A Prebiotic Stereospecific Synthesis of Biotin Analogues

Transcription

1 A Prebiotic Stereospecific Synthesis of Biotin Analogues Nigel Aylward School of Physical and Chemical Sciences Queensland University of Technology George St., Brisbane, Queensland 4000 AUSTRALIA Abstract: - A set of chemical reactions is proposed to account for the formation of biotin analogues from a primeval atmosphere composed of cyanoacetylene, acetylene, carbon monoxide, ammonia, thioformaldehyde, hydrogen and water. The first stereospecific center is determined by selective orientation by photochemical excitation of carbon monoxide and a long-chain unsaturated nitrile on a template of magnesium or ferrous porphin. The other two stereospecific centers arise from preferential chemical reaction on one side of the reactants absorbed as a charge transfer complex on the template surface. Most of the reactions appear to be exothermic except condensations involving carbon monoxide or ammonia. The reactions have been shown to be feasible from the overall enthalpy changes in the ZKE approximation at the HF and MP2 /6-31G* level. Key-Words: - biotin analogues, magnesium porphin, octa-8-al-2,4,6-triyne nitrile, cyanoacetylene, acetylene, carbon monoxide, ammonia, 1 Introduction Biotin, also called vitamin H or coenzyme R, isolated from yeast and other micro-organisms [1], is an essential dietary factor whose deficiency causes toxicity [2]. Biotin contains fused imidazole and thiophene rings and functions in the enzymatic transfer or incorporation of carbon dioxide in the form of a very labile carboxybiotin derivative, in which one of the imino groups has formed a carboxylate anion by nucleophilic attack on the carbon dioxide. This paper is the first to suggest a prebiotic route to the syntheis of biotin analogues based on spontaneous reactions in a presumed primeval atmosphere. The synthesis is based on reactant molecules known to exist in space such as, H-(C C) 3 -CN, and H-(C C) 4 -CN [3] and the two most common molecules in the universe, hydrogen and carbon monoxide. Also required as reactants are ammonia, and water [4]. The source of the sulfur is here taken to be hydrogen sulfide and thioformaldehyde which have also been detected [3]. For this work the assumption is also made that some of the components that are presently found on Titan [5] are also present, namely cyanoacetylene, and a study of its photochemistry indicated that diacetylene can be produced [6,7]. However, for a minor compound to be produced in a small quantity at least one of the steps in the synthesis is expected to be only marginally favourable. 2 Problem Formulation The computations tabulated in this paper used the GAUSSIAN98 [8] commercial package. The standard calculations at the HF and MP2 levels including zero-point energy corrections [9], together with scaling [10], using the same basis set, 6-31G*, are as previously published [11]. Enthalpy changes at the MP2 level not including scaled zero point energies are designated as H (MP2). The charge transfer complexes are less stable when calculated at the Hartree Fock level [9]. If the combined energy of the products is less than the combined energy of the reactants it may show that the reaction is also likely to be spontaneous at higher temperatures. 3 Problem Solution 3.1 Total Energies (hartrees) ISSN: Page 92 ISBN:

2 The total energies and zero point energies for the HF and MP2/6-31G* equilibrium geometries are given in Table 1. [3,4-d] 3 -iminazoline-2-one.porphin + (9) Table 1 MP2 /6-31G* total energies and zero point energies (hartrees) for the respective equilibrium geometries Molecule MP2 ZPE (HF) hartree hartree hexa-1,3,5-triyne (1) octa-1,8-dial-2,4,6-triyne (2) octa-8-al-2,4,6-triyne nitrile (3) Mg.octa-8-al-2,4,6-triyne nitrile.porphin Mg.octa-8-al-2,4,6-triyne nitrile.porphin.co. (4) Mg.N-1, 2-(7-al-1,3,5-triyne-heptyl azirine-3-one.porphin (5) Mg.N-1, 2-(7-al-1,3,5-triyne-heptyl) azirine-3-one ammonia.porphin (6) Mg.N-1, 2-(7-al-1,3,5-triyne-heptyl) azirine-3-one ammonia Mg.(8-al-2,4,6 -triyne-1-octenyl) N-3-urea.porphin (7) cis.mg.n-3,5-(6-al-2,4-diyne-1-hexenyl)- 3 - iminazolin-2one.porphin (8) trans.mg.n-3,5-(6-al-2,4-diyne-1-hexenyl)- 3 - iminazolin-2one.porphin (8) biotin Mg.porphin Mg.porphin.CO acetylene diacetylene cyanoacetylene CH 2 =S CO NH H H 2 S H The overall stoichiometry of the formation of biotin from initial reactants Here the initial reactants are taken as follows: H-C C C C-H + H-C C-CN + 2CO + NH3 + CH2=S + 4H2 H = h C10H16N2O2S biotin The enthalpy change is negative indicating that this may be the energetically favourable route to the initial formation of biotin. The intermediates by which this stoichiometric reaction may have occurred are as follows: 3.3The formation of octa-8-al-2,4,6-triyne nitrile Mg.4-(5-al-1,3-pentynyl) thieno ISSN: Page 93 ISBN:

3 The reaction of ynes with carbon monoxide to form an oxo compund which then rearranges has been previously investigated as a difficult, but a well known reaction (12). (1) (2) H = h Free radical reactions between diacetylene and cyanoacetylene are expected to yield the long chain cyanide with low activation energy. (3) H = h There are clearly a number of viable routes to this primary reactant. These are rate determining steps. 3.4 The formation of a magnesium.porphin adduct The way in which a magnesium.porphin complex can form a charge transfer complex with a carbon monoxide at the magnesium ion, which can then migrate to a pyrrole unit to form an excited state three membered ring aziridone under the influence of the magnetic field of the exciting radiation has previously been described (13). The Faraday effect is assumed to be the main determinant of the initial symmetry of the complex, as shown in Fig.1. The tetra-yne may then coordinate with the free magnesium ion. Mg.porphin + CO Mg.porphin.CO H = h Fig.1 The required initial orientation of the octa-8- al-2,4,6-triyne nitrile and carbon monoxide on the porphin catalyst. This appears to be another of the rate determining steps in the formation of biotin analogues which relies on photochemical excitation. Mg.porphin.CO + N C-(C C ) -CH=O 3 (4) N C-(C Mg.porphin.CO H = h C ) 3 -CH=O 3.5 The formation of the Mg.N-1, 2-(7-al- 1,3,5-triyne heptyl) azirine- 3-one ammonia. porphin The activation energy for the carbon monoxide to form a three membered ring was found to be, 0.04 h, whilst the activation energy to open the ring was 0.48 h. The enthalpy change for the addition of carbon monoxide is marginally negative. H = h ISSN: Page 94 ISBN:

4 3.6 The formation of the Mg. (8-al-2,4,6 - triyne-1-octenyl) N-3-urea.porphin (5) The activation energy to open the ring and form the urea is 0.03 h, whilst the energy to form the ring is 0.10 h. The potential energy surface for the formation of the azirine-3-one ring is shown in Fig.2 The enthalpy change is favourable. H = h The potential energy surface for the opening of the ring is given in Fig.3. (7) Fig.2. The potential energy surface for the formation of the azirine-3-one ring where the internal coordinates are: R1=N-CO, R2=C(2)-CO. The minimum of the nitrile and carbon monoxide is at (R1=2.0, R2=1.4). The minimum of the adduct is at (R1=1.4, R2=1.4). The saddle point is at (R1=1.7,R2=1.4). The azirine-3one may form an ammonia with an activation energy of the order of 0.07 h [14]. Fig.3. The potential energy surface for the opening of the azirine ammonia ring to form the urea. The internal coordinates are: A=bend (N-C-O), R1=C(2)-C(NH 2 ). The minimum for the ammonia is at (A=120, R1=1.5). The minimum for the urea is at (A=80.0, R1=2.24). The saddle point is at (A=105.0, R1=1.75). The enthalpy change is favourable. H = h (6) 3.7 The formation of the Mg.N-3, 5-(6-al-2,4- diyne-1-hexenyl)- 3 -iminazolin-2one.porphin ISSN: Page 95 ISBN:

5 The activation energy to close the ring was found to be 0.09 h, whilst the activation energy to open the ring was 0.11 h. The enthalpy change was most favourable for the product as shown, designated cis, The enthalpy change for the formation of the trans isomer was also favourable, H = h (8) The potential energy surface for the formation of the iminazolin-2one is shown in Fig The formation of the Mg.4-(5-al-1,3- pentynyl) thieno [3,4-d] 3 -iminazoline-2- one.porphin + The protonated Mg.porphin.N-3, 5-(6-al-2,4-diyne- 1-octenyl)- 3 -iminazolin-2one is calculated to react directly with thioformaldehyde without any activation energy to form the biotin precursor. Fig.4. The potential energy surface for the formation of the iminiazolin-2one. The internal coordinates are R1=C(2)-N(3), R2=C(3)-H(NH). The minimum for the urea is at (R1=2.3, R2=2.3). The minimum for the iminazoline-2one is at (R1=1.5, R2=1.1). The saddle point is at (R1=1.5, R2=1.75). The protonation of the adduct at any stage appears to be favourable, and greatly lowers the energy of the two isomeric products. (9) The enthalpy change is favourable, H = h The potential energy surface for the addition of thioformaldehyde is shown in Fig.5. For the cis isomer, H = h ISSN: Page 96 ISBN:

6 Fig.5. The potential energy surface for the 1,3 addition of thioformaldehyde. The internal coordinates are R1=C(4)-CH 2 (thioformaldehyde), R2=C(1)-S(thioformaldehyde). The minimum for the reactants is at R1>2.3, R2>2.6. The minimum for the adduct is at (R1=1.5, R2=1.8). There is not a saddle point on this depiction. Mild reduction of the slightly boat conformation fixes the symmetry of the ring to the cis hydrogen conformation in preference to that of the trans hydrogen isomer. 3.9 The formation of the biotin. Further reduction produces the correct biotin isomer and the original catalyst. The enthalpy change is, H = h 4. Conclusion From the postulates presented here it is clear that prebiotic paths to the biologically active molecules are kinetically accessible, if not unique. Further work at a higher level of accuracy may result in a correction to the enthalpies calculated here. The formation of biotin is thought to be representative of the prebiotic formation of compounds of major biological significance. References [1]. Loudon,J.D.: 1957, in Rodd,E.H.(ed), Chemistry of Carbon Compounds, Elsevier, Amsterdam,1V A,pp [2]. Lehninger,A.L.:1975, Biochemistry,Worth, New York,p.337. [3]. Thaddeus,P. in Leach,S,Smith,I, and Cockell,C (ed.) Conditions for the Emergence of Life on the Early Earth, Phil.Trans.R.Soc. B,361,(2006) p [4].Cheung,A.C.,Rank,D.M.,Townes,C.H.,Thornton, D.D. and Welch,W.J.Phys.Rev.Lett,21(1968),1701. [5]. Strobel,D.F.: (1983), Int.Rev.Phys.Chem. 3,145 [6]. Seki,K.,He,M.,Liu,R. and H.Okabe.:1996, J.Phys.Chem.100,3,5349. [7]. Clarke,D.W.:1994, Origins Life Evol. Biosphere 24,2/4,130. [8]. Gaussian98:1998 Users Reference,Gaussian Inc.,Carnegie Office Park, Bldg.6., Pittsburgh, PA 15106, USA. [9].Hehre,W.J.,Random,L,Schleyer,P.V.R.,and Pople,J.A.:1986,Ab Initio Molecular Orbital Theory, Wiley, New York. [10].Pople,J.A.,Schlegel,H.B.,Krishnan,R., DeFrees,D.J., Binkley,J.S., Frisch,M.J.,Whiteside, R.A.,Hout,R.J.,and Hehre,W.J.:1981, Int.J.Quantum Chem.Symp.S15,269. [11]. Aylward,N.N and Bofinger, N, OLEB,6(2001) p [12]. Aylward,N.N and Bofinger, N, OLEB,35 (4) (2005) p [13]. Aylward, N.N. and Bofinger,N, in Palyi,G.,Zucchi,C, Cagliot,L (eds.), Progress in Biological Chirality, Elsevier,Oxford (GB), (2004), ch2,p429. [14]Aylward,N.,and Bofinger,N. Biophysical Chemistry 121(3) (2006).. Acknowledgements Appreciation is expressed to Dr.N.Bofinger and the Centre for Instrumental and Developmental Chemistry for the equipment and facilities; to Mr.A.Lewis, S.Walsh, and Dr.J.Young and M.Barry of the Supercomputing Department N.Aylward is grateful for the award of a scholarship from QUT. ISSN: Page 97 ISBN: