A concise and stereoselective synthesis of both enantiomers of altholactone and isoaltholactone

Article abstract of DOI:10.1016/S0040-4039(03)01413-8

A concise and flexible stereoselective route to synthesize both enantiomers of the highly functionalized α,β-unsaturated-δ-lactones, altholactone and isoaltholactone, from readily available cinnamyl alcohol is described. This approach derived its asymmetry from Sharpless catalytic asymmetric epoxidation and Sharpless asymmetric dihydroxylation reactions. The resulting diols were produced in high enantiomeric excess and were cyclized in a stereoselective manner in the presence of a catalytic amount of camphor sulphonic acid.

Full text of DOI:10.1016/S0040-4039(03)01413-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5831–5833
A concise and stereoselective synthesis of both enantiomers of
altholactone and isoaltholactoneꢀ
J. S. Yadav,* G. Rajaiah and A. Krishnam Raju
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 22 April 2003; revised 19 May 2003; accepted 5 June 2003
Abstract—A concise and flexible stereoselective route to synthesize both enantiomers of the highly functionalized a,b-unsaturated-
d-lactones, altholactone and isoaltholactone, from readily available cinnamyl alcohol is described. This approach derived its
asymmetry from Sharpless catalytic asymmetric epoxidation and Sharpless asymmetric dihydroxylation reactions. The resulting
diols were produced in high enantiomeric excess and were cyclized in a stereoselective manner in the presence of a catalytic
amount of camphor sulphonic acid.
© 2003 Elsevier Ltd. All rights reserved.
Altholactone 1a and isoaltholactone 2a, furanopyrones
of the styryllactone family, were isolated from an
unknown Polythea (Annonacae) species,1 and from var-
ious Goniothalamous.2 This family of compounds share
a common 5-oxygenated-5,6-dihydro-2H-pyran-2-one
structural motif. Other members of this family include
5-acetoxygoniothalamin, goniodiol, etc.3 These natural
products possess anti-tumor,4 anti-fungal5 and anti-bac-
terial properties.5
design a concise and flexible stereoselective route
towards the construction of (+)-altholactone 1a, its
enantiomer (−)-altholactone 1b, (+)-isoaltholactone 2a
and its enantiomer (−)-isoaltholactone 2b from the
inexpensive and readily available cinnamyl alcohol.11
Retrosynthetically our approach is illustrated in
Scheme 1.
The synthesis began with the Sharpless asymmetric
epoxidation12 of cinnamyl alcohol 6 to afford 5a and 5b
in 82% and 83% yields, respectively. Oxidation of alco-
hols 5a and 5b using the Swern protocol13 afforded
both aldehydes, which without purification were sub-
jected to Wittig olefination14 with the stable ylide
Due to the wide distribution of the styryllactone class
of natural products in nature, many synthetic method-
ologies have been employed to synthesize them.6–10
Most syntheses use chiral pool starting materials such
as sugars, hydroxy acids and involve 11 to 16 steps.
Due to the unusual structure and biological significance
of this class of compounds, we were encouraged to
(ethoxycarbonyl–methylene)triphenylphosphorane
to
afford epoxy esters 7a and 7b, respectively, in 87% and
88% yields (2 steps) Schemes 2 and 3.
Scheme 1.
Keywords: altholactone; isoaltholactone; cinnamyl alcohol; sharpless asymmetric epoxidation; sharpless asymmetric dihydroxylation.
ꢀ IICT Communication No. 030410.
* Corresponding author. Fax: +91-40-27160512; e-mail: yadav@iict.ap.nic.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01413-8

5832
J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 5831–5833
a,b-Unsaturated epoxy ester 7a was subjected to a
Sharpless asymmetric dihydroxylation reaction using
AD-mix a, to yield 4a and 4b in a ratio of 20:115 (78%
yield) and treatment with AD-mix b afforded 4a and 4b
in a ratio of 1:1015 (75% yield), whilst treatment with
OsO4, NMO afforded 4a and 4b in a 13:7 ratio (78% yield).
The separation of these two isomeric diols 4a and 4b
was not feasible through simple column chromatography
because of their close Rf values. It was therefore decided
to purify the mixture in the forthcoming steps. The
mixture of 4a and 4b was subjected to treatment with
a catalytic amount of CSA to afford 3b and 3c (94% yield)
by cyclization. Subsequent treatment of this mixture
with 2,2-DMP afforded acetonide 8a and unreacted
3b which were readily separated by column chromatog-
raphy.
The ester 8a was reduced to the aldehyde, which was
subjected to Wittig olefination with the stable ylide
(ethoxycarbonylmethylene)triphenylphosphorane
in
methanol as the solvent to yield the cis-ester 9a (80% yield,
2 steps) predominantly (cis:trans 95:5).16 The trans-diol
3b was protected with TMSCl to yield 10b in 97% yield.
As with 8a, 10b was also reduced with DIBAL-H to afford
an aldehyde, which was transformed into the cis-ester 11b
(82% yield, 2 steps). Compounds 9a and 11b on treatment
with a catalytic amount of pTSA in methanol afforded
a mixture of diol esters and lactones 2a and 1b. Removal
of methanol by concentration under reduced pressure and
sonicationafterdilutingtheresiduewithbenzeneafforded
lactones 2a and 1b, respectively (both in 83% yields).
Epoxy ester 7b was transformed in a similar fashion to
afford 1a and 2b as illustrated in Scheme 3.
Scheme 2. Reagents and conditions: (a) (−)-DET, Ti(OiPr)4, TBHP, CH2Cl2, −33°C; (b) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C;
(c) Ph3PꢀCH-CO2Et, benzene, rt; (d) see Schemes 2 and 3; (e) CSA, CH2Cl2, rt; (f) 2,2-DMP, pTSA, acetone, rt; (g) DIBAL-H,
CH2Cl2, −78°C; (h) Ph3PꢀCH-CO2Et, CH3OH, rt; (i) pTSA, CH3OH, rt; then benzene, sonication 20–30 min; (j) TMS-Cl,
imidazole, CH2Cl2, 0°C to rt; (k) (+)-DET, Ti(OiPr)4, TBHP, CH2Cl2, −33°C.
Scheme 3. Reagents and conditions: (a) (−)-DET, Ti(OiPr)4, TBHP, CH2Cl2, −33°C; (b) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C;
(c) Ph3PꢀCH-CO2Et, benzene, rt; (d) see Schemes 2 and 3; (e) CSA, CH2Cl2, rt; (f) 2,2-DMP, pTSA, acetone, rt; (g) DIBAL-H,
CH2Cl2, −78°C; (h) Ph3PꢀCH-CO2Et, CH3OH, rt; (i) pTSA, CH3OH, rt; then benzene, sonication 20–30 min; (j) TMS-Cl,
imidazole, CH2Cl2, 0°C to rt; (k) (+)-DET, Ti(OiPr)4, TBHP, CH2Cl2, −33°C.

J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 5831–5833
5833
Thus, total syntheses of both enantiomers of altholactone
and isoaltholactone were achieved in efficient yields from
readily available cinnamyl alcohol 6. The syntheses
required only nine or ten chemical operations and were
highly stereoselective. Sharpless asymmetric dihydroxyla-
tion reactions of epoxy esters 7a and 7b and the CSA
catalyzed cyclization of 4a–d are the key steps of our
syntheses. Our route provides a general, efficient and
stereoselective access to related a,b-unsaturated-d-
lactones.
hedron Lett. 1996, 37, 5389; (b) Mukai, C.; Hirai, S.;
Hanaoka, M. J. Org. Chem. 1997, 62, 6619.
11. Our spectral data for synthetic 1a, 1b and 2b (1H NMR,
13C NMR, FTIR, EI-MS, and optical rotation) were
identical with those for the isolated natural products1,2 and
reported synthetic compounds.6–10
12. (a) Katzuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5954; (b) Sharpless, K. B.; Woodward, S. S.; Finn, M.
G. Pure Appl. Chem. 1983, 55, 1823; (c) Melloni, P.
Tetrahedron 1985, 41, 1391; (d) Peter, A. J. Chem. Soc.,
Perkin Trans. 1 1990, 2775.
13. (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165; (b)
Schmitz, W. D.; Messerschmidt, N. B.; Romo, D. J. Org.
Chem. 1998, 63, 2058.
Acknowledgements
14. (a) Wittig, G.; Rieber, M. Ann. 1949, 562, 187; (b) Wittig,
G.; Geissler, G. Ann. 1953, 580, 44; (c) Wittig, G.;
Schollkopf, V. Chem. Ber. 1954, 87, 1318; (d) Gensle, W.
J. Chem. Rev. 1957, 57, 191.
G. Rajaiah and A. Krishnam Raju thank the CSIR, New
Delhi for research fellowships.
15. Kim, N.; Choi, J.; Cha, J. K. J. Org. Chem. 1993, 58, 7096.
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G. Tetrahedron 1987, 43, 1895; (b) Tronchet, J. M. J.;
Gentile, B. Helv. Chim. Acta 1979, 62, 2091.
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Spectral data for selected compounds: Compound 7b (col-
orless liquid): [h]D=+121.9 (c 1.4 CHCl3); IR (KBr):
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MHz, CDCl3): l=1.32 (3H, t, J=5.9 Hz), 2.71 (1H, bs),
3.13–3.17 (1H, m), 3.32 (1H, bs), 3.89–3.92 (3H, m),
4.23–4.34 (2H, q, J=7.4 Hz), 7.23–7.29 (5H, m); EI-MS:
m/z=252 (M+).
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J=6.6 Hz), 4.43–4.53 (1H, m), 4.80 (1H, d, J=5.9 Hz), 5.02
(1H, d, J=5.9), 7.25-7.34 (5H, m); EI-MS: m/z=252 (M+).
Compound 8a (viscous liquid): [h]D=+17.5 (c 1.8 CHCl3);
IR (KBr): w=2986, 1761, 1453, 1378, 1207, 1107 cm−1; 1H
NMR (200 MHz, CDCl3): l=1.32 (3H, t, J=7.4 Hz), 1.33
(3H, s), 1.52 (3H, s), 4.25 (2H, q, J=7.4 Hz), 4.55 (1H, d,
J=5.2, 0.7 Hz), 4.80–4.98 (2H, m), 5.33 (1H, s), 7.25–7.32
(5H, m); EI-MS: m/z=292 (M+).
Compound 9a (viscous liquid): [h]D=+97.3 (c 1.5 CHCl3);
IR (KBr): w=2985, 1716, 1651, 1382, 1195 cm−1; 1H NMR
(200 MHz, CDCl3): l=1.29 (3H, t, J=7.4 Hz), 1.34 (3H,
s), 1.55 (3H, s), 4.15 (2H, q, J=7.4 Hz), 4.93–5.03 (2H, m),
5.21 (1H, s), 5.34–5.42 (1H, m), 5.95 (1H, dd, J=11.8, 1.4),
6.42 (1H, dd, J=11.8, 6.7 Hz), 7.21–7.36 (5H, m); EI-MS:
m/z=318 (M+).
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Compound 2a (colorless needles): Mp 102–103°C; [h]2D0=+
34.5 (c 0.50 EtOH); IR (KBr): w=3500, 3030, 1730, 1645
cm−1; 1H NMR (200 MHz, CDCl3): l=3.31 (1H, bs), 4.28
(1H, m) 4.78 (1H, d, J=7.5 Hz), 4.86 (1H, t, J=5.5, 4.4
Hz), 5.05 (1H, t, J=5.7 Hz), 6.20 (1H, dd, J=10.0, 0.7 Hz),
6.85 (1H, dd, J=9.9, 4.5 Hz), 7.25–7.40 (5H, m). 13C NMR
(CDCl3, 50 MHz): l=161.9, 141.7, 138.6, 128.5 (2), 128.1,
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