Total synthesis of 6-epiprelactone-V via a syn-selective oxygen tethered intramolecular Michael reaction

Article abstract of DOI:10.1016/j.tetlet.2005.12.012

The intramolecular protective group (benzylidene acetal) assisted syn-1,3-diol synthesis has been efficiently utilized in a short synthesis of 6-epiprelactone-V starting from (S)-malic acid.

Full text of DOI:10.1016/j.tetlet.2005.12.012

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1213–1215
Total synthesis of 6-epiprelactone-V via a syn-selective
oxygen tethered intramolecular Michael reactionI
S. Chandrasekhar,* Ch. Rambabu and S. Jaya Prakash
Organic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 12 September 2005; revised 24 November 2005; accepted 1 December 2005
Available online 20 December 2005
Abstract—The intramolecular protective group (benzylidene acetal) assisted syn-1,3-diol synthesis has been efficiently utilized in a
short synthesis of 6-epiprelactone-V starting from (S)-malic acid.
Ó 2005 Elsevier Ltd. All rights reserved.
Poly-substituted chiral d-lactones have attracted consid-
erable attention in recent years due to their importance
as building blocks in natural product synthesis1 and due
to the fact that they form part of the structures of poly-
ketide macrolides,2 which have various biological pro-
files. These include bafilomycin A,3 mevinolin and
compactin.4 Similarly, several substituted d-lactones
have been isolated from microorganisms. Prelactones
are examples of such d-lactones isolated from bafilo-
mycin producing microorganisms and other polyketide
macrolide producing organisms.5 The structures of these
compounds have been assigned on the basis of the pro-
posed biosynthesis of macrolides.6 Biologically, these
lactones exhibit properties such as ATpase inhibitor
and antibacterial, antifungal and immunosuppressive
activities.7
O
2
1O
4
6
H3C
OH
CH3
6-epiprelactone-V (1)
Figure 1.
of the syn-1,3-diol functionality through an intramole-
cular Michael addition of a benzyloxy tether.
Our approach to epiprelactone-V is depicted retrosyn-
thetically in Scheme 1. The key to this approach was
the synthesis of 3 and 11 starting from readily available
(S)-malic acid 4.
Commercially available (S)-malic acid 4 was subjected
to esterification11 using BF3ÆOEt2 in methanol to give
Our group has been engaged in the development of prac-
tical synthetic approaches towards the substituted pyran
scaffold in chiral form.8 In this letter, we report a total
synthesis of the non-natural enantiomer of prelactone,
(ꢀ)-6-epiprelactone-V 1 (Fig. 1) employing a highly che-
mo-regio- and stereoselective tandem ester reduction,
epoxide formation-reductive epoxide opening reaction
protocol9 and a base catalyzed oxygen tethered intra-
molecular Michael addition10 as key steps. The highlight
of the synthesis is the utilization of the chiral centre in
commercially available (S)-malic acid 4 and creation
O
OH
O
O
OEt
H3C
OH
CH3
2
CH3
1
OH O
OH
HO
OH
OH
Keywords: Keck allylation; Intramolecular oxy-Michael reaction;
(ꢀ)-Centrolobine, 2,6-Disubstituted tetrahydropyran.
q IICT Communication No. 050615.
O
CH3
(S)-malic acid
4
3
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail addresses: srivaric@iict.res.in; srivaric@gmail.com
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.012

1214
S. Chandrasekhar et al. / Tetrahedron Letters 47 (2006) 1213–1215
OH
O
Ph
OH
O
a
b
MeO
MeO
HO
OMe
OMe
a, b
O
O
O
OH
c
2
O
O
3
5
O
4
H3C
OEt
(S)-malic acid
CH3
11
O
OH
O
OTs O
c
d
MeO
O
OMe
d
O
CH3
CH3
H3C
OH
6
7
CH3
1
OTBS
CH3
OTBS
OH
f
e
Scheme 3. Regents and conditions: (a) IBX, THF, DMSO, rt, 1 h; (b)
Ph3P@CHCO2Et, benzene, rt, 6 h, 64% (two steps); (c) PHCHO,
KtOBu, THF, 0 °C, 45 min, 76%; (d) concd H2SO4 (cat), THF, rt, 12 h,
95%.
OTBS
OH
OH
CH3
9
CH3
8
3
OH
O
OTBS
CH3
O
i
1.1 equiv of benzaldehyde in the presence of 0.1 equiv
of potassium tert-butoxide at 0 °C in THF to furnish
benzylidene acetal 11 in good yield. The diastereoselec-
tivity was greater than 95% favouring the more stable
syn-isomer. Finally, hydrolysis of the benzylidene acetal
and cyclization were successfully achieved in one pot15
using catalytic concd H2SO4 in methanol to furnish
the target molecule 1 in 95% yield.16
g, h
OEt
OEt
CH3
2
10
Scheme 2. Regents and conditions: (a) BF3ÆOEt2, MeOH, 0 °C to rt,
98%; (b) LHMDS, CH3I, THF, ꢀ78 °C, 5 h, 86%; (c) TsCl, py,
CH2Cl2, rt, 30 h, 90%; (d) LAH, THF, 55 °C, 4 h, 79%; (e) TBDMSCI,
immidazole, CH2Cl2, 0 °C to rt, 6 h, 95% ; (f) PTSA (cat), MeOH,
0 °C, 15–30 min, 75%; (g) IBX, THF, DMSO, rt, 1 h; (h)
Ph3P@CHCO2Et, benzene, rt, 6 h, 87% (two steps); (i) PTSA (cat),
MeOH, rt, 1 h, 92%.
This letter describes a straightforward entry to tri-sub-
stituted d-lactones in optically pure form. The simplicity
of the approach should facilitate the total synthesis of
complex lactone containing natural products.
dimethyl malate 5 in 98% yield. Diester 5 was treated
with LHMDS and methyl iodide in THF at ꢀ78 °C to
yield a-alkylated dimethyl malate 6 in good yield with
high diasteroselectivity (12:1). However, the diastereo-
mers could not be separated by chromatography.
Tosylation of 6 gave a separable mixture of 7 and its
syn-diastereoisomers in 90% yield. Treatment of
the anti-isomer 7 with lithium aluminium hydride
(6 M equiv) in THF afforded the desired diol 3 in 79%
yield (Scheme 2).
Acknowledgements
Two of us (C.R. and S.J.P.) thank CSIR, New Delhi, for
research fellowships.
References and notes
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nol to provide the key synthon 2 in high yield (Scheme 3).
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25
16. Spectral data for compound 1: ½aꢁD ꢀ81.8 (c 1.3, CHCl3);
1H NMR (200 MHz, CDCl3); d 4.94–4.85 (m, 1H), 4.05 (q,
J = 3.8 Hz, 1H), 2.80 (dd, J = 5.4, 18.6 Hz, 1H), 2.54 (dd,
J = 3.3, 18.6 Hz, 1H), 2.41–2.18 (m, 1H), 1.96–1.85
(m, 1H), 1.32 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 7.2 Hz,
3H); 13C NMR (50 MHz, CDCl3): d 171.5, 75.4, 68.2,
37.8, 35.9, 18.0, 10.6; IR (KBr) cmꢀ1 3425, 2924,
1718, 1250, 1078; MS (LC): m/z 145.1 (M+H)+, 167.0
(M+Na)+, 127 (Mꢀ17)+; HRMS: Calcd for C7H13O3
(M+H)+: 145.0864. Found: 145.0862.