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

Abstract

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.

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 CH₂Cl₂ (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 POCl₃ 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.

Scheme 2.

Scheme 2.

Figure 1. ¹H-NMR spectra of compound 1 (trans)

Figure 1. ¹H-NMR spectra of compound 1 (trans)

Figure 1 (cont). ¹H-NMR spectra of compound 20 (cis)

Figure 1 (cont). ¹H-NMR spectra of compound 20 (cis)

Figure 2. ¹H-NMR spectra of compound 2 (trans)

Figure 2. ¹H-NMR spectra of compound 2 (trans)

Figure 2 (cont). ¹H-NMR spectra of compound 21 (cis)

Figure 2 (cont). ¹H-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.

Scheme 3.

Scheme 3.

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 ¹H-NMR spectra of 1 and 2 were compared with those of the cis-isomers (Figure 1 and Figure 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.

Table 1. Comparison of specific rotations

Compound
	1	ent-1	20	ent-20
Synthetic product (this work)	-73
Reported data	-96 [1] -77 [18]	+31 [7]	-22 [1, wrong] +43 [4] +33.4 [8]	-31 [17]
Compound
	2	ent-2	21	ent-21
Synthetic product (this work)	-24	-	-	-
Reported data	-	+38 [3]	+40[20]	-

Table 1. Comparison of specific rotations

Compound
	1	ent-1	20	ent-20
Synthetic product (this work)	-73
Reported data	-96 [1] -77 [18]	+31 [7]	-22 [1, wrong] +43 [4] +33.4 [8]	-31 [17]
Compound
	2	ent-2	21	ent-21
Synthetic product (this work)	-24	-	-	-
Reported data	-	+38 [3]	+40[20]	-

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 ¹³C-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.

Table 2. ¹³C-NMR data for the calamenes

No.	1	1	20	20	2	ent-2	21
	this work*	[18]	[20]*	[18]	this work*	[3]	[20]*
1	140.1	140.3	139.7	140.0	126.1	126.5	126.7
2	126.8	127.0	128.5	128.5	153.2	153.2	153.0
3	126.2	126.4	126.3	126.5	113.4	113.8	112.8
4	134.5	134.6	134.5	134.6	135.1	135.1	135.7
5	128.8	129.0	128.7	128.9	123.0	123.1	120.8
6	140.0	140.3	139.9	140.2	141.3	141.3	141.3
7	43.8	44.1	43.6	43.8	43.0	43.2	43.3
8	21.1	21.3	23.3	23.3	19.1	19.2	16.4
9	30.8	31.0	28.7	28.9	27.1	27.2	28.8
10	32.5	32.6	31.1	31.2	26.5	26.7	26.5
11	31.9	32.1	32.5	32.7	33.1	33.2	30.9
12	17.3	17.5	17.6	17.8	19.6	19.7	17.3
13	21.5	21.6	21.4	21.5	21.0	21.1	20.5
14	22.3	22.3	19.7	22.5	22.1	22.2	21.2
15	21.3	21.3	21.2	21.2	21.1	21.3	21.1

*assignment is tentative.

Table 2. ¹³C-NMR data for the calamenes

No.	1	1	20	20	2	ent-2	21
	this work*	[18]	[20]*	[18]	this work*	[3]	[20]*
1	140.1	140.3	139.7	140.0	126.1	126.5	126.7
2	126.8	127.0	128.5	128.5	153.2	153.2	153.0
3	126.2	126.4	126.3	126.5	113.4	113.8	112.8
4	134.5	134.6	134.5	134.6	135.1	135.1	135.7
5	128.8	129.0	128.7	128.9	123.0	123.1	120.8
6	140.0	140.3	139.9	140.2	141.3	141.3	141.3
7	43.8	44.1	43.6	43.8	43.0	43.2	43.3
8	21.1	21.3	23.3	23.3	19.1	19.2	16.4
9	30.8	31.0	28.7	28.9	27.1	27.2	28.8
10	32.5	32.6	31.1	31.2	26.5	26.7	26.5
11	31.9	32.1	32.5	32.7	33.1	33.2	30.9
12	17.3	17.5	17.6	17.8	19.6	19.7	17.3
13	21.5	21.6	21.4	21.5	21.0	21.1	20.5
14	22.3	22.3	19.7	22.5	22.1	22.2	21.2
15	21.3	21.3	21.2	21.2	21.1	21.3	21.1

*assignment is tentative.

Experimental

General

The IR spectra were measured with a JASCO FT/IR-500 spectrophotometer. The ¹H- and ¹³C-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 60F₂₅₄ plate (0.25 mm, Merck) were used for TLC. All reactions were carried out under an argon atmosphere. THF was distilled from LiAlH₄ 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.

Preparation of [1ξ,2ξ,3R,6S]-2-allyl-6-isopropyl-3-methyl-1-(2-methylpropyl)cyclohexan-1-ol (4).

l-Menthone (300 mg, 1.95 mmol) was treated with LDA (n-BuLi, 1.5 eq.; iPr₂NH, 1.5 eq.) in THF at -78°C for 1 h, then, allyl bromide (0.39 mL, 2.0 eq.) was added. The temperature was gradually raised to r.t. overnight. Water was added and the solvent was removed. The mixture was extracted with ether and the organic layer was washed with 1M HCl and brine, dried (MgSO₄), and evaporated to afford a residue which was purified by silica gel column chromatography (hexane-EtOAc, 0-25%) to give 2-allylmenthone (65.3g, 17%); FTIR: 1720 cm^-1; ¹H-NMR (200 MHz) δ 0.84 (3H, d, J = 6.4 Hz), 0.89 (3H, d, J = 6.4 Hz), 1.04 (3H, d, J = 6.4 Hz), 1.47 (3H, m), 1.87 (1H, m), 2.06 (4H, m), 2.34 (2H, m), 4.94 (1H, br d, J = 10.4 Hz), 5.00 (1H, br d, 16.8 Hz), 5.84 (1H, ddt, J = 16.8, 10.4, 5.6 Hz); ¹³C-NMR (50 MHz) δ 18.8 (CH₃), 20.5 (CH₃), 21.4 (CH₃), 26.1 (CH), 29.1 (CH₂), 30.4 (CH₂), 34.7 (CH₂), 39.9 (CH), 56.9 (CH), 57.5 (CH), 115.5 (CH₂), 137.3 (CH), 212.0 (C); MS (EI) m/z 194 [M]⁺ 194 (base), 179, 151, 138, 123, 109, 95, 81, 69, 55; HRMS (EI) Found m/z 194.1664 [M]⁺. C₁₃H₂₂O requires 194.1670.

The Grignard reagent was prepared from methallyl chloride (1 mL, 10 mmol) and Mg (243 mg, 10 mmol) in THF (8 mL) with aid of dibromoethane (0.05 mL, 0.1 eq.) at -15°C. One half of this Grignard reagent was introduced into a solution of 2-allylmenthone (100 mg, 0.52 mmol) in THF at -15°C over 2 h. Saturated NH₄Cl solution and water were added and the mixture was extracted with ether. The organic layer was washed with sat. NH₄Cl soln. and brine, dried (MgSO₄), and was evaporated to afford a residue which was purified by silica gel column chromatography (hexane-EtOAc, 0-10%) to give 4 (122 mg. 95%). 4; FTIR: 3600, 1640 cm^-1; ¹H-NMR (200 MHz) δ 0.92 (9H, m), 1.29 (2H, m), 1.41-1.58 (4H, m), 1.80 (1H, m), 1.83 (3H, m), 2.24 (1H, m), 2.36-2.72 (4H, m), 4.84 (1H, br s), 4.94 (1H, br s), 5.02 (1H, d, J = 9.6 Hz), 5.18 (1H, d, J = 17.4 Hz), 6.08 (1H, m); ¹³C-NMR (50 MHz) δ 18.2 (CH₃), 20.4 (CH₃), 20.9 (CH₃), 23.2 (CH₃), 25.1 (CH₃), 26.6 (CH), 31.7 (CH), 32.4 (CH₂), 35.9 (CH₂), 44.3 (CH₂), 48.3 (CH), 49.8 (CH), 79.6 (C), 114.7 (CH₂), 116.1 (CH), 138.7 (CH), 141.9 (C); MS (EI) m/z 250 [M]⁺ 250, 217, 195 (base), 177, 139, 121, 109, 97, 83, 69, 55; HRMS (CI) Found m/z 251.2373 [M+ H]⁺. C₁₃H₂₂O requires 251.2375.

Preparation of [1ξ,6ξ,7R,10S]-10-isopropyl-3,7-dimethylbicyclo[4.4.0]dec-3-en-1-ol (3).

To a stirred solution of 4 (350 mg, 1.4 mmol) in degassed CH₂Cl₂ (125 mL) was added a solution of Grubbs reagent (57.6 mg, 5 mol%) in CH₂Cl₂ (15 mL) under Ar at room temperature. The mixture was stirred overnight at r.t. The septum was removed and the mixture was stirred for further 30 min. and then the solvent was removed. The residue was directly purified by silica gel column chromatography (hexane-EtOAc, 0-20%) to afford 3 (298 mg, 96%): FTIR: 3450-3600 cm^-1; ¹H-NMR (600 MHz)δ 0.86 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.9 Hz), 0.94 (3H, d, J = 6.9 Hz), 1.02 (2H, m), 1.08 (1H, m), 1.38 (1H, m), 1.50 (2H, m), 1.67 (3H, s), 1.71 (1H, m), 1.73 (1H, m), 1.96 (1H, br d, J = 18 Hz), 2.21 (3H, m), 5.44 (1H, br s); ¹³C-NMR (50 MHz) δ 18.2 (CH₃), 19.9 (CH₃), 20.3 (CH₂), 23.7 (CH₃), 23.7 (CH₃), 25.5 (CH), 26.9 (CH₂), 33.3 (CH), 35.5 (CH₂), 42.8 (CH₂), 46.8 (CH), 51.9 (CH), 72.5 (C), 120.2 (CH), 130.8 (CH); MS (EI) m/z 222 [M]⁺ 204, 189, 179, 161 (base), 139, 119, 105, 93, 84, 69, 55; HRMS (EI) Found m/z 222.1991 [M]⁺. C₁₅H₂₆O requires 222.1983.

Preparation of (-)-calamenene (1) and [7S,10R]-2,5-dihydrocalamenene (6).

A solution of 3 (100 mg, 0.45 mmol) in pyridine (5 mL) was treated with POCl₃ (0.084 mL, 2.0 eq.) at r.t. overnight. Water was added and the mixture was extracted with ether. The organic layer was washed with 1M HCl and brine, dried (MgSO₄) and evaporated to afford a residue which was purified by silica gel column chromatography (hexane-EtOAc, 0-20%) to give (-)-calamenene (1) (12.0 mg, 13%) and 6 (15.4 mg, 17%). 1: [α]_D -73°(c 0.88, CHCl₃); FTIR: 1510-1470 cm^-1; ¹H-NMR (200 MHz) δ 0.72 (3H, d, J = 7.2 Hz), 1.00 (3H, d, J = 7.2 Hz), 1.26 (3H, d, J = 7.2 Hz), 1.39 (1H, m), 1.60 (1H, m), 1.81 (1H, m), 1.95 (1H, m), 2.22 (1H, m), 2.30 (3H, s), 2.70 (2H, m), 6.94 (1H, br d, J = 8.0 Hz), 7.02 (1H, br s), 7.12 (1H, d, J = 8.0 Hz); ¹³C-NMR (50 MHz) Table 1); MS (EI) m/z 202 [M]⁺ 202, 159 (base), 144, 129, 115, 115, 105, 91; HRMS (EI) Found m/z 202.1696 [M]⁺. C₁₅H_S requires 202.1722. 6; ¹H-NMR (200 MHz) δ 0.91(3H, d, J = 5.9 Hz), 0.93 (3H, d, J = 5.9 Hz), 0.98 (3H, d, J = 5.9 Hz), 1.68 (3H, br s), 5.42 (1H, m).

Preparation of [1ξ,6ξ,7S,10R]-6-hydroxy-7-isopropyl-4,10-dimethylbicyclo[4.4.0]dec-3-en-2-one (8).

A solution of 3 (100 mg, 0.45 mmol) in benzene (10 mL) was treated with Celite (1.05 g), tBuOOH (0.31 mL), and PDC (1.2 g, 1.35 mmol) at 0°C and the mixture was stirred overnight. The temperature was gradually raised to room temperature overnight. A solution of Na₂S₂O₃ was added and the mixture was filtered through Celite. The filtrate was extracted with ether and the organic layer was washed with brine, dried (MgSO₄) and evaporated to afford a residue which was purified by silica gel column chromatography (hexane-EtOAc, 0-30%) to give 8 (35.4 mg, 33%); FTIR: 3400, 1660 cm^-1; ¹H-NMR (200 MHz) δ 0.90 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 0.95 (1H, m), 1.08 (3H, d, J = 5.8 Hz), 1.30 (3H, m), 1.55 (1H, m), 1.85 (1H, m), 1.89 (3H, s), 2.10 (2H, m), 2.40 (1H, br d, J = 17.6 Hz), 2.65 (1H, d, J = 17.6 Hz), 5.79 (1H, s); ¹³C-NMR (50 MHz) δ 18.1 (CH₃), 19.6 (CH₂), 22.1 (CH₃), 23.7 (CH₃X2), 25.5 (CH), 27.3 (CH), 34.9 (CH₂), 44.2 (CH₂), 52.0 (CH), 60.7 (CH), 77.1 (C), 126.4 (CH), 153.7 (C) 200.5 (C); MS (EI) m/z 236 [M]⁺, 236, 221, 193, 175, 165, 151, 137 (base), 125, 111, 95, 83, 69, 55; HRMS (EI) Found m/z 236.1770 [M]⁺. C₁₅H₂₄O₂ requires 236.1777.

Preparation of (-)-[7S,10R]-2-hydroxycalamenene (2).

A solution of 8 (63 mg, 0.27 mmol) in pyridine (2 mL) was treated with POCl₃ (0.13 mL, 5 eq.) at 0°C. The mixture was stirred at r.t. overnight. Water was added and the mixture was extracted with ether. The organic layer was washed with 1M HCl, and brine, dried (MgSO₄) and evaporated to afford a residue which was purified by silica gel column chromatography (hexane-EtOAc, 0-50%) to give 2 (18.7 mg, 16%); [α]_D -24°(c 1.06, CHCl₃); FTIR: 3450, 1620, 1580 cm^-1; ¹H-NMR (200 MHz) δ 0.82 (3H, d, J = 7.2 Hz), 0.99 (3H, d, J = 7.2 Hz), 1.20 (3H, d, J = 7.2 Hz), 1.51 (1H, m), 1.81 (1H, m), 1.99 (2H, m), 2.24 (3H, s), 2.46 (1H, m), 3.05 (1H, s), 4.64 (1H, s), 6.43 (1H, s), 6.58 (1H, s); ¹³C-NMR (50 MHz). (Table 1); MS (EI) m/z 218 [M]⁺, 218, 175 (base), 160, 147, 121, 115, 105, 91; HRMS (EI) Found m/z 218.1691 [M]⁺. C₁₅H₂₂O requires 218.1671.