Ruthenium-Catalyzed Dynamic Kinetic Resolution Asymmetric Transfer Hydrogenation of β-Chromanones by an Elimination-Induced Racemization Mechanism

Article abstract of DOI:10.1021/acscatal.6b03191

Chiral chroman derivatives are important pharmacophores in natural and synthetic bioactive molecules. The discovery of catalytic asymmetric methods for the synthesis of these compounds is an important goal. Ruthenium-catalyzed asymmetric transfer hydrogenation under strongly basic conditions has been found to induce dynamic kinetic resolution of β-substituted chromanones, producing valuable chromanols in high yields and with high levels of stereocontrol. The reaction proceeds by base-catalyzed racemization of the β-stereocenter through a conjugate elimination/conjugate addition pathway in concert with a highly selective ketone transfer hydrogenation step. Computational analysis of the catalyst, substrate, and transition state structures has revealed the driving interactions for diastereoselectivity as well as unexpected CH-O stabilizing interactions between the catalyst sulfonamide and the reacting substrate.

Full text of DOI:10.1021/acscatal.6b03191

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Article
Ruthenium-Catalyzed Dynamic Kinetic Resolution
Asymmetric Transfer Hydrogenation of #-Chromanones
by an Elimination-Induced Racemization Mechanism
Eric R Ashley, Edward C. Sherer, Barbara Pio, Robert K. Orr, and Rebecca Tamra Ruck
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03191 • Publication Date (Web): 09 Jan 2017
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RutheniumꢀCatalyzed Dynamic Kinetic Resolution
Asymmetric Transfer Hydrogenation of βꢀ
Chromanones by an EliminationꢀInduced
Racemization Mechanism
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Eric R. Ashley,* † Edward C. Sherer,* † Barbara Pio, ‡ Robert K. Orr, † Rebecca T. Ruck†
†Process Research and Development, MRL, Merck & Co., Inc., Rahway, NJ USA
‡Discovery Chemistry, MRL, Merck & Co., Inc., Kenilworth, NJ USA
ABSTRACT: Chiral chroman derivatives are important pharmacophores in natural and synthetic
bioactive molecules. The discovery of catalytic asymmetric methods for the synthesis of these
compounds is an important goal. Rutheniumꢀcatalyzed asymmetric transfer hydrogenation under
strongly basic conditions has been found to induce dynamic kinetic resolution of βꢀsubstituted
chromanones, producing valuable chromanols in high yields and with high levels of
stereocontrol. The reaction proceeds by baseꢀcatalyzed racemization of the βꢀstereocenter
through a conjugate elimination/conjugate addition pathway in concert with a highly selective
ketone transfer hydrogenation step. Computational analysis of the catalyst, substrate, and
transition state structures has revealed the driving interactions for diastereoselectivity as well as
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unexpected CHꢀO stabilizing interactions between the catalyst sulfonamide and the reacting
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substrate.
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KEYWORDS: Dynamic kinetic resolution • asymmetric transfer hydrogenation • chroman • βꢀ
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epimerization • ruthenium
1. Introduction
Dynamic kinetic resolution (DKR) has become a powerful class of reactions for the synthesis
of complex chiral molecules, allowing multiple stereocenters to be set in a single transformation
from readily available racemic starting materials.1 Wellꢀknown examples include DKR
reductions of αꢀchiral ketones, which proceed through enolizationꢀinduced substrate
racemization (e.g. rac-1 to R,R-3, Scheme 1).2 DKR reductions of βꢀchiral ketones (e.g. rac-4 to
R,R-6), however, are rare and have required eliminationꢀinduced epimerization of a stereocenter
distal to the activating carbonyl moiety in order to achieve substrate racemization.3,4
Scheme 1. Prior art of DKR ketone reductions.
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In the context of our ongoing interest in the synthesis of valuable chroman pharmacophores,
we envisioned extending the DKR ketone reduction strategy to an important class of βꢀchiral
chromanones (7, Scheme 2). Inspired by Liu’s dynamic asymmetric phthalide reduction3 as well
as several related βꢀDKR examples,4 we hypothesized that chromanone epimerization could be
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achieved under basic conditions via βꢀelimination to form achiral enone 8, which could convert
back to either enantiomer of the starting material by conjugate addition.5Further inspired by
Metz’s rhodiumꢀcatalyzed kinetic resolution of flavanones,6 we expected that an appropriate
asymmetric transfer hydrogenation (ATH) catalyst would reduce chromanone enantiomer S-7 to
cisꢀchromanol S,S-9 while leaving R-7 untouched.We hypothesized that torsional strain7 in the
proꢀtrans transition state, as well as possible steric clash between the catalyst and the substrate’s
βꢀsubstituent, would inhibit reduction of the mismatched enantiomer R-7 and allow both
substrate enantiomers to funnel to a single product stereoisomer.
Scheme 2. Design of a DKRꢀATH of βꢀchiral chromanones via eliminationꢀinduced
racemization and torsional diastereocontrol.
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2. Results and Discussion
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To investigate the proposed DKRꢀATH, we subjected racemic chromanone 10 to modified
Noyori transfer hydrogenation conditions using ruthenium catalyst 12,8 13 equivalents of
triethylamine, and 10 equivalents of formic acid (Table 1, entry 1).9 The reduction was efficient
and highly enantioselective; however, chromanol 11 was isolated as a 1:1 cis:trans mixture,
indicating that no racemization had occurred under these conditions. After screening a variety of
bases, we were delighted to find that simply replacing triethylamine with 1,8ꢀ
diazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) allowed facile racemization10 (entry 2), and the desired
isomer S,S-11 was generated in 89% yield, 19:1 dr, and near perfect ee. The reaction proved
tolerant of a variety of solvents (entries 2 to 5) and the quantity of DBU and formic acid could be
reduced (entry 6). Moreover, the cis:trans ratio could be improved by reducing catalyst loading
to 1 mol% (entry 7); the slower reduction rate at lower catalyst loading allowed for racemization
to outꢀcompete reduction of the mismatched enantiomer. Lastly, a variety of Noyoriꢀtype
ruthenium catalysts performed well with TsDENEB complex 12 and TsDPENꢀmesitylene
complex 16 giving the best results (entries 7 and 13).
Table 1. DKR optimization studies.
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Entry
1
Solvent
iꢀPrOH
iꢀPrOH
ACN
B[a]
B:FA[b]
Catalyst
12 (2.5)
12 (2.5)
12 (2.5)
12 (2.5)
12 (2.5)
12 (2.5)
12 (1.0)
12 (1.0)
13 (1.0)
14 (1.0)
15 (1.0)
16 (1.0)
16 (1.0)
Assay yield
89%
cis:trans
1:1
cis ee
99%[c]
99%
99%
99%
99%
99%
99%
99%
99%
99%
99%
99%
99%
Et3N
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
13:10
13:10
13:10
13:10
13:10
5:2
2
89%
19:1
21:1
24:1
26:1
19:1
30:1
24:1
25:1
10:1
11:1
14:1
16:1
3
86%
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MeOH
DMF
ACN
87%
5
89%
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90%
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ACN
5:2
94%
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ACN
4:2
90%
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ACN
4:2
77%
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12
13
ACN
4:2
77%
ACN
4:2
72%
ACN
4:2
85%
ACN
5:2
93%
[a] Base. [b] Ratio of base to formic acid in equivalents. [c] Cis-11 99% ee, trans-11 98% ee.
We then investigated the scope of substrates that could be utilized in this novel DKR
transformation (Table 2). A wide range of alkyl substituents are viable at the chromanone 2ꢀ
position, including the full steric range from methyl to tertꢀbutyl (17, 19, 10, and 21) as well as
potentially reactive carbamates 23 and 25 and methyl ester 27. Excellent results were also
obtained with a wide range of arene substitution. Halogens are wellꢀtolerated at the chromanone
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6 and 7 positions. Substitution with highly electron withdrawing nitriles or strongly donating
methoxy groups also produced useful substrates (33, 35, 37, and 39), although modifications of
the base and base:formic acid ratio were necessary to balance the rates of racemization and
reduction.
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Importantly, the reaction was not limited to 2ꢀalkyl chromanones. Both flavanone 41 and Nꢀ
tosyl tetrahydroquinolone 43 could be reduced to highly enantioenriched products.11 The scope
also could be extended to disubstituted systems. β,βꢀDisubstituted chromanone 45 was reduced
to chromanol 46 with excellent enantioselectivity and modest diastereoselectivity. Moreover,
tricyclic chromanones 47 and 49 were exemplary substrates, forming allꢀcis chromanols 48 and
50 with excellent selectivity. Notably, these reactions set three contiguous stereocenters in a
single transformation.
Table 2. Substrate scope.
Isolated
Substrate
Product[a]
Cat
DBU: FA
dr
ee
Yield
17 (R=Me)
19 (R=iꢀBu)
10 (R=iꢀPr)
21 (R=tꢀBu)
18 (R=Me)
20 (R=iꢀBu)
11 (R=iꢀPr)
22 (R=tꢀBu)
16[b]
16[b]
12[b]
16[b]
5:2
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5:2
5:2
89%
86%
88%
96%
17:1
23:1
30:1
16:1
>99%
>99%
>99%
96%
16[b]
5:2
86%
>50:1 >99%
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16[b]
5:2
85%
79%
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>99%
>99%
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5:2
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12[c]
8:2
5:2
83%
78%
84%
80%
12:1
28:1
14:1
19:1
>99%
98%
12[b]
12[c,d] 12:4[h]
>99%
93%
12[c]
12:4
3:3
12[b]
96%
84%
82%
71%
>50:1 >99%
12[b]
4:3
28:1
16:1
10:1
94%
16[b,f] 3:3
>99%
95%
16[c,e] 5:2
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12[b,g] 8:5
90%
2.3:1
>99%[i]
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79%
>50:1 >99%
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16[c,e] 5:2
10:1
96%
[a] Substrate (1.0 mmol) and catalyst (1.0 mol%) were warmed with DBU and formic acid in
either ACN or DMF (4 mL) at 40 C for 24 h. [b] ACN. [c] DMF. [d] 70 C. [e] 2.0 mol%
catalyst. [f] 0.5 mol% catalyst. [g] 2.5 mol% catalyst. [h] 7ꢀMethylꢀ1,5,7ꢀ
o
o
triazabicyclo[4.4.0]decꢀ5ꢀene (MTBD) as base. [i] Both diastereomers >99% ee.
We were surprised by the observation of allꢀcisꢀchromanol 50 from the DKRꢀATH of substrate
49, given that the synthesis of substrate49 had yielded exclusively the trans
isomer.12Mechanistically, one can envision 50 arising via CurtinꢀHammett kinetics with rapid
reduction of minor quantities of cisꢀ49 formed under the epimerizing conditions (Scheme 3).
However, the chemoꢀ, diastereoꢀ, and enantioselective reduction of a single enantiomer of a
minor substrate diastereomer is remarkable and inspired us to further investigate the
stereochemical control elements of this reaction.
Scheme 3. Formation of all cis chromanol 50 under CurtinꢀHammett kinetics.
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To better understand the diastereoselectivity of these reactions we undertook a computational
investigation of the transition state architectures. We built our understanding with substrate 17
by analyzing transition states of the optimal catalyst geometry with four versions of the substrate,
specifically pseudoequatorial and pseudoaxial conformers of the R and S enantiomers (Figure
1).13For this reaction the lowest energy transition state 17A-R proceeds from the Rꢀ
pseudoequatorial chromanone toward the experimentally observed 2R,4Sꢀchromanol 18. 17A-R
exhibits a low energy staggered conformation around the reacting carbonyl and positions the βꢀ
methyl group in an open area away from the catalyst. The structure further shows a stabilizing
CHꢀπ interaction from the benzylic protons of the catalyst η6ꢀmesityl group to the substrate aryl
ring,14 a hydrogen bond from the forming alkoxide to the rutheniumꢀbound amine,15,16 and two
CHꢀO hydrogen bonds from the substrate C2 and C3 positions to the sulfonamide oxygens.
These CHꢀO hydrogen bonds appear important for proper substrate orientation and
stabilization.17
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Figure 1. Transition states for the DKRꢀATH of chromanone 17 (H = white, C = grey, N = blue,
O = red, S = yellow, Ru = green, Cl = lime).
The remaining transitions states for the ATH of 17 are markedly higher in energy than 17A-R.
17B-R and 17A-S are destabilized by torsional strain around the reducing CO bond. 17B-S has a
low energy staggered conformation around the reducing carbonyl, but the pseudoaxial βꢀmethyl
group clashes with the catalyst. Taken together, the correlation of these conformations and
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transition state energies supports the hypothesis that torsional strain is an important driver of
diastereoselectivity. Interaction of the catalyst with the pseudoaxial group at C2, either a
stabilizing CHꢀO hydrogen bond or a destabilizing alkyl steric clash, also appears important for
high selectivity.
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Figure 2. Transition states for the DKRꢀATH of chromanone 49 (H = white, C = grey, N = blue,
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O = oxygen, S = yellow, Ru = green).
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We then turned to the intriguing case of substrate transꢀ49, which produced allꢀcisꢀproduct 50
in the DKRꢀATH. Transition state 49-cis-RS(Figure 2)is favored by 2.68 kcal/mol over 49-
trans-RR, while the remaining transition states are dramatically higher in energy. 49-cis-RS is
essentially identical in structure to the low energy transition state 17A-R and exhibits the same
stabilizing interactions. Comparatively, in 49-trans-RR the orientation of the extra ring αꢀ
carbon forces the substrate to tilt away from the catalyst sulfonamide and the sulfonamide to
rotate toward the η6ꢀmesitylene. In order to accommodate this shift, the common CHꢀπ
interaction from the substrate arene to the benzylic proton of the catalyst mesitylene is disrupted
and replaced by an interaction with the mesitylene aromatic proton, allowing overall lesser
stabilization of 49-trans-RR relative to 49-cis-RS. The alternative trans structure 49-trans-SS is
destabilized by torsional strain, while transition state 49-cis-SR, in which the added ring projects
directly into the catalyst architecture, is least favorable and exhibited strain in stationary point
searches.
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Having developed a thorough understanding of the stereochemical underpinnings of the DKRꢀ
ATH, we investigated the practical aspects of this reaction. We first developed a oneꢀpot
through process for the cyclocondensation DKRꢀATH of acetophenone 51 and aldehyde 52,
which converted these simple starting materials directly to chromanol 24 with high yield and
exquisite stereocontrol (Scheme 4). Chromanol 24 was advanced to cis methyl ether 53 by
alkylation with iodomethane and to trans ether 54 by mesylation followed by displacement with
methanol. The free chroman 55 was generated by reduction with triethylsilane in the presence of
TFA via the intermediacy of a benzylic carbocation. Similarly, generation of the benzylic
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carbocation followed by trapping with dimethoxybenzene formed arylated chroman 56, a
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structure reminiscent of the Myristin class of natural products.18
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Scheme 4. Practical aspects of the chromanone DKRꢀATH.
3. Conclusions
We have discovered and developed a unique combination of baseꢀcatalyzedβꢀepimerization
and rutheniumꢀcatalyzed asymmetric transfer hydrogenation that enables facile reductive
dynamic kinetic resolution of βꢀsubstituted chromanones. Torsional strain and novel CHꢀO
sulfonamide hydrogen bonds have been shown to be important drivers of substrate preference
and stereoselectivity. These efficient and practical reactions provide access to a wide range of
synthetically useful chromanols and constitute a substantial advance in the nascent field of β–
DKR methods.
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ASSOCIATED CONTENT
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Supporting Information.
Supporting Information Available: Experimental details, analytical data, and supporting
calculations (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Eric R. Ashley* Eꢀmail: eric_ashley@merck.com
Edward C. Sherer* Eꢀmail: edward_sherer@merck.com
ACKNOWLEDGMENT
We thank Melissa Lin for NMR characterization, Wendy Zhong, Xiaoxia Qian, and Ye Tian
for HRMS support, and Scott Borges for chiral method development.
REFERENCES
[1]
Selected recent reviews: a) Echeverria, P.ꢀG.; Ayad, T.; Phansavath, P.; Ratovelomananaꢀ
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[11] For the DKRꢀATH of flavanone the use of equimolar amounts of DBU and formic acid is
necessary to limit conjugate reduction of the hydroxychalcone intermediate.
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[12] DFT calculations indicate that cisꢀ49 is approximately 0.51 kcal/mol higher in energy than
transꢀ49. See supporting information.
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[13] See supporting information for catalyst and substrate ground states and a discussion of
computational methods.
[14] Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem. Int. Ed.2001, 40, 2818–2821.
[15] Gas phase calculations converge to a concerted transition state, while solution phase
calculations indicate a stepwise process. Geometric differences in the transition states are
negligible. See reference 15 and supporting information.
[16] a) Dub, P.A.; Ikariya, T. J. Am. Chem. Soc.2013, 135, 2604–2619. b) Dub, P.A.; Henson,
N.J.; Martin, R.L.; Gordon, J. C. J. Am. Chem. Soc.2014, 136, 3505–3521. c) Dub, P. A.;
Gordon, J. C. J. Chem. Soc. Dalton Trans.2016, 45, 6756–6781.
[17] To our knowledge this is the first identification of these CHꢀO interactions in an ATH
transition state.
[18] Maloney, D. J.; Deng, J.ꢀZ.; Starck, S. R.; Gao, Z.; Hecht, S. M. J. Am. Chem. Soc.2005,
127, 4140–4141.
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