An efficient stereoselective approach for the synthesis of (+)-(4S,5S)-muricatacin

Article abstract of DOI:10.1002/hlca.201000291

An efficient stereoselective total synthesis of (+)-(4S,5S)-muricatacin was accomplished in good yields from inexpensive, commercially available chemicals ((+)-diethyl tartrate (DET) and undecan-1-ol) by utilizing Mitsunobu and Julia-Kocienski reactions, Wittig homologation, Swern oxidation, and lactonization. Copyright

Full text of DOI:10.1002/hlca.201000291

Helvetica Chimica Acta – Vol. 94 (2011)
669
An Efficient Stereoselective Approach for the Synthesis of (þ)-(4S,5S)-
Muricatacin
by Chiguru Srinivasa), Chebolu Naga Sesha Sai Pavan Kumara), Bhimapaka China Raju*b), and
Vaidya Jayathirtha Rao*a)
a) Organic Chemistry Division-II, Indian Institute of Chemical Technology, Uppal Road, Tarnaka,
Hyderabad-500607, India
b) Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road, Tarnaka,
Hyderabad-500607, India (phone: þ 914027191725; fax: þ 91-402716512;
e-mail: chinarajuiict@yahoo.co.in)
An efficient stereoselective total synthesis of (þ)-(4S,5S)-muricatacin was accomplished in good
yields from inexpensive, commercially available chemicals ((þ)-diethyl tartrate (DET) and undecan-1-
ol) by utilizing Mitsunobu and JuliaꢀKocienski reactions, Wittig homologation, Swern oxidation, and
lactonization.
Introduction. – Acetogenins are natural products isolated from tropical plants
Annonaceae, and they have potential biological activities such as antitumor,
antimicrobial, immunosuppressive, and pesticidal effects [1]. Muricatacin (1) is an
acetogenin, [2] isolated from the seeds of Annona muricata (Annonaceae) and related
to g-butyrolactone, with antiproliferative activity against certain cell lines. Several
syntheses of muricatacin and its congeners [3 – 6] have been developed in recent years
due to their chemical and biological properties. However, a general method for the
synthesis of functionalized muricatacin is still warranted. In continuation of our interest
on the synthesis of heterocycles with potential biological activities [7], here, we report
an alternative way for the synthesis of (þ)-(4S,5S)-muricatacin (1) from inexpensive,
commercially available (þ)-diethyl tartrate (DET) and undecan-1-ol in a convergent
manner.
Results and Discussion. – The retro-synthesis for (þ)-(4S,5S)-muricatacin (1) is
depicted in Scheme 1. The reaction of 1-phenyl-1H-tetrazole-5-thiol with undecan-1-ol
(6) under Mitsunobu conditions [8] in the presence of Ph3P and diisopropyl
azodicarboxylate (DIAD) afforded sulfide 7. The sulfide 7, upon oxidation with
m-CPBA (meta-chloroperbenzoic acid) provided sulfone 4 [9] (Scheme 2). The
acetonide ester 9 was prepared starting from the commercially available diethyl l-
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 1
Scheme 2
tartrate (8) by using 2,2-dimethoxypropane (2,2-DMP) and TsOH. The ester 9 was
reduced with LiAlH4 to give the corresponding diol 10; the selective monoprotection of
10 with 1 equiv. of (tert-butyl)(dimethyl)silyl chloride (TBSCl) in the presence of 1H-
imidazole afforded the alcohol 11 in 87% yield. The alcohol 11 was converted to the
corresponding aldehyde 5 by Swern oxidation [10] (Scheme 3). The coupling reaction
of sulfone 4 and aldehyde 5 was performed by the JuliaꢀKocienski olefination protocol
[9] using NaHMDS as base (Scheme 4). The geometrical isomers (E)-12 (major) and
(Z)-12 (minor) (1H-NMR) were obtained in 65% yield. The mixture of stereoisomers
was subjected to deprotection to give alcohol 13 by using Bu4NF (TBAF) [11]. The
alcohol 13 was oxidized to aldehyde 14 with TEMPO (¼(2,2,6,6-tetramethylpiperidin-
1-yl)oxyl) [12], followed by C2-Wittig olefination to furnish the unsaturated ester 15 in
Scheme 3

Helvetica Chimica Acta – Vol. 94 (2011)
671
Scheme 4
97% yield. This ester was converted to the corresponding saturated ester 16 upon
hydrogenation in the presence of 10% Pd/C. The deprotection of the acetonide and
subsequent in situ lactonization of ester 16 with TsOH in MeOH afforded (þ)-(4S,5S)-
muricatacin (1; Scheme 5) as white crystalline solid in 98% yield [13]. Compound 1 was
characterized by its spectral data (1H- and 13C-NMR, IR, MS, specific rotation), which
were in agreement with the data of 1 reported in [4].
Scheme 5
Conclusions. – In conclusion, we developed an efficient method for the asymmetric
synthesis of (þ)-(4S,5S)-muricatacin (1) by using Mitsunobu and JuliaꢀKocienski
reactions, Wittig homologation, Swern oxidation, and lactonization.

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The authors thank the Director, IICT, and Head, Organic Division-II, IICT, for encouragement. C. S.
and C. N. S. S. P. thank CSIR-New Delhi, for fellowships.
Experimental Part
General. All chemicals were of reagent grade and were used as obtained from local suppliers, Aldrich
and Fluka. Anal. TLC: E. Merck silica gel 60F glass plates. Flash chromatography (FC): E. Merck silica
gel (SiO2; 60 – 120 mesh). M.p.: MEL-TEMP II melting point apparatus; uncorrected. 1H-NMR spectra:
Gemini 200 MHz Varian instrument and Avance 300 MHz Bruker UX 300 FT NMR; in CDCl3, chemical
shifts in ppm rel. to TMS, coupling constants J in Hz; the data were compared with the reported literature
values. MS: VG Micromass 7070 H (EI), VG Autospec (FAB) using a Csþ ion gun, m-NBA (3-
nitrobenzyl alcohol) as a matrix, Applied Biosystems QSTAR XL high-resolution (HR) mass
spectrometer, Thermo-Finnigan ESI ion trap mass spectrometer, and GC/MS instruments.
1-Phenyl-5-(undecylsulfanyl)-1H-tetrazole (7). To a soln. of undecan-1-ol 6 (2.0 g, 11.62 mmol), PPh3
(3.65 g, 13.95 mmol), and 1-phenyl-1H-tetrazole-5-thiol (2.48 g, 13.95 mmol) in THF (40 ml) was added
a soln. of DIAD (2.81 g, 13.95 mmol) in 10 ml THF dropwise at 08. After 2 h at 08, the reaction was
quenched by addition of sat. aq. NH4Cl (10 ml), the org. layer was separated, washed with brine (10 ml),
dried (Na2SO4), the solvent was removed under reduced pressure, and the crude product was subjected
to FC (hexane/AcOEt 95 :5) to afford sulfide 7 (3.59 g, 93%). Colorless solid. M.p. 40 – 418. IR (neat):
2961, 2919, 2850, 1592, 1497, 1471, 1419, 1390, 1244, 757, 687. 1H-NMR (200 MHz): 0.88 (t, J ¼ 6.6, 3 H);
1.25 – 1.47 (m, 16 H); 1.75 – 1.90 (m, 2 H); 3.39 (t, J ¼ 6.6, 2 H); 7.53 – 7.60 (m, 5 H). ESI-MS: 333 ([M þ
H]þ).
1-Phenyl-5-(undecylsulfonyl)-1H-tetrazole (4). To a stirred soln. of 7 (2.0 g, 6.02 mmol) in CH2Cl2
(100 ml), NaHCO3 (1.26 g, 15.06 mmol) was added, followed by m-CPBA (5.18 g, 15.06 mmol) at 08. The
mixture was slowly brought to r.t., and stirring was continued for 12 h. After quenching the reaction with
sat. aq. Na2S2O3 (10 ml), the org. layer was separated, washed with brine (10 ml), dried (Na2SO4), the
solvent was removed under reduced pressure, and the crude product was subjected to FC (hexane/
1
AcOEt 95 :5) to give pure 4 (2.08 g, 95%). Colorless solid. M.p. 47 – 488. H-NMR (200 MHz): 0.88 (t,
J ¼ 6.6, 3 H); 1.26 – 1.55 (m, 16 H overlapped); 1.88 – 2.01 (m, 2 H); 3.72 (t, J ¼ 8.0, 2 H); 7.58 – 7.64 (m,
3 H); 7.69 – 7.73 (m, 2 H). IR (neat): 3070, 2952, 2919, 2852, 1592, 1498, 1473, 1354, 1148, 762, 720, 692,
542. ESI-MS: 365 ([M þ H]þ).
Diethyl (4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-dicarboxylate (9). To a stirred soln. of (þ)-diethyl
tartrate (8; 10 g, 48.54 mmol) in CH2Cl2 (100 ml), TsOH (100 mg) was added, followed by 2,2-
dimethoxypropane (2,2-DMP; 12 ml, 97.08 mmol) at r.t. The mixture was stirred for 4 h, then solid
NaHCO3 (5 g) was added. The mixture was filtered, the solvent was removed under reduced pressure,
and the crude product was subjected to FC (hexane/AcOEt 98 :2) to afford 9 (8.95 g, 75%). Colorless
liquid. IR (neat): 1757. 1H-NMR (200 MHz): 1.33 (t, J ¼ 7.1, 6 H); 1.47 (s, 6 H); 4.26 (q, J ¼ 7.1, 4 H); 4.69
(s, 2 H). ESI-MS: 247 ([M þ H]þ), 269 ([M þ Na]þ).
[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]dimethanol (10). To a suspension of LiAlH4 (3.7 g,
97.5 mmol) in THF (100 ml), 9 (6 g, 24.4 mmol) in THF (20 ml) was added slowly at 08, and the mixture
was stirred for 2 h at same temp. After completion of the reaction (TLC), the mixture was hydrolyzed
with sat. aq. NH4Cl (20 ml), filtered through Celite, dried (Na2SO4), and the solvent was removed under
reduced pressure. The crude product was subjected to FC (AcOEt) to afford 10 (3.35 g, 85%). Colorless
liquid. [a]2D5 ¼ ꢀ8.16 (c ¼ 1, CHCl3). IR (neat): 3386. 1H-NMR (200 MHz): 1.40 (s, 6 H); 2.45 (br. s,
2 OH); 3.63 – 3.78 (m, 4 H); 3.91 – 3.98 (m, 2 H). EI-MS: 162.
[(4S,5S)-5-({[(tert-Butyl)(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (11).
To a cooled soln. of 10 (3.0 g, 18.51 mmol) in dry DMF (30 ml) at 08, 1H-imidazole (3.14 g, 46.25 mmol)
and (tert-butyl)(dimethyl)silyl chloride (2.77 g, 18.51 mmol) were added, and stirring was continued for
2 h at same temp. After completion of the reaction, the mixture was hydrolyzed with sat. aq. NH4Cl
(15 ml), the layers were separated, dried (Na2SO4), the solvent was removed under reduced pressure,
and the crude product was subjected to FC (hexane/AcOEt 9 :1) to afford 11 (4.44 g, 87%). Colorless
liquid. IR (neat): 3469. 1H-NMR (300 MHz): 0.08 (s, 6 H); 0.90 (s, 9 H); 1.37 (s, 3 H); 1.38 (s, 3 H); 3.60 –
3.75 (m, 4 H); 3.80 – 3.86 (m, 1 H); 3.89 – 3.95 (m, 1 H). ESI-MS: 277 ([M þ H]þ).

Helvetica Chimica Acta – Vol. 94 (2011)
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(4R,5S)-5-({[(tert-Butyl)(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde
(5). The alcohol 11 (2.8 g, 10.14 mmol) in CH2Cl2 (10 ml) was added to the mixture of oxalyl chloride
(1.77 ml, 20.28 mmol) in CH2Cl2 and dry DMSO (2.38 ml, 40.57 mmol) held at ꢀ 788 slowly over a period
of 30 min, and the mixture was stirred for 3 h at the same temp. Then, NEt3 (7.3 ml, 50.72 mmol) was
added in one portion, stirring was continued for 30 min, and the mixture was slowly brought to r.t. The
org. layer was washed with a sat. aq. soln. of NH4Cl (5 ml) and brine (2 ꢁ 15 ml), dried (Na2SO4), the
solvent was removed under reduced pressure, and the crude product was subjected to FC (hexane/
AcOEt 9 :1) to afford 5 (2.6 g, 94%). Colorless oil. [a]2D5 ¼ þ25.36 (c ¼ 0.5, CHCl3). IR (neat): 1735.
1H-NMR (300 MHz): 0.08 (s, 6 H); 0.90 (s, 9 H); 1.40 (s, 3 H); 1.46 (s, 3 H); 3.76 – 3.79 (m, 2 H); 4.04 –
4.10 (m, 1 H); 4.26 (dd, J ¼ 7.5, 1.5, 1 H); 9.75 (d, J ¼ 1.5). ESI-MS: 275 ([M þ H]þ).
(tert-Butyl)({(4S,5S)-5-[(1E)-dodec-1-en-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methoxy)(dimethyl)-
silane and (tert-Butyl)({(4S,5S)-5-[(1Z)-dodec-1-en-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methoxy)(di-
methyl)silane ((E)- and (Z)-12, resp.). To a stirred soln. of 4 (2.2 g, 8.03 mmol) in THF (40 ml),
NaHMDS (8.83 ml of a 1.0m soln. in THF; 8.83 mmol) was added slowly dropwise at ꢀ 788, and stirring
was continued for another hour, then 5 (2.81 g, 8.03 mmol) in CH2Cl2 was added at the same temp. The
resulting yellow mixture was allowed to reach r.t., and stirring was continued for additional 2 h. The
reaction was quenched with sat. aq. NaCl (10 ml), and the mixture was extracted with AcOEt (2 ꢁ
25 ml). The org. layer was dried (Na2SO4), the solvent was removed under reduced pressure, and the
crude product was subjected to FC (hexane/AcOEt 95 :5) to afford the mixture (E)-12/(Z)-12 in 65%
yield. Colorless liquid. [a]2D5 ¼ ꢀ8.70 (c ¼ 1.55, CHCl3). IR (neat): 2926, 2858, 1462, 1373. 1H-NMR
(300 MHz): 0.05 (s, 6 H); 0.86 – 0.92 (m, 12 H, Me group overlapped with 9 H); 1.24 – 1.27 (m, 16 H); 1.38
(s, 3 H); 1.40 (s, 3 H); 1.97 – 2.13 (m, 2 H); 3.57 – 3.81 (m, 3 H); 4.68 – 4.77 (m, 1 H); 5.30 – 5.48 (m, 1 H);
5.56 – 5.83 (m, 1 H). ESI-MS: 435 ([M þ Na]þ).
{(4S,5S)-5-[Dodec-1-en-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol (13). To a soln. of (E)-12/
(Z)-12 (1.2 g, 2.91 mmol) in THF (20 ml) was added TBAF (4.36 ml of 1.0m soln. in THF; 4.36 mmol) at
r.t. After 2 h, the reaction was quenched with sat. aq. NH4Cl (5 ml), the org. layer was separated, washed
with brine (5 ml), dried (Na2SO4), the solvent was removed under reduced pressure, and the crude
product was subjected to FC (hexane/AcOEt 95 :5) to give 13 (0.82 g, 95%). Colorless liquid. [a]D25
¼
ꢀ14.13 (c ¼ 1.45, CHCl3). IR (neat): 3444, 1460, 1375. 1H-NMR (300 MHz): 0.88 (t, J ¼ 6.7, 3 H);
1.23 – 1.32 (m, 16 H, overlapped); 1.43 (s, 6 H); 1.72 (br. s, OH); 2.01 – 2.18 (m, 2 H); 3.48 – 3.56 (m, 1 H);
3.65 – 3.74 (m, 1 H); 3.76 – 3.83 (m, 1 H); 4.69 (t, J ¼ 8.3, 1 H); 5.31 – 5.46 (m, 1 H); 5.62 – 5.85 (m, 1 H).
ESI-MS: 321 ([M þ Na]þ).
(4R,5S)-5-[Dodec-1-en-1-yl]-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (14). To a soln. of 13
(0.56 g, 1.87 mmol), (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO; 0.03 g, 0.18 mmol), Bu4NCl
(TBACl; 0.062 g, 0.18 mmol) in 10 ml of CH2Cl2, 10 ml of an aq. soln. of NaHCO3 (0.42 g, 0.5m) and
K2CO3 (0.069 g, 0.05m) were added, and the mixture was vigorously stirred at r.t. The solid NCS (0.37 g,
2.8 mmol) was added, stirring was continued, and the reaction was monitored by TLC. After completion
of the reaction, the org. layer was separated, washed with brine (10 ml), dried (Na2SO4) and the solvent
was removed under reduced pressure. The residue was directly used for the next step without further
purification.
Ethyl (2E)-3-{(4S,5S)-5-[Dodec-1-en-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}prop-2-enoate (15). To a
soln. of Ph3P¼CHCOOEt (0.423 g, 1.21 mmol) in benzene (10 ml) at r.t. was added dropwise a soln. of 14
(0.3 g, 1.01 mmol) in benzene (3 ml). The mixture was stirred for 2 h at r.t., the solvent was removed
under reduced pressure, the crude product was subjected to FC (hexane/AcOEt 97:3) to furnish 15
1
(0.36 g, 97%). Colorless liquid. [a]2D5 ¼ þ25.2 (c ¼ 1.45, CHCl3). IR (neat): 1725, 1662, 1461. H-NMR
(300 MHz): 0.88 (t, J ¼ 6.7, 3 H); 1.23 – 1.34 (m, 21 H, Me); 1.40 – 1.45 (m, 6 H); 1.98 – 2.11 (m, 2 H);
4.08 – 4.23 (m, 2 H); 5.32 – 5.51 (m, 1 H); 5.64 – 5.88 (m, 1 H); 6.06 (dd, J ¼ 15.8, 1.5, 1 H); 6.79 (dd, J ¼
15.8, 4.5, 1 H). GC/MS: 351 ([M ꢀ 15]þ).
Ethyl 3-[(4S,5S)-5-Dodecyl-2,2-dimethyl-1,3-dioxolan-4-yl]propanoate (16). A soln. of 15 (0.3 g) in
MeOH (10 ml) was hydrogenated on 10% of Pd/C for 2 h at r.t. The suspension was filtered through
Celite and washed with MeOH. The combined filtrates were evaporated, and the crude product was
subjected to FC (hexane/AcOEt 95 :5) to afford pure 16 (0.297 g, 95%). Colorless liquid. [a]2D5 ¼ ꢀ18.66
(c ¼ 1.5, CHCl3). IR (neat): 1738, 1461, 1373. 1H-NMR (200 MHz): 0.88 (t, J ¼ 7.0, 3 H); 1.23 – 1.31 (m,

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23 H, Me); 1.34 (s, 6 H); 1.47 – 1.53 (m, 2 H); 1.61 – 2.04 (m, 2 H); 2.20 – 2.60 (m, 2 H); 3.55 – 3.58 (m,
2 H); 4.08 – 4.18 (q, J ¼ 7.0, 2 H). 13C-NMR (75 MHz): 14.2; 14.3; 22.7; 26.1; 27.3; 27.4; 27.9; 29.4; 29.5 –
29.8; 30.7; 31.9; 32.9; 60.2; 79.9; 80.7; 108.0; 172.9. GC/MS: 355 ([M ꢀ 15]þ).
(5S)-4,5-Dihydro-5-[(1S)-1-hydroxytridecyl]furan-2(3H)-one (1). To a soln. of 16 (0.25 g,
0.675 mmol) in MeOH (10 ml) was added a cat. amount of TsOH at r.t., and stirring was continued
for 4 h. After completion of the reaction, MeOH was removed under reduced pressure, and the crude
product was subjected to FC (hexane/AcOEt 1:1) to afford 1 (0.176 g, 93%). Colorless solid. M.p. 69 –
718. [a]2D5 ¼ þ25.33 (c ¼ 1.5, CHCl3; [4]: þ 23.6 (c ¼ 1.6, CHCl3)). IR (neat): 3399, 1744, 1472. 1H-NMR
(300 MHz): 0.88 (t, J ¼ 6.5, 3 H); 1.25 – 1.29 (m, 20 H); 1.47 – 1.58 (m, 2 H); 2.07 – 2.29 (m, 2 H); 2.45 –
2.65 (m, 2 H); 3.51 – 3.55 (m, 1 H); 4.36 – 4.41 (m, 1 H). 13C-NMR (75 MHz): 14.0; 22.6; 24.0; 25.4; 28.6;
29.2; 29.6 (6 C); 31.8; 32.9; 73.5; 82.9; 177.2. ESI-MS: 307 ([M þ Na]þ). HR-MS: 307.2249 (C17H32NaO3þ,
[M þ Na]þ; calc. 307.2249).
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Received August 4, 2010