First enantioselective synthesis of manoalide: Application of aldehyde- dioxinone enantioselective condensation

Article abstract of DOI:10.1016/S0957-4166(99)00529-7

Manoalide, an analgesic and anti-inflammatory sesterterpene, has been stereoselectively synthesized for the first time. The C-4 stereogenic centre has been introduced in an early step by enantioselective aldol condensation using a Ti(OiPr)₄/(R)

Full text of DOI:10.1016/S0957-4166(99)00529-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4481–4484
First enantioselective synthesis of manoalide: application of
aldehyde–dioxinone enantioselective condensation
Annunziata Soriente, Margherita De Rosa, Aniello Apicella, Arrigo Scettri ∗ and
Guido Sodano ∗
Dipartimento di Chimica, Università di Salerno, 84081 Baronissi (SA), Italy
Received 4 November 1999; accepted 22 November 1999
Abstract
Manoalide, an analgesic and anti-inflammatory sesterterpene, has been stereoselectively synthesized for the first
time. The C-4 stereogenic centre has been introduced in an early step by enantioselective aldol condensation using
a Ti(OiPr)4/(R)-(+)-binol complex. © 1999 Elsevier Science Ltd. All rights reserved.
Manoalide 1, a sesterterpene isolated from a marine sponge,1 is a potent analgesic and anti-
inflammatory agent,2 whose mechanism of action involves inhibition of phospholipase A2 (PLA2).
Because of its peculiar pharmacological activities, manoalide has become an interesting synthetic target,
leading to seven syntheses reported to date.3 Since the reported syntheses of manoalide afford only
racemic material, we have devised a synthetic approach leading to the first asymmetric synthesis of
manoalide.
Manoalide has three stereogenic centres (C-4, C-24 and C-25), only one of them being fixed (C-4).
In fact, the other two centres (C-24 and C-25) are hemiacetal carbons and thus, subject to epimerization
in solution. Therefore the problem of the stereocontrol in the synthesis of manoalide is reduced to the
control of the stereochemistry at C-4. Our strategy (Scheme 1) was essentially based on the synthesis of
the two fragments 2 and 3, the former being destined to become the polyisoprenic side chain of 1 and the
latter representing the chiral precursor of the pyranofuranone system of manoalide. The two fragments
could be assembled through alkylation of the 1,3-dicarbonyl moiety of 3.
Alkyl bromide 2a was prepared from β-ionone by Hoffmann’s procedure.3f However, an improvement
in the yields of the first step of the reported synthesis was achieved by selective reduction of β-ionone
via hydrosilylation as indicated by Ojima and Kogure.4 Compound 2a was obtained as a 9:1 E:Z mixture
in 45% total yield and was quantitatively converted into the corresponding iodide 2b by treatment with
NaI in refluxing acetone.
∗
Corresponding authors. E-mail: sodano@dia.unisa.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00529-7
tetasy 3164

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Scheme 1.
The second subunit 3 bearing the stereogenic centre with the desired R configuration was prepared
according to the two step sequence depicted in Scheme 2. The stereogenic centre at C-4 was introduced by
exploitation of an aldehyde–dioxinone enantioselective condensation recently utilized for the preparation
of chiral non-racemic 6-(furan-3-yl)-5,6-dihydro-pyran-2-ones.5 This approach consists of a titanium
catalyzed aldol reaction, based upon a modification of the methodology of Sato.6 Carreira’s methodology,
involving enantioselective aldol condensation of silyloxydienes of type 5 in the presence of chiral
Ti(IV)7 or Cu(II)8 catalysts, seemed particularly attractive both for its efficiency and high degree of
enantioselectivity leading to silylated aldols of type 6b. However, we have found that the reported acidic
work-up8 of 6b for the regeneration of the alcoholic function resulted in partial racemization. For this
reason, we used Sato’s procedure,6 based on the condensation of the silyloxydiene 5 with 3-formyl furan
4 in the presence of Ti(OiPr)4/(R)-(+)-binol complex for the synthesis of the aldol 6a.5 We have now
found that using 0.5 equiv. (instead of 0.17 equiv. used in the original procedure) of Ti(OiPr)4/(R)-(+)-
binol complex leads to an improvement both of yields and of e.e., leading to 6a in 65% yield and with an
87% e.e. (1H NMR analysis on the corresponding (S)-MTPA ester). The subsequent conversion of 6a into
the key intermediate 3 was performed in a very efficient way (>90%) by microwave (MW) irradiation of
a MeOH/PhMe solution of 6a.
Scheme 2.
Alkylation of 3 with the iodide 2b proved difficult under various conditions. In fact, very carefully
controlled experimental conditions had to be used in order to limit the occurrence of undesired com-
petitive side processes. Monoalkylation of 3 (Scheme 3) was eventually obtained in satisfactory yield
by using the tetrabutylammonium salt of 2-pyrrolidone anion 7 as a phase transfer catalyst, prepared by
chemical methods as previously described by Shono et al.9 The crude alkylation product 8 was reduced
with Et2BOMe/NaBH4 according to Prasad methodology10 to afford the diol 9 in 31% overall yield
from 3. The remaining part of the synthesis followed our previous methodology set up for the synthesis
of manoalide and cacospongionolide analogues.11,12 Thus, 9 was submitted to a three step sequence

A. Soriente et al. / Tetrahedron: Asymmetry 10 (1999) 4481–4484
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including hydrolysis to the acid 10, acetylation and simultaneous cyclization to 11 and finally, elimination
with DBU to afford the lactone 12 in 30% overall yield from 9. Reduction of 12 with DIBAL afforded
the unstable lactol 13 which was quickly photooxygenated to afford manoalide 1 in 35% yield from 12.
Synthetic 1 has [α]D +65 (c=0.2; MeOH) while for the natural product an [α]D +80 (c=0.2; MeOH) was
reported,13 suggesting an 81% e.e. for the synthetic manoalide which compares well with the 87% e.e.
of the starting chiral material 6a.
Scheme 3.
Acknowledgements
We thank Professor D. J. Faulkner, La Jolla, for a natural extract containing manoalide. The mass
spectra were obtained from the Servizio di Spettrometria di Massa del CNR e dell’Università di Napoli;
the staff is gratefully acknowledged. This work was financially supported by CNR (Rome) and by
MURST (PRIN ‘Chimica dei Composti Organici di Interesse Biologico’).
References
1. De Silva, E. D.; Scheuer, P. J. Tetrahedron Lett. 1980, 21, 1611.
2. For reviews, see: (a) Mayer, A. M. S.; Jacobs, R. S. In Biomedical Importance of Marine Organisms; Fautin, D. G., Ed.;
California Academy of Sciences: San Francisco, 1988; pp. 133–142; (b) Potts, B. C. M.; Faulkner, D. J.; Jacobs, R. S. J. Nat.
Prod. 1992, 55, 1701; (c) Mann, J. Nature 1992, 358, 540; (d) Soriente, A.; De Rosa, M.; Scettri, A.; Sodano, G.; Terencio,
M. C.; Paya, M.; Alcaraz, M. J. Curr. Med. Chem. 1999, 6, 415–431.
3. (a) Katsumura, S.; Fujiwara, S.; Isoe, S. Tetrahedron Lett. 1985, 26, 5827; (b) Garst, M. E.; Tallman, E. A.; Bonfiglio,
J. N.; Harcourt, D.; Ljungwe, E. B.; Tran, A. Tetrahedron Lett. 1986, 27, 4533; (c) Katsumura, J.; Fujiwara, S.; Isoe, S.
Tetrahedron Lett. 1988, 29, 1173; (d) Bury, P.; Hareau, G.; Kocienski, P.; Dhanak, D. Tetrahedron 1994, 50, 8793; (e)

4484
A. Soriente et al. / Tetrahedron: Asymmetry 10 (1999) 4481–4484
Pommier, A.; Kocienski, P. J. J. Chem. Soc., Chem. Commun. 1997, 1139; (f) Coombs, J.; Lattmann, E.; Hoffmann, H. M.
R. Synthesis 1998, 1367.
4. Ojima, I.; Kogure, T. Organometallics 1982, 1, 1390.
5. Soriente, A.; De Rosa, M.; Dovinola, P.; Sodano, G.; Scettri A. Tetrahedron: Asymmetry 1998, 9, 2197.
6. Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995, 41, 1435.
7. Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360.
8. Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837.
9. Shono, T.; Kashimura, S.; Sawamura, M.; Soejima, T. J. Org. Chem. 1988, 53, 907.
10. Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.
11. Soriente, A.; De Rosa, M.; Scettri, A.; Sodano, G. Tetrahedron Lett. 1996, 37, 8007.
12. De Rosa, M.; Giordano, S.; Scettri, A.; Sodano, G.; Soriente, A.; Garcia Pastor, P.; Alcaraz, M. J.; Paya, M. J. Med. Chem.
1998, 41, 3232.
13. Kobayashi, M.; Okamoto, T.; Hayashi, K.; Yokoyama, N.; Sasaki, T.; Kitagawa, I. Chem. Pharm. Bull. 1994, 42, 265.