Stereoselective synthesis of the ABC ring system of norzoanthamine

[reaction: see text] An efficient synthesis of enone 4, representing the ABC ring motif of norzoanthamine, is presented. The crucial C22 quaternary center was introduced via a stereoselective methylation of enone 8. The trans-anti-trans relative configuration of the ABC framework of 4 was installed via a sequence of reactions that included a hydroboration and a modified Robinson annulation.     

A short route to enantiomerically pure benzophenanthridinone skeleton: synthesis of lactone analogues of narciclasine and lycoricidine

Condensation of functionalized o-toluamide anions on a carbohydrate-derived lactone, followed by intramolecular aldol cyclization, provides enantiomerically pure 2-arylcyclohexenones. Different approaches for the stereoselective transformation of the carbonyl group of these key intermediates into an amino group were unsuccessful. However 1,4-addition of thiolate and concomitant ring closure to isocoumarine provided a useful method for the transformation of the tertiary amide function. Opening of the isocoumarin with ammonia provided the corresponding amide and recovery of the enone system. Subsequent reductive amination of this cyclohexenone was found to depend on the nature of the protecting groups and led to the protected form of 4-epi- and -iso-narciclasine. Oxo analogues of narciclasine and epi-narciclasine and lycoricidine were also obtained after reduction of the enone and subsequent lactonization. They showed no biological activity as antitumor agents.     

Stereoselective total synthesis of (±)-7-deoxy-trans-dihydronarciclasine, a potent antineoplastic phenanthridone alkaloid

A short and efficient stereoselective total synthesis of (±)-7-deoxy-trans-dihydronarciclasine, a highly potent antineoplastic agent and constituent of the Amaryllidaceae alkaloids, is described. Starting from a known arylcyclohexylamine-type precursor 6, the C-ring with the required stereochemistry is constructed using a chemo- and stereoselective enone reduction (NaBH₄/CaCl₂ system) and a Mitsunobu reaction. For the B-ring closure, the Banwell modification of the Bischler-Napieralski reaction was applied.     

Synthesis of

A series of 1,1'-dicinnamoylferrocenes were converted to the corresponding [3]ferrocenophane diols (4a-e) in a stereoselective manner by using samarium diiodide to effect the intramolecular coupling reaction, aldol reaction, and reduction in one-pot operation. The major reaction pathway might be derived from a samarium chelated transition state (I(A)()) having the moieties of s-cis enone and (Z)-enolate. A solid-state structure of such [3]ferrocenophane diol product showed that the cyclopentadienyl groups were in an eclipsed orientation and slightly tilted.     

A New,Stereoselective Approach to the [3.3.3]Propellane System: Synthesis of (±)-modhephene. Preliminary communication

The unusual propellane skeleton of the sesquiterpene modhephene ( 1 ) has been synthesized starting from cyclopentenone ( 2 ). The key step 6 → 7 is an efficient and highly stereoselective intramolecular thermal ene-reaction. Further elaboration of the propellane 7 gave the enone 10 which had been previously converted to (±)-modhephene ( 1 ) in three steps.     

Concise stereocontrolled formal synthesis of (+/-)-quinine and total synthesis of (+/-)-7- hydroxyquinine via merged Morita-Baylis-Hillman-Tsuji-Trost cyclization

Concise stereoselective syntheses of (+/-)-quinine and (+/-)-7-hydroxyquinine are achieved using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and the electrophilic features of the Tsuji-Trost reaction. Cyclization of enone-allyl carbonate 11 delivers the product of cycloallylation 13 in 68% yield. Diastereoselective conjugate reduction of the enone 13 (>20:1 dr) followed by exchange of the N-protecting group provides the saturated N-Boc-protected methyl ketone 19, which upon aldol dehydration provides quinoline containing enone 15, possessing all carbon atoms of quinine. Exposure of ketone 15 to L-selectride enables diastereoselective carbonyl reduction (>20:1 dr) to furnish the allylic alcohol 16. Stereoselective hydroxyl-directed epoxidation using an oxovanadium catalyst modified by N-hydroxy-N-Me-pivalamide delivers epoxide 17 (17:1 dr). Cyclization of the resulting amine-epoxide 17 provides (+/-)-7-hydroxyquinine in 13 steps and 11% overall yield from aminoacetaldehyde diethyl acetal. Notably, highly stereoselective formation of five contiguous stereocenters is achieved through a series of 1,2-asymmetric induction events. Deoxygenation of the N-Cbz-protected allylic acetate 22 provides olefin 23, which previously has been converted to quinine. Thus, (+/-)-quinine is accessible in 16 steps and 4% overall yield from commercial aminoacetaldehyde diethyl acetal.     

An expedient route to Montanine-type Amaryllidaceae alkaloids: total syntheses of (-)-brunsvigine and (-)-manthine

The first total syntheses of (-)-brunsvigine (1) and (-)-manthine (2) were accomplished in 10 and 18 steps, respectively. (-)-Quinic acid was converted to enone 12 in five steps. Iodination of enone 12 followed by stereoselective reduction yielded alpha-iodo allylic alcohol 16. Conversion of alcohol 16 into Weinreb amide 11 followed by anionic cyclization gave bicyclic enone 10. Stereoselective reduction of enone 10 and subsequent protection afforded pivaloate 9. Grignard addition of 8 to 9 and detosylation afforded amine derivative 19. Pictet-Spengler cyclization of 19 with Eschenmoser's salt and subsequent hydrolysis gave enantiomerically pure (-)-brunsvigine (1). For the total synthesis of (-)-manthine (2), the key intermediate 7 was hydrolyzed to diol 21. Conversion of 21 into 22 followed by regioselective cleavage with DIBAL furnished alcohol 25. Alcohol 25 was converted to the corresponding triflate 26, which on treatment with CsOAc and 18-crown-6 gave stereoinverted acetate 27. Hydrolysis of acetate 27 followed by methylation afforded compound 29. Detosylation of 29 afforded amine derivative 30. Pictet-Spengler cyclization of 30 followed by debenzylation gave alcohol 33. Finally, methylation of alcohol 33 afforded (-)-manthine (2).     

Synthetic study on efficient stereoselective construction of tricyclic core skeleton of manzamine A

Tricyclic core skeleton of manzamine A was constructed stereoselectively from the fused nitrogen-containing bicyclic enone 3 via a novel and efficient strategy including sequential stereoselective Diels-Alder reaction, Curtius rearrangement, and intramolecular lactam formation reaction.     

Stereoselective synthesis of the octahydroisobenzofuran skeleton of the eunicellins

A de novo asymmetric synthesis of the octahydroisobenzofuran skeleton contained within the eunicellin family of natural products has been completed. The key transformations involve the convergent assembly of a tetrasubstituted tetrahydrofuran by condensation of a functionalised allylsiloxane with an aldehyde; controlled epimerisation of a C4 aldehyde by intramolecular trapping; installation of the isopropyl substituent by stereoselective Michael addition to a 5,5-bicyclic enone; and ring expansion of the 5,5-system to the target structure by radical-mediated cyclopropane fragmentation.     

Cyclobutanones through SNi' ring closure, a mechanistic study

Mechanistic studies on the intramolecular nucleophilic substitution with allylic rearrangement (SNi' reaction) and a new stereoselective access to substituted cyclobutanones are reported. 4,4-Dialkyl-5-oxohex-2E-en-1-yl methanesulfonates 4 were converted to 2,2-dialkyl-3-vinylcyclobutanones 6 by SNi' ring closure. The stereochemical analysis of the reaction was achieved through ring closure of (6S)-6-chloro-3,3-diethylhept-4E-en-2-one (S)-17, defined by the absolute configuration of C(6), leading to (3S)-2,2-diethyl-3-(prop-1E-en-1-yl)cyclobutanone (S)-(E)-18 and (3R)-2,2-diethyl-3-(prop-1Z-en-1-yl)cyclobutanone (R)-(Z)-18, in a ratio of 85:15, with almost complete transfer of chirality (>97%). The absolute configuration of (S)-17 was determined by X-ray diffraction analysis of the camphanoate derivative 16. The absolute configuration of the cyclobutanone products (S)-(E)-18 and (R)-(Z)-18 was determined by Raman optical activity spectroscopy. Comparison of the absolute configuration of (S)-17 and the resulting (E)- and (Z)-cyclobutanones 18 allowed the conclusion that the SNi' reaction proceeds with syn geometry relative to the leaving group.     

Enantioselective synthesis of the dimeric pyranonaphthoquinone core of the cardinalins using a late-stage homocoupling strategy

The enantioselective synthesis of a dimeric pyranonaphthoquinone closely related to the cardinalins is described. Whilst attempts to effect a double Hauser-Kraus annulation of enone 5 were unsuccessful using both bis-phthalide 4 and bis-sulfone 21, a single annulation of cyanophthalide 28 with enone 5 furnished functionalised naphthalene 31. Suzuki-Miyaura homocoupling of the aryl triflate 29 derived from 31 effected a late-stage construction of the biaryl bond and facilitated access to the biaryl 3. Double stereoselective lactol reduction installed the 1,3-cis stereochemistry of the pyran rings and a final double oxidative demethylation step furnished model dimer 1, completing the enantioselective synthesis of a dimeric pyranonaphthoquinone bearing the core structure of cardinalin 3.     

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.     

Synthesis of iminomethano-dibenzo[a,e]cyclooctenes by transannular formation and cleavage of isoxazolidines

Regioselective formation of the 7-azabicyclo[4,2,2]decanone (4) was accomplished by reaction of hydroxylamine with the enone (10) and subsequent reduction of the isoxazolidine adduct (11); intramolecular nitrone cycloaddition of (19) gave a 2:1 mixture of the regioisomers (17) and (18) which were reduced to give the bridgehead methylated, -hydroxylated, [3,3,2] and [4,2,2] iminomethano compounds (5) and (6).     

Construction of tricyclic enone, a common precursor for aphidicolane and stemodane B/C/D-ring system

Synthesis of a tricyclic enone (B/C/D ring system), a common key precursor for the aphidicolane- and stemodane-type diterpene, is described. The key reaction for the construction of the quaternary carbon center is allylation of epoxide at the more substituted carbon with an organotitanium reagent. Asymmetric reduction with DIP-Cl followed by stereoselective cyclization of spirocyclic ketone and the functional group modification gave the desired tricyclic enone in good yield.     

Stereoselective synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-1-ones via intramolecular hetero-Diels-Alder reaction

The synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-1-ones via an intramolecular hetero-Diels-Alder reaction of easily accessible α,β-unsaturated γ-ketoesters was investigated. The reaction was found to proceed in a highly stereoselective way leading to single, cis-configured product isomers. The same diastereomer is formed, independently of the configuration of the enone double bond of the precursor. The respective E- and Z-isomers react either through an endo-E-syn or an exo-Z-syn transition state.     

An expedient total synthesis of ent-(−)-7-deoxy-trans-dihydronarciclasine

A short and efficient stereoselective total synthesis of (−)-7-deoxy-trans-dihydronarciclasine, an ent-form of a highly potent antineoplastic agent constituent of the Amaryllidaceae alkaloids, is described. Starting from the enantiopure form of a known arylcyclohexylamine type precursor 6, which was synthesized enantioselectively utilizing a highly enantioselective nitromethane addition, the three hydroxy groups on the C-ring with the required stereochemistry were introduced by a chemo- and stereoselective enone reduction (NaBH₄/CaCl₂ system) followed by a Mitsunobu reaction and subsequent osmylation. The ring closure of the B-ring was accomplished by the Banwell modification of the Bischler-Napieralski reaction.     

Synthesis of the ABC ring system of manzamine A

A synthesis of the core ABC ring system of the manzamine alkaloids is described, starting from arecoline. The key steps involve a Claisen rearrangement to set up a 4-substituted-3-methylenepiperidine and a stereoselective azomethine ylide dipolar cycloaddition reaction. Condensation of the aldehyde 6 and sarcosine ethyl ester hydrochloride salt gives an intermediate azomethine ylide, which undergoes an intramolecular cycloaddition reaction to set up two new rings and three new chiral centers stereoselectively. The aldehyde 6 was not a suitable substrate for related azomethine ylide cycloaddition reactions with other amines. However, the related dimethyl acetal 26 could be condensed with a variety of amines to give the desired tricyclic products. The cycloaddition reaction with N-methyl or N-allyl glycine ethyl ester gave almost exclusively the exo adduct, whereas cycloaddition with glycine ethyl ester gave the endo adduct.     

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%).     

Chemically induced anion radical cycloadditions: intramolecular cyclobutanation of bis(enones) via homogeneous electron transfer

The first examples of anion radical cycloaddition induced by homogeneous electron transfer from chemical agents are described. Specifically, upon exposure to chrysene anion radical, bis(enone) substrates are found to engage in stereoselective intramolecular [2 + 2] cycloaddition. These studies, along with the corresponding electrochemically initiated reactions, provide insight into this fundamentally new pattern of reactivity and support the feasibility of expanding this novel reaction type.     

Stereoselective syntheses of galanthamine and its stereoisomers by complementary Luche and L-selectride reductions

A diastereodivergent approach for the stereoselective syntheses of all four stereoisomers of galanthamine, (−)-galanthamine 1, (+)-galanthamine 2, (−)-epigalanthamine 3, and (+)-epigalanthamine 4, from (±)-narwedine 5 is reported. Thus (±)-narwedine 5 was resolved by dynamic kinetic resolution to obtain enantiomerically pure (−)-narwedine 6 and (+)-narwedine 7. Each enantiomerically pure isomer of narwedine was subjected to Luche and L-selectride reactions to obtain all four isomers of galanthamine. In these reactions, the (−)-galanthamine 1 and (+)-galanthamine 2 isomers were obtained with an enantiomeric purity of >99.5%, whereas (−)-epigalanthamine 3 and (+)-epigalanthamine 4 are obtained with a chiral purity of >97%. The axial hydride attack by the Luche reduction and the equatorial hydride attack by the L-selectride reduction on the cyclic enone system are explored in the stereoselective synthesis of the galanthamine isomers and thus it was demonstrated that the stereoselective synthesis involving the Luche and L-selectride reductions are complementary in yielding enantiomeric stereogenic centers from a prochiral carbonyl group on the cyclic enone system.