Solvolysis of a tetrahydropyranyl mesylate: Mechanistic implications for the Prins cyclization, 2-oxonia-Cope rearrangement, and Grob fragmentation

Article abstract of DOI:10.1021/ol0606738

A solvolysis reaction is used to demonstrate that a tetrahydropyranyl cation is a common intermediate for Prins cyclizations, 2-oxonia-Cope rearrangements, and Grob fragmentations of tetrahydropyran rings.

Full text of DOI:10.1021/ol0606738

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2175-2178
Solvolysis of a Tetrahydropyranyl
Mesylate: Mechanistic Implications for
the Prins Cyclization, 2-Oxonia-Cope
Rearrangement, and Grob Fragmentation
Ramesh Jasti and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
Received March 17, 2006
ABSTRACT
A solvolysis reaction is used to demonstrate that a tetrahydropyranyl cation is a common intermediate for Prins cyclizations, 2-oxonia-Cope
rearrangements, and Grob fragmentations of tetrahydropyran rings.
The Prins cyclization and the 2-oxonia-Cope rearrangement
are highly stereoselective carbon-carbon bond forming
reactions that have received considerable attention from
organic chemists.1-3 Both transformations are initiated by
an oxocarbenium ion and a tethered alkene and thus are
mechanistically related. Not surprisingly, the two processes
are often competing pathways.4 Recently, we reported our
investigations into the relative rates of 2-oxonia-Cope
rearrangements and Prins cyclization reactions.5 The mecha-
nistic model set forth in that document was inspired by
calculations from Alder suggesting a common cationic
intermediate for both transformations.6
Figure 1 outlines the proposed mechanistic pathways.5 In
this model, tetrahydropyranyl cation 3 serves as a branch
point in a 2-oxonia-Cope rearrangement (2 to 4) and Prins
cyclization reaction (2 to 5).7 Alder suggested that tetrahy-
dropyranyl cation 3 has increased stability due to extensive
delocalization. The optimal geometry for this delocalization
(1) For reviews on the Prins cyclization see: (a) Arundale, E.; Mikeska,
L. A. Chem. ReV. 1952, 52, 505-555. (b) Adams, D. R.; Bhatnagar, S. P.
Synthesis 1977, 661-672. (c) Snider, B. B. In The Prins Reaction and
Carbonyl Ene Reactions; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon Press: New York, 1991; Vol. 2, pp 527-561. (d) Overman, L.
E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143-7157.
(2) For recent work on the Prins cyclization see: (a) Bolla, M. L.;
Patterson, B.; Rychnovsky, S. D. J. Am. Chem Soc. 2005, 127, 16044-
16045. (b) Dalgard, J. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126,
15662-15663. (c) Yadav, K. V.; Kumar, N. V. J. Am. Chem. Soc. 2004,
126, 8652-8653. (d) Hart, D. J.; Bennet, C. E. Org. Lett. 2003, 5, 1499-
1502. (e) Barry, C. S. J.; Crosby, S. R.; Harding, J. R.; Huges, R. A.; King,
C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429-2432. (f)
Miranda, P. O.; Diaz, D. D.; Padron, J. I.; Bermejo, J.; Martin, V. S. Org.
Lett. 2003, 1979-1982.
(3) (a) For recent work on the 2-oxonia-Cope see: Nokami, J.; Yoshizane,
K.; Matsuura, H.; Sumida, S. I. J. Am. Chem. Soc. 1998, 120, 6609. (b)
Sumida, S. I.; Ohga, M.; Mitani, J.; Nokami, J. J. Am. Chem. Soc. 2000,
122, 1310. (c) Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T. J. Am. Chem. Soc. 2001,
123, 2450. (d) Loh, T.-P.; Ken Lee, C.-L.; Tan, K.-T. Org. Lett. 2002, 4,
2985-2987. (e) Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T. Org. Lett. 2002, 4, 2389-
2391. (f) Lee, C.-L. K.; Lee, C.-H. A.; Tan, K.-T.; Loh, T.-P. Org. Lett.
2004, 6, 1281-1283.
(4) (a) Lolkema, L. D. M.; Semeyn, C.; Ashek, L.; Hiemstra. H.;
Speckamp, W. N. Tetrahedron 1994, 50, 7129-7140. (b) Roush, W. R.;
Dilley, G. J. Synlett 2001, 955-959. (c) Rychnovsky, S. D.; Marumoto,
S.; Jaber, J. J. Org. Lett. 2001, 3, 3815-3818. (d) Crosby, S. R.; Harding,
J. R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4, 577-
580. (e) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett. 2002, 4, 3407-3410. (f) Hart, D. J.; Bennet, C. E. Org.
Lett. 2003, 5, 1499-1502.
(5) Jasti, R.; Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc.
2005, 127, 9939-9945.
(6) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002,
124, 4960-4961.
(7) For trapping experiments of proposed charged intermediates in Prins
cyclizations and 2-oxonia-Cope rearrangements see: (a) Barry, C. S.;
Bushby, N.; Harding, J. R.; Hughes, R. A.; Parker, G. D.; Roe, R.; Willis,
C. L. Chem. Commun. 2005, 29, 3727-3729. (b) Rychnovsky, S. D.;
Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3, 3815-3818.
10.1021/ol0606738 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/19/2006

Figure 1. Stepwise Prins cyclization reaction and 2-oxonia-Cope
rearrangement.
places the hydrogen in the pseudoaxial position, which directs
nucleophilic attack along an equatorial trajectory. The
extensive delocalization therefore provides rationale for the
2,4,6-cis stereoselectivity commonly observed for Prins
cyclization reactions.8,9
The energy diagram in Figure 2 further details the
calculations reported by Alder.6 Tetrahydropyranyl cation 6
was calculated to have a ground state energy 13.4 kJ/mol
higher than that of oxocarbenium ion 7. In addition, the
Figure 3. Racemization as an indicator for Grob fragmentation.
undergo a fast ring-opening process to generate achiral
oxocarbenium 11. Prins cyclization of achiral oxocarbenium
ion 11 would then necessarily lead to racemic 10. Therefore,
racemization of tetrahydropyran 10 can be used as an
indicator for a Grob fragmentation pathway.
With the racemization test in mind, we turned our attention
to the synthesis of optically active tetrahydropyranyl mesylate
17 (Scheme 1). Ester 14 was prepared in 42% yield from
Scheme 1. Synthesis of Mesylate 17
Figure 2. Energetics of a tetrahydropyranyl cation.
barrier for ring-opening was calculated to be only 1.9 kJ/
mol. On the basis of these calculations, we surmised that
generation of a tetrahydropyranyl cation should rapidly lead
to an oxocarbenium ion. Such a ring-opening process would
represent the first known Grob fragmentation of a tetrahy-
dropyran ring, the reverse of a Prins cyclization. In this way,
the delocalized tetrahydropyranyl cation may serve not only
as an intermediate for Prins cyclizations and 2-oxonia-Cope
rearrangements, but also for Grob fragmentations of tetrahy-
dropyran rings. In this Letter, we report a solvolysis reaction
linking all three processes to the delocalized tetrahydro-
pyranyl cation intermediate proposed by Alder.
Figure 3 outlines a test to identify a Grob fragmentation
pathway for a tetrahydropyran ring. A solvolysis reaction
of appropriately substituted tetrahydropyran 8 should gener-
ate tetrahydropyranyl cation 9. Cation 9 could then undergo
nucleophilic attack to produce optically active tetrahydro-
pyran 10. In contrast, tetrahydropyranyl cation 9 may
optically active alcohol 1210 and carboxylic acid 13.11
Reductive acetylation conditions developed in our laboratory
smoothly converted ester 14 to acetoxy ether 15 as a 1:1
mixture of diastereomers.12 Prins cyclization of 15 followed
by methanolysis delivered tetrahydropyran 16 in 67% yield
over 2 steps.13 Reduction and mesylation completed the
synthesis of tetrahydropyran 17.
Trifluoroacetolysis14 of optically active tetrahydropyran 17
followed by methanolysis provided racemic tetrahydropyran
18 as a single diastereomer in 82% yield (Scheme 2).15
(10) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467.
(8) Under standard Prins cyclization conditions, nucleophilic trapping
(3 to 5) is not reversible.
(11) Davies, H. M. L.; Boebel, T. A. Tetrahedron Lett. 2000, 41, 8189-
8192.
(9) For axial-selective Prins cyclizations, see: (a) Jasti, R.; Vitale, J.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126, 9904-9905. (b) Lolkema,
L. D. M.; Hiemstra, H.; Semeyn, C.; Speckamp, W. N. Tetrahedron 1994,
50, 7115-7128. (c) Miles, R. B.; Davis, C. E.; Coates, R. M. J. Org. Chem.
2006, 71, 1493-1501.
(12) (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.
(13) Barry, C. S. J.; Crosby, S. R.; Harding, J. R.; Huges, R. A.; King,
C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429-2432.
2176
Org. Lett., Vol. 8, No. 10, 2006

cyclization, 2-oxonia-Cope rearrangement, and Grob frag-
mentation all proceed through one common intermediate
(Figure 5). Trifluoroacetolysis of mesylate 17 leads to
Scheme 2. Trifluoroacetolysis of Mesylate 17
Racemization of tetrahydropyran 18 indicates that ring-
opening is faster than nucleophilic attack by trifluoroacetate.
This result provides the first evidence of a Grob fragmenta-
tion pathway for tetrahydropyran rings. One question re-
maining was whether this was a concerted or a stepwise
process. Figure 3 illustrates a Grob fragmentation of 8
occurring by way of discrete carbocation intermediate 9 (i.e.,
asynchronous Grob fragmentatation). Is it possible that
solvolysis of 8 in fact leads directly to achiral oxocarbenium
ion 11 via a synchronous Grob fragmentation?
Figure 5. Tetrahydropyranyl cation 21 as a common intermediate
for a Prins cyclization, a 2-oxonia-Cope rearrangement, and a Grob
fragmentation.
In his classic studies, Grob distinguished between asyn-
chronous and synchronous fragmentation reactions by com-
paring rates of solvolysis with carbon analogues (Figure 4).16
tetrahydropyranyl cation 21. Tetrahydropyranyl cation 21 can
then ring-open, presumably, with equal probability to either
oxocarbenium ion 23 or achiral oxocarbenium ion 24.
Tetrahydropyranyl cation 21 therefore is an intermediate for
a Grob fragmentation of tetrahydropyran 17. In addition,
oxocarbenium ions 23 and 24 can interconvert by undergoing
a ring-closure process followed by a ring-opening. In this
way, tetrahydropyranyl cation 21 also serves as an intermedi-
ate for a 2-oxonia-Cope rearrangement. Furthermore, the
asynchronous nature of the Grob fragmentation implies that
the reverse reaction, a Prins cyclization, is also asynchronous.
Thus, oxocarbenium ions 23 and 24 lead to 22 by way of
the same tetrahydropyranyl cation intermediate 21. Interest-
ingly, although the Prins cyclization proceeds through a
cationic intermediate, only one isomer is observed at C4.
This result is consistent with Alder’s description of extensive
delocalization for tetrahydropyranyl cations such as 21.5,6
Ring-opening of tetrahydropyranyl cation 21 to achiral
oxocarbenium 24 was assumed to be the only pathway for
racemization. To test the validity of this assumption, saturated
tetrahydropyran 25 was prepared. In this case, an achiral
intermediate is not available by a simple Grob fragmentation.
Surprisingly, trifluoroacetolysis of saturated tetrahydropyran
25 followed by methanolysis led to alcohol 26 in only 49%
ee (Scheme 3). The loss in optical activity for 26 indicates
the presence of a second racemization pathway that is
independent of achiral intermediate 24. The erosion in
Figure 4. Trifluoroacetolysis of carbon analogue 19 and tetrahy-
dropyran 20.
Cyclohexyltosylate 19 has been shown to have a half-life of
35 min in trifluoroacetic acid at room temperature.17 In
contrast, subjecting tetrahydropyran 20 to similar conditions
resulted in no reaction. In a synchronous fragmentation
reaction, the heteroatom substituted compound should un-
dergo solvolysis more rapidly or at a similar rate to the
carbon analogue due to favorable nO to σ*
interactions.
C-C
In an asynchronous fragmentation, the heteroatom inductively
destabilizes the C4 cationic intermediate, thus slowing the
rate of solvolysis relative to the carbon analogue. Our results
are consistent with an asynchronous fragmentation, in which
the inductive effect of the heteroatom decreases the reactivity
of tetrahydropyran 20 toward acid-catalyzed solvolysis.
With the results from the solvolysis reactions in hand, a
mechanistic scheme can be constructed in which the Prins
(14) Trifluoroacetic acid has been shown to have an exceptional
combination of high solvolytic power and low nucleophilicity. See the
following and references therein: Nordlander, J. E.; Gruetzmacher, R. R.;
Kelly, W. J.; Jindal, S. P. J. Am. Chem. Soc. 1974, 96, 181-185.
(15) Nucleophilic attack by trifloroacetate is not reversible. Subjecting
optically active tetrahydropyranyl trifluoroacetate to solvolysis conditions
results in no reaction.
Scheme 3. Trifluoracetolysis of Mesylate 25
(16) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535-546.
(17) Lambert, J. B.; Putz, G. J. J. Am. Chem. Soc. 1973, 95, 6313-
6319.
Org. Lett., Vol. 8, No. 10, 2006
2177

enantiomeric excess for this reaction may involve isomer-
ization of an (E)-oxocarbenium ion to a (Z)-oxocarbenium
ion followed by a 2-oxonia-Cope rearrangement.18 Efforts
to unravel this unusual racemization pathway are currently
underway in our laboratory and will be reported in due
course.
In conclusion, we have demonstrated a novel solvolysis
reaction of a tetrahydropyranyl mesylate. The outcome of
this solvolysis reaction correlates well with a mechanistic
model in which a delocalized tetrahydropyranyl cation serves
as an intermediate for Prins cyclizations, 2-oxonia-Cope
rearrangements, and Grob fragmentations of tetrahydropyran
rings. This knowledge should be useful for further develop-
ment and application of these transformations.
Acknowledgment. This work was supported by the
National Cancer Institute (CA-081635).
Supporting Information Available: Experimental pro-
cedures and NMR spectra of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) For similar racemization pathways in iminium ion cyclizations see:
(a) Daub, G. W.; Heerding, D. A.; Overman, L. E. Tetrahedron 1988, 44,
3919-3930. (b) Castro, P.; Overman, L. E. Tetrahedron Lett. 1993, 34,
5243-5246.
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