Asymmetric synthesis of tertiary benzylic alcohols

Article abstract of DOI:10.1021/ol102567h

Vinyl, aryl, and alkynyl organometallics add to ketones containing a stereogenic sulfoxide. Tertiary alcohols are generated in diastereomerically and enantiomerically pure form. Reductive lithiation converts the sulfoxide into a variety of useful function

Full text of DOI:10.1021/ol102567h

ORGANIC
LETTERS
2011
Vol. 13, No. 2
184-187
Asymmetric Synthesis of Tertiary
Benzylic Alcohols
Monika I. Antczak, Feng Cai, and Joseph M. Ready*
Department of Biochemistry, The UniVersity of Texas Southwestern Medical Center at
Dallas, 5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
joseph.ready@utsouthwestern.edu
Received October 22, 2010
ABSTRACT
Vinyl, aryl, and alkynyl organometallics add to ketones containing a stereogenic sulfoxide. Tertiary alcohols are generated in diastereomerically
and enantiomerically pure form. Reductive lithiation converts the sulfoxide into a variety of useful functional groups.
Efficient organic synthesis requires control over absolute and
relative stereochemistry. Among the many chemical trans-
formations that form stereogenic centers, additions to ketones
and aldehydes are especially important.1 Their value to
organic synthesis arises from several characteristics: many
types of nucleophiles will react with ketones and aldehydes;
addition reactions display high atom economy and represent
convergent fragment couplings; the products, secondary and
tertiary alcohols, are ubiquitous in natural products, phar-
maceutical agents, and other biologically active materials;
and the secondary and tertiary alcohol products are substrates
for a rich diversity of subsequent synthetic transformations.
proven more elusive.6,7 For example, amino alcohols and
phosphorylated diamines promote the addition of Ph2Zn to
ketones.8 Bis-sulfonamide ligands promote the same reaction
in the presence of stoichiometric Ti(OiPr)4,9 and aryl
aluminum reagents effect arylation in the presence of 10-20
mol % BINOL and excess Ti(OiPr)4.10 These approaches
generally require expensive arylating agents, often in large
excess, stoichiometric quantities of an additional metal salt,
and/or structurally complex ligands. With regard to alkeny-
lation, a bis-sulfonamide ligand enables the asymmetric
addition of terminal vinyl zinc reagents to ketones with high
selectivity.11 Finally, asymmetric catalytic additions of
alkynyl zinc reagents have been reported,12-15 but high
catalyst loadings, long reaction times, and large excesses of
reagent are generally required.6,16
Owing to the utility of secondary alcohols, significant
attention has focused on the asymmetric addition of hard
nucleophiles to aldehydes.2-5 In contrast, asymmetric ad-
ditions of alkynyl, vinyl, and aryl groups to ketones have
(6) Asymmetric addition of dalkyl zincs to ketones: (a) Ramo´n, D. J.;
Yus, M. Tetrahedron 1998, 54, 5651. (b) Yus, M.; Ramo´n, D. J.; Prieto,
O. Tetrahedron: Asymmetry 2002, 13, 2291. (c) DiMauro, E. F.; Kozlowski,
M. C. J. Am. Chem. Soc. 2002, 124, 12668. (d) Funabashi, K.; Jachmann,
M.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2003, 115, 5647. (e)
Jeon, S.-J.; Li, H.; Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Org. Chem.
(1) Trost, B. M.; Flemming, I. Eds. ComprehensiVe Organic Synthesis,
Vols. 1-2; Permagon Press: Oxford, 1991.
(2) Allylation: Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763
.
(3) Arylation: Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem.
2004, 70, 448
.
Soc. ReV. 2006, 35, 454
.
(7) Review: Hatano, M.; Ishihara, K. Synthesis 2008, 1647.
(4) Vinylation :(a) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992,
75, 170. (b) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454. (c) Salvi, L.;
Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc.
(8) (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (b)
Hatano, M.; Miyamoto, T.; Ishihara, K. Org. Lett. 2007, 9, 4535.
(9) (a) Prieto, O.; Ramo´n, D. J.; Yus, M. Tetrahedron: Asymmetry 2003,
14, 1955. (b) Garc´ıa, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641.
(10) Chen, C.-A.; Wu, K.-H.; Gau, H.-M. Angew. Chem., Int. Ed. 2007,
46, 5373.
2007, 129, 16119
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(5) Alkylation: (a) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833. (b)
Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757. (c) Muramatsu, Y.; Harada,
T. Angew. Chem., Int. Ed. 2008, 47, 1088
.
(11) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355.
10.1021/ol102567h  2011 American Chemical Society
Published on Web 12/13/2010

We considered the use of chiral auxiliaries to effect the
stereoselective addition of hard nucleophiles to ketones. Most
applications of chiral auxiliaries incorporate the stereodi-
recting group onto the nucleophilic component of the
reaction.17 The sulfoxide group represents a rare example
of a chiral auxiliary which usually resides on the electrophilic
reaction partner.18 The Ellman group has popularized the
use of tert-butyl sulfinamide for the synthesis of optically
active amines.19 Likewise, the groups of Colobert and Toru
have demonstrated the utility of sulfoxide chiral auxiliaries
in asymmetric additions to aldehydes.20 These applications,
in turn, built on a rich literature describing the use of
sulfoxides in asymmetric reductions, conjugate additions, and
Diels-Alder cycloadditions pioneered by the group of Garc´ıa
Ruano among others.18 Here we show that the toluene
sulfinyl group effectively controls the asymmetric addition
of simple alkynyl, aryl and vinyl organometallic reagents to
aryl ketones (eq 1). In contrast to most previous studies, the
methodology utilizes readily available Grignard reagents and
lithium acetylides. Furthermore, we demonstrate the reductive
lithiation of the sulfoxide and its conversion to other useful
functionality.
Table 1. Addition of Organometallic Reagents to Aryl Ketonesa
a Reactions carried out on a 20 mg scale at 0.07-0.08 M. b Conversion
1
(Conv) and diastereomeric ratio (dr) determined by H NMR analysis of
the crude reaction mixture. c 1.2 equiv of acetylide was used. d Isolated
yield shown in parentheses.
Toluene sulfinyl groups can be introduced onto an aromatic
nucleus through the stereospecific reaction of menthol
sulfinate with an aryl lithium reagent.20a,21 The requisite
sulfinate is commercially available but can also be prepared
conveniently in large scale from the reductive coupling of
toluene sulfonyl chloride with menthol.22 With these con-
siderations in mind, we prepared methyl ketone 1a23 and
examined its reactivity toward a variety of organometallic
reagents, initially focusing on the synthesis of propargylic
alcohols. The lithium anion of phenyl acetylene provided
tertiary alcohol 2a with good diastereoselectivity, but in
unsatisfactory yield (Table 1, entry 1). Alkynyl Grignard
reagents were even more selective but did not fully consume
the sulfoxide. A less basic organocerium reagent24 com-
pletely consumed the ketone and provided the tertiary alcohol
as a ca. 50:1 mixture of diastereomers (entry 4). Using less
than 2 equiv of the nucleophile resulted in incomplete
consumption of 1a (entry 3).
We extended our study to include the addition of aryl
nucleophiles. Using either the arylcerium reagent (entry 5)
or the aryl Grignard (entry 6), we obtained excellent
diastereoselectivity, as only one diastereomer was observed
in the crude reaction mixture. In contrast to the reactivity
profile observed with acetylides, however, the inclusion of
CeCl3 in the reaction mixture actually decreased conversion
when aryl nucleophiles were used. Nonetheless, simple
Grignard reagents generated the desired product in high yield.
Phenyl lithium proved equally selective, but conversion was
incomplete using this reagent (entry 7). Finally, alkyl and
allyl Grignard reagents displayed poor diastereoselectivity
(ca. 4:1) and yielded complex mixtures of products.
Using the optimal reaction conditions for the addition of
acetylides (Table 1, entry 4) and aryl Grignards (Table 1,
entry 6), we explored the generality of the methodology. As
shown in Table 2, a wide range of optically active, tertiary
benzylic alcohols were prepared in high yield. Alkyl-, aryl-,
and silyl-substituted alkynes added to methyl (entries 1-5,
24, 26), ethyl (entries 11-13), and aryl (entry 21) ketones
with crude diastereoselectivities > 10:1. Likewise, electron-
rich, -poor, and -neutral aryl Grignards added to several
ketones with at least 50:1 diastereoselectivities. Importantly,
the addition could accommodate alkenyl Grignard reagents
as well: vinyl (entry 9), 2-propenyl (entries 10, 18, 23) and
2-methyl-1-propenyl (entry 22) magnesium bromide yielded
benzylic, allylic alcohols in at least 20:1 dr. Additional
substitution was tolerated on the aryl sulfoxide fragment as
well, including halogens (entries 15-19, 24-25) and tri-
(12) (a) Saito, B.; Katsuki, T. Synlett 2004, 1557. (b) Jiang, B.; Chen,
Z.; Tang, X. Org. Lett. 2002, 4, 3451.
(13) (a) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451. (b) Lu,
G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem., Int. Ed.
2003, 42, 5057. (d) Chen, C.; Hong, L.; Xu, Z.-Q.; Liu, L.; Wang, R. Org.
Lett. 2006, 8, 2277.
(14) (a) Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448. (b) Zhou,
Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004,
6, 4147.
(15) Liu, L.; Wang, R.; Kang, Y.-F.; Cai, H.-Q.; Chen, C. Synlett 2006,
1245.
(16) For an alternative strategy, see: Bagutski, V.; French, R. M.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2010, 49, 5142.
(17) Evans, D. A.; Helmchen, G.; Ruping, M.; Wolfgang, J. In
Asymmetric Synthesis, 2nd ed.; Christmann, M. S. B. Ed.; Wiley-VCH:
Weinheim, 2007; pp 3-9.
(18) (a) Carreno, M. C. Chem. ReV. 1995, 95, 1717. (b) Garc´ıa Ruano,
J. L.; Mart´ın Castro, A. M.; Rodriguez, J. H. Tetrahedron Lett. 1991, 32,
3195. (c) Garc´ıa Ruano, J. L.; Ferna´ndez-Iba´n˜ez, M. A.; Ferna´ndez-Salas,
J. A.; Maestro, M. C.; Ma´rquez-Lo´pez, P.; Rodr´ıguez-Ferna´ndez, M. M. J.
Org. Chem. 2009, 74, 1200.
(19) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. ReV. 2010,
110, 3600.
(20) (a) Novodomska`, A.; Dudicova`, M.; Leroux, F. R.; Colobert, F.
Tetrahedron: Asymmetry 2007, 18, 1628. (b) Nakamura, S.; Oda, M.;
Yasuda, H.; Toru, T. Tetrahedron 2001, 57, 8469.
(21) (a) Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J.;
Perkins, R. I. J. Am. Chem. Soc. 1964, 86, 5637. (b) Drabowicz, J.; Bujnicki,
B.; Mikolajczyk, M. J. Org. Chem. 1982, 47, 3325
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(22) Klunder, J. M.; Sharpless, K. B. J. Org. Chem. 1987, 52, 2598.
(23) Full experimental details are provided in the Supporting Informa-
tion.
(24) Imamoto, T. Pure Appl. Chem. 1990, 62, 747.
Org. Lett., Vol. 13, No. 2, 2011
185

Table 2. Asymmetric Synthesis of Tertiary Benzylic Alcoholsa
a Reaction conditions same as those in Table 1, entry 4 (M ) [Ce]) or 6 (M ) MgBr) on a 0.4 mmol scale. The (S)-sulfoxides were used. b [Ce] )
reagent derived from alkynyl Li and CeCl3. c Yield of isolated single diastereomer except entry 5 (33:1 dr). The numbers in parentheses represent conversion
d
1
1
of 1 as determined by H NMR analysis of crude reaction mixture. dr determined by H NMR analysis of purified material. The numbers in parentheses
represent dr of crude reaction products. TBS ) tert-butyldimethyl silyl; Tol ) p-tolyl; Np ) naphthyl; Th ) thienyl.
fluoromethyl groups (entry 26). Illustrating the value of the
chiral auxiliary, a single diastereomer was isolated after either
column chromatography or trituration in all but one case
(entry 5, dr ) 33:1). X-ray crystallography established the
absolute and relative stereochemistry of representative
products derived from the addition of alkynyl (entries 1, 2,
11) and aryl (entry 7) organometallic reagents. Other products
in Table 2 were assigned by analogy.
Thus alcohol 2a was deprotonated with methyl lithium, then
lithiated with tert-butyl lithium, and trapped with diiodoet-
hane, CO2, or O2 to provide the iodide 4, lactone 5, or phenol
6 in good yields (Scheme 1). The lactone could have emerged
from either condensation or SN1 substitution with the
carboxylate, which could occur with racemization. Gratify-
ingly, the isolated lactone 5 was found to be optically pure.
Propargylic alcohols are valuable as precursors to other
functional groups including allenes. For example, SN2′
substitution of propargylic alcohols and their derivatives with
organometallic reagents yields allenes, but occasionally these
transformations are imperfectly stereospecific or are ac-
companied by racemization.26 In this context, the presence
of a chiral auxiliary could benefit both the synthesis of the
propargylic alcohol and its conversion to an allene. To
explore this possibility, alcohol 2z was acylated and con-
The sulfoxide chiral auxiliary can be reductively removed
in high yield.18b As shown in Table 3, several diversely
substituted sulfoxides were treated with n-butyl lithium, and
the corresponding tertiary alcohols (3) were obtained in high
ee. Optically pure materials could be prepared by simply
recrystallizing the sulfoxide prior to reductive cleavage.
Exposure of sulfoxides 2 to butyl lithium generates an aryl
lithium which can be trapped with various electrophiles.25
(25) (a) Lockard, J. P.; Schroeck, C. W.; Johnson, C. R. Synthesis 1973,
485. (b) Durst, T.; LeBelle, M. J.; Van den Elzen, R.; Tin, K. C. Can.
J. Chem. 1974, 52, 761. (c) Furukawa, N.; Ogawa, S.; Matsumura, K.;
Fujihara, H. J. Org. Chem. 1991, 56, 6341.
(26) (a) Tadema, G.; Everhardus, R. H.; Westmijze, H.; Vermeer, P.
Tetrahedron Lett. 1978, 19, 3935. (b) Jansen, A.; Krause, N. Inorg. Chim.
Acta 2006, 359, 1761.
186
Org. Lett., Vol. 13, No. 2, 2011

Table 3. Reductive Removal of Sulfinyl Moiety
Scheme 1. Synthetic Manipulations of Sulfoxide 2a
Scheme 2. Asymmetric Synthesis of Allenes
via reductive lithiation. Overall, this process should represent
a valuable component of the synthetic arsenal.
a Yield of isolated product. b Values in parentheses represent yield and
ee obtained using recrystallized 2.
Acknowledgment. This work was supported by the NSF
(CAREER), the NIH (R01 GM074822), Amgen, and the
Welch Foundation (I-1612). J.M.R. is a fellow of the A. P.
Sloan Foundation. We thank Akella Radha (UT Southwest-
ern) for crystallography.
verted to allene 7 which was isolated in 96% yield as a single
diastereomer (Scheme 2).
Tertiary alcohols are important functional groups in
organic synthesis, although their preparation in optically
active form has traditionally proven challenging. Here we
describe a general, high yielding, and selective approach to
their synthesis. Furthermore, the chiral auxiliary, a tolyl
sulfoxide, can be converted into other useful functionality
Supporting Information Available: Experimental details
and crystallographic information. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL102567H
Org. Lett., Vol. 13, No. 2, 2011
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