Total synthesis of (+/-)-flustramines A and C, (+/-)-flustramide A, and (-)- and (+)-debromoflustramines A

Here we describe the efficient total synthesis of the three title hexahydropyrrolo[2,3-b]indole alkaloids and debromo derivative from readily available indolin-3-ones using key domino reactions, olefination-isomerization-Claisen rearrangement (OIC), and reductive cyclization (RC). (+/-)-Flustramine C (5) was synthesized in five steps from 6-bromoindolin-3-one 9 via a key intermediate 13a. (+/-)-Flustramine A (1) has been obtained by reduction of flustramide A (6), which has been prepared in five steps from 13a. (+/-)-Debromoflustramine A (19) was provided in a similar manner from 13b. The (-)- and (+)-enantiomers of 19 were synthesized through optical resolution of (+/-)-carboxylic acid 17b using (R)-4-phenyloxazolidin-2-one.     

Stereoselective construction of a beta-isopropenyl alcohol moiety at the C(2) and (3) of kallolide A and pinnatin a using a [2,3] Wittig rearrangement of cyclic furfuryl ethers

A stereocontrolled synthesis of anti- and syn-beta-isopropenyl alcohol moieties at the C(2)-C(3) positions of kallolide A and pinnatin A was accomplished employing the [2,3] Wittig rearrangement of (E)-and (Z)-cyclic furfuryl ethers 8. Enantioselective Wittig rearrangement of (E)- and (Z)-furfuryl ethers 8 using butyllithium and a chiral bis(oxazoline) was also examined to provide (2R,3R)-homoallylic alcohol anti-9 in up to 61% ee and (2R,3S)-syn-9 in up to 93% ee, respectively.     

Lipase-catalyzed domino kinetic resolution/intramolecular Diels-Alder reaction: one-pot synthesis of optically active 7-oxabicyclo[2.2.1]heptenes from furfuryl alcohols and beta-substituted acrylic acids

The first lipase-catalyzed domino reaction is described in which the acyl moiety formed during the enzymatic kinetic resolution of furfuryl alcohols (+/-)-3 with a 1-ethoxyvinyl ester 2 was utilized as a part of the constituent structure for the subsequent Diels-Alder reaction. The preparation of ester 2 from carboxylic acid 1 and the subsequent domino reaction were carried out in a one-pot reaction. Therefore, this procedure provides a convenient preparation of the optically active 7-oxabicyclo[2.2.1]heptene derivatives 5, which has five chiral, non-racemic carbon centers, from achiral 1 and racemic 3. The overall efficiency of this process was dependent on the substituent at the C-3 position of 3, and the use of the 3-methylfurfuryl derivatives, (+/-)-3 b and (+/-)-3 f, exclusively produced diastereoselectivity with excellent enantioselectivity to give (2R)-syn-5 (91->/=99 % ee) and (S)-3 (96->/=99 % ee). Similar procedures starting from the 3-bromofurfuryl alcohols (+/-)-3 h-j provided the cycloadducts (2R)-syn-5 j-q (93->/=99 % ee), in which the bromo group was utilized for the installation of bulky substituents to the 7-oxabicycloheptene core.     

Ruthenium porphyrin catalyzed tandem sulfonium/ammonium ylide formation and [2,3]-sigmatropic rearrangement. A concise synthesis of (+/-)-platynecine

meso-Tetrakis(p-tolyl)porphyrinatoruthenium(II) carbonyl, [Ru(II)(TTP)(CO)], can effect intermolecular sulfonium and ammonium ylide formation by catalytic decomposition of diazo compounds such as ethyl diazoacetate (EDA) in the presence of allyl sulfides and amines. Exclusive formation of [2,3]-sigmatropic rearrangement products (70-80% yields) was observed without [1,2]-rearrangement products being detected. The Ru-catalyzed reaction of EDA with disubstituted allyl sulfides such as crotyl sulfide produced an equimolar mixture of anti- and syn-2-(ethylthio)-3-methyl-4-pentenoic acid ethyl ester. The analogous "EDA + N,N-dimethylcrotylamine" reaction afforded a mixture of anti- and syn-2-(N,N-dimethylamino)-3-methyl-4-pentenoic acid ethyl esters with a diastereoselectivity of 3:1. The observed catalytic activity of [Ru(II)(TTP)(CO)] for the ylide [2,3]-sigmatropic rearrangement is comparable to the reported examples involving [Rh(2)(CH(3)CO(2))(4)] and [Cu(acac)(2)] as catalyst. Similarly, cyclic sulfonium and ammonium ylides can be produced by intramolecular reaction of a diazo group tethered to allyl sulfides and amines under the [Ru(II)(TTP)(CO)]-catalyzed reaction conditions. The subsequent [2,3]-sigmatropic rearrangement of the cyclic ylides furnished 2-allyl-substituted sulfur and nitrogen heterocycles in good yields (>90%). By employing [Ru(II)(TTP)(CO)] as catalyst, the cyclic ammonium ylide [2,3]-sigmatropic rearrangement reaction was successfully applied for the total synthesis of (+/-)-platynecine starting from cis-2-butenediol.     

Facile synthesis of some novel pyrido[3',2':4,5]thieno[2,3-b][1,4]thiazine-8-carboxylic acids

Model tetrahydropyrido[3',2':4,5]thieno[2,3-b][1,4]thiazines 9a-c were synthesized via reductive lactamization, using sodium dithionite, of the respective 2-[(carboxyalkyl)thio]-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acids 7a-c. The latter derivatives were made via interaction of 2-chloro-7-cyclopropyl-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (6) with each of alpha-mercaptoacetic, alpha-mercaptopropionic, and alpha-mercaptosuccinic acids and triethylamine in aqueous acetone at room temperature. The structures of 7a-7c and 9a-9c are supported by microanalytical and spectral (IR, MS, NMR) data. Compounds 9a and 9c showed potent inhibitory activity against the IGROV1 (Ovarian Cancer) cell line.     

Ring closure reaction of 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride. Synthesis of pyrimido[5,4-c] [1,5]benzoxazepin-5(11H)ones

Syntheses of 11-acety1-2-phenylpyrimido[5,4-c][1,5]benzoxazepin-5(11H)one ( 16a ) and analogs ( 16b,c, 22 ) were described. The reaction of 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 7 ) with 2-aminophenol afforded 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidine-carboxylic acid ethyl ester ( 8a ). The latter was also prepared by catalytic reduction of 4-(2-nitrophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 9 ), which was obtained from 7 and 2-nitrophenol. Involvement of 4-(2-aminophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 12a ) in this reduction as an intermediate was demonstrated by an independent synthesis of 12a and its subsequent rearrangement to 8a. Hydrolysis of 8a or 12a gave 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid ( 15a ). Reaction of 15a with acetic anhydride afforded 16a , the first member of a novel ring system, the pyrimido[5,4- c ][1,5]-benzoxazepin. Additional examples ( 16b,c ) were prepared similarly. The corresponding 11-ethyl derivative ( 22 ) was prepared in similar fashion, starting with 7 and 2-ethylaminophenol. A possible reaction mechanism for the formation of 16a-c from 15a-c and acetic anhydride was discussed.     

Microwave assisted synthesis and unusual coupling of some novel pyrido[3,2-f][1,4]thiazepines

3-Amino-3-thioxopropanamide (1) reacted with ethyl acetoacetate to form 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (2), which reacted with α-haloketones 3 to produce 2,3-disubstituted-8-hydroxy-6-methyl-2H,5H-pyrido[3,2-f]-[1,4]thiazepin-5-ones 4a-c. Benzoylation of 4c led to the formation of the dibenzoate derivative 9. Compounds 4a-c could be prepared stepwise through the formation of S-alkylated derivatives 10a-c. Compounds 2, 4a-c, 9 and 10a-c were prepared using microwave as a source of heat, and gave better yields in shorter times than those achieved by traditional methods. Coupling of 4a-c with arenediazonium chlorides proceeded unusually to give the 6-hydroxy-4-methyl-2-(arylazo)thieno[2,3-b]pyridin-3(2H)-one ring contraction products 14. Structures of the newly synthesized compounds were proven by spectral and chemical methods.     

Synthesis,photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones

The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.     

Kinetic resolution of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates for the synthesis of homochiral 3-alkyl-cispentacin and 3-alkyl-transpentacin derivatives

High levels of stereocontrol are observed in the conjugate addition of lithium dibenzylamide to tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn), with addition occurring exclusively anti- to the 3-alkyl substituent. Treatment of a range of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (RS)-N-benzyl-N-[small alpha]-methylbenzylamide indicates that good enantiorecognition is observed (E > 80) in their mutual kinetic resolution. In these reactions, conjugate addition of the lithium amide occurs exclusively anti- to the 3-alkyl substituent, with subsequent C(1)-protonation occurring preferably anti- to the 2-amino group in the 3-Et, 3-Bn and 3-(i)Pr cases, giving predominantly the corresponding 1,2-syn-2,3-anti-diastereoisomers. Conjugate addition to (RS)-3-tert-butyl cyclopentene-1-carboxylate results in exclusive 2,3-anti -addition and a reversal in C(1)-protonation selectivity, giving predominantly the 1,2-anti-2,3-anti-diastereoisomer. Furthermore, the kinetic resolution of the tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds efficiently, giving, at between 47 and 51% conversion, the resolved 3-alkylcyclopentene-1-carboxylates in >85 to >98% ee and the beta-amino ester products of conjugate addition in high de, consistent with E > 80 in each case. Subsequent deprotection of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr) by hydrogenolysis and ester hydrolysis gives the corresponding 1,2-syn-2,3-anti-3-alkylcispentacins in >98% de and 98 +/- 1% ee. Selective epimerisation of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr, (t)Bu) by treatment with KO(t)Bu in (t)BuOH gives the corresponding 1,2-anti-2,3-anti-3-alkyl-beta-amino esters in quantitative yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving the corresponding 1,2-anti-2,3-anti-3-alkylcispentacin hydrochlorides in >98% de.     

Design and synthesis of novel quinoline derivatives bearing oxadiazole,isoxazoline, triazolothiadiazole,triazolothiadiazine, and piperazine moieties

A new series of 2,3-disubstituted quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2-chloroquinoline-3-carbaldehyde 1 , which was transformed to 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 by reaction with 4-phenylpiperazine in DMF-containing anhydrous K₂CO₃; then, compound 2 was oxidized by iodine in methanol, and methyl 2-(4-phenylpiperazin-1-yl)quinoline-3-carboxylate 3 was synthesized. The key intermediate 4 , 4-amino-5-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 6a-c , respectively. Moreover, compound 2 condensed with o-phenylenediamine to give 2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimidazole 7 . Interaction of 7 and 2-chloromethyl-5-aryl-1,3,4-oxadiazoles in the presence of K₂CO₃ led to the title compounds 8a-c . Furthermore, 4,5-dihydroisoxazoline derivatives 9a-c were obtained by the reaction of readily accessible starting materials including 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 , 1-phenyl-2-(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et₃N. The hydrazone intermediates 10a-c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3-acetyl-5-aryl-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazoles 11a-c . Structures of these compounds were established by their elemental analysis, IR, ¹H NMR, and mass spectral data.     

Total synthesis of (+/-)-kainic Acid with an aza-[2,3]-Wittig sigmatropic rearrangement as the key stereochemical determining step

A flexible route to the kainoid skeleton is exemplified by the synthesis of (+/-)-kainic acid from 3-butyn-1-ol. The route relies on the aza-[2,3]-Wittig sigmatropic rearrangement to efficiently install the relative stereochemistry between C2-C3. The C4 stereocenter was derived from a diastereocontrolled iodolactonization. The aza-[2,3]-Wittig rearrangement potentially allows structural diversity at C3 and the displacement of the tosyloxy group with retention of stereochemistry allows structural diversity at C4. The trans-C2 carboxylic acid functional group was found to be the most important for retention of stereochemistry at C4 upon treatment with a higher order cyano cuprate reagent.     

Application of furanyl carbamate cycloadditions toward the synthesis of hexahydroindolinone alkaloids

A convenient synthesis of various substituted hexahydroindolinones has been achieved by an intramolecular Diels--Alder cycloaddition reaction (IMDAF) of furanyl carbamates bearing tethered alkenyl groups. The initially formed [4 + 2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation of the resulting zwitterion to give the rearranged ketone. The stereochemical outcome of the IMDAF cycloaddition has the sidearm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. A synthetic route to (+/-)-mesembrane and (+/-)-crinane was accomplished using this methodology. It was possible to carry out a stereoselective reduction of the initially formed hexahydroindolinone ring to produce the cis-3a-aryl-hydroindole skeleton. A related [4 + 2]-cycloaddition/rearrangement sequence was also used for a formal synthesis of the Chinese ornamental orchid (+/-)-dendrobine. The tricyclic alkaloid core was formed stereoselectivity from the thermolysis of N-[(2-methyl-2-cyclopentenyl)methyl]-N-(4-isopropyl-furan-2-yl)carbamic acid tert-butyl ester. Kende's advanced intermediate 33 was prepared in seven additional steps by standard transformations, thereby completing a formal synthesis of (+/-)-dendrobine.     

A novel reaction of (2a7-trinito-9H-fluoren-9-ylidene)-propanedinitrile with N-arylisoindolines

N-Arylisoindolines 1a-c reacted with (2,4, 7-trinitro-9H-fluoren-9-ylidene)propanedinitrile ( A ) in pyridine with admission of air via a net α-H-atom abstraction and formation of [3-(2-aryl-3-arylimino-2,3-dihydro- 1H-isoindol-1-ylidene)-2-aryl-2,3-dihydro-1H-isoindol-1-ylidene]propanedinitriles 2a-c , N-[2-aryl-3-(2-aryl-3-arylimino-2,3-dihydro-1H-isoindolyl-1-idene)-2,3-dihydro-1H-isoindol-1-ylidene]arenamines 3a, b , N, N'-[2-aryl-1H-isoindole-1,3(2H)-diylidene]bisarenamines 4a, b and N-arylphthalimides 5a-c in moderate yields. 2,4,7-Trinitro-9-fluorenone as well as one reduction product each of the latter and of A, namely compounds 6 and 7 , respectively, are also found. The structure of 2b has been unambiguously confirmed by an X-ray crystal structure analysis. A rationale for the conversions observed is presented. These involve dehydrogenation and oxidative couplings of 1a-c as well as transfer of N-aryl fragment from 1a-c to intermediate products.     

Halogenated 7-deazapurine nucleosides: stereoselective synthesis and conformation of 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides

The stereoselective syntheses of 5-halogenated 7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine nucleosides 3b-d, 4a-c as well as 7-deaza-2'-deoxyisoguanosine are described. Nucleobase anion glycosylation of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (6) exclusively gave the beta-D-anomer, which was deblocked (--> 8), aminated at C4 (--> 3a) and selectively deaminated at C2 to yield 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl 7-deazaisoguanine (2). Condensation of the 5-halogenated 4-chloro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimidines 9a-c with 6 furnished the N7-nucleosides 10a-c together with N2,N7-bisglycosylated compounds 11a-c. The former was converted to the corresponding 2,4-diamino-compounds 3b-d, and the latter was deblocked by NaOMe/MeOH to yield the 4-methoxy-nucleosides 4a-c. Conformational analysis of the sugar moiety of the nucleosides 2 and 3a-d was performed on the basis of vicinal [1H,1H] coupling constants. The fluorine atom in the sugar moiety shifts the sugar conformation from S towards N by about 10%, while the halogen substituents in the base moiety increase the hydrophobicity and polarizability of the nucleobases.     

Synthesis of enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues

Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)- and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (+/-)-5, (+/-)-6, (+)-7, and (-)-7 were obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines (+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of peptide analogues.     

Condensation reactions of 3-oxo-2-arylhydrazonopropanals with active methylene reagents: formation of 2-hydroxy- and 2-amino-6-substituted-5-arylazonicotinates and pyrido[3,2-c]cinnolines via 6π-electrocyclization reactions

3-Oxo-3-phenyl-2-(p-tolylhydrazono)propanal (1a) undergoes condensation with ethyl cyanoacetate in acetic acid in the presence of ammonium acetate to yield either 2-hydroxy-6-phenyl-5-p-tolylazonicotinic acid ethyl ester (6a) or 2-amino-6-phenyl-5-ptolyl-azonicotinic acid ethyl ester (8), depending on the reaction conditions. Similarly, other 3-oxo-3-aryl-2-arylhydrazonopropanals 1a,b condense with active methylene nitriles 2c,d to yield arylazonicotinates 6b,c. In contrast, 2-[(4-nitrophenyl)-hydrazono]-3-oxo-3-phenyl-propanal (1c) reacts with ethyl cyanoacetate to yield ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2–c]cinnoline-3-carboxylate (11), via a novel 6π-electrocyclization pathway. Finally, 3-oxo-2-(phenylhydrazono)-3-p-tolylpropanal (1d) condenses with 2a-c to yield pyridazinones 13a-c.     

Synthesis of Novel Pyrrylthieno[2,3-d]Pyrimidines and Related Pyrrolo[1″,2″:1″,6″]Pyrazino[2″,3″:4,5]Thieno[2,3-d]Pyrimidines

4-Methyl-2-phenyl-5-(1-pyrryl)-6-substituted-thieno[2,3-d]pyrimidines ( 3a-c , 4a-c , 5a , b , and 6 ) have been synthesized. Some of the substituents in position 6 were used to build up different sulfur-, nitrogen- and/or oxygen-containing heterocyclic rings at that position. The 4-methyl-2-phenyl-5-(1-pyrryl)-thieno[2,3-d]pyrimidine-6-carboazide ( 20 ) was also used as a key intermediate in the synthesis of the target pyrrolo[1",2":1',6']pyrazino[2',3':4,5]thieno[2,3-d]pyrimidines.     

Total asymmetric syntheses of d-lividosamine and 2-acetamido-2,3-dideoxy-d-arabino-hexose derivatives.

The “naked sugar” (+)-(1R, 4R)-7-oxabicyclo[2.2.1]hept-5-en-one((+)-2) has been converted to D-lividosamine ((+)-1: 3-deoxy-D-glucosamine) and derivatives via (+)-2-chloro-2,3-dideoxy-5,6-O-isopropylidene-D-arabino-hexono-1,4-lactone ((+)-33) and (+)-2-azido-2,3-dideoxy-5,6-O-isopropylidene-D-ribo-hexono-1,4-lactone ((+)-34) in a highly stereoselective fashion. Similarly, 2-acetamido-2,3-dideoxy-D-arabino-hexose and derivatives were derived from the “naked sugar” (−)-(1S,4S-7-oxabicyclo[2.2.1]-hept-5-en-2-one ((−)-2) via the double hydroxylation of the C=C double bond in (−)-N-benzyl-N-[(1R,2S,4S)-6-bromo-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl] amine ((−)-40).     

A convenient synthesis of new isolable phosphaalkenes using the base-induced rearrangement of secondary vinylphosphines

The secondary vinylphosphines Ar(F)P(H)C(R)[double bond]CH(2) [2a, Ar(F) = 2,6-(CF(3))(2)C(6)H(3), R = CH(3); 2b, Ar(F) = 2,6-(CF(3))(2)C(6)H(3), R = C(6)H(5); 2c, Ar(F) = 2,4,6-(CF(3))(3)C(6)H(2), R = CH(3)] were prepared by treating the corresponding dichlorophosphine Ar(F)PCl(2) (1) with H(2)C[double bond]C(R)MgBr. In the presence of catalytic base (DBU or DABCO) the vinylphosphines (2a-c) undergo quantitative 1,3-hydrogen migration over 3 d to give stable and isolable phosphaalkenes Ar(F)P=C(R)CH(3) (3a, Ar(F) = 2,6-(CF(3))(2)C(6)H(3), R = CH(3); 3b, Ar(F) = 2,6-(CF(3))(2)C(6)H(3), R = C(6)H(5); 3c, Ar(F) = 2,4,6-(CF(3))(3)C(6)H(2), R = CH(3)). Under analogous conditions, only 90% conversion is observed in the base-catalyzed rearrangement of MesP(H)C(CH(3))[double bond]CH(2) to MesP[double bond]C(CH(3))(2). Presumably, the increase in acidity of the P-H group when electron-withdrawing groups are employed (i.e. 2a-c) favors quantitative rearrangement to the phosphaalkene tautomer (3a-c). Thus, the double-bond migration reaction is a convenient and practical method of preparing new phosphaalkenes with C-methyl substituents.     

Diastereoselective synthesis of cyclopropane amino acids using diazo compounds generated in situ

A simple and high-yielding method for the preparation of cyclopropane amino acids is described. The novel method involves the one-pot cyclopropanation of readily available dehydroamino acids using aryl and unsaturated diazo compounds generated in situ from the corresponding tosylhydrazone salts. It was found that thermal 1,3-dipolar cycloaddition followed by nitrogen extrusion gave the cyclopropane amino acid derivatives with good E selectivity, while reactions in the presence of meso-tetraphenylporphyrin iron chloride gave predominantly the corresponding Z isomers. The synthetic utility of this process was demonstrated in the synthesis of (+/-)-(Z)-2,3-methanophenylalanine [(+/-)-(Z)-1], the anti-Parkinson (+/-)-(E)-2,3-methano-m-tyrosine [(+/-)-(E)-2], and the natural product (+/-)-coronamic acid [(+/-)-3].