Concise syntheses of (+)-macrosphelides A and B

Article abstract of DOI:10.1021/ol0508429

(Chemical Equation Presented) Unified and highly convergent total syntheses of (+)-macrosphelides A and B are described. Key features of the syntheses include (1) concise synthesis of the optically active δ-hydroxy-γ- keto α,β-unsaturated acid fragment vi

Full text of DOI:10.1021/ol0508429

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3159-3162
Concise Syntheses of
)-Macrosphelides A and B
(+
Seung-Mann Paek,† Seung-Yong Seo,† Seok-Ho Kim,† Jong-Wha Jung,†
Yong-Sil Lee,† Jae-Kyung Jung,‡ and Young-Ger Suh*,†
College of Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea, and College
of Pharmacy, Chungbuk National UniVersity, Cheongju 361-763, Korea
ygsuh@snu.ac.kr
Received April 17, 2005
ABSTRACT
Unified and highly convergent total syntheses of (
+
)-macrosphelides A and B are described. Key features of the syntheses include (1) concise
-unsaturated acid fragment via the direct addition of a trans-vinylogous ester anion
synthesis of the optically active -hydroxy- -keto r,â
δ
γ
equivalent to the readily available Weinreb amide and (2) facile construction of the 16-membered macrolide core of the macrosphelide series
via an intramolecular nitrile-oxide cycloaddition (INOC).
Macrosphelides, a class of macrolactone polyketides consist-
ing of several unique components, were isolated from the
culture broth of the fungus (Microsphaeropsis sp. FO-5050)
by the Omura group and from the strain Periconia byssoides,
separated from the sea hare Aplysia kurodai, by the Numata
group.1 These 16-membered macrolides, that contain novel
structures with three ester linkages, strongly inhibit the
adhesion of human leukemia HL-60 cells to human-umbili-
cal-vein endothelial cells (HUVEC) in a dose-dependent
fashion.1a Moreover, macrosphelide B exhibited potent
immunosupressant activity equal to that of rapamycin, and
its analogues might therefore serve as powerful new immu-
nomodulators.2
Taken together, these attributes have led to considerable
interest in macrosphelides as targets for research in organic
synthesis. Several groups have reported synthetic studies in
this regard,3-6 although all of the syntheses typically
employed the Yamaguchi protocol for macrolactone con-
struction, except for Takahashi’s carbonylative macrolac-
tonization7 and Nemoto’s ring-closing metathesis (RCM)
strategy.8 However, despite these synthetic efforts, some
(2) Omura, S.; Komiyama, K. PCT Int. Appl. WO 0147516 A1.
(3) Sunazuka, T.; Hirose, T.; Harigaya, Y.; Takamatsu, S.; Hayashi, M.;
Komiyama, K.; Omura, S.; Sprengeler, P. A.; Smith, A. B., III. J. Am. Chem.
Soc. 1997, 119, 10247-10248.
(4) (a) Kobayashi, Y.; Kumar, B. G.; Kurachi, T. Tetrahedron Lett. 2000,
41, 1559-1563. (b) Kobayashi, Y.; Kumar, G. B.; Kurachi, T.; Acharya,
H. P.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 2001, 66, 2011-2018.
(c) Kobayashi, Y.; Acharya, H. P. Tetrahedron Lett. 2001, 42, 2817-2820.
(d) Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381-4384.
(5) (a) Ono, M.; Nakamura, H.; Konno, F.; Akita, H. Tetrahedron:
Asymmetry 2000, 11, 2753-2764. (b) Nakamura, H.; Ono, M.; Shiba, Y.;
Akita, H. Tetrahedron: Asymmetry 2002, 13, 705-713. (c) Nakamura, H.;
Ono, M.; Makino, M.; Akita, H. Heterocycles 2002, 57, 327-336.
(6) Sharma, G. V. M.; Mouli, C. C. Tetrahedron Lett. 2002, 43, 9159-
9161.
† Seoul National University.
‡ Chungbuk National University.
(1) (a) Hayashi, M.; Kim, Y.-P.; Hiraoka, H.; Natori, M.; Takamatsu,
S.; Kawakubo, T.; Masuma, R.; Komiyama, K.; Omura, S. J. Antibiot. 1995,
48, 1435-1439. (b) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.; Iraoka, H.;
Natori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95-98. (c)
Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori,
T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215-8218. (d) Yamada, T.;
Iritani, M.; Doi, M.; Minoura, K.; Ito, T.; Numata, A. J. Chem. Soc., Perkin
Trans. 1 2001, 3046-3053. (e) Yamada, T.; Iritani, M.; Minoura, K.;
Numata, A.; Kobayashi, Y.; Wang, Y.-G. J. Antibiot. 2002, 55, 147-154.
(7) (a) Takahashi, T.; Kusaka, S.-i.; Doi, T.; Sunazuka, T.; Omura, S.
Angew. Chem., Int. Ed. 2003, 42, 5230-5234. (b) Kusaka, S.-I.; Dohi, S.;
Doi, T.; Takahashi, T. Tetrahedron Lett. 2003, 44, 8857-8859.
10.1021/ol0508429 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/18/2005

problems such as racemization, or lack of substrate general-
ity, during ring closure, still limit the utility of these
pathways. Thus, the synthetically challenging structures of
these macrolides, combined with their interesting biological
activities, prompted us to explore a new synthetic route for
the macrosphelide series. Herein, we report total syntheses
of (+)-macrosphelides A and B that take advantage of the
powerful trans-vinylogous ester anion chemistry9 that we
have developed for monomeric δ-hydroxy-γ-keto R,â-
unsaturated acid fragment assembly.
In considering the options for devising an efficient and
practical synthetic plan, we sought a concise and convenient
method for accessing the common key intermediate 5, which
could be readily transformed into macrosphelide A (1) by
the coupling of each fragment and macrolactonization
(Scheme 1). For macrosphelide B, we also contemplated
oxabicyclo[2,2,2]octane) ester anions to a variety of carbonyl
electrophiles, the requisite allylic alcohol 5 was considered
accessible from a coupling of the vinylogous ester equivalent
6 with the PMB-protected Weinreb amide 8, followed by a
chelation-controlled, highly diastereoselective reduction of
the R-hydroxy ketone. Together, these two strategies would
provide significant synthetic divergence for a variety of
molecules of the macrosphelide series.
Our synthesis commenced with the preparation of the
γ-alkoxy R,â-unsaturated acid 10 as a common key inter-
mediate, as illustrated in Scheme 2. The PMB-protected (S)-
Scheme 2. Synthesis of Acid 10
Scheme 1. Retrosynthesis of (+)-Macrosphelides A (1)
and B (2)
(-)-lactic acid 711 was initially converted to the correspond-
ing Weinreb amide 8. The lithium anion of 6, generated by
the standard procedure,9 was reacted with the Weinreb amide
8 to afford the three-carbon homologated enone 9, in an
excellent yield, with latent ester functionality. With the enone
9 in hand, the chelation-controlled carbonyl reduction was
attempted. To our delight, the addition of Super-H to 9 at
-78 °C in a mixture of CH2Cl2/THF (12:1) furnished the
allylic alcohol 5 as a single detectable isomer.12,13 MEM
protection of 5, followed by hydrolysis, afforded the desired
acid 10. The simplicity of each step, the higher overall yield,
and the high enantiomeric purity in the synthesis of this
monomeric building block attest to the efficiency and
conciseness of our methodology.
Completion of our macrosphelide A synthesis proceeded
in a straightforward manner (Scheme 3). Protection of acid
10 with allyl bromide, followed by PMB deprotection under
buffered conditions, afforded the homoallylic alcohol 11.
Coupling of 10 and 11 by esterification employing the Keck
procedure14 and PMB deprotection provided the dimeric ester
12 in an excellent yield. With iterative esterifications of the
options for using an intramolecular nitrile-oxide cycloaddition
(INOC)10 for effecting macrocyclic ring closure. It was
envisioned that macrosphelide B (2) would finally be
obtained by reductive N-O cleavage of the isoxazoline 4
and dehydration of the resulting â-hydroxy ketone intermedi-
ate. The isoxazoline 4 would be generated from the common
key fragment 5 via a combination of iterative esterifications
and subsequent INOC. On the basis of our methodology9 of
the direct addition of a trans-vinylogous OBO (2,6,7-tri-
(8) (a) Matsuya, Y.; Kawaguchi, T.; Nemoto, H. Org. Lett. 2003, 5,
2939-2941. (b) Kawaguchi, T.; Funamori, N.; Matsuya, Y.; Nemoto, H.
J. Org. Chem. 2004, 69, 505-509.
(9) (a) Suh, Y.-G.; Seo, S.-Y.; Jung, J.-K.; Park, O.-H.; Jeon, L.-O.
Tetrahedron Lett. 2001, 42, 1691-1694. (b) Suh, Y.-G.; Jung, J.-K.; Seo,
S.-Y.; Min, K.-h.; Shin, D.-Y.; Lee, Y.-S.; Kim, S.-H.; Park, H.-J. J. Org.
Chem. 2002, 67, 4127-4137.
(10) For the previous applications of INOC for macrocyclization in
natural compound synthesis, see: (a) Asaoka, M.; Abe, M.; Mukata, T.;
Takei, H. Chem. Lett. 1982, 215-218. (b) Kim, D.; Lee, J.; Shim, P. J.;
Doi, T.; Kim, S. J. Org. Chem. 2002, 67, 772-781.
(11) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew.
Chem., Int. Ed. 2002, 41, 4573-4576.
(12) Faucher, A.-M.; Brochu, C.; Landry, S. R.; Duchesne, I.; Hantos,
S.; Roy, A.; Myles, A.; Legault, C. Tetrahedron Lett. 1998, 39, 8425-
8428.
(13) LAH and LiI in the ethereal solvent gave low selectivity in a 1.5:
1-3:1 ratio. See: Overman, L. E.; McCready, R. J. Tetrahedron Lett. 1982,
23, 2355-2358.
(14) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394-2395.
3160
Org. Lett., Vol. 7, No. 15, 2005

homoallylic alcohol 19 in a high yield. Finally, the alcohol
19 was acylated with acryloyl chloride, and the silyl ether
was deprotected by TBAF/AcOH in a near quantitative yield.
With the key precursor 20 in hand, we attempted the
projected INOC reaction.
Scheme 3. Synthesis of (+)-Macrosphelide A (1)
The successful macrocyclization and completion of the
synthesis of macrosphelide B (2) are depicted in Scheme 5.
Scheme 5. Completion of (+)-Macrosphelide B (2) Synthesis
PMB-protected 3-hydroxy butyric acid 13,15 we were able
to obtain the fully protected trimeric ester 3. Finally, PMB
and allyl deprotection of 3 gave the known seco acid 14, of
which conversion to macrosphelide A (1) was reported.3 The
structure of 14 was confirmed by comparison of its spectral
data with those of the authentic sample (optical rotation, 1H
NMR, 13C NMR, IR, HRMS).
After successful completion of the synthesis of mac-
rosphelide A, our interest turned to the synthesis of mac-
rosphelide B via intramolecular nitrile-oxide cycloaddition.
Our route commenced with the preparation of aldoxime 20,
as outlined in Scheme 4. Dehydrative addition of the TBS-
protected hydroxylamine to the known aldehyde 1516 gave
a separable E/Z mixture of aldoximes, which was directly
subjected to the next step without separation. PMB depro-
tection of the aldoxime ether with DDQ, esterification of
the resulting alcohol from 16 with the acid 13, and PMB
removal provided the hydroxy ester 17. Coupling of the ester
17 with the acid 10, under the Yamaguchi conditions,17 and
then DDQ treatment under neutral conditions yielded the
The initial INOC reaction of the aldoxime acrylate 20 in
CH2Cl2 proceeded smoothly, in a regioselective manner, and
in high yield, affording a 2:1 diastereomeric mixture of the
desired isoxazolines 21 in 96% yield.18 Further optimization
studies revealed that dioxane was highly superior to other
solvents in terms of diastereoselectivity. Cycloaddition in
dioxane produced mainly one diastereomer19 in >10:1 ratio
with 89% yield, although the stereochemical outcome was
not important at this stage.20 Notably, the high yield,
operational simplicity, and functional group tolerance of this
INOC ring closure potentially make this strategy attractive
for stereoselective synthesis of other macrosphelide family
members. For completion of our total synthesis, the remain-
ing tasks were chemoselective N-O bond cleavage of the
isoxazoline 21 and dehydration of the resulting â-hydroxy
ketone. After extensive screening of various methods for the
facile N-O bond reduction, Mo(CO)6 in wet CH3CN was
found to be the most effective.21 Thus, the selective reduction
Scheme 4. Synthesis of Aldoxime 20
(15) Eh, M.; Schomburg, D.; Schicht, K.; Kalesse, M. Tetrahedron 1995,
51, 8983-8992.
(16) Maezaki, N.; Hirose, Y.; Tanaka, T. Org. Lett. 2004, 6, 2177-
2180 and other references therein.
(17) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993. Esterification under other reaction
conditions such as EDCI-DMAP, DCC-DMAP, or DCC-DMAP-CSA
was not successful.
(18) Undesired regioisomer was not observed. This regiochemical
outcome is consistent with that of Asaoka’s previous studies. Refer to ref
10a.
(19) On the basis of extensive spectroscopic studies on the isoxazoline
21, the configuration of isoxazoline 21 is likely to be 12R (12H-R), which
is readily separable by flash column chromatography.
(20) Minor isomer of isoxazoline 21 was resistant to both reductive N-O
bond cleavage and dehydration.
Org. Lett., Vol. 7, No. 15, 2005
3161

of the N-O bond, followed by dehydration of the resulting
â-hydroxy ketone 22, with Burgess’ reagent22 afforded the
known MEM-protected macrosphelide B (23). Finally,
removal of the MEM group with TFA in CH2Cl2 afforded
efficient synthesis of the crucial monomeric fragment by a
direct addition of a trans-vinylogous ester anion to a Weinreb
amide and the intramolecular nitrile oxide cycloaddition for
the final macrolactonization, which proved to be highly
efficient and practical for the macrosphelide syntheses.
Further efforts employing this strategy, including the syn-
thesis of other macrosphelide series, are progressing well.
1
(+)-macrosphelide B (2) in 94% yield, which exhibited H
NMR, 13C NMR, optical rotation, HRMS, and IR spectral
data identical to those of the authentic natural product.3,8
In summary, we have achieved the formal synthesis of
(+)-macrosphelide A (12 steps, 30% overall yield, 90%
average yield) and the total synthesis of (+)-macrosphelide
B (13 steps, 20% overall yield, 88% average yield). The key
features of these synthetic routes involve the concise and
Acknowledgment. This research was supported by a
grant from Center for Bioactive Molecular Hybrids, Yonsei
University.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni, D.
Synthesis 1987, 276-278.
(22) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973,
38, 26-31.
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