This thesis presents four related projects, all united by the use of enantioselective iridium-catalyzed allylic alkylation to construct highly congested C-C bonds. Finally, the first enantioselective transition metal-catalyzed allylic alkylation is presented, giving access to acyclic products bearing nearby carbon-only quaternary centers. Asymmetric synthesis of all-carbon quaternary spirocycles via an enantioselective allylic alkylation strategy.” Tetrahedron Lett.
Scheme A13.1 Initial retrosynthetic analysis of (+)-isopalhinin A (221) via iridium-catalyzed allylic alkylation of endocyclic 1,3-dicarbonyl nucleophile 225. Scheme A13.7 Retrosynthetic analysis of (+)-isopalhinin A (221) via palladium catalyzed allylic alkylation of masked stabilized lactam enolate 253.
INTRODUCTION
The first diastereo-, enantio- and regioselective iridium-catalyzed allylic alkylation was revealed by Takemoto in 2003, and for a decade it remained the only report on such a transformation.5 Of the eleven published reports on enantio- and diastereoselective iridium-catalyzed allylic alkylation, 6,7,8 only five reports provide access to adjacent tertiary and all-carbon quaternary stereocenters.6 However, none of these protocols allow the use of alkyl-substituted electrophiles (Figure 1.1a). In contrast, four unique examples using alkyl-substituted electrophiles in two published papers do not allow the construction of all-carbon quaternary stereocenters (Figure 1.1b).7 While these protocols provide access to valuable chiral synthons, a wide variety of synthetic targets require the accommodation of alkyl-substituted stereodiad between adjacent tertiary and quaternary carbon atoms (Figure 1.2). Here we describe the first method for the iridium-catalyzed synthesis of alkyl-substituted vicinal tertiary and all-carbon quaternary stereocenters via allylic alkylation of prochiral enolates (Figure 1.1c).
BACKGROUND TO DIASTEREO-, ENANTIO-, AND REGIOSELECTIVE IRIDIUM-CATALYZED ALLYLIC ALKYLATION WITH REGIOSELECTIVE IRIDIUM-CATALYZED ALLYLIC ALKYLATION WITH
IRIDIUM CATALYST-CONTROLLED PROCESSES .1 Acyclic Nucleophiles .1 Acyclic Nucleophiles
- Cyclic Nucleophiles
This is one of only two reports of alkyl-substituted electrophiles in a diastereoselective iridium-catalyzed allylic alkylation. It should be noted that the use of electron-deficient aryl-substituted electrophiles leads to an erosion in regioselectivity (50:50 to 71:29 branched/linear) in reactions of bicyclic nucleophiles. Scheme 1.6 Allylic alkylation of a) bicyclic β-ketoesters 27 and b) monocyclic β-ketoesters 30 by Stoltz. In 2013, Hartwig found that unstabilized enolates 36 undergo selective iridium-catalyzed allylic alkylation reactions to form vicinal tertiary and carbon-only quaternary stereocenters using preformed iridium complex 22 and BaOt–Bu (Scheme 1.8).6d In all cases, products 37 give excellent enantioenrichment (>98% ee), and even simple cyclohexanone derivatives give good selectivity for allylic alkylation of the corresponding thermodynamic enolate.
DUAL CATALYST-CONTROLLED PROCESSES
In a second generation protocol, Carreira used proline-derived amine L6 for the formation of vicinal tertiary stereocenters (Scheme 1.10).8c Although seemingly simpler from a steric perspective, this transformation actually presents a number of additional challenges; specifically, both the starting material and allylic alkylation products are potential electrophiles for aldol processes, and the products are susceptible to. Unlike with the cinchona alkaloid-derived catalyst L4 (Scheme 1.9), a significant mismatched pair of catalysts is observed (7:1 dr mismatch versus 20:1 dr match). Our group developed a two-step procedure for the divergent synthesis of various stereoisomers of cyclohexanone derivatives (Scheme 1.11).6b Trimethylsilyl ethyl ester 46 is readily accessible via the aforementioned iridium-catalyzed allylic alkylation (Scheme 1.6).
REACTION OPTIMIZATION
Previous work demonstrating the pronounced effect of bases on regio- and diastereoselectivity in iridium-catalyzed allylic alkylations prompted an extensive. Efforts to increase the yield revealed that super-stoichiometric levels of LiCl were essential and correlated with conversion (entries 10 and 11). Finally, it should be noted that we observed optimal conversion and selectivity using a 2:1 ratio of nucleophile to electrophile; however, the nucleophile and electrophile stoichiometry can be varied (1:1 or 1:2) without dramatically affecting the conversion or selectivity of the reaction, making the reaction synthetically practical (entries 12 and 13).
SUBSTRATE SCOPE EXPLORATION
Using L11 , the allylic alkylation product 54 is obtained in excellent enantioselectivity (96% ee) with regio- and diastereoselectivities comparable to L2 , albeit in significantly lower yield (46%, entry 9). We found that increasing the size of the ester moiety (-CO2Me, -CO2Et, -CO2i-Pr) results in the formation of the corresponding products 54, 58a and 58b in increasingly improved regio- and diastereoselectivities, but decreased yields on average. Furthermore, we were pleased to find that a (2-trimethylsilyl)ethyl substrate undergoes allylic alkylation to provide 58c in good selectivity, albeit in modest yield.
The alkylation product 58c can undergo subsequent palladium-mediated fluoride-initiated allylic alkylation to provide either diastereomer of the bis-alkylation product under catalyst control. We tried to further study the scope of the reaction by investigating the variety of allowed substitutions on the tetralone aromatic ring. In contrast, substrates with electron-withdrawing groups (7-MeO–, 7-NO2–, 6-Br–) afforded the corresponding products 58f, 58g, and 58h with excellent enantioselectivities (94–98% ee).
Substrates with this nitrile- or ketone-substituted functionality provided the corresponding products 58j and 58k with reduced selectivity. Notably, no allylic alkylation is observed with alkyl substituted allylic chloride derivatives, except with crotyl chloride (57). In addition, we observed that monocyclic nucleophiles including lactones, lactams, and piperidones gave the corresponding products 60f , 60g , 60h , 60i , and 60j in only modest yields.
Furthermore, with linear nucleophiles, we observed minimal or no conversion to product when a quaternary stereocenter is formed in an allylic alkylation reaction (e.g., 60k, 60l, and 60m), and in the case of propargyl 60m, we hypothesize that the alkyne functionality leads to catalyst poisoning.
PRODUCT TRANSFORMATIONS
In summary, we have developed the first transition metal-catalyzed enantioselective allylic alkylation reaction that forms contiguous tertiary and all-carbon quaternary stereocenters between prochiral enolates and an alkyl-substituted electrophile. Key to the success of this new reaction is the identity and ubiquity of the chloride counterion in addition to the use of a proton mushroom, the combination of which enables excellent regio- and enantioselectivity along with good yields and diastereoselectivity. In addition, a number of transformations were performed on the alkylation products to demonstrate the value of this method in rapidly accessing highly functionalized, stereochemically rich polycyclic frameworks.
Preparation of Known Compounds
EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA
- Experimental Procedures and Spectroscopic Data for the Synthesis of Tetralone Substrates
- Additional Optimization of Reaction Parameters
- Spectroscopic Data for the Iridium-Catalyzed Allylic Alkylation Products Products
- Experimental Procedures and Spectroscopic Data for the Transformations of Allylic Alkylation Products Transformations of Allylic Alkylation Products
- Determination of Enantiomeric Excess
The residue was purified by preparative TLC (10% Et 2 O/hexanes) to give the isolated yield of the branched and linear products (38.0 mg, 74% combined yield). Product 58b was prepared according to the general procedure and isolated by preparative TLC (8% EtOAc/hexanes) to give the isolated yield of the branched and linear products (31.3 mg, 55% combined yield). Product 58c was prepared according to the general procedure and isolated by preparative TLC (5% Et 2 O/hexanes) to give the isolated yield of the branched and linear products (18.3 mg, 27% combined yield).
Product 58d was prepared according to the general procedure and isolated by preparative TLC (8% Et2O/hexanes) to give an isolated yield of branched and linear products (33.0 mg, 55% overall yield). The product 58e was prepared according to the general procedure and isolated by preparative TLC (10% EtOAc/hexanes) to give an isolated yield of branched and linear products (29.0 mg, 46% overall yield). Product 58f was prepared according to the general procedure and isolated by preparative TLC (8% Et2O/hexanes) to give an isolated yield of branched and linear products (41.0 mg, 68% overall yield).
Product 58g was prepared according to the general procedure and isolated by preparative TLC (20% EtOAc/hexanes) to give the isolated branched and linear inseparable products (52.0 mg, combined yield 82%): 93% EE; [α]D25. Product 58i was prepared according to the general procedure and isolated by preparative TLC (9% EtOAc/hexanes) to give the isolated yield of branched and linear products (31.0 mg, 52% combined yield). Product 58j was prepared according to the general procedure and isolated by preparative TLC (17% EtOAc/hexanes) to give the isolated yield of the branched and linear products (43.0 mg, combined yield 95%).
Product 10k was prepared according to the general procedure and isolated by preparative TLC (9% EtOAc/hexanes) to give an isolated yield of branched and linear products (11.0.
The alkylation product 58e (86% ee) was recrystallized from slow evaporation of hexanes to provide crystals suitable for X-ray analysis, m.p.
INTRODUCTION AND BACKGROUND
As part of our ongoing research program to develop iridium-catalyzed allylic alkylation methods,6 we became interested in exploring the reactivity of masked acyl cyanide (MAC) reagents as reverse-polarity nucleophiles with π-allyl electrophiles. After reaction with an electrophile, these unpolarized synthons, developed by .. a) Iridium-catalyzed allylic alkylation strategies. Yamamoto and Nemoto,7 can be revealed to reveal a transient acylcyanide intermediate that can be further converted to a carboxylic acid, amide, or ester.7,8 We envisioned that the novel use of MAC reagents for iridium-catalyzed allylic alkylation chemistry could provide access to highly desirable, enantioenriched vinylated α-arylcarbonyl derivatives that are otherwise difficult to prepare (Figure 1c, right).9.
REACTION OPTIMIZATION
SUBSTRATE SCOPE EXPLORATION
Masked Acyl Cyanide Equivalents. respectively) are observed for the more electron-poor products 71b (–CF3) and 71c (–F). In addition, we were pleased to find that pyridine 71j, furan 71k and thiophene 71l each have excellent enantioselectivities (90-96% ee) and moderate to high yields (73-94%). In addition, a propargyl-substituted electrophile does not give the desired product 71q in the allylic alkylation reaction, probably due to catalyst poisoning from binding of the alkyne to the metal source.
Finally, optimized reaction conditions fail to provide useful synthetic yields or high regioselectivity when using alkyl-substituted allylic electrophiles (e.g., 71q-u ). To demonstrate the synthetic utility of this method, a preparative-scale (4 mmol) reaction was performed (Scheme 2.1). Using cinnamyl carbonate (68), both the yield and enantioselectivity of the reaction are unchanged from those obtained on the 0.1 mmol scale.
In summary, we have developed the first enantioselective iridium-catalyzed allylic alkylation reaction of masked acyl cyanide (MAC) reagents. The umpolung strategy shown in this reaction deviates from the normal reactivity patterns used in all but two previously reported iridium-catalyzed allylic alkylations and is the first report of a carbon monoxide synthon in iridium-catalyzed allylic alkylation. Critical to the success of this new reaction is the identity of the methoxymethyl protecting group on the MAC reagent.
The developed methodology proceeds with moderate to excellent yields (up to 95%) and high levels of enantioselectivity (up to 98% ee) up to the gram scale for a wide range of aryl- and heteroaryl-substituted allylic electrophiles.
Preparation of Known Compounds
EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA .1 General Procedure for the Synthesis of Electrophiles .1 General Procedure for the Synthesis of Electrophiles
- Spectroscopic Data for the Synthesis of Electrophiles
- General Procedure for Optimization Reactions (Table 2.1)
- General Procedure for the Iridium-Catalyzed Allylic Alkylation Please note that the absolute configuration of product 69c was assigned by Please note that the absolute configuration of product 69c was assigned by
- Procedure for the Preparatory Scale Reaction
- Spectroscopic Data for the Iridium-Catalyzed Allylic Alkylation Products
Carbonate 70 g was prepared from methyl 3,4,5-trimethoxycinnamate 19 according to the general procedure and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a. The NMR yield (measured with reference to 1,2,4,5-tetrachloro-3-nitrobenzene 5 7.74 ppm (s, 1H)) was determined by 1H NMR analysis of the crude mixture. The crude mixture was concentrated and the resulting residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to give product 69c as a colorless oil (41 mg, 85% yield): 95% ee;.
The product 71a was prepared according to the general procedure and isolated by silica gel flash column chromatography (10% EtOAc/hexanes) to give a colorless oil (60 mg, 94% yield): 96%. Product 71b was prepared by the general procedure and isolated by preparative TLC (5% EtOAc/hexanes, plate eluted three times) to give a pale yellow oil (36 mg, 58%. Product 71c was prepared by the general procedure and isolated by preparative TLC (9% EtOAc/hexanes, plate eluted twice) to give a colorless oil (37 mg, 69% yield): 96%.
