Asymmetric synthesis of palitantin by an enzymatic and organocatalytic approach

Article abstract of DOI:10.1016/j.tetasy.2009.02.055

The natural enantiomer of the fungal metabolite (+)-palitantin has been synthesized by adopting a chemoenzymatic and organocatalytic approach. Lipase catalyzed kinetic resolution, Sharpless asymmetric dihydroxylation and organocatalytic asymmetric hydroxy

Full text of DOI:10.1016/j.tetasy.2009.02.055

Tetrahedron: Asymmetry 20 (2009) 610–615
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of palitantin by an enzymatic
and organocatalytic approach
*
Tridib Mahapatra, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The natural enantiomer of the fungal metabolite (+)-palitantin has been synthesized by adopting a che-
moenzymatic and organocatalytic approach. Lipase catalyzed kinetic resolution, Sharpless asymmetric
dihydroxylation and organocatalytic asymmetric hydroxymethylation are the key steps involved in the
total synthesis of the target molecule.
Received 19 January 2009
Accepted 26 February 2009
Available online 22 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
scaffold, for example, 5-hydroxymethyl-cyclohex-2-enone, Sharp-
less asymmetric dihydroxylation and an organocatalytic asymmet-
Palitantin and frequentin are highly oxygenated cyclohexane
derivatives. They are polyketide-derived fungal metabolites iso-
lated from Penicillium palitanst and Penicillium frequentans,1,
respectively. Frequentin has been shown to have antifungal and
antibiotic activities.2 Its structural correlation with palitantin has
been established through chemical transformation,3 and it was
shown that palitantin is the precursor molecule for frequentin. Till
date four asymmetric synthesis of the (+)-enantiomer of palitantin
have been reported in the literature. Organocatalytic Robinson
ric hydroxymethylation.
2. Results and discussion
The enantiomeric 5-hydroxymethyl-cyclohex-2-enone has been
prepared as depicted in the literature.8 Oxidation of the diol,
5-hydroxymethyl-cyclohex-2-enol A with PDC in ethyl acetate as
a solvent produced the required ketoalcohol compound 1 in 80%
yield.9 Irreversible enzymatic transesterification with vinylacetate
was applied to racemic 1 by using Lipase-PS (Burkholderia cepacia)
in benzene as a solvent to afford the (S)-acetate (ee: 98%) and the
(R)-alcohol (ee: 99%) with excellent enantioselection.10 Attempted
deacetylation of the (S)-acetate with K2CO3/MeOH yielded the (S)-
alcohol in 20% yield. Moreover lipase (Porcine pancreatic lipase)
catalyzed deacetylation of (S)-acetate in phosphate buffer
(100 mM, pH 7.0) afforded the (S)-alcohol in good yield (75%).
The (S) alcohol seems not to be useful in our synthetic steps, hence
we have decided to develop a racemization method so that we
have a steady supply of racemic 1. The primary hydroxyl group is
oxidized with PCC to yield the (S)-ketoaldehyde. The racemization
of (S)-ketoaldehyde to the corresponding racemic mixture is
achieved by treatment with catalytic DBU in tetrahydrofuran11 at
room temperature. Chemoselective reduction of the aldehyde
functionality is achieved with NaCNBH3 in methanol. So, by a
three-step methodology the undesired (S)-5-hydroxymethyl-2-
cyclohexenone has been racemized to ( )-5-hydroxymethyl-2-
cyclohexenone (Scheme 2). This can be used again in the initial
kinetic resolution step.
annulation of
a
,b-unsaturated aldehydes,4 diastereoselective cis-
hydroxylation of (5R)-tert-butyldimethylsiloxy-2-cyclohexenone
followed by a selective 1,4-addition of 1,3-heptadienyl cyanocup-
rate,5 regioselective dehydration of
a
homochiral alcohol
(1S,2S,3R)-2,3-isopropylideneoxycyclohexanol followed by cuprate
addition of 1,3-heptadienyl group6 and a chiron approach from
(ꢀ)-quinic acid affords (+)-palitantin.7
In our combinatorial biocatalysis project we have designed and
synthesized many small multifunctional scaffolds. After biocatalytic
and chemical modification the scaffolds will lead us to many natural
products and related compounds. Both the enantiomers of 5-hydro-
xymethyl-cyclohex-2-enone are such scaffolds which can be struc-
turally related to palitantin and frequentin by chemical analogy. In
this article we wish to report asymmetric synthesis of the natural
enantiomer of palitantin by a chemoenzymatic and organocatalytic
approach. The retrosynthetic analysis for (+)-palitantin is shown in
Scheme 1 starting from (R)-5-hydroxymethyl-cyclohex-2-enone.
Whereas the other enantiomer (S)-5-hydroxymethyl-cyclohex-2-
enone will lead to (ꢀ)-palitantin by the same chemical transforma-
tion pathway. The main highlights of our synthetic strategy are the
enzymatic synthesis of both enantiomers of the small molecular
With both enantiomeric 5-hydroxymethyl-cyclohex-2-enones
in our hand, we have opted to carry out the total synthesis of
(+)-palitantin from (R)-5-hydroxymethyl-cyclohex-2-enone. The
hydroxymethyl group was protected as its TBDPS ether by treat-
ment with imidazole/TBDPS-Cl in DMF to afford compound 2.
* Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.055

T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 20 (2009) 610–615
611
O
O
Organocatalytic asymetric
hydroxymethylation
HO
HO
R
OH
Asymmetric
dihydroxylation
Enzymatic transesterification
R = CH2OH; (+)-palitantin
R = CHO; (+)-frequentin
Scheme 1. Retrosynthetic analysis of palitantin and frequentin.
OH
O
O
O
Lipase-PS
PDC
EtOAC
+
OAc
OH
OH
NaCNBH3
OH
1
(R)
OAc
PPL
A
phosphate buffer
pH = 7.0
O
O
1. PCC, DCM
(S)
2. DBU, THF, RT
CHO
OH
Scheme 2. Enzymatic synthesis of both enantiomers of the ketoalcohol.
Asymmetric dihydroxylation with AD-Mix b of 2 yielded the dihy-
droxylated compound 3 in 60% yield.12 The origin of the stereose-
lectivity in the asymmetric dihydroxylation reaction can be
explained assuming a half-chair like conformation13 for the parent
cyclohexenone 2, in which the bottom face of the ring is blocked by
from 8. The undesired (E,Z) isomer is converted to (E,E) 9 by treat-
ment with 0.1 equiv of I2 and irradiation with 100 W mercury lamp
(Scheme 4).18 The introduction of hydroxymethyl in a regiocon-
trolled as well as stereocontrolled manner seems to be a challeng-
ing and daunting task as depicted by Hanessian et al.7 Attempted
monohydroxymethylation of 9 with several reagents leads to the
undesired regioisomer as the major product. The formation of
undesired regioisomeric hydroxymethylated compound can be
the bulky tert-butyl-diphenylsilyl group hence making the
a-face
inaccessible by the AD-mix reagent system. Thus the attack must
take place from the b-face (Scheme 3) of 2 yielding diol 3.
attributed to enhanced kinetic acidity of the a-hydrogen adjacent
to the acetonide group hence the enolization always takes place to-
wards the oxygen end. To circumvent this problem we choose a
model system 13 (racemic), where the diol functionality is pro-
tected as its TBS ether. The presence of a monocyclic O,O-bis-silyl-
ADmix-β
ADmix-β
H
H
protecting group instead of
a cyclic acetonide changes the
O
O
regiochemical outcome of the reaction. When racemic 13 was trea-
ted with LTMP (lithium tetramethylpiperidide) and N-hydroxy-
methyl phthalimide (as a formaldehyde equivalent) at ꢀ78 °C,20
the desired regioisomeric product 14 was obtained in 50% yield
with the corresponding dihydroxymethylated product in 20% yield.
The asymmetric aldol reaction is one of the most significant reac-
tions in modern catalytic synthesis.21 The possibility of using small
chiral organic molecules, for example, amino acids and their deriv-
atives to act like an enzyme for the catalytic intermolecular aldol
reaction has been explored by many research groups.22 It is worth
mentioning that, in a similar approach to enzymatic conversion
with type-I or II aldolases, a direct asymmetric variant of the aldol
reaction was achieved when proline (R or S) was used as catalyst.23
Accordingly, the use of enol derivatives of the parent ketone com-
pound is not necessary and the ketone can be used directly without
previous modification. This also means that a further reaction step
deprotonation or silylation in order to prepare the required eno-
lates and enol ethers, respectively, can be avoided. In the same line
of thinking when the substrate 13 was subjected to a proline cata-
lyzed organocatalytic aldol reaction with aq formaldehyde, the de-
OTBDPS
OTBDPS
half chair (envelope)
half chair (inverted envelope)
Scheme 3. Origin of the stereoselectivity in the dihydroxylation reaction.
The syn-diol 3 is protected as its acetonide by treatment with
2,2-dimethoxypropane (DMP) and PPTS in dichloromethane to af-
ford 4.14 The keto functionality in 4 was protected as its dithiane by
treatment with 1,3-propanedithiol to yield compound 5.15 Depro-
tection of the silylether (TBDPS) was achieved by treating com-
pound 5 with TBAF/THF at room temperature to afford 6 in 80%
yield from 5.16 Oxidation of 6 with the SO3–pyridine complex
yielded aldehyde 7 in good yield.17 Wittig olefination of aldehyde
7 with (E)-2-hexenyltriphenylphosphonium bromide at ꢀ78 °C18
afforded compound 8 in 3:1 ratio (E,E: E,Z) in 72% yield (by 1H
NMR analysis). Separation of the olefin geometrical isomers is
not possible at this step. The thioketal group in 8 was deprotected
to19 yield the keto compound 9 (mixture of E,E and E,Z) in 60% yield

612
T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 20 (2009) 610–615
O
O
O
O
HO
HO
a
O
O
b
c
d
OH
OTBDPS
OTBDPS
OTBDPS
3
4
2
1
S
S
S
S
S
S
O
O
O
O
O
e
f
g
O
CHO
OTBDPS
OH
i
5
6
7
O
O
O
S
S
TBSO
TBSO
O
O
HO
HO
j
O
O
h
R
R
R
R
9
10
11
8
(E, E: E,Z) = 3:1
R =
nPr
O
OH
R
k
l
TBSO
TBSO
m
(+)-palitantin
12
Scheme 4. Reagents and conditions: (a) TBDPS-Cl, imidazole, DMF, rt, 6 h, 90%; (b) AD-Mix-b, t-BuOH–H2O (1:1), MeSO2NH2, 60%; (c) 2,2-DMP, PPTS, rt, 12 h, 88%; (d) HS–
(CH2)3–SH, BF3ꢁOEt2, 12 h, 80%; (e) TBAF, THF, rt, 2 h, 80%; (f) SO3–Pyr, Et3N, DMSO, rt, 3 h, 86%; (g) n-BuLi, ꢀ78 °C, 1/2 h, (E)-2-hexenyltriphenylphosphonium bromide, then
add aldehyde 7, 0 °C, 2 h, 72%; (h) HgCl2, CH3CN, rt, 2 h, 60%, I2 (0.1 equiv), 100 W mercury lamp, 1 h; (i) MeOH–HCl, 3 h, rt, 90%; (j) 2,6-lutidine, TBSOTf, 24 h, rt, 80%; (k) (S)-
proline, HCHO, DMSO, 14 h, rt, 50%; (l) LTMP, N-hydroxymethyl phthalimide, ꢀ78 °C, 50%; (m) PPTS/MeOH, rt, 6 h, 92%.
sired product was obtained in 50% yield with no other side prod-
ucts (Scheme 5). Hence we have also planned to adopt an organo-
catalytic approach for installation of the required hydroxymethyl
functionality in an asymmetric fashion.
OTBS
H
H
O
N
TBSO
O
Thus when compound 9 was treated with MeOH–HCl, the aceto-
nide group was removed to afford diol 10, which was subsequently
treated with 2,6-lutidine/TBS-OTf to yield the bis silylated com-
pound 11 in 80% yield from 9. Compound 11 on treatment with
(S)-proline (10 mol %), and aq formaldehyde afforded compound
12 in 50% yield (Scheme 4). The origin of diastereoselection of the
hydroxymethylation reaction can be explained by Si-facial attack
of formaldehyde as an electrophile on the proline-derived enamine
of compound 11 (Scheme 6). Whereas the Re-face of the enamine is
blocked by the bulky (1E,3E)-hepta-1,3dienyl group. Base-induced
substrate-directed hydroxymethylation of substrate 11 was also
tried with N-hydroxymethyl phthalimide (as a formaldehyde
H
O
H
R
R=
Scheme 6. Reaction of formaldehyde with the Si-face of the proline-derived
enamine.
equivalent) to afford compound 12 in 50% yield. Deprotection of
the silyl ether functionality in 12 with MeOH/PPTS afforded the
(+)-palitantin in 16% overall yield from 1 (Scheme 4). The spectral
O
O
O
O
OH
HO
HO
TBSO
TBSO
TBSO
TBSO
a
b
c
or d
OTBDPS
OTBDPS
OTBDPS
OTBDPS
13
14
Racemic
Scheme 5. Reagents and conditions: (a) OsO4; NMO, Me2CO–H2O (9:1); (b) 2,6-lutidine, TBSOTf, 24 h; (c) LTMP, N-hydroxymethylphthalimide, ꢀ78 °C; (d) proline, HCHO,
DMSO, rt.

T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 20 (2009) 610–615
613
characteristic values of our synthesized (+)-palitantin are in perfect
agreement with those reported in the literature.
4.3. (2R,3R,5R)-5-(tert-Butyl-diphenyl-silyloxymethyl)-2,3-
dihydroxy-cyclohexanone 3
t-BuOH (41 ml), H2O (41 ml) and AD-mix b (11.27 g) were
mixed and the mixture was stirred for 15 min. Methanesulfonam-
ide (725 mg, 7.6 mmol) was then added and the stirring was
continued for a further 15 min. (R)-5-(tert-Butyl-diphenyl-silanyl-
oxymethyl)-cyclohex-2-enone 2 (2 g, 7.57 mmol) was then added
in one portion. The slurry was stirred vigorously at 20 °C for
24 h. After that time, sodium sulfite (15 g) was added and stirring
was continued for further 1 h. The reaction mixture was extracted
with EtOAc (4 ꢂ 100 ml). The organic layer was dried (Na2SO4) and
evaporated in vacuo. The diol was purified by flash chromatogra-
phy (1:1; hexane–EtOAc) to afford 1.36 g (60%) of the diol. 1H
NMR of 3 in CDCl3 (400 MHz), d: 7.6–7.5 (m, 4H), 7.45 (m, 6H),
4.42 (br s, 1H), 4.15 (br s, 1H), 3.9 (br s, 1H, –OH), 3.64 (br s, 2H),
2.58–2.46 (m, 4H), 2.2 (m, 1H), 1.9 (t, J = 13.2 Hz, 1H). 13C NMR
of 3 in CDCl3 (100 MHz), d: 210.11 (C), 135.63 (CH), 133.28,
129.63 (CH), 127.72 (CH), 76.96 (CH), 72.13 (CH), 65.44 (CH2),
42.07 (CH2), 36.14 (CH), 32.18 (CH2), 26.93 (CH3), 19.35 (C).
3. Conclusion
In conclusion we have developed an efficient asymmetric syn-
thesis of the natural enantiomer of palitantin by adopting a chemo-
enzymatic and organocatalytic approach.
4. Experimental
4.1. General
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF
and diethylether were distilled from sodiumbenzophenone ke-
tyl. Dichloromethane (DCM), dimethylformamide (DMF) and
dimethylsulfoxide (DMSO) were distilled from calcium hydride.
Benzene was refluxed over P2O5 and distilled prior to use. Vinyl
acetate was freshly distilled prior to use. Lipase PS (from B.
cepacia) was obtained from Wako pure chemicals, Japan. Reac-
tions were monitored by thin-layer chromatography(TLC) car-
ried out on 0.25 mm silica gel plates (Merck) with UV light,
ethanolic anisaldehyde and phosphomolybdic acid/heat as
developing agents. Silicagel 100–200 mesh was used for column
chromatography. Yields refer to chromatographically and spec-
troscopically homogeneous materials unless otherwise stated.
NMR spectra were recorded on Bruker 400 MHz spectrometers
at 25 °C in CDCl3 using TMS as the internal standard. Chemical
shifts are shown in d. 13C NMR spectra were recorded with a
complete proton decoupling environment. The chemical shift
value is listed as dH and dC for 1H and 13C, respectively. Mass
spectral analysis was performed in the Central Research Facility
(CRF), IIT-Kharagpur. Optical rotations were measured on a JAS-
CO P 1020 digital polarimeter.
½
a 2D9
ꢃ
¼ ꢀ18:5 (c 1.0, MeOH).
4.4. (3R,6R,7R)-6-(tert-Butyl-diphenyl-silyloxymethyl)-2,2-
dimethyl-tetrahydro-benzo[1,3]dioxol-4-one 4
Compound 3 (1.039 g, 3.49 mmol) was taken in 20 ml of dry
DCM. 2,2-Dimethoxypropane (DMP, 17.43 mmol, 2.14 ml) was
added to it followed by addition of catalytic amount of PPTS
(0.35 mmol, 94 mg). The reaction mixture was stirred at rt over-
night. The product was purified by flash chromatography (3:1;
hexane–EtOAc) to afford 940 mg of compound 4 in 80% yield. 1H
NMR of 4 in CDCl3 (400 MHz), d: 7.65 (m, 4H), 7.42 (m, 6H), 4.63
(m, 1H), 4.28 (d, J = 5.2 Hz, 1H), 3.61 (d, J = 3.6 Hz, 2H), 2.53 (m,
1H), 2.37–2.16 (m, 3H), 1.96 (m, 1H), 1.43 (s, 3H), 1.39 (s, 3H),
1.01 (s, 9H). 13C NMR of 4 in CDCl3 (100 MHz), d: 208.42, 135.50,
133.16, 129.77, 127.71, 109.68, 78.93, 76.39, 66.96, 43.31, 36.00,
31.71, 27.04, 26.82, 25.97, 19.27. ½a D29
¼ ꢀ5:5 (c 1.0, MeOH).
ꢃ
4.2. Acetic acid (S)-5-oxo-cyclohex-3-enylmethyl ester
4.5. Compound 6
Compound 1 (1 g, 7.94 mmol) was taken in 10 ml of anhydrous
benzene. Vinylacetate (0.36 ml, 3.97 mmol) was added to the reac-
tion mixture, followed by addition of Lipase-PS (500 mg) and pow-
dered molecular sieves (4 Å, 200 mg). The reaction mixture was
kept in an orbital shaker under an argon atmosphere. The progress
of the reaction was monitored by TLC measurement. After 50% con-
version, it was filtered on a Celite pad, and evaporated to dryness.
Purification by flash chromatography (1:1; hexane–EtOAc) affor-
ded the (S)-acetate and the (R)-alcohol. Attempted deacetylation
with K2CO3–MeOH yielded the (S)-alcohol in 20% yield. Henceforth
lipase catalyzed deacetylation was attempted. The (S)-acetate
(620 mg, 3.69 mmol) was taken in 25 ml of 100 mM phosphate
buffer (pH 7.0), followed by addition of PPL (500 mg). The reaction
mixture was kept in an orbital shaker (250 rpm) for 8 h. After that
time it was extracted twice with EtOAc (2 ꢂ 100 ml), and the or-
ganic layer was dried (Na2SO4) and evaporated to dryness. Flash
chromatography (1:1; hexane–EtOAc) afforded the (S)-alcohol in
90% yield.
Compound 5 (670 mg, 1.56 mmol) was taken in dry THF
(10 ml). TBAF (1 M in THF, 1.56 ml) was added to it, and the reac-
tion mixture was stirred for 3 h at room temperature. After that
time, THF was evaporated, and water (20 ml) was added to it, the
reaction mixture was extracted with EtOAc (2 ꢂ 50 ml), the organic
layer was washed with NaHCO3 and brine, and dried (Na2SO4). It
was purified by flash chromatography (1:1; hexane–EtOAc) to af-
ford 350 mg of compound 6 (80%). 1H NMR of 6 in CDCl3
(400 MHz), d: 4.62 (m, 1H), 4.53 (m, 1H), 3.54 (d, J = 5.2 Hz, 2H),
3.0 (m, 2H), 2.82 (m, 2H), 2.24 (m, 2H), 2.08 (m, 1H), 2.0–1.65
(m, 5H), 1.55 (s, 3H), 1.40 (s, 3H). 13C NMR of 6 in CDCl3
(100 MHz). d: 108.09 (C), 76.32 (CH), 73.22 (CH), 67.41 (CH2),
49.48, 35.26 (CH2), 30.13 (CH), 27.70 (CH2), 27.04 (CH2), 26.59
(CH2), 26.34 (CH3), 24.55 (CH2), 24.33 (CH3). ½a D29
¼ ꢀ5:9 (c 1.0,
ꢃ
MeOH). HRMS (ESIMS) calcd for C13H23O3S2 (M+H)+ 290.1083,
found 291.1076.
Specific rotation value for (R)-1, ½a D29
¼ ꢀ32:85 (c 1.0, MeOH),
ꢃ
4.6. (3R,6R,7R)-6-((1E,3E)-Hepta-1,3-dienyl)-2,2-dimethyl-
tetrahydro-benzo[1,3]dioxol-4-one 9
for (S)-acetate, ½a D29
ꢃ
¼ þ25:7 (c 1.0, MeOH). 1H NMR of 1 in CDCl3
(400 MHz), d: 7.0 (m, 1H), 6.0 (d, J = 9.6 Hz, 1H), 3.6 (d, J = 5.6 Hz,
2H), 2.5–2.2 (m, 5H). 13C NMR of 1 in CDCl3 (100 MHz), d:
200.11, 150.23, 129.47, 65.58, 40.56, 37.45, 28.48. 1H NMR of ace-
tate of 1 in CDCl3 (400 MHz), d: 6.98 (m, 1H), 6.0 (d, J = 9.6 Hz, 1H),
4.0 (d, J = 5.6 Hz, 2H), 2.57–2.2 (m, 5H), 2.05 (s, 3H). 13C NMR of
acetate of 1 in CDCl3 (100 MHz), d: 198.27, 170.80, 148.73,
129.78, 66.87, 40.65, 34.39, 28.56, 20.72.
Compound 8 (180 mg, 0.508 mmol, mixture of E,E and E,Z) was
taken in 80% aq acetonitrile (2 ml). HgCl2 (290 mg, 1.07 mmol) was
added to it at once. The reaction mixture was stirred at room tem-
perature for 2 h. after that time water was added and the reaction
mixture was extracted with EtOAc, the organic layer was succes-
sively washed with NaHCO3, brine and dried (Na2SO4). It was puri-

614
T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 20 (2009) 610–615
fied by flash chromatography (1:3; hexane–EtOAc) to yield 110 mg
of 9 (82% yield, mixture of E,E and E,Z). The mixture of isomers of 9
(32 mg, 0.12 mmol) was taken in anhydrous DCM (5 mL). Molecu-
lar I2 (0.012 mmol) was added to it followed by the irradiation with
a 100 W mercury lamp. The irradiation was continued for 1 h. After
that time, the reaction mixture was washed with sodium thiosul-
fate solution and the organic layer was purified by preparative
thin-layer chromatography to yield pure (E,E) 9 in 80% yield. 1H
NMR of 9 in CDCl3 (400 MHz), d: 6.06 (dd, J = 14.8, 10.8 Hz, 1H),
5.97 (dd, J = 14.8, 10.8 Hz, 1H), 5.66 (dt, J = 14.8, 7.2 Hz, 1H), 5.46
(dd, J = 14.8, 7.2 Hz, 1H), 4.59 (br s, 1H), 4.28 (d, J = 5.2 Hz, 1H),
2.8 (m, 1H), 2.52 (d, J = 13.6 Hz, 1H), 2.32 (m, 2H), 2.16 (m, 2H),
1.86 (m, 1H), 1.43 (s, 3H), 1.41 (m, 2H), 1.39 (s, 3H), 0.9 (t,
J = 7.2 Hz, 3H). 13C NMR of 9 in CDCl3 (100 MHz), d: 207.54 (C),
134.78 (CH), 132.36 (CH), 130.33 (CH), 129.64 (CH), 109.84 (C),
78.86 (CH), 76.30 (CH), 46.19 (CH2), 35.55 (CH), 34.71 (CH2),
29.71 (CH2), 27.09 (CH3), 26.04 (CH3), 22.40 (CH2), 13.74 (CH3).
71.50 (CH), 44.66 (CH2), 36.21 (CH), 35.42 (CH2), 34.70 (CH2),
22.50 (CH2), 13.73 (CH3). ½a D29
¼ ꢀ6:7 (c 1.0, CHCl3). HRMS (ESIMS)
ꢃ
calcd for C13H21O3 (M+H)+ 225.1485, found 225.1481.
4.9. (2R,3R,5R)-2, 3-Bis-(tert-butyl-dimethyl-silanyloxy)-5-
((1E,3E)-hepta-1,3-dienyl)-cyclohexanone 11
Diol 10 (35 mg, 0.156 mmol) was taken in dry DCM (2 ml). 2,6-
Lutidine was (0.05 ml, 0.312 mmol) added to it at 0 °C and kept for
5 min at the same temperature. TBs-OTf (0.11 ml, 0.468 mmol) was
added to the reaction mixture and the solution warmed to attain
room temperature. The reaction mixture was kept over night,
afterwards it was washed with NaHCO3, brine and dried (Na2SO4).
It was purified by flash chromatography (10:1; hexane–EtOAc) to
afford compound 11 in 78% yield. 1H NMR of 11 in CDCl3
(400 MHz), d: 6.0 (m, 2H), 5.65 (m, 1H), 5.47 (dd, J = 14.8, 7.2 Hz,
1H), 4.27 (br s, 1H), 4.17 (br s, 1H), 2.98 (m, 1H), 2.44 (m, 1H),
2.1–1.9 (m, 4H), 1.72 (m, 1H), 1.44 (q, J = 7.2 Hz, 2H), 0.9 (21H),
0.06 (s, 3H), 0.0.057 (s, 3H), 0.041 (s, 3H), 0.029 (s, 3H). 13C NMR
of 11 in CDCl3 (100 MHz), d: 206.301 (C), 134.0 (CH), 133.80
(CH), 129.81 (CH), 129.47 (CH), 80.0 (CH), 74.56 (CH), 45.86
(CH2), 38.70 (CH2), 35.97 (CH), 34.88 (CH2), 26.03 (CH3), 25.75
(CH3), 22.47 (CH2), 18.65, 18.05, 13.65 (CH3), ꢀ4.41 (CH3), ꢀ4.48
½
a 2D9
ꢃ
¼ ꢀ7:9 (c 1.0, CHCl3). HRMS (ESIMS) calcd for C16H25O3
(M+H)+ 265.1798, found 265.1792.
4.7. 2,3-Bis-(tert-butyl-dimethyl-silyloxy)-5-(tert-butyl-
diphenyl-silyloxymethyl)-6-hydroxymethyl-cyclohexanone 14
To a stirred solution of n-butyllithium (0.14 mL, 0.0855 mmol)
in anhydrous THF (2 mL) was added dropwise 2,2,6,6-tetramethyl-
piperidine (0.013 mL, 0.0855 mmol) at ꢀ10 °C. The solution was al-
lowed to stir at 0 °C for 30 min then cooled to ꢀ78 °C. Compound
13 (30 mg, 0.057 mmol) in anhydrous THF (1 mL) was added drop-
wise and stirred for an additional 1 h. N-Hydroxymethylphthali-
mide (20 mg, 0.114 mmol) in anhydrous THF (1 mL) was added
dropwise over a 10-min period and kept for 2 h at this tempera-
ture. The reaction was quenched with water (5 mL) extracted with
diethyl ether (50 mL) then washed successively with 4 M NaOH
(15 mL) and brine (15 mL). The organic layer was dried over
Na2SO4, filtered and concentrated in vacuo. The product was puri-
fied by flash chromatography (1:5; hexane–EtOAc) to afford 17 mg
(50%) of compound 14. 1H NMR of 14 in CDCl3 (400 MHz), d: 7.65
(m, 4H), 7.4 (m, 6H), 4.31 (br, 1H), 4.19 (br, 1H), 3.8 (m, 1H),
3.72 (dd, J = 10.6, 4.4 Hz, 1H), 3.66 (dd, J = 10.6, 3.2 Hz, 1H), 3.58
(m, 1H), 2.48 (m, 1H), 2.35 (m, 1H), 2.08 (t, J = 12.8 Hz, 1H), 1.9
(dt, J = 13.6, 4.4 Hz, 1H), 1.08 (s, 9H), 0.91 (s, 9H), 0.86 (s, 9H),
0.15 (s, 3H), 0.069 (s, 3H), 0.053 (s, 3H), 0.020 (s, 3H).13C NMR of
14 in CDCl3 (100 MHz), d: 210.85, 135.57, 129.90, 127.82, 116.15,
80.09, 74.84, 65.0, 59.52, 51.54, 36.91, 35.29, 26.94, 25.99, 25.69,
ꢀ4.41, ꢀ4.47, ꢀ5.05, ꢀ5.42.
(CH3), ꢀ5.14 (CH3), ꢀ5.50 (CH3). ½a D29
¼ ꢀ13:9 (c 0.7, CHCl3).
ꢃ
4.10. (2R,3R,5S,6R)-2,3-Bis-(tert-butyl-dimethyl-silyloxy)-5-
((1E,3E)-hepta-1,3-dienyl)-6-hydroxymethyl-cyclohexanone 12
Method k: In a typical hydroxymethylation experiment, formal-
dehyde (0.055 mmol, 37% in aq solution) was added to a vial con-
taining (S)-proline (10 mol %) and compound 11 (50 mg,
0.11 mmol) in DMSO (4.0 mL) at room temperature. After 24 h,
the reaction was quenched by the addition of brine and extracted
with EtOAc (3 ꢂ 15 mL). The combined organic extracts were con-
centrated and the crude product purified by flash chromatography
(hexane–EtOAc; 1:1) affording compound 12 in 50% yield.
Method l: To a stirred solution of n-butyllithium (0.14 mL,
0.0855 mmol) in anhydrous THF (2 mL) was added dropwise 2,2,
6,6-tetramethylpiperidine (0.013 mL, 0.0855 mmol) at ꢀ10 °C. The
solution was allowed to stir at 0 °C for 30 min then cooled to
ꢀ78 °C. Compound 13 (30 mg, 0.057 mmol) in anhydrous THF
(1 mL) was added dropwise and stirred for an additional 1 h.
N-Hydroxymethyl phthalimide (20 mg, 0.114 mmol) in anhydrous
THF (1 mL) was added dropwise over a 10-min period and kept for
2 h at this temperature. The reaction was quenched with water
(5 mL) extracted with diethyl ether (50 mL) then washed succes-
sively with 4 N NaOH (15 mL) and brine (15 mL). The organic layer
was dried over Na2SO4, filtered and concentrated in vacuo. The prod-
uct was purified by flash chromatography (1:5; hexane–EtOAc) to
afford 17 mg (50%) of compound 12. 1H NMR of 12 in CDCl3
(400 MHz), d: 6.06–5.95 (m, 2H), 5.65 (m, 1H), 5.38 (dd, J = 14.8,
7.2 Hz, 1H), 4.25 (br s, 1H), 4.21 (br s, 1H), 3.72 (br, 2H), 2.85 (br,
1H, –OH), 2.65 (t, J = 7.2 Hz, 1H), 2.2–2.1 (m, 1H), 2.0 (m, 2H), 1.9–
1.8 (m, 2H), 1.5–1.37 (q, J = 7.2 Hz, 2H), 1.0–0.9 (21H), 0.06 (s, 3H),
0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR of 12 in CDCl3
(100 MHz), d: 209.82 (C), 134.64 (CH), 132.22 (CH), 132.06 (CH),
129.57 (CH), 80.17 (CH), 74.87 (CH), 60.43 (CH2), 54.97 (CH), 38.88
(CH), 38.81 (CH2), 34.88 (CH2), 25.95 (CH3), 25.68 (CH3), 22.47
(CH2), 18.66, 18.09, 13.73 (CH3), ꢀ4.47 (CH3), ꢀ4.52 (CH3), ꢀ5.08
4.8. (2R,3R,5R)-5-((1E,3E)-Hepta-1,3-dienyl)-2,3-dihydroxy-
cyclohexanone 10
To a solution of 9 (70 mg, 0.265 mmol) in MeOH (6 mL) was
added a solution of methanolic HCl (0.25 mL, prepared from
0.05 mL concd HCl in 2 mL of MeOH). The resulting mixture was
stirred for 3 h at ambient temperature until the reaction was com-
plete (monitored by TLC). The reaction was quenched by the addi-
tion of aqueous saturated NaHCO3 solution (5 mL). The solution
was diluted with EtOAc (10 mL), washed with brine (2 mL), dried
over Na2SO4 and concentrated in vacuo to give the crude product.
The residue was purified by flash column chromatography (1:1;
hexane–EtOAc) to afford diol 10 in 95% yield. 1H NMR of 10 in
CDCl3 (400 MHz), d: 6.06 (dd, J = 14.8, 10.8 Hz, 1H), 5.97 (dd,
J = 14.8, 10.8 Hz, 1H), 5.66 (dt, J = 14.8, 7.2 Hz, 1H), 5.46 (dd,
J = 14.8, 7.2 Hz, 1H), 4.38 (br s, 1H), 4.18 (d, J = 5.2 Hz, 1H), 3.9
(br, 1H, –OH), 3.0 (m, 1H), 2.75 (br, 1H, –OH), 2.56 (m, 1H), 2.2
(m, 2H), 2.08 (m, 2H), 1.78 (m, 1H), 1.44 (m, 2H), 0.9 (t,
J = 7.2 Hz, 3H). 13C NMR of 10 in CDCl3 (100 MHz), d: 208.69 (C),
134.66 (CH), 132.79 (CH), 130.20 (CH), 129.59 (CH), 76.99 (CH),
(CH3), ꢀ5.46 (CH3). ½a D29
¼ þ6:8 (c 0.5, CHCl3).
ꢃ
4.11. (2R,3S,5R,6R)-3-((1E,3E)-Hepta-1,3-dienyl)-5,6-dihydroxy-
2-hydroxymethyl-cyclohexanone palitantin
Compound 12 (12 mg, 0.025 mmol) was taken up in 3 ml of
MeOH, PPTS (40 mg, 0.15 mmol) was added to it. The reaction mix-

T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 20 (2009) 610–615
615
5. Hareau, G.; Koiwa, M.; Hanazawa, T.; Sato, F. Tetrahedron Lett. 1999, 40, 7493.
6. Deruyttere, X.; Dumortier, L.; Van der Eycken, J.; Vandewalle, M. Synlett 1992,
51.
ture was stirred at room temperature overnight. After that time,
the MeOH was evaporated, and the residue was taken in DCM. It
was washed successively with NaHCO3 and brine. Purification by
flash chromatography (1:1; hexane–EtOAc) afforded the title com-
pound as a white solid. 1H NMR of palitantin in CDCl3 (400 MHz), d:
6.06 (m, 1H), 5.95 (m, 1H), 5.66 (m, 1H), 5.38 (dd, J = 14.8, 7.2 Hz,
1H), 4.38 (br s, 1H), 4.22 (br s, 1H), 3.85 (br s, 1H, –OH), 3.78 (d,
J = 4.8 Hz, 2H), 2.86 (m, 1H), 2.56 (br s, 1H, –OH), 2.42 (m, 1H),
2.28 (br s, 1H, –OH), 2.15 (m, 1H), 2.1–2.0 (m, 2H), 1.86 (m, 1H),
1.46–1.4 (q, J = 8.0 Hz, 2H), 0.9 (t, J = 8.0 Hz, 3H).13C NMR of palit-
antin in CDCl3 (100 MHz), d: 211.49 (C), 135.26 (CH), 132.79
(CH), 130.99 (CH), 129.36 (CH), 77.12 (CH), 71.76 (CH), 59.76
(CH2), 54.68 (CH), 39.15 (CH), 35.38 (CH2), 34.71 (CH2), 22.38
7. Hanessian, S.; Sakito, Y.; Dhanoa, D.; Baptistella, L. Tetrahedron 1989, 45, 6623.
8. (a) Barral, K.; Courcambeck, J.; Pepe, G.; Balzarini, J.; Neyts, J.; De Clercg, E.;
Camplo, M. J. Med. Chem. 2005, 48, 450; (b) Hatcher, M. A.; Peleg, S.; Dolan, P.;
Kensler, T. W.; Sarjeant, A.; Posner, G. H. Bioorg. Med. Chem. 2005, 13, 3964; (c)
Yu, S.-H.; Chung, S.-K. Tetrahedron: Asymmetry 2004, 15, 581; (d) Smith, A. B.;
Hale, K. J.; Laakso, L. M.; Chen, K.; Riera, A. Tetrahedron Lett. 1989, 30, 6963; (e)
Linde, R. G.; Egbertson, M.; Coleman, R. S.; Jones, A. B.; Danishefsky, S. J. J. Org.
Chem. 1990, 55, 2771.
9. Hodgson, D. M.; Gibbs, A. R.; Drew, M. G. B. Perkin Trans. 1 1999, 3579.
10. (a) Miyaoka, H.; Sagawa, S.; Inoue, T.; Nagaoka, H.; Yamada, Y. Chem. Pharm.
Bull. 1994, 42, 405; (b) Trost, B. M.; Richardson, J.; Yong, K. J. Am. Chem. Soc.
2006, 128, 2540; (c) The enantioselectivity was measured by chiral HPLC (OJ-H,
hexane–2-propanol/9:1) measurement of the benzoate derivative of (R) and
(S)-1.
(CH2), 13.73 (CH3). ½a D29
ꢃ
¼ þ4:4 (c 0.5, CHCl3); lit. ½a D22
ꢃ
¼ þ4:3 (c
11. Peng, J.; Clive, D. L. J. J. Org. Chem. 2009, 74, 513.
12. Tietze, L. F.; Eicher, T.; Diederichsen, U.; Speicher, A. In Reactions and Syntheses;
Springer: Weinheim, 2007; p 211.
2.3, CHCl3);4 lit. ½a D23
ꢃ
¼ þ4:5 (c 0.32, CHCl3);5 lit. ½a D23
ꢃ
¼ þ4:4 (c
0.8, CHCl3).7 HRMS (ESIMS) calcd for C14H23O4 (M+H)+ 255.1590,
found 255.1584.
13. Todoroki, Y.; Hirai, N. Tetrahedron 2000, 56, 8095.
14. Kitamura, M.; Isobe, M.; Ichikawa, Y.; Goto, T. J. Am. Chem. Soc. 1984, 106, 3252.
15. Marshall, J. A.; Belletire, J. L. Tetrahedron Lett. 1971, 12, 871. In the course of the
thioketalization reaction we noticed that acetonide deprotection takes place
with BF3ꢁOEt2, after usual workup we treat the reaction mixture (mixture of
compound 5 with acetonide deprotected diol) with 2,2-DMP and PPTS to yield
compound 5.
Acknowledgements
We are Thankful to DST (New Delhi, India) for providing finan-
cial support (DST Fast track scheme and IPHRA). One of the authors
16. Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975.
17. Dei, S.; Bellucci, C.; Buccioni, M.; Ferrarono, M.; Gualtieri, F.; Guandalini, L.;
Manetti, D.; Matucci, R.; Romanelli, M. N.; Scapecchi, S.; Deodori, E. Biorg. Med.
Chem. 2003, 11, 3153.
18. Watanabe, Y.; Lida, H.; Kibayashi, C. J. Org. Chem. 1989, 54, 4088.
19. Coldham, L.; Crapnell, K. M.; Moseley, J. D.; Rabot, R. Perkin Trans. 1 2001, 1758.
20. Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165.
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T.M. is thankful to CSIR (New Delhi, India) for
fellowship.
a research
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