Total synthesis of microcarpalide

Article abstract of DOI:10.1016/S0040-4039(03)00441-6

A total synthesis of the natural product microcarpalide is described. Ring-closing metathesis of a dienic ester was used as the key step. Mannose was used as the chiral pool material for the construction of the olefinic-acid and a Sharpless asymmetric dih

Full text of DOI:10.1016/S0040-4039(03)00441-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2873–2875
Total synthesis of microcarpalide
Mukund K. Gurjar,* Ravi Nagaprasad and C. V. Ramana
National Chemical Laboratory, Pune 411 008, India
Received 18 December 2002; revised 6 February 2003; accepted 14 February 2003
Abstract—A total synthesis of the natural product microcarpalide is described. Ring-closing metathesis of a dienic ester was used
as the key step. Mannose was used as the chiral pool material for the construction of the olefinic-acid and a Sharpless asymmetric
dihydroxylation reaction provided the chiral precursor for the synthesis of the olefinic-alcohol. © 2003 Elsevier Science Ltd. All
rights reserved.
Synthesis of the olefinic alcohol 2 (Scheme 2) was
Microcarpalide, a ten-membered cyclic lactone (a C16-
initiated by the Sharpless asymmetric dihydroxylation4
nonenolide) recently isolated and characterized by
Hemscheidt and co-workers1 from the fermentation
broths of an unidentified endophytic fungus growing on
the bark of Ficus microcarpa, has been shown to be a
promising microfilament disrupting agent. Herein, we
report a convergent approach for a total synthesis of
microcarpalide.
of the unsaturated ester 4 with commercially available
AD-mix-a. Isopropylidenation of the resulting diol 5
and subsequent reduction using DIBAL-H provided the
alcohol 6. The tosylate 7 obtained upon treating 6 with
p-TsCl in pyridine, following acid catalyzed deiso-
propylidenation, was reacted with 1.5 equiv. of K2CO3
in methanol and the free hydroxyl group of resulting
epoxide 8 was protected as its methoxyethoxymethyl
(MEM) ether to furnish 9. Opening the epoxide 9 with
an excess of lithium acetylide5 and partial hydrogena-
tion of the resulting acetylene 10 with Lindlar catalyst
achieved the olefinic alcohol 2.6
The retro-synthetic scheme for 1 was based on the
coupling reaction between two partners 2 and 3 via
esterification (Scheme 1) and subsequent ring closing
metathesis (RCM).2,3 Our general synthetic strategy
towards the total synthesis of microcarpalide envisaged
the enantioselective preparation of the key fragment 2
The synthesis of acid component 3 commenced with 11
via a Sharpless asymmetric dihydroxylation, and
D-
which was synthesized according to the literature
mannose as a chiral pool source with a zinc-mediated
elimination of an a-iodo acetonide derivative for the
preparation of the other coupling partner.
procedure7 from
D
-mannose (Scheme 3). Protection of
the hydroxyl group of 11 as its MEM-ether, hydrogena-
Scheme 1. Retrosynthetic analysis for microcarpalide 1.
* Corresponding author. Tel.: +91-20-5882456; fax: +91-20-5893614; e-mail: gurjar@dalton.ncl.res.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00441-6

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M. K. Gurjar et al. / Tetrahedron Letters 44 (2003) 2873–2875
Scheme 2. Reagents and conditions: (a) AD-mix-a, t-BuOH, H2O, 0°C, 10 h, 94%; (b) 2,2-dimethoxypropane, p-TsOH, CH2Cl2,
1.5 h, 96%; (c) DIBAL-H, CH2Cl2, −78°C, 1 h, 97%; (d) p-TsCl, pyridine, 0°C–rt, 96%; (e) conc. HCl (cat.), MeOH, 3 h, 87%;
i
(f) K2CO3 (1.5 equiv.), MeOH, rt, 1.5 h, 85%; (g) MEM-Cl, Pr2NEt, CH2Cl2, rt, 4 h, 91%; (h) LiCꢀCH:ethylenediamine, DMSO,
rt, 12 h, 86%; (i) H2, Pd/BaSO4, quinoline, benzene, 1 bar, rt, 0.5 h, 91%.
i
Scheme 3. Reagents and conditions: (a) MEM-Cl, Pr2NEt, CH2Cl2, rt, 10 h; (b) H2, 10% Pd–C, MeOH, 6 bar, 60°C, 4 h; (c)
LiAlH4, THF, rt, 1 h, 71% for three steps; (d) (CH3)3CCOCl, pyridine, 0°C–rt, 91%; (e) TBSCl, DMF, imidazole, rt, 4 h, 90%;
(f) DIBAL-H, CH2Cl2, −78°C, 1 h, 89%; (g) I2, PPh3, imidazole, ether–benzene (2:1), rt, 1.5 h, 86%; (h) Zn, ethanol, reflux, 1.5
h, 96%; (i) n-Bu4N+F−, THF, rt, 1 h, 85%; (j) NaH, BnBr, DMF, 0°C–rt, 88%; (k) PPTS, t-BuOH, 80°C, 1.5 h, 85%; (l) (COCl)2,
DMSO, Et3N, CH2Cl2, −78°C, 1 h; (m) NaClO2, DMSO, NaH2PO4, rt, 1.5 h, 83% for two steps.
tion using 10% Pd–carbon, and subsequent reduction
with lithium aluminum hydride gave the diol 12. The
TBS-ether 14 was obtained in 73% overall yield follow-
ing selective pivaloylation of the C1-OH, protection of
the C4-OH as its TBS ether, and reductive depivaloyl-
ation using DIBAL-H. Adopting the modified Corey
protocol8 for the conversion of a primary alcohol to the
corresponding iodide using I2, PPh3, imidazole, in an
ether–benzene (2:1) mixture, 14 was converted to the
iodoacetonide 15 in good yield. A facile elimination of
15 resulting in the corresponding allylic alcohol 16 was
then accomplished using freshly activated Zn in reflux-
ing ethanol.9 Removal of the TBS-protection and ben-
zylation using NaH and BnBr gave 17 in 73% overall
yield. The synthesis of the second key fragment, the
olefinic acid 3 was completed by deprotection of the
MEM-ether,10 oxidation of the resulting primary alco-
hol to the corresponding aldehyde using Swern condi-
tions and further oxidation using sodium chlorite in
DMSO under buffered conditions.11 The spectroscopic
data of 312 were in agreement with the assigned
structure.
Having completed the synthesis of both fragments 2
and 3, it remained to couple the two fragments and
achieve subsequent RCM. The coupling reaction of 2
and 3 was carried out using DCC to furnish the diene
ester 1814a in good yield. Following contemporary
results2,3 and the information provided by the Fu¨rstner2
and Marco3 groups, RCM of 18 with the first genera-
tion Grubbs’ catalyst (Scheme 4) under high dilution
conditions gave the E- and Z-isomers of 1914b in a 10:1
Scheme 4. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, rt, 18 h, 76%; (b) (PCy3)2Ru(Cl)2ꢁCH-Ph (20 mol%), CH2Cl2,
reflux, 28 h, 67%; (c) TiCl4, CH2Cl2, 0°C, 0.5 h, 76%.

M. K. Gurjar et al. / Tetrahedron Letters 44 (2003) 2873–2875
2875
ratio. Surprisingly and gratifyingly, attempted MEM-
deprotection using TiCl4 also resulted in debenzyla-
tion,13 thus furnishing microcarpalide 1 in 76% yield.
The spectroscopic and analytical data {[h]2D5=−23.2 (c
0.7, MeOH)} of compound 1 were in agreement with
the reported data.1,3
Am. Chem. Soc. 1993, 115, 5254–5266; (b) Coutrot, P.;
Grison, C.; Lecouvey, M. Bull. Soc. Chim. Fr. 1997, 134,
27–46.
8. Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J.
Am. Chem. Soc. 1995, 117, 12011–12012.
9. Rama Rao, A. V.; Reddy, E. R.; Joshi, B. V.; Yadav, J.
S. Tetrahedron Lett. 1987, 28, 6497–6500.
In conclusion, we have developed a total synthesis of
microcarpalide using both the chiral pool approach and
an asymmetric dihydroxylation which is characterized
by considerable flexibility for the construction of
related unnatural analogues for structure activity stud-
ies. Work in this direction is progressing in our
laboratory.
10. Monti, H.; Leandri, G.; Klos-Ringuet, M.; Corriol, C.
Synth. Commun. 1983, 13, 1021–1026.
11. Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51,
567–569.
12. Spectral data of 3: 1H NMR (200 MHz, CDCl3) l
1.61–1.80 (m, 1H), 1.83–1.99 (m, 1H), 2.33–2.44 (m, 2H),
3.52 (ddd, 1H, J=9.3, 6.0, 3.7 Hz), 3.90 (t, 1H, J=6.5
Hz), 4.38 (d, 1H, J=12.2 Hz), 4.52 (d, 1H, J=11.3 Hz),
4.64 (d, 1H, J=12.1 Hz), 4.76 (d, 1H, J=11.3 Hz), 5.32
(br. dd, 1H, J=18.4, 1.7 Hz), 5.36 (br. dd, 1H, J=9.1,
1.8 Hz), 5.81 (br. ddd, 1H, J=18.3, 10.9, 7.5 Hz), 7.25–
7.33 (m, 10H). 13C NMR (50 MHz, CDCl3) l 26.3, 30.9,
70.5, 73.3, 80.2, 82.7, 96.1, 118.8, 127.4, 127.6, 127.9,
128.2, 135.1, 138.5, 138.6, 178.7. Anal. calcd for
C21H24O4: C, 74.09; H, 7.11. Found: C, 74.16; H, 7.49.
13. (a) Corey, E. J.; Gras, J. L.; Ulrich, P. Tetrahedron Lett.
1976, 11, 809–812; (b) Bhatt, M. V.; Kulkarni, S. V.
Synthesis 1983, 249–334.
Acknowledgements
R.N. thanks CSIR for financial support in the form of
a research fellowship.
References
14. (a) Spectral data of 18: 1H NMR (500 MHz, CDCl3) l
0.87 (t, 3H, J=6.9 Hz), 1.21–1.34 (m, 8H), 1.46–1.54 (m,
2H), 1.67–1.74 (m, 1H), 1.88–1.95 (m, 1H), 2.25–2.46 (m,
4H), 3.37 (s, 3H), 3.49–3.54 (m, 3H), 3.58 (br. ddd, 1H,
J=6.2, 5.6, 4.3 Hz), 3.66–3.73 (m, 2H), 3.87 (t, 1H,
J=6.7 Hz), 4.38 (d, 1H, J=11.9 Hz), 4.52 (d, 1H,
J=11.4 Hz), 4.62 (d, 1H, J=11.9 Hz), 4.71–4.77 (m, 3H),
4.99–5.07 (m, 3H), 5.27–5.33 (m, 2H), 5.71 (dddd, 1H,
J=17.1, 10.1, 7.6, 6.6 Hz), 5.80 (ddd, 1H, J=17.3, 10.6,
7.6 Hz), 7.25–7.30 (m, 10H). 13C NMR (125 MHz,
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Anal. calcd for C36H52O7: C, 72.45; H, 8.78. Found: C,
72.08; H, 9.13. (b) Spectral data of 19: 1H NMR (500
MHz, CDCl3) l 0.87 (t, 3H, J=6.9 Hz), 1.26–1.32 (m,
8H), 1.54–1.59 (m, 3H), 2.02 (ddd, 1H, J=15.2, 10.6, 6.2
Hz), 2.17 (ddd, 1H, J=14.7, 10.6, 1.4), 2.24–2.30 (m,
2H), 2.61 (dd, 1H, J=14.7, 9.2 Hz), 3.38 (s, 3H), 3.54–
3.56 (m, 2H), 3.67–3.78 (m, 4H), 4.07 (br. d, 1H, J=4.5
Hz), 4.47 (d, 1H, J=11.9 Hz), 4.48 (d, 1H, J=12.5 Hz),
4.54 (d, 1H, J=11.9 Hz), 4.65 (d, 1H, J=12.5 Hz),
4.78–4.81 (m, 2H), 5.15 (dt, 1H, J=9.2, 4.6 Hz), 5.64 (dd,
1H, J=15.8, 2.1 Hz), 5.64–5.73 (m, 1H), 7.28–7.35 (m,
10H). 13C NMR (125 MHz, CDCl3) 14.01, 22.56, 25.03,
29.39, 31.15, 31.71, 36.06, 59.00, 67.40, 71.34, 71.54,
71.78, 78.19, 95.36, 126.47, 127.22, 127.52, 127.61, 128.30,
128.36, 131.69, 138.45, 138.79, 175.17. Anal. calcd for
C34H48O7: C, 71.80; H, 8.51. Found: C, 71.97; H, 8.98.
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3H, J=6.6 Hz), 1.21–1.38 (m, 8H), 1.44–1.61 (m, 2H),
2.10–2.39 (m, 2H), 2.81 (s, 1H, -OH), 3.37–3.49 (m, 1H),
3.39 (s, 3H, -OMe), 3.52–3.84 (m, 5H), 4.70–4.87 (m, 2H,
-OCH2O-), 5.06–5.17 (m, 2H), 5.88 (br. ddt, 1H, J=17.4,
10.6, 7.0 Hz). 13C NMR (50 MHz, CDCl3) l 14.1, 22.6,
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95.9, 117.1, 134.9. Anal. calcd for C15H30O4: C, 65.66; H,
11.02. Found: C, 65.07; H, 10.83.
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