Total Synthesis of Macrosphelides A, B, and E: First Application of Ring-Closing Metathesis for Macrosphelide Synthesis

Article abstract of DOI:10.1021/jo035435u

A new synthetic route for macrosphelides A, B, and E based on ring-closing metathesis (RCM) was established. The substrates for RCM could be synthesized starting from commercially available chiral materials, methyl (S)-lactate and methyl (S)- or (R)-3-hydroxybutyrate, in good overall yields. In the investigation of the key RCM step, it was found that the steric factor around the reaction site significantly affected the reaction rate of macrocyclization. A detailed account regarding this synthetic study is described herein.

Full text of DOI:10.1021/jo035435u

Tota l Syn th esis of Ma cr osp h elid es A, B, a n d E: F ir st Ap p lica tion
of Rin g-Closin g Meta th esis for Ma cr osp h elid e Syn th esis
Takanori Kawaguchi, Nobutaka Funamori, Yuji Matsuya, and Hideo Nemoto*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani,
Toyama 930-0194, J apan
nemotoh@ms.toyama-mpu.ac.jp
Received October 1, 2003
A new synthetic route for macrosphelides A, B, and E based on ring-closing metathesis (RCM) was
established. The substrates for RCM could be synthesized starting from commercially available
chiral materials, methyl (S)-lactate and methyl (S)- or (R)-3-hydroxybutyrate, in good overall yields.
In the investigation of the key RCM step, it was found that the steric factor around the reaction
site significantly affected the reaction rate of macrocyclization. A detailed account regarding this
synthetic study is described herein.
In tr od u ction
employed as a macrocyclization method, and no example
including RCM has been seen so far. In a previous
communication,8 we reported the first application of RCM
for the total synthesis of macrosphelides A and B,
demonstrating its efficiency for constructing the 16-
membered macrosphelide skeleton. In this paper, we
describe the full details of this RCM-based synthetic
study and its extension for the synthesis of macrosphelide
E.
Olefin metatheses using metal alkylidene complexes
is a unique and powerful method for C-C bond formation
or cleavage and occupies a greatly significant position in
modern synthetic organic chemistry.1 Among them, ring-
closing metathesis (RCM) has received much attention
for the construction of medium or large rings, and nu-
merous studies on its application for the synthesis of
biologically important molecules have been reported in
the past few years.2 In particular, it has been a promising
method for forming macrocyclic compounds, as seen
representatively in epothilone syntheses.3 As one of our
recent research projects for total synthesis of several
bioactive macrolides, development of a new efficient
synthetic methodology for macrosphelides, which have
a 16-membered trilactone linkage, has been carried out.4
This series of natural products were isolated from Mac-
rosphaeropsis sp. FO-5050 and Periconia byssoides5 and
have been reported to inhibit adhesion of human leuke-
mia HL-60 cells to human-umbilical-vein endothelial cells
with high selectivity5 and, consequently, to be potential
lead compounds for new anti-cancer drugs. Although
many synthetic studies have been reported6 since Omura
and Smith reported the first total synthesis of mac-
rosphelides A and B in 1997,6a in all cases, the macro-
lactonization protocol developed by Yamaguchi et al.7 was
Resu lts a n d Discu ssion
Retr osyn th esis. The approach we envisaged for the
synthesis of macrosphelides A, B, and E is shown in
Scheme 1. Of two olefinic parts in the 16-membered
(5) (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. (b) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.; Hiraoka,
H.; Natori, M.; Komiyama, K.; Omura, S. J . Antibiot. 1996, 49, 95. (c)
Takamatsu, S.; Hiraoka, H.; Kim, Y.-P.; Hayashi, M.; Natori, M.;
Komiyama, K.; Omura, S. J . Antibiot. 1997, 50, 878. (d) Fukami, A.;
Taniguchi, Y.; Nakamura, T.; Rho, M.-C.; Kawaguchi, K.; Hayashi, M.;
Komiyama, K.; Omura, S. J . Antibiot. 1999, 52, 501. (e) Numata, A.;
Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.;
Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215. (f) Yamada, T.; Iritani,
M.; Doi, M.; Minoura, K.; Ito, T.; Numata, A. J . Chem. Soc., Perkin
Trans. 1 2001, 3046. (g) Yamada, T.; Iritani, M.; Minoura, K.; Numata,
A.; Kobayashi, Y.; Wang, Y.-G. J . Antibiot. 2002, 55, 147.
(6) (a) 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. (b) Kobayashi, Y.; Kumar,
B. G.; Kurachi, T. Tetrahedron Lett. 2000, 41, 1559. (c) Kobayashi, Y.;
Kumar, B. G.; Kurachi, T.; Acharya, H. P.; Yamazaki, T.; Kitazume,
T. J . Org. Chem. 2001, 66, 2011. (d) Kobayashi, Y.; Acharya, H. P.
Tetrahedron Lett. 2001, 42, 2817. (e) Ono, M.; Nakamura, H.; Konno,
F.; Akita, H. Tetrahedron: Asymmetry 2000, 11, 2753. (f) Nakamura,
H.; Ono, M.; Makino, M.; Akita, H. Heterocycles 2002, 57, 327. (g)
Nakamura, H.; Ono, M.; Shida, Y.; Akita, H. Tetrahedron: Asymmetry
2002, 13, 705. (h) Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002,
43, 4381. (i) Ono, M.; Nakamura, H.; Arakawa, S.; Honda, N.; Akita,
H. Chem. Pharm. Bull. 2002, 50, 692. (j) Sharma, G. V. M.; Chandra
Mouli, Ch. Tetrahedron Lett. 2002, 43, 9159. (k) Akita, H.; Nakamura,
H.; Ono, M. Chirality 2003, 15, 352.
(1) For recent reviews on olefin metathesis, see: (a) Fu¨rstner, A.
Topics in Organometallic Chemistry; Springer-Verlag: Berlin, 1998;
Vol. 1. (b) Ivin, K. J .; Mol, J . C. Olefin Metathesis and Metathesis
Polymerization; Academic Press: San Diego, CA, 1997. (c) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(2) For recent reviews on RCM, see: (a) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012. (b) Armstrong, S. K. J . Chem. Soc., Perkin
Trans. 1 1998, 371. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413.
(3) Recent report in this field: Rivkin, A.; Yoshimura, F.; Gabarda,
A. E.; Chou, T.-C.; Dong, H.; Tong, W. P.; Danishefsky, S. J . J . Am.
Chem. Soc. 2003, 125, 2899. Also, a comprehensive review can be seen
in ref 1a, pp 75-92.
(4) Matsuya, Y.; Kawaguchi, T.; Nemoto, H.; Nozaki, H.; Hamada,
H. Heterocycles 2003, 59, 481.
(7) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
(8) Matsuya, Y.; Kawaguchi, T.; Nemoto, H. Org. Lett. 2003, 5, 2939.
10.1021/jo035435u CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/25/2003
J . Org. Chem. 2004, 69, 505-509
505

Matsuya et al.
SCHEME 1
by sodium periodate in 72% yield. Masamune-Roush
modification11 of HWE reaction proceeded cleanly to
afford conjugated ester 12 with no detectable (Z)-isomer.
Mild hydrolysis of the ester 12 provided the chiral
subunit 13 with high efficiency. When utilizing compound
6 as the C13-O16 unit, selection of the protecting group
is important because it is necessary to distinguish the
two hydroxyl groups (8- and 14-positions) for the syn-
thesis of macrosphelide B. To this end, the introduction
of a PMB group to the alcohol 6 was investigated.
However, attempts to synthesize the PMB ether 14 under
standard reaction conditions (PMBCl-NaH or Ag2O)
were unsuccessful, and instead, intra- and intermolecular
migration of TBS group took place to afford a complex
mixture. Although an efficient method for PMB etheri-
fication employing p-methoxybenzyl trichloroacetimidate
and lanthanum triflate was recently reported,12 the
application of the method also ended in failure. After
several investigations, p-methoxybenzyl trifluoroacetimi-
date13 was found to be an effective reagent for the
reaction to give a preferable result. Although p-TsOH or
CSA as an acid-catalyst resulted in the same scrambling
of the TBS group, the use of PPTS led to the formation
of our desired PMB ether 14 without any side reactions
in a high conversion yield. The amount of PPTS and
reaction temperature did not affect the yield of 14. After
desilylation of 14 with TBAF, introduction of the C1-
O4 subunit, (S)-3-silyloxybutyric acid (7), was performed
under dehydration conditions using EDC-DMAP to give
the ester 16 in 99% yield. Connection of 16 with the
carboxylic acid 13 and subsequent introduction of acryloyl
group were planned to be carried out through the same
desilylation-esterification sequence. In practice, the silyl
ether 16 was treated with TBAF to afford the alcohol 17
in 95% yield. For the reaction of 17 with 13, application
of the same dehydration condition as the formation of
16 afforded the ester 18 only in 16% yield, and 77% of
the alcohol 17 was recovered while the carboxylic acid
13 disappeared. This suggests that the “activated” car-
boxylic acid generated by reaction with the carbodiimide
was transformed into an inactive N-acylurea derivative
prior to reaction with the alcohol 17. In such cases, it
has been reported that addition of proton sources such
as amine hydrochlorides to the reaction medium sup-
pressed the undesired transformation.14 Therefore, a
DCC/DMAP/DMAP-hydrochloride system was applied
according to the reported procedure14 to improve the yield
of 18 up to 65%. However, this protocol lacked reproduc-
ibility of the yield, and a more reliable method was
explored. Eventually, employment of activated mixed
anhydride as an intermediate resulted in a striking
improvement in the coupling efficiency, giving nearly
quantitative yield with good reproducibility. In the next
desilylation step, special care was required because base-
induced cleavage of the C3-O4 bond of 18 rapidly
proceeded in a retro-Michael manner when treated with
TBAF. To circumvent this impasse, the reaction was
performed in AcOH-containing medium for a prolonged
macrosphelide skeleton, the C12-C13 olefin was chosen
as the position for macrocyclization by RCM. The sub-
strate for RCM (4 and 5) contains five chiral centers, one
of which (C3) would be able to originate from enantio-
merically enriched 3-hydroxybutyric acid derivatives (7
and 8). The availability of both enantiomers of 3-hy-
droxybutyrate from commercial sources provides a ver-
satile route to both C3-epimeric products, macrosphelide
A and E, alternatively. The other two pairs (C8-C9 and
C14-C15) of chiral centers have mutually identical
relative and absolute stereochemistry and analogous
arrangements of atoms, thereby allowing use of the
common chiral subunit 6, which can be prepared from
inexpensive methyl (S)-lactate (9). Assembly of 4 and 5
from these chiral blocks could be achieved based on our
previous success in constructing the macrosphelide core
structure,4 including a deprotection-esterification se-
quence and Horner-Wadsworth-Emmons (HWE) olefi-
nation.
Syn th esis of th e Su bstr a tes for RCM. As can be
seen from the retrosynthesis, the initial goal is the
synthesis of the RCM substrates 4 and 5. Our synthesis
began with the preparation of known chiral material 6,9
which corresponds to C7-O10 and C13-O16 units of the
target macrosphelides. According to the reported proce-
dure,9 methyl (S)-lactate (9) was converted into tert-
butyldimethylsilyl (TBS) ether and the ester function was
transformed into the formyl group with DIBAL reduction
followed by Swern oxidation. Addition of vinyl Grignard
reagent to the aldehyde resulted in the formation of
desired allyl alcohol 6 (6:1 diastereoselectivity),10 which
was purified with column chromatography. The synthesis
of 4 starting from 6 is depicted in Scheme 2. The C5-
O10 subunit 13 was synthesized in five steps, including
oxidative cleavage of the vinyl group and subsequent
HWE homologation. After protection of the alcohol 6 as
a MEM ether, the olefin 10 was converted into the
aldehyde 11 upon exposure to osmium tetroxide followed
(9) (a) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J . Org. Chem.
1983, 48, 5180. (b) Ley, S. V.; Armstrong, A.; Diez-Martin, D.; Ford,
M. J .; Grice, P.; Knight, J . G.; Kolb, H. C.; Madin, A.; Marby, C. A.;
Mukherjee, S.; Shaw, A. N.; Slawin, A. M. Z.; Vile, S.; White, A. D.;
Williams, D. J .; Woods, M. J . Chem. Soc., Perkin Trans. 1 1991, 667.
(10) An alternative method for preparing this type of compound with
high anti selectivity has been reported: Iio, H.; Mizobuchi, T.;
Tsukamoto, M.; Tokoroyama, T. Tetrahedron Lett. 1986, 27, 6373.
(11) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(12) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267.
(13) Nakajima, N.; Saito, M.; Ubukata, M. Tetrahedron Lett. 1998,
39, 5565.
(14) Boden, E. P.; Keck, G. E. J . Org. Chem. 1985, 50, 2394.
506 J . Org. Chem., Vol. 69, No. 2, 2004

Total Synthesis of Macrosphelides A, B, and E
SCHEME 2a
a
Reagents: (a) MEMCl, DIPEA, CH2Cl2 (70%); (b) OsO4, NMO, acetone; (c) NalO4, TBAB, CH2Cl2-H2O (72% in two steps);
(d) (EtO)2P(O)CH2CO2Et, DBU, LiCl, MeCN (95%); (e) NaOH, MeOH-THF-H2O (99%); (f) PMBOC(dNH)CF3, PPTS, CH2Cl2 (47%,
recovery ) 51%); (g) TBAF, THF (96%); (h) 7, EDC, DMAP, CH2Cl2 (99%); (i) TBAF, THF (95%); (j) 13, 2,4,6-Cl3C6H2COCl, Et3N, DMAP,
toluene, then 17 (99%); (k) TBAF, AcOH, THF (85%); (l) CH2dCHCOCl, DIPEA, CH2Cl2 (95%).
SCHEME 3a
CHART 1
TABLE 1. RCM of P MB Eth er (4)
entry
reagent
solventa
condition
rt, 24 h
reflux, 24 h
rt, 24 h
reflux, 24 h
reflux, 5 days
reflux, 24 h
yield (%)
a
Reagents: (a) 8, EDC, DMAP, CH2Cl2 (69%); (b) TBAF, THF
1
2
3
4
5
6
catalyst 1 (10 mol %)
catalyst 1 (10 mol %)
catalyst 2 (10 mol %)
catalyst 2 (10 mol %)
catalyst 2 (1 equiv)
catalyst 2 (10 mol %)b
DCM
DCE
DCM
DCE
DCE
DCE
0
0
0
(71%); (c) 13, 2,4,6-Cl3C6H2COCl, Et3N, DMAP, toluene, then 21
(94%); (d) TBAF, AcOH, THF (77%); (e) CH2dCHCOCl, DIPEA,
CH2Cl2(88%).
<10
65
<10
reaction time to furnish the alcohol 19 in 85% yield. The
final esterification was carried out using acryloyl chloride
and DIPEA in CH2Cl2 to accomplish the synthesis of the
RCM substrate 4.
a
b
DCM ) dichloromethane; DCE ) 1,2-dichloroethane. Ti(O-
iPr)4 (1 equiv) was added.
For the synthesis of 5, the C3-epimer of 4, the same
synthetic sequence depicted in Scheme 2 was applicable
only by replacing (S)-3-silyloxybutyric acid (7) to its (R)-
enantiomer 8 as shown in Scheme 3. Thus, the syntheses
of 4 and 5, the precursors for macrosphelides A and B
and macrosphelide E, respectively, were completed sat-
isfactorily by assembly from commercially available
chiral materials.
Rin g-Closin g Meta th esis of 4 a n d 5. The next phase
of our studies was directed at RCM of 4 and 5 to construct
a 16-membered macrosphelide nucleus. The recent re-
searchers in this area have developed various efficient
RCM catalysts,15 and our first choice among them was
Grubbs’ ruthenium complexes (Chart 1). The results of
RCM of the substrate 4 are summarized in Table 1. For
the macrocyclization, catalyst 1 was revealed to be
ineffective as an RCM initiator, and the starting material
was recovered completely even in refluxing 1,2-dichloro-
ethane (entries 1 and 2). When catalyst 2 was used,
formation of the cyclization product 24 was observed,
although heating was required (entries 3 and 4). How-
ever, the yield was quite low (<10%), implying that the
catalytic cycle was impeded. In fact, the use of equimolar
amounts of catalyst 2 under the same condition improved
the yield of 24 to 65%, although the reaction continued
for 5 days (entry 5). One possible explanation for this
extremely slow reaction would be a stabilizing effect for
an intermediate ruthenium-substrate complex by coor-
dination of the ester carbonyl to the ruthenium center
(15) Love, J . A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J . Am.
Chem. Soc. 2003, 125, 10103 and references therein.
J . Org. Chem, Vol. 69, No. 2, 2004 507

Matsuya et al.
TABLE 2. RCM of MOM Eth er (26) a n d Alcoh ol (25)
entry
substrate
reagent
solventa
condition
yield (%)
1
2
3
4
5
6
7
8
catalyst 1 (10 mol %)
catalyst 1 (10 mol %)
catalyst 2 (10 mol %)
catalyst 2 (10 mol %)
catalyst 2 (1 equiv)
catalyst 1 (10 mol %)
catalyst 1 (10 mol %)
catalyst 2 (10 mol %)
DCM
DCE
DCM
DCE
DCE
DCM
DCE
DCM
rt, 12 h
reflux, 12 h
rt, 12 h
reflux, 48 h
reflux, 48 h
rt, 12 h
reflux, 12 h
rt, 24 h
0
0
0
R ) MOM (26)
<10
60
0
0
77
R ) H (25)
a
DCM ) dichloromethane; DCE ) 1,2-dichloroethane.
CHART 2
SCHEME 4
SCHEME 5
in an intramolecular fashion.16 To avoid such interac-
tions, the reaction was performed in the presence of
Lewis acid,17 but this did not lead to positive results
(entry 6).
In these examinations, we noticed that a small amount
of benzylidene derivative 27 (Chart 2) was formed
especially in the case of entry 5, and it was found that
the compound did not change under the RCM conditions.
This observation suggests that the first reactive site
toward the ruthenium catalyst is the conjugated enone
part, and that participation of the ω-olefin to the reaction
is so sluggish that the reaction rate is comparable with
that of styrene originating from the catalyst. Taking this
finding into account, more sterically relaxed substrates
(25 and 26) were prepared from PMB derivative 4
according to Chart 2.
Results parallel to those in the case of 4 were obtained
when used the MOM derivative 26 as a substrate for
RCM (entries 1-5, Table 2), although the reaction rate
increased somewhat (entry 5). On the other hand, it was
found that the alcohol 25 has sufficient reactivity for our
desired macrocyclization. As shown in entry 8, RCM of
25 proceeded in the presence of 10 mol % catalyst 2 at
room temperature in 77% yield. In the cyclization pro-
cesses, no geometric isomer (cis isomer) was produced.
For the synthesis of macrosphelide E, compound 5 was
treated with DDQ to afford the alcohol 30, which was
subjected to RCM under the same conditions as the
substrate 25. Although 15 mol % of the catalyst was
necessary to achieve a practical yield, macrocyclization
proceeded satisfactorily to give 31 in a stereoselective
manner (Scheme 4). Thus, RCM-based construction of
two macrosphelide skeletons was accomplished by con-
trolling the bulkiness of the protecting group of 14-
hydroxyl group.
Com p letion of th e Tota l Syn th esis. The transfor-
mations of the compounds 29 and 31 constructed by RCM
into the natural macrosphelides were straightforward as
shown in Scheme 5. Removal of the MEM group of these
compounds with TFA produced macrosphelides A and E,
respectively. PDC oxidation of 29 and subsequent depro-
tection afforded macrosphelide B. The spectral data of
our synthetic macrosphelides agreed with those reported
for the natural products.5b,f
Con clu sion
We have described here a detailed account regarding
the total syntheses of macrosphelides A, B, and E based
on RCM strategy. We have shown that the array of chiral
centers can be assembled from readily available chiral
blocks, methyl lactate and methyl 3-hydroxybutyrate,
and first demonstrated that the RCM strategy is useful
in constructing 16-membered macrosphelide skeletons.
Further extensions of the synthetic methodology for the
(16) Fu¨rstner, A.; Langemann, K. J . Am. Chem. Soc. 1997, 119,
9130.
(17) Langer, P.; Albrecht, U. Synlett 2002, 1841.
508 J . Org. Chem., Vol. 69, No. 2, 2004

Total Synthesis of Macrosphelides A, B, and E
material is available free of charge via the Internet at
http://pubs.acs.org.
other macrosphelide syntheses are currently ongoing in
our laboratory and will be reported in due course.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details and characterization data for all new compounds. This
J O035435U
J . Org. Chem, Vol. 69, No. 2, 2004 509