Synthesis of the reported structure of trans-africanan-1α-ol

Article abstract of DOI:10.1021/jo2018558

A trisubstituted cyclopentane chiron has been prepared by dynamic kinetic reduction of a pulegone-derived β-keto ester. This chiron served as the starting material for the synthesis of the reported structure of the tricyclic sesquiterpene trans-africanan-

Full text of DOI:10.1021/jo2018558

Article
pubs.acs.org/joc
Synthesis of the Reported Structure of trans-Africanan-1α-ol
Douglass F. Taber,* Sha Bai, and Weiwei Tian
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: A trisubstituted cyclopentane chiron has been prepared by dynamic kinetic
reduction of a pulegone-derived β-keto ester. This chiron served as the starting material for
the synthesis of the reported structure of the tricyclic sesquiterpene trans-africanan-1α-ol.
The synthetic material was not congruent with the natural product.
Preparation of 2. Enantioselective yeast reductions2 of β-
keto esters have been known for many years. However, the
contrathermodynamic kinetic reduction of a cyclic β-keto ester
had not been described.3 We envisioned that yeast reduction of
the ester 6 (Scheme 2), a mixture of equilibrating
INTRODUCTION
■
trans-Africanan-1α-ol1 is a new sesquiterpene alcohol isolated
from Lippia integrifolia, which grows wild in the province of
Catamarca, Argentina. The indigenous population of Argentina
and Paraguay use Lippia integrifolia in traditional medicine for
the treatment of asthma. One of the unusual components of the
essential oil of L. intefriflia, trans-africanan-1a-ol (eq 1) was
Scheme 2
reported to have a tricyclic architecture 1 (eq 1), with five
contiguous stereogenic centers, making it a challenge for total
synthesis. We have completed the synthesis of 1 and have
found that the material so prepared is not congruent with the
reported natural product.
RESULTS AND DISCUSSION
We envisioned that the synthesis of 1 could start with the
cyclopentanol 2 (Scheme 1). The cis ester group of 2 presented
■
Scheme 1
diastereomers, could preferentially convert the minor cis
diastereomer to the corresponding secondary alcohol 2.
The original yeast protocols needed saccharose and water2b
or aqueous ethyl chloroacetate.2a Product recovery required
either extraction of the product from the aqueous saccharose
broth, or filtration, to wash the reaction products off the bulk
a particular problem for diastereocontrol. We anticipated that
after extension of the side chain 1,2-addition to the derived
cyclopentanone would give the tertiary alcohol 3, securing the
angular stereogenic center. After relay ring-closing metathesis,
Simmons−Smith cyclopropanation of the tertiary alcohol 4
would complete the preparation of 1.
Received: September 7, 2011
Published: November 4, 2011
© 2011 American Chemical Society
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yeast. In 1997, Smallridge reported an improved procedure
using yeast in water and light petroleum.2c This protocol had
not been applied to cyclic β-keto esters.
Scheme 5
The enantiomerically pure β-keto ester 6 was readily
available from (R)-(+)-pulegone.4 However, the reported
ozonolysis conditions gave low material recovery. We found
that simply carrying out the ozonolysis in aqueous acetone at 0
°C as described by Dussault5 worked well. The crude product
collected after extraction could be used directly in the yeast
reduction.
The Smallridge protocol using Baker’s yeast in a mixture of
water and petroleum ether at room temperature took 3 days to
go to completion. Simple filtration and washing of the yeast
residue with acetone and petroleum ether followed by
chromatography then delivered the cis β-hydroxy ester 2 as a
single dominant diastereomer. The stereocenters were proved
by X-ray crystallography of the derivative 8.
Preparation of 3. We anticipated that while propionitrile
could be allylated,6 the product would be of such low molecular
weight that it could be difficult to handle. Alternatively, the
nonvolatile nitrile 12 (Scheme 3) could be easily prepared from
NH4Cl(aq) was important to achieve acceptable product
recovery. The neat tertiary allylic alcohol 3 was sufficiently
stable to be stored at room temperature for several weeks.
Preparation of 4. The relay ring-closing metathesis8
(Scheme 6) proceeded smoothly to generate the cycloheptene
Scheme 3
Scheme 6
the inexpensive butadiene telomer 2,7-octadienol 9, setting the
stage for relay ring-closing metathesis. The intermediate 10 was
used directly without purification to alkylate6 excess depronated
propionitrile 11.
Bond formation (Scheme 4) proceeded smoothly without
protection of the secondary alcohol of 13. The two
ring. The nitrile 4 was crystalline, allowing us to assign the
relative configurations of 14a and 14b (Scheme 4) by X-ray
analysis. The diastereomeric nitrile 14b and the products
derived from it participated equally well in each of the
subsequent transformations, leading also to 1.
Scheme 4
Synthesis of 1. We envisioned that the traditional
Simmons−Smith reaction could set the cyclopropane ring.
However, it had been reported that the hydroxyl group would
direct the cyclopropane ring syn on a cyclohexene ring9a or
trans on a cyclooctene ring.9b On the basis of a computationally
derived model of our cycloheptene 4, it appeared that the
hydroxyl group should deliver the methylene on the bottom
face on the alkene.9c
In the event, Simmons−Smith cyclopropanation10 of the
cyclic alkene 4 (Scheme 6) proceeded smoothly to give 16, the
relative configuration of which was again secured by X-ray
crystallography. This became important because Dibal reduc-
tion followed by Wolff−Kishner deoxygenation11 delivered a
product tertiary alcohol 1 that was not congruent with the
reported natural product. Although many of the structures of
the africanane sesquiterpenes have been confirmed by total
synthesis,12,13 there is at least one other example12g of synthesis
uncovering an incorrect structural assignment.
diastereomers 14a and 14b could be readily separated by silica
gel chromatography.
To establish the tertiary alcohol stereocenter, we oxidized the
secondary alcohol 14a with the Dess−Martin reagent. Addition
of 2-propenylmagnesium bromide was not successful, even with
the direct addition of anhydrous CeCl3. With the addition of
anhydrous CeCl3 complexed with THF,7 however, we were
able to effect the 1,2-addition to the less hindered face of the
ketone 15 to give 3 (Scheme 5). The complex was prepared by
sonication of CeCl3 in anhydrous THF. Workup with 5%
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Hz), 2.33−2.42 (m, 1H), 1.78−1.90 (m, 2H), 1.66−1.77 (m, 1H),
1.53−1.63 (m, 1H), 1.25 (t, 3H, J = 7.1 Hz), 0.99 (d, 3H, J = 7.2 Hz).
13C NMR (400 MHz, CDCl3): δ d 14.2, 18.8, 34.6, 52.5, 74.0; u 31.4,
33.4, 60.3, 174.5. IR (film): 3501, 2962, 2878, 1713, 1459 cm−1. MS
(m/z): 55, 69, 87, 101, 115, 127, 144, 171. HRMS calcd for C9H17O3
173.1178; obsd 173.1176. [α]D −0.360 (c 3.89, CHCl3).
CONCLUSION
■
The ready availability of the cyclopentane chiron 2 enabled the
concise assembly of the tricyclic alcohol 1. It is clear that the
elucidation of the actual structure of trans-africanan-1α-ol will
require further study. We expect that both the cyclopentane
chiron 2 and the nitrile 12 will have many applications in target
directed synthesis.
(1S,2S,3R)-2-(Hydroxymethyl)-3-methylcyclopentanol (7).
To a gray suspension of LiAlH4 (7.21 g, 176 mmol) in Et2O (116
mL) was added a solution of the β-hydroxy ester 2 (7.49 g, 42.2
mmol) in Et2O (60 mL) dropwise over 10 min at 0 °C. The resulting
mixture was warmed to rt and stirred at rt for 4.5 h. Then H2O/THF
(1:9, 75 mL) was added dropwise over 17 min at 0 °C followed by
stirring at rt for 1.5 h. 15% NaOH (aq, 7.5 mL) was added in one
portion followed by stirring at rt for another 1.5 h. Water (22.5 mL)
was added in one portion followed by stirring overnight. The reaction
mixture was filtered with Et2O through a pad of MgSO4. The filtrate
was concentrated, and the residue was purified by chromatography to
yield the diol 7 as a colorless oil (5.09 g, 90% yield). TLC Rf (20%
EXPERIMENTAL SECTION
■
General. 1H NMR (at 400 MHz) and 13C NMR (at 100 MHz)
spectra were obtained as solutions in CDCl3, except as otherwise
indicated. 13C multiplicities were determined with the aid of a JVERT
pulse sequence, differentiating the signals for methyl and methine
carbons as “d” and for methylene and quaternary carbons as “u”. High-
resolution mass spectra (HRMS) were obtained by electronspray
ionization (ESI), except as otherwise indicated, and the errors between
observed and theoretical monoisotopic molecular masses were
typically ≤5 ppm. The infrared (IR) spectra were determined as
neat oils or a solution in dichloromethane as indicated. Rf values
indicated refer to thin layer chromatography (TLC) on 5.0 × 10 cm,
250 μm analytical plates coated with silica gel 60 F254, developed in the
solvent system indicated. Column chromatography was carried out by
using silica gel 60 particle size 40−63 μm. The solvent mixtures
reported are volume/volume mixtures. All glassware was oven-dried
and reactions were carried out under a flow of nitrogen. MTBE is
methyl tert-butyl ether. PE is petroleum ether.
1
MTBE/dichloromethane) = 0.26. H NMR (400 MHz, CDCl3): δ
4.43 (q, 1H, J = 11.0 Hz), 3.88 (t, 1H, J = 4.4 Hz), 3.77 (dd, 1H, J =
4.4 Hz, 10.4 Hz), 3.16 (m, 2H), 2.03−2.14 (m, 2H), 1.87−1.97 (m,
1H), 1.69−1.82 (m, 2H), 1.39−1.49 (m, 1H), 0.97 (d, 3H, J = 6.8
Hz). 13C NMR (400 MHz, CDCl3): δ d 16.6, 33.8, 47.8, 75.6; u 31.5,
33.3, 60.5. IR (film): 3354, 2952, 1458, 1338, 1040 cm−1. MS (m/z)
53, 55, 57, 68, 70, 79, 81, 83, 94, 97, 112. HRMS calcd for C7H12O
112.0888; obsd 112.0884. [α]D + 37.3 (c 1.94, CHCl3).
(Bis)-4-nitrobenzoate (8). To a mixture of the diol 7 (148 mg,
1.141 mmol), DMAP (72 mg, 0.59 mmol), and p-nitrobenzoic acid
(1.93 g, 11.6 mmol) in dichloromethane (11.5 mL) was added N,N′-
diisopropylcarbodiimide (2.99 g, 23.7 mmol) over 30 s at 0 °C. The
resulting mixture was warmed to rt, stirred at rt for 2 h, and then
filtered through a pad of silica gel with dichloromethane. The filtrate
was concentrated, and the residue was stirred with NaOH (aq, 6 M, 20
mL) and dichloromethane (20 mL) at rt overnight and then
partitioned between H2O and dichloromethane. The combined
organic extract was dried (Na2SO4) and concentrated, and the residue
was purified by chromatography to yield the derivative 8 as a pale
yellow solid (0.492 g). Recrystallization of a 0.160 g sample from
EtOAc yielded 148 mg of pale yellow crystals (93% yield from 7); mp
Ethyl (1R, 2R)-2-Methyl-5-(propan-2-ylidene)-
cyclopentanecarboxylate (Ethyl Pulegenate) (5). Following the
procedure of Marx,4c fresh NaOEt was prepared by dissolving Na
(23.16 g, 1.007 mol) in EtOH (400 mL). Bromine was added
dropwise into a mixture of pulegone (65.24 g, 428.5 mmol) and
NaHCO3 (10.82 g, 128.8 mmol) in Et2O (350 mL) over 2 h at 0 °C
with rapid stirring. Stirring was continued at 0 °C for another 2 h. The
mixture was filtered with Et2O (50 mL) through a pad of Celite into
the freshly made NaOMe solution in EtOH (400 mL) at 0 °C. The
reaction mixture was warmed to reflux overnight. The cooled reaction
mixture was filtered with Et2O (200 mL) through a pad of Celite. The
crude product was concentrated and purified by bulb to bulb
distillation (0.5 Torr, bp (pot) = 90 °C) to yield the ethyl ester 5
1
= 128−129 °C. TLC Rf (20% MTBE/PE) = 0.29. H NMR (400
MHz, CDCl3): δ 8.20−8.27 (m, 4H), 8.09−8.15 (m, 4H), 5.66 (dt,
1H, J = 2.7, 5.9 Hz), 4.55 (d, 2H, J = 7.6 Hz), 2.58−2.68 (m, 1H),
2.41−2.53 (m, 1H), 2.12−2.25 (m, 1H), 1.94−1.09 (m, 2H), 1.57−
1.68 (m, 1H), 1.16 (d, 3H, J = 7.1 Hz). 13C NMR (400 MHz, CDCl3):
δ d 16.9, 33.4, 45.3, 78.0, 123.4, 123.5, 130.2, 130.6; u 31.5, 31.8, 62.6,
135.2, 135.5, 150.4, 164.0, 164.5. IR (film): 3424, 2967, 2076, 1722,
1643 cm−1. [α]D + 5.33 (c 2.21, CHCl3).
as a pale yellow oil (63.11 g, 75% yield). The H and 13C NMR data
1
were consistent with those reported.4c TLC Rf (10% MTBE/PE) =
0.74.
Ethyl (1R,2S,5R)-2-Hydroxy-5-methylcyclopentanecarboxy-
late (2). Applying the protocol of Dussault,5 a mixture of the distilled
ethyl pulegenate 5 (14.05 g, 71.68 mmol) and 5% H2O/acetone (450
mL) was bubbled with O2/O3 at 0 °C for 6 h, when Sudan III
indicator was bleached. The reaction mixture was diluted with H2O
(200 mL) and stirred at rt until no more bubbles were observed and
then partitioned between dichloromethane and H2O. The combined
organic extract was concentrated to yield the crude β-keto ester 6 as a
pale yellow oil (14.58 g), which was used in the yeast reduction
without further purification. The NMR data were consistent with the
(2E)-2-Methyldeca-4,9-dienenitrile (12). LDA was prepared by
adding n-BuLi (2.5 M, 84.0 mL, 210 mmol) to a solution of
diisopropylamine (30.5 mL, 218 mmol) in THF (450 mL) at −78 °C
in one portion. Then a solution of propionitrile (14.3 mL, 200 mmol)
in THF (50 mL) was added dropwise over 7 min. Stirring was
continued at −78 °C for 1 h.
data reported.4d TLC Rf (5% MTBE/dichloromethane) = 0.72. H
1
At the same time, a solution of 2,7-octadienol (15.2 g, 120 mmol) in
THF (200 mL) was cooled to −78 °C. n-BuLi (2.5 M, 44.0 mL, 110
mmol) was added dropwise over 3 min followed by benzenesulfonyl
chloride (12.8 mL, 100 mmol) over 2 min. Stirring was continued at
−78 °C for 15 min to generate (2E)-octa-2,7-dienyl 4-bromobenze-
nesulfonate (10) in situ. The reaction mixture was quickly poured into
the stirring nitrile anion solution. The resulting mixture was stirred at
−78 °C (∼rt) overnight. The product was purified by chromatography
followed by bulb to bulb distillation (0.5 Torr, bp (pot) = 100 °C) to
yield the nitrile 12 as a colorless oil (15.2 g, 93% yield based on the
NMR (400 MHz, CDCl3): δ 4.15 (q, 2H, J = 7.2 Hz), 2.70 (d, 1H, J =
11.8 Hz), 2.50−2.58 (m, 1H), 2.22−2.40 (m, 2H), 2.10−2.18 (m,
1H), 1.38−1.48 (m, 1H), 1.24 (t, 3H, J = 7.2 Hz), 1.13 (d, 3H, J = 6.5
Hz). 13C NMR (400 MHz, CDCl3): δ d 14.1, 19.1, 36.3, 63.0; u 29.2,
38.6, 61.1, 169.1, 211.9. IR (film): 2963, 1755, 1726, 1459, 1374 cm−1
.
A mixture of the crude β-keto ester 6 (2.11 g), yeast (66.0 g), H2O
(52.8 mL), and petroleum ether (211 mL) was mechanically stirred at
rt for 3 days. The resulting broth was diluted with acetone (200 mL)
and filtered with petroleum ether (2.5 L). The filtrate was
concentrated, and the residue was purified by chromatography
followed by bulb to bulb distillation (0.5 Torr, bp (pot) = 110 °C)
to give the β-hydroxy ester 2 as a colorless oil (0.580 g, 32% yield from
the distilled ethyl pulegenate 5). TLC Rf (5% MTBE/dichloro-
methane) = 0.51. 1H NMR (400 MHz, CDCl3): δ 4.31−4.37 (m, 1H),
4.16 (q, 2H, J = 7.2 Hz), 3.80 (bs, 1H), 2.70−2.74 (dd, 1H, J = 4.6, 8.9
1
limiting reagent BsCl). TLC Rf (5% MTBE/PE) = 0.40. H NMR
(400 MHz, CDCl3): δ 5.74−5.85 (m, 1H), 5.54−5.63 (m, 1H), 5.37−
5.46 (m, 1H), 4.93−5.04 (m, 2H), 2.57−2.68 (m, 1H), 2.22−2.32 (m,
2H), 2.01−2.10 (m, 4H), 1.42−1.52 (m, 2H), 1.29 (d, 3H, J = 7.1
Hz). 13C NMR (400 MHz, CDCl3): δ d 17.4, 25.9, 124.7, 135.0, 138.6;
u 28.4, 31.8, 33.1, 36.9, 114.6, 122.7. IR (film): 2929, 2241, 1726,
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1642, 1451 cm−1. MS (m/z): 55, 67, 81, 95, 109, 121, 134, 148, 162.
HRMS calcd for C11H18N (M + H) 164.1439; obsd 164.1433.
((1S,2S,5R)-2-Hydroxy-5-methylcyclopentyl)methyl 4-Meth-
ylbenzenesulfonate (13). Triethylamine (4.10 mL, 29.6 mmol) was
added into a solution of the diol 7 (1.74 g, 13.4 mmol) in
dichloromethane (14.0 mL) in one portion followed by the addition of
TsCl (5.11 g, 26.8 mmol) in one portion. The reaction mixture was
stirred at rt overnight, then quenched with HCl (aq, 1 M, 13.4 mL),
and partitioned between dichloromethane and H2O. The combined
organic extract was dried (Na2SO4) and concentrated, and the residue
was purifed by chromatography to yield the tosylate 13 as a thick
yellow oil (3.51 g, 92% yield). TLC Rf (2% MTBE/dichloromethane)
= 0.25. 1H NMR (400 MHz, CDCl3): δ 7.79−7.83 (d, 2H, J = 8.2 Hz),
7.33−7.37 (d, 2H, J = 8.2 Hz), 4.28−4.38 (m, 2H), 4.12−4.17 (dd,
1H, J = 5.7, 9.9 Hz), 2.45 (s, 3H), 2.09−2.22 (m, 2H), 1.87−1.97 (m,
2H), 1.78−1.87 (m, 2H), 1.66−1.76 (m, 1H), 1.43−1.55 (m, 1H),
0.90 (d, 3H, J = 6.8 Hz). 13C NMR (400 MHz, CDCl3): δ d 17.1, 21.6,
33.2, 46.6, 73.6, 127.9, 129.9; u 32.1, 33.9, 68.8, 133.0, 144.8. IR
(film): 3555, 2954, 1922, 1598, 1456 cm−1. MS (m/z): 69, 82, 115,
139, 166. HRMS calcd for C14H20O4NaS 307.0980; obsd 307.0992.
[α]D − 5.56 (c 0.99, CHCl3).
5.73−5.87 (m, 1H), 5.53−5.63 (m, 1H), 5.41−5.52 (m, 1H), 4.92−
5.06 (m, 2H), 2.72−2.82 (m, 1H), 2.31−2.43 (m, 2H), 2.24−2.31 (m,
1H), 2.12−2.24 (m, 2H), 2.00−2.12 (m, 6H), 1.77−1.86 (m, 1H),
1.40−1.53 (m, 3H), 1.32 (s, 3H), 0.89 (d, 3H, J = 7.2 Hz). 13C NMR
(400 MHz, CDCl3): δ d 14.9, 24.8, 33.2, 51.9, 123.2, 136.4, 138.6; u
27.8, 28.4, 31.9, 33.1, 33.1, 33.4, 36.3, 42.0, 114.6, 124.0, 218.0. IR
(film): 3463, 3075, 2929, 2360, 2233, 1740 cm−1. MS (m/z): 43, 55,
67, 83, 98, 111, 123, 135, 149, 163, 258, 260, 273. HRMS calcd for (M
− H) = C18H28NO 274.2171; obsd 274.2174. [α]D − 104 (c 1.02,
CHCl3).
(2R,3E)-2-(((1R,2S,5R)-2-Hydroxy-5-methyl-2-(1-
methylethenyl)cyclopentyl)methyl)-2-methyldeca-4,9-diene-
nitrile (3). Isopropenylmagnesium bromide was prepared by adding a
solution of 2-bromopropene (0.90 mL, 10.1 mmol) in THF (10 mL)
into a suspension of Mg (367 mg, 15.1 mmol) and I2 (catalytic
amount) in THF (10 mL) dropwise over 5 min at reflux. The resulting
mixture was heated at reflux for 4 h and then cooled to rt to give a pale
gray solution.
A thick white suspension of anhydrous CeCl3 (790 mg, 3.21 mmol)
in THF (6.0 mL) was activated by sonication at rt for 4 h. The
resulting milky suspension was cooled to 0 °C followed by adding the
isopropenylmagnesium bromide solution (5.30 mL, 2.69 mmol)
dropwise over 5 min. The resulting mixture was stirred at 0 °C for
1 h, turning to a dark brown suspension. This was cooled to −78 °C.
Then the ketone 15 (230 mg, 0.842 mmol) in THF (12 mL) was
added dropwise over 5 min. The resulting mixture was stirred at −78
°C for 1 h, then quenched with 5% NH4Cl (aq, 18 mL), and
partitioned between H2O and dichloromethane. The combined
organic extract was dried (Na2SO4) and concentrated. The residue
was purified by chromatography to yield the ter-alcohol 3 as a yellow
(2R,3E)-2-(((1R,2S,5R)-2-Hydroxy-5-methylcyclopentyl)-
methyl)-2-methyldeca-4,9-dienenitrile (14a) and (2S,3E)-2-
(((1R,2S,5R)-2-Hydroxy-5-methylcyclopentyl)methyl)-2-meth-
yldeca-4,9-dienenitrile (14b). LDA was prepared by adding n-BuLi
(15.0 mL, 2.5 M, 37.5 mmol) into a solution of diisopropylamine
(5.70 mL, 40.7 mmol) in THF (40 mL) in one portion at −78 °C. A
solution of the nitrile 12 (5.75 g, 35.3 mmol) in THF (40 mL) was
added over 5 min. Stirring was continued at −78 °C for another 2 h. A
solution of the tosylate 13 (2.50 g, 8.80 mmol) in THF (20 mL) was
added in one portion. The resulting mixture was gradually warmed to
rt, and stirring was continued for 4 h. The reaction mixture was
concentrated, and the residue was purified by chromatography to yield
the mixture of the nitriles 14a and 14b as a pale yellow oil (2.38 g,
98% yield). TLC Rf (2% MTBE/dichloromethane) = 0.27. The
mixture (1.40 g) of 14a and 14b was further separated by silica gel
chromatography to yield 14a (0.35 g, 25% from 13), 14b (0.26 g, 18%
from 13), and a mixture of both (0.37 g, 26% from 13). 14a: TLC Rf
1
oil (121 mg, 46% yield). TLC Rf (2% MTBE/PE) = 0.29. H NMR
(400 MHz, CDCl3): δ 1H NMR (400 MHz, CDCl3) δ 5.72−5.86 (m,
1H), 5.38−5.61 (m, 2H), 4.90−5.10 (m, 4H), 2.41−2.54 (m, 1H),
2.26−2.34 (dd, 2H, J = 6.9, 13.7 Hz), 1.94−2.12 (m, 8H), 1.78 (s,
3H), 1.54−1.67 (m, 4H), 1.40−1.51 (m, 2H), 1.28 (s, 3H), 1.18 (s,
1H), 1.08 (d, 3H, J = 7.1 Hz). 13C NMR (400 MHz, CDCl3): δ d 18.7,
19.5, 24.2, 34.4, 45.1, 123.7, 135.9, 138.6; u 28.4, 31.9, 32.5, 32.8, 33.1,
37.0, 37.7, 43.0, 86.8, 111.0, 114.6, 124.6, 148.8. IR (film): 3500, 3077,
2931, 2233, 1640 cm−1. MS (m/z): 43, 55, 69, 81, 97, 109, 123, 135,
153, 164, 176, 190, 204, 218, 232, 246, 260, 274, 300, 314. HRMS
calcd for (M + H) = C21H34NO 316.2640; obsd 316.2639. [α]D + 4.4
(c 0.79, CHCl3).
1
(20% MTBE/PE) = 0.36. H NMR (400 MHz, CDCl3): δ 5.72−5.86
(m, 1H), 5.44−5.69 (m, 2H), 4.90−5.04 (m, 2H), 4.38 (bs, 1H),
2.33−2.41 (dd, 1H, J = 6.5, 14.4 Hz), 2.16−2.23 (dd, 1H, J = 7.1, 13.7
Hz), 2.10−2.16 (dt, 1H, J = 3.1, 7.6 Hz), 1.99−2.10 (m, 5H), 1.86−
1.98 (m, 2H), 1.76−1.85 (m, 1H), 1.65−1.76 (m, 2H), 1.40−1.53 (m,
4H), 1.30 (s, 3H), 0.96 (d, 3H, J = 7.2 Hz). 13C NMR (400 MHz,
CDCl3): δ d 17.5, 23.6, 35.8, 44.2, 74.4, 123.7, 136.0, 138.6; u 28.4,
31.4, 31.9, 33.1, 33.7, 34.5, 36.3, 43.7, 114.6, 125.3. IR (film): 3504,
3075, 2929, 2234, 1641 cm−1. MS (m/z): 43, 55, 67, 81, 95, 105, 111,
119, 133, 146, 160, 242, 260, 274. HRMS calcd for C18H28N 258.2222;
obsd 258.2215. [α]D + 17.4 (c 1.21, CHCl3).
(3R,3aR,5R,8aS)-1,2,3,3a,4,5,6,8a-Octahydro-8a-hydroxy-
3,5,8-trimethylazulene-5-carbonitrile (4). A mixture of the ter-
alcohol 3 (55.8 mg, 0.177 mmol) and Grubbs catalyst, second
generation (3.0 mg, 0.0035 mmol), in dichloromethane (36.0 mL) was
heated to reflux for 1 h. The reaction mixture was concentrated, and
the residue was purified by chromatography to yield the cyclized nitrile
4 as pale yellow crystals (36.9 mg, 95% yield). TLC Rf (20% MTBE/
PE) = 0.25; mp 90−93 °C. 1H NMR (400 MHz, CDCl3): δ 5.58 (bs,
1H), 2.65 (d, 1H, J = 14.7 Hz), 2.11−2.31 (m, 3H), 2.03−2.11 (m,
1H), 1.91−2.03 (m, 1H), 1.81 (s, 3H), 1.41 (s, 3H), 1.1−1.2 (m, 1H),
0.93 (d, 3H, J = 6.2 Hz). 13C NMR (400 MHz, CDCl3): δ d 18.5, 22.3,
29.3, 34.7, 45.5, 124.4; u 31.4, 36.0, 37.3, 38.3, 38.6, 83.4, 124.1, 145.5.
IR (neat): 3484, 2936, 2231, 1722, 1452, 1373 cm−1. MS (m/z): 42,
55, 79, 95, 108, 121, 135, 159, 177, 190, 204, 219. HRMS calcd for (M
+ H) = C14H22NO 220.1701; obsd 220.1695. [α]D − 97.4 (c 1.02,
CHCl3).
(1aS,3R,4aR,5R,7aS,7bR)-Decahydro-7a-hydroxy-3,5,7b-tri-
methyl-1H-cyclopropa[e]azulene-3-carbonitrile (16). Diiodo-
methane (0.11 mL, 1.35 mmol) was added into a solution of Et2Zn
(1 M in hexane, 0.66 mL, 0.66 mmol) over 2 min at 0 °C, and the
stirring was continued at 0 °C for 30 min. To the resulting white
suspension was added to a solution of the cyclized alkene 4 (25.2 mg,
0.115 mmol) in dichloromethane (1.64 mL) over 2 min. The reaction
mixture was warmed to rt, and stirring was continued at rt for 1 h. The
reaction mixture was quenched with 5% NH4Cl (aq, 2.0 mL) and
partitioned between H2O and dichloromethane. The combined
organic extract was dried (Na2SO4) and concentrated. The residue
was purified by chromatography to yield the cyclopropane 16 as
14b: TLC Rf (20% MTBE/PE) = 0.26. 1H NMR (400 MHz,
CDCl3): δ 5.72−5.86 (m, 1H), 5.42−5.63 (m, 2H), 4.90−5.04 (m,
2H), 4.34 (bs, 1H), 2.33−2.41 (dd, 1H, J = 6.7, 13.6 Hz), 2.12−2.21
(m, 2H), 2.01−2.11 (m, 4H), 1.88−1.99 (m, 2H), 1.75−1.88 (m, 2H),
1.67−1.88 (m, 1H), 1.60−1.67 (dd, 1H, J = 4.2, 13.8 Hz), 1.41−1.53
(m, 3H), 1.33 (s, 3H), 0.97 (d, 3H, J = 7.3 Hz). 13C NMR (400 MHz,
CDCl3): δ d 17.5, 24.8, 35.7, 44.2, 74.7, 123.7, 136.0, 138.6; u 28.4,
31.4, 31.9, 33.1, 34.0, 34.3, 36.3, 42.5, 114.6, 125.1. IR (film): 3504,
3075, 2928, 2261, 2234, 1641, 1455, 973 cm−1. MS (m/z): 43, 55, 67,
82, 95, 109, 119, 134, 146, 160, 174, 190, 200, 218, 242, 260, 274.
HRMS calcd for (M−OH) = C18H28N 258.2222; obsd 258.2225. [α]D
− 2.63 (c 1.52, CHCl3).
(2R,3E)-2-Methyl-2-(((1R,2R)-2-methyl-5-oxocyclopentyl)-
methyl)deca-4,9-dienenitrile (15). To a solution of the alcohol
14a (0.268 g, 0.975 mmol) in dichloromethane (10.0 mL) was added
Dess−Martin periodinane (823 mg, 1.94 mmol) in one portion. The
resulting white suspension was stirred at rt for 2 h. The reaction
mixture was filtered with Et2O through a pad of Celite. The filtrate was
concentrated, and the residue was purified by chromatography to yield
the ketone 15 as a pale yellow oil (0.25 g, 94% yield). TLC Rf (2%
1
MTBE/dichloromethane) = 0.58. H NMR (400 MHz, CDCl3): δ
9736
dx.doi.org/10.1021/jo2018558|J. Org. Chem. 2011, 76, 9733−9737

The Journal of Organic Chemistry
Article
colorless crystals (20.1 mg, 75% yield). TLC Rf (20% MTBE/PE) =
0.41. H NMR (400 MHz, CDCl3): δ 2.35−2.47 (m, 1H), 2.13−2.26
of this work. We thank Dr. Anubhav Narula of IFF for a gift of
pulegone.
1
(m, 2H), 2.04−2.13 (dd, 1H, J = 7.1, 13.9 Hz), 1.81−1.90 (m, 1H),
1.57−1.74 (m, 3H), 1.43−1.54 (m, 2H), 1.34 (s, 3H), 1.09 (s, 3H),
0.91 (d, 3H, J = 7.3 Hz), 0.86−0.96 (m, 1H), 0.77 (t, 2H, J = 4.8 Hz),
0.48 (dd, 1H, J = 4.4, 8.3 Hz). 13C NMR (400 MHz, CDCl3): δ d
17.0, 22.5, 23.6, 29.0, 36.1, 45.3; u 17.7, 25.6, 33.3, 37.1, 37.6, 39.1,
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(400 MHz, CDCl3): δ 9.67 (s, 1H), 2.05−2.31 (m, 4H), 1.56−1.67
(m, 2H), 1.45−1.56 (m, 4H), 1.27−1.34 (m, 1H), 1.24 (s, 3H), 0.98
(s, 3H), 0.94 (d, 3H, J = 7.1 Hz), 0.62−0.74 (m, 2H), 0.36−0.44 (m,
1H). 13C NMR (400 MHz, CDCl3): δ d 16.6, 21.6, 23.7, 25.7, 36.5,
44.6, 207.6; u 18.2, 26.0, 33.1, 33.3, 37.5, 39.1, 49.3, 82.1. This crude
material was used in the next step without further purification.
A mixture of the above crude material (13.2 mg), hydrazine hydrate
(80.3 mg, 1.60 mmol), and K2CO3 (72 mg, 0.52 mmol) in triethylene
glycol (0.52 mL) was heated at 90−100 °C for 2 h and was then
heated at 200 °C overnight. The reaction mixture was then cooled to
rt. The reaction mixture was directly chromatographed to yield the
alcohol 1 as a pale yellow oil (10.3 mg, 89% yield for two steps based
on the cyclized nitrile 16). TLC Rf (20% MTBE/PE) = 0.77. 1H NMR
(400 MHz, CDCl3): δ 2.17−2.26 (m, 1H), 2.01−2.13 (m, 2H), 1.75−
1.86 (m, 1H), 1.64−1.73 (ddd, 1H, J = 2.5, 6.6, 14.2 Hz), 1.40−1.54
(m, 3H), 1.27−1.38 (m, 2H), 1.11−1.17 (m, 1H), 1.03 (s, 3H), 0.99
(s, 3H), 0.90 (d, 3H, J = 7.3 Hz), 0.89 (s, 3H), 0.70 (t, 1H, J = 4.5
Hz), 0.50−0.60 (m, 1H), 0.32−0.39 (dd, 1H, J = 4.1, 8.6 Hz). 13C
NMR (400 MHz, CDCl3): δ d 17.2, 22.6, 24.1(2), 34.1, 36.4, 43.6; u
17.4, 24.9, 33.0, 33.3, 38.8, 39.9, 42.2, 82.4. 1H NMR (400 MHz,
C6D6): δ 2.08−2.17 (m, 1H), 1.96−2.03 (m, 1H),1.86−1.95 (m, 1H),
1.56−1.82 (m, 4H), 1.38−1.49 (m, 2H), 1.20−1.28 (m,1H), 1.11−
1.17 (m, 1H), 1.03 (s, 3H), 1.01 (d, 3H, J = 7.3 Hz), 0.97(s, 3H), 0.90
(s, 3H), 0.71 (t, 1H, J = 4.4 Hz), 0.49−0.58 (m, 1H), 0.29−0.33 (dd,
1H, J = 4.0, 8.8 Hz). 13C NMR (400 MHz, C6D6): δ d 17.5, 23.0, 24.1,
24.3, 34.4, 36.9, 44.0 ; u 17.7, 25.0, 33.2, 33.7, 39.0, 40.2, 42.3, 82.0. IR
(neat): 3426, 2962, 1640, 1410, 1260, 1090, 1021 cm−1. MS (m/z) 43,
55, 69, 77, 83, 95, 109, 125, 138, 151, 165, 179, 207, 222. HRMS calcd
for C15H26O 222.1984; obsd 222.1992. [α]D − 4.21 (c 1.26, CHCl3).
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
X-ray structures, H NMR and 13C NMR spectra for all new
compounds, and CIF files for 4, 8, and 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Taberdf@udel.edu.
ACKNOWLEDGMENTS
■
We thank John Dykins for high resolution mass spectrometry
under the financial support of NSF 054117, Dr. Shi Bai for
NMR spectra financially supported by NSF CRIF:MU, CHE
080401, Glenn Yap for X-ray crystallography help, and the
National Institutes of Health (GM060287) for financial support
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dx.doi.org/10.1021/jo2018558|J. Org. Chem. 2011, 76, 9733−9737