Diastereoselective amination of vinylic sulfoximines: Application to the asymmetric synthesis of functionalized β-substituted and β,β-disubstituted β-amino acids, and of γ-amino alcohols

Article abstract of DOI:10.1016/S0040-4039(00)00307-5

An asymmetric synthesis of protected β-substituted and β,β- disubstituted β-amino acids, which carry a hydroxyalkyl side chain, from sulfonimidoyl functionalized homoallylic alcohols is described. The method allows for an asymmetric synthesis of γ-amino alcohols as well. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00307-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2851–2854
Diastereoselective amination of vinylic sulfoximines: application
to the asymmetric synthesis of functionalized β-substituted and
β,β-disubstituted β-amino acids, and of γ-amino alcohols
Hans-Joachim Gais,∗ Ralf Loo, Parthasarathi Das and Gerhard Raabe
Institut für Organische Chemie der RWTH Aachen, Professor-Pirlet-Straße 1, 52056 Aachen, Germany
Received 2 February 2000; accepted 15 February 2000
Abstract
An asymmetric synthesis of protected β-substituted and β,β-disubstituted β-amino acids, which carry a hy-
droxyalkyl side chain, from sulfonimidoyl functionalized homoallylic alcohols is described. The method allows
for an asymmetric synthesis of γ-amino alcohols as well. © 2000 Elsevier Science Ltd. All rights reserved.
β-Peptides are currently of high interest because of their structure and biological activities.1 Recently,
β,β-disubstituted β-peptides have attracted attention due to novel secondary structures hitherto not
observed for β-peptides.2 Besides the β,β-disubstituted β-peptides, those carrying a hydroxy group in
the side chain would be of particular interest because of the synthesis of glyco-β-peptides as analogs
of glyco-α-peptides which are of high biological relevance.3 Whereas numerous methods exist for the
asymmetric synthesis of β-substituted β-amino acids,4,5 we are aware of only one method giving access
to β,β-disubstituted β-amino acids.5c,5f,6 We now describe a method for the asymmetric synthesis of
β-substituted and β,β-disubstituted β-amino acids of type A5a,5g and B, which carry a hydroxyalkyl
side chain, from sulfonimidoyl functionalized anti-homoallylic alcohols of type C7 and D7 (Scheme
1). The δ-hydroxy β-amino acids A and B may not only serve as starting materials for the synthesis
of β-peptides and their glycosides but also for that of analogs of sperabillin and negamycin which are
peptide-like natural products with interesting biological activities.8 An additional feature of the method
described is that it also provides for an asymmetric synthesis of substituted γ-amino alcohols which have
found much use in the synthesis of biologically active compounds.9
Treatment of the enantio- and diastereopure hydroxy sulfoximines 1a7 and 1b7 with trichloroacetyl
isocyanate followed by the cleavage of the corresponding intermediate N-trichloroacetyl carbamates
with aqueous NH3 gave the carbamates 2a (90%) and 2b (85%),10a respectively (Scheme 2). A similar
successive treatment of the enantio- and diastereopure hydroxy sulfoximine 47 with trichloroacetyl
isocyanate and NH3 furnished the carbamate 5 (94%). Reaction of carbamates 2a and 2b10b with
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00307-5
tetl 16587

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Scheme 1.
nBuLi at low temperatures and warming the reaction mixtures to room temperature led to a smooth
Hirama–Itô11 cyclization to afford, after aqueous work-up, the cyclic carbamates 3a (94%)12 and 3b
(93%),12 respectively, each as a single diastereomer (≥98% de).13,14 A similar cyclization of the β,β-
disubstituted carbamate 5 also proceeded readily and gave after aqueous work-up the bicyclic carbamate
6 (92%)12 as a single diastereomer (≥98% de). The configurations of carbamates 3a, 3b and 6 were
determined by 1H NMR spectroscopy in combination with NOE experiments and X-ray structure analysis
of derivatives thereof (vide infra).
Scheme 2. (i) 1. Cl3CCONCO, THF, 22°C, 2 h; 2. NH3 (aq), 22°C, 10−18 h. (ii) 1. 1.1 equiv. of nBuLi, THF, −78°C→22°C,
10−18 h; 2. H3O+
For the synthesis of amino acids from 3a, 3b and 6 the introduction of a carboxyl group at the α-
position of the sulfonimidoyl group was required. Key to the realization of this transformation was the
observation that the double lithiation of 3a, 3b and 6 with nBuLi proceeded readily to give quantitatively
the dilithium salts Li2-3a, Li2-3b and Li2-6, respectively, being stable at low temperatures in solution.
The reaction of Li2-3a and Li2-6 with ClCOOMe15 gave the ester 7 (66%) as a mixture of dia-
stereomers (84:16) and the ester 9 (70%)12 as a single diastereomer, respectively (Scheme 3). The
configurations of the new stereogenic center of esters 7 and 9 were provisionally assigned as depicted
based on NMR spectroscopic investigations. The conversion of sulfoximines 7 and 9 to the protected
amino acids 8 and 10, respectively, called for a reductive removal of the sulfonimidoyl group, which
was best accomplished with Raney nickel.16 Thus, reaction of 7 and 9 with Raney nickel furnished the
protected β-substituted β-amino acid 8 (90%)12 and the β,β-disubstituted β-amino acid 10 (86%),12
respectively (Scheme 3). The configuration of the ester 10 was established by X-ray structure analysis.17
The above results prompted us to also investigate the synthesis of functionalized γ-amino alcohols
from sulfoximines of type 3a and 6. Thus, reaction of Li2-3a with MeCHO afforded the hydroxy
sulfoximine 11 (67%, 28% de) as a mixture of only two diastereomers which are presumably epimers
in regard to the C atom bearing the hydroxy group. Treatment of Li2-3a with MeI and BnOCH2Cl
furnished with modest diastereoselectivities the substituted sulfoximines 12 (68% de) and 13 (de not

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Scheme 3. (i) 1. 2.2 equiv. of nBuLi, THF, −78°C; 2. ClCO2Me, −78°C, 4 h. (ii) Ra-Ni, THF, H2O, 22°C, 8 h
determined), respectively. The methylation of the dilithium salt Li2-3b with MeI proceeded with a higher
diastereoselectivity and gave the methylated sulfoximine 14 (80% de). Sulfoximines 12–1412 were easily
obtained diastereomerically pure by chromatography in 75%, 70% and 68% yield, respectively, based on
the starting sulfoximines. The configurations of the newly generated stereogenic center of 11–14 were
determined by NOE experiments. This assignment was verified in the case of 12 by X-ray structure
analysis.17 Finally, treatment of 3a, 12 and 6 with Raney nickel under similar conditions as used above
afforded the protected γ-amino alcohols 15 (88%),12 16 (79%)12 and 17 (90%),12 respectively (Scheme
4).
Scheme 4. (i) MeCHO, MeI or BnOCH2Cl, THF, −78°C. (ii) Ra-Ni, THF, H2O, 22°C, 5−18 h
In summary, the sulfoximine route provides for a new access to enantio- and diastereopure β-
substituted and β,β-disubstituted δ-hydroxy β-amino acids and to γ-amino alcohols. The starting
hydroxy sulfoximines are readily available enantio- and diastereopure through hydroxyalkylation of the
corresponding allylic sulfoximines which in turn are easily prepared from (+)- or (−)-N,S-dimethyl-
S-phenylsulfoximine.7 Although in the final reduction step the chirality of the sulfonimidoyl group is
lost, as it is the case in the other route to β,β-disubstituted β-amino acids,5c,5f this disadvantage is
compensated for by the ready accessibility of the enantiopure starting material either from commercial
sources, by catalytic asymmetric synthesis or by an efficient resolution amendable to large scale.18 The
synthesis of acyclic amino acids of type B is now underway in our laboratories.19

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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 11 and Son-
derforschungsbereich 380).
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