The diazo route to diazonamide A. Studies on the indole bis-oxazole fragment

[structure: see text] Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl compounds in key steps. Thus, 3-bromophenylacetaldehyde is converted into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Boc-valinamide resulted in N-H insertion of the intermediate rhodium carbene to give a ketoamide that readily underwent cyclodehydration to give (S)-2-(1-tert-butoxycarbonylamino)-2-methylpropyl]-5-(3-bromobenzyl)oxazole-4-carboxamide, after ammonolysis of the initially formed ester. This aryl bromide was then coupled to a 3-formyl-indole-4-boronate under Pd catalysis to give the expected biaryl. Subsequent conversion of the aldehyde group into a second alpha-diazo-beta-ketoester gave a substrate for an intramolecular carbene N-H insertion, although attempts to effect this cyclization were unsuccessful. A second approach to an indole bis-oxazole involved an intermolecular rhodium carbene N-H insertion, followed by oxazole formation to give (S)-2-[1-tert-(butoxycarbonylamino)-2-methylpropyl]-5-methyloxazole-4-carboxamide. A further N-H insertion of this carboxmide with the rhodium carbene derived from ethyl 2-diazo-3-[1-(2-nitrobenzenesulfonyl)indol-3-yl]-3-oxopropanoate gave a ketoamide, cyclodehydration of which gave the desired indole bis-oxazole. Finally, the boronate formed from 4-bromotryptamine was coupled to another diazocarbonyl-derived oxazole to give the corresponding biaryl, deprotection and cyclization of which produced a macrocyclic indole-oxazole derivative. Subsequent oxidation and cyclodehydration incorporated the second oxazole and gave the macrocyclic indole bis-oxazole.     

A tyrosine-derived benzofuranone related to diazonamide A

[formula: see text] Cyclization of 8 with PPA followed by MCPBA oxidation affords the benzofuranone 10. Treatment with a chiral chloroformate in the presence of DMAP affords the target benzofuranone 13 via an enol ester 12.     

The diazo route to 2-vinylcyclopropylidenes

2-Vinylcyclopropylidene(2),3-methyl-2-vinylcyclopropylidenes(79,81)and2-(1-propenyl)cyclopropylidenes (95,97) were generated from the corresponding nitrosoureas in methanol at room temperature. The diazo route is initiated by the formation of 2-vinylcyclopropanediazonium ions (e.g.43) which do not undergo 1,3-carbon shifts. No cyclopentenyl products were found in weakly basic methanol where the diazonium ions prevail. Ring opening of the diazonium ions gives pentadienyl cations and products derived therefrom. Delocalisation of the pentadienyl cations was demonstrated by the distribution of deuterium and methyl labels. In the presence of strong base, 1-diazo-2-vinylcyclopropanes (e.g.48) arise by deprotonation of the diazonium ions. Rearrangement of 48 was excluded by independent generation of the potential product, 4-diazocyclopentene (103). Substantial quantities of 3-methoxycyclopentene (108) were obtained from 103, but not from 48. The 2-vinylcyclopropylidenes 2,79 and 95, arising by loss of nitrogen from the corresponding diazo compounds, undergo allene formation and Skattebøl rearrangement competitively. Cis-oriented methyl groups at either C-2(81) or C-2'(97) prevent the Skattebøl rearrangement. The cyclopentenylidenes 3 and 83 yield 4-methoxycyclopentenes (52,86) in excess over cyclopentadiens (4,84). In the presence of methyl vinyl ether, cycloaddition of 3 and electrophilic addition of 3-cyclopentenyl cation (51) occurred in a 1:14 ratio. Stereospecific formation of 52 indicates protonation of a ‘foiled carbene’ (3a) to give a bishomocyclopropenyl ion (51a). Our studies confirm that the various routes to 2-vinylcyclopropylidenes converge at the carbene stage.     

Mechanistic studies on the diazo transfer reaction

The mechanism of the diazo transfer reaction which converts amines to azides has been studied with labeled amino acids and labeled imidazole-1-sulfonyl azides. Retention of amine nitrogen in the amine, and transfer of the two terminal nitrogen atoms of the imidazole-1-sulfonyl azide to the product, were unambiguously established.     

Biomimetic approaches to diazonamide A. Direct synthesis of the indole bis-oxazole fragment by oxidation of a TyrValTrpTrp tetrapeptide

Oxidation of a protected TyrValTrpTrp tetrapeptide results in direct formation of the indole bis-oxazole core of diazonamide A.     

Synthetic studies toward diazonamide A. A novel approach for polyoxazole synthesis

[Reaction in text]The indole-bisoxazole fragment of diazonamide A was prepared by a Chan-type rearrangement of a tertiary amide. This approach represents a remarkably direct strategy for polyoxazole synthesis.     

Biosynthetic studies on the azinomycins: the pathway to the naphthoate fragment

Isotopically labelled intermediates in a proposed biosynthesis of the naphthoate fragment of azinomycin B have been made and successfully incorporated by the azinomycin producing organism.     

Model studies directed toward the avermectins: A route to the oxahydrindene subunit

A Mlchael-Aldol sequence of an enoate-ketone triggered by the action of an aluminum thiophenoxy “ate” complex leads to the oxahydrindene subunit of the avermectins.     

Oxidative rearrangement of indoles: a new approach to the EFHG-tetracyclic core of diazonamide A

A new approach to the ring EFHG-tetracyclic core fragment of the marine secondary metabolite diazonamide A is described. The route is based on the oxidative rearrangement of 3-arylindole-2-carboxylates. Thus, a range of 3-arylindole-2-carboxylates (3, 8) underwent rearrangement to the corresponding 3,3-disubstituted oxindoles (4, 9) with migration of the ester group upon treatment with tert-butyl hypochlorite followed by acid. The oxindoles 9 with a 3-[2-(4-methoxybenzyloxy)]phenyl substituent underwent cyclization to the tetracyclic aminals 11 following N-protection, reduction, and treatment with methanesulfonic anhydride. The methodology was applied to the tyrosine-indole derivative 17 to give the EFHG-tetracyclic core of diazonamide A.     

A short route to chiral synthons for eicosanoids with a hydropyran fragment

Institute of Organic Chemistry, Ural Branch, Russian Academy of Sciences, 450054 Ufa. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 5, pp. 1233–1234, May, 1992.     

A concise route to the C3–C23 fragment of the macrolide palmerolide A

A concise route to the C3–C23 part of the macrolide palmerolide A was developed. This part features the 7,10,11-trihydroxy sector containing the 8E-double bond as well as the 14,16-diene subunit. The stereocenter at C-7 originated from a Noyori reduction on alkynone 8. The substrate 16 containing an enyne was obtained via a Claisen rearrangement. The vicinal diol at C10,C11 was created by a Sharpless asymmetric dihydroxylation. After selective protecting group manipulations the propargylic alcohol was reduced with Red-Al to the E-alkylic alcohol 26. The conjugated diene in the fragment 40 resulted from a Stille cross-coupling reaction between the vinylstannane derived from alkyne 30 and the vinyl iodide 39. The latter could conveniently be prepared by an aldol/Wittig strategy.     

Synthetic studies on antascomicin A: construction of the C18-C34 fragment

Stereoselective synthesis of the C18-C34 fragment of antascomicin A is described. Construction of the C27-C34 carbocycle moiety was achieved via catalytic Ferrier carbocylization and Johnson-Claisen rearrangement, which was converted to iodide 2 by use of asymmetric alkylation and Sharpless epoxidation as key transformations. Coupling of iodide 2 and sulfone 3 furnished the C18-C34 fragment.     

Rhodium-catalyzed synthesis of a C(3) disubstituted oxindole: an approach to diazonamide A

A two step synthesis of a C(3) disubstituted oxindoles via the rhodium(II)-catalyzed coupling of diazoketone (6) and 3-methyloxindole (9) is reported.     

Studies toward diazonamide A: initial synthetic forays directed toward the originally proposed structure

A brief introduction into the chemistry of diazonamide A (1) is followed by first-generation sequences to access the originally proposed structure for this unusual marine natural product. These explorations identified a route capable of delivering a model compound possessing the complete heteroaromatic core of the natural product, highlighting in the process several unanticipated synthetic challenges which led both to new methodology as well as an improved synthetic plan that was successfully applied to fully functionalized intermediates.     

Synthesis of C(3) benzofuran-derived bisaryl quaternary centers: approaches to diazonamide A

[reaction: see text] Two complementary strategies for the synthesis of the diazonamide A bisaryl quaternary center are described. The first strategy relies upon an extremely facile tandem cyclopropanation/ring-opening sequence, which has proven amenable to chiral catalysis to provide enantioenriched material. The second strategy relies upon a more concise alkylation route ideal for material advancement.     

A general route to 4-imidazolyl-containing multidentate ligands for biomimetic studies

[formula: see text] 4-iodo-1-tritylimidazole undergoes magnesium-iodine exchange with a Grignard reagent to give selectively the 4-magnesioimidazole derivative, which reacts with esters to form a variety of poly-4-imidazolyl carbinol compounds in 40-79% yields. A wide range of bi-, tri-, and pentadentate ligands featuring 4-substituted imidazole units have been efficiently synthesized.     

Remarkable wavelength-dependent photoreactions of the bis(diazo) ketone having inequivalent diazo groups: studies in fluid solutions and in low-temperature matrixes

The photoreactions of the bis(diazo) ketone 11, which has two inequivalent diazo groups, have been investigated in solutions at room temperature and in matrixes at 12 K. Irradiation of 11 in benzene containing methanol gave a mixture of the spironorcaradiene 13 and the diazo ketone 17 as primary isolable photoproducts. The former 13 originated from the diazo ketene 20, which was formed from the initial extrusion of N(2) from the 2-position of 11, while the latter product 17 was derived from the diazo ketene 24 which was generated by the initial decomposition of the diazo group at the 4-position of 11. The product distribution was remarkably dependent upon the excitation wavelength: 13 was predominantly obtained in the photolysis with light of >350 nm, while the irradiation with long-wavelength light (>420 nm) exclusively gave 17. The consistent wavelength effects were observed in photoreactions in an Ar matrix at 12 K. The irradiation of 11 matrix-isolated in Ar with light of >350 nm afforded 20 in preference to the isomer 24 as the first-formed intermediates, while 24 was mainly obtained in the long-wavelength irradiation (>420 nm). On the basis of these experimental data, we conclude that the short-wavelength irradiation of 11 causes a preferential cleavage of the diazo group at the 2-position and that the selective extrusion of N(2) from the 4-position is practically achieved by the irradiation with long-wavelength light. The reason for the selective cleavage of the two inequivalent diazo groups of 11 is discussed on the basis of theoretical calculations with the PM3 CI method.     

The convenient route to cd fragment for the synthesis of vitamin D3 relatives

The efficient degradation of $\text{1}$ to the α-methylene ketone $\text{4}$ is described. Compound $\text{4}$ was then converted to the allylic alcohol $\text{8a}$ - the precursor of vitamin D³ relatives.