A concise enantioselective total synthesis of (+)-epi-muricatacin, using asymmetric hydrogenation/intramolecular iodoetherification as key steps

Article abstract of DOI:10.1016/j.tetasy.2010.02.024

A concise enantioselective total synthesis of (+)-epi-muricatacin, a potent cytotoxic agent, is described. A key feature of this protocol is a catalytic asymmetric hydrogenation and a chiral auxiliary mediated intramolecular iodoetherification to ensure a high degree of distereo- and enantiocontrol.

Full text of DOI:10.1016/j.tetasy.2010.02.024

Tetrahedron: Asymmetry 21 (2010) 544–548
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A concise enantioselective total synthesis of (+)-epi-muricatacin, using
asymmetric hydrogenation/intramolecular iodoetherification as key steps
a
b
Gullapalli Kumaraswamy a, , Duggirala Ramakrishna , Kondapalli Santhakumar
*
a Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b NMR Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise enantioselective total synthesis of (+)-epi-muricatacin, a potent cytotoxic agent, is described. A
key feature of this protocol is a catalytic asymmetric hydrogenation and a chiral auxiliary mediated intra-
molecular iodoetherification to ensure a high degree of distereo- and enantiocontrol.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 January 2010
Accepted 26 February 2010
Available online 10 April 2010
1. Introduction
with tert-butyldimethylsilyloxy cis-butene mesylate 3, which are
readily available, inexpensive starting materials. Our retrosynthet-
The enantioenriched 5-hydroxyalkyl butan-4-olide is a chemi-
cally significant moiety and can be found in many natural product
molecules that exhibit interesting pharmacologically important
properties. This functional group array is mainly originated from
the Annonaceae acetogenin family.1 Among these, the most impor-
tant structural prototype molecule is muricatacin, which can be
isolated as a scalemic mixture from the seeds of Annona muricata.2
Muricatacin and epi-muricatacin have received interest due to
their anti-proliferative activity against certain cell lines.3a A pleth-
ora of synthetic strategies have been developed for muricatacin
and (+)-epi-muricatacin molecules. The genesis of chirality for
these synthetic strategies is either from the chiral pool,3 or initi-
ated through catalytic asymmetric transformations.4 Herein, we
report another alternative synthetic strategy for the synthesis of
the (+)-epi-muricatacin molecule by means of asymmetric hydro-
genation/intramolecular iodoetherification as key steps.
ic analysis is outlined in Scheme 1.
Accordingly, benzil 2 was subjected to Noyori’s catalytic asym-
metric transfer hydrogenation in the presence of 0.1 mol % of cata-
lyst A using formic acid–triethylamine.6 After 24 h at 40 °C, the
volatiles were removed under reduced pressure and the resulting
crude residue was dissolved in THF and to it sequentially added
NaH and tert-butyldimethylsilyloxy cis-butene mesylate 3. The ex-
pected product 4 was isolated in 70% yield with >97% diastereose-
lectivity with >99% enantiomeric excess7 (Scheme 2). Having
prepared hydroxylalkene 4, the enantioselective intramolecular
iodoetherification was then evaluated.
Thus, the reaction of 4 with N-iodosuccinimide (NIS) in THF at
ambient temperature for 6 h gave 5 in a 9:1 ratio of separable dia-
stereomers in a yield of 90%.8 The stereochemistry of the major
diastereomer 5 was determined by an NOE study. The significant
NOE correlations are shown in Figure 1. In the major diastereomer
5, the strong NOE between Hb–Hc and Hc–He confirms that they are
spatially closer and hence considered to be in a cis-relationship.9
The exposure of 5 to TBAF in THF at ambient temperature led
not only to desilylation, but also to concomitant nucleophilic
substitution of the resulting alcohol onto iodine to give highly
enantioenriched epoxy intermediate 6 in 85% isolated yield. The
relative stereochemistry of 6 was assigned by NOEs between
Hb–Hc and Hc–He (Fig. 1). The enantiomeric excess was deter-
mined by chiral HPLC analysis in comparison with a racemic
mixture (>99%ee, Chiralpak OD-H, 254 nm, flow rate = 0.5 mL/
min, n-hexane/2-propanol [95:5]). The nucleophilic opening of
epoxide 6 with undecylmagnesium bromide in the presence of
a catalytic amount of CuI led to 7 (89%).10 Removal of the chiral
auxiliary in Li/liq. NH3 at ꢀ78 °C gave 8. Then, under Mitsunobu
conditions11,3d (Ph3P/DIAD, THF), the triol 8 was converted into
epoxy alcohol 9 in 90% yield. Finally, substrate 9 was treated
with dilithioacetate dianion12 followed by acidification of the
2. Results and discussion
Recently, we have reported a highly enantioselective synthetic
route to the synthesis of functionalized scaffolds of medium-sized
oxacycles and carbocycles by employing a C2-symmetric diol teth-
ered with dizoacetate and methoxy cis-butene.5 Along this vein, we
envisioned utilizing a C2-symmetric diol to install the two stereo-
genic centers with the high degree of diastereo- and enantioselec-
tivity required for (+)-epi-muricatacin, 1. We wanted to generate
our critical starting material, that is, the C2-symmetric (S,S)-diol
tethered with tert-butyldimethylsilyloxy cis-butene 4, in a one-
pot procedure via a catalytic asymmetric hydrogenation of benzil
2 and subsequent monoprotection of the C2-symmetric (S,S)-diol
* Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193275.
E-mail address: gkswamy_iict@yahoo.co.in (G. Kumaraswamy).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.024

G. Kumaraswamy et al. / Tetrahedron: Asymmetry 21 (2010) 544–548
545
O
O
OH
(+)-epi-Muricatacin 1
OMs
Ar
O
Ar
Ar
O
OTBDMS
Ar
Ar
O
O
+
OH
O
Ar
O
4
6
OTBDMS
3
2
Scheme 1.
OMs
Ar
Ar
ii
i
O
OTBDMS
Ar
Ar
O
O
90%
70%
OH
4
OTBDMS
3
dr = >97%
ee = 99%
2
Ar
Ar
O
Ar
Ar
O
Ar
Ar
O
iv
OTBDMS
iii
85%
O
85%
O
C11H23
O
O
O
I
OH
7
6
5
HO
v
vi
90%
vii
80%
C12H25
C12H25
1
HO
89%
OH
OH
8
9
H
H
N
Ph
Ph
Ru
Cat.A
Cl
N
Ts
Scheme 2. Reagents and conditions: (i) (a) Cat. A 0.1 mol %, HCOOH/Et3N, 40 °C, 24 h; (b) NaH, THF, 0 °C to rt, 12 h; (ii) N-iodosuccinimide, THF, rt, 6 h; (iii) TBAF, THF, 0 °C,
30 min; (iv) C11H23MgBr, CuI (10 mol %), THF, 8 h; (v) Li/liq. NH3, ꢀ78 °C, 30 min; (vi) DIAD, PPh3, benzene, 0 °C, 30 min and in vacuo 130 °C, 20 min; (vii) (a) LiCH2CO2Li; (b)
H+.
rotation data of 1 are in full agreement with those reported in
the literature3a {½a D25
ꢁ
¼ þ32:0 (c 0.9, CHCl3), lit.3a
½
a 2D4
ꢁ
¼ þ34:3
Hd'
Ha
(c 2, CHCl3)}.
Hd'
Ar
Ar
Ha
Hd
H
O
f
I
O
Hf '
Hd
3. Conclusions
O
Ar
Ar
O
Hf
Hf '
Hc
Hb
He
OR
In conclusion, we have accomplished a concise enantioselective
total synthesis of (+)-epi-muricatacin. A key feature of this protocol
is a catalytic asymmetric hydrogenation as the genesis of chirality
and a chiral auxiliary mediated intramolecular iodoetherification
to ensure a high degree of distereo- and enantiocontrol. The critical
starting material 4 was prepared in high efficiency with a sub-
strate/catalyst molar ratio of 1000:1 using asymmetric hydrogena-
tion. Moreover, the flexibility built into the synthesis to generate a
library of analogues will be amenable to large-scale synthesis
Hc
O
He
Hb
R = SiMe2Bu-t
5
6
Figure 1. NOE study of 5 and 6.
resulting lithium carboxylate to furnish the title compound 1 in
80% isolated yield3a (Scheme 2). The spectroscopic and specific

546
G. Kumaraswamy et al. / Tetrahedron: Asymmetry 21 (2010) 544–548
while the intermediates generated in this protocol will be useful in
the total synthesis of biologically active compounds.
57.53 mmol) was added portionwise at 0 °C. After 30 min, mesy-
late 3 in THF (15 mL) was added over a period of 10 min. The
resulting mixture was warmed to rt and stirred overnight. The
reaction was quenched with water (ꢃ25 mL) until the mixture be-
came clear. The reaction mixture was then extracted with ethyl
acetate (4 ꢂ 50 mL). The combined organic layers were washed
with brine solution (2 ꢂ 50 mL) and dried over anhydrous Na2SO4.
The contents were filtered and concentrated under reduced pres-
sure to yield a crude residue. The residue was subjected to silica
gel (100–200 mesh) column chromatography eluting with hex-
ane/EtOAc (97:3) and furnished the pure product 4 as a light yel-
4. Experimental
4.1. General information
Starting materials: DCM was distilled from P2O5, THF from so-
dium benzophenone ketyl. All other chemicals used were commer-
cially available. All reactions were conducted under an atmosphere
of nitrogen (IOLAR Grade I). Progress of the reactions was moni-
tored by TLC on Merck Silica Gel 60 F-254 precoated. Evaporation
of solvents was performed at reduced pressure on a Buchi rotary
evaporator. Column chromatography was carried out with silica
gel grade 60–120 and 100–200 mesh. 1H NMR spectra were re-
corded at 300, 400, and 500 MHz and 13C NMR 75 and 125 MHz
in CDCl3. J values were recorded in hertz and abbreviations used
were s—singlet, d—doublet, m—multiplet, and br—broad. Chemical
shifts (d) are reported relative to TMS (d = 0.0) as an internal stan-
dard. IR spectra were recorded on Thermo Nicolet FT/IR-5700.
Mass spectral data were compiled using MS (ESI), HRMS mass
spectrometers. Optical rotations were recorded on HORIBA high
sensitive polarimeter with 10 mm cell.
low oil (14.57 g, 36.61 mmol, yield 70%); ½a D24
¼ ꢀ43:5 (c 1,
ꢁ
CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.20–7.10 (m, 6H), 6.98–
6.95 (m, 4H), 5.72–5.57 (m, 2H), 4.62 (d, J = 8.3 Hz, 1H), 4.21 (d,
J = 8.3 Hz, 1H), 4.07 (d, J = 5.3 Hz, 2H), 3.94–3.88 (m, 2H), 3.49 (br
s, 1H), 0.86 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3):
d = 142.0, 133.5, 128.3, 128.2, 127.8, 127.2, 126.7, 86.8, 85.3, 78.4,
29.6, 27.1, ꢀ5.3; IR (Neat): 3695, 3605, 3580, 2952, 2877, 2856,
1731, 1456, 1080, 838 cmꢀ1; MS (ESIMS) m/z: 399 (M+H)+, 418
(M+NH4)+, 421 (M+Na)+.
4.1.3. tert-Butyl((S)-2-((2S,5S,6S)-5,6-diphenyl-1,4-dioxan-2-yl)-
2 iodoethoxy)dimethylsilane 5
A solution of N-iodosuccinimide (11.25 g, 50.00 mmol) in dry
THF (40 mL) was added to a predissolved solution (40 mL, dry
THF) of 4 (9.95 g, 25.00 mmol) at rt and the resulting reaction mix-
ture was left for 6 h. The reaction was quenched with an aqueous
solution of hypo (120 mL of 0.63 M). The reaction mixture was ex-
tracted with ethyl acetate (4 ꢂ 100 mL). The combined organic lay-
ers were washed with brine solution (2 ꢂ 50 mL) and dried over
anhydrous Na2SO4. The contents were filtered, and concentrated
under reduced pressure to yield a crude residue. The crude residue
was subjected to silica gel (100–200 mesh) column chromatogra-
phy eluting with hexane/EtOAc (97:2) and furnished the pure
product 6 as an oil (11.79 g, 22.5 mmol, yield 90% and diastereo-
4.1.1. (Z)-4-(tert-Butyldimethylsilyloxy)but-2-en-1-ol
To a mixture of (Z)-but-2-ene-1,4-diol (43.0 mL, 0.52 mol) and
triethylamine (87.5 mL, 0.63 mol) in dry dichloromethane
(250 mL), a solution of TBDMSCl (75.30 g, 0.50 mol, DCM,150 mL)
was slowly added over a period of 3 h at room temperature. The
resulting contents were stirred further for 3 h at the same temper-
ature. Then, water (250 mL) was added and the reaction mixture
was extracted with ethyl acetate (3 ꢂ 500 mL). The combined or-
ganic layers were washed with brine solution (250 mL) and dried
(anhydrous Na2SO4). Removal of the solvent resulted in an oil
which was distilled at 85–90 °C at 1 mmHg to give pure product
a
colorless oil (93.48 g, 0.46 mmol, 89% Yield); 1H NMR
meric ratio is 9:1); ½a D24
ꢁ
¼ ꢀ39:0 (c 1, CHCl3); 1H NMR (500 MHz,
as
(400 MHz, CDCl3): d = 5.60–5.50 (m, 2H), 4.16 (d, J = 5.2 Hz, 2H),
4.14 (d, J = 4.2 Hz, 2H), 0.82 (s, 9H), 0.07 (s, 6H); 13C NMR
(125 MHz, CDCl3): d = 131.0, 128.9, 63.2, 63.1, 25.9, 14.4, ꢀ5.3; IR
CDCl3): d = 7.16–7.12 (m, 6H), 6.99–6.93 (m, 4H), 4.55 (d,
J = 9.1 Hz, 1H), 4.33 (d, J = 9.1 Hz, 1H), 4.10 (ddd, J = 2.9, 5.5,
9.2 Hz, 1H), 4.07 (dd, J = 2.9, 11.6 Hz, 1H), 3.97 (dd, J = 10.4,
11.6 Hz, 1H), 3.95 (dd, J = 9.2, 10.3 Hz, 1H), 3.89 (dd, J = 5.5,
10.3 Hz, 1H), 3.69–3.66 (m, 1H), 0.88 (s, 9H), 0.03 (s, 3H), 0.02 (s,
3H); 13C NMR (75 MHz, CDCl3): d = 137.7, 137.6, 128.3, 128.2,
127.8, 127.7, 127.5, 127.0, 126.6 84.1, 83.8, 72.1, 65.3, 33.1, 25.7,
(Neat): 3623, 3015, 2931, 2858, 2300, 1650, 1251, 838 cmꢀ1
;
(ESIMS) m/z: 203 (M+H)+ 225 (M+Na)+.
4.1.2. (1S,2S,Z)-2-(4-(tert-Butylmethoxysilyloxy)but-2-
enyloxy)-1,2-diphenylethanol 4
ꢀ5.5; IR (Neat): 3458, 3427, 2951, 2856, 1254, 1090, 839 cmꢀ1
;
MS (ESIMS) m/z: 525 (M+H)+, 542 (M+NH4)+, 547 (M+Na)+; HRMS
(ESIMS): calcd for C24H33O3NaSi (M+Na)+ 547.1141, found
547.1126.
Step 1: To a dry dichloromethane (100 mL) solution of (Z)-4-
(tert-butyldimethylsilyloxy)but-2-en-1-ol (11.62 g, 57.53 mmol)
was added Et3N (9.19 mL, 66.12 mmol). To this reaction mixture,
methanesulfonyl chloride (4.66 mL, 60.33 mmol) was added slowly
at 0 °C. Then, the mixture was allowed to stir for only a period of
2 min at 0 °C. The reaction was quenched with water (100 mL).
The organic layer was separated, washed with brine solution
(2 ꢂ 100 mL), and dried over anhydrous Na2SO4. The contents were
filtered and concentrated under reduced pressure. The crude mes-
ylate 3 was used in the next step without purification.
4.1.4. (2S,3S,5S)-5-((R)-Oxiran-2-yl)-2,3-diphenyl-1,4-dioxane 6
A 1 M solution of tetrabutyl ammonium fluoride (8.00 mL,
8.00 mmol) in THF was added to a predissolved solution of 5
(4.19 g, 8.00 mmol, THF, 32 mL) under a nitrogen atmosphere at
0 °C. The reaction was allowed to stir for 30 min at the same tem-
perature after which, the contents were concentrated under re-
duced pressure to give a crude residue. The crude residue was
subjected to silica gel (60–120 mesh) column chromatography
eluting with hexane/EtOAc (95:5) to give the pure product 6 as a
white solid (1.92 g, 6.80 mmol, Yield 85%); Chiral HPLC analysis
(>99%ee, Chiralpak OD-H, 254 nm, flow rate = 0.5 mL/min, n-hex-
ane/2-propanol [95:5]) the major isomer was eluted after
27.3 min and the minor isomer was eluted after 24.2 min; Mp:
Step 2: A 100 mL two-necked round-bottomed flask equipped
with a reflux condenser bearing a guard tube and a dropping fun-
nel was charged with triethylamine (18.92 mL, 136.00 mmol). The
triethylamine was cooled to 4 °C in an ice bath and formic acid
(8.67 mL, 230 mmol) was slowly added. To the mixture of formic
acid and triethylamine at ambient temperature were added benzil
(11.19 g, 52.30 mmol) and RuCl[(1R,2R)-N-p-toluenesulfonyl-1,2-
diphenylethanediamine](g
6-p-cymene) (33.3 mg, 0.0523 mmol)
89–91 °C; ½a 2D4
ꢁ
¼ þ39:5 (c 1, CHCl3); 1H NMR (500 MHz, CDCl3):
at ambient temperature. The combined reaction mixture was stir-
red at 40 °C for 24 h, after which time the volatiles were removed
under vacuum. The crude residue was dissolved in dry THF
(150 mL) and NaH (60% dispersion in mineral oil) (2.30 g,
d = 7.16–7.09 (m, 6H), 6.99–6.90 (m, 4H), 4.46 (d, J = 9.0 Hz, 1H),
4.36 (d, J = 9.0 Hz, 1H), 4.17 (dd, J = 1.9, 10.9 Hz, 1H), 3.83 (dd,
J = 10.3, 10.9 Hz, 1H), 3.79 (ddd, J = 1.9, 4.9, 10.3 Hz, 1H), 3.05
(ddd, J = 2.4, 3.7, 4.9 Hz, 1H), 2.83 (dd, J = 3.7, 4.9 Hz, 1H), 2.77

G. Kumaraswamy et al. / Tetrahedron: Asymmetry 21 (2010) 544–548
547
(dd, J = 2.4, 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 137.2, 128.1,
128.0, 127.8, 127.4, 127.3, 127.2, 126.6 83.9, 83.7, 75.4, 68.4, 50.6,
45.2; IR (Neat): 2866, 1254, 1101, 925, 698 cmꢀ1; MS (ESIMS) m/z:
283 (M+H)+, 300 (M+NH4)+, 305 (M+Na)+; HRMS (ESIMS): calcd for
C18H18O3Na (M+Na)+ 305.1153, found 305.1139.
4.1.7. (R)-1-((S)-Oxiran-2-yl)tridecan-1-ol 9
At 0 °C, diisopropyl azodicarboxylate (DIAD, 0.25 mL,
1.30 mmol) was added dropwise to a stirred solution of (2S,3R)-
pentadecane-1,2,3-triol, 8 (260 mg, 1.00 mmol) and triphenylphos-
phine (340 mg, 1.3 mmol) in dry benzene (2 mL). After stirring for
2 h at 0 °C, the benzene was removed in vacuo and the residue was
heated to 130 °C (4 mmHg) for 6 h. The crude product was sub-
jected to silica gel (100–200 mesh) column chromatography elut-
ing with hexane/EtOAc (90:10) to furnish the pure product
4.1.5. (R)-1-((2S,5S,6S)-5-6-Diphenyl-1,4-dioxan-2-yl)tridecan-
1-ol 7
To magnesium turnings (536.16 mg, 22.34 mmol) dried at
125 °C overnight, and a crystal of iodine to start the reaction, a
solution of 1-bromoundecane (3.58 mL, 16.00 mmol) in dry THF
(20 mL) was added dropwise at room temperature. The mixture
was kept at 60 °C for 2 h and then cooled to ꢀ25 °C. Copper io-
dide (301 mg, 1.6 mmol) was then added together with toluene
(ꢃ5 mL) to make the stirring more effective. After 40 min at
ꢀ25 °C, 6 (3.00 g, 10.64 mmol) was added over 10 min, after
which time the cooling bath was removed and allowed to stir
for 2 h at room temperature and then mixture was refluxed for
8 h. The reaction was quenched with saturated solution of NH4Cl.
The reaction mixture was extracted with ethyl acetate
(4 ꢂ 30 mL). The combined organic layers were washed with
brine (2 ꢂ 30 mL) and dried over anhydrous Na2SO4. The contents
were filtered, and concentrated under reduced pressure to yield
crude residue. The crude product was subjected to silica gel
(100–200 mesh) column chromatography eluting with hexane/
EtOAc (94:6) to give 7 as a white solid (4.14 g, 9.46 mmol, yield
(217 mg, 0.9 mmol, yield 90%). ½a D24
ꢁ
¼ ꢀ11:0 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d = 3.85 (m, 1H), 3.02 (dd, J = 3.2, 7.3 Hz,
1H), 2.82 (dd, J = 2.6, 5.0 Hz, 1H), 2.72 (dd, J = 4.1, 4.8 Hz, 1H),
1.72–1.20 (m, 22H), 0.86 (t, J = 6.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d = 68.3, 54.5, 43.4, 33.4, 31.8, 29.6, 29.5, 29.4, 25.2, 22.6,
14.1; MS (ESIMS) m/z 243 (M+H)+, 265 (M+Na)+; HRMS (ESIMS):
calcd for C15H30O2Na (M+Na)+ 265.2143, found 265.2149.
4.1.8. (+)-(4S,5R)-5-Hydroxyheptadeca-4-nolide 1
To an ice-cooled solution of LDA (1.6 M, 2 mmol) in THF (4 mL),
dry acetic acid (57.2 lL, 1 mmol) was added while stirring. After
30 min, the epoxy alcohol 9 (48.4 mg, 0.2 mmol) was added and
the resulting mixture was stirred overnight at reflux. It was then
cooled, acidified with saturated aqueous sodium hydrogen sulfate
and extracted with ether (2 ꢂ 5 mL). The combined extracts were
concentrated and treated with a benzene solution of p-toluene sul-
fonic acid (0.05 equiv in benzene, 5 mL) and refluxed for 1 h. The
reaction mixture was cooled to rt and then washed with an aque-
ous solution of sodium hydrogen carbonate. The organic layer was
dried (Na2SO4 anhydrous) and concentrated. The crude residue was
subjected to silica gel (100–200 mesh) column chromatography
eluting with hexane/EtOAc (50:50) to give the pure product 1 as
a white solid (45 mg, 0.16 mmol, yield 80%); Mp: 66–67 °C,
89%); Mp: 84–85 °C;
½
a 2D4
ꢁ
¼ ꢀ20:0 (c 1, CHCl3); 1H NMR
(300 MHz, CDCl3): d = 7.19–7.10 (m, 6H), 6.95–6.92 (m, 4H),
4.43 (d, J = 9.4 Hz, 1H), 4.28 (d, J = 8.3 Hz, 1H), 4.10 (d,
J = 9.3 Hz, 1H), 3.88–3.86 (m, 1H), 3.84–3.78 (m, 2H), 1.53–1.47
(m, 2H), 1.26–1.20 (m, 20H), 0.89 (t, J = 6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d = 137.6, 137.5, 128.3, 128.2, 128.0, 127.9,
127.8, 127.4, 127.3, 84.2, 83.8, 77.9, 71.8, 66.9, 32.2, 31.9, 29.6,
29.5, 29.4, 29.3, 25.8, 22.7, 14.1; IR(Neat): 3444, 2917, 2850,
1099, 760 cmꢀ1; MS (ESIMS) m/z: 439 (M+H)+, 456 (M+NH4)+,
461 (M+Na)+; HRMS (ESIMS): calcd for C29H42O3Na (M+Na)+
461.3031, found 461.3046.
½
a 2D4
ꢁ
¼ þ32:0 (c 0.9, CHCl3), lit. ½a D24
ꢁ
¼ þ34:5 (c 2, CHCl3); 1H
NMR (500 MHz, CDCl3): d = 4.45–4.25 (m, 1H), 3.96–3.80 (m, 1H),
2.57–2.40 (m, 2H), 2.3–2.0 (m, 2H), 1.82–1.20 (m, 22H), 0.88 (t,
J = 6.7 Hz, 3H): 13C NMR (125 MHz, CDCl3): d = 177.1, 82.5, 71.9,
31.9, 29.5, 29.2, 28.5, 25.9, 23.1, 21.8, 13.9; IR (Neat): 3400, 2918,
2849, 1780 cmꢀ1; MS (ESIMS): m/z 285 (M+H)+; HRMS (ESIMS):
calcd for C17H32O3Na (M+Na)+ 307.2249, found 307.2262.
4.1.6. (2S,3R)-Pentadecane-1,2,3-triol 8
A 50 mL two-necked RB was equipped with a dry-ice con-
denser with a guard tube and a stopper. Ammonia (15–20 mL)
was condensed at ꢀ78 °C. Then, Li granules (140 mg, 20.00 mmol)
Acknowledgments
We are grateful to Dr. J. S. Yadav, Director, IICT, for his constant
encouragement. Financial support was provided by the DST, New
Delhi, India (Grant No. SR/SI/OC-12/2007) and CSIR (New Delhi)
is gratefully acknowledged for awarding the fellowship to DSR.
Thanks are also due to Dr. G. V. M. Sharma for his support.
were slowly added.
A blue color then appeared. Then the
stopper was replaced by a septum. To this blue solution, above
(R)-1-((2S,5S,6S)-5-6-diphenyl-1,4-dioxan-2-yl)tridecan-1-ol,
7
(876 mg, 2 mmol) in THF (10 mL) was added while maintaining
the same temperature. After 30 min, the reaction was quenched
by addition of solid NH4Cl (ꢃ2 g). Then ammonia condenser
was removed so as to allow evaporation of the excess liquid
ammonia. To this reaction mixture water was added carefully
and the aqueous layer was extracted with ethyl acetate
(3 ꢂ 20 mL). The combined organic layers were dried over anhy-
drous Na2SO4. The contents were filtered, and concentrated under
reduced pressure to yield a crude residue. The crude residue was
subjected to silica gel (60–120 mesh) column chromatography
eluting with hexane/EtOAc (10:90) and furnished the pure prod-
uct 8 as a white solid (442 mg, 1.7 mmol, yield 85%); Mp: 95–
References
1. (a) Jefford, C. W.; Jaggi, D.; Sledeski, A. W.; Boukouvalas, J. Stud. Nat. Prod. Chem.
1989, 3, 157; (b) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504; (c) Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D.
Phytochemistry 1998, 48, 1087.
2. Rieser, M. J.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L. Tetrahedron Lett.
1991, 32, 1137.
3. (a) Figadere, B.; Harmange, J.-C.; Laurens, A.; Cave, A. Tetrahedron Lett. 1991, 32,
7539; (b) Pelletier, C. G.; Saniere, M.; Charvet, I.; Merrer, Y. L.; Depezay, J.-C.
Tetrahedron Lett. 1994, 35, 115; (c) Somfai, P. J. Chem. Soc., Perkin Trans. 1 1995,
817; (d) Saniere, M.; Charvet, I.; Merrer, Y. L.; Depezay, J.-C. Tetrahedron 1995,
51, 1653; (e) Yoon, S.-H.; Moon, H.-S.; Hwang, S.-K.; Choi, S. R.; Kang, S.-K.
Bioorg. Med. Chem. 1998, 6, 1043; (f) Marshall, J. A.; Welmaker, G. S. J. Org. Chem.
1994, 59, 4122; (g) van Aar, M. P. M.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett.
1995, 51, 11223; (h) Solladie, G.; Hanquet, G.; Izzo, I.; Crumbie, R. Tetrahedron
Lett. 1999, 40, 3071; (i) Bonini, C.; Federici, C.; Rossi, L.; Righi, G. J. Org. Chem.
1995, 60, 4803; (j) Rasu, G.; Pinna, L.; Spanu, P.; Zanardi, F.; Battistini, L.;
Casiraghi, G. J. Org. Chem. 1997, 62, 4513; (k) Chang, S.-W.; Hung, C.-Y.; Liu, H.-
H.; Uang, B.-J. Tetrahedron: Asymmetry 1998, 9, 521; (l) Szlosek, M.; Franck, X.;
Figadere, B.; Cave, A. J. Org. Chem. 1998, 63, 5169; (m) Couladouros, E. A.;
Mihou, A. P. Tetrahedron Lett. 1999, 40, 4861; (n) Baylon, C.; Prestat, G.; Heck,
M. P.; Mioskowski, C. Tetrahedron Lett. 2000, 41, 3833; (o) Chandrasekhar, M.;
96 °C; ½a 2D4
ꢁ
¼ þ6 (c 1, MeOH); 1H NMR (300 MHz, CDCl3 + DMSO):
d = 3.71–3.54 (m, 5H), 3.44–3.40 (m, 2H), 1.51–1.47 (m, 2H),
1.40–1.20 (m, 20H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (60 MHz,
CDCl3 + DMSO): d = 73.2, 71.2, 62.3, 31.7, 30.4, 28.3, 27.8, 27.7,
24.4, 21.1, 12.8; IR (Neat): 3728, 3194, 2915, 2849, 1467,
1076 cmꢀ1; MS (ESIMS) m/z 261 (M+H)+, 278 (M+NH4)+, 283
(M+Na)+; HRMS (ESIMS): calcd for C15H32O3Na (M+Na)+
283.2249, found 283.2255.

548
G. Kumaraswamy et al. / Tetrahedron: Asymmetry 21 (2010) 544–548
Chandra, K. L.; Singh, V. K. Tetrahedron Lett. 2002, 43, 2773; (p) Carda, M.;
6. Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikaria, T. Org. Lett. 1999,
1, 1119; Ikaria, T.; Hashiguchi, S.; Murata, K.; Noyori, R. Org. Synth. 2005, 82, 10.
7. The diastereomeric ratio and enantiomeric excess were estimated based on the
Rodriguez, S.; Gonzalez, F.; Castillo, E.; Villanueva, A.; Marco, J. A. Eur. J. Org.
Chem. 2002, 2649; (q) Popsavin, V.; Krstic, I.; Popsavin, M. Tetrahedron Lett.
2003, 44, 8897; (r) Sadagopan, R.; Joseph, S. C. Tetrahedron: Asymmetry 2003,
14, 101; (s) Yoshimitsu, T.; Makino, T.; Nagoaka, H. J. Org. Chem. 2003, 68, 7548;
(t) Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143; (u) Prasad, K.
R.; Vasudevarao, G. Tetrahedron: Asymmetry 2008, 19, 2616; (v) Popsavin, V.;
Sreco, B.; Benedekovic, G.; Popsavin, M.; Francuz, J.; Kojic, V.; Bogdanovic, G.
Bioorg. Med. Chem. Lett. 2008, 18, 5182.
specific rotation in comparison with an authentic sample of
4 prepared
independently from (S,S)-diphenylethanediol (Aldrich) and compound 3 (NaH,
THF, rt, 12 h). The resulting compound’s specific rotation was found to be
½
a 2D4
a 2D4
ꢁ
¼ ꢀ43:5 (c 1, CHCl3). The one-pot procedure also showed same magnitude
½
ꢁ
¼ ꢀ43:0 (c 1, CHCl3).
8. The enantioselective intramolecular iodoetherification was performed in
various solvent systems such as toluene, CH2Cl2, t-BuOMe, and THF. Only
THF gave better yields. When reaction was conducted at sub-zero temperature
and at 0 °C, ti gave 5 in lower yields.
4. (a) Saiah, M.; Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1993, 34, 1597; (b)
Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.; Sinha, A.-B.; Keinan, E.
Tetrahedron Lett. 1992, 33, 6407; (c) Makabe, H.; Tanaka, A.; Oritani, T. Biosci.,
Biotechnol., Biochem. 1993, 57, 1028; (d) Ahmed, M. M.; Cui, H.; O’Doherty, G. A.
J. Org. Chem. 2006, 71, 6686; (e) Barros, M. T.; Charmier, M. A. J.; Maycock, C. D.;
Michaud, T. Tetrahedron 2009, 65, 396.
5. (a) Kumaraswamy, G.; Sadaiah, K.; Ramakrishna, D. S.; Naresh, P.; Sridhar, B.;
Jagadeesh, B. Chem. Commun. 2008, 5324; (b) Kumaraswamy, G.; Ramakrishna,
G.; Naresh, P.; Jagadeesh, B.; Sridhar, B. J. Org. Chem. 2009, 74, 8468; (c)
Kumaraswamy, G.; Padmaja, M. J. Org. Chem. 2008, 73, 5198.
9. The absolute configuration of the major compound 5 was determined on the
basis of the ½a 2D5
ꢁ
value of the final product 1.
10. Stealberg, G. A. M. Acta Chem. Scand. 1990, 44, 368.
11. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Abushananab, E.; Vemishetti, P.; Leiby,
R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu, D. C. J.; Saibaba, R.; Panzica, R. P. J.
Org. Chem. 1988, 53, 2598.
12. Creger, P. L. J. Org. Chem. 1972, 37, 1907.