Enantioselective Synthesis of Cyclopropanone Equivalents and Application to the Synthesis of β-Lactams

Enantioselective Synthesis of Cyclopropanone Equivalents and Application to the Synthesis of β-Lactams. Cyclopropanone derivatives have long been considered unsustainable synthetic intermediates due to their extreme strain and kinetic instability. Herein, we report the enantioselective synthesis of 1-sulfonylcyclopropanols as stable yet powerful equivalents of the corresponding cyclopropanone derivatives, via α-hydroxylation of sulfonylcyclopropanes using a bis(silyl) peroxide as electrophilic oxygen source. Both the electronic and steric nature of the sulfonyl moiety, which serves as a base-labile protecting group and confers crystallinity to these cyclopropanone precursors, were found to have a crucial impact on the rate of equilibration to the corresponding cyclopropanone, highlighting the modular nature of these precursors and the potential for their widespread adoption as synthetic intermediates. The utility of these cyclopropanone surrogates is demonstrated in a mild and stereospecific formal [3+1] cycloaddition with simple hydroxylamines acting here as nitrene equivalents, leading to the efficient formation of chiral β-lactam derivatives. ABSTRACT: Cyclopropanone derivatives have long been considered unsustainable synthetic intermediates due to their extreme strain and kinetic instability. Herein, we report the enantioselective synthesis of 1-sulfonylcyclopropanols as stable yet powerful equivalents of the corresponding cyclopropanone derivatives, via α -hydroxylation of sulfonylcyclopropanes using a bis(silyl) peroxide as electrophilic oxygen source. Both the electronic and steric nature of the sulfonyl moiety, which serves as a base-labile protecting group and confers crystallinity to these cyclopropanone precursors, were found to have a crucial impact on the rate of equilibration to the corresponding cyclopropanone, highlighting the modular nature of these precursors and the potential for their widespread adoption as synthetic intermediates. The utility of these cyclopropanone surrogates is demonstrated in a mild and stereospecific formal [3+1] cycloaddition with simple hydroxylamines acting here as nitrene equivalents, leading to the efficient formation of chiral β -lactam derivatives.


INTRODUCTION
The rearrangement of strained ketone derivatives, typically yielding ring-expanded or ring-opened products, constitutes a key strategy for the elaboration of complex molecules relevant to the pharmaceutical industry. 1 While myriad transformations have been developed with small cyclic ketones such as cyclobutanones, 2 the analogous use of cyclopropanone derivatives as substrates has seriously lagged behind due to the kinetic instability often associated with these compounds, as a result of their extreme strain and multiple decomposition pathways. Indeed, while cyclopropane and cyclobutane derivatives generally possess similar strain energies, the corresponding cycloalkanones differ in this regard by ca. 20 kcal/mol (Scheme 1a). 3 Although cyclobutanone derivatives are known to be relatively stable and in some cases are commercially available, cyclopropanones often decompose instantly at room temperature, as they are kinetically unstable to heat, light and moisture. 4 The most common decomposition pathways involve either polymerization (heat-and moisture-induced), decarbonylation to alkenes (lightinduced), or nucleophilic ring-opening as in the Favorskii rearrangement. 5 Nevertheless, cyclopropanone itself has been previously prepared by reaction of diazomethane with ketene at -78 °C followed by distillation at the same temperature, 6 affording an ethereal solution that must be used immediately at low temperature. A more common and practical approach popularized by Wasserman in the 1960's involves the use of alcohol adducts of cyclopropanone derivatives, such as cyclopropanone hemiketal 1, that can be transformed in situ to the corresponding strained ketone via base-or acid-induced α-elimination (Scheme 1b). 4d,7 Due in part to the poor leaving group ability of alkoxides, these unstable precursors require harsh conditions to equilibrate to the corresponding cyclopropanones, which is problematic considering the kinetic instability of these highly strained species. This paradox is the critical reason why these hemiketal precursors to cyclopropanone are rarely suitable substrates and often lead to low yields of desired rearranged prod-ucts. 4d The absence of a general class of well-behaved cyclopropanone precursors has thus largely defined these highly strained species as chemical curiosities rather than useful building blocks in organic synthesis. By analogy to the use of sulfinic acid adducts as base-labile protecting groups for unstable aldehydes and imines in nucleophilic addition chemistry, 8 Chen reported that the phenylsulfinic acid adduct of unsubstituted cyclopropanone 2a, a white crystalline solid, is more reactive and surprisingly wellbehaved as compared with classical hemiketals, with equilibration to cyclopropanone taking place in mildly basic conditions at room temperature or below (Scheme 1c). 9 We envisioned that such stability and increased reactivity of 1-sulfonylcyclopropanols could be key to unlocking the tremendous potential of cyclopropanone derivatives as synthetic intermediates, allowing reactions to proceed under mild conditions and thus suppressing undesired decomposition pathways. Moreover, the steric and electronic tunability of the sulfinic acid leaving group in these compounds could prove beneficial to establishing a general class of cyclopropanone precursors. Herein, we report the first enantioselective synthesis of 1sulfonylcyclopropanols via an unprecedented α-hydroxylation of readily accessible cyclopropylsulfones using a bis(silyl) peroxide reagent as oxidant, and their application as substrates in a novel stereospecific formal [3+1] cycloaddition with simple hydroxylamines, leading to enantioenriched β-lactams (Scheme 1d). 10 Kinetic studies using a pyrazole trapping reaction reveal the crucial influence of the sulfinic acid leaving group's steric and electronic properties, where hindered and/or electron-poor derivatives led to considerably faster equilibration to cyclopropanone, highlighting the modular reactivity of these substrates. Considering the breadth of reported transformations using strained ketones in organic synthesis, 1 our studies should find widespread application in the elaboration of complex molecules using previously inaccessible cyclopropanone-based rearrangements.

RESULTS AND DISCUSSION
Synthesis of unsubstituted derivatives and kinetic study of their equilibration to cyclopropanone. We theorized that establishing the equilibrium between 1-sulfonylcyclopropanols and cyclopropanones would be key to subsequent reaction development efforts using these substrates. To do so, we sought to access electronically and sterically differentiated achiral sulfonylcyclopropanols (2) to evaluate the effect of the leaving group on such an equilibrium (Scheme 2). Prior to this work, only the phenylsulfonyl-(R = Ph, 2a) and p-tolylsulfonyl-(R = 4-Me-C6H4) substituted achiral sulfonylcyclopropanols had been reported by Chen in moderate yields, and the procedure required distillation and isolation of hemiketal intermediate 1, 7c as well as recrystallization of the final product. 9a Building on this approach, we first optimized a practical and general one-pot protocol leading to variously substituted 1sulfonylcyclopropanols 2a-2n in moderate to excellent yields (Scheme 2a). Starting from commercially available (1ethoxycyclopropoxy)trimethylsilane, acid-mediated cleavage of the silyl group rapidly affords a solution of hemiketal 1, which is directly treated with the corresponding sodium sulfinate salt in presence of formic acid and water at room temperature. Using these conditions, cyclopropanone precursors 2a-2n were directly obtained in pure form after aqueous workup without the need for isolation of 1, and the procedure was applied on gram-scale with similar efficiency. 11 With these substrates in hand, we employed a novel pyrazole substitution reaction leading to adduct 3 to evaluate the relative rate of conversion of the sulfonylcyclopropanols to cyclopropanones (Scheme 2b). Such a trapping reaction was found to be particularly clean and occurred at a rate that was easy to follow by NMR at room temperature. Considering the highly strained and energetic character of cyclopropanone, 3,4 it is anticipated that the initial equilibrium leading to its formation is rate-limiting of the overall process. Hence, the relative rates measured for each precursor 2 in this reaction should be indicative of their relative propensity to equilibrate to cyclopropanone. In a general manner, electronpoor sulfinate adducts were found to react faster (e.g. see 2a-2c vs 2d-2e), presumably due to the increased electronic stabilization and reduced nucleophilicity 12 of the corresponding sulfinate anion leaving group RSO2HNEt3 (Scheme 2b, top). Moreover, evaluation of alkylsulfinic acid adducts 2i-2m enabled an assessment of the effect of steric hindrance on the sulfonylcyclopropanol's propensity to equilibrate to cyclopropanone, where encumbered substrates (e.g. 2m) were generally found to be more reactive (Scheme 2b, bottom). This is likely due to the fact that sterically congested sulfonylcyclopropanols benefit from a greater torsional (Pitzer) strain release during the rate-limiting α-elimination process, even though ring (Baeyer) strain is significantly increased in all cases. These observed trends are further reinforced by the fact that particularly hindered 2h or electron-poor 2n 1-sulfonylcyclopropanols could not be obtained using our optimized procedure, as they were found to be too unstable to isolation and only led to decomposition, likely due to spontaneous equilibration to cyclopropanone. 13 The results of the kinetics observed using 2a-2n highlight the modular nature of 1-sulfonylcyclopropanols as cyclopropanone equivalents, where a wide spectrum of equilibration rates could be obtained through simple modification of the sulfonyl group.
Scheme 2. Synthesis of unsubstituted 1-sulfonylcyclopropanols (a) a and structure-reactivity relationship in a pyrazole substitution (b) b a Isolated yields. b NMR yields for each timepoint were determined by 1 H NMR analysis using 1,3,5-trimethoxybenzene as standard.
Enantioselective synthesis of substituted 1-sulfonylcyclopropanols. In order to apply the procedure detailed above to the formation of chiral, substituted 1-sulfonylcyclopropanol derivatives, one would need to access the corresponding enantioenriched hemiketal intermediates prior to addition of the sulfinate salt. While the Simmons-Smith cyclopropanation of α-substituted silyl ketene acetals, leading to such hemiketals, has previously been reported, 14 it is not general, leads to mixtures of diastereomers, and to date, cannot be efficiently performed in an enantioselective manner (Figure 1a

Electronic effects
slow

2a-2n 3
enantioenriched α-substituted β-chloroesters (Figure 1a, right), 10 although such a process is only known for a 2-methyl-substituted hemiketal (R 1 = H, R 2 = Me). Moreover, the radical character of this transformation strongly limits the nature of the possible substituents around the cyclopropane ring, in addition to the fact that access to such halogenated substrates in their enantioenriched form is not straightforward and generally requires multiple steps. For these reasons, we decided to design and optimize a more direct and practical approach involving a base-mediated α-hydroxylation of enantioenriched sulfonylcyclopropanes (Figure 1b), which are readily accessible substrates with a wide variety of possible substitution patterns (vide infra). 15 Unlike with carbonyl compounds and carboxylic acid derivatives, a significant challenge inherent to the α-hydroxylation of sulfones is the propensity of the resulting α-sulfonyl alkoxide intermediates to decompose to the corresponding carbonyl compound and sulfinic acid salt through α-elimination. 8,16 In this case, such an event would lead to the cyclopropanone that would likely decompose under the reaction conditions. Because of the endothermic nature of this undesired elimination, it was envisioned that performing the reaction with a highly reactive electrophilic reagent at -78 °C could minimize this undesired pathway and allow us to isolate reasonable amounts of the chiral 1-sulfonylcyclopropanols (Table 1). While the use of common electrophilic hydroxylation reagents such as oxaziridines led to either poor yield or undesired side-products (entries 1-3), it was found that the use of bis(triethylsilyl) peroxide D as oxidant, 17 previously reported for the radical alkylation of amides, 18,19 afforded promising results when added in the presence of BF3•OEt2 (entries 4-9). 11,20 In order to obtain a substantial yield of the hydroxylated product, it was found that quenching the reaction at -78 °C using a solution of AcOH in toluene was necessary to protonate the α-sulfonyl alkoxide intermediate initially formed at low temperature, and thus suppress its decomposition following αelimination (entry 4 vs 5). Changing the solvent from THF to either t-BuOMe or DME significantly increased the yield (entries 12-13), both affording similar results for 5a but later found to give significantly different yields depending on the substrate, likely due to variations in solubility. 11 A number of enantioenriched arylsubstituted substrates (4a-4e) were readily prepared using Iwasa's Ru-catalyzed asymmetric cyclopropanation of alkenes with αdiazomethyl phenyl sulfone (Scheme 3, Method A). 15a Using our αhydroxylation conditions, highly enantioenriched 1sulfonylcyclopropanols 5a-5e were obtained in moderate to excellent yields as single diastereomers favoring retention of configuration at the α-position, as evidenced by X-ray crystallographic analysis (5a). H NMR analysis of the crude mixture using either 1,3,5-trimethoxybenzene or maleic acid as standard. b The αbenzoylated product (57%) was obtained. c An α-dihydrocinnamoylated product (23%) was obtained resulting from equilibration to cyclopropanone. 11 d Reaction was quenched at -78 °C with a solution of AcOH in toluene prior to warming to rt. e Isolated yield. f Reaction was quenched after 15 min instead of 2 h. Scheme 3. Scope of accessible substituted 1-sulfonylcyclopropanols via α-hydroxylation of cyclopropylsulfones a,b a Isolated yields. b Enantiomeric excesses determined by HPLC analysis using a chiral stationary phase (ee of 4 in parentheses). c Racemic substrate 4 was used. d The corresponding cyclopropanone is achiral. The general reactivity trend observed revealed that electron-poor substrates afford higher isolated yields in this transformation (e.g. 5c and 5d), with most reactions proceeding with complete retention of stereochemical information. Aliphatic substrates 4f-4l were synthesized in a single step from phenyl methyl sulfone and the corresponding epoxides, building on a one-pot ringopening/activation/substitution sequence first reported by Tanaka and co-workers (Method B). 15c To our delight, this procedure was found to be fully stereospecific to form the methyl-substituted sulfonylcyclopropane 4f when starting from an enantioenriched epoxide, subsequently allowing us to access enantiopure cyclopropanone precursor 5f in good yield using our hydroxylation procedure. Importantly, trifluoromethyl-substituted cyclopropanone equivalent 5g could also be accessed by this protocol, in addition to 2,3-disubstituted derivatives 5h and 5i. A more sterically congested 2,2-dimethyl-substituted derivative was also found to be compatible (5j), as well as achiral ring-fused analogs 5k and 5l. Interestingly, these bicyclic derivatives constitute precursors of cyclopropanones commonly encountered as high energy intermediates in the Favorskii rearrangement, eventually affording ring-opened carboxylic acid derivatives in the presence of protic nucleophiles. 5 Synthesis of β-lactams by formal [3+1] cycloaddition. With general access to a wide variety of highly reactive cyclopropanone precursors, we sought to apply these substrates in strain-releasing rearrangements. Considering the biological relevance of β-lactam derivatives, 21 a particularly attractive transformation we were prompted to study is the formal [3+1] cycloaddition of cyclopropanones with nitrene equivalents to afford β-lactams. An analogous Schmidt-type rearrangement had previously been reported by Aubé and co-workers using (1-ethoxycyclopropoxy)trimethylsilane in the presence of organoazides and BF3•OEt2, 22 although only unsubstituted achiral β-lactam derivatives could be obtained in low to moderate yield. In that work, the relatively harsh conditions required for equilibration to cyclopropanone likely led to multiple decomposition pathways. 23,24 Moreover, we sought to avoid organoazides in order to improve the applicability of the method on a larger scale. After evaluating various other nitrene equivalents, 11 it was found that simple hydroxylamines or their corresponding ethers could play the same role when the reaction was run in presence of a Lewis acid (Scheme 4). Indeed, treatment of a chosen hydroxylamine with the 1-sulfonylcyclopropanol substrate leads to smooth formation of a stable hemiaminal intermediate under mild basic conditions, which then rearranges in situ to the corresponding β-lactam following addition of Al(OTf)3. Scheme 4. Scope of accessible β-lactams by formal [3+1] cycloaddition of cyclopropanone equivalents with hydroxylamines a a Isolated yields on 1 mmol scale. b Yield obtained from the corresponding O-benzyl-protected hydroxylamine. c Yield obtained from the corresponding hydroxylamine hydrochloride salt, using 2.2 equiv Et3N. Interestingly, the direct use of unprotected hydroxylamines as nitrene equivalents is unprecedented and might be applicable in other types of reactions involving nitrene precursors. A number of sterically and electronically distinct N-alkyl and N-aryl hydroxylamines were found to be compatible in the reaction when 2a was used as substrate, leading to a variety of unsubstituted β-lactams (6a-6h). Moreover, an N-hydroxy-amino acid derivative could be employed, effectively leading to an N-capped phenylalanine building block in similar yield (6i). Importantly, the reaction was found to be particularly efficient when performed from chiral 2substituted cyclopropanone precursors, leading to high yields of the corresponding 4-substituted β-lactams, either using N-alkylor N-aryl hydroxylamines (6j-6m). Sterically hindered cyclopropanone equivalent 5j was also found to be compatible in the transformation, providing access to congested β-lactam 6n in moderate yield. Bicyclic cyclopropanone precursor 5l led to formation of ring-fused lactam 6o, albeit in lower yield likely due to competitive ring-opening of the hemiaminal intermediate to a hydroxamic acid, similar to what is observed in the Favorskii rearrangement. 5 In an effort to increase the sustainability and cost-efficiency of this transformation, we sought to evaluate the viability of a catalytic version. Although direct application of our previous conditions with a substoichiometric amount of Lewis acid did not yield any of the βlactam product, 11 it was found that similar efficiency could be realized when the reaction was performed in a two-step manner using only 1 mol% of Al(OTf)3, where the hemiaminal intermediate was used crude after aqueous workup (Scheme 5). Considering the high nucleophilicity of sulfinate anions, 12 we believe that the leaving group liberated in the first step is capable of poisoning the Lewis acid catalyst, thus forming various aluminum species of type Al(PhSO2)x(OR)3-x too electron-rich to catalyze the subsequent rearrangement. Therefore, performing an aqueous workup after the first step eliminates all sulfinate salts initially formed and allows for the use of a catalytic amount of Lewis acid in the subsequent step.

Scheme 5. Catalytic version of the formal [3+1] cycloaddition developed with hydroxylamines
To assess the stereospecificity of our approach as well as its applicability on a larger scale, we synthesized gram quantities of enantiopure β-lactam 6j in three steps starting from methyl phenyl sulfone (Scheme 6). Using method B and commercially available (R)propylene oxide (see Scheme 3), chiral sulfonylcyclopropane 4f was obtained in reasonable yield and subjected to our αhydroxylation procedure, furnishing enantiopure cyclopropanone equivalent 5f in 80% isolated yield. Gratifyingly, directly submitting this chiral 1-sulfonylcyclopropanol to our formal [3+1] cycloaddition conditions afforded 1.25 gram of chiral β-lactam 6j in 88% yield and >99% ee, ultimately confirming the stereospecific nature of the 1,2-shift occurring during the ring expansion. Scheme 6. Asymmetric gram-scale synthesis of chiral cyclopropanone equivalent 5f and β-lactam 6j

CONCLUSION
In summary, we report the first enantioselective synthesis of 1sulfonylcyclopropanols, which constitute versatile precursors to highly energetic chiral cyclopropanone derivatives. Kinetic studies revealed the modular nature of these compounds with respect to their equilibration to cyclopropanones, where both the electronic and steric properties of the sulfinate group can readily be tuned to control their overall reactivity as cyclopropanone equivalents. Such a tunability should prove highly beneficial in future reaction development, allowing different sets of reaction conditions to be compatible with these cyclopropanone surrogates. To showcase their applicability in the synthesis of biologically relevant compounds, a mild and stereospecific formal [3+1] cycloaddition with readily available hydroxylamines was developed, efficiently affording a variety of chiral β-lactam derivatives. All synthetic methods developed herein were shown to proceed with similar efficiency on gram scale, and the use of an enantioenriched cyclopropanone equivalent led to complete transfer of the stereochemical information to the final β-lactam product. To the best of our knowledge, this work constitutes the first general enantioselective approach to cyclopropanone derivatives. 10 Considering the importance of strained ketone rearrangements in synthesis 1 and the tremendous potential of cyclopropanones as reactive intermediates, 4 this work should find widespread use in the elaboration of complex, biologically relevant molecules. The development of various other transformations using 1-sulfonylcyclopropanols as cyclopropanone surrogates is currently underway in our laboratories and will be reported in due course.

ASSOCIATED CONTENT Supporting Information
Experimental details and spectroscopic data. The Supporting Information is available free of charge on the ACS Publications website. Crystallographic data for compound 5a: C15H14O3S (CIF)

AUTHOR INFORMATION
Corresponding Author