Stereoselective total synthesis of (-)-colletol by Prins cyclisation

Article abstract of DOI:10.1055/S-0029-1218679

A simple and efficient asymmetric total synthesis of the bis-macrolactone (-)-colletol was accomplished, proving the versatility of the Prins cyclisation in natural product synthesis. The synthesis mainly relies upon reductive opening of a pyran ring, Mit

Full text of DOI:10.1055/S-0029-1218679

PAPER
1473
Stereoselective Total Synthesis of (–)-Colletol by Prins Cyclisation
Total
S
ynt
h
hesis of (–)-C
i
olleto
l
l
lu S. Yadav,* N. Mallikarjuna Reddy, P. Adi Narayana Reddy, Hissana Ather, Attaluri R. Prasad
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 23 November 2009; revised 16 December 2009
ic alcohol 15 and acetaldehyde in the presence of
trifluoroacetic acid6 to afford the trifluoroacetate of 2;
treatment of its crude with potassium carbonate in metha-
nol gave tetrahydropyrandiol 2 as the only isolable com-
Abstract: A simple and efficient asymmetric total synthesis of the
bis-macrolactone (–)-colletol was accomplished, proving the versa-
tility of the Prins cyclisation in natural product synthesis. The syn-
thesis mainly relies upon reductive opening of a pyran ring,
Mitsunobu inversion, the Wittig reaction, and Yamaguchi macro- pound in 55% yield. The stereochemical aspects of such
lactonisation as the key steps.
Prins cyclisations and structurally very close compounds
of 2were discussed in detail previously.5f Transformation
Key words: natural products, Prins cyclization, Mitsunobu reac-
tion, macrolactonization, lactones
of the primary hydroxy group of 2 into a tosylate was
achieved by the use of tosyl chloride (1.1 equiv) and tri-
ethylamine, and the secondary hydroxy group was pro-
tected as a methoxymethyl ether by reaction of 3 with
methoxymethyl chloride and N,N-diisopropylethylamine,
to result in intermediate 4. The tosyl group was substituted
by an iodo group by use of sodium iodide in acetone; this
was followed by reductive opening of the (iodometh-
yl)pyran to produce alcohol 6 with an anti-1,3-diol sys-
tem. Protection of the secondary hydroxy group in 6 as a
tert-butyldimethylsilyl ether was achieved by use of tert-
butyldimethylsilyl chloride and imidazole in dichlo-
romethane, to furnish 7 in 85% yield. Ozonolytic cleavage
of the olefinic bond of 77 was followed by Wittig olefina-
(–)-Colletol (III), a 14-membered bis-macrolactone, was
isolated from the fermentation broth of the plant pathogen
Colletotrichium capsici along with other bis-macrolac-
tones I, II, IV, and V (Figure 1) in 1973.1 Although no
biological activity has been reported for these macrolac-
tones, interest in these compounds was aroused by the re-
port of the isolation of grahamimycin A1, which showed
potent activity against bacteria, algae, and fungi.2,3 A fas-
cinating bis-macrolactone with a 1,3-diol system, for
which we have recently established a synthetic route by
Prins cyclisation, colletol4 (III) has inspired us to investi-
gate its synthesis.
O
COOH
X
Y
O
O
OH
colletalol (I)
H, OH H2
colletoketol (II)
colletol (III)
colletodiol (IV)
grahamimycin A1 (V)
O
H2
H, OH
O
H, OH
O
O
H, OH
H, OH
O
O
HO
MOMO
Y
X
O
O
O
O
13
O
Figure 1
III
Before undertaking the synthesis, a careful retrosynthetic
analysis was made (Scheme 1). We envisaged that the tar-
get molecule would be obtained by Yamaguchi macrolac-
tonisation of 13, which was regarded as being accessible
by Mitsunobu reaction between the two fragments A and
B. Fragment A could be obtained easily from pyran 2, by
a reductive opening followed by homologation, and in
turn pyranylmethanol 2 could be obtained by Prins cycli-
sation of known homoallylic alcohol 1 and acetaldehyde
according to our recently developed methodology.5 Frag-
ment B would be obtained from known homoallyl alcohol
9 after simple chemical modifications.
OH
OTBS
O
MOMO
+
EtO
OH
fragment B
fragment A
OH
MOMO
OH
9
6
OH
Our synthesis of fragment A of colletol (Scheme 2) com-
menced with Prins cyclisation between known homoallyl-
+
O
HO
HO
OH
O
SYNTHESIS 2010, No. 9, pp 1473–1478
x
x
.
x
x
.2
0
1
0
2
1
Advanced online publication: 19.02.2010
DOI: 10.1055/s-0029-1218679; Art ID: Z25009SS
Scheme 1 Retrosynthesis of colletol (III)
© Georg Thieme Verlag Stuttgart · New York

1474
J. S. Yadav et al.
PAPER
OH
OH
b
c
a
TsO
HO
HO
O
OH
O
1
2
3
OMOM
OMOM
MOMO
OH
e
d
f
TsO
I
6
O
O
4
5
O
MOMO
OTBS
MOMO
OTBS
h
g
A
EtO
7
8
Scheme 2 Synthesis of fragment A. Reagents and conditions: (a) MeCHO, TFA, CH2Cl2, 3 h, then K2CO3, MeOH, r.t., 0.5 h, 52%; (b) Et3N,
TsCl, CH2Cl2, 0 °C to r.t., 3 h, 95%; (c) MOMCl, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 3 h, 90%; (d) NaI, acetone, reflux, 24 h, 95%; (e) Zn,
EtOH, NaHCO3, reflux, 2 h, 92%; (f) DMAP, TBSCl, imidazole, CH2Cl2, 0 °C to r.t., 4 h, 85%; (g) O3, Ph3P, CH2Cl2, then Ph3P=CHCO2Et,
benzene, r.t., 74%; (h) NH4F, MeOH, reflux, 12 h, 86%.
tion with the stable ylide (ethoxycarbonylmethyl- yield. Acid 13 was macrolactonised under Yamaguchi’s
ene)triphenylphosphorane in benzene, to give a,b- conditions10 to afford the macrolactone 14, which, after
unsaturated ester 8.6 Deprotection of the tert-butyldimeth- treatment with hydrochloric acid, afforded (–)-colletol
ylsilyl ether was carried out by using ammonium fluoride (III) in 70% yield. The spectral and analytical data (1H
and methanol,4f to give fragment A in 86% yield.
and 13C NMR, IR, Rf, and [a]D) for the synthetic com-
pound were in accordance with the data reported in the lit-
erature.4
Synthesis of fragment B (Scheme 3) commenced from
commercially available optically active homoallylic alco-
hol 9.8 Compound 11 was obtained from 9 in a two-step In summary, we have described a stereoselective ap-
sequence, consisting of the same reagents and conditions proach to colletol from polyketide precursors, prepared by
as those described in Scheme 2 (for the synthesis of 8 Prins cyclisation according to our recently developed syn-
from 6). In the final step, ester 11 was hydrolysed in the thetic sequence. The approach can provide a means for
presence of sodium hydroxide and methanol–water to af- probing the structure–activity relationships of these and
ford the requisite acid B in 90% yield.
other related bioactive macrolides.1
OTBS
OH
OTBS
O
All reactions were carried out under an inert atmosphere unless
mentioned otherwise, and standard syringe–septa techniques were
followed. Solvents were dried and purified by conventional meth-
ods prior to use. The progress of all the reactions was monitored by
TLC, using glass plates precoated with silica gel 60 F254 to a thick-
ness of 0.5 mm (Merck). Column chromatography was performed
on silica gel (60–120 mesh) and neutral alumina, and Et2O, EtOAc,
and hexane were used as eluents. Optical rotation values were mea-
sured on a Perkin-Elmer P241 polarimeter and JASCO DIP-360
digital polarimeter at 25 °C, and IR spectra were recorded on a
a
b
c
B
OEt
9
10
11
Scheme 3 Synthesis of fragment B. Reagents and conditions: (a)
DMAP, TBSCl, imidazole, CH2Cl2, 0 °C to r.t., 85%; (b) O3, Ph3P,
CH2Cl2, then Ph3P=CHCO2Et, benzene, r.t., 98%; (c) 2 N aq NaOH,
MeOH–H2O (2:1), 6 h, 90%.
After construction of the two fragments A and B, they
were coupled under Mitsunobu conditions (Scheme 4).
Thus, acid B, upon treatment with alcohol A under stan-
dard Mitsunobu conditions9 (Ph3P, DEAD, THF),
smoothly formed ester 12. The tert-butyldimethylsilyl
group was deprotected, followed by hydrolysis of the es-
ter group, to form conjugated hydroxy acid 13 in 80%
1
Perkin-Elmer FT-IR spectrophotometer. H and 13C NMR spectra
were recorded on a Varian Gemini 200 MHz, Bruker Avance 300
MHz, Varian Unity 400 MHz, or Varian Inova 500 MHz spectro-
meter; TMS was used as an internal standard in CDCl3. Mass spec-
tra were recorded on Micro mass VG-7070 H (EI) and VG Autospec
M (MS–FAB) spectrometers.
O
OEt
COOH
OTBS
OH
O
O
b,c
a
d
ref. 4f
A +
B
colletol (III)
MOMO
MOMO
MOMO
O
O
O
O
O
O
12
14
13
Scheme 4 Coupling of fragments A and B. Reagents and conditions: (a) Ph3P, DEAD, then B, THF, 0 °C to r.t., 30 min, then r.t., 4 h, 75%;
(b) NH4F, MeOH, reflux, 6 h, 86%; (c) LiOH, THF–H2O (1:1), 6 h, 80%; (d) 2,4,6-Cl3C6H2COCl, Et3N, toluene, r.t., then DMAP, toluene,
110 °C, 60%.
Synthesis 2010, No. 9, 1473–1478 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (–)-Colletol
1475
(2S,4R,6S)-2-(Hydroxymethyl)-6-methyltetrahydro-2H-pyran-
4-ol (2)
crude by column chromatography (silica gel, EtOAc–hexane, 5:95)
afforded pure product 4.
TFA (21.50 mL) was added slowly to a soln of homoallylic alcohol
1 (1.5 g, 14.70 mmol) and acetaldehyde (3.8 g, 44.11 mmol) in
CH2Cl2 (50 mL) at 25 °C under a N2 atmosphere. The reaction mix-
ture was stirred for 3.0 h and then sat. aq NaHCO3 (150 mL) was
added and the pH was adjusted to >7 by the addition of Et3N. The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (4 × 50 mL). The organic layers were combined and the sol-
vent was removed under reduced pressure. The trifluoroacetate ob-
tained in this reaction was directly used in the next reaction without
purification. The residue was dissolved in MeOH (40 mL) and
stirred with K2CO3 (4.05 g) for 0.5 h. The MeOH was then removed
under reduced pressure and H2O (30 mL) was added. The mixture
was extracted with CH2Cl2 (3 × 30 mL) and the combined organic
layers were dried (Na2SO4) and the solvent was removed under re-
duced pressure. Purification of the crude by column chromatogra-
phy (silica gel, EtOAc–hexane, 6:4) yielded 2.
Yield: 1.85 g (90%); liquid; Rf = 0.5 (silica gel, EtOAc–hexane,
5:95); [a]D28 +7.60 (c 0.70, CHCl3).
IR (neat): 2924, 2852, 1598, 1451, 1361, 1178, 1039, 977, 817, 668,
555 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (d, J = 6.23 Hz, 3 H), 1.16–
1.26 (m, 2 H), 1.87–1.96 (dd, 2 H), 2.43 (s, 3 H), 3.33 (s, 3 H), 3.35–
3.43 (m, 2 H), 3.51–3.74 (m, 2 H), 3.93–4.04 (m, 2 H), 4.64 (s, 2 H),
7.32 (d, J = 7.93 Hz, 2 H), 7.77 (d, J = 8.49 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.44, 21.56, 34.15, 39.86, 55.24,
71.90, 72.02 72.31, 72.86, 94.40, 127.95, 129.71, 132.98, 144.70.
ESI-MS: m/z = 345 [M + H]+, 362 [M + NH4]+.
(2S,4R,6S)-2-(Iodomethyl)-4-(methoxymethoxy)-6-methyltet-
rahydro-2H-pyran (5)
NaI (6.97 g, 46 mmol) was added to a soln of 4 (1.6 g, 4.6 mmol) in
acetone (40 mL) and the mixture was heated to reflux for 24 h. The
acetone was removed under reduced pressure. H2O (40 mL) and
CH2Cl2 (3 × 40 mL) were added to the residue, the organic layer was
separated, dried (Na2SO4), and concentrated, and the crude was
chromatographed (silica gel, EtOAc–hexane, 1:32) to afford 5.
Yield: 1.32 g (52%); colourless liquid; Rf = 0.3 (silica gel, EtOAc–
hexane, 6:4); [a]D20 +9.7 (c 1.0, CHCl3).
IR (neat): 3398, 2925, 2856, 1452, 1363, 1178, 1030, 976 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.09–1.20 (m, 2 H), 1.22 (d,
J = 6.04 Hz, 3 H), 1.78–1.99 (m, 2 H), 3.38–3.62 (m, 4 H), 3.75–
3.86 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.6, 36.5, 42.3, 65.8, 67.3, 67.8,
72.1.
ESI-HRMS: m/z [M + Na]+ calcd for C7H14O3Na: 169.0840; found:
169.0839.
Yield: 1.32 g (95%); colourless liquid; Rf = 0.7 (silica gel, EtOAc–
hexane, 1:9); [a]D28 +15.30 (c 1.09, CHCl3).
IR (neat): 2939, 2885, 1379, 1144, 1099, 914 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (d, J = 6.04 Hz, 3 H), 1.88–
1.97 (m, 2 H), 2.16–2.25 (m, 2 H), 3.16–3.21 (dd, J = 2.45, 5.85 Hz,
2 H), 3.31–3.34 (m, 1 H), 3.36 (s, 3 H), 3.45–3.56 (m, 1 H), 3.63–
3.80 (m, 1 H), 4.69 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 8.84, 21.57, 37.92, 39.83, 55.32,
72.10, 72.51, 75.02, 94.48.
ESI-MS: m/z = 318 [M + NH4]+.
[(2S,4R,6S)-4-Hydroxy-6-methyltetrahydro-2H-pyran-2-
yl]methyl 4-Toluenesulfonate (3)
Et3N (1.38 mL, 13.6 mmol), followed by TsCl (1.56 g, 8.2 mmol)
were added over 2 h to a soln of diol 2 (1.0 g, 6.8 mmol) in anhyd
CH2Cl2 (15 mL) at 0 °C. The reaction mixture was allowed to warm
to r.t. and stirred for 3 h. The reaction mixture was treated with 1 M
aq HCl (7 mL) and extracted with CH2Cl2 (3 × 25 mL). The organic
layer was washed with sat. aq NaHCO3 (15 mL) and H2O (15 mL).
The combined organic phases were dried (Na2SO4) and concentrat-
ed under reduced pressure. Flash chromatography (silica gel,
EtOAc–hexane, 3:7) of the crude afforded tosylate 3.
(2S,4S)-4-(Methoxymethoxy)hept-6-en-2-ol (6)
Commercially obtained Zn dust (5.04 g, 80 mmol) was added to a
soln of iodide 5 (1.2 g, 4.0 mmol) in EtOH (60 mL). The mixture
was refluxed for 2 h and then cooled to 25 °C. Addition of solid
NH4Cl (6.5 g) and Et2O (100 mL) followed by stirring for 5 min
gave a grey suspension. The suspension was filtered through a pad
of Celite and the filtrate was concentrated in vacuo. Purification by
flash chromatography (silica gel, EtOAc–hexane, 1:9) gave 6.
Yield: 1.95 g (95%); gummy liquid; Rf = 0.6 (silica gel, EtOAc–
hexane, 6:4); [a]D20 +3.6 (c 1.25, CHCl3).
IR (neat): 3410, 2926, 2855, 1741, 1597, 1451, 1358, 1176, 974
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15 (d, J = 5.8 Hz, 3 H), 1.37–
1.41 (m, 2 H), 1.83–1.96 (m, 2 H), 2.46 (m, 3 H), 3.32–3.45 (m, 1
H), 3.48–3.61 (m, 1 H), 3.67–3.83 (m, 1 H), 3.90–4.02 (m, 2 H),
7.32 (d, J = 8.08 Hz, 2 H), 7.79 (m, J = 8.08 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.32, 21.51, 36.45, 42.26, 67.30,
71.78, 72.02, 72.71, 127.84, 129.70, 132.73, 144.75.
ESI-HRMS: m/z [M + H]+ calcd for C14H21O5S: 301.1104; found:
301.1097.
Yield: 0.64 g (92%); colourless liquid; Rf = 0.6 (silica gel, EtOAc–
hexane, 3:7); [a]D20 +69.50 (c 1.30, CHCl3).
IR (neat): 3443, 3076, 2934, 1641, 1442, 1373, 1099, 1039 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15 (d, J = 6.61 Hz, 3 H), 1.49–
1.55 (m, 2 H), 2.20–2.37 (m, 2 H), 2.55 (br, OH), 3.38 (s, 3 H),
3.73–3.88 (m, 1 H), 3.92–4.09 (m, 1 H), 4.57–4.67 (m, 2 H), 5.01–
5.10 (m, 2 H), 5.64–5.85 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.35, 39.34, 42.86, 55.85, 64.04,
75.26, 96.26, 117.59, 134.26.
ESI-MS: m/z = 175 [M + H]+, 192 [M + NH4]+.
[(2S,4R,6S)-4-(Methoxymethoxy)-6-methyltetrahydro-2H-pyr-
an-2-yl]methyl 4-Toluenesulfonate (4)
(tert-Butyl){[(2S,4S)-4-(methoxymethoxy)hept-6-en-2-
yl]oxy}dimethylsilane (7)
DIPEA (6.30 mL, 36.0 mmol), DMAP (cat.), and MOMCl (1.44 g,
18.0 mmol) were added successively to alcohol 3 (1.8 g, 9.13 mmol)
in anhyd CH2Cl2 (20 mL) at 0 °C, and the resulting mixture was
stirred for 3 h at r.t. and then quenched by the addition of H2O (10
mL) and extracted with CH2Cl2 (3 × 20 mL). The organic extracts
were washed with brine (10 mL), dried (Na2SO4), and concentrated
under reduced pressure to remove the solvent. Purification of the
DMAP (10 mg), imidazole (0.78 g, 11.4 mmol), in one portion, and
TBSCl (0.86 g, 5.73 mmol), in two portions, were sequentially add-
ed to a soln of 6 (0.5 g, 2.8 mmol) in anhyd CH2Cl2 (12 mL) at 0 °C.
The reaction mixture was stirred for 4 h while slowly warming to
r.t. It was quenched with sat. aq NH4Cl (10 mL), diluted with
CH2Cl2 (20 mL), washed with brine (10 mL), dried (Na2SO4), and
concentrated in vacuo. Purification of the crude by column chroma-
tography (silica gel, EtOAc–hexane, 1:32) afforded TBS ether 7.
Synthesis 2010, No. 9, 1473–1478 © Thieme Stuttgart · New York

1476
J. S. Yadav et al.
PAPER
Yield: 0.70 g (85%); colourless oil; Rf = 0.7 (silica gel, EtOAc–
hexane, 1:9); [a]D20 +19.31 (c 4.32, CHCl3).
13C NMR (75 MHz, CDCl3): d = 14.20, 23.48, 37.80, 43.31, 55.87,
60.26, 63.87, 74.44, 96.35, 123.92, 144.42, 166.28.
IR (neat): 2932, 2892, 2858, 1466, 1374, 1253, 1148, 1097, 1043,
916, 833, 773 cm–1.
MS (ESI): 247 [M + 1]+, 269 [M + Na]+.
tert-Butyldimethyl[(S)-pent-4-en-2-yloxy]silane (10)
Compound 10 was prepared from 9 according to the same proce-
dure used for the synthesis of 7 from 6.
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 6 H), 0.88 (s, 9 H), 1.14
(d, J = 6.04 Hz, 3 H), 1.48–1.54 (m, 2 H), 2.27–2.32 (m, 2 H), 3.34
(s, 3 H), 3.64–3.75 (m, 1 H), 3.88–4.01 (m, 1 H), 4.63 (s, 2 H), 5.02–
5.07 (m, 2 H), 5.70–5.84 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = –4.76, –3.92, 17.97, 24.49, 25.84,
39.79, 44.98, 55.46, 65.60, 75.15, 96.10, 117.07, 134.50.
Yield: 0.98 g (85%); colourless oil; Rf = 0.8 (silica gel, EtOAc–
hexane, 1:9); [a]D28 –3.0 (c 0.87, CHCl3).
IR (neat): 2955, 2931, 1467, 1254, 1051 cm–1.
ESI-MS: m/z = 289 [M + H]+, 311 [M + Na]+.
1H NMR (300 MHz, CDCl3): d = 0.02 (s, 3 H), 0.05 (s, 3 H), 0.87
(d, 9 H), 1.13 (d, J = 6.04 Hz, 3 H), 2.10–2.24 (m, 2 H), 3.79–3.89
(m, 1 H), 4.98–5.06 (m, 2 H), 5.74–5.88 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = –4.70, –4.52, 23.41, 25.70, 25.87,
44.28, 68.42, 116.51, 135.63.
Ethyl (2E,5S,7S)-7-(tert-Butyldimethylsiloxy)-5-(methoxy-
methoxy)oct-2-enoate (8)
O3 was bubbled through a soln of 7 (0.6 g, 2.08 mmol) in CH2Cl2 (8
mL) at –78 °C until no unreacted starting material was observed.
The reaction mixture was purged with N2 to remove the excess O3
and cooled to 0 °C; Ph3P (1.09 g, 4.16 mmol) was added and the
mixture was stirred for 2 h. The mixture was concentrated in vacuo.
After the addition of hexane (30 mL), the mixture was filtered
through a pad of Celite. The residue was washed with hexane. The
filtrate was dried (Na2SO4) and concentrated under reduced pres-
sure, and the crude aldehyde obtained was subjected to the next re-
action without further purification.
Ethyl (2E,5S)-5-(tert-Butyldimethylsiloxy)hex-2-enoate (11)
Compound 11 was prepared from 10 according to the same proce-
dure used for the synthesis of 8 from 7.
Yield: 603 mg (98%); colourless oil; Rf = 0.7 (silica gel, EtOAc–
hexane, 1:9); [a]D20 –10.4 (c 2.22, CHCl3).
IR (neat): 2958, 2932, 1722, 1655, 1259, 1175, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.04 (s, 6 H), 0.88 (s, 9 H), 1.16,
(d, J = 6.04 Hz, 3 H), 1.28 (t, J = 7.55, 14.35 Hz, 3 H), 2.25–2.33
(m, 2 H), 3.84–3.95 (m, 1 H), 4.13–4.20 (q, J = 7.55, 14.35 Hz, 2
H), 5.79 (d, J = 15.10 Hz, 1 H), 6.83–6.95 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = –4.89, –4.58, 14.22, 18.03, 23.75,
25.75, 42.39, 60.06, 67.60, 123.14, 145.98, 166.37.
ESI-MS: m/z = 295 [M + Na]+, 273 [M + H]+.
Ph3P=CHCO2Et (1.44 g, 4.14 mmol) was added in one portion to a
soln of the crude aldehyde in anhyd benzene (12 mL) at r.t. The
mixture was stirred for 2 h at the same temperature. The benzene
was removed under reduced pressure, EtOAc (15 mL) was added,
and the mixture was washed with brine (5 mL), dried (Na2SO4), and
concentrated in vacuo. Purification by column chromatography (sil-
ica gel, EtOAc–hexane, 1:24) afforded 8.
Yield: 0.56 g (74%, 2 steps); colourless oil; Rf = 0.7 (silica gel,
EtOAc–hexane, 1:9); [a]D28 +12.50 (c 1.96, CHCl3).
IR (neat): 2933, 2857, 1722, 1655, 1097, 775 cm–1.
(2E,5S)-5-(tert-Butyldimethylsiloxy)hex-2-enoic Acid (B)
To a soln of ester 11 (0.5 gm) in MeOH (30 mL), 2 N aq NaOH (13
mL) was added. The reaction mixture was stirred for 6 h at r.t., acid-
ified to pH 4 by the addition of 1 M aq HCl, and extracted with
EtOAc (2 × 15 mL). Removal of the solvent under reduced pressure
followed by flash chromatography (silica gel, EtOAc–hexane, 1:9)
afforded B.
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 6 H), 0.88 (s, 9 H), 1.14
(d, J = 6.04 Hz, 2 H), 1.29 (t, J = 7.55, 14.35 Hz, 3 H), 1.48–1.55
(ddd, J = 3.75, 8.30 Hz, 2 H), 2.35–2.55 (m, 2 H), 3.34 (s, 3 H),
3.75–3.84 (m, 1 H), 3.90–3.98 (m, 1 H), 4.13–4.20 (q, J = 7.50,
14.35 Hz, 2 H), 4.63 (d, J = 4.53 Hz, 2 H), 5.82 (d, J = 15.86 Hz, 1
H), 6.86–6.97 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = –4.75, –3.91, 14.20, 23.70, 24.46,
25.83, 38.25, 45.18, 55.61, 60.11, 65.49, 74.57, 96.30, 123.57,
144.93, 166.22.
Yield: 403 mg (90%); colourless liquid; Rf = 0.35 (silica gel,
EtOAc–hexane, 4:6); [a]D28 –7.6 (c 0.81, CHCl3).
IR (neat): 3442, 2931, 2858, 1701, 1653, 1255, 1255, 835, 775 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 6 H), 0.88 (s, 9 H), 1.16
(d, J = 6.04 Hz, 3 H), 2.32–2.37 (m, 2 H), 3.91–3.97 (m, 1 H), 5.84
(d, J = 15.64 Hz, 1 H), 7.03–7.12 (m, 1 H).
ESI-MS: m/z = 388 [M + Na]+, 361 [M + H]+.
13C NMR (75 MHz, CDCl3): d = –4.84, –4.56, 18.04, 23.78, 25.77,
Ethyl (2E,5S,7S)-7-Hydroxy-5-(methoxymethoxy)oct-2-enoate
(A)
42.48, 67.47, 122.49, 149.03, 171.52.
ESI-HRMS: m/z [M + Na]+ calcd for C12H24NaO3Si: 267.1392;
found: 267.1383.
NH4F (0.41 g, 11.08 mmol) was added to a soln of compound 8
(0.40 g, 1.1 mmol) in anhyd MeOH (12 mL). The reaction mixture
was refluxed for 12 h. After completion of the reaction, the mixture
was washed with brine (5 mL), dried (Na2SO4), and concentrated in
vacuo. Purification by column chromatography (silica gel, EtOAc–
hexane, 1:2.5) afforded A.
Ethyl (2E,5S,7R)-7-[(2E,5R)-5-(tert-butyldimethylsiloxy)hex-2-
enoyloxy]-5-(methoxymethoxy)oct-2-enoate (12)
DEAD (0.63 g, 3.65 mmol) was added by syringe to a stirred mix-
ture of A (0.3 g, 1.20 mmol), Ph3P (0.96 g, 3.6 mmol), and B (0.36
g, 1.46 mmol) in anhyd THF (10 mL) at 0 °C. The reaction mixture
was then stirred for 4 h at r.t., diluted with H2O (10 mL), and ex-
tracted with EtOAc (2 × 15 mL). Removal of the solvent under re-
duced pressure followed by flash chromatography (silica gel,
EtOAc–hexane, 1:20) afforded 12.
Yield: 235 mg (86%); colourless oil; Rf = 0.35 (silica gel, EtOAc–
hexane, 6:4); [a]D28 +28.5 (c 1.24, CHCl3).
IR (neat): 3475, 2936, 1717, 1653, 1371, 1270, 1154, 1098, 1037,
916 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.18 (d, J = 6.23 Hz, 3 H), 1.24–
1.30 (t, J = 7.17, 15.10 Hz, 3 H), 1.50–1.64 (m, 2 H), 2.43–2.48 (m,
2 H), 3.39 (s, 3 H), 3.91–3.98 (m, 1 H), 3.99–4.07 (m, 1 H), 4.14–
4.21 (q, J = 6.98, 13.07 Hz, 2 H), 4.66 (s, 2 H), 5.86 (d, J = 15.68
Hz, 1 H), 6.86–6.97 (m, 1 H).
Yield: 0.43g (75%); colourless liquid; Rf = 0.65 (silica gel, EtOAc–
hexane, 3:7); [a]D28 –1.8 (c 0.66, CHCl3).
IR (neat): 2927, 2855, 1721, 1655, 1462, 1261, 1371, 1261, 1174,
1097, 1038, 836, 776 cm–1.
Synthesis 2010, No. 9, 1473–1478 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (–)-Colletol
1477
1H NMR (300 MHz, CDCl3): d = 0.04 (s, 6 H), 0.88 (s, 9 H), 1.16
(d, J = 6.04 Hz, 3 H), 1.24–1.31 (m, 6 H), 1.56–1.73 (m, 1 H), 2.28–
2.34 (m, 2 H), 2.38–2.53 (m, 2 H), 3.36 (s, 3 H), 3.70–3.78 (m, 1 H),
3.95–3.89 (m, 1 H), 4.14–4.21 (q, J = 6.97, 13.97 Hz, 2 H), 4.62 (s,
2 H), 5.04–5.12 (m, 2 H), 5.83 (dd, J = 15.8 Hz, 2 H), 6.86–6.98 (m,
2 H).
13C NMR (75 MHz, CDCl3): d = –4.26, –4.42, 14.35, 18.14, 20.35,
23.93, 25.90, 29.76, 37.22, 40.76, 42.53, 55.72, 67.63, 73.42, 96.20,
123.44, 124.02, 144.50, 146.10, 165.56, 166.02.
in THF (5 mL). The reaction mixture was stirred for 2 h under an
argon atmosphere. Then a soln of DMAP (0.33 g, 2.72 mmol) in tol-
uene (15 mL) was heated at 100 °C for 1 h, and the above-prepared
soln of acid 13 in toluene (75 mL) was added to the DMAP–toluene
soln. The whole reaction mixture was stirred for 12 h at 100 °C. Af-
ter completion of the reaction, the mixture was washed with 7% aq
NaHCO3 (20 mL), 2 M aq HCl (20 mL), and brine (2 × 30 mL), and
extracted with EtOAc (2 × 50 mL). Removal of the solvent under
reduced pressure followed by flash chromatography (silica gel,
EtOAc–hexane, 1:3) afforded 14.
ESI-MS: m/z = 495 [M + Na]+.
Yield: 0.085 g (85%); colourless liquid; Rf = 0.62 (silica gel,
EtOAc–hexane, 4:6); [a]D20 –5.6 (c 0.7, CHCl3).
IR (neat): 2927, 1723, 1653, 1265, 1172, 1035 cm–1.
Ethyl (2E,5S,7R)-7-[(2E,5R)-5-Hydroxyhex-2-enoyloxy]-5-
(methoxymethoxy)oct-2-enoate (12a)
NH4F (0.31 g, 8.46 mmol) was added to a soln of 12 (0.4 g, 0.84
mmol) in anhyd MeOH (6 mL). The reaction mixture was refluxed
for 12 h, washed with H2O (15 mL), and extracted with EtOAc
(2 × 15 mL). Removal of the solvent under reduced pressure fol-
lowed by flash chromatography (silica gel, EtOAc–hexane, 1:3) af-
forded 12a.
1H NMR (200 MHz, CDCl3): d = 1.3 (d, J = 6.79 Hz, 3 H), 1.36 (d,
J = 6.79 Hz, 3 H), 1.66 (qd, J = 3.77, 15.86 Hz, 1 H), 1.91 (td,
J = 3.70 Hz, 15.80, 1 H), 2.15–2.36 (m, 2 H), 2.51 (td, J = 3.02 Hz,
11.33, 1 H), 2.66–2.76 (m, 1 H), 3.39 (s, 3 H), 3.81–3.89 (m, 1 H),
4.72 (d, J = 3.77 Hz, 2 H), 5.10–5.29 (m, 2 H), 5.72–5.83 (dt,
J = 4.5, 15.86 Hz, 2 H), 6.62–6.74 (m, 2 H).
Yield: 0.27 g (86%); colourless liquid; Rf = 0.35 (silica gel, EtOAc–
hexane, 4:6); [a]D28 –8.4 (c 0.91, CHCl3).
13C NMR (75 MHz, CDCl3): 18.21, 20.48, 36.94, 38.69, 40.81,
55.82, 68.0, 68.33, 74.24, 95.77, 125.06, 126.11, 143.7, 144.0,
165.20, 166.12.
ESI-HRMS: m/z [M + NH4]+ calcd for C16H28NO6: 330.1911;
found: 330.1913.
IR (neat): 3480, 2975, 2934, 1716, 1653, 1450, 1268, 1174, 1099,
984 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23–1.29 (m, 9 H), 1.58–1.76 (m,
1 H), 1.90–2.01 (m, 1 H), 2.33–2.38 (m, 2 H), 3.36 (s, 3 H), 3.72–
3.80 (m, 1 H), 3.93–4.0 (m, 1 H), 4.10–4.21 (m, 2 H), 4.63 (s, 2 H),
5.03–5.13 (m, 1 H), 5.88 (d, J = 15.674 Hz, 2 H), 6.87–7.00 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 14.22, 20.23, 23.26, 37.18, 40.61,
41.85, 60.25, 66.68, 67.93, 72.23, 95.41, 123.94, 144.52, 165.63,
166.24.
Colletol (III)
To a soln of 14 (0.06 g, 0.19 mmol) in THF (5 mL), 2 M aq HCl
(1 mL) was added. The reaction mixture was stirred for 12 h, neutr-
alised with NaHCO3 soln and extracted with EtOAc (2 × 10 mL).
Removal of the solvent under reduced pressure followed by flash
chromatography (silica gel, EtOAc–hexane, 1:2) afforded III.
Yield: 0.036 g (70%); white solid; Rf = 0.32 (silica gel, EtOAc–
hexane, 4:6); [a]D28 –28.7 (c 0.44, CHCl3).
ESI-HRMS: m/z [M + Na]+ calcd for C18H30O7Na: 381.1889; found:
381.1890.
IR (KBr): 3436, 2925, 2853, 1717, 1653, 1318, 1263, 1227, 1177,
1108, 1056, 983, 756 cm–1.
(2E,5S,7R)-7-[(2E,5R)-5-Hydroxyhex-2-enoyloxy]-5-(methoxy-
methoxy)oct-2-enoic Acid (13)
1H NMR (300 MHz, CDCl3): d = 1.29 (d, J = 5.28 Hz, 3 H), 1.35 (d,
J = 6.04 Hz, 3 H), 1.51 (qd, J = 3.0, 15.86 Hz, 1 H), 1.67 (br, OH, 1
H), 1.89–1.97 (m, 1 H), 2.15–2.35 (m, 2 H), 2.43–2.54 (m, 2 H),
3.97–4.06 (m, 1 H), 5.17–5.28 (m, 2 H), 5.68–5.82 (dt, J = 8.30,
15.86 Hz, 2 H), 6.70 (ddd, J = 6.04, 10.53, 15.86 Hz, 1 H), 6.70
(ddd, J = 4.5, 9.06, 15.86 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 18.15, 20.56, 29.70, 40.05, 40.30,
40.07, 68.14, 68.40, 125.06, 126.10, 143.74, 144.03, 165.24,
165.93.
LiOH (16 mg, 0.66 mmol) was added to a soln of 12a (0.25 g, 0.69
mmol) in THF–H2O (1:1), and the reaction mixture was stirred for
6 h. The mixture was acidified to pH 4 by the addition of 1 M aq
HCl, and diluted with EtOAc (20 mL). The layers were separated
and the organic layer was washed with brine (2 × 10 mL) and dried
(Na2SO4). Removal of the solvent under reduced pressure followed
by flash chromatography (silica gel, EtOAc–hexane, 2:1) afforded
13a.
Yield: 0.184 g (80%); colourless liquid; Rf = 0.3 (silica gel, EtOAc–
hexane, 7:3); [a]D28 –7.5 (c 0.49, CHCl3).
ESI-HRMS: m/z [M + Na]+ calcd for C14H20NaO5: 291.1208; found:
291.1194.
IR (neat): 3427, 2925, 2853, 1709, 1653, 1264, 1174, 1100, 1033,
983 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (d, J = 6.23 Hz, 2 H), 1.28 (d,
J = 6.23 Hz, 2 H), 1.62–1.74 (m, 1 H), 1.86–2.02 (m, 1 H), 2.31–
2.42 (m, 2 H), 2.44–2.58 (m, 2 H), 3.36 (s, 3 H), 3.74–3.82 (m, 1 H),
3.92–4.03 (m, 1 H), 4.64 (d, J = 2.64 Hz, 2 H), 5.03–5.14 (m, 1 H),
5.88 (dd, J = 1.70, 15.67 Hz, 2 H), 6.90–7.11 (m, 2 H).
Acknowledgment
N.M.R., P.A.N.R., and H.A. thank the CSIR, New Delhi for the
award of fellowships and also thank the DST for the financial assi-
stance under the J. C. Bose Fellowship Science.
13C NMR (75 MHz, CDCl3): d = 20.24, 20.75, 23.18, 37.28, 40.62,
41.77, 55.75, 66.79, 67.92, 73.16, 95.40, 123.17, 123.96, 145.30,
147.61, 165.74, 171.03, 277.67.
ESI-HRMS: m/z [M + Na]+ calcd for C16H26NaO7: 353.1576; found:
353.1580.
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Synthesis 2010, No. 9, 1473–1478 © Thieme Stuttgart · New York

1478
J. S. Yadav et al.
PAPER
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Synthesis 2010, No. 9, 1473–1478 © Thieme Stuttgart · New York