Total synthesis of macrosphelides B and A

Article abstract of DOI:10.1016/S0040-4039(99)02323-0

An efficient total synthesis of macrosphelide B has been developed in which the C(5)-O(10) and the C(11)-O(16) fragments were prepared from (S)-1- (2-furyl)ethanol of >98% ee via oxidation of the furan part. In addition, macrosphelide B was transformed stereoselectively into macrosphelide A by reduction followed by Mitsunobu inversion. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02323-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1559–1563
Total synthesis of macrosphelides B and A
Yuichi Kobayashi,∗ Biju G. Kumar and Tomoaki Kurachi
Department of Biomolecular Engineering, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8501, Japan
Received 15 November 1999; revised 6 December 1999; accepted 10 December 1999
Abstract
An efficient total synthesis of macrosphelide B has been developed in which the C(5)–O(10) and the
C(11)–O(16) fragments were prepared from (S)-1-(2-furyl)ethanol of >98% ee via oxidation of the furan part.
In addition, macrosphelide B was transformed stereoselectively into macrosphelide A by reduction followed by
Mitsunobu inversion. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: biologically active compounds; macrosphelide B; macrosphelide A; macrolide; oxidation of furans; stereocontrol.
Macrosphelides A and B, which are produced by Microsphaeropsis sp. FO-5050, were isolated by
Omura and co-workers1 and have been shown to strongly inhibit the adhesion of human leukemia HL-60
cells to human umbilical-vein endothelial cells without inhibiting the growth of various mammalian cell
lines and microorganisms; consequently, they are highly attractive compounds for use as next-generation
chemotherapeutical drugs against cancer.2 Recently, the 3D structures of macrosphelides A and B have
been determined as depicted in 1 and 2, respectively, and a total synthesis of 1 was accomplished by
collaboration of Omura and Smith.3 In their synthesis, the hydroxyl groups are installed on the sorbic
ester by using the Sharpless AD reaction4 with 85% ee,5 and the conversion of 1 into 2 by PDC oxidation
proceeds with low regioselectivity and efficiency, as expected. These results prompted us to investigate an
alternative strategy whereby synthesis of 2 is carried out first, and hydride reduction of 2 or a macrocyclic
intermediate thereof (ketone) follows to synthesize 1. Advantages of this strategy are probably that: (1)
synthesis of 2 would be accomplished more easily than that of 1 since there is one less chiral center in
2; and (2) reduction of 2 would proceed with high diastereoselectivity due to the conformational bias
provided by the macrocycle. Herein, we report a successful result of this strategy.
∗
Corresponding author. Tel: +00 81 45 924 5789; fax: +00 81 45 924 5789; e-mail: ykobayas@bio.titech.ac.jp (Y. Kobayashi)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02323-0
tetl 16251

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The target molecule 2 would be synthesized through macrocyclization of seco acid 3 (Scheme 1).
Based on the fact that chemically stable 2-alkyl furans are a synthetic equivalent of the rather unstable
γ-oxo-α,β-unsaturated carboxylic acids through the method developed by us (Eq. (1)),6 3 was dissected
into pieces 4–6. Acid 5 is available via the asymmetric reduction of acetoacetate,7 while methods for
the preparation of 6 have been published.8 Concerning fragment 4, the furan-ring oxidation (Eq. (1))
of an appropriately protected alcohol 6 followed by reduction of the resulting γ-keto acid would be an
appropriate method.
Scheme 1. Starting compounds and intermediates for synthesis of macrosphelide B (2)
Among possible sequences for assembling fragments 5 and 6, the route presented in Scheme 2 was
chosen on the basis of the number of reaction steps involved, in which chelation-controlled reduction
of ketone 11 to afford the desired anti alcohol 12 is a crucial step in the synthesis. Alcohol 6 of >98%
ee9 was prepared by the kinetic resolution of the corresponding racemic alcohol8a using the Sharpless
reagent10 (38% yield based on the racemic alcohol). Conversion of 6 into the PMB ether 7 was carried
out as usual, and 7 was then transformed into γ-keto acid 8 by the oxidative conversion shown in Eq. (1)
(48% yield from 6) (Scheme 2). On the other hand, condensation of acid 511,12 (99% ee)9 and alcohol
6 with DCC in the presence of DMAP and CSA13 produced ester 9, which upon desilylation furnished
alcohol 10 in good yield. Condensation of acid 8 and alcohol 10 was also accomplished with DCC to
afford 11 in 92% yield.
(1)
Next, reduction14 of 11 with Zn(BH4)2 was investigated. Unfortunately, a mixture of 12 and its epimer
was obtained in a ratio of 2:1 when 11 was added to an ethereal solution of Zn(BH4)2 even at ≤–90°C.
It might be reasonable to assume that Zn{BHn(OR)4−n}2, which was formed in the early stage of the
reduction, participated in the reduction of the remaining ketone 11 without chelation due to the steric
bulkiness of Zn{BHn(OR)4−n}2, thus furnishing the diastereomeric mixture after aqueous work-up. After
several unsuccessful trials, it was found that reverse addition could improve the ratio to a practical level
of 15:1 in 70% yield. The result is consistent with the above assumption. Protection of alcohol 12 with
MOMCl and subsequent deprotection of the PMB group with DDQ furnished alcohol 14 in 82% yield.
Without protection of the hydroxyl group, 14 was converted into the key acid 3 by the two-step oxidation

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Scheme 2. Reagents and conditions: (a) NaH, PMBCl, 93%. (b) NBS, acetone/H2O, 10:1, −15°C, 1 h then furan, C5H5N, rt, 6
h, 74%. (c) NaClO2, MeC(H)_CMe2, 70%. (d) DCC, DMAP, CSA, rt, overnight, 98% for 9 and 92% for 11. (e) TBAF, THF,
0°C, 24 h, 73%. (f) Zn(BH4)2, Et2O, ≤–90°C, 70%. (g) MOMCl, i-Pr2NEt, CH2Cl2, 88%. (h) DDQ, CH2Cl2/H2O, 93%. (i and
j) similar conditions to (b) and (c). (k) Cl3C6H2COCl, NEt3 then DMAP, toluene, 40°C, 5 h, 40% from 14. (l) TFA/CH2Cl2,
1:1, rt, 1.5 h, 92%
via aldehyde 15. Lactonization of crude seco acid 3 was carried out by the Yamaguchi method15 to
produce lactone 1616 in 40% yield from 14. Finally, deprotection of the MOM group with TFA in
24
23
CH2Cl2 furnished 2 in good yield: [α] =+9.1 (c 0.154, MeOH); lit.1b [α] =+4.10 (c 0.99, MeOH);
D
D
24
lit.3 [α] =+10.0 (c 0.39, MeOH). The 1H NMR and 13C NMR spectra of synthetic 2 were identical with
D
the data reported in the literature.1b,3
Next, we examined a synthesis of macrosphelide A (1) (Scheme 3). Theoretically, chelation-controlled
reduction14 of ketone 16 should provide 18 of the desired stereochemistry at C(14). However, reduction
of 16 with Zn(BH4)2 at −78°C resulted in a 1:1 mixture of 17 and 18. On the contrary, NaBH4 in MeOH
at −15°C provided 17 highly selectively (>10:1). These results indicate that macrocycle 16 takes one
stable conformer, where the undesired side of the carbonyl group at C(14) (pro-S face) is exposed to the
outside of the macrocyclic ring, thus furnishing a bias for stereoselective reduction even with a simple
reagent such as NaBH4. The newly-formed hydroxyl group in 17 was inverted by Mitsunobu reaction17
with HCO2H, DEAD, and PPh3, and methanolysis of the formate with NEt3 in MeOH furnished 18 in
30
72% yield. Finally, deprotection with TFA afforded 1 in 70% yield: [α] =+85 (c 0.046, MeOH); lit.1b
D
23
27
[α] =+84.1 (c 0.59, MeOH); lit.3 [α] =+82 (c 0.10, MeOH). Similarly, treatment of 17 with TFA
D
D
furnished 14-epimer of 1 (i.e., 19) in 86% yield.

1562
Scheme 3. Synthesis of macrosphelide A (1)
Acknowledgements
We gratefully acknowledge the generous supply of methyl (S)-3-hydroxybutanoate from Takasago
International Corporation and D-(−)-DIPT from Toray Industries, Inc.
References
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9. Enantiomeric excess (ee) was determined by 1H NMR spectroscopy of the derived MTPA ester.

1563
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16. Compound 16: [α]2D4=−80 (c 0.36, CHCl3); IR (neat) 1735, 1718, 1708, 1265, 1182, 1055 cm−1; 1H NMR δ 1.37 (d, J=6
Hz, 3H), 1.42 (d, J=7 Hz, 3H), 1.44 (d, J=7 Hz, 3H), 2.63 (dd, J=16, 3 Hz, 1H), 2.75 (dd, J=16, 10 Hz, 1H), 3.39 (s, 3H),
4.20 (dt, J=1, 6 Hz, 1H), 4.65 (br s, 2H), 4.96-5.06 (m, 1H), 5.18 (q, J=7 Hz, 1H), 5.32–5.44 (m, 1H), 6.06 (dd, J=16, 1
Hz, 1H), 6.76 (d, J=16 Hz, 1H), 6.82 (dd, J=16, 6 Hz, 1H), 7.00 (d, J=16 Hz, 1H); 13C NMR δ 196.2, 170.5, 164.6, 164.0,
144.2, 133.3, 132.6, 124.4, 95.2, 78.1, 75.4, 72.4, 68.3, 56.0, 40.9, 19.8, 17.7, 15.8. Anal. calcd for C18H24O9: C, 56.24; H,
6.29. Found: C, 55.99; H, 6.23.
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