Convenient synthesis of (3R, 4S)-4-methyl-3-hexanol and (S)-4-methyl-3-hexanone, the pheromones of ants

Article abstract of DOI:10.3390/50801051

Synthesis of enantiopure pheromones I and II, both of them bearing chiral methyl branching and an α-oxygenated carbon centre, has been accomplished using compound 2 prepared from D-mannitol as the chiral precursor.

Full text of DOI:10.3390/50801051

Molecules 2000, 5, 1051-1054
molecules
ISSN 1420-3049
© 2000 by MDPI
http://www.mdpi.org
Convenient Synthesis of (3R, 4S)-4-Methyl-3-hexanol and
(S)-4-Methyl-3-hexanone, the Pheromones of Ants
B. Dhotare, S. A. Hassarajani and A. Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Bombay-400,085, India
Fax: (022)-550-5151, E-mail: achat@apsara.barc.ernet.in
Received: 3 April 2000; revised form 28 July 2000 / Accepted: 1 August 2000 / Published: 28August 2000
Abstract: Synthesis of enantiopure pheromones I and II, both of them bearing chiral methyl
branching and an α-oxygenated carbon centre, has been accomplished using compound 2
prepared from D-mannitol as the chiral precursor.
Keywords: pheromones, chiral methyl branching, (R)-2,3-cyclohexylideneglyceraldehyde,
α-oxygenated carbon centre.
Introduction
(3R,4S)-4-Methyl-3-hexanol (I) is the pheromone of the ant Tetramorium impurum. In 1981,
Pasteels et al. isolated this compound together with 4-methyl-3-hexanone, from the heads of the all
adult castes of this ant [1]. The absolute configuration of I was determined to be 3R,4S by GLC analysis
of its (S)-α-acetoxypropionate. On the other hand, the ant Manica mutica uses (S)-4-Methyl-3-
hexanone (II) as an alarm pheromone [2]. So far a few syntheses of both I [3] and II [4-6] have been
reported in literature. However, it is observed that both the compounds possess a chiral methyl branch-
ing with an α-oxygenated carbon centre that is found in many other natural products. Hence, we have
chosen these two compounds as representative synthetic targets in order to demonstrate the usefulness
of a simple synthetic strategy developed by us to generate such functional moieties via a chiron ap-
proach. We felt that (R)-2,3-cyclohexylideneglyceraldehyde (1), which had earlier been prepared by us
on a practical scale [7] should be an ideal chiron for this endeavour.
Results and Discussion
In an earlier communication, 1 has been crotylated by us to afford reasonably good amounts of com-
pound 2 [8]. We felt that 2, having the required carbon skeleton along with the correct stereochemistry

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Molecules 2000, 5
at the appropriate positions as found in both I and II, had good prospects to be a useful precursor for
the synthesis of both target molecules. To prove this point, compound 2 was first benzylated and subse-
quently deketalised to produce the diol 3. Dimesylation of both the free hydroxyl groups of 3 afforded
compound 4. Next, the elimination of the vicinal disulfonyloxy groups of 4 was carried out by treatment
with excess Zn dust and NaI following a reported procedure [9] to give the diene 5. This step was fol-
lowed by catalytic hydrogenation of 5 along with concomitant debenzylation to yield the pheromone I.
This compound was subsequently oxidized with PCC [10] to afford target II (Scheme 1).
OH
O
O
O
O
i
ii,iii
O H
CHO
OBn
OH
3
1
2
OMs
iv
vi
v
OBn
OMs
OBn
5
4
vii
OH
O
I
II
(i) Crotyl Br, THF, Zn,Aq. NH4Cl, (ii) NaH, BnBr, THF, (iii) CF3COOH, H O (9:1), (iv) MsCl,TEA, CH2Cl2,
2
0
(v) NaI, Zn, DMF, 140 C, (vi) H2 10% Pd-C, EtO H, (vii) PCC, CH2Cl2.
Scheme 1.
Conclusions
I
II
A short and simple strategy has been developed for the preparation of both the pheromones and
with absolute enatiopurity. The success of the approach is achieved thanks to an easy and inexpensive
1
preparation of precursor on a practical scale and the use of a series of operationally simple reactions.
Consequently, this strategy should be amenable to extrapolation on a practical scale. It is noteworthy
II
α
that the reported procedures for the synthesis of [4-6] involving asymmetric C-alkylation at the po-
sition of the carbonyl do not give rise to the formation of the product with absolute enantiopurity.
Experimental
General
All boiling points are uncorrected. The IR spectra were scanned with a Perkin-Elmer model 837
1
spectrophotometer. The H-NMR spectra were recorded in CDCl on a Bruker-200 MHz instrument.
3
All the anhydrous reactions were carried out under an argon atmosphere using freshly distilled solvents.

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Molecules 2000, 5
In all the cases solvents were later removed under reduced pressure. Unless otherwise mentioned, the
organic extracts were dried over anhydrous Na SO
2
4.
(2R, 3S, 4S)-3-Benzyloxy-4-methyl-5-hexene-1,2-diol (3)
Compound 2 (3.39 g, 0.015 mol) in THF ( 50 mL) ) was added dropwise over a period of 1.5 h to a
stirred suspension of NaH (720 mg of a 50% suspension in oil, 0.015 mole, washed with hexane) in
THF (100 mL). The mixture was gently heated to 50°C for 1 h more. Benzyl bromide (2.6 g, 0.015
mol) in THF (50 mL) was then added dropwise to the stirred mixture at 50°C over a period of 3 h. Af-
ter stirring for 30 min more, the mixture was treated with water. Usual extraction and solvent removal
afforded the crude residue in quantitative yield. This was dissolved in 90% aqueous trifluroacetic acid
(20 mL) and the mixture was stirred for 6 hr at 0°C and then diluted with water. The mixture was ex-
tracted with CHCl . The combined organic layer was washed with water to remove residual acid, then
3
with brine and finally dried. Solvent removal and chromatography of the residue (silica gel, 0-5%
23
MeOH in CHCl ) afforded pure 3 (2.68 g, 75.5%). [α] + 27.8 (c 1.05, CHCl ); IR (film) 3500,
3
3
1
3075, 3005, 1365, 1178, 1095, 910 cm-1; H-NMR (CDCl ) δ 1.12 (d, J = 6.6 Hz, 3H), 2.4-2.6 (m,
3
1H), 3.16 (bs, D O exchangeable, 2H), 3.4-3.6 (m, 1H), 3.86-4.2 (m, 3H), 4.4-4.6 (m, 2H), 5.0-5.2 (m,
2
2H), 5.5-5.7 (m, 1H), 7.2-7.5 (m, 5H). Anal. Calcd. For C14H20O3 : %C 71.16, %H 8.53; Found: %C
70.88, %H 8.75.
(2R, 3S, 4S)-1,2-Dimesyloxy-3-benzyloxy-4-methyl-hex-5-ene (4)
Methanesulfonyl chloride (1.1 ml, 14.2 mmol) was added at 0°C over a period of 30 min. to a solu-
tion of compound 3 (1.9 g, 7 mmol) and triethylamine (5 mL) in CH2Cl2 (50 mL). The mixture was
stirred for 4 h and then treated with water. Usual extraction with CH2Cl2 was followed by successive
washing of the organic layer with dilute aqueous HCl, water and brine. Solvent removal afforded the
residue 4 in sufficiently pure form. This was used in the next step without being purified further. Yield:
-1
23
2.6 g, 83.6%. [α] + 26.45 (c 1.5, CHCl ); IR (film) 3032, 3005, 1654, 1360, 1178, 1003, 910 cm ;
3
1H NMR (CDCl ) δ 1.12 (d, J = 6.6 Hz, 3H), 2.4-2.6 (m, 1H), 3.03 ( s, 3H), 3.09 (s, 3H), 3.72 (t, J=
3
6.0 Hz, 1H), 4.4-4.6 (m, 5H), 5.0-5.2 (m, 2H), 5.5-5.7 (m, 1H), 7.2-7.5 (m, 5H).
(3S, 4S)-3-Benzyloxy-4-methyl-hex-1,5-diene (5)
A stirred mixture of 4 (2g, 5.1 mmol) in DMF (50 mL), Zn dust (18 g, 0.275 g-atom) and NaI (38 g,
0.255 mol) was heated at 140°C for 5 hr. It was cooled to room temperature, mixed with ether and fil-
tered. After washing the residue thoroughly with ether and water, the aqueous extract was thoroughly
extracted with ether. The combined organic extract was washed with water, brine and then dried. Sol-
vent removal and column chromatography (silica gel, 0-15% ether in hexane) of the residue afforded
1
23
pure 5. Yield: 530mg (51.2%). [α] 11.25 (c 1.64, CHCl ); IR (film) 3032, 3005, 1654, 995, 925; H
3
NMR (CDCl ) δ 1.02 (d, J = 6.6 Hz, 3H), 2.4-2.6 (m, 1H), 4.25 (m, 1H), 4.57 (m, 2H), 5.0-5.2 (m,
3
4H), 5.5-5.7 (m, 2H), 7.2-7.5 (m, 5H). Anal Calcd. For C14H18 O: %C 83.12, %H 8.97; Found: %C
83.39, %H. 9.25.

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Molecules 2000, 5
(3R, 4S)-4-Methyl-3-hexanol (I)
A stirred mixture of 10% Pd-C (100 mg) in a solution of 5 (500 mg) in ethanol (50 mL) (containing
a few drops of acetic acid) was subjected to hydrogenation for 40 hr under positive pressure of hydro-
gen and then filtered. After solvent removal under reduced pressure, the residue was mixed with ether.
The organic layer was washed with water and brine and then dried. Solvent removal and column chro-
matography (silica gel, 0-20% ethyl acetate in hexane) of the residue afforded pure I (400 mg, 88%).
[α]23 + 2.9 (c 2.8, CHCl ); lit. [3] [α]22 + 2.5 (c 2.07, CHCl ); IR (film) 3400, 2968, 2935, 1460, 1380,
3
3
1
1150, 1105, 1040, 970cm-1; H-NMR (CDCl ) δ 0.75-1.10 (9H, m), 1.15-1.8 (m, 5H), (3.0, bs, D2O
3
exchangeable, 1H), 3.3-3.4 (m, 1H).
(S)-4-Methyl-hexan-3-one (II)
To a stirred suspension of PCC (860 mg, 4 mmol) in CH2Cl2 (60 mL) was added a solution of I (300
mg, 2.6 mmol) in CH2Cl2 (50 mL). The mixture was stirred at room temperature for 2.5 hr until the dis-
appearance of I was complete (TLC). Dry ether (80 mL) was added to the stirred mixture, which was
then filtered through a pad of Florisil. Removal of solvent from the filtrate and column chromatography
23
(silica gel, 0-15% ether in hexane) of the residue afforded pure II (236 mg, 69%). [α] + 30.7 (c 3.4,
23
Et2O); lit. [5] [α] + 30.2 (c 3.7, Et2O, 94% ee); IR (film) 2970, 2944, 2900, 1722, 1470, 1380, 1179,
1105, 1036, 980cm-1;1H-NMR (CDCl ) δ 0.75-1.1 (9H, m), 1.2-1.5 (m, 2H), 2.3-2.6 (m, 3H).
3
References and Notes
1. Pasteels, J. M.; Verhaeghe, J. C.; Ottinger, R.; Braekman, J. C.; Daloze, D. Insect Biochem. 1981,
11, 675.
2. Mori, K. The Total Synthesis of Natural Products; John Wiley & Sons: 1992; Vol. 9, p.176.
3. Kato, M.; Mori, K. Agric. Biol. Chem. 1985, 49, 3073.
4. Enders, D.; Eichenauer, H. Angew. Chem. Int. Ed. Engl. 1979, 18, 397.
5. Enders, D.; Eichenauer, H.; Baus, U.; Schubert, H.; Kremer, K.A.M. Tetrahedron 1984, 40, 1345.
6. Brown, H.C.; Jadav, P.K.; Desai, M.C. Tetrahedron 1984, 40, 1325.
7. Chattopadhyay, A.; Mamdapur, V.R. J. Org. Chem. 1995, 59, 585.
8. Chattopadhyay, A. J. Org. Chem. 1996, 60, 6104.
9. Block, E. Organic Reactions; John Wiley & Sons: 1984; 30, 516.
10. Corey, E. J.; Suggs, J. W. Tetrahedron Letts. 1973, 2647.
Sample Availability: Available from the authors.
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