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Stereochemical outcome at four stereogenic centers during conversion of prephenate to tetrahydrotyrosine by BacABGF in the bacilysin pathway.

ABSTRACT: The first four enzymes of the bacilysin antibiotic pathway, BacABGF, convert prephenate to a tetrahydrotyrosine (H(4)Tyr) diastereomer on the way to the anticapsin warhead of the dipeptide antibiotic. BacB takes the BacA product endocyclic-?(4),?(8)-7R-dihydrohydroxyphenylpyruvate (en-H(2)HPP) and generates a mixture of 3E- and 3Z-olefins of the exocyclic-?(3),?(5)-dihydrohydroxyphenylpyruvate (ex-H(2)HPP). The NADH-utilizing BacG then catalyzes a conjugate reduction, adding a pro-S hydride equivalent to C(4) to yield tetrahydrohydroxyphenylpyruvate (H(4)HPP), a transamination away (via BacF) from 2S-H(4)Tyr. Incubations of the pathway enzymes in D(2)O yield deuterium incorporation at C(8) from BacA and then C(9) from BacB action. By (1)H NMR analysis of samples of H(4)Tyr, the stereochemistry at C(4), C(8), and C(9) can be assigned. BacG (followed by BacF) converts 3E-ex-H(2)HPP to 2S,4R,7R-H(4)Tyr. The 3Z isomer is instead reduced and transaminated to the opposite diastereomer at C(4), 2S,4S,7R-H(4)Tyr. Given that bacilysin has the 2S,4S stereochemistry in its anticapsin moiety, it is likely that the 2S,4S-H(4)Tyr is the diastereomer "on pathway". NMR determination of the stereochemistry of the CHD samples at C(8) and C(9) allows assignment of all stereogenic centers (except C(3)) in this unusual tetrahydro-aromatic amino acid building block, giving insights into and constraints on the BacA, BacB, and BacG mechanisms.

SUBMITTER: Parker JB

PROVIDER: S-EPMC3448026 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Stereochemical outcome at four stereogenic centers during conversion of prephenate to tetrahydrotyrosine by BacABGF in the bacilysin pathway.

Parker Jared B JB Walsh Christopher T CT

Biochemistry 20120705 28

The first four enzymes of the bacilysin antibiotic pathway, BacABGF, convert prephenate to a tetrahydrotyrosine (H(4)Tyr) diastereomer on the way to the anticapsin warhead of the dipeptide antibiotic. BacB takes the BacA product endocyclic-Δ(4),Δ(8)-7R-dihydrohydroxyphenylpyruvate (en-H(2)HPP) and generates a mixture of 3E- and 3Z-olefins of the exocyclic-Δ(3),Δ(5)-dihydrohydroxyphenylpyruvate (ex-H(2)HPP). The NADH-utilizing BacG then catalyzes a conjugate reduction, adding a pro-S hydride equi ...[more]

PMID: 22765234

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Project description:Installing quaternary stereogenic carbon is an arduous task of contemporary importance in the domain of asymmetric catalysis. To this end, an asymmetric allylic alkylation of α,α-disubstituted aldehydes by using allyl benzoate in the presence of Wilkinson's catalyst [Rh(Cl)(PPh3)3], (R)-BINOL-P(OMe) as the external ligand, and LiHMDS as the base has been reported to offer high enantioselectivity. The mechanistic details of this important reaction remain vague, which prompted us to undertake a detailed density functional theory (SMD(THF)/B3LYP-D3) investigation on the nature of the potential active catalyst, energetic features of the catalytic cycle, and the origin of high enantioselectivity. We note that a chloride displacement from the native Rh-phosphine [Rh(Cl)(PPh3)3] by BINOL-P(OMe) phosphite and an ensuing MeCl elimination can result in the in situ formation of a Rh-phosphonate [Rh(BINOL-P[double bond, length as m-dash]O)(PPh3)3]. A superior energetic span (δE) noted with such a Rh-phosphonate suggests that it is likely to serve as an active catalyst. The uptake of allyl benzoate by the active catalyst followed by the turnover determining C-O bond oxidative addition furnishes a Rh-π-allyl intermediate, which upon interception by (Z)-Li-enolate (derived from α,α-disubstituted aldehyde) in the enantiocontrolling C-C bond generates a quaternary stereogenic center. The addition of the re prochiral face of the (Z)-Li-enolate to the Rh-bound allyl moiety leading to the R enantiomer of the product is found to be 2.4 kcal mol-1 more preferred over the addition through its si face. The origin of the stereochemical preference for the re face addition is traced to improved noncovalent interactions (NCIs) and less distortion in the enantiocontrolling C-C bond formation transition state than that in the si face addition. Computed enantioselectivity (96%) is in very good agreement with the experimental value (92%), so is the overall activation barrier (δE of 17.1 kcal mol-1), which is in conformity with room temperature reaction conditions.

Dataset Information

Stereochemical outcome at four stereogenic centers during conversion of prephenate to tetrahydrotyrosine by BacABGF in the bacilysin pathway.

Publications

Stereochemical outcome at four stereogenic centers during conversion of prephenate to tetrahydrotyrosine by BacABGF in the bacilysin pathway.

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