Synthesis of (+)-(4S,5S)-muricatacin via Pd-catalyzed stereospecific hydroxy substitution reaction of γ,δ-epoxy α,β- unsaturated ester with B(OH)3

Article abstract of DOI:10.2174/157017812801264656

The stereoselective synthesis of (+)-(4S,5S)-muricatacin has been achieved involving the palladium-catalyzed stereospecific hydroxy substitution reaction of γ,δ-epoxy α,β-unsaturated ester with B(OH) ₃.

Full text of DOI:10.2174/157017812801264656

344
Letters in Organic Chemistry, 2012, 9, 344-346
Synthesis of (+)-(4S,5S)-Muricatacin via Pd-Catalyzed Stereospecific
Hydroxy Substitution Reaction of γ,δ-epoxy α,β-Unsaturated Ester with
B(OH)3
Gowravaram Sabitha*,a, G. Chandrashekhara, D. Vasudeva Reddya and J.S. Yadava,b
aOrganic Division I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
bBee Research Chair, College of Food and Agriculture Science, King Saud University, Riyadh, Saudi Arábia
Received December 02, 2011: Revised March 06, 2012: Accepted March 06, 2012
Abstract: The stereoselective synthesis of (+)-(4S,5S)-muricatacin has been achieved involving the palladium-catalyzed
stereospecific hydroxy substitution reaction of γ,δ-epoxy α,β-unsaturated ester with B(OH)3.
Keywords: γ-Lactone, Pd-catalyzed, γ,δ-epoxy α,β-unsaturated ester, muricatacin, stereospecific.
INTRODUCTION
The synthesis of target molecule started from
commercially available aldehyde 4 (Scheme 2). The required
allylic alcohol 3 was prepared in 87% overall yield (for 2
Muricatacin 1 was isolated by McLaughlin et al. from the
seeds of the tropical fruit, Annona muricata [1].
Interestingly, it was found that the isolated material was a
mixture of enantiomers, and both (+)- and (−)-muricatacins
exhibit potent cytotoxicity (~1 to 10 µg/mL) toward several
human tumor cell lines, immunosuppressant, antimalarial
and pesticidal activities [2]. Muricatacins served as
precursors in the synthesis of several bioactive natural
products [3]. Owing to its interesting biological properties,
steps) from aldehyde
4 as reported [4g] by Wittig
olefination/DIBAL-H reduction sequence. Then, 3 was
converted in to γ,δ-epoxy α,β-unsaturated ester 2 by a two-
step reaction sequence: a) Katsuki-Sharpless asymmetric
epoxidation [5] with L-(+)-DIPT, Ti(OiPr)4 and TBHP in
o
CH2Cl2 at –20 C, leading to epoxy alcohol 5 with 95% ee.
b) TEMPO-BAIB oxidation [6] followed by Wittig
OH
OH
O
O
(+)-(4S,5S)-Muricatacin 1a
O
(-)-(4R,5R)-Muricatacin 1b
O
Fig. (1). Structures of (+)- and (−)- muricatacins (1a and 1b).
muricatacin 1 has become a popular target for organic
chemists. Although many synthetic approaches [4] to this
biologically important molecule have been reported, there is
still a need for a new type of methodology that allows the
stereospecific synthesis of muricatacin. We herein report a
novel method for the synthesis of (+)-muricatacin using the
palladium-catalyzed stereospecific hydroxy substitution
reaction of γ,δ-epoxy α,β-unsaturated ester with Boric acid
as a key step.
olefination. The γ,δ-dihydroxy α,β-unsaturated ester 6 (syn
diol) was obtained with double inversion of configuration
(i.e., with retention of configuration) at the γ-position in 92%
yield by the reaction of epoxide 2 with boric acid in the
presence of palladium catalyst, Pd(PPh3)4 in THF [7]. The
reaction was very fast and completed in 10 min at room
temperature. After catalytic hydrogenation of the double
bond in 6 over Pd/C in EtOAc, treatment of the crude ester
with PTSA in MeOH afforded target (+)-muricatacin 1a in
62% yield (for two steps). (−)-Muricatacin should also be
readily available using L-(-)-DIPT by this route. The
synthetic material spectral data and optical rotation value
match with the reported data [4b].
Retrosynthetic analysis is depicted in Scheme 1. The
target molecule 1a was realized from γ,δ-epoxy α,β-
unsaturated ester 2 by Pd-catalyzed stereospecific hydroxy
substitution reaction with B(OH)3. The epoxy ester 2 was in
turn prepared from aldehyde by simple transformations.
In summary, we have applied a palladium-catalyzed
reaction of unsaturated epoxy esters to the stereospecific
synthesis of muricatacin in excellent yields. Further
investigations into the synthetic applications of this
methodology are ongoing.
*Address correspondence to this author at the Organic Division I, Indian
Institute of Chemical Technology, Hyderabad 500 607, India; Tel: +91-40-
27191629; Fax: +91-40-27160512; E-mail: gowravaramsr@yahoo.com
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis of (+)-(4S,5S)-Muricatacin
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
345
O
CHO
CO2Et
(+)-Muricatacin
10
OH
10
10
Scheme 1. Retrosynthetic analysis for 1a.
O
a
b
CHO
10
10
OH
d
OH
10
5
4
3
OH
O
c
CO2Et
CO2Et
10
2
OH
OH
6
e
10
O
O
1a
o
Scheme 2. Reagents and conditions a) ref 4g, overall yield 87%; b) (+)-DIPT, Ti(iOPr)4, TBHP, dry CH2Cl2, -20 C, 5 h, 90%, 95% ee; c)
o
(i) TEMPO, BAIB, CH2Cl2, 0 C – r. t, 1 h; (ii) PPh3=CHCO2Et, benzene, reflux, 1 h, (76% yield from two steps); d) B(OH)3, Pd(PPh3)4, dry
THF, r. t, 10 min, 92%; e) (i) Pd/C, H2, dry EtOAc, 3 h; (ii) p-TsOH, MeOH, r. t, 5 h (62% yield from two steps).
o
EXPERIMENTAL SECTION
resulting mixture was stirred for another 0.5 h at –24 C
followed by addition of TBHP (5M solution in CH2Cl2, 0.4
mL, 2.04 mmol) and the resulting mixture was stirred at the
Reactions were conducted under N2 in anhydrous
solvents such as CH2Cl2, THF and EtOAc. All reactions
were monitored by TLC (silica-coated plates and visualizing
under UV light). n-Hexane (bp 60–80 °C) was used. Yields
refer to chromatographically and spectroscopically (1H and
13C NMR) homogeneous material. Air sensitive reagents
were transferred by syringe or double-ended needle.
Evaporation of solvents was performed at reduced pressure
o
same temperature for 4 h. It was then warmed to 0 C,
quenched with 0.2 mL of water and stirred for 1 h at room
temperature. After that 30% aqueous NaOH solution
saturated with NaCl (0.5 mL) was then added and the
reaction mixture was stirred vigorously for another 0.5 h at
room temperature. The resulting mixture was then filtered
through Celite rinsing with CH2Cl2. The organic phase was
separated and the aqueous phase was extracted with CH2Cl2.
Combined organic phases were washed with brine and dried
over anhydrous Na2SO4. The solvent was removed under
reduced pressure and purified by silica gel column
chromatography (eluent: PE–EtOAc, 8.5:1.5) to afford 5
(0.31 g, 90%) as a white solid; mp = 60-62 °C; [α]D25: −19.6
1
on a Buchi rotary evaporator. H and 13C NMR spectra of
samples in CDCl3 were recorded on Bruker UXNMR FT-
300 MHz (Avance) and 500MHz (Inova) spectrometers.
Chemical shift δ is reported relative to TMS (δ = 0.0) as an
internal standard. Mass spectra were recorded E1 conditions
at 70 eV on LC-MSD (Agilent technologies) spectrometers.
All high resolution spectra were recorded on QSTAR XL
hybrid MS/MS system (Applied Biosystems/MDS sciex,
foster city, USA), equipped with an ESI source (IICT,
Hyderabad). Column chromatography was performed on
silica gel (60-120 mesh) supplied by Acme Chemical Co.,
India. TLC was performed on Merck 60 F-254 silica gel
plates. Melting points were determined in open glass
capillaries on a fischer-johns melting point apparatus and are
incorrect. Optical rotations were measured with a JASCO
DIP-370 Polarimeter at 25 °C. The % ee of the products was
determined using Chiral HPLC, DIONEX (chromeleon,
PDA).
1
(c = 1, CHCl3); H NMR (CDCl3, 300 MHz): δ 3. 97-3.88
(m, 1H), 3.68-3.58 (m, 1H), 2.99-2.90 (m, 2H), 1.71 (t, -OH,
J = 6.2 Hz), 1.56 (t, 1H, J = 6.0 Hz), 1.49-1.39 (m, 1H),
1.37-1.22 (m, 20H), 0.89 (t, 3H, J = 6.9 Hz); 13C NMR
(CDCl3, 75 MHz): 61.7, 58.4, 55.9, 31.8, 31.5, 29.6(5C),
29.4, 29.3, 25.9, 22.6, 14.0; IR (KBr): 3282, 2918, 1461,
1035 cm-1; ESI-MS: m/z: 265 [ M+Na]+; HRMS calcd for
C15H30O2Na: 265.21380; found: 265.21451.
(E)-ethyl 3-((2S,3S)-3-dodecyloxiran-2-yl)acrylate (2)
BAIB (0.4g, 1.23 mmol) was added to a solution of
alcohol 5 (0.25 g, 1.03 mmol) and TEMPO (0.03 g, 0.20
mmol) in 1 ml of CH2Cl2. The reaction mixture was stirred
until the alcohol was no longer detectable (TLC), and then it
was diluted with CH2Cl2 (20 mL). The mixture was washed
with a saturated aqueous solution of Na2S2O3 (10 mL) and
extracted with CH2Cl2 (3 x 20 mL). The combined organic
extracts were dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The unstable crude
aldehyde was immediately used for the next reaction.
[(2S,3S)-3-dodecyloxiran-2-yl]methanol (5)
In a 50 mL two neck round bottomed flask, 5 mL of
anhydrous CH2Cl2 was added to 4 Ao powdered activated
molecular sieves and suspension mixture was cooled to –20
oC, Ti(OiPr)4 (0.1 mL,0.30 mmol) and L-(+) DIPT (0.06 g,
0.30 mmol) in anhydrous CH2Cl2 (1 mL) were added
subsequently with stirring and the resulting mixture was
o
stirred for 0.5 h at –24 C. Compound 3 (0.33 g, 1.46 mmol)
in anhydrous CH2Cl2 (5 mL) was then added and the

346 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Sabitha et al.
1
To a solution of above crude aldehyde in C6H6 (10 mL)
was added Ph3P=CHCOOEt (0.31 g, 0.90 mmol) and the
reaction mixture was stirred for 1 h at reflux condition. After
completion of the reaction, monitored by TLC, C6H6 was
removed under reduced pressure, residue was dissolved in
ether, and petroleum ether was added to it. The
triphenylphosphine oxide crystallized out was filtered off
and the filtrate was concentrated to dryness. The crude
product was purified by column chromatography (eluent:
PE–EtOAc, 9.5:0.5) to afford the pure α,β-unsaturated ester
2 (0.19 g, 76% yield from two steps) as a colorless liquid;
66-68 °C; [α]D25: +24.4 (c = 1.5, CHCl3); H NMR (CDCl3,
500 MHz): δ 4.41-4.37 (m, 1H), 3.54-3.50 (m, 1H), 2.63-
2.43 (m, 2H), 2.29-2.08 (m, 2H,), 1.58-1.47 (m, 2H), 1.40-
1.22 (m, 20H), 0.89 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3,
75 MHz): 177.1, 82.9, 73.6, 32.9, 31.9, 29.6 (4C), 29.5, 29.4,
29.3, 28.6, 25.4, 24.0, 22.6, 14.0; IR (KBr): 3405, 2923,
1747, 1465, 1191 cm-1; ESI-MS: m/z: 307 [M+Na]+; HRMS
calcd for C17H32O3Na: 307.22437; found: 307.22542.
CONFLICT OF INTEREST
1
[α]D25: −5.0 (c = 1, CHCl3); H NMR (CDCl3, 500 MHz): δ
None declared.
6.68 (dd, 1H, J = 8.1, 16.3 Hz), 6.12 (d, 1H, J = 16.3 Hz),
4.20 (q, 2H, J = 7.0, 14.0 Hz), 3.20 (d, 1H, J = 7.0 Hz), 2.88
(t, 1H, J = 4.6 Hz), 1.51-1.38 (m, 2H), 1.36-1.22 (m, 23H),
0.88 (t, 3H, J = 7.0 Hz ); 13C NMR (CDCl3, 75 MHz):165.6,
144.8, 123.3, 61.4, 60.4, 56.3, 31.8(2C), 29.6, (5C), 29.4,
29.3, 25.7, 22.6, 14.1, 14.0; IR (Neat): 2925, 1723, 1462,
1261, 1039 cm-1; ESI-MS: m/z: 333 [M+Na]+.
ACKNOWLEDGEMENTS
GC thanks UGC, DVR thanks CSIR, New Delhi for the
award of fellowships. JSY acknowledges the partial support
by King Saud University for Global Research Network for
Organic Synthesis (GRNOS).
(4S,5S,E)-ethyl 4,5-dihydroxyheptadec-2-enoate (6)
SUPPLEMENTARY MATERIAL
To a solution of 2 (0.14 g, 0.45 mmol) in anhydrous THF
(5 mL) was added B(OH)3 (0.036 g, 0.58 mmol) and
Pd(PPh3)4 (0.026 g, 0.02 mmol) and the reaction mixture was
stirred at room temperature for 10 min. The reaction mixture
was passed through a silica gel column by the aid of EtOAc
and the elute was concentrated in vacuo to leave the crude
diol. The crude product was purified by silica gel column
Supplementary material is available on the publishers
web site along with the published article.
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25
syn diol (0.13 g, 92%) as a white solid; mp = 69°C; [α]D
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1
−19 (c = 1, CHCl3); H NMR (CDCl3, 500 MHz): δ 6.94
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7.0 Hz); 13C NMR (CDCl3, 75 MHz): 166.4, 147.0, 122.3,
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(S)-5-((S)-1-hydroxytridecyl)dihydrofuran-2(3H)-one
[(+)-Muricatacin] (1a)
To a solution of compound 6 (0.08 g, 0.24 mmol) in
anhydrous EtOAc (3 mL) was added catalytic amount of
10% Palladium adsorbed on carbon and stirred under H2
atmosphere for 3h. The reaction mixture was filtered through
Celite and the filtrate was concentrated under reduced
pressure.
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To a solution of above crude product in methanol (3 mL)
was added catalytic amount of p-TsOH. The reaction
mixture was stirred at room temperature for 5 h. Methanol
was removed under reduced pressure. The crude residue was
purified by silica gel column chromatography to afford 1a
(0.05 g, 62% yield from two steps) as a colorless solid; mp =
[6]
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