Utilization of an oxonia-Cope rearrangement as a mechanistic probe for Prins cyclizations

Article abstract of DOI:10.1021/ja0518326

An oxonia-Cope rearrangement was used as an internal clock reaction to probe the mechanism of the Prins cyclization reaction and the subsequent nucleophilic capture of the resultant tetrahydropyranyl cation. The oxonia-Cope rearrangement was shown to occu

Full text of DOI:10.1021/ja0518326

Published on Web 06/18/2005
Utilization of an Oxonia-Cope Rearrangement as a
Mechanistic Probe for Prins Cyclizations
Ramesh Jasti, Christopher D. Anderson, and Scott D. Rychnovsky*
Contribution from the Department of Chemistry, UniVersity of California, IrVine, California
92697-2025
Received March 22, 2005; E-mail: srychnov@uci.edu
Abstract: An oxonia-Cope rearrangement was used as an internal clock reaction to probe the mechanism
of the Prins cyclization reaction and the subsequent nucleophilic capture of the resultant tetrahydropyranyl
cation. The oxonia-Cope rearrangement was shown to occur rapidly under typical Prins cyclization conditions
when the oxocarbenium ion resulting from the rearrangement is similar to or lower in energy than the
starting oxocarbenium ion. Oxonia-Cope rearrangements can be disfavored by destabilizing the resultant
oxocarbenium ion or by stabilizing an intermediate tetrahydropyranyl cation. Stereoselectivity in the
nucleophilic capture was dramatically affected by the reactivity of the nucleophile and electrophile. More
reactive partners combined rapidly to give axial-substituted Prins products through a least-motion pathway.
High selectivity for the equatorial-substituted tetrahydropyran was observed for less reactive nucleophiles
and electrophiles.
Introduction
The Prins cyclization is a powerful transformation to generate
highly substituted tetrahydropyrans with excellent stereoselec-
tivity.1,2 Many variations of this transformation have been
investigated and continue to be explored. Although this cy-
clization has garnered significant attention from the chemical
community, the following two mechanistic aspects of this
transformation are not well understood: (1) the relative rates
of Prins cyclization versus a competing oxonia-Cope rearrange-
ment, and (2) the stereoselectivity of nucleophilic capture of
the resulting cation following cyclization (Figure 1).
Figure 1. Prins cyclization and oxonia-Cope rearrangement.
Cope rearrangements proceed rapidly at temperatures as low
as -78 °C. In fact, we have recently demonstrated a tandem
reaction in which an initial oxonia-Cope rearrangement is
followed by Prins cyclization to generate tetrahydropyranones
with quaternary centers (Figure 2).6 Inherent in the further
development and utilization of tandem reactions of this nature
is the need to have a general understanding of the rates of
oxonia-Cope rearrangements versus Prins cyclizations.
Prins cyclizations are typically highly selective for the all-
cis tetrahydropyran. A rationale for the all-cis stereoselectivity
has been set forth by computational work from Alder (Figure
3A).7 Alder suggests that initial Prins cyclization of an (E)-
oxocarbenium ion8 through a chair-like transition state leads to
tetrahydropyranyl cation 7. Tetrahydropyranyl cation 7 has
Several authors have reported the oxonia-Cope rearrangement
as a competitive process in Prins cyclizations and related
transformations.3,4 Although similar reactions such as Claisen
and Cope rearrangements typically require heating,5 oxonia-
(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) Yadav, K. V.; Kumar,
N. V. J. Am. Chem. Soc. 2004, 126, 8652-8653. (b) Cossey, K. N.; Funk,
R. L. J. Am. Chem. Soc. 2004, 126, 12216-12217. (c) Hart, D. J.; Bennet,
C. E. Org. Lett. 2003, 5, 1499-1502. (d) 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. (e) Miranda, P. O.; Diaz, D. D.; Padron,
J. I.; Bermejo, J.; Martin, V. S. Org. Lett. 2003, 5, 1979-1982. (f) Lopez,
F.; Castedo, L.; Mascarenas, J. L. J. Am. Chem. Soc. 2002, 124, 4218-
4219. (g) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett. 2002, 4, 3407-3410. (h) Crosby, S. R.; Harding, J. R.;
King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4, 577-580. (i)
Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.;
Chang, M. H. Org. Lett. 2002, 4, 2025-2028.
(3) (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.
(4) (a) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S. I. J. Am. Chem.
Soc. 1998, 120, 6609-6610. (b) Sumida, S. I.; Ohga, M.; Mitani, J.;
Nokami, J. J. Am. Chem. Soc. 2000, 122, 1310-1313. (c) Loh, T.-P.; Hu,
Q.-Y.; Ma, L.-T. J. Am. Chem. Soc. 2001, 123, 2450-2451. (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.
(5) For reviews on the Claisen and Cope rearrangements, see: (a) Martin Castro,
A. M. Chem. ReV. 2004, 104, 2939-3002. (b) Rhoads, S. J.; Raulins, N.
R. Org. React. 1975, 22, 1-252.
(6) Dalgard, J. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126, 15662-
15663.
9
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J. AM. CHEM. SOC. 2005, 127, 9939-9945
9939

A R T I C L E S
Jasti et al.
Experimental Design
In general, oxonia-Cope rearrangements occur rapidly and cannot
be detected by product analysis. Figure 4 outlines a test that we
previously used to demonstrate fast oxonia-Cope rearrangements in a
Prins cyclization substrate.12 Upon treatment with Lewis acid, acetoxy
ether 11 generates oxocarbenium ion 12. This oxocarbenium ion can
undergo rearrangement to oxocarbenium ion 13 via an oxonia-Cope
pathway. Either oxocarbenium ion 12 or 13 will lead to the same Prins
cyclization product 14. However, direct hydride addition to oxocarbe-
nium ion 12 produces (R)-15, whereas direct hydride addition to
oxocarbenium ion 13 produces (S)-15. When acetoxy ether 16 was
treated with BF3‚OEt2 in the presence of triethylsilane, ether 17 was
isolated in 3.5% enantiomeric excess. The significant loss in optical
activity demonstrates that oxonia-Cope rearrangement is a fast process
under these reaction conditions. Although this experiment suggests that
the oxonia-Cope rearrangement occurs at a faster rate than Prins
cyclization, it does not provide direct evidence to support this
conclusion. In this experiment, the oxonia-Cope rearrangement is shown
to be faster than [1,2]-hydride addition to an oxocarbenium ion. A more
exact experiment was needed to determine the relative rates of oxonia-
Cope rearrangement versus Prins cyclization.
Figure 2. Oxonia-Cope Prins cyclization.
Figure 5 outlines a test that would allow for the direct comparison
of the rate of oxonia-Cope rearrangement versus the rate of Prins
cyclization. In this case, treating acetoxy ether 18 with a Lewis acid
would generate oxocarbenium ion 19. In light of Alder’s model, 19
should cyclize to provide tetrahydropyranyl cation intermediate 20.
Alder suggests this cation is an intermediate for both Prins cyclizations
and oxonia-Cope rearrangements.7 This argument is supported by the
often simultaneous occurrence of the two processes and the evidence
of charged intermediates in similar rearrangements.13 Therefore, we
shall illustrate tetrahydropyranyl cation 20 as a branch point in the
mechanism of an oxonia-Cope rearrangement and Prins cyclization.
However, we cannot rule out a concerted pathway for oxonia-Cope
rearrangment. Direct nucleophilic trapping of tetrahydropyranyl cation
20 would lead to optically active tetrahydropyran 21. Tetrahydropyranyl
cation 20 could also undergo a ring-opening process that leads to either
initial oxocarbenium ion 19 or achiral oxocarbenium ion 22. The achiral
oxocarbenium ion 22 necessarily leads to racemic tetrahydropyran 21.
Thus, the oxonia-Cope rearrangement mediates racemization. Unlike
the test presented in Figure 4, this test would allow for the cyclization
of several acetoxy ethers under a variety of conditions that lead to Prins
cyclization. Measuring the enantiomeric excess of the product tetrahy-
dropyrans would then allow us to directly compare the rates of the
oxonia-Cope rearrangement (19 to 22) versus the Prins cyclization
reaction (19 to 21). The enantiomeric excess would reflect the difference
in rates of ring-opening (20 to 22) versus the rate of nucleophilic capture
(20 to 21). In addition, we hoped that analysis of enantiomeric excess
of axial-selective Prins cyclizations would shed light on our hypoth-
esized least-motion pathway mechanism.9
Figure 3. Diastereoselectivity of Prins cyclizations.
increased stabilility due to delocalization. Bonds a and b and
the lone pair on oxygen are in alignment with the empty p
orbital, creating a six-electron system in the equatorial plane
of the ring. The optimal geometry for delocalization places the
hydrogen at C4 in a pseudoaxial geometry, thereby favoring
nucleophilic trapping from an equatorial trajectory. Recently,
we have reported Prins cyclizations that are not consistent with
this rationale. Acetoxy ethers, upon treatment with bromotri-
methylsilane (TMSBr), cyclize to produce 2,6-cis-4-trans tet-
rahydropyrans (Figure 3B).9 We have proposed a least-motion
pathway10 from an intimate ion pair11 to explain the unusual
axial-selective Prins cyclization, but further experiments are
warranted to fully validate this hypothesis.
In this article, we describe experiments designed to investigate
the relative rates of oxonia-Cope rearrangement versus Prins
cyclization and the stereoselectivity of nucleophilic attack at
C4. We provide evidence that the oxonia-Cope rearrangement
is a rapid process relative to Prins cyclization under most
reaction conditions. We also demonstrate that certain structural
elements and reaction conditions alter the relative rates of Prins
cyclization versus oxonia-Cope rearrangement. In addition, we
show that these same structural elements and reaction conditions
also can have a dramatic effect upon the stereoselectivity of
nucleophilic capture.
Synthesis of Substrates
Acetoxy ethers were prepared by standard means developed in our
laboratory.14 Scheme 1 outlines the synthesis of acetoxy ether 25.
Asymmetric allylation of hydrocinnamaldehyde provided optically
active alcohol 23 in 97% ee.15 Alcohol 23 was then coupled to vinyl
acetic acid in 93% yield. Reductive acetylation of ester 24 then provided
acetoxy ether 25 in 97% yield.14 Other acetoxy ethers used in this study
were synthesized in similar fashion, and further details are provided in
the Supporting Information.
(7) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002, 124,
4960-4961.
(8) Cremer, D.; Gauss, J.; Childs, R. F.; Blackburn, C. J. Am. Chem. Soc.
1985, 107, 2435-2441.
(12) Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3, 3815-
(9) Jasti, R.; Vitale, J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126, 9904-
3818.
9905.
(13) Overman, L. E. Acc. Chem. Res. 1992, 25, 352-359.
(14) (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.
(10) March, J. AdVanced Organic Chemistry, 4th ed.; John Wiley & Sons: New
York, 1992; p 782. “Those reactions are favored which involve the least
change in atomic position and electronic configuration.”
(11) For a similar effect, see: Zhang, Y. D.; Reynolds, N. T.; Manju, K.; Rovis,
T. J. Am. Chem. Soc. 2002, 124, 9720-9721.
(15) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115,
8467-8468.
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9940 J. AM. CHEM. SOC. VOL. 127, NO. 27, 2005

Oxonia-Cope Rearrangement as a Probe for Prins Cyclizations
A R T I C L E S
Figure 4. Test for comparison of rate of oxonia-Cope rearrangement vs rate of [1,2]-hydride addition.
Figure 5. Test for direct comparison of rate of oxonia-Cope rearrangement vs rate of Prins cyclization.
Scheme 1. Synthesis of Optically Active Acetoxy Ether 25
ment. Entries 2, 3, and 4 suggest a significant solvent depen-
dence on relative rates of the two processes. A nonpolar solvent
such as hexanes led to higher levels of optical activity, whereas
a more polar solvent such as nitromethane produced racemic
products. Interestingly, polar solvent also led to higher selectivity
for the equatorial trapped tetrahydropyran 26. As expected, our
recently reported TMSBr conditions produced axial-substituted
tetrahydropyran 27. The TMSBr-initiated Prins cyclization was
the only reaction condition that led to tetrahydropyran products
with high levels of enantiomeric excess (79% ee).
With an initial survey of reaction conditions completed, our
attention turned to the effects of nucleophile concentration
(Table 2). We chose entry 1 in Table 1 as our standard reaction
conditions in which we would vary nucleophile concentration.
For the SnBr4-mediated cyclizations, the active nucleophile is
a tin-“ate” complex generated upon solvolysis of the acetoxy
ether. Tetrabutylammonium bromide was premixed with SnBr4
in order to generate a similar tin-“ate” complex that could serve
as a source of nucleophilic bromide. This additive could then
easily be prepared in different concentrations and utilized in
our concentration experiments. The data in Table 2 demonstrates
that the relative rates of oxonia-Cope versus Prins cyclization
are only minimally affected by nucleophile concentration.
Results
Our initial experiments focused on a variety of Prins
cyclization conditions for acetoxy ether 25 (Table 1). Cyclization
of acetoxy ether 25 with SnBr4 led to tetrahydropyrans 26 and
27 in a 1.8:1.0 ratio. Both diastereomers were shown to have
low levels of optical activity, 8% ee for 26 and 9% ee for 27.
The similar enantiomeric excess for both diastereomeric tet-
rahydropyrans is consistent with Alder’s suggestion of a
tetrahydropyranyl cation intermediate. Comparison of entries 1
and 2 demonstrates the lack of temperature dependence on the
relative rates of Prins cyclization versus oxonia-Cope rearrange-
We chose acetoxy ether 25 as our initial substrate in order to
analyze reaction conditions in a system that would not energeti-
cally favor either initial oxocarbenium ion 19 or achiral
oxocarbenium ion 22. We predicted that electron-withdrawing
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A R T I C L E S
Jasti et al.
Table 1. Effect of Reaction Conditions on Rate of Oxonia-Cope vs Prins Cyclization
entry
Lewis acid
X
solvent
temp (
°
C)
yielda (%)
26:27b
ee 26c (%)
ee 27c (%)
1
2
3
4
5
6
7
8
SnBr4
SnBr4
SnBr4
SnBr4
SnCl4
TMSBr
BF3‚OEt2
TFA
-Br
-Br
-Br
-Br
-Cl
-Br
CH2Cl2
CH2Cl2
hexanes
MeNO2
CH2Cl2
CH2Cl2
hexanes
CH2Cl2
-78
0
93
90
64
82
81
85
52
92
1.8:1.0
3.0:1.0
3.1:1.0
11:1.0
3.7:1.0
1.0:14
8
9
31
0
9
10
36
0
8
79
0
0
0
0
0
0
7
-O2CCH3
>19:1.0
>19:1.0
13
5
d
-O2CCF3
1
a Yield of product after flash chromatography. b Diastereoselectivity determined by H NMR analysis of crude material. c Enantioselectivity determined
by HPLC using a Chiracel OD-H column. Authentic racemates were synthesized by cyclization of racemic acetoxy ether. d Analysis was conducted after
hydrolysis of the trifluoroacetate with K2CO3/MeOH.
Table 2. Effect of Bromide Additive upon Rate of Prins Cyclization
vs Oxonia-Cope Rearrangement
Table 3. Substituent Effects on Rate of Prins Cyclization vs
Oxonia-Cope Rearrangement
-
entry
[SnBr5
]
a (M)
yieldb (%)
26:27c
ee 26d (%)
ee 27d (%)
starting
material
ee 28a
yieldb
(%)
ee 29d
ee 30d
29:30c
(%)
(%)
1
2
3
0.05
0.25
0.50
56
59
59
1.8:1.0
2.4:1.0
2.7:1.0
13
16
18
13
17
19
entry
R group
(%)
1
2
3
4
28a
28b
28c
28d
PhCH2CH2-
CH2CH-
TBDPSOCH2-
ClCH2-
97
92
98
99
80
66
69
55
3.0:1.0
19:1.0
1.0:1.5
1.0:4.0
9
0
57
96
10
n/a
56
a Tin-“ate” complex was prepared by premixing SnBr4 and Bu4N+Br-
in a 1:1 ratio. b Yield of product after flash chromatography. c Diastereo-
selectivity determined by 1H NMR analysis of crude material. d Enantiose-
lectivity determined by HPLC using a Chiracel OD-H column.
96
a Enantiomeric excess for acetoxy ethers was established from starting
homoallylic alcohols. Alcohols were assayed by either chiral HPLC or GC
analysis. b Yield of product after flash chromatography. c Diastereoselectivity
determined by 1H NMR analysis of crude material. d Enantioselectivity
determined by either chiral HPLC or GC analysis.
groups or stabilizing groups could have a significant influence
on the relative rates of the oxonia-Cope rearrangement versus
Prins cyclization. Table 3 highlights these results. Entry 2
demonstrated that stabilizing oxocarbenium ion 22 with a vinyl
substituent leads to total loss of optical purity. Interestingly, in
this case the Prins reaction was highly selective for the
equatorial-substituted product. Introduction of an electron-
withdrawing group (entry 3) led to higher levels of optical
activity and 1.0 to 1.5 selectivity in favor of the axial bromide
product. Introducing an even more powerful electron-withdraw-
ing group to destabilize achiral oxocarbenium ion 22 (entry 4)
resulted in a 4.0 to 1.0 axial-selective Prins cyclization with
virtually no loss of enantiomeric excess.
Discussion
Table 1 definitively shows that oxonia-Cope rearrangement
is a rapid process relative to Prins cyclization under standard
Prins cyclization conditions. Interestingly, conditions employing
TMSBr as a Lewis acid (Table 1, entry 6) were the only
conditions that led to tetrahydropyran with moderate levels of
optical activity. A rationale for this result is presented in Figure
6. Treatment of an acetoxy ether with SnBr4 generates oxocar-
benium ion 34 and a tin-“ate” complex. Cyclization results in
a higher energy tetrahydropyranyl cation 35.7 This intermediate
can then undergo either of two ring-opening process to generate
intermediates 34 or 36. Intermediate 36 will result in racemic
tetrahydropyran product. However, if 35 is attacked by bromide
before ring-opening can occur, 37 should be isolated with
Having probed stabilizing and destabilizing electronic effects
upon oxocarbenium ion 19, we turned our attention to tetrahy-
dropyranyl cation 20. Stabilizing the tetrahydropyranyl cation
intermediate with a third alkyl group could have significant
effects upon the rates of oxonia-Cope versus Prins cyclization.
To explore this concept, acetoxy ether 31 was synthesized.
Cyclization of acetoxy ether 31 with SnBr4 generated the axial
bromide tetrahydropyran 32 with no erosion of enantiomeric
excess (eq 1).
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Oxonia-Cope Rearrangement as a Probe for Prins Cyclizations
A R T I C L E S
Figure 6. Comparison of SnBr4 and bromotrimethylsilane-initiated Prins cyclizations.
enantiomeric excess identical to that of starting acetoxy ether
33. The significant racemization shown in Table 1 suggests that
k1 is typically greater than k2. Treatment of acetoxy ether 33
with TMSBr, however, generates bromoether 38, which can then
solvolyze to oxocarbenium ion 39.9 In this case, the nucleophile
generated is bromide, which should be much more reactive than
a tin-“ate” complex. As expected, k3 is greater than k1, and
tetrahydropyranyl cation 40 is trapped to generate axial tet-
rahydropyran 41 with moderate levels of enantiomeric excess.
The argument presented in Figure 6 would seem to imply
that nucleophile concentration should have an effect on the rates
of oxonia-Cope versus Prins cyclization. The results in Table
2, however, show that this is not the case. A 10-fold increase
in concentration of nucleophile only minimally affected the
enantiomeric excess of products. This can perhaps be explained
by the role of ion-pairing.16 Oxocarbenium ions such as 34 and
39 may exist as ion-pairs, retaining close proximity to a
counterion. This counterion also serves as a nucleophile.
Therefore, if internal return of a nucleophile (inside a solvent
cage) is fast relative to incorporation of an external nucleophile
(outside a solvent cage), nucleophile concentration would have
minimal effect. This hypothesis also seems to be consistent with
the solvent effects shown in Table 1, entries 3 and 4. A less
polar solvent such as hexanes should favor ion-pairing, thus
leading to higher levels of optical activity. In contrast, ni-
tromethane should disfavor ion-pairing and lead to more
racemization. Crossover experiments would be useful in a further
investigation of ion-pairing effects in Prins cyclizations.17
Figure 6 can also be used to analyze results presented in Table
3. An acetoxy ether possessing an electron-withdrawing group
such as a chloromethyl substituent (Table 3, entry 4) destabilizes
oxocarbenium ion 36. In this case, the rate of ring-opening to
36 is slower than nucleophilic attack by bromide. Consistent
with this explanation, tetrahydropyran 30d was isolated in 96%
ee. Replacing the electron-withdrawing group with a vinyl group
had the opposite effect. The vinyl group stabilizes oxocarbenium
ion 36 and is reflected in the transition state from 35 to 36. For
the vinyl-substituted acetoxy ether 28b, k1 is greater than k2
and racemic product 29b is isolated.
Stabilizing and destabilizing groups also had an effect on the
diastereoselectivity of the Prins cyclization. Electron-withdraw-
ing groups such as chloride and oxygen (Table 3, entries 3 and
4) lessen the extent of delocalization of tetrahydropyranyl cation
intermediate 35. The more reactive cation leads to more of the
axial product. This effect can be rationalized in a fashion similar
to the argument presented for trimethylsilyl bromide-initiated
cyclizations.9 Cyclizations utilizing TMSBr generate a very
reactive nucleophile, bromide. Bromide, because of its high
reactivity, tends to react through a least-motion pathway,10
leading to axial trapped product. The diastereoselectivity of the
reaction seems to be controlled by the probability of collision
as opposed to differences in energy of transition states.18 In other
words, approach from an equatorial trajectory should lead to a
lower transition state energy; however, collision from an axial
trajectory may have a greater probability of occurrence. In the
case of a very reactive nucleophile, most collisions may lead
to product, and differences in transition state energies would
have minimal effect on the diastereoselectivity. Similar to the
case for very reactive nucleophiles, more reactive electrophiles
should be trapped through a least-motion pathway (28d leads
to high axial selectivity). In contrast, the vinyl-substituted
acetoxy ether 28b generates a less reactive electrophile, and
stereoselectivity should reflect the differences in transition state
energies. Consistent with this reasoning, 28b produced equato-
rial-substituted tetrahydropyran 29b in high selectivity.
To provide further insight into the observed electronic effects,
DFT calculations were performed.19 The results of these
calculations are summarized in the energy diagrams shown in
Figure 7. Alder has shown that cis-2,6-dimethyl-4-tetrahydro-
(16) Sneen, R. A. Acc. Chem. Res. 1973, 6, 46-53.
(17) A reviewer suggested a crossover experiment utilizing tetrabutylammonium
chloride as a competitive nucleophile. We found that generation of a
bromoether from acetoxy ether 25 at -60 °C followed by addition of
tetrabutylammonium chloride and warming to 0 °C led to axial bromotet-
rahydropyran 27 in 83% ee. No chlorotetrahydropyrans were observed in
the crude reaction mixture. This result is consistent with an ion-pairing
argument in which recombination of a bromide anion from inside a solvent
cage is faster than incorporation of a chloride anion from outside a solvent
cage.
(18) Carbocations which are not highly stabilized are known to be quenched at
a diffusional rate: (a) McCelland, R. A. Tetrahedron 1996, 52, 6823. (b)
Richard, J. P.; Amyes, T. L.; Toteva, M. M. Acc. Chem. Res. 2001, 34,
981-988.
(19) Geometry optimizations were performed with B3LYP/6-31G* as imple-
mented in Gaussian 03.20 Minima were characterized by their vibrational
frequencies. Reported energies include unscaled zero-point corrections.
(20) Frisch, M. J.; et al. Gaussian 03, Revision C.02; Gaussian, Inc.: Walling-
ford, CT, 2004.
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A R T I C L E S
Jasti et al.
Figure 7. Substituent effects on energy profile of oxonia-Cope rearrangement.
pyranyl cation 47 is 13.4 kJ/mol less stable than its open form
and is protected from ring-opening by an activation energy of
1.9 kJ/mol. The incorporation of a chloromethyl substituent
results in a significant increase in activation energy of ring-
opening to oxocarbenium ion 45. Ring-opening from tetrahy-
dropyranyl cation 44 to oxocarbenium ion 45 requires an
activation energy of 7.8 kJ/mol, whereas ring-opening from 44
to 43 requires only 0.4 kJ/mol. This energy profile correlates
well with the high optical activity observed for the cyclization
of acetoxy ether 28d (Table 3). In addition, the isodesmic
reaction in eq 2 shows that the chloride-substituted tetrahydro-
pyranyl cation 44 is 19.6 kJ/mol higher in energy than cation
47. This destabilization is consistent with our hypothesis of more
reactive electrophiles leading to axial-selective Prins cyclizations
through a least-motion pathway. A more comprehensive set of
examples would be necessary to further validate this hypothesis.
Interestingly, we were not able to locate a tetrahydropyranyl
cation intermediate for the vinyl-substituted oxocarbenium ion
49, perhaps indicating a concerted pathway.
Cyclization of acetoxy ether 31 produced tetrahydropyran 32
with no loss of optical activity. This result is consistent with
tetrahydropyranyl cation stabilization. Lowering of the energy
of the tetrahydropyranyl cation intermediate effectively raises
the transition state energy for ring-opening to the achiral
oxocarbenium ion. Computational work supports this hypothesis
(Figure 8). Alder has shown that tetrahydropyranyl cation 47
is 13.4 kJ/mol less stable than oxocarbenium ion 46.7 Ring-
opening of cation 47 to oxocarbenium ion 46 is protected by
an activation barrier of only 1.9 kJ/mol. These results are
consistent with rapid oxonia-Cope rearrangements for mono-
substituted olefins. In contrast, oxocarbenium ion 53 is 40.9
kJ/mol higher in energy than tetrahydropyranyl cation 54.19
Equation 3 shows an additional experiment to further
investigate the least-motion pathway argument presented above.
We rationalized that cyclization of acetoxy 28d in the presence
of a less reactive nucleophile should lead to more of the
equatorial-substituted product. Indeed, treatment of acetoxy ether
28d with trifuoroacetic acid followed by hydrolysis of the
trifloroacetate produced tetrahydropyrans 52 in a 3:2 ratio
favoring the all-cis tetrahydropyran.
Figure 8. Stabilization of tetrahydropyranyl cation.
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9944 J. AM. CHEM. SOC. VOL. 127, NO. 27, 2005

Oxonia-Cope Rearrangement as a Probe for Prins Cyclizations
A R T I C L E S
Thus, acetoxy ether 31 cyclizes to tetrahydropyran 32 with no
loss of optical activity. In this case, cyclization is essentially
irreversible (ring-opening does not occur before nucleophilic
capture).
capture at C4 is highly dependent on the reactivity of the
nucleophile and electrophile. Highly reactive nucleophiles and
electrophiles provide axial-substituted tetrahydropyrans, whereas
less reactive nucleophiles and electrophiles provide equatorial-
substituted tetrahydropyrans.
Conclusion
Acknowledgment. This work was supported by the National
Institutes of Health (CA081635) and by a generous gift from
Schering-Plough Research Institute.
These results utilizing an oxonia-Cope rearrangement as an
internal clock reaction provide useful mechanistic insight into
the Prins cyclization. For a typical Prins cyclization substrate,
oxonia-Cope is fast relative to nucleophilic capture of an
intermediate tetrahydropyranyl cation. By stabilizing or desta-
bilizing the resultant oxocarbenium ion, the oxonia-Cope
rearrangement can be accelerated or decelerated. In addition,
stabilizing the tetrahydropyranyl cation intermediate raises the
transition state energy for ring-opening and effectively eliminates
oxonia-Cope rearrangement. Stereoselectivity of nucleophilic
Supporting Information Available: Complete experimental
details, complete ref 20, characterization of products, and
coordinates for structures presented in Figures 7 and 8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA0518326
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J. AM. CHEM. SOC. VOL. 127, NO. 27, 2005 9945