First total synthesis of (+/-)-stemonamide and (+/-)-isostemonamide

[structure: see text] The total synthesis of the tetracyclic alkaloids stemonamide (1) and isostemonamide (2) is presented. The key step is the reaction between a silyloxyfuran and an N-acyliminium ion. The second quaternary center is created by an intramolecular aldol spirocyclization. After 1,4-addition of an appropriate side chain, the methyl and double bond are installed by Mannich reaction. The seven-membered ring is closed by intramolecular nucleophilic displacement.     

Formal syntheses of (+/-)-pinnaic acid and (+/-)-halichlorine

[chemical reaction: see text]. Concise formal syntheses of marine alkaloids (+/-)-pinnaic acid (1) and (+/-)-halichlorine (2) have been accomplished from a common intermediate. The syntheses illustrate the utility of selective olefin cross metathesis methodologies for the elaboration of advanced synthetic intermediates in complex molecule synthesis.     

A stereospecific synthesis of (+/-)-5,8-disubstituted indolizidines and (+/-)-1,4-disubstituted quinolizidines found in poison frog skins

An efficient, high-yield stereospecific route to three (+/-)-5, 8-disubstituted indolizidines, (209B (I), 209I (II), 223J (III)) and two (+/-)-1,4-disubstituted quinolizidines (207I (IV), 233A (V)), racemates of alkaloids found in the skins of neotropical and Madagascan poison frogs is reported. The structures of the natural alkaloids were thereby established by chiral GC comparison with the exception of indolizidine 209B (I) for which a natural 209B could no longer be detected.     

General and efficient strategy for erythrinan and homoerythrinan alkaloids: syntheses of (+/-)-3-demethoxyerythratidinone and (+/-)-erysotramidine

[reaction: see text] A general and efficient strategy to both aromatic-type and nonaromatic-type erythrinan and homoerythrinan alkaloids has been developed. This approach involves a key two-step sequence, an alkylation of a ketone with various N-substituted iodoacetamides followed by a N-acyliminium ion promoted intramolecular cyclization, and represents one of the shortest routes to erythrinan and homoerythrinan alkaloids. As the application, the formal total synthesis of (+/-)-3-demethoxyerythratidinone and the total synthesis of (+/-)-erysotramidine have been achieved, respectively.     

Total synthesis of (+/-)-stemonamide and (+/-)-isostemonamide using a radical cascade

Total synthesis of stemonamide and isostemonamide is described. The concise construction of the tricyclic core of these alkaloids was achieved by radical cascade involving 7-endo and 5-endo cyclizations.     

An aza-Achmatowicz approach toward the hydroxylated piperidine alkaloids (+/-)-azimic acid and (+/-)-deoxocassine

[reaction: see text] The synthesis of several cis-2,3,6-trisubstituted piperidines has been developed employing the aza-Achmatowicz oxidation as the key reaction step. Its usage is illustrated by the facile synthesis of the piperidin-3-ol alkaloids (+/-)-deoxocassine and (+/-)-azimic acid.     

A short synthesis of (+/-)-cytisine

The synthesis of racemic cytisine has been completed using (i)N-selective alkylation of 6-bromopyridone with bromide and (ii) Pd(0) mediated intramolecular alpha-arylation of lactam as key steps to achieve rapid assembly of the tricyclic core skeleton of the lupin alkaloids.     

Total synthesis of (+/-)-alpha-isosparteine, (+/-)-beta-isosparteine, and (+/-)-sparteine from a common tetraoxobispidine intermediate

The three title alkaloids were separately prepared in stereocontrolled fashion from a common tetraoxobispidine precursor, 3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (16). Bisimide 16 was generated from malonate via acid promoted cyclization of the Knoevenagel condensation adduct 1,1,3,3-propanetetracarboxamide. (+/-)-alpha-Isosparteine (dl-2) was elaborated from 16 in 28% overall yield by a two-directional synthetic sequence composed of four reactions: double addition of allylmagnesium bromide, ring-closing olefin metathesis (RCM), hydrogenation, and borane mediated reduction. (+/-)-beta-Isosparteine (dl-3) was targeted along similar lines by a strategic reversal in allylation and reduction operations on the core synthon. Thus, 16 was advanced to dl-3 in five steps and 12% overall yield by a reaction sequence commencing with sodium borohydride mediated reduction and followed by double Sakurai-type allylation of the resulting bishemiaminal. The synthesis of dl-3 was concluded by RCM and then global reduction (H2, Pd/C; LiAlH4). The final target, (+/-)-sparteine (dl-1), was secured in six steps and 11% overall yield from 16 by monoreduction and Sakurai allylation, followed by allyl Grignard addition and then RCM and global reduction as before. Reasons for the inherent C2-type regioselectivity of net double nucleophilic additions to tetraoxobispidines are discussed and enantioselective oxazaborolidine mediated reduction of the N,N'-dibenzyl congener of 16 is reported.     

Syntheses of the Stemona alkaloids (+/-)-stenine, (+/-)-neostenine, and (+/-)-13-epineostenine using a stereodivergent Diels-Alder/azido-Schmidt reaction

A tandem Diels-Alder/azido-Schmidt reaction sequence provides rapid access to the core skeleton shared by several Stemona alkaloids including stenine, neostenine, tuberostemonine, and neotuberostemonine. The discovery and evolution of inter- and intramolecular variations of this process and their applications to total syntheses of (+/-)-stenine and (+/-)-neostenine are described. The stereochemical outcome of the reaction depends on both substrate type and reaction conditions, enabling the preparation of both (+/-)-stenine and (+/-)-neostenine from the same diene/dienophile combination.     

A short total synthesis of (+/-)-aspidospermidine

[STRUCTURE: SEE TEXT] A cascade radical cyclization starting from an amidyl radical has been used for the construction of (+/-)-aspidospermidine. This approach has also been developed for the preparation of a tricycle whose framework is contained in the stemona alkaloids.     

Total synthesis of (+/-)-flustramines A and C, (+/-)-flustramide A, and (-)- and (+)-debromoflustramines A

Here we describe the efficient total synthesis of the three title hexahydropyrrolo[2,3-b]indole alkaloids and debromo derivative from readily available indolin-3-ones using key domino reactions, olefination-isomerization-Claisen rearrangement (OIC), and reductive cyclization (RC). (+/-)-Flustramine C (5) was synthesized in five steps from 6-bromoindolin-3-one 9 via a key intermediate 13a. (+/-)-Flustramine A (1) has been obtained by reduction of flustramide A (6), which has been prepared in five steps from 13a. (+/-)-Debromoflustramine A (19) was provided in a similar manner from 13b. The (-)- and (+)-enantiomers of 19 were synthesized through optical resolution of (+/-)-carboxylic acid 17b using (R)-4-phenyloxazolidin-2-one.     

An efficient total synthesis of (+/-)-lycoramine

[reaction: see text] A short and unique approach to (+/-)-lycoramine as one of the galanthamine-type alkaloids has been efficiently developed. The alternative advantage lies in that three stereocenters, including a crucial quaternary carbon center, were constructed with high diasteroselectivity via a key one-step NBS-mediated semipinacol rearrangement of the allylic alcohol.     

Novel and efficient synthetic path to proaporphine alkaloids: total synthesis of (+/-)-stepharine and (+/-)-pronuciferine

[reaction: see text] A novel synthetic path to proaporphine alkaloids was established by employing aromatic oxidation with a hypervalent iodine reagent, where an unprecedented carbon-carbon bond forming reaction between the para-position of a phenol group and an enamide-carbon took place smoothly to give the desired spiro-cyclohexadienone.     

Total synthesis of the Kopsia lapidilecta alkaloid (+/-)-lapidilectine B

The total synthesis of Kopsia lapidilecta alkaloid (+/-)-lapidilectine B is described. Notable elements of this synthesis include the first natural products application of the Smalley azido-enolate cyclization to form the 1,2-dihydro-3H-indol-3-one (indoxyl) core and installation of the pyrrolidine ring by a 2-azaallyllithium [3+2] cycloaddition with the acetylene equivalent phenyl vinyl sulfide. Closure of the eight-membered perhydroazocine ring is accomplished via the intramolecular S(N)2 substitution of a mesylate. This constitutes the first synthesis of a member of the 5,6,12,13-tetrahydro-11a,13a-ethano-3H-pyrrolo[1',2':1,8]azocino[5,4-b]indole class of alkaloids.     

A general and efficient strategy for 7-aryloctahydroindole and cis-3a-aryloctahydroindole alkaloids: total syntheses of (+/-)-gamma-lycorane and (+/-)-crinane

A general and efficient approach to both 7-aryloctahydroindole and cis-3a-aryloctahydroindole alkaloids has been developed. The key step involves Michael additions of the corresponding kinetics and thermodynamics lithium enolates of ketone 9 to the versatile building blocks: nitroethylene 10. Two representative members, (+/-)-gamma-lycorane and (+/-)-crinane, have been synthesized in 22 and 36% overall yields, respectively.     

Cascade iminium ion reactions for the facile synthesis of quinolizidines. Concise syntheses of (+/-)-epilupinine and (-)-epimyrtine

Several novel cascade processes have been designed and developed that involve sequential reactions of imines and iminium ions to form substituted quinolizidine ring systems in a single step from simple and readily available starting materials. The utility and promise of these cascade reactions is evident from their application to extraordinarily concise syntheses of the representative quinolizidine alkaloids (+/-)-epilupinine and (-)-epimyrtine.     

An application of the phosphine-catalyzed [4 + 2] annulation in indole alkaloid synthesis: formal syntheses of (+/-)-alstonerine and (+/-)-macroline

[reaction: see text] An application of the phosphine-catalyzed [4 + 2] annulation in the formal synthesis of alstonerine and macroline is reported. A phosphine-catalyzed [4 + 2] reaction between imine 7a and allene 8 formed the D ring of the target indole alkaloids. A subsequent intramolecular Friedel-Crafts acylation provided the C ring of the bridged tetracycle. Deprotection, followed by methylation of the bridged nitrogen, deoxygenation of the C6 ketone, and reduction of the C16 carbethoxy group provided the previously known intermediate 3.     

A new glycociamidine ring precursor: syntheses of (Z)-hymenialdisine, (Z)-2-debromohymenialdisine, and (+/-)-endo-2-debromohymenialdisine

[chemical reaction: see text]. The synthesis of the C11H5 marine sponge alkaloids, (Z)-hymenialdisine and (Z)-2-debromohymenialdisine, is described. A key step was the condensation between aldisine or its monobromo derivative and a new, efficient imidazolinone-based glycociamidine precursor. In the first case, the main product turned out to be the unprecedented (+/-)-endo-2-debromohymenialdisine.     

Formal total synthesis of (+/-)-gamma-lycorane and (+/-)-1-deoxylycorine using the [4+2]-cycloaddition/rearrangement cascade of furanyl carbamates

The total syntheses of gamma-lycorane and (+/-)-1-deoxylycorine were accomplished using an intramolecular Diels-Alder cycloaddition of a furanyl carbamate as the key step. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. The key intermediate used in both syntheses corresponds to hexahydroindolinone 20. Removal of the t-Boc group in 20 followed by reaction with 6-iodobenzo[1,3]dioxole-5-carbonyl chloride afforded enamide 22. Treatment of this compound with Pd(OAc)(2) employing the Jeffrey modification of the Heck reaction provided the galanthan tetracycle 24 in good yield. Compound 24 was subsequently converted into (+/-)-gamma-lycorane using a four-step procedure to establish the cis-B,C-ring junction. A radical-based cyclization of the related enamide 33 was used for the synthesis of 1-deoxylycorine. Heating a benzene solution of 33 with AIBN and n-Bu(3)SnH at reflux gave the tetracyclic compound 38 possessing the requisite trans fusion between rings B and C in good yield. After hydrolysis and oxidation of 38 to 40, an oxidative decarboxylation reaction was used to provide the C(2)(-)C(3)(-)C(12) allylic alcohol unit characteristic of the lycorine alkaloids. The resulting enone was eventually transformed into (+/-)-1-deoxylycorine via known synthetic intermediates.     

Electrophilic C12 building blocks for alkaloids: formal total synthesis of (+/-)-maritidine

Silyl-protected benzyl alcohol derivatives and the salt 1 are used to form ortho-substituted C12 electrophilic organoiron building blocks which are converted into a spirocyclic cyclohexenone to complete a formal total synthesis of (+/-)-maritidine (5). The choice of TBDPS protection was shown to be better than TIPS and compatible with ipso nucleophile addition to form a quaternary center. The reaction sequence is the first example of a successful application in the synthesis of an arylcyclohexadienyliron complex with an ortho-carbon substituent in the position required for Amaryllidaceae alkaloids of this type.