Synthesis of the spiro fused β-lactone-γ-lactam segment of oxazolomycin

An effective synthetic strategy for construction of the novel spiro-bicyclic β-lactone-γ-lactam system present in oxazolomycin has been demonstrated. The 3,4-disubstituted pyrrolidine ring system was constructed via an Evans aldol reaction. The spiro-β-lactone ring was elaborated from a gem-hydroxymethyl moiety that was successfully installed by an aldol followed by a crossed Cannizzaro reaction.     

Toward the total synthesis of methyl isosartortuoate: construction of the backbone of the diene unit

The backbone of diene precursor in the proposed biogenesis of methyl isosartortuoate through a Diels-Alder reaction has been constructed via dehydration to establish the conjugated system; and double cyclization by using Horner-Wittig-Emmons reaction and the chiral epoxy ring opening.     

Imdazole systems. I. Imidzo[2,1-b][1,3,5]benzothiadiazepine derivatives as potential antipsychotic agents

Imidazo[2,1-b][1,3,5]benzothiadiazepine 3 constitutes a novel ring system, and its analogs 3a-i were synthesized to investigate their potential antipsychotic activity. The synthesis of the ring system was achieved by reaction of 2-aminophenylthioimidazoles 7 with phosgene or thiophosgene and by ring closure of the 1-[2-(2-imidazolyl)thiophenyliminocarbonyl]-1-piperazines 13 . An efficient method for the conversion of thioureas 8, 12 to guanidine 3a via the corresponding cyanothioamidines 11, 14 was developed.     

Synthetic studies on (-)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (1)

Construction of the ABCD ring system of (-)-FR182877 via the highly diastereoselective intramolecular Diels-Alder (IMDA) reaction is described. The IMDA reaction of the α,β-unsaturated aldehyde generated in situ from the corresponding acetal successfully provided the desired product 14 possessing the AB ring system as the single diastereomer. The CD ring system was constructed by the subsequent IMHDA reaction and the additional experiment suggested that the diastereoselectivity of the IMHDA reaction could be related to the E/Z geometry of alkene 17, which was generated in situ from 16.     

Total synthesis of the sesquiterpene (+/-)-illudin C via an intramolecular nitrile oxide cycloaddition

[reaction: see text] A convergent total synthesis of illudin C is described. The tricyclic ring system of the natural product was quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide-olefin cycloaddition.     

Studies toward the total synthesis of vinigrol. synthesis of the octalin ring

[reaction: see text] Herein, we disclose our results regarding various strategies toward the assembly of the octanyl ring of vinigrol. Attempts to generate the problematic eight-membered ring through a ring expansion or via unification of the terminal olefins using the ring-closing metathesis were not successful. The cyclooctane ring was created via a sequential hydroxy Diels-Alder/Claisen rearrangement reaction of diene 55 and N-benzylmaleimide.     

aza-Prins-pinacol approach to 7-azabicyclo[2.2.1]heptanes and ring expansion to [3.2.1]tropanes

[reaction: see text] The 7-azabicyclo[2.2.1]heptane ring system can be rapidly accessed from 5-(1-hydroxyallyl)-2-alkoxy-N-tosylpyrrolidines via an unusual aza-Prins-pinacol reaction mediated by Lewis acid. The products can undergo ring expansion to isomeric tropanones. These reactions show promise for a concise entry to biologically relevant azabicyclic targets.     

Synthesis of polycyclic aromatic fluoranthenes

A general synthetic approach to polycyclic aromatic hydrocarbons containing a fluoranthene ring system is described. The method entails fusion of an indeno ring to an alternant hydrocarbon via reaction of an aryllithium derivative with cyclohexene oxide.     

Ring expansion of substituted norbornadienes for the synthesis of mono- and disubstituted 2-azabicyclo[3.2.1]octadienes

We have studied the conversion of substituted norbornadienes into a substituted 2-azabicyclo[3.2.1]octadiene system via reaction with toluenesulfonyl azide. We have found that both and mono- and disubstituted norbornadienes will undergo the cycloaddition/rearrangement sequence to provide the bicyclooctadiene ring system as a single regioisomer. The 2-azabicyclo[3.2.1]octane ring system can be prepared from the unsaturated 2-azabicyclo[3.2.1]octadiene ring system.     

First and second generation total synthesis of the teicoplanin aglycon.

Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.     

Synthesis of substituted 5-aminomethyl tetrahydro-isoquinolines and dihydro-isoindoles

The synthesis of ten substituted aminomethylene tetrahydro-isoquinolines is described, proceeding in eight steps from 5-hydroxyisoquinoline via reductive amination of N-Boc tetrahydro-isoquinoline 5-carboxaldehyde. Likewise, reductive amination was used to prepare four substituted dihydro-isoindoles from the corresponding aldehyde. The dihydro-isoindole ring system was conveniently accessed via a 2+2+2 cycloaddition reaction.     

Total synthesis of the ristocetin aglycon

The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.     

Total synthesis of (+/-)-scopadulin.

The first total synthesis of (+/-)-scopadulin, an aphidicolane diterpene, is described. The core structure (A/B/C/D ring system) was constructed by an initial synthesis of the B/C/D ring system by our reported methods and a subsequent A ring cyclization by intramolecular aldol condensation. A highly stereoselective cyanation of the tetracyclic enone by Et2AlCN gave a trans-fused A/B ring system with a beta-cyanide at C-4. Stereoselective construction of a quaternary carbon at C-4 was achieved by alpha-alkylation of the cyano group and conversion of the sterically hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines into alcohols. Finally, the total synthesis of (+/-)-scopadulin was accomplished by a highly chemo- and stereoselective methylation at C-16 and modification of the C-4 alpha-functionality. The stereoselectivity observed in the MeTi(O-i-Pr)3-mediated methylation for the generation of a tertiary axial alcohol at C-16 is extremely high.     

非对称氮杂环丙烷的亲核开环反应及其区域选择性

本文系统地总结了各类亲核试剂对非对称氮杂环丙烷(吖丙啶)的亲核开环反应及开环的区域选择性.氮杂环丙烷亲核开环的区域选择性是一种空间效应和电子效应平衡的结果,非芳基和非烯基取代的氮杂环丙烷的亲核开环通常发生在氮杂环丙烷取代少的碳原子上,空间效应起主导作用;而芳基和烯基取代的氮杂环丙烷的亲核开环通常发生在氮杂环丙烷芳甲位和烯丙位的碳原子上,电子效应起主导作用,烯基取代的氮杂环丙烷的亲核开环还可以发生在烯基的β-碳原子上;分子内的亲核开环反应主要受成环时环大小的控制,成环时的倾向是五元环>六元环>七元环.对于亲核试剂,一般的亲核试剂也同时受电子效应和空间效应的影响; 而亲核性强的亲核试剂通常只受空间效应的影响.容易生成稳定自由基的亲核试剂容易发生单电子转移机理的开环反应,生成相当于亲核试剂进攻氮杂环丙烷中取代多的碳原子得到的开环产物.     

Asymmetric total synthesis of (-)-scabronine G via intramolecular double Michael reaction and Prins cyclization

The enantioselective total synthesis of (-)-scabronine G is described. The key features of the present synthesis include the construction of a 5-6 ring system containing two quaternary carbon centers via a diastereoselective intramolecular double Michael reaction and the formation of a seven-membered ring using a Prins cyclization.     

Generation of N-acyliminium ions via intramolecular conjugate addition reactions: a strategy for the total synthesis of nakadomarin A

[reaction: see text] The rapid construction of the tetracyclic core ring system of nakadomarin A via a tandem enecarbamate Michael addition/N-acyliminium ion cyclization is described.     

A strategy for the synthesis of the fargenone/fargenin family of natural products: synthesis of the tricyclic core

A synthesis of the core ring structure of the fargenin/fargenone family of natural products is presented. The general strategy is based upon biosynthetic speculation and exploits a cascade reaction, which transforms a spirocyclic dienone into the core ring system via a deprotonation-oxy-Michael-Wittig olefination sequence. This study represents the first synthesis work towards this family of natural products.     

cis-decalins from quinic acid: toward a synthesis of branimycin

[reaction: see text] Starting from (-)-quinic acid an efficient synthesis of highly functionalized cis-alpha,beta-unsaturated ketone 3, an advanced precursor of branimycin, has been accomplished via two key step reactions: a ring closing metathesis reaction to prepare the cis-decalin system, and a highly stereoselective epoxidation reaction.     

Enantioselective formal total synthesis of roseophilin

[formula: see text] An enantioselective formal total synthesis of roseophilin 3 is presented. The 13-membered ring of macrotricycle 1 was formed via an efficient ring-closing metathesis reaction of bicycle 4. A palladium-catalyzed methoxycarbonylation reaction of enol triflate 5 was utilized to functionalize the right-hand ring of bicycle 2. The allyl substituent was introduced by a radical allylation of alpha-bromoketone 17.     

An improved synthesis of (−)-brevisamide, a marine monocyclic ether amide of dinoflagellate origin

An improved synthesis of (−)-brevisamide a marine cyclic ether isolated from the red-tide dinoflagellate Karenia brevis was achieved. The ether ring portion was constructed from an unsaturated lactone, which was prepared enantioselectively via an Evans aldol reaction and one-pot lactonization in the presence of excessive base after an Ando reaction. The ether ring and a dienol side chain fragment were connected via Suzuki-Miyaura coupling.