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Letter
Incorporation of Axial Chirality into PhosphinoImidazoline Ligands for Enantioselective Catalysis Paulo H. S. Paioti, Khalil A. Abboud, and Aaron Aponick ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00133 • Publication Date (Web): 15 Feb 2017 Downloaded from http://pubs.acs.org on February 16, 2017
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ACS Catalysis
Incorporation of Axial Chirality into Phosphino-Imidazoline Ligands for Enantioselective Catalysis Paulo H. S. Paioti,† Khalil A. Abboud,‡ and Aaron Aponick*,† †
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
‡
Center for X-Ray Crystallography, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
KEYWORDS Asymmetric catalysis, homogeneous catalysis, ligand design, π-stacking, heterocycle synthesis
ABSTRACT: A complementary strategy for ligand tuning that enables controlling ligand conformation is described here. The concept is demonstrated with new ligands that are employed in the catalytic enantioselective preparation of the highly important C2-aminoalkyl fivemembered heterocycle motif. The alkynylation/cyclization sequence developed here is convergent, highly modular, and allows for a complementary scope to the heteroarylation of imines. This new ligand platform should offer new possibilities for expanding the use of PHIM-type ligands in a large variety of new transformations.
The development of new ligand classes for enantioselective catalysis has continued to be an important endeavor, enabling the preparation of essential molecules as single enantiomers for a variety of applications.1 Within this arena, there are select well-known ligands that function exceedingly well over a broad range of transformations. Jacobsen and Yoon have dubbed these compounds privileged ligands and this categorization underscores the difficulty encountered when trying to identify ligands exhibiting broad applicability with high selectivity.2 As such, these ligands often serve as the platform for tuning efforts whereby substituents are varied with the goal of modulating the steric and electronic properties to influence the stereochemical outcome of a reaction.3 Implicit in this approach is that it may be more straightforward to find a suitable derivative rather than a new scaffold, but not all selectivity problems can be solved in this fashion. To this end, we postulated that it might be possible to further tune known ligand-types by the introduction of substituents with a different intention. More specifically, we hypothesized that it may be possible to effect substantial conformational changes by employing stabilizing non-covalent interactions to bias ligand conformation (Figure 1). This concept could be advantageous because the requisite substituents could be supplementary to the structural elements responsible for asymmetric induction, allowing another design element to be incorporated to enhance selectivity. Herein we demonstrate the application of this concept to a well-known class of ligands (PHOX/PHIM) and show that high levels of selectivity can be achieved by making simple changes, thereby addressing ligand optimization with a quite different and complementary tactic to the modification of the steric and electronic parameters. To explore this concept, we drew inspiration from the seminal work of Pfaltz, Helmchen, Williams,4 Busacca,5 and others on PHOX and PHIM ligands, and hypothesized that these modular ligands could be tuned beyond variation of the substituents on the chiral backbone and the phosphine by restricting rotation about the aryl-oxazoline or aryl-imidazoline σ-bond (Figure 1). These ligands seemed to be an ideal test bed because they are not planar,
instead exhibiting a range of dihedral angles in metal complexes;6 however, it was unclear if modulating this parameter would prove to be advantageous or even possible as an extremely large number of ligands are known, but none have been reported to contain a configurationally stable chiral axis.7 Our approach utilizes groundstate stabilization via attractive arene-arene interactions to impact conformation and, to the best of our knowledge, our ligand StackPhos is currently the only chiral ligand that incorporates substituents for this purpose.8 Complementary New Strategy For Ligand Tuning? Ph Ph
Chiral Centers R O
N
R
R R' N
N
PAr2
R
PAr2
R PHOX
Conformational F5 Changes?
PHIM
High Modularity, Ideal For Tuning
N
N PPh2
StackPhim Additional Chiral Axis
• PHOX/PHIM ligand complexes not planar • Can defining the axial chirality enhance ligand/catalyst control?
Figure 1. A complementary ligand tuning strategy applied to PHOX/PHIM-type ligands.
To test the proposed new design concept, a reaction was needed as a vehicle to assay the effectiveness of this strategy. The ideal application would demonstrate that making conformational changes in the ligand could appreciably enhance levels of selectivity, preferably from unacceptable to meeting contemporary selectivity standards. As part of our programs in Cu-9 and Au-catalysis, 10 a new strategy for the synthesis of chiral 2-aminoalkyl electron rich heterocycles was envisaged. Five-membered heterocycles functionalized at the C2 position appear in many bioactive natural products as well as in lead compounds and clinical agents (Figure 2).
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Me Me N +
Me
Me
O
H N Me
muscarine receptor ligand
O
inhibition of endothelial differentiation gene 1 receptor
N
O
N R
H CO2Et
O
iPr
N Et
Me H
Cl
SO2C6H4Cl
Me O
Me NH
R NH
HN
HN Cl
dopamine D3-receptor ligand
O
+
inhibition of glucagon receptor
ajmalicine - α1-adrenergic antagonist receptor (+ innumerous others indole natural products)
Figure 2. Select examples of bioactive 2-aminoalkyl heterocycles.
Traditionally, the synthesis of this important non-racemic amine motif is accomplished using chiral auxiliary chemistry11 employing preformed imines and stoichiometric organometallics (Scheme 1A).12 In the context of enantioselective catalysis, one of the few examples is the Rh-catalyzed reaction of arylboronic esters with aromatic imines; however, the scope is limited and alkyl groups have not been employed.13 With limited catalytic examples, we envisioned that a modular approach utilizing an alkynylation/cyclization sequence could expand the availability of these compounds (Scheme 1B). For this strategy to work most efficiently, racemic substrates would have to be tolerated in the reaction and both substrate enantiomers lead to propargyl amine products of the same stereochemistry with high selectivity. Interestingly, using alkynes as building blocks for heterocycle synthesis has been extensively investigated,14 but has rarely been coupled to an asymmetric alkynylation reaction. 15 Scheme 1. Preparation of 2-Aminoalkyl Heterocycles. A. Previous Approach: Use of Preformed 5-Membered Heterocycles
NHR
NR
R
+ R [M]
H
X
+ H [M]
R
X
Very few catalytic enantioselective reactions
NR
or
X
typically diastereoselective (chiral auxiliary)
B. Our Approach: Alkynes as 5-Membered Heterocycle Surrogates
NR2 R
R1 X R2
[Au]
NR2
O XH
R LG R1
New Ligands? R
+ HNR2 H + XH
R2 Catalyst Control?
R2
LG R1
Initial attempts at the new reaction sequence were ineffective with respect to enantioselectivity using our StackPhos ligand, which has proven to be an extremely good ligand for Cu-catalyzed alkynylation reactions,8,9 an enantioselective reaction pioneered by Li and Knochel with 1° and 2° amines respectively.16 As seen in Scheme 2, using (S)-StackPhos in a Cu-catalyzed alkynylation reaction with butynyl diol rac -3, the reaction proceeded smoothly to yield 4 in 86% as a 1:1 mixture of diastereomers. Au-catalyzed dehydrative cyclization17 then afforded the furan 5, albeit in only 15% yield and 60% ee (4 was inseparable by chiral HPLC). Unfortunately, likely due to the presence of the racemic propargyl alcohol stereocenter in rac- 3, a system with higher levels of catalyst control was needed. Attempts at this reaction were made with the commercially available (S)-tBu-PHOX ligand and, much to our surprise, no reaction was observed after multiple attempts. Since
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the configurational stability of 5 under the dehydrative cyclization conditions was unknown, rac -6 was allowed to react under the same conditions to try to determine if the chiral center in the propargyl alcohol was negatively impacting the selectivity in the addition step. In the event, the amine 7a/b was isolated in high yield (1:1 dr), again with low ee’s; 72% and 69% ee at 0 °C; and, 69% and 69% ee at –30 °C, respectively. We sought to address the enantioselectivity issue using the aforementioned ligand design strategy with PHIM-type ligands. Scheme 2. Initial Alkynylation Attempts with Chiral Racemic Propargyl Alcohols. HNBn2 + O 1 Me iPr H a) 2 + rac-3 OH
OH
NBn2 OH b)
NBn2 Me Ph
Me 4
OH
Me
5
O
with (S)-StackPhos: a) 86% 4, 1:1 dr; b) 15% 5, 60%ee with (S)-tBuPHOX: a) no reaction HNBn2 NBn2 + O 1 a) (S)-StackPhos Me iPr H Ph 2 + Me CuBr, CH2Cl2, Ph MS 4Å 7a/b OH rac-6 OH 0 °C, 92% (1:1 dr); 72% and 69% ee -30 °C, 91% (1:1 dr); 69% and 69% ee
Ph
N
N PPh2
F5
(S)-StackPhos t-Bu O
N PPh2
(S)-tBu-PHOX
Conditions: a) 1.5 equiv 1, 1.0 equiv. 2, 1.0 equiv. 3/6, CuBr (5 mol %), (S)-StackPhos (5.5 mol %), CH2Cl2, MS4Å, 0 °C, 4h; b) JohnPhosAuCl/AgOTf (10 mol %), THF, MS4Å, rt, 12h.
Scheme 3 shows the synthesis of StackPhim ligands 9 and 10. The iodoimidazoline 8 was easily prepared following standard protocols, 18 and an Ullmann-type C-P coupling19 then provided the new ligands. The two diastereomeric phosphines were readily separated by simple column chromatography, which differs from protocols that utilize stoichiometric chiral palladacycles to obtain enantiomerically pure P,N-ligands.20 The sequence is straightforward and can be performed reproducibly on a gram scale. (R,R,R)- and (S,R,R)-StackPhim’s 9 and 10 proved to be configurationally stable in solution at room temperature for long periods of time. The barrier to interconversion in each direction was experimentally determined18 and found to be 26.8 kcal/mol and 27.5 kcal/mol at 50 °C, respectively (Scheme 3). These values for the free ligands21 are in good agreement with the thermodynamic ratio observed under equilibrating conditions and are similar to the barriers observed for StackPhos8 and Carreira’s PINAP ligand.22 The absolute stereochemistry of these ligands was confirmed after obtaining an X-ray crystal structure of 10, which shows the expected π,π-stacking between the naphthalene and the perfluorinated ring.23 This is, to the best of our knowledge, the first time that PHIM-type ligands with a configurationally stable chiral axis have been synthesized, separated, and characterized. It is relatively straightforward to introduce different substituents to this ligand; and, to probe the effects of the electron deficient arene (C6F5), the non-fluorinated analogues H5-9 and H5-10 were prepared. These compounds were found to be inseparable and not configurationally stable at room temperature with respect to the chiral axis. At 110 °C, upon preparation, H5-9 and H5-10 reached a 1:1.5 equilibrium ratio. With further experiments using mixtures obtained at non-equilibrium concentrations after chromatography, the barrier to rotation was found to be 25.3 and 25.5 kcal/mol at 25 °C in the forward and reverse direction respectively.18 Strikingly,
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comparison of the absolute values between the fluorinated and non-fluorinated ligands reveals a nearly 2 kcal/mol difference and distinguishes the fluorinated compounds as potentially useful ligands of well-defined stereochemistry.
Table 1. Ligand Evaluation. HNBn2 + O 1 iPr H 2 +
Scheme 3 . Synthesis of StackPhim ligands 9 and 10 and nonfluorinated control analogues. Ph
C6F5
CuI
Ph
N
rac-3 Ph
MeHN NHMe N HPPh , Cs CO 2 2 3
Ph
N
N
8
Ph
N + PPh2
PhMe, 16h F5 110 °C, 54%
I
Ph
9 (R,R,R)-StackPhim
F5
Ph
PPh2
Bn N
CuI
Ph
Ph
MeHN NHMe N HPPh , Cs CO Bn N 2 2 3 I
N
PhMe, 16h 110 °C, 37%
8 dr H5-9 : H5-10 (1:1.5); diastereomers inseparable & interconvert at rt
+ PPh2
Ph
1 2
N
N PPh2 F5
9 (R,R,R)-StackPhim
Ph N PPh2
12 (R,R)-F5-Phim
11 10
Me
OH Me
86 64
80 75
66 82
74 76
81 76
-94 -81
OH
NBn2
Ph
Bn N
Ph
O
yield 4/4' yield 5/ent -5 ee (%)b (%)c (%)d
producta
4
Ph
Ph
5
NBn2
ΔG75 °C (StackPhos) = 28.4 kcal/mol ΔG75 °C (PINAP) = 27.5 kcal/mol
Ph
N PPh2 F5
10 (S,R,R)-StackPhim
ΔG50 °C (10 to 9) = 27.5 kcal/mol
Me
Ph
N
F5
entry ligand
ΔG50 °C (9 to 10) = 26.8 kcal/mol
NBn2 Me
OH
Ph
N
N
11 (S)-StackPhos
10 (S,R,R)-StackPhim
barrier to rotation of P,N-ligands:
dr 9 : 10 (1 : 2.5) diastereomers separable & configurationally stable at rt
4
Ph
F5
b)
Me
OH
N
PPh2
OH
OH
Ph
N
NBn2 a) Me
3 4
N
9 12
Me
OH Me 4'
PPh2
OH
a
H5-9
H5-10
ΔG25 °C (H5-9 to H5-10) = 25.3 kcal/mol
Stereochemistry determined after step b; bConditions: 1.0 equiv 1, 1.5 equiv. 2, 1.0 equiv. 3, CuBr (5.0 mol %), ligand (5.5 mol %), CH2Cl2, MS4Å, 0 °C, 4h; cConditions: JohnPhosAuCl/ AgOTf (10 mol %), TFA (1.0 equiv), THF, MS4Å, rt, 9h; dDetermined by chiral HPLC.
ΔG25 °C (H5-10 to H5-9) = 25.5 kcal/mol
With a good source of ligands in hand, we set out to test the influence that the newly introduced chiral axis might have by systematically making changes. As can be seen in Table 1, StackPhos 11 and StackPhim 10 (same sense of axial chirality) both provide products 4 with the same absolute stereochemistry at the newly formed propargyl amine stereocenter; however, after Au-catalyzed cyclization to form 5, a large improvement in enantiomeric excess is observed with the StackPhim 10; 66% ee vs 82% ee, respectively (entries 1 and 2). It should be noted that the yield of the Aucatalyzed cyclization was also significantly improved by addition of TFA to the reaction medium. 17,24,25 With the diastereomeric ligand StackPhim 9 (opposite axial chirality), 4' with the opposite propargyl amine stereochemistry were observed; and notably, the enantioselectivity was further improved to 94% ee, albeit for ent-5 (entry 3). As a control experiment, PHIM ligand 12 was employed (no axial chirality), also providing 4', but with diminished selectivity (entry 4). These data indicate that the sense of chirality observed in the products is influenced by the chiral centers in the backbone (entry 4), but the axial chirality can overcome this bias to provide the opposite stereoisomer (4' vs 4, entry 4 vs 2) or enhance the selectivity (entry 4 vs 3). Furthermore, these results demonstrate the potential importance associated with controlling a somewhat obscured element of chirality in P,N-ligands such as PHOX and PHIM, namely axial chirality.26 With the widespread application of these highly successful ligands, this should have a farreaching impact on future applications.
The substrate scope for the alkynylation/cyclization sequence was next explored and found to be broad, tolerating aliphatic branched, straight chain, and aromatic aldehydes, as well as symmetrical and less common non-symmetrical secondary amines.27 In each case, very good yields and ee’s were obtained under standard conditions (Table 2, entries 1-5). The reaction not only tolerates the synthesis of simple furans (entries 1-5), but also substitution at the C2 and C3 positions (entries 6-7). Interestingly, racemic and even a diastereomeric mixture of the alkynes (entry 6) can be employed, demonstrating excellent control imparted by the StackPhim ligand. Moreover, in this sequence, substitution on the furan is achieved through the use of different alkynes, offering a complementary approach with a convergent pathway in contrast to latestage functionalization,28 which could be useful to work around the inherent electrophilic aromatic substitution selectivity.29 It is also important to note that other cyclization methods can be used to form additional heterocycles (entries 8-10).30 As a demonstration, the benzofuran 17h and the indoles 17i and 17j were prepared in good ee. Neither the phenol 16h nor the sulfonamides 16i/j were problematic in the alkynylation reactions, and the cyclization occurred smoothly under simple basic conditions for both substrate types.
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Table 2. Scope of Alkynylation/Cyclization Sequence. R1
R2 N 13 H
O
+ +
R3
R1 a)
H
14
StackPhim, 9
product (step a)a
entry
b)
yield (%)b
1
17a
OH
Me 16b
17b
OH
OH
O
88
67e
O
N OH
Me
N
61
Me
OH
16d N
Me
Ph OH
5
N
92
81e
92
76e
90
61e
91
Ph
82 O
17e
OH
16e
53e
Me O 17d
Me
NBn2
NBn2
Me
OH
Me
Me
83
Me 16f
O
OH 17f
NBn2
NBn2
Me
Me
Me OH
Me 16g
72
Me
Me
O
OH
17g
NBn2
NBn2
Me
Me Me
78
Me
81f
O
84
HO 16h
17h
NBn2
NBn2
Me
92
Me
N
Me
Ph
TsHN 16j a.
Ph
Me 7'
OH
0 °C, 4h, 94% (1:1 dr); 93% and 93% ee
Scheme 5. 1,4-Aminoalcohol Synthesis. NBn2 NBn2 1 (0.5 equiv.) + Cond. iPr iPr 2 (1.0 equiv.) Ph + + rac-6 (1.0 equiv.) 7'a 7'b OH 97% ee 89% ee (dr = 63:37)
Ph OH
+
78f
91
N
Ph
Me
89
Me
Me
(R)-6 20% ee
Ph OH
Conditions: CuBr (5.0 mol %), 9 (5.5 mol %), CH2Cl2, MS4Å, 0 °C.
17i
Me
10
CuBr, CH2Cl2, MS 4Å
43% Conversion (s = 2.0)
Me TsN
TsHN 16i
NBn2 StackPhim, 9
To further probe the issue of catalyst versus substrate control, the reaction was run to partial conversion to investigate potential kinetic resolution. Interestingly, using the amine as the limiting reagent, a low level of kinetic resolution was observed. As seen in Scheme 5, at 43% conversion, 7'a and 7'b (63:37 dr) were obtained in 97% and 89% ee, respectively, along with unreacted propargyl alcohol (R)-6 in 20% ee. The observed dr and ee are in good agreement and show that there is a small matched/mismatched effect with StackPhim 9 whereby (S)-6 reacts preferentially to form 7'a in high ee, even though the stereocenter in 6 is quite distal to the chiral ligand in the presumed Cuacetylide intermediate. When the reaction is allowed to proceed to full conversion, the observed product distribution (Scheme 4) must represent some crossover where the minor enantiomer of 7'a is formed from (R)-6 thereby lowering the ee from 97% to 93%. The high levels of selectivity with both enantiomers and relatively low level of kinetic resolution indicate a highly catalyst controlled reaction.
Me Me
9
HNBn2 + O 1 iPr H 2 + Ph rac-6 OH
93
Me O 17c
O
8
75e
Me
OH
16c
7
91
In more broad terms, with this new ligand, the reaction could be a good source of 1,4-aminoalcohols if the conditions proved to be general. To this end, StackPhim 9 was employed in a reaction with a simple propargyl alcohol rac- 6 (Scheme 4). When racemic 1phenyl-2-propyn-1-ol was allowed to react under the standard conditions, 7' was isolated in high yield with a 1:1 dr, and very high enantioselectivity for each diastereomer (93% ee) indicating a high level of catalyst control for each enantiomer of starting material.31 This is desirable since important syn- and anti-1,4-aminoalcohols32 would be accessible starting with readily available enantioenriched propargyl alcohols.33 Scheme 4. 1,4-Aminoalcohol Synthesis.
N
91
Me
6
50 e
O
Me
Me
ee (%)d
O
Me
N
4
yield (%)c
NBn2
95
O
3
R
NBn2
78
NBn2
2
17a-i
product (step b)
OH
16a
R2
X
R4
NBn2 OH
N
R3
R3 16a-i
R4
15
R1
R2
N
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Me TsN
79f
86
17j
Alkyne (1.0 equiv), aldehyde (1.5 equiv), amine (1.0 equiv), CuBr (5.0 mol %), 9 (5.5 mol %), CH2Cl2, MS4Å, 0 °C or rt; b.Yield of step a. c.Yield of step b. d.Measured after step b using chiral HPLC. e.Conditions step b: JohnPhosAuCl/ AgOTf (10 mol %), TFA (1.0 equiv), THF, MS4Å, rt, 924. f.Conditions step b: K2CO3 (5.0 equiv), MeCN, 70 °C.
In conclusion, the results reported here demonstrate that even highly successful ligands such as PHOX/PHIM can be tuned using a complementary strategy that alters their conformation. The modifications made to effect these changes do not impact the modularity of the ligand scaffold and one can envision making all manner of variations to arrive at highly selective new ligands to address challenging enantioselectivity issues. In this manuscript, the enantioselective preparation of valuable 2-aminoalkyl heterocyclic building blocks was used to demonstrate the concept. Using these new StackPhim ligands, a highly enantioselective sequence was realized. Remarkably, both the chiral centers and chiral axis embedded in the ligand have been demonstrated to be impact the selectivity of
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the reaction. Finally, we believe that this concept should offer new possibilities for expanding the use of many ligand classes in a large variety of selective new transformations. Studies to this end are underway in our laboratory and will be reported in due course.
ASSOCIATED CONTENT Supporting Information. Experimental procedures and spectral data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author *
[email protected] Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT We thank the National Science Foundation (CHE-1362498) and the University of Florida for their generous support of our programs.
REFERENCES
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R1
N H
R2
O
+ R3 +
HO
StackPhim
R1
H CuBr, CH Cl 2 2 R3 MS 4Å OH R
N
R2
R1 [Au+] HO
HO
R
N
R2
R3 X R up to 94% ee
• High level of ligand/catalyst control with new ligands • Racemic nucleophiles successfully employed
ACS Paragon Plus Environment
N
Ph N PPh2
F5
StackPhim Additional Chiral Axis High Modularity New Tuning Strategy
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