Intramolecular palladium(II)-mediated alkoxy carbonylation as a route to functionalized tetrahydropyrans. synthesis of the C9-C32 segment of phorboxazole A

Article abstract of DOI:10.1021/ol010193a

matrix presented Hydroxy alkene 12, synthesized stereoselectively from 2-methyloxazole-4-carboxaldehyde, underwent intramolecular methoxy carbonylation in the presence of palladium(II) acetate to give 13 in which all five stereogenic centers around the tetrahydropyran correspond to those in ring C of phorboxazole A. Aldehyde 15, derived from 13, was linked to hydroxy alkene 23 via a Wittig coupling, and the composite 25 was subjected to a second palladium(II) acetate mediated methoxy carbonylation to yield 26, accompanied by acetoxy ester 27.

Full text of DOI:10.1021/ol010193a

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4003-4006
Intramolecular Palladium(II)-Mediated
Alkoxy Carbonylation as a Route to
Functionalized Tetrahydropyrans.
Synthesis of the C9−C32 Segment of
Phorboxazole A
James D. White,* Christian L. Kranemann, and Punlop Kuntiyong
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
james.white@orst.edu
Received August 28, 2001
ABSTRACT
Hydroxy alkene 12, synthesized stereoselectively from 2-methyloxazole-4-carboxaldehyde, underwent intramolecular methoxy carbonylation in
the presence of palladium(II) acetate to give 13 in which all five stereogenic centers around the tetrahydropyran correspond to those in ring
C of phorboxazole A. Aldehyde 15, derived from 13, was linked to hydroxy alkene 23 via a Wittig coupling, and the composite 25 was subjected
to a second palladium(II) acetate mediated methoxy carbonylation to yield 26, accompanied by acetoxy ester 27.
The tetrahydropyran nucleus is a common structural motif
among many classes of natural products, some of which
exhibit striking biological properties. For example, phor-
boxazole A (1), a powerful cytotoxic agent isolated from
Phorbas species of sponges, features three substituted
tetrahydropyran units embedded within a 21-membered
lactone ring.1 We have previously reported that intra-
molecular palladium(II)-catalyzed alkoxy carbonylation of
hydroxy alkenes affords a convenient entry to tetrahydro-
pyrans.2 It was further shown that 2,6-disubstituted tetrahy-
dropyrans are generated exclusively with cis configuration
in this process. Our observations followed upon earlier results
of Semmelhack3 and Liotta,4 whose studies focused on the
application of intramolecular alkoxy carbonylation to the
synthesis of tetrahydrofurans. We have recently extended this
methodology to the synthesis of tetrahydropyrans of greater
stereochemical complexity, and we now wish to describe its
application to the stereocontrolled assembly of a segment
of phorboxazole A5,6 that includes two of the four tetrahy-
dropyrans, B and C, of this structure.
Synthesis of the C9-C32 portion of 1 commenced from
methyl 2-methyl-4-oxazolecarboxylate (2),8 which was re-
duced to aldehyde 3 and coupled in a Wittig reaction with
(1) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(2) White, J. D.; Hong, J.; Robarge, L. A. Tetrahedron Lett. 1999, 40,
1463.
(3) Semmelhack, M. F.; Zhang, N. J. Org. Chem. 1989, 54, 4483.
(4) McCormick, M.; Monahan, R., III; Soria, J.; Goldsmith, D.; Liotta,
D. J. Org. Chem. 1989, 54, 4485.
Figure 1.
10.1021/ol010193a CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/16/2001

Scheme 1a
Scheme 2a
a Reagents and conditions: (i) DIBALH, CH2Cl2, -78 °C, 98%;
(ii) (+)-(Ipc)2BOMe, CH2dCHCH2MgBr, Et2O, -100 °C, 84%,
er > 20:1; (iii) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 99%; (iv) OsO4
(cat.), NaIO4, H2O-THF, 70%; (v) (+)-(Ipc)2BOMe, CH2d
CHCH2MgBr, Et2O, -100 °C, 66%, dr 12:1; (vi) TBDPSOTf, 2,6-
lutidine, CH2Cl2, rt, 89%; (vii) HCl (3 N), THF-H2O, 95%.
terminal alkene to yield 8. Oxidative cleavage of this diol
furnished 9, and asymmetric crotylation of the resultant
aldehyde with the reagent enantiomeric with that used on 5
produced a pair of diastereomeric alcohols in the ratio 6:1.
These were separated chromatographically, and the major
diastereomer 10 was converted to its triisopropylsilyl (TIPS)
ether 11. Conventional methods for cleaving the PMB ether
from 11 were thwarted by side reactions; DDQ, for example,
yielded the R,â unsaturated ketone resulting from oxidation
of the allylic alcohol after PMB cleavage, whereas reductive
methods invariably led to saturation of one or both double
bonds. Fortunately, a method by Sauve´11 employing a mild
Lewis acid in the presence of ethanethiol proved highly
effective for the selective unmasking of the PMB ether of
11. This led to 12, our precursor to the ring C tetrahydropyran
moiety of 1. Conditions for successful intramolecular alkoxy
carbonylation of 11 required considerable experimentation.
Only palladium(II) acetate was effective in mediating the
reaction, and it was necessary to include either acetonitrile
a Reagents and conditions: (i) DIBALH, -78 °C, 3 h, 69%; (ii)
Ph3PdC(CH3)CHO (4), C6H6, ∆, 20 h, 93%; (iii) trans-CH3CHd
CHCH3, t-BuOK, n-BuLi, THF, then (+)-(Ipc)2BOMe, THF, -70
°C, 6 h; H2O2, NaHCO3, rt, 15 h, 67%, dr >96:4, er >96:4; (iv)
NaH, THF, ∆, 40 min, then PMBCl, n-Bu4NI, ∆, 6 h, 89%; (v)
OsO4 (cat.), NMO, THF-H2O, rt, 10 h, 84%; (vi) NaIO4, H2O-
THF, rt, 30 min, 98%; (vii) trans-CH3CHdCHCH3, t-BuOK,
n-BuLi, THF, then (-)-(Ipc)2BOMe; HOCH2CH2NH2, MeOH, rt,
3 h, 53%, dr 6:1; (viii) TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 2 h, 99%;
(ix) AlCl3, EtSH, CH2Cl2, -20 f -4 °C, 3.5 h, 78%; (x) Pd(OAc)2
(3 equiv), CO, MeOH-MeCN, 70 h, 86%; (xi) LiAlH4, Et2O, 0
°C, 3 h, 79%; (xii) Dess-Martin periodinane, CH2Cl2, rt, 3 h, 85%.
phosphorane 49 to give (E) R,â-unsaturated aldehyde 5
(Scheme 1). Carefully optimized asymmetric crotyl addition
to 5 under Brown’s conditions10 produced homoallylic
(7) For other synthetic studies on phorboxazoles, see: (a) Ye, T.;
Pattenden, G. Tetrahedron Lett. 1998, 39, 319. (b) Pattenden, G.; Plowright,
A. T.; Tornos, J. A.; Ye, T. Tetrahedron Lett. 1998, 39, 6099. (c) Paterson,
I.; Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185. (d) Wolbers, P.;
Hoffmann, H. M. R. Tetrahedron 1999, 55, 1905. (e) Misske, A. M.;
Hoffmann, H. M. R. Tetrahedron 1999, 55, 4315. (f) Williams, D. R.; Clark,
M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40, 2287. (g) Williams, D.
R.; Clark, M. P. Tetrahedron Lett. 1999, 40, 2291. (h) Wolbers, P.; Hoffman,
H. M. R. Synthsis 1999, 5, 797. (i) Evans, D. A.; Cee, V. J.; Smith, T. E.;
Santiago, K. J. Org. Lett. 1999, 1, 87. (j) Wolbers, P.; Misske, A. M.;
Hoffmann, H. M. R. Tetrahedron Lett. 1999, 40, 4527. (k) Wolbers, P.;
Hoffmann, H. M. R.; Sassee, F. Synlett 1999, 11, 1808. (l) Schaus, J. V.;
Panek, J. S. Org. Lett. 2000, 2, 469. (m) Pattenden, G.; Plowright, A. T.
Tetrahedron Lett. 2000, 41, 983. (n) Rychnovsky, S. D.; Thomas, C. R.
Org. Lett. 2000, 2, 1217. (o) Williams, D. R.; Clark, M. P.; Emde, U.;
Berliner, M. A. Org. Lett. 2000, 2, 3023. (p) Greer, P. B.; Donaldson, W.
A. Tetrahedron Lett. 2000, 41, 3081.
1
alcohol 6 as a single anti diastereomer according to H and
13C NMR. The 19F NMR spectrum of the Mosher ester of 6
indicated that the parent alcohol was obtained enantiomeri-
cally pure within the limits of the NMR measurement if the
crotylation was carried out within a narrow temperature range
around -70 °C. Etherification of 6 with p-methoxybenzyl
(PMB) chloride in the presence of tetra-n-butylammonium
iodide afforded 7, which was selectively osmylated at the
(5) For total syntheses of phorboxazole A, see: (a) Forsyth, C. J.; Ahmed,
F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597. (b) Smith,
A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem.
Soc. 2001, 123, 4834.
(6) For the total synthesis of phorboxazole B, see: (a) Evans, D. A.;
Fitch, D. M. Angew. Chem., Int. Ed. 2000, 39, 2536. (b) Evans, D. A.;
Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033.
(8) (a) Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1947, 96. (b)
White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Synth., in press.
(9) Boger, D. L.; Curran, T. T. J. Org. Chem. 1992, 57, 2235.
(10) Brown, H. C.; Bhat, K. S.; J. Am. Chem. Soc. 1986, 108, 5919.
(11) Bouside, A.; Sauve´, G. Synlett 1997, 9, 1153.
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Org. Lett., Vol. 3, No. 25, 2001

Scheme 3a
a Reagents and conditions: (i) Bu3P, DMF, rt, 3 h; (ii) 15, DBU, 0 °C, 1 h, 96%; (iii) Pd(OAc)2, CO, MeOH-MeCN (1:1), 120 h.
or benzonitrile as a cosolvent with methanol. Deactivation
of the palladium species occurs during the reaction and is
slowed by inclusion of a nitrile cosolvent, but successive
quantities of Pd(OAc)2 must be added to drive the reaction
to completion. Under optimized conditions, a high yield of
13 was produced as a single stereoisomer. The configuration
of the new stereocenter at C22 was established as (R) by
NOE experiments, which showed signal enhancements due
to Hb (9.7%) and Hc (6.2%) when Ha was irradiated. The
enhancements were even larger (20.6% and 9.0%, respec-
tively) when the TIPS ether of 13 was replaced by a tert-
butyldiphenylsilyl ether. In preparation for its coupling with
the C9-C19 subunit of 1, the ester group of 13 was reduced
via alcohol 14 to aldehyde 15.
Methyl 2-(chloromethyl)oxazole-4-carboxylate (16)12 pro-
vided the starting point for the synthesis of the C9-C19
portion of 1, and the ester function was reduced to aldehyde
17 in good yield with diisobutylaluminum hydride at low
temperature (Scheme 2). Asymmetric allyl addition13 to 17
gave (R) homoallylic alcohol 18 in high enantiomeric purity
(er > 20:1) as determined by NMR measurement of its
Mosher ester. After protection of 18 as its tert-butyldi-
methylsilyl ether 19, the vinyl group was cleaved oxidatively
to yield aldehyde 20. A second asymmetric allyl addition to
this aldehyde furnished syn product 21 accompanied by a
small quantity of its anti diastereomer (syn:anti 12:1), which
was removed chromatographically. Since the C3 alcohol
would remain blocked while the C5 ether was unmasked,
tert-butyldiphenylsilyl protection was chosen for the former,
so that acidic hydrolysis of 22 gave exclusively alcohol 23.
Coupling of 23 with 15 was accomplished by means of a
Wittig reaction in which ylide 24, prepared by displacement
of chloride from 23 with tri-n-butylphosphine followed by
deprotonation with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
was condensed with aldehdye 15 (Scheme 3). In common
with other routes to phorboxazoles5,6 that have employed this
strategy for assembling the C19-C20 double bond, 25 was
obtained exclusively with (E) configuration at the new alkene
linkage. Intramolecular alkoxy carbonylation of 25 again
required successive addition of portions of Pd(OAc)2, ac-
etonitrile as a cosolvent with methanol, and an extended
reaction time for completion of the process, but the reaction
delivered 26 as a single stereoisomer. The configuration of
the new stereocenter at C11 was established as (S) by a NOE
experiment in which irradiation of Ha produced a signal
enhancement (9.9%) at Hb. A byproduct obtained from this
reaction was acetate 27 (mixture of two diastereomers),
which underwent elimination to an R,â-unsaturated ester in
the presence of DBU in toluene at reflux.
In summary, a convergent route to the C9-C32 portion
of phorboxazole A (1) has been developed that assembles
each of the tetrahydropyran moieties in this segment by
palladium acetate mediated methoxy carbonylation of an
acyclic hydroxy alkene precursor. Advantages of this meth-
odology include a high degree of stereocontrol in constructing
the 2,6-cis disubstituted tetrahydropyrans present in 1, facile
access to the alkenol precursors via asymmetric synthesis,
and tolerance of functionality, which in this case includes
alkene units elsewhere in the substrate.
(12) Cardwell, K. S.; Hermitage, S. A.; Sjolin, A. Tetrahedron Lett. 2000,
41, 4239.
(13) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988,
110, 1535.
Acknowledgment. C.K. is indebted to the Deutsche
Forschungsgemeinschaft for a postdoctoral fellowship, and
P.K. is grateful to the Ministry of Science and Technology,
Org. Lett., Vol. 3, No. 25, 2001
4005

Thailand, for a scholarship. Financial support was provided
by the NIH (GM50574).
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and characterization data for 5-15 and 17-27. This
OL010193A
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Org. Lett., Vol. 3, No. 25, 2001