Highly Enantioselective Iridium-Catalyzed Hydrogenation of Conjugated Trisubstituted Enones.

Asymmetric hydrogenation of conjugated enones is one of the most efficient and straightforward methods to prepare optically active ketones. In this study, chiral bidentate Ir-N,P complexes were utilized to access these scaffolds for ketones bearing the stereogenic center at both the α- and β-positions. Excellent enantiomeric excesses, of up to 99%, were obtained, accompanied with good to high isolated yields. Challenging dialkyl substituted substrates, which are difficult to hydrogenate with satisfactory chiral induction, were hydrogenated in a highly enantioselective fashion.

Chirn class="Chemical">al class="Chemical">n class="Chemical">ketones bearing a stereogenic center at the α- or β-position are important compounds in organic synthesis.[1] A few reported methods to access optically active ketones include alkylation using auxiliaries,[2] catalytic asymmetric alkylation,[3] enantioselective Michael addition to unsaturated ketones,[4] or asymmetric conjugate reduction of enones.[5] However, all of the routes listed above to synthesize α- and β-chiral ketones face limitations, such as the challenge of installing/removing auxiliaries, high catalyst loading, or the use of sensitive reagents. In addition to these methods, catalytic asymmetric hydrogenation using hydrogen gas is often the method of choice, due to high enantioselectivity and atom economy. Over the years, the asymmetric olefin hydrogenation of α,β-unsaturated ketones has been reported using rhodium,[6] palladium,[7] and iridium[8] catalysts (Scheme ).

Scheme 1

Selected Examples of Previously Reported Iridium- and Rhodium-Catalyzed Asymmetric Hydrogenation of Unsaturated Enones and This Work

In 2008, n class="Chemical">Hou[8c] aclass="Chemical">nd class="Chemical">n class="Chemical">Bolm[8a,8b] independently reported the iridium-catalyzed olefin hydrogenation of enones. Since then, several research groups have evaluated iridium catalysts using various bidentate X,P-ligands (X = N, O, S) in the asymmetric hydrogenation of α,β-unsaturated ketones resulting in moderate to high enantiomeric excesses.[8d,8l] Despite the maturing of methodology for the hydrogenation of aromatic unsaturated enones, substrates having dialkyl olefin substituents are rarely reported and are hydrogenated with moderate enantioselectivity. Therefore, catalytic methodology that can hydrogenate challenging aliphatic substrates, both α- and β-prochiral, in high ee remains to be found.

In this report, the n class="Chemical">iridium-catclass="Chemical">n class="Chemical">alyzed asymmetric olefin hydrogenation of both α- and β-prochiral trisubstituted enones with high levels of stereoinduction is described. Excellent enantiomeric excesses accompanied with high isolated yields were obtained for all substrate classes (up to 96–99% ee), including aliphatic substitution patterns, which is complementary to previous reported catalytic systems for the asymmetric hydrogenation of enones.

Since limited examples on the n class="Chemical">hydrogenatioclass="Chemical">n of diclass="Chemical">n class="Chemical">alkyl-substituted enones have been reported, α,β-dialkyl substituted substrate 1a was first selected as the model substrate to test the asymmetric hydrogenation of α-prochiral unsaturated ketones (Table ). Initially, structurally diverse catalysts A–D were evaluated under 20 bar of hydrogen atmosphere in dichloromethane (DCM), resulting in poor to excellent ee (67%–99%; Table , entries 1–4). Although perfect enantioselection was obtained with catalyst B, it was accompanied with low reactivity (19% conversion). To our delight, bicyclic thiazole catalyst E faced higher reactivity and was very efficient, in terms of stereocontrol, giving full consumption of starting material with 99% ee of the hydrogenated product (Table , entry 5). The efficiency of catalyst A is also remarkably high, compared to the previously reported Ir–N,P catalyzed asymmetric hydrogenation of 1a, which gave 87% ee (Scheme ).[8b] Next, the hydrogenation of challenging β,β-dialkyl substituted enones was investigated. The use of catalysts B, D, and E on aliphatic substrate 3a resulted in a low ee values of 71%, 11%, and 77%, respectively (Table , entries 6–8). Further catalyst optimization was required (see Table S2 in the Supporting Information) and with optimal oxazoline-based catalyst F in hand, 88% ee was obtained (Table , entry 9). Modification of the phosphine substituents, the oxazoline substituent, and a solvent screening did not further enhance the enantioselectivity.

Table 1

Evaluation of Catalysts in the Hydrogenation of Aliphatic Model Substrates

entry	substrate	catalyst	conversion (%)	enantiomeric excess, ee (%)
1	1a	A	full	94 (+)
2	1a	B	19	99 (−)
3	1a	C	78	98 (+)
4	1a	D	full	67 (−)
5	1a	E	full	99 (+)
6	3a	B	full	71 (S)
7	3a	D	full	11 (S)
8	3a	E	full	77 (R)
9	3a	F	full	88 (R)

As n class="Chemical">already stated, the reported class="Chemical">n class="Chemical">hydrogenation of dialkyl-substituted enones are usually much less enantioselective, when compared to aromatic substitution patterns. Therefore, with the optimized catalysts for the hydrogenation of both classes of aliphatic conjugated trisubstituted enones in hand, the substrate scope was first further investigated for this type of substitution pattern around the olefin starting with α-prochiral substrates (Table ).[11] Substrate 1b, which was previously reported as not reactive (Scheme ),[8c] was hydrogenated with equally high enantioselectivity as 1a of 99% ee. The introduction of an i-butyl substituent on the olefin or the ketone scaffold gave a similar outcome of 99% ee (1c and 1d). Hydrogenation of the cyclohexyl-substituted olefin 1e proceeded with a slight decrease in ee (94%), whereas benzylic substrate 1f and methyl-substituted enone 1g were both well-tolerated, giving excellent selectivity of 99% ee.

Table 2

Asymmetric Hydrogenation of Dialkyl-Substituted Enones and Application in the Synthesis of anti-HIV Agent 7*

Reaction conditions: 0.2 mmol of substrate, 0.5 mol % catalyst, 2 mL of solvent, 20 bar of H2, 16 h, rt, unless stated otherwise. Absolute stereochemistry assigned by comparing optical rotation with literature values. If no reference is given then assignment is tentative. Yields given are in their isolated forms. Enantiomeric excess was determined by SFC or GC analysis, using chiral stationary phases.

1.0 mol % of catalyst.

1 bar of H2.

2 bar of H2.

Reaction conditions: 0.2 mmol of substrate, 0.5 mol % catn class="Chemical">alyst, 2 mL of solveclass="Chemical">nt, 20 bar of class="Chemical">n class="Chemical">H2, 16 h, rt, unless stated otherwise. Absolute stereochemistry assigned by comparing optical rotation with literature values. If no reference is given then assignment is tentative. Yields given are in their isolated forms. Enantiomeric excess was determined by SFC or GC analysis, using chiral stationary phases.

1.0 mol % of catn class="Chemical">alyst.

1 bar of n class="Chemical">H2.

2 bar of n class="Chemical">H2.

Then, the substrate scope of the n class="Chemical">hydrogenatioclass="Chemical">n of chclass="Chemical">n class="Chemical">allenging β,β-dialkyl substituted enones class was broadened using catalyst F. Compound 3b was hydrogenated with 95% ee and changing the ketone substituent to ethyl and phenyl provided good ee values of 92% and 96%, respectively (3c and 3d). Compound 3d was previously hydrogenated by iridium catalysts and rhodium catalysts (81% ee and 63% ee, respectively) with significantly lower enantiocontrol.[6b,8a] Linear n-propyl olefin 3e showed good selectivity (95% ee), whereas the sterically more demanding i-butyl olefin substituent on substrate 3f resulted in 94% ee.

To demonstrate the synthetic utility, this developed catn class="Chemical">alytic system for class="Chemical">n class="Chemical">dialkyl-substituted enones was applied in the partial synthesis of anti-HIV agent 7 (Table ). Hydrogenation of α,β-dialkyl substituted enone 5 yielded key intermediate α-chiral ketone 6 in 98% ee (97% isolated yield), which has previously been synthesized via a stereoselective alkylation, using an auxiliary strategy.[9]

Then, n class="Chemical">aromatic enones were evclass="Chemical">n class="Chemical">aluated and our library of ligands were shown to be well-tolerated in the hydrogenation of model substrate 8a, in terms of selectivity, showing excellent ee values of up to 99% (see Table S3 in the Supporting Information). Catalyst B was chosen for further studies on the class of α-prochiral aromatic enones (Table ).[11] The introduction of various electron-donating or electron-withdrawing substituents on the aromatic ring gave equal results and substrates 8b–8g gave uniformly excellent ee values of 99%. Moreover, the scalability of the methodology was demonstrated by the hydrogenation of 8b on a 1.3 mmol scale (99% yield). Changing the substituent to 2-naphthalene 8h led to a slight decrease in enantioselectivity (97% ee). Thereafter, substrates with a variety of substituents on the ketone side chain were hydrogenated and n-butyl, i-propyl, and phenyl ketones all yielded the desired product in perfect ee of 99% (8i–8k). An increase in the bulk of the α-substituent to ethyl (8l) gave a similar result. The ring size of cyclic enones with an exocyclic olefin was shown to affect the enantioselectivity. Whereas cyclopentanone derivative 8m was hydrogenation in moderate ee of 76%, six-membered and seven-membered cyclic enones were hydrogenated in excellent ee of 99% (8n–8o). Furthermore, heterocyclic substrates 8p–8t were also well-tolerated (99% ee, 93%–99% yield).

Table 3

Asymmetric Hydrogenation of Aromatic-Substituted Enones*

Reaction conditions: 0.2 mmol of substrate, 0.5 mol % catalyst, 2 mL of solvent, 20 bar of H2, 16 h, rt, unless stated otherwise. Absolute stereochemistry assigned by comparing optical rotation with literature values. If no reference is given then assignment is tentative. Yields given are in their isolated forms. Enantiomeric excess was determined by SFC or GC analysis, using chiral stationary phases.

1.3 mmol scale.

0.75 mol % of catalyst.

1.0 mol % of catalyst.

5 bar of H2.

2 bar of H2.

Reaction conditions: 0.2 mmol of substrate, 0.5 mol % catn class="Chemical">alyst, 2 mL of solveclass="Chemical">nt, 20 bar of class="Chemical">n class="Chemical">H2, 16 h, rt, unless stated otherwise. Absolute stereochemistry assigned by comparing optical rotation with literature values. If no reference is given then assignment is tentative. Yields given are in their isolated forms. Enantiomeric excess was determined by SFC or GC analysis, using chiral stationary phases.

1.3 mmol scn class="Chemical">ale.

0.75 mol % of catn class="Chemical">alyst.

1.0 mol % of catn class="Chemical">alyst.

5 bar of n class="Chemical">H2.

2 bar of n class="Chemical">H2.

Finn class="Chemical">ally, β-prochirclass="Chemical">n class="Chemical">al aromatic enone 10a was evaluated in the hydrogenation to the corresponding saturated ketone. Fortunately, catalyst D, which has successfully been applied in the hydrogenation of β-prochiral unsaturated esters,[10] gave higher chiral induction of 94% ee in the hydrogenation of substrate 10a (see Table S4 in the Supporting Information). Changing the carbonyl side chain to a methyl and ethyl group increased the enantioselectivity to 98% and 99% ee, respectively (10b and 10c). The presence of an electron-donating methyl group at the para position (10d) of the aryl substituent on the olefin was hydrogenated in similar ee (94%), compared to the unsubstituted equivalent 10a. Increasing the length of the β-alkyl group to ethyl did not affect either the conversion or the enantioselectivity and compound (E)-10e was hydrogenated in 99% ee. The isomeric purity of the olefin turned out to be important for the enantioselection of the catalyst. Whereas the hydrogenation of (E)-10e produces (S)-11e, an opposite enantiomeric outcome was formed when (Z)-10e was hydrogenated (57% ee), demonstrating that the reaction is enantiodivergent.

In conclusion, an efficient protocol for the synthesis of α- and β-chirn class="Chemical">al class="Chemical">n class="Chemical">ketones via asymmetric hydrogenation of conjugated unsaturated enones by Ir–N,P catalysis is described. Although dialkyl-substituted enones have previously been hydrogenated with moderate enantioinduction, efficient hydrogenation of these challenging substrates was achieved by using the conditions described in this study giving 88%–99% ee. The method was successfully applied in the synthesis of an anti-HIV agent. Furthermore, various (hetero)aromatic-substituted enones were well-tolerated, resulting in 94%–99% ee of the corresponding chiral ketones.