Diastereo‐ and Enantioselective Iridium‐Catalyzed Carbonyl Propargylation from the Alcohol or Aldehyde Oxidation Level: 1,3‐Enynes as Allenylmetal Equivalents

Abstract

Axial to axial to point chirality transfer: Exposure of conjugated enynes to alcohols in the presence of an iridium catalyst modified by a segphos ligand results in the generation of aldehyde–allenyliridium pairs and formation of enantiomerically enriched products of carbonyl anti-(α-methyl)propargylation (see scheme). An identical set of products are obtained from aldehydes under related transfer hydrogenation conditions by employing formic acid as a reductant. Carbonyl propargylation has been the topic of intensive investigation for over half a century.1, 2 An effective approach to enantioselective carbonyl propargylation involves the addition of chirally modified allenylmetal reagents,3–7 including axially chiral derivatives.5 Contributions include allenylboron reagents that are chirally modified at boron, as reported by Yamamoto,3a Corey,3b and Soderquist,3c,3d allenylstannanes that are chirally modified at tin, as first reported by Mukaiyama,4 as well as axially chiral allenylstannanes, allenylsilanes, allenylboron, and allenylzinc reagents that engage aldehydes in enantioselective propargylation, as described by Marshall,5a,5b,5e,5f Hayashi,5d and Panek,5c respectively. Increasingly effective protocols for carbonyl propargylation, which involve stoichiometric chirality transfer, continue to be developed.6, 7 Enantioselective aldehyde propargylation using allenyltin8 and allenylsilicon9 reagents may be catalyzed by chiral Lewis acids or chiral Lewis bases, as first reported by Keck8a and Denmark,8f respectively. Copper catalysts promote enantioselective carbonyl propargylation by employing allenylboron and propargylboron reagents, as reported by Kanai and Shibasaki and Boehringer–Ingelheim Pharmaceuticals Inc.10 More recently, Schaus, Antilla, and Reddy reported chiral H-bond donor and Brønsted acid catalyzed propargylations using allenylboron reagents.11 Finally, catalytic enantioselective Nozaki–Hiyama coupling of propargyl halides delivers products of carbonyl propargylation.12 Withstanding the Nozaki–Hiyama protocol,12 methods available for enantioselective carbonyl propargylation have relied on stoichiometric allenyl- or propargylmetal reagents. Moreover, while carbonyl propargylations for the construction of non-methylated polyacetate subunits are common, catalytic diastereo- and enantioselective propargylations that convert achiral reactants to polypropionate substructures remain undeveloped. We envisioned an alternative strategy for carbonyl propargylation based on the “transfer hydrogenative coupling”13 of 1,3-enynes and primary alcohols. Although related Rh- and Ni-catalyzed reductive couplings occur at the acetylenic terminus of the enyne,14, 15 ruthenium catalysts were found to promote enyne–alcohol CC coupling to form the desired products of propargylation as single regioisomers, but without stereocontrol.16 Herein, we report that iridium catalysts modified by (R)-segphos17 or (R)-DM-segphos promote highly anti-diastereo- and enantioselective enyne-mediated carbonyl propargylation from the alcohol or aldehyde oxidation level in the absence of stoichiometric allenyl- or propargylmetal reagents. Initial studies focused on the CC coupling of benzylic alcohol 2 b to enynes 1 a and 1 b, which are derived from 2-methyl-3-butyn-2-ol (47 USD/Kg).18 Whereas enyne 1 a failed to participate in CC coupling to benzylic alcohol 2 b under the conditions of iridium catalysis (Table 1, Entry 1), the corresponding TBS ether 1 b couples to benzylic alcohol 2 b to form the desired propargylation product 4 b-TBS in 69 % yield as a 1:1 mixture of diastereomers upon exposure to the catalyst generated from [{Ir(cod)Cl}2] and dppf (Table 1, Entry 2). At this stage, a series of chiral ligands were assayed (Table 1, Entries 3–5). Whereas (R)-segphos provides homopropargylic alcohol 4 b-TBS in 93 % enantiomeric excess, the yield and diastereoselectivity were poor (Table 1, Entry 3). Using (R)-DM-segphos, homopropargylic alcohol 4 b was isolated in 75 % yield with a promising 6:1 anti-diastereoselectivity and 80 % enantiomeric excess (Table 1, Entry 4). Increased anti-diastereoselectivity upon use of xylyl-substituted ligands also was observed in the binap and p-phos ligand classes, although segphos ligands17 consistently provided higher diastereo- and enantioselectivity. It was postulated that an even more sterically demanding ligand, (R)-DTBM-segphos, might promote higher stereoselectivities, however, this catalytic system did not produce 4 b-TBS (Table 1, Entry 5). Entry 1, R Ligand Solvent Yield [%] d.r. ee [%] 1 1 a, H dppf PhMe 0 – – 2 1 b, TBS dppf PhMe 69 1:1 – 3 1 b, TBS (R)-segphos PhMe 35 1:1 93 4 1 b, TBS (R)-DM-segphos PhMe 75 6:1 80 5 1 b, TBS (R)-DTBM-segphos PhMe 0 – – 6 1 c, TIPS (R)-segphos PhMe 81 3:1 94 7 1 c, TIPS (R)-DM-segphos PhMe 80 8:1 87 8 1 c, TIPS (R)-DM-segphos THF 81 12:1 90 9 1 c, TIPS (R)-DM-segphos CH3CN 50 13:1 93 10[b] 1 c, TIPS (R)-DM-segphos THF 75 12:1 92 Given these trends, it was postulated that increased steric demand of the enyne might enhance anti-diastereoselectivity. Indeed, use of the enyne 1 c, which incorporates a TIPS ether, and the (R)-segphos modified catalyst provided homopropargylic alcohol 4 b-TIPS in 81 % yield, 3:1 anti-diastereoselectivity, and 94 % enantiomeric excess (Table 1, Entry 6). Furthermore, by using the TIPS ether enyne 1 c in combination with (R)-DM-segphos, homopropargylic alcohol 4 b-TIPS was obtained in 80 % yield, 8:1 anti-diastereoselectivity, and 87 % enantiomeric excess (Table 1, Entry 7). Upon use of THF as solvent, 12:1 anti-diastereoselectivity and 90 % enantiomeric excess were observed (Table 1, Entry 8). Use of acetonitrile as solvent enhanced stereoselectivity (93 % ee, 13:1 d.r.), but diminished the yield of isolated product (Table 1, Entry 9). Use of acetonitrile as an additive in THF proved optimal, allowing the homopropargylic alcohol 4 b-TIPS to be generated in 75 % yield, 12:1 anti-diastereoselectivity, and 92 % enantiomeric excess (Table 1, Entry 10). The effect of solvent on stereoselectivity is more pronounced when the reaction is performed from the aldehyde oxidation level.19 The observed correlation between increased ability of the solvent to coordinate to the metal with selectivity may be consistent with a slowing of the overall reaction rate (see below). With these optimized conditions in hand, enyne 1 c was coupled to a diverse range of alcohols 2 a–2 k (Table 2). The homopropargylic alcohols 4 a–4 k were formed with uniformly high levels of anti-diastereo- and enantioselectivity, whether the reaction was performed in pressure tubes or round-bottomed flasks.20 While reactions of benzylic and allylic alcohols 2 a–2 h require (R)-DM-segphos to enforce stereoselectivity, reactions of aliphatic alcohols 2 i–k were highly stereoselective by using (R)-segphos as ligand. Reactions with alcohols 2 g–k were higher yielding in the presence of either isopropanol or formic acid, although the reason for this observation remains unclear. Aliphatic alcohols branched at the α position are converted to homopropargylic alcohols with exceptional levels of stereoselectivity, however, diminished yields of isolated products were observed for this substrate class. Using formic acid as terminal reductant, enyne 1 c participates in reductive couplings to aldehydes 3 a–3 i to furnish an equivalent set of homoallylic alcohols 4 a–4 i in good to excellent yield with outstanding levels of anti-diastereo- and enantioselectivity (Table 2). As observed in the coupling of benzylic and allylic alcohols, (R)-DM-segphos was required to enforce stereoselectivity in the propargylation of (hetero)aryl and α,β-unsaturated aldehydes 3 a–3 h, whereas aliphatic aldehydes 3 i–3 k undergo stereoselective propargylation using (R)-segphos as ligand. For aldehydes 3 i–3 k, higher yields were obtained upon use of Na2SO4 (1 equiv) as additive.21 Propargylation products 4 c, 4 g, and 4 i are directly converted to the corresponding terminal alkynes 5 c, 5 g, and 5 i upon exposure to TBAF and NaOH in refluxing toluene (Scheme 1). As terminal alkynes 5 c and ent-5 i are known compounds of established relative and absolute stereochemistry, their preparation served to confirm the stereochemical assignment of adducts 4 a–4 k. Deprotection of homopropargyl alcohols 4 c, 4 g, and 4 i to generate terminal alkynes 5 c, 5 g, and 5 i. Yields of isolated materials are given. See the Supporting Information for details. TBAF=tetra-n-butylammonium fluoride. Entry Oxidation level Lig. Solv. Product Yield [%] d.r. ee [%] 1 alcohol A THF 85 19:1 91[b] aldehyde A THF 79 12:1 86[b] 2 alcohol A THF 75 12:1 92[b] aldehyde A THF 86 10:1 90[b] 3 alcohol A THF 87 12:1 89[b] aldehyde A THF 89 11:1 87[b] 4 alcohol A THF 77 18:1 92[b] aldehyde A THF 82 20:1 89[b] 5 alcohol A THF 82 22:1 94[b] aldehyde A THF 89 12:1 90[b] 6 alcohol A THF 81 29:1 95[b] aldehyde A THF 78 12:1 95[b] 7 alcohol A PhMe 38 ≥40:1 99[c] aldehyde A THF 67 22:1 94 8 alcohol A PhCF3 62 32:1 90[d] aldehyde A THF 82 24:1 89[f] 9 alcohol B PhCF3 53 40:1 99[d,e] aldehyde B THF 89 17:1 99[f] 10 alcohol B PhCF3 54 ≥50:1 99[d,e] aldehyde B THF 68 ≥50:1 99[f] 11 alcohol B PhCF3 48 ≥50:1 96[d,e] aldehyde B THF 68 ≥50:1 96[f] A plausible catalytic mechanism is as follows. The combination of [{Ir(cod)Cl}2], ligand, and reactant alcohol provides the iridium(I) alkoxide I, which dehydrogenates to form an aldehyde and generate iridium(I) hydride II. For reactions conducted from the aldehyde oxidation level, the formate complex Ib is converted to iridium(I) hydride II. Enyne hydrometallation provides the σ-propargyl- and allenyliridium species III and IV, respectively. Coordination of the aldehyde by the latter provides V, which engages in carbonyl addition through a closed transition structure to furnish the homopropargylic iridium(I) alkoxide VI. Alkoxide exchange with a reactant alcohol delivers the product and regenerates the iridium(I) alkoxide I (Scheme 2). Although undescribed for iridium, the stoichiometric reaction of 1,3-enynes and [RuHCl(CO)(PPh3)3] to form σ-allenyl complexes that have been characterized by single crystal X-ray diffraction is known.22a Additionally, the allenyliridium(III) complex [IrCl(PPh3)2(NHSO2Ph)(CO)(η1-CHCCH2)] has been isolated, and characterized by single crystal X-ray diffraction.22b The stereochemical outcome of the transformation is predicted on the basis of the indicated model, which involves carbonyl addition through the closed six-centered transition state A (Scheme 2). Regarding the conformation of such square-planar allenyliridium species A–D, it is shown in a related η1-allenylplatinum(II) complex, trans-[Pt(PPh3)2(Br)(η1-CHCCH2)], that the allenyl moiety lies roughly perpendicular to the square coordination plane.22c General catalytic mechanism and stereochemical model accounting for the observed anti-diastereo- and enantioselectivity. As the allenyliridium substructures of transition states A and B exhibit enantiomeric axial chirality, enantioselective enyne-mediated propargylation requires high kinetic stereoselectivity in the enyne hydrometalation event to form a single diastereomeric allenyliridium intermediate, or reversible enyne hydrometalation to correct for incomplete stereoselectivity, should the less stable allenyliridium species be formed. To probe this issue, the coupling of enyne 1 c and [D2]-benzyl alcohol 2 a was performed under standard conditions (Scheme 3). The distribution of deuterium in deuterated 4 a suggests that the enyne hydrometalation is reversible and that the carbonyl addition occurs by way of a single diastereomeric allenyliridium intermediate, even if the kinetic stereoselectivity of the hydrometalation is incomplete. Deuterium labeling studies suggest reversible enyne hydrometallation in advance of CC coupling. See the Supporting Information for 1H NMR spectra. In summary, we report highly anti-diastereo- and enantioselective iridium-catalyzed enyne-mediated carbonyl propargylations from the alcohol or aldehyde oxidation level. This methodology provides an alternative to stoichiometric (organo)metallic reagents in enantioselective carbonyl propargylation. Additionally, reactions performed directly from the alcohol oxidation level bypass redox manipulations otherwise required for discrete aldehyde generation. Future studies will focus on the development of related CC bond forming transfer hydrogenations, including the catalytic CC coupling of propargyl chlorides and alcohols. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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