Total synthesis of (-)-sarain A

This article describes the details of our synthetic studies toward the complex marine alkaloid sarain A. Various strategies were conceived, setbacks encountered, and solutions developed, ultimately leading to a successful enantioselective total synthesis. Our route to (-)-sarain A features a number of key steps, including an asymmetric Michael addition to install the C4'-C3'-C7' stereotriad, an enoxysilane-N-sulfonyliminium ion cyclization to set the C3 quaternary carbon stereocenter, and assemble the diazatricycloundecane core, a ring-closing metathesis to construct the 13-membered ring, an intramolecular Stille coupling to fashion the unsaturated 14-membered macrocycle, and a late-stage installation of the tertiary amine-aldehyde proximity interaction.     

Synthetic studies toward sarain A. Formation of the western macrocyclic ring

Starting with the tricyclic core 2b, annulation to form the 13-membered western ring of sarain A has been achieved to afford the macrocycle 30a by initial construction of the sterically congested quaternary center at C-3, followed by elaboration of the C-3 side-chain and ring-closing olefin metathesis. Also included is a parallel conversion of tricycle 2c to macrocycle 30b containing a functionalized side-chain at N-1 suitable for attachment of the eastern macrocyclic ring.     

Diastereoselective synthesis of a highly substituted cis-decahydroquinoline via a Knoevenagel condensation

A diastereoselective approach to 3,7,8-trisubstituted cis-decahydroquinolines is described. This ring system forms the core of rings B and E of the norditerpenoid alkaloid methyllycaconitine. This approach starts with a known disubstituted cyclohexene. The remaining carbons are attached via a Knoevenagel condensation followed by an intramolecular lactam formation. The stereochemistry of the substituents is controlled by the cis-substitution of the starting cyclohexene ring.     

A concise synthesis of the functionalized [5-7-6] tricyclic skeleton of guanacastepene A

The six membered ring of guanacastepene A was constructed by a Diels-Alder reaction of 1,1,4-trisubstituted diene to set up the correct relative stereochemistry at the C8 quaternary center and the remote C5 stereocenter. In 10 efficient steps from the Diels-Alder adduct 9, the desired highly functionalized [5-7-6] tricyclic skeleton 2 was synthesized. Key steps involve trimethylsilyl chloride (TMSCl) assisted Michael addition to form enol ether and the usage of the enol ether in the following intramolecular Mukaiyama aldol reaction to form the middle seven membered ring of guanacastepene A.     

Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the Daphniphyllum alkaloids

A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyclization (N-alkylation), followed by intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. The reaction was most successful using hydroxylamine, and when the dipolarophile was an unsaturated ester, subsequent reduction of the N-O bond and cyclization to the lactam provided the core ring system of the yuzurimine, daphnilactone B, and bukittinggine type Daphniphyllum alkaloids.     

Total synthesis and absolute stereochemical assignment of (+)- and (-)-galbulimima alkaloid 13

We describe the total synthesis of (+)- and (-)-galbulimima alkaloid 13. The absolute stereochemistry of natural (-)-galbulimima alkaloid 13 is revised to 2S. Sequential use of catalytic cross-coupling and cross-metathesis reactions followed by an intramolecular Diels-Alder reaction provided the required trans-decalin AB-ring system and masked the C16 carbonyl as an N-vinyl carbamate for late-stage unveiling in the form of the necessary C16 enone. A vinyl radical cyclization secured the C-ring, while successful execution of our strategy for introduction of the CDE-ring system in complex galbulimima alkaloids provided the target pentacycle with complete diastereoselection.     

Total synthesis of optically active chanoclavine-I

The total synthesis of optically active chanoclavine-I, an ergot alkaloid, was accomplished using palladium-catalyzed intramolecular cyclization (Heck reaction) as a key step. The conjugate ester (6) was obtained in 2 steps from optically active 4-bromotryptophan (10), and the cyclization of 6 proceeded smoothly without racemization to give the key intermediate, tricyclic tetrahydrobenz[c,d]indole derivative (7), in high yield.     

Tandem oxidative dearomatization/intramolecular Diels-Alder reaction for construction of the tricyclic core of palhinine A

A concise construction of the 6/6/5 tricyclic core of Lycopodium alkaloid palhinine A (1) has been accomplished. The developed synthetic strategy featured a tandem oxidative dearomatization/intramolecular Diels-Alder reaction to construct C/D rings and an intramolecular 5-exo-trig radical cyclization to install the B ring of palhinine A (1). The developed approach paves the way for the total synthesis of palhinine A (1).     

Intermolecular one-pot cyclization of formyl-pyrroles of amino acid esters with norephedrine: stereoselective routes to new tricyclic pyrrole–pyrazine–oxazole fused structures

The treatment of esters of amino acids with dimethoxytetrahydrofuran furnished pyrrole derivatives of amino acid esters. The Wilsmeier–Haack formylation followed by the reaction of the formylated pyrroles with norephedrine afforded a selective formation of the tricyclic pyrrole–pyrazine–oxazole fused structures in one step via the formation of an oxazoline structure and intramolecular lactam formation. Pyrrole–pyrazine–oxazole fused structures were achieved in good yields. The cyclization reaction for the formation of an oxazole ring worked selectively to form only one stereoisomer. The configuration of the newly generated stereogenic center in the oxazole ring is dependent on the stereogenic centers of norephedrine.     

A Radical Cyclization Approach to Isoindolobenzazepines. Synthesis of Lennoxamine

The alkaloid lennoxamine (1) was synthesized by transannular cyclization of a 10-membered lactam obtained by intramolecular addition of an aryl radical to a (trimethylsilyl)acetylene. The isoindolo[1,2-b][3]benzazepine skeleton present in lennoxamine was also obtained by means of regioselective 7-endo-trig radical cyclization of methylenephthalimidines.     

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3′-oxindole] Alkaloids

A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3′-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps of the synthesis are the generation of the tetracyclic spirooxindole ring system by stereoselective spirocyclization from a tryptophanol-derived oxazolopiperidone lactam, the removal of the hydroxymethyl group, and the stereoselective introduction of the E-ethylidene substituent by acetylation at the α-position of the lactam carbonyl, followed by hydride reduction and elimination. Following this route, the 21-oxo derivative of the enantiomer of the alkaloid 7(S)-geissoschizol oxindole has been prepared.     

Carbodiimide-mediated preparation of the tricyclic pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine ring system and its application to the synthesis of the potent antitumoral marine alkaloid variolin B and analog

A total synthesis of the marine alkaloid variolin B has been completed in 13 steps in an overall yield of 6.5% from 3-formyl-4-methoxypyridine. Our approach is based on the sequential formation of the 7-azaindole ring, the tricyclic pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine ring system, and finally installation of the 2-aminopyrimidine ring at C5. The required 7-azaindole ring appropriately substituted is formed by a modified indole synthesis involving a nitrene insertion process (two steps). Formation of the annelated pyrimidine ring is achieved by two routes both involving a carbodiimide-mediated cyclization process, which allow incorporation of the amine functionality at C9 of the core tricyclic (six steps). Installation of the northeast 2-aminopyrimidine ring at C5 is performed using the Bredereck protocol (three steps). Ultimate, thermal decarboxylation with concomitant O-methyl deprotection and further N-benzyl deprotection by the action of triflic acid completed the synthesis of the target natural product variolin B.     

Synthesis and chemistry of bridgehead allylsilanes. Stereoselective reactions with aldehydes

A type II intramolecular Diels-Alder reaction provides access to bicyclo[5.3.1] ring systems with an imbedded bridgehead allylsilane. The Lewis acid catalyzed reactions of these compounds with aldehydes proceed efficiently and with control of stereochemistry. [reaction: see text]     

Total Synthesis of the Monoterpenoid Indole Alkaloid (±)‐Aspidophylline A

Aspidophylline A belongs to the akuammiline alkaloid family, the members of which possess intriguing cagelike structures and diverse biological activities. Herein we report a 15‐step synthesis of this alkaloid from conveniently available starting materials. The key elements of the synthesis include an intramolecular oxidative coupling to create the tetracyclic furoindoline motif of the natural product and a [Ni(cod)₂]‐mediated cyclization to install its piperidine ring.     

Enantiospecific synthesis of the proposed structure of the antitubercular marine diterpenoid pseudopteroxazole: revision of stereochemistry.

An enantiospecific synthesis of structure 1, previously assigned to the antitubercular marine natural product pseudopteroxazole, has been accomplished as outlined in Scheme 1. Coupling of diene acid 3 and amino phenol 4 produced the amide 5, which was subjected to a novel oxidative intramolecular Diels-Alder reaction to generate the tricyclic lactam 6a stereoselectively. This product was transformed via intermediates 7-11 into the diene 13. Cationic cyclization of 13 afforded two diastereomeric tricyclic amphilectanes which were separated and transformed by parallel four-step sequences into 1 and 2, respectively. Neither 1 nor 2 were identical with pseudopteroxazole, indicating a need for revision of the structure, probably to 16.     

Biogenetic syntheses of kopsijasminilam and deoxykopsijasminilam

The hexacyclic ketoester 7, derived from cyclization of racemic minovincine (6), was reduced to two C-19 epimeric alcohols 8 and 9. Stereoelectronically controlled fragmentations of corresponding O-sulfonyl derivatives provided, respectively, the hexacyclic enamine 14 and, after oxidation of the olefin 16, the pentacyclic lactam 17 with a brigehead double bond. Formation of a carbamate, introduction of a second double bond at C-16, and conjugate reductive hydroxylation at C-20, or hydrogenation, gave the title products.     

A concise synthesis of tetrabenazine: an intramolecular aza-Prins-type cyclization via oxidative C-H activation

A concise synthesis of tetrabenazine and dihydrotetrabenazine is described. The key feature of this synthesis is the intramolecular aza-Prins-type cyclization of an amino allylsilane via oxidative C-H activation.     

Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy

Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper-catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid-catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (+/-)-lepadiformine (6). The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R),5(S),10(S),13(S).     

Rhodium(II)-catalyzed aziridination of allyl-substituted sulfonamides and carbamates

Several unsaturated sulfonamides underwent intramolecular aziridination when treated with PhI(OAc)(2), MgO, and catalytic Rh(2)(OAc)(4) to give bicyclic aziridines in excellent yield. Treatment of the resulting azabicyclic sulfonamides in methanol in the presence of p-TsOH resulted in exclusive opening of the aziridine ring at the most substituted position affording six- and seven-membered ring products in high yield. In contrast, the intramolecular aziridination of several cycloalkenyl-substituted carbamates did not require a Rh(II) catalyst and proceeded via an iminoiodinane intermediate. The resulting tricyclic aziridines underwent ring opening when treated with various nucleophiles to give anti-derived products as expected for nucleophilic attack at the three-membered ring. The iodine(III)-mediated reaction of a 3-indolyl-substituted carbamate, however, required a Rh(II) catalyst. The expected aziridine was not observed, but rather simultaneous spirocyclization of C(3) and stereoselective syn-acylation at C(2) occurred to give compound 41, whose structure was unequivocally established by an X-ray crystallographic study. The reaction proceeds in a stepwise manner via a metal-free zwitterionic intermediate which is attacked by a nucleophilic reagent on the same side of the amide anion. Related reactions occurred with both a 2-indolyl- and 3-benzofuranyl-substituted carbamate but with lower stereoselectivity.     

A novel approach to ring A analogues of the marine pyridoacridine alkaloid ascididemin

A novel approach to ring A analogues of the marine pyridoacridine alkaloid ascididemin starting from readily available 4-bromobenzo[c][2,7]naphthyridine (10) comprises a high-yield Minisci-type homolytic methoxycarbonylation at C-5, followed by introduction of the ring A scaffold via Suzuki cross-coupling reaction, and a trifluoromethanesulfonic acid-aided Friedel–Crafts-type intramolecular acylation. This protocol allows for the introduction of various electron-rich carbocyclic and heterocyclic ring A substitutes.