Iodotrimethylsilane—a versatile synthetic reagent

Preparation of trifluoromethyl ketones and related fluorinated ketones

With nitrogen too: The first catalytic [3+2] annulation of aminocyclopropanes with enol ethers is reported (see scheme; Phth=phthaloyl). The reaction worked with easily accessible phthalimidocyclopropanes using 5 mol % of SnCl4 in nearly quantitative yields. Polysubstituted cyclopentylamines, which are often present in bioactive compounds, were obtained with high diastereoselectivity and enantiospecificity.

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Catalytic [3+2] Annulation of Aminocyclopropanes for the Enantiospecific Synthesis of Cyclopentylamines

The stereoselective construction of highly functionalized small- and medium-sized carbocycles from simple substrates is an ongoing objective in organic synthesis. One approach to this goal is the use of small organic molecules that have been designed as efficient catalysts for selective cascade reactions.[1] Over the last decade, N-heterocyclic carbenes (NHCs)[2] have provided new opportunities for the development of catalytic systems based on polarity reversal or Umpolung.[3] Notably, the NHC-catalyzed generation of homoenolate equivalents from enals has emerged as a powerful tool for the synthesis of hetero- and carbocycles.[4,5]

An important discovery by Nair et al.[6] was the ability of NHCs to catalyze the addition of homoenolates to unsaturated ketones to yield 3,4-disubstituted cyclopentenes. This approach was recently extended by the addition of methanol to afford a highly substituted racemic cyclopentane with a pendent methyl ester.[5l] Although these processes expanded the reaction repertoire of carbene catalysis, the coupling partner with the enal is limited to chalcones and oxobutenoates,[7] and the products from this reaction typically have only a single alkene functional group. To advance this carbene-driven carbocycle synthesis, we envisioned that β,γ-unsaturated α-ketoesters would be a suitable class of homoenolate acceptors for the synthesis of compounds with potentially more functional groups adorning the periphery of the carbocycle framework.[8] Unfortunately, initial attempts at NHC catalysis with Lewis base activation were unsuccessful, and addition of the homoenolate intermediate to the β,γ-unsaturated α-ketoester was not observed (Scheme 1). We have been engaged recently in developing a cooperative carbene catalysis strategy by employing different Lewis acids in combination with NHCs.[9] We have shown that a MgII Lewis acid enhances the reaction rate and yield of the products in an NHC-catalyzed homoenolate addition to hydrazones.[9a] A Lewis acid in combination with carbene catalysis also completely reverses the facial selectivity of an NHC-bound homoenolate equivalent, presumably as a result of the multiple coordination sites on the metal.[9b]



Scheme 1

NHC/Lewis acid homoenolate strategy.



Even with these advances, a major challenge in the field of carbene catalysis is to develop processes that employ new classes of electrophiles that fail as competent substrates when only NHCs are used. With this prospect in mind, we turned our attention to the activation of β,γ-unsaturated α-ketoesters with bidentate Lewis acids: a strategy that has proven successful in stereoselective Lewis acid catalyzed processes (Scheme 1).[10] Cooperative carbene catalysis might allow access to NHC-bound homoenolates in the presence of Lewis acids that coordinate and activate unsaturated α-ketoesters. Herein, we report the use of a Lewis acid as an essential component for an NHC-catalyzed annulation of enals with a new class of electrophiles. This reaction generates highly substituted cyclopentanols containing four contiguous stereogenic centers.

We began our studies by combining cinnamaldehyde (1) with (E)-methyl 2-oxo-4-phenylbut-3-enoate (2) in the presence of the azolium precatalyst A (20 mol%), DBU (40 mol%), and Ti(OiPr)4 (2 equiv). Under these conditions, cyclopentanol 3 was isolated in 69% yield as a single diastereomer (Table 1, entry 2). The excellent diastereoselectivity of this conjugate addition prompted us to develop an enantioselective version of the reaction. Use of the chiral azolium precatalysts B–D resulted in varying yields and selectivity levels (Table 1, entries 3–5). The (S,R)-aminoindanol-derived triazolium precatalyst E[9] furnished the desired cyclopentanol in 68% yield with a 7:1 d.r. and 90% ee (Table 1, entry 6).[11] The addition of 2-propanol (6 equiv) promoted a faster transesterification, and surprisingly, we observed a small increase in the diastereo- and enantioselectivity to d.r. 18:1 and 96% ee (Table 1, entry 7).[12] A decrease in the quantity of the Lewis acid used to a substoichiometric amount resulted in incomplete conversion (results not shown).[13] An increase in the amount of the Lewis acid used to 5 equivalents led to an increase in the yield to 84% (Table 1, entry 8). When this reaction was performed under our optimized conditions but in the absence of the Lewis acid, 3 was not obtained (Table 1, entries 9 and 10). This result illustrates the importance of this Lewis acid as a key component.[14]



Table 1

Reaction optimization.



Having optimized the reaction conditions, we surveyed several β,γ-unsaturated α-ketoesters with varying substitution at the γ position (Table 2). Electron-withdrawing and electron-donating substituents on the aromatic ring were well-accommodated, with only a slight decrease in diastereoselectivity (13:1 d.r.) for the substrate with an ortho-chloro substituent (Table 2, entry 3). Heterocyclic compounds were competent substrates in the presence of TiIV; the products were obtained in moderate to good yields (52–85%) with good to excellent diastereo- and enantioselectivity (Table 2, entries 7–9). Finally, γ-cyclopropyl and γ-alkynyl substitution was well-tolerated (Table 2, entries 10 and 11), whereas only modest conversion was observed for substrates with alkyl and alkenyl groups in the γ position (results not shown).



Table 2

Scope of the reaction with respect to the β,γ-unsaturated α-ketoester.[a]



Modification of the aldehyde component was also explored (Table 3). Electron-withdrawing groups were well-tolerated at all positions of the aromatic ring, although a slight decrease in diastereo- and enantioselectivity was observed in some cases (Table 3, entries 3 and 5). The presence of electron-donating groups led to moderate yields and good enantioselectivities. However, the diastereoselectivity dropped for methoxy-substituted aryl enals (Table 3, entries 7 and 8). Finally, naphthyl-derived enals furnished the desired cyclopentanols in good yields with good enantioselectivity but with slightly decreased diastereoselectivity (Table 3, entries 9 and 10).[15]



Table 3

Scope of the reaction with respect to the aldehyde substrate.[a]



Our proposed pathway for this reaction is illustrated in Scheme 2. Initial coordination of the α,β-unsaturated alde-hyde to the titanium(IV) Lewis acid, followed by the addition of the NHC, induces the formation of the extended Breslow intermediate I, presumably coordinated to the oxophilic titanium center. The Lewis acid concurrently coordinates to the β,γ-unsaturated α-ketoester to give II, thereby activating the α-ketoester and promoting the conjugate addition.[16] Following C—C bond formation, the bisenolate III undergoes protonation, tautomerization, and an intramolecular aldol reaction to afford intermediate IV. Subsequent acylation and catalyst turnover gives the mixed ester V, which then undergoes transesterification to furnish 3.[17] Surprisingly, neither the β-lactone nor the cyclopentene is observed, even though the metal alkoxide and the acyl azolium moiety are cis in intermediate IV: an arrangement that could lead to an intramolecular acylation. Our current proposal is that the titanium Lewis acid prevents intramolecular acylation of IV as a result of the stability of the various titanium–oxygen interactions/ligations, which undergo hydrolysis upon workup and release of the product.



Scheme 2

Proposed reaction pathway.



The synthetic utility of this annulation reaction was initially demonstrated by further elaboration of the product cyclopentanols. The treatment of bisester 22 with lithium aluminum hydride followed by silica-gel-supported sodium periodate resulted in the formation of β-hydroxyketone 26 (Scheme 3).[18] Additionally, reduction of the bisester 22 with sodium borohydride in a THF/methanol mixture at 0 °C was regioselective (> 20:1) in favor of the 1,2-diol (the 1,3-diol was not observed), which was isolated in 71% yield. Subsequent oxidative cleavage under the aforementioned conditions, followed by decarboxylation in DMSO/H2O at 130 °C, afforded the 3,4-cis-disubstituted cyclopentanone 28.[19] Overall, these transformations demonstrate the utility of the carbonyl units that remain during this novel process promoted by an NHC and a Lewis acid. These reactions also enable efficient differentiation of the two esters as well as the formation of compounds that are challenging to access otherwise, such as 3,4-cis-substituted cyclopentanones.



Scheme 3

Synthetic transformations: a) LiAlH4, THF, 0–25 °C; b) NaIO4·SiO2, CH2Cl2, 25 °C; c) NaBH4, THF/MeOH (2:1), 0 °C. d) NaIO4·SiO2, CH2Cl2, 25 °C; e) DMSO/H2O, 130 °C. DMSO = di-methyl sulfoxide. ...



In conclusion, we have developed the first NHC-catalyzed addition of homoenolates to β,γ-unsaturated α-ketoesters. The use of Ti(OiPr)4 as a mild Lewis acid compatible with NHC catalysis is essential for activation of the electrophile and promotion of the conjugate addition. This powerful NHC–Lewis acid combination enables the rapid assembly of highly substituted and functionalizable cyclopentanols from simple substrates with excellent levels of diastereo- and enantioselectivity. Furthermore, derivatization of the products provides enantiomerically enriched cyclopentanones. The two esters in the products can be differentiated by directed reduction. The powerful strategy combining Lewis basic NHC catalysis with Lewis acid activation can provide innovative ways of incorporating new reaction components and continues to be a promising area of research. New directions related to this strategy are under way and will be reported in due course.

Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes by the N-Heterocyclic Carbene Catalyzed Addition of Homoenolate Equivalents to Unsaturated Ketoesters†

An asymmetric total synthesis of the Akuammiline alkaloid (-)-vincorine (18 steps from 5-methoxytryptamine, 5% overall yield) is described. The key steps include Pd-catalyzed direct C-H functionalization of indole derivatives, organocatalyzed asymmetric Michael addition of aldehydes to alkylidene malonates, and intramolecular oxidative coupling between indole and malonate moieties.

Total synthesis of Akuammiline alkaloid (-)-vincorine via intramolecular oxidative coupling.

Synthetic applications and mechanism studies of the decarbalkoxylations of geminal diesters and related systems effected in dimethyl sulfoxide by water and/or by water with added salts

Decarbalkoxylations of geminal diesters and β-keto esters in wet dimethyl sulfoxide. Effect of added sodium chloride on the decarbalkoxylation rates of mono- and di-substituted Malonate esters

A. J. Lovey

Papers

Synthetic applications and mechanism studies of the decarbalkoxylations of geminal diesters and related systems effected in dimethyl sulfoxide by water and/or by water with added salts

Decarbalkoxylations of geminal diesters and β-keto esters in wet dimethyl sulfoxide. Effect of added sodium chloride on the decarbalkoxylation rates of mono- and di-substituted Malonate esters

A synthetic route to highly substituted ketones. Acylations of .alpha. anions of carboxylic acid salts with acid chlorides