A concise total synthesis of diospongins A and B

Article abstract of DOI:10.1002/hlca.200890242

The total synthesis of the diarylheptanoids (-)-diospongin A (1) and B (2) was achieved stereoselectively via the δ-lactone intermediate 6. The key reactions involved are a stereoselective reduction of β-keto ester and the Horner-Wadsworth-Emmons and intramolecular oxy-Michael reactions.

Full text of DOI:10.1002/hlca.200890242

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A Concise Total Synthesis of Diospongins A and B
by Gowravaram Sabitha*, Pannala Padmaja, and Jhillu S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
(phone: þ 91-40-27160512; fax: þ 91-40-27160512; e-mail: gowravaramsr@yahoo.com)
The total synthesis of the diarylheptanoids (ꢀ)-diospongin A (1) and B (2) was achieved
stereoselectively via the d-lactone intermediate 6. The key reactions involved are a stereoselective
reduction of b-keto ester and the Horner– Wadsworth – Emmons and intramolecular oxy-Michael
reactions.
Introduction. – The 1,7-diarylheptanoids are present in a great variety of natural
products which possess interesting biological [1] and pharmacological activities such as
antioxidant [2], anticancer [3], and inhibitory activity on nitric oxide production [4],
and anti-inflammatory [5] and antileishmanial activity [6]. (ꢀ)-Diospongin A (1) and B
(2) are cyclic 1,7-diarylheptanoids which have been isolated from the rhizomes of
Dioscorea spongiosa in 2004 via bioassay-guided fractionation [7]. Diospongins A and
B possess a 2,6-cis- and 2,6-trans-substituted tetrahydro-2H-pyran ring, respectively,
and these rings are assumed to be formed by an intramolecular oxy-Michael reaction in
their biosynthesis. (ꢀ)-Diospongin B (2) has exerted potent inhibitory activities on
bone resorption induced by parathyroid hormone in a bone-organ culture system and
could be used for the treatment of osteoporosis, a skeletal disease. Due to the
interesting antiosteoporotic activity of diospongins, syntheses of these natural products
have been recently reported [8]. In continuation of our studies on the stereoselective
synthesis of natural products [9], we report here a short and efficient total synthesis of
(ꢀ)-diospongins A (1) and B (2).
Results and Discussion. – The synthesis was initiated from the known chiral 1-
phenylbut-3-en-1-ol (3), prepared from benzaldehyde by Keck allylation [10] with
allyltributyltin in the presence of (S)-BINOL (¼(S)-[1,1’-binaphthalene]-2,2’-diol) and
Ti(OiPr)4 in 73% yield. The enantiomeric excess of 3 was 97% by chiral HPLC. The
oxidative cleavage of the terminal olefin moiety of 3 produced the corresponding
aldehyde, which without isolation was treated with ethyl diazoacetate in the presence of
a catalytic amount of tin(II) chloride [11] to afford the b-keto ester 4 in 80% yield
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 91 (2008)
(Scheme 1). The ꢂsynꢃ-selective reduction of d-hydroxy-b-keto ester 4 was performed
with catecholborane (¼1,3,2-benzodioxaborol) [12] (2.2 equiv.) in dry THF at ꢀ 108 to
afford the ꢂsynꢃ-1,3-diol 5 in 75% yield. Cyclization of ester 5 was accomplished by
reacting it with a catalytic amount of TsOH (¼4-methylbenzenesulfonic acid) in dry
CH2Cl2 to afford d-lactone 6 [8e] in 68% yield.
Scheme 1
a) 1. OsO4 (0.1m in toluene), 4-methylmorpholine 4-oxide (NMO), acetone/H2O 4 :1, overnight; 2.
NaIO4, CH2Cl2, sat. NaHCO3 soln., 4 h; 85%. b) anh. SnCl2 (cat.), N2CHCOOEt, CH2Cl2, 08 to r.t.,
40 min; 80%. c) Catecholborane, dry THF, ꢀ 108, 5 h; 75%. d) TsOH, CH2Cl2, ꢀ 788, 30 min; 68%.
e) 1. DIBAL-H, dry CH2Cl2, ꢀ 788, 30 min; 2. 7, Ba(OH)2 · 8 H2O, THF/H2O 4 :1, r.t., 5 h; 81%.
Next, the reduction of lactone 6 with DIBAL-H (¼diisobutylaluminium hydride)
[13] and treatment with Hornerꢃs phosphonate 7 [14] and BuLi as base was performed
as recently reported [9j], but the reaction was found to be sluggish, and the products
could not be isolated in pure form. However, the reduction of lactone 6 with DIBAL-H
[13] and treatment with Hornerꢃs phosphonate 7 [14]1) and Ba(OH)2 · 8 H2O as base
[15] in THF/H2O 4 :1 afforded a 4 :6 diastereomer mixture of 2,6-cis/trans isomers, 1
and 2, i.e., (ꢀ)-diospongin A and (ꢀ)-diospongin B in an overall yield of 60%,
achieving Wittig – Horner and intramolecular oxy-Michael reactions in one-pot (for
recent examples of the oxy-Michael reaction, see [16]). Diastereoisomers 1 and 2 were
separated by column chromatography, and their structures were confirmed by spectral
1
)
The required Hornerꢃs phosphonate 7 was synthesized from commercially available ethyl benzoate
by treatment with diethyl methylphosphonate and BuLi (Scheme 2).
Scheme 2

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data. The physical data of the synthetic materials was fully consistent with those
reported for the natural products [8b].
In summary, a short synthesis of (ꢀ)-diospongins A (1) and B (2) was achieved via a
common intermediate lactone 6 by means of Keck allylation, stereoselective reduction
of a b-keto ester, and Horner – Wadsworth – Emmons and intramolecular oxy-Michael
reactions as key steps. The application of the method to further natural products is in
progress and will be reported in due course.
P. P. Thanks UGC, New Delhi, for the award of a fellowship.
Experimental Part
General. Reactions were conducted under N2 with anh. solvents such as CH2Cl2 and THF. Light
petroleum ether 60 – 808 was used. Yields refer to chromatographically and spectroscopically (1H, 13C)
homogeneous material. Air-sensitive reagents were transferred by syringe or with a double-ended
needle. Evaporation of solvents was performed under reduced pressure with a Bꢀchi rotary evaporator.
Column chromatography (CC): silica gel (60 – 120 mesh) supplied by Acme Chemical Co., India. TLC:
Merck-60-F254 silica gel plates; visualization under UV light. Optical rotations: Jasco-DIP-370
1
polarimeter; at 208. H-NMR Spectra: Varian-FT-200MHz (Gemini) and Bruker-UXNMR-FT-300MHz
(Avance) spectrometers; CDCl3 solns.; chemical shifts d in ppm rel. to Me4Si (d 0.0) as an internal
standard; J in Hz. Mass spectra: LC-MSD (Agilent Technologies); electron impact at 70 eV; in m/z.
Ethyl (5S)-5-Hydroxy-3-oxo-5-phenylpentanoate (4). To anh. tin(II) chloride (0.37 g, 2 mmol) was
added CH2Cl2 (15 ml) followed by ethyl diazoacetate (2.5 g, 22 mmol) with stirring at r.t. To this
suspension were added slowly few drops of crude aldehyde (3 g, 20 mmol; from 3) in dry CH2Cl2. When
N2 evolution began, the remaining soln. of crude aldehyde was added dropwise within 10 min. After N2
evolution had stopped (30 min), the mixture was transferred to a separatory funnel with sat. NaCl soln.
(30 ml) and extracted with Et2O (2 ꢁ 20 ml). The combined org. layer was dried (Na2SO4), the solvent
evaporated, and the residue purified by CC (silica gel): 4 (3.7 g, 80%). Yellow liquid. [a]2D5 ¼ ꢀ30.2 (c ¼
1.15, CHCl3). IR (neat): 3487, 2982, 2926, 1739, 1648, 1451, 1314, 1030, 757, 701. 1H-NMR (CDCl3,
200 MHz): 7.47 – 7.18 (m, 5 H); 5.15 (dd, J ¼ 4.4, 3.6, 1 H); 4.18 (q, J ¼ 7.3, 2 H); 3.43 (s, 2 H); 2.96 – 2.87
(m, 2 H); 1.29 (t, J ¼ 7.3, 3 H). 13C-NMR (CDCl3, 75 MHz): 192.1; 168.3; 142.7; 129.6; 128.7; 126.4; 69.0;
61.2; 52.4; 49.8; 14.1. ESI-MS: 259 ([M þ Na]þ). HR-MS: 259.1616 (C13H16NaO4þ, [M þ Na]þ; calc.
259.0964).
Ethyl (3R,5S)-3,5-Dihydroxy-5-phenylpentanoate (5). The soln. of 4 (2.5 g, 10 mmol) in dry THF
was chilled in a MeOH/ice bath (ꢀ108) and charged with freshly distilled catecholborane (2.48 ml,
23 mmol). After 5 h, the mixture was quenched by the addition of anh. MeOH (1 ml) and sat. aq. sodium
potassium tartrate soln. (2 ml). This mixture was stirred at r.t. for 1 h, and the desired product was
isolated by CC (silica gel): 5 (1.89 g, 75%). Brown liquid. [a]2D5 ¼ ꢀ15.8 (c ¼ 0.7, CHCl3). IR (neat): 3436,
2924, 2854, 1728, 1642, 1452, 1215, 1068, 760, 701. 1H-NMR: (CDCl3, 300 MHz): 7.41 – 7.17 (m, 5 H); 4.94
(dd, J ¼ 6.8, 3.0, 1 H); 4.35 – 4.22 (m, 1 H); 4.16 (q, J ¼ 7.5, 2 H); 3.85 (br., 1 H, OH); 3.56 (br., 1 H,
OH); 1.88 (dd, J ¼ 14.3, 3.7, 2 H); 1.75 (t, J ¼ 2.3, 2 H); 1.28 (t, J ¼ 7.5, 3 H). 13C-NMR (CDCl3, 75 MHz):
172.5; 143.7; 128.4; 127.7; 125.5; 74.3; 68.5; 60.8; 44.6; 41.6; 14.0. LC/MS: 261 ([M þ Na]þ). HR-MS:
261.1745 (C13H18NaO4þ, [M þ Na]þ; calc. 261.1103).
(4R,6S)-Tetrahydro-4-hydroxy-6-phenyl-2H-pyran-2-one (6) [8e]. To a soln. of 5 (2 g, 8.40 mmol) in
anh. CH2Cl2 (20 ml) was added a catalytic amount of TsOH under N2. The mixture was stirred at r.t. for
6 h, then the reaction was quenched by the addition of solid NaHCO3 (0.004 g, 0.05 mmol). The mixture
was filtered, the solvent of the filtrate evaporated, and the residue purified by CC (hexane/AcOEt 4 :6): 6
(1.09 g, 68%). Colorless liquid. [a]2D5 ¼ ꢀ9.4 (c ¼ 1.35, CHCl3). IR (neat): 3416, 2924, 2854, 1726, 1455,
1249, 1044, 758, 700. 1H-NMR (CDCl3, 200 MHz): 7.48 – 7.18 (m, 5 H); 5.7 (dd, J ¼ 11.3, 3.0, 1 H); 4.40
(m, 1 H); 2.82 – 2.65 (m, 2 H); 2.31 – 1.98 (m, 2 H). 13C-NMR (CDCl3, 75 MHz): 170.8; 139.1; 128.6;
128.3; 125.8; 77.3; 62.5; 38.5; 38.1. LC/MS: 215 ([M þ Na]þ). HR-MS: 215.1298 (C11H12NaO3þ, [M þ
Na]þ; calc. 215.0684).

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(ꢀ)-Diospongin A (¼1-Phenyl-2-[(2R,4S,6S)-tetrahydro-4-hydroxy-6-phenyl-2H-pyran-2-yl]etha-
none; 1) and (ꢀ)-Diospongin B (¼1-Phenyl-2-[(2S,4S,6S)-tetrahydro-4-hydroxy-6-phenyl-2H-pyran-2-
yl]ethanone; 2). To a soln. of 6 (0.1 g, 0.52 mmol) in dry CH2Cl2 at ꢀ 788 was added DIBAL-H (0.7 ml),
and the mixture was stirred at ꢀ 788 for 30 min. Then, the reaction was quenched by slow addition of
MeOH followed by sat. sodium potassium tartrate soln. The mixture was extracted with CH2Cl2, the
combined org. layer washed with H2O, dried (Na2SO4), and concentrated, and the crude lactol used
without any further purification for the next reaction.
Activated Ba(OH)2 · 8 H2O (0.32 g, 1 mmol) was added to a stirred soln. of Horner– Wittig reagent 7
(0.23 g, 1 mmol) in THFat 08 for 30 min, then the above crude lactol (0.1 g, 0.51 mmol) in THF/H2O 4 :1
was added, and after 5 h, the mixture was extracted with AcOEt. The combined org. layer was washed
with H2O and dried (Na2SO4), the solvent evaporated, and the residue purified by CC (silica gel, hexane/
AcOEt 7:3): 1 and 2 as liquids.
(ꢀ)-Diospongin A (1): [a]2D5 ¼ ꢀ21.1 (c ¼ 0.8, CHCl3). IR (neat): 3443, 2921, 2853, 1678, 1512, 1450,
1286, 1215, 1058, 758, 694. 1H-NMR: (CDCl3, 300 MHz): 7.95 (dd, J ¼ 7.6, 1.4, 2 H); 7.48 (t, J ¼ 7.5, 1 H);
7.35 (t, J ¼ 7.5, 2 H); 7.19 – 7.12 (m, 5 H); 4.87 (dd, J ¼ 11.7, 1.9, 1 H); 4.61 – 4.49 (m, 1 H); 4.29 (m, 1 H);
3.32 (dd, J ¼ 15.8, 5.3, 1 H); 2.97 (dd, J ¼ 16.6, 7.5, 1 H); 2.31 (br., OH); 1.98 – 1.79 (m, 2 H); 1.71 – 1.45
(m, 2 H). 13C-NMR (CDCl3, 50 MHz): 198.4; 142.6; 137.2; 133.1; 128.5; 128.3; 128.2; 127.2; 125.7; 73.7;
69.0; 64.6; 45.1; 39.9; 38.4. LC/MS: 297.1 ([M þ 1]þ). HR-MS: 297.1475 (C19H21O3þ, [M þ H]þ; calc.
297.1491).
(ꢀ)-Diospongin B (2): [a]2D5 ¼ ꢀ22.5 (c ¼ 0.6, CHCl3). IR (neat): 3404, 2924, 2854, 1680, 1599, 1452,
1378, 1214, 1054, 756, 693. 1H-NMR: (CDCl3, 300 MHz): 7.98 (d, J ¼ 8.2, 2 H); 7.56 (t, J ¼ 7.4, 1 H); 7.45
(t, J ¼ 7.9, 2 H); 7.38 – 7.12 (m, 5 H); 5.12 (t, J ¼ 4.2, 1 H); 4.25 – 4.12 (m, 1 H); 4.03 – 3.89 (m, 1 H); 3.41
(dd, J ¼ 15.6, 7.0, 1 H); 3.11 (dd, J ¼ 15.7, 6.5, 1 H); 2.45 (d, J ¼ 13.6, 1 H); 2.00 (d, J ¼ 12.8, 1 H); 1.86
(ddd, J ¼ 13.6, 9.8, 5.3, 1 H); 1.46 (dd, J ¼ 9.5, 3.2, 1 H). 13C-NMR (CDCl3, 75 MHz): 198.4; 140.3; 137.1;
133.1; 128.6; 128.5; 128.3; 127.1; 126.3; 72.3; 67.0; 64.2; 44.6; 40.6; 36.7. LC/MS: 297.1 ([M þ 1]þ). HR-MS:
297.1483 (C19H21O3þ, [M þ H]þ; calc. 297.1491).
REFERENCES
[1] S. Kadota, Y. Tezuka, J. K. Prasain, M. S. Ali, A. H. Banskota, Curr. Top. Med. Chem. 2003, 3, 203; J.
Zhu, G. Islas-Gonzalez, M. Bois-Choussy, Org. Prep. Proced. Int. 2000, 32, 505; P. Claeson, U. P.
Claeson, P. Tuchinda, V. Reutrakul, in ꢂStudies in Natural Product Chemistryꢃ, Ed. Atta-ur-Rahman,
Elsevier Science B.V, Amsterdam, 2002, Vol. 26, p. 881.
[2] H. Mohamad, N. H. Lajis, F. Abas, A. M. Ali, M. A. Sukari, H. Kikuzaki, N. Nakatani, J. Nat. Prod.
2005, 68, 285; K. Akiyama, H. Kikuzaki, T. Aoki, A. Okuda, N. H. Lajis, N. Nakatani, J. Nat. Prod.
2006, 69, 1637.
[3] M. S. Ali, Y. Tezuka, S. Awale, A. H. Banskota, S. Kadota, J. Nat. Prod. 2001, 64, 289; J. Ishida, M.
Kozuka, H. Tokuda, H. Nishino, S. Nagumo, K.-H. Lee, M. Nagai, Bioorg. Med. Chem. 2002, 10,
3361; K.-S. Chun, K.-K. Park, J. Lee, M. Kang, Y.-J. Surh, Oncol. Res. 2002, 13, 37.
[4] H. Matsuda, S. Ando, T. Kato, T. Morikawa, M. Yoshikawa, Bioorg. Med. Chem. 2006, 14, 138; H.-J.
Kim, S.-H. Yeom, M.-K. Kim, J.-G. Shim, I.-N. Paek, M.-W. Lee, Arch. Pharm. Res. 2005, 28, 177.
[5] P. N. Yadav, Z. Liu, M. M. Rafi, J. Pharmacol. Exp. Ther. 2003, 305, 925.
[6] M. Takahashi, H. Fuchino, S. Sekita, M. Satake, Phytother. Res. 2004, 18, 573.
[7] J. Yin, K. Kouda, Y. Tezuka, Q. L. Trans, T. Miyahara, Y. Chen, S. Kadota, Planta Med. 2004, 70, 54.
[8] a) R. W. Bates, P. Song, Tetrahedron 2007, 63, 4497; b) N. Kawai, S. Mahadeo, J. Uenishi, Tetrahedron
2007, 63, 9049; c) J. S. Yadav, B. Padmavani, B. V. S. Reddy, C. Venugopal, A. B. Rao, Synlett 2007,
2045; d) M. A. Hiebel, B. Pelotier, O. Piva, Tetrahedron 2007, 63, 7874; e) K. B. Sawant, M. P.
Jennings, J. Org. Chem. 2006, 71, 7911; f) C. Bressy, F. Allais, J. Cossy, Synlett 2006, 3455; g) S.
Chandrasekhar, T. Shyamsunder, J. S. Prakash, A. Prabhakar, B. Jagadeesh, Tetrahedron Lett. 2006,
47, 47.
[9] a) G. Sabitha, K. Sudhakar, N. M. Reddy, M. Rajkumar, J. S. Yadav, Tetrahedron Lett. 2005, 46, 6567;
b) G. Sabitha, F. Narjis, R. Swapna, J. S. Yadav, Synthesis 2006, 17, 2879; c) G. Sabitha, E. V. Reddy,

Helvetica Chimica Acta – Vol. 91 (2008)
2239
K. Yadagiri, J. S. Yadav, Synthesis 2006, 19, 3270; d) G. Sabitha, K. Sudhakar, J. S. Yadav,
Tetrahedron Lett. 2006, 47, 8599; e) G. Sabitha, V. Bhaskar, J. S. Yadav, Tetrahedron Lett. 2006, 47,
8179; f) G. Sabitha, R. Swapna, E. V. Reddy, J. S. Yadav, Synthesis 2006, 24, 4242; g) G. Sabitha, M.
Bhikshapathi, J. S. Yadav, Synth. Commun. 2007, 37, 561; h) G. Sabitha, P. Gopal, J. S. Yadav, Synth.
Commun. 2007, 37, 1495; i) G. Sabitha, K. Yadagiri, J. S. Yadav, Tetrahedron Lett. 2007, 48, 1651; j) G.
Sabitha, K. Yadagiri, J. S. Yadav, Tetrahedron Lett. 2007, 48, 8065.
[10] G. E. Keck, K. H. Tarbet, L. S. Geraci, J. Am. Chem. Soc. 1993, 115, 8467.
[11] C. R. Holmquist, E. J. Roskamp, J. Org. Chem. 1989, 54, 3258.
[12] A. D. Evans, A. H. Hoveyda, J. Org. Chem. 1990, 55, 5190.
[13] G. Vidari, S. Ferrino, P. A. Grieco, J. Am. Chem. Soc. 1984, 106, 3539.
[14] G. Solladie, N. Wilb, C. Bauder, J. Org. Chem. 1999, 64, 5447.
[15] I. Paterson, K.-S. Yeung, J. B. Smaill, Synlett 1993, 774.
[16] T. Honda, F. Ishikawa, J. Org. Chem. 1999, 64, 5542; T. Kubota, M. Tsuda, Kobayashi, J. Org. Lett.
2001, 3, 1363; H. Kigoshi, M. Kita, S. Ogawa, M. Itoh, D. Uemura, Org. Lett. 2003, 5, 957.
Received April 1, 2008