Proline-based N-oxides as readily available and modular chiral catalysts. Enantioselective reactions of allyltrichlorosilane with aldehydes

Article abstract of DOI:10.1021/ol050814q

(Chemical Equation Presented) A proline-based N-oxide is identified that serves as an effective catalyst for the reaction of allyltrichlorosilane with aryl and α,β-unsaturated aldehydes at room temperature to afford the desired homoallylic alcohols in up to 92% ee. The chiral catalyst can be easily prepared from optically pure proline in three simple steps and 60% overall yield.

Full text of DOI:10.1021/ol050814q

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3151-3154
Proline-Based N-Oxides as Readily
Available and Modular Chiral Catalysts.
Enantioselective Reactions of
Allyltrichlorosilane with Aldehydes
John F. Traverse, Yu Zhao, Amir H. Hoveyda,* and Marc L. Snapper*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467
marc.snapper@bc.edu
Received April 14, 2005
ABSTRACT
A proline-based N-oxide is identified that serves as an effective catalyst for the reaction of allyltrichlorosilane with aryl and
r,â-unsaturated
aldehydes at room temperature to afford the desired homoallylic alcohols in up to 92% ee. The chiral catalyst can be easily prepared from
optically pure proline in three simple steps and 60% overall yield.
Amino acid based chiral molecules have emerged as versatile
and effective platforms in the development of catalysts that
promote a range of enantioselective transformations.1 The
lure of this class of catalyst candidates is due to several
important reasons.2 A number of amino acids are available
in optically pure form (both antipodes). Furthermore, catalyst
candidates can be easily altered, not only by variations in
the identity of amino acid constituent(s) but also by
incorporation of additional structural features through the
amide bond linkage. Such characteristics render amino acid
based catalysts easily modular: a diverse set of catalyst
candidates can be readily prepared (on solid support or in
solution) and examined in parallel to search for optimal
reactivity and selectivity.
Research in these laboratories during the past few years
has focused on the development of amino acid based ligands
that can participate in metal-catalyzed C-C bond-forming
reactions.3 The aforementioned attributes have played a
critical role in allowing us to introduce metal-catalyzed
enantioselective reactions that offer unique levels of ef-
ficiency and enantioselectivity. More recently, we have set
out to introduce a new class of easily accessible and readily
modifiable amino acid-based N-oxides that can serve as chiral
nucleophilic catalysts. This initiative was partly inspired by
the observation that chiral N-oxides have been shown to
promote several synthetically useful transformations ef-
ficiently.4 Our efforts were encouraged by the fact that the
majority of chiral N-oxide catalysts developed thus far are
molecules that are prepared through nontrivial synthesis
(1) For recent reviews, see: (a) Berkessel, A.; Gro¨ger, H.; MacMillan,
D. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications
in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005; pp 1-454. (b)
Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A. Chem. Commun. 2004,
1779-1785. (c) Miller, S. J. Acc. Chem. Res. 2004, 37, 601-610. (d)
Groeger, H.; Wilken, J.; Berkessel, A. Org. Synth. Highlights V 2003, 178-
186.
(2) For a discussion, see: Hoveyda, A. H. In Handbook of Combinatorial
Chemistry; Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.: Wiley-VCH:
Weinheim, 2002; pp 991-1016.
(3) For representative examples, see: (a) Cole, B. M.; Shimizu, K. D.;
Krueger, C. A.; Harrity, J. P. A.; Snapper, M. L.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 1996, 35, 1668-1671. (b) Krueger, C. A.; Kuntz, K. W.;
Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 4284-4285. (c) Luchaco-Cullis, C.
A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2001, 40, 1456-1460. (d) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J.
Am. Chem. Soc. 2001, 123, 755-756. (e) Akullian, L. C.; Snapper, M. L.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4244-4247. (f)
Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2004, 126, 3734-3735.
10.1021/ol050814q CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

routes and their structural modification often requires lengthy
and cumbersome manipulations.
Scheme 1. Allylation Reactions Promoted by N-Oxides 1-3
As the first step in the development of amino acid-based
chiral N-oxide catalysts, we decided to explore the possibility
of an enantioselective method for allylation of aldehydes.
Syntheses of optically enriched homoallylic alcohols through
addition of B-,5 Ti-,6 and Si-based7 reagents as well as
catalytic protocols involving allylstannanes8 and allylsilanes9
have been reported.10 In several cases, chiral N-oxides are
used as catalysts.4d-i,11 Nonetheless, in many of the reported
cases, the requisite catalysts are not easily prepared and the
available synthesis methods require low reaction temperatures
(e-40 °C) to ensure high asymmetric induction.
Herein, we report the catalytic activity of a proline-based
N-oxide that promotes the reaction of trichloroallylsilane with
aryl and R,â-unsaturated aldehydes in up to 92% ee. The
catalyst is easily prepared from commercially available
optically pure proline in three straightforward steps in 60%
overall isolated yield without the need for silica gel chro-
matography. The structural modularity of this new class of
chiral Lewis base catalysts is exploited in efforts to optimize
reaction efficiency and enantioselectivity.
proved promising. Although low enantioselectivity was
observed, there was appreciable conversion for reactions at
ambient temperature. Notably, with catalyst 3, >90%
conversion was detected within 12 h at 22 °C. It should be
noted that there is <2% conversion in the absence of
N-oxides 1-3.
Encouraged by the above findings, we set out to identify
a more effective chiral catalyst by systematic modification
of the catalyst’s C- and N-termini. Accordingly, we prepared
various proline-based N-oxides with different C-termini (3a-
m) and examined their ability to promote enantioselective
allylations at 22 °C. The results of these studies are
summarized in Table 1.
We initiated our studies by examining the ability of
proline-based N-oxides 1-3,12 prepared by directed oxidation
of the tertiary amine with m-CPBA,13 as catalysts for the
transformation in Scheme 1.14 These initial investigations
Table 1. Effect of the Identity of the C-Terminus of Catalyst
on Efficiency and Enantioselectivity of Allylations of
Benzaldehyde
(4) (a) O’Neil, I. A.; Turner, C. D.; Kalindjian, S. B. Synlett 1997, 777-
780. (b) Tao, B.; Lo, M. M-C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
353-354. (c) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233-
4235. (d) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4,
2799-2801. (e) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.;
Langer, V.; Meghani, P.; Kocovsky, P. Org. Lett. 2002, 4, 1047-1049. (f)
Malkov, A. V.; Bell, M.; Orsini, M.; Parnazza, D.; Massa, A.; Herrmann,
P.; Meghani, P.; Kocovsky, P. J. Org. Chem. 2003, 68, 9659-9668. (g)
Malkov, A. V.; Dufkova, L.; Farrugia, L.; Kocovsky, P. Angew. Chem.,
Int. Ed. 2003, 42, 3674-3677. (h) Shimada, T.; Kina, A.; Hayashi, T. J.
Org. Chem. 2003, 68, 6329-6337. (i) Kina, A.; Shimada, T.; Hayashi, T.
AdV. Synth. Catal. 2004, 346, 1169-1174.
(5) For representative examples, see: (a) Gung, B. W.; Xue, X.; Roush,
W. R. J. Am. Chem. Soc. 2002, 124, 10692-10697. (b) Racherla, U. S.;
Liao, Y.; Brown, H. C. J. Org. Chem. 1992, 57, 6614-6617.
(6) Duthaler, R.; Hafner, A.; Bold, G. Chem. ReV. 1992, 92, 807-832.
(7) For select examples, see: (a) Kubota, K.; Leighton, J. L. Angew.
Chem., Int. Ed. 2003, 43, 946-948. (b) Kinnard, J. W. A.; Ng, P. Y.;
Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920-
7921.
(8) For representative examples, see: (a) Yanagisawa, A.; Nakashima,
H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723-4724.
(b) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199-6200.
(c) Lu, J.; Hong, M.-L.; Ji, S.-J.; Loh, T.-P. Chem. Commun. 2005, 1010-
1012 and references therein.
(9) (a) Furuta, K.; Mouri, M.; Yamamoto, H. Synlett 1991, 561-563.
(b) Ishihara, K.; Mouri, M.; Gao, Q.; Maruyama, T.; Furuta, K.; Yamamoto,
H. J. Am. Chem. Soc. 1993, 115, 11490-11495. (c) Gauthier, D. R.;
Carreira, E. M. Angew. Chem., Int. Ed. 1996, 35, 2363-2365. (d) Bode, J.
W.; Gauthier, D. R.; Carreira, E. M. Chem. Commun. 2001, 2560-2561.
(10) (a) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-2794. (b)
Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316.
(11) For a review of pyridine N-oxides as chiral catalysts, see: Chelucci,
G.; Murineddu, G.; Pinna, G. A. Tetrahedron: Asymmetry 2004, 15, 1373-
1389.
(12) O’Neil, I. A.; Potter, A. J. Chem. Commun. 1998, 1487-1488 and
references therein.
(13) For a review of directed reactions, see: Hoveyda, A. H.; Evans, D.
A.; Fu, G. C. Chem. ReV. 1993, 93, 1306-1360.
(14) Catalysts bearing a secondary amide with the indicated relative
stereochemistry were selected, since the intramolecular H-bonding between
the amide and N-oxide is reported to be critical to stability of these
compounds. See: O’Neil, I. A.; Miller, N. D.; Peake, J.; Barkley, J. V.;
Low, C. M. R.; Kalindjian, S. B. Synlett 1993, 515-518.
a Determined by the analysis of 400 MHz 1H NMR spectra. b Determined
by chiral HPLC analysis; see the Supporting Information for details.
3152
Org. Lett., Vol. 7, No. 15, 2005

Table 2. Effect of the Catalyst N-Terminus on Efficiency and
Table 3. Reexamination of the Catalyst C-Terminus
Enantioselectivity of Allylations of Benzaldehyde
a,b See Table 1.
As illustrated in entries 1-5 (Table 1), a change in the
amide substituent (3a-e) results in little or no difference in
efficiency or enantioselectivity. When a chiral group is
incorporated within the catalyst structure, a more notable
effect is observed in some cases. Processes in entries 6-7
remain efficient but nonselective, whereas reactions in entries
8-11 are inefficient as well. A significant enhancement in
enantioselectivity arises, as depicted in entry 12, when (R)-
R-methylbenzylamine was incorporated within the amide
terminus (catalyst 3l): the desired homoallylic alcohol was
isolated in 45% ee while the reaction proceeded to 98% conv
(12 h). The alternative catalyst diastereomer (3m, entry 13)
promotes a significantly less selective transformation to
afford the alternative product antipode (-31% ee).
a,b See Table 1.
catalyst (>98% conversion, -18% ee under identical condi-
tions shown in Table 3).
Further optimization studies indicated that dichloroethane
is the solvent of choice.15 Lowering of the reaction temper-
ature results in reduced conversion16 without improvement
in enantioselectivity (e.g., 85% ee and 48% conversion at 4
°C, 24 h). When the representative allylation is carried out
at elevated temperatures, enantioselectivity suffers (e.g., 77%
ee at 40 °C).
Next, we investigated the effect of altering the catalyst
N-terminus (Bn in 3l); a variety of proline N-oxides, bearing
the optimal (R)-R-methylbenzylamide terminus, were pre-
pared and examined. These studies, the results of which are
summarized in Table 2, led us to establish that when the
proline N-oxide bears a cyclohexyl group (3r, entry 5),
reaction enantioselectivity improves significantly: the desired
homoallylic alcohol is obtained in 87% ee (91% conv; 12 h
at 22 °C). Increasing the size of the amine substituent leads
to higher product optical purity (entries 1-5), although
catalysts 3t and 3u (entries 7 and 8), bearing a cycloheptyl
and a cyclooctylamine, promote reactions less efficiently and
with lower enantioselectivity than 3r.
As the data summarized in Table 4 indicate, catalyst 3r
can be used to promote the enantioselective allylation of a
Table 4. Enantioselective Reactions of Allyltrichlorosilane
Catalyzed by 3r
To determine whether cooperative effects involving the
two termini of the catalyst can give rise to a more effective
catalyst, chiral proline N-oxides with a cyclohexyl N-terminus
but different C-termini (see Table 1) were prepared and
investigated (Table 3). Catalysts bearing electron-rich (3y,
entry 4) and electron-poor (3z, entry 5) (R)-R-methylben-
zylamine derivatives were included in this search. A more
effective catalyst than 3r was not identified. Nonethless, the
data in Table 3 suggest that the presence of an aryl-containing
C-terminus leads to higher asymmetric induction. Finally,
the diastereomer of N-oxide 3r is a significantly less effective
entry
Ar
yielda (%)
eeb (%)
1
2
Ph
82
81
74
76
81
73
89
89
59
64
87
82
85
72
88
92
79
83
71
82
2-BrC6H4
4-ClC6H4
3
4
3-NO2C6H4
4-OMeC6H4
3,4-(OMe)2C6H3
1-napththyl
2-naphthyl
2-furyl
5
6c
7
8
9
10
3-furyl
a Yield after chromatography. b See Table 1. c 15 mol % catalyst loading
used.
Org. Lett., Vol. 7, No. 15, 2005
3153

allyl group may thus be enhanced as it is situated trans to
the donor N-oxide, and the aldehyde carbonyl might be acti-
vated through coordination trans to the electron-withdrawing
amide carbonyl.18 It is plausible that the large N-terminus
moiety (cyclohexyl group) ensures that substrate coordination
proceeds so as to minimize unfavorable steric interactions
with the cyclohexyl substituent; the presence of the phen-
ethylamine at the C-terminus may be required so that
aldehyde association with the Si center cis to the bulky chiral
moiety is discouraged. Nonetheless, it is difficult to explain
why other sizable C-termini or the alternative diastereomer
(Table 1) give rise to significantly lower enantioselectivity.
As mentioned previously, one of the strengths of the
present protocol is that the requisite catalyst can be prepared
in three steps in high yield (60% overall) from commercially
available optically pure proline. Thus, the synthesis route
used to access 3r (Scheme 3) involves a reductive amination
Scheme 2. Reactions of E- and Z-Crotyltrichlorosilanes 4 and
5 Promoted by 3r and a Proposed Transition Model
Scheme 3. Synthesis of Chiral Catalyst 3r from Proline
variety of aromatic aldehydes at 22 °C. All reactions proceed
to >98% conversion within 24 h. Electron-rich and electron-
poor substrates give rise to appreciable levels of asymmetric
induction; the highest optical purity is observed with electron-
rich 3,4-dimethoxybenzaldehyde (92% ee, entry 6). Reactions
of sterically hindered aldehydes (entry 8) and those that bear
a heterocyclic substituent can be effected in 71-83% ee
(entries 9 and 10).
As the examples in eq 1 indicate, catalytic enantioselective
allylations promoted by N-oxide 3r are not limited to
aromatic aldehydes. Although their transformations proceed
with lower enantioselectivity, R,â-unsaturated aldehydes can
also be utilized as substrates.17
in the presence of cyclohexanone to afford 8 (88% yield),
followed by formation of amide 9 (90% yield) and directed
amine oxidation to generate 3r as a single diastereomer in
75% isolated yield. The only purification required in the
above procedure is a simple precipitation of 3r from CH2-
Cl2 (addition of hexanes).
In summary, we have identified a readily available and
modifiable chiral amino acid based Lewis base catalyst that
promotes the enantioselective allylation of unsaturated al-
dehydes. Attractive features of the method include the ease
of catalyst preparation and mild reaction conditions (22 °C).
Future studies will include design of new amino acid based
N-oxides and examination of their utility as catalysts for
useful catalytic asymmetric protocols.
As depicted in Scheme 2, E- and Z-crotyltrichlorosilanes
4 and 5 can be employed in enantio- and diastereoselective
additions promoted by 3r. The high levels of diastereose-
lectivity (92 and 94% de), where the E-silane leads to the
formation of the anti product diastereomer 6 and Z-silane
affords the syn isomer 7, suggest that a six-membered ring
transition structure, such as I (Scheme 2), is involved in this
class of asymmetric allylations. The nucleophilicity of the
Acknowledgment. Financial support was provided by the
National Institutes of Health (GM-57212). We are grateful
to Schering-Plough for a Graduate Fellowship in Synthetic
Organic Chemistry to J.F.T. and support of the X-ray
facilities at Boston College.
(15) THF, CH3CN, and toluene led to 80-82% ee but low conversion
(<30%). Use of dichloromethane and CH3NO2 gives rise to low conversion
and ee. With DMF >98% conversion and <2% ee is observed (see:
Kobayashi, S.; Nishio, K. J. J. Org. Chem. 1994, 59, 6620-6628).
(16) The lower conversion at higher temperatures can be attributed to
loss of catalyst through reduction of the N-oxide; the derived reduced product
was isolated in several representative cases.
Supporting Information Available: Experimental and
analytical data for substrates and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050814Q
(17) Presumably due to formation of O-silyl chlorohydrins, attempts to
effect additions to aliphatic aldehydes were unsuccessful. See: Denmark,
S. E.; Fu, J. Org. Lett. 2002, 4, 1951-1953.
(18) Cotton, F. A. AdVanced Inorganic Chemistry, 5th ed.; John Wiley
& Sons: New York, 1988; pp 1299-1300.
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