A concise synthetic approach to (+)-valienamine starting from Garner's aldehyde

Article abstract of DOI:10.1055/s-0031-1290614

A synthesis of (+)-valienamine was achieved starting from Garner's aldehyde in ten steps and 23% overall yield. A unique feature of the synthetic route is that an acyclic precursor was constructed, using diastereoselective antireductive coupling reaction of alkyne and Garner's aldehyde as the key step, which was then cyclized in an intramolecular aldol reaction to form the valienamine skeleton. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290614

LETTER
913
A Concise Synthetic Approach to (+)-Valienamine Starting from Garner’s
Aldehyde
Synthetic
A
pproa
i
chto(
n
g
ne Zhou,a,1 Zhi Luo,a,1 Sui Lin,b Yuanchao Li*a
a
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park,
Shanghai 201203, P. R. of China
Fax +86(21)50807288; E-mail: ycli@mail.shcnc.ac.cn
Fujian Institute of Medical Sciences, Fuzhou 350001, P. R. of China
b
Received 15 December 2011
We reasoned that 1 can be obtained by Luche reduction of
aldehyde group and removing ethoxymethyl and Boc pro-
tecting group in 3 (Scheme 1). Disconnection via intramo-
lecular aldol condensation led to the acyclic precursor 4.
Abstract: A synthesis of (+)-valienamine was achieved starting
from Garner’s aldehyde in ten steps and 23% overall yield. A
unique feature of the synthetic route is that an acyclic precursor was
constructed, using diastereoselective antireductive coupling reac-
tion of alkyne and Garner’s aldehyde as the key step, which was The requisite precursor 4 can in turn be synthesized from
then cyclized in an intramolecular aldol reaction to form the valie-
namine skeleton.
the monoprotected tetraol 5, the product of a diastereose-
lective dihydroxylation of 6. We envisioned that the high-
Key words: (+)-valienamine, Garner’s aldehyde, diastereoselec-
tive, hydrozirconation–transmetalation, intramolecular aldol reac-
tion
ly functionalized key intermediate 6 could be obtained by
reductive coupling of Garner’s aldehyde 711 and protected
3-butyn-1-ol 8, which is commercially available. Com-
pounds 7 and 8 can also be synthesized from readily avail-
able starting materials L-serine and 3-butyn-1-ol,
respectively.
Valienamine (1) is an a-glucosidase inhibitor2 that was
isolated from the microbial degradation of validoxyl-
amine A (2) with Pseudomonas denitrificans,3 Flavobac-
terium saccharophilum,4 or from the NBS cleavage of
validoxylamine A or its derivatives (Figure 1).5 More-
over, valienamine (1) is also an essential core unit in many
kinds of pseudo-oligosaccharidic a-D-glucosidase inhibi-
tors.6 In view of these desirable properties, a considerable
amount of effort7–10 has been put into the enantiospecific
syntheses of valienamine, among which most reported to-
tal syntheses employ cyclitol quebrachitol,7 D-glucose de-
rivatives,8 or (–)-quinic acid9 as the chiral building block.
However, such strategies are often limited by the use of
relatively expensive chiral building blocks and/or the
need for lengthy protecting-group manipulation. In some
other methods the cyclohexene skeleton of 1 was con-
structed through Diels–Alder reaction or ring-closing
metathesis of an acyclic diene.10 In this letter, we report a
novel synthetic approach that leads from a construction of
an acyclic precursor and its cyclization at a later stage to
form the valienamine skeleton.
O
CH2OH
HO
HO
EOMO
EOMO
NH2
NHBoc
OEOM
OH
1
3
O
Boc
HO
EOMO
O
N
O
TBSO
EOMO
NHBoc
OH OH
OEOM
5
4
Boc
N
OTBS
OHC
O
O
TBSO
N
Boc
OH
6
8
7
Scheme 1 Retrosynthetic analysis of 1
HO
OH
OH
H
N
Generally, the design of addition of nucleophiles to a-
chrial aldehyde 7 could be based on models of either che-
lation-control transition state12 or Felkin–Anh transition
state,13 which would lead to syn or anti addition. Some
methodologies for alkyne addition of Garner’s aldehyde
have been previously investigated,14 and Herold14a and co-
workers further investigated the effect of additives and
found that the anti selectivity increased in the presence of
HMPA, a cation-complexing agent. However, this type of
alkyne-addition method requires an additional step, that
NH2
OH
HO
HO
OH
valienamine (1)
OH HO
OH
HO
HO
validoxylamine A (2)
Figure 1
SYNLETT 2012, 23, 913–916
Advanced online publication: 15.03.2012
x
x.
x
x.
2
0
1
2
DOI: 10.1055/s-0031-1290614; Art ID: W77411ST
© Georg Thieme Verlag Stuttgart · New York

914
B. Zhou et al.
LETTER
is, reduction of the triple bond to an E-olefin. In the search With all the stereocenters in place, we set out to prepare
for a complementary method for producing the anti dia- for the cyclization. Exposure of triol 5 to EOMCl gave
stereomer we turned to vinylzinc nucleophiles, generated compound 9 in 93% yield. The 13C NMR spectra of com-
conveniently from an alkyne such as 8 by a hydrozircon- pound 9 was complex due to the presence of the Boc pro-
ation–transmetalation sequence,15 which have been re- tecting group, which resulted in a number of rotational
ported to add to Garner’s aldehydes with high anti isomers at 23 °C. Selective deprotection of TBS ethers by
diastereoselectivity in the presence of ZnBr2.16 Herein we exposure of 9 to TsOH in MeOH, followed by removal of
further show the utility of this reaction.
the N,O-acetonide with CuCl2 in MeCN provided diol 10
in 90% yield for the two steps.
hydrochloride15 in THF, followed by addition of Garner’s In order to execute the planned aldol-type cyclization, the
As depicted in Scheme 2, treatment of 8 with zirconocene
aldehyde 7 and ZnBr2 delivered the desired allylic alcohol terminal dihydroxy group needed to be oxidized to the
6
17 in good yield (84%) with virtually complete diastere- level of aldehyde. A protocol involving Dess–Martin pe-
ocontrol (anti/syn > 15:1). The ratio of anti/syn was deter- riodinane oxidation was found to be superior to other con-
mined by HPLC analysis. Similar results regarding the ditions, and the desired dialdehyde 4, without further
diastereoselectivity have been published by Murakami et purification, was directly converted to the six-membered
al.16 Dihydroxylation of allylic alcohol using osmium ring structure 3 through an intramolecular aldol condensa-
tetroxide with TMEDA18 produced the syn,syn-triol 5 in tion reaction under mild conditions19 (cat. TsOH, piperi-
an acceptable 73% yield with a small amount of syn,anti dine, r.t., 2 h), followed by b-elimination of the formed
diastereomer (15%). The diastereoselectivity was good hydroxyl group with MsCl and Et3N. Attempt at other in-
(syn/anti = 4.5:1~5:1), and the unwanted syn,anti diaste- tramolecular aldol condensation cyclization conditions20
reomer could be separated by column chromatography at failed to give our desired compound 3. Thus, the intramo-
this point. When AD-mix-b was used, the product ob- lecular aldol-type cyclization provided the valienamine
tained was a 2:1 mixture of the diastereomeric triols, with skeleton. Controlled reduction of enal 3 with NaBH4 in
the desired syn,syn diastereomer as the major product. methanol solution containing cerium chloride, followed
Boc
OTBS
Schwartz reagent, r.t.
N
O
then 7, ZnBr2, THF, 24 h
TBSO
84%
OH
6
8
Boc
HO
N
EtOCH2Cl
DIPEA, CH2Cl2
TMEDA, OsO4
CH2Cl2, –78 °C
O
TBSO
OH OH
73%
93%
5
OH
Boc
EOMO
EOMO
N
i. TsOH, MeOH
ii. CuCl2, MeCN
HO
O
TBSO
NHBoc
EOMO
OEOM
90%
EOMO
OEOM
10
9
O
i. piperidine, TsOH, benzene
ii. MsCl, Et3N, CH2Cl2
Dess–Martin
periodinane
EOMO
EOMO
O
66% over 3 steps
CH2Cl2
NHBoc
OEOM
4
CH2OR
CHO
i. CeCl3, NaBH4, MeOH
ii. TFA, CH2Cl2
iii. Ac2O, pyridine
RO
RO
EOMO
EOMO
NHR
NHBoc
68% over 3 steps
OR
OEOM
3
1 R = H
11 R = Ac
Scheme 2 Synthesis of valienamine (1) from Garner’s aldehyde
Synlett 2012, 23, 913–916
© Thieme Stuttgart · New York

LETTER
Synthetic Approach to (+)-Valienamine
915
Soc. Jpn. 1985, 58, 3387. (b) Knapp, S.; Naughton, A. B. J.;
Dhar, T. G. M. Tetrahedron Lett. 1992, 33, 1025. (c) Trost,
B. M.; Chupak, L. S.; Lubbers, T. J. Am. Chem. Soc. 1998,
120, 1732. (d) Chang, Y. K.; Lo, H. J.; Yan, T. H. Org. Lett.
2009, 11, 4278.
by removal of the EOM ether and Boc in TFA–CH2Cl2
provided (+)-valienamine (1), which was characterized as
its pentaacetate 1121 (68%). Comparison of the physical
properties to those recorded confirms its identity.9b This
synthesis, based on a diastereoselective anti-reductive
coupling reaction of alkyne and chiral aldehyde followed
by intramolecular aldol-type cyclization, requires ten
steps from readily available Garner’s aldehyde 7 to give
(+)-valienamine in 23.0% overall yield.
(11) Garner, P. Tetrahedron Lett. 1984, 25, 5855.
(12) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81,
2748.
(13) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett.
1968, 9, 2119. (b) Cherest, M.; Felkin, H. Tetrahedron Lett.
1968, 9, 2205. (c) Anh, N. T.; Eisenstein, O. E. Nouv. J.
Chim. 1977, 1, 61. (d) Anh, N. T. Top. Curr. Chem. 1980,
88, 145.
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P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53, 4395.
(c) Radunz, H.-E.; Devant, R. M.; Eiermann, V. Liebigs Ann.
Chem. 1988, 1103.
(15) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197.
(16) Murakami, T.; Furusawa, K. Tetrahedron 2002, 58, 9257.
(17) Procedure for the Synthesis of 6
In conclusion, a synthesis of (+)-valienamine was
achieved starting from Garner’s aldehyde and well-estab-
lished, highly efficient reactions were employed in this
synthesis. A unique feature of the synthetic route is that an
acyclic precursor was constructed, which was then cy-
clized in an intramolecular aldol reaction to form the (+)-
valienamine skeleton.
To an ice-cooled stirred suspension of Cp2Zr(H)Cl (5.05 g,
19.6 mmol) in THF (50 mL) under argon protection was
added tert-butyl(but-3-ynyloxy)dimethylsilane (3.61 g, 19.6
mmol), the mixture was stirred at r.t. for 1 h, and then cooled
to 0 °C. To the resulting orange solution was added aldehyde
7 (2.25g, 9.8 mmol) in THF (35 mL) followed by ZnBr2 (552
mg, 2.45 mmol, dried under vacuum for 1 h before use), and
the mixture was stirred for 24 h at r.t. The mixture was
diluted with EtOAc (100 mL) and aq potassium sodium
(+)-tartrate (5.7 g, 19.6 mmol), and stirred for 10 min. The
resulting suspension was filtered off and washed thoroughly
with EtOAc (100 mL). The combined filtrate was transferred
into a separatory funnel and successively washed with H2O
and brine. The aqueous phase was extracted with EtOAc
(2 × 200 mL), and the combined organic layers were dried
over anhyd Na2SO4. The mixture was concentrated and
purified by silica gel chromatography to afford 6 (3.625 g,
84%) as a colorless oil: [a]D20 –27.0 (c 1.2, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 5.72 (m, 1 H), 5.49 (dd, J = 15.0, 6.0
Hz, 1 H), 4.02 (m, 4 H), 3.61 (t, J = 6.0, 2 H), 2.26 (m, 2 H),
1.48 (s, 15 H), 0.86 (s, 9 H), 0.01 (s, 6 H). 13C NMR (100
MHz, CDCl3): d = 153.8, 130.6, 128.7, 94.1, 80.7, 73.6,
64.7, 62.7, 61.9, 35.9, 28.2, 28.2, 28.2, 26.3, 25.8, 25.8, 25.8,
24.5, 18.1, –5.4, –5.4. IR (film): 3454, 2931, 2858, 1699,
1473, 1387, 1255, 1174, 1097, 837, 775 cm–1. MS (EI): m/z
(%) = 415 (0.04)[M+], 100 (64.29), 57 (100.00). HRMS (EI):
m/z calcd for C21H41NSiO5 [M+]: 415.2754; found:
415.2765.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by National Science & Technology Major
Project ‘Key New Drug Creation and Manufacturing Program’,
P. R. of China (2009ZX09102-026).
References and Notes
(1) Those authors contributed equally.
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(21) Procedure for the Synthesis of 11
To a suspension of 3 (40 mg, 0.09 mmol) and CeCl3·7H2O
(52 mg, 0.135 mmol) in MeOH (3 mL) was added NaBH4 (4
mg, 0.1 mmol) at 0 °C. The mixture was stirred for 15 min,
and the solvent was removed under reduced pressure. Then,
H2O (3 mL) was added to the residue, which was then
extracted with EtOAc (3 × 6 mL). The organic layer was
washed with H2O (3 mL) and brine (3 mL), dried (Na2SO4),
filtered, and and the solvent was removed under reduced
© Thieme Stuttgart · New York
Synlett 2012, 23, 913–916

916
B. Zhou et al.
LETTER
pressure to give the colorless oil, which was directly
3 steps) as a white solid; mp 91–93 °C; [a]D20 +20.0 (c 0.075,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 2.02 (s, 6 H), 2.06
(s, 3 H), 2.07 (s, 6 H), 4.39 and 4.64 (ABq, J = 13.2 Hz, 2 H),
5.02–5.11 (m, 2 H), 5.36 (br d, J = 6.8 Hz, 1 H), 5.45 (dd,
J = 10.0, 6.4 Hz, 1 H), 5.70 (br d, J = 8.4 Hz, 1 H), 5.89 (dd,
J = 5.2, 1.2 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 20.7,
20.8, 20.8, 20.8, 23.3, 44.9, 62.9, 68.5, 69.0, 71.2, 126.1,
134.3, 169.9, 170.0, 170.2, 170.3, 170.4. IR (film): 3363,
3269, 2924, 2850, 1743, 1649, 1556, 1469, 1371, 1223, 1024
cm–1. MS (EI): m/z (%) = 385 (0.67) [M+], 326 (100.00), 223
(57.20), 164 (68.60). HRMS (EI): m/z calcd for C17H23NO9
[M+]: 385.1373; found: 385.1370.
dissolved in CH2Cl2 (4 mL), and TFA (2 mL) was added.
The mixture was stirred for 4 h at 0 °C. Then, the solvent was
removed in vacuum to give the crude product 1, which was
dissolved in pyridine (2 mL) and Ac2O (1 mL) containing a
catalytic amount of DMAP. The mixture was stirred at r.t.
for 24 h. The reaction mixture was diluted with EtOAc (10
mL) and washed with sat. NaHCO3 (10 mL). The aqueous
layer was extracted with EtOAc (2 × 20 mL). The combined
organic extracts were washed with brine (10 mL), dried over
Na2SO4, and filtered. Concentration of the filtrate followed
by chromatography gave pentaacetate 11 (23 mg, 68% over
Synlett 2012, 23, 913–916
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