First total synthesis of macrosphelides C and F

Article abstract of DOI:10.1016/S0040-4039(01)00285-4

Macrosphelides C and F were synthesized by lactonization of 14-oxo seco acids at the O(10)-C(11) bond followed by reduction and Mitsunobu inversion of the resulting hydroxyl group. The seco acids were prepared from the corresponding furans by furan ring-opening with NBS followed by further oxidation of the 4-oxo-2-alkenals with NaClO₂.

Full text of DOI:10.1016/S0040-4039(01)00285-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2817–2820
First total synthesis of macrosphelides C and F
Yuichi Kobayashi* and Hukum P. Acharya
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama 226-8501, Japan
Received 25 January 2001; accepted 16 February 2001
Abstract—Macrosphelides C and F were synthesized by lactonization of 14-oxo seco acids at the O(10)ꢀC(11) bond followed by
reduction and Mitsunobu inversion of the resulting hydroxyl group. The seco acids were prepared from the corresponding furans
by furan ring-opening with NBS followed by further oxidation of the 4-oxo-2-alkenals with NaClO2. © 2001 Elsevier Science Ltd.
All rights reserved.
Macrosphelides A–L are a family of compounds iso-
lated from the culture medium of Microsphaeropsis sp.
FO-5050 and/or Periconia byssoides by the Omura
group1–3 and the Numata group,4–6 and their planar
structures have been determined by spectroscopic meth-
ods and by chemical transformations. Among them,
macrosphelides A and B (1 and 2) have been shown to
strongly inhibit the adhesion of human-leukemia HL-60
cells to human-umbilical-vein endothelial cells.7 Discov-
ery of this property is probably the reason that
prompted elucidation of the stereochemistry and the
first total synthesis of 1 and 2 shortly after the isola-
tion.8 Consequently, investigation of the biological
property and determination of the stereochemistry of
other macrosphelides should urgently be undertaken.
However, it was quite recently that Numata elucidated
the stereochemistry of macrosphelides C, F, G, I and L
by X-ray analysis and/or chemical degradation.6,9
O
O
14
14
HO
X
OH
O
O
O
O
8
O
1
R
3
O
O
O
O
O
3
OH
H
Macrosphelide C (3): R = β-Me
Macrosphelide F (4): R = α-Me
Macrosphelide A (1): X =
Macrosphelide B (2): X = O
(1) lactonization
(2) reduction
CO2H
O
O
OH
OH
O
14
3
O
O
O
O
O
O
O
5
6
Scheme 1. A sequence to macrosphelide C (3).
Keywords: asymmetric synthesis; furans; macrolides; macrosphelide C; macrosphelide F.
* Corresponding author. Tel.: +00 81 45 924 5789; fax: +00 81 45 924 5789; e-mail: ykobayas@bio.titech.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00285-4

2818
Y. Kobayashi, H. P. Acharya / Tetrahedron Letters 42 (2001) 2817–2820
Macrosphelides are triesters possessing a 4-hydroxy (or
4-oxo)-2-hexenoic acid moiety (or moieties). With
regard to this structural unit, we recently reported a
simple method for conversion of the 2-alkylfurans into
4-oxo-2-alkenoic acids as illustrated in Eq. (1).10
sation, while acid 10 was synthesized through the Wit-
tig reaction of the corresponding aldehyde derived from
(S)-7.15 Esterification of alcohol 9 and acid 10 with
DCC in the presence of DMAP and CSA furnished
ester 11, and subsequent deprotection of the THP
group yielded the key compound 5 in 53% yield from 9.
Furan 5 was converted into aldehyde 12 with NBS and
then to the 14-oxo seco acid 6, which, without purifica-
tion, was subjected to the Yamaguchi lactonization.16
The standard procedure16 involving the following steps
of (i) Cl3C6H2COCl, Et3N, THF; (ii) filtration; (iii) slow
addition to DMAP in toluene, produced the 14-oxo
lactone 13 in 35–42% yield, while a modified method
(step i of Scheme 2), which is reported by Yonemitsu17
and is known to be operationally simpler, furnished
lactone 13 after chromatography in 61% yield from
furan 5. Higher temperatures of 40–50°C for the lac-
tonization did not result in any further improvement in
the yield of 13.
O
1) NBS, pyridine
(1)
CO2H
R
R
O
2) NaClO2
This transformation, though oxidation, is compatible
with a free hydroxyl group. In addition, several meth-
ods are available for synthesis of 2-substituted furans.
With the best use of these synthetic advantages, con-
struction of the seco acid of 2 was accomplished quite
efficiently.11 Furthermore, reduction of the 14-oxo
macrocyclic intermediate was found to proceed
stereoselectively to yield 14-epi alcohol, and inversion
of the hydroxyl group afforded 1. The conformational
bias provided by the macrocyclic lactone is probably
responsible for the high stereoselectivity observed in the
reduction. This result strongly suggests the feasibility of
synthesis of other macrosphelides as well. Based on this
concept, we report the first synthesis of macrosphelides
C and F (3 and 4).
Reduction of the carbonyl group at C(14) of 13 was
investigated with NaBH4 in MeOH at −70°C. The
reaction proceeded stereoselectively to afford 14-epi
macrosphelide C (i.e. 14) with high stereoselectivity of
22:1 in 82% yield. Mitsunobu inversion of 14 with
3,5-(NO2)2C6H3CO2H, PPh3, and DEAD produced
ester 15. However, chromatographic separation of 15
and the co-produced dicyclohexylurea was unsuccessful
due to the almost identical Rf values on TLC. Fortu-
nately, the problem was averted with diisopropyl azo-
dicarboxylate (DIAD), and ester 15 was isolated in 71%
yield as the sole product. Finally, methanolysis of 15
An outline of the synthesis of macrosphelide C (3) is
depicted in Scheme 1, which involves transformation of
furan 5 into 14-oxo seco acid 6 followed by macrocy-
clization and reduction. A synthesis along this line is
summarized in Scheme 2. Alcohol 9 was prepared from
methyl (S)-3-hydroxybutanoate ((S)-7)12 of 98% ee and
furyl alcohol 813,14 of 92–95% ee through DCC conden-
O
O
8
OH
O
a,b,c,d
O
HO
OTHP
10
O
OR
g
e
CO2Me
9
HO
O
(S)-7
O
O
O
CO2H
11: R = THP
5: R = H
f
R
O
O
O
14
OR
OH
O
O
O
O
O
O
i
j
k
O
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
h
12: R = CHO
6: R = CO2H
15: R = 3,5-(NO2)2C6H3CO
3: R = H
13
14
l
Scheme 2. (a) DHP, H+, 97%; (b) 2N LiOH, THF, H2O, 92%; (c) 8 (1 equiv.), acid from 7 (1.5 equiv.), DCC (1.2 equiv.), DMAP
(0.3 equiv.), CSA (0.15 equiv.), 82%; (d) PPTS (cat.), MeOH, 80%; (e) 10, DCC (1.5 equiv.), DMAP (0.3 equiv.), CSA (0.15
equiv.), CH2Cl2, rt, 8 h, 69%; (f) PPTS (0.2 equiv.), MeOH, 77%; (g) NBS (1.2 equiv.), NaHCO3, acetone/H2O (10:1), −15°C, 3
h then furan (5 equiv.), C5H5N (1.2 equiv.), rt, 12 h; (h) NaClO2, Me2CꢁCHMe, t-BuOH, buffer (pH 3.6); (i) Cl3C6H2COCl,
DMAP, toluene, rt, o.n., 61% from 5; (j) NaBH4, MeOH, −70°C, 82%; (k) DIAD (2 equiv.), (NO2)2C6H3CO2H (5 equiv.), PPh3
(2 equiv.), THF, 71%; (l) Et3N, MeOH, rt, 2 h, 84%.

Y. Kobayashi, H. P. Acharya / Tetrahedron Letters 42 (2001) 2817–2820
2819
O
10
8
CO2R2
R1O
O
c,d
e,f
(R)-7: R1 = H, R2 = Me
16: R1 = THP, R2 = H
HO
O
a,b
17
O
O
O
OH
O
g,h,i
O
j
O
O
O
O
O
O
O
18
19
O
X
O
O
O
O
O
20: X = α-OH, β-H
k
21: X = α-H, β-OCOC6H3(NO2)2
4: X = α-H, β-OH
l
Scheme 3. For (a) and (b), see: (a) and (b) in Scheme 2, 90%; (c) 16, 8, DCC, DMAP, CSA, CH2Cl2; (d) PPTS, MeOH, 75%;
(e) DCC, DMAP, CSA, CH2Cl2, 79%; (f) PPTS, MeOH, 73%; (g) NBS, NaHCO3, acetone/H2O (10:1), −15°C then furan, C5H5N,
rt; (h) NaClO2, Me2CꢁCHMe, t-BuOH, buffer (pH 3.6); (i) Cl3C6H2COCl, DMAP, toluene, rt, o.n., 56% from 18; (j) NaBH4,
MeOH, −70°C, 80%; (k) DIAD, (NO2)2C6H3CO2H, PPh3, THF, 69%; (l) Et3N, MeOH, rt, 79%.
1
furnished macrosphelide C (3) in good yield. The H
NMR spectrum and [h]D value of synthetic 3 were in
full agreement with the data reported: [h]2D6=+31 (c
0.065, MeOH); lit.2 [h]2D0=+29.5 (c 0.10, MeOH).
conformers of 13 and 19 is exposed to the outside of the
ring in the reduction with NaBH4. On the basis of the
present and previous results, this strategy, involving (1)
convenient preparation of 14-oxo seco acid; (2) cycliza-
tion; (3) formation of the C(14)ꢀOH by reduction fol-
lowed by inversion, is undoubtedly applicable to the
synthesis of other macrosphelides. In addition, we
unexpectedly observed the product-selective formation
of ester 21 from a 4:1 mixture of 20 and 4. This result
strongly indicates that alcohols 20 and 4 also take the
same conformations as that of ketone 19, in which the
OH group at C(14) is projected into the inside and the
outside of the macrocyclic ring, respectively, and that
the benzoate anion attacked the PPh3 complex of the
major alcohol 20 from the outside of the ring to
produce 21, while the attack on the PPh3 complex
derived from the minor alcohol 4 was strongly pre-
vented by the ring, thereby inducing other reaction(s)
such as the elimination.
Macrosphelide F (4) is a C(3) stereoisomer of macro-
sphelide C (3), and thence (R)-7 (98% ee) was the
starting compound. As illustrated in Scheme 3, (R)-7
was converted into acid 16 by the standard transforma-
tion (Scheme 3). Condensation of 16 with furyl alcohol
8 and subsequent deprotection of the THP group pro-
duced alcohol 17 in 75% yield. Esterification of 17 with
acid 10 followed by deprotection furnished the key
intermediate 18. Oxidative transformation of 18 and
macrolactonization of the resulting 14-oxo seco acid
again under the Yonemitsu conditions17 produced lac-
tone 19 in 56% yield from furan 18. Reduction of 19
with NaBH4 in MeOH at −70°C proceeded with some-
what lower selectivity than that of 13 (vide infra), and
a mixture of 20 and 4 was obtained with a 4:1 ratio in
80% combined yield. Fortunately, the mixture under-
went kinetic separation during the Mitsunobu inversion
to furnish dinitrobenzoate 21 as the sole product, which
Acknowledgements
1
upon methanolysis furnished 4 in 69% yield. The H
NMR spectrum and [h]D value of 4, thus synthesized,
were in good agreement with the data reported: [h]2D6=
+21 (c 0.02, EtOH); lit.4 [h]D=+23.3 (c 0.09, EtOH).
We thank Professor A. Numata at Osaka University of
Pharmaceutical Science for providing us with the abso-
lute structures of macrosphelides C and F. We also
thank Takasago International Corporation for a gener-
ous supply of (R)- and (S)-7.
The results described above clearly show that the Re
face of the carbonyl group at C(14) in the stable

2820
Y. Kobayashi, H. P. Acharya / Tetrahedron Letters 42 (2001) 2817–2820
Soc. 1997, 119, 10247–10248. Cf. recent synthesis of 1: (a)
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