Evolution of a total synthesis of (-)-kendomycin exploiting a Petasis-Ferrier rearrangement/ring-closing olefin metathesis strategy

Article abstract of DOI:10.1021/ja060369+

A convergent stereocontrolled total synthesis of (-)-kendomycin (1) has been achieved. The synthesis proceeds with a longest linear sequence of 21 steps, beginning with commercially available 2,4-dimethoxy-3-methylbenzaldehyde (12). Highlights of the synthesis include an effective Petasis-Ferrier union/rearrangement tactic to construct the sterically encumbered tetrahydropyran ring, a ring-closing metathesis to generate the C(4a-13-20a) macrocycle, an effective epoxidation/deoxygenation sequence to isomerize the C(13,14) olefin, and a biomimetic quinone-methide-lactol assembly to complete the synthesis.

Full text of DOI:10.1021/ja060369+

Published on Web 03/24/2006
Evolution of a Total Synthesis of (-)-Kendomycin Exploiting a
Petasis-Ferrier Rearrangement/Ring-Closing Olefin
Metathesis Strategy
Amos B. Smith, III,* Eugen F. Mesaros, and Emmanuel A. Meyer
Contribution from the Department of Chemistry, Monell Chemical Senses Center, and
Laboratory for Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
Received January 17, 2006; E-mail: smithab@sas.upenn.edu
Abstract: A convergent stereocontrolled total synthesis of (-)-kendomycin (1) has been achieved. The
synthesis proceeds with a longest linear sequence of 21 steps, beginning with commercially available 2,4-
dimethoxy-3-methylbenzaldehyde (12). Highlights of the synthesis include an effective Petasis-Ferrier union/
rearrangement tactic to construct the sterically encumbered tetrahydropyran ring, a ring-closing metathesis
to generate the C(4a-13-20a) macrocycle, an effective epoxidation/deoxygenation sequence to isomerize
the C(13,14) olefin, and a biomimetic quinone-methide-lactol assembly to complete the synthesis.
Scheme 1
In 1996, Funahashi and co-workers disclosed the isolation
of kendomycin (-)-1 (Scheme 1), an architecturally novel
polyketide macrocycle derived from Streptomyces Violaceoru-
ber, possessing activity as an endothelin receptor antagonist.1
Two years later, the same macrocycle was reported to have
antiosteoporotic properties.2 However, it was not until 2000 and
the re-isolation of kendomycin (-)-1 by the Zeeck group from
various strains of Actinomycetes that the full three-dimensional
structure, including absolute stereochemistry, was established
via single-crystal X-ray analysis in conjunction with the
modified Mosher ester protocol.3 Additional in vitro cell assays
revealed kendomycin (-)-1 to possess significant activity as
an anti-bacterial, against multi-resistant strains of Staphylococcus
aureus, as well as remarkable cytotoxicity, having potency
similar to that of the clinically important drugs doxorubicin and
cisplatin, against a series of human tumor cell lines (HMO2,
HEP G2, MCF7, GI50 < 0.1 µM).3a
From the synthetic perspective, kendomycin (-)-1 comprises
a significant challenge, given the densely substituted C(5-9)
tetrahydropyran ring directly linked to the distinctive C(4a-19)
quinone-methide-lactol chromophore, in conjunction with the
C(10-18) aliphatic ansa chain, possessing an E-13,14-trisub-
stituted olefin, which completes the all-carbon macrocyclic ring
(Scheme 1). Recognition of the intricate architecture, as well
as the extraordinary panel of biological properties, rapidly
promoted kendomycin (-)-1 to center stage in a number of
synthetic laboratories,4 with the first total synthesis reported by
Lee and co-workers in 2004.5 Given our longstanding interest
(1) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japan Patent 08231551
[A2960910], 1996; Chem. Abstr. 1997, 126, 6553. (b) Funahashi, Y.;
Kawamura, N.; Ishimaru, T. Japan Patent 08231552, 1996; Chem. Abstr.
1996, 125, 326518.
(2) Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston, Terra L. U.S. Patent
in the synthesis of architecturally complex natural products
possessing significant bio-regulatory properties, we recently
disclosed our endeavors also culminating in the total synthesis
5728727 [A 980317], 1998; Chem. Abstr. 1998, 128, 239489.
(3) (a) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000, 323-328.
(b) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000, 2665-
2670.
9
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J. AM. CHEM. SOC. 2006, 128, 5292-5299
10.1021/ja060369+ CCC: $33.50 © 2006 American Chemical Society

Stereocontrolled Total Synthesis of (−)-Kendomycin
A R T I C L E S
of (-)-kendomycin (1).6 Herein we present a full account of
that work.
stituted tetrahydropyrans.8,9 Required here would be the steri-
cally congested aromatic aldehyde 6 and â-hydroxy acid 7.
For End Game B, the advanced C(4a-19) chromophore of
(-)-kendomycin (1) was envisioned to emerge from benzofuran
8 via oxidation/hydration. After initiation of our synthetic
program, the viability of such an approach was demonstrated
independently, both by the Mulzer group in model studies4c and
by Lee and co-workers in their total synthesis of (-)-kendo-
mycin (1).5 From our perspective, disconnection of the C(19)-O
bond in 8 reveals alkyne 9 as the intermediate of choice. In the
forward sense, benzofuran 8 would arise from acetylene 9 via
a [Hg2+]-mediated 5-endo-dig cyclization.10 Application of the
C(13,14) RCM retron and the C(20,20a) Sonogashira union to
9 then leads to alkyne 10 and tetrahydropyran 4, the common
intermediate proposed in route A. Epoxide 5 (required for route
A) and alkyne 10 (required for route B) would each be available
in one step also from a common intermediate, aldehyde 11.
Should either the high-risk RCM or the biomimetic tactics in
route A meet with difficulties, route B would provide access
both to a different RCM substrate and to an alternate tactic to
construct the quinone-methide-lactol core. Importantly, the
two strategies are unified via the proposed Petasis-Ferrier
union/rearrangement to construct tetrahydropyran 4.
From the outset, we envisioned two possible scenarios for
the construction of (-)-kendomycin (1) (Scheme 1, routes A
and B). The cornerstone of both strategies would comprise ring-
closing metathesis (RCM) to construct the macrocyclic system.
To the best of our knowledge, however, RCM construction of
R-branched, trisubstituted olefins embedded in 16-membered
macrocycles had not been reported. Further raising the level of
risk of the RCM tactic was the disclosure by the Mulzer group
that attempts to construct (-)-kendomycin (1) employing a
RCM tactic had proven unsuccessful.4a Nonetheless, we envi-
sioned that, by careful design of the RCM substrate, this problem
might be overcome and thereby permit use of this powerful
transformation (vide infra).
With this scenario in mind, two distinct end games were
envisioned to introduce the potentially labile C(4a-19) quinone-
methide-lactol (Scheme 1). The first, End Game A, was
inspired by the biosynthetic postulate, introduced by Zeeck et
al.,3a that the C(19) lactol in kendomycin (-)-1 derives from
an open-chain C(19) ketone tautomer. We reasoned that
hydrolysis of the C(1) methyl enol ether in o-quinone 2 (or a
p-quinone congener) would occur with simultaneous cyclization
of the intermediate C(1) alcohol onto the C(19) carbonyl to
generate the thermodynamically more stable C(19) lactol.
Quinone 2, in turn, would derive from homobenzylic alcohol 3
via oxidation of both the C(19) hydroxyl and the electron-rich
aromatic ring. Continuing with route A, disconnection of the
C(13,14) olefin and the C(20,20a) σ-bond in 3 reveals tetrahy-
dropyran 4 and known epoxides 5.4a Importantly, tetrahydro-
pyran 4 comprises a common intermediate for both the A and
B synthetic strategies (vide infra). In the synthetic sense, an
aryl anion equivalent obtained from aromatic bromide 4 via
lithium-halogen exchange would effect epoxide ring-opening
of 5 to deliver the substrate for ring-closing metathesis.
To facilitate the RCM process, we envisioned a substrate
wherein the C(4)-phenol would be protected with a bulky tert-
butyldimethylsilyl (TBS) group (Scheme 1) to induce hindered
rotation about the C(4a,5) bond (i.e., sp2-sp3 atropisomerism).7
The potential advantage of the bulky C(4) substituent would
be to increase the population of the C(4)-OTBS-C(5)-H
synclinal rotamer of the RCM substrate (vide infra), thereby
bringing the terminal olefins into close proximity, as required
for productive ring-closure.
Early Intermediates 5-7 and 10. We initiated the synthesis
of kendomycin (-)-1 with construction of the C(1-5) aldehyde
6 (Scheme 2). Commercially available, albeit expensive, alde-
Scheme 2
hyde 12 was readily prepared on multigram scale from
inexpensive 2,6-dimethoxytoluene via formylation with dichlo-
romethyl methyl ether in the presence of TiCl4 (93% yield).11
Aldehyde 12 was then converted to known phenol 13 via
Baeyer-Villiger oxidation, followed by hydrolysis of the
intermediate formate.12 Duff ortho-formylation13 next provided
Continuing with this analysis, recognition of the cis-5,9-disub-
stituted tetrahydropyran in (-)-kendomycin (1) suggested the
Petasis-Ferrier union/rearrangement tactic recently developed
in our laboratory to construct similarly substituted cis-2,6-disub-
(8) (a) Petasis, N. A.; Lu, S. P. Tetrahedron Lett. 1996, 37, 141-144. (b)
Ferrier, R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779-2831. (c) For an
extension of this methodology to the conversion of cyclopropyl diols to
oxepanes, see: O’Neil, K. E.; Kingree, S. V.; Minbiole, K. P. C. Org.
Lett. 2005, 7, 515-517. (d) For a mechanistically related Prins cyclization
entry to tetrahydropyrans, see: Cossey, K. N.; Funk, R. L. J. Am. Chem.
Soc. 2004, 126, 12216-12217.
(4) Synthetic studies: (a) Mulzer, J.; Pichlmair, S.; Green, M. P.; Marques,
M. M. B.; Martin, H. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11980-
11985 and references cited therein. (b) Martin, H. J.; Drescher, M.; Kahlig,
H.; Schneider, S.; Mulzer, J. Angew. Chem., Int. Ed. 2001, 40, 3186-
3188. (c) Green, M. P.; Pichlmair, S.; Marques, M. M. B.; Martin, H. J.;
Diwald, O.; Berger, T.; Mulzer, J. Org. Lett. 2004, 6, 3131-3134. (d)
Sengoku, T.; Arimoto, H.; Uemura, D. Chem. Commun. 2004, 1220-1221.
(e) White, J. D.; Smits, H. Org. Lett. 2005, 7, 235-238. (f) Williams, D.
R.; Shamim, K. Org. Lett. 2005, 7, 4161-4164. (g) Lowe, J. T.; Panek, J.
S. Org. Lett. 2005, 7, 1529-1532.
(5) Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720-14721.
(6) Smith, A. B., III; Mesaros, E. F.; Meyer, E. A. J. Am. Chem. Soc. 2005,
127, 6948-6949.
(7) Even though documented, this type of atropisomerism is little explored
relative to sp2-sp2 atropisomerism: (a) Reference 4b. (b) Eliel, E. L.; Wilen,
S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994; p
1150. (c) Oki, M. Top. Stereochem. 1983, 14, 1-81.
(9) (a) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org. Lett.
1999, 1, 909-912. (b) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.;
Beauchamp, T. J. Org. Lett. 1999, 1, 913-916. (c) Smith, A. B., III;
Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001,
123, 4834-4836. (d) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.;
Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942-10953. (e) Smith, A.
B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2001, 123, 12426-
12427. (f) Smith, A. B., III; Safonov, I. G. Org. Lett. 2002, 4, 635-637.
(g) Smith, A. B., III; Sfouggatakis, C.; Gotchev, D. B.; Shirakami, S.; Bauer,
D.; Zhu, W.; Doughty, V. A. Org. Lett. 2004, 6, 3637-3640. (h) Smith,
A. B., III; Fox, R. J.; Vanecko, J. A. Org. Lett. 2005, 7, 3099-3102. (i)
Smith, A. B., III; Razler, T. M.; Pettit, G. R.; Chapuis, J.-C. Org. Lett.
2005, 7, 4403-4406. (j) Smith, A. B., III; Razler, T. M.; Ciavarri, J. P.;
Hirose, T.; Ishikawa, T. Org. Lett. 2005, 7, 4399-4402.
(10) Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984, 106, 4218-4227.
(11) Shawe, T. T.; Liebeskind, L. S. Tetrahedron 1991, 47, 5643-5666.
9
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A R T I C L E S
Smith et al.
known aldehyde 14,12 which upon bromination and protection
of the C(4) phenol as the TBS ether furnished aldehyde 6 in
46% overall yield from 12.
Construction of C(7-13) â-hydroxy acid 7 began with com-
mercially available â-citronellene (+)-15, which via the literature-
reported ozonolysis furnished known aldehyde (+)-1614 (Scheme
3). In our hands, a two-step procedure comprising epoxidation/
selectivity (98:2). Removal of the auxiliary from (-)-21 was
next achieved in one step by partial reduction to provide
aldehyde (+)-11.18 This transformation was not without con-
siderable variability in the yield, due primarily to formation of
the cyclic aminal byproduct 22, the latter tentatively assigned
by 1H NMR. We therefore turned to a two-step sequence
involving reduction of (-)-21 to the corresponding alcohol with
in situ-generated lithium amidotrihydroborate,18 followed by
Parikh-Doering oxidation to provide aldehyde (+)-11 (Scheme
4).19 Matteson methylenation20 with CH2Br2/n-BuLi then secured
the requisite C(14-20) epoxide (5)4a,21 in gram quantities as a
difficult-to-separate mixture of C(19) epimers (ca. 1.8:1); the
overall yield from methallyl chloride (18) was 20%. The low
diastereoselectivity at this stage in the synthesis was viewed as
inconsequential, given that C(19) becomes a carbonyl group in
route A (vide infra).
Scheme 3
To access the C(14-20) alkyne (10) for route B (Scheme
1), aldehyde (+)-11 was treated with dimethyl(1-diazo-2-
oxopropyl)phosphonate (Bestmann’s reagent);22 unfortunately,
racemization at the C(18) R-center occurred (Scheme 4). This
difficulty could be completely overcome with the Seyferth-
Gilbert reagent (dimethyl-diazomethylphosphonate);23 under
these conditions, alkyne (+)-10 was obtained in 77% yield
without noticeable epimerization.
olefin cleavage (m-CPBA/H5IO6)14a was found to be superior
when working on a relatively small scale (ca. 1 g). Diastereo-
selective Evans aldol condensation15 with known oxazolidinone
(+)-17, followed by removal of the chiral auxiliary, then led to
the requisite â-hydroxy acid (+)-7 in 66% yield from citronel-
lene.
Construction of epoxide 5, the coupling partner required to
elaborate tetrahydropyran 4 (Scheme 1, route A), began via
Finkelstein conversion of commercial methallyl chloride (18)
to the more reactive iodide, followed in turn by a highly dia-
stereoselective Evans alkylation16 with oxazolidinone (+)-17
and reduction of the resulting adduct to furnish alcohol (+)-19
(Scheme 4).17 Introduction of the second chiral center, after
The Petasis-Ferrier Union/Rearrangement: Construction
of Tetrahydropyran 4. Having secured gram quantities of both
aldehyde 6 and â-hydroxy acid (+)-7, we embarked on the
construction of tetrahydropyran 4 via the Petasis-Ferrier union/
rearrangement tactic.8,9 Condensation of 6 with (+)-7 was
performed by initial conversion of the hydroxy acid to the
corresponding bis-TMS derivative, followed by treatment with
aldehyde 6 in the presence of TMSOTf to furnish (+)-23
(Scheme 5).9 The yield of dioxanone (+)-23 was at best modest
(ca. 59%), presumably due to the steric hindrance of the bis-
ortho-substituted carbonyl in aldehyde 6. Better results were
obtained by exploiting the recently introduced Kurihara con-
densation protocol24 involving i-PrOTMS and TMSOTf to effect
in situ bis-silylation. In this fashion, the dioxanone was
consistently generated in 77% yield as a single stereoisomer
(by NMR). Needless to say, we were quite pleased with the
enhanced efficiency of this union tactic. Continuing with the
Petasis-Ferrier union/rearrangement, initial attempts to execute
a Takai ethylidenation25 of the carbonyl in dioxanone (+)-23
[e.g., CH3CHBr2; Zn/TiCl4/PbCl2(cat.)], which upon Ferrier
Scheme 4
(14) (a) Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.;
McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983,
105, 1988-2006. (b) Barrett, A. G. M.; Carr, R. A. E.; Attwood, S. V.;
Richardson, G.; Walshe, N. D. A. J. Org. Chem. 1986, 51, 4840-4856.
(15) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-
2129.
(16) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77-82. (b) Evans, D.
A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737-1739.
(17) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem. 2002, 67,
5176-5183.
(18) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(19) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.
(20) Michnick, T. J.; Matteson, D. S. Synlett 1991, 631-632.
(21) Even though epoxides 5 were previously reported (ref 4a), to the best of
our knowledge this is the first account where spectroscopic analysis for
these species is provided (see Supporting Information).
conversion of (+)-19 to the corresponding iodide, was achieved
via a Myers alkylation with pseudoephedrine propionate 2018
to provide adduct (-)-21 in both excellent yield and diastereo-
(22) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-
522.
(23) (a) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36, 1379-
1386. (b) Okada, N.; Nishimura, S. J. Biol. Chem. 1979, 254, 3061-3066.
(c) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47, 1837-1845.
(d) Ohira, S. Synth. Commun. 1989, 19, 561-564.
(12) Kitahara, Y.; Nakahara, S.; Numata, R.; Kubo, A. Chem. Pharm. Bull. 1985,
33, 2122-2128.
(13) Duff, J. C.; Bills, E. J. J. Chem. Soc. 1934, 1305-1308.
(24) Kurihara, M.; Hakamata, W. J. Org. Chem. 2003, 68, 3413-3415.
9
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Stereocontrolled Total Synthesis of (−)-Kendomycin
A R T I C L E S
Scheme 5
skewed-boat-like transition state presumably takes place to
introduce the C(6) methyl group in (+)-26 in the equatorial
position. This stereochemical outcome can be understood in
terms of severe 1,3-diaxial steric repulsion between the C(8)
methyl group and the incoming methyl electrophile, thereby
disfavoring a chair-like transition state.
Tetrahydropyran (+)-4 was next generated via two straight-
forward steps: diastereoselective reduction of the carbonyl with
NaBH4 and protection of the C(7) hydroxyl of the derived major
epimer as the TBS ether (Scheme 5). The relative stereochem-
istry of (+)-4, assigned initially via analysis of vicinal coupling
constants, was later confirmed by X-ray analysis of macrocycle
(+)-30 (Scheme 6).
Scheme 6
rearrangement would directly install the required C(6) methyl
group, failed.9d This result was not totally unexpected, given
that neighboring olefins are known to reduce significantly the
yield of such olefinations, due to the metathesis activity of the
Ti2+ species.25 It also appeared that proto-debromination of
(+)-23 had occurred (LRMS), presumably by Zn insertion in
the C-Br bond.26 Undaunted, we turned to a Petasis-Tebbe
methylidenation27 of (+)-23. Success with this tactic would
require installation of the requisite C(6) methyl group after the
Ferrier rearrangement. Pleasingly, the Petasis-Tebbe reaction
led to a somewhat unstable enol-acetal, 24, in good yield, which
was immediately subjected to the Petasis-Ferrier rearrangement
(Me2AlCl) to furnish tetrahydropyran (+)-25 in 85% yield
(Scheme 5).9 Diastereoselective methylation then led to the
equatorial methyl ketone (+)-26 in 70% yield after careful
chromatographic removal of minor amounts of the axial isomer
and bis-alkylation products.9j Although axial alkylation of simple
cyclohexanones via a chair-like transition state is the antici-
pated process, exceptions have been documented.28 For ketone
(+)-25, axial attack of the kinetically derived enolate via a
Construction of Macrocycle 3: Route A. With both tetra-
hydropyran (+)-4 and epoxides 5 in hand, we advanced toward
construction of macrocycle 3 (Scheme 1). The first issue was
union of bromide (+)-4 with epoxides 5. Despite earlier reports
on uncatalyzed nucleophilic additions of aryl-lithiums possessing
bis-ortho substitutents to simple epoxides,29 a similar process
in our hands failed to deliver coupled product 27 (Scheme 6).
Addition of catalytic amounts of CuI to the reaction did not
change the outcome. Quenching the reaction with CD3OD did,
however, lead to both good mass recovery (95-99%) and
high levels of deuterium incorporation (85-89% by NMR) in
the debromination product 28 (Scheme 6), suggesting that the
(25) (a) Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1987,
52, 4410-4412. (b) Takai, K.; Kataoka, Y.; Miyai, J.; Okazoe, T.; Oshima,
K.; Utimoto, K. Org. Synth. 1996, 73, 73-84.
(26) For a mechanistic study of the Zn insertion in the C-Br bond, see: Guijarro,
A.; Rosenberg, D. M.; Rieke, R. D. J. Am. Chem. Soc. 1999, 121, 4155-
4167.
(27) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-6394.
(28) (a) Valls, J.; Toromanoff, E. Bull. Soc. Chim. Fr. 1961, 758-764. (b)
Toromanoff, E. Bull. Soc. Chim. Fr. 1962, 1190-1192.
(29) (a) Wilson, R. M.; Wunderly, S. W.; Walsh, T. F.; Musser, A. K.; Outcalt,
R.; Geiser, F.; Gee, S. K.; Brabender, W.; Yerino, L., Jr.; Conrad, T. T.;
Tharp, G. A. J. Am. Chem. Soc. 1982, 104, 4429-4446. (b) Ramacciotti,
A.; Fiaschi, R.; Napolitano, E. J. Org. Chem. 1996, 61, 5371-5374.
9
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A R T I C L E S
Smith et al.
aryl anion derived from (+)-4 does not undergo adventitious
protonation during reaction. Taken together, these results support
our suspicion that the C(18) R-branched epoxide 5 is simply
not sufficiently reactive. Eventually, the successful union of the
lithium anion derived from (+)-4 was achieved by activating
epoxide 5 with BF3‚OEt2 at low temperature (Scheme 6). Under
these conditions, diene 27 was obtained as a 2:1 mixture of
C(19) epimers in 60% yield, accompanied by variable amounts
of 28; Dess-Martin oxidation then led to (+)-29 as a single
ketone.30 Unfortunately, albeit not surprising in view of the
Mulzer precedent,4a all attempts to effect ring-closing metathesis
of (+)-29 to the corresponding 16-membered macrocycle proved
fruitless. Aware that subtle structural changes in RCM substrates,
even at positions remote from the reacting olefins, can signifi-
cantly influence the outcome of RCM reactions, we subjected
alcohols 27 to the second-generation Grubbs catalyst in dichlo-
romethane at reflux. Pleasingly, ring-closure proceeded in 57%
yield (based on the mixture of epimers 27) to furnish a single
macrocycle.31 Eventually, we determined that only the major
diastereomer, 19(S)-27, reacted.32 The stereogenicity of C(19),
assigned first via the modified Mosher esters procedure, was
later confirmed by X-ray analysis of macrocycle (+)-30
(vide infra).33 To our dismay, however, the geometry of the
C(13,14) olefin was exclusively Z, as assigned via NOESY
NMR experiments [cf. (+)-30 in Scheme 6]. Single-crystal
X-ray analysis later confirmed the Z configuration (Scheme 6).
Despite the incorrect Z geometry in (+)-30, this result is not-
able as the first example of ring-closing metathesis leading to
the construction of an R-branched trisubstituted olefin in a
16-membered macrocyclic ring.4a,34
Figure 1. Rotational equilibrium associated with the C(4a,5) bond in
19(S)-27. The syn rotamer has the reacting side-chain olefins R1 and R2 in
a favorable cisoid orientation.
bond restrictive (i.e., atropisomerism) at the reaction temperature
(Curtin-Hammett principle),35 as previously implied by Mulzer
et al. to be the case for their systems4a,b and observed when the
RCM process failed with unprotected C(4)-hydroxyl substrates
analogous to 27.
Construction of Macrocycle 9: Route B. Having obtained
solely the cis-olefin [(+)-30] in the RCM of 19(S)-27 instead
of the desired trans-olefin, we directed our attention toward a
different RCM substrate (route B, Scheme 1). Despite extensive
efforts, we could not couple the advanced bromide (+)-4 with
alkyne (+)-10 via Sonogashira reaction (see Scheme 1). Suc-
cess was, however, achieved upon Sonogashira union of alkyne
(+)-10 with bromo-aldehyde 6 rather than with bromide (+)-4
(Scheme 7);36 degassing of the reaction mixture to avoid facile
Scheme 7
Although currently we do not have a complete understanding
of the RCM reactivity difference between alcohol 19(S)-27 and
congeners 19(R)-27 and (+)-29, we suggest that a hydrogen
bond between C(19)-OH and the C(1)-OMe in 19(S)-27 may
play a significant role in positioning the C(14-19) side chain
in close proximity to C(10-13) RCM counterpart. The distance
derived from the X-ray crystal structure of (+)-30 between the
C(19)-OH and C(1)-OMe groups [i.e., C(19)sO‚‚‚OsC(1)
) 2.778 Å] and the corresponding O‚‚‚H‚‚‚O angle (159.6°)
both suggest a strong hydrogen bond between these groups,
albeit in the RCM product.
We also reasoned that the C(4) TBS ether holds considerable
importance for the success of this reaction, by ensuring a
preponderance of the productive C(4a,5) rotamer [i.e., wherein
the large C(4)-OTBS group and the small C(5)-H are
synclinal; see syn-19(S)-27 in Figure 1], thereby placing the
terminal olefins in close proximity to each other.7b This
conformational bias becomes relevant only when the rotational
barrier is sufficiently high as to render rotation about the C(4a,5)
(30) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(31) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (b)
Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155-7158.
(32) We revisited the synthesis of epoxides 5 at this point with the purpose to
obtain epimeric mixtures enriched in the major isomer, that in turn would
maximize the yield of 19(S)-27 and thus the yield of macrocycle (+)-30.
However, treatment of aldehyde (+)-11 with (R)-(dimethylamino)meth-
ylphenyloxosulfoxonium fluoroborate generated 5 as a diastereomeric
mixture (3.7:1) in favor of the desired epimer, which we considered only
a modest improvement relative to Matteson methylenation. See: (a)
Johnson, C. R.; Haake, M.; Schroeck, C. W. J. Am. Chem. Soc. 1970, 92,
6594-6598. (b) Johnson, C. R.; Schroek, C. W. J. Am. Chem. Soc. 1973,
95, 7418-7423.
(33) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092-4096. (b) Kusumi, T.; Fukushima, T.; Ohtani, I.;
Kakisawa, H. Tetrahedron Lett. 1991, 32, 2939-2942.
9
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Stereocontrolled Total Synthesis of (−)-Kendomycin
A R T I C L E S
Scheme 8
dimerization of the alkyne was a significant prerequisite. Adduct
(+)-31 was then coupled with acid (+)-7, again employing the
protocol of Kurihara (i-PrOTMS/TMSOTf) to generate diox-
anone (+)-32; the yield in this case was modest.24 Varying the
concentration of TMSOTf and decreasing the temperature from
-20 to -78 °C did not improve the outcome.
Carrying forward, Petasis-Tebbe methylenation provided
enol ether (+)-33 in good yield,27 which in turn was subjected
to the Me2AlCl-promoted Petasis-Ferrier rearrangement to
furnish pyranone (+)-34, the substrate for the RCM in route
B.8,9 Unfortunately, neither the Grubbs second-generation cata-
lyst nor the Hoveyda-Grubbs second-generation catalyst proved
effective for ring-closure.37 Only trace amounts of 35 were gen-
erated (ca. <5% by 1H NMR); assignment of the olefin geom-
etry, given the small amount of material available, was not
possible.38
Dioxanone (+)-32, on the other hand, proved to be a viable
RCM substrate with the Grubbs second-generation catalyst when
the reaction was carried out in dichloromethane at reflux.
However, again the C(13,14) olefin possessed the Z configu-
ration, as assigned via careful NOESY and COSY NMR
experiments; the unoptimized yield was 35% (Scheme 7).39
In retrospect, the alkyne moiety in (+)-34 presumably
rigidifies the C(18-20a) segment when combined with the
locked chair conformation of the C(5-9) tetrahydropyran, to
reduce the rotational degrees of freedom within the C(14-20a)
segment, thereby placing the requisite olefins too far apart for
productive RCM. On the other hand, NOESY experiments
suggest that dioxanone (+)-32 adopts a boat or skewed-boat
conformation, thus orienting the C(14-20a) fragment closer to
the olefin in the C(10-13) side chain.
Having achieved access to two RCM macrocycles, albeit both
possessing a cis-olefin, we turned to the possibility of olefin
isomerization. We selected macrocycle (+)-30 to explore first,
given the potential for additional complications with (+)-36,
possessing both a labile dioxanone ring and an alkyne within
the macrocyclic structure.
Isomerization of the C(13,14) Olefin: Route A Revisited.
Initially, we attempted to effect isomerization of the C(13,14)
Z-olefin in (+)-30 by exploiting equilibrating conditions,
specifically treatment of (+)-30 with a catalytic amount (10
mol %) of iodine to achieve free radical isomerization. This
tactic led primarily to migration of the olefin to the C(14,15)
position, to furnish a mixture (7:1) of the E- and Z-olefins 37
and 30 (Scheme 8).40 Again, this result was not totally
unexpected, given that Mulzer4a had observed olefin migration
in the context of an attempted Barton free radical deoxygenation
protocol employing a similar substrate. Taken together, these
results directed us to kinetically controlled conditions to achieve
and maintain the required isomerization.
We first explored a Vedejs isomerization41 exploiting the cis-
C(13,14) epoxide derived from olefin (+)-30 via m-CPBA
oxidation. Although a single epoxide was obtained in 68% yield,
the relative stereochemistry was not established. Unfortunately,
we were unable to open the epoxide with Ph2PLi. Only
recovered starting material was found; under more forcing
conditions, complete decomposition occurred (Scheme 8). We
turned next to the Oshima isomerization protocol, which calls
for anti methoxyiodination of the olefin, followed by syn
elimination (Scheme 8).42 Again, under the described condi-
tions,42 methoxyiodination of macrocycle (-)-39, the latter
derived from (+)-30 by protection of the C(19) hydroxyl as a
TES ether, could not be achieved. We reasoned, based on
analysis of the ORTEP diagram of (+)-30 (Scheme 6) and the
assumption that the solid-state conformation also pertains in
solution, that epoxide opening in (-)-38 and methoxyiodination
of (-)-39 fail because attack of the corresponding nucleophiles
(i.e., Ph2P- and MeOH, respectively) must occur from the
internal face of the macrocycle, syn to the C(12) Me group.
Clearly, there is a significant barrier. We were thus led to the
idea of an intramolecular nucleophilic inversion.
(34) Macrocyclization to access a variety of small and medium rings via RCM
that generate olefins with a dense substitution pattern have been documented
but were unprecedented in 16-membered or larger rings. For a recent review
on RCM, see: Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-
2238.
(35) Seeman, J. I. Chem. ReV. 1983, 83, 83-134.
(36) Sonogashira, K.; Tohda, Y.; Hagihara, N. A. Tetrahedron Lett. 1975, 50,
4467-4470.
(37) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179. (b) Kingsbury, J. S.; Harrity, J. P. A.;
Bonitatebus, P. J., Jr.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791-
799.
Our earlier observation of a single epoxide [(-)-38] upon
m-CPBA oxidation of (+)-30 suggested that cis-dihydroxylation
(38) The 1H NMR of the reaction mixture revealed a doublet of low intensity
at 5.05 ppm (J ) 10.1 Hz), characteristic of the vinyl proton expected in
35; correct mass for the RCM product was observed by LRMS.
(39) A NOESY cross-peak was also observed between the methyl of the 4-OTBS
group and the C(5)-H benzylic proton in (+)-36, supporting a C(4)-
OTBS-C(5)-H synclinal orientation.
(41) (a) Vedejs, E.; Fuchs, P. L. J. Am. Chem. Soc. 1973, 95, 822-825. (b)
Vedejs, E.; Snoble, K. A. J.; Fuchs, P. L. J. Org. Chem. 1973, 38, 1178-
1183.
(40) COSY and NOESY NMR experiments were employed to assign the regio-
and stereochemistry of the C(14,15) E-olefin 37.
(42) Maeda, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1996, 61, 6770-
6771.
9
J. AM. CHEM. SOC. VOL. 128, NO. 15, 2006 5297

A R T I C L E S
Smith et al.
would also afford a similar single diol, from which we might
be able to generate the corresponding trans-epoxide via a
stereospecific intramolecular ring-closure. Precedent for this
tactic in a 14-membered macrocycle, in a system more rigid
compared to (-)-39, can be found in the elegant total synthesis
of (()-crassin by McMurry and co-workers.43 Subsequent
stereospecific deoxygenation of the epoxide, exploiting the
kinetic Sharpless WCl6/n-BuLi conditions, would then afford
the desired trans-olefin (Scheme 9).44
Application of the Zeeck Biosynthetic Postulate: Total
Synthesis of Kendomycin (-)-1. With the E-olefin (-)-42 in
hand, we focused on the proposed biomimetic end game strate-
gy. Treatment of (-)-42 with pyridinium p-toluenesulfonate in
methanol selectively removed the C(19) TES protecting group
in the presence of the C(7) TBS ether (Scheme 10).46 Dess-
Scheme 10
Scheme 9
With this scenario in mind, dihydroxylation of the C(13,14)
olefin in TES ether (-)-39 led, as expected, to a single cis-diol
(1H and 13C NMR); the relative stereochemistry vis-a`-vis the
macrocyclic ring was not defined. Selective mesylation of the
C(13) secondary hydroxyl over the tertiary C(14) alcohol
furnished monomesylate (+)-40, which was exposed to benzyl-
trimethylammonium hydroxide. Pleasingly, the C(13,14) trans-
epoxide was obtained, albeit with simultaneous removal of the
C(4) TBS group to yield (+)-41 as a single isomer (Scheme
9). Although the relative stereochemistry of the epoxide was
not assigned rigorously, we suggest an anti disposition with
respect to the C(12) Me group based on earlier arguments
involving hydroxylation of the double bond from the periphery
of the macrocycle (cf. the ORTEP diagram of (+)-30 in Scheme
6). Pleasingly, Sharpless deoxygenation44a of epoxide (+)-41
led to olefin (-)-42, accompanied by 10-12% of an unidentified
isomer. The E-olefin configuration at C(13,14), secured initially
via a series of COSY and NOESY NMR experiments, was
subsequently confirmed by single-crystal X-ray analysis of (-)-2
(vide infra).45
Martin oxidation of the resulting alcohol (-)-43,30 conditions
known to effect oxidation of an aromatic ring to the corre-
sponding o-quinone, furnished (-)-2 as a highly crystalline solid.
Single-crystal X-ray analysis unequivocally confirmed not only
the overall connectivity but in particular both the correct position
and E geometry of the C(13,14) olefin, as assigned initially by
NMR.
Final conversion of (-)-2 to (-)-kendomycin (1) entailed
exposure to concentrated aqueous HF, which cleanly resulted
in concomitant cleavage of the C(7) TBS ether46 and hydrolysis
of the C(1) vinylogous methyl ester,47 which in turn underwent
1,2-addition to the C(19) carbonyl to construct the C(4a-C19)
quinone-methide-lactol, as inspired by the biosynthetic path-
way proposed by Zeeck.3a The spectroscopic data of synthetic
1
kendomycin (-)-1 (i.e., 500 MHz H NMR, 125 MHz 13C
NMR, IR, HRMS, and chiroptic properties) were identical in
all respects to those reported for the natural3 and synthetic
kendomycin (-)-1.5
Summary. We have achieved a stereocontrolled total syn-
thesis of kendomycin (-)-1. The synthesis proceeded with a
longest linear sequence of 21 steps, beginning with commercially
available 2,4-dimethoxy-3-methylbenzaldehyde (12), with an
(43) (a) McMurry, J. E.; Dushin, R. G. J. Am. Chem. Soc. 1989, 111, 8928-
8929. (b) McMurry, J. E.; Dushin, R. G. J. Am. Chem. Soc. 1990, 112,
6942-6949.
(44) (a) Sharpless, K. B.; Umbreit, M. A.; Nieh, M. T.; Flood, T. C. J. Am.
Chem. Soc. 1972, 94, 6538-6540. (b) For a computational study, see:
Ba¨ckvall, J. E.; Bo¨kman, F.; Blomberg, M. R. A. J. Am. Chem. Soc. 1992,
114, 534-538. (c) For a recent application in the synthesis of epothilone
analogues, see: Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J.
A.; Kim, S.-H.; DiMarco, J. D.; Fairchild, C. R.; Gougoutas, J. Z.; Lee, F.
Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem. Soc. 2000, 122, 8890-8897.
(45) Prior to 2D NMR and crystallographic analyses, our first hint that (-)-42
might indeed have the desired trans-olefin came from the following
chemical correlation: the C(4) phenol derived directly from cis-olefin (-)-
39 by removal of the TBS ether with BnNMe3OH revealed 1H NMR signals
distinct from those of (-)-42, indicating that the two samples were isomers.
(46) For a review, see: Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031-
1069.
(47) For a related example of acid-catalyzed hydrolysis of a vinylogous methyl
ester in a p-quinone system, see: Ling, T.; Poupon, E.; Rueden, E. J.;
Theodorakis, E. A. Org. Lett. 2002, 4, 819-902.
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5298 J. AM. CHEM. SOC. VOL. 128, NO. 15, 2006

Stereocontrolled Total Synthesis of (−)-Kendomycin
A R T I C L E S
overall yield of 0.49% (i.e., an average yield of 78% per step).
Highlights of the synthesis include an effective Petasis-Ferrier
union/rearrangement to construct the sterically encumbered
tetrahydropyran ring, a ring-closing metathesis to generate the
C(4a-13-20a) macrocycle, an effective epoxidation/deoxy-
genation sequence to isomerize the C(13,14) olefin, and a
biomimetic quinone-methide-lactol assembly to complete the
total synthesis of kendomycin (-)-1.
to E.F.M. and from the Swiss National Science Foundation to
E.A.M. We thank Drs. Patrick J. Carroll, George T. Furst, and
Rakesh Kohli of the University of Pennsylvania for the X-ray
analyses, assistance with the 2D NMR experiments, and the
Mass Spectrometry analyses, respectively.
Supporting Information Available: Experimental procedures,
spectroscopic and analytical data for the new compounds (PDF),
and X-ray crystallographic data for compounds (+)-30 and
(-)-2 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by the
National Institutes of Health (Institute of General Medical
Sciences) through grant GM-29028 and by Postdoctoral Fel-
lowships from the U.S. Department of Defense (PC-030136)
JA060369+
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