Thiopyran Route to Polypropionates:  Exploiting and Overcoming Double Stereodifferentiation and Mutual Kinetic Enantioselection in Aldol Couplings of Chiral Fragments

Abstract

The aldol reaction of tetrahydro-4H-thiopyranone with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (I) gives four possible diastereomeric adducts (II). Aldol reactions of I with each of the diastereomers of II and their corresponding methoxymethyl ethers III via the Ti enolates were investigated. Using racemic reactants, reactions with II proceeded with high levels of mutual kinetic enantioselection (MKE) and double stereodifferentiation (DS) to give one of the eight possible bisaldol adducts. Similar reactions of III proceeded with low levels of MKE and DS and gave two bisaldol adducts, one from each of the possible combinations of enantiomeric reactants. By extension, 11 of the 20 possible diastereomers of the bisaldol adduct could be obtained selectively. These adducts are useful for polypropionate synthesis.

Total Synthesis of Muamvatin

“…During the last decade, the essential elements of this strategy were explored extensively in the Ward group (Scheme 1.1). Different approaches such as the iterative aldol reaction of tetrahydro-4H-thiopyran-4-one 7 with carboxaldehyde 6 4,5 or a simultaneous aldol reaction of dialdehyde 8 with tetrahydro-4H-thiopyran-4-one 7 were developed. 6 All these efforts provided rapid access to tetra and hexapropionate synthons.…”

“…Previous results demonstrated that all 20 possible diastereomers could be obtained through iterative two-directional aldol reactions or simultaneous aldol reaction of tetrahydro-4H-thiopyran-4-one 7 and dialdehyde 8 (Scheme 1.1). 4,6,7 Controlling the stereoselectivity of these aldol couplings is an ongoing objective in the Ward group. To date, the thiopyran route has been used successfully in total syntheses of several polypropionate natural products such as serricornin, …”

“…As mentioned previously, all twenty possible diastereomeric forms of hexapropionates 10 are known and methodology studies established access to all possible diastereomers. 4,5,7,13,17 In order to understand the diastereoselectivity in the aldol reaction of ketones 9a-d and aldehyde 6, some terms should be identified. Seebach and Prelog proposed the terms like and unlike to differentiate the reactions of two chiral reactants, 18 in this case ketones 9a-d and aldehyde 6.…”

“…Previous results of aldol reactions between ketone 9a-d and aldehyde 6 were based on Ti(IV) enolates formed by reaction of the ketones with TiCl 4 or Ti(O i Pr)Cl 3 and an amine base (Figure 1.1). 4 Analysis of the product distributions of these reactions illustrates both the diastereoselectivities and the relative rates of the like and unlike reactions.…”

On the Origin of Siphonariid Polypropionates: Total Synthesis of Caloundrin B and Its Isomerization to Siphonarin B

“…3,5-trans selectivity) of a protecting group on the C-1' OH group. 45 In addition, the diastereoface selectivity of the aldehyde 173 was shown to be highly Felkin selective; i.e., leading to products with a 1",6"-syn relative configuration. 45 In this research, the development of conditions to switch the relative topicity (5,1"-anti or 5,1"-syn)…”