Formal [3 + 3] cycloaddition approach to chromenes and chromanes. Concise total syntheses of (+/-)-rhododaurichromanic acids A and B and methyl (+/-)-daurichromenic ester

[reaction: see text] Total syntheses of (+/-)-rhododaurichromanic acids A and B and methyl (+/-)-daurichromenic ester are described here. Despite the complex appearances of these compounds, their syntheses are completed in six steps with a 15% overall yield as a mixture by featuring our formal oxa-[3 + 3] cycloaddition methodology.     

A two-directional synthesis of (+/-)-perhydrohistrionicotoxin

An entirely two-directional synthesis of (+/-)-perhydrohistrionicotoxin is presented, utilizing a tandem oxime formation/Michael addition/[3 + 2] cycloaddition as the key step. This approach also constitutes formal syntheses of (+/-)-histrionicotoxin and (+/-)-histrionicotoxin 235A.     

Total syntheses of (+/-)-beta-erythroidine and (+/-)-8-oxo-beta-erythroidine by an intramolecular Diels-Alder cycloaddition of a 2-amidoacrolein

[reaction: see text] The total syntheses of (+/-)-beta-erythroidine and (+/-)-8-oxo-beta-erythroidine are described. The tetracyclic ring system of the natural products was quickly assembled by a strategy that features a retrocycloaddition/cycloaddition reaction of an amidodioxin, an intramolecular Heck reaction, and a 6pi-electrocyclic ring closure of a dienoic acid.     

Efficient synthesis of (+/-)-erysotramidine using an NBS-promoted cyclization reaction of a hexahydroindolinone derivative

An NBS-promoted intramolecular electrophilic aromatic substitution reaction of a hexahydroindolinone derivative was used to assemble the tetracyclic core of the erythrinane skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps. The cyclization reaction is also successful using variously substituted aryl and furanyl bicyclic lactams under acidic conditions. [reaction: see text]     

Application of furanyl carbamate cycloadditions toward the synthesis of hexahydroindolinone alkaloids

A convenient synthesis of various substituted hexahydroindolinones has been achieved by an intramolecular Diels--Alder cycloaddition reaction (IMDAF) of furanyl carbamates bearing tethered alkenyl groups. The initially formed [4 + 2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation of the resulting zwitterion to give the rearranged ketone. The stereochemical outcome of the IMDAF cycloaddition has the sidearm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. A synthetic route to (+/-)-mesembrane and (+/-)-crinane was accomplished using this methodology. It was possible to carry out a stereoselective reduction of the initially formed hexahydroindolinone ring to produce the cis-3a-aryl-hydroindole skeleton. A related [4 + 2]-cycloaddition/rearrangement sequence was also used for a formal synthesis of the Chinese ornamental orchid (+/-)-dendrobine. The tricyclic alkaloid core was formed stereoselectivity from the thermolysis of N-[(2-methyl-2-cyclopentenyl)methyl]-N-(4-isopropyl-furan-2-yl)carbamic acid tert-butyl ester. Kende's advanced intermediate 33 was prepared in seven additional steps by standard transformations, thereby completing a formal synthesis of (+/-)-dendrobine.     

Total synthesis of (+/-)-culmorin and (+/-)-longiborneol: an efficient construction of Tricyclo[6.3.0.0(3,9)]undecan-10-one by intramolecular double Michael addition

The treatment of 4-[(5E)-6-methoxycarbonyl-5-hexenyl]-3, 4-dimethyl-2-cyclopenten-1-one (5) with LHMDS, TMSI-HMDS, Bu(2)OTf-HMDS, or TMSCl-NEt(3)-ZnCl(2) caused the intramolecular double Michael addition to afford tricyclo[6.3.0.0(3, 9)]undecan-10-one 12 in high yields with perfect stereoselectivity. The methodology was further elaborated to achieve efficient total syntheses of (+/-)-culmorin (1) and (+/-)-longiborneol (2). The common precursor 13 of them was obtained from 14 in 94% yield as a single isomer by the treatment with LHMDS. After the conversion of 13 into the corresponding acid 24 by hydrolysis, oxidative decarboxylation using S-(1-oxido-2-pyridinyl)-1,1,3, 3-tetramethylthiouronium hexafluorophosphate (HOTT, 27), followed by the Birch reduction, stereoselectively afforded (+/-)-culmorin (1). (+/-)-Longiborneol (2) was synthesized from 24 by the standard transformation. Additionally, the treatment of 24 with Pb(OAc)(4) led to 28 via uncommon migration. Its structure was determined by X-ray analysis after the transformation into the diketone 29.     

Synthesis of some members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family

The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family has been carried out. (+/-)-Lycoricidine and (+/-)-7-deoxypancratistatin were assembled through a one-pot Stille/intramolecular Diels-Alder cycloaddition cascade to construct the core skeleton. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further heating at 160 degrees C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used for the stereocontrolled installation of the remaining functionality present in the C-ring of the target molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/decarboxylation/elimination sequence to introduce the required pi-bond in the C-ring of (+/-)-lycoricidine, and (2) conversion of the initially formed Diels-Alder adduct into an aldehyde intermediate which then undergoes a stereospecific decarbonylation reaction mediated by Wilkinson's catalyst to set the trans-B-C ring junction of (+/-)-7-deoxypancratistatin.     

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.     

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.     

Electrophilic-induced cyclization reaction of hexahydroindolinone derivatives and its application toward the synthesis of (+/-)-erysotramidine

A convenient synthesis of variously substituted octahydroindolo[7a,1a]-isoquinolinones has been achieved by an acid-induced cyclization of hexahydroindolinones bearing tethered phenethyl groups. The formation of a single lactam diastereomer is the result of the stereoelectronic preference for axial attack by the aromatic ring onto the initially formed N-acyliminium ion from the least hindered side. Additional experiments showed that a variety of hexahydroindolinones containing tethered pi-bonds undergo a related acid-induced cyclization reaction. Treatment of the 3-methylbut-3-enyl-substituted hexahydroindolinone with acid furnished a 3:1 mixture of isomeric octahydropyrido[2,1-i]indolinones in near-quantitative yield. Interestingly, cyclization of the closely related 1-(3-methoxybut-3-enyl)-substituted hexahydroindolin-one afforded a pyrrolo[3,2,1-ij]quinolinone as the exclusive product. With this system, initial protonation takes place on the more nucleophilic enol ether pi-bond and the resulting carbonium ion undergoes a subsequent cyclization with the enamido pi-bond to give the observed product. The electrophilic promoted cyclizations were extended to include the related hexahydro[1]pyrindinone and 1H-quinolinone systems. An NBS-promoted intramolecular electrophilic aromatic substitution reaction of 1-[2-(3,4-dimethoxyphenyl)ethyl]-1,4,5,6-tetrahydroindolinone was used to assemble the tetracyclic core of the erythrinone skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps.     

Stereoselective syntheses of (+/-)-komaroviquinone and (+/-)-faveline methyl ether through intramolecular Heck reaction

[reaction: see text] An efficient, flexible, and stereoselective convergent route for constructing the trans-10-hydroxy-1,1-dimethyloctahydrodibenzo[a,d]cyclohepten-7-ones (5a-c) was achieved via intramolecular Heck reaction. This strategy has been successfully implemented for the syntheses of (+/-)-komaroviquinone (3) through (+/-)-coulterone dimethyl ether (5c) and (+/-)-faveline methyl ether (1a).     

Total synthesis of (+/-)-didehydrostemofoline (asparagamine A) and (+/-)-isodidehydrostemofoline

The first total syntheses of (+/-)-didehydrostemofoline (1) and (+/-)-isodidehydrostemofoline (3) are reported. The synthesis begins with the Diels-Alder reaction of readily available pyrrole 9 and ethyl (E)-3-nitroacrylate, the latter serving as a regioinverted equivalent of ketene. After hydrogenation to prevent retro-Diels-Alder reaction, the major cycloadduct is transformed to 7-azabicyclo[2.2.1]heptanol 14. Aza-Cope-Mannich reaction of the formaldiminium derivative of 14 delivers 1-azatricyclo[5.3.0.04.10]decane 15, which in 15 additional steps is converted to 1 and 3.     

An aza-Wittig/pi-furan cyclization approach toward the homoerythrina alkaloid (+/-)-selaginoidine

[reaction: see text] A one-pot procedure was developed to efficiently prepare hexahydroindolinones containing a tethered furan ring. Reaction of a furanyl azide with Bu3P delivered the iminophosphorane, which was allowed to react with 1-methyl-(2-oxocyclohexyl)acetic acid to give the desired hexahydroindolinone ring system. Further treatment with trifluoroacetic acid afforded the tetracyclic lactam skeleton found in the alkaloid (+/-)-selaginoidine.     

Remarkable control of radical cyclization processes of cyclic enyne: total syntheses of (+/-)-methyl gummiferolate, (+/-)-methyl 7beta-hydroxykaurenoate, and (+/-)-methyl 7-oxokaurenoate and formal synthesis of (+/-)-gibberellin a(12) from a common synthetic precursor.

Total syntheses of (+/-)-methyl gummiferolate (13b), (+/-)-methyl 7beta-hydroxykaurenoate (14b), and (+/-)-methyl 7-oxokaurenoate (14d) and a formal synthesis of (+/-)-gibberellin A(12) (15) have been accomplished through the common synthetic precursor, (3aR,7aR)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisobenzofuranone (16). The homoallyl-homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived from 16 in two steps, afforded the bicyclo[2.2.2]octane compound 26, which was converted to (+/-)-methyl gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19, leading to (+/-)-methyl 7beta-hydroxykaurenoate (14b) and (+/-)-methyl 7-oxokaurenoate (14d). Transformation of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal total synthesis of gibberellin A(12) (15).     

Sequential cycloaddition approach to the tricyclic core of vibsanin E. Total synthesis of (+/-)-5-epi-10-epi-vibsanin E

[chemical reaction: see text]. A direct access to (+/-)-5-epi-10-epi-vibsanin E is described, based on three key cycloaddition steps, a rhodium-catalyzed [4 + 3] cycloaddition, a heteronuclear [4 + 2] cycloaddition, and a photochemically induced [4 + 2] cycloaddition.     

An efficient synthesis of (+/-)-Lycoricidine featuring a Stille-IMDAF cycloaddition cascade

[reaction: see text] A highly efficient total synthesis of (+/-)-Lycoricidine is described. The synthesis features the ready preparation of the Lycoricidine skeleton by a Stille-IMDAF cycloaddition cascade. The resulting cycloadduct is then used for the stereocontrolled installation of the other functionality present in the C-ring of the target molecule.     

Total syntheses of (+/-)-cis-trikentrin A and (+/-)-cis-trikentrin B via electrocyclic ring closures of 2,3-divinylpyrrolines

[Structure: see text] A convergent and versatile strategy for the diastereoselective syntheses of (+/-)-cis-trikentrin A and B in 10 and 12 steps, respectively, from commercially available N-BOC-2-pyrrolidinone is described. The key step in each of the total syntheses is the construction of the central benzene ring via a facile 6pi-electrocyclic ring closure of an appropriately substituted 2,3-divinylpyrroline, in turn, readily available by a Stille coupling reaction.     

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.     

Total Synthesis of (+/-)-Leporin A

An efficient synthesis of (+/-)-leporin A (1) has been developed using a tandem Knoevenagel condensation-inverse electron demand intramolecular hetero Diels-Alder reaction to construct the key tricyclic intermediate 3 from pyridone 5 and dienal 6 in one pot in 35% yield. Hydroxylation (71%) of 3 and methylation (77%) of the resulting hydroxypyridone 2 completed the first total synthesis of (+/-)-leporin A (1).     

Stereocontrolled synthesis of polyfunctionalized cis-decalins from 2-methoxyphenols: total syntheses of (+/-)-eremopetasidione, (+/-)-3 beta-angeloyloxyfuranoeremophilane, and (+/-)-3 beta-methacryloyloxyfuranoeremophilane

A four-step stereocontrolled synthesis of polyfunctionalized cis-decalins is described, involving oxidation of 2-methoxyphenol, intermolecular Diels-Alder reaction, olefination, and Cope rearrangement. Application of this efficient strategy to the total syntheses of (+/-)-eremopetasidione, (+/-)-3 beta-angeloyloxyfuranoeremophilane, and (+/-)-3 beta-methacryloyloxyfuranoeremophilane was accomplished from creosol and ethyl vinyl ketone via a common intermediate 21.