Preparative-Scale, Facile Synthesis of (2R,4E)-2-Methyl-4-hexenal: A Key Intermediate of (2S,3R,4R,6E)-3-Hydroxy-4-methyl-2-methylamino-6-octenoic Acid (MeBmt)

Deyo, Donald T.; Aebi, Johannes D.; Rich, Daniel H.

doi:10.1055/s-1988-27650

Cited by 11 publications

(2 citation statements)

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“…Finally, we focused our attention on the synthesis of building blocks 25 − 27 for the polypropionate fragment C 13 −C 18 . The preparation of all three fragments was based on the same chiral aldehyde, ( S , E )-2-methyl-hex-4-enal 37 , which was available in multigram quantities . The corresponding ( R )-enantiomer of 37 is a crucial intermediate for the synthesis of a unique amino acid, MeBmt, which is part of the structure of cyclosporin A …”

Section: Chemistrymentioning

confidence: 99%

Sanglifehrin−Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure, and Binding Data

Sedrani

Kallen²,

Cabrejas³

et al. 2003

J. Am. Chem. Soc.

106

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Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC(50) = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C(26)=C(27) exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC(50) = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 A of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.

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Section: Chemistrymentioning

confidence: 99%

Sanglifehrin−Cyclophilin Interaction: Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure, and Binding Data

Sedrani

Kallen²,

Cabrejas³

et al. 2003

J. Am. Chem. Soc.

106

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“…With the DKR step optimized for the model substrate, we proceeded to complete the synthesis of MeBmt 2, Scheme 4. Based on a method originally reported by Rich et al 29 starting from (AE)-3-buten-2-ol 18, a Johnson-Claisen rearrangement followed by transformation of the crude ethyl ester gave (S,R)-phenylglycinol amide 19, which could be separated from its (S,S) diastereomer by gradient column chromatography in multigram amounts. The amide was quantitatively hydrolysed under acid catalysis aided by neighbouring OH-group participation to afford carboxylic acid (2R)-20.…”

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confidence: 99%