Tuning the Reactivity of Ketones through Unsaturation: Construction of

Subscriber access provided by WESTERN SYDNEY U

Article

Tuning the Reactivity of Ketones through Unsaturation: Construction of Cyclic and Acyclic Quaternary Stereocenters via Zn-ProPhenol Catalyzed Mannich Reactions Barry M. Trost, Chao-I (Joey) Hung, and Elumalai Gnanamani ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04685 • Publication Date (Web): 11 Jan 2019 Downloaded from http://pubs.acs.org on January 12, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Tuning the Reactivity of Ketones through Unsaturation: Construction of Cyclic and Acyclic Quaternary Stereocenters via Zn-ProPhenol Catalyzed Mannich Reactions Barry M. Trost,* Chao-I (Joey) Hung, Elumalai Gnanamani Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States.

ABSTRACT: Introduction of unsaturation adjacent to the carbonyl drastically improves the reactivity of the Zn-ProPhenol catalyzed Mannich reactions between N-carbamoyl imines and abranched ketones. Despite only a small change in the substrate acidity, the bimetallic catalyst can preferentially recognize and activate unsaturated ketones over their fully saturated counterparts, providing a chemo-, diastereo- and enantioselective route to valuable β-aminoketones bearing both cyclic and acyclic quaternary stereocenters, which are common motifs in numerous biologically active alkaloids. Unsaturated ketones and imines with various substitution patterns are viable substrates, and the reaction can be performed on multi-millimole scale at low catalyst loading without impacting its efficiency. More importantly, the unsaturation introduced via the nucleophile provides a useful platform for structural diversification.

ACS Paragon Plus Environment

1

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 23

KEYWORDS: Catalysis; Asymmetric Catalysis; Zinc; ProPhenol; Quaternary Stereocenters; Mannich Reactions.

1. Introduction One of the major goals for modern synthetic chemists is transforming readily available materials into complex targets with high efficiency, selectivity, and atom-economy.1 Among numerous developed methodologies, C−C bond formation through enolate chemistry is one of the most fundamental and broadly utilized. Over the past decade, significant progress in this field has been made - not only in achieving excellent efficiency and stereocontrol among diverse substrates, but also in developing processes that no longer require stoichiometric activation of either the nucleophilic or electrophilic partners.2 Ketones are important and valuable nucleophiles in this area of active research. Their propensity to act as nucleophiles mainly depends on the ease and readiness of enolization, which strongly correlates with the intrinsic pKa of the α-protons. In this context, introducing an electron-withdrawing component adjacent to the carbonyl group - such as an α,β-unsaturated moiety - should, in principle, increases the rate of enolization due to its higher s character than an alkyl group.3 Although being minimal, this subtle change in acidity can indeed be exploited if a catalyst or reagent can effectively recognize and differentiate one enolizable site over the other.


2

Page 3 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Our initial interest in this concept derived from an unsuccessful attempt to perform a regioselective Mannich reaction with 2-methylcyclohexanone A at the more substituted position using the Zn-ProPhenol catalyst (Scheme 1b).4 Although our group recently demonstrated the utility of this bimetallic complex for generating quaternary stereocenters via Mannich reactions (Scheme 1a),4c,d A exhibited low reactivity as well as regioselectivity for the less sterically hindered position. To eliminate the problem of regioselectivity for the Zn-ProPhenol-catalyzed process, another experiment was conducted using 2,6-dimethylcyclohexanone B as the pronucleophile. Even in refluxing toluene with 20 mol% catalyst loading, no desired reactivity was detected between the two reaction partners. To date, selective generation of more substituted enolates for nucleophilic additions in asymmetric catalysis remains underexplored,5 and efforts toward such a Mannich process have been particularly limited.6 Moreover, most methods require the use of an electron-withdrawing substituent, such as an aryl or vinyl group, at the α-position of the carbonyl instead of a simple alkyl chain. The lack of reactivity using A and B can be attributed to the low acidity of the fully saturated ketones. We strategized that we could overcome this problem by introducing an alkenyl moiety adjacent to the carbonyl group, believing that the newly adjusted pKa would be amenable to deprotonation by the Zn-ProPhenol catalyst (Scheme 1c). If installation of the alkene indeed enables catalytic enolization, the unsaturated moiety can also serve as a blocking group to overcome the problem of regioselectivity.7 After facilitating the nucleophilic addition, the unsaturation can then be transformed into other functional groups, including a fully saturated alkane by simple hydrogenation. For these reasons, we decided to evaluate cyclic ketones bearing either endo- or exocyclic olefins adjacent to the carbonyl. For acyclic ketones, an alkynyl moiety is a more attractive activating and blocking group due to higher s character and versatility


3

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 23

for structural derivation of alkynes relative to alkenes. However, to achieve high stereoselectivity, the catalyst must exert good control over enolate geometry, which can be highly challenging when two substituents are similar in size.8 Moreover, to the best of our knowledge, the use of α-branched ynones as nucleophiles in asymmetric catalysis has never been reported.9

Scheme 1. Background information and reaction development The proposed Mannich reaction utilizing unsaturated α-branched ketones is highly attractive. First, it can potentially be employed to construct biologically active alkaloids featuring a quaternary stereocenter adjacent to a nitrogen moiety (Scheme 1d).10 For example, isoquinolinetype alkaloids isolated from Corydalis bulleyana Diels, including (+)-corynoline and (+)-12-


4

Page 5 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

hydroxycorynoline, exhibit potent anti-inflammatory effects by regulating the production of NO, TNF-a, IL-6, and IL-1b.10c,d Additionally, aspidofractinine alkaloids isolated from Kopsia singapurensis, including kopsimalines A and kopsiloscine J, have been shown to reverse multidrug-resistance in vincristine-resistant KB cells.10e Second, the formation of quaternary carbons is still an immense challenge in asymmetric catalysis.11 Despite significant advances,12 the construction of quaternary stereocenters via direct Mannich reactions has been largely restricted to highly activated pronucleophiles, including 1,3-dicarbonyl and α-cyanocarbonyl compounds (Scheme 1e).13 3-Substituted oxindoles are also frequently utilized to generate C3quaternary oxindoles that are applicable to the syntheses of natural products and pharmaceutical molecules.14 To the best of our knowledge, there are only two reports by other groups using nonactivated enolate precursors. The first is a proline-catalyzed process using branched aldehydes developed by Barbas and co-workers.15 Despite exhibiting great reactivity and enantioselectivity in most cases, this method is restricted to N-PMP-protected glyoxylate ethyl ester as the electrophile, and the reaction generally proceeds with moderate diastereoselectivities. The second process is an organosuperbase-catalyzed Mannich reaction between thionolactones and N-aryl-ketimines. This method offers products featuring vicinal tetrasubstituted stereocenters in high yields and stereoselectivities, although only 5-membered thionolactones were utilized.16 2. Results and Discussion We initiated our studies with enone 1a, which can be readily synthesized in one step via an aldol condensation, as the model pronucleophile (Table 1).17 N-Cbz aldimine 2a was selected as the electrophile not only due its potential for bidentate coordination with the Zn-ProPhenol catalyst, but also its easy and chemoselective cleavability under mild hydrogenolysis conditions.


5

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 23

When 1.2 equivalents of 1a reacted with aldimine 2a in the presence of 10 mol% Zn-(R,R)-L1 in refluxing ether (entry 1), the desired Mannich adduct 3a was obtained in low conversion and selectivities, presumably due to low substrate solubility. Table 1. Optimization of the reaction conditionsa

drb

ee (%)c

1.2:1

6

50

4:1

89

42

4.3:1

92

45

45

7.2:1

85

PhMe

45

60

9:1

86

THF

45

70

16:1

98

10

THF

60

>95

16:1

97

5

THF

60

95d

>20:1

99

entry

x

solvent Et2O

temp. (°C) 45

conv. (%)b 20:1 dr and 99% ee. More sterically hindered systems were also tolerated, affording o-bromo 3c and 1napthyl 3d adducts in excellent enantio- and diastereoselectivity. Notably, N-Boc imines gave similar results to the Cbz counterparts; 3i (N-Cbz) and 3a (N-Boc) were obtained with identical selectivities, allowing the use of orthogonal protecting group strategies. Furthermore, this process is not restricted to aromatic imines; cyclopropyl (3h) and vinyl (3j and 3k) systems were well-tolerated, generating Mannich adducts in 85-95 % yield with excellent enantio- and diastereoselectivity. Other readily enolizable aliphatic imines; however, did not offer the desired Mannich adducts. To establish the absolute stereochemistry, we obtained a crystal structure of adduct 3b, and the stereochemical outcome of all other products was assigned by analogy. Other exocyclic enones 2 were also viable pronucleophiles for this transformation (Scheme 2b), offering five-membered ring 3l, furylidene 3m, and propylidene 3n adducts as single diastereomers in good to excellent yields and up to 99% ee. Furthermore, the process is not restricted to exocyclic systems. Due to their ease of preparation, the endocyclic enones were employed to investigate the effects of substituents α- to the carbonyl group (Scheme 2c). With small substituents, such as a methyl or propargyl group, adducts 3o and 3p were obtained in high yields and excellent stereoselectivities. Interestingly, when bigger groups were installed, a noticeable decrease in diastereoselectivity was observed, with allyl 3q and isobutenyl 3r Mannich adducts forming in 11:1 and 9:1 dr, respectively. Analogous to the exocyclic systems, the substituent on the olefin is not restricted to a simple phenyl group (Scheme 2d). Vinylogous thioester 3t, which can potentially undergo a Stork-Danheiser transposition to the corresponding


8

Page 9 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

enone, was obtained in 99% ee.18 Additionally, alkynyl adduct 3u was obtained in 92% yield and 99% ee, providing a versatile handle for structural elaboration. Finally, simple cyclic enones, including methyl cyclohexenone, methyl cycloheptenone, and methyl cyclooctenone were viable substrates (Scheme 2e), affording adducts 3v, 3w, and 3x in high yields and selectivities. The greater reactivity of methyl cyclohexanone to generate 3v in contrast to A and B (Scheme 1b) under nearly identical reaction conditions demonstrates that the subtle change in the acidity of αprotons is indeed recognized and differentiated by the Zn-ProPhenol catalyst. To further demonstrate the superiority of unsaturated ketones over the fully saturated ones using our catalytic system, a competition experiment between 2-methylcycloheptenone 2m and 2-methylcycloheptanone C was performed under the optimized conditions (Scheme 3). 2m was fully consumed and adduct 3w was formed in 70% yield and >20:1 dr. On the other hand, saturated ketone C remained largely intact, and none of the corresponding Mannich adducts were detected. The results clearly indicate that Zn-ProPhenol exhibits high chemoselectivity towards the unsaturated ketones.

Scheme 3. Competition experiment between enone 2m and ketone C For acyclic systems, the more electron-withdrawing alkynes on the pronucleophiles can be used as the activating groups to generate the Mannich adducts 5 (Scheme 4). First, we investigated the scope of imines 1 (Scheme 4a). Since ynones 4 are more readily enolizable


9

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 23

under our catalytic system than the corresponding enones 2 - presumably due to the higher s character of the acetylenic moiety - these reactions reach full conversion at room temperature or below. In general, a variety of N-Boc and N-Cbz aldimines successfully reacted under our optimized reaction conditions to afford highly functionalized chiral β-amino ketones 5a-5i. Electron-withdrawing and electron-donating groups were tolerated on the aromatic ring, and heteroaromatic imines participated as well. As with the cyclic nucleophiles, this reaction is not restricted to aromatic imines; vinyl imine was utilized to afford adduct 5f in 76% yield and 88% ee. Next, we evaluated other substituents at the acetylenic moiety of the pronucleophiles (Scheme 4b). Adduct 5k with a cyclohexenyl group was obtained in similar yield and enantioselectivity to the analogous phenyl Mannich adduct 5a. An alkyl substituent was also tolerated, affording 5j in good yield despite a slight decrease in enantioselectivity. Pleasingly, an alkynyl group can be installed to generate the corresponding diyne adduct 5l in reasonable yield and ee. Pronucleophiles featuring cyclic substituents at the enolizable site were also successfully employed (Scheme 4c). Cyclohexyl adduct 5m was generated in 88% yield and 85% ee. Notably, the triethylsilyl group in 5m can potentially be removed to liberate the terminal alkyne for subsequent functionalization. Surprisingly, the catalytic system can also effectively activate an α-cyclobutyl ketone to generate the corresponding Mannich adduct 5n in high yield and enantioselectivity. To the best of our knowledge, this is the first successful application of such a ketone enolate in asymmetric catalysis. Finally, by using unsymmetrical ynones (R3 ≠ R4) 4 (Scheme 4d), our system can furnish Mannich adducts featuring an acyclic quaternary stereocenter in addition to a chiral secondary


10

Page 11 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

amine. Despite the small steric difference between a methyl and benzyl group, 5o was generated as a single diastereomer in 84% yield and 99% ee. Similar results were observed for sterically comparable systems (5p and 5q). These outstanding results show that the catalyst can effectively control the enolate geometry. In alkyl-versus-phenyl cases, electronically differentiated ligand (S,S)-L2 was required to achieve high diastereoselectivity, affording adducts 5r in 72% yield and 12:1 dr and 5s in 85% yield and 16:1 dr, while (S,S)-L1 generally gave an inferior dr around 2:1.

a

Conditions: imine 1 (0.15 mmol), ynone 4 (0.125 mmol), (S,S)-L1 (0.0125 mmol), Et2Zn (1.0 M in hexanes, 0.025 mmol), and 3

Å molecular sieves (5 mg) in THF (0.2 M) at rt for 16 h. bReaction ran at 4 °C for 24 h. c(S,S)-L2 was used as the ligand.

Scheme 4. Scope of the reaction using α-branched alkynyl ketonesa


11

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 23

In addition to exhibiting broad scope and providing valuable products featuring a quaternary stereocenter in high enantiomeric purity, our process is scalable, and millimole-scale reactions could be performed utilizing both cyclic and acyclic ketones at decreased catalyst loading without impacting yield or selectivity (Scheme 5). Using 2.5 mol% Zn-(S,S)-L1, methyl cycloheptenone 2m reacted with N-Cbz imine 1a to afford 3w in 88% yield, >20:1 dr, and 95% ee. Notably, 79% of ligand L1 was recovered via simple acid-base extraction, further reducing the effective catalyst loading. Using 5 mol% of Zn-(S,S)-L1, acyclic ketone 4h reacted with NCbz imine 1i to afford 5p in 76% yield, >20:1 dr, and 95% ee, and 82% of L1 was recovered using the same extraction protocol. Finally, 4k successfully reacted with imine 1a to afford adduct 5s in 82% yield, 11:1 dr, and 99% ee. In this case, 75% of L2 was recovered via chromatography.

Scheme 5. Millimole-scale reactions and recovery of ligands After establishing the scope of this reaction, we then further elaborated the Mannich products (3 and 5) to demonstrate their synthetic utility (Scheme 6). Using conditions reported by


12

Page 13 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Lipshutz and coworkers,19 adduct 3w was reduced to ketone 6 in 98% yield using a silane as the hydride source while leaving the Cbz and ketone groups intact. Notably, only 1 mol% of Cu(OAc)2 and 0.1 mol% of dppBz (1,2-bis(diphenylphosphino)benzene) were required to reach full conversion. The generation of fully saturated ketone 6 demonstrates a highly efficient and selective approach to products from direct functionalization of ketone C at the more sterically hindered position. Using a similar strategy, a Pd-C catalyzed hydrogenation offered ketone 7 in 95% yield, formally achieving the selective functionalization of acyclic ketone D. Highlighting the versatility of the ynone, the Mannich adducts 5 were transformed into several structural derivatives. In the presence of 5 mol% IPrAuNTf2, a 6-endo-dig cyclization occurred to convert 5p into piperidone 8 featuring a quaternary stereocenter in 97% yield. Spiroheterocycle 10 was generated quantitatively using the same NHC Au-catalyst. It is noteworthy that many spirocyclic nitrogen-containing compounds, such as CCR1 antagonist E, demonstrate unique pharmaceutical properties.20


13

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 23

Scheme 6. Synthetic applications Condensation of 5p with hydrazine monohydrate in EtOH furnished pyrazole 9 in 72% yield, while a Ru-catalyzed [2+2+2] cycloaddition between diyne 5s and 1-hexyne offered indanone 11 in 73% yield as a single regioisomer.21 Compounds with similar structural motifs, such as NPS receptor antagonist E, exhibit potential biological activity.22


14

Page 15 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Scheme 7. Proposed transition-states for the Mannich processes Based on the absolute and relative configuration of 3b as determined by X-ray crystallographic analysis, we propose a model to rationalize the stereochemical outcome of the reaction (Scheme 7). After enolization of the pronucleophile 2a, the N-Cbz imine 1b enters the reaction cycle and binds to the catalyst in bidentate fashion, while minimizing steric interactions with the diphenyl-prolinol motifs. The reaction partners can adopt two possible six-membered transition states (TS-1 and TS-2). The energetically more favorable chair-like TS-1 leads to the observed Mannich adduct 3b. For acyclic systems such as adduct 5p, the imine 1i adopts the same bidentate coordination to the catalyst. The pronucleophile 4h, on the other hand, can


15

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 23

generate two possible regioisomeric enolates and both can adopt a six-membered chair-like transition state (TS-3 and TS-4). In this case, TS-3 is more favorable since the (E)-enolate minimizes 1,3-diaxial interactions with the bulky Boc group, generating 5p as the major product. 3. Conclusion In summary, we have developed a highly efficient Mannich reaction between N-carbamoyl imines and simple α-branched ketones catalyzed by Zn-ProPhenol. Key to this strategy is the introduction of unsaturation on one side of the ketone pronucleophiles, which drastically improves the reactivity and overcomes the challenge of regioselectivity at the more substituted position. The ability of the catalyst to selectively recognize and activate unsaturated ketones over the fully saturated counterparts was further demonstrated by a competition experiment between 2-methylcycloheptenone 2m and 2-methylcycloheptanone C (Scheme 3). Overall, the subtle change in acidity due to installation of unsaturation on the ketone pronucleophiles allows enantio- and diastereoselective access to a broad range of functionalized β-amino ketones featuring cyclic or acyclic all-carbon quaternary stereogenic centers. Moreover, this methodology can be run on millimole-scale with low catalyst loading and easy recovery of the ProPhenol ligands. Furthermore, two convenient and orthogonal protecting groups on the imine can be employed without impacting the reaction efficiency. Finally, the alkenes and alkynes introduced via the unsaturated nucleophiles can be further elaborated to a broad range of structural derivatives, including the fully saturated systems via simple reduction. The application of this chemo- and stereoselective Mannich strategy to the synthesis of alkaloids or nitrogencontaining pharmaceuticals bearing a quaternary stereocenter contiguous to an amine is a major goal of our future efforts and will be reported in due course.


16

Page 17 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

AUTHOR INFORMATION Corresponding Author *[email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. Supporting Information Supporting information includes experiment details, compound characterization data, spectra, and crystallographic data. The following files are available free of charge via the Internet at http://pubs.acs.org. Experiment details and compound characterization data (PDF) NMR spectra (PDF) Crystallographic data (CIF)

Acknowledgements We thank Dr. Jana Maclaren (Stanford University) for X-ray crystallographic analysis and Dr. Stephen Lynch (Stanford University) for conducting NOE experiments. We also thank Christopher Kalnmals (Stanford University) for technical assistance. Finally, C-I. H. acknowledges support from the William S. Johnson Fellowship.


17

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 23

REFERENCES 1.

Trost, B. M. The Atom Economy - a Search for Synthetic Efficiency. Science 1991, 254, 1471–1477.

2.

For selected reviews, see: (a) Mahrwald, R. Modern Methods in Stereoselective Aldol Reactions; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2013; pp. 293-375. (b) Notz, W.; Tanaka, F.; Barbas, C. F. Enamine-Based Organocatalysis with Proline and Diamines: the Development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels-alder Reactions. Acc. Chem, Res. 2004, 37, 580–591. (c) Saito, S.; Yamamoto, H. Design of Acid-Base Catalysis for the Asymmetric Direct Aldol Reaction. Acc. Chem, Res. 2004, 37, 570–579. (d) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471–5569. (e) MacMillan, D. W. C. The Advent and Development of Organocatalysis. Nature 2008, 455, 304-308. (f) Han, S. B.; Hassan, A.; Krische, M. J. Diastereo- and Enantioselective Reductive Aldol Addition of Vinyl Ketones via Catalytic Hydrogenation. Synthesis 2008, 2008, 2669–2679. (g) Trost, B. M.; Brindle, C. S. The Direct Catalytic Asymmetric Aldol Reaction. Chem. Soc. Rev. 2010, 39, 1600-1632. (h) Gati, W.; Yamamoto, H. Second Generation of Aldol Reaction. Acc. Chem, Res. 2016, 49, 1757–1768. (i) Yamashita, Y.; Yasukawa, T.; Yoo, W.-J.; Kitanosono, T.; Kobayashi, S. Catalytic Enantioselective Aldol Reactions. Chem. Soc. Rev. 2018, 47, 4388–4480.

3.

Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N. R. Equilibrium Acidities of Carbon Acids. VI. Establishment of an Absolute Scale of Acidities in Dimethyl Sulfoxide Solution. J. Am. Chem. Soc. 1975, 97, 7006–7014.

4.

(a) Trost, B. M.; Bartlett, M. J. ProPhenol-Catalyzed Asymmetric Additions by Spontaneously Assembled Dinuclear Main Group Metal Complexes. Acc. Chem. Res. 2015, 48, 688–701. (b) Trost, B. M.; Ito, H. A Direct Catalytic Enantioselective Aldol Reaction via a Novel Catalyst Design. J. Am. Chem. Soc. 2000, 122, 12003– 12004. (c) Trost, B. M.; Saget, T.; Hung, C.-I. Direct Catalytic Asymmetric Mannich Reactions for the Construction of Quaternary Carbon Stereocenters. J. Am. Chem. Soc. 2016, 138, 3659–3662. (d) Trost, B. M.; Hung, C.-I.; Saget, T.; Gnanamani, E. Branched Aldehydes as Linchpins for the Enantioselective and Stereodivergent Synthesis of 1,3-Aminoalcohols Featuring a Quaternary Stereocentre. Nat. Cat. 2018, 1, 523– 530. (e) Trost, B. M.; Hung, C.-I.; Scharf, M. J. Direct Catalytic Asymmetric Vinylogous Additions of α,β- and β,γ-Butenolides to Polyfluorinated Alkynyl Ketimines. Angew. Chem. Int, Ed. 2018, 57, 11408–11412.


18

Page 19 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

5.

(a) Pousse, G.; Le Cavelier, F.; Humphreys, L.; Rouden, J.; Blanchet, J. Brønsted Acid Catalyzed Asymmetric Aldol Reaction: a Complementary Approach to Enamine Catalysis. Org. lett. 2010, 12, 3582–3585. (b) Kang, J. Y.; Carter, R. G. Primary Amine, Thiourea-Based Dual Catalysis Motif for Synthesis of Stereogenic, AllCarbon Quaternary Center-Containing Cycloalkanones. Org. let. 2012, 14, 3178–3181. (c) Kano, T.; Hayashi, Y.; Maruoka, K. Construction of a Chiral Quaternary Carbon Center by Catalytic Asymmetric Alkylation of 2Arylcyclohexanones Under Phase-Transfer Conditions. J. Am. Chem. Soc. 2013, 135, 7134–7137. (d) Chen, W.; Chen, M.; Hartwig, J. F. Diastereo- and Enantioselective Iridium-Catalyzed Allylation of Cyclic Ketone Enolates: Synergetic Effect of Ligands and Barium Enolates. J. Am. Chem. Soc. 2014, 136, 15825–15828. (e) Yang, X.; Phipps, R. J.; Toste, F. D. Asymmetric Fluorination of α-Branched Cyclohexanones Enabled by a Combination of Chiral Anion Phase-Transfer Catalysis and Enamine Catalysis Using Protected Amino Acids. J. Am. Chem. Soc. 2014, 136, 5225–5228. (f) Horinouchi, R.; Kamei, K.; Watanabe, R.; Hieda, N.; Tatsumi, N.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers Through the Primary Amine-Catalyzed Michael Addition Reaction of α-Substituted Cyclic Ketones at High Pressure. Eur. J. Org. Chem. 2015, 2015, 4457–4463. (g) Yang, X.; Toste, F. D. Asymmetric Addition of αBranched Cyclic Ketones to Allenamides Catalyzed by a Chiral Phosphoric Acid. Chem. Sci. 2016, 7, 2653– 2656.

6.

For a single example of Mannich reaction, see: Yang, X.; Toste, F. D. Direct Asymmetric Amination of αBranched Cyclic Ketones Catalyzed by a Chiral Phosphoric Acid. J. Am. Chem. Soc. 2015, 137, 3205–3208.

7.

For the use of olefins as blocking groups on one side of a ketone, see: (a) Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W. M. The Total Synthesis of Steroids 1. J. Am. Chem. Soc. 1952, 74, 4223– 4251. (b) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. An Improved Catalyst for the Asymmetric Arylation of Ketone Enolates. J. Am. Chem. Soc. 2002, 124, 1261–1268. (c) Kano, T.; Hayashi, Y.; Maruoka, K. Construction of a Chiral Quaternary Carbon Center by Catalytic Asymmetric Alkylation of 2Arylcyclohexanones Under Phase-Transfer Conditions. J. Am. Chem. Soc. 2013, 135, 7134–7137.

8.

(a) Doyle, A. G.; Jacobsen, E. N. Enantioselective Alkylation of Acyclic a,a-Disubstituted Tributyltin Enolates Catalyzed by a {Cr(salen)} Complex. Angew. Chem. Int. Ed. 2007, 46, 3701–3705. (b) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Enantio- and Diastereodivergent Dual Catalysis: α-Allylation of Branched Aldehydes. Science 2013, 340, 1065–1068. (c) Minko, Y.; Marek, I. Stereodefined Acyclic Trisubstituted Metal


19

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 23

Enolates Towards the Asymmetric Formation of Quaternary Carbon Stereocentres. Chem. Commun. 2014, 50, 12597–12611. 9.

For leading examples of using linear ynones as nucleophiles in asymmetric catalysis, see: (a) Trost, B. M.; Fettes, A.; Shireman, B. T. Direct Catalytic Asymmetric Aldol Additions of Methyl Ynones. Spontaneous Reversal in the Sense of Enantioinduction. J. Am. Chem. Soc. 2004, 126, 2660–2661. (b) Silva, F.; Sawicki, M.; Gouverneur, V. Enantioselective Organocatalytic Aldol Reaction of Ynones and Its Synthetic Applications. Org. Lett. 2006, 8, 5417–5419. (c) Shi, S.-L.; Kanai, M.; Shibasaki, M. Asymmetric Synthesis of Dihydropyranones from Ynones by Sequential Copper(I)-Catalyzed Direct Aldol and Silver(I)-Catalyzed Oxy-Michael Reactions. Angew. Chem. Int. Ed. 2012, 51, 3932–3935. (d) Trost, B. M.; Hung, C.-I. Broad Spectrum Enolate Equivalent for Catalytic Chemo-, Diastereo-, and Enantioselective Addition to N-Boc Imines. J. Am. Chem. Soc. 2015, 137, 15940–15946. (e) Liu, W.; Zou, L.; Fu, B.; Wang, X.; Wang, K.; Sun, Z.; Peng, F.; Wang, W.; Shao, Z. A Multifaceted Directing Group Switching Ynones as Michael Donors in Chemo-, Enantio-, and γ-Selective 1,4Conjugate Additions with Nitroolefins. J. Org. Chem. 2016, 81, 8296–8305. (f) Peng, S.; Wang, Z.; Zhang, L.; Zhang, X.; Huang, Y. Streamlined Asymmetric α-Difunctionalization of Ynones. Nat. Commun. 2018, 9, 375.

10. (a) Jin, Z. Amaryllidaceae and Sceletium alkaloids. Nat. Prod. Rep. 2013, 30, 849–868. (b) Hao, H.; Qicheng, F. Chemical Study on Alkaloids from Corydalis Bulleyana. Planta Med. 1986, 52, 193–198. (c) Kim, D. K. Inhibitory Effect of Corynoline Isolated from the Aerial Parts of Corydalis Incisa on the Acetylcholinesterase. Arch. Pharmacal Res. 2002, 25, 817–819. (d) Yang, C.; Zhang, C.; Wang, Z.; Tang, Z.; Kuang, H.; Kong, A.-N. T. Corynoline Isolated from Corydalis Bungeana Turcz. Exhibits Anti-Inflammatory Effects via Modulation of Nfr2 and MAPKs. Molecules 2016, 21. 975–989. (e) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama, K.; Kam, T.-S. Biologically Active Aspidofractinine Alkaloids from Kopsia Singapurensis. J. Nat. Prod. 2008, 71, 53–57. 11. For selected reviews, see: (a) Das, J. P.; Marek, I. Enantioselective Synthesis of All-Carbon Quaternary Stereogenic Centers in Acyclic Systems. Chem. Commun. 2011, 47, 4593–4623. (b) Quasdorf, K. W.; Overman, L. E. Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocentres. Nature 2014, 516, 181–191. (c) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740–751. (d) Büschleb, M.; Dorich, S.; Hanessian, S.; Tao, D.; Schenthal, K. B.;


20

Page 21 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Overman, L. E. Synthetic Strategies Toward Natural Products Containing Contiguous Stereogenic Quaternary Carbon Atoms. Angew. Chem. Int. Ed. 2016, 55, 4156–4186. (e) Zeng, X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Catalytic Enantioselective Desymmetrization Reactions to All-Carbon Quaternary Stereocenters. Chem. Rev. 2016, 116, 7330–7396. 12. For selected reviews, see: (a) Shibasaki, M.; Yoshikawa, N. Lanthanide Complexes in Multifunctional Asymmetric Catalysis. Chem. Rev. 2002, 102, 2187–2210. (b) Córdova, A. The Direct Catalytic Asymmetric Mannich Reaction. Acc. Chem. Res. 2004, 37, 102–112. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471–5569. (d) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Organocatalysed Asymmetric Mannich reactions. Chem. Soc. Rev. 2008, 37, 29–41. (e) Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N. Recent Progress in Asymmetric Bifunctional Catalysis Using Multimetallic Systems. Acc. Chem. Res. 2009, 42, 1117–1127. (f) Vesely, J.; Rios, R. Enantioselective Methodologies Using N-Carbamoyl-Imines. Chem. Soc. Rev. 2014, 43, 611–630. (g) Kumagai, N.; Shibasaki, M. Recent Advances in Catalytic Asymmetric C–C Bond-Forming Reactions to Ketimines Promoted by Metal-Based Catalysts. BCSJ 2015, 88, 503–517. 13. For leading examples, see: (a) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A. Direct Organocatalytic and Highly Enantio- and Diastereoselective Mannich Reactions of α-Substituted αCyanoacetates. Angew. Chem. Int. Ed. 2005, 44, 2896–2899. (b) Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Catalytic Asymmetric Addition of β-Ketoesters to Various Imines by Using Chiral Palladium Complexes. Angew. Chem. Int. Ed. 2005, 44, 1525–1529. (c) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Which is the Actual Catalyst: Chiral Phosphoric Acid or Chiral Calcium Phosphate? Angew. Chem. Int. Ed. 2010, 49, 3823–3826. (d) Hatano, M.; Horibe, T.; Ishihara, K. Chiral Lithium(I) Binaphtholate Salts for the Enantioselective Direct Mannich-Type Reaction with a Change of Syn/Anti and Absolute Stereochemistry. J. Am. Chem. Soc. 2010, 132, 56–57. (e) Bahlinger, A.; Fritz, S. P.; Wennemers, H. Stereoselective Metal-Free Synthesis of β-Amino Thioesters with Tertiary and Quaternary Stereogenic Centers. Angew. Chem. Int. Ed. 2014, 53, 8779–8783. (f) Yurino, T.; Aota, Y.; Asakawa, D.; Kano, T.; Maruoka, K. NBoc-Aminals as Easily Acessible Precursors for Less Accessible N-Boc-Imines: Facile Synthesis of Optically Active Propargylamine Derivatives Using Mannich-Type Reactions. Tetrahedron 2016, 72, 3687–3700. (g)


21

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 23

You, Y.; Zhang, L.; Cui, L.; Mi, X.; Luo, S. Catalytic Asymmetric Mannich Reaction with N-Carbamoyl Imine Surrogates of Formaldehyde and Glyoxylate. Angew. Chem. Int. Ed. 2017, 56, 13814–13818. 14. (a) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Organocatalytic Stereoselective Mannich Reaction of 3Substituted Oxindoles. Org. Lett. 2008, 10, 3583–3586. (b) Cheng, L.; Liu, L.; Jia, H.; Wang, D.; Chen, Y.-J. Enantioselective Organocatalytic Anti-Mannich-Type Reaction of N-Unprotected 3-Substituted 2-Oxindoles with Aromatic N-Ts-Aldimines J. Org. Chem. 2009, 74, 4650–4653. (c) He, R.; Ding, C.; Maruoka, K. Phosphonium Salts as Chiral Phase-Transfer Catalysts: Asymmetric Michael and Mannich Reactions of 3Aryloxindoles Angew. Chem. Int. Ed. 2009, 48, 4559–4561. (d) Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Amino-Indanol-Catalyzed Asymmetric Michael Additions of Oxindoles to Protected 2-Amino-1Nitroethenes for the Synthesis of 3,3'-Disubstituted Oxindoles Bearing α,β-Diamino Functionality J. Org. Chem. 2011, 76, 4008–4017. (e) Shimizu, S.; Tsubogo, T.; Xu, P.; Kobayashi, S. Calcium-Catalyzed Asymmetric Synthesis of 3-Tetrasubstituted Oxindoles: Efficient Construction of Adjacent Quaternary and Tertiary Chiral Centers. Org. Lett. 2015, 17, 2006–2009. (f) Torii, M.; Kato, K.; Uraguchi, D.; Ooi, T. Chiral Ammonium Betaine-Catalyzed Asymmetric Mannich-Type Reaction of Oxindoles. Beilstein J. Org. Chem. 2016, 12, 2099– 2103. (g) Jin, Q.; Zheng, C.; Zhao, G.; Zou, G. Enantioselective Direct Mannich Reactions of 3-Substituted Oxindoles Catalyzed by Chiral Phosphine via Dual-Reagent Catalysis. Tetrahedron 2018, 74, 4134–4144. 15. Chowdari, N. S.; Suri, J. T.; Barbas, C. F. Asymmetric Synthesis of Quaternary α- and β-Amino Acids and βLactams via Proline-Catalyzed Mannich Reactions with Branched Aldehyde Donors. Org. Lett. 2004, 6, 2507– 2510. 16. Takeda, T.; Kondoh, A.; Terada, M. Construction of Vicinal Quaternary Stereogenic Centers by Enantioselective Direct Mannich-Type Reaction Using a Chiral Bis(guanidino)iminophosphorane Catalyst. Aryloxindoles. Angew. Chem. Int. Ed. 2016, 55, 4734–4737. 17. Thanigaimalai, P.; Lee, K.-C.; Sharma, V. K.; Rao, E. V.; Roh, E.; Kim, Y.; Jung, S.-H. Structural Requirements of (E)-6-Benzylidene-4a-methyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one Derivatives as Novel Melanogenesis Inhibitors. Bioorganic Med. Chem. Lett. 2011, 21, 1922–1925. 18. (a) Stork, G.; Danheiser, R. L. Regiospecific Alkylation of Cyclic β-Diketone Enol Ethers. General Synthesis of 4-Alkylcyclohexenones. J. Org. Chem. 1973, 38, 1775–1776. (b) Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Enantioselective Total Synthesis of (+)-Cassiol. Org. Lett. 2009, 11, 293–295.


22

Page 23 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

19. Baker, B. A.; Bosković, Z. V.; Lipshutz, B. H. (BDP)CuH: a "Hot" Stryker's Reagent for Use in Achiral Conjugate Reductions. Org. Lett. 2008, 10, 289–292. 20. (a) Gardner, D. S.; Santella, J. B.; Duncia, J. V.; Carter, P. H.; Dhar, T. G. M.; Wu, H.; Guo, W.; Cavallaro, C.; van Kirk, K.; Yarde, M.; Briceno, S. W.; Grafstrom, R. R.; Liu, R.; Patel, S. R.; Tebben, A. J.; Camac, D.; Khan, J.; Watson, A.; Yang, G.; Rose, A.; Foster, W. R.; Cvijic, M. E.; Davies, P.; Hynes, J. The discovery of BMS457, a Potent and Selective CCR1 Antagonist. Bioorganic Med. Chem. Lett. 2013, 23, 3833–3840. (b) Smith, A. C.; Cabral, S.; Kung, D. W.; Rose, C. R.; Southers, J. A.; García-Irizarry, C. N.; Damon, D. B.; Bagley, S. W.; Griffith, D. A. The Synthesis of Methyl-Substituted Spirocyclic Piperidine-Azetidine (2,7-Diazaspiro3.5nonane) and Spirocyclic Piperidine-Pyrrolidine (2,8-Diazaspiro4.5decane) Ring Systems. J. Org. Chem. 2016, 81, 3509– 3519. 21. Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. Ruthenium(II)-Catalyzed Selective Intramolecular [2 + 2 + 2] Alkyne Cyclotrimerizations. J. Am. Chem. Soc. 2003, 125, 12143–12160. 22. Fretz, H; Gatfield, J; Isler, M; Kimmerlin, T; Koberstein, R; Lyothier, I; Monnier, L; Pothier, J; Valdenaire, A. Indanone and Indandione Derivatives and Heterocyclic Analogs. WO2013068785 (A1), May 16, 2013.


23

Tuning the Reactivity of Ketones through Unsaturation: Construction of

Recommend Documents