Stereoselective synthesis of (4S,6S)-6-hydroxy-4-undecanolide: A pheromone of the giant white butterfly Idea leuconoe

Article abstract of DOI:10.1055/s-0031-1289671

The stereoselective synthesis of (4S,6S)-6-hydroxy-4-undecanolide, a major pheromone component in the secretion of Idea leuconoe has been accomplished employing Prins cyclization to produce anti-1,3-diols and hydroboration/ oxidation of terminal olefin to

Full text of DOI:10.1055/s-0031-1289671

PAPER
579
Stereoselective Synthesis of (4S,6S)-6-Hydroxy-4-undecanolide: A Pheromone
of the Giant White Butterfly Idea leuconoe
S
tereosele
h
ctive
S
ynthe
i
sis of (4
l
S
,6
S
)-
6
-Hydr
u
oxy-4-undecanolid
S
e
ingh Yadav,*a,b Poli Adi Narayana Reddy,a Hissana Ather,a Alleni Suman Kumar,a Attaluri R. Prasad,a
Basi V. Subba Reddy,a Ahmad Al Khazimb
a
Pheromone Group, Natural product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia
b
Received 11 October 2011; revised 6 December 2011
tuted tetrahydropyran ring followed by hydroboration/
Abstract: The stereoselective synthesis of (4S,6S)-6-hydroxy-4-
oxidation of the terminal olefin. The pyran derivative 7
undecanolide, a major pheromone component in the secretion of
could in turn be prepared via the Prins cyclization of a
Idea leuconoe has been accomplished employing Prins cyclization
homoallylic alcohol 3 and hexanal. The chemoselective
oxidation of 1,4-diol 11 using 2,2,6,6-tetramethylpiperid-
inyloxy (TEMPO) and (diacetoxyiodo)benzene would
give the g-lactone 1b. In another strategy, 1,4-diol 11
could be alternatively prepared from compound 15 by
ozonolytic oxidative cleavage of the olefin 15 followed by
alkynylation of the resulting aldehyde and subsequent hy-
drogenation.
to produce anti-1,3-diols and hydroboration/oxidation of terminal
olefin to introduce primary alcohol as the key steps.
Key words: pheromones, Prins cyclization, Mitsunobu inversion,
anti-1,3-diol, chemoselective oxidation of 1,4-diols
The males of the giant white butterfly Idea leuconoe pos-
sess hairpencils on the end of their abdomen, which re-
lease a mixture of compounds, namely, alkaloids,
aromatics, terpenoids, hydrocarbons, and lactones, to act
as courtship pheromones.1 The lactones, which are isolat-
ed from the hairpencil extract, are hydroxyalkanolides
with two chiral centers. The lactone ring size differs from
four- to six-membered and the chain lengths vary from C10
to C13.2 Of these lactones, the major components of the
hairpencil secretion are the g-lactones, 6-hydroxy-4-al-
kanolides 1a–c, which are accompanied by trace amounts
of the respective b-lactones 2a (Figure 1). The first syn-
thesis of a 6-hydroxy-4-alkanolide has been reported by
Schulz et al. involving enantioselective hydrogenation of
4,6-diketo esters using a ruthenium–BINAP catalyst.3
OH
OH OMOM
HO
O
O
1b
11
OH
OH OMOM
HO
O
BnO
4
17b
OTBS
OMOM
I
O
O
O
15
O
7
OH
O
HO
R
R
1a R = C4H9
1b R = C5H11
1c R = C6H13
2a R = i-Pr
2b R = Et
+ hexanal
13
HO
OH
3
Figure 1 Lactones 1a–c and 2a
route A
route B
Scheme 1
In continuation of our research on the use of Prins cycliza-
tion in total synthesis of biologically active natural prod-
ucts,4 we herein report an efficient approach for the
synthesis of (4S,6S)-6-hydroxy-4-undecanolide (1b), a
pheromone of the giant white butterfly Idea leuconoe.
The synthetic approach (route A, Scheme 2) commenced
from a chiral homoallylic alcohol 3, which was prepared
via the copper-mediated regioselective opening of (S)-
benzylglycidyl ether (obtained via the Jacobsen’s HKR
methodology)5 with vinylmagnesium bromide (formed in
situ from vinyl bromide and Mg metal in THF) followed
by debenzylation with sodium in liquid ammonia (overall
yield for two steps 69%). Prins cyclization of the homoal-
lylic alcohol 3 with n-hexanal in the presence of trifluoro-
acetic acid followed by hydrolysis of the resulting
trifluoroacetate gave the trisubstituted tetrahydropyran 4
In the retrosynthetic analysis (Scheme 1), we envisaged
that the target molecule could be prepared from com-
pound 7 via the reductive opening of iodomethyl-substi-
SYNTHESIS 2012, 44, 579–584
x
x
.x
x
.2
0
1
1
Advanced online publication: 16.01.2012
DOI: 10.1055/s-0031-1289671; Art ID: Z97011SS
© Georg Thieme Verlag Stuttgart · New York

580
J. S. Yadav et al.
PAPER
(52%).6 The stereochemistry was assumed to be in accor- cording to a reported procedure11 in three steps (overall
dance with the literature as it was well examined and es- yield 30%). Compound 14 was protected as its meth-
tablished previously.7 Moreover, the assumption was oxymethyl ether gave 15 (98%). Ozonolytic oxidative
confirmed when compound 4 was elaborated to synthe- cleavage of 15 gave the aldehyde 16 (85%), which was
size the target molecule 1b (overall yield 15%), which in then treated with O-benzylpropargyl alcohol in the pres-
all respects was identical with the reported data.3 Tosyl- ence of n-butyllithium in tetrahydrofuran at –78 °C. The
ation of the compound 4 with 1.2 equivalents of tosyl resulting propargylic alcohol was obtained as a mixture of
chloride in the presence of triethylamine in dichlo- syn-17a and anti-17b in a 1:1 ratio. To assign the stereo-
romethane gave the corresponding primary tosylate 5 chemistry, both the isomers were converted into the cor-
(95%). Protection of the secondary alcohol as a silyl ether responding acetonides 18a and 18b in a three-step
in the presence of tert-butyldimethylsilyl chloride and im- sequence. Upon exposure of both the isomers 17a/17b to
idazole in dichloromethane gave the compound 6 (97%). 10% Pd/C in methanol resulted in the reduction of triple
Treatment of tosylate 6 with sodium iodide in refluxing bond with concomitant removal of benzyl group to furnish
acetone gave the corresponding iodo derivative 7 (95%). the diols, which were then treated with aqueous 3 M hy-
Reductive opening of the iodo derivative 7 with activated drochloric acid in tetrahydrofuran to give the triols (struc-
zinc in refluxing ethanol furnished the compound 8 tures not shown). Upon treatment of the triols with 2,2-
(92%).8 The secondary alcohol of compound 8 was pro- DMP in acetone the acetonides 18a and 18b were ob-
tected as its methoxymethyl ether 9 (98%) in the presence tained. The stereochemistry of the diastereomers could be
of N-diisopropylethylamine and methoxymethyl chloride established by 13C NMR analysis. In 18a, the two methyl
in dichloromethane. Upon exposure of compound 9 to di- groups resonate at d = 19.8 and 30.5 ppm and quaternary
cyclohexylborane and 30% hydrogen peroxide afforded carbon shows a peak at d = 98.5 ppm representing the 1,3-
the primary alcohol 10 (77%).9 Subsequent removal of the syn orientation of two hydroxy groups. However, the two
silyl group from compound 10 using tetra-n-butylammo- methyl groups and quaternary carbon resonate at d = 24.7,
nium fluoride in tetrahydrofuran furnished the 1,4-diol 11 24.9, and 100.3 ppm, respectively, indicating the 1,3-anti-
(97%), which was readily converted into lactone 12 (87%) orientation of the two hydroxy groups in 18b.12 The un-
by chemoselective oxidation using TEMPO and (diacet- desired isomer 17a was converted into 17b (overall yield
oxyiodo)benzene in dichloromethane.10 Deprotection of 70%) under standard Mitsunobu condition.13 Reduction of
methoxymethyl ether 12 using trifluoroacetic acid in the triple bond with a concomitant debenzylation of com-
dichloromethane (1:4) gave the final product 1b (97%), pound 17b was achieved using Pd/C in methanol to give
which in all respects was identical to the reported struc- the key fragment 1,4-diol 11 (97%). The chemoselective
ture.3
oxidation of 1,4-diol 11 using TEMPO and (diacetoxy-
iodo)benzene in dichloromethane gave the lactone 12
(87%).10 Deprotection of the methoxymethyl ether 12 us-
The alternative synthetic approach (route B, Scheme 3)
commenced from 13, which was converted into 14 ac-
OH
OH
a
b
HO
HO
TsO
O
OH
O
4
5
3
OTBS
OTBS
c
d
I
TsO
O
O
6
7
TBSO
TBSO
TBSO
OMOM
OH
e
f
8
9
OMOM
OH OMOM
g
i
h
HO
HO
10
12
11
OMOM
j
1b
O
O
Scheme 2 Route A. Reagents and conditions: (a) n-hexanal, TFA, CH2Cl2, 3 h; then K2CO3, MeOH, 25 °C, 0.5 h, 52%; (b) Et3N, TsCl, CH2Cl2,
0–25 °C, 3 h, 95%; (c) TBSCl, imidazole, DMAP, CH2Cl2, 0 to 25 °C, 3 h, 97%; (d) NaI, acetone, reflux, 24 h, 95%; (e) Zn, EtOH, reflux, 2 h,
92%; (f) MOMCl, DIPEA, DMAP, CH2Cl2, 0–25 °C, 3 h, 98%; (g) Cy2BH, THF, 30% H2O2, NaOH, 77%; (h) TBAF, THF, 0–25 °C, 4 h, 97%;
(i) TEMPO, PhI(OAc)2, CH2Cl2, 25 °C, 4 h, 87%; (j) TFA, CH2Cl2 (1:4 ), 0–25 °C, 2 h, 97%.
Synthesis 2012, 44, 579–584
© Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of (4S,6S)-6-Hydroxy-4-undecanolide
581
OMOM
OMOM
OH
k
l
ref. 11
O
13
14
15
16
OH OMOM
OH OMOM
OH OMOM
m
o
+
HO
BnO
BnO
17a
17b
11
n
100.2
24.8
98.5
19.8
25.3
30.5
O
O
O
O
p
+
HO
HO
18b
OMOM
18a
j
i
1b
11
O
O
12
Scheme 3 Route B. Reagents and conditions: (a) MOMCl, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 3 h, 98%; (b) O3, TPP, CH2Cl2, –78 °C to
r.t.; (c) BnOCH2C≡CH, n-BuLi, THF, –78 °C, 2 h, 85%; (d) DEAD, TPP, p-nitrobenzoic acid, THF, 0 °C to r.t., 88%; (e) Pd/C, MeOH, r.t.,
4 h, 97%; (f) 1. aq 3 M HCl, THF, 0 °C to r.t., 4 h, 2. 2,2-DMP, acetone, PTSA, r.t., 2 h; (g) TEMPO, PhI(OAc)2, CH2Cl2, 25 °C, 4 h, 87%;
(h) TFA–CH2Cl2 (1:4), 0– 25 °C, 2 h, 97%.
was removed under reduced pressure. The trifluoroacetate obtained
in this reaction was directly used in the next step without purifica-
tion. The residue was dissolved in MeOH (40 mL) and stirred with
K2CO3 (6.0 g) for 0.5 h. The mixture was extracted with CH2Cl2
(3 × 30 mL) and the combined organic layers were dried (Na2SO4)
and the solvent was removed under reduced pressure. Purification
of the crude by column chromatography on silica gel gave 4 (3.08
g, 52%) as a colorless gummy liquid; Rf = 0.3 (silica gel, 60%
EtOAc in hexane); [a]D20 +2.4 (c 2.8, CHCl3).
ing trifluoroacetic acid in dichloromethane (1:4) gave the
final product 1b in 97% yield (overall yield 17%)
(Scheme 3), which in all respects was identical to the re-
ported one.3
Using the above two synthetic approaches, optically ac-
tive 1a and 1c should be accessed readily.
In summary, we have described a stereoselective formal
total synthesis of (4S,6S)-6-hydroxy-4-undecanolide (1b)
employing two alternative strategies. These methods
would be very useful to generate a wide variety of five-
membered-ring lactones.
IR (neat): 3380, 2930, 2859, 1722, 1651, 1458, 1373, 1025 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.7 Hz, 3 H), 1.05–1.64
(m, 10 H), 1.78–1.84 (m, 1 H), 1.88–1.94 (m, 1 H), 3.26–3.60 (m, 4
H), 3.73–3.81 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.4, 25.0, 31.6, 35.8, 36.7,
All reactions were carried out under inert atmosphere. Solvents
were dried and purified by conventional methods prior to use. The
progress of the reaction was monitored by TLC using glass plates
precoated with silica gel 60 F254 to a thickness of 0.5 mm (Merck).
Column chromatography was performed on silica gel (60–120
mesh) and neutral alumina using Et2O, EtOAc, and hexanes as elu-
ents. Optical rotation values were measured on PerkinElmer P241
polarimeter and JASCO DIP-360 digital polarimeter at 25 °C. IR
spectra were recorded on PerkinElmer FT-IR spectrophotometer.
1H and 13C NMR spectra were recorded on Varian Gemini 200
MHz, Bruker Avance 300 MHz, Varian Unity 400 MHz, or Varian
Inova 500 MHz spectrometer using TMS as an internal standard in
CDCl3. Mass spectra were recorded on Micromass VG-7070H for
EI and VG Autospec M for FAB-MS.
40.9, 65.6, 67.7, 75.2, 75.89.
HRMS (ESI): m/z calcd for C11H22O3 + Na: 225.1466; found:
225.1471.
[(2S,4R,6S)-4-6-Pentyltetrahydro-2H-pyran-2-yl]methyl
4-Methylbenzenesulfonate (5)
To stirred solution of diol 4 (2.5 g, 12.3 mmol) in anhyd CH2Cl2 (25
mL) was added Et3N (8.68 mL, 61.88 mmol) at 0 °C, and then TsCl
(2.82 g, 14.8 mmol) was added over 2 h. The reaction mixture was
allowed to warm to 25 °C and then allowed to stir for 3 h. The mix-
ture was then treated with aq 1 M HCl (10 mL) and extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with sat. aq NaHCO3 (15 mL), followed by H2O (15 mL). The com-
bined organic phases were dried (Na2SO4) and concentrated under
reduced pressure. Flash chromatography of the crude product af-
forded tosylate 5 (4.18 g, 95%) as a gummy liquid; Rf = 0.6 (silica
gel, 40% EtOAc in hexane); [a]D20 –3.0 (c 1.0, CHCl3).
(2S,4R,6S)-2-(Hydroxymethyl)-6-pentyltetrahydro-2H-pyran-
4-ol (4)
TFA (48.34 mL) was added slowly to a solution of 3 (3 g, 29.40
mmol) and n-hexanal (8.82 g, 88.23 mmol) in anhyd CH2Cl2 (95
mL) at 25 °C under N2 atmosphere. The reaction mixture was
stirred at r.t. for 3 h and then diluted with sat. aq NaHCO3 (150 mL).
The pH was then adjusted to >7 by the addition of Et3N. The layers
were separated and the aqueous layer was extracted with CH2Cl2
(3 × 70 mL) and the organic layers were combined and the solvent
IR (neat): 3410, 2930, 2860, 1598, 1454, 1360, 1176, 1097, 1030,
979, 816, 668 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.6 Hz, 3 H), 1.03–
1.49, (m, 10 H), 1.87–1.93 (m, 2 H), 2.44 (s, 3 H), 3.18–3.26 (m, 1
H), 3.50–3.58 (m, 1 H), 3.71–3.82 (m, 1 H), 3.94–4.05 (m, 2 H),
7.32 (d, J = 8.1 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H).
© Thieme Stuttgart · New York
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582
J. S. Yadav et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 13.9, 21.5, 22.4, 24.9, 31.6, 35.6,
36.7, 40.5, 67.4, 72.0, 72.6, 75.7, 127.8, 129.6, 132.7, 132.7, 144.6.
4.07 (m, 2 H), 4.97–5.09 (m, 2 H), 5.01–5.08 (m, 2 H), 5.61–5.82
(m, 1 H).
HRMS (ESI): m/z calcd for C18H28O5S + Na: 379.1555; found:
379.156.
13C NMR (75 MHz, CDCl3): d = –4.5, –4.8, 14.0, 17.9, 22.6, 25.2,
25.7, 31.8, 37.9, 41.0, 41.2, 68.1, 71.2, 117.3, 134.6.
HRMS (ESI): m/z calcd for C17H36O2Si + Na: 323.2382; found:
323.2389.
[(2S,4R,6S)-4-(tert-Butyldimethylsilyloxy)-6-pentyltetrahydro-
2H-pyran-2yl]methyl 4-Methylbenzenesulfonate (6)
To a stirred solution of alcohol 5 (3.8 g, 10.67 mmol) in anhyd
CH2Cl2 (30 mL) at 0 °C were added TBSCl (1.93 g, 12.8 mmol),
DMAP (cat.), and imidazole (2.9 g, 42.6 mmol) successively, The
mixture was stirred for 3 h at 25 °C, quenched with H2O (10 mL),
and extracted with CH2Cl2 (3 × 20 mL). The combined organic ex-
tracts were washed with brine (10 mL) and dried (Na2SO4). Remov-
al of the solvent followed by purification by column
chromatography afforded the pure product 6 (4.86 g, 97%) as a col-
orless liquid; Rf = 0.7 (silica gel, 10% EtOAc in hexane); [a]D20 –1.6
(c 2.0, CHCl3).
(5S,7S)-7-Allyl-9,9,10,10-tetramethyl-5-pentyl-2,4,8-trioxa-9-
silaundecane (9)
To a solution of alcohol 8 (1.8 g, 6 mmol) in anhyd CH2Cl2 (15 mL)
at 0 °C were added successively DIPEA (3.10 mL, 17.95 mmol),
DMAP (cat.), and MOMCl (0.96 g, 11.99 mmol). The mixture was
stirred for 3 h at 25 °C, quenched with H2O (10 mL), and extracted
with CH2Cl2 (2 × 20 mL). The combined organic extracts were
washed with brine (10 mL), dried (Na2SO4), and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography to afford the pure product 9 (2.02 g, 98%) as a col-
20
IR (neat): 2931, 2857, 1598, 1463, 1364, 1254, 1178, 1122, 1079,
982, 837 cm–1.
orless liquid; Rf = 0.7 (silica gel, 10% EtOAc in hexane); [a]D
+19.0 (c 1.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.03 (s, 6 H), 0.85–0.9 (m, 12 H),
1.06–1.45 (m, 10 H), 1.69–1.77 (m, 2 H), 2.43 (s, 3 H), 3.16–3.23
(m, 1 H), 3.48–3.56 (s, 1 H), 3.65–3.76 (m, 1 H), 3.92–4.02 (m, 2
H), 7.32 (d, J = 7.9 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = –4.5, 14.0, 18.0, 21.6, 22.5, 25.0,
25.7, 31.8, 35.7, 37.4, 41.2, 68.2, 72.2, 72.7, 75.8, 127.9, 129.7,
132.9, 144.6.
IR (neat): 3076, 2953, 2930, 1640, 1466, 1379, 1253, 1150, 1044,
1001, 916, 834 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.06 (s, 6 H), 0.88–0.92 (m, 12 H),
1.25–1.63 (m, 10 H), 2.20–2.24 (t, J = 6.4 Hz, 2 H), 3.34 (s, 3 H),
3.55–3.63 (m, 1 H), 3.81–3.89 (m, 1 H), 4.59 (s, 2 H), 5.01–5.05 (m,
2 H), 5.71–5.85 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = –4.5, –4.0, 14.0, 18.0, 22.6, 24.7,
25.8, 31.9, 35.2, 42.3, 42.6, 55.4, 69.2, 75.7, 95.8, 116.9, 134.7.
MS (ESI): m/z = 493 [M + Na].
HRMS (ESI): m/z calcd for C19H40O3Si + Na: 367.2644; found:
367.2631.
tert-Butyl[(2S,4R,6S)-2-(iodomethyl)-6-pentyltetrahydro-2H-
pyran-4-yloxy]dimethylsilane (7)
To a solution of 6 (3.8 g, 8.08 mmol) in acetone (70 mL) was added
NaI (6.06 g, 40.43 mmol) and the mixture was heated to reflux for
24 h. After completion, the solvent was removed under reduced
pressure. The residue was quenched with H2O (20 mL) and extract-
ed with CH2Cl2 (2 × 20 mL). The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. Purification of the crude
product by column chromatography gave 7 (3.27 g, 95%) as a col-
(4S,6S)-4-(tert-Butyldimethylsilyloxy)-6-(methoxymethoxy)un-
decan-1-ol (10)
To a stirred solution of cyclohexene (2.64 mL, 26 mmol) in anhyd
THF (2 mL) was added Me2S·BH3 (1.22 mL, 13 mmol) at 0 °C. The
mixture was stirred for 1 h at 0 °C, and then a solution of 9 (1.50 g,
4 mmol) in anhyd THF (15 mL) was added slowly over 10–15 min
at 0 °C. The resulting solution was allowed to warm to 25 °C and
then allowed to stir for 6 h. Upon completion, the mixture was
quenched at 0 °C with EtOH (5 mL), and treated with 1 M aq NaOH
(21.8 mL, 21.8 mmol) and 30% H2O2 (10 mL, 87 mmol). After stir-
ring at r.t. for 1 h, the resulting mixture was quenched with 1 M aq
Na2S2O3 (10 mL). The aqueous phase was extracted with EtOAc
(2 × 30 mL). The combined organic extracts were washed with 1 M
aq Na2S2O3 (10 mL) followed by brine (10 mL), dried (Na2SO4),
and concentrated under reduced pressure. The residue was purified
by column chromatography to afford the alcohol 10 (1.21 g, 77%)
as a colorless liquid; Rf = 0.3 (silica gel, 20% EtOAc in hexane);
[a]D20 +15.8 (c 1.2, CHCl3).
20
orless liquid; Rf = 0.8 (silica gel, 10% EtOAc in hexane); [a]D
+10.8 (c 1.65, CHCl3).
IR (neat): 2930, 2856, 1465, 1378, 1254, 1148, 1125, 1076, 893,
839, 774 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.05 (s, 6 H), 0.88–0.93 (m, 12 H),
1.06–1.57 (m, 10 H), 1.66–1.74 (m, 1 H), 1.97–2.06 (m, 1 H), 3.08–
3.16 (m, 2 H), 3.21–3.38 (m, 2 H), 3.63–3.81 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = –4.5, 9.0, 14.0, 18.0, 22.6, 25.2,
25.8, 31.7, 35.8, 41.3, 41.2, 68.5, 75.1, 75.9.
HRMS (ESI): m/z calcd for C17H35IO2Si + Na: 449.1348; found:
449.1365.
IR (neat): 3417, 2931, 2858, 1466, 1380, 1253, 1212, 1150, 1041,
919, 835 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.07 (s, 6 H), 0.88–0.89 (m, 12 H),
1.29–1.88 (m, 15 H), 3.34 (s, 3 H), 3.53–3.61 (m, 3 H), 3.83–3.90
(m, 1 H), 4.59 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = –4.6, –4.1, 13.9, 18.0, 22.5, 24.0,
24.5, 25.4, 25.8, 27.7, 31.9, 41.9, 55.4, 69.3, 70.2, 75.6, 95.6.
(4S,6S)-4-(tert-Butyldimethylsilyloxy)undec-1-en-6-ol (8)
To a solution of iodide 7 (3.0 g, 7.04 mmol) in EtOH (90 mL) was
added activated Zn dust (4.6 g, 70.36 mmol). The resulting mixture
was stirred under reflux for 2 h and then cooled to 25 °C. Addition
of solid NH4Cl (7.55 g) and Et2O (110 mL) followed by stirring for
5 min gave a gray suspension, which was filtered through Celite and
the filtrate was concentrated in vacuo. Purification of the residue by
flash chromatography gave 8 (1.94 g, 92%) as a colorless liquid;
MS (ESI): m/z = 385 [M + Na].
20
Rf = 0.5 (silica gel, 10% EtOAc in hexane); [a]D –0.7 (c 1.1,
CHCl3).
(4S,6S)-6-(Methoxymethoxy)undecan-1,4-diol (11)
To an ice cold solution of silyl ether 10 (0.75 g, 2.07 mmol) in an-
hyd THF (10 mL) was added TBAF (2.48 mL, M in THF, 2.48
mmol). After stirring for 15 min, the reaction mixture was brought
to 25 °C and the stirring was continued for 4 h. The mixture was
then cooled to 0 °C and quenched with sat. aq NH4Cl (10 mL) and
IR (neat): 3379, 2931, 2858, 1641, 1465, 1254, 1073, 999, 913, 835
cm–1.
1H NMR (200 MHz, CDCl3): d = 0.08 (s, 6 H), 0.83–0.97 (m, 12 H),
1.21–1.57 (m, 10 H), 2.33 (t, J = 7.3 Hz, 2 H), 2.82 (br, OH), 3.85–
Synthesis 2012, 44, 579–584
© Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of (4S,6S)-6-Hydroxy-4-undecanolide
583
extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo. The residue was
purified by column chromatography to afford the alcohol 11 (0.49
mg, 97%) as a colorless gummy liquid; Rf = 0.2 (silica gel, 20%
EtOAc in hexane); [a]D20 –17.1 (c 1.2, CHCl3).
–78 °C, the reaction was quenched by sat. aq NH4Cl (15 mL), ex-
tracted with EtOAc (2 × 30 mL), and the combined organic layers
were dried (Na2SO4). Evaporation of the solvent followed by puri-
fication on column chromatography afforded alcohols 17b (2.76 g
43%) and 17a (2.70 g, 42%). Unwanted 17a was converted into 17b
by Mitsunobu inversion; 17b (total yield: 4.53 g, 70%) was ob-
tained as a viscous liquid; Rf = 0.4 (SiO2, 30% EtOAc in hexane);
[a]D20 +23.5 (c 0.9, CHCl3).
IR (neat): 3413, 2931, 1639, 1456, 1377, 1214, 1148, 1097, 1036,
914 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.83 (t, J = 6.7 Hz, 3 H), 1.12–1.28
(m, 6 H), 1.43–1.71 (m, 8 H), 2.74 (br, OH), 3.35 (s, 3 H), 3.56–3.66
(m, 2 H), 3.70–3.91 (m, 2 H), 4.58–4.68 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.4, 25.0, 29.2, 31.8, 34.5,
34.7, 41.2, 55.7, 62.7, 67.7, 76.1, 96.2.
IR (neat): 3399, 3019, 2930, 1215, 1095, 757 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.81 (t, J = 6.7 Hz, 3 H), 1.26–1.30
(m, 6 H), 1.45–1.50 (m, 2 H), 1.79–1.84 (m, 2 H), 3.31 (s, 3 H),
3.36–3.41 (m, 1 H), 3.71–3.76 (m, 1 H), 4.14 (s, 2 H), 4.51 (s, 2 H),
4.55–4.63 (m, 2 H), 7.27 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.5, 24.4, 31.8, 34.3, 42.4,
53.5, 55.7, 57.3, 71.5, 76.0, 80.6, 87.3, 95.3, 127.7, 127.9, 128.3,
137.3.
HRMS (ESI): m/z calcd for C13H28O4 + Na: 271.1909; found:
271.1894.
(4S)-4-(Methoxymethoxy)non-1-ene (15)
To a solution of alcohol 14 (5.0 g, 35.2 mmol) in anhyd CH2Cl2 (25
mL) at 0 °C were added successively DIPEA (12.13 mL, 70.4
mmol), DMAP (20 mg, cat.), and MOMCl (8.02 mL, 105.5 mmol).
The mixture was stirred for 3 h at 25 °C, quenched with H2O (25
mL), and extracted with CH2Cl2 (3 × 20 mL). The combined organ-
ic extracts were washed with brine (25 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
column chromatography to afford the pure product 15 (6.35 g, 97%)
as a colorless liquid; Rf = 0.8 (silica gel, 10% EtOAc in hexane);
[a]D20 –17.8 (c 1.5, CHCl3).
MS (ESI): m/z = 357 [M + Na].
(4S,6S)-6-(Methoxymethoxy)undecan-1,4-diol (11)
To a solution of 17b (2.0 g) in anhyd MeOH (15 mL) was added a
catalytic amount of 10% Pd/C and the resulting mixture was stirred
under H2 atmosphere at r.t. for 4 h. After completion, the catalyst
was filtered and then washed with EtOAc (3 × 10 mL). The filtrate
was concentrated under reduced pressure and the residue was puri-
fied by column chromatography to afford the alcohol 11 (1.44 g,
97%) as a colorless gummy liquid; Rf = 0.2 (silica gel, 20% EtOAc
in hexane); [a]D20 –17.1 (c 1.2, CHCl3).
IR (neat): 3367, 3019, 1215, 1096, 1038 cm–1.
IR (neat): 3413, 2931, 1639, 1456, 1377, 1214, 1148, 1097, 1036,
914 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.83 (t, J = 6.7 Hz, 3 H), 1.12–1.28
(m, 6 H), 1.43–1.71 (m, 8 H), 2.74 (br, OH), 3.35 (s, 3 H), 3.56–3.66
(m, 2 H), 3.70–3.91 (m, 2 H), 4.58–4.68 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.4, 25.0, 29.2, 31.8, 34.5,
34.7, 41.2, 55.7, 62.7, 67.7, 76.1, 96.2.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 6.7 Hz, 3 H), 1.26–1.47
(m, 8 H), 2.23–2.27 (m, 2 H), 3.33 (s, 3 H), 3.52–3.58 (m, 1 H),
4.57–4.63 (m, 2 H), 5.00–5.06 (m, 2 H), 5.72–5.83 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.5, 24.9, 31.8, 34.0, 38.8,
55.3, 76.7, 95.2, 116.8, 134.7.
MS (ESI): m/z = 209 [M + Na].
(3S)-3-(Methoxymethoxy)octanal (16)
HRMS (ESI): m/z calcd for C13H28O4 + Na: 271.1909; found:
271.1894.
O3 was bubbled through a solution of 15 (4.5 g, 24.19 mmol) in
CH2Cl2 (35 mL) at –78 °C until no unreacted starting material was
observed on TLC (eluent: 10% EtOAc in hexanes). The reaction
mixture was then purged with N2 to remove the excess O3 and
cooled to 0 °C. Ph3P (7.6 g, 29.0 mmol) was added and the mixture
was stirred for 2 h and concentrated in vacuo. After adding hexane
(10 mL), the mixture was filtered through a Celite pad and the resi-
due was washed with hexane (30 mL). The filtrate was dried
(Na2SO4) and concentrated under reduced pressure. The resulting
residue was purified by column chromatography to afford the pure
product 16 (3.64 g, 80%) as a colorless liquid; Rf = 0.6 (silica gel,
10% EtOAc in hexane); [a]D20 +20.1 (c 1.5, CHCl3).
(S)-5-[(S)-2-(Methoxymethoxy)heptyl]dihydrofuran-2(3H)-one
(12)
To a stirred solution of diol 11 (0.23 g, 0.92 mmol) in anhyd CH2Cl2
(5 mL) were added sequentially PhI(OAc)2 (943 mg, 2.93 mmol)
and TEMPO (33 mg, 0.21 mmol). After stirring the reaction mixture
at 25 °C for 3.5 h, sat. aq Na2S2O3 (10 mL) was added, and the mix-
ture was extracted with Et2O (2 × 10 mL). The combined organic
extracts were washed with sat. aq NaHCO3 (10 mL) and brine (6
mL), and concentrated in vacuo. The residue was subjected to col-
umn chromatography to afford the lactone 12 (0.196 g, 87%) as a
20
colorless liquid; Rf = 0.5 (silica gel, 40% EtOAc in hexane); [a]D
+48.5 (c 1.9, CHCl3).
IR (neat): 3019, 2932, 1724, 1215, 1036, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (t, J = 6.7 Hz, 3 H), 1.16–1.60
(m, 8 H), 2.50–2.56 (m, 2 H), 3.28 (s, 3 H), 3.97–4.06 (m, 1 H),
4.57–4.63 (m, 2 H), 9.73 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.5, 24.8, 31.7, 34.8, 48.7,
55.5, 73.1, 95.7, 201.4.
IR (neat): 2933, 1773, 1730, 1455, 1333, 1278, 1181, 1102, 1035,
918, 798, 737, 651 cm–1.
1H NMR (300 MHz CDCl3): d = 0.90 (t, J = 6.7 Hz, 3 H), 1.30–1.61
(m, 8 H), 1.71–1.91 (m, 3 H), 2.28–2.39 (m, 1 H), 2.46–2.53 (m, 2
H), 3.35 (s, 3 H), 3.71–3.79 (m, 1 H), 4.57–4.71 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 13.7, 22.3, 24.2, 28.3, 29.6, 31.7,
34.7, 41.1, 55.4, 74.6, 77.7, 95.8, 176.8.
MS (ESI): m/z = 209 [M + Na].
(4S,6S)-1-(Benzyloxy)-6-(methoxymethoxy)undec-2-yn-4-ol
(17b)
MS (ESI): m/z = 245 [M + 1].
A solution of n-BuLi in hexane (14.73 mL, 19.14 mmol, 1.3 M so-
lution in hexane) was added to a solution (10 mL) of O-benzylpro-
pargyl alcohol (2.79 g, 19.11 mmol) in THF at –78 °C under N2
atmosphere and the mixture was allowed to stir for 20 min. To this
mixture, a solution of aldehyde 16 (3.0 g, 15.95 mmol) in anhyd
THF (15 mL) was added. After stirring the mixture for 2 h at
(S)-5-[(S)-2-Hydroxyheptyl]dihydrofuran-2(3H)-one (1b)
To a solution of 12 (0.13 g, 0.53 mmol) in anhyd CH2Cl2 (0.92 mL)
was added TFA (0.23 mL, 2.13 mmol) dropwise at 25 °C. After stir-
ring the mixture at the same temperature for 2 h, it was quenched
with sat. aq NaHCO3 (6 mL) and extracted with CH2Cl2 (2 × 6 mL).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 579–584

584
J. S. Yadav et al.
PAPER
The combined organic extracts were washed with brine (6 mL) and
concentrated in vacuo. The residue was purified by column chroma-
tography to afford the pure alcohol 1b (0.103 g, 97%) as a colorless
oil; Rf = 0.3 (silica gel, 40% EtOAc in hexane); [a]D20 +59.6 (c 1.2,
Et2O).
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1H NMR (300 MHz, CDCl3): d = 0.83 (t, J = 6.6 Hz, 3 H), 1.18–1.46
(m, 8 H), 1.69 (ddd, J = 3.5, 9.8, 14.3 Hz, 1 H), 1.78 (ddd, J = 2.8,
9.2 Hz, 1 H), 1.90 (ddt, J = 8.4, 9.4, 12.6 Hz, 1 H), 2.13 (br, OH),
2.25–2.36 (m, 1 H), 2.45–2.51 (m, 2 H), 3.76–3.85 (m, 1 H), 4.70–
4.78 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.5, 25.0, 28.4, 28.8, 31.6,
37.9, 43.1, 68.3, 78.1, 177.2.
HRMS (ESI): m/z calcd for C11H20O3 + Na: 223.1310; found:
223.1336.
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Acknowledgment
P.A.N.R. and H.A. thank CSIR, New Delhi for the award of fel-
lowships. The correspondence author acknowledges the partial sup-
port by King Saud University for Global Research Network for
Organic Synthesis (GRNOS).
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Synthesis 2012, 44, 579–584
© Thieme Stuttgart · New York