Total synthesis of (+)-lysergic acid

A stereocontrolled total synthesis of (+)-lysergic acid (1) is achieved using three metal-catalyzed methodologies for the construction of three key rings. Highlights of the synthesis include Pd-catalyzed indole synthesis to form the B ring, a RCM reaction to form the D ring, and an intramolecular Heck reaction to form the C ring.     

Enantioselective total synthesis of (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol by palladium-catalyzed domino cyclization of allenes bearing amino and bromoindolyl groups

Enantioselective total synthesis of the biologically important indole alkaloids (+)-lysergol, (+)-isolysergol, and (+)-lysergic acid is described. Key features of these total synthesis include (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0)- and In(I)-mediated reductive coupling reaction between L-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki-Hiyama-Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an allene bearing amino and bromoindolyl groups. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.     

Formal total synthesis of (+)-lysergic acid via zinc(II)-mediated regioselective ring-opening reduction of 2-alkynyl-3-indolyloxirane

Asymmetric formal synthesis of (+)-lysergic acid was achieved with a reductive ring-opening reaction of chiral 2-alkynyl-3-indolyloxirane with NaBH(3)CN as the key step. With Zn(OTf)(2) as an additive, the ring-opening reaction proceeded regioselectively at the 3-position to give the corresponding propargyl alcohol, which was a precursor of the allenic amide for palladium-catalyzed domino cyclization to construct the ergot alkaloid core structure.     

Diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid

A diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid, common members of the paraconic acids is described. The synthesis is based on a diastereoselective orthoester Johnson–Claisen rearrangement of a (Z)-allyl alcohol with a vicinal dioxolane moiety as key steps. The synthesis is completed in 10 steps and with overall yields of 15.9% for (+)-nephrosterinic acid and 16.4% for (+)-protolichesterinic acid.     

The first stereoselective synthesis of (+)-nuciferol and (+)-nuciferal

Using (S)-benzyl 2,3-epoxypropyl ether (1), the first stereoselective synthesis of (+)-nuciferol (14) and (+)-nuciferal (16) has been achieved. Employing the same methodology an enantioselective synthesis of (+)--curcumene (17) is also described.     

Versatile asymmetric synthesis of the kavalactones: first synthesis of (+)-kavain

[reaction: see text] Three asymmetric pathways to the kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates, prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings with aryl halides.     

Stereocontrolled synthesis of (+)-methoxyphenylkainic acid and (+)-phenylkainic acid

The efficient total syntheses of (+)-methoxyphenylkainic acid (3) and (+)-phenylkainic acid (4) were achieved using a rhodium carbenoid-mediated intermolecular C-H insertion reaction. Complete stereoselective construction of the kainoid skeleton was accomplished by utilizing the stereochemistry at the C-4 position as a pivotal stereogenic center.     

The first total synthesis of (+)-mucosin

The first total synthesis of (+)-mucosin has been completed allowing assignment of the absolute stereochemistry of the natural product. A zirconium induced co-cyclisation was utilised to install the correct stereochemistry of the four contiguous stereocentres around the unusual bicyclo[4.3.0]nonene core.     

(+)-saxitoxin: a first and second generation stereoselective synthesis

A stereoselective synthesis of the bis-guanidinium toxin (+)-saxitoxin (STX), the agent infamously associated with red tides and paralytic shellfish poisoning, is described. Our approach to this unique natural product advances through an unusual nine-membered ring guanidine intermediate 39 en route to the tricyclic skeleton that defines STX. The effectiveness of this strategy is notable, as only four steps are needed to transform 39 into the target molecule, including a four-electron alkene oxidation catalyzed by OsCl3. Construction of the critical monocyclic guanidine has been achieved through two channels, the first of which makes use of Rh-catalyzed C-H amination and highlights a novel class of heterocyclic N,O-acetals as iminium ion equivalents for crafting functionalized amines. A second route to 39 relies on a stereoselective acetylide dianion addition to a serine-based nitrone, thereby facilitating the preparation of STX in just 14 linear steps from commercial material.     

Total synthesis of (+)-bongkrekic acid

Total synthesis of bongkrekic acid, an important apoptosis inhibitor, has been accomplished. The strategy includes inexpensive starting materials, asymmetric alkylation, anionic allyl coupling and oxidative manipulations. This process would provide a sufficient amount of bongkrekic acid and its analogues.     

EPC synthesis of (+)-heptelidic acid

Summary An EPC (enantiomerically pure compound) synthesis of the antibiotic natural product (+)-heptelidic acid (1) is presented. Key step of the synthesis is a conjugate addition of the acetal protected vinyl cuprate4 to the auxiliary shielded enoate5n which gives the adduct7n as a single diastereomer. After cleavage of the acetal protecting group and of the chiral auxiliary the enantiomerically pure -ketoester12 has been obtained which has been transformed to the title compound1 (11 steps starting from5n, 10.6% overall yield).

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EPC-Synthese von (+)-heptelidsäure

Zusammenfassung Eine EPC-Synthese (EPC = enantiomerically pure compound) des antibiotischen Naturstoffes (+)-Heptelidsäure (1) wird präsentiert. Schlüsselschritt der Synthese ist dieMichael-Addition des acetal-geschützten Vinylcuprates4 an das auxiliargeschützte Enoat5n, wobei das Addukt7n in diastereomerenreiner Form erhalten wird. Nach der Abspaltung der Acetalschutzgruppe und des chiralen Auxiliars läßt sich der enantiomerenreine -Ketoester12 herstellen, der in die Titelverbindung1 umgewandelt werden kann (11 Stufen ausgehend von5n, 10.6% Gesamtausbeute).

     

Asymmetric synthesis of (+)-trachyspic acid

Aldol reaction of di-tert-butyl 4-(4-methoxybenzyloxy)-2-oxobutanoate with pent-4-enal using (S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(pyrrolidin-2-ylmethyl)thiourea hydrochloride as a catalyst, followed by Pinnick oxidation and tert-butyl esterification, gave (2S,3S)-di-tert-butyl 2-(2-(4-methoxybenzyloxy)ethyl)-3-allyl-2-hydroxysuccinate in high optical purity (85% ee), from which the total synthesis of (+)-trachyspic acid, a tumor cell heparanase inhibitor, was accomplished.     

The first enantiospecific total synthesis of (+)-seychellene

The first enantiospecific total synthesis of the tricyclic sesquiterpene (+)-seychellene, starting from (R)-carvone via (S)-3-methylcarvone, has been accomplished employing a combination of an intermolecular Michael addition-intramolecular Michael addition sequence and an intramolecular alkylation reaction for the generation of the two vicinal quaternary carbon atoms.     

The first synthesis of marine sesterterpene (+)-scalarolide

The synthesis of the first example of C12 oxygenated marine scalaranic sesterterpenes (+)-scalarolide was achieved through three key steps including the ring-opening rearrangement of epoxide, stereoselective Diels-Alder addition and one-pot γ-butenolide formation process, and the absolute configuration of natural scalarolide was confirmed.     

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.     

Total synthesis of (+)-zaragozic acid C

A total synthesis of (+)-zaragozic acid C is described. Key features of the synthesis are the use of a double Sharpless asymmetric dihydroxylation reaction of diene 6 to control stereochemistry at four contiguous stereocenters from C3 to C6; the introduction of the C1-side chain by reaction between the anion derived from the dithiane monosulfoxide 27 and the core aldehyde 12; a high yielding, acid-mediated simultaneous acetonide deprotection-dithiane removal-ketalization procedure leading exclusively to the 2, 8-dioxabicyclo[3.2.1]octane core 34; and a novel triple oxidation procedure allowing installation of the tricarboxylic acid.     

Total synthesis of (+)-prelog-djerassi lactonic acid

Optically active Prelog-Djerassi Lactonic Acid $\text{1}$ was synthesized from D-glucal: the crucial point being the elaboration of the carboxylic group as shown in eq. 1 and 2 which involve the sequential process [i] asymmetric addition of methyl anion onto the hetero-olefin 2, [ii] trapping the carbanion intermediate $\text{3}$ [E=Li to SePh] and [iii] oxidative hydrolysis of $\text{3}$$\text{via}$ sila-pummerer rearrangement into $\text{4}$.     

An enantioselective synthesis of (+)-azimic acid

Herein we report a concise enantioselective synthesis of (+)-azimic acid starting from (5S,6S)-6-methyl-5-benzyloxy-2-piperidinone 8a, which was prepared from protected (S)-3-hydroxyglutarimide 6 according to a method recently disclosed in our laboratory. The key step is a stepwise regioselective reductive alkylation of the imide 10, which established the 2,6-cis-stereochemistry in excellent diastereoselectivity.     

Concise total synthesis of (+)-carpamic acid

We report herein an efficient enantioselective synthesis of (+)-carpamic acid, with nine steps as the longest linear sequence, the key strategy being based on a novel sequence of a cross-metathesis (CM) reaction and a subsequent cyclizing reductive amination to form the piperidine ring.     

Total synthesis of (+)-spiculoic acid A

The total synthesis of natural (+)-spiculoic acid A, a new cytotoxic marine natural product of polyketide origin, has been accomplished for the first time. The key step of the total synthesis was a stereoselective and high-yielding intramolecular Diels-Alder reaction of a highly functionalized (E,E,E)-2,7,9-dodecanal derivative for the construction of the core tetrahydroindan-2-one skeleton.