Synthesis of the C22-C26 tetrahydropyran segment of phorboxazole by a stereoselective Prins cyclization

Article abstract of DOI:10.1021/ol005646a

(forrmula presented)Tetrahydropyran rings are found in many complex natural products, and the segment-coupling Prins cyclization is an effective strategy for their synthesis. We report a four-step, stereoselective synthesis of the C20-C27 tetrahydropyran

Full text of DOI:10.1021/ol005646a

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1217-1219
Synthesis of the C22−C26
Tetrahydropyran Segment of
Phorboxazole by a Stereoselective Prins
Cyclization
Scott D. Rychnovsky* and Christian R. Thomas
Department of Chemistry, UniVersity of California, IrVine, California 92697-2020
srychnoV@uci.edu
Received February 10, 2000
ABSTRACT
Tetrahydropyran rings are found in many complex natural products, and the segment-coupling Prins cyclization is an effective strategy for
their synthesis. We report a four-step, stereoselective synthesis of the C20−C27 tetrahydropyran segment of phorboxazole. The key step is
a Prins cyclization induced by catalytic BF3‚OEt2.
Phorboxazoles A and B have attracted the attention of
synthetic chemists because of their very high potency in the
NCI anticancer screens (mean GI50 1.6 × 10-9 M), the
difficulty of securing material from natural sources, and their
interesting architecture.1 Forsyth’s group led the way with
the first total synthesis of phorboxazole A in 1998.2 A
number of other groups have reported work directed toward
the total syntheses of the phorboxazoles.3 Our recent interest
in these compounds has focused on the assembly of the four
tetrahydropyran rings present in the structures. We describe
an enantioselective and stereoselective synthesis of the C22-
C26 tetrahydropyran ring of phorboxazole A.
The Prins reaction between a homoallylic alcohol and an
aldehyde in acidic solution is a well-established synthesis
of tetrahydropyrans.4 Protic and Lewis acid promoted cy-
Tetrahedron 1999, 55, 1905-1914. (k) Misske, A. M.; Hoffmann, H. M.
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Snider, B. B. The Prins Reaction and Carbonyl Ene Reactions; Trost, B.
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10.1021/ol005646a CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/12/2000

clizations work well in simple cases, and these reactions are
often stereoselective.5 Prins cyclizations have occasionally
been used in the synthesis of more complex targets.6 Our
recently reported reductive acetylation of esters to R-acetoxy
ethers7 provides a facile entry into the oxocarbenium ion
intermediates that are ideal precursors for segment-coupling
Prins cyclizations.8
configuration in the tetrahydropyran. Esterification and
reductive acetylation proceeded uneventfully to give R-ace-
toxy ether 6 in 80% overall yield from alcohol 4. Activation
with BF3‚OEt2 and acetic acid in hexanes at 0 °C gave
tetrahydropyran 7 as a single isomer in 69% yield. The
configuration of 7 was confirmed by NOE measurements
and coupling constant analysis (Figure 2). A chair conforma-
Segment 1, which includes the C20-C26 tetrahydropyran
of the phorboxazoles, is shown in Figure 1. There are a
Figure 1. The C22-C26 tetrahydropyran segment of phorbox-
azole A.
Figure 2. Geometry of the Prins cyclization transition state leading
to tetrahydropyran 7; NOE data and coupling constants supports
the assignment.
number of possible Prins cyclization precursors for 1, but
none of them are ideal for our strategy because they either
involve (a) reductive acetylation of an R,â-unsaturated ester
or (b) Prins cyclization of an allylic alcohol that might be
expected to fragment. To avoid these potential problems, we
settled on a strategy in which the trisubstituted alkene would
be incorporated after the Prins cyclization. The key elements
of this approach were explored in the model study shown in
Scheme 1. Aldehyde 2 was coupled with Hoffmann’s (Z)-
tion of the oxocarbenium ion intermediate and a trans
addition across the alkene are consistent with the observed
configuration of the product, Figure 2. The successful
synthesis of tetrahydropyran 7, which incorporates the five
contiguous stereogenic centers of 1, led us to investigate the
optically active substrate.
A viable precursor to the C20-C26 tetrahydropyran
segment of phorboxazole would need to be optically pure
and need to incorporate a functional handle for the introduc-
Scheme 1. Prins Cyclization in a Model System
Scheme 2. Synthesis of the Optically Pure Phorboxazole
Tetrahydropyran 12
pentenyl boronate 39 to produce homoallylic alcohol 4.10
Alcohol 4 incorporates the requisite syn stereochemistry and
the (E)-alkene geometry that should lead to the correct
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Org. Lett., Vol. 2, No. 9, 2000

tion of the C27-C28 trisubstituted alkene. Tetrahydropyran
12 fulfills these requirements, and our approach to 12 is
shown in Scheme 2. Aldehyde 2 was coupled with Hoff-
mann’s optically pure (Z)-pentenyl boronate 811 to give
alcohol 9 with 98% ee.12 A DCC coupling with O-benzyl
S-lactic acid led to ester 10 as a single diastereomer. The
yield of 10 was 53% overall from 3-O-(tert-butyldiphenyl-
silyl)propane-1,3-diol, the precursor to aldehyde 2. Reductive
acetylation of 11 worked well on a 100 mg scale and gave
R-acetoxy ether 11 in 91% yield. On a 10 g scale, the yield
was 70%, and the product was accompanied by 18% of the
overreduced product. Normally reductive acetylations scale
well,7 and in this case the problem was probably a too rapid
addition of DIBAL-H that led to overreduction. Initial
cyclization experiments on a diastereomer of 11 produced
significant amount of fluoride trapping along with the desired
product. We found that the use of catalytic BF3‚OEt2 with
acetic acid largely alleviated this problem. Cyclization of
R-acetoxy ether 11 with 10 mol % of Lewis acid and 5 equiv
of acetic acid gave the desired tetrahydropyran 12 in 52%
yield, accompanied by 5% of the corresponding fluoride. This
is the first example of which we are aware where a Prins
cyclization was catalyzed by a Lewis acid. Compound 12
incorporates the five contiguous centers of the C20-C26
ring of phorboxazole and was prepared in four steps and
25% overall yield from aldehyde 2.
crystalline solid, mp ) 88 °C. X-ray analysis confirmed the
relative and absolute configuration of 14; the structure is
shown in Figure 3.14 Horner-Emmons reaction with the
Figure 3. Crystal structure of ketone 14 is shown; the silyl
substituents have been omitted for clarity.
triethyl phosphonoacetate anion gave alkene 15 in 73% yield.
The desired (E)-alkene predominated in a 3.9:1 ratio. Ester
14 has all of the key features of the C20-C26 tetrahydro-
pyran segment 1 from phorboxazole A except for the oxazole
ring.
Introduction of the trisubstituted alkene was evaluated as
illustrated in Scheme 3. The benzyl ether of 12 was removed
We have described a practical and enantioselective syn-
thesis of the C20-C26 tetrahydropyran of phorboxazole A.
This work demonstrates that the segment-coupling Prins
cyclization is suitable for the synthesis of highly substituted
tetrahydropyran rings.
Scheme 3. Synthesis of the Trisubstituted Alkene
Acknowledgment. We thank the National Cancer Insti-
tute (CA81635) for support of this work. C.R.T. thanks the
Deutscher Akademischer Austauschdienst (DAAD) for a
NATO Fellowship. We thank Dr. Joe Ziller for solving the
crystal structure of ketone 14.
Supporting Information Available: Structural informa-
tion for ketone 14 as a crystallographic information file.
Experimental procedures for the preparation of 15. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL005646A
by hydrogenation, and the resulting alcohol was oxidized
1
(10) All new compounds were characterized by H and 13C NMR, IR,
using Swern’s conditions.13 Ketone 14 was isolated as a
and MS analysis. All compounds except 9, which was contaminated with
starting material, gave satisfactory elemental analyses.
(11) (a) Hoffmann, R. W.; Ditrich, K.; Ko¨ster, G.; Stu¨rmer, R. Chem.
Ber. 1989, 122, 1783-9. (b) Hiscox, W. C.; Matteson, D. S. J. Org. Chem.
1996, 61, 8315-8316.
(12) Alcohol 9 was analyzed for optical purity by using a Chiralcel OD-H
column with 98:2 hexane:i-PrOH as the eluent, using the racemate as a
standard. The 3R,4R enantiomer (9) eluted first.
(13) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482.
(14) The X-ray data are available as Supporting Information. We thank
Dr. Joe Ziller for determining the structure of 14.
(6) For example, see: Overman, L. E.; Thompson, A. S. J. Am. Chem.
Soc. 1988, 110, 2248-2256.
(7) (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,
8317-8320. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000,
65, 191-198.
(8) Rychnovsky, S. D.; Hu, Y. Q.; Ellsworth, B. Tetrahedron Lett. 1998,
39, 7271-7274.
(9) Andersen, M.; Hildebrandt, B.; Ko¨ster, G.; Hoffmann, R. W. Chem.
Ber. 1989, 122, 1777-82.
Org. Lett., Vol. 2, No. 9, 2000
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