Asymmetric synthesis of heterocycles using sulfinimines ( N -sulfinyl imines)

The efficient asymmetric synthesis of nitrogen heterocycles including the quinolizidine alkaloid (-)-epimyrtine, indolizidine alkaloids 209B and 223A, and (-)-agelastatin A using easily prepared sulfinimine-derive chiral building blocks is described


Introduction
Sulfinimines, N-sulfinyl imines (R 1 -S(O)N=CR 2 R 3 ), developed in our laboratory, provide a general solution to the problem of addition of organometallic reagents to chiral imines.The electron-withdrawing sulfinyl group activates the C=N bond for addition, is highly stereodirecting, and is easily removed to give the enantiopure amine product. 1 In fact the most direct and reliable method for the asymmetric construction of diverse amine derivatives having nitrogen attached to a stereogenic center is the addition of an organometallic reagent to the C=N bond of an enantiopure sulfinimine.This includes the asymmetric synthesis of nitrogen heterocycles.
The current focus of our research is the design and synthesis of sulfinimine-derived polyfunctionalized chiral building blocks for the asymmetric synthesis of multi-substituted nitrogen heterocycles.We required these building blocks to be easily prepared in both enantiomerically pure forms and provide access to diverse classes of nitrogen heterocycles with a minimum of chemical manipulation and protecting group chemistry.In this context we have prepared N-sulfinyl δ-amino β-ketoesters for the asymmetric synthesis of 2,4,6-trisubstituted piperidines 2 and 2,3,5-trisubstituted pyrrolidines (prolines); 3 N-sulfinyl δ-amino β-ketoester enaminones for the synthesis of 2,4,6-trisubstituted piperidines; 4 β-amino Weinreb amides and β-amino ketones for the synthesis of 2,3,4,6-tetrasubstitued piperidines 5.6 and 2,3,4,5,6pentasubstituted piperidines; 7 aziridine 2-carboxylates for the synthesis of 2H-azirine 2carboxylates; 8 and aziridine-2-phosphonates for 2H-azirine-3-phosphonates (Figure 1). 9 Generally these building blocks are prepared in one pot by addition of an enolate species to a sulfinimine.The following examples demonstrate the utility of δ-amino β-ketoesters and β-amino ketones for the asymmetric synthesis of piperidine alkaloids.The piperidine ring system is a common motif found in many natural products, as well as drugs and drug candidates.Furthermore piperidines are precursors of more elaborate heterocycles including the quinolizidine and indolizidine ring systems.
The intramolecular Mannich reaction is a particularly useful transformation for the rapid and stereoselective assembly of functionalized piperidines and is illustrated by a short asymmetric synthesis of the quinolizidine alkaloid (-)-epimyrtine (8) (Scheme 1).2f Our synthesis employs δamino β-ketoester (+)-3 as a key intermediate.This sulfinimine-derived chiral building block is readily prepared by reacting N-sulfinyl β-amino ester (+)-2 with the sodium enolate of tert-butyl acetate.The β-amino ester (+)-2 is prepared in excellent yield and de by treating sulfinimine (+)-1 with the sodium enolate of methyl acetate.Removal of the sulfinyl group in (+)-3 with TFA/MeOH affords salt 4 that on reaction with acetaldehyde gives tetrasubstituted piperidine (+)-5 in 78% isolated yield for the two-step sequence.The fact that a single isomer was obtained is in accord with an intramolecular Mannich transition state TS-1.Decarboxylation of (+)-5, followed by deprotection and cyclization affords (-)-epimyrtine (Scheme 1) and represents a general route to this class of heterocycles.

Asymmetric Synthesis of (-)-Indolizidine 209B
To prepare a 2,3,6-trisubstituted piperidine employing the intramolecular Mannich protocol requires access to β-amino ketones.While β-amino ketones are found in several natural products and are precursors of the 1,3-amino alcohols they have been under utilized as chiral ARKAT building blocks because of the lack of methods to prepare them in enantiomerically pure form.We solved this problem by introducing β-amino Weinreb amides. 51 β-Amino Weinreb amides N-Sulfinyl β-amino Weinreb amides such as (+)-11 are prepared by reaction of the potassium enolate of N-methoxy-N-methylacetamide (9) with sulfinimine (S)-(+)-10 or lithium N,Odimethylhydroxylamine with the corresponding β-amino ester (+)-12 (Scheme 2). 5 This Weinreb amide reacts with excess methylmagnesium bromide to give the methyl ketone 13, with phenylmagnesium bromide to give the phenyl ketone 14; with 1-propynylmagnesium bromide to give the alkynyl ketone 15; and with DIBAL-H to give the aldehyde 16 (Scheme 2).These βamino ketones are stable, can be stored for long periods of time, and provide additional evidence for superb amine protecting group ability of the N-sulfinyl group.3.2 β-Amino ketones β-Amino ketones can be prepared directly, with excellent diastereoselectivity, by reacting the potassium enolates of methyl ketones with sulfinimines.6 For example, the potassium enolate of methyl ethyl ketone reacts with sulfinimine (R)-(-)-17 to give β-amino ketone (-)-18 in >96% de (Scheme 3).One-pot deprotection/protection of 18 with TsOH and 1,3-propanediol afforded the corresponding β-amino ketal (-)-19 in 87% isolated yield.This protected amino ketone is a valuable chiral building block for the asymmetric synthesis of polysubstituted, cis-2,6disubstitute piperidines: on reaction with aldehydes such as 20 it undergoes a facile, highly stereoselective intramolecular Mannich cyclization to give piperidine (-)-21 in 61% yield for the two steps (Scheme 3).Deprotection of the benzyloxy group and cyclization gave (-)-22.Removal of the keto group afforded the dendrobatide frog skin toxin (-)-indolizidine 209B (23).6 This synthesis represents the most efficient asymmetric synthesis of this alkaloid recorded to date.

Scheme 5
The major product was the syn-β-amino ketone (-)-28 isolated in 78% yield with the anti isomer being obtained in less than 8% yield.We noted an unusual solvent effect on the formation of the syn-and anti-isomers.The E enolate of 27 is believed to give to the synproduct 28.In diethyl ether the syn/anti-ratio was 10:1, but dropped to 4:1 in THF.These results were rationalized in terms of Ireland's transition state model: in the poorly coordinating diethyl ether solvent, increased steric interactions between the ethyl group and the carbonyl-LiN(TMS) 2 moiety destabilized the transition state leading to the Z enolate. 11ith the syn-β-amino ketone (-)-29 in hand the N-sulfinyl group was removed and free amine was immediately treated with crotonaldehyde to give the crude imine 29 in better than 93% yield.Treatment of 29 with TsOH afforded two Mannich products (+)-30 and (+)-31 in 18% and 58% yields, respectively (Scheme 5).Allyl bromide and (+)-31 gave diene 32 which when subject to ring-closing metathesis using 5% of Grubbs first generation catalyst, followed by hydrogen gave indolizidine (+)-33 in 72% yield.To remove the 7-oxo group the only method found to be successful was a radical deoxygenation protocol wherein the oxo group was reduced and the alcohol (+)-34 was transformed into the phenylthionocarbonate 35.On reaction with tri-ARKAT n-butyltin hydride and AIBN 35 afforded indolizidine alkaloid (-)-223A (24) in 74% yield.Our synthesis of (-)-24, the most concise to date was accomplished in nine steps (9.3% overall yield) from sulfinimines (-)-26.

Summary and Conclusions
Sulfinimine-derived chiral building blocks including δ-amino-β-ketoesters, β-amino Weinreb amides, β-amino ketones, and syn-2,3-diamino esters provide efficient access to enantiopure nitrogen heterocycles.Asymmetric syntheses using these polyfunctionalized building blocks are concise and require a minimum of protecting group chemistry.The examples given here illustrate new and general methodology for the asymmetric syntheses of complex nitrogen heterocycles in a highly stereocontrolled manner.

Figure 1 .
Figure 1.Examples of sulfinimine-derived chiral building blocks for the asymmetric synthesis of nitrogen heterocycles.