Efficient synthesis of α-quaternary α-hydroxy-β-amino esters via silyl glyoxylate-mediated three-component reactions

Article abstract of DOI:10.1021/ol403388w

An efficient method has been developed for the enantioselective synthesis of fully protected α-quaternary α-hydroxy-β-amino esters via the coupling of three components: aryl Grignard reagents (or methyllithium), silyl glyoxylate, and N-tert-butanesulfinyl imines. This protocol enables successive formation of two C-C bonds and two adjacent chiral carbons with high stereocontrol in a one-pot operation.

Full text of DOI:10.1021/ol403388w

Letter
pubs.acs.org/OrgLett
Efficient Synthesis of α‑Quaternary α‑Hydroxy-β-amino Esters via
Silyl Glyoxylate-Mediated Three-Component Reactions
Jiu-Long Jiang, Ming Yao, and Chong-Dao Lu*
The Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics & Chemistry, Chinese
Academy of Sciences, Urumqi 830011, China, and University of the Chinese Academy of Sciences, China
S
* Supporting Information
ABSTRACT: An efficient method has been developed for the
enantioselective synthesis of fully protected α-quaternary α-
hydroxy-β-amino esters via the coupling of three components:
aryl Grignard reagents (or methyllithium), silyl glyoxylate, and
N-tert-butanesulfinyl imines. This protocol enables successive
formation of two C−C bonds and two adjacent chiral carbons
with high stereocontrol in a one-pot operation.
α-Hydroxy-β-amino acids and their congeners are important
building blocks in natural products and biologically active
agents.1 Representative examples are taxoid-based anticancer
agents, such as paclitaxel (Taxol), docetaxel, and cabazitaxel, all
of which carry (2R, 3S)-3-phenylisoserine on C-13.2 The
success of these anticancer agents has stimulated tremendous
efforts to develop efficient methods to synthesize this side
chain.3 In addition, preliminary SAR studies of taxoids with
structurally different side chains suggest that installing a methyl
group at the 2-position on the side chain without changing its
absolute configuration of (2R, 3S) enhances cytotoxic activity.4
General and straightforward methods for enantioselective
synthesis of β-amino acids derivatives bearing an α-tertiary
carbinol center are relatively scarce.5−7 Nevertheless, Hu and
co-workers recently described an impressive synthetic protocol
using Rh2(OAc)4-catalyzed three-component coupling of diazo
compounds, alcohols, and imines.8 This approach can be used
to construct enantioenriched syn-α-aryl-α-hydroxy-β-amino
esters in the presence of a catalytic amount of chiral phosphoric
acid with high enantioselectivity (Scheme 1, pathway A). As
part of our continuing investigations into multicomponent
transformations,9 we have developed an analogous synthetic
method for constructing α-quaternary α-hydroxy-β-amino
esters in which the three components that undergo coupling
are aryl Grignard reagents 1 (or methyllithium 4), silyl
glyoxylate 2, and N-tert-butanesulfinyl imine 3 (Scheme 1,
pathway B).10
Scheme 1. Three-Component Reactions to Construct α-
Tertiary α-Hydroxy β-Amino Esters
N-tert-butanesulfinyl aldimine 39a have proven to be good
electrophilic trapping reagents in three-component couplings in
the presence of lithium aza-enolates.13 We speculated that
suitable organometallic reagents might also initiate similar
transformations that would efficiently generate α-quaternary α-
hydroxy-β-amino esters.
We began our investigation by employing phenylmagnesium
bromide 1a as a nucleophilic initiator to react with silyl
glyoxylate 2 and (RS)-N-tert-butanesulfinyl aldimine 3a (Table
1, entry 1). To our delight, treating 2 with 1a and 3a at −78 °C
gave the expected, fully protected α-phenyl α-hydroxy-β-amino
ester 4a with excellent diastereoselectivity (dr >20:1:0:0) and
moderate yield (70%). The moderate yield was due to
incomplete conversion of tBS-imine 3a. This problem was
overcome by introducing 3.0 equiv of boron trifluoride etherate
The compound tert-butyl 2-(tert-butyldimethylsilyl)-2-oxoa-
cetate 2, a member of the family of silyl glyoxylates known for
their usefulness as conjunctive reagents,11 works effectively as a
linchpin reagent in the coupling of nucleophiles and electro-
philes at a glycolic acid junction. This coupling has allowed the
synthesis of a range of α,α-disubstituted glycolic acid
derivatives.12 The success of these silyl glyoxylate-mediated
coupling reactions sometimes requires careful selection of
coupling partners.9a,12d,h For example, activated imines such as
Received: November 21, 2013
Published: December 5, 2013
© 2013 American Chemical Society
318
dx.doi.org/10.1021/ol403388w | Org. Lett. 2014, 16, 318−321

Organic Letters
Letter
with 2 and 3a proceeded smoothly at −78 °C and led to a
mixture of two inseparable diastereomers (4o, dr = 5.5:1:0:0) in
96% yield. When methyllithium was used to initiate the three-
component reaction (Table 2, entry 1), coupling product 6a
Table 1. Synthesis of α-Aryl-α-hydroxy-β-amino Esters via
Three-Component Coupling
a
Table 2. Synthesis of α-Methyl-α-hydroxy-β-amino Esters via
a
Three-Component Coupling
b
entry
1 (Ar)
1a (Ph)
3 (R)
products yield (%)
c
1
3a (4-BrC6H4)
3b (2-BrC6H4)
3c (3-BrC6H4)
3d (4-MeOC6H4)
3e (Ph)
4a
4b
4c
4d
4e
4f
98 (91)
67
2
1a (Ph)
3
1a (Ph)
73
b
c
entry
3 (RL, RS)
products
yield (%)
dr
4
1a (Ph)
61
5
1a (Ph)
82
1
2
3
3a (4-BrC6H4, H)
3b (2-BrC6H4, H)
3c (3-BrC6H4, H)
3e (Ph, H)
6a
6b
6c
6d
6e
6f
92
71
55
90
75
61
81
41
89
89
87
>20:1:0:0
>20:1:0:0
>20:1:0:0
>20:1:0:0
>20:1:0:0
>20:1:0:0
15:1:0:0
6
1a (Ph)
3f (2-thienyl)
3g (trans-PhCHCH)
3h (trans-MeCHCH)
3i (Et)
93
7
1a (Ph)
4g
4h
4i
85
8
1a (Ph)
82
d
4
9
1a (Ph)
76
5
6
7
8
3k (4-MeC6H4, H)
3l (2-furyl, H)
10
11
12
13
1a (Ph)
3j (i-Pr)
4j
45
1b (2-naphthyl)
1c (4-FC6H4)
3a (4-BrC6H4)
3a (4-BrC6H4)
3a (4-BrC6H4)
4k
4l
70
3m (3-pyridine, H)
3i (Et)
6g
6h
6i
d
63 (98)
69
>20:1:0:0
>20:1:0:0
>20:1:0:0
>20:1:0:0
1d (4-
Me2NC6H4)
4m
e
9
3n (Ph, Me)
e
10
3o (4-BrC6H4, Me)
3p (4-MeOC6H4, Me)
6j
14
1e (cyclohexyl)
3a (4-BrC6H4)
4n
67
11
6k
a
All reactions were carried out in THF with 3.05 equiv of 1 and 3.0
a
All reactions were carried out in THF with 2.1 equiv of 5 and 2.0
equiv of 2 unless otherwise noted; see the Supporting Information for
equiv of 2 at −78 °C unless otherwise noted; see the Supporting
1
Information for details. The dr was determined by H NMR of the
b
c
b
details. Isolated yield after silica gel chromatography. Determined by
crude reaction mixture. Isolated yield after silica gel chromatography.
d
1H NMR spectroscopy of the crude reaction mixture. 3.0 equiv of 5
c
d
1 g scale reaction. 5.0 equiv of 1c and 5.0 equiv of 2 were used.
e
and 3.0 equiv of 2 were used. 2.5 equiv of 5 and 2.5 equiv of 2 were
used.
in the reaction, which increased the isolated yield of 4a to 98%
without reducing the dr.14 Using these optimized reaction
conditions, we scaled up the reaction to 1 g and obtained a 91%
yield. Notably, performing the reaction at temperatures above
−20 °C in the absence of boron trifluoride etherate reduced the
dr. In fact, adding the imine 3a to the reaction at −78 °C and
then quickly warming the mixture to room temperature led to
inversion of diastereoselectivity (dr = 1:4:0:0). The reason for
the observed inverted diastereoselectivity is unclear.
Studies of the scope of this three-component coupling
reaction (Table 1) revealed that tBS-imines derived from
various aryl aldehydes (entries 1−6), α,β-unsaturated aldehydes
(entries 7 and 8), or unbranched and branched alkyl aldehydes
(entries 9 and 10) can couple with 1a and 2 to furnish the
desired products 4a−h in yields of 45−98%. However, attempts
to extend this method to acetophenone-derived tBS-imines
were unsuccessful. In addition to phenylmagnesium bromide
1a, other aryl Grignard reagents 1b−d and cyclohexylmagne-
sium bromide 1e were well tolerated under the reaction
conditions, allowing easy generation of diverse substitutions at
the 2-position in product 4 (Table 1, entries 11 and 13).
Phenyllithium, on the other hand, did not react as desired in
this coupling protocol, giving rise to an uncharacterizable
complex. In the particular case of synthesizing 4l (entry 12),
increasing the amount of 1c and 2 from 3.0 to 5.0 equiv
improved the yield from 63% to 98%. In all reactions in Table
1, only one diastereomer was observed (dr >20:1:0:0). The
absolute configuration of compound 4e was established to be
(2R, 3R, RS) by single-crystal X-ray analysis.15 The config-
uration of the other products was assigned by analogy.
was generated in 92% yield with excellent diastereoselectivity.16
The absolute stereochemistry of 6a was assigned to be (2R, 3S,
RS) by single-crystal X-ray analysis of its desilylation product
7,15 which differed from that of 4o.
We were able to extend the methyllithium-initiated cascade
transformation to several different tBS-imines bearing a variety
of aryl and heteroaryl substituents (Table 2, entries 1−7). In
particular, the fully protected (2R, 3S)-α-methyl-α-hydroxy-β-
amino ester 6d (entry 4) should be an appropriate precursor
for the side chain of 2′-methyl-taxoids.4 Linear alkyl tBS-imine
3i participated in the coupling reaction to give a relatively low
yield of product with excellent diastereoselectivity (entry 8).
Using tBS-imines derived from acetophenones (entries 9−11)
led to α-hydroxy-β-amino esters possessing vicinal stereogenic
quaternary carbon centers in good yields with excellent
diastereocontrol (dr >20:1:0:0). Rather than with methyl
lithium, a similar coupling reaction could not be initiated by
lithium hydride even at elevated temperatures. Instead, the
starting materials 2 and 3a were intact. Attempts to extend the
described coupling reaction to a sterically hindered lithium
reagent (tBuLi) were unsuccessful. In this case, no three-
component coupling products were obtained.
The stereochemical outcome for product 4 was consistent
with Ellman’s chelated 6/4-membered bicyclic transition state
TS-1 in the chair conformation17 (Scheme 2). In this pathway,
mixing aryl Grignard reagent 1 with silyl glyoxylate 2 leads to
1,2-silyl migration from carbon to oxygen, preferentially
forming (Z)-glycolate enolate 8.12g The observed stereo-
selectivity of 6 may be rationalized by invoking Aitken’s 6/6
chelated bicyclic chairlike transition state TS-2, or a non-
We then applied this synthetic strategy to the construction of
α-methyl-α-hydroxy-β-amino esters. The reaction of MeMgBr
319
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Organic Letters
Letter
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Scheme 2. Model for Diastereoselection
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In summary, we have developed an efficient protocol for
synthesizing fully protected α-aryl or α-methyl α-hydroxy-β-
amino esters via three-component coupling of aryl Grignard
reagents or methyllithium, tert-butyl 2-TBS-2-oxoacetate, and
N-tert-butanesulfinyl imines. This method allows rapid, highly
stereocontrolled construction of diverse, enantioenriched α-
quaternary α-hydroxy-β-amino esters.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) (a) Yao, M.; Lu, C.-D. Org. Lett. 2011, 13, 2782. (b) Han, X.-J.;
Yao, M.; Lu, C.-D. Org. Lett. 2012, 14, 2906.
AUTHOR INFORMATION
Corresponding Author
■
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Malinowski, J. T.; Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.;
Steward, K. M. J. Org. Chem. 2012, 77, 4503.
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D. A.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 6170. (b) Nicewicz,
D. A.; Satterfield, A. D.; Schmitt, D. S.; Johnson, J. S. J. Am. Chem. Soc.
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*E-mail: clu@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 (21172251 and 21372255), the Young
Creative Sci-Tech Talents Cultivation Project of Xinjiang
Uygur Autonomous Region (2013711017), the High-tech
R&D Program of Xinjiang Uygur Autonomous Region
(201110111), and the Chinese Academy of Sciences.
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