(R)-2,3-Cyclohexylideneglyceraldehyde, a novel template for stereoselective preparation of functionalized δ-lactones: Synthesis of mosquito oviposition pheromone

Article abstract of DOI:10.1016/j.tetlet.2005.07.063

(R)-2,3-Cyclohexylideneglyceraldehyde 1 has been used to prepare functionalized δ-lactones. This was exemplified by a simple and efficient synthesis of the oviposition pheromone 10 of Culex pipens fatigans.

Full text of DOI:10.1016/j.tetlet.2005.07.063

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6219–6221
(R)-2,3-Cyclohexylideneglyceraldehyde, a novel template
for stereoselective preparation of functionalized
d-lactones: synthesis of mosquito oviposition pheromone
Bhaskar Dhotare, Dibakar Goswami and Angshuman Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 25 May 2005; revised 8 July 2005; accepted 14 July 2005
Abstract—(R)-2,3-Cyclohexylideneglyceraldehyde 1 has been used to prepare functionalized d-lactones. This was exemplified by a
simple and efficient synthesis of the oviposition pheromone 10 of Culexpipens fatigans .
Ó 2005 Elsevier Ltd. All rights reserved.
Chiral functionalized d-lactones have drawn consider-
able attention in recent years due to their importance
as building blocks in natural product synthesis.1 In addi-
tion, the moiety is present in a large number of biologi-
hydroxyacetylene.5o We report herein, a simple and effi-
cient synthesis of 10 starting from (D)-mannitol by
employing an asymmetric strategy which could also be
applied for the synthesis of various other functionalized
d-lactones with varied stereochemistries.
,
cally important natural products.1 2 6(S)-Acetoxy-5(R)-
hexadecanolide 10, a functionalized d-lactone, is the ma-
jor component of the apical droplets that form on the
eggs of the mosquito Culexpipens fatigans ,3 which is a
possible vector of filarial diseases. The compound acts
as an oviposition pheromone attracting gravid females
of the same species and inducing them to oviposit in
the same spot where the original eggs are found. The
natural compound was shown to possess 5(R),6(S)-ste-
reochemistry.4 The synthesis of 10 in homochiral form
assumes importance because of its utility from a social
perspective. So far several syntheses of this chiral lac-
tone 10 have been reported5 where the required (R,S)-
1,2-diol unit was obtained from suitable chiron sour-
ces5g,k,m,n or generated asymmetrically following differ-
ent routes via microbial/metal hydride reduction5d of
hydroxy ketones, Sharpless asymmetric epoxydation of
allylic alcohols,5a–c,i,j Sharpless asymmetric dihydroxyla-
tions5p of an olefin, stereodifferentiating reactions,5e,q
etc. Alternately, d-lactone moiety of 10 was generated
via a Ru catalyzed oxidative cyclization of a chiral 5-
We envisaged that the entire hydroxylactone moiety of
10 with its desired stereochemistry, could be obtained
from the easily accessible (R)-2,3-cyclohexylideneglycer-
aldehyde 1.6a Earlier, it had been observed that addition
of n-decyl Grignard reagent to 1 took place with moder-
ate anti selectivity, to produce (2R,3S)-2b as the major
product (yield, 73%; 2a:2b, 35:65).6b In the present
work, 1 was treated with freshly prepared n-decyllithium
in hexane or ether according to methods A and B.7 In
both the cases, the reagents (n-decyl bromide and lith-
ium) were used in excess to ensure total consumption
of the aldehyde. To our great delight, for both the cases
the reactions took place with good yields and most
importantly with very good anti selectivities, compared
to that for the corresponding Grignard addition. (Meth-
od A: yield, 75%; 2a:2b, 7:93; Method B: yield, 78%;
2a:2b, 5:95). The anti-selectivity suggests that the alkyl
attack in both Grignard and organolithium cases, takes
place preferably via a Felkin–Anh model,8 like hydride
reductions of ketones derived from 1.6b–d However, for
both these organometallic additions there is some degree
of possibility for a-chelate attack9 under such anhydrous
conditions. Probably, because of the presence of the
bulky cyclohexylidene moiety in 1, attack takes place
predominantly via the thermodynamically favorable
conformation OC1 of the Felkin–Anh model rather than
Keywords: (R)-2,3-Cyclohexylideneglyceraldehyde; Organolithium;
anti Stereoselectivity; Felkin–Anh model; Functionalized d-lactones;
Mosquito oviposition pheromone.
*
Corresponding author. Tel.: +91 22 25570015; fax: +91 22
25505151; e-mail: achat@apsara.barc.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.063

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B. Dhotare et al. / Tetrahedron Letters 46 (2005) 6219–6221
mity with those reported5j for the natural product
(Scheme 2).
M
O
O
α-chelate model
syn-2a
Thus, a simple and efficient synthetic route to 10, a rep-
resentative chiral hydroxy d-lactone has been developed
starting from easily accessible 1.6a Stereodifferentiating
organolithium addition to 1 in hexane and ether was
found to be highly anti selective. Earlier, conversions
of 1 into syn-alkane-1,2,3-triols,6b–d several anti homoal-
lylic,15a,b and homopropargyl alcohols15a with highly
diastereoselectivity were described. The easy availability
of these chiral carbinols and also of (S)-116 would
extend the scope of the present protocol for the synthesis
of different stereoisomers of the hydroxy d-lactones with
varied functional features.
H
O
-
R
() R
O
H
O
O
anti-2b
Felkin-Anh model
O
R
-
R
R
()
O
O
-
R
H
OC1
OC2
Scheme 1.
the OC2 or a-chelate model, in order to avoid steric
interactions (Scheme 1). However, the production of a
small amount of syn-2a during organolithium addition
may reflect the smaller size of lithium, favoring chelate
attack, with respect to the larger magnesium atom in
the Grignard addition. This is supported by the fact that
organocopper additions to the corresponding isopropyl-
idene derivative of 1 were effected with high syn
selectivity.10
References and notes
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Silylation of 2b with TBDPS–Cl afforded 3, which was
deketalized in the presence of aqueous CF3COOH
(TFA) to obtain the diol 4 in good overall yield. Com-
pound 4 was converted to the terminal epoxide 611 via
monotosylation of the primary hydroxyl group then
base treatment of the resulting 5. Regioselective ring
opening of the epoxide of 6 with the Grignard reagent
from 3-butenyl bromide produced 7.12 Following a
known procedure,13 7 was subjected to ozonolysis under
basic conditions to afford the d-lactone 8 directly, in
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ation produced the title compound 1014 in appreciable
yield, the spectroscopic and optical data being in confor-
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+
ia/ib
CHO
O
O
O
O
O
O
C
10H21
C10H21
1
2a
2b
OH
OH
ii
O
O
O
OR OH
2b
v
iii, iv
C10H21
C
10H21
C
10H21
6
3
4, R = H
5, R = Ts
OTBDPS
OTBDPS
OTBDPS
vi
OH
C10H21
viii, ix
vii
C10H21
C10H21
(CH2)3
O
O
O
O
H
H
OTBDPS
OR
7
OTBDPS
8
9, R = H
10, R = Ac
Scheme 2. (ia) n-decyllithium, hexane, ꢀ40 °C to rt, 75%; (ib) n-decyllithium, ether, ꢀ40to 0 °C, 78%; (ii) TBDPS–Cl, Im, rt; (iii) CF3CO2H, H2O,
0 °C, 91% (two steps); (iv) p-TosCl, Py, 0 °C; (v) K2CO3, MeOH, rt, 89% (two steps); (vi) 3-butenyl-MgBr, CuBr, ꢀ40 °C to rt, 77%; (vii) O3, MeOH,
NaOH, ꢀ15 °C, 77%; (viii) TBAF, THF, rt, 69%; (ix) Ac2O, Py, 0to ꢀ10 °C, 79%.

B. Dhotare et al. / Tetrahedron Letters 46 (2005) 6219–6221
6221
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7. Method A: n-Bromodecane (0.035 mol) in hexane (50 mL)
was added over a period of 2 h to a stirred suspension of
finely cut lithium (0.077 mol) in dry hexane (100 mL) at
10–15 °C under argon. The mixture was stirred at that
temperature for 3 h more when the majority of lithium had
dissolved. The suspension was cooled to ꢀ40 °C. To it a
solution of 1 (0.01 mol) in THF (50 mL) was added over a
period of 30min. The mixture was stirred at ꢀ40 °C for
1 h, at 0 °C for 3 h and at room temperature overnight. It
was then filtered quickly and the residue containing the
unreacted lithium metal was washed with dry THF. [This
excess lithium was later decomposed by treatment with
cold MeOH.] The combined filtrates were treated with
water and extracted with EtOAc. Solvent removal under
reduced pressure and column chromatography of the
residue (0–20% EtOAc in hexane) afforded 2a and
2b.Method B: n-Bromodecane (0.035 mol) in ether
(50mL) was added over a period of 3 h to a stirred
suspension of finely cut lithium (0.077 mol) in dry ether
(150mL) at around ꢀ10 °C under argon. The mixture was
stirred at ꢀ10 °C for 1 h further to dissolve the most of the
lithium. The suspension was cooled to ꢀ40 °C. To it, a
solution of 1 (0.01 mol) in ether (50 mL) was added over a
period of 30min. The mixture was stirred at ꢀ40 °C for
2 h, at ꢀ10 °C for 6 h, then filtered. After a normal work
up, the products were isolated as in Method A.
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25
11. Compound 6: ½aꢁD +7.8 (c 2.1, CHCl3); IR (film):
3070, 3048, 2855 cmꢀ1 1H NMR (200 MHz, CDCl3): d
;
0.86 (br t, 3H), 1.04 (s, 9H), 1.2–1.4 (m, 18H), 2.12 (dd,
J = 5.4, 2.6 Hz, 1H), 2.45 (dd, J = 5.06, 3.92 Hz, 1H),
2.83–2.98 (m, 1H), 3.38 (dd, J = 11.0, 5.2 Hz, 1H), 7.39
(m, 6H), 7.64 (m, 4H).
25
12. Compound 7: ½aꢁD +5.9 (c 2.8, CHCl3); IR (film): 3500,
3075, 3005, 2857, 1095, 910 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d 0.86 (br t, 3H), 1.04 (s, 9H), 1.2–1.6 (m, 22H
overlapped with s at 1.58 for 1H, OH), 1.9–2.05 (m, 2H),
3.4–3.6 (m, 2H), 5.0–5.2 (m, 2H), 5.7–5.9 (m, 1H), 7.36 (m,
6H), 7.65 (m, 4H).
13. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58,
3675–3680.
25
14. Compound 10: ½aꢁD ꢀ36.5 (c 1.8, CHCl3); Lit.5j [a]D ꢀ36.7
(c 1.2, CHCl3); IR (film): 1740, 1365, 1235, 1050 cmꢀ1; 1H
NMR (200 MHz, CDCl3): d 0.86 (t, J = 7.2 Hz, 3H), 1.22
(br m, 16H), 1.4–1.95 (m, 6H), 2.05 (s, 3H), 2.3–2.6 (m,
2H), 4.29–4.32 (m, 1H), 4.9–5.0(m, 1H).
15. (a) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104–6107;
(b) Chattopadhyay, A.; Dhotare, B.; Hassarajani, S. A.
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