Stereoselective synthesis of (R)-(+)-1-methoxyspirobrassinin, (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether and their enantiomers or diastereoisomers

Stereoselective synthesis of cruciferous indole phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(−)-enantiomer was achieved by spirocyclization of 1-methoxybrassinin in the presence of (+)- and (−)-menthol and subsequent oxidation of the obtained menthyl ethers. Methanolysis of menthyl ethers in the presence of TFA afforded (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether as well its unnatural (2S,3S)-, (2R,3S)-, and (2S,3R)-isomers.     

Convenient resolution of (±)-piperidine-2-carboxylic acid ((±)-pipecolic acid) by separation of palladium(II) diastereomers containing orthometallated (S)-(−)-1-[1-(dimethylamino)ethyl]naphthalene

(±)-Piperidine-2-carboxylic acid ((±)-pipecolic acid) has been resolved by the fractional crystallisation of diastereomeric palladium(II) complexes containing orthometallated (S)-(−)-1-[1-dimethylamino)ethyl]naphthalene. The enantiomers of the acid were liberated from the individual configurationally homogeneous diastereomers of the complex in high yield with []_D ± 26.0 (c 1.00, H₂O). The crystal and molecular structures of both diastereomers of the complex have been determined.     

The chemistry of vicinal tricarbonyls : A synthesis of (±)-slaframine and (±)-6-epi-slaframine

A synthesis of (±)-slaframine and (±)-6-epi-slaframine is described. The approach makes use of the intramolecular alkylation of an N-substituted 3-hydroxypyrrole-2-carboxylate ester.     

Vicinal Dianion of Triethyl Ethanetricarboxylate: Syntheses of (±)‐Lichesterinic Acid, (±)‐Phaseolinic Acid, (±)‐Nephromopsinic Acid, (±)‐Rocellaric Acid,and (±)‐Dihydroprotolichesterinic Acid

The vicinal dianion 2 derived from triethyl ethanetricarboxylate reacted regioselectively with aldehydes and ketones at C(β) to provide paraconic acid derivatives 5a – f in moderate to high yields as mixtures of diastereoisomers. The paraconic acid derivatives 5e and 5f were utilized as the starting materials for the syntheses of (±)‐lichesterinic acid ( 12 ), (±)‐phaseolinic acid ( 13 ), (±)‐nephromopsinic acid ( 14 ), (±)‐rocellaric acid ( 15 ), and (±)‐dihydroprotolichesterinic acid ( 16 ).     

Total Syntheses of (±)‐Fawcettimine, (±)‐Fawcettidine, (±)‐Lycoflexine,and (±)‐Lycoposerramine‐Q

The total syntheses of four fawcettimine‐related Lycopodium alkaloids, (±)‐fawcettimine, (±)‐fawcettidine, (±)‐lycoposerramine‐Q, and (±)‐lycoflexine, were completed in a highly stereoselective manner. The Pauson–Khand reaction of 4‐methylidene‐6‐siloxyoct‐1‐en‐7‐yne followed by regio‐ and stereoselective hydrogenation led to the short‐step preparation of the bicyclo[4.3.0]nonenone intermediate bearing a methyl group with the required stereochemistry. The subsequent chemical manipulation of the bicyclic compound afforded the 6‐5‐9‐membered tricyclic dioxo compound, which was then transformed into the four targeted alkaloids in an alternative and more efficient fashion.     

A Stereoselective Total Synthesis of (±)-Maritimol, (±)-2-Deoxystemodinone, (±)-Stemodinone,and (±)-Stemodin

A simple and stereoselective total synthesis of (±)-maritimol ( 2d ) and its conversion into the other title compounds (±)-( 2a ), ((±)- 2b ), and ((±)- 2c ) is described. The unique bicyclo[3.2.1]octane moiety, constituting their C/D-ring system, is stereospecifically obtained by solvolytic rearrangement of the methanesulfonate 23 .     

Stereoselective Syntheses of (±)-epi-β-Santalene and (±)-epi-β-Santalol

Stereoselective syntheses of (±)-epi-β-santalene (1) and (±)-epi-β-santalol (2) , minor constituents of East Indian sandalwood oil, are described. The starting material for both syntheses is the tricyclic hemiacetal 4 , readily accessible in two steps from norbornene.     

Total Synthesis of (±)-3-Deoxy-7,8-dihydromorphine, (±)-4-Methoxy-N-methylmorphinan-6-one and 2,4-Dioxygenated (±)-Congeners

A total synthesis of racemic 3-deoxy-7,8-dihydromorphine ((±)- 2 ) and 4-me-thoxy-ALmethylmorphinan-6-one ((±)- 3 ) is described. The key intermediate was 2,4-dihydroxy-N-formylmorphinan-6-one (11) , obtained from 3,5-dibenzyloxy-phenylacetic acid (4) in 41.8% overall yield. Bromination of 11 , and treatment with aqueous N_aOH-solution afforded, after N-deblocking and reductive N-methylation with concomitant removal of the aromatic bounded Br-atom, the morphinanone 14. Elimination of the HO–C(2) group in 14 was accomplished by hydrogenolysis of its N-phenyltetrazolyl ether 15 , to give 3-deoxy-6,0-didehydro-7,8-dihydromorphine (16). Reduction of 16 with L-Selectride at low temperature provided (±)- 2 in high yield. The ether 15 directly afforded, under more vigorous reduction conditions, 4-hydroxy-N-methylmorphinan-6-one (17). and after O-methylation of 17 , the methyl ether (±)- 3 was obtained. A (1:l)-mixture of 4-hydroxy-2-methoxy-N-methylmor-phinan-6-one (28) and its 2-hydroxy-4-methoxy isomer 30 svere obtained by Grewe-cyclization of a mono-methoxylated aromatic precursor similar to that which afforded 11. The 2,4-dioxygenated N-methylmorphinan-6-ones 29 , 31 and 38 were also prepared and characterized.     

Total syntheses of (+)- and (−)-syringolides 3 and of (+)- and (−)-syributins 1, 2 and 3

The first total syntheses of (−)-syringolide 3, (+)-syributin 3 and their unnatural enantiomers (+)-syringolide 3 and (−)-syributin 3 using a common intermediate as starting material are described. In addition, total syntheses of (−)- and (+)-syributins 1 and 2 were accomplished by means of the same methodology.     

Diastereoselective Total Syntheses of (±)‐Caseabalansin A and (±)‐18‐Epicaseabalansin A via Intramolecular Robinson‐type Annulation

Highly diastereoselective total syntheses of (±)‐caseabalansin A ( 1 ) and (±)‐18‐epicaseabalansin A ( 2 ) are described in this paper. We revealed that the intramolecular Robinson‐type annulation of an alkynone was effective in the stereocontrolled construction of the bicyclic skeleton of 1 and 2 . Further transformation of the resulting enone, including diastereoselective reduction by LiAlH(OtBu)₃, hydroxy‐group‐directed hydrogenation, cyclization to form the cyclic acetal moiety, and introduction of a side chain by a C(sp³)?C(sp³) Stille coupling reaction, resulted in the total syntheses of (±)‐ 1 and (±)‐ 2 .     

Synthesen makrocyclischer Lactone durch Ringerweiterung Herstellung von (±)-Phoracantholid I, (±)-Dihydrorecifeiolid und (±)-15-Hexadecanolid

Syntheses of Macrocyclic Lactones by Ring Enlargement Reaction Reaction. Preparation of (±)-Phoracantholide I, (±)-Dihydrorecifeiolide and (±)-15-Hexadecanolide A general procedure for the synthesis of macrocyclic lactones is described. The Michael adducts of 2-nitrocycloalkanones and acrylaldehyde were regiospecifically methylated with CH₃Ti[OCH(CH₃)₂]₃ or (CH₃)₂Ti[OCH(CH₃)₂]₂ at the aldehyde carbonyl group. Treatment of the so-formed alkohols with tetrabutylammonium fluoride gave the lactones enlarged by four ring members. This method was used to synthesize the 10-membered (±)-phoracantolide I ( 11 ), the 12-membered (±)-dihydrorecifeiolide ( 17 ), and (±)-15-hexadecanolide ( 24 ) in 52%, 26.5%, and 58.7% respectively.     

Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine,and (±)‐Spiramines C and D

The first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.     

Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine,and (±)‐Spiramines C and D

The first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.     

Synthesis of (±)‐Nephromopsinic, (−)‐Phaseolinic,and (−)‐Dihydropertusaric Acids

The formal syntheses of (±)‐nephromopsinic acid, (−)‐phaseolinic acid, and the first total synthesis of (−)‐dihydropertusaric acid from (±)‐ and (−)‐7‐oxabicyclo[2.2.1]hept‐5‐en‐2‐one are described. These syntheses take advantage of a previously reported radical rearrangement (1,2‐acyl migration). A remarkable iodide‐mediated cleavage of a bicyclic system, followed by the introduction of the γ‐chains via a mixed Kolbe electrolysis, are the key steps of these syntheses. This approach is general and could be applied for the preparation of all kinds of paraconic acids with excellent control of the stereochemistry.     

Synthesis of Aristotelia-type alkaloids. Part V. Biomimetic synthesis of (±)-aristomakine and (±)-aristomakinine

Biomimetic syntheses of racemic aristomakinine ((±)- 3 ) and aristomakine ((±)- 4 ), an unusual indole alkaloid bearing an N-isopropyl group, are described. The key step is a Grob-type fragmentation of anti-15-aristotelinyl methanesulfonate ((±)- 2 ) to the intermediate iminium ion I which, upon subsequent hydrolysis, furnished aristomakinine ((±)- 3 ). On the other hand, the same intermediate could be reduced in situ to aristomakine ((±)- 4 ). The controversial relative configurations of the two alkaloids have been firmly established by means of NOE difference experiments.     

Synthese stereoselective DU (±)-β-santalol

We describe here a new convergent and stereoselective synthesis of (±)-β-santalol. This synthesis involves in the last step an original deprotective method of methoxyethoxymethyl ether using pyridinium tosylate.     

Synthese der Spermidin-Alkaloide (±)-Inandenin-10-ol,Inandenin-10-on und (±)-Oncinotin

Syntheses of the Spermidine Alkaloids (±)-Inandenin-10-ol, Inandenin-10-one, and (±)-Oncinotine New syntheses of the title compounds using two-ring-enlargement reactions are described. Starting from the aldehyde 1 , the corresponding 4′-aza derivative 15 could be obtained by reductive amination with the appropriate and protected spermidine derivative 14 (Scheme 4). Enlargement of the carbocyclic ring in 15 by five members gave, after further transformations, the hydroxylactam 18 . Transamidation of 18 , the second ring-enlargement step, led to (±)-inandenin-10-ol (7;22.9% overall yield) and, after oxidation, to inandenin-10-one ( 8 ; 22.5%, overall yield). (±)-Oncinotine 6 was synthesized by two pathways (Scheme 6): protection of the terminal NH₂ group by treatment with the Nefkens reagent and replacement of the OH group by Cl gave 24 , which by thermal transamidation followed by direct ring closure led to the oncinotine derivative 26 . The same intermediate could be obtained in higher yield via 28 by oxidation and protection of 18 followed by transamidation and reductive ring closure. Treatment of 26 with hydrazine finally gave (±)-oncinotine 6 in 15.9% overall yield.     

(±)-5′-Nor ribofuranoside carbocyclic guanosine

The synthesis of the guanine derivative (±)-2-amino-1,9-dihydro-9-[(1′α,2′β,3′β,4′α)-(2′,3′,4′-trihydroxy-1′-cyclopentyl]-6H-purin-6-one ( 2 ) is described. This compound is viewed as the carbocyclic ribofuranoside guanine nucleoside analogue lacking the 5′-methylene.     

Synthesis of Aristotelia-type alkaloids. Part VII. Syntheses of (±)-sorelline, (±)-serratenone,and (±)-aristotelin-19-one

The imine obtained by condensing indole-protected 2-(indol-3-yl)acetaldehyde ( 5 ) with the terpinylamine derivative (±)- 4 was cyclized in 51% yield to the 19-substituted hobartine derivative (±)- 20 upon exposure to anhydrous HCOOH. This pivotal intermediate was further elaborated into the indole alkaloids (±)-serratenone ((±)- 22 ) and (±)-sorelline ((±)- 29 ). In the course of these investigations, a novel rearrangement was uncovered; a Lewis acid-catalyzed 1,3-migration of an arylsulfonyl group from the indole N-atom into the benzene ring. The discovery that synthetic (±)-aristotelin-19-one ((±)- 34 ) has decidedly different spectroscopic properties than aristolasicone, a metabolite for which the structure has been recently proposed, led to a revision of the structure of the latter.     

A Flexible Stereoselective Synthesis of the Spirosesquiterpenes (±)-β-Acorenol, (±)-β-Acoradiene, (±)-Acorenone-B and (±)-Acorenone via an Intramolecular Ene-Reaction

The racemic spirosesquiterpenes β-acorenol ( 1 ), β-acoradiene ( 2 ), acorenone-B ( 3 ) and acorenone ( 4 ) (Scheme 2) have been synthesized in a simple, flexible and highly stereoselective manner from the ester 5 . The key step (Schemes 3 and 4), an intramolecular thermal ene reaction of the 1,6-diene 6 , proceeded with 100% endo-selectivity to give the separable and interconvertible epimers 7a and 7b . Transformation of the ‘trans’-ester 7a to (±)- 1 and (±)- 2 via the enone 9 (Scheme 5) involved either a thermal retro-ene reaction 10 → 12 or, alternatively, an acid-catalysed elimination 11 → 13 + 14 followed by conversion to the 2-propanols 16 and 17 and their reduction with sodium in ammonia into 1 which was then dehydrated to 2 . The conversion of the ‘cis’-ester 7b to either 3 (Scheme 6) or 4 (Scheme 7) was accomplished by transforming firstly the carbethoxy group to an isopropyl group via 7b → 18 → 19 → 20 , oxidation of 20 to 21 , then alkylative 1,2-enone transposition 21 → 22 → 23 → 3 . By regioselective hydroboration and oxidation, the same precursor 20 gave a single ketone 25 which was subjected to the regioselective sulfenylation-alkylation-desulfenylation sequence 25 → 26 → 27 → 4 .