Abstract
Enantioselective transfer hydrogenation of carbonate 1a in the presence of aromatic, allylic or aliphatic alcohols 2a–2i employing a cyclometallated iridium C,O-benzoate derived from allyl acetate, 4-cyano-3-nitrobenzoic acid and (S)-SEGPHOS delivers products of (hydroxymethyl)allylation 4a–4i in good isolated yields (60–74%), good anti-diastereoselectivities (5:1–10:1 dr) and exceptional levels of enantiocontrol (93–99% ee). Under identical reaction conditions, but in the presence of isopropanol, aldehydes 3a–3i are converted to an equivalent set of adducts 4a–4i in good isolated yields (58–74%), good anti-diastereoselectivities (4:1–14:1 dr) and exceptional levels of enantiocontrol (95–99% ee). Thus, identical sets of adducts 4a–4i are produced with equal facility from the alcohol or aldehyde oxidation level. These studies represent the first general method for enantioselective carbonyl (hydroxymethyl)allylation, a process that has no highly stereoselective counterpart in conventional allylmetal chemistry.
The hydroxymethyl 1,3-diol motif appears in numerous natural products,1–4 yet asymmetric methods for carbonyl (hydroxymethyl)allylation are largely unexplored.5–7 In most cases, catalytic carbonyl hydroxymethylation has been accomplished through umpolung of palladium π-allyl complexes derived from 2-butene-1,4-diol carboxylates5 or vinyl epoxides6 in combination with metallic reductants, such as SnCl2 or InI. However, control of regio- and diastereoselectivity has proven challenging. Nakajima, as well as Cozzi and Umani-Ronchi, each report a single example of catalytic syn-(hydroxymethyl)allylation but only moderate enantioselectivities were observed.7 To our knowledge, corresponding protocols for enantioselective anti-(hydroxymethyl)allylation are unknown.8
We have found that chiral ortho-cyclometallated iridium C,O-benzoates catalyze carbonyl allylation,9a,b,e–h crotylation9c,f and tert-prenylation9d,f employing allyl acetate, α-methyl allyl acetate and 1,1-dimethylallene as allyl donors, respectively. For such C-C bond forming transfer hydrogenations,10 alcohols function both as hydrogen donors and carbonyl precursors, enabling identical sets of carbonyl addition products to be generated from either the alcohol or aldehyde oxidation level.1,2 In more recent work, it was found that use of the isolated iridium C,O-benzoate complex was essential for efficient reductive couplings of allylic gem-dibenzoates.9i This outcome prompted us to reexamine processes that failed using in situ generated catalysts, including reactions of allylic carbonates.
Here, we report that complex (S)-I, which is modified by the chiral phosphine ligand (S)-SEGPHOS,11 serves as a single-component catalyst for the coupling of cyclic carbonate 1a to alcohols 2a–2i to furnish (hydroxymethyl)allylation products 4a–4i in highly enantiomerically enriched form. Under similar conditions in the presence of isopropanol, cyclic carbonate 1a couples to aldehydes 3a–3i to furnish an identical set of adducts 4a–4i with comparable levels of selectivity. These studies represent the first general method for enantioselective carbonyl (hydroxymethyl)allylation - a process that has no highly stereoselective counterpart in conventional allylmetal chemistry.
A principle concern regarding use of cyclic carbonate 1a is the requirement that alcohols 2 selectively dehydrogenate in the presence of diol-containing products 4. To probe this issue and to explore the feasibility of utilizing allylic carbonates as allyl donors, cyclic carbonate 1a was exposed to benzyl alcohol 2a in the presence of the cyclometallated complex derived from [Ir(cod)Cl]2, 4-cyano-3-nitrobenzoic acid, allyl acetate and BIPHEP (2,2'-bis(diphenylphosphino)biphenyl). Remarkably, decarboxylative anti-(hydroxymethyl)allylation occurs smoothly to furnish the desired diol 4a in good isolated yield. Dehydrogenation of the diol product is not observed as the homoallylic olefin of 4a binds the coordination site required for β-hydride elimination.10d,11 Exclusive formation of the branched regioisomer and anti-diastereoselectivity are consistent with carbonyl addition from the primary (E)-σ-allyl iridium haptomer by way of a chair-like transition structure. Finally, unlike analogous reactions of allylic acetates which require added base,9a–c,e–i the decarboxylative process occurs in the absence of base or any other additive.
This result prompted an assay of chiral iridium C,O-benzoates. Among the complexes assayed, (S)-I, which is modified by the chiral phosphine ligand (S)-SEGPHOS,12 was superior. By simply combining carbonate 1a with alcohols 2a–2i in the presence of (S)-I in THF solvent at 90 °C, products of (hydroxymethyl)allylation 4a–4i are generated with good anti-diastereoselectivities (5:1–10:1 dr) and exceptional levels of enantiocontrol (93–99% ee). The isolated yields were moderate (60–74%) due to incomplete consumption of alcohols 2a–2i (Table 1). Higher yields are obtained if reaction time is extended.
Table 1.
Enantioselective (hydroxymethyl)allylation from the alcohol oxidation level.a
 | ||
|---|---|---|
| 2a, R = Ph | 2b, R = m-MeOPh | 2c, R = p-BrPh |
| 2d, R = p-(CO2Me)Ph | 2e, R = 2-Furyl | 2f, R = CH=CHPh |
| 2g, R = Geranyl | 2h, R = (CH2)2Ph | 2i, R = (CH2)7Me |
 | ||
Yields are of material isolated by silica gel chromatography. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. See Supporting Information for further details.
Aldehydes 3a–3i are converted to an equivalent set of adducts 4a–4i under similar conditions employing isopropanol as the terminal reductant. Comparable isolated yields (58–74%), anti-diastereoselectivities (4:1–14:1 dr) and enantioselectivities (95–99% ee) are observed (Table 2). Thus, identical adducts 4a–4i are produced with equal facility from the alcohol or aldehyde oxidation level. Construction of oxetane 5c in 2 steps from adduct 4c serves to illustrate the utility of the (hydroxymethyl)allylation process. Similarly, pyrans 6c and 7c are prepared in 3 and 2 steps from adduct 4c, respectively (Scheme 1).
Table 2.
Enantioselective (hydroxymethyl)allylation from the aldehyde oxidation level.a
 | ||
|---|---|---|
| 3a, R = Ph | 3b, R = m-MeOPh | 3c, R = p-BrPh |
| 3d, R = p-(CO2Me)Ph | 3e, R = 2-Furyl | 3f, R = CH=CHPh |
| 3g, R = Geranyl | 3h, R = (CH2)2Ph | 3i, R = (CH2)7Me |
 | ||
As described for Table 1.
Scheme 1.
Conversion of diol 4c to compounds 5c, 6c and 7c.a
aReagents: (a) NaH, TsCl, THF, 82%. (b) n-BuLi, THF, 92%. (c) NaH, H2C=CHCH2Br, THF, 82%. (d) Grubbs I, DCM, 90%. (e) TBSCl, Et3N, DMAP, DCM, 88%. (f) NaH, H2C=CHCH2Br, THF, 90%. (g) Grubbs I, DCM, 91%. See Supporting Information for further details.
The ability of allylic carbonate 1a to participate in intermolecular decarboxylative C-C bond forming transfer hydrogenation prompted us to investigate the decarboxylative C-C coupling of allyl-benzyl carbonates 1b and 1c. Remarkably, using the achiral iridium catalyst BIPHEP-I, the desired products of CC bond formation 8 and 9 were produced in modest yield along with recovered benzyl alcohol. As a molar excess of allyl donor is required to enforce high conversion in the iridium catalyzed carbonyl allylations we describe, high-yielding decarboxylative C-C coupling of allyl carbonates will require improved second generation catalysts.
In summary, we report the first general method for enantioselective carbonyl (hydroxymethyl)allylation. Future studies will focus on the development of related C-C couplings of alcohols and π-unsaturated reactants.
Supplementary Material
Acknowledgments
Acknowledgment is made to the Robert A. Welch Foundation and the NIH-NIGMS (RO1-GM069445). Dr. Yasunori Ino and Dr. Wataru Kuriyama of Takasago are thanked for the generous donation of (S)-SEGPHOS. YJZ acknowledges partial financial support from Shanghai Jiao Tong University.
Footnotes
Supporting information available: Experimental procedures, spectral data for new compounds, including scanned images of HPLC traces, as well as 1H and 13C NMR spectra. This material is available free of charge via the internet at http://pubs.acs.org.
References
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