Enantiodivergent synthesis of both enantiomers of gypsy moth pheromone disparlure

Article abstract of DOI:10.1021/jo070060o

(Chemical Equation Presented) Enantiodivergent synthesis of both (-)- and (+)-disparlure, a bioactive pheromone, possessing a cis-epoxide has been accomplished. The key step involves the cross metathesis of a chiral homoallylic alcohol derived from L-(+)-tartaric acid.

Full text of DOI:10.1021/jo070060o

of pheromones.6 Herein, we disclose the synthesis of both
enantiomers of 1, utilizing cross metathesis of a homoallylic
alcohol, derived from L-(+)-tartaric acid. As shown in retrosyn-
thesis (Scheme 1), synthesis of both enantiomers of disparlure
is envisaged from the diol 8, by stereoselective cyclization of 8
to either enantiomer of the epoxide. Synthesis of diol 8 was
anticipated from cross metathesis of homoallylic alcohol 7 and
4-methyl-1-pentene. Allylation of benzyloxyaldehyde 6 was
identified for the synthesis of homoallylic alcohol 7. Synthesis
of aldehydes similar to 6 from tartaric acid has been established
in our laboratory.7
Enantiodivergent Synthesis of Both Enantiomers
of Gypsy Moth Pheromone Disparlure
Kavirayani R. Prasad* and Pazhamalai Anbarasan
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
prasad@orgchem.iisc.ernet.in
ReceiVed January 11, 2007
The synthetic sequence commenced with the addition of
n-decylmagnesium bromide to the bis-Weinreb amide 28 derived
from L-(+)-tartaric acid, affording the diketone 3 in 92% yield.
Under conditions that were optimized for the reduction of similar
ketones, reduction of diketone 3 with K-selectride furnished the
1,4-diol 4 as the single diastereomer.9 Protection of 1,4-diol 4
as the dibenzyl ether and further deprotection of the acetonide
resulted in 1,2-diol 5 in 89% yield. Treatment of diol 5 with
Pb(OAc)4 produced the aldehyde 6, which on allylation with
allyltributyltin under Keck allylation10 conditions afforded the
homoallylic alcohol 7 (Scheme 2), in 79% yield in two steps.
Homoallylic alcohol 7 served as the precursor for the synthesis
of both enantiomers of 1.The synthesis of (-)-disparlure
(Scheme 3) was accomplished as follows. Homoallylic alcohol
7 was converted to the tosylate 9, which underwent facile cross
Enantiodivergent synthesis of both (-)- and (+)-disparlure,
a bioactive pheromone, possessing a cis-epoxide has been
accomplished. The key step involves the cross metathesis
of a chiral homoallylic alcohol derived from L-(+)-tartaric
acid.
(5) For recent synthesis of disparlure, see: (a) Koumbis, A. E.;
Chronopoulos, D. D. Tetrahedron Lett. 2005, 46, 4353. (b) Fukusaki, E.;
Satoda, S.; Senda, S.; Omata, T. J. Biosci. Bioeng. 1999, 87, 103. (c)
Marshall, J. A.; Jablonowski, J. A.; Jiang, H. J. Org.Chem. 1999, 64, 2152.
(d) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem. 1999, 64,
3719. (e) Tsuboi, S.; Yamafuji, N.; Utaka, M. Tetrahedron: Asymmetry
1997, 8, 375. (f) Li, L. H.; Wang, D.; Chan, T. H. Tetrahedron Lett. 1997,
38, 101. (g) Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa, A. Tetrahedron
Lett. 1995, 36, 5831. (h) Sinha-Bagchi, A.; Sinha, S. C.; Keinan, E.
Tetrahedron: Asymmetry 1995, 6, 2889. (i) Paolucci, C.; Mazzini, C.; Fava,
A. J. Org. Chem. 1995, 60, 169. (j) Ko, S. Y. Tetrahedron Lett. 1994, 35,
3601. (k) Tsuboi, S.; Furutani, H.; Ansari, M. H.; Sakai, T.; Utaka, M.;
Takeda, A. J. Org. Chem. 1993, 58, 486. (l) Brevet, J.-L.; Mori, K. Synthesis
1992, 1007. (m) Keinan, E.; Sinha, S. C.; Sinha-Bagchi, A.; Wang, Z.-M.;
Zhang, X.-L.; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 6411.
(6) (a) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2005, 16,
3951. (b) Prasad, K. R.; Anbarasan, P. Tetrahedron Lett. 2006, 47, 1433.
(c) Prasad, K. R.; Anbarasan, P. Synlett 2006, 2087. (d) Prasad, K. R.;
Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 1146. (e) Prasad, K. R.;
Anbarasan, P. Tetrahedron 2006, 62, 8303. (f) Prasad, K. R.; Chandrakumar,
A.; Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 1979. Synthesis of
styryl lactones: (g) Prasad, K. R.; Gholap, S. L. Synlett 2005, 2260. (h)
Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71, 3643.
Disparlure (cis-7,8-epoxy-2-methyloctadecane) 1 is the sex
pheromone produced by the female gypsy moth, Porthetria
dispar L., a widespread forest pest, which causes severe forest
losses during outbreaks.1 Iwaki et al. established the configu-
ration of 1 by synthesis and also observed that natural (+)-1 is
relatively more active than the (-)-enantiomer.2 It has been
recently shown that the two pheromone binding proteins from
the gypsy moth bind differently for both enantiomers of
disparlure.3 Because of the different bioactivity associated with
both antipodes, disparlure has been a synthetic target for a long
time.4 Of the many enantioselective syntheses disclosed for 1,
most of the approaches utilize chiral pool starting materials,5a,i
chiral stannanes,5c asymmetric chloroallylboration,5d besides
Sharpless asymmetric epoxidation,5f dihydroxylation,5h,j,m and
enzymatic procedures.5b,k
Our interest in the synthesis of bioactive natural products from
chiral pool tartaric acid resulted in the synthesis of a number
(7) Prasad, K. R.; Chandrakumar, A. Tetrahedron: Asymmetry 2005,
16, 1897.
(8) (a) Nugiel, D. A.; Jakobs, K.; Worley, T.; Patel, M.; Kaltenbach,
R. F., III; Meyer, D. T.; Jadhav, P. K.; De Lucca, G. V.; Smyser, T. E.;
Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J. Med. Chem.
1996, 39, 2156. (b) McNulty, J.; Grunner, V.; Mao, J. Tetrahedron Lett.
2001, 42, 5609.
(9) Formation of the other possible diastereomers was not observed within
detectable limits by NMR. For a systematic study on the factors governing
the diastereoselectivity in the reduction and Grignard reagent addition to
similar C2-symmetric diketones derived from tartaric acid, see: Prasad,
K. R.; Chandrakumar, A. Synthesis 2006, 2159.
* Corresponding author. Fax: +918023600529.
(1) Bierl, B. A.; Beroza, M.; Collier, C. W. Science 1970, 170, 87.
(2) Iwaki, S.; Marumo, S.; Saito, T.; Yamada, M.; Katagiri, K. J. Am.
Chem. Soc. 1974, 96, 7842.
(3) Plettner, E.; Lazar, J.; Prestwich, E. G.; Prestwich, G. D. Biochemistry
2000, 39, 8953.
(4) For a review on the synthesis of insect pheromones, see: (a) Mori,
K. Curr. Org. Synth. 2004, 1, 11. (b) Mori, K. Acc. Chem. Res. 2000, 33,
102.
10.1021/jo070060o CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/17/2007
J. Org. Chem. 2007, 72, 3155-3157
3155

SCHEME 1. Retrosynthesis of Disparlure
SCHEME 3. Synthesis of (-)-Disparlure 1
SCHEME 2. Stereoselective Synthesis of Homoallylic
Alcohol 7
SCHEME 4. Synthesis of (+)-Disparlure 1
the tosylate 15 in 90% yield. Treatment of 15 with TBAF
furnished (+)-1 in 89% yield: [R]D +1.0 (c 1.5, CCl4); lit.5c
[R]D +0.9 (c 1.1, CCl4).In summary, a facile enantiodivergent
synthesis of the bioactive pheromone, disparlure, was achieved.
Homoallylic alcohol derived from chiral pool L-(+)-tartaric acid
served as the key building block for the synthesis of both (-)-
and (+)-disparlure, involving cross metathesis as the pivotal
step.
metathesis11 with 4-methyl-1-pentene in presence of 5 mol %
of Grubbs second generation catalyst to afford the alkene 1012
in 92% yield. Hydrogenation of the alkene 10 with Pd/C led to
the formation of hydroxytosylate 11,13 which on treatment with
K2CO3 furnished (-)-1 in 89% yield: [R]D -1.0 (c 1.7, CCl4);
lit.5c [R]D -0.9 (c 0.21, CCl4); the spectral data of which are
identical to those reported in literature.5cFor the synthesis of
(+)-1 (Scheme 4), the alcohol group in homoallylic alcohol 7
was protected as the tert-butyldimethylsilyl ether under standard
conditions to yield 12 in 98% yield. Cross metathesis of 12
with 4-methyl-1-pentene resulted in alkene 13,14 which on
hydrogenation with Pd/C afforded the alcohol 14 in 81% yield
in two steps. Reaction of 14 with TsCl and DMAP produced
Experimental Section
(4R,5R)-5-(Benzyloxy)pentadec-1-en-4-ol (7): To a solution of
5 (0.2 g, 0.34 mmol) in 3 mL of benzene at room temperature was
added Pb(OAc)4 (0.27 g, 0.6 mmol) under argon atmosphere. The
reaction mixture was stirred for 1.5 h at the same temperature,
quenched with water (0.2 mL), and stirred for 10 min at room
temperature. The reaction mixture was filtered through a short pad
of Celite, and the Celite pad was washed with CH2Cl2 (25 mL).
The combined organic layers were dried over Na2SO4, and the
solvent was evaporated under reduced pressure to yield R-benzyl-
oxyaldehyde 6 as a colorless oil. It was subjected to the next reaction
without purification.
A suspension of aldehyde 6 (obtained above) and MgBr2‚Et2O
(0.23 g, 0.9 mmol) in 3 mL of CH2Cl2 at -78 °C was stirred under
argon atmosphere for 1 h. Allyltributyltin (0.3 mL, 0.9 mmol) was
introduced dropwise over a period of 5 min at the same temperature.
The reaction mixture was stirred for 2 h, poured into water (10
mL), and extracted with ether (3 × 8 mL). Combined ethereal
extracts were washed with 1% aqueous NH3 (three times) to remove
tin impurities, brine, and dried over Na2SO4. Evaporation of solvent
followed by column chromatography of the resulting residue using
petroleum ether/EtOAc (96:4) as an eluent yielded 7 as a colorless
oil in 79% (for two steps, 0.18 g): [R]D -18.8 (c 1, CHCl3); IR
(neat) 3442, 2952, 2854, 1456, 1090, 1070, 912, 697 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 5.94-5.78 (m, 1H),
5.14-5.06 (m, 2H), 4.65 (d, J ) 11.4 Hz, 1H), 4.50 (d, J ) 11.4
Hz, 1H), 3.67-3.60 (m, 1H), 3.36-3.28 (m, 1H), 2.39-2.18 (m,
3H), 1.71-1.49 (m, 2H), 1.41-1.18 (m, 16H), 0.88 (t, J ) 7.2
(10) (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265.
Chelation-controlled addition of allyltributyltin to similar aldehydes is well
documented in literature. (b) Schlessinger, R. H.; Graves, D. D. Tetrahedron
Lett. 1987, 28, 4381. (c) Keck, G. E.; Andrus, M. B.; Romer, D. R. J. Org.
Chem. 1991, 56, 417. (d) Murga, J.; Falomir, E.; Garcia-Fortanet, J.; Carda,
M.; Marco, J. A. Org. Lett. 2002, 4, 3447. (e) Prasad, K. R.; Penchalaiah,
K.; Choudhary, A.; Anbarasan, P. Tetrahedron Lett. 2007, 48, 309. For a
review on Lewis acid mediated allylation with allyltin compounds, see:
(f) Nishigaichi, Y.; Takuwa, A.; Naruta, Y.; Maruyama, K. Tetrahedron
1993, 34, 7395.
(11) (a) Grubbs, R. H.; Trnka, T. M.; Sanford, M. S. Curr. Meth. Inorg.
Chem. 2003, 3, 187. (b) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed.
2003, 42, 1900.
(12) Evaluation of the ratio of E/Z regioisomers in 10 resulting from the
cross metathesis was inconclusive from NMR. No further efforts were made
to estimate the E/Z ratio. The stereochemistry of the double bond is of no
consequence because it is saturated in the next step by hydrogenation.
(13) A minor amount (6%) of product resulting from the displacement
of the tosyl group is also observed.
(14) It was difficult to separate the product alkene 13 from homoallylic
alcohol 12 at this stage. However, further hydrogenation of the alkene 13
resulted in the alcohol 14, which was easily purified.
3156 J. Org. Chem., Vol. 72, No. 8, 2007

Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 138.4 (Cq), 134.9 (CH),
128.4 (CH), 127.8 (CH), 127.7 (CH), 117.2 (CH2), 81.4 (CH), 72.3
(CH2), 71.9 (CH), 38.0 (CH2), 31.9 (CH2), 30.1 (CH2), 29.8 (CH2),
29.6 (CH2), 29.5 (CH2), 29.3 (CH2), 25.1 (CH2), 22.6 (CH2), 14.0
(CH3); HRMS for C22H36O2 + Na calcd 355.2613; found 355.2612.
(7R,8R)-8-(Benzyloxy)-7-(p-toluenesulfonyloxy)-2-methyloc-
tadec-4-ene (10): A mixture of 9 (50 mg, 0.1 mmol), 4-methyl-
1-pentene (0.07 mL, 0.5 mmol), and Grubbs second generation
catalyst (5 mg, 0.005 mmol) in 1 mL of CH2Cl2 was refluxed for
6 h. The solvent was removed, and the syrup thus obtained was
chromatographed using petroleum ether/EtOAc (97:3) as an eluent
to yield 10 in 92% (51 mg) as a colorless oil, as an E/Z mixture
(the ratio of the geometrical isomers is inconclusive from 1H NMR;
since the next step is the reduction of the double bond, no efforts
were made to separate the E/Z isomers and is used as such in the
next step): IR (neat) 2924, 2853, 1599, 1455, 1367, 1188, 1176,
CDCl3) δ 2.91-2.87 (m, 2H), 1.57-1.15 (m, 27H), 0.90-0.84 (m,
9H); 13C NMR (75 MHz, CDCl3) δ 57.2 (CH), 38.9 (CH2), 31.9
(CH2), 29.5 (CH2), 29.3 (CH2), 27.9 (CH), 27.8 (CH2), 27.3 (CH2),
26.8 (CH2), 26.6 (CH2), 22.7 (CH2), 22.6 (CH3), 14.1 (CH3).
(7R,8R)-7-(tert-Butyldimethylsilyloxy)-2-methyloctadecan-8-
ol (14): A mixture of 12 (60 mg, 0.13 mmol), 4-methyl-1-pentene
(0.09 mL, 0.67 mmol), and Grubbs second generation catalyst (6
mg, 0.0065 mmol) in 1 mL of CH2Cl2 was refluxed for 8 h. After
the reaction was complete (indicated by TLC), it was concentrated
to a syrup. Column chromatography of the syrup using petroleum
ether/EtOAc (98:2) as an eluent yielded 13, admixed with a small
amount of 12 which was not separable by column chromatography.
It was subjected to the next reaction without further purification.
To a solution of the crude 13 obtained above in 2.5 mL of
methanol at room temperature was added activated 10% Pd/C (30
mg). The reaction mixture was stirred for 3 h under hydrogen
atmosphere (balloon) at the same temperature. After the reaction
was complete (TLC), it was filtered through a short pad of Celite
and the Celite pad was washed with ether (15 mL). Residue obtained
after evaporation of solvent was purified by column chromatography
using petroleum ether/EtOAc (98:2) to yield 14 as a colorless oil
in 81% (45 mg): [R]D -3.8 (c 3.2, CHCl3); IR (neat) 3439, 2927,
1
1098, 1055, 899 cm-1; H NMR (300 MHz, CDCl3) δ 7.73 (d,
J ) 8.4 Hz, 2H), 7.37-7.24 (m, 7H), 5.41-5.27 (m, 1H), 5.18-
4.96 (m, 1H), 4.58-4.50 (m, 1H), 4.51 (s, 2H), 3.57-3.49 (m,
1H), 2.51-2.40 (m, 1H), 2.42 (s, 3H), 2.28-2.19 (m, 1H), 1.83-
1.12 (m, 21H), 0.92-0.80 (m, 9H); 13C NMR (75 MHz, CDCl3) δ
144.4 (Cq), 138.3 (Cq), 134.2 (Cq), 133.1 (CH), 129.6 (CH), 128.3
(CH), 127.9 (CH), 127.8 (CH), 127.6 (CH), 125.1 (CH), 83.0 (CH),
78.8 (CH), 72.6 (CH2), 41.9 (CH2), 32.7 (CH2), 31.9 (CH2), 29.6
(CH2), 29.5 (CH2), 29.3 (CH2), 29.1 (CH2), 28.2 (CH), 25.5 (CH2),
22.7 (CH2), 22.3 (CH3), 22.2 (CH3), 21.6 (CH3), 14.1 (CH3).
(7R,8R)-7-(p-Toluenesulfonyloxy)-2-methyloctadecan-8-ol (11):
To a solution of 10 (40 mg, 0.07 mmol) in 2 mL of methanol at
room temperature was added activated 10% Pd/C (20 mg). The
reaction mixture was stirred for 3 h under hydrogen atmosphere
(balloon) at the same temperature. After the reaction was complete
(TLC), it was filtered through a short pad of Celite and the Celite
pad was washed with ether (15 mL). Evaporation of solvent
followed by column chromatography of the resulting residue using
petroleum ether/EtOAc (94:6) yielded 11 as a colorless solid in
90% (30 mg) yield: mp 40.4-41.5 °C; [R]D +12.3 (c 2.4, CHCl3);
lit.15 mp 41.0-41.5 °C; [R]D -12.3 (c 2.0, CHCl3) for the
enantiomer; IR (neat) 3393, 2924, 2853, 1600, 1455, 1364, 1175,
2856, 1463, 1255, 1084, 836, 775 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 3.44-3.31 (m, 2H), 2.06 (d, J ) 6.9 Hz, 1H, exchange-
able with D2O), 1.61-1.05 (m, 27H), 0.86-0.75 (m, 18H), 0.01
(s, 3H), -0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 75.1 (CH),
72.6 (CH), 38.9 (CH2), 36.1 (CH2), 34.1 (CH2), 33.9 (CH2), 31.9
(CH2), 29.7 (CH2), 29.6 (CH2), 29.3 (CH2), 27.9 (CH), 27.6 (CH2),
25.9 (CH2), 25.8 (CH3), 25.2 (CH2), 22.6 (CH2), 22.5 (CH3), 18.1
(Cq), 14.1 (CH3), -4.1 (CH3), -4.6 (CH3); HRMS for C25H54O2-
Si + Na calcd 415.3971; found 415.3978.
(+)-Disparlure (cis-7,8-Epoxy-2-methyloctadecane) (1): To a
solution of 15 (30 mg, 0.05 mmol) in 1.5 mL of THF was added
TBAF (0.15 mL, 0.15 mmol) at 0 °C under argon atmosphere. The
reaction mixture was stirred for 10 h at room temperature. After
the reaction was complete (indicated by TLC), it was poured into
water (5 mL) and extracted with ether (3 × 8 mL). The combined
ethereal extracts were washed with brine and dried over Na2SO4.
Evaporation of solvent followed by column chromatography using
petroleum ether/EtOAc (99:1) as an eluent yielded (+)-1 in 89%
as a colorless oil: [R]D +1.0 (c 1.5, CCl4); lit.5c [R]D +0.9 (c 1.1,
1
1019, 896 cm-1; H NMR (300 MHz, CDCl3) δ 7.81 (d, J ) 8.4
Hz, 2H), 7.34 (d, J ) 8.4 Hz, 2H), 4.49 (dt, J ) 6.0, 5.4 Hz, 1H),
3.50-3.68 (br m, 1H), 2.45 (s, 3H), 1.79 (d, J ) 6.6 Hz, OH,
exchangeable with D2O), 1.75-0.95 (m, 27H), 0.88 (t, J ) 7.2
Hz, 3H), 0.83 (d, J ) 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
144.7 (Cq), 134.3 (Cq), 129.7 (CH), 127.7 (CH), 86.7 (CH), 71.8
(CH), 38.6 (CH2), 32.9 (CH2), 31.9 (CH2), 30.6 (CH2), 29.6 (CH2),
29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 27.8 (CH), 27.1 (CH2), 25.5
(CH2), 25.1 (CH2), 22.7 (CH2), 22.5 (CH3), 21.6 (CH3), 14.1 (CH3).
(-)-Disparlure (cis-7,8-Epoxy-2-methyloctadecane) (1): To a
solution of 11 (25 mg, 0.055 mmol) in 1 mL of methanol was added
potassium carbonate (12 mg, 0.08 mmol) at room temperature under
inert atmosphere. The reaction mixture was stirred for 1 h at the
same temperature, poured into water (4 mL), and extracted with
ether. The combined ethereal layer was washed with brine and dried
over Na2SO4. Evaporation of solvent followed by column chro-
matography of the resulting residue using petroleum ether/EtOAc
(99:1) yielded (-)-1 as a colorless oil in 89% (14 mg): [R]D -1.0
(c 1.7, CCl4); lit.5c [R]D -0.9 (c 0.21, CCl4); 1H NMR (300 MHz,
1
CCl4); H NMR (300 MHz, CDCl3) δ 2.93-2.88 (m, 2H), 1.59-
1.15 (m, 27H), 0.91-0.84 (m, 9H); 13C NMR (75 MHz, CDCl3) δ
57.2 (CH), 38.9 (CH2), 31.9 (CH2), 29.5 (CH2), 29.3 (CH2), 27.9
(CH-), 27.8 (CH2), 27.3 (CH2), 26.8 (CH2), 26.6 (CH2), 22.6 (CH2),
22.5 (CH3), 14.1 (CH3).
Acknowledgment. We thank the Department of Science and
Technology (DST), New Delhi, for funding of this project. One
of us (P.A.) thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, for a senior research fellowship.
Supporting Information Available: Experimental procedures
1
and spectroscopic data for the compounds and copies of H NMR
and 13C NMR spectra are provided. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) Mori, K.; Takigawa, T.; Matsui, M. Tetrahedron 1979, 35, 833.
JO070060O
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