Enantiospecific synthesis of 6-methylheptadec-(9E)-enoic acid enantiomers, the antimicrobial principles of Sporothrix species

Article abstract of DOI:10.1016/S0957-4166(98)00265-1

An efficient synthesis of the title compound I in both its enantiomeric forms has been developed starting from (R)-citronellol. This involved the introduction of the required alkyl chain and the acidic component at the termini of the starting chiron via judicious derivatization of its bifunctionality to provide the enantiomers of I. The other key features of the synthesis were: (i) use of easily accessible and inexpensive materials/reagents; (ii) operational simplicity; and (iii) brevity.

Full text of DOI:10.1016/S0957-4166(98)00265-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2627–2633
Enantiospecific synthesis of 6-methylheptadec-(9E)-enoic acid
enantiomers, the antimicrobial principles of Sporothrix species
∗
Sivaraman Sankaranarayanan and Subrata Chattopadhyay
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai-400 085, India
Received 19 May 1998; accepted 6 July 1998
Abstract
An efficient synthesis of the title compound I in both its enantiomeric forms has been developed starting from
R)-citronellol. This involved the introduction of the required alkyl chain and the acidic component at the termini
(
of the starting chiron via judicious derivatization of its bifunctionality to provide the enantiomers of I. The other
key features of the synthesis were: (i) use of easily accessible and inexpensive materials/reagents; (ii) operational
simplicity; and (iii) brevity. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The role of antifungal molecules in disease suppression is of considerable importance and the screen-
ing of mycelial cultures of some biocontrol agents has led to the discovery of a great number of metabo-
1
lites with antimicrobial activity. In this context, the isolation of several compounds with antibiotic
activity from the Sporothrix species is revealing. One of the members of the family viz. S. flocculosa is
2
a,b
known to be a potential antagonist
against powdery mildew fungi and thus promises to be an efficient
3
biocontrol device. Very recently, Hajlaoui et al. suggested the involvement of extracellular diffusible
molecules for the disintegration of the host S. flocculosa cytoplasm by Sphaerotheca pannosa. Earlier,
several such organic compounds possessing wide spectrum anti-fungal and anti-bacterial activities were
isolated from the liquid culture of S. flocculosa and other Sporothrix species. Very recently, a structurally
similar but new compound viz. 6-methylheptadec-(9E)-enoic acid I was isolated, which exhibited potent
4
5
anti-fungal activity against Cladosporium cucumerinum. Until now, no information is available about its
absolute configuration nor about the dependence of its bioactivity on the stereochemistry. This can be
attributed to its low natural abundance and can be resolved by synthesizing its enantiomers, correlating
their chiroptical data with those of the natural product and carrying out bioassays of the individual
isomers.
∗
Corresponding author. Fax: 91-22-5560750; e-mail: bod@magnum.barct1.ernet.in
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00265-1

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S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 2627–2633
Against the above background, it was imperative to formulate an efficient enantiospecific synthesis of
the antipodes of I. Consequently, we developed an enantiospecific route for both (R)- and (S)-I starting
from (R)-citronellol 1 as described below. To the best of our knowledge, so far no synthesis of I has been
reported in the literature.
2. Results and discussion
6
7
Synthesis of (R)-I: For this, the alcohol 1 was converted to the bromide 2 and used for the alkylation
of 1-nonyne 3 to give the hydrocarbon 4. Its reaction with 1.0 equiv. of m-CPBA (meta-chloroperbenzoic
acid) at −78°C proceeded regioselectively at the olefinic site furnishing 5. This, on H IO cleavage,
5
6
gave the aldehyde 6 which was converted to the ester 7 via Wittig–Horner olefination with triethyl
8
phosphonoacetate. Its alkaline hydrolysis furnished the acid 8 which, on Na/NH reduction in the
3
presence of a proton donor, directly afforded the desired (R)-acid I (Scheme 1).
Scheme 1.
9
Synthesis of (S)-I: The same alcohol (R)-1 was pyranylated to 9 which was converted to the ozonide
10
and subsequently reduced with triphenylphosphine (TPP) to give the aldehyde 10. This, on reaction
1
1
with CBr –TPP and subsequent treatment with EtMgBr, gave the alkynol derivative 11. Its alkylation
4
9
6
with 1-bromoheptane gave 12, which on acid catalyzed deprotection to 13 followed by bromination
afforded 14. Alkylation of propiolic acid 15 with 14 furnished the acid 16 which was converted to (S)-I
as in the case of the (R)-antipode.
5
The spectral data of both the enantiomers of I were commensurate with the reported values. For the
estimation of the enantiomeric purity of the starting chiron (R)-1, it was oxidized with PDC (pyridinum
dichromate)/DMF and the resultant acid was subsequently reacted with (R)-phenylethylamine in the

S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 2627–2633
2629
presence of DCC (1,3-dicyclohexyl carbodiimide) to give the corresponding diastereomeric amide. Its
12
GLC analysis (3% OV-17 column, 40 ml/min N ) revealed its ee to be 94.3%. Since the subsequent
2
reactions were carried out under non-racemizing conditions and retain the chiral integrity of (R)-1, the ee
of both (R)- and (S)-I should also be same. This was further confirmed by capillary GLC analysis (β-Dex
1
20, 30 m×0.25 mm, split ratio 100:1, temp. prog. 100–200°C @ 4°C/min, 1 ml/min He) of the methyl
esters of I, the t s being 16.8 and 15.7 mins, respectively, for (R)- and (S)-I. However, due to a lack of
R
available specific rotation data, the configuration for the natural I could not be established.
3. Experimental
All the boiling points are uncorrected. The IR spectra were scanned as thin films with a Perkin–Elmer
1
spectrophotometer model 837. The H NMR spectra were recorded in CDCl with a Bruker AC-200 (200
3
MHz) instrument. The optical rotations were measured with a Jasco DIP 360 polarimeter. Anhydrous
reactions were carried out under Ar using freshly dried solvents. All the reactions except depyranylation
were carried out using dry solvents (THF, ether and HMPA dried over Na and CH Cl over P O ). The
2
2
2
5
organic extracts were dried over anhydrous Na SO .
2
4
3.1. (R)-Citronellyl bromide 2
To a stirred and cooled (0°C) solution of Ph P (15.74 g, 0.06 mol) in CH Cl (80 ml) was dropwise
3
2
2
added Br (10.0 ml, 0.055 mol, 5.5 M in CCl ). After 0.5 h, a mixture of the alcohol (R)-1 (7.8 g, 0.05
2
4
mol) and pyridine (4.45 ml, 0.055 mol) in CH Cl (20 ml) was added to the resulting white solid and
2
2
stirring continued at room temperature for 3 h. Most of the solvent was removed in vacuo and the residue
dissolved in hexane. The hexane extract was passed through a small pad (2 in.) of silica gel and the
2
2
eluent concentrated to furnish pure 2. Yield: 8.75 g (80%); bp: 108–110°C/10 mmHg, [α]
−6.27 (c
D
−1 1
4
.5, CHCl ); IR: 1480, 1380 cm ; H NMR: δ 0.93 (d, J=7 Hz, 3H), 1.0–1.4 (m, 4H), 1.58 (s, 3H), 1.62
3
(s, 3H), 1.8–2.2 (m, 3H), 3.54 (t, J=7 Hz, 2H), 5.06 (t, J=6 Hz, 1H).
3.2. (6R)-2,6-Dimethylheptadec-2-en-9-yne 4
To a stirred and cooled (−25°C) solution of 3 (2.5 g, 20.16 mmol) in THF (40 ml) was slowly injected
n-BuLi (12.5 ml, 20.06 mmol, 1.6 M in hexane). After 0.5 h, the mixture was cooled to −78°C, HMPA
(hexamethylphosphoramide) (5.0 ml) was added and stirring continued for a further 15 min. The bromide
2
(4.0 g, 18.26 mmol) in THF (20 ml) was added and the mixture stirred for 3 h at the same temperature
and for 18 h at room temperature. It was poured into ice-cold water, the organic layer separated and the
aqueous portion was extracted with ether. The combined organic extract was thoroughly washed with
water and brine, and finally dried. The crude product was purified by column chromatography (silica gel,
hexane) to give 4. Yield: 3.8 g (80%); [α]D22 −1.23 (c 0.9, CHCl ); IR: 2210, 1460, 1380 cm ; H
−1
1
3
NMR: δ 0.9 (merged d and t, 6H), 1.29 (br. s, 14H), 1.62 (s, 3H), 1.68 (s, 3H), 1.8–2.2 (m, 7H), 5.06 (t,
J=6 Hz, 1H). Anal. calcd for C H : C 86.94, H 13.06; found: C 86.78, H 13.22.
19
34
3.3. (2RS,6S)-2,6-Dimethyl-2-epoxyheptadec-9-yne 5
To a cooled (−78°C) and stirred solution of 4 (1.1 g, 4.2 mmol) in CH Cl (30 ml) was added m-CPBA
2
2
(
1.6 g, 4.64 mmol, 50%) in portions. After stirring for 3 h at the same temperature, when there was no

2630
S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 2627–2633
starting material left, the mixture was filtered and the precipitate washed with cold CHCl . The combined
3
organic layer was washed successively with 10% aqueous Na SO , water, 10% aqueous Na S O , water
2
3
2
2
3
and brine, and dried. Removal of the solvent followed by chromatography of the product (silica gel,
2
2
0
1
3
–5% ether:hexane) furnished pure 5. Yield: 1.0 g (86%); [α]
−4.1 (c 1.1, CHCl ); IR: 2210, 1480,
D
3
−1 1
380, 1200, 1120 cm ; H NMR: δ 0.9–1.0 (d and t merged, 6H), 1.3 (br. s, 14H), 1.54 (s, 3H), 1.60 (s,
H), 1.8–2.0 (m, 3H), 2.1–2.3 (m, 4H), 2.62 (t, J=4.8 Hz, 1H).
3.4. (4S)-4-Methylpentadec-7-ynal 6
To a cooled (0°C) and stirred solution of 5 (1.0 g, 3.6 mmol) in THF:H O (2:1, 20 ml) was added
2
H IO (1.23 g, 5.39 mmol). After 3 h, ether was added to the mixture, the organic layer separated and
5
6
was worked up as detailed for 5 to give pure 6 after isolation and column chromatography (silica gel,
−1
0
–10% ether:hexane). Yield: 0.764 g (90%); [α]D22 +5.31 (c 0.78, CHCl ); IR: 2715, 2370, 1730 cm ;
3
1
H NMR: δ 0.9–1.0 (d and t merged, 6H), 1.32 (br. s, 14H), 1.8–2.1 (m, 5H), 2.2–2.3 (m, 2H), 9.78 (t,
J=1.5 Hz, 1H). Anal. calcd for C H O: C 81.29, H 11.94; found: C 81.48, H 12.15.
16
28
3.5. Ethyl (6R)-6-Methylheptadec-(2E)-en-9-ynoate 7
To a cooled (0°C) and stirred suspension of pentane-washed NaH (0.192 g, 4.0 mmol, 50% suspension
in oil) in THF (20 ml) was added triethyl phosphonoacetate (0.896 g, 4.0 mmol) in THF (10 ml). After
stirring for 0.5 h at the same temperature, compound 6 (0.75 g, 3.18 mmol) in THF (10 ml) was added
to the reaction mixture and stirring was continued for 3 h at 0°C and at room temperature for 12 h.
The mixture was poured into ice-cold water, the organic layer separated and the aqueous portion was
extracted with ether. The combined organic extract was washed with water and brine, and dried. Removal
of the solvent followed by column chromatography (silica gel, 0–10% ether:hexane) of the crude product
furnished pure 7. Yield: 0.593 g (61%); [α]D22 −6.12 (c 2.94, CHCl ); IR: 1720, 1650, 985 cm ; H
−1
1
3
NMR: δ 0.9–1.0 (d and t merged, 6H), 1.16 (t, J=6 Hz, 3H), 1.3 (br. s, 14H), 1.9–2.3 (m, 7H), 4.14 (q,
J=7 Hz, 2H), 5.89 (d, J=15.6 Hz, 1H), 6.91 (dt, J=15.6, 6 Hz, 1H). Anal. calcd for C H O : C 78.38,
20
34
2
H 11.18; found: C 78.68, H 11.06.
.6. (6R)-6-Methylheptadec-(2E)-en-9-ynoic acid 8
A mixture of 7 (0.5 g, 1.6 mmol) and alcoholic KOH (2 N, 10 ml) was stirred at room temperature
3
for 4 h. Most of the solvent was removed in vacuo, the residue extracted with EtOAc, the organic
extract washed with water and brine, and dried. Concentration of the extract and preparative TLC and
2
2
chromatography (silica gel, 5% MeOH:CHCl ) of the product gave pure 8. Yield: 0.304 g (67%); [α]
3
D
−1 1
−
8.92 (c 1.3, CHCl ); IR: 3700–3500, 1710, 980 cm ; H NMR: δ 0.9–1.0 (d and t merged, 6H),
3
1
6
7
.3–1.6 (m containing a br. s at δ 1.32, 14H), 1.9–2.3 (m, 7H), 5.90 (d, J=15.6 Hz, 1H), 6.91 (dt, J=15.6,
Hz, 1H), 9.7 (br. s, D O exchangeable, 1H). Anal. calcd for C H O : C 77.65, H 10.86; found: C
2
18 30
2
7.88, H 11.17.
.7. (6R)-6-Methylheptadec-(9E)-enoic acid I
To a stirred solution of 8 (0.28 g, 1.01 mmol) in a mixture of liquid NH (20 ml), EtOH (10 ml)
3
3
and ether (20 ml) was added Na metal (0.244 g, 10.6 mmol) in pieces at −78°C. After 3 h, NH was
3
allowed to evaporate, and ice-cold water was added to the flask followed by ether. The organic layer was

S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 2627–2633
2631
separated and discarded, the aqueous portion acidified with aqueous HCl (2 N) and extracted with ether.
The ether layer was washed with water and brine, and dried. Removal of the solvent and preparative
2
2
chromatography (silica gel, 5% MeOH:CHCl ) gave pure (R)-I. Yield: 0.202 g (71%); [α]
−5.0 (c
3
D
−
1 1
0
.88, CHCl ); IR: 3700–2500, 1720, 980 cm ; H NMR: δ 0.9–1.0 (d and t merged, 6H), 1.32 (br. s,
9H), 1.9–2.2 (m, 4H), 2.34 (t, J=6 Hz, 2H), 5.3–5.6 (m, 2H), 8.6 (br. s, D O exchangeable, 1H). Anal.
3
1
2
calcd for C H O : C 76.54, H 12.13; found: C 76.81, H 12.37.
18
34
2
3.8. (3R)-1-Tetrahydropyranyloxycitronellol 9
A mixture of 1 (2.0 g, 12.82 mmol), DHP (1.29 g, 15.36 mmol) and PPTS (pyridinium p-
toluenesulphonate) (0.1 g) in CH Cl (50 ml) was stirred at room temperature for 12 h. The reaction was
2
2
quenched with 10% aqueous NaHCO , the organic layer separated and the aqueous portion was extracted
3
with CHCl . The combined organic extract was washed with water and brine, and dried. Removal of
3
22
solvent followed by column chromatography of the residue furnished pure 9. Yield: 2.8 g (91%); [α]
D
−1 1
+
1.1 (c 2.0, CHCl ); IR: 1480, 1380, 880, 810 cm ; H NMR: δ 0.9 (d, J=7 Hz, 3H), 1.0–1.4 (m, 4H),
3
1
0
7
.5–1.7 (m, containing two s at δ 1.58 and 1.62, 12H), 1.8–2.2 (m, 3H), 3.6–3.7 (m, 4H), 4.48 (br. s,
.5H), 4.57 (br. s, 0.5H), 5.06 (t, J=6 Hz, 1H). Anal. calcd for C H O : C 74.95, H 11.74; found: C
15
28
2
5.18, H 11.88.
3.9. (4R)-6-Tetrahydropyranyloxy-4-methylhexanal 10
Ozone was bubbled through a cooled (−78°C) solution of 9 (2.7 g, 11.25 mmol) in CH Cl (50 ml)
2
2
until saturation. The mixture was warmed to 0°C and excess ozone was removed by purging with N .
2
Ph P (4.43 g, 16.88 mmol) was added to the mixture and stirring was continued for 60 h. Most of the
3
solvent was removed in vacuo, the residue dissolved in hexane and the hexane solution cooled to 0°C.
The solution was filtered, the precipitated solid was washed with cold hexane and the organic extract was
concentrated. The residue obtained was given the same treatment thrice before purification by column
2
2
chromatography (silica gel, 0–15% EtOAc:hexane) to afford 10. Yield: 2.05 g (85%); [α]
+3.4 (c 0.6,
D
−1 1
CHCl ); IR: 2710, 1720, 880, 810 cm ; H NMR: δ 0.9 (d, J=7 Hz, 3H), 1.4–1.8 (m, 11H), 2.1–2.3 (m,
3
2H), 3.6–3.8 (m, 4H), 4.51 (br. s, 0.5H), 4.55 (br. s, 0.5H), 9.78 (t, J=1.5 Hz, 1H).
3.10. (3R)-1-Tetrahydropyranyloxy-3-methylhept-6-yne 11
To a cooled (0°C) and stirred solution of Ph P (6.36 g, 24.26 mmol) in CH Cl (15 ml) was added
3
2
2
CBr (4.10 g, 12.39 mmol). The aldehyde 10 (2.0 g, 9.35 mmol) in CH Cl (10 ml) was then introduced
4
2
2
into it at such a rate as to maintain the reaction temperature <15°C. The mixture was again cooled to
0°C and triethylamine (TEA) (1.3 ml, 9.35 mmol) was added. It was stirred at the same temperature for
0.5 h, brought to room temperature and stirred for another hour. The mixture was poured into hexane (50
ml) and passed through a pad of Celite (2 in.), eluting with ether. The organic layer was concentrated in
vacuo, taken up in cold hexane and filtered. The filtrate on concentration gave the crude product which
was used as such for the next step.
To the ice-cooled and stirred solution of the above compound in THF (20 ml) was added EtMgBr
(18.7 mmol) [prepared from EtBr (2.04 g, 18.72 mmol) and Mg (0.545 g, 22.44 mmol) in THF (30 ml)].
The mixture was brought to room temperature and stirred for 12 h. It was poured into water, extracted
with ether and the organic extract was washed with water and brine, and dried. Removal of the solvent
and subsequent column chromatography (silica gel, 0–10% ether:hexane) gave 11. Yield: 1.37 g (70%);

2632
S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 2627–2633
α]D22 −5.09 (c 0.51, CHCl ); IR: 3340, 2230, 880, 810 cm ; H NMR: δ 0.88 (d, J=7 Hz, 3H),
−1
1
[
1
3
.2–1.6 (m, 4H), 1.7–2.1 (m, 10H), 3.55–3.72 (m, 4H), 4.55 (br. s, 0.5H), 4.65 (br. s, 0.5H). Anal. calcd
for C H O : C 74.24, H 10.54; found: C 74.14, H 10.68.
13
22
2
3.11. (3R)-3-Methyltetradec-6-yn-1-ol 13
To a cooled (−30°C) and stirred solution of 11 (1.3 g, 6.19 mmol) in THF (30 ml) was added n-BuLi
(
4.1 ml, 6.56 mmol, 1.6 M in hexane). After stirring for 0.5 h, HMPA (2 ml) was added followed by
1-bromoheptane (1.33 g, 7.43 mmol) in THF (10 ml). The mixture was stirred at the same temperature
for 4 h and at room temperature overnight. It was poured into water, extracted with ether and the organic
extract was washed with water and brine, and dried. Removal of the solvent and subsequent column
2
2
chromatography (silica gel, 0–10% ether:hexane) gave 12. Yield: 1.49 g (78%); [α]
+6.0 (c 1.18,
D
−1 1
CHCl ); IR: 1470, 1380, 880, 810 cm ; H NMR: δ 0.88 (t, J=7 Hz, 3H), 0.93 (d, J=7 Hz, 3H), 1.32
br. s, 14H), 1.7–1.9 (m, 7H), 2.0–2.19 (m, 4H), 3.55–3.68 (m, 4H), 4.5 (br. s, 0.5H), 4.55 (br. s, 0.5H).
3
(
Anal. calcd for C H O : C 77.86, H 11.76; found: C 78.12, H 12.02.
20
36
2
A solution of 12 (1.49 g, 4.84 mmol) and PTS (p-toluenesulphonic acid) (0.05 g) in MeOH (30 ml)
was refluxed for 4 h, at which time there was no starting material left. Most of the solvent was removed
in vacuo, the residue was taken up in ether and the ether layer was washed successively with aqueous
1
0% NaHCO , water and brine, and dried. Solvent removal followed by column chromatography of the
3
22
product (silica gel, 0–15% EtOAc:hexane) furnished 13. Yield: 0.91 g (84%); [α]
+3.0 (c 0.8, CHCl );
3
D
−1 1
IR: 3440, 1480, 1380 cm ; H NMR: δ 0.88 (t, J=7 Hz, 3H), 0.95 (d, J=7 Hz, 3H), 1.29 (br. s, 14H),
1.9–2.2 (m, 5H), 2.84 (br. s, D O exchangeable, 1H), 3.68 (t, J=7 Hz, 2H). Anal. calcd for C H O: C
2
15 28
80.29, H 12.58; found: C 80.48, H 12.65.
3.12. (3R)-1-Bromo-3-methyltetradec-6-yne 14
As described for 2, bromination of 13 (0.91 g, 4.06 mmol) with Ph P (1.28 g, 4.88 mmol), Br (0.82
3
2
ml, 4.51 mmol, 5.5 M solution in CCl ) and pyridine (0.36 ml, 4.47 mmol) gave 14. Yield: 0.793 g (68%);
4
22
−1
1
[
1
α]D +4.62 (c 0.78, CHCl ); IR: 1480, 1380 cm ; H NMR: δ 0.93 (d and t merged, 6H), 1.32 (br. s,
4H), 1.8–2.1 (m, 5H), 3.59 (t, J=7 Hz, 2H).
3
3.13. (6R)-6-Methylheptadeca-2,9-diynoic acid 16
As described for 12, alkylation of 15 (0.29 g, 4.14 mmol) with 14 (0.79 g, 2.75 mmol) was carried out
at −78°C using n-BuLi (5.16 ml, 8.26 mmol, 1.6 M in hexane) as the base in a mixture of THF (10 ml)
and HMPA (10 ml). The product obtained after work-up was purified by column chromatography (silica
2
2
gel, 0–5% MeOH:CHCl ) to give pure (R)-16. Yield: 0.456 g (60%); [α]
+5.3 (c 1.24, CHCl ); IR:
3
3
D
−1 1
3
5
1
700–3500, 1720, 1480 cm ; H NMR: δ 0.9–1.0 (d and t merged, 6H), 1.32 (br. s, 14H), 1.9–2.2 (m,
H), 2.34 (t, J=6 Hz, 2H), 8.6 (br. s, D O exchangeable, 1H). Anal. calcd for C H O : C 78.21, H
2
18 28
2
0.21; found: C 78.48, H 10.39.
.14. (6S)-6-Methylheptadec-(9E)-enoic acid I
Reduction of 16 (0.41 g, 1.45 mmol) with Na metal (0.667 g, 29.0 mol) in a mixture of NH (50
3
3
ml), EtOH (15 ml) and ether (35 ml) gave (S)-I after purification by preparative TLC (silica gel, 5%

S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 2627–2633
2633
22
MeOH:CHCl ). Yield: 0.289 g (71%); [α]D +4.8 (c 0.95, CHCl ). The spectral data of (S)-I were
3
3
identical with those for its antipode.
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