Chemo-enzymatic total synthesis of 3-epiaustraline, australine, and 7-epialexine

Sequential enzymatic aldol reaction and bis-reductive amination leads to the total syntheses of tetrahydroxylated pyrrolizidine alkaloids, 3-epiaustaline (14), australine (1), and 7-epialexine (11). This approach allows for their rapid construction without the need for protecting group manipulation of the hydroxyl functionality. In addition, an improved procedure for the asymmetric epoxidation of divinyl carbinol (3) was described, and the product was used in a concise synthesis of the required triol 7 and ent-7.     

A Convenient Method for Synthesis of Novel Cyclic Ethers (1R,2R,3R,5S,7S,9R,12R)-3-(t-Butyldimethylsilyl)oxy-7-methoxymethyl-oxy-2,10-dimethyl-12-oxatricyclo [7.2.1.0~(5,12)] dodecane

Coloradocin, a novel macrolide antibiotic from cultures of Actinoplanes coloradoensis1exhibits activity against pathogenic anaerobic and microaerophilic species2. Because itslow toxicity and substantial oral activity3, , as well as its unusual structure5, several 4research groups initiated approaches towards the synthesis of coloradocin6, whichculminated in the synthesis of 18-deoxynargenicin A1 by Kallmerten et al.7. …     

Total synthesis of (-)-(6S,7S,8S,9R,10S,2'S)-membrenone-A and (-)-(6S,7S,8S,9R,10S)- membrenone-B and structural assignment of membrenone-C

[reaction: see text] (-)-(6S,7S,8S,9R,10S,2'S)-Membrenone-A and (-)-(6S,7S,8S,9R,10S)-membrenone-B were prepared in 11 steps (3% and 2.4% overall yield, respectively). Key steps included a tin(II)-mediated aldol followed by a syn selective reduction, giving the C7-C9 stereocenters, a second chain extending aldol coupling, and a p-TsOH-promoted cyclization/dehydration giving the common gamma-dihydropyrone precursor. We have thus established that synthetic (-)-(6S,7S,8S,9R,10S,2'S)-membrenone-A, (-)-(6S,7S,8S,9R,10S)-membrenone-B, and (-)-(6S,7S,8S,9R,10S)-membrenone-C are the enantiomers of the natural products.     

Heterotricyclodecane VIII. (−)-(1S, 3R, 6R, 8R)-2, 7-Dioxaisotwistan und (−)-(1R, 3R, 6R, 8R)-2, 7-Dioxa-twistan; Synthese und Bestimmung der absoluten Konfiguration

A synthesis and the determination of the absolute configuration of (?)-(1S, 3R′ 6R, 8R)-2, 7-dioxa-isotwistane ( 13 ) and (?)-(1R, 3R, 6R, 8R)-2, 7-dioxa-twistane ( 14 ) is described. The results for 14 are compared with those for carboeyclic (+)-twistane ( 2 ) of known chirality.     

Enantiospecific synthesis of polhydroxylated indolizidines related to castanospermine: 1 (6R,7S,8aR)-6,7-dihydroxyindolizidine and (6R,7R,8S,8aR)-6,7,8-trihydroxyindolizidine.

Enantiospecific syntheses of (6R,7S,8aR)-6,7-dihydroxy-indolizidine (3) and (6R,7R,8S,8aR)-6,7,8-trihydroxy-indolizidine (4) from methyl 2-azido-4,6-O-benzylidene-2-deoxy-α-D-altropyranoside (7) are reported. The two synthetic indolizidines (3) and (4) have been tested against a wide range of enzymes.     

Enantiospecific synthesis of (6R,7S,8aR)-dihydroxyindolizidine and (6R,7R,8S,8aR)-trihydroxyindolizidine from D-glucose.

Enantiospecific syntheses of (6R,7S,8aR)-dihydroxyindolizidine (1) and (6R,7R,8S,8aR)-trihydroxyindolizidine (2) from readily available methyl 2-azido-4,6-O-benzylidene-2-deoxy-α-D-altropyranoside (5) are described.     

Total syntheses of (+)-australine and (-)-7-epialexine

Three approaches were examined for the synthesis of 3-(hydroxymethyl)pyrrolizidines, a class of compounds that includes the polyhydroxylated pyrrolizidine alkaloids alexine (1), australine (2), and various stereoisomers of thereof. In the first approach, the intramolecular cycloaddition of an azide onto an electron-rich 1, 3-diene bearing a terminal alkoxymethyl substituent (i.e., 21) afforded the dehydropyrrolizidines 22a and 22b, with 22a predominating. A rationale for this stereoselectivity was proposed. Transformation of the major diastereomer 22a into a natural 3-(hydroxymethyl)pyrrolizidine was not possible due to difficulties encountered in transforming the phenyl vinyl sulfide functionality into other useful functional groups. A second approach was examined, wherein the intramolecular cycloaddition of an azide with an optically pure S-t-Bu-substituted diene (i.e., 30) was found to produce the pyrrolizidine 31. In this case, the alkoxymethyl substituent was incorporated into the tether between the azide and the diene, rather than on the diene itself. A key transformation in the synthesis of the diene 30 was the use of the allylic borane R(2)BCH(2)CH=C(TMS)(StBu) for the stereoselective conversion of the D-arabinose-derived azido aldehyde 28 to the E-isomer of 30. The cyclization of 30 to 31 also produced the bicyclic triazene 32, the result of 1,3-dipolar cycloaddition of the azide onto the distal double bond of the diene. Again, difficulties in transformation of the vinyl sulfide functionality of 31 into useful oxygen functionality limited this approach to naturally occurring 3-(hydroxymethyl)pyrrolizidines. A third approach to these compounds was successful. The transformation of L-xylose into the azido epoxy tosylate 46 was accomplished using two Wittig reactions and an epoxidation, in addition to other standard functional group manipulations. Reductive double-cyclization of 46 afforded the pyrrolizidines 47a and 47b, which were debenzylated to afford (+)-australine 2 and (-)-7-epialexine 4, respectively. In the preliminary report of this work, erroneous spectroscopic data in the original literature on the structural assignment of australine led to the conclusion that the synthetic material obtained herein was actually (+)-7-epiaustraline. Recently corrected spectroscopic data have appeared which verify that (+)-australine 2 was indeed synthesized for the first time.     

Cyclization and rearrangements of diterpenoids. IX. Isomerization of (1R,2S,7S,10S,11R,12S,13S)-2,6,6,10,12-pentamethylpentacyclo[10.2.1.01,10.02,7.011,13]pentadecane by fluorosulfonic acid

It has been shown that the opening of the cyclopropane ring in (1R, 2S, 7S, 10S, 11R, 12S, 13S)-2,6,6,10,12-pentamethylpentacyclo[10.2.1.0^1,10.0^2,7.0^11,13]pentadecane takes place under the action of fluorosulfonic acid at all three carbon-carbon bonds, but at low temperatures the main isomerization product is (1R, 2S, 7S, 10S, 12S, 13S)-2,6,6,10,12-pentamethyltetracyclo[10.2.1.0^1,10.0^2,7]pentadecan-13-ol, and at the ordinary temperature the main products are (1R, 2S, 7S, 11S, 12R, 13R)-2,6,6,11,13-pentamethyltetracyclo[10.2.1.0^1,10.0^2,7]pentadeca-9-ene and (1S, 2R, 11S, 12R, 15R)-2,7,7,11,15-pentamethyltetracyclo[10.2.1.0^2,11.0^3,8]pentadeca-3(8)-ene.     

A convenient preparation of (1R,2S,7S,8R)-3,5-diaza-2,7-dimethyl-1,8-diphenyloctan-1,8-diol and its enantiomer

The synthesis of (1R,2S,7S,8R)-3,5-diaza-2,7-dimethyl-1,8-diphenyloctan-1,8-diol 6 and its enantiomer 7 are described utilising (-)-(1R,2S)- or (+)-(1S,2R)-norephedrine, respectively.     

Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate

Conjugate addition of lithium dibenzylamide to tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate occurs with high levels of stereocontrol, with preferential addition of lithium dibenzylamide to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the 3-methyl substituent. High levels of enantiorecognition are observed between tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate and an excess of lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide (10 eq.) (E > 140) in their mutual kinetic resolution, while the kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds to give, at 51% conversion, tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate consistent with E > 130, and in 39% yield and 99 +/- 0.5% de after purification. Subsequent deprotection by hydrogenolysis and ester hydrolysis gives (1R,2S,3R)-3-methylcispentacin in > 98% de and 98 +/- 1% ee. Selective epimerisation of tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate by treatment with KO'Bu in 'BuOH gives tert-butyl (1S,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate in quantitative yield and in > 98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving (1S,2S,3R)-3-methyltranspentacin hydrochloride in > 98% de and 97 +/- 1% ee.     

Terpenes in organic synthesis. 8. Synthesis of optically active (2R/S, 3S, 7R/S)-(-)-diprionyl acetate from (S)-(+)-3,7-dimethyl-1,6-octadiene

Conclusions A seven-stage synthesis has given optically active (2R/S, 3S, 7R/S)-2-acetoxy-3,7-dimethylpentadecane from the readily available (S)-(+)-3,7-dimethyl-1,6-octadiene, in an overall yield of 36%. The synthetic route utilizes all ten carbon atoms of the starting chiral diene.For previous communication, see [1].Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1142–1146, May, 1988.     

Effective, high-yielding, and stereospecific total synthesis of D-erythro-(2R,3S)-sphingosine from D-ribo-(2S,3S,4R)-phytosphingosine

The synthesis of naturally occurring D-erythro-(2R,3S,4E)-sphingosine from commercially available D-ribo-(2S,3S,4R)-phytosphingosine is described. The key step in the reaction sequence comprises TMSI/DBN promoted regio- and stereoselective oxirane opening of intermediate 2-phenyl-4-(S)-[(1S,2S)-1,2-epoxyhexadecyl]-1,3-oxazoline followed by the in situ trans-elimination of 2-phenyl-4-(S)-[(1S,2R)-1,2-dideoxy-2-iodo-1-trimethylsilyloxyhexadecyl]-1,3-oxazoline.     

Synthesis of (+/-)-leucomalure [(3Z,6R*,7S*,9R*,10S*)-cis-6,7-cis-9,10-diepoxy-3-henicosene], the major components of the female sex pheromone of the satin moth

The racemate of leucomalure [(3Z,6R*,7S*,9R*,10S*)-cis-6,7-cis-9,10-diepoxy-3-henicosene (1)] and its (3Z,6R*,7S*,9S*,10R*)-isomer were synthesized via acetylenic intermediates in an unambiguous manner.     

On the structure of passifloricin A: asymmetric synthesis of the delta-lactones of (2Z,5S,7R,9S,11S)- and (2Z,5R,7R,9S,11S)tetrahydroxyhexacos-2-enoic acid

Stereoselective syntheses of the delta-lactone of (2Z,5S,7R,9S,11S)-tetrahydroxyhexacos-2-enoic acid, the structure reported for passifloricin A, and of its (5R)-epimer are described. The creation of all stereogenic centers relied upon Brown's asymmetric allylation methodology. The lactone ring was created via ring-closing metathesis. The NMR data of both synthetic products, however, were different from those of the natural product. The published structure of passifloricin A is thus erroneous and will require further synthetic work to be unambiguously assigned. [structure: see text]     

Cyclization and rearrangements of diterpenoids. IX. Isomerization of (1R,2S,7S,10S,11R,12S,13S)-2,6,6,10,12-pentamethylpentacyclo[10.2.1.01,10.02,7.011,13]pentadecane by fluorosulfonic acid

It has been shown that the opening of the cyclopropane ring in (1R, 2S, 7S, 10S, 11R, 12S, 13S)-2,6,6,10,12-pentamethylpentacyclo[10.2.1.0^1,10.0^2,7.0^11,13]pentadecane takes place under the action of fluorosulfonic acid at all three carbon-carbon bonds, but at low temperatures the main isomerization product is (1R, 2S, 7S, 10S, 12S, 13S)-2,6,6,10,12-pentamethyltetracyclo[10.2.1.0^1,10.0^2,7]pentadecan-13-ol, and at the ordinary temperature the main products are (1R, 2S, 7S, 11S, 12R, 13R)-2,6,6,11,13-pentamethyltetracyclo[10.2.1.0^1,10.0^2,7]pentadeca-9-ene and (1S, 2R, 11S, 12R, 15R)-2,7,7,11,15-pentamethyltetracyclo[10.2.1.0^2,11.0^3,8]pentadeca-3(8)-ene.Institute of Chemistry, Moldavian SSR Academy of Sciences, Kishinev. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 497–500, July–August, 1989.     

A convenient 3-step synthesis of (R)-7-hydroxycarvone from (S)-alpha-pinene

A convenient 3-step synthesis of (R)-7-hydroxycarvone (2) has been developed starting from (S)-alpha-pinene (7), using photooxygenation, oxidation, and fragmentation reactions. An improved synthesis of epoxy alcohol 6 and an unusual Ti(OiPr)(4) catalyzed hydroxy epoxide to keto alcohol rearrangement are also described.     

Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid

Conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in > 95% de. Amination of the lithium (E)-enolates of tert-butyl (3S,alphaR)-3-N-benzyl-N-alpha-methylbenzylamino-3-phenylpropanoate or tert-butyl (3S,alphaS)-3-N-benzyl-N-alpha-methylbenzylaminobutanoate with trisyl azide gives the (2R,3R,alphaR)- and (2S,3S,alphaS )-anti-2-azido-3-amino esters in good yields and in 85% de and > 95% de respectively. Alternatively, tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate may be converted selectively to tert-butyl anti-(2S,3S,alphaS)-2-azido-3-N-benzyl-N-alpha-methylbenzylaminobutanoate by aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S,3S,alphaS)-2-azido-3-aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S,3S)-diaminobutanoic acid in 98%, de and 98% ee. The asymmetric synthesis of the diastereomeric syn-(2R,3S)-diaminobutanoic acid (98% de and 98% ee) was accomplished via functional group manipulation of tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate in a protocol involving azide inversion of tert-butyl (2S,3S)-2-mesyloxy-3-N-Boc-butanoate and subsequent deprotection.     

Cyclization and rearrangements of diterpenoids. VIII. Products of dehydration of (1S,2S,7S,10R,11S,12S)-2,6,6,10,12-pentamethyltetracyclo[10.2.1.01,10.02,7]-pentadecan-11-ol by phosphorus oxychloride

On the dehydration of (1S, 2S, 7S, 10R, 11S, 12S)-2,6,6,10,12-pentamethyltetracyclo[10.2.1.0^1,10.0^2,7]pentadecan-11-ol by phosphorus oxychloride in pyridine a mixture of three hydrocarbons is formed: the known (1R, 2S, 7S, 10S, 11R, 12S, 13S)-2,6,6,10,12-pentamethyltetracyclo[10.2.1.0^1,10.0^2,7.0^11,13]pentadecane and the previously undescribed (1R, 2S, 7S, 10S, 11S)-2,6,6,10,12-pentamethyltetra-cyclo[9.2.2.0^1,10.0^2,7]pentadeca-12-ene and (1R, 2S, 7S, 10S, 11S)-2,6,6,10-tetramethyl-12-methylenetetracyclo[9.2.2.0^1,10.0^2,7]pentadecane, based on a new carbon skeleton.     

Lipase-catalyzed resolution of (2R*,3S*)- and (2R*,3R*)-3-methyl-3-phenyl-2-aziridinemethanol at low temperatures and determination of the absolute configurations of the four stereoisomers

[reaction: see text] Lipase-catalyzed resolution of (2R*,3S*)-3-methyl-3-phenyl-2-aziridinemethanol, (+/-)-2, at low temperatures gave synthetically useful (2R,3S)-2 and its acetate (2S,3R)-2a with (2S)-selectivity (E = 55 at -40 degrees C), while a similar reaction of (2R*,3R*)-3-methyl-3-phenyl-2-aziridinemethanol, (+/-)-3, gave (2S,3S)-3 and its acetate (2R,3R)-3a with (2R)-selectivity (E = 73 at -20 degrees C). Compound (+/-)-2 was prepared conveniently via diastereoselective addition of MeMgBr to tert-butyl 3-phenyl-2H-azirine-2-carboxylate, (+/-)-1a, which was successfully prepared by the Neber reaction of oxime tosylate of tert-butyl benzoyl acetate 7a. The tert-butyl ester was requisite to promote this reaction. For determination of the absolute configuration of (2S,3R)-2a, enantiopure (2S,3R)-2 was independently prepared in three steps involving diastereoselective methylation of 3-phenyl-2H-azirine-2-methanol, (S)-10, with MeMgBr. The absolute configuration of (2S,3S)-3 was determined by X-ray analysis of the corresponding N-(S)-2-(6-methoxy-2-naphthyl)propanoyl derivative (S,S,S)-13.     

Cyclization and rearrangement of diterpenoids. VI. Products of dehydration of (1R,2S,7S,10S,12S,13S)-2,6,6,10,12-pentamethyltetracyclo[10.2.1.01,10.02,7]pentadecan-13-ol by phosphorus oxychloride

It has been established that on the dehydration of (1R,2S,7S,10S,12S,13S)-2,6,6,10,12-pentamethyltetracyclo[10.2.1.0^1,10.0^2,7]pentadecan-13-ol with phosphorus oxychloride in pyridine a mixture of six substances is formed, from which three previously undescribed hydrocarbons have been isolated and identified: (1R,2S,7S,10S,11R,12S,13S)-2,6,6,10,12-pentamethylpentacyclo[10.2.1.0^1,10.0^2,7.-0^11,13]pentadecane, (1R,2S,7S,10S,12R)-2,6,6,10,13-pentamethyltetracyclo[10.2.1.0^1,10.0^2,7]pentadec-13(14)-ene, and (1R,2S,7S,10S,12R)-2,6,6,10-tetramethyltetracyclo[10.2.1.0^1,10.0^2,7]pentadec-13(16)-ene, these being based on two new carbon skeletons.Institute of Chemistry, Institute of Applied Physics, MSSR Academy of Sciences, Kishinev. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 203–211, March–April, 1988.