Short synthesis of (+)-1-deoxynojirimycin via a diastereoselective reductive coupling of alkyne and -chiral aldehyde

Article abstract of DOI:10.1055/s-0031-1289546

A short, highly diastereoselective synthesis of (+)-1-deoxynojirimycin from readily available l-isoserine with overall yield of 32.0% in eight steps is described. The key step includes a diastereoselective syn-coupling reaction of Cbz-protected (S)-iso-serinal acetonide 6 and vinylzinc nucleophile, generated conveniently from a protected propargyl alcohol 7 by a hydrozirconation- transmetalation sequence. Significantly, not only does this simple flexible strategy provide a concise approach to (+)-1-deoxynojirimycin, but it also can readily be adopted for the synthesis of other stereoisomers of the 1-deoxynojirimycin family from l- or d-iso-serine through different coupling conditions and stereoselective -epoxidation of allylic alcohol 4 by the same procedures. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289546

LETTER
2709
Short Synthesis of (+)-1-Deoxynojirimycin via a Diastereoselective Reductive
Coupling of Alkyne and a-Chiral Aldehyde
S
hor
t
Synthesis
o
i
f
(+)-1
n
-
Deoxynojiri
g
mycin Zhou, Huanyu Tang, Huijin Feng, Yuanchao Li*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, 555 Zu Chong Zhi Road,
Shanghai 201203, P. R. of China
Fax +86(21)50807288; E-mail: ycli@mail.shcnc.ac.cn
Received 24 July 2011
We reasoned that 1 can be obtained by a regio- and stereo-
Abstract: A short, highly diastereoselective synthesis of (+)-1-
selective opening of epoxide 3 which can be synthesized
from the allylic alcohol 4, itself being expected to derive
from the key intermediate 5 (Scheme 1). We envisioned
deoxynojirimycin from readily available L-isoserine with overall
yield of 32.0% in eight steps is described. The key step includes a
diastereoselective syn-coupling reaction of Cbz-protected (S)-iso-
serinal acetonide 6 and vinylzinc nucleophile, generated conve- that the highly functionalized intermediate 5 could be ob-
niently from a protected propargyl alcohol 7 by a hydrozirconation–
tained by reductive coupling of aldehyde 6 and protected
transmetalation sequence. Significantly, not only does this simple
flexible strategy provide a concise approach to (+)-1-deoxynojiri-
the Cbz-protected (S)-isoserinal acetonide 6, is readily
mycin, but it also can readily be adopted for the synthesis of other
propargyl alcohol 7. The necessary chiral building block,
available from the commercially available L-isoserine 8,
stereoisomers of the 1-deoxynojirimycin family from L- or D-iso-
and we synthesized this compound following the Schmidt
protocol10 (Scheme 2). Briefly, aldehyde 6 was synthe-
sized in 64% yield from L-isoserine 8 via a short sequence
of reactions. With the aldehyde 6 in hand, the stage was
set for the stereoselective addition reaction of alkyne and
aldehyde 6. Generally, the design of addition of nucleo-
philes to a-alkoxy aldehyde 6 could be based on models
of either chelation-control transition state,11,12 which
would lead to syn addition, or the Felkin–Anh transition
state.13 In search for a complementary method for produc-
ing the syn diastereomers, we turned to vinylzinc nucleo-
phile, generated conveniently from an alkyne by a
hydrozirconation–transmetalation sequence,14 which has
been reported to add to Garner’s aldehyde15 with high syn
diastereoselectivity.16 Here we report for the first time this
coupling reaction of vinylzinc nucleophiles and a-alkoxy
aldehyde 6.
serine through different coupling conditions and stereoselective
epoxidation of allylic alcohol 4 by the same procedures.
Key words: (+)-1-deoxynojirimycin, diastereoselective coupling,
L-isoserine, diastereoselective synthesis, chelation-control transi-
tion state
Since the discovery of nojirimycin over 40 years ago,1
iminosugars have been of great value in treating a variety
of diseases such as diabetes,2 cancer,3 viral diseases4 and
metabolic and neurological disorders.5 Moreover, a-glu-
cosidase inhibitors 1-deoxynojirimycin (DNJ, 1) and
N-butyl-1-deoxynojirimycin (NB-DNJ, Zavesca 2;
Figure 1) have been shown to inhibit human immunodefi-
ciency virus (HIV) replication and HIV-mediated syncy-
tium formation in vitro6 and NB-DNJ has reached phase II
clinical trials as an anti-HIV agent.7 In addition, NB-DNJ
has been the first iminosugar medicine to receive approv-
al, in 2002 in the European Union and in 2003 in the
United States, for use in patients with mild to moderate
type 1 Gaucher disease.8 Because of important bioactivi-
ties, a great deal of efforts9 was made on the stereoselec-
tive synthesis of such compounds. In this letter, we report
a novel protocol for the synthesis of 1-deoxynojirimycin
by utilizing L-isoserine as the starting material.
OH
O
HO
OH
OH
Cbz
OH
N
H
O
O
N
H
1
3
O
Cbz
OH
N
Cbz
OH
N
OH
OH
O
H
O
HO
OH
OH
HO
OH
OH
OTBS
4
5
N
N
H
Cbz
Bu
N
+
1
2
OTBS
CHO
1-deoxynojirimycin
N-butyl-1-deoxynojirimycin
O
(Zavesca®)
7
6
Figure 1
SYNLETT 2011, No. 18, pp 2709–2712
Scheme 1 Retrosynthetic analysis of 1-deoxynojirimycin
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.10.2011
DOI: 10.1055/s-0031-1289546; Art ID: W16111ST
© Georg Thieme Verlag Stuttgart · New York

2710
B. Zhou et al.
LETTER
Table 1 The Reductive Coupling of 6 and 7a
Cbz
N
Cbz
OH
N
+
CHO
OTBS
O
O
6
7
OTBS
Entry
Additive
Et2Zn
Et2Zn
Et2Zn
ZnBr2
ZnBr2
ZnBr2
Solvent
Yield (%)b
dr (syn/anti)c
1
2
3
4
5
6
CH2Cl2
THF
76
7.5:1
1:6
25 (55)
8
Et2O
1:3
CH2Cl2
THF
n.r.
n.r.
n.r.
Et2O
a To the solution of Alkenyl zirconocene reagent (1.2 mmol), Et2Zn (1.2 mmol) at –30 °C or ZnBr2 (0.5 mmol) at 0 °C was added, followed by
6 (1 mmol). The reaction was allowed to warm to 0 °C or r.t. and stirred until completion.
b Isolated yields. Yields in parentheses are based on recovered starting material.
c Determined by HPLC analysis.
O
O
stereoselectivity was obtained (entry 1), indicating that
the addition would occur mainly via a chelation-control
transition state.11,12 When this Et2Zn-mediated reaction
was carried out in THF or Et2O, the anti/syn ratio was en-
tirely reversed to anti-selective (entries 2 and 3). In addi-
tion, no reaction took place on changing the zinc source to
ZnBr2 in THF, CH2Cl2 or Et2O (entries 4–6).
Me2C(OMe)2
BF3 OEt2
SOCl2, MeOH
CbzCl
aq NaHCO3/CH2Cl2
94%
⋅
H2N
Cbz
OH
CbzHN
OMe
75%
OH
OH
8
9
DIBAL-H
PhMe
Cbz
O
N
N
CHO
With the optimal conditions in hand, addition of vinylzinc
species, generated in situ from diethylzinc and the vi-
nylzirconium intermediate, prepared from 7 with zir-
conocene hydrochloride, to 6 in CH2Cl2 predominantly
afforded the desired allylic alcohol 517 in 76% yield and
good diastereoselectivity (dr = 7.5:1; Scheme 3). Remov-
al of the N,O-acetonide and the silyl protection by expo-
sure of 5 to TsOH in MeOH followed by protection of the
resulting diol provided 4 in 83% yield for the two steps.
Sharpless epoxidation18 of 4 gave 319 in 93% yield and
high diastereoselectivity (de >96%). With all the stereo-
centers in place, we set out to prepare for the cyclization.
–78 °C, 2 h
90%
O
O
OMe
6
10
Scheme 2 Synthesis of Cbz-protected (S)-isoserinal acetonide from
L-isoserine
At the outset of the investigation of the reductive coupling
of 6 and 7, we focused our attention on solvents and zinc
source (Table 1). Murakami16 reported that Et2Zn-mediat-
ed reaction carried out in CH2Cl2 predominantly gave the
syn-isomer. In our study, similar result regarding the dia-
Cbz
OH
zirconocene hydrochloride
then Et2Zn, 6, –30 to 0 °C
N
OTBS
O
CH2Cl2, 76%
OTBS
5
7
O
1) TsOH, MeOH
2) Me2C(OMe)2, DMF
(+)-DIPT, Ti(Oi-Pr)4
t-BuOOH, CH2Cl2, –20 °C
Cbz
OH
N
H
O
83% over two steps
93%
4
OH
O
HO
OH
OH
Pd/C, H2, EtOH, reflux
then concd HCl
Cbz
N
OH
⋅HCl
H
O
N
O
96%
H
3
1 ⋅HCl
Scheme 3 Synthesis of (+)-1-deoxynojirimycin
Synlett 2011, No. 18, 2709–2712 © Thieme Stuttgart · New York

LETTER
Short Synthesis of (+)-1-Deoxynojirimycin
2711
Tetrahedron: Asymmetry 2002, 13, 795. (h) Takahata, H.;
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fluxing EtOH20 followed by deprotection by aqueous HCl
in EtOH gave (+)-1-deoxynojirimycin (1) as its hydro-
chloride salt in 96% yield by one-pot reaction. The phys-
ical and spectral properties for compound 1 were in good
agreement with the previously reported data.20,21
In summary, we have developed an efficient, highly dia-
stereoselective synthesis of (+)-1-deoxynojirimycin from
readily available L-isoserine. The key step involves the di-
astereoselective syn addition reaction of a-alkoxy alde-
hyde and vinylzinc nucleophile, generated conveniently
from alkyne 7 by a hydrozirconation–transmetalation se-
quence and this synthesis of 1 necessitates the purification
of only four intermediates. More importantly, other stereo-
isomers of the 1-deoxynojirimycin family could be acces-
sible from L- or D-isoserine through different reductive
coupling conditions and stereoselective epoxidation of
allylic alcohol 4 by the same procedures.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
OHC
This work was supported by the National Science & Technology
Major Project ‘Key New Drug Creation and Manufacturing Pro-
gram’, China (Number: 2009ZX09102-026).
O
N
Boc
Figure 2
References and Notes
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(17) Procedure for the Synthesis of 5: To a 250-mL flame-dried
flask loaded with zirconocene chloride hydride (4.63 g, 18.0
mmol) under argon was added anhyd CH2Cl2 (35 mL). The
resulting suspension was cooled to 0 °C after which 7 (3.06
g, 18.0 mmol) was added dropwise. The mixture was then
stirred at r.t. until the suspension had fully dissolved forming
a yellow solution (1 h). The solution was cooled to –30 °C
after which diethylzinc (16.5 mL, 18.0 mmol, 1.1 M in
toluene) was added dropwise. After 15 min of stirring
aldehyde 6 (3.95 g, 15.0 mmol) was added as a CH2Cl2
solution (20 mL) via cannula. After 15 min of further stirring
at –30 °C, the solution was allowed to warm to 0 °C and the
orange mixture was stirred overnight. The reaction mixture
was diluted with CH2Cl2 (80 mL) followed by addition of
sodium potassium tartrate (15 g) and H2O (30 mL, added
slowly). The resulting mixture was stirred for 45 min and
filtered through a pad of celite. The phases were separated
and the aqueous phase was extracted with CH2Cl2 (3 × 40
mL). The organic layer was dried over Na2SO4, and
concentrated to give a crude product, which was chromatog-
raphed on silica gel (10% EtOAc in cyclohexane) to give
compound 5 (4.96 g, 76%) as a colorless oil; [a]D25 –12.1 (c
= 2.0, CH2Cl2). 1H NMR (400 MHz, DMSO): d = 7.31–7.40
(m, 5 H), 5.81 (dt, J = 15.2, 4.0 Hz, 1 H), 5.65 (dd, J = 15.2,
5.2 Hz, 1 H), 5.16 (d, J = 4.8 Hz, 1 H), 5.01–5.10 (m, 2 H),
4.02–4.17 (m, 4 H), 3.46–3.53 (m, 1 H), 3.19 (t, J = 8.8 Hz,
1 H), 1.51 (s, 3 H), 1.44 (s, 3 H), 0.85 (s, 9 H), 0.02 (s, 6 H).
13C NMR (100 MHz, DMSO): d = 152.0, 137.2, 131.4,
128.8, 128.7, 128.3, 128.0, 93.8, 77.2, 71.2, 66.1, 62.9, 46.7,
26.3, 26.2, 24.3, 18.4, –4.8. IR: 3436, 2929, 1710, 1411 cm–1.
LRMS (EI, 70 eV): m/z (%) = 420 (8) [M+ – Me], 91 (100).
Synlett 2011, No. 18, 2709–2712 © Thieme Stuttgart · New York

2712
B. Zhou et al.
LETTER
HRMS (EI): m/z [M+ – Me] calcd for C22H34NO5Si:
420.2206; found: 420.2201.
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Synlett 2011, No. 18, 2709–2712 © Thieme Stuttgart · New York

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