Synthesis of (+)-prelactone B

Article abstract of DOI:10.1016/S0040-4039(03)00326-5

Radical-mediated opening of a trisubstituted epoxy alcohol using cp₂TiCl was followed by diastereoselective reduction of the resulting product with a centrally located methylene group, flanked on both sides by two chiral hydroxyl-bearing carbon

Full text of DOI:10.1016/S0040-4039(03)00326-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2541–2543
Synthesis of (+)-prelactone B
Tushar K. Chakraborty* and Subhasish Tapadar
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 November 2002; revised 24 January 2003; accepted 31 January 2003
Abstract—Radical-mediated opening of a trisubstituted epoxy alcohol using cp2TiCl was followed by diastereoselective reduction
of the resulting product with a centrally located methylene group, flanked on both sides by two chiral hydroxyl-bearing carbons,
to build all the three chiral centers of (+)-prelactone B 1 in their desired stereochemistries leading to the total synthesis of the
molecule. © 2003 Elsevier Science Ltd. All rights reserved.
The prelactone B 1 and prelactone C 2, isolated from
the culture-filtrate extract (0.2 mg/l) of Streptomyces
griseus (strain Tu¨ 2599 and 18) and the mycelium
extract of Streptomyces sp. (strain Go¨ 22/15), are highly
functionalized chiral d-lactones which are of interest as
starting materials or as building blocks for the synthesis
of biologically active natural products.1 They are the
first wild-strain-derived metabolites representing the
early steps of the polyketide pathway.2 An expeditious
route to these molecules will help to prepare them in
large quantities for use as standards during the mecha-
nistic studies of the polyketide synthases and related
biological studies.3
In this paper, we describe the total synthesis of (+)-
prelactone B.4 Retrosynthetically, lactone 1 can be
was prepared in two steps—Swern oxidation of 5 to an
aldehyde and then a three carbon stabilized Wittig
olefination to give exclusively the E-isomer of the
unsaturated ester 69 in 70% overall yield. Reduction of
6 with LAH furnished an allylic alcohol, which on
Swern oxidation followed by isopropyl Grignard addi-
tion gave compound 7 in 65% yield from 6. Sharpless
kinetic resolution8 of 7 with titanium(IV) isopropoxide
obtained from its linear precursor 3, a ‘2-methyl-1,3-
diol’ containing molecule. It was envisaged the ‘2-
methyl-1,3-diol’ moiety of 3 having all the stereocenters
of the final product could be built by a radical mediated
opening of the trisubstituted epoxide 4 using cp2TiCl, a
method developed by us earlier5,6 and used in the
synthesis of many polyketide natural products.7 The
chiral epoxide 4 could be easily prepared by kinetic
resolution of the corresponding allylic alcohol using the
Sharpless asymmetric epoxidation method.8 The actual
synthesis is outlined in Scheme 1.
and unnatural diethyl
D
-(−)-tartrate gave the chiral
epoxy alcohol 8 in 30% yield. While the enantiomeric
outcome of the reaction is yet to be determined, the
diastereoisomeric purity of product 8 was ascertained
on the basis of 1H NMR studies and verified after
subsequent steps by studying the 1H and 13C NMR
spectra of the acetonide of the final ‘2-methyl-1,3-diol’
moiety.
Starting with the monoprotected propane-1,3-diol 5,
synthesized from the diol using NaH, BnBr and a
catalytic amount of TBAI, the a,b-unsaturated ester 6
With the trisubstituted chiral epoxide 8 in hand, the
stage was now set to carry out the radical-mediated ring
Keywords: prelactone B; Sharpless kinetic resolution; epoxide open-
ing; 2-methyl-1,3-diol.
opening reaction. However, treatment of
cp2TiCl, generated in situ according to the procedure
8 with
* Corresponding author. Fax: +91-40-7160387, 7160757; e-mail:
chakraborty@iict.ap.nic.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00326-5

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T. K. Chakraborty, S. Tapadar / Tetrahedron Letters 44 (2003) 2541–2543
Scheme 1. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C to rt, 1.5 h. (b) Ph3PꢀC(CH3)CO2Et, CH2Cl2, 0°C
to rt, 2 h, yield 70% from 5. (c) LAH, Et2O, 0°C, 10 min. (d) Same as in step a. (e) (CH3)2CHMgBr, Et2O, 0°C, 10 min, yield
i
,
65% from 6. (f) Ti(O Pr)4, (−)-DET, TBHP (3.32 M in CH2Cl2), 4 A MS, CH2Cl2, −23°C, 30 min, yield 30%. (g) Cp2TiCl2, Zn
dust, cyclohexa-1,4-diene, THF, −23°C to rt, 6 h, yield 50%. (h) H2, 10% Pd/C, CH3OH, rt, 30 min, yield 20%. (i) TBDPSCl,
Et3N, DMAP, CH2Cl2, 0°C to rt, 2 h. (j) 2,2-Dimethoxypropane, CSA, CH2Cl2, 0°C to rt, 2 h, yield 91% from 10. (k) TBAF,
THF, 0°C to rt, 2 h. (l) (i) RuCl3·3H2O, NaIO4, CH3CN:CCl4:H2O (2:2:3), rt to 0°C, 1 h; (ii) CH2N2, Et2O, 0°C, 5 min, yield 40%
from 11. (m) AcOH:H2O (4:1), 0°C to rt, 2 h, yield 80%.
reported by us earlier,5,6 and cyclohexa-1,4-diene did
not give the desired ‘2-methyl-1,3-diol’ moiety. Instead,
it gave a b-hydride eliminated product 9 in 50% yield.
The formation of such olefins during the Ti(III)-medi-
ated epoxide opening reaction has been observed earlier
by us in certain sterically hindered substrates10,11 and
also by others.12 Next, the olefin 9 was subjected to
hydrogenation and debenzylation with H2, 10% Pd/C to
furnish the triol 10 with the desired stereochemistry at
the C-5 methyl group. Although excellent diastereose-
lectivity (9:1, determined by 1H NMR method) was
achieved in this step, the yield was poor due to the
formation of some side products that include a 3,6-
and concomitant cyclization using the AcOH/H2O sys-
tem to give the final product 1 in 80% yield.
Our synthetic prelactone B showed rotation [h]2D0 +37.2
(c 0.22, MeOH), matching with the lit.1 value: [h]D20
+38.3 (c 0.6, MeOH). Furthermore, the spectroscopic
data, namely, IR, NMR and mass spectra of our syn-
thetic product15 were in conformity with those of the
naturally occurring prelactone B.
Acknowledgements
dihydro-2H-pyran moiety,
a
major side-product,
The authors wish to thank CSIR, New Delhi for a
research fellowship (S.T.).
formed by an intramolecular cycloetherification process
involving the debenzylated free hydroxyl group and the
C-5 methylene unit. Further study of this step to
improve the yield has not yet been carried out. Protec-
tion of the primary hydroxyl group of 10 was followed
by acetonide protection of the secondary hydroxyls to
give the intermediate 11 in 91% yield in two steps.
Deprotection of the silyl group of 11 and subsequent
oxidation of the primary hydroxyl group using
RuCl3·3H2O and NaIO4 to the acid, followed by O-
methylation with CH2N2 furnished the methyl ester 12
in 40% yield from 11. In this step the major and minor
diastereoisomers were separated by standard silica gel
column chromatography. The 13C NMR spectrum of
the major isomer 12 shows that the gem dimethyls of
the acetonide unit resonate at 23.9 and 25.1 ppm and
that of the ketal carbon at 100.5 ppm, proving the anti
relationship between C1%-OH and C3%-OH with a twist-
boat conformation.13 Coupling constant measurements,
J1%,2%=7.5 Hz and J2%,3%=5.2 Hz certainly suggested the
anti relationship between C1%-OH and C2%-Me and syn
relationship between C2%-Me and C3%-OH.14 The major
isomer 12 was then subjected to acetonide deprotection
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T. K. Chakraborty, S. Tapadar / Tetrahedron Letters 44 (2003) 2541–2543
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IR (KBr): wmax 3473, 2966, 2923, 1714, 1276, 1231, 1005
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C6-H), 2.95 (dd, J=17, 6 Hz, 1H, C3-H), 2.48 (dd, J=17,
8 Hz, 1H, C3-H%), 1.99 (m, 1H, C1%-H), 1.78 (ddq, J=10,
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