Diastereoselective synthesis of unsaturated 1,2-amino alcohols from α-hydroxy allyl ethers using chlorosulfonyl isocyanate

Article abstract of DOI:10.1016/j.tetlet.2004.12.100

Diastereoselective synthesis of 1,2-amino alcohols was achieved from a highly diastereoselective allylic amination reaction of α-hydroxy allyl ethers using chlorosulfonyl isocyanate. Diastereoselectivities varied depending on the stereochemistry of the ethers used and the stability of the carbocation intermediate obtained during the reaction. We propose that this CSI reaction is the results of either a S_Ni or S_N1 mechanism, according to the stability of the carbocation intermediate.

Full text of DOI:10.1016/j.tetlet.2004.12.100

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1079–1082
Diastereoselective synthesis of unsaturated 1,2-amino alcohols from
a-hydroxy allyl ethers using chlorosulfonyl isocyanate
Ji Duck Kim, In Soo Kim, Jin Cheng Hua, Ok Pyo Zee and Young Hoon Jung*
College of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea
Received 26 August 2004; revised 17 December 2004; accepted 21 December 2004
Available online 8 January 2005
Abstract—Diastereoselective synthesis of 1,2-amino alcohols was achieved from a highly diastereoselective allylic amination reac-
tion of a-hydroxy allyl ethers using chlorosulfonyl isocyanate. Diastereoselectivities varied depending on the stereochemistry of
the ethers used and the stability of the carbocation intermediate obtained during the reaction. We propose that this CSI reaction
is the results of either a SNi or SN1 mechanism, according to the stability of the carbocation intermediate.
Ó 2004 Elsevier Ltd. All rights reserved.
OR3
The stereoselective synthesis of 1,2-amino alcohols has
been the focus of recent studies in the synthetic and
1) CSI, Na2CO3
R1
R2
2) Na2SO3, KOH
industrial fields, because of their important roles in
organic synthesis as fundamental building blocks, and
because of their occurrence in a number of natural
products, drugs and chiral auxiliaries or ligands.1 The
common synthetic routes to these compounds include
the reduction of a-amino acids, a-amino ketones or a-
hydroxy imines,2 the nucleophilic substitution of 1,2-
diols,3 epoxides,4 aziridines,5 cyclic carbonates or cyclic
sulfates,6 the aminohydroxylation or oxymecuration of
olefins,7 the hydroboration of enamines,8 nucleophilic
addition to N-protected a-amino aldehyde9 or to an
O-protected a-hydroxy imine10 and the coupling of car-
banions with imines.11 Many of these procedures have
one or more problems, for example, low stereoselectiv-
ity, limited application and the use of heavy metals.
OPG
NHCOOR3
NHCOOR3
R2
1
R1
R1
R2
+
OPG
OPG
2
3
Scheme 1.
Herein, we describe a new synthetic approach to a
variety of unsaturated 1,2-amino alcohols 5 from the
appropriate stereoisomers, that is, protected syn- and
anti-a-hydroxy allyl ethers 4,13 as an extension of the
CSI reaction,14 and describe how to control diastereo-
selectivity in this reaction (Scheme 2).
Recently we reported a novel regioselective and diaste-
reoselective synthetic approach using the chlorosulfonyl
isocyanate (CSI) reaction for the unsaturated aromatic
1,2-amino alcohols from an epimeric mixture of opti-
cally active allylic ethers having a hydroxyl group at-
tached to an allylic chiral center to the p-system
(Scheme 1).12
Our initial studies examined the diastereoselective
effect of the protecting group of the hydroxyl moiety
in (1S,2S)-2-methoxy-1-phenyl-but-3-ene 4 (R1 = Ph,
R2 = H) as shown in Table 1. The treatment of syn-
TBS protected methyl ether 4a with CSI furnished
syn-1,2-amino alcohol 5a with high diastereoselectivity
1) CSI, Na2CO3
OMe
*
NHCOOMe
CH2Cl2
R1
R1
R2
R2
*
OPG
2) Na2SO3, KOH
OPG
Keywords: 1,2-Amino alchohols; Diastereoselective allylic amination;
Chlorosulfonyl isocyanate.
4
5
*
Corresponding author. Tel.: +8231 290 7711; fax: +8231 290 5403;
e-mail: yhjung@skku.edu
Scheme 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.100

1080
J. D. Kim et al. / Tetrahedron Letters 46 (2005) 1079–1082
Table 1. Conversions of protected a-hydroxy allyl ethers to the corresponding 1,2-amino alcohols
Entries
1
Allyl ethers
OMe
Allylic amines
NHCOOMe
Yield (%), ds ratioa
41, 95:5
OTBS
4a
OTBS
5a
OMe
NHCOOMe
2
3
4
5
6
7
41, 97:3
44, >99
41, >99
76, 93:7
81, >99
89, 1:1.4
OTIPS
OTIPS
4b
5b
OMe
NHCOOMe
OTBS
4c
OTBS
5c
OMe
NHCOOMe
OTIPS
4d
OTIPS
5d
OMe
NHCOOMe
OTBS
4e
OTBS
5e
OMe
NHCOOMe
OTBS
4f
OTBS
5f
OMe
NHCOOMe
NHCOOMe
+
OTBS
OTBS
OTBS
12
4g
5g
6
OMe
NHCOOMe
8
84, >99
34, 94:6
82, 1:1.7
84, 91:9
OTBS
OTBS
5h
4h
OMe
NHCOOMe
9
OTBS
4i
OTBS
5i
OMe
NHCOOMe
NHCOOMe
+
10
11
OTBS
OTBS
OTBS
12
12
8
4j
5j
OMe
NHCOOMe
OTBS
OTBS
4k
5k
All the reactions were carried out at 20 °C, except for entries 7, 8 and 10, 11 (À78 °C). Isolated yield of pure material.
a Based on integrals of OCH3 signals in carbamates.
(95:5) in 41% chemical yield (entry 1). The product (1,4-
amino alcohol) derived from attack at the vinylic posi-
tion was not detected. Using the syn-TIPS protected
methyl ethers 4b, the result was similar to that obtained
in the TBS case (entry 2). The stereochemistry of major
products was confirmed by converting the carbamates
by Bu4NF and NaH treatment in THF at 0 °C, into
the oxazolidinones.12 Moreover, the isomeric anti-pro-
tected methyl ethers 4c and 4d, under the same reaction
conditions, gave anti-1,2-amino alcohols with high dia-

J. D. Kim et al. / Tetrahedron Letters 46 (2005) 1079–1082
1081
stereoselectivity (>99) (entries 3 and 4). Next, we inves-
1) CSI, Na2CO3
CH2Cl2
OMe
tigated the substituent effect on the diastereoselectivity
by varying the alkyl moiety (R1 and R2). The results
are summarized in Table 1. Using the syn- and anti-
TBS protected methyl ethers 4e and 4f, the diastereo-
meric ratios were similar to that obtained in entries 1
and 3, respectively, except the increased chemical yields
(entries 5 and 6). Contrary to previous results, CSI reac-
tion of 4f afforded a 1:1.4 inseparable mixture of syn-1,2-
amino alcohol 5f and the anti-stereoisomer 612 in 89%
chemical yield (entry 7). For anti-ether 4g, anti-1,2-ami-
no alcohol 5g was obtained as a sole product in 84%
yield with high diastereoselectivity (>99) (entry 8). In
the cases of entries 9–11, the results were similar to those
obtained in entries 1–8, except for the formation of 1,4-
amino alcohol, (4S)-methyl N-[4-(tert-butyldimethylsi-
lyloxy)pent-2-enyl]carbamate (7) in 6% chemical yield
from 4i (entry 9) and a reduction in diastereoselectivity
(entry 11).
2) Na2SO3, KOH
9
erythro : threo = 3.9 : 1
NHCOOMe
+
NHCOOMe
11 (9%)
10
erythro : threo = 4.0 : 1
69%
Scheme 3.
From the results of Table 1 and Scheme 3, in the case of
vinyl ethers (R2 = H), the SNi mechanism predominates
to retain the configuration (entries 1–6 and 9 in Table 1)
due to the formation of the less stable carbocation inter-
mediate. These results showed that the protecting group,
the stereochemistry of starting materials, and the pres-
ence of a chiral hydroxyl group have no effect on diaste-
reoselectivity. However, in the case of cinnamyl ethers
(R2 = Ph), the formation of the more stable carbocation
intermediate partially drives this CSI reaction via a SN1
mechanism to produce a competitive SNi/SN1 mecha-
nism. Therefore, in the case of syn-ethers (entries 7
and 10), mixtures of diastereomer were obtained, be-
cause the SNi mechanism afforded the syn-1,2-amino
alcohol and the SN1 mechanism afforded the anti-stereo-
isomer. This anti-selectivity via a SN1 mechanism may
be explained by the Cieplak electronic model during
conversion from ethers to carbamates.12 In the case of
anti-ethers (entries 8 and 11), the anti-stereoisomer was
produced exclusively by both SNi and SN1 mechanisms
(Scheme 5).
Furthermore, in order to determine the role of the pro-
tected hydroxy group, we introduced a methyl moiety
instead of the protected hydroxyl group at the benzylic
position. The reaction of the inseparable methyl ethers
9 (erythro:threo = 3.9 : 1) with CSI produced a 4.0:1
inseparable mixture of the erythro-stereoisomer and
the threo-stereoisomer 10 at a yield of 69% and (4R)-
methyl N-(4-phenylpent-2-enyl)carbamate (11) in 9%
yield (Scheme 3). This result is similar to those shown
in Table 1.
From the above results, we suggest that the CSI reac-
tions might proceed via SNi and/or SN1 mechanisms,
and that the mechanism route depends on the stability
of the carbocation obtained during the reaction. Plausi-
ble reaction pathways are shown in Scheme 4.
Nu
NHCOOMe
R1
H
SNi
R1
R2
R2
OMe
OTBS
OTBS
R1
R2
Nu
OTBS
NHCOOMe
R2
H
SN1
R1
R1
R2
OTBS
OTBS
Nu = ClO2S
N
COOMe
Scheme 4.
12, THF, -78oC
OMe
1)
PGCl, Imidazole
DMF, rt
H
2) H2NCH2CH2CH2OH, 0oC
62%
O
OH
13
OMe
B
OMe
2
12
OPG
4a PG = TBS (92%)
4b PG = TIPS (90%)
Scheme 5.

1082
J. D. Kim et al. / Tetrahedron Letters 46 (2005) 1079–1082
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In conclusion, we developed a novel diastereoselective
synthetic approach to unsaturated 1,2-amino alcohols
from the corresponding a-hydroxy allyl ethers using
the CSI reaction. The diastereoselectivity of this ap-
proach was investigated by varying the alkyl substitu-
ents. Based on these results, we confirm that both the
stereochemistry of the protected hydroxyl moiety and
the stability of the carbocation intermediate affect the
diastereoselectivity. Moreover, our results establish that
the described CSI reaction is a competitive reaction that
proceeds via a SNi and/or a SN1 mechanism, the balance
of which depends on the stability of the carbocation
intermediate.
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Acknowledgements
This work was supported by Korea Research Founda-
tion Grant (KRF-2003-015-E00232).
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Vallee, Y. Angew. Chem., Int. Ed. 2002, 41, 1772; (c)
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2004.
12.100.
13. The preparations of optically active compounds 4 are as
follows: Compounds 4a and 4b were prepared using
Brown methodology15 and protection of the hydroxyl
moiety (Scheme 5) 4c and 4d were prepared from 13 by
Mitsunobu inversion16 and protection of the hydroxyl
moiety. Compounds 4g and 4h were prepared from 4a and
4c by oxidation of the double bond (OsO4, NaIO4, 2,6-
lutidine)17 and by using the HWE reaction18 using diethyl
benzylphosphonate in the presence of NaHMDS, respec-
tively. Preparations of 4e,f,i–k are similar to the above
synthetic methodology.
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