Stereoretentive Addition of N-tert-Butylsulfonyl-α-Amido Silanes to Aldehydes, Ketones, α,β-Unsaturated Esters, and Imines

Article abstract of DOI:10.1002/asia.201600270

Enantioenriched N-tert-butylsulfonyl-α-amido silanes were successfully reacted with aldehydes, ketones, imines, and α,β-unsaturated esters in the presence of a sub-stoichiometric amount of CsF (0.5 equiv) in 1,2-dimethoxyethane (DME) at -20 °C to afford the corresponding coupling products with up to 89 % enantiospecificity in a retentive manner. Keep your cool! Enantioenriched N-tert-butylsulfonyl-α-amido silanes were successfully reacted with aldehydes, ketones, imines, and α,β-unsaturated esters in the presence of a sub-stoichiometric amount of CsF (0.5 equiv) in 1,2-dimethoxyethane (DME) at -20 °C to afford the corresponding coupling products with up to 89 % enantiospecificity in a retentive manner.

Full text of DOI:10.1002/asia.201600270

DOI: 10.1002/asia.201600270
Communication
Stereospecific Reactions
Stereoretentive Addition of N-tert-Butylsulfonyl-a-Amido Silanes
to Aldehydes, Ketones, a,b-Unsaturated Esters, and Imines
Tsuyoshi Mita,* Keisuke Saito, Masumi Sugawara, and Yoshihiro Sato*[a]
us to develop a new method with a high level of enantiospeci-
Abstract: Enantioenriched N-tert-butylsulfonyl-a-amido si-
lanes were successfully reacted with aldehydes, ketones,
ficity for versatile electrophiles under mild conditions.
Our research group already reported a stereoretentive car-
imines, and a,b-unsaturated esters in the presence of
boxylation of a-amino silanes 1 with CO2 in the presence of
a sub-stoichiometric amount of CsF (0.5 equiv) in 1,2-di-
CsF in N,N-dimethylformamide (DMF) solvent at À208C, afford-
methoxyethane (DME) at À208C to afford the correspond-
ing the corresponding a-amino acids with up to 86% enantio-
ing coupling products with up to 89% enantiospecificity
specificity (Figure 1).[9,10] The starting enantioenriched N-tert-
in a retentive manner.
butylsulfonyl-a-amido silanes 1 can be synthesized either from
Ellman’s chiral sulfinyl imines by diastereoselective silylation[11]
followed by oxidation or from sulfonyl imines by CuI-catalyzed
enantioselective silylation recently developed by our group.[10]
The construction of CÀC bonds with preservation of the optical
purity of nucleophiles is a formidable challenge in organic syn-
thesis.[1] Although transition-metal-catalyzed stereospecific
cross-coupling reactions have been actively studied in this
field,[2] much attention is still being paid to non-catalytic pro-
cesses using highly reactive nucleophiles.[3–6] Among the latter
examples, stereospecific additions of secondary and tertiary al-
kyllithium species have been extensively studied over the past
three decades.[3] For instance, enantioenriched organolithium
species, which are prepared by tin–lithium exchange from the
corresponding optically active organostannanes and n- or s-
BuLi,[4] deprotonation of enantioenriched carbamate-protected
derivatives with BuLi and tetramethylethylenediamine
(TMEDA),[5] or asymmetric deprotonation of achiral substrates
using BuLi and (À)-sparteine as a chiral ligand,[6] reacted with
a range of electrophiles in a stereoretentive/invertive manner.
However, a very low temperature (below À788C) was often re-
quired in order to maintain their optical purities as much as
possible. Moreover, the use of highly nucleophilic BuLi attenu-
ates the synthetic utility due to the low functional-group toler-
ance and the need for strictly anhydrous conditions. On the
other hand, less reactive alkylboran[7] and silane[8] reagents
were also employed for the stereospecific addition in combina-
tion with an appropriate activator. Although g-addition of
enantioenriched allylboranes and allylsilanes has already been
established,[7a–d,8a–c] stereospecific transformation of C(sp3)ÀB/Si
into C(sp3)ÀC bonds is still challenging, and this has motivated
In contrast, the use of N-Boc-a-amido silanes 1b under the
same conditions gave racemic compounds,[12] suggesting that
the Boc substitution enhances carbanion generation, whereas
the sulfonyl group might stabilize a fluorosilicate intermediate
in the stereoretentive transformation. We describe herein the
detection of a fluorosilicate species using 19F-29Si 2D NMR spec-
troscopy in addition to other potential transformations of N-
tert-butylsulfonyl-a-amido silane 1a (R=Ph) with various elec-
trophiles including aldehydes, ketones, a,b-unsaturated esters,
and imines, affording the coupling products 2 with up to 89%
enantiospecificity.
First, to confirm that a fluorosilicate or a carbanion is an
actual nucleophilic species, 19F NMR experiments were con-
ducted in DMF at room temperature under Ar using 1a (R=
Ph) and N-Boc-a-amido silane 1b in the presence of TBAT
(tetra-n-butylammonium triphenyldifluorosilicate: Ph3SiF2·NBu4)
instead of CsF as a fluoride source, because TBAT is readily
soluble in DMF to keep the solution homogeneous during the
analysis (Figure 2). When 1a was subjected to 19F NMR analysis,
a strong peak at À114 ppm other than TBAT (À104 ppm),
PhMe2SiF (À165 ppm), and a peak (À124 ppm) tentatively as-
signed as PhMe2SiF2·NBu4, which was prepared from TBAT and
PhMe2SiF, was clearly observed.[13] To obtain more information
about this species, we then conducted a 19F-detected 19F-29Si
gradient-enhanced heteronuclear multiple-quantum coherence
(gHMQC) experiment with full 29Si decoupling mode, and the
results indicated that À114 ppm in 19F NMR was correlated
with the peak around À110 ppm in 29Si NMR (JFSi =207 Hz).
Peaks in this region of 29Si NMR generally represent silicate
species,[14] suggesting that fluorosilicate species 3 was present,
probably due to the assistance of sulfonyl oxygen.
[a] Dr. T. Mita, K. Saito, M. Sugawara, Prof. Dr. Y. Sato
Faculty of Pharmaceutical Sciences
Hokkaido University
Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan)
Fax: (+81)11-706-3722
E-mail: tmita@pharm.hokudai.ac.jp
biyo@pharm.hokudai.ac.jp
Homepage: http://gouka.pharm.hokudai.ac.jp/FSC/jpn/page/top_page.htm
19F NMR experiments using N-Boc-a-amido silane 1b were
also conducted, and the results showed only three peaks
(TBAT, PhMe2SiF, and PhMe2SiF2·NBu4).[13] The presence of
PhMe2SiF and PhMe2SiF2·NBu4 indicated that activation of the
Supporting information for this article can be found under http://
dx.doi.org/10.1002/asia.201600270.
Chem. Asian J. 2016, 11, 1528 – 1531
1528
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Figure 1. Carboxylation of N-tert-butylsulfonyl-a-amido silanes with CO2.
Table 1. Conditions screening.
Entry PhCHO CsF
t
[h]
Solvent Total Yield of 2a d.r.
ee
[X]
[Y]
[%][a]
[anti/
syn][b]
[%][c]
anti/
syn
1[d]
2
1.2
1.2
1.2
1.2
2
5
5
5
5
0.5
0.5
4
DMF
60
71
61
89
91
95 (94)
1/1
1/1
1.1/1
1/1.3
1/1.3
1/1.2
36/31
64/63
62/67
79/79
82/84
83/88
23 DMF
23 DMF
23 DME
24 DME
24 DME
3[e]
4
5
6
3
[a] Yields were determined by 1H NMR spectroscopy using 1,3,5-trime-
thoxybenzene as an internal standard. Isolated yields are given in paren-
theses. [b] Determined by 1H NMR spectroscopy. [c] Determined by chiral
HPLC analysis. [d] The reaction was conducted at room temperature.
[e] The reaction was conducted at À308C.
Figure 2. 19F–29Si gradient-enhanced heteronuclear multiple-quantum coher-
ence (gHMQC) experiment. (19F irradiated, 19F observed, and 29Si decoupled
mode)
changed from DMF to 1,2-dimethoxyethane (DME), the ee
values increased to 79% ee (Entry 4). The ee values were fur-
ther increased to around 82%/84% when the reaction was
PhMe2Si moiety of 1b by TBAT actually occurred. However, the
formation of a carbanion from the fluorosilicate would be ac-
celerated due to the lack of a stabilization effect of the sulfonyl
group. Thereby, a reactive carbanion would be produced, fol-
lowed by its racemization with loss of stereochemical informa-
tion of original 1b. Based on a comparison of the results of
the experiments, the production of the fluorosilicate species 3
was thought to be involved in the stereoretentive transforma-
tion.
conducted using
a
sub-stoichiometric amount of CsF
(0.5 equiv) and an excess of benzaldehyde (2 equiv; Entry 5). Fi-
nally, the yield was improved to 95% by using 3 equiv of ben-
zaldehyde (Entry 6). 1a was completely consumed for all en-
tries, but undesired protodesilylation proceeded, resulting in
a decrease in the yield of 2a (Entry 1: 10%; Entry 2: 2%;
Entry 3: 10%; Entry 3: 11 %; Entry 4: 9%; Entry 5: 5%).
Given information about the fluorosilicate intermediate by
NMR, nucleophilic addition of 1a with benzaldehyde was next
investigated (Table 1). When the reaction was conducted in
DMF at room temperature, amino alcohol 2a was obtained in
60% yield with almost 1:1 d.r. with low ee values (Entry 1).
With decrease in temperature from room temperature to
À208C, the yield was slightly increased to 71% and the ee
values of both diastereomers rose to about 60% ee (Entry 2).
Further decrease of the temperature did not improve the yield
and selectivities (Entry 3). When the reaction solvent was
Taking into account the possibility of a catalytic pathway,
a reasonable reaction mechanism is proposed (Figure 3). a-
Amino silane 1a is first activated by CsF to produce fluorosili-
cate species 3, which then undergoes nucleophilic addition to
benzaldehyde. The generated cesium alkoxide 4 is then
quenched by H3O+ to produce 2a (stoichiometric pathway).
On the other hand, cesium alkoxide 4 would also work as
a Lewis base for activation of 1a to produce 5, which then un-
dergoes nucleophilic addition to benzaldehyde to afford 6. The
silylated alcohol 6 is then quenched by H3O+ to produce 2a
Chem. Asian J. 2016, 11, 1528 – 1531
www.chemasianj.org
1529
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Scheme 1. Preparation of optically active 1,2-diamine.
Next, nucleophilic addition of 1a to N-tert-butylsulfonyl
imine was investigated under the optimal conditions
(Scheme 1).[15] The reaction smoothly proceeded at À208C and
the target diamine 2m was obtained in 62% yield with a mix-
ture of anti(meso)/syn(dl) diastereomers. The ee of (S,S)-syn-2m
was determined to be 82%. Although the ratio of anti/syn was
not satisfactory, it is noteworthy that a-amino silane reacted
with imines to afford C2 symmetric 1,2-diamines, which can be
seen as backbones of various chiral ligands.
Figure 3. Proposed reaction mechanism.
(catalytic pathway). Although both pathways are operative in
this system, the catalytic activation seems to be effective in
terms of enantiospecificity.
The stereochemistry of the stereogenic center adjacent to
the nitrogen atom of the product was confirmed by its deriva-
tization (Figure 5). Amino alcohol 2a containing anti/syn dia-
stereomers was oxidized by Dess–Martin periodinane into
a known a-amino ketone 7 in 79% yield.[16] The absolute con-
figuration of the stereogenic center of a-carbon was deter-
mined to be (S) based on comparison of its optical rotation
value with the reported one.[16] This result suggested that the
present nucleophilic addition proceeded in a retentive manner
similar to the case of carboxylation of 1a.[10]
One of the diastereomers of 2a (more polar product on
silica gel column chromatography) derived from benzaldehyde
as well as 2c (less polar product on silica gel column chroma-
tography) derived from cyclohexanecarboxaldehyde were both
(S,S)-syn-diastereomers based on comparison of their NMR
spectra and optical rotation values with the reported data
(Figure 6).[17] In addition, the sulfonyl group of the other diaste-
With optimal catalytic conditions in hand, the reaction scope
and limitations were examined using 1a as a substrate
(Figure 4). Not only benzaldehyde but also aliphatic aldehydes
bearing acidic a-protons were all tolerated to produce 2a–2d
with up to 89% enantiospecificity, but their diastereoselectivi-
ties were almost 1:1. The use of cinnamaldehyde as an electro-
phile led to selective 1,2-addition. When symmetrical ketones
were employed, the coupling products 2 f–2i were obtained in
moderate to good yields with almost 80% ee. The use of un-
symmetrical ketones such as acetophenone and 2,2,2-trifluor-
oacetophenone slightly improved their diastereoselectivities,
and products 2j and 2k were obtained with high enantiospe-
cificity. Additionally, 1a underwent 1,4-addition of ethyl acry-
late to afford g-amino acid 2l in moderate yield with 76% ee.
Figure 4. Substrate scope using a-amino silane 1. Isolated yields are shown unless otherwise noted.
Chem. Asian J. 2016, 11, 1528 – 1531 www.chemasianj.org
1530
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Ohmura, T. Awano, M. Suginome, J. Am. Chem. Soc. 2010, 132, 13191;
g) T. Awano, T. Ohmura, M. Suginome, J. Am. Chem. Soc. 2011, 133,
20738; h) J. C. H. Lee, R. McDonald, D. G. Hall, Nat. Chem. 2011, 3, 894;
i) M. Goli, A. He, J. R. Falck, Org. Lett. 2011, 13, 344; j) G. A. Molander,
S. R. Wisniewski, J. Am. Chem. Soc. 2012, 134, 16856; k) L. Li, C.-Y. Wang,
R. Huang, M. R. Biscoe, Nat. Chem. 2013, 5, 607.
[3] For reviews on enantioenriched organolithium species, see: a) P. Beak,
A. Basu, D. J. Gallagher, Y. S. Park, S. Thayumanavan, Acc. Chem. Res.
1996, 29, 552; b) A. Basu, S. Thayumanavan, Angew. Chem. Int. Ed. 2002,
41, 716; Angew. Chem. 2002, 114, 740.
[4] For the first finding of stereospecific lithiation of optically active orga-
nostannanes with BuLi, see: W. C. Still, C. Sreekumar, J. Am. Chem. Soc.
1980, 102, 1201.
Figure 5. Determination of the absolute configuration of a-carbon of nitro-
gen.
[5] D. Hoppe, A. Carstens, T. Krämer, Angew. Chem. Int. Ed. 1990, 29, 1424;
Angew. Chem. 1990, 102, 1455.
[6] a) D. Hoppe, F. Hintze, P. Tebben, Angew. Chem. Int. Ed. 1990, 29, 1422;
Angew. Chem. 1990, 102, 1457; b) S. T. Kerrick, P. Beak, J. Am. Chem. Soc.
1991, 113, 9708.
[7] a) R. W. Hoffmann, B. Landmann, Angew. Chem. Int. Ed. Engl. 1984, 23,
437; Angew. Chem. 1984, 96, 427; b) E. Beckmann, D. Hoppe, Synthesis
2005, 217; c) H. Ito, S. Ito, Y. Sasaki, K. Matsuura, M. Sawamura, J. Am.
Chem. Soc. 2007, 129, 14856; d) H. Ito, S. Kunii, M. Sawamura, Nat.
Chem. 2010, 2, 972; e) V. K. Aggarwal, M. Binanzer, M. Carolina de Ceglie,
M. Gallanti, B. W. Glasspoole, S. J. F. Kendrick, R. P. Sonawane, A.
Vµzquez-Romero, M. P. Webstar, Org. Lett. 2011, 13, 1490; f) R. Larouche-
Gauthier, T. G. Elford, V. K. Aggarwal, J. Am. Chem. Soc. 2011, 133, 16794;
g) M. Mohiti, C. Rampalakos, K. Feeney, D. Leonori, V. K. Aggarwal,
Chem. Sci. 2014, 5, 602; h) A. Bonet, M. Odachowski, D. Leonori, S.
Essafi, V. K. Aggarwal, Nat. Chem. 2014, 6, 584; i) J. Llaveria, D. Leonori,
V. K. Aggarwal, J. Am. Chem. Soc. 2015, 137, 10958.
[8] a) T. Hayashi, M. Konishi, H. Ito, M. Kumada, J. Am. Chem. Soc. 1982, 104,
4962; b) T. Hayashi, M. Konishi, M. Kumada, J. Am. Chem. Soc. 1982, 104,
4963; c) T. Hayashi, Y. Matsumoto, T. Kiyoi, Y. Ito, Tetrahedron Lett. 1988,
29, 5667; d) B. F. Bonini, S. Masiero, G. Mazzanti, P. Zani, Tetrahedron Lett.
1991, 32, 815; e) S. Thayumanavan, Y. S. Park, P. Farid, P. Beak, Tetrahe-
dron Lett. 1997, 38, 5429.
[9] Enantiospecificity=[(ee of product)/(ee of starting material)]”100.
[10] T. Mita, M. Sugawara, K. Saito, Y. Sato, Org. Lett. 2014, 16, 3028.
[11] D. M. Ballweg, R. C. Miller, D. L. Gray, K. A. Scheidt, Org. Lett. 2005, 7,
1403.
Figure 6. Determination of stereochemistry of the products.
reomer of 2a was removed according to the reported meth-
ods,[10,18] giving the corresponding free amino alcohol 8 in
73% yield. Its optical rotation value and NMR spectra perfectly
matched those of (S,R)-anti-diastereomer.[19]
[12] a) T. Mita, J. Chen, M. Sugawara, Y. Sato, Org. Lett. 2012, 14, 6202. For a-
amino stannanes, see: b) T. Mita, M. Sugawara, H. Hasegawa, Y. Sato, J.
Org. Chem. 2012, 77, 2159.
[13] TBAT also promoted stereoretentive carboxylation with CO2, but slightly
decreased the enantiospecificity. See the Supporting Information for
details.
[14] a) K. C. Kumura-Swamy, V. Chandrasekhar, J. J. Harland, J. M. Holmes,
R. O. Day, R. R. Holmes, J. Am. Chem. Soc. 1990, 112, 2341; b) I. Kalikh-
man, B. Gostevskii, O. Girshberg, A. Sivaramakrishna, N. Kocher, D.
Stalke, D. Kost, J. Organomet. Chem. 2003, 686, 202; c) E. P. A. Couzijn,
D. W. F. van den Engel, J. C. Slootweg, F. J. J. de Kanter, A. W. Ehlers, M.
Schakel, K. Lammertsma, J. Am. Chem. Soc. 2009, 131, 3741. For reviews,
see; d) C. Chuit, R. J. P. Corriu, C. Reye, J. C. Young, Chem. Rev. 1993, 93,
1371; e) R. R. Holmes, Chem. Rev. 1996, 96, 927.
In summary, we have developed stereoretentive addition of
N-tert-butylsulfonyl-a-amido silanes to various electrophiles in-
cluding aldehydes, ketones, a,b-unsaturated ester, and imines.
Enantiospecificity was up to 89% at À208C in DME. Further
substrate scope including nucleophiles other than 1a is now
actively underway.
Acknowledgements
This work was financially supported by Grants-in-Aid for Scien-
tific Research (C) (No. 26410108), Grants-in-Aid for Scientific Re-
search (B) (No. 26293001) from JSPS, and also by ACT-C, JST.
[15] For a recent example of the synthesis of racemic diamines from a-
amino silanes, see: C.-Y. Lin, Z. Sun, Y.-J. Xu, C.-D. Lu, J. Org. Chem.
2015, 80, 3714.
[16] K. W. Kells, J. M. Chong, J. Am. Chem. Soc. 2004, 126, 15666.
[17] F. Schmidt, F. Keller, E. Vedrenne, V. K. Aggarwal, Angew. Chem. Int. Ed.
2009, 48, 1149; Angew. Chem. 2009, 121, 1169.
Keywords: aldehydes · cesium fluoride · ketones · silanes ·
stereospecific reactions
[18] a) D. Enders, M. Seppelt, T. Beck, Adv. Synth. Catal. 2010, 352, 1413. For
the original procedure, see: b) P. Sun, S. M. Weinreb, J. Org. Chem. 1997,
62, 8604.
[19] The chemical properties of 8 (CAS. 23190-16-1) including its optical ro-
tation and 1H and 13C NMR spectra are reported by Sigma–Aldrich Co.
LLC (Product Number: 331899.).
[1] For a recent review of this topic, see: a) A. H. Cherney, N. T. Kadunce,
S. E. Reisman, Chem. Rev. 2015, 115, 9587; b) E. J. Tollefson, L. E. Hanna,
E. R. Jarvo, Acc. Chem. Res. 2015, 48, 2344.
[2] For transition-metal-catalyzed stereospecific coupling reaction of opti-
cally active organometallic nucleophiles, see: a) J. Ye, R. K. Bhatt, J. R.
Falck, J. Am. Chem. Soc. 1994, 116, 1; b) J. R. Falck, R. K. Bhatt, J. Ye, J.
Am. Chem. Soc. 1995, 117, 5973; c) R. Kalkofen, D. Hoppe, Synlett 2006,
1959; d) D. Imao, B. W. Glasspoole, V. S. Laberge, C. M. Crudden, J. Am.
Chem. Soc. 2009, 131, 5024; e) D. L. Sandrock, L. Jean-GØrard, C.-Y. Chen,
S. D. Dreher, G. A. Molander, J. Am. Chem. Soc. 2010, 132, 17108; f) T.
Manuscript received: March 2, 2016
Accepted Article published: March 30, 2016
Final Article published: April 21, 2016
Chem. Asian J. 2016, 11, 1528 – 1531
www.chemasianj.org
1531
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim