Coltart Research Group
Synthetic organic chemistry is the unifying feature of all research in the Coltart group. We are particularly interested in the development of new synthetic methods and the use of those methods to enable the total synthesis of structurally complex biologically active natural products. The methods development research in our group focuses mainly on asymmetric carbon–carbon bond formation, especially the α-alkylation of carbonyl compounds. We have been developing two programs in parallel along these lines. One centers on the use of soft enolization of thioesters as an operationally simple alternative to conventional hard enolization procedures. The second focuses on the use of activated hydrazones to achieve the longstanding, yet unrealized goal of developing a general approach to the asymmetric a-alkylation of ketones.
Asymmetric α-Alkylation of Ketones via Activated Hydrazones
While a variety of methods are currently available for conducting synthetic transformations asymmetrically, very few address the asymmetric α-alkylation of ketones. Given the importance of ketone α-alkylation to synthetic chemistry, the lack of asymmetric variants is striking. We have been studying asymmetric ketone a-alkylation via primary and secondary activated hydrazones according to two general reaction manifolds: 1) those based on electrophilic addition to azaenolates and 2) those based on nucleophilic addition to N-sulfonyl azoalkenes, nitrosoalkenes, and related compounds. We define activated hydrazones as those having at least one electron withdrawing group attached to the distal nitrogen (Y or Z in Figure below).
We have developed a new approach to the asymmetric α-alkylation of ketones using N-amino cyclic carbamate (ACC) auxiliaries. Alkylation via ACCs offers a number of advantages over conventional methods. For instance, the auxiliaries are both easily introduced into and removed from ketones, with near quantitative recovery. Deprotonation is rapid, and alkylation does not require extreme low temperature, yet proceeds with excellent stereoselectivity. ACCs also enable a fundamentally new type of alkylation not possible using other methods. This stems from their ability to actively participate in deprotonation through coordination to LDA (complex induced syn-deprotonation – CIS-D), which leads to deprotonation on the same side of the carbon–nitrogen double bond as the auxiliary. This overrides the normal preference of LDA for the most sterically accessible proton, thus enabling the direct asymmetric α,α–bisalkylation of ketones possessing both α and α’ protons, which is a useful yet previously unattainable transformation. In contrast, LDA-mediated bisalkylation of ketones, imines, and dialkyl hydrazones (e.g., SAMP/RAMP) gives exclusively α,α´–bisalkylation.
While we have studied several different ACC auxiliaries, we have narrowed our focus to the two shown below in red. The simple phenylalanine derived auxiliary is ideal for situations in which the α’-carbon has greater steric bulk than the α-carbon. When that is not the case, the camphor derived auxiliary gives superior results. Hydrolytic conditions have been established that allow the auxiliary to be removed without causing epimerization. The er of ketones produced is typically >98:2 and yields are excellent.
We have developed the first method for the asymmetric a,a-bisalkylation of ketones having both α- and α’-protons, enabled by complex induced syn-deprotonation (CIS-D) of chiral N-amino cyclic carbamate (ACC) hydrazones. This method is remarkable in producing near perfect levels of both stereo- and regioselectivity. Moreover, the regiochemical outcome is the opposite of that normally obtained for kinetic LDA-mediated deprotonation of ketones and SAMP/RAMP hydrazones. Conveniently, this strategy allows access to either ketone enantiomer using a single enantiomer of the auxiliary.
Umpolung alkylation, wherein an organometallic species adds to an electrophilic α-carbon provides an alternative to enolate methods. This strategy is well suited to catalysis and could prove general given the wide range of structures available as organometallic reagents (e.g., 1˚, 2˚,3˚ alkyl, aryl, vinyl, alkynyl). We are currently exploring ways to achieve this through the use of activated alkenes (e.g., azo- and nitrosoalkenes) obtained by oxidation of hydrazones and related compounds. Along these lines, we have developed the first Cu(I)-catalyzed addition of Grignard reagents to in situ-derived N-sulfonyl azoalkenes. This umpolung alkylation reaction enables the synthesis of extremely hindered compounds that would be inaccessible using traditional enolate chemistry, and also provides a unique approach to regiocontrolled α,α-bisalkylation.
Direct Carbon-Carbon Bond Formation via Soft Enolization of Thioesters
One of our primary research objectives is the development of mild and operationally simple approaches to key carbon–carbon bond-forming reactions. In terms of developing mild synthetic methods, Nature’s repertoire of reactions is an ideal source of inspiration given that these reactions are conducted in an aqueous environment and, typically, under aerobic conditions. Moreover, years of evolution have led to the refinement of these transformations and much can be learned from the way they are carried out. When is comes to carbon–carbon bond formation, Nature has a predilection for the use of thioesters. An important example of the utility of thioesters in biological carbon–carbon bond formation occurs in the enzyme citrate synthase (CS). CS is a component of the Citric Acid Cycle responsible for the condensation of acetyl-CoA and oxaloacetate to give citrate. During catalysis acetyl-CoA is situated within the active site in proximity to an imidazole group and an ordered water molecule that hydrogen bond to the thioester carbonyl, activating it to the extent that a weakly basic carboxylate group can effect deprotonation. Viewed in this way, deprotonation in citrate synthase may be thought of as a form of soft enolization. There is little doubt that Nature’s choice to use thioesters over other simple carboxylate species is a deliberate one. This has led to the central hypothesis of this portion of our research program, which is that thioesters are particularly well suited to soft enolization in comparison to other simple carboxylate species, and that the derived enolates can be trapped by various nucleophiles.
Soft enolization was pioneered by Mike Rathke in 1985. In contrast to hard enolization, wherein deprotonation is achieved irreversibly using a very strong base such as LDA, soft enolization occurs when a relatively weak base and Lewis acid act in concert to effect reversible deprotonation. Here, the Lewis-acid interacts with the carbonyl oxygen to polarize it beyond its normal state, resulting in a substantial increase in the acidity of the α-proton, such that it can be removed to an appreciable extent by a weak base. Since a strong base is not used, this approach to enolization is inherently milder and can be conducted under much less stringent conditions (e.g., open to the air, untreated solvent, rt) than are required of hard enolization procedures. Moreover, it is conducted in a direct fashion in the presence of the electrophilic species, which can further simplify the procedure.
Soft enolization offers the potential for the development of mild and operationally simple direct approaches to key carbon–carbon bond-forming methods. Despite the considerable potential of this mode of enolization, very little research has been conducted on it. We have been studying soft enolization using primarily thioesters, and to a lesser extent ketones. Our results to date firmly establish the viability of this approach to direct carbon–carbon bond formation in the context of important transformations, several of which are summarized below.
Natural Products Total Synthesis
Much of the methodology that we have developed has been, or is being applied in the context of natural product total synthesis. Often the final objective is not the synthesis of the natural product, which in and of itself is a worthwhile and challenging goal. Instead, the completed synthesis marks the transition into biological investigations. Some targets that are either completed or in progress include the following.
