Highly diastereoselective indium-mediated allenylation of N-tert-butanesulfinyl imino ester: Efficient synthesis of optically active α-allenylglycines

Article abstract of DOI:10.1002/adsc.201000688

An efficient and practical asymmetric synthesis of highly enantiomerically enriched α-allenylglycines by room temperature indium-mediated allenylation of chiral N-tert-butanesulfinyl imino esters with propargylic halides is described. The synthetic utilit

Full text of DOI:10.1002/adsc.201000688

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DOI: 10.1002/adsc.201000688
Highly Diastereoselective Indium-Mediated Allenylation of N-
tert-Butanesulfinyl Imino Ester: Efficient Synthesis of Optically
Active a-Allenylglycines
Shen-Shuang Jina and Ming-Hua Xua,*
a
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, Peopleꢀs
Republic of China
Fax : (+86)-21-5080-7388; e-mail: xumh@mail.shcnc.ac.cn
Received: September 6, 2010; Revised: November 6, 2010; Published online: December 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000688.
Abstract: An efficient and practical asymmetric
synthesis of highly enantiomerically enriched a-alle-
nylglycines by room temperature indium-mediated
allenylation of chiral N-tert-butanesulfinyl imino
esters with propargylic halides is described. The
synthetic utilities of the approach were demonstrat-
ed by the rapid and convenient preparation of chal-
lenging cis-substituted proline derivatives.
allene functionality.[3] Despite considerable efforts,[4]
however, successful asymmetric syntheses of a-alle-
nylglycines remain scarce. The three reported asym-
metric approaches to access these compounds include
allenyl transfer of allenyltriphenyltin,[5a] copper/chiral
diphosphine-catalyzed allenyltributyltin addition,[5b]
and diastereoselective bislactim ether homocuprate-
based coupling.[5c] Nevertheless, these methods gener-
ally have low reaction efficiencies and suffer from
clear drawbacks, including limited availability of alle-
nyltins,[5a,b] tedious pre-generation of less stable homo-
cuprates[5c] as well as inevitable competitive propargy-
lation.[5b,c] Herein, we present a highly efficient asym-
metric approach that allows for the rapid and practi-
cal preparation of a wide range of optically active a-
allenylglycines under extremely mild conditions.
Keywords: allenylation; a-allenylglycine; N-tert-bu-
tanesulfinyl imino ester; indium; cis-substituted
proline
In recent years, optically active non-proteinogenic a-
N-tert-Butanesulfinyl imines have recently shown
amino acids have attracted a great deal of attention versatile applications in the asymmetric synthesis of
among scientists due to their significant applications various chiral amines.[6,7] In our previous work,[7h–l] we
in the elaboration of peptides and proteins and syn- demonstrated that the reactions of N-tert-butanesul-
thesis of structurally relevant natural and unnatural finyl imines with in situ formed simple or substituted
products.[1] Among the various amino acids devel- allylmetal reagents promoted by zinc or indium could
oped, the a-allenylglycines represent a particularly in- conveniently lead to the highly diastereoselective syn-
teresting class of compounds containing a unique thesis of various chiral homoallyic amines. Given
allene group with adjacent perpendicular p-orbitals. these successful developments, we became intrigued
Besides the potential biological activities,[2] allenyl- by the possibility of asymmetric allenylation of prop-
ACHTUNGTRENNUNGamino acids should be potentially useful for the con- argylmetal reagents to N-tert-butanesulfinyl imino
struction of a wide range of complex molecules be- esters for the synthesis of the valuable allenylamino
cause of the remarkable synthetic versatility of the acids (Scheme 1).
Scheme 1. Synthetic proposal.
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Adv. Synth. Catal. 2010, 352, 3136 – 3140

Highly Diastereoselective Indium-Mediated Allenylation of N-tert-Butanesulfinyl Imino Ester
Table 1. Screening and optimization of the reaction conditions.[a]
Entry
Metal
X
Solvent
Additive
Yield [%][b]
de [%][c]
1
2
3
4
5
6
7
8
In
In
In
In
In
In
In
In
In
In
Zn
Br
Br
Br
Br
Br
Br
Br
Br
I
THF
–
–
–
–
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF
38
83
59
56
77
80
94
89
92
22
98
98
98
98
96
97
98
96
96
75
CuI
CuCl
CuBr
LiI
ZnI2
NaI
–
9
10
11
I
Br
–
NaI
THF/H2O
[a]
Reaction was carried out with 0.2 mmol of 1, 0.6 mmol of 2, 0.8 mmol of additives and 1.2 mmol of In or Zn in 4 mL of
solvent at room temperature.
Isolated yield.
[b]
[c]
The de was measured as enantiomeric excess for the acetate derivative of 3a after the removal of the sulfinyl group; de-
termined by chiral HPLC analysis.
Initial reaction development and optimization was
With the optimal conditions established, we sought
performed with (S)-N-tert-butanesulfinyl imino ester 1 to explore the reaction generality. As indicated in
and readily available (3-bromoprop-1-ynyl)benzene Table 2, a variety of propargylic bromides with di-
(2a) mediated by indium.[8] The results are summar- verse steric and electronic properties were examined
ized in Table 1. Although the imino ester 1 failed to in reactions with (S)-N-tert-butanesulfinyl imino ester
react with propargylic bromide 2a in anhydrous THF 1 at room temperature.[10] To our delight, all reactions
at room temperature (entry 1), we were pleased to went smoothly, giving the corresponding a-allenylgly-
notice that the reaction in a 1: 1 solution mixture of cine products in good yields with excellent diastereo-
water and THF resulted in the desired allenylation selectivities (95–99%). It appeared that the substitut-
product in 38% yield with an exciting 98% de ed position and electronic properties of the substitu-
(entry 2). Interestingly, when CuI was used as addi- ent on the phenyl ring of aromatic propargyl bro-
tive, the reaction proceeded smoothly and led to a sig- mides did not affect the stereoselectivity of the reac-
nificantly increased yield (83%) while maintaining the tion (entries 1–9). For aliphatic substrates, it should
excellent diastereoselectivity (98% de) (entry 3). be noted that the minor formation of propargylation
After extensive screening of additives, we found that products in all cases was detected,[11] but the high dia-
the best result was accomplished in the presence of stereoselectivity was not influenced significantly (en-
NaI in THF/H2O (1:1) at room temperature for 4 h tries 10–13). When TMS-substituted propargyl bro-
(94% yield, 98% de) (entry 8), other salts such as mide was subjected to the reaction, a maximum of
CuCl, CuBr, LiI and ZnI2 proved to be less effective 16% of propargylamino acid was isolated (entry 13).
(entries 4–7). Use of iodide additives is important to
While the reactions are efficient to produce a-alle-
obtain higher yields, it is likely that the iodide anion nylamino acid products, we next turned our attention
in aqueous solution will displace bromide in 2a to to the synthetic applicability of these compounds. It
produce a propargylic iodide in situ, thus facilitating has been well known that transition metal-mediated
the formation of reactive propargylindium.[9] Such an cyclizations of functionalized allenes are useful meth-
assumption was proved by the comparable result ob- ods for the construction of carbocycles and heterocy-
tained from the direct use of iodide 2a’ in the same cles.[12] We therefore tested the feasibility of employ-
reaction (entries 9 and 10). We also attempted the re- ing this strategy. As illustrated in Scheme 2, 3a was
action mediated by zinc under optimal conditions, but used as the starting material to access optically active
both yield and de declined sharply (entry 11).
3- and 3,4-substituted proline derivatives via a simple
reaction sequence. The key step for constructing pyr-
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asc.wiley-vch.de
3137

Shen-Shuang Jin and Ming-Hua Xu
COMMUNICATIONS
highly diastereoselective way.[14] Substituted proline
derivatives are of great interest because of their con-
siderable application in asymmetric synthesis and
drug discovery.[15] To the best of our knowledge, the
preparation of thermodynamically less stable cis-iso-
mers is a challenging topic.[15b] The absolute configu-
ration of the resulting 3-phenylproline product 9 was
determined to be (S,S) by X-ray crystallographic anal-
ysis of the corresponding N-4-bromophenylsulfonyl
derivative 11[16] (Figure 1).
Table 2. In-mediated allenylation of N-tert-butanesulfinyl
imino ester.[a]
Entry
2
R
3
Yield de
[%][b] [%][c]
Based on the observed diastereofacial selectivity, a
plausible five-membered chelation transition state
model for this asymmetric allenylation is depicted in
Figure 2 (TS-1), in which the uncoordinated N-sulfinyl
group adopts an approximate syn-periplanar configu-
ration.[17] Because of the bulky tert-butyl group, the al-
lenyl adds to the sterically less hindered Si-face of the
C=N bond, thus facilitating the formation of the cor-
1
2
3
4
5
6
7
8
2a C6H5
3a 94
3b 85
3c 83
3d 87
3e 80
3f 90
3g 87
3h 84
86
98
97
98
99
99
99
98
98
98
98
97
98
95
2b 2-MeC6H4
2c 3-MeC6H4
2d 4-MeC6H4
2e 4-MeOC6H4
2f 4-t-BuC6H4
2g 4-ClC6H4
2h 4-BrC6H4
9
2i
2j
6-methoxynaphthalen-2-yl 3i
n-butyl 3j
3k 68
3l 69
3m 54
10
11
12
13
84
2k cyclohexyl
2l
2m TMS
cyclohexylmethyl
[a]
Reactions were carried out with 0.2 mmol of 1, 0.6 mmol
of 2, 0.8 mmol of NaI and 1.2 mmol of indium in 4 mL of
solvent at room temperature.
[b]
[c]
Isolated yield.
The de was measured as enantiomeric excess for the ace-
tate or benzoate derivative of 3a after the removal of the
sulfinyl group; determined by chiral HPLC analysis, see
Supporting Information for details.
rolines 5 and 7 relies on PdCl2- and AgBF4-mediated
cyclization of N-sulfonylated aminoallene 4,[13] respec-
tively, without lose of enantioselectivity. Notably, hy-
drogenation of compounds 5 and 7 over Pd/C provid-
ed all cis-substituted proline products 9 and 10 in a Figure 1. X-ray structure of compound 11.
Scheme 2. Synthetic appliability of allenylamino acids.
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Highly Diastereoselective Indium-Mediated Allenylation of N-tert-Butanesulfinyl Imino Ester
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Experimental Section
General Procedure for Allenylation of Chiral N-tert-
Butanesulfinylimino Ester
To
a solution of (S)-N-tert-butanesulfinylimino ester 1
(41 mg, 0.2 mmol) and propargylic bromide 2 (0.6 mmol) in
THF (2 mL) was added indium powder (138 mg, 1.2 mmol),
NaI (120 mg, 0.8 mmol) and H2O (2 mL) at room tempera-
ture. The mixture was protected from light by aluminum foil
wrapped around the flask. The reaction was stirred at room
temperature for about 4 h, until starting material 1 had been
completely consumed as monitored by TLC. Then the resul-
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cake was washed with ethyl acetate several times. The or-
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flash column chromatography to afford the desired allenyla-
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Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (20721003), the Chinese Academy of Sciences,
the State key Laboratory of Drug Research, SIMM and Na-
tional Science & Technology Major Project (2009ZX09301-
001, 2008ZX09401-004) is acknowledged.
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Adv. Synth. Catal. 2010, 352, 3136 – 3140