The first total synthesis of concanamycin F (concanolide A)

Article abstract of DOI:10.1021/jo001377q

A highly stereoselective total synthesis of the macrolide antibiotic concanamycin F (1), a specific and potent inhibitor of vacuolar H⁺-ATPase, has been achieved by a convergent route involving the synthesis and coupling of its 18-membered tetraenic lactone and β-hydroxyl hemiacetal side chain subunits. The C1-C19 18-membered lactone aldehyde 4 was synthesized through the intermolecular Stille coupling of the C5-C13 vinyl iodide 24 and the C14-C19 vinyl stannane 25, followed by construction of the C1-C4 diene and macrolactonization. Synthesis of 4 via a second convergent route including the esterification of the C1-C13 vinyl iodide 45 and the C14-C19 vinyl stannane 47 followed by the intramolecular Stille coupling was also realized. The highly stereoselective aldol coupling of 4 and the C20-C28 ethyl ketone 5 followed by desilylation provided 1 which was identical with natural concanamycin F.

Full text of DOI:10.1021/jo001377q

1708
J . Org. Chem. 2001, 66, 1708-1715
Th e F ir st Tota l Syn th esis of Con ca n a m ycin F (Con ca n olid e A)
Kazunobu Toshima,* Takaaki J yojima,1 Naoki Miyamoto, Masataka Katohno,
Masaya Nakata, and Shuichi Matsumura
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, J apan
toshima@applc.keio.ac.jp
Received September 15, 2000
A highly stereoselective total synthesis of the macrolide antibiotic concanamycin F (1), a specific
and potent inhibitor of vacuolar H+-ATPase, has been achieved by a convergent route involving
the synthesis and coupling of its 18-membered tetraenic lactone and â-hydroxyl hemiacetal side
chain subunits. The C1-C19 18-membered lactone aldehyde 4 was synthesized through the
intermolecular Stille coupling of the C5-C13 vinyl iodide 24 and the C14-C19 vinyl stannane 25,
followed by construction of the C1-C4 diene and macrolactonization. Synthesis of 4 via a second
convergent route including the esterification of the C1-C13 vinyl iodide 45 and the C14-C19 vinyl
stannane 47 followed by the intramolecular Stille coupling was also realized. The highly
stereoselective aldol coupling of 4 and the C20-C28 ethyl ketone 5 followed by desilylation provided
1 which was identical with natural concanamycin F.
In tr od u ction
structural feature of this class of macrolides is an
unusual 18-membered tetraenic lactone ring with a
methyl enol ether and a â-hydroxy hemiacetal side chain
with/without the 2-deoxy-â-D-rhamnose moiety. Although
the other polyketide macrolides such as the bafilomy-
cins,6,7 the hygrolidins,8,9 and the recently discovered
formamicin10 are closely related to the concanamycins,
the concanamycins possess one of the most complex
architectures among them. Because of the unique struc-
tural and impressive biological features of concanamy-
cins, great effort has been devoted to the chemical
synthesis of 1 and 2. Previously, we reported the syn-
thesis of the C20-C28 fragment of 1 and 2 starting from
carbohydrate building blocks11 and the first total syn-
thesis of 1 as communications.12 Elegant synthetic studies
of the C19-C28 and C1-C13 segments of 1 and 2 have
The concanamycins A-F,2 a new class of 18-membered
macrolide antibiotics, are potent and specific inhibitors
of vacuolar H+-ATPase attracting particular interest.3
The ability of the concanamycins to disrupt cellular
acidification leads to a wide range of diverse biological
activity such as antiviral4a and immunosuppressant4b
activity and the attenuation of resistance in MDR tumor
cell lines.4c Furthermore, concanamycins as well as
bafilomycins have attracted attention as candidates of
novel therapeutic agents for osteoporosis.4d,e Concana-
mycin A (2), first isolated in 1981 by Kinashi et al.,2a,c is
a major component of concanamycins; the structure and
absolute configuration have been established by chemical
degradation,2a NMR analysis,2a and X-ray crystallo-
graphic analysis2d of its diacetate derivative. On the other
hand, concanolide A (1) is the common aglycon of both
concanamycins A (2) and C (3); it also identical with
natural concanamycin F.2e,5 The most striking and unique
(5) Bindseil, K. U.; Zeeck, A. J . Org. Chem. 1993, 58, 5487.
(6) Isolation: (a) Werner, G.; Hagenmaier, H.; Albert, K.; Kohlshorn,
H.; Drautz, H. Tetrahedron Lett. 1983, 24, 5193. (b) Werner, G.;
Hagenmaier, H.; Drautz, H.; Baumgartner, A.; Za¨hner, H. J . Antibiot.
1984, 37, 110.
* To whom correspondence should be addressed. Tel: +81-45-566-
1576. Fax: +81-45-566-1576.
(7) Synthesis: (a) Toshima, K.; J yojima, T.; Yamaguchi, H.; Murase,
H.; Yoshida, T.; Matsumura, S.; Nakata, M. Tetrahedron Lett. 1996,
37, 1069. (b) Toshima, K.; Yamaguchi, H.; J yojima, T.; Noguchi, Y.;
Nakata, M.; Matsumura, S. Tetrahedron Lett. 1996, 37, 1073. (c)
Toshima, K.; J yojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida, T.;
Murase, H.; Nakata, M.; Matsumura, S. J . Org. Chem. 1997, 62, 3271.
(d) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871. (e)
Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 33, 3587. (f)
Roush, W. R.; Bannister, T. D.; Wendt, M. D. Tetrahedron Lett. 1993,
34, 8387. (g) Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M.
D.; Roush, W. R. Angew. Chem., Int. Ed. 1999, 38, 1652. (h) Paterson,
I.; Bower, S.; Mcleod, M. D. Tetrahedron Lett. 1995, 36, 175-178.
(8) Isolation: (a) Seto, H.; Akao, H.; Furihata, K.; Otake, N.
Tetrahedron Lett. 1982, 23, 2667. (b) Seto, H.; Tajima, I.; Akao, H.;
Furihata, K.; Otake, N. J . Antibiot. 1984, 37, 610.
(9) Synthesis: (a) Makino, K.; Kimura, K.; Nakajima, N.; Hashimoto,
S.; Yonemitsu, O. Tetrahedron Lett. 1996, 37, 9073. (b) Makino, K.;
Nakajima, N.; Hashimoto, S.; Yonemitsu, O. Tetrahedron Lett. 1996,
37, 9077.
(10) Isolation: (a) Igarashi, M.; Kinoshita, N.; Ikeda, T.; Nakagawa,
E.; Hamada, M.; Takeuchi, T. J . Antibiot. 1997, 50, 926. (b) Igarashi,
M.; Nakamura, H.; Naganawa, H.; Takeuchi, T. J . Antibiot. 1997, 50,
932.
(1) Taken in part from the Ph.D. thesis of Takaaki J yojima, Keio
University, 2000.
(2) (a) Kinashi, H.; Someno, K.; Sakaguchi, K.; Higashijima, T.;
Miyazawa, T. Tetrahedron Lett. 1981, 22, 3857 and 3861. (b) Kinashi,
H.; Sakaguchi, K.; Higashijima, T.; Miyazawa, T. J . Antibiot. 1982,
35, 1618. (c) Kinashi, H.; Someno, K.; Sakaguchi, K. J . Antibiot. 1984,
37, 1333. (d) Westley, J . W.; Liu, C.-M.; Sello, L. H.; Evans, R. H.;
Troupe, N.; Blount, J . F.; Chiu, A. M.; Todaro, L. J .; Miller, P. A. J .
Antibiot. 1984, 37, 1738. (e) Woo, J .-T.; Shinohara, C.; Sakai, K.;
Hasumi, K.; Endo, A. J . Antibiot. 1992, 45, 1108. (f) Ishii, T.; Hida, T.;
Iinuma, S.; Muroi, M.; Nozaki, Y. J . Antibiot. 1995, 48, 12.
(3) (a) Bowman, E. J .; Siebers, A.; Altendorf, K. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 7972. (b) Dro¨se, S.; Bindseil, K. U.; Bowman, E.
J .; Siebers, A.; Zeeck, A.; Altendorf, K. Biochemistry 1993, 32, 3902.
(4) (a) Guinea, R.; Carrasco, L. Biochem. Biophys. Res. Commun.
1994, 201, 1270. (b) Kataoka, T.; Shinohara, N.; Takayama, H.;
Takaku, K.; Kondo, S.; Yonehara, S.; Nagai, K. J . Immunol. 1996, 156,
3678. (c) Altan, N.; Chen, Y.; Schindler, M.; Simon, S. M. J . Exp. Med.
1998, 187, 1583. (d) Woo, J .-T.; Ohba, Y.; Tagami, K.; Sumitani, K.;
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S.; Nadler, G.; Consolandi, E.; Parini, C.; Morvan, M.; Legave, M. N.;
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M.; Farina, C. J . Med. Chem. 1998, 41, 1568.
(11) Toshima, K.; Misawa, M.; Ohta, K.; Tatsuta, K.; Kinoshita, M.
Tetrahedron Lett. 1989, 30, 6417.
10.1021/jo001377q CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/07/2001

Total Synthesis of Concanamycin F
J . Org. Chem., Vol. 66, No. 5, 2001 1709
ethyl ketone 5 and aldol coupling of 4 and 5 leading to
the total synthesis of 1, are described in the following
discussion.
Resu lts a n d Discu ssion
Syn th esis of th e C5-C13 Segm en t 24. The synthe-
sis of the suitably protected vinyl iodide 24 corresponding
to the C5-C13 segment of 1 is summarized in Scheme
1. The 1,3-diol of the starting material 8 (erythro/threo
) 85:15), which was readily obtained from D-malic acid
by Seebach’s alkylation method,18 was first regioselec-
tively protected by formation of the p-methoxyben-
zylidene to give the pure primary alcohol 9 in 64% yield.
Swern oxidation of 9 followed by Grignard reaction using
EtMgBr in Et2O at 25 °C for 3 h afforded the secondary
alcohol 11 in 87% overall yield. The secondary alcohol
11 was subjected to Swern oxidation and then Wittig
reaction employing Ph3PdCH2 in benzene to furnish 13
in 88% overall yield. As expected from our bafilomycin
A1 synthesis,7a,c substrate-controlled hydroboration of 13
utilizing dicyclohexylborane in THF at room temperature
for 3 h proceeded with complete stereoselectivity to give
only the desired alcohol 14 in 89% yield after the
subsequent oxidative workup. Swern oxidation of the
resultant alcohol 14 yielded the aldehyde 15 which was
subjected to Evans’ aldol reaction19 using N-propionyl-
(4S)-benzyl-2-oxazolidinone, n-Bu2BOTf, and Et3N in
CH2Cl2 at -78-0 °C for 2 h to give the desired aldol 16
as the sole isomer in 81% overall yield from 14. Removal
of the chiral auxiliary in 16 using LiBH4 and EtOH in
Et2O at -10 °C for 1 h gave the diol 17 in quantitative
yield. Regioselective tosylation of the primary alcohol in
17 (TsCl, Py, 97%) and the silylation with tert-butyldi-
methylsilyl (TBS) group (TBSOTf, 2,6-lutidine, CH2Cl2,
99%) of the resultant alcohol 18 yielded the tosylate 19
which was subjected to the reaction with 5 equiv of
lithium acetylide in dimethyl sulfoxide (DMSO) to give
the acetylene 20 in 69% yield. Unfortunately, introduc-
tion of acetylene into the tosylate 18 under similar
conditions was unsuccessful. After concurrent deprotec-
tion of the p-methoxybenzylidene and silyl groups in 20
under acidic conditions (HF (aq), THF-MeCN, 70%), the
resultant triol 21 was selectively pivaloylated (PvCl, Py,
4-(dimethylamino)pyridine (4-DMAP), CH2Cl2) at the
primary alcohol and then silylated with diethylisopro-
pylsilyl (DEIPS) group20 using DEIPSOTf and 2,6-luti-
dine in CH2Cl2 to furnish the acetylene 23 in 82%
overall yield. Finally, treatment of 23 with Cp2ZrCl2,
F igu r e 1. Molecular structures of concanamycin F (concano-
lide A), concanamycin A, and concanamycin C.
been announced by Paterson’s group, and the total
synthesis of concanamycin F (1) has also been described
recently by his group.13 In this paper, we describe the
full account of our first total synthesis of the architectur-
ally and biologically attractive natural product, concana-
mycin F (concanolide A) (1) (Figure 1).
Syn th etic P la n . The retrosynthetic analysis of con-
canamycin F (concanolide A) (1) is shown in Figure 2.
Central to our synthetic strategy for 1 was the stereo-
selective aldol reaction14 of macrocyclic lactone aldehyde
B and ethyl ketone C, followed by deprotection of aldol
A. The synthetic plan for the 18-membered lactone B was
based on the effective three-component assembly of the
suitably protected C1-C4 D, C5-C13 E, and C14-C19
F . In the synthetic direction, each of these analogues’
bond constructions is based on powerful synthetic reac-
tions. For example, the synthesis of dienes through the
Pd(0)-catalyzed coupling of vinyl halides and vinyl stan-
nanes (Stille coupling)15,16 is reported to work well with
highly functionalized coupling partners. The synthesis
of dienes by the Wittig reaction also has a high potential.
Furthermore, the highly evolved methods for esterifica-
tion or macrolactonization are currently available.17 The
highly stereoselective synthesis of an appropriately pro-
tected 18-membered lactone aldehyde 4, which makes use
of the fragments 6, 7, and D, and a suitably protected
(12) For our preliminary communications of this work, see: (a)
J yojima, T.; Katohno, M.; Miyamoto, N.; Nakata, M.; Matsumura, S.;
Toshima, K. Tetrahedron Lett. 1998, 39, 6003. (b) J yojima, T.; Miya-
moto, N.; Katohno, M.; Nakata, M.; Matsumura, S.; Toshima, K.
Tetrahedron Lett. 1998, 39, 6007.
(13) (a) Paterson, I.; McLeod, M. D. Tetrahedron Lett. 1995, 36, 9065.
(b) Paterson, I.; McLeod, M. D. Tetrahedron Lett. 1997, 38, 4183. (c)
Paterson, I.; Doughty, V. A.; McLeod, M. D. Trieselmann, T. Angew.
Chem., Int. Ed. 2000, 39, 1308.
(17) For references on macrolactonization in macrolide synthesis,
see: (a) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569. (b)
Boeckman, R. K.; Goldstein, S. W. In The Total Synthesis of Natural
Products; Aspimon, J ., Ed.; Wiley: New York, 1988; Vol. 7, p 1. (c)
Tatsuta, K. In Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G., Ohno, M., Eds.; Springer-Verlag: Berlin Heidelberg, 1990;
p 1.
(14) For some reviews on stereoselective aldol reaction, see: (a)
Evans, D. A.; Nelson, J . V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(b) Mukaiyama, T. Org. React. 1882, 28, 203. (c) Heathcock, C. H. In
Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: New
York, 1984; Vol. 3, p 111. (d) Braun, M. Angew. Chem., Int. Ed. Engl.
1987, 26, 24. (e) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987,
26, 489. (f) Paterson, I.; Cowden, C. J . Org. React. 1997, 51, 1.
(15) (a) Milstein D.; Stille, J . K. J . Am. Chem. Soc. 1978, 100, 3636.
(b) Milstein, D.; Stille, J . K. J . Am. Chem. Soc. 1979, 101, 4992.
(16) For some reviews on Stille coupling, see: (a) Stille, J . K. Angew.
Chem., Int. Ed. Eng. 1986, 25, 508. (b) Duncton, M. A. J .; Pattenden
G. J . Chem. Soc., Perkin Trans. 1 1999, 1235.
(18) Zuger, M.; Weller, T.; Seebach, D. Helv. Chim. Acta 1980, 63,
2005.
(19) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc.
1981, 103, 2127. (b) Gage, J . R.; Evans, D. A. Org. Synth, 1989, 68, 77
and 83.
(20) (a) Toshima, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron Lett.
1986, 27, 4741. (b) Toshima, K.; Tatsuta, K.; Kinoshita, M. Bull. Chem.
Soc. J pn. 1988, 61, 2369. (c) Toshima, K.; Mukaiyama, S.; Kinoshita,
M.; Tatsuta, K. Tetrahedron Lett. 1989, 30, 6413. (d) Toshima, K.;
Yanagawa, K.; Mukaiyama, S.; Tatsuta, K. Tetrahedron Lett. 1990,
31, 6697. The silylating reagents, DEIPS-Cl and DEIPS-OTf, are now
commercially available from Tokyo Kasei Kogyo Co., Ltd.

1710 J . Org. Chem., Vol. 66, No. 5, 2001
Toshima et al.
F igu r e 2. Retrosynthetic analysis of concanamycin F (1).
Me3Al, and I2 in 1,2-dichloroethane21 afforded the trisub-
stituted trans vinyl iodide 24 in 88% yield. The trans
configuration of the trisubstituted olefin of 24 was clearly
confirmed by NOE experiments. Thus, NOE between the
vinyl hydrogen and the methylene hydrogens was ob-
served while no NOE between the vinyl hydrogen and
the methyl group at the vinyl position was detected.
Furthermore, the DEIPS groups in 24 were key protect-
ing groups for the total synthesis of 1 because it was
found that, in contrast to the corresponding triethylsilyl,
tert-butyldimethylsilyl, and p-methoxybenzyl ethers, this
silyl ether had sufficient stability in subsequent reac-
tions, while still offering reasonable lability in the final
deprotection step using tetrabutylammonium fluoride
(TBAF) in THF.
Syn th esis of th e C1-C19 Ma cr ocyclic La cton e via
Ma cr ola cton iza tion . With the suitably protected vinyl
iodide 24 corresponding to the C5-C13 fragment of 1 in
hand, the synthesis of the C1-C19 macrocyclic lactone
via macrolactonization was first addressed (Scheme 2).
We examined the cross coupling reaction between the
vinyl iodide 24 and the vinyl stannane 25, which was
recently synthesized in our laboratory,7a,c by Stille
method15,16 under several conditions. From the results
shown in Table 1, the use of Pd2(dba)3 in the presence of
Ph3As and LiCl in N-methylpyrrolidinone (NMP) was
found to be superior in this coupling reaction. Thus, the
reaction of 1 equiv of 24 and 1 equiv of 25 using a
catalytic amount of Pd2(dba)3 in the presence of Ph3As
and LiCl in N-methylpyrrolidinone (NMP)22 at 40 °C for
16 h proceeded effectively to afford the desired E,E-diene
26 in 72% yield as the only isolated product. The 1H NMR
spectrum of 26, interestingly, showed that it consisted
1
of a ca. 3:1 inseparable mixture. The H NMR spectra of
29, 30, and 33 also showed similar phenomenon. On the
1
other hand, it was found that the H NMR spectra of the
desilylation product of 26 and the conformationally rigid
lactone 37 indicated that they are single compounds.
Therefore, it is reasonable to assume that this insepa-
rable mixture should be due to the conformational
isomers.7c Deprotection of the pivaloyl group in 26 using
methyllithium in Et2O, followed by Swern oxidation of
the resultant alcohol 27, gave the aldehyde 28. At this
stage, we first tried the Horner-Wadsworth-Emmons
(21) (a) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J .
Org. Chem. 1981, 46, 4093. (b) Yoshida, Y.; Negishi, E. J . Am. Chem.
Soc. 1981, 103, 4985.
(22) (a) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J . Org. Chem. 1994, 59, 5905.

Total Synthesis of Concanamycin F
J . Org. Chem., Vol. 66, No. 5, 2001 1711
Sch em e 1a
a
Reagents and conditions: (a) (MeO)2CHC6H4OMe, CSA, CH2Cl2, r.t., 16 h, 64%; (b) (COCl)2, DMSO, TEA, CH2Cl2, -78 °C, 20 min;
(c) EtMgBr, Et2O, r.t., 3 h, 87% from 9; (d) (COCl)2, DMSO, TEA, CH2Cl2, -78 °C, 20 min; (e) Ph3PdCH2, PhH, r.t., 0.5 h, 88% from 11;
(f) BH3‚Me2S, C6H10, THF, r.t., 3 h then NaOH-H2O, H2O2, 50 °C, 1 h, 89%; (g) (COCl)2, DMSO, TEA, CH2Cl2, -78 °C, 20 min; (h)
N-propionyl-(4S)-benzyl-2-oxazolidinone, n-Bu2BOTf, Et3N, CH2Cl2, -78-0 °C, 2 h, 81% from 14; (i) LiBH4, EtOH, Et2O, -10 °C, 1 h,
100%; (j) TsCl, Py, r.t., 2 h, 97%; (k) TBSOTf, 2,6-lutidine, CH2Cl2, r.t., 2 h, 99%; (l) HCtCLi, DMSO, r.t., 3 h, 69%; (m) HF (aq), THF,
MeCN, 40 °C, 48 h, 70%; (n) PvCl, 4-DMAP, Py, CH2Cl2, r.t., 16 h, 83%; (o) DEIPSOTf, 2,6-lutidine, CH2Cl2, r.t., 4 h, 99%; (p) Cp2ZrCl2,
Me3Al, I2, (ClCH2)2, r.t., 16 h, 88%.
Sch em e 2a
a
Reagents and conditions: (a) Pd2(dba)3, Ph3As, LiCl, NMP, 40 °C, 16 h, 72%; (b) MeLi, Et2O, r.t., 0.5 h, 96%; (c) (COCl)2, DMSO,
Et3N, CH2Cl2, -78 °C, 20 min; (d) Ph3PdC(Me)CO2Et, PhMe, 100 °C, 16 h, 89% from 27; (e) DIBAL, PhMe, -78 °C, 0.5 h, 90%; (f) MnO2,
CH2Cl2, r.t., 1.5 h, 100%; (g) KHMDS, 18-crown-6, THF, -20 °C, 16 h, 99%; (h) PPTS, MeOH, r.t., 1 h, 96%; (i) MTrCl, Et3N, 4-DMAP,
CH2Cl2, r.t., 3 h, 100%; (j) 1 N KOH, 1,4-dioxane, 80 °C, 3 h, 82%; (k) 2,4,6-trichlorobenzoyl chloride, Et3N, THF (0.01 M for 36), 4-DMAP,
PhMe (0.002 M for 36), 110 °C, 14 h, 82%.
reaction of 28 and D′7c to construct the C1-C4 diene in
one step. However, this reaction in the presence of several
bases such as lithium bis(trimethylsilyl)amide (LiH-
MDS), sodium bis(trimethylsilyl)amide (NaHMDS), po-
tassium bis(trimethylsilyl)amide (KHMDS), and NaH
caused only â-elimination of 28 even at low temperature,
and the desired tetraene 33 was not obtained at all.
Therefore, stepwise construction of the diene, which

1712 J . Org. Chem., Vol. 66, No. 5, 2001
Toshima et al.
yield (%)
Ta ble 1. Th e Cr oss Cou p lin gs of 24 a n d 25 by P d Ca ta lyts
24 (1 equiv) + 25 (1 equiv) f 26
entry
Pd catalyst (equiv)
additive(s) (equiv)
solvent
T (°C)
time (h)
1
2
3
4
PdCl2(dppf) (0.25)
PdCl2(dppf) (0.2)
Pd2(dba)3 (0.2)
none
LiCl (3.0)
CuI (0.4), Ph3As (0.8)
LiCl (3.0), Ph3As (2.0)
DMF
NMP
NMP
NMP
40
40
40
40
15
16
16
16
43
49
68
72
Pd2(dba)3 (0.25)
Sch em e 3a
a
Reagents and conditions: (a) DIBAL, PhMe, -78 °C, 15 min, 90%; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 20 min; (c)
Ph3PdC(Me)CO2Et, PhMe, 100 °C, 16 h, 92% from 38; (d) DIBAL, PhMe, -78 °C, 15 min, 92%; (e) Cp2ZrCl2, AlMe3, I2, (CH2Cl)2, r.t., 16h,
84%; (f) MnO2, CH2Cl2, r.t., 1.5 h, 96%; (g) KHMDS, 18-crown-6, THF, -20 °C, 16 h, 96%; (h) 1 N KOH, 1,4-dioxane, 80 °C, 3 h, 95%; (i)
PPTS, MeOH, r.t., 2 h, 81%; (j) MTrCl, Et3N, 4-DMAP, CH2Cl2, r.t., 1 h, 96%; (k) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 4-DMAP,
PhMe, r.t., 16 h, 79%; (l) Pd2(dba)3, Ph3As, i-PrNEt2, DMF-THF, 60 °C, 18 h, 72%.
included the use of the base free Wittig reagent in the
first step, was next carried out. The Wittig reaction of
28 with ethyl 2-(triphenylphosphoranylidene)propionate
in toluene at 100 °C for 16 h proceeded smoothly to yield
only the trans isomer 29 in 89% overall yield from 27.
Reduction of the ethyl ester in 29 using diisobutylalu-
minum hydride (DIBAL) in toluene at -78 °C afforded
the allyl alcohol 30 in 90% yield. Oxidation of 30
employing MnO2 provided the R,â-unsaturated aldehyde
31 which was subjected to Horner-Wadsworth-Emmons
reaction with phosphonic ester 3223 using potassium bis-
(trimethylsilyl)amide (KHMDS) in the presence of 18-
crown-612b,24 in THF at -20 °C to give the desired cis-
isomer 33 (E/Z ) 1:>99) in 99% overall yield. The
isopropylidene group in 33 was removed under mild
acidic conditions using pyridinium p-toluenesulfonate
(PPTS) in MeOH, and then the resultant diol 34 was
selectively protected with a monomethoxytrityl (MTr)
group (MTrCl, Et3N, 4-DMAP, CH2Cl2) to afford the
secondary alcohol 35 in 96% overall yield. Hydrolysis of
the methyl ester of 35 under basic conditions (1 N KOH,
1,4-dioxane) yielded the carboxylic acid 36 in 82% yield.
The macrolactonization of the seco-acid 36 to construct
the 18-membered lactone ring was best effected by the
Yamaguchi method25 under high dilution conditions to
give the macrocyclic lactone 37 in 82% yield. We found
that the low concentration of 36 in THF (0.01 M) in the
formation of the mixed anhydride of 36 and 2,4,6-
trichlorobenzoyl chloride was very important to get a high
yield of 37. When the mixed anhydride formation was
performed at normal concentration (0.1 M), significant
amounts of a byproduct from the isomerization of the
C1-C4 diene in 36 was produced.
Syn th esis of th e C1-C19 Ma cr ocyclic La cton e via
In tr a m olecu la r Stille Cou p lin g. The effective synthe-
sis of the macrocyclic lactone 37 was also achieved by
another route involving intramolecular Stille coupling16b
(Scheme 3). The fully protected acetylene 23 was first
converted into the allyl alcohol 41 in high overall yield
(4 steps, 76% overall yield) by a series of reactions
presented in the synthesis of 30 from 26. At this stage,
the acetylene 41 was effectively transformed to the vinyl
iodide 42 in 84% yield via zirconium-catalyzed carboalu-
mination.21 Oxidation of 42 using MnO2 provided the R,â-
unsaturated aldehyde 43 which was subjected to the
previously mentioned Horner-Wadsworth-Emmons re-
action with 3223 to give the desired cis isomer 44 (E/Z )
1:>99) in 92% overall yield. Hydrolysis of 44 under basic
conditions using 1 N KOH in 1,4-dioxane yielded the
carboxylic acid 45 in 95% yield. The esterification of the
carboxylic acid 45 and the secondary alcohol 47 were
examined at this stage. The secondary alcohol 47 was
derived from 25 in two steps involving deisopropylide-
nation and regioselective protection with MTr group.
From the results shown in Table 2, the esterification of
the carboxylic acid 45 and the secondary alcohol 47
proceeded smoothly by the modified Yamaguchi method25
at 25 °C to give the ester 48 in 79% yield. It was found
that when 1,3-dicyclohexylcarbodiimide (DCC) was used
as an esterification reagent, only dimeric anhydride 45′
was produced. The cyclization of 48 by intramolecular
Stille coupling16b was next examined under several
(23) Grell, W.; Machleidt, H. Liebigs Ann. Chem. 1966, 699, 53.
(24) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 41, 4405.
(25) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.

Total Synthesis of Concanamycin F
J . Org. Chem., Vol. 66, No. 5, 2001 1713
Ta ble 2. Ester ifica tion of 45 w ith 47
Ta ble 3. In tr a m olecu la r Stille Cou p lin g Rea ction of 48
48 f 37
entry
Pd catalyst (equiv)
additive(s) (equiv)
solvent
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
Pd(Ph3)4 (0.2)
PdCl2(dppf) (0.2)
Pd2(dba)3 (0.2)
Pd2(dba)3 (0.2)
Pd2(dba)3 (0.2)
Pd2(dba)3 (0.2)
Pd2(dba)3 (0.2)
i-Pr2NEt (3.0)
i-Pr2NEt (3.0)
Ph3As (2.0)
LiCl (3.0), Ph3As (2.0)
CuI (3.0), Ph3As (2.0)
i-Pr2NEt (3.0), Ph3As (2.0)
i-Pr2NEt (3.0), Ph3As (2.0)
DMF-THF
DMF-THF
NMP
NMP
NMP
DMF-THF
DMF-THF
60
60
25
25
25
60
25
18
16
15
18
18
18
18
67
57
61
66
35
72
55
conditions. From the results shown in Table 3, 48 was
effectively cyclized using a catalytic amount of Pd2(dba)3
in the presence of Ph3As and i-PrNEt2 in DMF-THF(1:
1)22 at 60 °C for 18 h to furnish the 18-membered lactone
37 in 72% yield as the only isolated product. Further-
more, it was found that high dilution conditions were not
necessary for getting a high yield of 37.
Regioselective dihydroxylation of the terminal olefin in
52 was best effected by Sharpless method29,30 using the
bulky reagent, AD-mix-R, in t-BuOH-H2O to give the diol
53 in 50% yield. Oxidative cleavage of the diol in 53 using
NaIO4 gave the aldehyde 54 in 95% yield. Mukaiyama
aldol reaction31 of 54 and the silyl enol ether 55 using
BF3‚Et2O in CH2Cl2 at -78 °C for 1 h proceeded smoothly
to furnish the Cram product, ethyl ketone 56, in 60%
yield as a sole aldol product. Treatment of 56 with DDQ
in CH2Cl2 gave the fully protected ethyl ketone 57 in 69%
yield.32 However, the ethyl ketone 57 was unfortunately
found to be not suitable for aldol reactions using several
boron reagents due to the removal of the p-methoxyben-
zylidene group. Therefore, 57 was converted into the
Syn th esis of th e C20-C28 Segm en t 5. The im-
proved11 asymmetric synthesis of the ethyl ketone 5
corresponding to the C20-C28 segment of concanamycin
F (1) from trans-crotonaldehyde (49) is depicted in
Scheme 4. The reaction of trans-crotonaldehyde and
Brown’s chiral (E)-crotyldiisopinocamphenylborane 50,26
which was prepared from trans-2-butene, n-BuLi, and
(-)-Ipc2BOMe, in the presence of BF3‚Et2O in THF-Et2O
at -78 °C for 2 h, gave the allyl alcohol 51 (>99% ee)27
in 58% yield with 1:14 syn/anti selectivity. p-Methoxy-
benzylation of the resultant alcohol 51 with p-methoxyl-
benzyl trichloroacetimidate28 gave 52 in 75% yield.
(28) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139.
(29) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(30) Andrus, M. B.; Lepore, S. D.; Sclafani, J . A. Tetrahedron Lett.
1997, 38, 4043.
(31) Mukaiyama, T.; Banno, K.; Narasaka, K. J . Am. Chem. Soc.
1974, 96, 7503.
(32) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889.
(26) Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 22, 1037.
(27) Hiyama, T.; Kimura, K.; Nozaki, H. Tetrahedron Lett. 1981,
22, 1037.

1714 J . Org. Chem., Vol. 66, No. 5, 2001
Toshima et al.
Sch em e 4a
a
Reagents and conditions: (a) BF3‚Et2O, THF/Et2O, -78 °C, 2h, 58%; (b) MeOC6H4CH2OC(dNH)CCl3, CSA, CH2Cl2, r.t., 14 h, 75%;
(c) AD-mix-R, t-BuOH/H2O, r.t., 19 h, 50%; (d) NaIO4, MeOH/H2O, r.t., 0.5 h, 95%; (e) BF3‚Et2O, CH2Cl2, -78 °C, 1 h, 60%; (f) DDQ,
CH2Cl2, 0 °C, 1.5 h, 69%; (g) NaBH4, MeOH/CH2Cl2, 0 °C, 2 h, 67%; (h) Ac2O, 4-DMAP, Py, r.t., 17 h, 95%; (i) AcOH/THF/H2O ) 1:1:1,
40 °C, 0.5 h, 90%; (j) t-Bu2Si(OTf)2, 2,6-lutidine, DMF, 0 °C, 2 h, 84%; (k) NaOMe, MeOH, r.t., 4 h, 91%; (l) Dess-Martin periodinane, Py,
CH2Cl2, r.t., 2.5 h, 93%.
Sch em e 5a
a
Reagents and conditions: (a) PPTS, MeOH, r.t., 5 h, 94%; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 20 min, 94%; (c) PhBCl2, i-Pr2NEt,
CH2Cl2, -78 °C, 1.5 h, 84%; (d) HF-Py, THF, 0 °C, 15 min, 94%; (e) TBAF, THF, r.t., 2.5 h, 59%.
suitably protected ethyl ketone 5 by standard procedures.
Reduction of 57 using NaBH4, followed by acetylation,
gave the acetate 59 in 64% overall yield. Deprotection of
p-methoxybenzylidene group under acidic conditions gave
the diol 60, which was silylated with a di-tert-butylsilyl
group to give 61 in 76% overall yield. Finally, deacetyl-
ation of 61 followed by Dess-Martin oxidation33 gave the
suitably protected ethyl ketone 5 in 85% overall yield.
The cyclic protection at the C5 and C7 positions in 5 was
required for a high level of aldol stereoselectivity as
suggested by bafilomycin A1 syntheses.7b-d
which was subjected to Swern oxidation to furnish the
18-membered macrolactonic aldehyde 4 in 89% overall
yield. We next attempted the stereoselective connection
of 4 and 5 by an aldol reaction. The aldol condensation
between 1 equiv of 4 and 2 equiv of 5 was best achieved
5b-d,9b,34,35
using PhBCl2
and i-Pr2NEt in CH2Cl2 at -78
°C for 1.5 h to produce the desired aldol 64 as the sole
isomer in 84% yield. Finally, successful removal of the
silyl protecting groups of 64 necessitated stepwise treat-
ment with HF-Py to give the hemiacetal 65 (94%),
followed by tetrabutylammonium fluoride (TBAF) treat-
ment to remove the DEIPS ethers (59%). Thus, the
obtained 1 was identical to an authentic sample of
natural concanamycin F (concanolide A) based on 1H
Tot a l Syn t h esis of 1. With the effective synthesis
of the 18-membered lactone 37 and the ethyl ketone 5,
total synthesis of 1 was addressed (Scheme 5). Treat-
ment of 37 with PPTS in MeOH gave the alcohol 63
(34) Evans, D. A.; Fitch, D. M. J . Am. Chem. Soc. 1997, 62, 454.
(35) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984,
1729.
(33) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.

Total Synthesis of Concanamycin F
J . Org. Chem., Vol. 66, No. 5, 2001 1715
NMR, [R]D (synthetic, [R]25 +10.3° (c 0.17, CHCl3);
m), 1.77 (1H, dd, J ) 14.0 and 14.0 Hz), 1.72 (3H, dd, J ) 1.8
and 7.0 Hz), 1.35-1.15 (2H, m), 1.16 (3H, d, J ) 7.2 Hz), 1.10-
0.85 (59H, m), 0.76-0.69 and 0.55-0.40 (each 4H, m). Anal.
Calcd for C61H112O10Si3: C, 67.23; H, 10.36. Found: C, 67.42;
H, 10.29.
D
natural, [R]20D +11.0° (c 0.30, CHCl3)), and TLC behaviors
in several solvent systems.2e,5
Con clu sion s
Di-DEIP S-Con ca n a m ycin F 65. Rf 0.38 (3/2 n-hexane/
EtOAc); [R]25 +62.49° (c 0.24, CHCl3); mp 96.9-97.5 °C (n-
D
The first total synthesis of concanamycin F, a specific
inhibitor of vacuolar H+-ATPase, has been completed
using three principle subunits. Our total synthesis is
characterized by high convergency and stereocontrol at
several stages. This synthetic strategy should find wide
application in the synthesis of other structurally related
and biologically important macrolide antibiotics and for
the synthesis of designed concanamycin analogues with
potential applications in biology and medicine.
hexane, thin plate); 1H NMR δ 6.60 (1H, dd, J ) 11.2 and 15.2
Hz), 6.07 (1H, s), 5.85 (1H, d, J ) 11.2 Hz), 5.76 (1H, s), 5.70
(1H, d, J ) 9.6 Hz), 5.52 (1H, dq, J ) 6.8 and 15.2 Hz), 5.27
(1H, d, J ) 15.2 Hz), 5.23 (1H, d, J ) 15.2 Hz), 5.01 (1H, d, J
) 9.8 Hz), 4.56 (1H, br d, J ) 3.0 Hz), 4.01-3.80 (5H, m), 3.71
(1H, m), 3.49 (3H, s), 3.28 (3H, s), 2.58-2.42 (2H, m), 2.30 (1H,
dd, J ) 4.8 and 11.6 Hz), 2.25 (1H, m), 2.17 (1H, dd, J ) 13.2
and 6.8 Hz), 1.98 (3H, s), 1.98-1.84 (4H, br s), 1.84-1.72 (2H,
m), 1.70-1.58 (4H, m), 1.35-0.80 (48H, m), 0.54-0.35 (8H,
m). Anal. Calcd for C53H96O10Si2: C, 67.04; H, 10.19. Found:
C, 66.90; H, 10.22.
Con ca n a m ycin F (1). Rf 0.28 (1/1 n-hexane/EtOAc); [R]25
Exp er im en ta l Section
D
+10.3° (c 0.17, CHCl3) [[R]20 of natural concanamycin F:
D
Eth yl Keton e 5. Rf 0.40 (5/1 n-hexane/EtOAc); [R]23
D
+11.0° (c 0.30, CHCl3); mp 96.6-97.2 °C (n-hexane, thin plate);
1H NMR δ 6.54 (1H, dd, J ) 15.0 and 10.5 Hz), 6.38 (1H, s),
5.79 (1H, d, J ) 10.5 Hz), 5.73 (1H, br s), 5.68 (1H, br d, J )
10.0 Hz), 5.55 (1H, dq, J ) 15.0 and 6.0 Hz), 5.29 (1H, ddd, J
) 15.0, 7.8 and 1.8 Hz), 5.23 (1H, dd, J ) 15.0 and 9.0 Hz),
5.02 (1H, br d, J ) 9.0 Hz), 4.60 (1H, br s), 4.02 (1H, ddd, J )
2.8, 4.1 and 10.0 Hz), 3.96 (1H, dd, J ) 10.0 and 7.8 Hz), 3.85
(1H, dd, J ) 9.0 and 9.0 Hz), 3.90-3.78 (1H, m), 3.73 (1H,
ddd, J ) 4.2, 10.1 and 11.1 Hz), 3.63 (3H, s), 3.26 (3H, s), 3.27-
3.23 (1H, m), 2.74 (1H, m), 2.31 (1H, dd, J ) 4.2 and 12.1 Hz),
2.37-2.25 (1H, m), 2.17 (1H, m), 2.07-1.92 (3H, m), 1.96 (3H,
br s), 1.94 (3H, br s), 1.92-1.79 (2H, m), 1.77-1.12 (3H, m),
1.57 (3H, dd, J ) 6.0 and 1.8 Hz), 1.12-1.02 (3H, m), 1.06
(3H, d, J ) 6.2 Hz), 1.06 (3H, d, J ) 6.8 Hz), 1.00 (3H, d, J )
6.5 Hz), 0.92 (3H, d, J ) 6.4 Hz), 0.82 (3H, d, J ) 7.0 Hz),
0.82 (3H, br d, J ) 7.0 Hz). Anal. Calcd for C39H64O10: C, 67.60;
H, 9.31. Found: C, 67.60; H, 9.70; HRMS (FAB, matrix,
m-nitrobenzyl alcohol) m/z 715.4397 (M+Na)+, calcd for
+101.6° (c 0.50, CHCl3); 1H NMR δ 5.61 (1H, dq, J ) 6.4 and
15.2 Hz), 5.41 (1H, ddq, J ) 1.7, 7.3 and 15.2 Hz), 4.65 (1H,
ddd, J ) 2.0, 3.3 and 10.8 Hz), 4.16 (1H, dd, J ) 7.3 and 9.9
Hz), 2.72 (1H, dd, J ) 10.8 and 15.0 Hz), 2.55 (2H, q, J ) 7.6
Hz), 2.43 (1H, dd, J ) 3.3 and 15.0 Hz), 2.17 (1H, ddq, J )
2.0, 9.9 and 7.2 Hz), 1.72 (3H, dd, J ) 1.7 and 6.4 Hz), 1.08
(3H, t, J ) 7.6 Hz), 1.00 and 0.99 (each 9H, each s), 0.69 (3H,
d, J ) 7.2 Hz). Anal. Calcd for C19H36O3Si: C, 67.01; H, 10.65.
Found: C, 66.91; H, 10.84.
Ma cr ola cton ic Ald eh yd e 4. Rf 0.55 (4/1 n-hexane/EtOAc);
[R]26D -0.8° (c 0.25, CHCl3), [R]26435 -14.4° (c 0.25, CHCl3); 1H
NMR δ 9.72 (1H, d, J ) 2.0 Hz), 6.62 (1H, dd, J ) 11.5 and
16.5 Hz), 6.12 (1H, s), 5.87 (1H, d, J ) 11.5 Hz), 5.71 (1H, d,
J ) 9.5 Hz), 5.27 (1H, dd, J ) 9.0 and 16.5 Hz), 5.18 (1H, dd,
J ) 4.0 and 9.5 Hz), 3.98 (1H, br d, J ) 2.0 Hz), 3.85 (1H, m),
3.78 (1H, dd, J ) 9.5 and 9.0 Hz), 3.54 (3H, s), 3.27 (3H, s),
2.90 (1H, m), 2.62-2.42 (2H, m), 2.20 (1H, dd, J ) 7.2 and 7.2
Hz), 1.96 (3H, s), 1.98-1.94 (4H, m), 1.86-1.74 (1H, m), 1.25
(2H, m), 1.15-0.85 (38H, m), 0.83-0.68 (4H, m), 0.48 (4H, q,
J ) 7.1 Hz). Anal. Calcd for C42H76O7Si2: C, 67.33; H, 10.22.
Found: C, 67.61; H, 10.58.
C
39H64O10Na 715.4440.
Ack n ow led gm en t. We are grateful to Prof. Dr. K.
Ald ol 64. Rf 0.43 (5/1 n-hexane/EtOAc); [R]25D +62.5° (c 0.24,
CHCl3); mp 69.0-69.5 °C (n-hexane, thin plate); 1H NMR δ
6.60 (1H, dd, J ) 11.2 and 15.0 Hz), 6.16 (1H, s), 5.86 (1H, d,
J ) 11.2 Hz), 5.74 (1H, d, J ) 9.8 Hz), 5.63 (1H, dq, J ) 7.0
and 15.2 Hz), 5.41 (1H, ddd, J ) 1.8, 7.0 and 15.2 Hz), 5.27
(1H, dd, J ) 9.2 and 15.0 Hz), 5.12 (1H, dd, J ) 1.2 and 10.0
Hz), 4.69 (1H, ddd, J ) 3.4, 5.2 and 9.8 Hz), 4.07 (1H, dd, J )
7.0 and 10.2 Hz), 3.99 (1H, br d, J ) 1.4 Hz), 3.88-3.72 (4H,
m), 3.58 (3H, s), 3.27 (3H, s), 2.83 (1H, dd, J ) 9.8 and 16.0
Hz), 2.76 (1H, m), 2.60-2.42 (2H, m), 2.48 (1H, dd, J ) 5.4
and 16.0 Hz), 2.26-2.07 (3H, m), 1.98 (3H, s), 1.96-1.92 (4H,
Hasumi (Tokyo Noko University) and Prof. Dr. H.
Kinashi (Hiroshima University) for kindly providing
authentic samples of concanamycin A and concanamycin
F (concanolide A).
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data and experimental procedures for all synthetic
intermediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O001377Q