Asymmetric synthesis of A-240610.0 via a new atropselective approach for axially chiral biaryls with chirality transfer

Article abstract of DOI:10.1021/ja0171198

A new approach for atropselective preparation of axially chiral biaryl was developed. This process proceeded through a chirality transfer from a stereogenic center of a secondary alcohol to the stereogenic axis via regioselective intramolecular silyl grou

Full text of DOI:10.1021/ja0171198

Published on Web 03/23/2002
Asymmetric Synthesis of A-240610.0 via a New Atropselective
Approach for Axially Chiral Biaryls with Chirality Transfer
Yi-Yin Ku,* Tim Grieme, Prasad Raje, Padam Sharma, Steve A. King, and
Howard E. Morton
Contribution from D-R450, Process Chemistry, Global Pharmaceutical Research and
DeVelopment, Abbott Laboratories, North Chicago, Illinois 60064-4000
Received September 19, 2001
Abstract: A new approach for atropselective preparation of axially chiral biaryl was developed. This process
proceeded through a chirality transfer from a stereogenic center of a secondary alcohol to the stereogenic
axis via regioselective intramolecular silyl group migration. This methodology allowed for the preparation
of a single atropisomer 2 in good yield (85%) with high diastereoselectivity (99:1), which subsequently led
to the successful development of an efficient asymmetric synthesis of A-240610.0, 1.
Introduction
of two or more stable (noninterconverting) rotational isomers,
has played an important role in asymmetric synthesis.6 The
Glucocorticoids have been used for the treatment of inflam-
matory diseases for the last 40 years,1 but many undesirable
side effects2 are associated with the current therapies. These
side effects largely occur because glucocorticoids have poor
selectivity toward the glucocorticoid receptor3 and have cross-
reactivity with other steroid receptors.4 A-240610.05 has dem-
onstrated equivalent antiinflammatory activity relative to that
of the synthetic glucocorticoids, such as prednisolone,1c and has
shown an improved side effect profile in vivo.
increasing awareness of the importance of axial chirality in
organic chemistry is partially due to the growing number of
isolated chiral biaryl natural products.7 Currently, considerable
efforts are directed toward effective generation and control of
axial chirality for the synthesis of axially chiral biaryls.8 Besides
the commonly used methodology of resolution of a racemic
mixture, several regio- and stereoselective approaches have been
recently developed.9
We were not able to achieve an efficient synthesis of
A-240610.0 using the existing methodologies. For example,
(6) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994; (b) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis
1992, 503. (c) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92, 1007. (d)
Narasaka, K. Synthesis 1991, 1. (e) Bao, J.; Wulff, W. D.; Rheingold, A.
L. J. Am. Chem. Soc. 1993, 115, 3814 and references therein.
(7) (a) Meyers, A. I.; Willemsen, J. J. Tetrahedron 1998, 54, 10493. (b) Torssell,
K. B. G. Natural Product Chemistry; Taylor and Fancis: New York, 1997.
(c) Bringmann, G.; Pokorny, F. In The Alkaloids; Cordell, G. A., Ed.:
Academic: New York, 1995; Vol. 46, p 127. (d) Okuda, T.; Yoshida, T.;
Hatano, T. In Progress in the Chemistry of Organic Natural Products; Herz,
W., Kirby, G. W., Moore, R. E., Steglich, W., Tamm, C., Eds.; Springer:
Wien, 1995; Vol. 66, p1.
During the process of developing an asymmetric synthesis
for A-240610.0, we needed to prepare the homoallylic alcohol
2 as a single atropisomer to effect an efficient ether-forming
reaction (vide infra). Axial chirality, resulting from the formation
(8) (a) Review: Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 4,
525. (b) Review: Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 977. (c) Review: Bringmann, G.; Walter, R.;
Weirich, R. Methods of Organic Chemistry (Houben-Weyl); Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schumann, E., Eds.; Georg Thieme Verlag:
Stuttgart, 1995; Vol. E21a, p 567. (d) Hattori, T.; Hotta, H.; Suzuki, T.;
Miyano, S. J. Chem. Soc., Chem. Commun. 1991, 1375. (e) Hattori, T.;
Hotta, H.; Suzuki, T.; Miyano, S. Bull. Chem. Soc. Jpn. 1993, 66, 613. (f)
Miyano, S.; Koike, N.; Hattori, T. Tetrahedron: Asymmetry 1994, 5, 1899.
(g) Moorlag, H.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 6989. (h)
Moorlag, H.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 6993. (i) Nelson,
T. D.; Meyers, A. I. J. Org. Chem. 1994, 59, 2655. (j) Nelson, T. D.;
Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259. (k) Meyers, A. I.;
McKennon, M. J. Tetrahedron Lett. 1995, 36, 5869. (l) Meyers, A. I.; Meir,
A.; Rawson, D. J. Tetrahedron Lett. 1992, 33, 853. (m) Shindo, M.; Koga,
K.; Tomioka, K. J. Am. Chem. Soc. 1992, 114, 8732. (n) Uemura, M.;
Kamikawa, K. J. Chem. Soc., Chem. Commun. 1994, 2697. (o) Kamikawa,
K.; Watanabe, T.; Uemura, M. Synlett 1995, 1040. (p) Watanabe, T.;
Kamikawa, K.; Uemura, M. Tetrahedron Lett. 1995, 37, 6695. (q)
Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375.
(r) Osa, T.; Kashiwagi, Y.; Yanagisawa, Y.; Bobbitt, J. M. J. Chem. Soc.,
Chem. Commun. 1994, 2535. (s) Itoh, T.; Chika, J.; Shirakami, S.; Ito, H.;
Yoshida, T.; Kubo, Y.; Uenishi, J. J. Org. Chem. 1996, 61, 3700. (t)
Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.; Noji, M.; Koga,
K. J. Org. Chem. 1999, 64, 2264.
* To whom correspondence should be addressed. E-mail: yiyin.ku@
abbott.com.
(1) (a) Schimmer, B. P.; Parker, K. L. In Goodman and Gilman’s The
Pharmacological Basis of Therapeutics, 9th ed.; Hardman, J. G., Limbird,
L. E., Molinoff, P. B., Ruddon, R. W., Eds.; McGraw-Hill: New York,
1996; pp 1459. (b) Cohen, E. M. Anal. Profiles Drug Subst. 1973, 2, 163.
(c) Ali, S. L. Prednisolone. Anal. Profiles Drug Subst. Excipients 1992,
21, 415.
(2) (a). Gennari, C. Br. J. Rheumatol. 1993, 32, 11. (b) Anon. Effects of
Dexamethasone on Glucose Metabolism. Nutr. ReV. 1976, 34, 185-187.
(3) Weinberger, C.; Hollenberg, S. M.; Ong, E. S.; Harmon, J. M.; Brower, S.
T.; Cidlowski, J.; Thompson, E. B.; Rosenfeld, M. G.; Evans, R. M. Science
1985, 228, 740-742.
(4) (a) Mulatero, P.; Veglio, F.; Pilon, C.; Rabbia, F.; Zocchi, C.; Limone, P.;
Boscaro, M.; Sonino, N.; Fallo, F. J. Clin. Endocrinol. Metab. 1998, 83,
2573. (b) Neef, G.; Beier, S.; Elger, W.; Henderson, D.; Wiechert, R.
Steroids 1984, 44, 349-372.
(5) Coughlan, M. J.; Elmore, S. W.; Kort, M. E.; Kym, P. R.; Moore, J. L.;
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J. AM. CHEM. SOC. 2002, 124, 4282-4286
10.1021/ja0171198 CCC: $22.00 © 2002 American Chemical Society

Asymmetric Synthesis of A-240610.0
A R T I C L E S
Scheme 1
Scheme 3
Scheme 4
using the Bringmann’s lactone approach8a to open the lactone
3 with the chiral O-nucleophile (namely, the alkoxy anion
generated from (+)-menthol and n-BuLi) only resulted in a
mixture of atropisomers 5 and 6 with a ratio of 65:35 (Scheme
1). Using CBS reduction of the lactone 3 also gave unsatisfac-
tory results.
We report here the synthesis of A-240610.0 utilizing a novel
concept to achieve atropisomeric control of axial chirality. In
this approach, the chirality is transferred efficiently from an
easily accessible stereogenic center of a secondary alcohol to
the stereogenic axis via stereoselective intramolecular group
migration (Scheme 2).
Scheme 2
intermediate 10 without detectable amounts of aldehyde 7.
Oxidation of the alcohol 10 to the aldehyde 7 was not
straightforward. After considerable experimentation using a
variety of oxidation conditions (Swern, Jones, Corey-Kim,
Dess-Martin, MnO2, PDC, TPAP, PCC, SO3‚Py), the Dess-
Martin-precursor [1-hydroxy-1,2-benziodoxol-3(1 H)-one 1-ox-
ide]10 was found to be the only oxidizing reagent to produce
the desired aldehyde 7 in 76% yield. Later, a more efficient
process for the aldehyde analogue was developed which
involved DIBAL-reduction of lactone followed by the ring
opening of the lactol to produce the aldehyde derivative directly
(Scheme 6). Asymmetric allylation was carried out with H. C.
Brown’s chiral allylboron reagent,11 prepared in-situ from
commercially available DIP-Cl and allyl Grignard reagents,11a
to produce the homoallylic alcohols 11 and 12 as a diastereo-
meric mixture with a ratio of about 50:50. The allylation
proceeded in high yield (95%) and with high enantioselectivity12
(90-95% ee, depending on the % ee of DIP-Cl used).
This approach converts a molecule with one easily accessible
stereogenic center to a molecule possessing two stereogenic
centers, of which one is axial and much more difficult to control.
The success of this methodology and subsequent Mitsunobu
cyclization of 2 was crucial for the synthesis of multigram
quantities of A-240610.0.
Results and Discussion
Our initial retrosynthetic analysis for the asymmetric synthesis
of 1 is outlined in Scheme 3. The chiral homoallylic alcohol 2
was envisioned to arise from an asymmetric allylation of
aldehyde 7 to introduce the chirality to the molecule. It should
subsequently undergo cyclization under the Mitsunobu reaction
conditions to produce the desired final product 1. The aldehyde
7 could be derived from the lactone derivative 3, which has
been previously prepared.5
Initially, preparation of aldehyde 7 was accomplished as
follows (Scheme 4): the lactone 3 was first treated with NaOMe
to generate the phenolic anion intermediate 8 in situ, which was
trapped with TBSCl to obtain the ester intermediate 9. Attempted
direct reduction of the ester to aldehyde was unsuccessful. The
reduction with DIBAL at -78 °C produced the alcohol
We speculated that use of this atropisomeric mixture for the
cyclization could result in a low yield. Three-dimensional
structures of 2 and 13 after energy minimization clearly indicated
that only one atropisomer could have the correct stereoconfor-
(10) (a) Hartman, C.; Meyer, V. Chem. Ber. 1893, 26, 1727. For some recent
examples, see: (b) Breuilles, P.; Uguen, D. Tetrahedron Lett. 1998, 39,
3149. (c) Varadarajan, S.; Mohapatra, D. K.; Datta, A. Tetrahedron Lett.
1998, 39, 1075. (d) Hulme, A. N.; Howells, G. E. Tetrahedron Lett. 1997,
38, 8245. (e) Pearson, W. H.; Clark, R. B. Tetrahedron Lett. 1997, 38,
7669. (f) Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780. (g)
Boehm, T. L.; Showalter, H. D. H. J. Org. Chem. 1996, 61, 6498.
(11) (a) Brown, H. C.; Jadhav, P.; J. Am. Chem. Soc. 1983, 105, 2092. (b) Brown,
H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla, U. S. J. Am.
Chem. Soc. 1990, 112, 2389. (c) Racherla, U. S.; Brown, H. C. J. Org.
Chem. 1991, 56, 401.
(9) (a) Pawal, V. H.; Florjancic, A. S.; Singh, S. P. Tetrahedron Lett. 1994,
35, 8985. (b) Sugimura, T.; Yamada, H.; Inoue, S. Tai, A. Tetrahetron:
Asymmetry 1997, 8, 649. (c) Lin, G-Q.; Zhong, M. Tetrahetron: Asym-
metry 1997, 8, 1369. (d) Spring, D. R.; Krishnan, S.; Schreiber, S. L. J.
Am. Chem. Soc. 2000, 122, 5656. (e) Harada, T.; Yoshida, T.; Inoue, A.;
Tekeuchi, M.; Oku, A. Synlett. 1995, 283. (f) Tuyet, T. M. T.; Harada, T.;
Hashimoto, K.; Hatsuda, M.; Oku, A. J. Org. Chem. 2000, 65, 1335. (g)
Meyers, A. I.; Price, A. J. Org. Chem. 1998, 63, 412. (h) Kamikawa, T.;
Uozumi, Y.; Hayash, T. Tetrahedron Lett. 1996, 37, 3161.
(12) The % ee of the diastereomeric mixture 11 and 12 was determined by chiral
HPLC analysis using a Chiralcel OJ 4.6 mm × 250 mm column eluting
with Super Critical Fluid CO2/5% EtOH.
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A R T I C L E S
Ku et al.
Scheme 5
Scheme 6
Scheme 7
mation to undergo an SN2-type cyclization under Mitsunobu
reaction conditions. This atropisomer has its leaving group and
attacking group opposite to each other. The other atropisomer
has both leaving group and attacking group on the same side
so that its stereoconformation would be unfavorable for the
cyclization. In addition, racemization under the Mitsunobu
reaction conditions could be problematic,13 because the atrop-
isomers, 2 and 13, are not only benzylic but also homoallylic.
After desilylation of the mixture of atropisomers 11 and 12,
a mixture of atropisomers 2 and 13 was obtained and was
subjected to the Mitsunobu reaction conditions.14 As predicted,
low yield (42%) of the desired cyclization product 1 was
obtained with the elimination product 14 as the major byproduct
(Scheme 5). However, it was encouraging to find that race-
mization was minimal.
Interestingly, when the Mitsunobu reaction was carried out
at low temperature (0 °C), only homoallylic alcohol 13 reacted,
producing predominately the elimination product and other
byproducts. When the reaction temperature was raised to room
temperature, the atropisomer 2 then reacted, producing the
desired cyclization product. The atropisomers 2 and 13 were
found to be stable at room temperature (the ratio of a mixture
of the atropisomers had not changed after 30 days in a THF
solution). However, when the mixture was heated to 80 °C for
24 h, the ratio changed from 50:50 to 30:70 with the atropisomer
13 as the major product. As expected, when this new atrop-
isomer mixture with a ratio of 30:70 (2:13) was subjected to
the Mitsunobu reaction conditions, the reaction produced lower
yield (26%) of the desired cyclization product. These experi-
ments provided further evidence that only atropisomer 2
produces the desired cyclization product, while atropisomer 13
only leads to the elimination and other byproducts.
To overcome the atropisomer issue, we have attempted to
prepare the single enantiomer 21 (Scheme 6) containing a
symmetric bis-hydroxylphenol. It was hoped that the cyclization
of this homoallylic alcohol would produce a higher yield of
the cyclization product.
A more efficient process (Scheme 6) for the preparation of
the aldehyde 19 was developed to overcome the drawbacks
associated with the earlier route involving an impractical
oxidation of the alcohol 10. The 10-OH lactone derivative 15,
previously synthesized,5 was silylated to give the lactone
derivative 16. The lactone 16 was then reduced to the lactol 17
with DIBAL. Upon treatment with KOt-Bu, the lactol ring of
17 was opened, producing the phenolic anion 18, in situ. This
phenolic anion 18 was then reacted with TBSCl to generate
the symmetric biaryl aldehyde 19 in good yield (80%). The
allylation of the aldehyde 19 was carried out following the same
procedure as described in Scheme 4 using the chiral allylboron
reagent to afford the bis-OTBS homoallylic alcohol 20 in high
yield (95%) and with high enantioselectivity (90% ee). Desi-
lylation under the conditions of TBAF/HCO2H afforded the
symmetric triol 21 in good yield (83%).
The triol 21 was subjected to the Mitsunobu reaction (Scheme
7); again a low yield (41%) was obtained where the major
byproduct was the elimination product. Attempts to improve
the reaction yield by changing the reaction parameters, such as
temperature, solvent, diazo compounds, phosphine compounds,
did not improve the reaction. It was interesting to find out that
when the trialkylphosphine compound was used, the reaction
gave much higher yield, however, complete racemization
occurred. Presumably, when trialkylphosphine compounds were
used in the Mitsunobu reaction, the reaction completely
underwent undesired SN1 pathway. These experiments suggested
that although the starting material is symmetric, the equilibrium
between the phenolic anions generated in situ is slow enough
so that the atropisomerism still exists. Subsequently, only one
To improve the cyclization, other approaches using the
sulfonates (tosylate, mesylate) to activate the secondary alcohol
for the ring closure were also attempted. These reactions
produced complex mixtures composed of several unidentified
byproducts in addition to the cyclization and elimination
products.
(13) Santhosh, K. C. Balasubramanian, Synth. Commun. 1994, 24, 1049.
(14) For reviews see: (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L.
Org. React. 1992, 42, 335. (c) Hughes, D. L. Org. Prep. Proced. Int. 1996,
28, 127.
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Asymmetric Synthesis of A-240610.0
A R T I C L E S
Scheme 9
Scheme 10
Figure 1. X-ray structure of bis-OTBS homoallylic alcohol 20.
Scheme 8
phenolic anion atropisomer 22 has the right stereoconformation
leading to the cyclization product 24. The other atropisomer
23 has the wrong conformation which leads to elimination
product 25 and other byproducts. These results are similar to
the earlier results obtained in the case when the two atropisomers
2 and 13 were subjected to the Mitsunobu reaction condition
(Scheme 5).
The X-ray structure of 20 (Figure 1) clearly shows that the
two OTBS groups have very different spatial relationships with
respect to the chiral homoallylic alcohol. Considering the fact
that the stability difference between a TBS group on a secondary
alcohol and on a phenolic alcohol is quite noticeable, the
approach to achieve control of axial chirality via intramolecular
silyl group migration was proposed. When bis-OTBS homoal-
lylic alcohol 20 was treated with KOt-Bu in THF at 0 °C, a
clean intramolecular silyl group migration occurred (Scheme
8) to form a more stable phenolic anion 26. The intermediate
26 was then trapped with methyl iodide to obtain the atropisomer
27 in high yield (85%) with high diastereoselectivity (99:1).
The original chirality was unaffected (90% ee). Similarly, the
phenolic anion 26 was trapped with N-phenylbis(trifloromethane-
sulfonimide) to generate the triflate 28.
Thus, a single atropisomer was easily prepared by a simple
intramolecular silyl group migration process. The easily acces-
sible chirality of molecule 20 was transferred to molecule 27
along with generating a new axial chirality that is normally not
easily installed.
With the single atropisomer 27 in hand, desilylation with
TBAF provided the pure atropisomer 2 in good yield (85%).
Two-dimensional NMR experiments of 2 showed a strong NOE
between the hydroxyl group of homoallylic alcohol and the
methoxy group, which indicated that the hydroxyl group of
homoallylic alcohol was in a proximal relationship to the 10-
methoxy group. The Mitsunobu reaction of 2 (Scheme 9)
produced the desired cyclization product 1 in good yield (82%)
and satisfactory optical purity (85% ee). The % ee of the product
can be further improved by crystallization with IPA to greater
than 99%.
To further confirm that atropisomer 13 leads to elimination
product and other byproducts under the Mitsunobu reaction
conditions. The isolation of the opposite atropisomer 13 was
attempted (Scheme 10). The initially formed atropisomers 11
and 12 (Scheme 4) from the asymmetric allylation were found
to be inseparable by column chromatography, as were the
desilylation products 2 and 13. By using the strategy of proximal
silyl group migration, separation of the two atropisomers was
achieved. Thus, when a mixture of atropisomers 11 and 12
(ratio: 50:50) was reacted with KOt-Bu, the regioselective
intramolecular silyl group migration occurred only with the
atropisomer 12 containing an OTBS group proximal to the
hydroxyl group of the homoallylic alcohol. The phenolic
hydroxyl anion 29 generated was trapped with TBSCl to produce
a highly nonpolar bis-OTBS compound 30. No intramolecular
silyl group migration was observed with atropisomer 11, because
the OTBS group was distal to the hydroxyl group of homoallylic
alcohol. The alkoxyl anion 11A generated was too bulky to be
silylated. Now the bis-OTBS atropisomer 30 obtained had very
different physical properties compared to the unreacted mono-
OTBS derivative 11. These two atropisomer derivatives were
now easily separated by crystallization.
The bis-OTBS homoallylic alcohol 30 was then desilylated
to produce the atropisomer 13 (Scheme 11). Two-dimensional
NMR experiments of 13 provide strong evidence of a proximal
relationship between the phenolic hydroxyl group and the
hydroxyl group of homoallylic alcohol. A strong NOE was
observed between the 10-methoxy group and the proton on the
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A R T I C L E S
Ku et al.
Scheme 11
Scheme 12
adjacent aryl ring, and a weak NOE was observed between the
phenolic hydroxyl group and the allyl methylene group.
When the homoallylic alcohol 13 was subjected to Mitsunobu
reaction conditions, the elimination product 14 was confirmed
as the major product along with several other unidentified
byproducts. A very small amount (<5%) of cyclization product
was also produced, presumably through the undesired SN1
pathway.
The further application of this methodology for atropselective
transformation to produce axially chiral biaryls is demonstrated
by an additional example (Scheme 12). The aldehyde intermedi-
ate 36 was prepared using a protocol similar to that described
in Scheme 6. Thus, the lactone intermediate 31, prepared using
the literature procedure,15 was demethylated using BBr3 followed
by protecting the phenolic hydroxy groups with TBSCl. The
TBS protected lactone 33 was then reduced with (t-BuO)3AlHLi
to give lactol 34 in 57% yield; the ring opening of lactol with
KOt-Bu followed by trapping the phenolic intermediate 33 with
TBSCl gave the aldehyde 36 in 81% yield. The asymmetric
allylation was achieved using the procedure similar to that
described in Scheme 4 with the chiral allylboron reagent to
afford the tris-OTBS homoallylic alcohol 37 in high yield (95%)
and with good enantioselectivity (86% ee). The single atrop-
isomer 39 was then prepared in 90% yield with high diaste-
reoselectivly (other diastereomers were not detected by both
HPLC and NMR) using the same procedure as described in
Scheme 8 involving an intramolecular silyl group migration
process. Desilylation of 39 produced the single atropisomer 40
in 92% yield.
transfer from an easily accessible stereogenic center of a
secondary alcohol to the stereogenic axis can be easily ac-
complished by a regioselective intramolecular silyl group
migration. This methodology has been successfully demon-
strated in the synthesis of the single atropisomer intermediate
27, ultimately leading to an efficient and practical process for
the asymmetric synthesis of A-240610.0 1
Acknowledgment. This paper is dedicated to Emeritus
Professor Y. H. Ku of the University of Pennsylvania on the
occasion of his 100th birthday. We thank Mike Fitzgerald for
performing the chiral HPLC assays for all the chiral compounds
reported, Dr. Casey Zhou, of the Structural Chemistry Depart-
ment, for performing the NMR experiments and structure
elucidations, and Roger Henry, of the Structural Chemistry
Department, for obtaining the X-ray structure of compound 20.
Supporting Information Available: Complete experimental
procedures, spectroscopic data, and X-ray structure data (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed a new methodology for
atropselective preparation of axially chiral biaryls. The chirality
(15) Bringmann, G.; Hartung, T.; Gobel, L.; Schupp, O.; Ewers, C. L.; Schoner,
B.; Zagst, R.; Peters, K.; Schnering, H. G.; Burschka, C. Liebigs Ann. Chem.
1992, 225.
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