New strategy for the total synthesis of macrosphelides A and B based on ring-closing metathesis

Article abstract of DOI:10.1021/ol0350689

(Matrix presented) A new total synthesis of macrosphelides A and B using ring-closing metathesis (RCM) as a macrocyclization step is described. The substrate of the RCM could be synthesized from readily available chiral materials, methyl (S)-(+)-3-hydroxybutyrate and methyl (S)-(-)-lactate, with a high efficiency. The RCM proceeded in the presence of Grubbs' Ru-complex, providing a new effective synthetic route to these natural products.

Full text of DOI:10.1021/ol0350689

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2939-2941
New Strategy for the Total Synthesis of
Macrosphelides A and B Based on
Ring-Closing Metathesis
Yuji Matsuya, Takanori Kawaguchi, and Hideo Nemoto*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical UniVersity,
Sugitani 2630, Toyama 930-0194, Japan
nemotoh@ms.toyama-mpu.ac.jp
Received June 12, 2003
ABSTRACT
A new total synthesis of macrosphelides A and B using ring-closing metathesis (RCM) as a macrocyclization step is described. The substrate
of the RCM could be synthesized from readily available chiral materials, methyl (S)-(+)-3-hydroxybutyrate and methyl (S)-(−)-lactate, with a
high efficiency. The RCM proceeded in the presence of Grubbs’ Ru-complex, providing a new effective synthetic route to these natural products.
Macrosphelides A-L are characteristic 16-membered mac-
rolides isolated from Microsphaeropsis sp. FO-5050 and
Periconia byssoides.1 These natural products have been
reported to exhibit a potent cell-cell adhesion inhibitory
activity, and much attention has been paid to them as
potential lead compounds for new anti-cancer drugs.1 Con-
sequently, synthetic research of this attractive macrosphelide
family has been carried out2 by several groups, and all
include Yamaguchi’s macrolactonization protocol3 for the
macrocyclization. In the course of our study on the structure-
activity relationship of the macrosphelides and its analogues,
we have reported the synthesis of a simple macrosphelide
core4 in which the same macrolactonization method was
employed. However, the lability of the substrates of the
lactonization toward basic conditions seems to give rise to
several problematic issues, such as a lack of reproducibility
of the yield or partial epimerization2h of the product. In this
research, we explored the first application of the ring-closing
metathesis (RCM) as a neutral macrocyclization condition
to the total synthesis of macrosphelides to accomplish the
development of a new approach to macrosphelides A (1) and
(2) (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, 10247-10248. (b) Kobayashi, Y.; Kumar, B. G.;
Kurachi, T. Tetrahedron Lett. 2000, 41, 1559-1563. (c) Kobayashi, Y.;
Kumar, B. G.; Kurachi, T.; Acharya, H. P.; Yamazaki, T.; Kitazume, T. J.
Org. Chem. 2001, 66, 2011-2018. (d) Kobayashi, Y.; Acharya, H. P.
Tetrahedron Lett. 2001, 42, 2817-2820. (e) Ono, M.; Nakamura, H.; Konno,
F.; Akita, H. Tetrahedron: Asymmetry 2000, 11, 2753-2764. (f) Nakamura,
H.; Ono, M.; Makino, M.; Akita, H. Heterocycles 2002, 57, 327-336. (g)
Nakamura, H.; Ono, M.; Shida, Y.; Akita, H. Tetrahedron: Asymmetry
2002, 13, 705-713. (h) Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002,
43, 4381-4384. (i) Ono, M.; Nakamura, H.; Arakawa, S.; Honda, N.; Akita,
H. Chem. Pharm. Bull. 2002, 50, 692-696. (j) Sharma, G. V. M.; Chandra
Mouli, Ch. Tetrahedron Lett. 2002, 43, 9159-9161. (k) Akita, H.;
Nakamura, H.; Ono, M. Chirality 2003, 15, 352-359.
(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.; Hiraoka, H.;
Natori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95-98. (c)
Takamatsu, S.; Hiraoka, H.; Kim, Y.-P.; Hayashi, M.; Natori, M.;
Komiyama, K.; Omura, S. J. Antibiot. 1997, 50, 878-880. (d) Fukami, A.;
Taniguchi, Y.; Nakamura, T.; Rho, M.-C.; Kawaguchi, K.; Hayashi, M.;
Komiyama, K.; Omura, S. J. Antibiot. 1999, 52, 501-504. (e) Numata, A.;
Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.; Tsuruo,
T. Tetrahedron Lett. 1997, 38, 8215-8218. (f) Yamada, T.; Iritani, M.;
Doi, M.; Minoura, K.; Ito, T.; Numata, A. J. Chem. Soc., Perkin Trans. 1
2001, 3046-3053. (g) Yamada, T.; Iritani, M.; Minoura, K.; Numata, A.;
Kobayashi, Y.; Wang, Y.-G. J. Antibiot. 2002, 55, 147-154.
(3) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(4) Matsuya, Y.; Kawaguchi, T.; Nemoto, H.; Nozaki, H.; Hamada, H.
Heterocycles 2003, 59, 481-484.
10.1021/ol0350689 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/17/2003

B (2) using inexpensive chiral blocks as substrates. This
communication describes these results.
ester 11 was converted into the required carboxylic acid 6
by alkaline saponification (Scheme 2).6
Macrosphelides A (1) and B (2) were first synthesized by
Omura and co-workers, in which asymmetric dihydroxylation
was used,2a and recently, the synthetic approaches utilizing
a chiral R-furylethanol, a carbohydrate, and an enzymatic
method have been reported.2b-k Our new synthetic plan is
outlined in Scheme 1. Although the oxidative conversion of
Scheme 2. Synthesis of Intermediate 6
Scheme 1. Synthetic Strategy for Macrosphelides A and B
Another chiral subunit 5 was assembled from 7 as shown
in Scheme 3. The first step we attempted was found to be
Scheme 3. Synthesis of Intermediate 5
macrosphelide A (1) to B (2)2a and the reductive transforma-
tion of B (2) to A (1)2c were described in previous reports,
there is a difficulty in the point of chemoselectivity or
stereoselectivity in these processes.
To achieve the effective synthesis of macrosphelides A
(1) and B (2) via a common synthetic process, we selected
the macrocycle 3 as their precursor, which contains distin-
guishable protecting groups. For the construction of the
macrocyclic system, RCM of 4 was our choice. On the basis
of this strategy, a synthetic route to the intermediate 4 was
designed from two commercially available chiral materials,
methyl (S)-(+)-3-hydroxybutyrate and methyl (S)-(-)-lactate
(8). The former corresponds to the left segment of 5, and
the latter is used to synthesize the right segment of 5 and 6
via a common intermediate 7.
difficult due to intra- and intermolecular migration of the
TBS group under the basic (NaH or amine bases) or acidic
(p-TsOH or CSA) conditions. To overcome this problem,
we employed p-methoxybenzyl trifluoroacetimidate as a
reagent developed by Ubukata et al.7 Under this condition,
the migration of the TBS group was suppressed, and a high
conversion yield (based on the consumed alcohol) was
realized. After the removal of the TBS group, the alcohol
13 was subjected to dehydrative condensation with another
chiral carboxylic acid derived from methyl (S)-(+)-3-
hydroxybutyrate to give the ester 14, which was treated with
TBAF to afford the alcohol 5 in high yields.
The preparation of the intermediate 7 was carried out from
methyl (S)-(-)-lactate (8) in four steps according to a
reported procedure, i.e., silylation, DIBAL reduction, and
Swern oxidation followed by Grignard addition (6:1 dia-
stereoselectivity).5 The alcohol 7 was protected as a meth-
oxyethoxymethyl (MEM) ether, which was subjected to
oxidative cleavage of the vinyl group upon treatment with
osmium tetroxide and sodium periodate successively to afford
the aldehyde 10. Horner-Wadsworth-Emmons olefination
of 10 using ethyl diethylphosphonoacetate proceeded with
an exclusive stereoselectivity, and the resulting conjugated
(5) (a) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983,
48, 5180-5182. (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-
692.
(6) Although compound 6 was previously synthesized by Omura et al.
using asymmetric dihydroxylation and Mitsunobu inversion (ref 2a), we
employed the alternative method shown in Scheme 2 because of the
efficiency from 7, which is a common intermediate for 5.
(7) Nakajima, N.; Saito, M.; Ubukata, M. Tetrahedron Lett. 1998, 39,
5565-5568.
2940
Org. Lett., Vol. 5, No. 16, 2003

With the chiral subunits 5 and 6 in hand, we examined a
connection of these compounds. Our first attempt was
dehydrative condensation of 5 and 6 using DCC or EDC,
providing the desired ester 15 in a moderate yield (65%).
After several investigations, it was found that the yield of
15 greatly improved when applying the method using mixed
anhydride as an active intermediate (Scheme 4). Desilylation
Scheme 5. Ring-Closing Metathesis (RCM)
Scheme 4. Synthesis of RCM Substrate 4
of 15 and introduction of the acryloyl group to the resulting
alcohol 16 proceeded smoothly to afford a key material 4, a
substrate for RCM.
spectral data of which were in good agreement with those
reported (Scheme 6).1b,2a
Unexpectedly, the RCM of 4 was found to be sluggish,
as shown in Scheme 5. Using Grubbs’ catalysts (catalyst 1
and catalyst 2)8 at room temperature, the cyclization did not
proceed and the starting material was recovered completely.
When the reaction was carried out using equimolar amounts
of catalyst 2 in refluxing 1,2-dichloroethane (DCE), the
cyclized product 3 was obtained in 65% yield after 5 days.
On the other hand, it is noteworthy that the allyl alcohol 17
prepared by deprotection of 4 showed sufficient reactivity
to RCM. The cyclization proceeded in the presence of 10
mol % catalyst 2 at room temperature to yield a macrocyclic
alcohol 18, which was identical with the product obtained
by removal of the PMB group of 3. In these cyclization
processes, the geometric isomer (cis isomer) could not be
detected.
Scheme 6. Completion of the Total Synthesis
In conclusion, we have developed a new synthetic route
for macrosphelides A and B with a high efficiency. In this
strategy, the synthesis of macrosphelides A and B was
accomplished from the common intermediate 18 using RCM
as a key macrocyclization step. Extension of these studies
to the synthesis of the other natural macrosphelides as well
as nonnatural analogues is in progress.
To complete the total synthesis, the remaining operations
were quite simple. Removal of the MEM group of 18 with
TFA afforded macrosphelide A, and PDC oxidation of 18
followed by the deprotection provided macrosphelide B,9 the
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953-956.
(9) Satisfactory spectral data for all new compounds were obtained; see,
Supporting Information.
OL0350689
Org. Lett., Vol. 5, No. 16, 2003
2941