SubscribeThe hydronaphthalene skeleton is found in a wide range of compounds possessing diverse biological activities. A number of drug candidates in various clinical phases, as well as natural and launched products, contain this privileged scaffold with chiral substituents (a selection is depicted in figure 1).
Producing these compounds synthetically often relies on racemate resolution technologies and, in many cases, no simple, cost-efficient synthesis is available.
The powerful chemo-catalytic method developed by Professor Mark Lautens and his research group at the University of Toronto, Canada provides a novel technique enabling the production of these core structures in enantioenriched form [1]. Meso-oxabenzononorbornadienes are easily prepared from readily available low-cost starting materials. From these achiral intermediates Lautens developed an efficient asymmetric ringopening reaction providing access to a myriad of highly functionalised hydronaphtalene scaffolds which are labor intensive and relatively expensive to prepare by other synthetic means.
Figure 1) Selected examples containing the hydronaphthlene skeleton
Lautens' asymmetric ring opening reaction
The basic transformation in Lautens' process consists of a Rh-catalyzed asymmetric ringopening reaction of meso-oxabenzononorbornadienes with soft nucleophiles such as alcohols, phenols, aliphatic amines, anilines, carboxylates, malonates and sulfides. This desymmetrization creates two chiral centers with perfect diastereo- and very high enantio-selectivity. Screening and development of the method identified the optimal catalyst (best performance, broadest scope) to be a bulky, electron-rich Solvias Josiphos Ligand, SL-J002-1, in combination with Rh and a selected halide depending upon the nucleophile employed. The phosphine substitution pattern (tuning of required steric bulk and electron-poor vs electron-rich substituents) is essential for high yields and selectivities in the reaction [2, 3].
Industrial relevance
In demonstrating the versatility of this synthetic method and its potential to rapidly build highly functionalized and complex molecules Lautens also addressed commercially important parameters such as substrate-to-catalyst loading, showing that even at S/C = 10,000, high yields and selectivities for O- and N-nucleophiles are feasible [3]. These studies indicate that the synthetic methodology had the potential to fulfill industrial requirements. Further investigation into the applicability of Lautens Technology to industrial processes was conducted by the Synthesis Group of Dirk Spielvogel at Solvias.
Figure 2) Nu = R-OH, Ph-OH, (Ralk)2NH, (Raryl)2NH, R-CO2H, RSH, malonates
a) Protocol optimisation
Key to the industrial feasibility of the method was the reduction of the large excess nucleophile required to drive the reaction to completion. Initially, five or more equivalents of most nucleophiles were required to achieve high yields. Spielvogel found that tuning of the ligand/Rh ratio from 2/1 to 6/1 significantly reduces the amount of nucleophile required. In combination with a solvent switch to more polar solvents an optimized Ligand/Rh ratio led to a successful transformation with only 1.05 to 1.1 equivalents of nucleophile. This was a crucial breakthrough enabling complex and expensive nucleophiles to be used efficiently without compromising yields or selectivities and permitting reactions such as that depicted in figure 3 to be effectively carried out.
b) Scale-up
Successful scale-up of the Lautens process to the kilogram level using a range of O- and N-nucleophiles, followed by further selective transformations of the scaffolds, has been demonstrated at Solvias. As required for industrial applications the chemistry is robust and both enantiomers of the products are equally well accessible. The current portfolio of chiral scaffolds that have been successfully scaled to kg amounts is depicted in figure 4.
Figure 3) Example of stoichiometric use of nucleophile with Lautens Technology
Immediate access to the Solvias line of Lautens-Technology-based products is available in multigram and multikilogram amounts for applications in medicinal and early stage development chemistry. Custom-made special derivatives can also be readily prepared by Solvias to support customers' drug development programs. The following page describes the available kits containing these highly functionalized products in both enantiomeric forms and with a built-in orthogonal protecting group strategy.
Figure 4. 1) Chemoselective reduction of double bond, 2) access to cis-series, 3) deoxygenation, 4) highly regioselective functionalization of cis-series, 5) and 6) selective á- and â-epoxydation
Lautens Technology product line and custom-manufactured derivatives
[1] Review: Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res., 2003, 36, 48-58.
[2] Lautens, M.; Fagnou, K., PNAS, 2004, 101, 15, 5455-5460.
[3] Lautens, M.; Fagnou, K.; Yang, D., J. Am. Chem. Soc., 2003, 125, 14884-14892.