Carbasugar Synthesis via Vinylogous Ketal: Total Syntheses of (+)-MK7607, (-)-MK7607, (-)-Gabosine A, (-)-Epoxydine B, (-)-Epoxydine C, epi-(+)-Gabosine e and epi-(+)-MK7607

Article abstract of DOI:10.1021/acs.joc.6b01876

Carbasugars, the carbocyclic analogues of sugars, constitute an important class of natural products with more than 140 members known and have attracted much attention due to their diverse biological activities like anticancer, antibacterial, herbicidal, and various enzyme inhibitory activities. As many carbohydrates are involved in various cellular signaling pathways, there is great interest in synthesis and biological exploration of carbasugars. Herein, we have developed a methodology to install an α,β-unsaturated aldehyde functionality on different inositols and derivatives by vinylogous elimination of the O-protecting group under mildly acidic condition. We have illustrated the versatility and utility of our methodology by the total syntheses of seven carbasugars viz. (-)-MK7607, (-)-gabosine A, (-)-epoxydine B, (-)-epoxydine C, (+)-MK7607, 1-epi-(+)-MK7607 and 1-epi-(+)-gabosine E.

Full text of DOI:10.1021/acs.joc.6b01876

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Article
Carbasugar synthesis via vinylogous ketal: Total syntheses
of (+)-MK7607, (-)-MK7607, (-)-Gabosine A, (-)-Epoxydine
B, (-)-Epoxydine C, epi-(+)-Gabosine E and epi-(+)-MK7607
Soumik Mondal, and Kana M. Sureshan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01876 • Publication Date (Web): 03 Nov 2016
Downloaded from http://pubs.acs.org on November 3, 2016
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Carbasugar synthesis via vinylogous ketal: Total syntheses of (+)-
MK7607, (-)-MK7607, (-)-Gabosine A, (-)-Epoxydine B, (-)-
Epoxydine C, epi-(+)-Gabosine E and epi-(+)-MK7607
Soumik Mondal, and Kana M. Sureshan*
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Indian Institute of Science Education and Research Thiruvananthapuram, Keralaꢀ695016 (India).
Email: kms@iisertvm.ac.in
Keywords: Carbasugars • Natural products • Vinylogy • Total synthesis • Inositols
Abstract
MeO
P1O
(+)-MK7607
(-)-MK7607
CHO
OP3
P1O
P2O
OMe
OP4
(-)-Gabosine A
(-)-Epoxydine B
(-)-Epoxydine C
1-epi-(+)-Gabosine E
1-epi-(+)-MK7607
OP4
P2O
OP3
Vinylogous ketal
Key intermediate
Carbasugar Natural
Products
Carbasugars, the carbocyclic analogs of sugars, constitute an important class of natural
products with more than 140 members known and have attracted much attention due to their
diverse biological activities like anticancer, antibacterial, herbicidal, and various enzyme
inhibitory activities. As many carbohydrates are involved in various cellular signaling pathways,
there is great interest in synthesis and biological exploration of carbasugars. Herein, we have
developed a methodology to install an α,βꢀunsaturated aldehyde functionality on different
inositols and derivatives by vinylogous elimination of the Oꢀprotecting group under mildly acidic
condition. We have illustrated the versatility and utility of our methodology by the total
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syntheses of seven carbasugars viz. (ꢀ)ꢀMK7607, (ꢀ)ꢀgabosine A, (ꢀ)ꢀepoxydine B, (ꢀ)ꢀepoxydine
C, (+)ꢀMK7607, 1ꢀepiꢀ(+)ꢀMK7607 and 1ꢀepiꢀ(+)ꢀgabosine E.
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Carbasugars, a subclass of cyclitols, are structural mimics of glycopyranosides wherein
the ring oxygen is replaced by a methylene (or methyne) group. More than 140 natural
carbasugars are known and they are known to possess a diverse range of biological activities.1 A
major fraction of carbasugars are C7ꢀcyclitols with polyhydroxylated cyclohexene having a oneꢀ
carbon side chain in the form of methyl, hydroxymethyl, carboxyl or formyl group (Chart 1).
HO
HO
R1O
BzO
R1O
R1O
HO
R2O
BzO
R1O
R2
R2O
R3
OR4
R2O
OR4
OR3
R1 R2 R3 R4
OH
OH
R1 R2 R3
Uvacalol F Ac Bz Cl
Uvacalol G OBz
OR3
R1
R2
R1 R2 R3 R4
Lincitol A
OCOPri
Lincitol B COPri OH
H
Uvacalol A Ac Bz H Et
Uvacalol B Ac H Bz Et
Uvacalol C Ac H H Et
Uvacalol D H Me H H
Uvacalol E Ac H H Bz
Uvacalol I Bz Bz H Et
Uvacalol J Bz H Bz Et
Uvacalol K Bz Bz H H
Uvamalol A Bz H Bz H
Gabosine K Ac H H H
H
H
Uvacalol H Bz Ac OH
Piperenol A H Bz OH
Piperenol B H Bz OAc
Streptol
H
OH
Valienamine H
NH2
R1
O
RO
O
R
R
COOMe
COOMe
HO
HO
Cl
MeO
HO
O
HO
R2O
OH
HO
OH
OH
OH
O
HO
OH
OH
OH
OH
OH
OH
OH
R
R1 R2
R
R
Gabosine G OAc
Gabosine H
Gabosine I OH
Pericosine A
COOMe
Gabosine D Ac
Gabosine E H
Gabosine C OH
Gabosine N H
Pericosine B
Gabosine A H
H
H
Unnamed OH Ac
COTC
OCOCHCHMe
Epoxidine B OH Furoyl
HO
HO
HO
HO
COOMe
Me
COOMe
Cl
Cl
OH
O
MeO
HO
HO
OH
OH HO
OH
OH
HO
OH
HO
HO
O
OH
Pericosine D
OH
MK7607
OH
Gabosine J
OH
OH
Gabosine L
Pericosine D0
Pericosine C
Chart 1. Representative C7ꢀcarbasugar natural products with cyclohexenyl core
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By using this basic structural motif, Nature has made a combinatorial library of diverse natural
products by exploiting the variables such as stereochemistry, double bond, oxidation states,
position and number of substituents.2 Due to their structural diversity and promising biological
activities, there is great interest in the synthesis of carbasugars and their analogs.3 The crucial
step in all these syntheses is the construction of cyclohexenyl ring.4 Synthesis from inositol
derivatives would be ideal as it not only eliminates the tedious cyclization step but also offers
several preꢀinstalled stereogenic centers. In this context, recently, we have developed a
methodology for the synthesis of C7ꢀcyclitols from myoꢀinositol by incorporating an α,βꢀ
unsaturated aldehyde moiety through a vinylogous ring opening of its orthoester cage under
mildly acidic condition. By applying this methodology, we have synthesized several natural
carbasugars in their racemic form.5 However, this methodology is limited to syntheses starting
from inositols which can form stable orthoesters. Herein, we report a general method for the
synthesis of carbasugar natural products and demonstrate the utility of this method by
synthesizing five carbasugar natural products and two unnatural carbasugars, viz. (+)ꢀMK7607, (ꢀ
)ꢀMK7607, (ꢀ)ꢀGabosine A, (ꢀ)ꢀEpoxydine B, (ꢀ)ꢀEpoxydine C, 1ꢀepiꢀ(+)ꢀMK7607 and 1ꢀepiꢀ(+)ꢀ
Gabosine E.
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A
OH
OH
OH
OH
OH
OH
OH
5
6
7
8
HO
HO
HO
HO
OMe
OH
OMe
OH
HO
OH
OH
HO
HO
OMe
OH
MeO
9
OH
D-Pinitol
2
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D-Bornesitol
D-Ononitol
4
L-Quebrachitol
1
3
B
MeO
P1O
MeO
P1O
OH
CHO
P1O
H
HO
HO
OMe
OH
OMe
OP4
OMe
H2O
H
P2O
OP3
OP4
P2O
P2O
OP3
OP4
OP3
OH
Vinylogous ketal
II
Enal
IV
Methylated cyclitol
I
III
Figure 1. (A) Chiral methyl inositol. (B) Proposed generation of C7ꢀcyclitol skeleton via
vinylogous ketal cleavage.
Several chiral Oꢀmethylꢀinositols occur in nature; LꢀQuebrachitol (2ꢀOꢀmethylꢀLꢀchiroꢀ
inositol) and Dꢀpinitol (3ꢀOꢀmethylꢀDꢀchiroꢀinositol) are abundant and cheaply available.
Though they have been used as chiral pool for the synthesis of many natural products,6 they have
not been used for the synthesis of carbasugars. We envisaged to use these cyclitols as chiral
pools for the synthesis of carbasugars. One of the limitations for their use as starting material is
the laborious and lowꢀyielding demethylation. To use them for carbasugar synthesis, in addition
to the introduction of the double bond and the side chain, an effective demethylation strategy is
also essential. We envisioned to do all these three structural modifications by a single reaction;
via the introduction of a methoxymethylidene group at the vicinal carbon with respect to the
methoxy group and cleavage of the vinylogous ketal thus formed under mildly acidic condition
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(Figure 1). Homologation of pyranosides by vinylogous elimination of alkoxy group has been
reported.7
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Results and Discussion
To test our hypothesis, Lꢀquebrachitol (1) was converted to the ketone 5,8 which on Wittig
n
reaction with methoxymethyltriphenylphosphonium chloride and BuLi produced the enolꢀether
6. Similarly, Dꢀpinitol (2) was converted to the enolꢀether 9 through a sequence of ketalization,
oxidation9 and Wittig reactions. While the enol ether 6 was obtained as an inseparable mixture of
E/Z isomers, the enol ether 9 was obtained as a single isomer. However, we have not assigned
the geometry of the double bond as it is inconsequential for further reactions. The enolꢀether 6 on
treatment with CSA in wet acetone at rt produced the diol aldehyde 7 in 94% yield. On the other
hand, the pinitol derived enolꢀether 9 under similar condition gave the aldehyde 10 as the
exclusive product. It is interesting to note that compound 6 having three different kinds of ketals;
a cisꢀketal, a transꢀketal and a vinylogous ketal, underwent hydrolysis cleaving the latter two, but
the enolꢀether 9 having two cisꢀketals and a vinylogous ketal, underwent hydrolysis cleaving the
latter alone. It is clear that the cisꢀketals are stable irrespective of their position, under the
conditions for cleavage of vinylogous ketal (Scheme 1). The relatively higher stability of cisꢀ
ketals over transꢀketals under mildly acidic condition is documented in the literature.10 In both 6
and 9, the methoxymethylidene motif is flanked by a methoxy group and a cisꢀketal group. It was
delighting to note the regiospecific vinylogous ketal cleavage leading to the cleavage of the
methyl ether alone leaving the cisꢀketal unaffected. The advanced intermediates 7 and 10 can be
used for the synthesis of several carbasugar natural products.
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OMe
OH
OH
O
O
7
5
HO
HO
OMe
OH
O
O
OMe
O
OMe
O
O
O
a
ref. 8
O
O
b
1
3
OH
O
5
O
6
OH
Quebrachitol (1)
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O
O
MeO
O
7
5
OH
O
OMe
O
HO
HO
OMe
OH
O
OMe
O
ref. 9
a
b
1
3
O
O
O
O
O
8
OH
Pinitol (2)
O
10
O
9
Scheme 1. Demethylative construction of cyclohexenal intermediate by vinylogous ketal
n
cleavage. Reagents and conditions: a) Ph3PCH2OMeCl, BuLi, THF, 8 h, (6: 55%; 9: 62%); b)
CSA, acetone, rt, (7: 1 h, 94%; 10: 30 min., 94%).
(ꢀ)ꢀGabosine A, isolated from the Streptomyces strain,11 shows DNA binding activity and it
has been a target for total synthesis.12 In order to illustrate the utility of our methodology, we
have planned to synthesize (ꢀ)ꢀgabosine A (Scheme 2). Thus, the aldehyde 10 was reduced to the
primary alcohol 11 in 90% yield. The alcohol 11 was mesylated and the mesylate 12 (97%) was
o
treated with LiAlH4 in THF at 0 C to get the diacetonide 13 in 91% yield. The diketal 13 was
treated with CSA in methanol to get an inseparable mixture of diols. These diols were alkylated
with PMBCl and the resulting diꢀPMB derivatives were also inseparable. Deprotection of the
remaining isopropylidene group with CSA in methanol afforded two diols and the major isomer
14 was isolated in 60% yield over three steps. Then it was envisaged that gabosine A could be
obtained from diol 14 by chemoselective oxidation of the allylic hydroxyl group followed by the
deprotection of protecting groups. Chemoselective allylic oxidation of diol 14 with PDC in DCM
gave the ketone 15 (85%) as expected. The structure of the ketone 15 was confirmed by the 2D
NMR techniques. The coupling of Hꢀ2 with Hꢀ1 and Hꢀ3 with coupling constants 3.5 Hz and
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10.6 Hz respectively suggested that Hꢀ2 is flanked by Hꢀ1 and Hꢀ3, suggesting that the allylic
hydroxyl group (4ꢀOH) was oxidized selectively. Finally, deprotection of PMB groups gave (ꢀ)ꢀ
7
8
9
gabosine A (16) in 81% yield (overall yield from pinitol: 20%).
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MsO
HO
O
7Me
7
5
5
O
O
O
O
O
O
O
a
g
c
b
1
1
3
O
O
3
O
O
O
O
12
O
13
O
10
O
11
d
HO
HO
Me
Me
Me
O
O
HO
HO
f
e
HO
HO
OH
OPMB
OPMB
HO
OH
OH
OPMB
OPMB
OH
14
15
(-)-MK7607 (17)
(-)-gabosine A (16)
Scheme 2. Total syntheses of (ꢀ)ꢀGabosine A (16), and (ꢀ)ꢀMK7607 (17). Reagents and
o
conditions: a) NaBH4, MeOH, rt, 30 min., 90%; b) MsCl, Et3N, 0 C, 20 min., 97%; c) LiAlH4,
o
o
THF, 0 C to rt, 1 h, 91%; d) i. CSA, MeOH, 2 h; ii. PMBCl, NaH, DMF, 0 C, 30 min.; iii.
CSA, MeOH, rt, 2 h, (60% in 3 steps); e) PDC, DCM, rt, 30 min., 85%; f) TFA, DCM, rt, 20
min., 81%; g) TFA, DCM, rt, 10 min., 100%.
(+)ꢀMK7607, is an αꢀgalactose mimic and was isolated from the cultures of Curvularia
eragrostidis D2452. Due to its potent herbicidal activity,13 there is considerable interest in total
synthesis of both natural2c,3e and unnatural14 enantiomers. We have decided to synthesize (ꢀ)ꢀ
MK7607 from alcohol 11 by cleavage of the ketal protecting groups. Thus the treatment of 11
with TFA gave (ꢀ)ꢀMK7607 (17) in quantitative yield (Scheme 2). To the best of our knowledge,
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this sixꢀstep synthesis from Dꢀpinitol (overall yield of 40%) is the shortest synthesis of (ꢀ)ꢀ
MK7607.
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Epoxydine B (20) and epoxydine C (22) are two structurally related natural carbasugars
known to possess antibacterial, antifungal and antialgal activities.15 Though the compound 22
was not given any name in the literature, as it was isolated from the same source as epoxydine B
and its structure is similar to epoxydine B, for the sake of convenience, we tentatively named it
as epoxydine C. To the best of our knowledge, no synthesis of any of these natural products has
been reported so far. Hence, we have planned to synthesize and validate the structures of these
two carbasugars by using our methodology. Partial cleavage of the ketal groups in the alcohol 11
by the treatment with CSA in methanol, gave an inseparable mixture of two triols, which on
alkylation with excess PMBCl followed by the acid catalyzed cleavage of the remaining ketal
group gave the diol 18 (46%) as the major product (Scheme 3). Furoylation of the diol 18 gave
an inseparable mixture of two monoꢀesters in 1:1 ratio (92%). Interestingly, both hydroxyl
groups of the cisꢀdiol 18 (one pseudoequatorial and one pseudoaxial hydroxyl groups) have
shown similar reactivity towards esterification. This could be due to the ring puckering of
cyclohexene ring to form either Cꢀ3 endo (A) or Cꢀ2 endo (B) conformers, which can
interconvert rapidly at the room temperature. While in the Cꢀ2 endo conformer 3ꢀOH is
pseudoaxial and 4ꢀOH is pseudoequatorial, in the Cꢀ3 endo conformer, 3ꢀOH is pseudoequatorial
and 4ꢀOH is pseudoaxial. The plausible interconversion of these conformers could make both the
hydroxyl groups almost equivalent (both attain pseudoaxial and pseudoequatorial orientation) in
reactivity. This is a probable reason for the formation of both the esters in equal amounts (Chart.
2).
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OPMB
H
3
OPMB 2
PMBO
H
HO
OPMB
H
H
1
4
OPMB
4
H
1
H
HO
H
OH
OPMB
2
3
H
OH
B
A
C-3-Endo
C-2-Endo
10
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Chart 2. Plausible conformations of diol 18
As one of the esters is having an allylic alcohol, we envisioned that this compound can be
selectively oxidized in preference of the nonꢀallylic alcohol. Thus the mixture of esters was
treated with PDC in DCM and to our satisfaction, the ester containing allylic hydroxyl group
underwent selective oxidation to give the ketone 19 in 38% yield over two steps. COSY NMR
spectrum of the ketone 19 revealed that Hꢀ2 couples with Hꢀ1 and Hꢀ3 with coupling constants
3.4 Hz (3JH1H2) and 10.6 Hz (3J H2H3), which is possible only if the allylic alcohol is oxidized.
Final deprotection of the hydroxyl groups by treatment of the ketone 19 with 10% TFA in DCM
gave (ꢀ)ꢀepoxydine B (20) in 81% yield (Scheme 3). H and 13C NMR spectra were found to
1
match with the reported data.15b
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PMBO
HO
PMBO
7
5
7
5
O
O
O
HO
HO
b
a
1
1
3
3
OPMB
O
O
OPMB
OPMB
19
O
OPMB
18
O
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11
O
c
d
HO
HO
PMBO
O
7
5
O
O
e
1
O
OH
AcO
3
OH
AcO
OPMB
OH
OH
(-)-Epoxydine C (22)
OPMB
O
21
O
(36% in 2 steps)
(-)-Epoxydine B (20)
Scheme 3. Total synthesis of (ꢀ)ꢀepoxydine B (20) and (ꢀ)ꢀepoxydine C (22). Reagents and
conditions: a) i. CSA, MeOH, 3 h; ii. PMBCl, NaH, DMF, 0 oC, 30 min.; iii. CSA, MeOH, rt, 4
h, (46% in 3 steps); b) i. furoyl chloride, pyr, 0 oC to rt, 2 h; ii. PDC, DCM, rt, 30 min., 38% in 2
o
steps; c) TFA, DCM, rt, 20 min., 81%; d) AcCl, pyr, 0 C to rt, 2 h; ii. PDC, DCM, rt, 25 min,
36% from 2 steps; e) TFA, DCM, rt, 20 min., 87%.
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Scheme 4. Total synthesis of (+)ꢀMK7607 (30). Reagents and conditions: a) 2ꢀmethoxypropene,
o
DMF, 60 C, 1 h, 89%; b) TBDMSCl, imidazole, DCM, rt, 4 h, 91%; c) DMP, DCM, rt, 1 h,
o
94%; d) Ph3PCH2OMeCl, nBuLi, THF, ꢀ 40 C to rt, 8 h, 56%; e) CSA, acetone, rt, 1 h, 92%; f)
NaBH4, MeOH, rt, 30 min., 91%; g) TFA, DCM, rt, 20 min., 100%.
Similarly, for the total synthesis of the epoxydine C, the diol 18 was treated with one
equivalent of acetyl chloride in pyridine to introduce one acetyl group at 3ꢀposition. But, in this
case also, an inseparable mixture of two monoꢀacetates (3ꢀester and 4ꢀester) was obtained in 1:1
ratio. These monoesters on treatment with PDC in DCM underwent selective oxidation of only
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the compound having the allylic alcohol giving the ketone 21. Structure of the ketone 21 was
confirmed by COSY NMR spectroscopy. Coupling of Hꢀ2 with Hꢀ1 and Hꢀ3 with coupling
constants 3.5 Hz (JH1H2) and 10.6 Hz (JH2H3) respectively proved that Hꢀ2 is flanked by Hꢀ1 and
Hꢀ3 and this is possible only if the allylic position is oxidized. The ketone could be separated
(36% over two steps) from the unreacted monoester by column chromatography. The ketone 21
on treatment with TFA in DCM underwent smooth PMB cleavage to give epoxydine C (22) in
87% yield (Scheme 3). The Hꢀ3 signal appeared as a doublet with JH2H3 coupling constant of 10.5
Hz suggesting that no epimerization has happened at Cꢀ3 during the hydrolysis. The NMR data
were found to match with the reported data.15a
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We wondered whether this methodology is applicable in polyols having other Oꢀprotecting
groups than methyl ether. In order to test this, we have decided to use TBDMS ether instead of
methyl ether (Scheme 4). Thus, Lꢀchiro inositolꢀderived diol 2416 was monosilylated and the
resultant alcohol 25 (91% yield) was oxidized to the ketone 26, in 94% yield. Wittig reaction of
the ketone 26 gave the enolꢀether 27 (56%) as a single isomer. However, the stereochemistry of
the double bond was not assigned as it is irrelevant for further reactions. The enolꢀether 27 on
treatment with the catalytic amount of CSA gave the aldehyde 28 in 92% yield. It is worthy to
note that change of methyl ether to silyl ether neither affected the course of the reaction nor the
regiospecificity suggesting that our methodology can be extended to systems not having a
methoxy unit also. As observed earlier, the cisꢀketal was found to be more stable than TBDMS
ether. Reduction of the aldehyde 28 gave the alcohol 29 (91%), which on global deprotection
with TFA yielded (+)ꢀMK7607 (30) in quantitative yield. Thus, we could achieve the total
synthesis of (+)ꢀMK7607 in seven steps from Lꢀchiroꢀinositol in 31% overall yield. To the best
of our knowledge, this is the shortest synthesis of (+)ꢀMK7607, so far.
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O
O
O
O
O
O
OH
O
O
O
O
O
b
a
OMe
RO
BzO
BzO
O
O
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33
R = H, 31
R = Bz, 32
34a (E)+34b (Z)
c
OH OH
O
OH
O
O
HO
O
O
7
5
e
d
3
HO
HO
BzO
1
OH
OH
36
OH
35
1-epi-(+)-MK7607 (37)
f
OH OPMB
O
OPMB
O
OPMB
HO
HO
O
h
g
PMBO
PMBO
PMBO
OPMB
39
OPMB
40
OPMB
38
i
O
OH
HO
HO
OH
1-epi-(+)-Gabosine E (41)
Scheme 5. Total synthesis of 1ꢀepiꢀ(+)ꢀMK7607 (37) and 1ꢀepiꢀ(+)ꢀGabosine E (41). Reagents
and conditions: a) DMP, DCM, 1 h, 94%; b) Ph3PCH2OMeCl, tBuOK, THF, ꢀ0 oC to rt, 8 h, 73%
(E:Z, 1:1); c) CSA, acetone, rt, 30 min., 92%; d) i. NaBH4, MeOH, rt, 30 min.; ii. NaOH, MeOH,
rt, 10 min., 85% from 2 steps; e) HCl, MeOH, 10 min., 100%; f) PMBCl, NaH, DMF, 0 oC to rt,
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20 min., 92%; g) CSA, MeOH, 1 h, 89%; h) DMP, DCM, rt, 15 min, 89%; i) TFA, DCM, rt, 20
min., 85%.
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1ꢀepiꢀ(+)ꢀMK7607 (37) is a synthetic carbasugar having the high affinity for galactoseꢀ
binding lectin and thus has the potential to be a competitive inhibitor for this lectin.2c Another
carbasugar having antimicrobial activity and spermicidal activity, isolated from Aspergillus
varians (KMM4630) was given the structure 41 (1ꢀepiꢀgabosine E).17 We have planned to
synthesize these carbasugars from myoꢀinositol derived diol (+)ꢀ31 (Scheme 5).18 Diol 31 was
converted to the ketone 33. Wittig reaction provided E and Z isomers of the enolꢀether 34 (73%),
which on treatment with CSA in wet acetone yielded the enal 35 exclusively (92%). In the enolꢀ
ether 34, the transꢀketal is also part of the vinylogous ketal. It is interesting to note that, in this
case, the transꢀketal prefers to be cleaved vinylogously. Reduction of the enal 35 gave the diol,
which on alcoholysis provided the triol 36 (85% in two steps). Hydrolytic removal of the ketal
motif provided 1ꢀepiꢀ(+)ꢀMK7607 (37) in quantitative yield.
For the synthesis of 1ꢀepiꢀgabosine E, the triol 36 was converted to the diol 39 in an overall
yield of 82% over two steps through alkylation using PMBCl followed by the cleavage of the
cisꢀketal. Chemoselective oxidation of the allylic alcohol in 39 gave the enone 40 (89%), which
on treatment with TFA provided 41 in 85% yield. The Hꢀ3 signal appeared as a doublet with
JH2H3 coupling constant of 10.9 Hz suggesting that no epimerization has happened at Cꢀ3 during
the hydrolysis. The NMR data of 41 are in agreement with its structure. Though this is the first
synthesis of 1ꢀepiꢀgabosine E, the NMR data (chemical shifts, coupling constants and the
pattern) of this compound did not match with the reported data17 of the natural carbasugar. For
instance, reported chemical shifts of Hꢀ1, Hꢀ2, Hꢀ3, Hꢀ6 and Hꢀ7 signals of the natural
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carbasugar were 4.43, 3.68, 4.57, 6.86 and 4.13 ppm respectively, but those of 41 were found to
be 4.67, 3.65, 4.10, 6.93 and 4.24 ppm respectively. Similarly, the 13C NMR data were also
different from the reported data. This suggests that the structural assignment of the carbasugar
isolated from Asperigillus varians was wrong.
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Conclusions
In conclusion, we have developed a new methodology to install α,βꢀunsaturated aldehyde
group in different protected cyclitols by vinylogous ketal cleavage under mildly acidic condition.
We could demonstrate the utility of this methodology by total syntheses of seven structurally
different carbasugars viz. (+)ꢀMK7607, (ꢀ)ꢀMK7607, (ꢀ)ꢀGabosine A, (ꢀ)ꢀepoxidine B, (ꢀ)ꢀ
epoxydine C, 1ꢀepiꢀ(+)ꢀMK7607 and 1ꢀepiꢀ(+)ꢀGabosine E by simple protecting groups
manipulations. It could also be possible to achieve several carbasugars with different
stereochemistry by inserting the enolꢀether group at different position of cyclitols. Also, this
vinylogous ketal cleavage to introduce α,βꢀunsaturated aldehyde can be applied to other polyols.
This methodology would allow the conversion of cheap and abundant natural polyols with
preinstalled stereogenic centers such as sugars and cyclitols to advanced value added feedstocks
for various total syntheses.
Experimental Section
General procedure. TLC analyses were performed using silica gel TLC plates. UV active
compounds were spotted on silica gel TLC plates and were visualized under UV light and also,
1
by spraying ceric ammonium molybdate stain followed by heating with a hot air gun. The H
NMR, 13C NMR, DEPT, COSY and HMQC spectra were recorded using a 500 MHz NMR
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spectrometer at 25 °C. Proton chemical shifts were reported in ppm (δ) relative to
tetramethylsilane (TMS, δ 0.0 ppm) as the internal standard or with the solvent reference relative
to TMS (CDCl3, δ 7.26 ppm; D2O, δ 4.79 ppm). Data were reported as follows: chemical shift
[multiplicity (s for singlet, d for doublet, t for triplet, q for quartet, and m for multiplet), coupling
constants in Hz, peak integration and peak identification]. All unknown compounds were
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characterized by 1H NMR, C NMR, DEPT, COSY and HMQC experiments. C spectra were
recorded with complete proton decoupling. Carbon chemical shifts were recorded in ppm (δ)
relative to TMS as the internal standard. Melting points were determined using a melting point
apparatus and are uncorrected. Flash column chromatography was performed using silica gel
(200−400 mesh). All moisture sensitive reactions were carried out under inert atmosphere (argon
or nitrogen) using ovenꢀdried glassware.
(1S,2R,3R,4R)-5-formyl-3,4-O-isopropylidene-cyclohex-5-ene-1,2,3,4-tetrol (7). To
a
suspension of (methoxymethyl)triphenylphosphonium chloride (207.73 mg, 0.61 mmol) in THF
(10 mL), nBuLi (0.5 mL, 0.81 mmol, 1.6 M solution in hexane) was added slowly at ꢀ40 oC under
N2 atmosphere. To the resultant orange suspension, a solution of ketone 5 (110 mg, 0.40 mmol)
in dry THF (5 mL) was added slowly at the same temperature. The mixture was allowed to warm
to room temperature slowly and then further stirred for 8 h. After the completion of the reaction,
THF was evaporated under reduced pressure and the residue was dissolved in dichloromethane
(DCM) (100 mL) and washed with water and brine. The organic layer was separated, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude product thus obtained
was purified by flash column chromatography (EtOAc/petroleum ether, 1:5; v/v, TLC: Rf = 0.45)
to get the enol ether 6 (66.0 mg, 54.4%) as an inseparable mixture of E/Zꢀisomers with some
impurities as a colorless oil. This mixture of E/Zꢀisomers was used for the next step without
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further purification. Thus, the enol ether 6 was dissolved in wet acetone (15 mL) and CSA (50.0
mg) was added to it at room temperature. The reaction mixture was stirred for 1 h at the same
temperature. After the completion of the reaction (1 h), the solvent was evaporated under
reduced pressure and the crude product thus obtained was purified by flash column
chromatography (EtOAc/petroleum ether, 1:1; v/v) to get the aldehyde 7 (52.5 mg, 94%) as a
colorless liquid. 1H NMR (500 MHz in CDCl3): δ 1.39 (s, 3H, ꢀCH3), 1.44 (s, 3H, ꢀCH3), 3.69 (t,
J = 8.7 Hz, 1H, Hꢀ2), 4.08 (dd, J = 8.7 Hz, 6.2 Hz, 1H, Hꢀ3), 4.29 (d, J = 8.5 Hz, 1H, Hꢀ1), 4.88
(d, J = 6.1 Hz, 1H, Hꢀ4), 6.79 (d, J = 2.0 Hz, 1H, Hꢀ6), 9.55 (s, 1H, ꢀCHO); 13C NMR (125 MHz
in CDCl3): δ 26.2, 28.3, 69.2 (Cꢀ4), 70.3 (Cꢀ1), 74.2 (Cꢀ2), 77.5 (Cꢀ3), 111.6, 150.9 (Cꢀ6), 191.3.
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[α]D +7.6 (c 0.14, acetone). Elemental analysis calcd for C10H14O5: C, 56.07; H, 6.59. Found:
C, 55.81; H, 6.72.
(1R,2R,3R,4R,6S)-6-O-methyl-5-methoxymethylene-1,2:3,4-di-O-isopropylidene-
cyclohexane-1,2,3,5,6-pentol (9). To a suspension of (methoxymethyl)triphenylphosphonium
chloride (1.48 g, 4.31 mmol) in dry THF (30 mL), nBuLi (2.69 mL, 4.31 mmol, 1.6 M solution in
o
hexane) was added slowly added at ꢀ40 C under N2 atmosphere. To the resultant orange
suspension, a solution of the ketone 8 (469.72 mg, 1.73 mmol) in dry THF (20 mL) was added
slowly at the same temperature. The mixture was allowed to warm to room temperature slowly
and then further stirred for 8 h. After The completion of the reaction, THF was evaporated under
reduced pressure. The residue was dissolved in DCM (150 mL) and washed with water and
brine. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. Purification by flash column chromatography (EtOAc/petroleum ether, 1:5;
v/v) yielded the enol ether 9 (321.2 mg, 62%) as a colorless oil. 1H NMR (500 MHz in CDCl3): δ
1.24 (s, 3H, ꢀCH3), 1.27 (s, 3H, ꢀCH3), 1.28 (s, 3H, ꢀCH3), 1.37 (s, 3H, ꢀCH3), 3.16 (s, 3H, ꢀ
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OCH3), 3.34 (s, 1H, Hꢀ5), 4.36 (d, J = 7.0 Hz, 1H, Hꢀ3), 4.45 (d, J = 8.0 Hz, 1H, Hꢀ1), 4.55 (d, J
= 6.5 Hz, 1H, Hꢀ2), 5.09 (d, J = 7.5 Hz, 1H, Hꢀ6), 6.16 (s, 1H, Hꢀ7); 13C NMR (125 MHz in
CDCl3): δ 24.0, 25.8, 26.4, 55.3, 60.5, 67.1 (Cꢀ3), 72.8 (Cꢀ1), 73.1 (Cꢀ2), 75.7 (Cꢀ6), 79.4 (Cꢀ5),
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106.3, 107.4, 108.4, 152.2 (Cꢀ7). [α]D +70.6 (c 0.16, acetone). Elemental analysis calcd for
C15H24O6: C, 59.98; H, 8.05. Found: C, 59.71; H, 8.33.
(1R,2R,3R,4R)-5-formyl-1,2:3,4-di-O-isopropylidene-cyclohex-5-ene-1,2,3,4-tetrol (10). To a
solution of the enol ether 9 (220 mg, 0.73 mmol) in acetone (15 mL), CSA (20 mg) was added at
room temperature and the reaction mixture was stirred for 30 min. at the same temperature. After
the completion of the reaction, CSA was quenched with triethylamine and the reaction mixture
was concentrated under reduced pressure. The crude product thus obtained was purified by flash
column chromatography (EtOAc/petroleum ether, 1:5, v/v) to get the enal 10 (159.3 mg, 94%) as
a colorless liquid. 1H NMR (500 MHz, CDCl3): δ 1.31 (s, 6H, ꢀCH3), 1.40 (s, 6H, ꢀCH3), 4.64 (d,
J = 3.5 Hz, 1H, Hꢀ2), 4.70 (dd, J = 5.6 Hz, 2.5 Hz, 1H, Hꢀ3), 4.79 (d, J = 2.5 Hz, 1H, Hꢀ1), 4.95
(d, J = 5.8 Hz, 1H, Hꢀ4), 6.60 (s, 1H, Hꢀ6), 9.60 (s, 1H, ꢀCHO); 13C NMR (125 MHz, CDCl3): δ
25.5, 26.2, 27.4, 27.9, 67.0 (Cꢀ4), 70.5 (Cꢀ1), 72.0 (Cꢀ3), 74.0 (Cꢀ2), 109.5, 109.9, 137.2, 145.5
25
(Cꢀ6). [α]D ꢀ19.0 (c 0.1, acetone). Elemental analysis calcd for C13H18O5: C, 61.40; H, 7.14.
Found: C, 61.28; H, 7.31.
(1R,2R,3R,4R)-5-hydroxymethyl-1,2:3,4-di-O-isopropylidene-cyclohex-5-ene-1,2,3,4-tetrol
(11). To a solution of the aldehyde 10 (112 mg, 0.44 mmol) in methanol (10 mL), NaBH4 (16.65
mg, 0.44 mmol) was added at room temperature and the reaction mixture was stirred for 30 min.
at the same temperature. After the completion of the reaction (checked by the TLC), methanol
was evaporated off under reduced pressure and the crude product was dissolved in ethyl acetate
(100mL) and washed with water and brine. The organic layer was separated, concentrated under
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reduced pressure and purified by flash column chromatography (EtOAc/petroleum ether, 1:4,
v/v) to get the alcohol 11 (101.6 mg, 90%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.28
(s, 3H, ꢀCH3), 1.29 (s, 3H, ꢀCH3), 1.31 (s, 3H, ꢀCH3), 1.32 (s, 3H, ꢀCH3), 4.14ꢀ4.21 (m, 2H, Hꢀ
7A & 7B), 4.49ꢀ4.56 (m, 4H, Hꢀ1, Hꢀ2, Hꢀ3, Hꢀ4), 5.63 (s, 1H, Hꢀ6); 13C NMR (125 MHz,
CDCl3): δ 26.2, 26.4, 27.7, 28.0, 64.4 (Cꢀ7), 70.8, 71.4, 73.3, 73.4, 109.2, 109.4, 122.8 (Cꢀ6),
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136.1. [α]D +7.1 (c 0.17, acetone). Elemental analysis calcd for C13H20O5: C, 60.92; H, 7.87.
Found: C, 60.78; H, 7.98.
(1R,2R,3R,4R)-5-(mesyl(oxy)methyl)-1,2:3,4-di-O-isopropylidene-cyclohex-5-ene-1,2,3,4-
tetrol (12). To a solution of the alcohol 11 (91 mg, 0.36 mmol) in triethylamine (10 mL), mesyl
chloride (0.4 mL, 0.54 mmol) was added at 0 oC and the reaction mixture was stirred for 20 min.
at the same temperature. When TLC showed completion of the reaction (after 20 min.), the
reaction mixture was concentrated under reduced pressure. The crude product was dissolved in
DCM (100 mL) and washed with water and brine. The organic layer was separated and
concentrated under reduced pressure. The crude product thus obtained was purified by flash
column chromatography (EtOAc/petroleum ether, 1:5; v/v) to get the mesylate 12 (115.2 mg,
1
97%) as a colorless oil. H NMR (500 MHz, CDCl3): δ 1.26 (s, 3H, ꢀOCH3), 1.28 (s, 3H, ꢀ
OCH3), 1.31 (s, 3H, ꢀOCH3), 1.32 (s, 3H, ꢀOCH3), 2.98 (s, 3H, ꢀSCH3), 4.52ꢀ4.53 (brd, J = 5.3
Hz, 3H), 4.58 (dd, J = 5.0 Hz, 1.4 Hz, 1H), 4.65 (d (AB), J = 12.0 Hz, 1H), 4.81 (d (AB), J =
13
11.9 Hz, 1H), 5.76 (s, 1H); C NMR (125 MHz, CDCl3): δ 26.3, 26.4, 27.7, 27.9, 37.7, 69.5,
25
69.7, 70.4, 72.9, 73.2, 109.6, 109.7, 127.2, 130.7. [α]D
+37.7 (c 0.94, acetone). Elemental
analysis calcd for C14H22O7S: C, 50.29; H, 6.63; S 9.59. Found: C, 50.04; H, 6.82; S 9.38.
(1R,2R,3R,4R)-5-methyl-1,2:3,4-di-O-isopropylidene-cyclohex-5-ene-1,2,3,4-tetrol (13). To a
solution of mesylate 12 (109 mg, 0.33 mmol) in THF (10 mL), LiAlH4 (12.5 mg, 0.33 mmol)
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was added at 0 C and the reaction mixture was stirred for 1 h at room temperature. After the
completion of the reaction (1 h), the reaction mixture was passed through a celite bed, washed
with acetone (two times), and collected. The combined organic layer was concentrated under
reduced pressure and the crude product thus obtained was purified by flash column
chromatography (EtOAc/petroleum ether, 1:9; v/v) to get the diketal 13 (71.3 mg, 91%) as a
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colorless liquid. H NMR (500 MHz, CDCl3): δ 1.27 (s, 3H, ꢀOCH3), 1.29 (s, 3H, ꢀOCH3), 1.30
(s, 3H, ꢀOCH3), 1.31 (s, 3H, ꢀOCH3), 1.75 (s, 3H, ꢀCH3), 4.30 (d, J = 5.0 Hz, 1H, Hꢀ4), 4.43ꢀ4.47
13
(m, 3H, Hꢀ1, Hꢀ2, Hꢀ3), 5.37 (d, J = 1.1 Hz, 1H, Hꢀ6); C NMR (125 MHz, CDCl3): δ 19.6,
26.4, 26.5, 27.6, 27.9, 29.7, 71.2, 73.3, 73.68, 73.72 (Cꢀ4), 108.9, 109.1, 122.3 (Cꢀ6), 134.1. [α]D
25
ꢀ105.5 (c 0.2, acetone). Elemental analysis calcd for C13H20O4: C, 64.98; H, 8.39. Found: C,
64.76; H, 8.57.
(1R,2S,3R,4R)-1,2-bis((4-methoxybenzyl)oxy)-5-methyl-cyclohex-5-ene-1,2,3,4-diol (14). To
a solution of the diketal 13 (65 mg, 0.27 mmol) in methanol (20 mL), CSA (10 mg) was added at
the room temperature and the reaction mixture was stirred for 2 h at the same temperature. After
the
completion
of
the
reaction,
the
solvent
was
evaporated under reduced pressure and the crude product thus obtained was purified by flash
column chromatography (EtOAc/petroleum ether, 1:1, v/v) to get an inseparable mixture of 1,2ꢀ
diol and 3,4ꢀdiol (46.1 mg, 85%, brsm) as a colorless oil. This mixture of diols (46.1 mg) was
treated with NaH (27.6 mg, 0.69 mmol, 60% dispersed in mineral oil) and PMBCl (0.093 mL,
o
0.69 mmol) at 0 C for 30 min. to get an inseparable mixture of diPMB ethers (96.4 mg, 95%).
Then this mixture of compounds was treated with CSA (50 mg) in MeOH (10 mL) for 2 h to get
the diol 14 (71.8 mg, 60% after 3 steps) as the major isomer after purification by column
1
chromatography (EtOAc/petroleum ether, 1:1.5, v/v). H NMR (500 MHz, CDCl3): δ 1.79 (s,
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3H, ꢀCH3), 2.67 (s, 1H, OHꢀ3 or OHꢀ4), 2.69 (s, 1H, OHꢀ3 or OHꢀ4), 3.66 (dd, J = 9.6 Hz, 3.8
Hz, 1H, Hꢀ2), 3.74 (s, 6H, ꢀOCH3), 3.99 (t, J = 4.4 Hz, 1H, Hꢀ1), 4.09ꢀ4.36 (m, 2H, Hꢀ3 & Hꢀ4),
4.34 (d, J = 11.4 Hz, 1H, ꢀCHaPhOMe), 4.51 (d, J = 11.4 Hz, 1H, ꢀCHaPhOMe), 4.54 (d, J = 13.2
Hz, 1H, ꢀCHbPhOMe), 4.57 (d, J = 11.4 Hz, 1H, ꢀCHbPhOMe), 5.59 (s, 1H, Hꢀ6), 6.80ꢀ7.22 (m,
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8H, ArꢀH); C NMR (125 MHz, CDCl3): δ 21.2, 55.3, 67.9, 69.7, 70.1, 71.5, 71.6, 76.1, 113.8,
25
114.0, 123.0, 129.5, 129.6, 130.0, 130.6, 138.3, 159.3, 159.5. [α]D ꢀ91.5 (c 0.20, acetone).
Elemental analysis calcd for C23H28O6: C, 68.98; H, 7.05. Found: C, 68.71; H, 7.21.
(1R,2S,3S)-1,2-bis((4-methoxybenzyl)oxy)-5-methyl-cyclohex-5-ene-4-one-1,2,3-triol
(15).
To a solution of the diol 14 (30 mg, 0.075 mmol) in DCM (10 mL), PDC (56.4 mg, 0.15 mmol)
was added at room temperature and the reaction mixture was stirred for 30 min. at the same
temperature. After the completion of the reaction (checked by TLC), the reaction mixture was
concentrated under reduced pressure and the crude product thus obtained was purified by flash
column chromatography (EtOAc/petroleum ether, 1:3, v/v) to get the enone 15 (25.4 mg, 85%)
as a colorless liquid. 1H NMR (500 MHz, CDCl3): δ 1.74 (s, 3H, ꢀCH3), 3.36 (d, J = 1.8 Hz, 1H,
OHꢀ4), 3.53 (dd, J = 10.5 Hz, 3.6 Hz, 1H, Hꢀ2), 3.74 (s, 6H, ꢀOCH3), 4.09 (dd, J = 5.7 Hz, 3.5
Hz, 1H, Hꢀ1), 4.56 (d (AB), J = 11.5 Hz, 1H, ꢀCHaPhOMe), 4.62 (d (AB), J = 11.8 Hz, 1H, ꢀ
CHaPhOMe), 4.70 (dd, J = 10.5 Hz, 1.8 Hz, 1H, Hꢀ3), 4.77 (d (AB), J = 11.4 Hz, 1H, ꢀ
CHbPhOMe), 4.78 (d (AB), J = 11.8 Hz, 1H, ꢀCHbPhOMe), 6.52 (dd, J = 6.1 Hz, 1.4 Hz, 1H, Hꢀ
6), 6.81 (d, J = 8.6 Hz, 4H, ArꢀH), 7.21ꢀ7.25 (m, 4H, ArꢀH); 13C NMR (125 MHz, CDCl3): δ
15.4, 55.29, 55.3, 71.1 (Cꢀ1), 72.7, 73.1, 74.4 (Cꢀ3), 79.7 (Cꢀ2), 113.85, 113.9, 129.5, 129.7,
130.4, 136.1, 140.6 (Cꢀ6), 159.3, 159.5, 199.1. [α]D 25 ꢀ55.8 (c 0.24, acetone). Elemental analysis
calcd for C23H26O6: C, 69.33; H, 6.58. Found: C, 69.11; H, 6.82.
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(-)-Gabosine A (16). To a solution of ketone 15 in DCM (10 mL), TFA (0.05 mL) was added at
room temperature and the reaction mixture was stirred for 20 min. at the same temperature. After
the completion of the reaction (checked by TLC), the reaction mixture was concentrated under
the reduced pressure and the crude product thus obtained was purified by flash column
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chromatography (EtOAc) to get (ꢀ)ꢀgabosine A (16) (8.2 mg, 81%). H NMR (500 MHz,
CD3OD): δ 1.72 (s, 3H, ꢀCH3), 3.63 (dd, J = 10.0 Hz, 4.0 Hz,1H), 4.23 (d, J = 10.0 Hz, 1H), 4.29
1
(t, J = 5.0 Hz, 1H), 6.65 (dd, J = 4.0 Hz, 1.0 Hz, 1H); H NMR (125 MHz, CD3OD): δ 14.1,
66.0, 72.5, 73.7, 135.5, 141.6. 1H and 13C are similar to the reported data.12b
(-)-MK7607 (17). To a solution of the alcohol 11 (40 mg, 0.156 mmol) in DCM (10 mL), TFA
(0.01 mL) was added at room temperature and the reaction mixture was stirred for 10 min. at the
same temperature. After the completion of the reaction, the reaction mixture was concentrated
under reduced pressure and the residue was purified by flash column chromatography
1
(EtOAc/acetone, 1:4) to get (ꢀ)ꢀMK7607 17 (27.49 mg, 100%) as a colorless liquid. H NMR
(500 MHz, D2O): δ 3.81ꢀ3.87 (m, 2H), 4.11 (s, 2H), 4.21 (d, J = 3.5 Hz, 1H), 4.28 (apr t, 1H),
5.82 (d, J = 4.5 Hz, 1H); 13C NMR (125 MHz, D2O): δ 62.1, 66.1, 66.7, 68.4, 68.7, 124.1, 140.3.
1H and 13C values are similar to the reported data.2c
(1R,2S,3R,4R)-1,2-bis((4-methoxybenzyl)oxy)-5-(((4-methoxybenzyl)oxy)methyl)cyclohex-5-
ene-1,2,3,4-tetrol (18). To a solution of the alcohol 11 (240 mg, 0.93 mmol) in methanol (20
mL), CSA (15 mg) was added at room temperature and the reaction mixture was stirred for 3 h at
the same temperature. After completion of the reaction, the solvent was
evaporated off under reduced pressure and the residue was purified by flash column
chromatography (EtOAc) to get an inseparable mixture of triols (155.7 mg, 78%, brsm, overall
yield) as a colorless oil. The mixture of triols (157.7 mg) was dissolved in DMF (20 mL), NaH
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(102.4 mg, 2.56 mmol) and PMBCl (0.35 mL, 2.56 mmol) were added to it at 0 C and the
reaction mixture was stirred for 30 min. at room temperature. After the completion of the
reaction, excess NaH was quenched with iceꢀcold water and the reaction mixture was
concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and washed
with water and brine. The organic layer was separated, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product thus obtained was purified by flash
column chromatography (EtOAc/petroleum ether, 1:4, v/v) to get an inseparable mixture of
triPMB ethers (383.2 mg, 91%). The remaining acetonide group of the triPMB ethers (383.2 mg)
was deprotected by the treatment with CSA (100 mg) in methanol (20 mL) at room temperature
for 4 h. After the completion of the reaction, the reaction mixture was concentrated under
reduced pressure and the residue was purified by flash column chromatography
(EtOAc/petroleum ether,1:1, v/v) to get the diol 18 (276.0 mg, 46% after three steps) as a
colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.73 (d, J = 1.8 Hz, 1H, OHꢀ3), 3.09 (d, J = 1.1 Hz,
1H, OHꢀ4), 3.73 (s, 9H, ꢀOCH3), 3.79 (dd, J = 9.1 Hz, 3.9 Hz, 1H, Hꢀ2), 4.00 (s, 2H, Hꢀ7A &
7B), 4.09ꢀ4.10 (m, 2H, Hꢀ1 & Hꢀ3), 4.31 (d, J = 4.0 Hz, 1H, Hꢀ4), 4.38 (s, 2H, ꢀCH2PhOMe),
4.41 (d (AB), J = 11.5 Hz, 1H, ꢀCHaPhOMe), 4.48 (d (AB), J = 11.6 Hz, 1H, ꢀCHaPhOMe), 4.52
(d (AB), J = 11.6 Hz, 1H, ꢀCHbPhOMe), 4.57 (d (AB), J = 11.5 Hz, 1H, ꢀCHbPhOMe), 5.82 (d, J
= 4.9 Hz, 1H, Hꢀ6), 6.78ꢀ6.81 (m, 6H, ArꢀH), 7.17ꢀ7.19 (m, 6H, ArꢀH); 13C NMR (125 MHz,
CDCl3): δ 55.3, 67.6 (Cꢀ4), 68.1 (Cꢀ3), 70.4 (Cꢀ1), 71.4, 71.9, 72.0, 72.4 (Cꢀ7), 75.9 (Cꢀ2),
113.8, 113.88, 113.9, 125.2 (Cꢀ6), 129.5, 129.6, 129.8, 130.2, 130.6, 137.1, 159.3, 159.35,
159.38. [α]D 25 ꢀ87.5 (c 0.12, acetone). Elemental analysis calcd for C31H36O8: C, 69.39; H, 6.76.
Found: C, 69.21; H, 6.95.
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(1R,2R,3S)-1,2-bis((4-methoxybenzyl)oxy)-5-(((4-methoxybenzyl)oxy)methyl)-4-
5
6
oxocyclohex-5-en-3-yl furan-2-carboxylate (19). To a solution of the diol 18 (100 mg, 0.19
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8
9
o
mmol) in pyridine (15 mL), furoyl chloride (0.037 mL, 0.38 mmol) was added at 0 C and the
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reaction mixture was stirred for 2 h at room temperature. When TLC showed completion of the
reaction (after 2 h), the reaction mixture was concentrated under reduced pressure. The crude
product thus obtained was dissolved in DCM (100 mL) and washed with water and brine. The
organic layer was separated and dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product thus obtained was purified by flash column chromatography
(EtOAc/petroleum ether, 1:1; v/v) to get an inseparable mixture (1:1) of alcohols (104.6 mg,
89%) as a colorless oil. This mixture of alcohols (104.6 mg) was taken in DCM (10 mL) under
nitrogen atmosphere and treated with PDC (124.8 mg, 0.33 mmol) at room temperature for 30
min. When the reaction was approximately 40% advanced as judged by the disappearance of the
starting materials (checked by TLC), the reaction mixture was concentrated under reduced
pressure and the crude product thus obtained was purified by flash column chromatography
1
(EtOAc/petroleum ether, 1:2, v/v) to get the enone 19 (44.5 mg, 38% after two steps). H NMR
(500 MHz, CDCl3): δ 3.72 (s, 3H, ꢀOCH3), 3.74 (s, 6H, ꢀOCH3), 3.96 (dd, J = 10.6 Hz, 3.4 Hz,
1H, Hꢀ2), 4.03 (d (AB), J = 14.8 Hz, 1H, Hꢀ7A), 4.14 (d (AB), J = 14.9 Hz, 1H, Hꢀ7B), 4.21 (dd,
J = 5.7 Hz, 3.6 Hz, 1H, Hꢀ1), 4.38 (d (AB), J = 11.4 Hz, 1H, ꢀCHaPhOMe), 4.41 (d (AB), J =
11.5 Hz, 1H, ꢀCHbPhOMe), 4.53ꢀ4.60 (m, 3H, ꢀCHPhOMe), 4.73 (d (AB), J = 11.6 Hz, 1H, ꢀ
CHaPhOMe), 5.97 (d, J = 10.6 Hz, 1H, Hꢀ3), 6.47 (dd, J = 3.5 Hz, 1.7 Hz, 1H, ArꢀH), 6.74 (d, J
= 8.6 Hz, 2H, ArꢀH), 6.80ꢀ6.82 (m, 4H, ArꢀH), 6.86 (d, J = 6.1 Hz, 1H, Hꢀ6), 7.13ꢀ7.23 (m, 7H,
13
ArꢀH), 7.55 (t, J = 0.7, 1H, ArꢀH); C NMR (125 MHz, CDCl3): δ 55.27, 55.31, 65.7, 70.3 (Cꢀ
1), 72.5, 72.8, 72.9 (Cꢀ3), 75.2 (Cꢀ2), 112.0, 113.8, 113.86, 113.91, 118.8, 129.4, 129.6, 129.7,
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129.8, 130.1, 137.9, 139.5 (Cꢀ6), 144.2, 146.7, 157.7, 159.4, 159.5. [α]D
ꢀ101.5 (c 0.1,
5
6
acetone). Elemental analysis calcd for C36H36O10: C, 68.78; H, 5.77. Found: C, 68.59; H, 5.84.
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(-)-Epoxydine B (20). To a solution of the ketone 19 (20 mg, 0.031 mmol) in DCM (10 mL),
TFA (0.1 mL) was added at room temperature and the reaction mixture was stirred for 20 min. at
the same temperature. After the completion of the reaction, the reaction mixture was
concentrated under reduced pressure and the crude product was purified by flash column
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chromatography (EtOAc) to get epoxydine B (20) (10 mg, 81%) as a colorless liquid. H NMR
(500 MHz, CD3OD): δ 4.16 (dd, J = 10.8 Hz, 4.0 Hz, 1H), 4.26 (dd (AB), J = 15.5 Hz, 1.3 Hz,
1H), 4.29 (d (AB), J = 15.5 Hz, 1H)4.56 (t, J = 4.9 Hz, 1H), 5.80 (d, J = 10.8 Hz, 1H), 6.66 (dd,
J = 3.5 Hz, 1.7 Hz, 1H), 7.07 (dt, J = 6.0 Hz, 1.6 Hz, 1H), 7.35 (dd, J = 2.9 Hz, 0.6 Hz, 1H), 7.80
(d, J = 0.9 Hz, 1H); 13C NMR (125 MHz, CD3OD): δ 57.96, 65.8, 69.7, 75.7, 111.7, 118.5,
25
139.1, 140.7, 144.1, 147.1, 192.5. [α]D ꢀ120.5 (c 0.1, acetone). Elemental analysis calcd for
1
13
C12H12O7: C, 53.74; H, 4.51. Found: C, 53.51; H, 4.73. H and C NMR are similar with the
reported data.15b The specific rotation of epoxydine B was reported in chloroform (ꢀ72.7, c 0.11),
but in our hand the solubility of 20 in chloroform was very low and hence we have measured its
specific rotation in acetone (ꢀ120.5, c 0.1). The large difference could be due to the change of
solvent. However, we could measure the specific rotation in chloroform at very low
concentration of c = 0.04 and the value was ꢀ60.4 which was close to the reported value.
(1R,2R,3S)-1,2-bis((4-methoxybenzyl)oxy)-5-(((4-methoxybenzyl)oxy)methyl)-4-
oxocyclohex-5-en-3-yl acetate (21). To a solution of the diol 18 (110 mg, 0.20 mmol) in
o
pyridine (10 mL), acetyl chloride (0.029 ml, 0.4 mmol) was added at 0 C and the reaction
mixture was stirred for 2 h at room temperature. When the TLC showed completion of the
reaction (after 2 h), the reaction mixture was concentrated under reduced pressure. The residue
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was dissolved in DCM (100 mL) and washed with water and brine. The organic layer was
separated and concentrated under reduced pressure. The crude product thus obtained was
purified by flash column chromatography (EtOAc/petroleum ether, 1:1; v/v) to get an
inseparable mixture (1:1) of two esters (104.4 mg, 88%) as a colorless oil. Then, the mixture of
esters (104.4 mg) was taken in DCM (10 mL) under the nitrogen atmosphere and treated with
PDC (135.4 mg, 0.36 mmol) at room temperature for 25 min. When the reaction was
approximately 40% advanced as judged by the disappearance of the starting materials (checked
by TLC), the reaction mixture was concentrated under reduced pressure and the crude product
thus obtained was purified by flash column chromatography (EtOAc/petroleum ether, 1:2, v/v) to
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get the enone 21 (42.1 mg, colorless oil, 36% after two steps) selectively. H NMR (500 MHz,
CDCl3): δ 2.10 (s, 3H, ꢀCH3), 3.74 (s, 9H, ꢀOCH3), 3.83 (dd, J = 10.6 Hz, 3.5 Hz, 1H, Hꢀ2), 4.00
(dd (AB), J = 14.9 Hz, 1.7 Hz, 1H, Hꢀ7A), 4.12 (d (AB), J = 14.9 Hz, 1H, Hꢀ7B), 4.16 (dd, J =
5.6 Hz, 3.7 Hz, 1H, Hꢀ1), 4.37 (d (AB), J = 11.5 Hz, 1H, ꢀCHaPhOMe), 4.40 (d (AB), J = 11.5
Hz, 1H, ꢀCHbPhOMe), 4.51 (d (AB), J = 11.9 Hz, 1H, ꢀCHaPhOMe), 4.54 (d (AB), J = 9.1 Hz,
1H, ꢀCHaPhOMe), 4.57 (d (AB), J = 9.4 Hz, 1H, ꢀCHbPhOMe), 4.70 (d (AB), J = 13.4 Hz, 1H, ꢀ
CHbPhOMe), 5.76 (d, J = 10.6 Hz, 1H, Hꢀ3), 6.79ꢀ6.82 (m, 7H, ArꢀH & Hꢀ6), 7.15ꢀ7.17 (m, 6H,
13
ArꢀH); C NMR (125 MHz, CDCl3): δ 20.8, 55.3, 65.7, 70.3 (Cꢀ1), 72.5, 72.7, 72.9 (Cꢀ3), 74.8
(Cꢀ2), 113.86, 113.89, 129.4, 129.5, 129.7, 129.8, 129.9, 130.1, 137.8, 139.4, 159.4, 159.5,
25
170.0, 192.3. [α]D ꢀ80.5 (c 0.1, acetone). Elemental analysis calcd for C33H36O9: C, 68.74; H,
6.29. Found: C, 68.58; H, 6.71.
(-)-Epoxydine C (22). To a solution of the ketone 21 (25 mg, 0.043 mmol) in DCM (10 mL),
TFA (0.1 mL) was added at room temperature and the reaction mixture was stirred for 20 min. at
the same temperature. After the completion of the reaction, the reaction mixture was
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concentrated under reduced pressure and the crude product thus obtained was purified by flash
column chromatography (EtOAc) to get epoxydine C 22 (12.7 mg, 87%) as a colorless liquid. 1H
NMR (500 MHz, CD3COCD3): δ 2.1 (s, 3H, CH3), 4.05 (dd, J = 11.0 Hz, 4.0 Hz, 1H, Hꢀ2), 4.19ꢀ
4.25 (m, 2H, Hꢀ7A & 7B), 4.58 (dd, J = 5.0 Hz, 4.5 Hz, 1H, Hꢀ1), 5.57 (d, J = 10.5 Hz, 1H, Hꢀ
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3), 7.04 (d, J = 5.5 Hz, 1H, Hꢀ6); C NMR (125 MHz, CD3COCD3): δ 19.8, 58.2, 65.7, 69.9,
75.4, 139.4, 140.2, 169.7. Elemental analysis calcd for C9H12O6: C, 50.00; H, 5.59. Found: C,
49.61; H, 5.95. 1H NMR data were similar to the reported data.15a
The reported NMR data for epoxydine C in acetoneꢀd6: 2.10 (s, 3H, ꢀOCOCH3), 4.01 (dd, J
=10.8 Hz, 5.4 Hz, 1H, Hꢀ2), 4.21 (2H, Hꢀ7A & Hꢀ7B), 4.54 (t, J = 5.4 Hz, 1H, Hꢀ1), 5.54 (d, J =
10.8 Hz, 1H, Hꢀ3), 7.01 (dt, J = 5.4 Hz, 2.0 Hz, 1H, Hꢀ6).
(1R,2R,3S,4S,5S,6R)-1,2:3,4-di-O-isopropylidene-6-O-((tert(butyl)-di-(methyl)silyl))-
cyclohexane-1,2,3,4,5,6-hexol (25).19 To a solution of the diol 24 (400 mg, 1.54 mmol) in dry
DCM (20 mL), TBDMSCl (278.83 mg, 1.85 mmol) and imidazole (314.52 mmol, 4.62 mmol)
were added at the room temperature and the reaction mixture was stirred for 4 h at the same
temperature. After the completion of the reaction (4 h), DCM (100 mL) was added to the
reaction mixture and the organic layer was washed with water, and brine, separated, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude product thus obtained
was purified by flash column chromatography (EtOAc/petroleum ether, 1:9, v/v) to get the
1
alcohol 25 (523.79 mg, 91%) as a colorless oil. H NMR (500 MHz, CDCl3): δ 0.15 (s, 3H, ꢀ
CH3), 0.18 (s, 3H, ꢀCH3), 0.93 (s, 9H, ꢀC(CH3)3), 1.33 (s, 3H, ꢀCH3), 1.36 (s, 3H, ꢀCH3), 1.50 (s,
3H, ꢀCH3), 1.52 (s, 3H, ꢀCH3), 2.63 (s, 1H, OH), 3.52ꢀ3.58 (m, 2H), 4.09ꢀ4.11 (m, 1H), 4.19ꢀ4.26
13
(m, 3H); C NMR (125 MHz, CDCl3): δ ꢀ5.0, ꢀ4.3, 18.1, 25.00, 25.03, 25.9, 27.6, 27.7, 72.4,
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74.2, 76.8, 77.1, 78.2, 79.5, 109.5, 110.0. [α]D 25 +22.0 (c 0.1, acetone). Elemental analysis calcd
for C18H34O6Si: C, 57.72; H, 9.15. Found: C, 57.51; H, 9.37.
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4
5
6
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(1S,2S,3R,4R,6R)-3-O-tert(butyl)-di-(((methyl)silyl)-4-(methoxymethylene))-1,2:5,6-di-O-
isopropylidene-cyclohexane-1,2,3,4,6-pentol (27). To a solution of the alcohol 25 (510 mg,
1.36 mmol) in dry DCM (10 mL), DessꢀMartin periodinane (691.35 mg, 1.63 mmol) was added
at room temperature and the reaction mixture was stirred for 1 h at the same temperature. When
the TLC showed completion of the reaction (after 1 h), the reaction mixture was diluted by
adding DCM (100 mL) and then the organic layer was washed successively with aq. Na2S2O3,
water and brine. The organic layer was separated, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product thus obtained was purified by flash
column chromatography (EtOAc/petroleum ether, 1:2; v/v) to get the ketone 26 (476.8 mg, 94%)
as a colorless liquid. The ketone 26 exists in equilibrium with its gemꢀdiol. So, the ketone was
used for the next step after coꢀevaporation with toluene (3 times). This ketone (374.5 mg, 1.0
mmol) in dry THF (20 mL) was added to the orange suspension, formed by the addition of nBuLi
10
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26
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56
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(1.88 mL, 3.0 mmol, 1.6
M
solution in hexane) to
a
suspension of
methoxymethyltriphenylphosphonium chloride (1.03 g, 3.0 mmol) in dry THF (20 mL), at ꢀ40 oC
under N2 atmosphere. The mixture was allowed to warm to room temperature and then further
stirred for 8 h. THF was evaporated under reduced pressure. The residue was dissolved in DCM
(100 mL) and washed with water and brine. The organic layer was separated, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column
chromatography (EtOAc/petroleum ether, 1:9; v/v) gave the enol ether 27 (261.8 mg, 56%) as a
colorless oil. 1H NMR (500 MHz, CDCl3): δ ꢀ0.02 (s, 3H, ꢀCH3), 0.00 (s, 3H, ꢀCH3), 0.79 (s, 9H,
ꢀCH3), 1.21 (s, 3H, ꢀCH3), 1.26 (s, 6H, ꢀCH3), 1.38 (s, 3H, ꢀCH3), 3.57 (s, 3H, ꢀOCH3), 3.91 (d, J
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= 3.1 Hz, 1H, Hꢀ6), 4.11 (dd, J = 7.0 Hz, 3.1 Hz, 1H, Hꢀ1), 4.25 (dd, J = 7.2 Hz, 3.1 Hz, 1H, Hꢀ
5
6
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3), 4.35 (dd, J = 7.0 Hz, 3.5 Hz, 1H, Hꢀ2), 5.01 (d, J = 7.3 Hz, 1H, Hꢀ4), 6.12 (s, 1H, Hꢀ7); C
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8
9
NMR (125 MHz, CDCl3): δ18.0, 25.5, 25.6, 26.2, 27.4, 27.9, 50.9, 67.0, 70.5, 72.0, 74.0, 109.5,
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109.9, 137.2, 145.5, 192.7. [α]D
ꢀ67.1 (c 0.24, acetone). Elemental analysis calcd for
C20H36O6Si: C, 59.97; H, 9.06. Found: C, 59.77; H, 9.17.
(1S,2S,3S,4S)-5-formyl-1,2:3,4-di-O-isopropylidene-cyclohex-5-ene-1,2,3,4-tetrol (28). To a
solution of the enol ether 27 (110 mg, 0.27 mmol) in acetone (15 mL), CSA (10 mg) was added
at room temperature and the reaction mixture was stirred for 1 h at the same temperature. After
the completion of the reaction, the CSA was quenched with triethylamine and the reaction
mixture was concentrated under reduced pressure. The crude product was purified by flash
column chromatography (EtOAc/petroleum ether, 1:5, v/v) to get the aldehyde 28 (64.24 mg,
92%) as a colorless liquid. 1H NMR is similar to the compound 10 which is its enantiomer. H
1
NMR (500 MHz, CDCl3): δ 1.32 (s, 3H), 1.33 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 4.65ꢀ4.67 (m,
1H), 4.71ꢀ4.72 (m, 1H), 4.81ꢀ4.82 (m, 1H), 4.97 (d, J = 5.5 Hz, 1H), 6.62ꢀ624 (m, 1H), 9.62 (s,
1H).
1H NMR (500 MHz, DMSOꢀd6): δ 1.15 (s, 3H, ꢀCH3); 1.16 (s, 3H, ꢀCH3), 1.24 (s, 3H, ꢀCH3),
1.25 (s, 3H, ꢀCH3), 4.48ꢀ4.49 (m, 1H), 4.55ꢀ4.56 (m, 1H), 4.73ꢀ4.76 (m, 2H), 6.74 (s, 1H), 9.51
13
(s, 1H); C NMR (500 MHz, DMSOꢀd6): δ 25.8, 26.5, 27.6, 28.2, 66.5, 70.5, 72.0, 72.1, 74.3,
25
108.8, 109.3, 136.9, 147.1, 194.1. [α]D +23.1 (c 0.12, acetone). Elemental analysis calcd for
C13H18O5: C, 61.40; H, 7.14. Found: C, 61.31; H, 7.41.
(1S,2S,3S,4S)-5-hydroxymethyl-1,2:3,4-di-O-isopropylidene-cyclohex-5-ene1,2,3,4-tetrol
(29). To a solution of the aldehyde 28 (45.5 mg, 0.18 mmol) in methanol (10 mL), NaBH4 (6.8
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