γ-Selective Directed Catalytic Asymmetric Hydroboration of 1,1-Disubstituted Alkenes

Abstract

Directed catalytic asymmetric hydroborations of 1,1-disubstituted alkenes afford γ-dioxaborato amides and esters in high enantiomeric purity (90–95% ee).

Chiral organoboronates are useful synthetic intermediates for a growing number of stereospecific transformations.¹ As such, there is renewed interest in enantioselective methods for their preparation.^{2,3,4,5,6,7,8,9} We reported advances in the carbonyl-directed catalytic asymmetric hydroboration (CAHB) of (E)- and (Z)-disubstituted and trisubstituted alkenes contained within a β,γ-unsaturated amide framework.^10,11 Their rhodium-catalysed reactions employ simple chiral monophosphite ligands to produce β-borylated products regio- and enantioselectively. For example, directed-CAHB of 1 by pinacolborane (pinBH) or 4,4,6-trimethyl-1,3,2-dioxaborinane (tmdBH, 5)¹² using Rh(nbd)₂BF₄ in conjunction with TADDOL-derived phosphite (R,R)-6 gives β-dioxaborato amide (S)-2 in high enantiomeric purity (tmdBH: 79% (96% ee); pinBH: 77% (95% ee), Figure 1). Only trace amounts of the regioisomeric γ-substituted product are formed (<3%).

Figure 1.

Regio- and enantioselective carbonyl-directed CAHB of 1,2- and 1,1-disubstituted alkenes (ee determined after oxidation).

As highlighted in several recent reports,¹³ 1,1-disubstituted alkenes (i.e., methylidene substrates) are particularly challenging substrates for asymmetric hydroboration.¹⁴ Directed-CAHB of the methylidene substrate, β,γ-unsaturated amide 3, affords predominantly (R)-4 (tmdBH: 72% (95% ee); pinBH: 68% (60% ee); Figure 1). In contrast to unsaturated amide 1, the isomeric substrate 3 affords the γ-borylated, rather than β-borylated, product predominantly. Equally unexpected, using the same chiral ligand and catalyst, tmdBH adds to opposite faces of the alkene in the isomeric substrates.

The results obtained for a series of methylidene substrates are summarized in Table 1. Amides 7a–e bearing a primary or secondary alkyl substituent and the phenyl-substituted amide 7f each give their respective γ-borylated product predominantly (i.e., 8a–f, 90–94% ee). Our previous reports of carbonyl-directed CAHB used amide directing groups exclusively (i.e., -C(O)N(H)Ph and -C(O)N(Me)OMe). Here, we find the β,γ-unsaturated tert-butyl esters serve equally well; 7g–i afford γ-borylated esters 8g–i (91–94% ee). Competing alkene reduction and formation of the β-borylated regioisomer 9 account for the remainder of products formed; regiocontrol is most problematic for amide substrates bearing relatively small substituents (i.e., 7a-b, R = Me or Et).

Table 1.

Enantioselective CAHB of 1,1-Disubstituted Alkenes 7a–7i.^a

7	X	R	γ-isomer	% yld (% ee)a	% yld 9b
a	NHPh	Me	(S)-8a	53 (94)	11
b	NHPh	Et	(R)-8b	60 (92)	10
cc	NHPh	(CH2)2Ph	(R)-8c	73 (94)	3
dc	NHPh	(CH2)3Ph	(R)-8d	70 (92)	3
ec	NHPh	c-C6H11	(S)-8e	72 (90)	2
fc	NHPh	C6H5	(S)-8f	71 (93)	4
g	O-tBu	Me	(S)-8g	62 (94)	6
h	O-tBu	Et	(R)-8h	65 (91)	5
i	O-tBu	i-Bu	(R)-8i	78 (91)	4

^aIsolated yield and (% ee) of 8; enantiomeric purity determined by chiral HPLC analysis after oxidation and for 7g–i subsequent amidation.

^bIsolated yield of β-isomer 9.

^cReaction run at 40 °C.

Trifluoroborate salts are excellent reagents for Suzuki-Miyaura cross-coupling reactions.¹⁵ Using Molander’s conditions,⁸ the γ-borylated amide (S)-8a is cleanly converted to γ-trifluoroborato amide (S)-10a (65%). The latter readily undergoes palladium-catalyzed cross-coupling with several representative aryl halides (70–81%, Table 2 entries 1–3) complementing the cross-couplings of β-borylated carbonyl derivatives.¹⁶ The tert-butyl ester derivatives (S)-10g and (R)-10i react similarly (80–94%, entries 4–9). Heteroaromatic cross-couplings are also promising (entries 10–12). For example, trifluoroborate (R)-10h couples to 3-chlorothiophene (80%, entry 13) giving the precursor to a chiral antispasmodic compound previously reported only as the racemate.¹⁷

Table 2.

Efficient Cross-Coupling of γ-Borylated Esters and Amides.

Entry	Trifluoroboratea	Aryl halide	% Yield
1	(S)-10a	chlorobenzene	81
2b	(S)-10a	3-bromoanisole	71
3	(S)-10a	methyl-4-bromobenzoate	70
4	(S)-10g	chlorobenzene	82
5	(S)-10g	3-bromoanisole	82
6	(S)-10g	methyl-4-bromobenzoate	88
7	(R)-10i	chlorobenzene	80
8	(R)-10i	3-bromoanisole	92
9	(R)-10i	methyl-4-bromobenzoate	94
10	(R)-10i	3-chlorothiophene	98
11	(R)-10i	5-chloro-2-furaldehyde	84
12	(R)-10i	5-chloro-2-fluoropyridine	51
13	(R)-10h	3-chlorothiophene	80

^aEnantiomeric purity of 8 is given in Table 1.

^bReaction was run with SPhos in place of RuPhos.

Directed CAHB can also be used to set the stage for intramolecular cross-couplings. CAHB of tert-butyl ester 12 produces (R)-13 (74%, 90% ee, Scheme 1). Subsequent conversion to the corresponding trifluoroborate (76%) followed by palladium-catalyzed intramolecular cross-coupling affords (S)-14 in excellent yield (91%). Alternatively, hydroboration followed by mild oxidation with NaBO₃ produces γ-hydroxyester (R)-15 (73%, 90% ee). The latter undergoes palladium-catalyzed C-O cross-coupling¹⁸ to afford the novel seven-membered ring ether (R)-16 (75%).

Scheme 1.

(a) 2% Rh(nbd)₂BF₄, 4.1% (R,R)-6, 2 equiv tmdBH, THF, 40 °C (74%, 90% ee). (b) KHF₂, MeCN/H₂O (76%). (c) 5% Pd(OAc)₂, 10% RuPhos, K₂CO₃, PhMe/H₂O, 85 °C, 24 h (91%). (d) NaBO₃, THF/H₂O (98%). (e) 5% Pd(OAc)₂, 10% RuPhos, K₃PO₄, PhMe, 85 °C, 24 h (75%).

Directed CAHB of amides 3 and 7c using (R,R)-6 followed by oxidative work-up with basic H₂O₂ gives the respective γ-hydroxyamides (R)-17 and (R)-18 (71% yield for each, 95 and 94% ee, respectively) (Figure 2). Similarly, CAHB of tert-butyl ester 7i followed by mild oxidation with NaBO₃ affords the labile γ-hydroxyester (R)-19 (77%, 91% ee). However, under basic H₂O₂ work-up conditions, the intermediate γ-hydroxyester spontaneously lactonizes to afford a chiral β-substituted γ-lactone. For example, CAHB of tert-butyl ester 7i using ligand (S,S)-6 affords lactone (S)-20 (78%, 91% ee); the latter has been used as a precursor to the anticonvulsant drug pregabalin.¹⁹ Similarly, tert-butyl ester 21a gives (R)-22a (80%, 95% ee) and 21b gives (R)-22b (79%, 95% ee) using the catalyst with (R,R)-6. With the enantiomeric ligand (i.e., (S,S)-6),CAHB-oxidation of 21c affords (S)-22c (75%, 92% ee). β-Substituted butyrolactones undergo diastereoselective alkylation and have been used in syntheses of the lignan natural products (-)-enterolactone and (+)-arctigenin.²⁰

Figure 2.

Preparation of chiral γ-hydroxy amides and esters and β-substituted γ-lactones via CAHB-oxidation.

The relative energies of a series of octahedral intermediates formed upon two-point binding of amide substrates followed by oxidative addition of borane were evaluated by DFT (Figure 3, 23A/C and 24B/D).²¹ The modelled structures employ the symmetric borane pinBH and the caged phosphite P(OCH₂)₃CH to simplify the calculations. In line with experiment, the overall lowest energy structure for the model methylidene substrate is consistent with favored formation of the γ-borylated product upon alkene insertion into the Rh-H bond (i.e., A); the lowest energy structure leading to β-borylation (i.e., B) is calculated to be about 1.9 kcal higher in energy and arises from complexation to the opposite face of the π-system. Structures C and D model a simple 1,2-disubstituted alkene with with the (E)-geometry (i.e., a model for amide 1). Consistent with the experimental observations, the β-leading isomer D is favored for this substitution pattern.

Figure 3.

Relative energies of model octahedral intermediates leading to γ- and β-borylation for 1,1- and (E) 1,2-disubstituted substrates (A/B and C/D, respectively; only the vinyl C-H and Rh-H included for clarity.

In contrast to tri- and other disubstitution patterns, CAHBs of β,γ-unsaturated methylidene amides and esters afford the γ-borylated product and proceed with the opposite sense of asymmetric induction. Chiral γ-borylated derivatives are intermediates for inter- and intramolecular cross-couplings, the formation of chiral γ-hydroxy carbonyl derivatives, and β-substituted-γ-lactones. Preliminary computational studies suggest that the preferred conformation of the chelated substrate relative to the Rh-H bond may explain the observed regio- and π-facial selectivity. Further studies are in progress.