(Diisopinocampheyl)borane-Mediated Reductive Aldol Reactions: Highly Enantio and Diastereoselective Synthesis of Syn-Aldols from N-Acryloylmorpholine

Abstract

An efficient and highly enantio- and diastereoselective synthesis of syn propionamide aldols is described. Formation of the Z-enolborinate via the hydroboration of 4-acryloylmorpholine with (diisopinocampheyl)borane followed by aldol reactions with representative achiral and chiral aldehydes provided syn-α-methyl-β-hydroxy morpholine carboxamides with excellent enantio- and diastereoselectivity (96–98% ee and d.r. >20:1).

The reductive aldol reaction of α,β-unsaturated carbonyl compounds is an important, emerging method for stereocontrolled C-C bond formation.^[1] Numerous recent studies^[2–6] have focused on reductive aldol reactions of enones and enoates catalyzed by transition-metal complexes. Many such reactions provide excellent levels of enantio- and diastereoselectivity in reductive aldol reactions with aromatic aldehydes, however reductive aldol reactions with aliphatic aldehydes have been generally less selective.^{[1,2a,b,d,i,3,4c,i,6]} Catalytic enantioselective aldol reactions have also been developed that are very effective including reactions with aliphatic aldehydes.^[7]

It is well established that boron enolates are exceptionally useful intermediates for asymmetric aldol reactions.^[7] We reasoned that the synthetic utility of reductive aldol reactions could be enhanced by utilizing enolborinate intermediates, in view of the tight (B-O bond length 1.4–1.5 Ǻ), closed, structurally well-defined transition states that are invoked to rationalize the enhanced stereochemical control in aldol reactions of enolborinates compared to other metal enolates.^[7] While examples of borane-mediated 1,4-reductions of enone and enoate Michael acceptors have been reported (including use of diisopinocampheylborane as the reducing agent),^[8] with subsequent reactions with aldehydes leading to syn aldols, these processes have not yet been found to deliver the syn aldol products with synthetically useful enantioselectivity.^[8b,c]

We report herein the development of a highly enantio- and diastereoselective boron-mediated reductive aldol reaction that delivers syn aldols with exceptionally high levels of stereocontrol (≥96% ee; ≥20:1 d.r). As depicted in Scheme 1, it was anticipated that hydroboration of a Michael acceptor 1 with (Ipc)₂BH would proceed via transition state 2 and lead directly to a Z(O)-enolate.^[8a–c] However, Z-E enolborinate equilibration through a reversible 1,3-boratropic shift was suspected to occur in prior studies of this process, thereby delivering a mixture of syn (6) and anti (7) aldol adducts from the Z(O) and E(O)-enolborinates, respectively.^[8c,9] As such, two major objectives of this study became (1) the identification of a substrate that would undergo 1,4-reduction to give the Z(O)-enolborinate 3 with high kinetic (if not thermodynamic) control, and (2) identification of a chiral hydroborating reagent capable of inducing excellent enantioselectivity in the subsequent aldol reaction. We elected to pursue (diisopinocampheyl)enolborinates, which are known to be useful intermediates for enantioselective aldol reactions, albeit frequently undergoing aldol reactions with only moderate levels of enantioselectivity.^[8c,10]

Scheme 1.

Hydroboration of α,β-unsaturated carbonyl compounds with (Ipc)2BH and subsequent aldol reactions.

We selected commercially available (and very inexpensive)^[11] 4-acryloylmorpholine (8) as substrate for the studies reported herein.^[12] Morpholine amides are a safe alternative^[13] to Weinreb amides but have similar modes of reactivity and comparable ease of manipulation.^[14] We quickly found that excellent results were obtained when the hydroboration of 8 with (^lIpc)₂BH[15] was performed in Et₂O at 0 °C for 2 h, followed by addition of 0.85 equiv of aldehyde at −78 °C (Scheme 2). By using this procedure, the syn-α-methyl-β-hydroxy morpholine amides 11a–f were obtained in good to excellent yields (68–91%) and with excellent enantio- and diastereoselectivities (96–98% ee, d.r. >20:1). Separation of aldols 11 from pinene-derived byproducts is trivial, essentially constituting a short column filtration, owing to the large polarity difference. The enantiofacial selectivity derived from (^lIpc)₂BH in these reactions is the same as in the very well studied allylboration reaction.^[17]

Scheme 2.

Enantioselective synthesis of syn-α-methyl-β-hydroxy morpholine amides 11 from achiral aldehydes. [a] Isolated yields of aldols 11 obtained after column chromatography. [b] Diastereomer ratios (d.r.) determined by ¹H NMR analysis of crude reaction mixtures. [c] Enantiomeric excess (% ee) and absolute configurations determined by using the Mosher ester analysis.^[16]

The very high selectivity realized in these reactions reflects, in part, the essentially exclusive (≥99%) formation of the Z(O)-enol diisopinocampheylborinate 9Z (which we characterized by 1D and 2D NMR experiments; see SI). Isomerization of 9Z to 9E evidently does not occur to any significant extent owing to A^1,3strain between the morpholine unit and the terminal methyl substituent of the enolborinate.^[18] Most remarkable, however, is the exceptional level of enantioselectivity realized in these reactions, which significantly exceeds that obtained in previous studies of enantioselective aldol reactions of (diisopinocampheyl)enolborinates.^[8c,10] The relative and absolute stereochemistry determined for aldols 11 is consistent with transition state 10 being dominant in these reactions. That other aldol reactions^[8c,10] using the (Ipc)₂B– auxiliary proceed with significantly lower levels of enantioselectivity implies that at least one heterochirally related transition state is competitive in those cases, but significantly less so in the reactions of 9Z reported here.^[19]

In order to test the utility of this reductive aldol procedure in more complex synthetic contexts, we examined the aldol reactions of 9Z (generated in situ from acrylamide 8 and (Ipc)₂BH as described for the reactions in Scheme 2) in the double asymmetric manfold^[20] with four chiral aldehydes, 12a, 12b,^[21a] 12c,^[21b] 12d (Scheme 3). The intrinsic diastereofacial preferences of these aldehydes was determined to be 1.5:1 (in favor of 13a), 1:2 (in favor of 13d), 3:1 (in favor of 13e) and 1.3:1 (in favor of 13g), respectively, by aldol reactions with the achiral enolborinate generated from 8 and dicyclohexylborane (see SI). Remarkably, the double asymmetric aldol reactions of 12a, 12b, 12c and 12d using the chiral Z-enolborinate 9Z deriving from 8 with either (^lIpc)₂BH or (^dIpc)₂BH proceeded with excellent stereocontrol (d.r. >20:1; in each case, the minor diastereomer could not be detected in any of the experiments by ¹H NMR analysis of crude reaction mixtures) in both the stereochemically matched and mismatched combinations for each aldehyde substrate. The mismatched double asymmetric reaction of 2c yielding 13f (56% yield, 71% based on recovered 2c) was very slow and had not reached completion even after 48 h at −78 °C; all other experiments were complete after overnight at −78 °C. Knowing the intrinsic facial selectivity of aldehyde 12c (d.r. 3:1, see SI), the enantiofacial selectivity of the Z-enol diisopinocampheyborinate 9Z, expressed in energetic terms, must be at least 1.57 kcal/mol in order to override the intrinsic diastereofacial preference of 12c to the extent of >20:1. This corresponds to a reagent enantioselectivity of 96.5% ee, fully consistent with the data provided in Scheme 1 for reactions of 9Z with achiral aldehydes.

Scheme 3.

Double asymmetric aldol reactions of chiral aldehydes and the chiral Z-enolborinate generated from 8. [a] Yields of aldol adducts are for isolated products obtained by column chromatography. [b] Diastereomer ratios (d.r.) determined by ¹H NMR analysis of crude reaction mixtures. [c] Absolute and relative configurations of 13a–13h determined by using Mosher ester analysis^[16] and the Rychnovsky acetonide method^[22] (see SI). [d] Very slow reaction, not complete after 48 h at −78 °C.

This method for synthesis of syn-α-methyl-β-hydroxy morpholine carboxamides 11 and 13 is a highly attractive and highly competitive alternative to existing methods for the enantioselective synthesis of syn aldols.^[1–7,23] It also sheds light on the great potential of boron-mediated reductive aldol reactions, despite the less than stellar history associated with prior studies of (diisopinocampheyl)enolborinates in enantioselective aldol transformations of achiral substrates.^[8c,10]

The aldol reactions of 9Z described here are performed under exceptionally mild and simple conditions, with no added bases. The results summarized in Schemes 2 and 3 demonstrate that standard (e.g., TBDPS, PMB, DMPM) as well as potentially sensitive protecting groups such as dimethoxytrityl (DMTr, see 11e) are fully compatible. The diastereo- and enantioselectivity of this procedure rivals that of the very best technology currently available.^[1–7,23] The morpholine amide unit in the aldol products exhibits Weinreb amide-like ease of manipulation in subsequent steps.^[13,14] Our procedure requires only two steps, starting with the straightforward synthesis of diisopinocampheylborane.^[15] Strikingly, the cost of raw materials required for the synthesis of enolborinate 9Z (including the synthesis of diisopinocampheylborane) is less than $0.25 per mmol scale aldol reaction (2012 Sigma-Aldrich prices for bulk quantities of reagents).^[11] Integrating over cost, reagent accessibility, selectivity (both enantio- and diastereoselectivity), substrate scope and generality, and the ease of manipulation of the morpholine amide aldol products,^[14] we submit that the new reductive aldol procedure described here is the least expensive^[24] and ranks high among the most highly enantio- and diastereoselective, substrate-general methods for synthesis of syn aldols compared to all other currently available procedures.

In summary, we have developed a highly enantioselective synthesis of syn-α-methyl-β-hydroxy morpholine amides 11 and 13 from achiral and chiral aldehydes, respectively, via the hydroboration of 4-acryloylmorpholine (8) with diisopinocampheylborane. This reaction produces the Z-(diisopinocampheyl)enolborinate 9Z with excellent selectivity, which undergoes highly enantioselective aldol reactions with achiral aldehydes (96–98% ee, Scheme 2) and equally highly diastereoselective double asymmetric reactions with a range of chiral aldehydes (Scheme 3). The exceptional enantioselectivity of this process is also noteworthy, especially given that the vast majority of literature examples of aldol reactions of (diisopinocampheyl)enolborinates generally proceed with lower levels of enantioselectivity, which suggests that transition state control in the aldol reactions reported herein is more precise than with the previously studied aldol reactions of (diisopinocampheyl)enolborinates.^[8c,10] Extensions of this methodology to other aldol substrates, as well as applications in the synthesis of natural products are currently under investigation and will be reported in due course.

Experimental Section

At 0 °C, to a suspension of (^{l or d}Ipc)₂BH (weighed in a glovebox, 72 mg, 0.25 mmol) or (Cy)₂BH (weighed in a glovebox, 45 mg, 0.25 mmol) in Et₂O (1.0 mL) was added 4-acryloylmorpholine (8) (35 μL, 0.275 mmol). The solution was stirred 2 h at 0 °C at which time it became homogeneous. The resulting mixture was cooled to −78 °C, aldehyde (0.213 mmol) was added, and the solution was stirred overnight at −78 °C. 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 three times with CH₂Cl₂ (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 through a short plug of silica gel (1:1 CH₂Cl₂-ethyl acetate) provided the corresponding β–hydroxymorpholine amide 11 or 13.