Site-Selective Primary Alcohol Dehydrogenation Enables Protecting Group-Free Diastereoselective C-C Coupling of 1,3-Glycols and Allyl Acetate

The ability to discriminate between like functional groups, so as to transform organic molecules in a “site-selective” or “chemoselective” manner,^[1] precludes the requirement of protecting groups and, hence, carries the potential to dramatically enhance synthetic efficiency.^[2] Though an exceptionally daunting challenge, systematic efforts toward catalytic methods for the site-selective transformation of polyfunctional molecules have begun to emerge. For example, Miller^[3] and Taylor^[4] report catalytic methods for the site-selective manipulation of diols and higher polyols. Site-selective metal catalyzed cross-couplings have been catalogued.^[5] Further, in what is perhaps the most formidable theatre for site-selectivity, impressive advances in catalytic methods for C-H functionalization have been achieved, as illustrated in the seminal work of Barton,^[6a] Murai and Kakiuchi,^[6b] and in more recent studies by Davies,^[6c] Sanford,^[6d] Yu,^[6e] Daugulis,^[6f] Baran^[6g] and others.

Although methods for the site-selective diol oxidation have been reported, including iridium catalyzed methods,^[7,8] merged redox-C-C bond construction events involving chemoselective polyol oxidation are unknown.^[9] In connection with ongoing studies of C-C bond forming hydrogenation, we recently found that certain iridium and ruthenium complexes catalyze hydrogen exchange between primary alcohols and π-unsaturated reactants to generate organometal-aldehyde pairs that combine to form products of carbonyl addition.^[10] In these transformations, primary alcohol reactants are subject to oxidation, yet the secondary alcohol products are not. This fact, and the ability to perform certain transfer hydrogenative couplings in aqueous organic media, suggested unprotected polyols might engage in site-selective carbinol CH-functionalization. Here, we report that the cyclometallated π-allyliridium C,O-benzoate complex derived from (R)- or (S)-SEGPHOS and 4-cyano-3-nitro-benzoic acid catalyzes the redox-triggered allylation^[11,12] of unprotected diols and higher polyols with a pronounced kinetic preference for primary alcohol dehydrogenation. In this way, chemo- and stereoselective carbinol CH-allylation of polyols is achieved in the absence of protecting groups, chiral auxiliaries, premetallated reagents and discrete alcohol-to-aldehyde oxidation (Scheme 1).

Scheme 1.

Site selective dehydrogenation enables protecting group-free allylation of diols.

In an initial set of experiments, a series of chromatographically isolated π-allyliridium complexes modified by (S)-SEGPHOS and 4-substituted-3-nitro-C,O-benzoate moieties were assayed in the allylation of diol 1 (Figure 1). The iridium complexes (R)-Ir-b-NO₂ and (S)-Ir-a-CN, displayed roughly equal efficiency, with the latter providing the 1,3-syn-diol 2a in 67% yield with complete levels of catalyst-directed diastereoselectivity^[13] and without any detectable oxidation of the unprotected secondary alcohol. Similarly, using the enantiomeric catalyst (R)-Ir-CN, diol 1 was transformed to the 1,3-anti-diol 2b in 59% yield without any detectable over-oxidation. Inspired by these results, diols 3, 5, and 7 and were subjected to the enantiomeric catalysts (S)- and (R)-Ir-CN. In each case, the corresponding products of allylation 4a and 4b, 6a and 6b, and 8a and 8b, respectively, were formed in good to excellent yields with exceptional control of diastereoselectivity and without oxidation of the unprotected secondary hydroxyl moieties. Notably, the preparation of 4b in four steps through iterative redox-triggered allylation represents a synthesis of the C11-C18 fragment of the oxopolyene macrolide RK-397, which was previously prepared in 7 steps from the same starting material (Scheme 2).^[14] Finally, even the unprotected triol 9 is converted to adducts 10a and 10b using the enantiomeric catalysts (S)- and (R)-Ir-CN, respectively, in good yields and complete levels of catalyst directed diastereoselectivity (Table 1).

Figure 1.

Cyclometallated iridium catalysts for site-selective allylation.

Scheme 2.

Synthesis of the C11-C18 fragment of RK-397.^a

^aAs described for Table 1.

Table 1.

Protecting group-free catalyst-directed diastereoselective C-C coupling of chiral diols 1, 3, 5, 7 and 9 with allyl acetate.^a

^aCited yields are of diastereomeric mixtures isolated by silica gel chromatography. Stereoisomeric ratios were determined by ¹H NMR analysis of crude reaction mixtures (major diastereomer:sum of two minor diastereomers). See Supporting Information for further experimental details.

An even more challenging class of substrate is represented by the unprotected chiral β,γ-stereogenic alcohols 11 and 13. Exposure of 1,3-glycol 11 to the catalyst (S)-Ir-NO₂ under standard conditions delivers the product of allylation 12a as a 9:1 mixture of diastereomers. In this case, the diastereofacial bias of the catalyst matches the preference of the transient aldehyde for Felkin-Anh addition.^[15] In the mismatched case using the enantiomeric catalyst (R)-Ir- NO₂, the diastereomeric product 12b is formed as a 3:1 mixture of diastereomers. Similarly, the 1,3-glycol 13 is converted to diastereomeric allylation products 14a (5:1 dr) and 14b (3:1 dr) using (S)-Ir-NO₂ and (R)-Ir-NO₂, respectively. For the allylation of unprotected chiral β,γ-stereogenic alcohols 11 and 13, the minor diastereomer obtained principally stems from epimerization of the transient α-stereogenic aldehyde (Table 2). Although the levels of catalyst-directed diastereoselectivity are modest, these results are significant in view of the intractability of β-hydroxy-α-substituted aldehydes. Whereas substrate-directed allylation of unprotected β-hydroxyaldehydes is possible with allylindium reagents to provide anti-1,3-diols,^[16a] the corresponding 1,3-syn-allylation is only possible with stoichiometric allyltitanium-TADDOL complexes.^[16b]

Table 2.

Protecting group-free catalyst-directed diastereoselective C-C coupling of chiral β,γ-stereogenic alcohols 11 and 13 with allyl acetate.^a

^aAs described for Table 1.

It has been posited, and generally appreciated, that an ideal synthesis would be composed solely of construction events.^[9,17] As organic compounds, by their very definition, are compounds composed of carbon and hydrogen, catalytic C-C bond constructions that occur through the addition, transfer or removal of hydrogen potentially provides a direct means of accessing native molecule structure in a highly atom efficient manner. Site-selectivity further enhances efficiency by dispensing with the need to install and remove protecting groups. The site-selective redox-allylations described in this account, which occur by virtue of the strong kinetic preference of the iridium catalyst for primary alcohol dehydrogenation, allow chemo- and stereoselective carbinol CH-allylation in the absence of protecting groups, chiral auxiliaries, premetallated reagents and discrete alcohol-to-aldehyde redox manipulations, thus representing one step toward fulfillment of these ideals.