Total synthesis of optically active liverwort sesquiterpenes, trifarienols A and B, using phenylethylamine as a chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(99)00067-1

The imine of (rac)-2,3-dimethylcyclohexanone 10a with (S)-(-)- phenylethylamine was reacted with methyl acrylate to yield methyl (1'S,6'R)- 3-(1',6'-dimethyl-2'-oxocyclohexyl)propanoate 4a in 26% (97% ee) after hydrolysis. When (2RS,3R)-2,3-dimethylcycloh

Full text of DOI:10.1016/S0957-4166(99)00067-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 961–971
Total synthesis of optically active liverwort sesquiterpenes,
trifarienols A and B, using phenylethylamine as a chiral auxiliary
Motoo Tori,∗ Kenji Hisazumi, Tomonari Wada, Masakazu Sono and Katsuyuki Nakashima
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro cho, Tokushima 770-8514, Japan
Received 8 February 1999; accepted 22 February 1999
Abstract
The imine of (rac)-2,3-dimethylcyclohexanone 10a with (S)-(−)-phenylethylamine was reacted with methyl
acrylate to yield methyl (10S,60R)-3-(10,60-dimethyl-20-oxocyclohexyl)propanoate 4a in 26% (97% ee) after
hydrolysis. When (2RS,3R)-2,3-dimethylcyclohexanone 10b was used, the same product 4b was obtained in 59%
yield (>99.5% ee) after hydrolysis. When (2RS,3R)-2,3-dimethylcyclohexanone10b and (R)-(+)-phenylethylamine
were used, the reaction underwent in only 5% yield, the products being 4c, 12, 13, 14, and 15. Thus, the reaction of
3b with methyl acrylate is a matched case, while that of 3c is a mismatched case. These phenomena are explained
by the nonbonded interaction of methyl acrylate with chiral phenylethylamine and the methyl group at the 60-
position of the cyclohexanone ring in the transition state. The propanoate product 4b was successfully transformed
into liverwort sesquiterpene (+)-trifarienol A 1 and (−)-trifarienol B 2 in 10 steps. We have developed an HPLC
method to determine the ees of 2,2-disubstituted and 2,2,3-trisubstituted cyclohexanones using the corresponding
pentafluorophenyl esters. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
2,2-Disubstituted chiral cyclohexanones can be easily prepared using the homochiral phenylethyl-
amine methodology developed by Pfau and d’Angelo.1 This method is widely applied to total syn-
theses of natural products.2 We have previously used this reaction with methyl propiolate to prepare
α,β-unsaturated keto ester.3 This reaction was used for 2-methylcyclopentanone and the product was
converted into herbertene.3 Trifarienols A 1 and B 2 have been found in liverworts4 and they belong to
an unusual skeleton, trifarane.4,5 In the trifarane class, only upial6 is known other than 1 and 2. Recently,
Huang and Forsyth have reported a total synthesis of racemic 1 and 2 by cyclization using mercury
techniques.7 We planned to synthesize these compounds as optically active forms using phenylethylamine
methodologies. Vicinal dimethyl groups are usually constructed by alkylation of the thermodynamically
∗
Corresponding author. Tel: +81-88-622-9611, ext. 5631; fax: +81-88-655-3051; e-mail: tori@ph.bunri-u.ac.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00067-1

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more stable enolate.8,9 However, it is not always easy to control the stereochemistry.9 We have studied the
details of the reaction between the phenylethylimine of 2,3-dimethylcyclohexanone and methyl acrylate
and found that the use of (2RS,3R)-dimethylcyclohexanone 10b and (S)-(−)-phenylethylamine gives the
best results. The keto aldehyde 7 derived from keto ester 4 may be cyclized into ketol 8 by aldol reaction
(Scheme 1). One more carbon could be introduced after the formyl group was added. Then conversion
of aldehyde 9 into trifarienols A 1 and B 2 constitutes the first total synthesis of optically-active natural
products. Alternatively, intramolecular 1,4-cyclization of ester 5 into ketone 6 was unsuccessful. We now
report these results in detail.
Scheme 1.
2. Results and discussion
The imine prepared from (S)-(−)-phenylethylamine and (rac)-2,3-dimethylcyclohexanone 10a was
subjected to reaction with methyl acrylate without solvent for a week. Slow reaction afforded the desired
keto ester 4a in 26% yield (from 10a) after hydrolysis (AcOH:H2O=9:1). The stereochemistry and
conformation of 4a were determined by careful analysis of the 600 MHz 2D NMR spectra as well as
decoupling experiments. When the sec-methyl group was decoupled, the proton at 60-position appeared
as double doublets, which is in axial orientation. The NOEs were observed between H-60 and H-40α,
and between Me-10 and H-50β, respectively, suggesting the stereochemistry as well as the conformation
(Fig. 1).10 The absolute configuration of 4 was established as shown in Fig. 1 by the CD spectrum,
because the (−)-Cotton effect was observed at 297.5 nm.
In this reaction a considerable amount of 10a (37%) was recovered. This disappointingly low yield
should be mainly due to the fact that a half amount of 3a does not give 4a (maximum yield 50%).11
Therefore, we next prepared (2RS,3R)-2,3-dimethylcyclohexanone 10b from (−)-pulegone in two steps.12
Then the similar reaction was carried out to isolate keto ester 4b in 59% yield from 10b after hydrolysis.
Both the diastereomer excess and enantiomer excess were determined by HPLC and GC techniques
applied to the corresponding pentafluorophenyl ester 11 derived from 4. When ester 11a was analyzed by
GC (DB-17), the main peak was detected at 25.5 min with the small one at 24.7 min corresponding to the

M. Tori et al. / Tetrahedron: Asymmetry 10 (1999) 961–971
963
Figure 1. The configuration, conformation and absolute configuration of 4
diastereoisomers, being 81% de. In the case of HPLC (Chiralcel OD-H), three peaks were detected (peak
1: 7.2 min; peak 2: 8.4 min; peak 3: 10.4 min), the fastest moving one (peak 1) being the enantiomer of
11a, (10R,60S)-isomer, the second (peak 2) (10S,60R)-isomer 11a, and the third (peak 3) the mixture
of diastereoisomers, (10S,60S)- and (10R,60R)-isomers, being calculated as 97% ee.13 However, 11b
displayed only one peak in the GC at 25.5 min, being >99.5% de. The HPLC analysis of 11b showed
only one peak of (10S,60R)-isomer at 8.4 min, being >99.5% ee.13 This combination of the GC and HPLC
is very effective to determine both de and ee. The phenyl ester, unlike the pentafluorophenyl ester, did
not give a good separation. Use of the pentafluorophenyl ester is essential and this method can also be
applied to determine the ee of methyl 3-(10-methyl-20-oxo-cyclohexyl)propanoate.14
When the imine prepared from (R)-(+)-phenylethylamine and 10b was treated with methyl acrylate,
conversion was very low and the isolated products were 4c (0.3%), 12 (1.5%), 13 (0.4%), 14 (0.3%), and
15 (2%), respectively. This is a mismatched case and the transition state disfavored the desired addition
reaction (Scheme 2), which was indicated by the calculation.15 The reaction of 3b with methyl acrylate
should be a matched case. These phenomena are explained by the nonbonded interaction of methyl
acrylate with the chiral phenylethylamine and the methyl group at the 60-position of the cyclohexanone
ring in the transition state.15
The keto ester 4b with high enantiomeric excess was reduced (LiAlH4) and reoxidized (DMSO, oxalyl
chloride) to keto aldehyde 7 in 91% yield (Scheme 3). Intramolecular aldol cyclization was induced by
5% KOH in MeOH to afford a mixture of ketol 8a and 8b (1:1) in 67% yield. The stereochemistry at the
3-position of compound 8 was tentatively assigned. Because this position is later oxidized into ketone,
the synthesis was carried out without separation of the diastereoisomers. Although the olefination of the
carbonyl group was unsuccessful with the Wittig reagent (Ph3P_CH2), the Tebbe reagent16 afforded the
desired olefin 16 (16a:16b=1:1) in 71% yield. The Swern oxidation of 16 gave the ketone 17 as a single
isomer. The Horner–Emmons olefination of 17 and separation of the isomers (by HPLC) gave 20E as the
major product (E:Z=81:19), whose spectral data was compared with those of Huang and Forsyth.7 The 1H
NMR spectrum of 20E corresponded to the major peaks of that of Huang and Forsyth.7 We could isolate
20E as a single isomer by HPLC and this constitutes the formal total synthesis of trifarienols A and B.7
We have further developed our synthetic route to complete the synthesis of optically active trifarienols A
and B. The Wittig reaction with Ph3P_CHOMe followed by hydrolysis yielded aldehyde 18 as a mixture
of two diastereoisomers (α:β=1:1.5). Hydrolysis of the Wittig product was somewhat complicated and
the yield was not good, presumably due to decomposition of the aldehyde produced. Methylation using
t-BuOK and MeI gave the desired one-carbon homologated aldehyde 9 as a result of attack from the less
hindered side of the molecule. The β orientation of the methyl group was established by the NOE between

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Scheme 2. (a) (S)-(−)-1-Phenylethylamine, TsOH, PhH, reflux, 1 day; (b) CH2_CHCO2Me, rt, 7 days; (c) AcOH:H2O (9:1),
60, 1 h; (d) (R)-(+)-phenylethylamine, TsOH, PhH, reflux, 1 day; (e) KOH, H2O–MeOH; (f) EDCI, C6F5OH, CH2Cl2
H-13 and H-10. The final steps were accomplished by epoxidation using trimethylsulfonium iodide17 and
opening of this ring into natural products. The diastereoisomers of epoxides 19a and 19b were separated
by HPLC and the stereochemistry was determined by conversion into the natural products. The major
isomer 19a was actually transformed into (+)-trifarienol A 1 and the minor one 19b into (−)-trifarienol
B 2. Spectral data including the specific rotations of these compounds were identical with those of the
natural products.4,18
In summary, we have succeeded in preparation of cis-arranged 2,2,3-trisubstituted cyclohexanone
derivative 4 in high enantiomeric excess using chiral phenylethylamine and have found that there
are matched and mismatched cases in this reaction. (+)-Trifarienol A 1 and (−)-trifarienol B 2 were
synthesized from 4 in 10 steps as optically active forms for the first time.
3. Experimental
3.1. General
1
The IR spectra were measured with a Jasco FT/IR-5300 spectrophotometer. The H and 13C NMR
spectra were taken with a Varian Unity 200 (200 MHz), a Unity 600 (600 MHz), or a Jeol JNM GX400

M. Tori et al. / Tetrahedron: Asymmetry 10 (1999) 961–971
965
Scheme 3. (a) LiAlH4, Et2O, rt, 5 h; (b) Swern oxid.; (c) 5%KOH, MeOH, rt, 3 days; (d) Tebbe reagent, rt, 1 day; (e)
Ph3P+CH2OCH3Cl−, n-BuLi, THF, reflux, 2 days; (f) 1 M HCl, THF–H2O, rt, 1 day; (g) t-BuOK, MeI, THF, rt, 1.5 h; (h)
(CH3)3S+I−, NaH, DMSO, THF; (I) HClO4, THF–H2O, rt; (j) (MeO)2POCH2CO2Me, NaH, THF, reflux, 5 days; then HPLC
(400 MHz) spectrometer. The mass spectra, including high resolution mass spectra, were taken with a
Jeol JMS AX-500 spectrometer. Chemcopak Nucleosil 50-5 (10×250 mm) was used for HPLC (Jasco
pump system). For the measurement of % ee a Daicel Chiralcel OD-H (4.6×25 cm) column was used in
the HPLC system. A DB-17 (0.25 mm×30 m) column was used for GC with the temperature program
from 50°C to 25°C (Shimadzu GC 14B gas chromatograph with FID detector). Silica gel 60 (70–230
mesh, Merck) was used for column chromatography and silica gel 60 F254 plates (Merck) were used for
TLC.
3.2. Preparation of ester 4a from racemic 2,3-dimethylcyclohexanone 10a
(S)-(−)-1-Phenylethylamine (39 mL, 0.3 mol) and TsOH (4 g) were added to a solution of (rac)-2,3-
dimethylcyclohexanone 10a (37 g, 0.3 mol) in benzene (300 mL) and the mixture was refluxed for 24 h
with the aid of a Dean–Stark water separator. The mixture was washed with water, saturated NaHCO3
solution and brine, dried (MgSO4), and concentrated to afford an imine, which was subjected to reaction
with methyl acrylate (26 mL, 0.29 mol) under ice cooling. The mixture was then stirred at rt for 7 days.
Acetic acid and water (9:1, 300 mL) was added to the mixture and kept at 60°C for 1 h. The mixture
was extracted with ether and the organic layer was washed with water, 1 M HCl solution, saturated
NaHCO3 solution and brine, dried (MgSO4), and evaporated to afford a residue. Purification by silica
gel column chromatography (hexane–EtOAc, in gradient) gave ester 4a (16.5 g, 26%, 97% ee) and 2,3-

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M. Tori et al. / Tetrahedron: Asymmetry 10 (1999) 961–971
dimethylcyclohexanone (14 g, 37%); 4a; oil: [α]D20.5 −6.2 (c 1.04, CHCl3); CD [θ]300nm −410 (CHCl3);
∆ε=−0.13; FT-IR 1740, 1700 cm−1; 1H NMR (600 MHz, CDCl3): δ 0.93 (3H, d, J=6.8 Hz), 1.02 (3H,
s), 1.60 (1H, m), 1.67 (1H, m), 1.76 (1H, m), 1.80 (1H, m), 1.84 (1H, m), 1.95 (1H, m), 2.01 (1H, ddd,
J=14, 11.2, 5.2 Hz), 2.22 (1H, ddd, J=12.9, 11.2, 5.1 Hz), 2.31 (1H, m), 2.33 (1H, ddd, J=12.9, 11.2, 5.1
Hz), 2.43 (1H, ddd, J=14.3, 10.7, 5.9 Hz), 3.67 (3H, s); 13C NMR (50 MHz, CDCl3): δ 15.3 (CH3), 18.4
(CH3), 24.4 (CH2), 28.9 (CH2), 29.1 (CH2), 30.4 (CH2), 38.1 (CH2), 38.4 (CH), 51.2 (C), 51.4 (CH3),
174.1 (C), 215.0 (C); MS m/z 212 (M+), 197, 181, 168, 153, 139, 126 (base), 111, 96, 83, 69, 55, 41;
HRMS found m/z 212.1436; calcd for C12H20O3 212.1413.
3.3. Preparation of ester 4b from (2RS,3R)-2,3-dimethylcyclohexanone 10b
The imine was similarly prepared from (2RS,3R)-2,3-dimethylcyclohexanone 10b (18.4 g, 0,15 mol),
(S)-(−)-1-phenylethylamine (23 mL, 0.17 mol), and TsOH (2 g) in benzene (200 mL), followed by
Michael addition to methyl acrylate (15.8 mL, 0.17 mol). Workup and purification as described before
22
afforded ester 4b (18.3 g, 59%, >99.5% ee); [α]D −19.1 (c 1.2, CHCl3); CD [θ]297.5nm −970 (CHCl3);
∆ε=−0.29.
3.4. Reaction of imine 3c, prepared from (2RS,3R)-2,3-dimethylcyclohexanone 10b and (R)-(+)-1-
phenylethylamine, with methyl acrylate
The imine 3c was similarly prepared from (2RS,3R)-2,3-dimethylcyclohexanone 10b (1.4 g, 11.1
mmol), (R)-(+)-1-phenylethylamine (1.5 mL, 11.1 mmol), and TsOH (140 mg) in benzene (15 mL),
followed by Michael addition to methyl acrylate (1 mL, 11.1 mmol). Workup and purification as
described before in combination of HPLC afforded ester 4c (7.1 mg, 0.3%), 12 (35 mg, 1.5%), 13 (9.4
mg, 0.4%), 14 (7.1 mg, 0.3%), and 15 (47 mg, 2%).
12; oil: [α]D20 +56.7 (c 1.04, CHCl3); CD [θ]295nm +5300 (CHCl3) ∆ε=+1.6; FT-IR 1740, 1705 cm−1;
1H NMR (600 MHz, C6D6) δ 0.70 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz), 1.10 (1H, m), 1.18 (1H,
m), 1.26 (1H, m), 1.32 (1H, m), 1.43 (1H, m), 1.50 (1H, m), 1.90 (1H, m), 1.93 (1H, m), 2.10 (1H, m),
2.11 (1H, m), 2.24 (1H, m), 3.37 (3H, s); 13C NMR (100 MHz, CDCl3): δ 13.4 (CH3), 20.4 (CH3), 26.2
(CH2), 28.7 (CH2), 29.9 (CH2), 31.9 (CH2), 40.0 (CH), 48.1 (CH), 49.1 (CH), 51.6 (CH3), 173.5 (C),
215.6 (C); MS m/z 212 (M+), 180 (base), 165, 152, 126, 111, 95, 83, 69, 55; HRMS found m/z 212.1393;
calcd for C12H20O3 212.1422.
13; oil: [α]D21 −43.5 (c 0.54, CHCl3); CD [θ]295nm −3300 (CHCl3); ∆ε=−1.0; FT-IR 1740, 1710 cm−1;
1H NMR (600 MHz, CDCl3): δ 0.92 (3H, d, J=6.9 Hz), 1.02 (3H, d, J=7.4 Hz), 1.37 (1H, ddd, J=13, 11,
4.1 Hz), 1.57 (1H, m), 1.61 (1H, m), 1.67 (1H, dq, J=13, 4.1 Hz), 2.01 (1H, m), 2.03 (1H, m), 2.05 (1H,
m), 2.32 (1H, ddd, J=15.9, 8.2, 6.8 Hz), 2.37 (1H, ddd, J=15.9, 8.5, 6.6 Hz), 2.46 (1H, m), 2.52 (1H,
ddd, J=12, 7.1, 4.9 Hz), 3.66 (3H, s); MS m/z 212 (M+), 180 (base), 165, 152, 138, 126, 111, 95, 83, 69,
55; HRMS found m/z 212.1426; calcd for C12H20O3 212.1412.
14; oil: [α]D21+6.4 (c 0.95, CHCl3); CD [θ]299nm +1100 (CHCl3); ∆ε=+0.32; FT-IR 1740, 1705 cm−1;
1H NMR (600 MHz, CDCl3) δ 1.01 (3H, d, J=6.3 Hz), 1.05 (3H, d, J=6.3 Hz), 1.34 (1H, ddd, J=13, 13,
3.7 Hz), 1.45 (1H, m), 1.50 (1H, m), 1.53 (1H, m), 1.83 (1H, dq, J=13.5, 3.3 Hz), 2.04 (1H, m), 2.06 (1H,
m), 2.08 (1H, m), 2.32 (1H, ddd, J=16, 8, 6.5 Hz), 2.35 (1H, m), 2.41 (1H, ddd, J=16, 8, 6.5 Hz), 3.66
(3H, s); 13C NMR (50 MHz, CDCl3) 11.9 (CH3), 20.8 (CH3), 24.9 (CH2), 31.8 (CH2), 33.7 (CH2),34.6
(CH2), 42.4 (CH), 49.3 (CH), 51.6 (CH3), 52.1 (CH), 173.9 (C), 213.0 (C); MS m/z 212 (M+), 180 (base),
165, 152, 138, 126, 111, 95, 83, 69, 55; HRMS found m/z 212.1412; calcd for C12H20O3 212.1412.

M. Tori et al. / Tetrahedron: Asymmetry 10 (1999) 961–971
967
21
15; oil: [α]D −91.6 (c 0.86, CHCl3); CD [θ]302nm −1700 (CHCl3); ∆ε=−0.52; FT-IR 1740, 1705
1
cm−1; H NMR (600 MHz, CDCl3) δ 0.99 (3H, d, J=6.3 Hz), 1.06 (3H, s), 1.65–1.73 (5H, m), 1.93
(1H, ddd, J=16.5, 12, 4.5 Hz), 1.99 (1H, m), 2.12 (1H, ddd, J=14, 12, 4.6 Hz), 2.22 (1H, ddd, J=16, 12,
4.6 Hz), 2.31 (1H, dt, J=14, 4.6 Hz), 2.44 (1H, ddd, J=14, 12, 6 Hz), 3.66 (3H, s); 13C NMR (50 MHz,
CDCl3) δ 15.6 (CH3), 19.3 (CH3), 25.6 (CH3), 26.9 (CH2), 28.7 (CH2), 29.1 (CH2), 38.4 (CH), 43.4
(CH), 51.6 (CH3), 51.6 (C), 174.1 (C), 215.5 (C); MS m/z 212 (M+), 197, 181, 152, 139, 126 (base), 111,
96, 83, 69, 55; HRMS found m/z 212.1390; calcd for C12H20O3 212.1412.
3.5. General procedure for preparation of pentafluorophenyl ester 11
Methyl ester 4 was treated with 10% KOH in MeOH at rt for 30 min and MeOH was then removed. The
mixture was extracted with ether and the aqueous layer was acidified with 1 M HCl to pH=1. The solution
was extracted with ether and the organic layer was dried (MgSO4) and evaporated to afford an acid. A
solution of the acid in CH2Cl2 was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide–HCl
and pentafluorophenol at rt overnight. More CH2Cl2 was added and the organic layer was washed with
1 M HCl, 1 M NaOH solution, and brine. Silica gel column chromatography afforded pentafluorophenyl
ester, which was analyzed with HPLC (Chiralcel OD-H, hexane:i-PrOH=98.5:1.5).
20
Pentafluorophenyl ester 11b; oil: [α]D −19.0 (c 0.88, CHCl3); CD [θ]302nm −190 (CHCl3);
∆ε=−0.06; FT-IR 1790, 1705 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.98 (3H, d, J=6.4 Hz), 1.09 (3H, s),
1.67 (2H, m), 1.75 (1H, m), 1.84 (1H, m), 1.89 (1H, m), 1.99 (1H, m), 2.13 (1H, ddd, J=16.1, 10.7, 5.4
Hz), 2.31 (1H, dt, J=13.7, 4.2 Hz), 2.50 (1H, m), 2.62 (1H, ddd, J=16.6, 10.6, 5.4 Hz), 2.70 (1H, ddd,
J=16.6, 10.6, 5.8 Hz); 13C NMR (50 MHz, CDCl3): δ 15.4, 18.3, 24.9, 28.6, 29.2, 29.7, 29.9, 38.2, 38.7,
51.3, 169.9, 215.1; MS (CI) m/z 365 (M+H)+, 347, 267, 181 (base), 163, 111, 99; CI-HRMS found m/z
365.1168 (M+H)+; calcd for C17H18O3F5 365.1176.
3.6. Preparation of [10S,60R]-3-(10,60-dimethyl-20-oxocyclohexyl)propanal 7
A solution of keto ester 4 (17.6 g, 83 mmol) in dry ether (500 mL) was reduced with LiAlH4 (16
g, 42 mmol) at rt for 5 h. Excess reagent was decomposed by ethyl acetate, and water (17 mL), 15%
NaOH solution (17 mL) and water (51 mL) were added, successively. After filtration, the solvent was
evaporated to give diol (18 g), which was used in the next step without purification. A solution of diol (18
g) in CH2Cl2 (600 mL) was oxidized with oxalyl chloride (24 mL, 0.28 mol) and dimethyl sulfoxide (42
mL, 0.59 mol) at −60 to −50°C for 15 min, followed by Et3N (168 mL, 1.2 mol). Usual workup afforded
a residue (21 g), which was purified by silica gel column chromatography (hexane–EtOAc, in gradient)
to give aldehyde 7 (13.8 g, 91%); oil; FT-IR 1740, 1720 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.93 (3H,
d, J=6.6 Hz), 1.04 (3H, s), 1.55–1.85 (5H, m), 1.9–2.1 (2H, m), 2.2–2.6 (4H, m), 9.78 (1H, t, J=1.6 Hz);
13C NMR (50 MHz, CDCl3) δ 15.3 (CH3), 18.6 (CH3), 24.7 (CH2), 27.3 (CH2), 29.1 (CH2), 38.2 (CH2),
38.5 (CH), 39.3 (CH2), 51.2 (C), 202.3 (CH), 215.3 (C); MS (CI) m/z 183 (M+H)+ (base), 165, 147, 137,
126, 101, 95, 85, 71, 55; CI-HRMS found m/z 183.1394 (M+H)+; calcd for C11H19O2 183.1385.
3.7. Preparation of [1S,2R,5S,6S]-1,2-dimethylbicyclo[3.3.1]nonan-6-ol-9-one 8a and [1S,2R,5S,6R]-
1,2-dimethylbicyclo[3.3.1]nonan-6-ol-9-one 8b
Aldehyde 7 (6.9 g, 38 mmol) was treated with 5% KOH in MeOH at rt for 3 days. The solvent was
evaporated and the mixture was extracted with ether. The organic layer was washed with 1 M HCl and
brine, dried (MgSO4), and evaporated to afford a residue (6.8 g). The residue was purified by silica gel

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column chromatography (hexane–EtOAc, in gradient) to give a mixture of ketol 8a and 8b (4.6 g, 1:1,
67%), a part of which was separated by HPLC (Nucleosil 50-5, hexane:EtOAc=4:1) into each isomer for
characterization; α-isomer 8a; oil; FT-IR 3400, 1710 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.91 (3H, d,
J=7.2 Hz), 0.95 (3H, s), 1.3–1.6 (2H, m), 1.9–2.2 (5H, m), 2.2–2.5 (2H, m), 2.61 (1H, t, J=5.3 Hz), 4.03
(1H, m); 13C NMR (50 MHz, CDCl3): δ 18.1 (CH3), 21.4 (CH3), 22.9 (CH2), 29.1 (CH2), 30.5 (CH2),
36.8 (CH2), 44.8 (CH), 49.0 (C), 54.5 (CH), 73.6 (CH), 219.0 (C); MS m/z 182 (M+), 167, 138, 125
(base), 109, 97, 81, 69, 55; HRMS found m/z 182.1311; calcd for C11H18O2 182.1307.
β-Isomer 8b; oil; FT-IR 3400, 1710 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.88 (3H, d, J=7.2 Hz), 0.97
(3H, s), 1.38 (1H, m), 1.6–2.2 (7H, m), 2.3–2.5 (2H, m), 4.33 (1H, br d, J=3 Hz); 13C NMR (50 MHz,
CDCl3): δ 17.4 (CH3), 21.7 (CH3), 26.4 (CH2), 27.4 (CH2), 29.6 (CH2), 37.8 (CH2), 44.9 (CH), 49.6
(C), 54.5 (CH), 77.0 (CH), 219.0 (C); MS m/z 182 (M+), 167, 149, 138, 125 (base), 109, 97, 81, 69, 55;
HRMS found m/z 182.1300; calcd for C11H18O2 182.1307.
3.8. Preparation of [1R,2S,5S,6R]-5,6-dimethyl-9-methylenebicyclo[3.3.1]nonan-2-ol 16a and [1R,2R,
5S,6R]-5,6-dimethyl-9-methylenebicyclo[3.3.1]nonan-2-ol 16b
A solution of keto alcohol 8 (87 mg, 0.48 mmol) in dry THF (15 mL) was treated with the Tebbe
reagent (0.5 M, 2.9 mL, 1.5 mmol) at rt for 4 h. Ether (50 mL) and 10% NaOH aqueous solution (2
mL) were added. The mixture was extracted with ether and the organic layer was washed with brine.
Evaporation of the solvent after drying (MgSO4) afforded a residue, which was purified by silica gel
column chromatography (hexane–EtOAc, in gradient) to give a mixture of olefin 16a and 16b (61 mg,
1
71%); oil; FT-IR 3300, 1650 cm−1; H NMR (600 MHz, CDCl3) δ 0.86 (d, J=6.8 Hz), 0.87 (d, J=6.8
Hz), 0.93 (s), 0.97 (s), 3.86 (m), 4.60 (d, J=1.8 Hz), 4.78 (d, J=1.8 Hz), 4.86 (d, J=1.8 Hz), 4.94 (d, J=1.8
Hz); MS m/z 180 (M+), 162, 147, 136, 123 (base), 105, 93, 81, 67, 55, 41; HRMS found m/z 180.1518;
calcd for C12H20O 180.1514.
3.9. Preparation of [1R,5S,6R]-5,6-dimethyl-9-methylenebicyclo[3.3.1]nonan-2-one 17
A solution of alcohol 16 (1.7 g, 9.4 mmol) in CH2Cl2 (150 mL) was oxidized with dimethyl sulfoxide
(4.7 mL, 66 mmol) and oxalyl chloride (2.5 mL, 28 mmol) at −60 to −50°C for 15 min, followed
by Et3N (20 mL, 140 mmol). Usual workup and purification by silica gel column chromatography
22
(hexane–EtOAc, in gradient) afforded ketone 17 (1.5 g, 88%); oil; [α]D +121 (c 0.78, CHCl3); CD
[θ]306nm +6870 (CHCl3); ∆ε=+2.1; FT-IR 1730, 1660 cm−1; 1H NMR (200 MHz, CHCl3) δ 0.91 (3H,
d, J=7.0 Hz), 1.23 (3H, s), 1.36 (1H, m), 1.82 (6H, m), 2.45 (2H, m), 2.99 (1H, br t, J=3.0), 4.78 (1H, d,
J=1.2 Hz), 4.94 (1H, d, J=1.2 Hz); 13C NMR (50 MHz, CDCl3) δ 15.4 (CH3), 25.8 (CH3), 27.4 (CH2),
27.8 (CH2), 35.1 (CH2), 39.4 (CH2), 39.9 (C), 42.1 (CH), 56.5 (CH), 109.0 (CH2), 149.3 (C), 216.0
(C); MS m/z 178 (M+, base), 163, 136, 123, 107, 93, 79, 67, 55; HRMS found m/z 178.1349; calcd for
C12H18O 178.1358.
3.10. Preparation of [1S,2R,5S]-6-formyl-1,2-dimethyl-9-methylenebicyclo[3.3.1]nonane 18
A solution of ketone 17 (610 mg, 3.4 mmol) in dry THF (80 mL) was treated with the ylide prepared
from methoxymethyltriphenylphosphonium chloride (9 g, 34 mmol) and n-BuLi (1.6 M, 21 mL, 34
mmol) under reflux for 5 days. Water was added and the solvent was evaporated. The mixture was
extracted with ether and the organic layer was washed with brine, dried (MgSO4), and evaporated
to afford an olefin (1.2 g). The olefin was treated with 1 M HCl in THF (40 mL) overnight. The

M. Tori et al. / Tetrahedron: Asymmetry 10 (1999) 961–971
969
mixture was extracted with ether and the organic layer was washed with sat. NaHCO3 solution and
brine, dried (MgSO4), and evaporated to give a residue. The residue was purified by silica gel column
chromatography (hexane–EtOAc, in gradient) to give aldehyde 18 (119 mg, 19%); oil; FT-IR 1720, 1640
cm−1; 1H NMR (200 MHz, CHCl3) β-isomer; δ 0.85 (3H, d, J=6.8 Hz), 0.92 (3H, s), 1.2–2.4 (8H, m),
2.45 (1H, m), 2.4 (1H, m), 2.9 (1H, br s), 4.58 (1H, d, J=1.6 Hz), 4.86 (1H, d, J=1.6 Hz), 9.58 (1H, s);
α-isomer; δ 0.85 (3H, d, J=6.8 Hz), 0.96 (3H, s), 1.2–2.4 (8H, m), 2.45 (1H, m), 2.6 (1H, m), 2.9 (1H, br
s), 4.60 (1H, d, J=1.8 Hz), 4.94 (1H, d, J=1.8 Hz), 9.73 (1H, s); MS m/z 192 (M)+, 177, 163, 149, 135,
121, 107 (base), 93, 81; HRMS found m/z 192.1532; calcd for C13H20O 192.1515.
3.11. Preparation of [1S,2R,5R,6S]-6-formyl-1,2,6-trimethyl-9-methylenebicyclo[3.3.1]nonane 9
A solution of aldehyde 18 (61 mg, 0.32 mmol) was treated with t-BuOK (175 mg, 1.6 mmol) at rt for
30 min. Then MeI (0.2 mL, 3.2 mmol) was added at 0°C and the mixture was kept for 15 min at the same
temperature. Water was added and the solvent was evaporated. The mixture was extracted with ether and
the organic layer was washed with brine, dried (MgSO4), and evaporated to afford a residue. The residue
was purified by silica gel column chromatography (hexane–EtOAc, in gradient) to give aldehyde 9 (47
mg, 71%); oil; FT-IR 1730, 1645 cm−1; 1H NMR (200 MHz, CHCl3) δ 0.84 (3H, d, J=7.2 Hz), 0.96 (3H,
s), 1.03 (3H, s), 1.25 (2H, td, J=14.8, 7.6 Hz), 1.4–1.9 (5H, m), 2.1–2.4 (2H, m), 2.53 (1H, td, J=14.4,
7.2 Hz), 4.72 (1H, d, J=1.8 Hz), 4.88 (1H, d, J=1.8 Hz), 9.49 (1H, s); 13C NMR (50 MHz, CDCl3) δ
17.5 (CH3), 21.5 (CH3), 25.7 (CH3), 26.0 (CH2), 27.6 (CH2), 29.0 (CH2), 29.9 (C), 37.6 (CH2), 40.0 (C),
40.8 (CH), 46.4 (CH), 108.1 (CH2), 150.6 (C), 206.9 (CH); MS m/z 206 (M)+, 177, 163, 149, 136, 121
(base), 107, 95, 81; HRMS found m/z 206.1674; calcd for C14H22O 206.1671.
3.12. Preparation of [1S,2R,5R,6S]-1,2,6-trimethyl-9-methylene-6-oxiranylbicyclo[3.3.1]nonane 19
A solution of trimethylsulfonium iodide (475 mg, 2.3 mmol) in DMSO (2 mL) was added into a
mixture of NaH (90 mg, 2.3 mmol), DMSO (3 mL), and THF (4 mL) at −20°C. A solution of aldehyde
9 (47 mg, 0.23 mmol) in DMSO (2 mL) was added to this solution and the mixture was kept at 0°C for
25 min. Water was added and the solvent was evaporated. The mixture was extracted with ether and the
organic layer was washed with brine, dried (MgSO4), and evaporated to afford a residue. The residue was
purified by silica gel column chromatography (hexane–EtOAc, in gradient) to give a mixture of epoxides
19 (47 mg, 94%), which was further separated by HPLC to afford 19a (16.6 mg, 33%) and 19b (5.4
mg, 11%); 19a; oil; [α]D19+3.1 (c 1.7, CHCl3); FT-IR 1640 cm−1; 1H NMR (200 MHz, CHCl3) δ 0.85
(3H, s), 0.87 (3H, d, J=6.8 Hz), 0.94 (3H, s), 1.1–1.3 (2H, m), 1.5–1.8 (4H, m), 1.9–2.1 (3H, m), 2.23
(1H, m), 2.73 (1H, dd, J=4.0, 4.0 Hz), 2.81 (1H, dd, J=4.0, 3.0 Hz), 2.90 (1H, dd, J=4.0, 3.0 Hz), 4.63
(1H, d, J=1.8 Hz), 4.80 (1H, d, J=1.8 Hz); 13C NMR (50 MHz, CDCl3) δ 17.8 (CH3), 22.3 (CH3), 25.2
(CH2), 25.8 (CH3), 29.7 (CH2×2), 38.1 (CH2), 38.3 (C), 40.0 (C), 41.0 (CH), 44.8 (CH2), 48.8 (CH),
59.1 (CH), 106.8 (CH2), 152.6 (C); MS m/z 220 (M)+, 189, 175, 161, 147, 133, 119, 107 (base), 93, 81,
67, 55; HRMS found m/z 220.1836; calcd for C15H24O 220.1827.
19
1
19b; oil; [α]D −21 (c 0.54, CHCl3); FT-IR 1640 cm−1; H NMR (200 MHz, CHCl3) δ 0.85 (3H,
d, J=6.8 Hz), 0.87 (3H, s), 0.93 (3H, s), 1.21 (1H, m), 1.5–1.9 (4H, m), 1.9–2.4 (5H, m), 2.47 (1H, dd,
J=4.0, 3.0 Hz), 2.59 (1H, dd, J=4.0, 4.0 Hz), 2.80 (1H, dd, J=4.0, 3.0 Hz), 4.61 (1H, d, J=1.8 Hz), 4.78
(1H, d, J=1.8 Hz); MS m/z 220 (M+), 205, 189, 175, 161, 133, 119, 105 (base), 93, 81, 67; HRMS found
m/z 220.1809; calcd for C15H24O 220.1827.

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M. Tori et al. / Tetrahedron: Asymmetry 10 (1999) 961–971
3.13. Preparation of trifarienols A 1 and B 2
Epoxide 19a (16.6 mg, 0.076 mmol) was treated with 70% HClO4 (13 mL) in THF:H2O (3:2, 5
mL) at rt for 4 h. The mixture was extracted with ether and the organic layer was washed with brine,
dried (MgSO4), and evaporated to afford a residue. The residue was purified by silica gel column
chromatography (hexane–EtOAc, in gradient) to give trifarienol A (1) (11.4 mg, 63%); mp 82–82.5°C
(from hexane) [lit.4 59–60°C]; [α]D +15 (c 0.57, CHCl3) [lit.4 +10.2 (c 0.63, CHCl3]; FT-IR 3400,
20
1
1640 cm−1; H NMR (200 MHz, CHCl3) δ 0.85 (3H, s), 0.86 (3H, d, J=6.8 Hz), 0.92 (3H, s), 1.1–1.3
(2H, m), 1.5–1.8 (4H, m), 1.8–2.0 (3H, m), 2.1–2.3 (3H, m), 3.55 (1H, dd, J=10.6, 9.4 Hz), 3.73 (1H,
dd, J=10.6, 2.6 Hz), 3.81 (1H, dd, J=9.6, 2.6 Hz), 4.63 (1H, d, J=1.8 Hz), 4.80 (1H, d, J=1.8 Hz); 13
C
NMR (50 MHz, CDCl3) δ 17.7 (CH3), 19.2 (CH3), 24.6 (CH2), 25.9 (CH3), 29.7 (CH2), 32.7 (CH2),
38.5 (CH2), 39.8 (C), 40.7 (C), 41.0 (CH), 47.0 (CH), 63.5 (CH2), 76.8 (CH), 107.0 (CH2), 152.7 (C);
MS m/z 238 (M+), 220, 207, 189, 177 (base), 161, 136, 123, 107, 95, 81, 69; HRMS found m/z 238.1927;
calcd for C15H24O 238.1933.
Epoxide 19b (5.4 mg, 0.024 mmol) was similarly treated with 70% HClO4 (1.2 mL) in THF:H2O
(3:2, 5 mL) at rt for 7 h to afford trifarienol B (2) (2.9 mg, 50%); mp. 108–109.5°C (from hexane) [lit.4
21
1
105–105.5°C]; [α]D −3.5 (c 1.01, CHCl3) [lit.4 −3.6 (c 1.62, CHCl3)]; FT-IR 3400, 1640 cm−1; H
NMR (200 MHz, CHCl3) δ 0.82 (3H, s), 0.85 (3H, d, J=7.0 Hz), 0.93 (3H, s), 1.2–1.3 (2H, m), 1.5–1.8
(4H, m), 1.8–2.1 (3H, m), 2.2–2.4 (3H, m), 3.51 (1H, dd, J=11, 9.8 Hz), 3.73 (1H, dd, J=11, 2.8 Hz), 3.82
(1H, dd, J=9.8, 2.8 Hz), 4.60 (1H, d, J=1.8 Hz), 4.76 (1H, d, J=1.8 Hz); 13C NMR (50 MHz, CDCl3)
δ 17.7 (CH3), 19.0 (CH3), 24.5 (CH2), 25.9 (CH3), 29.5 (CH2), 33.6 (CH2), 38.3 (CH2), 39.7 (C), 40.9
(CH, C), 48.2 (CH), 62.1 (CH2), 78.4 (CH), 106.7 (CH2), 152.7 (C); MS m/z 238 (M+), 220, 207, 189,
177 (base), 161, 136, 123, 107, 95, 81, 69; HRMS found m/z 238.1913; calcd for C15H26O 238.1933.
3.14. Preparation of unsaturated ester 20
A solution of ketone 17 (65 mg, 0.37 mmol) in dry PhH (30 mL) was treated with trimethylphospho-
noacetate (0.1 mL, 0.61 mmol) and sodium hydride (35 mg, 0.88 mmol) and the mixture was refluxed for
5 days. Water was added and the mixture was extracted with ether and the organic layer was washed with
brine, dried (MgSO4), and evaporated to afford a residue. The residue was purified by silica gel column
chromatography (hexane–EtOAc, in gradient) to give a mixture of (E)- and (Z)-ester 20 (42 mg, 48%)
(E:Z=81:19),7 a part of which was further separated by HPLC (hexane:EtOAc, 99:1) to afford (E)-20
(8.2 mg) and (Z)-20 (3.5 mg); (E)-20; FT-IR 1720, 1640 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.87 (3H,
d, J=7.0 Hz), 1.00 (3H, s), 1.3 (1H, m), 1.5–1.7 (2H, m), 1.7–2.2 (4H, m), 3.0–3.2 (3H, m), 3.67 (3H, s),
4.61(1H, d, J=1.4 Hz), 4.88 (1H, d, J=1.4 Hz), 5.66 (1H, br q, 1.5 Hz); MS m/z 234 (M+, base), 219, 203,
175, 159, 145, 133, 119, 105, 91; HRMS found m/z 234.1631; calcd for C15H22O2 234.1620. (Z)-20;
FT-IR 1720, 1640 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.87 (3H, d, J=7.0 Hz), 1.02 (3H, s), 1.28 (1H,
m), 1.5–1.8 (2H, m), 1.8–2.1 (4H, m), 2.2–2.6 (2H, m), 3.68 (3H, s), 4.27 (1H, m), 4.63 (1H, d, J=1.8
Hz), 4.96 (1H, d, J=1.8 Hz), 5.64 (1H, br q, J=1.4 Hz); MS m/z 234 (M+, base), 219, 202, 187, 175, 159,
145, 133, 119, 105, 91; HRMS found m/z 234.1604; calcd for C15H22O2 234.1620.
Acknowledgements
We thank Professor Yoshinori Asakawa and Dr. Toshihiro Hashimoto (Tokushima Bunri University)
for providing us with the 1H and 13C NMR spectra of natural trifarienols A and B and helpful comments.

M. Tori et al. / Tetrahedron: Asymmetry 10 (1999) 961–971
971
We also thank Professor C. Forsyth, University of Minnesota, for sending us the 1H and 13C NMR spectra
of compound 20. The 600 MHz NMR and MS spectra were taken by Dr. M. Tanaka and Miss Y. Okamoto
(Tokushima Bunri University), respectively, to whom many thanks are due. Donation of (R)-(+)-pulegone
from Mr. Haruyasu Shiota, Shiono Koryo Kaisha Ltd, is gratefully acknowledged.
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10. The conformation 4(F) is favored to 4(D).
11. Because 10a is racemic, there are two diastereoisomers in imine 3a. Only one half of 3a could yield 4a, while the other
half remains unattached (Fig. 2).
Figure 2.
12. Tori, M.; Uchida, N.; Sumida, A.; Furuta, H.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1 1995, 1513–1517.
13. Conditions for HPLC: Chiralcel OD-H (4.6 mm×250 mm), hexane:iPrOH=98.5:1.5, 1 mL/min.
14. Unpublished results: we have succeeded in determination of ees of several 2,2-disubstituted cyclohexanones and
cyclopentanones by this methodology. Although we have reported that the ees of cyclopentanone derivatives were directly
determined by chiral HPLC in Stereochemistry Abstracts in Ref. 3, this should be corresponding pentafluorophenyl esters.
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18. The melting point of the synthetic sample was ca. 20° higher than that of the natural one. This is presumably due to the
fact that the natural sample includes the water in its crystal, which was indicated by the X-ray crystallography (see Ref. 4)
although both crystals were made from hexane (private communication with Dr. T. Hashimoto).