Studies directed towards the synthesis of botcinolides: synthesis of the nonalactone ring of 2-epibotcinolide

Article abstract of DOI:10.1016/j.tetlet.2006.05.010

Synthesis of the polyoxygenated nonalactone ring of 2-epibotcinolide was achieved using a highly stereoselective aldol reaction of the titanium enolate from a lactate-derived chiral ketone, a stereoselective dihydroxylation and a Yamaguchi macrolactonizat

Full text of DOI:10.1016/j.tetlet.2006.05.010

Tetrahedron Letters 47 (2006) 4917–4919
Studies directed towards the synthesis of botcinolides: synthesis
of the nonalactone ring of 2-epibotcinolideI
Tushar Kanti Chakraborty* and Rajib Kumar Goswami
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 1 April 2006; revised 28 April 2006; accepted 4 May 2006
Available online 22 May 2006
Abstract—Synthesis of the polyoxygenated nonalactone ring of 2-epibotcinolide was achieved using a highly stereoselective aldol
reaction of the titanium enolate from a lactate-derived chiral ketone, a stereoselective dihydroxylation and a Yamaguchi macrolacto-
nization reaction.
Ó 2006 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 that is responsible for both the
so-called noble and grey rot in fruits.1 The pronounced
biological activities of botcinolides as phytotoxins with
relatively low acute toxicity2 and their structures with
a polyhydroxylated nonalactone ring acylated with a
fatty acid side chain, make them attractive targets to
synthetic organic chemists. While the biosynthesis of
the botcinolide skeleton has been investigated in detail,
no synthesis of any member of this family has yet been
achieved.3 The relative configurations of these molecules
have been deduced by extensive spectroscopic meth-
ods.1c However, their absolute stereochemistries are
yet to be determined. We envisaged that the total syn-
thesis of these molecules would not only provide access
to larger quantities necessary for further biological stud-
ies, but also help to establish their absolute stereochem-
istries. As part of our studies directed towards the
synthesis of 2-epibotcinolide 1, we describe herein the
first synthesis of the polyhydroxylated nonalactone ring
of the molecule 2 in suitably protected form for further
synthetic work.
O
O
OPMB
OH
OH
OH
OTBS
OTES
8
O
O
1
O
O
OH
OTBS
1
2
methylpropionate 3 with O-benzyl trichloroacetimidate
under acidic conditions4 was followed by reduction of
the ester with lithium aluminium hydride (LAH) to pro-
vide the chiral alcohol 4. Oxidation of 4 gave an alde-
hyde, which was subjected to olefination using the
stabilized ylide Ph3P@C(CH3)CO2Et to furnish, exclu-
sively, the E-olefin 5. Compound 5 was next transformed
into the aldehyde 6 in two steps—reduction with LAH to
an alcohol followed by oxidation to the aldehyde. Aldol
reaction of 6 with the titanium enolate derived from the
chiral ketone 75 gave the desired syn isomer 8 as the
major product in a 6:1 ratio.6 The product was purified
and silylation of the allylic hydroxyl was carried out
followed by protective group manipulations, necessitated
in order to achieve selective deprotection at a later stage,
to furnish the intermediate 9. Diastereoselective 1,3-syn
hydride reduction of the b-alkoxy ketone 9 with DIBAL-
H gave the all syn product 10 as the major isomer.7
The minor anti-isomer could be easily separated by stan-
dard silica gel column chromatography. The stereochem-
istry of the major product 10 was determined after three
more steps.
Scheme 1 outlines the details of the synthesis of 2. Benzyl-
ation of commercially available methyl (S)-3-hydroxy-2-
Keywords: Botcinolides; 2-Epibotcinolide; Dihydroxylation; Aldol
reaction; Yamaguchi reaction.
q IICT Communication No. 060401.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193108/
27160757; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.010

4918
T. K. Chakraborty, R. K. Goswami / Tetrahedron Letters 47 (2006) 4917–4919
ii
iii
i
iv
BnO
BnO
HO
OMe
BnO
OH
CO2Et
CHO
OTBS
7
O
4
5
6
3
O
OTBS
OTES
OTES
v
vi
vii
BnO
BnO
BnO
OH
O
O
TIPSO
O
TIPSO
+ anti (10 : 1)
OH
10
8
9
O
OH
O
OH
O
ix
viii
HO
BnO
BnO
PMP
O
TBSO
OTBS
OH
PMP
PMP
OH OH
O
11
12
13
OH
OH
OPMB
OH
x
HO
HO
+
TBSO
OTBS OPMB
14
TBSO
OTBS OH
15
[3:2]
OAc
OH
OH
OTES
xii
xi
xiii
AcO
14
HO
TBSO
O
OTBS OPMB
16
TBSO
OTBS OPMB
17
OH
OTES
OTES
xiv
xv
HO
HO
2
OTBS OPMB
OTBS OPMB
O
O
OTBS
OTBS
19
18
Scheme 1. Reagents and conditions: (i) (a) CCl3C(OBn)@NH, TfOH, cyclohexane/CH2Cl2 (2:1), 0 °C, 5 h; (b) LAH, dry ether, 0 °C, 5 min, 85%
yield after two steps; (ii) (a) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C; (b) Ph3P@C(CH3)CO2Et, CH2Cl2, rt, 3 h, 84% yield after two steps; (iii) (a)
i
LAH, dry ether, 0 °C, 10 min; (b) SO3–Py, Et3N, DMSO/CH2Cl2 (2:1.6), 0 °C, 30 min, 87% yield after two steps; (iv) 7, TiCl4, Pr2NEt, CH2Cl2,
ꢀ78 °C, 3 h, 85%; (v) (a) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C, rt, 1 h; (b) CSA, CH2Cl2/MeOH, 0 °C, 8 h; (c) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C,
5 min, 67% after three steps; (vi) DIBAL-H, CH2Cl2, ꢀ78 °C, 15 min, quantitative yield; (vii) (a) CSA, CH2Cl2/MeOH (4:1), 0 °C, 15 min; (b) PMP–
C(OMe)2, CSA, CH2Cl2, 0 °C, rt, 1 h; (c) TBAF, THF, 0 °C, rt, 6 h, 80% after three steps; (viii) OsO4, acetone/H2O (20:1), 0 °C, rt, 12 h, 84% yield;
˚
(ix) (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, rt, 2 h; (b) H2, Pd/C, dry EtOAc, 5 h, 74% after two steps; (x) NaCNBH3, TMSCl, CH3CN, 4 A MS,
0 °C, 10 min, 54% of 14; (xi) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C, 30 min, quantitative yield; (xii) (a) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, rt, 36 h; (b)
˚
DIBAL-H, CH2Cl2, ꢀ78 °C, 10 min, 75% after two steps; (xiii) (a) TPAP, 4 A MS, NMO, CH2Cl2, 10 min; (b) NaClO2, NaH2PO4ÆH2O, 2-methyl-2-
butene: tBuOH (1:2), rt, 30 min, 86% after two steps; (xiv) DIBAL-H, CH2Cl2, ꢀ78 °C, 10 min, 85%; (xv) 2,4,6-trichlorobenzoyl chloride, Et3N, dry
THF, rt, 4 h; the mixed anhydride was then slowly added to DMAP in dry toluene, 10ꢀ3 M, 100 °C, 2 h, 62%.
Compound 10 was next treated with CSA to deprotect
selectively the TES-group and the resulting 1,2-diol
was protected as its p-methoxybenzylidene acetal. The
to give the keto acid 18. Diastereoselective reduction
of the keto group of 18 using DIBAL-H furnished
the syn product 19. Although the stereochemistry of
the newly generated C8-OH was to be determined,
based on earlier work on the reduction of a-alkoxy
ketones, it was assumed to have the desired S
stereochemistry.12
3
1H NMR spectrum at this stage showed a J coupling
of 5.3 Hz between C7-H and C8-H supporting the struc-
ture assigned to the major product during the hydride
reduction.8 Finally, TIPS-deprotection with TBAF fur-
nished 11.
With the requisite intermediate 19 in hand, the stage was
now set to carry out the crucial Yamaguchi macrolacto-
nization reaction.13 Following a reverse-addition proto-
col, the mixed anhydride from 19 dissolved in toluene,
after evaporation of THF under reduced pressure, was
slowly added using a syringe pump over ca. 5 h to a
solution of DMAP in toluene (final concentration
10ꢀ3 M) at 100 °C to furnish the desired nonalactone 2
in 62% yield.14
cis-Hydroxylation of 11 with a catalytic amount of
OsO4 gave the all syn triol 12.9,10 Selective silylation
of the two secondary hydroxyl groups of 12 was fol-
lowed by debenzylation to furnish 13. Reductive ring
opening of the p-methoxybenzylidene acetal of 13 gave
a mixture of products 14 and 15, in a 3:2 ratio, which
could be separated by standard silica gel column chro-
matography.11 The requisite intermediate 14 was dia-
cylated to give 16. The tert-hydroxyl group of 16
was next protected as its TES-ether and hydride reduc-
tion was carried out to deprotect the acetates to fur-
nish 17. A two-step oxidation protocol then followed
Work is now in progress to attach the side chain at the
C7-OH to complete the total synthesis of the target mole-
cule and assign its absolute stereochemistry.

T. K. Chakraborty, R. K. Goswami / Tetrahedron Letters 47 (2006) 4917–4919
4919
9. To prove the stereochemistry of the hydroxylated product
12, compound 13 was oxidized to a c-lactone 20, which
was desilylated and the resulting 1,3-diol was protected as
an acetonide 21.
Acknowledgement
The authors wish to thank CSIR, New Delhi, for
research fellowships (R.K.G.).
O
TPAP, NMO, 4Ao MS,
10% CH3CN/CH2Cl2, 30 min
O
O
References and notes
13
PMP
O
95%
TBSO
OTBS O
´
´
´
1. (a) Collado, I. G.; Aleu, J.; Hernandez-Galan, R.; Duran-
20
´
Patron, R. Curr. Org. Chem. 2000, 4, 1261–1286; (b)
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O
i) TBAF, THF, 0 oC, 1 h, 83%
O
´
´
656–658; (c) Collado, I. G.; Aleu, J.; Hernandez-Galan,
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1980–1982.
ii) 2,2-DMP, CSA, CH2Cl2, 0 oC, rt,
30 min, 56%
PMP
O
O
O
21
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of the methyl carbons of the acetonide function at 21.4
and 31.8 ppm and that of ketal carbon at 96.2 ppm
confirming it to be a 1,3-syn acetonide (Ref. 10).
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´
´
´
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32
diethyl ether in n-hexane eluant); ½aꢁD ꢀ10.0 (c 2.6 in
CHCl3); IR (KBr): mmax 2930, 2881, 2857, 1734, 1613,
1513, 1463, 1249 cmꢀ1 1H NMR (500 MHz, CDCl3): d
;
´
´
3. Reino, J. L.; Duran-Patron, R. M.; Daoubi, M.; Collado,
´
´
I. G.; Hernandez-Galan, R. J. Org. Chem. 2006, 71, 562–
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Ar–H), 5.27 (dq, J = 4.9, 6.7 Hz, 1H, H-8), 4.78 (d,
J = 2.1 Hz, 1H, H-5), 4.55 (ABq, 2H, –O–CH2–Ar), 3.8 (s,
3H, Ar–O–CH3), 3.64 (d, J = 1.8 Hz, 1H, H-3), 3.48 (dd,
J = 4.9, 1.0 Hz, 1H, H-7), 2.55 (dq, J = 1.8, 7.3 Hz, 1H,
H-2), 2.29 (ddq, J = 1, 2.1, 7.3 Hz 1H, H-6), 1.35 (s, 3H,
C4–Me), 1.31 (d, J = 6.7 Hz, 3H, C8–Me), 1.24 (d,
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t
J = 7.3 Hz, 3H, C2–Me), 0.98–0.93 (m, 21H, Bu–Si, Si–
CH2–CH3, C6–Me), 0.83 (s, 9H, tBu–Si), 0.66 (q,
J = 8.0 Hz, 6H, Si–CH2–CH3), 0.11, 0.08, ꢀ0.06 and
ꢀ0.07 (four s, 12H, –Si–Me); 13C NMR (100 MHz,
CDCl3): d 174.4, 158.8, 130.7, 129.2, 113.3, 85.3, 85.0,
84.9, 75.1, 71.9, 71.6, 55.2, 45.5, 37.1, 30.5, 26.7, 26.1, 19.2,
18.2, 17.1, 17.0, 16.4, 7.5, 7.4, ꢀ3.2, ꢀ3.4, ꢀ3.9, ꢀ5.1; MS
(ESI): m/z (%) 748 (5) [M+Na]+.
´
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