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.     

Synthesis of Aristotelia-type alkaloids. Part VIII. Synthesis of (±)-aristolasicone

The revised structure of the indole alkaloid aristolasicone ( 2 ) was confirmed through a convergent total synthesis of the racemic form of this metabolite. The key step involves a one-pot condensation/cyclization reaction between 1-(4-methoxyphenylsulfonyl)-1H-indole-2-acetaldehyde ( 9 ) and (±)-trans-5-(2,6-difluorobenzyloxy)-p-menth-l-en-8-amine ((±)-7). The resulting allohobartine derivative (±)- 13 , obtained in 84% yield, was deprotected and oxidized to (±)-alloscrratenone ((±)- 15 ) which cyclized smoothly to the target molecule (±)-2 upon exposure to BF₃ · Et₂O.     

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 .     

Synthesis of Aristotelia-Type Alkaloids.. Part IV. Synthesis of (±)-aristoserratine

A convergent diastereoselective synthesis of racemic aristoserratine ((±)- 24 ) via an intramolecular iminium-ion cyclization is described. The pivotal imine (±)- 19 was prepared by condensation of the two building blocks (± )-trans-8-amino-3-(2,6-difluorobenzyloxy)-1-p-menthene ((±)- 11 ) and N-(p-methoxybenzenesulfonyl)-3-indo-leacetaldehyde ( 18 ) which were synthesized from (±)-trans-1-p-menthene-3,8-diol ((±)- 7 ) and 3-indoleacetic acid, respectively. On the route to the target (±)- 24 , two previously unknown indole alkaloids have been characterized, namely (±)-‘anti’-hobartin-15-ol ((±)- 22 ) and (±)-‘anti’-aristotelin-15-ol ((±)- 23 ).     

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.     

Synthesis of Aristotelia-type alkaloids. Part IX. Synthesis of (±)-alloaristoteline

The probably most straightforward plan to synthesize the indole alkaloid alloaristoteline ( 5 ) failed, because– in marked contrast to the regular Aristotelia series-electrophilic reagents attack with preference C(3) of the indole moiety in the key intermediate allohobartine ((?)- 12 ), instead of C(18). The only product that could be isolated when (?)- 12 was treated with mineral acid was isomer (+)- 15 of 5 (Scheme 2). As a consequence, the crucial electrophilic site at C(17) was created by taking recourse to the preparation of the stabilized allylic cation VI . Gratifyingly, this alleged intermediate, obtained from precursor (±)- 18 , cyclized smoothly to protected (±)-18,19-didehydroalloaristoteline (±)- 17 , which was transformed in two high-yield steps into the racemic form of the target molecule 5 (Scheme 4). This successful alternative provides unambiguous evidence that the recently revised structure of 5 is indeed correct.     

Syntheses of (±)- and Enantiomerically Pure (+)-Longifolene and of (±)- and Enantiomerically Pure (+)-Sativene by an Intramolecular de Mayo Reaction

Starting from 2-cyclopentenoyl chloride ((RS)- or (S)- 8 ), the racemic as well as the enantiomerically pure (+)-sesquiterpenes longifolene ((±)- and (+)- 1 , resp.) and sativene ((±)- and (+)- 2 , resp.) were synthesized efficiently by a sequence of nine and ten steps, respectively. The key sequence 10 → 16 → 3 is the first strategic application of an intramolecular photoaddition/retro-aldolization sequence (intramolecular de Mayo reaction) in organic synthesis.     

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 .     

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.     

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.     

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.     

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 ).     

Kurze Totalsynthesen von (±)-Sativen und (±)-cis-Sativendiol

Short Total Syntheses of (±)-Sativene and (±)-cis-Sativenediol Our approach to (±)-sativene (7) and (±)-cis-sdtivenediol (9) involves: (a) reaction of 3-methylbutanoyl chloride with Et₃N/cyclopentadiene to give the endo-isopropyl-ketone 1 (here improved to 71%), (b) NBS bromination of 1 to a 5:1 mixture (87%) of the bromo-ketones 2 and 3 , (c) NFD-reaction sequence initiated by the attack of 1,2-butadienyl titanate (complex of 15 , obtained from 2-butine) on 2/3 to afford 52% of the brexenone derivative 4 (along with 8% of its epimer 16 ), (d) addition of dibromomethane to 4 forming 63% of the diene-alcohol 5 (along with 13% of the diene-carbaldehyde 38 ), and (e) carbenoid ring-expansion with MeLi applied to 5 resulting in 41% the diene-ketone 6 (along with 15% of a 1:3 mixture of the diene-ketones 32 and 33 ). Wolff-Kishner reduction of 6 led to 81% of (±)-sativene (7), when enough O₂ was present, but to 97% of the diene 8 in the strict absence of O₂. (±)-cis-Sativenediol (9) was obrained (86%) by OsO₄ hydroxylation of 8 . The brexenone derivatives 4 and 16 (6:1, 50%) were also produced when the NFD-reaction sequence was applied to the isomeric bromo-ketone mixture 13/13 (1:3). The latter was obtained by NBS bromination of 10 , which in turn was available by base epimerization of 1 , followed by destructive removal of unreacted 1 by repeated gas-flow thermolysis. An analogous (less convenient) route to (±)-sativene (7) passed through a series of dihydro compounds (the ene series) it started with the methylidene-ketone 36 , which was the product (97%) of a partial hydrogenation of 4 . Addition of dibromomethane to 36 led t 62% of the methylidene-alcohol 39 (along with a little tetracyclic ether 40 ). Carbenoid ring expansion of 39 with MeLi afforded ca. 42% of the methylidene-ketone 41 (along with 7% of the methylidene-ketone 43 or, under slightly different condition, along with 9% of the methylidene-ketone 42 and 10% of the methylidene-carabaldehyde 44 ). The methylidene-alcohol 39 and the methylidene-ketone 43 were also obtained by partial hydrogenation of 5 and 33 , respectively. Wolff-Kisher reduction converted 41 into (±)-sativene ( 7 99%); the same conditons applied to 42 afforded only ca. 8% 7 (along with three other hydrocarbons, one of them (ca. 21%) probably being (±)-copacamphene (45)). In the diene series, the two succeeding reactions ( 4→5 and 5→6 ) competed with the same side reaction, a rearrangement leading to the brendene-aldehyde 38. In the ene series, the corresponding dihydro-by-product 44 was found in the reacton 39→41 , but not during 36→39. These side reactons could largely be suppressed by keeping the reaction temperature low. An explanation is proposed.     

A Stereoselective Synthesis of (±)-cis-γ-Irone

(±)-cis-γ-Irone( 1 ), a main constitutent of natural iris oil, has been stereoselectively synthesized from methyl (2E)-3 -[(2,2,4-trimethyl-3-cyclohexen-1-yl)methoxy]-2-propenoate (3) (6 steps, overall yield 14%). The cis-configuration as the exocyclic position of the double bond of 1 were secured by the thermal ene reaction of the β-(alkenyloxy)acrylate 3 yielding the 3-oxabicyclo [3,3,1] nonane derivative 5 .     

A Short Synthesis of (±)-Muscone

(±)-Muscone ((±)-1) has been synthesised in three steps from 2-(2′-methylprop-2′-enyl)cyclododecan-1-one ( 2 ). The synthesis involves two key transformations: a Lewis-acid-mediated intramolecular ene reaction ( 2→3 ) and the β-cleavage of the bicyclic potassium alkoxide 3a′ to the macrocyclic enone (Z)- 11 .     

Enzyme-Mediated Preparation of (+)- and (–)-cis-α-Irone and (+)- and (–)-trans-α-Irone

The preparation of (−)- and (+)-trans-α-irone ( 1a and 1b , resp.) and of (+)- and (−)-cis-α-irone ( 1c and 1d , resp.) from commercially available Irone alpha ^® is reported. The relevant step in the synthetic sequence is the initial chromatographic separation of crystalline (±)-4,5-epoxy-4,5-dihydro-cis-α-irone ((±)- 5 ) from oily (±)-4,5-epoxy-4,5-dihydro-trans-α-irone ((±)- 4 ). The latter was subsequently converted, after NaBH₄ reduction, into the crystalline 3,5-dinitrobenzoate ester (±)- 8 , thus allowing a complete separation of the two corresponding diastereoisomeric alcohol derivatives. Suitable enantiomerically pure precursors of the desired products 1a – d were obtained by kinetic resolution of the racemic allylic alcohols derived from (±)- 5 and (±)- 8 , mediated by lipase PS (Amano). The last steps consisted of MnO₂ oxidation and removal of the epoxy moiety with Me₃SiCl/NaI in MeCN. External panel olfactory evaluation showed that (−)-cis-α-irone ( 1d ) has the finest and most distinct `orris butter' character.     

Synthese von (±)-Muscopyridin über eine C-ZIP-Ringerweiterungsreaktion

Synthesis of (±)-Muscopyridine via C-ZIP Ring Enlargement Treatment of 4-(1-nitro-2-oxocyclododec-1-yl)butanal ( 1 ) and of its methyl derivative 5 with pentylamine in EtOH at room temperature gave the ring-enlarged aminomethylidene derivatives 6 and 7 , respectively (Scheme 1). After hydrolysis of the aminomethylidene group in 6 and 7 and deformylation followed by a reductive Nef-type reaction, the macrocyclic diketones 10 and 11 , respectively, were obtained. They were transformed by a modified Hantzsch procedure to the title compound (±)-muscopyridine ( 13 ) and normuscopyridine ( 12 ), respectively.     

A Bioinspired Synthesis of (±)‐Rubrobramide, (±)‐Flavipucine,and (±)‐Isoflavipucine

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α‐bromo‐β‐ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β‐epoxy‐γ‐lactam. Furthermore, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism. (±)‐Flavipucine and (±)‐isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α‐bromo‐β‐ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)‐flavipucine, which was converted into (±)‐isoflavipucine by thermal isomerization.     

A Bioinspired Synthesis of (±)‐Rubrobramide, (±)‐Flavipucine,and (±)‐Isoflavipucine

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α‐bromo‐β‐ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β‐epoxy‐γ‐lactam. Furthermore, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism. (±)‐Flavipucine and (±)‐isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α‐bromo‐β‐ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)‐flavipucine, which was converted into (±)‐isoflavipucine by thermal isomerization.     

(±)-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.