Total Synthesis of (-)-(7S,10R)-Calamenene and (-)-(7S,10R)- 2-Hydroxycalamenene by Use of a Ring-Closing Metathesis Reaction. A Comparison of the cis- and trans-Isomers

The title compounds have been synthesized starting from l-menthone by application of a ring-closing metathesis reaction to confirm their reported absolute and relative stereochemistry. Comparisons of the NMR spectra and specific rotations are also discussed.


Introduction
The absolute configurations of both (7S,10R)-calamenene (1), isolated from Chamaecyparis nootkatensis by Andersen et al. [1] and (+)-2-hydroxycalamenene (2) [2], isolated from Dysoxylum acutangulum by Nishizawa et al. [3] were determined using CD spectra or X-ray analysis and chemical transformations. The stereochemistry of 1 was later revised after X-ray analysis [4]. We have been working on natural products found in the liverwort [5,6] and have reported the isolation of several calamenenes [7,8], including 5-hydroxycalamenene, whose structure was determined by X-ray analysis [8]. Up to now, total syntheses of these chiral substances have never been clearly reported because the final products were always a mixture of cis-and trans-isomers [9]. We are currently working on the ring-closing metathesis reaction (RCM) [10,11] and planned to synthesize these natural products possessing trisubstituted double bonds, in optically active forms, by application of RCM. As shown in Scheme 1, our synthetic plan is to construct the trisubstituted double bond by RCM [12][13][14] starting from l-menthone (5).

Scheme 1
Results and Discussion l-Menthone (5) was first allylated with LDA and then a Grignard reaction of this ketone with methallylmagnesium chloride afforded alcohol 4. No attempt was made to determine the stereochemistry because the newly created chiral center of compound 4 will be lost at a later stage. Now, the diene alcohol 4 was treated with Grubbs' catalyst (5 mol%) in CH 2 Cl 2 (10 mM) at r.t. overnight to produce alkene 3 in 96% yield. The stereochemistry of alkene 3 was analyzed by NOESY, however, due to the overlapping of the protons the cis/trans stereochemistry at the ring junction was not known. Dehydration of alcohol 3 with POCl 3 afforded calamenene (1) and a small amount of diene 6. The diene 6 was oxidized by DDQ to afford only cadalene (7) and no calamenene (1) was obtained. The alcohol 3 was also transformed into enone 8 by allylic oxidation and then dehydration of 8 produced phenol 2, although the yield was low (Scheme 2).
The spectral data of 1 were identical in all aspects to those reported in the literature [1], including the specific rotation. The spectral data of compound 2 were also identical to those found in the literature [3], however, the sign of the rotation was opposite to that reported. Thus, we conclude that the synthetic compound was the enantiomer of the natural product found by Nishizawa et al. [3] and the assigned absolute configuration was correct.

Figure 2 (cont). 1 H-NMR spectra of compound 21 (cis)
We next attempted the synthesis of compounds 18 or 19, which are potential intermediates for the synthesis of tamariscol [15,16] and other terpenoids. Thus, dihydrocarvone (9) was allylated with LDA and allyl bromide, however, the desired product 10 was only formed in minute amounts. Instead, compounds 11 and 12 were produced in larger quantities. Therefore, allylation of carvone (13) itself was tried. Again the yield was low, however, the RCM was attempted with Grubbs' catalyst. No reaction occurred in the case of compound 14. In an alternate approach, the carbonyl group in 14 was reduced and protected with a TES group to afford 16. Then, compound 16 was treated with Grubbs' catalyst, but the cyclized product 17 was produced only in 6% yield (Scheme 3).

Conclusions
We have applied the RCM reaction to the construction of a trisubstituted alkene and thus synthesized two calamenene-type natural products, 1 and 2. The 1 H-NMR spectra of 1 and 2 were compared with those of the cis-isomers (Figures 1 and 2) [8]. Confusion about the stereochemistry (Table 1) as well as the different numbering systems and names used for these compounds [2], made it very difficult to identify each compound unambiguously. The original assignment by Andersen et al. [1] was later revised by Croft et al. [4] and other syntheses have always afforded mixtures of cis and trans products. We now offer reliable data for the trans derivatives and also give NMR data for comparison with those of cis-isomers [7,8,18,19]. The 13 C-NMR spectrum for compound 20 in ref. [18] was measured with an 80 MHz machine, while our spectrum was taken with a 400 MHz spectrometer (Table 2). Because some peaks are congested in a narrow region, some problems could have resulted with the assignments and our data have not yet been fully assigned [20]. It is noteworthy that a condensed cyclopentene ring was not easy to construct by the RCM reaction, presumably due to the fact that stereochemistry was not correct for cyclization.

General
The IR spectra were measured with a JASCO FT/IR-500 spectrophotometer. The 1 H-and 13 C-NMR spectra were recorded on a JEOL ECP-400, a Varian Unity 200, or a Varian Gemini 200 spectrometer. Deuteriochloroform was used for NMR and chemical shifts were expressed in ppm and the coupling constant in Hz. The mass spectra, including high-resolution mass spectra, were taken with a JEOL AX-500 spectrometer. The specific rotation was measured with a JASCO DIP-100 polarimeter. Silica gel BW-300 (200-400 mesh, Fuji silycia) was used for column chromatography, and silica gel 60F 254 plate (0.25 mm, Merck) were used for TLC. All reactions were carried out under an argon atmosphere. THF was distilled from LiAlH 4 and then from Na-benzophenone prior to use. RCM reagent was weighed in a dry box and was used without purification. Anhydrous dichloromethane and benzene used for the reactions were purchased from Kanto Chemical, Japan and were used without further purification.