Towards the synthesis of scyphostatin

Article abstract of DOI:10.3987/com-00-8987

Stereocontrolled synthesis of the substituted cyclohexenone segment (2) of scyph-ostatin (1) is described starting from D-glucose.

Full text of DOI:10.3987/com-00-8987

HETEROCYCLES, Vol.53, No. 9, 2000, pp. 1885 - 1889, Received, 26th June, 2000
TOWARDS THE SYNTHESIS OF SCYPHOSTATIN
Mukund K Gurjar* and Srinivas Hotha
Division of Organic Chemistry: Technology
National Chemical Laboratory, Pune-411 008, India
Abstract - Stereocontrolled synthesis of the substituted cyclohexenone segment
(2) of scyph-ostatin (1) is described starting from D-glucose.
Scyphostatin (1) is a novel neutral sphingomyelinase (N-Smase) inhibitor isolated1 during the search for N-
Smase inhibitors from the fermentation broth of Dascysphus mollissimus SANK-13892. N-Smase inhibitors are
useful in the regulation of ceramide level and thus are of immense need in the therapy of autoimmune diseases
and inflammation.2 Scyphostatin (1) is a structurally unique natural product containing an unprecedented
cyclohexenone epoxide moiety in which the tertiary chiral center at C-4 is linked to an n-propylamino alcohol
and a lipophilic side chain[C(1´)-C(20´)]. The structure of scyphostatin (1) was determined by NMR and MS
spectral studies. Chemical and spectroscopic analysis, coupled with modified Mosher’s method, provided stereo-
7
BnO
6
8
O
4
5
9
BnO
BnO
O
O
O
HO
3
NHR
2
2
1
O
20' 19' 18' 17'
8' 10'
OH
16'
1'
1 R =
3'
O
chemical configuration of the cyclohexenone epoxide ring structure of scyphostatin. However, the initial report1
did not confirm the absolute configuration of the lipophilic side chain. Later Saito et al. has confirmed3 the
absolute and relative configurations by degradation of 1 and chemical correlation to synthetic fragments. Hoye
et al.4 have synthesized the lipophilic side chain and till date there is no single report on synthesis of polar
cyclohexenone moiety. As part of our interest, we have embarked on developing a carbohydrate based strategy
to prepare the suitably substituted cyclohexenone derivative (2) present in the scyphostatin (1). D-Glucose was
converted5 into methyl 3-O-benzyl-4,6-benzylidene-α-D-glucopyranoside (3) whose oxidation at C-2 under

Swern conditions, gave the 2-ulose derivative (4) (Scheme 1).6 Subsequent C-allylation of 4 was studied7 under
various conditions. However, we observed that 4 with allylmagnesium bromide in anhydrous ether/CH2Cl2 at –
o
78 C gave a 9:1 diastereomeric mixture of tertiary alcohols (5a) and (5b) which were separated by silica gel
column chromatography. The major product was subjected to NOE studies which unequivocally proved the
structure as 5a while the structure of the minor product (5b) was unambiguously assigned based on interesting
chemical transformations.7b
Ph
Ph
O
O
OH
O
O
O
HO
HO
O
O
BnO
BnO
Ref. 3
a
b
O
HO
HO
OH
OMe
OMe
4
D-Glucose
3
H
H
Ph
Ph
Ph
O
Ph
O
O
O
O
O
OH
O
OH
O
OBn
O
BnO
O
O
O
BnO
BnO
c
BnO
+
H
HO
OMe
OMe
OMe
OMe
5b
5a
6
5a: NOE signals
o
Scheme 1: a) (COCl)2, DMSO, Et3N, CH2Cl2, -78 C, 89 %; b) allylmagnesium bromide, Et2O:CH2Cl2
(4:1), -78 oC, 68 %; c) NaH, BnBr, DMF, n-Bu4NI, , 0 oC-rt, 97 %.
The derived O-benzyl derivative (6) was reduced8 with LiAlH4-AlCl3 to give rise to the 4-O-benzyl derivative
(7) containing a primary hydroxy group at C-6. Treatment of 7 with Ph3P-I2-imidazole in toluene gave9 the 6-
deoxy-6-iodo derivative (8) (Scheme 2). Catalytic osmylation of 8 in t-butanol-water gave a 4:1 mixture of
diastereomeric products whose acetonide derivatives (9a/9b) could be separated by silica gel column
chromatography. In accordance with Sharpless modifications,10 use of AD-MIX-α provided predominantly the
diastereomer (9b) whose stereochemical assignments were based on hypothesis reported by Sharpless et al .10
Compound (9b) was treated with DBU in DMF at 100oC for 12 h to give the 5,6-ene derivative (10). The
Ferrier rearrangement11 of 10 in the presence of Hg(OAc)2 in aqueous acetone gave the carbocyclic derivative
(11) whose dehydration in the presence of MsCl-Et3N-CH2Cl2 provided the α, β-unsaturated derivative (12)
(Scheme 3). In order to rearrange 12, into the target structure (2), an approach based on Barton’s radical opening
reaction12 of α,β-epoxythioimidazolide was investigated (Scheme 3).
Compound (12) was epoxidised with 30 % hydrogen peroxide-K2CO3 in THF-H2O to give 13 which was
consequently reduced with NaBH4 in methanol to give the epoxy alcohol (14). In the IH-NMR spectrum of
14, epoxy protons were clearly visible at 3.23 (doublet, J = 3.8 Hz) and 3.35 ppm (triplet, J = 3.8 Hz).
Conversion of 14 into the thiocarbonate derivative (15) was accomplished with N,N’-thiocarbonyldiimidazole in

refluxing C6H6. The 1H-NMR spectrum of 15 showed characteristic downfield shift of the proton carrying
Ph
O
OH
I
O
BnO
BnO
OBn
OBn
OBn
O
O
O
BnO
BnO
BnO
a
b
c,d
OMe
OMe
OMe
6
7
8
I
I
O
BnO
BnO
BnO
BnO
OBn
OBn
OBn
BnO
BnO
O
O
O
g
f
BnO
BnO
e
12
+
OH
O
O
BnO
O
OMe
O
OMe
OMe
9a
9b
10
O
O
11
O
O
Scheme 2: a) LiAlH4, AlCl3, Et2O, 15 min, 90 %; b) PPh3, Im, I2, C6H5Me, reflux, 2 h, 95 %; c) AD-mix-
α, t-BuOH-H2O (1:1), 0 oC, 24 h, 89 %; d) DMP, PTSA, CH2Cl2, rt, 30 min, 98 %; e) DBU, DMF, 100 oC,
12 h, 48 %; f) Hg(OAc)2, MeCOMe, H2O (3:1), reflux, 5 h, 80 %;g) MsCl, Et3N, CH2Cl2, rt, 3 h, 85 %
thiocarbonate group. Treatment of 15 with Bu3SnH and cat. AIBN in refluxing benzene gave a mixture of
products from which the major product was isolated (30 %) by silica gel chromatography. Subsequent oxidation
with MnO2 in refluxing CH2Cl2 provided the target cyclohexenone derivative (2). In the 1H-NMR spectrum of
2, the characteristic13 signals due to olefinic protons were located at 5.96 (dd, J = 2.04, 10.39 Hz) and 6.85 ppm
(dd, J = 1.89, 10.39 Hz) . Rest of the spectral data was in conformity with the assigned structure (2).14
O
O
OH
BnO
BnO
BnO
BnO
BnO
BnO
a
b
O
O
BnO
BnO
BnO
O
O
O
O
O
O
S
12
13
14
O
Im
O
BnO
BnO
BnO
d, e
c
BnO
BnO
O
O
BnO
O
O
O
15
2
Scheme 3: a) H2O2, K2CO3, H2O, THF, 0 oC , 6 h, 65 %; b) NaBH4, MeOH, -40 oC, 15 min, 93 %; c) Im-
C(=S)Im, C6H6, 80 oC , 12 h, 98 %; d) Bu3SnH, AIBN, C6H6, 80 oC, 4 h, 30 %; e) MnO2, CH2Cl2, 45 oC,
87%.

In conclusion we have reported for the first time the stereocontrolled synthesis of a novel and highly
substituted cyclohexenone ring system of scyphostatin.
ACKNOWLEDGEMENT
SH thanks CSIR, New Delhi for the financial support in the form of Senior Research Fellowship.
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OH
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
a,b
c
d
5b
BnO
BnO
BnO
OMe
OMe
OMe
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1
14. Structures of new compounds were established by H NMR, FABMS/HRMS or microanalysis. The 1H
NMR spectral data of some key intermediates are given below:
5a (400 MHz, CDCl3): 2.29 (dd, 1 H, J = 7.6, 15.3 Hz), 2.57 (dd, 1 H, J = 3.8, 15.3 Hz), 3.35 (s, 3 H), 3.65
(d, 1 H, J = 7.7 Hz), 3.83 (m, 2 H), 4.10 (m, 1 H), 4.32 (m, 1 H), 4.40 (s, 1 H), 4.65, 4.95 (ABq, 2 H, J =
15.6 Hz), 5.10 (m, 2 H), 5.60 (s, 1 H), 5.85 (m, 1 H), 7.30 (m, 10 H); 8 (200 MHz, CDCl3): 2.27 (dd, 1 H, J
= 9.0, 14.5 Hz), 3.09 (dd, 1 H, J = 4.5, 14.5 Hz), 3.27 (dd, 1 H, J = 6.8, 10.0 Hz), 3.38 (s, 3 H), 3.45 (m, 2
H), 3.75 (d, 2 H, J = 4.5 Hz), 4.52, 4.73 (ABq, 2 H, J = 10.2 Hz), 4.61, 4.79 (ABq, 2 H, J = 11.4 Hz), 4.65,
4.88 (ABq, 2 H, J = 10.9 Hz), 4.72 (s, 1 H), 5.11 (m, 2 H), 5.81 (m, 1 H), 7.30 (m, 15 H); 9 (200 MHz,
CDCl3): 1.29, 1.36 (2s, 6 H), 1.70 (dd, 1 H, J = 9.0, 15.9 Hz), 2.77 (dd, 1 H, J = 4.3, 15.9 Hz), 3.29 (dd, 1
H, J = 8.1, 11.3 Hz), 3.40 (s, 3 H), 3.47 (t, 3 H, J = 9.0 Hz), 3.75 (m, 2 H), 3.95 (dd, 1 H, J = 6.8 Hz), 4.20
(m, 1 H), 4.45 (s, 1 H), 4.63, 4.79 (ABq, 2 H, J = 11.5 Hz), 4.70, 4.90 (ABq, 2 H, J = 11.2 Hz), 4.75, 5.06
(ABq, 2 H, J = 11.5Hz), 7.30 (m, 15 H); 12 (200 MHz, CDCl3): 1.15, 1.31 (2s, 6 H), 2.04 (m, 1H), 2.18
(dd, 1 H, J = 2.3, 15.9 Hz), 3.25 (m, 1 H), 3.56 (m, 2 H), 3.88 (d, 1 H, J = 9.0 Hz), 4.54, 4.77 (ABq, 2 H, J =
10.5 Hz), 4.61, 5.00 (ABq, 2 H, J = 11.4 Hz), 4.67, 5.11 (ABq, 2 H, J = 11.4 Hz), 4.68 (d, 1 H, J = 9.0 Hz),
6.04 (d, 1 H, J = 9.0 Hz), 6.90 (d, 1 H, J = 9.0 Hz), 7.30 (m, 15 H); 2 (500 MHz, CDCl3): 1.22, 1.30 (2s, 6
H), 2.05 (dd, 1 H, J = 5.0, 13.8 Hz), 2.69 (dd, 1 H, J = 7.5, 13.7 Hz), 3.53 (t, 1 H, J = 7.7 Hz), 3.98 (d, 1 H, J
= 7.4 Hz), 4.00 (t, 1 H, J = 7.6 Hz), 4.14 (m, 1 H), 4.42, 4.60 (ABq, 2 H, J = 11.6 Hz), 4.78 (s, 2 H), 4.75,
5.13 (ABq, 2 H, J = 11.6 Hz), 4.77 (ddd, 1 H, J = 1.9, 2.1, 7.7 Hz), 5.96 (dd, 1 H, J = 2.1, 10.4 Hz), 6.85 (dd,
1H, J = 1.89, 10.4 Hz), 7.3 (m, 15 H).