Revision of the stereochemistry of elisabethatriene, a putative biosynthetic intermediate of pseudopterosins

Article abstract of DOI:10.1248/cpb.60.681

In the past, we have questioned the accuracy of the stereochemistry of elisabethatriene, a putative biosynthetic intermediate of pseudopterosins, in light of the configuration of elisabethatrienol isolated from Pseudopterogorgia elisabethae, which was represented as 1S,4R,9S,11S. We have reinvestigated the stereochemistry of elisabethatriene. Elisabethatriene with the reported 1S,4R,9R,11S configuration was synthesized starting from (-)-isopulegol in its enantiomeric form. The ¹H- and ¹³C-NMR data of the synthesized compound differed from those reported for elisabethatriene. In addition to the fact that elisabethatriene is converted into pseudopterosins, this finding has allowed us to propose that elisabethatriene should have the 1S,4R,9S,11S stereochemistry, which is identical to that of elisabethatrienol.

Full text of DOI:10.1248/cpb.60.681

May 2012
Note
Chem. Pharm. Bull. 60(5) 681–685 (2012)
681
Revision of the Stereochemistry of Elisabethatriene, a Putative
Biosynthetic Intermediate of Pseudopterosins
Masayuki Nasuda, Miho Ohmori, Kiyoshi Ohyama, and Yoshinori Fujimoto*
Department of Chemistry and Materials Science, Tokyo Institute of Technology; Meguro-ku, Tokyo 152–8551, Japan.
Received February 17, 2012; accepted March 5, 2012
In the past, we have questioned the accuracy of the stereochemistry of elisabethatriene, a putative bio-
synthetic intermediate of pseudopterosins, in light of the configuration of elisabethatrienol isolated from
Pseudopterogorgia elisabethae, which was represented as 1S,4R,9S,11S. We have reinvestigated the stereo-
chemistry of elisabethatriene. Elisabethatriene with the reported 1S,4R,9R,11S configuration was synthe-
1
sized starting from (ꢀ)-isopulegol in its enantiomeric form. The H- and 13C-NMR data of the synthesized
compound differed from those reported for elisabethatriene. In addition to the fact that elisabethatriene is
converted into pseudopterosins, this finding has allowed us to propose that elisabethatriene should have the
1S,4R,9S,11S stereochemistry, which is identical to that of elisabethatrienol.
Key words elisabethatriene; elisabethatrienol; pseudopterosin; Pseudopterogorgia elisabethae
Pseudopterosins are glycosylated tricyclic diterpenes isolat- preparation yielded erogorgiaene (3),8) which was further
ed from marine octocoral, Pseudopterogorgia elisabethae, and converted to pseudopterosins8) (Chart 1). Elisabethatrienol (1),
more than thirty compounds in this class have been reported1) a hydroxylated analogue of elisabethatriene, isolated by our
since the first isolation of pseudopterosins A–D.2) Our group group was determined to have the 1S,4R,9S,11S configura-
reported the isolation and characterization of pseudopterosins tion on the basis of detailed nuclear Overhauser effect (NOE)
P–V as well as related non-glycosylated diterpenes, including experiments.4) It is of note that compounds elisabethatrienol
elisabethatrienol (1) and seco-pseudopterosin K from P. elisa- and elisabethatriene have the opposite configuration at C-9,
bethae collected in San Andres and Providencia Islands in the even though the stereogenic center disappears in the following
Colombian Caribbean.3,4) It has been reported that pseudo- intermediate 3. This finding raised the possibility that elisa-
pterosin A displays potent anti-inflammatory activity2) by in- bethatriene could have the 1S,4R,9S,11S configuration (namely
hibiting both phospholipase A2 and 5-lipoxygenase.5)
compound 4) rather than the reported 1S,4R,9R,11S configura-
’
The biosynthesis of pseudopterosins was studied by Kerr s tion, since it would be reasonable to assume that the identical
group.6) These researchers reported the formation of a bicyclic stereochemical mechanism is operating in the cyclization of
compound named elisabethatriene (2a) upon incubation of GGPP leading to the two compounds.4)
geranylgeranyl diphosphate (GGPP) with a cell free prepara-
In this article, we report the results from the reinvestigation
tion of P. elisabethae. Elisabethatriene has four stereogenic of the stereochemistry that was reported for elisabethatriene.
centers that were represented as 1S,4R,9R,11S (the pseudo- This study establishes that the stereochemistry of elisa-
pterosin numbering system is applied).7) These researchers bethatriene was incorrect and the correct stereochemistry is
also reported that incubation of elisabethatriene with the same 1S,4R,9S,11S.
Chart 1. Biosynthesis of Pseudopterosins
The present study indicated that the structure of the bicyclic intermediate arising from GGPP is compound 4 rather than compound 2a.
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: fujimoto@cms.titech.ac.jp
© 2012 The Pharmaceutical Society of Japan

682
Vol. 60, No. 5
Chart 2. Synthesis of Compound 2b
The tosylate derivative 6 obtained from 5 was subjected to
Results and Discussion
We decided to synthesize the structure proposed for elisa- copper catalyzed Grignard reaction using 3-methylbut-2-enyl
bethatriene and compare the NMR data with those reported magnesium chloride to yield coupling product 7 in moderate
for elisabethatriene to examine whether the reported structure yield. A small amount (approximately 10%) of 2-isopropyl-
is correct. The outline of our retro-synthesis for the target 5-methylcyclohexan-1-ol MOM ether was also obtained. The
compound 2b (the antipode of 2a, vide infra) is described acidic treatment of compound 7 under reflux conditions in
below. The methylene moiety found in compound 2b could tetrahydrofuran (THF) yielded a deprotected product, which
be introduced easily onto the corresponding enone (see com- was purified by silica gel chromatography to remove the
pound 11 in Chart 2). Thus, the enone having the desired minor product, 2-isopropyl-5-methylcyclohexan-1-ol, and af-
configuration at the C-1, C-4 and C-11 positions becomes a forded cyclohexanol 8 in 39% yield from 6. TPAP oxidation of
requisite precursor. Such an enone could be readily obtained 8 gave cyclohexanone 9. The reaction of an enolate generated
by the Robinson annulation strategy from an appropriate from 9 by lithium diisopropylamide (LDA) treatment with
trans-2-alkyl-5-methylcyclohexanone, such as compound 9.9–11) 3-trimethylsilylbut-3-en-2-one followed by exposure of the
Manipulation of the 6-methylhept-5-en-2-yl moiety at the reaction mixture to acidic conditions yielded the 3-oxobutyl-
C-2 position of an appropriate 5-methylcyclohexanone ring cyclohexanone 10 in 49% yield.9–11) Robinson annulation of 10
at an early stage would simplify the synthesis. The analysis under the condition of Ba(OH)2 in EtOH afforded enone 11 in
led to a p-menthanediol derivative such as 2-(1-hydroxyprop- 39% yield. Syn orientation of H-4 and H-9 in 11 was expected
2-yl)-5-methylcyclohexan-1-ol methoxymethyl (MOM) ether based on results in the literature,9–11) and this expectation was
5 (cyclohexane numbering system is applied) as a candidate confirmed by NOE experiments, in which the NOE correlation
of the starting material. The (1S,2S,5R,2′S)-MOM ether 5 is was observed between the two hydrogens [H-4 (δ 1.62) and
a known compound that can be prepared from commercially H-9 (δ 1.27), in benzene-d6]. Tebbe olefination of enone 11
available (−)-(1R,3R,4S)-isopulegol.12,13) The use of (−)-iso- completed the synthesis of 2b.
1
pulegol would lead to the antipode of the target molecule 2b
The H and 13C signals of 2b were assigned by 2D-NMR
(1S,4R,9R,11S configuration). This is acceptable in the present experiments, including H–H correlation spectroscopy (COSY),
study, because we are concerned with the relative stereochem- heteronuclear multiple quantum coherence (HMQC) and het-
istry of 2a. Thus, compound 2b was chosen as our synthetic eronuclear multiple bond connectivity (HMBC) spectra (Table
target.
A
1, in benzene-d6). Extensive decoupling experiments allowed
sample of (−)-isopulegol purchased from Tokyo us to determine the coupling constants of JH-9,H-8ax=7.5Hz,
Kasei Co., Japan was an approximately 5:1 mixture of JH-9,H-8eq=5.7Hz, JH-9,H-1=10.2Hz. The large coupling con-
(−)-(1R,3R,4S)-isopulegol and (+)-(1R,3S,4S)-neoisopulegol stants of JH-9,H-8ax and JH-9,H-1 implied that these three hydro-
(the menthane numbering system is applied). The mixture gens exhibit nearly axial orientation. Furthermore, irradiation
was converted to neoisopulegol via oxidation and reduction of H-9 (δ 1.50) caused NOE enhancement to the signals of
according to a previously published protocol.14) The sample of H-4 (δ 1.74), one of the methylene protons at C-2 (δ 1.05) and
neoisopulegol was determined to be 66% enantiomeric excess H3-20 (δ 0.84). These findings provided evidence for the syn
’
(ee) by the application of the Mosher s ester method with the relationships of H-4 and H-9. The most stable conformation
(+)-(1R,3S,4S)-form being predominant ([α]D25 +20.2 (c=1.63, deduced from MM2 calculation is depicted in Fig. 1. Thus, the
CHCl3), lit.13) −22.2 for (−)-(1S,3R,4R)-form). For the sake synthesized material 2b has the 1R,4S,9S,11R configuration,
of simplicity, we hereafter describe compounds of 66% ee by and its antipode 2a should have the 1S,4R,9R,11S configura-
prefixing the R/S stereochemical designation to the compound tion.
names. The sample of (1R,3S,4S,2′S)-MOM ether 5 obtained
by hydroboration-oxidation of the (1R,3S,4S)-neoisopulegol as since elisabethatriene was analyzed in the same solvent) of
described previously12) was used in the present synthesis.
the stereochemically defined 2b with those of elisabethatriene
Comparison of the 13C-NMR data (recorded in benzene-d6,

May 2012
683
Table 1. 1H- (500MHz) and 13C- (125MHz) NMR Data (in Benzene-d6) for Compounds 2b and 2a
2b
2aa)
Position
δH (mult., J Hz)
δC
HMBC (H
→C)
δH (mult., J Hz)
δC
1
2
1.13 (mb))
1.05 (m)
1.65 (m)
1.03 (m)
1.72 (m)
1.74 (m)
6.15 (s)
—
39.5
35.9
1.70 (m)
1.20 (m)
1.60 (m)
1.45 (m)
1.58 (m)
2.24 (m)
6.12 (d, 2)
—
31.9
23.2
3
28.0c)
27.5
C-1
4
5
6
7
49.6
121.7
144.6
29.4
C-5, C-18
37.1
127.5
144.0
29.8
2.18 (m)
2.32 (m)
1.40 (mb))
1.89 (mb))
1.50 (mb))
—
2.15 (m)
2.34 (m)
1.02 (m)
1.59 (m)
1.80 (m)
—
8
27.9c)
C-9
35.2
9
10
11
12
45.3
146.4
31.9
49.9
143.9
35.5
1.98 (m)
1.05 (m)
1.65 (m)
2.07 (m)
2.18 (m)
5.31 (brt, 7.5)
—
1.77 (m)
1.20 (m)
1.63 (m)
1.96 (m)
2.15 (m)
5.19 (m)
—
32.8
29.6
C-4
13
26.6
C-11, C-12, C-14
C-14
25.9
14
15
16
17
18
19
125.4
131.2
25.9
125.6
130.9
25.9
1.71 (s)
1.61 (s)
0.99 (d, 6.8)
4.85 (s)
4.96 (s)
0.84(d, 6.4)
C-14, C-15
C-14, C-15
C-4, C-11, C-12
C-5, C-7
1.63 (d, 4.5)
1.57 (s)
17.6
17.7
18.9
0.85 (d, 7.5)
4.76 (dd, 1.5, 1.0)
4.85 (s)
15.1
108.9
109.0
C-5, C-7
20
20.4
C-1, C-2, C-9
0.89 (d, 6.5)
17.6
a) Adopted from ref. 7. b) For the accurate coupling constants revealed by decoupling experiments, see text. c) Interchangeable.
reported by Coleman and Kerr7) indicated that the two com-
pounds are apparently different from each other (even though
some of their 13C assignments were interchanged). In par-
ticular, the 13C shifts of C-1, C-4, C-5 and C-8 deviated by
more than five ppm (Table 1). Therefore, the stereochemical
assignment of elisabethatriene was incorrect and needs to be
revised. Elisabethatriene was reported to be metabolized into
pseudopterosins. This result implies that the configurations at
C-1, C-4 and C-11 positions of elisabethatriene are identical
with those of pseudopterosins (i.e., 1S,4R,11S). Thus, we con-
clude that elisabethatriene has the 1S,4R,9S,11S configuration
and is represented as 4.
The reason for the erroneous stereochemical assignment
was not apparent but may be due to the quality and interpreta-
tion of the NOE data. The assignments failed to describe the
NOE correlation between H-9 and H-4 that should have been
observed for the assigned structure to be correct.
Fig. 1. Pertinent NOE Correlations and Most Stable Conformation for
Compound 2b
In conclusion, the present study reinvestigated the stereo- but not compound 2a, as indicated in Chart 1. It remains an
chemistry of elisabethatriene, and the previously reported open question as to whether elisabethatrienol (1) is a biosyn-
stereochemistry for elisabethatriene was revised to be thetic intermediate leading to erogorgiaene (3).
1S,4R,9S,11S. This reassignment confirmed that the identical
stereochemical mechanism is operating in the enzymic forma-
tion of elisabethatriene and elisabethatrienol. A sesquiterpene
Experimental
General Experimental Procedures Melting point was
analogue of elisabethatriene, nephthene (12), isolated from an determined on a Yazawa hot-stage melting point apparatus
1
Okinawan soft coral of Nephthea sp.,15) could be formed by an and are uncorrected. H- and 13C-NMR spectra were obtained
1
enzyme that cyclizes farnesyl diphosphate in the same stereo- on a JEOL AL-400 (400MHz for H and 100MHz for 13C)
1
chemical mode as 1 and 4. The present study indicated that spectrometer in CDCl3. H chemical shifts are reported rela-
the biosynthesis of pseudopterosins proceeds via compound 4, tive to tetramethylsilane (δ 0.00) or benzene-d6 (δ 7.16), while

684
Vol. 60, No. 5
13C chemical shifts are reported relative to CDCl3 (δ 77.00). THF (30mL) at −20 C under N2 and the mixture was stirred
°
Compounds 11 and 2b were recorded on a Bruker DRX-500 at the same temperature for 1h. The resulting Grignard solu-
1
(500MHz for H and 125MHz for 13C) spectrometer in CDCl3 tion was warmed to 0 C, and CuI (200mg, 1.05mmol) and
°
and benzene-d6. When recorded in benzene-d6, H and 13C then a solution of the tosylate 6 (1.67g, 4.51mmol) in dry
1
°
chemical shifts are referenced to the signals of benzene-d6, THF (1.0mL) were added. The mixture was stirred at 40 C
δ 7.16 and δ 128.00, respectively. IR spectra were recorded for 2h and cooled with an ice water bath. Ether and brine
on a JASCO FT/IR 5300 spectrophotometer, and UV on a were added to the mixture and the ether layer was washed
Shimadzu UV-1600PC spectrometer. Optical rotations were with aq. NH4Cl, dried over Na2SO4, and concentrated to give
measured on a JASCO P-2200 polarimeter. High resolution an oily product. This product was chromatographed by MPLC
(HR)-FAB-MS (3-nitrobenzylalcohol as matrix) was obtained with hexane–toluene (1:1) as an eluent to afford coupling
on a JEOL JMS-700 spectrometer. Silica gel 60N (spherical product 7 (690mg, 57%) as a colorless oil. [α]D25 +11.3 (c=1.20,
neutral, 40–100µm, Kanto Chemical, Japan) was used for CHCl3). IR (CHCl3) cm−1: 2924, 1455, 1377, 1150, 1091, 1040,
1
column chromatography. Medium-pressure liquid chromatog- 913. H-NMR δ: 0.86 (d, J=6.8Hz, CH3-5), 0.93 (d, J=6.6Hz,
raphy (MPLC) was performed on a Yamazen pump-540 appa- CH3-2′), 1.60 (s, CH3-6′), 1.67 (s, H3-7′), 3.37 (s, OCH3), 3.92
ratus using an ULTRA PACK glass column (silica gel, 40µm, (m, H-1), 4.59, 4.72 (1H each, d, J=6.8Hz, OCH2O), 5.10 (brt,
size B) (Yamazene, Japan). THF and CH2Cl2 were distilled J=6.5Hz, H-5′). 13C-NMR δ: 17.0, 17.6, 22.4, 24.6, 25.1, 25.7,
from LiAlH4 and P2O5, respectively. (−)-Isopulegol was pur- 26.4, 33.4, 34.2, 35.2, 39.3, 46.3, 55.6, 74.0, 95.4, 125.1, 130.9.
chased from Tokyo Chemical Industry Co., Japan
HR-FAB-MS m/z: 269.2486 [M+H]+ (Calcd for C17H33O2:
Ee Determination of (+)-Neoisopulegol Neoisopu- 269.2481). The NMR analysis revealed the material to be
legol prepared from commercial (−)-isopulegol as described accompanied by approximately 10% (1S,2S,5R)-2-isopropyl-
previously exhibited a positive sign of the optical rotation, 5-methylcyclohexan-1-ol methoxymethyl ether that was pro-
[α]D25 +20.2 (c=1.63, CHCl3); lit.13) −22.2 for (−)-(1R,3S,4S)- duced by the reduction of the tosyloxy group and could not be
form)). (S)- and (R)-α-Trifluoromethyl-α-methoxyphenylacetic separated by MPLC.
acid (MTPA) ester were prepared from neoisopulegol (1mg)
(1S,2S,5R)-5-Methyl-2-[(R)-6-methylhept-5-en-2-yl]-
by reacting (R)- and (S)-MTPA chlorides, respectively, in cyclohexan-1-ol (8) A solution of the coupling product 7
1
pyridine as described in our previous paper.16) Pertinent H- (420mg, 1.56mmol) in THF (5.0mL) and 4M HCl (0.50mL)
NMR (500MHz, CDCl3) data for the (S)-MTPA, δ: 5.56 (m, was heated under reflux for 3h and was cooled to room tem-
0.17H, H-3), 5.52 (m, 0.83H, H-3), 4.85 (s, 0.83H, H-9a), 4.71 perature. The usual work-up with ether for extraction gave
(s, 0.83H, H-9b), 4.68 (s, 0.17H, H-9a), 4.56 (s, 0.17H, H-9b), an oily product, which was chromatographed on silica gel
1.77 (s, 2.49H, H-10), 1.71 (s, 0.51H, H-10), 0.90 (d, J=6.7Hz, with hexane–ether (20:1) as an eluent to afford alcohol 8
0.51H, H-7), 0.81 (d, J=6.6Hz, 2.49H, H-7). The (R)-MTPA (240mg, 68%). Further elution with the same solvent yielded
1
exhibited the complimentary H-NMR data.
(1S,2S,5R)-2-isopropyl-5-methylcyclohexan-1-ol (20mg) as a
(−)-Isopulegol separated by silica gel chromatography of colorless oil. [α]D25 –2.9 (c=1.90, CHCl3), IR (CHCl3) cm−1:
the commercially available isopulegol was determined to be 3618, 2920, 1451, 1377. H-NMR δ: 0.87 (d, J=6.3Hz, CH3-5),
1
’
66% ee by the Mosher s ester method. This finding supported 0.96 (d, J=6.6Hz, CH3-2′), 1.60 (s, CH3-6′), 1.67 (s, H3-7′),
the above ee value of (+)-neoisopulegol and implied that the 4.10 (m, H-1), 5.10 (brt, J=7.2Hz, H-5′). 13C-NMR δ: 16.8,
optical rotation of enantimerically pure neoisopulegol is larger 17.6, 22.3, 24.2, 25.1, 25.7, 26.0, 33.8, 34.4, 35.1, 42.7, 45.9,
than the reported value.
67.8, 124.9, 131.1. Anal. Calcd for C15H28O: C, 80.29; H, 12.58.
(1S,2S,5R)-5-Methyl-2-[(S)-1-p-toluensulfonyloxypropan- Found: C, 80.01; H, 12.32.
2-yl]cyclohexan-1-ol Methoxymethyl Ether (6) A solution
(2S,5R)-5-Methyl-2-[(R)-6-methylhept-5-en-2-yl]cyclo-
containing compound 5 (1.07g, 4.95mmol) and TsCl (2.00g, hexan-1-one (9) Tetrapropylammonium perruthenate (18mg,
10.5mmol) in pyridine (7.00mL) was stirred at room tempera- 51.2µmol), 4-methylmorpholine-N-oxide (176mg, 1.50mmol)
ture for 2h. The mixture was stirred for 10min after addition and molecular sieves 4A (powdered, 500mg) were added to a
of a piece of ice. The usual work-up with EtOAc for extraction stirred solution of alcohol 8 (220mg, 980µmol) in dry CH2Cl2
gave an oily product, which was chromatographed on silica (3.0mL) under N2, and the mixture was stirred at room tem-
gel with hexane–EtOAc (10:1) as an eluent to afford the to- perature for 1h. The reaction mixture was diluted with ether
°
sylate (1.67g, 91%) as colorless needles, mp 65–66 C (from (15mL), subjected to a Florisil column and eluted with ether.
hexane). [α]D25 +17.3 (c=2.20, CHCl3). IR (CHCl3) cm−1: 2926, Concentration of the filtrate yielded an oily product, which
1
1597, 1455, 1359, 1175, 1150, 1097, 1038, 963, 938. H-NMR was chromatographed on silica gel with hexane–toluene
δ: 0.84 (d, J=6.0Hz, CH3-5), 0.97 (d, J=6.8Hz, CH3-2′), 2.45 (2.5:1) as an eluent to afford ketone 9 (175mg, 80%) as a
(s, p-CH3), 3.32 (s, OCH3), 3.82 (m, H-1), 3.97 (dd, J=9.2, colorless oil. [α]D25 −17.5 (c=1.90, CHCl3), IR (CHCl3) cm−1:
1
5.6Hz, Ha-1′), 4.07 (dd, J=9.2, 3.2Hz, Hb-1′), 4.52, 4.66 (1H 2928, 1703, 1455, 1377. H-NMR δ: 0.92 (d, J=7.0Hz, CH3-5),
each, d, J=6.8Hz, OCH2O), 7.34, 7.78 (2H each, d, J=8.0Hz, 1.00 (d, J=6.5Hz, CH3-2′), 1.60 (s, CH3-6′), 1.68 (s, H3-7′),
aromatic). 13C-NMR δ: 15.3, 21.7, 22.3, 23.9, 26.0, 34.1, 34.6, 5.12 (brt, J=7.2Hz, H-5′). 13C-NMR δ: 17.5, 17.6, 22.3, 25.7,
38.7, 42.9, 55.7, 73.3, 74.0, 95.0, 127.8, 129.6, 133.0, 144.5. 26.0, 28.1, 31.0, 33.2, 34.0, 35.2, 50.9, 55.3, 124.8, 131.2, 212.2.
Anal. Calcd for C19H30O5S: C, 61.59; H, 8.16; S, 8.65. Found: Anal. Calcd for C15H26O: C, 81.02; H, 11.79. Found: C, 80.96;
C, 61.42; H, 8.00; S, 8.74.
H, 11.50.
(2S,5R,6S)-5-Methyl-2-[(R)-6-methylhept-5-en-2-yl]-6-
(1S,2S,5R)-5-Methyl-2-[(R)-6-methylhept-5-en-2-yl]cy-
clohexan-1-ol Methoxymethyl Ether (7) 3-Methyl-2-butenyl (3-oxobutyl)cyclohexan-1-one (10) n-BuLi (1.40M, 0.80mL,
chloride (1.73mL, 17.8mmol) was added dropwise to a stirring 1.12mmol) was added to a solution of diisopropylamine
°
suspension of magnesium turnings (340mg, 14.0mmol) in dry (158µL, 1.21mmol) in dry THF (3.0mL) at −78 C under N2

May 2012
685
and the mixture was stirred at the same temperature for 1h. A 55µmol) in dry THF (0.40mL) and the mixture was stirred
°
solution of ketone 9 (75mg, 337µmol) in dry THF (0.50mL) at 0 C for 40min. The mixture was, diluted with hexane and
was added to the resulting lithium diisopropylamide solution applied to a silica gel column. Elution of the column with
and the mixture was stirred at −78 C for 1h. 3-Trimethylsilyl- hexane furnished compound 2b (10.5mg, 70%). [α]D25 −72.2
°
but-3-en-2-one (154mg, 1.08mmol) was added dropwise, and (c=1.05, CHCl3). UV λmax (MeOH) nm (logε): 240 (3.92). IR
the mixture was warmed up from −78 to 0 C over a period of (CHCl3) cm−1: 2927, 1635, 1456, 1377, 885, 870. 1H-NMR
°
1h. Next, 4N HCl (3.00mL) was added, and the mixture was (500MHz, CDCl3) δ: 0.94 (d, J=6.3Hz, H3-20), 0.98 (d,
stirred without cooling for 20min. The usual work-up with J=6.8Hz, H3-18), 1.64 (s, H3-17), 1.71 (s, H3-16), 4.66 (s, H-
ether for extraction afforded an oily product, which was chro- 19a), 4.70 (s, H-19b), 5.19 (brt, J=6.7Hz, H-14), 5.90 (s, H-5).
matographed on silica gel with hexane–toluene (1:1) as an 13C-NMR (125MHz, CDCl3) δ: 17.6, 18.7, 20.3, 25.8, 26.2,
eluent to recover the starting ketone (17mg). Further elution 27.5, 27.6, 28.9, 31.6, 32.3, 35.7, 39.3, 45.1, 49.3, 108.3, 120.8,
1
with hexane–ether (10:1) afforded diketone 10 (48mg, 49%) 125.0, 131.4, 144.6, 147.0. H- and 13C-NMR data recorded in
as a colorless oil. [α]D25 −34.4 (c=0.86, CHCl3), IR (CHCl3) benzene-d6, see Table 1. HR-FAB-MS m/z: 273.2598 [M+H]+
1
cm−1: 2931, 1706, 1451, 1377. H-NMR δ: 0.90 (d, J=6.8Hz, (Calcd for C20H33, 273.2582). Compound 2b was unstable in
CH3-5), 1.06 (d, J=6.1Hz, CH3-2′), 1.61 (s, CH3-6′), 1.68 (s, CDCl3 based on the NMR results in which approximately half
H3-7′), 2.13 (s, H3-4″), 5.12 (brt, J=7.2Hz, H-5′). 13C-NMR δ: of 2b was decomposed after 24h.
17.7, 17.7, 20.3, 20.7, 25.7, 25.8, 29.5, 29.9, 31.2, 33.1, 34.9, 40.4,
41.4, 56.4, 57.0, 124.8, 131.2, 209.2, 213.3. HR-FAB-MS m/z:
References
293.2474 [M+H]+ (Calcd for C19H33O2: 293.2481).
1) Berrué F., McCulloch M. W. B., Kerr R. G., Bioorg. Med. Chem.,
19, 6702–6719 (2011).
The Enone (11) A mixture of 10 (45mg, 154µmol) and
Ba(OH)2·8H2O (81mg, 257µmol) in EtOH (0.40mL) was
stirred at room temperature for 2h under N2. The usual work-
up with ether for extraction gave an oily product, which was
chromatographed on silica gel with hexane–CHCl3 (1:1) as
an eluent to afford enone 11 (16mg, 38%) as a colorless oil.
[α]D25 −31.4 (c=0.28, CHCl3). UV λmax (MeOH) nm (logε):
241 (4.32). IR (CHCl3) cm−1: 2927, 1662, 1614, 1454, 1379.
1H-NMR (500MHz, CDCl3) δ: 0.98 (d, J=6.7Hz, H3-20), 1.03
(d, J=6.5Hz, H3-18), 1.62 (s, H31-17), 1.69 (s, H3-16), 5.12 (brt,
J=7.2Hz, H-14), 5.83 (s, H-5). H-NMR (500MHz, benzene-
d6) δ: 0.70 (d, J=6.4Hz, H3-20), 0.84 (m, H-2ax), 0.86 (d,
J=6.8Hz, H3-18), 0.90 (m, H-3ax), 0.98 (m, H-12a), 1.00 (m,
H-1), 1.27 (m, H-8ax, H-9), 1.46 (m, H-2eq, H-12b), 1.62 (m,
H-4), 1.62 (s, H3-17), 1.67 (m, H-3eq), 1.73 (m, H-8eq), 1.75
(s, H3-16), 1.77 (m, H-11), 1.97 (m, H-13a), 2.06 (m, H-7ax, H-
13b), 2.25 (m, H-7eq), 5.25 (brt, J=7.3Hz, H-14), 6.03 (s, H-5).
13C-NMR (125MHz, CDCl3) δ: 17.8, 18.4, 20.3, 25.6, 25.7,
25.9, 28.7, 31.7, 32.5, 35.1, 35.1, 39.1, 45.8, 50.6, 122.1, 124.4,
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1997, 3435–3442 (1997).
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V. J., Alemán C., J. Org. Chem., 66, 3775–3782 (2001).
131.7, 169.6, 200.1. 13C-NMR (125MHz, benzene-d6) δ: 17.7, 13) Yadav J. S., Bhasker E. V., Srihari P., Tetrahedron, 66, 1997–2004
(2010).
18.5, 20.2, 25.8, 26.0, 26.2, 28.0, 31.6, 32.7, 35.2, 35.6, 39.0,
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45.4, 50.2, 122.9, 124.9, 131.8, 166.5, 197.6. HR-FAB-MS m/z:
275.2373 [M+H]+ (Calcd for C19H31O, 275.2375).
Compound (2b) Tebbe reagent in toluene (0.5M, 180µL,
90.0µmol) was added to a solution of enone 11 (15mg,