Stereoselective Synthesis of (10 S,12 S)-10-Hydroxy-12-methyl-1-oxacyclododecane-2,5-dione via Prins Cyclization

Article abstract of DOI:10.1055/s-0029-1217107

The total synthesis of (10S,12S)-10-hydroxy-12-methyl-1-oxacyclododecane-2,5-dione is described proving the versatility of the Prins cyclization in natural products synthesis. The approach is convergent and highly stereoselective. Prins cyclization, ester

Full text of DOI:10.1055/s-0029-1217107

PAPER
73
Stereoselective Synthesis of (10S,12S)-10-Hydroxy-12-methyl-1-oxacyclo-
dodecane-2,5-dione via Prins Cyclization
(10
S,12
S
)-
.
10-Hydroxy
S
-12-methyl-1-
.
oxacyclodod
Y
ecane-2,5-dione adav,* N. Thrimurtulu, M. Venkatesh, K. V. Raghavendra Rao, A. R. Prasad, B. V. Subba Reddy
Division of Organic Chemistry I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 29 July 2009; revised 26 August 2009
O
O
O
O
Abstract: The total synthesis of (10S,12S)-10-hydroxy-12-methyl-
1-oxacyclododecane-2,5-dione is described proving the versatility
of the Prins cyclization in natural products synthesis. The approach
is convergent and highly stereoselective. Prins cyclization, esterifi-
cation, ring-closing metathesis and oxidation reactions are utilized
as key steps in the synthesis of this macrolactone.
1
12
10
OH
OH
5
O
O
2
1
proposed
revised
Key words: Prins cyclization, esterification, ring-closing metathe-
sis, macrolactone
Figure 1
In our retrosynthetic analysis (Scheme 1), we envisaged
that the target molecule 1 could be achieved from 9
through ring-closing metathesis (RCM). Compound 9
could be obtained from alcohol 8 and acid 17 by an ester-
ification reaction. We proposed to obtain the protected
1,3-diol 8 from the 2,4,6-trisubstituted pyran 4, which in
turn could be obtained via Prins cyclization of (2S)-pent-
4-ene-1,2-diol and acetaldehyde. Compound 17 could be
obtained from the pent-4-en-1-ol derivative 13b.
(10S,12S)-10-Hydroxy-12-methyl-1-oxacyclododecane-
2,5-dione, whose absolute stereochemistry of the two hy-
droxy functionalities at C10 and C12 was originally as-
signed as depicted in 1 (Figure 1), was isolated from the
endophytic fungal strain Cladosporium tenuissimum
LR463 of Maytenus hookeri.1 It has been found to induce
rapid systematic defense responses in plants, i.e. the pro-
duction of peroxidase, phenylalanine ammonia lyase, lig-
nin and salicylic acid. Recently, the revised structure of
the macrolide has been reported after synthesis of both the
natural product, (10S,12R)-10-hydroxy-12-methyl-1-oxa-
cyclododecane-2,5-dione (2), and its C12 epimer 1.2
Accordingly, the total synthesis of 1 began with the chiral
homoallylic alcohol 3 (Scheme 2). Copper-mediated regio-
selective ring opening5 of benzyl (S)-(+)-glycidyl ether6
with vinylmagnesium bromide, followed by debenzyla-
tion with lithium or sodium in liquid ammonia, gave the
homoallylic alcohol 3. Prins cyclization of compound 3
with acetaldehyde in the presence of trifluoroacetic acid,
followed by hydrolysis of the resulting trifluoroacetate,
gave the trisubstituted pyran 4 in 52% yield.7 The stereo-
chemistry of compound 4 was assumed to be in the antic-
ipated line, as it has been well examined and established
previously.3,4 Furthermore, it was proved after elaborating
compound 4 to the target molecule, which was identical in
all respects to the reported structure. Tosylation of com-
pound 4 with 1.1 equivalents of tosyl chloride in the pres-
The Prins cyclization has emerged as a powerful synthetic
tool for the construction of multisubstituted tetrahydropy-
ran derivatives and has been utilized in the synthesis of
several natural products.3 Our group has made a signifi-
cant effort to explore the utility of the Prins cyclization for
the synthesis of various polyketide intermediates which
have subsequently been applied to the synthesis of some
natural products.4 As a part of our interest in the synthesis
of biologically active molecules, herein we report the syn-
thesis of (10S,12S)-10-hydroxy-12-methyl-1-oxacyclo-
dodecane-2,5-dione (1).
OH
TBSO
OH
O
O
O
O
OH
OTBS
O
8
OH
+
4
BnO
OBn
O
OP
OH
1
9
O
13b P = THP
17
Scheme 1 Retrosynthetic analysis
SYNTHESIS 2010, No. 1, pp 0073–0078
x
x
.
x
x
.2
0
0
9
Advanced online publication: 24.11.2009
DOI: 10.1055/s-0029-1217107; Art ID: Z15909SS
© Georg Thieme Verlag Stuttgart · New York

74
J. S. Yadav et al.
PAPER
OH
OH
O
c
b
a
OH
OTs
OH
OH
O
3
5
4
OTBS
OTBS
OH OTBS
f
d
e
OTs
I
O
O
8
6
7
O
O
O
O
O
O
OTBS
OTBS
g
OTBS
h
BnO
BnO
HO
OH
10
11
9
O
O
O
O
i
OTBS
j
O
O
12
1
Scheme 2 Reagents and conditions: a) CH3CHO, TFA, CH2Cl2, then K2CO3, MeOH, 52%; b) TsCl, Et3N, CH2Cl2, 96%; c) TBSCl, DMAP,
imidazole, CH2Cl2, 97%; d) NaI, acetone, reflux, 24 h, 94%; e) Zn, EtOH, reflux, 1 h, 96%; f) acid 17, DCC, DMAP, CH2Cl2, 6 h, 85%; g)
Grubbs II catalyst, CH2Cl2, reflux, 12 h, 65%; h) Pd/C, MeOH, 6 h, 85%; i) DMP, CH2Cl2, 2 h, 92%; j) TBAF, THF, 0 °C, 83%.
ence of triethylamine in dichloromethane afforded the rahydropyranyl ether 13b, which upon epoxidation with
corresponding primary tosylate 5 in 96% yield.8 TBS pro- m-chloroperoxybenzoic acid resulted in the terminal
tection of the secondary alcohol of 5 with tert-butyldi- epoxide 14 (Scheme 3). Regioselective opening6 of the
methylsilyl chloride, 4-(dimethylamino)pyridine and epoxide 14 with vinylmagnesium bromide gave the sec-
imidazole gave the corresponding TBS ether 6. Treatment ondary alcohol 15. Protection of the free hydroxy group of
of tosylate 6 with sodium iodide in refluxing acetone gave 15 as its benzyl ether using benzyl bromide in the pres-
the corresponding iodo compound 7. Exposure of com- ence of sodium hydride and a catalytic amount of tetrabu-
pound 7 to unactivated zinc in refluxing ethanol gave the tylammonium iodide, followed by deprotection of the
key intermediate 8 (anti-1,3-diol) in 96% yield.
tetrahydropyranyl ether with p-toluenesulfonic acid in
methanol, gave the primary alcohol 16b. Oxidation of the
primary alcohol with Dess–Martin periodinane (DMP) in
dichloromethane, followed by further oxidation of the re-
sulting crude aldehyde with sodium chlorite and sodium
dihydrogen phosphate, furnished benzyloxy acid 17
(78%), the key component used in the formation of bis-
olefin 9 (see Scheme 2).
Esterification of the free hydroxy group of 8 with 4-(ben-
zyloxy)hept-6-enoic acid (17) in the presence of N,N¢-di-
cyclohexylcarbodiimide and a catalytic amount of 4-
(dimethylamino)pyridine gave the diene 92 and set the
stage for macrocyclization by RCM.
Compound 17 was synthesized starting from pent-4-en-1-
ol (13a); accordingly, alcohol 13a was protected as its tet-
OH
O
b
c
OP
OP
OP
OP
15
13a
14
P = H
a
13b P = THP
OBn
OBn
f
d
OH
O
16 a
16 b
P = THP
P = H
17
e
Scheme 3 Reagents and conditions: a) DHP, PTSA, CH2Cl2, 98%; b) MCPBA, NaHCO3, CH2Cl2, 0 °C to r.t., 89%; c) CH2=CHMgBr, CuCN,
–78 to –40 °C, 4 h, 80%; d) BnBr, NaH, TBAI, THF, 0 °C to r.t., 94%; e) PTSA, MeOH, 92%; f) i) DMP, CH2Cl2, 95%; ii) NaClO2, NaH2PO4,
78%.
Synthesis 2010, No. 1, 73–78 © Thieme Stuttgart · New York

PAPER
(10S,12S)-10-Hydroxy-12-methyl-1-oxacyclododecane-2,5-dione
75
The residue was dissolved in MeOH (40 mL) and stirred with
K2CO3 (8.11 g) for 0.5 h. The MeOH was then removed under re-
duced pressure and H2O (30 mL) was added. The mixture was ex-
tracted with CH2Cl2 (3 × 30 mL), the combined organic layers were
dried (Na2SO4) and the solvent was removed under reduced pres-
sure. Purification of the crude product by column chromatography
on silica gel (EtOAc–hexane, 8:2) gave 4 as a colorless liquid; yield:
2.23 g (52%).
Compound 9 possessed all the structural requirements as
well as the sense of chirality to be converted into the target
macrolide via RCM. The RCM reaction provides a re-
markable scope for the synthesis of medium-sized rings
and macrocyclic products and has been used extensive-
ly.4g,9 The presence of a suitable functionality and its dis-
tance from the olefins play key roles in the success of the
metathesis reaction. It has been reported2 that the RCM re-
action proceeds satisfactorily with substrates possessing a
hept-6-enoate moiety, which is present in the dienic deriv-
ative 9. Thus, treatment of the diene 9 with 5 mol%
Grubbs II catalyst under high dilution conditions in
CH2Cl2 gave compound 10 exclusively in 65% yield
(Scheme 2).2 Treatment of the cyclic ester 10 with palla-
dium on carbon in methanol afforded 11 (85%) wherein
the two reactions, benzyl deprotection along with reduc-
tion of the double bond, were accomplished in a single
step. The resulting secondary hydroxy was oxidized using
Dess–Martin periodinane in dichloromethane to give the
ketone 12 (92%). Subsequent deprotection of the TBS
ether by tetrabutylammonium fluoride in tetrahydrofuran
afforded macrolactone 1 (83%) as a white solid, mp 70–
[a]D25 +13.3 (c 0.5, CHCl3); Rf = 0.3 (EtOAc–hexane, 6:4).
IR (neat): 3562, 2921, 2851, 1742, 1599, 1366.
1H NMR (200 MHz, CDCl3): d = 3.87–3.78 (m, 1 H), 3.65–3.45 (m,
4 H), 1.95 (dd, J = 3.9, 2.4 Hz, 2 H), 1.84 (dd, J = 3.7, 2.2 Hz, 2 H),
1.25 (d, J = 6.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 72.1, 67.8, 67.3, 65.8, 42.3, 36.5,
21.6.
EI-MS: m/z = 169 [M + Na]+.
(2S,4R,6S)-6-Methyl-2-(tosyloxymethyl)tetrahydro-2H-pyran-
4-ol (5)
To a soln of diol 4 (2.0 g, 13.7 mmol) in anhyd CH2Cl2 (15 mL),
Et3N (3.81 mL, 27.4 mmol) was added at 0 °C. Then, TsCl (2.86 g,
15.0 mmol) was added over 2 h. The reaction mixture was allowed
to warm to 25 °C and stirred for 3 h. The mixture was then treated
with aq 1 N HCl (10 mL) and extracted with CH2Cl2 (3 × 30 mL).
The organic layer was washed with sat. NaHCO3 soln (15 mL) and
H2O (15 mL). The combined organic phases were dried (Na2SO4)
and concentrated under reduced pressure. Flash chromatography on
silica gel (EtOAc–hexane, 3:7) of the crude product afforded tosy-
late 5 as a gummy liquid; yield: 3.94 g (96%).
[a]D25 +34.8 (c 3.0, CHCl3); Rf = 0.5 (EtOAc–hexane, 8:2).
IR (neat): 3398, 2925, 2856, 1452, 1363, 1178, 1030, 976 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.82–7.70 (d, J = 8.0 Hz, 2 H),
7.39–7.29 (d, J = 8.0 Hz, 2 H), 4.04–3.87 (m, 2 H), 3.82–3.64 (m, 1
H), 3.58–3.42 (m, 1 H), 3.42–3.28 (m, 1 H), 2.45 (s, 3 H), 2.13 (m,
1 H), 1.90–1.80 (m, 3 H), 1.13 (d, J = 5.9 Hz, 3 H).
25
25
72 °C, [a]D +68.5 (c 1.0, MeOH) {Lit.2 [a]D +68.1 (c
0.25, MeOH)}, which was identical in all respects to the
reported material.2
In conclusion, we have proved the versatility of the Prins
cyclization in natural products synthesis by achieving the
stereoselective synthesis of (10S,12S)-10-hydroxy-12-
methyl-1-oxacyclododecane-2,5-dione in a 10-step se-
quence. Further applications of the Prins cyclization in the
synthesis of natural products are in progress and will be
disclosed in due course.
13C NMR (75 MHz, CDCl3): d = 145.1, 132.7, 129.7, 127.8, 72.8,
All reactions were carried out under inert atmosphere, unless men-
tioned, following standard syringe/septa techniques. Solvents were
dried and purified by conventional methods prior to use. The
progress of all reactions 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 hexane as the
eluents. Optical rotation values were measured with a Perkin-Elmer
P241 polarimeter and a JASCO DIP-360 digital polarimeter at
25 °C, and IR spectra were recorded with a Thermo-Nicolet
72.1, 67.35, 42.4, 36.5, 21.7.
ESI-MS: m/z = 301 [M + H]+.
(2S,4R,6S)-4-(tert-Butyldimethylsilyloxy)-6-methyl-2-(tosyl-
oxymethyl)tetrahydro-2H-pyran (6)
To alcohol 5 (3.80 g, 12.7 mmol) in anhyd CH2Cl2 (30 mL) at 0 °C
were added TBSCl (1.93 g, 12.8 mmol), DMAP (cat.) and imida-
zole (2.90 g, 42.6 mmol) successively, and the mixture was stirred
at 25 °C for 3 h. Then, the reaction mixture was quenched with H2O
(10 mL) and extracted with CH2Cl2 (3 × 20 mL). The organic ex-
tracts were washed with brine (10 mL), dried (Na2SO4) and concen-
trated under reduced pressure. The crude product was purified by
column chromatography on silica gel (EtOAc–hexane, 1:9) to af-
ford pure 6 as a colorless liquid; yield: 5.08 g (97%).
1
NEXUS 670 FT-IR spectrophotometer. H and 13C NMR spectra
were recorded in CDCl3 with a Varian Gemini 200 MHz or a Bruker
Avance 300 MHz spectrometer using tetramethylsilane as an inter-
nal standard. Mass spectra were recorded on a Micromass VG-
7070H instrument for EI-MS and a VG Autospec M instrument for
FABMS.
[a]D25 +8.1 (c 1.0, CDCl3); Rf = 0.8 (EtOAc–hexane, 1:9).
IR (neat): 3410, 2926, 2855, 1741, 1597, 1451, 1358, 1176, 974
cm–1.
(2S,4R,6S)-2-(Hydroxymethyl)-6-methyltetrahydro-2H-pyran-
4-ol (4)
TFA (43.8 mmol) was added slowly to a soln of the homoallylic al-
cohol 3 (3.0 g, 29.4 mmol) and acetaldehyde (3.87 g, 88.1 mmol) in
CH2Cl2 (90 mL) at 25 °C under N2 atmosphere. The reaction mix-
ture was stirred for 3 h and then sat. NaHCO3 soln (200 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 × 70 mL); the organic layers were combined and the sol-
vent was removed under reduced pressure. The resulting trifluoro-
acetate was directly used in the next reaction without purification.
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.0 Hz, 2 H), 7.32 (d,
J = 8.0 Hz, 2 H), 4.03–3.87 (m, 2 H), 3.82–3.63 (m, 1 H), 3.60–3.45
(m, 1 H), 3.42–3.27 (m, 1 H), 2.45 (s, 3 H), 1.81–1.66 (m, 2 H),
1.36–1.32 (m, 2 H), 1.13 (d, J = 5.8 Hz, 3 H), 0.85 (s, 9 H), 0.03 (s,
6 H).
13C NMR (75 MHz, CDCl3): d = 144.6, 132.9, 129.7, 127.9, 72.8,
72.2, 71.8, 68.0, 43.0, 37.1, 25.7, 21.5, 21.4, 17.9, –4.6.
ESI-MS: m/z = 415 [M + H]+.
Synthesis 2010, No. 1, 73–78 © Thieme Stuttgart · New York

76
J. S. Yadav et al.
PAPER
tert-Butyl [(2S,4R,6S)-2-(Iodomethyl)-6-methyltetrahydro-2H-
pyran-4-yloxy]dimethylsilane (7)
CH2Cl2 (40 mL). The reaction mixture was stirred at reflux for 12 h
by which time all of the starting material was consumed (TLC). The
solvent was removed under reduced pressure and the crude product
was purified by column chromatography on silica gel (EtOAc–hex-
ane, 1:49) to obtain 10 as a colorless oil; yield: 0.183 g (65%).
[a]D25 +15.8 (c 1.0, EtOH); Rf = 0.3 (EtOAc–hexane, 3:7).
IR (neat): 3442, 2959, 2927, 1725, 1630, 1383 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.27 (m, 5 H), 5.83–5.59 (m,
1 H), 5.49–5.29 (m, 1 H), 5.02–4.84 (m, 1 H), 4.71–4.60 (m, 2 H),
3.97–3.83 (m, 1 H), 3.80–3.47 (m, 1 H), 2.69–1.69 (m, 7 H), 1.34–
1.21 (m, 3 H), 1.18 (d, J = 6.1 Hz, 3 H), 0.89 (s, 9 H), 0.09 (s, 6 H).
NaI (14.49 g, 96.6 mmol) was added to a solution of 6 (4.0 g, 9.66
mmol) in acetone (40 mL) and the mixture was heated at reflux for
24 h. Acetone was removed under reduced pressure. To the residue
was added H2O and the whole was extracted with CH2Cl2 (3 × 15
mL). The combined organic phases were dried (Na2SO4) and con-
centrated under reduced pressure. Flash chromatography on silica
gel (EtOAc–hexane, 5:95) afforded 7 as a colorless liquid; yield:
3.36 g (94%).
[a]D20 +15.10 (c 1.0, CHCl3); Rf = 0.8 (EtOAc–hexane, 15:85).
IR (neat): 2939, 2885, 1379, 1144, 1099 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.81–3.69 (m, 1 H), 3.36–3.21 (m,
2 H), 3.22–3.19 (dd, J = 2.45, 5.85 Hz, 2 H), 2.06–1.90 (m, 2 H),
1.75–1.38 (m, 2 H), 1.23 (d, J = 6.04 Hz, 3 H), 0.89 (s, 9 H), 0.08
(s, 6 H).
ESI-MS: m/z = 455 [M + Na]+.
(10S,12S)-10-(tert-Butyldimethylsilyloxy)-5-hydroxy-12-meth-
yl-1-oxacyclododecan-2-one (11)
To a stirred soln of 10 (0.15 g, 0.35 mmol) in MeOH (2 mL), 10%
Pd/C (cat.) was added under H2 atmosphere and the mixture was
stirred for 6 h. Then, the reaction mixture was filtered through a pad
of Celite® and the filtrate was concentrated under reduced pressure.
The crude residue thus obtained was purified by column chromatog-
raphy on silica gel (EtOAc–hexane, 1:4) to afford cyclic alcohol 11
as a colorless syrup; yield: 0.101 g (85%).
[a]D25 +31.7 (c 0.15, CHCl3).
IR (neat): 3480, 2925, 1720, 1475, 1250 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.19–5.11 (m, 1 H), 4.13–3.98 (m,
1 H), 3.81–3.70 (m, 1 H), 2.50–2.28 (m, 2 H), 1.95–1.31 (m, 12 H),
1.20 (d, J = 5.8 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H).
ESI-MS: m/z = 371 [M+ + H].
(2S,4S)-4-(tert-Butyldimethylsilyloxy)hept-6-en-2-ol (8)
To the iodide 7 (2.20 g, 5.94 mmol) in EtOH (80 mL), commercial
Zn dust (5.82 g, 89.10 mmol) was added. The mixture was refluxed
for 1 h and then cooled to 25 °C. Addition of solid NH4Cl (8.17 g)
and Et2O (120 mL) followed by stirring for 5 min gave a gray sus-
pension. The suspension was filtered through Celite® and the filtrate
was concentrated under reduced pressure. Purification by flash
chromatography on silica gel (EtOAc–hexane, 4:46) gave the prod-
uct 8 as a colorless liquid; yield: 1.39 g (96%).
[a]D25 +36.6 (c 2.5, CHCl3); Rf = 0.4 (EtOAc–hexane, 1:9).
IR (neat): 3452, 2942, 1640, 1098, 1034, 916, 702 cm–1.
ESI-MS: m/z = 345 [M + H]+.
1H NMR (300 MHz, CDCl3): d = 5.82–5.60 (m, 1 H), 5.12–5.00 (m,
2 H), 4.19–3.82 (m, 2 H), 2.35–2.21 (m, 2 H), 1.59–1.50 (m, 2 H),
1.16–1.12 (d, J = 6.2 Hz, 3 H), 0.89 (s, 9 H), 0.08 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 135.0, 117.3, 71.1, 64.3, 43.0,
32.4, 25.7, 18.6, –4.2.
(10S,12S)-10-(tert-Butyldimethylsilyloxy)-12-methyl-1-oxacy-
clododecane-2,5-dione (12)
To a stirred soln of alcohol 11 (0.09 g, 0.26 mmol) in CH2Cl2 (2
mL), DMP (0.13 g, 0.31 mmol) was added and the mixture was
stirred at r.t. for 2 h. Then, the reaction mixture was quenched with
aq NaHCO3–Na2S2O3 (1:1, 1 mL) and extracted with CH2Cl2 (2
mL). The organic layer was washed with brine (2 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude resi-
due so obtained was purified by column chromatography on silica
gel (EtOAc–hexane, 1:9) to afford ketone 12 as a colorless syrup;
yield: 0.082 g (92%).
[a]D25 –11.9 (c 1.0, CHCl3).
IR (neat): 2928, 1729, 1670, 1252 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.03–4.89 (m, 1 H), 3.74–3.60 (m,
1 H), 2.91–2.32 (m, 6 H), 1.82–1.24 (m, 8 H), 1.23 (d, J = 6.2 Hz, 3
H), 0.89 (s, 9 H), 0.05 (m, J = 4.3 Hz, 6 H).
ESI-MS: m/z = 245 [M + H]+, 243 [M – 1]+.
(2S,4S)-4-(tert-Butyldimethylsilyloxy)hept-6-en-2-yl 4-(Benzyl-
oxy)hept-6-enoate (9)
To a soln of alcohol 8 (0.2 g, 0.82 mmol) in CH2Cl2 (10 mL) were
added acid 17 (3 g, 12.8 mmol) and DCC (0.24 g, 1.16 mmol) at
25 °C. DMAP (0.06 g, 0.53 mmol) was added after stirring the mix-
ture at the same temperature and stirring was continued for 6 h. Fil-
tration of the reaction mixture was followed by evaporation of the
solvent and column chromatography on silica gel (EtOAc–hexane,
1:9) of the resulting crude product which afforded ester 9 as a col-
orless oil; yield: 0.320 g (85%).
13C NMR (50 MHz, CDCl3): d = 208.1, 171.9, 70.9, 69.1, 41.3,
38.7, 37.4, 29.6, 25.8, 23.8, 21.1, 20.9, 19.9, –4.3, –4.6.
ESI-MS: m/z = 343 [M + H]+.
[a]D25 –81.0 (c 0.75, CHCl3); Rf = 0.2 (EtOAc–hexane, 2:8).
IR (neat): 3168, 2928, 1732, 1631, 1384, 1244, 1154, 1100, 1033
cm–1.
1H NMR (200 MHz, CDCl3): d = 7.36–7.28 (m, 5 H), 5.91–5.73 (m,
2 H), 5.19–5.01 (m, 4 H), 4.98–4.89 (m, 1 H), 4.64–4.41 (m, 2 H),
3.82–3.72 (m, 1 H), 3.54–3.46 (m, 1 H), 2.94–2.17 (m, 6 H), 1.97–
1.46 (m, 4 H), 1.20 (d, J = 6.2 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 173.1, 138.4, 134.3, 128.3, 127.7,
127.5, 117.2, 71.0, 70.9, 68.4, 68.2, 43.1, 38.1, 30.4, 28.9, 20.7,
17.9, –4.2, –4.9.
(10S,12S)-10-Hydroxy-12-methyl-1-oxacyclododecane-2,5-di-
one (1)
To a stirred soln of 12 (0.05 g, 0.14 mmol) in anhyd THF (2 mL),
TBAF (0.3 mL, 0.3 mmol) was added and the mixture was stirred at
0 °C for 2 h. The reaction mixture was quenched with H2O (1 mL)
and extracted with EtOAc (2 × 2 mL), and the combined organic
layer was washed with brine (2 mL), dried (Na2SO4) and concen-
trated under reduced pressure. The crude residue was purified by
column chromatography on silica gel (EtOAc–hexane, 3:7) to af-
ford 1 as a white solid; yield: 0.027 g (83%).
ESI-MS: m/z = 461 [M + H]+.
(10S,12S,E)-5-(Benzyloxy)-10-(tert-butyldimethylsilyloxy)-12-
methyl-1-oxacyclododec-7-en-2-one (10)
Grubbs II catalyst (0.275 g, 5 mol%) dissolved in CH2Cl2 (10 mL)
was added dropwise to a soln of the ester 9 (0.3 g, 0.65 mmol) in
Mp 70–72 °C; [a]D25 +68.5 (c 1.0, MeOH).
IR (neat): 3444, 2920, 1710, 1662, 1251 cm–1.
Synthesis 2010, No. 1, 73–78 © Thieme Stuttgart · New York

PAPER
(10S,12S)-10-Hydroxy-12-methyl-1-oxacyclododecane-2,5-dione
77
1H NMR (200 MHz, CDCl3): d = 4.98–4.81 (m, 1 H), 3.75 (dd,
J = 11.1, 6.8 Hz, 1 H), 2.94–2.63 (m, 2 H), 2.60–2.53 (m, 3 H), 2.42
(t, J = 5.1 Hz, 2 H), 1.89–1.36 (m, 7 H), 1.21 (d, J = 6.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 209.9, 172.0, 70.9, 68.6, 44.0,
41.5, 38.8, 36.1, 29.8, 23.2, 21.8, 21.0.
ESI-MS: m/z = 215 [M + H]+.
2-{[4-(Benzyloxy)hept-6-enyl]oxy}tetrahydro-2H-pyran (16a)
To a stirred soln of alcohol 15 (1.0 g, 4.6 mmol) in THF (10 mL),
NaH (0.3 g, 13.0 mmol) was added at 0 °C and the mixture was
stirred for 30 min. Then, BnBr (0.7 mL, 5.6 mmol) and a catalytic
amount of TBAI were added and the mixture was stirred at r.t. for 2
h. The reaction mixture was quenched with sat. aq NH4Cl soln (10
mL) and extracted with EtOAc (2 × 20 mL). The combined organic
layers were washed with brine (50 mL), dried (Na2SO4) and concen-
trated under reduced pressure. The crude residue was purified by
column chromatography on silica gel (EtOAc–hexane, 1:9) to af-
ford compound 16a as a light yellow syrup; yield: 1.3 g (94%).
ESI-MS: m/z = 251 [M + Na]+.
Tetrahydro-2-(pent-4-enyloxy)-2H-pyran (13b)
To a solution of pent-4-en-1-ol (5.0 g, 58.0 mmol) in anhyd CH2Cl2
(100 mL) at 0 °C was added a catalytic amount of PTSA (200 mg).
DHP (9.76 g, 116.3 mmol) was then added and the reaction mixture
was stirred at r.t. for 2 h. The reaction mixture was quenched with
NaHCO3, then washed with H2O and brine, dried (Na2SO4), and
concentrated under reduced pressure. The crude residue so obtained
was purified by column chromatography on silica gel (EtOAc–hex-
ane, 4:96) to afford 13b (9.68 g, 98%) as a colorless liquid.
IR (neat): 3070, 1640, 1135, 1120, 990, 910 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.75 (m, 1 H), 5.01 (m, 2 H), 4.54
(s, 1 H), 3.54 (m, 4 H), 2.10 (m, 2 H), 1.65 (m, 8 H).
IR (neat): 2928, 2857, 1221, 939 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.69–7.25 (m, 5 H), 5.90–5.75 (m,
1 H), 5.16–5.05 (m, 2 H), 4.58 (dd, J = 10.9, 11.3 Hz, 3 H), 3.85–
3.70 (m, 2 H), 3.54–3.34 (m, 3 H), 2.32–2.11 (m, 2 H), 1.82–1.45
(m, 10 H).
13C NMR (75 MHz, CDCl3): d = 133.4, 132.7, 130.0, 129.5, 128.2,
127.7, 98.8, 67.5, 67.1, 66.9, 62.3, 38.6, 30.6, 30.3, 25.5, 25.4, 19.5.
ESI-MS: m/z = 171 [M + H]+.
ESI-MS: m/z = 304 [M]+.
2-[3-(Oxiran-2-yl)propoxy]tetrahydro-2H-pyran (14)
To a soln of 13b (8.85 g, 52.05 mmol) in CH2Cl2 (120 mL) at 0 °C,
MCPBA (55% absorbed in H2O; 11.10 g, 64.44 mmol) was added
portionwise with vigorous stirring. After 30 min at r.t., the reaction
mixture was quenched with sat. NaHCO3 soln (30 mL) and extract-
ed with EtOAc (2 × 100 mL). The combined organic extracts were
washed with brine (20 mL), dried (Na2SO4) and concentrated under
reduced pressure. Column chromatography on silica gel (18–22%
EtOAc in hexane) gave pure 14 as a syrupy liquid; yield: 8.23 g
(89%).
4-(Benzyloxy)hept-6-en-1-ol (16b)
To a stirred soln of compound 16a (1.3 g, 4.2 mmol) in MeOH (10
mL), PTSA (0.02 g) was added at 0 °C and the mixture was stirred
at r.t. for 4 h. The reaction mixture was quenched with sat. aq
NaHCO3 soln (2 mL) and extracted with EtOAc (2 × 15 mL). The
combined organic layers were washed with brine (50 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude resi-
due was purified by column chromatography on silica gel (EtOAc–
hexane, 1:9) to afford compound 16b as a colorless liquid; yield:
0.84 g (90%).
Rf = 0.45 (EtOAc–petroleum ether, 35:65).
IR (neat): 2926, 2857, 1334, 1221, 939 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.57 (s, 2 H), 3.90–3.71 (m, 2 H),
2.98–2.90 (m, 1 H), 2.75 (dd, J = 4.5, 8.8 Hz, 1 H), 2.49–2.45 (m, 1
H), 1.86–1.45 (m, 11 H).
13C NMR (75 MHz, CDCl3): d = 98.8, 66.9, 62.3, 52.0, 47.1, 30.7,
29.3, 26.0, 25.4, 19.6.
FAB-MS: m/z = 187 [M + H]+.
IR (neat): 3480, 2930, 2860, 1215, 952 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.39–7.24 (m, 5 H), 5.90–5.75 (m,
1 H), 5.16–5.05 (m, 2 H), 4.52 (dd, J = 11.3, 11.5 Hz, 2 H), 3.57 (t,
J = 6.0 Hz, 2 H), 3.54–3.43 (m, 1 H), 2.46–2.28 (m, 2 H), 1.72–1.54
(m, 4 H).
13C NMR (75 MHz, CDCl3): d = 135.1, 128.5, 128.0, 127.9, 117.0,
78.8, 70.8, 62.9, 38.0, 30.9, 28.2.
ESI-MS: m/z = 243 [M + Na]+.
7-(Tetrahydro-2H-pyran-2-yloxy)hept-1-en-4-ol (15)
4-(Benzyloxy)hept-6-enoic Acid (17)
To a solution of Mg (2.06 g, 86.0 mmol) in anhyd THF (140 mL) at
r.t. were sequentially added 1,2-dibromoethane (0.6 mL, 6.85
mmol) and freshly prepared vinyl bromide (9.11 mL, 86.0 mmol) in
a dropwise manner. CuCN (617 mg, 6.85 mmol) was added after al-
lowing the reaction mixture to stir for 0.5 h. Then the mixture was
cooled to –78 °C and epoxide 14 (8.0 g, 43.01 mmol) in THF (30
mL) was added, and the mixture was allowed to warm to –40 °C.
After the mixture was stirred for 4 h at that temperature, sat. NH4Cl
solution (100 mL) was added and the mixture was extracted with
EtOAc (2 × 30 mL). The combined organic layers were washed
with brine (50 mL), dried over Na2SO4 and concentrated under re-
duced pressure. Purification by column chromatography on silica
gel (EtOAc–hexane, 1:9) afforded 15 (7.76 g, 80%) as a colorless
liquid.
To a stirred soln of alcohol 16b (0.75 g, 3.4 mmol) in CH2Cl2 (4
mL), DMP (1.00 g, 2.28 mmol) was added and the mixture was
stirred at 25 °C for 2 h. Then, the reaction mixture was quenched
with aq NaHCO3–Na2S2O3 soln (1:1, 1 mL) and concentrated under
reduced pressure to afford the corresponding aldehyde (0.70 g,
95%) as a colorless liquid which was directly used for further reac-
tion.
To a stirred soln of the aldehyde (0.70 g, 3.2 mmol) in t-BuOH–2-
methylbut-2-ene (2:1, 6 mL) were added aqueous solns of NaClO2
(0.62 g, 6.8 mmol) and NaH2PO4 (1.1 g, 9.1 mmol) in H2O (2 mL)
and the mixture was stirred at 25 °C for 6 h. The solvent was re-
moved under reduced pressure and the remainder was extracted
with EtOAc (2 × 5 mL). The combined organic layers were washed
with brine (5 mL), dried (Na2SO4) and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy on silica gel (EtOAc–hexane, 1:4) to afford acid 17 as a color-
less liquid; yield: 0.58 g (78%).
IR (neat): 3452, 2925, 2861, 1229, 950 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.90–5.73 (m, 1 H), 5.14–5.03 (m,
2 H), 4.58 (t, J = 3.7 Hz, 2 H), 3.88–3.72 (m, 2 H), 3.66 (sept, J =
12.0, 8.3, 4.5 Hz, 1 H), 3.52–3.33 (m, 2 H), 2.30–2.12 (m, 2 H),
1.88–1.41 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 132.2, 118.2, 98.6, 71.6, 67.2, 66.9,
38.5, 30.6, 25.5, 25.3, 19.4.
IR (neat): 3580, 2932, 2870, 1701, 1280, 689 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.38–7.21 (s, 5 H), 5.92–5.74 (m,
1 H), 5.20–5.06 (m, 2 H), 4.53 (dd, J = 11.2, 11.5 Hz, 2 H), 3.49 (dd,
J = 11.8, 8.2 Hz, 1 H), 2.44–2.23 (m, 4 H), 1.91–1.76 (m, 2 H).
Synthesis 2010, No. 1, 73–78 © Thieme Stuttgart · New York

78
J. S. Yadav et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 180.0, 134.1, 129.2, 128.4, 127.9,
3022. (m) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126,
2425. (n) Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.;
Gunasekar, D. Synthesis 2001, 885. (o) Yadav, J. S.; Reddy,
B. V. S.; Reddy, M. S.; Niranjan, N. J. Mol. Catal. A: Chem.
2004, 210, 99. (p) Yadav, J. S.; Reddy, B. V. S.; Reddy, M.
S.; Niranjan, N.; Prasad, A. R. Eur. J. Org. Chem. 2003,
1779.
127.9, 117.8, 77.9, 71.1, 38.1, 30.2, 28.1.
ESI-MS: m/z = 235 [M + H]+.
Acknowledgment
N.T., M.V. and K.V.R. thank CSIR, New Delhi for the award of fel-
lowships.
(4) (a) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R.
Tetrahedron Lett. 2006, 47, 4397. (b) Yadav, J. S.; Reddy,
M. S.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 4937.
(c) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron
Lett. 2005, 46, 2133. (d) Yadav, J. S.; Reddy, M. S.; Prasad,
A. R. Tetrahedron Lett. 2006, 47, 4995. (e) Yadav, J. S.;
Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synlett 2007, 2049.
(f) Yadav, J. S.; Rao, P. P.; Reddy, M. S.; Rao, N. V.; Prasad,
A. R. Tetrahedron Lett. 2007, 48, 1469. (g) Yadav, J. S.;
Kumar, N. N.; Reddy, M. S.; Prasad, A. R. Tetrahedron
2007, 63, 2689. (h) Rao, A. V. R.; Reddy, E. R.; Joshi, B. V.;
Yadav, J. S. Tetrahedron Lett. 1987, 28, 6497.
(5) Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullex, M.;
Colobert, F.; Solladie, G. Tetrahedron Lett. 2003, 44, 2695.
(6) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem.
1998, 63, 6776.
(7) (a) Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991, 32,
1613. (b) Walsh, T. F.; Toupence, R. B.; Ujjainwalla, F.;
Young, J. R.; Goulet, M. T. Tetrahedron 2001, 57, 5233.
(c) Yadav, J. S.; Thrimurtulu, N.; Uma Gayathri, K.; Reddy,
B. V. S.; Prasad, A. R. Tetrahedron Lett. 2008, 49, 6617.
(8) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R.
Tetrahedron Lett. 2006, 47, 4397.
References
(1) Dai, H.-Q.; Kang, Q.-J.; Li, G.-H.; Shen, Y.-M. Helv. Chim.
Acta 2006, 89, 527.
(2) Radhakrishna, P.; Srinivas, R. Tetrahedron: Asymmetry
2008, 19, 1153.
(3) For the Prins cyclization, see, for example: (a) Barry, C. St.
J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429.
(b) Yang, X.-F.; Mague, J. T.; Li, C.-J. J. Org. Chem. 2001,
66, 739. (c) Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew.
Chem. Int. Ed. 2005, 44, 3485. (d) Barry, C. S.; Bushby, N.;
Harding, J. R.; Willis, C. S. Org. Lett. 2005, 7, 2683.
(e) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
12216. (f) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker,
G. D.; Willis, C. L. Org. Lett. 2002, 4, 3407. (g)Marumoto,
S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett.
2002, 4, 3919. (h) Kozmin, S. A. Org. Lett. 2001, 3, 755.
(i) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem.
2001, 66, 4679. (j) Kopecky, D. J.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2001, 123, 8420. (k) Rychnovsky, S. D.;
Thomas, C. R. Org. Lett. 2000, 2, 1217. (l) Rychnovsky, S.
D.; Yang, G.; Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62,
(9) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1996, 118, 100. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953.
Synthesis 2010, No. 1, 73–78 © Thieme Stuttgart · New York