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. Author manuscript; available in PMC: 2011 Sep 1.
Published in final edited form as: Org Lett. 2010 May 7;12(9):2112–2115. doi: 10.1021/ol100604m

Vinylogous Aldol Products From Chiral Crotylsilanes Obtained By Enantioselective Rh(II) and Cu(I) Carbenoid Si-H Insertion

Jie Wu 1, Yu Chen 1, James S Panek 1,*
PMCID: PMC3164278  NIHMSID: NIHMS196197  PMID: 20387893

Abstract

graphic file with name nihms196197u1.jpg

Enantioenriched homoallylic ethers linked to an 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-H insertion to an α-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

Scheme 1.

Scheme 1

Complementary Chrial Silane Reagents

Homoallylic ethers linked to an α,β-unsaturated functional group can be further elaborated to construct amides, acids, and lactones. These “building blocks“ possess exended 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 subunits, reagents used to gain access to these structural-types 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 α,β-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 complexs6 were evaluated for their effectiveness in insertions to α-diazovinylacetates. Although the idea of Cu(I) catalysis has been used to promote Si-H insertions prior to the application of rhodium catalysis, 7, 8 the field remains under developed and few cases of asymmetric variants have been reported.9 In that regard, we reported earlier that useful levels of selectivity with α-diazophenylacetates 10 and anticipated that we could extend the Cu(I) catalysis to α-diazovinylacetates (Table 1, entries 1 and 2), thereby complementing Landais and Davies’ earlier contributions, 11 who were the first to describe examples of Rh(II) promoted asymmetric Si-H insertion to α-diazovinylacetates. In this paper we report an efficient synthesis of chiral allylic silanes with C-centered chirality, and these experiments 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

Table 1.

Preparation of (R)-2a Bearing Dimethyl Phenyl Silyl Groupc

graphic file with name nihms196197u2.jpg
entry catalyst temperature (°C) solvent yield (%)a ee (%)b
1 (R, R)-5a (5 mol %) 0 benzene 44–51 70–73
2 (R, R)-5b (5 mol %) 0 benzene 45–55 78
3 (S)-6 (1–5 mol %) −78 hexane 65–70 88–97

graphic file with name nihms196197t1.jpg
a

Isolated yields were determined after purification over silica gel.

b

Based on HPLC data of silane alcohol, which was reduced from ester 2a by using LAH.

c

When (S, S)-5a or (R)-6 Rh2(R-DOSP)4 was used, the opposite enantiomer was obtained in comparable yield and ee.

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 results 13 suggested that TMSOTf and dicloromethane were the optimal choices. The crotylation generally resulted in high yields but moderate diastereoselectivity (Table 2). Ee measurements 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.

Table 2.

Crotylation Using Silane (R)-2a

graphic file with name nihms196197u3.jpg
entry aldehyde dra yield (%)b ee (%)d product 3
1 benzaldehyde 3.5:1 79 ND 3a
2c 2,5-dimethoxybenzaldehyde 2.5:1 88 ND 3b
3 p-tolualdehyde 3.0:1 73 ND 3c

4 o-bromobenzaldehyde 18:1 81 97 3d

5 p-bromobenzaldehyde 4.2:1 83 ND 3e

6 o-nitrobenzaldehyde 16:1 61 95 3f

7 hydrocinnamaldehyde 4.0:1 71 91e 3g
8 cyclohexanecarboxaldehyde 5.0:1 63 ND 3h
a

Diastereomeric ratios (dr) were determined by 1H NMR analysis on crude material.

b

Isolated yields after purification over silica gel.

c

Using TMSOTf 0.2 equiv.

d

Selected data basded on chiral HPLC.

e

Using silane (S)-2a.

As anticipated, the reaction favored the syn product, consistent with the well established anti-SE’ mode of addition,3 where the steric destablizing 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 (o, m, p) 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 respectively as representative activated and deactivated aldehydes. As shown in Table 3, reaction of anisyl derivative, which was reported to have greater stability and enhanced nucleophilicity (compared to Ph),14 led to slightly lower selectivity (entries 1 and 2). Increasing the nucleophilicity of silane by incorporating additional TMS groups showed no improvement (entries 3–6). For the cases of silane 2f to 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 decreased reactivity 15 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 concentration drove the reactions to completion with good selectivity (entries 13–16).

Table 3.

Effect of Silyl Group on Simple Diastereoselection

graphic file with name nihms196197u4.jpg
entry silane R1 R2 R3 aldehyde conversion (%)a dra
1 rac-2c Me Me anisyl p-tolualdehyde 100 2.8:1
2 rac-2c Me Me anisyl p-bromobenzaldehyde 80 3.0:1
3 rac-2d Me Me TMS p-tolualdehyde 100 3.2:1
4 rac-2d Me Me TMS p-bromobenzaldehyde 100 4.7:1
5 rac-2e Me TMS TMS p-tolualdehyde 100 3.0:1
6 rac-2e Me TMS TMS p-bromobenzaldehyde 100 3.5:1
7 rac-2f Et Et Et p-tolualdehyde 45 4.2:1
8 rac-2f Et Et Et p-bromobenzaldehyde 90 4.4:1
9 rac-2g Bu Bu Bu p-tolualdehyde 45 3.7:1
10 rac-2g Bu Bu Bu p-bromobenzaldehyde 91 4.1:1
11 rac-2h hexyl hexyl hexyl p-tolualdehyde 40 3.8:1
12 rac-2h hexyl hexyl hexyl p-bromobenzaldehyde 90 4.5:1

13b rac-2i Ph Ph Ph p-tolualdehyde 93 5.2:1
14b rac-2i Ph Ph Ph p-bromobenzaldehyde 95 6.8:1
15b rac-2j TMS TMS TMS p-tolualdehyde 95 >20:1
16b rac-2j TMS TMS TMS p-bromobenzaldehyde 98 >20:1
a

Conversion, syn/anti ratio were based on crude 1H NMR.

b

Reaction was carried out at −60 °C.

With useful levels of diastereoselectivity obtained in the racemic series, we prepared enantioenriched silane reagents 2f to 2j. Comparable selectivity was achieved with tributylsilane compared with dimethylphenyl silane (Table 4, entry 1). In contrast, Rh2(S-DOSP)4 afforded only moderate ee of 2j16 (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 (2x) from petroleum ether (entry 4).

Table 4.

Enantioselective Si-H Insertion

graphic file with name nihms196197u5.jpg
entry catalyst R3SiH temperature (°C) product yield (%)a ee (%)b
1 (S)-6 nBu3SiH −78 (R)-2g 48 86
2 (S)-6 TMS3SiH −40 (R)-2j 30 40
3 (S)-6 Ph3SiH 0 (R)-2i NR NR
4c (R,R)-5a Ph3SiH 0 (R)-2i 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.

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 slightly higher selectivity than silane 2a in the crotylation. Branched aliphatic aldehydes 3h-3l gave the homoallylic ethers with higher selectivity than aliphatic aldehydes 3g.

Table 5.

Crotylation Using Chiral Silane (R)-2g and (R)-2i

graphic file with name nihms196197u6.jpg
entry silane aldehyde TMSOR′ dra yield (%)b ee (%)d product 3
1 (R)-2g hydrocinnamaldehyde TMSOMe 5.3:1 57 ND 3g
2 (R)-2g cyclohexanecarboxaldehyde TMSOMe 7.6:1 61 ND 3h
3 (R)-2g isobutyraldehyde TMSOMe 6.6:1 41c ND 3i
4 (R)-2g isobutyraldehyde TMSOBn 7.0:1 63 ND 3j
5 (R)-2g trimethylacetaldehyde TMSOMe 11:1 39c ND 3k
6 (R)-2g trimethylacetaldehyde TMSOBn 15:1 79 85 31
7 (R)-2i benzaldehyde TMSOMe 6.3:1 79 97 3a
8 (R)-2i benzaldehyde TMSOBn 6.4:1 68 ND 3m
9 (R)-2i p-tolualdehyde TMSOMe 5.2:1 75 ND 3c
10 (R)-2i p-bromobenzaldehyde TMSOMe 6.8:1 67 ND 3e
11 (R)-2i o-bromobenzaldehyde graphic file with name nihms196197t2.jpg 15:1 75 ND 3n
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 basded on chiral HPLC, ND = not determoned.

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 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 produced tetrahydrofuran byproducts17a that were not observed with silane 2a. This pathway was minimized by adding excess TMSOMe (3 equiv).

Table 6.

Crotylation Using Chiral Silane (R)-2b

graphic file with name nihms196197u7.jpg
entry aldehyde TMSOR′ dra yield (%)b ee (%)e product 4
1c 2,3-dimethoxybenzaldehyde TMSOMe >20:1 92 ND 4a
2c 2,5-dimethoxybenzaldehyde TMSOMe 8:1 91 ND 4b
3 p-tolualdehyde TMSOMe 11:1 79 ND 4c
4 benzaldehyde TMSOMe 15:1 77 ND 4d
5 p-bromobenzaldehyde TMSOMe 16:1 55 ND 4e
6 o-bromobenzaldehyde TMSOMe >20:1 58 ND 4f
7 2-naphthaldehyde TMSOMe 10:1 73 ND 4g
8c 2,5-dimethoxybenzaldehyde TMSOBn >20:1 87 ND 4h
9 benzaldehyde TMSOBn 11:1 51 97 4i
10d cyclohexanecarboxaldehyde TMSOMe >20:1 76 ND 4j
11d valeraldehyde TMSOMe >20:1 61 ND 4k
12d hydrocinnamaldehyde TMSOMe 16:1 47 ND 4l
13 benzaldehyde graphic file with name nihms196197t3.jpg >20:1 72 ND 4m
14 benzaldehyde graphic file with name nihms196197t4.jpg ND trace ND 4n
a

Diastereomeric ratios were determined by 1H NMR analysis on crude material.

b

Isolated yields after purification over silica gel.

c

Using TMSOTf 0.2 equiv.

d

Using excess TMSOMe, see Supporting Information.

e

Selected data basded on chiral HPLC, ND = not determined.

In summary, we have extended the use of Jacobsen’s C2-symmetric copper(I) diimine complexes to carbene insertions with α-diazovinylacetates, resulting in the formation of crotylsilanes bearing C-centered chirality with high enantioenrichment. The silanes described in this work complement our earlier work to afford 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, 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 latter time.

Supplementary Material

1_si_001
2_si_002

Acknowledgments

Financial support was obtained from NIH CA 53604. The authors are grateful to Professor Scott Schaus (Boston University) and Professor Hisashi Yamamoto (University of Chicago), Dr. Yun Zhang, Dr. Paul Ralifo and Dr. Norman Lee at Boston University for helpful discussions and assistance with NMR and HRMS measurements.

Footnotes

Supporting Information Available Experimental details and new selected spectral for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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Supplementary Materials

1_si_001
2_si_002

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