An enantiodivergent route to α-cuparenone utilizing chiral cyclopentenol having a latent meso structure

Article abstract of DOI:10.1016/S0040-4039(00)00235-5

An efficient enantiodivergent route to α-cuparenone, a sesquiterpene isolated in both enantiomeric forms, has been developed utilizing a chiral cyclopentanoid starting material having a latent meso structure. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00235-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2639–2642
An enantiodivergent route to α-cuparenone utilizing chiral
cyclopentenol having a latent meso structure
Hiromi Nakashima, Masayuki Sato, Takahiko Taniguchi and Kunio Ogasawara ∗
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 11 January 2000; revised 31 January 2000; accepted 4 February 2000
Abstract
An efficient enantiodivergent route to α-cuparenone, a sesquiterpene isolated in both enantiomeric forms, has
been developed utilizing a chiral cyclopentanoid starting material having a latent meso structure. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: cyclopentanones; enantiocontrol; diastereoselection; hydroxylation; terpenes and terpenoids.
Recently, we obtained1 enantiopure (cis-1,4)-4-cumyloxy-2-cyclopenten-1-ol 1 in both enantiomeric
forms in excellent yields via resolution of the racemic alcohol (±)-1 under lipase-mediated kinetic
transesterification conditions (Scheme 1). Since the alcohol 1 has a latent meso structure, both of the
enantiomers may be utilized as a common chiral precursor capable of carrying out either enantiodi-
vergent or enantioconvergent synthesis if its hydroxy and cumyloxy functionalities can be chemically
discriminated. We wish to report here an enantiodivergent route to α-cuparenone2,3 18, a sesquiterpene
occurring in both enantiomeric forms in nature,4 where the single enantiomer (−)-1 plays a double role.
Scheme 1.
The enantiopure alcohol (−)-1 was first transformed into the tert-butyldimethylsilyl (TBS) ether (−)-
31
3, [α]D −47.01 (c 1.00, CHCl3). Catalytic dihydroxylation5 of (−)-3 occurred diastereoselectively
∗
Corresponding author. Fax: +81-22-217-6845; e-mail: konol@mail.cc.tohoku.ac.jp (K. Ogasawara)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00235-5
tetl 16515

2640
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from the opposite side of the 1,4-substituents to give the single diol (−)-4, mp 48–49°C, [α]D −10.25
30
(c 0.75, CHCl3), which was converted into the acetonide (+)-5, [α]D +20.76 (c 0.95, CHCl3), under
standard conditions.
Desilylation of (+)-5 with tetrabutylammonium fluoride (TBAF) gave the cyclopentanol (+)-6, mp
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110–111°C, [α]D +19.75 (c 0.75, CHCl3). Although (+)-6 suffered considerable decomposition under
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standard oxidation conditions, it produced the ketone (+)-7, mp 98–99°C, [α]D +144.15 (c 0.92,
CHCl3), excellently, under Dess–Martin conditions.6 Despite its double β-oxyketone structure, the (+)-7
obtained was found to be quite stable under ordinary conditions. Reaction of (+)-7 with methyllithium
in the presence of cerium(III) chloride7 occurred diastereoselectively from the convex face to give the
tertiary alcohol (+)-8, [α]D31 +36.67 (c 0.92, CHCl3), as the single product. Removal of the cumyl group
of (+)-8 under hydrogenolysis conditions proceeded without difficulty to afford the cyclopentanediol
(+)-9, mp 88–89°C, [α]D32 +11.74 (c 0.95, CHCl3). Overall yield of (+)-9 from (−)-1 was 55% in seven
steps.
25
On the other hand, (+)-5 was first subjected to hydrogenolysis to give the siloxy-alcohol (+)-10, [α]D
+5.52 (c 1.02, CHCl3). Dess–Martin conditions allowed facile oxidation of (+)-10 to give the ketone
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(−)-11, [α]D −136.59 (c 1.22, CHCl3), without initiation of β-elimination. Reaction of (−)-11 with
methyllithium in the presence of cerium(III) chloride as above gave, diastereoselectively, the tertiary
alcohol (+)-12, [α]D29 +0.65 (c 1.30, CHCl3), which, on desilylation by TBAF, afforded the enantiomeric
28
diol (−)-9, mp 88–89°C, [α]D −11.16 (c 1.01, CHCl3). Overall yield of (−)-9 from (−)-1 was 61%
in seven steps. It was noted that the 1,2-addition occurred stereoselectively from the opposite side of the
2,3-acetonide functionality in both (+)-7 and (−)-11 irrespective of the presence of a bulky substituent
on the convex face, respectively (Scheme 2).
Scheme 2. Reagents and conditions: (i) TBSCl, imidazole, DMF (95%); (ii) OsO4 (cat.), NMO, 50% aq. THF (90%); (iii)
2,2-dimethoxypropane, PPTS (cat.), CH2Cl2 (99%); (iv) TBAF, THF (93% for 6 and 88% for (−)-9); (v) Dess–Martin oxidation
(96% for 7 and 97% for 11); (vi) MeLi, CeCl3, THF, −78°C (86% for 8 and 88% for 12); (vii) H2, 10% Pd–C, CHCl3 (cat.),
AcOEt (85% for (+)-9 and 96% for 10)
Having accomplished the enantiodivergent transformation of (−)-1 into both enantiomeric diols (+)-
and (−)-9, synthesis of α-cuparenone (−)-18 was next examined using one of the enantiomers, (−)-9,
to establish an enantiodivergent synthesis in the formal sense. Thus, oxidation of (−)-9 with pyridinium
chlorochromate (PCC) in dichloromethane proceeded neatly to give the β-hydroxyketone (+)-13, mp
72°C, [α]D28 +189.61 (c 1.19, CHCl3), without initiation of β-elimination. The generation of the tertiary
β-hydroxyketone (+)-13 in a stable form was synthetically of interest as it allows further modification at

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this stage if such is considered desirable. Facile dehydration occurred to give the enone (+)-14, [α]D
+20.71 (c 1.03, CHCl3), when (+)-13 was warmed in acetic acid at 40°C. Treatment of (+)-14 with
a Grignard reagent in the presence of copper(I) bromide and trimethylsilyl chloride8 allowed convex-
28
face selective 1,4-addition to yield the single cyclopentanone (+)-15, [α]D +178.14 (c 1.08, CHCl3),
carrying a benzylic quaternary stereogenic center. Conversion of (+)-15 into the known enone (+)-17,
serving as the key intermediate of (−)-α-cuparenone 18, was carried out efficiently in a sequential
two-step reaction involving the reductive cleavage of the α-oxyketone functionality using aluminum
amalgam.9 Thus, treatment of (+)-15 with aluminum amalgam in ethanol allowed facile α-cleavage to
28
give the β-hydroxyketone (+)-16, [α]D +40.48 (c 1.35, CHCl3), excellently, as a stable product. This
was stirred with diluted hydrochloric acid in dioxane at 40°C to initiate β-elimination to give rise to
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22
the target enone (+)-17, [α]D +141.70 (c 1.04, EtOH) [lit.2: [α]D −139.15 (c 0.95, EtOH) for the
enantiomer], from which (−)-α-cuparenone 18 has been obtained in three steps.2,3c Overall yield of
(+)-17 from (−)-9 was 54% in five steps (Scheme 3).
Scheme 3. Reagents and conditions: (i) PCC, CH2Cl2 (90%); (ii) AcOH, 40°C (93%); (iii) 4-MeC6H4MgBr, CuBr·SMe2,
HMPA, TMSCl, THF, −78°C, then TBAF, THF (87%); (iv) Al–Hg, EtOH (91%); (v) 10% HCl:dioxane (1:1), 40°C (81%)
In summary, we have devised an enantiodivergent route to α-cuparenone on the basis of the latent
meso structure of the chiral starting material. The present procedure also constitutes an enantioconvergent
route to both (+)- and (−)-cuparenones in the formal sense as the enantiomeric starting material could
give the same enantiomeric pair, enantiodivergently. Although only the synthesis of α-cuparenone was
shown in this report, a series of the polyoxygenated bicyclic cyclopentanoids involved in the synthesis
may be widely utilized as versatile chiral building blocks owing to their biased structures which make
diastereocontrol very easy.
References
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