Furan ring oxidation strategy for the synthesis of macrosphelides A and B

Article abstract of DOI:10.1021/jo001495d

By using the convenient protocol for conversion of 2-substituted furans into 4-oxo-2-alkenoic acids ((i) NBS, (ii) NaClO₂), macrosphelide B (2) was synthesized from furyl alcohol 5 (> 98% ee) and acid 6 (99% ee). The protocol was first applied to the PMB ether of 5 to afford acid 13b. On the other hand, DCC condensation of acid 6 with 5 gave 16 after deprotection of the TBS group. Condensation was again carried out between 13b and 16 to furnish the key ketone 17, which upon reduction with Zn(BH₄)₂ afforded anti alcohol 18 stereoselectively (15:1). After protection/deprotection steps, the furan 18 was converted to seco acid 3 by using the furan oxidation protocol mentioned above, and lactonization of 3 with Cl₃C₆H₂COCl, Et₃N, and DMAP afforded 22 (MOM ether of 2), which upon deprotection with TFA produced 2. Transformation of 22 to macrosphelide A (1) was then investigated. Although the chelation-controlled reduction of 22 should afford the desired anti alcohol 24, Zn(BH₄)₂ at < - 90 °C gave a 2～1:1 mixture of anti/syn alcohols. On the contrary, reduction with NaBH₄ in MeOH at -15 °C produced the syn isomer 23 with > 10:1 diastereoselectivity. Mitsunobu inversion of the resulting C(14)-hydroxyl group and deprotection of the MOM group with TFA afforded 1. Similarly, reduction of 2 with NaBH₄ afforded the C(14)-epimer of 1 stereoselectively. The observed stereoselectivity in the reductions of 22 and 2 could be explained on the basis of computer-assisted calculation, which showed presence of the low-energy conformers responsible for the stereoselective reduction. In addition, conversion of 2 to 1 was established, for the first time.

Full text of DOI:10.1021/jo001495d

J . Org. Chem. 2001, 66, 2011-2018
2011
F u r a n Rin g Oxid a tion Str a tegy for th e Syn th esis of
Ma cr osp h elid es A a n d B
Yuichi Kobayashi,*,† G. Biju Kumar,† Tomoaki Kurachi,† Hukum P. Acharya,†
Takashi Yamazaki,*,‡ and Tomoya Kitazume‡
Department of Biomolecular Engineering and Department of Bioengineering, Tokyo Institute of
Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, J apan
ykobayas@bio.titech.ac.jp
Received October 18, 2000
By using the convenient protocol for conversion of 2-substituted furans into 4-oxo-2-alkenoic acids
((i) NBS, (ii) NaClO2), macrosphelide B (2) was synthesized from furyl alcohol 5 (>98% ee) and
acid 6 (99% ee). The protocol was first applied to the PMB ether of 5 to afford acid 13b. On the
other hand, DCC condensation of acid 6 with 5 gave 16 after deprotection of the TBS group.
Condensation was again carried out between 13b and 16 to furnish the key ketone 17, which upon
reduction with Zn(BH4)2 afforded anti alcohol 18 stereoselectively (15:1). After protection/
deprotection steps, the furan 18 was converted to seco acid 3 by using the furan oxidation protocol
mentioned above, and lactonization of 3 with Cl3C6H2COCl, Et3N, and DMAP afforded 22 (MOM
ether of 2), which upon deprotection with TFA produced 2. Transformation of 22 to macrosphelide
A (1) was then investigated. Although the chelation-controlled reduction of 22 should afford the
desired anti alcohol 24, Zn(BH4)2 at <-90 °C gave a 2∼1:1 mixture of anti/syn alcohols. On the
contrary, reduction with NaBH4 in MeOH at -15 °C produced the syn isomer 23 with >10:1
diastereoselectivity. Mitsunobu inversion of the resulting C(14)-hydroxyl group and deprotection
of the MOM group with TFA afforded 1. Similarly, reduction of 2 with NaBH4 afforded the C(14)-
epimer of 1 stereoselectively. The observed stereoselectivity in the reductions of 22 and 2 could be
explained on the basis of computer-assisted calculation, which showed presence of the low-energy
conformers responsible for the stereoselective reduction. In addition, conversion of 2 to 1 was
established, for the first time.
In tr od u ction
constitute the major part of the lactone backbones.3 These
Recently, we published a convenient two-step trans-
formation of 2-alkylfurans into 4-oxo-2-alkenoic acids (eq
1).1 This oxidative conversion proceeds under mild condi-
tions and is compatible with functional groups such as
carbonyl groups, acid labile protecting groups, and a free
hydroxyl group at a distal position. In addition to these
synthetic advantages, furans with a substituent at C(2)
are prepared by several methods quite easily. Conse-
quently, there is no doubt that this transformation
provides an attractive method for the synthesis of
biologically important molecules with 4-oxo- as well as
4-hydroxy-2-alkenoic acid moieties.2
natural products strongly inhibit the adhesion of human-
leukemia HL-60 cells to human-umbilical-vein endothe-
lial cells, while they do not inhibit the growth of other
mammalian cell lines or microorganisms.3a Accordingly,
macrosphelides A and B would serve as valuable leads
for development of a new drug against cancer,4 and
hence, a synthetic method for producing these molecules
and their analogues is urgently required.
Recently, Omura and Smith published a total synthesis
of 1,5 in which the vicinal hydroxyl groups were installed
on the sorbic ester by using AD-mix-R6 with 85% ee7 and
Among these molecules are macrosphelides A and B,
produced by Microsphaeropsis sp. FO-5050, in which 4,5-
dihydroxy- and 5-hydroxy-4-oxo-2-alkenoic acid moieties
(3) (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.;
Hiraoka, H.; Natori, M.; Komiyama, K.; Omura, S. J . Antibiot. 1996,
49, 95-98.
(4) (a) Omura, S.; Shiomi, K. Baiosaiensu to Indasutori 1996, 54,
633-635; Chem. Abstr. 1996, 125, 299445v. (b) Ishizuka, M. Nippon
Nogei Kagaku Kaishi 1997, 71, 527-529; Chem. Abstr. 1997, 127,
12893x.
† Department of Biomolecular Engineering.
‡ Department of Bioengineering.
(1) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J . Org.
Chem. 1998, 63, 7505-7515.
(2) (a) Boeckman, R. H., J r.; Goldstein, S. W. In The Total Synthesis
of Natural Products; ApSimon, J ., Ed.; Wiley: New York, 1988; Vol.
7, Chapter 1. (b) Asaoka, M.; Takei, H. J . Synth. Org. Chem. J pn. 1986,
44, 819-828.
10.1021/jo001495d CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/23/2001

2012 J . Org. Chem., Vol. 66, No. 6, 2001
Kobayashi et al.
Sch em e 1. Retr osyn th esis of Ma cr osp h elid e B (2)
Sch em e 2
Although the most reliable reagent for the anti selective
reduction in general is Zn(BH4)2,9 rather low diastereo-
selectivities have been reported for R-alkoxy- (or R-hy-
droxy-)ethyl alkyl ketones.10 Ketone 4 is one such com-
pound. Consequently, reduction of the model ketones
7a -c with R ) THP, MOM, PMB (p-MeOC6H4CH2) was
investigated (Scheme 2) in order to obtain practical
information about the protective group R2 in the real
ketone 4. The choice of R2 is expected to be crucial in
order to realize high stereoselectivity. In addition, R2
should be appropriate for the subsequent routine trans-
formation to 3 involving protection of the alcohol at C(8)
and deprotection at C(9).
Racemic ketones 7a -c, prepared in reasonable yields
by the sequence summarized in Scheme 2, were used for
the reduction. When an ethereal solution of Zn(BH4)2 was
added to THP ether 7a in Et2O at -78 °C or even below
-90 °C, a mixture of 8a and 9a was produced in a 1:1
ratio.11 However, MOM and PMB ethers 7b and 7c
furnished 8b and 8c with acceptable ratios of ca. 10:1 in
83% and 91% yields, respectively.12 Next, protection of
the resulting hydroxyl group in 8b and 8c was examined.
Attempted protection of 8b with PMBCl and NaH in THF
afforded many products, whereas reaction of 8c with
MOMCl and i-Pr2NEt furnished the corresponding MOM
ether in good yield. On the basis of these results and with
the expectation that PMB can be removed by DDQ
the subsequent inversion of one of the hydroxyl groups.
They also attempted conversion of 1 into 2 by PDC
oxidation, which resulted in rather low regioselectivity
and efficiency. These results prompted us to conceive an
alternative route involving a synthesis of 2 and subse-
quent hydride reduction of the intermediate to furnish
1. Since 2 possesses one less chiral center than 1,
synthesis of 2 would be accomplished more easily than
1. Moreover, we expected high diastereoselectivity in the
reduction of 2 due to the conformational bias provided
by the macrocycle, producing either the desired (14R)
alcohol or the (14S) isomer. In practice, this idea has
proved to be correct as was reported previously in a
communication.8 Herein, we disclose the synthesis of 1
and 2 in detail. In addition, the conversion of 2 to 1 is
presented, and the stereoselective reduction of the mac-
rocyclic ketones is discussed with the stable conformers
obtained by a computer-assisted calculation.
Resu lts a n d Discu ssion
Syn th esis of Ma cr osp h elid e B. Keeping the furan
methodology in mind, furan 4 was proposed as the key
intermediate for synthesis of macrosphelide B (2) (Scheme
1) and was dissected into the two starting compounds 5
and 6, both of which are easily produced by several
methods. Furyl alcohol 5 serves as the C(5)-O(10) and
C(11)-O(16) moieties (macrosphelide numbering), while
acid 6 provides the C(1)-O(4) moiety. We envisioned that
the chelation-controlled reduction of ketone 4 would
produce the desired anti stereochemistry in the C(8)-
C(9) region, and that subsequent oxidation of the furan
ring would produce the C(11)-C(14) unit of seco acid 3.
(9) (a) Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. Chem. Pharm.
Bull. 1984, 32, 1411-1415. (b) Oishi, T.; Nakata, T. Acc. Chem. Res.
1984, 17, 338-344.
(10) (a) Reduction of R-hydroxyethyl and R-alkoxyethyl alkyl ketones
MeCH(OR1)-C(dO)-R2 with Zn(BH4)2 has been reported occasionally,10b,c
where selectivity of anti and syn alcohols is somewhat lower than that
of other ketones of R3CH(OR1)-C(dO)-R2 (R3 > Me). (b) Nakata, T.;
Tanaka, T.; Oishi, T. Tetrahedron Lett. 1983, 24, 2653-2656. (c)
Takahashi, T.; Miyazawa, M.; Tsuji, J . Tetrahedron Lett. 1985, 26,
5139-5142.
(11) To indicate the relative stereochemistry in the compounds, one
enantiomer for each compound is shown for convenience.
(12) The anti stereochemistry of 8c was confirmed by the 1H NMR
spectra (300 MHz, CDCl3) of ethyl 4,5-dihydroxy-2E-hexenoate derived
from 8c [(1) DDQ, CH2Cl2/H2O (19:1), rt; (2) NaH (cat.), EtOH, rt].
The authentic sample and its syn isomer were prepared by epoxidation
of ethyl sorbate followed by acid hydrolysis (Hirama, M.; Shigemoto,
T.; Yamazaki, Y.; Ito, S. Tetrahedron Lett. 1985, 26, 4133-4136) or
OsO4-catalyzed dihydroxylation of ethyl sorbate (Hirama, M.; Shige-
moto, T.; Ito, S. Tetrahedron Lett. 1985, 26, 4137-4140). The 1H NMR
signals (in CDCl3) characteristic of the anti diol are as follows: δ 3.93-
4.02 (m, 1H), 4.32-4.38 (m, 1 H), 6.12 (dd, J ) 16, 2 Hz, 1 H), 6.94
(dd, J ) 16, 5 Hz, 1 H). Those of the syn diol are: δ 3.66-3.77 (m, 1
H), 4.03-4.11 (m, 1 H), 6.14 (dd, J ) 16, 2 Hz, 1 H), 6.92 (dd, J ) 16,
5 Hz, 1 H).
(5) 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.
(6) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-
M.; Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768-2771. (b) Kolb,
H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483-2547.
(7) In theory, this selectivity lowers yield and the product ratio of
the desired stereoisomer over the other isomers in the step of joining
the two diol parts, though details are not given in their communication.
(8) Kobayashi, Y.; Kumar, B. G.; Kurachi, T. Tetrahedron Lett. 2000,
41, 1559-1563.

Synthesis of Macrosphelides A and B
J . Org. Chem., Vol. 66, No. 6, 2001 2013
Sch em e 3. Syn th esis of Ma cr osp h elid e B (2)a
a
Reagents and conditions: (a) t-BuOOH, Ti(OPr)4, D-(-)-DIPT, 38% based on rac-5; (b) NaH, PMBCl, 93%; (c) NBS, acetone/H2O, 10:1,
-15 °C, 1 h then furan, C5H5N, rt, 6 h, 74%; (d) NaClO2, MeC(H)dCMe2, 70%; (e) TBSCl, imidazole, 98%; (f) 1 N NaOH, MeOH, 93%; (g)
DCC, DMAP, CSA, rt, overnight, 98% for 15 and 92% for 17; (h) TBAF, THF, 0 °C, 24 h, 73%; (i) Zn(BH4)2, Et2O, <-90 °C, 70%; (j)
MOMCl, i-Pr2NEt, CH2Cl2, 88%; (k) DDQ, CH2Cl2/H2O, 93%; (l) and (m) conditions similar to (c) and (d); (n) Cl3C6H2COCl, NEt3 then
DMAP, toluene, 40 °C, 5 h, 40% from 20; (o) TFA/CH2Cl2, 1:1, rt, 1.5 h, 92%.
without affecting the MOM-oxy group, the MOM and
PMB groups were chosen as the R1 and R2 groups,
respectively, in the synthesis (Scheme 1).
17 was carried out with Zn(BH4)2 in Et2O at -78 °C.
Unfortunately, a mixture of 18 and its C(8)-epimer epi-
18 (structure not shown) was produced in a ratio of 2:1.
A lower temperature, below -90 °C, slightly improved
the ratio (3:1). It is likely that Zn{BHn(OR)4-n}2, which
was probably formed in the early stage of the reduction,
somehow participated in the reduction of 1718 without
chelation to the oxygens present in the PMB-oxy and
carbonyl groups, thus furnishing the mixture of 18 and
epi-18. This hypothesis prompted us to examine the
reduction with intact Zn(BH4)2. Thus, an ethereal solu-
tion of ketone 17 was slowly added to excess Zn(BH4)2 in
Et2O at <-90 °C, and this procedure was found to be
successful, producing alcohol 18 and epi-18 with a practi-
cal selectivity of 15:1 in 70% yield. The anti stereochem-
istry in the resulting diol part was tentatively assigned
at this stage and was proved by the total synthesis of 2.
Reaction of alcohol 18 with MOMCl followed by depro-
tection of the PMB group with DDQ furnished alcohol
20 in 82% yield. Since a hydroxyl group has been shown
to be compatible with the furan ring oxidation, 20 was
submitted to this transformation to afford the key acid
3. Lactonization of crude 3 was carried out under the
conditions of Yamaguchi19 at 40 °C to produce lactone
22 in 40% yield from the furan 20. Finally, deprotection
of the MOM group with TFA in CH2Cl2 furnished 2 in
Synthesis of macrosphelide B (2) is presented in
Scheme 3, in which alcohol 5 of >98% ee13 was prepared
by the kinetic resolution of the corresponding racemic
alcohol rac-514a using the Sharpless asymmetric epoxi-
dation reagent15 in 38% yield based on rac-5. The
hydroxyl group of 5 was protected as PMB ether, and
oxidation of the furan ring in the resulting ether 12
produced γ-keto acid 13b, the C(5)-O(10) segment of 2,
in 48% yield. Intermediate 16 was prepared from alcohol
1416 of 99% ee.13 Reaction of 14 with TBSCl followed by
ester hydrolysis afforded acid 6 in 91% yield. Condensa-
tion of acid 6 and alcohol 5 with DCC in the presence of
DMAP and CSA5,17 produced ester 15, which upon
deprotection of the TBS group yielded ester alcohol 16
in 73% yield. Condensation was again performed with
acid 13b and alcohol 16 with DCC to afford 17 in 92%
yield, which is the key intermediate 4 with R2 ) PMB
proposed in Scheme 1.
On the basis of the results obtained with the model
ketones 7 in Scheme 2 (vide supra), reduction of ketone
(13) Enantiomeric excess (ee) was determined by 1H NMR spectros-
copy of the derived MTPA ester.
(14) (a) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J . Org.
Chem. 1989, 54, 2085-2091. Other methods: (b) Drueckhammer, D.
G.; Barbas, C. F., III; Nozaki, K.; Wong, C.-H. J . Org. Chem. 1988, 53,
1607-1611. (c) Sammes, P. G.; Thetford, D. J . Chem. Soc., Perkin
Trans. 1 1988, 111-123.
good yield: [R]24 ) +9.1 (c 0.154, MeOH) [lit.3b [R]23
)
D
D
+4.10 (c 0.99, MeOH); lit.5 [R]24D ) +10.0 (c 0.39, MeOH)].
1
The H NMR (300 MHz) and 13C NMR (75 MHz) spectra
(15) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.;
Ikeda, M.; Sharpless, K. B. J . Am. Chem. Soc. 1981, 103, 6237-6240.
(b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780.
(16) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J . Am. Chem. Soc. 1987, 109, 5856-
5858.
(18) Chelation of Zn{BHn(OR)4-n
} to the other oxygen(s) present
2
in 17 perhaps accelerates the reduction, but nonstereoselectively, since
the reverse mode did not change the selectivity in the reduction of the
simple ketones shown in eq 2.
(19) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(17) Boden, E. P.; Keck, G. E. J . Org. Chem. 1985, 50, 2394-2395.

2014 J . Org. Chem., Vol. 66, No. 6, 2001
Kobayashi et al.
Sch em e 4. Syn th esis of Ma cr osp h elid e A (1)
Sch em e 5. Con ver sin of Ma cr osp h elid e B to A
of synthetic 2 were identical with the data reported in
the literature.3b,5
the two hydroxyl groups at C(8) and C(14) in 25 by the
Mitsunobu inversion or by protection seems difficult, the
route shown in Scheme 4 is definitely the best choice to
obtain 1 from ketone 22.
Syn th esis of Ma cr osp h elid e A fr om th e MOM
Eth er of Ma cr osp h elid e B. In theory, reduction of
MOM ether 22 with a hydride reagent which coordinates
to the oxygen atoms in the Od(14)-C(15)-O(16) part
should afford alcohol 24, the precursor of macrosphelide
A (1). However, attempted reduction of 22 with Zn(BH4)2
in Et2O even at <-90 °C furnished 24 with a low
stereoselection of 2∼1:1. In contrast, reduction with
NaBH4 in MeOH at -15 °C was found to produce the
14-epi alcohol 23 in 74% yield with high diastereoselec-
tivity of >10:1 (Scheme 4). These results strongly indicate
the existence of stable conformer(s) for 22 in which the
undesired side of the carbonyl group (re face) is less
congested, thus allowing the hydride attack to afford 23
selectively. The origin of the stereoselective reduction is
discussed below with the stable conformer(s) of 22,
obtained by computer-assisted calculation. Finally,
Mitsunobu inversion20 of alcohol 23 followed by metha-
nolysis of the resulting formate ester and deprotection
of the MOM group with TFA afforded 1 in 70% yield. The
1H NMR and 13C NMR spectra of synthetic 1 were in good
Con ver sion of Ma cr osp h elid e B to Ma cr osp h elid e
A. Reaction of macrosphelide B (2) with MOMCl in the
presence of i-Pr2NEt in CH2Cl2 at room temperature was
somewhat slow, but was completed after 2.5 days to
afford the MOM ether 22 in 75% yield (Scheme 5). The
1H NMR spectrum of 22 showed no epimerization had
occurred during the reaction. Since ether 22 was already
converted into macrosphelide A (1) (see Scheme 4), this
successful protection establishes the conversion of 2 to
1. In the future, this conversion would be important when
2 is prepared by another method such as a biosynthetic
one.
Con for m a tion a l An a lysis for th e Ster eoselective
R ed u ct ion . Stable conformers of macrosphelide B (2)
and the MOM ether 22 were calculated by using the
software Conflex,21,22 known as one of the most potent
and efficient programs for automatic generation-opti-
mization of low energy conformations. As listed in Table
1, 23 independent structures were eventually found
within a range of 2 kcal/mol energy difference from the
global minimum conformation.
agreement with those reported:3b,5 [R]30 ) +85 (c 0.046,
D
MeOH) [lit.3b [R]23 ) +84.1 (c 0.59, MeOH); lit.5 [R]27
D
D
) +82 (c 0.10, MeOH)]. Similarly, treatment of 14-epi
alcohol 23 with TFA furnished 14-epi macrosphelide A
(i.e., 25) in 86% yield (eq 2).
The partial structures of the most and the second most
stable conformers of macrosphelide B (2), MB-1 and MB-
2, respectively, are shown in Figure 1 as representative
examples for obtaining a clearer picture around the Od
C(14) group where the diastereoselective reduction was
experimentally observed.23 In MB-1, the re and si faces
are blocked efficiently by the macrocyclic ring and the
(21) Conflex,22 implemented in the CAChe Worksystem (version
4.1.1; Fujitsu Limited, J apan), was performed for generation of various
conformers which were automatically optimized with Mechanics
included in the same system until convergence to 0.00001 kcal/mol
was attained. This sequence was carried out four times with the search
limit of 0.001% to furnish 740 conformers.
Next, macrosphelide B (2) as such was subjected to the
reduction with NaBH4, which resulted in production of
the 14-epimer of 1 (i.e., 25) with high stereoselectivity
(>20:1) in 82% yield (Scheme 5), as was observed in the
case of 22. This result indicates that the stable and/or
reactive conformer(s) of 2 is quite similar to that of 22.
A bias for the stereoselective reduction is discussed with
the stable conformers of 2 below. Since differentiation of
(22) (a) Suginome, H.; Kondoh, T.; Gogonea, C.; Singh, V.; Goto, H.;
Osawa, E. J . Chem. Soc., Perkin Trans. 1 1995, 69-81. (b) Goto, H.;
Kawashima, Y.; Kashimura, M.; Morimoto, S.; Osawa, E. J . Chem. Soc.,
Perkin Trans. 2 1993, 1647-1654. (c) Goto, H.; Osawa, E. THEOCHEM
1993, 285, 157-168. (d) Shimazaki, K.; Mori, M.; Okada, K.; Chuman,
T.; Kuwahara, S.; Kitahara, T.; Mori, K.; Goto, H.; Osawa, E.;
Sakakibara, K.; Hirota, M. J . Chem. Soc., Perkin Trans. 2 1993, 1167-
1173. (e) Shimazaki, K.; Mori, M.; Okada, K.; Chuman, T.; Goto, H.;
Osawa, E.; Sakakibara, K.; Hirota, M. J . Chem. Soc., Perkin Trans. 2
1992, 811-818.
(23) Ball and stick models of MB-1 and MB-2 are shown in Figure
2 in the Supporting Information.
(20) Mitsunobu, O. Synthesis 1981, 1-28.

Synthesis of Macrosphelides A and B
J . Org. Chem., Vol. 66, No. 6, 2001 2015
Ta ble 1. Ca lcu la ted En er gies a n d P r op er ties of
Ma cr osp h elid e B (MB) w ith in 2 k ca l/m ol fr om th e Globa l
Min im u m Str u ctu r e
conformers of the MB-2 type, thus furnishing overall
stereoselective reduction to yield 25, the epimer of 1, as
shown in Scheme 5.
dihedral anglesb (deg)
∆E
populationa
(%)
Because the MOM group at C(8) of 22 significantly
increases the number of possible conformers, we have
performed a rough conformational estimation for the
MOM ether 22 to find 18 different conformers within a
2 kcal/mol range from the global minimum (data not
shown). In this case, all of the low-energy conformers take
Felkin-Anh-type conformations similar to MB-2 due to
absence of the hydroxyl group at C(8). This computational
result is consistent, at least qualitatively, with the
stereoselective production of the epimeric alcohol 23
(Scheme 4).
conformer (kcal/mol)
A
B
C
MB-1
MB-2
MB-3
MB-4
MB-5
MB-6
MB-7
MB-8
0.000
0.157
0.247
0.379
0.540
0.562
0.565
0.699
0.803
0.810
0.905
1.049
1.095
1.293
1.364
1.435
1.446
1.707
1.888
1.909
1.948
1.952
1.999
17.7
13.3
11.2
8.8
6.5
6.3
6.2
4.9
4.0
4.0
3.3
2.6
2.4
1.6
1.4
1.3
1.2
0.8
0.5
0.5
0.5
0.5
0.4
-131.1 -13.9
97.1
-81.5
100.9
-86.4
-82.7
-87.0
-89.6
142.9
37.3 157.9
-126.9
-9.9
32.2 152.7
35.8 156.4
31.6 151.7
29.8 149.9
-95.3
24.1
MB-9
-6.0 112.4 -131.6
MB-10
MB-11
MB-12
MB-13
MB-14
MB-15
MB-16
MB-17
MB-18
MB-19
MB-20
MB-21
MB-22
MB-23
25.5 145.2
26.2 146.3
-94.1
-93.2
128.6
-109.3
11.9
As described above, Zn(BH4)2-mediated reduction of 22
resulted in the unexpectedly low diastereofacial selectiv-
ity of 2-1:1, though the OdC(14)-C(15)-O(16) moiety
was, in principle, a site to form chelation with Zn2+.9 In
the conformers with up to 10 kcal/mol higher energy
levels from the global minimum, the two oxygen atoms
were found to be placed separately, thus preventing the
chelation. Instead, some conformers have approximately
3.3-3.4 Å distance27 between the two carbonyl oxygen
atoms OdC(14) and OdC(1), and this alignment is not
suitable for providing a steric bias for the stereoselective
reduction, thus furnishing a mixture of 24 and 23 in the
2∼1:1 ratio (vide supra).
16.7 135.9 -102.9
-96.9
-124.8
22.5
-3.2
141.2
112.3
90.9
-88.4
-89.1
-137.8 -20.5
29.8 149.6
30.2 150.3
8.8 129.8 -110.3
29.9 149.8
-89.7
139.2
93.1
-98.8
20.6
-135.3 -18.1
37.2 158.1
-82.0
a
b
Calculated at 0 °C. A: OdC(14)-C(15)-CH3. B: OdC(14)-
C(15)-H. C: OdC(14)-C(15)-O(16).
Con clu sion
In summary, we have established a stereoselective
synthesis of macrosphelide A (1) and macrosphelide B
(2). Since the furan ring-oxidation is not only independent
of a substituent on the ring but also compatible with
protective and/or functional groups, especially a free OH
group, the method is amenable to synthesis of other
macrosphelides.28,29 For example, macrosphelide E29 could
be synthesized starting with methyl (R)-3-hydroxybu-
tanoate, and other macrosphelides similarly. Further-
more, synthesis of analogues of 1 and 2 would spur
biochemical research of these important compounds in
development of a drug against cancer.
(24) It has been reported that nucleophilic reactions with 2-fluoro-
(X ) F)25 or 2-chloropropionaldehyde (X ) Cl)26 were anticipated by
ab initio calculations to occur predominantly via conformation A rather
than conformer B.
F igu r e 1. Partial structures of the most and the second most
stable conformers of macrosphelide B (2).
Me group at C(15), respectively. On the other hand, the
re face of MB-2 is sterically less congested, while the si
face is encumbered by the ring (the Felkin-Anh-type
conformation between C(14) and C(15), though slightly
distorted). In other words, the OdC(14) group in MB-2
is susceptible to the hydride attack from the re face, while
somewhat higher activation energy is required when the
hydride attacks MB-1 from either face.24-26 Consequently,
MB-2 and the conformers of the MB-2 type in Table 1
(e.g., MB-4, -5, -6, -7, etc.) are consumed faster than other
conformers with high stereoselectivity. On the contrary,
conformer MB-1 and the other conformers of the MB-1
type (e.g., MB-3) first undergo conversion to the reactive
(25) (a) Wong, S. S.; Paddon-Row, M. N. J . Chem. Soc., Chem.
Commun. 1991, 327-330. (b) Wong, S. S.; Paddon-Row, M. N. J . Chem.
Soc., Chem. Commun. 1990, 456-458.
(26) Frenking, G.; Ko¨hler, K. F.; Reetz, M. T. Tetrahedron 1991, 47,
9005-9018.
(27) Because the van der Waals radius of oxygen and the size of
tetracoordinated Zn2+ were reported to be 1.52 and 0.6 Å, respectively,
the distance of ca. 3.3-3.4 Å between two carbonyl oxygens would be
sufficient for the bidentate interaction (seven-membered chelation).
See, Bondi, A. J . Phys. Chem. 1964, 68, 441-451 for the van der Waals
radii, and Dean, J . A. Lange’s Handbook of Chemistry, 14th ed.;
MacGraw-Hill, Inc.; New York, 1992 for the ionic radius.
(28) Takamatsu, S.; Hiraoka, H.; Kim, Y.-P.; Hayashi, M.; Natori,
M.; Komiyama, K.; Omura, S. J . Antibiot. 1997, 50, 878-880.
(29) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura,
E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215-8218.

2016 J . Org. Chem., Vol. 66, No. 6, 2001
Kobayashi et al.
(2E,5S)-5-(4-Meth oxyben zyloxy)-4-oxo-2-h exen oic Acid
(13b). To a solution of aldehyde 13a (1.54 g, 6.20 mmol) and
2-methyl-2-butene (6.70 mL, 62.0 mmol) in t-BuOH (14 mL)
and the phosphate buffer (7 mL, pH 3.6) was added a solution
of NaClO2 (841 mg, 80% purity, 7.44 mmol) in H2O (2 mL).
The reaction mixture was stirred at room temperature for 2
h. Most of the solvent was removed by using a vacuum pump,
and the residue was diluted with EtOAc (10 mL) and brine
(10 mL). The mixture was stirred vigorously, and the layers
were separated. The aqueous layer was acidified to pH 4 with
1 N HCl and extracted with EtOAc several times. The
combined extracts were dried and evaporated to furnish a
mixture of acid 13 and Me2C(Cl)CHClMe. The mixture was
used for the next reaction without further purification (1.73
Exp er im en ta l Section
Gen er a l Meth od s. Infrared (IR) spectra are reported in
wavenumbers (cm-1). Unless otherwise noted, H NMR (300
1
MHz) and 13C NMR (75 MHz) spectra were measured in CDCl3
using SiMe4 (δ ) 0 ppm) and the center line of CDCl3 triplet
(δ ) 77.1 ppm) as internal standards, respectively. The
following solvents were distilled before use: THF (from Na/
benzophenone), Et2O (from Na/benzophenone), and CH2Cl2
(from CaH2). Methyl (S)-3-hydroxybutanoate was kindly of-
fered by Takasago International Corporation, J apan. The
phosphate buffer of pH 3.6 was prepared by mixing Na2HPO4‚
12H2O (2.31 g), citric acid (1.31 g), and H2O (98.6 g). Routinely,
organic extracts were dried over MgSO4 and concentrated
using a rotary evaporator, and residues were purified by
chromatography on silica gel.
1
g, calculated yield of 13b by H NMR integration: 70%). The
1H NMR signals for 13b: δ 1.37 (d, J ) 7 Hz, 3 H), 3.80 (s, 3
H), 4.10 (q, J ) 7 Hz, 1 H), 4.47 (s, 2 H), 6.76 (d, J ) 16 Hz,
1 H), 6.88 (d, J ) 9 Hz, 2 H), 7.25 (d, J ) 9 Hz, 2 H), 7.49 (d,
J ) 16 Hz, 1 H).
(S)-1-(2-F u r yl)eth a n ol (5). The title compound was pre-
pared according to the literature procedure.14a Briefly, a
solution of t-BuOOH in CH2Cl2 (5.67 mL, 4.72 M, 26.8 mmol)
was added to a mixture of rac-5 (5.00 g, 44.6 mmol), powdered
4 Å molecular sieves (1.5 g), Ti(O-i-Pr)4 (2.64 mL, 8.93 mmol),
D-(-)-DIPT (2.28 mL, 10.7 mmol), and CH2Cl2 (20 mL) at -30
°C. The mixture was stirred at -15 °C for 16 h and treated
with Me2S (1.99 mL, 27.2 mmol) at -15 °C for 30 min. Aqueous
tartaric acid (5%, 10 mL), NaF (20 g), and Et2O (100 mL) were
added to the mixture. The resulting mixture was stirred
vigorously at room temperature for 2 h and filtered through a
pad of Celite. The filtrate was concentrated, and the crude
product dissolved in Et2O (100 mL) was treated with 3 N
NaOH (50 mL) for 30 min at 0 °C with vigorous stirring to
give 5 (1.92 g, 38% based on rac-5) after chromatography. The
1H NMR spectrum of 5 was identical with that reported,14b,c
and the enantiomeric excess (ee) was determined to be >98%
by 1H NMR spectroscopy of the corresponding MTPA ester. 5:
Meth yl (S)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]bu ta n oa te.
A solution of methyl (S)-3-hydroxybutanoate (99% ee, 3.00 g,
25.4 mmol), imidazole (2.59 g, 38.1 mmol), and TBSCl (4.59 g,
30.5 mmol) in DMF (50 mL) was stirred at room temperature
overnight and poured into saturated NaHCO3 with Et2O. The
resulting mixture was stirred vigorously for 30 min. The layers
were separated, and the aqueous layer was extracted with
Et2O twice. The combined extracts were dried and concen-
trated to give an oil, which was subjected to chromatography
(hexane/EtOAc) to furnish the title compound (5.75 g, 98%):
bp 100 °C (5 Torr); [R]29 ) +31 (c 0.674, CHCl3); IR (neat)
D
1
1743, 1086, 837, 777 cm-1; H NMR δ 0.03 (s, 3 H), 0.05 (s, 3
H), 0.84 (s, 9 H), 1.18 (d, J ) 6 Hz, 3 H), 2.37 (dd, J ) 15, 5
Hz, 1 H), 2.47 (dd, J ) 15, 8 Hz, 1 H), 3.64 (s, 3 H), 4.21-4.32
(m, 1 H); 13C NMR δ 172.3, 65.9, 51.5, 44.8, 25.7, 23.9, 17.9,
-4.6, -5.1. Anal. Calcd for C11H24O3Si: C, 56.85; H, 10.41.
Found: C, 56.47; H, 10.48.
bp 75-80 °C (5 Torr); [R]28D ) -22 (c 0.506, CHCl3) [lit.14a [R]25
) +20.8 (c 1.27, CHCl3)] for the enantiomer of >95% ee.
D
(S)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]bu ta n oic Acid (6).
A solution of the above ester (4.30 g, 18.5 mmol) and 1 N NaOH
(93 mL, 93 mmol) in MeOH (160 mL) was stirred at room
temperature for 3 h. Most of the MeOH was removed by
evaporation, and the residue was extracted with Et2O. The
aqueous layer was acidified to pH 4 by addition of 1 N HCl,
and the mixture was extracted with Et2O three times. The
combined extracts were dried and concentrated to afford an
oil, which was subjected to chromatography (hexane/Et2O) to
afford 6 (3.76 g, 93%). The IR (neat) and 1H NMR spectra of
synthetic 6 were identical with those reported:30a,b [R]27D ) +15
(c 1.47, CHCl3) [lit.30a [R]D ) +11.9 (c 1.29, CHCl3) for 6 of
(S)-1-(2-F u r yl)-1-(4-m eth oxyben zyloxy)eth a n e (12). To
an ice-cold suspension of oil-free NaH, prepared from NaH (576
mg, 50% dispersion in mineral oil, 12 mmol) by washing with
hexane, in DMF (10 mL) was added 5 (0.89 g, 8.0 mmol), and
the reaction mixture was stirred at room temperature for 1 h.
p-Methoxybenzyl chloride (1.41 mL, 10.4 mmol) was added to
the mixture. After 2 h, brine was added to it and the product
was extracted with Et2O twice. The combined extracts were
dried and concentrated to leave a residue, which was subjected
to chromatography (hexane/EtOAc) to furnish 12 (1.73 g,
93%): bp 175 °C (1 Torr); [R]29 ) -117 (c 0.798, CHCl3); IR
D
(neat) 1612, 1585, 1514, 1248, 818, 742 cm-1; 1H NMR δ 1.52
(d, J ) 7 Hz, 3 H), 3.79 (s, 3 H), 4.33 (d, J ) 11 Hz, 1 H), 4.46
(d, J ) 11 Hz, 1 H), 4.53 (q, J ) 7 Hz, 1 H), 6.27 (d, J ) 3 Hz,
1 H), 6.34 (dd, J ) 3, 2 Hz, 1 H), 6.86 (d, J ) 9 Hz, 1 H), 7.25
(d, J ) 9 Hz, 1 H), 7.40 (br s, 1 H); 13C NMR δ 159.3, 155.9,
142.2, 130.6, 129.5, 113.9, 110.1, 107.1, 69.9, 69.4, 55.3, 19.9.
Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.36;
H, 6.99.
85% ee; lit.30b [R]26 ) +14.3 (c 1.83, CHCl3) for 6 of 80% ee];
D
13C NMR δ 177.0, 65.7, 44.2, 25.7, 23.6, 17.9, -4.6, -5.2.
(2S,6S)-6-[(ter t-Bu t yld im et h ylsilyl)oxy]-2-(2-fu r yl)-3-
oxa -4-h ep ta n on e (15). To a solution of acid 6 (3.27 g, 15.0
mmol) in CH2Cl2 (22 mL) were added alcohol 5 (>98% ee, 1.29
g, 11.5 mmol), DMAP (342 mg, 2.80 mmol), CSA (318 mg, 1.37
mmol), and DCC (3.56 g, 17.3 mmol). The reaction was
continued overnight at room temperature and quenched with
H2O. The resulting mixture was extracted with CH2Cl2, and
the extract was dried and concentrated to give a residue, which
was purified by chromatography (hexane/EtOAc) to furnish 15
(3.52 g, 98%): bp 120 °C (1 Torr); [R]29D ) -56 (c 0.68, CHCl3);
IR (neat) 1738, 1178, 1005, 837, 777 cm-1; 1H NMR δ 0.02 (s,
3 H), 0.04 (s, 3 H), 0.84 (s, 9 H), 1.17 (d, J ) 6 Hz, 3 H), 1.57
(d, J ) 7 Hz, 3 H), 2.36 (dd, J ) 15, 6 Hz, 1 H), 2.48 (dd, J )
15, 7 Hz, 1 H), 4.21-4.32 (m, 1 H), 5.95 (q, J ) 7 Hz, 1 H),
6.29-6.33 (m, 2 H), 7.36 (dd, J ) 2, 1 Hz, 1 H); 13C NMR δ
171.0, 153.7, 142.6, 110.3, 107.9, 65.7, 65.0, 44.9, 25.7, 23.8,
18.3, 17.9, -4.6, -5.1. Anal. Calcd for C16H28O4Si: C, 61.50;
H, 9.03. Found: C, 61.77; H, 9.11.
(2E,5S)-5-(4-Meth oxyben zyloxy)-4-oxo-2-h exen a l (13a ).
To a mixture of 12 (1.01 g, 4.35 mmol) and NaHCO3 (0.73 g,
8.7 mmol) in acetone/H2O (10:1, 11 mL) was added NBS (851
mg, 4.78 mmol) dissolved in acetone/H2O (10:1, 11 mL) at -15
°C, and the mixture was stirred for 1 h. Furan (0.32 mL, 4.4
mmol) and, after 30 min of stirring at -15 °C, pyridine (0.70
mL, 9.1 mmol) were added to the mixture. The resulting
mixture was stirred at room temperature for 6 h and poured
into 0.5 M CuSO4 solution (20 mL). The product was extracted
with Et2O three times, and the combined extracts were dried
and evaporated to furnish a residue, which on chromatography
(hexane/EtOAc) afforded aldehyde 13a (796 mg, 74%): [R]28
D
) -72 (c 0.522, CHCl3); IR (neat) 1693, 1612, 1514, 1250 cm-1
;
(2S,6S)-2-(2-F u r yl)-6-h yd r oxy-3-oxa -4-h ep ta n on e (16).
To an ice-cold solution of 15 (2.55 g, 8.16 mmol) in THF (80
mL) was added a solution of Bu4NF in THF (10.6 mL, 1 M,
1H NMR δ 1.39 (d, J ) 7 Hz, 3 H), 3.80 (s, 3 H), 4.13 (q, J )
7 Hz, 1 H), 4.46 (d, J ) 11 Hz, 1 H), 4.53 (d, J ) 11 Hz, 1 H),
6.81-6.91 (m, 3 H), 7.22-7.29 (m, 3 H), 9.72 (d, J ) 8 Hz, 1
H); 13C NMR δ 201.4, 193.2, 159.9, 139.8, 138.2, 130.1, 129.1,
114.0, 79.9, 72.1, 55.2, 17.3. Anal. Calcd for C14H16O4: C, 67.73;
H, 6.50. Found: C, 67.65; H, 6.61.
(30) (a) Liu, L.; Tanke, R. S.; Miller, M. J . J . Org. Chem. 1986, 51,
5332-5337. (b) Sakaki, J .; Kobayashi, S.; Sato, M.; Kaneko, C. Chem.
Pharm. Bull. 1989, 37, 2952-2960.

Synthesis of Macrosphelides A and B
J . Org. Chem., Vol. 66, No. 6, 2001 2017
10.6 mmol) dropwise. The solution was stirred at 0 °C for 24
h and poured into saturated NH4Cl with vigorous stirring. The
mixture was extracted with EtOAc twice, and the combined
extracts were dried and evaporated to give a residue, which
was purified by chromatography (hexane/EtOAc) to yield 16
1 H), 4.52 (s, 2 H), 4.64 (d, J ) 11 Hz, 1 H), 4.66 (d, J ) 11 Hz,
1 H), 5.29-5.41 (m, 1 H), 5.96 (q, J ) 7 Hz, 1 H), 6.01 (dd, J
) 16, 1.5 Hz, 1 H), 6.31 (br s, 2 H), 6.83-6.91 (m, 3 H), 7.25
(d, J ) 9 Hz, 2 H), 7.37 (dd, J ) 2, 1 Hz, 1 H); 13C NMR δ
169.5, 165.3, 159.3, 153.3, 145.7, 142.7, 130.5, 129.4, 123.2,
113.9, 110.3, 108.0, 95.1, 77.5, 76.2, 70.8, 67.5, 65.3, 55.7, 55.3,
41.0, 19.8, 18.0, 15.6. Anal. Calcd for C26H34O9: C, 63.66; H,
6.99. Found: C, 63.61; H, 7.10.
(1.18 g, 73%): [R]29 ) -91 (c 0.604, CHCl3); IR (neat) 3431,
D
1
1736, 744 cm-1; H NMR δ 1.20 (d, J ) 6 Hz, 3 H), 1.59 (d, J
) 7 Hz, 3 H), 2.43 (dd, J ) 16, 8 Hz, 1 H), 2.47 (dd, J ) 16, 5
Hz, 1 H), 3.2 (br s, 1 H), 4.13-4.25 (m, 1 H), 6.00 (q, J ) 7 Hz,
1 H), 6.33 (br s, 2 H), 7.38 (br s, 1 H); 13C NMR δ 172.0, 153.2,
142.6, 110.2, 107.9, 65.2, 64.1, 42.9, 22.3, 18.0. Anal. Calcd
for C10H14O4: C, 60.59; H, 7.12. Found: C, 60.60; H, 7.18.
(2S,6S,9E,12S)-6,12-Dim eth yl-2-(2-fu r yl)-14-(4-m eth ox-
yp h en yl)-3,7,13-tr ioxa -9-tetr a d ecen e-4,8,11-tr ion e (17).
To a mixture of alcohol 16 (197 mg, 0.997 mmol), crude acid
13 (658 mg, obtained as a mixture with Me2C(Cl)CHClMe,
calculated amount of 13 by 1H NMR integration: 429 mg, 1.62
mmol), DMAP (29 mg, 0.24 mmol), and CSA (30 mg, 0.13
mmol) in CH2Cl2 (15 mL) was added DCC (617 mg, 2.99 mmol)
and the mixture was stirred overnight. The reaction was
quenched by addition of H2O. The layers were separated, and
the aqueous layer was extracted with CH2Cl2. The combined
extracts were dried and evaporated to leave a residue, which
was purified by chromatography (hexane/EtOAc) to furnish 17
(2S,6S,9E,11R,12S)-2-(2-F u r yl)-12-h yd r oxy-11-(m et h -
oxym eth oxy)-3,7-d ioxa -9-tr id ecen e-4,8-d ion e (20). A solu-
tion of 19 (324 mg, 0.660 mmol) and DDQ (225 mg, 0.990
mmol) in CH2Cl2/H2O (18:1, 7 mL) was stirred at room
temperature for 30 min. The precipitate formed by the reaction
was removed by filtration, and the filtrate was concentrated
to furnish a gummy mass, which was purified by chromatog-
raphy (hexane/EtOAc) to yield 20 (226 mg, 93%): [R]29D ) -99
1
(c 0.564, CHCl3); IR (neat) 3464, 1738, 1720 cm-1; H NMR δ
1.16 (d, J ) 6 Hz, 3 H), 1.31 (d, J ) 6 Hz, 3 H), 1.56 (d, J ) 7
Hz, 3 H), 2.50 (br s, 1 H), 2.55 (dd, J ) 15, 6 Hz, 1 H), 2.69
(dd, J ) 15, 7 Hz, 1 H), 3.41 (s, 3 H), 3.88-4.01 (m, 1 H), 4.17
(ddd, J ) 6, 3.5, 1.5 Hz, 1 H), 4.67 (s, 2 H), 5.29-5.40 (m, 1
H), 5.97 (q, J ) 7 Hz, 1 H), 6.02 (dd, J ) 16, 1.5 Hz, 1 H),
6.30-6.35 (m, 2 H), 6.84 (dd, J ) 16, 6 Hz, 1 H), 7.38 (dd, J )
2, 1 Hz, 1 H); 13C NMR δ 169.5, 165.1, 153.4, 144.0, 142.7,
124.2, 110.3, 108.0, 95.5, 80.4, 69.2, 67.7, 65.4, 55.9, 41.0, 19.8,
18.1, 17.8. Anal. Calcd for C18H26O8: C, 58.37; H, 7.08.
Found: C, 58.31; H, 7.08.
(409 mg, 92%): [R]28 ) -85 (c 0.430, CHCl3); IR (neat) 1736,
D
1705, 1612, 1514, 822, 750 cm-1; 1H NMR δ 1.34 (d, J ) 6 Hz,
3 H), 1.36 (d, J ) 7 Hz, 3 H), 1.56 (d, J ) 7 Hz, 3 H), 2.57 (dd,
J ) 16, 6 Hz, 1 H), 2.70 (dd, J ) 16, 8 Hz, 1 H), 3.80 (s, 3 H),
4.08 (q, J ) 7 Hz, 1 H), 4.43 (d, J ) 11 Hz, 1 H), 4.47 (d, J )
11 Hz, 1 H), 5.33-5.46 (m, 1 H), 5.97 (q, J ) 7 Hz, 1 H), 6.31
(br s, 2 H), 6.72 (d, J ) 16 Hz, 1 H), 6.87 (d, J ) 9 Hz, 2 H),
7.24 (d, J ) 9 Hz, 2 H), 7.37 (br s, 1 H), 7.40 (d, J ) 16 Hz, 1
H); 13C NMR δ 201.2, 169.4, 164.7, 159.8, 153.2, 142.8, 134.9,
132.0, 130.0, 129.3, 114.0, 110.3, 108.1, 79.8, 71.9, 68.5, 65.4,
55.3, 40.8, 19.7, 18.0, 17.3. Anal. Calcd for C24H28O8: C, 64.85;
H, 6.35. Found: C, 64.68; H, 6.19.
MOM Eth er of Ma cr osp h elid e B (22). To a mixture of
20 (129 mg, 0.334 mmol) and NaHCO3 (56 mg, 0.67 mmol) in
acetone/H2O (10:1, 3.5 mL) was added NBS (77 mg, 0.43 mmol)
dissolved in acetone/H2O (10:1, 1.6 mL) at -15 °C. The mixture
was stirred at -15 °C for 2 h, and excess NBS was quenched
with furan (0.024 mL, 0.33 mmol) at -15 °C for 15 min. After
addition of pyridine (0.054 mL, 0.67 mmol), the mixture was
stirred at room temperature overnight and poured into 0.5 M
CuSO4 solution (5 mL). The product was extracted with EtOAc
twice. The combined extracts were dried and evaporated to
furnish a mixture of aldehyde 21 and succinimide, which was
used without separation for the next reaction. The 1H NMR
signals of 21: δ 1.17 (d, J ) 6 Hz, 3 H), 1.37 (d, J ) 6 Hz, 3
H), 1.47 (d, J ) 7 Hz, 3 H), 2.61-2.85 (m, 3 H), 3.40 (s, 3 H),
3.90-4.00 (m, 1 H), 4.12-4.20 (m, 1 H), 4.68 (br s, 2 H), 5.31-
5.47 (m, 2 H), 6.05 (dd, J ) 16, 1 Hz, 1 H), 6.84-6.98 (m, 2
H), 7.04 (d, J ) 16 Hz, 1 H), 9.79 (d, J ) 7 Hz, 1 H).
To a solution of the above aldehyde 21 dissolved in t-BuOH
(4 mL) were added the phosphate buffer (2 mL, pH 3.6),
2-methyl-2-butene (0.48 mL, 3.4 mmol), and NaClO2 (60 mg,
80% purity, 0.53 mmol) dissolved in H2O (1 mL). The reaction
mixture was stirred at room temperature for 2 h. Most of the
solvents were removed by using a vacuum pump, and the
residue was diluted with EtOAc and brine. The layers were
separated, and the aqueous layer, after acidification to pH 4
with 1 N HCl, was extracted with EtOAc several times. The
combined extracts were dried and concentrated to yield a
mixture of acid 3, succinimide, and Me2C(Cl)CHClMe, which
was used for the next reaction without purification. The 1H
NMR signals of 3: δ 1.19 (d, J ) 7 Hz, 3 H), 1.38 (d, J ) 6 Hz,
3 H), 1.45 (d, J ) 7 Hz, 3 H), 2.60-2.85 (m, 2 H), 3.42 (s, 3 H),
3.93-4.02 (m, 1 H), 4.12-4.19 (m, 1 H), 4.69 (s, 2 H), 5.24-
5.47 (m, 2 H), 6.06 (d, J ) 16 Hz, 1 H), 6.5 (br peak, 2 H),
6.75-6.93 (m, 2 H), 7.23 (d, J ) 16 Hz, 1 H).
A solution of the above acid 3 and NEt3 (0.068 mL, 0.49
mmol) in THF (1 mL) was stirred at room temperature for 20
min, and a solution of Cl3C6H2COCl (0.070 mL, 0.45 mmol) in
THF (1 mL for dilution and 1 mL for washing) was added.
The resulting mixture was stirred at room temperature for 2
h and concentrated by using a rotary evaporator to afford the
mixed anhydride, which was diluted with toluene. The cloudy
solution was filtered quickly through a pad of Celite with
toluene (total volume used for this operation was 120 mL). To
a solution of DMAP (65 mg, 0.53 mmol) in toluene (10 mL) at
40 °C was added the above toluene solution over 3 h. After
the addition, the solution was stirred at 40 °C further for 2 h
and directly evaporated to leave an oil, which was purified by
chromatography (hexane/EtOAc) to afford lactone 22 (55 mg,
(2S,6S,9E,11R,12S)-6,12-Dim eth yl-2-(2-fu r yl)-11-h ydr oxy-
14-(4-m eth oxyp h en yl)-3,7,13-tr ioxa -9-tetr a d ecen e-4,8-d i-
on e (18). To a solution of Zn(BH4)2 (18 mL, 0.151 M in Et2O,
2.71 mmol) maintained at -94 °C was added a solution of 17
(241 mg, 0.543 mmol) dissolved in Et2O (10 mL) over 20 min.
After the addition, the solution was stirred at the temperature
below -90 °C for 1 h and poured into a mixture of brine and
Et2O. The layers were separated, and the aqueous layer was
extracted with Et2O. The combined extracts were dried and
concentrated to give an oil, which was a 15:1 mixture of 18
1
and its epimer by H NMR spectroscopy. Finally, chromatog-
raphy (hexane/EtOAc) of the crude product furnished 18 (170
mg, 70%): IR (neat) 3464, 1737, 1720, 822, 746 cm-1; 1H NMR
δ 1.13 (d, J ) 6 Hz, 3 H), 1.31 (d, J ) 6 Hz, 3 H), 1.55 (d, J )
7 Hz, 3 H), 2.37 (d, J ) 4.5 Hz, 1 H), 2.54 (dd, J ) 15, 6 Hz,
1 H), 2.68 (dd, J ) 15, 8 Hz, 1 H), 3.65 (dq, J ) 3.5, 6 Hz, 1
H), 3.82 (s, 3 H), 4.39-4.45 (m, 1 H), 4.45 (d, J ) 12 Hz, 1 H),
4.56 (d, J ) 12 Hz, 1 H), 5.28-5.38 (m, 1 H), 5.97 (q, J ) 7
Hz, 1 H), 6.08 (dd, J ) 16, 2 Hz, 1 H), 6.31 (br s, 2 H), 6.83-
6.92 (m, 3 H), 7.23-7.30 (m, 2 H), 7.37 (dd, J ) 2, 1 Hz, 1 H);
13C NMR δ 169.6, 165.6, 159.6, 153.4, 146.0, 142.7, 130.2,
129.5, 122.0, 114.1, 110.3, 108.0, 76.3, 72.7, 70.6, 67.5, 65.3,
55.3, 41.1, 19.8, 18.1, 14.0. Anal. Calcd for C24H30O8: C, 64.56;
H, 6.77. Found: C, 64.60; H, 7.03.
(2S,6S,9E,11R,12S)-6,12-Dim eth yl-2-(2-fu r yl)-11-(m eth -
oxym et h oxy)-14-(4-m et h oxyp h en yl)-3,7,13-t r ioxa -9-t et -
r a d ecen e-4,8-d ion e (19). To a solution of 18 (389 mg, 0.871
mmol) and (i-Pr)2NEt (0.910 mL, 5.22 mmol) in CH2Cl2 (10
mL) was added MOMCl (0.264 mL, 3.48 mmol). The solution
was stirred at room temperature for 16 h and diluted with
saturated NaHCO3. The layers were separated, and the
aqueous layer was extracted with CH2Cl2. The combined
extracts were dried and evaporated to leave an oil, which was
purified by chromatography (hexane/EtOAc) to yield 19 (324
mg, 88%): [R]28D ) -68 (c 0.410, CHCl3); IR (neat) 1738, 1720,
1658, 1612, 1514, 822, 746 cm-1; 1H NMR δ 1.19 (d, J ) 6 Hz,
3 H), 1.31 (d, J ) 6 Hz, 3 H), 1.55 (d, J ) 7 Hz, 3 H), 2.54 (dd,
J ) 15, 6 Hz, 1 H), 2.69 (dd, J ) 15, 7 Hz, 1 H), 3.38 (s, 3 H),
3.55-3.67 (m, 1 H), 3.80 (s, 3 H), 4.29 (ddd, J ) 6, 4, 1.5 Hz,

2018 J . Org. Chem., Vol. 66, No. 6, 2001
Kobayashi et al.
40% from the furan 20): [R]24D ) -80 (c 0.36, CHCl3); IR (neat)
1735, 1718, 1708, 1265, 1182, 1055 cm-1; 1H NMR δ 1.37 (d, J
) 6 Hz, 3 H), 1.42 (d, J ) 7 Hz, 3 H), 1.44 (d, J ) 7 Hz, 3 H),
2.63 (dd, J ) 16, 3 Hz, 1 H), 2.75 (dd, J ) 16, 10 Hz, 1 H),
3.39 (s, 3 H), 4.20 (dt, J ) 1, 6 Hz, 1 H), 4.65 (br s, 2 H), 4.96-
5.06 (m, 1 H), 5.18 (q, J ) 7 Hz, 1 H), 5.32-5.44 (m, 1 H), 6.06
(dd, J ) 16, 1 Hz, 1 H), 6.75 (d, J ) 16 Hz, 1 H), 6.82 (dd, J )
16, 6 Hz, 1 H), 7.00 (d, J ) 16 Hz, 1 H); 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
A solution of the above MOM ether 24 in CH2Cl2 (0.7 mL)
and CF3CO2H (0.7 mL) was stirred at room temperature for 2
h and concentrated to afford a residue, which was purified by
chromatography to furnish macrosphelide A (1) (12 mg, 70%),
whose 1H NMR and 13C NMR spectra were identical with those
reported:3b,5 [R]30D ) +85 (c 0.046, MeOH) [lit.3b [R]23D ) +84.1
(c 0.59, MeOH); lit.5 [R]27 ) +82 (c 0.10, MeOH)].
D
14-epi Ma cr osp h elid e A (25). (a ) F r om th e MOM Eth er
23. According to the procedure for preparation of mac-
rosphelide B (2), a reaction involving 23 (11 mg, 0.028 mmol),
CF3CO2H (0.7 mL), and CH2Cl2 (0.7 mL) at room temperature
for 2 h afforded 25 (8 mg, 86%) after purification by chroma-
tography: IR (THF) 3393, 1745, 1730 cm-1; 1H NMR (DMSO-
d6)31 δ 1.19 (d, J ) 6 Hz, 3 H), 1.22 (d, J ) 7 Hz, 3 H), 1.32 (d,
J ) 6 Hz, 3 H), 2.4-2.7 (m), 3.94-4.04 (m, 1 H), 4.22-4.29
(m, 1 H), 4.61-4.74 (m, 1 H), 5.04-5.20 (m, 2 H), 5.43 (d, J )
6 Hz, 1 H), 5.69 (d, J ) 6 Hz, 1 H), 5.78 (dd, J ) 16, 1 Hz, 1
H), 5.92 (dd, J ) 16, 2 Hz, 1 H), 6.65 (dd, J ) 16, 6 Hz, 1 H),
6.78 (dd, J ) 16, 4 Hz, 1 H).
(b) F r om Ma cr osp h elid e B (2). According to the procedure
for preparation of 23 from ketone 22, a reaction involving
macrosphelide B (2) (7.7 mg, 0.023 mmol), NaBH4 (1 mg, 0.026
mmol), and MeOH (1 mL) at 0 °C for 1 h afforded 25 (6.3 mg,
82%) with a >20:1 ratio of 25 and 1.
MOM P r otection of Ma cr osp h elid e B (2). According to
the procedure for preparation of 19, a solution of 2 (6.2 mg,
0.018 mmol), MOMCl (0.007 mL, 0.094 mmol), and i-Pr2NEt
(0.032 mL, 0.18 mmol) in CH2Cl2 (0.5 mL) was stirred at room
temperature for 2.5 d to afford 22 (5.2 mg, 75%) after
purification by chromatography. The 1H NMR spectrum of
synthetic 22 was identical with that obtained by the macro-
cyclization of seco acid 3 (vide supra).
C
18H24O9: C, 56.24; H, 6.29. Found: C, 55.99; H, 6.23.
Ma cr osp h elid e B (2). To a solution of 22 (16 mg, 0.042
mmol) in CH2Cl2 (0.5 mL) was added CF3CO2H (0.5 mL). The
solution was stirred at room temperature for 1.5 h and
concentrated to leave an oil, which was subjected to chroma-
tography to furnish 2 (13 mg, 92%): [R]26 ) +9.1 (c 0.154,
D
1
MeOH) [lit.5 [R]24D ) +10.0 (c 0.39, MeOH)]. The H NMR and
13C NMR spectra of synthetic 2 were identical with the data
reported in the literatures.3b,5
8-MOM Eth er of 14-epi-Ma cr osp h elid e A (23). To a
solution of 22 (19 mg, 0.049 mmol) in MeOH (2 mL) was added
NaBH4 (2 mg, 0.053 mmol) at -15 °C, and the solution was
stirred at -15 °C for 20 min. Brine was added to the solution,
and the resulting mixture was extracted with EtOAc twice.
The combined extracts were dried and concentrated to give a
residue. The ratio of 23 and 24 was >10:1 by 1H NMR
spectroscopy. Finally, purification by chromatography (hexane/
1
EtOAc) afforded 23 (14 mg, 74%): IR (CHCl3) 1728 cm-1; H
NMR δ 1.28 (d, J ) 6 Hz, 3 H), 1.37 (d, J ) 7 Hz, 3 H), 1.40
(d, J ) 6 Hz, 3 H), 1.9 (br s, 1 H), 2.48 (dd, J ) 16, 1.5 Hz, 1
H), 2.61 (dd, J ) 16, 11 Hz, 1 H), 3.39 (s, 3 H), 4.02 (t, J ) 8
Hz, 1 H), 4.27 (br s, 1 H), 4.58 (d, J ) 7 Hz, 1 H), 4.66 (d, J )
7 Hz, 1 H), 4.92-5.03 (m, 1 H), 5.17-5.25 (m, 1 H), 5.32-5.44
(m, 1 H), 5.88 (d, J ) 16 Hz, 1 H), 6.02 (dd, J ) 16, 2 Hz, 1 H),
6.71 (dd, J ) 16, 8 Hz, 1 H), 6.87 (dd, J ) 16, 4 Hz, 1 H).
Ma cr osp h elid e A (1). To a solution of 23 (25 mg, 0.065
mmol), DEAD (0.016 mL, 0.10 mmol), and PPh3 (26 mg, 0.099
mmol) in THF (1.5 mL) was added HCO2H (0.044 mL, 1.1
mmol), and the mixture was stirred at room temperature for
1.5 h. The phosphate buffer (2 mL, pH 3.6) was added, and
the resulting mixture was extracted with EtOAc. The extract
was dried and concentrated to give a residue, which was
passed through a short column of silica gel with hexane/EtOAc
to afford the semipurified formate ester.
Ack n ow led gm en t. We gratefully acknowledge the
generous supply of methyl (S)-3-hydroxybutanoate from
Takasago International Corp. and D-(-)-DIPT from
Toray Industries, Inc.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds lacking elemental analyses (23 and 25) and ball
and stick models of MB-1 and MB-2. This material is available
free of charge via the Internet at http://pubs.acs.org.
A solution of the above formate and NEt3 (1 drop) in MeOH
(2 mL) was stirred at room temperature for 1 h and concen-
trated to leave a residue, which was purified by chromatog-
raphy (hexane/EtOAc) to afford the 8-MOM ether 24 (18 mg,
72%).
J O001495D
(31) Compound 25 was sufficiently dissolved in CDCl3.