Facile synthesis of the cyclopentane moiety of (all-E,2R,5R,6S)-2,6-cyclolycopene-1,5-diol

Article abstract of DOI:10.1016/S0040-4039(00)01268-5

The carotenoid (2R,5R,6S)-2,6-cyclolycopene-1,5-diol (1) bears a tetrasubstituted cyclopentane ring with three neighbouring stereogenic centers. The cyclic aldehyde 2 with the correct substitution pattern was synthesized in four steps from (R)-α-terpineol (3). From 2 the carotenoid 1 was prepared and investigated by CD spectroscopy. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01268-5

Tetrahedron Letters 41 (2000) 7197±7198
Facile synthesis of the cyclopentane moiety of
(all-E,2R,5R,6S)-2,6-cyclolycopene-1,5-diol
Bruno Traber and Hanspeter Pfander*
Department of Chemistry and Biochemistry, University of Berne, Freiestr. 3, CH-3012 Berne, Switzerland
Received 16 June 2000; revised 14 July 2000; accepted 17 July 2000
Abstract
The carotenoid (2R,5R,6S)-2,6-cyclolycopene-1,5-diol (1) bears a tetrasubstituted cyclopentane ring with
three neighbouring stereogenic centers. The cyclic aldehyde 2 with the correct substitution pattern was
synthesized in four steps from (R)-a-terpineol (3). From 2 the carotenoid 1 was prepared and investigated
by CD spectroscopy. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: terpene; carotenoid; aldol addition.
Numerous terpenes and derivatives thereof serve as cheap and readily available starting
materials in chemical synthesis. In contrast to its six-membered analogues, cyclopentane building
blocks are scarce. We report here on the synthesis of a tetrasubstituted cyclopentane derivative
which was used in the course of our studies on the total synthesis of optically active (all-
E,2R,5R,6S)-2,6-cyclolycopene-1,5-diol (1),1 which possesses anticancer activities against prostate
cancer.2 The preparation of racemic 1 has been reported earlier3 (Fig. 1).
Figure 1.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01268-5

7198
(R)-a-Terpineol (3) was acetylated with acetic anhydride, 4-dimethylaminopyridine and
triethylamine to (R)-a-terpinyl acetate (4) and dihydroxylated with potassium permanganate to
give 5. Oxidative cleavage with lead tetraacetate to 6 and cyclization by an intramolecular aldol
addition, catalyzed by acetic acid and piperidine gave the cyclic aldehyde 2 (Scheme 1). NMR
studies show the carbaldehyde function to be trans to the substituent at C(3) and cis to the
hydroxy group at C(1).
Scheme 1. Synthesis of (1R,2S,3R)-2 and (all-E,2R,5R,6S)-1. Reagents and conditions. (a) Ac2O, DMAP, NEt3, pyri-
dine, rt; (b) KMnO4, THF/H2O, 0ꢀC; (c) Pb(OAc)4, Na2CO3, CH2Cl2, 0ꢀC; (d) piperidine, AcOH, H2O, THF, rt
(all-E,2R,5R,6S)-2,6-Cyclolycopene-1,5-diol (1) was prepared from 2 as reported in Ref. 3 for
the racemic compound. The CD spectrum (EPA, ^180ꢀC) shows relative maxima at 228, 297.5,
455, 498 and 515.5 nm and relative minima at 214.5, 244, 283.5, 443.5, 469 and 504 nm in a
spectrum close to conservative in type.
Acknowledgements
We thank F. Ho€mann±La Roche Ltd. for scienti®c samples, technical assistance and ®nancial
support, and the Swiss National Science Foundation for ®nancial support. B.T. is grateful to
S. Gruaz for technical assistance.
References
1. For a review on carotenoid synthesis, see: Carotenoids, Vol. 2; Britton, G.; Liaaen-Jensen, S.; Pfander, H., Eds.
Synthesis. Birkhauser, Basel, 1996.
2. King, T. J.; Khachik, F.; Bortkiewicz, H.; Fukushima, L. H.; Morioka, S.; Bertram, J. S. Pure Appl. Chem. 1997,
69, 2135. Khachik, F.; Beecher, G. R.; Can®eld, L.; Steck, A.; Pfander, H. 11th International Symposium on
Carotenoids; Leiden, 1996, O.P. 1.3. M. Pastori, Thesis, University of Bern, Switzerland.
3. Traber, B.; Pfander, H. Tetrahedron 1998, 54, 9011.