Synthesis of Enantioenriched α‐(Hydroxyalkyl)‐tri‐n‐butylstannanes

Abstract

A catalytically asymmetric synthesis of α-(hydroxyalkyl)-tri-n-butylstannanes 1 in good-excellent yields and enantioselectivities (up to 98% e.e.) via addition of ethyl(tri-n-butylstannyl)zinc to aldehydes was achieved. In practice, 1 was isolated after protection as its more stable ester or thiocarbamate (PG). The reagent was prepared from equimolar amounts of tri-n-butylstannyl hydride and Et 2 Zn in DME so as to avoid contamination by lithium and magnesium ions which suppress enantioselectivity. Keywordsaldehydes; asymmetric synthesis; organometallic compounds; tin; zinc α-(Hydroxyalkyl)triorganostannanes are versatile synthetic intermediates that have found wide applicability in natural products total synthesis. [1] Most notably, they offer a higher level of structural and stereochemical complexity compared with their tetraorganotin congeners, yet still participate in a variety of stereospecific transformations including transition metal catalyzed cross-couplings, [2] generation of configurationally stable anions, [3] Wittig rearrangements, [4] S E '-additions to carbonyls, [5] nucleophilic displacements, [6] and other reactions. [7] Numerous synthetic strategies to enantioenriched α-(hydroxyalkyl)triorganostannanes have been devised, inter alia, (i) asymmetric reduction of acyl stannanes, [8] (ii) classical resolution, [9] (iii) enzymatic resolution, [10] (iv) cleavage of C 2 -symmetric stannyl acetals, [11] (v) electrophilic stannylation, [12] and (vi) nucleophilic stannylation, [13] however, the goal of a widely applicable, economic and operationally simple synthesis from readily available starting materials remains elusive. Herein, we report the catalytically asymmetric synthesis of α-(hydroxyalkyl)-tri-n-butylstannanes 1 i n g o o d-excellent yields and enantioselectivities via addition of ethyl(tri-n-butylstannyl)zinc to aldehydes (eq 1). In practice, 1 was isolated after protection as its more stable ester or thiocarbamate (PG).[**] We thank the NIH (GM31278, DK38226) and the Robert A. Welch Foundation for financial support. Bolstered by the precedent of catalytic, asymmetric organozinc additions to carbonyls [14] and the equally well documented preparation of racemic α-(hydroxyalkyl)triorganostannanes from aldehydes and ketones using triorganostannyl nucleophiles, [15] we were attracted to the possibility of comparable asymmetric additions of tri-n-butylstannylzinc reagents to aldehydes. Yet, this proved not to be straightforward. Despite extensive attempts using tri-n-butylstannyllithium or Grignard [16] in combination with various ratios with zinc halides and chiral ligands, 1 (PG = Ac) was generated with little, if any, useful enantioselectivity, albeit in good yield. Reasoning the Li or Mg-ions might have detrimental effects, alternative approaches to stannylzinc generation were systematically investigated. Finally, we were gratified to discover that addition of ethyl(trin-butylstannyl)zinc, [17] generated in situ via transmetalation of tri-n-butyltin hydride with diethylzinc, [...

Enantioselective methodologies using N-carbamoyl-imines

“…39 The same year, an interesting reaction was reported by Falck regarding the stannation of N-Boc imines using ethyl(tri-nbutylstannyl)zinc (41) and an aminoalcohol XIX as catalysts. 40 Despite only one single example being shown (with moderate ee), this reaction opened a new window for the synthesis of chiral a-aminoalkylstannanes (Scheme 21).…”

Studies towards asymmetric synthesis of 4(S)-11-dihydroxydocosahexaenoic acid (diHDHA) featuring cross-coupling of chiral stannane under mild conditions

“…Notably, our group has recently established a powerful protocol. 6 In this process, copper thiophene carbonate mediated and palladium catalyzed cross-coupling between chiral stannanes with different coupling partners was developed. Herein, we disclose an efficient route to construct the core segment of 4(S)-11-diHDHA and trials towards this novel compound.…”

“…Chiral stannane (3), the most challenging segment with a continuous allylic motif and one chiral α-hydroxy α-stannane group, can be achieved using the ligand-controlled asymmetric synthesis of aldehyde 4, which was previously developed by our group. 6 The aldehyde 4 was synthesized through multistep linear synthesis from commercially available eicosapentaenoic acid (EPA). Conjugated bromide (5), a continuous triple-double-triple unit, was prepared through multistep synthesis, which mainly relied on the renowned palladium catalyzed Sonogashira cross-coupling 7 under optimized reaction conditions.…”

Enantiospecific Synthesis and Allylation of All‐Carbon‐Substituted α‐Chiral Allylic Stannanes

“…[6] Herein, we report an exceptionally facile synthesis of a-chiral allylic stannanes through both enantiospecific and regioselective allylic substitution [7] with an undervalued tin-based zinc compound. [8,9] We also showcase the value of these new allyl-transfer reagents in enantiospecific and diastereoselective thermal [1,4] and Lewis acid promoted [1,10] carbonyl allylation.…”