β-Hydroxy Esters as Malonic Semialdehyde Proelectrophiles in Enantioselective Butadiene-Mediated Crotylation: Total Synthesis of Octalactins A and B

Graphical Abstract

Tractable and commercially available esters (and amides) of β-hydroxy propionic acid serve as malonic semialdehyde proelectrophiles in enantioselective ruthenium-catalyzed hydrogen auto-transfer crotylations mediated by butadiene. Through iterative asymmetric butadiene-mediated crotylations of ethyl 3-hydroxypropanoate, total syntheses of the polyketide natural products octalactins A and B were achieved in fewer steps than previously possible.

As evident in the structure of erythromycin A, the first commercial polyketide antibiotic (1952), propionate motifs are pervasive among polyketides natural products, including macrolides (Figure 1). In connection with efforts to develop hydrogen auto-transfer reactions for the stereo- and site-selective conversion of lower alcohols to higher alcohols, our laboratory has advanced catalytic methods for the assembly of diverse polyketide substructures,¹ including methods for diastereo- and enantioselective carbonyl crotylation via hydrogen auto-transfer from primary alcohol proelectrophiles using iridium² or ruthenium³ catalysts and α-methyl allyl acetate or butadiene as crotylmetal pronucleophiles, respectively. Applicability of these methods to alcohols that dehydrogenate to form unstable aldehydes⁴ suggested the feasibility of utilizing 3-hydroxy propionates as malonic semialdehyde proelectrophiles in carbonyl crotylations via hydrogen auto-transfer. Here, using iodide-bound ruthenium-JOSIPHOS complexes recently developed in our laboratory,⁵ we report efficient diastereo- and enantioselective butadiene-mediated anti-crotylations^3f of 3-hydroxy propionate esters and amides to form a structural motif found in diverse polyketide natural products. Using this method, total syntheses of octalactins A and B, were completed in fewer steps than previously possible.^6,7

Figure 1.

Crotylation of 3-hydroxy propionates streamlines the total syntheses of octalactins A and B (LLS = Longest Linear Sequence). See Supporting Information for graphical summaries of prior syntheses.

In an initial experiment, ethyl 3-hydroxy propionate 2a (100 mol%) was exposed to butadiene 1 (1 atm) in the presence of the iodide-bound ruthenium catalyst derived from Ru(I)(CO)₃(η³-C₃H₅) (5 mol%) and the JOSIPHOS ligand SL-J502–1 (5 mol%) in isooctane solvent (0.5 M) with added trifluoroethanol (300 mol%) at 100 °C.^3f To our dismay, only trace quantities of the targeted product of anti-crotylation 3a was formed. However, upon a survey of different solvents it was found that reactions run in methyl tert-butyl ether (MTBE) were highly efficient, delivering the product of anti-crotylation 3a in 78% yield as a 5:1 mixture of diastereomers favoring the anti-isomer with high levels of enantiomeric enrichment (92% ee) at 3 mmol scale (Scheme 1). These conditions for butadiene-mediated diastereo- and enantioselective anti-crotylation were applicable to diverse 3-hydroxy propionate esters and amides 2a-2h. Reactions of β-hydroxy ketones were inefficient, but conversion of Weinreb amide 2f to adduct 3f potentially provides access to ketone-containing derivatives.⁸

Scheme 1.

Enantioselective butadiene-mediated anti-crotylation of β-hydroxy esters and amides 2a-2h.^a

^aYields of material isolated by silica gel chromatography. Diastereoselectivities were determined by ¹H NMR analysis of crude reaction mixtures. Enantioselectivities were determined by chiral stationary phase HPLC analysis. ^bCsI (10 mol%). ^c115 ⁰C. See Supporting Information for further details.

As described above, compound 3a comprises a structural motif that is ubiquitous among type I polyketide natural products (Figure 1). Hence, to highlight the utility of the present method for anti-crotylation, it was applied to the synthesis of octalactins A and B.^6,7 Retrosynthetically, it was envisioned that octalactin A, the more complex congener, could be accessed via triorganozincate-mediated vinylation⁹ of the aldehyde, Fragment A (Scheme 2). While this disconnection has been used frequently in prior syntheses of the octalactins (under Nozaki-Hiyama-Kishi (NHK) conditions^7a,g,h,l or using vinyllithium reagents^7b,i,j,m), it has never been achieved with high levels of substrate-directed or catalyst-directed stereocontrol. However, our experience with triorganozincate-mediated vinylation^4,9f suggest these reagents are uniquely effective in substrate-directed stereoselective aldehyde vinylations. Fragment A is potentially accessible via iterative butadiene-mediated anti-crotylation of ethyl hydroxy propionate 2a. Fragment B was envisioned to arise via enantioselective iridium-catalyzed allylation of isobutanol¹⁰ followed by cross-metathesis of the resulting homoallylic alcohol with vinylpinacolboronate followed by iodination of the carbon-boron bond.¹¹

Scheme 2.

Retrosynthetic analysis of octalactin A.

The synthesis of Fragment A begins with butadiene-mediated anti-crotylations of ethyl hydroxy propionate 2a, which on 3 mmol scale gave the homoallylic alcohol 3a in 78% yield with 5:1 the anti-diastereoselectivity and 92% ee (Scheme 3). In Cossy’s synthesis of octalactin B, an analogous crotylation was performed.^7m The malonic semi-aldehyde (generated via ozonlysis of methyl 3-butenoate) was reacted with a TADDOL-modified crotyltitanium reagent that requires a 5-step preparation.¹² Hence, our butadiene-mediated process streamlines the formation of 3a by removing a total of 6 steps. Triisopropylsilylation of the secondary alcohol followed by hydroformylation-reduction using a rhodium-xantphos catalyst provides the homologous alcohol 4 with good linear vs branched regioselectivity (8:1).¹³ A second butadiene-mediated anti-crotylation provided adduct 5 in 91% yield with high stereocontrol. Silanolate-mediated ester hydrolysis¹⁴ followed by Shiina lactonization¹⁵ and oxidative cleavage of the terminal olefin¹⁶ provides Fragment A.

Scheme 3.

Synthesis of Fragment A.^a

^aYields of material isolated by silica gel chromatography. Diastereoselectivities and linear:branched regioselectivities were determined by ¹H NMR analysis of crude reaction mixtures. See Supporting Information for further details.

The preparation of Fragment B begins with the π-allyliridium-C,O-benzoate-catalyzed allylation of isobutanol¹⁰ to provide homoallylic alcohol 6 in 88% yield with high levels of enantiocontrol (94% ee) (Scheme 4). Exposure of homoallylic alcohol 6 to (2-propenyl)pinacolboronate in the presence of the Hoveyda-Grubbs II catalyst (added via syringe pump addition), affects cross-metathesis with complete (Z)-stereoselectivity.^11a Subsequent TBS protection and iodination of the C-B bond¹¹ provides Fragment B in a total of 4 steps (LLS). O-Silylation prior to cross-metathesis led to an inseparable mixture of (Z:E)-diastereomers (5:1).

Scheme 4.

Synthesis of Fragment B.^a

^aYields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. See Supporting Information for further details.

With Fragments A and B in hand, the triorganozincate-mediated fragment union was attempted. To our delight, the allylic alcohol 7 was isolated in 60% yield with complete diastereocontrol (>20:1) to form the desired C9-(R) epimer, as confirmed by conversion to octalactin A (vide infra) (Scheme 5). The observed stereochemistry is consistent with Evans’ models for merged 1,2- and 1,3-asymmetric induction.¹⁷ Notably, in all prior syntheses that enact fragment union under NHK conditions^7a,g,h,l or using vinyllithium reagents,^7b,i,j,m modest selectivities were observed (1:1 to 2:1 dr). Evans observed in aldol additions to β-OAc aldehydes that 1,3-anti- and 1,3-syn-products formed with low diastereocontrol (43:57 ratio) with calculations suggesting the minimally reinforcing nature of the β-acyloxy moiety.¹⁷ Hence, stereocontrol in additions to aldehydes akin to Fragment A are anticipated to depend more on the α-stereocenter vis-à-vis the Felkin-Anh model, which, in turn, depends on nucleophile size. Triorganozincates are larger than neutral vinylchromium (NHK) and vinyllithium reagents, augmenting interactions with the α-stereocenter for heightened Felkin-Anh control. Indeed, beyond octalactin, the enhanced diastereoselectivity of triorganozincate versus NHK or vinyllithium addition has been documented,^9c,f and the triorganozincate-mediated fragment union requires only a slight excess of the vinyliodide, unlike corresponding NHK reactions.^7a,g,h,l The allylic alcohol 7 was subjected to hydroxyl-directed epoxidation per Buszek’s report,^7a Dess-Martin oxidation and HF•pyridine-mediated silyl deprotection to deliver octalactin A in 11 steps (LLS) from tractable, commercial ethyl 3-hydroxy propionate. In accordance with previous synthetic reports,⁷ an analogous oxidation-deprotection sequence delivered octalactin B in 10 steps (LLS).

Scheme 5.

Union of Fragments A and B via triorganozincate addition and total syntheses of octalactins A and B ^a

^aYields of material isolated by silica gel chromatography. See Supporting Information for further details.

In summary, we demonstrate that highly tractable β-hydroxy propionates serve as malonic semialdehyde proelectrophiles in enantioselective butadiene-mediated crotylations, thus enabling direct access to ubiquitous polyketide substructures. Using this method, octalactins A and B were prepared in fewer steps than previously possible. It is our hope the present method will aid other researchers engaged in the daunting enterprise of target-oriented synthesis.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.