The total synthesis of macrosphelides A and E from carbohydrate precursors

Article abstract of DOI:10.1016/S0040-4039(02)02284-0

The total synthesis of macrolide antibiotics, macrosphelide A and E has been achieved starting from carbohydrate precursors.

Full text of DOI:10.1016/S0040-4039(02)02284-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9159–9161
The total synthesis of macrosphelides A and E from
carbohydrate precursors†
G. V. M. Sharma* and Ch. Chandra Mouli
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007,
India
Received 3 September 2002; revised 27 September 2002; accepted 4 October 2002
Abstract—The total synthesis of macrolide antibiotics, macrosphelide A and E has been achieved starting from carbohydrate
precursors. © 2002 Elsevier Science Ltd. All rights reserved.
Macrosphelides A–L are 16-membered macrolide
antibiotics having three lactone bridges in the ring
structure. Macrosphelide A, isolated from the culture
broth of Microsphaeropsis sp FO-5050, was found to
inhibit strongly the adhesion of human leukemia HL-60
cells to an LPS-activated human-umbilical-vein
endothelial cells (HUVETC) monolayer (IC50, 3.5 mm)
in a dose dependent fashion.1 Macrosphelide E, the
C(3) stereoisomer of macrosphelide A, was isolated
from a strain of Periconia byssoides separated from the
gastrointestinal tract of the sea hare Aplysia kurodai.2
It was also found to inhibit the adhesion of human-
leukemia HL-60 cells to human-umbilical-vein endothe-
lial cells as potently as macrosphelide A. Consequently,
macrosphelides have received much attention as valu-
able lead compounds for the development of new anti-
cancer chemotherapeutical drugs, thus resulting in
synthetic routes for generating these molecules and
their analogues. Recently, the syntheses of macrosphe-
lides A 13–5 and E 25 has been reported. Herein, we
report the first carbohydrate based total synthesis of
macrosphelides A 1 and E 2 from
L
(+)-arabinose.
Scheme 1. Retrosynthesis of macrosphelide A 1 and E 2.
* Corresponding author. E-mail: esmvee@iict.ap.nic.in
† IICT Communication No. 020807.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02284-0

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G. V. M. Sharma, Ch. C. Mouli / Tetrahedron Letters 43 (2002) 9159–9161
The synthetic strategy presented here involved the
preparation of trans (4R,5S)-5-hydroxy-4-p-methoxy-
benzyloxy-2-hexenoate 4, condensation with commer-
cially available 3S- or 3R-hydroxy butanoic acid unit 5
or 6, respectively, and recoupling with one more unit of
trans 4, to give seco acids 3 and 3a, respectively, which
on Yamaguchi macrolactonisation afford the target
molecules 1 and 2. The retrosynthesis of macrosphelides
A and E is presented in Scheme 1.
with TMSCl and NaI in CH3CN (−20°C) afforded 17
in 77% yield, which on selective hydrolysis with DBN in
C6H6 provided seco acid 3 in 79% yield. Finally, macro-
lactonisation of 3 under Yamaguchi conditions8 (2,4,6-
trichlorobenzoyl chloride, Et3N, DMAP, toluene) gave
18 in 67% yield, [h]D −90.4 (c 0.215, CHCl3), which on
reaction with DDQ in CH2Cl2/H2O gave 1 (90%), [h]D
+83.8 (c 0.10, MeOH); lit.1b [h]D +84.1 (c 0.59, MeOH);
lit.3 [h]D +82 (c 0.10, MeOH); mp 139–141°C; lit.1b mp
141–142°C.
Accordingly, 1,2-O-isopropylidene-b-L
-arabinofuranose6
7 was selectively tosylated (p-TsCl, pyridine, CH2Cl2)
to give 8 in 75% yield, which on subsequent reduction
with LiAlH4 afforded 9 in 80% yield, [h]D −12.6 (c 0.65,
CHCl3). Protection of hydroxy group in 9 with p-
methoxybenzyl bromide (NaH, THF) afforded 10
(95%), which on hydrolysis of the 1,2-acetonide (cat.
H2SO4 in 60% aq. AcOH) furnished 11 (75%). Oxida-
tive cleavage of 11 (NaIO4, MeOH–H2O) and
subsequent olefination of the unstable aldehyde 12
Total synthesis of macrosphelide E (2)
Similarly, esterification of acid 6 with alcohol 4
(Scheme 3) in the presence of 2,4,6-trichlorobenzoyl
chloride (Et3N, THF) and DMAP in toluene afforded
the ester 14a in 83% yield, [h]D −13.13 (c 0.75, CHCl3),
which on selective hydrolysis with DBN in C6H6, fur-
nished 15a (80%). Esterification of carboxylic acid 15a
with alcohol 4 using 2,4,6-trichlorobenzoyl chloride
(Et3N, THF) and DMAP in toluene gave 16a (84%),
[h]D −78.7 (c 0.25, CHCl3). MEM deprotection of 16a
with TMSCl, NaI, in CH3CN, afforded 17a in 81%
yield, which on selective hydrolysis with DBN in ben-
zene gave 3a (80%). Finally, 3a under Yamaguchi
macrolactonisation conditions (2,4,6-trichlorobenzoyl
chloride, Et3N, DMAP, toluene) gave 18a in 70% yield.
Deprotection of 18a with DDQ in CH2Cl2/H2O) gave 2
in 93% yield, [h]D +54.9 (c 0.28, EtOH); lit.2b [h]D +56.8
(c 0.46, EtOH); mp 104–106°C; lit.2b mp 105–107°C.
The target molecules 1 and 2 were fully characterised9,10
with
(p-toluenesulfonylethoxy
carbonylmethylene)
triphenylphosphorane7 gave 13 in 75% yield. Finally,
de-O-formylation of 13 with catalytic HCl (1,4-diox-
ane:water, 1:1) afforded the key intermediate 4 in 80%
yield, [h]D −39.1 (c 2.2, CHCl3), in enantiopure form
(Scheme 2).
Total synthesis of macrosphelide A (1)
Condensation of alcohol 4 with acid 5 (Scheme 3)
through the mixed anhydride prepared on reaction of 5
with 2,4,6-trichlorobenzoyl chloride (Et3N, THF), in
the presence of DMAP in toluene, afforded the ester 14
in 84% yield, [h]D −39.3 (c 0.95, CHCl3). Selective
hydrolysis of the p-toluenesulfonylethyl group in 14
was effected with DBN7 (C6H6, rt) to furnish 15 in 81%
yield. Esterification of carboxylic acid 15 with alcohol 4
using 2,4,6-trichlorobenzoyl chloride (Et3N, THF) and
DMAP in toluene gave 16 in 82% yield. Reaction of 16
1
by H, 13C NMR, FAB MS and IR spectra.
Acknowledgements
Ch.C.M. is thankful to the UGC, New Delhi, India, for
financial support.
Scheme 2. Reagents and conditions: (a) p-TsCl, pyridine, dry CH2Cl2, 0°C–rt, 14 h; (b) LiAlH4, dry THF, 0°C–rt, 18 h; (c) NaH,
PMBBr, dry THF, 0°C–rt, 4 h; (d) 60% aq. AcOH, cat. HCl, rt, 14 h; (e) NaIO4, MeOH/H2O (2:1), rt, 2 h; (f)
Ph3PꢀCHCOO(CH2)2SO2Tol, 110°C, 1 h; (g) cat. HCl, dioxane/water (1:1), rt, 12 h.

G. V. M. Sharma, Ch. C. Mouli / Tetrahedron Letters 43 (2002) 9159–9161
9161
Scheme 3. Synthesis of macrosphelide A 1 and E 2. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 4,
DMAP, toluene, rt, 12 h; (b) DBN, benzene, rt, 8 h; (c) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 4, DMAP, toluene, rt, 12
h; (d) TMSCl, NaI, CH3CN, −20°C, 6 h; (e) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, 90°C, 24 h; (f) DDQ,
CH2Cl2/H2O, rt.
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993.
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cm−1 1H NMR (500 Hz, CDCl3) l 1.33 (d, 3H, J=6.6
;
Hz), 1.37 (d, 3H, J=6.3 Hz), 1.40 (d, 3H, J=6.6 Hz),
2.43 (d, 1H, J=6.9 Hz), 2.57 (dd, 1H, J=3.6, 15.7 Hz),
2.68 (dd, 1H, J=9.1, 15.7 Hz), 2.81 (d, 1H, J=7.4 Hz),
4.16 (br d, 1H, J=5.7 Hz), 4.23 (br d, 1H, J=5.2 Hz),
4.86 (dq, 1H, J=5.7, 6.3 Hz), 4.95 (dq, 1H, J=5.2, 6.3
Hz), 5.39 (m, 1H), 6.03 (dd, 1H, J=1.6, 9.3 Hz), 6.06
(dd, 1H, J=1.4, 9.0 Hz), 6.85 (dd, 1H, J=3.8, 15.6 Hz),
6.88 (dd, 1H, J=4.4, 15.6 Hz); 13C NMR (300 Hz,
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;
3H, J=6.1 Hz), 1.39 (d, 3H, J=6.1 Hz), 1.44 (d, 3H,
J=6.7 Hz), 2.61 (dd, 1H, J=7.3, 15.8 Hz), 2.73 (dd, 1H,
J=3.0, 15.8 Hz), 3.11 (d, 1H, J=6.7 Hz), 3.39 (d, 1H,
J=7.9 Hz), 4.14–4.25 (m, 1H), 4.39 (br s, 1H), 4.99 (dq,
1H, J=4.2, 6.7 Hz), 5.13 (dq, 1H, J=2.0, 6.7 Hz), 5.34
(ddq, 1H, J=3.0, 6.7, 6.7 Hz), 6.08 (dd, 1H, J=1.2, 15.8
Hz), 6.12 (dd, 1H, J=1.2, 15.3 Hz), 6.81 (dd, 1H, J=4.8,
15.2 Hz), 7.03 (dd, 1H, J=4.3, 15.9 Hz); 13C NMR (300
Hz, CDCl3) l 17.3, 17.7, 19.5, 40.0, 66.6, 73.7, 75.1, 75.3,
75.9, 122.3, 122.9, 145.0, 145.3, 165.2, 166.6, 170.1; FAB
MS (m/z, %): 343 (M++1, 5), 307 (52), 289 (42), 259 (53),
221 (68), 207 (59), 176 (100).
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