1,n‐Glycols as Dialdehyde Equivalents in Iridium‐Catalyzed Enantioselective Carbonyl Allylation and Iterative Two‐Directional Assembly of 1,3‐Polyols

Abstract

Natures vast collection of polyketide natural products comprises thousands of compounds incorporating polyacetate-derived 1,3-diol or higher 1,3-polyol substructures. Although numerous procedures for the synthesis of these ubiquitous structural motifs have been advanced, [1] the iterative allylmetallation of aldehydes has found exceptionally broad use. [1][2][3][4][5][6] For example, asymmetric iterative allylchromation (Nozaki-Hiyama coupling), [2] allyltitanation, [3] allylstannation, [4] allylsilation, [5] and allylboration [6] have been employed in synthetic approaches to 1,3-diols and higher homologues. Browns allylborane (n-C 3 H 5 )Ipc 2 B (Ipc = isopinocampheyl) [7] has found the most extensive use in iterative asymmetric carbonyl allylation.[6] Although superstoichiometric generation of isopinocampheol poses a barrier to large-volume applications, [8] both enantiomers of a-pinene are available at low cost and excellent levels of stereocontrol are observed, making the Brown method attractive for use in academic laboratories. However, use of traditional allylmetallation procedures in iterative two-directional syntheses of 1,3-polyol substructures is prohibited by the instability of malondialdehyde.In connection with efforts to exploit catalytic hydrogenation in C À C couplings beyond hydroformylation, [9] we have developed an enantioselective method for carbonyl allylation from the alcohol oxidation level under the conditions of iridium-catalyzed transfer hydrogenation that employ allyl acetate as an allyl donor.[10] The reactant alcohol serves both as a source of hydrogen and as an aldehyde precursor, enabling formation of highly optically enriched homoallylic alcohols directly from the alcohol oxidation level by way of a transient aldehyde. Whereas reductive coupling of allylic carboxylates, alcohols, or ethers to carbonyl partners is typically achieved using metallic reductants, such as SmI 2 , SnCl 2 , Et 2 Zn, or Et 3 B, [11][12][13][14][15] transfer-hydrogenative carbonyl allylation precludes the use of any stoichiometric metallic reagents. Here, using a chiral iridium C,O-benzoate complex modified by 4-chloro-3-nitrobenzoic acid and (R)-or (S)-Cl,MeO-biphep (2,2'-bis(diphenylphosphino)-5,5'-dichloro-6,6'-dimethoxy-1,1'-biphenyl), we report an iterative twodirectional bis allylation of glycols. The method is demonstrated by the rapid assembly of protected 1,3-polyol substructures with exceptional levels of enantiocontrol and catalyst-directed diastereoselectivity.[16] Notably, this process successfully exploits 1,3-diols as synthetic equivalents to unstable malondialdehydes.Although malondialdehyde can be generated through the hydrolysis of 1,1,3,3-tetramethoxypropane, capture of this dialdehyde is impeded by the fact that it is highly unstable and is generated under aqueous conditions, which promote hydration, oligomerization, and self-condensation, and preclude the use of most organometallic reagents. The ability to bypass stoichiometric pre-formation of aldehyde electrophiles, as in carbonyl allyl...

Catalytic Enantioselective Carbonyl Allylation and Propargylation via Alcohol-Mediated Hydrogen Transfer: Merging the Chemistry of Grignard and Sabatier

“…Dehydrogenation of the secondary alcohol products is prevented by internal chelation of the homoallylic olefin. Mechanistic studies 8b corroborate the indicated catalytic mechanism wherein carbonyl addition represents the turnover limiting event. These processes embody an inversion of polarity (umpolung) with respect to π-allyl species evident in related allylic substitutions catalyzed by iridium 23 and represent a departure from the longstanding (1978) 24 use of chiral allylmetal reagents in carbonyl addition.…”

“…8–22 As illustrated in the catalytic mechanism (Scheme 3-A), the internal carboxylate of the ortho - C,O -benzoate moiety maintains neutrality of the π-allyliridium intermediate and, hence, nucleophilic character. Dehydrogenation of the secondary alcohol products is prevented by internal chelation of the homoallylic olefin.…”

“…3g,8f,g As illustrated in reactions of ( S )-butanediol, this capability not only applies to the parent allylations. 8f,g High levels of catalyst-directed diastereoselectivity also are evident in tert -(hydroxy)-prenylations mediated by isoprene oxide (Scheme 5-B) 18 and (α-aminomethyl)allylations mediated by N -( p -nitrophenylsulfonyl) protected vinyl aziridines (Scheme 5-C).…”

Stereoarrays with an All‐Carbon Quaternary Center: Diastereoselective Desymmetrization of Prochiral Malonaldehydes

“…The short de novo synthesis of polysubstituted cyclohexenes 23, which are highly functionalized building blocks for novel carbasugar and inositol analogues containing a quaternary center, is an illustration of the synthetic usefulness of the method. While the aforementioned enantioselective bidirectional process developed by Krishe and co-workers [4] is a superior way to obtain pseudo-C 2 -symmetric allylation products, our current [f] Precise diastereomeric ratio could not be determined. The thermal ellipsoids of the X-ray crystal are shown at 35 % probability.…”

Strategies and Methods for the Synthesis of Anticancer Natural Product Neopeltolide and its Analogs

“…[30] Their synthesis commenced with an efficient iridium-catalyzed double asymmetric carbonyl allylation developed by the Krische group to convert 1,3-propanediol 136 to the C 2 -symmetric diol 138 in 72% yield. [31] The latter was then subjected to the Semmelhack’s palladium-catalyzed alkoxycarbonylation reaction[32] to provide tetrahydropyran 139 in excellent yield and stereoselectivity (d.r. > 20:1).…”