Role of 2-oxonia Cope rearrangements in Prins cyclization reactions

Article abstract of DOI:10.1021/ol0168465

Figure presented The 2-oxonia Cope rearrangement is undetectable in typical Prins cyclization reactions. We have investigated the Cope rearrangement in a Prins cyclation reaction using a competitive reduction of the oxocarbenium ion intermediate, and a ra

Full text of DOI:10.1021/ol0168465

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3815-3818
Role of 2-Oxonia Cope Rearrangements
in Prins Cyclization Reactions
Scott D. Rychnovsky,* Shinji Marumoto, and James J. Jaber
Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697-2025
srychnoV@uci.edu
Received October 2, 2001
ABSTRACT
The 2-oxonia Cope rearrangement is undetectable in typical Prins cyclization reactions. We have investigated the Cope rearrangement in a
Prins cyclization reaction using a competitive reduction of the oxocarbenium ion intermediate, and a racemization reaction mediated by the
rearrangement. In our unactivated substrate, the 2-oxonia Cope rearrangement was much faster than Prins cyclization. An enantioselective
allyl transfer reaction also was developed using a 2-oxonia Cope rearrangement.
The 2-oxonia Cope rearrangement has been invoked as a
competitive pathway in Prins cyclizations and related
transformations.1,2 Direct evidence for the 2-oxonia Cope
rearrangement as a side reaction in Prins cyclizations comes
from Speckamp’s work. He found products arising from the
2-oxonia Cope rearrangement in attempted Prins cyclizations
of vinyl silanes.3 The rearrangement also was implicated in
a synthesis of cis- and trans-2,6-disubstituted tetrahydropy-
rans.4 More recently Roush found exchange products arising
from 2-oxonia Cope rearrangements in Prins cyclization
reactions, once again with vinyl silane substrates.5 The
2-oxonia Cope rearrangement also has been invoked to
explain allyl transfer reactions developed by Nokami6 and
by Loh.7 In this communication we demonstrate that 2-oxonia
Cope rearrangements are faster than Prins cyclizations in
simple substrates and use this rearrangement in an enanti-
oselective allyl transfer reaction.
Our attention was drawn to the 2-oxonia Cope rearrange-
ment by an unexpected epimerization in a Prins cyclization,
Scheme 1. The R-acetoxy ether 1, a possible precursor to
ratjadone,8 was cyclized with SnBr4 to produce the expected
Scheme 1. Unexpected C3 Epimerization in a Prins
Cyclization
(1) (a) Brown, M. J.; Harrison, T.; Herrinton, P. M.; Hopkins, M. H.;
Hutchinson, K. D.; Mishra, P.; Overman, L. E. J. Am. Chem. Soc. 1991,
113, 5365-5378. (b) Gasparski, C. M.; Herrinton, P. M.; Overman, L. E.;
Wolfe, J. P. Tetrahedron Lett. 2000, 41, 9431-9435.
(2) Al-Mutairi, E. H.; Crosby, S. R.; Darzi, J.; Hughes, R. A.; Simpson,
T. J.; Smith, R. W.; Willis, C. L.; Harding, J. R.; King, C. D. Chem.
Commun. 2001, 835-836. This paper includes an example (e.g., 13 to 17)
where a 2-oxonia Cope rearrangement is implicated. We thank Professor
Willis for bringing it to our attention.
(3) (a) Lolkema, L. D. M.; Hiemstra, H.; Semeyn, C.; Speckamp, W. N.
Tetrahedron 1994, 50, 7115-7128. (b) Lolkema, L. D. M.; Semeyn, C.;
Ashek, L.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1994, 50, 7129-
7140.
(4) (a) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J.
Org. Chem. 1997, 62, 3426-3427. (b) Huang, H. B.; Panek, J. S. J. Am.
Chem. Soc. 2000, 122, 9836-9837.
(5) Roush, W. R.; Dilley, G. J. Synlett 2001, 955-959.
10.1021/ol0168465 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001

product 2 in 58% yield. It was accompanied by 26% of
product 3, epimeric at C3. The configuration at C3 had been
established in 1, and epimerization was completely unex-
pected.
The most plausible mechanism for the epimerization
invokes a 2-oxonia Cope rearrangement, Figure 1. Oxocar-
ions 8 and 7. We conclude that the 2-oxonia Cope rear-
rangement plays an important role in this unusual Prins
cyclization.
Does the 2-oxonia Cope rearrangement compete with the
Prins cyclization with a typical substrate? This question is
difficult to answer because the 2-oxonia Cope rearrangement
is usually undetectable by product analysis. Figure 2 shows
Figure 1. The chair and boat 2-oxonia Cope rearrangements that
lead to tetrahydropyran 2 and its C3 epimer 3.
Figure 2. Racemization test for a 2-oxonia Cope rearrangement
in a Prins cyclization reaction.
benium ion 6 could rearrange to 7 via a chair transition state.
Both 6 and 7 would cyclize to the expected product 2.9
Product 3 could arise by a 2-oxonia Cope rearrangement in
a boat transition state to produce the oxocarbenium ion 8.
Cyclization of 8 from a chair transition state would produce
3, the C3 epimer. A 2-oxonia Cope rearrangement from a
chair transition state (e.g., 6 to 7) leads to the expected
product 2. Epimerization at C3 requires a boat transition state
in the Cope rearrangement. Nokami’s crotyl transfer reactions
proceed with good stereochemical fidelity and suggest that
such a boat transition state is unexpected.6 Further evidence
of the intermediacy of 8 in the formation of 3 comes from
the treatment of 1 with TMSOTf (Scheme 1.) The E-alkene
5 was produced as a minor product, along with Z-alkene 4.
Both presumably arise from hydrolysis of the oxocarbenium
a typical Prins cyclization substrate 9. Oxocarbenium ion
10 can rearrange via a chair transition state to 11, or cyclize
to 12. Compound 11, however, also cyclizes to 12. The
2-oxonia Cope rearrangement with a chair transition state
does not affect the outcome of a Prins cyclization and in
most cases can be ignored.9
Figure 2 outlines a test for the 2-oxonia Cope rearrange-
ment in a Prins cyclization substrate. If we add a nucleophile
to the Prins cyclization reaction, it could add to the
oxocarbenium ions 10 and 11 in competition with the Prins
cyclization. If the two alkyl groups are not equivalent, two
different compounds, 13 and 14, would be produced.
Producing both 13 and 14 would be good evidence for a
2-oxonia Cope rearrangement, but it would be difficult to
analyze the relative rate of the reactions, as 13 and 14 could
be formed as a kinetic or a thermodynamic mixture. A more
sensitive test uses optically pure 9. In this case, 13 and 14
are enantiomers, and the 2-oxonia Cope rearrangement
mediates racemization of the substrate. Racemization is a
one-way process, and so a thermodynamic (racemic) mixture
of 13 and 14 can be easily distinguished from a kinetic
(optically active) mixture. Racemization of the side products
would be good evidence for the 2-oxonia Cope rearrangement
competing with the Prins cyclization.
(6) (a) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S.-i. J. Am.
Chem. Soc. 1998, 120, 6609-6610. (b) Nokami, J.; Anthony, L.; Sumida,
S.-I. Chem. Eur. J. 2000, 6, 2909-2913. (c) Nokami, J.; Ohga, M.;
Nakamoto, H.; Matsubara, T.; Hussain, I.; Kataoka, K. J. Am. Chem. Soc.
2001, 123, 9168-9169.
(7) (a) Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T. J. Am. Chem. Soc. 2001, 123,
2450-2451. (b) Loh, T.-P.; Tan, K.-T.; Hu, Q.-Y. Angew. Chem., Int. Ed.
2001, 40, 2921-2922.
(8) (a) Gerth, K.; Schummer, D.; Hoefle, G.; Irschik, H.; Reichenbach,
H. J. Antibiot. 1995, 48, 973-6. (b) Christmann, M.; Bhatt, U.; Quitschalle,
M.; Claus, E.; Kalesse, M. Angew. Chem., Int. Ed. 2000, 39, 4364-4366.
(c) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse, M. J.
Org. Chem. 2001, 66, 1885-1893. (d) Williams, D. R.; Ihle, D. C.;
Plummer, S. V. Org. Lett. 2001, 3, 1383-1386.
(9) (a) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem. 2001,
66, 4679-4686. (b) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2,
1217-1219.
The 2-oxonia Cope rearrangement was evaluated as
outlined in Scheme 2. Optically active 1610 was prepared as
3816
Org. Lett., Vol. 3, No. 23, 2001

Scheme 2. Evidence for a 2-Oxonia Cope Rearrangement in a
Typical Prins Cyclization from Racemization of a Side Product
Table 1. Reduction the R-Acetoxy Ether 16 and Competitive
Racemization in the Presence of Bu3SnH
entry
[Bu3SnH]
ee, %a
yield, %
1
2
3
4
0.4
0.2
0.1
0.04
47
38
31
17
88
91
92b
83c
a The ees were determined by HPLC analysis on a chiracel OD-H column.
b Contains 1% of a cyclic alkene. c Contains 3% of a cyclic alkene.
trapping agent results in further racemization. At 0.04 M Bu3-
SnH, 18 was isolated with just 17% ee. Qualitatively, these
results show that 2-oxonia Cope rearrangements are much
faster than typical Prins cyclizations.
Several examples of the 2-oxonia Cope rearrangement
were identified in allyl migration reactions.6 We became
interested in enantioselective allyl transfer reactions. The
initial investigation of an enantioselective allyl transfer
mediated by the 2-oxonia Cope rearrangement is outlined
in Table 2. In this case, the two oxocarbenium ions
interconverted by the 2-oxonia Cope rearrangements are not
enantiomers but are constitutional isomers. The oxocarbe-
nium ion leading to 22 is more stable than that leading to
23 because of conjugation with the phenyl ring. This
increased stability should favor formation of 22 and lead to
an enantioselective allyl transfer reaction. Optically active
a mixture of diastereomers and subjected to low-temperature
Prins cyclization conditions. Triethylsilane was added as a
nucleophile to compete with the cyclization. The expected
cyclic products 19 and 20 were identified by GC and
comparison with authentic standards.11 Hydride addition
products 17 and 18 were isolated as an inseparable mixture,
and the optical purity of 18 was evaluated by HPLC on a
Chiracel OD-H column. Trapping product 18 was nearly
racemic, thus demonstrating that the 2-oxonia Cope rear-
rangement was fast under these conditions. Roughly com-
parable amounts of cyclic products and direct trapping
product 18 were isolated, suggesting that the rates of
formation of these products are roughly comparable and are
much slower than the 2-oxonia Cope rearrangement.
Table 2. Enantioselective 2-Oxonia Cope Rearrangement and
Regioselective Reduction
The rate of 2-oxonia Cope rearrangement is much faster
than reduction by triethylsilane. The rate of the rearrangement
can be evaluated qualitatively using a stronger reducing
agent. Bu3SnH is a much more nucleophilic in the reduction
of stabilized carbenium ions than triethylsilane.12 The results
of the reduction of optically active 16 with Bu3SnH at low
temperature are shown in Table 1. Under these conditions,
little or no Prins cyclization takes place. Even at high
concentrations of Bu3SnH, the reduction product 18 was
isolated in only 47% ee. Lowering the concentration of the
entry [Bu3SnH] temp, °C
22:23
yield, % ee, %a (22)
1
2
3
4
0.044
0.015
0.007
0.015
-78
-78
-78
0
56:44
80:20
85:15
93:7
94
85
84
70
95c
93b
-
(10) (a) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-
Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001-7002. (b) Keck, G. E.;
Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467-8468. (c)
Keck, G. E.; Krishnamurthy, D. Org. Synth. 1996, 75, 12-17. (d) Kopecky,
D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191-198.
(11) Tetrahydropyrans 19 and 20 were prepared from racemic 15. See
Supporting Information for details.
-
a The ees were determined with the alcohol after debenzylation (Na/
NH3). b The ee was determined by HPLC on a Chiracel OD-H column.
c The ee was determined by GC on a â-cyclodextrin permethylated
hydroxypropyl column (but without baseline separation.)
(12) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-
957.
Org. Lett., Vol. 3, No. 23, 2001
3817

21 was prepared using standard methods10 and subjected to
reductive rearrangement conditions with Bu3SnH. High
concentrations of Bu3SnH lead to 1:1 mixtures of 22 and
23, but lower concentrations of the reducing agent produced
22 and 23 as >4:1 mixtures in good yield. The optical purity
of 22 was identical to that of 21. Under these conditions,
the 2-oxonia Cope rearrangement proceeded with complete
stereochemical fidelity. This allyl transfer reaction is an
interesting alternative to enantioselective allylation reactions13
and produces benzyl protected products directly.
Competitive reductions of the intermediate oxocarbenium
ions demonstrate that the 2-oxonia Cope rearrangement is
typically much faster than Prins cyclization. Although usually
invisible, 2-oxonia Cope rearrangements can produce sur-
prising stereochemical outcomes in Prins cyclizations.
Acknowledgment. The National Institutes of Health (CA-
81635) and Sankyo Co., Ltd. provided financial support.
Supporting Information Available: Preparation and
characterization of the compounds described in the paper
are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) Roush, W. R. in ComprehensiVe Organic Synthesis, Trost, B. M.,
Fleming, I. and Heathcock, C. H., Ed.; Pergamon Press: New York, 1991;
Vol. 2, pp 1-53.
OL0168465
3818
Org. Lett., Vol. 3, No. 23, 2001