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. Author manuscript; available in PMC: 2023 May 6.
Published in final edited form as: Org Lett. 2022 Apr 21;24(17):3217–3222. doi: 10.1021/acs.orglett.2c01004

Diastereoselective substitution reactions of acyclic β-alkoxy acetals via electrostatically stabilized oxocarbenium ion intermediates

Amanda Ramdular †, K A Woerpel †,*
PMCID: PMC9817112  NIHMSID: NIHMS1860688  PMID: 35446592

Abstract

Substitution reactions of acyclic β-alkoxy acetals proceeded with generally high diastereoselectivities (>90:10) to form the anti product. Mechanistic experiments supplemented with computational studies suggest that, upon activation of the acetal, the resulting oxocarbenium ion is electrostatically stabilized by the β-alkoxy group. This stabilization defines the conformation of the reactive intermediate, which can be attacked preferentially from the more exposed face, leading to the observed products.

Graphical Abstract

graphic file with name nihms-1860688-f0003.jpg

The choice of protecting groups in carbohydrate chemistry has consequences on the stereochemical courses of substitution reactions.1–4 Acyloxy groups on the neighboring carbon atom can control stereoselective reactions of carbohydrates by forming fused bicyclic dioxocarbenium ion intermediates that are subsequently opened by a nucleophile.1-6 Participation by a neighboring acyloxy group can also control the stereoselectivities of reactions involving acyclic acetals.7 By contrast, alkoxy groups are generally considered to not participate in substitution reactions of carbohydrates through formation of onium ions4,8-11 because these intermediates would not be stabilized by electron delocalization as observed for acyloxy groups, and, many cases, such onium ion intermediates would be strained.12

In this manuscript, we demonstrate that alkoxy groups two carbon atoms away from an acetal can control the stereochemical course of substitution reactions. Substitution reactions of acetals bearing β-alkoxy groups proceeded with high diastereoselectivities (dr >90:10) in many cases (eq 1). The products would be the same as those expected from chelation-controlled additions to β-alkoxy, α-substituted aldehydes,13-15 but such intermediates cannot be invoked in the case of acetal substitution reactions. The alkoxy groups appear to stabilize the oxocarbenium ion intermediates by electrostatic interactions to form four-membered-ring structures resembling 2. This participation defines the conformation of the intermediate and thus establishes which face of the oxocarbenium ion is attacked.

graphic file with name nihms-1860688-f0004.jpg

The influence of a β-alkoxy group on the stereoselective substitution reactions of acetals was first observed for the Lewis acid-mediated reaction of acetal 4, which possesses a β-benzyloxy group, with a nucleophile, the silyl ketene acetal 5 (Table 1). The anti stereoisomer 6, whose structure was established by X-ray crystallography of a derivative,16 was favored regardless of solvent, temperature, or Lewis acid. Reactions in more and less polar solvents gave the product with similar diastereoselectivity.17,18 The reactions were the cleanest and highest-yielding using Me3SiOTf and EtCN at −78 °C, however. Although nitrilium-ion intermediates17,19 or covalent triflates could be responsible for stereoselectivity,19 the consistent selectivities observed under all conditions suggest that these intermediates are not involved in these reactions.

Table 1.

Optimization of reaction conditions.

graphic file with name nihms-1860688-t0008.jpg
solvent Lewis acid temp (°C) dr (anti:syn)
EtCN Me3SiOTf −78 91 : 9
EtCN BF3·OEt2 −78 90 : 10a
EtCN TiCl4 −78 88 : 12b
EtCN SnC14 −78 90 : 10
EtCN TfOH −78 88 : 12b
EtCN BC13(1 M in C6H14) −78 91 : 9
EtCN AlCl3 −78 91 : 9
EtCN Me3SiOTf −40 91 : 9
CH2Cl2 Me3SiOTf −78 90 : 10
CH2Cl2 Me3SiOTf −40 82 : 18
MePh Me3SiOTf −78 88 : 12
C6Hl4 Me3SiOTf −78 88 : 12
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a

Reaction conducted using 4 equiv of BF3·OEt2 and proceeded to 40% conversion.

b

Reaction produced multiple side products.

Experiments to evaluate the generality of the stereoselective substitution reactions involved determining the optimal acetal and protecting group for the β-hydroxyl group. These β-alkoxy acetals were sensitive to handling and storage, suggesting some interaction between the alkoxy group and the acetal functional group.20-22 Ethyl acetals, because of their ease of synthesis, purification, and lower sensitivity to hydrolysis than methyl acetals,23 proved to be optimal. Methyl or benzyl acetals were particularly sensitive to handling and storage,24 which primarily led to decomposition and low conversion using these substrates. In contrast to specificity with respect to the acetal, the reactions were general for several β-alkoxy groups. Reactions of alkyl-, benzyl-, and silyl-protected β-hydroxy acetals afforded the anti products with >90:10 diastereomer ratios (Scheme 1).16 The stereoselectivity was sensitive to the electron-donating ability of the benzyloxy group, however.25,26 Substitution of acetal 8 bearing a PMB-protected hydroxyl group produced the product as a single diastereomer (dr >99:1), which is higher stereoselectivity than that observed for the benzyl-protected acetal 4 (dr = 91:9).27 By contrast, when the benzyl group was substituted with an electron-withdrawing nitro group, lower stereoselectivity (dr = 82:18) was observed.27 Considering that the size of the protecting group does not affect stereoselectivity, it is unlikely that a steric interaction between the nucleophile and the protecting group is involved. Instead, an electronic interaction between the oxygen atom of the alkoxy group and the electrophilic oxocarbenium ion carbon8,20,28 is most likely responsible for the observed diastereoselectivity.29

Scheme 1. Influence of alkoxy group on diastereoselectivity.

Scheme 1.

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Although the anti stereochemistry of the product is consistent with chelation-controlled reactions involving the oxygen atom of the protecting group and the acetal group, chelation is not possible. These reactions, which likely involve oxocarbenium ion intermediates,13,14,30 would require the Lewis acid to complex to the formally positively charged oxygen atom.31 In the case of acetal 7, chelation would require complexation to a silyloxy group, which is generally disfavored.14,32

Reactions of benzyloxy acetal 4 with different nucleophiles showed that diastereoselectivity depends on the size of the nucleophile.12,33 Unlike the reactions of other acetals,20,29,31,34,35 the reactivity of the nucleophile, as defined by the N parameter,36,37 does not correlate consistently with stereoselectivity. Comparisons of sterically similar nucleophiles with different reactivities shows either small increases or decreases in stereoselectivity. By comparison, stereoselectivity correlates more strongly with the size of the nucleophile. Reactions with silyloxy-substituted alkenes with substituents at the nucleophilic carbon atom gave the highest stereoselectivities (Table 2, entries 1 and 2). Nucleophiles without those substituents showed lower stereoselectivity (entry 6), even though the absence of such groups would not change the reactivity of the carbon–carbon double bond.36,37 Methallylmetal nucleophiles gave similar stereoselectivities regardless of their different reactivities (entries 3 and 5). In all cases, reactions with monosubstituted alkenes occurred with lower selectivities (entries 4 and 7). These trends do not follow what would be expected based upon any correlation between reactivity and selectivity.12 Instead, steric interactions play a larger role in determining diastereoselectivity in this series.

Table 2.

Influence of nucleophilicity and size on diastereoselectivity.

graphic file with name nihms-1860688-t0009.jpg
Entry N–[M] N 36,37 Prod. dr (anti:syn) % yield
1 Me2C=C(OMe)(OTBS), 5 9.1a 6 91 : 9 94
2 Me2C=C(Ph)(OTBS) N/A 19 93 : 7 54
3 H2C=C(Me)CH2SnBu3 7.48 20 73 : 27 62
4 H2C=CHCH2SnBu3 5.46 21 58 : 42 68
5 H2C=C(Me)CH2SiMe3 4.41 20 74 : 26 77
6 H2C=C(tBu)(OTBS), 23 3.78a 22 66 : 34 69
7 H2C=CHCH2 SiMe3 1.68 21 52 : 48 84
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a

N parameter for the corresponding Me3Si-protected nucleophile.

An experiment was performed to confirm that the stereoselectivities of the reactions were not governed by rates of diffusion.38 A competition experiment where two nucleophiles competed for the oxocarbenium ion intermediate formed from benzyloxy acetal 4 gave only the product from the more reactive alkene nucleophile, 5 (eq 2). The product ratio is consistent with a five-orders-of-magnitude difference in reactivity, indicating that these reactions likely occur below the diffusion rate limit.38,39 This observation contrasts with the results for cyclic oxocarbenium ions, where π-systems of different nucleophilicity reacted with oxocarbenium ion intermediates at similar rates, suggesting that these rates were limited by diffusion.38

graphic file with name nihms-1860688-f0005.jpg

The isolation of side products from the substitution reaction of p-methoxybenzyl-substituted acetal 8 suggested the origin of stereoselectivity. In addition to forming the substitution product 14, the reaction of acetal 8 gave products 28–30 (Scheme 2). Such products were not formed with the benzyl ether 4 or the p-nitrobenzyl ether 11. When the reaction was repeated in more dilute solutions (0.01 M), no substitution product 14 was formed, and only compounds 28–30 could be identified. The major side product was oxetane 30. Formation of this oxetane would require loss of both ethoxy groups of the acetal 8, possibly through oxetanium ion 25: one ethoxy group by substitution with the β-oxygen atom accompanied by loss of the p-methoxybenzyl group,40-42 and the other ethoxy group by substitution by the nucleophile, 5, on acetal 27. Side products 28 and 29 resulted from transfer of the p-methoxybenzyl group lost from the starting material to a nucleophile. The Ritter product,43 28, would be formed upon reaction with the solvent, EtCN, and ester 29 would be formed by reaction with the silyl ketene acetal 5. Because amide 28 and ester 29 must be formed by reactions of less reactive, neutral nucleophiles,37,43 it is likely that formation of these products requires reactions with a highly electrophilic intermediate such as a carbocation, 26.44

Scheme 2. Reactive pathways of the electrostatically stabilized oxocarbenium ion intermediate 24.

Scheme 2.

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aYield reported of impure compound.

The formation of products 28 and 29 from the p-methoxybenzyl-protected acetal 8 cannot be attributed to initial deprotection of the acetal followed by subsequent reactions of the resulting products (Scheme 2).45 If deprotection occurred first to give the deprotected alcohol, 10, substitution should have occurred to form ester 16 instead (Scheme 1). This product was not formed. Deprotection can also be discounted because treatment of PMB-protected menthol, 31, under the reaction conditions gave p-methoxybenzyl alcohol (32) and menthol and no other products (eq 3).45 Because the addition products, 28 and 29, were not observed in this reaction, the deprotection of PMB-protected alcohols45 likely does not form the same reactive intermediate, a benzylic carbocation, 26.

graphic file with name nihms-1860688-f0006.jpg

The formation of products 28–30 can be explained by considering the formation of an oxetanium ion intermediate 25 in the case of the p-methoxybenzyl-substituted acetal 8 (Scheme 2). This oxetanium ion intermediate, which may or not be the major intermediate formed, could react by direct displacement to form the substitution product 14, or it could undergo fragmentation to give the p-methoxybenzyl cation 26 and oxetane 27.41,46 The cation 26 could be trapped by the weaker nucleophiles to form the amide 28 and the ester 29. The oxetane 27, in turn, could undergo Lewis acid-catalyzed nucleophilic substitution to give oxetane 30. The formation of 14 at higher concentrations is consistent with the proposal that the reaction to give 14, Pathway A, is a bimolecular reaction of an intermediate such as 24. By contrast, the formation of products 28–30 would result from initial intramolecular fragmentation of 25 (Pathway B) to give a carbocationic intermediate such as 26. At lower concentrations, Pathway A would be slower, leading to more products formed from Pathway B.

Studies with a related substrate, a β-hydroxy acetal with an isopropyl group, 33,47 provided additional insight into what factors might contribute to stereoselectivity. The reaction with the nucleophile 5 gave the substitution product 34 with low stereoselectivity (eq 4). This result suggests that, with the acetal 4, the alkoxymethyl group likely adopted a position in the reactive intermediate where it was the larger group at the α-carbon atom, while the methyl group was the smaller substituent. In the case of acetal 33, the isopropyl group may occupy a similar space as the hydroxymethyl group would, leading to the low diastereoselectivity observed.

graphic file with name nihms-1860688-f0007.jpg

A model can be proposed that accommodates these experimental results. Computational studies (B3LYP/6-31G*)48 suggest that the oxocarbenium ion derived from acetal 4 adopts a conformation resembling 35. This conformation, with the four-membered-ring core structure, is flattened compared to the structure of a cyclobutane, a general trend observed for the conformations of four-membered-ring ethers.49 Other conformers, such as the conformer 36 where the two hydrogen atoms are eclipsed, are considerably higher in energy, suggesting that transition states through such intermediates would be inherently high energy. Both conformers 35 and the more sterically hindered conformer 36 place the oxygen atom of the alkoxymethyl group about 2.2 Å from the cationic carbon atom.48 This distance is considerably greater than the carbon–oxygen bond lengths of trivalent oxonium ion such as the Et3O+ cation (1.5 Å).50 The sum of the bond angles at the cationic carbon atom is 360°, which indicates that this atom is trigonal, not tetrahedral, so a new covalent bond has not been formed in this intermediate. Instead, this four-membered arrangement of atoms maximizes electrostatic interactions between the cationic carbon atom and the oxygen atom, as illustrated for 35. This electrostatic stabilization29,48 has been suggested computationally for β-alkoxy oxocarbenium ions,25 but it has only been identified experimentally for γ-alkoxy oxocarbenium ions through a five-membered arrangement of atoms.12 The conformation of oxocarbenium ion 35 resembles the structure observed in the solid state for β-alkoxy aldehydes,21,22 which would also have considerable positive charge on the carbonyl group’s carbon atom.21,22 The electrostatic interaction between the carbon atom of 35 and the alkoxy group makes the face bearing the alkoxy group less sterically accessible than the face with the methyl group. In the case of small nucleophiles, minimal steric interactions develop upon attack at either diastereoface, leading to low diastereoselectivity. As the nucleophile becomes larger, however, interactions with the alkoxy group become more significant, leading to preferential attack from the side of the smaller methyl group, as illustrated in transition state 35. In the case of the isopropyl-substituted substrate 33, the two faces of the intermediate become more similarly sterically hindered, leading to lower stereoselectivity.

The trend of diastereoselectivity for the benzyl-protected acetals is consistent with an electrostatic interaction controlling diastereoselectivity. Computational studies (B3LYP/6-31G*)48 indicate that, among the three benzyloxy-substituted oxocarbenium ions, the distance between the carbon atom of the oxocarbenium ions and the oxygen atom of the alkoxy group is shortest for the p-methoxy-substituted oxocarbenium ion, 37, and longest for the p-nitro-substituted one, 38 (Figure 1). The close interaction in the p-methoxy-substituted oxocarbenium ion 37 would be more likely to lead to formation of an oxetanium ion, which is consistent with the experimental observation of products obtained in that reaction (Scheme 2). The longer distance in carbocation 38 changes the conformation of the oxocarbenium ion enough that the two faces are no longer as well differentiated and the face bearing the alkoxy group is no longer as sterically hindered. As a result, the nitro-substituted acetal would react with lower diastereoselectivity.

Figure 1. Conformations of the oxocarbenium ion derived from acetal 4.

Figure 1.

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In summary, β-alkoxy groups can control the stereochemical outcomes of substitution reactions of acyclic acetals by stabilizing an oxocarbenium ion intermediate electrostatically. This stabilized intermediate, which has diastereofaces with different steric requirements, underwent nucleophilic addition with sterically larger nucleophiles to form the products with high diastereoselectivity. These reactions can be used to control the facial selectivities of substitution reactions, which should make them useful in stereoselective synthesis.51,52

Supplementary Material

Benzyloxy SI

Figure 2. Change in distance between C3 to O with aryloxy groups of varying electron-donating ability.

Figure 2.

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ACKNOWLEDGMENT

This research was supported by National Institutes of Health, National Institute of General Medical Sciences (1R01GM129286). We acknowledge NYU’s Shared Instrumentation Facility and the support provided by NSF award CHE-01162222 and NIH award S10-OD016343. We thank Dr. Chin Lin (NYU) and Dr. Chunhua (Tony) Hu (NYU) for their help with NMR and X-ray data, respectively.

Footnotes

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

Experimental procedures, characterization of new compounds, stereochemical proofs, kinetic data, X-ray data, and 1H and 13C NMR spectra of new compounds (PDF)

Crystallographic files for compound S20 (CIF)

Accession Codes

CCDC 2159762 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_re-quest@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

The authors declare no competing financial interest.

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Associated Data

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Supplementary Materials

Benzyloxy SI
NIHMS1860688-supplement-Benzyloxy_SI.pdf (5.8MB, pdf)

RESOURCES