Enantio- and diastereoselective addition of cyclohexyl Meldrum's acid to β- and α,β-disubstituted nitroalkenesvia N-sulfinyl urea catalysis

Abstract

Using N-sulfinyl urea catalysis, a method has been developed for the asymmetric synthesis of biologically important γ-amino acids with a high level of efficiency, practicality and unprecedented control of multiple stereocenters. This method is based upon the highly enantio- and diastereoselective addition of cyclohexyl Meldrum's acid as an easily deprotectable monocarboxylic acid equivalent. The addition to both β-substituted and α,β-disubstituted nitroalkenes using N-sulfinyl urea organocatalyst 8 is described. The utility of this new method toward drug production is demonstrated by the mole scale preparation of a key precursor to the commercial drug Lyrica using catalyst 8 at only 0.2 mol% loading. Moreover, α,β-disubstituted nitroalkene addition products were efficiently converted to γ-amino acid derivatives without epimerization of either stereocenter.

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Introduction

γ-Amino acids are present in numerous drugs, drug candidates and bioactive natural products (Fig. 1).^1,2 Moreover, this structure can readily be transformed into pyrrolidinones and pyrrolidines, which are also present in a large number of bioactive compounds.

Fig. 1 Representative examples of bioactive γ-amino acid derivatives.

Consequently, highly effective organocatalytic methods have been developed for the asymmetric addition of malonates to β-substituted nitroalkenes at low catalyst loading to provide efficient and practical access to γ-amino acid derivatives (eqn 1).³ In contrast, for additions to α,β-disubstituted nitroalkenes only a narrow set of cyclic substrates have been reported.⁴ Moreover, despite considerable effort, only moderate enantioselectivity has been achieved for the organocatalytic addition of Meldrum's acid derivatives to nitroalkenes (eqn 2).⁵ For each of the reported examples, high catalyst loading was also used.

The successful asymmetric addition of Meldrum's acid with high selectivity and catalyst efficiency is a worthwhile and important goal due to two distinctive properties of the Meldrum's acid structure. First, Meldrum's acid derivatives are more acid labile than malonates due to their acetal framework, thereby enabling a mild and convenient single step, acid-catalyzed process for tandem deprotection/decarboxylation to form the corresponding γ-amino acid derivatives.⁶ Second, Meldrum's acid derivatives (pK_a in DMSO = 7–8)⁷ are considerably more acidic than malonates (pK_a in DMSO = 16–17),⁷ resulting in new opportunities for reactivity and selectivity. In particular, the previously reported addition of malonates to cyclic nitroalkenes (eqn 1), presumably provides the more stable trans-disubstituted products through thermodynamic control as a consequence of the comparable acidity of the malonate nucleophile and the nitroalkane product (pK_a in DMSO = 16–17).⁷ Unfortunately, only a very modest thermodynamic ratio of trans-/cis-isomers for acyclic nitroalkene addition products with α- and β-stereocenters is likely to be observed (see below). The much greater acidity of Meldrum's acids relative to both malonates and nitroalkanes should enable efficient kinetic control and potentially high selectivity for additions to α,β-disubstituted nitroalkenes.⁸

Herein, we report that N-sulfinyl urea^9,10catalyst 8 at low catalyst loadings (0.2–3 mol%) provides the first highly enantio- and diastereoselective organocatalytic addition of Meldrum's acid derivatives to nitroalkenes (eqn 3). This work also provides the first example of the organocatalytic addition of any carbon nucleophile to acyclic α,β-disubstituted nitroalkenes to set both the α- and β-stereocenters in acyclic products with high enantio- and diastereoselectivity.¹¹ Significantly, the Meldrum's acid addition products undergo facile hydrolysis and decarboxylation under acidic conditions followed by reduction to directly afford enantioenriched γ-amino acids without epimerization. A representative addition product of Meldrum's acid to an α,β-disubstituted nitroalkene has also been converted to useful γ-amino acid-derivatives without epimerization. The practicality of our method is further demonstrated by the mole scale addition of cyclohexyl Meldrum's acid to nitroalkene 1b at only 0.2 mol% organocatalyst loading followed by one-step hydrolysis/decarboxylation to provide a known precursor to the drug S-Pregabalin (Lyrica),¹² which is used extensively for the treatment of neuropathic pain, as well as other disorders.^1b,c

Results

Reaction development

N-Sulfinyl ureas have emerged as promising enantioselective organocatalysts with the sulfinyl group serving as both a chiral directing group and electron withdrawing substituent^10a and have proven to be particularly effective for the addition of the acidic thioacetic acid pronucleophile.^10b The previously reported N-sulfinyl urea catalyst 3^10b (see Fig. 2) was used for initial screening in the enantioselective addition of Meldrum's acid to nitroalkenes 1. In cyclopentyl methyl ether (CPME), which has seen increasing use as solvent for large scale industrial applications,¹³ the addition to trans-β-nitrostyrene 1a proceeded at rt with 95% ee, while the alkyl nitroalkene 1b, which notably leads to the drug Lyrica,¹² provided the addition product 2b in 87% ee (eqn 4). With the goal of ultimately applying the method to the synthesis of Lyrica, we focused subsequent optimization studies on substrate 1b.

Recent reports for other urea catalysts have shown dramatic differences in the selectivity and activity arising from different tertiary amine moieties.¹⁴ On this basis, several new sulfinyl ureas were synthesized and tested in the enantioselective addition of Meldrum's acid to aliphatic nitroalkene 1b (Table 1). Catalysts 4–6, all bearing acyclic tertiary amines, uniformly reduced the enantioselectivity (entries 2–4). Cyclic tertiary amine catalysts, such as pyrrolidine 7 and piperidine 8, showed more promise, with catalyst 8 propelling the reaction to 91% conversion and 92% ee (entry 6). Free amine catalyst 9 exhibited poor solubility and poor conversion (entry 7). Interestingly, diastereomeric catalyst 10 gave drastically reduced selectivity, indicating a substantial matched–mismatched effect arising from the relative configurations of the sulfinyl and 1,2-diamine stereocenters (entry 8). tert-Butanesulfinyl urea 11 was also tested, but was found to be less selective than the corresponding trisyl sulfinyl urea 3 (entry 9).¹⁵

Fig. 2 Catalysts tested in the addition of Meldrum's acid to nitroalkenes.

Table 1 Identification of optimal catalyst

Entry	Catalyst	Conversion^a (%)	ee^b^,^c (%)
a Conversion was determined by ^1H NMR from the ratio of the product to starting material. b Enantiomeric excess was determined by chiral HPLC. c Absolute stereochemistry was determined by the correlation of the optical rotation of product 2b to the literature value.^5b
1	3	76	87
2	4	62	80
3	5	71	77
4	6	82	81
5	7	83	91
6	8	91	92
7	9	29	70
8	10	73	−64
9	11	70	79

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Low catalyst loading was sought to enhance the practical utility of this transformation. However, the reaction rate was limited by the low solubility of Meldrum's acid in CPME and other nonpolar solvents (more polar solvents result in diminished enantioselectivities). We postulated that using a more hydrophobic Meldrum's acid derivative might circumvent this problem. Indeed, cyclohexyl Meldrum's acid exhibited enhanced (∼4-fold at 23 °C) solubility in CPME. The resulting increase in the effective concentration allowed the catalyst loading to be reduced to 1 mol% at room temperature. Additionally, a slight increase in enantioselectivity was observed upon switching to cyclohexyl Meldrum's acid (Table 2, entry 2).

Table 2 Catalytic enantioselective addition of cyclohexyl Meldrum's acid to β-substituted nitroalkenes

Entry	R	Product^a	Yield^b (%)	ee^c (%)
a Reactions were performed with 1.0 mol% catalyst loading at 0.3 M concentration of substrate with 1.5 equiv. of cyclohexyl Meldrum's acid. b Isolated yield of analytically pure material after chromatography. c Enantiomeric excess was determined by chiral HPLC. d Reaction was run using 3.0 equiv. of cyclohexyl Meldrum's acid.
1	C6H5	12a	95	98
2	i-Bu	12b	90	94
3	o-MeC6H4	12c	94	96
4	p-MeC6H4	12d	99	98
5	p-CF3C6H4	12e	82	98
6	p-MeOC6H4	12f	99	96
7	o,p-Cl2C6H3	12g ^d	95	96
8	n-Pr	12h	94	94
9	c-Hex	12i	73	96

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Synthetic scope

The substrate scope was explored for the addition of cyclohexyl Meldrum's acid to various aromatic and aliphatic nitroalkenes 1 using 1 mol% of catalyst ent-8 (the enantiomer of catalyst 8) (Table 2). trans-β-Nitrostyrene 1a underwent addition in 95% yield and 98% ee (entry 1) and the aliphatic Lyrica precursor 1b gave the product 12b in 90% yield and 94% ee (entry 2). Substitution around the aromatic ring was well tolerated, giving up to 99% yield and 98% ee over a range of aromatic substrates (entries 3–7). The enantioselectivity was also excellent for both electron-deficient and -rich derivatives (entries 5 and 6, respectively). 2,4-Dichlorophenyl substrate 1g reacted more slowly, but increasing the amount of cyclohexyl Meldrum's acid afforded the product in 95% yield and 96% ee (entry 7). Moreover, both linear (entry 8) and branched (entries 2 and 9) β-alkyl substituted nitroalkenes provided addition products in good yields and with high selectivities (≥94% ee).

Additions to α,β-disubstituted nitroalkenes 13 would generate products 14 (Table 3) with two stereocenters, which are desirable for the preparation of bioactive compounds (e.g., see Fig. 1). However, these more highly substituted nitroalkenes present several additional challenges. Firstly, under basic conditions, the acidity of the proton α to the nitro group of 14 can cause epimerization of that stereocenter, leading to a thermodynamic ratio of diastereomers. Secondly, for acyclic nitroalkane products 14, the thermodynamic product ratio is very modest.¹⁶ Finally, the more substituted nitroalkenes 13 were expected to undergo addition at much slower rates. Nevertheless, we were pleased to find that using catalyst ent-8, α,β-disubstituted nitroalkene 13a afforded addition product 14a with almost perfect diastereoselectivity (Table 3, entry 1). An X-ray crystal structure of product 14a revealed that the relative stereochemistry is consistent with delivery of the nucleophile and proton to the same face of the nitroalkene.

Table 3 Catalytic enantio- and diastereoselective addition of cyclohexyl Meldrum's acid to α,β-disubstituted nitroalkenes

Entry	R1	R2	Product^a	Yield^b (%)	Crude d.r.^c	ee^d (%)
a Reactions were performed with 3.0 mol% catalyst loading at 0.6 M concentration of substrate and with 3.0 equiv. of cyclohexyl Meldrum's acid. b Isolated yield of analytically pure single diastereomers after chromatography. c Crude diastereomeric ratios were determined by ^1H NMR. d Enantiomeric excess was determined by chiral HPLC. e Absolute and relative stereochemistry was determined from an X-ray crystal structure. f Reaction was performed using 1.0 mol% catalyst. g Reaction was performed at 0.05 M concentration. h Reaction was performed at 0.3 M concentration using 1.5 equiv. of cyclohexyl Meldrum's acid.
1	C6H5	Me	14a ^e	90	97 : 3	93
2	p-CF3C6H4	Me	14b	71	95 : 5	94
3	p-MeOC6H4	Me	14c	91	96 : 4	92
4	p-ClC6H4	Me	14d	77	96 : 4	91
5	p-MeC6H4	Me	14e	91	97 : 3	92
6	C6H5	Bn	14f	74	98 : 2	90
7	C6H5	n-Bu	14g	70	99 : 1	83
8	–(CH2)4–	–(CH2)4–	14h ^f ^, ^g	78	87 : 13	91
9	–(CH2)3–	–(CH2)3–	14i ^f ^, ^g	93	98 : 2	97
10	–(CH2)5–	–(CH2)5–	14j ^f ^, ^h	92	>99 : 1	98

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We investigated the substrate scope for the enantioselective addition of cyclohexyl Meldrum's acid to a number of cyclic and acyclic α,β-disubstituted nitroalkenes 13 (Table 3). Despite the lower reactivity of these more challenging substrates, only 3 mol% of catalyst ent-8 was necessary for efficient conversion to addition products 14. Parent substrate 13a afforded the product in 97 : 3 dr, 93% ee, and after chromatography, a 90% isolated yield of a single diastereomer. Variation of the aromatic ring shows a high tolerance for both electron-rich and electron-poor derivatives, as well as various para-substituents (entries 2–5). The substituent alpha to the nitro group can also be varied from a simple methyl group to other groups such as benzyl (entry 6) and butyl (entry 7) groups. The less challenging cyclic α,β-disubstituted nitroalkenes are also effective substrates, affording products 14h–14j with high selectivities and yields. In fact, these cyclic substrates required only 1 mol% catalyst loading.

Applications to the synthesis of γ-amino acid derivatives

We then sought to demonstrate the utility of these addition products for the construction of biologically relevant γ-amino acid derivatives. Importantly, adduct 14a with two stereocenters can be readily converted to γ-amino acid derivatives² with retention of the stereochemical information (Scheme 1). The TsOH-catalyzed one-pot hydrolysis/decarboxylation¹² of 14a affords monoacid 16 in 93% yield and in a diastereomerically and analytically pure form after simple extractive isolation. Monacid 16 can then be reduced either using Zn dust and HCl to give diastereomerically pure γ-amino acid 17^2d in 97% yield or by SnCl₂ reduction/esterification conditions to provide the amino ethyl ester 18 in 61% overall yield, also in diastereomerically pure form.

Scheme 1 The synthesis of γ-amino acid scaffolds from adduct 14a.

Finally, we sought to demonstrate the utility of our method for drug production with the mole scale synthesis of Lyrica precursor 15 (Scheme 2). Although 1 mol% catalyst loading is sufficient for laboratory scale chemistry, further reduction of the catalyst loading is desirable for large scale drug production. With mild heating to 35 °C, complete conversion can be achieved with only 0.2 mol% of catalyst 8 and with only a very slight reduction in enantioselectivity. The crude addition product can be taken on directly to a one-pot hydrolysis/decarboxylation step, allowing for a telescoped overall process. Key Lyrica intermediate 15 was synthesized by this route on a one mole scale in 90% overall yield from nitroalkene 1b. A one-step conversion of intermediate 15 to Lyrica viahydrogenation has been reported in the literature.¹²

Scheme 2 Large-scale production of the key Lyrica intermediate.

Conclusion

In summary, we have introduced a practical method for constructing optically active γ-amino acids that utilizes cyclohexyl Meldrum's acid as a versatile monocarboxylic acid equivalent and piperidinyl sulfinyl urea 8 as a highly selective and efficient organocatalyst. Decarboxylation and nitro reduction can be performed to provide γ-amino acid derivatives without any loss of stereochemistry even for α,β-disubstituted nitroalkene inputs. The viability of this method toward drug production was demonstrated with the mole scale synthesis of Lyrica precursor 15 using only 0.2 mol% of catalyst 8. This method is not only the first example of the highly enantioselective addition of Meldrum's acid derivatives to nitroalkenes, but also provides the first example of the organocatalytic addition of any type of carbon nucleophile to acyclic α,β-disubstituted nitroalkenes to set both the α- and β-stereocenters in acyclic products with high enantio- and diastereoselectivity. The key to obtaining high diastereoselectivity is the acidic nature of Meldrum's acid vs. the more traditional malonate esters. We believe that Meldrum's acid will be similarly advantageous for a variety of transformations that are currently under investigation.

Acknowledgements

This work was supported by the NSF (CHE-1049571). We are grateful to Chris Incarvito and the Yale X-ray crystallography for solving the crystal structure of 14a, and to Chris Senanayake and Steve Han for providing trisyl sulfinamide at the early project stage.

Notes and references

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16. (a) The thermodynamic ratio of diastereomers 14a was found to be 1.3 : 1. The ratio was determined by ¹H NMR after the α-nitro stereocenter of 14a had been epimerized in the presence of excess triethylamine at 60 °C; (b) For an example of addition to acyclic α,β-disubstituted nitroalkenes in which low dr was observed, see: M. Ganesh and I. N. N. Namboothiri, Tetrahedron, 2007, 63, 11973–11983.

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Footnote

† Electronic supplementary information (ESI) available: CCDC reference numbers 833178. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1sc00441g

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