Enantio- and Diastereoselective, Lewis Base-Catalyzed, Cascade Sulfenoacetalization of Alkenyl Aldehydes

Abstract

A catalytic, enantio- and diastereoselective formation of sulfenyl acetals bearing multiple stereogenic centers is reported. Alkenyl aldehydes undergo a chiral thiiranium-ion initiated cascade starting with intramolecular capture by a formyl group and termination by capture with HFIP solvent. This method provides a one-pot synthesis of dihydropyran and 1,3-disubstituted isochroman acetals in good to excellent yield and with high levels of diastereo- (up to >99:1 dr) and enantiocontrol (up to 99:1 er).

Graphical Abstract

A diastereo- and enantioselective Lewis base-catalyzed sulfenoacetalization of alkenyl aldehydes is reported. A chiral thiiranium-ion initiated cascade starts with intramolecular capture by a formyl group followed by capture with HFIP solvent. Resulting dihydropyran and 1,3-disubstituted isochroman acetals are formed in good to excellent yield and with high levels of diastereo- (up to >99:1 dr) and enantiocontrol (up to 99:1 er).

Chiral, stereochemically defined isochroman motifs are present in many natural products and bioactive molecules (Figure 1).^[1] Historically, chiral isochromans have been prepared by diastereoselective oxa-Pictet-Spengler cyclization of enantioenriched starting materials.^[2] Pioneering, enantioselective syntheses of 1-substituted isochroman derivatives were reported by Jacobsen^[3], Watson^[4] and Meng.^[5] In addition, Fu^[6] and Ghorai^[7] reported syntheses of enantioenriched, 1- or 3-substituted isochromans. Although substantial effort has been devoted to access monosubstituted isochroman derivatives in both racemic and enantiomerically enriched fashion, methods to prepare 1,3-disubstituted analogs stereoselectively are rare. To the best of our knowledge, there are only two reports that disclose access to enantioenriched 1,3-disubstituted isochromans from White^[8] and Ghorai.^[9]

Figure 1.

Mono- and disubstituted isochroman structural motifs in natural products and bioactive molecules.

Consequently, there is significant interest in the development of a general method that allows the use of achiral substrates to construct isochromans containing multiple stereogenic centers in enantiomerically pure form. To this end, multicomponent reaction strategies are particularly attractive because of their operational simplicity and high degree of convergence.^[10]

The concept of Lewis base activation of Lewis acids^[11] pioneered in these laboratories has proven to be a powerful method to functionalize unactivated olefins with high levels of stereocontrol. Combination of a suitable electrophilic sulfur source with a chiral selenophosphoramide catalyst results in a cationic donor−acceptor complex with increased electrophilic character on sulfur. The active catalytic species then transfers the sulfenium ion to the olefin to generate an enantiomerically enriched thiiranium ion, followed by a diastereospecific capture with a suitable nucleophilic partner (Scheme 1A).^[12] The current scope of nucleophiles includes oxygen,^[13] nitrogen^[14] and carbon^[15] moieties, acting in both an intra- and intermolecular fashion. This method also provides access to a wide variety of enantioenriched carbo- and heterocycles including complex polycyclic natural products.^[16]

Scheme 1.

Lewis Base-Catalyzed Sulfenofunctionalization of Unactivated Alkenes.

Given our interest in developing a general and enantioselective process for the construction of substituted isochromans (and their tetrahydropyran parents) we envisioned the sulfenium-ion-initiated, cascade acetalization in Scheme 1B. In this case, a tetrahydropyran ring is generated by the opening of a thiiranium ion with a suitably disposed aldehyde oxygen,^[17] and the resulting oxocarbenium ion is then captured by a second nucleophile in an intermolecular fashion. In view of the rich chemistry of sulfur that allows for downstream manipulations,^[18–19] this strategy was appealing for the further generalization of sulfenofunctionalization.

Preliminary experiments employing various alcohols as stoichiometric nucleophiles to trap an oxocarbenium intermediate generated from opening a thiiranium ion were unsuccessful (See Supporting Information for full details). Thus, a search for a nucleophile that could be employed in solvent quantities was initiated. A recent disclosure from these laboratories identified hexafluoroisopropyl alcohol (HFIP) as an effective solvent for the Lewis base-catalyzed polyene sulfenocyclization.^[16] HFIP has recently become a popular solvent or additive with applications across a spectrum of organic chemistry because it possesses unique properties owing to its mild acidity, attenuated nucleophilicity, as well as hydrogen bond donating ability.^[20] Inspired by this finding, we tested HFIP for the desired sulfenoacetalization reaction. A number of orienting experiments revealed a combination of 5-hexenal 1a, sulfenylating agent 3 and HFIP in the presence of Lewis base catalyst 2 to give sulfenyl acetal 5a in 81% yield as a mixture of diastereomers (85:15 dr) with moderate enantioselectivity (70:30 er) (Table 1, entry 1). The relative configuration of the major product at this point was determined using NOE experiments. Lowering the temperature significantly decreased the reaction rate with no improvement of stereoselectivity (entry 2). However, much higher enantioselectivity was obtained using 2,6-diisopropylphenyl-substituted sulfenylating agent 4 without compromising yield of the acetal product 6a (entry 3). In agreement with our previous work,^[12] discrimination of the enantiotopic faces of the alkene is predominantly governed by steric effects of the sulfenylating agent. Hence, increasing the steric bulk around the sulfur atom by incorporating ortho-isopropyl groups leads to enhanced enantiomeric ratio. Varying the concentration did not improve the reactivity or selectivity (entries 4–5), whereas using a slight excess of alkenal 1a relative to sulfenylating agent resulted in 94% isolated yield of acetal 6a while maintaining high enantioselectivity (entry 6).

Table 1.

Reaction Optimization.

Entry	PhthSAr	HFIP (M)	Temp (°C)	Yield 5a or 6a (%)[a],[b]	dr (α:β)[c]	er[d]
1	3	0.1	25	76 (81)	85:15	70:30
2[e]	3	0.1	0	35 (41)	85:15	70:30
3	4	0.1	25	85 (87)	80:20	98:2
4	4	0.05	25	72 (77)	80:20	98:2
5	4	0.2	25	81 (84)	75:25	98:2
6[f]	4	0.1	25	94 (97)	80:20	98:2

^[a]Yield in parentheses determined by ¹H NMR spectroscopic analysis using 1,1,1,2-tetrachloroethane as an internal standard.

^[b]Isolated yield of the combined diastereomers.

^[c]Diastereomeric ratio determined by ¹H NMR spectroscopic analysis of the crude reaction mixture using an internal standard.

^[d]Determined by CSP-HPLC analysis for the major diastereomer.

^[e]Reaction performed for 48 h.

^[f]Reaction performed using 1.1 equiv of 1a.

Next, the substrate scope of the cascade sulfenoacetalization process was explored using a variety of linear alkenals (Table 2). Under optimized conditions the substrate bearing a trans-olefin gave product 6b in 89% yield with enhanced diastereoselectivity (88:12 dr) and high enantiomeric purity (97:3 er). The dr was further improved when the alkenal containing a gem-dimethyl moiety at the α-position to the carbonyl group was applied. Sulfenyl acetal 6c was obtained in good yield and excellent diastereo- and enantioselectivity (>99:1 dr; 99:1 er). Equally high levels of stereocontrol were observed using a benzannulated substrate. The cyclization process proceeded smoothly to give isochroman-derived product 6d as a single diastereomer in 90% yield and 95:5 er. X-ray crystallographic analysis of 6d revealed the (S,S)-configuration,^[21] which is in agreement with the preliminary assignment using NOE experiments and the predicted facial selectivity based on our previous studies.^[12a] The preferential formation of the α-anomer may be a manifestation of the kinetic anomeric effect^[22] resulting in the placement of the HFIP group in the axial position, however experimental confirmation was not possible. In addition, the enhanced diastereomeric ratio of the benzannulated product could be attributed to stabilization of the cationic oxocarbenium intermediate by the adjacent aryl substituent.^[23]

Table 2.

Initial Studies of the Reaction Scope.^[a–d]

^[a]All reactions performed on a 1.00 mmol scale.

^[b]Yield of isolated, analytically pure product.

^[c]Diastereomeric ratio determined by ¹H NMR spectroscopic analysis of the crude reaction mixture.

^[d]Enantiomeric ratio determined by CSP-HPLC analysis.

^[e]Reaction performed for 24 h using 1.00 mmol of 1d and 1.05 mmol of sulfenylating agent 4. Enantiomeric ratio in parentheses was obtained upon recrystallization.

Encouraged by the high levels of stereoselectivity observed in the sulfenoacetalization of the benzannulated alkenal, we continued our investigation of the reaction scope by evaluating this scaffold (Table 3). Various alkenals bearing electronically diverse substituents on the aromatic ring were effective substrates for this transformation. 4-Methyl-substituted isochroman derivative 6e was generated in 88% yield with excellent diastereo- and enantiocontrol.

Table 3.

Sulfenoacetalization of Benzannulated Alkenals.^[a–e]

^[a]All reactions performed on a 1.00 mmol scale.

^[b]Yield of isolated, analytically pure product.

^[c]Diastereomeric ratio determined by ¹H NMR spectroscopic analysis of the crude reaction mixture.

^[d]Enantiomeric ratio determined by CSP-HPLC analysis.

^[e]Diastereomeric and enantiomeric ratio in brackets were obtained upon trituration or single recrystallization.

Electron-withdrawing groups on the aromatic ring were compatible and afforded highly enantioenriched acetal products 6f-6i, with slightly reduced dr for the substrate bearing a CF₃-group in the 4-position (88:12 dr). Single diastereomers were obtained using 4- and 3-OMe-substituted alkenals with high and moderate enantioselectivity of the corresponding products 6j and 6k. Sulfenoacetalization of the electron-rich benzodioxole and naphthyl substrates, as well as the indole-derived alkenal proceeded efficiently to give isochromans 6l-6n in high yield, excellent dr and er. Notably, when benzannulation was changed to a cyclohexene-derived substrate, the reactivity dropped dramatically. Sulfenyl acetal 6o was obtained in a moderate 45% yield, although diastereo- and enantioselectivity remained high. The scope was further extended by varying the alkene substituent. An (E)-configured alkene performed well to afford product 6p bearing three stereocenters in a highly efficient and stereoselective manner (>99:1 dr; 95:5 er). Sulfenyl acetal 6q generated from a (Z)-alkenal was isolated in excellent yield and diastereoselectivity but poor enantioselectivity (62:38). The reason for the poor recognition of (Z)-alkenes is the topology of BINAM-derived catalyst 2. Having diagonally symmetric quadrants of occupied and unoccupied space, the catalytically active species is suited for differentiating the enantiotopic faces of (E)-alkenes, but not other alkenes.^[12] 1,1,2-Trisubstituted olefin underwent the sulfenoacetalization process in good yield and high diastereocontrol, however moderate enantioselectivity (6r, 75:25 er). Using a homologated substrate led to formation of highly enantioenriched 7-membered acetal 6s in synthetically useful yield and good diastereoselectivity. Importantly, the dr can be further improved by a single recrystallization (98:2 dr).

In the next stage of this work, synthetic manipulation of the isochroman-derived sulfenyl acetals was explored using enantiomerically enriched product 6d (>99:1 dr, 99:1 er) (Table 4). The acetal moiety allowed for a variety of useful derivatizations. For example, mild reduction with a Lewis acid and triethylsilane in CH₂Cl₂/HFIP afforded the enantioenriched sulfenyl ether 7 in 93% yield.^[24] Transacetalization with MeOH under acidic conditions gave corresponding methyl acetal 8 preserving high diastereo- and enantioselectivity (93:7 dr; 99:1 er).^[24a] Treatment of 6d with allyltrimethylsilane or TMSCN resulted in a stereoselective C-C-bond formation, and corresponding products 9 and 10 were obtained in 98% and 90% yield respectively, with good levels of diastereocontrol.^[24]

Table 4.

Synthetic Manipulations of Sulfenyl Acetal 6d.^[a–e]

^[a]All reactions performed on a 1.00 mmol scale.

^[b]Yield of isolated, analytically pure product.

^[c]Diastereomeric ratio determined by ¹H NMR spectroscopic analysis of the crude reaction mixture.

^[d]Enantiomeric ratio determined by CSP-HPLC analysis.

^[e]Diastereomeric and enantiomeric ratio in brackets were obtained upon trituration or single recrystallization.

^[f]Enantiomeric ratio of the corresponding alcohol was determined by CSP-HPLC analysis.

Furthermore, exchange of HFIP acetal with (phenylthio)trimethylsilane afforded thioacetal 11 in 98% yield, which is an effective precursor of oxocarbenium intermediates.^[25] The acetal moiety can also be oxidized in the presence of Raney nickel^[26] in HFIP to furnish lactone 12 in 78% yield and 98:2 er. To further demonstrate the product diversification, thioether moiety of 6d was selectively oxidized with H₂O₂ in HFIP to give a 1:1 mixture of sulfoxides 13 in 84% yield. Treatment of the obtained sulfoxides with triflic anhydride and 2,6-lutidine followed by basic hydrolysis enabled efficient one-pot Pummerer rearrangement.^[27] Corresponding aldehyde 14 was isolated in 79% yield as a single diastereomer without erosion of enantiopurity (>99:1 dr; 99:1 er).

In summary, a diastereo- and enantioselective Lewis base-catalyzed sulfenoacetalization of alkenyl aldehydes has been described. Under mild conditions (no strong acid/base, ambient temperature, in air), the reaction proceeds via intramolecular capture of the enantioenriched thiiranium ion with the aldehyde functionality followed by intermolecular acetalization. This method enables preparation of highly enantioenriched dihydropyran and 1,3-disubstituted isochroman motifs bearing multiple stereogenic centers in synthetically useful yields. The products were shown to undergo further synthetic transformations to afford valuable building blocks by exploiting both acetal and thioether moieties.