Remote chirality control based on the organocatalytic asymmetric Mannich reaction of α-thio acetaldehydes

Article abstract of DOI:10.1039/c3cc47827k

Remote chirality control leading to 1,4-difunctionalized compounds such as 1,4-amino alcohols and 1,4-diamines was achieved by both syn- and anti-selective asymmetric Mannich reactions of α-thio acetaldehydes, the subsequent olefination and the stereospec

Full text of DOI:10.1039/c3cc47827k

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Remote chirality control based on the
organocatalytic asymmetric Mannich reaction
of a-thio acetaldehydes†
Cite this: Chem. Commun., 2014,
50, 942
Received 11th October 2013,
Accepted 11th November 2013
Taichi Kano, Ryu Sakamoto and Keiji Maruoka*
DOI: 10.1039/c3cc47827k
www.rsc.org/chemcomm
Remote chirality control leading to 1,4-difunctionalized compounds
such as 1,4-amino alcohols and 1,4-diamines was achieved by both
syn- and anti-selective asymmetric Mannich reactions of a-thio
acetaldehydes, the subsequent olefination and the stereospecific
2,3-sigmatropic rearrangement.
Remote chirality control such as 1,4-asymmetric induction is not an
easy task in current asymmetric synthesis. In developing such a
synthetic method for the preparation of chiral 1,4-difunctionalized
compounds including 1,4-amino alcohols and 1,4-diamines, we
focused on a new stereoselective approach to chiral 1,2-amino
sulfides, which can be stereospecifically converted to chiral 1,4-
amino alcohols and 1,4-diamines (Scheme 1). Chiral 1,2-amino
sulfides (and 1,2-amino thiols) also constitute important structural
motifs which are found in a broad variety of biologically active
compounds1–4 and chiral catalysts in various asymmetric reac-
Scheme 1 Diastereo- and enantioselective synthesis of 1,4-amino alcohols and
1,4-diamines based on the organocatalytic Mannich reaction of a-thio acetalde-
hydes 1. (a) Organocatalytic asymmetric Mannich reaction. (b) Olefination.
(c) Sulfoxidation or sulfimination. (d) 2,3-Sigmatropic rearrangement.
We first examined the Mannich reaction of (benzylthio)ace-
tions.5,6 Some catalytic asymmetric methods, mostly based on the taldehyde (1a)10 (2 equiv.) with an N-Boc-protected imine 2a
ring-opening of meso-aziridines with thiols and the conjugate (R = Ph) derived from benzaldehyde in the presence of 30 mol%
addition of nitrogen or sulfur nucleophiles to a,b-unsaturated of L-proline. After optimization of the reaction conditions,16
carbonyl compounds, have been developed for the synthesis of the desired syn-Mannich product syn-3a (R = Ph) was obtained
chiral 1,2-amino sulfides.7–9 However, efficient methods for the as
enantio- and diastereoselective synthesis of both syn- and anti-1,2-
amino sulfides from the same set of reactants are scarce, despite
the high synthetic utility.10 We then became interested in the use of
a-thio acetaldehydes 1 (ref. 11) as nucleophiles in the amine-
catalyzed asymmetric Mannich reaction, which can afford both
diastereomers through C–C bond formation (Scheme 1).10,12 The
resulting chiral 1,2-amino sulfides would be applied to the stereo-
selective synthesis of chiral 1,4-amino alcohols and 1,4-diamines
a major diastereomer in excellent enantioselectivity
Table 1 Mannich reaction of a-thio acetaldehyde 1a with imine 2a
through olefination13 and subsequent 2,3-sigmatropic rearrange-
ment14,15 by utilizing the unique property of the sulfide moiety.
Here we wish to report our initial results on this subject.
Entry
R
Yieldb (%)
syn/antic
eed (%)
1e
2
3
Ph
77
80
70
68
64
7.7/1
11/1
13/1
14/1
8.2/1
99
99
99
98
99
4-MeOC6H4
4-ClC6H4
2-MeC6H4
2-Naphthyl
4e
5e
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo,
Kyoto 606-8502, Japan. E-mail: maruoka@kuchem.kyoto-u.ac.jp;
Fax: +81-75-753-4041; Tel: +81-75-753-4041
a
The reaction of 1a (0.375 mmol) with 2 (0.125 mmol) was carried out
in the presence of L-proline (0.0375 mmol) in THF (0.25 mL) at À30 1C
for 24 h. Isolated yield. Determined by 1H NMR analysis. Deter-
b
c
d
† Electronic supplementary information (ESI) available: Experimental details. See
DOI: 10.1039/c3cc47827k
e
mined by HPLC using a chiral column. Isolated as an aldehyde.
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Scheme 2 Deprotection of benzyl thioether 3a.
(Table 1, entry 1). Other imines generally afforded the corresponding
syn-Mannich products in similar yield and stereoselectivity (entries
2–5). The benzyl group on the benzylthio group of Mannich product
3a (syn/anti = >20/1) could be removed under Birch conditions, thus
leading to the corresponding thiol 4 (syn/anti = >20/1) (Scheme 2).
The present method was then applied to the reactions of
(4-methoxyphenylthio)acetaldehyde (1b) and synthetically more
important chiral 1,2-amino sulfides syn-5, which are more
suitable for further transformations, were obtained with high
stereoselectivities (Table 2). The relative and absolute configu-
ration of syn-5 (P = Cbz, R = Ph) was determined by conversion to
the known compound and comparing the optical rotation with
the literature value.16
Scheme 3 Synthesis of 1,4-amino alcohols 8 and 1,4-diamine 9. Reagents
and conditions: (a) RCHX2, CrCl2, DMF, THF, 76% (R = Ph, X = Br), 65% (R = Bn,
X = I), 54% (R = Me, X = I); (b) mCPBA, CH2Cl2; P(OMe)3, MeOH, 70% (R = Ph),
75% (R = Bn); (c) chloramine-T, MeCN; P(OMe)3, MeOH, 95%.
We then studied the stereoselective synthesis of chiral 1,4-amino
alcohols and 1,4-diamines by using the Mannich product 6
(Scheme 3).17,18 Thus, the Mannich product 6 (syn/anti = >20/1)
was converted to the allyl sulfides 7a (syn/anti = 15/1) and 7b
(syn/anti = 16/1) by Takai olefination.13 Subsequent sulfoxida-
tion with mCPBA and treatment with trimethyl phosphite gave
1,4-amino alcohols 8a (syn/anti = 15/1) and 8b (syn/anti = 16/1),
respectively.14 On the other hand, sulfimination of 7c (syn/anti = 16/1)
with chloramine-T19 and treatment with trimethyl phosphite
afforded 1,4-diamine 9 (syn/anti = 16/1) in good yield.15 In these
transformations, neither formation of Z-isomers nor loss of
optical purity was observed.16
When we employed a binaphthyl-based amino sulfonamide
(S)-10 (ref. 20) instead of L-proline as the catalyst, anti-Mannich
product 11 was obtained as a major diastereomer in virtually
perfect enantioselectivity, albeit with moderate yield (Scheme 4).
The observed diastereoselectivity was contrasted sharply with
the syn-selective Mannich reaction catalyzed by proline. The
Scheme 4 anti-Selective Mannich reaction of 1b with 2a.
Scheme 5 Synthesis of 1,4-diamine 13. Reagents and conditions: (a) MeCHI2,
CrCl2, DMF, THF, 65%; (b) chloramine-T, MeCN; P(OMe)3, MeOH, 81%.
Mannich product 11 (anti/syn = 7.9/1) could also be converted to
the corresponding 1,4-diamine 13 (anti/syn = 4.7/1) through allyl
sulfide 12 (anti/syn = 5.2/1) without loss of optical purity (Scheme 5).
When we examined the aldol reaction of 1b (3 equiv.) with
tert-butyl glyoxylate (14) in the presence of 5 mol% of (S)-10 in
Table 2 Mannich reaction of a-thio acetaldehyde 1b with imine 2a
Entry
P
R
Yieldb (%)
syn/antic
eed (%)
1e
2
3
Boc
Boc
Boc
Cbz
Ph
78
67
81
83
>20/1
>20/1
16/1
99
99
99
98
4-MeOC6H4
4-BrC6H4
Ph
4
>20/1
a
The reaction of 1b (0.375 mmol) with 2 (0.125 mmol) was carried out in
the presence of L-proline (0.0375 mmol) in THF (0.25 mL) at À30 1C for
Scheme 6 Synthesis of 1,4-diol 16. Reagents and conditions: (a) (S)-10
(5 mol%), NMP; Ph3P = CHCO2Bn, CHCl3, 74% (syn/anti = 4.6/1), 93% ee
(syn); (b) mCPBA, CH2Cl2; P(OMe)3, MeOH, 73% (syn/anti = 4.6/1).
20 h. Isolated yield. Determined by 1H NMR analysis. Determined by
HPLC using a chiral column. The reaction was performed for 22 h.
b
c
d
e
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anti = 4.6/1) without loss of diastereo- and enantioselectivity.
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and enantioselectivity (syn/anti = 5.7 : 1, 98% ee) but lower yield
(36%) when performed in one pot as compared to the stepwise
method.
944 | Chem. Commun., 2014, 50, 942--944
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