Asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-D-glucitol [(+)-DGDP] and (?)-1-deoxymannojirimycin [(?)-DMJ] via an extended chiral 1,3-oxazine

Article abstract of DOI:10.1016/j.tetlet.2018.05.026

The asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-D-glucitol [(+)-DGDP] 1 and (?)-1-deoxymannojirimycin [(?)-DMJ] 2 were achieved using an extended chiral 1,3-oxazine. The key synthetic strategies included extension of the chirality of anti,syn-oxazine 3 using diastereoselective dihydroxylation, and piperidine and pyrrolidine ring formation. Starting from readily available anti,syn-oxazine 3, (+)-DGDP 1 was synthesized in 5 steps with 31.6% overall yield and (?)-DMJ 2 was synthesized in 4 steps with 60.6% overall yield.

Full text of DOI:10.1016/j.tetlet.2018.05.026

Accepted Manuscript
Asymmetric Total Syntheses of (+)-2,5-Dideoxy-2,5-imino-D-glucitol [(+)-
DGDP] and (−)-1-Deoxymannojirimycin [(−)-DMJ] via an Extended Chiral
1
,3-Oxazine
In-Soo Myeong, Changyoung Jung, Ji-Yeon Kim, Seok-Hwi Park, Won-Hun
Ham
PII:
S0040-4039(18)30625-7
https://doi.org/10.1016/j.tetlet.2018.05.026
TETL 49973
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 March 2018
8 May 2018
11 May 2018
Please cite this article as: Myeong, I-S., Jung, C., Kim, J-Y., Park, S-H., Ham, W-H., Asymmetric Total Syntheses
of (+)-2,5-Dideoxy-2,5-imino-D-glucitol [(+)-DGDP] and (−)-1-Deoxymannojirimycin [(−)-DMJ] via an Extended
Chiral 1,3-Oxazine, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.026
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Asymmetric Total Syntheses of (+)-2,5-Dideoxy-2,5-imino-D-glucitol [(+)-DGDP] and
−)-1-Deoxymannojirimycin [(−)-DMJ] via an Extended Chiral 1,3-Oxazine
(
In-Soo Myeong, Changyoung Jung, Ji-Yeon Kim, Seok-Hwi Park, Won-Hun Ham*
*
Corresponding author.
e-mail address: whham@skku.edu (W.-H. Ham)
Tel: +82 31 290 7706
Fax: +82 31 292 8800
School of Pharmacy, Sungkyunkwan University, Seobu-ro 2066, Suwon-si, Gyeonggi-do
1
6419, Republic of Korea
ABSTRACT
TBSO
TBSO
N
OH
OH
H
OH
N
HO
OH
OH
TBSO
TBSO
HO
OH
N
O
O
N
H
HO
OH
Ph
anti,syn-oxazine 3
Ph
anti,syn,anti-oxazine 5
(
+)-DGDP 1
(
)-DMJ 2
The asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-D-glucitol [(+)-DGDP] 1
and (−)-1-deoxymannojirimycin [(−)-DMJ] 2 were achieved using an extended chiral 1,3-
oxazine. The key synthetic strategies included extension of the chirality of anti,syn-oxazine 3
using diastereoselective dihydroxylation, and piperidine and pyrrolidine ring formation.
Starting from readily available anti,syn-oxazine 3, (+)-DGDP 1 was synthesized in 5 steps
with 31.6% overall yield and (−)-DMJ 2 was synthesized in 4 steps with 60.6% overall yield.
Keywords: Asymmetric total synthesis, (+)-DGDP, (−)-DMJ, stereoselective dihydroxylation, chiral
1
,3-oxazine
1
. Introduction
(+)-2,5-Dideoxy-2,5-imino-D-glucitol [(+)-DGDP] 1 is a polyhydroxylated pyrrolidine
possessing four contiguous stereogenic centers (Fig. 1), which was first isolated from the
1
leaves of the legume Derris elliptica in 1976. DGDP 1 has been reported as a selective
inhibitor of α-galactosidase and exhibits inhibitory activities against α- and β-glucosidases as
2
, 3
well as α-mannosidases. (−)-1-Deoxymannojirimycin [(−)-DMJ] 2 is a polyhydroxylated
piperidine possessing four contiguous stereogenic centers, which was first isolated from
Lonchocarpus sericeus in 1979 and is likely derived from the biosynthetic reduction of
4
, 5
mannojirimycin.
Polyhydroxylated piperidines, such as (−)-DMJ 2, have demonstrated
6
-11
potent biological activities.
fucosidase, α-D-mannnosidase, and α-D-glucosidase.
(−)-DMJ 2 exhibits biological activity as an inhibitor of α-L-
1
2
OH
H
N
HO
OH
OH
HO
OH
N
H
HO
OH
(
+)-DGDP 1
()-DMJ 2
Figure 1. Structures of (+)-DGDP 1 and (−)-DMJ 2
Recently, we reported the synthesis of a novel chiral building block anti,syn,syn-oxazine
from anti,syn-oxazine 3 (Scheme 1) and successfully applied it to the total syntheses of (−)-
4
1

1
3
14
14
15
conduramine F-1, (+)-hyacinthacine A , (−)-sphingofungin B, (+)-1-deoxynojirimycin,
2
2
1
5
16
,5-dihydroxymethyl-3,4-dihydroxypyrrolidine [(+)-DMDP], and (+)-radicamine B. As
part of a research program directed at expanding the synthetic utility of anti,syn-oxazine 3,
we report herein the synthesis of a novel chiron anti,syn,anti-oxazine 5 and its application to
the asymmetric total syntheses of (+)-DGDP 1 and (−)-DMJ 2.
OTBS
TBSO
OH
TBSO
OH
O
1
) O3, MeOH; Me2S
TBSO
TBSO
TBSO
TBSO
OCH3
N
O
N
O
N
O
2
) Method A or
Method B
NHBz
56.8% (5 steps)
protected D-serine
Ph
Ph
Ph
anti,syn-oxazine
anti,syn,syn-oxazine
anti,syn,anti-oxazine
3
4
4'
Method A: ZnCl2, vinylMgBr, THF, 0 oC; 64%, dr. : 10 : 1
Method B: (vinyl)2Zn, THF, 78 oC to rt; 85%, dr. : > 20 : 1
Scheme 1. Previous research regarding chiral anti,syn,syn-oxazine 3.
2
. Results and Discussion
Our retrosynthetic analysis (Scheme 2) suggested that 1 and 2 could be obtained from
anti,syn,anti-oxazine 5 via cyclization; compound 5 could be synthesized by the
stereoselective dihydroxylation of anti,syn-oxazine 3.
H
N
HO
OH
TBSO
N
OH
OTBS
HO
OH
OH
(
+)-DGDP 1
TBSO
TBSO
O
N
O
OH
Ph
Ph
HO
OH
OH
anti,syn,anti-oxazine
anti,syn-oxazine
5
3
N
H
(
)-DMJ 2
Scheme 2. Retrosynthetic analysis of 1 and 2.
Osmium tetroxide mediated dihydroxylation was performed to introduce a new
stereogenic center for the formation of anti,syn,anti-oxazine 5 (Table 1). Using Upjohn
conditions, a highly anti-selective reaction was eventually achieved with good yield (Entry 1).
17, 18
Donohoe’s method was also used, anti-product 5 was achieved with a 5:1 ratio (Entry 5).
According to Donohoe and co-workers, the absence of a hydrogen bond donor has an
1
9
influence on the stereochemical outcome.
Table 1. Osmium tetroxide mediated stereoselective dihydroxylation of anti,syn-oxazine 3
OTBS
TBSO
OH
TBSO
OH
OH
OH
TBSO
TBSO
TBSO
Conditions
N
O
N
O
N
O
Ph
Ph
Ph
anti,syn-oxazine
anti,syn,anti-oxazine
anti,syn,syn-oxazine
3
5
5'
a
b
Entry Conditions
Ratio (anti:syn) Yield (%)
1
2
3
4
5
OsO (5 mol%), acetone, H O, NMO (2 equiv.), rt, 8 h
8:1
94
89
91
81
52
4
2
OsO (5 mol%), acetone, H O, NMO (1.1 equiv.), rt, 8 h
8:1
4
2
OsO (10 mol%), acetone, H O, NMO (2 equiv.), rt, 8 h
7.5:1
4:1
4
2
OsO (1.2 equiv.), CH Cl , −78 °C to rt, 1 h
4
2
2
OsO (1.2 equiv.), TMEDA (1.2 equiv), CH Cl , −78 °C to rt, 1 h 5:1
4
2
2
a
1
Ratio was determined by integrating the relevant H NMR spectra
Yields refer to the isolated mixture of products
b
2

The proposed mechanism for the stereoselective dihydroxylation is shown in Figure 2.
2
0
Based on the conformation of our previously reported oxazines, conformation A has proved
to be disfavored due to steric hindrance between the olefin and the bulky TBS protecting
group, and conformation B is favored.
H
TBSO
OH
H
OH
N
O
OTBS
CH OTBS
TBSO
Ph
N
O
2
TBSO
N
H
Ph
anti,syn,syn-oxazine
O
Os
O
H
O
O
TBSO
5
'
O
A
Ph
H
H
TBSO
N
OH
anti,syn-oxazine
H
OTBS
3
OH
N
O
TBSO
Ph
O
CH OTBS
2
Ph
O
H
O
anti,syn,anti-oxazine
Os
O
O
5
B
favored
Figure 2. Proposed mechanism for the dihydroxylation of anti,syn-oxazine 3.
The synthesis of (+)-DGDP 1 is shown in Scheme 3. A TES protecting group was
installed, because it can be introduced with regioselectivity. Furthermore, the TES group has
been reported to be cleaved by palladium-catalyzed hydrogenation, implying that variations
in the protecting groups are possible without the need for a deprotection step after
21, 22
cyclization.
Mesylate 7 was synthesized from 6 without difficulty. Pyrrolidine 8 was
produced from 7 by catalytic hydrogenation, proceeding through oxazine ring cleavage
followed by cyclization. The total synthesis of (+)-DGDP 1 was completed by treatment of 8
2
5
with 1 N HCl. The specific rotation of 1 [α]
+20.5 (c 1.0, H O), as compared to the
D
2
2
0
23
28
24
reported values of [α]D +22.2 (c 0.5, H O) and [α] +22.7 (c 0.14, H O), confirmed the
absolute configuration. The H and C NMR data for 1 were in good agreement with the
literature data. Thus (+)-DGDP 1 was synthesized from anti,syn-oxazine in 5 steps with
2
D
2
1
13
2
3
3
1.6% overall yield.
TBSO
N
OH
TBSO
N
OH
OH
OTES
TBSO
TBSO
a
b
O
O
Ph
Ph
anti,syn,anti-oxazine
6
5
TBSO
OMs
H
N
H
OTES
N
TBSO
c
d
TBSO
TBSO
OH
HO
OH
N
O
OH
HO
OH
Ph
8
(+)-DGDP 1
7
Scheme 3. Total synthesis of (+)-DGDP 1. Reagents and conditions: (a) TESCl, Et N, CH Cl , 0 °C to rt, 6 h,
3
2
2
9
5%; (b) MsCl, Et N, CH Cl , 0 °C to rt, 1 h 96%; (c) Pd(OH) /C, H , MeOH, rt, 12 h, 50%; (d) 1 N HCl,
3 2 2 2 2
MeOH, rt, 12 h, 70%
The synthesis of (−)-DMJ 2 is shown in Scheme 4. Mesylation of 5 (1 equiv. of MsCl)
gave only the primary mesylated compound. Piperidine 9 was obtained by catalytic
hydrogenation of the mesylate, proceeding through oxazine ring cleavage, followed by
cyclization. The total synthesis of (−)-DMJ 2 was completed by treatment of 9 with 1 N HCl.
3

2
5
The specific rotation of 2 [α]
−40.5 (c 0.9, H O), as compared to the reported values of
2
D
2
5
25
20
26
[
α]D −39.0 (c 0.1, H O) and [α]D −40.2 (c 0.33, H O), confirmed the absolute
2
2
1
13
configuration. The H and C NMR data of 2 were in good agreement with the previously
reported data. (−)-DMJ 2 was synthesized from anti,syn-oxazine 3 in 4 steps with 60.6%
2
7
overall yield.
TBSO
OH
OH
OH
OH
HO
OTBS
OTBS
TBSO
HO
OH
OH
a
b
N
O
N
H
N
H
Ph
anti,syn,anti-oxazine
9
()-DMJ 2
5
Scheme 4. Total synthesis of (−)-DMJ 2. Reagents and conditions: (a) i. MsCl, Et N, CH Cl , 0 °C , 1 h; ii.
3
2
2
Pd(OH) /C, H , MeOH, rt, 12 h, 75% (2 steps); (b) 1 N HCl, MeOH, rt, 12 h, 86%
2
2
3
. Conclusion
In conclusion, we have reported a new synthetic method based on dihydroxylation for the
development of a novel chiral synthon, anti,syn,anti-oxazine 5. The resulting chiral synthon
was used for the total syntheses of (+)-DGDP 1 and (−)-DMJ 2. Further applications of more
complex natural products will be reported in the future.
Acknowledgements
The assistance of Yonsung Fine Chemicals Corporation is appreciated.
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5

Reporting a total synthesis of (+)-DGDP, a polyhydroxylated pyrrolidine
Reporting a total synthesis of (−)-DMJ, a polyhydroxylated piperidine
Highly stereoselective dihydroxylation was accomplished by Osmium tetroxide
A novel chiral synthon anti,syn,anti-oxazine was used for the total syntheses
6