Studies directed towards the total synthesis of botcinic acid, the revised structure of botcinolide: synthesis of the highly substituted tetrahydropyran moiety

Article abstract of DOI:10.1016/j.tetlet.2007.07.068

Synthesis of the highly substituted polyoxygenated tetrahydropyran ring of botcinic acid, the revised structure of botcinolide is achieved using, as key steps, a highly stereoselective aldol reaction of the titanium enolate from a lactate-derived chiral k

Full text of DOI:10.1016/j.tetlet.2007.07.068

Tetrahedron Letters 48 (2007) 6463–6465
Studies directed towards the total synthesis of botcinic acid,
the revised structure of botcinolide: synthesis of the
highly substituted tetrahydropyran moietyI
Tushar Kanti Chakraborty* and Rajib Kumar Goswami
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 16 May 2007; revised 2 July 2007; accepted 11 July 2007
Available online 17 July 2007
Abstract—Synthesis of the highly substituted polyoxygenated tetrahydropyran ring of botcinic acid, the revised structure of botcin-
olide is achieved using, as key steps, a highly stereoselective aldol reaction of the titanium enolate from a lactate-derived chiral
ketone and a stereoselective dihydroxylation.
Ó 2007 Elsevier Ltd. All rights reserved.
Botcinolides belong to a family of novel phytotoxic
metabolites, isolated from a strain of the plant pathogen
Botrytis cinerea, a fungus responsible for both the
so-called noble and gray rot in fruits.1 The structure of
botcinolide, which was originally reported as a nine-
membered lactone,1 was subsequently revised on the ba-
sis of spectroscopic data and chemical conversions.2 The
revised structure was found to have a highly substituted
tetrahydropyran ring and, very surprisingly, a free
carboxylic group. This prompted the investigators to
rename the molecule botcinic acid (1). The pronounced
biological activities of botcinolides as phytotoxins with
relatively low acute toxicity3 and their highly substituted
structures make them attractive targets to synthetic
organic chemists. While synthetic studies towards the
earlier reported structure of epibotcinolides have been
published,4 no synthesis of the revised structure has
yet been reported. As part of our studies directed to-
wards the synthesis of various molecules of the botcino-
lide family, we describe herein the first synthesis of the
polyhydroxylated tetrahydropyran ring 2 of botcinic
acid 1 in suitably protected form for further synthetic
work (Fig. 1).
Scheme 1 outlines the details of the synthesis of 2. Aldol
reaction of the titanium enolate derived from the chiral
ketone 3, prepared from (S)-lactic acid ethyl ester by a
known procedure,5 with methacrolein 4 gave the desired
syn-isomer 5 as the major product in a 7:1 ratio.6 The
diastereomers were separated by column chromatogra-
phy to afford pure syn-5. Protective group manipula-
tions were required at this stage to silylate the
hydroxyl groups appropriately for carrying out selective
deprotection at a later stage. Thus, TIPS protection of
the allylic alcohol of 5, TBS deprotection of the second-
ary hydroxyl and finally TES-protection furnished inter-
OH
TBSO
TBSO
OH
HO
O
TBSO
O
HO
O
O
O
OH
1
2
Figure 1. Revised structure of botcinic acid (1, Ref. 2) and our synthetic target 2.
Keywords: Botcinolides; Botcinic acid; Dihydroxylation; Aldol reaction; Sharpless epoxidation.
q IICT Communication No. 070521.
*
Corresponding author. Fax: +91 40 27193275/27193108; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.068

6464
T. K. Chakraborty, R. K. Goswami / Tetrahedron Letters 48 (2007) 6463–6465
OTES
OTBS
OTBS
OTES
i
ii
iii
4
OH
O
+ anti
OH
O
O
CHO
TIPSO
TIPSO
3
7
6
5
(7:1)
syn
:
anti = 9:1
OH
O
O
OH
vii
iv
v
vi
HO
PMP
PMP
OH
O
O
TIPSO
TIPSO
TIPSO
9
10
8
OH
TIPSO
OPMB
TIPSO
TBSO
OPMB
OH
ix
viii
TBSO
EtO
O
O
OPMB
TIPSO
O
13
12
11
HO
O
OPMB
HO
OH
OPMB
x
xi
xii
2
HO
HO
O
O
14
15
i
Scheme 1. Reagents and conditions: (i) 4, TiCl4, Pr2NEt, CH2Cl2, ꢀ78 °C, 2 h, 76%; (ii) (a) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 30 min; (b)
CSA, CH2Cl2/MeOH (1:1), 0 °C, 9 h; (c) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 5 min, 70% in three steps; (iii) DIBAL-H, CH2Cl2, ꢀ78 °C, 10 min,
quantitative yield; (iv) CSA, CH2Cl2/MeOH (4:1), 0 °C, 5 min, 68% with respect to syn-product 8; (v) PMB(OMe)2, CH2Cl2, 0 °C to rt, 30 min, 90%;
(vi) OsO4, NMO, acetone/H2O (20:1), rt, 3 d, 91%; (vii) (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 5 min; (b) DIBAL-H, CH2Cl2, ꢀ78 °C, 20 min, 58%
in two steps; (viii) (a) MsCl, Et3N, DMAP, CH2Cl2, 0 °C, 15 min; (b) K2CO3, MeOH, rt, 18 h, 52% in two steps; (ix) (a) CSA, CH2Cl2/MeOH (1:1),
0 °C, 6 h; (b) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 2 h; (c) Ph3P@CHCO2Et, CH2Cl2, rt, 3 d, 78% in three steps; (x) (a) DIBAL-H, CH2Cl2,
i
˚
ꢀ78 °C, 15 min; (b) TBAF, THF, 0 °C to rt, 6 h; (c) Ti(O Pr)4, (+)-DIPT, TBHP, 4 A MS, CH2Cl2, ꢀ20 °C, 8 h, 43% in three steps; (xi) (a) Me2CuLi,
Et2O, ꢀ20 °C to rt, overnight; (b) NaIO4, THF/H2O (1:1), 0 °C to rt, 3 h, 55% in two steps; (xii) (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 2 d; (b)
DDQ, CH2Cl2/phosphate buffer (pH 7) (20:1), 1.5 h, 55% in two steps.
mediate 6. Diastereoselective 1,3-syn hydride reduction
of b-silyloxy ketone 6 with DIBAL-H gave the all syn-
product 7 as the major diastereomer.7 The minor anti-
isomer could be easily separated by standard silica gel
column chromatography. The stereochemistry of the
major product 7 was confirmed after two further
transformations.
bond in 13. Reduction of the ester group of 13 gave
an allylic alcohol, which, after TIPS-deprotection, was
subjected to Katsuki–Sharpless epoxidation11 to furnish
the epoxy alcohol 14. Opening of the epoxide ring of 14
with Me2CuLi furnished ‘2-methyl-1,3-diol’ 15 as the
major product, which was subjected to oxidative cleav-
age with NaIO4 to remove the minor 1,2-diol. The puri-
fied triol 15 was persilylated followed by deprotection of
the PMB–ether to furnish the desired intermediate 2.12
Compound 7 was treated with CSA to selectively depro-
tect the TES-group and the resulting 1,2-diol 8 was pro-
1
tected as p-methoxybenzylidene acetal 9. The H NMR
In conclusion, we have described here the first synthesis
of the highly substituted tetrahydropyran moiety 2 of
the revised structure of botcinic acid 1 in suitably pro-
tected form for further synthetic work, currently in
progress.
3
spectrum of 9 showed a J coupling of 5.9Hz between
C2–H and C3–H supporting the structure assigned to
the major product of the hydride reduction.8 Diastereo-
selective cis-hydroxylation of 9 with a catalytic amount
of OsO4 gave the desired diol 10.9 Selective silylation
of the primary hydroxyl group of 10 was followed by
reductive ring opening of the p-methoxybenzylidene ace-
tal to give diol 11.10 Mesylation of the methyl carbinol
of 11 was followed by treatment with anhydrous
K2CO3 in dry methanol to enable a facile ring closing
reaction involving an intramolecular 6-exo SN2 type
substitution of the –OMs group to furnish the cyclized
tetrahydropyran ring 12.
Acknowledgement
The authors wish to thank CSIR, New Delhi, for a
research fellowship (R.K.G.).
References and notes
´
´
´
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T. K. Chakraborty, R. K. Goswami / Tetrahedron Letters 48 (2007) 6463–6465
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34
(SiO2, 10% EtOAc in petroleum ether); ½aꢁD ꢀ20.0 (c 0.15,
1
CHCl3); IR (neat): mmax 3446, 2925, 2854, 1627cmꢀ1; H
NMR (300MHz, CDCl3): d 4.17–4.01 (m, 2H), 3.85 (d,
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9.8Hz, 1H), 3.23 (br d, J = 7.6Hz, 1H), 2.38–2.24 (m, 2H),
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t
methyls), 0.93 (s, 9H, Bu), 0.89–0.87 (two s, 18H, two
tBu), 0.17–0.03 (six s, 18H, six Si–CH3); HRMS (ESI):
[M+Na]+ calcd for C30H66O5NaSi3, 613.4115; found,
613.4103.