Diastereo- and Enantioselective Synthesis of Homoallylic Amines Bearing Quaternary Carbon Centers.

Abstract

A Cu-catalyzed method for the efficient enantio- and diastereoselective synthesis of chiral homoallylic amines bearing a quaternary carbon and an alkenylboron is disclosed. Transformations are promoted by a readily prepared (phosphoramidite)–Cu complex, and involve bench-stable γ-disubstituted allyldiborons and benzyl imines; products are obtained in up to 82% yield, >20:1 dr, and >99:1 er. Reactions proceed via stereodefined boron-stabilized allylic Cu species formed by an enantioselective transmetalation. Utility of the 1-amino-3-alkenylboronate products is highlighted by a variety of synthetic transformations.

Graphical Abstract

Development of catalytic enantioselective methods for the synthesis of chiral amines and all-carbon quaternary stereocenters are both critical objectives in organic synthesis.^1,2 In this regard, the enantioselective allyl addition to imines with appropriately substituted C-based nucleophiles represents a direct route for the concomitant generation of both of these important chemical motifs.³ While a number of catalytic methods have been reported for the enantio- and diastereoselective additions of γ-substituted allyl reagents (e.g., crotyl) to imines that afford secondary homoallylic amines bearing a vicinal tertiary stereocenter,^4,5 the corresponding quaternary stereocenter variants remain lacking.⁶ One example involves the diastereoselective and enantiospecific addition of chiral allylborons to TMS-aldimines via the borinic ester recently reported by Aggarwal (Scheme 1A).⁷ In contrast, only two catalytic protocols have been introduced for the enantio- and diastereoselective synthesis of homoallylamines bearing quaternary carbon stereocenters. First, chiral amino alcohols have been shown to catalyze an efficient enantio- and diastereoselective addition of a chiral allyl-B(pin) to aldimines that proceeds by stereospecific allyl transfer to the catalyst (Scheme 1B).⁸ Secondly, chiral binaphthyl diols have been shown to catalyze the enantio- and diastereoselective additions of γ,γ-disubstituted allyl boronic acids to cyclic imines in high stereoselectivity (Scheme 1C).⁹ Nevertheless, both catalytic protocols present limitations related to the requirement of either pre-formed enantioenriched γ,γ-disubstituted allylboron reagents or unstable achiral allyl boronic acids. To-date, metal-free catalytic methods have proven to be most effective for the enantioselective synthesis of quaternary carbon stereogenic centers in allylic nucleophile additions to imines. Such catalytic protocols possess mechanistic characteristics that maintain the E or Z alkene isomer of the allyl reagent.^7,8 In contrast, due to their configurational instability, reactions of most π-allylmetal complexes lead to poor diastereoselectivity or are limited to the synthesis of one stereoisomer.^10,11,12

Scheme 1.

Enantio- and Diastereoselective Additions to Imines with γ,γ-Disubstituted Allyl Reagents

An emerging strategy for the construction of contiguous stereogenic centers via allylic nucleophile additions to C=O and C=N electrophiles involves the use of allylic gem-diboronate esters. Murakami reported the in situ generation of these reagents via Pd- or Ru-catalyzed olefin isomerization, followed by enantio- and diastereoselective addition to aldehydes promoted by a chiral phosphoric acid.¹³ Subsequently, Cho reported the diastereoselective addition of isolated allyldiboron ester 5 to a variety of cyclic sulfonyl imines, although, the report is limited to the E-crotyl reagent (Eq 1).¹⁴

(1)

At this juncture, based on our previous work with 1,1-diborylalkanes,^15,16 we postulated that stereodefined γ,γ-disubstituted allyldiboron (e.g., 2) would result in increased reagent stability, and their participation in enantioselective Cu-catalyzed additions to imines would result in the enantioselective synthesis of secondary homoallylic amines bearing a quaternary carbon stereogenic center (e.g., 3) (Scheme 1D). A key aspect of this strategy requires reactions to proceed by enantioselective transmetalation through a chiral α-boryl–Cu–allyl nucleophile.

Successful implementation of our plan required the development of a general method for the synthesis of allylic gem-diboronate esters (e.g., 2). To accomplish this goal, we hypothesized that the direct Pd-catalyzed cross coupling of lithiated organodiboron 7, which can be prepared by deprotonation of diborylmethane with bulky lithium amide bases (LDA or LTMP) on gram-scale with readily available stereodefined vinyl halides would provide the most direct strategy for the synthesis of a variety of stereodefined bis-allylic 1,1-diborons. Building on work by Feringa,¹⁷ we found a wide variety of stereodefined alkenyl halides undergo Pd-catalyzed cross coupling with organolithium 7, to afford chromatographically stable stereodefined allyldiborons 2a–i isolated in 32–75% yield (Scheme 2); for example, n-butyl 2b is often isolated in up to 75% yield on a multigram-scale. As the synthesis of 2c and 2e illustrate, the presence of silyl ethers and aryl groups result in equally efficient coupling. The method can also be extended to alkenyl iodides containing α-branched alkyl groups (2g–h). Moreover, ethyl-substituted variants 2d, 2f, and E/Z-2i can be prepared efficiently.

Scheme 2.

Synthesis of γ,γ,-Disubstituted Allyldiboronate Esters ^a

^aSee SI for details.

Next, we began by identifying catalytic conditions for the enantioselective reaction of phosphinoylimine 9 with 2a (Table 1). Investigation of a variety of bidentate and monodentate phosphine ligands (L1–L5, entries 1–5) revealed monodentate phosphoramidite L4 to be the most effective, delivering 11 in 77% conv. and 85:15 er (entry 4). Similar low enantio- and diastereoselectivity was observed in reactions with Me/n-Bu reagent 2b (entries 6–8), with L5 affording 12 in 94% ¹H NMR yield, 1.1:1.0 dr, and 90:10 and 91:9 er (entry 8). In addition, phosphoramidite ligands L6 and L7 bearing 3,3’ mesityl and 3,5-xylyl groups, delivered 12 in low dr but with an increase in enantioselectivity. At this point we hypothesized that the high enantioselectivity of each diastereoisomer of 12 afforded with L7 is a result of a chiral (L7)-Cu-allyl formed in high er by an enantioselective transmetalation, but reacts with both prochiral faces of 9 with limited bias. Such an outcome would be consistent with the poor enantioselectivity observed in reverse prenyl additions (entries 1–5), and likely the result of non-selective binding of imine 9 to the Cu-allyl species. Changing the imine activating group to p-MeO-benzyl (PMB) 10, which results in a less electrophilic imine but more Lewis basic nitrogen, resulted in marked improvement in dr. Treatment of 10 and 2b with 5 mol % Cu-OtBu, 10 mol % L7, and 1 equivalent of MeOH at −40 °C for 18 h delivered 14 in 77% yield, >20:1 dr, and 99:1 er (entry 11). Furthermore, reaction of 2a with PMB imine 10 under identical conditions resulted in 13 in 36% yield and 99:1 er (entry 12). In reactions of PMB imine 10 with both 2a and 2b it was noted that significant quantities (15–55%) of protodeborated allyldiboron is formed through competitive reaction of the allylic Cu with methanol. To suppress protonation of the Cu-allyl species, we employed CD₃OD to utilize a deuterium isotope effect.¹⁸ As illustrated in entries 13 and 14, reaction in the presence of CD₃OD results in an increase in yield, furnishing 14 in 84% yield (>20:1 dr, and 99:1 er), and 13 in 65% yield (99:1 er).

Table 1.

Reaction Optimization of Enantio- and Diastereoselective Cu-Catalyzed Additions to Imines^a

^aReactions performed under N₂ atmosphere.

^bYield and diastereomeric ratios (dr) determined by analysis of 400, 500, or 600 MHz ¹H NMR spectra of crude reactions with hexamethyldisiloxane as internal standard.

^cEnantiomeric ratios (er) determined by HPLC or SFC analysis; see the SI for details.

^d15% proto-deboration of 2b.

^e55% proto-deboration of 2a.

^f<2% proto-deboration of 2a or 2b.

To investigate substrate scope of the allylic nucleophile addition reaction, we first focused on enantioselective reverse prenyl addition to aryl imines with allyldiboron 2a (Scheme 4). The catalytic method can be used to prepare a wide array of secondary amines bearing an alkenylboron in good yield (>55%) and high selectivity (>98:2 er). Parent phenyl imine (13a), as well as aryl imines bearing electron-donating (13c), electron-withdrawing substituents (13b, d–f), and halogens (13b, h–i) in various positions are suitable substrates. Naphthyl-derived imines also undergo efficient and selective reverse prenyl addition (13g). As the synthesis of 13j–l illustrates, use of heteroaryl imines, including pyridyl groups, results in equally efficient and enantioselective reactions.¹⁹

Scheme 4.

Enantio- and Diastereoselective Cu-Catalyzed Synthesis of Quaternary Carbon Stereogenic Centers^a–d

^aReactions performed under N₂ atmosphere. ^bConversion and diastereomeric ratios (dr) determined by analysis of 400, 500, or 600 MHz ¹H NMR spectra of crude reactions with hexamethyldisiloxane as internal standard. ^cEnantiomeric ratios (er) determined by HPLC or SFC analysis; see the SI for details. ^dYields of isolated product after SiO₂ chromatography and represent an average of at least two runs.

The catalytic method is equally effective for reactions of non-symmetric allyldiboron reagents 2b–j with aryl imines (Scheme 4), providing stereoselective access to a range of complex homoallylic amines bearing a vicinal quaternary carbon stereogenic center, and a pendant alkenylboron group. Reaction of E-allyldiboron reagents that contain n-alkyl groups (14a-b), a pendant silyl ether (14c-d) or a homobenzyl unit (14e-f) react smoothly to furnish secondary amines bearing quaternary carbon stereogenic centers in good yield, dr, and er. Notably, reaction of smaller 2-furyl derived-imine with 2e, affords 14e with excellent stereocontrol (>20:1 dr, and 97:3 er). Stereoselective synthesis of ethyl-substituted quaternary stereocenters can be achieved with high selectivity through the application of ethyl-derived E-allyldiborons 2d-f; for example, secondary amines 14d and 14f are both isolated as single enantio- and diastereomers. Allyldiboron reagents containing more sterically congested α-branched alkyl groups participate under the reaction conditions, although, with mixed results. Cyclohexyl-substituted organodiboron reagent 2g affords 14g in 64% yield and >20:1 dr but 93:7 er. In comparison, a smaller cyclopropyl group (e.g., 2h) results in a restoration in selectivity (14h: 74% yield, >20:1 dr, and 98:2 er).

The efficient transfer of E and Z alkene stereochemistry from the allyldiboron to the product, indicated that the catalytic method could provide an effective strategy for the stereoselective synthesis of Me/Et quaternary carbon stereogenic centers. Potential diminution in selectivity could arise from poor enantioselective transmetalation and/or stereochemical isomerization of the transient allylic Cu species prior to C–C bond formation. As shown in Scheme 5, reactions of both E- and Z-2i were found to proceed stereospecifically with naphthyl imine 10m to access both diastereoisomers in high dr and er. For example, Cu-catalyzed reaction of E-2i delivers R,S-14i in 63% yield, >20:1 dr, and 97.5:2.5 er, whereas, transformation of Z-2i results in R,R-14j in 59% yield, >20:1 dr, and 97.5:2.5 er. These results indicate that the reaction proceeds by an enantioselective transmetalation, followed by Cu-allyl addition to the imine, which is either faster than isomerization or nucleophilic addition via a diastereomeric Cu-allyl isomer. The same mechanism must also be operative for the reverse prenyl addition (Scheme 3).

Scheme 5.

Cu-Catalyzed Stereospecific Additions with E- and Z-Methyl/Ethyl AllylDiborons^a

^aSee SI for details.

Scheme 3.

Enantioselective Cu-Catalyzed Reverse Prenyl Addition to Aldimines^a–d

^aReactions performed under N₂ atmosphere. ^bConversion determined by analysis of 400, 500, or 600 MHz ¹H NMR spectra of crude reactions with hexamethyldisiloxane as internal standard. ^cEnantiomeric ratios (er) determined by HPLC or SFC analysis; see the SI for details. ^dYields of isolated product after SiO₂ chromatography and represent an average of at least two runs.

A proposed catalytic cycle and stereochemical model for the enantio- and diastereoselective synthesis of complex homoallylic amines is depicted in Scheme 6. In situ generated (L)-Cu–OMe (I) undergoes enantioselective transmetalation with allyldiboron II via III to generate enantioenriched allylic Cu species IV. The orientation of the B(pin) units will be positioned to minimize A(1,3)-strain. Isomerization to less congested and boron-stabilized allylic Cu E-V is followed by reaction with the E-PMB imine via 6-membered cyclic transition state VI. Coordination of the E-imine to (L)-Cu places both the aryl substituent and the PMB groups axial.²⁰ Furthermore, to minimize additional 1,3-diaxial interactions, the B(pin) unit is placed in the equatorial position. Following allyl transfer in a highly diastereoselective manner, CD₃OD (or MeOH) then releases the homoallylic amine VIII and regenerates (L)-Cu-OCD₃.

Scheme 6.

Proposed Catalytic Cycle and Stereochemical Model

The secondary amines prepared through the Cu-catalyzed protocol are amenable to a range of subsequent chemical transformations (Scheme 7). For example, homoallylic amine 14e undergoes efficient Suzuki-Miyaura cross coupling with p-CF₃-C₆H₄Br to afford alkenylarene 15 in 66% isolated yield. Allylboronic ester 16 can be efficiently prepared in 72% yield via the one carbon homologation of 14f. Additionally, proto-deboration of alkenylboronate 13a proceeds smoothly in the presence of AgF to furnish terminal olefin 17 in 67% yield.²¹ Of note, this two-step process represents an example of a formal enantioselective reverse prenylation of an acyclic imine.²² Finally, the secondary amines can be transformed into pyrrolidines by a two-step sequence. Treatment of alkenylboronates 13b, 14b-c with NaBO₃•4H₂O, results in conversion to the corresponding cyclic hemiaminal, which can be reduced with NaBH₃CN to afford functionalized pyrrolidines 18, 19 and 20 in 49%, 57%, and 47% yield, respectively over two steps (Scheme 7D). Absolute stereochemistry of the products was determined through X-Ray crystallographic analysis of dimethyl-substituted pyrrolidine 18, which revealed the stereochemical orientation of the secondary amine to be R (Scheme 7D). Furthermore, examination of pyrrolidine 19 by 1D-NOESY confirmed a cis-relationship between the benzylic methine and adjacent methyl group.

Scheme 7.

Synthetic Utility of Products

^aSee SI for details. ^bContains ~10% by-product that cannot be removed.

In conclusion, we have developed the first catalytic enantio- and diastereoselective process for the synthesis of complex homoallylic amines via the reaction of allyldiboronates with aldimines. A (phosphoramidite)-Cu catalyst promotes enantioselective transmetalation, generating a highly reactive α-boryl-Cu-allyl species. This nucleophile reacts efficiently with a variety of aryl aldimines to generate enantioenriched homoallylic amines in excellent dr and er, bearing either gem-dimethyl substitution or a quaternary carbon stereogenic center. Significantly, both product diastereoisomers are rendered accessible by choice of E- and Z-allyldiboron stereochemistry. Furthermore, utility of the products is highlighted through representative transformations that included cross coupling, homologation, and conversion to functionalized pyrrolidines. Further catalytic stereoselective reactions of allyldiborons are ongoing.