Formal synthesis of tetrahydrolipstatin and tetrahydroesterastin

Article abstract of DOI:10.1016/j.tetasy.2012.05.025

A versatile and efficient approach to (3S,5R)-methyl 3-(benzyloxy)-5- (methoxymethoxy)hexadecanoate, a key chiral building block and a common polyol fragment of the anti-tumor and anti-obesity agents tetrahydrolipstatin 3 and tetrahydroesterastin 4 using both hydrolytic kinetic resolution (HKR) and proline catalyzed sequential α-aminoxylation, followed by HWE-olefination reaction is described.

Full text of DOI:10.1016/j.tetasy.2012.05.025

Tetrahedron: Asymmetry 23 (2012) 884–890
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Tetrahedron: Asymmetry
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Formal synthesis of tetrahydrolipstatin and tetrahydroesterastin
⇑
Divya Tripathi, Pradeep Kumar
Organic Chemistry Division, National Chemical Laboratory, Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A versatile and efficient approach to (3S,5R)-methyl 3-(benzyloxy)-5-(methoxymethoxy)hexadecanoate,
a key chiral building block and a common polyol fragment of the anti-tumor and anti-obesity agents tet-
rahydrolipstatin 3 and tetrahydroesterastin 4 using both hydrolytic kinetic resolution (HKR) and proline
Received 3 May 2012
Accepted 29 May 2012
Available online 11 July 2012
catalyzed sequential
a-aminoxylation, followed by HWE-olefination reaction is described.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Despite the numerous strategies available to synthesize polyols
through substrate-controlled asymmetric induction, interest in
new methods of synthesis remains.10 We have developed an itera-
tive approach for the synthesis of enantiopure syn- and anti-1,3
polyols via Jacobsen’s hydrolytic kinetic resolution (HRK)11a as well
as via organocatalysis, which is based on proline-catalyzed sequen-
Tetrahydrolipstatin (THL) marketed under the trade name Orli-
stat, or Xenical belongs to the trans-3,4-dialkyl-b-lactone class of
compounds, and is an FDA-approved anti-obesity drug. It works
primarily on pancreatic and gastric lipases within the gastrointes-
tinal (GI) tract.1 Recent findings have important implications in the
consideration of THL as a potential anticancer drug at its early
stages of development for cancer therapy. THL is cytotoxic and
cytostatic to tumor cells in vitro and can inhibit tumor growth
in vivo.2 It is a potent inhibitor of the thioesterase domain of fatty
acid synthase (FAS), an enzyme essential for the growth of cancer
cells but not required for normal cells.3a FAS is currently generating
a great deal of excitement as an interesting drug target in oncol-
ogy; by effectively blocking the cellular FAS activity, THL induces
endoplasmic reticulum stress in tumor cells, and inhibits endothe-
lial cell proliferation and angiogenesis, consequently delaying tu-
mor progression in a wide variety of cancer cells, including
breast,4a,b prostate,4c,d ovary,4e and melanoma cancer cells.3 As a
result, THL (as well as other THL-like analogues with improved po-
tency and bioavailability)5 has been proposed as a promising anti-
cancer drug.
Lipstatin 1, esterastin 2, valilactone 5, and panclicin D 6 (Fig. 1)
are analogous b-lactone 3,4-disubstituted 2-oxetanones isolated
from Streptomyces species6 that differ only in the structure of side
chain and the nature of the amino acid linked to it. The saturated
derivatives of 1 and 2, tetrahydrolipstatin 3,6–8 and tetrahydroes-
terastin 47 exhibit comparable pharmacological properties, but
are more stable than the parent compounds. The unique structural
features of these trans-b-lactone class of drugs, and their potential
applications as thioesterase inhibitors have resulted in a large
amount of efforts directed at the synthesis of these challenging tar-
get molecules9 and their variants.
tial
a-aminoxylation, followed by Horner–Wadsworth–Emmons
(HWE) olefination of aldehydes.11b As part of our ongoing research
interest in the asymmetric synthesis of bioactive molecules,12 we
became interested in devising a general route to a key chiral build-
ing block, which will eventually lead to all of the above stated
trans-3,4-dialkyl-b-lactones. As a synthetic application, we have
applied this strategy to a common fragment, which would inevita-
bly lead to both (ꢀ)-tetrahydrolipstatin 3 and tetrahydroesterastin
4. Herein we report our successful endeavor toward target mole-
cules 3 and 4.
2. Results and discussion
As retrosynthetically outlined in Scheme 1, 2-oxetanone (b-lac-
tone) 7 can have variations at the C-3 and C-6 side chains as well as
any amino acid linked to the b-hydroxy group, thus it can be con-
sidered as a common structure for all trans-3,4-dialkyl-b-lactones.
b-Lactone 7, in turn, can be obtained from its open chain structure
8, which can have a required parent C-6 long chain and a C-2 side
chain attached to it. Functionalization of the ester group is possible
via coupling with the b-hydroxy group. Compound 8 can, in turn,
be obtained from the chiral building block 9, which can have the
stereogenic centers derived from our iterative approach to the syn-
thesis of syn- and anti-1,3-polyols via hydrolytic kinetic resolution
(HRK)11a or via organocatalysis, which is based on proline-
catalyzed sequential a-aminoxylation, followed by Horner–Wads-
worth–Emmons (HWE) olefination of aldehydes.11b Building block
9 can be synthesized from chiral epoxide 10 or from aldehyde 11.
Coupling9a of the (S)-N-formylleucine group in tetrahydrolipstatin
3 or (S)-N-acetylasparagine group in tetrahydroesterastin 4 could
⇑
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.025

D. Tripathi, P. Kumar / Tetrahedron: Asymmetry 23 (2012) 884–890
885
NHCHO
O
O
O
O
O
NHCOCH3
O
H
N
n-C6H13
O
H3N
O
H
O
O
O
O
O
O
lipstatin 1
n-C6H13
n-C7H15
n-C10H21
panclicin D 6
esterastin 2
OH
*
OH
O
R
O
OH
COOMe
*
*
R'
R'
R
NHCHO
O
O
H
N
O
O
O
H
O
O
n-C11H23
tetrahydrolipstatin 3
n-C6H13
O
O
O
NHCOCH3
O
n-C5H11
n-C6H13
H3N
O
valilactone 5
O
O
n-C11H23
tetrahydroesterastin 4
Figure 1. Various trans-3,4-dialkyl-b-lactone esterase inhibitors.
n-C6H13
be effected by their respective b-lactone 12. We envisioned that b-
lactone 12 in turn could be derived from alkylated b-hydroxy ester
13, which could in turn be derived from 1,3-polyol system 14. Ester
14 can, in turn, be obtained from epoxide 15, which can be pro-
duced either by HKR of epoxide 16 or by organocatalysis of alde-
hyde 17.
the reagent (
Overall these findings are in correlation with those observed for
the synthesis of anti-1,3-diols from
-hydroxy esters.11b On the
contrary, a decrease in the diastereoselectivity was observed by
us in the case of syn-1,3-polyols using -proline, which may be be-
D-proline) and the substrate acts synergistically.
c
L
cause of the opposite influences of the chiral reagent and substrate
(mismatched case).11b The selective primary hydroxyl tosylation of
20 and its subsequent treatment with K2CO3 in methanol led to
enantiomerically pure epoxide 21 in 85% yield and >95% de.
Alternatively, epoxide 21 could be prepared from racemic epox-
ide 16, (Scheme 2) which was subjected to Jacobsen’s HKR by using
(R,R)-Salen-CoIIIOAc catalyst to give chiral (S)-diol 22 along with
chiral (R)-epoxide 23 as a single isomer in 95% ee. The enantio-
meric excess of epoxide 23 was determined by converting it into
an alcohol by treating it with NaBH4 followed by Mosher ester
analysis of the 19F spectrum. The chiral epoxide 23 was easily iso-
lated from the more polar chiral diol 22 by silica gel column chro-
matography. With enantiomerically pure epoxide 23 in hand, our
next task was to construct the anti-1,3-diol. In order to establish
the second stereogenic center with the required stereochemistry,
the chiral epoxide 23 was treated with vinylmagnesium bromide
in the presence of CuI to give the homoallylic alcohol 24 in 89%
yield. The newly generated hydroxyl group of homoallylic alcohol
24 was protected using methoxymethyl chloride in the presence
As illustrated in Scheme 2, the synthesis of target compounds 3
and 4 commenced with aldehyde 17, which was subjected to
a-aminoxylation using L-proline as the catalyst and then Horner–
Wadsworth–Emmons olefination followed by Pd/C reduction to
furnish ester 18 in 62% yield and 97% ee. The enantiomeric excess
was determined by converting alcohol 18 into its Mosher ester and
analyzing the 19F spectrum. The hydroxyl protection of 18 with
methoxymethyl chloride in the presence of di-isopropyl amine as
base afforded ester 19 in 89% yield. The temperature controlled DI-
BAL-H reduction of ester 19 furnished the corresponding aldehyde,
which upon aminoxylation using
D-proline as the catalyst followed
by in situ reduction with NaBH4, furnished the required
a
-amino
substituted diol, which was subjected to reductive hydrogenation
to afford the required diol 20 as the major diastereomer [the 1H
NMR analysis of the crude reaction mixture revealed the
diastereomeric purity (de) of the reaction to be >95%] in 72% yield.
The high diastereoselectivity obtained in this case could be
regarded as a matched case where the chirality information of

886
D. Tripathi, P. Kumar / Tetrahedron: Asymmetry 23 (2012) 884–890
our or ganocatalytic methodology of 1,3-polyol
required parent
or
long chain extension
our HKR methodology of 1,3-polyol
O
R
OP
*
OH
*
O
O
OH
COOMe
*
R'
*
R'
OP
*
OH
*
10
R'
R
COOMe
functionalization
R'
8
or
trans-3,4-dialkyl-β-lactone
9
chiral building
block
7
O
required side
chain addition
R'
H
NHCHO
O
O
NHCOCH3
11
O
H3N
O
O
or
O
O
O
O
n-C6H13
n-C6H13
n-C6H13
tetrahydroesterastin 4
3
tetrahydrolipstatin
O
OR
OH
*
OR
*
OH
*
OH
*
O
*
COOMe
COOMe
*
*
10
10
*
n-C6H13
n-C6H13
14
n-C6H13
12
13
O
OMOM
O
or
*
O
10
*
*
11
10
17
16
15
Scheme 1. Retrosynthetic route to the key building blocks of trans-dialkyl-b-lactones and a formal synthesis of tetrahydrolipstatin 3 and tetrahydroesterastin 4.
OMOM
89%
OH
O
a,b
OH
d,e,f
c
9
COOMe
COOMe
62%, 97% ee
9
9
17
18
19
MOMO
OH
OMOM
O
g,h
9
9
20
72%, >95% de
21
85%, >95% de
21
Synthesis of fragment
via organocatalysis
OH
OH
O
O
OH
i
j
+
10
10
10
10
16
23
43%, 95% ee
22
45%, 93% ee
24
89%, 95% ee
OMOM
OMOM
O
OR
OH
OMOM
O
m
OH
k
l
+
10
10
9
10
25
26
27
89%
85%, 92% de
96%
21
93%, 94% de
R = MOM
Synthesis of fragment 21 via HKR
Scheme 2. Reagents and conditions: (a) nitroso benzene,
L
-proline, DMSO, 30 min, then trimethyl phosphonoacetate, DBU, LiCl, CH3CN, 1 h; (b) Pd/C, EtOAc, overnight; (c)
MOMCl, DIPEA, DCM, 8 h; (d) DIBAL-H, DCM, ꢀ78 °C, 1 h; (e) nitroso benzene,
D-proline, DMSO, 30 min, then NaBH4, MeOH; (f) Pd/C, EtOAc, 12 h; (g) TsCl, Et3N, DCM, Bu2SnO,
6 h; (h) K2CO3, MeOH, 1 h; (i) (R,R)-Salen-CoIII(OAc) (0.5 mol %), dist. H2O (0.55 equiv), isopropanol, 24 h; (j) vinylmagnesium bromide, THF, CuI, -20 °C, 4 h; (k) MOMCl,
DIPEA, DCM, overnight; (l) m-CPBA, CH2Cl2, 10 h; (m) (S,S)-Salen-CoIII(OAc) (0.5 mol %), dist. H2O (0.55 equiv), THF, 24 h.
of di-isopropyl ethylamine to afford 25 as the MOM ether in 89%
yield. Epoxidation of 25 with m-CPBA furnished epoxide 26 in a
3:2 diastereomeric ratio (as determined from 1H and 13C NMR
spectroscopic analysis of the crude reaction mixture) in 96% yield.

D. Tripathi, P. Kumar / Tetrahedron: Asymmetry 23 (2012) 884–890
887
OMOM
MOMO
OH
MOMO
OBn
MOMO
OBn
O
COOH
c
a
b
9
9
9
9
21
92%
28
30
29 95%
NHCHO
O
O
MOMO
OBn
O
OH
O
Ref 9a, t
Ref 9t
COOMe
O
O
d
9
4
9
n-C11H23
tetrahydrolipstatin
n-C6H13
85%
31
Ref 9a
3
O
NHCOCH3
O
H3N
O
O
O
n-C11H23
tetrahydroesterastin
n-C6H13
4
Scheme 3. Synthesis of advanced intermediate and formal synthesis of tetrahydrolipstatin and tetrahydroesterastin. (a) vinylmagnesium bromide, CuI, dry THF, ꢀ30 °C, 12 h;
(b) BnBr, NaH, DMF, 4 h; (c) RuCl3ꢂ3H2O, NaIO4 CCl4ꢀCH3CNꢀH2O, 2:2:3, 3 h; (d) MeI, K2CO3, DMF, 30 min.
The next step in the synthesis was to construct the diastereomer-
ically pure epoxide by means of Jacobsen’s hydrolytic kinetic
resolution. To this end, the epoxide 26 was treated with an (S,S)-
Salen-Co–OAc complex and water in THF to afford the epoxide
21 as a single stereoisomer [the 1H NMR analysis revealed the
diastereomeric purity (de) of the reaction to be 94%] in 93% yield
and diol 27 in 85% yield (based on the ratio of starting material)
and 92% de.
It should be mentioned here that while the proline catalyzed
organocatalytic route afforded epoxide 21 in 33.8% overall yield,
the Jacobsen’s hydrolytic kinetic resolution route to the same
epoxide gave an overall yield of 18.3% (Scheme 2).
As shown in Scheme 3, the copper-catalyzed (CuI) regioselec-
tive ring-opening of epoxide 21 with a Grignard reagent, derived
from vinyl bromide and Mg in THF at ꢀ30 °C furnished the homo-
allylic alcohol 28 in 92% yield. Benzyl protection of the newly gen-
erated homoallylic alcohol 28 was accomplished by its reaction
with benzyl bromide in the presence of sodium hydride to afford
the protected homoallylic alcohol 29 in 95% yield. One-pot oxida-
tive cleavage and conversion into an acid of terminal olefin 29
were carried out by employing ruthenium trichloride and sodium
metaperiodate to furnish the corresponding acid 30 in 85% yield.
Finally acid 30 was esterified using MeI and K2CO3 to give methyl
Thus, our synthetic strategy described herein has significant poten-
tial for stereochemical and structural variations in the synthesis of
a wide variety of b-lactone analogues, as well as other Orlistat-like
analogues with improved potency and bioavailability, which can
be explored as various potential drug targets.
4. Experimental
4.1. General
All reactions requiring anhydrous conditions were performed
under a positive pressure of argon using oven-dried glassware
(110 °C), which was cooled under argon. Solvents used for chroma-
tography were distilled at respective boiling points using known
procedures. All commercial reagents were obtained from Sigma–
Aldrich Chemical Co. and Lancaster Chemical Co. (UK). The
progress of the reactions was monitored by TLC using precoated
aluminum plates (silica gel 60 F254, Merck). Column chromatogra-
phy was performed on silica gel 60–120/100–200/230–400 mesh
obtained from S.D. Fine Chemical Co. India or Spectrochem India.
Typical syringe and cannula techniques were used to transfer
air- and moisture-sensitive reagents. IR spectra were recorded on
a Perkin–Elmer infrared spectrometer model 599-B and model
1620 FTIR. 1H NMR spectra were recorded on Bruker AC-200, Bru-
ker AV-400, and Bruker DRX-500 instruments using deuterated
solvents. Chemical shifts are reported in ppm. Proton coupling con-
stants (J) are reported as absolute values in Hz and multiplicity (br.
broad, s singlet, d doublet, t triplet, m multiplet). 13C NMR spectra
were recorded on Bruker AC-200, Bruker AV-400, and Bruker DRX-
500 instruments operating at 50, 100, and 125 MHz, respectively.
13C NMR chemical shifts are reported in ppm relative to the central
line of CDCl3 (d = 77.0 ppm). Microanalytical data were obtained
using a Carlo–Erba CHNS-0 EA1108 elemental analyzer. All the
melting points were recorded on a Büchi B-540 electrothermal
melting point apparatus. Yields refer to chromatographically and
spectroscopically pure compounds.
ester 31 in 85% yield.
½
a 2D5
ꢁ
¼ ꢀ24:4 (c 3.3, CHCl3); lit.9t
½
a 2D5
ꢁ
¼ ꢀ24:5 (c 3.3, CHCl3). The physical and spectroscopic data
of 31 were compared with those reported earlier and were found
to be similar9t in all respects. The final stage of the synthesis could
be achieved through the known procedure9t of incorporation of the
C8 side chain, cyclization to the b-lactone, and coupling9a of either
the (S)-N-formylleucine group to give tetrahydrolipstatin 3 or the
(S)-N-acetylasparagine group to give tetrahydroesterastin 4.
3. Conclusion
In conclusion we have developed a short organocatalytic as well
as hydrolytic kinetic resolution (HKR) approach to a common pol-
yol fragment 31, which serves as an important precursor to both
tetrahydrolipstatin 3 and tetrahydroesterastin 4. While the long
chain of the b-lactone can be varied by changing the aldehyde,
the stereochemistry of the polyol can be manipulated by simply
changing the catalyst in the aminoxylation step or the HKR step.
4.2. Preparation of (R)-methyl 4-hydroxypentadecanoate 18
To a solution of tridecanal 17 (10.0 g, 50.4 mmol) and nitroso
benzene (3.41 g, 50.4 mmol) in anhydrous DMSO (100 mL) was

888
D. Tripathi, P. Kumar / Tetrahedron: Asymmetry 23 (2012) 884–890
added
L
-proline (1.46 g, 12.7 mmol) at rt. The mixture was
into a vigorously stirred biphasic solution of Et2O and aqueous
HCl (1 M). The organic layer was separated, and the aqueous phase
was extracted with EtOAc (3 ꢃ 20 mL). The combined organic
phase was dried over anhydrous Na2SO4, concentrated, and puri-
fied by column chromatography over silica gel using EtOAc/Pet.
ether (40:60) as eluent to give pure aminoxy alcohol. The aminoxy
alcohol was dissolved in EtOAc (10 mL) and to the solution was
added 10% Pd/C (0.050 g). The reaction mixture was then stirred
under a hydrogen atmosphere (1 atm, balloon pressure) for 12 h.
After completion of the reaction (monitored by TLC) the reaction
mixture was filtered through a Celite pad, concentrated, and the
crude product was then purified by silica gel chromatography
using petroleum ether: ethyl acetate (2:3) as eluent to give pure
vigorously stirred for 30 min under argon (the color of the reaction
changed from green to orange during this time), then cooled to
0 °C. Thereafter, a premixed and cooled (0 °C) solution of trimethyl
phosphonoacetate
(20 mL,
100.8 mmol),
DBU
(15.4 mL,
100.8 mmol), and LiCl (4.3 g, 100.8 mmol) in CH3CN (100 mL)
was added quickly (1–2 min) at 0 °C. The resulting mixture was al-
lowed to warm to room temperature over 1 h, and quenched by the
addition of ice pieces. The acetonitrile was evaporated under vac-
uum. This reaction mixture was then poured into water (50 mL)
and extracted with Et2O (5 ꢃ 50 mL). The combined organic layer
was washed with water and brine, dried (Na2SO4), and concen-
trated in vacuo to give a crude product, which was subjected
directly to the next step without purification. To the crude allylic
alcohol in ethyl acetate was added Pd-C (10%) under hydrogena-
tion conditions and the reaction mixture was allowed to stir over-
night. Upon completion of the reaction (after 1H NMR analysis of
the crude mixture indicated complete conversion), the mixture
was filtered through a pad of Celite and concentrated in vacuo to
diol 20 (2.9 g, 72%) as a colorless liquid. ½a D25
¼ ꢀ6:7 (c 1.92, CHCl3),
ꢁ
IR (CHCl3):
m
= 3392, 3018, 2854, 1458, 1263, 1099, 759 cmꢀ1;1H
NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3H), 1.26 (br s,
18H), 1.56–1.74 (m, 4H), 3.42 (s, 3H), 3.59–3.70 (m, 1H), 3.81–
3.87 (m, 1H), 4.07–4.18 (m, 2H), 4.64–4.77 (m, 2H). 13C NMR
(50 MHz, CDCl3): d = 14.1, 22.6, 29.3, 29.5, 29.6, 31.8, 34.3, 37.8,
55.7, 60.4, 70.4, 80.1, 96.3. Anal. Calcd for C17H36O4 (304.47): C,
67.06; H, 11.92. Found: C, 67.10; H, 11.97.
give a c-hydroxy ester. The crude product was then purified by
using flash column chromatography using pet ether: EtOAc
(85:15) as eluent to give 18 (8.5 g, 62%) as a colorless liquid.
½
a 2D5
ꢁ
¼ þ4:8 (c 1.7, CHCl3). IR (CHCl3):
m
= 3444, 2840, 1737, 1455,
4.5. Preparation of (S)-2-((R)-2-(methoxymethoxy)
tridecyl)oxirane 21
1275, 1075, cmꢀ1 1H NMR (200 MHz, CDCl3): d = 0.88 (t,
;
J = 6.9 Hz, 3H), 1.26 (br s, 18H), 1.48–1.65 (m, 4H), 2.40–2.46 (m,
2H), 3.65–3.73 (m, 4H). 13C NMR (50 MHz, CDCl3): d = 14.7, 23.3,
25.9, 29.9, 30.1, 30.2, 32.5, 35.0, 37.9, 52.0, 70.1, 175.1; Anal. Calcd
for C16H32O3 (272.42): C, 70.54; H, 11.84. Found: C, 70.50; H, 11.78.
To a mixture of diol 20 (2.8 g, 9.19 mmol), in dry DCM (5 mL) was
added dibutyltin oxide (45.7 mg, 0.18 mol) followed by the addition
of p-toluenesulfonyl chloride (1.74 g, 9.19 mmol) and triethylamine
(1.27 mL, 9.19 mmol). Thereactionwas thenstirredat roomtemper-
ature under nitrogen. The reaction was monitored by TLC, after com-
pletion of the reaction, the mixture was quenched by adding water.
The solution was extracted with DCM (3 ꢃ 20 ml) and then the com-
bined organic phase was washed with water, dried (Na2SO4), and
concentrated. To this crude mixture in MeOH at 0 °C was added
K2CO3 (1.52 g, 11.0 mmol) and the resultant mixture was allowed
to stir for 1 h at the same temperature. After completion of the reac-
tion as indicated by TLC, the reaction was quenched by the addition
of ice pieces and methanol was evaporated. The concentrated reac-
tion mixture was then extracted with ethyl acetate (3 ꢃ 20 mL),
and the combined organic layer was washed with brine, dried
(Na2SO4), and concentrated. Column chromatography of the crude
product using pet ether: ethyl acetate (9:1) gave epoxide 21
4.3. Preparation of (R)-methyl 4-(methoxymethoxy)
pentadecanoate 19
To a solution of alcohol 18 (6.0 g, 22.02 mmol) and diisopropyl-
ethylamine (11.51 mL, 44.04 mmol) in dry CH2Cl2 (30 mL) was
added MOMCl (2.0 mL, 26.42 mmol) under argon over 5 min at
0 °C, and the mixture was allowed to warm to room temperature
and stirred for 8 h. After cooling to 0 °C, the reaction mixture was
quenched with water and extracted with CH2Cl2 (3 ꢃ 30 mL). The
combined organic extracts were washed with water (3 ꢃ 50 mL)
and brine, dried (Na2SO4), and concentrated. Silica gel column chro-
matography of the crude product using petroleum ether/EtOAc (9:1)
gave 19 (6.20 g, 89%) as a colorless liquid. ½a D25
¼ þ7:1 (c 1.6, CHCl3).
ꢁ
IR (neat):
m
= 2928, 2856, 1742, 1216, 1038 cmꢀ1. 1H NMR (200 MHz,
(2.24 g, 85%) as a colorless liquid. ½a D25
¼ ꢀ7:9 (c 1.04, CHCl3). IR
ꢁ
CDCl3): d = 0.88 (t, J = 6.8 Hz, 3H), 1.26 (br s, 18H), 1.48–1.65 (m, 4H),
(neat): m = 2954, 2932, 2893, 2859, 1471, 1376, 1361, 1252, 1215,
2.40–2.46 (m, 2H), 3.37 (s, 3H), 3.65–3.73 (m, 4H), 4.66 (s, 2H). 13
C
1102, 1042, 919 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 0.88 (t,
.
NMR (50 MHz, CDCl3): d = 14.1, 22.6, 25.3, 29.3, 29.5, 29.6, 31.9,
34.4, 37.3, 51.4, 55.5, 79.7, 95.4, 174.5; Anal. Calcd for C18H36O4
(316.48): C, 68.31; H, 11.47. Found: C, 68.27; H, 11.41.
J = 7 Hz, 3H), 1.26 (br s, 18H), 1.50–1.70 (m, 4H), 2.50–2.52 (m,
1H), 2.80–2.84 (m, 1H), 3.03–3.10 (m, 1H) 3.41 (s, 3H), 3.79–3.82
(m, 1H), 4.70–4.72 (m, 2H). 13C NMR (50 MHz, CDCl3): d = 14.1,
22.7, 29.3, 29.6, 29.7, 31.9, 34.5, 44.7, 44.8, 55.6, 83.1, 95.6. Anal.
Calcd for C17H34O3 (286.45): C, 71.28; H, 11.96. Found: 71.32; H,
11.91.
4.4. (2S,4R)-4-(Methoxymethoxy)pentadecane-1,2-diol 20
To a solution of ester 19 (5.0 g, 183.6 mmol) in dry DCM (30 mL)
at ꢀ78 °C was added dropwise DIBAL-H (18.35 mL, 183.6 mmol,
1 M in toluene). The reaction mixture was stirred for 1 h, then trea-
ted with a sat. aqueous solution of sodium potassium tartrate
(50 mL). The organic phase was separated and the aqueous layer
was extracted with CH2Cl2 (3 ꢃ 50 mL). The combined organic ex-
tracts were washed with water and brine, dried (Na2SO4), filtered,
and concentrated to give the crude aldehyde, which was used for
the next step without purification. To a stirred solution of aldehyde
(5.0 g, 20.94 mmol) and nitrosobenzene (2.24 g, 20.94 mmol) in
4.6. Preparation of (S)-tridecane-1,2-diol 22 and (R)-2-
undecyloxirane 23
A solution of epoxide 16 (5 g, 25.25 mmol) and (R,R)-Salen-CoIII-
OAc (0.10 g, 0.15 mmol) in isopropanol (0.3 mL) was stirred at 0 °C
for 5 min and then distilled water (454 mL, 25.25 mmol) was
added. After stirring for 24 h, this mixture was concentrated and
purified by silica-gel column chromatography (petroleum ether/
EtOAc 19:1) to afford 23 (2.15 g, 43%) as a yellow liquid. Continued
chromatography with petroleum ether/EtOAc 3:2) provided diol 22
(2.45 g, 45%) as a brown liquid and as a single diastereomer. Data
DMSO (42 mL) was added D-proline (0.9 g, 8.3 mmol, 20 mol %) in
one portion at 25 °C. After 30 min, the temperature was lowered
to 0 °C, followed by dilution with anhydrous MeOH (10 mL) and
the careful addition of excess NaBH4 (2.78 g, 73.3 mmol). The reac-
tion was quenched after 20 min by pouring the reaction mixture
for oxirane 23: ½a D25
ꢁ
¼ þ11:2 (c 1.1, Et,O); Lit13
½
a 2D0:1
ꢁ
¼ þ11:8 (c
1.09, ether). IR (CHCl3):
m
= 3050, 910, 830, 720 cmꢀ1;1H NMR
(200 MHz, CDCl3): d = 0.87 (t, J = 7.2 Hz, 3H), 1.25 (br s, 18H),

D. Tripathi, P. Kumar / Tetrahedron: Asymmetry 23 (2012) 884–890
889
1.33–1.50 (m, 2H), 2.43–2.47 (m, 1H), 2.71–2.76 (m, 1H), 2.85–2.91
(m, 1H). 13C NMR (50 MHz, CDCl3): d = 14.1, 22.7, 25.9, 29.4, 29.5,
29.6, 29.7, 31.9, 32.5, 47.1, 52.3. Anal. Calcd for C13H26O (198.34):
C, 78.68; H, 13.21. Found: C, 78.78; H, 13.24.
4.10. Preparation of (2R,4R)-4-(methoxymethoxy) pentadecane-
1,2-diol 27 and (S)-2-((R)-2-(methoxy methoxy) tridecyl) oxirane
21
A solution of epoxide 26 (6 g, 20.9 mmol) and (S,S)-Salen-CoIII-
OAc (90 mg, 0.1 mmol) in THF (3 mL) was stirred at 0 °C for
5 min and then distilled water (0.21 mL, 11.5 mmol) was added.
After stirring for 24 h, this mixture was concentrated and purified
by silica-gel column chromatography (petroleum ether/EtOAc
19:1) to afford 21 (3.36 g, 93%) as a yellow liquid. Continued chro-
matography with petroleum ether/EtOAc 3:2) provided diol 27
(2.16 mg, 85%) as a brown liquid and as a single diastereomer. Data
4.7. Preparation of (R)-pentadec-1-en-4-ol 24
A round bottom flask was charged with copper(I) iodide (0.20 g,
1.06 mmol), gently heated under vacuum, and slowly cooled with a
flow of argon, after which dry THF (20 mL) was added. This suspen-
sion was cooled to ꢀ20 °C and stirred vigorously, after which vinyl-
magnesium bromide (5.5 M in THF, 4.8 mL, 26.51 mmol) was
injected to it. A solution of epoxide 23 (2.1 g, 10.60 mmol) in THF
(10 mL) was added slowly to the above reagent, and the mixture
was stirred at ꢀ20 °C for 4 h. The reaction mixture was quenched
with a saturated aqueous solution of NH4Cl. The organic layer
was washed with brine, dried (Na2SO4), concentrated, and purified
by silica-gel column chromatography (petroleum ether/EtOAc 9:1)
for oxirane 21 IR (CHCl3):
m = 3392, 3018, 2854, 1458, 1263, 1099,
759 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3H),
;
1.26 (br s, 18H), 1.56–1.74 (m, 4H), 3.42 (s, 3H), 3.59–3.70 (m,
1H), 3.81–3.87 (m, 1H), 4.07–4.18 (m, 2H), 4.64–4.77 (m, 2H). 13C
NMR (50 MHz, CDCl3): d = 14.1, 22.6, 29.3, 29.5, 29.6, 31.8, 34.3,
37.8, 55.7, 60.4, 70.4, 80.1, 95.1. Anal. Calcd for
(304.47): C, 67.06; H, 11.92. Found: C, 67.09; H, 11.96.
C17H36O4
to afford 24 (2.1 g, 89%) as a yellow liquid. ½a D25
¼ þ6 (c 1.7, CHCl3).
ꢁ
IR (CHCl3):
m = 3360, 2920, 2840, 1700, 1455, 1115, 1075, 1018,
;
985, 900 cmꢀ1
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz,
4.11. Preparation of (4R,6R)-6-(methoxymethoxy)heptadec-1-
3H), 1.26 (br s, 18H), 1.38–1.54 (m, 2H), 2.10 -2.35 (m, 2H),
3.59–3.71 (m, 1H), 5.09–5.20 (m, 2H), 5.74–5.94 (m, 1H). 13C
NMR (50 MHz, CDCl3): d = 14.1, 22.7, 25.7, 29.3, 29.6, 29.7, 31.9,
36.8, 41.9, 70.7, 117.9, 134.9. Anal. Calcd for C15H30O (226.40): C,
79.58; H, 13.36. Found: C, 79.63; H, 13.32.
en-4-ol 28
A round bottom flask was charged with copper(I) iodide (0.19 g,
1.04 mmol), gently heated under vacuum, and then slowly cooled
with a flow of argon, after which dry THF (25 mL) was added. This
suspension was cooled to ꢀ30 °C and vigorously stirred, after
which vinylmagnesium bromide (1.6 M in THF, 16.3 mL,
26.18 mmol) was injected into it. A solution of epoxide 21 (3 g,
10.47 mmol) in THF (10 mL) was added slowly to the above re-
agent, and the mixture was stirred at ꢀ30 °C for 12 h. The reaction
mixture was quenched with a saturated aqueous solution of NH4Cl.
The organic layer was washed with brine, dried (Na2SO4), and con-
centrated to afford the crude homoallylic alcohol, which upon sil-
ica gel column chromatography of the crude product using
petroleum ether/EtOAc (8:2) as eluent furnished 28 (3.03 g, 92%)
4.8. Preparation of (R)-4-(methoxymethoxy)pentadec-1-ene 25
To a solution of alcohol 24 (2.0 g, 8.84 mmol) and diisopropyl-
ethylamine (4.62 mL, 26.54 mmol) in dry CH2Cl2 (20 mL) was
added MOMCl (0.8 mL, 10.61 mmol) under argon over 5 min at
0 °C, and the mixture was allowed to warm to room temperature
overnight. After cooling to 0 °C, the reaction mixture was quenched
with water and extracted with CH2Cl2 (3 ꢃ 20 mL). The combined
organic extracts were washed with water (3 ꢃ 20 mL) and brine,
dried (Na2SO4), and concentrated. Silica gel column chromatogra-
phy of the crude product using petroleum ether/EtOAc (19:1) gave
as a colorless liquid. ½a D25
ꢁ
¼ ꢀ14:35 (c 1.06, CHCl3), IR (CHCl3):
m
= 3342, 3018, 1610, 1556, 1492, 1284, 1089, 759 cmꢀ1 1H NMR
;
25 (2.12 g, 89%) as a colorless liquid. ½a D25
ꢁ
¼ þ5:3 (c 1.5, CHCl3). IR
(200 MHz, CDCl3): d = 0.88 (t, J = 7 Hz, 3H), 1.26 (br s, 18H), 1.51–
1.68 (m, 4H), 1.96–2.10 (m, 2H), 3.40 (s, 3H), 3.77–3.88 (m, 2H),
4.62–4.77 (m, 2H), 5.08–5.16 (m, 2H), 5.79–5.96 (m,1H). 13C NMR
(50 MHz, CDCl3): d = 14.2, 22.7, 29.4, 29.6, 29.8, 31.9, 34.8, 40.7,
42.0, 55.8, 67.2, 76.0, 96.3, 117.5, 135.1; Anal. Calcd for C19H38O3
(314.50): C, 72.56; H, 12.18. Found: C, 72.61; H, 12.12.
(CHCl3):
m = 2932, 2859, 1471, 1378, 1284, 1234, 1128, 1068, 910.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.9 Hz, 3H), 1.26 (br s,
18H), 1.42–1.56 (m, 2H), 2.26–2.32 (m, 2H), 3.39 (s, 3H), 3.58–
3.67 (m, 1H), 4.63–4.71 (m, 2H), 5.04–5.12 (m, 2H), 5.73–5.93
(m,1H). 13C NMR (50 MHz, CDCl3): d = 14.1, 22.7, 25.3, 29.3, 29.6,
31.9, 34.1, 38.9, 55.4, 76.4, 95.3, 116.9, 134.9. Anal. Calcd for
C17H34O2 (270.45): C, 75.50; H, 12.67. Found: C, 75.54; H, 12.62.
4.12. Preparation of (((4R,6R)-6-(methoxymethoxy)heptadec-1-
en-4-yloxy)methyl)benzene 29
4.9. Preparation of 2-((R)-2-(methoxymethoxy)tridecyl) oxirane
26
To a solution of alcohol 28 (2.0 g, 6.36 mmol) in dry THF (50 mL)
was added sodium hydride (50%, 0.30 g, 7.63 mmol) at 0 °C. The
reaction mixture was then stirred at room temperature for
30 min after which it was again cooled to 0 °C. To this was slowly
added benzyl bromide (0.9 mL, 7.63 mmol) with further stirring for
4 h at room temperature. The reaction mixture was quenched by
the addition of cold water at 0 °C. The two phases were separated
and the aqueous phase was extracted with EtOAc (3 ꢃ 50 mL). The
combined organic layer was washed with water (3 ꢃ 25 mL), brine,
dried (Na2SO4), and concentrated. Silica gel column chromatogra-
phy of the crude product using petroleum ether/EtOAc (9:1) as elu-
To a stirred solution of olefin 25 (1.0 g, 3.69 mmol) in CH2Cl2
(25 mL) at 0 °C was added mCPBA (50%, 7.65 g, 4.43 mmol). The
reaction mixture was stirred at room temperature for 10 h and
then quenched with a saturated NaHCO3 solution. The resulting
mixture was extracted with CH2Cl2, washed with saturated NaH-
CO3 and brine, dried (Na2SO4), concentrated, and then purified by
silica-gel column chromatography (petroleum ether/EtOAc 9:1)
to yield epoxide 26 (1.0 g, 96%) as a colorless liquid and as a diaste-
reomeric mixture (3:2). IR (neat):
m
= 2954, 2932, 2893, 2859,
1471, 1376, 1361, 1252, 1215, 1102, 1042, 919 cmꢀ1
.
1H NMR
ent furnished 29 (2.44 g, 95%) as a colorless liquid. ½a D25
¼ ꢀ20:3 (c
ꢁ
(200 MHz, CDCl3): d = 0.88 (t, J = 7 Hz, 3H), 1.26 (br s, 18H), 1.50–
1.70 (m, 4H), 2.50–2.52 (m, 1H), 2.80–2.84 (m, 1H), 3.03–3.10
(m, 1H), 3.41 (s, 3H), 3.79–3.82 (m, 1H), 4.70–4.72 (m, 2H). 13C
NMR (50 MHz, CDCl3): d = 14.1, 22.7, 29.3, 29.6, 29.7, 31.9, 34.5,
44.7, 44.8, 55.6, 83.1, 95.6. Anal. Calcd for C17H34O3 (286.45): C,
71.28; H, 11.96. Found: 71.22; H, 11.92.
1.04, CHCl3). IR (CHCl3): m = 2867, 1455, 1115, 1075, 985,
900 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 3H),
;
1.26 (br s, 18H), 1.39–1.57 (m, 4H), 2.35–2.42 (m, 2H), 3.37 (s,
3H), 3.57–3.80 (m, 2H), 4.45–4.65 (m, 4H), 5.08–5.16 (m, 2H),
5.76–5.94 (m, 1H), 7.32–7.37 (m, 5H). 13C NMR (50 MHz, CDCl3):
d = 14.2, 22.7, 29.4, 29.7, 29.8, 29.9, 31.9, 35.4, 38.5, 40.1, 55.6,

890
D. Tripathi, P. Kumar / Tetrahedron: Asymmetry 23 (2012) 884–890
F. D.; Hennigar, R. A.; Jacobs, L. B.; Dick, J. D.; Pasternack, G. R. Proc. Natl. Acad.
Sci. U.S.A. 1994, 91, 6383; (c) Pizer, E. S.; Chrest, F. J.; DiGiuseppe, J. A.; Han, W.
F. Cancer Res. 1945, 5, 4611.
70.9, 74.9, 75.4, 96.1, 117.3, 127.6, 127.9, 128.4, 134.5, 138.8. Anal.
Calcd for C26H44O3 (404.63): C, 77.18; H, 10.96. Found: C, 77.12; H,
10.91.
4. (a) Alo, P. L.; Visca, P.; Marci, A.; Mangoni, A.; Botti, C.; Di Tondo, U. Cancer
1996, 77, 474; (b) Swinnen, J. V.; Roskams, T.; Joniau, S.; Van Poppel, H.; Oyen,
R.; Baert, L.; Heyns, W.; Verhoeven, G. Int. J. Cancer 2002, 98, 19; (c) Rossi, S.;
Graner, E.; Febbo, P.; Weinstein, L.; Bhattacharya, N.; Onody, T.; Bubley, G.;
Balk, S.; Loda, M. Mol. Cancer Res. 2003, 1, 707; (d) Pizer, E. S.; Wood, F. D.;
Heine, H. S.; Romantsev, F. E.; Pasternack, G. R.; Kuhajda, F. P. Cancer Res. 1996,
56, 1189; (e) Gansler, T. S.; Hardman, W., III; Hunt, D. A.; Schaffel, S.; Hennigar,
R. A. Hum. Pathol. 1997, 28, 686.
5. (a) Ma, G.; Zancanella, M.; Oyola, Y.; Richardson, R. D.; Smith, J. W.; Romo, D.
Org. Lett. 2006, 8, 4497; (b) Richardson, R. D.; Ma, G.; Oyola, Y.; Zancanella, M.;
Knowel, L. M.; Cieplak, P.; Romo, D.; Smith, J. W. J. Med. Chem. 2008, 51, 5285.
and references cited therein..
6. (a) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.; Lengsfeld, H. J. Antibiot.
1987, 40, 1081; (b) Hochuli, E.; Kupfer, E.; Maurer, R.; Meister, W.; Mercadal, Y.;
Schmidt, K. J. Antibiot. 1987, 40, 1086.
7. (a) Kondo, S.; Uotani, K.; Miyamoto, M.; Hazato, T.; Naganawa, H.; Aoyagi, T.;
Umezawa, H. J. Antibiot. 1978, 31, 797; (b) Barbier, P.; Schneider, F. J. Org. Chem.
1988, 53, 1218.
4.13. Preparation of (3S,5R)-methyl 3-(benzyloxy)-5-
(methoxymethoxy)hexadecanoate 31
Compound 29 (300 mg, 0.74 mmol) was dissolved in 7 ml of
2:2:3 CCl4ꢀCH3CNꢀH2O, NaIO4 (318 mg, 1.48 mol) after which
RuCl3.3H2O (10 mg, 0.003 mmol) was added. The resulting mixture
was stirred vigorously at room temperature for 3 h. The mixture
was extracted with CH2Cl2 (3 ꢃ 10 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated. To the above crude
product, (225 mg, 0.53 mmol) under ice cold conditions in DMF
(2 mL) was added solid K2CO3 (0.29 g, 1.06 mmol). After stirring
for 10 min in an ice bath, methyl iodide (0.09 g, 0.64 mmol) was
added to the white suspension and stirring was continued at 0 °C
for 30 min. after which the mixture solidified. The reaction was
warmed to room temperature and stirred for an additional 1 h or
when TLC analysis indicated the complete formation of the methyl
ester. The reaction mixture was filtered by suction and the filtrate
was partitioned between EtOAc and water. The organic phase was
washed with brine, dried, filtered, and concentrated. Silica gel col-
umn chromatography of the crude product using petroleum ether/
EtOAc (9:1) as eluent gave methyl ester 31 (185 mg, 85%) as a thick
8. (a) Hadváry, P.; Sidler, W.; Meister, W.; Vetter, W.; Wolfer, H. J. Biol. Chem.
1991, 266, 2021; (b) Lüthi-Peng, Q.; Märki, H. P.; Hadváry, P. FEBS Lett. 1992,
299, 111; (c) Lüthi-Peng, Q.; Winkler, F. K. Eur. J. Biochem. 1992, 205, 383.
9. (a) Barbier, P.; Schneider, F. Helv. Chim. Acta 1987, 70, 196; (b) Pons, J. M.;
´
Kocienski, P. Tetrahedron Lett. 1989, 30, 1833; (c) Fleming, I.; Larwence, N. J.
Tetrahedron Lett. 1990, 31, 3645; (d) Case-Green, S. C.; Davies, S. G.; Hedgecock,
C. J. R. Synlett 1991, 781; (e) Chadha, N. K.; Batcho, A. D.; Tang, P. C.; Courtney, L.
´
F.; Cook, C. M.; Wovkulich, P. M. Uskokovic M. R. J. Org. Chem. 1991, 56, 4714; (f)
Hanessian, S.; Tehim, A.; Chen, P. J. Org. Chem. 1993, 58, 7768; (g) Landl, J. J., Jr.;
Garofolo, L. M.; Ramig, K. Tetrahedron Lett. 1993, 34, 277; (h) Giese, B.; Roth, M.
J. Braz. Chem. Soc. 1996, 7, 243; (i) Fleming, I.; Larwence, N. J. J. Chem. Soc., Perkin
Trans. 1998, 1, 2679; (j) Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743; (k)
Wedler, C.; Costisella, B.; Schick, H. J. Org. Chem. 1999, 64, 5301; (l) Dirat, O.;
Kouklovsky, C.; Langlois, Y. Org. Lett. 1999, 1, 753; (m) Paterson, I.; Doughty, V.
A. Tetrahedron Lett. 1999, 40, 393; (n) Ghosh, A. K.; Fidanze, S. Org. Lett. 2000, 2,
2405; (o) Honda, T.; Endo, K.; Ono, S. Chem. Pharm. Bull. 2000, 48, 1545; (p)
Bodkin, J. A.; Humphries, E. J.; McLeod, M. D. Aust. J. Chem. 2003, 56, 795; (q)
Thadani, A. N.; Batey, R. A. Tetrahedron Lett. 2003, 44, 8051; (r) Bodkin, J. A.;
Humphries, E. J.; McLeod, M. D. Tetrahedron Lett. 2003, 44, 2869; (s) Polkowska,
J.; Lukaszewicz, E.; Kiegiel, J.; Jurczak, J. Tetrahedron Lett. 2004, 45, 3873; (t)
Yadav, J. S.; Rao, K. V.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2006, 47,
4393; (u) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2006, 47,
4995; (v) Kumaraswamy, G.; Markondaiah, B. Tetrahedron Lett. 2008, 49, 327;
(w) Case-Green, S. C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.
Tetrahedron: Asymmetry 2008, 19, 2620; (x) Ghosh, A. K.; Shurrush, K.; Kulkarni,
S. J. Org. Chem. 2009, 74, 4508; (y) Raghavan, S.; Rathore, K. Synlett 2009, 1285.
10. (a) Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247; (b)
Chen, C.; Luo, S.; Jordan, R. F. J. Am. Chem. Soc. 2008, 130, 12892.
yellow liquid. ½a D25
ꢁ
¼ ꢀ24:4 (c 3.3, CHCl3); lit.9t
½
a 2D5
ꢁ
¼ ꢀ24:5 (c 3.3,
CHCl3). IR (neat):
m
= 2926, 2854, 1740, 1459, 1038, 740 cmꢀ1 1H
.
NMR (200 MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 3H), 1.26 (br s,
18H), 1.48–1.57 (m, 4H), 2.35–2.42 (m, 2H), 3.37 (s, 3H), 3.64–
3.80 (m, 4H), 4.03–4.05 (m, 1H) 4.45–4.57 (m, 4H), 7.30–7.37 (m,
5H), 13C NMR (50 MHz, CDCl3): d = 14.1, 22.7, 24.9, 29.6, 29.9,
31.9, 35.4, 38.5, 40.1, 52.2, 55.5, 70.9, 74.8, 75.4, 96.1, 127.5,
127.8, 128.4, 134.5, 174.7.
Acknowledgments
The authors thank UGC New Delhi for financial assistance.
Financial support from DST, New Delhi (Grant No. SR/OC-44/
2009) is gratefully acknowledged.
11. (a) Gupta, P.; Naidu, S. V.; Kumar, P. Chem. Eur. J. 2006, 12, 1397; (b) Kondekar,
N. B.; Kumar, P. Org. Lett. 2009, 11, 2611.
12. (a) Kumar, P.; Naidu, S. V. J. Org. Chem. 2006, 71, 3935; (b) Gupta, P.; Kumar, P.
Eur. J. Org. Chem. 2008, 1195; (c) Tripathi, D.; Kumar, P. Tetrahedron Lett. 2008,
49, 7012; (d) Dubey, A.; Kumar, P. Tetrahedron Lett. 2009, 50, 3425; (e) Tripathi,
D.; Pandey, S. K.; Kumar, P. Tetrahedron 2009, 65, 2226; (f) Dubey, A.; Puranik,
V. G.; Kumar, P. Org. Bio. Chem. 2010, 8, 5074; (g) Jha, V.; Kondekar, N. B.;
Kumar, P. Org. Lett. 2010, 12, 2762; (h) Show, K.; Gupta, P.; Kumar, P.
Tetrahedron: Asymmetry 2011, 22, 1212; (i) Dwivedi, N.; Tripathi, D.; Kumar, P.
Tetrahedron: Asymmetry 2011, 22, 1749.
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