Synthesis of (-)-pinolidoxin: Divergent synthetic strategy exploiting a common silacyclic precursor

Article abstract of DOI:10.1021/ol026433j

(figure presented) We describe a highly convergent and efficient synthesis of (-)-pinolidoxin, a potent modulator of plant pathogenesis, providing unambiguous determination of the relative and absolute stereostructure of this highly oxygenated fungal meta

Full text of DOI:10.1021/ol026433j

ORGANIC
LETTERS
2002
Vol. 4, No. 17
3005-3007
Synthesis of (−)-Pinolidoxin: Divergent
Synthetic Strategy Exploiting a Common
Silacyclic Precursor
Dong Liu and Sergey A. Kozmin*
The UniVersity of Chicago, Department of Chemistry, 5735 South Ellis AVe.,
Chicago, Illinois 60637
skozmin@uchicago.edu
Received June 27, 2002
ABSTRACT
We describe a highly convergent and efficient synthesis of (−)-pinolidoxin, a potent modulator of plant pathogenesis, providing unambiguous
determination of the relative and absolute stereostructure of this highly oxygenated fungal metabolite. Our unique strategy highlights the
applications of novel silacyclic precursors for stereocontrolled polyol synthesis and features the finding of the reversible ring-closing metathesis.
Occurrence of diverse polyol-containing motifs in many
complex synthetic targets stimulates the development of
efficient chemical methods for their construction. Recently,
we have introduced a new strategy for stereocontrolled polyol
synthesis exploiting a highly enantioselective, catalytic
desymmetrization of readily available silacyclopentene ox-
ides.1 In this letter, we extend this concept to the synthesis
of (-)-pinolidoxin, a potent modulator of plant pathogenesis,
providing unambiguous stereochemical determination of this
highly oxygenated fungal metabolite. The synthesis further
highlights our independent finding of the reversibility of the
ring-closing metathesis.2,3
implications. Isolated from the fungus Ascochyta pinodes in
1993,4 pinolidoxin (1, Scheme 1) was shown to possess
potent suppression of phenylalanine ammonia-lyase (PAL)
activity, a key regulatory enzyme in the phenylpropanoid
metabolic pathway activated following the pathogen attack.4
Interestingly, pinolidoxin had no phytotoxic effects on cell
growth and respiration, suggesting a specific mechanism of
action.5 Structure elucidation of pinolidoxin (1) entailed
extensive spectroscopic investigation combined with degra-
dation-reconstitution studies.6 While the relative stereo-
chemistry of the three stereogenic centers at C7, C8, and C9
was firmly established, the configuration at the C2 remained
unknown.6
Small molecule regulation of plant defense responses
during pathogenesis has important mechanistic and practical
Our strategy to pinolidoxin (Scheme 1) was designed to
explore two pivotal tactical issues. First, we envisioned a
convergent disconnection of the macrolide exploiting esteri-
fication and ring-closing metathesis. Second, we designed a
divergent assembly of the two required advanced fragments
2 and 3 starting from a common silacyclic precursor 8. Thus,
(1) Liu, D.; Kozmin, S. A. Angew. Chem., Int. Ed. 2001, 40, 4757.
(2) For another synthesis of pinolidoxin reported during submission of
the present manuscript, see: (a) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.;
Goddrad, R.; Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124,
7061-7069. For an earlier communication, see: (b) Fu¨rstner, A.; Rad-
kowski, K. Chem. Commun. 2001, 671.
(3) For previous observations pertaining to the reversibility of large ring-
closing olefin metathesis, see: (a) Smith, A. B., III; Kozmin, S. A.; Adams,
C. M.; Paone, D. V. J. Am. Chem. Soc. 2000, 122, 4984. (b) Lee, C. W.;
Grubbs, R. H. Org. Lett. 2000, 2, 2145. (c) Fu¨rstner, A.; Thiel, O. R.;
Kindler, N.; Bartkowska, B. J. Org. Chem. 2000, 65, 7990. (d) Smith, A.
B. III; Adams, C. M.; Kozmin, S. A. J. Am. Chem. Soc. 2001, 123, 990.
(e) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett. 2001, 3, 449.
(4) Evidente, A.; Lanzetta, R.; Capasso, R.; Vurro, M.; Bottalico, A.
Phytochemistry 1993, 34, 999.
(5) Vurro, M.; Ellis, B. E. Plant Sci. 1997, 126, 29.
(6) Napoli, L.; Messere, A.; Palomba, D.; Piccialli, V. J. Org. Chem.
2000, 65, 3432.
10.1021/ol026433j CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/23/2002

followed by chemoselective Swern oxidation of the primary
silyl ether afforded aldehyde 10.8 Final elaboration entailed
Wittig methylenation and proto-desilylation furnishing the
C6-C12 subunit (2) with excellent overall efficiency (nine
steps from known epoxide 8,9 42% overall yield).
Scheme 1
The synthesis of the C1-C5 segment (3) was commenced
with another diastereoselective opening of the epoxide
derived from silane 71 utilizing 3-butenyl cuprate (Scheme
3). Acetonide formation, followed by Woerpel oxidation gave
Scheme 3
1,4-diol 11.7 Bis-acylation with sorbic acid (DCC, DMAP)
afforded acetonide 12. Final elaboration entailed oxidative
cleavage with Pb(OAc)4, followed by oxidation of the
resulting aldehyde (NaClO2, NaH2PO4), to give fully func-
tionalized C1-C5 fragment 3 (nine steps, 28% overall yield).
While the union of the two advanced fragments 2 and 3
proved to be initially problematic, this highly convergent step
was successfully executed using the Yamaguchi protocol to
give the coupling product 13 in 82% yield (Scheme 4).10
creation of all stereogenic centers of the target would rely
on diastereoselective functionalization of silacyclic alcohols
6 and 7 assembled via our recent catalytic enantioselective
desymmetrization of meso silacyclic epoxides.1
Construction of the C6-C12 fragment (2, Scheme 2) began
Scheme 4
Scheme 2
Incorporation of the unsaturated side chain prior to cycliza-
tion was envisioned to enhance the overall efficiency of the
synthesis by avoiding the additional protection-deprotection
manipulations. The caveat, however, was the risk of com-
petitive participation of the sorbate moiety in the metathesis
step.
with highly diastereoselective and efficient epoxidation-
cuprate opening sequence starting with alcohol 6, available
in high enantiomeric purity via enantioselective isomerization
of epoxide 8.1 Installation of the acetonide protection and
oxidative cleavage of the silacyclic scaffold (t-BuOOH, KH,
DMF) revealed acyclic diol 9.7 Bis-silylation (TESCl, Et3N),
(7) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044.
(8) Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron
Lett. 1999, 40, 5161.
(9) Manuel, G.; Boukherroub, R. J. Organomet. Chem. 1993, 447, 167.
(10) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
3006
Org. Lett., Vol. 4, No. 17, 2002

Treatment of tetraene 13 with the Grubbs dihydroimida-
zolylidene catalyst A (10 mol %)11 resulted in efficient ring
closure to afford 10-membered lactone 14 as a single, albeit
undesired, cis-olefin isomer (Scheme 5).12 Subjection of 13
Scheme 6
Scheme 5
diastereoselectivity (Scheme 6).15 Interestingly, treatment of
the cis product of this reaction with catalyst A resulted in
formation of the two alkene isomers in the same ratio,
providing additional support for the reversible nature of this
cyclization. 1H NMR (500 MHz) and 13C NMR (125 MHz)
spectra of synthetic pinolidoxin (1) were in excellent
agreement with those reported in the literature,4 firmly
establishing the relative stereochemistry at C2. Optical
to Cl2(PCy3)2RudCHPh13 afforded a mixture of cis- and
trans-olefin isomers in ca. 1:1 ratio. A complete conforma-
tional search14 revealed that cis-isomer 14 was 2.7 kcal/mol
lower in energy compared to the trans-alkene suggesting that
the outcome of the ring-closing metathesis employing catalyst
A can be a result of thermodynamic control.12
28
rotation of 1 ([R]D -140°) indicated its enantiomeric
25
relationship to the natural product (lit. [R]D 142.9°),4
necessitating the revision of the originally postulated absolute
configuration.6
Additional molecular modeling revealed that removal of
the acetonide in silico reversed the thermodynamic stability
of the two isomeric macrocycles, favoring the trans-alkene
by 1.0-1.3 kcal/mol.14 This theoretical study suggested the
possibility of obtaining pinolidoxin directly by subjecting
diol 15 (see Scheme 6) to the ring-closing metathesis under
thermodynamic control.
In closing, we have described a highly convergent and
efficient synthesis of (-)-pinolidoxin, providing unambigu-
ous stereochemical determination of this fungal metabolite.
Our unique strategy highlighted the utilization of novel
silacyclic platforms for stereocontrolled polyol synthesis and
featured the design of the final reversible ring-closing
metathesis.
To this end, acid-mediated hydrolysis of acetonide 13
(TFA, THF-H2O) proceeded to give diol 15 in 81% yield.
Subjection of diol 15 to the Grubbs catalyst A (10 mol %)
indeed afforded predominantly the desired trans isomer,
providing direct access to pinolidoxin (1), albeit with modest
Acknowledgment. Support of this work was provided
by the Donors of the Petroleum Research Fund, administered
by the American Chemical Society, and the University of
Chicago.
Supporting Information Available: Characterization of
new compounds and experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(12) For similar independent observations, see ref 2a.
(13) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
OL026433J
(14) Conformational search was carried out using MMFF force field,
followed by AM1 energy minimization; Mac Spartan Pro 1.0.4, Wave-
function, Inc.; www.wavefun.com.
(15) Higher diastereoselectivity was observed under the same conditions
in the absence of the sorbate side chain (trans:cis ) 83:17).
Org. Lett., Vol. 4, No. 17, 2002
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