Asymmetric Synthesis of β-Amino Amides by Catalytic Enantioconvergent 2-Aza-Cope Rearrangement

Abstract

Dynamic kinetic resolutions of α-stereogenic-β-formyl amides in asymmetric 2-aza-Cope rearrangements are described. Chiral phosphoric acids catalyze this rare example of a non-hydrogenative DKR of a β-oxo acid derivative. The [3,3]-rearrangement occurs with high diastereo- and enantiocontrol, forming β-imino amides that can be deprotected to the primary β-amino amide or reduced to the corresponding diamine.

The hydrogenative dynamic kinetic resolution (DKR) of β-oxo esters is an indispensable synthetic technology used to generate hectoton quantities of optically enriched β-hydroxy esters annually (Scheme 1a).¹ Since Noyori’s foundational report² describing DKRs of α-alkyl and α-amino substituted β-oxo acid derivatives, a wide array of additional α-substitution patterns have been reduced with high stereoselection.³ Conversely, involvement of β-oxo esters and their congeners in non-hydrogenative DKR reactions remain surprisingly scarce.^4,5 Toward the advancement of this latter process, this communication describes enantioconvergent and diastereoselective aza-Cope rearrangements of racemic β-formyl amides for the generation of new β-amino acid derivatives.⁶ The reaction is catalyzed by a chiral organic acid and concurrently establishes new C–N and C–C bonds and vicinal stereogenic centers (Scheme 1b).

Scheme 1.

Dynamic Kinetic Resolutions with β-Oxo Acid Derivatives

While catalytic asymmetric sigmatropic rearrangements are well-established,⁷ examples of enantioselective 2-aza-Cope rearrangements are comparatively rare,⁸ and the 2-aza-Cope reaction as a DKR process has only been demonstrated utilizing stereochemically defined aminoallyl reagents.⁹ Chiral acid catalyzed aza-allylations of simple aldehydes have been reported from the laboratories of Rueping and Wulff, and this body of work provided the mechanistic framework for our experimental plan.⁸ Our initial investigations were guided by our recent successes using α-keto ester (±)-1 in stereoconvergent reactions.¹⁰ In combination with allyl amine 2a under chiral phosphoric acid catalysis,¹¹ productive reactivity was observed, but we were unable to achieve any promising diastereo- or enantioselectivity (Scheme 2a).¹² A racemization study of enantioenriched 1 revealed that under the buffered reaction conditions racemization via tautomerization was slower than the rate of sigmatropic rearrangement.¹³ Due to the inability of 1 to achieve kinetically useful enantiomerization, we switched to β-formyl ester 4, which we hypothesized would favor enamine formation relative to 1, thereby enhancing the rate of enantiomer interconversion. Unfortunately, the derived enamine 5 was impervious to [3,3]-rearrangement under any conditions that could be rendered catalytic (Scheme 2b), a circumstance we attribute to a debilitating thermodynamic preference for the unreactive enamine relative to the needed iminium ion 5·H⁺.¹⁴ Considering our inadvertent overcorrection, we speculated that replacing the ester with a more sterically demanding dialkyl amide might provide a proper balance by destabilizing the enamine tautomer through A(1,3) strain¹⁵ while still maintaining a faster rate of enantiomerization than was observed with α-keto ester 1.¹⁶

Scheme 2.

Primary and Secondary Substrate Designs for Enantioconvergent 2-Aza-Cope Rearrangement

When β-formyl amide (±)-6a and allyl amine 2a were subjected to chiral phosphoric acid A, β-amino amide 7a was formed in 7:1 dr and 96:4 er (Table 1, entry 1). A screen of chiral phosphoric acids revealed A¹⁷ and B¹⁸ as the best candidates for further optimization.¹⁹ Elevating the reaction temperature increased the reaction rate with little loss of stereoselection (Table 1, entry 3 and 4). Using cyclopentyl methyl ether (CPME) as a solvent increased the stereoselectivity for both catalysts A and B (Table 1, entry 5 and 6). With catalyst A and CHCl₃ as the solvent, ketimine 7a was obtained in 10:1 dr and 97:3 er (Table 1, entry 7). Lowering the catalyst loading to 2.5 mol % had no detrimental effects on reactivity or selectivity (Table 1, entry 9).²⁰

Table 1.

Optimization of Aza-Allylation Conditions^a

entry	cat.	T (°C)	solvent	conv (%)	drb	erc
1	A	rt	PhCH3	100	7:1	96:4
2	B	rt	PhCH3	50
3	A	80	PhCH3	100	7:1	95:5
4	B	80	PhCH3	100	20:1	87:13
5	A	60	CPME	100	8:1	98:2
6	B	60	CPME	100	>20:1	89:11
7	A	60	CHCl3	100	10:1	97:3
8	B	60	CHCl3	100	>20:1	93:7
9d	A	60	CHCl3	100	10:1	97:3

^aAll reactions were run on a 0.10 mmol scale.

^bDetermined by ¹H NMR analysis of the crude reaction mixture.

^cDetermined by chiral HPLC analysis.

^d2.5 mol % of catalyst.

With suitable conditions in hand we began to probe the allowable steric and electronic parameters of this rearrangement, initially by varying the α-substituent (Table 2). The phenylacetic acid derivative 7b was obtained in 1.1:1 dr and 85:15 er. An α-allyl aldehyde provided 7c in 8:1 dr and 91.5:8.5 er, while inclusion of a pendant heteroatom provided 7d in 2:1 dr and 90.5:9.5 er. The less sterically demanding α-methyl substitution gave 7e in 3:1 dr and 82:18 er. The use of larger α-substituents, as represented by 7f (R = ^cHex) and 7g (R = ⁱPr), restored higher levels of stereoselection. An X-ray diffraction study of 7g was carried out (Scheme 3) to assign the product stereochemistry as (2R,3S).²¹ Electronically differentiated benzyls provided 7i and 7j with >10:1 dr and 97:3 er. Using fur-2-yl and thien-2-yl variants instead of benzyl derivatives yielded products 7k and 7l with high stereocontrol.

Table 2.

Variation of the α-Substituent in the [3,3]-Rearrangement of α-Stereogenic-β-formyl Esters^a

^aAll reactions were run on a 0.20 mmol scale at 60 °C for 24 h. Diastereomeric ratios were determined by ¹H NMR or HPLC analysis of the crude reaction mixture; enantiomeric ratios by chiral SFC or HPLC. Yields are of isolated products.

^bYield reported is of the primary amine after hydrolysis of the benzophenone imine.

^cRun at 130 °C under microwave irradiation for 6 h.

^dRun on a 0.10 mmol scale.

Scheme 3.

Determination of Relative and Absolute Stereochemistry of the [3,3]-Aza-Cope Rearrangement

Cognizant that modifying the amide identity would result in differentiated diamines after amide reduction, we next examined structural variation at that position (Table 3). The β-amino amides generated from piperidine 7m, pyrrolidine 7n, and dimethyl amine 7o were all formed in high yield and stereoselectivity. We also probed the allowed variance of the allyl amine donor. Internally substituted allyl amine 2b provided the formal aza-methallyation adduct 7p in 60% yield with 5:1 dr and 80:20 er. Terminally substituted allyl amine donors condensed with the β-formyl amide 6, but did not undergo [3,3]-rearrangement, results we attribute to greater steric encumbrance at the reaction site.

Table 3.

Variation of Amide and Allyl Amine Identity in the [3,3]-Rearrangement of α-Stereogenic-β-formyl Esters^a

^aAll reactions were run on a 0.20 mmol scale at 60 °C for 24 h. Diastereomeric ratios were determined by ¹H NMR or HPLC analysis of the crude reaction mixture; enantiomeric ratios by chiral SFC or HPLC. Yields are of isolated products.

^bYield reported is of the primary amine after hydrolysis of the benzophenone imine.

For our final investigations we turned our attention to assessing the reactivity of the product β-imino amides. Hydrolysis of 7a to form primary amine 8 proceeded under mild conditions and in 99% yield (Scheme 4a). Initial reduction of 7a with LiAlH₄ results in an intermediate aldehyde, which can be further reduced by sodium borohydride to form benzhydryl-protected amino alcohol 9 in 95% yield (Scheme 4b). If the benzophenone imine is cleaved prior to reduction, the diamine 10 is obtained in good yield (Scheme 4c). Finally, diene 7c underwent facile ring-closing metathesis with Grubbs’s second generation catalyst to provide cyclohexene 11 in 98% yield (Scheme 4d).

Scheme 4.

Chemical Transformation of Aza-Cope Products

In conclusion, we have developed stereoconvergent 2-aza-Cope reactions employing stereocontrol from a chiral organic acid catalyst. This DKR between homoallylic amines and α-stereogenic-β-formyl amides constitutes a rare example of a non-hydrogenative DKR reaction of β-oxo acid derivatives and delivers new β-amino amides in high diastereo- and enantioselectivity. These products can be readily converted into an array of functional small molecule building blocks. Mechanistic studies delineating the factors that lead to the observed stereoselectivity and the use of this information in the development of other stereoconvergent reactions of racemization-prone β-oxo carboxylic acid derivatives will be reported in due course.