Synthetic Approach toward Enantiopure Cyclic Sulfinamides.

A synthetic approach toward densely substituted enantiopure cyclic sulfinamides possessing up to four consecutive stereogenic centers was developed based on a completely diastereoselective SN2' cyclization/tert-Bu cleavage sequence. Diastereospecific transformation of the obtained scaffold into chiral SVI derivatives such as sulfoximines and sulfonimidamides is demonstrated.

General utility of sulfinamides[1] may be largely obscured by the amount and versatility of synthetic applications[2] developed around Ellman’s and Davis’ chiral auxiliaries (Figure ). Yet the sulfinamide moiety has also found use in asymmetric synthesis as an integral part of organocatalysts[3] and ligands in metallocatalysis.[4] Although underappreciated[5] as structural fragments in drug discovery, sulfinamides have been established as a convenient synthetic platform[6] for more medicinally acknowledged sulfonamides and chiral SVI-compounds. In particular, recently developed stereoselective methodologies toward increasingly more popular[7] sulfoximines and sulfonimidamides rely on enantiopure sulfinamides as synthetic precursors.[8] The fact that the general value of enantiopure sulfinamides has been long recognized is eloquently demonstrated by the sheer effort dedicated to their preparation over the years.[9]

Figure 1

Utility of enantiopure sulfinamides.

However, despite a considerably wide scope existing entries are generally[10] inapplicable to cyclic structures. Hence the library of known enantiopure cyclic sulfinamides so far is limited to six- and five-membered congeners. Whereas the former have been approached[11] via hetero Diels–Alder reaction of N-sulfinyl dienophiles, the latter have been obtained[12] exclusively from Ellman’s sulfinamide derivatives (Scheme a) exploiting the lability of the t-Bu-substituent. Thus, the susceptibility of the t-Bu-group to radical scission was used in the synthesis of benzo-fused scaffolds.[12a] Radical SHi substitution at the S-atom directly delivers sulfinamides with configurational inversion at the S-stereocenter (eq 1, Scheme a). The rest of the known methods are based on stereoretentive acid-induced cleavage of S-tert-butylated sulfoximines. The sulfoximines in turn have been synthesized via [3 + 2] cycloaddition of N-sulfinyl imines with benzynes (eq 2),[12b,12c] AgNO3-catalyzed cyclization[12d] of ynol ethers (eq 3), and base-mediated cyclization[12e] of acetylenes (eq 4, Scheme a).

Scheme 1

Entries toward Enantiopure Five-Membered Cyclic Sulfinamides

The common feature of the listed approaches consists of the limited capacity to introduce new stereocenters due to unsaturation dictated by the structure of the substrate. On the other hand, denser stereodefined substitution would be not only highly desirable by modern diversity-oriented synthesis[13] but also rather realistic considering the richness of chemistry[2a] around Ellman’s auxiliary. Therefore, we envisioned a transformation starting with a novel 5-exo-trig cyclization of sulfinamides 1 to sulfoximines 2 (Scheme b). The intended S-allylation via SN2′ substitution would simultaneously install a new stereocenter and a synthetically useful vinyl handle. Subsequently, already well precedented t-Bu-removal would deliver sulfinamides 3 potentially accommodating up to four consecutive stereocenters. Previous success[14] in S-alkylation of N-alkyl t-Bu-sulfinamides added soundness to the hypothesis and encouraged us to put it to practical scrutiny.

The investigation began with the cyclization of the iodide 1a-I (Table ). Gratifyingly, deprotonation of 1a-I with non-nucleophilic NaH indeed led to the requisite sulfoximine 2a in moderate yield accompanied by the isomeric 4a (entry 1). More importantly 2a was formed as a single diastereomer, and its structure could be unambiguously determined by X-ray crystallographic analysis. Configuration of the S-atom in 2a was apparently retained with respect to the precursor 1a-I, while the newly installed vinyl opposed the t-Bu-group. On the other hand, independent conversion of 2a to 4a upon exposure to NaH ascertained that deprotonation at the allylic position should be responsible for the observed isomerization. While attempting chromatographic purification of 2a, we also determined that the intended t-Bu-cleavage leading to sulfinamide 3a is quite facile and can be accomplished with as weak an acid as silica gel. Therefore, the outcome of subsequent cyclization experiments was assessed by 1H NMR and sulfinamide 3a was isolated only in selected entries.

Table 1

Optimization of Reaction Conditionsa

Entry	Hal	Base	Solvent	2a (%)b	4a (%)b	5a (%)b	3a (%)c
1	I	NaH	THF	60	5
2	I	LiHMDSd	THF	20	5	20
3	I	NaHMDSd	THF	64	4		60
4	I	KHMDSd	THF	18	36
5	I	NaHMDSd	Et2O	62	4
6	I	NaHMDSd	DCM	79
7	I	NaHMDSd	Toluene	80			75
8	I	NaHMDSe	Toluene	85			80
9	Br	NaHMDSe	Toluene	84			80
10	Cl	NaHMDSe	Toluene	71
11	Cl	KOH	DMA		26	57

Performed on 0.15 mmol scale with 2.2 equiv of base in 15 mL of solvent.

1H NMR yield measured against mesitylene as internal standard.

Isolated yield.

In THF.

In toluene.

In order to explore the counterion effect we switched to hexamethyldisilamide bases conveniently available as THF solutions (Table , entries 2–4). Reaction with LiHMDS reflected the usual[15] propensity of sulfinamides for N-alkylation manifested in formation of azetidine 5a. While KHMDS produced a dramatically increased amount of isomerization, NaHMDS performed similarly to NaH. The degree of NaHMDS aggregation has been reported to depend significantly on the solvent.[16] Therefore, we speculated that excessive basicity leading to poorly separable 4a could be mitigated by weaker coordinating media (entries 5–7). Although Et2O failed to improve the situation, DCM and toluene performed equally well affording 2a with markedly improved yields without formation of 4a. Additional improvement was obtained by complete exclusion of THF from the reaction media utilizing NaHMDS in toluene (entry 8). Thus, the yield of the intermediate 2a was increased to 85% and subsequent t-Bu-cleavage delivered sulfinamide 3a with 80% yield. Finally, bromide 1a-Br was found to be an equally competent substrate in the cyclization (entry 9), while chloride 1a-Cl displayed slightly inferior behavior (entry 10). Interestingly, the selectivity of cyclization with 1a-Cl could be largely reversed in favor of N-alkylation (entry 11).

In view of the limited stability of allylic iodides, the scope of the transformation was explored using bromide substrates 1-Br (Scheme ). Excellent reactivity was observed in the case of monoalkyl substituted 1a–d-Br. Aryl containing precursors 1e–g-Br were also efficiently converted to the corresponding sulfinamides 3e–g. The crystal structure[17] obtained for 3e decisively confirmed the stereoretentive character of the t-Bu-cleavage. Notably, the developed standard conditions were successfully applied in a gram-scale synthesis of 3g. However, for reasons not fully understood heteroaryl-containing sulfinamides 3h,i were obtained with considerably lower yields. Quaternary centers in 3j,k and additional substitution at the double bond in 3l were found to be a small hurdle for the transformation. Importantly, no loss of enantiopurity could be detected in the corresponding conversion of 1k-Br to 3k. Furthermore, the crystal structure obtained for 3k mirrored syn S-O and vinyl alignment already established for 3e. Successful preparation of sulfinamide 3m conformed well to our declared aim at densely substituted structures.

Scheme 2

Transformation Scope

Finally, transformation of epimers epi-1a-Br and epi-1d-Br addressed the influence of stereocenters next to the N-atom. The respective sulfinamides iso-3a and epi-3d were obtained with the anti arrangement of the vinyl and α-N-substituent contrary to 3a and 3d. Complementary to the case of 3k, this observation concludes that the new stereocenter must be controlled solely by the initial configuration at the S-atom placing the vinyl syn to S–O in an entirely stereospecific manner. Of additional note may be the attempt to expand the cyclization scope to the 6-exo-trig mode using homologous substrate 6. Despite favorable all equatorial positioning of substituents in the speculative S-alkylation product, only the five-membered N-alkylation 7 was obtained. This result suggests that the dominant S- instead of N-alkylation in the case of substrates 1 is most likely determined by the typical kinetic preference[18] for five-membered cycles.

Analysis of the acquired data allowed us to devise a stereochemical model accounting for the net stereochemical outcome of the transformation (Scheme ).[19] The envelope geometry of the transition state proposed for the cyclization step may be derived from the crystal structures obtained for sulfoximines 2a and 2g. Nucleophilic Si attack of the S-lone pair on the double bond of 1 leads to the favored TS1 and consequently to 2 with the vinyl opposed to the t-Bu-group. Subsequent stereoretentive removal of the latter affords sulfinamides 3 with the observed syn vinyl and S–O arrangement. Conversely, Re attack would result in congested TS2 featuring pronounced steric clash between the t-Bu-group and the halomethylene unit of 1. Hence, the corresponding anti vinyl and S–O alignment has not been detected in either sulfoximines 2 or sulfinamides 3.

Scheme 3

Stereochemical Model

Since the chemistry of cyclic sulfinamides like 3 is scarcely presented in literature, we decided to screen the behavior of the obtained scaffold in relevant synthetic transformations using 3g as a typical representative (Scheme ). Thus, chemoselective S-oxidation[20] delivered sulfonamide 8, which belongs to the class of medicinally privileged γ-sultams.[21] Another modification at the S-atom resulted in sulfenimine 9 in the course of a Pummerer-like reaction.[22] The reactivity of the double bond was probed in reductive ozonolysis cleanly affording 10. In spite of the previously noted base-induced isomerization of 2a, N-alkylation of 3g leading to 11 could be accomplished with a synthetically useful yield. As an alternative option to utilize the double bond in 3g we considered Simmons–Smith cyclopropanation.[23] Surprisingly, the respective fairly standard conditions delivered sulfoximine 12 as the major product rather than the expected cyclopropane. The single comparable example of such atypical reactivity was reported by Zercher et al. and regarded primarily as an undesirable synthetic obstacle.[24] Meanwhile, intrigued by the chemo- and stereospecificity observed in the formation of 12 we plan to explore this valuable transformation in greater detail. Further modifications of 3g included diimide reduction[25] to 13, which in turn was smoothly converted to the tertiary sulfinamide 14. Finally, electrophilic NH transfer under reported conditions[26] resulted in stereospecific formation of sulfonimidamide 15 with anticipated configurational retention at S-atom as confirmed by X-ray crystallographic analysis.

Scheme 4

Synthetic Modifications of the Product Scaffold

In summary, the transformation presented herein opens access to enantiopure sulfinamide scaffold 3 via a facile cyclization–deprotection sequence. The cyclization proceeds with retention of configuration at the S-atom and stereospecific introduction of the additional vinyl substituent, while subsequent mild deprotection completely preserves the installed stereochemical arrangement. These features enable synthesis of densely substituted structures accommodating up to four consecutive stereocenters. Complementary to the existing methods[12] our methodology considerably enriches the library of yet underexplored cyclic sulfinamides. Moreover, disclosed additional modifications at S- and N-atoms as well as at the vinyl handle suggest the promising potential of the obtained scaffold in synthetic and medicinal chemistry. Specific relevance for the latter is demonstrated by preparation of γ-sultam 8, sulfoximine 12, and sulfonimidamide 15.