Figure 3.12 summarizes the effects of variations in several structural features of trisubstituted styrenyl substrates similar to (E)-41a on the overall outcome of CAHB: (1) the effect of ring size (5 vs. 6 membered ring) of the arene appended at the β-position, (2) the stereochemistry of the alkene (E vs. Z substrates), and (3) the presence of aryl substituents on both the carbon atoms of the alkene undergoing reaction. Substrate 41b bears a 5-membered thiophene ring at the β-position and an alkyl chain bearing a chiral dioxolane at the γ-position. Catalyst controlled diastereoselective CAHB of both (E)- and (Z)-41b occurs with similar efficiency: β-boration leads to the formation of chiral tertiary benzylic boronic ester 42b in excellent yield and high levels of stereoinduction. Use of (R,R)-T2 results in (2S,5S)-42b (structure shown in Figure 3.10) and use of (S,S)-T2 leads to the diastereomeric boronic ester (2R,5S)-42b from either diastereomer of 41b. Thus, depending on the choice of the ligand used, either diastereomer of the boronic ester 42b can be accessed with ease and the alkene stereochemistry does not impact overall yield or product diastereoselectivity. The chiral dioxolane unit appended at the γ-position is not a requirement for the reaction, however, its presence allows for the ease of diastereomer differentiation via 31P NMR analysis of the crude CAHB mixture.
Substrates similar to 41b, but bearing a 6-membered phenyl ring at the β-position (e.g. 41c) in place of the five membered thiophene ring, exhibit more pronounced differences in CAHB results when diastereomeric (E)- and (Z)- stereoisomers were used.
The trans-isomer (E)-41c undergoes CAHB with (R,R)-T1 forming the tertiary benzylic boronic ester (2R,5S)-42c (80%, 91:9 dr) in excellent yield but in moderate levels of
diastereoselectivity as compared to the cis-isomer (Z)-41b. CAHB of (E)-41c with (S,S)-T1 leads to formation of (2S,5S)-42c (78%, 85:15 dr) in high yields but with reduced levels of diastereoselectivity. However, the corresponding cis isomer (Z)-41c undergoes CAHB with much higher efficiency in terms of yield and diastereoinduction. CAHB using (R,R)-T1 results in the formation of (2R,5S)-42c (83%, 96:4 dr) in excellent yield and stereochemistry in case of substrate 41b, the alkene stereochemistry in case of 41c plays a crucial role in CAHB: the (Z)-substrate has superior performance as compared to the (E)-isomer.
In contrast to 41c, substrate 41d bears phenyl groups in both the β- and γ-positions, presenting a potential competition for regiocontrol. CAHB of β-aryl methylidene substrate 5a results in preferential β-boration leading to chiral tertiary boronic esters such as 6a, and CAHB of γ-aryl 1,2-disubstituted substrate 18a results in preferential γ-boration leading to chiral secondary benzylic boronic esters such as 19a (Chapter 2). The case of 41d naturally raises the question as to which one of the two phenyl groups will determine the regiochemistry? In the event of CAHB with (R,R)-T2, (E)-41d yields the β-borated product (R)-42d (60%, 3:1 β:γ, 97:3 er) in moderate yield and regioselectivity yet in high levels of enantiocontrol. However, unlike the improved enantioselectivity seen for the (Z)- isomer
of 41c, CAHB of diastereomeric (Z)-41d affords (R)-42d (71%, ~4:1 β:γ, 70:30 er) with a slightly improved yield but in much lower degree of enantioinduction. The presence of γ-phenyl group in (Z)-41d exerts a deleterious steric effect resulting in much lower levels of enantioinduction.
Figure 3.12. Phosphonate-directed CAHB of styrenyl trisubstituted alkenes: effect of ring size, alkene stereochemistry and the presence of aryl substituents in both carbon atoms of the alkene. (Adapted with permission from Ref. 9. Copyright 2018 American Chemical Society)
Substrates bearing a 2-thienyl moiety in the β-position as in 41b, but with a simple alkyl substituent in the γ-position (e.g. 41e), also undergo β-boration, yielding the corresponding tertiary benzylic boronic ester product (S)-42e (85%, 93:7 er) (Figure 3.13).
The chiral substrate derived from citronellal (i.e., 41f) bears a pendant alkene as well a
remote stereocenter. It undergoes catalyst-controlled diastereo- and site-selective β-boration, leaving the distal alkene intact. CAHB of 41f with (R,R)-T2 affords (2S,5S)-42f (55%, 92:8 dr), and (S,S)-T2 affords (2R,5S)-42f (58%, 92:8 dr). For substrate 41f, a higher catalyst loading (2 mole percent) is used. However, even using the higher catalyst loading, the reaction of this substrate did not proceed to completion, perhaps due to the presence of multiple chelating sites in the substrate leading to catalyst deactivation. It is worth noting that while 41f undergoes site selective CAHB of the proximal trisubstituted vinyl arene leaving the distal trialkyl substituted alkene untouched under the reaction conditions, the corresponding substrate bearing a methyl group at the β-position (compound 37r shown in Figure 3.8) did not undergo selective CAHB. In case of 37r, the distal alkene was also found to undergo competitive reaction, albeit not cleanly to a single product, even when using a limiting amount of pinBH. We speculate that the reactivity of the trisubstituted vinyl arene in case of 41f is significantly higher and the directed CAHB leads to site-selective CAHB. However, in case of 37r, while there is activation for the proximal alkene from that of the directing group, the distal alkene also underwent partial consumption because of the similar substitution pattern.
While substrates bearing a simple thiophene ring (e.g. 41b) undergoes β-selective CAHB affording tertiary benzylic boronic esters in high yields and high levels of diastereoinduction, the corresponding substrates bearing extended ring aromatics such as the benzothiophene derivative (41g) undergoe CAHB with lesser efficiency.
Diastereoselective CAHB of 41g with (R,R)-T2 leads to the formation of (2S,5S)-42g (68%, 92:8 dr), and CAHB with (S,S)-T2 leads to the formation of (2R,5S)-42g (69%, 92:8 dr). The corresponding benzofuran derivative 41h gives comparable results using
(R,R)-T2, affording (2R,5S)-42h (76%, 93:7 dr), but exhibits an unusual mismatched effect with (S,S)-T2 to give (2S,5S)-42h (72%, 80:20 dr) with a much reduced level of diastereoselectivity.
Figure 3.13. Substrate scope of phosphonate-directed CAHB of styrenyl trisubstituted alkenes. Note: Trans substrates were used. The E/Z descriptor of the substrate and the R/S descriptor of the chiral products is dependent on the nature of the β-substituent. Results highlighted in yellow are obtained using (R,R)-T2; nonhighlighted data are from reactions carried out using (S,S)-T2. (Adapted with permission from Ref. 9. Copyright 2018 American Chemical Society)
Finally, we find that allylic phosphonates bearing β-phenyl substituents, for example, (E)-41i-k, tend to undergo highly regioselective β-boration albeit with somewhat
lower diastereoselectivity. A significant electronic effect is also observed in this class of substituents. The 4-methoxyphenyl substrate 41i behaves like the phenyl substituted substrate (E)-41c; either diastereomer of 42i is formed with catalyst control in 75% yield but with modest diastereoselectivity (90:10 dr). However, presence of an electron-withdrawing substituent lowers the yield and diastereoselectivity. For example, substrates 41j (4-chlorophenyl derivative) and 41k (4-trifluoromethyl derivative) afford much lower yields (56-63%) of the corresponding chiral tertiary benzylic boronic esters 42j (83:17 dr) and 42k (ca. 85:15 dr), respectively.