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.     

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.     

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 ).     

New Synthetic Routes to Biologically Interesting Geranylated Flavanones and Geranylated Chalcones: First Total Synthesis of (±)‐Prostratol F,Xanthoangelol, and (±)‐Lespeol

A new and efficient synthetic approach to biologically interesting geranylated flavanones and geranylated chalcones is described. Thus, the first total syntheses of the geranylated flavanones (±)‐prostratol F ( 1 ), (±)‐8‐geranyl‐3′,4′,7‐trihydroxyflavanone ( 2 ), and (±)‐6‐geranyl‐5,7‐dihydroxy‐3′,4′‐dimethoxyflavanone ( 3 ) were carried out starting from 2,4‐dihydroxyacetophenone ( 10 ) and 2,4,6‐trihydroxyacethophenone ( 17 ) in five to six steps (Schemes 2 and 3). The geranylated chalcones xanthoangelol ( 4 ), 3‐geranyl‐2,3′,4,4′‐tetrahydroxychalcone ( 5 ), (±)‐lespeol ( 6 ), and lespeol derivatives (±)‐ 7 – 9 were synthesized starting from 2,4‐dihydroxyacetophenone ( 10 ) in three to four steps (Schemes 2 and 6).     

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.     

Enzyme‐Mediated Preparation of (+)‐ and (−)‐β‐Irone and (+)‐ and (−)‐cis‐γ‐Irone from Irone alpha®

The (−)‐ and (+)‐β‐irones ((−)‐ and (+)‐ 2 , resp.), contaminated with ca. 7 – 9% of the (+)‐ and (−)‐trans‐α‐isomer, respectively, were obtained from racemic α‐irone via the 2,6‐trans‐epoxide (±)‐ 4 (Scheme 2). Relevant steps in the sequence were the LiAlH₄ reduction of the latter, to provide the diastereoisomeric‐4,5‐dihydro‐5‐hydroxy‐trans‐α‐irols (±)‐ 6 and (±)‐ 7 , resolved into the enantiomers by lipase‐PS‐mediated acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (+)‐ and (−)‐ 8 and (+)‐ and (−)‐ 9 , upon treatment with POCl₃/pyridine, were converted to the β‐irol acetate derivatives (+)‐ and (−)‐ 10 , and (+)‐ and (−)‐ 11 , respectively, eventually providing the desired ketones (+)‐ and (−)‐ 2 by base hydrolysis and MnO₂ oxidation. The 2,6‐cis‐epoxide (±)‐ 5 provided the 4,5‐dihydro‐4‐hydroxy‐cis‐α‐irols (±)‐ 13 and (±)‐ 14 in a 3 : 1 mixture with the isomeric 5‐hydroxy derivatives (±)‐ 15 and (±)‐ 16 on hydride treatment (Scheme 1). The POCl₃/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic resolution of (±)‐ 13 and (±)‐ 14 , provided enantiomerically pure cis‐α‐irol acetate esters, from which ketones (+)‐ and (−)‐ 22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (+)‐ 13 and (−)‐ 14 , treated first with MnO₂, then with POCl₃/pyridine (Scheme 4). Conversely, the dehydration with POCl₃/pyridine of the enantiomerically pure 2,6‐cis‐5‐hydroxy derivatives obtained from (±)‐ 15 and (±)‐ 16 gave rise to a mixture in which the γ‐irol acetates 25a and 25b and 26a and 26b prevailed over the α‐ and β‐isomers (Scheme 5). The (+)‐ and (−)‐cis‐γ‐irones ((+)‐ and (−)‐ 3 , resp.) were obtained from the latter mixture by a sequence involving as the key step the photochemical isomerization of the α‐double bond to the γ‐double bond. External panel olfactory evaluation assigned to (+)‐β‐irone ((+)‐ 2 ) and to (−)‐cis‐γ‐irone ((−)‐ 3 ) the strongest character and the possibility to be used as dry‐down note.     

Synthesis of the Macrocyclic Spermidine Alkaloid (±)‐(2R*,3R*)‐3‐Hydroxycelacinnine

The macrocyclic lactam alkaloid (±)‐(2R*,3R*)‐3‐hydroxycelacinnine ( 1 ) derived from spermidine was synthesized via stereoselective epoxide‐ring opening with magnesium azide and cesium carbonate promoted macrocyclization of the ditosylated diamino precursor 12 with 1,4‐dibromobutane in the two key steps (Scheme 2). ¹H‐ and ¹³C‐NMR Signal assignments from COSY, HSQC, and HMBC 2D NMR data of the synthesized 1 were compared with the earlier‐described data of the natural 3‐hydroxycelacinnine. The similarity of their ¹³C‐NMR spectra point to the correctness of the proposed constitutional formula for natural 3‐hydroxycelacinnine; however, different ¹H‐NMR chemical shifts and coupling constants (J(2,3)=9.0 vs. 1.2 Hz, resp.) in the α‐hydroxy‐β‐amino lactam moiety suggest that natural 3‐hydroxycelacinnine is the 2,3‐cis‐epimer of one synthetic (±)‐ 1 .     

(±)-Yaequinolone A2的简洁全合成

由廉价的邻氨基苯甲酸为起始原料经6步反应以27.8%的总产率首次合成了2-喹啉酮类生物碱(±)-yaequinolone A2,关键步骤为MOM保护的α-羟基酰胺进行的高非对映选择性分子内aldol 反应。     

A Biomimetic Synthesis of (±)‐Basiliolide B

A highly diastereoselective and practical biomimetic total synthesis of (±)‐basiliolide B has been achieved through the study of the two proposed biosynthetic pathways (O‐methylation and O‐acylation) for the unprecedented 7‐methoxy‐4,5‐dihydro‐3H‐oxepin‐2‐one (C ring). The synthesis featured a cyclopropanation/ring opening strategy for establishing the stereogenic centers at C8 and C9, a biomimetic 2‐pyrone Diels–Alder cycloaddition for the synthesis of the ABD ring system, and finally a highly efficient biomimetic intramolecular O‐acylation for the C ring formation. This result provides an important perspective on the biosynthetic origin of the unprecedented 7‐membered acyl ketene acetal moiety of the C ring.     

Total Syntheses of the Spermine Alkaloids (−)‐(R,R)‐Hopromine and (±)‐Homaline

The diastereoselective synthesis of the spermine alkaloid (R,R)‐hopromine ( 2 ) is described. The as yet unknown absolute configuration of naturally occurring (−)‐hopromine ( 2 ) is (R,R) and was established by comparison of the reported specific rotation of the natural product with that of the synthetic one. Preparation of the characteristic bis‐8‐membered lactam scaffold was carried out by convergent build‐up of basic chiral azalactam units 21a and 21b and subsequent iterative linking (Schemes 5 and 6). Key steps in the analogous syntheses of 4‐alkyl‐hexahydro‐1,5‐diazocin‐2(1H)‐ones 21a and 21b were the introduction of the unbranched alkyl side chains into their common precursor 14 via cuprate reaction and the Sb(OEt)₃‐assisted cyclization of the open‐chain intermediates 20a and 20b , respectively (Schemes 3 and 4). The chiral iodoester 14 was prepared from commercially available (+)‐L ‐aspartic acid ( 12 ). Based on the synthetic strategy developed for (R,R)‐hopromine ( 2 ), a rapid access to the parent alkaloid homaline ( 1 ) in its (±)‐form is given.     

Conformational Studies of (±)‐11,12‐Didehydro‐11‐deoxycorynoline and (+)‐11,13‐Didehydro‐11‐deoxychelidonine,Hexahydrobenzo[c]phenanthridine‐Type Alkaloid Derivatives,by X‐Ray Crystal Structure and NMR Analyses

The X‐ray crystal analyses of the two 11‐deoxy‐didehydrohexahydrobenzo[c]phenanthridine‐type alkaloid derivatives 3 and 4 , derived from (±)‐corynoline ( 1 ) and (+)‐chelidonine ( 2 ), established their structures as (±)‐(5bRS,12bRS)‐5b,12b,13,14‐tetrahydro‐5b,13‐dimethyl[1,3]benzodioxolo[5,6‐c]‐1,3‐dioxolo[4,5‐i]phenanthridine ( 3 ) and (+)‐rel‐(12bR)‐7,12b,13,14‐tetrahydro‐13‐methyl[1,3]benzodioxolo[5,6‐c]‐1,3‐dioxolo[4,5‐i]phenanthridine ( 4 ). The conformations of 3 and 4 in CDCl₃ were determined on the basis of ¹H‐ and ¹³C‐NMR spectroscopy.     

Metabolism of Deuterated Isomeric 6,7‐Dihydroxydodecanoic Acids in Saccharomyces cerevisiae – Diastereo‐ and Enantioselective Formation and Characterization of 5‐Hydroxydecano‐4‐lactone (=4,5‐Dihydro‐5‐(1‐hydroxyhexyl)furan‐2(3H)‐one) Isomers

The chemical synthesis of deuterated isomeric 6,7‐dihydroxydodecanoic acid methyl esters 1 and the subsequent metabolism of esters 1 and the corresponding acids 1a in liquid cultures of the yeast Saccharomyces cerevisiae was investigated. Incubation experiments with (6R,7R)‐ or (6S,7S)‐6,7‐dihydroxy(6,7‐²H₂)dodecanoic acid methyl ester ((6R,7R)‐ or (6S,7S)‐(6,7‐²H₂)‐ 1 , resp.) and (±)‐threo‐ or (±)‐erythro‐6,7‐dihydroxy(6,7‐²H₂)dodecanoic acid ((±)‐threo‐ or (±)‐erythro‐(6,7‐²H₂)‐ 1a , resp.) elucidated their metabolic pathway in yeast (Tables 1–3). The main products were isomeric ²H‐labeled 5‐hydroxydecano‐4‐lactones 2 . The absolute configuration of the four isomeric lactones 2 was assigned by chemical synthesis via Sharpless asymmetric dihydroxylation and chiral gas chromatography (Lipodex ^® E). The enantiomers of threo‐ 2 were separated without derivatization on Lipodex ^® E; in contrast, the enantiomers of erythro‐ 2 could be separated only after transformation to their 5‐O‐(trifluoroacetyl) derivatives. Biotransformation of the methyl ester (6R,7R)‐(6,7‐²H₂)‐ 1 led to (4R,5R)‐ and (4S,5R)‐(2,5‐²H₂)‐ 2 (ratio ca. 4 : 1; Table 2). Estimation of the label content and position of (4S,5R)‐(2,5‐²H₂)‐ 2 showed 95% label at C(5), 68% label at C(2), and no ²H at C(4) (Table 2). Therefore, oxidation and subsequent reduction with inversion at C(4) of 4,5‐dihydroxydecanoic acid and transfer of ²H from C(4) to C(2) is postulated. The 5‐hydroxydecano‐4‐lactones 2 are of biochemical importance: during the fermentation of Streptomyces griseus, (4S,5R)‐ 2 , known as L‐factor, occurs temporarily before the antibiotic production, and (?)‐muricatacin (=(4R,5R)‐5‐hydroxy‐heptadecano‐4‐lactone), a homologue of (4R,5R)‐ 2 , is an anticancer agent.     

Syntheses of the Macrocyclic Spermine Alkaloids (±)‐Budmunchiamine A – C

The syntheses of four macrocyclic spermine alkaloids, (±)‐budmunchiamine A – C ( 1a – c ) and (±)‐budmunchiamine L4 ( 1 ), were accomplished by Michael addition of spermine to the α,β‐unsaturated esters 3a – d , followed by cyclization of the resulting α,ω‐tetraamino esters 4a – d with triethoxyantimony; N‐methylation of the amino lactams 6a – c yielded the budmunchiamines A – C ( 1a – c ).     

Supramolecular structures of bis‐thionooxalamic acid esters derived from (±)‐cyclohexane‐1,2‐diamine and (±)‐1,2‐diphenylethylenediamine

The bis‐thionooxalamic acid esters trans‐(±)‐diethyl N,N′‐(cyclohexane‐1,2‐diyl)bis(2‐thiooxamate), C₁₄H₂₂N₂O₄S₂, and (±)‐N,N′‐diethyl (1,2‐diphenylethane‐1,2‐diyl)bis(2‐thiooxamate), C₂₂H₂₄N₂O₄S₂, both consist of conformationally flexible molecules which adopt similar conformations with approximate C₂ rotational symmetry. The thioamide and ester parts of the thiooxamate group are significantly twisted along the central C—C bond, with the S=C—C=O torsion angles in the range 30.94 (19)–44.77 (19)°. The twisted s‐cis conformation of the thionooxamide groups facilitates assembly of molecules into a one‐dimensional polymeric structure via intermolecular three‐center C=S...NH...O=C hydrogen bonds and C—H...O interactions formed between molecules of the opposite chirality.     

A New Preparation of 1,3,3‐Trimethylbicyclo[2.2.2]octan‐2,6‐dione,a Never Isolated Intermediate in a Total Synthesis of (+)‐Norpatchoulenol. Formal Total Synthesis of (±)‐Iso‐Norpatchoulenol

A new preparation and the isolation and spectroscopic characterization of 1,3,3‐trimethylbicyclo[2.2.2]octan‐2,6‐dione ( 3 ), a so far elusive key intermediate in the Liu–Ralitsch total synthesis of (+)‐norpatchoulenol ((+)‐ 1a ), is described. The preparation of 3 constitutes also a formal total synthesis of (±)‐iso‐norpatchoulenol ((±)‐ 1b ), since 3 is correlated to an intermediate in the Monti and co‐workers synthesis of (±)‐ 1b .     

First Total Synthesis of (±)‐Celaphanol A

The first total synthesis of (±)‐Celaphanol A was accomplished starting from α‐cyclocitral and 3,4‐dimethoxy benzyl chloride in six steps. The intramolecular cyclization with BF₃·Et₂O and enolization in t‐BuOK/t‐BuOH were the key steps. The process of intramolecular cyclization afforded an all‐cis isomer intermediate for synthesis of aromatic tricyclic diterpenes.     

1‐Methoxyhexane‐3‐thiol,a Powerful Odorant of Clary Sage (Salvia sclarea L.)

The peculiar and highly diffusive odor signal of flowering clary‐sage plants (Salvia sclarea L.) was identified to derive from trace amounts of 1‐methoxyhexane‐3‐thiol ( 1 ) by mass‐spectrometry analysis and confirmed by comparison with synthetic racemic thiol (±)‐ 1 . The enantiomers (S)‐ and (R)‐ 1 were prepared by enantioselective synthesis, and the absolute configuration of (S)‐ 1 was fully corroborated by X‐ray‐diffraction analysis of the crystalline thioester (1′S,1S)‐ 2 . Compound (S)‐ 1 is one of the most powerful odorants known, with a detection threshold of 0.04⋅10⁻³ ng/l air, and is, with its herbaceous‐green, alliaceous, and perspiration profile, key to the fragrance of clary‐sage flowers and of the freshly distilled essential oil. As a consequence of its unique odor, 1 was also suspected to be part of the volatiles of a Ruta species where it was subsequently identified together with its homologue, 1‐methoxyheptane‐3‐thiol ( 3 ), 1‐methoxy‐4‐methylpentane‐3‐thiol ( 4 ), and the known 4‐methoxy‐2‐methylbutane‐2‐thiol ( 5 ). The syntheses of (±)‐ 3 and (±)‐ 4 as well as of the enantiomer (R)‐ 4 are described. In both natural fractions, the ratio (S)‐ 1 /(R)‐ 1 was slightly in favor of the (S)‐enantiomer. Natural 4 has (R)‐configuration.     

Total syntheses of (±)‐cis‐ and trans‐11‐methoxydeethyleburnamonine

The total syntheses of 11‐methoxydeethyleburnamonines ( 4 ) and ( 13 ) were carried out with use of 6‐methoxytryptophyl bromide ( 5 ) as starting material. Compound 5 was converted in three steps to trans‐ester 8 . Acid‐catalysed epimerization of 8 , lithium aluminum hydride reduction of the ester group, tosylation and substitution with cyanide gave the cis‐nitrile 12 . Acid‐induced cyclization of 12 yielded mainly (±)‐trans‐11‐methoxydeethyleburnamonine ( 13 ), whereas base‐induced cyclization gave (±)‐cis‐11‐methoxydeethyleburnamonine ( 4 ).     

Synthesis and Optical Resolution of the Floral Odorant (±)‐2,3‐Dihydro‐2,5‐dimethyl‐1H‐indene‐2‐methanol,and Preparation of Analogues

The title compound (±)‐ 1 , a recently discovered, valuable, floral‐type odorant, has been synthesized by a straightforward procedure (Scheme 1). To determine the properties of the enantiomers of 1 , their separation by preparative HPLC and the determination of their absolute configuration by X‐ray crystallography were carried out (Figure). Furthermore, the analogues 2 – 6 were synthesized, either from differently methylated 2‐methylindan‐1‐ones (Schemes 2 and 3) or, in the case of the 2,4,6‐trimethylated homologue 6 , by a completely different synthetic approach (Scheme 4). An evaluation of (+)‐(S)‐ 1 , (−)‐(R)‐ 1 , and (±)‐ 1 showed only minor differences in terms of odor (Table).