Stereoselective total synthesis of a potent natural antifungal compound (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one

Article abstract of DOI:10.1016/j.bmcl.2009.09.063

A practical stereoselective synthesis of (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one (1), a potent natural antifungal compound, is described. The sequence involves diastereoselective iodine-induced electrophilic cyclization, epoxide

Full text of DOI:10.1016/j.bmcl.2009.09.063

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6396–6398
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Bioorganic & Medicinal Chemistry Letters
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Stereoselective total synthesis of a potent natural antifungal compound
(6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one q
*
Biswanath Das , Keetha Laxminarayana, Martha Krishnaiah, Duddukuri Nandan Kumar
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2009
Revised 10 September 2009
Accepted 15 September 2009
Available online 19 September 2009
A practical stereoselective synthesis of (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-
one (1), a potent natural antifungal compound, is described. The sequence involves diastereoselective
iodine-induced electrophilic cyclization, epoxide ring opening with a vinyl Grignard reagent and ring
closing metathesis (RCM) as the key steps.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
6-Substituted 5,6-dihydro 2H-pyran-2-one
Antifungal compound
Total synthesis
Diastereoselective iodo cyclization
Ring closing metathesis
Several natural products with
a
-pyrone (6-substituted 5,6-
the compound 9 by treatment with vinyl Grignard reagent fol-
lowed by acrylation. Subsequently RCM of 9 can be used to con-
struct the target molecule 1.
dihydro 2H-pyran-2-one or
a,b-unsaturated-d-lactone) structural
units have been found to exhibit a wide range of biological activi-
ties.1 They possess antifungal, antifeedent, antibacterial and cyto-
toxic properties.2 Such important biological activities made them
attractive targets to the total synthesis.3 The simplest structure
O
OH
O
with
a syn-1,3-diol/5,6-dihydro pyran-2-one moiety is (6S)-
5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one
(1) isolated by Hostettmann and co-workers from Ravensara crossi-
folia.4 It exhibits an antifungal activity against the phytopathogenic
fungus Cladosporium cucumerinum in bioautographic TLC assay and
the minimum amount required to inhibit this fungal growth was
1
The synthesis of 1 (Scheme 2) was initiated from commercially
available 5-phenyl pentan-1-ol 2, which was converted into the
known homoallyl alcohol 3 (ee 97%) through oxidation under
Swern conditions followed by Maruoka asymmetric allylation.5a
Treatment of 3 with di-tert-butyl dicarbonate in the presence of
DMAP in acetonitrile6 formed the homoallylic tert-butyl carbonate
4 in 89% yield. The second stereogenic center with the required ste-
reochemistry was established by using diastereoselective iodine-
induced electrophilic cyclization of 4. The compound 4 was treated
with excess I2 in CH3CN at low temperature (ꢀ20 °C) to furnish the
iodocarbonte 5 in 72% yield and with high diastereoselectivity (de
95%) favoring syn-isomer.7 The pure syn-isomer was separated by
column chromatography. The treatment of this compound with
3 equiv of K2CO3 in MeOH gave the desired syn-epoxy alcohol 6
(81%).7 The secondary hydroxyl group of epoxide 6 was protected
as its tert-butyl dimethylsilyl ether to form 7 in 88% yield. The
Cu mediated opening8 of the epoxide 7 with vinyl magnesium bro-
mide in tetrahydrofuran (THF) at ꢀ78 to ꢀ40 °C yielded corre-
sponding homoallyl alcohol 8 (80%).
1 lg. This amount was comparable to the minimum quantity in
the same assay of miconazole (1
lg) a commercially available ref-
erence antifungal compound.
Because of interesting antifungal activity and its structure con-
taining an
a,b-unsaturated d-lactone moiety with a fixed syn-1,3-
diol system 1 is an important target for total synthesis.5 We have
recently synthesized the compound 1 with an efficient approach,
which we would like to mention here.
Our retrosynthetic analysis of 1 is depicted in Scheme 1, whose
salient features involves the diastereoselective iodine-induced
electrophilic cyclization of 4 to fix syn-1,3-diol system following
the method developed by Bartlett and Cardillo. The cyclization
product 5 can be converted into the epoxide 6 which can furnish
q
Part 30 in the series ‘synthetic studies on natural products’.
* Corresponding author. Tel./fax: +91 40 7160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.063

B. Das et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6396–6398
6397
O
O
O
O
OH
OH
OH
O
6
9
1
O
OH
OBOC
O
O
I
3
4
5
OH
2
Scheme 1. Retrosynthetic analysis.
OH
OBOC
ref.5a
a
b
OH
4
3
2
O
O
O
OH
O
OTBS
O
c
d
I
5
6
7
O
OTBS
OTBS
OH
O
g
f
e
9
8
O
O
O
O
OTBS
OH
h
10
1
Scheme 2. Reagents and conditions, yields: (a) BOC2O, DMAP, CH3CN, 0 °C–rt, 10 h, 89%; (b) I2, CH3CN, ꢀ20 °C, 6 h, 72%; (c) K2CO3, MeOH, rt, 30 min, 81%; (d) TBSCl,
imidazole, DCM, 0 °C–rt, 5 h, 88%; (e) vinyl magnesium bromide, CuBr, THF, ꢀ78 to 40 °C, 7 h, 80%; (f) acryloyl chloride, Et3N, DMAP, DCM, 0 °C–rt, 4 h, 85%; (g) Grubb’s 2nd
generation catalyst (5 mol %), DCM, reflux, 6 h, 81%; (h) PTSA, MeOH, rt, 10 min, 82%.
The alcohol 8 was esterified with acryloyl chloride in presence
of Et3N and catalytic amount of DMAP to afford the acryloyl ester
9 (85%).9 Subsequently ring closing metathesis of ester 9 with com-
mercially available Grubbs 2nd generation catalyst in refluxing
the earlier syntheses a chiral homoallylic alcohol was converted
into
protected 1,3-hydroxyaldehyde5a or an unsaturated
a
hydroxyester5c to install the stereogenic center at C-6 position.
In an alternative approach the intermediate 1,3-diol with syn-
selectivity was prepared by diastereoselective reduction of a
protected 1,3-hydroxyketone which was obtained from a chiral
epoxide (synthesized following a reported method12) through a
sequence of reactions.5b Thus, only in the present synthesis of 1
a straightforward method for the generation of the second chiral
center (with syn-stereochemistry) to a chiral homoallyl alcohol
has been utilized. The method is easily accessible with a readily
available reagent.
DCM formed the
a
,b-unsaturated d-lactone 10 (81%).10 Finally
deprotection of TBS group in 10 with PTSA in MeOH gave the target
molecule 1 in 82% yield. The physical and spectroscopic data of 1
were in identical to those reported for natural product.11 The over-
all yield of the compound was 17.4%.
In our present synthesis we have utilized Maruoka asymmetric
allylation to generate the stereogenic center at C-20 position5a and
the diastereoselective iodine-induced electrophilic cyclization to
generate the stereogenic center at C-6 position.7b The latter pro-
tocol has not been used earlier for the synthesis of 1 to install
a new chiral carbon center. The advantage of the method is that
the protected chiral homoallylic alcohol 4 was directly used to
produce 5 with a second chiral center with syn-selectivity. In
In conclusion the stereoselective total synthesis of the naturally
occurring potent antifungal compound 1 has been achieved by
employing diastereoselective iodine-induced electrophilic cycliza-
tion for installing 1,3 syn-system, followed by vinyl Grignard addi-
tion and RCM as key reactions.

6398
B. Das et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6396–6398
Maruthi, Ch.; Yadav, J. S. Synthesis 2007, 3886; (c) Radhakrishna, P.; Srinivas, R.
Acknowledgments
Tetrahedron: Asymmetry 2007, 18, 2197.
6. Felpin, F.-X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192.
The authors thank CSIR and UGC, New Delhi for financial
assistance.
7. (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt, K. K. J.
Org. Chem. 1982, 47, 4013; (b) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.;
Sandri, S. J. Org. Chem. 1982, 47, 4626.
8. (a) Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullex, M.; Colobert, F.; Solladie,
G. Tetrahedron Lett. 2003, 44, 2695; (b) Kumar, P.; Gupta, P.; Naidu, S. V. Chem.
Eur. J. 2006, 12, 1397.
References and notes
9. Yadav, J. S.; Kumar, N. N.; Reddy, M. S.; Prasad, A. R. Tetrahedron 2007, 63, 2689.
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Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783; (c) Trnka, T.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
11. Physical and spectral data of synthesized 1: melting point: 34–35 °C,
1. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94; (b)
Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021.
2. (a) Drewes, S. E.; Schlapelo, B. M.; Horn, M. M.; Scott-Shaw, R.; Sandor, O.
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Garcia-Rojas, C. M. Tetrahedron 2001, 57, 47; (d) Carda, M.; Gonzalez, F.;
Castillo, E.; Rodriguez, S.; Marco, J. A. Eur. J. Org. Chem. 2002, 2649; (e) Murga, J.;
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½
a 2D5
ꢁ
= ꢀ63.0 (c 0.60, CHCl3); IR (neat): 3450, 2926, 1720, 1636, 1456,
1260 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.24–7.03 (5H, m), 6.82 (1H, m),
;
5.97 (1H, d, J = 9.0 Hz), 4.59 (1H, m), 3.80 (1H, m), 2.55 (2H, t, J = 7.0 Hz), 2.37–
2.28 (2H, m), 1.93–1.70 (2H, m), 1.62–1.41 (6H, m); 13C NMR (50 MHz, CDCl3):
d 163.9, 145.1, 142.4, 128.3, 128.2, 125.6, 121.2, 76.6, 69.1, 41.9, 37.4, 35.8,
31.3, 29.4, 25.0; Ms (ESI): m/z 297 [M+Na]+; HRMS (ESI): m/z 297.1459
[M+Na]+ calcd for C17H22O3Na; m/z 297.1466.
12. Simpson, T. J.; Smith, R. W.; Westaway, S. M.; Wills, C. L. Tetrahedron Lett. 1997,
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Randriantsoa, A.; Hostettmann, K. Helv. Chim. Acta 2001, 84, 3470.
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