Synthesis of (+)- and (-)-gossonorol and cyclisation to boivinianin B

Article abstract of DOI:10.1002/ejoc.201000391

The first enantioselective synthesis of gossonorol has been achieved in good overall yield and excellent enantioselectivity, demonstrating the utility of a novel approach to enantiopure tertiary benzylic alcohols. Epoxidation of enantiopure gossonorol followed by acid-catalysed cyclisation gave a diastereoisomeric mixture of boivinianin B, typical of the diastereoisomeric mixtures of this compound found in nature. Separation of the diastereoisomers and determination of their enantiopurity revealed that the stereochemical integrity of the benzylic alcohol of gossonorol had been preserved during the epoxidation/cyclisation reaction.

Full text of DOI:10.1002/ejoc.201000391

FULL PAPER
DOI: 10.1002/ejoc.201000391
Synthesis of (+)- and (–)-Gossonorol and Cyclisation to Boivinianin B
Keren Abecassis[a] and Susan E. Gibson*[a]
Keywords: Asymmetric synthesis / Natural products / Alcohols / Chiral base / Chromium
The first enantioselective synthesis of gossonorol has been
achieved in good overall yield and excellent enantio-
selectivity, demonstrating the utility of a novel approach to
enantiopure tertiary benzylic alcohols. Epoxidation of
enantiopure gossonorol followed by acid-catalysed cycli-
sation gave a diastereoisomeric mixture of boivinianin B,
typical of the diastereoisomeric mixtures of this compound
found in nature. Separation of the diastereoisomers and de-
termination of their enantiopurity revealed that the stereo-
chemical integrity of the benzylic alcohol of gossonorol had
been preserved during the epoxidation/cyclisation reaction.
The key disconnection involves the breaking of two car-
bon–carbon bonds in 1 and requires the benzylic carbon to
twice react as a nucleophile with electrophilic sources of R1
and R2.
Introduction
The synthesis of enantiopure tertiary alcohols is more
difficult than the synthesis of enantiopure secondary
alcohols. This may be attributed in part to the challenges
associated with developing conditions for the selective ad-
dition of nucleophiles to ketones compared to aldehydes i.e.
lower reactivity of ketones, smaller steric and electronic dif-
ferences between the two substituents on the prochiral car-
bon, and also to the steric demands of tertiary alcohols and
their derivatives, which have rendered them a challenge to
enantiomer separation methods such as those based on en-
zymatic kinetic resolutions. Contemporary responses to
these challenges include the use of carefully chosen combi-
nations of metal catalyst, enantiopure chiral ligand, ketone
and nucleophile,[1–2] such as the use of zinc-based nucleo-
philes in the presence of titanium tetraisopropoxide and C2-
symmetric bis(camphorsulfonamide) ligands,[3–6] the use of
mutated forms of esterases to hydrolyse acetates of tertiary
alcohols,[7] a diastereoselective SN2Ј allylic substitution on
pentafluorobenzoates of enantiopure trisubstituted allylic
alcohols followed by oxidation and a Baeyer–Villiger reac-
tion,[8] and the conversion of enantiopure secondary
alcohols into enantiopure tertiary alcohols via a lithiation–
borylation–oxidation sequence.[9]
Scheme 1. A retrosynthetic analysis of enantiopure tertiary benzylic
alcohols.
We recently reported a new approach to the synthesis of
enantiopure benzylic alcohols that is based on tricarbonyl-
chromium(0) complexes of protected benzyl ethers.[10]
Whilst most of the alcohols we synthesized during the
course of this methodology study were secondary alcohols,
a single attempt to make a tertiary alcohol proved success-
ful. A retrosynthetic analysis of this new route to enantio-
pure tertiary benzylic alcohols is presented in Scheme 1.
In order to start to define the scope and limitations of
this methodology in synthesis, we decided to use it to carry
out the first enantioselective synthesis of 6-methyl-2-p-tol-
ylhept-5-en-2-ol or gossonorol. Gossonorol (structure 3 in
Figure 1) was first isolated from a natural source, the cotton
plant, in 1984 as part of a study of into chemical communi-
cation between the cotton plant (genus: Gossypium) and the
parasitoid Campoletis sonorensis.[11] It was described as hav-
ing a heavy, slightly floral scent, somewhat reminiscent of
commercial air-freshner.[11] Gossonorol has since been
found in many other species, such as Artemisia sieberi, an
odiferous plant that grows in the region around Tehran,[12]
[a] Department of Chemistry, Imperial College London,
South Kensington Campus, London SW7 2AY, UK
Fax: +44-207-594-5804
E-mail: s.gibson@imperial.ac.uk
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Synthesis of Enantiopure tert-Alcohols
Chamomilla recutita, a medicinal plant rich in oils known lowed by the addition of allyl bromide gave ether 8.[26]
for their beneficial effects,[13] and Laurencia tristicha, a red Ether 8 was then heated with hexacarbonylchromium(0) to
alga found in Chinese waters.[14]
give the novel complex 10 as an orange oil. By reversing
the allylation and complexation steps and proceeding via 4-
methylbenzyl alcohol complex 9,[27] the overall yield for the
formation of 10 from 4-methylbenzyl alcohol was improved
from 76% to 86%.
Figure 1. (6-Methyl-2-p-tolylhept-5-en-2-ol), isolated from the cot-
ton plant in 1984.
Gossonorol has been used in the synthesis of many target
compounds[15–23] including dehydro-α-curcumene 4,[16]
boivinianin B 5,[18] and yingzhaosu C 6[23] (Figure 2). The
latter is the active constituent of extracts from the roots of
yingzhao (Artabotrys uncinatus), a rare vine that grows on
the island of Heinan and in coastal regions of Guangdong,
which have been used in China for many centuries as a rem-
edy for malaria.[23]
Scheme 3. Activation/protection of 4-methylbenzyl alcohol.
With electrophile 7 and chromium complex 10 in hand,
the only remaining reagents that were required for our pro-
posed synthesis of enantiopure gossonorol were the chiral
diamines (+)- and (–)-11 (Figure 3). These were prepared
according to a literature procedure that involved the con-
densation of α-methylbenzylamine with glyoxal followed by
the addition of phenylmagnesium chloride.[28]
Figure 2. The structures of typical compounds synthesized from
racemic gossonorol.
Despite its widespread occurrence in nature, its interest-
ing biological properties and its frequent use in synthetic
work, gossonorol has always been reported as a racemic
compound. No enantioselective synthesis has been reported
and, to the best of our knowledge, its optical rotation has
not been recorded. We report herein the first enantioselec-
tive synthesis of gossonorol, and its cyclisation to give
enantiopure samples of the two diastereomers of boivini-
anin B (5).
Figure 3. Structure of the chiral base (+)-11.
As preliminary studies had revealed that the second de-
protonation/alkylation was more efficient with a relatively
small benzylic substituent in place, it was decided to first
introduce the methyl substituent. Deprotonation of com-
plex 10 with the chiral bases derived from (+)- and (–)-11
at –78 °C followed by the addition of iodomethane and
work-up gave the methyl-substituted complexes (+)- and
(–)-12 respectively [Scheme 4; synthesis of (–)-enantiomer
not depicted]. Analysis of both products by chiral HPLC
revealed that they had both been formed in Ն 98% ee. The
absolute configuration of (+)- and (–)-12 was assigned by
comparison of these experiments with deprotonations per-
formed on a range of closely related complexes, the out-
come of which was supported either by correlation with
known compounds[29,30] or by X-ray crystallographic analy-
sis.[31–33] Deprotonation of (+)- and (–)-12 with tBuLi fol-
lowed by quenching with freshly distilled 5-iodo-2-meth-
ylpent-2-ene 7 gave the disubstituted ethers (+)- and (–)-13
in moderate yield (41 and 60% yield, respectively). It was
deduced that (+)- and (–)-13 were formed with overall re-
Results and Discussion
The benzylic position of gossonorol is substituted by a
methyl group and an unsaturated hydrocarbon chain. Ad-
hering to the synthetic strategy depicted in Scheme 1, it was
planned to introduce the methyl group using iodomethane,
and the unsaturated hydrocarbon substituent using 5-iodo-
2-methylpent-2-ene 7. The latter was synthesised according
to a slightly modified literature procedure (Scheme 2).[24,25]
Scheme 2. Preparation of the electrophile 7.
The substrate required for elaboration by two deproton- tention of configuration by comparison of the tBuLi depro-
ation/electrophilic quench sequences, allyl benzyl ether tonation/alkylation reactions that led to their formation
chromium complex 10, was synthesized from commercially with a tBuLi deprotonation/benzylation reaction on a com-
available 4-methylbenzyl alcohol using two different routes plex closely related to (+)-12, the result of which was veri-
(Scheme 3). Deprotonation of 4-methylbenzyl alcohol fol- fied by X-ray crystallography.[34]
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K. Abecassis, S. E. Gibson
FULL PAPER
scent in 85% and 78% respectively. The analytical data ob-
tained for the two enantiomers of 3 correlated well with the
literature values available for gossonorol, and analysis of
both products by chiral HPLC revealed that (–)-gossonorol
had been formed in Ն 97% ee and (+)-gossonorol had been
formed in Ͼ99% ee.
Access to enantiopure gossonorol has the potential to
provide direct routes to further enantiopure compounds
such as boivinianin B, 5, and yingzhaosu C 6. In the latter
case, radical cyclisation of the hydroperoxide derived from
racemic gossonorol has been shown to give 6.[23] The fate
of the enantiopure tertiary benzylic alcohol of gossonorol
in further reactions, however, was open to question, and so
we decided to examine the conversion of gossonorol into
boivinianin B in order to determine whether or not the ab-
solute stereochemistry that had been created in our synthe-
sis of gossonorol would be maintained or destroyed.
The two diastereoisomers of the sesquiterpene 5, were
first isolated from a natural source in 2005 when they were
found alongside gossonorol in the red alga Laurencia tris-
ticha.[14] A year later, the two diastereoisomers of 5 were
isolated from the plant Cipadessa boiviniana and the dia-
stereoisomeric mixture was named boivinianin B.[36] Before
it was isolated from natural sources, compound 5 had been
synthesised twice,[18,21] on both occasions by the epoxid-
ation and cyclisation of racemic gossonorol which lead in
both cases to a mixture of diastereoisomers. Although a
diastereoselective synthesis of racemic cis-boivinianin B,
based on a rhodium-catalysed reaction of alkynyl oxiranes
with arylboronic acids that produces syn-configured α-al-
lenols with high diastereoselectivity,[37] and an enantioselec-
tive synthesis of cis-(7R,10S)-boivinianin B, based on a
Sharpless dihydroxylation of dehydro-α-curcumene 4 fol-
lowed by a moderately diastereoselective iodoetherification
of the resulting diol,[38] have been reported very recently,
the possibility of accessing enantiopure boivinianin B by
the epoxidation and cyclisation of enantiopure gossonorol
has not been considered to date.
Scheme 4. Synthesis of the (–)-enantiomer of gossonorol.
There is precedent in the literature for a one-pot chiral
base/tBuLi double deprotonation/electrophilic quench se-
quence,[35] and so it was decided at this point to determine
whether or not a one-pot approach would lead to a more
efficient conversion of substrate 10 to dialkylated product
13. To 1.08 equiv. of deprotonated (+)-11 in THF at –78 °C
was added 1.01 equiv. of iodomethane (Scheme 5). To this
solution was added complex 10 over a 10 min period after
which the resulting mixture was stirred for 45 min at
–78 °C. Subsequent addition of 2.3 equiv. of tBuLi at
–78 °C and stirring for 50 min were followed by the ad-
dition of 3 equiv. of electrophile 7. Finally stirring for a
further 2.5 h, quenching with methanol and work-up gave
(+)-13 in 60% yield, a significantly greater yield than the
combined yield of the two separate steps (Scheme 4). Inter-
estingly, isolation of (+)-13 from this protocol revealed that
deprotonated (+)-11 acted predominantly as a base rather
than as a nucleophile under the reaction conditions em-
ployed.
In order to maintain neutral conditions during the epox-
idation of gossonorol, it was decided to use dimethyldioxir-
ane (DMDO) for the oxidation. DMDO was thus added to
a sample of (–)-gossonorol in acetone and the mixture was
stirred at room temperature for 15 min. After changing the
solvent to chloroform, a catalytic amount of acid was added
and stirring was continued for a further 15 min (Scheme 6).
Work-up and column chromatography yielded a sample of
the trans isomer of 5 (27%), a sample of the cis isomer of
5 (11%), and a sample that contained both isomers (36%).
The cis and trans isomers of 5 were assigned by correlation
Scheme 5. A one-pot double deprotonation/alkylation conversion
of 10 to (+)-13.
To complete the synthesis of the two enantiomers of gos- with literature NMR spectroscopic data.[36] In particular,
sonorol it was necessary to remove the tricarbonylchro- H-10 in the trans isomer of 5 resonates at δ = 3.79 whilst
mium(0) unit and the allyl protecting group. The former H-10 in the cis isomer resonates at δ = 3.98 ppm. (The num-
was readily achieved by air/light oxidation and gave ethers bering used for boivinianin B herein is based on the system
(–)- and (+)-14 in 91 and 95% yield respectively (Scheme 4). defined in reference 36.) Chiral HPLC of the two diastereo-
The ethers were successfully deprotected using 5 mol-% isomers revealed that the trans and cis isomers of 5 had
Pd(PPh3)4 and potassium carbonate.[10] After careful neu- both been formed in the same enantiopurity as the gos-
tralization with 1  HCl and work-up, the two alcohols sonorol starting material (ee Ն 97%). The diastereopurity
1
(–)- and (+)-3 were obtained as colourless oils with a floral of the samples was assessed from their H NMR spectra
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Synthesis of Enantiopure tert-Alcohols
were recorded on an AA 10 polarimeter from Index Instruments
or on a Perkin–Elmer 241 polarimeter using a 1 dm path length;
concentrations are given as g/100 mL. IR spectra were recorded on
Perkin–Elmer Spectrum RX and 100 FT-IR spectrometers. NMR
spectra were recorded at room temperature on a Bruker AV 400
instrument in CDCl3 at 400 MHz (1H) and 100 MHz (13C). Mass
spectra were recorded on Micromass Platfrom II and Micromass
AutoSpec-Q instruments by the mass spectrometry service at Impe-
rial College London. Elemental analyses were performed by the
London Metropolitan University microanalytical service.
and their HPLC analyses: no trace of the cis isomer was
found in the trans sample but the cis sample was contami-
nated with a small amount (Յ5%) of the trans isomer.
5-Iodo-2-methylpent-2-ene (7):[24,25] To a stirred solution of methyl-
magnesium iodide in diethyl ether (25.0 mL, 3  in diethyl ether,
75.0 mmol) was added dropwise a solution of cyclopropyl methyl
ketone (5 mL, 50.5 mmol) in dry diethyl ether (25 mL). The reac-
tion mixture was heated under reflux for 2 h then slowly added to
a stirred and cooled (0 °C) solution of concentrated sulfuric acid
(7.5 mL) in water (15 mL) at a rate to maintain the temperature
below 10 °C. After the addition was complete, stirring was contin-
ued for 30 min. The ethereal layer was separated and the aqueous
layer was extracted with diethyl ether (2ϫ50 mL). The combined
ethereal phases were decolorised by the addition of 5% aqueous
NaHSO3 (150 mL), neutralised with 5% aqueous NaHCO3
(150 mL), washed with brine (150 mL) and dried with MgSO4. The
solvent was removed in vacuo and the residue distilled in vacuo to
give 7 (8.22 g, 78%) as a colourless liquid; b.p. 44–46 °C, 3 Torr
Scheme 6. Synthesis of (7S,10S)- and (7S,10R)-boivinianin B.
The enantiopurity of the boivinianin B diastereoisomers
suggests that the stereochemical integrity of gossonorol has
been maintained during their formation. This is consistent
with epoxide formation followed by an acid-catalysed ring-
opening of the epoxide by the benzylic alcohol, in which
either stereochemically uncontrolled formation of the epox-
ide and/or the formation of a partial carbocation during
ring-opening result in poor control over the formation of
the new stereocentre at C-10. On the basis of this model,
the two diastereoisomers were assigned as (7S,10S)- and
(7S,10R)-boivinianin B.
(ref.[24] 65 °C, 10 Torr). IR (neat): ν = 1670 (w, C=C), 600 cm–1 (s,
˜
C–I). 1H NMR: δ = 1.61 (s, 3 H, CH3), 1.70 (s, 3 H, CH3), 2.57
3
[apparent q, 3J(H,H) = 7.5 Hz, 2 H, CH2CH2I], 3.11 (t, JH,H
=
3
7.5 Hz, 2 H, CH2CH2I), 5.09 ppm (t, JH,H = 7 Hz, 1 H, CH=C).
Conclusions
13C NMR:
δ = 6.1 (CH2I), 18.0 (CH3), 25.7 (CH3), 32.5
The first enantioselective synthesis of both enantiomers
of the naturally occurring sesquiterpene gossonorol has
been achieved in good overall yield and excellent enantio-
selectivity, demonstrating the utility of our novel approach
to enantiopure tertiary benzylic alcohols. A similar ap-
proach could be adopted for the synthesis of 7-hydroxynuc-
iferol, a benzylic tertiary alcohol isolatd from sandal-
wood.[39] Epoxidation of enantiopure gossonorol followed
by acid-catalysed cyclisation led to the production of a dia-
stereoisomeric mixture of boivinianin B, typical of the dia-
stereoisomeric mixtures of this compound found in nature.
Separation of samples of the diastereoisomers and measure-
ment of their enantiopurity revealed that the stereochemical
integrity of the benzylic alcohol of gossonorol had been
preserved during the epoxidation/cyclisation reaction.
(CH2CH2I), 123.1 (CH=C), 134.5 ppm (CH=C). MS (CI): m/z (%):
228 (11) [M + NH4]+, 211 (26) [M + H]+, 100 (100) [M – HI +
NH4]+.
1-Allyloxymethyl-4-methylbenzene (8):[26] 4-Methylbenzyl alcohol
(4.00 g, 32.8 mmol) was added to a suspension of sodium hydride
(1.56 g, 60% dispersion in mineral oil, 39.3 mmol, previously
washed with hexane) in THF (100 mL) and the mixture was stirred
for 1 h at 0 °C before allyl bromide (5.6 mL, 64.7 mmol) was added
in one portion. After stirring for 16 h at room temperature, meth-
anol (2 mL) was added and the solvent was removed in vacuo. The
crude product was filtered through a long silica gel column in hex-
ane and then hexane/diethyl ether, 90:10 to yield ether 8 (5.26 g,
99%) as a slightly yellow oil. IR (neat): ν = 1650 cm–1 (w, C=C),
˜
1081 cm–1 (s, C–O). 1H NMR: δ = 2.37 (s, 3 H, CH3), 4.04 (d,
3JH,H = 5.5 Hz, 2 H, OCH2CH=CH2), 4.52 (s, 2 H, OCH2Ar), 5.23
3
3
(d, JH,H = 10.5 Hz, 1 H, CH=CHH(E)), 5.33 (d, JH,H = 17 Hz, 1
3
H, CH=CHH(Z)), 5.98 (ddt, JH,H = 17, 10.5, 5.5 Hz, 1 H,
CH=CH2), 7.19 (d, JH,H = 8 Hz, 2 H, CArHϫ2), 7.27 ppm (d,
3
3JH,H = 8 Hz, 2 H, CArHϫ2). 13C NMR: δ = 20.8 (CH3), 71.0
(OCH2CH=CH2), 72.0 (OCH2CAr), 116.7 (CH=CH2), 125.9, 129.1
(CArHϫ4), 134.9 (CH=CH2), 135.3 (CArCH2), 137.3 ppm
(CArCH3). MS (CI): m/z (%): 180 (100) [M + NH4]+, 162 (4) [M]+,
122 (30) [M – (CH2=CH–CH2)]+, 105 (9) [M – (CH2=CH–CH2–
O)]+.
Experimental Section
General: Syntheses were carried out under an atmosphere of nitro-
gen in oven-dried glassware using standard Schlenk techniques. Re-
actions involving the use of arene tricarbonylchromium(0) com-
plexes were protected from light. Tetrahydrofuran and diethyl ether
were distilled from sodium benzophenone ketyl and used immedi-
ately. Dichloromethane was distilled from calcium hydride. The
concentration of nBuLi was determined by titration against di-
phenylacetic acid in tetrahydrofuran.[40] The diamines (+)-
and (–)-11,[28] and the dimethyldioxirane solution in acetone[41]
were prepared according to literature procedures. All other reagents
are commercially available and were used as received. Melting
points were recorded on a Sanyo Gallenkamp melting point appa-
ratus in open capillaries and are uncorrected. Optical rotations
(4-Methylbenzyl alcohol)tricarbonylchromium(0) (9):[27] Dry di-n-
butyl ether (230 mL) and THF (23 mL) were added to 4-meth-
ylbenzyl alcohol (5.00 g, 40.9 mmol) and hexacarbonylchro-
mium(0) (10.80 g, 49.1 mmol) and the mixture was saturated with
nitrogen and shielded from ambient light. The reaction mixture was
heated under reflux for 39 h and then cooled to room temperature.
The mixture was filtered through a pad of Celite® and rinsed with
dichloromethane. The solvent was removed in vacuo and the crude
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K. Abecassis, S. E. Gibson
FULL PAPER
mixture was purified by column chromatography (SiO2; dichloro-
84%) as a yellow oil. Rf = 0.33 (SiO2; hexane/diethyl ether, 90:10);
enantiomeric excess was determined by HPLC analysis (Chiralcel
OD-H, n-hexane/iPrOH, 90:10, 0.5 mL/min, UV 330 nm); (S)-en-
antiomer tr = 11.7 min (minor); (R)-enantiomer tr = 12.4 min
methane) to yield complex 9 (9.27 g, 88%) as a yellow powder; m.p.
80–81 °C (ref.[27] 80–82 °C). IR (neat): ν = 3309 cm–1 (br., OH),
˜
3
1942 (s, CO), 1844 cm–1 (s, CO). 1H NMR: δ = 1.82 (t, JH,H
=
6 Hz, 1 H, OH), 2.19 (s, 3 H, CH3), 4.38 (d, JH,H = 6 Hz, 2 H,
(major): Ն 98% ee. [α]2D0 = +39 (c = 0.97, CHCl ). IR (neat): ν =
3
˜
3
CH2OH), 5.22 (d, 3JH,H = 6 Hz, 2 H, CCrHϫ2), 5.50 ppm (d, 3JH,H 1953 cm–1 (s, CO), 1853 cm–1 (s, CO). 1H NMR: δ = 1.43 (d, JH,H
3
= 6 Hz, 2 H, CCrHϫ2). 13C NMR: δ = 20.5 (CH3), 63.1 (CH2OH),
= 6.5 Hz, 3 H, CHCH3), 2.19 (s, 3 H, CH3Ar), 4.03–4.16 (m, 3 H,
92.8, 92.9 (CCrHϫ4), 108.6, 109.1 (CCrCϫ2), 233.1 ppm (COϫ3). CHCH3 + OCH2CH=CH2), 5.12 (apparent t, 3JH,H = 5.5 Hz, 2 H,
MS (CI): m/z (%): 276 (99) [M + NH4]+, 259 (94) [M + H]+, 258
CCrHϫ2), 5.21 (d, JH,H = 10.5 Hz, 1 H, CH=CHH(E)), 5.32 (d,
3
(28) [M]+, 241 (100) [M – OH]+, 174 (3) [M – 3CO]+, 122 (17) [M – 3JH,H = 17.5 Hz, 1 H, CH=CHH(Z)), 5.45 (d, JH,H = 6 Hz, 1 H,
3
Cr(CO)3]+. C11H10CrO4 (258.19): calcd. C 51.17, H 3.90; found C
51.26, H 3.92.
CCrH), 5.61 (d, JH,H = 6 Hz, 1 H, CCrH), 5.93 ppm (ddt, JH,H =
3
3
17.5, 10.5, 5.5 Hz, 1 H, CH=CH2). 13C NMR: δ = 20.5 (CH3Ar),
23.3 (CHCH3), 70.4 (OCH2CH=CH2), 74.4 (CHCH3), 91.4, 91.8,
92.8, 93.5 (CCrHϫ4), 109.9 (CCrCH3), 110.4 (CCrCH), 117.5
(CH=CH2), 134.4 (CH=CH2), 233.3 ppm (COϫ3). MS (CI): m/z
(%): 330 (6) [M + NH4]+, 312 (2) [M]+, 256 (39) [M – 2CO]+, 255
(100) [M – (OCH2CH=CH2)]+. C15H16CrO4 (312.05): calcd. C
57.69, H 5.16; found C 57.63, H 5.11.
(1-Allyloxymethyl-4-methylbenzene)tricarbonylchromium(0)
(10):
i) From 8: Allyl ether 8 (5.03 g, 31.0 mmol) and hexacarbonylchro-
mium(0) (8.18 g, 37.2 mmol) were added to dry di-n-butyl ether
(175 mL) and THF (17 mL) and the mixture was saturated with
nitrogen and shielded from ambient light. The reaction mixture was
heated under reflux for 44 h and then cooled to room temperature.
The solvents were removed under reduced pressure and the crude
mixture was purified by column chromatography (SiO2; hexane/
(–)-(S)-[1-(1-Allyloxyethyl)-4-methylbenzene]tricarbonylchromium(0)
[(–)-12]: Complex (–)-12 was prepared from 10 (1.19 g, 4.00 mmol)
diethyl ether, 100:0–80:20) to yield complex 10 (7.08 g, 77%) as an and diamine (–)-11 (1.68 g, 4.00 mmol) following the procedure de-
orange oil.
scribed for (+)-11. 87% yield, yellow oil; ee Ն 98%. [α]2D0 = –41 (c
= 1.01, CHCl3); all other analytical data were identical to those
obtained for (+)-12.
ii) From 9: Alcohol 9 (8.00 g, 31.0 mmol) was added under nitrogen
to a suspension of sodium hydride (1.48 g, 60% dispersion in min-
eral oil, 37.2 mmol, previously washed with hexane) in THF
(100 mL) and the mixture was stirred for 1 h at 0 °C before allyl
bromide (5.4 mL, 62.4 mmol) was added in one portion. After stir-
ring for a further 19 h at room temperature, methanol (2 mL) was
added and the solvent was removed in vacuo. The resulting crude
product was purified by column chromatography (SiO2; hexane/
(+)-(S)-[1-(2-Allyloxy-6-methylhept-5-en-2-yl)-4-methylbenzene]tri-
carbonylchromium(0) [(+)-13]: i) From (+)-12: tert-Butyllithium
(3.12 mL, 1.6  in pentane, 5.00 mmol) was added to a solution of
complex (+)-12 (1.20 g, 3.85 mmol) in THF (38 mL) at –78 °C. Af-
ter stirring for 45 min at –78 °C, iodide 7 (2.42 g, 11.5 mmol) was
added. Stirring was continued for a further 3 h after which the reac-
diethyl ether, 95:5–90:10) to yield complex 10 (8.98 g, 97%) as an tion was quenched with methanol (1.5 mL). After removal of the
orange oil.
solvent in vacuo, purification by column chromatography (SiO2;
hexane/diethyl ether, 100:0–98:2) yielded (+)-13 (619 mg, 41%) as
yellow crystals.
Rf = 0.24 (SiO ; hexane/diethyl ether, 90:10). IR (neat): ν =
˜
2
1950 cm–1 (s, CO), 1856 cm–1 (s, CO). H NMR: δ = 2.17 (s, 3 H,
1
3
CH3), 4.08 (d, JH,H = 5.5 Hz, 2 H, OCH2CH=CH2), 4.15 (s, 2 H,
OCH2Ar), 5.19 (d, JH,H = 6.5 Hz, 2 H, CCrHϫ2), 5.25 (d, JH,H
= 10.5 Hz, 1 H, CH=CHH(E)), 5.32 (d, JH,H = 17 Hz, 1 H,
ii) One-pot synthesis from 10: n-Butyllithium (0.86 mL, 2.5  in
hexanes, 2.16 mmol) was added to a solution of diamine (+)-11
(454 mg, 1.08 mmol) in THF (10 mL) at –78 °C. The solution was
warmed to room temperature over a period of 30 min. The deep
red solution was cooled to –78 °C. A solution of heat gun-dried
3
3
3
3
CH=CHH(Z)), 5.46 (d, JH,H = 6.5 Hz, 2 H, CCrHϫ2), 5.92 ppm
(ddt, 3JH,H = 17, 10.5, 5.5 Hz, 1 H, CH=CH2). 13C NMR: δ = 20.5
(CH3), 70.1 (OCH2CH=CH2), 71.9 (OCH2CCr), 92.7, 94.1 lithium chloride (45 mg, 1.08 mmol) dissolved in THF (5 mL) was
(CCrHϫ4), 104.6 (CCrCH3), 108.7 (CCrCH2), 117.9 (CH=CH2), added and the reaction mixture was stirred for a further 5 min be-
134.0 (CH=CH2), 233.0 ppm (COϫ3). MS (CI): m/z (%): 316 (61)
fore iodomethane (143 mg, 1.01 mmol) was added. Then a solution
[M + NH4]+, 299 (34) [M + H]+, 242 (38) [M – 2CO]+, 241 (100) of complex 10 (298 g, 1.00 mmol) in THF (3.5 mL) was added via
[M – (CH2=CH–CH2–O)]+. C14H14CrO4 (298.03): calcd. C 56.38,
H 4.73; found C 56.38, H 4.75.
a cannula over 10 min. Stirring was continued for a further 45 min
after which time tert-butyllithium (1.44 mL, 1.6  in pentane,
2.30 mmol) was added and the reaction mixture was stirred for a
further 50 min before 7 (630 mg, 3.00 mmol) was added. Stirring
was continued for a further 2.5 h after which the reaction was
quenched with methanol (1 mL). The solvent was removed in
vacuo. The crude residue was dissolved in diethyl ether and the
chiral base was extracted with 1  HCl (3ϫ50 mL). The organic
layer was washed with brine (50 mL), dried with MgSO4, filtered,
and concentrated in vacuo. Purification by column chromatog-
raphy (SiO2; hexane/diethyl ether, 100:0–98:2) afforded complex
(+)-13 (238 mg, 60%) as yellow crystals.
(+)-(R)-[1-(1-Allyloxyethyl)-4-methylbenzene]tricarbonylchromium(0)
[(+)-12]: n-Butyllithium (6.25 mL, 1.6  in hexanes, 10.0 mmol) was
added to a solution of diamine (+)-11 (2.10 g, 5.00 mmol) in THF
(50 mL) at –78 °C. The solution was warmed to room temperature
over a period of 30 min. The deep red solution was cooled to
–78 °C. A solution of heat gun-dried lithium chloride (210 mg,
5.00 mmol) dissolved in THF (25 mL) was added and the reaction
mixture was stirred for a further 5 min before a solution of complex
10 (1.49 g, 5.00 mmol) in THF (12.5 mL) was added. After stirring
for 30 min at –78 °C, iodomethane (1.0 mL, 15.0 mmol) was added.
Stirring was continued for a further 30 min after which the reaction
was quenched with methanol (1.5 mL). The solvent was removed
in vacuo, the crude residue dissolved in diethyl ether and the chiral
base was extracted with 1  HCl (3ϫ75 mL). The organic layer
was washed with brine (75 mL), dried with MgSO4, filtered, and
concentrated in vacuo. Purification by column chromatography
(SiO2; hexane/diethyl ether, 90:10) afforded complex (+)-12 (1.31 g,
Rf = 0.47 (SiO2; hexane/diethyl ether, 95:5); m.p. 32–34 °C. [α]2D0
+17 (c = 1.05, CHCl3). IR (neat): 1947 (s, CO), 1873 (s, CO),
1849 cm–1 (s, CO). 1H NMR:
1.48–2.08 [m, 13 H,
=
δ
=
CH2CH2CH=C(CH3)2 + CH2CH2CH=C(CH3)2 + CH2CH2CH=
2
C(CH3)2 + OCCH3], 2.20 (s, 3 H, CH3Ar), 3.95 (dd, JH,H = 12.5,
3JH,H = 5 Hz, 1 H, OCHHCH=CH2), 4.10 (dd, 2JH,H = 12.5, 3JH,H
=
5 Hz,
1
H, OCHHCH=CH2), 4.97–5.09 [m,
3
H,
2942
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2938–2944

Synthesis of Enantiopure tert-Alcohols
CH2CH2CH=C(CH3)2 + CCrHϫ2], 5.16 (d, 3JH,H = 10.5 Hz, 1 H, chromatography (SiO2; hexane/diethyl ether, 90:10) afforded (–)-3
3
OCH2CH=CHH(E)), 5.36 (d, JH,H = 17 Hz, 1 H, OCH2CH=
(249 mg, 85%) as a colourless oil. Enantiomeric excess was deter-
3
CHH(Z)), 5.42 (d, JH,H = 6.5 Hz, 1 H, CCrH), 5.87–6.00 ppm (m, mined by HPLC analysis (Chiralcel OB, n-hexane/iPrOH, 98:2,
2 H, OCH2CH=CH2 + CCrH). 13C NMR: δ = 17.6 [CH=
0.5 mL/min, UV 220 nm); (R)-enantiomer tr = 14.9 min (minor);
C(CH3)2 ϫ1], 20.4 (CH3Ar), 22.3 [CH2CH2CH=C(CH3)2], 24.6 (S)-enantiomer tr = 24.1 min (major): Ն 97% ee. [α]2D0 = –18 (c =
(CH=C(CH3)2 ϫ1), 25.7 (CCH3), 42.8 [CH2CH2CH=C(CH3)2], 1.00, CHCl ). IR (neat): ν = 3430 cm–1 (br., OH). H NMR: δ =
1
˜
3
63.2 (OCH2CH=CH2), 76.7 (OCCH3), 90.5, 90.7, 93.1, 94.1
(CCrHϫ4), 110.3 (CH3CCr), 114.5 (CCrC), 115.6 (CH=CH2), 123.6
1.49 [s, 3 H, C(CH3)2], 1.52 [s, 3 H, C(CH3)2], 1.65 (s, 3 H, CCH3),
1.76–2.03 [m, 5 H, CH2CH2CH=C(CH3)2 + CH2CH2CH=C-
3
[CH=C(CH3)2], 132.0 [CH=C(CH3)2], 135.1 (CH=CH2), (CH3)2 + OH], 2.34 (s, 3 H, CH3Ar), 5.09 [t, JH,H = 6.5 Hz, 1
233.6 ppm (COϫ3). MS (CI): m/z (%): 412 (2) [M + NH4]+, 337
H, CH2CH2CH=C(CH3)2], 7.15 (d, JH,H = 8 Hz, 2 H, CArHϫ2),
3
3
(100) [M
–
(CH2=CH–CH2–O)]+, 336 (30) [M 2CO]+. 7.31 ppm (d, JH,H = 8 Hz, 2 H, CArHϫ2). 13C NMR: δ = 17.6
–
C21H26CrO4 (394.12): calcd. C 63.95, H 6.64; found C 63.95, H
6.68.
[CH=C(CH3)2 ϫ1], 20.9 (CH3Ar), 23.0 [CH2CH2CH=C(CH3)2],
25.7 (CCH3), 30.7 [CH=C(CH3)2 ϫ1], 43.7 [CH2CH2CH=C-
(CH3)2], 74.9 (OCCH3), 124.2 [CH=C(CH3)2], 124.7, 128.8
(CArHϫ4), 132.1 [CH=C(CH3)2], 136.0, 144.9 ppm (CAr ϫ2). MS
(CI): m/z (%): 236 (1) [M + NH4]+, 219 (7) [M + H]+, 218 (39)
[M]+, 201 (100) [M – OH]+. C15H22O (218.17): calcd. C 82.52, H
10.16; found C 82.62, H 10.19.
(–)-(R)-[1-(2-Allyloxy-6-methylhept-5-en-2-yl)-4-methylbenzene]tri-
carbonylchromium(0) [(–)-13]: Complex (–)-13 was prepared from
(–)-12 (598 mg, 1.91 mmol) following the procedure described for
(+)-13. 60% yield, yellow crystals. [α]2D0 = –17 (c = 1.06, CHCl3);
all other analytical data were identical to those obtained for (+)-
13.
(+)-(R)-6-Methyl-2-p-tolylhept-5-en-2-ol [(+)-Gossonorol] [(+)-3]:
Alcohol (+)-3 was prepared from (+)-14 (100 mg, 0.39 mmol) fol-
lowing the procedure described for (–)-3. 78% yield, colourless oil;
ee Ͼ 99%. [α]2D0 = +15 (c = 1.00, CHCl3); all other analytical data
were identical to those obtained for (–)-3.
(–)-(S)-1-[2-(Allyloxy)-6-methylhept-5-en-2-yl]-4-methylbenzene
[(–)-14]: Complex (+)-13 (595 mg, 1.51 mmol) in diethyl ether (600
mL) was exposed to air and light for 24 h. The reaction mixture
was filtered through a pad of Celite® and rinsed with diethyl ether.
The solvent was removed in vacuo and the crude mixture was puri-
fied by column chromatography (SiO2; hexane/diethyl ether, 100:0–
98:2) to afford (–)-14 (355 mg, 91%) as a colourless oil. (The chro-
mium-contaminated Celite was packaged for disposal in a secure
(7S,10S)- and (7S,10R)-Boivinianin B 5: Dimethyldioxirane solution
in acetone (8.0 mL, 0.072 , 0.58 mmol) was added to a solution
of (–)-gossonorol (–)-3 (111 mg, 0.51 mmol) in acetone (2.5 mL)
and the mixture was stirred at room temperature for 15 min. After
removal of the acetone in vacuo, the paste remaining was dissolved
in dichloromethane (2 mL), and reduced to dryness in vacuo twice
and then dried under high vacuum. The crude mixture was dis-
solved in CDCl3 (2.5 mL) and a catalytic amount of p-toluenesul-
fonic acid monohydrate (1.4 mg, 0.007 mmol) was added. The mix-
ture was stirred for 15 min and then the solvent was removed in
vacuo. The mixture was dissolved in diethyl ether and filtered
through a short pad of alumina. After removal of the solvent in
vacuo, purification by column chromatography [SiO2; hexane/di-
ethyl ether, 100:0–90:10 (very slow gradient), then 90:10–70:30] af-
forded (7S,10S)-5 (32 mg, 27%), (7S,10R)-5 (13 mg, 11%) and a
landfill.) [α]2D0 = –1 (c = 1.00, CHCl ). IR (neat): ν = 1649 cm–1 (w,
˜
3
C=C). 1H NMR: δ = 1.53 [s, 3 H, C(CH3)2], 1.55 [s, 3 H, C-
(CH3)2], 1.65 (s, 3 H, OCCH3), 1.77–1.85 [m, 2 H, CH2CH2-
CH=C(CH3)2], 1.86–1.98 [m; 2 H, CH2CH2CH=C(CH3)2], 2.35 (s,
2
3
3 H, CH3Ar), 3.68 (dd, JH,H = 12.5, JH,H = 5 Hz, 1 H,
2
3
OCHHCH=CH2), 3.78 (dd, JH,H = 12.5, JH,H = 5 Hz, 1 H,
O C H H C H = C H 2 ) , 5 . 0 6 [ t , J H , H = 7 H z , 1 H ,
CH2 CH2 CH=C(CH3 )2 ], 5.13 (d, JH , H = 10.5 Hz, 1 H,
O C H 2 C H = C H H ( E ) ) , 5 . 3 2 ( d , J H , H = 1 7 H z , 1 H ,
3
3
3
3
OCH2CH=CHH(Z)), 5.92 (ddt, JH,H = 17, 10.5, 5 Hz, 1 H,
3
OCH2CH=CH2), 7.15 (d, JH,H = 8 Hz, 2 H, CArHϫ2), 7.28 ppm
(d, JH,H = 8 Hz, 2 H, CArHϫ2). 13C NMR: δ = 17.6 [CH=C-
3
mixture of both (43 mg, 36%) as colourless oils. IR (neat): ν = 3445
˜
(br., OH), 1099(s, C–O), 1078 cm–1 (s, C–O). MS (CI): m/z (%): 486
(6) [2M + NH4]+, 252 (100) [M + NH4]+, 235 (4) [M + H]+, 217
(90) [M – OH]+. C15H22O2 (234.16): calcd. C 76.88, H 9.46; found
C 76.78, H 9.35. (7S,10S)-5: Enantiomeric excess was determined
by HPLC analysis (Chiralcel OD-H, n-hexane/iPrOH, 98:2,
0.3 mL/min, UV 220 nm); (7R,10S)-enantiomer tr = 18.5 min
(minor); (7S,10S)-enantiomer tr = 21.3 min (major): Ն 97% ee, Ն
(CH3)2 ϫ 1], 21.0 (CH3Ar), 22.7 [CH2CH2CH=C(CH3)2], 23.9
[CH=C(CH3)2 ϫ1], 25.7 (CCH3), 42.6 [CH2CH2CH=C(CH3)2],
63.6 (OCH2CH=CH2), 78.9 (OCCH3), 115.4 (CH=CH2), 124.4
[CH=C(CH3)2], 126.0, 128.8 (CArH ϫ4), 131.3 [CH=C(CH3)2],
135.8 (CH=CH2), 136.2, 142.5 ppm (CAr ϫ2). MS (CI): m/z (%):
276 (1) [M + NH4]+, 218 (60) [M – (CH2CH=CH2) + H]+, 201
(100) [M – (OCH2CH=CH2)]+. C18H26O (258.20): calcd. C 83.67,
H 10.14; found C 83.62, H 10.17.
1
99% de. [α]2D0 = –10 (c = 1.01, CHCl3). H NMR: δ = 1.17 [s, 3 H,
C(CH3)2], 1.29 [s, 3 H, C(CH3)2], 1.50 (s, 3 H, CCH3), 1.62 (br. s,
1 H, OH), 1.70–1.79 (m, 1 H, CCH2CHHCHO), 1.84–1.94 (m, 1
H, CCH2CHHCHO), 2.00–2.07 (m, 1 H, CCHHCH2CHO), 2.19–
2.27 (m, 1 H, CCHHCH2CHO), 2.33 (s, 3 H, CH3Ar), 3.80 (appar-
(+)-(R)-1-[2-(Allyloxy)-6-methylhept-5-en-2-yl]-4-methylbenzene
[(+)-14]: Ether (+)-14 was prepared from (–)-19 (425 mg,
1.08 mmol) following the procedure described for (–)-14. 95%
yield, colourless oil. [α]2D0 = +1 (c = 1.01, CHCl3); all other analyti-
cal data were identical to those obtained for (–)-14.
3
3
ent t, JH,H = 7.5 Hz, 1 H, CH2CH2CHO), 7.14 (d, JH,H = 8 Hz,
3
2 H, CArHϫ2), 7.28 ppm (d, JH,H = 8 Hz, 2 H, CArHϫ2). 13C
(–)-(S)-6-Methyl-2-p-tolylhept-5-en-2-ol [(–)-Gossonorol] [(–)-3]: NMR: δ = 21.0 (CH3Ar), 24.2 [C(CH3)2], 26.5 (CCH2CH2CHO),
Ether (–)-14 (347 mg, 1.34 mmol) was dissolved in anhydrous meth-
anol (14 mL) and placed under a nitrogen atmosphere. Pd(PPh3)4
(77.7 mg, 0.067 mmol) was added and the resulting yellow solution
was stirred for 5 min before K2CO3 (558 mg, 4.03 mmol) was
added. The mixture was heated under reflux for 72 h. After cooling
to room temperature, the mixture was carefully neutralised with
1  HCl and extracted with dichloromethane (3ϫ100 mL). The
combined organic layers were washed with brine (100 mL), dried
with MgSO4 and concentrated in vacuo. Purification by column
27.3 [C(CH3)2], 30.6 (CCH3), 39.6 (CCH2CH2CHO), 71.1 (COH),
84.6 (CCH3), 85.4 (CHO), 124.6, 128.9 (CArHϫ4), 136.0
(CArCH3), 145.3 ppm (CArCO). (7S,10R)-5: Enantiomeric excess
was determined by HPLC analysis (Chiralcel OD-H, n-hexane/
iPrOH, 98:2, 0.3 mL/min, UV 220 nm); (7R,10R)-enantiomer tr =
20.0 min (minor); (7S,10R)-enantiomer tr = 20.7 min (major),
20
(7S,10S)-diastereomer tr = 21.3 min: Ն 97% ee, Ն 90% de. [α]
=
365
20
20
20
+5.1, [α] = +1.6, [α] = +0.7, [α] = +0.2 (c = 1.04, CHCl3).
436
546
578
1H NMR: δ = 1.12 [s, 3 H, C(CH3)2], 1.29 [s, 3 H, C(CH3)2], 1.48
Eur. J. Org. Chem. 2010, 2938–2944
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2943

K. Abecassis, S. E. Gibson
FULL PAPER
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Published Online: April 20, 2010
2944
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2938–2944