A short, stereoselective, and common approach for the synthesis of 4,5-disubstituted δ-lactones simplactone B and its C-5 analogue

Article abstract of DOI:10.1016/j.bmcl.2005.02.059

A short, stereoselective, and a common approach for the synthesis of 4,5-disubstituted δ-lactones simplactone B and its analogue using Evans protocol is described.

Full text of DOI:10.1016/j.bmcl.2005.02.059

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2085–2086
A short, stereoselective, and common approach for the synthesis of
4,5-disubstituted d-lactones simplactone B and its C-5 analogueI
A. Ravi Kumar,a N. Sudhakar,a B. Venkateswara Rao,a,* N. Raghunandan,b
A. Venkateshb and M. Sarangapanib
aOrganic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
bUniversity College of Pharmaceutical Sciences, Kakatiya University, Warangal 506009, India
Received 2 November 2004; accepted 15 February 2005
Available online 19 March 2005
Abstract—A short, stereoselective, and a common approach for the synthesis of 4,5-disubstituted d-lactones simplactone B and its
analogue using Evans protocol is described.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
activities. Cafieri et al.2 expressed that incorporation
of long alkyl chains may increase the activity of simplac-
tones. Herein we report the novel and short strategy for
the synthesis of simplactone B and its C-5 analogue
using asymmetric aldol reaction. This strategy is also
helpful to make analogues with various chain lengths.
Sato et al.5 synthesized simplactones A and B and they
proposed that these spectral values are identical with
the proposed (isolated) simplactones B and A, respec-
tively, rather A and B. Our synthesis gives strong evi-
dence to the above statement because the spectral data
of simplactone B which we synthesized is identical with
the proposed (isolated) simplactone A (see Scheme 1).
Many natural products, which contains c- and d-lactone
moieties isolated from marine and terrestrial natural
sources differing in chain length, branching and function-
alization of alkyl chain, possesses interesting and peculiar
biological activities.1 Hitherto a number of c- and d-lac-
tones are isolated, possessing activities like antifungal
and antibiotic activities. Among these, recently simplac-
tone A and B compounds were isolated from the Carib-
bean sponge,2 Plakortis simplex and these compounds
possesses in vitro cytotoxic activity against WEHI 164.
Some other interesting d-lactones are homomevanolac-
tone,3 a structural isomer of simplactones, malyngo-
lide,4a,b etc.,4c which possess long alkyl chains.
Our synthetic route for simplactones involves Evans
asymmetric aldol methodology to set up the stereochem-
istry of the two contiguous stereogenic centers. Com-
pound 4 was coupled with corresponding different
Some of the c- and d-lactones, which contain long alkyl
chain unit mainly possess antibiotic and antifungal
OH
OH
OH
H C
3
H C
3
O
O
O
O
O
O
Simplactone A 1
simplactone B 2
5
C- analogue of simplactone 3
(Proposed)
(Proposed)
Keywords: Chiral auxiliary; Evans-asymmetric aldol methodology; Tempo oxidation; d-Lactones; Cytotoxic activity.
qIICT Communication number: 040707.
*
Corresponding author. Tel.: +91 040 271 60123x2614; fax: +91 040 271 60512; e-mail: venky@iict.res.in
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.059

2086
A. Ravi Kumar et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2085–2086
O
O
OH
O
O
O
OH HO
R
a
b
R
c
O
O
N
OBn
NH
O
N
OBn
R
Ph
Ph
Ph
4
8a R = C2H5
8b R = C14H29
7a R = C2H5
7b R = C14H29
5a R = C2H5
5b R = C14H29
OH
O
R
O
O
O
O
d
e
f
OBn
OH
O
R
R
2
3
R = C2H5
R = C14H29
9a R = C2H5
9b R = C14H29
10a R = C2H5
10b R = C14H29
Scheme 1. Reagents and condition: (a) CH3CH2CH2COOH (for 5a), C15H31COOH (for 5b), pivaloyl chloride, Et3N, LiCl, THF, ꢁ20 °C, 5 h, 95%
for 5a, 96% for 5b; (b) Bu2BOTf, Et3N, ꢁ78 °C, 1 h, then CHO(CH2)2OBn (6), ꢁ78 °C to ꢁ10 °C, 2 h, 82%, for 7a, 81% for 7b; (c) aq NaBH4, THF,
0 °C to rt, 2 h, 96% for 8a, 95% for 8b; (d) 2,2-DMP, CH2Cl2, PTSA (Cat amount), rt, 8 h, 97% for 9a, 95% for 9b; (e) Li/liq NH3, ꢁ78 °C, 0.5 h, 91%,
for 10a, 92% for 10b; (f) NaOCl, TEMPO free radical, TBAI (cat. amount), NaBr, EtOAc, toluene, H2O, NaHCO3, rt, then PTSA, CH2Cl2, rt, 3 h,
72% for 2, 73% for 3.
acids in the presence of pivaloyl chloride and triethyl
amine to get 5a,b. Treatment of the boron enolate6
derived from compounds 5a,b with the aldehyde 6 pro-
vided 7a in 82% and 7b in 81% yield, which were con-
verted to diols 8a,b after removing the oxazolidinone
auxiliary with aq NaBH4. Then the diols underwent ace-
tonide protection using 2,2-DMP to get compounds
9a,b, which on treatment with Li/liq NH3 conditions
yielded 10a,b. Under Tempo oxidation conditions 10a
and b were converted to acids, which were simulta-
neously treated with PTSA in DCM to afford lactones
2 and 3, in one pot. The spectral data of 2 is well in
Yadav and Late Dr. A. K. Singh for their support and
encouragement and Dr. S. Chandrasekhar for his help.
References and notes
1. Guzman, D.; Schmitz, F. J. J. Nat. Prod. 1990, 53, 926–931.
2. Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Di
Rosa, M.; Ianaro, I. Tetrahedron 1999, 55, 13831–13840.
3. (a) Jennings, R. C.; Judy, K. J.; Schooley, D. A. J. Chem.
Soc., Chem. Commun. 1975, 21–22; (b) Lee, E.; Schooley,
D. A.; Hall, M. S.; Judy, K. J. J. Chem. Soc., Chem.
Commun. 1978, 290–292.
4. (a) Cardellina, J. H., II; Moore, R. E.; Arnold, E. V.;
Clardy, J. J. Org. Chem. 1979, 44, 4039–4042; (b) Enders,
D.; Knopp, M. Tetrahedron 1996, 52, 5805–5818; (c)
Toshima, H.; Watanabe, A.; Sato, H.; Ichihara, A. Tetra-
hedron Lett. 1998, 39, 9223–9226.
5. Sato, M.; Nakashima, H.; Hanada, K.; Hayashi, M.;
Honzumi, M.; Taniguchi, T.; Ogasawara, K. Tetrahedron
Lett. 2001, 42, 2833–2837.
6. Evans, D. A.; Batroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127–2129.
agreement with the reported values, whose optical rota-
25
D
tion value (½aꢀ ꢁ23.1 (c 1, CHCl3)) is matching with the
25
synthetic compound prepared by Sato et al. {lit.5 (syn-
thetic) ½aꢀ ꢁ23.9 (c 0.8, CHCl3)}. Whereas optical rota-
D
tion value of natural product is lower than the synthetic
25
D
compounds. {lit.2 (natural) ½aꢀ ꢁ3 (c 0.002, CHCl3)}.
We have evaluated both lactones 2 and 3 for cytotoxic
activity against human breast cancer cell lines (HBL-
100) by MTT method.7 Compound 38 (C-5 analogue)
possesses moderate cytotoxic activity with IC50 of
0.176 lM, whereas on these cell lines lactone 2 has not
shown any activity. This clearly shows that side chain
length variation of these lactones will certainly influence
the activity.
7. Feasibility of high flux anti-cancer drug screen using diverse
panel of cultured human tumor cell lines. (a) Monks, A.;
Scudiero, P.; Shoemaker J. Natl. Cancer Inst. 1991, 83, 11;
(b) Scudiero, D. A.; Shoemaker, R. H.; Paul, K. D.
Evaluation of soluble tetrazolium/formazan assay for cell
growth and drug sensitivity in cultures using human and
other tumor cell lines. Cancer Res. 1988, 48, 4827–4833; (c)
Alley, M. C.; Scudiero, D. A.; Monks, A. Feasibility of
drug screening with panels of human tumor cell lines using
microculture tetrazolium assay. Cancer Res. 1998, 48, 589–
601.
In summary we have developed a short and highly ste-
reoselective synthesis of d-lactones using the well-known
diastereoselective Evans protocol which is useful
to make analogues of different chain lengths for more
therapeutic activity.
25
8. Spectral data for compound 3: ½aꢀD ꢁ3.07 (c 1.1, CHCl3);
Mp: 74 °C; (1H NMR, 400 MHz, CDCl3): d 0.9 (t, 3H,
J = 6.2), 1.2–1.45 (m, 24H), 1.51–1.62 (m, 1H), 1.77–1.95
(m, 2H), 2.5 (dd, 1H, J = 6.1, 17.7), 2.84 (dd, 1H, J = 5.3,
16.9), 3.92 (t, 2H, J = 10.1), 4.46 (dd, 1H, J = 3.8, 11.5);
(13C, 75 MHz, CDCl3): 170.3, 69.3, 68.4, 41.1, 38.2, 31.9,
29.6, 29.4, 29.3, 28.8, 26.8, 22.6, 14.03. FABMS: (M++1)
313.
Acknowledgements
A.R.K. and N.S.R. thank CSIR and U.G.C. New Delhi,
for their research fellowship. We also thank Dr. J. S.