Total synthesis and absolute configuration of riccardiphenols A and B, isolated from the Liverwort Riccardia crassa

Article abstract of DOI:10.1021/jo952253u

The title compounds were synthesized as optically active forms using chiral Michael addition of the imine, prepared from 2-methylcyclohexanone and (S)-(-)-phenylethylamine, to methyl propiolate. The etherification of the intermediate triol was accomplished by TsOH-catalyzed cyclization. The absolute configurations of the natural products, riccardiphenols A and B, were established as 1 and 2, respectively.

Full text of DOI:10.1021/jo952253u

5362
J . Org. Chem. 1996, 61, 5362-5370
Tota l Syn th esis a n d Absolu te Con figu r a tion of Ricca r d ip h en ols A
a n d B, Isola ted fr om th e Liver w or t Ricca r d ia cr a ssa
Motoo Tori,* Tomonobu Hamaguchi, Kumiko Sagawa, Masakazu Sono, and
Yoshinori Asakawa
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770, J apan
Received December 22, 1995X
The title compounds were synthesized as optically active forms using chiral Michael addition of
the imine, prepared from 2-methylcyclohexanone and (S)-(-)-phenylethylamine, to methyl propi-
olate. The etherification of the intermediate triol was accomplished by TsOH-catalyzed cyclization.
The absolute configurations of the natural products, riccardiphenols A and B, were established as
1 and 2, respectively.
In tr od u ction
Riccardiphenols A (1) and B (2) were isolated from the
liverwort Riccardia crassa by Toyota and Asakawa1 and
have a seco-eudesmane skeleton connected to a phenol,
which is rare in nature.2 Similar examples have recently
been isolated from another liverwort.3 Wu and co-
workers reported the isolation of tridensone (3)4 and
tridensenal (4),5 which were thought to have seco-
eremophilane and seco-eudesmane skeletons, respectively
(Scheme 1). On the other hand, terpenoids having a
benzylic substituent are well precedented.6 We are
interested in the absolute configuration of terpenoids
isolated from liverworts2 and have reported several
synthetic studies concerning the absolute configuration.7
Now we report the details of a total synthesis of riccar-
diphenols A (1) and B (2) and their absolute configura-
tion.
Resu lts a n d Discu ssion
Syn th esis of Ar om a tic P a r t. When gentisic acid (5)
was treated with diazomethane, a mixture of the mono-
methyl ether methyl ester (two positional isomers) and
a permethylated compound were produced. The reaction
of 5 with methyl iodide in the presence of potassium
carbonate afforded the permethylated compound. Thus
methyl gentisate (6) was treated with dihydropyran to
give a mono-protected ester 7 in excellent yield (Scheme
2). The ortho phenolic hydroxyl group was protected with
a MOM group, followed by deprotection of the THP group
and treatment with MeI and K2CO3 to afford the desired
ester 9. Reduction of 9 with LiAlH4 and chlorination with
PPh3 and CCl4 gave chloride 10. If the corresponding
alcohol was treated with PPh3 and CBr4, the reaction was
messy, presumably due to the instability of the bromide.
In order to synthesize riccardiphenol A (1), a bis-MOM-
protected chloride 12, prepared by a route analogous to
that of 10, was used for the sake of convenience of
deprotection.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) Toyota, M.; Asakawa, Y. Phytochemistry 1993, 32, 137-140.
(2) (a) Asakawa, Y. Progress in the Chemistry of Organic Natural
Products; Herz, W., Grisebach, H., and Kirby, G. W., Ed.; Springer-
Verlag: Wien, 1982; Vol. 42, pp 1-285. (b) Asakawa, Y. Bryophytes:
Their Chemistry and Chemical Taxonomy; Zinsmeister, H. D., Mues,
R., Ed.; Oxford University Press: Oxford, 1990; pp 369-410. (c)
Asakawa, Y. Bioactive Natural Products: Detection, Isolation and
Structural Determination; Colegate, S. M., Molyneux, R. J ., Ed.; CRC
Press: Boca Raton, Florida, 1993; pp 319-347.
(3) Perry, N. B.; Foster, L. M. J . Nat. Prod. 1995, 58, 1131-1135.
(4) Wu, C.-L.; Chen, C.-L. Phytochemistry 1992, 31, 4213-4217.
(5) (a) Wu, C.-L. Bryophytes: Their Chemistry and Chemical Tax-
onomy; Zinsmeister, H. D., Mues, R., Ed.; Oxford University Press:
Oxford, 1990; pp 71-82. (b) Wu, C.-L.; Chang, S.-J .; Tori, M.; Furuta,
H.; Sumida, A.; Asakawa, Y. J . Chin. Chem. Soc. 1990, 37, 387-391.
(6) (a) Gerwick, W. H.; Fenical, W. J . Org. Chem. 1981, 46, 22-27.
(b) Muhammad, I.; Waterman, P. G. J . Nat. Prod. 1988, 51, 719-724.
(c) Talpir, R.; Rudi, A.; Kashman, Y.; Loya, Y.; Hizi, A. Tetrahedron
1994, 50, 4179-4184. (d) Sanchez-Ferrando, F.; San-Martin, A. J . Org.
Chem. 1995, 60, 1475-1478.
P r ep a r a tion of th e Op tica lly Active Keton es 20
a n d 21. Pfau et al. reported a highly practical method
for constructing the quaternary center using a chiral
phenylethylamine.8 For example, the imine of 2-meth-
ylcyclohexanone of (S)-(-)-phenylethylamine 13 was
reacted with methyl acrylate without any solvent at rt
for 5 days. A slow Michael reaction proceeded to yield a
keto ester 14, after acid hydrolysis of the imine (Scheme
3). The chemical yield and %ee were generally good. We
explored this type of reaction using methyl propiolate as
(7) (a) Tori, M.; Kosaka, K.; Asakawa, Y. J . Chem. Soc., Perkin
Trans. 1 1994, 2039-2041. (b) Tori, M.; Uchida, N.; Sumida, A.;
Furuta, H.; Asakawa, Y. J . Chem. Soc., Perkin Trans 1 1995, 1513-
1517.
(8) Pfau, M.; Revial, G.; Guingant, A.; D’Angelo, J . J . Am. Chem.
Soc. 1985, 107, 273-274.
S0022-3263(95)02253-5 CCC: $12.00 © 1996 American Chemical Society

Riccardiphenols A and B
Sch em e 1
J . Org. Chem., Vol. 61, No. 16, 1996 5363
ketone 19. The methylation was accomplished using
LDA/MeI to yield the cis-20 and trans-ketone 21. The
ratio of these ketones was almost 1:1, but separation was
easily carried out by HPLC. The assignment of the
stereochemistry was realized using the NOESY spectra.
Because the two substituents at the 2 and 6 positions of
these ketones adopt equatorial positions due to 1,3-
diaxial repulsion, the two methyl groups of ketone 20 are
in equatorial positions, and the diene chain is in an axial
position. Thus, in the case of ketone 20, the NOE
between the olefinic proton at C-1′ and the R axial proton
at C-4 and between the methine proton at C-6 and the R
axial proton at C-4 was observed. For ketone 21, the
NOE between the tertiary methyl group and the methine
proton at C-6 was observed. These conformations of
ketones 20 and 21 also influence the stereochemistry of
the subsequent Grignard reactions.
Tota l Syn th esis. The Grignard reagent derived from
chloride 10 attacked the ketone 20 to give the equatorial
alcohol 22 predominantly (Scheme 4). It was deduced
from the NOESY spectrum of adduct 22 that both the
benzyl group and the side chain adopted axial positions.
NOEs between the olefinic proton at C-7 and the methine
proton at C-4, between the benzylic proton and the
secondary methyl group, and between the tertiary methyl
group and the benzylic proton were observed. The ratio
of 22 and 23 was 4:1 according to GC. However, the
minor axial alcohol 23 was not isolated pure by chro-
matographic separation. In the case of the trans methy-
lated ketone 21, the equatorial alcohol 26 was the major
and 27 was the minor product; the ratio of 26:27 was
96:4. The structure of 26 was established by NOESY as
well. However, the minor alcohol 27 could not be isolated
pure by chromatographic separation.
Sch em e 2
We next used bis-MOM chloride 12 for the Grignard
reaction with ketones 20 and 21. The major product of
these reactions were the adducts 24 and 28, both being
the equatorial alcohols (Scheme 4). The minor com-
pounds were isolated pure after hydrolysis of the MOM
groups in each case. The protecting groups of 24, 25, 28,
and 29 were cleaved by treatment with hydrochloric acid
in THF to give triols 30, 31, 32, and 33, respectively.
The triol 31 was treated with TsOH10 in PhH at 65 °C
for 5 h to afford riccardiphenol A (1), as well as the
diastereoisomers 34 and 35 (Scheme 5); unfortunately,
the yield of 1 was very poor. The spectral data (1H and
13C NMR, IR, and MS) of 1 were identical with those of
the natural product.1 The specific rotation of the syn-
thetic product was [R]21 + 107.6° (c 0.7, CHCl3), while
D
the literature value was [R]D + 143° (c 0.51, CHCl3). The
difference is attributable to the 80% ee obtained in the
chiral Michael addition reaction. Thus the absolute
configuration of riccardiphenol A was established as
depicted in formula 1. The structure of the major
compound was assigned as 34 by careful analysis of the
NOESY spectrum. The benzylic protons at C-15 had
NOEs relative to the proton at C-4 and the olefinic proton
at C-7, which indicated that the benzylic protons were
in the equatorial and hence â-position. The fact that the
major compound was the diastereoisomer of riccardiphe-
nol A (1) is attributed to the same reason why the major
one for the Grignard reaction was produced by an attack
from the opposite side of the axially oriented substituent.
The cationic center at C-6 produced by abstraction of the
hydroxyl group was attacked by a phenolic hydroxyl
group at C-2′ from the opposite side of the axially oriented
side chain. The third product was isolated from the
a Michael acceptor because our synthetic targets have
diene units in their side chains. Thus the reaction of the
imine 13 with methyl propiolate proceeded smoothly to
give an R,â-unsaturated ester 159 in 79% yield and with
80% ee after hydrolysis. The absolute configuration of
the product 15 was established by hydrogenation of the
double bond into the known ester 14.8 Keto ester 14
could also be converted into an R,â-unsaturated ester 16.9
Ketalization of 15 to 16 was followed by LiAlH4
reduction, Swern oxidation, and the Wittig olefination
(Ph3P+CH(CH3)2I-, nBuLi) to afford diene 18. The ketal
group was removed (TsOH, aqueous acetone) to yield a
(9) Takemoto, T.; Fukaya, C.; Yokoyama, K. Tetrahedron Lett. 1989,
30, 723-724.

5364 J . Org. Chem., Vol. 61, No. 16, 1996
Tori et al.
Sch em e 3
Sch em e 4
by treatment with TsOH in PhH (Scheme 6). This
mixture could not be separated by acetylation to 37a . The
structure 37a was established by examination of the 2D
NMR spectra including HMQC, HMBC, COSY, and
NOESY spectra. Namely, it had eight sets of sp2 carbons
(6 aromatic and one double bond) and four oxygen-
bearing carbons (two sp3 and two sp2). Moreover, there
were two sets of olefinic methyl groups (δ 1.58, 1.58, 1.64,
1.64). These data indicate that the tertiary hydroxyl
group at C-5 was not abstracted, but that one double bond
reacted under the acidic conditions. The methine proton
2
at C-8 attached to the oxygen atom had the J and 3J
correlations to the olefinic carbons and also to the
quaternary center at C-6 in the HMBC spectrum. This
means that the cyclization occurred not at C-5 but at C-8
to form an eight-membered ring. Because the hydroxyl
group at C-5 was equatorial, the abstraction by proto-
nation was rather hindered or very slow, but instead
protonation at C-7 occurred followed by an attack of the
C-2′ phenolic hydroxyl group. The C-5′ hydroxyl group
did not react because of the steric nature. However, the
minor product 33, derived from 29, afforded a single
product 38. The structure was easily deduced from the
NMR spectrum. The presence of the secondary methyl
group as well as the tertiary methyl group and the diene
system was easily detected in the NMR spectrum. The
benzylic protons appeared as an AB pattern. The ster-
eochemistry was established from the NOESY spectrum.
The phenolic hydroxyl group at C-2′ attacked the cationic
center at C-5 from the side opposite to the axially oriented
tertiary methyl group.
mixture by acetylation with Ac2O in Py. The structure
of 35a was assigned by careful examination of the
NOESY spectrum. Even if the lifetime of the cation was
long enough to rearrange, the hydrogen could not be in
the R position at C-4. The reason why compound 35 was
produced is not yet clear.
When triol 30, which was derived from the major
adduct 24, was subjected to similar cyclization conditions,
the product was not a spiro compound nor a benzopyran
derivative (Scheme 5). The product was a mixture of two
inseparable compounds in the ratio of 1:1. They could
Riccardiphenol B (2) could be derived from either 22,
23, 26, or 27 by dehydration of the tertiary hydroxyl
group. The major product 26 was treated with thionyl
chloride in pyridine to yield 39 (Scheme 7). Deprotection
of the MOM group afforded riccardiphenol B (2), whose
1H and 13C NMR spectra as well as the IR and MS spectra
were identical with those of the natural product.1 The
1
not be separated after acetylation. The H NMR spec-
trum of 36a showed the presence of two sets of olefinic
methyl groups (δ 1.58, 1.58, 1.68, 1.69) for each isomer.
The structure having an eight-membered ring was re-
vealed after the analogous compound 37a was isolated
from the reaction of 32 with TsOH and was fully analyzed
by the 2D NMR method (vide infra).
specific rotation of the synthetic material was [R]21
D
-59.4° (c 1.1, CHCl3) [lit.1 -72° (c 0.73 (CHCl3)]. The
discrepancy can again be ascribed to the % ee obtained
in the initial Michael addition of the chiral imine. The
In the case of the major adduct 28, the corresponding
triol 32 afforded a mixture of inseparable compounds 37

Riccardiphenols A and B
J . Org. Chem., Vol. 61, No. 16, 1996 5365
Sch em e 5
Sch em e 6
F igu r e 1. The NOEs detected for compound 41.
bis-MOM ether 28 was also dehydrated followed by
deprotection to yield the diol 40. Acid-catalyzed cycliza-
tion of this compound 40 unexpectedly afforded the
tetracyclic compound 41 as a single product.10 The
structure was deduced by 2D NMR. There were no
olefins except for the one at C-4 and C-5. The gem-
dimethyl groups were deshielded (1.20 and 1.35 ppm) due
to the attachment of the electron-withdrawing substitu-
ent. The methine proton at 2.90 ppm had 2J and 3J
correlation peaks to quaternary carbon centers at C-6 and
C-10 as well as one of the aromatic carbon at C-6′.
Furthermore the NOEs as shown in Figure 1 were
detected. Therefore, the structure of 41 was established
as formulated. This presumably arose by protonation at
C-7 followed by an attack of the hydroxyl group at C-5′
on the resulting cationic center at C-10 by rearrangement
of the double bond. Finally, the Friedel-Crafts type
cyclization occurred to form the C-C bond between C-6′
and C-8. Because there is a double bond between C-4
and C-5, the hydroxyl group at C-2′ cannot attack the
cationic center at C-10 due to steric hindrance.
the steric nature of the tertiary hydroxyl groups present.
The diol 40 reacted much differently to give the tetra-
cyclic phenol 41.
Exp er im en ta l Section
Gen er al. For the measurement of %ee a DAICEL CHIRAL-
CEL OB-H (4.6 × 20 cm) column was used in the HPLC
system. Silica gel 60 (70-230 mesh, Merck) was used for
column chromatography and silica gel 60F254 plates (0.25, 0.5,
1.0 mm, Merck) were used for TLC.
Meth yl 2-Hyd r oxy-5-(tetr a h yd r op yr a n yloxy)ben zoa te
(7). A solution of methyl gentisate (6) (26.7 g, 0.16 mol) in
CH2Cl2 (400 mL) was treated with dihydropyran (24.0 mL, 0.26
mol) and PPTS (2.7 g) at rt overnight. Water was added, and
the mixture was extracted with CH2Cl2. The organic phase
was washed with water, saturated NaHCO3, and brine, dried
(MgSO4), and evaporated to give pale yellow crystalline ether
In conclusion, we have completed the total synthesis
of riccardiphenols A (1) and B (2) from the chiral Michael
addition product 15 by combination of a Grignard reac-
tion and an acid-catalyzed cyclization reaction of the
corresponding triol. The absolute configurations of these
natural products were established as formulated by 1 and
2. The reactivity for the four kinds of the Grignard
adducts, 30, 31, 32, and 33, were very different due to
1
7 (39.9 g, 99%): FTIR 3220, 1700, 1630, 1500 cm-1; H NMR
(200 MHz, CDCl3) δ 1.5-2.1 (6 H, m), 3.5-3.9 (2 H, m), 3.94
(3 H, s), 5.3-5.4 (1 H, m), 6.91 (1 H, d, J ) 9.0 Hz), 7.20 (1 H,
dd, J ) 9.0, 3.0 Hz), 7.52 (1 H, d, J ) 3.0 Hz); 13C NMR (50
MHz, CDCl3) δ 18.7 (t), 25.2 (t), 30.3 (t), 52.3 (q), 61.9 (t), 97.2
(d), 112.0 (s), 116.3 (d), 118.2 (d), 125.9 (d), 149.2 (s), 156.6
(s), 170.3 (s); MS (EI) m/z 252 (M+), 221, 194, 169, 168, 137
(base), 136, 108, 85; EI-HRMS m/z calcd for C13H16O5: 252.0998.
Found: 252.1005.
(10) (a) Fish, P. V.; Pattenden, G. Tetrahedron Lett. 1988, 31, 3857-
3860. (b) Begley, M. J .; Fish, P. V.; Pattenden, G. J . Chem. Soc., Perkin
Trans. 1 1990, 2263-2271.

5366 J . Org. Chem., Vol. 61, No. 16, 1996
Tori et al.
Sch em e 7
Meth yl 5-Hyd r oxy-2-(m eth oxym eth yloxy)ben zoa te (8).
A suspension of THP ether 7 (49.9 g, 0.20 mol) and NaH (15.8
g, 0.40 mol) in dry THF (600 mL) was stirred for 1 h.
Chloromethyl methyl ether (30 mL, 0.40 mol) was added to
the mixture, and the reaction was stirred for 6 h at rt. Water
and saturated NH4Cl were added to adjust the pH to 7.0, and
the solvent was evaporated. The residue was extracted with
ether, and the organic phase was washed with water and brine.
The ether layer was dried (MgSO4) and evaporated to afford
the MOM ether (57.4 g, 98%) as a brown oil: 1H NMR (200
MHz, CDCl3) δ 1.4-2.1 (6 H, m), 3.52 (3 H, s), 3.89 (3 H, s),
5.15 (2 H, s), 6.94 (1 H, dd, J ) 9.0, 3.0 Hz), 7.07 (1 H, d, J )
9.0 Hz), 7.30 (1 H, d, J ) 3.0 Hz); 13C NMR (50 MHz, CDCl3):
δ 20.2 (t), 25.1 (t), 31.9 (t), 52.3 (q), 56.3 (q), 63.9 (t), 94.5 (d),
96.3 (t), 117.6 (d), 119.3 (d), 120.6 (d), 122.0 (s), 150.5 (s), 150.7
(s), 166.7 (s).
A solution of the MOM ether (57.4 g, 0.19 mol) in MeOH
(400 mL) was treated with PPTS (5.9 g) overnight at rt. Water
was added, and the solvent was evaporated to afford a residue,
which was extracted with ether. The organic phase was
washed with water and brine, dried (MgSO4), and evaporated.
The residue was purified by silica gel column chromatography
(elution with hexane-EtOAc in gradient) to give alcohol 8 (24.1
g, 57% from 7) as an oil: FTIR 3400, 1710, 1500 cm-1; 1H NMR
(200 MHz, CDCl3) δ 3.50 (3 H, s), 3.89 (3 H, s), 5.15 (2 H, s),
6.40 (1 H, br s), 6.95 (1 H, dd, J ) 9.0, 3.0 Hz), 7.07 (1 H, d, J
) 9.0 Hz), 7.30 (1 H, d, J ) 3.0 Hz); 13C NMR (50 MHz, CDCl3)
δ 52.3 (q), 56.3 (q), 96.3 (t), 117.6 (d), 119.2 (d), 120.7 (d), 122.0
(s), 150.6 (s), 150.8 (s), 166.8 (s); MS (EI) m/z 212 (M+), 182,
165, 151, 136, 121, 108, 93, 83, 75, 45 (base); EI-HRMS m/z
calcd for C10H12O5: 212.0684. Found: 212.0705.
stirred for 3 h. EtOAc (30 mL) was slowly added followed
successively by water (3.5 mL), 15% aqueous NaOH solution
(3.5 mL), and water (10.0 mL). The mixture was filtered, and
the solvent was evaporated to give the alcohol (9.0 g, quant):
1
FTIR: 3440, 1600, 1510 cm-1; H NMR (200 MHz, CDCl3) δ
3.48 (3 H, s), 3.78 (3 H, s), 4.70 (2 H, br d, J ) 4.5 Hz), 5.14 (2
H, s), 6.76 (1 H, dd, J ) 9.0, 3.0 Hz), 6.91 (1 H, d, J ) 3.0 Hz),
7.02 (1 H, d, J ) 9.0 Hz); 13C NMR (50 MHz, CDCl3) δ 55.6
(q), 56.2 (q), 61.6 (t), 95.6 (t), 113.5 (d), 114.3 (d), 116.0 (d),
131.5 (s), 149.0 (s), 154.7 (s); MS (EI) m/z 198 (M+), 166, 152,
136 (base), 125, 108, 93, 85, 77; EI-HRMS m/z calcd for
C10H14O4: 198.0892. Found: 198.0895.
A mixture of the alcohol (10.6 g, 53.6 mmol), CCl4 (64.0 mL,
0.66 mol), Ph3P (27.0 g, 0.10 mol), and CH3CN (56 mL) was
stirred at rt under Ar in the dark. The solvent was evaporated,
and the residue was separated by silica gel column chroma-
tography (elution with hexane-EtOAc in gradient) to give
chloride 10 (8.42 g, 73%); FTIR 1600, 1510 cm-1; 1H NMR (200
MHz, CDCl3) δ 3.50 (3 H, s), 3.77 (3 H, s), 4.64 (2 H, s), 5.18
(2 H, s), 6.81 (1 H, dd, J ) 9.0, 3.0 Hz), 6.93 (1 H, d, J ) 3.0
Hz), 7.05 (1 H, d, J ) 9.0 Hz); 13C NMR (50 MHz, CDCl3) δ
41.5 (t), 55.7 (q), 56.1 (q), 95.2 (t), 115.0 (d), 115.8 (d), 116.1
(d), 127.7 (s), 149.0 (s), 154.4 (s); MS (EI) m/z 218, 216 (M+),
187, 171, 151, 136 (base), 121, 108, 91, 83; EI-HRMS m/z calcd
for C10H13O3Cl: 216.0553. Found: 216.0554.
Meth yl 2,5-Bis(m eth oxym eth yloxy)ben zoa te (11).
A
solution of methyl gentisate (6) (27.3 g, 0.16 mol) in dry THF
(50 mL) was added into a suspension of NaH (19.5 g, 0.81 mol)
in dry THF (500 mL) and was stirred for 1 h. Chloromethyl
methyl ether (38.5 mL, 0.51 mol) was added, and the mixture
was stirred for 5 h at rt under Ar. Water and saturated NH4-
Cl was added to adjust the pH to ∼7. The solvent was
evaporated, and the residue was extracted with ether. The
organic phase was washed with water and brine, dried
(MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (elution with hexane-EtOAc in
gradient) to give bis-MOM ether 11 (55.8 g, quant): FTIR
Meth yl 5-Meth oxy-2-(m eth oxym eth yloxy)ben zoa te (9).
A suspension of alcohol 8 (21.7 g, 0.10 mol), MeI (68 mL, 1.1
mol), and K2CO3 (42 g, 0.30 mol) in acetone (350 mL) was
heated under reflux overnight. The precipitates were filtered
off, and the solvent was evaporated. The residue was extracted
with ether, and the organic phase was washed with water and
brine, dried (MgSO4), and evaporated. The residue was
purified by silica gel column chromatography (elution with
hexane-EtOAc in gradient) to give methyl ether 9 (21.5 g,
1
1740, 1500, 1410 cm-1; H NMR (200 MHz, CDCl3) δ 3.47 (3
H, s), 3.52 (3 H, s), 3.89 (3 H, s), 5.14 (2 H, s), 5.18 (2 H, s),
7.13 (2 H, d, J ) 2.0 Hz), 7.46 (1 H, t, J ) 2.0 Hz); 13C NMR
(50 MHz, CDCl3) δ 52.1 (q), 55.9 (q), 56.2 (q), 94.9 (t), 96.1 (t),
118.7 (d), 118.7 (d), 121.5 (d), 122.4 (s), 151.6 (s), 151.7 (s),
166.1 (s); MS (EI) m/z 256 (M+), 225, 196, 181, 180, 165, 150,
45 (base); EI-HRMS m/z calcd for C12H16O6: 256.0946.
Found: 256.0948.
1
92%) as an oil: FTIR 1750, 1620, 1600, 1510 cm-1; H NMR
(200 MHz, CDCl3) δ 3.53 (3 H, s), 3.80 (3 H, s), 3.90 (3 H, s),
5.17 (2 H, s), 6.99 (1 H, dd, J ) 9.0, 3.0 Hz), 7.13 (1 H, d, J )
9.0 Hz), 7.30 (1 H, d, J ) 3.0 Hz); 13C NMR (50 MHz, CDCl3)
δ 52.1 (q), 55.7 (q), 56.2 (q), 96.4 (t), 115.4 (d), 119.2 (d), 119.4
(d), 122.4 (s), 150.8 (s), 154.2 (s), 166.4 (s); MS (EI) m/z 226
(M+), 196, 181, 165, 150, 135, 122, 107, 92, 79, 75, 45 (base);
EI-HRMS m/z calcd for C11H14O5: 226.0841. Found: 226.0847.
5-Meth oxy-2-(m eth oxym eth yloxy)ben zyl Ch lor ide (10).
A solution of the ether 9 (10.0 g, 44.3 mmol) in dry ether (50
mL) was slowly added into a suspension of LiAlH4 (3.56 g, 93.8
mmol) in dry ether (25 mL), and the mixture was further
2,5-Bis(m eth oxym eth yloxy)ben zyl Ch lor id e (12).
A
solution of ester 11 (13.5 g, 44.3 mmol) in dry ether (100 mL)
was slowly added into a suspension of LiAlH4 (4.0 g, 0.11 mol)
in dry ether (300 mL) and was stirred for 4 h. EtOAc was
added followed in order by water (4 mL), 15% aqueous NaOH
(4 mL), and water (12.0 mL). Evaporation after filtration gave
the alcohol (10.2 g, quant): FTIR 3450, 1600, 1500, 1460 cm-1
;

Riccardiphenols A and B
J . Org. Chem., Vol. 61, No. 16, 1996 5367
1H NMR (200 MHz, CDCl3) δ 2.28 (1 H, br s), 3.46 (3 H, s),
3.48 (3 H, s), 4.66 (2 H, s), 5.11 (2 H, s), 5.16 (2 H, s), 6.91 (1
H, dd, J ) 9.0, 3.0 Hz), 7.02 (1 H, d, J ) 9.0 Hz), 7.04 (1 H, d,
J ) 3.0 Hz); 13C NMR (50 MHz, CDCl3) δ 55.8 (q), 56.1 (q),
61.4 (t), 95.0 (t), 95.3 (t), 115.7 (d), 116.3 (d), 117.0 (d), 131.5
(s), 150.0 (s), 152.1 (s); MS (EI) m/z 228 (M+), 196, 166, 151,
136, 122, 85, 83, 45 (base); EI-HRMS m/z calcd for C11H16O5:
228.0998. Found: 228.0991.
The alcohol (8.4 g, 36.8 mmol) was similarly chlorinated by
using Ph3P (19.4 g, 74.0 mmol), CCl4 (44.0 mL, 0.46 mol), and
CH3CN (40 mL). Similar workup and chromatography af-
forded chloride 12 (5.3 g, 59%) as a colorless oil: FTIR 1600,
1510 cm-1; 1H NMR (200 MHz, CDCl3) δ 3.48 (3 H, s), 3.50 (3
H, s), 4.63 (2 H, s), 5.12 (2 H, s), 5.19 (2 H, s), 6.96 (1 H, dd,
J ) 9.0, 3.0 Hz), 7.05 (1 H, d, J ) 9.0 Hz), 7.08 (1 H, d, J ) 3.0
Hz); 13C NMR (50 MHz, CDCl3) δ 41.5 (t), 55.9 (q), 56.1 (q),
95.0 (t), 95.1 (t), 115.7 (d), 117.7 (d), 118.6 (d), 127.6 (s), 150.0
(s), 152.0 (s); MS (EI) m/z 248, 246 (M+), 215, 166, 136, 78, 45
(base); EI-HRMS m/z calcd for C11H15O4Cl: 246.0553. Found:
246.0663.
NMR (50 MHz, CDCl3) δ 20.9 (t), 21.4 (q), 23.6 (t), 31.5 (t),
35.7 (t), 44.1 (s), 64.3 (q), 65.0 (t), 65.0 (t), 112.0 (s), 127.4 (d),
137.8 (d); MS (EI) m/z 212 (M+), 195, 181, 167, 155, 139, 130,
125, 112, 99 (base), 93, 86, 78; EI-HRMS m/z calcd for
C12H20O3: 212.1413. Found: 212.1424.
(1E)-(1′R)-4-Meth yl-1-[2′-(eth ylen ed ioxy)-1′-m eth ylcy-
cloh exyl]p en ta -1,3-d ien e (18). The alcohol 17 (8.1 g, 38.0
mmol) was treated with oxalyl chloride (7.0 mL, 80.2 mmol)
and DMSO (46 mL, 0.648 mol) in CH2Cl2 (150 mL) at -78 °C.
In 15 min Et3N (53 mL, 0.38 mol) was added, and the mixture
was stirred at 0 °C for 10 min. Water was added, and the
mixture was extracted with CH2Cl2. The organic phase was
washed with 1 M HCl and brine, dried over MgSO4, and
evaporated to afford the aldehyde (10.9 g) as an oil: FTIR
1
1700, 1650 cm-1; H NMR (200 MHz, CDCl3) δ 1.14 (3 H, s),
1.4-1.8 (8 H, m), 3.94 (4 H, m), 3.75 (3 H, s), 6.16 (1 H, dd, J
) 16.2, 7.8 Hz), 7.10 (1 H, d, J ) 16.2 Hz), 9.54 (1 H, d, J )
7.8 Hz); 13C NMR (50 MHz, CDCl3) δ 20.7 (q), 20.8 (t), 23.4
(t), 31.7 (t), 34.8 (t), 46.0 (s), 65.1 (t), 65.2 (t), 111.3 (s), 131.3
(d), 164.4 (d), 194.7 (d); MS (EI) m/z 210 (M+), 195, 182, 167,
148, 125, 112, 99 (base), 86, 73.
Met h yl
(1′R)-3-(1′-Met h yl-2′-oxocycloh exyl)p r op -2-
en oa te (15). A solution of 2-methylcyclohexanone (95.1 g, 0.85
mol), (S)-(-)-phenylethylamine (106 mL, 0.82 mol), and TsOH
(9.1 g) in PhH (600 mL) was heated under reflux with the aid
of the Dean-Stark water separator overnight. The mixture
was washed with water, 5% aqueous NaHCO3, and brine, dried
(MgSO4), and evaporated to afford a residue (115.4 g). The
residue was distilled under reduced pressure. The imine 13
was immediately reacted with methyl propiolate (50 mL, 0.562
mol) without the solvent at rt for 4 days. A mixture of AcOH:
H2O ) 9:1 (750 mL) was added into the mixture, and the
solution was heated at 60 °C for 1 h. The mixture was
extracted with ether, and the organic phase was washed with
water, saturated NaHCO3, 1 M HCl, and brine, dried (MgSO4),
and evaporated. The residue was purified by silica gel column
chromatography (elution with hexane-EtOAc in gradient) to
give keto-ester 15 (131.3 g, two steps 79%; 80% ee) as an oil:
Isopropyltriphenylphosphonium iodide (23.7 g, 54.8 mmol)
was treated with nBuLi (1.69 mol/L: 46 mL, 77.7 mmol) in
dry ether (200 mL), and the mixture was stirred at rt for 1 h.
A solution of the aldehyde (10.9 g) in dry ether (10 mL) was
added into the mixture, and the solution was stirred for 50
min. Water was added, and the mixture was extracted with
ether. The organic phase was washed with brine, dried
(MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (elution with hexane-EtOAc in
gradient) to give the diene 18 (5.2 g, two steps 52%) as a pale
yellow oil: [R]21D +18.2° (c 1.1, CHCl3); FTIR 1660, 1620, 1450,
970 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.08 (3 H, s), 1.4-1.6
(8 H, m), 1.75 (3 H, s), 1.76 (3 H, s), 3.91 (4 H, m), 5.80 (1 H,
d, J ) 15.6 Hz), 5.83 (1 H, br dt, J ) 11.0, 1.0 Hz), 6.28 (1 H,
dd, J ) 15.6, 11.0 Hz); 13C NMR (50 MHz, CDCl3) δ 18.4 (q),
21.0 (t), 21.6 (q), 23.8 (t), 26.0 (q), 31.8 (t), 35.9 (t), 44.6 (s),
65.1 (t), 65.2 (t), 112.2 (s), 124.7 (d), 125.9 (d), 133.1 (s), 137.1
(d); MS (EI) m/z 236 (M+), 221, 193, 179, 165, 149, 140, 125
(base) 107, 99, 86, 79; EI-HRMS m/z calcd for C15H24O2:
236.1776. Found: 236.1807.
[R]21 +63.4° (c 1.2, CHCl3); CD [θ]305
+ 7700 (CHCl3) ∆ꢀ )
D
nm
+2.3; FTIR 1730, 1710, 1660, 1450, 1190 cm-1; 1H NMR (200
MHz, CDCl3) δ 1.24 (3 H, s), 1.7-1.8 (4 H, m), 1.9-2.1 (2 H,
m), 2.4-2.5 (2 H, m), 3.75 (3 H, s), 5.78 (1 H, d, J ) 16.2 Hz),
7.15 (1 H, d, J ) 16.2 Hz); 13C NMR (50 MHz, CDCl3) δ 21.6
(t), 23.2 (q), 27.4 (t), 39.4 (t), 39.6 (t), 51.7 (q, s), 120.8 (d), 151.7
(d), 166.7 (s), 211.4 (s); MS (EI) m/z 196 (M+), 181, 168, 165,
152, 137, 125, 114, 108, 93 (base), 82; EI-HRMS m/z calcd for
C11H16O3: 196.1099. Found: 196.1105.
(1′E)-(2R)-2-Met h yl-2-(4′-m et h ylp en t a -1′,3′-d ien yl)cy-
cloh exa n on e (19). A solution of the diene 18 (1.26 g, 5.36
mmol) and TsOH (55 mg) in acetone:H2O ) 1:2 (20 mL) was
stirred at 50 °C overnight. Acetone was evaporated, and the
residue was extracted with ether. The organic phase was
washed with water, saturated NaHCO3, and brine, dried
(MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (elution with hexane-EtOAc in
gradient) to give ketone 19 (761.4 mg, 74%) as a pale yellow
oil: [R]21D + 119.6° (c 1.1, CHCl3); CD [θ]297 nm +12000 (CHCl3)
Meth yl (1′R)-3-[2′-(Eth ylen edioxy)-1′-m eth ylcycloh exyl]-
p r op -2-en oa te (16). A solution of keto-ester 15 (5.0 g, 25.5
mmol), ethylene glycol (14.0 mL, 0.251 mol), and TsOH (1.1
g) in PhH (200 mL) was heated under reflux with the Dean-
Stark water separator overnight. The mixture was washed
wth water, saturated NaHCO3, and brine, dried (MgSO4), and
evaporated. The residue was purified by silica gel column
chromatography (elution with hexane-EtOAc in gradient) to
1
∆ꢀ ) +3.6; FTIR 1710, 1660, 1610, 1460, 970 cm-1; H NMR
(200 MHz, CDCl3) δ 1.18 (3 H, s), 1.6-1.9 (4 H, m), 1.9-2.1 (2
H, m), 2.2-2.4 (1 H, m), 2.5-2.7 (1 H, m), 1.72 (3 H, s), 1.77
(3 H, s), 5.70 (1 H, d, J ) 15.6 Hz), 5.80 (1 H, br d, J ) 10.7
Hz) 6.16 (1 H, dd, J ) 15.6, 10.7 Hz); 13C NMR (50 MHz,
CDCl3) δ 18.4 (q), 21.8 (t), 24.6 (q), 26.0 (q), 27.7 (t), 39.3 (t),
40.5 (t), 51.5 (s), 124.8 (d), 126.8 (d), 134.9 (d), 135.3 (s), 213.5
(s); MS (EI) m/z 192 (M+, base), 177, 164, 149, 135, 121, 112,
107, 97, 93, 79; EI-HRMS m/z calcd for C13H20O: 192.1515.
Found: 192.1514.
give ketal 16 (5.19 g, 85%) as a greenish yellow oil: [R]21
D
+50.0° (c 1.1, CHCl3); FTIR 1730, 1660, 1450, 1190 cm-1; H
1
NMR (200 MHz, CDCl3) δ 1.10 (3 H, s), 1.5-1.9 (8 H, m), 3.73
(3 H, s), 3.94 (4 H, m), 5.78 (1 H, d, J ) 16.2 Hz), 7.23 (1 H, d,
J ) 16.2 Hz); 13C NMR (50 MHz, CDCl3) δ 20.7 (q), 20.8 (t),
23.5 (t), 31.7 (t), 35.0 (t), 45.3 (s), 51.4 (q), 65.1 (t), 65.2 (t),
111.4 (s), 119.4 (d), 154.6 (d), 167.5 (s); MS (EI) m/z 240 (M+),
225, 209, 183, 167, 158, 139, 125, 113, 99 (base), 86, 79; EI-
HRMS m/z calcd for C13H20O4: 240.1362. Found: 240.1366.
(1′R)-3-[2′-(Eth ylen ed ioxy)-1′-m eth ylcycloh exyl]p r op -
2-en -1-ol (17). A solution of ketal 16 (9.0 g, 37.5 mmol) in
dry ether (100 mL) was slowly added into a suspension of
LiAlH4 (4.08 g, 0.107 mol) in dry ether (300 mL), and the
mixture was stirred for 3 h. Ethyl acetate (40 mL) was slowly
added into the mixture, and then water (4 mL), 15% aqueous
NaOH solution (4 mL), and water (12.0 mL) were added
successively. The precipitates were filtered off, and the solvent
was evaporated to give alcohol 17 (8.1 g, quant): [R]21D +17.2°
(1′E)-(2R,6S)-2,6-Dim eth yl-2-(4′-m eth ylp en ta -1′,3′-d ien -
yl)cycloh exa n on e (20) a n d (1′E)-(2R,6R)-2,6-Dim eth yl-2-
(4′-m eth ylp en ta -1′,3′-d ien yl)cycloh exa n on e (21). A solu-
tion of the ketone 19 (652.1 mg, 3.40 mmol) in dry THF (5
mL) was added into a solution of LDA, prepared from diiso-
propylamine (1.0 mL, 7.63 mmol), nBuLi (1.69 M: 4.5 mL, 7.61
mmol), in dry THF (10 mL) at -78 °C. In 1 h, MeI (1.2 mL,
19.3 mmol) was added into the mixture, and the solution was
stirred for 9 h. Water was added and the solvent was
evaporated to afford a residue, which was extracted with ether.
The organic phase was washed with 1 M HCl and brine, dried
(MgSO4), and evaporated to afford a residue (570.6 mg). The
residue was purified by silica gel column chromatography
(elution with hexane-EtOAc in gradient) followed by HPLC
(Develosil 60-10, 20 × 250 mm; hexane-EtOAc ) 95:5) to give
1
(c 1.1, CHCl3); FTIR (KBr) 3400, 1660, 1620, 1450 cm-1; H
NMR (200 MHz, CDCl3) δ 1.06 (3 H, s), 1.4-1.8 (8 H, m), 1.96
(1 H, br s), 3.92 (4 H, m), 4.13 (2 H, dd, J ) 5.8, 1.2 Hz), 5.67
(1 H, dt, J ) 16.0, 5.8 Hz), 5.95 (1 H, dt, J ) 16.0, 1.2 Hz); 13
C

5368 J . Org. Chem., Vol. 61, No. 16, 1996
Tori et al.
ketone 20 (255.7 mg, 37%), ketone 21 (252.1 mg, 36%), and
unreacted ketone 19 (20.5 mg).
Hz), 6.82 (1 H, dd, J ) 8.4, 3.0 Hz), 7.00 (1 H, d, J ) 8.4 Hz);
13C NMR (50 MHz, CDCl3) δ 16.7 (q), 18.3 (q), 21.5 (t), 22.3
(q), 26.0 (q), 31.6 (t), 37.8 (d, t), 39.2 (t), 45.6 (s), 55.8 (q), 56.4
(q), 77.7 (s), 94.9 (t), 95.5 (t), 115.1 (d), 115.2 (d), 121.7 (d),
124.8 (d), 126.0 (d), 130.8 (s), 133.1 (s), 137.2 (d), 150.4 (s),
151.9 (s); MS (EI) m/z 418 (M+), 386, 374, 373, 355, 323, 299,
255, 245, 224, 212, 207, 205, 189, 180, 167, 161, 149, 135, 123,
109, 93, 45 (base); EI-HRMS m/z calcd for C25H38O5: 418.2720.
Found: 418.2718.
Compound 20: [R]21 + 134.3° (c 1.1, CHCl3); CD [θ]297
D
nm
+17500 (CHCl3) ∆ꢀ ) +5.3; FTIR 1720, 1660, 1620, 1460, 960
1
cm-1; H NMR (200 MHz, CDCl3) δ 1.00 (3 H, d, J ) 6.6 Hz),
1.15 (3 H, s), 1.2-2.1 (6 H, m), 1.72 (3 H, s), 1.77 (3 H, s),
2.6-2.8 (1 H, m), 5.69 (1 H, d, J ) 15.6 Hz), 5.79 (1 H, br dt,
J ) 11.0, 1.0 Hz), 6.14 (1 H, dd, J ) 15.6, 11.0 Hz); 13C NMR
(50 MHz, CDCl3) δ 14.9 (q), 18.4 (q), 22.0 (t), 24.9 (q), 26.0 (q),
37.0 (t), 41.3 (t), 42.0 (d), 51.6 (s), 124.8 (d), 127.0 (d), 135.2
(d), 135.4 (d), 214.7 (s); MS (EI) m/z 206 (M+), 163, 149, 135,
126, 107, 96, 78 (base), 69, 52, 39; EI-HRMS m/z calcd for
C14H22O: 206.1670. Found: 206.1664.
(1′′E)-(1R,2R,6S)-1-(2′,5′-Dih ydr oxyben zyl)-2,6-dim eth yl-
2-(4′′-m eth ylp en ta -1′′,3′′-d ien yl)cycloh exa n -1-ol (30) a n d
(1′′E)-(1S,2R,6S)-1-(2′,5′-Dih yd r oxyben zyl)-2,6-d im eth yl-
2-(4′′-m et h ylp en t a -1′′,3′′-d ien yl)cycloh exa n -1-ol (31).
A
Compound 21: [R]21 -37.1° (c 0.98, CHCl3); CD [θ]293
mixture of 24 and 25 (289.9 mg, 0.69 mmol) was treated with
THF:3 M HCl ) 1:1 (15 mL) at 50 °C for 4.5 h. The solvent
was evaporated, and the residue was extracted with ether. The
organic phase was washed with water, dried (MgSO4), and
evaporated. The residue was purified by silica gel column
chromatography (elution with hexane-EtOAc in gradient) and
HPLC (Develosil 60-10, 20 × 250 mm, hexane-EtOAc ) 1:1)
to give 30 (102.3 mg) and 31 (78.4 mg) (combined yield; 79%).
D
nm
1H
-4500 (CHCl3) ∆ꢀ ) -1.4; FTIR 1710, 1460, 1390 cm-1
;
NMR (200 MHz, CDCl3): δ 1.01 (3 H, d, J ) 6.6 Hz), 1.32 (3
H, s), 1.74 (3 H, s), 1.76 (3 H, s), 1.6-2.1 (6 H, m), 2.6-2.8 (1
H, m), 5.87 (1 H, br dt, J ) 11.0, 1.0 Hz), 5.92 (1 H, d, J )
15.6 Hz), 6.21 (1 H, dd, J ) 15.6, 11.0 Hz); 13C NMR (50 MHz,
CDCl3) δ 15.4 (q), 18.3 (q), 20.9 (t), 23.6 (q), 26.0 (q), 35.7 (t),
39.2 (t), 41.2 (d), 50.4 (s), 124.1 (d), 125.2 (d), 134.0 (s), 136.1
(d), 215.5 (s); MS (EI) m/z 206 (M+, base), 191, 178, 163, 149,
135, 121, 107, 96, 81, 67, 55, 41; EI-HRMS m/z calcd for
C14H22O: 206.1670. Found: 206.1664.
Compound 30: [R]21 +74.6° (c 1.0, CHCl3); FTIR: 3250,
D
1640, 1610, 1500 cm-1; 1H NMR (200 MHz, CDCl3): δ 0.94 (3
H, s), 0.98 (3 H, d, J ) 6.6 Hz), 1.2-1.7 (6 H, m), 1.78 (3 H, s),
1.81 (3 H, s), 1.9-2.1 (1 H, m), 2.49 (1 H, br s), 2.71 (1 H, d, J
) 15.0 Hz), 2.99 (1 H, d, J ) 15.0 Hz), 4.65 (1 H, br s), 5.89 (1
H, dt, J ) 10.6, 1.2 Hz), 6.02 (1 H, d, J ) 15.4 Hz), 6.26 (1 H,
dd, J ) 15.4, 10.6 Hz), 6.49 (1 H, d, J ) 3.0 Hz), 6.58 (1 H, dd,
(1′′E )-(1R ,2R ,6S )-1-[5′-Me t h oxy-2′-(m e t h oxym e t h yl-
oxy)b en zyl]-2,6-d im et h yl-2-(4′′-m et h ylp en t a -1′′,3′′-d ien -
yl)cycloh exa n -1-ol (22). Chloride 10 (4.5 g, 20.8 mmol) was
converted to its Grignard reagent by treatment with Mg (506.5
mg, 20.83 mmol) in dry THF (8 mL) containing catalytic
amount of I2. The mixture was stirred at rt for 1 h, and a
solution of ketone 20 (448.5 mg, 2.18 mmol) in dry THF (0.5
mL) was added slowly. The mixture was stirred for 40 min,
and saturated NH4Cl was added. The mixture was extracted
with ether, and the ethereal solution was washed with water
and brine, dried (MgSO4), and evaporated. The residue was
purified by silica gel column chromatography (elution with
hexane-EtOAc in gradient) to give a mixture of 22 and 23
J ) 8.6, 3.0 Hz), 6.72 (1 H, d, J ) 8.6 Hz), 8.52 (1 H, br s); 13
C
NMR (50 MHz, CDCl3): δ 16.4 (q), 18.4 (q), 20.7 (t), 22.4 (q),
26.1 (q), 31.2 (t), 36.9 (d), 37.4 (t), 40.1 (t), 44.8 (s), 80.7 (s),
114.6 (d), 117.4 (d), 119.3 (d), 125.5 (d), 125.9 (d), 127.6 (s),
134.5 (s), 134.9 (d), 148.5 (s), 149.8 (s); MS (EI) m/z 330 (M+),
312, 277, 269, 255, 243, 232, 219, 215, 207, 189, 180, 161, 150,
139, 123, 109 (base), 95; EI-HRMS m/z calcd for C21H30O3:
330.2195. Found: 330.2188.
Compound 31: [R]21 +10.1° (c 1.0, CHCl3); FTIR 3300,
D
(4:1 by GC) (381.0 mg, 45%) as a yellow oil: [R]21 +20.1° (c
1640, 1610, 1500 cm-1; 1H NMR (200 MHz, CDCl3): δ 0.71 (3
H, d, J ) 7.0 Hz), 1.15 (3 H, s), 1.4-1.9 (7 H, m), 1.78 (6 H, s),
2.53 (1 H, br s), 2.91 (1 H, d, J ) 15.0 Hz), 3.02 (1 H, d, J )
15.0 Hz), 5.51 (1 H, br s), 5.83 (1 H, d, J ) 10.6 Hz), 6.00 (1 H,
d, J ) 15.4 Hz), 6.37 (1 H, dd, J ) 15.4, 10.6 Hz), 6.58 (1 H,
dd, J ) 8.2, 2.8 Hz), 6.62 (1 H, d, J ) 2.8 Hz), 6.72 (1 H, d, J
) 8.2 Hz), 8.82 (1 H, br s); 13C NMR (50 MHz, CDCl3) δ 16.0
(q), 18.5 (q), 20.5 (t), 22.8 (q), 26.0 (q), 31.6 (t), 34.8 (t), 36.5
(t), 40.0 (d), 45.6 (s), 80.9 (s), 114.2 (d), 117.6 (d), 119.2 (d),
125.1 (d), 127.0 (s), 128.3 (d), 134.7 (d), 135.7 (s), 148.5 (s),
150.1 (s); MS (EI) m/z 330 (M+), 312, 277, 269, 255, 243, 232,
219, 215, 207, 189, 180, 161, 150, 139, 123, 109 (base), 95; EI-
HRMS m/z calcd for C21H30O3: 330.2195. Found: 330.2203.
Ricca r d ip h en ol A (1). A solution of 31 (78.4 mg, 0.24
mmol) and TsOH (16 mg) in PhH (50 mL) was heated at 65
°C for 4.5 h. The mixture was washed with water, saturated
NaHCO3, and brine, dried (MgSO4), and evaporated. The
residue was purified by HPLC (Develosil 60-10, 20 × 250 mm,
hexane-EtOAc ) 4:1) to give riccardiphenol A (1) (3.0 mg, 4%),
34 (61.7 mg, 83%), and the mixture of the third compound (10.0
mg). The mixture was treated with acetic anhydride (1 mL)
in pyridine (1 mL) at rt overnight. The mixture was worked
up as usual, and the residue was purified by HPLC (Develosil
50-5, 10 × 250 mm, hexane-EtOAc ) 9:1) to give acetate 35a
(8.4 mg) as a yellow oil.
D
1.1, CHCl3); FTIR 3550, 1620, 1600, 1500 cm-1; (for the major
isomer) 1H NMR (200 MHz, CDCl3) δ 0.90 (3 H, s), 0.96 (3 H,
d, J ) 6.6 Hz), 1.1-2.0 (7 H, m), 1.76 (3 H, s), 1.80 (3 H, s),
2.77 (1 H, d, J ) 14.6 Hz), 2.99 (1 H, d, J ) 14.6 Hz), 3.51 (3
H, s), 3.71 (3 H, s), 5.15 (2 H, s), 5.89 (1 H, br d, J ) 9.0 Hz),
6.18 (1 H, d, J ) 2.6 Hz), 6.19 (1 H, d, J ) 9.0 Hz), 6.65 (1 H,
d, J ) 3.2 Hz), 6.67 (1 H, dd, J ) 7.4, 3.2 Hz), 7.00 (1 H, d, J
) 7.4 Hz); 13C NMR (50 MHz, CDCl3) δ 16.7 (q), 18.3 (q), 21.6
(t), 22.2 (q), 26.0 (q), 31.6 (t), 37.9 (d, t), 39.5 (t), 45.5 (s), 55.4
(q), 56.4 (q), 77.7 (s), 95.7 (t), 112.3 (d), 115.4 (d), 119.0 (d),
124.9 (d), 126.0 (d), 130.8 (s), 133.2 (s), 137.2 (d), 149.4 (s),
154.4 (s); MS (CI) m/z 388 (M+, base), 371, 357, 343, 339, 325,
301, 289, 251, 229, 215, 181, 149, 137, 109, 95; CI-HRMS m/z
calcd for C24H36O4: 388.2614. Found: 388.2617.
(1′′E)-(1R,2R,6S)-1-[2′,5′-Bis(m eth oxym eth yloxy)ben zyl]-
2,6-d im eth yl-2-(4′′-m eth ylp en ta -1′′,3′′-d ien yl)cycloh exa n -
1-ol (24) a n d (1′′E)-(1S,2R,6S)-1-[2′,5′-Bis(m eth oxym eth -
yloxy)b e n zyl]-2,6-d im e t h yl-2-(4′′-m e t h ylp e n t a -1′′,3′′-
d ien yl)cycloh exa n -1-ol (25). Chloride 12 (1.46 g, 5.93 mmol)
was converted to its Grignard reagent by treatment with Mg
(140.2 mg, 5.77 mmol) in dry THF (3.5 mL) containing the
catalytic amount of I2. The mixture was stirred for 30 min at
rt. A solution of ketone 20 (146.0 mg, 7.09 mmol) in dry THF
(0.5 mL) was added, and the mixture was stirred for 20 min.
Saturated NH4Cl was added, and the mixture was extracted
with ether. The organic phase was washed with water and
brine, dried (MgSO4), and evaporated. The residue was
purified by silica gel column chromatography (elution with
hexane-EtOAc, in gradient) to give 24 (165.5 mg) and a
mixture of 24 and 25 (105.0 mg) (combined yield: 91%, 24:25
) 80:20 from GC-MS).
Riccardiphenol A (1): [R]21 +107.6° (c 0.7, CHCl3); FTIR:
D
3400, 1670, 1620, 1500 cm-1
;
1H NMR (200 MHz, CDCl3) δ
0.76 (3 H, d, J ) 6.6 Hz), 0.91 (3 H, s), 1.1-1.7 (6 H, m), 2.1-
2.2 (1 H, m), 1.79 (3 H, s), 1.80 (3 H, s), 2.85 (1 H, d, J ) 16.8
Hz), 3.15 (1 H, d, J ) 16.8 Hz), 3.74 (3 H, s), 5.86 (1 H, d, J )
10.4 Hz), 5.87 (1 H, d, J ) 15.6 Hz), 6.33 (1 H, dd, J ) 15.6,
10.4 Hz), 6.55 (1 H, dd, J ) 8.2 Hz), 6.58 (1 H, d, J ) 8.2 Hz),
6.64 (1 H, d, J ) 1.4 Hz); 13C NMR (150 MHz, CDCl3) δ 14.8
(q), 18.3 (q), 21.0 (t), 24.1 (q), 26.0 (q), 31.0 (t), 31.8 (t), 34.0
(t), 37.4 (d), 45.3 (s), 95.6 (s), 108.1 (d), 111.7 (d), 114.1 (d),
125.3 (d), 126.1 (d), 128.4 (s), 132.8 (s), 136.2 (d), 148.8 (s),
154.9 (s); MS (EI) m/z 312 (M+, base), 297, 277, 269, 255, 243,
241, 227, 215, 201, 189, 174, 162, 161, 147, 133, 123, 109, 91;
EI-HRMS m/z calcd for C21H28O2: 312.2089. Found: 312.2096.
Compound 24: [R]21 +49.4° (c 0.9, CHCl3); FTIR: 3550,
D
1
1670, 1600, 1500 cm-1; H NMR (200 MHz, CDCl3) δ 0.93 (3
H, s), 0.94 (3 H, d, J ) 6.0 Hz), 1.1-2.0 (7 H, m), 1.76 (3 H, s),
1.80 (3 H, s), 2.81 (1 H, d, J ) 14.6 Hz), 2.96 (1 H, d, J ) 14.6
Hz), 3.44 (3 H, s), 3.51 (3 H, s), 3.53 (1 H, br s), 5.07 (2 H, s),
5.15 (2 H, s), 5.89 (1 H, dt, J ) 9.6, 1.2 Hz), 6.10 (1 H, d, J )
15.2 Hz), 6.24 (1 H, dd, J ) 15.2, 9.6 Hz), 6.80 (1 H, d, J ) 3.0

Riccardiphenols A and B
J . Org. Chem., Vol. 61, No. 16, 1996 5369
5-epi-Riccardiphenol A (34): [R]21 +81.9° (c 1.1, CHCl3);
a n -1-ol (28) a n d (1′′E)-(1R,2R,6R)-1-[2′,5′-Bis(m eth oxy-
m eth yloxy)ben zyl]-2,6-d im eth yl-2-(4′′-m eth ylp en ta -1′′,3′′-
d ien yl)cycloh exa n -1-ol (29). Grignard reaction was simi-
larly carried out as described above using 12 (5.3 g, 21.7 mmol),
Mg (516.0 mg, 21.2 mmol), and ketone 21 (362.0 mg, 1.76
mmol) in dry THF (10 mL). The residue was purified by silica
gel column chromatography (elution with hexane-EtOAc in
gradient) and HPLC (Develosil 60-10, 20 × 250 mm, hexane-
EtOAc ) 85:15) to give 28 (465.1 mg, 63%) and 29 (19.0 mg,
3%).
D
FTIR: 3600, 3400, 1670, 1620, 1500 cm-1; 1H NMR (200 MHz,
CDCl3) δ 0.77 (3 H, d, J ) 6.2 Hz), 0.97 (3 H, s), 1.4-1.9 (7 H,
m), 1.78 (6 H, s), 2.81 (1 H, d, J ) 16.8 Hz), 3.12 (1 H, d, J )
16.8 Hz), 4.44 (1 H, br s), 5.84 (1 H, d, J ) 10.4 Hz), 5.85 (1 H,
d, J ) 15.8 Hz), 6.32 (1 H, dd, J ) 15.8, 10.4 Hz), 6.45-6.60
(3 H, m); 13C NMR (50 MHz, CDCl3) δ 15.1 (q), 18.4 (q), 21.4
(t), 22.0 (q), 26.0 (q), 30.7 (t), 35.8 (t), 35.9 (t), 38.0 (d), 44.8
(s), 93.3 (s), 108.1 (d), 111.6 (d), 114.1 (d), 125.6 (d), 126.1 (d),
128.6 (s), 134.1 (s), 135.2 (d), 148.7 (s), 155.3 (s); MS (EI) m/z
312 (M+, base), 297, 277, 269, 255, 243, 241, 227, 215, 201,
189, 174, 162, 161, 147, 133, 123, 109, 91; EI-HRMS m/z calcd
for C21H28O2: 312.2089. Found: 312.2075.
Compound 28: [R]24D -3.2° (c 1.0, CHCl3); FTIR 3550, 2950,
2850, 1620, 1600, 1500 cm-1 1H NMR (200 MHz, CDCl3) δ
;
0.92 (3 H, d, J ) 6.6 Hz), 1.22 (3 H, s), 1.3-1.6 (6 H, m), 1.66
(3 H, s), 1.69 (3 H, s), 1.8-2.0 (1 H, m), 2.82 (1 H, d, J ) 14.4
Hz), 2.94 (1 H, d, J ) 14.4 Hz), 3.45 (3 H, s), 3.48 (3H, s), 5.07
(2 H, s), 5.11 (2 H, s), 5.51 (1 H, d, J ) 10.6 Hz), 5.57 (1 H, d,
J ) 15.6 Hz), 6.05 (1 H, dd, J ) 15.6, 10.6 Hz), 6.77 (1 H, dd,
J ) 8.8, 3.0 Hz), 6.89 (1 H, d, J ) 3.0 Hz), 6.95 (1 H, d, J ) 8.8
Hz); 13C NMR (50 MHz, CDCl3) δ 16.7 (q), 18.2 (q), 20.4 (q),
21.4 (t), 25.8 (q), 31.5 (t), 35.6 (t), 37.4 (d), 39.2 (t), 44.9 (s),
55.7 (q), 56.2 (q), 77.8 (s), 95.1 (t), 95.5 (t), 114.8 (d), 115.1 (d),
121.5 (d), 123.9 (d), 126.2 (d), 130.6 (s), 132.0 (s), 139.9 (d),
150.6 (s), 151.9 (s); MS (EI) m/z 418 (M+), 386, 373, 355, 341,
323, 267, 245, 224, 205, 167, 161, 149, 133, 123, 107, 93, 45
(base); EI-HRMS m/z calcd for C25H38O5: 418.2719. Found:
418.2710.
4,5-Diepi-Riccardiphenol A 5′-O-acetate (35a ): [R]21D -57.6°
(c 0.9, CHCl3); FTIR 1760, 1500, 1380, 1210 cm-1 1H NMR
;
(200 MHz, CDCl3) δ 0.86 (3 H, d, J ) 6.8 Hz), 1.40 (3 H, s),
1.50 (3 H, s), 1.69 (3 H, s), 1.3-1.8 (6 H, m), 1.8-2.0 (1 H, m),
2.26 (3 H, s), 2.52 (1 H, d, J ) 17.2 Hz), 3.02 (1 H, d, J ) 17.2
Hz), 5.47 (1 H, d, J ) 15.6 Hz), 5.74 (1 H, dt, J ) 10.6, 1.2
Hz), 6.01 (1 H, dd, J ) 15.6, 10.6 Hz), 6.72 (1 H, d, J ) 8.4
Hz), 6.76 (1 H, dd, J ) 8.4, 2.7 Hz), 6.84 (1 H, d, J ) 2.7 Hz);
13C NMR (50 MHz, CDCl3) δ 16.4 (q), 18.1 (q), 21.1 (q), 22.3
(q), 22.5 (t), 25.9 (q), 26.4 (t), 29.2 (t), 33.6 (t), 36.3 (d), 42.9
(s), 80.3 (s), 117.1 (d), 119.9 (d), 121.4 (s), 121.5 (d), 125.4 (d),
127.0 (d), 133.8 (s), 134.9 (d), 143.5 (s), 150.5 (s), 169.9 (s);
MS (EI) m/z 354 (M+, base), 339, 312, 297, 269, 257, 244, 243,
230, 215, 201, 189, 174, 162, 147, 133, 123, 119, 109, 91; EI-
HRMS m/z calcd for C23H30O3: 354.2195. Found: 354.2196.
Cycliza tion of Tr iol 30. A solution of triol 30 (49.1 mg,
0.15 mmol) and TsOH (14 mg) in PhH (50 mL) was heated at
65 °C for 4.5 h. The mixture was washed with water,
saturated NaHCO3, and brine, dried (MgSO4), and evaporated.
As the products could not be separated by HPLC, the residue
(12.6 mg) was acetylated with Ac2O (1 mL) in pyridine (1 mL)
overnight. Workup as usual afforded a residue, which was
purified by HPLC (Develosil 60-3, 4.6 × 20 cm, hexane-EtOAc
) 9:1) to give the inseparable mixture 36a (15.3 mg, 29%) as
a yellow oil: FTIR 1760, 1500, 1370, 1210 cm-1; 1H NMR (200
MHz, CDCl3) δ 0.79 (3 H, d, J ) 7.2 Hz), 0.86 (3 H, d, J ) 7.2
Hz), 1.06 (3 H, s), 1.10 (3 H, s), 1.2-2.2 (14 H, m), 1.58 (6 H,
s), 1.68 (3 H, s), 1.69 (3 H, s), 2.25 (6 H, s), 2.31 (3 H, s), 2.32
(3 H, s), 2.57 (1 H, d, J ) 15.6 Hz), 2.65 (1 H, d, J ) 15.6 Hz),
2.79 (1 H, d, J ) 15.6 Hz), 2.86 (1 H, d, J ) 15.6 Hz), 4.7-5.0
(2 H, m), 5.34 (2 H, tt, J ) 9.6, 1.4 Hz), 6.9-7.0 (4 H, m), 7.64
(1 H, d, J ) 2.4 Hz), 7.83 (1 H, d, J ) 2.6 Hz); MS (EI) m/z 414
(M+), 372, 354, 330, 315, 273, 231, 207 (base), 189, 179, 165,
149, 139, 123, 109, 95, 81; HRMS m/z calcd for C24H34O5:
414.2406. Found: 414.2397.
Compound 29: [R]24 + 75.5° (c 0.95, CHCl3); FTIR: 3550,
D
1
1620, 1600, 1500 cm-1; H NMR (200 MHz, CDCl3) δ 0.88 (3
H, d, J ) 7.0 Hz), 1.13 (3 H, s), 1.2-1.8 (6 H, m), 1.74 (6 H, s),
1.9-2.1 (1 H, m), 2.95 (2 H, s), 3.45 (3 H, s), 3.49 (3 H, s), 5.05
(1 H, d, J ) 6.6 Hz), 5.10 (1 H, d, J ) 6.6 Hz), 5.12 (1 H, d, J
) 6.6 Hz), 5.16 (1 H, d, J ) 6.6 Hz), 5.69 (1 H, d, J ) 10.6 Hz),
5.83 (1 H, d, J ) 15.6 Hz), 6.16 (1 H, dd, J ) 15.6, 10.6 Hz),
6.81 (1 H, dd, J ) 8.8, 3.0 Hz), 6.89 (1 H, d, J ) 3.0 Hz), 6.98
(1 H, d, J ) 8.8 Hz); 13C NMR (50 MHz, CDCl3) δ 16.2 (q),
18.3 (q), 25.9 (q x 2), 33.3 (t x 2), 33.7 (t x 2), 37.5 (d), 45.3 (s),
55.8 (q), 56.3 (q), 78.3 (s), 94.9 (t), 95.4 (t), 115.0 (d), 115.1 (d),
121.9 (d), 122.8 (d), 126.1 (d x 2), 129.9 (s), 132.4 (s), 150.7 (s),
151.8 (s); MS (EI) m/z 418 (M+), 386, 373, 355, 341, 323, 267,
245, 224, 205, 167, 161, 149, 133, 123, 107, 93, 45 (base).
(1′′E)-(1S,2R,6R)-1-(2′,5′-Dih ydr oxyben zyl)-2,6-dim eth yl-
2-(4′′-m et h ylp en t a -1′′,3′′-d ien yl)cycloh exa n -1-ol (32).
A
solution of 28 (200 mg, 0.48 mmol) in THF:3 M HCl ) 10:1
(15 mL) was heated at 50 °C for 4.5 h. The solvent was
evaporated, and the residue was extracted with ether. The
organic phase was washed with water and brine, dried
(MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (elution with hexane-EtOAc in
gradient) to give 32 (64.8 mg, 41%) as a brown oil: FTIR 3400,
(1′′E )-(1S ,2R ,6R )-1-[5′-Me t h oxy-2′-(m e t h oxym e t h yl-
oxy)b en zyl]-2,6-d im et h yl-2-(4′′-m et h ylp en t a -1′′,3′′-d ien -
yl)cycloh exa n -1-ol (26). Grignard reaction was carried out
similarly as described above using chloride 10 (3.92 g, 18.2
mmol), Mg (424.3 mg, 17.5 mmol), and 21 (392.7 mg, 1.91
mmol) in dry THF (5 mL). Saturated NH4Cl was added, and
the solvent was evaporated. The residue was extracted with
ether, and the organic phase was washed with water and brine,
dried (MgSO4), and evaporated. The residue was purified by
silica gel chromatography (elution with hexane-EtOAc in
gradient) to give a mixture of 26 and 27 (96:4 by GC) (315.8
1
1620, 1600, 1500 cm-1; H NMR (200 MHz, CDCl3) δ 0.92 (3
H, d, J ) 6.8 Hz), 1.24 (3 H, s), 1.3-1.6 (6 H, m), 1.68 (6 H, s),
1.8-2.0 (1 H, m), 2.66 (1 H, br s), 2.78 (1 H, d, J ) 14.8 Hz),
2.95 (1 H, d, J ) 14.8 Hz), 5.40 (1 H, br s), 5.54 (1 H, d, J )
10.6 Hz), 5.63 (1 H, d, J ) 15.6 Hz), 6.11 (1 H, dd, J ) 15.6,
10.6 Hz), 6.54 (1 H, dd, J ) 8.2, 2.8 Hz), 6.57 (1 H, d, J ) 2.8
Hz), 6.68 (1 H, d, J ) 8.2 Hz), 8.50 (1 H, br s); 13C NMR (50
MHz, CDCl3) δ 16.4 (q), 18.3 (q), 19.8 (t), 21.4 (q), 25.9 (q),
30.9 (t), 35.6 (t), 36.2 (d), 39.6 (t), 44.4 (s), 80.2 (s), 114.5 (d),
117.4 (d), 119.0 (d), 125.4 (d), 125.5 (d), 127.0 (s), 133.7 (s),
137.1 (d), 148.8 (s), 149.5 (s); MS (EI) m/z 330 (M+), 312, 297,
269, 255, 241, 207, 193, 189, 180, 161, 149, 139, 133, 123, 109
(base), 95; EI-HRMS m/z calcd for C21H30O3: 330.2195.
Found: 330.2205.
mg, 43%) as an oil: [R]21 -2.2° (c 0.99, CHCl3); FTIR: 3550,
D
1620, 1600, 1500 cm-1; (for the major isomer) H NMR (200
1
MHz, CDCl3) δ 0.93 (3 H, d, J ) 6.6 Hz), 1.23 (3 H, s), 1.3-2.0
(7 H, m), 1.67 (3 H, s), 1.70 (3 H, s), 2.82 (1 H, d, J ) 14.6 Hz),
2.95 (1 H, d, J ) 14.6 Hz), 3.49 (3 H, s), 3.73 (3 H, s), 5.11 (2
H, s), 5.51 (1 H, br d, J ) 11.0 Hz), 5.57 (1 H, d, J ) 15.6 Hz),
6.06 (1 H, dd, J ) 15.6, 11.0 Hz), 6.63 (1 H, dd, J ) 9.0, 3.0
Hz), 6.76 (1 H, d, J ) 3.0 Hz), 6.97 (1 H, d, J ) 9.0 Hz); 13C
NMR (50 MHz, CDCl3) δ 16.7 (q), 18.2 (q), 20.4 (q), 21.4 (t),
25.9 (q), 31.5 (t), 35.5 (t), 37.4 (d), 39.2 (t), 44.9 (s), 55.5 (q),
56.2 (q), 77.7 (s), 95.6 (t), 111.7 (d), 115.3 (d), 119.1 (d), 123.9
(d), 126.2 (d), 130.6 (s), 132.0 (s), 139.9 (d), 149.7 (s), 154.3 (s);
MS (CI) m/z 388 (M+, base), 371, 357, 343, 339, 325, 301, 289,
251, 229, 215, 181, 149, 137, 109, 95; CI-HRMS m/z calcd for
C24H36O4: 388.2614. Found: 388.2617.
Cycliza tion of 32 to 37. A solution of triol 32 (64.8 mg,
0.196 mmol) and TsOH (16 mg) in PhH (40 mL) was heated
at 60 °C for 4.5 h. Workup as usual afforded a residue, which
was purified by HPLC (Develosil 60-10, 20 × 250 mm,
hexane-EtOAc ) 4:1) to give a mixture of products 37. The
mixture was acetylated with Ac2O (1 mL) in pyridine (1 mL)
overnight. Workup as usual afforded a residue, which was
purified by HPLC (Develosil 60-3, 4.6 × 20 cm, hexane-EtOAc
) 9:1) to give a mixture of products 37a (26.7 mg, two steps:
1
33%) as an oil: FTIR 1760, 1500, 1370, 1210 cm-1; H NMR
(600 MHz, CDCl3) δ 0.70 (3 H, d, J ) 7.2 Hz), 0.72 (3 H, d, J
) 6.6 Hz), 1.07 (3 H, s), 1.12 (3 H, s), 1.2-2.2 (14 H, m), 1.58
(6 H, s), 1.64 (3 H, s), 1.64 (3 H, s), 2.25 (3 H, s), 2.26 (3 H, s),
(1′′E)-(1S,2R,6R)-1-[2′,5′-Bis(m eth oxym eth yloxy)ben zyl]-
2,6-d im et h yl-2-(4′′-m et h ylp en t a -1′′,3′′-d ien yl)cycloh ex-

5370 J . Org. Chem., Vol. 61, No. 16, 1996
Tori et al.
2.32 (6 H, s), 2.60 (1 H, d, J ) 15.6 Hz), 2.65 (1 H, d, J ) 15.0
Hz), 2.73 (1 H, d, J ) 15.0 Hz), 2.74 (1 H, d, J ) 15.6 Hz),
4.6-4.7 (1 H, m), 4.88 (1 H, q, J ) 8.8 Hz), 5.24 (1 H, dt, J )
8.5, 1.5 Hz), 5.42 (1 H, dt, J ) 8.3, 1.5 Hz), 6.93 (2 H, dd, J )
8.8, 2.9 Hz), 6.99 (1 H, d, J ) 8.8 Hz), 6.99 (1 H, d, J ) 8.8
Hz), 7.45 (1 H, d, J ) 2.9 Hz), 7.56 (1 H, d, J ) 2.9 Hz); 13C
NMR (150 MHz, CDCl3) δ 169.3, 169.2, 148.0, 147.7, 146.5,
146.3, 135.1, 134.24, 134.18, 134.1, 128.4, 128.1, 125.0, 124.6,
122.5, 122.5, 119.67, 119.58, 87.7, 87.2, 73.1, 71.3, 47.8, 47.2,
45.6, 45.5, 38.7, 37.8, 37.8, 37.0, 36.4, 35.3, 32.3, 32.3, 32.1,
32.0, 25.9, 25.8, 22.1, 21.8, 21.4, 21.2, 21.1, 20.9, 18.7, 18.5,
18.2, 18.1; MS (EI) m/z 414 (M+), 372, 354, 330, 315, 273, 231,
207 (base), 189, 179, 165, 149, 139, 123, 109, 95, 81; EI-HRMS
m/z calcd for C25H34O5: 414.2406. Found: 414.2379.
NMR (400 MHz, CDCl3) δ 1.01 (3 H, s), 1.4-2.2 (6 H, m), 1.60
(3 H, s), 1.74 (3 H, s), 1.75 (3 H, s), 3.20 (1 H, d, J ) 17.0 Hz),
3.37 (1 H, d, J ) 17.0 Hz), 3.73 (3 H, s), 4.71 (1 H, br s), 5.47
(1 H, d, J ) 15.4 Hz), 5.77 (1 H, br d, J ) 10.7 Hz), 6.11 (1 H,
dd, J ) 15.4, 10.7 Hz), 6.59 (1 H, dd, J ) 8.6, 3.0 Hz), 6.63 (1
H, d, J ) 8.6 Hz); 13C NMR (100 MHz, CDCl3) δ 18.4 (q), 18.9
(t), 20.7 (q), 25.5 (q), 25.9 (q), 29.6 (t), 32.5 (t), 38.4 (t), 41.8
(s), 55.7 (q), 110.8 (d), 115.4 (d), 115.5 (d), 124.6 (d), 125.3 (d),
128.0 (s), 131.3 (s), 133.0 (s), 133.2 (s), 140.5 (d), 147.8 (s), 153.6
(s); MS (EI) m/z 326 (M+), 311, 283, 257, 244, 229 (base), 215,
201, 189, 175, 161, 149, 137, 133, 109, 107, 93.
Dem eth yl Ricca r d ip h en ol B (40). A solution of 28 (147.0
mg, 0.35 mmol) in pyridine (2 mL) was treated with SOCl2
(0.2 mL, 2.74 mmol) at 0 °C for 30 min. Workup as usual
afforded a residue, which was purified by silica gel column
chromatography (elution with hexane-EtOAc in gradient) to
give the olefin (77.9 mg, 55%). A solution of the olefin (93.4
mg, 0.23 mmol) in THF:3 M HCl ) 10:1 (6 mL) was heated at
50 °C for 3.5 h. Workup as usual and purification by short
silica gel afforded the diol 40 (63.8 mg, two steps 48%): 1H
NMR (200 MHz, CDCl3) δ 1.00 (3 H, s), 1.1-2.1 (6 H, m), 1.57
(3 H, s), 1.72 (3 H, s), 1.74 (3 H, s), 3.17 (1 H, d, J ) 17.2 Hz),
3.33 (1 H, d, J ) 17.2 Hz), 5.01 (1 H, br s), 5.45 (1 H, d, J )
15.4 Hz), 5.76 (1 H, d, J ) 10.6 Hz), 6.11 (1 H, dd, J ) 15.4,
10.6 Hz), 6.50 (1 H, dd, J ) 8.2, 3.0 Hz), 6.56 (1 H, d, J ) 3.0
Hz), 6.61 (1 H, d, J ) 8.2 Hz); 13C NMR (50 MHz, CDCl3) δ
18.3 (q), 18.9 (t), 20.6 (q), 25.4 (q), 25.9 (q), 29.4 (t), 32.4 (t),
38.3 (t), 41.8 (s), 112.9 (d), 115.8 (d), 115.9 (d), 116.0 (s), 124.5
(d), 125.3 (d), 131.2 (s), 132.9 (s), 133.2 (s), 140.5 (d), 147.5 (s),
149.2 (s); MS (EI) m/z 312 (M+), 297, 269, 255, 243, 230, 215
(base), 201, 189, 175, 147, 133, 123, 107, 91; EI-HRMS m/z
calcd for C21H28O2: 312.2089. Found: 312.2112.
Cycliza tion of 40. A solution of 40 (63.8 mg, 0.20 mmol)
and TsOH (16 mg) in PhH ((50 mL) was heated at 65 °C for
6.5 h. Workup as usual afforded a residue, which was purified
by HPLC (Develosil 60-3, 4.6 × 20 cm, hexane-EtOAc ) 9:1)
to give 41 (26.7 mg, 42%); [R]21D +10.7° (c 1.05, CHCl3); FTIR:
3400, 1590, 1450, 1370, 1250 cm-1; 1H NMR (600 MHz, CDCl3)
δ 1.12 (3 H, s), 1.21 (3 H, s), 1.35 (3 H, s), 1.53 (3 H, s), 1.2-
2.1 (10 H, m), 2.90 (1 H, m), 3.03 (1 H, d, J ) 16.2 Hz), 3.94 (1
H, d, J ) 16.2 Hz), 4.50 (1 H, br s), 6.53 (1 H, d, J ) 8.6 Hz),
6.47 (1 H, d, J ) 8.6 Hz); 13C NMR (125 MHz, CDCl3) δ 19.2
(q), 19.4 (t), 24.5 (q), 26.0 (t), 26.1 (q), 28.0 (d), 30.1 (t), 32.1
(t), 35.1 (t), 38.0 (s), 42.9 (t), 46.2 (t), 73.3 (s), 113.9 (d), 114.6
(d), 126.2 (s), 126.3 (d), 129.6 (s), 133.2 (s), 145.8 (s), 147.6 (s);
MS (EI) m/z 312 (M+, base), 297, 269, 255, 241, 229, 215, 175,
161, 147, 109, 95; EI-HRMS m/z calcd for C21H28O2: 312.2089.
Found: 312.2104.
(1′′E)-(1R,2R,6R)-1-(2′,5′-Dih ydr oxyben zyl)-2,6-dim eth yl-
2-(4′′-m eth ylpen ta-1′′,3′′-dien yl)cycloh exan -1-ol (33). Com-
pound 29 (19.0 mg, 0.046 mmol) was similarly treated with
THF:3 M HCl ) 10:1 (6 mL) to afford 33 (8 mg, 53%): FTIR
3340, 1620, 1600, 1500 cm-1 1H NMR (200 MHz, CDCl3) δ
;
0.82 (3 H, d, J ) 7.2 Hz), 1.13 (3 H, s), 1.0-2.1 (7 H, m), 1.75
(6 H, s), 2.81 (1 H, d, J ) 15.0 Hz), 3.04 (3 H, d, J ) 15.0 Hz),
5.75 (1 H, br d, J ) 10.6 Hz), 5.85 (1 H, d, J ) 15.4 Hz), 6.19
(1 H, dd, J ) 15.4, 10.6 Hz), 6.5-6.8 (3 H, m); 13C NMR (50
MHz, CDCl3): δ 16.1 (q), 18.3 (q), 25.9 (q), 26.0 (q), 33.9 (t ×
2), 35.5 (t × 2), 37.8 (d), 44.9 (s), 81.7 (s), 114.5 (d), 117.4 (d),
119.6 (d), 123.8 (d), 125.6 (d), 126.7 (s), 133.6 (s), 137.8 (s),
148.6 (s), 149.8 (s); MS (EI) m/z 330 (M+), 312, 297, 269, 255,
241, 207, 193, 189, 180, 161, 149, 139, 133, 123, 109 (base),
95; EI-HRMS m/z calcd for C21H30O3: 330.2195. Found:
330.2193.
4-epi-Ricca r d ip h en ol A (38). A solution of 33 (36.8 mg,
0.11 mmol) and TsOH (14 mg) in PhH (30 mL) was heated at
65 °C for 4 h. The mixture was worked up as usual and the
residue was purified by HPLC (Develosil 60-3, 4.6 × 20 cm,
hexane-EtOAc ) 9:1) to give 38 (7.7 mg, 54%) as a pale yellow
oil: [R]21D -72.7° (c 0.77, CHCl3); FTIR: 3400, 1670, 1620, 1500
1
cm-1; H NMR (200 MHz, CDCl3) δ 0.68 (3 H, d, J ) 6.8 Hz),
1.06 (3 H, s), 1.2-1.9 (7 H, m), 1.81 (6 H, s), 2.69 (1 H, d, J )
16.6 Hz), 2.93 (1 H, d, J ) 16.6 Hz), 4.40 (1 H, br s), 5.86 (1 H,
d, J ) 15.8 Hz), 5.90 (1 H, br d, J ) 10.2 Hz), 6.27 (1 H, dd, J
) 15.8, 10.2 Hz), 6.5-6.67 (3 H, m); 13C NMR (125 MHz,
CDCl3) δ 16.4 (q), 18.5 (q), 21.1 (t), 23.1 (q), 26.0 (q), 29.3 (t),
30.0 (t), 32.2 (d), 34.7 (t), 42.7 (s), 78.5 (s), 114.5 (d), 115.6 (d),
117.1 (d), 121.1 (s), 125.6 (d), 127.5 (s), 131.4 (s), 134.1 (d),
146.5 (s), 148.5 (s); MS (EI) m/z 312 (M+, base), 297, 277, 269,
255, 243, 241, 227, 215, 201, 189, 174, 162, 161, 147, 133, 123,
109, 91; EI-HRMS m/z calcd for C21H28O2: 312.2089. Found:
312.2096.
Ricca r d ip h en ol B (2). A solution of 26 (101.3 mg, 0.26
mmol) in pyridine (1 mL) was treated with SOCl2 (0.2 mL,
2.74 mmol) at 0 °C for 1 h. Water was added, and the mixture
was extracted with ether. The organic phase was washed with
1 M HCl and brine, dried (MgSO4), and evaporated. The
residue was purified by preparative TLC to give 39 (31.5 mg,
33%) as a pale yellow oil and 26 (12.1 mg): 1H NMR (200 MHz,
CDCl3) δ 0.98 (3 H, s), 1.3-2.2 (6 H, m), 1.56 (3 H, s), 1.75 (6
H, s), 3.57 (3 H, s), 3.74 (3 H, s), 5.13 (2 H, s), 5.46 (1 H, d, J
) 15.4 Hz), 5.77 (1 H, br d, J ) 10.6 Hz), 6.11 (1 H, dd, J )
15.4, 10.6 Hz), 6.65-7.00 (3 H, m).
Ack n ow led gm en t. We thank Dr. Masao Toyota
(T.B.U.) for the sample of riccardiphenol A, the spectra
of riccardiphenols A and B, and helpful discussions. The
600 MHz NMR and MS spectra were taken by Mis.
Yukiko Kan and Yasuko Okamoto, respectively (T.B.U.),
to whom our thanks are due. We are grateful to Mr. S.
Takaoka (T.B.U.) for carrying out the X-ray crystal-
lographic analysis. This work was supported (to Y.A.)
in part by a Grant-in-Aid for Cancer Research from the
Ministry of Health and Welfare, J apan.
A solution of 39 (31.5 mg, 0.085 mmol) in THF:3 M HCl )
1:1 (2 mL) was heated at 50 °C for 14 h. The solvent was
evaporated, and the residue was extracted with ether. The
organic phase was washed with water and brine, dried
(MgSO4), and evaporated. The residue was purified by pre-
parative TLC and HPLC (Develosil 60-3, 4.6 × 20 cm, hexane-
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra (35 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
EtOAc ) 9:1) to give riccardiphenol B (2) (8.8 mg, 32%): [R]21
D
-59.4° (c 1.1, CHCl3); FTIR: 3400, 1670, 1620, 1510 cm-1; 1H
J O952253U