Highly Diastereo- and Enantioselective Aldol Reactions of Stereochemically Defined Tetrasubstituted Enolborinates Generated By 1,4-Hydroboration of α,β-Unsaturated Morpholine Carboxamides with (Diisopinocampheyl)borane

The enantioselective synthesis of acyclic all-carbon quaternary centers remains a significant challenge in organic synthesis.^[1] In view of the tremendous utility of enantioselective aldol reactions in organic synthesis, extension of this reaction to the enantioselective synthesis of all-carbon quaternary centers from stereochemically defined tetrasubstituted enolates would be highly valuable.^[2,3] However, attempts to generate such enolates or enolate equivalents by deprotonation of acyclic carbonyl compounds in most cases lead to geometric mixtures, which translates to poor diastereoselectivity in the subsequent aldol reaction.^[3.4] Thus, alternative methods for generation of acyclic tetrasubstituted enolates or their synthetic equivalents have been developed.^[5–8] Noteworthy among these, a highly stereoselective carbocupration of chiral ynamides followed by oxidation of the resultant vinylcuprate has been developed by Marek and co-workers..^[8] Nevertheless, the development of a simple, highly stereocontrolled method for synthesis of stereochemically defined tetrasubstituted enolates from readily available achiral starting materials remains an important objective. Toward this end, we report herein a simple procedure by which stereodefined tetrasubstituted enolborinates are generated with exceptional stereoselectivity via 1,4-hydroboration reactions^[9,10] of unsaturated morpholine carboxamides with (diisopinocampheyl)borane ((Ipc)₂BH), and demonstrate that the tetrasubstituted enolborinates undergo highly enantio- and diastereoselective aldol reactions with representative achiral aldehydes.

We recently reported that the 1,4-hydroboration of morpholine acrylamide 1 with (^lIpc)₂BH provides enolborinate Z(O)-2 via TS-I (Scheme 1, where R² = R³ = H).^[11a] Treatment of Z(O)-2 with aldehydes provided syn-aldols 3 with exceptional diastereo- and enantioselectivity (≥20:1 d.r. and 96–98% ee). By virtue of transition state TS-I proposed for the 1,4-hydroboration reaction,^[9,12] we anticipated that this procedure could be used to generate stereodefined tetrasubstituted enolborinates 5 from substituted α,β-unsaturated amides 4. Subsequent aldol reactions of enolborinates 5 should faithfully relay the enolborinate geometry to the all-carbon quaternary stereocenter in 6 via transition state TS-II.^[2] To the best of our knowledge, stereodefined tetrasubstituted enolates have not been successfully generated with high stereochemical control by using alternative reductive aldol procedures,^[9,10,12,13] but several have been generated by 1,4-addition of organometallic reagents to unsaturated carbonyl derivatives.^[5m,q,r,14]

Scheme 1.

1,4-Reductive aldol reactions of substituted α,β-unsaturated amides with (^lIpc)₂BH.

We began by using α-methylacryl carboxamide 7 as the substrate to probe the effect of an α-substituent on the 1,4-hydroboration and the following aldol reaction. Compounds bearing a α,α-dimethyl-β-hydroxy quaternary center are often generated by using Mukaiyama aldol methods.^[15] 1,4-Hydroboration of 7 (1.1 equiv) with (^dIpc)₂BH (1 equiv) in Et₂O at ambient temperature for 3 h followed by addition of an aldehyde (0.85 equiv) and heating the reaction mixture at 50 °C in sealed tube for 16 h gave aldols 9 (see SI for variables studied during the optimization of this reaction). Results of the reductive aldol reactions of 7 with a range of representative aldehydes are presented in Scheme 2. The aldol reactions of enolborinate 8 are more sluggish than conventional aldol reactions of less substituted enolborinates owing to the hindered nature of 8, and required heating at reflux overnight. Nevertheless aldols 9a–9e were obtained in good yield (66–84%) and with excellent enantioselectivity (91–96% ee). The absolute stereochemistry of aldols 9 was assigned by using the Mosher method,^[16] and is consistent with product formation occurring via transition state TS-IV. The aldol reaction proved to be sensitive to steric effects, as aldols 9b and 9c deriving from aliphatic aldehydes were obtained in lower yield than those from aromatic or unsaturated aldehydes, and aldols derived from α-branched aldehydes such as cyclohexanecarboxaldehyde were obtained in much lower yield (<10%, not shown).^[17]

Scheme 2.

Reductive aldol reactions of α-methacrylamide 7. [a] Reactions were performed with 0.25 mmol of (^dIpc)₂BH at a concentration of 0.25 M. [b] Isolated yields are reported. [c] Enantiomeric purity and absolute configuration of the hydroxyl stereocenter was determined by Mosher ester analysis.^[16] [d]

Reaction of enolate 8 with cinnamaldehyde in Et₂O at reflux using a standard cooling system yielded product 9a in similar efficiency (83%, 92% ee, performed on 1 mmol scale). DMTr = dimethoxytrityl.

Having established that α-substituted α,β-unsaturated carboxamide substrates are compatible with this reductive aldol procedure, we elected to study the 1,4-hydroboration and aldol reactions of α,β-dimethyl acrylamide 10 (tigloyl carboxamide). If both steps proceed with synthetically useful stereochemical control, aldol adducts 12 with an α-quarternary center bearing a methyl group syn and an ethyl group anti to the β-hydroxyl group would be obtained. Thus, 1,4-hydroboration of unsaturated amide 10 with (^lIpc)₂BH (Et₂O, 23 °C) followed by treatment of the intermediate enolborinate Z(O)-11 with representative aliphatic and aromatic aldehydes provided β-hydroxy amides 12 (Scheme 3). The 1,4-hydroboration of 10 was slower than that of 7 and was 80–90% complete after 3 h at 23 °C, as determined by ¹H NMR analysis. Attempts to push the hydroboration to completion by using longer reaction times were not successful. This led us to decrease the amount of aldehyde used in the aldol step from 0.85 to 0.75 equiv in order to compensate for the incomplete hydroboration. Under these conditions, the reductive aldol reactions of 10 provided aldols 12a–12e in moderate to good yields (40–90%). The least efficient aldol reaction of those presented in Scheme 3 was with hydrocinnamaldehyde, which gave 12b in 40% yield. However, synthetically useful yields are obtained with α,β-unsaturated aldehydes (12a, 12d), which can serve as surrogates for a saturated aldehyde substrate. Gratifyingly, aldols 12 with syn-relationships between the α-ethyl and the β-hydroxyl groups were obtained with high diastereoselectivity in all cases (d.r. >20:1), and excellent enantioselectivity (93–95% ee). The relative stereochemistry of 12a was assigned as described in the Supporting Information, and absolute configurations of aldols 12 were assigned by using the Mosher method (see SI).^[16] Collectively, these data indicate that enolborinate 11 has Z(O) stereochemistry, which is consistent with 1,4-hydroboration of 10 via TS-V, and that aldols 12 arise via chair-like transition state TS-VI.

Scheme 3.

Reductive aldol reactions of (E)-α,β-dimethylacrylamide 10. [a] Reactions were performed with 0.25 mmol of (^lIpc)2BH at a concentration of 0.25 M. [b] Aldol diastereomer ratios were determined by ¹H NMR analysis of crude products; only 12 was usually observed. [c] Isolated yields are reported. [d] Enantiomeric purity and absolute configuration of the hydroxyl stereocenter was determined by Mosher ester analysis.^[16] TMS = trimethylsilyl.

Complementary aldol diastereoselectivity is achieved by using α-ethyl acrylamide 13 as the substrate for the 1,4-hydroboration reaction (Scheme 4). Treatment of 13 with (^lIpc)₂BH in Et₂O at ambient temperature for 3 h, followed by addition of an aldehyde and heating the resulting mixture at 50 °C overnight provided aldols 15 with high diastereoselectivity (d.r. >20:1) and excellent enantioselectivity (92–95% ee).

Scheme 4.

1 Reductive aldol reactions of α-ethyl acrylamide 13. [a] Reactions were performed with 0.25 mmol of (^lIpc)2BH at a concentration of 0.25 M. [b] Aldol diastereomer ratios were determined by ¹H NMR analysis of crude products; only 15 was usually observed. [c] Isolated yields are reported. [d] Enantiomeric purity and absolute configuration of the hydroxyl stereocenter was determined by Mosher ester analysis.^[16] TMS = trimethylsilyl.

Aldols 15 so obtained have anti-relationships between the α-ethyl and β-hydroxyl groups and are diastereomers of 12, which in most cases were not detected by ¹H NMR analysis of the crude reaction mixtures. These results are consistent with the 1,4-hydroboration reaction of 13 proceeding via TS-VII to give enolborinate E(O)-14 stereoselectively, and with the aldol reaction of E(O)-14 occurring preferentially via the chair-like transition state TS-VIII. The chemical efficiency of these sterically demanding aldol reactions is acceptable (46–67%) with aromatic and unsaturated aldehydes. The lower yields of aldols 15 obtained from acrylamide 13, compared to the better yields for the reductive aldol reactions of 7 (Scheme 2) and 10 (Scheme 3) can be attributed to a destabilizing syn-pentane interaction in TS-VIII between the enolborinate equatorial ethyl substituent and the aldehyde “R¹” substituent (of R¹CHO).^[18]

The exceptional diastereoselectivity of these reactions is remarkable, especially in view of the fact that enolborinates are known to isomerize by reversible 1,3-shifts.^[9b,19] The results presented in Schemes 3 and 4 demonstrate that enolborinates Z(O)-11 (from 10, Scheme 3) and E(O)-14 (from 13, Scheme 4) are configurationally stable and do not isomerize via reversible formation of a C-boryl species (not shown), under the conditions of the hydroboration or the subsequent aldol reactions. The kinetic stability of these enolborinates^[20] undoubtedly reflects the increase in nonbonded steric interactions that must develop in the (unobserved) O- to C- 1,3-boratropic isomerization reaction.

In summary, 1,4-hydroboration reactions of substituted morpholine acrylamides with (diisopinocampheyl)borane provide stereodefined tetrasubstituted enolborinates with exceptional stereochemical control. As such, the results presented here demonstate a simple solution to the stereoselective synthesis of tetrasubstituted enolates, which are not accessible with synthetically useful stereoselectivity by using conventional enolate forming reactions.^[5]

Aldol reactions of 8 (deriving from 7) with a panel of representative aldehydes provided α,α-dimethyl-β-hydroxy carboxamides 9 with excellent enantioselectivity (91–96 % ee, Scheme 2). Syn and anti α-methyl-α-ethyl-β-hydroxy amides 12 and 15 are obtained with excellent diastereoselectivity (d.r. >20:1) and high enantioselectivity (92->95% ee) from acrylamides 10 and 13 respectively (Schemes 3 and 4). Morpholine carboxamides are known to have reactivity analogous to Weinreb amides and are valuable intermediates for a variety of subsequent synthetically useful transformations.^[11a] Thus, this simple and experimentally convenient procedure for synthesis of tetrasubstituted enolborinates via highly stereoselective 1,4-hydroboration of unsaturated morpholine carboxamides and subsequent aldol reactions provide a useful, new method for stereocontrolled synthesis of all-carbon quaternary stereocenters.

Experimental Section

To a room temperature suspension of (^{d or l}Ipc)₂BH (weighed in the glovebox, 72 mg, 0.25 mmol, and then crushed into a fine powder) in Et₂O (1.0 mL) was added acryloylmorpholine derivative 7, 10 or 13 (0.275 mmol). The solution was stirred for 3 h (at which point all of the (Ipc)₂BH had dissolved) and then aldehyde (0.213 mmol) was added. The solution was heated at 50 °C in a sealed tube overnight and then was allowed to cool to room temperature. An aqueous pH 7 buffer solution (0.5 mL), MeOH (0.5 mL) and THF (0.5 mL) were added and the reaction was stirred for 6 h at room temperature. The aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification of the crude product by flash chromatography (CH₂Cl₂-ethyl acetate, 1:1) provided the aldol adducts 9, 12 or 15.