Synthesis of (3S*,4R*,6E,10Z)-3,4,7,11-tetramethyltrideca6,10-dienal (faranal) using stereospecific 1,4-cis-hydrogenation of conjugated double bonds

Article abstract of DOI:10.1039/b002343o

(±)-Faranal was synthesised by a convergent route involving 1,4-cis-hydrogenation of two properly substituted conjugated diene building blocks to introduce stereospecifically the 6(E) and 10(Z) double bonds of the final target molecule. meso-2,3-Dimethyls

Full text of DOI:10.1039/b002343o

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Synthesis of (3S*,4R*,6E,10Z)-3,4,7,11-tetramethyltrideca-
6,10-dienal (faranal) using stereospecific 1,4-cis-hydrogenation
of conjugated double bonds
1
Andrei A. Vasil’ev,a Lars Engmanb and Edward P. Serebryakov*a
a N.D.Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
117913 Moscow, Russia
b Institute of Chemistry, Department of Organic Chemistry, Uppsala University,
Box 531, 751 21 Uppsala, Sweden
Received (in Cambridge, UK) 24th March 2000, Accepted 25th May 2000
Published on the Web 27th June 2000
( )-Faranal was synthesised by a convergent route involving 1,4-cis-hydrogenation of two properly substituted
conjugated diene building blocks to introduce stereospecifically the 6(E) and 10(Z) double bonds of the final target
molecule. meso-2,3-Dimethylsuccinic acid was used to prepare a building block for the ‘right-hand’ part of faranal
carrying two vicinal erythro-configured methyl groups.
The tiny Pharaoh’s ant, Monomorium pharaonis L., can be a
vector of salmonellosis or post-operational microbial infections
in hospitals. Its trail pheromone, faranal [(3S,4R,6E,10Z)-
3,4,7,11-tetramethyltrideca-6,10-dienal] 1,1 could be a good
tool to control this insect. Faranal contains two trisubstituted
double bonds and a chiral vicinal erythro dimethyl structural
motif. Since the 3R,4S-antipode of natural faranal does
not inhibit the biological effect of 1,2 both the natural (3S,4R)
and the racemic forms of the erythro-configured ‘right-hand’
building block have been used in the syntheses of this
semiochemical.
from 46:54 to 85:15 for Wittig olefination3,5 to practically
100:0 for using Normant’s organocuprate addition to an
alkyne4 or for using geraniol as a starting material.6 In the latter
work the formation of the Z-configured ∆10 bond of 1 was
implemented in five steps to result in a Z:E ratio of 92:8.6
Here we report a novel synthesis of racemic (3S*,4R*)-
faranal where 1,4-cis-hydrogenation of conjugated dienes over
(η6-arene)chromium tricarbonyl complexes is used (for a review,
see ref. 11) for stereospecific construction of both trisubstituted
double bonds in compound 1. Recent success in stereospecific
synthesis of insect pheromones based on this reaction12,13
prompted us to develop a synthetic protocol for faranal.
Retrosynthetic analysis of faranal (Scheme 1) suggested the
conjugated diene 2 as a crucial intermediate. Compound 2,
in turn, could be prepared by olefination of the properly substi-
tuted acrolein 3. For the olefination, we reasoned, organo-
selenium chemistry14–16 would be superior to conventional
Wittig-type methodology which is often substrate-dependent.
The Z-configured double bond in aldehyde 3 could be formed
via 1,4-cis-hydrogenation of the dienoic ester 4, which in turn
is readily available from tiglic aldehyde 5.17 Selenoacetal 6 with
an erythro-configured CHMe-CHMe fragment, we envisaged,
could be prepared from commercially available meso-2,3-
dimethylsuccinic acid 7 (the corresponding diol 14 was earlier
used in the synthesis of lasiol,18 which contains the same
structural motif).
To create the (10Z) double bond, the addition of organo-
copper reagents to terminal acetylenes,3,4 the use of (Z)-1-
bromo-3-methylpent-2-ene as a building block5 and a five-step
protocol of geraniol homologation involving stereospecific
epoxidation of an intermediate allylic alcohol6 were explored.
For construction of the (6E) double bond the same organo-
copper approach4 and the Horner–Emmons–Wadsworth
(HEW) olefination5 were employed, as well as a protocol using
geraniol as a starting material.6 To provide for the erythro
arrangement of the two vicinal methyls, the use of suitably
functionalised building blocks (all derived from cis-1,2,3,6-
tetrahydrophthalic anhydride),3–5,7 substituent-directed anti-
alkylation of a 3-methylpentan-5-olide carbanion,6 erythro
addition of an alkenylmanganese chloride to methyl crotonate,8
1,2-syn-hydrogenation of a Z-tetrasubstituted olefin,9 as well
as biocatalytic reduction of the corresponding α,β-enal2 were
reported.
Results and discussion
Tiglic aldehyde 5 proved to be a good starting material for the
preparation of the ‘left-hand’ part of faranal (Scheme 2). Its
reaction with triethyl phosphonoacetate (TEPA) promoted
by NaH17a afforded dienoic ester 4 in 90% yield (the use
of aqueous K2CO3 19 gave only a 57% yield). 1,4-cis-Hydrogen-
ation of diene 4 was performed at 70–75 ЊC and 50 atm H2,
employing (η6-naphthalene)chromium tricarbonyl as the cata-
lyst. Ethyl (Z)-4-methylhex-3-enoate 8 thus formed (diagnostic
4-Me signal at δ 22.8 in the 13C NMR) furnished, upon LiAlH4
reduction, (Z)-4-methylhex-3-en-1-ol, which was transformed
into bromide 9 (67% yield based on ester 8). Previous stereo-
selective syntheses of (Z)-4-methylhex-3-en-1-ol were either
tedious and difficult to scale up4,20a–c or did not proceed cleanly
enough for our purposes.20d–g
In comparison with the efforts spent on creating the right
configuration at stereogenic atoms C(3) and C(4),5–10 little
attention had been paid in recent years to rational ways of
securing the right configuration of the double bonds of faranal.
In earlier syntheses of 1 the E/Z ratio for the ∆6 bond varied
DOI: 10.1039/b002343o
J. Chem. Soc., Perkin Trans. 1, 2000, 2211–2216
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meso-2,3-Dimethylsuccinic acid 7 served as the starting
material for the preparation of the ‘right-hand’ part of faranal
(Scheme 3). Esterification of 7 followed by LiAlH4 reduction in
Scheme 3 Reagents and conditions: i, EtOH, benzene, TsOH; ii,
LiAlH4, THF; iii, Ac2O (1 equiv.), AcOH, 20 ЊC, 12 h; iv, (COCl)2,
DMSO, CH2Cl2, Ϫ50 ЊC; then DIPEA; v, PhSeH, ZnCl2, CCl4, 0–20 ЊC;
vi, MeOH, K2CO3; vii, TBDMSCl, imidazole, DMF.
Scheme 1
Further transformation of bromide 9 into acrolein 3 via
acrylate 10 involved C-alkylation with TEPA followed by HEW
olefination with formaldehyde. Previous procedures employing
THF afforded meso-2,3-dimethylbutane-1,4-diol 14 in 81%
yield (56% in diethyl ether23). The diol 14 was treated with
Ac2O (1 equiv.) to give monoacetate 15 in 50% yield along with
the corresponding diacetate (16%) and recovered diol (26%).
Alcohol 15 was subjected to Swern oxidation using diisopropyl-
ethylamine (DIPEA) instead of triethylamine to minimise the
risk of racemisation of the resulting aldehyde.24 The crude
aldehyde 16 was converted into a selenoacetal using PhSeH in
the presence of ZnCl2.14a The acyl group was replaced by tert-
butyldimethylsilyl (TBDMS) via transesterification and silyl-
ation of alcohol 17. The total yield of the TBDMS-protected
selenoacetal 6 was 27.9% over seven steps (or 45.7% taking the
recovery of diol 14 and its diacetate into account).
The coupling of the ‘left-hand’ and ‘right-hand’ building
blocks of ( )-faranal is shown in Scheme 4. Lithium–selenium
exchange in selenoacetal 6 promoted by n-BuLi gave a selenium-
stabilised carbanion14b which on treatment with aldehyde 3
afforded the β-phenylseleno alcohol 18 as a mixture of four
diastereomers. Elimination of the vicinal phenylseleno and
hydroxy substituents occurred on treatment with methanesul-
fonyl chloride and triethylamine.15 After removal of the
TBDMS group, the conjugated diene was isolated as a 3:2
mixture of (4E)- and (4Z)-isomer. 1,4-cis-Hydrogenation of
conjugated dienes with this substitution pattern has previ-
ously13a,b,25 been shown to cleanly afford E-trisubstituted
alkenes. In fact, hydrogenation of 19 over (η6-naphthalene)-
chromium tricarbonyl led to the known Mori intermediate
K2CO3 or EtONa in EtOH22 proved to be inefficient for
21
the preparation of the alkylated phosphonate 12. Similarly,
LDA in THF (although causing complete deprotonation of
the starting phosphonate), did not lead to alkylation, probably
because THF is not the optimal solvent for nucleophilic substi-
tution. By contrast, polar solvents such as DMSO or DMF
accelerated the alkylation of TEPA with bromide 9. In the most
convenient procedure, NaH in DMSO was used as a base,
and the in situ-produced phosphonate 12 was treated with
K2CO3 and aq. formaldehyde to afford the acrylate 10 in
76% yield. The most high-yielding transformation of ester 10
into aldehyde 3 involved DIBAL-H reduction (to give alcohol
11) followed by Swern oxidation (85% yield over two steps).
Low-temperature DIBAL-H reduction of ester 10 to aldehyde 3
was unselective. As an alternative, nitrile 13 was prepared in a
good yield from bromide 9 analogously to the preparation of
ester 10. However, DIBAL-H reduction of 13 gave aldehyde
3 in only 40% yield. The overall yield of aldehyde 3 from 5 was
30.7%.
Scheme 2 Reagents and conditions: i, NaH, (EtO)2P(O)CH2CO2Et, benzene; ii, H2 (50 atm), (naphthalene)Cr(CO)3, THF, 70 ЊC, 4 h; iii, LiAlH4; iv,
TsCl, Py; v, NaBr, DMF, 50 ЊC, 4 h; vi, NaH, (EtO)2P(O)CH2CO2Et, DMSO, 50 ЊC, 6 h; vii, CH2O, K2CO3; viii, DIBAL-H, (2 equiv.), Ϫ30 ЊC; ix,
(COCl)2, DMSO, CH2Cl2, Ϫ50 ЊC; then Et3N.
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Scheme 4 Reagents and conditions: i, BuLi, THF, Ϫ78 ЊC; then 3; ii, MsCl, Et3N, CH2Cl2, 3 h; iii, Bu4NF, THF; iv, H2 (50 atm), (naphtha-
lene)Cr(CO)3, THF, 50 ЊC, 3 h; v, TsCl, Py, CH2Cl2; vi, NaCN, DMSO, 50 ЊC, 3 h; vii, DIBAL-H, toluene, Ϫ15 ЊC
205 as the sole product. The (9Z)-olefinic bond remained
unaffected in this reaction. Conversion of alcohol 20 into hom-
ologous nitrile 21 was performed according to the method of
Mori and Ueda.5 Simple DIBAL-H reduction of nitrile 21 in
toluene at Ϫ15 ЊC produced ( )-faranal 1 with a better than
94.5% isomeric purity (GLC using a capillary column) in better
yield (75%) than the saponification–reduction–PCC oxidation
sequence previously used.5
In summary, we have demonstrated that 1,4-cis-hydrogen-
ation of conjugated dienes over (η6-arene)tricarbonylchromium
catalysts is an efficient reaction for the stereospecific construc-
tion of both the 6E- and 10Z-trisubstituted double bonds of
faranal. The corresponding conjugated diene precursors were
readily accessible by the HEW and Krief reactions. Provided
the non-racemic erythro-building block is used, the scheme
developed is applicable to the preparation of optically active
faranal. The yield of ( )-faranal 1 from tiglic aldehyde 5 is
14.9% over fifteen steps (or 10.0% from the meso acid 7 over
fourteen steps, unoptimised).
(15 mmHg); δH 0.97 (t, J 7.6 Hz, 3H), 1.25 (t, J 7.1 Hz, 3H), 1.72
(q, J 1.2 Hz, 3H), 2.03 (q, J 7.2 Hz, 2H), 3.02 (d, J 7.2 Hz, 2H),
4.12 (q, J 7.1 Hz, 2H), 5.27 (br t, J 7.2 Hz, 1H); δC 12.5 q, 14.2 q,
22.8 q, 25.0 t, 33.4 t, 60.5 t, 115.3 d, 141.0 s, 172.5 s.
(Z)-1-Bromo-4-methylhex-3-ene 9
Ethyl (Z)-4-methylhex-3-enoate 8 (7.20 g, 46.1 mmol) was
reduced with LiAlH4 (1.226 g, 32.3 mmol) in diethyl ether
(30 mL). After conventional work-up the crude (Z)-4-methyl-
hex-3-en-1-ol thus obtained was treated with TsCl (9.668 g,
51 mmol) in CH2Cl2 (30 mL) in the presence of pyridine (5.46 g,
69.2 mmol) at 0 ЊC for 15 h. Methanol (2 mL) was added to
quench excess of TsCl, the mixture was poured into ice-cold
water and extracted with diethyl ether. The combined extracts
were consecutively washed with 5% HCl, brine, NaHCO3 (aq.)
and again with brine, dried (MgSO4), and concentrated in
vacuo. The crude tosyl ester was vigorously stirred with NaBr
(30 g) in DMF (60 mL) at 50 ЊC for 4 h. The mixture was
diluted with water, extracted with pentane, and the combined
extracts were washed with brine and dried (CaCl2). The solvents
were distilled off at normal pressure through a 30 cm Vigreux
column. Distillation of the residue afforded 5.45 g (67%
from compound 8) of the title bromide 9, bp 100–103 ЊC
(100 mmHg). 1H NMR data were in close agreement with
the literature;20b δC 12.8 q, 22.9 q, 24.9 t, 31.4 t, 33.0 t, 120.5 d,
140.7 s.
Experimental
NMR spectra were recorded in CDCl3 at 399.95 MHz (1H),
100.57 MHz (13C) and 57.21 MHz (77Se). Multiplicities of
signals in the 1H NMR spectra are given as observed. 77Se
Chemical shifts are given in ppm relative to neat Me2Se.
Elemental analyses were performed by Analytical Laboratories,
Lindlar, Germany. (η6-Naphthalene)tricarbonylchromium26
and benzeneselenol27 were prepared according to the literature.
Tiglic aldehyde 5 and TEPA (Lancaster) and meso-2,3-dimeth-
ylsuccinic acid 7 (Aldrich) were used as purchased. Column
chromatography was performed using silica gel MATREX LC
60A/35-70 MY 80/25 85040 (GRACE Davison) and mixtures of
pentane and ethyl acetate as eluent (both freshly distilled).
Ethyl (Z)-6-methyl-2-methyleneoct-5-enoate 10
Sodium hydride (0.480 g of a 60% dispersion in mineral oil,
12 mmol) was washed four times with pentane, and DMSO
(15 mL) was added. TEPA (2.69 g, 12 mmol) was then added
dropwise under nitrogen with stirring until the evolution of
hydrogen ceased. (Z)-1-Bromo-4-methylhex-3-ene 9 (1.779 g,
10 mmol) was added in one portion and the mixture was stirred
at 50 ЊC for 6 h. After cooling of the mixture to r.t., K2CO3
(4.14 g, 30 mmol) was added followed by formaldehyde (4 mL;
37% aq.), and the mixture was stirred for 3 h at ambient tem-
perature and then for another 3 h at 60 ЊC. The mixture was
diluted with water (40 mL) and extracted with diethyl ether. The
combined extracts were washed with brine, dried (CaCl2), and
concentrated in vacuo. Column chromatography (50 mL silica;
1–3% EtOAc in pentane) afforded 1.483 g (76%) of the title
ester 10 as a colourless oil, δH 0.96 (t, J 7.5 Hz, 3H), 1.30 (t,
J 7.2 Hz, 3H), 1.67 (q, J 1.2 Hz, 3H), 2.01 (q, J 7.6 Hz, 2H), 2.16
(q, J 7.8 Hz, 2H), 2.32 (t, J 7.8 Hz, 2H), 4.21 (q, J 7.2 Hz, 2H),
5.08 (br t, J 7.1 Hz, 1H), 5.51 (br s, 1H), 6.14 (br s, 1H); δC 12.8
q, 14.2 q, 22.8 q, 24.7 t, 26.6 t, 32.4 t, 60.5 t, 123.0 d, 124.6 t,
138.0 s, 140.6 s, 167.3 s. (Calc. for C12H20O2: C, 73.43; H, 10.27.
Found: C, 73.26; H, 10.35%).
Ethyl (E,E)-4-methylhexa-2,4-dienoate 4
This product, bp 110 ЊC (15 mmHg), was prepared as
described.17a 1H NMR data were in a good agreement with the
literature;17b δC 11.7 q, 14.3 q, 14.5 q, 60.1 t, 115.2 d, 133.7 s,
136.2 t, 149.4 t, 167.6 s.
Ethyl (Z)-4-methylhex-3-enoate 8
A solution of diene ester 4 (8.85 g) and (η6-naphthalene)-
chromium tricarbonyl (0.75 g) in absolute THF (35 mL) was
placed in a stainless steel autoclave under an atmosphere of
argon. The vessel was sealed and filled/evacuated three times
with H2 (at 10 atm) to remove traces of O2. The hydrogen
pressure was then adjusted to 50 atm, and hydrogenation was
carried out at 70–75 ЊC for 4 h. After decompression, the auto-
clave was rinsed with diethyl ether, and the resulting solution
concentrated under reduced pressure. After dissolution in
pentane, filtration through Celite and concentration under
reduced pressure, final distillation in vacuo afforded 7.20 g
(80%) of the title compound 8 as a colourless liquid, bp 80 ЊC
(Z)-6-Methyl-2-methyleneoct-5-en-1-ol 11
To a stirred solution of ethyl (Z)-6-methyl-2-methyleneoct-5-
enoate 10 (1.15 g, 5.86 mmol) in pentane (20 mL) was added a
J. Chem. Soc., Perkin Trans. 1, 2000, 2211–2216
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solution of DIBAL-H in toluene (1.5 M solution; 8.5 mL, 12.75
mmol) at Ϫ30 ЊC and the mixture was kept at this temperature
for 3 h. The temperature was then allowed to raise to 0 ЊC and
methanol (1 mL) and water (10 mL) were added. Cold 5% HCl
was added to dissolve the solid formed. After diethyl ether
extractions, washings of the extract with aq. NaHCO3, drying
(MgSO4), concentration in vacuo and column chromatography
(50 mL silica; 5, 10 and 15% EtOAc in pentane), 0.836 g (92%)
of the title alcohol 11 was isolated as a colourless oil, δH 0.97
(t, J 7.6 Hz, 3H), 1.49 (br s, 1H), 1.68 (q, J 1.3 Hz, 3H), 2.03 (q,
J 7.6 Hz, 2H), 2.08–2.15 (several peaks, 4H), 4.08 (s, 2H), 4.98
(s, 1H), 5.03 (s, 1H), 5.09 (br t, J 6.8 Hz, 1H); δC 12.8 q, 22.8 q,
24.8 t, 26.0 t, 33.3 t, 66.0 t, 109.3 t, 123.4 d, 137.7 s, 148.9 s.
(Calc. for C10H18O: C, 77.87; H, 11.76. Found: C, 77.70; H,
11.69%).
pentane afforded 0.646 g (16%) of erythro-2,3-dimethylbutane-
1,4-diyl diacetate.
Continued elution with 30–40% EtOAc in pentane gave 1.642
g (50%) of the title monoacetate 15, δH 0.92 (d, J 6.9 Hz, 3H),
0.96 (d, J 7.0 Hz, 3H), 1.70 (m, 1H), 1.75 (br s, 1H), 1.91 (m,
1H), 2.04 (s, 3H), 3.50 (dd, J 10.8, 6.5 Hz, 1H), 3.62 (dd, J 10.8,
6.2 Hz, 1H), 3.89 (dd, J 10.9, 7.2 Hz, 1H), 4.12 (dd, J 10.9, 5.6
Hz, 1H); δC 13.5 q, 14.7 q, 21.0 q, 34.2 d, 38.0 d, 65.8 t, 67.3 t,
171.3 s.
Finally, elution with 80% EtOAc in pentane gave 0.637 g
(26%) of recovered diol 14.
erythro-2,3-Dimethyl-4,4-bis(phenylseleno)butan-1-ol 17
A solution of oxalyl dichloride (1.485 g, 11.8 mmol), CH2Cl2
(34 mL) and DMSO (1.7 mL) was stirred at Ϫ50 ЊC for 5 min.
To this solution was added acetoxy alcohol 15 (1.642 g, 10.2
mmol). Then, after 15 min, DIPEA (9.0 mL) was added drop-
wise and the mixture was allowed to warm to r.t. After aqueous
work-up and ethereal extraction, the organic phase was washed
successively with 5% HCl and brine, dried (CaCl2) and concen-
trated in vacuo. The crude aldehyde 16 thus obtained was mixed
under argon with benzeneselenol (3.365 g, 21.4 mmol) and CCl4
(3 mL), and this solution was added dropwise at 0 ЊC under
argon to a vigorously stirred suspension of anhydrous ZnCl2
(0.695 g, 5.1 mmol) in CCl4 (2 mL). After 2 h of stirring at r.t.,
the mixture was diluted with diethyl ether (20 mL). The organic
phase was washed with HCl (5% aq.) and several times with
NaHCO3 (aq.) until the aqueous washings remained clear. The
organic phase was dried (CaCl2), and concentrated in vacuo.
The residue was stirred overnight in methanol (20 mL) in the
presence of K2CO3 (0.05 g). The solvent was removed in vacuo
and the residue subjected to column chromatography (100 mL
silica; 5–20% gradient EtOAc in pentane) to afford 2.923 g
(69%) of seleno alcohol 17 as a colourless, viscous oil, δH 0.89
(d, J 6.3 Hz, 3H), 1.22 (d, J 6.3 Hz, 3H), 1.87 (m, 2H), 3.49 (dd,
J 10.7, 5.4 Hz, 1H), 3.66 (dd, J 10.7, 3.7 Hz, 1H), 4.73 (d, J 2.7
Hz, 1H), 7.20–7.32 (several peaks, 6H), 7.47 (m, 2H), 7.61 (m,
2H); δC 15.0 q, 15.6 q, 39.0 d, 41.3 d, 52.8 d, 65.9 t, 127.8 d,
127.9 d, 129.0 d, 129.1 d, 130.2 s, 131.8 s, 134.2 d, 134.4 d;
δSe 346.5, 410.9 (Calc. for C18H22OSe2: C, 52.44; H, 5.38. Found:
C, 52.53; H, 5.32%).
(Z)-6-Methyl-2-methyleneoct-5-enonitrile 13
A mixture of (diethylphosphono)acetonitrile (2.12 g, 12 mmol),
bromide 9 (1.779 g, 10 mmol), K2CO3 (6.62 g, 48 mmol) and
DMSO (15 mL) was stirred at ambient temperature overnight
and then treated with formaldehyde (4 mL; 37% aq.). After
additional stirring for 1 h, the mixture was diluted with water
and extracted with diethyl ether. Drying (MgSO4), concen-
tration in vacuo and column chromatography (70 mL silica;
1–5% EtOAc in pentane) afforded 1.081 g (72%) of nitrile 13 as
a colourless oil, δH 0.97 (t, J 7.5 Hz. 3H), 1.68 (s, 3H), 2.03 (q,
J 7.5 Hz, 2H), 2.26 (br s, 4H), 5.01 (br t, J 7.0 Hz, 1H), 5.70 (s,
1H), 5.83 (s, 1H); δC 12.8 q, 22.8 q, 24.8 t, 25.7 t, 35.0 t, 118.7 s,
121.1 d, 122.9 s, 130.4 t, 139.4 s. (Calc. for C10H15N: C, 80.48;
H, 10.13. Found: C, 80.20; H, 10.23%).
(Z)-6-Methyl-2-methyleneoct-5-enal 3
(a) Standard Swern oxidation28 of alcohol 11, followed by
column chromatography (1–2% EtOAc in pentane), afforded
91% of the title compound 3.
(b) DIBAL-H reduction of nitrile 13 followed by usual
work-up and column chromatography afforded 40% of the title
compound 3, δH 0.94 (t, J 7.8 Hz, 3H), 1.66 (q, J 1.3 Hz, 3H),
1.99 (q, J 7.8 Hz, 2H), 2.14 (q, J 8.0 Hz, 2H), 2.27 (t, J 7.0 Hz,
2H), 5.04 (br t, J 7.0 Hz, 1H), 5.99 (s, 1H), 6.24 (s, 1H), 9.53
(s, 1H); δC 12.8 q, 22.8 q, 24.7 t, 25.8 t, 28.2 t, 122.8 d, 134.2 t,
138.2 s, 149.8 s, 194.7 d.
erythro-4-(tert-Butyldimethylsilyloxy)-2,3-dimethyl-1,1-bis-
(phenylseleno)butane 6
erythro-4-Acetoxy-2,3-dimethylbutan-1-ol 15
A mixture of meso-2,3-dimethylsuccinic acid 7 (3.0 g, 20.5
mmol), ethanol (7 mL), benzene (18 mL) and toluene-p-sulfonic
acid (0.05 g) was refluxed for 12 h using a Dean–Stark trap. By
this time the white solid in the reaction flask had disappeared.
The reaction mixture was concentrated in vacuo, dissolved in
absolute THF (10 mL) and added dropwise to a stirred suspen-
sion of LiAlH4 (1.1 g, 28 mmol) in THF (40 mL). When the
exothermic reaction was over, the mixture was stirred for an
additional 2 h, cooled to 0 ЊC and quenched by a slow addition
of a solid mixture of finely powdered Na2SO4ؒ10H2O (6 g) and
an equal volume of Celite. Water (4 mL) was then added, and
after the grey colour of the solid phase had turned white, the
reaction mixture was filtered through Celite, and the filter cake
was rinsed with diethyl ether. Concentration of the filtrate,
followed by pumping (6 h at 1 mmHg), afforded practically
pure meso-2,3-dimethylbutane-1,4-diol 14 (2.658 g, 81%) as a
colourless, viscous syrup [δH 0.89 (d, J 7.0 Hz, 6H), 1.81 (m,
2H), 3.50 (dd, J 10.9, 4.1 Hz, 2H), 3.55 (dd, J 10.9, 6.8 Hz, 2H),
3.64 (br s, 2H); δC 13.4 q, 38.7 d, 65.4 t].
To a stirred solution of alcohol 17 (2.697 g, 6.55 mmol) and
imidazole (0.535 g, 7.86 mmol) in DMF (6 mL) was added
tert-butyldimethylsilyl chloride (1.085 g, 7.2 mmol) in small
portions during 20 min, and the mixture was kept at ambient
temperature for an additional 1 h. The mixture was then treated
with NaHCO3 (aq.) and extracted with diethyl ether–pentane
(1:1 v/v). After drying (MgSO4) and concentration in vacuo,
column chromatography (150 mL silica; 1–2% EtOAc in pen-
tane) afforded 3.366 g (97%) of the required TBDMS derivative
6 as a yellowish viscous oil, δH Ϫ0.02 (s, 6H), 0.82 (s, 9H), 0.84
(d, J 6.3 Hz, 3H), 1.20 (d, J 6.2 Hz, 3H), 1.85 (m, 2H), 3.53
(dd, J 10.0, 4.7 Hz, 1H), 3.56 (dd, J 10.0, 3.2 Hz, 1H), 4.78 (d,
J 2.3 Hz, 1H), 7.20–7.31 (several peaks, 6H), 7.47 (m, 2H), 7.63
(m, 2H); δC Ϫ5.5 q, 14.9 q, 16.0 q, 18.2 s, 25.8 q, 38.9 d, 40.7 d,
52.9 d, 65.9 t, 127.7 d, 127.8 d, 128.3 d, 128.9 d, 129.0 d, 130.3
s, 131.8 s, 134.1 d, 134.4 d; δSe 339.2, 406.1 (Calc. for C24-
H36OSe2Si: C, 54.75; H, 6.89. Found: C, 54.91; H, 7.00%).
(2S*,3R*,9Z)-1-(tert-Butyldimethylsilyloxy)-2,3,10-trimethyl-6-
methylene-4-(phenylseleno)dodec-9-en-5-ol 18
The diol thus obtained was acetylated with Ac2O (2.0 g) in
AcOH (10 mL) during overnight stirring at r.t. The mixture was
concentrated in vacuo, neutralised with NaHCO3 (aq., followed
by portions of the solid), and extracted with diethyl ether. The
extracts were dried (MgSO4) and subjected to column chrom-
atography on 100 mL of silica. Elution with 15% EtOAc in
To a stirred solution of selenoacetal 6 (1.137 g, 2.16 mmol) in
THF (15 mL) at Ϫ78 ЊC was added n-BuLi (1.6 M solution
in hexane; 1.35 mL, 2.16 mmol). The mixture was stirred for
5 min and treated with a solution of dienal 3 (0.329 g, 2.16
2214
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mmol) in THF (1.5 mL). The temperature was raised to 20 ЊC,
and the reaction mixture was quenched with NaHCO3 (aq.) and
extracted with diethyl ether. The extracts were dried (MgSO4),
concentrated in vacuo, and subjected to column chromato-
graphy (80 mL silica; 1–2% EtOAc in pentane) to afford 1.059 g
(93%) of seleno alcohol 18 as a mixture of four diastereomers,
δH (characteristic peaks) 0.01 and 0.03 (both s, Σ 6H), 0.86–1.06
(several peaks, 18H), 1.60–2.21 (several peaks, 11H), 2.40, 2.46,
2.68 and 2.99 (all br d, Σ 1H), 3.38–3.68 (several peaks, 3H),
4.18–4.36 (several peaks, 1H), 4.90–5.30 (several peaks, 3H),
7.18–7.30 (several peaks, 3H), 7.42–7.63 (several peaks, 2H);
δC (characteristic peaks) 56.4 d, 56.9 d, 60.0 d, 61.6 d, 65.4 t,
65.6 t, 65.7 t, 65.8 t, 73.5 d, 75.1 d, 76.1 d, 78.0 d, 110.9 t, 111.0
t, 112.0 t, 113.2 t, 123.3 d, 123.4 d, 123.6 d, 123.7 d, 137.5 s,
137.6 s, 147.4 s, 148.1 s, 149.4 s, 149.9 s; δSe 238.3, 255.2, 268.7,
321.6.
31.3 t, 35.5 d, 40.2 d, 40.3 t, 66.2 t, 123.6 d, 123.9 d, 135.6 s,
137.1 s.
(6E,10Z)-erythro-3,4,7,11-Tetramethyltrideca-6,10-dienonitrile
21
This was prepared in 85% yield from (5E,9Z)-erythro-2,3,6,10-
tetramethyldodeca-5,9-dien-1-ol 20 as described.5 The NMR
1H data were in good agreement with the literature;5 δC 12.8 q,
16.2 q, 17.1 q, 21.5 t, 22.9 q, 24.8 t, 26.2 t, 31.5 t, 34.8 d, 37.6 d,
40.1 t, 119.5 s, 122.4 d, 123.8 d, 136.4 s, 137.2 s.
(6E,10Z)-erythro-3,4,7,11-Tetramethyltrideca-6,10-dienal (rac-
faranal) 1
To a stirred solution of (6E,10Z)-erythro-3,4,7,11-tetramethyl-
trideca-6,10-dienonitrile 21 (0.100 g, 0.4 mmol) in toluene
(2 mL) was added DIBAL-H (1.5 M solution in toluene; 0.29
mL, 0.43 mmol) at Ϫ15 ЊC. Then, during 30 min, the temper-
ature was allowed to reach 20 ЊC, and the reaction mixture was
quenched with NH4Cl (aq.). The thick solid precipitate was dis-
solved by adding cold 5% HCl, and the mixture was extracted
with diethyl ether. The extract was washed successively with
brine and aq. NaHCO3, dried (MgSO4), and concentrated in
vacuo. Column chromatography (10 mL silica; 1.5% EtOAc in
pentane) afforded 0.076 g (75%) of the title compound 1 as a
colourless oil. 1H NMR data were in good agreement with the
literature;4–6 δC 12.8 q, 16.0 q, 16.1 q, 17.6 q, 22.9 q, 24.8 t, 26.2
t, 31.9 t, 32.0 d, 38.5 d, 40.1 t, 47.4 t, 123.1 d, 123.9 d, 135.9 s,
137.1 s, 203.3 d.
(4EZ,9Z)-erythro-2,3,10-Trimethyl-6-methylenedodeca-4,9-
dien-1-ol 19
To a stirred solution of selenide 18 (0.900 g, 1.72 mmol) and
triethylamine (1.2 mL) in CH2Cl2 (9 mL) was added meth-
anesulfonyl chloride (0.42 mL) dropwise at r.t. After 3 h the
mixture was treated with NaHCO3 (aq.) and extracted with
diethyl ether. After drying (CaCl2), and concentration in vacuo,
the residue was subjected to column chromatography (60 mL
silica; 1–1.5% EtOAc in pentane) to afford 0.576 g (93%) of
TBDMS-protected title alcohol.
Deprotection was effected by overnight stirring in THF in
the presence of tetrabutylammonium fluoride (1.7 mL; 1 M
solution in THF). The alcohol 19 thus formed [a 3:2 mixture
of (4E,9Z)- and (4Z,9Z)-isomer] was difficult to free from
some tert-butyldimethylsilanol by-product by column chrom-
atography. An analytically pure sample was obtained after
acetylation, column chromatography (40 mL silica; 2% EtOAc
in pentane), transesterification (MeOH–K2CO3, for the pro-
cedure see compound 17) and chromatography (15% EtOAc in
pentane). During this operation, two fractions substantially
enriched in the (4Z)-19 (eluted first) and (4E)-19 isomers of the
title alcohol were obtained. (4Z,9Z)-Isomer: δH 0.89 (d, J 7.0
Hz, 3H), 0.96 (t, J 7.6 Hz, 3H), 1.02 (d, J 6.9 Hz, 3H), 1.43 (br s,
1H), 1.57 (m, 1H), 1.67 (s, 3H), 2.02 (q, J 7.7 Hz, 2H), 2.10 (m,
4H), 2.83 (m, 1H), 3.44 (dd, J 10.7, 6.2 Hz, 1H), 3.54 (dd,
J 10.7, 6.1 Hz, 1H), 4.87 (s, 1H), 4.96 (s, 1H), 5.08 (br t, J 6.5
Hz, 1H), 5.34 (t, J 11.4 Hz, 1H), 5.82 (d, J 11.8 Hz, 1H); δC 12.8
q, 12.9 q, 19.1 q, 22.9 q, 24.8 t, 26.4 t, 33.2 d, 37.8 t, 41.1 d, 66.6
t, 112.8 t, 123.8 d, 129.8 d, 135.0 d, 137.5 s, 145.7 s. (4E,9Z)-
Isomer: δH 0.88 (d, J 7.1 Hz, 3H), 0.96 (t, J 7.5 Hz, 3H), 1.05 (d,
J 6.9 Hz, 3H), 1.42 (br s, 1H), 1.65 (m, 1H), 1.68 (s, 3H), 2.02 (q,
J 7.6 Hz, 2H), 2.12–2.24 (several peaks, 4H), 2.36 (m, 1H), 3.45
(dd, J 10.5, 6.3 Hz, 1H), 3.55 (dd, J 10.5, 6.2 Hz, 1H), 4.88 (s,
1H), 4.91 (s, 1H), 5.12 (br t, J 6.0 Hz, 1H), 5.60 (dd, J 15.9, 8.7
Hz, 1H), 6.05 (d, J 15.9 Hz, 1H); δC 12.9 q (two peaks), 18.4 q,
22.8 q, 24.8 t, 26.6 t, 32.6 t, 38.4 d, 41.0 d, 66.5 t, 113.7 t, 123.7
d, 131.9 d, 132.5 d, 137.4 s, 145.9 s. Total yield: 0.333 g (82% on
18) (Calc. for C16H28O: C, 81.29; H, 11.94. Found: C, 81.10; H,
11.83%).
Acknowledgements
This work was supported by the Russian Foundation for Basic
Research (grant No. 99-03-32992) and the Swedish Natural
Science Research Council. We also thank the Royal Swedish
Academy of Sciences for a research grant for cooperation
between Sweden and the former Soviet Union.
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