Formal [4 + 2]-Annulation of Chiral Crotylsilanes: Synthesis of the C19-C28 Fragment of Phorboxazoles

Article abstract of DOI:10.1021/ol015893u

(matrix presented) A stereoselective synthesis of the C19-C28 fragment of phoborxazole A and B is described. The key step is an enantioselective [4 + 2]-annulation of a crotylsilane 10 with a propargylic aldehyde 11 affording a functionalized dihydropyran 12. A solvent-dependent stereoselective epoxidation of dihydropyrans is also documented.

Full text of DOI:10.1021/ol015893u

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1693-1696
Formal [4 + 2]-Annulation of Chiral
Crotylsilanes: Synthesis of the
C19−C28 Fragment of Phorboxazoles
Hongbing Huang and James S. Panek*
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for
Science and Engineering, 590 Commonwealth AVenue, Boston UniVersity,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received March 26, 2001
ABSTRACT
A stereoselective synthesis of the C19−C28 fragment of phoborxazole A and B is described. The key step is an enantioselective [4 + 2]-annulation
of a crotylsilane 10 with a propargylic aldehyde 11 affording a functionalized dihydropyran 12. A solvent-dependent stereoselective epoxidation
of dihydropyrans is also documented.
Isolated from the Indian Ocean sponge Phorbos sp., phorb-
oxazoles A and B are among the most cytostatic natural
products discovered to date, displaying a mean GI50 value
of 1.58 × 10-9 M against the entire NCI panel of 60 tumor
cell lines.1 The unique structure and impressive biological
activity of the phorboxazoles have attracted wide interest of
synthetic chemists.2 Recently, Forsyth3 and Evans4 have
reported the first total synthesis of phorboxazoles A and B,
respectively. In this letter, we describe a stereoselective
synthesis of the C19-C28 tetrahydropyran ring of the
phorboxazoles.
We have recently reported our findings concerning the
development of a stereoselective [4 + 2]-annulation, which
results in the formation of enantiomerically enriched dihydro-
pyrans.5 The annulation provides stereochemically well-
defined dihydropyrans bearing three stereogenic centers and
complementary cis or trans stereochemistry across the pyran
oxygen. Accordingly, we hope this methodology will find
utility in natural product synthesis bearing functionalized
pyrans. Further, we anticipate highly substituted tetrahydro-
pyrans can be assembled by functionalization of the double
bond.
(1) For isolation and biological data see: (a) Searle, P. A.; Molinski, T.
T. J. Am. Chem. Soc. 1995, 117, 8126-8131. (b) Searle, P. A.; Molinski,
T. T. J. Am. Chem. Soc. 1996, 118, 9422-9423. (c) Molinski, T. F.
Tetrahedron Lett. 1996, 37, 7879-7880.
(2) Ye, T.; Pattenden, G. Tetrahedron Lett. 1998, 39, 319-322. (b)
Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T. Tetrahedron Lett.
1998, 39, 6099-6102. (c) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998,
39, 7185-7188. (d) Williams, D. R.; Clark, M. P.; Berliner, M. A.
Tetrahedron Lett. 1999, 40, 2287-2290. (e) Williams, D. R.; Clark, M. P.
Tetrahedron Lett. 1999, 40, 2291-2294. (f) Smith, A. B., III; Verhoest, P.
R.; Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909-912. (g) Smith, A.
B., III; Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T. J. Org. Lett. 1999,
1, 913-916. (h) Wolbers, P.; Misske, A. M.; Hoffmann, H. M. R.
Tetrahedron Lett. 1999, 40, 4527-4530. (i) Wolbers, P.; Hoffmann, H. M.
R. Synthesis 1999, 797-802. (j) Wolbers, P.; Hoffmann, H. M. R.
Tetrahedron 1999, 55, 1905-1914. (k) Misske, A. M.; Hoffmann, H. M.
R. Tetrahedron 1999, 55, 4315-4324. (l) Rychnovsky, S. D.; Thomas, C.
R. Org. Lett. 2000, 2, 1217-1219. (m) Donaldson, W. A.; Greer, P. B.
Tetrahedron Lett. 2000, 41, 3801-3803.
(3) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc.
1998, 120, 5597-5598. (b) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett.
1996, 37, 6449-6452. (c) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997,
62, 5672-5673. (d) Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39,
183-186.
(4) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew.
Chem., Int. Ed. 2000, 39, 2533-2536. (b) Evans, D. A.; Fitch, D. M. Angew.
Chem., Int. Ed. 2000, 39, 2536-2540. (c) Evans, D. A.; Fitch, D. M.; Smith,
T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033-10046
(5) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836-9837.
10.1021/ol015893u CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/28/2001

Our retrosynthetic analysis of phorboxazole A leads to
subunits 3, 4, and 5 (Scheme 1). We envisioned a transition
Scheme 2
Scheme 1
oxygenation of the double bond was required. We anticipated
that suitable facial bias could be imposed by the dihydro-
pyran, which would result in a stereoselective epoxidation.
Regioselective epoxide ring opening followed by inversion
of stereochemistry of the derived alcohol 20 would provide
fully functionalized tetralhydropyran containing all of the
required stereocenters of subunit 4.
Our initial studies on the epoxidation of this substrate gave
the â-epoxide with poor diastereoselectivity. For the epoxi-
dation of 9, there appears to be an interesting solvent effect
as CH2Cl2 and aromatic solvents were less selective in the
conversion of 9 to 13 (compare entries 2-4 with 5, Table
1). Thus, the desired â-epoxide 18 was obtained in good
yield and selectivity (85%, dr ) 13:1) using CCl4 as the
solvent (Scheme 3).
metal catalyzed sp2-sp2 coupling strategy for the construc-
tion of the C18-C19 and C28-C29 σ-bonds as an efficient
and direct route for their assembly.6 In the synthetic direction,
this analysis holds the potential for completion of the
macrolide either by lactonization or intramolecular Stille
coupling. Focusing on the C19-C28 tetrahydropyran subunit,
we explored the use of the dihydropyran annualtion meth-
odology as an effective way to synthesize 4.
In the presence of a catalytic amount of TMSOTf (-20
°C), trisubstituted dihydropyrans can be obtained with high
levels of selectivity from chiral silanes bearing a TMS ether
and a range of branched aldehydes.5 However, under the
same conditions, the reaction of siloxy crotylsilane 6 and
propargylic aldehyde 7 produced both desired dihydropyran
8 and byproduct furan 9 with low selectivity (Scheme 2).7
The same reaction, when performed at higher temperature
(20 °C), provided dihydropyran as the major product with
modest yield. After further experiments, we have learned
that silane reagent 10 bearing a triethylsiloxyl (TESO) group
adjacent to the ester provided the desired dihydropyran in
much higher yield. The enhanced nucleophilic character of
a triethylsilyl ether is a subtle but important observation
originally documented by Angle.8 For instance, reaction of
10 and aldehyde 11 afforded dihydropyran 12 in 60-70%
yield with no trace of the furan byproduct.
Table 1. Diastereoselective Epoxidation of Dihydropyran 9
To complete the synthesis of the fully functionalized
tetrahydropyran of the phorboxazoles, a stereoselective
(6) Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469-471.
(7) We have reported that enantiomerically enriched tetrahydrofurans can
be obtained by the reaction of crotylsilanes and aldehydes; see: (a) Panek,
J. S.; Yang, M. J. Am. Chem. Soc. 1991, 26, 9868-9870. (b) Beresis, R.
T.; Panek, J. S. Bioorg. Med. Chem. Lett. 1993, 13, 1609-1613. (c) For a
related tetrahydrofuran synthesis, see: Micalizio, G. C.; Roush, W. R. Org.
Lett. 2000, 2, 461-464.
a Diastereoselectivity was determined by 1H NMR (400 MHz) analysis.
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Org. Lett., Vol. 3, No. 11, 2001

yield. Gratifyingly, regioselective epoxide ring opening
provided the diol 20 as a single diastereomer in excellent
yield and without the need for purificiation.10 It is worth
noting that the copper-catalyzed ring opening takes place
with complete conversion to the secondary alcohol. The
reaction was much less efficient when excess Gilman reagent
was used (5 equiv, 8 h). The efficiency of the ring opening
leading to the trans-diaxial product 20 (J3H4,H5 ) 2.6 Hz) is
consistent with Furst-Plattner considerations.11
Scheme 3
With the epoxide ring opening now solved, the synthesis
of fully functionalized pyran was addressed. Treatment of
the intermediate diol 20 with triflic anhydride and pyridine
afforded the chromatographically stable primary triflate 21
in quantitative yield. Following protection of the secondary
alcohol as its TMS ether, displacement of the primary triflate
with lithium (trimethylsilyl)acetylide provided alkyne 22 in
80% overall yield.12
Completion of the C19-C28 fragment was carried out in
a straightforward sequence beginning with a Dess-Martin
oxidation13 of the secondary alcohol, which was followed
by a LiAlH4 reduction of the derived ketone 23 producing
the equatorial alcohol 24 in 90% overall yield (Scheme 4).
Scheme 4
The epoxidation on the primary alcohol 15, derived from
the reduction of the ester, was also evaluated as a substrate
that may provide useful levels of diastereoselectivity in the
introduction of the epoxide. However, LiAlH4 reduction of
9 afforded alcohol 15, and subsequent reaction with m-CPBA
under conditions identical to those in Table 1 provided
â-epoxide as major isomer with lower levels of selectivity
(Table 2).9
Table 2. Diastereoselective Epoxidation of 15
The vinyl stannane was introduced through a Pd-catalyzed
hydrostannation.14 Accordingly, the secondary alcohol was
protected as its TMS ether, which was followed by selective
(9) The lower diastereoselectivity can be attributed to existence of
homoallylic acohol which facilitates the formation of R-epoxide. For a
review on substrate-directed reaction, see: Hoveyda, A. H.; Evans, D. A.;
Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(10) For studies on the mechanism of organocuprate epoxide ring
opening, see: (a) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000,
39, 3750-3771. (b) Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem.
Soc. 2000, 122, 7294-7307.
a Diastereoselectivity was determined by 1H NMR (400 MHz) analysis.
(11) (a) Furst, A.; Plattner, A. HelV. Chim. Acta 1949, 32, 275-283. (b)
Hewbest, H. B.; Smith, M.; Thomas, A. J. Am. Chem. Soc. 1958, 80, 3293-
3297.
Selective reduction of the methyl ester 18 in the presence
of the epoxide cleanly provided epoxy-alcohol 19 in high
(12) For the similar displacement of primary trifluoromethanesulfonates
with the lithium anion of (trimethylsilyl)acetylene, see ref 4
(13) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(14) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857-1867.
(8) Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc. 1999, 121, 10211-
10212.
Org. Lett., Vol. 3, No. 11, 2001
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brominaiton (NBS)15 of the TMS-protected alkyne, affording
the 1-bromoalkyne. This material was treated with tributyltin
hydride (2.2 mmol) and catalytic PdCl2(PPh3)2 (5% mol) in
THF, producing the desired (E)-vinyl stannane 4 in 70%
overall yield.
methodology is suitably versatile for the synthesis of highly
substituted tetrahydropyran rings. Further synthetic studies
concerning the phoborxazoles will be forthcoming.
Acknowledgment. Financial support was obtained from
In conclusion, we have described an effective and enan-
tioselective synthesis of the fully functionalized C19-C28
tetrahydropyran subunit of phoborxazoles. This work dem-
onstrates that the [4 + 2]-annulation using chiral crotylsilane
the NIH/NCI (Grant R01GM55740).
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin Trans.
1 1996, 2417-2419.
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