Acylnitroso Dienophiles Research Articles

π-Facial Stereoselectivity in Acyl Nitroso Cycloadditions to 5,5-Unsymmetrically Substituted Cyclopentadienes: Computational Exploration of Origins of Selectivity and the Role of Substituent Conformations on Selectivity.

The π-facial selectivity of Diels-Alder cycloadditions of 5-monosubstituted cyclopentadienes is known experimentally and has been extensively studied computationally. Previous studies on 5-monosubstituted cyclopentadienes by the Burnell and Houk groups showed that facial selectivity arises principally from hyperconjugative aromaticity or antiaromaticity of polar groups that cause distortion of the cyclopentadiene; steric effects of nonpolar groups can also be important. We have now explored the stereoselective cycloaddition of 5,5-unsymmetrically substituted cyclopentadienes to an acyl nitroso dienophile reported by Kan and co-workers. Computational studies with M06-2X/6-311+G(d,p) indicate that the stereoselectivity in the cycloadditions of 5,5-unsymmetrically substituted cyclopentadienes is not just a simple combination of effects found for monosubstituted counterparts. Substituent conformations and diene-dienophile steric and electronic interaction effects all influence stereoselectivity. Predictions are made about several as-yet-unstudied cyclopentadiene cycloadditions.

Photochemical locking and unlocking of an acyl nitroso dienophile in the Diels–Alder reaction

Photochromic Diels–Alder cycloadducts consisting of acyl nitroso dienophiles, which are known nitroxyl (HNO) donors, and dithienyldienes are presented. The dithienylethene-type photochromic cycloadducts were found to exhibit reversible electrocyclic ring closing and ring opening reactions to ‘lock’ or ‘unlock’ the retro Diels–Alder reaction, respectively. The release of an acyl nitroso dienophile via a retro Diels–Alder reaction at 92°C was shown to occur only from the open or ‘unlocked’ form of a photochromic dithienylcyclopentene and not from the closed or ‘locked’ isomer.

New aminocyclitols with quaternary stereocentres via acylnitroso cycloaddition with an ipso,ortho arene dihydrodiol

Microbial ipso,ortho-dihydroxylation of benzoic acid by the B9 mutant strain of Ralstonia eutropha permits rapid construction of aminocyclitols containing a quaternary stereocentre. Installation of the amine functionality is achieved by use of an acylnitroso dienophile for a hetero-Diels–Alder reaction. Both aminotetrols and aminohexols are accessible as single enantiomers by this route. Both NOESY spectroscopic and X-ray crystallographic analyses were required to distinguish cycloadduct isomers. Notably, subsequent to the biooxidation step, all new stereocentres are installed under substrate control. Thus, all stereochemical information is ultimately of enzymatic origin.

ChemInform Abstract: Single and Double Asymmetric Induction in Diels-Alder Cycloadditions with Chiral Acylnitroso Dienophiles.

Abstract Diels-Alder reaction of the achiral 1-silyloxybutadiene 1a with the chiral acyinitroso dienophile 2a gave cycloadduct 4 in high diastereomeric excess (d.e. > 98 %), a result which is undoubtedly due to the C-2 symmetrical chiral dimethylpyrrolidine inductor. Excellent d.e. was also observed when the (R)-prolinol dienophile 2d was reacted with the chiral diene 1b (d.e. = 96 %), whereas cycloaddition of the (S) enantiomer 2e with 1b gave only poor asymmetric induction (d.e. = 4 %). These two latter examples nicely illustrate the influence of “matched pair” (1b/2d) versus “mismatched pair” (1b/2e) upon double asymmetric induction. All herein reported Diels-Alder cycloadditions were regiospecific.

ChemInform Abstract: Asymmetric Diels-Alder Reactions of a Nitroso Compound Derived from D- Bornane-10,2-sultam.

Abstract Acylnitroso dienophile 3 derived from D-bornane-10,2-sultam undergoes cycloaddition with high yields and complete facial selectivity to cyclopentadiene and cyclohexadiene. When the nitroso group is attached to the sultam nitrogen, it is no longer reactive in Diels-Alder reactions.

Synthesis of 1,2- and 1,4-amino alcohols from 1,3-dienes via oxazines. Rearrangements of 1,4-amino alcohol derivatives to oxazolines

Conjugated dienes were converted to 1,2-oxazines by reaction with an acyl nitroso dienophile. The oxazines were reduced to 1,4- N-acetylamino alcohols, which were rearranged to the corresponding oxazolines upon treatment with methanesulfonyl chloride or anhydride. The oxazolines yielded 1,2- N-acetylamino alcohols upon hydrolysis. Thus either 1,4- or 1,2- N-acetylamino alcohols are available from 1,3-dienes via this methodology. Experimental and spectral data are provided for all new compounds.

Investigation of steric and functionality limits in the enzymatic dihydroxylation of benzoate esters. Versatile intermediates for the synthesis of pseudo-sugars, amino cyclitols, and bicyclic ring systems

A series of benzoate esters (methyl, ethyl, n-Pr, i-Pr, n-Bu, t-Bu, allyl, and propargyl) were subjected to enzymatic dihydroxylation by E. coli JM 109(pDTG 601) strain in a whole-cell fermentation. The cis-cyclohexadienediols were obtained in yields of approximately 1g/L except for n-propyl- and i-propyl benzoate which were found to be poor substrates. n-Butyl and t-butyl benzoates were not oxidized at all. The absolute stereochemistry for all metabolites was determined by comparison with a standard prepared from (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol, whose absolute configuration is well established. The free diols were found to be quite stable compared to other cis-dihydrodiols of this type, however, their acetonides underwent a dimerization via a regio- and stereoselective Diels-Alder cycloaddition. The diol derived from ethyl benzoate was subjected to a stereo- and regioselective inverse electron demand Diels-Alder cycloadditions with several dienophiles. The new adducts were completely characterized. The hetero-Diels-Alder reaction of this diol with an acyl nitroso dienophile yielded regio- and stereoselectively a bicyclic oxazine, which upon reduction provided a useful derivative of amino shikimate that can be exploited in an approach to oseltamivir (Tamiflu) and other amino cyclitols. The diol was also converted to carba-alpha-L-galactopyranose to demonstrate its potential utility as a source of pseudo sugars. Experimental and spectral data are provided for all new compounds.

Solid-Supported Nitroso Hetero Diels–Alder Reactions. 1. Acylnitroso Dienophiles: Scope and Limitations

Polymer-supported acylnitroso dienophiles were prepared and used in hetero Diels-Alder (HDA) reactions with a variety of dienes. The transient acylnitroso dienophiles were prepared in situ from immobilized hydroxamates, which were attached to solid supports via several linkers each cleavable by different cleavage reagents, and served for the synthesis of both N-unsubstituted and N-derivatized HDA adducts. Model compounds were used to (i) optimize reaction conditions for solid-supported HDA reactions, (ii) evaluate the outcome of the reactions with various dienes, (iii) compare relative reactivities of dienes, and (iv) assess the stability of HDA adducts toward cleavage conditions typically used in solid-phase syntheses. Cleaved products were submitted to biological assays, and the results are reported. The accompanying paper, focused on complementary arylnitroso HDA reactions, includes a comparison of both HDA reactions.

Development of new transition metal catalysts for the oxidation of a hydroxamic acid with in situ Diels–Alder trapping of the acyl nitroso derivative

New transition metal catalysts have been prepared and applied for in situ formation of acyl nitroso dienophiles.

Switch in asymmetric induction sense in cycloadditions using camphor-based nitroso dienophiles

We have observed a unique reversal in the absolute stereochemistry of the principal adducts from the cycloadditions of camphor-based acylnitroso dienophiles as compared to the adducts obtained through reactions of the corresponding camphor-based chloronitroso compounds.

The development and application of ruthenium catalysed oxidations of a hydroxamic acid and in situ Diels–Alder trapping of the acyl nitroso derivative

Ruthenium( II) complexes can be used to oxidise N-Boc-hydroxylamine in the presence of tert-butyl hydroperoxide (TBHP) to the corresponding nitroso dienophile, which is trapped by cyclohexa-1,3-diene as the hetero-Diels–Alder adduct. Direct evidence has been obtained for the intervention of a triphenylphosphine oxide-stabilised ruthenium( IV) oxo-complex as the catalytically active species. Use of a chiral bidentate bis-phosphine derived ruthenium ligand (BINAP or PROPHOS) results in very low asymmetric induction (8 and 11%). Ruthenium( II) salen complexes also catalyse the oxidation of N-Boc-hydroxylamine in the presence of TBHP, to give the N-Boc-nitroso compound which can be efficiently trapped with a range of dienes. However, use of an enantiopure ruthenium salen complex does not produce asymmetric induction via the trapping of the intermediate acyl nitroso dienophile with cyclohexadiene, which strongly suggests that the intermediate dissociates readily from the chiral ruthenium complex involved in the oxidation step prior to Diels–Alder cycloaddition.

A Formal Asymmetric Synthesis of (−)-Epibatidine Using a Highly Diastereoselective Hetero Diels–Alder Reaction

A formal asymmetric synthesis of (−)-epibatidine is reported. The key step of the synthesis is a regio- and diastereoselective cycloaddition of silyloxycyclohexadiene with the acylnitroso dienophile derived from (+)-camphorsultam. The resulting cycloadduct was readily transformed into the N-protected-7-azabicyclo[2.2.1]heptan-2-one derivative which has previously been transformed into (−)-epibatidine.

Total Synthesis of (−)-Epibatidine Using an Asymmetric Diels−Alder Reaction with a Chiral N-Acylnitroso Dienophile

An asymmetric total synthesis of (−)-epibatidine (1), isolated from the skin of the Ecuadorian poison frog, Epipedobates tricolor, of the family Dendrobatidae, has been achieved by virtue of the development of asymmetric hetero Diels−Alder (D−A) cycloaddition with an N-acylnitroso dienophile bearing the optically active 8-arylmenthol as a chiral source. Thus, in situ oxidation of the hydroxamic acid ent-12f incorporating the (1S,2R,5S)-8-(2-naphthyl)menthyl auxiliary was performed using the Swern conditions to produce the acylnitroso dienophile, which reacted at once with 2-chloro-5-(1,5-cyclohexadienyl)pyridine (7) to provide the (1S,4R)-meta-aza cycloadduct 24 as a major diastereoisomer. The observed facial diastereoselectivity is consistent with a transition-state model with the naphthyl group in “stacked” position and with the acylnitroso group in the s-cis conformation, wherein π attractive interaction between the naphthyl and nitrosocarbonyl groups may contribute to facial control. Compound 24 under...

Asymmetric synthesis of an important precursor to 5′-nor carbocyclic nucleosides

An asymmetric hetero-Diels-Alder reaction involving an amino acid-derived acylnitroso dienophile was utilized to synthesize (1 S, 4 R)-4-[ N-( tert-butoxycarbonyl)amino]-2-cyclopentene-1-ol ( 4). The amino acid chiral auxiliary was removed by the Edman degradation. This enantiomerically pure aminoalcohol is a key intermediate in the synthesis of 5′-nor carbocyclic nucleosides.

Stereoselective synthesis of D,L-erythrose-, and of D,L-1,4-dideoxy-4-aminoerythrose derivatives bearing a β-lactam at C-4

Acylnitroso dienophiles react with azetidinodiazepines 1, with high stereoselectivity from the α-side, to give cycloadducts 2 and 3. Catalytic osmylation of these latter compounds proceeded with total face-selectivity to give diols 4 and 8, respectively. Hydrogenolysis, followed by molecular rearrangements, ultimately led to dideoxyaminoerythrose derivatives 6 (from 4) and to erythrose derivatives 10 (from 8). The hydrochlorides of 6a and 6b were assessed for their anti-HIV in vitro activity; they were found to be less potent than castanospermine.

Chiral N-dienyl-L-pyroglutamic esters in asymmetric hetero-Diels-Alder reactions with acylnitroso dienophiles

Asymmetric Diels-Alder reaction of the N-dienyl-L-pyroglutamic esters 1a-h with acyl nitroso dienophiles 4a-h gave diastereoisomeric adducts 6a-n, 7a-n with 12–90 % de, depending on solvents and temperature. An interpretation was gived. The “allylic effect” ( π C=C − σ ∗ N-C MO interactions) was found to be effective to account for the conformations of the adducts.

Synthesis of novel hydantoin analogs of 5′-nor carbocyclic nucleosides: Versatility of a chiral acylnitroso cycloaddition

An asymmetric hetero-Diels-Alder reaction involving an amino acid-derived acylnitroso dienophile was utilized to synthesize novel hydantoin analogs ( 12) of carbocyclic nucleosides. The hydantoins were formed during an attempted protection of an amide nitrogen.

(±)‐4‐Amino‐4,5‐dideoxyribose, (±)‐4‐amino‐4‐deoxyerythrose, and (±)‐dihydroxyproline derivatives from N‐dienyl‐γ‐lactams

AbstractHetero‐Diels‐Alder cycloaddition of acylnitroso dienophile 4 with the N‐(butadienyl)pyrrolidinone derivatives 2a, b led with complete regioselectivity to the oxazine adducts 5a, b (Scheme 1). Sequential osmylation, protection of the ensuing glycol, and reduction of the NO bond gave the expected hemiaminals 11a, b which were characterized by their crystalline sulfite adducts 12a, b (Schemes 1 and 2). Deprotection and saponification of the latter led to aminodeoxyerythrose and to aminodeoxyribose derivatives as an equilibrium of pyrrolidinose equivalents, i.e., hemiaminals 14a, b, imines 14′a, b, and dimers 14″a,b, respectively (Scheme 3). Hydrocyanic acid addition to 11a, b led ultimately to the proline derivatives 16a, b (Scheme 2). Compound 11b proved to be an inhibitor of syncytium formation in AIDS‐infected cells.

Amino Acid-Derived Chiral Acyl Nitroso Compounds: Diastereoselectivity in Intermolecular Hetero Diels-Alder Reactions

The diastereoselectivities of chiral acyl nitroso dienophiles derived from optically pure N-protected α-amino hydroxamic acids have been de- termined in intermolecular hetero Diels-Alder reactions. The cycloaddi- tion reactions afforded synthetically useful quantities of functionally rich, optically pure cycloadducts, useful for the preparation of a vari- ety of compounds of potential biological interest. Molybdenum hexacar- bonyl reduction of the cycloadducts gave optically pure allylic alco- hols. Osmium tetraoxide-catalyzed dihydroxylation of several bis-ally- lically substituted intermediates gave only the diastereomerically pure diols corresponding to naturally occurring 2',3'-dihydroxynucleoside analogs

A Straightforward Synthesis of (±)-4-Amino-4-deoxyerythrose via Its Bisulfite Anomer

Hetero-Diels-Alder reaction of N-butadienyl-2-pyrrolidone (1a) with acylnitroso dienophile (3) led with very high regioselectivity to the racemic cycloadduct (6). A sequence of stereospecific reactions, as well as some protection/deprotection steps, gave the bisulfite derivative (2b) of (±)-4-amino-4-deoxyerythrose (2a) as a single and crystalline anomer. Asymmetric induction as applied to the Diels-Alder cycloaddition step with various N-butadienylpyroglutamate esters (1 b-e) permitted to work out optimal experimental conditions, the best d.e. value being 76%