Racemization in Prins Cyclization Reactions

Abstract

Isotopic labeling experiments were performed in order 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

The Prins cyclization¹ is a very powerful synthetic transformation to rapidly assemble tetrahydropyran rings.^2,3 Tetrahydropyran 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, we illustrate the existence of a third racemization pathway and elucidate its mechanism.

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 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 1.

Stereochemical Outcome for Prins Cyclizations

Another important feature for a synthetically useful transformation is the ability to convert optically active starting materials into optically active products. Although typically proceeding with high stereochemical fidelity, the Prins cyclization reaction has at times been plagued by racemization.^8,13 Willis has 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 tetrahydropyran 5 (Mechanism A). Due to this solvolysis mechanism, Prins cyclization reactions utilizing electron-rich aromatic substrates are often problematic.^8a

Figure 2.

Loss of Enantiomeric Excess in Prins Cyclizations of Electron-Rich Benzylic Homoallylic Alcohols (Mechanism A)

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 hydrocinnamaldehyde and acetic acid led to tetrahydropyran 9 in 67% 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 hydrocinnamaldehyde to generate oxocarbenium ion 12 and liberate a molecule of water. Oxocarbenium ion 12 can then undergo a 2-oxonia-Cope rearrangement^14,15 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, Mechanism B relies on the presence of water. Direct Prins cyclizations utilizing homoallylic alcohols and aldehydes generate 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.

Figure 3.

Racemization of Prins Cyclization Products by Symmetric 2-Oxonia-Cope Rearrangement (Mechanism B)

Recently, we have 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 oxocarbenium 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 cyclization 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. Mechanism B also was considered unlikely because symmetric tetrahydropyran products were not observed in either reaction.

Figure 4.

Unusual Racemization in Prins Cyclizations

In this article, we describe experiments designed to elucidate a third mechanism for racemization in Prins cyclization reactions. 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 or not the initial enantiomeric excess of the starting material is preserved.

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 cyclopropyl 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.

Figure 5.

Racemization of Prins Cyclization Products By Achiral Cyclobutyl Cation Intermediate (Mechanism C)

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 expected to occur in an unselective manner leading to a loss in enantiomeric excess for Prins cyclization reactions.

Figure 6.

Racemization of Prins Cyclization Products Due to Homoallylic Cation Intermediate (Mechanism D)

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 isomerization 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 cyclizations.²⁰

Figure 7.

Racemization of Prins Cyclization Products Due to E/Z Isomerization and 2-Oxonia-Cope Rearrangement (Mechanism E)

Results

The Effect of Reaction Conditions and Substrate Structure on Loss of Optical Activity in Prins Cyclizations

The loss 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%).

Table 1.

Effect of Reaction Conditions on Loss of Optical Activity in Prins Cyclizations

Entry	Lewis Acid	X	Solvent	Temp	% Yielda	% ee 31b
1	TFA	-O2CCF3c	TFA	55 °C	74	66
2	TFA	-O2CCF3c	TFA	25 °C	72	77
3	TFA	-O2CCF3c	TFA	0 °C	73	84
4	TFAd	-O2CCF3c	CH2Cl2	25 °C	78	84
5	TFAd	-O2CCF3c	pentane	25 °C	80	91
6	BF3·OEt2e	-O2CCH3	CH2Cl2	25 °C	86	77
7	SnBr4e	-Br	CH2Cl2	25 °C	75	91
8	TMSOMse	-OMs	CH2Cl2	25 °C	30	68
9f	TFA	-O2CCF3c	TFA	25 °C	47	71

^aYield of product after flash chromatography.

^bEnantiomeric excess determined by HPLC using a Chiracel OD-H column. Authentic racemates were synthesized by cyclization of racemic acetoxy ether.

^cAnalysis was conducted after hydrolysis of the trifluoroacetate with K₂CO₃/MeOH.

^d10 equivalents of TFA were employed.

^e3 equivalents of Lewis acid was employed.

^fDirect Prins cyclization of corresponding homoallylic alcohol and aldehyde.

In addition to reaction conditions, substrate structure played an important role in whether or not optical activity was preserved in Prins cyclization reactions (Table 2). By utilizing a chloromethyl substituent (entry 2) as opposed to an alkyl substituent (entry 1), a total retention of enantiomeric excess was observed 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 section.²²

Table 2.

Effect of Substrate Structure on Loss of Optical Activity in Prins Cyclizations

Entrya	SM	R1	R2	%ee 32b	% Yieldc	%ee 33d
1	32a	-n-propyl	-H	91	70	78
2	32b	-CH2Cl	-H	91	62	91
3	32c	-n-propyl	-CH3	99	82	99

^aThe reaction conditions employed in Table 2 are slightly different than 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.¹⁷

^bEnantiomeric excess for acetoxy ethers was established from starting homoallylic alcohols. Alcohols were assayed by either chiral HPLC or GC analysis.

^cYield of product after flash chromatography.

^dEnantiomeric excess determined by either chiral HPLC or GC analysis.

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 Equation 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 tetrahydropyran 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 equivalents 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 equation 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 reactions that would result from these higher energy intermediates.

(1)

We were intrigued by the result shown in Table 2 (entry 3) in which Prins cyclization of acetoxy ether 32c proceeded with 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 Equation 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. In order to unambiguously determine the mechanism for racemization in Prins cyclizations, we designed three isotopic labeling experiments to test the validity of the proposed mechanisms.

(2)

(3)

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 is 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

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 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. In this case, we observed complete retention of deuteration at the aldehyde position.

One additional isotopically labeled substrate was prepared in order 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.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. Hydroboration 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. In order 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, tetrahydropyran 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 to 0.92 ratio (Figure 8).

Figure 8.

²H NMR Spectra For Tetrahydropyran 59 and Tetrahydropyran 60

Discussion

Prins cyclization of the differentially labeled acetoxy ethers 43, 51, and 57 provides definitive evidence regarding the roles 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 rationale for this conclusion. Treatment of acetoxy ether with trifluoroacetic acid generates oxocarbenium ion 61. If oxocarbenium 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 intermediate 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.

Figure 9.

Loss of Optical Activity for Prins Cyclizations is not due to Mechanism C

Having ruled out one fragmentation pathway, we turned our attention to Mechanism D. In order to probe Mechanism D, we utilized acetoxy ether 51 as a 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 tetrahydropyran 69. Alternatively, a 2-oxonia-Cope rearrangement 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 tetrahydropyran 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 Equation 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.

Figure 10.

Loss of Optical Activity for Prins Cyclizations is not due to Mechanism D

Prins cyclization of acetoxy ether 57 resulted in no deuterium scrambling for the major enantiomer but a 0.92 to 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 illustration, we have shown 2-oxonia-Cope rearrangements and Prins cyclizations occurring through a common tetrahydropyranyl cation intermediate⁹ in order provide a complete mechanistic picture. Treatment of acetoxy ether 57 with trifluoroacetic acid initially generates oxocarbenium ion 75. Oxocarbenium ion 75 can then cyclize to generate tetrahydropyranyl cation 76 which upon nucleophilic trapping results in tetrahydropyran 77. Alternatively, tetrahydropyranyl 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 rearrangements proceed through (Z)-oxocarbenium ion intermediates. 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 oxocarbenium ion can then lead to oxocarbenium ion 80 by way of a 2-oxonia-Cope rearrangement. Carbon-carbon bond rotation in order to place the methyl group in a pseudo equatorial 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 11.

2-Oxonia Cope Rearrangement Through a (Z)-Oxocarbenium Ion Leads to Loss in Optical Activity For Prins Cyclizations

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 or not 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 vs. 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 or not loss in optical activity is observed in these reactions (entry 2 vs. entry 5). Prins cyclization promoted by trifluoroacetic acid in pentane resulted in complete retention of enantiomeric excess whereas the same reaction performed in dichloromethane underwent partial racemization. In a nonpolar medium, the rate of nucleophilic addition to tetrahydropyranyl 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 optical activity for Prins cyclizations can also be rationalized from the mechanism shown in Figure 11. Racemization by Mechanism E relies on 2-oxonia-Cope rearrangements occurring many times before nucleophilic trapping. Only under these circumstances will the higher energy, less-populated (Z)-oxocarbenium ion intermediates have a noticable 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 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 vs. 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.

Figure 12.

Structural Features Can Reduce the Rate of 2-Oxonia-Cope Rearrangement

Computational studies were performed to further investigate the pathway associated with Mechanism E. The energy diagram shown in Figure 13 demonstrates the different energetics 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 activation 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.

Figure 13.

Energetics of Enantiomerization

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 k_E and the rate of the enantiomerization process (101 to ent-102) is represented by k_Z. 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.

Figure 14.

Oxonia-Cope Rearrangement Must Occur Many Times for a Significant Loss in Optical Purity

Scheme 3.

Synthesis and Prins Cyclization of Deuterated Acetoxy Ether 57

Conclusion

We have elucidated a pathway involving 2-oxonia-Cope rearrangements proceeding through (Z)-oxocarbenium ion intermediates 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 the of 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.

Scheme 2.

Synthesis and Prins Cyclization of Deuterated Acetoxy Ether 51