Silyllithium-Initiated Coupling of α-Ketoamides with tert-Butanesulfinylimines for Stereoselective Synthesis of Enantioenriched α-(Silyloxy)-β-amino Amides

Article abstract of DOI:10.1021/acs.orglett.6b00006

A silyllithium-initiated coupling of α-ketoamides with tert-butanesulfinylimines was developed for the efficient, stereoselective synthesis of enantioenriched α-(silyloxy)-β-amino amides. Nucleophilic addition of silyllithium to α-ketoamides, followed by 1,2-Brook rearrangement, generates nucleophilic enolates, which are then intercepted by chiral imines to provide three-component coupling products. Use of α-ketoamides is critical for achieving high yields and diastereoselectivities in the resulting α-hydroxy-β-amino acid derivatives.

Full text of DOI:10.1021/acs.orglett.6b00006

Letter
pubs.acs.org/OrgLett
Silyllithium-Initiated Coupling of α‑Ketoamides with tert-
Butanesulfinylimines for Stereoselective Synthesis of
Enantioenriched α‑(Silyloxy)-β-amino Amides
Zhao Sun,† Hui Liu,‡ Yong-Ming Zeng,† Chong-Dao Lu,*,†,‡ and Yan-Jun Xu*,‡
†Department of Chemistry and Applied Chemistry, Changji University, Changji 831100, China
‡The Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics & Chemistry, Chinese
Academy of Sciences, Urumqi 830011, China
S
* Supporting Information
ABSTRACT: A silyllithium-initiated coupling of α-ketoa-
mides with tert-butanesulfinylimines was developed for the
efficient, stereoselective synthesis of enantioenriched α-
(silyloxy)-β-amino amides. Nucleophilic addition of silyl-
lithium to α-ketoamides, followed by 1,2-Brook rearrange-
ment, generates nucleophilic enolates, which are then
intercepted by chiral imines to provide three-component coupling products. Use of α-ketoamides is critical for achieving high
yields and diastereoselectivities in the resulting α-hydroxy-β-amino acid derivatives.
Scheme 1. Buildup of α,α-Disubstituted α-Hydroxy-β-amino
Acid Derivatives by Three-Component Coupling Involving
Alcoholic Oxonium Ylides (a) and Silyloxy Enolates (b and
c)
nantioenriched α-hydroxy-β-amino acids are important
building blocks in bioactive molecules such as taxoid
E
anticancer agents.1,2 A straightforward way to generate these
subunits is by directly coupling α-hydroxy acid derivatives or
their equivalents to suitable azomethines.3 This strategy also
allows for the preparation of β-amino acid derivatives
containing an α-tertiary carbinol center.4 Such derivatives are
sometimes obtained with moderate diastereoselectivity when
chiral imines are used as coupling partners.
In situ formation of reactive equivalents of α-hydroxy acid
derivatives has recently been achieved. Hu and co-workers used
a cooperative catalytic system of rhodium(II) salt and chiral
phosphoric acid to achieve enantioselective three-component
coupling of α-diazoesters, alcohols and imines. In this approach,
rhodium carbenoids and alcohols react to generate alcoholic
oxonium ylides, which behave analogously to α-substituted
glycolic esters by undergoing Mannich addition to imines
(Scheme 1a).5 Our laboratory has developed alternative three-
component protocols6 in which imines are coupled with α-
substituted α-silyloxy enolate intermediates; these intermedi-
ates are generated in situ via an acylsilane addition/1,2-silyl
migration, also known as a 1,2-Brook rearrangement7,8
(Scheme 1b). Since this approach requires the relatively
tedious preparation of acylsilanes, we wondered whether
adding nucleophilic silyl reagents to α-ketoacid derivatives
could initiate a similar silyl migration/Mannich coupling
cascade. If so, this would provide a simpler and faster method
for constructing α,α-disubstituted α-silyloxy-β-amino amides
(Scheme 1c).
products 4a/4′a, although yields varied substantially (45−
85%), as did diastereoselectivities (3:1:0:0−1:1:0:0 dr). Both
yield and dr were found to depend on the batch of PhMe2SiLi,
reaction temperature, and other unexplained factors. This
variability did not improve by introducing Lewis acids such as
BF3·Et2O into the reaction.14 In contrast, modifying the
structure of the α-ketoacid derivative by using α-ketoamide
5a rather than α-ketoester 2 dramatically improved the reaction
First, we examined whether phenyldimethylsilyllithium
(1),9,10 a nucleophilic silyl reagent that is easy to prepare and
handle, would react with α-ketoester 2 and tert-butanesulfiny-
limine 3a (Scheme 2a).11−13 Adding 3a to the reaction mixture
of 3 equiv of 1 and 2 afforded the three-component coupling
Received: January 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00006
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Organic Letters
Letter
Scheme 2. Examination of the Silyllithium-Initiated
Coupling of α-Keto Acid Derivatives with tert-
Butanesulfinylimines
Table 1. Substrate Scope of Three-Component Coupling of
Silyllithiums, α-Ketoamides, and tert-Butanesulfinylimines
a
b
product 6, yield (%)
c
entry
amide 5 (Ar)
5a (Ph)
imine 3 (Ar′)
(dr)
d
1
3a (4-BrC6H4)
3b (Ph)
6a, 99% (>20:1:0:0)
2
5a (Ph)
6b, 94% (>20:1:0:0)
6c, 98% (>20:1:0:0)
6d, 99% (>20:1:0:0)
6e, 77% (>20:1:0:0)
6f, 77% (>20:1:0:0)
3
5a (Ph)
3c (4-ClC6H4)
3d (4-FC6H4)
3e (4-MeC6H4)
3f (4-MeOC6H4)
3g (4-CF3C6H4)
3h (4-t-BuC6H4)
3i (4-CNC6H4)
3j (3-BrC6H4)
3k (3-MeC6H4)
3l (2-BrC6H4)
3m (2-ClC6H4)
3n (2-MeC6H4)
3o (2-naphthyl)
3p (3-pyridine)
3q (2-thienyl)
3r (2-furyl)
4
5a (Ph)
5
5a (Ph)
6
5a (Ph)
e
7
5a (Ph)
6g, 99% (>20:1:0:0)
6h, 80% (>20:1:0:0)
6i, 85% (6:1:0:0)
e
8
5a (Ph)
9
5a (Ph)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
5a (Ph)
6j, 99% (>20:1:0:0)
6k, 92% (>20:1:0:0)
6l, 99% (>20:1:0:0)
5a (Ph)
5a (Ph)
5a (Ph)
6m, 92% (>20:1:0:0)
6n, 47% (>20:1:0:0)
6o, 92% (>20:1:0:0)
6p, 98% (>20:1:0:0)
6q, 98% (2.5:1:0:0)
5a (Ph)
5a (Ph)
outcomes. This allowed the reproducible formation of coupling
product 6a in 94% yield and >20:1:0:0 dr (Scheme 2b).15 The
procedure was scaled up to 1 g of 6a with even higher yield of
99% and excellent dr (Table 1, entry 1). The absolute
configuration of 6a was assigned to be (2R,3R,RS) based on
analysis of its desilylation product.16
Excess amounts of silyllithium and α-ketoamide (2.0−3.0
equiv) are necessary for achieving high yield. Control
experiments suggested that the undesired reduction of α-
ketoamide occurs in the presence of PhMe2SiLi: quenching the
reaction of 1 and 5a with aqueous solutions led to a mixture of
addition/silyl migration product 7 and reduction product 8 in
ratios of 1.2:1−1:1 (Scheme 2c).17
5a (Ph)
5a (Ph)
e
5a (Ph)
6r, 83% (2:1:0:0)
5a (Ph)
3s (2-pyridine)
3a (4-BrC6H4)
3a (4-BrC6H4)
3a (4-BrC6H4)
6s, 87% (4:1:1:0)
5b (4-MeC6H4)
5c (4-tBuC6H4)
5d (3-MeC6H4)
6t, 91% (>20:1:0:0)
6u, 98% (>20:1:0:0)
6v, 99% (>20:1:0:0)
6w, 98% (>20:1:0:0)
6x, 89% (11:1:0:0)
5e (3,4-Me2C6H3) 3a (4-BrC6H4)
5f (4-MeOC6H4) 3a (4-BrC6H4)
5g (3-MeO C6H4) 3a (4-BrC6H4)
e
6y, 79% (15:1:0:0)
5h (2-naphthyl)
5i (2-thienyl)
5a (Ph)
3a (4-BrC6H4)
3a (4-BrC6H4)
3a (4-BrC6H4)
6z, 96% (>20:1:0:0)
6zz, 99% (>20:1:0:0)
f
6a′, 99% (>20:1:0:0)
a
Next, we assessed the suitability of various aryl imines and
aryl α-ketoamides in this three-component coupling reaction
(Table 1). Aryl imines bearing electron-rich, -poor, and -neutral
substituents reacted smoothly, yielding the desired products in
high yields and with excellent diastereocontrol in most cases.
Aryl imines functionalized at the ortho-, meta-, and para-
positions were well tolerated. Imines derived from hetero-
aromatic 2-carboxaldehydes provided the corresponding α-
hydroxy-β-amino amides 6q−s in good total yields, albeit with
diminished dr values (entries 17−19). Imines derived from
enolizable or nonenolizable aliphatic aldehydes such as EtCHO,
BnCHO, and t-BuCHO did not react, leaving the imines intact.
Several electron-rich aryl α-ketoamides 5b−h participated in
the cascade transformations (entries 20−27), while other aryl
α-ketoamides 5 did not (Ar = 4-FC6H4, 4-ClC6H4, 4-BrC6H4,
4-CNC6H4, 2-MeC6H4, 1-naphthyl, 2-pyridyl, trans-PhCH
CH). In the latter case, silyllithium 1 reacted with the α-
ketoamides 5 to give complex mixtures of uncharacterized
products, and most of the imine was recovered. Using
enolizable piperidine pyruvamide gave no detectable three-
component coupling product; instead, silyllithium-initiated
pinacol homocoupling of this α-ketoamide predominated.
Like PhMe2SiLi, the silyllithium reagent Ph2MeSiLi18 initiated
the coupling reaction, giving the desired product in high yield
and excellent dr (entry 28).
PhMe2SiLi (0.60 mmol), ketoamide (0.60 mmol), and imine (0.20
mmol) in anhydrous THF under argon at −70 °C unless otherwise
b
c
1
noted. Isolated yield. Ratios were determined by H NMR analysis
d
of crude reaction mixtures. 2.0 mmol scale (1.28 g scale in the case of
e
6a). Product and α-hydroxyamide 8 were inseparable, necessitating
silylation of the resulting mixture (using Et3SiCl/imidazole/DMAP/
f
CH2Cl2), followed by column chromatography. Ph2MeSiLi was used.
Purifying products 6g, 6h, or 6r via silica gel column
chromatography proved impossible because their Rf values are
identical to those of α-hydroxy amide 8. We managed to
achieve complete removal of 8 by using Et3SiCl/imidazole/
DMAP/CH2Cl2 to silylate it in the mixture obtained from the
first column chromatography, after which we performed a
second column chromatography. Purifying 6y required the
same procedure.
We propose the following mechanism for the three-
component coupling (Scheme 3): addition of silyllithium
reagents to α-ketoamides and subsequent 1,2-Brook rearrange-
ment generate the α-silyloxy (Z)-enolates19 10, which are
trapped by (E)-(RS)-tert-butanesulfinylimines 3 via a well-
known Ellman’s chairlike 6/4-membered bicyclic transition
state20 TS-1 to afford the (2R,3R,RS)-products. We also
envisioned the possibility of a nonbonding transition state
TS-2, in which nonbonding interactions among the t-BS group
B
DOI: 10.1021/acs.orglett.6b00006
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Organic Letters
Letter
Scheme 3. Plausible Models of Stereoselection and a Control
Experiment
Scheme 4. Trapping Reactive Intermediates via Methylation,
Acylation, and Aldol Reactions
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00006.
Experimental details and characterization data of all new
compounds (PDF)
of the imine and the silyloxy and amide groups of the enolate
are minimized. In the case of TS-2, imine attack on the Si face
predominates to avoid repulsion between the enolate and tert-
butyl groups of t-BS. A control experiment supports the
rationality of TS-2: the same diastereomer 6a was obtained in
high yield with excellent dr with or without the addition of
excess HMPA to solvate lithium cations in the reaction of 1 and
5a before addition of imine 3a to the reaction mixture (Scheme
2b). Although the proposed transition-state models can explain
the observed stereochemical outcomes, why the α-ketoester 2 is
associated with such poor diastereocontrol (Scheme 2a)
remains unclear.21
Finally, we examined the feasibility of using other electro-
philes to trap the reactive intermediate generated from the
reaction of silyllithium and α-ketoamide. We succeeded in
methylating the intermediate using MeOTf, acylating it using
BzCl, and causing it to undergo aldol coupling with 4-
ClC6H4CHO, all in high yield (Scheme 4). Diastereoselectivity
was only moderate in the aldol process.
In conclusion, we have developed an efficient method for
synthesizing enantioenriched α,α-disubstituted α-hydroxy-β-
amino acid derivatives via three-component coupling of
silyllithiums, α-ketoamides, and chiral t-BS-imines. Use of α-
ketoamides ensures high diastereocontrol. These nucleophilic
silyl group-triggered reductive couplings of two electrophiles
proceed in good yield with high diastereoselectivity, allowing
the placement of a silyl group on the oxygen atom of the keto
group of α-ketoamides via an addition/1,2-silyl migration
cascade.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: clu@ms.xjb.ac.cn.
*E-mail: xuyj@ms.xjb.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21572262, U1403301, and 21372255),
the YCSTTC Project of Xinjiang Uygur Autonomous Region
(2013711017), the Recruitment Program of Global Experts
(Xinjiang Program), and the Director Foundation of XTIPC
(2015RC014). Z.S. is grateful for support from The Graduate
Innovation Projects of Changji University (2015YJSYB05).
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DOI: 10.1021/acs.orglett.6b00006
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Organic Letters
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