.2394; found 728.2395.
[0168] c.
{4-[8-(tert-Butyl-diphenyl-silanyloxy)-3,7-dimethyl-octa-2,6-die-
nyl]-3,5-bis-methoxymethoxy-benzyl}-phosphonic acid diethyl ester
(51) A solution of iodide 50 (68 mg, 0.093 mmol) and sodium iodide
(39 mg, 0.26 mmol) in triethyl phosphite (1.5 mL) was heated at
100.degree. C. for 20 h, allowed to cool to rt, and poured into
ether (5 mL). The resulting mixture was extracted with ether, dried
(MgSO.sub.4), and concentrated in vacuo. The initial yellow oil was
purified by flash chromatography (50% EtOAc in hexanes) to afford
phosphonate 51 (63.5 mg, 92%) as light yellow oil: .sup.1H NMR
.delta. 7.70-7.67 (m, 4H), 7.42-7.34 (m, 6H), 6.70 (d, J.sub.HP=2.3
Hz, 2H), 5.42-5.39 (tm, J=5.7 Hz, 1H), 5.21-5.17 (trm, J=7.0 Hz,
1H), 5.17 (s, 4H), 4.10-4.00 (m, 6H), 3.45 (s, 6H), 3.37 (d, J=7.0
Hz, 2H), 3.09 (d, J.sub.pH=21.5 Hz, 2H), 2.14-1.95 (m, 4H), 1.80
(s, 3H), 1.58 (s, 3H), 1.28 (trm, J=7.08 Hz, 6H), 1.06 (s, 9H);
.sup.13C NMR .delta. 155.8 (d, J.sub.CP=3.2 Hz, 2C), 135.8 (4C),
134.7, 134.1 (2C), 134.0, 130.5 (d, J.sub.CP=9.0 Hz), 129.7 (2C),
127.7 (4C), 124.7, 123.0, 118.9 (d, J.sub.CP=3.9 Hz), 109.8 (d,
J.sub.CP=6.6 Hz, 2C), 94.6 (2C), 69.2, 62.3 (d, J.sub.CP=6.7 Hz,
2C), 56.2 (2C), 39.8, 34.1 (d, J.sub.CP=138.3 Hz), 27.0 (3C), 26.5,
22.7, 19.5, 16.6 (d, J.sub.CP=5.8 Hz, 2C), 16.3, 13.6; .sup.31P NMR
.delta. +26.2. Anal. Calcd for C.sub.41H.sub.59O.sub.8PSi: C,
66.64; H, 8.05. Found: C, 66.58; H, 8.32.
[0169] d.
[4-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymetho-
xy-benzyl]-phosphonic acid diethyl ester (52) TBAF (0.3 mL, 1M in
THF, 0.3 mmol) was added to a solution of phosphonate 51 (55.1 mg,
0.075 mmol) in THF (3 mL) and the solution was stirred for 3 h at
rt. The reaction was quenched by addition of water and EtOAc, and
then extracted with EtOAc. The combined organic layer was washed
with brine, dried (MgSO.sub.4), and concentrated in vacuo. Final
purification of the residue by flash column chromatography
(gradient, 60-100% EtOAc in hexanes) afforded compound 52 (36 mg,
96%) as a clear oil: .sup.1H NMR .delta. 6.66 (broad s, 2H),
5.30-5.24 (m, 1H), 5.13-5.06 (m, 5H), 4.04-3.97 (m, 4H), 3.83 (s,
2H), 3.42 (s, 6H), 3.32 (d, J=7.0 Hz, 2H), 3.04 (d, J.sub.PH=21.5
Hz, 2H), 2.07-1.95 (m, 4H), 1.73 (s, 3H), 1.53 (s, 3H), 1.24 (trm,
J=6.8 Hz, 6H); .sup.13C NMR .delta. 155.8 (d, J.sub.CP=3.4 Hz, 2C),
135.1, 134.1, 130.4 (d, J.sub.CP=9.1 Hz), 125.9, 123.4, 119.1 (d,
J.sub.CP=3.9 Hz), 109.9 (d, J.sub.CP=6.6 Hz, 2C), 94.7 (2C), 68.9,
62.3 (d, J.sub.CP=6.7 Hz, 2C), 56.2 (2C), 39.5, 34.0 (d,
J.sub.CP=138.3 Hz), 26.1, 22.7, 16.6 (d, J.sub.CP=6.1 Hz, 2C),
16.2, 13.8; .sup.31P NMR .delta. +26.2; HRMS (EI) calcd for
C.sub.25H.sub.41O.sub.8P [M.sup.+], 500.2539; found 500.2531.
[0170] e.
7-{2-[4-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxy-
methoxy-phenyl]-vinyl}-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro--
1H-xanthen-2-ol (58) To a suspension of NaH (12 mg, 0.3 mmol) and
15C5 (5 .mu.L, 3 mol %) in THF (5 mL) was added phosphonate 52 (34
mg, 0.068 mmol) and aldehyde 28 (16 mg, 0.053 mmol) at 0.degree. C.
and the reaction mixture was allowed to warm to rt over 10 h. The
reaction was quenched by addition of water and extracted with
EtOAc. The combined organic layers were washed with brine, dried
(MgSO.sub.4), and concentrated in vacuo. Purification of the
resulting oil by flash column chromatography (50% EtOAc in hexanes)
afforded compound 58 (20.5 mg, 60%) as a clear oil: .sup.1H NMR
.delta. 6.99-6.87 (m, 6H), 5.37-5.33 (tm, J=6.0 Hz, 1H), 5.24-5.18
(m, 5H), 3.95 (s, 2H), 3.91 (s, 3H), 3.52-3.39 (m, 9H), 2.74-2.72
(m, 1H), 2.72-2.70 (m, 1H), 2.17-1.98 (m, 5H), 1.90-1.57 (m, 10H),
1.26 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); .sup.13C NMR .delta.
156.1 (2C), 149.2, 142.8, 137.0, 134.9, 134.4, 129.1, 128.6, 126.6,
126.2, 123.3, 122.8, 120.8, 119.7, 107.1, 106.3 (2C), 94.8 (2C),
78.3, 77.4, 69.2, 56.2 (2C), 47.0, 39.6, 38.6, 37.9, 28.5, 27.6,
26.3, 23.4, 22.9, 20.1, 16.3, 14.5, 14.3, 13.9; HRMS (EI) calcd for
C.sub.39H.sub.54O.sub.8 [M.sup.+], 650.3819; found 650.3812. This
compound is also a compound of the invention.
Example 8
7-[2-(3-Hydroxy-phenyl)-vinyl]-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-he-
xahydro-1H-xanthen-2-ol (61)
##STR00065##
[0172] CSA (17 mg, 0.073 mmol) was added to a stirred solution of
stilbene 55 (16 mg, 0.036 mmol) in methanol (5 mL) and the reaction
mixture was allowed to stir for 15 h at rt. The reaction mixture
was concentrated in vacuo and the residue was dissolved in EtOAc
and water. The mixture was extracted with ether, the organic layer
was washed with brine, dried (MgSO.sub.4), and concentrated in
vacuo. Purification of the residue by flash column chromatography
(60% EtOAc in hexanes) afforded compound 61 (9 mg, 63%) as a clear
oil: .sup.1H NMR .delta. 7.26-7.19 (m, 1H), 7.06-6.85 (m, 6H),
6.73-6.70 (m, 1H), 5.05 (s, 1H, exchangeable with D.sub.2O), 3.83
(s, 3H), 3.46-3.43 (m, 1H), 2.75-2.66 (m, 2H), 2.18-1.61 (m, 5H),
1.49 (br. s, 1H, exchangeable with D.sub.2O), 1.26 (s, 3H), 1.11
(s, 3H), 0.89 (s, 3H); .sup.13C NMR .delta. 156.1, 149.2, 142.9,
139.6, 130.0, 129.4, 129.0, 126.1, 122.9, 120.9, 119.3, 114.4,
112.9, 107.2, 78.3, 77.4, 56.2, 46.9, 38.6, 37.8, 28.5, 27.6, 23.4,
20.1, 14.5; HRMS (EI) calcd for C.sub.25H.sub.30O.sub.4(M+H.sup.+),
395.2222; found 395.2237.
[0173] The intermediate stilbene 55 was prepared as follows.
##STR00066##
[0174] a. (3-Methoxymethoxy-benzyl)-phosphonic acid diethyl ester
(38) Methanesulfonyl chloride (1.0 mL, 12.9 mmol) was added
dropwise to a solution of alcohol 36 (500 mg, 2.97 mmol) and
Et.sub.3N (0.5 mL 3.6 mmol) in CH.sub.2Cl.sub.2 (10 mL) and the
solution was stirred for 2 h at 0.degree. C. The reaction mixture
was allowed to warm to rt over 5 h, quenched by addition of
H.sub.2O, and extracted with EtOAc. The combined organic layers
were washed with NH.sub.4Cl (sat), brine, dried (MgSO.sub.4), and
concentrated in vacuo. The resulting yellow residue was treated
with NaI (1 g, 3.6 mmol) in acetone (15 mL) for 24 h at rt. This
reaction mixture was concentrated in vacuo to afford a red solid,
which was dissolved in EtOAc. After the resulting yellow solution
was washed once with NaHCO.sub.3 and then with
Na.sub.2S.sub.2O.sub.3 until the color faded, it was extracted with
ether and the combined organic layers were dried (MgSO.sub.4) and
concentrated in vacuo. The resulting yellow oil was added to
triethyl phosphite (4 mL) and the solution was heated at
100.degree. C. for 20 h. After the solution was allowed to cool to
rt, it was poured into ether (10 mL). The mixture was extracted
with ether, dried (MgSO.sub.4), and concentrated in vacuo. The
initial yellow oil was purified by flash chromatography (50% EtOAc
in hexanes) to afford phosphonate 38 (709 mg, 83%) as a light
yellow oil: .sup.1H NMR .delta. 7.20 (tr, J=7.9 Hz, 1H), 7.08-6.89
(m, 3H), 5.17 (s, 2H), 4.15-3.97 (m, 4H), 3.44 (s, 3H), 3.11 (d,
J.sub.PH=21.6 Hz, 2H), 1.27-1.22 (m, 6H); .sup.13C NMR .delta.
157.1 (d, J.sub.CP=3.2 Hz), 132.9 (d, J.sub.CP=8.9 Hz), 129.2 (d,
J.sub.CP=3.1 Hz), 123.1 (d, J.sub.CP=6.5 Hz), 117.5 (d,
J.sub.CP=6.5 Hz), 114.5 (d, J.sub.CP=3.5 Hz), 94.1, 61.8 (d,
J.sub.CP=6.7 Hz, 2C), 55.6, 33.4 (d, J.sub.CP=137.2 Hz), 16.1 (d,
J.sub.CP=6.0 Hz, 2C); .sup.31P NMR .delta. +25.8. Anal. Calcd for
C.sub.13H.sub.21O.sub.5P: C, 54.16; H, 7.34. Found: C, 53.98; H,
7.35.
[0175] b.
5-Methoxy-7-[2-(3-methoxymethoxy-phenyl)-vinyl]-1,1,4a-trimethyl-
-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (55). To a stirred
suspension of NaH (27 mg, 0.68 mmol) and 15C5 (5 .mu.L, 3 mol %) in
THF was added phosphonate 38 (50 mg, 0.173 mmol) and aldehyde 28
(20 mg, 0.066 mmol) at 0.degree. C. and the reaction mixture was
allowed to warm to rt over 10 h. The reaction was quenched by
addition of water and extracted with EtOAc. The combined organic
layers were washed with brine, dried (MgSO.sub.4), and concentrated
in vacuo. Final purification of the residue by flash column
chromatography (50% EtOAc in hexanes) afforded compound 55 (18 mg,
62%) as a clear oil: .sup.1H NMR .delta. 7.29-6.87 (m, 8H), 5.21
(s, 2H), 3.90 (s, 3H), 3.51 (s, 3H), 3.46-3.39 (m, 1H), 2.74-2.72
(m, 2H), 2.16-1.59 (m, 5H), 1.26 (s, 3H), 1.11 (s, 3H), 0.89 (s,
3H); .sup.13C NMR .delta. 157.8, 149.2, 142.9, 139.5, 129.8, 129.3,
129.0, 126.3, 122.9, 120.9, 120.3, 115.3, 113.9, 107.2, 94.7, 78.2,
77.3, 56.3, 46.9, 38.6, 37.9, 29.9, 28.5, 27.6, 23.4, 20.1, 14.5;
HRMS (ES+) calcd for C.sub.27H.sub.34O.sub.5 (M+H).sup.+, 439.2484;
found 439.2475. This compound is also a compound of the
invention.
[0176] All publications, patents, and patent documents are
incorporated by reference herein, as though individually
incorporated by reference. The invention has been described with
reference to various specific and preferred embodiments and
techniques. However, it should be understood that many variations
and modifications may be made while remaining within the spirit and
scope of the invention.
* * * * *