A stereocontrolled synthetic route to anti-β-amino alcohols

Article abstract of DOI:10.1016/S0040-4039(01)01611-2

A physiologically indispensable β-amino hydroxy functionality has been constructed with complete anti-stereoselectivity by intramolecular iodoamidation of (Z)-olefinic homoallylic trichloroacetimidates 4-6, 18, 20, 30 and 32, which comprise bulky substituents at the vinylic positions.

Full text of DOI:10.1016/S0040-4039(01)01611-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7599–7603
A stereocontrolled synthetic route to anti-b-amino alcohols
Sung Ho Kang,a,* Yu Sang Hwanga and Joo-Hack Younb
aDepartment of Chemistry, School of Molecular Science (BK21), Korea Advanced Institute of Science and Technology,
Taejon 305-701, South Korea
bDepartment of Chemical Engineering, Sun Moon University, Asan Si, Chung-Nam 336-840, South Korea
Received 25 July 2001; revised 27 August 2001; accepted 31 August 2001
Abstract—A physiologically indispensable b-amino hydroxy functionality has been constructed with complete anti-stereoselectivity
by intramolecular iodoamidation of (Z)-olefinic homoallylic trichloroacetimidates 4–6, 18, 20, 30 and 32, which comprise bulky
substituents at the vinylic positions. © 2001 Elsevier Science Ltd. All rights reserved.
A plethora of pharmaceutically and biologically valu-
able compounds comprise 1,2-amino hydroxy func-
tional groups. The substances are usually involved in
exhibiting a variety of biological activities. The repre-
sentatives are the glycosidase inhibitors (−)-swain-
sonine,1 (+)-castanospermine2 and azasugars,3 and
(−)-statine as the key constituent of the aspartic
protease inhibitor pepstatin.4 In addition, others
include the neurotrophic agent (+)-lactacystin,5 the
antibiotic (+)-furanomycin,6 the antifungal agent (−)-
anisomycin7 and so forth. The stereoselective installa-
tion of the b-amino hydroxy functionality has been
implemented via the intramolecular Michael addition of
allylic and homoallylic carbamates,8 the halocyclization
of aminoalkenes9 and thiocarbamidates,10 the
organometallic addition reaction and the hetero-Diels–
Alder reaction of a-amino aldehydes,11 the aldol reac-
tion of the chiral oxazolidinones,12 the epoxide opening
reaction with nitrogen nucleophiles,13 the diastereo-
selective hydroxylation of allylic carbamates,14 the
reduction of a-amino ketones,11a,15 and the apposite
functionalization of carbohydrates.16 Remarkably, b-
amino alcohols also have been enantioselectively syn-
thesized by employing chiral catalysts in the amino
hydroxylation,17 the nitroaldol reaction,18 the Mannich-
type reaction of aldimines19and the aldol reaction of
b-amino enol ether.20
moted intramolecular amidation of (Z)-olefinic allylic21
and terminal olefinic homoallylic trichloroacetimi-
dates.22 Since it is ideal and complementary to generate
anti-b-amino alcohols diastereoselectively by the same
protocol, we have been engaged in developing the con-
ceived synthetic methodology. In this paper, we
describe a diastereoselective synthesis of anti-b-amino
alcohols via the intramolecular iodoamidation of (Z)-
olefinic homoallylic trichloroacetimidates, which have
bulky substituents at the terminal olefinic positions to
induce the conformational change by introducing A1,3
-
strain. In the involved transition state, it was envisioned
Table 1. Iodoamidation of trichloroacetimidates 1–6
I
TBSO
TBSO
TBSO
I
R
IBr, K2CO3
R
R
+
O
NH
O
N
O
N
EtCN, -78oC
CCl3
1 - 6
CCl3
CCl3
7s - 9s
( syn )
7a - 9a, 10 - 12
( anti )
Entry
R
Substrate
Stereo-
Yield (%)
selectivity
1
2
3
4
5
6
Me
Et
CHMe2
CMe3
TMS
C(OH)Me2
1
2
3
4
5
6
7a:7s=4:1
8a:8s=8:1
9a:9s=11:1 96
10 only
11 only
12 only
88
97
In this context, we established the stereoselective syn-
thesis of syn-b-amino alcohols via the electrophile-pro-
95
98
92
* Corresponding author. Tel.: +82-42-869-2825; fax: 82-42-869-2810;
e-mail: shkang@kaist.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01611-2

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S. H. Kang et al. / Tetrahedron Letters 42 (2001) 7599–7603
mixture of anti- and syn-amino alcohols was produced
from 29 and 31 without any appreciable formation of
seven-membered oxazepines (entries 1 and 3). On the
other hand, only anti-isomers were obtained from 30
and 32 (entries 2 and 4).
that the steric effect between the allylic and the vinylic
substituents would be more predominant than the elec-
tronic effect caused by the eclipsing stabilization23
between the allylic heteroatomic substituent and the
olefinic double bond to dictate the formation of anti-b-
amino alcohols.
While the structures of 30a, 33s and 34 were concluded
by the coupling constant data and NOEs, those of 35a
and 35s were deduced by their chemical conversion into
ent-27 ([h]2D5 −31.3, c 0.5, MeOH) and 27 ([h]2D5 +30.8, c
0.4, MeOH), and also supported by the coupling con-
stant data (Scheme 2). The stereochemistry of 36 was
confirmed by the coupling constant data and NOEs of
37, which was prepared from 36 via reductive
elimination.
Substrates 1–6 with various sizes of substituents at the
vinylic positions were prepared from
D-glyceraldehyde
acetonide in 40–57% overall yields. Iodoamidation of
1–6 was conducted with IBr in the presence of K2CO3
in propionitrile at −78°C. The cyclization reactions
proceeded efficiently as described in Table 1. When the
size of the R group becomes bulkier, the stereoselectiv-
ity increases. The complete anti-stereoselectivity was
observed with the substrates having the tertiary R
groups (entries 4–6). The stereochemistry of products
7–12 was determined by the coupling constant data and
NOE experiments, as summarized in Table 2. On the
other hand, the triol precursory to 6 was treated with
trichloroacetonitrile in the presence of DBU in EtCN
and the resulting bis(imidate) was cyclized under identi-
cal conditions to those in Table 1 to afford anti-b-
amino alcohol 13 in 79% yield along with 14% of
syn-isomer 14 (Fig. 1).
Table 2. The coupling constants and NOEs of 7–12
The other type of substrates which comprise sub-
stituents not only at the vinylic positions but also
homoallylic positions was employed to explore the
iodoamidation because the stereoselectively generated
amino alcohols could be more versatile for further
functionalization. While imidates 17–20 were prepared
from aldehyde 1524 in 57–73% yields, imidates 29–32
were rendered from aldehyde 1625 in 52–75% yields
(Fig. 2). Subjection of 17–20 to iodoamidation was
performed under the aforementioned conditions and
the results are presented in Table 3. While 17 and 19
provided a mixture of anti, syn-b-amino alcohols and
oxazepines in favor of anti-isomers (entries 1 and 3), 18
and 20 gave anti-isomers exclusively (entries 2 and 4).
The structural proof of products 21–24 is explained in
Scheme 1. Since ent-25 ([h]2D5 −14.9, c 0.9, MeOH) could
Compound
J5H, 6Ha (Hz)
Compound
J5H, 6Ha (Hz)
7a
8a
9a
10
11
10.0
11.4
10.4
9.8
12
7s
8s
9s
10.1
1.1
1.5
1.2
10.0
CCl3
CCl3
HN
I
O
N
O
OH
O
OH
N
OCCCl3
NH
I
be procured from
L
-glutamic acid, 21a and 21s were
CCl3
converted into carbamates 25 ([h]2D3 +14.3, c 1.0,
MeOH) and ent-25 ([h]2D5 −14.8, c 0.5, MeOH), respec-
tively, for comparison. Analogous derivatization of
23a, 23s and 23o produced carbamates 27 ([h]2D1 +30.7,
c 0.8, MeOH), ent-27 ([h]2D5 −31.4, c 0.6, MeOH) and
ent-27 ([h]2D5 −30.6, c 0.4, MeOH), respectively. Their
stereochemistry was also assigned by comparing their
[h]D values with that of ent-27 ([h]2D6 −32.3, c 1.1,
14
13
Figure 1.
MeOH) derived from
L-aspartic acid. On the other
OH
OH
hand, the structures of 22, 21o and 24 were determined
by NOE experiments and the coupling constant data of
22, 26 and 28, of which the latter two were derived
from 21o and 24, respectively.
CHO
CHO
O
O
O
O
Ph
Ph
16
15
Intramolecular iodocyclization of 29–32 was also car-
ried out under the described iodoamidation conditions
and the experimental data are shown in Table 4. A
Figure 2.

S. H. Kang et al. / Tetrahedron Letters 42 (2001) 7599–7603
7601
Table 3. Iodoamidation of trichloroacetimidates 17–20
CCl3
NH
CCl3
N
CCl3
N
CCl3
lBr
K2CO3
N
O
O
O
O
R
+
I
I
+
EtCN
-78oC
I
O
O
R
O
O
R
O
O
R
O
O
Ph
Ph
Ph
Ph
21s, 23s
17 - 20
21a, 22, 23a, 24
21o, 23o
(
( syn )
oxazepine )
( anti )
Entry
R
Substrate
Stereoselectivity
Yield (%)
1
2
3
4
(CH2)2OTBDPS
COOEt
CH2OTBDPS
C(OH)Me2
17
18
19
20
21a:21s:21o=6.8:1.8:1
22 only
23a:23s:23o=1.8:1.1:1
24 only
96
64
95
89
Scheme 1. (a) 6N HCl, MeOH, 55°C; (b) Boc2O, NaHCO3, MeOH, 0°C to rt; (c) n-Bu3SnH, Et3B, THF, 0°C; (d) NaIO4, MeOH,
H2O, 0°C, then NaBH4, 0°C; (e) Boc2O, NaOH, H2O, dioxane, rt; (f) CH2N2, Et2O, 0°C; (g) LiBH4, THF, rt; (h) CbzCl,
NaHCO3, MeOH, rt; (i) NaH, THF, 0°C; (j) Ac2O, DMAP, pyridine, rt; (k) TFAA, Et3N, CH2Cl2, 0°C; (l) NaI, DMF, 0°C.
In summary, we have developed a stereoselective syn-
thetic route to anti-b-amino alcohols via the
intramolecular iodoamidation of (Z)-olefinic homo-
allyic trichloroacetimidates, which is complementary to
our previously reported synthesis of syn-b-amino
alcohols.21,22
Acknowledgements
This work was supported by Creative Research Initia-
tives of the Korean Ministry of Science and Technol-
ogy, and the Brain Korea 21 Project.

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S. H. Kang et al. / Tetrahedron Letters 42 (2001) 7599–7603
Table 4. Iodoamidation of trichloroacetimidates 29–32
CCl3
N
5
4
CCl3
CCl3
N
5
4
O
6
O
NH
O
6
IBr, K2CO3
I
I
+
EtCN, -78oC
O
R
O
R
O
O
R
O
O
Ph
Ph
Ph
33a, 34, 35a, 36
33s, 35s
( syn )
29 - 32
( anti )
Entry
R
Substrate
Stereoselectivity
Yield (%)
1
2
3
4
(CH2)2OTBDPS
COOEt
CH2OTBDPS
C(OH)Me2
29
30
31
32
33a:33s=3.8:1
34 only
35a:35s=4.7:1
36 only
95
95
98
96
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