Figure 3: Comparison of the hydroformylation route (left) to β-siloxyisobutraldehyde with conversion of the Roche ester (right)
(6). (UNIVERSITY OF WISCONSIN-MADISON)
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"Because the synthetic versatility of aldehydes is so great, enantioselective hydroformylation could be a key step in the
synthesis of many pharmaceutical building blocks," says Landis. The synthesis of β-siloxyisobutyraldehyde, a key starting
material for polyketide syntheses, shows the opportunities provided by enantioselective hydroformylation (6). As shown in
Figure 3, the traditional synthesis of β-siloxyisobutyraldehyde (6) begins with an expensive Roche ester and, in three steps,
converts the acid to an aldehyde. The hydroformylation route, in contrast, begins with a commodity chemical, allyl alcohol,
and converts it into the desired product in a two-step process, the second of which generates no byproducts that must be separated
and disposed.
"Preliminary results in my group demonstrate that the hydroformylation step can be effected with high enantioselectivity (97%
enantiomeric excess) and high rates (10,000 catalyst turnovers/h), making hydroformylation a vast improvement over traditional
synthesis," says Landis. "Should hydroformylation prove similarly effective for other functionalized alkene substrates, the
barrier to the application of enantioselective hydroformylation technology will shift from catalyst performance to incorporating
chiral aldehydes into retrosynthetic thought processes when devising new syntheses," he adds.
Asymmetric hydrogentation
Upcoming conferences on chirality
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While a catalyst selection is crucial in an asymmetric reaction, so is the choice of the substrate, an approach researchers
at Sepracor (Marlborough, MA) showed in making an enamide substrate for asymmetric hydrogenation for the large-scale stereoselective
process for (1R, 4S)-trans-norsertraline, a chiral amine structurally similar to sertraline, the API in Pfizer's (New York) "Zoloft."
"Our first approach used to produce kilogram quantities of clinical study material began with (S)-tetralone and a chiral auxiliary (R)-tert-butylsulfinamide," outlines Surenda Singh, research fellow at Sepracor. Singh also spoke at Chiral USA. "The synthesis
was very quick to develop and was scaled up to produce ~5 kg of API in >50% overall yield" (17).
Sepracor, however, wanted a more efficient and economical process for larger-scale commercial applications. "After an extensive
route-scouting effort, we selected the approach of catalytic asymmetric hydrogenation of the enamide," says Singh. Initial
in-house catalyst screening efforts resulted in identification of R,R-Me-BPE-Rh(COD)BF4, a commercially available catalyst. Later in collaboration with Dowpharma another catalyst, Norphos, was identified. "Once
we identified the multiple catalysts," says Singh, "we were then faced with two new challenges on how to make the enamide
approach a scalable process: availability of limited methods for an efficient synthesis of enamides, and as one would expect,
the hydrolysis of the resulting chiral amide did not prove to be a trivial task."
"Fortunately, we were able to solve both of these issues for our substrate, and in a short time developed novel chemistries
for the efficient synthesis of enamides and also for the facile cleavage of chiral acetamides," says Singh. The process was
scaled up to produce more than 50 kg of API in 63% overall yield and in 99.9% chiral purity with total impurities of < 0.05
A% by high-performance liquid chromatography.
Biocatalysis in asymmetric reactions
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