Novel rearrangements of sesquiterpenoid panasinsane derivatives under acidic conditions

The sesquiterpenoid panasinsane derivatives 11 and 14-16 have been prepared from caryophyllene oxide (7). The novel rearrangement reactions of compounds 11 and 14 under TCNE-catalyzed solvolysis conditions and the reactions of compounds 15 and 16 under superacid conditions (HSO3F/Et2O, -63 degrees C) have been investigated. The ginsenol derivative 17 is obtained from compounds 11 and 14 under TCNE-catalyzed conditions. The rearrangement of compounds 15 and 16 under superacid conditions leads to the novel sesquiterpene derivatives (1S,4S,7S,10S,11S)-3,3,10,11-tetramethyltricyclo[5.3.1.0(4,10)]undecan-1,11-yl sulfate (19) and (1S,4S,5S,8S)-2,2,4,8-tetramethyl tricyclo[3.3.2.1(4,8)]undecan-11-one (20). The influence of the secondary hydroxyl group at C-5 of the panasinsane derivatives on the course of these rearrangements is discussed.     

Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para-f oxide-bridged phenylmorphan isomers

In an attempt to obtain the para-f isomer, rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol, via mesylation of an intermediate 9[small alpha]-hydroxyphenylmorphan, we obtained, instead, a rearranged chloro compound with a 5-membered nitrogen ring, 7-chloro-3a-(2,5-dimethoxyphenyl)-1-methyl-octahydroindole. This indole underwent a second rearrangement to give us the desired para-f isomer. The structures of the intermediate indole and the final product were unequivocally established by X-ray crystallography. A resynthesis of the known rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-8-ol, the ortho-f isomer, was achieved using the reaction conditions for the para-f isomer, as well as under Mitsunobu reaction conditions where, unusually, the oxide-bridge ring in the 5-phenylmorphan was closed to obtain the desired product. The synthesis of the para-f isomer adds an additional compound to those oxide-bridged phenylmorphans that were initially visualized and synthesized; the establishment of the structure and configuration of 8 of the theoretically possible 12 racemates has now been achieved. The X-ray crystallographic structure analysis of the para-f isomer provides essential data that will be needed to establish the configuration of a ligand necessary to interact with an opioid receptor.     

An unexpected rearrangement during mitsunobu epimerization reaction of sugar derivatives

Mitsunobu reaction on the glucose derivative (3S,4R,5R,6R)-3,4,5, 7-tetrabenzyloxy-6-hydroxy-1-heptene yielded an unexpected rearrangement major product. Its structure was determined as (3R,4R, 5R,6S)-4,5,6,7-tetrabenzyloxy-3-hydroxy-1-heptene. The suggested rearrangement mechanism involves an initial intramolecular cyclization, followed by ring opening by the nucleophile p-nitrobenzoate. Product distribution of the Mitsunobu reaction was substrate-dependent, with the corresponding mannose derivative (the 3R epimer) giving less of the initial intramolecular reaction products and the corresponding galactose derivative (the 5S epimer) yielding almost exclusively the expected epimerization product. Varying the Mitsunobu reaction conditions (addition of base and using nonpolar solvent) led to the expected epimerization product of the glucose derivative.     

An Efficient Synthesis of 8-Amino-9-Benzylguanine

The reaction of 2,5-diamino-4-benzylamino-pyrimidin-6(III)-one (6) with benzoyl isothiocyanate furnished 2-amino-4-benzylamino-5-[1-(3-benzoylthioureido)]-pyrimidin-6(1H)-one (7) in good yield. The title compound I was synthesized from compound 7 via a cyclodesulfurative reaction with DCC in DMF at 80°C directly to form 8-benzoylamino-9-benzylguanine (9) which was subsequently treated with 1 N sodium hydroxide.     

Design and synthesis of all diastereomers of cyclic pseudo-dipeptides as mimics of cyclic CXCR4 pentapeptide antagonists

The four diastereomers of 2,5-bis[(3-guanidino)propyl]-1-[3-(4-hydroxyphenyl)propionyl]-7-(2-naphthylacetyl)-1,4,7-triazacycloundec-9-en-3-one (-) and of 2,5-bis[(3-guanidino)propyl]-1-(4-hydroxyphenylacetyl)-7-(2-naphthylacetyl)-1,4,7-triazacycloundec-9-en-3-one (-) were synthesized by a divergent methodology from l- and D-glutamic acids. The 11-membered ring core was made by ring closing metathesis of linear bis(allylamines), and the guanidyl functions were introduced by a simultaneous double Mitsunobu reaction using bis(Boc)guanidine. These compounds were designed to mimic cyclic pentapeptide FC131 (c[Gly-D-Tyr-Arg-Arg-Nal]).     

Rearrangement of 1,4-benzodiazepin-2,4-diones to 3,l-benzoxazin-4-ones

Treatment of 7-chloro-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (Ia) with refluxing acetic anhydride in the presence of pyridine afforded 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (IIa). A plausible reaction path for this novel rearrangement reaction is described: Ia → 4-acetyl-7-chloro-3,4-dihydro-lH-1,4-benzodiazepin-2,5-dione → 7-chloro-1,4-diacetyl-3,4-dihydro-lH-1,4-benzodiazepin-2,4-dione → IIa. When 7-chloro-3,4-dihydro-4-methyl-lH-1,4-benzodiazepin-2,5-dione (Ib), 3,4-dihydro-4-methyl-1H-1,4-benzodiazepin-2,5-dione (Id) and 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Ie) were allowed to react with acetic anhydride under conditions similar to those used for the rearrangement reaction, only acetylation occurred.     

Insights into regioselective oxy (-O-) and imino (-NH-) group insertions of 3-nortricyclanone.

Lactam 4-azatricyclo[3.2.1.0(2,7)]octan-3-one (16a) was proven to be formed in a previously reported reaction that claimed production of lactam 3-azatricyclo[3.2.1.0(2,7)]octan-4-one (17a). In a related reaction, bicyclo[3.1.0]hex-2-ene-endo-6-carbonitrile (15), lactam (16a), and novel hydroxycarbonitriles 19-21 were selectively formed when 3-nortricyclanone (1) was treated with aqueous hydroxylamine-O-sulfonic acid (HOSA). Since nitrile 15 neither hydrolyzed nor underwent intramolecular Ritter reaction under these conditions, mechanisms involving Beckmann rearrangement of 3 to nitrilium ion 9 (normal) and Beckmann fragmentation of 3 to cation 8 (abnormal) were investigated using semiempirical calculations. When alkaline HOSA was employed, lactams 16a and 17a were formed in a 1:2 ratio, perhaps via oxaziridine 6a. A similar selectivity was observed using an NH(3)/NaOCl reagent solution, which afforded lactone 4-oxatricyclo[3.2.1.0(2,7)]octan-3-one (16b) in addition to both lactams. Consequently, the Baeyer-Villiger oxidation of 1 with NaOCl gave 16b exclusively. Finally, the Schmidt reaction of ketone 1 gave only the lactam 17a, via cyclopropyl migration, and the same fragmentation products obtained from the acidic HOSA reaction. Migration selectivities are rationalized in terms of nucleofugacity, electronic effects, cyclopropyl regulation, and MO theory.     

Synthesis of two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids

[structures: see text] Two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids, 6-hydroxy-3-methyl-8-(phenylethyl)-2,5-dihydro-1-benzoxepin-9-carboxylic acid (radulanin E) (1) and 9-hydroxy-3-methyl-2,5-dihydro-1-benzoxepin-7-carboxylic acid (2), were synthesized using Stille coupling followed by Mitsunobu cyclization.     

Intramolecular sulfoxide electrophilic sulfenylation in 1- and 3-acylindoles

Heating 1-(2-ethylsulfinyl)benzoylindole (1) in refluxing p-xylene [thermal Sulfoxide Electrophilic Sulfenylation (SES)] produces indolo[2,1-b][1,3]benzothiazin-12-one (2) in 66% yield. Similar treatment of 1-methyl-3-(2-ethylsulfinyl)benzoylindole (8) provides three products: sulfide 7 and cyclized products 9 and 10 in 10, 19 and 15% yield, respectively. Conversion of 10 to 9 under the reaction conditions is demonstrated and a spirocyclic intermediate 12 , which may form from both 9 and 10 but undergoes only preferential S-migration, is postulated to account for the rearrangement.     

Revision of the absolute configuration of the tricyclic sesquiterpene (+)-kelsoene by chemical correlation and enantiospecific total synthesis of its enantiomer

The absolute configuration of the recently identified sesquiterpene (+)-kelsoene was revised by chemical correlation with (R)-(+)-pulegone; the correct structure is (1R,2S,5R,6R,7R,8S)-2,8-dimethyl-6-(1-methylethenyl)tricyclo[5.3.0.0 (2,5)]decane.     

Antimalarial and cytotoxic activities of bicycl

Biological evaluations of bicyclo[6.4.0]dodecenone derivatives on antimalarial activity in vitro against Plasmodium falciparum and cytotoxicity against human KB cells were made. (+/-)-(1R*,4S*,7R*,8S*)-4-tert-Butyl-dimethylsiloxy-5,5-dimethyl-1-methyl-9-methylene-7-phenylsulfonylbicyclo[6.4.0]dodec-2,11-dien-10-one (15) exhibited potent antimalarial activity, whereas (+/-)-(1R*,7R*,8S*)-1-methyl-9-methylene-7-phenylsulfonylbicyclo[6.4.0]dodec-2,11-dien-10-one (14) showed significant cytotoxic activity in human KB cells. Both 14 and 15 possess, as a structural character, the exo-methylene moiety in their 6-membered ring of the 8-6 fused ring system.     

Conformationally constrained dipeptide surrogates with aromatic side-chains: synthesis of 4-aryl indolizidin-9-one amino acids by conjugate addition to a common alpha,omega-diaminoazelate enone intermediate

Four methyl 9-oxo-8-(N-(Boc)-amino)-4-phenyl-1-azabicyclo[4.3.0]nonane carboxylates (11, 4-Ph-I(9)aa-OMe) were synthesized from (2S,8S,5E)-di-tert-butyl-4-oxo-5-ene-2,8-bis[N-(PhF)amino]azelate [(5E)-7, PhF = 9-(9-phenylfluorenyl)] via a seven-step process featuring a conjugate addition/reductive amination/lactam cyclization sequence. Various nucleophiles were used in the conjugate addition reactions on enone (5E)-7 as a general route for making alpha,omega-diaminoazelates possessing different substituents in good yield albeit low diastereoselectivity except in the case of aryl Grignard reagents (9/1 to 15/1 drs). 6-Phenylazelates (6S)-8d and (6R)-8d were separated by chromatography and diastereoselective precipitation and independently transformed into 4-Ph-I(9)aa-OMe. From (6S)-8d, (2S,4R,6R,8S)-4-Ph-I(9)aa-OMe 11 was prepared selectively in 51% yield. Reductive amination of (6R)-8d provided the desired pipecolates 9 along with desamino compound 10, which was minimized by performing the hydrogenation in the presence of ammonium acetate. Subsequent ester exchange, lactam cyclization, and amine protection provided three products (2R,4S,6S,8R)-, (2R,4S,6S,8S)-, and (2S,4S,6R,8S)-4-Ph-I(9)aa-OMe 11 in 10, 6, and 6% yields, respectively, from (6R)-8d. Ester hydrolysis of (2S,4R,6R,8S)-11 furnished 4-phenyl indolizidin-9-one N-(Boc)amino acid 3 as a novel constrained Ala-Phe dipeptide surrogate for studying conformation-activity relationships of biologically active peptides.     

Constructing conformationally constrained macrobicyclic musks

To investigate the structure-odor correlation of musks, (12R)-12-methyl-13-tridecanolide (1), a macrocyclic musk, and 13-tridecanolide, its non-musky demethyl analogue, were conformationally constrained by introduction of methylene bridges between C-3 and C-8 or C-9. These [7.5.1]- and [8.4.1]-macrobicycles were synthesized starting from bicyclo[5.3.1]undec-8-en-9-one (3) and bicyclo[4.3.1]dec-7-en-8-one (8), respectively, by a sequence consisting of catalytic hydrogenation, alpha-alkylation with a TBS-protected (tert-butyldimethylsilyl) hydroxy halide, acid-catalyzed cyclization, oxidative cleavage of the formed enol ether double bond, and subsequent reduction of the carbonyl group via its tosylhydrazone. The compound (1R,6R,9R)-(+)-6-methyl-4-oxa-bicyclo[7.5.1]pentadecan-3-one (22) was found to possess the most pronounced musk odor, and this was rationalized by a superposition analysis with the polycyclic aromatic musk odorant (4S,7R)-Galaxolide (2). In its (1S,6R,9S)-(+)-stereoisomer 23 as well as in (1S,6R, 10R)-(+)-6-methyl-4-oxabicyclo[8.4.1]-pentadecan-3-one (18) the (6R)-methyl group seems to hinder the interaction with the musk receptor, while the demethyl compounds 7 and 12 showed only very faint odors.     

Chiral lithium amide base-mediated rearrangement of meso-cyclohexene oxides: asymmetric synthesis of amino- and aziridinocyclohexenols

Two different chiral lithium amide base routes for the synthesis of amino- and aziridino-containing cyclohexenols have been explored. The first strategy involved the diastereoselective preparation of novel meso-aziridinocyclohexene oxides and their subsequent enantioselective rearrangement using chiral bases. In this approach, the diphenylphosphinoyl nitrogen protecting group proved optimal and aziridinocyclohexenols of 47-68% ee were obtained. Of particular note was the smooth rearrangement of the epoxide to an allylic alcohol in the presence of an aziridine: under optimised chiral base conditions, the aziridine remained essentially unaffected. A second more straightforward strategy for introduction of an amino functionality was also investigated: (1S,4R,5S)- and (1R,4R,5S)-4,5-bis(tert-butyldimethylsilyloxy)cyclohex-2-enols, readily prepared in > 95% ee using a chiral base approach, were subjected to Mitsunobu substitution using a sulfonamide and Overman rearrangement.     

Design, synthesis, and 1,3-dipolar cycloaddition of (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones

Optically pure (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1, 4-oxazin-2-one N-oxides [(5R)- and (5S)-2] were designed as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones 1. The nitrones (5R)- and (5S)-2 were synthesized by three-step oxidation of (R)- and (S)-phenylglycinols [(R)- and (S)-3], condensation of the resulting (R)- and (S)-2-hydroxylamino-2-phenylethanols [(R)- and (S)-5] with glyoxylic acid, and cyclization of the intermediary nitrones (R)- and (S)-6b. The nitrone (5R)-2reacted with olefins 7-14 under mild conditions to afford the corresponding cycloadducts 15-22 as the main products via the least sterically demanding exo modes. Cycloadduct 30 obtained from (5S)-2 and cyclopentadiene was effectively elaborated to (1S,4S, 5R)-4-benzyloxycarbonylamino-2-oxabicyclo[3.3.0]oct-7-en-3-one (28), the key synthetic intermediate of carbocyclic polyoxin C.     

Formation of novel polycyclic cage compounds through ‘uncaging’ of readily accessible higher cage compounds

The synthesis of the novel cage compounds 7-halomethyl-8-(carbomethoxy)tetracyclo[4.2.1.1^4,7.0^2,5]deca-3-(11)-ene-10-ones, methyl-4-methylene-6-oxopentacyclo[5.4.0.0.^2,5.0^3,10.0^7,9]undecane-9-carboxylate, 3-chloromethyl-4-(carbomethoxy)tetracyclo[4.2.1.1.^3,8.0^2,5]deca-7(11)ene-10-one, 2-bromo-5-methyl-8-methylene-6-oxotricyclo[5.3.0.0^3,9]decane-4-carboxylic acid and 2-bromo-5-methyl-8-methylene-6-oxotricyclo[5.3.0.0^3,9]decane-4-methyl carboxylate, achieved through base catalyzed rearrangement, is described.     

Synthesis of enantiopure 7-[3-azidopyl]indolizidin-2-one amino acid. A constrained mimic of the peptide backbone geometry and heteroatomic side-chain functionality of the ala-lys dipeptide

Enantiopure N-(BOC)amino-7-[3-azidopropyl]indolizidin-2-one acid 1 has been synthesized by displacement of the methanesulfonate of its 7-hydroxypropyl counterpart 11 with sodium azide and subsequent ester hydrolysis. N-(BOC)Amino-7-[3-hydroxypropyl]indolizidin-2-one ester 11 was obtained from a sequence commencing with the alkylation of (2S,8S)-di-tert-butyl 5-oxo-2,8-di-[N-(PhF)amino]azelate 5 (PhF = 9-(9-phenylfluorenyl)). Stereoselective allylation of 5, regioselective olefin hydroboration, selective primary alcohol protection as a silyl ether, and oxidation of the secondary alcohol gave (2S,4R,8S)-di-tert-butyl 4-[3-tert-butyldimethylsiloxypropyl]-5-oxo-2,8-di-[N-(PhF)amino]azelate 9 as a pure diastereomer in 33% overall yield. Linear ketone 9 was then converted into the indolizidinone heterocycle by a route featuring reductive amination, lactam cyclization, and isolation by way of a silyl ether which provided the (6S,7R)-isomer of 11.     

Diverse modes of reactivity of dialkyl azodicarboxylates with P(III) compounds: synthesis, structure, and reactivity of products other than the Morrison-Brunn-Huisgen intermediate in a Mitsunobu-type reaction

The reactivity of diethyl azodicarboxylate (DEAD)/diisopropyl azodicarboxylate (DIAD) with P(III) compounds bearing oxygen or nitrogen substituents is explored. Compounds with structures quite different from that of Morrison-Brunn-Huisgen intermediate R'(3)P(+)N(CO(2)R)N(-)(CO(2)R) (1), observed in the Mitsunobu reaction, have been established by using X-ray crystallography and NMR spectroscopy. Thus reactions with X(6-t-Bu-4-Me-C(6)H(2)O)(2)P-NH-t-Bu [X = S (8), CH(2) (9)] or XP(mu-N-t-Bu)(2)P-NH-t-Bu [X = Cl (14) or NH-t-Bu (15)] and DEAD/DIAD lead to phosphinimine-carbamate-type of products X[6-t-Bu-4-Me-C(6)H(2)O](2)P[N-t-Bu][N(CO(2)R)NH(CO(2)R)] [X = S, R = Et (16); X = CH(2), R = Et (17); X = CH(2), R = i-Pr (18)] or XP(mu-N-t-Bu)(2)P(N-t-Bu)[N-(CO(2)-i-Pr)-N(H)(CO(2)-i-Pr) [X = Cl (19), NH-t-Bu (20)]. Treatment of 19 with 2,2,2-trifluoroethanol afforded the product [(CF(3)CH(2)O)P(mu-N-t-Bu)(2)P(+)(NH-t-Bu)[N(CO(2)-i-Pr)(HNCO(2)-i-Pr)]][Cl(-)] (21) whose structure is close to one of the intermediates proposed in the Mitsunobu reaction. The isocyanate CH(2)(6-t-Bu-4-Me-C(6)H(2)O)(2)P-NCO (10) underwent 1,3-(P,C) cycloaddition with DEAD/DIAD to lead to CH(2)(6-t-Bu-4-Me-C(6)H(2)O)(2)P[N(CO(2)R)N(CO(2)R)-C(O)-N] [R = Et (22), i-Pr (23)]. Reaction of 22-23 with 1,1'-bi-2-naphthol or catechol leads to novel tetracoordinate CH(2)(6-t-Bu-4-Me-C(6)H(2)O)(2)P(2,2'-OC(10)H(6)-C(10)H(6)-OH)[NC(O)-(CO(2)R)NH(CO(2)R)] [R = Et (24), i-Pr (25)] or pentacoordinate CH(2)(6-t-Bu-4-Me-C(6)H(2)O)(2)P(1,2-O(2)C(6)H(4))[NHC(O)-N(CO(2)R)NH(CO(2)R)] [R = Et (26), i-Pr (27)] compounds in which the original NCO residue is retained; this mode of reactivity is quite different from that observed for the MBH betaine 1. In 27, the nitrogen, rather than the oxygen, occupies an apical position of the trigonal bipyramidal phosphorus violating the commonly assumed preference rules for apicophilicity. It is shown that the previously reported azide derivative 3, obtained from the reaction of 11 with DIAD, undergoes a Curtius-type rearrangement to lead to the fused cyclodiphosphazane [(CH(2)(6-t-Bu-4-Me-C(6)H(2)O)(2))P(OC(O-i-Pr)NN(CO(2)-i-Pr)N)](2) (28); this compound is in equilibrium with its monomeric form in solution at >300 K. Finally, reaction of S(6-t-Bu-4-Me-C(6)H(2)O)(2)P(OPh) (13) with DIAD gave the hexacoordinate compound S[6-t-Bu-4-Me-C(6)H(2)O](2)P(OPh)[N(CO(2)-i-Pr)NC(O-i-Pr)O] (30) with an intramolecular S-->P bond. X-ray crystallographic evidence for compounds 16, 19, 21, 22, 25, 27, 28, and 30 has been provided.     

seco-limonoids and quinoline alkaloids from Raputia heptaphylla and their antileishmanial activity

A novel seco-limonoid, rel-(1S,5R,9S,7R,8S,9R,10S,11R,13S,14R,15R,17R)-11,19-dihydroxy-7-acetoxy-7-deoxoichangin (raputiolide) (1), and two novel quinolone alkaloids N-methyl-2-phenoxyquinolin-4(1H)-one (heptaphyllone A) (2) and 6-methylbenzofuro[2,3-b]quinolin-4(1H)-one (heptaphyllone B) (3), along with the known seco-limonoid ichangin (4), were isolated from Raputia heptaphylla PITTIER (Rutaceae) stem bark. Five known alkaloids, N-methyl-8-methoxyflindersine (5), skimmianine (6), kokusaginine (7), dictamnine (8) and flindersiamine (9), were also isolated from R. heptaphylla leaves. Their structures were established on the basis of full spectroscopic data interpretation supported by data from the pertinent literature. seco-Limonoid 1 configuration was determined by enhanced nuclear Overhauser effect spectroscopy (NOESY) experiments and density functional theory (DFT) molecular modeling. The antileishmanial effect of the isolated compounds was evaluated on Leishmania Viannia panamensis (promastigotes and amastigotes). Whereas alkaloids 2-3, 6-8 and limonoid 4 exhibited no significant parasitocide activity against internalized L. (V.) panamensis amastigotes, limonoid 1 and alkaloid 5 had leishmanicidal activity on intracellular amastigotes (EC??: 8.7 μg/ml) and promastigotes (EC(50): 14.3 μg/ml), respectively.     

Organocatalytic entry to chiral bicyclo[3.n.1]alkanones via direct asymmetric intramolecular aldolization

[reaction: see text] The facile stereoselective syntheses of endo-8-hydroxybicyclo[3.3.1]nonan-2-one and endo-7-hydroxybicyclo[3.2.1]octan-2-one, featuring an alpha-amino acid catalyzed intramolecular aldolization of sigma-symmetric substrates, are described. A high enantioselectivity and a high catalytic efficiency have been exhibited by (4R,2S)-tetrabutylammonium 4-TBDPSoxy-prolinate in the aldolization of 3-(4-oxocyclohexyl)propionaldehyde to give highly enantiomerically enriched (1S,5R,8R)-8-hydroxybicyclo[3.3.1]nonan-2-one.