A concise stereoselective formal total synthesis of the cytotoxic macrolide (+)-Neopeltolide via Prins cyclization

Article abstract of DOI:10.1016/j.tet.2009.11.054

A convergent and highly stereoselective formal total synthesis of the naturally occurring, cytotoxic 14-membered macrolide neopeltolide has been achieved via two Prins cyclizations.

Full text of DOI:10.1016/j.tet.2009.11.054

Tetrahedron 66 (2010) 480–487
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Tetrahedron
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A concise stereoselective formal total synthesis of the cytotoxic macrolide
(þ)-Neopeltolide via Prins cyclization
*
Jhillu Singh Yadav , Gunda Gopala Krishana Satya Narayana Kumar
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad–500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent and highly stereoselective formal total synthesis of the naturally occurring, cytotoxic
14-membered macrolide neopeltolide has been achieved via two Prins cyclizations.
Ó 2009 Published by Elsevier Ltd.
Received 30 September 2009
Received in revised form 11 November 2009
Accepted 12 November 2009
Available online 15 November 2009
Keywords:
Prins cyclization
Ozonolysis
Esterification
Macrolide
1. Introduction
oxazol- and a carbamate-containing side chain. This substituent
occupies an axial position in the pyran ring. The side chain is
During the past 40–50 years, numerous novel compounds have
been isolated from marine organisms and many of these have been
reported to have range of biological activities such as cytotoxic,
antibiotic, anti-inflammatory, antispasmodic, antiviral, cardiotonic,
cardiovascular, antioxidant, and enzyme inhibition activities. In-
terestingly, some of which are of interest from the point of view of
potential drug development. These compounds provide an enor-
mous reservoir of structurally diverse secondary metabolites with
unique molecular architectures.1 Their synthetic analogues con-
tinue to provide fascinating insights into the mechanisms of many
important biological processes, and for this reason, chemical in-
terest in the synthesis of such structures remains high.2
In 2007, the search for new bioactive marine natural products
resulted in the discovery of neopeltolide 1 (Fig. 1), isolated from
a deep-water Caribbean sponge by Wright et al.3 Initial testing
demonstrated cytotoxic activity against several cancer lines, in-
cluding P388 murine leukemia, A-549 human lung adenocarci-
noma, and NCI-ADR-RES human ovarian sarcoma, with their
respective IC50 values of 0.56, 1.2, and 5.1 nM, respectively. The key
structural features of neopeltolide include a 14-membered mac-
rolactone ring 3 (Fig. 1), containing an ether bridge forming a tet-
rahydropyran subunit. Moreover, there are six stereogenic centers
in this structure. The hydroxyl group at C5 is acylated with an
identical to another macrolide leucascandrolide A 4 (Fig. 1), which
displays a similar biological profile.4,12d Other related natural
products with a macrolactone part similar to neopeltolide include
polycavernoside,5 lyngbyaloside,6 lyngbouilloside,7 aurisides,8 and
callipeltoside.9
The Prins cyclization has emerged as a powerful synthetic tool for
the construction of multi-substitued tetrahydropyran derivatives
and has been utilized in the synthesis of several natural products.15
Our group has made a significant effort to explore the utility of Prins
cyclization for the synthesis of various polyketide intermediates and
has subsequently applied to the synthesis of some natural prod-
ucts.16 As a part of our interest on the synthesis of biologically active
molecules, we herein report the synthesis of neopeltolide macro-
lactone 3, which directly relates to neopeltolide 2.10–14
The synthesis of Scheidt11, Lee12a, and Maier12b utilized a Prins
cyclization to fashion the pyran ring of neopeltolide by combining
a C1–C6 fragment with a C7–C16 part having an aldehyde function
at C7. Our plan was to develop a novel synthesis of a C7–C16 al-
dehyde by starting from a fragment containing the methyl-bearing
stereocenter at C9 and to create the C11–C13 diol region by in-
termolecular Prins–cyclization strategy. This plan led to (S)-citro-
nellol as starting material.
2. Results and discussion
Protection of (S)-citronellol with benzyl bromide followed by
the oxidation with PhSeOH-t-BuOOH yielded an allylic alcohol 6.
* Corresponding author. Tel.: þ91 40 27193030; fax: þ91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.11.054

J.S. Yadav et al. / Tetrahedron 66 (2010) 480–487
481
Me
Me
16
16
OMe
OMe
11
13
O
H
3
11
13
O
H
3
O
Me
O
Me
9
1
9
1
H
H
O
O
7
7
OMe
OMe
HN
HN
5O
5O
O
O
O
O
O
O
N
N
1
2
structure proposed by Wright et al.
revised structure of neopeltolide
11S, 13S
11R, 13R
H
Me
16
O
OMe
Me
MeO
O
H
O
11
13
O
O
O
H
Me
H
H
9
1
H
O
3
7
OMe
HN
5OH
O
O
O
O
3
N
4
macrolactone of neopeltolide
leucascandrolide A
Figure 1. Structure proposed by Wright et al. (1), revised structure of neopeltolide (2), macrolactone of neopeltolide (3), leucascandrolide A (4).
This was ozonized in MeOH. The resulting ozonide was reduced
with Me2S to give the desired aldehyde 7.17 Intermolecular Prins
cyclization of aldehyde 7 with (S)-pent-4-ene-1,2-diol18 in the
presence of TFA followed by hydrolysis of the resulting tri-
fluoroacetate gave trisubstituted pyran 8 in 56% yield.18,19 The
stereochemistry of compound 8 was assumed to be in anticipated
line as it was well examined and established previously.15,16
Furthermore, tosylation of 8 with 1.1 equiv of tosyl chloride in the
presence of TEA in DCM afforded corresponding primary tosylate
9 in 92% yield.16a TBDPS protection of the secondary alcohol 9
with TBDPSCl, DMAP, and imidazole gave corresponding TBDPS
ether 10. Treatment of tosylate 10 with NaI in refluxing acetone
gave corresponding iodo compound 11. Upon exposure of com-
pound 11 to unactivated zinc in refluxing ethanol gave key in-
termediate 12 in 96% yields. The alcohol functionality in the 12
was protected using Meerwein’s salt in the presence of proton
sponge.20 One-pot olefin reduction and benzyl ether deprotection
with Raney nickel gave saturated primary alcohol21 14. Oxidation
of 14 with Dess–Martin periodinane (DMP) yielded aldehyde 15.
One-pot aldehyde protection and silyl ether deprotection led to
seco-alcohol 16 using trimethyl orthoformate with PTSA as cat-
alyst (Scheme 1).
BnO
BnO
a
b
HO
c
CHO
BnO
7
5
6
OH
S-Citronellol
OH
OTBDPS
OH
d
e
f
i
OH
OTs
OTs
BnO
O
BnO
BnO
O
O
BnO
8
10
9
OTBDPS
OTBDPS
OH
OTBDPS
OMe
h
g
BnO
I
BnO
O
12
13
11
OTBDPS
OMe
OMe
OMe
OH
OMe
OTBDPS
j
l
k
OHC
HO
MeO
14
15
16
Scheme 1. Reagents and conditions: (a) NaH, BnBr, TBAI, THF, 12 h, 92%; (b) H2O2, PhSeSePh, t-BuOOH, MgSO4, CH2Cl2, 27 h, 80%; (c) O3, Me2S, CH3OH, 88%; (d) (S)-pent-4-ene-1,2-
diol, TFA, CH2Cl2 then K2CO3, CH3OH, 3.5 h, 56%; (e) TsCl, Et3N, CH2Cl2, 5 h, 92%; (f) TBDPSCl, DMAP, imidazole, CH2Cl2, 3 h, 97%; (g) NaI, acetone, reflux, 24 h, 94%; (h) Zn, EtOH,
reflux, 1 h, 96%; (i) Me3OBF4, proton sponge, CH2Cl2, 48 h, 86%; (j) H2, Raney nickel, EtOH, 6 h, 93%; (k) DMP, NaHCO3, CH2Cl2,1 h, 93%; (l) PTSA, CH(OMe)3, CH3OH, 6 h, 76%.

482
J.S. Yadav et al. / Tetrahedron 66 (2010) 480–487
Compound 21 was synthesized starting from known chiral ep-
4. Experimental section
4.1. General
oxide 17.22 Cu- mediated regioselective opening of epoxide 17
provided homoallylic alcohol 18. Conversion of the alcohol to PMB
ether 19 was accomplished by reacting with p-methoxybenzyl
trichloroacetimidate in the presence of catalytic CSA. Deprotection
of the primary TBDPS ether with TBAF and subsequent oxidation of
20 with DMP and NaClO2, NaH2PO4, 2-methyl-2-butene in t-BuOH/
H2O afforded the acid fragment 21 in 96% yield (Scheme 2).
All reactions were carried out under inert atmosphere unless
mentioned otherwise. Solvents were dried and purified by conven-
tional methods prior to use. The progress of all the reactions was
monitored by thin-layer chromatography (TLC) using glass plates
OH
O
OPMB
a
TBDPSO
b
TBDPSO
TBDPSO
17
18
19
O
OPMB
OPMB
c
d
HO
HO
20
21
Scheme 2. Reagents and conditions: (a) CuI, CH2]CHMgBr, THF, ꢂ20 ꢀC, 2 h, 92%; (b) PMBOC(NH)CCl3, CSA, CH2Cl2, 12 h, 76%; (c) TBAF, THF, 12 h, 90%; (d) DMP, CH2Cl2; NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH, 6 h, 96%.
Esterification of free OH group of 16 with (R)-3-(4-methoxy-
benzyloxy)hex-5-enoic acid 21 in the presence of DCC and a cata-
lytic amount of DMAP gave compound 22, which on treatment with
DDQ yielded the corresponding aldehydic homoallylic alcohol 23
required for intramolecular Prins cyclization. The compound 23
was treated with triethylsilyl trifluoromethanesulfonate (TESOTf)
in acetic acid in the presence of trimethylsilyl acetate (TMSOAc) and
subsequently treated under basic conditions to yield bicyclic mac-
rolactone 312a (Scheme 3), whose data was identical in all respects
with the data reported in literature.12
precoated with silica gel-60 F254 to a thickness of 0.5 mm (Merck).
Column chromatography was performed on silica gel (60-mesh) and
neutral alumina using diethyl ether, ethyl acetate, and hexane as the
eluents. Optical rotation values were measured with a Perkin-Elmer
P241 polarimeter and JASCO DIP-360 digital polarimeter at 25 ꢀC and
IR spectra were recorded with a Perkin-Elmer FTIR spectrophoto-
meter. 1H and 13C NMR spectra were recorded with Varian Gemini
200 MHz, Bruker Avance 300 MHz, Varian Unity 400 MHz, or Varian
Inova 500 MHz spectrometer using trimethylsilane as an internal
standard in CDCl3. Mass spectra were recorded on Micro mass
VG-7070H for EI and VG Autospec M for FABMS.
H3C
O
OMe
OMe
O
OPMB
CH3
CH3
OH
a
O
O
+
MeO
HO
OPMB
OMe
OMe
22
16
21
Me
O
H3C
OMe
Me
O
CH3
CH3
O
H
b
O
O
c
H
O
OH
CHO
23
3
OH
Scheme 3. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 3 h, 92%; (b) DDQ, pH buffer, CH2Cl2, 36 h, 92%; (c) TESOTf, TMSOAc, AcOH then K2CO3, CH3OH, 0.5 h, 66%.
3. Conclusion
4.1.1. (S)-((3,7-Dimethyloct-6-enyloxy)methyl)benzene (5). To a stir-
red suspension of NaH (10 g, 416 mmol, 60% W/V dispersion in
mineral oil) in dry THF (460 mL) was added dropwise a solution of
S-citronellol (26 g, 167 mmol) at 0 ꢀC. After stirring for 30 min at
0 ꢀC, TBAI (0.7 g) and benzyl bromide (34.2 g, 200 mmol) were
added subsequently and stirred overnight at room temperature.
The reaction mixture was quenched with small ice-pieces and
extracted with ethyl acetate (2ꢁ250 mL). The combined organic
layers were washed with water (150 mL), brine (150 mL) and dried
In summary, we have accomplished a convergent and enantio-
selective total synthesis of (þ)-neopeltolide macrolide 3 in 15-step
sequence from the known (S)-pent-4-ene-1,2-diol, epoxide 17 and
the commercially available (S)-Citronellol. The present synthesis
features an efficient route to 3 using two consequtive Prins cycli-
zations. Further applications of the Prins cyclization in the syn-
thesis of natural products are in progress.

J.S. Yadav et al. / Tetrahedron 66 (2010) 480–487
483
over anhydrous Na2SO4. Solvent was removed under vacuo and the
residue was purified by silica gel column chromatography to afford
was added slowly to a solution of the (S)-pent-4-ene-1,2-diol (3 g,
29.37 mmol) and aldehyde 7 (7.87 g, 38.2 mmol) in CH2Cl2 (90 mL)
at 25 ꢀC under nitrogen atmosphere. The reaction mixture was
stirred for 3 h and then saturated sodium hydrogen carbonate so-
lution (200 mL) was added and pH was adjusted to >7 by addition
of triethylamine. The layers were separated and the aqueous layer
was extracted with CH2Cl2 (4ꢁ70 mL). The organic layers were
combined and the solvent was removed under reduced pressure.
The trifluoroacetate obtained in this reaction was directly used in
the next reaction without purification. The residue was dissolved in
methanol (40 mL) and stirred with potassium carbonate (8.11 g) for
0.5 h. The methanol was removed under reduced pressure and
water (30 mL) was added. The mixture was extracted with CH2Cl2
(3ꢁ30 mL) and the combined organic layers were dried (Na2SO4)
and the solvent was removed under reduced pressure. Purification
of the crude product by column chromatography on silica yielded 8
5 (37.7 g, 92% yield) as a colorless liquid. Rf¼0.8 (SiO2, 10% EtOAc in
20
hexane). [
d
a
]
ꢂ2.6 (c 1.45, CHCl3); 1H NMR (CDCl3, 300 MHz):
D
7.36–7.13 (5H, m, ArH), 5.10–5.00 (1H, m, Olefin), 4.46 (2H, s,
OCH2Ph), 3.46 (2H, t, J 6.0 Hz, OCH2), 2.05–1.85 (2H, m, CH2), 1.70–
1.50 (2H, m, CH2), 1.66 (3H, s, CH3), 1.58 (3H, s, CH3), 1.48–1.22 (2H,
m, CH2), 1.20–1.08 (1H, m, CHMe), 0.88 (3H, d, J 6.0 Hz, CH3); 13C
NMR (CDCl3, 75 MHz):
d
138.6, 130.9, 128.2, 127.5, 127.3, 124.7, 72.8,
3398, 3062,
68.6, 37.1, 36.6, 29.5, 25.6, 25.4, 19.5, 17.5; IR (neat):
y
3030, 2960, 2921, 2856,1453,1371,1204,1102,1028, 829, 736 cmꢂ1
;
O
ESI-MS: m/z 247 [MþH]þ; HRMS (ESI): Calculated for C17H27
[MþH]þ: 247.2061. Found: 247.2066.
4.1.2. (S,E)-8-(Benzyloxy)-2,6-dimethyloct-3-en-2-ol (6). 30% H2O2
(6.24 g) was added to a stirred and ice-cooled solution of PhSeSePh
(17.12 g, 54.9 mmol) in CH2Cl2 (260 ml). After the addition, the
mixture was stirred for 30 min at 0 ꢀC. Powdered anhydrous MgSO4,
(9.22 g) was added to the mixture and stirring was continued for
30 min. The ice-bath was removed and 5 (9.0 g, 36.6 mmol) was
added to the mixture. The stirring was continued for 6 h at room
temperature. Subsequently 70% t-BuOOH (25.35 g) was added to the
stirred and ice-cooled mixture, which was stirred for 20 h at room
temperature. The mixture was filtered and the filtrate was concen-
trated in vacuo. The residue was dissolved in ether (400 mL). The
ether solution was washed with 5% Na2CO3 solution and water. Then
it was added dropwise to a vigorously stirred aq soln of FeSO4, (10%,
360 mL). The ether layer was separated, washed with water, satd
NaHCO3 soln, water and brine, dried over Na2SO3, and concentrated
under vacuo. The crude alcohol was purified by silica gel column
(2.44 g, 56%) as a colorless liquid. Rf¼0.3 (SiO2, 70% EtOAc in
25
hexane). [
a]
–5.6 (c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz):
D
d
7.37–7.17 (5H, m, ArH), 4.47 (2H, s, OCH2Ph), 3.82–3.67 (1H, m,
OCH), 3.59–3.31 (6H, m, OCH), 2.33 (1H, br s, OH), 1.90–1.53 (5H, m,
aliphatic), 1.50–1.36 (1H, m, CHMe), 1.28–1.05 (3H, m, aliphatic),
0.89 (3H, d, J 6.6 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
d
138.3, 128.2,
127.5, 127.4, 75.9, 73.4, 72.7, 68.2, 67.6, 65.7, 43.1, 41.5, 36.9, 36.6,
26.4, 19.5; IR (neat):
y 3400, 2924, 2862, 1453, 1369, 1090, 1027,
740 cmꢂ1; ESI-MS: m/z 326 [MþNH4]þ; HRMS (ESI): Calculated for
C18H32NO4 [MþNH4]þ: 326.2331. Found: 326.2340.
4.1.5. ((2S,4R)-6-((R)-4-(Benzyloxy)-2-methylbutyl)-4-hydroxy-tet-
rahydro-2H-pyran-2-yl)methyl4-methylbenzenesulfonate (9). To the
solution of diol 8 (2.0 g, 6.49 mmol) in dry CH2Cl2 (15.0 mL), tri-
ethylamine (1.31 g, 12.97 mmol) was added at 0 ꢀC. Tosyl chloride
(1.36 g, 7.14 mmol) was added over 2 h. The reaction mixture was
allowed to warm to room temperature and stirred for 3 h. The re-
action was treated with aqueous 1 N HCl (10 mL) and extracted
with CH2Cl2 (3ꢁ30 mL). The organic layer was washed with satu-
rated NaHCO3 (15 mL) and water (15 mL). The combined organic
phases were dried over Na2SO4 and concentrated under reduced
pressure. Silica gel column chromatography of the crude afforded
chromatography to afford pure alcohol 6 (7.67 g, 80% yield) as
25
a colorless liquid. Rf¼0.3 (SiO2, 20% EtOAc in hexane). [
a
]
ꢂ3.2 (c
D
1.00, CHCl3); 1H NMR (CDCl3, 300 MHz):
d
7.41–7.17 (5H, m, ArH),
5.65–5.54 (2H, m, Olefin), 4.46 (2H, s, OCH2Ph), 3.46 (2H, t, J 6.0 Hz,
OCH2), 2.09–1.80 (2H, m, CH2), 1.76–1.58 (2H, m, CH2), 1.53–1.08 (7H,
m, 2ꢁCH3, 1ꢁCHMe), 0.87 (3H, d, J 6.8 Hz, CH3); 13C NMR (CDCl3,
75 MHz):
d 139.4, 138.5, 128.2, 127.5, 127.4, 125.2, 72.8, 70.5, 68.4,
39.6, 36.1, 29.9, 29.7, 19.6, 19.4; IR (neat):
y 3422, 3029, 2964, 2924,
2863,1718,1455,1367,1270,1101,1026, 973, 914, 800, 739 cmꢂ1; ESI-
MS: m/z 280 [MþNH4]þ; HRMS (ESI): Calculated for C17H30NO2
[MþNH4]þ: 280.2276. Found: 280.2284.
tosylate 9 (2.76 g, 92%) as a gummy liquid. Rf¼0.5 (SiO2, 60% EtOAc
25
in hexane). [
d
a
]
ꢂ10.6 (c 1.00, CHCl3); 1H NMR (CDCl3, 300 MHz):
D
7.74 (2H, d, J 8.3 Hz, ArH), 7.36–7.17 (7H, m, ArH), 4.45 (2H, s,
OCH2Ph), 3.99–3.88 (2H, m, OCH), 3.75–3.65 (1H, m, OCH), 3.52–
3.14 (3H, m, OCH), 3.35–3.25 (1H, m, OCH), 2.42 (3H, s, ArCH3),
1.90–1.69 (4H, m, aliphatic), 1.65–1.32 (3H, m, aliphatic), 1.16–1.00
(3H, m, aliphatic), 0.85 (3H, d, J 7.6 Hz, CH3); 13C NMR (CDCl3,
4.1.3. (R)-5-(Benzyloxy)-3-methylpentanal (7). O3 was bubbled into
a cooled solution of 6 (10.0 g) in MeOH (70 mL) at ꢂ50 ꢀC. When 6
disappeared as checked by TLC, the solution was cooled to ꢂ60 ꢀC.
N2 was bubbled into the solution to remove O3. Then Me2S (5 mL)
was added dropwise to the stirred solution and the temperature
was gradually raised to room temperature. After stirring overnight,
the mixture was concentrated under vacuo. The residue was diluted
with water and extracted with ether. The ether solution was
washed with water and brine, dried over Na2SO3 and concentrated
under vacuo. The crude aldehyde was purified by silica gel column
75 MHz):
d 144.6, 138.4, 132.7, 129.7, 128.2, 127.8, 127.5, 127.3, 73.4,
72.8, 72.7, 71.9, 68.4, 67.3, 43.0, 41.1, 36.9, 36.7, 26.2, 21.5, 19.4; IR
(neat): y 3422, 3030, 2924, 2862, 1598, 1452, 1361, 1176, 1189, 1097,
1029, 977, 814, 743, 698 cmꢂ1; ESI-MS: m/z 480 [MþNH4]þ; HRMS
(ESI): Calculated for C25H38NO6S [MþNH4]þ: 480.2419. Found:
480.2429.
chromatography to afford pure aldehyde 7 (6.92 g, 88% yield) as
4.1.6. ((2S,4R)-6-((R)-4-(Benzyloxy)-2-methylbutyl)-4-(tert-butyldi-
phenylsilyloxy)-tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesul-
fonate (10). To a solution of alcohol 9 (2.6 g, 5.63 mmol) in anhyd
CH2Cl2 (16 mL) at 0 ꢀC were added TBDPSCl (1.85 g, 6.75 mmol),
DMAP (Cat.) and imidazole (1.15 g, 16.88 mmol) successively and
the mixture was stirred for 3 h at 25 ꢀC. The reaction mixture was
quenched by adding H2O (10 mL) and extracted with CH2Cl2
(3ꢁ20 mL). The organic extracts were washed with brine solution
(10 mL), dried over anhydrous Na2SO4 and concentrated under
vacuum and the crude was purified by silica gel column chroma-
25
a colorless liquid. Rf¼0.7 (SiO2, 10% EtOAc in hexane). [
a
]
þ4.3 (c
D
1.00, CHCl3); 1H NMR (CDCl3, 500 MHz):
d
9.71 (1H, s, CHO), 7.31–
7.18 (5H, m, ArH), 4.46 (2H, s, OCH2Ph), 3.42 (2H, t, J 6.8 Hz, OCH2),
2.41–2.35 (1H, m, CHaCHbCHO), 2.24–2.19 (1H, m, CHaCHbCHO),
2.09–2.02 (1H, m, CHMe),1.45–1.38 (1H, m, CHaCHb), 1.34–1.23 (1H,
m, CHaCHb), 0.97 (3H, d, J 6.8 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
d
202.2, 138.2, 127.9, 127.2, 127.1, 72.5, 69.9, 50.5, 32.9, 26.8, 19.5; IR
(neat): y 3032, 2960, 2930, 2873, 1708, 1454, 1408, 1277, 1178, 1096,
1027, 948, 741, 703 cmꢂ1; ESI-MS: m/z 229 [MþNH4]þ; HRMS (ESI):
Calculated for C13H18NaO2 [MþNa]þ: 229.1204. Found: 229.1210.
tography to afford the pure product 10 (3.82 g, 97%) as a colorless
25
liquid; Rf¼0.8 (SiO2,10% EtOAc in hexane). [
1H NMR (CDCl3, 400 MHz):
m, ArH), 4.44 (2H, s, OCH2Ph), 3.90–3.78 (2H, m, OCH), 3.74–3.61
a
]
ꢂ4.1 (c 1.00, CHCl3);
D
4.1.4. (4R,6S)-2-((R)-4-(Benzyloxy)-2-methylbutyl)-6-(hydroxy-
methyl)-tetrahydro-2H-pyran-4-ol (8). Trifluoroacetic acid (47.5 mL)
d 7.74–7.54 (6H, m, ArH), 7.44–7.14 (13H,

484
J.S. Yadav et al. / Tetrahedron 66 (2010) 480–487
(1H, m, OCH), 3.40 (2H, t, J 6.4 Hz, OCH2), 3.32–3.22 (1H, m, OCH),
3.12–3.02 (1H, m, OCH), 2.40 (3H, s, ArCH3), 1.72–1.56 (2H, m, ali-
phatic), 1.54–1.30 (3H, m, aliphatic), 1.25–1.15 (1H, m, aliphatic),
1.06–0.96(3H, m, aliphatic), 1.02 (9H, s, Me3CSi), 0.76 (3H, d, J
(CDCl3, 400 MHz): d 7.71–7.65 (4H, m, ArH), 7.42–7.25 (11H, m,
ArH), 5.80–5.69 (1H, m, Olefin), 4.99–4.89 (2H, m, Olefin), 4.48 (2H,
s, OCH2Ph), 3.93–3.88 (1H, m, OCH), 3.49–3.40 (2H, m, OCH), 3.34–
3.28 (1H, m, OCH), 3.07 (3H, s, OCH3), 2.25–2.11 (2H, m, aliphatic),
1.80–1.52 (3H, m, aliphatic), 1.48–1.32 (3H, m, aliphatic), 1.05 (9H, s,
6.4 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
d 144.4, 138.4, 135.5, 133.9,
133.8, 132.8, 129.5, 128.1, 127.7, 127.4, 127.3, 73.2, 72.7, 72.5, 71.9,
68.8, 68.3, 42.9, 41.4, 36.9, 36.8, 26.7, 26.1, 21.4, 19.3, 18.9; IR (neat):
Me3CSi), 0.95–0.89 (1H, m, aliphatic), 0.83 (3H, d, J 6.6 Hz, CH3); 13
C
NMR (CDCl3, 75 MHz):
127.6, 127.5, 127.4, 117.0, 75.3, 72.8, 70.2, 68.6, 55.6, 41.9, 41.8, 41.7,
37.1, 27.0, 26.6, 19.8, 19.3; IR (neat): 3067, 2928, 2856, 2777, 1575,
d 138.6, 135.9, 134.5, 134.1, 129.5, 128.2,
y
3020, 2926, 2855, 1741, 1597, 1451, 1358, 1176, 974 cmꢂ1; ESI-MS:
m/z 718 [MþNH4]þ; HRMS (ESI): Calculated for C41H56NO6SSi
y
[MþNH4]þ: 718.3597. Found: 718.3594.
1456, 1428, 1380, 1184, 1106, 1030, 999, 936, 820, 738, 702 cmꢂ1
;
ESI-MS: m/z 567 [MþNa]þ; HRMS (ESI): Calculated for
4.1.7. ((4R,6S)-2-((R)-4-(Benzyloxy)-2-methylbutyl)-6-(iodomethyl)-
tetrahydro-2H-pyran-4-yloxy)(tert-butyl)diphenylsilane(11). To a stir-
red solution of 10 (3.6 g, 5.14 mmol) in dry acetone (66 mL) under
nitrogen atmosphere was added NaI (2.45 g, 16.46 mmol) at 0 ꢀC.
The reaction mixture was stirred at reflux for 24 h and filtered.
Removal of solvent under vacuo and purification on silica gel col-
C35H48NaO3Si [MþNa]þ: 567.3270. Found: 567.3278.
4.1.10. (3R,5S,7S)-7-(tert-Butyldiphenylsilyloxy)-5-methoxy-3-meth-
yldeca-1-ol (14). Raney Nickel 10 g was added in one portion to
a stirred solution of 13 (3.0 g, 6.89 mmol) in 20 mL of absolute
ethanol. The flask was fitted with a balloon of H2, and the reaction
mixture was stirred at room temperature for 6 h. The reaction
mixture was filtered through a pad of Celite, and the filtrate was
concentrated under vacuo and the residue was purified by silica gel
umn chromatography afforded 11 (3.17 g, 94%) as a colorless liquid.
25
Rf¼0.6 (SiO2, 20% EtOAc in hexane). [
a
]
þ8.1 (c 1.00, CHCl3); 1H
D
NMR (CDCl3, 400 MHz):
d
7.64–7.54 (4H, m, ArH), 7.36–7.15 (11H, m,
ArH), 4.40 (2H, s, OCH2Ph), 3.76–3.62 (1H, m, OCH), 3.44–3.55 (2H,
m, OCH), 3.16–3.06 (1H, m, OCH), 3.05–3.01 (1H, m, OCH), 3.01–
2.96 (2H, m, CH2I), 1.89–1.73 (2H, m, aliphatic), 1.59–1.45 (2H, m,
aliphatic), 1.40–1.30 (1H, m, aliphatic), 1.24–1.11 (2H, m, aliphatic),
1.06–0.96(2H, m, aliphatic), 0.97 (9H, s, Me3CSi), 0.76 (3H, d, J
column chromatography to afford 14 (2.33 g, 93% yield) as a color-
25
less liquid. Rf¼0.3 (SiO2, 30% EtOAc in hexane). [
a
]
ꢂ10.6 (c 1.00,
D
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.76–7.61 (4H, m, ArH), 7.44–
7.28 (6H, m, ArH), 3.89–3.78 (1H, m, OCH), 3.65–3.49 (2H, m, OCH),
3.30–3.18 (1H, m, OCH), 3.06 (3H, s, OCH3), 1.70–1.55 (2H, m, ali-
phatic), 1.47–1.17 (10H, m, aliphatic), 1.04 (9H, s, Me3CSi), 0.83 (3H,
d, J 6.6 Hz, CH3), 0.73 (3H, t, J 7.1 Hz, CH3); 13C NMR (CDCl3,
6.3 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
129.6, 128.2, 127.5, 127.3, 75.0, 73.4, 72.8, 69.2, 68.6, 43.1, 41.6, 41.0,
d 138.7, 135.6, 134.7, 134.1,
37.1, 26.9, 26.4, 19.3, 19.0, 8.94; IR (neat):
y
3067, 2931, 2857, 1460,
75 MHz): d 135.9,134.6,129.4,127.4, 75.9, 70.5, 60.6, 55.9, 42.0, 41.6,
1427, 1368, 1188, 1110, 1074, 824, 740, 702 cmꢂ1; ESI-MS: m/z 679
[MþNa]þ; HRMS (ESI): Calculated for C34H45INaO3Si [MþNa]þ:
679.2080. Found: 679.2086.
40.2, 39.4, 27.0, 26.1, 19.9, 19.3, 17.7, 13.9; IR (neat): y 3395, 3056,
2935, 2867, 1459, 1377, 1260, 1098, 787, 703 cmꢂ1; ESI-MS: m/z 457
[MþH]þ; HRMS (ESI): Calculated for C28H45O3Si [MþH]þ: 457.3137.
Found: 457.3140.
4.1.8. (3R,5S,7S)-1-(Benzyloxy)-7-(tert-butyldiphenylsilyloxy)-3-
methyldec-9-en-5-ol (12). To a solution of 11 (2.2 g, 3.35 mmol) in
ethanol (80 mL), commercial zinc dust (3.27 g, 50.30 mmol) was
added. The mixture was refluxed for 1 h and cooled to 25 ꢀC. Ad-
dition of solid ammonium chloride (8.17 g) and ether (120 mL)
followed by stirring for 5 min gave a gray suspension. The sus-
pension was filtered through Celite and filtrate was concentrated
under vacuo and purification on silica gel column chromatography
4.1.11. (3R,5S,7S)-7-(tert-Butyldiphenylsilyloxy)-5-methoxy-3-meth-
yldecanal (15). To a solution of alcohol 14 (0.296 g, 0.65 mmol) in
CH2Cl2 (5 mL) was added NaHCO3 (0. 17 g, 2.0 mmol) and Dess–
Martin periodinane (DMP) (0.43 g, 1.0 mmol) at 0 ꢀC. After 0.5 h at
this temperature, a saturated aqueous NaHCO3 solution was added
and the bilayer system was allowed to stir at 0 ꢀC for an additional
0.5 h. The organic phase separated, the aqueous layer extracted
with CH2Cl2 (2ꢁ5 mL), and the combined organic extracts were
washed with brine, dried over anhydrous Na2SO4 and filtered.
After concentration under vacuo, the crude aldehyde was purified
afforded 12 (1.70 g, 96%) as a colorless liquid. Rf¼0.3 (SiO2, 10%
25
EtOAc in hexane). [
a]
þ1.9 (c 1.0, CHCl3); 1H NMR (CDCl3,
D
400 MHz): d 7.72–7.66 (4H, m, ArH), 7.56–7.19 (11H, m, ArH), 5.64–
5.46 (1H, m, Olefin), 4.96–4.78 (2H, m, Olefin), 4.46 (2H, s, OCH2Ph),
4.03–3.96 (1H, m, OCH), 3.94–3.86 (1H, m, OCH), 3.58–3.40 (2H, m,
OCH), 2.42–2.07 (2H, m, allylic CH2), 1.86–1.70 (1H, m, aliphatic),
1.63–1.37 (5H, m, aliphatic), 0.97 (9H, s, Me3CSi), 1.04–0.95 (1H, m,
aliphatic), 0.84 (3H, d, J 6.6 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
by silica gel column chromatography to afford 15 (0.27 g, 93%
25
yield) as a liquid. Rf¼0.6. (SiO2, 10% EtOAc in hexane). [
a
]
ꢂ10.6
D
(c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz):
d
9.71 (1H, s, CHO),
7.72–7.68 (4H, m, ArH), 7.43–7.33 (6H, m, ArH), 3.86–3.76 (1H, m,
OCH), 3.29–3.21 (1H, m, OCH), 3.06 (3H, s, OCH3), 2.34–2.24 (1H,
m, CHaHbCHO), 2.20–2.09 (2H, m, 1ꢁCHaHbCHO, 1ꢁCHCH3),
1.74–1.66 (1H, m, aliphatic), 1.52–1.36 (3H, m, aliphatic), 1.36–1.16
(3H, m, aliphatic), 1.04 (9H, s, Me3CSi), 0.98–1.02 (1H, m, ali-
phatic), 0.86 (3H, d, J 6.6 Hz, CH3), 0.73 (3H, t, J 7.1 Hz, CH3); 13C
d
138.6, 135.8, 134.2, 133.6, 133.3, 129.8, 128.2, 127.5, 127.3, 117.2,
72.8, 71.5, 68.5, 65.5, 45.2, 42.3, 41.0, 37.3, 26.9, 26.3, 19.2, 19.1; IR
(neat):
y 3505, 3069, 2930, 2858, 1460, 1427, 1365, 1107, 999, 914,
821, 738, 702 cmꢂ1; ESI-MS: m/z 553 [MþNa]þ; HRMS (ESI): Cal-
culated for C34H46NaO3Si [MþNa]þ: 553.3113. Found: 553.3116.
NMR (CDCl3, 75 MHz):
d 202.7, 136.0, 134.6, 134.3, 129.6, 127.5,
127.4, 75.6, 70.5, 55.6, 51.4, 42.0, 41.4, 39.6, 27.0, 24.8, 20.0, 19.3,
4.1.9. ((4S,6S,8R)-10-(Benzyloxy)-6-methoxy-8-methyldec-1-en-4-
yloxy)(tert-butyl)diphenylsilane (13). To a solution of alcohol 12
(3.4 g, 6.42 mmol) in CH2Cl2 (100 mL) in the dark at room tem-
perature was added Me3OBF4 (3.32 g, 22.45 mmol) and proton
sponge (6.86 g, 32.07 mmol). The mixture was allowed to stir for
48 h. After complete reaction (monitored by TLC), H2O was added
(50 mL) and the mixture extracted with CH2Cl2 (3ꢁ100 mL). The
combined organic extracts were washed with 1 N HCI, saturated
NaHCO3, and saturated NaCl solution, dried over anhydrous Na2SO4,
filtered, and concentrated under vacuo. Purification by silica gel
17.7, 13.9; IR (neat): y 3032, 2966, 2942, 2876, 1706, 1456, 1408,
1278, 1178, 1096, 1027, 948, 741, 703 cmꢂ1; ESI-MS: m/z 477
[MþNa]þ; HRMS (ESI): Calculated for C28H42NaO3Si [MþNa]þ:
477.2800. Found: 477.2808.
4.1.12. (4S,6S,8S)-6,10,10-Trimethoxy-8-methyldeca-4-ol (16). A so-
lution of 15 (0.121 g, 0.27 mmol) in 3 mL of dry methanol was treated
with trimethyl orthoformate (0.178 g, 1.68 mmol) and PTSA (0.01 g,
0.05 mmol) and the resulting solution was stirred for 2 h at rt, di-
luted with ether (100 mL), treated with K2CO3 (0.129 g, 0.93 mmol)
filtered through Celite, and concentrated under vacuo. The crude oil
was purified by silica gel column chromatography to give the acetal
chromatography gave the 13 (3.0 g, 86%) as a colorless liquid. Rf¼0.4
25
(SiO2, 10% EtOAc in hexane). [
a
]
þ8.2 (c 1.00, CHCl3); 1H NMR
D

J.S. Yadav et al. / Tetrahedron 66 (2010) 480–487
485
25
16 (0.053 g, 76% yield) as a liquid. Rf¼0.6. (SiO2,10% EtOAcin hexane).
yield) as colorless oil. Rf¼0.3 (SiO2, 40% EtOAc in hexane). [
a
]
D
25
[
a
]
þ12.6 (c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz):
d
4.43 (1H, dd,
ꢂ31.9 (c 1.02, CHCl3); 1H NMR (CDCl3 400 MHz):
d 7.28–7.14 (2H, m,
D
J 4.8, 8.1 Hz, CH(OMe)3), 3.99–3.86 (1H, m, OCH), 3.66–3.54 (1H, m,
OCH), 3.37 (3H, s, OCH3), 3.32 (3H, s, OCH3), 3.31 (3H, s, OCH3), 2.97
(1H, br s, OH), 1.75–1.69 (3H, m, aliphatic), 1.66–1.61 (1H, m, ali-
phatic), 1.55–1.50 (1H, m, aliphatic), 1.60–1.36 (5H, m, aliphatic),
1.26–1.20 (1H, m, aliphatic), 0.86 (3H, d, J 6.6 Hz, CH3), 0.73 (3H, t, J
ArH), 6.81 (2H, d, J 8.4 Hz, ArH), 5.82–5.71 (1H, m, olefin), 5.12–5.03
(2H, m, olefin), 4.54 (2H, s, OCH2Ph), 3.80 (3H, s, OCH3), 3.76–3.61
(3H, m, OCH), 2.50–2.16 (2H, m, allylic CH2), 1.82–1.68 (2H, m, ali-
phatic); 13C NMR (CDCl3, 75 MHz):
d
159.1, 134.7, 134.1, 129.3, 117.3,
113.7, 77.2, 70.5, 60.4, 55.1, 37.9, 35.8; IR (neat): 3422, 3072, 2932,
y
7.1 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
52.3, 41.3, 40.0, 39.8, 39.3, 26.0, 20.1, 18.6, 13.9; IR (neat):
d
103.1, 77.6, 68.4, 56.6, 52.9,
3446,
1612, 1512, 1463, 1436, 1346, 1301, 1247, 1175, 1036, 916, 820,
771 cmꢂ1; ESI-MS: m/z 259 [MþNa]þ; HRMS (ESI): Calculated for
C14H20NaO3 [MþNa]þ: 259.1310. Found: 259.1316.
y
2930, 2859, 1730, 1460, 1378, 1188, 1111, 1078, 958, 797, 740,
703 cmꢂ1; ESI-MS: m/z 285 [MþNa]þ; HRMS (ESI): Calculated for
C14H30NaO4 [MþNa]þ: 285.2041. Found: 285.2036.
4.1.16. (R)-3-(4-Methoxybenzyloxy)hex-5-enoic acid (21). Dess–
Martin periodinane (4.35 g, 10.3 mmol) was added to a solution of
20 (1.21 g, 5.14 mmol) in CH2Cl2 (100 mL). The reaction mixture was
stirred at rt for 1 h and the reaction was quenched by addition of
satd Na2S2O3 solution (45 mL). The reaction mixture was extracted
with CH2Cl2 (90 mLꢁ3). The organic extracts were dried over
Na2SO4, filtered, and concentrated under vacuo. This crude alde-
hyde was dissolved in t-BuOH (240 mL) and 2-methyl-2-butene
(60 mL). After cooling to 0 ꢀC, NaClO2 (1.21 g, 13.34 mmol) and
NaH2PO4 (2.23 g, 13.38 mmol) in water (40 mL) was added to the
solution. The reaction mixture was stirred vigorously for 30 min at
rt, diluted with EtOAc (300 mL), and quenched by water (150 mL).
The aqueous phase was extracted with EtOAc (300 mLꢁ2) and the
combined organic phase was washed with brine (150 mL), dried
over Na2SO4, filtered, and concentrated under vacuo. Purification
4.1.13. (R)-1-(tert-Butyldiphenylsilyloxy)hex-5-en-3-ol (18). 36.8 mL
of vinylmagnesiumbromide (1 M solution in THF) was quickly
added to a THF solution of epoxide 17 (6 g, 18.4 mmol) and CuI
(0.524 g, 2.76 mmol) at ꢂ20 ꢀC. The reaction was monitored by TLC
and after completion a saturated solution of NH4Cl was added. The
organic layer was washed with brine, dried over Na2SO4 and con-
centrated under vacuum affording a yellow oil and the crude
product was chromatographed on silica gel to afford 18 (5.99 g,
92%) as a colorless liquid. Rf¼0.7 (SiO2, 30% EtOAc in hexane).
25
[
a]
þ2.3 (c 1.40, CHCl3); 1H NMR (CDCl3, 400 MHz):
d 7.72–7.69
D
(4H, m, ArH), 7.48–7.40 (6H, m, ArH), 5.87 (1H, m, Olefin), 5.16–5.10
(2H, m, Olefin), 4.02–3.96 (1H, m, OCH), 3.93–3.84 (2H, m, OCH),
2.34–2.25 (2H, m, allylic CH2), 1.79–1.68 (2H, m, aliphatic), 1.08 (9H,
s, Me3CSi); 13C NMR (CDCl3, 75 MHz):
d
135.6, 135.2, 135.0, 134.8,
was accomplished by silica gel column chromatography, which
25
129.9, 129.7, 127.8, 127.8, 117.5, 70.9, 63.3, 42.0, 37.9, 26.6, 19.1; IR
provided 21 (1.25 g, 96%). Rf¼0.2 (SiO2, 30% EtOAc in hexane). [
a]
D
(neat):
y
3449, 3069, 2930, 2858, 1466, 1426, 1251, 1107, 1000, 821,
ꢂ15.6 (c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz):
d 7.19 (2H, d, J
741, 702 cmꢂ1; ESI-MS: m/z 377 [MþNa]þ; HRMS (ESI): Calculated
8.0 Hz, ArH), 6.80 (2H, d, J 8.0 Hz, ArH), 5.85–5.74 (1H, m, olefin),
5.16–5.06 (2H, m, olefin), 4.53–4.46 (2H, m, OCH2Ph), 3.96–3.85
(1H, m, OCH), 3.78 (3H, s, OCH3), 2.60–2.45 (2H, m, CH2COOH),
for C22H30NaO2Si [MþNa]þ: 377.1912. Found: 377.1916.
4.1.14. (R)-tert-Butyl-(3-(4-methoxybenzyloxy)hex-5-enyloxy)-
diphenylsilane (19). To a stirring solution of alcohol 18 (1.34 g,
3.94 mmol), freshly prepared 4-methoxybenzyl trichloroacetimidate
(1.66 mg, 5.92 mmol), and CH2Cl2 (10 mL) in a 15 mL round bottom
flask, under an atmosphere of N2, was added (ꢃ)-camphor-10-sul-
fonic acid (0.092 g, 0.394 mmol) in one portion. The reaction was
allowed to proceed for 12 h at rt, after which TLC analysis indicated
essentially complete consumption of starting material. The reaction
mixture was concentrated under reduced pressure, diluted with 20%
EtOAc/hexanes (100 mL), filtered over a pad of Celite, and concen-
trated under vacuo to give red slurry. Purification was accomplished
2.41–2.30 (2H, m, allylic CH2); 13C NMR (CDCl3, 75 MHz):
d
177.0,
159.1, 133.6, 130.0, 129.3, 118.0, 113.7, 74.6, 71.1, 55.1, 39.1, 38.2; IR
(neat):
y 3074, 2927, 1711, 1642, 1612, 1513, 1437, 1349, 1300, 1247,
1176, 1078, 1034, 919, 821 cmꢂ1; ESI-MS: m/z 273 [MþNa]þ; HRMS
(ESI): Calculated for C14H18NaO4 [MþNa]þ: 273.1102. Found:
273.1103.
4.1.17. (S)-((4S,6S,8S)-6,10,10-Trimethoxy-8-methyldecan-4-yl)3-(4-
methoxybenzyloxy)hex-5-enoate (22). Acid 21 (0.077 g, 0.31 mmol),
DCC (0.124 g, 0.60 mmol), DMAP (0.007 g, 0.06 mmol) were added to
a solution of alcohol 16 (0.053 g, 0.2 mmol) in CH2Cl2 (2 mL) at rt. This
mixture was stirred at rt for 3 h, the reaction mixture was concen-
trated under vacuo. Purification of the residue by silica gel column
bysilicagelcolumnchromatography to give PMB ether 19 (1.42 g, 76%
25
yield) as colorless oil: Rf¼0.5 (SiO2, 20% EtOAc in hexane). [
a
]
ꢂ10.6
D
(c 0.40, CHCl3); 1H NMR (CDCl3, 300 MHz):
d
7.63–7.50 (4H, m, ArH),
chromatography provided ester 22 (0.091 g, 92%). Rf¼0.40 (SiO2, 20%
25
7.40–7.18 (6H, m, ArH), 7.14–7.03 (2H, m, ArH), 6.79–6.66(2H, m, ArH),
5.85–5.62 (1H, m, olefin), 5.09–4.88 (2H, m, olefin), 4.47–4.24 (2H, m,
OCH), 3.83–3.56 (3H, m, OCH), 3.76 (3H, s, OCH3), 2.34–2.14 (2H, m,
allylic CH2),1.74–1.60 (2H, m, aliphatic),1.03 (9H, s, Me3CSi); 13C NMR
d 158.9,135.5,135.2,134.7,133.8,130.8,129.5,129.2,
127.6,116.9,113.6, 75.0, 70.7, 60.4, 55.1, 38.4, 36.9, 26.8,19.1; IR (neat):
EtOAc in hexane). [
a]
ꢂ5.5 (c 1.00, CHCl3); 1H NMR (CDCl3,
D
400 MHz): d 7.20 (2H, d, J 8.1 Hz, ArH), 6.81 (2H, d, J 8.1 Hz, ArH), 5.84–
5.74 (1H, m, olefin), 5.13–5.06 (1H, m, OCH), 5.13–5.07 (2H, m, olefin),
4.50–4.46 (2H, m, OCH2Ph), 4.42 (1H, dd, J 5.2, 7.9 Hz, CH(OMe)3),
3.96–3.90 (1H, m, OCH), 3.76 (3H, s, OCH3), 3.30 (3H, s, OCH3), 3.28
(3H, s, OCH3), 3.26 (3H, s, OCH3), 3.24–3.20 (1H, m, OCH), 2.53–2.46
(2H, m, CH2COOH), 2.36–2.33 (2H, m, allylic CH2), 1.74–1.66 (1H, m,
aliphatic), 1.64–1.44 (5H, m, aliphatic), 1.39–1.34 (2H, m, aliphatic),
1.33–1.23 (2H, m, aliphatic), 1.18–1.14 (1H, m, aliphatic), 0.93 (3H, d, J
6.6 Hz, CH3), 0.83 (3H, t, J 7.1 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
(CDCl3, 75 MHz):
y
3069, 3001, 2931, 2857, 1612,1511, 1464, 1428,1246, 1107, 1037, 820,
739, 702 cmꢂ1;ESI-MS: m/z497 [MþNa]þ;HRMS(ESI):Calculatedfor
C30H38NaO3Si [MþNa]þ: 497.2487. Found: 497.2482.
4.1.15. (R)-3-(4-Methoxybenzyloxy)hex-5-en-1-ol (20). To a stirring
solution of PMB ether 19 (4.74 g, 10.0 mmol) and THF (80 mL) in
a 250 mL round bottom flask under an atmosphere of N2, at rt, was
added a 1.0 M solution of tetrabutylammonium fluoride (20.0 mL,
20.0 mmol) in THF, dropwise via syringe. The reaction was allowed
to proceed for 12 h at rt, after which time TLC analysis indicated
complete consumption of starting material. The reaction mixture
was concentrated under reduced pressure. Purification was ac-
complished by silica gel column chromatography and concentrated
under reduced pressure to give primary alcohol 20 (2.12 g, 90%
d
171.4, 159.3, 134.3, 130.6, 129.4, 117.9, 113.6, 103.1, 75.6, 75.3, 71.6,
71.4, 57.0, 55.4, 53.1, 52.1, 42.4, 40.1, 40.0, 39.9, 38.6, 37.3, 26.0, 20.4,
18.6, 13.9; IR (neat): y 2930, 2830, 1728, 1614, 1514, 1663, 1383, 1320,
1174, 1091, 915, 820, 797, 740, 703 cmꢂ1; ESI-MS: m/z 517 [MþNa]þ;
HRMS (ESI): Calculated for C28H46NaO7 [MþNa]þ: 517.3141. Found:
517.3146.
4.1.18. (S)-((4S,6S,8S)-6,10,10-Trimethoxy-8-methyldecan-4-yl)3-(4-
methoxybenzyloxy)hex-5-enoate (23). DDQ (0.4 g, 1.76 mmol) was
added to a solution of ester 22 (0.087 g, 0.18 mmol) in CH2Cl2

486
J.S. Yadav et al. / Tetrahedron 66 (2010) 480–487
(20 mL) and pH 7 buffer solution (4 mL) at rt. After 36 h, the reaction
was quenched by the addition of saturated NaHCO3 (13 mL). The
reaction mixture was extracted with CH2Cl2 (3ꢁ25 mL), dried over
Na2SO4, filtered, and concentrated under vacuo. Purification of the
residue by silica gel column chromatography (hexanes–EtOAc, 10:1)
References and notes
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Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M.
R. Nat. Prod. Rep. 2009, 26, 190; (d) Jin, Z. Nat. Prod. Rep. 2009, 26, 382; (e) Cragg,
G. M.; Grothaus, P. G.; Newman, D. J. Chem. Rev. 2009, 109, 3012.
2. Monograph: The Chemical Synthesis of Natural Products; Hale, K. J., Ed.; Sheffield
Academic: Sheffield, 2000.
3. Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.; Linley, P.; McCarthy, P. J.;
Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod. 2007, 70, 412.
4. (a) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv. Chim. Acta 1996,
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A.; Andrews, W. J. Angew. Chem., Int. Ed. 2008, 47, 5426.
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1147; (b) Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J. Am.
Chem. Soc. 1998, 120, 10770; (c) Paquette, L. A.; Barriault, L.; Pissarnitski, D.;
Johnston, J. N. J. Am. Chem. Soc. 2000, 122, 619; (d) Blakemore, P. R.; Browder,
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provided aldehyde 23 (54 mg, 92%). Rf¼0.6 (SiO2, 20% EtOAc in
25
hexane). [
d
a
]
ꢂ12.6 (c 0.30, CHCl3); 1H NMR (CDCl3, 400 MHz):
D
9.71 (1H, s, CHO), 5.84–5.76 (1H, m, olefin), 5.16–5.06 (1H, m, OCH),
5.16–5.10 (2H, m, olefin), 4.10–4.06 (1H, m, OCH), 3.31–3.26 (1H, m,
OCH), 3.29 (3H, s, OCH3), 3.16 (1H, d, J 4.1 Hz, aliphatic), 2.51–2.40
(3H, m, aliphatic), 2.30–2.16 (4H, m, aliphatic), 1.74–1.51 (4H, m,
aliphatic),1.49–1.21 (4H, m, aliphatic), 0.97 (3H, d, J 6.4 Hz, CH3), 0.89
(3H, t, J 7.3 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
d
202.5, 172.0, 134.1,
118.2, 76.0, 71.7, 67.8, 56.7, 51.1, 41.5, 41.4, 41.0, 38.9, 37.1, 25.1, 20.6,
18.6,14.0; IR (neat): y 3480, 3076, 2960, 2717, 2350, 2310, 1730, 1642,
1564,1383,1173, 837, 822, 797, 702 cmꢂ1; ESI-MS: m/z 351 [MþNa]þ;
HRMS (ESI): Calculated for C18H32NaO5 [MþNa]þ: 351.2147 Found:
351.2146.
4.1.19. Macrolactone of neopeltolide (3).
16 Me
H
3
O
H
H
14
15
5
4
O
1
13
6. (a) Luesch, H.; Yoshida, W. Y.; Harrigan, G. G.; Doom, J. P.; Moore, R. E.; Paul, V. J.
J. Nat. Prod. 2002, 65, 1945; (b) Klein, D.; Braekman, J. C.; Daloze, D.; Hoffmann,
L.; Demoulin, V. J. Nat. Prod. 1997, 60, 1057.
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9. (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis, C. J. Am. Chem.
Soc. 1996, 118, 11085; (b) Wittmann, V. Nachr. Chem. Tech. Lab. 2002, 50, 841; (c)
Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124,
10396; (d) Evans, D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002,
124, 5654; (e) Paterson, I.; Davies, R. D. M.; Heimann, A. C.; Marquez, R.; Meyer,
2
12
H
HO
O
7
H
6
OMe
10
8
9
11
H
Me
TMSOAc (0.6 mL, 3.82 mmol) was added to a solution of alde-
hyde 23 (0.042 g, 0.127 mmol) in AcOH (12.6 mL) at rt. TESOTf
(0.56 mL, 2.55 mmol) was added dropwise to the resulting solution
at the same temperature. After 30 min, the reaction mixture was
poured into ether (30 mL), and saturated NaHCO3 (30 mL). The
layers were separated, and the aqueous layer was extracted with
ether (3ꢁ30 mL). The combined organic layers were dried over
Na2SO4, filtered and concentrated under vacuo. This crude product
was dissolved in MeOH (3 mL) and then K2CO3 (175 mg, 1.27 mmol)
was added. This reaction mixture was stirred for 3 h at rt and
concentrated. The residue was dissolved in water (6 mL), and ether
(6 mL). The layers were separated, and the aqueous layer was
extracted with ether (3ꢁ10 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under vacuo. The
residue as purified by silica gel column chromatography to afford
A. Org. Lett. 20
03, 5, 4477.
10. Youngsaye, W.; Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S. Angew. Chem., Int. Ed.
2007, 46, 9211.
11. Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 804.
12. (a) Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 3242; (b)
Vintonyak, V. V.; Maier, M. E. Org. Lett. 2008, 10, 1239; (c) Fuwa, H.; Naito, S.;
Goto, T.; Sasaki, M. Angew. Chem., Int. Ed. 2008, 47, 4737; (d) Ulanovskaya, O. A.;
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Nat. Chem. Biol. 2008, 4, 418; (e) Paterson, I.; Miller, N. A. Chem. Commun. 2008,
4708; (f) Kartika, R.; Gruffi, T. R.; Taylor, R. E. Org. Lett. 2008, 10, 5047; (g) Tu, W.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2009, 48, 4567; (h) Kim, H.; Park, Y.;
Hong, J. Angew. Chem., Int. Ed. 2009, 48, 7577; (i) Guinchard, X.; Roulland, E. Org.
Lett. 2009, 11, 4700.
13. Vintonyak, V. V.; Kunze, B.; Sasse, F.; Maier, M. E. Chem.dEur. J. 2008, 14, 11132.
14. Custar, D. W.; Zabawa, T. P.; Hines, J.; Crews, C. M.; Scheidt, K. A. J. Am. Chem.
Soc. 2009, 131, 12406.
15. For the Prins cyclisation, see for example, (a) Barry, C. S. J.; Crosby, S. R.; Har-
ding, 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) Rych-
novsky, S. D.; Yang, G.; Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62, 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, 6, 885; (o) Yadav, J. S.; Reddy, B. V. S.;
Reddy, M. S.; Niranjan, N.; Prasad, A. R. Eur. J. Org. Chem. 2003, 1779; (p) Yadav,
J. S.; Subba Reddy, B. V.; Narayana Kumar, G. G. K. S.; Swamy, T. Tetrahedron Lett.
2007, 48, 2205; (q) Yadav, J. S.; Subba Reddy, B. V.; Narayana Kumar, G. G. K. S.;
Reddy, M. G. Tetrahedron Lett. 2007, 48, 4903; (r) Yadav, J. S.; Subba Reddy, B. V.;
Maity, T.; Narayana Kumar, G. G. K. S. Tetrahedron Lett. 2007, 48, 7155; (s) Yadav,
J. S.; Subba Reddy, B. V.; Maity, T.; Narayana Kumar, G. G. K. S. Tetrahedron Lett.
2007, 48, 8874; (t) Yadav, J. S.; Subba Reddy, B. V.; Aravind, S.; Narayana Kumar,
G. G. K. S.; Madhavi, C.; Kunwar, A. C. Tetrahedron 2008, 64, 3025; (u) Yadav, J. S.;
Subba Reddy, B. V.; Narayana Kumar, G. G. K. S.; Aravind, S. Synthesis 2008, 48, 395.
16. (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.
neopeltolide macrolactone 3 (0.028 g, 66%) as a colorless oil. Rf¼0.3
25
(SiO2, 50% EtOAc in hexane). [
a
]
þ20.6 (c 1.00, CHCl3); 1H NMR
D
(CDCl3, 400 MHz): d 5.06–5.16 (1H, m, 13-H), 3.85–3.66 (2H, m, 3-H,
5-H), 3.62–3.53 (1H, m, 7-H), 3.29 (3H, s, 11-CHOCH3), 3.20–3.15
(1H, m, 11-H), 2.59 (1H, dd, J 14.5, 4.0 Hz, 2-H), 2.43 (1H, dd, J 14.5,
11.0 Hz, 2-H), 1.98–1.92 (1H, m, 4-Ha), 1.89–1.81 (2H, m, 14-H, 4-
He), 1.74–1.63 (m, 1H, 9-H), 1.63–1.25 (9H, m, 2ꢁ10-H, 2ꢁ12-H,
2ꢁ15-H, 8-H, 14-H, OH), 1.26–1.07 (3H, m, 6-Ha, 6-He, 8-H), 0.97
(3H, d, J 6.8 Hz, 9-CH3), 0.89 (3H, t, J 7.3 Hz, 16-CH3); 13C NMR
(CDCl3, 75 MHz):
d 170.8 (C-1), 78.6 (C-7), 75.7 (C-11), 73.2 (C-3),
72.3 (C-13), 68.0 (C-5), 56.0 (11-CHOCH3), 44.0 (C-8), 42.2 (C-10),
42.1 (C-2), 41.9 (C-12), 40.7 (C-6), 40.0 (C-14), 37.1 (C-4), 31.1 (C-9),
25.4 (9-CH3), 18.9 (C-15), 13.9 (C-16); IR (neat):
y 3414, 2916, 2870,
1732, 1646, 1270, 1456, 1087, 1386, 1246, 1156, 1087, 794 cmꢂ1
;
ESI-MS: m/z 351 [MþNa]þ; HRMS (ESI): Calculated for C18H32O5
[MþNa]þ: 351.2147. Found: 351.2146.
Acknowledgements
GGKSNK thanks CSIR, New Delhi for the award of fellowship.

J.S. Yadav et al. / Tetrahedron 66 (2010) 480–487
487
S.; Rao, P. P.; Prasad, A. R. Synlett 2007, 2049; (f) Yadav, J. S.; Rao, P. P.; Reddy, M. S.;
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17. Mori, G.; Kuwahar, S. Tetrahedron 1982, 38, 521.
18. (S)-pent-4-ene-1,2-diol: (ꢃ)-Epichlorohydrin was converted into benzyl pro-
tected glycidol by treating with NaH and benzyl alcohol in THF at 0 ꢀC in 82%
yield. The Jacobsen’s hydrolytic kinetic resolution of the racemic epoxide
(1 equiv) with 0.55 equiv of H2O in the presence of 0.005 mol% (salen)
Co(III) (OAc) complex [(R, R)-N, N-bis-(3,5-di-tert-butylsalicylidene)-1,2-cyclo-
hexanediamino-Co(III)-acetate] gave chiral epoxide, (S)-benzyl glycidyl ether in
48% yield with >99% ee. Cu- mediated regioselective opening of (S)-benzyl
glycidyl ether with vinylmagnesium bromide followed by debenzylation with Li
or Na in liquid ammonia gave (S)-pent-4-ene-1,2-diol in 70% yield (for two
20. Diem, M. J.; Burow, D. F.; Fry, J. L. J. Org. Chem. 1977, 42, 1801.
21. Yadav, J. S.; Chetia, L. Org. Lett. 2007, 9, 4587.
22. Epoxide 17: The commercially available but-3-en-1-ol was protected as it
tert-butyldiphenylsilyl ether in 99% yield. The double bond was oxidised
with m-CPBA to give racemic epoxide in 98% yield. The racemic epoxide was
subjected to Jacobsen’s hydrolytic kinetic resolution [(S,S)-N, N-bis-(3,5-di-
tert-butylsalicylidene)-1,2-cyclohexanediamino-Co(III)-acetate] to give ster-
eochemically pure (ee>99%) epoxide 17 in 44% yield; See Brioche, J. C. R.;
Goodenough, K. M.; Whatrup, D. J.; Harrity, J. P. A. Org. Lett. 2007, 9, 3941.