A formal total synthesis of (+/-)-cephalotaxine using sequential N-acyliminium ion reactions

[reaction: see text] Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrroloisoquinoline 4 to pyrrolobenzazepine 12, and the construction of cyclopentapyrrolobenzazepine ring system 6, all of which are derived from N-acyliminium ion intermediates.     

A formal total synthesis of (-)-cephalotaxine.

A formal total synthesis of (-)-cephalotaxine (1) has been achieved. The key step is an intramolecular aldol condensation of the diketone 9, which in turn was obtained in three steps from the azabicyclic compound 6 derived from D-proline according to Seebach's procedure. Treatment of 9 with a catalytic amount of sodium 2-methyl-2-butanolate in benzene at room temperature gave the alpha, beta-unsaturated ketone 8 in 43% yield. Catalytic hydrogenation of 8 followed by reduction of the ketone 22 with sodium borohydride and acetylation of the resulting alcohol 23 gave the acetoxy derivative 24, which, after deprotection, was acylated with (methylthio)acetic acid to give the amide 26. Compound 26 was converted into optically active ketolactam 4 following the synthetic operations developed for the synthesis of the racemic compound.     

A formal synthesis of (-)-cephalotaxine

An enantioselective formal synthesis of the alkaloid (-)-cephalotaxine has been completed, using an alkylidene carbene 1,5-CH insertion reaction as a key step to construct the spiro[4.4]azanonane core D/E-ring system. A Heck-type cyclization was used to close the tetrahydroazepine C-ring and a selective epoxidation-rearrangement sequence was used to elaborate the E-ring.     

A second generation formal synthesis of (-)-cephalotaxine

A second generation formal synthesis of the alkaloid (-)-cephalotaxine has been achieved using an alkylidene carbene 1,5-CH insertion reaction to establish a key quaternary stereocenter. The carbene precursor was readily derived from L-proline, and the 1,5-CH insertion reaction was performed under Ohira's conditions using lithiotrimethylsilyldiazomethane (LTDM), which gave the desired spirocyclic product in 74% yield. The hydroxymethyl group was then oxidized and then decarbonylated (93%), and this material was easily transformed into the desired Friedel-Crafts cyclization precursor. Exposure of this material to SnCl4 then gave the desired pentacyclic product, which was identical to that previously prepared by Mori and thus represents a formal total synthesis of (-)-cephalotaxine.     

A formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid

[reaction: see text] A stereocontrolled approach for the preparation of the Danishefsky intermediates has been developed starting with the azaspirobicyclic ketone as a common precursor, representing a formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid. This approach involves the construction of the 1,7-disubstituted 6-azaspiro[4.5]decane with the proper stereochemistry established by olefin hydrogenation followed by C-methylation of the spirotricyclic lactam and the subsequent processes involving lactam ring-opening using methyl triflate and RCM to form the azaspirotricyclic quinolizidine skeleton.     

A formal total synthesis of (+/-)-neplanocin A

Stereoselective formal synthesis of (+/-)-neplanocin A from a cyclopentane derivative employing an elegant strategy involving reiterative usage of an already existing acetonide protecting group is reported. The acetonide protecting group that is carried forward intact right from the starting adduct to an advanced intermediate is shuffled around twice as in a "relay race" through the synthetic sequence, thus avoiding unnecessary employment of additional protecting groups.     

An improved total synthesis of (+)-macroline and alstonerine as well as the formal total synthesis of (-)-talcarpine and (-)-anhydromacrosalhine-methine

An intramolecular Pd-catalyzed alpha-vinylation process is described. This cyclization has been employed for the enantiospecific total synthesis of gram quantities of both (+)-macroline 3 and the macroline equivalent 4. This sequence is compared to the enolate-driven cross-coupling process. The intermediate 4 was also converted into (-)-alstonerine 1 via modification of an intramolecular Tsuji-Wacker oxidation. This sequence resulted in an improved total synthesis of (-)-talcarpine 5 and (-)-anhydromacrosalhine-methine 6 as well.     

A (formal) total synthesis of (+) - strigol,the witchweed germination factor

A synthetic route to (+)-1 commencing from (S)-malic acid and 20 is reported. Key steps are the coupling of 20 and 15 to give 21, an intramolecular Wittig reaction (25-→27), and an oxidative cyclization (28-→1).     

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide and approaches to the syntheses of (+/-)-6-epi-, (+/-)-15-epi-, and (+/-)-6,15-bisepidysidiolide

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide (1), a structurally novel sponge metabolite that inhibits the cdc25A protein phosphatase, and approaches to the syntheses of (+/-)-15-epi- (34), (+/-)-6-epi- (36), and (+/-)-6, 15-bisepidysidiolide (39) are described.     

Concise stereocontrolled formal synthesis of (+/-)-quinine and total synthesis of (+/-)-7- hydroxyquinine via merged Morita-Baylis-Hillman-Tsuji-Trost cyclization

Concise stereoselective syntheses of (+/-)-quinine and (+/-)-7-hydroxyquinine are achieved using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and the electrophilic features of the Tsuji-Trost reaction. Cyclization of enone-allyl carbonate 11 delivers the product of cycloallylation 13 in 68% yield. Diastereoselective conjugate reduction of the enone 13 (>20:1 dr) followed by exchange of the N-protecting group provides the saturated N-Boc-protected methyl ketone 19, which upon aldol dehydration provides quinoline containing enone 15, possessing all carbon atoms of quinine. Exposure of ketone 15 to L-selectride enables diastereoselective carbonyl reduction (>20:1 dr) to furnish the allylic alcohol 16. Stereoselective hydroxyl-directed epoxidation using an oxovanadium catalyst modified by N-hydroxy-N-Me-pivalamide delivers epoxide 17 (17:1 dr). Cyclization of the resulting amine-epoxide 17 provides (+/-)-7-hydroxyquinine in 13 steps and 11% overall yield from aminoacetaldehyde diethyl acetal. Notably, highly stereoselective formation of five contiguous stereocenters is achieved through a series of 1,2-asymmetric induction events. Deoxygenation of the N-Cbz-protected allylic acetate 22 provides olefin 23, which previously has been converted to quinine. Thus, (+/-)-quinine is accessible in 16 steps and 4% overall yield from commercial aminoacetaldehyde diethyl acetal.     

Stereocontrolled formal synthesis of (+/-)-platensimycin

The caged structure of platensimycin, known as Nicolaou's key intermediate for total synthesis of platensimycin, was synthesized stereoselectively by using the following key steps: (i) diastereoselective Diels-Alder reaction between gamma-benzoyloxy enone and tert-butyldimethylsiloxydiene, (ii) formation of a dihydropyran ring by intramolecular catalytic oxypalladation, and (iii) transannular radical cyclization of monothioacetal with tributyltin hydride and AIBN.     

Tandem radical cyclizations with iodoaryl azides: formal total synthesis of (+/-)-aspidospermidine

An iodoazide radical cascade cyclization strategy has been used as the key step in a formal synthesis of aspidospermidine. Specifically, this step generated the alkaloid's B- and E-rings in the ethylidene-functionalized tetracycle 5. In turn, this was converted into pentacycle 25, a known advanced synthetic precursor of aspidospermidine.     

Chemoenzymatic formal synthesis of (-)- and (+)-epibatidine

The cis-dihydrocatechol, derived from enzymatic cis-dihydroxylation of bromobenzene using the microorganism Pseudomonas putida UV4, was converted into (-)-epibatidine in eleven steps with complete stereocontrol. In addition, an unprecedented palladium-catalysed disproportionation reaction gave the (+)-enantiomer of an advanced key intermediate employed in a previous synthesis of epibatidine.     

A concise stereocontrolled formal total synthesis of (+/-)-podophyllotoxin using sulfoxide chemistry

A short stereoselective formal total synthesis of (+/-)-podophyllotoxin has been carried out from a sulfoxide, using a one-pot tandem conjugate addition/aldol/electrophilic aromatic substitution reaction to form a tetralin, which was converted into picropodophyllin in two steps.     

First total synthesis of (+/-)-stemonamide and (+/-)-isostemonamide

[structure: see text] The total synthesis of the tetracyclic alkaloids stemonamide (1) and isostemonamide (2) is presented. The key step is the reaction between a silyloxyfuran and an N-acyliminium ion. The second quaternary center is created by an intramolecular aldol spirocyclization. After 1,4-addition of an appropriate side chain, the methyl and double bond are installed by Mannich reaction. The seven-membered ring is closed by intramolecular nucleophilic displacement.     

Electrophilic C12 building blocks for alkaloids: formal total synthesis of (+/-)-maritidine

Silyl-protected benzyl alcohol derivatives and the salt 1 are used to form ortho-substituted C12 electrophilic organoiron building blocks which are converted into a spirocyclic cyclohexenone to complete a formal total synthesis of (+/-)-maritidine (5). The choice of TBDPS protection was shown to be better than TIPS and compatible with ipso nucleophile addition to form a quaternary center. The reaction sequence is the first example of a successful application in the synthesis of an arylcyclohexadienyliron complex with an ortho-carbon substituent in the position required for Amaryllidaceae alkaloids of this type.     

Efficient formal synthesis of (+/-)-hyphodermin B

An efficient formal synthesis of hyphodermin B 1, a metabolite of Hyphoderma radula, has been completed in 15% overall yield. The tricyclic carbon skeleton 3 was rapidly assembled from a novel vinyl enone via a Diels-Alder reaction, followed by dehydrogenation and anhydride formation. Selective reduction of anhydride 3 with LiAlH(t-BuO)3 gave hyphodermin B 1 in 99% yield. The structure of hyphodermin B 1 was confirmed by X-ray crystallographic analysis. The anhydride 3, bearing a gamma-carbonyl group, displayed unexpected reactivity with the anhydride carbonyl closest to the gamma-ketone being the most electrophilic site. This was confirmed by HF/6-31G calculations. In the presence of base, 3 underwent a rearrangement to the novel lactone 16.     

Total synthesis of (+/-)-flustramines A and C, (+/-)-flustramide A, and (-)- and (+)-debromoflustramines A

Here we describe the efficient total synthesis of the three title hexahydropyrrolo[2,3-b]indole alkaloids and debromo derivative from readily available indolin-3-ones using key domino reactions, olefination-isomerization-Claisen rearrangement (OIC), and reductive cyclization (RC). (+/-)-Flustramine C (5) was synthesized in five steps from 6-bromoindolin-3-one 9 via a key intermediate 13a. (+/-)-Flustramine A (1) has been obtained by reduction of flustramide A (6), which has been prepared in five steps from 13a. (+/-)-Debromoflustramine A (19) was provided in a similar manner from 13b. The (-)- and (+)-enantiomers of 19 were synthesized through optical resolution of (+/-)-carboxylic acid 17b using (R)-4-phenyloxazolidin-2-one.     

First total synthesis of (+/-)-taxifolial a and (+/-)-iso-caulerpenyne

The first synthesis of (+/-)-taxifolial A and iso-caulerpenyne was accomplished. The key steps in the sequence are (1) the stereoselective assembly of a vinyltin derived from butynediol and a functionalized aldehyde and (2) the construction of the dienyne moiety via a Stille cross-coupling.     

Diastereoselective total synthesis of (+)-13-stemarene by fourth generation methods: a formal total synthesis of (+)-18-deoxystemarin

The problem of constructing diastereoselectively the C/D ring system of stemarane diterpenes from a bicyclo[2.2.2]octane intermediate was solved resulting in very simple synthesis of (+)-13-stemarene 1. The obtaining of the latter represents also a formal synthesis of (+)-18-deoxystemarin 2. In the key step, the epimeric mixture 10, dissolved in toluene, was converted by the action of TsOH into (+)-stemar-13-en-15-one 28.