Cundari Th.R. -- Computational Organometallic Chemistry-0824704789

228	Taber et al.

Scheme 8

complex 36 is in fact an efficient catalyst (1610 turnovers) for the cyclization of

37 to 38.

10. DESIGN OF AN ENANTIOSELECTIVE CATALYST

With the assurance that our computational approach permitted the reliable prediction of the three-dimensional shape of the carboxylate ligands around the Rh– Rh complex, we turned our attention to the rational design of chirally substituted analogs (27,28) that might direct the absolute sense of the cyclization of 37 to 38 (Scheme 8). The best catalyst reported to date for the cyclization of 37 is that of Hashimoto (29), which effects (Scheme 8) C–H insertion with 27% ee.

There are two competing transition states for C–H insertion, 39 and 40 (Scheme 9). In transition state 39, insertion is taking place into HA. In transition state 40, insertion is taking place into the enantiotopic HB. The challenge is to design a chiral rhodium catalyst such that transition state 39 is favored over transition state 40 by at least the 2.5 kcal/mol we have observed is necessary to expect substantial diastereoselectivity in the C–H insertion reaction.

In cartoon form, what is needed is a carboxylate that will extend sterically to set up the three-dimensional environment around the apical position of the Rh, where the carbene binds and where the C–H insertion reaction is taking place. This is depicted schematically in Scheme 10. The challenge, then, is to design a ligand such that the resulting chiral environment favors transition state

Scheme 9

Rhodium-Mediated Intramolecular C–H Insertion

229

Scheme 10

41, leading to one enantiomer, over transition state 42, leading to the competing enantiomer.

We used our computationally based model to design and assess a series of chiral Rh(II) carboxylates. It was quickly apparent that designs based on simple mono carboxylates were too flexible—there was never an unequivocal energy difference between the two competing diastereomeric transition states. We are therefore pursuing two complementary strategies: the use of ortho-metalated head-to-tail triarylphosphine complexes, and the use of diacids that can bridge two sites on the dirhodium core.

11. TRIARYLPHOSPHINE-DERIVED CATALYSTS

This part of the work (30) was carried out in collaboration with Professor Pascual Lahuerta of the University of Valencia, Spain. Most of the work was done by Salah Stiriba, a Ph.D. student from Valencia who also spent three months in our laboratory.

All approaches to the design of enantiomerically pure Rh(II) catalysts (28– 30) had depended on the attachment of enantiomerically pure ligands to the rhodium core. We undertook a complementary strategy (Scheme 11), the preparation

Scheme 11

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of Rh(II)-dimer (P)-44 and its enantiomer (M)-44 having backbone chirality (31,32).

Our proposed transition state for Rh-mediated C–H insertion seemed to fit the chiral twist of complexes (P)-44 and (M)-44 particularly well. In fact, using the approach outlined earlier we calculated that the transition state 46a (Scheme 12) should be sterically favored over the transition state 46b by 4.2 kcal/mol.

Motivated by this possibility, we considered strategies by which complexes such as (P)-44 and (M)-44 might be obtained as single enantiomers. Our first approach, separation of the diastereoisomers resulting from addition of chiral ligands to the axial positions of the dimers [to make Rh2(PC)2(O2CR)2L2*], turned out not to be practical, due to the high kinetic lability of those ligands. We therefore turned to an alternate possibility, separation of the diastereomers derived from the attachment of chiral carboxylate groups [Rh2(PC)2(O2CR*)2L2].

As a chiral auxiliary (Scheme 13) we used the inexpensive N-(4-methylphe- nylsulfonyl-(L)-prolinate), (Protos, 48). Replacement of acetate by Protos in the orthometalated acetate mixture (P)-44 and (M)-44 yielded the expected 1:1 mixture of the desired diastereomers 49a and 49b. These were separable by silica gel chromatography (10% Et2O/CH2Cl2).

The two enantiomerically enriched complexes (P)-50 and (M)-50 were obtained via ligand exchange of 49a and 49b (separately) with trifluoroacetic acid. The enantiomeric purities of (P)-50 and (M)-50 ( 98% ee) were checked by 31P NMR in the presence of ( )-1-1(1-naphthyl)ethylamine. The absolute configurations of (M)-50 and (P)-50 were established by X-ray diffraction. Further exchange with pivalic acid then gave (M)-51 and (P)-51.

Scheme 12

Rhodium-Mediated Intramolecular C–H Insertion

231

Scheme 13

11.1.Assessment of Catalyst Reactivity

It is not likely that a highly reactive catalyst will be highly selective. Electron donation from the target C–H bond, and concomitant commitment to bond formation will be too early, when the target C–H is at too great a distance to feel the chirality of the ligands on Rh. We therefore needed a method to establish the relative reactivity of a series of Rh catalysts. We have developed ester 52 (Scheme 14) as our standard substrate. We have observed (4) that on exposure to rhodium [tetrakis]trifluoroacetate, 52 gave only the eliminated product 54. On exposure to rhodium [tetrakis]pivalate, on the other hand (pivalate is the most electron-donating ligand we have yet found), 52 gave an 8:1 ratio of 53 to 54. Rhodium [tetrakis]acetate gave about a 2.3:1 ratio of 53 to 54, and rhodium [tetrakis]octanoate gave a 4:1 ratio. We have therefore taken the 53/54 ratio to be a useful measure of the reactivity (correlating with the electrophilicity and thus with the length of the incipient C–C bond at the point of commitment to cyclization) of a rhodium complex. Unfortunately, the chiral Rh complexes prepared by Doyle (27) gave only elimination from 52, with no 53 being observed at all. By

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Scheme 14

this same analysis, it was apparent that the orthometallated triphenylphosphine catalysts are somewhat more reactive than the [tetrakis]carboxylates.

11.2.Enantiomeric Excess

We knew from the cyclization/elimination ratio that the Rh carbenes derived from (P)-50 and (P)-51 were very reactive, and so we did not expect them to be highly selective. We were delighted to observe that even these very reactive catalysts, with commitment to bond formation occurring far from the chiral environment of the ligands, still gave significant enantiomeric excess. It is noteworthy that each of the three substrate types, 52, 55, and 57 (Scheme 15), showed about

Scheme 15

Rhodium-Mediated Intramolecular C–H Insertion

233

the same degree of enantioselectivity. It is especially encouraging that the major enantiomer observed is in each case the one predicted by our computational model.

12. DIRECTIONS FOR THE FUTURE

At 27% enantiomeric excess, we are observing a ∆∆G of about 0.4 kcal/mol, or about 10% of that estimated computationally. Our hypothesis is that the enantiomeric excess is low because commitment to bond formation with the reactive carbene is occurring very early. With an early, open transition state, the substrate is not feeling the full influence of the chiral ligands on rhodium. We propose to test this hypothesis by preparing Rh complexes that will give less reactive carbenes and assessing their catalytic activity. We are pursuing the following two complementary strategies.

12.1.More Electron-Donating Ligands

It is apparent from the results with the cyclization of 52 to 53 vs. 54 (Scheme 14) that more electron-withdrawing ligands on the Rh make the derived carbene more reactive. Thus, we should be using more electron-donating phosphines to prepare analogs of (M)-50 and (M)-51. So far, attempts to prepare such analogs have failed at the orthometallation stage.

12.2.Chiral Analogs of Pivalate

Electronically, it is important that the carboxylate ligand on Rh be as electrondonating as possible. In practice, this means that α,α,α-trialkylated carboxylates are going to be the most effective. Combination of this concept with the bridged design 59 (Scheme 16) and the need to make the ligand usefully chiral led to the ligand 60. It was envisioned that as 60 wrapped equatorially around the Rh– Rh core, the cyclohexyl rings would extend outward. The phenyl substituents would then project upward and downward, creating a chiral space around the apical position of the Rh, where the carbene would be located.

We have not yet prepared 60, but we have calculated that one of the two diastereomeric transition states for C–H insertion (Scheme 17) would be favored over the other by 8.2 kcal/mol. This suggests that 61 and 62 could be highly selective catalysts for C–H insertion.

One advantage of this approach is that we plan to assemble 60 in a modular fashion (Scheme 18). By systematically varying the pendant arene, the cycloalkane with its substituents, and the group that bridges the two carboxylates, we should be able prepare a combinatorial family of catalysts.

234	Taber et al.

Scheme 16

Scheme 17

Scheme 18

Rhodium-Mediated Intramolecular C–H Insertion

235

REFERENCES

1.(a) DF Taber, EH Petty. J Org Chem 47:4808–4809, 1982. (b) DF Taber, RE Ruckle Jr. J Am Chem Soc 108:7686–7693, 1986.

2.For general reviews of rhodium mediated C–H insertions see: (a) DF Taber. Comprehensive Organic Synthesis. In G Pattenden, ed. Oxford: Pergamon Press, 1991, Vol 3, pp 1045–1062. (b) A Padwa, DJ Austin. Angew Chem Int Ed Engl 33:1797– 1815, 1994. (c) T Ye, MA McKervey. Chem Rev 94:1091–1160, 1994. (d) MP Doyle, MA McKervey, Y Tao. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds, New York: Wiley, 1998.

3.DF Taber, RE Ruckle, Jr., MJ Hennessy. J Org Chem 51:4077–4084, 1986.

4.DF Taber, MJ Hennessy, JP Louey. J Org Chem 57:436–441, 1986.

5.DF Taber, K You, Y Song. J Org Chem 60:1093–1094, 1995.

6.DF Taber, KK You, AL Rheingold. J Am Chem Soc 118:547–556, 1996.

7.For related analyses of transition states for Rh carbene insertions, see: (a) MP Doyle, LJ Westrum, WNE Wolthius, MM See, WP Boone, V Bagheri, MM Pearson. J Am Chem Soc 115:958–964, 1993. (b) KC Brown, T Kodadek. J Am Chem Soc 114: 8336–8338, 1992. (c) MC Pirrung, AT Morehead Jr. J Am Chem Soc 116:8991– 9000, 1994. (d) HML Davies, NJS Huby, WR Cantrell Jr, JL Olive. J Am Chem Soc 115:9468–9479, 1993.

8.Alternatively, the initial complex of the electron-deficient carbon with the electron density in the target C–H could be depicted as a three-center, two-electron bond (Ref. 7a). We initially took this approach computationally, but found that the results did not correlate with the diastereoselectivity observed for the reaction.

9.DF Taber, EH Petty, EHK Raman. J Am Chem Soc 107:196–199, 1985.

10.For reversible Rh-complexation with a C–H bond, see: (a) BH Weiller, EP Wasserman, RG Bergman, CB Moore, GC Pimentel. J Am Chem Soc 111:8288–8290, 1989. (b) EP Wasserman, CB Moore, RG Bergman. Science 255:315–318, 1992.

11.Mechanics was used as implemented on the Tektronix CAChe workstation. Although our initial work (Ref. 6) included minimizing the Rh–Rh core with ZINDO, we have subsequently found that this approach works just as well with mechanics alone. The CAChe workstation is particularly well suited to the sort of analysis outlined here, for its superb three-dimensional visualization facilitates understanding of the competing transition states.

12.DF Taber, KK You. J Am Chem Soc 117:5757–5762, 1995.

13.DF Taber, SL Malcolm. J Org Chem 63:3717–3721, 1998.

14.MP Doyle. Chem Rev 86:919–939, 1986.

15.(a) MP Doyle, LJ Westrum, WNE Wolthuis, MM See, WP Boone, V Bagheri, MM Pearson. J Am Chem Soc 115:958–964, 1993. (b) MP Doyle, Recl Trav Chim PaysBas 110:305–316, 1991. (c) HML Davies, NJS Huby, WR Cantrell Jr, JL Olive. J Am Chem Soc 115:9468–9479.

16.DF Taber, K Raman, MD Gaul. J Org Chem 52:28–34, 1987.

17.Rhodium pivalate {dirhodium tetrakis[µ-(2,2-dimethylpropanato O:O′)]} was synthesized by refluxing commercially available rhodium trifluoroacetate in eight equivalents of pivalic acid for 24 hours followed by removal of excess acid under vacuum. The crude catalyst was purified by flash chromatography using an MTBE:petroleum

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ether gradient. TLC Rf (10% MTBE/petroleum ether) 0.52. For leading references to the preparation of other rhodium carboxylates see: (a) TR Felthouse. Prog Inor Chem 29:73–166, 1982. (b) FH Jardine, PS Sheridan. In: G Wilkinson, ed. Comprehensive Coordination Chemistry. Vol IV. New York: Pergamon Press, 1987, pp 901–1096.

18.DF Taber, RJ Herr, SK Pack, JM Geremia. J Org Chem 61:2908–2910, 1996.

19.DF Taber, RP Meagley, JP Louey, AL Rheingold. Inorg Chim Acta 239:25–28, 1995.

20.Tetrakis(carboxylato)dimetal complexes have been prepared from Cr, Cu, Mo, Re, Rh, Ru, Tc, and W. For leading references, see: FA Cotton, RA Walton. Multiple Bonds Between Metal Atoms. New York: Wiley, 1982.

21.Chisholm has reported diacids that can connect two tungsten (or molybdenum) dimers, to make tetramers. RH Cayton, MH Chisholm, JC Huffman, EB Lobkovsky. J Am Chem Soc 113:8709–8721, 1991.

22.ZINDO was used as implemented on the Tektronix CAChe workstation. For leading references to ZINDO, a semiempirical program that has been paramaterized for the first two rows of transition metals, see: (a) MC Zerner, GW Loew, RF Kirchner, UT Mueller-Westerhoff. J Am Chem Soc 102:589–599, 1980. (b) WP Anderson, TR Cundari, RS Drago, MC Zerner. Inorg Chem 29:1–3, 1990.

23.Although ZINDO was originally parameterized to give good spectroscopic results, it had also been used in studies of the energetics and structures of transition metal– based catalytic systems. (a) GL Estiu, MC Zerner. J Phys Chem 97:13720–13729, 1993. (b) GL Estiu, MC Zerner. Int J Quantum Chem 26:587, 1992.

24.Diacid 35 was prepared by coupling α,α′-dibromo m-xylene with allyl magnesium chloride, followed by RuO4-mediated cleavage of the resultant diene (26).

25.Diacid 35, prepared by an alternative route, was already a known compound. P Ruggli, P Bucheler. Helv Chim Acta 30:2048–2057, 1947.

26.(a) PHJ Carlsen, T Katsuki, VS Martin, KB Sharpless. J Org Chem 46:3936–3938, 1981. (b) M Caron, PR Carlier, KB Sharpless. J Org Chem 53:5185–5187, 1983.

(c) LM Stock, K W-T Tse. Fuel 62:974–976, 1983.

27.MP Doyle, WR Winchester, JAA Hoorn, V Lynch, SH Simonsen, R Ghosh. J Am Chem Soc 115:9968, 1993.

28.(a) HML Davies, PR Bruzinski, DH Lake, N Kong, MJ Fall. J Am Chem Soc 118: 6897–6907, 1996. (b) For a very effective chiral modification of 36, see HML Davies, N Kong. Tetrahedron Lett 38:4203–4206, 1997.

29.S-i Hashimoto, N Watanabe, T Sato, M Shiro, S Ikegami. Tetrahedron Lett 34:5109– 5112, 1993. This catalyst works much better with other substrates, giving ee’s approaching 90% for insertion into benzylic C–H.

30.DF Taber, SC Malcolm, K Bieger, P Lahuerta, M Sanau, S-E Stiriba, J Perez-Prieto, MA Monge. J Am Chem Soc 121:860–861, 1999.

31.(a) FA Cotton, RA Walton. Multiple Bonds Between Metal Atoms. 2nd ed. Oxford: Oxford University Press, 1993. (b) AR Chakravarty, FA Cotton, DA Tocher, JH Tocher. Organometallics 4:8–13 1985. (c) F Estevan, P Lahuerta, J Perez-Prieto, M Sanau, S-E Stiriba, MA Ubeda. Organometallics 16:880–886, 1997.

32.For a description of the use of ‘‘P-’’ and ‘‘M-’’ designators for helical molecules, see EL Eliel, SH Wilen, LN Mander. Stereochemistry of Organic Compounds. New York: Wiley Interscience, 1994.

10

Molecular Mechanics Modeling of

Organometallic Catalysts

David P. White and Warthen Douglass

University of North Carolina at Wilmington,

Wilmington, North Carolina

1. INTRODUCTION

Organometallic chemistry is interesting in part because it has applications to catalytic processes. Since the discovery of C–H bond activation and the homogeneous hydrogenation of olefins, the importance of organometallic complexes has been undisputed. Many experimental studies of organometallic catalysis have focused on catalyst and substrate structure, kinetics of transformations, mechanisms, thermochemical properties, turnover, selectivity, etc., and a massive quantity of experimental data has been accumulated. Molecular mechanics can be used to compile and analyze these data in order to direct the design of novel catalytic systems.

Organometallic chemists have long attempted to employ molecular mechanics to the rational design of catalysts. However, molecular mechanics was developed in order to study organic molecules, whose structures are well defined and show easily predicted trends in structure. Organometallic complexes, on the other hand, exhibit a wide variety of different structures, most of which are specific to the metal under investigation (see Chapter 2) (1). This diversity of both coordination number and geometry has resulted in individual workers developing

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