Development of a concise and diversity-oriented approach for the synthesis of plecomacrolides via the diene-ene RCM

Article abstract of DOI:10.1021/ol060221v

A concise synthesis of the core structures of plecomacrolide with ring sizes varying from 16 to 19 atoms was achieved for the first time by the diene-ene ring-closing olefin metathesis reaction. This approach should allow access to the structurally divers

Full text of DOI:10.1021/ol060221v

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1193-1196
Development of a Concise and
Diversity-Oriented Approach for the
Synthesis of Plecomacrolides via the
Diene−Ene RCM
Kui Lu, Mengwei Huang, Zheng Xiang, Yongxiang Liu, Jiahua Chen,* and
Zhen Yang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry, State Key Laboratory of Natural and Biomimetic
Drugs, School of Pharmaceutical Science, and Laboratory of Chemical Genetics,
Shenzhen Graduate School of Peking UniVersity, Beijing 100871, China
zyang@pku.edu.cn
Received January 25, 2006
ABSTRACT
A concise synthesis of the core structures of plecomacrolide with ring sizes varying from 16 to 19 atoms was achieved for the first time by
the diene ene ring-closing olefin metathesis reaction. This approach should allow access to the structurally diverse analogues of plecomacrolide.
−
Plecomacrolides, such as bafilomycins,1 hygrolidins,2 and
concanamycins,3 are a set of cyclic macrolides with ring sizes
varying between 16 and 18 atoms and different stereo-
chemical orientations at the cores.4 These molecules showed
biological activities, including antitumor,5 antiviral,6 and
immunosuppressant7 properties. Bafilomycin A1 is also a
inhibitor for vacuolar H+-ATPases,8 the release of â-amyl-
oid,9 and mitogen-induced DNA synthesis.10
Because of their unique structural features, together with
their biological activities, plecomacrolides have attracted
ever-increasing attention for their efficient syntheses,11 and
several inventive total syntheses have been reported.12
Biologically, bafilomycins and concanamycins are not
selective for any particular type of V-ATPases, toxicity was
observed in the animal testing.13 Thus, searching for an
efficient access to quick construction of structurally diverse
analogues is necessary for further studying their selectivity.
(1) Werner, G.; Hagenmaier, H.; Albertm K.; Kohlshorn, H.; Drautz, H.
Tetrahedtron Lett. 1983, 24, 5193.
(2) Seto, H.; Akao, H.; Furihara, K.; Otake, N. Tetrahedron Lett. 1982,
23, 2667.
(3) Kinashi, H.; Someno, K.; Sakaguchi, K.; Higashijima, T.; Miyazawa,
T. Tetrahedron Lett. 1981, 22, 3857.
(4) (a) Kinashi, H.; Sakaguchi, K.; Higashijima, T.; Miyazawa, T. J.
Antibiot. 1982, 35, 1618. (b) Werner, G.; Hagenmaier, H.; Drautz, H.;
Baumgartner, A.; Za¨hner, H. J. Antibiot. 1984, 37, 110. (c) Seto, H.; Tajima,
I.; Akao, H.; Furihara, K.; Otake, N. J. Antibiot. 1984, 37, 610. (d) Kinashi,
H.; Someno, K.; Sakaguchi, K. J. Antibiot. 1984, 37, 1333. (e) Deeg, M.;
Hagenmaier, H.; Kretschmer, A. J. Antibiot. 1987, 40, 320. (f) Woo, J.-T.;
Shinohara, C.; Sakai, K.; Hasumi, K.; Endo, A. J. Antibiot. 1992, 45, 1108.
(g) Ishii, T.; Hida, T.; Iinuma, S.; Muroi, M.; Nozaki, Y. J. Antibiot. 1995,
48, 12.
(5) Wilton, J. H.; Hokanson, G. C.; French, J. C. J. Antibiot. 1985, 38,
1449.
(6) Ochiai, H.; Sakai, S.; Hirabayashi, T.; Shimizu, Y.; Terasawa, K.
AntiViral Res. 1995, 27, 425.
(7) Kataoka, T.; Magae, J.; Kasamo, K.; Yamanishi, H.; Endo, A.;
Yamasaki, M.; Nagae, K. J. Antibiot. 1992, 45, 1618.
(8) Bowman, E. M.; Siebers, A.; Altendorf, K. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 7972.
(9) (a) Knops, J.; Suomensaari, S.; Lee, M.; McConlogue, L.; Seubert,
P.; Sinha, S. J. Biol. Chem. 1995, 270, 2419. (b) Haas, C.; Capell, A.; Citron,
M.; Teplow, D. B.; Selkoe, J. J. Biol. Chem. 1995, 270, 6186.
(10) Saurin, A. J.; Hamlett, J.; Clague, M. J.; Pennington, R. Biochem.
J. 1996, 313, 65.
(11) For recent reviews regarding the synthesis see: (a) Toshima, K.
Curr. Org. Chem. 2004, 8, 185. (b) Dai, W.-M.; Guan, Y.; Jin. J. Curr.
Med. Chem. 2005, 12, 1947.
10.1021/ol060221v CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/11/2006

However, in most of the previous publications, the
macrolides of plecomacrolides were constructed by Yamagu-
chi’s method, which limits the flexibility to make structurally
diverse plecomacrolide analogues.11,14
Recently, because ruthenium carbene complexes not only
exhibit high synthetic efficiency and activity, but also tolerate
a range of functional groups,15 application of those complexes
for assembly of complex macrolides has opened up new
avenues for large-ring construction.16
In view of the existing conjugated double bonds in
plecomacrolides, we envisioned that the top conjugated
double bonds could be installed by diene-ene ring-closing
metathesis (RCM)17 with simultaneous formation of the
macrocycles. Interestingly, no such report appeared in the
literature, which encouraged us to initiate our study. In this
paper, we present our progress toward the synthesis of a
structural macrolide via RCM. Our goal has always been
the development of a versatile approach for diversity-oriented
syntheses of the plecomacrolide analogues.
Figure 1. Naturally occurring plecomacrolides.
Our generic approach to the syntheses of plecomacrolides
is shown in Figure 2. Retrosynthetically, macrolide A was
expected to be formed via intramolecular RCM reaction from
B, which could be made from C and D by dehydration.
Intermediate C would be derived from E by two sequential
double bond formations via Wittig and HWE reactions. This
illustrated strategy demonstrated the potential to synthesize
structurally diverse plecomacrolides by systematically cleav-
ing three major regions (highlighted as purple, green, and
blue in A).
Our study began with testing the feasibility of constructing
16-membered marcolide 10 via RCM (Scheme 1) from
substrate 9 as illustrated in Scheme 1.
To this end, we designed an approach for synthesis of 9.
Accordingly, ester 4 was reduced to its alcohol by DIBAL-
H, which was then oxidized to aldehyde 5 by Dess-Martin
Periodinane (DMP). This aldehyde was reacted with carbo-
methoxyethylidene triphenylphosphorane followed by de-
silyilation and oxidation (DMP) to give aldehyde 6.
To make substrate 9, aldehyde 6 was coupled with the
ylide derived from phosphonium salt Ph3PCH3Br (KHMDS,
(12) (a) Evans, D.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871. (b)
Toshima, K.; Jyojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida, T.;
Murase, H.; Nakata, M.; Matsumura, S. J. Org. Chem. 1997, 62, 3271. (c)
Paterson, I.; Doughty, V. A.; McLeod, M. D.; Trieselmann, T. Angew.
Chem., Int. Ed. 2000, 39, 1308. (d) Toshima, K.; Jyojima, T.; Miyamoto,
N.; Katohno, M.; Nakata, M.; Matsumura, S. J. Org. Chem. 2001, 66, 1708.
(e) Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall, B.
M.; Fegley, G. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 6981. (f)
Hanessian, J. A.; Ma. J.; Wang, W. J. Am. Chem. Soc. 2002, 123, 10200.
(g) Marshall, J. A.; Adams, N. D. J. Org. Chem. 2002, 67, 733. (h) Makino,
K.; Nakajima, N.; Hashimoto, S.; Yonemitsu, O. Tetrahedron Lett. 1996,
37, 9077.
(13) (a) Keeling D. J.; Herslo¨f, M.; Mattsson, J. P.; Ryberg, B. Acta
Physiol. Scand. 1998, 163, 195. (b) Gaglisrdi, S.; Rees, M.; Farina, C. Curr.
Med. Chem. 1999, 6, 1197. (c) Yoshimoto, Y.; Jyojima, T.; Arita, T.; Ueda,
M.; Imoto, M.; Matsumura, S.; Toshima, K. Bioorg. Med. Chem. Lett. 2002,
12, 3525.
(14) (a) Werner, G.; Hagenmaier, H.; Albert, K.; Kohlshorn, H.
Tetrahedron Lett. 1983, 24, 5193. (b) Baker, G. H.; Brown, P. J.; Dorgan,
R. J. J.; Everett, J. R.; Ley, S. V.; Slawin, A. M. Z.; Williams, D. J.
Tetrahedron Lett. 1987, 28, 5565. (c) Deeg, M.; Hagenmaier, H.; Kretschmer,
A. J. Antibiot. 1987, 40, 320. (d) Gagliardi, S.; Gatti, P. A.; Belfiore, P.;
Zocchetti, A.; Clarke, G. D.; Farania, C. J. Med. Chem. 1998, 41, 1883.
(15) For recent reviews of olefin metathesis see: (a) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (c) Furstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012. (d) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2037. (e) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900. (f) (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490.
(16) (a) Cabrejas, L. M. M.; Rohrbach, S.; Wagner, D.; Kallen, J.; Zenke,
G.; Wagner, J. Angew Chem., Int. Ed. 1999, 38, 2443. (b) Dvorak, C. A.;
Schmitz, W. D.; Poon, D. J.; Pryde D. C.; Lawson, J. P.; Amos, R. A.;
Meyers, A. I. Angew. Chem., Int. Ed. 2000, 39, 1664. (c) Garbaccio, R.
M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. Am. Chem. Soc.
2001, 123, 10903. (d) Lacombe, F.; Radkowski, K.; Seidel, G.; Fu¨rstner,
A. Tetrahedron 2004, 60, 7315.
(17) (a) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky,
S. J. J. Am. Chem. Soc. 2001, 123, 10903. (b) Dvorak, C. A.; Schmitz, W.
D.; Poon, D. J.; Pryde, D. C.; Lawson, J. P.; Amos, R. A.; Meyers, A. I.
Angew. Chem., Int. Ed. 2000, 39, 1664. (c) Wagner, J.; Cabrejas, L. M.
M.; Grossmith, C. E.; Papageorgiou, C.; Senia, F.; Wagner, D.; France, J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 9255. (d) Biswas, K.; Lin, H.;
Njardarson, J. T.; Chappell, M. D.; Chou, T. C.; Guan, Y.; Tong, W. P.;
He, L.; Horwitz, S. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124,
9825. (e) Yamamoto, K.; Biswas, K.; Caul, C.; Danishefsky, S. J.
Tetrahedron Lett. 2003, 44, 3297. (f) Evano, G.; Schaus, J. V.; Panek, J. S.
Org. Lett. 2005, 7, 525.
Figure 2. Retrosynthetic analysis.
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Org. Lett., Vol. 8, No. 6, 2006

Scheme 1. Attempted Formation of Macrolide 10 by RCM
Scheme 2. Formation of Macrolides via RCM Reaction
the coupling constants for the newly formed double bond at
13,14
∆
are 15.0 and 15.3 Hz for compounds 15 and 16,
respectively, indicating the E-double bond was formed.12b
For product 16 the E/Z ratio for the newly formed double
bond at ∆13,14 is about 10/1.
Although we succeeded in making the 16-membered
macolides, one limitation of the above results was the
absence of a conjugated double bond at the bottom of
plecomacrolides. We therefore turned our attention to study-
ing the syntheses of 17-, 18-, and 19-membered macrolides
with essentially conjugated double bonds at both the bottom
and the top.
We envisaged that cyclization tendency for the larger ring
systems could be improved by addition one or more
methylene units to 9, in consideration of the ease of
attainment of proximity for reactive termini (head-to-tail).
With this regard, we first tested 17-membered macrolide
formation, and 17 and 19 (Scheme 3) were selected as
models, and their syntheses are provided in the Supporting
Information.
THF), and the formed product was converted to its acid 7
by treatment with TMSOK. Thus, after coupling it with
homoallylic alcohol 8, the expected product 9 was obtained
in 88% yield.
Unfortunately, when 9 was subjected to the treatment of
both Grubbs’ first- and second-generation catalysts under a
variety of reaction conditions, no desired product 10 was
obtained, and in most cases the starting material was
decomposed.
We attributed the difficulty in forming the macrocycle 10
to a problem in attaining the desired proximity of the reactive
termini (head-to-tail) due to the existing conjugated double
bond at ∆3,4 and ∆5,6. Thus, removal of the double bond at
∆
5,6 should improve the flexibility of substrate, which might
As expected, after treatment of 17 and 19 with Grubbs’
catalyst, the products 18 and 20 were obtained in 69% and
induce the cyclization.
Accordingly we made compound 11 without a double bond
at ∆5,6, and its annulation was tested with Grubbs’ first-
generation catalyst (10 mol %) under the conditions listed
in Scheme 2. We were very pleased to find that the expected
product 14 was obtained in 80% yield as a mixture of Z and
E isomers at ∆13,14 (Scheme 2).
Scheme 3. Syntheses of Macrolides 18 and 20
Although we tried to identify the ratio of the Z and E
isomers by 1H NMR analysis, the complexity of the splitting
pattern derived from the protons in the range of C11-C12
prevented this assignment. To overcome this difficulty, we
believed that by addition of a methyl group at C11 or a
methoxyl group at C15, the splitting patterns could be
simplified. To this end, we proposed two additional models
12 and 13, and the details for their preparation are provided
in the Supporting Information.
The annulation of 12 and 13 was carried out with Grubbs’
first-generation catalyst, and products 15 and 16 were
obtained in 40% and 78% yields, respectively. To our delight,
Org. Lett., Vol. 8, No. 6, 2006
1195

48% yields, respectively. However, their annulations needed
40 h to complete.
To this end, substrates 27 and 29 were made accordingly,
and their annulation was tested by Grubbs’ first-generation
catalyst, and the results are listed in Scheme 5. As expected,
It is of particular note that compounds 18 and 20 were
formed as an exclusive E-isomer. This result, together with
the observation for formation of compound 15 (Scheme 2)
from 12, illustrated that the presence of the methyl group at
C11 (12) and C12 (17) or the methoxyl group at C16 (19)
probably either promotes a favorable conformation for the
formation of E-isomer during the RCM reaction or increases
the final thermodynamic stability of the E-isomer versus the
Z-isomer.
Scheme 5. Syntheses of 19-Membered Macrolides via RCM
At this stage, it seemed to be that both the atom lengths
of the substrates and the substituents on the backbone have
a profound influence on the outcomes of the RCM reaction
speed and double bond geometry.
To evaluate this notion, substrates 21, 23, and 25 were
made and their cyclizations were evaluated with Grubbs’
first-generation of catalyst for making their corresponding
18-membered macrolides. As expected, the annulation
proceeded smoothly, yielding the products 22, 24, and 26 in
85%, 86%, and 65% yields, respectively (Scheme 4).
products 28 and 30 were obtained in 84% and 83% yields,
respectively. On the geometrical aspect, the cyclyzation
tendency for the formation of 19-membered macrolides is
less effective than the formation of 17- and 18-membered
macrolides, as evidence by the fact that the E/Z ratio at ∆16,17
for product 28 is about 6/1, while the exclusive E-isomers
for 18 and 24 were isolated from the reaction mixture.
In summary, we have shown for the first time that diene-
ene RCM is a suitable method for the formation of the
framework of plecomacrolides. This strategy was used for
the generation of a set of cyclic macrolides with ring sizes
varying from 16 to 19 atoms. It was found that conformation
and flexibility of substrates have a profound influence on
the geometrical outcomes of macrolides.18 Notably, we have
achieved geometrical control of the macrolides by addition
of substituents on the substrate backbones. Further studies
aimed at synthesizing some plecomacrolides are currently
underway in our laboratory and the results will be reported
in due course.
Scheme 4. Syntheses of 18-Membered Macrolides via RCM
Acknowledgment. We thank Professor Wei-Min Dai for
the helpful suggestion in this project. This work is funded
by the CNSF (grants 20272003 and 20472002.
Supporting Information Available: Experimental pro-
cedure and NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
Interestingly, the cyclization time for effecting annulation
extended as the substitutents on the backbone increased (cf.
5 h for 21, 18 h for 23, and 28 h for 25). As for the
geometrical outcomes, for product 22, we can observe the
E/Z isomers in the NMR spectrum for the newly formed
double bond at ∆15,16, while for products 23 and 25, the
exclusive E-isomers were isolated from the reaction mixtures,
indicating the critical influence of methyl and methoxyl
groups at C13 and C17 on substrate reaction speed and
geometrical product outcomes.
OL060221V
(18) The control of substrate conformation in determining the success
of RCM reactions, see: (a) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs,
R. H. J. Am. Chem. Soc. 1995, 117, 2108. (b) Martin, S. F.; Chen, H.-J.;
Courtney, A. K.; Liao, Y.; Patzel, M.; Ramser, M. N.; Wagman, A. S.
Tetrahedron 1996, 52, 7251. (c) Furstner, A.; Langeman, K. J. Org. Chem.
1996, 61, 8746. (d) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38,
127. (e) Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda,
A. H. J. Am. Chem. Soc. 1996, 118, 4291. (f) Furstner, A.; Langemann, K.
J. Org. Chem. 1996, 61, 3942. (g) Delgado, M.; Martin, J. D. Tetrahedron
Lett. 1997, 38, 6299. (h) Crimmins, M. T.; Choy, A. L. J. Org. Chem.
1997, 62, 7548. (i) Linderman, R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H.
J. Am. Chem. Soc. 1997, 119, 6919. (j) Commeureuc, A. G. J.; Murphy, J.
A.; Dewis, M. L. Org. Lett. 2003, 5, 2785.
Encouraged by the above results, we would like to extend
the scope of this method for making 19-membered mac-
rolides 28 and 30 from substrates 27 and 29 by the diene-
ene RCM.
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