Stereocontrolled Total Synthesis of (+)‐trans‐Dihydronarciclasine

A highly stereoselective and efficient total synthesis of trans‐dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester–enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six‐ring vinylogous ester intermediate, which is generated from the γ,δ‐unsaturated ester functional group of the Claisen rearrangement product in an efficient three‐step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel–Crafts‐type cyclization to form the B ring via an isocyanate intermediate derived from an N‐Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N‐Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.     

Preparation,Modification, and Evaluation of Cruentaren A and Analogues

An expeditious total synthesis of the highly cytotoxic F‐ATPase inhibitor cruentaren A ( 1 ) is described based on a ring‐closing alkyne metathesis (RCAM) reaction for the formation of the macrocylic ring. Other key transformations comprise a C‐acylation of the benzyl lithium reagent derived from orsellinic acid ester 9 with Weinreb amide 7 , a CBS reduction of the resulting ketone 10 , and a Soderquist propargylation of aldehyde 21 with allenylborane (S)‐ 27 to set the C‐15 chiral center of the required alcohol fragment 25 . The RCAM precursor 33 was assembled by acylation of 25 with acid fluoride 32 , since more conventional methods for ester bond formation were unproductive. Moreover, the choice of the protecting groups, in particular for the secondary alcohol at C‐9, which is prone to engage in translactonization, turned out to be critical; a relatively stable TBDPS ether had to be chosen for this site, which was removed in the final step of the synthesis with aqueous HF since other fluoride sources met with failure. The successful synthetic route was then expanded beyond the natural product, bringing a series of analogues into reach that feature incremental but deep‐seated structural modifications. Three of these fully synthetic compounds turned out to be as or even more cytotoxic than cruentaren A itself against L‐929 mouse fibroblast cells, reaching IC₅₀ values as low as 0.7 ng mL^?1.     

The diazo route to diazonamide A: studies on the tyrosine-derived fragment

Various approaches to the tyrosine-derived fragment of the marine secondary metabolite diazonamide A are described. Initial efforts were focused on the originally proposed structure of the natural product, and a feasibility study established that a model 4-aryltryptamine could be readily prepared. Protected 4-bromotryptamine underwent Pd0-catalyzed coupling with the boronic acid derived from 2-bromophenyl allyl ether by Claisen rearrangement, O-methylation and lithiation-boration. The resulting biaryl was elaborated into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Z-valinamide gave the desired tryptamine-oxazole following cyclodehydration of the intermediate ketoamide. A potential precursor to the benzofuran ring of the original structure of diazonamide A was prepared in eight steps from N-Z-tyrosine tert-butyl ester. Iodination, O-protection and Stille coupling gave the cinnamyl alcohol 25, converted via the bromide into the allyl aryl ether 27. Subsequent Claisen rearrangement and oxidative cleavage of the alkene gave the lactol 29, converted into the desired benzofuranone 31. The revision in the structure of diazonamide A to 2 resulted in the targeting of an alternative tyrosine-derived model benzofuranone 41 synthesized in four steps from N-Z-tyrosine methyl ester 36 by a route involving Claisen rearrangement of cinnamyl ether 37. Poor yields in this sequence prompted an investigation into the intramolecular Heck reaction as a route to benzofuranone 50. Coupling of 3-iodotyrosine 44 with 2-phenylbutenoic acid 48 gave ester 49 that readily underwent intramolecular Heck reaction to give benzofuranone 50, albeit with poor stereocontrol.     

Divergent Total Synthesis of the Tricyclic Marine Alkaloids Lepadiformine,Fasicularin, and Isomers of Polycitorols by Reagent‐Controlled Diastereoselective Reductive Amination

We describe a flexible and divergent route to the pyrrolo‐/pyrido[1,2‐j]quinoline frameworks of tricyclic marine alkaloids via a common intermediate formed by the ester–enolate Claisen rearrangement of a cyclic amino acid allylic ester. We have synthesized the proposed structure of polycitorols and demonstrated that the structure of these alkaloids requires revision. In addition to asymmetric formal syntheses, stereoselective and concise total syntheses of (?)‐lepadiformine and (?)‐fasicularin were also accomplished from simple, commercially available starting materials in a completely substrate‐controlled manner. The key step in these total syntheses was the reagent‐dependent stereoselective reductive amination of the common intermediate to yield either indolizidines 55 a or 55 b . Aziridinium‐mediated carbon homologation of the hindered C‐10 group to the homoallylic group facilitated the synthesis.     

Total Synthesis of (−)‐Apratoxin A, 34‐Epimer,and Its Oxazoline Analogue

A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18‐step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent β‐hydroxyl group at the C35‐position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization of all individual transformations. In the synthesis of 3,7‐dihydroxy‐2,5,8,8‐tetramethylnonanoic acid (Dtena), the three reagent‐controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically‐unfavorable N‐methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf₂O and Ph₃PO‐mediated dehydrative cyclization, and final macrocyclization was achieved between N‐methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereocenters of Dtena and their amino acids.     

Total synthesis of (-)-salicylihalamide

A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B (la, b) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of beta-keto esters 18 and 32 catalyzed by [((S)-BINAP)Ru-Cl2]2. NEt3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the "second-generation" ruthenium carbene complex 24 as the catalyst which bears an imidazol-2-ylidene ligand. The EIZ ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl2-mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper-catalyzed cross-coupling process with the (Z,Z)-configurated carboxamide 42 to form the labile enamide moiety of 1. Compound 42 was derived from a palladium-catalyzed Negishi coupling between butynylzinc chloride and 3-iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.     

Enantioselective (4+2) Annulation of Donor–Acceptor Cyclobutanes by N‐Heterocyclic Carbene Catalysis

Herein we report the enantioselective (4+2) annulation of donor–acceptor cyclobutanes and unsaturated acyl fluorides using N‐heterocyclic carbene catalysis. The reaction allows a 3‐step synthesis of cyclohexyl β‐lactones (25 examples) in excellent chemical yield (most ≥90 %) and stereochemical integrity (all >20:1 d.r., most ≥97:3 e.r.). Mechanistic studies support ester enolate Claisen rearrangement, while derivatizations provide functionalized cyclohexenes and dihydroquinolinones.     

Stereocontrolled Total Synthesis of (+)-trans-Dihydronarciclasine

A highly stereoselective and efficient total synthesis of trans-dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester-enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six-ring vinylogous ester intermediate, which is generated from the γ,δ-unsaturated ester functional group of the Claisen rearrangement product in an efficient three-step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel-Crafts-type cyclization to form the B ring via an isocyanate intermediate derived from an N-Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N-Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.     

Synthesis of Sporochnol A,a Marine Fish Deterrent

Abstract

A synthesis of the methyl ether of the fish‐deterrent sporochnol A is described. The route involves the application of Claisen ortho‐ester rearrangement to generate the key quaternary carbon.     

Highly Efficient Catalysis of Retro‐Claisen Reactions: From a Quinone Derivative to Functionalized Imidazolium Salts

A new and efficient method for the preparation of several imidazolium salts containing an ester group in the C4 position of the aromatic ring through a retro‐Claisen reaction pathway between a quinone derivative and several alcohols is described. This new organic transformation proceeds in the absence of a catalyst, but it is greatly catalyzed by different Lewis acids, especially with AgOAc at a very low catalyst loading and in very short reaction times. The process takes place by the nucleophilic attack of the carbonyl groups by the alcohol functionality, thus promoting a double C?C bond cleavage and C?H and C?O bond formation. This reaction represents the first example of this type between a quinone derivative and alcohols.     

Total Synthesis of Aurantoside G,an N‐β‐Glycosylated 3‐Oligoenoyltetramic Acid from Theonella swinhoei

The first synthesis of a natural N‐glycosylated 3‐acyltetramic acid is reported. Aurantoside G ( 1 g ), a deep‐red metabolite of the marine sponge Theonella swinhoei, is highly delicate in the pure state. It features a chlorinated dodecapentaenoyl side chain at an l ‐asparagine‐derived tetramic acid, the ring nitrogen atom of which is linked to a β‐configured d ‐xylose. The side chain was built through consecutive Wittig and HWE reactions and used to N‐acylate the amino group of an asparaginate that had already been N‐xylosylated through a Fukuyama–Mitsunobu reaction. This N‐acylation step fixes the β‐configuration of the xylose, which is essential for the antifungal activity, but only if the sugar carries bulky, electron‐rich protecting groups such as PMB. In the final step, the heterocycle was closed quantitatively through a basic Lacey–Dieckmann condensation of an entirely unprotected precursor.     

Pteridines,Part CXI,Pteridine‐Based Photoaffinity Probes for Nitric Oxide Synthase and Aromatic Amino Acid Hydroxylases

Various 6‐substituted pteridines and 5,6,7,8‐tetrahydropterins carrying photolabile functions at the side chain (see 7 , 20 – 22 , 34 – 36 , 38 , and 39 ) as well as at the 5‐position (see 27 – 29 ) were synthesized from pterin and from 6‐phenylpterin ( 1 ) and 6‐(hydroxymethyl)pterin ( 10 ). Attachment of the photoaffinity labels via ester bonds required a special protecting‐group strategy based upon acid‐labile (see 30 – 33 ) and β‐eliminating blocking groups (see 17 – 19 ). The 6‐(4‐azidophenyl)pterin ( 7 ) was obtained from 6‐phenylpterin ( 1 ) via intermediates 2 and 4 – 6 , due to the low solubility of simple pterins in general. The pteridine derivatives 21 , 22 , 25 , 26 , 28 , 29 , 32 , 33 , 35 , 36 , 38 , and 39 were screened as inhibitors of neuronal (type I) NO synthase (see Table) from porcine cerebellum, of which 22 , 35 , 36 , and 38 showed interesting inhibitory activity with similar potency and effectiveness.     

Benzylidene Acetal Protecting Group as Carboxylic Acid Surrogate: Synthesis of Functionalized Uronic Acids and Sugar Amino Acids

Direct oxidation of the 4,6‐O‐benzylidene acetal protecting group to C‐6 carboxylic acid has been developed that provides an easy access to a wide range of biologically important and synthetically challenging uronic acid and sugar amino acid derivatives in good yields. The RuCl₃–NaIO₄‐mediated oxidative cleavage method eliminates protection and deprotection steps and the reaction takes place under mild conditions. The dual role of the benzylidene acetal, as a protecting group and source of carboxylic acid, was exploited in the efficient synthesis of six‐carbon sialic acid analogues and disaccharides bearing uronic acids, including glycosaminoglycan analogues.     

Total Synthesis of Ovafolinins A and B: Unique Polycyclic Benzoxepin Lignans through a Cascade Cyclization

Ovafolinins A and B, isolated from Lyonia ovalifolia var. elliptica, are lignans that contain a unique bridged structure containing a penta‐ and tetracyclic benzoxepin and an aryl tetralin. We report the first total synthesis of these natural products in which an acyl‐Claisen rearrangement was initially utilized to construct the lignan backbone with correct relative stereochemistry. Judicious use of a bulky protecting group placed reactive moieties in the correct orientation, thereby resulting in a cascade reaction to form the bridged benzoxepin/aryl tetralin from a linear precursor in a single step. Modification of this route allowed the enantioselective synthesis of (+)‐ovafolinins A and B, which confirmed the absolute stereochemistry, and comparison of optical rotation suggests that these compounds are found as scalemic mixtures in nature.     

Formal synthesis of berkelic acid: a lesson in α-alkylation chemistry

The full details of our enantioselective formal synthesis of the biologically active natural product berkelic acid are described. The insertion of the C-18 methyl group proved challenging, with three different approaches investigated to install the correct stereochemistry. Our initial Horner-Wadsworth-Emmons/oxa-Michael approach to the berkelic acid core proved unsuccessful upon translation to the natural product itself. However, addition of a silyl enol ether to an oxonium ion, followed by a one-pot debenzylation/spiroketalisation/thermodynamic equilibration procedure, afforded the tetracyclic structure of the berkelic acid core as a single diastereoisomer.     

Novel sequential sigmatropic rearrangements of allylic diols: application to the total synthesis of (-)-kainic acid

Sequential sigmatropic rearrangements (Claisen/Claisen and Claisen/Overman) of enantiopure allylic diols are described. The reactions proceeded in complete diastereoselectivity without protecting group manipulations. The sequential Claisen/Overman rearrangement was successfully applied to the total synthesis of (-)-kainic acid.     

One Pot Synthesis of Amphiphilic Hyperbranched Poly-(amino ester)and Its Dynamic Surface Activity

Amphiphilic hyperbranched poly(amino ester)s with hydrophilic multi‐ethoxylated triacrylate backbone and hydrophobic long alkyl side chain were firstly synthesized via one pot Michael addition polymerization. The poly‐(amino ester) could dissolve in cold water and self‐assemble into loose micelle. Under 50–1000 ms bubble, the dynamic surface tension (DST) of the poly(amino ester) aqueous solution (0.5 wt%) still maintained in the range of 32–28 mN/m. The aqueous solutions of poly(amino ester)s with different molecular weights showed the lower critical solution temperature (LCST) in the range of 8–50°C, which could also be tuned by its pH. Capped with hydrophobic groups on the terminal units and partially neutralized with acid, the poly(amino ester)s still kept their stable dynamic surfactant behaviors, indicating promising application.     

A short practical synthesis of 2′-deoxymugineic acid

A short and practical synthesis of 2′-deoxymugineic acid (DMA) has been developed via reductive alkylation with the aldehyde intermediates. No protection of azetidine-2-carboxylic acid was required and the presence of free carboxylic acid function facilitated purification by simple acid and base extractions. Furthermore, the intermediates were conveniently purified by HPLC due to the presence of chromophoric benzyl ester protecting group(s). Hydrogenolysis of the benzyl protecting groups in the final step furnished DMA in overall good yield.     

Synthesis of a novel ether-bridged GM3-lactone analogue as a target for an antibody-based cancer therapy

We describe herein the synthesis of a new analogue of the GM3-lactone containing a cyclic ether moiety. The ether moiety was chosen as a replacement for the regular lactone group since it shows high resemblance with the lactone and is completely stable under biological conditions. The cyclic ether moiety was formed by reduction of the corresponding lactone to give the lactol followed by formation of the S,O-hemiacetal and hydrogenation. In addition, we have prepared haptens with a hexanoic acid moiety, which can be used for the preparation of poly- and monoclonal antibodies after binding to BSA or KLH. This is the first example of an analogue of the GM3-lactone which is stable under hydrolytic conditions in vitro and probably also in vivo. Reaction of lactone 18 with a Red/Al derivative led to the lactol 19 which was transformed into the S,O-hemiacetal 20 using 2,2'-bis(pyridinium) disulfide in quantitative yield. Hydrogenation with Raney Nickel gave 21 from which after removal of the protecting group at C-1a the trichloroacetimidate 25 was prepared. Reaction with azidosphingosine to give 26 followed by reduction of the azido group with NHEt3+[(PhS)3Sn], acylation with stearic acid using EDC and removal of the protecting groups led to the desired ether analogue of GM3 lactone 4. In addition the trichloroacetimidate 25 was glycosidated with 6-hydroxyhexanoic acid methyl ester, which was deprotected to give 29. The compound will be used for the preparation of poly- and monoclonal antibodies after coupling with BSA and KLH.     

Synthesis and properties of hyperbranched polyurethanes,hyperbranched polyurethane copolymers with and without ether and ester groups using blocked isocyanate monomers

Starting from 3,5‐diamino benzoic acid, 2‐hydroxy propyl[3,5‐bis{(benzoxycarbonyl)imino}]benzyl ether, an AB₂‐type blocked isocyanate monomer with flexible ether group, and 2‐hydroxy propyl[3,5‐bis{(benzoxycarbonyl)imino}]benzoate, an AB₂‐type blocked isocyanate monomer with ester group, were synthesized for the first time. Using the same starting compound, 3,5‐bis{(benzoxycarbonyl)imino}benzylalcohol, an AB₂‐type blocked isocyanate monomer, was synthesized through a highly efficient short‐cut route. Step‐growth polymerization of these monomers at individually optimized experimental conditions results in the formation of hyperbranched polyurethanes with and without ether and ester groups. Copolymerizations of these monomers with functionally similar AB monomers were also carried out. The molecular weights of the polymers were determined using GPC and the values (M_w) were found to vary from 1.5 × 10⁴ to 1.2 × 10⁶. While hyperbranched polyurethanes having no ether or ester group were found to be thermally stable up to 217 °C, hyperbranched poly(ether–urethane)s and poly(ester–urethane)s were found to be thermally stable up to 245 and 300 °C, respectively. Glass transition temperature (T_g) of polyurethane was reduced significantly when introducing ether groups into the polymer chain, whereas T_g was not observed even up to 250 °C in the case of poly(ester–urethane). Hyperbranched polyurethanes derived from all the three different AB₂ monomers were soluble in highly polar solvents and the copolymers showed improved solubility. Polyethylene glycol monomethyl ether of molecular weight 550 and decanol were used as end‐capping groups, which were seen to affect the thermal, solution, and solubility properties of polymers. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 3877–3893, 2007