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Direct Catalytic Enantioselective Benzylation from Aryl Acetic Acids Patrick J. Moon, Zhongyu Wei, and Rylan J. Lundgren J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11390 • Publication Date (Web): 18 Nov 2018 Downloaded from http://pubs.acs.org on November 18, 2018
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Journal of the American Chemical Society
Direct Catalytic Enantioselective Benzylation from Aryl Acetic Acids Patrick J. Moon,† Zhongyu Wei,† Rylan J. Lundgren* Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada Supporting Information Placeholder ABSTRACT: We demonstrate that metal-‐catalyzed enantiose-‐ lective benzylation reactions of allylic electrophiles can occur directly from aryl acetic acids. The reaction proceeds via a pathway in which decarboxylation is the terminal event, oc-‐ curring after stereoselective carbon–carbon bond formation. This mechanistic feature enables enantioselective benzylation without the generation of a highly basic nucleophile. Thus, the process has broad functional group compatibility that would not be possible employing established protocols.
carbonyl substrates in aldol reactions and related additions to 2a, 7, 9 thus their larger potential in selective p-‐electrophiles, synthesis remains unrealized. A Decarboxylation Generates Reactive Intermediate R
– CO2 – H+
R'
R
Carboxylic acids are stable and abundant chemical feed-‐ stocks, making them ideal starting materials in chemical syn-‐ 1 thesis. The extrusion of CO2 from organic acids and their de-‐ rivatives is a key mechanistic step in both classical and emerg-‐ ing bond-‐forming methodologies used in the preparation of 2 functional molecules. Unmodified carboxylic acids are typi-‐ cally directly engaged in catalytic enantioselective processes through mechanistic pathways initiated by decarboxylation to generate a reactive intermediate. Ionic decarboxylation leads to a carbanion intermediate which can be intercepted stere-‐ 3 oselectively with electrophiles (Fig. 1a). Alternatively, single electron oxidation leads to the loss of CO2 by homolysis, gen-‐ eration of a radical species, and stereoselective trapping with 4 a chiral catalyst and a suitable reaction partner (Fig. 1a). In both these reaction manifolds, acid substrates that are other-‐ wise recalcitrant towards decarboxylation can be covalently 2f, modified by fragments that can undergo oxidative insertion 5 6 or those that induce homolysis in order to initiate reactivity. These indirect acid coupling strategies decrease overall pro-‐ cess economy and efficiency. A third mechanistic framework involves a stereoselective 7 bond-‐forming event prior to decarboxylation (Fig. 1b). As the selectivity-‐determining bond forming event is separate from the decarboxylation step, this pathway has potential ad-‐ vantage over methods relying upon the irreversible generation and trapping of reactive intermediates. Functionality that would quench highly nucleophilic species (protic groups, elec-‐ trophiles) or intercept radicals (p-‐systems, weak abstractable CH bonds) could be tolerated in this pathway, providing broad chemoselectivity and functional group compatibility – 8 hallmarks of enabling synthetic methodologies. The ability to induce an enantioselective metal-‐catalyzed cross-‐coupling event adjacent to a free carboxylate unit without irreversible interference from the acid itself however, presents a major dif-‐ ficulty. Efforts to exploit this type of reactivity have been re-‐ stricted to the use of malonic half esters and related a-‐carboxy
R
[cat]
R'
E R'
carbanion
– 1e –
CO2H
G
R
– CO2 – H+
R'
E+
R
CO2H
R
[cat]
R'
G R'
radical
• stereoselective trapping of reactive intermediate [challenging] • electrophiles, R• acceptors quench intermediate [chemoselectivity problem] B Decarboxylation Post Coupling Event R' R
X
CO2H
R' R
[cat]
R'
XH CO2H
R
– CO2
XH
• selectivity-determining step prior to decarboxylation [improved compatibility] • limited to addition reactions to polarized π-units [Aldol, Mannich] C Potential Mechanism for Decarboxylative Benzylation Ar
Ar
X
CO2H R'
R'
R
R
cat. [M] O
R'
Ar
O
– CO2
re-enters cycle
R
Ir- or Pdbased catalyst
III
R
X R'
= R
R'
O Ar R'
R
R
R' O
[M] R'
X
cat. [M] [M] =
OH
R'
R
I
O Ar
allylic alcohol derivative
R II
[M] cat. allylic alcohol derivatives X X R
• catalytic benzylation without a highly basic intermediate [tolerant to reactive functionality]
X
R • enantioselective generation of II not contingent on irreversible decarboxylation step
Figure 1. Mechanisms for enantioselective decarboxylative reac-‐ tions. (A) Ionic or radical paths. (B) Decarboxylation after ste-‐ reodetermining step. (C) Mechanistic hypothesis for an enanti-‐ oselective benzylation process from aryl acetic acids.
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In considering new transformations that could leverage the advantage of pre-‐decarboxylative coupling of acids in en-‐ antioselective catalysis, we questioned whether aryl acetic ac-‐ 10 ids could be used as benzylating reagents in metal-‐catalyzed asymmetric coupling reactions. In particular, we sought to de-‐ velop the stereocontrolled benzylation of allylic electro-‐ 11, 12 philes, owing to the diverse utility of chiral allylated prod-‐ ucts and the known ability of transition metals to affect nucle-‐ 13 ophile allylation processes. This approach would contrast methods that require stoichiometric quantities of strong base to generate highly reactive benzyl anions from 2-‐pyridinyl 14 15 substrates or Cr(CO)3 complexed toluenes. A pathway for the decarboxylative benzylation could in-‐ volve reversible metal-‐catalyzed carboxylate O-‐allylation from an allylic electrophile to generate an allyl aryl acetate (I in Fig. 1c). This species could undergo a second metal-‐catalyzed al-‐ lylic substitution at the enolate position to form a new car-‐ bon–carbon bond (II). Reversible O-‐deallylation via oxidative insertion would generate a new metal-‐allyl fragment for re-‐ entry into the catalytic cycle and liberate the functionalized carboxylic acid (III). At this stage, the decarboxylation event 3 3 would generate the benzylated C(sp )–C(sp ) coupled prod-‐ uct. As the key stereocenter is generated prior to decarboxyla-‐ tion, substrates less prone to CO2 extrusion could be subjected to reaction conditions to enable product formation without impacting the selectivity determining step (ie by heating). This strategy would allow for enantioselective benzylation to occur without the generation of a strongly basic, functional group-‐intolerant benzyl anion, enabling the reaction to occur 16 in the presence of protic and electrophilic groups. Further-‐ more, the process has the potential to be highly chemoselec-‐ tive for benzylic acids in the presence of other carboxylic acid groups typically employed in radical-‐ or ionic-‐decarboxylative cross-‐coupling reactions, should O-‐allylation be reversible 17, 18 over the course of the reaction. Fig. 2a provides an example of the enantioselective decar-‐ boxylative benzylation of allylic electrophiles. In the presence 19 of Ir-‐catalyst [Ir]-‐1 and DBU, the diacid substrate (1) under-‐ goes enantioselective coupling exclusively at the benzylic po-‐ sition to generate 2a without interference from the benzoic acid unit. Monitoring of reaction mixtures using a series of simpler aryl acetic acids clearly showed the rapid generation and slow decay of intermediate I which converts to II that is formed as an ultimately inconsequential mixture of diastere-‐ omers with high enantioselectivity at the allylic position. Spe-‐ cies II readily O-‐deallylates to form III which decarboxylates to give the chiral benzylated product. These observations, along with cross-‐over experiments, confirmed the mechanis-‐ tic hypothesis outlined in Fig 1c (see Fig S1-‐S2 in the SI for de-‐ tails). The generality of the approach is demonstrated with the benzylation of cyclic allylic electrophiles (3a) via Pd-‐catalysis 20 using a Trost-‐type system and BSA as the base (Fig. 2b). In cases where decarboxylation is not spontaneous at room tem-‐ perature, heating the reaction at 70–90 °C for short periods of time delivers product with high yield and no impact on enan-‐ tioselectivity (2b–2g, Fig. 2c). A comprehensive functional group compatibility survey showed the reaction proceeded with similar yields and enan-‐ tioselectivities in the presence of electrophilic and protic
Page 2 of 5
groups (aldehyde, ketone, free NH-‐groups, alkyl chloride, N-‐ Boc amino acid, alkyl alcohol, phenol, alternative carboxylic acids, conjugate acceptors, N-‐heterocycles Fig. 2d, see Figs S3– S5 for more examples). Many of these groups would quench or undergo other reactions with organometallic nucleophiles, or species generated upon single-‐electron oxidation, highlight-‐ ing the advantage of the current approach. A Ir-Catalyzed Decarboxylative Benzylation NO 2
Ph
DBU, rt – CO2
CO2H
HO 2C
NO 2
OBoc 5% [Ir]-1
HO 2C
1
Ph 2a 88%, 99% ee
B Pd-Catalyzed Decarboxylative Benzylation R OCO 2Me CO2H 5% Pd(dba) 2, 5.5% L1 BSA, 0ºC – CO2
O 2N
O 2N 3a 80%, 91% ee
C Post-Coupling Thermal Decarboxylation Ar
CO2H
Ph
Ar
[Ir]-1
CO2H
Ph
OBoc
heat
Ar
70 to 90 ºC – CO2
Ph
N
R N CN 2b 94%, >99% ee SO2Me 2c 90%, 99% ee CF3 2d 85%, 99% ee
N
N
2e 2f 60%, >99% ee 90%, 99% ee
2g 75%, 99% ee
D Functional Group Compatibility Me
CHO
Br
Bpin
OH
CO2H
N H N
O Ph
N Boc
Me O
Ph
HO 6
NH 2 Ph
Ir
Ph
L1
O P
O
O Me [Ir]-1
Ar Ar = 2-OMeC6H 4
OH
EtOH CO2Me [5% by vol.]
Ph
ClO 4
N Ar
Me
CO2H
O NH HN P Ph 2
P Ph 2
Cl 8
Me Me
Ph
compatibility 1 equiv. of additive: 2b obtained in >65% y, 97% ee 99% ee [B]
O 2N
O O S
O
HO 2C
NO 2
2w R’ = NH 2 86%, 99% ee [2 steps] 2x R’ = Cl 52%, 98% ee [3 steps] 2y R’ = H 66%, 97% ee [3 steps] [R = 3-Br-C6H 4]
R’
N Me 2v 80%, >99% ee [B]
EtO 2C
2u 85%, 99% ee [B]
2s 67%, >85% ee [A] a
2r 61% (ee nd) [A]
O
MeO
O O
NO 2
N
2q 78%, >99% ee [B]
Me Me i-PrO
O
HO 2C
N
2p 58%, 98% ee [B]
NO 2
2m 95%, 99% ee [A] a 87%, 98% ee [B]
2l 76%, >99% ee [B]
O
F
2o 77%, 98% ee [B]
2t 74%, >99% ee [A]
2g 75%, 99% ee [A] a 90%, 99% ee [B] CN
2k 70%, 99% ee [A]
CF3
F 3C
HO
N
NO 2 I
2n 77%, 97% ee [B]
[Ir]-1Ar = 2-OMeC6H 4 [Ir]-2 Ar = Ph
H
2h 2i 85%, 99% ee [A] a 82%, 99% ee [B] 0.1 mol% [Ir-1] 65%, 99% ee [B] a CF3 Cl NO 2 Br
Me
Ar
N 2f 90%, 99% ee [A] a 93%, 97% ee [B]
2e 60%, >99% ee [A] a 61%, >99% ee [B]
O
O
Ar
N
2d 85%, 99% ee [A] a 65%, 99% ee [B]
O
O 2N
P N
R
F 3C
2c 90%, 99% ee [A] a 87%, 99% ee [B]
O
Ir
N 2b 94%, >99% ee [A] a 85%, 99% ee [B]
ClO 4
Ar
O
DBU, THF, rt [then heat]
R
[condition A]
Ph
O
1% [Ir]-2
allylic partner [Ar = 4-(NO2)-C6H 4 or indicated] Br
O Cl
F 3C
MeO
4a 94%, 98% ee [B]
4b 78%, 98% ee [B]
Cl
F
Br
4h 75%, 90% ee [B]b
4g 90%, 93% ee [B]
Me
4d 74%, 98% ee [B]
N 4i 80%, 94% ee [B]
S
N
4m R’ = NO 2 83%, 97% ee [B] 4n R’ = CN 66%, 99% ee [B] 4o R’ = NH 2 86%, 98% ee [2 steps]
R’
O
BocHN
4c 91%, 95% ee [B]
4j 86%, 96% ee [B] NC
4e 85%, 98% ee [B]
4f 86%, 99% ee [B] 3 gram scale
Me
BzO
4k 78%, 99% ee [B]
4l 80%, 97% ee [B]
MeO 2S
NC
N Me 4p 68%, >99% ee [B]
BocHN
Me 4q 64%, >99% ee [B]
4r 50%, >99% ee [B]
Me 4s 65%, 99% ee [B]
B Scope: Pd-Catalyzed Decarboxylative Benzylation
Ar
5% Pd(dba) 2 5.5% L1
MeO 2CO CO2H
BSA, DCE, rt [then heat]
[condition A] O 2N
3a 80%, 91% ee [A]b
Ar
Ac
3b 73%, 84% ee [B]
L1
5% Pd(dba) 2 5.5% L1 BSA, DCE, rt [then heat]
NC
3c 91%, 89% ee [A]
O
O
NH HN
Ar
O
P Ph 2
[condition B] CN
3d 99%, 88% ee [A]
N N 3e 84%, 86% ee [B]
O
P Ph 2
N 3f 73%, 86% ee [B]
Figure 3. Scope of the enantioselective decarboxylative benzylation (A) Ir-‐catalyzed process (B) Pd-‐catalyzed process. Unless noted, yields are of isolated material. See SI for complete details. aYield determined by 1H NMR using an internal standard; bConducted at 0 °C.
be easily accessed in reasonable yield by nitro group manipu-‐ lations (52–86% yield, 97–99% ee 2w, 2x, 2y). The allyl frag-‐ ment can vary in structure and also host a number of poten-‐ tially reactive functional groups without significant change to process efficiency (halogens, NH-‐groups, N-‐ and S-‐heterocy-‐ cles, 90–99% ee). Alkyl-‐ substituted allylic electrophiles are competent partners, giving access to simple methyl 4m–4p), long-‐chain alkyl (4k, 4q), and heteroatom-‐substituted (4l, 4r) 22 chiral benzylated products. Pd-‐catalyzed processes can be used to access benzylated cyclic allylic stereocenters with
slightly lower selectivity (83–91% ee), but similarly broad scope of aryl acetic acid partner from either allylic carbonates or allylic ester electrophiles (3a–3f). The use of this method to access high-‐value, chiral ben-‐ zylated intermediates of importance to human health was demonstrated by the expedient preparation of the core frag-‐ ments of Elacestrant and Taranabant (Fig 4). Briefly, conden-‐ sation between aryl acetic acids and suitably functionalized al-‐ lylic alcohols, followed by Ir-‐catalyzed enantioselective
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OMe
1. EDCl, DMAP 2. 2% [Ir]-1, DBU
Ar HO
CO2H R
51%, 99% ee [2 steps]
O 2N
5a
1. Zn, MeOH 2. t-BuONO, CuCl 3. [Pd], TBHP 4. L-Selectride
1. EDCl, DMAP 2. 0.5% [Ir]-2, DBU 71%, 99% ee [2 steps] 2.3 grams
1. GH-II 2. Pd/C, H 2 3. NaNO 2, H 2O
OMe
4f
H
5b 76%, 99% ee [3 steps]
HO
OMe
Elacestrant
H
EtN
HO
Et
NH
Taranabant CN
Br O 2N
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Cl
HO
Br 5c 40%, 98% ee Me [4 steps]
Cl
HN O
Me O
N
Me Me
Figure 4. Applications: Synthesis of the cyclic core of Elacestrant and a late-‐stage intermediate of Taranabant, see the SI for details.
decarboxylative benzylation gives effectively single-‐enantio-‐ mer products (5a, 4f both 99% ee) primed for conversion to bioactive targets, including at multi-‐gram scale. Ring-‐closing metathesis, hydrogenation, and Sandmeyer hydroxylation converts 5a to cyclic product 5b which bears the chiral core of 23 Elacestrant. Conversion of the nitro group in 4f to chlorine, 24 followed by ketone-‐selective Wacker oxidation and diaster-‐ oselective reduction gives product 5c, which can be converted 25 to (ent)-‐Taranabant via an established route. The enantioselective benzylation of allylic electrophiles, directly from aryl acetic acids has been established. The reac-‐ tion proceeds via a pathway in which decarboxylation is the terminal event, occurring after stereoselective carbon–carbon bond formation, enabling the tolerance of protic and electro-‐ philic functionality. Collectively, these studies show this ap-‐ proach has value in generating carbon–carbon bonds with high levels of enantioselectivity in the presence of complex chemical functionality.
Supporting Information Experimental procedures and compound characterization data. This material is available free of charge via the Internet at http://pubs.acs.org.
Corresponding Author *
[email protected] † These authors contributed equally
ACKNOWLEDGMENT We thank S. Bachman and D. Hall for helpful analysis of this manuscript. We are grateful to NSERC Canada (Discovery Grant to R.J.L., CGS fellowships to P.J.M), the Killam Trusts (I.W.K. fellowship to P.J.M) and the Canadian Foundation for Innovation for support of this work.
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Journal of the American Chemical Society 12. For examples of enantioselective allylic alkylations using alkyl-zinc reagents, see: (a) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M., IridiumCatalyzed Enantioselective Allylic Alkylation with Functionalized Organozinc Bromides. Angew. Chem. Int. Ed. 2015, 54, 7644; (b) Petrone, D. A.; Isomura, M.; Franzoni, I.; Rossler, S. L.; Carreira, E. M., Allenylic Carbonates in Enantioselective Iridium-Catalyzed Alkylations. J. Am. Chem. Soc. 2018, 140, 4697. 13. (a) Trost, B. M.; VanVranken, D. L., Asymmetric transition metalcatalyzed allylic alkylations. Chem. Rev. 1996, 96, 395; (b) Hartwig, J. F.; Stanley, L. M., Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution Acc. Chem. Res. 2010, 43, 1461. (c) Grange, R. L.; Clizbe, E. A.; Evans, P. A., Recent Developments in Asymmetric Allylic Amination Reactions. Synthesis 2016, 48, 2911. (d) Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M., Intermolecular Stereoselective Iridium-Catalyzed Allylic Alkylation: An Evolutionary Account Synlett, DOI: 10.1055/s-0037-1610217 14. (a) Trost, B. M.; Thaisrivongs, D. A.; Hartwig, J., Palladium-catalyzed asymmetric allylic alkylations of polynitrogen-containing aromatic heterocycles. J. Am. Chem. Soc. 2011, 133, 12439; (b) Liu, X. J.; You, S. L., Enantioselective Iridium-Catalyzed Allylic Substitution with 2Methylpyridines. Angew. Chem. Int. Ed. 2017, 56, 4002; (c) Murakami, R.; Sano, K.; Iwai, T.; Taniguchi, T.; Monde, K.; Sawamura, M., PalladiumCatalyzed Asymmetric C(sp(3))-H Allylation of 2-Alkylpyridines. Angew. Chem. Int. Ed. 2018, 57, 9465. 15. Mao, J. Y.; Zhang, J. D.; Jiang, H.; Bellomo, A.; Zhang, M. N.; Gao, Z. D.; Dreher, S. D.; Walsh, P. J., Palladium-Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles. Angew. Chem. Int. Ed. 2016, 55, 2526. 16. For chemoselective carbonyl addition reactions that proceed via the catalytic generation of metal-allyl nucleophiles, see: (a) Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische, M. J., Catalytic Enantioselective C-H Functionalization of Alcohols by Redox-Triggered Carbonyl Addition: Borrowing Hydrogen, Returning Carbon. Angew. Chem. Int. Ed. 2014, 53, 9142; (b) Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.; Krische, M. J., Metal-catalyzed reductive coupling of olefin-derived nucleophiles: Reinventing carbonyl addition. Science 2016, 354, 300 (and references therein). 17. For reports that aryl acetic esters similar in structure to proposed intermediate I are suitable nucleophiles in metal-catalyzed enantioselective allylic alkylations, see: (a) Schwarz, K. J.; Amos, J. L.; Klein, J. C.; Do, D. T.; Snaddon, T. N., Uniting C1-Ammonium Enolates and Transition Metal Electrophiles via Cooperative Catalysis: The Direct Asymmetric alphaAllylation of Aryl Acetic Acid Esters. J. Am. Chem. Soc. 2016, 138, 5214;
(b) Jiang, X. Y.; Beiger, J. J.; Hartwig, J. F., Stereodivergent Allylic Substitutions with Aryl Acetic Acid Esters by Synergistic Iridium and Lewis Base Catalysis. J. Am. Chem. Soc. 2017, 139, 87. 18. During our studies, Kanai reported that allylic esters can undergo Pd/B catalyzed fragmentation and recombination to generate chiral homoallylic acids (analogous to the conversion of I to III with linear allylic substitution): Fujita, T.; Yamamoto, T.; Morita, Y.; Chen, H. Y.; Shimizu, Y.; Kanai, M., Chemo- and Enantioselective Pd/B Hybrid Catalysis for the Construction of Acyclic Quaternary Carbons: Migratory Allylation of OAllyl Esters to alpha-C-Allyl Carboxylic Acids. J. Am. Chem. Soc. 2018, 140, 5899. 19. (a) Kiener, C. A.; Shu, C. T.; Incarvito, C.; Hartwig, J. F., Identification of an activated catalyst in the iridium-catalyzed allylic amination and etherification. Increased rates, scope, and selectivity. J. Am. Chem. Soc. 2003, 125, 14272; (b) Lipowsky, G.; Miller, N.; Helmchen, G., Regio- and enantioselective iridium-catalyzed allylic alkylation with in situ activated P,C-chelate complexes. Angew. Chem. Int. Ed. 2004, 43, 4595. See the SI for optimization details. 20. Trost, B. M.; Fandrick, D. R., Palladium-catalyzed dynamic kinetic asymmetric allylic alkylation with the DPPBA ligands. Aldrichimica Acta 2007, 40, 59. 21. For scope examples using cinnamyl derivatives, only the branched regioisomer was observed. For allylic acetates bearing long-chain linear alkyl groups, the linear regioisomer is observed as a minor product (typically
