Studies directed toward the total synthesis of pinnatoxin A: synthesis of the 6,5,6-dispiroketal (BCD ring) system by double hemiketal formation/hetero-Michael addition strategy

An efficient, highly stereoselective synthesis of the C10–C26 portion of pinnatoxin A has been achieved, wherein the key step is a highly stereoselective construction of the 6,5,6-dispiroketal (BCD ring) system by an intramolecular hetero-Michael addition of a hemiketal alkoxide reversibly formed under the influence of lithium methoxide.     

Enantioselective total syntheses of trichodermamides A and B

Starting from commercially available (-)-quinic acid, the enantioselective total syntheses of trichodermamides A and B were achieved. The key reactions involve the stereoselective construction of the oxazine ring via an intramolecular epoxide ring opening reaction and an EDCI-assisted peptide coupling reaction.     

Total synthesis of (+/-)-scopadulin.

The first total synthesis of (+/-)-scopadulin, an aphidicolane diterpene, is described. The core structure (A/B/C/D ring system) was constructed by an initial synthesis of the B/C/D ring system by our reported methods and a subsequent A ring cyclization by intramolecular aldol condensation. A highly stereoselective cyanation of the tetracyclic enone by Et2AlCN gave a trans-fused A/B ring system with a beta-cyanide at C-4. Stereoselective construction of a quaternary carbon at C-4 was achieved by alpha-alkylation of the cyano group and conversion of the sterically hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines into alcohols. Finally, the total synthesis of (+/-)-scopadulin was accomplished by a highly chemo- and stereoselective methylation at C-16 and modification of the C-4 alpha-functionality. The stereoselectivity observed in the MeTi(O-i-Pr)3-mediated methylation for the generation of a tertiary axial alcohol at C-16 is extremely high.     

Stereoselective total syntheses of uncommon sesquiterpenoids isolated from Jatropha neopauciflora

The first total syntheses of two tricyclic sesquiterpenes 1 and 2, isolated from Jatropha neopauciflora, were completed from dimethyl D-tartrate in a stereoselective manner. The crucial steps in these syntheses involved not only the Rh(I)-catalyzed Pauson-Khand-type reaction of the allenene derivative leading to the exclusive formation of the bicyclo[4.3.0]nonenone framework possessing an angular methyl group but also a highly stereoselective construction of the isopropylcyclopropane ring.     

First Total Syntheses of Tetracenomycins C and X

The first total syntheses of tetracenomycins C and X were achieved, featuring 1) preparation of a hexasubstituted naphthonitrile oxide by successive benzyne cycloadditions and an oxidative ring‐opening reaction; 2) a novel ortho ‐quinone mono‐acetal as the A‐ring unit; 3) construction of three contiguous stereogenic centers by an asymmetric benzoin cyclization, an isoxazole oxidation, and a stereoselective reduction.     

Enantioselective Total Synthesis of (+)‐Ophiobolin A

The enantioselective total synthesis of (+)‐ophiobolin A is described. This total synthesis features the construction of the spiro CD ring of (+)‐ophiobolin A through a stereoselective intramolecular Hosomi–Sakurai cyclization reaction, the joining of the A ring to the CD ring by using a reaction reported by Utimoto, and the construction of the ophiobolin eight‐membered carbocyclic ring through ring‐closing metathesis (RCM), which was performed for the first time in this study. This successful RCM reaction required the use of a substrate that contained either a benzyloxy or a methoxymethoxy group at the C5 position and either an isopropenyl group or its hydroxylated form at the C6 position.     

A Flexible Approach to Grandisine Alkaloids: Total Synthesis of Grandisines B,D, and F

This article describes in detail the first total synthesis of grandisine alkaloids, grandisines B, D, and F, which show affinity for the human δ‐opioid receptor. The key steps in this synthesis are construction of the isoquinuclidinone moiety of 2 by intramolecular imine formation and the tetracyclic ring system of 4 by stereoselective ring closure of the enolate of amine 8 generated by 1,4‐addition of ammonia to 9 . Synthesis of key intermediate 9 featured a highly stereoselective Brønsted acid mediated Morita–Baylis–Hillman (MBH) reaction via the N‐acyl iminium ion.     

Synthetic studies on chartelline C: stereoselective construction of the core skeleton

What a core-ker! The title synthesis was achieved using a route featuring an intramolecular Mitsunobu reaction of a nosyl amide, stereoselective construction of the β-lactam, and formation of an enamide moiety by selenoxide elimination. The stereochemistry of the alkylation for the formation of the β-lactam was controlled by a secondary hydroxy group on the ten-membered ring. SEM=2-(trimethylsilyl)ethoxymethyl; TBS=tert-butyldimethylsilyl.     

A new nucleophilic addition/ring-closure sequence. Enantioselective synthesis of 3-deoxy-8-oxatropanes

[reaction: see text] A study of new nucleophilic addition/ring-closure (NARC) sequences has resulted in the development of a stereoselective synthetic route to 3-deoxy-8-oxatropanes. The new sequences consisted of either a syn or anti aldol addition, employing an omega-alkenoyl sultam, followed by two-step bicyclic ring construction involving, consecutively, ring-closing metathesis and intramolecular oxymercuration.     

A New Enantioselective Approach to Total Synthesis of the Securinega Alkaloids: Application to (-)-Norsecurinine and Phyllanthine

An inexpensive proline derivative and chiral control feature in the total synthesis of securinega alkaloids (-)-norsecurinine (1) and phyllanthine (2). Key steps in the synthesis of 1 include an intramolecular ketonitrile coupling and application of a radical-based generation of N-acylimines. The total synthesis of 2 utilizes a stereoselective imino Diels - Alder construction of the methoxypiperidine ring.     

Synthesis of the ABCD fragment of gymnocin-B

A convergent synthesis of the ABCD fragment of gymnocin-B was accomplished. The tetracyclic ether ring system was synthesized by the construction of the BC ring system via the oxiranyl anion alkylation and ring expansion reaction, followed by the formation of the five-membered A-ring via a stereoselective radical cyclization reaction of a neopentyl-type iodide.     

Diastereoselective total synthesis of 8-epigrosheimin

The first diastereoselective total synthesis of 8-epigrosheimin was accomplished relying entirely on substrate-controlled methods. 8-Epigrosheimin, isolated as an amoebicidal and antibiotic compound from Crepis virens, is a multi-chiral-centered guaianolide with a cis-hydroazulene and a trans-annulated γ-butyrolactone ring. Our approach featured that the γ-butyrolactone unit was formed firstly before the construction of the cycloheptane ring system. The key steps of the synthesis involved (1) a stereoselective Mukaiyama aldol addition; (2) an oxidative γ-lactonization; and (3) an intramolecular aldehyde-ene cyclization.     

Asymmetric total syntheses of two phlegmarine-type alkaloids, lycoposerramines-V and -W, newly isolated from Lycopodium serratum

Two new Phlegmarine-type alkaloids, lycoposerramines-V and -W, were isolated from Lycopodium serratum, and their structures including the absolute configuration were established by asymmetric total synthesis involving such key steps as Johnson-Claisen rearrangement, asymmetric allylation, and ring-closing metathesis (RCM)- or SmI(2)-mediated stereoselective piperidine ring construction.     

Stereoselective synthesis of (-)-acanthoic acid

[reaction: see text] The first stereoselective synthesis of (-)-acanthoic acid (1) has been designed and accomplished. Our synthetic plan departs from (-) Wieland-Miesher ketone (7) and calls upon a Diels-Alder cycloaddition reaction for the construction of the C ring of 1. The described synthesis confirms the proposed stereochemistry of 1 and represents an efficient entry into an unexplored class of biologically active diterpenes.     

Synthesis of the C1‐C10 Fragment of Muamvatin

This report delineates our efforts towards the synthesis of a stereochemically well‐defined ketone, the C₁?C₁₀ fragment of muamvatin, the first example of a 2, 4, 6‐trioxaadamantane ring skeletal polypropionate marine natural product, using two non‐aldol variants. i) The Shimizu reaction, a Pd(0) mediated stereoselective epoxy‐ring opening of alkenyl oxiranes, was employed for the stereoselective installation of methyl groups in syn‐fashion and ii) Bode's protocol, a NHC‐mediated reaction on β‐epoxy aldehydes, was utilized for stereoselective construction of methyl and hydroxyl groups in anti‐fashion.     

Stereoselective synthesis of sugar fused β-disubstituted γ-butyro-lactones: C-spiro-glycosides from 1,2-cyclopropanecarboxylated sugars

A stereoselective methodology was developed for the construction of C-spiro-glycosides in two steps involving bromonium ion activated solvolytic ring opening of sugar derived 1,2-cyclopropanecarboxylates followed by a one-pot dehydrohalogenation, intramolecular hetero-Michael addition (IHMA) and ester hydrolysis. The obtained spirocyclic lactols were further converted to enantiomerically pure spirolactones.     

Atom-economic and stereoselective syntheses of the ring a and B subunits of the bryostatins

This article describes chemoselective and atom-economic methods for the stereoselective assembly of the ring A and B subunits of bryostatins. A Ru-catalyzed tandem alkene-alkyne coupling/Michael addition reaction was developed and applied to the synthesis of bryostatin ring B. We explored an acetylide-mediated epoxide-opening/6-exo-dig cyclization route to access the bryostatin ring A, although ring A was eventually furnished through an acid-catalyzed tandem transketalization/ketalization sequence. In addition, a dinuclear zinc-catalyzed methyl vinyl ketone (MVK) aldol strategy was evaluated for the construction of the polyacetate moiety. Utilization of these methods ultimately led to the rapid assembly of the northern bryostatin fragment containing both the ring A and B subunits.     

Stereoselective synthesis of deuterated β-cyclohexenylserine, a biosynthetic intermediate of the salinosporamides

A straightforward, highly stereoselective protocol toward the synthesis of deuterium-labeled (2R,3S,4S)-β-cyclohexenylserine has been developed. Key steps are a Nozaki-Hiyama-Kishi reaction generating the stereogenic centers and a ring-closing metathesis for the construction of the cyclohexenyl ring system. The labeled amino acid was further activated as an SNAc-ester for feeding experiments.     

Epoxide-initiated cationic cyclization of azides: a novel method for the stereoselective construction of 5-hydroxymethyl azabicyclic compounds and application in the stereo- and enantioselective total synthesis of (+)- and (-)-indolizidine 167B and 209D

A novel and general method has been developed for the stereoselective construction of 5-hydroxymethyl azabicyclic ring skeletons based on epoxide-initiated cationic cyclization of azides. The key cyclization reaction was systematically studied with the model compound, 3-(1-oxa-spiro[2.4]hept-4-yl)propyl azide 3a, and EtAlCl(2) was found to be an ideal choice as the catalyst. The generality of this transformation was further tested with different ring sizes, where six- and seven-membered epoxyazides 3b,c underwent smooth cyclization to give 5-hydroxymethyl azepine 4b and 5-hydroxymethyl azocine 4c, respectively, as a single detectable diastereomer. This novel methodology was elegantly applied in the stereoselective total synthesis of indolizidine alkaloids 167B and 209D. Further, the enantioselective total synthesis of natural and unnatural indolizidine alkaloids 167B and 209D was accomplished by using Sharpless asymmetric dihydroxylation as a key step.     

Synthetic studies of halichondrin B, an antitumor polyether macrolide isolated from a marine sponge. 8. Synthesis of the lactone part (C1---C36) via horner-emmons coupling between C1---C15 and C16---C36 fragments and Yamaguchi lactonization

The lactone part (2) of halichondrin B (1) was synthesized by Yamaguchi macrolactonization of the seco-acid (3), which was synthesized via coupling of C1---C15(4) with C16---C36 (5), prepared through stereoselective construction of the E ring starting from C16---C26 (7) and C27---C36 (8).