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.     

Total synthesis of (+)-blennolide C and (+)-gonytolide C via spirochromanone

We report the asymmetric total synthesis of (+)-blennolide C and (+)-gonytolide C isolated from endophytic fungi. The synthesis involved construction of a spirochromanone with a chiral quaternary carbon by the aldol reaction of o-hydroxyacetophenones and optically active α-oxygenated cyclohexenone, followed by cyclization under acidic conditions. Oxidative cleavage of the alkene moiety of the spirochromanone furnished the chromanone diester. Through treating the diester with a Lewis acid, the first total synthesis of (+)-blennolide C was achieved by deprotecting the oxygen functionality of the diester and simultaneous Dieckmann condensation. Total synthesis of (+)-gonytolide C was also achieved by lactone formation from the deprotected diester.     

Total synthesis of (+)-epiepoformin and (−)-phyllostine

An efficient asymmetric total synthesis of naturally occurring cyclohexeneoxides, (+)-epiepoformin and (−)-phyllostine has been achieved using the chiral building block available from the base-catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone. Since (−)-theobroxide was derived from the same precursor of (+)-epiepoformin, the formal total synthesis of (−)-theobroxide has also been achieved.     

Total synthesis of (+)-achalensolide based on the rh(i)-catalyzed allenic Pauson-Khand-type reaction

The first total synthesis of (+)-achalensolide was achieved from a commercially available d-(-)-isoascorbic acid. The known epoxide, derived from d-(-)-isoascorbic acid, was converted into the allenyne, the Rh(I)-catalyzed Pauson-Khand-type reaction of which directly provided the bicyclo[5.3.0]decane system, a core framework of the title natural product. The construction of the gamma-lactone moiety and some chemical modifications resulted in the completion of the total synthesis of (+)-achalensolide.     

Total synthesis of natural (+)-sesbanimide a and (-)-sesbanimide b

The first total synthesis of natural (+)-sesbanimide A (1) and (-)-sesbanimide B (2), potent antitumor alkaloids isolated from the seeds of the leguminous plant, Sesbania drummondii, has been accomplished starting from D-(+)-xylose. This total synthesis involves efficient construction of the optically active AB-ring system from D-(+)-xylose, introduction of the C₅-unit into the AB-ring system in a form of exo-methylene-γ-lactone, and elaboration of the labile C-ring system at the last stage of the synthesis. The absolute configurations of natural 1 and 2 could be obviously established by our total synthesis.     

Total synthesis of (+)-pederin. 2. Stereocontrolled synthesis of (+)-benzoylselenopederic acid and total synthesis of (+)-pederin

(+)-Benzoylselenopederic acid (1), a left half of (+)-pederin (3), was synthesized stereoselectively based on the Zn(BH₄)₂ reduction and total synthesis of (+)-pederin (3) was accomplished from 1 and the previously synthesized 2.     

Enantioselective total synthesis of (+)-gliocladine C: convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors

A concise second-generation total synthesis of the fungal-derived alkaloid (+)-gliocladin C (11) in 10 steps and 11% overall yield from isatin is reported. In addition, the epipolythiodioxopiperazine (ETP) natural product (+)-gliocladine C (6) has been prepared in six steps and 29% yield from the di-(tert-butoxycarbonyl) precursor of 11. The total synthesis of 6 constitutes the first total synthesis of an ETP natural product containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter in the pyrrolidine ring.     

Total synthesis of (+)-acutiphycin

Synthetic studies toward the total synthesis of (+)-acutiphycin (1) resulted in the discovery of additive-free, highly regioselective nickel-catalyzed reductive coupling reactions of aldehydes and 1,6-enynes and the construction of an advanced intermediate in studies directed toward the synthesis of 1. Ultimately, although not employing the nickel-catalyzed reaction, a highly convergent total synthesis of (+)-acutiphycin featuring an intermolecular SmI2-mediated Reformatsky coupling reaction and macrolactonization initiated by a retro-ene reaction of an alkoxyalkyne was achieved. The resulting synthesis was 18 steps in the longest linear sequence from either methyl acetoacetate or isobutyraldehyde.     

Enantioselective synthesis of (+)-crocacin C. An example of a highly challenging mismatched double asymmetric δ-stannylcrotylboration reaction

A concise, enantioselective synthesis of (+)-crocacin C is described, featuring a highly diastereoselective mismatched double asymmetric δ-stannylcrotylboration of the stereochemically demanding chiral aldehyde 9 with the bifunctional crotylborane reagent (S)-E-10. The total synthesis of (+)-crocacin C was accomplished in seven steps (longest linear sequence) starting from commercially available precursors.     

Total synthesis of (+)-frondosin A. Application of the Ru-catalyzed [5+2] cycloaddition

The first total synthesis of (+)-frondosin A was accomplished in 19 longest linear and 21 total steps from commercially available materials. The key features of the synthesis include a Ru-catalyzed [5+2] cycloaddition, a Claisen rearrangement, and a ring expansion to construct the core of the frondosin A in a diastereoselective and regioselective fashion. This is the first application of a Ru-catalyzed [5+2] cycloaddition in the total synthesis of a natural product. Through this synthesis, the absolute configuration of (+)-frondosin A was established.     

Chemoenzymatic Total Synthesis of (+)‐Galanthamine and (+)‐Narwedine from Phenethyl Acetate

The stereoselective total synthesis of unnatural (+)‐galanthamine starting from phenethyl acetate is described. Chirality was introduced via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis‐cyclohexadi–enediol, configuration of which provided the absolute stereochemistry of the ring C of (+)‐galanthamine. Intramolecular Heck cyclization was used to form the quaternary carbon and dibenzofuran functionality. The synthesis of (+)‐galanthamine was completed in a total of ten steps and an overall yield of 5.5 %. Experimental and spectral data are provided for all new compounds.     

Palladium-catalyzed asymmetric allylic substitution of 2-arylcyclohexenol derivatives: asymmetric total syntheses of (+)-crinamine, (-)-haemanthidine, and (+)-pretazettine

Much interest has been shown in Amaryllidaceae alkaloids as synthetic targets due to their wide range of biological activities. Over 100 alkaloids have been isolated from members of the Amaryllidaceae family; most of them can be classified into eight skeletally homogeneous groups. We have succeeded in the first asymmetric total syntheses of the crinane-type alkaloids (+)-crinamine (1), (-)-haemanthidine (2), and (+)-pretazettine (3). The starting cyclohexenylamine 14 was obtained from allyl phosphonate 11c by palladium-catalyzed asymmetric amination in 82% yield and with 74% ee. The product was recrystallized from MeOH. Interestingly, (-)-14 with 99% ee was obtained from the mother liquor (74% recovery). Intramolecular carbonyl-ene reaction of (-)-10 proceeds in a highly stereoselective manner to give hexahydroindole derivative 9 as the sole product. In the Lewis-acid-catalyzed carbonyl-ene reaction, an interesting rearrangement product, 20, was isolated in high yield. From 9, (+)-crinamine was synthesized. Thus, the asymmetric total synthesis of (+)-crinamine was achieved in 10 steps from 11c, and the overall yield is 19%. The total synthesis of (-)-haemanthidine was also achieved from 9 by a short sequence of steps.     

p-Menthane-3-carboxaldehyde: a useful chiral auxiliary for the synthesis of chiral quaternary carbons of high enantiomeric purity

(+)- or (-)-p-Menthane-3-carboxaldehyde is made in two easy steps from (+)- or (-)-menthone, respectively. This auxiliary allows for the synthesis of carbonyl compounds bearing a alpha-chiral quaternary carbon. The flexibility, efficiency, and ease of use of the method are demonstrated in a series of examples, which include the total synthesis of (+)-cuparenone as well as a partial synthesis of (-)-cassiol.     

A concise stereoselective total synthesis of (+)-artemisinin

A protective group free, concise, and stereoselective total synthesis of (+)-artemisinin, starting from readily available (R)-(+)-citronellal, is described. Asymmetric 1, 4-addition, Aldol condensation, Ene reaction, regioselective hydroboration are the key steps involved in the total synthesis of the target molecule.     

Total synthesis of (+)-quassin

A total synthesis of (+)-quassin from naturally occurring (S)-(+)-carvone is described. The total number of steps was 28, and the overall yield was about 2.6%. The synthetic strategy for the construction of the tetracyclic carbon framework was based on a C-->ABC-->ABCD ring annulation sequence, involving an aldol reaction, an intramolecular Diels-Alder reaction, and an intramolecular acylation as the key steps. Subsequent functionalization of ring A and ring C then afforded the target (+)-quassin.     

A Facile Approach to Synthesis of the Di-O-methyl Ethers of （-）-Agatharesinol, （-）-Sugiresinol, （＋）-Nyasol and （＋）-Tetrahydronyasol

The facile enantioselective synthesis of the di-O-methyl ethers of （-）-agatharesinol （1b）, （-）-sugiresionl （2b）, （＋）-nyasol （3b） and （＋）-tetrahydronyasol （4） were achieved in high yield. The absolute configuration of （＋）-3a was confirmed via first total synthesis of （＋）-3b and （＋）-4.     

Total synthesis of the strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck-iminium ion cyclization

A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A cascade catalytic asymmetric Heck-iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity. Two sequences were developed for advancing 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 27 to (+)-minfiensine. In our first-generation approach, a reductive Heck cyclization was employed to form the fifth ring of (+)-minfiensine. In a second more concise total synthesis, an intramolecular palladium-catalyzed ketone enolate vinyl iodide coupling was employed to construct the final ring of (+)-minfiensine. This second-generation total synthesis of enantiopure (+)-minfiensine was accomplished in 6.5% overall yield and 15 steps from 1,2-cyclohexanedione and anisidine 13. A distinctive feature of this sequence is the use of palladium-catalyzed reactions to form all carbon-carbon bonds in the transformation of these simple precursors to (+)-minfiensine.     

Iminium ion-enamine cascade reaction enables the asymmetric total syntheses of aspidosperma alkaloids vincadifformine and ervinceine

Asymmetric total synthesis of (+)-vincadifformine and (+)-ervinceine is reported by utilizing an iminium ion triggered cascade reaction using chiral 3,3-disubstituted piperidine imine and 2,3-disubstituted indole derivatives coupling partner. In the first generation total synthesis, the pivotal imine is prepared in excellent stereoselectivity but in moderate yield involving a Birch reduction-alkylation strategy. Furthermore, to improve upon the synthesis of the decisive imine, the more practical second generation route is devised through a Johnson-Claisen rearrangement to access chiral 3,3-disubstituted piperidinone in excellent yield and stereoselectivity. Apart from synthesizing (+)-vincadifformine, this strategy is also exploited for the first asymmetric total synthesis of (+)-ervinceine employing an iminium ion mediated cascade reaction. This distinctive strategy simultaneously sets up two new rings, two new stereogenic centers, and three new sigma bonds in a single operation.     

Total synthesis of (+)-dactylolide

[reaction: see text] The total synthesis of the new cytotoxic marine macrolide (+)-dactylolide (1) has been achieved in nine steps from known vinyl bromide (-)-AB. In addition, (+)-zampanolide (2) has been converted to (+)-dactylolide (1) via thermolysis.     

A practical and scaleable total synthesis of the jaborandi alkaloid (+)-pilocarpine

The total synthesis of (+)-pilocarpine (as its nitrate salt) has been achieved in nine steps and 30% overall yield starting from racemic 2-(2′,2′-dimethoxyethyl)propane-1,3-diol, which was desymmetrised via an enzymatic protocol. A high yielding synthesis of a key α-ethylidene lactone precursor has been developed, which involves the palladium-catalysed decarboxylation/carbonylation of a 1,3-dioxan-2-one for formation of the γ-butyrolactone ring. Subsequent hydrogenation of the α-ethylidene lactone introduces the C(3)-stereochemistry to give a 72:28 mixture of (+)-pilocarpine and (+)-isopilocarpine, which are readily separable via recrystallisation of the (+)-pilocarpine nitrate salt.