Studies directed towards the total synthesis of feigrisolide B

Article abstract of DOI:10.1016/j.tetasy.2004.06.023

Attempts directed towards the total synthesis of feigrisolide B resulted in the synthesis of lactones 1 and 2. The synthesis of 1 and 2 was achieved from d-glucose and l-malic acid, respectively, with a Ti(IV) mediated diastereoselective aldol reaction as

Full text of DOI:10.1016/j.tetasy.2004.06.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2323–2326
Studies directed towards the total synthesis of feigrisolide Bq
G. V. M. Sharma* and K. Raman Kumar
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Received 19 May 2004; accepted 18 June 2004
Abstract—Attempts directed towards the total synthesis of feigrisolide B resulted in the synthesis of lactones 1 and 2. The synthesis
of 1 and 2 wasachieved from D-glucose and L-malic acid, respectively, with a Ti(IV) mediated diastereoselective aldol reaction as the
key step. The structures of both 1 and 2 revealed that the structure proposed for feigrisolide B is incorrect.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
2. Results and discussion
Thiericke et al.1 have isolated four new lactone com-
Antithetic analysis revealed that 1 could be synthesised
from seco acid 3. A diastereoselective aldol reaction on
aldehyde 4 wasenvisaged to give the alcohol with a com-
plete array of stereocentres, which would give 3, while 4
would be derived from D-glucose, wherein the C-2 and
C-4 hydroxy centresof D-glucose are retained as C-6
and C-8 stereocentres in the target molecule, respec-
tively. Thus, a C-6 framework along with two stereocen-
tresare derived from D-glucose, while the remaining two
stereocentres are introduced by Ônon-EvansÕ aldol con-
densation (Scheme 1).
poundsnamed feigrisolidesA to D from
Streptomyces
griseus. Structurally, feigrisolides A and B are hepta-lac-
tones, while feigrisolides C and D are 16 membered
macrolides. Feigrisolide B exhibits strong antibacterial,
aswell asmedium cytotoxic and antiviral activitie.s
Feigrisolides A, C and D are medium inhibitors of 3a-
hydroxy steroid dehydrogenase (3a-HSD) inhibiting
activity. Thiericke et al. confirmed the relative stereo-
chemistry of the ring of feigrisolide B based on NOESY
NMR experiments and established the absolute configu-
ration at C-8 asR by Helmchen Õsmethod 2 and proposed
1 asthe structure of feigrisolide B. A major goal of the
present first total synthesis for feigrisolide B was to
establish the absolute configuration of the natural com-
pound. Herein, we report our attemptsdirected towards
the total synthesis of feigrisolide B, which resulted in the
synthesis of lactones 1 and 2.
Accordingly, the known3 olefin 7, prepared from D-glu-
cose, on methanolysis with catalytic H2SO4 in methanol
(Scheme 2), gave methyl glycosides 8. Alkylation of 8
with NaH/BnBr in THF afforded 9 (75%), which on
treatment with 60% aq AcOH and catalytic H2SO4,
afforded lactols 10. NaBH4 reduction of lactols 10 in
methanol gave diol 11 (90%). Reaction of 11 with trityl
chloride and Et3N gave trityl ether 12 (78%), which on
further reaction with TBDPSCl and imidazole, fur-
nished 13 (70%). Further, deprotection of the trityl
group in 13 with trifluoroacetic acid in CH2Cl2 afforded
alcohol 14.
O
O
OH
OH
O
O
HO
HO
1
2
IBX oxidation of 14 in DMSO gave 15, which on subse-
quent reaction with (carbethoxymethylene)triphenyl-
phosphorane
afforded
16
(79%).
Catalytic
q IICT Communication No. 040413.
*
hydrogenation of 16 with PtO2 and further reduction
of 17 with LAH in THF gave 18 (88%). Alcohol 18
wasoxidised with IBX to afford 4 (90%). The addition
Corresponding author. Fax: +91-40-27160757; e-mail: esmvee@iict.
res.in
0957-4166/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2004.06.023

2324
G. V. M. Sharma, K. R. Kumar / Tetrahedron: Asymmetry 15 (2004) 2323–2326
O
TPSO
8
OH
6
TPSO
OBn
OH
O
HO
HO
O
D-glucose
COOH
4
3
OTBS
1
O
TPSO
OH
OH
O
TPSO
OBn
O
L-malic acid
COOH
5
2
OTBS
6
Scheme 1. Retro synthesis of 1 and 2.
OH OBn
O
OH
O
O
O
OCH3
d, e
f, g
c
a, b
OR
OBn
O
OR
11 R = H (90%)
12 R = Tr (78%)
7
8 R = H (79%)
9 R = Bn (75%)
10 (90%)
TPSO
OBn
TPSO
OBn
TPSO
OBn
TPSO
OBn
i
j, k, h
OEt
h
O
R
OR
O
17 R = CO2Et (90%)
18 R = CH2OH (88%)
4 R = CHO (90%)
16 (79%)
15 (91%)
13 R = Tr (70%)
14 R = H (74%)
Ph
Ph
Ph
S
O
N
TPSO
OBn
TPSO
OBn
A
m
O
S
O
N
O
N
l
OTBSO
20 (78%)
S
OH
O
19 (61%)
O
TPSO
OR'
r
O
OTPS
q
n, o, p
1 (72%)
TBSO
R
OTBS
23 (89%)
21 R = CHO; R' = Bn (80%)
22 R = COOH; R' = Bn (92%)
3 R = COOH; R' = H (62%)
Scheme 2. Reagentsand conditions: (a) cat. H 2SO4, MeOH, 60°C, 12h; (b) NaH, BnBr, THF, rt, 6h; (c) cat. H2SO4, 60% aq AcOH, 60°C, 12h; (d)
NaBH4, MeOH, rt, 1h; (e) TrCl, Et3N, CH2C12, rt, 4h; (f) TBDPSCl, imidazole, CH2C12, rt, 4h; (g) trifluoroacetic acid, CH2C12, 0°C, 1h; (h) IBX,
DMSO, rt, 6h; (i) PPh3@CHCOOEt, benzene, 80°C, 1h; (j) PtO2, EtOAc, H2, rt, 12h; (k) LAH, THF, rt, 1h; (l) A, TiCl4, DIPEA, CH2C12, 0°C,
30min then 4 at ꢀ78°C, 30min; (m) TBDMSOTf, 2,6-lutidine, CH2C12, rt, 30min; (n) DIBAL-H, CH2C12, ꢀ78°C, 15min; (o) NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH, rt, 3h; (p) DDQ, aq CH2C12 (19:1), 40°C, 5h; (q) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, 90°C,
14h; (r) HF–pyridine, pyridine, THF, 2days.
of the titanium enolate derived from propanoyl oxazol-
O
O
idinethione A to 4, gave the Ônon-EvanÕs syn aldol4 prod-
uct 19 as the only isolable diastereomer in 61% yield.
Adduct 19 wastreated with TBDMSOTf and 2,6-luti-
dine in CH2Cl2 to afford 20, which on further treatment
with DIBAL-H in CH2Cl2 at ꢀ78°C gave 21 (80%).
Oxidation of 21 with NaClO2 and NaH2PO4 in t-BuOH
gave acid 22 (92%), which on debenzylation with DDQ
afforded the seco acid 3. Lactonisation of 3 under Yam-
aguchi reaction conditions5 and deprotection of the two
silyl ethers by treatment with HF–pyridine complex af-
forded 1 in 72% yield. The structure of 23 wasunambig-
uously assigned based on the spectral and NOE studies
(Fig. 1).
O
O
H
H
H
H
OTPS
OTPS
H
H
H
TBSO
TBSO
38
23
Figure 1. NOE studies on 23 and 38.
of feigrisolide B with [a]D =0 (c 0.2, CH3OH). Thissyn-
thesis thus implies that the proposed structure1 for feig-
risolide B is incorrect. Hence, to arrive at the first
synthesis of feigrisolide B and to determine the absolute
stereochemistry as well, a further study was undertaken
for the synthesis of 2, with enantiomeric C-2, -3 and -6
stereocentres, as indicated in retro analysis (Scheme 1),
starting from L-malic acid.
The spectroscopic data (Table 1) and specific rotation
value [a]D =ꢀ39.1 (c 0.23, CHCl3) of 1 did not corre-
spond to the spectroscopic data and specific rotation1

G. V. M. Sharma, K. R. Kumar / Tetrahedron: Asymmetry 15 (2004) 2323–2326
2325
Table 1. 1H NMR (500MHz, CDC13) and 13C (75MHz, CDC13) data of the feigrisolide B and 1, 2
Position
Feigrisolide B1
d H1 (multi, J=Hz)
1
2
d
13C
d
13C
d H1 (multi, J=Hz)
d
13C
d H1 (multi, J=Hz)
1
2
3
4
177.6
45.3
81.0
29.1
176.6
46.3
77.9
29.8
178.4
51.7
76.9
30.4
2.50 (dq, 8.3, 7.0)
3.98 (br q, 8.3)
2.03 (a, m)
1.68 (b, m)
1.65 (a, m)
2.01 (b, m)
4.21 (m)
3.22 (dq, 7.55, 5.22)
3.905 (m)
3.15 (dq, 8.05, 6.59)
3.84 (m)
2.08 (a, m)
1.86 (b, m)
1.70 (a, m)
1.98 (b, m)
4.65 (m)
2.10 (a, m)
1.79 (b, m)
1.66 (a, m)
1.95 (b, m)
4.73 (m)
5
30.6
31.8
31.3
6
77.3
40.7
70.4
29.9
10.0
13.7
72.2
44.4
70.9
31.0
11.1
14.5
71.22
44.6
70.3
31.0
11.1
14.7
7
1.70 (m)
3.78 (m)
1.98 (m)
3.72 (m)
1.95 (m)
3.84 (m)
8
9
1.51 (m)
0.92 (t, 7.5)
1.16 (d, 7.0)
1.52 (m)
0.96 (t, 7.5)
1.38 (d, 7.8)
1.46 (m)
0.98 (t, 7.5)
1. 39 (d, 7.55)
10
10
Accordingly 246, derived from L-malic acid, wastreated
with IBX in DMSO to give 25 (Scheme 3), which on fur-
ther treatment with allyl bromide and activated zinc in
THF–aq NH4Cl at 0°C, under Barbier reaction condi-
tions,7 gave carbinols 26 (38%) and 26a (34%) asa sep-
arable diastereomeric mixture (60/120 silica gel, 1:16
O
OR
OH OBn
O
RO
d, e
d, e
26 R = H (38%)
27 R = Bn (75%)
28 R = H (94%)
29 R = Ts (59%)
b, c
O
O
a
O
O
OH
O
OH OBn
RO
24
25 (76%)
O
OR
O
28a R = H (85%)
29a R = Ts (66%)
26a R = H (34%)
27a R = Bn (83%)
BnO
TPSO
RO
BnO
OBn
i
O
g, h
f
R
29
33 R =CH2OH (61%)
31 R = H (87%)
32 R = TBDPS (91%)
30 (81%)
Ph
O
N
BnO
TPSO
OBn
BnO
RO
O
i, a
O
S
j
A
f
g, h
29a
R
30a (88%)
33a R = CH2OH (56%)
6 R = CHO (98%)
31a R = H (93%)
32a R = TBDPS (92%)
Ph
Ph
TPSO
OBn
l, m, n
TPSO
OBn
k
O
N
O
N
O
S
TBSO
OH
O
S
35 (80%)
34 (54%)
O
TPSO
OR'
O
OTPS
p
o
2 (75%)
TBSO
R
TBSO
38 (83%)
36 R = CHO; R' = Bn (83%)
37 R = COOH; R' = Bn (92%)
5 R = COOH; R' = H (65%)
Scheme 3. Reagentsand conditions: (a) IBX, DMSO, rt, 6h; (b) allyl bromide, activated zinc, THF–aq NH 4C1 solution, 0°C–rt, 4h; (c) BnBr, NaH,
THF, rt, 6h; (d) CSA, MeOH–H2O, rt, 12h; (e) TsCl, Et3N, CH2C12, rt, 16h; (f) K2CO3, MeOH, rt, 1h; (g) Me3Al, n-BuLi, toluene, ꢀ20°C to rt,
12h; (h) TBDPSC1, imidazole, CH2C12, rt, 4h; (i) BH3–DMS, THF, MeOH, aq NaOH, H2O2, rt, 12h; (j) A, TiCl4, TMEDA, CH2C12, 0°C, 30min
then 6 at ꢀ78°C, 30min; (k) TBDMSOTf, 2, 6-lutidine, CH2C12, rt, 30min; (l) DIBAL-H, CH2C12, ꢀ78°C, 15min; (m) NaClO2, NaH2PO4, 2-
methyl-2-butene, t-BuOH, rt, 3h; (n) DDQ, CH2C12, 40°C, 5h; (o) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, 90°C, 14h; (p)
HF–pyridine, pyridine, THF, 2days.

2326
G. V. M. Sharma, K. R. Kumar / Tetrahedron: Asymmetry 15 (2004) 2323–2326
EtOAc–hexane). A few more steps were carried out on
both diastereomers. Thus, 26 and 26a were converted
into benzyl ethers 27 and 27a, respectively, and sub-
jected to acid (CSA) catalysed hydrolysis in aq MeOH
to give diols 28 and 28a. Selective tosylation (p-TsCl,
Et3N, CH2Cl2) of 28 and 28a and further treatment of
29 and 29a with K2CO3 in CH3OH afforded the corre-
sponding epoxides 30 (81%) and 30a (88%). Selective
opening of 30 and 30a with Me3Al in toluene gave
31 (87%) and 31a (93%), which on reaction with
TBDPSCl–imidazole, furnished 32 and 32a, respec-
tively. Hydroboration of 32 and 32a gave 33 (61%)
and 33a (56%). Diastereoisomer 33 wasfound to be
identical in the 1H NMR and specific rotation data with
18 derived from D-glucose, hence isomer 33a wasused
for the further synthesis of 2.
3. Conclusion
We therefore, can conclude that the structure proposed
for feigrisolide B is incorrect. It does not correspond to
the proposed structure 1 or itsC-2, -3 and -6 epimer 2.
However, synthesisof other enantiomersaswell asdia-
stereomers by using diastereoselective aldol reactions
may offer an opportunity to arrive at the correct struc-
ture of natural product. A comparative study of the
spectral and specific rotation values of the derivatives
of both the natural and synthetic materials, paves the
way for the determination of the structure and absolute
stereochemistry of feigrisolide.
Acknowledgements
K.R.K. isthankful to the CSIR, New Delhi, India, for
financial support.
Accordingly, oxidation of 33a gave aldehyde 6, which
on aldol reaction with titanium enolate (derived from
the treatment of propanoyl oxazolidinethione A with
TiCl4, TMEDA, CH2Cl2), afforded the syn aldol4
adduct 34 (54%), whose structure was unambiguously
assigned from NOE studies. Treatment of 34 with
TBDMSOTf, controlled reduction of 35 with DIBAL-
H and further oxidation of 36 with NaClO2 and NaH2-
PO4 in t-BuOH gave acid 37. Debenzylation of 37
with DDQ gave the seco acid 5 (65%), which finally on
lactonisation under Yamaguchi conditions gave 38
(Fig. 1), which on desilylation with HF–pyridine com-
plex, afforded 2 (75%). The structure of 38 wasthor-
oughly characterised from NMR studies. The
spectroscopic data (Table 1) and specific rotation
[a]D =ꢀ70.0 (c 0.25, CHCl3) of 2 also was found to be
different from that of feigrisolide B, reported1 in the
literature.
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