A total synthesis of macrosphelides C and F from L-(+)-arabinose

Article abstract of DOI:10.1016/j.tetlet.2003.09.034

A total synthesis of the 16-membered macrolides, macrosphelides C and F has been achieved starting from L-(+)-arabinose.

Full text of DOI:10.1016/j.tetlet.2003.09.034

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8161–8163
A total synthesis of macrosphelides C and F from
-(+)-arabinoseꢀ
L
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 25 July 2003; revised 20 August 2003; accepted 3 September 2003
Abstract—A total synthesis of the 16-membered macrolides, macrosphelides C and F has been achieved starting from
L
-(+)-arabinose.
© 2003 Elsevier Ltd. All rights reserved.
Macrosphelides A–L were isolated as inhibitors of the
adhesion of HL-60 cells to a monolayer of LPS-acti-
vated human-umbilical-vein endothelial cells. Macro-
sphelide C (1) was isolated from the culture broth of
Microsphaeropsis sp. FO-5050,1 whereas macrosphelide
F (2) was obtained from a strain of Periconia byssoides
separated from the gastrointestinal tract of the sea hare
Aplysia kurodai.2a The absolute stereostructures of
macrosphelides C (1) and F (2) have been described by
the Numata group.2 These compounds were found to
inhibit strongly the adhesion of human-leukemia HL-60
cells to human-umbilical-vein endothelial cells
(HUVETC). Consequently these are highly attractive
compounds for use as the next generation chemothera-
peutical drugs against cancer and hence different syn-
thetic methods for producing these molecules and their
analogues is urgently required. In addition to their
biological interest, the four chiral centres and the three
ester linkages present in macrosphelides evoke interest
for the synthesis of these target molecules. Earlier syn-
theses of macrosphelides C and F have been reported
by three groups,3,4 while we have recently reported a
total synthesis of macrosphelides A and E.5 Herein, we
report the first ‘chiron approach’ based total synthesis
condensation with commercially available 3S- or 3R-
hydroxybutanoic acid units 6 or 7, respectively would
give seco acids 3 and 3a. Yamaguchi macrolactonisa-
tion of seco acids 3 and 3a, would thus afford the target
molecules 1 and 2. Both segments 4 and 5 were to be
derived from a common synthon 8.
Accordingly, 5-deoxy-1,2-O-isopropylidene-L-arabino-
furanose6 (8) was treated with CS2, MeI, NaH in THF
to give 9 (90% yield), which on deoxygenation using
n-Bu3SnH (toluene) afforded 10 in 61% yield. Hydroly-
sis of the 1,2-acetonide (cat. HCl in 60% aq. AcOH)
furnished 11 in 75% yield. Oxidative cleavage of 11
(NaIO4, CH2Cl2) and subsequent olefination of the
unstable aldehyde 12 with (p-toluenesulfonylethoxy car-
bonylmethylene)triphenylphosphorane7 gave 13 in 70%
yield. Finally, de-O-formylation of 13 with catalytic
HCl (1, 4 dioxane:water, 1:1) afforded the key interme-
diate 4 in 78% yield, [h]D −5.15 (c 1.1, CHCl3) (Scheme
2).
Trans-(4R,5S)-5-hydroxy-4-p-methoxybenzyloxy-2-hex-
enoate5 14 (Scheme 3) which was reported earlier by
our group, was silylated (TBDMSCl, Et3N, CH2Cl2) to
of 1 and 2 (Fig. 1) from -(+)-arabinose.
L
Our approach to the construction of 1 and 2 (Scheme
1), entailed the preparation of trans-(5S)-5-hydroxy-p-
toluenesulfonylethyl-2-hexenoate (4) and trans-(4R,5S)-
5-tert-butyldimethylsilyloxy-4-p-methoxybenzyloxy-2-he
xenoic acid (5). Esterification of 4 and 5 and further
ꢀ IICT Communication No. 030713.
* Corresponding author. E-mail: esmvee@iict.ap.nic.in
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.034

8162
G. V. M. Sharma, Ch. C. Mouli / Tetrahedron Letters 44 (2003) 8161–8163
Scheme 1. Retrosynthesis of macrosphelide C 1 and F 2.
Scheme 2. Reagents and conditions: (a) NaH, CS2, MeI, THF, 0°C–rt, 2 h; (b) n-Bu3SnH, AIBN, toluene, 110°C, 12 h; (c) 60%
aq. AcOH, cat. HCl, rt, 14 h; (d) NaIO4, CH2Cl2, 0°C–rt, 6 h; (e) Ph3P=CHCOO(CH2)2SO2Tol, toluene 110°C, 1 h; (f) cat. HCl,
1:1 dioxane/water, rt, 12 h.
give 15 in 80% yield, [h]D −73.80 (c 0.21, CHCl3), which
on ester cleavage with DBN7 (C6H6) furnished acid 5 in
76% yield. Condensation of acid 5 with alcohol 4
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 ester 16 in 88%
Scheme 3. Synthesis of macrosphelide C (1) and F (2). Reagents and conditions: (a) TBDMSCl, imidazole, CH2Cl2, rt, 24 h; (b)
DBN, benzene, rt, 8 h; (c) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 4, DMAP, toluene, rt, 12 h; (d) TMSCl, H2O, CH3CN,
rt, 8 h; (e) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, rt, 24 h; (f) TMSCl, NaI, CH3CN, −20°C, 6 h; (g)
2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, 90°C, 24 h; (h) DDQ, aq CH2Cl2 (19:1), rt, 4 h.

G. V. M. Sharma, Ch. C. Mouli / Tetrahedron Letters 44 (2003) 8161–8163
8163
yield, [h]D −24.73 (c 0.31, CHCl3). Desilylation of 16
with TMSCl and H2O in CH3CN afforded 17 in 84%
yield, [h]D −34.2 (c 0.91, CHCl3), which on esterifica-
tion (2,4,6-trichlorobenzoyl chloride (Et3N, THF) in
the presence of DMAP in toluene) independently with
acids 6 and 7 furnished 18 (76% yield), [h]D −10.80 (c
0.735, CHCl3) and 18a (75% yield), [h]D −27.19 (c
0.815, CHCl3), respectively. Exposure of 18 and 18a to
TMSCl and NaI in CH3CN, facilitated removal of the
MEM protection to afford 19 (80% yield), [h]D −16.90
(c 0.56, CHCl3) and 19a (81% yield), respectively. Selec-
tive cleavage of the p-toluylsulphonylethyl group in 19
and 19a was effected with DBN (C6H6) to furnish seco
acids 3 (80% yield) and 3a (84% yield), respectively.
Macrolactonisation of 3 and 3a, under Yamaguchi
reaction conditions8 (2,4,6-trichlorobenzoyl chloride
Et3N, THF, DMAP, toluene) furnished 20 in 62% yield
and 20a in 58% yield, respectively. Finally, oxidative
deprotection of 20 and 20a with DDQ in aq CH2Cl2
gave synthetic 1 (85% yield) as a white solid, mp
151–153°C, [h]D +52.1 (c 0.10, MeOH); and 2 (80%
yield), as a colourless oil, [h]D +22.5 (c 0.10, MeOH).
The target molecules 1 and 2 were fully characterised9,10
2. (a) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.;
Matusumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron
Lett. 1997, 38, 8215–8218; (b) Yamada, T.; Iritani, M.;
Doi, M.; Minoura, K.; Ito, T.; Numata, A. J. Chem.
Soc., Perkin. Trans. 1 2001, 3046–3053.
3. Nakamura, H.; Ono, M.; Shida, Y.; Akita, H. Tetra-
hedron: Asymmetry 2002, 13, 705–713.
4. Kobayashi, Y.; Acharya, H. P. Tetrahedron Lett. 2001,
42, 2817–2820.
5. Sharma, G. V. M.; Mouli, Ch. C. Tetrahedron Lett. 2002,
43, 9159–9161.
6. Rauter, A. P.; Ramoa-Ribeiro, F.; Fernandes, A.;
Figueiredo, J. A. Tetrahedron 1995, 51, 6529–6540.
7. Colvin, E. W.; Purcell, T. A.; Raphael, R. A. J. Chem.
Soc., Perkin. Trans. 1 1976, 1718.
8. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993.
9. Spectral data of macrosphelide-C (1): white solid, mp
151–153°C; lit.3 mp 152–155°C, [h]D +52.1 (c 0.10,
MeOH); lit.3 [h]D +53.3 (c 0.08, EtOH); IR (KBr): 3458,
1725 cm-1; 1H NMR (500 Hz, CDCl3) l 1.33 (d, 3H,
J=6.5 Hz), 1.36 (d, 3H, J=6.5 Hz), 1.38 (d, 3H, J=6.8
Hz), 2.0 (br. d, 1H, J=6.3 Hz), 2.36 (dd, 1H, J=8.6, 13.7
Hz), 2.51 (dd, 1H, J=8.5, 14.6 Hz), 2.56 (m, 1H), 2.63
(dd, 1H, J=3.0, 14.6 Hz), 4.16 (br d, 1H, J=4.8 Hz),
4.92 (q, 1H, J=6.3 Hz), 5.1 (m, 1H), 5.3 (m, 1H), 5.8 (dd,
1H, J=1.5, 15.6 Hz), 6.06 (dd, 1H, J=1.5, 15.5 Hz), 6.85
(dd, 1H, J=6.2, 9.3 Hz), 6.89 (dd, 1H, J=4.8, 15.5 Hz);
13C NMR (300 Hz, CDCl3) l 17.5, 19.5, 20.5, 38.8, 40.9,
67.4, 69.0, 72.9, 73.7, 123.0, 124.7, 143.7, 144.8, 164.9,
165.0, 170.0; FAB MS (m/z, %): 327 (M++1, 3), 309 (2),
289 (3), 154 (40), 107 (33), 83 (39), 69 (100), 55 (95).
10. Spectral data of macrosphelide-F (2): colourless oil, [h]D
+22.5 (c 0.10, MeOH); lit.2 [h]D +23.3 (c 0.09, EtOH); IR
(neat): 3442, 1719 cm-1; 1H NMR (500 Hz, CDCl3) l 1.31
(d, 3H, J=6.4 Hz), 1.35 (d, 3H, J=6.4 Hz), 1.38 (d, 3H,
J=6.4 Hz), 2.39 (dd, 1H, J=6.4, 14.3 Hz), 2.58 (dd, 1H,
J=7.9, 15.8 Hz), 2.66 (dd, 1H, J=3.2, 15.8 Hz), 2.7 (m,
1H), 4.21 (dddd, 1H, J=1.7, 3.8, 4.0, 7.9 Hz), 4.93 (qd,
1H, J=3.8, 6.4 Hz), 5.14 (dqd, 1H, J=5.0, 6.4, 11.4 Hz),
5.30 (dqd, 1H, J=3.2, 6.4, 7.6 Hz), 5.79 (dd, 1H, J=1.7,
15.8 Hz), 6.09 (dd, 1H, J=1.7, 15.8 Hz), 6.85 (dd, 1H,
J=4.1, 15.5 Hz), 6.89 (dd, 1H, J=7.6, 15.8 Hz); FAB
MS (m/z, %): 327 (M++1, 18), 309 (30), 289 (4), 154 (32),
137 (52), 83 (43), 69 (74), 55 (100).
1
by H, NMR, FAB MS and IR spectra.
Thus, in conclusion, an enantioselective synthesis of 1
and 2 has been achieved very efficiently from -(+)-ara-
L
binose. Both the requisite segments with three asym-
metric centres were prepared from a common chiral
intermediate. The flexible strategy adopted in the
present report will help in the design and synthesis of a
variety of new chemical entities based on 1 and 2, by
the replacement of the 3-hydroxybutyric acid unit.
Acknowledgements
Ch.C.M. is thankful to the UGC, New Delhi, India, for
financial support.
References
1. Takamatsu, S.; Hiraoka, H.; Kim, Y-P.; Hayashi, M.;
Natori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1997,
50, 878–880.