of the dienyne side chain and the enantioselective synthesis
of the trans-chlorocyclopropane ring.
In our synthetic strategy of callipeltoside A, we envision
the construction of the sp-sp2 bond of the dienyne side chain
(C17-C18) late in the synthesis (Scheme 2). Installation of
lipases. It has been suggested that increasing the size of the
large substituent on the stereocenter of the primary alcohol
can help to increase the enantiomeric discrimination.10 To
take advantage of this consideration, we turned our attention
to dichloro alcohol 3, in which the chiral center has a larger
substituent than the initially studied monochloro alcohol 4
(Scheme 4). After some optimization of the enzymatic
Scheme 2
Scheme 4
either (+)- or (-)-enantiomers of trans-chlorocyclopropane
acetylene to the terminal diene will allow us to prepare both
possible diasteromeric structures of callipeltoside A to solve
the relative configuration problem. Initially, we decided to
investigate the construction of the dienyne side chain to pave
the way to secure a total synthesis.
Diisobutylaluminum hydride (DIBAL-H) reduction of tert-
butyldichlorocyclopropane carboxylate (2)5 in dichloromethane
furnished dichlorocyclopropanemethanol (3) when the reac-
tion was carried out at 0 °C for 4 h (Scheme 3). The major
transesterification conditions using immobilized enzyme
Novozym-435 and vinyl propionate, we were delighted to
obtain unreacted dichloro alcohol (+)-3 with >97% ee11,12
and propionate ester 5 with 74% ee (E ) 27.2). Separation
of ester 5 and alcohol 3 in gram scale was possible using
extractive techniques. Lipase hydrolysis of enantioenriched
ester 5 using the same immobilized enzyme in an acetone-
aqueous buffer mixture gave dichloro alcohol (-)-3 with >
97% ee. The absolute stereochemistry of the resolution
product was determined applying Kazlauskas’ empirical
rule,13 which predicts the enantiomer that reacts faster in
reactions catalyzed by lipases on the basis of the sizes of
the substituents at the stereocenter. Lithium aluminum
hydride reduction of both enantioenriched dichloro alcohols
(+)- and (-)-3 gave the monochloro alcohols (-)- and (+)-
4, respectively.14
Scheme 3
Having the two enantioenriched alcohols of 4 in hand, we
proceeded to homologate the molecule to the corresponding
acetylene, Scheme 5.15 Alcohol 4 was readily oxidized using
product of the reduction of ester 2 was the trans-chlorocy-
clopropanemethanol (4) when the reaction was carried out
with lithium aluminum hydride in diethyl ether at 40 °C for
several days.6
Scheme 5
Biocatalysis has proved to be a powerful tool in asym-
metric synthesis.7 Our laboratory has reported the application
of biocatalysis in the synthesis of alkaloids and medicinally
important compounds.8 We decided to use a lipase kinetic
resolution for the preparation of enantiomerically enriched
trans-chlorocyclopropane methanol (4). However, lipase
kinetic resolution of monochloro alcohol 4 was disappointing
(E < 10)9 after screening 20 different commercially available
(5) Fedorynski, M.; Ziolkowska, W.; Jonczyk, A. J. Org. Chem. 1993,
58, 6120-6121.
PCC-Celite to aldehyde 6.16 Aldehyde 6 was immediately
(6) Nadim, A. M.; Romashin, Y. N.; Kulinkovich, O. G. J. Org. Chem.
(USSR) 1992, 1419-1422.
(7) Faber, K. Biotransformations in Organic Chemistry; Springer-
Verlag: Berlin, 1995.
(8) (a) Hemenway, M. S.; Olivo, H. F. J. Org. Chem. 1999, 64, 8968-
8969. (b) Olivo, H. F.; Yu, J. J. Chem. Soc., Perkin Trans. 1 1998, 391-
392.
(9) The E value is the enantiomeric ratio as defined in the following:
Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
1982, 104, 7294-7299.
(10) Bornscheuer, U. T.; Kazlauskas, R. J. In Hydrolases in Organic
Synthesis; Wiley-VCH: Weinheim, 1999.
(11) Enantiomeric ratios were determined by gas chromatography, using
a Chiraldex G-TA capillary column.
(12) Dichlorocyclopropylmethanol (S)-3: [R]27 +4.0 (c 1.0, CHCl3).
D
(13) Weissfloch, A. N. E.; Kazlauskas, R. J. J. Org. Chem. 1995, 60,
6959-6969.
(14) Reduction of dichloro alcohol (+)-(S)-3 gave monochloro alcohol
(-)-4: [R]27D -68 (c 1.0, CHCl3). Reduction of dichloro alcohol (-)-(R)-3
gave monochloro alcohol (+)-4: [R]27 +68 (c 1.0, CHCl3).
D
(15) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-72.
(16) Baldwin, J. E.; Villarica, K. A. J. Org. Chem. 1995, 60, 186-190.
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Org. Lett., Vol. 2, No. 25, 2000