Transannular Diels-Alder entry into stemodanes: First asymmetric total synthesis of (+)-maritimol [10]

Full text of DOI:10.1021/ja000728f

4526
J. Am. Chem. Soc. 2000, 122, 4526-4527
Scheme 2a
Transannular Diels-Alder Entry into Stemodanes:
First Asymmetric Total Synthesis of (+)-Maritimol
Andra´s Toro´, Pawel Nowak, and Pierre Deslongchamps*
Laboratoire de Synthe`se Organique
UniVersite´ de Sherbrooke
Quebec, Canada, J1H 5N4
ReceiVed February 29, 2000
(+)-Maritimol (1), a member of the stemodane diterpenoids
(1-3), was isolated1 from Stemodia maritima L. (Scrophulari-
aceae) and used as a Caribbean folk medicine for treatment of
venereal diseases. It represents a long-standing synthetic chal-
lenge2 with its unique tetracyclic stemodane framework and the
construction of its seven chiral centers, particularly the two central,
adjacent quaternary carbons at positions 9 and 10. Reported in
this contribution is the first asymmetric total synthesis of (+)-
maritimol, applying the TADA strategy, developed in our
laboratory (Scheme 1).3a
Scheme 1
a Reagents: (a) NaBH4, MeOH, >73%. (b) Imidazole, TBS-Cl, 95%.
(c) NaOH, THF, 5 °C, 96%. (d) Carbonyldiimidazole then Et3N and
NH(OMe)Me‚HCl, 89%. (e) DIBALH, CH2Cl2, -78 °C then MeOH,
89%. (f) SAMP, PTSA (cat.), PhH, 80 °C, 93%. (g) Imidazole, TBDPS-
Cl, 100%. (h) LDA, 0 °C then 8, THF, -100 °C, 83%. (i) Mg-
monoperoxyphthalate, MeOH/Et2O, 98%. (j) Py‚HF, THF then 9,
PdCl2‚(MeCN)2, DMF, 52%. (k) (Cl3C)2CO, PPh3, CH2Cl2, -78 to 0
°C, 94%. (l) Cs2CO3, CsI, MeCN, 80 °C, 75%. (m) TBAF, THF, 87%.
(n) Dess-Martin periodinane, 91%.
Retrosynthetic analysis suggests that tetracycle 4, a central
advanced intermediate of stemodanes,2a is available via TSC-
tricycle 5 corresponding4 to macrocycle 6 (Scheme 1). This chiral
macrocycle, in turn, can be made in a highly convergent manner,
starting from tetrasubstituted cis-dienophile 7. Following an
introduction of the requisite asymmetry via (S)-N-amino-2-
(methoxymethyl)pyrrolidine (SAMP)5 hydrazone-based alkylation
with Z-1,3-diiodo-propene (8),6 a Stille coupling7 with stannane
98 delivers the ω-functionalized acyclic â-ketoester substrate for
macrocyclization.
The actual synthesis began with aldehyde 10 (Scheme 2),
available in two steps (70%) from commercial Hagemann’s ester.9
NaBH4 reduction and silyl protection provided tetrasubstituted
cis-dienophile 12 (70%), which was selectively hydrolyzed to
monoacid 13 (93%) and further transformed into Weinreb amide
14 (89%).10 Parallel reduction (DIBAL-H) of both carbonyls
afforded, after a methanol quench, methoxytetrahydropyran 15,
which could be easily transformed to SAMP5 hydrazone 16 (83%).
From a synthetic point of view, the A.B.C[6.6.5] trans-syn-
cis (TSC) ring system of maritimol correlated well4a with our
previous fundamental TADA model studies, having demonstrated
the stereospecific transformation of 14- and 15-membered trans-
cis-cis (TCC) macrocyclic trienes to the respective A.B.C[6.6.6]4b
and [6.6.7]4c TSC-tricycles. It was also shown that even tetra-
substituted dienophiles were tolerated, particularly when they were
activated.4a,c Moreover, a discovery that a stereogenic center on
the macrocycle at the maritimol pro-12 position may induce
perfect diastereoface selection in the TADA reaction was also
made.4a
(1) Hufford, C. D.; Guerrero, R. D.; Doorenbos, N. J. J. Pharm. Sci. 1976,
95, 778-780.
(2) For a recent review on the synthesis of stemodane diterpenoids, see:
(a) Toyota, M.; Ihara, M. Tetrahedron 1999, 55, 5641-5679. See also: (b)
Pearson, A. J.; Fang, X. J. Org. Chem. 1997, 62, 5284-5292 and references
therein. (c) Piers, E.; Abeysekera, B. F.; Herbert, D. J.; Suckling, I. D. Can.
J. Chem. 1985, 63, 3418-3432.
(3) (a) Deslongchamps, P. Pure Appl. Chem. 1992, 64, 1831-1847. For
other TADA approaches to natural products, see: (b) Takahashi, T.; Shimizu,
K.; Doi, T.; Tsuji, J. J. Am. Chem. Soc. 1988, 110, 2674-2676. (c) Wood, J.
L.; Porco, J. A.; Taunton, J.; Lee, A. Y.; Clardy, J.; Schreiber, S. L. J. Am.
Chem. Soc. 1992, 114, 5898-5900. (d) Shing, T. K. M.; Yang, J. J. Org.
Chem. 1995, 60, 5785-5789. (e) Roush, W. R.; Koyama, K.; Curtin, M. L.;
Moriarty, K. J. J. Am. Chem. Soc. 1996, 118, 7502-7512. (f) Vanderwal, C.
D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Org. Lett. 1999, 1, 645-648.
(4) (a) Toro´, A.; Lemelin, C.-A.; Pre´ville, P.; Be´langer, G.; Deslongchamps,
P. Tetrahedron 1999, 55, 4655-4684. (b) Lamothe, S.; Ndibwami, A.;
Deslongchamps, P. Tetrahedron Lett. 1988, 29, 1641-1644. (c) Hall, D. G.;
Caille´, A-S.; Drouin, M.; Lamothe, S.; Mu¨ller, R.; Deslongchamps, P.
Synthesis 1995, 1081-1088.
(5) Enders, D.; Kipphardt, H.; Fey, P. Org. Synth. 1987, 65, 183-202.
(6) (a) Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron 1994,
50, 371-382. (b) Piers, E.; Renaud, J.; Rettig, S. J. Synthesis 1998, 590-
602.
(7) (a) Stille, J. K.; Tanaka, M. J. Am. Chem. Soc. 1987, 109, 3785-3786.
For a comprehensive review see: (b) Farina, V.; Krishnamurthy, V.; Scott,
W. J. In Organic Reactions; Paquette, L. A., Ed.; John Wiley and Sons: New
York, 1997; Vol.50, pp 1-652.
(8) Prepared in two steps in 67% overall yield according to: (a) Cliff, M.
D.; Pyne, S. G. Tetrahedron Lett. 1995, 36, 763-766. (b) Crabtree, S. R.;
Mander, L. N.; Sethi, S. P. Org. Synth. 1991, 70, 256-264.
10.1021/ja000728f CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/21/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4527
Scheme 3
Scheme 4a
Silylation followed by alkylation5 of 17 with iodide 86 gave chiral
vinyl iodide 18 (83%, >90% de). Oxidation11 of 18 afforded the
corresponding nitrile 19. Selective deprotection and Stille cou-
pling7 with stannane 98 delivered acyclic triene 20 in 68% yield.
Chlorination12 produced ω-chloro-â-ketoester 21 (94%) which,
upon macrocyclization4 with Cs2CO3 under high dilution, gave
13-membered TCC macrocycle 22 (75%).13 Desilylation to
alcohol 23 (87%) and oxidation14 provided macrocyclic aldehyde
6 (91%).
a Reagents and conditions: (a) TMS-CH(CN)B(OiPr)2, THF, -78 °C,
79% (84% corr.). (b) H2/Pd/C, EtOAc, AcOH, 1 bar, 87%. (c) Mg, MeOH,
0 °C, 64%. (d) KOtBu, tBuOH, 85 °C then AcOH/H3PO4, 115 °C, 68%.
(e) H2/Pt/C, EtOAc, 40 bar then Dess-Martin periodinane, CH2Cl2, 84%.
Treatment of a dichloromethane solution of 6 (Scheme 3) with
MeAlCl2 for 7 h at 23 °C, provided exclusively TSC tri-
cycle 24 (75%)15 in its completely enolized form. Thermal deme-
thoxycarbonylation16 of 24 for 3 h gave tricycle 5. Moreover,
heating 6 under the same conditions for 4 h gave directly tricycle
5 (87%) offering an efficient procedure for large-scale prepara-
tions.17 It is remarkable that both Lewis acid catalyzed and thermic
TADA reactions exhibit similar complete stereoface- and dias-
tereospecificity induced by a small remote nitrile group. This
observation is in total accord with our previous model studies.4a
Construction of ring D of the stemodane skeleton was started
with a Peterson olefination18 affording a 6:1 isomeric mixture of
cis- and trans-enenitrile 25a and 25b, respectively, (79%) (Scheme
4). Due to an easy separation of these isomers with flash column
chromatography, the subsequent reductions could be optimized
individually. Accordingly, while 25a could be reduced by catalytic
hydrogenation without difficulty, the higher pressure, necessary
to reduce the trans-olefin, was not compatible with 25b. However,
this reduction could be achieved via a magnesium-methanol
system19 in a moderate 64% yield to converge the sequence in
dinitrile 26. Conclusion of the synthesis was developed from Piers’
racemic synthesis.2c A Thorpe-Ziegler annulation of 26 and an
acidic hydrolysis of the intermediate enaminonitrile provided
tetracycle 27 (68%). Catalytic hydrogenation and a subsequent
oxidative adjustment14 delivered dione 4 (85%).20 Since (()-4
has long been established as a central advanced intermediate in
the syntheses of stemodane diterpenoids (()-1, (()-2, and (()-
3,2a our synthesis constitutes a formal asymmetric total synthesis
of these stemodanes. Accordingly,2c our representative target 1
could be acquired in two further steps from 4.21
In summary, a highly convergent 22-step asymmetric synthesis
of (+)-maritimol has been achieved from easily available aldehyde
10. At the heart of the synthesis is a TADA reaction of an appro-
priately functionalized, 13-membered TCC macrocycle with a te-
trasubstituted, activated dienophile prepared in only 15 steps. This
strategic step displays a complete stereoface- and diastereospeci-
ficity to generate four new stereogenic centers induced by a remote
nitrile appendage. A detailed account will follow in due course.
(9) (a) Baker, M. V.; Ghitgas, C.; Haynes, R. K.; Hilliker, A. E.; Lynch,
G. J.; Sherwood, G. V.; Yeo, H.-L. Aust. J. Chem. 1984, 37, 2037-2058. (b)
Montforts, F.-P.; Schwartz, U. M. Liebigs Ann. Chem. 1991, 709-725.
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(11) Enders, D.; Plant, A.; Backhaus, D. Reinhold, U. Tetrahedron 1995,
51, 10699-10714.
(12) Magid, R. M.; Fruchey, O. S.; Johnson, W. L.; Allen, T. G. J. Org.
Chem. 1979, 44, 359-363.
(13) Easily separable O-alkylated macrocycle (3%) was also formed as a
single isomer.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(15) When demethoxycarbonylated 6 was subjected to TADA reaction,
Lewis acid treatment or heating caused intensive decomposition. A detailed
investigation of the TADA reaction including the origin of its stereoface- and
diastereospecificity will be the subject of another article.
(16) Krapcho, A. P. Synthesis 1982, 805-822.
Acknowledgment. We are grateful to Professor Charles D. Hufford
of University of Mississippi for an authentic sample of (+)-maritimol. A
Basic Research Chair in organic chemistry granted to Pierre Deslong-
champs by BioChem Pharma and a financial support from NSERC-
Canada are highly appreciated.
Supporting Information Available: Experimental procedures and
listing of spectral data (IR, MS, 1H and 13C NMR) for all synthetic
compounds, and 1H and 13C NMR spectra of natural and synthetic 1
(PDF). This material is available free of charge via the Internet at
http//pubs.acs.org.
(17) It was also demonstrated, with parallel oxidations of separated epimers
of 23, and subsequent Lewis acid catalyzed or thermic TADA reactions that
the epimers of 6 would converge into tricycles 24 or 5, respectively, with
comparable yields. In large-scale preparations, an epimeric mixture of 6 was
used.
(18) (a) Furuta, K.; Ishiguro, M.; Haruta, R.; Ikeda, N.; Yamamoto, H.
Bull. Chem. Soc. Jpn. 1984, 57, 2768-2776. For a comprehensive review,
see: (b) Ager, D. J. In Organic Reactions; Paquette, L. A., Ed.; John Wiley
and Sons: New York, 1990; Vol.38, pp 1-223.
JA000728F
(19) Jenn, T.; Heissler, D. Tetrahedron 1998, 54, 97-106.
(20) An unusually large catalyst load and high pressure is required to
hydrogenate the extra double bond in ring B. Although these extreme
conditions had prevented an earlier parallel hydrogenation of diene 25, here
an inevitable overreduction was not terminal.
(21) Synthetic (+)-maritimol is identical in all respects (1H and 13C NMR,
IR, TLC) with a natural sample.