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Total asymmetric synthesis of (–)-Phenylhistine, (–)-Aurantiamine and related compounds. Part I

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Abstract

A new general, short, and efficient strategy for the construction of dehydro-diketopiperazines was developed. Horner–Emmons type coupling between a phosphinyl glycine ester and a formyl heterocycle is the key coupling reaction, which proceeds in good-to-excellent yields on several sterically-hindered substrates. Moreover, racemization of the parent L-amino acids is avoided as a result of the mild basic conditions used. The selection of the NH protective group of the formyl heterocycle was crucial. N-tosylated heterocycles proved ideal for this reaction sequence. Thus, the title compounds, (–)-Phenylhistine and (–)-Aurantiamine, were prepared in high yield (four steps, 47% overall) and optical purity. Furthermore, the synthesis of unnatural derivatives including an indole analogue was successfully completed.

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Abbreviations

DHP:

3,4-dihydro-2H-pyrane

PPTS:

pyridinium p-toluenesulfonate

TEMPO:

2,2,6,6-tetramethyl-piperidin-1-yloxy

Im2CO:

N,N′-carbonyldiimidazole

DBU:

1,8-diazabicyclo[5.4.0]undec-7-ene

HOBt:

1-hydroxybenzotriazole

EDC HCl:

N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride

TFA:

trifluoroacetic acid

TBAF:

tetrabutylammonium fluoride

Et3N:

triethylamine

LDA:

lithium diisopropylamide

TBSCl:

tert-butyldimethylsilyl chloride

TLC:

thin layer chromatography

HRMS:

high resolution mass spectroscopy

FAB:

fast atom bombardment

MALDI-FTMS:

matrix-assisted laser desorption/ionization-fourier transform mass spectroscopy

EI:

electron ionization

m.p.:

melting point

DMSO:

dimethyl sulfoxide

THP:

tetrahydropyrane

r.t.:

room temperature

TosCl:

p-toluenesulfonyl chloride.

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Authors and Affiliations

  1. Chemistry Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 118 55, Greece

    Elias A. Couladouros & Alexandros D. Magos

  2. Organic and Bioorganic Chemistry Laboratory, NCSR “DEMOKRITOS”, 153 10 Ag. Paraskevi Attikis, POB 60228, Athens, Greece

    Elias A. Couladouros & Alexandros D. Magos

Authors
  1. Elias A. Couladouros
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  2. Alexandros D. Magos
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Correspondence to Elias A. Couladouros.

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Couladouros, E.A., Magos, A.D. Total asymmetric synthesis of (–)-Phenylhistine, (–)-Aurantiamine and related compounds. Part I. Mol Divers 9, 99–109 (2005). https://doi.org/10.1007/s11030-005-1294-x

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