Synthesis and redox properties of novel alkynyl flavins

Article abstract of DOI:10.1016/S0040-4039(99)02327-8

The synthesis of C7 and/or C8 alkynyl flavins is described. The yields range from 14-48% over six steps. The reduction potentials of these compounds are in good agreement with the values expected based on the Hammett substituent coefficients. (C) 2000 Els

Full text of DOI:10.1016/S0040-4039(99)02327-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1515–1518
Synthesis and redox properties of novel alkynyl flavins
Nakyen Choy, K. C. Russell,∗ Julio C. Alvarez and Alexa Fider
University of Miami, Department of Chemistry, 1301 Memorial Drive, Coral Gables, FL 33124, USA
Received 11 November 1999; accepted 14 December 1999
Abstract
The synthesis of C7 and/or C8 alkynyl flavins is described. The yields range from 14–48% over six steps. The
reduction potentials of these compounds are in good agreement with the values expected based on the Hammett
substituent coefficients. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkynes; electrochemistry; enediyne; flavins.
Flavoenzymes are an ubiquitous and diverse class of biological redox catalysts.1 The redox activity
centers of these enzymes are derivatives of riboflavin (vitamin B2, 1a), which consists of an isoalloxazine
ring system substituted with methyl groups at C7 and C8 and a ribityl group at N10. A plethora of models
have been prepared to better understand flavin redox properties and to serve as structural and mechanistic
probes.2 The synthesis of modified flavins with different redox potentials has allowed the possibility of
altering enzyme function. In particular, 8-cyano-8-desmethyl-riboflavin (1b)3 has been used as a new
catalyst for the enzymatic oxidation of carbonyl compounds.4 Recently, our group has been interested
in biomolecules appended with o-alkynyl substituents.5 Such molecules possess potential applications as
molecular probes or as anticancer agents via thermal or photochemical Bergman cyclization.6,7 Here we
wish to disclose the synthesis and redox properties of C7 and/or C8 alkynyl flavin derivatives (4–6).
∗
Corresponding author. E-mail: krussell@umiami.ir.miami.edu (K. C. Russell)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02327-8
tetl 16255

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The synthesis of flavin analogues 4–6 is depicted in Scheme 1. Nitration of 7a–c followed by
nucleophilic substitution with isobutylamine afforded 9a–c in good yields.8 Coupling 9a–c with TIPS-
or TBDMS-protected acetylene and using Pd(PPh3)4 as a catalyst in diisopropylamine gave 10a–c.
Reduction of the nitro group in 10a and 10b was accomplished with zinc in 30% aqueous NH4OH–THF,9
and the crude N-isobutyl-o-phenylenediamines were used without further purification. Condensation of
the diamine with alloxane in acetic acid gave 11a–b. Unprotected 4 and 5 were prepared by removal of the
silyl groups with tetrabutylammonium fluoride with 14 and 48% overall yield, respectively, from 7a–b.
Compound 6 was prepared by silyl deprotection of 10c prior to reduction and condensation with alloxane
(43% overall yield from 7c). Flavin analogues 210 and 3,11 prepared for comparison, were synthesized
according to the literature procedures12 from commercially available 3,4-dimethyl-5-nitroaniline and 1-
chloro-2-nitrobenzene, respectively.
Scheme 1. Reagent: (i) NaNO3 (1.5 equiv.), H2SO4, 3 h, 40°C; (ii) iBuNH2 (5 equiv.), Et3N (1.5 equiv.), THF, 10–20 h, ∆;
(iii) TIPS-C^CH (2.5 equiv.), Pd(PPh3)4 (10% w/w), iPr2NH, 3–10 h, 120–140°C; (iv) TBDMS-C^CH (1.5 equiv.), Pd(PPh3)4
(10% w/w), iPr2NH, 3 h, 120°C; (v) Zn (dust, 5 equiv.), 30% aq. NH4OH–EtOH, 5 h, rt; (vi) alloxane (1.2 equiv.), boric acid
(1.5 equiv.), AcOH, 12 h, rt; (vii) TBAF (2.5 equiv.), THF, 1 h, 0°C
The redox properties of flavins 2–6 were examined by cyclic voltammetry (CV) in
dichloromethane.11,13 The observed reduction potentials14 of the flavin analogues along with ∆E
values are summarized in Table 1. Bis(desmethyl)flavin, 2, was taken as the base value and had a
reduction potential of −709 mV(E1/2°). The redox potential of compound 4 was determined as −559
mV, 150 mV more positive than 2. The mono C7/C8 alkynyl flavins, 5 and 6, showed reduction
potentials of 4 mV and 41 mV more positive than 2, respectively. As expected, the electron-withdrawing
properties of the alkynyl moiety moved the potential to more positive values. Those substituent effects
corresponded favorably with the electron-withdrawing effect based on the Hammett σ values.15
In conclusion, the first ethynylflavin analogues (4–6) were synthesized with 14–48% overall yield in
six steps. These compounds exhibit electrochemical properties consistent with previous studies. These
compounds may find further utility as handles for other electroactive and functional moieties by the
rich coupling chemistry available to terminal acetylenes. Investigations into the synthesis of riboflavins
containing enediynes are in progress.

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Table 1
Reduction potentials (mV) of flavins 2–6a
Acknowledgements
Financial support for Alexa Fider was provided by a HHMI grant (No. 71199514104). We thank
Dr. A. Kaifer, University of Miami, for providing cyclovoltammerty equipment. We also thank Mr. X
Calyptratus for technical assistance.
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FL, 1991; Vol. 1, pp. 401–425.
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Bard, A. J. Electroanal. Chem. 1968, 17, 411. (c) Sawyer, D. T.; Komai, R. Y.; McCreery, R. L. Experientia Suppl. 1971,
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14. A standard three-electrode cell with a glassy carbon working electrode, Ag/AgCl reference electrode, and platinum wire
counter electrode were used.
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1
17. Characterization of compound 4; mp 280 (decomp); H NMR (300 MHz, CDCl3) δ 8.53 (br, NH), 8.42 (s, 1H), 7.73 (s,
1H), 4.60 (br, 2H), 3.74 (s, 1H), 3.51 (s, 1H), 2.44 (m, 1H), 1.08 (d, 6H, J=6.7 Hz); 13C NMR (100 MHz, DMSO-D6) δ

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159.3, 155.4, 151.1, 140.0, 135.0, 134.1, 133.0, 129.1, 121.1, 120.6, 89.1, 86.1, 81.1, 79.9, 50.2, 26.6, 19.5; FAB-MS calcd
1
318.3, found 319 (M+1). Cyclization of 4 in DMSO with 100 equiv. of 1,4-cyclohexadiene was examined. The H NMR
spectrum of the reaction products did show the presence of new aromatic hydrogens consistent with Bergman cyclization.
Further kinetic experiments, including the redox dependant cyclization, are in progress.
18. All new compounds gave satisfactory spectral data (1H NMR, 13C NMR, FAB-MS).