59th Annual Report on Research 2014

The goal of the proposed research is to develop reagents and catalysts for stereoselective homoallylation and homocrotylation (Scheme 1). In the second year of this grant, we have made progress in 1) asymmetric syn and anti homocrotylation, and 2) homoallylation with additional substitution patterns

Scheme 1

Area 1: Asymmetric syn and anti homocrotylation. Since the last reporting period, there have been several advances in the syn and anti homocrotylation. Although we had already prepared reagents X and X by the routes shown, in the most recent period we have a) developed practical routes for multigram synthesis of these reagents b) expanded their substrate scope and c) applied them to natural product synthesis.

1a) Improved reagent synthesis. Our previous methods for synthesis of 1 and 2 required several unnecessary exchanges of the boronate ligand, as well as chromatography at several steps. Our streamlined, 2^nd-generation synthetic routes (Scheme 2) now provide these reagents in 16-17g batches.Scheme 1. First and second generation routes to X

Scheme 1. First and Second-Generation Routes to 1

Scheme 2. Second-Generation Route to 2

1b) Improved scope. Although we had already known that homocrotylation of aliphatic aldehydes was a clean reaction, initial attempts at homocrotylation of aromatic aldehydes resulted in complex mixtures. More recently, we have found that such reactions can afford moderate to high yields of products if the reactions are quenched very quickly and if the aromatic system is not too electron rich. Scheme 3 shows representative homocrotylation examples with aromatic aldehydes. Note that electron rich- or vinylogous aromatic aldehydes are still a challenge, providing epimers, likely due to ionization of the product C–O bond.

Scheme 3. Homocrotylation of aromatic aldehydes

We have also extensively explored double diastereoselection with these reagents. Selected examples are shown in Scheme 4, in which we manage to obtain all possible stereotriads in adducts to chiral aldehydes, containing either all-carbon stereocenters (11) or oxygenated stereocenters (12).

Scheme 4. Double diastereoselection studies

1c) Natural product synthesis. We are very close to the completion of the natural product (-)-spongidepsin (Scheme 5). Previous syntheses of spongidepsin have been longer than 20 steps; by comparison, assuming that our final reduction and deprotection steps proceed as planned (dotted arrow at end), our synthesis will be 12 steps total, with a longest linear sequence of 9 steps.

Scheme 5. Progress toward the synthesis of (-)-spongidepsin

Area 2: Additional substitution patterns. We have found Varinder Aggarwal’s chiral carbenoid insertion chemistry to be useful for the preparation of cyclopropylcarbinyl boronates with greater substitution than we had previously made (13 and 14). Enantiomeric boronates 8 and ent-8 were prepared as usual. These boronates were then homologated by insertion of chiral lithio species 15. 14 was obtained with high (> 10:1) d.r., whereas diastereomeric 13 was obtained in somewhat lower (~3-4:1) d.r. Both reagents were then employed in additions to aldehydes. Our expectation was that cyclopropane stereochemistry would entirely control the stereochemical outcome of both addition reactions, forcing 14 to yield product 17 with a Z alkene. However, addition reactions with both reagents proceeded to give the same major product, apparently the trans alkene 16. We are still working to confirm the structure of product 16, as well as obtain reagent 13 in high purity, so that these results can be confirmed. However, if our assignments are correct, it seems that a transition state other than a simple chair might be operating in this addition.

Scheme 6. Synthesis and testing of diastereomeric reagents to give E and Z alkene products