4th WSEAS International Conference on MATHEMATICAL BIOLOGY and ECOLOGY (MABE'08) Acapulco, Mexico, January 25-27, 2008

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 [email protected] http://www.qut.edu.au

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 study of its photochemistry indicated that Biotin, also called vitamin H or coenzyme R, diacetylene can be produced [6,7]. isolated from yeast and other micro-organisms [1], However, for a minor compound to be produced in a is an essential dietary factor whose deficiency small quantity at least one of the steps in the causes toxicity [2]. Biotin contains fused imidazole synthesis is expected to be only marginally and thiophene rings and functions in the enzymatic favourable. 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 2 Problem Formulation carboxylate anion by nucleophilic attack on the The computations tabulated in this paper used the carbon dioxide. GAUSSIAN98 [8] commercial package. The standard calculations at the HF and MP2 levels This paper is the first to suggest a prebiotic route to including zero-point energy corrections [9], together the syntheis of biotin analogues based on with scaling [10], using the same basis set, 6-31G*, spontaneous reactions in a presumed primeval are as previously published [11]. Enthalpy changes atmosphere. The synthesis is based on reactant at the MP2 level not including scaled zero point molecules known to exist in space such as, energies are designated as ∆H(MP2). The charge H-(C≡C)3 -CN, and H-(C≡C)4-CN [3] and the two transfer complexes are less stable when calculated at most common molecules in the universe, hydrogen the Hartree Fock level [9]. and carbon monoxide. Also required as reactants If the combined energy of the products is less than are ammonia, and water [4]. The source of the sulfur the combined energy of the reactants it may show is here taken to be hydrogen sulfide and that the reaction is also likely to be spontaneous at thioformaldehyde which have also been detected [3]. higher temperatures. For this work the assumption is also made that some of the components that are presently found on Titan 3 Problem Solution [5] are also present, namely cyanoacetylene, and a 3.1 Total Energies (hartrees)

ISSN: 1790-2769 Page 92 ISBN: 978-960-6766-32-9 4th WSEAS International Conference on MATHEMATICAL BIOLOGY and ECOLOGY (MABE'08) Acapulco, Mexico, January 25-27, 2008

The total energies and zero point energies for the HF [3,4-d] ∆3-iminazoline-2-one.porphin + and MP2/6-31G* equilibrium geometries are given (9) in Table 1. -2225.72718 0.44561

Table 1 biotin -1046.24222 0.28066

MP2 /6-31G* total energies and zero point energies Mg.porphin -1185.12250 (hartrees) for the respective equilibrium geometries Mg.porphin.CO -1297.93784 ______Molecule MP2 ZPE (HF) acetylene -77.06679 0.02945 hartree hartree ______diacetylene -153.00240 0.04203 hexa-1,3,5-triyne (1) cyanoacetylene -169.07910 0.02989 -228.92175 0.05261 octa-1,8-dial-2,4,6-triyne CH2=S -436.75511 0.02389 (2) -454.96369 0.07734 CO -113.02818 0.02431 octa-8-al-2,4,6-triyne nitrile (3) NH3 -56.35738 0.03529 -433.95605 0.06573 Mg.octa-8-al-2,4,6-triyne nitrile H2 -1.14414 0.01034

.porphin H2S -398.43613 0.01127 -1619.10088 0.35021 Mg.octa-8-al-2,4,6-triyne nitrile H- -0.42891 .porphin.CO. ______(4) -1732.06121 0.35940 3.2 The overall stoichiometry of the Mg.N-1, 2-(7-al-1,3,5-triyne-heptyl formation of biotin from initial reactants azirine-3-one.porphin (5) -1732.07697 0.36001 Here the initial reactants are taken as follows: Mg.N-1, 2-(7-al-1,3,5-triyne-heptyl) azirine-3-one ammonia.porphin H-C C C C-H + H-C C-CN + 2CO + NH3 + CH2=S + 4H2 (6) -1788.45113 0.40428 C10H16N2O2S Mg.N-1, 2-(7-al-1,3,5-triyne-heptyl) + biotin azirine-3-one ammonia -1788.75381 0.41541 ∆ H = -0.33024 h Mg.(8-al-2,4,6 -triyne-1-octenyl) N-3-urea.porphin (7) The enthalpy change is negative indicating that this -1788.50664 0.40272 may be the energetically favourable route to the 3 cis.Mg.N-3,5-(6-al-2,4-diyne-1-hexenyl)-∆ - initial formation of biotin. The intermediates by iminazolin-2one.porphin which this stoichiometric reaction may have (8) occurred are as follows: -1788.93867 0.42119 3 trans.Mg.N-3,5-(6-al-2,4-diyne-1-hexenyl)-∆ - 3.3The formation of octa-8-al-2,4,6-triyne iminazolin-2one.porphin nitrile (8) -1788.92178 0.42172

Mg.4-(5-al-1,3-pentynyl) thieno

ISSN: 1790-2769 Page 93 ISBN: 978-960-6766-32-9 4th WSEAS International Conference on MATHEMATICAL BIOLOGY and ECOLOGY (MABE'08) Acapulco, Mexico, January 25-27, 2008

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 = 0.02782 h

Free radical reactions between diacetylene and cyanoacetylene are expected to yield the long chain cyanide with low activation energy.

(3)

∆ H = 0.00886 h Fig.1 The required initial orientation of the octa-8- al-2,4,6-triyne nitrile and carbon monoxide on the porphin catalyst. There are clearly a number of viable routes to this primary reactant. These are rate determining steps. This appears to be another of the rate determining steps in the formation of biotin analogues which relies on photochemical excitation. 3.4 The formation of a magnesium.porphin Mg.porphin.CO + N C-(C C ) -CH=O adduct 3

N C-(C C ) -CH=O The way in which a magnesium .porphin complex 3 can form a charge transfer complex with a carbon monoxide at the magnesium ion, which can then Mg.porphin.CO migrate to a pyrrole unit to form an excited state (4) three membered ring aziridone under the influence of the magnetic field of the exciting radiation has ∆ H = -0.16824 h 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 3.5 The formation of the Mg.N-1, 2-(7-al- magnesium ion. 1,3,5-triyne heptyl) azirine- 3-one ammonia. porphin Mg.porphin + CO → Mg.porphin.CO The activation energy for the carbon monoxide to ∆ H = 0.21284 h 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 = -0.01431 h

ISSN: 1790-2769 Page 94 ISBN: 978-960-6766-32-9 4th WSEAS International Conference on MATHEMATICAL BIOLOGY and ECOLOGY (MABE'08) Acapulco, Mexico, January 25-27, 2008

3.6 The formation of the Mg. (8-al-2,4,6 - triyne-1-octenyl) N-3-urea.porphin

The activation energy to open the ring and form the urea is 0.03 h, whilst the energy to form the ring is

(5) 0.10 h.

The potential energy surface for the formation of the azirine-3-one ring is shown in Fig.2

(7)

The enthalpy change is favourable.

∆ H = - 0.05690 h

The potential energy surface for the opening of the ring is given in Fig.3.

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(NH2). 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).

(6) The enthalpy change is favourable. ∆ H = -0.06323 h

3.7 The formation of the Mg.N-3, 5-(6-al-2,4- diyne-1-hexenyl)-∆∆∆3-iminazolin-2one.porphin

ISSN: 1790-2769 Page 95 ISBN: 978-960-6766-32-9 4th WSEAS International Conference on MATHEMATICAL BIOLOGY and ECOLOGY (MABE'08) Acapulco, Mexico, January 25-27, 2008

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 = -0.40921 h

3.8 The formation of the Mg.4-(5-al-1,3- (8) pentynyl) thieno [3,4-d] ∆∆∆3-iminazoline-2- + The potential energy surface for the formation of the one.porphin iminazolin-2one is shown in Fig.4. 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 (9) 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 The enthalpy change is favourable, for the iminazoline-2one is at (R1=1.5, R2=1.1). The saddle point is at (R1=1.5, R2=1.75). ∆ H = -0.05414 h

The protonation of the adduct at any stage appears to The potential energy surface for the addition of be favourable, and greatly lowers the energy of the thioformaldehyde is shown in Fig.5. two isomeric products.

For the cis isomer, ∆ H = -0.42658 h

ISSN: 1790-2769 Page 96 ISBN: 978-960-6766-32-9 4th WSEAS International Conference on MATHEMATICAL BIOLOGY and ECOLOGY (MABE'08) Acapulco, Mexico, January 25-27, 2008

Fig.5. The potential energy surface for the 1,3 References addition of thioformaldehyde. The internal coordinates are R1=C(4)-CH2(thioformaldehyde), [1]. Loudon,J.D.: 1957, in Rodd,E.H.(ed), R2=C(1)-S(thioformaldehyde). The minimum for Chemistry of Carbon Compounds, Elsevier, the reactants is at R1>2.3, R2>2.6. The minimum Amsterdam,1V A,pp.310-311. for the adduct is at (R1=1.5, R2=1.8). There is not a [2]. Lehninger,A.L.:1975, Biochemistry,Worth, saddle point on this depiction. New York,p.337. [3]. Thaddeus,P. in Leach,S,Smith,I, and Cockell,C (ed.) Conditions for the Emergence of Life on the Mild reduction of the slightly boat conformation Early Earth, Phil.Trans.R.Soc. B,361,(2006) fixes the symmetry of the ring to the cis hydrogen p.1681. conformation in preference to that of the trans [4].Cheung,A.C.,Rank,D.M.,Townes,C.H.,Thornton, hydrogen isomer. D.D. and Welch,W.J.Phys.Rev.Lett,21(1968),1701. [5]. Strobel,D.F.: (1983), Int.Rev.Phys.Chem. 3,145 3.9 The formation of the biotin. [6]. Seki,K.,He,M.,Liu,R. and H.Okabe.:1996, J.Phys.Chem.100,3,5349. Further reduction produces the correct biotin isomer [7]. Clarke,D.W.:1994, Origins Life Evol. Biosphere and the original catalyst. 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) p481-500.

The enthalpy change is, [12]. Aylward,N.N and Bofinger, N, OLEB,35 (4) ∆ H = -0.64777 h (2005) p345-368 [13]. Aylward, N.N. and Bofinger,N, in Palyi,G.,Zucchi,C, Cagliot,L (eds.), Progress in 4. Conclusion Biological Chirality, Elsevier,Oxford (GB), (2004),

ch2,p429. From the postulates presented here it is clear that [14]Aylward,N.,and Bofinger,N. Biophysical prebiotic paths to the biologically active molecules Chemistry 121(3)185-193(2006). 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.

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: 1790-2769 Page 97 ISBN: 978-960-6766-32-9