Phorboxazole synthetic studies. 2. Construction of a C(20-28) subtarget, a further extension of the Petasis-Ferrier rearrangement.

Article abstract of DOI:10.1021/ol990829m

[formula: see text] In this, the second of two Letters, we describe the efficient assembly of (+)-4, a C(20-28) subtarget for the total synthesis of phorboxazoles A (1) and B (2). The synthesis was achieved in 12 linear steps (20% overall yield) via Petas

Full text of DOI:10.1021/ol990829m

ORGANIC
LETTERS
1999
Vol. 1, No. 6
913-916
Phorboxazole Synthetic Studies. 2.
Construction of a C(20−28) Subtarget, a
Further Extension of the Petasis−Ferrier
Rearrangement
Amos B. Smith, III,* Kevin P. Minbiole, Patrick R. Verhoest, and
Thomas J. Beauchamp
Department of Chemistry, Laboratory for Research on the Structure of Matter, and
Monell Chemical Senses Center, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received July 19, 1999
ABSTRACT
In this, the second of two Letters, we describe the efficient assembly of (+)-4, a C(20−28) subtarget for the total synthesis of phorboxazoles
A (1) and B (2). The synthesis was achieved in 12 linear steps (20% overall yield) via Petasis−Ferrier rearrangement of an E/Z mixture of
trisubstituted enol ethers (15) to assemble the C(22−26) cis-tetrahydropyran. A mechanism for the observed diastereoconvergence of 15 is
proposed. In addition, a new tactic for the synthesis of enol ethers (e.g., 15) based on the elegant work of Julia is described.
Phorboxazoles A (1) and B (2), rare marine macrolides
comprised of three tetrahydropyrans, two oxazoles, and a
21-membered macrolactone, display extraordinary cancer cell
growth inhibition, and as such have attracted considerable
interest in the synthetic community.1-3 In the preceding
Letter,4 we outlined a strategy for the construction of 1 and
2, in conjunction with an efficient synthesis of the C(3-19)
subtarget (-)-5, exploiting an extension of the Petasis-
Ferrier rearrangement5,6 to assemble the C(11-15) tetrahy-
dropyran ring (Scheme 1). The success of the Petasis-Ferrier
rearrangement encouraged us to explore a similar tactic for
construction of the fully substituted C(22-26) tetrahydro-
pyran moiety present in the C(20-28) subtarget 4.
Our modification of the Petasis-Ferrier rearrangement
permits direct conversion of a 4-alkylidenyl-1,3-dioxane (9)-
to the corresponding cis-tetrahydropyranone (10) when Me2-
AlCl is employed as the Lewis acid. This protocol avoids
the Meerwein-Ponndorf-Verley reduction of the initially
derived tetrahydropyranone by i-Bu3Al, as observed by
Petasis. To extend the Petasis-Ferrier rearrangement to
assemble a fully substituted tetrahydropyran such as 4
(Scheme 1), trisubstituted enol ether 7 would be required.
No information on the stereochemical outcome for trisub-
stituted enol ethers however was available. To explore this
stereochemical issue, we prepared and rearranged (-)-11,7
a model of enol ether 7 (Scheme 2).
(1) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(2) (a) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J.
Am. Chem. Soc. 1996, 118, 9422. (b) Molinski, T. F. Tetrahedron Lett.
1996, 37, 7879.
(3) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc.
1998, 120, 5597. For references to other synthetic efforts, see ref 4.
(4) Smith, A. B., III.; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org.
Lett. 1999, 1, 909.
(5) Petasis, N. A.; Lu, S. P. Tetrahedron Lett. 1996, 36, 141.
(6) Ferrier, R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779.
10.1021/ol990829m CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/31/1999

Scheme 1
Scheme 3
aluminum enolate; rotation of the enolate by 180° (i f iii)
and reclosure via a chair conformation would afford (+)-
12.
Armed with this insight, we envisioned the oxygen-
transposed enol ether 15 to be an appropriate substrate for
the construction of 4 (Scheme 4). Rearrangement involving
Scheme 4
Scheme 2
bond rotation of 180° would lead via a chair conformation
to 16 possessing the requisite axial methyl at C(23).
Assembly of 15 began with aldol condensation of the
boron enolate derived from Evans oxazolidinone (+)-179
with aldehyde 8;7c hydrolysis (LiOH, H2O2) afforded â-hy-
droxy acid (+)-1810 in 84% yield for the two steps (Scheme
5). Bis-silylation with hexamethyldisilazane (HMDS),11
followed by TMSOTf12-promoted condensation with alde-
Scheme 5
Although Petasis suggests the rearrangement proceeds via
a chair conformation, we rationalized that a least motion
mechanism involving a boat conformation (i f ii, Scheme
3) held promise of delivering the required stereochemical
outcome (e.g., 14). In the event, however, Petasis-Ferrier
rearrangement of (-)-11 furnished only the all equatorial
tetrahydropyran (+)-12 (58% unoptimized); the configuration
of (+)-12 was secured via 1D-NOE experiments.8 Presum-
ably, Lewis acid complexation at the enol ether oxygen of
(-)-11 triggers ring opening, reversibly liberating the
914
Org. Lett., Vol. 1, No. 6, 1999

hyde 1913 furnished dioxanone (+)-2010 in 66% yield, along
with 19% of the C(26) epimer, the latter readily removed
by flash chromatography.14 The configuration of (+)-20 was
again determined by 1D-NOE experiments. Unfortunately,
ethylidenation via the Takai protocol7d failed to yield 15,
furnishing instead the C(23) epimeric enol ether as a E/Z
mixture (21). Related olefination strategies were equally
unsuccessful.15
Scheme 7
Undaunted, we explored the Julia protocol for olefination
of sulfones with electrophilic carbenoids.16 This protocol calls
for R-alkylation of a sulfone (22a) with R-halo Grignard
reagents (23); subsequent elimination furnishes the alkene
(24a; Scheme 6). We reasoned that a similar reaction with
Toward this end, reduction of dioxanone (+)-20 (DIBAL)
followed by in situ acylation of the alkoxide (Ac2O, DMAP)
afforded acetal (+)-2510 (Scheme 7).18 Treatment of (+)-25
Scheme 6
19
with PhSTMS in the presence of ZnI2 then led to the
corresponding sulfide which upon oxidation (mCPBA)
generated sulfone (+)-2610 in 68% yield for the two steps.
Deprotonation of (+)-26 with n-BuLi and exposure to
Grignard 2716,20 furnished the desired enol ether 15 in
excellent yield (95%), albeit with no E/Z selectivity. Careful
flash chromatography permitted separation of the E and Z
diastereomers; again the stereochemistry was secured by
NOE experiments.
To our delight, treatment of the 1:1 mixture of enol ethers
(15) with Me2AlCl afforded only the desired tetrahydropyran
(+)-1610,21 in a 91% yield (Scheme 8). The individual
diastereomers also rearranged to tetrahydropyran (+)-16 in
similarly high yields.
sulfone 22b (R2 ) OR) would afford 24b, contingent on
preferential expulsion of phenyl sulfinate over the alkoxide.17
(7) (a) Enol ether (-)-11 was prepared by condensation of â-hydroxy
acid (+)-67b and aldehyde 8,7c hydrogenation of the resultant dioxanone,
and Takai ethylidenation.7d (b) (+)-6 was prepared according to Oppolzer’s
protocol: Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993, 34, 4321. (c)
Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. H. J. Am.
Chem. Soc. 1987, 109, 7553. (d) Okazoe, T.; Takai, K.; Oshima, K.;
Utimoto, K. J. Org. Chem. 1987, 52, 4410.
Scheme 8
(8) That 12 is not the result of epimerization of the axial methyl group
was demonstrated via exposure of 14 to the reaction conditions; no
epimerization occurred.
(9) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(10) The structure assigned to each new compound is in accord with its
1
infrared, 500 MHz H NMR, and 125 MHz 13C NMR spectra, as well as
appropriate ion identification by high-resolution mass spectrometry.
(11) (a) Harada, T.; Yoshida, T.; Kagamihara, Y.; Oku, A. J. Chem. Soc,
Chem. Commun. 1993, 1367. (b) Seebach, D.; Imwinkelried, R.; Stucky,
G. HelV. Chim. Acta 1987, 70, 448.
(12) Initial difficulties in the scale-up of this reaction suggested that TfOH
is the actual catalyst. Advantageous water, more pronounced on smaller
scale, may generate TfOH in situ from TMSOTf (as well as TMS2O). Large-
scale reactions do not proceed until catalytic TfOH (2-4 mol %) is added.
Yields and diastereoselectivity were similar with the added TfOH.
(13) (a) Lange, T.; van Loon, J.-D.; Tykwinski, R. R.; Schreiber, M.;
Diederich, F. Synthesis, 1996, 537. (b) For an improved general route to
R,â-acetylenic aldehydes, see: Journet, M.; Cai, D.; DiMichele, L. M.;
Larsen, R. D. Tetrahedron Lett. 1998, 39, 6427.
(14) Although all attempts to epimerize the undesired C(26) isomer to
(+)-20 were unsuccessful (e.g., with TMSOTf), hydrolysis of the epimer
(LiOH, H2O/THF) afforded (+)-18 in 97% yield.
(15) Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T. J. Am. Chem.
Soc. 1997, 119, 1127.
Although (+)-15Z presumably rearranges through a chair
transition state as anticipated in Scheme 3, formation of (+)-
16 from (+)-15E implies that the unfavorable 1,3-diaxial
interactions in transition state ii (Scheme 9) preclude a chair
(18) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317.
(19) Evans, D. A.; Trotter, B. W.; Cote´, B.; Coleman, P. J. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 24, 2741.
(16) De Lima, C.; Julia, M.; Verpeaux, J.-N. Synlett 1992, 133.
(17) R-Amido sulfones in a similar reaction, see: Alonso, D. A.; Alonso,
E.; Najera, C.; Ramon, D. J.; Yus, M. Tetrahedron Lett. 1997, 53, 4835.
(20) Simpson, M. M. Bull. Soc. Chem. Fr. 1879, 31, 411.
(21) The stereochemistry of (+)-16 was secured by NOE experiments
and coupling constant analysis.
Org. Lett., Vol. 1, No. 6, 1999
915

Scheme 9
Scheme 10
conformation and instead lead to a boatlike transition state
(iii), wherein the re face of the enolate approaches the
oxocarbenium species. Presumably, the small steric require-
ments of the alkyne as well as the propargylic stabilization
of the oxocarbenium ion22 lower the transition state energy
of ii and iii comparably. However, the 1,3 diaxial interactions
in ii evidently outweigh the energetic penalty of adopting
the boat conformation in iii.
An alternative mechanism would entail E to Z isomeriza-
tion of the enol ether followed by rearrangement through a
chair conformation.23 All attempts, however, to observe 15Z
upon interruption of the Petasis-Ferrier rearrangement failed
to provide evidence for this isomerization.
With an efficient synthesis of tetrahydropyranone (+)-16
in hand, four steps remained to complete subtarget 4 (Scheme
10): reduction of (+)-16 with NaBH4 (91% yield, 15:1 dr)
followed by protection of the alcohol (Bz2O, >99% yield)
provided benzoate (+)-29.10 Desilylation (TBAF, 96% yield)
and Dess-Martin24 oxidation then furnished aldehyde (+)-
410 in 93% yield.
26) tetrahydropyran in subtarget (+)-4. The synthesis
proceeded in 12 linear steps and 20% overall yield. In
addition, we have developed a new tactic for enol ether
synthesis, extending the elegant work of Julia. Finally, a
mechanistic rationale for the diastereoconvergent Petasis-
Ferrier rearrangement of E and Z trisubstituted enol ethers
is presented. Studies to assemble the phorboxazole macro-
cycle and ultimately phorboxazoles A (1) and B (2) continue
in our laboratory.
Acknowledgment. Support was provided by the National
Institutes of Health (National Cancer Institute) through grant
CA-19033.
Supporting Information Available: Spectroscopic and
analytical data for 4, 6, 11-13, 15, 16, 18, 20, 25, 26, and
29 and selected experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
In summary, the Petasis-Ferrier rearrangement has been
extended to permit assembly of the fully substituted C(22-
OL990829M
(22) For an example of an acetylene stabilizing an oxocarbenium ion in
an acetal opening, see: Denmark, S. E.; Almstead, N. G. J. Am. Chem.
Soc. 1991, 113, 8089.
(23) For an example of silyl enol ether isomerization, see: Duffy, J. L.;
Yoon, T. P.; Evans, D. A. Tetrahedron Lett. 1995, 36, 9245.
(24) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
916
Org. Lett., Vol. 1, No. 6, 1999