Highly Stereoselective Synthesis of syn‐1,3‐Diols through a Sequential Titanium‐Mediated Aldol Reaction and LiBH₄ Reduction

Abstract

A sequential transformation based on a titanium-mediated aldol reaction from chiral α-tert-butyldimethylsilyloxy ketones followed by reduction of the resultant aldolates with LiBH 4 provides a straightforward access to syn-1,3-diols. These diols, containing up to three new stereocentres, can

Highly stereoselective titanium-mediated aldol reactions from chiral α-silyloxy ketones. A reliable tool for the synthesis of natural products

“…This approach was right and provided straightforward access to the desired syn-diols 34 in a one-pot transformation. 15 In view of this successful transformation, we studied a similar procedure from allyl ketone 5 that would supply highly functionalized syn-diols 38. The results are summarized in Table 6.…”

“…7,15 Taking advantage of these results, the stereochemistry of aldol adducts 9, 10, 12 and 15 from lactate-derived ketones 2e5 was initially assigned as 2,4-syn-4,5-syn and was later confirmed during the application to the synthesis of natural products. In turn, the absolute configuration of aldol adducts from ketones containing bulky R 2 groups, 19ae20a, or different silicon protecting groups, 24ae26a, was confirmed by chemical correlation.…”

Synthesis and Biological Evaluation of 1‐Deoxy‐5‐hydroxysphingosine Derivatives

“…Importantly, both steps could be integrated into a single transformation, because the putative titanium aldolate could be cleanly reduced by the simple addition of 2 equiv. of LiBH 4 to the reaction mixture 15. This sequential transformation increased the efficiency of the synthesis and afforded syn ‐1,3‐diol 5 as a single diastereomer in 60 % yield on the 1–2.5 mmol scale.…”

“…This sequential transformation increased the efficiency of the synthesis and afforded syn ‐1,3‐diol 5 as a single diastereomer in 60 % yield on the 1–2.5 mmol scale. The all‐ syn configuration of this diol was initially determined on the basis of previous studies on the stereochemical outcome of the titanium‐mediated aldol reaction of bromo ketone 3 12,15. Its relative stereochemistry was eventually secured through spectroscopic analysis of acetonide 6 ,16,17 which was subsequently debrominated under tin‐free radical conditions in excellent yield 18.…”

Total synthesis of the actinoallolides and a designed photoaffinity probe for target identification

“…Romea and Urpí have reported the use of titanium Lewis acids for the highly selective aldol reactions of protected β-hydroxy ketones 29 and α-hydroxy ketones with an in situ reduction to afford the syn-1,3-diol. 30 It was reasoned that combining these two processes would afford the desired 'all-syn' stereotetrad in diol 12. In the event, application of this in situ reduction with LiBH 4 to the aldol addition of ketone 13 and methacrolein provided diol 12 in 90% yield as a single diastereomer (Scheme 2).…”