Ate Complexes of Secondary Boronic Esters as Chiral Organometallic-Type Nucleophiles for Asymmetric Synthesis

Abstract

The addition of an aryllithium reagent to a secondary boronic ester leads to an intermediate boron-ate complex that behaves as a chiral nucleophile, reacting with a broad range of electrophiles with inversion of stereochemistry. Depending on the electrophile, the C-B bond can be converted into C-I, C-Br, C-Cl, C-N, C-O, and C-C, all with very high levels of stereocontrol. This discovery now adds a new, readily available, configurationally stable, chiral organometallic-type reagent to the arsenal of methods for use in asymmetric organic synthesis.

Enantiospecific sp2–sp3 coupling of secondary and tertiary boronic esters

“…They needed to be sufficiently electron rich (phenyllithium and 3-methylphenyllithium were unsuccessful) and have a donor substituent meta to the boronate complex (2-or 4-methoxyphenyllithium were not effective whereas 3-methoxyphenyllithium was [9a]) otherwise competing electrophilic attack at the sp 3 carbon centre occurred. 38 In the case of the least electron rich aromatic, 3-methylphenyllithium, a 28:72 mixture of products comprising of the desired coupled product and 2-bromo-4-phenylbutane 12 were obtained showing the lower limit of the aromatic group that can be employed. This aspect is discussed in the mechanism.…”

“…Figure 3, Path B). 38,48 In order to promote nucleophilic reaction of the boronate complex at the aromatic ring rather than the sp 3 centre (as required for an arylation process) we reasoned that more electron rich aromatics were required and initially selected furan. These boronate complexes reacted with NBS at the aromatic ring and, following 1,2 migration and elimination, gave the furyl-coupled product stereospecifically as illustrated in Figure 1.…”

“…Presumably, the combined difficulties associated with handling air sensitive boranes, creating stereodefined boranes and in particular, issues of which group would migrate in non-symmetrical boranes, thwarted its development. The intermediate boronate complex I could also react with electrophiles at the sp 3 carbon [35][36][37][38] (Path B) and so conditions/reagents would need to be carefully tuned in order to promote the desired reaction (Path A). In this paper we describe our success in promoting this pathway and thus achieving a practical, stereospecific coupling of secondary and tertiary boronic esters with electron rich aromatics.…”

Mild and Phosphine-Free Iron-Catalyzed Cross-Coupling of Nonactivated Secondary Alkyl Halides with Alkynyl Grignard Reagents

“…The following known starting materials (alkyl halides and terminal alkynes) were prepared according to the literature procedures: [2][3][4][5][6][7][8][9][10][11][12][13] …”

“…Yields reported in the publication are of isolated materials. All 3-iodononane [2] 5-iodononane [2] I 2-iodo-2,3-dihydro-1H-indene [3] I iodocycloheptane [4] I 6-iodo-2-methylhept-2-ene [5] I 6-iodo-2-methylhept-2-ene [5] I (3-iodobutyl)benzene [5,6] I (2-iodobutyl)benzene [2] O I 4-iodotetrahydro-2H-pyran [7] BocN I…”