Enantioselective γ-borylation of unsaturated amides and stereoretentive Suzuki–Miyaura cross-coupling

Amide-directed CAHB provides a direct route to chiral acyclic secondary γ-borylated carbonyl compounds which undergo a variety of stereospecific transformations including stereoretentive palladium-catalyzed Suzuki–Miyaura cross-coupling.

In contrast to amides 5a-d, the analogous ester 8 is largely recovered unchanged upon attempted CAHB; only trace amounts of borylated products are identied along with some evidence for alkene isomerization. d,3-Unsaturated amide 9, a one-carbon homologue of benzyl amide (E)-5d, is found to be considerably less reactive and less selective. Complete consumption of starting material requires 2% catalyst loading to afford 56% yield of a mixture of borylated products. 25 Benzyl amides 5e-g containing heteroaromatic ring systems are nonetheless good substrates under the standard CAHB/ oxidation conditions yielding 7e-g, respectively. Certain branched alkyl substituents (i.e., 5h-j) are also well tolerated. In particular, the chiral substrate (E)-5j demonstrates that (i) the proximal disubstituted alkene with respect to the amide directing group undergoes CAHB while the more distal trisubstituted alkene is untouched and (ii) the stereochemical course of g-borylation is efficiently catalyst controlled. CAHB/oxidation with (R)-L2 affords (4S,7S)-7j; (S)-L2 affords (4R,7S)-7j. The silyl ether moiety in 5k is tolerated and affords 7k (78%, 97 : 3 er). Chiral acetal 5l again undergoes catalyst controlled g-borylation with high diastereoselectivity; (R)-L1 affords (S,S)-7l (72%, 95 : 5 dr); (S)-L1 affords (R,S)-7l in the same yield and diastereomer ratio. However, substrate 5m, in which the chiral acetal moiety is in closer proximity to the site of hydroboration, shows a strong matched/mismatched effect. While (R)-L1 affords (R,S)-7m (70%, 92 : 8 dr), the catalyst employing (S)-L1 gives rise to a complex mixture of regioisomers 10. Substrate 5n (R 1 ¼ Me) also exhibits only modest regioselectivity (3 : 1), perhaps due to pinBH, THF, 40 C (12 h) followed by oxidation using H 2 O 2 /aq. NaOH. Unless otherwise noted, the isolated yield is that of the major regioisomer and reflects the average of three experiments generally exhibiting a spread of AE2%; regioselectivity is determined from the crude 1 H NMR of 7. Enantiomer ratios (er) are determined by chiral HPLC analysis; diastereomer ratios (dr) are determined for the purified mixture of diastereomers by integrating major and minor 13  the size of the vinyl substituent compared to other derivatives described above; however, CAHB proceeds in good yield and high enantioselectivity (61%, 95 : 5 er).
Having developed an efficient method for the g-borylation of g,d-unsaturated amides, Suzuki-Miyaura cross-coupling of 11 was examined (Fig. 3). Stereochemical aspects of the palladiumcatalyzed cross-coupling of chiral secondary organoboron derivatives have recently attracted a great deal attention. Molander, 26 Suginome, 27 and Hall 28 reported that b-borylated carbonyl derivatives 12-14, whether as the boronic ester or the triuoroborate salt, undergo cross-coupling with stereoinversion. The stereochemical course is rationalized by intramolecular coordination between the carbonyl oxygen and the boron atom of the boronic ester or the partially hydrolyzed tri-uoroborate. The intramolecular coordination promotes invertive transmetallation resulting in overall stereoinversion for cross-coupling. Biscoe 19a,29 also found stereoinversion for simple substrates lacking functionality needed for coordination to boron during the course of transmetallation (e.g., 15). On the other hand, Suginome 30 reported that boracyclic intermediate 16 undergoes cross-coupling with stereoretention. Similarly, Morken 31 reported that 17 undergoes hydroxyl-directed, innersphere, retentive transmetallation and overall cross-coupling with stereoretention. However, when the hydroxyl is onecarbon further removed, 18 fails to undergo cross-coupling under the otherwise same conditions. We have previously shown that 19 undergoes cross-coupling with overall stereoretention. 22 Chiral boronic ester 6c (i.e., the morpholine amide) was converted to its corresponding triuoroborate salt 11c 32 and subjected to palladium-catalyzed cross-coupling using the Buchwald cataCXium® A Pd G3 (20) precatalyst. 22,33 Crosscoupling with chlorobenzene yields amide (S)-21c (63%); 4chloroanisole yields (S)-22c (52%). The products are obtained with essentially complete overall stereoretention. 34 We nd that the nature of the amide is important to the success of the crosscoupling. In contrast to the tertiary morpholine amide, the analogous secondary amide 11d does not undergo crosscoupling under the conditions employed for 11c. Hall et al. 28a reported that b-boronic esters of secondary amides failed to cross-couple in cases where the corresponding tertiary amide coupled smoothly. Chiral organoboronates are useful for a variety of other stereospecic transformations. Fig. 4 illustrates several examples starting from chiral boronic esters 6b-d; the latter are isolated in 69-82% yield from the corresponding alkenes. Treating 6b with H 2 O 2 /aq. NaOH affords the known chiral 5substituted-g-lactone 23 (95%). 35 As an alternative to palladiumcatalyzed cross-coupling, the morpholine amide derivative 6c undergoes stereoretentive cross-coupling with 2-lithiothiofuran under the conditions developed by Aggarwal 2e to give 24c (84%). Compound 6c also undergoes BCl 3 -assisted amination with benzyl azide under the conditions reported by Knochel 36 to form the g-amino acid derivative 25c (65%). Phenyl azide also serves as a good nucleophile in such amination reactions, and 6c is converted to the corresponding N-phenyl g-amino acid en route to the 5-substituted-g-lactam 26 (68%) by acid catalyzed cyclization. Benzyl amide derivative 6d is efficiently converted to 1,4aminoalcohol 27d aer oxidation of the C-B bond followed by amide reduction with LAH (94%). While the secondary N-benzyl amide 11d failed in the attempted palladium-catalyzed crosscoupling described above, 6d undergoes efficient vinylation in a sequence initiated the by treatment with excess vinyl Grignard; 2h amide 28d is formed in high yield (93%).
Conclusions g,d-Unsaturated secondary (i.e., N-phenyl and N-benzyl) and tertiary (i.e., Weinreb and morpholine) amides undergo efficient rhodium-catalyzed CAHB to afford g-borylated derivatives in good yield and with high levels of asymmetric induction; enantioselectivity as high as 97 : 3 er is observed. While two  good alternative methods are available to prepare chiral secondary b-borylated carbonyl compounds, the present method of directed-CAHB provides to our knowledge the rst direct route to chiral acyclic secondary g-borylated carbonyl compounds with high regio-and enantioselectivity.
A previous study found band g-borylation of related substrates differ in the sense of stereoinduction, i.e., p-facial discrimination. 20a However, it is not the case in the present study; b-borylation of b,g-unsaturated amide 1 and g-borylation of the one-carbon homologue g,d-unsaturated amide 5 add to the same face of the alkene. In the present study, CAHB of a substrate bearing both di-and trisubstituted alkene moieties (i.e., 5j) occurs only on the disubstituted double bond proximal to the carbonyl group. Chiral substrates 5j and 5l undergo highly diastereoselective CAHB with catalyst control; however, substrate 5m, in which the resident oxygen-bearing stereocenter resides adjacent to the alkene, exhibits a strong matched and mismatched effect with enantiomeric catalysts.
The g-borylated products are found to undergo stereoretentive palladium-catalyzed Suzuki-Miyaura cross-coupling, presumably via amide-directed inner-sphere stereoretentive transmetallation, as well as stereoretentive C-B to C-C transformations using main group organometallic reagents (e.g., lithium and magnesium). In addition, a variety of other stereospecic transformations are highlighted by the conversions of chiral, secondary g-boronic esters 6b-d to 1,4-amino alcohols, g-amino acid derivatives, and 5-substituted-g-lactone and g-lactam ring systems. Further studies are in progress.