ONE GOOD THING GIVES RISE TO ANOTHER
Johns Hopkins chemists make optically active -lactams in linked functional columns

Lectka, a professor of chemistry at Johns Hopkins University, has been devoting much of his research to asymmetric syntheses. His efforts in the area of -lactams have paid off with a highly enantioselective synthesis based on a nucleophile-catalyzed [2+2] addition of ketenes and imines [J. Am. Chem. Soc., 122, 7831 (2000); 124, 6626 (2002)].

The chiral catalyst is a cinchona alkaloid derivative. It attacks the ketene to form a chiral nucleophilic enolate. This in turn reacts with the imine. When the lactam ring forms, the catalyst is released for another cycle.

But in some cases the synthesis has serious practical problems. Work-up is laborious, and chromatographic recovery of the catalyst is tedious. More important, the reaction requires a pure solution of ketene, which is difficult to get with monosubstituted ketenes, which were of particular interest to Lectka.

"Many of the compounds we want to make would be derived from monosubstituted ketenes," Lectka says. He notes that although -lactams are well known for their use as antibiotics, interest in these compounds also is due to their nonantibiotic activity, such as inhibition of the serine proteases elastase, cytomegalovirus protease, and thrombin. -Lactams with such activity can be made with monosubstituted ketenes when paired with -imino esters, he points out.

For this reason, the Lectka lab has concentrated on -lactams derived from monosubstituted ketenes. Earlier this year, Gregory C. Fu, a chemistry professor at Massachusetts Institute of Technology, developed a complementary method based on disubstituted ketenes and a planar chiral heterocycle as catalyst (C&EN, Feb. 25, page 32).

	INNOVATORS Lectka (clockwise from lower left), France, Hafez, and Taggi with a mock setup for column asymmetric catalysis. PHOTO BY WILL KIRK/JOHNS HOPKINS

"The problem with monosubstituted ketenes is that they are very reactive," Lectka says. "You usually can't stop to purify them before taking them to the next step. Disubstituted ketenes, however, can be distilled."

Lectka generates monosubstituted ketenes by dehydrochlorination of acid chlorides with a base. To obtain pure solutions of product, he and coworkers--including graduate students Andrew E. Taggi and Ahmed M. Hafez--initially used a phosphazine base attached to a resin. Filtering off the solid-phase-bound salt of the base gives a pure solution of ketene. "We discovered that it was easier to do the reaction and cleanup on a column," Lectka says. "We would pour a solution of the acid chloride at the top, and out comes the ketene solution at the bottom."

Taking that approach has led to a new way to run catalytic asymmetric reactions, which Lectka and coworkers call column asymmetric catalysis [Org. Lett., 2, 3963 (2000)]. It's solid-phase-based synthesis. But unlike the usual practice, in which substrates linked to a solid phase are transformed by reagents and catalysts in solution, here substrates in solution are converted to products by flowing through solid-phase-bound reagents and catalysts.

That alone does not make column asymmetric catalysis new. What's new is the linking of discrete columns with unique functions--to generate substrates, hold reagents and/or catalysts, or scavenge by-products--to execute a synthetic sequence and deliver a pure product. Yields of -lactams prepared this way are comparable with those of -lactams prepared in solution, Lectka says.

The technique has generated much interest. Lectka says that since their first full paper on this subject was published [J. Am. Chem. Soc., 123, 10853 (2001)], he has received three requests from U.S. and European journals for feature articles on the topic.

The synthetic sequence determines how columns are linked. For -lactam synthesis, for example, an assembly could be as simple as two columns in sequence. The first column, which is dual function, is loaded with fine-mesh potassium or sodium carbonate--for dehydrohalogenation--mixed with the resin-bound chiral catalyst--for enantioselective -lactam formation.

Solutions of acid chloride (the ketene precursor) and imine flow through the column, where the ketene is generated and the -lactam is formed. The product flows to the second column, which contains solid-bound reagents that pick up ketene by-products. The column releases a solution from which pure -lactam crystallizes.

Sometimes the base and the chiral catalyst must be in separate columns, such as when the base is sodium hydride mixed with Celite (diatomaceous earth). The Hopkins team likes this reagent because it is much less expensive than other bases they have tried to use. However, it could epimerize the product.

In this case, the ketene is generated in a column loaded with sodium hydride in Celite. It flows to a column loaded with resin-bound chiral catalyst, to which the imine is also introduced. The product in solution then flows to a purifying column.

The catalyst also would have to be separated when the recipe involves compounds that can form tight adducts with the alkaloid catalyst. Recently, for example, the Lectka group has found that yields of optically pure -lactams from ketenes and imines can increase by more than 40% when an achiral Lewis acid is used in tandem with the chiral catalyst [Org. Lett., 4, 1603 (2002)].

SUCH A REACTION in solution would be limited by the compatibility of the Lewis acid and the chiral catalyst, Lectka points out. If they can bind tightly, a catalytically inactive adduct will form. Stefan France, a graduate student in the group, is now adapting the system for column asymmetric catalysis, he says. "We're hoping that immobilizing the incompatible compounds will overcome the limitations of the reaction in solution."

Comparing -lactam synthesis in solution with column asymmetric catalysis, Lectka says of the former: "We have to do an aqueous work-up--dilute the solution with an organic solvent, and wash with dilute acid followed by bicarbonate and brine. Then we have to remove the solvent by rotary evaporation and purify the product by column chromatography. And we discard the catalyst, because recovering it is tedious."

Of column asymmetric catalysis, he says, "We just have to keep the columns at the right temperature and monitor flow rates." But he quickly adds: "That's not to say that the technology has arrived. A lot of optimization has to occur before it becomes really useful."

Depending on the recipe, the chiral catalyst performs other roles. For example, it can also act as the catalytic ketene-generating dehydrohalogenating agent in the presence of another base to which it can transfer protons.

In a synthetic sequence the Lectka group recently reported, the alkaloid derivative performs four functions: as catalytic dehydrohalogenating agent to generate both ketene and imine starting materials, as chiral catalyst for the [2+2] addition of the ketene and the imine to form a -lactam, and as a catalyst for ring opening of the -lactam to an amino acid derivative [Org. Lett., 4, 387 (2002)].

Versatile as it is, trying to recover the catalyst is not a good use of time at the milligram scales at which the reactions are being run, Lectka points out. But now that the group is scaling up to gram quantities, simply discarding the catalyst could be too wasteful. "It is so much easier to recycle catalyst when bound to a solid phase," Lectka says. "We've used our catalyst-loaded column more than 100 times for different experiments. Catalyst integrity and efficacy have been maintained."

Lectka's group is trying column asymmetric catalysis on other reactions, including catalytic asymmetric halogenations, and catalytic asymmetric additions of ketenes to nitrones to form unnatural amino acids. "If you have a purification issue, this system can be very appealing," Lectka says. "If chromatography is highly objectionable, if you have reactive intermediates that you can't clean up but need to be contaminant-free, column asymmetric catalysis is worth considering."

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Copyright © 2002 American Chemical Society