Syntheses of c20 gibberellin a36 and a37 methyl esters from gibberellic acid

Gibberellic acid 1 has been stereospecifically transformed into the methyl esters of the C₂₀ gibberellins A₃₆4 and A₃₇5 through a sequence which features three concurrent reductive processes and a novel oxidative cleavage of a ketone enolate.     

Photosensitive protection of carboxyl group and the synthesis of three o-methyl derivatives of gibberellin a3

The methylation of p-methoxyphenacyl ester of gibberellin A₃ (5) and its isomeric monoacetates 6, 7 followed by the removal of p-methoxyphenacyl group gives rise to 3,13-O-dimethylgibberellin A₃14 and to the isomeric O-acetyl-O-methyl-derivatives 15 and 16; the latter afford 3-O-methylgibberellin A₃(17) and 13-O-methylgibberellin A₃18 upon Zemplén deacetylation. The removal of p-methoxyphenacyl group can be achieved either upon photolysis in abs ethanol or with zinc-acetic acid. This protective group survives the conditions of Koenigs-Knorr synthesis as well as oxidation with manganese dioxide. The limitations of this way of protecting the carboxyl group can be seen on the example of the enone ester 20.     

Total synthesis of gibberellin A4

A general approach to the preparation of 13-deoxy C₁₉ gibberellins has been established with the total synthesis of (±) gibberellin A₄ ($\text{3}$).     

Stereocontrolled synthesis of gibberellin A19 from gibberellic acid

The biosynthetically important C-20 gibberellin, gibberellin A₁₉5, has been prepared from the readily obtained C-19 gibberellin, gibberellic acid 8, by means of an efficient stereocontrolled ten step sequence.     

Synthesis of gibberellins A8 and A56 from gibberellin A3

A mixture of gibberellin A₃ derivatives with 1(10)-ene-2β,3β-diol and 1(10)-ene-2α,3β-diol (2:5) groups, readily obtained from gibberellin A₃, has been used for a new and simple synthesis of gibberellin A₈ and its esters. The hydrolysis of GA₃ and the iodolactonization of a mixture of the 2-epimers was carried out in aqueous solution in a single flask, as also was a synthesis of GA₅₆ from GA₃ by a method that we have modified. The mixture of 1β-iodides of GA₈ and GA₅₆ was separated by chromatography on SiO₂ in the form of methyl or p-bromophenacyl esters which were then deiodinated and the methyl or p-bromphenacyl ester of GA₈ was isolated. Free GA₈ was obtained by the dephenylation of the latter ester. By two-dimensional NMR spectroscopy we succeeded in assigning all the signals in the¹³C and¹H NMR spectra of the methyl esters of GA₈ and GA₅₆. In an attempt to obtain GA₅ methyl ester by the action of trimethylchlorosilane/sodium iodide on the 2α,3β-diol system in GA₅₆ methyl ester, the 8,13-epimer of the latter was formed, the structure of its molecule being established from the results of X-ray structural analysis.     

The mechamism of action of vitamin B12

A novel rearrangement reaction is introduced as a model for the rearrangement of methylitaconic acid (III) to α-methyleneglutaric acid (IV), one of three enzyme catalyzed, coenzyme B₁₂-dependent, carbonskeleton rearrangements whose mechanism has been a source of puzzlement for many years. The key feature of the new model is the direct attachment of the substrate, methylitaconic acid, to the cobalt atom of vitamin B₁₂ This was accomplished by reacting butadiene-2,3-decarboxylic acid with hydrobromic acid generating bromomethylitaconic acid (VIII). Use of two moles of hydrobromic acid yielded bis-2,3-(bromomethyl)succinic acid (IX). Reaction of the monobromide VIII with vitamin B_12s did not yield the desired carbon-cobalt bonded adduct. Instead, the lactone ηa- methylene-γbutyrolactone-β-carboxylic acid (X) was formed. Accordingly, the ester, dimethyl bromomethylitaconate (XIa), was reacted with vitamin B_12s and yielded the carbon-cobalt bonded adduct XIIa. Bis-trimethylsilyl bromomethylitaconate did not yield an adduct when reacted with vitamin B_12s, but bis-tetrahydropyranyl bromomethylitaconate (XIb) did yield the adduct XIIb. The ester cobalamin XIIb undergoes spontaneous decomposition at room temperature, in aqueous solution, at pH 8 and in the dark - biochemically ideal circumstances - yielding a mixture of butadiene-2,3-decarboxylic acid (VII), methylitaconic acid (III) and α- methyleneglutaric acid (IV). The presence of the latter indicates that a skeletal change has taken place in a way which mimics the enzymatic reaction. This is the first non-enzymic model in this carbon-skeleton rearrangement series. The methyl ester cobalamin XIIa was stable in the dark but did decompose on irradiation with a sunlamp to butadiene-2,3decarboxylic acid (VII) and methylitaconic acid (III). No α-methyleneglutaric acid IV was observed in the latter reaction.Authentic methylitaconic acid (III) was prepared by alkylation of triethyl prop-2-ene-l,l,2-tricarboxylate (XIII) with methyl iodide followed by hydrolysis and decarboxylation. The lactone X and lactone α-methyl-γ-butyrolactone-β-carboxylic acid (XVI) were prepared by condensing the triester XIII with formaldehyde, hydrolyzing the lactone diester XV to the lactone X and hydrogenating to the saturated lactone XVI.     

Photochemische reaktionen—XXV : Photochemische synthese von ring A-annelierten gibberellinen der GA1-reihe

The photochemical [2 + 2]-cycloaddition of ethylene and tetramethylethylene to 3-dehydro gibberellin A₃ (1) under n → π^*-excitation conditions has been investigated. The reaction leads to a 3 : 1 ratio of the cis-fused α- and β-cyclobutane annelated epimers 3 and 5 as well as 18 and 20 in 70 and 86% yield, respectively, besides small amounts of the phenolic acid 22 and dimeric material. NaBH₄-reduction of 3 gives stereospecifically the 3α-hydroxy compound 7 whereas the 1β,2β-epimer 5 yields the corresponding ring A annelated gibberellin A₁ analogues 12 and 16 in a 6:1 ratio. The constitution and stereochemistry of the products are deduced by physical methods and some mechanistical aspects discussed on the basis of qualitative quenching experiments.     

Acidic ent-kauranoids from the metabolism of ent-kaura-2,16-dien-19-ol in gibberella fujikuroi

Three acidic ent-kauranoid metabolites have been obtained as the methyl esters (7, 8, and 9) from incubation of the [17-¹⁴C]-labelled dienol (1) with Gibberella fujikuroi. Spectroscopic studies of the triol ester (7) and chemical degradation of B-ring cleaved products establish the assigned structure (7). The structures of the other two metabolite esters are indicated to be 8 and 9 from the spectroscopic data.     

Photochemische reaktionen—XXXIII: Molekular- und kristallstruktur eines photoprodukts aus gibberelun C

In connection with studies concerning the photochemistry of carbonyl gibberellins, the structure of a ring D seco photoproduct 1 obtained upon UV irradiation of gibberellin C has been established by X-ray analysis and the molecular packing determined. The lattice parameters are a=b=11.935 Å and c=31.717 Å; the space group is P4₃2₁2. The final discrepancy factor R was 0.063.     

Mass spectrometry of natural products: VIII—Mass spectrometric studies of ring a saturated gibberellins

The fragmentation behaviour of gibberellin A₁ methyl ester and gibberellin C methyl ester has been studied by means of positive and negative ion mass spectrometry, high resolution techniques and metastable ion transitions. The results obtained allow a mass spectrometric distinction to be made between both structural types.     

Radical addition of RFI to alkenylsuccinic anhydrides and gem-substituted alkenyl triesters : Zinc and radical induced, or spontaneous radical cyclization, of the δ-iodoalkanoic esters to γ-lactones

Radical addition of R_FI to alkenylsuccinic anhydrides affords ω-(perfluoroalkyl)-δ-iodoalkyl-2-butane-1,4-dioc acid anhydrides, and these adducts are reductively dehalogenated and esterified by zinc and acid in ethanol without lactonization. However, the R_FI adducts react with KOH in ethanol to give the alkenyl half esters (but no γ-lactone), which convert to the γ-lactones by acid catalysis. When treated with water, ethanol, Zn and 48% HBr, the R_FI adduct from but-3-en-2-yl-succinic anhydride converts to the iodo half ester, R_FCH₂CHICH(CH₃)CH(CO₂H)CH₂CO₂Et, which undergoes Zn induced (S_Hi) conversion to γ-lactone. R_FI (AIBN) and the triester CH₂CHCH₂C(CO₂Et)₂CH₂CO₂Et yield R_FCH₂CHICH₂C(CO₂Et)₂CH₂CO₂Et (95%). When heated to 140 °C, the adduct loses iodoethane.and cyclizes to diester γ-lactones (94%). With benzoyl peroxide, R_FI and the triester at 99 °C, spontaneous radical cyclization of the adduct to lactone occurs. Evidently, the gem-disubstituted triester readily forms a five-membered lactone as a consequence of steric compression in the open chain form.     

Practical method for the synthesis of (R)-homopipecolinic acid and (R)-homoproline esters from ω-chloroalkanoic acids and available chiral amines

A practical synthesis of (R)-homopipecolinic acid methyl ester 1 and (R)-homoproline methyl ester 2 was performed utilizing (i) a direct intramolecular cyclization of ω-chloro-β-enamino esters 11 and 12, which were prepared from available (S)-1-phenylethylamine or (S)-1-(1-naphthyl)ethylamine and ω-chloro-β-keto esters 5 and 10, respectively and (ii) a highly diastereoselective NaBH₄ reduction followed by hydrogenolysis. The present method is a short-step process using inexpensive and readily available substrates and reagents with fewer wasted materials.     

Gibberellins and substances related to them

Summary 1. Column and thin-layer chromatography have been used to analyze the metabolite composition of the culture liquid ofFusarium moniliforme. 2. On fermentation in a medium containing sunflower oil and ammonium nitrate, the content of gibberellins of the A₃-A₁ group was 650–680 mg/l, of the gibberellins of the A₄-A₇ group 85–90 mg/l, and of gibberellin A₉ about 5 mg/l.Khimiya Prirodnykh Soedinenii, Vol. 2, No. 1, pp. 55–58, 1966     

Synthesis of 1-fluoroindan-1-carboxylic acid (FICA) and its properties as a chiral derivatizing agent

1-Fluoroindan-1-carboxylic acid (FICA) (1) was designed and synthesized as its methyl ester (FICA Me ester) (4) in order to develop an efficient chiral derivatizing agent (CDA) which excels α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) in capability. FICA Me ester (4) was prepared by fluorination of methyl 1-hydroxyindan-1-carboxylate (3) with (diethylamino)sulfur trifluoride (DAST) and derived to the esters of racemic secondary alcohols by ester exchange reaction. The resulting Δδ_F value was large in the case of 2-butyl ester of FICA (5a), whereas not detectable in the case of the corresponding MTPA ester (6a). The magnitude of the Δδ_H values was similar to that of MTPA esters. The diastereomers of (R)-(−)-8-phenylmenthyl ester of FICA (5i) was separated and their ¹H NMR analyses revealed that the concept of the modified Mosher's method was successfully applied to 5i.     

Neighbouring group participation in the reaction of 7-oxo-ent-kaur-16-ene derivatives with diacetoxyiodobenzene. Synthesis of gibberellin analogues

The reaction of different 7-oxo-ent-kaur-16-ene derivatives with diacetoxyiodobenzene has been evaluated for the preparation of gibberellin analogues. Thus, the reaction of 7-oxo-ent-kaur-16-en-18-oic acid methyl ester (3) with this reagent afforded 4-epi-GA₁₂ dimethyl ester (6). This reaction constitutes a good procedure for the preparation of this type of compounds. In some cases, alternative reactions that led to the introduction in the substrate of a conjugated 5,6-double bond or to the formation of a ketal at the 6-position were also produced. The formation of these compounds, or of gibberellin analogues, depends on the neighbouring group participation of the different C-18 and C-19 substituents at C-4.     

Some diterpenes from the sea pen stylatula SP.

The sea pen Stylatula sp. from the Gulf of California contained one major and several minor metabolites. The structure of stylatulide (2), the major metabolite, has been reported previously. In this paper, the structural elucidations of four minor metabolites, 17-epi-stylatulide (13), the lactone 14, the primary alcohol 15 and related methyl ester 17 are described. We have described several reactions of stylatulide (2) and its derivatives which illustrate the complexity of reactions on these compounds.     

A new route for synthesizing cholesterol analogs with fluorocarbon side chains and their liquid-crystalline aliphatic esters

A new and efficient route has been developed to synthesize 17β-(1-methyl-3-perfluoroalkyl)propyl-3β-androsterol (1) in nine steps from hyodeoxycholic acid via selective addition of 1-perfluoroalkyl iodide to 24-norchola-5,22-dien-3β-ol. From (1), the first series of steroidal liquid crystalline aliphatic esters (smectic A) with fluorocarbon side chains has been prepared.     

Novel synthetic strategy toward abietane and podocarpane-type diterpenes from (−)-sclareol: synthesis of the antitumor (+)-7-deoxynimbidiol

A new route to abietane and podocarpane-type terpenoids from labdane diterpenes is reported. The key step is the transformation of β-ketoester 9 into the corresponding O-acetylsalicylate ester 18, via a manganese(III)-based oxidative free-radical cyclization carried out in Ac₂O. Utilizing this, the synthesis of the antitumor (+)-7-deoxynimbidiol (5) from (−)-sclareol (11) has been achieved. (+)-Nimbidiol (6) and the natural terpenoid 20 have also been synthesized.     

Novel biotransformation of pentacyclic triterpenoid acids by Nocardia sp. NRRL 5646

Six pentacyclic triterpene acids, ursolic acid, oleanolic acid, betulinic acid, 23-hydroxybetulinic acid, glycyrrhetinic acid, and senegenin, were metabolized by the microbe Nocardia sp. NRRL 5646 to selectively furnish their corresponding 28-methyl esters. Notably, ursolic acid (1) was converted to oleanolic acid methyl ester (4) via two intermediates, oleanolic acid (2), and ursolic acid methyl ester (3), which are formed by participation of ‘retro-biosynthetic’ methyl migration from C-19 to C-20. Senegenin (11) was selectively converted to a nortriterpene methyl ester, senegenic acid methyl ester (12), via an unprecedented C-C bond cleavage. The stereochemical assignments of compounds 11 and 12 were made unambiguously for the first time using 2D NMR spectroscopy.