Diversity-oriented synthesis of enantiomerically pure steroidal tetracycles employing Stille/Diels-Alder reaction sequences

Various steroid analogues were synthesized by Stille coupling of bicyclo[4.3.0]nonenylstannanes cis-/trans-8 and 14 with cyclohexenol triflates 17 and 18 and subsequent Diels-Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0]nonenylstannanes cis- and trans-8 were prepared in good yields via the enol triflates cis- and trans-7, obtained from the bicyclo[4.3.0]non-2-en-3-one 5. The alkenylstannane 14 was obtained from the [2+2] cycloadduct 10 a produced from addition of dichloroketene to the enantiomerically pure and protected bishydroxycyclohexadiene 9 a (65 %). Treatment of 10 a with diazomethane, reduction of the dichloromethylene group, and trapping with tributyltin chloride after lithium-for-bromine exchange, yielded the bicyclo[4.3.0]nonenylstannane 14 (23 % over four steps). Stille couplings provided the tricyclic dienes cis-/trans-19 in good yields (73-77 %), whereas the tricyclic diene 20 was obtained in only 34 % yield at best. Diels-Alder reactions of trans-19 with various reactive dienophiles yielded the novel steroidal compounds trans-21 to trans-26 with complete diastereoselectivity. Heating the dienes cis-19 or 20 with maleic acid derivatives provided the corresponding tetracycles cis-23alpha,beta and 27alpha,beta with a cis-C,D ring junction, each as mixtures of two diastereomers. Less reactive dienophiles required higher temperatures to promote the relevant cycloaddition with trans-19 to furnish several stereoisomeric forms of trans-28 and trans-29 in significantly lower yields (31-45 %). The selected steroid analogues trans-22 and trans-23 were deprotected in two steps by using acid catalysis to provide trans-31 and trans-33 (91 and 80 % over two steps). Cyclopropanation of trans-30 yielded the cyclopropasteroid analogue 34 (74 %), treatment of which with trifluoroacetic acid furnished the cyclopropasteroid 35 and the 2-methyl-substituted steroid analogue 36 in 40 and 12 % yield, respectively. Aromatic B-ring steroids 38 (69 %) and 39 (5 %) were accessed by dehydrogenation of trans-24 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.     

A novel mode of access to polyfunctional organotin compounds and their reactivity in Stille cross-coupling reaction

Mono-, di-, tri- and tetra-functional organotin compounds were easily prepared in a sonicated Barbier reaction using ultrasound technology via coupling reaction of organo halides with tin halides (Bu₃SnCl, Bu₂SnCl₂, BuSnCl₃, SnCl₄) mediated by magnesium metal. The di- and tri-functional organotin compounds were tested in a Stille cross-coupling reaction in order to ascertain how many groups were transferred.     

Tandem Pauson-Khand reaction and Diels-Alder reaction for access to polycycles in a one-pot reaction

Starting from easily available cyclic alkenes, enynes, and dienophiles, a tandem intermolecular Pauson-Khand reaction and Diels-Alder reaction yields polycyclic compounds in high yields.     

Stille reaction over cis-halocyclohexadienediol derivatives

Stille reaction was performed with several halo cis-diol derivatives by reaction with allyltributyltin in the presence of a palladium catalyst forming allyl cis-dihydrodiol derivatives. These couplings were conducted with conventional heating as well as with microwave irradiation. Allylbenzene cis-dihydrodiol was obtained with excellent yield using mild conventional heating. However, if the diol moiety is protected with the isopropylidene group, the expected product is obtained only under microwave irradiation. The unusual reactivity observed for the polyoxygenated derivatives suggests assistance of the free hydroxyls in the catalytic cycle.     

Copper-catalyzed multicomponent reaction: facile access to novel phosphorus amidines

The synthesis of a novel class of phosphorus amidines via a copper-catalyzed multicomponent reaction of sulfonyl azides, alkynes and iminophosphoranes is described. The protocol is efficient and general.     

Asymmetric Michael reaction: novel efficient access to chiral β-ketophosphonates

The asymmetric Michael reaction between chiral β-enaminophosphonates derived from (S)-1-phenylethylamine and various electrophilic alkenes furnished β,β-disubstituted ketophosphonates in good yields and with excellent enantioselectivity.     

An unusual transformation of 5-acyl-1,2,4-triazines into 3-pyridyl-1,2,4-triazines via tandem Stille cross-coupling/aza Diels-Alder reaction

A new route to 3-heteroaryl-1,2,4-triazines possessing a keto substituent at C-5 of the 1,2,4-triazine core using a Stille cross-coupling procedure and their unexpected ring transformation into pyridyltriazines as a result of enolization of an acyl group catalyzed by metal ions, are reported.     

A novel Ireland-Claisen rearrangement/Diels-Alder tandem reaction of propargylic acrylates with acyclic dienophiles

A novel DABCO-catalyzed Ireland-Claisen rearrangement/Diels-Alder tandem reaction of propargylic acrylates 3 with dienophiles 4 was developed in the presence of an excess TMSCl and DBU with 1% hydroquinone as polymerization inhibitor in acetonitrile at refluxing temperature under air.This protocol gave cyclicα,β-unsaturated carboxylic acids 5 with complete regioselectivity.     

One-pot three-component tandem metathesis/Diels-Alder reaction

[reaction: see text] A tandem enyne, diene-ene metathesis reaction followed by Diels-Alder reaction accomplished a stereoselective three-component reaction protocol with four stereocenters.     

The reaction of decaborane with hydrazoic acid: A novel access to azaboranes

The reaction of B₁₀H₁₂(SMe₂)₂ ( 1 ) with HN₃ yields arachno-B₁₀H₁₂(N₃)(NH₂) ( 2 ), a product with a μ-NH₂ group. Compound 2 can be hydrolysed to give the known arachno-B₉H₁₃(NH₃) ( 3 ). nido-NB₉H₁₁(N₃) ( 4 ) is formed from 2 by a deprotonation/protonation sequence. The azaborane nido-NB₁₀H₁₃ ( 5 ) is a product of the thermolysis of 2 . The structures of 2–5 are elucidated by 2-D COSY ¹¹B–¹¹B NMR spectra; the structure of 2 is also elucidated by an X-ray structure analysis.     

Consecutive Rh(I)-catalyzed Alder-ene/Diels-Alder/Diels-Alder reaction sequence affording rapid entry to polycyclic compounds

Conversion of acyclic allenynes to polycyclic compounds using consecutive transition metal catalyzed carbon-carbon bond forming reactions in a single chemical operation is described. Reaction of an allenyne with a Rh(I) catalyst affords a cross-conjugated triene via a formal Alder-ene reaction. The triene then participates in a Rh(I)-catalyzed intramolecular [4+2] cycloaddition reaction to generate a new conjugated diene. An external dienophile is added to this diene which then undergoes a second [4+2] cycloaddition reaction to afford a complex polycyclic ring system. This reaction sequence demonstrates the synthetic potential of allenynes and cross conjugated trienes and highlights the rapid increases in molecular complexity that are possible by one-pot sequential transition metal catalyzed carbon-carbon bond forming reactions.     

Endo-selective Diels-Alder reaction of methacrylonitrile: application to the synthesis of Georgywood

Diels-Alder reactions of alkyl-substituted dienes with acrylonitriles give good yields and endo-selectivities if catalyzed by (organo)aluminum, (organo)boron or gallium halides. The activity of these group IIIa Lewis acids in this reaction correlates with the coordination strength of their nitrile complexes, which deactivate Lewis acids sufficiently, so that the subsequently added diene partner undergoes the Diels-Alder reaction without serious side-reactions. Boron trichloride is the most effective catalyst for this purpose. This method gives the best endo/exo-ratios reported so far for these components and was applied in the selective synthesis of the olfactory vector of Georgywood^®.     

A novel Diels-Alder approach to carbapenems

An inverse electron demand hetero-Diels-Alder reaction between 2-acylaminomethylene-3-oxobutanoic acid derivatives (5) and ketene acetals (6) yields crystalline dihydropyrans, which are versatile intermediates in the synthesis of carbapenems.     

One-pot enyne metathesis/Diels-Alder reaction for the construction of highly functionalized novel polycyclic aza-compounds

Various tricyclic dienes were synthesized via enyne metathesis using the first generation Grubbs catalyst. The enyne metathesis proceeded smoothly in refluxing CH₂Cl₂ with a low catalyst loading (3.0 mol %), giving good yields (72-89%) of the tricyclic products 6 and 16. The resulting 1,3-dienes are suitable precursors of polycyclic structures via a Diels-Alder process. One-pot RCM/Diels-Alder reactions of the enyne products with dienophiles proceeded smoothly to afford polycyclic compounds as a single cycloadduct. The structures of the Diels-Alder adducts were determined by ¹H NMR spectra and X-ray analysis. The cycloadducts were formed via the approach of the dienophiles towards the diene in endo mode.     

Asymmetric hetero Diels-Alder as an access to carbacephams.

A short and efficient asymmetric synthesis of the (6R,7S)-7-tert-butoxycarbonylamino-2-ketocarbacepham is described. The key step involves the hetero Diels-Alder reaction of the benzylimine derived from the enantiomer of Garner's aldehyde with Danishefsky's diene.     

Total synthesis of (+/-)-crinine via the regioselective Stille coupling and Diels-Alder reaction of 3,5-dibromo-2-pyrone

The regioselective synthesis and Diels-Alder cycloaddition of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone provided a new synthetic route to crinine. The vinyl bromide group can be used as a handle for further derivatization.     

Synthesis of isocoumarins and alpha-pyrones via tandem Stille reaction/heterocyclization

A general route to alpha-pyrones and 3-substituted isocoumarins from (Z)-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c is described, including compounds bearing a substituent on the aromatic ring. Treatment of (Z)-beta-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c with various allenyltributyltin reagents in the presence of palladium acetate, triphenylphosphine, and tetrabutylammonium bromide in dimethylformamide provided good yields of the corresponding alpha-pyrones 3a-k or 3-substituted isocoumarins 5a-g via tandem Stille reaction and 6-endo-dig oxacyclization.     

A novel application of the Diels-Alder reaction: nitronaphthalenes as normal electron demand dienophiles

Thermal reactions between nitronaphthalenes and butadienes were studied. It was demonstrated that these reactions are capable of undergoing the normal electron demand Diels-Alder reaction, with a variety of dienes affording the phenanthrene derivatives. The influence of the extension and type of substitution was also discussed. When the electron-withdrawing activation of the naphthalenic nucleus or the donor properties of the dienes were not enough, N-naphthylpyrroles were detected as main product, suggesting that a competitive reaction would probably take place. The results clearly confirmed the dienophilic nature of nitronaphthalenic double bonds and provided an alternative procedure for phenanthrene derivatives and N-naphthylpyrroles' synthesis. The relative reactivity of the reactants and the viability of the reactions were discussed from a theoretical point of view.     

Hetero Diels-Alder synthesis of 3-hydroxypyridines: access to the nosiheptide core

The 1-azadiene hetero Diels-Alder reaction of silylated enol oximes with alkynes was investigated and was optimized to furnish 2,5,6-trisubstituted 3-hydroxypyridines in high yields in one simple operation. Importantly, monosubstituted alkynyl ketones were found to lead to the formation of the 6-isomer with exceptional regioselectivity (>95:5). This methodology was applied to a scaleable synthesis of the core structure of the potent antibiotic nosiheptide. Protecting groups were optimized, which led to a racemization-free seven-step synthesis of the key building block.     

Intramolecular diels-alder reaction with furan-diene. A novel potential entry to steroids.

Depending on the reaction conditions the intramolecular Diels-Alder reaction of furan-diene $\text{14}$ yields predominantly either one of two adducts $\text{16a}$ and $\text{16b}$, which possess the necessary functionality for eventual transformation into corticosteroids. The dienophile was introduced via alkylation of the enolate, formally obtained upon lithium-liq. ammonia reduction of 3-furyl-2-methyl-2-cyclopentenone ($\text{7}$).