New multicomponent approach for the creation of chiral quaternary centers in the carbonyl allylation reactions

Article abstract of DOI:10.1021/ja060498q

The combined regio- and stereo-controlled carbometalation reaction of alkynyl sulfoxide followed by a zinc homologation and finally an allylation reaction led, in a single-pot operation, to chiral homoallylic alcohols in excellent yields and diastereosele

Full text of DOI:10.1021/ja060498q

Published on Web 03/21/2006
New Multicomponent Approach for the Creation of Chiral
Quaternary Centers in the Carbonyl Allylation Reactions
Genia Sklute and Ilan Marek*
Contribution from the Mallat Family Laboratory of Organic Chemistry, Department of
Chemistry, Institute of Catalysis Science and Technology and The Lise Meitner-MinerVa Center
for Computational Quantum Chemistry, Technion-Israel Institute of Technology,
Haifa 32000 Israel
Received January 22, 2006; E-mail: chilanm@tx.technion.ac.il
Abstract: The combined regio- and stereo-controlled carbometalation reaction of alkynyl sulfoxide followed
by a zinc homologation and finally an allylation reaction led, in a single-pot operation, to chiral homoallylic
alcohols in excellent yields and diastereoselectivities for the creation of chiral quaternary and tertiary centers.
The key features in all of the reactions that are described in this article are the high degree of stereocontrol,
the level of predictability, and “the ease of execution” which ensures success in the application of such
methods. The chiral sulfinyl moiety can be finally removed by simple treatment with alkyllithiums, which
allows further functionalizations of the carbon skeleton. By using one of these methods, the creation of
chiral quaternary centers with the smallest possible difference, namely CD3 versus CH3 and 13CH3 versus
CH3, was easily performed.
Introduction
This high degree of organization in the transition structure led
to the development of a myriad of chirally modified allylic boron
The reaction of allylmetal reagents and carbonyl compounds
is an important transformation in organic synthesis.1 Advances
in stereoselective carbonyl allylation reactions have been spurred
by interest in the stereoregulated synthesis of conformationally
nonrigid complex molecules such as polypropionate-derived
natural products, carbohydrates, and other polyhydroxylated
compounds.1b This widespread stereocontrolled use of allylic
organometallics in organic synthesis appears to have been
triggered by the original articles from Buse and Heathcock,2
Hoffmann and Zeiss,3 and Yamamoto et al.4 Since then, the
most powerful reagents are the semimetallic allylic reagents such
as boron, silicon, and tin. This popularity stems mainly from
their ease of formation and more particularly from their stability.
The reaction of substituted E- and Z-2-butenylboronates with
achiral aldehydes has been used to prepare syn and anti homo-
allylic alcohols in high diastereoselectivity, respectively.5 Allyl
boronic ester reagents are usually involved in closed, six-
membered cyclic chairlike transition states that are characterized
by internal activation of the carbonyl group by the boron atom.6
reagents for asymmetric allylation of carbonyl compounds.1a
Similarly, the internal stereocontrol of allylic trihalosilanes,
which are electrophilic at the silicon center, is also generated
through a chairlike transition structure.7 The use of chiral Lewis
bases as promoters for the asymmetric allylation and 2-bute-
nylation of trihalosilane derivatives of aldehydes led to high
enantioselectivities.8 This mechanism contrasts with the allyl
trialkylsilane and -stannane analogues, which generally react
with aldehydes under the activation of an external Lewis acid
by way of open transition structures.9 More recent examples
were reported where external chiral ligands play the role of
Lewis acid activators.10 When more anionic allylic organome-
tallic derivatives are used such as allylic lithium, magnesium,
and zinc reagents, the corresponding substituted alkenylmetal
reagents are configurationally unstable, existing as mixtures of
rapidly equilibrating E- and Z-isomers (Scheme 1), even at very
(7) (a) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620. (b) Wang, C.;
Wang, D.; Sui, X. Chem. Commun. 1996, 2261. (c) Wang, D.; Wang, Z.
G.; Wang, M. W.; Chen, Y. J.; Liu, L.; Zhu, Y. Tetrahedron: Asymmetry
1999, 10, 327. (d) Zhang, L. C.; Sakurai, H.; Kira, M. Chem. Lett. 1997,
129.
(8) (a) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J. Org. Chem.
1994, 59, 6161. (b) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y.
Tetrahedron 1999, 55, 977. (c) Nakajima, M.; Saito, M.; Shiro, M.;
Hashimoto, S. J. Am. Chem. Soc. 1998, 120, 6419.
(9) (a) Yamamoto, Y.; Yatagai, H.; Maruyama, K. J. Org. Chem. 1980, 45,
195. (b) Koreeda, M.; Tanaka, Y. J. Chem. Soc., Chem. Commun. 1982,
845. (c) Kahn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J. J. Am.
Chem. Soc. 1987, 109, 650. (d) Yamamoto, Y.; Yatagai, H.; Naruta, Y.;
Maruyama, K. J. Am. Chem. Soc. 1980, 102, 7107. (e) Marshall, J. A.
Chem. ReV. 1996, 96, 31.
(10) (a) Ishihara, K.; Mouri, M.; Gao, Q.; Murayama, T.; Furata, K.; Yamamoto,
H. J. Am. Chem. Soc. 1993, 115, 11490. (b) Aoki, S.; Mikami, K.; Terada,
M.; Nakai, T. Tetrahedron 1993, 49, 1783. (c) Hauthier, D. R.; Carreira,
E. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2363.
(1) (a) Denmark, S.; Almstead, N. G. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VCH: Weinheim, 2000; p 299. (b) Chemler, S. R.; Roush,
W. R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000; p 403. (c) Denmark, S.; Fu, J. Chem. ReV. 2003, 103,
2763. (d) StereoselectiVe Synthesis, Methods of Organic Chemistry
(Houben-Weyl), ed. E21; Helmchen, G., Hoffmann, R., Mulzer, J.,
Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 3. (e) Yamamoto, Y.;
Asao, N. Chem. ReV. 1993, 93, 2207.
(2) Buse, C. T.; Heathcock, C. H. Tetrahedron Lett. 1978, 1865.
(3) Hoffmann, R. W.; Zeiss, H. J. Angew. Chem., Int. Ed. Engl. 1982, 18,
306.
(4) Yamamoto, Y.; Yatagai, H.; Naruta, Y.; Maruyama, K. J. Am. Chem. Soc.
1980, 102, 7107.
(5) (a) Hoffmann, R. W.; Zeiss, H.-J. J. Org. Chem. 1981, 46, 1309. (b)
Hoffmann, R. W.; Kemper, B.; Matternich, R.; Lehmeier, T. Liebigs Ann.
Chem. 1985, 2246.
(6) Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1989, 111, 1236.
9
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J. AM. CHEM. SOC. 2006, 128, 4642-4649
10.1021/ja060498q CCC: $33.50 © 2006 American Chemical Society

Creation of Chiral Quaternary Centers
A R T I C L E S
Scheme 1
Scheme 3
Scheme 2
sped up (12-16-h reaction time) by the presence of certain
metallic salts.16 However, the homoallylic alcohols can be
obtained enantiomerically enriched only by using a dual
auxiliary approach in the thermal condition (reaction time of
14 days).17 A single-pot tandem catalytic diene diboration/
carbonyl allylation18 or hydroboration of allene/carbonyl ally-
lation19 reactions were recently described as new methods for
the creation of quaternary stereocenters. Although racemic, a
notable exception is the addition 3,3′-disubstituted allylchro-
mium(III) reagents to aldehydes, which proceeds in a stereo-
divergent manner. This method allows the preparation of a
variety of homoallylic alcohols bearing a quaternary center of
defined relative configuration in the R-position.20
low temperature.11 Therefore, the diastereoselectivity of such
processes is usually very low.
The “state of the art” in this field belongs to Denmark and
Fu, who reported the first catalytic enantioselective addition of
3,3′-disubstituted allylic trichlorosilanes 4 to aromatic aldehydes
by the use of chiral 2,2′-bispyrrolidine-based bisphosphoramide
3 (Scheme 3).21
A notable exception is the use of masked allylic zinc reagents.
Indeed, as the addition of allylic organozinc reagents to carbonyl
derivatives was known to proceed in a reversible manner, the
sterically hindered tertiary homoallylic alcohol 1 could, upon
generation of a zinc alkoxide, undergo fragmentation to generate
the allylic zinc reagent 2, which could then undergo reaction
with a suitable in situ aldehyde.12 The high diastereoselectivity
obtained is attributed to the generation of pure E-2-butenylzinc
in the presence of the electrophile (Scheme 2).
Despite all these efforts, if one needed to construct chiral
quaternary carbon centers13 by using one of these methods,
major problems still arose. With respect to stereogenic quater-
nary centers, Hoffmann and Schlapbach were the first to show
that 3,3′-disubstituted allylboronates could be used to generate
stereodefined quaternary carbon centers.14 Although these
allylboronates reacted with aldehydes in the expected Zimmer-
man-Traxler transition structure, these reactions required 5-8
days to reach completion and the diastereoisomeric purity of
the homoallylic alcohol products was lower than the initial purity
of the initial allylboronates. Suzuki et al. reported a comparable
stereochemical problem a few years later in similar studies.15
More recent investigations revealed that the reaction could be
However, all of these previously described methods required
several chemical steps for the preparation of the desired 3,3-
disubstituted allylmetal species. One of the major challenges
in synthesis nowadays is to assemble target molecules (here,
namely homoallylic alcohols such as 5 from the reaction of 3,3′-
disubstituted allylic organometallic derivatives and aldehydes)
from readily available starting materials in a one-step synthesis,22
and in a simple and straightforward manner. Therefore, we
thought to develop a totally different retrosynthetic approach
based on a four-component reaction.23 Although allylzinc species
were unknown for the enantioselective preparation of chiral
quaternary centers due to the metallotropic equilibrium described
in Scheme 1, we envisaged that these 3,3-disubstituted allylzinc
derivatives should be the best candidates in synthesis if we could
combine all the chemical steps in a single-pot operation. Indeed,
it was recently reported by Knochel et al. that the homologation
reaction of alkenyl compounds 6 with (iodomethyl)zinc iodide
represents a unique method for the direct conversion of
(16) (a) Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004, 69, 4412. (b) Gravel,
M.; Lachance, H.; Lu, X.; Hall, D. G. Synthesis 2004, 1290. (c) Rauniyar,
V.; Hall, D. G. J. Am. Chem. Soc. 2004, 126, 4518. (d) Kennedy, J. W. J.;
Hall, D. G. Angew. Chem., Int. Ed. 2003, 42, 4732. (e) Yu, S. H.; Ferguson,
M. J.; McDonald, R.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 12808.
(17) Kennedy, J. W. J.; Hall, D. H. J. Am. Chem. Soc. 2002, 124, 898.
(18) Morgan, J. B.; Morken, J. P. Org. Lett. 2003, 5, 2573.
(11) (a) Courtois, G.; Miginiac, L. J. Organomet. Chem. 1974, 69, 1. (b) Felkin,
H.; Gault, Y.; Roussi, G. Tetrahedron 1970, 26, 3761. (c) Fraenkel, G.;
Winchester, W. R. J. Am. Chem. Soc. 1989, 111, 3794.
(12) (a) Jones, P.; Millot, N.; Knochel, P. Chem. Commun. 1988, 2405. (b) Jones,
P.; Knochel, P. Chem. Commun. 1998, 2407. (c) Jones, P.; Knochel, P. J.
Org. Chem. 1999, 64, 186.
(13) For reviews, see: (a) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005,
347, 1473. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,
4591. (c) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (d) Fuji, K. Chem. ReV. 1993, 93, 1037. (e) Martin, S. F.
Tetrahedron 1980, 36, 419.
(19) (a) Heo, J.-N.; Micalizio, G. C.; Roush, W. R. Org. Lett. 2003, 5, 1693.
(b) Lambert, W. T.; Roush, W. R. Org. Lett. 2005, 7, 5501.
(20) (a) Jubert, C.; Nowotny, S.; Kornemann, D.; Antes, I.; Tucker, C. E.;
Knochel, P. J. Org. Chem. 1992, 57, 6384. (b) Nowotny, S.; Tucker, C.
E.; Jubert, C.; Knochel, P. J. Org. Chem. 1995, 60, 2762.
(14) (a) Hoffmann, R. W.; Schlapbach, A. Liebigs Ann. Chem. 1990, 1243. (b)
Hoffmann, R. W.; Schlapbach, A. Liebigs Ann. Chem. 1991, 1203. (c)
Hoffmann, R. W.; Schlapbach, A. Tetrahedron 1992, 48, 1959.
(15) (a) Sato, M.; Yamamoto, Y.; Hara, S.; Suzuki, A. Tetrahedron Lett. 1993,
34, 7071. (b) Yamamoto, Y.; Hara, S.; Suzuki, A. Synlett 1996, 883. (c)
Ramachandran, P. V.; Prabhudas, B.; Chandra, J. S.; Reddy, M. V. R.;
Brown, H. C. Tetrahedron Lett. 2004, 45, 1011.
(21) (a) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488. (b) Denmark,
S. E.; Fu, J. Org. Lett. 2002, 4, 1951. (c) Denmark, S. R.; Fu, J.; Lawler,
M. J. J. Org. Chem., 2006, 71, 1523. (d) Denmark, S. R.; Fu, J.; Coe, D.
M.; Su, X.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 2006, 71, 1513.
(22) Chinkov, N.; Levin, A.; Marek, I. Angew. Chem., Int. Ed. 2006, 45, 465.
(23) For a recent review, see: Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.
2005, 44, 1602.
9
J. AM. CHEM. SOC. VOL. 128, NO. 14, 2006 4643

A R T I C L E S
Scheme 4
Sklute and Marek
Scheme 6
Scheme 7
Scheme 5
Scheme 8
alkenylcopper derivatives into allylic zinc (or -copper) com-
pounds 7.24 Moreover, the reaction has to be performed in the
presence of an electrophile, to trap efficiently the intermediate
7 and to furnish the corresponding homoallylic alcohols 8 in
good yields (Scheme 4).
Results and Discussion
Without the presence of this in situ electrophilic partner, the
allylic species 7 undergo further reactions with (iodomethylzinc)
iodide to lead to the double homologated product 9 (the
reactivity of allylzinc is higher than vinylcopper toward the zinc
carbenoid and should be therefore trapped in situ). On the basis
of these results, we reasoned that the homologation allylation
reactions of alkenylmetal species such as 11 (Scheme 5) should
be the most convenient in situ preparation of homoallylic alcohol
derivatives 10. With respect to quaternary centers, one has to
start with stereodefined â,â-disubstituted alkenylmetal com-
pounds 11, which may easily come from a controlled carbo-
metalation reaction of substituted alkynes 12 (Scheme 5).
Various alkynyl sulfoxides were easily prepared, in the range
of 70-80% yields, by the Andersen synthesis25 using (-)-
menthyl (-)-(S)-p-toluenesulfinate26 14 in toluene with a
solution of alkynylmagnesium bromide 13 in Et2O at -20 °C.27
The absolute configuration of these acetylenic sulfoxides 15a-f
were assigned on the basis that the Grignard reaction with
sulfinate esters proceeds stereospecifically with inversion of
configuration at the sulfur atom and the enantiomeric excess
was determined to be of 98% for 15a by high-performance liquid
chromatography analysis on a chiral stationary phase (chiralpak
AD-H Daicel) and assigned by analogy for 15b-f (Scheme 7).28
Our first investigation concerned the regio- and stereospecific
carbocupration of 15 with organocopper derivatives 16 (easily
obtained from 1 equiv of alkylmagnesium halide and 1 equiv
of CuX; X ) Br, I), which provides the corresponding metalated
â,â-dialkylated R,â-ethylenic sulfoxide 17 in quantitative yields
(Scheme 8).29 Then, to the reaction mixture, benzaldehyde was
added followed by bis(iodomethyl)zinc carbenoid 18, indepen-
However, even by following this new retrosynthetic approach,
we still have to avoid the potential metallotropic equilibrium
of 3,3-disubstituted allylzinc species 10. Therefore, we thought
to (1) increase the stability of the allylic organometallic species
in its R-position by an intramolecular chelation of the zinc atom
by an A-B unit (Scheme 6) and (2) use this A-B chelating
moiety as a source of chirality and as a regiocontrol element
for the carbocupration reaction (to lead only to a species with
copper geminated to the A-B unit). By combining all of these
parameters, we designed our lead starting materials as alkynyl
sulfoxides (Scheme 6), easily available in large quantities.
(25) (a) Andersen, K. K. Tetrahedron Lett. 1962, 93. (b) Andersen, K. K. J.
Org. Chem. 1964, 29, 1953. (c) Andersen, K. K.; Foley, J.; Perkins, R.;
Gaffield, W.; Papanikalaou, N. J. Am. Chem. Soc. 1964, 86, 5637. (d)
Axelrod, M.; Bickart, P.; Jacobus, J.; Green, M. M.; Mislow, K. J. Am.
Chem. Soc. 1968, 90, 4835.
(26) Solladie, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
(27) Kosugi, H.; Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J. Org. Chem.
1987, 52, 1078.
(24) (a) Knochel, P.; Chou, T.-S.; Chen, H. G.; Yeh, M. C. P.; Rozema, M. J.
J. Org. Chem. 1989, 54, 5202. (b) Knochel, P.; Jeong, N.; Rozema, M.;
Yeh, M. C. P. J. Am. Chem. Soc. 1989, 111, 6474. (c) Sidduri, A. R.;
Knochel, P. J. Am. Chem. Soc. 1992, 114, 7579. (d) Sidduri, A. R.; Rozema,
M. J.; Knochel, P. J. Org. Chem. 1993, 58, 2694.
(28) (a) Abbott, D. J.; Colonna, S.; Sterling, C. L. M. J. Chem. Soc. D 1971,
471. (b) Posner, G. H.; Tang, P. W. J. Org. Chem. 1978, 43, 4131.
(29) (a) Truce, W. E.; Lusch, M. J. J. J. Org. Chem. 1974, 39, 3174. (b) Truce,
W. E.; Lusch, M. J. J. J. Org. Chem. 1978, 43, 2252. (c) Fiandanese, V.;
Marchese, G.; Naso, F. Tetrahedron Lett. 1978, 5131.
9
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Creation of Chiral Quaternary Centers
A R T I C L E S
Table 1. Stereocontrol in the Allylation Reaction
entry
R1
R2
R3
Pdts
de %a
yield, %b
1
2
3
4
5
6
7
8
9
Et 16a
Bu 16b
Me 16c
Me 16c
Et 16a
Et 16a
Bu 16b
Et 16a
Me 16c
Bu 15a
Et 15b
Bu 15a
Et 15b
H 15d
Bu 15a
Et 15b
Bu 15a
Et 15b
Ph 20a
Ph 20a
Ph 20a
Ph 20a
Ph 20a
Ph 20c
Ph 20c
Bu 20b
Bu 20b
21a
21b
21c
21d
21e
21f
21g
21h
21i
>98
>98
>98
>98
60
>98
>98
94
78
68
66
66
78
72
70
60
60
Figure 1.
94
a Determined on the crude 1H and 13C NMR. b Determined after
purification by chromatography on silica gel.
(21d; Table 1, entry 4). Interestingly, when a tertiary carbon
center is created (21e, R1 ) Et, R2 ) H; Table 1, entry 5), the
diastereoselectivity was eroded and two isomers were formed
in a 80/20 ratio. To understand the origin of this lower
diastereoselectivity, we first removed the chirality at the
sulfoxide center of 21e by simple oxidation with oxone and
the corresponding sulfone 22 was obtained as a unique isomer
(Scheme 9).
Scheme 9
Thus, we can conclude that the enantiofacial choice of the
allylation reaction was not completely controlled when the R2
substituent on the alkyne was a hydrogen37 (the cis relationship
between the ethyl and phenyl substituents in the tetrahydrofuran
ring 23 was obtained by a 5-endo-trig cyclization of 22 and
determined by NOE experiments).38 Since the S-O bond
operates as an acceptor site for Lewis acids, the conformation
of the sulfoxide is strongly influenced by complexation of the
zinc atom and also by the Z-substituent (syn to the sulfoxide
moiety)39 of the carbon-carbon double bond (compare entries
1-4 with 5, Table 1).40 Thus, for an allylic system 19 having
a Z-substituent at the double bond, a unique conformation should
be favored, avoiding 1,3-allylic strains as described in Figure
1. Therefore, the groups on the sulfur atom are disposed in such
positions that the difference in their active or inert volume may
optimally induce facial selectivity for reactions, which occur at
the double bond.41 Thus, the combination of this intramolecular
chelation with the related allylic strain leads to a unique con-
formation of the allylzinc derivatives as described in Figure 1.
The combination of the stereoselective carbometalation
(introduction of the R1 substituent), the zinc homologation
(introduction of the CH2 unit of the allylzinc fragment), the
intramolecular chelation of the zinc atom by the sulfoxide (which
prevents the metallotropic equilibrium),42 the presence of the
p-tolyl group (shields one face), and the 1,3-allylic strain leads
to very high diastereoselectivity when the allylzinc reacts with
benzaldehyde (aryl groups occupies a pseudoequatorial position)
in a Zimmerman-Traxler chairlike transition state (Figure 2).
Imine 20c can also be used as an electrophilic partner in this
one-pot transformation (see Table 1, entries 6 and 7); both
diastereomers of the homoallylic amines 21f,g are easily
obtained with very high diastereoselectivities. Finally, aliphatic
dently prepared from 1 equiv of Et2Zn and 2 equiv of CH2I2.30
Neither the vinylic organocopper 1731 (the nucleophilicity of
organocopper reagents is strongly influenced by the nature of
the organocopper itself32 and particularly organocopper bearing
sulfur functionality at the R-position33) nor the zinc carbenoid
is reactive enough to add to aldehydes or imines; however, 17
is readily homologated by a methylene unit with the zinc
carbenoid. The in situ reactive chelated allylzinc species 19
reacts diastereoselectively with benzaldehyde 20a to give after
hydrolysis the corresponding adducts 21a-d in good overall
yields and in excellent diastereoselectivities (Scheme 8, Table
1, entries 1-4).34
The stereochemistry observed in this one-pot reaction was
confirmed by X-ray analysis of 21a and 21c, and the config-
urations of other reaction products were assigned by analogy.
As shown with 21a (R1 ) Et, R2 ) Bu; Table 1, entry 1)
and 21b (R1 ) Bu, R2 ) Et; Table 1, entry 2), permutation
of the alkyl groups of the alkyne and the organocopper reagent
allows the independent formation of the two isomers at the
quaternary carbon center, respectively.35 Even the methyl-
copper, known to be a sluggish group in carbocupration
reaction,36 adds cleanly to the alkynyl sulfoxide 15a and gives
after the homologation allylation reactions the expected ho-
moallylic alcohol as only one isomer (21c; see Table 1, entry
3). By using this simple methodology, a chiral quaternary
carbon center with two sterically very similar alkyl groups such
as ethyl and methyl can be easily prepared as a single isomer
(30) (a) Charette, A. B.; Marcoux, J. F.; Molinaro, C.; Beauchemin, A.; Brochu,
C.; Isabel, E. J. Am. Chem. Soc. 2000, 122, 4508. (b) Denmark, S. E.;
O’Connor, S. P. J. Org. Chem. 1997, 62, 3390.
(37) The hydrometalation of 15a does not lead to the opposite stereoisomer.
See: Huang, X.; Duan, D.; Zheng, W. J. Org. Chem. 2003, 68, 1958.
(38) Auvray, P.; Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985, 26, 4455.
(39) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(31) Piazza, C.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 3263.
(32) Posner, G. H.; Harrison, W.; Wettlaufer, D. G. J. Org. Chem. 1985, 50,
5141.
(40) Tietze, L. F.; Schuffenhauer, A.; Schreiner, P. R. J. Am. Chem. Soc. 1998,
120, 7952.
(33) Rao, S. A.; Chou, T.-S.; Schipor, I.; Knochel, P. Tetrahedron 1992, 48,
2025.
(41) For examples of 1,3-allylic strains controlling diastereoselective reactions
of vinyl sulfoxides, see: (a) Koizumi, T.; Hakamada, I.; Yoshii, E.
Tetrahedron Lett. 1984, 25, 87. (b) Posner, G. H. Acc. Chem. Res. 1987,
20, 72. (c) Pyne, S. G.; Griffith, R.; Edwards, M. Tetrahedron Lett. 1988,
29, 2089.
(42) When the same reaction was repeated on terminal alkyne (without the chiral
sulfoxide as chelating unit), the reaction proceeds but leads to two
diastereomers in a 1:1 ratio.
(34) Sklute, G.; Amsallem, D.; Shibli, A.; Varghese, J. P.; Marek, I. J. Am.
Chem. Soc. 2003, 125, 11776.
(35) Both diastereomers at the carbinols centers are different by 1H NMR; both
of them were independently prepared by oxidation of the benzylic alcohol
into phenyl ketone followed by further nonselective reduction.
(36) Normant, J. F.; Alexakis, A. Synthesis 1981, 841.
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J. AM. CHEM. SOC. VOL. 128, NO. 14, 2006 4645

A R T I C L E S
Sklute and Marek
Table 2. Allylation Reaction with in Situ Preparation of Zinc
Carbenoid
Figure 2.
Scheme 10
aldehydes were tested in this reaction, but the reaction was found
to be more difficult to control. Although the diastereoselectivity
is usually excellent (see Table 1, entries 8 and 9; dr 30/1; 94%
de), the reaction is very dependent on the experimental
conditions, and more studies are currently underway to extend
the scope with aliphatic aldehydes.
a Determined on the crude 1H and 13C NMR and correlated by chiral
HPLC (chiralpak AD-H). b Determined after purification by chromatography
on silica gel.
Although these carbometalation-homologation-allylation
reactions led, with very high diastereoselectivity, to the corre-
sponding homoallylic alcohol and amine derivatives, we had
to prepare independently the bis(iodomethyl)zinc carbenoid and
further transferred it into the reaction mixture at low temperature.
To improve our reaction sequence, we developed an easier and
more straightforward procedure described as follows.
Scheme 11
The first step, namely the regio- and stereoselective carbocu-
pration of alkynyl sulfoxides 15 with organocopper derivatives
16, still provides the corresponding metalated â,â-dialkylated
R,â-ethylenic sulfoxide 17 in quantitative yields as originally
described in Scheme 8, but now aldehydes Et2Zn and CH2I2
are all added to the reaction mixture at -20 °C (Scheme 10).
As discussed previously, neither vinylcopper 17 nor Et2Zn reacts
with aldehydes, and as the transmetalation from vinylcopper to
vinylzinc is a slow process at -20 °C, the reaction between
Et2Zn and CH2I2 occurs first to lead to the in situ formation of
the zinc carbenoid 18. This carbenoid readily homologates the
vinylcopper 17 into the allyl species 19, which reacts diaste-
reoselectively with aldehydes to give the expected homoallylic
alcohols in very high diastereoselectivities (Scheme 10 and
Table 2).
This improved in situ procedure led to identical diastereo-
selectivities as compared to the one previously described
(compare entry 1 of Tables 1 and 2) in slightly better yields.
Several different alkyl groups were easily introduced in the
carbocupration reaction, which shows the flexibility of the
described method (Table 2, entries 1-3). Functionalized alde-
hydes can also be used in this allylation reaction, such as
4-chlorobenzaldehyde 20d, 4-carbomethoxybenzaldehyde 20e,
and even 4-acetylbenzaldehyde 20f. In the last two cases, the
reaction proceeds chemoselectively on the aldehyde (no trace
of reaction either on the ester or on the ketone moieties).
Control of the absolute configuration of remote stereocenters
is also a topic of considerable interest,43 and when the quaternary
centers possess two identical alkyl groups (Table 2, entries 5,
6, and 10, R1 ) R2 ) Me), a useful level of 1,4-stereocontrol
is obtained (de 96-98%). The absolute configuration was
determined by X-ray analysis of 21m and 21r and assigned by
analogy for 21n. Finally, even heteroaromatic aldehydes can
be used as electrophilic partners in this reaction (Table 2, entries
9-11). This new approach for the allylation reaction can be
even further simplified by a real four-component reaction. In
this case, one only needs to prepare an alkylcopper derivative.
Indeed, alkynyl sulfoxide, benzaldehyde, dialkylzinc, and CH2I2
are added simultaneously to the organocopper species in the
flask as described in Scheme 11.
Initially, we checked that this four-component reaction
proceeds well with identical alkyl groups such as alkylcopper
and dialkylzinc (R1 ) R3 ) Bu) in order to avoid crossover
reactions. The chiral homoallylic alcohol 21t was isolated in
84% yield and 94% diastereomeric excess for the remote 1,4-
induction (see Table 3, entry 1). When the same reaction with
the same two organometallic species (BuCu, MgBr2, and Bu2-
Zn) was performed on a different alkynyl sulfoxide such as 15c
(R2 ) Me), the corresponding chiral homoallylic alcohol 21u
was obtained in good yield and diastereomeric ratio (see Table
3, entry 2). Then, both alkyl groups of the alkylcopper and
alkynyl sulfoxide were identical (R1 ) R2 ) Bu), whereas the
nature of the alkyl group on the dialkylzinc was different (R3
) Et). Even in this condition, the reaction leads to 21t in
(43) (a) Donnelly, S.; Thomas, E. J.; Arnott, E. A. Chem. Commun. 2003, 1460.
(b) Mikami, K.; Shimizu, M.; Zhang, H.-C.; Maryanoff, B. E. Tetrahedron
2001, 57, 2917 and references therein.
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Creation of Chiral Quaternary Centers
A R T I C L E S
Table 3. Four-Component Carbonyl Allylation Reaction
Table 4. Copper-Catalyzed Allylation Reaction
entry
R1
R2
R3
Pdts
de %a
yield, %b
entry
R1
R2
Pdts
de %a
yield, %b
1
2
3
4
5
Bu 16b
Bu 16b
Bu 16b
Et 16a
Et 16a
Bu 15a
Me 15c
Bu 15a
Bu 15a
Me 15c
Bu
Bu
Et
Et
Et
21t
21u
21t
21a
21v
94
90
96
>98
95
84
74
78
80
75
1
2
3
4
Et 16a
Et 16c
Me 16c
Bu 16b
Bu 15a
Hex 15f
Bu 15a
Hex 15f
21a
21j
21c
21w
95
>98
96
80
65
81c
57d
>98
a Determined on the crude 1H and 13C NMR. b Determined after
purification by chromatography on silica gel. c Et2Zn was added after the
copper-catalyzed carbozincation. d BuZnBr was used as initial organome-
tallic species.
a Determined on the crude 1H and 13C NMR. b Determined after
purification by chromatography on silica gel.
Scheme 12
titatively with dialkylzinc to lead to the corresponding vinyl
alkylzinc species 17Zn. Subsequently, benzaldehyde and CH2I2
were added to 17ZN, and the corresponding homoallylic
alcohols 21 were obtained in good yields and excellent
diastereomeric ratio, as shown in Scheme 12 and Table 4.
Mechanistically, we can rationalize the formation of 21 by
an insertion of CH2I2 into the sp3 carbon-zinc bond of 17Zn
to lead to the corresponding vinyl(iodomethyl)zinc carbenoid
24 with concomitant formation of R-I. The sp2 carbon ligand
bound to the zinc then undergoes a 1,2-shift to the electrophilic
carbon attached to the same metal to furnish the new allylzinc
species, which finally adds to the benzaldehyde already present
in the reaction mixture.45 This type of rearrangement has been
already used in the tandem zirconocene homologation-aldimine
allylation reaction.46
When Et2Zn was used for both the copper-catalyzed car-
bozincation and the in situ formation of the vinyl(iodomethyl)-
zinc 24, yields were moderate to good and the diastereoselec-
tivities were excellent (see Table 4, entries 1 and 2). On the
other hand, when Me2Zn was used, the carbozincation of 15a
still led to 17Zn but the transformation into the carbenoid
intermediate 24 (with formation of MeI) was sluggish and yields
in homoallylic alcohols were therefore low (vinyl sulfoxide 17
coming from the hydrolysis of 17Zn was isolated in 40% yield,
not represented in the table). To have a better transformation,
Et2Zn should be also added to transform the vinyl methylzinc
into the corresponding vinyl ethylzinc, via the Schlenk equi-
librium, which then leads to the vinyl(iodomethyl)zinc 24 and
then to the corresponding allylzinc derivative (Table 4, entry
3). Finally, alkylzinc halide such as BuZnBr can also be used
for the carbometalation reaction (Table 4, entry 4), but Et2Zn
needs to be added for the homologation reaction. Even in this
condition, yields are only moderate.
excellent yield and diastereomeric excess (Table 3, entry 3)
without any crossover addition products having an ethyl group
on it. However, when Et2Zn was used instead of Bu2Zn, a higher
diastereomeric ratio was obtained (de 96% instead of 94%,
compare entries 3 and 1, Table 3). This discrepancy may be
rationalized by a faster in situ preparation of zinc carbenoid
with Et2Zn than with Bu2Zn. Therefore, we can conclude from
this experiment that the carbocupration of alkynyl sulfoxide 15
with an organocopper is faster than any copper to zinc
transmetalation (no formation of EtCu which would have led
to the formation of the homoallylic alcohol 21a). Only when
methylcopper was used for the carbometalation reaction, some
crossover reactions were detected in trace amounts (not reported
in Table 3), due to the very slow carbocupration reaction. Then,
in the last two experiments (Table 3, entries 4 and 5), two
different alkyl groups for the organocopper and the alkynyl
sulfoxide were used with Et2Zn as a precursor for the zinc
carbenoid; in both cases, chiral quaternary and tertiary centers
were created with excellent diastereoselectivities and in good
overall yields.
Four different protocols are described herein for the one-pot
preparation of homoallylic alcohols for the creation of quaternary
and tertiary chiral centers. In all these methods, very high
diastereoselectivities were usually obtained due to the unique
combination of (1) stereocontrolled carbometalation reaction,
(2) homologation into allylzinc species without scrambling the
stereochemistry of the double bond, and (3) diastereoselective
Thus, each of these reagents reacts specifically in the
appropriate order with its specific “partners”, without any
crossover reactions (with the exception of MeCu); the organo-
copper reagent reacts first and only with alkynyl sulfoxide, R2-
Zn and CH2I2 form only zinc carbenoid, and these two later in
situ generated nucleophilic species give the allylzinc derivatives
that subsequently allylate the benzaldehyde.
(44) Maezaki, N.; Sawamoto, H.; Yoshigami, R.; Suzuki, T.; Tanaka, T. Org.
Lett. 2003, 5, 1345.
(45) (a) Marek, I. Tetrahedron 2002, 58, 9463. (b) Charette, A. B.; Marcoux, J.
F. J. Am. Chem. Soc. 1996, 118, 4539. (c) McWilliams, J. C.; Amstrong,
J. D.; Zheng, N.; Bhupathy, M.; Volante, R. P.; Reider, P. J. J. Am. Chem.
Soc. 1996, 118, 11970. (d) Shibli, A.; Varghese, J. P.; Knochel, P.; Marek,
I. Synlett 2001, 818.
To further increase the efficiency of this new approach, we
finally developed an unprecedented catalytic assembly from
these four simple precursors: alkynes, dialkylzinc, aldehyde,
and diiodomethane as reported in Scheme 12. The copper-
catalyzed carbozincation of alkynyl sulfoxide44 proceeds quan-
(46) (a) Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773. (b) Wipf, P.; Kendall,
C.; Stephenson, C. R. J. Am. Chem. Soc. 2001, 123, 5122. (c) Wipf, P.;
Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125, 761. (d)
Wipf, P.; Pierce, J. G. Org. Lett. 2005, 7, 3537. (e) Wipf, P.; Stephensom,
C. R. J. Org. Lett. 2005, 7, 1137. (f) Wipf, P.; Werner, S.; Woo, G. H. C.;
Stephenson, C. R. J.; Walczak, M. A. A.; Coleman, C. M.; Twining, L. A.
Tetrahedron 2005, 61, 11488.
9
J. AM. CHEM. SOC. VOL. 128, NO. 14, 2006 4647

A R T I C L E S
Scheme 13
Sklute and Marek
Scheme 14
one of the most interesting transformations, although the sul-
foxide cannot be reused, since further functionalization may
increase the complexity of the carbon skeleton.48 In this context,
we49 and others50 have recently described the unique preparation
of vinylmetal derivatives from vinyl sulfoxides. When 21a and
21r were first treated with MeLi and then with t-BuLi in Et2O
at -78 °C, the corresponding vinyllithium species 25a,r were
obtained, via a sulfoxide-lithium exchange reaction, in excellent
yields as determined after acidic hydrolysis (Scheme 14). The
enantiomeric ratio (er ) 96/4) of 26a and 26r was determined
by chiral HPLC (chiral column Chiralpak AD-H) and was
found to be similar to the starting alkynyl sulfoxide 15a,c
(er ) 96/4).
allylation reaction of aldehydes controlled by the stereogenic
center of the homochiral sulfoxide. Having in hands these
methods, we thought to apply them for the diastereoselective
preparation of a chiral quaternary centers with the smallest
possible difference between the two alkyl groups. For this
purpose, we initially prepared 1,1,1-trideuteriopropynylsulfoxide
15e and submitted it to our copper-catalyzed methylzincation
reaction as originally described in Scheme 12. Once the
carbometalated product 17Zn was obtained, Et2Zn, CH2I2, and
benzaldehyde were subsequently added in the reaction mixture
to lead to the expected homoallylic alcohol 21x with very high
diastereoselectivity (de 94% in 82% yield) as described in
Scheme 13. An even smaller difference for the creation of a
quaternary center was achieved by the following labeled
experiment: 13CH3MgI, easily prepared from iodomethane-
13C and Mg°, was transformed into its corresponding organo-
copper reagent 13CH3Cu and added to propynyl sulfoxide 15c.
To the vinylcopper 17 was subsequently added Et2Zn, CH2I2,
and benzaldehyde to give the corresponding product in 60%
yield and 95% diastereomeric excess (Scheme 13). The dias-
tereoselectivity of these reactions can be easily determined on
the crude NMR (the two parents Me groups of 21m are
diastereotopics), but the absolute configurations were deduced
by analogy from all our previously prepared homoallylic
alcohols.
The sulfoxide-lithium exchange reaction leading to 25a can
be used for further functionalization; for instance, the addition
(47) For a review, see: Posner, G. H. The Chemistry of Sulphones and
Sulphoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.; Wiley:
Chichester, 1988.
(48) (a) Leroux, F.; Schlosser, M.; Zohar, E.; Marek, I. The Preparation of
Organolithium Reagents and Intermediates. In The Chemistry of Organo-
lithium Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: New York,
2004; p 435. (b) Cohen, T.; Doubleday, M. D. J. Org. Chem. 1990, 55,
4784. (c) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152. (d)
Yus, M. Arene-Catalyzed Lithiation. In The Chemistry of Organolithium
Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: New York, 2004; p
647.
(49) (a) Farhat, S.; Marek, I. Angew. Chem., Int. Ed. 2002, 41, 1410. (b) Farhat,
S.; Zouev, I.; Marek, I. Tetrahedron 2004, 60, 1329. (c) Abramovitch, A.;
Varghese, J. P.; Marek, I. Org. Lett. 2004, 6, 621. (d) Varghese, J. P.;
Zouev, I.; Aufauvre, L.; Knochel, P.; Marek, I. Eur. J. Org. Chem. 2002,
4151. (e) Chinkov, N.; Chechik, H.; Majumdar, S.; Marek, I. Synthesis
2002, 2473. (f) Chinkov, N.; Majumdar, S.; Marek, I. J. Am. Chem. Soc.
2002, 124, 10282. (g) Chinkov, N.; Majumdar, S.; Marek, I. J. Am. Chem.
Soc. 2003, 125, 13258.
In all the examples cited above, the chiral sulfinyl group plays
a unique role as chiral auxiliaries for the creation of two new
stereogenic centers. However, for further applications, sulfoxide
should only be a chiral synthetic tool and must be disposed of
at the end of the sequence.47 Among all the possible methods,
the ligand exchange reaction of sulfoxides with alkylmetals is
(50) For some representative examples of sulfoxide-Li exchange, see: (a) Satoh,
T. Chem. ReV. 1996, 96, 3303. (b) Satoh, T.; Itoh, N.; Watanabe, H.; Koide,
H.; Matsuno, H.; Matsuda, K.; Yamakawa, K. Tetrahedron 1995, 51, 9327.
(c) Satoh, T.; Hanaki, N.; Kumarochi, Y.; Inoue, Y.; Hosaya, K.; Sakai,
K. Tetrahedron 2002, 58, 2533. (d) Satoh, T.; Yamada, N.; Asano, T.
Tetrahedron Lett. 1998, 39, 6935.
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4648 J. AM. CHEM. SOC. VOL. 128, NO. 14, 2006

Creation of Chiral Quaternary Centers
A R T I C L E S
of iodine to 25a gave the corresponding vinyl iodide 29a in
70% yield.
the level of predictability, and the ease of execution. Finally, a
simple sulfoxide-lithium exchange allows further functional-
ization of these sulfoxide-free chiral substrates.
Conclusions
The combination of the (1) regio- and stereoselective carbo-
metalation reaction, (2) in situ homologation of the resulting
organocopper with the zinc carbenoid, (3) intramolecular
chelation of the zinc moiety by the sulfinyl group, and (4)
diastereoselective allylation reaction led to the preparation of
chiral homoallylic alcohol derivatives with quaternary and
tertiary centers in a single-pot operation from common alkynyl
precursors. Even when four components were added at the
beginning on organocopper derivatives, each organometallic
species present in the flask reacts with a single partner to give
the expected product at the end of the sequence. The key features
in all of these reactions are the high degree of stereocontrol,
Acknowledgment. This research was supported by a grant
from GIF, the German-Israeli Foundation for Scientific Re-
search and Development (I-693-7.5/2001), and by the Fund for
Promotion of Research at the Technion. I.M. is holder of the
Sir Michael and Lady Sobell Academic Chair.
Supporting Information Available: Experimental procedure,
spectra data of all compounds, as well as X-ray analysis of
selected compounds (CIF, PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JA060498Q
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