S S symmetry Article Highly Diastereoselective Chelation-Controlled 1,3-anti-Allylation of (S)-3-(Methoxymethyl)hexanal Enabled by Hydrate of Scandium Triflate Uladzimir S. Masiuk 1,2, Iryna V. Mineyeva 1,* and Dzmitry G. Kananovich 2,* 1 Department of Organic Chemistry, Belarusian State University, Leningradskaya 14, 220050 Minsk, Belarus; [email protected] 2 Department of Chemistry and Biotechnology, School of Science, Tallinn University of Technology, Akadeemia Tee 15, 12618 Tallinn, Estonia * Correspondence: [email protected] (I.V.M.); [email protected] (D.G.K.) Abstract: En route to the total synthesis of (+)-Neopeltolide, we explored Lewis acid-assisted diastere- oselective allylation of MOM-protected 3-hydroxylhexanal with β-(2,2-diethoxyethyl)-substituted (allyl)tributylstannane. The hydrated form of scandium triflate was found to be essential for attain- ing high 1,3-anti-diastereoselectivity (d.r. 94:6), while the use of anhydrous catalyst resulted in a modest diastereocontrol (d.r. 76:24). The preferred 1,3-anti-selectivity in this transformation can be rationalized in the framework of the Reetz chelate model of asymmetric induction. The 1,3-anti- configuration of the product was confirmed by its conversion into the known C7-C16 building block of (+)-Neopeltolide. We also report an improved protocol for the synthesis of β-(2,2-diethoxyethyl)- substituted (allyl)tributylstannane, which can be utilized as a cost-efficient bipolar isoprenoid-type Citation: Masiuk, U.S.; Mineyeva, C5-building block in the synthesis of natural compounds. I.V.; Kananovich, D.G. Highly Diastereoselective Keywords: Reetz–Keck-type allylation; stannylation; Lewis acids; organotin compounds; β- Chelation-Controlled oxyaldehydes; scandium triflate; chelation control; asymmetric synthesis; asymmetric induction 1,3-anti-Allylation of (S)-3-(Methoxymethyl)hexanal Enabled by Hydrate of Scandium Triflate. Symmetry 2021, 13, 470. 1. Introduction https://doi.org/10.3390/sym13030470 Stereoselective allylation of carbonyl compounds allows to assemble a carbon–carbon bond along with installation of a new stereocenter [1–4]. The produced homoallylic alcohols Academic Editor: Eugenijus Butkus provide multiple opportunities for the subsequent modifications and therefore are widely used in the target-oriented synthesis of natural and bioactive compounds [2–5]. Received: 19 February 2021 In the event of asymmetric induction, the transfer of chirality to the newly formed Accepted: 11 March 2021 Published: 13 March 2021 stereocenters is typically enabled either by a chiral catalyst/reagent or a chiral substrate itself. The latter case commonly occurs in the multistep synthesis of natural products and Publisher’s Note: MDPI stays neutral could require fine tuning of the reaction parameters to attain a high level of stereocontrol. α β with regard to jurisdictional claims in In that sense, diastereoselective allylation of chiral - and -oxysubstituted aldehydes is published maps and institutional affil- advantageous [4,6–14] since its stereochemical outcome can be usually [15] predicted in the iations. framework of Felkin-Ahn [16–21], Cornforth-Evans [16,17,22–24], or Cram [16,17,25–27] and Reetz chelation [16,17,28–30] models. The Reetz model is valid in the case of stere- oselective addition of allylstannanes to β-oxysubstituted aldehydes, where the high 1,3- anti-selectivity is commonly achieved due to the formation of a chelate complex between a Lewis acid catalyst and the aldehyde substrate [31,32]. On the other hand, the successful Copyright: © 2021 by the authors. β Licensee MDPI, Basel, Switzerland. chelation control takes place only for a limited set of known -hydroxy-protecting groups This article is an open access article and Lewis acids [7–14,31–35]. Moreover, rather ordinary unsubstituted allylic organotin distributed under the terms and reagents are commonly employed in these transformations, with only rare examples of conditions of the Creative Commons β-functionalized analogues [8,14,36–39]. The development of more complex allyl-transfer Attribution (CC BY) license (https:// reagents is appealing in view of their evidently high synthetic value [40–48]. creativecommons.org/licenses/by/ During the implementation of our research programs devoted to the synthesis of natu- 4.0/). ral and bioactive compounds from cyclopropanols [49–52] and cyclopropanol-derived build- Symmetry 2021, 13, 470. https://doi.org/10.3390/sym13030470 https://www.mdpi.com/journal/symmetry Symmetry 2021, 13, x FOR PEER REVIEW 2 of 17 functionalized analogues [8,14,36–39]. The development of more complex allyl-transfer Symmetry 2021, 13, 470 2 of 17 reagents is appealing in view of their evidently high synthetic value [40–48]. During the implementation of our research programs devoted to the synthesis of nat- ural and bioactive compounds from cyclopropanols [49–52] and cyclopropanol-derived building blocksing [5 blocks3–56], [we53– 56expected], we expected to develop to develop a bifu anctional bifunctional allylation allylation reag reagentent A A (Scheme1) (Scheme 1) basedbased on metal on metalationation of easily of easily available available allyl allylbromide bromide 1 [53]1. The[53]. reagent The reagent A can A can act as a act as a syntheticsynthetic equivalent equivalent of a bipolar of a bipolarisopentane isopentane synthon, synthon, as it was as previously it was previously demon- demonstrated strated by the synthesisby the synthesis of retinoid of retinoidcompounds compounds via the Barbier via the-type Barbier-type chemistry chemistry[53,56]. We [ 53,56]. We en- envisioned thatvisioned besides thatthe assembly besides the of assemblypolyene scaffolds, of polyene organometallic scaffolds, organometallic derivatives of derivatives of 1, 1, especially itsespecially organotin itsderivative organotin 2, could derivative also be2, couldsuitable also for be the suitable stereoselective for the stereoselectiveallyla- allyla- tion of carbonyltion compounds of carbonyl and compounds therefore applied and therefore in the asymmetric applied in the synthesis asymmetric of natural synthesis of natural products. Our products.preliminary Our tests preliminary revealed that tests organotin revealed thatcompound organotin 2 [57] compound, along with2 [57 its], along with its carboxymethylcarboxymethyl analogue [54,55 analogue], are suitable [54,55 for], are highly suitable enantioselective for highly enantioselective Keck allylation Kecks. allylations. However, the substrateHowever,-controlled the substrate-controlled stereoselective stereoselectivecoupling of 2 with coupling oxy-functionalized of 2 with oxy-functionalized aldehydes has aldehydesnot been examined. has not been Moreover, examined. we required Moreover, towe develop required an expedient to develop syn- an expedient syn- thetic protocol theticfor the protocol preparation for the of preparation2 in multigram of 2 amount.in multigram As a result amount. of our As endeavors a result of, our endeavors, here we reporthere a convenient we report and a convenient cost-efficient and procedure cost-efficient for multigram procedure preparation for multigram of 2, preparation of and its application2, and in itsthe application Lewis acid- inmediated the Lewis diastereoselective acid-mediated diastereoselective1,3-anti-allylation of 1,3- (Santi)- -allylation of 3-(methoxymethyl)hexanal(S)-3-(methoxymethyl)hexanal 3. The stereochemical3. outcome The stereochemical of the reaction outcome was furthe of ther val- reaction was fur- 7 16 idated by the synthesisther validated of known by theC7-C synthesis16 bulding of block known of (+) C --CNeopeltolidebulding block[55], containing of (+)-Neopeltolide [55], three stereocentcontainingers. three stereocenters. SchemeScheme 1. Preparation 1. Preparation of a of bifunctional a bifunctional allylation allylation reagent reagent A andA and outline outline of the of the current current work work.. 2. Results and 2.Discussion Results and Discussion 2.1. Improved Protocol2.1. Improved for the P Protocolreparation for theof F Preparationunctionalized of ( FunctionalizedAllyl)Tributylstannane (Allyl)Tributylstannane 2 2 Multistep synthesisMultistep commonly synthesis requires commonly substantial requires quantity substantial of starting quantity materials of starting at materials the initial stages.at Therefore, the initial stages.a facile and Therefore, cost-efficient a facile access and cost-efficientto large quantities access of to2 was large of quantities of 2 primary importance.was of Using primary the importance.advantages of Using cyclopropanol the advantages chemistry of cyclopropanol [58,59], allyl bro- chemistry [58,59], mide 1 was readilyallyl prepared bromide in1 was multigram readily amount prepareds and in multigram 94% overall amounts yield from and cheap 94% and overall yield from easily availablecheap ethyl and 3,3- easilydiethoxypropionate available ethyl 3,3-diethoxypropionate(4) via the consequent (Kulinkovich4) via the consequent cyclo- Kulinkovich propanation [60cyclopropanation], mesylation, and [60 MgBr], mesylation,2-mediated and cyclopropyl MgBr2-mediated-allyl rearrangement cyclopropyl-allyl steps rearrangement (Scheme 2) [53,steps61–63 (Scheme]. The reaction2)[ 53,61 sequence–63]. The reactionwas flawlessly sequence performed was flawlessly in a single performed run in a single run starting from 20starting g of ester from 4 (see 20 g the of esterexperimental4 (see the part). experimental No purification part). No was purification required for was required