An Improved Three Step Synthesis of (-)-3β-Hydroxycarvone from (-)-Carvone

(-)-Carvone (3) has been efficiently transformed into (-)-3β-hydroxycarvone (1), which is expected to be a useful synthon or chiral template in the synthesis of natural molecules. This short and efficient synthesis of compound 1 involves regioselective and stereoselective α-hydroxylation of carvone via the trimethylsilyl-dienyl-ether derivative.


Introduction
Carvone (3) is an important chiron for the synthesis of complex natural products [1]. However, its versatility could be greatly enhanced by the development of efficient and selective methodologies for the synthesis of 3-oxy-derivatives. trans-3-Hydroxycarvone (1) has many structural features found in several naturally occurring compounds [2], and therefore can be considered a useful synthon provided that it can be obtained from readily available natural sources such as carvone (3).
In connection with the synthesis of a bisabolane sesquiterpene isolated from Senecio lividus [3], we required multi-gram quantities of 3β-hydroxycarvone (1) for use as our starting material and needed to develop an effective and short method to synthesise this compound. A literature survey revealed three different approaches to the synthesis of the title compound. Hosokawa et al [4] described the stereoselective preparation of trans-3-hydroxycarvone (1), by oxidation of carvone silyl-dienyl ether with O 2 catalysed by PdCl 2 (MeCN) 2 /CuI in HMPA. Schulz et al [5] reported the hydroxylation of carvone titanium enolate using a mixture of tert-butylhydroperoxide and MgO, resulting in a mixture of 3β-and 3α-hydroxycarvone (1) and (2), with 40% d.e. Finally, Nagaoka et al [6] described the synthesis of 3-hydroxycarvone from (+)-carvone, in 45% overall yield, via oxidation of its silyl-dienyl ether with m-chloroperbenzoic acid.
These methodologies all provided the desired compound in poor yield. In Hosokawa and Schulz's methods the yields were only 11 and 20% of trans-3-hydroxycarvone and mixture of diastereomers respectively [4,5]. Furthermore, from the spectroscopic data in Schulz's paper, it seems that the minor diastereomer should be assigned as cis-isomer (5S,6R) and not (5S,6S) that correspond to the trans isomer. Nagaoka et al. [6], have improved the synthesis yield of 3-hydroxycarvone to 45%. However, the product was probably a mixture of diastereoisomers, since no assignment has been made nor were spectroscopic data and complete experimental details included.
We report herein a short improved methodology based on oxidation of silyl-dienyl ether to prepare (-)-3β-hydroxycarvone (1) by an easy experimental procedure starting from (R)-(-)-carvone (3). This methodology allowed the full characterization of the diastereomeric products formed.
Use of aqueous NaHCO 3 solution results in a better yield due to quenching of m-chlorobenzoic acid generated during the reaction. Apparently, this by-product causes hydrolysis of the dienyltrimethylsilyl ether (4) prior to epoxidation. In agreement with this, use of 50% m-chloroperbenzoic acid lead to a decreased yield of 3-hydroxycarvone as well as recovery of carvone.
The stereochemistry of the stereogenic center at C-3 of (1) and (2) was assigned on the basis of their 1 H-NMR spectra and are consistent with the published data [4,5]. The 1 H-NMR spectrum of isomer (1) showed a coupling constant of J 3-4 = 12.5 Hz for the carbinolic hydrogen, characteristic of a trans relative configuration. For the minor isomer (2), the 1 H-NMR spectrum showed a coupling constant of J 3-4 = 5.9 Hz for the carbinolic hydrogen, characteristic of a cis relative configuration.

Conclusions
A short and simple strategy has been developed for the synthesis of (-)-3β-hydroxycarvone (1). This modified methodology improved effectively the total yield [from (-)-carvone to (-)-3βhydroxycarvone (1)] from 45% (ref. [6], cis and trans mixture) to 68% as a mixture and 58% as a single isomer. The success of the approach is achieved due to an easy and inexpensive experimental procedure, which consequently should be amenable to extrapolation to a much larger scale.

General
Optical rotations were taken on a Perkin-Elmer polarimeter model 241. Column chromatography was performed on silica gel 60 (70-230 mesh ASTM Merck). Radial thin-layer chromatography was carried out on a Chromatotron 8924 (silica gel 60PF 254 Merck). Infrared spectra were recorded either with a Bomen Michelson model 102 FTIR or with a Bomem Hartman & Braun MB-Series. 1 H-and 13 C-NMR spectra were recorded either on a Bruker ARX-200 (200 MHz), a Bruker ARX-400 (400 MHz) or a Varian FT-80A (80 MHz) spectrometer in CDCl 3 with TMS as an internal standard. Microanalyses were performed on a Fisons EA 1108 CHNS-0 Analyzer, at the Department of Chemistry, UFSCar. Solvents were distilled prior to use: triethylamine was refluxed over CaH 2 , distilled and stored over KOH; acetonitrile and dichloromethane were refluxed over P 2 O 5 , distilled and stored over molecular sieves. Chlorotrimethylsilane was distilled over CaH 2 . NaI was dried for 24 h under vacuum at 140 o C and stored under nitrogen.