Control of chemoselectivity in asymmetric tandemreactions: Direct synthesis of chiral aminesbearing nonadjacent stereocentersZhe Lia, Bin Hua, Yongwei Wua, Chao Feia, and Li Denga,1

aDepartment of Chemistry, Brandeis University, Waltham, MA 02454-9110

Edited by Phil S. Baran, The Scripps Research Institute, La Jolla, CA, and approved January 9, 2018 (received for review October 21, 2017)

This paper describes the mechanistic insight-guided development ofa catalyst system, employing a phenolic proton donor catalyst inaddition to a cinchonium-derived phase-transfer catalyst, to controlthe chemoselectivity of two distinct intermediates, thereby enablingthe desired asymmetric tandem conjugate addition–protonation path-way to dominate over a number of side-reaction pathways to providea synthetic approach for the direct generation of optically activeamines bearing two nonadjacent stereocenters.

phase-transfer catalysis | umpolung | asymmetric tandem reactions |chemoselectivity | chiral amines

Catalytic asymmetric tandem reactions are recognized as anoptimal strategy for the synthesis of complex chiral compounds

(1–9). The power of catalytic asymmetric tandem reactions isparticularly compelling in providing direct transformations ofreadily available achiral starting materials into complex acyclicchiral products bearing nonadjacent stereocenters, as constructionsof such structural motifs typically require a multistep process.Accordingly, great efforts have been directed toward the devel-opment of such catalytic asymmetric tandem reactions, where thefocus has been on how to design and develop synthetic catalysts toachieve high diastereoselectivity and enantioselectivity (10–22). Itis illuminating to observe that enzymes not only routinely achievehigh diastereoselectivity and enantioselectivity in mediating asym-metric tandem reactions but are also equally at ease in the controlof chemoselectivity, thereby creating divergent biosynthetic path-ways to convert a common intermediate into structurally distinctnatural products (23, 24). As shown in Scheme 1, enzymaticcontrol of whether guanidinium enolate 1 undergoes an intra-molecular conjugate addition or a protonation dictates whether1 is an intermediate for the biosynthesis of polycyclic guanidinealkaloids ptilocaulin or batzelladine K. In this paper, we wish todescribe the development of a small-molecule catalyst system toachieve high stereoselectivity and control of chemoselectivity oftwo different reaction intermediates. Specifically, this catalyst sys-tem not only directs a 2-azaallylanion intermediate to preferen-tially engage in a conjugate addition over a protonation (4 to 9 vs. 4to 12, see Fig. 2) but also allows the resulting enolate intermediateto proceed next predominantly in an intermolecular protonationinstead of an intramolecular Mannich reaction (9 to 10 vs. 9 to 15).This catalyst system thus enables an asymmetric tandem conjugateaddition–protonation reaction pathway (13–21) to realize directand asymmetric formation of chiral acyclic amines containing1,3 stereocenters from readily available achiral precursors.Chiral amines are widely presented in biologically active nat-

ural products and synthetic molecules. Great strides have beenmade in the development of efficient catalytic asymmetric C–Cbond-forming nucleophilic additions to imines for the directgeneration of chiral amines bearing either a sole stereocenter ortwo adjacent stereocenters (25–27). On the other hand, theasymmetric construction of chiral amines bearing 1,3 stereo-centers, a motif presented in a variety of biologically active andmedicinally interesting compounds (Fig. 1), typically requires a

multistep process as the two nonadjacent stereocenters are cre-ated in separated bond-forming steps (28–31). We demonstratedthat cinchonium salts such as 2a could promote the deprotonationof N-benzyl imines 3 to form the corresponding 2-azaallylanions 4,and then mediate chemo-, regio-, diastereo-, and enantioselectiveC–C bond-forming reactions between 4 and acrolein as well asβ-substituted enals to form chiral amino aldehydes 6 containingeither a sole stereocenter or two adjacent stereocenters (Scheme2A) (32–43). This development prompted us to investigate how 4would react with α-substituted enals 8 with the hope of estab-lishing an efficient asymmetric tandem conjugate addition–protonation cascade to directly generate optically active chiralamines containing 1,3 stereocenters (Scheme 2B).The desired asymmetric tandem conjugate addition–

protonation reaction is just one among the several possible re-action pathways by which 4 could react with 8 (Fig. 2). At theoutset of our investigation, we were concerned about how toestablish this tandem reaction as the dominant reaction pathway,in addition to how to achieve it in a highly diastereoselective andenantioselective fashion (44–46). Cinchonium salt 2a was foundto exercise catalytic control over the chemoselectivity (conjugateaddition vs. protonation vs. [3 + 2] addition) and regioselectivity(C1 vs. C3 bond formation) with respect to how 2-azaallylanions

Significance

Enzymes efficiently facilitate biosynthetic pathways towardcomplex natural products by achieving not only precise con-struction of stereocenters, but also specific induction of par-ticular reaction modes for each of the multiple reactionintermediates. We report the development of a small moleculecatalyst system inspired by such traits of biocatalysts, whichenables asymmetric tandem reactions to directly transformachiral precursors into complex chiral amines. Specifically, acatalyst system, based on synergistic cooperation between acinchonium salt and a phenolic proton donor, mediated chemo-,regio-, diastereo-, and enantioselective asymmetric tandem re-actions by controlling how two distinct reaction intermediatesreact, thereby establishing an asymmetric conjugate addition–protonation reaction cascade to generate optically active aminesbearing two nonadjacent stereocenters.

Author contributions: Z.L., B.H., Y.W., and L.D. designed research; Z.L., B.H., Y.W., and C.F.performed research; Z.L., B.H., C.F., and L.D. analyzed data; and Z.L. and L.D. wrotethe paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Published under the PNAS license.

Data deposition: Crystallography, atomic coordinates, and structure factors have beendeposited in the Cambridge Structural Database, Cambridge Crystallographic Data Cen-tre, Cambridge CB2 1EZ, United Kingdom, www.ccdc.cam.ac.uk (CSD reference nos.1567596–1567599).1To whom correspondence should be addressed. Email: deng@brandeis.edu.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1718474115/-/DCSupplemental.

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4 participated in reactions with acrolein and β-substituted enals.We wished such catalytic control could be extended to reactionsof 4 with α-substituted enals 8, thereby allowing the formation ofthe desired product 10 to be favored over those of side products12, 14, and 16. Furthermore, we were uncertain how interme-diate 9, upon its formation from 4 and 8, would partition be-tween the downstream Mannich cyclization (9 to 15) and thedesirable protonation pathways (9 to 10).We began with an investigation of the 2a-mediated model

reaction of phenyl trifluoromethyl imine 3A and methacrolein(8a). We found that the [3 + 2] adduct 16Aa was formed as al-most the exclusive product albeit in high diastereomeric ratio(dr) and enantiomeric excess (ee) (Table 1, entry 1). Electronicor steric tuning of the terphenyl group in the phase-transfercatalyst was found to have no significant impact on the re-action outcome (Table 1, entries 2–3). We next examined thetandem reaction of an alkyl trifluoromethyl imine, ethyltrifluoromethyl imine 3H, mediated by catalysts 2a-c. In thesereactions the [3 + 2] adduct 16Ha was consistently formed in asignificant amount, leading to a mixture of 10Ha and 16Ha in aratio ranging from 41:59–58:42 (Table 1, entries 4–6). On theother hand, 2c did afford noticeably higher diastereoselectivityand enantioselectivity. Importantly, the major diastereomers forboth products were found to be formed in identical ee, sug-gesting they were likely derived from a common intermediate.To elucidate by which pathway the [3 + 2] adduct was gen-

erated, we carried out NMR studies to measure the carbonisotope effect on carbons a-c in 16Aa using Singleton’s method atnatural abundance (47–51). As summarized in Scheme 3, acarbon isotope effect was detected at only carbon c. These re-sults indicated that 16Aa was formed not by a [3 + 2] cycload-dition pathway, but the stepwise conjugate addition–Mannich

reaction pathway with the intermolecular conjugate addition asthe rate-determining step. This mechanistic insight into the for-mation of 16Aa revealed that the challenge in realizing the de-sired tandem conjugate addition–protonation reaction was toswitch the chemoselectivity of enolate 9 from favoring the intra-molecular Mannich reaction to the intermolecular protonationpathway.Considering that water is the most likely agent for the pro-

tonation of 9, we reasoned that, by introducing a more acidicspecies than water as a cocatalyst, we might be able to acceleratethe protonation of 9 and consequently render the tandem con-jugate addition–protonation the dominant reaction pathway. Atthe same time, we were cognizant that this cocatalyst must se-lectively promote the protonation of 9 vs. protonations of anionicintermediates 4 and 15 along the undesirable isomerization (4 to12) and pyrrolidine-forming pathways (15 to 16), respectively.These considerations guided us to investigate the impact of

phenol derivatives as cocatalysts on the 2c-mediated reaction of3A and methacrolein (8a). Phenol derivatives (52, 53) werepreviously reported as either an additive or a cocatalyst in chiralphase-transfer catalyst-mediated conjugate additions and aldoladditions to increase reaction yield by promptly protonating theenolate intermediates that would otherwise undergo reverseconjugate additions and aldol reactions (54–56). Although suchphenolic derivatives, to our knowledge, were not documented aseffective catalyst for the protonations of enolates to override anintramolecular C-C bond-forming reaction (57), we were hopefulthat, by electronic and steric tuning via modifying the phenyl ringwith substituents of varying electronic and steric properties, wemight identify a phenol derivative to achieve this challenginggoal while affording optimal selectivity with respect to the pro-tonation of enolate 9 vs. other carbanions such as 4 or 15.Phenol (17a) in an amount of 10 mol % was initially employed

as a cocatalyst in our model reaction (Table 2, entry 1), whichled to a significant increase of the desired tandem conjugate

Fig. 1. Examples for biologically active and medicinally important com-pounds.

Scheme 1. An example of enzyme-controlled chemoselective transforma-tions from a common intermediate to distinct natural products.

A

B

Scheme 2. Chiral amines synthesis via umpolung strategy. (A) Previous work. (B) Present work.

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addition–protonation reaction product 10Aa with concomitantdecrease of the [3 + 2] adduct 16Aa in the reaction productmixture (Table 2, entry 1 vs. Table 1, entry 3). Importantly, 10Aawas formed in high dr and ee. Next we investigated the samereaction with p-methoxy and p-chloro phenols (17b-c), re-spectively (Table 2, entries 2–3). The results from these inves-tigations suggested that the more acidic the phenol derivative thebetter it was as a cocatalyst. However, p-nitro phenol (17d) as acocatalyst was found to increase the formations of both the de-sired 10Aa and the undesirable isomerization product 12A,resulting in a reaction product mixture of 10Aa:16Aa:12A in a20:33:47 ratio (Table 2, entry 4). Considering that enolate 9, incomparison with 2-azaallylanion 4 and amide 15, is a sterically

less hindered substrate toward protonation, we next turned ourattention to the commercially available, steric bulky phenolderivative 4-chloro-2,6-dimethylphenol (17e). Indeed, 17e wasshown to be more effective than 17c in promoting the forma-tion of 10Aa (Table 2, entry 5 vs. 3). As we increased theloading of 17e from 10 mol % to 50 mol % and to 100 mol %, theformation of 10Aa increased in relation to 16Aa and 12A to reachthe optimal ratio of 85:12:3 (Table 2, entries 5–7). Although thereaction conversion decreased from 100% to 54% with catalyst 2cin 1.0 mol % loading, a complete reaction could be attained byincreasing the loading of 2c to 2.5 mol % while maintaining theoptimal chemoselectivity, the high diastereoselectivity, and theenantioselectivity of the tandem asymmetric reaction pathway(Table 2, entry 8).We applied 17e to the reaction of alkyl trifluoromethyl imine

3H and methacrolein 8a, and found that 17e also significantlyenhanced the desired tandem asymmetric conjugate addition–protonation reaction. Even in the presence of only 10 mol % of17e, the reaction with 2.5 mol % of 2c proceeded to completionto afford the desired amine product 10Ha as virtually the ex-clusive product and in high diastereo- and enantio-selectivity(Table 2, entry 9). This result represented a drastic improve-ment in chemoselectivity over that of the same 2c-mediatedreaction in the absence of 17e while retaining the high dia-stereoselectivity and enantioselectivity (Table 2, entry 9 vs.

Scheme 3. Carbon isotope effects study for 16Aa.

Table 2. Development of cocatalyst for control ofchemoselectivity

Entry 3 2c, mol %Cocatalyst,y mol % Conv., % 10 j 16 j 12 10 dr j ee%

1 3A 1.0 17a (10) 100 25 j 73 j 2 91:9 j 892 3A 1.0 17b (10) 100 17 j 81 j 2 91:9 j 903 3A 1.0 17c (10) 82 30 j 67 j 3 94:6 j 874 3A 1.0 17d (10) 27 20 j 33 j 47 –– j -–5 3A 1.0 17e (10) 100 40 j 58 j 2 95:5 j 926 3A 1.0 17e (50) 80 76 j 22 j 2 95:5 j 927 3A 1.0 17e (100) 54 85 j 12 j 3 94:6 j 928 3A 2.5 17e (100) 100 83 j 14 j 3 94:6 j 929† 3H 2.5 17e (10) 100 >95 j 5 j 0 86:14 j 93*Reactions were performed with 3 (0.05 mmol), 8a (0.10 mmol), cocatalyst (ymol %), and aqueous KOH (0.6 μL, 50 wt %, 10 mol %) in toluene (0.5 mL)with 2c (x mol %) at −20 °C.†Monitoring the reaction after 12 h, the ratio of 10 j 16 j 12 was determinedto be 94 j 6 j 0 and the dr of 10 decreased to 76/24. ee for the major di-astereomer of 10 was unchanged (93%).

Fig. 2. Potential reaction pathways analysis.

Table 1. Screening of chiral phase-transfer catalysts

Entry 3Catalyst,x mol % 10 j 16 j 12 10‡dr j ee% 16§dr j ee%

1 3A 2a (1.0) 5 j 93 j 2 –– j –– 98:2 j 922 3A 2b (1.0) 4 j 94 j 2 –– j –– 98:2 j 923 3A 2c (1.0) 3 j 95 j 2 –– j –– 98:2 j 944 3H 2a (1.0) 58 j 42 j 0 74:26 j 87 72:28 j 875 3H 2b (1.0) 41 j 59 j 0 75:25 j 87 75:25 j 876 3H 2c (1.0) 50 j 50 j 0 78:22 j 91 79:21 j 91*Reactions were performed with 3 (0.05 mmol), 8a (0.10 mmol), and aque-ous KOH (0.6 μL, 50 wt %, 10 mol %) in toluene (0.5 mL) with 2 (1.0 mol %)at −20 °C. All reactions proceeded to completion after 1 h.†Conversion, product ratio (10j16j12), and diastereoselectivity were deter-mined by 19F NMR analysis; see SI Appendix for details.‡The absolute configuration of 10Aa obtained from the 2c catalyzed reac-tion was determined to be (R, R); see SI Appendix for details.§The absolute configuration of 16Aa obtained from the 2c catalyzed reac-tion was determined to be (R, S, R); see SI Appendix for details.

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Table 1, entry 6). The fact that it is sufficient to use 17e in acatalytic amount indicates that it serves as cocatalyst, which isnecessary to enable the tandem asymmetric conjugate addition–protonation reaction.We applied this optimized protocol with both 2c and 17e to

mediate reactions of a broad range of trifluoromethyl imines andα-substituted enals. As summarized in Table 3, these reactionsproceeded to near completion in 0.5–1.5 h and in high chemo-,diastereo-, and enantioselectivity, after which the amino alde-hyde products 10 were converted to either amino alcohols 18 orN-benzyl amino alcohols 19. Aryl trifluoromethyl imines (3A-E)bearing either a para- or a meta substituent of varying electronicproperties were readily tolerated, and the tandem reactions ofthese imines with methacrolein afforded the desired chiral tri-fluoromethylated amines bearing 1,3 stereocenters in high yieldsand high ee (Table 3, entries 1–5). In addition, the reactionemploying a trifluoromethyl alkenyl imine (3F) also proceededin high diastereoselectivity, enantioselectivity, and exceedinglyhigh chemoselectivity in the presence of 30 mol % 17e and1.0 mol % 2c (Table 3, entry 6). Similarly high chemoselectivityand stereoselectivity could be attained with both 2c and 17e incatalytic amount for reactions of linear, α- and β-branched alkyl

trifluoromethyl imines and methacrolein (Table 3, entries 7–12).We also examined the scope of α-substituted enals and found thereaction also tolerated significant variations of the α-substituentin enals 8 (Table 3, entries 13–15). Importantly, the scope of thistandem asymmetric reaction could be extended to simple aldimines.As presented in Table 4, we have demonstrated that this tan-dem asymmetric reaction accepted aryl aldimines bearing ei-ther electron-withdrawing or -donating groups (Table 4, entries4–5). In addition, substituents at both para- and ortho positionson the phenyl ring were tolerated. Extending the aromatic ringfrom the phenyl to the naphthyl group was found to have no neg-ative impact on the reaction outcome (Table 4, entry 6). Signifi-cantly, synthetically useful diastereoselectivity and excellentenantioselectivity could be secured for the tandem reactionemploying a heteroaryl aldimine (Table 4, entry 7). In parallel,we also examined the impact of significantly extending the lengthof the α-substituent of the enal and found such variations werewell allowed (Table 4, entries 8–10). Notably, in contrast to the2c-catalyzed reaction of trifluoromethyl imine 3A with 8a, we didnot detect the formation of any [3 + 2] adduct. The only de-tectable side product was 14, a regioisomer of the desired product10. Nevertheless, the reaction proceeded with consistently high

Table 3. Substrate scope for reactions of trifluoromethyl imines with α-substituted enals

Entry 3 8 17e, mol % time (h) 10 j 16 j 12 dr (10) Yield, % dr (18 or 19) ee% (18 or 19)

1 3A 8a 100 1 83 j 14 j 3 94:6 76 (18Aa) 96:4 922 3B 8a 100 1 86 j 11 j 3 96:4 77 (18Ba) 96:4 933 3C 8a 100 1 80 j 15 j 5 94:6 74 (18Ca) 96:4 924 3D 8a 100 1.5 87 j 10 j 3 95:5 74 (18Da) 96:4 945 3E 8a 100 0.5 72 j 22 j 6 89:11 66 (18Ea) 90:10 936† 3F 8a 30 0.5 96 j 4 j 0 93: 7 89 (18Fa) 96:4 917 3G 8a 10 1 99 j 1 j 0 86:14 94 (19Ga) 86:14 948 3H 8a 10 1 98 j 2 j 0 85:15 91 (19Ha) 87:13 939 3I 8a 10 1 98 j 1 j 1 87:13 94 (19Ia) 90:10 9410 3J 8a 10 1 98 j 2 j 0 90:10 93 (19Ja) 94:6 8511 3K 8a 10 1 97 j 1 j 2 82:18 94 (19Ka) 89:11 9512‡ 3L 8a 10 1 99 j 1 j 0 88:12 89 (19La) 95:5 9213§ 3H 8b 20 1 96 j 4 j 0 83:17 88 (19Hb) 89:11 9114§ 3H 8c 20 1 96 j 4 j 0 79:21 80 (19Hc) 88:12 8915§ 3H 8d 20 1 94 j 6 j 0 76:24 79 (19Hd) 86:14 83

*Unless noted, reactions were performed with 3 (0.20 mmol), 8 (0.40 mmol), 17e (10–100 mol %), and aqueous KOH (2.2 μL, 50 wt %, 10 mol %) in toluene(2.0 mL) with 2c (2.5 mol %) at −20 °C.†Reaction was performed with 1.0 mol % of catalyst 2c.‡The absolute configuration of 10La obtained from the 2c catalyzed reaction was determined to be (R, R); see SI Appendix for details.§Reaction was performed with 5.0 mol % of catalyst 2c.

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regioselectivity (Table 4, entries 1–10). The elimination of the [3 +2] adduct as a side product in these tandem reactions with simplealdimines could be attributed to the lack of a tetra-substitutedcarbon center in the enolate intermediate 9 formed from theconjugate addition step. Without the Thorpe–Ingold effectcaused by such a tetra-substituted carbon center, the intra-molecular Mannich reaction was apparently slower than theprotonation reaction.In summary, we have realized an asymmetric tandem conjugate

addition–protonation reaction with imines as the nucleophile andα-alkyl acroleins as the electrophile. Mechanistic insights-guideddevelopment of a catalyst system employing a phenol derivativeand a cinchonium salt allows the control of chemoselectivity oftwo distinct intermediates. Consequently, the desired tandem re-action is established as the dominant pathway over severalside-reaction pathways, including those intrinsically preferred bysubstrate control. This asymmetric tandem reaction is highlystereoselective while tolerating a significant range of variations inboth the imines and the α-alkyl acroleins. Consequently it provides

a valuable synthetic approach for the direct asymmetric generationof chiral acyclic amines containing nonadjacent stereocenters.

MethodsThe opposite enantiomer of 10 (or 16) was obtained from the reactioncatalyzed by 2d (pseudoenantiomer of 2c; see SI Appendix for structure of2d). In Tables 1–3, conversion, product ratio (10j16j12), and diaster-eoselectivity (10, 18, and 19) were determined by 19F NMR analysis. In Table4, product ratio (10/14) and diastereoselectivity of 10were determined by 1HNMR analysis and diastereoselectivity of 20 was determined by both 1H NMRand HPLC analysis. Unless noted, the diastereomers in compounds 18, 19, 20were not separable upon flash-chromatography purification and isolated asa mixture of two diastereomers. ee of the major diastereomer for com-pounds 18, 19, 20 were measured by HPLC analysis. For details, please seeSI Appendix.

ACKNOWLEDGMENTS. We are grateful to Dr. Mark Bezpalko and Prof.Bruce Foxman for X-ray crystallographic characterizations of structures. Weare also grateful for financial support from National Institutes of Health(Grant GM-61591) and the Keck Foundation.

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Table 4. Substrate scope for reactions of aldimines with α-substituted enals

Entry 3 8 Time, h 10/14 dr (10) Yield, % dr (20) ee, % (20)

1 3M 8a 2.5 95/5 85:15 85 (20Ma) 86:14 952†,‡ 3N 8a 1.5 >95/5 92:8 84 (20Na) >95:5 933 3O 8a 4.0 >95/5 94:6 83 (20Oa) >95:5 984 3P 8a 4.0 74/26 75:25 65 (20Pa) 76:24 905§ 3Q 8a 2.5 95/5 74:26 51 (20Qa) 78:22 946 3R 8a 4.0 92/8 83:17 77 (20Ra) 92:8 967 3S 8a 2.5 >95/5 79:21 80 (20Sa) 87:13 968 3M 8b 1.5 95/5 91:9 89 (20Mb) >95:5 879 3N 8c 1.5 95/5 90:10 64 (20Nc) >95:5 8910 3M 8d 1.5 95/5 91:9 86 (20Md) 91:9 90

*Unless noted, reactions were performed with 3 (0.20 mmol), 8 (0.40 mmol), and aqueous KOH(2.2 μL, 50 wt %, 10 mol %) in toluene (2.0 mL) with catalyst 2c (2.5 mol %) at −20 °C.†Reaction was performed with 1.0 mol % of catalyst 2c.‡The absolute configuration of 10Na obtained from the 2c catalyzed reaction was determined to be(S, R), see SI Appendix for details.§Reaction was performed at 0 °C.

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