Ferrocene Derivatives Find Use As Chiral Catalysts

• Applications of novel ferrocenes include catalysis of key reactions in commercial production ofbiotin and a herbicide

Stu Borman, C&EN Washington

In the past few years, there has been a flurry of activity in the design and synthesis of chiral ferrocene deriva­

tives. Aside from their intrinsic interest as a focus of basic research, these fer­rocenes are finding practical use as cata­lysts for preparing chiral compounds with tailor-made properties.

"People are interested in developing new catalysts because of current con­cerns to make chemical processes more efficient and environmentally friendly/' says chemistry professor Victor Snieckus of the University of Waterloo, Ontario. "Those are the practical elements that are driving work in this field."

Ferrocenes that have at least two different substituents in the same cy-clopentadienyl ring can't be superim­posed upon their own mirror images and are therefore chiral—a type of stereoisomerism called planar chirali-ty. The first synthesis of planar-chiral disubstituted ferrocenes was achieved in 1970 by Ivar Ugi and coworkers at the Institute for Organic Chemistry & Biochemistry of the Technical Univer­sity of Munich, Germany. The syn­thetic method developed by Ugi's group consists of a resolution step in which a chiral aminoferrocene precur­sor is isolated, a diastereoselective re­action in which the precursor is lithia-ted, and a substitution reaction in which lithium is replaced with an electrophilic group.

Another key development in the chiral ferrocene field occurred in 1974, when Tamio Hayashi and coworkers in the department of chemistry at Kyoto

University, Japan, first used the Ugi method to prepare chiral ferrocenyl-phosphine ligands. Hayashi's group found that these ligands bound metals and that the resulting complexes acted as stereoselective catalysts in asymmet­ric syntheses.

Based on Hayashi's work, Antonio Togni and Felix Spindler of the cataly­sis group at Ciba-Geigy in Basel, Swit­zerland, developed a class of chiral substituted ferrocenyldiphosphines. These compounds are now used indus-

Disubstituted ferrocenes may exhibit planar chirality

X H ,

C02H ι

Fe =

XCQ2H

Fe =

2-Methylferrocenecarboxylic acid

C02H

trially on a large scale—at Ciba to cata­lyze the reduction of an imine interme­diate in the stereoselective synthesis of a herbicide, and at Lonza, in Visp, Switzerland, to catalyze the synthesis of a biotin intermediate.

After Togni's appointment as a chem­istry professor at the Swiss Federal Insti­tute of Technology (ΕΤΗ) in Zurich, he and his coworkers also synthesized a ferrocenyldiphosphine catalyst that pro­vides the highest enantioselectivities ever attained in the hydroboration of

styrènes with catecholborane (98.5% enantiomeric excess) and in the sub­stitution of allylic acetates and car­bonates with benzylamine (about 99% enantiomeric excess). Togni re­cently reviewed research on planar-chiral ferrocenes [Angew. Chem. Int. Ed. Engl 35,1475 (1996)].

Several teams have developed diastereoselective metalation reac­tions of ferrocenes containing di­recting groups such as chiral ac-etals or oxazolines—the aim being to create disubstituted planar-chiral ferrocenes. The acetal or oxazoline group directs the diastereoselective metalation of the ferrocene with lithium (or another metal), which is then replaced by an organic functional group. The techniques developed by these teams are more convenient than the Ugi

Ugi and coworkers developed diastereoselective metalation

H3C N(CH3)2

RLi

H 3 Q^(CH 3 ) 2 H3C N(CH3)2

Fe Fe ι

Fe

96% 4% RLi = alkyllithium Ε = electrophile

38 JULY 22,1996 C&EN

SCIENCE/TEeHNOLOGY

Snieckus (far right) with coworkers (from left) Costa Metallinos, Brian Chapell, Anna Roglans, Radek Laufer, and Michael Tinkl.

method for synthesis of disubstituted ferrocenes because they do not require a prior resolution step.

One of these asymmetric lithiation techniques was developed by chemistry professor Henri B. Kagan and coworkers at the University of Paris-South, Orsay, France [/. Am. Chem. Soc, 115, 5835 (1993)]. The technique, which uses chiral

acetals as directing groups, permits easy recovery of the enantiopure chiral re­agents used to prepare the acetals.

Techniques for the directed lithiation of ferrocenyloxazolines have been de­veloped independently by the groups of chemistry professors C. J. Richards of the University of Wales, Cardiff [Synlett, 1995, 74], Sakae Uemura of

Diphosphine ligands catalyze industrial syntheses

* i i>

H3q o x

N">JH

I Fe

P[C(CH3)3]2

'CH,

Rh, H2 (+)-Biotin

99% diastereoselectivity

N^°-o .

^ lr, r, H2S04

80% enantiomeric excess

(S)-Metolachlor

Kyoto University, Japan [Synlett, 1995, 79], and Tarek Sammakia of the Uni­versity of Colorado, Boulder [/. Org. Chem., 60, 6002 (1995)].

The Richards and Uemura groups have focused on the synthesis of phosphinoferrocenyloxazolines and applications of the resulting ligands for asymmetric catalysis—to catalyze reactions such as Grignard cross-cou­pling (Richards) and asymmetric hy-drosilylation (Uemura). "The design and preparation of new ligands for transition-metal-catalyzed reactions are [needed] for effective transforma­tion of organic compounds/7 Uemura says. "These new ligands should be useful for various asymmetric cataly­sis as well as enantioselective synthe­sis [applications]."

Sammakia and coworkers have con­centrated on details of the diastereose-lective lithiation process. By optimizing solvents and additives, they have achieved reproducible selectivities of 500 to 1 or better in the metalation re­action. In studies of the mechanism of the metalation reaction, they found that the directing heteroatom was the nitro­gen of the oxazoline and proposed a transition-state model for the reaction [/. Org. Chem., 61,1629 (1996)].

Snieckus and coworkers recently de­veloped a directed ortho-metalation route to fer­rocenes with planar chiral-ity [/. Am. Chem. Soc, 118, 685 (1996)]. They use ferro­cene carboxamides as start­ing materials (instead of the amine, acetal, and ox­azoline derivatives used in prior syntheses) and the al­kaloid (-)-sparteine as a chiral inducing agent. The synthesis can be used to obtain chiral ferrocenyl-phosphines and other ferrocenes that act as cata­lysts for organometallic reactions.

Snieckus says he looks forward to "the extension and application of our re­sults for the synthesis of new ferrocenes for asym­metric catalysis, polymer-support catalysis, and . . . materials science applica­tions. We are working to­ward the development of new catalysts completely

JULY 22,1996 C&EN 39

SCIENCE/TECHNOLOGY

Sparteine-mediated metalation is highly enantioselective

^ ^ ^ — ^ / C H t C H ^

Fe \

^

E = electrophile

CH(CH3)2 n-Butyllithium, (C2H5)20, E+

CH(CH3)2

CH(CH3)2

81-99% enantiomeric excess

different from the ones that are known and to chiral biferrocene derivatives, which again are poorly known/'

A similar technique for directed or-tho lithiation of substituted ferrocenes was reported at about the same time by Uemura and coworkers [/. Org. Chem., 61,1172 (1996)]. However, the enantio-selectivity of this technique is much lower than that of the technique devel­oped by Snieckus' group.

Snieckus says his technique was based in part on earlier work by chemistry professor Dieter Hoppe's group at the Institute of Organic Chemistry of the University of Mini­ster, Germany, which in 1989 first used a sparteine-lithium complex as a chiral inducing agent for a highly enantiose­lective deprotonation reaction. Snieck­us also credits chemistry professor Pe­ter Beak and coworkers at the Univer­sity of Illinois, Urbana-Champaign, who adapted the use of sparteine to in­duce enantioselectivity in a variety of reactions. The first use of sparteine as a chiral ligand to induce enantioselectivi­ty was achieved about 25 years ago by a Japanese group, but the enantiomeric excess was low.

Ciba currently uses a chiral ferro­cene-based iridium catalyst for an en­antioselective hydrogenation reaction in the production of the herbicide (S)-Metolachlor. 'This is the biggest pro­cess using asymmetric hydrogenation catalysts/' generating more than 10,000 tons of Metolachlor per year, says Rolf Bader, head of the firm's catalysis R&D group.

Novartis, the new corporate entity emerging from Ciba's pending merger with Sandoz, is planning to make fur­ther use of asymmetric catalysis, in­cluding planar-chiral ferrocene cataly­sis, to produce enantiomerically pure

pharmaceuticals, agrochemicals, and fine chemicals, Bader says.

The Ciba process and a biotin pro­cess at Lonza are currently the only two commercial operations in which planar-chiral ferrocenes are used as cat­alysts. But Bader points out that other ferrocene-based industrial processes are now in the development pipeline and that chiral ferrocenyldiphosphine ligands will soon be available commer­cially in research quantities. So indus­trial use of such catalysts is likely to grow significantly in the future, he says. •

Clues to DNA interaction with RNA enzyme found A team of scientists at the Public Health Research Institute in New York City has uncovered clues as to how DNA inter­acts with the enzyme RNA polymerase. The researchers have developed a strate­gy that allows them to identify the points of interaction between the en­zyme and DNA. These points have pre­viously eluded investigators because the massive enzyme, with a mass of about 449 kilodaltons in Escherichia coli, wraps around a fairly long segment of the DNA strand, effectively shielding more subtle interactions from view.

The research team has overcome this problem by inducing the enzyme to "jump" onto a short synthetic piece of DNA and stay there. By manipulating the composition of these short DNA seg­ments, they can piece together whafs needed to stabilize the DNA-enzyme complex [Science, 273,211 (1996)].

The team is headed by Alex Gold-farb, an associate member of the re­search institute, and includes postdoc­

toral fellow Evgeny Nudler and gradu­ate students Ekaterina Avetissova and Vadim Markovtsov.

RNA polymerase synthesizes messen­ger RNA. The enzyme binds to DNA at controlled locations, unwinds the double helix, and moves along the unwound template strand, using the information coded in the strand to synthesize a com­plementary RNA polymer.

The way the enzyme interacts with DNA has long fascinated biochemists: It binds to DNA tightly enough to recog­nize specific sites and for the complex to hold together until the nascent RNA chain is completed, but loosely enough to move along the DNA strand. In re­sponse to control signals, it can also stop, slow down, or even jump over short segments of the DNA strand.

The new work began "when we no­ticed a new kind of reaction that RNA polymerase can do, which is to jump from one DNA template to another," Nudler explains.

Many researchers had noted that the RNA transcripts produced by RNA polymerase in vitro are sometimes long­er than expected. Normally, the enzyme initially binds to DNA at a specific re­gion called the promotor and begins transcribing just downstream from that region. But the New York researchers noticed that when the polymerase makes transcripts that are too long, these transcripts include segments transcribed from DNA upstream of the promoter.

"This could only happen if the RNA polymerase first transcribed a primary template then jumped to a second DNA template and started transcribing it from the very end, before the promo­tor region," Nudler notes.

Knowing that under the right condi­tions RNA polymerase will jump onto the end segment of DNA gave the team another tool to study enzyme-DNA in­teractions. The researchers already knew how to halt the polymerase's progress along the DNA strand by withholding one of the building blocks of RNA. For example, by withholding uridine triphosphate, they can make RNA synthesis stop as soon as the en­zyme comes to a place in the DNA strand that calls for insertion of a uri­dine. They can also add reagents to their synthetic DNA strands that, when irradiated, cross-link the DNA to the nearest molecules of the protein, there­by locating the regions of the protein that interact with the DNA.

40 JULY 22,1996 C&EN