Synthesis of optically pure highly functionalized gamma-lactams via 2-azetidinone-tethered iminophosphoranes

A synthesis of optically pure densely functionalized gamma-lactams starting from 2-azetidinone-tethered iminophosphoranes has been developed. Full chirality transfer has been accomplished from the enantiomerically pure 2-azetidinones. The addition of lithium acetylides to 4-oxoazetidine-2-carbaldehydes at -78 degrees C smoothly yielded propargylic alcohols with excellent diastereoselectivities. Propargylic alcohols were converted to mesylates, which by exposure to sodium azide afforded the corresponding azides. Treatment of beta-lactams bearing an azido side chain with triphenylphosphine (TPP) gave lambda(5)-phosphazenes (iminophosphoranes, phosphine imines), which were not isolated. The sodium methoxide promoted reaction of the phosphazene beta-lactams smoothly provided gamma-lactams, through a N1-C2 bond breakage process on the four-membered lactam with concomitant ring expansion, followed by hydrolysis.     

Base-promoted isomerization of cis-4-formyl-2-azetidinones: chemoselective C4-epimerization vs rearrangement to cyclic enaminones

Two simple, efficient, and complementary methods for the regiospecific C4-epimerization of cis-4-formyl-2-azetidinones 1-3 are described. The first method uses 40% aqueous dimethylamine as reagent in heterogeneous medium with benzene at room temperature, in the presence of benzyltributylammonium bromide (3-4 mol%) as the phase-transfer catalyst. This transformation tolerates alkyl, alkenyl, alkynyl, aryl, and alkoxy substituents at the C3 of the 2-azetidinone ring. However, limitations of this isomerization are as follows: (i) only N-(p-methoxyphenyl)-beta-lactams can be used, and (ii) transformation is less compatible with heteroatomic substituents bonded to the C3 position of the 2-azetidinone ring. A highly general solution to these problems relies on the use of sodium carbonate as the isomerization reagent in different solvents. We also describe a novel base-promoted rearrangement of the beta-lactam ring to cyclic enaminones 6 and 21, involving an E1cB-elimination reaction in cis-4-formyl-2-azetidinones.     

The Intramolecular Aldol Condensation Route to Fused Bi- and Tricyclic beta-Lactams(1)(,)(2)

Staüdinger cycloaddition of activated acid chlorides to 1,3-ketoaldimines, prepared in quantitative yields from 1,3-ketoaldehydes and amino esters, gave in excellent yields cis-2-azetidinones, 6-8, having the adequate functionality to obtain fused bi- and tricyclic beta-lactams. Reaction of compounds 6 with LHMDS at low temperature gave a single diastereomer of fused bicyclic compounds with a carbapenam or carbacefam skeleton. Treatment of diastereomeric cis-2-azetidinones, 7/8, in analogous conditions resulted either in the exclusive cyclization of one of the two diastereomers to form tricyclic [4.n.m] (n = 5, 6; m = 5, 6) compounds, or in the cyclization of both diastereomers to form tricyclic [4.n.7] (n = 5, 6) 2-azetidinones. In all cases the cyclization step was totally stereoselective. Alternatively, trans-carbapenams and one example of a tricyclic system having a trans-2-azetidinone ring have been obtained by using longer reaction times and higher temperatures. Epimerization at C3 of the 2-azetidinone nucleus occurs in these reaction conditions to obtain a single diastereomer of the final products. This approach to fused policyclic 2-azetidinones is one of the scarce syntheses of this kind of compound making use of the aldol condensation.     

Spectroscopic characterization of the 1-substituted 3,3-diphenyl-4-(2'-hydroxyphenyl)azetidin-2-ones: application of (13)C NMR, (1)H-(13)C COSY NMR and mass spectroscopy

The article deals with spectroscopic characterization of azetidin-2-ones. The presence of substituents like hydroxyl, fluoro, methoxy and benzhydryl, etc., on the azetidin-2-one ring significantly affects the IR absorption and (13)C NMR frequencies of the carbonyl group present in these compounds. The presence of an ester carbonyl group or too many methine protons in the molecule has been observed to limit the scope of IR and (1)H NMR spectroscopy in unambiguous assignment of the structure. The application of (13)C NMR, 2D NMR ((1)H-(13)C COSY) and mass spectroscopy in characterization of complex azetidin-2-ones is discussed. An application of the latter two techniques is described in deciding unequivocally between an azetidin-2-one ring and chroman-2-one ring structure for the product obtained by treatment of the 1-substituted 3,3-diphenyl-4-[2'-(O-diphenylacyl)hydroxyphenyl]-2-azetidinones with ethanolic sodium hydroxide at room temperature.     

A trans-stereoselective synthesis of 3-Halo-4-alkyl(aryl)-NH-azetidin-2-ones

[formula: see text] Conrotatory ring closure of 1-halo-3-aza-4-alkyl-1,3-dienes in refluxing toluene gives rise to 3-halo-4-aryl-2-azetidinones in satisfactory yields. Dehalogenation of the resulting beta-lactams by tris(trimethylsilyl)silane furnished 3-unsubstituted azetidinones, valuable intermediates in the synthesis of biologically active compounds.     

Diastereoselective ring expansion of beta-lactams toward gamma-lactams via N-acyliminium intermediates

[reaction: see text] The diastereoselective synthesis of highly functionalized gamma-lactams starting from 4-(1-bromoalkyl)-2-azetidinones via N-acyliminium intermediates is described. The carbenium ions, formed by dissociation of bromide from 4-(1-bromoalkyl)-2-azetidinones in polar medium, are converted via a ring expansion toward N-acyliminium ions, which are susceptible to attack of oxygen, nitrogen, and carbon nucleophiles. In this way, a variety of 5-hydroxy-, 5-alkoxy, 5-cyano-, 5-allylamino- and 5-azido-4,4-dimethyl-2-pyrrolidinones were synthesized. It was found that dehydrobromination of 4-(1-bromoalkyl)-2-azetidinones constituted an important side reaction when the title reactions were carried out in DMSO. When THF was used as a solvent, generally no dehydrobromination was observed, implying that higher yields of gamma-lactams were obtained in THF compared to reactions performed in DMSO. Also substituents of the 4-(1-bromoalkyl)-2-azetidinones play an important role concerning the obtained diastereoselectivity and the degree of dehydrobromination.     

Facile conversion of 2-azetidinones to 2-piperidones: application to a formal synthesis of Prosopis and Cassia alkaloids

Nonracemic 5,6-disubstituted 2-piperidones were prepared from readily accessible 3,4-disubstituted-2-azetidinones having pre-installed substituents by reductive ring opening of 2-azetidinones followed by stereoselective installation of Z-α,β-unsaturated ester and lactam formation. For the synthetic application to the naturally occurring piperidine alkaloids, such as Prosopis and Cassia alkaloids, 5-hydroxy-2-piperidones (+)-13 and (−)-24 were prepared from 2-azetidinones (−)-6b and (+)-18 via two-carbon ring homologation.     

Three- and four-membered rings from cycloadditions of 1,3-thiazolium-4-olates and aldehydes

2-Aminothioisomünchnones, a well-known family of masked dipoles, react with aromatic aldehydes in a domino cascade reaction that produces episulfides (thiiranes) or beta-lactams (2-azetidinones). This sequence is initiated by a [3+2] dipolar cycloaddition followed by ring opening of cycloadducts and intramolecular rearrangement to afford these unusual ring contractions. The nature of the reaction products depends on the structural characteristics of the starting dipole and the experimental conditions. Episulfides are obtained selectively as cis isomers with respect to both aryl groups, whereas beta-lactams are produced as cis/trans mixtures. These structural features were determined unequivocally by X-ray crystallographic analysis. The beta-lactams still possessed a flexible acyclic chain containing sulfur, a salient lead modification of the bioactive cyclic penems and cephems. The preferential production of exo transition structures was rationalized with the aid of computational calculations at the B3LYP/6-31G* level.     

Theoretical study of the mechanism of the formation of 3-unsubstituted 4,4-disubstituted beta-lactams by silver-induced ring expansion of alkoxycyclopropylamines: a new synthetic route to 4-alkoxycarbonyl-4-alkyl-2-azetidinones

The mechanisms of formation of 4,4-dialkyl- and 4-alkoxycarbonyl-4-alkyl-2-azetidinones by silver-induced ring expansion of the corresponding 2,2-disubstituted N-chloro-1-hydroxycyclopropylamines were theoretically investigated by means of the B3LYP method and the PCM solvation model. The obtained results indicate that these reactions are facile two-step regioselective processes proceeding through a short-life nitrenium intermediate. The theoretical results thus predict that this synthetic strategy, which has already been used to obtain 4,4-dialkyl-2-azetidinones, could also be a new route to efficiently obtain in a regio- and stereoselective way 4-alkoxycarbonyl-4-alkyl-2-azetidinones, which are precursors of conformationally constrained amino acids.     

Synthesis of 4,4-Disubstituted beta-Lactams by Regiospecific Electrophile- and Silver-Induced Ring Expansion of 2,2-Disubstituted 1-Methoxycyclopropylamines

2,2-Disubstituted 1-methoxycyclopropylamines underwent regiospecific ring expansion to 1,4,4-trisubstituted 2-azetidinones by N-chlorination with tert-butyl hypochlorite and subsequent rearrangement with silver tetrafluoroborate. Upon thermolysis, 4,4-disubstituted beta-lactams suffer a characteristic ring opening to afford beta,gamma-unsaturated carboxylic amides. The reduction of 1,4,4-trisubstituted 2-azetidinones with lithium aluminum hydride afforded 1,2,2-trisubstituted azetidines.     

General approach for the stereocontrolled construction of the beta-lactam ring in amino acid-derived 4-alkyl-4-carboxy-2-azetidinones

The first general approach toward the asymmetric synthesis of 4-alkyl-4-carboxy-2-azetidinones derived from amino acids is described. The stereoselective construction of the beta-lactam ring was achieved through base-mediated intramolecular cyclization of the corresponding N(alpha)-chloroacetyl derivatives bearing (+)- or (-)-10-(N,N-dicyclohexylsulfamoyl)isoborneol as chiral auxiliary (ee up to 82%).     

Synthesis of Cytotoxic 1,3,4-trisubstituted 2-azetidinones

A series of 1,3,4-trisubstituted and 3,4-disubstituted 2-azetidinones were synthesized in order to study the relation between their structure and biological characteristics. Study of the cytotoxic activity of these compounds revealed an anticancer effect in (3S,4S)-1-(4-methoxyphenyl)-3-methyl-2-azetidinones containing 2-acetoxybenzoyloxymethyl and 2,2-dicyanovinyl substituents at position 4 in vitro with respect to a wide range of monolayer cultures of cancer cells.     

Synthesis and Crystal Structure of α-(N-Protected amino) β-lactam Derivative of 1,5-Benzothiazepine

The crystal of the title compound C, C30H30N2O3S has been prepared by reaction of 1,5-benzothiazepine with N-protected glycine and determined by X-ray single crystal diffraction. Crystal data: Mr=498.62, triclinic with P space group, a=10.880(2), b=13.955(3), c=9.537(2)(A), α=99.34(3)°, β=110.43(3)°, γ=88.56(3)°, V=1338.2(5)(A)3, F(000)=528, λ(MoKα)=0.71073(A), Z=2, Dc=1.237g/cm3, μ=0.154mm-1. Final R=0.0453, wR=0.1256 for 3491 observed reflections [I>2σ(I)]. Structure analysis reveals that the substituents at C(23) and C(7) in four-membered ring are located on the same side. The conformation of seven-membered ring is chair-like.     

Diels-Alder reaction-aromatization approach toward functionalized ring C allocolchicinoids. Enantioselective total synthesis of (-)-7S-allocolchicine

Allocolchicinoids are analogues of the important antimitotic compound (-)-colchicine 1. A strategy is reported for the synthesis of ring C functionalized allocolchicinoids, which is based on a Diels-Alder reaction-aromatization sequence. This route is complementary to the previously disclosed benzannulation approach involving Fischer carbene complexes and alkynes. Dienes 12 and 14 incorporate the natural substitution pattern on ring A and undergo Diels-Alder reactions with various dienophiles. Subsequent aromatization affords the set of differently functionalized ring C allocolchicinoids 15-19, 23, and 25, with high regioselectively and in moderate to good yields. An intramolecular Diels-Alder reaction-aromatization sequence allows for access to allocolchicinoids with reversed regiochemical introduction of ring C substituents. The equilibria of the atropisomers of 15 and 19 are studied in three NMR solvents. Reactions of the dienes 12 and 14 with DMAD lead to the corresponding cycloadducts, but the subsequent aromatization is complicated. A regioselective Diels-Alder reaction-aromatization sequence is utilized as the key step in the first stereoselective total synthesis of (-)-allocolchicine 2. Asymmetric introduction of hydroxy group at C7 is achieved by the enantioselective reduction of ketone 29. The correct stereochemistry is then established by Mitsunobu inversion reaction using Zn(N(3))(2)-2Py.     

Synthesis of the C1-C9 fragment of callipeltoside-A

[reaction: see text] The C1-C9 fragment of callipeltoside (17) was prepared in 12 steps and 7.2% overall yield from bicyclic lactone (+)-4. Key steps include a stereoselective epoxidation and further regiocontrolled nucleophilic opening of the oxirane ring to install two vicinal stereocenters (C5 and C6), and the use of bis(trimethylsilyl) peroxide and a catalytic amount of Sn(IV) chloride for the chemoselective Baeyer-Villiger oxidation of unsaturated cyclopentanone 15.     

Blue Tetrakis(diisopropylamino)-cyclo-tetraborane and Yellow Tetrakis(tetramethylpiperidino)tetrabora-tetrahedrane

The colored boranes closo- 1 and cyclo- 2 are obtained upon dehalogenation of sterically hindered diaminodichlorodiborane(4) 3 . The TMP groups of 1 cause the formation of a tetrahedrane, whereas in 2 the diisopropylamino substituents stabilize the bent four-membered ring. TMP=2,2,6,6-tetramethylpiperidino.     

Rearrangement of 4-(1-haloalkyl)- and 4-(2-haloalkyl)-2-azetidinones into methyl omega-alkylaminopentenoates via transient aziridines and azetidines

The synthesis of 4-(1-haloalkyl)-2-azetidinones and 4-(2-haloalkyl)-2-azetidinones was investigated with use of the Staudinger reaction between in situ generated ketenes and alpha-haloimines or beta-haloimines. This new class of functionalized 2-azetidinones was further evaluated for its potential use as intermediates in the synthesis of highly functionalized compounds. The reaction of 4-(1-haloalkyl)-2-azetidinones and 4-(2-haloalkyl)-2-azetidinones with sodium methoxide in methanol yielded ring-opened products, i.e., methyl 2-alkoxy-4-(alkylamino)pentenoate and methyl 5-(alkylamino)pentenoate, respectively. Further attention was paid in detail to the reaction mechanism involved in this peculiar transformation. It was proven that these reactions proceeded via intermediate aziridines or azetidines.     

Stereoselective allylation of 4-oxoazetidine-2-carbaldehydes. Application To the stereocontrolled synthesis of fused tricyclic beta-lactams via intramolecular diels-alder reaction of 2-azetidinone-tethered trienes

Allylation reactions of racemic and optically pure 4-oxoazetidine-2-carbaldehydes were investigated both under anhydrous conditions and in aqueous media. Different Lewis acid or metal mediators showed varied diastereoselectivities on product formation during allylation reactions of the above aldehydes with allyltrimethylsilane, allyltributylstannane, or allyl bromide. Under standard reaction conditions, tin(IV) chloride-promoted addition of allyltrimethylsilane to 4-oxoazetidine-2-carbaldehydes provided the highest diastereoselectivity and the best yield. Boron trifluoride-diethyl ether-promoted reaction of allyltributylstannane provided slightly lower diastereoselectivity with the same facial preference. Indium-promoted allylation showed a reverse diastereofacial preference, although the observed selectivity is not synthetically useful. The mesylates of these homoallylic alcohols were used for the stereoselective preparation of cis-4-butadienyl-2-azetidinones. Interestingly, mesylates having an extra alkene or alkyne tether at position 1 or 3 of the beta-lactam ring, on heating in a sealed tube with equimolecular amounts of DBU in toluene, yielded fused tricyclic 2-azetidinones through a tandem one-pot elimination-intramolecular Diels-Alder reaction.     

Total synthesis of the tricyclic marine alkaloids (-)-lepadiformine, (+)-cylindricine c, and (-)-fasicularin via a common intermediate formed by formic acid-induced intramolecular conjugate azaspirocyclization

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).     

Synthetic studies on C14 cembranoids: synthesis of C4-12 fragment of sarcophytonolides E-G and L and C5-11 fragment of sarcophytonolide L

An efficient stereoselective synthesis of C4-12 fragment of the cembranoids, sarcophytonolides E-G and L and C5-11 fragment of sarcophytonolide L is described. The C4-12 building block is efficiently assembled starting from chiral pool material (R)-carvone employing the Baeyer-Villiger oxidation, modified Knoevenagel condensation and asymmetric dihydroxylation as the key steps. The synthesis of C5-11 fragment is based on orthoester Johnson-Claisen rearrangement as the key step.