Enantioselective synthesis of the C18-C25 segment of lasonolide A by an oxonia-Cope Prins cascade

Article abstract of DOI:10.1021/ol050270s

(Chemical Equation Presented) A 2-oxonia-Cope Prins cascade was developed that led to a facile and stereoselective synthesis of the C18-C25 segment of lasonolide A. The strategy nicely handles the introduction of the quaternary center in the tetrahydropyr

Full text of DOI:10.1021/ol050270s

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1589-1591
Enantioselective Synthesis of the
C18 C25 Segment of Lasonolide A by
−
an Oxonia-Cope Prins Cascade
Jackline E. Dalgard and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697-2025
srychnoV@uci.edu
Received February 8, 2005
ABSTRACT
A 2-oxonia-Cope Prins cascade was developed that led to a facile and stereoselective synthesis of the C18−C25 segment of lasonolide A. The
strategy nicely handles the introduction of the quaternary center in the tetrahydropyran ring, and all of the stereogenic centers in the product
arise from a single stereocenter introduced in a catalytic enantioselective reaction.
Tetrahydropyran rings are common structural motifs in
marine natural products. Enantioselective synthesis of such
rings has been a topic of interest in recent years, and general
solutions to this problem include enantioselective hetero-
Diels-Alder reactions,1 Prins cyclizations,2 and intra-
molecular etherification of a suitable acyclic precursor.3
Quaternary centers make the synthesis of tetrahydropyran
rings more challenging. The first two strategies are not well
suited to tetrahydropyrans with quaternary centers, and the
final approach is hampered by the synthesis of acyclic
quaternary centers. We describe a tandem oxonia-Cope
Prins cyclization4,5 that nicely meets this challenge and
illustrate the concept with a synthesis of the C18 to C25
segment of lasonolide A (Figure 1).
Lasonolide A was isolated from a shallow water Caribbean
sponge, species Forcepia.6 It shows potent activity against
A-549 human lung carcinoma. Lee’s seminal synthetic work
included a correction of the structure and a reassignment of
the absolute configuration.7 Lee prepared the C18-C25
segment of lasonolide through a radical cyclization with a
silyl tether. More recently, Kang has reported an efficient
total synthesis of lasonolide A.8 Kang prepared the C15-
C25 segment through a clever desymmetrization strategy to
introduce the quaternary center prior to tetrahydropyran
cyclization.8b Several other groups have synthesized the
C19-C23 tetrahydropyran of lasonolide A.9 Lasonolide A’s
interesting structure, potent anticancer activity, and natural
(1) (a) Taylor, M. S.; Jacobsen, E. N. PNAS 2004, 101, 5368-5373. (b)
Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749-3754.
(2) (a) Hart, D. J.; Bennett, C. E. Org. Lett. 2003, 5, 1499-1502. (b)
Barry, C. S. J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429-2432. (c) Marumoto,
S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919-
3922. (d) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217-
1219.
(3) For example, see: Ye, T.; Pattenden, G. Tetrahedron Lett. 1998, 39,
319-322.
(4) Dalgard, J. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126,
15662-15663.
(5) For a related tetrahydropyran synthesis, see: (a) Petasis, N. A.; Lu,
S. P. Tetrahedron Lett. 1996, 37, 141-144. (b) Smith, A. B., III; Minbiole,
K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942-
10953. (c) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216-
12217.
Figure 1. Structure of (-)-lasonolide A (1) and the C18-C25
tetrahydropyran segment.
10.1021/ol050270s CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/18/2005

scarcity have made it an attractive target for synthetic
chemists.
Scheme 2. Proposed 2-Oxonia-Cope Prins Cyclization
Cascade To Produce C18-C25 Tetrahydropyran of Lasonolide
The segment-coupling Prins cyclization strategy is versatile
and allows diverse cyclizations to be investigated.10 A simple
approach to the requisite C19-C23 tetrahydropyran of
lasonolide might arise from cyclization of a trisubstituted
alkene as shown in Scheme 1. Not unexpectedly, this strategy
A
Scheme 1. Segment-Coupling Prins Cyclization with
Trisubstituted Alkene Favors Tetrahydrofurans
fails. A trisubstituted alkene such as 2 favors cyclization on
the less substituted position to produce the undesired
tetrahydrofuran 3.11 We had hoped that inclusion of electron-
withdrawing groups on the alkene, such as the acetate in 2,
would favor the other regioisomer in the cyclization. The
effect is real, but the best outcome only led to 14% yield of
the tetrahydropyran 4. Prins cyclizations with trisubstituted
alkenes are not useful for the synthesis of tetrahydropyrans
with quaternary centers at C3.
We developed a new approach to the lasonolide A
tetrahydropyran based on a tandem carbenium ion reaction.4
Scheme 2 illustrates the proposed 2-oxonia-Cope Prins
cyclization cascade. If one solvolyzed R-acetoxy ether 5, the
resulting oxocarbenium ion would undergo a facile 2-oxonia
Cope rearrangement to produce oxocarbenium ion 7.12 Both
6 and 7 could react in a standard Prins cyclization. However,
the much more nucleophilic enol ether should react more
rapidly, particularly if a favorable geometry could be
achieved. The rearrangement to 7 sets up a very favorable
cyclization of chair conformer 8 that leads to oxocarbenium
ion 9. Hydrolysis of 9 would produce 10, the ketone
corresponding to the C18-C25 segment of lasonolide A.
This proposal, though speculative, was attractive in that all
of the stereogenic centers of 10 would arise from a single
stereogenic center.
Substrate 5 was prepared as illustrated in Scheme 3.
Optically active 11 was prepared by Keck allylation of the
corresponding aldehyde.13 Esterification with phenylsulfanyl-
acetic acid led to 13. Aldol reaction with racemic 14,
followed by MOM cyclization on Lewis acid treatment, gave
1,3-dioxane 15. Oxidation of thiophenyl ether 15 to the
sulfoxide and elimination generated the alkene 16. Decon-
(6) Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J.
Am. Chem. Soc. 1994, 116, 6015-6016.
(7) (a) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Joo,
J. M. J. Am. Chem. Soc. 2002, 124, 384-385. (b) Lee, E.; Song, H. Y.;
Joo, J. M.; Kang, J. W.; Kim, D. S.; Jung, C. K.; Hong, C. Y.; Jeong, S.;
Jeon, K. Bioorg. Med. Chem. Lett. 2002, 12, 3519-3520. (c) Song, H. Y.;
Joo, J. M.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Kwak, H. S.; Park, J. H.;
Lee, E.; Hong, C. Y.; Jeong, S.; Jeon, K.; Park, J. H. J. Org. Chem. 2003,
68, 8080-8087.
Scheme 3. Synthesis of the Optically Active Cyclization
Substrate 5
(8) (a) Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi, H.-w.; Jun, H.-S.;
Lee, B. M.; Park, C. M.; Jeong, J. W. Angew. Chem., Int. Ed. 2003, 42,
4779-4782. (b) Kang, S. H.; Choi, H.-W.; Kim, C. M.; Jun, H.-S.; Kang,
S. Y.; Jeong, J. W.; Youn, J.-H. Tetrahedron Lett. 2003, 44, 6817-6819.
(c) Kang, S. H.; Kang, S. Y.; Choi, H.-w.; Kim, C. M.; Jun, H.-S.; Youn,
J.-H. Synthesis 2004, 1102-1114.
(9) (a) Gurjar, M. K.; Kumar, P.; Rao, B. V. Tetrahedron Lett. 1996,
37, 8617-8620. (b) Nowakowski, M.; Hoffmann, H. M. R. Tetrahedron
Lett. 1997, 38, 1001-1004. (c) Hart, D. J.; Patterson, S.; Unch, J. P. Synlett
2003, 1334-1338. (d) Yoshimura, T.; Bando, T.; Shindo, M.; Shishido, K.
Tetrahedron Lett. 2004, 45, 9241-9244.
(10) (a) Rychnovsky, S. D.; Hu, Y.; Ellsworth, B. Tetrahedron Lett. 1998,
39, 7271-7274. (b) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org.
Chem. 2001, 66, 4679-4686.
(11) (a) Hu, Yueqing, Ph.D. Thesis, University of California, Irvine, 1998.
(b) Frater, G.; Mueller, U.; Kraft, P. HelV. Chim. Acta 2004, 87, 2750-
2763. (c) For a related example, see Mohr, P. Tetrahedron Lett. 1993, 34,
6251-6254.
(12) (a) Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001,
3, 3815-3818. (b) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G.
D.; Willis, C. L. Org. Lett. 2002, 4, 577-580.
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Org. Lett., Vol. 7, No. 8, 2005

jugation produced ester 17 and reductive acetylation deliv-
ered the R-acetoxy ether substrate 5. The preparation of
compound 5 is straightforward, and the substrate was easily
prepared for further study.
The proposed rearrangement and cyclization of R-acetoxy
ether 5 is presented in Table 1. All of the Lewis acids
lasonolide A was completed by L-Selectride reduction of
the ketone to the axial alcohol 18 (Scheme 4). The config-
uration of alcohol 18 was confirmed by NOE analysis.
A final variation of the cyclization was investigated. In
situ reduction of oxocarbenium ion 9 would generate directly
a protected form of the C18-C25 diol. There are many other
oxocarbenium ions that might be reduced in the sequence,
but surprisingly enough, they did not interfere. Treatment
of R-acetoxy ether 5 with TMSOTf and tributyltin hydride
in the presence of DTBMP led to the dioxane 19 in a
remarkable 80% yield (Scheme 5). Even the 5:1 diastereo-
Table 1. Cascade Cyclization of R-Acetoxy Ether 5 with
Different Lewis Acids
Scheme 5. In Situ Hydride Reduction of an Oxocarbenium Ion
Intermediate with Bu3SnH
entrya Lewis acid (equiv)
T (°C)
-78
-78 to -30
-78
time (h) yield (%)
1
2
3
4
BF3‚OEt2 (1.0)
TiCl4 (2.4)
TiBr4 (2.0)
3
6
1
2
36
59
45
74
TMSOTf (3.0)
-78
a All reactions were conducted in the presence of 1.0-1.5 equiv of
DTBMP.
investigated led to significant quantities of the rearranged
and cyclized product 10. The 2,6-di-tert-butyl-4-methyl-
pyridine (DTBMP) was added to suppress proton-induced
side reaction. Side products include the Prins cyclization
products arising from cyclization of oxocarbenium ion 6 on
the terminal alkene (not shown). The best results were found
with TMSOTf (entry 4), which promotes oxocarbenium ion
formation but does not encourage Prins cyclization, presum-
ably due to the poorly nucleophilic counterion. TMSOTf
treatment led to the formation of 10 as a single diastereomer
in 74% yield. HPLC analysis demonstrated that the cycliza-
tion took place with no loss of optical activity, even though
the original stereogenic center is lost in the course of the
reaction.14 The synthesis of the C18-C25 segment of
selectivity in the reduction favors the lasonolide A config-
uration.15 Tributyltin hydride is a powerful reducing agent,16
and the high yield suggests that this tandem rearrangement
and cyclization reaction occurs very rapidly.
We have developed a rapid and efficient route to the C18-
C25 segment of lasonolide A based on a 2-oxonia-Cope Prins
cyclization cascade. This strategy introduces the quaternary
center with excellent diastereoselectivity and should be useful
in the synthesis of other highly functionalized tetrahydro-
pyran rings.
Acknowledgment. This work was supported by the
National Institutes of Health (CA081635).
Supporting Information Available: Preparation and
characterization of the described compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 4. Stereoselective Reduction and Stereochemical
Assignment
OL050270S
(13) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467-8468.
(14) See the Supporting Information for details of the HPLC analysis of
10.
(15) The relative stereochemistry of 19 was confirmed by COSY and
NOESY studies. A NOESY correlation was observed between the C4-H
and the C3-methyl group. There was no observed correlation between the
C4-H and the C2 and C6 hydrogens, which showed enhancements to each
other. The coupling constants for the C4-H (3.19 ppm; t, J ) 2.9 Hz)
combined with the NOESY data confirm that it is an equatorial proton.
(16) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-
957.
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