Total synthesis of (+)-boronolide, (+)-deacetylboronolide,and (+)-dideacetylboronolide

Total synthesis of (+)-boronolide, (+)-deacetylboronolide, and (+)-dideacetylboronolide has been achieved from a single intermediate 26, which was synthesized in 11 steps from a d-mannitol-derived intermediate 8 in an overall yield of 10%. The key steps in the synthesis are inversion of a chiral center by taking an advantage of the inherent mechanism involved in the ring closing to an epoxide via intramolecular S(N)2 reaction and lactonization of a diol using Fetizons reagent. The strategy is amenable to preparation of analogues of (+)-boronolide in sufficient amount for further screening of biological activity.     

Synthesis of (+)-lagerstronolide from (+)-sclareol

The γ-acetoxybutenolide (+)-lagerstronolide was synthesized from (+)-sclareol, with an overall yield of 10%. The absolute stereochemistry for the natural compound (−)-lagerstronolide has been correctly established.     

Chemoenzymatic synthesis of (+)-totarol, (+)-podototarin, (+)-sempervirol, and (+)-jolkinolides E and D

The enzymatic resolution products [(1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-7 (98% ee) and {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal} (8aS)-9 (>99% ee)] obtained by the lipase-catalyzed enantioselective acetylation of (±)-7 in the presence of vinyl acetate as an acyl donor were converted to the ,β-unsaturated ketones (8aR)-6 and (8aS)-6, respectively. Concise syntheses of (+)-totarol 1, (+)-podototarin 2 and (+)-sempervirol 3 were achieved based on Michael reactions between (8aS)-6 and the appropriate β-keto ester followed by aldol condensation. The first chiral syntheses of (+)-jolkinolides E 4 and D 5 were achieved from (5R,10R,12R)-12-hydroxypodocarpa-8(14)-en-13-one 15 derived from (8aR)-6.     

Total synthesis of (+)-condylocarpine, (+)-isocondylocarpine, and (+)-tubotaiwine

The first enantioselective total syntheses of indole alkaloids of the condylocarpine type are reported. (+)-Condylocarpine, (+)-isocondylocarpine, and (+)-tubotaiwine were prepared in high enantiomeric purity (er > 99:1) from (1S,5R)-hexahydro-1,5-methano-1H-azocino[4,3-b]indole-12-one 7b by way of five or six isolated intermediates.     

Enantioselective Total Synthesis of (+)-Nordasycarpidone, (+)-Dasycarpidone,and (+)-Uleine

The structure of uleine type alkaloids is characterized by the presence of a bridged tetracyclic hexahydro-1H-1,5-methanoazocino[4,3-b]indole ring system 1 . Various strategies have been developed to access this polycyclic structural motif. We report herein a one-step conversion of appropriately functionalized 1,3,4-trisubstituted cyclopent-1-ene to 1 by way of an integrated oxidation/reduction/cyclization (iORC) process. This domino sequence, initiated by oxidative cleavage of cyclopentene ring, generated subsequently a cyclohexenone, an indole and a 1,3-bridged piperidine ring through formation of one C−C and two C−N bonds. Compound 1 is subsequently converted to nordasycarpidone, dasycarpidone and uleine. The chirality of the molecule was introduced by enzymatic desymmetrization of commercially available meso cis-3,5-diacetoxy-1-cyclopentene.     

Stereoselective total synthesis of styryl-lactones: (+)-crassalactones B and C, (+)-howiionol A, (+)-tricinnamate, (+)-goniofufurone and (+)-dicinnamoyl goniofufurone

The total synthesis of (+)-crassalactone B, (+)-crassalactone C, (+)-howiionol A, (+)-tricinnamate, (+)-goniofufurone, and (+)-dicinnamoyl goniofufurone is achieved by a ‘chiron approach’ starting from diacetone d-glucose (DAG). Mitsunobu inversion, Wittig olefination and ring closing metatheses were used as key steps for (+)-howiionol A and (+)-tricinnamate. Meldrum’s acid was used for the synthesis of (+)-crassalactone C, (+)-goniofufurone, and (+)-dicinnamoyl goniofufurone. Yamaguchi esterification was used for (+)-crassalactone B, while a Grignard reaction followed by concomitant deallylation was first reported in the synthesis of (+)-dicinnamoyl goniofufurone.     

Concise enantioselective total syntheses of (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine and (+)-norchelidonine by a Pd II-catalyzed ring-opening strategy

New enantioselective syntheses of the B/C hexahydrobenzo[c]phenanthridine alkaloids (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine, and (+)-norchelidonine are described. Our rapid and convergent route to this class of natural products involved the development and application of a Pd II-catalyzed asymmetric ring-opening reaction of a meso-azabicyclic alkene with an aryl boronic acid as the key step. By screening a variety of functionalized ortho-substituted aryl boronic acids, chiral ligands and reaction conditions we were able to prepare the requisite cis-1-amino-2-aryldihydronaphthalenes in high yield and in up to 90 % ee. Early attempts to complete the synthesis of (+)-homochelidonine using an N-Boc azabicyclic alkene are described in full. The successful route required a protecting group alteration followed by B ring formation and then stereoselective installation of the C-11 syn-hydroxy group by regioselective epoxide ring-opening using a hydride source. Ring-opening of the same epoxide intermediate with water ultimately led to the synthesis of (+)-chelamidine. The same strategy was then used to synthesize the other structurally similar B/C hexahydrobenzo[c]phenanthridine alkaloids, (+)-chelidonine, (+)-chelamidine, and (+)-norchelidonine.     

Total Syntheses of (+)-Longicamphor and (+)-Longiborneol

Recent total syntheses within the longifolane class of sesquiterpenes have included such elaborately bridged structures as longicyclene,¹ longifolene,^2,3 isolongifolene,⁴ and culmorin.⁵ A tricyclic member of this interesting group of naturally occurring compounds; namely, longicamphor (6) has previously been synthesized from natural (+)-longifolene via (+)-longiborneol (7).⁶ Longiborneol (Juniperol, macrocarpol) was isolated from Cupressus macrocarpa, the famous Monterey cypress.^7,8 We wish to report herein stereoselective total syntheses of (+)-longicamphor (6) and (+)-longiborneol (7).     

Stereoselective total synthesis of bioactive styryllactones (+)-goniofufurone, (+)7-epi-goniofufurone, (+)-goniopypyrone, (+)-goniotriol, (+)-altholactone, and (-)-etharvensin

Stereoselective total synthesis of biologically active styryllactones 7-epi-goniofufurone, goniofufurone, goniopypyrone, goniotriol, altholactone, and etharvensin was achieved in high overall yields from a common intermediate derived from d-(-)-tartaric acid. It is based on the utility of a masked tetrol, comprising an alkene tether and four contiguous hydroxy groups. The pivotal reaction sequence involves hydroxy-directed lactonization via the oxidation of alkene, and subsequent elaboration to styryllactones. The masked tetrol was prepared by the extension of gamma-phenyl-gamma-hydroxy butyramide, readily obtained from the bis-dimethylamide of tartaric acid, employing a combination of selective Grignard additions and a stereoselective reduction.     

Synthesis of (+)-perillyl alcohol from (+)-limonene

(+)-Perillyl alcohol (1) has been synthesised in four steps and 39% overall yield from commercially available limonene oxide (4). The sequence features, as its key step, a palladium(0)-mediated transformation of a secondary allylic acetate (6) into its primary isomer (7). An application of (+)-perillyl alcohol (1) in a formal synthesis of naturally occurring (−)-mesembrine (2) and (−)-mesembranol was demonstrated.     

Asymmetric synthesis of (+)-vertine and (+)-lythrine

The total syntheses of the Lythracea alkaloids (+)-vertine and (+)-lythrine are described. Enantioenriched pelletierine is used as a chiral building block and engaged into a two step pelletierine condensation leading to two quinolizidin-2-one diastereomers in a 8 : 1 ratio. The major product is used in the synthesis of (+)-vertine via aryl-aryl coupling and ring closing metathesis to provide a Z-alkene α to the lactone carbonyl function. The same procedure was used for (+)-lythrine after base induced epimerization of the main quinolizidin-2-one diastereomer. Alternative classical ring closure strategies like macrolactonisation or aryl-aryl coupling failed.     

Short syntheses of (+)-ferruginol from (+)-dehydroabietylamine

Short syntheses of bioactive (+)-ferruginol in five or six synthetic steps starting from commercially available (+)-dehydroabietylamine are described. The oxygenated function at C12 was introduced via a Friedel-Crafts acylation of N-phthaloyldehydroabietylamine followed by Baeyer-Villiger oxidation. Then, overall deprotection of functional groups, reductive deamination or biomimetic oxidative deamination, and final Wolff-Kishner reduction provided (+)-ferruginol in 21 and 23% overall yields, respectively.     

Synthesis of (+)-carpamic acid from (+)-alanine

(+)-Carpamic acid [(2′R,5′S,6′S)-8-(5′-hydroxy-6′-methylpiperidin-2′-yl)octanoic acid, 1] was synthesized from (S)-alanine, employing intramolecular and reductive amination of acyclic amino ketone 8 as the key step to generate the piperidine ring.     

Synthesis of (+)-agelasine D from (+)-manool

(+)-Agelasine D, originally isolated from the marine sponge Agelas nakamurai, is synthesized for the first time. The terpenoid side chain was readily available from the diterpene alcohol (+)-manool.     

First synthesis of (+)-alpha- and (+)-gamma-polypodatetraenes

First synthesis of (+)-alpha-polypodatetraene (1) and (+)-gamma-polypodatetraene (2) was achieved from (+)-albicanol (6) and (-)-drimenol (8), respectively. The absolute structure of natural (+)-2 was established to be (5S,9S,10S)-polypoda-7,13(E),17(E),21-tetraene.     

Total syntheses of (+)-castanospermine and (+)-deoxynojirimycin

The absolute configuration of castanospermine has been determined by total synthesis to be as shown in 1.     

Enantioselective total synthesis of (+)-azimine and (+)-carpaine

[reaction: see text] The enantioselective total syntheses of (+)-azimine and (+)-carpaine have been developed, starting with (S)-1,2,4-butanetriol as a single source of chirality. The key common feature in these syntheses involves stereoselective intramolecular hetero-Diels-Alder reaction of an acylnitroso compound. The critical macrocyclic dilactonization of the N-Cbz derivatives of azimic acid and carpamic acid was efficiently achieved by using the Yamguchi macrocyclization conditions.     

(+)-Trans-chrysanthemic acid from (+)-Δ3-carene

A new and more efficient route for the conversion of the readily available (+)-Δ³-carene into (+)-trans-chrysanthemic acid is described.     

Enantioselective synthesis of (+)-trypargine and (+)-crispine E

Asymmetric transfer hydrogenation was used as a key step in the synthesis of two guanidine-derived alkaloids (+)-trypargine and (+)-crispine E. The enantiomeric compositions of key intermediates were established on the basis of ¹H NMR spectra with chiral solvating agents. The absolute stereochemistry was proven by X-ray crystallography.