Palladium-catalyzed regio-, diastereo-, and enantioselective allylic alkylation of acylsilanes with monosubstituted allyl substrates

Article abstract of DOI:10.1021/ja106703y

Acylsilanes as a new type of "hard" carbon prenucleophile reacted with monosubstituted allyl reagents under Pd-catalyzed asymmetric allylic alkylation reaction conditions to provide products with high regio-, diastereo-, and enantioselectivities. The usef

Full text of DOI:10.1021/ja106703y

Published on Web 10/14/2010
Palladium-Catalyzed Regio-, Diastereo-, and Enantioselective Allylic
Alkylation of Acylsilanes with Monosubstituted Allyl Substrates
Jian-Ping Chen,† Chang-Hua Ding,‡ Wei Liu,‡ Xue-Long Hou,*,†,‡ and Li-Xin Dai‡
State Key Laboratory of Organometallic Chemistry and Shanghai-Hong Kong Joint Laboratory in Chemical
Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
Received July 28, 2010; E-mail: xlhou@mail.sioc.ac.cn
Abstract: Acylsilanes as a new type of “hard” carbon prenucleo-
phile reacted with monosubstituted allyl reagents under Pd-
catalyzed asymmetric allylic alkylation reaction conditions to
provide products with high regio-, diastereo-, and enantioselec-
tivities. The usefulness of the protocol has been demonstrated
by the ready conversion of the allylated products into the
corresponding alcohols, esters, and ketones with retention of
stereochemistry as well as by the enantioselective synthesis of
cis-3-ethyl-4-phenylpiperidine and cinnamomumolide.
Considering that acylsilanes bearing a bulky silyl group behave
Palladium-catalyzed asymmetric allylic alkylation (AAA) is one
like typical ketones in reactions as well as like carboxylic acid
of the most important methods for asymmetric formation of
carbon-carbon bonds and has found widespread application in
derivatives in transformations,8 we envisioned that they could serve
as suitable nucleophile precursors in Pd-catalyzed AAA of mono-
organic synthesis.1 Recent achievements allow the use of “hard”
substituted allyl substrates to achieve high regio-, diastereo-, and
carbanions derived from simple ketones2 and aldehydes3 as
enantioselectivities. The advantage of acylsilanes for further
nucleophiles. Two adjacent chiral centers can also be installed in
elaboration would enable the resulted products to be used as
the products, although 1,3-disubstituted symmetric allyl reagents
versatile starting materials in organic synthesis.8 To test our idea,
have been used in most cases.4 Carboxylic acid derivatives, a
the reaction of 1-(trimethylsilyl)propan-1-one (1a) and cinnamyl
powerful class of organic compounds with an easily transformable
methyl carbonate (2a) was carried out in the presence of [Pd(η3-
functional group, are also viable nucleophile precursors.5 Only one
C3H5)Cl]2 and (Rphos,R)-SIOC-Phox (L1) as the catalyst with LiCl
as an additive. Delightfully, allylated products were obtained in
44% yield with a 3a/4a product ratio of 96/4, an anti/syn ratio of
11/1 for 3a, and an ee of 96% for the anti isomer (Table 1, entry
chiral center can be formed usually,5 although products with two
vicinal chiral centers have been obtained using some special
carboxylic acid derivatives with additional carbanion-stabilizing
factors at the position R to the carboxylic acid group.6 It remains
1).
a great challenge to establish two chiral centers by Pd-catalyzed
AAA of “hard” carbanions with monosubstituted allyl substrates
with high regio-, diastereo-, and enantioselectivities as well as with
Table 1. Optimization of Reaction Conditions for the Pd-Catalyzed
Reaction of Acylsilanes 1 and Allyl 2aa
more readily transformable functional groups in the products.7 To
address this issue, several in situ-generated nucleophiles derived
from aliphatic ketones and amide 1 were subjected to Pd-catalyzed
AAA of cinnamyl methyl carbonate (2a) (eq 1). Though the
diastereoselectivity was low in all cases, two indicative clues were
found: (1) better diastereoselectivity was obtained with bulkier R
groups and (2) ketones gave better regioselectivities than amide.
To achieve high selectivities in the reaction, a new type of
nucleophile had to be developed (Figure 1).
entry
L
R
yield (%)b
3/4c
anti/sync
anti ee (%)d
1e,f
2e
3
4
5
L1
L1
L1
L2
L3
L1
L1
TMS
TMS
TMS
TMS
TMS
TBS
44
73
93
56
86
41
20
96/4
95/5
96/4
46/54
92/8
98/2
97/3
11/1
9/1
10/1
10/1
10/1
5/1
96
96
96
93
94
g
6
7
-
g
DMPS
13/1
-
a 1/2a/LiHMDS/[Pd(η3-C3H5)Cl]2/ligand molar ratio ) 133/100/133/2/
5. b Isolated yields of isomers 3 and 4. c Determined by 1H NMR
spectroscopy. d Determined by chiral HPLC. e With 133% LiCl added.
f 1/2a molar ratio ) 100/110. g Not measured.
Figure 1. Demands on the New Type of “Hard” Carbon Nucleophile.
Inspired by this promising result, we set out to optimize the
reaction conditions (Table 1). Changing the 1/2a substrate ratio
† Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis.
‡ State Key Laboratory of Organometallic Chemistry.
9
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J. AM. CHEM. SOC. 2010, 132, 15493–15495 15493

C O M M U N I C A T I O N S
Table 2. Reaction Scope for Pd-Catalyzed AAA of Acylsilanes 1
with Allyls 2a-d
from 1/1.1 to 1.3/1 increased the yield from 44 to 73%, and the
selectivity remained high (entry 2 vs entry 1). In contrast to our
early findings,7 LiCl had little effect on the selectivity of the present
reaction (entry 3 vs entry 2). The structure of the ferrocene ligand
(Figure 2) was crucial for the control of the stereoselectivity. The
regioselectivity was poor, notwithstanding the good diastereo- and
enantioselectivities acquired when (Sphos,R)-L2 was used as the
ligand (entry 4 vs entry 3). The regio- and enantioselectivities were
slightly lower using L3, suggesting that the chiral center on the
oxazoline ring was not beneficial in this reaction (entry 5 vs entry
3). The steric hindrance of the silyl group of the acylsilane indeed
influenced the reaction. Changing the trimethylsilyl (TMS) group
to a bulkier tert-butyldimethylsilyl (TBS) or dimethylphenylsilyl
(DMPS) group made the reaction sluggish, although the regiose-
lectivity was still fine (entries 6 and 7 vs entry 3) and even better
diastereoselectivity was obtained (entry 7 vs entry 3). Further
investigation of the impact of the reaction parameters revealed that
the tert-butoxycarbonyl carbonate (OBoc) is the best leaving group
for allyl substrates 2 and that 1,2-dimethoxyethane (DME) is the
solvent of choice (see the Supporting Information).
Figure 2. Ferrocene-based ligands L1-L3.
Next, the substrate scope of the reaction was examined (Table
2).The reaction proceeded well in all cases, affording alkylation
products in high yields with excellent regio-, diastereo-, and
enantioselectivities, with 3/4 ratios of 88-99/12-1, anti/syn ratios
of 10-50/1 for 3, and ee values of 96-99% for anti-3; the only
exception was 3f bearing a phenoxy group at the γ-position (see
below). The length of the alkyl chain of the acylsilane did not affect
the regio- and enantioselectivities of the reaction, though the
diastereoselectivity decreased from 19/1 to 10/1 or 12/1 when the
alkyl chain was lengthened (3a vs 3b or 3c, respectively). A
substrate with a heteroatom at the γ-position was also tolerated,
providing the corresponding product in high regio- and diastereo-
selectivity but a little bit lower enantioselectivity (3f). Interestingly,
when the R1 group was phenyl ring, the anti/syn ratio of products
reached 50/1 (3e). The reaction is tolerant of functional groups on
the phenyl group of allyl 2 (3g-i), although the diastereoselectivity
decreased slightly for allyl 2 with an electron-donating group (3i).
Remarkably, allyl 2 with a furanyl substituent was suitable for the
reaction, affording the allyl products in high yield with excellent
selectivity (3j). The reaction also worked well for the methyl-
substituted allyl substrate, affording allyl product 3k with high
diastereo- and enantioselectivity, though the yield was moderate
and the regioselectivity was slightly lower. It is worthwhile to note
that the diastereoselectivity of the current reaction is much better
than that using acyclic ketones.7a The reaction proceeded smoothly
even on a gram scale. Treatment of 0.82 g of 1-(trimethylsilyl)butan-
1-one with 1.02 g of cinnamyl tert-butoxycarbonyl carbonate under
the given conditions still furnished an 86% yield of products 3b
and 4b with the same regio-, diastereo-, and enantioselectivity as
shown in Table 2. In addition, when the catalyst loading was
decreased to 0.5 mol % [Pd(η3-C3H5)Cl]2 and 1.1 mol % (Rphos,R)-
L1, the products 3b and 4b were obtained in 87% yield with a
a 1/2/LiHMDS/[Pd(η3-C3H5)Cl]2/L1 molar ratio ) 133/100/133/2/5.
b Isolated yields of isomers 3 and 4. c Regio- and diastereoselectivities
were determined by 1H NMR spectroscopy. d Enantioselectivities were
determined by chiral HPLC. e The enantioselectivity was determined by
chiral HPLC after conversion of the -COSiMe3 group of 3c into the
corresponding -CH2OH group. f Run at 5 °C.
Scheme 1. Transformation of the Allylated Product 3b to Other
Functionalized Compounds
3b/4b ratio of 95/5, an anti/syn ratio of 8/1 for product 3b, and an
ee of 98% for the anti isomer.
The synthetic utility of the alkylated acylsilanes was illustrated
by the versatile conversion of the allyl product 3b bearing two chiral
centers into other functionalized compounds, such as ester 5, ketone
6, and alcohol 7, without changes in the diastereo- and enantiose-
lectivities (Scheme 1). It is worth noting that chiral ketone 6 is
usually difficult to obtain because of the difficulty in controlling
the regioselectivity of unsymmetric ketones. The usefulness of our
methodology was also demonstrated by the synthesis of chiral
piperidine 8 possessing dopaminergic activity9 from 3b in seven
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C O M M U N I C A T I O N S
Scheme 2. Enantioselective Synthesis of Cinnamomumolide
configuration of 3a. This material is available free of charge via the
Internet at http://pubs.acs.org.
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diastereo-, and enantioselectivities. The advantages of the acylsilane
functional group have been revealed by the transformation of the
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Acknowledgment. This paper is dedicated to Professor Henry
N. C. Wong on the occasion of his 60th birthday. We are grateful
for financial support from the Major Basic Research Development
Program (2010CB833300), NSFC (20872161, 20821002, 20932008),
CAS, the External Cooperation Program of CAS (GJHZ200816),
STCSM (10ZR1436800), and the Croucher Foundation of Hong
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Supporting Information Available: Experimental procedures,
spectral data for compounds 3-11, and determination of the absolution
JA106703Y
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