Racemization in prins cyclization reactions

Article abstract of DOI:10.1021/ja064783l

Isotopic labeling experiments were performed to elucidate a new mechanism for racemization in Prins cyclization reactions. The loss in optical activity for these reactions was shown to occur by 2-oxonia-Cope rearrangements by way of a (2)-oxocarbenium ion

Full text of DOI:10.1021/ja064783l

Published on Web 09/22/2006
Racemization in Prins Cyclization Reactions
Ramesh Jasti and Scott D. Rychnovsky*
Contribution from the Department of Chemistry, UniVersity of California, IrVine, 1102 Natural
Sciences II, IrVine, California 92697-2025
Received July 5, 2006; E-mail: srychnov@uci.edu
Abstract: Isotopic labeling experiments were performed to elucidate a new mechanism for racemization
in Prins cyclization reactions. The loss in optical activity for these reactions was shown to occur by 2-oxonia-
Cope rearrangements by way of a (Z)-oxocarbenium ion intermediate. Reaction conditions such as solvent,
temperature, and the nucleophile employed played a critical role in whether an erosion in enantiomeric
excess was observed. Additionally, certain structural features of Prins cyclization precursors were also
shown to be important for preserving optical purity in these reactions.
Introduction
we illustrate the existence of a third racemization pathway and
elucidate its mechanism.
The Prins cyclization1 is a very powerful synthetic transfor-
mation to rapidly assemble tetrahydropyran rings.2,3 Tetrahy-
dropyran rings are common structural motifs in numerous
biologically relevant molecules such as the phorboxazoles,4
spongistatins,5 and bryostatins.6 In fact, several groups have
taken advantage of this transformation in elegant approaches
to natural product targets.7 While this reaction has shown great
potential for organic synthesis, two deleterious racemization
pathways have been previously demonstrated.8 In this article,
As with any reaction creating new stereogenic centers, the
utility of the Prins cyclization is highly dependent on the degree
of stereoselectivity associated with the transformation. Several
factors are involved when rationalizing the stereochemical
outcome for Prins cyclization reactions. Ring closure of an
alkene onto an oxocarbenium ion through a chair transition state
leads to tetrahydropyranyl cation intermediate 29 (Figure 1). In
this ring-closure step, the C210 substituent lies in a favorable
equatorial position and the (E)-oxocarbenium ion geometry is
preferred11 over the (Z)-oxocarbenium ion geometry. Therefore,
chirality is transferred from C2 to the newly formed carbon-
carbon bond. The stereocenter formed at C4 is controlled by
the extensive delocalization of tetrahydropyranyl cation 2.9a
Favorable orbital overlap places the hydrogen at C4 in a
pseudoaxial geometry, and, therefore, nucleophilic attack occurs
(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 a recent review on the synthesis of tetrahydropyran rings, see: Santos,
S.; Clarke, P. A. Eur. J. Org. Chem. 2006, 2045-2053.
(3) For recent work on Prins cyclization methodology, see: (a) Miranda, P.
O.; Ramirez, M. A.; Martin, V. S.; Padron, J. I. Org. Lett. 2006, 8, 1633-
1636. (b) Lee, C.-H. A.; Loh, T.-P. Tetrahedron Lett. 2006, 47, 1641-
1644. (c) Overman, L. E.; Velthuisen, E. J. J. Org. Chem. 2006, 71, 1581-
1587. (d) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.;
Harding, J. R.; Willis, C. L. Chem. Commun. 2005, 40, 5097-5099. (e)
Jasti, R.; Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc. 2005,
127, 9939-9945. (f) Bolla, M. L.; Patterson, B.; Rychnovsky, S. D. J.
Am. Chem Soc. 2005, 127, 16044-16045. (g) Yadav, K. V.; Kumar, N.
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L. J. Am. Chem. Soc. 2004, 126, 12216-12217. (i) Dalgard, J. E.;
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9
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J. AM. CHEM. SOC. 2006, 128, 13640-13648
10.1021/ja064783l CCC: $33.50 © 2006 American Chemical Society

Racemization in Prins Cyclization Reactions
A R T I C L E S
Figure 1. Stereochemical outcome for Prins cyclizations.
Figure 2. Loss of enantiomeric excess in Prins cyclizations of electron-
rich benzylic homoallylic alcohols (Mechanism A).
along an equatorial trajectory to deliver tetrahydropyran 3.12 In
this way, four stereogenic centers of the tetrahydropyran ring
can be formed with high stereoselectivity from one initial
stereocenter and a defined alkene geometry.
Figure 3. Racemization of Prins cyclization products by symmetric
2-oxonia-Cope rearrangement (Mechanism B).
ee along with symmetric tetrahydropyrans 10 and 11 (Figure
3).8b The mechanism for racemization in this case relies on an
allyl transfer process. Alcohol (R)-8 can condense with hydro-
cinnamaldehyde to generate oxocarbenium ion 12 and liberate
a molecule of water. Oxocarbenium ion 12 can then undergo a
2-oxonia-Cope rearrangement14,15 to generate oxocarbenium ion
13. Readdition of water to oxocarbenium ion 13 leads to a
fragmentation process generating benzaldehyde and alcohol (R)-
14. The formation of benzaldehyde and alcohol (R)-14 now
allows for a symmetric 2-oxonia-Cope rearrangement. Initial
alcohol (R)-8 can condense with benzaldehyde, rearrange via a
2-oxonia-Cope rearrangement, then fragment with the addition
of water to generate epimeric (S)-8. Likewise, alcohol (R)-14
can generate epimeric (S)-14. In this way, allyl transfer processes
can lead to a loss in optical activity for Prins cyclization
reactions (Mechanism B). Racemization by Mechanism B is
easily identifiable in that it is accompanied by the formation of
symmetric tetrahydropyran products (10 and 11). Additionally,
Another important feature for a synthetically useful trans-
formation is the ability to convert optically active starting
materials into optically active products. Although typically
proceeding with high stereochemical fidelity, the Prins cycliza-
tion reaction has at times been plagued by racemization.8,13
Willis et al. have demonstrated that Prins cyclizations of benzylic
alcohols can lead to an extensive loss in enantiomeric excess
by way of a solvolysis mechanism (Figure 2).8a For example,
treatment of optically enriched alcohol 4 with BF3‚OEt2 in the
presence of propanal and acetic acid led to tetrahydropyran 5
in less than 5% ee. In this case, stabilized benzylic cation 6 can
be generated by a solvolysis reaction of initial alcohol 4 or
oxocarbenium ion 7. This stabilized, achiral benzylic cation then
recombines with propanal, ultimately leading to racemic tet-
rahydropyran 5 (Mechanism A). Due to this solvolysis mech-
anism, Prins cyclization reactions utilizing electron-rich aromatic
substrates are often problematic.8a
In addition to the solvolysis pathway shown in Mechanism
A, we have previously demonstrated a process for racemization
in Prins cyclizations that does not require the presence of an
electron-rich aromatic ring. For instance, treatment of optically
enriched alcohol 8 with BF3‚OEt2 in the presence of hydrocin-
namaldehyde and acetic acid led to tetrahydropyran 9 in 67%
(14) For recent work on the 2-oxonia-Cope rearrangement, see: (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. (g) Chen,
Y.-H.; McDonald, F. E. J. Am. Chem. Soc. 2006, 128, 4568-4569.
(15) For 2-oxonia-Cope rearrangements as competing processes in Prins
cyclizations, see: (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. (g) Jasti, R.; Anderson, C. D.; Rychnovsky, S.
D. J. Am. Chem. Soc. 2005, 127, 9939-9945.
(12) 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.
(13) (a) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C. L.
Org. Lett. 2002, 4, 3407-3410. (b) 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. (c) Lee, C.-H. A.; Loh, T.-P. Tetrahedron Lett. 2006,
47, 1641-1644. (d) Chan, K.-P.; Loh, T.-P. Org. Lett. 2005, 7, 4491-
4494.
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A R T I C L E S
Jasti and Rychnovsky
Figure 5. Racemization of Prins cyclization products by achiral cyclobutyl
cation intermediate (Mechanism C).
Proposed Mechanisms for Racemization in Prins
Cyclization Reactions
At the outset of this study, we considered three additional
mechanisms that might lead to a loss in optical activity for Prins
cyclization reactions. The first mechanism relies on an achiral
cyclobutane intermediate (Mechanism C). Treatment of optically
active acetoxy ether 21 with an acid will initially generate
oxocarbenium ion 22 (Figure 5). Oxocarbenium ion 22 could
then proceed by normal Prins cyclization and nucleophilic
termination to deliver optically active tetrahydropyran 23.
Alternatively, oxocarbenium ion 22 could undergo internal
displacement by the alkene to generate a chiral cyclopropyl
carbinyl cation 24 and expel aldehyde 25. Racemization may
then occur by ring expansion of intermediate 24 to achiral
cyclobutyl cation 26. Cyclobutyl cation 26 then has an equal
probability of either a ring contraction leading back to cyclo-
propyl carbinyl cation 24 or a ring contraction leading to
cyclopropyl carbinyl cation ent-24. By recombining with
aldehyde 25, cation ent-24 could eventually lead to the formation
of tetrahydropyran ent-23. In this way, the formation of
cyclobutyl cation 26 would lead to a loss of optical activity in
Prins cyclization reactions.
The second mechanism we considered for loss of optical
activity in Prins cyclizations is similar to Mechanism A that
has already been demonstrated. In this case, homoallylic cation
27 is generated from oxocarbenium ion 22, but this time the
fragmentation process does not rely on the presence of an
electron-rich aromatic ring (Figure 6). The reaction conditions
shown in Figure 4 in which high concentrations of trifluoroacetic
acid were employed may induce solvolysis of an oxocarbenium
ion even without a good stabilizing group due to the exceptional
solvolytic properties of trifluoroacetic acid.18 In addition,
solvolysis reactions of homoallylic systems have been shown
to be accelerated due to stabilization from the alkene.19
Therefore, the combination of a reaction medium with high
solvolytic power and the presence of homoallylic participation
may in fact facilitate fragmentation of oxocarbenium ion 22 to
homoallylic cation 27 and aldehyde 25 (Mechanism D).
Recombination of cation 27 and aldehyde 25 would then be
Figure 4. Unusual racemization in Prins cyclizations.
Mechanism B relies on the presence of water. Direct Prins
cyclizations utilizing homoallylic alcohols and aldehydes gener-
ate water upon condensation. Prins cyclizations of acetoxy
ethers, however, do not generate water in situ and therefore can
be used to avoid racemization by Mechanism B.
Recently, we observed a loss of enantiomeric excess in a
tandem Grob fragmentation/Prins cyclization reaction that does
not seem to be consistent with either Mechanism A or B (Figure
4, 15 to 16).16 Treatment of mesylate 15 with trifluoroacetic
acid initially generates tetrahydropyranyl cation 17. This cation
can then undergo a ring-opening process to generate oxocar-
benium ion 18. Oxocarbenium ion 18 then eventually undergoes
a Prins cyclization followed by nucleophilic trapping to deliver
tetrahydropyran 19. Surprisingly, the product of this Grob
fragmentation/Prins cyclization pathway had undergone a
significant loss in optical activity (91% ee to 49% ee).
Furthermore, treatment of acetoxy ether 20 under Prins cycliza-
tion conditions promoted by trifluoroacetic acid17 also led to a
significant decrease in enantiomeric excess. In both of these
cases, an electron-rich aromatic group is not present as is
required for the solvolysis pathway in Mechanism A. Mecha-
nism B also was considered unlikely because symmetric
tetrahydropyran products were not observed in either reaction.
In this article, we describe experiments designed to elucidate
a third mechanism for racemization in Prins cyclization reac-
tions. We provide evidence that the loss in optical activity is
due to rapid 2-oxonia-Cope rearrangements involving a (Z)-
oxocarbenium ion intermediate. We also demonstrate that
reaction conditions such as solvent, temperature, and the
nucleophile employed can influence the extent of racemization.
In addition, we illustrate that structural features such as the type
of alkene employed can also play a critical role in whether the
initial enantiomeric excess of the starting material is preserved.
(18) 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.
(19) Lambert, J. B.; Featherman, S. I. J. Am. Chem. Soc. 1977, 99, 1542-
1546.
(16) Jasti, R.; Rychnovsky, S. D. Org. Lett. 2006, 8, 2175-2178.
(17) Barry, C. St. 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.
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Racemization in Prins Cyclization Reactions
A R T I C L E S
Table 1. Effect of Reaction Conditions on Loss of Optical Activity
in Prins Cyclizations
entry
Lewis acid
X
solvent
temp (
°C)
% yielda
% ee 31b
c
c
c
c
c
1
2
3
4
5
6
7
8
9f
TFA
TFA
TFA
-O2CCF3
-O2CCF3
-O2CCF3
-O2CCF3
-O2CCF3
TFA
TFA
TFA
CH2Cl2
pentane
55
25
0
25
25
25
25
25
25
74
72
73
78
80
86
75
30
47
66
77
84
84
91
77
91
68
71
TFAd
TFAd
BF3‚OEt2
Figure 6. Racemization of Prins cyclization products due to homoallylic
cation intermediate (Mechanism D).
e
-O2CCH3 CH2Cl2
e
SnBr4
-Br
CH2Cl2
CH2Cl2
TFA
TMSOMse -OMs
c
TFA
-O2CCF3
a Yield of product after flash chromatography. b Enantiomeric excess
determined by HPLC using a Chiracel OD-H column. Authentic racemates
were synthesized by cyclization of racemic acetoxy ether. c Analysis was
conducted after hydrolysis of the trifluoroacetate with K2CO3/MeOH. d 10
equivalents of TFA was employed. e 3 equivalents of Lewis acid was
employed. f Direct Prins cyclization of corresponding homoallylic alcohol
and aldehyde.
in enantiomeric excess for the Prins cyclization reaction shown
in Figure 4 (20 to 16) occurred under very specific conditions.
We decided to explore the generality of this result by surveying
the effect of a wide variety of reaction conditions upon the loss
of optical activity in Prins cyclization reactions (Table 1). The
acetoxy ethers used for this study were prepared by standard
means developed in our laboratory21 and are further documented
in the Supporting Information. Entries 1-3 demonstrate the
importance of temperature for the loss of optical activity in Prins
cyclizations. Prins cyclization at an elevated temperature (entry
1) resulted in a greater loss in enantiomeric excess than when
conducted at lower temperatures (entry 3). Entries 2, 4, and 5
highlight the significance of polarity for the loss of optical
activity in Prins cyclization reactions. Entry 2, the most polar
reaction conditions, resulted in the greatest loss in enantiomeric
excess, whereas the least polar conditions, entry 5, resulted in
no loss in enantiomeric excess. The nucleophile employed also
proved to be important for the preservation of optical activity
in Prins cyclizations. Prins cyclization reaction utililizing a
bromide nucleophile (entry 7) proceeded with no loss in
enantiomeric excess. In contrast, Prins cyclization terminated
by a mesylate nucleophile (entry 8) resulted in tetrahydropyran
31d in only 68% ee. The last entry in Table 1 demonstrates the
difference between a direct Prins cyclization between an
aldehyde and alcohol (entry 9) and one utilizing an acetoxy ether
(entry 2). Direct Prins cyclization results in a slightly lower
optical activity due to symmetric 2-oxonia-Cope rearrangements
(Mechanism B, Figure 3). Consistent with this hypothesis, entry
9 was the only Prins cyclization condition that resulted in
symmetric tetrahydropyran products (ca. 8%).
Figure 7. Racemization of Prins cyclization products due to E/Z isomer-
ization and 2-oxonia-Cope rearrangement (Mechanism E).
expected to occur in an unselective manner, leading to a loss
in enantiomeric excess for Prins cyclization reactions.
The final proposed mechanism relies on unselective 2-oxonia-
Cope rearrangements. Typically, an intervening 2-oxonia-Cope
rearrangement is not deleterious to the stereochemical outcome
of the Prins cyclization reaction. For instance, oxocarbenium
ions 22 and 28 will both lead to tetrahydropyran 23 (Figure 7).
However, if (E)-oxocarbenium ion 22 undergoes an isomeriza-
tion to (Z)-oxocarbenium ion 29, a 2-oxonia-Cope rearrangement
will then lead to oxocarbenium ion 30. Oxocarbenium ion 30
upon C-C bond rotation can generate oxocarbenium ion ent-
22, which will eventually lead to tetrahydropyran ent-23. In this
way, 2-oxonia-Cope rearrangement proceeding through a (Z)-
oxocarbenium ion can lead to an erosion of optical purity in
Prins cyclization reactions (Mechanism E). A similar pathway
for racemization has been suggested for iminium ion cycliza-
tions.20
In addition to reaction conditions, substrate structure played
an important role in whether optical activity was preserved in
Prins cyclization reactions (Table 2). By utilizing a chloromethyl
substituent (entry 2) as opposed to an alkyl substituent (entry
Results
The Effect of Reaction Conditions and Substrate Structure
on Loss of Optical Activity in Prins Cyclizations. The loss
(20) (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.
(21) (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.
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A R T I C L E S
Jasti and Rychnovsky
Table 2. Effect of Substrate Structure on Loss of Optical Activity
in Prins Cyclizations
complete retention of optical purity while cyclization of acetoxy
ether 32a showed a significant loss in optical purity. Could this
surprising outcome be a result of different solvolysis behavior
for terminal homoallylic systems versus substituted homoallylic
systems? Solvolysis reactions of homoallylic systems with
substituted alkenes have been shown at times to proceed with
retention of stereochemistry.19 We investigated this possibility
with the reactions shown in eqs 2 and 3. Indeed, treatment of
tosylate 35 with trifluoroacetic acid followed by methanolysis
provided racemic alcohol 36, whereas solvolysis of tosylate 37
led to optically pure alcohol 38. Although this result correlates
well with a solvolysis mechanism leading to racemization
(Mechanism C or D), it does not provide definitive evidence.
To unambiguously determine the mechanism for racemization
in Prins cyclizations, we designed three isotopic labeling
experiments to test the validity of the proposed mechanisms.
entrya
SM
R1
R2
% ee 32b
% yieldc
% ee 33d
1
2
3
32a
32b
32c
-n-propyl
-CH2Cl
-n-propyl
-H
91
91
99
70
62
82
78
91
99
-H
-CH3
a The reaction conditions employed in Table 2 are slightly different from
those utilized for entry 4, Table 1. For the entries in Table 2, a 2.5:1 ratio
of TFA/CH2Cl2 was employed as reported by Willis et al.17 b Enantiomeric
excess for acetoxy ethers was established from starting homoallylic alcohols.
Alcohols were assayed by either chiral HPLC or GC analysis. c Yield of
product after flash chromatography. d Enantiomeric excess determined by
either chiral HPLC or GC analysis.
1), we observed a total retention of enantiomeric excess for Prins
cyclizations promoted by trifluoroacetic acid.17 Likewise,
incorporation of a substituted alkene (entry 3) instead of a
terminal alkene also led to a total retention of enantiomeric
excess. These interesting structural effects will be further
addressed in the Discussion.
Exploring the Mechanism for Loss of Optical Activity in
Prins Cyclizations. Initially, we investigated the validity of
Mechanisms C and D by the simple crossover experiment shown
in eq 1. Both Mechanisms C and D rely on a fragmentation/
recombination pathway involving a cation and an aldehyde. If
either of these mechanisms is operable, Prins cyclization in the
presence of an exogenous aldehyde might result in tetrahydro-
pyran products incorporating the aldehyde. Equation 1 clearly
demonstrates that this is not the case. Prins cyclization of
acetoxy ether 20 in the presence of 5 equiv of butyraldehyde
did not produce symmetric tetrahydropyran 34. This result is
consistent with the conclusion that neither Mechanism C nor D
is operable and that Mechanism E is the pathway that leads to
racemization. Although tempting, we were wary of drawing this
conclusion too quickly. Solvent cage effects could potentially
render the crossover experiment shown in eq 1 irrelevant. In
other words, if recombination occurs faster than escape from
the solvent cage, incorporation of a second aldehyde would not
be expected. In addition, Mechanism E involves unfavorable
(Z)-oxocarbenium ion intermediates. We have never observed
2,6-trans-tetrahydropyran products from Prins cyclization reac-
tions that would result from these higher energy intermediates.22
Acetoxy ether 43 containing a 13C label at the terminal
position of the alkene was designed to probe the validity of
Mechanism C. The synthesis and Prins cyclization reaction of
the isotopically labeled acetoxy ether 43 are shown in Scheme
1. Ozonolysis followed by reductive workup of optically active
alkene 39 delivered aldehyde 40 in 88% yield. At this stage, a
Wittig reaction installed the desired 13C label and the silyl
protecting group was removed to deliver homoallylic alcohol
41. Esterification and reductive acetylation21 then provided the
desired acetoxy ether 43. Prins cyclization and methanolyis17
delivered tetrahydropyran 44 in 71% ee. Analysis of the 13C
NMR spectra clearly demonstrated that no scrambling of the
13C label had occurred.
Scheme 1. Synthesis and Prins Cyclization of 13C-Labeled
Acetoxy Ether 43
We were intrigued by the result shown in Table 2 (entry 3)
in which Prins cyclization of acetoxy ether 32c proceeded with
Deuterated acetoxy ether 51 was synthesized to investigate
the role of Mechanism D. The synthesis began with optically
active homoallylic alcohol 45 available from a Keck asymmetric
allylation.23 Carboxylation and esterification proceeded in
(22) (a) Trans products have been observed for vinylsilane-terminated cycliza-
tions of ester-substituted oxocarbenium ion intermediates: Semeyn, C.;
Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62,
3426-3427. (b) Trans products have been observed when employing a
substrate with a small sp-hybridized side chain: Hart, D. J.; Bennett, C. E.
Org. Lett. 2003, 5, 1499-1502.
(23) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115,
8467-8468.
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Racemization in Prins Cyclization Reactions
A R T I C L E S
Scheme 2. Synthesis and Prins Cyclization of Deuterated Acetoxy
Ether 51
Scheme 3. Synthesis and Prins Cyclization of Deuterated Acetoxy
Ether 57
moderate yield to deliver alcohol 46. Treatment of alcohol 46
with lithium aluminum deuteride followed by selective primary
alcohol protection led to deuterated alcohol 48. Esterification
and reductive acetylation21 then provided acetoxy ether 50. Silyl
deprotection and benzylic oxidation completed the synthesis of
the desired deuterated acetoxy ether 51. Prins cyclization
reaction then provided tetrahydropyran 52 in 46% yield and
77% ee (Scheme 2). In this case, we observed complete retention
of deuteration at the aldehyde position.
One additional isotopically labeled substrate was prepared
to examine the potential role of Mechanism E in the loss of
optical activity for Prins cyclization reactions. The synthesis of
deuterated acetoxy ether 57 began with optically active epoxide
53 available from Jacobsen’s hydrolytic kinetic resolution
(Scheme 3).24 Lithiated alkyne addition to the epoxide followed
by deprotection provided alcohol 54 in 94% yield. The alkyne
was then deprotonated with butyllithium and treated with
deuterated acetic acid to install deuterium quantitatively at the
terminal position of the alkyne. The alcohol was then esterified
under standard conditions to provide compound 55. Hydrobo-
ration followed by protonation led to ester 56, which underwent
reductive acetylation21 smoothly to provide deuterated acetoxy
ether 57. Prins cyclization and methanolysis17 then delivered
tetrahydropyran 58 in 70% ee. At this point, we wished to
determine the stereochemistry of the deuterium for each
enantiomer. To facilitate this analysis, tetrahydropyran 58 was
treated with an optically active chiral isocyanate25 to generate
diastereomeric tetrahydropyrans 59 and 60. Tetrahydropyrans
59 and 60 were then carefully separated by preparatory HPLC
and analyzed by deuterium NMR. The major isomer, tetrahy-
dropyran 59, had deuterium exclusively in the axial position,
whereas the minor isomer, tetrahydropyran 60, had deuterium
located in both the equatorial and axial positions in a 1.0:0.92
ratio (Figure 8).
Figure 8. 2H NMR spectra for tetrahydropyran 59 and tetrahydropyran
60.
of Mechanisms C, D, and E for the loss of optical activity in
Prins cyclization reactions. Prins cyclization of acetoxy ether
43, in which no scrambling of the 13C label was observed, can
be used to rule out Mechanism C. Figure 9 illustrates the
rationale for this conclusion. Treatment of acetoxy ether with
trifluoroacetic acid generates oxocarbenium ion 61. If oxocar-
benium ion 61 continues on to tetrahydropyran 62, the 13C label
will end up adjacent to the methyl side chain. However, if a
fragmentation reaction occurs that eventually leads to intermedi-
ate cyclobutane 64, the enantiomeric tetrahydropyran 67 will
have the 13C label adjacent to the R group instead of the methyl
side chain. Analysis of the 13C NMR spectra clearly revealed
that the 13C label had been completely retained in the position
adjacent to the methyl group, therefore ruling out Mechanism
C.
Having ruled out one fragmentation pathway, we turned our
attention to Mechanism D. To probe Mechanism D, we utilized
acetoxy ether 51 as an internal crossover probe that would take
into account the possibility of solvent cage effects. Figure 10
illustrates this crossover experiment. Treatment of acetoxy ether
51 with trifluoroacetic acid initially generates oxocarbenium ion
68. Oxocarbenium ion 68 can then lead to optically active
Discussion
Prins cyclization of the differentially labeled acetoxy ethers
43, 51, and 57 provides definitive evidence regarding the roles
(24) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K.
B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 1307-1315.
(25) Pirkle, W. H.; Boeder, C. W. J. Org. Chem. 1978, 43, 1950-1952.
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A R T I C L E S
Jasti and Rychnovsky
2-oxonia-Cope rearrangements and Prins cyclizations occurring
through a common tetrahydropyranyl cation intermediate9 to
provide a complete mechanistic picture. Treatment of acetoxy
ether 57 with trifluoroacetic acid initially generates oxocar-
benium ion 75. Oxocarbenium ion 75 can then cyclize to
generate tetrahydropyranyl cation 76, which upon nucleophilic
trapping results in tetrahydropyran 77. Alternatively, tetrahy-
dropyranyl cation 76 could reopen to oxocarbenium ion 84,
which upon reclosure and nucleophilic trapping would also lead
to tetrahydropyran 77. Thus, both oxocarbenium ions 75 and
84 can lead to the major enantiomer, tetrahydropyran 77,
containing deuterium in an axial position. Loss in optical activity
for these Prins cyclizations occurs when 2-oxonia-Cope rear-
rangements proceed through (Z)-oxocarbenium ion intermedi-
ates. For instance, (E)-oxocarbenium ion 75 could isomerize to
(Z)-oxocarbenium ion 78. Isomerization likely occurs by an
addition-elimination pathway as opposed to higher energy
mechanisms involving rotation or inversion.11 This oxocarbe-
nium ion can then lead to oxocarbenium ion 80 by way of a
2-oxonia-Cope rearrangement. Carbon-carbon bond rotation to
place the methyl group in a pseudoequatorial position then leads
to oxocarbenium ion 81. Ring closure followed by nucleophilic
trapping leads to the minor enantiomer, tetrahydropyran 83. In
this case, deuterium is incorporated into an equatorial position
of the tetrahydropyran ring. Analogous to this enantiomerization
pathway, oxocarbenium ion 84 can isomerize to oxocarbenium
ion 85, which then leads to tetrahydropyran 89. For this pathway,
however, tetrahydropyran 89 retains deuterium in an axial
position in the tetrahydropyran ring. The 0.92 to 1.0 deuterium
scrambling observed in the minor enantiomer is consistent with
the lack of preference for formation of either oxocarbenium 78
or 85. Interestingly, we did not observe trans-tetrahydropyrans
resulting from nucleophilic trapping of either tetrahydropyranyl
cation 79 or 86.27
Figure 9. Loss of optical activity for Prins cyclizations is not due to
Mechanism C.
With a clearly defined mechanistic picture, the effects of
reaction conditions (Table 1) can be further analyzed. The
nucleophilicity of the anion is a key determinant in whether a
loss in optical activity is observed for Prins cyclization reactions.
Weak nucleophilic anions such as trifluoroacetate anion lead
to a loss in optical activity (Table 1, entry 2), whereas stronger
nucleophiles such as the tin-“ate” complex (Table 1, entry 7)
preserve the optical activity of the starting material. This trend
is easily rationalized from the fact that nucleophilic termination
is a competing process to 2-oxonia-Cope rearrangements. More
reactive nucleophiles, therefore, decrease the opportunity for
unselective 2-oxonia-Cope rearrangements. The effects of
temperature shown in Table 1 are also easily rationalized from
Mechanism E. Higher temperatures (entry 1 versus entry 3) are
necessary to access the higher energy intermediates such as
cations 78, 79, and 80 that eventually lead to a loss in optical
activity. Interestingly, solvent was also shown to play a crucial
role in whether loss in optical activity is observed in these
reactions (entry 2 versus entry 5). Prins cyclization promoted
by trifluoroacetic acid in pentane resulted in complete retention
of enantiomeric excess, whereas the same reaction performed
Figure 10. Loss of optical activity for Prins cyclizations is not due to
Mechanism D.
tetrahydropyran 69. Alternatively, a 2-oxonia-Cope rearrange-
ment of oxocarbenium ion 68 should be rapid in this case to
generate the more stable benzylic oxocarbenium ion 72.3e
Oxocarbenium ion 72 would lead to optically active tetrahydro-
pyran 69. If Mechanism D is operable, however, oxocarbenium
ion 72 could also lead to fragmentation products 70 and 71.
Upon recombination, bis-aldehyde 70 could lead to either
tetrahydropyran 73 or 74. In contrast to the crossover experiment
shown in eq 1, this more sensitive crossover experiment relies
only on rotation of bis-aldehyde 70 occurring more rapidly than
recombination with homoallylic cation 71. Prins cyclization of
acetoxy ether 51, however, did not result in any observable
amount of tetrahydropyran 74. With this result in hand, we
deemed Mechanism D extremely unlikely.
Prins cyclization of acetoxy ether 57 resulted in no deuterium
scrambling for the major enantiomer but a 0.92:1.0 mixture of
axial and equatorial deuterium for the minor enantiomer. This
result clearly demonstrates that loss of optical activity in these
Prins cyclization reactions occurs due to a 2-oxonia-Cope
rearrangement by way of a (Z)-oxocarbenium (Mechanism E).26
Rationale for this conclusion is depicted in the detailed
mechanism shown in Figure 11. In this figure, we show
(26) Racemization by Mechanism D would not result in deuterium scrambling.
The microscopic reverse of Mechanism E is also possible in which 2-oxonia-
Cope rearrangement proceeds through the favorable E-oxocarbenium ion,
but with the alkyl substituent in a pseudoaxial orientation.
(27) We did not isolate or observe the trans isomer by 1H NMR. We cannot
rule out the possibility that the trans isomer may be formed in very small
quantity as a minor component.
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Racemization in Prins Cyclization Reactions
A R T I C L E S
Figure 11. 2-Oxonia-Cope rearrangement through a (Z)-oxocarbenium ion leads to loss in optical activity for Prins cyclizations.
Figure 12. Structural features can reduce the rate of 2-oxonia-Cope
Figure 13. Energetics of enantiomerization.
rearrangement.
destabilizing effect of the chloromethyl group. This effect upon
the rate of 2-oxonia-Cope rearrangement allows Prins cyclization
of acetoxy ether 32b to occur with no loss in optical activity.
The same logic can be applied for Prins cyclization of (E)-alkene
32c. In this case, 2-oxonia-Cope rearrangement of an (E)-alkene
resulting in a terminal alkene should be slower than in the
degenerate case (Table 2, entry 3 versus entry 1). In fact,
oxocarbenium ion 94 is predicted to be 22.8 kJ/mol higher in
energy than oxocarbenium ion 93.29,31 Additionally, one of the
two possible pathways leading to racemization shown in Figure
11 (78 to 83) will lead to a diastereomer, not an enantiomer, in
the case of a substituted alkene. A fast, reversible 2-oxonia-
Cope rearrangement is required to allow the (Z)-oxocarbenium
pathway to racemize the substrate.
in dichloromethane underwent partial racemization. In a non-
polar medium, the rate of nucleophilic addition to tetrahydro-
pyranyl cation intermediate 76 (Figure 11) is expected to be
greater due to decreased solvation of the nucleophile and the
electrophile.28
The effects of structural features (Table 2) on the loss of op-
tical activity for Prins cyclizations can also be rationalized from
the mechanism shown in Figure 11. Racemization by Mecha-
nism E relies on 2-oxonia-Cope rearrangements occurring many
times before nucleophilic trapping. Only under these circum-
stances will the higher energy, less-populated (Z)-oxocarbenium
ion intermediates have a noticeable influence on the optical
activity of the tetrahydropyran products. Acetoxy ether 32b
incorporating a chloromethyl substituent does not satisfy these
conditions. Treatment of acetoxy ether 32b with trifluoroacetic
acid will initially generate an oxocarbenium ion intermediate
similar to 90 (Figure 12).3e This higher energy oxocarbenium
ion will then rearrange via tetrahydropyranyl cation 91 to the
more stable oxocarbenium ion 92. Subsequent 2-oxonia-Cope
rearrangement (92 to 90), however, will be slow due to the
Computational studies were performed to further investigate
the pathway associated with Mechanism E. The energy diagram
shown in Figure 13 demonstrates the different energetics
(29) Geometry optimizations were performed with B3LYP/6-31G* as imple-
mented in Gaussian 03 (ref 30). Minima were characterized by their
vibrational frequencies.
(30) Frisch, M. J.; et al. Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford,
CT, 2004.
(31) The unexpectedly large difference in energy between 93 and 94 can be
attributed to more effective stabilization of the oxocarbenium ion in 93 by
π-complex formation with the more highly substituted alkene.
(28) See ref 3e for a similar effect.
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A R T I C L E S
Jasti and Rychnovsky
Figure 14. Oxonia-Cope rearrangement must occur many times for a significant loss in optical purity.
associated with the enantiomerization process (98 to 100) as
opposed to the typical 2-oxonia-Cope rearrangement (95 to
97).29 By utilizing the calculated energies, we can estimate
relative rates of the enantiomerization process versus the rate
of a standard 2-oxonia-Cope rearrangement. The highest activa-
tion barrier for the enantiomerization process is 14.0 kJ/mol
greater than the highest activation barrier for the degenerate
2-oxonia-Cope rearrangement. This difference in activation
energies translates to approximately a 300-fold difference in
rates at room temperature. Therefore, we estimate that the
normal 2-oxonia-Cope rearrangement occurs 300 times faster
than the epimerizing 2-oxonia-Cope rearrangement.
With this calculated difference in rates, we can estimate the
average number of 2-oxonia-Cope rearrangements required to
result in the levels of racemization observed for these Prins
cyclizations. This analysis is depicted in Figure 14a. The rate
of the normal 2-oxonia-Cope rearrangement (101 to 102) is
termed kE, and the rate of the enantiomerization process (101
to ent-102) is represented by kZ. If every molecule on average
underwent one oxonia-Cope rearrangement before nucleophilic
trapping, approximately 0.33% of the material would be
expected to proceed through the higher energy pathway and
result in the enantiomeric tetrahydropyran. For the Prins
cyclizaton shown in Scheme 3, acetoxy ether 57 (>99% ee)
results in tetrahydropyran 58 in 70% ee. In other words, 15%
of the material proceeded through the higher energy 2-oxonia-
Cope rearrangement. If every 2-oxonia-Cope rearrangement
results in 0.33% enantiomerization, on average every molecule
must undergo approximately 45 2-oxonia-Cope rearrangements
(45 repeats) before nucleophilic trapping to result in the observed
loss in enantiomeric excess (Figure 14a). This simplified analysis
does not take into account the fact that the epimerized material
can correct itself through another 2-oxonia-Cope rearrangement
by way of a (Z)-oxocarbenium ion. This process should be
negligible at low levels of racemization but will become more
significant as the amount of the minor enantiomer increases.
When taking this back reaction into account (Figure 14b), a
slightly greater number of repeats (54) are necessary for the
level of racemization illustrated in Scheme 3.32 This analysis
highlights the fact that many 2-oxonia-Cope rearrangements
must occur before nucleophilic trapping for Mechanism E to
result in a significant loss in optical activity.
Conclusion
We have elucidated a pathway involving 2-oxonia-Cope
rearrangements proceeding through (Z)-oxocarbenium ion in-
termediates that lead to a loss in optical purity for Prins
cyclization reactions. These higher energy oxocarbenium ion
intermediates become relevant when poor nucleophilic anions
are used in the Prins cyclization reaction. By modifying reaction
conditions such as solvent and temperature, this undesirable
pathway can be minimized. In addition, structural features such
as electron-withdrawing groups and alkene substitution can
reduce the reversibility of the 2-oxonia-Cope rearrangement and,
therefore, eliminate racemization in the Prins cyclization. These
insights should be useful in expanding the scope and application
of Prins cyclizations in synthesis.
Acknowledgment. This work was supported by the National
Cancer Institute (CA081635) and by a generous gift from the
Schering-Plough Research Institute. We thank Dr. Phil Dennison
for assistance with NMR spectroscopy and Dr. John Greaves
for mass spectrometry.
Supporting Information Available: Experimental details,
complete ref 30, characterization of products, and coordinates
for structures presented in Figures 12 and 13. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA064783L
(32) An expanded table for this calculation is provided in the Supporting
Information.
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13648 J. AM. CHEM. SOC. VOL. 128, NO. 41, 2006