Cooperative Hydrogen-Bond-Donor Catalysis with Hydrogen Chloride Enables Highly Enantioselective Prins Cyclization Reactions

Abstract

Cooperative asymmetric catalysis with hydrogen chloride (HCl) and chiral dual-hydrogen-bond donors (HBDs) is applied successfully to highly enantioselective Prins cyclization reactions of a wide variety of simple alkenyl aldehydes. The optimal chiral catalysts were designed to withstand the strongly acidic reaction conditions and induce rate accelerations of 2 orders of magnitude over reactions catalyzed by HCl alone. We propose that the combination of strong mineral acids and chiral hydrogen-bond-donor catalysts may represent a general strategy for inducing enantioselectivity in reactions that require highly acidic conditions.

Graphical Abstract

Reactions catalyzed by Brønsted acids are of central utility in organic chemistry, and extensive research efforts have been directed over the past two decades toward the development of enantioselective variants.¹ Attainment of high levels of absolute stereocontrol requires the creation of well-defined and differentiated geometries about the protonated electrophile, and fundamentally different approaches have been taken to address this challenge. One involves the application of chiral Brønsted acids, and systems based on bis-aryloxide ligated phosphoric acids have been deployed with outstanding success, particularly in the promotion of reactions involving imine electrophiles.^1,2 Extension to less basic functional groups such as simple carbonyl and olefin derivatives requires catalysts with enhanced Brønsted acidity,³ and effective catalyst platforms have been identified including N-triflyl phosphoramides by Yamamoto,⁴ imidodiphosphorimidates by List,⁵ pentacarboxycyclopentadienes by Lambert,⁶ and bis(sulfuryl)imides by Berkessel.⁷ Enhanced acidity of chiral Brønsted acid catalysts has also been achieved through the introduction of achiral cocatalysts including simple Lewis acids and hydrogen-bond donors.⁸

An alternative strategy for accessing enantioselective Brønsted acidic catalyst systems has relied on the anion binding abilities of chiral dual-hydrogen-bond donors (HBDs).⁹ Chiral urea, thiourea, and squaramide-based catalysts have been shown to impart enantioselectivity in reactions catalyzed by both weak¹⁰ and strong¹¹ achiral Brønsted acids (Scheme 1A). While this cocatalytic strategy has found use in activation of several classes of nitrogenous electrophiles including aldimines^10,11b and aziridines,^11a we recognized the possibility that the innate acidity of a strong mineral acid could be leveraged to activate substantially less Lewis basic oxygen-centered electrophiles.¹² In this regard, our group recently identified adventitious hydrogen bromide as an effective cocatalyst in highly enantioselective chiral squaramide catalyzed ring-opening reactions of oxetanes.^11c We hypothesized that this mode of cooperative catalysis could be applied broadly to the activation of other challenging classes of electrophiles such as simple carbonyls.^3b

Scheme 1.

(A) Cocatalytic strategy in activation of nitrogenous electrophiles (B) Application of Brønsted acid and HBD cocatalysis to enantioselective Prins cyclization reactions.

We chose to explore the concept of strong Brønsted acid/chiral HBD cocatalysis in the context of the addition of alkenes to carbonyl compounds (the Prins reaction), a venerable transformation that provides access to stereochemically defined homoallylic alcohol products (Scheme 1B).¹³ Although numerous advances in asymmetric Lewis¹⁴ and Brønsted¹⁵ acid catalysis of Prins and carbonyl-ene reactions have been made, protonation of simple aldehyde substrates toward reaction with simple alkenes remains a formidable challenge. Highly enantioselective methods operating on such substrates are rare and have been limited primarily to 5-membered ring-forming carbonyl-ene reactions.^16,17 We recognized that enantioselective catalysis of Prins cyclizations could provide complementary strategies to access six-membered ring homoallylic alcohol products, for which general highly enantioselective methods have not yet been developed.¹⁸ Herein, we report highly enantioselective chiral HBD/HCl cocatalysis of Prins cyclizations of simple alkenyl aldehydes. The successful implementation of cooperativity between simple mineral acids and chiral hydrogen-bond donors points to a potentially general approach to enantioselective catalysis of organic reactions involving weakly Brønsted basic substrates.

The cyclization of prenylated salicylaldehyde derivative 1a, which affords access to valuable 4-chromanol products, was selected as a model reaction.¹⁹ While the dual hydrogen-bond donor catalyst 4 alone did not catalyze the cyclization of 1a (Table 1, entry 1), the inclusion of catalytic hydrogen chloride (8 mol%, as a solution in Et₂O) at room temperature promoted smooth conversion to homoallylic alcohol product 2a along with tertiary chloride product 3a arising from trapping of the presumed tertiary carbocation intermediate (Scheme 1B). Under these conditions, 2a and 3a were formed in a 3.5:1 ratio with similar enantiomeric excess (76% and 74% ee respectively) (Table 1, entry 2). A variety of other achiral Brønsted acids were surveyed with catalyst 4 (Table 1, entries 3-6), in all cases providing product 2a in diminished levels of both diastereo- and enantioselectivity relative to reactions carried out with HCl.²⁰ Weaker Brønsted acids such as benzoic acid and diphenyl phosphoric acid failed to provide any measurable level of conversion after 24 hours (Table 1, entries 5 and 6). The use of urea catalyst 5 bearing a pyrrole moiety derived from trans-1,2 diaminocyclohexane led to improvements in both diastereo- and enantioselectivity as well as an increase in the 2a:3a ratio (Table 1, entry 7). However, HCl was found to promote undesired addition reactions²¹ between the electron-rich pyrrole of 5 and substrate 1a, resulting in catalyst decomposition (Table 1, bottom; see SI for details). Introduction of an electron-withdrawing ester substituent to attenuate the nucleophilicity of the pyrrole led to complete suppression of the undesired addition pathways, with catalyst 6a affording a significantly cleaner reaction while also providing products 2a and 3a with enhanced ee (Table 1, entry 8). A further improvement in enantioselectivity was achieved with the more reactive thiourea analog 6b, which delivered products 2a and 3a both in 98% ee using an 8 mol% loading of HCl (Table 1, entry 9).

Table 1.

Optimization of HBD catalyst structure and reaction conditions^a

entry	HX (mol%)	HBD (mol%)	conversion (%)b	yield (%)b	d.r. 2ab	2a : 3ab	ee 2a (%)c	ee 3a (%)c
1	—	4 (10)	n.r.	n.r.	—	—	—	—
2	HCl (8)	4 (10)	33	28	10 : 1	3.5 : 1	76	74
3	MsOH (8)	4 (10)	100	trace	—	—	—	—
4	TsOH H2O (8)	4 (10)	87	30	4 : 1	—	31	—
5	BzOH (8)	4 (10)	n.r.	n.r.	—	—	—	—
6	HOP(O)(OPh)2 (8)	4 (10)	n.r.	n.r.	—	—	—	—
7	HCl (8)	5 (10)	41	32	22 : 1	6.5 : 1	89	77
8	HCl (8)	6a (10)	45	44	23 : 1	4.4 : 1	96	95
9	HCl (8)	6b (10)	34	32	49 : 1	3.0 : 1	98	98
10	HCl (8)	7 (10)	35	25	12 : 1	2.4 : 1	87	89
11	HCl (30)	6b (10)	96	94	> 50 : 1	3.1 : 1	96	98
12	HCl (30)	6b (5)	88	85	30 : 1	3.1 : 1	92	94
13	AcCl + EtOH (30)	6b (5)	93	91	38 : 1	3.0 : 1	95	97
14d	AcCl + EtOH (30)	6b (5)	—	82	36 : 1	—	95	—

^aConducted using 0.08 mmol of 1a with Brønsted acid cocatalysts delivered as solutions in Et₂O.

^bDetermined from crude reaction mixtures using ¹H NMR spectroscopy with mesitylene internal standard. Yield refers to the combined yield of products trans/cis 2a and 3a except for entry 14.

^cDetermined by GC analysis using a chiral stationary phase. n.r. = no reaction.

^dReaction was quenched by the addition of 60 mol% KHMDS.

The stoichiometric consumption of HCl in the generation of product 3a resulted in limited reaction conversions when 8 mol% loadings of HCl were employed. Increased conversion was achieved with higher (30 mol%) loadings of HCl, affording comparable enantioselectivity with 10 mol% 6b (Table 1, entry 11). However, lowering the loading of 6b to 5 mol% with the increased HCl loadings resulted in diminished enantioselectivity, presumably due to intervention of a competing racemic HCl-catalyzed background reaction (Table 1, entry 12). We surveyed methods for the controlled in situ generation of HCl, and found that the use of 30 mol% equimolar combinations of acetyl chloride (AcCl) and anhydrous ethanol (EtOH) restored nearly optimal levels of yield and ee with catalyst 6b (Table 1, entry 13).²² Finally, conversion of tertiary chloride 3a to 2a via potassium hexamethyldisilazide (KHMDS)-promoted elimination could be effected as a quench at the end of the reaction without the need for initial purification (Table 1, entry 14). Under these conditions, 2a was generated as the exclusive product in 82% NMR yield and 95% ee.²³

Efforts to further reduce the loading of 6b were met by the observation of decreasing enantioselectivity over the course of the reactions (Figure 1A, entries 1-2), suggesting the participation of a competitive catalyst deactivation pathway. Indeed, subjecting 6b to HCl in the absence of substrate led to the clean formation of heterocycle 8 and the corresponding aryl pyrrolidine arising from Edman degradation^24,25 (Figure 1B, see SI for details). Variation of the arylpyrrolidine catalyst component led to the identification of 2-naphthyl derivative 9, which displayed minimal decreases in enantioselectivity over the same timeframe (Figure 1A, entries 3-4).²⁶ In principle, the observed increased robustness of reactions catalyzed by 9 can be attributed to either increased catalyst stability to HCl or to increased reactivity in the Prins reactions.²⁷ In fact, 6b and 9 were found to undergo Edman degradation at identical rates, while 9 catalyzes the Prins cyclization of 1b at twice the rate compared to 6b (Figure 1C). Hence, the higher rate of Prins cyclization allows 9 to more effectively outcompete Edman degradation, resulting in higher levels of enantioselectivity at lower catalyst loadings.²⁸

Figure 1.

Optimization of HBD aryl pyrrolidine. ^aDetermined from crude reaction mixtures using ¹H NMR spectroscopy with mesitylene internal standard. ^bDetermined by GC analysis using a chiral stationary phase.

With optimal hydrogen-bond donor catalyst 9 and conditions for the cyclization of 1a in-hand, we evaluated the scope of the newly developed method (Figure 2). A variety of electronically and sterically differentiated analogs of 1a were found to undergo smooth cyclization and elimination at room temperature to provide chromanols 2b-2h in good yields with high diastereoselectivities (≥17:1) and enantioselectivities (95-98% ee). Lower but nonetheless significant levels of enantioselectivity were obtained in the cyclization of arylaldehyde derivatives lacking a ring-conjugated oxygen atom, with 1i reacting to form product in 81% ee and 1j affording the carbocylic five-membered ring product 2j in 80% ee.

Figure 2.

Catalytic enantioselective Prins cyclization reactions. Reactions were carried out using 0.3 mmol of substrates 1, except for substrates 1k and 1l which were carried out on 0.1 mmol scale. Isolated yields are reported, except where noted. d.r. determined using ¹H NMR spectroscopy of crude reaction mixtures. Reported ee values correspond to the major trans products. The absolute stereochemical configuration of 2c was determined via X-ray crystallographic analysis. All stereochemistry of products 2 is inferred from this result. ^a10 mol% 9 used, ^bNMR yield of trans diastereomer, ^cNMR yield of diastereomeric mixture, ^disolated yield of trans diastereomer, ^eisolated yield of diastereomeric mixture, ^f15 mol% AcCl, EtOH used.

The new method was extended to simple olefinic aldehydes, with the cyclization of aliphatic substrates 1k-1o taking place in high ee and moderate-to-good yields. Although products 2k and 2l were formed with low diastereoselectivities, the trans cyclohexanol products were generated in high enantioselectivities (89% and 91% ee respectively), a noteworthy result considering that substrates without conformationally biasing disubstitution²⁹ have rarely been documented in direct enantioselective Brønsted acid catalyzed additions of alkenes to carbonyls.³⁰ In contrast to the benzo-fused products 2a and 2i, the presence or identity of a heteroatom linker had negligible effects on stereoselectivity, with oxygen-, nitrogen-, and carbon-linked alkenyl aldehydes 2k-2o all affording similar levels of ee and d.r. The cyclization of simple alkenyl aldehyde substrates represents a long-standing challenge in asymmetric Brønsted/Lewis acid catalysis, so the successful access provided by this method to trans-configured six-membered ring products in high enantioselectivities under mild reaction conditions is particularly significant.

Substrates 1p and 1q bearing tetrasubstituted alkenyl components also underwent highly enantioselective cyclizations, forging congested quaternary stereogenic centers in products 2p and 2q. Although compounds possessing quaternary centers of this type have been synthesized racemically,³¹ highly enantioselective methods for their preparation are rare.³² Finally, conjugated enal electrophiles provided access to new allylic alcohol products 2r-2t possessing natural product-like features in good enantioselectivity (88-90% ee) and d.r. (≥ 9:1).³³

The chiral thiourea and HCl cocatalyzed Prins reaction was readily adapted to preparative synthesis, as demonstrated by the cyclization of 1b conducted on gram scale (Figure 3A). The loading of 9 could be reduced to 1 mol% while maintaining a highly enantioselective reaction outcome (96% ee), good yield (71%), and a short reaction time (1h). The enantiomeric purity of 2b was upgraded to 99% following a single recrystallization.

Figure 3.

(A) Gram-scale synthesis of 2b. (B) Rate acceleration using catalyst 9 in reaction of 1b.

Thiourea 9 was found to induce substantial rate acceleration in cyclization of substrates 1 relative to the HCl-catalyzed background reaction. Monitoring the HCl-catalyzed reaction of 1b in the presence and absence of 2 mol% 9 using in situ infrared spectroscopy revealed rate enhancement of approximately two orders of magnitude (93 times) (Figure 3B). The observation of such effects with a chiral cocatalyst is reminiscent of ligand-accelerated catalysis using transition metals.³⁴ Our current efforts are directed towards elucidating the basis of this rate acceleration as well as identifying the mode of stereoinduction across multiple substrate classes.

In summary, we have developed a highly enantioselective Prins cyclization of alkenyl aldehydes catalyzed by the combination of hydrogen chloride and chiral hydrogen-bond donors. The catalytic method displays broad substrate scope, providing valuable chromanol derivatives and related natural product-like compounds in high levels of ee. Given the ability of dual hydrogen bond donors to recognize anions with widely varying steric and electronic properties,³⁵ we anticipate general application of the cooperative action of strong Brønsted acids and chiral HBDs in asymmetric catalysis.