C O M M U N I C A T I O N S
Scheme 4 a
Scheme 5 a
a (a) NaBH4, CeCl3, MeOH, 98%; (b) NaH, PMBI, DMF, 88%; (c)
ClCO2Me, py, CH2Cl2, 95%; (d) 6 M NaOH, DMSO, 130 °C, 93%; (e) I2,
KI, NaHCO3‚H2O/CH2Cl2: 94%; (f) Bu3SnH, AIBN, tol, reflux, 91%; (g)
1. LDA/PhSeCl, 2. H2O2 66%; (h) DDQ, 1.3 equiv, CH2Cl2/H2O, 80%; (i)
1. DIBAL, tol, -40 °C 2. AcOH, 73%; (j) Ac2O, py, DMAP, CH2Cl2, 92%.
a (a) D-Valinol, Et2O, rt; (b) NaH, MeI, THF, rt, 73% (a, b one pot); (c)
8, THF, -78 °C; (d) HMPA, MeI, 5 bar CO, -78 °C to rt; (e) NaOEt,
MeI, -78 °C to rt, 53% (c-e one pot); (f) HCl 2N, THF, 80 °C, 89%; (g)
NaBH4, CeCl3, MeOH, 98%; (h) NaH, PMBI, DMF, 88%; (i) I2, THF,
H2O, 73%.
to the ortho′ position is based on steric congestion state between a
Ph group of the chiral ligand and the Cr(CO)3 group in transition
state II.
Reduction of (4aR,8aS)-5 under Luche conditions afforded diol
11 as a single diastereoisomer with the hydride adding to the ketone
from the less hindered, convex face of the molecule.9 Selective
protection of the primary alcohol as p-methoxybenzyl ether and
conversion of the secondary alcohol into the carbonate 12 set the
stage for the Pd-catalyzed allylic alkylation. The reaction with
NaCMe(CO2Me)2 in the presence of Pd(dppe)2 afforded regiose-
lectively the product resulting from addition to C(7), and overall
retention was the major pathway. The ratio of the diastereoisomers
13 at C(7) was 50:1. The transformation of 13 into acetoxytubi-
pofuran 2 is depicted in Scheme 4, and details are given in the
Supporting Information.
on the synthesis followed that shown in Scheme 4. (S,S)-Tubipo-
furan ((S,S)-2) showed a [R]2D0 of +100.3 (c ) 0.29, CHCl3).
In summary, this Communication reports new asymmetric
methodology of Cr(CO)3-mediated dearomatization and its applica-
tion to the synthesis of (+)- and (-)-acetoxytubipofuran. Chiroptical
data show that a revision of the assigned structure of the natural
product is required.
Acknowledgment. We thank the Swiss National Science
Foundation and Novartis for financial support of this work.
Supporting Information Available: Experimental procedures and
physical data of all compounds. This material is available free of charge
As mentioned above, the conversion of santonin into (+)-
tubipofuran required a reassignment of the absolute configuration
in the natural product.3 Moreover, the observed [R]2D0 value was
much larger (33) than that reported earlier (5.6), suggesting that
the natural product isolated may not have been pure. A parallel
situation exists for acetoxytubipofuran 2. The natural product was
assigned the R,R-configuration and its [R]2D0 value reported as
+10.7 (c ) 0.5, CHCl3). Our measured value for (R,R) is -120 (c
) 0.653, CHCl3) and the CD spectrum showed a negative Cotton
effect λmax 274 (∆ꢀ -3), opposite to that reported (λmax 270 (∆ꢀ
+3)).2a
In parallel to the synthesis of (-)-2, we have developed a
modified route to the natural product (+)-2. Condensation of the
benzaldehyde complex 3 with D-valinol10 followed by in situ
methylation gave the chiral arylimine complex 7b (Scheme 5).
Diastereoselective nucleophilic addition/acylation/alkylation yielded
(-)-(4aS,8aR)-9. Both the yield and the enantiomeric purity of the
product were superior to the procedure used for the keto aldehyde
(+)-(4aR,8aS)-9. Conversion of (+)-9 by the same route as detailed
before (Schemes 2 and 4) afforded (-)-15. The four-step sequence
of formation of carbonate, Pd-catalyzed allylic substitution, hy-
drolysis/decarboxylation, and lactonization that was used in the
synthesis of (R,R)-2 was replaced now by the very efficient
Eschenmoser-Claisen rearrangement-lactonization sequence11,12
which afforded 14 as a 3:2 mixture of diastereoisomers. From here
References
(1) Pape, A.; Kaliappan, K.; Ku¨ndig, E. P. Chem. ReV. 2000, 100, 2917-
2940.
(2) (a) Iguchi, K.; Mori, K.; Suzuki, M.; Takahashi, H.; Yamada, Y. Chem.
Lett. 1986, 1789. (b) Brieskorn, K. H.; Noble, P. Phytochemistry 1983,
22, 187.
(3) Blay, G.; Cardona, L.; Garcia, B.; Pedro, J.; Sanchez, J. J. J. Org. Chem.
1996, 61, 3815.
(4) Ojida, A.; Tanoue, F.; Kanematsu, K. J. Org. Chem. 1994, 59, 5970-
5976.
(5) Wollenberg, R. H.; Albizati, K. F.; Peries, R. J. Am. Chem. Soc. 1977,
99, 7365-7367.
(6) Ku¨ndig, E. P.; Ripa, A.; Liu, R. G.; Amurrio, D.; Bernardinelli, G.
Organometallics 1993, 12, 3724-3737.
(7) Ku¨ndig, E. P.; Ripa, A.; Liu, R. G.; Bernardinelli, G. J. Org. Chem. 1994,
59, 4773-4783.
(8) Amurrio, D.; Khan, K.; Ku¨ndig, E. P. J. Org. Chem. 1996, 61, 2258-
2259.
(9) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454-5459.
(10) (a) Meyers, A. I.; McKennon, M. J.; Drauz, K.; Schwarm, M. J. Org.
Chem. 1993, 58, 3568-3571. (b) Meyers, A. I. Tetrahedron 1992, 48,
2589-2612. (c) Devine, P. N.; Reilly, M.; Oh, T. Tetrahedron Lett. 1993,
34, 5827-5830. (d) Betz, J.; Heuschmann, M. Tetrahedron Lett. 1995,
36, 4043. (e) Meyers, A. I.; Matulenko, M. A. J. Org. Chem. 1996, 61,
573-580. (f) Negoro, N.; Yanada, R.; Okaniwa, M.; Yanada, K.; Fujita
T. Synlett 1998, 835-836. (g) Yanada, R.; Negoro, N.; Okaniwa, M.;
Miwa, Y.; Taga, T.; Yanada, K.; Fujita, T. Synlett 1999, 537-540.
(11) (a) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HelV. Chim. Acta
1964, 47, 2425-2430. (b) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1993,
58, 3840-3849.(c) Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.;
Chida, N. Tetrahedron 1999, 55, 3855-3870.
(12) Feugeas, P. C.; Olschwang, D. Bull. Soc. Chim. Fr. 1968, 4985-4990.
JA029957N
9
J. AM. CHEM. SOC. VOL. 125, NO. 19, 2003 5643