Indian Journal of Chemistry Vol. 45A, Jan uary 2006. pp. 45-50

Effect of electrostatic potential of transition state on the stereoselectivity in ' ene cyclisation: A theoretical study

Sukhendu Roy, Kuheli Chakrabarty, Nityagopal Mondal & Gourab Kanti Das*

Departme nt of Chemistry, Visva-B harati, Santiniketan 731 235, West Bengal, India Email: bubuldas@hotmail.com

Received 16 November 2004; revised 31 October 2005

In vest igation on the iransition structure of the ene reaction between propyne and forma ldehyde reveal s that negati ve electrostatic potential is generated around the carbonyl oxygen and acetylenic group. The generated electrostatic potential cont ro ls the o ri en tation of the oxygenated substituent present on the forming cyclohexane ring in ene cycli sati on. Data from the study of mono substi tuted transition structures have been used to ra tionalize the stereoselec ti vity of an ene cyc li sation with poly oxygenated substituents.

Inositol 1,4,5-trisphosphate is an important secondary messenger in cells, which causes the rapid release of Ca2

+ from intracellular stores- the endoplasmic

reticulum and III smooth muscle cells- the sarcoplasmic reticulum i

. The elevated Ca2+ level then

initiates various biological processes in the cell. Overall this compound couples activity of cell surface receptors with various cellular responses . So, it is not surprising that inositol and other similar compounds are the object of a great deal of sy nthetic work 1.2 . For the synthesis of optically pure compounds many methods utilize the technique of resolution3

. However Clive et al.4 have reported a synthetic route by which it is possible to obtain thi s product from another chiral compound. The key step in this total synthesis is based on an ene cyclisation, which converts a linear chain containing a carbonyl enophile and acetylenic ene into a six membered ring compound (Scheme 1).

PmbO OBn

R~opmb ene cyciization .

OBn

Scheme 1

pm~bH OBn OPmb

y OBn

H

The preference of various oxygenated substituents to take different orien tations on the forming cyclohexane ring is found to be quite abnormal according to the conventional concepts. The general trend for a substituent to occupy the eq uatorial position on the forming cyclohexane ring in chair conformation has not always been observed here. Two oxygenated substituents always prefer to retain ax ial orientation in the product while others remain in equatorial orientation. The rationali zation of stereoselectivity by determining the relative stabi lity of different transition structures on the basis of quantum mechanical calculation, is the subject matter of this paper.

Our previous reports6.7 show that a strong negative

electrostatic field is generated around the transi tion state of basic ene reaction with carbonyl or acetylenic enophile. In some ene cyclisations, this electrostatic field coupled with other steric interactions , controls the orientation of other oxygenated substituents present on the forming cyclohexane or cyclopentane ring. In the present study , our aim is to show how the generated electrostatic field' in a carbonyl ene cyclisation containing an acetylenic group as reactant affects the overall stereoselectivity of the reaction product. The knowledge acquired from such study of mono substituted transition structures can help us to ~vf\ l "jll the abnormal h ph ? ";",,r :,f <tprenselert; vit" "c

• I " \ , ~ '" : ; '", " "':' ! ! ' . , ~ ,. : 'J ". ' , ',

i " : i . ' ,~,

46 [NOlAN J CHEM. SEC A, JANUARY 2006

experimental observations. Our experiences also show that the stereoselectivity of ene cyclisation can be predicted with a sufficient accuracy using the energies of the TSs at the similar level of calculation6

.9

, lo. We have used the same level of theory to rationalize the stereoselectivity in forming six membered ring compound.

Methodology Molden II software was used to construct all the

trial transition structures and these structures were optimized at HF level using 6-31G* basis set. Single point energies were calculated using B3L YP/6-31 G* method I2

•13

• For optimization and energy calculation GAMESS software l4 was used. Each optimized species was characterized as corresponding to a saddle point on the energy hypersurface by means of vibrational analysis; a transition structure (TS) possesses only a single imaginary vibrational frequency. Further confirmation of the transition structure was done by following the intrinsic reaction co-ordinate (lRC) pathway. The end points of the IRC pathway were found to be reactant and product. The electrostatic potential IS (ESP) surface for different TSs was calculated and plotted uSing Molden software.

Results and Discussion Basic transition structure and its electrostatic potential surface

The basic intermolecular ene reaction with an acetylenic group may be formulated as shown In

Scheme 2. 3 CH

CH

' Ii /~' iC

\ II + III 0 C

5 0 " , : a C

I ' H . . . . ' 1 ' H \, CH, CH2

TS

Scheme 2

In the concerted process shown in Scheme 2, the reaction passes through the single transition structure (TS). The propyne molecule on reaction with methanal forms the allene type of compound by transferring one hydrogen atom from the methyl group of propyne to the carbonyl oxygen and simultaneous formation of f C-C bond. The optimized transition structure in ball and stick model and its isosurface plot of the ESP generated around the system is shown in Fig.l.

I

B II

II

Fig. I--(a) Transition structure of intermolecular ene reaction between propyne and methanal, and. (b) the corresponding isodensity surface color mapped with ESP of the same structure (blue> 0. 1; light blue=0.005; green=O.OO; yellow=-0.005 and red < -0.01), and, (c) transition structure viewed along the formin g C(3)-C(4) bond.

Fig . 2-Possible binding modes in basic transition structures to generate TS for ene cycli sation.

The surface map (1 b) clearly reveals that a negative electrostatic field is generated at the outer surface of carbonyl oxygen and acetylenic moiety . however, the former field is stronger than the latter. It is expected that the electrostatic effects play a vital role in directing the stereoselectivity in a more complex situation such as cyclisation reactions. In the next section, a detailed investigation for the substituent effect on the stereoselectivity in a cyclisation process has been shown.

Transition structure of the ene cyclisation forming a six­membered ring

Transition structures of ene cyclisation were constructed by connecting the 3 and 4 atoms of Fig. I with an alkyl chain of four carbon atoms. The possible two binding modes, as shown in Fig. 2, give

ROY et 01.: EFFECT OF ELECTROSTATrC POTENTIAL ON STEREOSELECTIVITY IN ENE CYCLISATION 47

two degenerate structures. Both these structures are chiral and one is the enantiomer of the other.

Previous reports show that the six membered ring structure, formed in an ene cyclisation, generally prefers to adopt a chair-like conformation9

. To avoid any torsional strain the constructed forming ring has been given a chair conformation. The optimized transition state is shown in Fig. 3.

Hydrogen atoms connected to the atom number 4',5',6' and 7' are axially (marked as 'a') or equatorially (marked as 'e') oriented. With the help of this TS, other methyl or methoxy substituted TSs were constructed and optimized, The total and relative energies of the substituted systems are gathered in Table I.

For methoxy substituted TS , we have selected the lowest energy conformations amongst the different conformations. The relative energies of methyl substituted TSs, as shown in Table I, clearly suggest

Fig. 3--Oplimi zed TSs for ene cyc lisati on forming a six membered ring stn; ~·l. ure. The forming ring is in chair conformation and the hydrogen on the forming ring are oriented in axia l or equatorial positi on.

that all equatorial isomers are favoured Over the axial isomer and this fact supports the general rule that the substituent prefers equatorial position over the axial one on a cyclohexane ring in its chair conformation. However, the stability order of methoxy derivati ves are found to be quite anomalous and position dependent. In particular, the axial orientation at 5' and 7' positions is more favoured over the equatOlial one. It occurred to us that the consideration of electrostatic effect along with the steric effect is· necessary while determining the stability of the transition state in a methoxy substituted cyclisation reaction. To reveal the fact in more detail, we have analyzed electrostatic potential around the cyclisation TS containing nicthoxy substituent (Figs 4-6).

It is evident that the methoxy group in its axial orientation at 4' position suffers from the repulsive effect of negative electrostatic field generated by the carbonyl oxygen as well as that of acetylenic group (Fig. 4).

However, equatorially oriented methoxy group experiences the negative field due to carbonyl oxygen only and acts as the favourable TS . The favorable TS with methoxy group at 5' and 7' positions are shown in Figs 5 and 6. These figures clearly indicate that the axially oriented methoxy group at 5' or 7' positions is spatially very close to the carbonyl carbon of the enophile and as a result, these groups feel the attractive force from the positive center at the carbonyl carbon. The 6' position is far away from the actual reaction center and the spatial orientation of its axial position (Fig.7a) may feel the repulsive electrostatic

Table I-,Total and relative energies of the methyl and methoxy substituted TSs

Orientation and positi on of Total energy of the TSs ( a. u. ) Relative energies of axia l/equatorial TS (kcalmor')

the substitutents (Fig. 3) R=CH3 R=OCH3 R=CH3 R=OCH,

4 'a -423.45250 1" -498.289810" 1.17" 0.47" -426.214593 h -501.384800h 1.12h LBh

4 'e -423.454361 " -498.290552" 0.00" 0.00" -426.21 6383b -501.386918b O.OOb O.OOh

5'a -423.450393" -498.29 1530" 2.60" 0.00" -426.212197h -501.386859h 2.23h O.OOh

5'e -423.454539" -498.290394" 0.00" CUI" -426.215752b -501.385255h O.OOb 1.0l h

6'a -423.452456" -498.290378" 1.64" 0.92" -426.214120h -5 01.385615 h 1.40h 0.73"

6'e -423.45507 1" -498.291851 " 0.00" 0.00" -426.216342 ~.50 1.386776h O.OOh Cl.OD

7'a -423.451431 "-498.290657" 2. 19" 0.00" -426.214593b -501..385986b 1.05h O.OOh

7'e -423.454914" -498.290255" 0.00" 0.25" -426.216266b -50 1~385527h O.OOh 0.23h

"HF/6-3 1 G* (energies are ZPE corrected) . hB3L YP/6-3 1G*//HF/6-3 1 G*.

48 INOlAN J CHEM. SEC A, JANUARY 2006

Fig. 4--Axial isomer of the 4'methoxy derivative of TS. [(a) TS viewed along the forming C-C bond; (b) its top view; and, (c) the corresponding isodensity surface color mapped with ESP. The electrostatic potential shows the interacting three negative regions, originated from acetylenic groups and two oxygen atoms of carbonyl and methoxy groups.

+veesp around carbonyl carbon

Fig. 5--TS with the methoxy group at 5' position oriented ax ially. [(a) Ball and stick model of the optimized TS, and, (b) the isodensity surface color mapped with ESP].

field generated at the reaction center. Probably, this effect makes equatorial isomer (Fig.7b) at 6' position as a favorable TS over the axial one. Stereoselectivity in ene cyclisation for a po\yoxygenated substrate

Discussion in the above section clearly reveals that the methoxy group at 5' or 7' positions prefers to orient axially, whereas the same group when placed at 4' or 6'-position favors equatorial orientation. Hence, without considering the mutual effect of adjacent substituents it may be predicted that compound 2 will be a preferred isomer by ene cyclisation from a polyoxygenated substrate like compound I (Scheme 3).

Comparison of the orientation of the oxygenated groups in product 2 (Scheme 3) and that found in experimentally observed product (Scheme I) reveals that maximum similarity I;l,ctween their stereochemistry may be obtained if ring flipping occurs in compound 2 to compound 3. The only difference between the compound 3 and the reported one is at the chiral center at 6'-position. Our prediction shows that the group at 6' position prefers to orient axially (compound 3 in Scheme 3), whereas in actual practice it orients equatorially (Scheme 1).

It appears to us that the orientation of the substituent at 6' position is altered due to the effect of the adjacent oxygenated groups. The presence of two oxygenated groups in their favorable axial orientation at 5' and 7'

Fig. 6--TS with the methoxy group at 7' position oriented axially. [(a) Ball and stick model of the optimized TS, and, (b) the isodensity surface color mapped with ESP].

OM H2C~6' e ::::::--... 7' H3C~OMe OMe

-.....0:::: - HO 5' 0 ..... OMe 4'0 e

OMe OMe OMe

-7'

OH 6' 5'

Me~OMe o 4' ,0 0 e

H2C OMe

2 3

Scheme 3

ROY el at.: EFFECT OF ELECTROSTATIC POTENTIAL ON STEREOSELECTIVITY IN ENE CYCLISATTON 49

Fig. 7-TS with methoxy group at 6'position oriented (a) axially or (b) cq uatorially.

Fig. 8--TSs with methoxy substituents at 5',6' and 7' positions. Relative energy ca lculation shows that 6'-axial con former (a) is stabili zed by 4.21 kca lmor i over the 6' equatorial conformer (b).

H

H c-O 3

H

±ap (a)

H H

H c-O 3

H

positions during the formation of TS interacts somehow with the 6' equatorial isomer and makes the methoxy at 6' position to orient axially. To prove this interaction, we have constructed TS with methoxy groups at 5' and 7' positions in their favourable axial orientation and placed another methoxy group at 6' position in equatorial or in axial orientation. Optimized TSs of these two structures are shown in Fig. 8.

A close observation of the conformation of the TS (Fig. 8b) with equatorial methoxy group at 6'position reveals that the substituent orients in ± ap conformation in its favorable state. This conformation suffers from two butane-gauche interactions (Fig. 9a) , which appears to make it sterically more congested than two other possible conformers in -sc or +sc orientations (Fig. 9(b & c)) . However, the latter two conformers suffer from the oxygen lone-pair lone-pair interaction with other meth~xy groups at 5' or 7'

position. As a result, the ± ap conformer, in spite of suffering from two butane-gauche interactions, acts as a low energy conformer in the possible set of orientations in equatorial direction.

We feel that due to such butane gauche interactions, the equatorial configuration at 6' position is less favorable than the axial one. The energy calculation of the optimized geometries also supports this fact (Fig. 8). This implies that the methoxy group at 6'-position in compound 2 (Scheme 3) should be oriented axially. In actual reaction conditions, ring flipping makes it an equatorially orientated isomer and the overall stereoselectivity of the reaction agrees with the experimental result.

Conclusions The preference for the orientation of alkyl

substituents on the forming ring in ene cyclisation can be predicted on the basis of steric interaction only. However, consideration of the electrostatic potential

H

H H H

H C-O 3

-sc +sc (b) (c)

Fig. 9--Possibl e low energy conformers of the TSs with 6'-methoxy group in its equatorial orientations. Conformers (b) and (c) suffer from one butane-gauche interaction whereas conformer (a) suffers from two such interactions.

so IN DIAN J C HEM, SEC A. JANUA RY 2006

generated at TS is necessary when preferred ori entati on of the oxygenated substituent is to be determined. For the rati onalization of the stereoselec ti vity in ene cycli sation with poly substituents. as fo und in the key step of the synthesis of inositol deri vati ve, quantum mechanical method will be very helpful.

Acknowledgements We gratefull y acknowledge the help of Dr.

Dhananj ay Bhattacharyya, Biophysics Division, Saha Inst itu te of Nuclear Phys ics, Kolkata, for optimizing some transition structures in his computati onal laboratory. We are also thankful to UGC, New Delhi , Indi a, for prov iding fi nancial support for this research work.

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