Showing papers on "Enone published in 2007"

Metal-Catalyzed [1,2]-Alkyl Shift in Allenyl Ketones: Synthesis of Multisubstituted Furans†

Abstract: Cycloisomerization of allenyl ketones is an efficient approach for the assembly of the furan ring, an important heterocyclic unit.[1] This transformation in the presence of transition-metal catalysts was first reported by Marshall et al.[2] and later by Hashmi et al.[3] for the synthesis of furans [G = H, Eq. (1)]. Recently, we have developed a set of transition-metal-catalyzed cascade transformations of allenyl ketones involving 1,2-migration of various groups (G = SR,[4] Hal,[5] OP(O)(OR)2, OC(O)R, OSO2R[6]) to produce up to tetrasubstituted furans [Eq. (1)]. Herein, we wish to report a novel metal-catalyzed [1,2]-alkyl shift in allenyl ketones as a key step in the formation of up to fully carbon-substituted furans [Eq. (1)]. (1) Recently, we reported the Au-catalyzed regiodivergent synthesis of halofurans.[5] It was found that in the presence of AuI catalysts clean hydrogen migration from 1 occurs to form 2 [Eq. (2)]. The absence of H/D-scrambling, in contrast to that observed in the Cu/base-assisted synthesis of pyrroles,[7] supported the clean [1,2]-hydrogen shift to the carbenoid center in intermediate i.[5] (2) It occurred to us that 1,2-migration of an alkyl/aryl group by this mechanism is also feasible,[8–11] which may allow for the assembly of fully carbon-substituted furans. To this end, we have tested the possible cycloisomerization of allene 3 to give furan 4 in the presence of different catalysts (Table 1). We have found that employment of AuI and AuIII halides gave low yields of furan 4 (Table 1, entries 1 and 2). Gratifyingly, switching to cationic AuI complexes led to formation of 4k in nearly quantitative yield (Table 1, entries 3 and 4). In analogy to gold halides, PtII, PtIV, and PdII salts were inefficient in this reaction (Table 1, entries 5–7). Use of CuI halides resulted in no reaction (Table 1, entry 8), while employment of cationic AgI, CuI, and CuII salts produced 4 in moderate to high yields (Table 1, entries 9–13). Encouraged by these results, we also tested main-group metals in this reaction. Surprisingly, Al, Si, Sn, and In triflates provided moderate to excellent yields of desired furan 4 (Table 1, entries 14, 16–19). Although [Au(PPh3)]OTf, AgOTf, In(OTf)3, Sn(OTf)2, and TIPSOTf were nearly equally efficient in the cascade cycloisomerization of 3 to give 4, In(OTf)3 appeared to be a more general catalyst with respect to the substrate scope.[12] Table 1 Optimization of reaction conditions.a Next, cycloisomerization of differently substituted allenyl ketones 3a–m was examined under the optimized conditions (Table 2). Thus, cycloisomerization of 4,4-diphenyl-substituted allenyl ketones 3b–d proceeded smoothly to provide good to high yields of furans 4b–d (Table 2, entries 2–4). Selective migration of the phenyl over the methyl group occurred in allenyl ketone 3e to give 4e in 72% yield (Table 2, entry 5). Not surprisingly, cycloisomerization of allenyl ketone 3i, possessing two methyl groups, provided the corresponding furan 4i in low yield only (Table 2, entry 8). In contrast to the disfavored methyl-group migration in Table 2, entry 5, migration of the ethyl group competed with the phenyl group in 3f, which resulted in formation of a 2.3:1 mixture of regioisomeric furans 4f and 4g, respectively (Table 2, entry 6). Cyclopentylidene allenyl ketone 3h underwent smooth cyclization with ring expansion[13] to give fused furan 4h in 75% yield (Table 2, entry 7). It was also demonstrated that a variety of functional groups such as methoxy (Table 2, entry 9), bromo (Table 2, entry 10), nitro (Table 2, entry 11), and cyano (Table 2, entry 12) were perfectly tolerated under these reaction conditions. Table 2 Lewis acid catalyzed synthesis of furans. In addition, we have shown that trisubstituted furan 4b can be obtained directly from alkynyl ketone 5b [Eq. (3)]. However, the yield for this one-pot transformation was somewhat lower than that for cycloisomerization of allene 3b (Table 2, entry 2). (3) We propose the following mechanism for the cascade transformation of allenyl ketone 3 into furan 4 (Scheme 1). Cycloisomerization in the presence of oxophilic Lewis acids, such as In, Sn, and Si triflates, follows path A, according to which, the Lewis acid activates the enone moiety (see 6) to form vinyl cation 7.[14] [1,2]-Alkyl shift in 7 produces the regioisomeric vinyl cation 8,[15] which, upon cyclization, transforms into furan 4 and regenerates the Lewis acid catalyst. Alternatively, π-philic catalysts, such as AgI, CuI, and AuI salts, activate the carbon–carbon double bond of allene (see 9) and trigger nucleophilic attack of a carbonyl oxygen lone pair at the terminal carbon of the allene moiety to form cyclic oxonium intermediate 10.[2c,5] [1,5]-Alkyl shift[16] (Scheme 1, path B) to form 11 with subsequent elimination of metal gives 4. The involvement of an electrophilic mechanism (Scheme 1, paths A and B) is supported by the data presented in Table 2. Thus, the migratory aptitude of a phenyl vs. that of a methyl group (> 100:1) is in good agreement with that reported in the literature for rearrangements of cations.[17] Although a mechanism involving [1,2]-alkyl shift in the carbenoid intermediate 12[5,8] (Scheme 1, path C) cannot be completely ruled out at this point, it is considered to be less likely.[18,19] Scheme 1 Proposed mechanisms for the synthesis of furans 4. In summary, we have developed a novel metal-catalyzed method for the synthesis of furans, which proceeds by an unprecedented [1,2]-alkyl shift in allenyl ketones. This method allows for efficient synthesis of up to fully carbon-substituted and fused furans.

[(NHC)AuI]-Catalyzed Formation of Conjugated Enones and Enals: An Experimental and Computational Study

Abstract: The [(NHC)AuI]-catalyzed (NHC = N-heterocyclic carbene) formation of α,β-unsaturated carbonyl compounds (enones and enals) from propargylic acetates is described. The reactions occur at 60 °C in 8 h in the presence of an equimolar mixture of [(NHC)AuCl] and AgSbF6 and produce conjugated enones and enals in high yields. Optimization studies revealed that the reaction is sensitive to the solvent, the NHC, and, to a lesser extent, to the silver salt employed, leading to the use of [(ItBu)AuCl]/AgSbF6 in THF as an efficient catalytic system. This transformation proved to have a broad scope, enabling the stereoselective formation of (E)-enones and -enals with great structural diversity. The effect of substitution at the propargylic and acetylenic positions has been investigated, as well as the effect of aryl substitution on the formation of cinnamyl ketones. The presence or absence of water in the reaction mixture was found to be crucial. From the same phenylpropargyl acetates, anhydrous conditions led to the formation of indene compounds via a tandem [3,3] sigmatropic rearrangement/intramolecular hydroarylation process, whereas simply adding water to the reaction mixture produced enone derivatives cleanly. Several mechanistic hypotheses, including the hydrolysis of an allenol ester intermediate and SN2′ addition of water, were examined to gain an insight into this transformation. Mechanistic investigations and computational studies support [(NHC)AuOH], produced in situ from [(NHC)AuSbF6] and H2O, instead of cationic [(NHC)AuSbF6] as the catalytically active species. Based on DFT calculations performed at the B3LYP level of theory, a full catalytic cycle featuring an unprecedented transfer of the OH moiety bound to the gold center to the CC bond leading to the formation of a gold–allenolate is proposed.

Comparison of three enoate reductases and their potential use for biotransformations

Abstract: Enoate reductases (ERs) selectively reduce carbon-carbon double bonds in α,β-unsaturated carbonyl compounds and thus can be employed to prepare enantiomerically pure aldehydes, ketones, and esters. Most known ERs, most notably Old Yellow Enzyme (OYE), are biochemically very well characterized. Some ERs have only been used in whole-cell systems, with endogenous ketoreductases often interfering with the ER activity. Not many ERs are biocatalytically characterized as to specificity and stability. Here, we cloned the genes and expressed three non-related ERs, two of them novel, in E. coli: XenA from Pseudomonas putida, KYE1 from Kluyveromyces lactis, and Yers-ER from Yersinia bercovieri. All three proteins showed broad ER specificity and broad temperature and pH optima but different specificity patterns. All three proteins prefer NADPH as cofactor over NADH and are stable up to 40 °C. By coupling Yers-ER with glucose dehydrogenase (GDH) to recycle NADP(H), conversion of >99 % within one hour was obtained for the reduction of 2-cyclohexenone. Upon lowering the loadings of Yers-ER and GDH, we discovered rapid deactivation of either enzyme, especially of the thermostable GDH. We found that the presence of enone substrate, rather than oxygen or elevated temperature, is responsible for deactivation. In summary, we successfully demonstrate the wide specificity of enoate reductases for a range of α,β-unsaturated carbonyl compounds as well as coupling to glucose dehydrogenase for recycling of NAD(P)(H); however, the stability limitations we found need to be overcome to envision large-scale use of ERs in synthesis.

Phosphine-catalyzed cycloadditions of allenic ketones: new substrates for nucleophilic catalysis.

Abstract: A range of phosphine-catalyzed cycloaddition reactions of allenic ketones have been studied, extending the scope of these processes from the more widely used 2,3-butadienoates to allow access to a number of synthetically useful products. Reaction of allenyl methyl ketone 4 with exo-enones afforded spirocyclic compounds in good regioselectivity and promising enantioselectivity via a [2 + 3] cycloaddtion. Aromatic allenyl ketones undergo a phosphine-promoted dimerization to afford functionalized pyrans, leading to a formal [2 + 4] Diels−Alder product, but did not react in the [2 + 3] cycloaddition. The results from other reactions that had found utility with 2,3-butadienoates are also reported.

Two-step formal [3+2] cycloaddition of enones/enals and allenyl MOM ether: gold-catalyzed highly diastereoselective synthesis of cyclopentanone enol ether containing an all-carbon quaternary center.

Abstract: A two-step, highly diastereoselective formal [3+2] cycloaddition between allenyl MOM ether and an enal/enone is developed. Au activation of allenyl ethers is proposed to yield all-carbon 1,3-dipoles, which can undergo concerted intramolecular 1,3-dipolar cycloadditions. Synthetically useful cyclopentanone enol ethers containing an all-carbon quaternary center can be readily prepared with excellent diastereocontrol.

Enantioselective Route to Platensimycin: An Intramolecular Robinson Annulation Approach

Abstract: An enantioselective route to the tetracyclic core structure of the novel antibiotic lead compound platensimycin is accomplished in 10 steps from simple commercially available starting materials. Highlights of this synthesis include (1) a regio- and enantioselective Diels−Alder reaction between methyl acrylate and methyl cyclopentadiene to give adduct 2 with essentially complete regio-, diastereo-, and enantiocontrol; (2) oxidative decarboxylation of ester 2 using nitrosobenzene; (3) a one-pot reductive cyanation of lactone 4; (4) a stereoselective intramolecular Michael addition between an α-branched aldehyde moiety and a β-substituted enone part of 8, followed by aldol dehydration in one pot to give the Robinson annulation product 9.

Asymmetric aza-Michael reactions catalyzed by cinchona alkaloids.

Abstract: The organocatalysed asymmetric aza-Michael addition of hydrazones to cyclic enones has been achieved in good yield and stereoselection using cheap and commercially available cinchona alkaloids as catalysts. A systematic study of the influence of the structure of the enone on the stereoselectivity was carried out, leading to optically active products with up to 77% ee. The products can be recrystallized to give nearly enantiopure products, and furthermore it was shown that the products could be reduced to the corresponding 1,3-benzylidenehydrazino alcohol derivatives with high diastereoselectivity.

Biosynthetic Studies of Platensimycin

Abstract: Platensimycin is a novel Gram-positive broad spectrum antibiotic that inhibits bacterial growth by specifically and potently inhibiting the condensing enzyme (FabF) of the fatty acid biosynthesis pathway. It is produced by several strains of Streptomyces platensis and comprises a 3-amino-2,4-dihydroxybenzoic acid and C-17 tetracyclic enone moieties linked by an amide bond. Feeding experiments using 13C precursors suggest that the aminobenzoic acid unit is derived from the TCA cycle, and the tetracyclic enone moiety of platensimycin in S. platensis is derived from the non-mevalonate MEP terpenoid pathway by oxidative excision of three carbons from ent-kaurene.

A novel ionic liquid supported organocatalyst of pyrrolidine amide: Synthesis and catalyzed Claisen–Schmidt reaction

Abstract: A novel organocatalyst of pyrrolidine amide based on room temperature ionic liquid (RTIL) has been developed to perform Claisen–Schmidt reaction with acetone or cyclic ketone and various aromatic aldehydes at room temperature under free-solvent condition. The ( E )-α,β-unsaturated ketone products were obtained in good yields. The ionic liquid supported pyrrolidine amide catalyst can be readily recovered and reused successfully without any significant loss of catalytic activity.

Enantioselective Synthesis of Natural Polyoxygenated Cyclohexanes and Cyclohexenes from [(p-Tolylsulfinyl)methyl]-p-quinols

Abstract: Exploitation of the beta-hydroxysulfoxide fragment present in a number of enantiomerically pure (SR)- and (SS)-[(p-tolylsulfinyl)methyl]-p-quinols allowed chemo- and stereocontrolled conjugate additions of different organoaluminium reagents to the cyclohexadienone moiety. The same fragment was also shown to act as an efficient chiral masking carbonyl group, after oxidation to sulfone and retroaddition in basic medium, with elimination of methyl p-tolyl sulfone. Through the use of both transformations as key steps, enantiocontrolled syntheses of different natural products-such as the two enantiomers of dihydroepiepoformin, (-)-gabosine O, (+)-epiepoformin, (-)-theobroxide and (+)-4-epigabosine A (an epimer of the natural product gabosine A)-has been achieved. The presence of the beta-hydroxy sulfone moiety makes the cyclic structures rigid, allowing a number of stereoselective transformations such as carbonyl reductions, enone epoxidations or cis-dihydroxylations, en route to the natural structures. The observed selectivities were dependent on the particular substitution in each substrate, providing evidence of a strong influence of remote groups on the preferred approach of the reactants to the reactive conformations. An advanced precursor of natural (+)-harveynone was also synthesized, but the isolation of the natural product was not possible because of the instability of the corresponding enone, containing a triple bond, under the basic conditions necessary to eliminate the beta-hydroxy sulfone. This demonstrated that the limitations of the use of the beta-hydroxy sulfoxide as a chiral protecting carbonyl group were dependent on the relative stabilities of the final targets in the presence of the required base.

Functional characterization of enone oxidoreductases from strawberry and tomato fruit.

Abstract: Fragaria x ananassa enone oxidoreductase (FaEO), earlier putatively assigned as quinone oxidoreductase, is a ripening-induced, negatively auxin-regulated enzyme that catalyzes the formation of 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF), the key flavor compound in strawberry fruit by the reduction of the α,β-unsaturated bond of the highly reactive precursor 4-hydroxy-5-methyl-2-methylene-3(2H)-furanone (HMMF). Here we show that recombinant FaEO does not reduce the double bond of straight-chain 2-alkenals or 2-alkenones but rather hydrogenates previously unknown HMMF derivatives substituted at the methylene functional group. The furanones were prepared from 4-hydroxy-5-methyl-3(2H)-furanone with a number of aldehydes and a ketone. The kinetic data for the newly synthesized aroma-active substrates and products are similar to the values obtained for an enone oxidoreductase from Arabidopsis thaliana catalyzing the α,β-hydrogenation of 2-alkenals. HMMF, the substrate of FaEO that is formed during strawberry f...

Intramolecular Aza-Anti-Michael Addition of an Amide Anion to Enones: A Regiospecific Approach to Tetramic Acid Derivatives

Abstract: A novel intramolecular aza-anti-Michael addition was disclosed in the one-pot reactions between 3-oxobutanamides and aryl (heteroaryl) aldehydes under basic conditions, in which amide anions regiospecifically attacked the α-carbon of an enone fragment, providing a new route to biologically important tetramic acid derivatives. An explanation for the unexpected regioselectivity is proposed based on the results of experiments and theoretical calculations, which is ascribed to (1) the conjugated and rigid molecular skeleton, and (2) proximity effects of the nucleophilic site and the enone α-carbon.

A novel environmentally friendly process for carbon–sulfur bond formation catalyzed by montmorillonite clays

Abstract: Montmorillonite clays are reported as efficient, inexpensive, and reusable catalysts for carbon–sulfur bond formation by conjugate addition of thiols to α,β-unsaturated ketones/ester/nitrile. The reaction of aryl and aryl alkyl thiols with cyclic/acyclic α,β-unsaturated ketones/ester afforded excellent yields after 5 min to 20 h. The reaction rate was found to be influenced by the (i) size of the ring in case of cyclic enone, (ii) electronic nature of the thiol, and (iii) presence of aryl/alkyl substituent at the β position of the acyclic α,β-unsaturated ketone/nitrile. The conjugate addition of thiols took place at faster rates for five-membered and acyclic α,β-unsaturated ketones than the six-membered analogue. Aryl thiols reacted at faster rates than aryl alkyl and alkane thiols and the differential reaction rates were attributed to the relative acidic strength of the thiols. The reaction of α,β-unsaturated ketones having an aryl/alkyl group at the β-carbon took longer times and higher temperature. The difference in the reactivity between six and five membered enones and various thiols was utilized to demonstrate selective thia-Michael addition reaction during intermolecular competition studies.

Stereoselective intermolecular formal [3+3] cycloaddition reaction of cyclic enamines and enones.

Abstract: The development of new tandem C-C bond forming reactions with control of stereochemistry is of fundamental interest in organic synthesis.[i] Important discoveries in conjugate addition chemistry have resulted in a variety of valuable catalytic and asymmetric methodologies for fine chemical synthesis.[ii] Herein we report a new highly diastereoselective reaction involving cyclic enamines and enones that provides rapid access to tricyclic imino alcohols and derivatives thereof (Scheme 1). Additionally, we discuss our findings in the development of catalytic and asymmetric variants of this formal [3+3]-cycloaddition reaction. Scheme 1 Formal [3+3] cycloaddition reaction. Enamines and metalloenamines have served as powerful nucleophiles in a wide range of bond forming reactions,[iii,iv] including many cycloaddition reactions.[v] Motivated by the efficiency of the transient δ-iminoketone strategy that we employed[vi] for the introduction of the CDE-ring system of Class II and Class III galbulimima alkaloids[vii] (Figure 1) we sought to develop a new formal [3+3]-cycloaddition reaction. We postulated that the conjugate addition of the readily available iminium chloride 5a-derived organocuprate reagent[viii] to cyclopent-2-enone (6a) would afford the imino ketone 7a (Scheme 2) which could spontaneously undergo tautomerization and carbonyl addition to give the tricyclic imino alcohol 10a.[ix,x] Gratifyingly, introduction of enone 6a to a cold solution of the homocuprate (1.5 equiv)[9,xi] followed by warming gave the corresponding tricyclic imino alcohol 10a as a single diastereomer in 82% isolated yield. The introduction of thiophenol (1.5 equiv) and strict exclusion of dioxygen during workup were critical in isolation of this sensitive product.[9] Reduction of the imine with sodium borohydride gave the tricyclic aminoalcohol 11a which constitutes the CDE-tricyclic substructure of Class II and III galbulimima alkaloids (Figure 1).[xii] The relative stereochemistry of the four stereocenters in amino alcohol 11a, secured by X-ray analysis,[9] is consistent with the chair-like transition state structure 9a for the intramolecular carbonyl addition step.[xiii] Figure 1 Representative galbulimima alkaloids. Scheme 2 Rapid synthesis of the CDE-ring system of Class II and III galbulimima alkaloids. The iminium chloride 5a was used along with enones 6b-d (Table 1, entries 1-3) under the optimum reaction conditions described above to afford the corresponding tricyclic imino alcohols in a single-step. The imino alcohols 10c and 10d proved highly sensitive toward air-oxidation, prompting their derivatization to tricycles 11c and 11d (Table 1, entries 2-3), respectively, for ease of isolation. Interestingly, the C12-stereochemistry[9] of amino alcohol 11c is consistent with transient formation of the imino ketone 7c, followed by intramolecular carbonyl addition of the enamine. The rapid introduction of five contiguous stereocenters in amino alcohol 11c is noteworthy. The stereoselective formation of tricycles 11a-c via the corresponding iminoketones 7a-c is consistent with our proposed biogenesis of this substructure in the galbulimima alkaloids.[6] The use of iminium chloride 5b[9] under the same reaction conditions resulted in stable imino ketones 7e-g (Table 1, entries 4-6). The isolation and greater stability of these imino ketones is likely due to slower imine/enamine tautomerization (vide infra). Treatment of the isolated imino ketones 7e-g with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in ethanol provided the desired tricyclic imino alcohols 10e-g (Table 1, entries 4-6) as a single diastereomer. Imine reduction proceeded with complete diastereoselection to give the corresponding amino alcohols (Table 1, entries 4-6). Similarly, 1,2-addition of allyl magnesium chloride to imine 10e gave the corresponding tertiary amine as a single diastereomer.[xiv] Table 1 Highly diastereoselective sequential 1,4- and 1,2-addition of cyclic imines to cyclic enones.[[a]] The resistance of cyclic imines toward hydrolysis renders them more effective substrates than acyclic imines for this chemistry. The use of acyclic imine 5c and enone 6a under the optimal reaction conditions described above provided the desired imino alcohol 10h (52%), along with the competitive hydrolysis product 12 (28%, eq 1).[xv] Use of acyclic enones (e.g., PhCH=CHCOPh or PhCH=CHCOMe) under the standard reaction conditions did not provide any tandem addition products. Interestingly, incomplete double deprotonation of iminium ion 5a prior to cuprate formation led to equilibration between the isomeric metalloenamines. Monitoring a solution of the 6-membered ring imine 13a in DMSO-d6–D2O (3:2, [0.5mM]) revealed >90% deuterium incorporation at C3 and C2-Me within 10 min and 9 h, respectively (Scheme 3).[9] However, the 5-membered ring imine 13b required 96 h before 90% deuterium incorporation at C2-Me was observed at which time less than 25% C3-deuterium incorporation was detected. Scheme 3 Equilibration of Enamine Tautomers.[9] The observed preferences of these enamine tautomers prompted us to explore the direct utilization of the enamines in place of the corresponding metalloenamine derivatives as nucleophiles in this formal [3+3]-cycloaddition chemistry. Inspired by the recent advances in organocatalytic transformations,[xvi] we envisioned the activation of the enone in the form of an unsaturated iminium ion to facilitate the conjugate addition of the enamines. After screening various catalysts and solvents, proline[xvii] proved particularly effective as the catalyst in a trifluoroethanol (TFE)–water mixture.[9] Heating a solution of imine 13a and enone 6a in TFE–water (10:1) gave the desired tricyclic imino alcohol 10i in 91% isolated yield as a single diastereomer (Table 2, entry 1).[xviii] The relative stereochemistry of imino alcohol 10i was secured by X-ray crystallography.[9] It should be noted that the tricyclic iminoalcohol 10i (Table 2, entry 1) is isomeric with the product obtained using the cuprate chemistry (10a, Scheme 1), consistent with the intermediacy of the preferred endocyclic 6-membered ring enamine (Scheme 3). Introduction of water as co-solvent increased the overall yield of the desired tricyclic imino alcohol products. The use of the free–base imines 13a-b in place of the corresponding iminium chloride derivatives 5a-b was found to be optimal. In only one case (Table 2, entry 3) was the intermediate 1,4-addition product isolated along with the desired tricyclic iminoalcohol. The use of the protic solvent system and higher temperatures allowed direct conversion of recalcitrant intermediates to the corresponding tricyclic iminoalcohols (i.e., imino ketones 7e and 7g). Table 2 Single-step Catalytic Diastereoselective Intermolecular Formal [3+3] Cycloaddition Reaction.[[a]] Intrigued by the above results, we explored the extension of this chemistry to catalytic asymmetric synthesis. The use of chloroform as solvent in place of TFE–water provided a modest level of enantioselection in the conjugate addition of imine 13b to enone 6a (Scheme 4).[9] Warming a solution of imine 13b and enone 6a in chloroform provided the initial 1,4-conjugate addition product, which upon treatment with DBU gave the desired tricyclic imino alcohol (–)-10e with 52% enantiomeric excess (ee). The optical activity was increased to 90% ee after a single recrystallization from npentane–diethyl ether (1:1).[9] The absolute stereochemistry of the imino alcohol (–)-10e was secured by X-ray analysis of the corresponding amino alcohol co-crystallized with L-tartaric acid (1 equiv).[9] This transformation, provides the first example of a catalytic asymmetric variant of the herein described intermolecular formal [3+3] cycloaddition reaction. Scheme 4 Catalytic Asymmetric Synthesis of (–)-10e. Conditions: [a] L-Proline (20 mol%), CHCl3, 45 °C, 48 h (50%); 1,8-Diazabicyclo-[5.4.0]undec-7-ene, EtOH, 78 °C, (80%). The chemistry described here relies on the sequential C-α- and C-α’-alkylation of unsymmetrical ketoimines, allowing rapid generation of molecular complexity with excellent stereochemical control. This new formal [3+3] cycloaddition reaction provides a practical solution for the synthesis of fused tricyclic iminoalcohol derivatives.[xix] We envision further development and application of this chemistry to target oriented synthesis based on advances in catalyst and substrate controlled conjugate addition chemistry.[2,16,xx] The complementary copper promoted and proline–catalyzed variants of this chemistry enable a highly selective and rapid introduction of at least three stereocenters in a convergent assembly of these tricyclic products, offering a valuable addendum to methodologies for complex molecule synthesis.

Internal Azomethine Ylide Cycloaddition Methodology for Access to the Substitution Pattern of Aziridinomitosene A

Abstract: Highly substituted, tethered alkyne dipolarophiles participate in the internal 2 + 3 cycloaddition with azomethine ylides generated by treatment of oxazolium salts with cyanide ion. Starting from oxazole 26, a sequence of N-methylation, cyanide addition, and electrocyclic ring opening of a 4-oxazoline intermediate affords the indoloquinone 31 in a one-pot process. A similar reaction from the protected alkynol derivative 25 affords the sensitive, but isolable, enone 32, and subsequent oxidation affords 31 and the deprotected quinone alcohol 34. Related azomethine cycloaddition methodology via intramolecular oxazolium salt formation from 43 or 46 is also demonstrated and allows the synthesis of quinone 45 and derived structures having the substitution pattern of aziridinomitosene A. Removal of the N-trityl protecting group could not be achieved without aziridine cleavage.

Asymmetric 1,4-Addition Reaction of Arylboronic Acid to Eneone Catalyzed by Palladium with Ferrocene-based Phosphine Ligand

Abstract: Asymmetric 1,4-addition reaction of arylboronic acid to cyclic enone was carried out in the presence of a chiral ferrocene-based phosphine ligand–palladium catalyst. The reaction of 2-cyclohexen-1-...

Rhodium-catalyzed reductive mannich coupling of vinyl ketones to N-sulfonylimines mediated by hydrogen.

Abstract: Catalytic hydrogenation of methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) in the presence of N-(o-nitrophenylsulfonyl)imines 8a−13a at ambient pressure with tri-2-furylphosphine-ligated rhodium catalysts enables formation of Mannich products 8b−13b and 8c−13c with moderate to good levels of syn-diastereoselectivity. As revealed by an assay of various N-protecting groups, excellent yields of reductive Mannich product also are obtained for N-arylimines 1a−4a, although diminished levels of syn-diastereoselectivity are observed. Coupling of MVK to imine 8a under a deuterium atmosphere provides deuterio-8b, which incorporates a single deuterium atom at the former enone β-position.

Total syntheses of schulzeines B and C.

Abstract: Schulzeines B (2) and C (3) were synthesized by a convergent strategy using epimeric tricyclic lactam building blocks, 4 and 5, and the C28 fatty acid side chain 6. Syntheses of tricyclic lactams (4/5) were achieved by Bischler-Napieralski reaction. Sharpless asymmetric dihydroxylation and BINAL-H-mediated asymmetric reduction of an enone was employed to prepare the key fatty acid side chain 6. The spectral as well as analytical data of 2 and 3 were in good agreement with the reported data for the natural products, thus confirming their assigned structures.

Sodium bicarbonate-catalyzed stereoselective isomerizations of electron-deficient propargylic alcohols to (Z)-enones.

Abstract: Redox isomerization is a synthetically important process because it creates two new functional groups in the product, among which is the isomerization of propargylic alcohols to conjugated enones. Although E-enones have been prepared by this approach, Z-enones could not be accessed. We previously reported DABCO-catalyzed E-selective isomerization of electron-deficient propargylic alcohols to enones and its mechanism. Based on this mechanism, we have now developed the first Z-selective redox isomerization of electron-deficient propargylic alcohol to enone using sodium bicarbonate as a catalyst.

Organic acid formation in the gas-phase ozonolysis of α-pinene

Abstract: The mechanism of formation of pinonic and norpinonic acids from α-pinene ozonolysis has been investigated by studying the products of the ozonolysis of an enone derived from α-pinene using gas chromatography coupled to mass spectrometry.

Organocatalytic Enantioselective Nucleophilic Vinylic Substitution by α-Substituted-α-Cyanoacetates under Phase-Transfer Conditions

Abstract: The organocatalytic enantioselective formation of vinyl-substituted all-carbon quaternary stereocenters via nucleophilic vinylic substitution by alpha-substituted-alpha-cyanoacetates is presented. The reaction proceeds well for different alpha-substituted-alpha-cyanoacetates and beta-chloroalkenones using a dimeric cinchona alkaloid phase-transfer catalyst giving the products in good yield and with enantioselectivities up to 98% ee.

Mechanistic studies of UV assisted [4 + 2] cycloadditions in synthetic efforts toward vibsanin E.

Abstract: Quantum chemical DFT calculations at the B3LYP/6-31G(d) level have been used to study the stereochemical course of the photochemical cycloaddition of enone 9 with dienes. The observed products of this photochemically induced cycloaddition showed a stereoselectivity, which is opposite to what would be expected by FMO considerations. The quantum chemical calculations revealed that the unusual stereoselectivity of the reaction can be rationalized by assuming a stereospecific photochemical cis-trans isomerization of enone 9 to trans isomer 9a followed by a thermal Diels-Alder reaction of the diene onto the highly reactive trans enone. The photochemical reaction step involves the selective formation of a twisted triplet intermediate, which accounts for the selectivity of the reaction.