Enantioselective synthesis of allylsilanes bearing tertiary and quaternary si-substituted carbons through Cu-catalyzed allylic alkylations with alkylzinc and arylzinc reagents

Article abstract of DOI:10.1002/anie.200700841

All sorts of allylsilanes including, for the first time, those that contain a Si-bonded quaternary carbon, were synthesized through efficient and highly enantioselective Cu-catalyzed asymmetric allylic alkylations. Reactions may involve dialkyl- as well as diarylzinc reagents and are promoted by various chiral N-heterocyclic carbene complexes.

Full text of DOI:10.1002/anie.200700841

Communications
DOI: 10.1002/anie.200700841
Allylic Alkylation
Enantioselective Synthesis of Allylsilanes Bearing Tertiary and
Quaternary Si-Substituted Carbons through Cu-Catalyzed Allylic
Alkylations with Alkylzinc and Arylzinc Reagents**
Monica A. Kacprzynski, Tricia L. May, Stephanie A. Kazane, and Amir H. Hoveyda*
Allylsilanes are widely used in stereoselective organic syn-
thesis.[1] Design and development of efficient catalytic asym-
metric methods that furnish chiral allylsilanes in high
enantiomeric purity would significantly expand the utility of
these versatile nucleophiles. Herein, we report an efficient
method for enantioselective synthesis of a range of allylsi-
lanes by Cu-catalyzed asymmetric allylic alkylation (AAA)[2]
of Si-substituted unsaturated phosphates with dialkyl- and
diarylzinc reagents [Eq. (1)]. Transformations are promoted
many cases, however, products are obtained in less than
optimal enantiomeric purity (< 90% ee). To address such
complications and identify a more efficient method, we
investigated the possibility of accessing allylsilanes of high
enantiomeric purity through catalytic AAA of organozinc
reagents to electrophilic Si-substituted alkenes [Eq. (1)].
Such transformations would be catalyzed by chiral Cu
complexes generated in situ from amino acid based[12] or
bidentate NHC-based[13,14] ligands developed in these labo-
ratories (see Scheme 1). Our interest was
further fueled by the realization that, thus
far, all catalytic AAA involving hard
alkylmetals have been with substrates
that carry a C-based substituent (i.e.,
versus a silyl group in this study).
by 1–2.5 mol% of chiral N-heterocyclic carbene based (NHC-
based) catalysts and afford enantiomerically enriched allylsi-
lanes in up to 98% ee and over 70% yield. Catalytic
asymmetric reactions that afford tertiary as well as those
that deliver quaternary Si-substituted carbon stereogenic
centers are presented. To the best of our knowledge, this
disclosure puts forth the first method for catalytic asymmetric
synthesis of quaternary carbon stereogenic centers that bear a
silyl group,[3,4] as well as the first catalytic AAA that utilizes
arylmetal reagents.[5]
A number of protocols for catalytic enantioselective
synthesis of allylsilanes have been developed. Such trans-
formations include enantioselective couplings of 1-(silyl)-
alkyl Grignard reagents with vinyl halides,[6] hydrosilylations
of 1,3-dienes,[7] silylations of allylic chlorides,[8] hydride
additions to silyl-substituted allylic carbonates,[9] and silabo-
rations of allenes.[10] These processes, all Pd-catalyzed, largely
À
À
involve formation of C Si or C H bonds (with the exception
of cross-coupling reactions)[11] and deliver an array of
synthetically useful allylsilanes in the non-racemic form. In
[*] Dr. M. A. Kacprzynski, T. L. May, S. A. Kazane, Prof. A. H. Hoveyda
Department of Chemistry
Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
Scheme 1. Chiral ligands and complexes used for in situ generation of
chiral Cu-based catalysts.
E-mail: amir.hoveyda@bc.edu
We began by examining the reaction of vinylsilane 5 with
Et2Zn in the presence of amino acid based ligand 1, shown to
be highly effective in promoting Cu-catalyzed AAA of
alkylzinc reagents to di- and trisubstituted alkenes.[12c] As
shown in entry 1 of Table 1, with 10 mol% 1 and 5 mol%
(CuOTf)2·C6H6 (À158C, 24 h) there is only 50% conversion
[**] Financial support was provided by the NIH (GM-47480) and the
NSF (CHE-0213009). M.A.K. and S.A.K. are grateful for a Novartis
Graduate Fellowship and a Pfizer Undergraduate Fellowship,
respectively.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angew. Chem. Int. Ed. 2007, 46, 4554 –4558

Angewandte
Chemie
Table 1: Initial catalyst screening.[a]
obtained in 92–98% ee, with greater than 98% site-selectivity
(SN2’/SN2) and in over 70% yields with 1–2 mol% catalyst
loading. A variety of alkylmetals, including the less reactive
Me2Zn (entry 4, Table 2), heteroatom-containing (entry 5) as
well as secondary (entries 7 and 8) dialkylzinc reagents may
be used with high efficiency. Catalytic alkylations can be
readily performed with easy-to-handle and air-stable Cu salts
(entries 2, 3, and 8, Table 2); higher catalyst loadings
(2 mol% 2 and 4 mol% Cu salt) are required, however, to
attain complete conversion. Moreover, Cu-catalyzed AAA
can be carried out in undistilled THF and on the bench top:
the Cu-catalyzed AAA in entry 2 of Table 2 proceeds to
afford 6a in 98% ee and 79% yield under such user-friendly
conditions (0.8-mmol scale).
A unique attribute of the chiral catalysts developed in
these programs is the ability to promote additions to sterically
congested trisubstituted olefins, furnishing quaternary carbon
stereogenic centers efficiently and in high ee.[12a,c,d,13a–c] We
thus sought to determine whether chiral NHC·Cu complexes
initiate efficient AAA of trisubstituted allylic phosphate 7 in
spite of the increased steric hindrance projected by the Si-
based substituent, an attribute that might be offset by a longer
Entry Ligand; mol% Cu salt; mol%
Conv. SN2’/
ee
[%][b]
SN2[b]
[%][c]
1
2
3
4
5
6
7
8
9
1; 10
2; 1
3; 1
4; 1
2; 1
2; 1
2; 1
2; 1
2; 1
2; 1
(CuOTf)2·C6H6; 5
(CuOTf)2·C6H6; 1
(CuOTf)2·C6H6; 1
(CuOTf)2·C6H6; 1
(CuOTf)2·toluene; 1 >98
CuOAc; 2
50
>98
>98
98
>98:2 69
>98:2 98
>98:2 94
>98:2 92
>98:2 98
>98:2 98
>98:2 98
>98:2 70
>98:2 95
>98:2 95
70
80
12
20
25
CuCl; 2
Cu(OTf)2; 2
Cu(OAc)2; 2
CuCl2·2H2O; 2
10
[a] Reactions performed under N2 atmosphere. [b] Conversions and SN2’/
SN2 ratios determined by analysis of 400-MHz 1H NMR spectra.
[c] Enantioselectivities determined by chiral GLC and HPLC analysis;
see the Supporting Information for details.
to the desired allylsilane; although over 98% SN2’/SN2
selectivity is observed, 6a is generated in 69% ee. In contrast,
with 1 mol% NHC·AgI complex 2[13a] and 1 mol%
(CuOTf)2·C6H6 (entry 2, Table 1), the reaction proceeds to
over 98% conversion, affording 6a
À
À
C Si bond (vs. a C Cbond). The results of these studies,
summarized in Table 3, illustrate that different dialkylzinc
reagents, including the sterically demanding iPr2Zn can be
in 98% ee (> 98% SN2’/SN2). As
Table 2: Cu-catalyzed enantioselective synthesis of tertiary alkyl-substituted allylsilanes.[a]
illustrated in entries 3 and 4 of
Table 1, complexes 3[13b] and 4[14]
furnish similar reactivity and regio-
selectivity levels but enantioselec-
tivities are slightly diminished
(94% ee and 92% ee, respec-
tively). Commercially available
(CuOTf)2·toluene can also be
used under otherwise identical
conditions to afford the desired
allylsilane 6 in over 98% conver-
Entry (Alkyl)2Zn; equiv
Cu salt
2 [mol%];
Cu salt [mol%]
Prod. SN2’/
Yield ee
[%][c] [%][d]
SN2[b]
1
2
3
4
5
6
7
8
Et2Zn; 3
Et2Zn; 3
Et2Zn; 3
Me2Zn; 6
(CuOTf)2·C6H6 1; 1
CuOAc
CuCl
(CuOTf)2·C6H6 1; 1
(CuOTf)2·C6H6 1; 1
6a
6a
6a
6b
6c
6d
6e
6e
>98:2 72
>98:2 84
98
95
92
96
92
98
96
97
2; 4
2; 4
>98:2 80
>98:2 94
>98:2 76
>98:2 74
>98:2 75
>98:2 75
[AcO(CH2)4]2Zn; 2
[Me2CH(CH2)3]2Zn; 2 (CuOTf)2·C6H6 1; 1
iPr2Zn; 3
iPr2Zn; 3
(CuOTf)2·C6H6 1; 1
CuOAc 2; 4
sion
and
98% ee
(entry 5,
Table 1,). Although high activity is
provided by (CuOTf)2·C6H6, as the
data in entries 6 and 7 of Table 1
indicate, air-stable CuOAc and
CuCl (commercial samples, not
purified) can be used to promote
the catalytic AAA in 98% ee; the
latter transformations, however,
proceed to 70% and 80% conver-
sion, respectively, under the same
reaction conditions [vs. > 98%
conv. with (CuOTf)2·C6H6]. Finally,
as the data in entries 8–10 in
Table 1 show, CuII salts provide
[a] Reactions performed under N2 atmosphere; >98% conversion in all cases. [b] Conversions and SN2’/
SN2 ratios determined by analysis of 400-MHz 1H NMR spectra. [c] Yields of isolated purified products.
[d] Enantioselectivities determined by chiral GLC and HPLC analysis; see the Supporting Information for
details.
Table 3: Cu-Catalyzed enantioselective synthesis of quaternary alkyl-substituted allylsilanes.[a]
Entry (Alkyl)2Zn; equiv
Cu salt
2 [mol%];
Cu salt [mol%]
Prod. SN2’/
Yield ee
[%][c] [%][d]
SN2[b]
1
2
3
4
Et2Zn; 3
Et2Zn; 3
(CuOTf)2·C6H6 2.5; 2.5
CuOAc 5; 10
8a
8a
8d
8e
>98:2 75
>98:2 87
>98:2 78
>98:2 81
91
91
91
92
significantly
lower
activity,
[Me2CH(CH2)3]2Zn; 2 (CuOTf)2·C6H6 2.5; 2.5
iPr2Zn; 3 (CuOTf)2·C6H6 2.5; 2.5
although in two instances, 6a is
isolated in 95% ee.
As illustrated by the data sum-
marized in Table 2, a range of
tertiary allylsilanes (6a–e) may be
[a] Reactions performed under N2 atmosphere; >98% conversion in all cases. [b] Conversions and SN2’/
SN2 ratios determined by analysis of 400-MHz 1H NMR spectra. [c] Yields of isolated purified products.
[d] Enantioselectivities determined by chiral GLC and HPLC analysis; see the Supporting Information for
details.
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4555

Communications
used in the enantioselective synthesis of allylsilanes 8a, 8d, 9a and 11a in 90–92% ee and over 80% yield as a single
and 8e in 91–92% ee and 75–87% yields. The corresponding regioisomer (> 98% SN2’). Cu-catalyzed AAA with
achiral SN2 product remains undetected (> 98% SN2’ by 400- (pOMeC6H4)2Zn is equally efficient and selective (entry 4,
MHz 1H NMR analysis).
Table 4). When (pCF3C6H4)2Zn is employed as the alkylating
Next, we focused our attention on catalytic AAA involv- agent, although the reaction remains highly efficient (1 mol%
ing diarylzinc reagents. Initial studies, summarized in Equa- 3, > 98% conversion, 77% yield), 9c is obtained in 57% ee
tion (2) indicated that, in contrast to reactions with dialkyl- and, for the first (and only) time, we can detect the undesired
zinc reagents, chiral NHCcomplex 3 is significantly more SN2 addition product (11:1 SN2’/SN2).
The advantages that arise from avail-
ability of a range of sterically and electroni-
cally distinct chiral NHCcomplexes are
further highlighted by the initial studies in
connection with AAA of trisubstituted
alkene 7 by Ph2Zn. As shown in Equa-
tion (3), it is now chiral complex
4
(Scheme 1), recently shown to be optimal
in asymmetric conjugate additions of orga-
nozinc reagents to cyclic g-ketoesters,[14]
effective in promoting the reaction of 5 with commercially that is optimal (> 98% conversion, 67% ee). As the data in
available Ph2Zn. Thus, in the presence of 1 mol% 3, AAA entry 1 of Table 5 indicate, when the reaction is performed at
proceeds to over 98% conversion to afford 9a in 90% ee and À788C[vs. À158Cin Eq. (3)], in the presence of 1 mol% 4,
with greater than 98% SN2’ selectivity. With NHCcomplex 2, 12a is isolated in 72% yield and 85% ee (> 98% SN2’);
there is only 50% conversion, affording 9a
in 65% ee, and with the typically more
reactive carbene complex 4, although
greater than 98% conversion is obtained,
the desired product is formed in 77% ee.
As illustrated in entries 1–3 of Table 4,
reactions with Ph2Zn proceed readily with
1 mol% 3 to afford the desired allylsilanes
Table 4: Cu-catalyzed AAA of diarylzinc reagents to disubstituted vinylsilanes.[a]
Entry
Substrate
(Aryl)2Zn; equiv
Cu salt
3 [mol%];
Product
SN2’/SN2[b]
Yield [%][c]
ee [%][d]
Cu salt [mol%]
1
2
3
4
5
5
Ph2Zn; 2
Ph2Zn; 2
Ph2Zn; 2
pOMeC6H4; 2
pCF3C6H4; 2
(CuOTf)2·C6H6
(CuOTf)2·C6H6
CuOAc
(CuOTf)2·C6H6
(CuOTf)2·C6H6
1; 1
1; 1
1; 2
1; 1
1; 1
9a
>98:2
>98:2
>98:2
>98:2
11:1
82
91
86
88
77
90
92
91
91
57
10
10
5
11a
11a
9b
5
9c
[a] Reactions performed under N2 atmosphere; >98% conversion in all cases. [b] Conversions and SN2’/SN2 ratios determined by analysis of 400-MHz
1H NMR spectra. [c] Yields of isolated purified products. [d] Enantioselectivities determined by chiral GLC and HPLC analysis; see the Supporting
Information for details.
Table 5: Cu-catalyzed AAA of trisubstituted vinylsilanes by diarylzinc reagents.[a]
Entry
(Aryl)2Zn; equiv
Cu salt
4 [mol%];
Cu salt [mol%]
T [8C]; t [h]
Product
SN2’/SN2[b]
Conv. [%][b]
Yield [%][c]
;
ee [%][d]
1
2
3
4
Ph2Zn; 2
Ph2Zn; 2
pOMeC6H4; 2
pOMeC6H4; 2
(CuOTf)2·C6H6
CuOAc
(CuOTf)2·C6H6
(CuOTf)2·C6H6
1; 1
1; 2
2.5; 2.5
2.5; 2.5
À78; 24
À78; 24
À78; 48
À15; 24
12a
12a
12b
12b
>98:2
>98:2
>98:2
>98:2
>98; 72
>98; 77
30; 25
85
84
90
76
>98; 80
[a] Reactions performed under N2 atmosphere; >98% conversion in all cases. [b] Conversions and SN2’/SN2 ratios determined by analysis of 400-MHz
1H NMR spectra. [c] Yields of isolated purified products. [d] Enantioselectivities determined by chiral GLC and HPLC analysis; see the Supporting
Information for details.
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Chemie
similar results are obtained with the more robust CuOAc
(entry 2, Table 5). Catalytic AAA reactions involving
(pOMeC6H4)2Zn (entries 3 and 4, Table 5) are less efficient.
Thus, at À788C, high enantioselectivity (90% ee, entry 3) is at
the cost of low conversion (30% conversion, 25% yield); to
achieve complete reaction, the temperature must be raised to
À158C, an adjustment that causes diminution of selectivity
(76% ee, entry 4 in Table 5). It is possible that the lower
efficiency of the above process is partly due to stabilization of
the intermediate CuIII complex by the electron-donating p-
OMe substituent (leading to a slower rate of reductive
elimination)[15] as well as the more sterically demanding
olefinic site (vs. disubstituted alkenes in Table 4).
furnishes tertiary alcohol 17 with greater than 98% retention
of stereochemistry and in 80% yield.
We thus introduce an efficient catalytic method for
enantioselective synthesis of allylsilanes, including those
that contain a quaternary Si-substituted carbon stereogenic
center. The present study further underlines the rapidly
emerging and significant utility of chiral bidentate NHC
complexes in asymmetric catalysis and enantioselective syn-
thesis. These investigations illustrate the significance of the
availability of a diverse set of chiral NHCs to the develop-
ment of catalytic asymmetric alkylations that can be effected
on a range of substrates and with alkyl- as well as arylmetal
nucleophiles.[20]
As mentioned previously, the utility of allylsilanes as
chiral reagents for Lewis acid catalyzed additions to carbonyl-
and imine-based electrophiles, is well appreciated.[1,2] Non-
etheless, additional examples are presented below. As exem-
plified by the reaction shown in Equation (4), tertiary
allylsilanes, such as 6a (98% ee), undergo catalytic cross-
Received: February 24, 2007
Published online: May 8, 2007
Keywords: allylation · allylsilanes · asymmetric catalysis ·
.
N-heterocyclic carbenes · quaternary stereocenters
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www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 4554 –4558