Total synthesis of (-)-kendomycin exploiting a petasis-ferrier rearrangement/ring-closing olefin metathesis synthetic strategy

Article abstract of DOI:10.1021/ja051420x

The total synthesis of (-)-kendomycin (1), a novel macrocyclic polyketide with antibacterial and antitumor activity, was achieved in 21 steps (longest linear sequence) exploiting an effective Petasis-Ferrier union/rearrangement tactic to construct the tet

Full text of DOI:10.1021/ja051420x

Published on Web 04/23/2005
Total Synthesis of (-)-Kendomycin Exploiting a Petasis-Ferrier
Rearrangement/Ring-Closing Olefin Metathesis Synthetic Strategy
Amos B. Smith, III,* Eugen F. Mesaros, and Emmanuel A. Meyer
Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received March 5, 2005; E-mail: smithab@sas.upenn.edu
Kendomycin, (-)-1, a novel macrocyclic polyketide first isolated
in 19961 from Streptomyces Violaceoruber, possesses potent activity
as both an endothelin receptor antagonist1 and an antiosteoporotic
agent.2 Reisolation by the Zeeck group3 revealed, in addition,
significant antibacterial activity against multiresistant bacteria,
including vancomycin-resistant strains, and remarkable cytotoxicity
against a series of human tumor cell lines (GI50 < 0.1 µM).3 The
impressive biological profile, in conjunction with the challenging
architecture, defined by X-ray and Mosher ester analysis,3 triggered
considerable synthetic efforts,4 culminating in 2004 with the first
total synthesis.5 The structure of kendomycin comprises a unique
quinone-methide-lactol chromophore, attached to a densely
substituted tetrahydropyran ring, in conjunction with an aliphatic
ansa ring.
(+)-7 (3 steps from citronellene), available respectively in 19, 46,
and 67% overall yields (see Supporting Information).
With ample quantities of both 6 and (+)-7, execution of the
Petasis-Ferrier protocol8,9 involving union as the dioxanone,
Petasis-Tebbe methylenation,10 and rearrangement of the unstable
enol-acetal 8 furnished tetrahydropyran (+)-9 in 85% yield.
Diastereoselective methylation of the kinetic enolate of (+)-9,
followed by diastereoselective reduction of the C(7) ketone and
TBS protection led to (+)-5 as the major product (Scheme 2);
assignment of the relative stereochemistry was secured by vicinal
1H coupling constants.
Scheme 2
Recently, we launched a synthetic program targeting (-)-
kendomycin (1). Our end-game was envisioned to rely on the Zeeck
biosynthetic hypothesis3 that the more stable C(19) lactol arises
via addition of the C(1) hydroxyl (Scheme 1), available in this case
upon hydrolysis of vinylogous methyl ester 2 to the C(19) ketone.
In turn, oxidation state adjustment at C(19) and disconnection of
the C(13,14) and C(20,20a) bonds in 3 reveals known epoxides
44a and the tetrahydropyran 5. In the forward sense, union of 4 and
the aryl anion derived from 5 would deliver a prospective ring-
closing metathesis substrate. Ring-closing metathesis (RCM) was
of course not without considerable risk given the required R-branched,
trisubstituted olefin in a 16-membered ring.6 Notwithstanding this
challenge, we reasoned that phenol 3 protected as the TBS ether
would maximize the population of the atropisomer required for a
productive RCM process (vide infra).7 Finally, cis-5,9-disubstituted
tetrahydropyran 5 suggested the powerful Petasis-Ferrier union/
rearrangement8 tactic, developed recently in our laboratory.9
Coupling of the anion derived from (+)-5 with 4 (Scheme 3),
promoted by BF3‚OEt2 next yielded diene 10, obtained as a 2:1
mixture of C(19) epimers, which upon oxidation, furnished a single
ketone (+)-11.11 Ring-closing metathesis, however, proved inef-
fective.
Scheme 1
Scheme 3
We began the synthesis of (-)-kendomycin (1) with known
epoxides 4 (7 steps from methallyl chloride),4a aldehyde 6 (5 steps
from 2,4-dimethoxy-3-methylbenzaldehyde), and â-hydroxy acid
9
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10.1021/ja051420x CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Undaunted, we exposed alcohols 10 to the second generation
Grubbs catalyst; pleasingly, macrocycle (+)-12 was obtained as a
single isomer (Scheme 3).12 Only the major epimer, 19(S)-10,
however, underwent RCM. The configuration of the C(13,14) olefin,
assigned initially via NOESY experiments and confirmed by X-ray
analysis, proved to be Z. Notwithstanding the Z configuration, this
outcome is noteworthy as the first example of a 16-membered ring
formation by RCM, possessing a sterically encumbered olefin.6
While the RCM reactivity behavior of 19(S)-10 versus 19(R)-
10 and (+)-11 currently eludes our full understanding, we reason
that a hydrogen bond between C(19)-OH and the C(1)-OMe in
19(S)-10 may play a significant role in orienting the side chains.13
Equally important was selection of the TBS protecting group to
ensure the productive C(4a,5) rotamer [i.e., C(4)-OTBS and the
C(5)-H are synclinal].7b,4a Ring-closing metathesis reactions on
substrates analogous to 10, but devoid of bulky protection at C(4),
fail.
Isomerization of the Z olefin to the desired E diastereomer was
thus required. Initial attempts involving various free radical
processes proved unrewarding; only migration of the olefin to the
C(14,15) position was observed.14 Mulzer and co-workers observed
a similar isomerization upon attempted Barton deoxygenation of a
related substrate.4a Vedejs isomerization15 also proved ineffective.
We next explored generation of the trans epoxide. Precedent for
the conversion of syn vicinal diols to trans epoxides, when set in
a relatively rigid 14-membered ring, is available in the work of
McMurry;16 deoxygenation with [W4+] with retention of configu-
ration is also precedented.17 To this end, protection of the C(19)
hydroxyl as the TES ether (Scheme 4), followed by cis dihydroxy-
lation of the C(13,14) olefin, furnished a single diol (13C NMR).
isomer. NMR studies (COSY and NOESY) confirmed the olefin
configuration. Selective removal of the C(19) TES group in the
presence of the C(7) TBS ether, followed by Dess-Martin
periodinane oxidation11 of the resulting C(19) hydroxyl in (-)-15,
which also led to oxidation of the phenol, furnished a single
crystalline o-quinone (-)-2. X-ray analysis confirmed the structural
assignment. Final exposure of (-)-2 to concentrated aqueous HF
led to hydrolysis of both the C(7) TBS ether and C(1) vinylogous
methyl ester,18 followed by addition, as per the biosynthetic
hypothesis,3 of the resultant C(1) hydroxyl to the C(19) carbonyl
to complete construction of (-)-kendomycin (1). Spectroscopic data
(i.e., 500 MHz 1H NMR, 125 MHz 13C NMR, IR, and HRMS) and
chiroptic properties of (-)-1 were identical to those reported for
the natural product.3,5
Acknowledgment. Support was provided by the National
Institutes of Health (Institute of General Medical Sciences) through
Grant GM-29028, and by Postdoctoral Fellowships from the U.S.
Department of Defense (PC-030136) to E.F.M., and from the Swiss
National Science Foundation to E.A.M.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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Scheme 4
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