Vinylogous Aldol products from chiral crotylsilanes obtained by enantioselective Rh(II) and Cu(I) carbenoid Si-H insertion

Article abstract of DOI:10.1021/ol100604m

Figure presented Enantioenriched homoallylic ethers containing a α,β-unsaturated ester (syn-vinylogous aldol products) were directly accessed by Lewis acid catalyzed crotylation utilizing chiral silane 2. The reagents were prepared by enantioselective Si-

Full text of DOI:10.1021/ol100604m

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2112-2115
Vinylogous Aldol Products from Chiral
Crotylsilanes Obtained by
Enantioselective Rh(II) and Cu(I)
Carbenoid Si-H Insertion
Jie Wu, Yu Chen, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, 590 Commonwealth
AVenue, Boston UniVersity, Boston, Massachusetts 02215
panek@bu.edu
Received March 13, 2010
ABSTRACT
Enantioenriched homoallylic ethers containing a r,ꢀ-unsaturated ester (syn-vinylogous aldol products) were directly accessed by Lewis acid
catalyzed crotylation utilizing chiral silane 2. The reagents were prepared by enantioselective Si-H insertion to an r-diazovinylacetates using
Davies’ Rh2(DOSP)4 catalyst or chiral Cu(I) Schiff base complex.
The asymmetric allylation and crotylation of aldehydes
utilizing chiral allyl- and crotylmetal reagents as carbon
nucleophiles remains an important and useful transformation
in orgainc chemistry.1 In that context, allylsilanes are widely
used owing to their versatility, ease of handling, and low
toxicity.2 Well-documented studies from our laboratory have
established chiral crotylsilane 1 as carbon nucleophiles in
highly diastereo- and enantioselective reactions with acetals
and aldehydes to construct homoallylic ethers with an isolated
E-olefin subunit (Scheme 1).3
Homoallylic ethers linked to an R,ꢀ-unsaturated functional
group can be further elaborated to construct amides, acids,
and lactones. These “building blocks” possess extended
functionality and therefore are likely to have utility in natural
product and complex molecule synthesis.4 Despite recent
advances toward the synthesis of polypropionate-like sub-
units, reagents used to gain access to these structural types
(1) (a) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 10. (b) Chemler, S. R.;
Roush, W. R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000; Chapter 11. (c) Yamamoto, Y.; Asao, N. Chem. ReV.
1993, 93, 2207. (d) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123,
9488.
(3) (a) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293–1316. (b)
Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868–9870. (c) Panek,
J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57, 5790–5792.
(2) (a) Chabaud, L.; James, P.; Landais, Y. Eur. J. Org. Chem. 2004,
3173–3199. (b) Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.;
Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920–7921. (c) Grote, R. E.;
Jarvo, E. R. Org. Lett. 2009, 11, 485–488. (d) Kubota, K.; Leighton, J. L.
Angew. Chem., Int. Ed. 2003, 42, 946–948. (e) Hackman, B. M.; Lombardi,
P. J.; Leighton, J. L. Org. Lett. 2004, 6, 4375–4377.
(4) (a) O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340–
5341. (b) Shin, Y.; Fournier, J.-H.; Fukui, Y.; Bruckner, A. M.; Curran,
D. P. Angew. Chem., Int. Ed. 2004, 43, 4634–4637. (c) Fukui, Y.; Bruckner,
A. M.; Shin, Y.; Balachandran, R.; Day, B. W.; Curran, D. P. Org. Lett.
2006, 8, 301–304. (d) Shin, Y.; Choy, N.; Balachandran, R.; Madiraju, C.;
Day, B. W.; Curran, D. P. Org. Lett. 2002, 4, 4443–4446.
10.1021/ol100604m  2010 American Chemical Society
Published on Web 04/13/2010

Scheme 1
.
Complementary Chrial Silane Reagents
Table 1. Preparation of (R)-2a Bearing a Dimethyl Phenyl Silyl
Groupc
entry
catalyst
temp (°C) solvent yield (%)a ee (%)b
1
2
3
(R,R)-5a (5 mol %)
(R,R)-5b (5 mol %)
(S)-6 (1-5 mol %)
0
0
-78
benzene 44-51 70-73
benzene 45-55 78
hexane
65-70 88-97
a Isolated yields were determined after purification over silica gel.
b Based on HPLC data of silane alcohol, which was obtained from ester 2a
by LAH reduction. c When (S,S)-5a or (R)-6 Rh2(R-DOSP)4 was used, the
opposite enantiomer was obtained in comparable yield and ee.
have limited substrate scope.5 In efforts to continue the
development of chiral silane reagents capable of delivering
useful levels of asymmetric induction, we report the synthesis
of syn-homoallylic ethers linked to an R,ꢀ-unsaturated ester
(vinylogous aldol products). The crotylation takes place with
useful dr and ee utilizing chiral silane 2 (Scheme 1).
This study was initiated by establishing a reproducible
asymmetric Si-H metal carbenoid insertion to synthesize
chiral silane 2a. The known and readily available C2-
symmetric copper(I) diimine complexes6 were evaluated for
their effectiveness in insertions to R-diazovinylacetates.
Although the idea of Cu(I) catalysis has been used to promote
Si-H insertions prior to the application of rhodium cataly-
sis,7,8 the field remains underdeveloped, and few cases of
asymmetric variants have been reported.9 In that regard, we
reported earlier useful levels of selectivity with R-diazophe-
nylacetates10 and anticipated that we could extend the Cu(I)
catalysis to R-diazovinylacetates (Table 1, entries 1 and 2),
thereby complementing Landais and Davies’ earlier contribu-
tions,11 who were the first to describe examples of Rh(II)-
promoted asymmetric Si-H insertion to R-diazovinylace-
tates. In this paper we report an efficient synthesis of chiral
allylic silanes with C-centered chirality, and these experi-
ments also allow a comparison of chiral Cu(I) vs Rh(II)
catalysis. Consistent with Davies’ studies, the Rh2(DOSP)4
[(R)-6 and (S)-6] catalyst provided both enantiomers of
crotylsilane 2a in excellent ee (entry 3).12
Once reproducible conditions for the insertion were found,
our efforts turned to the use of the enantioenriched silane
reagents in Lewis acid promoted reaction with in situ derived
oxonium ions. Lewis acid and solvent screening results13
suggested that TMSOTf and dicloromethane were the optimal
choices. The crotylation generally resulted in high yields but
moderate diastereoselectivity (Table 2). Measurements of ee
Table 2. Crotylation Using Silane (R)-2a
(5) (a) Hasfeld, J.; Christmann, M.; Kalesse, M. Org. Lett. 2001, 3, 3561–
3564. (b) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125,
7800–7801. (c) Kalesse, M.; Simsek, S. Tetrahedron Lett. 2009, 50, 3485–
3488.
(6) Larrow, J. F.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 1939–1942.
(7) Rijkens, F.; Janssen, M. J.; Drenth, W.; van der Kerk, G. J. M. J.
Organomet. Chem. 1964, 2, 347
.
(8) For selected examples of chiral Cu-mediated X-H insertions, see:
(a) Maier, T. C.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594–4595. (b)
Lee, E. C.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066–12067. (c) Liu,
B.; Zhu, S. F.; Zhang, W.; Chen, C.; Zhou, Q. L. J. Am. Chem. Soc. 2007,
129, 5834. (d) Chen, C.; Zhu, S. F.; Liu, B.; Wang, L. X.; Zhou, Q. L.
a
1
Diastereomeric ratios (dr) were determined by H NMR analysis on
crude material. b Isolated yields after purification over silica gel. c Using
0.2 equiv of TMSOTf. d Selected data based on chiral HPLC, ND ) not
determined. e Using silane (S)-2a.
J. Am. Chem. Soc. 2007, 129, 12616
.
(9) Zhang, Y. Z.; Zhu, S. F.; Wang, L. X.; Zhou, Q. L. Angew. Chem.,
Int. Ed. 2008, 47, 8496–8498.
(10) (a) Dakin, L. A.; Schaus, S. E.; Jacobsen, E. N.; Panek, J. S.
Tetrahedron Lett. 1998, 39, 8947–8950. (b) Dakin, L. A.; Ong, P. C.; Panek,
J. S.; Staples, R. J.; Stavropoulos, P. Organometallics 2000, 19, 2896–
2908.
were carried by HPLC analysis, and select examples showed
that the enantioenrichment of the silane reagent was fully
transferred into vinylogous-aldol products and were obtained
in up to 97% ee when the (R)-2a was used.
(11) (a) Davies, H. M.; Hansen, T.; Rutberg, J.; Bruzinski, P. R.
Tetrahedron Lett. 1997, 38, 1741–1744. (b) Bulugahapitiya, P.; Landais,
Y.; Rapado, L. P.; Planchenault, D.; Weber, V. J. Org. Chem. 1997, 62,
1630–1641.
(13) TMSOTf, BF3·OEt2, Sc(OTf)3, In(OTf)3, and TiCl4 were screened
as Lewis acid in the reaction with benzaldehyde and silane (R)-2a. Solvents
screening included DCM, toluene, pentane, and THF.
(12) For reaction modification and optimization, see Supporting Informa-
tion.
Org. Lett., Vol. 12, No. 9, 2010
2113

As anticipated, the reaction favored the syn product,
consistent with the well-established anti-SE′ mode of addi-
tion,3 where the steric destabilizing interaction between the
aldehyde substituent and the vinyl methyl group on the allyl
silane is minimized in an open transition state model.
However, the magnitude of selectivity was dependent on the
aldehyde type; activated aromatic aldehydes were less
selective than those containing deactivating substituents
(Table 2, entries 3b, 3c vs 3d, 3e, 3f). Additionally, the
position of substituents (ortho, meta, para) influenced the
magnitude of diastereoselectivity; aldehydes containing an
ortho deactivating group afforded excellent syn/anti ratios
(3d, 3f). In terms of aliphatic aldehydes, the branched
substrate (3h) gave higher selectivity than the straight chain
system (3g).
Efforts to improve the syn-selectivity of the crotylation
by modification of the silane group were achieved, and eight
racemic silane reagents with different nucleophilicities were
prepared by carbene insertion.11b As such, p-tolualdehyde
and p-bromobenzaldehyde were chosen as representative
activated and deactivated aldehydes, respectively. As shown
in Table 3, reaction of the anisyl derivative, which was
no improvement (entries 3-6). For the cases of silane 2f-2h,
the size of the silicon group did not alter the magnitude of
selectivity, as three different alkyl silanes afforded similar
levels (entries 7-12), although slightly enhanced with respect
to silane 2a. Gratifyingly, when silane reagents with de-
creased reactivity15 were used, higher levels of selectivity
were obtained. At -78 °C, reactions with triphenyl silane
2i and trisTMS silane 2j afforded less than 10% conversion
after two days. However, increased temperature or concen-
tration drove the reactions to completion with good selectivity
(entries 13-16).
With useful levels of diastereoselectivity obtained in the
racemic series, we turned to prepare enantioenriched silane
reagents 2f-2j. Comparable selectivity was achieved with
tributylsilane compared with dimethylphenyl silane (Table
4, entry 1). In contrast, Rh2(S-DOSP)4 afforded 2j16 with
Table 4. Enantioselective Si-H Insertion
entry catalyst
R3SiH temp (°C) product yield (%)a ee (%)b
Table 3. Effect of a Silyl Group on Simple Diastereoselection
1
2
3
(S)-6
(S)-6
(S)-6
nBu3SiH
TMS3SiH
Ph3SiH
-78
-40
0
(R)-2g
(R)-2j
(R)-2i
(R)-2i
48
30
NR
86
40
NR
4c (R,R)-5a Ph3SiH
0
41/25d 70/97d
a Isolated yields were determined after purification over silica gel.
b Based on HPLC data of silane alcohol, which was reduced from ester by
using LAH. c Reaction run in benzene. d Yield and % ee before and after
recrystallization from petroleum ether.
moderate ee (entry 2). Owing to the poor solubility of SiPh3H
in pentane, the rhodium catalyst was ineffective for preparing
enantioenriched 2i (entry 3). Alternatively, our preliminary
results showed that using Cu(MeCN)4BF4 and diimine ligand
complex (R,R)-5a afforded 2i with good selectivity (>70%
ee), which could be improved to 97% ee by recrystallization
(2×) from petroleum ether (entry 4).
We next explored the substrate scope with silanes 2i and
2g (Table 5). Crotylation with 2i and aromatic aldehydes
gave useful levels of selectivity. However, with less reactive
aliphatic aldehydes, only trace amounts of produts were
observed spectroscopically. To solve this problem, we
evaluated tri-n-butyl silane 2g, which exhibited selectivity
slightly higher than that of silane 2a in the crotylation.
Branched aliphatic aldehydes 3h-3l gave the homoallylic
ethers with selectivity higher than that of aliphatic aldehydes
3g.
a Conversion and syn/anti ratio were based on crude 1H NMR. b Reaction
was carried out at -60 °C.
The parent silane 2a was converted to a primary TBDPS
ether 2b17 by reduction of the ester group and silylation of
the resulting alcohol (two steps, 91% yield) in an attempt to
increase selectivity. Subsequent reaction of 2b with a variety
reported to have greater stability and enhanced nucleophi-
licity (compared to that of Ph),14 led to slightly lower
selectivity (entries 1 and 2). Increasing the nucleophilicity
of silane by incorporating additional TMS groups showed
(15) Hagen, G.; Mayr, H. J. Am. Chem. Soc. 1991, 113, 4954–4961.
(16) Freeze-pump-thaw degassed pentane was required to avoid
oxidation of TTMSSH.
(14) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc.
2007, 129, 1020–1021.
2114
Org. Lett., Vol. 12, No. 9, 2010

Table 5. Crotylation Using Chiral Silane (R)-2g and (R)-2i
Table 6. Crotylation Using Chiral Silane (R)-2b
a Diastereomeric ratios were determined by 1H NMR analysis on crude
material. b Isolated yields after purification over silica gel. c Low yields
due to volatility of products. d Selected data based on chiral HPLC, ND )
not determined.
a Diastereomeric ratios were determined by 1H NMR analysis on crude
material. b Isolated yields after purification over silica gel. c Using 0.2 equiv
of TMSOTf. d Using excess TMSOMe, see Supporting Information.
e Selected data based on chiral HPLC, ND ) not determined.
of aliphatic and aromatic aldehydes exhibited good to
excellent syn-selectivity and typically good yields (Table 6).
Notably, even the straight chain aliphatic systems (4k, 4l),
which normally gave poor diastereoselectivity, afforded
satisfactory syn/anti ratios. Aliphatic aldehydes often pro-
duced tetrahydrofuran byproducts17a that were not observed
with silane 2a. This pathway was minimized by adding
excess TMSOMe (3 equiv).
In summary, we have extended the use of Jacobsen’s C2-
symmetric copper(I) diimine complexes to carbene insertions
with R-diazovinylacetates, resulting in the formation of
crotylsilanes bearing C-centered chirality with high enan-
tioenrichment. The silanes described in this work comple-
ment our earlier work, affording vinylogous-aldol products
(syn-polypoprionate building blocks) with high levels of
diastereo- and enantioselectivity. Presently, the Davies’
catalyst Rh2(DOSP)4 provides slightly higher levels of
selectivity, and as such, development of more selective Cu(I)
catalysts as an effective approach to chiral silane reagents
and their use in complex molecule synthesis are currently
underway and will be reported at a later time.
Acknowledgment. Financial support was obtained from
NIH CA 53604. The authors are grateful to Professor Scott
Schaus (Boston University), Professor Hisashi Yamamoto
(University of Chicago), and Dr. Yun Zhang, Dr. Paul Ralifo,
and Dr. Norman Lee at Boston University for helpful
discussions and assistance with NMR and HRMS measure-
ments.
Supporting Information Available: Experimental details
and new selected spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) For related silane reagents, see: (a) Heitzman, C. L.; Lambert, W. T.;
Mertz, E.; Shotwell, J. B.; Tinsley, J. M.; Va, P.; Roush, W. R. Org. Lett.
2005, 7, 2405–2408. (b) Komatsu, K.; Tanino, K.; Miyashita, M. Angew.
Chem., Int. Ed. 2004, 43, 4341–4345.
OL100604M
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