Using neighboring-group participation for acyclic stereocontrol in diastereoselective substitution reactions of acetals

Abstract

Neighboring-group participation of an ester enabled stereocontrol in substitution reactions of acyclic acetals. The ester group formed a trans-fused dioxolenium ion intermediate, which underwent a substitution reaction at the acetal carbon atom to afford the product with high diastereoselectivity. Neighboring-group participation was confirmed by isolating dioxolane products resulting from nucleophilic addition at C-2 of a 1,3-dioxolenium ion intermediate. Using a pivaloate ester as the participating group in combination with strong nucleophiles produced substitution products with diastereoselectivities of ≥90:10.

Graphical Abstract

Neighboring-group participation is a widely used approach to control stereochemistry in substitution reactions of carbohydrate compounds.^1–3 Most commonly, acyloxy groups, namely the acetate, benzoate, and pivaloate esters,^1,4,5 are used to favor the 1,2-trans products with high selectivity.^1,4,6 Neighboring-group participation has not emerged as a useful approach for controlling stereochemistry in reactions involving acyclic acetals, however.^7–18 The use of neighboring-group participation to control stereochemistry in acyclic systems, as illustrated in eq 1, would be significant because it would provide access to the products expected from nucleophilic additions to α-alkoxy aldehydes that would be governed by the Felkin–Anh or related^19–21 stereochemical models. Such transformations, however, often give products with modest diastereoselectivity.^8,16,22–24

(1)

In this paper, we demonstrate that neighboring-group participation of an ester group adjacent to an acetal can provide high diastereoselectivity in substitution reactions. These reactions likely proceed through five-membered ring intermediates, such as 2, which then undergoes nucleophilic ring opening to provide the 1,2-syn product 3 (eq 1).

The rates of hydrolysis of acyclic acetals indicated that an acyloxy group near an acetal can influence the rate of ionization by neighboring-group participation, as observed for cyclic acetals.²⁵ The rates of hydrolysis of acetals 4a,d and 7a,b bearing α-acyloxy groups were accelerated compared to ionization of an acetal with an α-methoxy group, 6 (Scheme 1). This rate acceleration likely reflects stabilization of developing positive charge by neighboring-group participation, considering that the magnitude of the rate acceleration is similar to that observed for carbohydrates.^5,26 As the donating ability of the acyl group increased,⁵ the rate of ionization increased, which is consistent with participation by the carbonyl group (eq 1). The similar rates of hydrolysis of acetals bearing alkyl and aryl groups (i.e., 4a and 4d) indicate that the generation of the cationic intermediates in these reactions is dominated by the electron donation from the acyloxy group.^1,27 This observation contrasts with studies of β-phenyl substituted acetals, where the phenyl group inductively destabilized the cationic intermediate, leading to a >20-fold slower ionization compared to an acetal without a phenyl group.²⁸

Scheme 1.

Rate of hydrolysis of acetals with different neighboring-groups.

More direct evidence supporting the participation of the acyloxy group was obtained upon treatment of pivaloate esters 4a–c with Me₃SiCN in the presence of a Lewis acid (Scheme 2).²⁹ The formation of the dioxolane products 8a–c represents an unusual case of nucleophilic addition at the participating pivaloyl group, which is generally sterically disfavored.^1,4,5,30,31 The dioxolane-substituted products 8a and 8c were obtained as 97:3 mixtures of diastereomers (Scheme 2).²⁵ The relative stereochemical configuration of these compounds were assigned by NOE measurements, and the structure of 8c was confirmed by X-ray crystallography. These experiments reveal that the dioxolane favors a 1,2-trans relationship between the ethoxy and aryl groups (i.e. 11 in Scheme 3), likely because these groups would be eclipsed in the essentially planar five-membered ring intermediate in the cis isomer (9).³² The stereochemical configuration at the nitrile-bearing carbon atom can be explained as resulting from preferential nucleophilic attack on the major dioxolenium ion 11 from the more accessible face. Substitution reactions of acetal 4b with Me₃SiCN, however, showed a decrease in diastereoselectivity of the dioxolane product (Scheme 2). The amount of the trans diastereomer of dioxolenium ion 11 (Scheme 3) with the smaller substituent decreases likely because the unfavorable eclipsing interactions are not as prominent between the alkyl and ethoxy groups.

Scheme 2.

Reactions of pivaloate esters to give dioxolane products.

Scheme 3.

Equilibrium of oxocarbenium and dioxolenium ions.

The high diastereoselectivities observed for the formation of dioxolanes 8a and 8a (Scheme 2) suggests that formation of dioxolenium ion 11 (Scheme 3) is reversible. If this ionization step were not reversible, it would need to differentiate the two diastereotopic ethoxy groups, which is unlikely.³³ This reversibility would require that the acyclic oxocarbenium ion 10 was not too high in energy compared to the dioxolenium ions 9 and 11 (Scheme 3).^2,3,34,35

Experiments with an acetal bearing a tert-butyl carbonate group provided additional evidence that a dioxolenium ion was an intermediate in these reactions.³⁶ Upon treatment of carbonate 12 with a Lewis acid or SiO₂ gel, the cyclic carbonate 14 was formed (Table 1), likely upon release of the tert-butyl cation from the dioxolenium ion 13.³⁶ These products were prone to epimerization upon purification using SiO₂, so the diastereoselectivities are likely not representative of the kinetic products of cyclization.

Table 1.

Formation of cyclic carbonate.

acid	nucleophile	d.r. (anti:syn)	% yield
Me3SiOTf	None	96:4	71
SiO2	None	76:24	39
Me3SiOTf	H2C=CHCH2SnBu3	76:24	9a

^aThe low yield resulted from difficulty purifying the product.

With the demonstration that neighboring-group participation was possible with acyclic acetals, attention turned to the development of the ring-opening of dioxolenium ions with carbon nucleophiles. The successful formation of acetal substitution products using allyltributylstannane as the nucleophile depended upon the reaction conditions. Ionization of acetal 4a bearing the pivaloyl protecting group using numerous Lewis acids were unsuccessful, likely because of the strongly electron-withdrawing nature of the acetoxy group.^5,26 The Lewis acids BF₃·OEt₂, SiCl₄, SnCl₄, and Et₃SiOTf activated the acetal group, but only at temperatures above −40 °C. The use of Me₃SiOTf proved to be most successful, although TiCl₄ and Bi(OTf)₃ could also be used to form the desired products at low temperatures. The fact that the presence of the triflate ion was not necessary for high selectivity argues against a covalently bound triflate species as a reactive intermediate. These reactions provided both the desired product 15a and the undesired dioxolane 16a. With more polar solvents MeCN and EtCN, significant quantities of the undesired dioxolane product 16a were formed (Table 2).^37,38 The major diastereomer of the acyclic substitution product 15a in the nitrile solvents was the same as for reactions with CH₂Cl₂ as the solvent, which indicates that there is no special influence of the nitrile solvent.^39–41 The non-polar solvent toluene gave the highest proportion of the desired acyclic product 15a (Table 2). This observation is consistent with studies of product distributions as a function of solvent for carbohydrates with neighboring acyloxy groups.³⁷ Lower concentrations (0.1 M), which favor neighboring-group participation in reactions of carbohydrates,⁴² gave the highest stereoselectivities. At temperatures below −45 °C, it is likely that ionization was too slow (Table 2).^43,44

Table 2.

Optimization of reaction conditions.

solvent	polarity (ET)	temp. (°C)	15a:16a	d.r. (15a)	% yield (15a)
MeCN	46	−40	47:53	75:25	39
EtCN	43.7	−78	49:51	80:20	36
CH2Cl2	41	−45	70:30	90:10	53
CH2Cl2	41	−78	68:32	90:10	61
MePh	33.9	−45	95:5	90:10	82
MePh	33.9	−78	>99:1a	82:18	29

^aReaction proceeded to 30% completion.

A control experiment indicated the importance of neighboring-group participation for obtaining the products with high diastereoselectivity. The substitution reaction of acetal 6 (eq 3) afforded the substitution product with no selectivity. This result confirms that reactions through an open transition state resembling the Felkin–Anh transition state will not be stereoselective.

(3)

Substitution reactions of pivaloyl-substituted acetals 4a, 18, and 19 with different alkoxy groups (Scheme 4) under the optimized conditions provided additional support that these reactions involve equilibration of dioxolenium ions 9 and 11 and acyclic oxocarbenium ion 10 (Scheme 3). Substitution reactions of the methyl acetal 18 gave small quantities of two dioxolane products, 22 and 23. The benzyl acetal 19 reacted with the highest diastereoselectivity, but the yields were lower because this acetal was particularly prone to decomposition. The observation that increasing the size of the alkoxy groups of the acetal increased the diastereoselectivity of the products was not expected (Scheme 4). The fact that the ethyl acetal 4a reacted with lower diastereoselectivity (90:10, Scheme 4) than observed for the reaction with Me₃SiCN (97:3, Scheme 2) suggests that an equilibrium is established with the dioxolenium ions 9 and 11 and the acyclic oxocarbenium ion 10 (Scheme 3). Formation of both isomers of product requires that both the cis- and tras-substituted dioxolenium ions 9 and 11 are present (Scheme 3), and that the product ratio reflects different rates of reaction of these intermediates with nucleophiles.

Scheme 4.

Influence of the size of the alkoxy group on selectivity.

The ability of a group to participate exerted a strong influence on the outcomes of these substitution reactions.^5,26 For the ester participating groups, increasing the donating ability of the participating group, as defined by the kinetic studies (Scheme 1), resulted in the increased formation of the undesired dioxolane regioisomer (in particular for acetal 7b, Table 3). It is likely that the dioxolenium ion is more stabilized by the strong participating group, so the nucleophile cannot readily open it to form the acyclic product. By contrast, reactions of the carbamate 7d did not give products derived from attack at C-2 of the dioxolenium ion 28, likely because it is too stabilized.²⁶

Table 3.

Influence of neighboring-groups on selectivity.

acetal	R	Major prod	ester: dioxolane	d.r. (ester)	% yield (ester)
7a	4-O2NC6H4	24a	>99:1	78:22	65
4a	tBu	15a	70:30	90:10	53
7c	C6H5	25a	79:21	85:15	54
7b	4-MeOC6H4	26b	<1:99	–	72a
7d	NH tBu	27a	>99:1	78:22	66

^aYield of dioxolane product, 26b.

The stabilizing influence of the acyloxy group is reflected in both the reactivity and stereoselectivity of these reactions. Attempted substitution reactions with nucleophiles that are weaker than allyltributylstannane,⁴³ such as allyltrimethylsilane and methallyltrimethylsilane, did not occur in PhMe. These reactions did proceed in CH₂Cl₂, however, producing the substitution products with little stereoselectivity (Table 4). These results can be understood by postulating an increased concentration of the oxocarbenium ion 10 compared to the dioxolenium ion 11 in the more polar solvent (Scheme 5). This change in concentration would result because dioxolenium ions, which have lower charge density, would be favored in the non-polar medium. In the more polar solvent, the oxocarbenium ion 10, although formed in only small amounts, would be electrophilic enough to react with the allylic silane nucleophiles. Considering that these reactions would proceed through open carbocations, it is reasonable that they would react with comparable diastereoselectivity to the reaction of the methoxy substrate (eq 3).³⁵ By contrast, reactions with a stronger nucleophile, methallyltrimethylstannane,⁴³ occurred with higher diastereoselectivity (Table 3). The increased diastereoselectivity observed with increasing the nucleophilicity of the nucleophile suggests that this reaction proceeds through the stabilized intermediate 11 (Scheme 5).⁴⁵

Table 4.

Influence of nucleophile and solvent on reactivity.

Nu–M	N factor43	solvent	product	d.r.	% yield
H2C=C(Me) CH2SnBu3	7.48	MePh	29	93:7	53
H2C=CHCH2 SnBu3	5.46	MePh	15	90:10	82
H2C=C(Me) CH2SiMe3	4.41	CH2Cl2	29	70:30	89
H2C=CHCH2 SiMe3	1.68	CH2Cl2	15	54:46	87

Scheme 5.

Nucleophiles react through different pathways.

The scope of the reaction demonstrates that the general features of the substitution reaction hold for other substrates. Substitution reactions of acetals 4a–f demonstrated that increasing the steric demand of the side chain in comparison to the alkoxy group increased the diastereoselectivity of the reaction (Scheme 6). This correlation of steric size and reactivity could reflect a decreased preference for the trans diastereomer of the dioxolenium ion with smaller substituents. Useful levels of stereochemical control can be achieved provided that the substituent is branched. The similar diastereomeric ratios of 15a and 15e, which have side chains of similar size, suggests that steric effects of the side chain influence stereoselectivity more so than electronic effects, which is supported by the kinetic data (Scheme 1). The reaction of optically pure α-pivaloyloxy acetal 4f (Scheme 6), which was readily prepared by enzymatic kinetic resolution⁴⁶, demonstrates that this reaction can be used to prepare enantiomerically enriched products.^12,15

Scheme 6.

Influence of side-chain on selectivity.

In summary, neighboring-group participation to control the diastereoselectivity of acetal substitution reactions can be extended from carbohydrates to encompass acyclic acetals. This reaction provides a highly stereoselective alternative route to prepare products expected from Felkin–Anh additions to carbonyl compounds.