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.     

Synthesis of 2-substituted (+/-)-(2r,3r,5r)-tetrahydrofuran-3,5-dicarboxylic acid derivatives

An efficient synthesis of 2-substituted (+/-)-(2R,3R,5R)-tetrahydrofuran-3,5-dicarboxylic acid derivatives has been developed. Starting from 5-norborne-2-ol, the key intermediate (+/-)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) was synthesized in an efficient six-step sequence. The key transformation is the base-catalyzed methanolysis-rearrangement of (+/-)-6,7-exo,exo-(isopropylidenedioxy)-4-exo-iodo-2-oxabicyclo[3.2.1]octan-3-one (14). Further manipulation of the 3-substituent of (+/-)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) followed by deprotection of the diol moiety and ring opening catalyzed by RuCl(3)/NaIO(4) gave the title compounds in good yield.     

Total synthesis of (+/-)-symbioimine

The synthesis of (+/-)-symbioimine (1) has been completed in only 12 linear steps in 8% overall yield. The key step is the treatment of 13b with BF3.Et2O to generate N-carboalkoxydihydropyridinium cation 14b, which undergoes a novel stereospecific intramolecular Diels-Alder reaction to give adduct 16b in 42% yield. Cleavage of the N-Troc group of 16b afforded imine 24b stereospecifically. Cleavage of the TBDMS ethers and sulfation provided (+/-)-symbioimine (1). [reaction: see text].     

General route to 4a-methylhydrofluorene diterpenoids: total syntheses of (+/-)-taiwaniaquinones d and h, (+/-)-taiwaniaquinol B, (+/-)-dichroanal B, and (+/-)-dichroanone

A general and convergent route for the synthesis of the 4a-methylhydrofluorene diterpenoids has been established through a common hexahydrofluorenone intermediate (10) obtained via Pd(0)-catalyzed reductive cyclization of a substituted 2-(2-bromobenzyl) methylene cyclohexane (13). The strategy has been successfully utilized for the synthesis of (+/-)-taiwaniaquinones D (3) and H (5), (+/-)-taiwaniaquinol B (1), (+/-)-dichroanal B (7), and (+/-)-dichroanone (8).     

Total synthesis of (+/-)-cameroonanol

[reaction: see text]The structure and relative stereochemistry of the novel silphiperfolane-type sesquiterpene cameroonan-7alpha-ol (1) were confirmed by a total synthesis of (+/-)-1 from 3,3,5-trimethylbicyclo[3.3.0]oct-1(8)-en-2-one (6) by means of a Sakurai reaction with (Z)-crotylsilane, free radical hydrobromination, base-induced cyclization, and LiAlH4 reduction.     

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).     

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.     

First Resolution of a Free Fluorophosphine Chiral at Phosphorus. Resolution and Reactions of Free and Coordinated (+/-)-Fluorophenylisopropylphosphine

The trivalent fluorophosphine (+/-)-PFPh(i-Pr), (+/-)-1, has been prepared by halogen exchange of the corresponding chlorophosphine with sodium fluoride in hot sulfolane. The neat fluorophosphine rapidly decomposes by equilibrium redox disproportionation into PF(3)Ph(i-Pr) and (R,R)/(R,S)-Ph(i-Pr)PPPh(i-Pr), but in benzene, (+/-)-1 has considerable thermodynamic stability. The resolution of (+/-)-1 was achieved by a fractional crystallization of the diastereomers (R,R(P))- and (R,S(P))-chloro[1-[1-(dimethylamino)ethyl]-2-naphthalenyl-C,N](fluorophenylisopropylphosphine)palladium(II), (R,R(P))- and (R,S(P))-5, whereby the less soluble (R,R(P)) diastereomer selectively crystallized in 64% yield in a typical second-order asymmetric transformation. Optically pure (S)-(-)-1, -210 (c 0.59, C(6)H(6)), was liberated from (R,R(P))-5 with (R,S)-1,2-phenylenebis(methylphenylphosphine). The optically active phosphine in benzene racemizes over 6 h without significant redox disproportionation. The methoxyphosphine (+/-)-P(OMe)Ph(i-Pr), (+/-)-9, was also resolved by the method of metal complexation. Thus, fractional crystallization of (R,R(P))- and (R,S(P))-chloro[1-[1-(dimethylamino)ethyl]-2-naphthalenyl-C,N](methoxyphenylisopropylphosphine)palladium(II), (R,R(P))- and (R,S(P))-8, followed by liberation of the respective optically active methoxyphosphines from the separated diastereomers with 1,2-bis(diphenylphosphino)ethane, gave (R)-(+)- and (S)-(-)-9 of 92% and 96% ee, respectively. The barrier to unimolecular inversion for (+/-)-9 was determined to be >82.9 +/- 0.5 kJ mol(-)(1) by variable temperature (1)H NMR spectroscopy. The substitution of fluoride in (R,R(P))-5 by methoxide proceeds with predominant inversion of the configuration at phosphorus to give (R,R(P))- and (R,S(P))-8 with (R,S(P))/(R,R(P)) = (1)/(5). The crystal structures of (R,R(P))-5 and (R,R(P))-8 have been determined: (R,R(P))-5 (C(23)H(28)ClFNPPd) crystallizes in the orthorhombic space group P2(1)2(1)2(1) with a = 9.967(2) ?, b = 10.998(4) ?, c = 21.324(3) ?, Z = 4, and R = 0.031; (R,R(P))-8 (C(24)H(31)ClNOPPd) crystallizes in the space group P2(1)2(1)2(1) with a = 10.444(3) ?, b = 12.146(3) ?, c = 19.047(2) ?, Z = 4, and R = 0.026.     

Formal synthesis of (+/-)-platensimycin

[reaction: see text] Reductive alkylation of 5-methoxy-1-tetralone (6) with 2,3-dibromopropene gave an equilibrium mixture of bicyclic diones 7 (51%) and 8 (35%). Radical cyclization of 7 afforded tricyclic dione 5 (84%), which was reduced, cyclized, and dehydrated to give tetracyclic alkene 13 in 63% yield. Allylic oxidation of 13 with SeO2 and activated MnO2 afforded enone 2 in 85% yield, thereby completing a short formal synthesis of (+/-)-platensimycin.     

Co2(CO)8-catalyzed intramolecular hetero-Pauson-Khand reaction of alkynecarbodiimide: synthesis of (+/-)-physostigmine

[reaction: see text] Herein we describe a novel Co(2)(CO)(8)-catalyzed intramolecular aza-Pauson-Khand-type reaction of alkynecarbodiimide derivatives affords pyrrolo[2,3-b]indol-2-one ring systems in reasonable yields. This is the first reported Co(2)(CO)(8) successfully applied in the hetero-Pauson-Khand reaction. Significantly, the transformation of one of our pyrrolo[2,3-b]indol-2-one derivatives into the indole alkaloid, (+/-)-physostigmine, was completed in a highly stereoselective manner.     

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.     

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 stereoselective approach to the azaspiro[5.5]undecane ring system using a conjugate addition/dipolar cycloaddition cascade: application to the total synthesis of (+/-)-2,7,8-epi-perhydrohistrionicotoxin

An efficient stereocontrolled route to the spirocyclic perhydrohistrionicotoxin derivative (+/-)-2,7,8-epi-PHTx (4) is described. The reaction of 2-butyl-3-(methoxymethoxy)cyclohexanone oxime with 2,3-bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to give a transient nitrone which then undergoes an intramolecular dipolar cycloaddition. Treatment of the cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish an azaspiro[5.5]undecane. Elaboration to the dihydropyridin-4(1H)-one 24 was followed by stereoselective conjugate addition using n-pentyl cuprate to give azaspirocycle 25. The stereochemistry of the product was deduced from an X-ray crystal structure of the corresponding N-tosylhydrazone derivative. The dominant factor controlling the stereochemistry of the conjugate addition is the A(1,3)-strain present in the planar vinylogous amide. A stereoelectronically preferred axial attack by the organocuprate at the beta-position leads to the observed diastereoselectivity. Azaspirocycle 25 was transformed into 2,7,8-epi-PHTx (4) in five additional steps. Utilizing this tandem conjugate addition/dipolar cycloaddition cascade, we have also successfully synthesized azaspiro[5.5]undecane 36, which had previously been converted into (+/-)-perhydrohistrionicotoxin (2), thereby completing a formal total synthesis of this alkaloid.     

An Efficient and Stereoselective Total Synthesis of (+/-)-Serricornine

An efficient and stereoselective total synthesis of (+/-)-serricornine (1) the sex pheromone produced by the female cigarette beetle Lasioderma serricorne F, is described. (3SR, 5SR, 6SR)-6-Ethyltetrahydro-3,5-dimethyl-2H-pyran-2-one (10) is prepared in 65% yield through lactonization of a 1:1 mixture of C-2 epimers of the corresponding esters.     

Total syntheses of (+/-)-crinine, (+/-)-crinamine, and (+/-)-6a-epi-crinamine via the regioselective synthesis and Diels-Alder reaction of 3-aryl-5-bromo-2-pyrone

We have devised a new unified synthetic protocol to (+/-)-crinine, (+/-)-crinamine, and (+/-)-6a- epi-crinamine from the Diels-Alder cycloadduct of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone with TBS vinyl ether. The requisite 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone was prepared from the C3-selective Stille coupling reaction of 3,5-dibromo-2-pyrone. Also noted is that the vinyl bromide can be used as a handle for further derivatization.     

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).     

Utilization of a Michael addition: dipolar cycloaddition cascade for the synthesis of (+/-)-cylindricine C

A new approach to the marine alkaloid (+/-)-cylindricine C has been devised. The key element of the synthesis consists of a Michael addition/dipolar cycloaddition cascade between 2,3-bis(phenylsulfonyl)-1,3-butadiene and 9-triisopropylsilanyloxy-non-1-en-5-one oxime. The resulting cycloadduct was converted into (+/-)-cylindricine C by a sequence of reactions including a reductive cyclization, intramolecular enolate alkylation, and conjugate addition to introduce the n-hexyl side chain.     

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).     

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.     

Biogenetically inspired approach to the Strychnos alkaloids. Concise syntheses of (+/-)-akuammicine and (+/-)-strychnine

A linear synthesis of the indole alkaloid (+/-)-akuammicine (2) was completed by a novel sequence of reactions requiring only 10 steps from commercially available starting materials. The approach features a tandem vinylogous Mannich addition and an intramolecular hetero Diels-Alder reaction to rapidly assemble the pentacyclic heteroyohimboid derivative 8 from the readily available hydrocarboline 6. Oxidation of the E ring of 8 gave the lactone 9 that was converted into deformylgeissoschizine (11). The subsequent elaboration of 11 into 2 was effected by a biomimetically patterned transformation that involved sequential oxidation and base-induced skeletal reorganization. A variation of these tactics was then applied to the synthesis of the C(18) hydroxylated akuammicine derivative 36. Because 36 had previously been converted into strychnine (1) in four steps, its preparation constitutes a concise, formal synthesis of this complex alkaloid.