Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine

The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and trans-chiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.     

Enantioselective Norrish-Yang cyclization reactions of N-(omega-oxo-omega-phenylalkyl)-substituted imidazolidinones in solution and in the solid state

The four N-(omega-oxo-omega-phenyl-alkyl)-substituted imidazolidinones 5-8 were prepared from N-acetylimidazolidinone (4). Upon irradiation, these substrates underwent Norrish-Yang cyclization to the racemic products rac-9-rac-12 (51-75%). The reactions of the N-2-oxoethylimidazolidinones 5 and 6 were conducted in tBuOH, and yielded 1:1 mixtures of exo/endo diastereoisomers rac-9a/rac-9b and rac-10a/rac-10b, accompanied by Norrish type II cleavage products. The reactions of the N-3-oxopropylimidazolidinones 7 and 8 were performed in toluene. The exo diastereoisomers rac-11a and rac-12a were the major diastereoisomers (d.r. approximately equal to 4:1). In the presence of the chiral compounds 1-3, the photocyclization of substrate 8 proceeded with significant enantiomeric excess (5-60% ee). The more sophisticated complexing agents 3 and ent-3 provided better enantiofacial differentiation (up to 60% ee) than the lactams 1 and 2 (up to 26% ee). Low temperatures and an excess of the complexing agent helped to increase the enantioselectivity. The absolute configuration of the major exo product 12a obtained from compound 8 in the presence of complexing agent 3 was unambiguously established by single-crystal X-ray crystallography of its chiral N-methoxyphenylacetyl derivative 15a. In a similar fashion, the absolute configurations of the endo products 12b and ent-12b were established. The N-2-oxoethylimidazolidinone 5, which crystallized in a chiral space group, was irradiated in the solid state. At low levels of conversion, the product 9a/ent-9a was formed with high enantiomeric excess (78% ee). The enantioselectivity deteriorated at higher levels of conversion.     

Asymmetric synthesis of 2,3-dihydrofurans and of unsaturated bicyclic tetrahydrofurans through alpha-elimination and migratory cyclization of silyloxy alkenyl aminosulfoxonium salts. Generation and intramolecular O,Si-bond insertion of chiral disubstituted beta-silyloxy alkylidene carbenes

Treatment of the bis(allylsulfoximine)titanium complexes derived from the beta-methyl-substituted acyclic allylic sulfoximines 13a and 13b with aldehydes gave with high selectivities the corresponding sulfoximine-substituted homoallylic alcohols which were isolated as the silyl ethers 15a-h. Methylation of sulfoximines 15a-h afforded the aminosulfoxonium salts 5a-h which upon treatment with LiN(H)tBu gave in high yields the enantio- and diastereomerically pure silyl-substituted 2,3-dihydrofurans 4a-h. Treatment of the titanium complexes derived from the cyclic allylic sulfoximines 17a, 17b, and ent-17c with p-MeOC(6)H(4)CHO delivered with high selectivities the corresponding sulfoximine-substituted cyclic homoallylic alcohols which were isolated as the silyl ethers 18a, 18b, and ent-18c, respectively. Methylation of sulfoximines 18a, 18b, and ent-18c furnished the aminosulfoxonium salts 8a, 8b, and ent-8c, respectively, whose treatment with LiN(H)t-Bu gave the enantio- and diastereomerically pure fused bicyclic 2,3-dihydrofurans 6a, 6b, and ent-6c, respectively, in good yields. It is proposed that the 1-alkenyl aminosulfoxonium salts 5a-h, 8a, 8b, and ent-8c react with the base under alpha-elimination and formation of the acyclic and cyclic beta-silyloxy alkylidene carbenes 2a-h, 7a, 7b, and ent-7c, respectively, which then undergo a 1,5-O,Si-bond insertion and 1,2-silyl migration. The cyclic aminosulfoxonium salts 8a, 8b, and ent-8c upon treatment with 1,8-diazabicyclo[5.4.0]-7-undecene did not undergo an alpha-elimination but suffered a novel migratory cyclization with formation of the enantio- and diastereomerically pure bicyclic tetrahydrofurans 9a, 9b, and ent-9c, respectively. It is proposed that the 1-alkenyl sulfoxonium salts 8a, 8b, and ent-8c are isomerized to the allylic aminosulfoxonium salts 10a, 10b, and ent-10c, respectively, which then suffer an intramolecular substitution of the (dimethylamino)sulfoxonium group by the silyloxy group followed by a desilylation. The syntheses of the 2,3-dihydrofurans 4a-h, 6a, and 6b and of the tetrahydrofurans 9a and 9b are accompanied by the formation of sulfinamide 16 of >or=98% ee, which can be converted via sulfoxide 28 of >or=98% to the starting sulfoximine 11 of >or=98% ee.     

Enantioselective [6pi]-photocyclization reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation

The [6pi]-photocyclization of the anilides 1a and 5 was studied in the absence and in the presence of the enantiomerically pure chiral lactam 4. The relative configuration of the products was unambiguously established by single-crystal X-ray crystallography and by NMR spectroscopy. A significant enantiomeric excess was observed upon reaction of compound 1a to its photocyclization products at -55 degrees C employing lactam 4 as a chiral complexing agent in toluene as the solvent (66% yield). The trans product ent-3a was obtained in 57% ee, and the minor diastereoisomer (trans/cis = 73/27), cis product ent-2a, was obtained in 30% ee. DFT calculations were conducted modeling the complexation of intermediates 8 and ent-8 to host 4. In agreement with steric arguments concerning the conrotatory ring closure of 1a, the formation of ent-8 is favored leading to the more stable complex 4.ent-8 as compared to 4.8. Whereas the enantioselectivity in the photocyclization to trans compound ent-3a increased upon reduction in the reaction temperature, the enantiomeric excess in the formation of cis compound ent-2a went through a maximum at -15 degrees C (45% ee) and decreased at lower temperatures. Deuteration experiments conducted with the pentadeuterated analogue of 1a, d(5)-1a, revealed that the protonation of the intermediates 8 and ent-8 is influenced by chiral amide 4. In the formation of ent-3a/3a, both the enantioselective ring closure and the enantioselective protonation by amide 4 favor the observed (6aS,10aS)-configuration of the major enantiomer ent-3a. In the formation of ent-2a/2a, the enantioselective ring closure (and the subsequent diastereoselective protonation) favors the (6aR,10aS)-configuration that is found in compound 2a. Contrary to that, the enantioselective protonation by amide 4 shows a preference for ent-2a with the (6aS,10aR)-configuration.     

Regioselective intramolecular ring closure of 2-amino-6-bromo-2,6-dideoxyhexono-1,4-lactones to 5- or 6-membered iminuronic acid analogues: synthesis of 1-deoxymannojirimycin and 2,5-dideoxy-2,5-imino-D-glucitol

1-Deoxymannojirimycin (8c) was synthesised from 2-amino-6-bromo-2,6-dideoxy-D-mannono-1,4-lactone (7) by intramolecular direct displacement of the C-6 bromine employing non-aqueous base treatment followed by reduction of the intermediate methyl ester. Likewise, using aqueous base at pH 12, ring closure took place by 5-exo attack on the 5,6-epoxide leading to 2,5-dideoxy-2,5-imino-L-gulonic acid (9b), which was reduced to 2,5-dideoxy-2,5-imino-D-glucitol (9b). The method was further applied to 2-amino-6-bromo-2,6-dideoxy-D-galacto- as well as D-talo-1,4-lactones (14 and 15). However, only the corresponding six-membered ring 1,5-iminuronic acid mimetics, namely (2R,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-galactonic acid, 16) and (2S,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-talonic acid, 17), were obtained. The corresponding enantiomers, L-galacto- as well as L-talo-2-amino-6-bromo-2,6-dideoxy-1,4-lactones ent-14 and ent-15, reacted accordingly to give the D-galacto- and L-altro-1,5-iminuronic acid mimetics, (2S,3S,4R,5S)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-L-galactonic acid, ent-16) and (2R,3S,4R,5S)-3,4,5-trihydroxypipecolic acids (2,6-dideoxy-2,6-imino-L-talonic acid, ent-17), respectively.     

Application of Rh-catalyzed cyclization to the formation of a chiral quaternary carbon

Rh-Catalyzed cyclization was applied to the formation of a chiral quaternary carbon. It has become clear that the Rh-complex can discriminate between isopropenyl and 2-isopentenyl (or isopentyl) substituents, and the cyclization afforded 3,3,4-trisubstituted cyclopentanones with a chiral quaternary carbon in a stereoselective manner. The cyclization of 4-pentenals 6a, b by an achiral neutral Rh(PPh3)3Cl afforded 3,3,4-cis-trisubstituted cyclopentanones (+/-)-7a,b in 86-96%, and the cyclization by a cationic Rh[(R)-BINAP]CIO4 afforded 3,3,4-trans-trisubstituted cyclopentanones (-)-8a, b of 82-86% ee in 88-98% yields. The mechanism of stereoselection by Rh-complexes is also discussed.     

Asymmetric total synthesis of ent-(-)-roseophilin: assignment of absolute configuration

An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine --> 1,2-diazine --> pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([alpha](25)(D), CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing an unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.     

Cyclization reactions of 1-[3'-hydroxy-2'-(hydroxymethyl)prop-1'-enyl]pyrimidine nucleobases: intramolecular Michael additions to the C(5)=C(6) bonds and intramolecular dehydrations

The tendency of a series of acyclic nucleoside analogues 1a-f to undergo intramolecular cyclization reactions was investigated. All compounds, when treated with NaOD, were in equilibrium with the bicyclic compounds 2a-f, arising from Michael addition of a hydroxy group to the C(5)=C(6) bonds. Derivatives of 2,4-pyrimidinediones (1a,b) had the highest tendency to undergo intramolecular Michael addition when treated with triethylamine, whereas the cyclization of 4-amino-2-pyridones (1c-f) proceeded best with acid. The exocyclic double bond of was essential for the cyclization to occur. Commonly used N-protecting groups as the benzoyl- and the dibutylaminomethylene group enhanced cyclization. Under acidic anhydrous conditions 1b and 1e cyclized to the 2,4'-anhydro compounds 1b and 1e.     

A synthesis of 3-phenyl-1,2,3,4-tetrahydroisoquinoline and 2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine via Pummerer-type cyclization: enhancing effect of boron trifluoride diethyl etherate on the cyclization

A synthesis of 6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (14a) and 7,8-dimethoxy-2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine (14b) was achieved via the cyclization of N-(3,4-dimethoxyphenyl)methyl-1-phenyl-2-(phenylsulfinyl)ethylformamide (6a) and N-2-(3,4-dimethoxyphenyl)ethyl-1-phenyl-2-(phenylsulfinyl)-ethylformamide (6b) using the Pummerer reaction as a key step, respectively. The Pummerer reaction of 6a,b under usual conditions using trifluoroacetic anhydride yielded the vinyl sulfides (8a, b), non-cyclized products, as a major product. The cyclization proceeded when boron trifluoride diethyl etherate was used as an additive reagent, thus giving rise to the corresponding cyclized products (7a) and (7b) in moderate yields. We propose that the enhancing effect of the Lewis acid on the cyclization may be attributable to the involvement of a dicationic intermediate, sulfonium-carbenium dication (23).     

New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester

A new, enantioselective synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate 1 (Tamiflu) and its enantiomer ent-1 starting from cheap, commercially available 2,6-dimethoxyphenol 10 is described. The main features of this approach comprise the cis-hydrogenation of 5-(1-ethyl-propoxy)-4,6-dimethoxy-isophthalic acid diethyl ester (6a) and the desymmetrization of the resultant all-cis meso-diesters 7a and 7b, respectively. Enzymatic hydrolysis of the meso-diester 7b with pig liver esterase afforded the (S)-monoacid 8b, which was converted into cyclohexenol 17 via a Curtius degradation and a base-catalyzed decarboxylative elimination of the Boc-protected oxazolidinone 14. Introduction of the second amino function via S(N)2 substitution of the corresponding triflate 18 with NaN3 followed by azide reduction, N-acetylation, and Boc-deprotection gave oseltamivir phosphate 1 in a total of 10 steps and an overall yield of approximately 30%. The enantiomer ent-1 was similarly obtained via an enzymatic desymmetrization of meso-diester 7a with Aspergillus oryzae lipase, providing the (R)-monoacid ent-8a.     

Novel,racemic or nearly-racemic antibacterial bromo- and chloroquinols and γ-lactams of the verongiaquinol and the cavernicolin type from the marine sponge Aplysina (= Verongia) cavernicola

Butanolic extracts of the Mediterranean sponge Aplysina (= Verongia) cavernicola have given, by reverse-phase HPLC, the antibacterial quinols (±)-3-bromoverongiaquinol (= (±)-3-bromo-1-hydroxy-4-oxo-2,5-cyclohexadine-1-acetamide; 1d) and (±)-3-bromo-5-chloroverongiaquinol (= (±)-3-bromo-5-chloro-1-hydroxy-4-oxo-2,5-cyclohexadine-1-acetamide; 1c ) besides the products of their formal cyclization 5-chlorohexadiene-1-acetamide; 1c ) besides the products of their formal cyclization 5-chlorocavernicolin (= 5-cloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 6) , the C(7)-epimerizing 7β-bromo-5-chlorocavernicolin (=7 β-bromo-5-chloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 4a and 7α-bromo-5-chlorocavernicolin (4b) , and the C(7)-epimerizing 5-bromo-7β-chlorocavernicolin ( = 5-bromo-7β-chloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 5a) and 5-bromo-7α-chlorocavernicolin (5b) . The latter four were isolated as mixtures of C(7)-epimerizing monoacetates 4a′/4b′ and 5a′/5b′. Both 1 and 1c proved to be racemic from NMR examination of their esterification products with (–)-methyl-oxyacetic acid, whilst 6 had a ca. 6% enantiomeric purity as shown by a ¹H-NMR study of its monoacetate 6′ in the presence of a chiral shift reagent. These chiroptical data of the first chiral quinols from the Verongida and of 6 suggest phenol oxidative routes from tyrosine precursors for their formation. In view of their bioactivities, 1d and 1c have been synthesized from (p-hydroxyphenyl)acetic acid byt phenol oxidative routes.     

Cytotoxic diterpenoids from Vietnamese medicinal plant Croton tonkinensis GAGNEP

Six new ent-kaurane-type diterpenoids were isolated from the leaves of the endemic Vietnamese medicinal plant Croton tonkinensis GAGNEP. (Euphorbiaceae) together with three known ent-11alpha-acetoxy-7beta,14alpha-dihydroxykaur-16-en-15-one (1), ent-kaur-16-en-15-one 18-oic acid (5) and ent-18-hydroxykaur-16-ene (7). Their structures were determined by spectroscopic analyses to be ent-7beta-acetoxy-11alpha-hydroxykaur-16-en-15-one (2), ent-18-acetoxy-11alpha-hydroxykaur-16-en-15-one (3), ent-11alpha-acetoxykaur-16-en-18-oic acid (4), ent-15alpha,18-dihydroxykaur-16-ene (6), ent-11alpha,18-diacetoxy-7beta-hydroxykaur-16-en-15-one (8), and ent-(16S)-1alpha,14alpha-diacetoxy-7beta-hydroxy-17-methoxykauran-15-one (14). ent-Kaurane-type diterpenoids from Croton tonkinensis 2-4, 6, and 9-13, were tested for toxicity in the brine shrimp lethality assay. Compounds 9, 10, and 12 demonstrated significant activity, compounds 2, 3, 6, and 11 showed weak activity, and compounds 4 and 13 were inactive.     

Synthesis of conformationally restricted analogs of baclofen, a potent GABAB receptor agonist, by the introduction of a cyclopropane ring.

Conformationally restricted analogs of baclofen (2), i.e., 5, 6, and their enantiomers ent-5, and ent-6, the conformations of which were restricted by introducing a cyclopropane ring, were designed as potential GABAB receptor ligands. Reaction of (R)-epichlorohydrin [(R)-7] and (4-chlorophenyl)acetonitrile in the presence of NaNH2 in benzene/tetrahydrofuran gave chiral cyclopropane derivatives 11 and 12, which were then converted into the target compounds 5 and 6, respectively. Their corresponding enantiomers, ent-5 and ent-6, were also synthesized starting from (S)-epichlorohydrin [(S)-7].     

Construction of a cis-cyclopropane via reductive radical decarboxylation. Enantioselective synthesis of cis- and trans-1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic agents

(1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a, 3, and ent-3, respectively), which were designed as conformationally restricted analogues of haloperidol (1), a clinically effective antipsychotic agent, were synthesized from chiral epichlorohydrins using the Barton reductive radical decarboxylation as the key step. (1S,2R)-1-(tert-Butyldiphenylsilyloxy)methyl-2-carboxy-2-phenylcyclopropane (5), which was prepared from (S)-epichlorohydrin ((S)-7), was converted into its N-hydroxypyridine-2-thione ester 12, the substrate for the reductive radical decarboxylation. When 12 was treated with TMS3SiH in the presence of Et3B or AIBN, the decarboxylation and subsequent hydride attack on the cyclopropyl radical intermediate from the side opposite to the bulky silyloxymethyl moiety occurred, resulting in selective formation of the corresponding reductive decarboxylation product 4-cis with the cis-cyclopropane structure. From 4-cis, the cis-cyclopropane-type target compound 3 was readily synthesized. Starting from (R)-epichlorohydrin ((R)-7), ent-3 was similarly synthesized. Epimerization of the cyclopropanecarboxamide ent-16-cis, a synthetic intermediate for ent-3, on treatment with a base prepared from Bu2Mg and i-Pr2NH in THF occurred effectively to give the corresponding trans isomer 16-trans, which was converted into 2a with the trans-cyclopropane structure.     

Expeditious synthesis of tri- and tetrahydroxyazepanes from D-(-)-quinic acid as potent glycosidase inhibitors

Several new stereoisomers of 3,4,6-trihydroxyazepanes and 7-hydroxymethyl-3,4,5-trihydroxyazepanes as well as known 3,4,5-trihydroxyazepanes were synthesized as potent glycosidase inhibitors from D-(-)-quinic acid in an efficient manner. The key step employs dihydroxylation of protected chiral 1,4,5-cyclohex-2-enetriols under RuCl3/NaIO4/phosphate buffer (pH 7) condition, followed by reductive amino cyclization. We found the choice of an appropriate protecting group to C1-OH of chiral 1,4,5-cyclohex-2-enetriols would increase the yields of cyclization. The preliminary biological data indicate some of these azepanes possess potent inhibition against alpha-mannosidase and alpha-fucosidase.     

Photochemical deconjugation of chiral 3-methyl-2-butenoates derived from carbohydrate-based alcohols: the influence of the sugar backbone on the facial diastereoselectivity

The photodeconjugation of the alpha-(4-trimethylsilyl-3-butynyl)-substituted senecio acid esters 7 was studied. Chiral alcohols ROH (9) were employed as auxiliaries to control the facial diastereoselectivity of the protonation step. The conversion of the four sugar alcohols diacetone-D-glucofuranose, diacetone-D-allofuranose, diacetone-D-gulofuranose, and diacetone-D-fructopyranose (9a-d) to the esters 7 was achieved in four steps employing 4-iodo-1-trimethylsilylbut-1-yne (3) as the alkylating agent (27-45% yield overall). Their photodeconjugation gave the corresponding beta,gamma-unsaturated (R)-esters 14a-d with moderate to excellent diastereomeric excess. The best results were achieved with diacetone-D-glucofuranose and diacetone-D-fructopyranose as the auxiliary (>95% de). To achieve the synthesis of the target compound 1 which has the (S)-configuration, the deconjugation was conducted with the diacetone-L-fructopyranose (ent-9d) derived ester ent-7d. L-Fructose (20) was prepared from L-sorbose (15) in a modified procedure that allowed for the isolation of intermediates. The 2-fold inversion of configuration worked nicely, and the fructofuranose 19 was obtained in 19% yield from L-sorbose. The conversion of L-fructose to the ester ent-7d was conducted in full analogy to the synthesis of its enantiomer 7d. Deconjugation of ester ent-7d yielded the product 2d (70% yield), which was reduced to the alcohol 1 (85% yield).     

Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (Altohyrtin A)

A synthesis of the C(29)-C(45) bis-pyran subunit 2 of spongistatin 1 (1a) is described. The synthesis proceeds in 19 steps from the chiral aldehyde ent-7, and features highly diastereoselective alpha-alkoxyallylation reactions using the gamma-alkoxy substituted allylstannanes 17 and 19, as well as a thermodynamically controlled intramolecular Michael addition to close the F-ring pyran. The E ring was assembled via the Mukaiyama aldol reaction of F-ring methyl ketone 3 and the 2,3-syn aldehyde 4.     

Enantioselective Entry to the Homalium Alkaloid Hoprominol: Synthesis of an (R,R,R)‐Hoprominol Derivative

The diastereoselective synthesis of the N‐ and O‐protected hoprominol derivative (R,R,R)‐ 6 is described. The building up of the bicyclic O‐silylated and di(N‐tosylated) asymmetric scaffold 6 succeeded by convergent preparation of the two basic chiral azalactam units 7a and 7b and their subsequent iterative linking by a known method (Scheme 5). Both 4‐alkyl‐hexahydro‐1,5‐diazocin‐2(1H)‐ones 7a and 7b were prepared from the chiral β‐amino acid portions 10a and 10b , respectively, by application of a set of reactions (e.g., N‐alkylation of 10a , b and Sb(OEt)₃‐assisted cyclization of the resulting open‐chain intermediates) already known. In comparison with the total syntheses of homaline ( 1 ) and homoprine ( 2 ), the newness of the described synthesis lies in the asymmetric approach to the difunctionalized fatty acid derivative 10b starting from (?)‐(S)‐malic acid ( 9 ) (Schemes 3 and 4). Key step in the preparation of 10b was the diastereoselective amination of the optically pure α,β‐unsaturated δ‐hydroxy homoallylic ester 14 via conjugate intramolecular aza‐Michael cyclization of the acylic δ‐(carbamoyloxy) intermediate 11 .     

Asymmetric synthesis of (-)-eburnamonine and (+)-epi-eburnamonine from (4S)-4-ethyl-4-[2-(hydroxycarbonyl)ethyl]-2-butyrolactone.

The key chiral nonracemic 4,4-disubstituted 2-butyrolactone carboxylic acid, (S)-4, is readily accessible via an efficient and stereospecific dirhodium(II) tetraacetate catalyzed tertiary C-H insertion reaction of the diazomalonate (S)-5. The coupling of the acid (S)-4 with tryptamine produces the amide (S)-3, which is then transformed into the aldehyde 23 and hydroxy-lactam 24. Acid-mediated Pictet-Spengler cyclization of 23 and 24 produces the tetracyclic indole lactams (1S,12bS)-25a and (1S,12bR)-25b. Compounds 25a and 25b are converted, via the lactam alcohols 30a and 30b, to (-)-eburnamonine (1a) and (+)-epi-eburnamonine (1b).     

Synthesis of plagiochiline N from santonin.

This article reports the transformation of O-acetylisophotosantonin, obtained by photochemical rearrangement of santonin, into plagiochiline N, an ent-2,3-secoaromadendrane isolated from Plagiochila ovalifolia. The synthesis was carried out in a sequence involving as the key steps (a) the substitution of the lactone moiety by a gem-dimethylcyclopropane ring through a synthetic intermediate having a C(6)-C(7) double bond and (b) the ozonolysis of the C(2)-C(3) bond followed by cyclization to the dihydropyran ring characteristic of plagiochiline N. Spectroscopic data of the synthetic product fully coincided with the reported data for the natural product.