An efficient synthesis of (+)-prelactone B

Article abstract of DOI:10.1016/j.tetlet.2004.06.121

An enantioselective synthesis of (+)-prelactone B 1 has been achieved on a multigram scale starting from a known bicyclic precursor 2. The key feature of the strategy is the generation of 3-stereogenic centres from a single bicyclic precursor, which has b

Full text of DOI:10.1016/j.tetlet.2004.06.121

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6475–6476
An efficient synthesis of (+)-prelactone Bq
J. S. Yadav,* K. Bhaskar Reddy and G. Sabitha
Organic Chemical Sciences, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 May 2004; revised 16 June 2004; accepted 25 June 2004
Available online 19 July 2004
Abstract—An enantioselective synthesis of (+)-prelactone B 1 has been achieved on a multigram scale starting from a known bicyclic
precursor 2. The key feature of the strategy is the generation of 3-stereogenic centres from a single bicyclic precursor, which has been
utilized as a chiral building block for the synthesis of various natural products.
Ó 2004 Elsevier Ltd. All rights reserved.
The prelactones are highly functionalized chiral d-lac-
tones isolated from various polyketide macrolide pro-
ducing microorganisms.1 They represent essential
structural motifs in a large number of bioactive natural
products, such as mevinolin and compactin, inhibitors
of cholesterol biosynthesis;2 phomalactone3 and
asperlin,4 antibiotics; massoialactone5 and tetrahydro-
6-(1-hydroxyundecyl)-2H-pyran-2-one;6 attractant or
defence substances for animals and insects. (+)-Prelac-
tone B 1 was isolated from bafilomycin producing
microorganisms, Streptomyces griseus (strain Tu 2599
¨
Our synthetic approach towards the target molecule was
based on the utilization of the bicyclic precursor 2 and
the key feature of our strategy is that all the three stereo-
genic centres of the molecule at C-4, C-5 and C-6 are
generated from this precursor. This bicyclic precursor
was earlier used by our group towards the synthesis of
rifamycin S11 and discodermolide.12
ana 18) by Zeeck and Bindseil in 1993.7 It is believed
to be the product of polyketide synthase (PKS), and is
used as a standard for investigations concerning the
mechanism of PKS. To the best of our knowledge, to
date, only three asymmetric syntheses8 of prelactone B
and one leading to the racemate9 have been reported.
In connection with our ongoing research into the total
synthesis of the macrolide antibiotic, bafilomycin A1,10
which is a specific vacular-type H+-ATPase inhibitor,
possessing interesting activities, such as antibacterial,
antifungal and immunosuppressive activities, we needed
a new method for the preparation of a large amount of
(+)-prelactone B. We report herein a concise method for
the multigram scale preparation of (+)-prelactone B 1 by
a convergent route.
Asymmetric hydroboration of the olefin 2 using (ꢀ)-diiso-
pinocampheylborane gave 3 in high optical purity.
The alcohol 3 was converted to the lactone 4 by a two
step sequence, PCC oxidation followed by Baeyer–Vil-
liger oxidation of the resulting ketone. The key reaction
is opening of the appropriately functionalized bicyclic
lactone. The reduction of lactone 4 with LAH furnished
the triol 5 in 85% yield. The 1,3-diol moiety was con-
verted to the acetonide and the primary hydroxyl group
was tosylated with TsCl in the presence of NEt3 in DCM
to afford the tosylate 6 in 95% yield. The –CH2OTs
group of 6 was transformed into a methyl group by
LAH in refluxing THF, followed by acetonide deprotec-
tion to give the diol 7 in 88% yield. Selective oxidation of
the primary hydroxyl group using IBX afforded the
Keywords: Prelactone B; Bicyclic precursor; Streptomyces griseus;
Bafilomycin.
q IICT Communication No: 040426.
*
Corresponding author. Tel.: +91-40-27193434; fax: +91-40-
27160512; e-mail: yadavpub@iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.121

6476
J. S. Yadav et al. / Tetrahedron Letters 45 (2004) 6475–6476
bafilomycin A1 are in progress and the results will be
published in due course.
O
O
O
b,c
a
HO
O
O
Acknowledgements
OBn
OBn
4
3
2
OBn
K.B.R. thanks UGC, New Delhi for the award of a fel-
lowship.
e,f
g,h
d
OTs OBn
O
O
OH OBn OH OH
References and notes
6
5
1. (a) Cortes, J.; Wiesman, K. E. H.; Roberts, G. A.; Brown,
M. J. B.; Staunton, J.; Leadlay, P. F. Science 1995, 268,
1487; (b) Kao, C. M.; Luo, G.; Katz, L.; Cane, D. E.;
Khosla, C. J. Am. Chem. Soc. 1994, 116, 11612; (c)
Gerlitz, M.; Hammann, P.; Thiericker, R.; Rohr, J. J. Org.
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2. Endo, J. A. J. Med. Chem. 1985, 28, 401.
3. Honda, T. J. Chem. Soc., Perkin Trans. 1 1990, 1733.
4. Argoudelis, A. D.; Zieserl, J. F. Tetrahedron Lett. 1996,
18, 1969.
j,k
i
CHO
OBn OH
OBn OH OH
8
7
O
O
l
CO2Me
OBn OH
OH
9
1
5. Cavil, G. W. K.; Clark, D. V.; Whitefield, F. B. Aust. J.
Chem. 1968, 21, 2819.
Scheme 1. Reagents and conditions: (a) (ꢀ)-Ipc2BH, ꢀ23°C, THF,
24h, then 3N NaOH, 30% H2O2, rt, 6h, 95%. (b) PCC, DCM, rt, 3h,
94%. (c) m-CPBA, NaHCO3, DCM, rt, 10h, 88%. (d) LAH, THF,
0°C–rt, 4h, 85%. (e) 2,2-DMP, CSA, acetone, 3h, 73%. (f) TsCl, NEt3,
DMAP, DCM, 95%. (g) LAH, THF, reflux, 3h, 92%. (h) CSA,
MeOH, 2h, rt, 88%. (i) IBX, DMSO, DCM, 0°C–rt, 3h, 83%. (j)
NaClO2, NaH2PO4Æ2H2O, DMSO, H2O, 30min. (k) CH2N2, Et2O,
30min, yield 85% from 8. (l) H2/Pd(OH)2, EtOH, rt, 1h, 93%.
6. Laurence, B. R. J. Chem. Soc., Chem. Commun. 1982, 59.
7. Bindseil, K. V.; Zeeck, A. Helv. Chim. Acta 1993, 76, 150.
8. (a) Hanefeld, U.; Hooper, A. M.; Staunton, J. Synthesis
1999, 401; (b) Chakraborty, T. K.; Tapadar, S. Tetrahe-
dron Lett. 2003, 44, 2541; (c) Dias, L. C.; Steil, L. J.;
Vasconcelos, V. de A. Tetrahedron: Asymmetry 2004, 15,
147; (d) Csa˜k, A. G.; Mba, M.; Plumet, J. Synlett 2003,
2092.
9. Fournier, L.; Gaudel-sin, A.; Kocienski, P. J.; Pons, J.-M.
Synlett 2003, 107.
10. Toshima, K.; Yamaguchi, H.; Jyojima, T.; Noguchi, Y.;
Nakata, M.; Matsumura, M. Tetrahedron Lett. 1996, 37,
1073, and references cited therein.
11. Yadav, J. S.; Rao, C. S.; Chandrashekar, S.; Ramarao, A.
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aldehyde 8, which was characterized by the presence of
an aldehyde proton at d 9.80 in the H NMR spectrum.
1
The aldehyde was converted into its methyl ester 10 by
oxidation using NaClO2, NaH2PO4Æ2H2O in DMSO fol-
lowed by in situ esterification of the resulting acid using
diazomethane. Finally, hydrogenation using H2 on
Pd(OH)2 in EtOH at rt resulted in smooth removal of
the Bn protecting group and concomitant lactonization
afforded (+)-prelactone B 1 as a crystalline solid (mp
97–98°C, lit.8c mp 97–98°C). The synthetic substance
13. Selected physical data for 1. Rf =0.45 (silica, 60% EtOAc
25
D
exhibited spectral properties13 (1H, 13C NMR, IR, mass)
in petroleum ether); ½aŠ þ38:7 (c=0.75, MeOH); mp 97–
25
D
98°C; IR (KBr) mmax 3475, 2969, 2925, 1718, 1465, 1274,
and specific rotation, ½aŠ þ38:7 (c=0.75, MeOH) {lit.8c
1
1004cmꢀ1 ; H NMR (200MHz, CDCl3) d 3.72 (m, 2H),
25
½aŠ þ39:1 (c 0.6, MeOH)}, in accord with those re-
D
ported (Scheme 1).
2.89 (dd, J=17.6, 5.9Hz, 1H), 2.52 (br s, OH), 2.48 (dd,
J=17.8, 8.0Hz, 1H), 1.98 (m, 1H), 1.76 (ddq, J=10.0, 7.0,
6.1Hz, 1H), 1.12 (d, J=6.5Hz, 3H), 1.08 (d, J=6.0Hz,
3H), 0.92 (d, J=6.5Hz, 3H); 13C NMR (75MHz, CDCl3):
d 171.33, 86.38, 69.65, 38.96, 38.89, 28.89, 19.94, 14.04,
13.60; MS (EI): m/z 173 (M+H).
In conclusion, we have achieved a short and highly effi-
cient asymmetric synthesis of (+)-prelactone B in 24%
overall yield. Efforts towards the total synthesis of