Total synthesis of (-)-baconipyrone C

Article abstract of DOI:10.1016/j.tet.2008.12.049

A highly stereoselective asymmetric total synthesis of marine polypropionate (-)-baconipyrone C has been achieved. Utilization of desymmetrization technique to create five stereogenic centres, Sharpless epoxidation, Gilman's reaction and resolution of met

Full text of DOI:10.1016/j.tet.2008.12.049

Tetrahedron 65 (2009) 3545–3552
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Total synthesis of (ꢀ)-baconipyrone C
*
J.S. Yadav , K. Sathaiah, R. Srinivas
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective asymmetric total synthesis of marine polypropionate (ꢀ)-baconipyrone C has
been achieved. Utilization of desymmetrization technique to create five stereogenic centres, Sharpless
epoxidation, Gilman’s reaction and resolution of methyl group using enzyme PS-C is the highlight of the
synthesis.
Received 19 September 2008
Received in revised form 11 December 2008
Accepted 12 December 2008
Available online 24 December 2008
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-Baconipyrone C
Desymmetrization
Enzymatic resolution
Sharpless epoxidation
Gilmans’ reaction
1. Introduction
skeleton with noncontiguous, ester-type backbone.6,7 In baconi-
pyrone A and B
linkage to a highly substituted
in baconipyrone C and D, through an acyclic
g
-pyrone moiety is connected through an ester
-hydroxy cyclohexanone, whereas
-hydroxy 1,5-dike-
Natural products derived from marine molluscs gained interest
for their variety of bioactive secondary metabolities, unusual
structures and concomitant biological activities (antimicrobial ac-
tivities and cytotoxicities).1 The original role of these bioactive
substances has been considered to be a defensive function from
predators, prevention of fouling, inhibition of overgrowth and the
protection from ultraviolet radiation.2
Baconipyrones A–D (1–4) were isolated in 1989 by Faulkner
et al. from Siphonaria baconi collected from intertidal rock plat-
forms near Melbourne, Australia.3
b
b
tone. The first total synthesis of (ꢀ)-baconipyrone C was reported
by Paterson et al. in 2000.8 The full absolute stereochemistry of
baconipyrone C and D and structural revision of baconipyrone A and
B were reported by Vogel et al. via C–C bond forming reaction based
on the sulfurdioxide induced condensation of 1,3-dioxy-1,3-dienes
to enoxysilanes, by synthesizing (ꢀ)-(4S,6S)-4,6-dimethyl-5-hydroxy-
nonan-3,7-dione and (þ)-(2S,3S,4S,5S,6S)-3-ethyl-3,5-dihydroxy-
2,4,6-trimethyl cyclohexanone derivatives.9 A baconipyrone type
ester has been reported from siphonarins on chromatographic
purification lending support to the baconipyrone may be isolation
artifacts.1b
O
O
O
O
11
O
O
14
9
O
5
O
OH
O
O
OH
O
O
19
OH
O
28
2. Results and discussion
R
R
Baconipyrone A 1, R = Me
Baconipyrone, B 2, R = H
Baconipyrone C 3, R = Me
Baconipyrone D 4, R = H
As part of our studies in the synthesis of marine poly-
propionates,10 we now report on the second total synthesis of
(ꢀ)-baconipyrone C. Our retrosynthetic analysis envisions that 3
Marine pulmonates of the genus siphonaria are the sources of
diverse range of polyketides,4 macrolides1c and polyether antibi-
otics.5 The baconipyrones all contain a tetrasubstituted
-pyrone
could be obtained from coupling of alcohol 5 and g-pyrone carbo-
xylic acid 6 via Yonemitsu–Yamaguchi esterification (Scheme 1).
Enzymatic resolution, functional group transformations and Gil-
man’s opening of chiral epoxide obtained from 2-methyl 1,3-pro-
pane diol result in the C2-symmetric alcohol 5 and 6 in turn
obtained from lactone 11 where we employed desymmetrization
technique to create five consecutive stereogenic centres and
g
with a polypropionate side chain lacking normal polypropionic
* Corresponding author. Fax: þ91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.049

3546
J.S. Yadav et al. / Tetrahedron 65 (2009) 3545–3552
The protection of diol 7 as its di-tert-butyl dimethylsilyl ether
11
HO
9
O
+
was achieved by using tert-butyl dimethylsilyl [trifluoro-
methanesulfonate] and 2,6-lutidine in CH2Cl2, which results in the
di TBS ether 17 in high yield. Hydrogenolysis of benzyl and primary
TBS ethers 17 using Pd/C in methanol gave 1,5-diol 18 in 76% yield.
Swern oxidation of compound 18, followed by the immediate ad-
dition of EtMgBr at 0 ꢁC in dry THF furnished a diastereomeric
mixture 19 in 60% yield. The dialdehyde was not purified, the dia-
stereomers were not separated and were used as crude in sub-
sequent steps. Swern oxidation of 19, followed by TBS ether
deprotection of 20 with HF/pyridine in THF gave compound 5 in
84% yield.
3
5
14
O
OPMB
6
O
O
O
OH
5
O
19
+
28
CHO
OBn OPMB OMOM
OBn OH OH
7
O
O
9
8
2.2. Synthesis of the C9–C19 fragment (6)
O
O
The synthesis of fragment 6 started with lactone 1110 by
a desymmetrization technique where we used to create five stereo-
genic centres at once. Reductive opening of methylated lactone 11
with LiAlH4 in dry THF furnished triol 21 in 90% yield (Scheme 3).
The 1,3-diol group of 21 was protected as an acetonide employing
2,2-dimethoxy propane and CSA in CH2Cl2/Et2O (9:1) and the free
primary hydroxy group was protected as its benzyl ether using NaH
and BnBr to furnish 22. Benzyl ether 22 was treated with aq 2 N HCl
to furnish 23 and selective protection of the primary hydroxy group
as its benzoyl ester 24 was achieved in 90% yield under standard
conditions (C6H5COCl/Et3N/DMAP). The secondary hydroxyl group
24 was protected as its MOM-ether 25 using MOMCl, DIPEA and
DMAP in CH2Cl2 and the subsequent removal of benzoyl group
furnished 26 in 90% yield after treating with aq 3 N KOH in THF/
MeOH (1:1:1). Oxidation of primary alcohol 26 with IBX-DMSO
gave the corresponding aldehyde 27 in 90% yield.
OH OH
O
10
11
OPMB
Scheme 1. Retrosynthetic analysis of (ꢀ)-baconipyrone C.
explore the synthesis of rifamycin S,11 discodermolide,12 scyto-
phycin C,13 membrenone C,10a prelactone B14 and bafilomycin A1.15
2.1. Synthesis of the C1–C8 fragment (5)
The synthesis of intermediate 5 commenced with compound 10,
which we protected as its monobenzyl ether using NaH and BnBr in
THF to furnish 12 in 78% yield (Scheme 2). Enzymatic resolution of
methyl group 12 with PS-C enzyme resulted in compound 13 in 35%
yield.16,17 Swern oxidation of primary alcohol and reaction with
stable ylide (ethoxycarbonylmethylene) triphenyl phosphorane
Aldehyde 27 was added to the lithium enolate of 920 generated
by the addition of LDA at ꢀ78 ꢁC, resulted compound 28, which was
subjected to Dess–Martin periodinane21 oxidation followed by
furnished trans-a,b-unsaturated ester 14 in 90% (E/Z, 95:5) yield.
The DIBAL-H reduction of 14 in CH2Cl2 furnished 15 in high yield.
Sharpless18 asymmetric epoxidation of 15 using (þ)-DIPT, Ti(OiPr)4
and TBHP in CH2Cl2 gave the chiral epoxy alcohol 16 in 89% yield.
Opening of epoxide 16 with Gilman’s19 reagent (Me2CuLi) followed
by the NaIO4 chopping in THF/H2O (4:1) gave the pure diol 7 in 65%
yield (from 16).
Ph3P/CCl4 cyclization22 in THF to give the desired
g
-pyrone 29 in
-Pyrone 29 formed via cyclization/
elimination process was confirmed by the presence of two singlets
for two vinylic methyl groups at 1.94 and 1.90, a triplet for one
methyl group at 1.07 and a quartet for two allylic protons at 2.49
45% yield over three steps.
g
d
d
d
d
corresponding to
g-pyrone moiety.
OEt
a
b
c,d
OH OH
OBn
OH
OBn OH
OBn
O
10
12
13
14
f
OH
k,l
OH
g,h
e
O
OBn
OBn
OBn
OBn OH OH
15
16
7
j
i
OTBS
OTBS
OH OTBS OH
OH
OH OTBS
19
17
18
m
n
O
OH
5
O
O
OTBS O
20
Scheme 2. Reagents and conditions: (a) NaH, BnBr, TBAI, THF, 0 ꢁC to rt, 12 h, 78%; (b) PS-C,
, iPr2O, 30 ꢁC, 7 h, 35%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC to 0 ꢁC, 2 h; (d)
OAC
Ph3PCHCO2Et, CH2Cl2, rt, 12 h, 90%; (e) DIBAL-H, CH2Cl2, 0 ꢁC, 2 h, 90%; (f) (þ) DIPT, Ti(OiPr)4, TBHP, CH2Cl2, ꢀ30 ꢁC, 89%, 8 h; (g) Me2CuLi, Et2O, ꢀ30 ꢁC, 6 h; (h) NaIO4, THF/H2O
(4:1), rt, 2 h, 65%; (i) TBSOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC to rt, 2 h, 86%; (j) Pd/C, H2, MeOH, 12 h, 76%; (k) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC to ꢀ30 ꢁC, 3 h; (l) EtMgBr, 0 ꢁC to rt, 1 h;
(m) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC to ꢀ30 ꢁC, 3 h, 79%; (n) HF/pyridine, THF, 0 ꢁC, 2 h, 84%.

J.S. Yadav et al. / Tetrahedron 65 (2009) 3545–3552
3547
O
b, c
a
d
O
O
OBn OPMB
22
O
OH
OPMB
21
OH
OH
O
11
OPMB
H
h
f
i
OPMBOR
OPMBOR
OR
OBn
OR1
OBn OPMB
OBn
O
OR1
27 R = MOM
23 R = H, R1 = H
24 R = H, R1 = Bz
25 R = MOM, R1 = Bz
26 R = MOM, R1 = H
e
g
j, k
m
O
OR
OPMB
OR
OBn
l
O
O
O
OBn OPMB
OH
29 R = MOM
30 R = H
28 R = MOM
n,o
O
HO
O
OPMBOH
31
OPMB
6
O
OH
O
O
O
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, 0 ꢁC to rt, 4 h, 90%; (b) 2,2-DMP, CSA, CH2Cl2: Et2O (9:1), 0 ꢁC to rt, 1 h, 92%; (c) NaH, BnBr, THF, reflux, 5 h, 95%; (d) aq 2 N HCl,
THF, 25 ꢁC, 5 h, 89%; (e) C6H5COCl, Et3N, DMAP, CH2Cl2, 0 ꢁC to rt, 5 h, 94%; (f) MOMCl, DIPEA, DMAP, CH2Cl2, 0 ꢁC to rt, 20 h, 80%; (g) aq 3 N KOH, MeOH, THF (1:1), rt, 5 h, 90%; (h)
IBX/DMSO, CH2Cl2, rt, 1 h, 90%; (i) 9, LDA, THF, ꢀ78 ꢁC, 2 h; (j) Dess–Martin periodinane, CH2Cl2, 0 ꢁC to rt, 1 h; (k) TPP/CCl4, THF, 36 h, 45%; (l) TMSBr, CH2Cl2, ꢀ10 ꢁC, 14 h, 76%; (m)
Raney-Ni, H2, rt, 5 h, 90%; (n) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC to ꢀ30 ꢁC, 3 h; (o) NaClO2, NaH2PO4$2H2O, DMSO, H2O, 2 h, 80%.
2.3. Coupling of fragments 5 and 6 to obtain 3
After successful synthesis of -pyrone moiety, now we focused
synthesis of (2S)-3-(benzyloxy)-2-methylpropan-1-ol by using PS-
C from readily available starting materials.
g
on the deprotection of MOM-ether 29 in the presence of PMB ether.
It was achieved by using TMSBr23 in CH2Cl2 at ꢀ10 ꢁC conditions to
furnish 30 and its benzyl ether was deprotected with Raney-Ni in
ethanol, which resulted in compound 31.24 Swern oxidation of 31
4. Experimental
4.1. General
followed by further oxidation of aldehyde with NaClO2, NaH2
PO4$2H2O in DMSO resulted in compound 6 in 80% yield over two
steps.
-
Commercial reagents were used without further purification. All
solvents were purified by standard techniques. All reactions were
monitored by TLC (silica-coated plates and visualizing under UV
light). Ethylacetate and hexane were used as eluent. Air sensitive
reagents were transferred by syringe or double-ended needle.
Evaporation of solvents was performed at reduced pressure on
a Buchi rotary evaporator. Infrared (IR) spectra were recorded on
a Perkin–Elmer 683 spectrometer. Optical rotations were obtained
on a Jasco Dip 360 digital polarimeter at 25 ꢁC. Melting points are
uncorrected. 1H and 13C NMR spectra were recorded in CDCl3 on
varian Gemini 200, Bruker 300, varian unity 400 and 500 NMR
The esterification carried out between fragments 5 and 6
resulted in compound 32 in 35% yield by modified Yonemitsu–
Yamaguchi protocol as previously reported by Paterson et al.8
(Scheme 4). Finally oxidative removal of the PMB ether with DDQ in
buffered CH2Cl2 gave (ꢀ)-baconipyrone C 3 as a colourless oil. The
spectroscopic (1H NMR, 13C NMR, IR, mass) and physical data of
(ꢀ)-baconipyrone C 3 were in good agreement with the reported
data.8
spectrometers. Chemical shifts (d) are quoted in parts per million
and referenced to tetramethylsilane (TMS) as internal standard.
Coupling constants (J) are quoted in hertz. Mass spectra were
recorded in E1 conditions at 70 eV on an LC-MSD (Agilent tech-
nologies) spectrometers. All high resolution spectra were recorded
on QSTAR XL hybrid MS/MS system equipped with an ESI source
(IICT, Hyderabad). Column chromatographic separations were
performed on silica gel (60–120 and 100–200 mesh) supplied by
Acme Chemical Co., India.
O
a
O
O
6
5
+
OPMB
O
O
O
O
32
b
(-) Baconipyrone-C3
4.1.1. Ethyl (E,4S)-5-(benzyloxy)-4-methyl-2-pentenoate (14)
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP,
toluene, ꢀ78 ꢁC to ꢀ20 ꢁC, 1 h, 35%; (b) DDQ, CH2Cl2/pH 7 buffer (9:1), 1 h, 70%.
To a stirred solution of oxalyl chloride (10.58 g, 83.33 mmol) in
dry CH2Cl2 (120 mL) at ꢀ78 ꢁC, dry DMSO (7.81 g, 99.99 mmol) was
added drop wise. After 30 min, alcohol 13 (10.00 g, 55.55 mmol) in
CH2Cl2 (30 mL) was added over 10 min. After stirring for 2 h at
ꢀ78 ꢁC, Et3N (46.46 mL, 333.33 mmol) was added and stirred for
30 min, at ꢀ78 ꢁC, warmed to ꢀ30 ꢁC over 1 h and then to 0 ꢁC for
15 min. To this reaction mixture (ethoxycarbonylmethylene)
3. Conclusion
In conclusion, the total synthesis of (ꢀ)-baconipyrone C has
been achieved in stereocontrolled manner by the creation of five
consecutive stereogenic centres via desymmetrization and the

3548
J.S. Yadav et al. / Tetrahedron 65 (2009) 3545–3552
triphenyl phosphorane (29.00 g, 83.33 mmol) in 100 mL CH2Cl2
was added and stirred for 12 h at room temperature and then
quenched by the addition of water and extracted with CH2Cl2
(3ꢂ100 mL). The combined organic layers were washed with water,
brine, dried (Na2SO4) and concentrated. The crude was purified by
288.24 mmol, 2.0 M) in ether was added drop wise until it become
a clear solution. After 30 min at this temperature, the solution was
cooled to ꢀ30 ꢁC and epoxy alcohol 16 (8.00 g, 36.03 mmol) in
ether 40 mL was added drop wise. After being stirred for 2 h at
ꢀ30 ꢁC, and then 4 h at ꢀ20 ꢁC, the mixture was poured into sat-
urated aqueous NH4Cl and the blue aqueous layer was thoroughly
extracted with CH2Cl2 (3ꢂ100 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated un-
der reduced pressure. The contamination of the 1,2-diol was
eliminated by exposing the crude reaction mixture to NaIO4 fol-
silica gel column chromatography (1:9 EtOAc/hexane) to give yel-
25
low oil 14 in 85% (11.71 g) yield. Rf (1:9 EtOAc/hexane) 0.62; [a]
D
ꢀ6.4 (c 1.88, CHCl3); IR (KBr): 3030, 2974, 1718, 1653, 1184, 1096,
741, 698 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
7.27 (5H, m, Ar–H),
6.90 (1H, dd, J¼15.6, 7.4 Hz, olefin), 5.8 (1H, dd, J¼15.6, 1.5 Hz,
olefin), 4.49 (2H, s, benzylic CH2), 4.17 (2H, q, J¼7.4 Hz, OCH2CH3),
3.45–3.28 (2H, m, CH2OBn), 2.73–2.52 (1H, m, CHCH3), 1.30 (3H, t,
J¼7.4 Hz, OCH2CH3), 1.10 (3H, d, J¼6.7 Hz, CHCH3); 13C NMR
lowed by silica gel column chromatography (2:3, EtOAc/hexane) to
25
give pure 1,3-diol 7 (5.57 g, 65%). Rf (2:3, EtOAc/hexane) 0.38; [a]
D
ꢀ4.2 (c 1.22, CHCl3); IR (Neat): 3431, 3030, 2966, 2875, 1638, 1456,
(75 MHz, CDCl3):
d
166.4,150.9,128.4,128.2,127.5,127.4,120.8, 73.7,
1095, 1027, 739, 698 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
7.36–7.24
73.0, 59.9, 36.6, 15.8, 14.1; ESI-MS: m/z 249 [MH]þ. HRMS (ESI):
(5H, m, Ar-H), 4.50 (2H, s, benzylic CH2), 3.72 (1H, dd, J¼9.4, 1.7 Hz,
CHOH), 3.65–3.49 (4H, m, CH2OBn, CH2OH), 3.36 (2H, br s, OH),
1.92–1.75 (2H, m, 2ꢂCHCH3), 1.01 (3H, d, J¼6.8 Hz, CHCH3), 0.75
[MNa]þ, found 271.1297. C15H20O3Na requires 271.1310.
4.1.2. (E,4S)-5-(Benzyloxy)-4-methyl-2-penten-1-ol (15)
(3H, d, J¼6.8 Hz, CHCH3); 13C NMR (75 MHz, CDCl3):
d 137.8, 128.4,
To a cooled (0 ꢁC) solution of 14 (11.00 g, 44.35 mmol) in dry
CH2Cl2 (120 mL), DIBAL-H (63.36 mL, 88.66 mmol, 20% solution in
toluene) was added slowly for 15 min and stirred for 2 h at 0 ꢁC,
before being quenched with methanol (3 mL) and sodium potas-
sium tartarate solution (100 mL). The reaction mixture was passed
through a short pad of Celite. The filtrate was concentrated and
purified the residue by column chromatography (1:4, EtOAc/hex-
127.7, 127.5, 79.9, 75.6, 73.5, 68.9, 37.3, 35.2, 13.4, 9.4; ESI-MS: m/z
239 [MH]þ. HRMS (ESI): [MNa]þ, found 261.1465. C14H22O3Na re-
quires 261.1466.
4.1.5. [((2R,3S,4R)-5-(Benzyloxy)-3-[1-(tert-butyl)-1,1-
dimethylsilyl]oxy-2,4-dimethylpentyl)oxy](tert-
butyl)dimethylsilane (17)
ane) to furnish allylic alcohol 15 (8.72 g, 95%) as a colourless liquid.
2,6-Lutidine (14.66 mL, 126.06 mmol) was added drop wise to
a cooled solution (0 ꢁC) of alcohol 7 (5.00 g, 21.01 mmol) in dry
CH2Cl2 (30 mL). After 10 min, tert-butyldimethylsilyltrifluoro-
methane sulfonate (TBSOTf, 14.47 mL, 63.03 mmol) was added
drop wise and stirring was continued for 2 h at 0 ꢁC. The re-
action mixture was diluted with CH2Cl2 (50 mL) and washed
with 5% aq H2SO4, NaHCO3, water and brine. The organic layer
was dried and concentrated in vacuo. The residue was purified
by column chromatography (1:19, EtOAc/hexane) to give di TBS
25
Rf (1:4, EtOAc/hexane) 0.48; [
a]
ꢀ4.85 (c 2.13, CHCl3); IR (Neat):
D
3444, 2925, 2856, 1637, 1094, 756, 698 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): 7.30 (5H, m, Ar–H), 6.69 (2H, m, olefin), 4.56 (2H, s,
d
benzylic CH2), 4.38–4.27 (2H, m, CH2OBn), 4.08 (2H, d, J¼3.8 Hz,
CH]CHCH2), 2.52 (1H, m, CHCH3), 1.6 (1H, br s, OH), 1.08 (3H, d,
J¼6.8 Hz, CHCH3); 13C NMR (75 MHz, CDCl3):
d 138.1, 134.3, 128.8,
128.0, 127.3, 127.2, 74.8, 72.6, 63.0, 36.2, 16.7; ESI-MS: m/z 229
[MNa]þ. HRMS (ESI): [MNa]þ, found 229.1198. C13H18O2Na requires
229.1204.
ether 17 as a colourless oil (8.41 g, 86%). Rf (1:19, EtOAc/hexane)
25
0.58; [
a
]
þ7.93 (c 0.91, CHCl3); IR (Neat): 2956, 2837, 1466,
D
4.1.3. (2S,3S)-3-[(1R)-2-(Benzyloxy)-1-methylethyl]oxiran-2-
ylmethanol (16)
1253, 1177, 1092, 836 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.28
(5H, m, Ar–H), 4.45 (2H, ABq, J¼12.0 Hz, benzylic CH2), 3.76 (1H,
dd, J¼7.17, 1.8 Hz, CHOTBS), 3.63 (1H, dd, J¼9.8, 4.9 Hz, 1H,
CH2OBn), 3.40–3.30 (2H, m, CH2OTBS), 3.20 (1H, dd, J¼8.7,
6.8 Hz, CH2OBn), 2.01–1.89 (1H, m, CHCH3), 1.81–1.69 (1H, m,
CHCH3), 0.94–0.84 (24H, m, 2ꢂ(CH3)3, 2ꢂCHCH3), 0.04 (6H, s,
(CH3)2Si), 0.02 (6H, s, (CH3)2Si); 13C NMR (75 MHz, CDCl3):
To a solution of (þ) DIPT (1.93 g, 8.25 mmol) in dry CH2Cl2
(100 mL) at ꢀ30 ꢁC containing 4 Å MS (3.50 g), sequentially
Ti(OiPr)4 (2.11 g, 7.43 mmol) and TBHP (8.18 g, 90.78 mmol) were
added and stirred for 30 min. A solution of alcohol 15 (8.50 g,
41.26 mmol) in CH2Cl2 (30 mL) was added and stirred for 10 h at
ꢀ30 ꢁC. It was then quenched with 45 mL of water and 30% aqueous
NaOH solution, saturated with NaCl (20 mL) and the resulting
mixture stirred vigorously for another 30 min at room temperature.
The resulting mixture was vacuum filtered through Celite and the
filter cake was washed well with CH2Cl2. The organic phase was
separated and the aqueous phase was extracted with CH2Cl2
(3ꢂ100 mL). Combined organic phases were washed with brine
and dried over Na2SO4. Removal of solvent under reduced pressure
and purification by column chromatography (3:7, EtOAc/hexane)
d
138.8, 128.3, 127.5, 127.4, 74.0, 73.3, 72.7, 65.5, 40.6, 36.0, 26.1,
26.0, 18.4, 18.3, 14.1, 11.2, –4.0, –4.2, ꢀ5.3, ꢀ5.4; ESI-MS: m/z 467
[MH]þ. HRMS (ESI): [MH]þ, found 467.3371. C26H51O3Si2 requires
467.3376.
4.1.6. (2R,4R)-3-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,4-
dimethylpentane-1,5-diol (18)
To a solution of di TBS ether 17 (8.00 g, 17.16 mmol) in methanol
(30 mL) was added 10% Pd/C (1.70 g) and the reaction mixture was
stirred under hydrogen atmosphere for 12 h at room temperature.
After completion of the reaction, mixture was filtered through
Celite pad to remove the catalyst. Concentrated in vacuo and pu-
rified by column chromatography (2:3, EtOAc/hexane) to give 1,5-
afforded 16 (8.20 g, 89%) as a viscous liquid. Rf (3:7, EtOAc/hexane)
25
0.42; [
a]
ꢀ26.12 (c 1.25, CHCl3);1 IR (Neat): 3442,1638,1455,1365,
D
1092, 741, 699 cmꢀ1; H NMR (200 MHz, CDCl3):
d 7.29 (5H, m, Ar–
H), 4.50 (2H, s, benzylic CH2), 3.84 (1H, m, CHOH), 3.57 (1H, dd,
J¼12.4, 3.8 Hz, CHOH), 3.44 (1H, dd, J¼5.2, 1.5 Hz, epoxide), 3.39
(1H, dd, J¼7.8, 3.7 Hz, epoxide), 2.93 (2H, m, CH2OBn), 1.84–
1.61(1H, m, CHCH3),1.60 (1H, br s, OH),1.0 (3H, d, J¼6.8 Hz, CHCH3);
diol 18 as a viscous liquid (3.41 g, 76%). Rf (2:3, EtOAc/hexane) 0.35;
25
[a
]
ꢀ1.2 (c 0.91, CHCl3); IR (Neat): 3457, 2956, 1466, 1177,
D
1092 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
3.82 (1H, dd, J¼5.3, 3.0 Hz,
13C NMR (75 MHz, CDCl3):
d
138.2, 128.3, 127.5, 127.4, 73.0, 72.6,
CHOTBS), 3.62–3.50 (5H, m, 2ꢂCH2OH, OH), 2.03 (1H, br s, OH),
2.01–1.89 (1H, m, CHCH3), 1.88–1.82 (1H, m, CHCH3), 0.99 (3H, d,
J¼7.2 Hz, CHCH3), 0.92 (9H, s, (CH3)3), 0.90 (3H, d, J¼7.5 Hz, CHCH3),
0.12 (3H, s, CH3Si), 0.10 (3H, s, CH3Si); 13C NMR (75 MHz, CDCl3):
61.8, 58.6, 58.0, 35.8, 13.4; ESI-MS: m/z 245 [MNa]þ. HRMS (ESI):
[MNa]þ, found 245.1148. C13H18O3Na requires 245.1153.
4.1.4. (2R,3R,4R)-5-(Benzyloxy)-2,4-dimethylpentane-1,3-diol (7)
d
76.2, 65.7, 65.5, 39.5, 39.0, 26.0, 18.3, 15.0, 12.1, ꢀ4.3,ꢀ4.4; ESI-MS:
To
a
cold (0 ꢁC) suspension of copper(I) iodide (27.45 g,
m/z 263 [MH]þ. HRMS (ESI): [MNa]þ, found 285.1850. C13H30O3Si
144.12 mmol) in dry ether (100 mL), MeLi (144.14 mL,
Na requires 285.1861.

J.S. Yadav et al. / Tetrahedron 65 (2009) 3545–3552
3549
4.1.7. (4R,6R)-5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4,6-
dimethylnonane-3,7-diol (19)
ddd, J¼11.7, 7.8, 3.9 Hz, CHOH), 3.20 (1H, d, J¼4.9 Hz, OH), 2.70–2.57
(2H, m, 2ꢂCHCH3,), 2.56–2.35 (4H, m, 2ꢂCH2CH3), 1.14 (3H, d,
J¼7.2 Hz, CHCH3), 1.05 (3H, t, J¼7.2 Hz, CH2CH3), 1.04 (3H, d,
J¼7.2 Hz, CHCH3), 1.03 (3H, t, J¼7.2 Hz, CH2CH3); 13C NMR (75 MHz,
To a solution of oxalyl chloride (5.81 g, 45.80 mmol) in dry
CH2Cl2 (30 mL) at ꢀ78 ꢁC, dry DMSO (7.15 g, 91.60 mmol) was
added drop wise. After 30 min, alcohol 18 (3.0 g, 11.45 mmol) in
CH2Cl2 (10 mL) was added over 10 min. After stirring for 2 h at
ꢀ78 ꢁC, Et3N (13.90 g, 137.40 mmol) was added slowly and stirred
for 30 min, and then warmed to ꢀ30 ꢁC and stirred further for
30 min. Hexane/toluene (3:1, 400 mL) was added to the reaction
mixture at ꢀ30 ꢁC, the resulting suspension was filtered through
Celite and concentrated in vacuo to give the dialdehyde.
CDCl3): d 215.6, 215.5, 73.4, 47.6, 47.3, 36.2, 34.7, 13.8, 10.0, 7.5, 7.30;
ESI-MS: m/z 223 [MNa]þ. HRMS (ESI): [MNa]þ, found 223.1308.
C11H20O3Na requires 223.1310.
4.1.10. (2R,3R,4S,5R,6R)-5-[(4-Methoxybenzyl)oxy]-2,4,6-trimethyl
heptane-1,3,7-triol (21)
To a stirred suspension of LiAlH4 (4.66 g, 124.60 mmol) in dry
THF (150 mL) at 0 ꢁC was added drop wise a solution of methyl
lactone 11 (16.00 g, 49.84 mmol) in dry THF (30 mL). The reaction
mixture was allowed to warm to 25 ꢁC and stirred for 4 h. Reaction
mixture was then cooled to 0 ꢁC and quenched with drop wise
addition of saturated aqueous NH4Cl. The precipitate formed was
filtered and washed with ethylacetate. The combined organic ex-
tracts were dried over Na2SO4 and concentrated under reduced
pressure, and the crude was purified by silica gel column chroma-
Freshly prepared EtMgBr (prepared in situ from 1.37 g
(57.25 mmol) of Mg and 6.24 g (57.25 mmol) of ethyl bromide in
20 mL of dry THF) was added drop wise to a stirred solution of the
above dialdehyde in dry THF (10 mL) at 0 ꢁC. After addition was
complete, the reaction mixture was stirred for 1 h before being
quenched with saturated aqueous NH4Cl, extracted with EtOAc
(3ꢂ50 mL), washed with brine and concentrated in vacuo. Column
chromatography using (1:5, EtOAc/hexane) afforded 19 (2.18 g,
60%) as mixture of diastereomers. Rf (1:5, EtOAc/hexane) 0.45; IR
tography (3:2, EtOAc/hexane) to afford the pure product 21
(Neat): 3437, 2928, 2855, 1712 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
(14.66 g, 90%) as a viscous liquid. Rf (3:2, EtOAc/hexane) 0.34; [a]
D
25
d
3.89–3.82 (1H, m, J¼8.7, 6.2 Hz, CHOTBS), 3.7 (1H, dd, J¼6.8,
þ1.8 (c 2.51, CHCl3); IR (Neat): 3445, 1032 cmꢀ1; 1H NMR (300 MHz,
2.6 Hz, CHOH), 3.55–3.48 (1H, dd, J¼5.9, 3.0 Hz, CHOH), 3.08 (1H, br
s, OH), 1.88–1.81 (1H, m, CHCH3), 1.77–1.70 (1H, m, CHCH3), 1.55–
1.45 (2H, m, CH2CH3), 1.33 (2H, m, CH2CH3), 0.99 (3H, d, J¼7.5 Hz,
CHCH3), 0.93 (6H, m, 2ꢂCH2CH3), 0.92 (9H, s, (CH3)3), 0.91 (3H, d,
J¼7.5 Hz, CHCH3), 0.14 (3H, s, CH3Si), 0.11 (3H, s, CH3Si); 13C NMR
CDCl3):
d
7.22 (2H, d, J¼8.7 Hz, Ar–H), 6.84 (2H, d, J¼8.5 Hz, Ar–H),
4.60 (2H, ABq, J¼10.4 Hz, benzylic CH2), 3.77 (4H, m, Ar–OCH3,),
3.75 (1H, dd, J¼10.5, 3.8 Hz, CHOPMB), 3.65 (1H, dd, J¼10.7, 4.2 Hz,
CHOH), 3.58 (2H, m, CHOH, CHOH), 3.50 (1H, dd, J¼9.2, 2.5 Hz,
CHOH), 2.01 (1H, m, CHCH3), 1.90–1.78 (2H, m, 2H, CHCH3), 1.42
(3H, br s, OH), 1.14 (3H, d, J¼6.7 Hz, CHCH3), 0.94 (3H, d, J¼6.7 Hz,
CHCH3), 0.72 (3H, d, J¼6.7 Hz, CHCH3); 13C NMR (75 MHz, CDCl3):
(75 MHz, CDCl3):
d 80.9, 74.0, 72.5, 40.9, 37.8, 29.7, 28.6, 27.6, 26.2,
11.7, 10.6, 9.7, ꢀ3.3, ꢀ3.9; ESI-MS: m/z 341 [MNa]þ. HRMS (ESI):
[MNa]þ, found 341.2488. C17H38O3 SiNa requires 341.2487.
d 159.8, 129.7,129.4, 114.2, 88.0, 76.4, 76.0, 68.6, 65.0, 55.1, 37.8, 37.0,
35.4, 14.6, 13.1, 11.4; ESI-MS: m/z 349 [MNa]þ. HRMS (ESI): [MNa]þ,
4.1.8. (4S,6S)-5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4,6-
found 349.2006. C18H30O5Na requires 349.1990.
dimethylnonane-3,7-dione (20)
To a stirred solution of oxalyl chloride (4.00 g, 31.45 mmol) in
dry CH2Cl2 (20 mL) at ꢀ78 ꢁC was added dry DMSO (4.92 g,
63.00 mmol) drop wise. After 30 min, alcohol 19 (2.00 g,
6.30 mmol) in CH2Cl2 (10 mL) was added over 10 min. After stirring
for 2 h at ꢀ78 ꢁC, Et3N (9.54 g, 94.35 mmol) was added slowly and
stirred for 30 min, and then warmed to ꢀ30 ꢁC and stirred further
for 30 min. Hexane/toluene (3:1, 300 mL) was added to the reaction
mixture at ꢀ30 ꢁC, the resulting suspension was filtered through
Celite, concentrated in vacuo and purification by column chroma-
4.1.11. 3-(4-Methoxybenzyloxy)-2-methyl-4-[2,2,5-trimethyl-
(4S,5S)-1,3-dioxan-4-yl]-(2R,3R,4R)-pentan-1-ol
2,2-Dimethoxypropane (22.40 mL, 184 mmol) and CSA (1.68 g,
36.80 mmol) were added successively to a solution of triol 21
(12.00 g, 36.80 mmol) in 120 mL mixture of CH2Cl2/Et2O (9:1). The
solution was stirred for 1 h at room temperature and then
quenched with saturated aqueous NaHCO3. The aqueous layer was
extracted with ether (4ꢂ100 mL). The organic layers were washed
with brine, dried over Na2SO4 and concentrated. The crude com-
pound was purified on column chromatography (2:3, EtOAc/hex-
tography (1:19, EtOAc/hexane) afforded diketo compound 20
25
(1.57 g, 79%) as a colourless oil. Rf (1:19, EtOAc/hexane) 0.50; [
a
]
ane) to afford the monoacetonide (12.36 g, 92%) as a white
crystalline solid. Rf (2:3, EtOAc/hexane) 0.65; mp: 92–93 ꢁC; [
D
25
þ35.93 (c 2.51, CHCl3); IR (Neat): 2928, 2855, 1712 cmꢀ1
;
1H NMR
a]
D
(300 MHz, CDCl3):
d
4.37 (1H, dd, J¼14.4, 6.2 Hz, CHOTBS), 2.74–
ꢀ39.5 (c 3.41, CHCl3); IR (Neat): 3475 cmꢀ1
;
1H NMR (300MHz,
7.19 (2H, d, J¼8.8 Hz, Ar–H), 6.83 (2H, d, J¼8.5 Hz, Ar–H),
2.61 (2H, m, CHCH3), 2.56–2.35 (4H, m, CH2CH3), 1.05 (3H, d,
J¼7.0 Hz, CH3CH), 1.03 (3H, t, J¼7.0 Hz, 3H, CH2CH3), 1.01 (3H, t,
J¼7.0 Hz, CH2CH3), 0.94 (3H, d, J¼7.0 Hz, CH3CH), 0.86 (9H, s,
CDCl3):
d
4.55 (2H, ABq, J¼10.4 Hz, benzylic CH2), 3.91–3.80 (2H, m, 2H,
CH2OH), 3.79 (3H, s, Ar–OCH3), 3.67 (1H, dd, J¼11.7, 5.8 Hz,
OCHCHCH3), 3.56–3.41 (3H, m, CH3CH2O and CH), 2.77–2.59 (1H, br
s, OH), 2.01–1.79 (3H, m, 3ꢂCHCH3), 1.39 (3H, s, CH3), 1.35 (3H, s,
CH3), 1.20 (3H, d, J¼7.2 Hz, CHCH3), 0.86 (3H, d, J¼7.2 Hz, CHCH3),
(CH3)3), 0.04 (6H, s, (CH3)2Si); 13C NMR (75 MHz, CDCl3):
d 213.2,
212.9, 74.7, 73.4, 51.3, 50.6, 36.1, 35.9, 18.0, 12.0, 11.4, 7.4, 7.3, ꢀ4.6,
ꢀ4.9; ESI-MS: m/z 315 [MH]þ. HRMS (ESI): [MNa]þ, found 337.2170.
C17H34O3SiNa requires 337.2174.
0.73 (3H, d, J¼7.2 Hz, CHCH3); 13C NMR (75 MHz, CDCl3):
d 159.0,
130.5, 128.5, 113,7, 97.8, 85.1, 75.0, 73.2, 66.0, 64.0, 55.2, 37.3, 36.0,
30.2, 29.7,19.5,16.3, 12.4, 9.8; ESI-MS: m/z 389 [MNa]þ. HRMS (ESI):
[MNa]þ, found 389.2309. C21H34O5Na requires 389.2303.
4.1.9. (4S,6S)-5-Hydroxy-4,6-dimethylnonane-3,7-dione (5)
To the above diketone 20 (0.50 g, 1.60 mmol) in THF (5 mL) was
added pyridinium hydrogen fluoride (2 mL) at 0 ꢁC and the reaction
mixture was stirred at 0 ꢁC for 2 h before being quenched with
saturated aqueous NaHCO3 until no further effervescence and
neutral pH was obtained. The reaction mixture was extracted with
EtOAc (3ꢂ30 mL), washed with saturated CuSO4, brine, dried
(Na2SO4) and concentrated in vacuo, and purification by column
4.1.12. (4R,5R)-4-{(1R,2R,3R)-4-(Benzyloxy)-2-[(4-methoxy-
benzyl)oxy]-1,3-dimethylbutyl}-2,2,5-trimethyl-1,3-dioxane (22)
To a stirred suspension of NaH (2.04 g, 42.60 mmol) in dry THF
(120 mL) under nitrogen atmosphere was added monoacetonide
(10.40 g, 28.40 mmol) in dry THF (40 mL) drop wise at 0 ꢁC. The
reaction mixture was allowed to warm to 25 ꢁC and then heated
under reflux for 1 h. It was then cooled to 25 ꢁC and benzyl bromide
(3.72 mL, 31.24 mmol) was added drop wise. Refluxed for 3 h and
cooled to 0 ꢁC, and then quenched with ice and extracted with
chromatography (3:7, EtOAc/hexane) afforded the pure alcohol 5
25
(0.26 g, 84%) as a colourless oil. Rf (3:7, EtOAc/hexane) 0.22; [a]
D
20
ꢀ15.60 (c 2.0, CHCl3) (lit.8
[
a
]
D
ꢀ16.4 (c 1.1, CHCl3)); IR (Neat):
3495, 2927, 2854,1711 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 3.94 (1H,

3550
J.S. Yadav et al. / Tetrahedron 65 (2009) 3545–3552
ether (3ꢂ100 mL). The combined extracts were washed with brine,
[MNa]þ. HRMS (ESI): [MNa]þ, found 543.2715. C32H40O6Na requires
543.2722.
dried over Na2SO4 and purified by column chromatography (1:5,
EtOAc/hexane) to afford 22 (12.28 g, 95%) as a colourless oil. Rf (1:5,
25
EtOAc/hexane) 0.55; [
a
]
ꢀ27.1 (c 5.64, CHCl3); IR(Neat): 1083,
4.1.15. 1-[1-[2-Benzyloxy-1-methyl-(1R)-ethyl]-3-methoxymethoxy-
2,4-dimethyl-5-phenylcarbonyloxy-(1R,2R,3R,4R)-
D
1036 cmꢀ1
;
1H NMR (300MHz, CDCl3):
d 7.30–7.21 (5H, m, Ar–H),
7.16 (2H, d, J¼8.3 Hz, Ar–H), 6.80 (2H, d, J¼8.3 Hz, Ar–H), 4.51 (2H,
ABq, J¼11.3 Hz, benzylic CH2), 4.45 (2H, s, benzylic CH2), 3.83 (1H, d,
J¼10.5 Hz, CHOH), 3.79 (3H, s, OCH3), 3.65 (1H, d, J¼5.2 Hz, CHOBn),
3.61 (1H, d, J¼4.5 Hz, CHOBn), 3.44 (1H, t, J¼11.3 Hz, CHOPMB),
3.37–3.28 (2H, m, CH2O), 2.14 (1H, m, CHCH3), 1.96–1.75 (2H, m,
CHCH3), 1.36 (3H, s, CH3), 1.34 (3H, s, CH3), 1.11 (3H, d, J¼6.7 Hz,
CHCH3), 0.86 (3H, d, J¼6.7 Hz, CHCH3), 0.66 (3H, d, J¼6.5 Hz,
pentyloxymethyl]-4-methoxybenzene (25)
DIPEA (25.52 mL,147.52 mmol) was added drop wise to a stirred
and cooled (0 ꢁC) solution of alcohol 24 (9.60 g, 18.44 mmol) in
CH2Cl2 (100 mL). After 15 min, methoxymethylene chloride
(MOMCl) (4.20 mL, 73.76 mmol) followed by DMAP (2.24 g,
18.44 mmol) was added drop wise over a period of 10 min and
stirring was continued for 1 h. The cold bath was removed and
stirring was continued for 20 h. The reaction mixture was diluted
with water and extracted with CH2Cl2 (3ꢂ50 mL). The combined
organic extracts were washed with brine, dried and evaporated.
The residue was purified by silica gel column chromatography (1:5,
CHCH3); 13C NMR (75 MHz, CDCl3):
d 158.8, 138.8, 129.4, 128.4,
128.2, 127.3, 127.3, 113.6, 97.9, 82.8, 74.4, 73.4, 73.0, 72.0, 66.3, 55.2,
36.9, 36.0, 30.3, 29.8, 19.5, 16.7, 12.4, 9.8; ESI-MS: m/z 479 [MNa]þ.
HRMS (ESI): [MNa]þ, found 479.2760. C28H40O5Na requires
479.2773.
EtOAc/hexane) to give MOM-ether 25 (8.32 g, 80%) as a pale yellow
25
oil. Rf (1:5, EtOAc/hexane) 0.58; [
a]
ꢀ9.1 (c 2.76, CHCl3); IR (Neat):
D
4.1.13. 7-Benzyloxy-5-(4-methoxybenzyloxy)-2,4,6-trimethyl-
(2R,3R,4S,5R,6R)-heptane-1,3-diol (23)
1719, 1610, 1034 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.94 (2H, d,
J¼6.8 Hz, Ar–H), 7.50 (1H, t, J¼7.5 Hz, Ar–H), 7.34 (2H, t, J¼7.5 Hz,
Ar–H), 7.28 (5H, m, Ar–H), 7.16 (2H, d, J¼8.3 Hz, Ar–H), 6.74 (2H, d,
J¼9.0 Hz, Ar–H), 4.63 (2H, s, benzylic CH2), 4.56 (2H, ABq, J¼11.3 Hz,
benzylic CH2), 4.47 (2H, s, CH2OBz), 4.39 (1H, dd, J¼10.5, 3.7 Hz,
CHOCH3), 4.22 (1H, dd, J¼10.5, 6.0 Hz, CHOCH3), 3.81 (1H, d,
J¼8.3 Hz, CHOH), 3.76 (3H, s, Ar–OCH3), 3.60 (1H, dd, J¼9.0, 5.2 Hz,
CHOPMB), 3.43 (2H, m, CH2OBn), 3.35 (3H, s, CH2OCH3), 2.19 (1H,
m, CHCH3), 2.06 (1H, m, CHCH3), 1.95 (1H, m, CHCH3), 1.14 (3H, d,
J¼6.7 Hz, CHCH3), 1.00 (3H, d, J¼7.5 Hz, CHCH3), 0.92 (3H, d,
To a solution of 22 (11.60 g, 25.44 mmol) in THF (80 mL) was
added aqueous 2 N HCl (63.60 mL, 127.2 mmol) and the resulting
reaction mixture was stirred for 5 h at 25 ꢁC. It was diluted with
ethylacetate and extracted the aqueous layer twice with ethyl-
acetate (2ꢂ100 mL). The combined organic layers were washed
with brine, dried over Na2SO4, evaporated the solvent under re-
duced pressure and purified by column chromatography (4:6,
EtOAc/hexane) to afford diol 23 (9.40 g, 89%) as a viscous liquid. Rf
25
(2:3, EtOAc/hexane) 0.45; [
a]
þ50.2 (c 1.38, CHCl3); IR(Neat):
J¼6.7 Hz, CHCH3); 13C NMR (75 MHz, CDCl3):
d 166.5, 158.8, 138.7,
D
3446 cmꢀ1
;
1H NMR (400MHz, CDCl3):
d
7.34–7.24 (5H, m, Ar–H),
132.7, 131.3, 130.4, 129.4, 128.6, 128.3, 128.2, 127.4, 127.3, 113.6, 98.3,
83.7, 81.0, 73.7, 73.04, 72.3, 76.2, 55.7, 55.2, 38.0, 36.7, 36.0, 16.2,
14.8, 11.0; ESI-MS: m/z 587 [MNa]þ. HRMS (ESI): [MNa]þ, found
587.2962. C34H44O7Na requires 587.2984.
7.09 (2H, d, J¼8.4 Hz, Ar–H), 6.80 (2H, d, J¼8.4 Hz, Ar–H), 4.49 (2H,
s, benzylic CH2), 4.45 (2H, ABq, J¼10.7 Hz, benzylic CH2), 4.00 (1H,
br s, OH), 3.79 (3H, s, Ar–OCH3), 3.77 (1H, br s, OH), 3.67 (1H, dd,
J¼8.4, 3.8 Hz, CHOH), 3.60–3.43 (5H, m, CH2OH, CH2OBn, CHOPMB),
2.13–2.04 (1H, m, CHCH3), 1.88–1.78 (2H, m, 2ꢂCHCH3), 1.11 (3H, d,
J¼6.9 Hz, CHCH3), 0.98 (3H, d, J¼6.9 Hz, CHCH3), 0.70 (3H, d,
4.1.16. 7-Benzyloxy-5-(4-methoxybenzyloxy)-3-methoxymethoxy-
2,4,6-trimethyl-(2R,3R,4R,5R,6R)-heptane-1-ol (26)
J¼6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3):
d
159.3, 138.4,
To a solution of benzoate ester 25 (7.60 g, 13.44 mmol), aqueous
3 N KOH solution (67.20 mL, 201.6 mmol), methanol (67.20 mL) and
THF (67.20 mL) were added in 1:1:1 ratio. The reaction mixture was
stirred for 5 h at 25 ꢁC. Removed the solvent under reduced pres-
sure, diluted with ethylacetate and extracted the aqueous layer
twice with ethylacetate. The combined organic layers were washed
with brine, dried over Na2SO4 and concentrated in vacuo, and the
crude product obtained was purified by column chromatography
130.0,129.3,128.3,127.6,127.5,113.8, 86.8, 76.7, 75.6, 73.1, 72.1, 69.0,
55.2, 37.2, 36.7, 34.6, 14.8,13.2,11.6; ESI-MS: m/z 439 [MNa]þ. HRMS
(ESI): [MNa]þ, found 439.2454. C25H36O5Na requires 439.2460.
4.1.14. 1-[1-[2-Benzyloxy-1-methyl-(1R)-ethyl]-3-hydroxy-2,4-
dimethyl-5-phenylcarbonyloxy-(1R,2S,3R,4R)-pentyloxymethyl]-
4-methoxybenzene (24)
To a solution of diol 23 (9.03 g, 21.67 mmol) in dry CH2Cl2
(80 mL) at 0 ꢁC were added Et3N (9.03 mL, 65.01 mmol), benzoyl
chloride (3.01 mL, 26.01 mmol) and catalytic amount of DMAP. It
was allowed to stir at room temperature for 3 h. The reaction
mixture was diluted with DCM and washed with 10% NaHCO3 so-
lution, water and brine successively. The organic layer was dried
over anhydrous Na2SO4 and concentrated in vacuo, the crude
obtained was purified through column chromatography (1:4,
(1:3, EtOAc/hexane) to get 26 (5.56 g, 90%) as a colourless viscous
25
liquid. Rf (1:3, EtOAc/hexane) 0.55; [
a]
þ12.2 (c 3.08, CHCl3); IR
D
(Neat): 3466, 1034 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d 7.31–7.22
(5H, m, Ar–H), 7.16 (2H, d, J¼9.0 Hz, Ar–H), 6.79 (2H, d, J¼8.3 Hz,
Ar–H), 4.62 (1H, d, J¼6.8 Hz, benzylic CH), 4.55 (1H, d, J¼10.5 Hz,
benzylic CH), 4.51–4.43 (4H, m, benzylic CH2, CH2OCH3), 3.78 (3H, s,
OCH3), 3.71 (1H, d, J¼8.3 Hz, CHOMOM), 3.64 (1H, m, CHOBn), 3.54
(1H, dd, J¼9.0, 5.2 Hz, CHOPMB), 3.48–3.38 (2H, m, CHOBn, CHOH),
3.35 (3H, s, CH2OCH3), 3.31 (1H, m, CHOH), 2.72 (1H, br s, OH), 2.13
(1H, m, CHCH3), 1.86 (1H, m, CHCH3), 1.75 (1H, m, CHCH3), 1.08 (3H,
d, J¼6.8 Hz, CHCH3), 0.94 (3H, d, J¼6.8 Hz, CHCH3), 0.87 (3H, d,
EtOAc/hexane) to get 24 as a pale yellow liquid in 94% (10.61 g)
25
yield. Rf (1:4, EtOAc/hexane) 0.38; [
a
]
D
þ40.4 (c 2.35, CHCl3); IR
(Neat): 3479, 1717, 1611, 1032 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
8.01 (2H, d, J¼6.5 Hz, Ar–H), 7.51 (1H, t, J¼7.8 Hz, Ar–H), 7.40 (2H,
J¼6.8 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3):
d 159.0, 138.7,
t, J¼7.8 Hz, Ar–H), 7.29 (5H, m, Ar–H), 7.09 (2H, d, J¼9.1 Hz, Ar–H),
6.75 (2H, d, J¼9.1 Hz, Ar–H), 4.52–4.43 (5H, m, benzylic CH2,
CHOBz), 4.38–4.32 (1H, m, CHOBz), 3.77 (4H, s, Ar–OCH3, CHOH),
3.63 (1H, m, CHOPMB), 3.58 (1H, br s, OH), 3.54 (1H, d, J¼7.8 Hz,
CHOBn), 3.47 (1H, d, J¼7.8 Hz, CHOBn), 2.11 (1H, m, CHCH3), 1.99
(1H, m, CHCH3), 1.90 (1H, m, CHCH3), 1.08 (3H, d, J¼6.5 Hz, CHCH3),
1.03 (3H, d, J¼7.8 Hz, CHCH3), 0.93 (3H, d, J¼6.5 Hz, CHCH3); 13C
131.0, 129.0, 128.3, 127.5,127.5,113.7, 98.3, 84.5, 81.4, 74.2, 73.1, 72.3,
65.4, 55.9, 55.2, 39.0, 37.6, 36.3, 15.9, 14.5, 11.9; ESI-MS: m/z 483
[MNa]þ. HRMS (ESI): [MNa]þ, found 483.2710. C27H40O6Na requires
483.2722.
4.1.17. 7-Benzyloxy-5-(4-methoxybenzyloxy)-3-methoxymethoxy-
2,4,6-trimethyl-(2S,3S,4R,5R,6R)-heptanal (27)
To a clear solution of IBX (4.92 g, 17.52 mmol) in DMSO
(17.40 mL, 1 M) at 25 ꢁC was added drop wise a solution of alcohol
26 (5.40 g, 11.7 mmol) in dry DCM. The resulting mixture was
NMR (75 MHz, CDCl3):
d
166.9, 159.3, 138.4, 132.6, 130.6, 130.2,
129.5, 129.4, 128.3, 128.2, 127.6, 127.5, 113.9, 86.5, 75.6, 73.2, 72.2,
70.9, 67.4, 55.3, 36.8, 36.3, 34.4, 15.0, 13.6, 11.1; ESI-MS: m/z 543

J.S. Yadav et al. / Tetrahedron 65 (2009) 3545–3552
3551
stirred for 1 h at 25 ꢁC. Diluted with ether and the solid was filtered
through Celite pad. The filtrate was washed twice with saturated
aqueous NaHCO3 solution, water and brine, and purified by flash
C]CCH2CH3), 2.27–2.17 (1H, m, CHCH3), 1.97 (1H, m, CHCH3), 1.94
(3H, s, CCH3), 1.90 (3H, s, CCH3), 1.13 (6H, d, J¼7.4 Hz, CHCH3,
CHCH3), 1.08 (3H, t, J¼7.4 Hz, CH2CH3), 0.93 (3H, d, J¼7.4 Hz,
column chromatography (1:4, EtOAc/hexane) afforded aldehyde 27
CHCH3); 13C NMR (75 MHz, CDCl3):
d 179.8, 164.9, 164.0, 158.8,
25
(4.83 g, 90%) as viscous liquid. Rf (1:4, EtOAc/hexane) 0.52; [
a
]
138.7, 131.6, 128.7, 128.2, 127.4, 119.2, 117.8, 113.6, 97.8, 83.5, 81.5,
73.8, 73.1, 72.2, 55.6, 55.2, 39.2, 38.0, 36.1, 29.6, 24.8, 16.3, 15.0, 11.2,
10.3, 9.5, 9.4; ESI-MS: m/z 581 [MH]þ. HRMS (ESI): [MH]þ, found.
581.3470. C35H49O7 requires 581.3478.
D
þ9.1 (c 2.45, CHCl3); IR (Neat): 1724, 1032 cmꢀ1; 1H NMR (300 MHz,
CDCl3):
d
9.60 (1H, d, J¼2.9 Hz, CHO), 7.30–7.26 (5H, m, Ar–H), 7.16
(2H, d, J¼8.8 Hz, Ar–H), 6.80 (2H, d, J¼8.8 Hz, Ar–H), 4.60 (1H, d,
J¼6.5 Hz, benzylic CH), 4.56 (1H, d, J¼8.0 Hz, benzylic CH), 4.45 (4H,
m, benzylic CH2, CH2OBn), 4.02 (1H, dd, J¼8.0, 2.1 Hz, CHOMOM),
3.79 (3H, s, Ar–OCH3), 3.55 (1H, dd, J¼8.7, 5.1 Hz, CHOCH3), 3.41
(1H, dd, J¼8.7, 6.5 Hz, CHOCH3), 3.37 (1H, dd, J¼8.0, 4.3 Hz,
CHOPMB), 3.29 (3H, s, CH2OCH3), 2.55 (1H, dqd, J¼7.3, 6.5, 2.9 Hz,
CH3CHCHO), 2.15 (1H, m, CHCH3), 1.87 (1H, m, CHCH3), 1.09 (3H, d,
J¼7.3 Hz, CHCH3), 0.97 (3H, d, J¼6.5 Hz, CHCH3), 0.93 (3H, d,
4.1.19. 2-(1S,2S,3S,4R,5R)-6-(Benzyloxy)-2-hydroxy-4-[(4-methoxy-
benzyl)oxy]-1,3,5-trimethylhexyl-6-ethyl-3,5-dimethyl-4H-
4-pyranone (30)
Bu4NBr (1.67 g, 5.16 mmol) was added to the solution of TMSCl
(0.67 mL, 5.16 mmol) in dry CH2Cl2 at 0 ꢁC. After stirring for 1 h,
a solution of compound 29 (1.00 g, 1.72 mmol) in CH2Cl2 was in-
troduced and the mixture was stirred at ꢀ10 ꢁC for 14 h. The mix-
ture was quenched with saturated aqueous NaHCO3, the aqueous
layer was extracted with CH2Cl2, the combined organic layers were
washed with brine, dried over Na2SO4, filtered and evaporated.
Purification of the residue by column chromatography (2:3, EtOAc/
J¼7.3 Hz, CHCH3); 13C NMR (75 MHz, CDCl3):
d 204.1, 159.0, 138.6,
131.0, 128.9, 128.2, 127.6, 127.4, 113.7, 97.8, 83.7, 79.6, 73.9, 73.0,
72.2, 55.7, 55.1, 50.4, 38.3, 36.2, 15.9, 11.6, 11.4; ESI-MS: m/z 481
[MNa]þ. HRMS (ESI): [MNa]þ, found 481.2548. C27H38O6Na requires
481.2566.
hexane) afforded a secondary free hydroxy compound 30 (0.70 g,
25
4.1.18. 13-Benzyloxy-7-hydroxy-11-(4-methoxybenzyloxy)-9-
methoxymethoxy-4,6,8,10,12-pentamethyl-(8R,9R,10R,11R,12R)-
tridecane-3,5-dione (29)
76%) as a colourless liquid. Rf (2:3, EtOAc/hexane) 0.45; [
a
]
D
þ12.21
(c 1.5, CHCl3); IR (Neat): 3447, 1653, 1592, 1513, 1457, 1037,
758 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
7.37–7.28 (5H, m, Ar–H),
A solution of LDA in THF was prepared by adding n-BuLi (2.5 M
in n-hexane, 8.73 mL, 21.82 mmol) to a solution of (iPr)2NH
(3.30 mL, 23.52 mmol) in dry THF (20 mL) at 0 ꢁC with stirring
under argon. After 20 min, it was cooled to ꢀ78 ꢁC and diketone 9
(1.24 g, 8.73 mmol) in THF (4 mLþ4 mL) was added drop wise to the
stirred solution. HMPA (8 mL) was added and the mixture was
stirred for 15 min at ꢀ78 ꢁC then gradually brought to 0 ꢁC over
a period of 1 h. Again the mixture was cooled to ꢀ78 ꢁC, then al-
dehyde 25 (4.00 g, 8.73 mmol) in THF (8 mLþ8 mL) was added drop
wise to the mixture and then stirring was continued for 1 h at
ꢀ78 ꢁC. The reaction was quenched with saturated NH4Cl solution
at ꢀ78 ꢁC and gradually brought to room temperature. It was di-
luted with ether and the aqueous layer extracted twice with ether.
The combined organic phases were successively washed with wa-
ter and brine, and dried over Na2SO4. The solvent was removed in
vacuo to afford the diastereomeric mixture of aldol products 28 as
viscous liquid.
To the above crude mixture (5.3 g, 8.83 mmol) in dry CH2Cl2
(20 mL) under argon atmosphere was added Dess–Martin period-
inane (7.50 g, 17.68 mmol) at 0 ꢁC. The reaction mixture was stirred
for 1 h at 25 ꢁC and diluted with ether. The solid was filtered, the
combined organic layers washed with saturated aqueous NaHCO3
and dried. Solvent was evaporated under reduced pressure to afford
the triketone.
7.14 (2H, d, J¼9.0 Hz, Ar–H), 6.81 (2H, d, J¼8.3 Hz, Ar–H), 4.52 (2H, s,
benzylic CH2), 4.51 (2H, ABq, J¼10.6 Hz, benzylic CH2), 4.18 (1H, d,
J¼9.8 Hz, 1H, CHOH), 3.78 (3H, s, Ar–OCH3), 3.66 (1H, dd, J¼5.3 Hz,
CHOBn), 3.60–3.50 (3H, m, 3H, CH–OBn, CH–OPMB,
CH]CHCHCH3), 3.13–3.02 (1H, m, CHCH3), 2.62 (2H, q, J¼7.6 Hz,
CH2CH3), 2.20–2.08 (1H, m, CHCH3), 2.00 (4H, m, CCH3, CHCH3),
1.94 (3H, s, CCH3), 1.88 (3H, s, CCH3), 1.20 (3H, t, J¼7.5 Hz, CH2CH3),
1.16 (3H, d, J¼7.5 Hz, CHCH3), 1.08 (6H, d, J¼6.0 Hz, CHCH3, CHCH3);
13C NMR (75 MHz, CDCl3):
d 179.8, 164.8, 163.8, 159.3, 138.4, 130.0,
129.3, 128.3, 127.63, 127.6, 119.2, 117.2, 113.8, 86.5, 75.6, 73.2, 72.2,
71.9, 55.2, 38.6, 36.8, 34.2, 24.7, 15.03, 15.0, 14.4, 11.1, 9.6, 9.5; ESI-
MS: m/z 559 [MNa]þ. HRMS (ESI): [MNa]þ found 559.3043.
C33H44O6Na requires 559.3035.
4.1.20. 2-(1S,2S,3S,4R,5R)-2,6-Dihydroxy-4-[(4-methoxybenzyl)oxy]-
1,3,5-trimethylhexyl-6-ethyl-3,5-dimethyl-4H-4-pyranone (31)
To a stirred suspension of Raney-Ni (1.20 g) in ethanol was
added alcohol 30 (0.60 g, 1.12 mmol) in ethanol under hydrogen
atmosphere at room temperature. The reaction mixture was stirred
for 5 h at room temperature. The reaction mass was filtered
through Celite, concentrated in vacuo and purified by column
chromatography (3:2, EtOAc/hexane) to afford product 31 (0.45 g,
25
90%) as a viscous liquid. Rf (3:2, EtOAc/hexane) 0.22; [
a
]
D
ꢀ9.8 (c
0.91, CHCl3); IR (Neat): 3447, 2969, 2930, 1653, 1592, 1037,
758 cmꢀ1 1H NMR (300 MHz, CDCl3):
7.21 (2H, d, J¼8.7 Hz, Ar–
The crude triketone (w5.3 g, 8.86 mmol) in dry THF (20 mL) was
added to the stirred solution of TPP (11.62 g, 44.3 mmol) and CCl4
(8.55 mL, 88.6 mmol) in THF (50 mL) under an atmosphere of argon
and the reaction mixture was allowed to stir at room temperature
for 36 h. The reaction mixture was diluted with ether and filtered
through Celite pad. The combined organic layers were washed with
NaHCO3 solution, brine and dried over Na2SO4. The solvent was
removed in vacuo and purified by flash column chromatography
;
d
H), 6.81 (2H, d, J¼8.3 Hz, Ar–H), 4.61 (2H, s, benzylic CH2), 4.17 (1H,
d, J¼9.8 Hz, CHOH), 3.81 (1H, m, CH]CHCHCH3), 3.77 (3H, s, OCH3),
3.66 (1H, dd, J¼10.5, 3.8 Hz, CHOH), 3.57 (1H, dd, J¼4.6, 3.0 Hz,
CHOPMB), 3.37 (1H, br s, OH), 3.08 (1H, td, J¼13.6, 7.5 Hz, CHOH),
2.58 (2H, q, J¼7.5 Hz, CH2CH3), 2.04–1.92 (2H, m, CHCH3), 1.95
(3H, s, CCH3), 1.87 (3H, s, CCH3), 1.19 (3H, t, J¼7.5 Hz, CH2CH3), 1.14–
1.04 (9H, m, 3ꢂCHCH3); 13C NMR (75 MHz, CDCl3):
d 179.6, 164.8,
(1:3, EtOAc/hexane) to afford
steps) as viscous liquid. Rf (1:3, EtOAc/hexane) 0.28; [
1.92, CHCl3); IR (Neat): 1656,1611 cmꢀ1; 1H NMR (400 MHz, CDCl3):
7.28 (5H, m, Ar–H), 7.17 (2H, d, J¼8.9 Hz, Ar–H), 6.79 (2H,
g
-pyrone 29 (2.27 g, 45% over three
163.8, 159.4, 129.8, 129.3, 117.7, 113.9, 96.1, 87.5, 75.9, 71.8, 64.9, 55.1,
38.8, 37.7, 35.3, 24.7, 15.0, 14.4, 11.2, 10.8, 9.7, 9.5; ESI-MS: m/z
447 [MH]þ. HRMS (ESI): [MH]þ, found 447.2753. C26H38O6 requires
447.2746.
25
a]
ꢀ39.6 (c
D
d
d, J¼8.9 Hz, Ar–H), 4.63 (1H, d, J¼10.4 Hz, benzylic CH2), 4.51 (1H, d,
J¼11.8 Hz, benzylic CH2), 4.48 (2H, s, benzylic CH2), 4.31 (1H, d,
J¼5.9 Hz, OCH–OCH3), 4.17 (1H, d, J¼5.9 Hz, OCH–OCH3), 4.02 (1H,
d, J¼8.9 Hz, CHOMOM), 3.78 (3H, s, Ar–OCH3), 3.62 (1H, dd, J¼5.9,
8.9 Hz, CH–OBn), 3.43–3.37 (2H, m, CH–OBn, CH–OPMB), 3.16 (3H,
s, OCH2–OCH3), 3.12 (1H, m, C]CCHCH3), 2.50 (2H, q, J¼7.4 Hz,
4.1.21. (2S,3S,4R,6R)-6-(6-Ethyl-3,5-dimethyl-4-oxo-4H-2-
pyranyl)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-
oxoheptanoic acid (6)
To a stirred solution of oxalyl chloride (0.51 g, 4.02 mmol) in dry
CH2Cl2 (3 mL) at ꢀ78 ꢁC, dry DMSO (0.63 g, 8.04 mmol) was added

3552
J.S. Yadav et al. / Tetrahedron 65 (2009) 3545–3552
drop wise. After 30 min, diol 31 (0.30 g, 0.67 mmol) in CH2Cl2
(2 mL) was added over 10 min. After stirring for 2 h at –78 ꢁC, Et3N
(1.7 mL, 12.06 mmol) was added slowly and stirred for 30 min, and
then warmed to ꢀ30 ꢁC and stirred further for 30 min. Hexane/
toluene (3:1, 300 mL) was added to the reaction mixture at ꢀ30 ꢁC,
the resulting suspension was filtered through Celite and concen-
trated in vacuo to give the keto aldehyde.
4.1.23. Baconipyrone C (3)
To a stirred solution of 26 (0.03 g, 0.047 mmol) in 2 mL mixture
of CH2Cl2/pH 7 buffer (9:1), DDQ (0.021 g, 0.094 mmol) was added
at 0 ꢁC. The reaction mixture was stirred for 1 h at room tempera-
ture before being quenched with NaHCO3. The product was purified
by flash column chromatography (7:3, EtOAc/hexane) to afford 3
25
(0.017 g, 70%) as colourless oil. Rf (7:3, EtOAc/hexane) 0.28; [a]
D
20
To a solution of crude keto aldehyde (w0.30 g, 0.67 mmol) in
DMSO (2 mL) was added sodium dihydrogen phosphate (0.10 g,
0.64 mmol) solution at 0 ꢁC. To this well stirred mixture at 0 ꢁC
was added saturated sodium chlorite (0.092 g, 1.01 mmol) solution
and allowed it to stir at room temperature over 2 h before being
poured into brine solution and extracted with diethyl ether
(6ꢂ20 mL). The combined organic layers were dried and concen-
trated in vacuo. Silica gel column chromatography (1:3, acetone/
hexane) gave a pure keto acid 6 (0.25 g, 80%) as a viscous liquid. Rf
ꢀ70.20 (c 0.4, MeOH) (lit.8 [
a
]
D ꢀ73.3 (c 0.77, MeOH)); IR (Neat):
3443, 1718, 1652, 1596 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
5.47 (1H,
dd, J¼9.2, 3.7 Hz, CHO(C]O)), 4.14 (1H, q, J¼6.9 Hz, C]CCHCH3),
3.55 (1H, t, J¼7.3 Hz, CHOH), 3.39 (1H, br s, OH), 2.86 (1H, dq, J¼8.7,
7.3 Hz, CHCH3), 2.83 (2H, m, CHCH3), 2.75 (1H, dq, J¼18.3, 7.3 Hz,
CHaCHbCH3), 2.55 (2H, q, J¼7.3 Hz, CH2CH3), 2.54 (1H, m, CHCH3),
2.51 (1H, dq, J¼18.3, 7.3 Hz, CHaCHbCH3), 2.40 (1H, dq, J¼18.3,
7.3 Hz, CHaCHbCH3), 2.34 (1H, dq, J¼18.3, 7.3 Hz, CHaCHbCH3), 2.09
(3H, s, CCH3), 1.93 (3H, s, CCH3), 1.39 (3H, d, J¼7.3 Hz, CHCH3), 1.22
(3H, d, J¼7.3 Hz, CHCH3), 1.16 (3H, t, J¼7.3 Hz, CH2CH3), 1.09 (3H, d,
J¼7.3 Hz, CHCH3),1.02 (3H, d, J¼7.3 Hz, CHCH3),1.01 (3H, t, J¼7.3 Hz,
CH2CH3), 0.91 (3H, t, J¼7.3 Hz, CH2CH3), 0.86 (3H, d, J¼6.6 Hz,
25
20
(1:3, acetone/hexane) 0.45; [
a]
ꢀ94.2 (c 0.75, CHCl3) (lit.8
[a]
D
D
ꢀ96.5 (c 0.4, CHCl3)); IR (Neat): 3440–2700, 1730, 1651, 1585, 1177,
1037, cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
7.16 (2H, d, J¼8.3 Hz, Ar–
H), 6.85 (2H, d, J¼8.3 Hz, Ar–H), 4.55 (1H, d, J¼10.6 Hz, benzylic
CH), 4.26 (1H, d, J¼10.6 Hz, benzylic CH), 3.92 (1H, q, J¼6.8 Hz,
C]CCHCH3), 3.85 (1H, d, J¼7.6, 2.3 Hz, CHOPMB), 3.79 (3H, s,
OCH3), 3.06 (1H, dq, J¼9.8, 6.7 Hz, CHCH3), 2.82 (1H, qd, J¼7.2,
2.6 Hz, CHCH3), 2.54 (2H, q, J¼7.6 Hz, CH2CH3), 1.95 (3H, s, CCH3),
1.93 (3H, s, CCH3), 1.25 (3H, d, J¼6.7 Hz, CHCH3), 1.24 (3H, d,
J¼6.7 Hz, CHCH3), 1.14 (3H, t, J¼7.5 Hz, CH2CH3), 0.87 (3H, d,
CHCH3); 13C NMR (75 MHz, CDCl3):
d 211.9, 210.8, 210.4, 179.7, 174.1,
164.6, 160.6, 120.4, 118.30, 77.50, 73.8, 51.0, 48.6, 47.3, 45.8, 41.1,
35.1, 24.7, 15.1, 14.1, 13.4, 13.1, 11.3, 9.9, 9.7, 9.5, 7.7, 7.3; ESI-MS: m/z
521.3 [MH]þ. HRMS (ESI): [MNa]þ, found 543.2932. C29H44O8 re-
quires 543.2933.
Acknowledgements
J¼6.7 Hz, CHCH3); 13C NMR (75 MHz, CDCl3):
d 209.6, 180.0, 176.4,
165.0, 160.0, 159.3, 129.8, 129.5, 120.4, 118.4, 113.7, 84.7, 74.0, 55.2,
51.0, 46.3, 41.2, 24.8, 13.5, 12.7, 12.5, 11.2, 9.9, 9.5; ESI-MS: m/z 459
[MH]þ. HRMS (ESI): [MH]þ, found 459.2377. C26H35O7 requires
459.2382.
K.S. thanks UGC, India for the award of research fellowship.
References and notes
1. (a) Review: Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75; (b) Davies-Coleman, M. T.;
Garson, M. J. Nat. Prod. Rep. 1998, 15, 477; (c) Norcross, R. D.; Paterson, I. Chem.
Rev. (Washington, D.C.) 1995, 95, 2041.
4.1.22. p-Methoxybenzyl baconipyrone C (32)
2,4,6-Trichlorobenzoyl chloride (0.71 mL, 4.62 mmol) was
added to a stirred solution of 6 (0.10 g, 0.22 mmol) and Et3N
(0.7 mL, 5.06 mmol) in toluene (10 mL) at ꢀ78 ꢁC. After stirring for
20 min, compound 5 (0.065 g, 0.33 mmol) and DMAP (1.33 g,
11.00 mmol) in toluene were added to the above compound, and
the reaction mixture was warmed to ꢀ20 ꢁC and the resulted white
slurry was stirred at ꢀ20 ꢁC for 30 min, before being quenched with
saturated aqueous NaHCO3. The aqueous layer was extracted with
ethylacetate (4ꢂ20 mL), dried over Na2SO4 and concentrated in
vacuo. Silica gel column chromatography (1:4, acetone/hexane)
2. Pawlik, R. Chem. Rev. 1993, 93, 1911.
3. Manker, C. D.; Faulkner, D. J.; Stout, J. T.; Clardy, J. J. Org. Chem. 1989, 54, 5371.
4. (a) O’ Hagan, D. Nat. Prod. Rep. 1989, 6, 205; (b) O’ Hagan, D. The Polyketide
Metabolites; Horwood: Chichester, UK, 1991; (c) O’ Hagan, D. J. Nat. Prod. Rep.
1995, 12, 1.
5. (a) Garson, M. J. Chem. Rev. 1993, 93, 1699; (b) Garson, M. J.; Jones, D. D.; Small,
C. J.; Liang, J.; Clardy, J. Tetrahedron Lett. 1994, 35, 6921; (c) Garson, M. J.;
Goodman, J. M.; Paterson, I. Tetrahedron Lett. 1994, 35, 6929.
6. Brecknell, D. J.; Collett, L. A.; Davies-Coleman, M. T.; Garson, M. J.; Jones, D. D.
Tetrahedron 2000, 56, 2497.
7. Gillingham, D. G.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 3860.
8. Paterson, I.; Chen, D. Y.-K.; Acena, J. L.; Franklin, A. S. Org. Lett. 2000, 2, 1513.
9. Turks, M.; Murcia, M. C.; Scopelliti, R.; Vogel, P. Org. Lett. 2004, 6, 3031.
10. (a) Yadav, J. S.; Srinivas, R.; Sathaiah, K. Tetrahedron Lett. 2006, 47, 1603; (b)
Yadav, J. S.; Ravindar, K.; Reddy, B. V. S. Synlett 2007, 1957.
11. Yadav, J. S.; Rao, C. S.; Chandrasekhar, S.; Ramarao, A. V. Tetrahedron Lett. 1995,
36, 7717.
gave 32 (0.048 g, 35%) as a colourless oil. Rf (1:4, acetone/hexane)
25
0.54; [
a]
ꢀ29.20 (c 1.2, CHCl3); IR (Neat): 2929, 2855, 1719, 1653,
D
1612, 1459, 1249, 1177, 1037 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d 7.15
(2H, d, J¼8.5 Hz, Ar–H), 6.86 (2H, d, J¼8.5 Hz, Ar–H), 5.50 (1H, dd,
J¼7.7, 5.2 Hz, CHO(C]O)), 4.46 (1H, d, J¼10.7 Hz, benzylic CH),
4.21(1H, d, J¼10.7 Hz, benzylic CH), 3.94 (1H, q, J¼6.8 Hz,
C]CCHCH3), 3.83–3.78 (1H, m, CHOPMB), 3.80 (3H, s, OCH3), 2.92
(1H, dq, J¼9.8, 6.8 Hz, CHaCHbCH3, CHaCHbCH3), 2.87 (1H, dq,
J¼15.0, 7.2 Hz, CHaCHbCH3), 2.77–2.67 (2H, m, CHCH3, CHCH3),
2.54 (2H, q, J¼7.6 Hz, CH2CH3), 2.54 (1H, m, CHCH3), 2.47 (1H, m,
CHaCHbCH3), 2.38 (1H, dq, J¼7.2, 18.0 Hz, CHaCHbCH3), 1.98 (3H, s,
CCH3), 1.93 (3H, s, CCH3), 1.25 (3H, d, J¼7.2 Hz, CHCH3), 1.22 (3H, d,
J¼7.3 Hz, CHCH3), 1.14 (3H, t, J¼7.2 Hz, 3H, CH2CH3), 1.11 (3H, d,
J¼7.2 Hz, CHCH3), 1.07 (3H, d, J¼7.2 Hz, 3H, CHCH3), 1.03–0.96 (9H,
m, CHCH3, CH2CH3, CH2CH3), 0.75 (3H, d, J¼6.8 Hz, CHCH3); 13C
12. Yadav, J. S.; Abraham, S.; Reddy, M. M.; Sabitha, G.; Sankar, A. R.; Kunwar, A. C.
Tetrahedron Lett. 2002, 43, 3453.
13. Yadav, J. S.; Md. Ahmed, M. Tetrahedron Lett. 2002, 43, 7147.
14. Yadav, J. S.; Reddy, K. B.; Sabitha, G. Tetrahedron Lett. 2004, 45, 6475.
15. Yadav, J. S.; Reddy, K. B.; Sabitha, G. Tetrahedron 2008, 64, 1971.
16. Grisenti, P.; Ferraboschi, P.; Manzocchi, A.; Santaniello, E. Tetrahedron 1992, 48,
3827.
17. White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57, 5292.
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J. Am. Chem. Soc. 1987, 109, 5765.
19. Komatsu, K.; Tanino, K.; Miyashita, M. Angew. Chem. 2004, 116, 4441.
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2309.
21. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
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Franklin, A. S. Tetrahedron Lett. 1994, 35, 6925.
NMR (75 MHz, CDCl3):
d 211.5, 209.4, 179.6, 172.3, 164.7, 160.6,
159.3, 130.0, 129.4, 120.2, 118.3, 113.7, 83.3, 74.4, 73.1, 55.3, 50.6,
47.5, 46.2, 46.3, 41.2, 35.4, 34.9, 24.7, 13.2, 13.1, 12.9, 11.5, 11.3, 10.8,
9.8, 9.8, 7.7, 7.6; ESI-MS: m/z 641.3 [MH]þ. HRMS (ESI): [MH]þ,
found 641.3710. C37H52O9 requires 641.3690.
23. Aissa, C.; Riveiros, R.; Ragot, J.; Furstner, A. J. Am. Chem. Soc. 2003, 125, 15512.
24. Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Anne Lister, M. J. Am. Chem.
Soc. 1994, 116, 11287.