Intramolecular methylation of an allyl sulfone via lithium alkoxyaluminate; Application to the enantioselective synthesis of the CD ring of vitamin D 3

Article abstract of DOI:10.1021/ol301144a

Alcohol-directed intramolecular methylation of an enantiopure allyl sulfone using AlMe₃ provides a trans-hydrindane CD ring alcohol. The substrate cis-CD ring allyl sulfone alcohol is prepared via intramolecular allyl sulfonyl anion addition to aldehyde using Ba(OH)₂.

Full text of DOI:10.1021/ol301144a

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2922–2924
Intramolecular Methylation of an Allyl
Sulfone via Lithium Alkoxyaluminate;
Application to the Enantioselective
Synthesis of the CD Ring of Vitamin D3
Vikas Sikervar and Philip L. Fuchs*
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907,
United States
pfuchs@purdue.edu
Received April 27, 2012
ABSTRACT
Alcohol-directed intramolecular methylation of an enantiopure allyl sulfone using AlMe3 provides a trans-hydrindane CD ring alcohol. The
substrate cis-CD ring allyl sulfone alcohol is prepared via intramolecular allyl sulfonyl anion addition to aldehyde using Ba(OH)2.
1R,25(OH)2D3 is the most biologically active metabolite
of Vitamin D3 and is involved in the regulation of calcium
homeostasis and bone metabolism (Figure 1). In addition,
it suppresses the growth of numerous human cancer cell
lines by inhibiting cell cycle progression and inducing cell
death. There has been enormous research on the develop-
ment of analogs of Vitamin D3 that are more potent than
natural Vitamin D3. CD ring modification has also made a
substantial contribution to this area. A major problem in
the de novo synthesis of steroidal CD rings has been the
efficient construction of the enantiopure trans-hydrindane
system.1 It has also been reported that the trans
Grundmann’s ketone obtained from oxidative degradation
of Vitamin D is less stable than the cis form by >0.76
kcal/mol.2 The Hajos dione 2 produced by an organo-
catalytic reaction of 2-methylcyclopentane-1,3-dione with
methyl vinyl ketone has been routinely used for the con-
struction of the CD ring system.1,34 The chemistry herein
provides a complementary synthesis of the enantiopure
trans CD ring from cyclohexadienyl sulfone 3.
Figure 1. Structure of 1R,25(OH)2D3 1 and Hajos dione 2.
Alcohol-directed allylation of sulfone 45 using 2.5 equiv
of allyl magnesium bromide gave allyl sulfone 6 after TBS
protection in 81% yield (Scheme 1). Selective hydroborationꢀ
oxidation of allyl sulfone 6 with 9-BBN afforded allyl
sulfone 7 in 90% yield. Allyl sulfone 7 was oxidized using
Dess-Martin Periodinane (DMP) to give aldehyde 8 in
92% yield.
(1) Jankowski, P.; Marczak, S.; Wicha, J. Tetrahedron 1998, 54,
12071.
(2) Rodriguez, R.; Chapelon, A.; Ollivier, C.; Santelli, M. Tetrahe-
dron 2009, 65, 7001.
(3) (a) Hajos, Z. G.; Parish, D. R. J. Org. Chem. 1974, 39, 1615.
(b) Hajos, Z. G.; Parish, D. R. Org. Synth. 1990, Coll. Vol. 7, 363.
(4) (a) Daniewski, A. R.; Liu, W. J. Org. Chem. 2001, 66, 626.
(b) Daniewski, A. R.; Kiegiel, J. J. Org. Chem. 1988,53,5534. (c) Baggiolini,
E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A. D.; Sereno, J. F.;
Intramolecularsulfonyl anion addition tothealdehyde 8
using 5 equiv of Ba(OH)2 gave the CD ring alcohol 9 in
(5) (a) Chen, Y.; Evarts, J. B.; Torres, E.; Fuchs, P. L. Org. Lett. 2002,
4, 3571. (b) Sikervar, V.; Fuchs, P. L. Chem. Commun. 2011, 47, 3472.
(6) Ba(OH)2 and K2CO3 were found to be very selective for this
transformation. Cs2CO3/ DMF/H2O gives the product only in 32%
yield, while DBU, LiHMDS, and KO-tBu lead to no reaction.
ꢀ
Uskokovic, M. R. J. Org. Chem. 1986, 51, 3098. (d) Wovkulich, P. M.;
Barcelos, F.; Batcho, A. D.; Sereno, J. F.; Baggiolini, E. G.; Hennessy,
ꢀ
B. M.; Uskokovic, M. R. Tetrahedron 1984, 40, 2283.
r
10.1021/ol301144a
Published on Web 05/16/2012
2012 American Chemical Society

was synthesized in 70% yield by reacting the dithiane
dianion 11 with dienyl sulfone 10 followed by oxidiz-
ing the allyl alcohol using DMP.
Scheme 1. Synthesis of CD Ring Alcohol 9 and Its X-ray
To methylate and desulfonylate the allyl sulfone 9,
AlMe3 was used. Aluminum reagents (AlMe3, AlCl3,
EtAlCl2, MeAl(OTf)2) have been widely used for desulfo-
nylating substrates to either trap the carbocation with
nucleophiles or to effect eliminationtogenerateanolefin.9,10
In this study, AlMe3 was found to be effective for activation
of the allylic sulfone which was then intramolecularly
methylated by the lithium alkoxyaluminate.
Scheme 3. Methylation of Allyl Sulfone 9
92% yield. K2CO3/18-Crown-6 could also be used for the
above transformation which proceeded in 86% yield.6
X-ray crystallography confirmed the stereochemistry of
alcohol 9. The competing enolization of aldehydes is a
probleminthese types of reactions, asmostof the reactions
have employed syringe pump techniques.7 Ba(OH)2 and
K2CO3/18-Crown-6 have been found to be very mild and
selective in this kind of transformation without employing
syringe pump techniques.
When CD ring alcohol 9 was treated with 1.1 equiv of
BuLi and then subsequently with 4 equiv of AlMe3, this led
to installation of a methyl group at the quaternary carbon
via displacement of phenyl sulfinate, to provide alcohol 19
in 71% yield. Oxidation of 19 using 1.4 equiv of DMP
smoothly afforded ketone 20 in 95% yield. The mechanism
of the phenyl sulfone substitution presumably involves the
following: (1) deprotonation of the alcohol using BuLi,
(2) formation of lithium alkoxyaluminate complex, (3) Lewis
acid assisted desulfonylation using AlMe3, and (4) intra-
molecular methylation (Scheme 3). Similar treatment of CD
ring alcohol 9 with 4 equiv of AlMe3 in the absence of base
provided only SE20 displacement of phenyl sulfinate to give
alcohol 16 in 81% yield without any 19 being detectable.
BuLi/AlMe3 was not able to substitute the phenyl sulfone
when not activated by a double bond. Treatment of 21 under
the same conditions employed for 9 returned 21 in >95%
yield with no evidence for the formation of any 22 (Scheme4).
The test substrate sulfone 21 was prepared by hydrogenating
allyl sulfone 9 using Pd/C in the presence of 1 atm of H2.
In summary, we have reported a short synthesis of the
trans-hydrindane CD ring of Vitamin D3 from cyclohexa-
dienyl sulfone. The synthesis features intramolecular allyl
sulfone addition to aldehyde to construct the CD ring and
Scheme 2. Intramolecular Allyl Sulfone Addition to Enone and
the X-ray of Ketone 14
It was also found that K2CO3/18-Crown-6 affects
intramolecular Michael addition of the allyl sulfone
with enone 13 to provide CD ring ketone 14 in 44%
yield (Scheme 2) which could potentially be used for
the synthesis of Vitamin D3 analogs.8 The enone 13
(7) (a) Takeda, K.; Kawanishi, E.; Nakamura, H.; Yoshii, E. Tetra-
hedron Lett. 1991, 32, 4925. (b) Grimm, E. L.; Levac, S.; Trimble, L. A.
Tetrahedron Lett. 1994, 35, 6847.
Scheme 4. Unreactivity of Dihydro Sulfone 21
(8) Three new stereogenic centers were created during the intramo-
lecular allyl sulfone addition to enone. The methyl stereochemistry in the
side chain could be anticipated because of the steric effects between the
phenyl sulfone and the methyl group in the other diastereomer.
(9) El-Awa, A.; Noshi, M. N.; Jourdin, X. M.; Fuchs, P. L. Chem.
Rev. 2009, 109, 2315.
(10) Trost, B. M.; Matsmoka, R. T. Synlett 1992, 27.
Org. Lett., Vol. 14, No. 11, 2012
2923

alcohol directed AlMe3 induced bridgehead methylation of
allyl sulfones.
Supporting Information Available. Experimental pro-
1
cedures and copies of H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Arlene Rothwell (Purdue
University) and Karl Wood (Purdue University) for pro-
viding MS data.
The authors declare no competing financial interest.
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Org. Lett., Vol. 14, No. 11, 2012