Asymmetric alkylation or silylation of (S)-(-)-diphenylprolinol-derived α-silyl amide to synthesize optically pure α-monosilyl or bis(silyl) amides

Article abstract of DOI:10.1016/j.tetlet.2016.05.058

Asymmetric alkylation or silylation of (S)-(-)-diphenylprolinol-derived α-silyl amide has been developed to synthesize optically pure α-monosilyl or bis(silyl) amides in good yields with high diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2016.05.058

Accepted Manuscript
Asymmetric Alkylation or Silylation of (S)-(−)-Diphenylprolinol-derived α-
Silyl Amide to Synthesize Optically Pure α-Monosilyl or Bis(silyl) Amides
Zhenggang Huang, Lu Gao, Zhenlei Song
PII:
S0040-4039(16)30581-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.058
TETL 47677
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
5 April 2016
12 May 2016
16 May 2016
Please cite this article as: Huang, Z., Gao, L., Song, Z., Asymmetric Alkylation or Silylation of (S)-(−)-
Diphenylprolinol-derived α-Silyl Amide to Synthesize Optically Pure α-Monosilyl or Bis(silyl) Amides,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.058
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Asymmetric Alkylation or Silylation of (S)-
(−)-Diphenylprolinol-derived α-Silyl Amide
to Synthesize Optically Pure α-Monosilyl or
Bis(silyl) Amides
Leave this area blank for abstract info.
Zhenggang Huang, Lu Gao and Zhenlei Song

Tetrahedron Letters
Asymmetric Alkylation or Silylation of (S)-(−)-Diphenylprolinol-derived α-Silyl
Amide to Synthesize Optically Pure α-Monosilyl or Bis(silyl) Amides
Zhenggang Huang, Lu Gao* and Zhenlei Song
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University,
Chengdu, 610041, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Asymmetric alkylation or silylation of (S)-(−)-diphenylprolinol-derived α-silyl amide has been
developed to synthesize optically pure α-monosilyl or bis(silyl) amides in good yields with high
diastereoselectivity.
2014 Elsevier Ltd. All rights reserved.
Available online
Keywords:
chiral organosilane
asymmetric alkylation
geminal bis(silane)
diphenylprolinol-derived α-silyl amide 2 proves being an
Optically active C-centered chiral organosilanes 1, in which
the chiral center is adjacent to a silyl group, are useful synthons
in organic synthesis.1 The species can be converted into diverse
chiral building blocks. For example, the steric effect of silicon
has been utilized to create a new stereogenic center in the
valuable scaffold for the asymmetric alkylation or silylation,
giving the optically pure α-monosilyl or bis(silyl) amides 3 in
good yields with high diastereoselectivity (Scheme 1, lower).
Scheme 1. Previous Methods to Synthesize Chiral α-Silyl
Carbonyl Compounds (Upper); Asymmetric Alkylation or
Silylation to Form α-Monosilyl or Bis(silyl) Amides (Lower)
structure of
1
diastereoselectively.2 By Fleming-Tamao
oxidation, 1 (R1 = H) can be transformed directly into chiral
secondary alcohols with configurational retention.3 The
asymmetric Sakurai allylation of 1 (R1 = vinyl) with aldehydes
has been also used to generate chiral homoallylic alcohols.4 The
stereoelectronic effect of silicon ensures an efficient chirality
transfer from the chiral allylsilane into the product.
Among various chiral organosilanes, α-silyl carbonyl
compounds (1, R1 = COR) possessing both silyl and carbonyl
functional groups represent an attractive type of synthons. While
these species can be synthesized enantioselectively by
asymmetric insertion of diazoacetates into the Si-H bond, the α-
substitution in diazoacetates are generally limited to aryl groups
(Scheme 1, upper a).5 Paquette et al. developed an asymmetric
alkylation of α-silyl L-menthyl ester to generate chiral
organosilane, but most of the cases only showed poor
diastereoselectivity (Scheme 1, upper b).6 It is noteworthy that
amides containing a chiral amine as the auxiliary have shown a
wide utility for obtaining a diastereoselective α-alkylation.7
However, the process was used only in a few of examples to
synthesize chiral α-silyl amides.8 Herein we report that (S)-(−)-
We initially examined synthesis of 3 via α-silylation of chiral
amide 4, which was prepared in 85% yield by N-acylation of (S)-
(−)-diphenylprolinol with propanoic acid. While the lithium
enolate of ester generally undergoes O-silylation to give silyl
ketene acetal, silylation of the lithium enolate of amide can occur
 Corresponding authors. Tel.: +86-28-85501876; E-mail: lugao@scu.edu.cn; zhenleisong@scu.edu.cn

Table 1. Scope of Alkyl Halides.a
at the C- rather than O-position to give α-silyl amide
regioselectively (Scheme 2).9 As expected, treatment of 4 with
LDA at -78 °C followed by silylation with 1.2 equiv of Me3SiCl
gave rise to the desired α-silyl amide 3a as a single diastereomer,
albeit in 35% yield. The stereochemistry of 3a was ambiguously
confirmed by its X-ray analysis.10 No O-silylation was observed
on both enolate and diphenylprolinol moieties. Recovery of 50%
of amide 4 implied the low α-trimethylsilylation reactivity of its
enolate. Silylation was even completely prohibited to form 3b
when using bulkier Et3SiCl. Interestingly, despite Me3SiMe2SiCl
is bulkier than both Me3SiCl and Et3SiCl, the corresponding α-
silyl amide 3c was obtained in a much higher yield of 80% with
≥ 95:5 dr.11
entry
1
RX
product
yieldb
81%
drc
3e
3f
94:6
2
3
4
63%
83%
87%
≥95:5
≥95:5
≥95:5
Scheme 2. Asymmetric α-Silylation of Amide 4 to Form 3
3g
3h
5
6
7
3i
3j
85%
80%
78%
≥95:5
95:5
We next tested the feasibility of synthesizing chiral α-silyl
amide by the process featuring silylation followed by alkylation
(Scheme 3). In the presence of 2.5 equiv of Me3SiCl, acetamide
5 underwent a dual silylation on its α-position (C-silylation) and
the diphenylprolinol moiety (O-silylation) to give 2a in 83%
yield. α-Methylation of 2a with MeI and the subsequent acidic
work-up to remove the silyl group on the diphenylprolinol
provided the α-silyl amide in 83% yield with ≥ 95:5 dr. This
product shows the identical NMR spectral character to that of 3a
obtained by α-silylation of amide 4 (Scheme 2). In addition,
reaction of Me3SiMe2Si-substituted 2b generated the desired α-
silyl amide 3d in 30% yield as a single diastereomer, in which
the Me3SiMe2Si group on the diphenylprolinol moiety was stable
to the acidic work-up conditions. The bulky Me3SiMe2Si group
might inhibit to a large extent the α-methylation of 2b, leading to
3k
90:10
8
3l
53%
≥95:5
9
3m
3n
N. R.
77%
N. D
95:5
Scheme 3. Asymmetric α-Methylation of Amide 2 to Form 3
10
11
12
3o
3p
73%
58%
≥95:5
≥95:5
a Reaction conditions: 2a (0.2 mmol), LDA (0.4 mmol) and RX (0.24 mmol)
in THF at -78 oC to rt for 3 h. b Isolated yields after purification by silica gel
c
column chromatography.
The ratios were determined by 1H NMR
spectroscopy of the crude products.
the low yield of 3d. We also examined α-methylation of 6
containing
a non-protected diphenylprolinol moiety. The

reaction gave 3a in 80% yield with ≥ 95:5 dr. This result
suggests that α-methylation of 2a and 6 proceeds by the same
stereochemical control. A one-pot synthesis of 3a from 5 was
carried out by sequential addition of Me3SiCl and MeI.
Unfortunately, the reaction only provided a complex mixture.
Scheme 5. Attempts to Form Quaternary Carbon-substituted 7
by Asymmetric α-Alkylation of 3a
With the optimized reaction conditions in hands, the scope of
the approach was next examined using 2a with various alkyl
halides. The approach was tolerated with unbranched n-butyl
iodide and terminal BnO-substituted propyl iodide to give 3e and
3f, respectively, in good yields with high diastereoselectivity
(Table 1, entries 1 and 2). Branched alkyl halides, in which the
sterically demanding substituent is located either away from or
closed to the electrophilic site, are also suitable substrates for the
asymmetric α-alkylation to give 3g-3j with high dr (entries 3-6).
The results in entries 7-9 indicate a steric bias of allyl bromides
for the efficiency of allylation. While using simple allyl bromide
gave 3k in 78% yield, the yield decreased to 53% when 3,3-
dimethyl allyl bromide was used to generate 3l. No allylation
occurred with 2-methyl allyl bromide to form 3m. The 2-methyl
group, which is adjacent to the electrophilic α- and γ-positions,
might inhibit the attack of the enolate of 2a. In contrast, the
reaction showed a good applicability to less sterically demanding
propargyl bromides (entries 10-12). α-Silyl amides 3n-3p were
obtained in good yield with high dr by exclusive propargylation,
rather than allenylation through a γ-substitution pathway.
reactions with either MeI or allyl bromide only led to recovery of
3a; no desired alkylated product 7 was formed (Scheme 5).
Probably, the bulky silyl group prohibits α-alkylation of 3a to
form the sterically congested quaternary carbon center.
Scheme 6. Models to Explain The Stereochemical Outcome
As shown in Schemes 2 and 3, α-silylation of 4 and α-
methylation of 2a provided the identical product 3a as a single
diastereomer. These results imply that the processes might
proceed by two contrasting stereochemical courses. We assumed
that while a chelated enolate 8a might be involved in the
silylation of 4, a non-chelated enolate 8b most likely dominates
the methylation of the silyl-protected 2a (Scheme 6).16 In 8a, the
enolate moiety should adopt a Z-configuration to minimize the
allylic strain between the α-methyl group and the pyrrolidine
moiety.17 Thus, silylation of the conformationally fixed 8a from
the less hindered Si-face would give 3a. On the other hand, the
enolate moiety in 8b should also adopt a Z-configuration, but
probably in a different orientation to minimize the non-bonded
interaction with the diphenylprolinol moiety. This orientation
allows the Si-face in 8b sterically more accessible for
methylation, affording 3a predominantly.
Scheme 4. Asymmetric α-Silylation of 2a to Form Chiral
Geminal Bis(silanes) 3q and 3r
In summary, we have described an efficient approach to
synthesize optically pure organosilanes by asymmetric alkylation
of (S)-(−)-diphenylprolinol-derived α-silyl amide. The approach
has also shown a good applicability to construct the synthetically
challenging chiral geminal bis(silanes) via asymmetric α-
silylation. Further applications of this methodology are ongoing
in our group.
The process also provided an effective manner to construct
structurally unique chiral geminal bis(silanes). These species
contains two bulky silyl groups attached to one carbon center,
making their synthesis kinetically and thermodynamically very
challenging.12 In the past few years, we have launched a series of
studies on the synthesis and reactivity of geminal bis(silanes).13
Those organosilanes generally possess two identical silyl groups,
and hence they are achiral. To the best of our knowledge, little
investigation has been made to construct the optically pure
geminal bis(silanes),14 which contain two different silyl groups
and should have great synthetic potentials for the down-stream
asymmetric transformations. As shown in Scheme 4, asymmetric
α-silylation of 2a with disilyl chloride gave rise to chiral geminal
bis(silanes) 3q and 3r with ≥ 95:5 dr in 85% and 72% yield,
respectively. We also tested the feasibility of installing others
silyl groups into 2a. However, neither Et3SiCl nor PhMe2SiCl
led to the desired α-silylation to form 3s.15 These results are
consistent with the observation that Me3SiMe2SiCl is more
reactive than Me3SiCl for α-silylation, even though it is sterically
bulkier (Scheme 2).
Acknowledgments
We are grateful for financial support from the NSFC
(21321061, 21290180).
References and notes
1. For a selected review, see: Fleming, I.; Barbero, A.; Walter, D. Chem.
Rev. 1997, 97, 2063−2192.
2. (a) Wang, K. K.; Gu, Y. G.; Liu, C. J. Am. Chem. Soc. 1990, 112, 4424-
4431; (b) Wipf, P.; Pierce, J. G. Org. Lett. 2005, 7, 3537-3540; (c)
Lambert, W. T.; Roush, W. R. Org. Lett. 2005, 7, 5501-5504; (d) Gao, F.;
McGrath, K. P.; Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132,
14315-14320.
3. (a) Roush, W. R.; Grover, P. T. Tetrahedron 1992, 48, 1981-1998; (b)
Hunt, J. A.; Roush, W. R.; J. Org. Chem. 1997, 62, 1112-1124; (c)
Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 5579-
5581; (d) Okamoto, k.; Tamura, E.; Ohe, K. Angew. Chem. Int. Ed.
2014, 53, 10195-10199; (e) Kitanosono, T.; Zhu, L.; Liu, C.; Xu, P.; Y.;
Kobayashi, S. J. Am. Chem. Soc. 2015, 137, 15422-15425.
Further α-alkylation of 3a would give rise to 7 containing a
silicon-substituted quaternary carbon center. However, the

4. For a selected review, see: Panek, M.; Masse, C. E. Chem. Rev. 1995,
95, 1293-1316.
17. Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233-4236.
5. (a) Zhang, Y. Z.; Zhu, F. Z.; Wang, L. X.; Zhou, Q. L. Angew. Chem. Int.
Ed. 2008, 47, 8496-8498; (b) Yasutomi, Y.; Suematsu, Y.; Katsuki, T. J.
Am. Chem. Soc. 2010, 132, 4510-4511; (c) Sambasivan, R.; Ball, Z. T. J.
Am. Chem. Soc. 2010, 132, 9289-9291; (d) Chen, D.; Zhu, D. X.; Xu, M.
H. J. Am. Chem. Soc. 2016, 138, 1498-1501.
6. (a) Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989, 54,
1399-1408; (b) Paquette, L. A.; Gilday, J. P.; Ra, C. S. Hoppe, M. J.
Org. Chem. 1988, 53, 704-706.
7. (a) Sonnet, P. E.; Heath, R. R. J. Org. Chem. 1980, 45, 3137-3139; (b)
Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1984, 25, 6015-
6016; (c) Moon, H. S.; Eisenberg, S. W. E.; Wilson, M. E.; Schore, N.
E.; Kurth, M. J. J. Org. Chem. 1994, 59, 6504-6505; (d) Price, M. D.;
Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 7769-7773.
8. (a) Coggins, P.; Simpkins; N. S. Synlett . 1992, 313–314; (b) Enders, D.;
Teschner, P.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2001, 4463-
4477; (c) Papadopoulos, K.; Young, D. W. Tetrahedron Letters 2002, 43,
3951–3955; (d) Bag, S. S.; Kundu, R.; Basak, K.; Slanina, Z. Org. Lett.
2009, 11, 5722-5725.
9. For the regioselectivity of silylation see: (a) Rathke, M. W.; Sullivan, D.
F. Synth. Commun. 1973, 3, 67-72; (b) Hudrlik, P. F.; Peterson, D.; Chou,
D. Synth. Commun. 1975, 5, 359-365; (c) Larson, G. L.; Fuentes, L. M. J.
Am. Chem. Soc. 1981, 103, 2418-2419; (d) Shtelman, A. V.; Becker, J.
Y. Tetrahedron Letters. 2008, 49, 3101-3103; (e) Holan, M.; Pohl, R.;
Císařová, I.; Jahn, U. Eur. J. Org. Chem. 2012, 18 3459–3475; (f)
Ermolovich, Y. V.; Zhabinskii, V. N.; Khripach, V. A. Steroids. 2013,
78, 683-692.
10. CCDC 1471145 [3a] contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
11. Currently, we do not know the exact reason why the bulkier
Me3SiMe2SiCl shows higher α-silylation reactivity than smaller
Crystallographic
Data
Centre
via
a
Me3SiCl. Probably, the electronic property of the Si-Si bond plays one of
the important roles in this case. Previous studies have shown that the Si-
H
bond in R3SiH can be dramatically weakened by successive
substitution of the alkyl group with the silyl group, although the origin of
this effect is unclear (See references below). We assumed that the Si-Cl
bond in Me3SiMe2SiCl might be weakened by the similar effect,
rendering Me3SiMe2SiCl more reactive than Me3SiCl. In addition, due to
the Si-Si bond (≈ 2.39 Å) is longer than the Si-C bond (≈ 1.93 Å),
switching Me to Me3Si group may not increase the steric effect as much
as one expect. (a) Walsh, R. Acc. Chem. Res. 1981, 14, 246-252. (b)
West, R. Pure Appl. Chem. 1982, 54, 1041-1050. (c) Sakurai, H. Pure
Appl. Chem. 1987, 59, 1637-1946. (d) Kanabus-Kaminska, J. M.;
Hawari, J. A.; Griller, D.; Chatgilialoglu, C. J. Am. Chem. Soc. 1987,
109, 5267-5268. (e) Shimizu, M.; Oda, K.; Bando, T.; Hiyama, T. Chem.
Lett. 2006, 35, 1022-1023.
12. For selected references, see: (a) Luo, Q.; Wang, C.; Li, Y. X.; Ouyang,
K. B.; Gu, L; Uchiyama, M; Xi, Z. F. Chem. Sci. 2011, 2, 2271-2274; (b)
Li, H.; Liu, L. T.; Wang, Z. T.; Zhao, F.; Zhang, S. G.; Zhang, W. X.;
Xi, Z. F. Chem. Eur. J. 2011, 17, 7399-7403; (c) Groll, K.; Manolikakes,
S. M.; du Jourdin, X. M.; Jaric, M.; Bredihhin, A.; Karaghiosoff, K.;
Carell, T.; Knochel, P. Angew. Chem. Int. Ed. 2013, 52, 6776-6780; (d)
Cui, H. Y.; Zhang, J. Y.; Cui, C. M. Organometallics 2013, 32, 1-4; (e)
Werner, V.; Klatt, T.; Fujii, M.; Markiewicz, J.; Apeloig, Y.; Knochel, P.
Chem. Eur. J. 2014, 20, 8338-8342; (f) Bai, X. F.; Deng, W. H.; Xu, Z.;
Li, F. W.; Deng, Y.; Xia, C. G.; Xu, L.W. Chem. Asian J. 2014, 9, 1108-
1115; (g) Liu, Z. X.; Tan, H. C.; Fu, T. R.; Xia, Y.; Qiu, D.; Zhang, Y.;
Wang, J. B. J. Am. Chem. Soc. 2015, 137, 12800-12803.
13. (a) Liu, Z. J.; Lin, X. L.; Yang, N.; Su, Z. S.; Hu, C. W.; Xiao, P. H.; He,
Y. Y.; Song, Z. L. J. Am. Soc. Chem. 2016, 138, 1877-1883; (b) Li, L. J.;
Sun, X. W.; He, Y. Y.; Gao, L.; Song, Z. L. Chem. Commun 2015, 51,
14925-14928; (c) Wu, Y.; Li, L. J.; Li, H. Z.; Gao, L.; Xie, H. M.;
Zhang, Z. G.; Su, Z. S.; Hu, C. W.; Song, Z. L. Org. Lett. 2014, 16,
1880-1883; (d) Lin, X. L.; Ye, X. C.; Sun, X. W.; Zhang, Y. B.; Gao, L.;
Song, Z. L. Org. Lett. 2014, 16, 1084-1087; (e) Sun, X. W.; Lei, J.; Sun,
C. Z.; Song, Z. L.; Yan. L. J. Org. Lett. 2012, 14, 1094-1097; (f) Song,
Z. L.; Lei, Z; Lu, G.; Wu, X.; Li, L. J. Org. Lett. 2010, 12, 5299−5302.
14. One of the previous studies have shown that the lithium enolate of α-
silyl acetamide underwent O-silylation to form silyl enol ether, rather
than C-silylation to give geminal bis(silyl) amide. For a reference, see:
Urayama, S.; Inoue, S.; Sato, Y. J. Organomet. Chem. 1988, 354, 155–
160.
15. Trimethylstannylation of amides 2a with Me3SnCl showed similarly
inert reactivity.
16. Andersson, F.; Hedenström, E. Tetrahedron: Asymmetry 2004, 15,
2539–2545.

Highlights
 (S)-(−)-diphenylprolinol is shown as an efficient auxiliary to ensure the high diastereoselectivity of
alkylation.
 A range of optically pure chiral α-monosilyl amides were obtained in good yields with high
diastereoselectivity.
 The approach is applicable to synthesize sterically congested chiral α-bis(silyl) amides.