Showing papers on "Total synthesis published in 1994"

Facile synthesis of homogeneous artificial proteins

Abstract: A new approach, involving oxime formation, is described for the synthesis of stable macromolecules of defined structure and is exemplified with polypeptides. In a first step, purified polypeptide fragments, carrying either aldehyde or aminooxy groups but devoid of protecting groups, are prepared. In a second step, these fragments spontaneously self-assemble on an appropriate synthetic template under very mild conditions through formation of oxime bonds. The resulting oximes are stable in water at room temperature at pH 2-7. One of the compounds made, the covalent structure of which was defined by electrospray mass spectrometry [observed MW 19 916.61±3.05 D; calculated MW 19 916.10(average isotopic composition)], would seem to be the largest artificial protein ever made, in pure form in good yield, by controlled total synthesis

Total synthesis of taxol

Abstract: The present invention provides two basic routes for the total synthesis of taxol having the structure: ##STR1## The present invention also provides the intermediates produced in the above processes, processes for synthesizing these intermediates as well as analogs to taxol. Both the intermediates and analogs to taxol may prove to be valuable anticancer agents.

Total synthesis of the gilvocarcins

Abstract: Convergent total syntheses of the aryl C-glycoside antibiotics gilvocarcin M (1a) and gilvocarcin V (1b) have been accomplished. Key steps include (1) contrasteric coupling of D-fucofuranosyl acetate 27 with iodophenol 26, which was achieved by employing Cp 2 HfCl 2 -AgClO 4 or the related organosilane-derived reagents, and (2) regioselective [4+2] cycloaddition of a sugar-bearing benzyne species, generated by treatment of o-haloaryl triflate 33-α with n-BuLi at -78 o C, with 2-methoxyfuran (6). The naphthol derivative 34, selectively synthesized by these two tactics, served as the common intermediate to both 1a and 1b. Acylation of 34 with benzoic acid derivative 39 followed by Pd-catalyzed cyclization gave gilvocarcin M (1a), and a similar synthetic sequence starting with the coupling of 34 with 49 led to the first total synthesis of gilvocarcin V (1b)

Application of intramolecular Heck reactions for forming congested quaternary carbon centers in complex molecule total synthesis

Abstract: Palladium-catalyzed cyclizations of aryl halides, vinyl halides and vinyl mflates with tethered alkenes have proven to be powerful reactions for forging congested quaternary carbon centers in complex organic molecules. I'n some cases, the use of enantiopure ligands allows the new quaternary center to be formed with excellent enantioselectivity. The scope, stereochemical nuances and power of this organometallic chemistry is illustrated by briefly considering our recent total syntheses of (*)- pretazettine, (2)-tazettine, (-)- and (+)-morphine, (-)- and (+)-physostigmine, (&)- scopadulcic acid A and (*)-scopadulcic acid B.

Synthesis of C-aryl glycosides

Abstract: Methods for the preparation of C-aryl glycosides, and their application to the total synthesis of naturally occurring C-aryl glycosides, are reviewed

Total Synthesis and Determination of the Absolute Configuration of Epibatidine

Abstract: The synthesis of (+)- and (-)-epibatidine (exo-2-(2-chloropyridin-5-yl)-7-azabicyclo[2.2.1]heptane) via reaction of 5-lithio-2-chloropyridine with (+)- and (-)-N-BOC-7-azabicyclo [2.2.1]heptan-2-one is described. The absolute configuration of the natural product is shown to be 1R,2R,4S

Total synthesis of discodermolide

Abstract: Novel compounds of formulae (2) and (13> and the enantiomeric and diastereoisomeric forms thereof are disclosed as are methods for their preparation and novel intermediates used in such methods. Their use in the total synthesis of a compound of formula (1> and enantiomeric and diastereoismeric forms thereof is disclosed. Also claimed are various intermediates prepared in synthesising (1) from (2) and (13).

Total Synthesis of (-)-Balanol

Abstract: (-)-Balanol, a fungal metabolite with potent protein kinase C inhibitory properties, has been prepared in a total synthesis which makes use of an anionic homo-Fries rearrangement approach to the benzophenone subunit and in which the azepane subunit is obtained from (2S,3R)-3-hydroxyly- sine

Total Synthesis of (+)-Lactacystin from (R)-Glutamate

Abstract: The discovery by dmura' of (+)-lactacystin (1) in Streptomycessp. OM-65 19 and the finding that it possesses neurotrophic activity have created much excitement, since the role of neurotrophic proteins, such as nerve growth factors (NGFs), in diseases is the center of much current interest.2 This substance consists of two a-amino acids, (R)-N-acetylcysteine and a novel pyroglutamic acid derivative 2. The combination of biological activity and the unique structure of lactacystin encouraged us to develop a synthesis which could permit variations of both the substituents and their stereochemistry. During the course of our work two elegant syntheses were r e p ~ r t e d , ~ . ~ which are strategically different from our route. The key reaction in our synthesis involves the stereoselective aldol reaction of a siloxypyrrole, readily available from pyroglutamate, with an aldehyde, thereby assembling the quaternary center and secondary alcohol in the correct stereochemical form, Scheme 1. The bicyclic oxazolidine 3 was prepared from (R)-glutamic acid in three steps (57%)5 and was elaborated to the unsaturated derivative 4 by sequential methylation6 and selenenylation/ozonolysis (65%, Scheme 2). The key siloxypyrrole 5 was obtained as a crystalline solid (89%) by treatment with TBSOTf and 2,6-lutidine.' The aldol reaction of 5 with isobutyraldehyde was achieved at -78 OC in ether in the presence of 2 equiv of SnC14 to afford 68 and its secondary alcohol epimers in the ratio 9: 1. The major isomer 6 was obtained as a crystalline solid after chromatography (55% yield). The surprising *-facial selectivity observed here, i.e., addition to the same face as the phenyl substituent, was revealed by X-ray crystallography of thep-bromobenzoate derivative of er1t-6.~ Use of other Lewis acids and solvents led to the formation of other isomers at the quaternary and secondary alcohol centers,1° thereby permitting access to these substances. Following acetylation 7 was converted to the diol 8 as a single isomer (87%) by osmylation (OsO,, N-methylmorpholine N-oxide). The tertiary hydroxyl group was removed via the cyclic thiocarbonate with Bu3SnH in

A six-step synthesis of (±) camptothecin

Abstract: A six-step synthesis of (±)-camptothecin has been achieved starting from 2-methoxypyridine and 2-bromoquinoline

Total Synthesis of (-)-Grayanotoxin III

Abstract: Total synthesis of (-)-grayanotoxin III (3), a unique tetracyclic diterpene isolated from the leaves of various plants of the family Ericaceae, has been successfully accomplished featuring the highly stereoselective cyclization reactions induced by SmI 2

Chemistry of Cyclic Tautomers of Tryptophan: Formation of a Quaternary Center at C3a and Total Synthesis of the Marine Alkaloid (+)-ent-Debromoflustramine B

Abstract: A diastereoselective synthesis of the unnatural (+)-enantiomer of the marine alkaloid (-)-debromoflustramine B (1) from a cyclic tautomer (9) of L-tryptophan is described. The optical rotation of the synthetic 1 is opposite to that of the natural material enabling the configuration of the natural product to be established as 3aS,8R. As natural flustramine B has been converted to (-)-debromoflustramine B its absolute configuration may also be set as 3aS,8aR. The synthetic scheme involves radical bromination of 9 at C3a followed by allylation, at C3a, with allyltributyltin to give 21. The allyl group is then converted to the C3a prenyl derivative 23 by oxidative cleavage and Wittig reaction. The remainder of the synthesis involves removal of the now extraneous carbomethoxy group from C2 and selective removal of the two nitrogen protecting groups and alkylation of the resulting amines. Oxidation of 9 with ceric ammonium nitrate to give mixtures of the C3a nitrato- and hydroxy-derivatives 18 and 19 is also described

Stereocontrolled Elaboration of Quaternary Carbon Centers through the Asymmetric Michael Reaction Using Chiral Imines: Enantioselective Synthesis of (+)-Aspidospermidine

Abstract: An enantioselective synthesis of (+)-aspidospermidine (1b) has been developed. The key strategic element was the stereocontrolled elaboration of quaternary carbon centers through the asymmetric Michael reaction, using chiral imines under neutral conditions. Thus, addition of imine 21, prepared from 2-ethylcyclohexanone and (R)-1-phenylethylamine, to methyl acrylate, led to cyclohexanone (S)-20 with 90% stereoselectivity (Scheme 3). The latter compound was then converted in sir steps into dione 19 (Chart 6). Synthesis of [ABC]-type tricyclic carbazolone 18 was next accomplished, starting from this dione, by using the indole synthesis protocol developed by Suzuki. Critical to the success of this approach was the evolution, after extensive experimentation, of an efficient sequence for assembing D ring to carbazolone 18, having controlled during the events the natural, cis CD ring junction. Thus, treatment of alcohol 57 with trifuoroacetic acid led to tetracycle 58 obtained as a single isomer with 94% yield. The intramolecular capture of a putative intermediary iminium ion, as illustrated in 52, by the carbamate nitrogen atom of 57 has been evoked to rationalize the observed stereoselectivity. The strategy we have adopted for the construction of the fifth E ring of 1b was in fact the methodology proposed by Magnus, based on an intramolecular Pummerer rearrangement. Thus, synthesis of (+)-aspidospermidine (1b) has been avhieved by a linear sequence of 22 chemical operations, starting with 2-ethylcyclohexanone, with an overall yield of 2.7%

Total Synthesis of Uleine-Type and Strychnos Alkaloids through a Common Intermediate

Abstract: A stereoselective total synthesis of the alkaloids of the uleine group, dasycarpidone, dasycarpidol, and nordasycarpidone, has been accompli- shed from the tetracyclic intermediate (1), which has been prepared by two alternative routes, either by Fischer indolization of 2-azabicyclo- [3.3.1]nonanone (9) or, more efficiently, by stereocontrolled cycliza- tion of 2-[(2-cyano-3-ethyl-4-piperidyl)methyl]indoles (24a) and (24b). From the same tetracyclic intermediate (1), the Strychnos alkaloid tu- botaiwine was also synthesized, the key step being the construction of the quaternary spiranic center by cyclization of a thionium ion upon the indole β-position

Synthetic Studies of the Pyrroloquinoline Nucleus of the Makaluvamine Alkaloids. Synthesis of the Topoisomerase II Inhibitor Makaluvamine D

Abstract: A new synthesis of the pyrrolo[4,3,2-de]quinoline system characteristic of a class of marine alkaloids which includes the prianosins, discorhabdins, and other antineoplastic agents has been developed. The approach is exemplified in a total synthesis of makluvamine D, a topoisomcrase II inhibitor isolated from the sponge Zyxxya cf. marsailis. The route begins with a Fischer indole synthesis employing (2,3-dimethoxyphenyl)hydrazine (29) and dihydrofuran, and the resulting tryptophol 32 is protected as its ditosylate 34. Nitration at C4 of the indole, followed by reduction and cyclization, affords the tricycle 41, which is oxidized to the iminoquinone 42 with ceric ammonium nitrate. Replacement of the C7 methoxy substituent of the pyrroloquinoline by tryptamine could only be effected via the salt 42 and, after cleavage of the N-tosyl group followed by treatment with trifluoroacetic acid, gives makaluvamine D (3), which was isolated as its trifluoroacetate 48. Exposure of iminoquinone 42 to sodium azide unexpectedly produced the fully unsaturated pyrroloquinoline 44

Convergent Synthesis of the Polyene Macrolide (-)-Roxaticin

Abstract: (-)-Roxaticin has been synthesized from polyol tetraacetonide 5, which was prepared by a threefold convergent route. Each of the optically pure building blocks (2, 3, and 4) was prepared using a Noyori asymmetric hydrogenation. Sequential alkylation of dibromide 3 with cyanohydrin acetonides 2 and 4 followed by stereoselective reductive decyanation gave tetraacetonide 5. The initial approach to roxaticin using a 1-methylcyclopropyl ether in a key protection step was unsuccessful due to the instability of the polyene chain to oxydative deprotection. A 1,3-benzodithiolan-2-yl (BDT) ether performed well in a model study and was used in the roxaticin system. Protection of the roxaticin precursor as a BDT ether followed by elaboration of the polyene using Wollenberg's method gave a tetraenal. The macrocyclic ring was closed using an intramolecular Horner-Emmons Wittig reaction, and acid-catalyzed deprotection completed the synthesis of roxaticin. Our synthesis of roxaticin illustrates a first generation approach to the highly convergent synthesis of polyene macrolide antibiotics that should ultimately by useful for preparing stereochemical and structural analogs

A remarkable substituent effect on the enantioselectivity of tandem asymmetric epoxidation and enantiospecific ring expansion of cyclopropylidene alcohols: a new enantiocontrolled synthesis of (-)-debromoaplysin and (-)-aplysin

Abstract: A remarkable substituent effect by the tert-butyldimethylsiloxy group on the enantioselectivity of the tandem asymmetric epoxidation and enantiospecific ring expansion of 2-[2-(tert-butyldimethylsiloxy)-4-methylphenyl]-2-cyclopropylideneethanol (18), affording (S)-(-)-2-[2-(tert-butyldimethylsiloxy)-4-methylphenyl]-2-hydroxymethylcyclobutanone (21) in high yield and high enantiomeric excess, was observed. This enabled us to accomplish a concise and highly enantioselective total synthesis of (-)-debromoaplysin (2) and (-)-aplysin (1), providing a new and general strategy for the enantioselective synthesis of biologically important substances having the dihydrobenzofuran framework

Microbial oxidation of aromatics in enantiocontrolled synthesis. 2. Rational design of aza sugars (endo-nitrogenous). Total synthesis of +-kifunensine, mannojirimycin, and other glycosidase inhibitors.

Abstract: A general method of synthesis for lactones and lactams related to carbohydrates has been developed that relies on the biocatalyticgeneration of 1-chloro-2,3-dihydroxycyclohexa-4,6-diene (l), obtained in excellent yield by fermentation of chlorobenzene with Pseudomonasputida 39D, followed by further functionalization to nitrogen-substituted cyclitols. These amino or azido cyclitols of type 15 are then subjected to controlled ozonolysis, which yields either lactones such as 27 or lactams containing five-membered (28) or six-membered (20 and 23) rings. Such compounds are useful intermediates for the preparation of aza sugars. Mannojirimycin (84 has been synthesized in seven steps from chlorobenzene. Kifunensine (7) has been prepared in 11 steps from chlorobenzene following an intersection with Hashimoto's procedure. Full experimental and spectral details are provided for all compounds. The potential of this general method and implications of the disclosed design features in the field of amino sugar and aza sugar synthesis are indicated.

A formal total synthesis of the ACE inhibitor K-13. An application of arene-ruthenium chemistry to complex chemical synthesis

Abstract: Stoichiometric ruthenium activation of 4-chlorophenylalanine derivatives toward nucleophilic substitution, using phenoxide nucleophiles that are derived from protected dipeptides, allowed the formation of isodityrosine derivatives that are synthetic precursors to the ACE inhibitor K-13. An evaluation of carboxyl blocking groups revealed that a 2-bromoethyl ester is the most useful in terms of its compatibility with ruthenium complexation and subsequent nucleophile addition but that its removal is problematic. Conversion to iodoethyl ester using Finkelstein reaction conditions, in the presence of the peptide and amino acid functionality, provided a solution to this problem, since the iodoethyl group was easily removed on treatment with samarium diiodide