A simple enantioselective synthesis of serratenediol.

Article abstract of DOI:10.1021/ol016543a

[reaction: see text] A short synthesis of serratenediol is described, which involves a number of powerful key steps including (1) catalytic enantioselective syntheses of the phenyl sulfone and acylsilane shown above, (2) their coupling, and (3) further st

Full text of DOI:10.1021/ol016543a

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3215-3216
A Simple Enantioselective Synthesis of
Serratenediol
Junhu Zhang and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received August 7, 2001
ABSTRACT
A short synthesis of serratenediol is described, which involves a number of powerful key steps including (1) catalytic enantioselective syntheses
of the phenyl sulfone and acylsilane shown above, (2) their coupling, and (3) further stereoselective cationic cyclizations.
Serratenediol (1),1 a pentacyclic triterpenoid containing a
unique seven-membered central ring, is the parent member
of a skeletal class of more than 30 natural products.2
Although the biosynthesis of 1 probably involves the (S,S)-
2,3,22,23-bisepoxide of squalene, it is not clear whether the
final cyclization involves tricyclization of the bicyclic
epoxide 2 or monocyclization of onocerin (3).3 In this paper
we describe the first enantioselective synthesis of 1 by a
short, biomimetic pathway involving a tricyclization of the
N-phenylcarbamate 13 (Scheme 1).4
(4) for enantio- and position-selective terminal dihydroxyl-
ation of polyprenoids that has recently been described.5 Thus,
reaction of (E,E)-farnesyl acetate with 1 mol % of 4, 0.5
mol % of K2OsO4‚2H2O, 3 equiv of K3Fe(CN)6, 3 equiv of
K2CO3, and 1 equiv of CH3SO2NH2 in 1:1 t-BuOH/H2O at
0 °C for 4 h produced the triol monoacetate 55,6 of 97% ee
in 72% yield (84% based on recovered farnesyl acetate).
Transformation of 5 to the bromo acetonide 6 was effected
by acetonide formation, deacetylation, and allylic bromide
formation, as shown in Scheme 1. Displacement of bromide
in 6 by CuCH2COOEt7 afforded the bishomologated ester
7, which was sequentially transformed into the corresponding
alcohol, primary iodide, and phenyl sulfone 8, as outlined.
Reaction of the R-lithio derivative of 8 with the acylsilane
98 provided stereoselectively the Z-coupled silyl enol ether
(1) (a) Inubushi, Y.; Sano, T.; Tsuda, Y. Tetrahedron Lett. 1964, 1303.
(b) Rowe, J. W. Tetrahedron Lett. 1964, 2347. (c) Rowe, J. W.; Bower, C.
L. Tetrahedron Lett. 1965, 2745.
(2) Dev, S.; Gupta, A. S.; Potwardhan, S. A. CRC Handbook of
Terpenoids. Triterpenoids; CRC Press: Boca Raton, FL, 1987; Vol. II, pp
565-584.
(3) Barton, D. H. R.; Overton, K. H. J. Chem. Soc. 1955, 2639.
(4) For an earlier synthesis of racemic 1 (in less than 0.01% yield), see:
Prestwich, G. D.; Labovitz, J. N. J. Am. Chem. Soc. 1974, 96, 7103.
(5) Corey, E. J.; Zhang, J. Org. Lett. 2001, 3, 3211-3214.
(6) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36, 8741.
(7) Coates, R. M.; Ley, D. A.; Cavender, P. L. J. Org. Chem. 1978, 43,
4915.
The control of absolute stereochemistry in the synthesis
was achieved using a transition structure designed catalyst
(8) (a) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765. (b)
Corey, E. J.; Lin, S.; Luo, G. Tetrahedron Lett. 1997, 38, 5771.
10.1021/ol016543a CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001

silyl ethers formed during this conversion and then metha-
nolic base to convert any C(R) axial diastereomer to the more
stable equatorial form 11. The hydroxyl group of 11 was
protected as the phenylcarbamate, and the acetonide unit was
transformed in the usual way to the epoxide subunit of 13.
Finally, MeAlCl2-catalyzed tricyclization of 13 followed by
deprotection and silica gel chromatography gave levorotatory
serratenediol corresponding to the natural product by com-
Scheme 1a
1
parison of H and 13C NMR spectra, infrared spectrum,
optical rotation, and melting point.1,2,9
The success of the short and simple synthesis of the
complex serratenediol structure 1 by the pathway shown in
Scheme 1 depended on several crucial steps, including the
application of catalyst 4 to the construction of chiral glycol
5, the stereoselective coupling of 8 and 9 to form 10, and
the cationic cyclizations used to generate 11 and 14. The
power of these epoxide-initiated, stereoselective cationic
cyclizations, nonenzymic mimics of biosynthetic processes,
is clearly demonstrated here, as it has been in other recent
syntheses.10
a (a) (MeO)2 CMe2, cat. p-TsOH, 0.5 h, 23 °C. (b) K2CO3,
MeOH, 1 h, 23 °C. (c) CH3SO2Cl, Et3N, CH2Cl2, 1 h, -42 °C,
then 0.5 h, 0 °C; then LiBr, THF, 1 h, 0 °C (91% of 6 from 5). (d)
2 equiv of LDA, 2 equiv of EtOAc, 4 equiv of CuI, THF at -110
°C, then -110 to -30 °C and 1 h at -30 °C (92% of 7 from 6).
(e) LiAlH4, Et2O, 1 h at 23 °C, then 0.5 h at 40 °C. (f) Ph3P,
imidazole, I2, CH2Cl2, 0.5 h, 23 °C. (g) 2 equiv of PhSO2Na, DMF,
24 h, 23 °C (78% of 8 from 7). (h) 8 + BuLi in 1:1 THF/Et2O for
0.5 h at -78 °C, then 9 for 0.5 h at 0 °C (89% of 10). (i) 1.2 equiv
of MeAlCl2, CH2Cl2, 0.3 h at -94 °C. (j) Bu4NF, THF then 10%
KOH in CH3OH for 3 h at reflux (75% of 11 from 10). (k) PhNCO,
py, 12 h at 23 °C. (l) CH3PPh3Br, KOtBu, C6H6, 2 h at 80 °C
(68% of 12 from 11). (m) 3:1 HOAc/H2O, 5 h at 50 °C. (n)
CH3SO2Cl, py, 12 h at 23 °C. (o) K2CO3/MeOH, 5 h at 23 °C
(80% of 13 from 12). (p) 1.3 equiv of MeAlCl2, CH2Cl2, 1 h at
-78 °C. (q) 40% KOH, MeOH, 1.5 h at 100 °C, then silica gel
chromatography (21% of 1 from 13).
Acknowledgment. This research was supported by a
Canadian NSERC fellowship and by Pfizer Inc.
Supporting Information Available: Full experimental
procedures for the synthesis of 1 from geranyl and farnesyl
acetate. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL016543A
(9) Fang, J.-M.; Tsai, W.-Y.; Cheng, Y.-S. Phytochemistry 1991, 30,
1333.
(10) See, for example: (a) Huang, A. X.; Xiong, Z.; Corey, E. J. J. Am.
Chem. Soc. 1999, 121, 9999. (b) Corey, E. J.; Lin, S. J. Am. Chem. Soc.
1996, 118, 8765. (c) Corey, E. J.; Luo, G.; Lin, S. J. Am. Chem. Soc. 1997,
119, 9927. (d) Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873. (e)
Corey, E. J.; Lee, J.; Liu, D. R. Tetrahedron Lett. 1994, 35, 9149.
10, in a second key step in the synthesis of 1. Conversion of
10 to the bicyclic hydroxy ketone 11 was effected by
MeAlCl2-catalyzed, epoxide-initiated cationic cyclization
followed by treatment of the product with Bu4NF to cleave
3216
Org. Lett., Vol. 3, No. 20, 2001