Stereoselective total synthesis of (+)-valienamine and (+)-4-epi- valienamine via a ring-closing enyne metathesis protocol

Article abstract of DOI:10.1055/s-0028-1087669

Stereoselective total synthesis of (+)-valienamine is reported utilizing Sharpless asymmetric dihydroxylation, diastereoselective Carreira alkynylation, and ring-closing enyne metathesis (RCEYM) as key steps from L-serine. A similar strategy is also reported for the first total synthesis of (+)-4-epi- valienamine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087669

LETTER
209
Stereoselective Total Synthesis of (+)-Valienamine and (+)-4-epi-Valienamine
via a Ring-Closing Enyne Metathesis Protocol
(
+)-Valienami
a
ne and (+)-
laalienaminekodety Radha Krishna,* P. Srinivas Reddy
D-206/B, Discovery Laboratory, Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax +91(40)27160387; E-mail: prkgenius@iict.res.in
Received 15 September 2008
6
6
OH
OH
OH
OH
Abstract: Stereoselective total synthesis of (+)-valienamine is re-
ported utilizing Sharpless asymmetric dihydroxylation, diastereose-
lective Carreira alkynylation, and ring-closing enyne metathesis
(RCEYM) as key steps from L-serine. A similar strategy is also re-
ported for the first total synthesis of (+)-4-epi-valienamine.
5
3
5
O
1
4
1
H2N
4
HO
2
2
3
HO
valienamine (1)
OH
OH
OH
HO
OH
Key words: Sharpless asymmetric dihydroxylation, Carreira alky-
nylation, Grubbs’ catalyst, ring-closing enyne metathesis, valien-
amine, 4-epi-valienamine
α-D-glucose
OH
OH
O
H2N
HO
Glycosidases are the enzymes that cleave the glycosidic
bonds and are responsible for the glycoprotein processing
and carbohydrate digestion in animals. Hence, inhibition
of these enzymes has significant implications in both an-
tiviral and diabetic chemotherapy.1 Valienamine
[(1S,2S,3S,4R)-1-amino-5-(hydroxymethyl)cyclohex-5-
ene-2,3,4-triol] (Figure 1), a carbasugar, was first isolated
from microbial degradation of validoxylamine A with
Pseudomonas denitrificans2 or Flavabacterium saccharo-
philum3 or from the NBS cleavage of validoxylamine A
and its derivatives.4 Valienamine is a core unit of many
pseudo-oligosaccharides and pseudo-amino sugars such
as validamycins, acarbose, amylostatins, adiposins, ac-
arviosin, and trestatins.5a Valienamine shows strong a-
glycosidase inhibitory activity against various hydrolases6
inhibiting 50% activity of maltase and sucrase at concen-
trations of 3.4 × 10–4 and 5.3 × 10–5 M and antibiotic ac-
tivity against Bacillus species.7 Due to its varied and
important biological activities, several syntheses5 were re-
ported in an effort to arrive at more potent modified ana-
logues.
Ever since the pioneering work of Paulsen8 et al. and oth-
ers,9 elegant syntheses of valienamine were reported.5
While, most of them used D-glucose or its
derivatives10,11a,c as the chiral starting material and built
the carbocyclic framework using various key reactions,
the most interesting to us was the use of ring-closing al-
kene metathesis protocol.11 Owing to our broad interest in
applying metathesis-based synthetic routes to access bio-
active natural products,12 herein we report the stereoselec-
tive total synthesis of valienamine (1) and the first
synthesis of 4-epi-valienamine (2) wherein ring-closing
enyne metathesis (RCEYM) is employed as the key step
HO
OH
HO
OH
4-epi-valienamine (2)
α-D-galactose
Figure 1
for constructing the carbocyclic ring system. We envi-
sioned that the ensuing vinylic double bond would serve
as a masked ‘hydroxymethyl side chain’ as well as a han-
dle for designing New Chemical Entities (NCEs).13
Thus, the synthesis (Scheme 1) began following the liter-
ature procedure. The known14 compound 3, obtained from
L-serine, on Sharpless asymmetric dihydroxylation (AD-
mix-a, OsO4, MeSO2NH2, t-BuOH–H2O, 0 °C) provided
a separable mixture of diastereomers in 99:1 ratio. Diol 4
was protected as its MOM ether 5 (MOMCl, DIPEA,
CH2Cl2, r.t., 93%). Next, reduction of 5 with LiAlH4 in
THF gave the primary alcohol 6 (75%). Alcohol 6 on
Swern oxidation and quenching the ensuing aldehyde
with TMS–acetylenic anion (TMS–acetylene, n-BuLi,
THF, –78 °C) afforded propargylic alcohol which upon
TMS deprotection (K2CO3, MeOH) furnished 7a and 7b
(70% overall yield for three steps) as an inseparable dia-
stereomeric mixture (8.0:2.0, anti/syn). The ratio of dia-
1
stereomers was determined by the H NMR analysis via
the relative integration of the separable methoxy protons
of the MOM groups. Herein, the predominant 1,2-anti se-
lectivity maybe explained due to non-chelation addition
protocol. In order to alter the stereoisomer in favor of the
desired stereochemistry, various strategies were tried.
Firstly, additives such as ZnCl2, ZnBr2 and MgBr2·OEt2
were used in an attempt to augment the chelation-con-
trolled addition as the means of enhancing the syn selec-
tivity, but the observed de values were 5%, 16% and 32%,
respectively. Later, the diastereomeric mixture of 7a and
7b was subjected to
NO2C6H4COOH, DIAD, TPP, THF, r.t.) followed by
methanolysis (K2CO3, MeOH, r.t.) to provide the desired
a Mitsunobu reaction (p-
SYNLETT 2009, No. 2, pp 0209–0212
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087669; Art ID: G28008ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

210
P. Radha Krishna, P. Srinivas Reddy
LETTER
diastereomer as the major product (8.0:2.0 ratio). Howev- The thus-obtained diastereomer 8b was taken up for fur-
er, practical separation of 7a and 7b diastereomeric mix- ther use.
ture into individual entities was possible after
derivatization (MOMCl, DIPEA, CH2Cl2, 0 °C to r.t.) as
MOM ethers 8a and 8b.
Further, the independently accessed 8a and 8b were cor-
related with those obtained earlier and found to have iden-
tical spectral data.
In order to enhance the diastereoselectivity in favor of the
To continue the synthesis, 8b on selective cleavage of ac-
etonide group using CuCl2·2H2O in acetonitrile at 0 °C
gave the free primary alcohol 9b (92%; Scheme 2). Swern
desired stereoisomer, Carreira asymmetric alkynylation
reaction15 [(–)-N-methylephedrine, Zn(OTf)2, Et3N,
TMS–acetylene, toluene, r.t.] was conducted on the corre-
sponding aldehyde to furnish propargyl alcohol 7b in
higher yield (86%) and selectivity (96% de). Likewise,
Carreira alkynylation reaction using (+)-N-methylephe-
drine as the chiral ligand under similar reaction conditions
gave 7a in equal optical and chemical yield. The absolute
stereochemistry of the newly created stereogenic center of
oxidation of 9b followed by Wittig olefination
(Me+PPh3I–, t-BuOK, THF, 0 °C) furnished enyne 10b
(64%). Compound 10b was characterized by its spectral
1
data, wherein its H NMR spectrum revealed the charac-
teristic acetylenic proton at d = 2.46 ppm as a doublet (J =
1.8 Hz) and the olefinic protons as multiplets at d = 6.01
and at d = 5.20–5.34 ppm. The IR spectrum displayed the
7a was assigned as
S based on the literature
characteristic C–H and C–C stretching frequencies at
3252 and 2154 cm–1 respectively. The critical ring-closing
enyne metathesis reaction17a of 10b was conducted with
the Grubbs II catalyst [A (10 mol%), solvent, reflux, 12 h]
precedence15,16 and that of 7b as R. Next, the secondary
hydroxy group in 7b was protected as its MOM ether
(MOMCl, DIPEA, CH2Cl2, 0 °C, r.t.) to afford 8b (90%).
HO
CO2Me
OH
MOMO
OH
OMOM
6
MOMO
CO2Me
CO2Me
b
a
c
OMOM
NBoc
NBoc
NBoc
O
O
O
NBoc
O
3
5
4
MOMO
MOMO
HO
HO
MOMO
MOMO
MOMO
O
MOMO
OMOM
OMOM
f
OMOM
OMOM
+
d
+
NBoc
O
NBoc
O
NBoc
NBoc
O
7a (anti)
7b (syn)
8a
8b
1. 7a/7b = 80:20
2. 7a/7b = 2:98
3. 7a/7b = 96:4
e
Scheme 1 Reagents and conditions: (a) AD-mix-a, OsO4, MeSO2NH2, t-BuOH–H2O, 0 °C, 16 h, 84%; (b) DIPEA, MOMCl, CH2Cl2, 0 °C
to r.t., 17 h, 93%; (c) LiAlH4, THF, 0 °C to r.t., 1 h, 75%; (d) (i) COCl2, DMSO, Et3N, –78 °C; (ii) 1. TMS–acetylene, n-BuLi, –78 °C, 4 h; 2.
Zn(OTf)2, (–)-N-methylephedrine, Et3N, toluene, 86%; 3. Zn(OTf)2, (+)-N-methylephedrine, Et3N, toluene, 80%; (iii) K2CO3, MeOH, 0 °C, 1 h;
(e) (i) p-NO2C6H4COOH, DIAD, TPP, THF, 0 °C to r.t., 1.5 h; (ii) K2CO3, MeOH, 0 °C (84% over two steps); (f) DIPEA, MOMCl, CH2Cl2, 0
°C to r.t., 8 h.
MOMO
OMOM
MOMO
OMOM
BocHN
MOMO
OMOM
OMOM
b
c
a
HO
BocHN
8b
BocHN
OMOM
10b
OMOM
9b
11b
OH
OAc
OAc
OAc
N
N
Mes
Cl
Cl
Mes
Ph
e
d
BocHN
MOMO
OMOM
AcHN
AcO
Ru
PCy3
OMOM
12b
A
Mes = 2,4,6-(Me)3C6H2
13b
Scheme 2 Reagents and conditions: (a) CuCl2·2H2O, MeCN, 0 °C, 0.5 h, 92%; (b) (i) COCl2, DMSO, Et3N, –78 °C; (ii) Me+PPh3I–, t-BuOK,
THF, 0 °C, 8 h, 64%; (c) Grubbs II (A, 10 mol%), ethylene atmosphere, toluene, 110 °C, 12 h, 92%; (d) (i) OsO4, NMMO (0.05 equiv), acetone–
H2O (4:1), 5 h; (ii) NaIO4, MeOH–H2O (9:1), 0 °C, 1 h; (iii) NaBH4, MeOH, 0 °C, 5 min (62% over three steps); (e) (i) TFA, CH2Cl2, 0 °C,
4 h; (ii) Ac2O, pyridine, DMAP, CH2Cl2, r.t., 14 h (70% over two steps).
Synlett 2009, No. 2, 209–212 © Thieme Stuttgart · New York

LETTER
(+)-Valienamine and (+)-4-epi-Valienamine
211
MOMO
OMOM
MOMO
OMOM
c
a
b
HO
BocHN
8a
BocHN
OMOM
10a
OMOM
9a
OAc
OAc
OH
OMOM
OMOM
AcHN
BocHN
BocHN
OMOM
OMOM
d
e
AcO
OAc
13a
MOMO
MOMO
11a
12a
Scheme 3 Reagents and conditions; (a) CuCl2·2H2O, MeCN, 0 °C, 0.5 h, 89%; (b) (i) COCl2, DMSO, Et3N, –78 °C; (ii) Me+PPh3I–, t-BuOK,
THF, 0 °C, 12 h, 61%; (c) Grubbs II (10 mol%), ethylene atmosphere, toluene, 110 °C, 8 h, 95%; (d) (i) OsO4, NMMO (0.05 equiv), acetone–
H2O (4:1), 5 h; (ii) NaIO4, MeOH–H2O (9:1), 0 °C, 1 h; (iii) NaBH4, MeOH, 0 °C, 5 min (70% over three steps); (e) (i) TFA, CH2Cl2, 0 °C,
4 h; (ii) Ac2O, pyridine, DMAP, CH2Cl2, r.t., 14 h, (68% over two steps).
under two different solvents systems, in CH2Cl2 and in tive 13a (68% overall yield for two steps). Interestingly,
toluene independently. Both the reactions offered the de- aminocyclitol 2 (Figure 1) might be considered as a po-
sired product 11b, albeit in low yields. Gratifyingly, the tential a-galactosidase inhibitor.
same reaction in toluene (110 °C) under an ethylene
In conclusion, a stereoselective total synthesis of (+)-
valienamine and (+)-4-epi-valienamine, a hitherto unre-
ported diastereomer has been accomplished by the ring-
closing enyne metathesis approach to access the carbo-
atmosphere17b furnished vinylcyclohexene derivative 11b
in high yield (92%). Compound 11b was identified from
its spectral data. The 1H NMR spectrum of 11b indicated
the absence of the acetylenic and terminal olefinic protons
cyclic framework possessing a vinylic olefin which was
whilst displaying the characteristic olefinic protons at d =
selectively transformed into a hydroxymethyl group. In-
6.24 ppm as a double doublet (J = 10.9, 17.3 Hz), at d =
terestingly a closer derivative N-octyl-4-epi-b-valien-
5.78 ppm as a double doublet (J = 3.0, 15.8 Hz), at d =
5.44 as a doublet (J = 16.9 Hz) and at d = 5.10 ppm as a
doublet (J = 10.9 Hz). The mass spectrum had an [M + H]
peak at m/z = 404 in support of the assigned structure.
amine (NOEV)19 was found useful in molecular therapy
for certain patients with b-galactosidosis and other lyso-
somal storage associated diseases involving the central
nervous system.
With the vinylcyclohexene derivative 11b in hand, the
next task was the selective transformation of the vinylic
double bond into a hydroxymethyl side chain. The con-
version was planned via a sequential dihydroxylation–
oxidative cleavage–reduction protocol. For example, se-
lective dihydroxylation of the vinylic olefin 11b (OsO4,
NMO, acetone–H2O) and the oxidative cleavage of the
ensuing diol (NaIO4, MeOH–H2O, r.t.) gave the corre-
sponding aldehyde which was reduced (NaBH4, MeOH,
0 ºC) to afford the carbocyclic methanol 12b (62% overall
yield for three steps) without any purification of the inter-
mediates. Global deprotection of MOM and Boc protect-
ing groups with TFA in CH2Cl2 at room temperature
afforded valienamine (1) which on acetylation (Ac2O, py-
ridine, DMAP, CH2Cl2, r.t., 14 h) furnished the pentaace-
tate derivative 13b (70% overall yield for two steps) to
facilitate its easy isolation and characterization. The phys-
ical and spectroscopic data of 13b {mp 94 ºC, [a]25D +22.7
(c = 0.62, CHCl3)} were identical to the reported values
{lit.11b mp 91.5–93 ºC; [a]D +21.1 (c = 0.9, CHCl3) and
lit.9a mp 92–94 ºC; [a]20 D +20.1 (c = 0.8, CHCl3)}.
Acknowledgment
One of the authors (P.S.R.) thanks the CSIR, New Delhi, for finan-
cial support in the form of a fellowship.
References and Notes
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In a related approach (Scheme 3), when 8a was used as
the starting material and subjected to the same set of trans-
formations (Scheme 2), a non-natural 4-epi-valienamine
(2; Figure 1) was obtained as the product. Compound 2
was thoroughly characterized18 as its pentaacetate deriva-
Synlett 2009, No. 2, 209–212 © Thieme Stuttgart · New York

212
P. Radha Krishna, P. Srinivas Reddy
LETTER
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1980, 19, 904. (b) Paulsen, H.; Heiker, F. R. Liebigs Ann.
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1987, 26, 482. (b) Nicotra, F.; Panza, L.; Ronchetti, F.;
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55.8, 55.6, 29.0. IR (neat): 3416, 2925, 2854, 1717, 1609,
1510, 1156, 1024 cm–1. HRMS: m/z [M + H]+ calcd for
C19H34NO8: 404.2284; found: 404.2279. Compound 13b:
white solid; mp 94 °C; [a]D25 +22.7 (c = 0.62, CHCl3). 1H
NMR (300 MHz, CDCl3): d = 5.87 (d, 1 H, J = 4.4 Hz), 5.79
(br d, 1 H, J = 8.4 Hz), 5.43 (dd, 1 H, J = 6.4, 9.4 Hz), 5.34
(d, 1 H, J = 6.3 Hz), 4.98–5.10 (m, 2 H), 4.63 (d, 1 H, J =
13.2 Hz), 4.36 (d, 1 H, J = 13.2 Hz), 2.01–2.06 (m, 15 H).
13C NMR (75 MHz, CDCl3): d = 170.3, 170.2, 170.1, 169.9,
169.8, 134.3, 126.1, 71.2, 69.0, 68.5, 62.9, 44.8, 23.3, 20.7.
IR (neat): 3287, 2925, 1746, 1658, 1371, 1225, 1031 cm–1.
HRMS: m/z [M + Na]+ calcd for C17H23NO9Na: 408.1270;
25
found: 408.1263. Compound 10a: syrupy liquid; [a]D
–187.0 (c = 0.55, CHCl3). 1H NMR (300 MHz, CDCl3): d =
5.79–5.97 (m, 1 H), 5.15–5.32 (m, 2 H), 4.91 (q, 1 H, J = 8.3,
15.1 Hz), 4.75 (dd, 3 H, J = 6.0, 17.3 Hz), 4.60 (t, 2 H, J =
6.8, 15.1 Hz), 4.37–4.46 (m, 1 H), 3.91 (t, 1 H, J = 5.2 Hz),
3.78 (m, 2 H), 3.44 (s, 3 H), 3.37 (m, 6 H), 2.44 (d, 1 H, J =
2.2 Hz), 1.44 (s, 9 H). 13C NMR (75 MHz, CDCl3): d =
155.3, 134.9, 112.3, 98.6, 96.9, 92.7, 79.8, 79.1, 78.4, 77.2,
66.8, 57.4, 56.7, 56.0, 52.9, 28.2. IR (neat): 3438, 3210,
2927, 2852, 2140, 1715, 1610, 1506, 1156, 1026 cm–1.
HRMS: m/z calcd for C19H34NO8: 404.2284; found:
404.2291. Compound 11a: light yellow syrup; [a]D25 +62.68
(c = 2.6, CHCl3). 1H NMR (300 MHz, CDCl3): d = 6.27 (dd,
1 H, J = 11.0, 17.5 Hz), 5.80 (br d, 1 H, J = 2.8 Hz), 5.44 (d,
1 H, J = 17.5 Hz), 5.06–5.12 (m, 2 H), 4.80 (d, 1 H, J = 7.0
Hz), 4.60–4.74 (m, 6 H), 4.28 (br s, 1 H), 4.10 (dd, 1 H, J =
2.1, 5.2 Hz), 3.86 (t, 1 H, J = 5.2 Hz), 3.42 (s, 3 H), 3.41 (s,
3 H), 3.39 (s, 3 H), 1.45 (s, 9 H). 13C NMR (75 MHz,
CDCl3): d = 155.4, 136.8, 133.4, 129.0, 112.6, 97.5, 96.9,
96.3, 80.1, 74.7, 71.9, 71.0, 57.2, 56.0, 55.7, 28.3. IR (neat):
3366, 2925, 1714, 1158, 1020 cm–1. HRMS: m/z [M + H]+
calcd for C19H34NO8: 404.2284; found: 404.2280.
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2007, 63, 3995. (d) Radha Krishna, P.; Narsingam, M.
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(18) Spectral data for selected compounds: Compound 10b: light
yellow syrup; [a]D25 +11.96 (c = 0.59, CHCl3). 1H NMR (300
MHz, CDCl3): d = 6.01 (m, 2 H), 5.20–5.34 (m, 2 H), 4.89
(q, 1 H, J = 8.8, 15.4 Hz), 4.80 (dd, 1 H, J = 4.0, 7.0 Hz),
4.66–4.76 (m, 2 H), 4.50–4.62 (m, 2 H), 4.38 (br s, 1 H), 4.02
(t, 1 H, J = 3.3 Hz), 3.76–3.83 (m, 2 H), 3.46 (s, 3 H), 3.43
(s, 3 H), 3.36 (s, 3 H), 2.46 (d, 1 H, J = 1.8 Hz), 1.44 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 155.6, 135.1, 116.6, 99.3,
97.2, 94.4, 79.5, 79.4, 77.9, 76.0, 67.1, 56.8, 56.1, 55.9, 53.8,
28.3. IR (neat): 3425, 3252, 2930, 2250, 2154, 1714, 1640,
1502, 1158, 1026 cm–1. HRMS: m/z [M + Na]+ calcd for
C19H33NO8Na: 426.2103; found: 426.2107. Compound 11b:
light yellow syrup; [a]D25 –77.21 (c = 0.76, CHCl3). 1H
NMR (300 MHz, CDCl3): d = 6.24 (dd, 1 H, J = 11.0, 17.4
Hz), 5.78 (dd, 1 H, J = 3.0, 15.9 Hz), 5.44 (d, 1 H, J = 16.9
Hz), 5.10 (d, 1 H, J = 10.9 Hz), 4.90 (dd, 1 H, J = 3.4, 7.1
Hz), 4.60–4.82 (m, 6 H), 4.50 (br d, 1 H, J = 2.2 Hz), 4.29
(br s, 1 H), 4.10 (dd, 1 H, J = 2.2, 5.2 Hz), 3.86 (t, 1 H, J =
4.9 Hz), 3.42 (s, 3 H), 3.40 (s, 3 H), 3.39 (s, 3 H), 1.45 (s,
9 H). 13C NMR (75 MHz, CDCl3): d = 155.6, 136.6, 135.2,
129.5, 114.4, 96.4, 96.3, 95.9, 79.4, 73.5, 72.7, 72.4, 56.3,
Compound 13a: thick white syrup; [a]D25 +69.6 (c = 0.58,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 5.99 (d, 1 H, J =
5.3 Hz), 5.82 (d, 1 H, J = 8.3 Hz), 5.44 (dd, 1 H, J = 6.8, 11.5
Hz), 5.27 (br dd, 1 H, J = 4.1, 6.2 Hz), 4.96–5.07 (m, 2 H),
4.66 (dd, 1 H, J = 1.5, 12.8 Hz), 4.33 (dd, 1 H, J = 1.5, 13.6
Hz), 2.07 (s, 3 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 2.02 (s, 3 H),
2.00 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 170.5, 170.2,
170.1, 169.9, 169.8, 132.2, 127.0, 72.7, 70.9, 66.0, 62.2,
46.7, 23.1, 20.6. IR (neat): 3447, 2963, 1742, 1647, 1260,
1020 cm–1. HRMS: m/z [M + Na]+ calcd for C17H23NO9Na:
408.1270; found: 408.1265.
(19) Matsuda, J.; Suzuki, O.; Oshima, A.; Yamamoto, Y.;
Noguchi, A.; Takimoto, K.; Itoh, M.; Matsuzaki, Y.;
Yasuda, Y.; Ogawa, S.; Sakata, Y.; Nanba, E.; Hizaki, K.;
Ogawa, Y.; Tominaga, L.; Ohno, K.; Iwasaki, H.; Watanabe,
H.; Brady, R. O.; Suzuki, Y. Proc. Natl. Acad. Sci. U.S.A.
2003, 100, 15912.
Synlett 2009, No. 2, 209–212 © Thieme Stuttgart · New York

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