Stereoselective reaction of 2-carboxythioesters-1,3-dithiane with nitroalkenes: an organocatalytic strategy for the asymmetric addition of a glyoxylate anion equivalent

Abstract

An efficient organocatalytic methodology has been developed to perform the stereoselective addition of 2-carboxythioesters-1,3-dithiane to nitroalkenes. Under mild reaction conditions γ-nitro-β-aryl-α-keto esters with up to 92% ee were obtained, realizing a formal catalytic stereoselective conjugate addition of the glyoxylate anion synthon. The reaction products are versatile starting materials for further synthetic transformations; for example, the simultaneous reduction of the nitro group and removal of the dithiane ring was accomplished, allowing the preparation of a GABA_B receptor agonist baclofen.

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Introduction

Chiral α-keto esters are considered products of great importance, as starting materials for the preparation of highly functionalized compounds via synthetic manipulation of their functional groups.¹ They also find successful applications in biochemistry and are an integral part of several biologically active natural compounds.² Therefore, it is not surprising that the stereoselective synthesis of chiral α-keto esters is still the object of intense studies. Recently a novel approach was proposed by Johnson, who described a copper(II)-catalyzed aerobic oxidation reaction as a key step for the preparation of β-substituted α-keto esters, in a procedure where acetoacetate esters were used as glyoxylate anion synthons.³

However, most of the reported synthesis of chiral α-keto esters rely on the umpolung strategy that allows the introduction of a nucleophilic acyl anion synthon,⁴N-heterocyclic carbenes are known for their ability to reverse the polarity of aldehydes, to generate acyl anion equivalents that have been widely employed in benzoin and Stetter-type reactions.⁵ More traditional methods involve the use of metalated aminonitriles⁶ and 1,3-dithiane-protected glyoxylates,⁷ prepared by deprotonation with stoichiometric amounts of a strong base.⁸ It must be noted that all of these methods suffer from intrinsic limitations and problems (limited general applicability, low yields, modest stereoselectivity, and strongly depending on reactant substrates); in addition, examples of direct synthesis of enantiomerically enriched keto esters are still very rare, especially those related to the preparation of enantiopure β-aryl-α-keto esters, where the strong acidity of the proton in the β position represents a real issue for any successful stereoselective methodology.

With the goal to develop a metal-free catalytic strategy for the synthesis of chiral β-substituted-α-keto esters, we decided to study the addition of 1,3-dithiane-2-carboxy derivatives to nitroalkenes. Surprisingly, a catalytic stereoselective version of this powerful transformation seems to be unknown.⁹ Here we wish to report the first enantioselective organocatalytic conjugate addition of 2-carboxythioesters-1,3-dithiane to nitroalkenes.

At the beginning of our investigation the chemical reactivity of different 2-carboxyester 1,3-dithianes was investigated in the presence of a cinchona-derived bifunctional catalyst A (Scheme 1)¹⁰.

Scheme 1 Preliminary studies of organocatalytic addition of dithianes to nitrostyrene.

Commercially available 1,3-dithiane-2-ethylcarboxylate 2 in the presence of 20 mol% of quinine-thiourea derivative A did not react at all with nitrostyrene. The corresponding S-phenyl thioester 4 showed poor reactivity, affording the corresponding addition product 5 in low yields, even after prolonged reaction times, although in a remarkable 89% enantioselectivity (entries 2 and 3, Table 1). As expected 2-pyridylthioester 6 afforded adduct 7 in higher yields; unfortunately the reaction product turned out to be not very stable, thus preventing the determination of its enantiomeric excess. Finally the use of 2-S-trifluoroethyl carboxy-thioester-1,3-dithiane 8 gave the best results; after 24 hours at RT the stable conjugate addition product 9 was obtained in 71% yield and 87% ee.¹¹

Table 1 Chemical activity of 2-substituted 1,3-dithianes

Entry^a	X	Product	t (h)	Yield^b (%)	ee^c (%)
a Typical reaction conditions: 0.1 mmol of nitroalkene, 0.2 mmol of dithiane, 0.02 mmol of catalyst A, 1 mL of toluene. b Yields were determined after chromatographic purification. c Enantiomeric excess determined by HPLC on a chiral stationary phase.
1	OEt	3	24	—	—
2	SPh	5	24	16	89
3	SPh	5	72	25	87
4	SPy	7	24	41	n.d.
5	SCH2CF3	9	24	71	87

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The use of 1,1,1-trifluoroethyl thioester was documented for the first time by Barbas in an organocatalytic Michael reaction.¹² Later, our group took advantage of low pK_a of the protons in the α position of the carboxy group in the trifluoroethyl thioesters to realize the first organocatalytic direct aldol reaction between a thioester and an aromatic aldehyde.¹³ Due to its favorable reactivity profile (entry 5, Table 1), thioester 8 was selected as a reagent of choice and its addition to nitrostyrene was studied in the presence of different chiral bifunctional organocatalysts (Scheme 2).

Scheme 2 Chiral organocatalysts investigated in the 1,3-dithiane addition to nitrostyrene.

In the model reaction performed in toluene for 24 hours at room temperature 2 mol eq. of thioester 8 were reacted with 1 mol eq. of nitrostyrene in the presence of 0.2 mol eq. of a catalyst. Based on the good results obtained with catalyst A, another successful thiourea-based bifunctional catalyst, Takemoto catalyst B,¹⁴ was tested; the product was isolated in higher yield but lower enantioselectivity than the cinchona-derived catalyst A (entries 1 and 2 of Table 2, 67% ee for catalyst Bvs. 87% ee for A).

Table 2 Screening of chiral organocatalysts in the 1,3-dithiane addition to nitrostyrene

Entry^a	Catalyst	Yield^b (%)	ee^c (%)
a Typical reaction conditions: 0.1 mmol of nitroalkene, 0.2 mmol of dithiane, 0.02 mmol of catalyst A, 1 mL of toluene. b Yields were determined after chromatographic purification. c Enantiomeric excess determined by HPLC on a chiral stationary phase.
1	A	71	87
2	B	81	67
3	C	55	75
4	D	53	51
5	E	41	37
6	F	53	<5
7	G	55	31
8	H	73	37
9	I	15	<5
10	L	51	21
11	M	47	7
12	N	57	<5

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Therefore we turned our attention to the variation of different structural elements of quinine-derived catalyst A; for example with the cinchonidine derivative C, lacking the methoxy group on the quinolone ring, a little decrease in enantioselection was observed (75% vs. 87%). A modification of the same alkoxy group was deleterious for enantioselectivity (see entries 4 and 5, catalysts D and E). Compounds F–I clearly demonstrated the crucial role exerted by the thiourea moiety which cannot be replaced by alternative hydrogen bond donor groups. In addition, when squaramides L–N,¹⁵ derived from quinine or trans-diamine-cyclohexane, were tested, very low enantioselectivities were obtained.

Once compound A was selected as a catalyst of choice, a few reaction parameters were optimized (Table 3).

Table 3 Solvent screening for the organocatalyzed addition of dithiane 8 to nitrostyrene

Entry^a	Solvent	Temp. (°C)	Yield^b (%)	ee^c (%)
a Typical reaction conditions: 0.1 mmol of nitroalkene, 0.2 mmol of dithiane, 0.02 mmol of catalyst A, 1 mL of toluene. b Yields were determined after chromatographic purification c Enantiomeric excess determined by HPLC on a chiral stationary phase. d Reaction run with 10 mol% of a catalyst. e Reaction run with 5 mol% of a catalyst.
1	Toluene	25	71	87
2	DCM	25	55	80
3	CH3CN	25	80	41
4	Hexane	25	75	57
5	Et2O	25	73	67
6	Toluene	0	60	92
7	Toluene	−20	61	66
8^d	Toluene	25	55	81
9^e	Toluene	25	47	80

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The reaction tolerates different solvents, although only dichloromethane guaranteed the same level of ee as toluene (80% ee at RT). Lowering the reaction temperature to 0 °C had a positive effect, allowing isolating the product in 92% ee; lower temperatures did not give satisfactory results. It is noteworthy that the loading of the catalyst could be decreased to 10 mol% and even to 5 mol% with only a marginal loss of enantioselectivity, albeit with diminished chemical yield. The general applicability of the methodology was then investigated (Scheme 3, eqn (a)).

Scheme 3 Organocatalytic 1,3-dithiane addition to different nitroalkenes.

Differently substituted nitro alkenes were easily prepared¹¹ and reacted with dithiane 8 in the presence of catalyst A (Table 4).

Table 4 General applicability of the catalytic methodology

Entry^a	R	Product	Yield^b (%)	ee^c (%)
a Typical reaction conditions: 0.1 mmol of nitroalkene, 0.2 mmol of dithiane, 0.02 mmol of catalyst A, 1 mL of toluene at 25 °C. b Yields were determined after chromatographic purification. c Enantiomeric excess determined by HPLC on a chiral stationary phase. d Reaction run at 0 °C.
1	Ph	9	71	87
2^d	Ph	9	60	92
3	4-CF3Ph	10	41	53
4	4-ClPh	11	81	86
5	4-CH3Ph	12	71	73
6	2-CH3Ph	13	43	67
7	4-OCH3Ph	14	75	73
8	2-OCH3Ph	15	80	71
9	2-OAcPh	16	55	85
10	i-Pr	n.r.	—	—
11	CH2CH2Ph	n.r.	—	—

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The reaction works with nitrostyrenes substituted both in ortho and in para positions, with electron rich or poor substituents, leading to products with enantioselectivities ranging typically between 70% and 92%. Typically less reactive alkyl nitro alkenes¹⁶ did not react under the present conditions (entries 10 and 11); however, 4-nitro-1-phenyl butadiene reacted smoothly to afford product 17, bearing a styryl moiety in 61% yield and 71% ee (eqn (b), Scheme 3).

In order to establish the absolute configuration of the addition products, compound 11 was treated with powdered zinc and 6 M HCl¹⁷ to afford enantiomerically enriched lactam 18, which was determined to be in the (S) configuration by comparison of optical rotation power values. Indeed final hydrolysis with hydrochloridric acid afforded (S)-baclofen 19 (Scheme 4).¹⁸

Scheme 4 Synthesis of baclofen.

Therefore, the method offers a straightforward access to a direct precursor of baclofen-type derivatives, GABA_B receptor agonists used in the treatment of spasticity and alcohol dependence.¹⁹

Finally, conversion of the addition products into the corresponding α-ketothioesters was achieved by reaction with N-bromosuccinimide in acetone (Scheme 5).²⁰

Scheme 5 Synthesis of β-aryl-α-keto thioesters.

For example, compounds 9–11 were quantitatively converted to α-ketothioesters 20–22. Interestingly, upon treatment of 20–22 with silver trifluoroacetate, β-nitro esters 23–25 were obtained (Scheme 5).²¹

The procedure afforded compounds 20–22 without affecting the stereochemical integrity of the starting materials. For instance, a sample of (R)-9 (53% ee) was quantitatively transformed into α-ketothioester 20 through a 4 hour reaction with NBS in acetone at 0 °C, and then reacted with CF₃CO₂Ag in methanol to give the known (R)-β-nitro methylester 23²² in 70% yield, its absolute configuration reflecting that of the starting compound 9 without appreciable variation of the enantiomeric excess.²³

In proposing a stereoselection model, the coordination of both reaction partners to the bifunctional catalyst may be envisaged, the substrate nitro group being engaged in hydrogen bonds by the thiourea moiety, and the charged quinuclidine nitrogen possibly forming an ion pair with the nucleophile (Fig. 1).

Fig. 1 Proposed stereoselection model.

Accordingly, with the quinine-derived catalyst, the thioester attack occurs on the nitroalkene Si face, affording the experimentally observed (S)-configured product.

In conclusion, the enantioselective organocatalyzed conjugate addition of a newly activated thioester acting as an acyl anion mimic has been performed. The use of chiral bifunctional catalysts to control the stereochemical outcome through a hydrogen bond network imposed by the thiourea moiety afforded good yields and enantioselectivities up to 92%. This methodology represents an entry to highly functionalized, enantiomerically enriched products, such as γ-nitro-β-aryl-α-keto thioesters, valuable precursors of a wide variety of chiral organic compounds.

Acknowledgements

M. B. thanks COST action CM9505 “ORCA” Organocatalysis. E. M. and A. G. thank the University of Milan for PhD fellowships.

References

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23. See the ESI† for HPLC traces.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details for nitrostyrene derivatives synthesis, catalysts preparation and organocatalytic reactions. Characterization details for Michael addition products and Baclofen synthesis. Determination of absolute configuration of the reaction products. ¹H-NMR, ¹³C-NMR and ¹⁹F-NMR spectra and HPLC chromatograms on the chiral stationary phase of addition products. See DOI: 10.1039/c5ob00492f

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