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Tandem Allylation/1,2-Boronate Rearrangement for the Asymmetric Synthesis of Indolines with Adjacent Quaternary Stereocenters SANTANU PANDA, and Joseph M. Ready J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 21 Sep 2018 Downloaded from http://pubs.acs.org on September 21, 2018
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Journal of the American Chemical Society
Tandem Allylation/1,2-Boronate Rearrangement for the Asymmetric Synthesis of Indolines with Adjacent Quaternary Stereocenters Santanu Panda and Joseph M. Ready* Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, 75390-9038, USA Supporting Information Placeholder ABSTRACT: A three-component coupling using lithiated indoles, boronate esters and allylic acetates generates chiral indolines with adjacent quaternary stereocenters. Successful stereocontrol required the use of phosphoramadite ligands not previously described for orgranopalladium chemistry. Mechanistic studies indicate a monodentate PdL intermediate, and a stepwise allylation-aryl/alkyl migration. A protodeborylation strategy was used to install a C-H bond in place of the C-B bond. A photoredox coupling was used to replace C-B bond with a C-C bond in a highly diastereoselective manner. In the specific case of methylvinyl ketone, a novel radical-mediated annulation provides polycyclic products with high enantio- and diastereoselectivity.
1. INTRODUCTION Synthesis of enantiopure heterocyclic compounds remains an important challenge for pharmaceutical development and natural products synthesis. More than 50% of FDA approved drug contain heterocycles. Moreover, of the top 200 prescription drugs in 2016, 40 were optically active heterocycles featuring stereocenters on the heterocycle itself. For these reasons, synthetic methods that provide access to heterocyclic products in optically active form will help drive drug discovery efforts. In this regard, multicomponent coupling strategies offer the opportunity to further streamline synthesis by generating multiple stereocenters in a single operation and by combining several simple fragments to generate more complex products. Organoboron reagents have proven particularly useful in muti-component couplings. Boron forms stable bonds to carbon and features an empty p orbital that can facilitate precomplexation of nucleophilic reagents. For example, the Petasis reaction involves the addition of vinyl or aryl boronic acids to in situ-generated imines.1 Alternatively, 3-boryl allyl boranes serve as lynchpins to conjoin two aldehydes. An initial allyboration generates a complementary allyl boronic ester, which can undergo the second allylation reaction.2 Yamamoto used the coordinating ability of boron to facilitate heterotrimerization of alkynes.3 Additionally, several three-component couplings feature organoboron reagents that participate in a transmetallation event to a transition metal catalyst. Selected examples include Jamison’s coupling of alkynes, imines and organoboron reagents,4 Larock’s alkyne 1,2diarylation,5 Sigman’s three-component coupling of dienes with vinyl triflates and aryl boronic acids,6 and Toste’s oxyarylation of
alkenes.7 Finally, arylborylation of olefins represents a threecomponent coupling that introduces the boron moiety into the coupling product.8 Many of the most valuable transformations of organoboranes involve 1,2-metallate rearrangements. These processes involve a 1,2-migration of an organic fragment from boron to carbon (Scheme 1A). Migration to an sp3 hybridized carbon generally results in expulsion of a leaving group, as in the Matteson ho-
mogoation.9 Over the last decade, Aggarwal has extended this reactivity concept to asymmetric synthesis. They have accessed stereo-defined, lithiated carbamates (Scheme 1B) or esters (not shown), which can add to various B(pin) reagents. Next, a stereospecific 1,2-metallate shift expels the carbamate or ester to provide the optically active boronic ester.10 Notably, the process can be iterated or combined with more traditional Matteson homologation,11 and this strategy has enabled several remarkably efficient
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total syntheses.12 Alternatively, 1,2-migrations onto sp2 hybridized carbons requires electrophilic activation of the olefin or radical addition to a vinyl boronic ester. For instance, halogenation can activate olefins, as in the Zweifel olefination,13 or can activate arenes, as in the Aggarwal arylation (Scheme 1C).14 Likewise, Nacylation of pyridines can initiate dearomatizing 1,2-migration onto the heterocyclic ring (Scheme 1D).15 Alternatively, several recent reports document radical addition to vinyl boron species followed by 1,2-metallate rearrangement (Scheme 1E).16 Morken’s group reported methods to prepare the same products as are shown in Scheme 1E, but in an enantioselective manner.15b,17 Specifically, they activated the vinyl boronate for 1,2-metalate rearrangement using an ArPd+ species featuring a chiral nonracemic ligand that effectively discriminates the enantiotopic faces of the vinyl group. This method was the first highly enantioselective method leveraging the 1,2-metalate shift from boron.18 Our group has been interested in developing an enantioselective 1,2-boronate rearrangement for the asymmetric synthesis of indoles and indolines. Indoles and indolines are prized substructures in drug discovery and natural products research.19 A Reaxys search revealed over 6500 naturally occurring indoles and 143 indoline natural products. Likewise, a DrugBank search revealed 270 indoles in preclinical development and 69 approved drugs.20 Prior work documented enantioselective indole allylation and 1,4conjugate addition.21,22 Chiral non-racemic indolines have been synthesized via asymmetric reduction,23 kinetic resolution,24 and cyclopropanation.25 Most existing methods introduce substituents only at C2 or C3, or they require substrates that are prefunctionalized at those positions.
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that provided achiral or racemic indoles.26 Building on their pioneering work, we developed an enantioselective three component coupling of boronic esters, indoles and allylic acetates using either (BINAP)PdCl2 or (H8-BINAP)PdCl2 (Scheme 1a).27 Mechanistically, the reaction involves formation of an indole boronate species, indole addition to the chiral Pd(π-allyl) complex, and 1,2boronate rearrangement as shown in structure A. This process provides optically active indoline boronic esters (4), which could undergo oxidation to yield indoles (5) or stereospecific protodeborylation to yield indolines with three contiguous stereocenters (6). More recently, lithiated indoles have been harnessed in other asymmetric synthetic methods. For example, Aggarwal described an alkylation/1,2-metalate rearrangement in which the stereochemistry of the boronic ester is maintained (Scheme 2b),28 while the Studer group reported a four-component coupling involving cyclopropane ring-opening (Scheme 2c).29 Our initial studies on the three-component coupling of indoles, boronic esters and allylic acetates examined indoles lacking substitution at C3 (Scheme 2a). By contrast, C3-substitued indoles would give rise to adjacent quaternary stereocenters (Scheme 3a). The enantioselective construction of quaternary stereocenters remains a challenging and ongoing area of investigation.30,31, 32,33 More than 10% of top selling FDA approved drugs contain at least one quaternary carbon center. In nearly every case the quaternary stereocenter is derived from a natural product, highlighting the need for new synthetic methods.32c Additionally, numerous indoline-containing natural products possess quaternary stereocenters at C3 and/or C2. For these reasons, we elected to examine the asymmetric three component coupling to form an all carbon quaternary stereocenter at C3 and a tertiary boronic ester at C2. Earlier studies incorporated symmetrical disubstituted allylic acetates. In those allylations, the Pd catalyst was able to differentiate the enantiotopic carbons of the Pd(π-allyl) complex. In the case of an unsubstituted allylic acetate, however, the catalyst must distinguish the enantiotopic faces of the indole (D in Scheme 3a), which appeared more challenging since the allyl electrophile would presumably be positioned between the indole and palladium center in the transition state. Here we describe conditions to effect the highly enantioselective three component coupling of
Ishikura and coworkers previously discovered a three component coupling of trialkyl boranes, indoles and allylic acetates
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allyl acetate, boronic esters, and C3-substituted indoles. We then describe functionalization of the resulting tertiary boronic esters through protodeborylation, C-O and C-C bond formation (Scheme 3b). 2. RESULTS AND DISCUSSION. Table 1. Ligand Optimization for Three-Component Coupling a t-BuLi; PhB(pin); [PdL*] (5 mol%)
Me
Me B(pin)
allyl acetate N Me THF entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16b 17c
R 2P
ligand
yield (%)
((R)-BINAP)PdCl2 ((R)-p-Tol-BINAP)PdCl2 ((R)-H8-BINAP)PdCl2 ((S)-SEGPHOS)PdCl2 (R)-DTBM-SEGPHOS Josiphos L1 Josiphos L2 DIOP L3 DuPhos L4 Phenyl Trost Ligand L5 Napthyl Trost Ligand L6 PHOX Ligand L7 Phosphoramidite L8 Phosphoramidite L9 Phosphoramidite L10 Phosphoramidite L10 Phosphoramidite L10 PPh2
P(tBu)2 Fe
12a
N Ph Me
CH3
73 65 72 69 68 54 42 55 64 62 68 53 48 46 72 70 72
PPh2 N L7
Ph
55 oC 13a
N Me
er
dr
55:45 56:44 56:44 40:60 64:36 65:35 59:41 62:38 65:35 77:23 80:20 32:68 70:30 77:23 90:10 94:06 96:04
87:13 80:20 88:12 86:14 88:12 91:09 89:11 84:16 82:18 91:09 86:14 85:15 85:15 86:14 88:12 88:12 88:12
O
P
O
Me P Me PPh2 Me L3 L4
R O
Me
Me
O L1, R = Cy L2, R = 2-Furyl
Bu4NF• 3H2O
O P N O R
O NH
R
HN
Ph Ph P P Ph Ph
R
L5, R = Phenyl L6, R = Napthyl R1
O P N O
R1
L8, R = H, R1 = H L9, R = Ph, R1 = Me
L10
at-BuLi
(1.3 equiv), N-methyl-3-methyindole (1.3 equiv), PhB(Pin) (1 equiv), allyl acetate (2 equiv), 5 mol% Pd(L*)Cl2 or 2.5 mol% [Pd(allyl)Cl] 2 + 15 mol% ligand in THF. Isolated yeilds. Er determined by HPLC. Dr determined by 1H NMR. bReaction at -10 oC. cReaction at -20 oC using 3 mol% [Pd(allyl)Cl] 2, with 12 mol% ligand.
Synthesis of adjacent quaternary stereocenters. We initiated our study by using lithiated 3-methyl-N-methylindole (11), phenyl boronic ester, and allyl acetate. The racemic coupling worked well with Pd(PPh3)4 to yield (±)-12a as a single observable diastereomer. In situ proto-deborylation provide indoline 13a with retention of stereochemistry at C2.34 Previously, C3-unsubstituted indoles were allylated with high enantioselectivity using (BINAP)PdCl2. However, this catalyst system formed indoline 12a in good yield after deborylation, but with poor enantioselectivity (Table 1). Other C2 symmetric bisphosphines including BINAP derivatives, SEGPHOS ligands and others (more details see supporting information) similarly provided reasonable yield and diastereoselectivity, but little asymmetric induction. Marginal improvement was seen with by using SEGPHOS ligands, Josiphos
ligands (L1, L2), DIOP (L3) or DuPhos (L4), although er’s were still 15:1)
Me HO 16a (dr > 15:1)
Me
15a
1. OsO4, NMO, PhI(OAc)2
Ar
COMe
Me Ph N B(pin) Me
2:1 2:1 >20:1 2:1 5:1 >1:20
N
17: 64% yield
Yield (%)
d. Other acceptors
72 65 62 66 52 58
15a:16ac
Ar
N Ph Me
O dr >15:1 er 96:4
Ph (15a) 4-Me-C 6H4 (15b) 4-F-C6H4 (15c) 4-OMe-C 6H4 (15d)
20 acetone/MeOH 20 acetone/MeOH 20 acetone 20 MeOH 100 acetone/MeOH 0 acetone/MeOH
yield (%)b
Me
Me
2. NaOMe
N Me
2 1 1 1 1 2
solvent
c. Substrate scope annulatione
b. Substrate scope 1,4 additiond
Ar
1 2 3 4 5 6
Me Ph
DMAP (y mol%) 419 nm O
(±)-12a
PC DMAP (mol%) (mol%)
HO
Me
Ar
60 62 60 63
419 nm EWG
Yield (%)
Ph (16a) 4-Me-C 6H4 (16b) 4-F-C6H4 (16c) 4-OMe-C 6H4 (16d)
17
2 mol% PC 20 mol% DMAP Acetone/methanol (1:1)
dr>15:1 er 96:4
Me
58 62 59 63
16d
Me Ph
N Me
Ph
CO2Me
18: 65% yield, er 96:4, dr>15:1
N Me
CN
19: 70% yield, er 96:4, dr>15:1
19
a Reactions were conducted using boronate ester (0.3 mmol), Ir(dF(CF 3)ppy) 2(dtbbpy)PF 6 (0.006 mmol), 4-dimethylaminopyridine, methylvinyl ketone (3 mmol), 0.3 M in the solvent indicated. bCombined isolated yield of 15a + 16a. cRatio determined by 1H NMR followin filtration through SiO2. d Reactions were conducted as in entry 3. eReactions were conducted as in entry 6.
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cleaved, and the resulting aldehyde was subject to aldol cyclization. X-ray crystallography confirmed the trans ring fusion in tetrahydrocarbazole 17. Similarly, we used the optimized conditions for the annulation to briefly explore the scope of this transformation (Scheme 5c). The tricyclic products 16a-16d were formed with high diastereoselectivity, no loss of optical purity, a. Role of olefin present in the azepine ring of L1 a,b t BuLi, 0 C - rt; PhB(pin), -78 C - rt; Me 3 mol% [Pd(allyl)Cl] 2 12 mol% L, -30 oC
Me Ph
N Me
OAc 2. Bu4NF•3H 2O 55 oC
N 13a Me
O O P N
O O P N
L10 72% yield, 96:4 er
L11 70% yield, 96:4 er
b. 31P NMR study of metal-ligand complex 31
P NMR L10
31
P NMR, Pd:L10 = 1:1
31
P NMR, Pd:L10 = 1:2
c. Corelation between the ee of ligand and the product
a,b,c
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trile addition product 19 crystallized, indicating that the addition proceeded with inversion of stereochemistry at C2, consistent with observations above. The relative stereochemistry of ester 18 was assigned by analogy. Additions to acrolein gave complex reaction mixtures, while no desired addition product was observed with phenyl vinyl sulfone. Mechanistic considerations. The asymmetric allylation/1,2boronate rearrangement and the subsequent photochemical functionalizations raised several mechanistic questions. First, we wanted to understand the unique success of the phosphoramidite ligand L10 in the allylation. Previously described Ir and Rh complexes all involved coordination of the azepine olefin to the metal. For example, Carreira described an achiral version of L10 (bisphenol rather than BINOL) for use in amination of allylic alcohols and reported X-ray crystal structures showing bidentate (P, olefin) coordination to two phosphoramidites.37a A more recent publication suggested that the olefin from at least one of the ligands might be hemi-labile. Specifically, the Carreira group obtained X-ray crystal data for an Ir(L10)2(substrate) complex in which one equivalent of L10 coordinated through both phosphorus and the olefin, while the olefin of the second equivalent had been displaced by substrate.37d In cases where it has been studied, the olefin is absolutely required for activity.37b,d Similarly, structural studies on Rh complexes of related dibenzazepine-containing phosphoramidites revealed bidentate coordination of the P, olefin ligand.38a The olefin of L10 was required for high enantioselectivity in a Rh-catalyzed hydroacylation and required for reactivity in Rh-catalyzed additions of 1,3-diketones to allenes38b,c and allylation of 1,3-diketones.38d Since there were no reports of Pd complexes of L10, we elected to explore the nature of this interaction and the requirements for reactivity and selectivity. As shown in Figure 1a, L10 and its reduced form, L11, provided 13a in indistinguishable yield and er. Thus, the olefin of L10 is not required for activity or enantioselectivity, in contrast to prior results with Ir and Rh. Next, we sought to understand the stoichiometry of the Pd(L10) complex. The preponderance of Pd(π-allyl) complexes used in enantioselective transformations feature bidentate ligands, so it appeared plausible that two equivalents of monodentate L10 might coordinate to Pd to form a similar Pd(P)2 complex in the indole allylation. However, 31P NMR indicated a ~1:1 ratio of free L10 and a Pd(L10) complex when they were mixed in a 1:2 Pd:L10 ratio (Figure 1b). Consistent with this observation, we observed a linear relationship between the ee of L10 and the ee of the boronic ester 12a (Figure 1c). Taken together, the results suggest that L10 acts as a monomeric ligand, and that the active species may be a [κ1L10)Pd(π-allyl)]+ or (κ1-L10)Pd(π-allyl)OAc species.42 Efforts are underway to understand how this ligand environment induces asymmetry in the reaction.
Figure 1. Mechanism studies. aIsolated yeilds. Er determined by HPLC. Dr determined by 1H NMR. bt-BuLi (1.5 equiv), N-methyl3-methylindole (1.5 equiv), PhB(Pin) (1 equiv, 0.11 M), allyl acetate (2 equiv), 3 mol% [Pd(allyl)Cl] 2,12 mol% ligand. c Baseline corrected 31P NMR spectra in THF using 10 mM [Pd(allyl)Cl] 2and 20 mM L10, or 10 mM [Pd(allyl)Cl] 2 and 40 mM L10. cSynthesis of 12a under the standard conditions.
and in approximately 60% yields. Finally, we extended the radical functionalization to alternative acceptors. Methyl acrylate provided the ester 18, and cyanoacrylate yielded nitrile 19. Both products were formed in enantioenriched form with high diastereoselectivity. The acryloni-
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Journal of the American Chemical Society events occur simultaneously or sequentially. In our previous studies, which focused on indoles lacking a C3 substituent, we speculated that the high diastereoselectivity observed was consistent with a concerted process.27 New data casts doubt on that conclusion. While substrates with a C3 methyl group reacted with high diastereoselectivity, lower diastereoselectivity was observed with larger C3 groups. For instance, allylation to provide 12r additionally formed a diastereomer in a 3:1 ratio. Both diastereomers displayed the same high er (Scheme 6). Hydrogenation of the allyl group removed the C3 stereocenter and provided indoline 20 in 3:1 er. The loss in enantiomeric purity indicates that the minor diastereomer was the C2 epimer C2-epi-12r; had the minor diastereomer been epimeric at C3, then hydrogenation would have returned indoline 20 with high er. These observations are most simply explained by a stepwise allylation/migration process in which the palladium catalyst exerts high facial selectivity in the allylation event, followed by a 1,2-migration with selectivity dictated by the new C3 stereocenter. Alternatively, the cis- and transaddition products could arise from separate concerted pathways. However, the observation of identical enantioselectivity for both epimers seems most consistent with a single enantiodermining
Scheme 6. Stepwise Allylation-Migration n
n
Pr
standard conditions
N Me
OAc
Pr
n
B(pin) N Ph Me 12r
Pr Ph
+
N B(pin) Me C2-epi-12r
75% yield, 96:4 er 3:1 dr
n
Pr
B(pin) N Ph Me
Pd/C, H2 Methanol n
n
Pr
Pr B(pin)
N Ph Me
20: 74% yield, 75:25 er
The overall mechanism of the allylation/1,2-metallate rearrangement appears relatively clear: indole addition to a Pd(πallyl) complex prompts a 1,2-alkyl shift from boron to the indole C2 position. It has been unclear, however whether these two
Scheme 7. Mechanistic Considerations for Photoredox Functionalization a. Proposed mechanism for 1,4-addition and annulation [Ir +3]
h
[Ir+2]
[Ir+3]*
Me
Me
-MeOB(pin) Ph
Ph
+e-/+H+ path a
N
22
23
O
H
H
H path b
N Me
15a
O
path b [1,5]-H shift Me
[Ir +2]
-
Me
Ph
N Me
Me
Me
Ph
N
[Ir +2]
[Ir +3]*
Me
[Ir+3]
[Ir +3]*
Ph
+e /+H HO
Ph B(pin)
N Me 21
h
16a
Me
Me
Ph B(pin)
N Me
[Ir +3]
h
N
+
Me
25
Ph
Ph
N
N O
Me
H
24'
H
24
O
O
b. Experiments to probe the reaction mechanism Me Ph
Ph
COMe
Me OH 16a: Not Detected
15a
Me B(pin)
B(pin) N Ph Me
O
N CD3
[DMAP]
15a (%)
16a (%)
20 mol% none
68 10
