Synthesis of quaternary carbon stereogenic centers through enantioselective Cu-catalyzed allylic substitutions with vinylaluminum reagents

Article abstract of DOI:10.1021/ja106829k

Catalytic enantioselective allylic substitution (EAS) reactions, which involve the use of alkyl- or aryl-substituted vinylaluminum reagents and afford 1,4-dienes containing a quaternary carbon stereogenic center at their C-3 site, are disclosed. The C-C bond-forming transformations are promoted by 0.5-2.5 mol % of sulfonate bearing chiral bidentate N-heterocyclic carbene (NHC) complexes, furnishing the desired products efficiently (66-97% yield of isolated products) and in high site (>98% S_N2′)- and enantioselectivity [up to 99:1 enantiomer ratio (er)]. To the best of our knowledge, the present report puts forward the first cases of allylic substitution reactions that result in the generation of all-carbon quaternary stereogenic centers through the addition of a vinyl unit. The aryl- and vinyl-substituted vinylaluminum reagents, which cannot be prepared in high efficiency through direct reaction with diisobutylaluminum hydride, are accessed through a recently introduced Ni-catalyzed reaction of the corresponding terminal alkynes with the same inexpensive metal-hydride agent. Sequential Ni-catalyzed hydrometalations and Cu-catalyzed C-C bond-forming reactions allow for efficient and selective synthesis of a range of enantiomerically enriched EAS products, which cannot be accessed by previously disclosed strategies (due to inefficient vinylmetal synthesis or low reactivity and/or selectivity with Si-substituted derivatives). The utility of the protocols developed is demonstrated through a concise enantioselective synthesis of natural product bakuchiol.

Full text of DOI:10.1021/ja106829k

Published on Web 09/22/2010
Synthesis of Quaternary Carbon Stereogenic Centers through
Enantioselective Cu-Catalyzed Allylic Substitutions with
Vinylaluminum Reagents
Fang Gao, Kevin P. McGrath, Yunmi Lee, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
Received July 30, 2010; E-mail: amir.hoveyda@bc.edu
Abstract: Catalytic enantioselective allylic substitution (EAS) reactions, which involve the use of alkyl- or
aryl-substituted vinylaluminum reagents and afford 1,4-dienes containing a quaternary carbon stereogenic
center at their C-3 site, are disclosed. The C-C bond-forming transformations are promoted by 0.5-2.5
mol % of sulfonate bearing chiral bidentate N-heterocyclic carbene (NHC) complexes, furnishing the desired
products efficiently (66-97% yield of isolated products) and in high site (>98% SN2′)- and enantioselectivity
[up to 99:1 enantiomer ratio (er)]. To the best of our knowledge, the present report puts forward the first
cases of allylic substitution reactions that result in the generation of all-carbon quaternary stereogenic centers
through the addition of a vinyl unit. The aryl- and vinyl-substituted vinylaluminum reagents, which cannot
be prepared in high efficiency through direct reaction with diisobutylaluminum hydride, are accessed through
a recently introduced Ni-catalyzed reaction of the corresponding terminal alkynes with the same inexpensive
metal-hydride agent. Sequential Ni-catalyzed hydrometalations and Cu-catalyzed C-C bond-forming
reactions allow for efficient and selective synthesis of a range of enantiomerically enriched EAS products,
which cannot be accessed by previously disclosed strategies (due to inefficient vinylmetal synthesis or low
reactivity and/or selectivity with Si-substituted derivatives). The utility of the protocols developed is
demonstrated through a concise enantioselective synthesis of natural product bakuchiol.
Introduction
based electrophile is utilized in conjunction with a vinylboronic
acid;4 related catalytic enantioselective allylic substitution (EAS)
A significant challenge in chemical synthesis concerns the
development of efficient catalytic enantioselective reactions that
furnish all-carbon quaternary stereogenic centers.1 One general
strategy for promoting such processes relates to additions of
C-based nucleophiles to electrophilic carbon sites. The corre-
sponding transformations with vinylmetal reagents represent an
attractive option: the products, bearing a quaternary carbon
stereogenic center at the allylic position, can be functionalized
and/or utilized in the synthesis of natural products. Nonetheless,
catalytic enantioselective protocols delivering quaternary carbon
stereogenic centers by addition of a vinylmetal are scarce.2,3
There has been only one method developed in which an alkene-
reactions that generate quaternary carbons5-7 and involve
addition of a vinyl group8 have not yet been introduced (eq 1).
Herein, we report the first examples of catalytic EAS processes
with alkyl- or aryl-substituted vinylaluminums, affording 1,4-
dienes that contain a quaternary carbon stereogenic center at
their C-3 site. Transformations are promoted by 0.5-2.5 mol
% of chiral bidentate N-heterocyclic carbene (NHC) complexes,
furnishing the desired products efficiently and in high site (>98%
SN2′)- and enantioselectivity [up to 99:1 enantiomer ratio (er)].
Whereas alkyl-substituted vinylaluminums are obtained through
reaction of the corresponding alkynes with diisobutylaluminum
hydride (dibal-H),8a the aryl- or vinyl-substituted vinylmetal
variants are accessed through a recently introduced Ni-catalyzed
(1) (a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christophers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
2006. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363–5367. (c) Cozzi, P. G.; Hilgraf, R.; Zimmermann,
N. Eur. J. Org. Chem. 2007, 5969–5994.
(2) For Ti-catalyzed enantioselective additions of vinylzinc reagents to
ketones, see: (a) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126,
6538–6539. (b) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127,
8355–8361. For Ti-catalyzed enantioselective additions of vinylalu-
minums to aryl ketones, see: (c) Biradar, D. B.; Gau, H.-M. Org. Lett.
2009, 11, 499–502.
(4) For Rh-catalyzed additions of vinylboronic acids to R,ꢀ-unsaturated
pyridylsulfones, see: (a) Mauleo´n, P.; Carretero, J. C. Chem. Commun.
2005, 4961–4963. Two isolated cases of alkyl-containing vinylalu-
minum conjugate additions to ꢀ-substituted cyclic enones, promoted
by Feringa-type chiral phosphoramidite ligands and which proceed in
75:25 and 86.5:13.5 er, have been reported. See: (b) Vuagnoux-
d’Augustin, M.; Alexakis, A. Chem.-Eur. J. 2007, 13, 9647–9662.
(c) Palais, L.; Alexakis, A. Chem.-Eur. J. 2009, 15, 10473–10485.
(5) For reviews on catalytic allylic alkylation reactions with “hard” C-based
nucleophilic reagents, see: (a) Hoveyda, A. H.; Hird, A. W.;
Kacprzynski, M. A. Chem. Commun. 2004, 1779–1785. (b) Yorimitsu,
H.; Oshima, K. Angew. Chem., Int. Ed. 2005, 44, 4435–4439. (c)
Alexakis, A.; Ba¨ckvall, J. E.; Krause, N.; Pa`mies, O.; Die´guez, M.
Chem. ReV. 2008, 108, 2796–2823.
(3) Molecules that bear a benzylic vinyl unit at an all-carbon quaternary
stereogenic center have been synthesized enantioselectively through
Ni-catalyzed reactions of styrene precursors with ethylene. See: (a)
Shi, W.-J.; Zhang, Q.; Xie, J.-H.; Zhu, S.-F.; Hou, G.-H.; Zhou, Q.-
L. J. Am. Chem. Soc. 2006, 128, 2780–2781. (b) Zhang, A.;
RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 5620–5621. (c) Smith,
C. R.; Lim, H. J.; Zhang, A.; RajanBabu, T. V. Synthesis 2009, 2089–
2900.
9
10.1021/ja106829k  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 14315–14320 14315

A R T I C L E S
Gao et al.
Scheme 1. Proposed Synthesis of Bakuchiol through Site- and Enantioselective NHC-Cu-Catalyzed Allylic Substitution with a Vinylmetal
Reagent
hydroalumination.9,10 The sequential Ni- and Cu-catalyzed
processes allow for efficient and selective synthesis of a range
of enantiomerically enriched EAS products, which cannot be
accessed by previously disclosed strategies (due to inefficient
vinylmetal synthesis or low reactivity and/or selectivity with
Si-substituted derivatives).
H.8a We later addressed the problem of inefficiency in preparing
aryl-substituted vinylaluminums through hydrometalations of
the derived silyl-containing aryl alkynes;8b desilylation with a
protic acid subsequent to Cu-catalyzed alkylation delivers the
desired enantiomerically enriched 1,4-diene. However, the more
sterically demanding Si-containing aryl-substituted vinylalumi-
nums cannot be utilized effectively in the synthesis of the more
congested quaternary carbon centers. An alternative approach
for efficient preparation of aryl-substituted vinylaluminums, as
will be described below, had to be introduced. From inception,
we considered Cu-catalyzed EAS reactions of aryl-substituted
vinylmetals to be a key component of the our investigations;
the present studies were partly driven by the question as to
whether a concise synthesis of enantiomerically enriched
bakuchiol and related natural products might be devised by the
use of the targeted class of reactions (Scheme 1).11
We have designed methods for enantioselective formation
of tertiary C-C bonds through additions of vinylaluminums to
allylic phosphates, catalyzed by chiral bidentate NHC-Cu
complexes.6,8 The requisite alkyl-substituted vinylmetals were
accessed by hydroalumination of terminal alkynes with dibal-
Results and Discussion
1. NHC-Cu-Catalyzed Enantioselective Allylic Substitution
(EAS) Reactions with Vinylaluminum Reagents Derived from
Alkyl-Substituted Alkynes. We first established the feasibility of
the proposed catalytic transformations. We focused our attention
on alkyl-substituted vinylaluminums, because such entities can
be easily accessed through site-selective hydroalumination with
dibal-H. Initial screening pointed to Cu complexes derived from
sulfonate-containing bidentate Ag carbenes 1a-c12 (Scheme 2)
as optimal (see below for further discussion).
(6) For catalytic enantioselective allylic substitutions promoted by chiral
bidentate NHC-Cu complexes developed in these laboratories, see:
(a) Larsen, A. O.; Leu, W.; Nieto Oberhuber, C.; Campbell, J. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130–11131. (b) Van
Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H.
J. Am. Chem. Soc. 2005, 127, 6877–6882. (c) Kacprzynski, M. A.;
May, T. L.; Kazane, S. A.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2007, 46, 4554–4558. For application of such transformations to natural
product synthesis, see: (d) Gillingham, D. G.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 3860–3864. For reactions promoted by the
corresponding Mg(II)-based complexes, see: (e) Lee, Y.; Hoveyda,
A. H. J. Am. Chem. Soc. 2006, 128, 15604–15605. For transformations
promoted by the corresponding Zn(II)- and Al(III)-based complexes,
see: (f) Lee, Y.; Li, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131,
11625–11633. For EAS reactions involving aryl- and hetero-arylmetal
reagents and promoted by the same class of NHC-Cu complexes,
see: (g) Gao, F.; Lee, Y.; Mandai, K.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2010, 49, in press.
(10) For a review on hydroaluminations of alkynes and alkenes, see:
Eisch, J. J. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Schreiber, S. L., Eds.; Pergamon: Oxford, 1991; Vol. 8,
pp 733-761.
(11) For previous enantioselective syntheses of bakuchiol, see: (a) Takano,
S.; Shimazaki, Y.; Ogasawara, K. Tetrahedron Lett. 1990, 31, 3325–
3326. (b) Du, X.-L.; Chen, H.-L.; Feng, H.-J.; Li, Y.-C. HelV. Chim.
Acta 2008, 91, 371–378. (c) Esumi, T.; Shimizu, H.; Kashiyama, A.;
Sasaki, C.; Toyota, M.; Fukuyama, Y. Tetrahedron Lett. 2008, 49,
6846–6849. (d) Bequette, J. P.; Jungong, C. S.; Novikov, A. V.
Tetrahedron Lett. 2009, 50, 6963–6964.
(7) For Cu-catalyzed EAS reactions involving amino acid-based ligands
developed in these laboratories, see: (a) Luchaco-Cullis, C. A.;
Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2001, 40, 1456–1460. (b) Kacprzynski, M. A.; Hoveyda, A. H. J. Am.
Chem. Soc. 2004, 126, 10676–10681. (c) Murphy, K. E.; Hoveyda,
A. H. Org. Lett. 2005, 7, 1255–1258.
(12) For initial reports on sulfonate-based bidentate NHC-Cu complexes,
see: (a) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2007, 46, 1097–1100. (b) May, T. L.; Brown,
M. K.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2008, 47, 7358–7362.
For applications in complex molecule synthesis, see: (c) ref 6d. (d)
Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 12904–
12906. (e) Peese, K. M.; Gin, D. Y. Chem.-Eur. J. 2008, 14, 1654–
1665.
(8) For Cu-catalyzed EAS reactions with vinylaluminum reagents that
afford tertiary C-C bonds and are promoted by sulfonate-based
bidentate chiral NHC-Cu complexes, see: (a) Lee, Y.; Akiyama, K.;
Gillingham, D. G.; Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc.
2008, 130, 446–447. (b) Akiyama, K.; Gao, F.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2010, 49, 419–423.
(9) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961–10963.
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Synthesis of Quaternary Carbon Stereogenic Centers
A R T I C L E S
Scheme 2. Chiral Bidentate NHC-Ag(I) Complexes Used in This
Scheme 3
Studya
a Mes ) 2,4,6-Me3C6H2.
Table 1. NHC-Cu-Catalyzed Additions of an Alkyl-Substituted
Vinylaluminum Reagent to Allylic Phosphates Bearing a
Trisubstituted Alkenea
Scheme 4. NHC-Cu-Catalyzed EAS with Aryl Alkynes or Enynes
Leads to Significant Amounts of Alkynyl Addition Products
mol %
1a
SN2′ yield
entry
substrate (G)
Ph
temp (°C); time (%)b (%)c
erd
1
2
3
4
5
6
7
8
0.5
1.0
2.5
2.0
0.5
2.0
0.5
2.0
1.0
0.5
0.5
-15; 3 h
22; 10 min
-15; 3 h
22; 10 min
22; 30 min
-15; 3 h
22; 10 min
-50; 6 h
-50; 24 h
-15; 3 h
-15; 3 h
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
82
92
96
89
83
87
91
91
77
97
85
93.5:6.5
96.5:3.5
98:2
96.5:3.5
97.5:2.5
96.5:3.5
94.5:5.5
95:5
o-BrC6H4
o-CF3C6H4
o-NO2C6H4
o-MeOC6H4
o-MeC6H4
p-NO2C6H4
Cy
Me2CCH(CH2)2
CO2t-Bu
SiMe2Ph
9
10
11
92.5:7.5
90:10
95.5:4.5
a Reactions were performed under N2 atmosphere; >98% conversion
in all cases, except 91% conv. in entry 9; >98% E product isomer in all
cases. b Determined by analysis of 400 MHz 1H NMR of unpurified
mixtures. c Yields of isolated and purified products. d Determined by
HPLC analysis; see the Supporting Information for details.
As illustrated through Cu-catalyzed synthesis of 1,4-dienes
3-6 (Scheme 3), a variety of vinylaluminum reagents, including
one that contains a sterically demanding tert-butyl substituent
(3), a halide (4), or heteroatom units (5-6),15 can be used. Such
transformations proceed with similarly high efficiency and
stereoselectivity (single olefin isomer and 91:9-96:4 er) as
observed in processes that involve alkyl-substituted alkynes
(Table 1).
2. NHC-Cu-Catalyzed Enantioselective Allylic Substitution
(EAS) Reactions with Vinylaluminum Reagents Derived from
Vinyl- or Aryl-Substituted Alkynes. i. Inefficient Synthesis of
Vinylaluminum Reagents. In contrast to NHC-Cu-catalyzed
reactions that involve alkyl-substituted vinylaluminum reagents,
when the vinylmetal is derived from hydrometalation of an
enyne or an aryl alkyne (e.g., 7 and 8, Scheme 4), although
high er values are obtained, product mixtures are contaminated
with alkynyl addition products (up to 45%).16 Presumably,
during hydroalumination, the vinylmetal serves as an efficient
base to deprotonate the starting alkyne, affording alkynylalu-
A considerable range of allylic phosphates undergo facile
EAS reactions in the presence of 0.5-2.5 mol % 1a13 with
n-hexyl-substituted vinylaluminum 2 to furnish the desired 3,3-
disubstituted 1,4-dienes in 90:10-98:2 er and 77-97% yield
(Table 1). Aryl-substituted substrates (entries 1-7) bearing
electron-donating (entry 5) and -withdrawing substituents
(entries 2-4 and 7), as well as those that carry an alkyl group
(entries 8-9), serve as effective starting materials. Reactions
with aryl-substituted allylic phosphates are sufficiently selective
to be performed at -15 to 22 °C and are complete in 3 h.
Transformations that involve alkyl-substituted electrophiles
(entries 8-9, Table 1) must be performed at -50 °C for
maximum enantioselectivity14 and might require longer reaction
times (6-24 h vs 10 min-3 h), unless higher catalyst loading
is used (e.g., 2 mol %, -50 °C, 6 h, entry 8, Table 1). The
Cu-catalyzed process can be used to access 1,4-dienes containing
a carboxylic ester or silyl-substituted quaternary carbon stereo-
genic center at the C3 position (entries 10-11).
(13) Similar efficiencies and selectivities are observed with complexes
derived from 1b and 1c. Use of the NHC-Cu derived from 1a is due
to the slightly shorter route used for the preparation of the latter Ag
complex.
(14) For example, reaction in entry 9 of Table 1, when performed at 22
°C, affords the desired product in 88.5:11.5 er.
(15) For directed (Z-selective) hydroalumination of terminal propargyl ethers
(cf., 6), see: Alexakis, A.; Duffault, J. M. Tetrahedron Lett. 1988, 29,
6243–6246.
(16) The ability of NHC-Cu complexes to promote addition of an alkyne
unit is noteworthy. Development of the corresponding enantioselective
variants is in progress and will be disclosed shortly.
9
J. AM. CHEM. SOC. VOL. 132, NO. 40, 2010 14317

A R T I C L E S
Gao et al.
Scheme 5. Use of a Si-Substituted Vinylaluminum Reagent
Derived from an Aryl Alkyne in NHC-Cu-Catalyzed EAS
Scheme 6. Ni-Catalyzed Hydroalumination of an Enyne and in Situ
Use in an NHC-Cu-Catalyzed EAS Reaction
Table 2. NHC-Cu-Catalyzed Additions of Aryl-Substituted
Vinylaluminum Reagents to Allylic Phosphates Containing a
Trisubstituted Alkenea
minum and the corresponding protonated alkene. The above
complication is exacerbated by reaction of the alkynylaluminum,
which appears to be somewhat more efficient relative to addition
of the vinylmetal reagent. Control experiments indicate that,
whereas 25% alkyne deprotonation occurs in hydroalumination
of phenylacetylene, 45% alkynyl addition product17 is generated
along with 1,4-diene 8 (1.5 equiv of hydroalumination product
mixture used; see Scheme 4).
ii. The First Approach: Hydroalumination of Silyl-Substituted
Alkynes. Our first attempt to bypass the inefficiency of the
aforementioned hydroaluminations led us to examine the
formerly reported catalytic EAS reactions with silyl-substituted
vinylaluminum;8b the outcome of these investigations is shown
in Scheme 5. In a Cu-catalyzed process with allylic phosphate
10, applicable to enantioselective synthesis of bakuchiol (Scheme
1), use of trisubstituted vinylaluminum 9, generated from
reaction of the corresponding trimethylsilylethynyl-4-anisole
with dibal-H, gives rise to substantial amounts of the i-Bu
addition product and furnishes 1,4-diene 11 with low enanti-
oselectivity (52.5:47.5-61:39 er). Stabilization of electron
density at the vinylic carbon by the silyl substituent likely retards
the rate of vinyl transfer, resulting in the formation of 17-45%
of 12 in the product mixture.
iii. The Second Approach: Efficient Ni-Catalyzed Hydroalu-
mination of Vinyl- or Aryl-Substituted Terminal Alkynes. In the
course of searching for an effective solution to the problem of
efficient vinylaluminum synthesis with minimal alkynylalumi-
num contamination, we discovered that in the presence of 3.0
mol % of commercially available Ni(PPh3)2Cl2, reaction of
dibal-H with enynes or aryl-substituted alkynes proceeds
efficiently (within 2-12 h at 4-22 °C) to afford the desired
organometallic reagent with high selectivity [85% to >98%
terminal:internal (ꢀ:R)] and with <5% alkyne deprotonation.
Thus, as depicted in Scheme 6, 1,4-diene 7 can be obtained in
89% yield when the Ni-catalyzed hydroalumination is utilized
in conjunction with the NHC-Cu-catalyzed process (vs 66%
yield with uncatalyzed hydroalumination in Scheme 4); the
amount of alkynyl addition side product is reduced to 5% (vs
time
alkyne (Ar) (h)
yield
b
entry
substrate (R)
Ph
Ph
Ph
Ph
o-BrC6H4
o-NO2C6H4
o-MeC6H4
p-NO2C6H4
p-CF3C6H4
ꢀ:R
SN2′:SN2b (%)c
erd
1
2
3
4
5
6
7
8
9
Ph
3
6
6
3
3
95:5
>98:2
>98:2
87:13
96:4
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
78 96:4
e
o-MeC6H4
p-MeOC6H4
p-CF3C6H4
Ph
95:5
88
84 96.5:3.5
82 94:6
91 98:2
92 98:2
82 98:2
84 93:7
89 94:6
Ph
24 >98:2
p-MeOC6H4
Ph
p-MeOC6H4
3
3
3
3
6
6
3
>98:2
92:8
>98:2
93:7
>98:2
>98:2
85:15
10 Me2CCH(CH2)2 Ph
81 90:10
e
11 Me2CCH(CH2)2 o-MeC6H4
12 Me2CCH(CH2)2 p-MeOC6H4
13 Me2CCH(CH2)2 p-CF3C6H4
91:9
85
90 91:9
79 87:13
a Reactions were performed under N2 atmosphere; >98% conversion
in all cases. b Determined by analysis of 400 MHz 1H NMR spectra of
the unpurified mixtures. c Yields of isolated and purified ꢀ products.
d Enantiomer ratio of the ꢀ product, determined by HPLC analysis; see
the Supporting Information for details. e Alkynyl product (∼10%)
present in the product mixture.
29%). Formation of the desired 1,4-diene (7) in 99:1 er indicates
that the presence of the Ni salt in the reaction mixture does not
adversely effect on the EAS process; this contention is
substantiated by reactions of aryl alkynes, described below.
As the data in Table 2 illustrate, an assortment of aryl-
substituted alkynes is readily and selectively converted to the
derived ꢀ-vinylaluminums, which are then used in situ for highly
efficient as well as site- and enantioselective EAS reactions
(78-92% yield of pure ꢀ product, >98% SN2′, 87:13-98:2 er).
In stark contrast to the process involving uncatalyzed hydroalu-
mination (45% alkynyl addition; Scheme 4), the transformation
illustrated in entry 5 of Table 2 does not afford any products
derived from alkynylaluminum addition (<2% by 400 MHz 1H
NMR analysis of the unpurified mixture). Only in cases where
the aryl unit of the alkyne bears an electron-withdrawing p-CF3
substituent is >10% of the R-vinylaluminum adduct observed;
otherwise, the desired ꢀ-substituted 1,4-diene products are
obtained in g92% selectivity. It is worthy of note that the
(17) The higher preponderance of alkynyl product (45%) versus alkyne
deprotonation (25%) is because 1.5 equiv of alkyne substrate (and
1.5 equiv of dibal-H) is used, which indicates that Cu-catalyzed
addition of alkynylaluminum is faster than that of the vinylaluminum
reagent.
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14318 J. AM. CHEM. SOC. VOL. 132, NO. 40, 2010

Synthesis of Quaternary Carbon Stereogenic Centers
A R T I C L E S
Scheme 7. Application of Sequential Ni-Catalyzed Alkyne
Hydroalumination/NHC-Cu-Catalyzed EAS to Enantioselective
Synthesis of Bakuchiol
substantiated by X-ray structures and rationalized in a previous
report regarding the corresponding Zn and Al complexes.6f The
above stereochemical attribute allows the vinyl unit to be
positioned properly for SN2′ addition to the coordinated alkene,19
while the equatorially positioned sulfonate oxygen facilitates
addition by Lewis acid activation of the allylic phosphate.
Such features are absent in phenoxy-bridged or monodentate
NHC-Cu complexes. High enantioselectivity likely arises,
because mode of addition II engenders unfavorable steric
interactions, as shown in Scheme 8; furthermore, examination
of molecular models indicates that the aforementioned Lewis
acid activation involving the phosphate group (cf., I) cannot be
easily assisted by the sulfonate unit in II. Consistent with the
proposed model, when the corresponding Z-trisubstituted allylic
phosphates are used, the opposite product enantiomer is gener-
ated predominantly but in low enantioselectivity, because
reaction via I would lead to unfavorable steric interactions
shown in II; the example in eq 2 is representative.
Conclusions
presence of the Ni catalyst enhances the rate of hydroalumination
such that higher conversion is attained for the overall process
(vinylaluminum formation/EAS). As an example, only 72%
conversion is achieved in formation of 8 under the conditions
shown in Scheme 4, largely due to lower amounts of available
vinylaluminum reagent, whereas complete consumption of the
allylic phosphate is observed in reaction in entry 5 of Table 2.
In cases where the alkyne substrate contains a sterically
demanding o-substituted aryl group (entries 2 and 11, Table
2), ∼10% of the alkynyl addition product is formed, likely as
a result of diminution in the rate of hydroalumination.
The utility of the sequential ꢀ-selective Ni-catalyzed terminal
alkyne hydroalumination/NHC-Cu-catalyzed EAS is high-
lighted in the synthesis of enantiomerically enriched bakuchiol
shown in Scheme 7. The three-vessel process, involving geraniol
and a readily available terminal alkyne as starting materials,
proceeds in 72% overall yield. The route depicted in Scheme 7
is substantially more concise than the most efficient of the
previously reported approaches, the shortest of which requires
10 steps and delivers the target in 49% yield.11b
3. Mechanistic Considerations and the Significance of Vari-
ous Structural Features of Bidentate Sulfonate-Containing NHC-
Cu Complexes. The efficiency and high site- and enantioselec-
tivities in the catalytic EAS reactions described above arise from
unique catalytic abilities of sulfonate-based bidentate NHC-Cu
complexes 1a-c;18 as shown in Scheme 8, phenoxy-bridged
or monodentate NHC-Cu variants are ineffective catalysts. The
above findings can be explained through mode of reaction I
(Scheme 8). The syn relationship between the phenyl backbone
of the NHC and the sulfonate, which is in contrast to the anti
stereochemistry in the phenoxy-bridged systems, has been
Among various types of C-based nucleophiles used in C-C
bond-forming reactions, products arising from transformations
with vinylmetal reagents are among the most versatile and
useful. Nonetheless, related catalytic enantioselective proto-
cols,20-22 particularly those that furnish quaternary carbon
stereogenic centers,2,4 continue to be relatively uncommon. In
addition to the challenges associated with the design of effective
chiral catalysts that promote vinylmetal additions to a sterically
(19) An NHC-Cu-catalyzed EAS process might proceed through a Cu(I)
mechanism (direct transfer of the vinyl unit) or a pathway that involves
a Cu(III) complex (cuprate addition followed by alkyl-vinyl reductive
elimination). Either scenario benefits from the Lewis acid activation
proposed, whereas the possibility of situating the vinyl group vis-a`-
vis the coordinated substrate in the manner shown in I would facilitate
the Cu(I) pathway (proper alignment of C-Cu and alkene π*). It is
not clear at present which pathway is energetically preferred. Although
previous mechanistic studies point to Cu(III) mechanism being
operative, such investigations were in connection to alkyl- or allyl-
copper complexes, considered allyl halides as substrates, and did not
involve a catalyst. The more polarized nature of a Cu-C bond in a
vinylmetal complex, particularly a strongly Lewis base-activated
NHC-Cu-vinyl complex (see ref 6f), and the associated steric
demands of forming a Cu(III)-substituted quaternary carbon, could
favor the Cu(I) pathway. For recent reports regarding the mechanism
of non-catalytic allylic substitution reactions with alkyl- and allylcopper
reagents, see: (a) Sofia, A.; Karlstro¨m, E.; Ba¨ckvall, J.-E. Chem.-Eur.
J. 2001, 7, 1981–1989. (b) Yoshikai, N.; Zhang, S.-L.; Nakamura, E.
J. Am. Chem. Soc. 2008, 130, 12862–12863. (c) Bartholomew, E. R.;
Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A. J. Am. Chem. Soc.
2008, 130, 11244–11245.
(20) For examples of catalytic enantioselective vinyl conjugate additions
to unsaturated carbonyls, affording tertiary C-C bonds, see: (a) Oi,
S.; Taira, A.; Honma, Y.; Inoue, Y. Org. Lett. 2003, 5, 97–99. (b) Oi,
S.; Sato, T.; Inoue, Y. Tetrahedron Lett. 2004, 45, 5051–5055. (c)
Otomaru, Y.; Hayashi, T. Tetrahedron: Asymmetry 2004, 15, 2647–
2651. (d) Nicolaou, K. C.; Tang, W.; Dagneau, P.; Faraoni, R. Angew.
Chem., Int. Ed. 2005, 44, 3874–3879. (e) Nakao, Y.; Chen, J.; Imanaka,
H.; Hiyama, T.; Ichikawa, Y.; Duan, W.-L.; Shintani, R.; Hayashi, T.
J. Am. Chem. Soc. 2007, 129, 9137–9143. (f) Lee, K.-s.; Hoveyda,
A. H. J. Org. Chem. 2009, 74, 4455–4462.
(18) Cu complexes derived from NHC-Ag complexes 1a-c afford the
desired EAS products in similar yields ((5%) and enantioselectivities
((3%).
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A R T I C L E S
Gao et al.
Scheme 8. Proposed Mechanistic Model and Key Features of the Chiral Bidentate NHC-Cu Complex
congested electrophilic site, identification of a class of vinylmetal
reagents, which can be easily and efficiently accessed and are
only sufficiently nucleophilic to allow the catalytic process to
predominate, has been a longstanding complication. The present
investigations put forth protocols that address both of the
aforementioned challenges: a Ni-catalyzed reaction involving
readily available alkynes and inexpensive dibal-H, generating
vinylaluminums that are used in situ for efficient and highly
site- and enantioselective EAS reactions promoted by chiral
NHC-Cu complexes.
based catalysts that exhibit exceptional reactivity and deliver
high selectivity and the development of corresponding catalytic
enantioselective protocols, including those that involve various
vinyl units, are in progress and will be disclosed in due course.
Acknowledgment. The NIH (GM-47480) provided financial
support. Y.L. is grateful for an AstraZeneca graduate fellowship.
We thank Tricia L. May for helpful discussions. Mass spectrometry
facilities at Boston College are supported by the NSF (DBI-
0619576).
Together with previous disclosures regarding metal-catalyzed
EAS as well as conjugate additions involving alkyl- and aryl-
substituted zinc and aluminum reagents,12 and the more recent
examples delivering boron-substituted quaternary carbon ste-
reogenic centers,23 the present findings further underline the
unique catalytic activity of sulfonate-based bidentate chiral
NHC-Cu complexes. The design of additional classes of NHC-
Supporting Information Available: Experimental procedures
and spectral data for substrates and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA106829K
(22) For examples of catalytic enantioselective vinyl additions to aldimines,
affording tertiary C-C bonds, see: (a) Patel, S. J.; Jamison, T. F.
Angew. Chem., Int. Ed. 2004, 43, 3941–3944. (b) Kong, J.-R.; Cho,
C.-W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269–11276.
(c) Ngai, M.-Y.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc. 2007,
129, 12644–12645. (d) Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008,
130, 6922–6923. (e) Nakao, Y.; Takeda, M.; Chen, J.; Salvi, L.;
Hiyama, T.; Ichikawa, Y.; Shintani, R.; Hayashi, T. Chem. Lett. 2008,
37, 290–291.
(21) For examples of catalytic enantioselective vinyl additions to carbonyls,
affording tertiary C-C bonds, see: (a) Oppolzer, W.; Radinov, R. N.
J. Am. Chem. Soc. 1993, 115, 1593–1594. (b) Miller, K. M.; Huang,
W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442–3443. (c)
Tomita, D.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 4138–4139. (d) Yang, Y.; Zhu, S.-F.; Zhou, C.-Y.; Zhou,
Q.-L. J. Am. Chem. Soc. 2008, 130, 14052–14053. (e) Kerrigan, M. H.;
Jeon, S.-J.; Chen, Y. K.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc.
2009, 131, 8434–8445.
(23) Guzman-Martinez, A.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132,
10634–10637.
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