Bacterial Biotransformation of Isoprene and Related Dienes

Summary.  The bacterium Pseudomonas putida ML 2 was used in the oxidative biodegradation of the acyclic dienes isoprene, trans-piperylene, cis-piperylene, and 1,3-butadiene. Regioselective dioxygenase-catalyzed dihydroxylation of alkenes yielded vicinal diols in the preferred sequence monosubstituted > cis-disubstituted > gem-disubstituted > trans-disubstituted. The isolated diol metabolites had an excess of the R configuration (9–97%ee), and further diol oxidation was controlled by addition of propylene glycol as an inhibitor. Stereoselectivity using the ML2 strain resulted from both enzymatic asymmetric alkene dihydroxylation and kinetic resolution of diols. Enantioselective oxidation of the allylic secondary alcohol group of R configuration yielded the corresponding unsaturated ketoalcohol; the residual diol was recovered with a large excess (≥ 93%ee) of the S configuration. In addition to the enzymatic diene oxidation steps yielding unsaturated diols and ketoalcohols, evidence was also found of enzymatic alkene hydrogenation to yield saturated ketoalcohols and diols. Received December 20, 1999. Accepted (revised) February 7, 2000     

Bacterial Biotransformation of Isoprene and Related Dienes

 The bacterium Pseudomonas putida ML 2 was used in the oxidative biodegradation of the acyclic dienes isoprene, trans-piperylene, cis-piperylene, and 1,3-butadiene. Regioselective dioxygenase-catalyzed dihydroxylation of alkenes yielded vicinal diols in the preferred sequence monosubstituted > cis-disubstituted > gem-disubstituted > trans-disubstituted. The isolated diol metabolites had an excess of the R configuration (9–97%ee), and further diol oxidation was controlled by addition of propylene glycol as an inhibitor. Stereoselectivity using the ML2 strain resulted from both enzymatic asymmetric alkene dihydroxylation and kinetic resolution of diols. Enantioselective oxidation of the allylic secondary alcohol group of R configuration yielded the corresponding unsaturated ketoalcohol; the residual diol was recovered with a large excess (≥ 93%ee) of the S configuration. In addition to the enzymatic diene oxidation steps yielding unsaturated diols and ketoalcohols, evidence was also found of enzymatic alkene hydrogenation to yield saturated ketoalcohols and diols.     

A short synthesis of nonracemic iodocyclohexene carboxylate fragment for kibdelone and congeners

A previously reported nonracemic iodocyclohexene carboxylate intermediate used in the asymmetric preparation of kibdelone C and its congeners was prepared in two synthetic steps from the product of microbial dihydroxylation of methyl 2-iodobenzoate.     

Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis

A diastereoselective synthesis of the nucleoside adducts corresponding to a cis ring-opening of the carcinogen (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE-2) by 2'-deoxyadenosine and 2'-deoxyguanosine is described. The key intermediate (+/-)-10alpha-amino-7beta,8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene was synthesized by a highly diastereoselective dihydroxylation wherein phenylboronic acid was a water surrogate. The resulting boronate ester was converted to a tetraol derivative in which two of the four hydroxyl groups (trans 7, 8) were protected as benzoate esters while the remaining two (cis 9, 10) were free. The cis glycol entity was then subjected to a reaction with 1-chlorocarbonyl-1-methylethylacetate to yield an intermediate chloro monoacetoxy dibenzoate. Displacement of the halide with azide, complete cleavage of the esters, and catalytic reduction of the azide yielded the requisite amino triol. Fluoride displacement from appropriately protected nucleoside derivatives, 6-fluoropurine 2'-deoxyribonucleoside and 2-fluoro-2'-deoxyinosine, by the amino triol then yielded diastereomeric pairs of diol epoxide-adducted 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) nucleosides. Small aliquots of these adducts were separated for characterization purposes. The present approach provides the first diastereoselective synthesis of the cis adducts of BaP DE-2 with 2'-deoxyguanosine as well as the first synthesis of both dA and dG adducts from a common intermediate. An informative analysis of the 1H NMR spectra of the cis adducts synthesized and comparisons to the trans adducts are reported. To gain insight into the diastereoselectivity in the key dihydroxylation step, a computational analysis, including molecular mechanics (MMFF94) and semiempirical AM1 geometry optimizations, yielded results that are in fairly good agreement with the experimental observations.     

Short Chemoenzymatic Total Synthesis of ent‐Hydromorphone: An Oxidative Dearomatization/Intramolecular [4+2] Cycloaddition/Amination Sequence

A short synthesis of ent‐hydromorphone has been achieved in twelve steps from β‐bromoethylbenzene. The key transformations involved the enzymatic dihydroxylation of the arene to the corresponding cis‐dihydrodiol, Mitsunobu coupling with the ring A fragment, oxidative dearomatization of the C3 phenol, and the subsequent [4+2] cycloaddition to form ring B of the morphinan. The synthesis was completed by intramolecular amination at C9.     

Substrate-dependent dihydroxylation of substituted cyclopentenes: toward the syntheses of carbocyclic sinefungin and noraristeromycin

Carbocyclic nucleosides are of considerable interest for the development of new therapeutic agents. A key reaction in the preparation of many such nucleoside analogues is dihydroxylation of appropriately substituted cyclopentenes. Although often considered a routine reaction, in this paper, we report the dramatic influence of substituents on the facial selectivity of dihydroxylations. The substituted cyclopentene substrates are derived from acylnitroso cycloaddition reactions of cyclopentadiene, followed by N-O reduction and efficient enzymatic resolution. The results are directly utilized in a very efficient asymmetric synthesis of an antiviral carbocyclic nucleoside, noraristeromycin 5. Extensions toward the synthesis of carbocyclic sinefungin 7 document the importance of realizing the substituent dependence of the dihydroxylation reaction.     

Biocatalytic Approach for the Total Synthesis of (–)‐Malyngolide and Its C(5)‐Epimer

An enzymatic approach has been successfully utilized in the total synthesis of (–)‐malyngolide and its C(5)‐epimer. The required configuration was established by an enzymatic kinetic resolution and Sharpless asymmetric dihydroxylation.     

A novel and enantioselective synthesis of d-(+)-biotin via a Sharpless asymmetric dihydroxylation strategy

A novel and enantioselective synthesis of d-(+)-biotin has been accomplished starting from commercially available cyclohexanone. The key steps in the sequence are the Sharpless asymmetric dihydroxylation of a (E)-ethyl 3-(2-chlorocyclohex-1-en-1-yl)acrylate derivative to establish the stereocenters of d-(+)-biotin, the carboxyalkyl side chain is introduced by unmasking the cyclohexene by ozonolysis and enzymatic hydrolysis of a thioacetate.     

Click chemistry and biocatalysis for the preparation of pancratistatin analogs

Tricyclic compounds that are advanced precursors for the synthesis of analogs of the antitumoral alkaloid pancratistatin were prepared by a short sequence that involved enzymatic dihydroxylation, epoxidation, and intramolecular Huisgen cycloaddition.     

Identification of bupropion urinary metabolites by liquid chromatography/mass spectrometry

Human urinary metabolism of the antidepressant bupropion was studied using liquid chromatography/time-of-flight mass spectrometry (LC/TOFMS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). A total of 20 metabolites were detected and identified. The phase I metabolism included formation of morpholinohydroxybupropion, threo- and erythrohydrobupropion, aromatic hydroxylation, butyl group hydroxylation with ketone hydrogenation and dihydroxylation. These metabolites were detected either as the free form or as glucuronide and/or sulphate conjugates. In addition also m-chlorohippuric acid was detected. Of the phase I metabolites, a dihydroxylation to the aromatic ring and to the methyl group in the middle of the substrate molecule was reported here for the first time, as well as eight of the glucuronide conjugates (to hydroxy, dihydroxy, hydroxy and hydrogenation metabolites) and three of the sulphate conjugates (to aromatic hydroxy and hydroxy and hydrogenation metabolites).     

Stereoselective Synthesis of Tetrahydropyran D-Ring of Methyl Sartortuoate

A stereoselective synthesis of functionalized tetrahydropyran D‐ring of methyl sartortuoate ( 1 ) was achieved starting from geraniol in a high yield. Sharpless asymmetric kinetic resolution, asymmetric dihydroxylation as well as asymmetric epoxidation were applied as key steps to establish all the four stereocenters of the D‐ring.     

Asymmetric synthesis of aryl cyclitols based on 1,2,3,4-tetrahydronaphthalene scaffolds

A series of aryl cyclitols based on a 1,2,3,4-tetrahydronaphthalene scaffold have been synthesized in a stereocontrolled manner. These cyclitols possess four contiguous stereocenters amongst which one is a quaternary stereocenter, which has been constructed by applying enzymatic kinetic resolution reaction. The remaining stereocenters have been created by substrate directed asymmetric dihydroxylation reaction and stereoselective keto-reduction process.     

Enantioselective syntheses of the assigned structures of the helibisabonols A and B

The enantioselective syntheses of the compounds with the assigned structures of the helibisabonols A and B have been accomplished. Using an enzymatic desymmetrization of the σ-symmetrical diol (route a) and a diastereoselective conjugate addition of the methyl to the enone with a chiral auxiliary (route b) we constructed the key tertiary stereogenic center at the benzylic position (C7) and then used an asymmetric dihydroxylation for assembling the C10 stereogenic center. In addition, possible diastereoisomers of the natural products were prepared and detailed comparisons of the ¹H and ¹³C NMR spectra were conducted. As a result, the structure originally assigned to helibisabonol A may be revised to (7R,10R)-1. In the case of helibisabonol B, the (7R,10R)-2 would be reasonable based on a comparison of the NMR data and the biogenetic parallelism with helibisabonol A.     

Efficient formal synthesis of (±)-axamide-1 and (±)-axisonitrile-1 via an intramolecular Hosomi-Sakurai reaction

A formal synthesis of (±)-axamide-1 and (±)-axisonitrile-1 was achieved by using an intramolecular Hosomi-Sakurai reaction of the allylsilane derivative, as a key step, in which [(3-but-3-en-1-yl-3-methylcyclohex-1-en-1-yl)methyl](trimethyl)silane was transformed to a bicyclic compound possessing a core carbon framework under the oxidative dihydroxylation reaction conditions, in one step.     

First asymmetric enantioselective total synthesis of phenanthridine alkaloid, (S)-(+)-asiaticumine and its enantiomer

In this study, the first asymmetric enantioselective total syntheses of (+)-asiaticumine A (2) and its enantiomer were accomplished through a seven-step sequence using the bond formation between the C4a and N5 positions of the phenanthridine framework based on the microwave-assisted electrocyclization of cyclohexenylbenzaldoxime methyl ether as an aza 6π-hexatriene system followed by the Sharpless asymmetric dihydroxylation as the key step. In addition, the absolute configuration of natural (+)-2 was determined to be S by Mosher’s method.     

Asymmetric total syntheses of (+)-goniopypyrone and (+)-9-deoxygoniopypyrone

Asymmetric total syntheses of (+)-goniopypyrone (1) and (+)-deoxygoniopypyrone (2) from methyl cinnamate (7) via (DHQ)2-PHAL-OsO4 catalyzed asymmetric dihydroxylation and highly stereoselective 2-furylcopper addition in eight steps and eleven steps with overall yield of 20% and 13%,respectively,are described.     

Enantioselective syntheses of colletodiol,colletol, and grahamimycin A

[reaction: see text] The enantioselective synthesis of colletodiol has been achieved in 11 steps from methyl 1,3,5-octatrienoate and 16 total steps from both ethyl sorbate and methyl 1,3,5-octatrienoate. The route relies upon an enantio- and regioselective Sharpless dihydroxylation and a palladium-catalyzed reduction to form a 5-hydroxy-1-enoate and an 7-hydroxy-1,3-dienoate. These esters were further functionalized, coupled, and macrolactonized to provide colletodiol after deprotection. Grahamimycin A and colletol were synthesized in one and two steps, respectively, from colletodiol.     

The synthesis of the anti-malarial natural product polysphorin and analogues using polymer-supported reagents and scavengers

A general asymmetric route to both enantiomers of polysphorin has been developed. The route utilizes polymer-supported reagents, catalysts and scavengers to minimise the need for aqueous work-up and chromatography. This includes application of a method to scavenge 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and a "catch-and-release" procedure to extract the resultant diol following Sharpless asymmetric dihydroxylation. A novel enzymatic selective protection and investigations of a new asymmetric dihydroxylation using microencapsulated osmium tetroxide were also investigated during the course of this study.     

Aldehyde-selective Wacker oxidation in a thiyl-mediated vinyl group transfer route to daunosamine

[reaction: see text] Asymmetric dihydroxylation, thiyl radical mediated transfer of a silicon-tethered vinyl group to a hydrazone and an unconventional aldehyde-selective Wacker oxidation are sequenced for an efficient synthesis of methyl N-trifluoroacetyl-L-daunosaminide in 32% overall yield from crotonaldehyde.     

De novo asymmetric syntheses of D- and L-talose via an iterative dihydroxylation of dienoates

[reaction: see text] A short and highly efficient route to D- and L-talo-gamma-lactones has been developed. The key transformation was the sequential osmium-catalyzed bis-dihydroxylation reaction of substituted 2,4-dienoates. When the first dihydroxylation reaction is performed on (2Z,4E)-dienoates with use of the Sharpless AD-mix procedure, a regio- and enantioselective dihydroxylation resulted along with an in situ lactonization. A subsequent dihydroxylation, using OsO4/NMO in MeOH conditions, resulted in an exceedingly diastereo- and enantioselective synthesis of talo-gamma-lactone.