β-Siloxy-α-Haloketones via Highly Diastereoselective Single and Double Mukaiyama-Aldol Reactions

Halogens, in particular fluorine and chlorine play pivotal role in modern medicinal chemistry due to their strong impact on biological properties of organic molecules.^[1] In nature, organohalogens are mainly chlorine compounds of marine origin, and many of them exhibit potent antiproliferative or antibiotic properties.^[2] Recently, synthetic chemists turned their attention to chlorosulfolipids^{[3, 14j]} due to their unclear biological role and curious architecture resembling polyketides, a class of natural products that hold a prominent position among pharmaceuticals.^[4] For these reasons, it seems especially attractive for future medicinal research, to develop efficient synthetic methods for preparation of stereodefined, halogen-modified polyketide structures. β-Oxy-α-haloketones, which are valuable intermediates of epoxyketones,^{[5, 13e, 13l]} natural products,^[6] heterocycles,^[7] and carbohydrate mimetics,^[8] could also be very useful building blocks for the above mentioned task. Especially, terminal methyl ketones may potentially be utilized as a convenient linchpin for interconnection with aldehyde fragments, to efficiently gain molecular complexity through bi-directional assembly of polyketide subunits.^[14h-i] Methods for preparation of β-oxy-α-haloketones to date include: aldol reactions of metal enolates, which are especially efficient with bulkier ketones,^{[5, 7b, 9]} Mukaiyama-aldol reactions, which unfortunately generate only diastereoisomeric mixtures,^[10] oxyhalogenation of certain unsaturated ketones,^[11] enzymatic,^[12] and organocatalytic^[13] aldol reactions, which are particularly useful for conversion of aromatic aldehydes. Despite tremendous progress in this field, a truly flexible and highly diastereoselective method to access simple chloroacetone aldol products is still required.

Herein, we describe the first highly diastereoselective Mukaiyama-aldol reaction of chloroacetone and fluoroacetophenone, as well as the implementation of these substrates into the one-pot sequential-aldol protocol.^[14]

α-Chloroketone-derived “super-silyl” [tris(trimethylsilyl)silyl, TTMSS] enol ethers 2a-b were prepared^[15] in excellent regio- and diastereoselectivities via rearrangement of lithium carbenoid species^[10a] generated from “super-silyl”-protected trichloromethyl alcohols 1a-b, which are ready available by the nucleophilic addition of chloroform to aldehydes^[16a] or equivalents thereof^[16b-c] (Scheme 1). The fluorine-containing silyl enol ether 2c was prepared directly from fluoroketone 3, which was accessible by sequential monodefluorinaton^[16d] of trifluoroacetophenone (Scheme 1).

Scheme 1.

Synthesis of α-haloketone-derived silyl enol ethers. [a] Z/E ratio based on integration of the ¹H NMR signals of crude material.

In an analogous fashion, we have also prepared chloroacetone-derived silyl enol ethers bearing few other common silyl groups, and briefly compared their performance in the acid-catalyzed aldol reaction with benzaldehyde under conditions optimized previously for similar reactions (Table 1).^[14j] Results clearly show the superiority of the super-silyl group, which was essential for providing the product in excellent diastereoselectivity and yield.

Table 1.

Influence of the silyl group on the aldol reaction.

Entry	R	Yield[a]	dr[a]
1	Me	54%	60:40
2	Et	74%	68:32
3	i-Pr	82%	86:14
4	SiMe3	97%	99:1

^[a]Yield and dr by integration of the ¹H NMR signals of crude material.

Having starting materials in hand we have systematically explored the scope of the Mukaiyama-aldol reaction with silyl enol ether 2a, which reacted smoothly with a remarkably broad range of aldehydes, furnishing β-siloxy-α-chloroketones 4-30 with exceptionally high anti-diastereoselectivities (Table 2).

Table 2.

Synthesis of β-siloxy-α-chloroketones.

Yields of isolated ketones. Dr based on integration of the ¹H NMR signals of the crude reaction mixture.

^[a]From previous examples of super-silyl enol ether addition to 2-phenylpropanal^[14a,f,k] we expect 11 to be the anti,syn diastereoisomer, however the stereochemical assignment was not performed in this case.

^[b]2 eq. of the silyl enol ether 2a were used.

Reactions with propanal and longer-chain, as well as bulkier, α-branched aliphatic aldehydes afforded products 4-9 in excellent diastereoselectivities and very good yields. The chloroacetaldehyde furnished bishalogenated 10 in very good yield and dr of 10:1. The 2-phenylpropanal provided 11a having three contiguous stereocenters with a remarkably high diastereoselectivity. Reaction was also applicable to α,β-unsaturated and heterocyclic aldehydes giving products 12-15 in good yields and excellent diastereoselectivities. Indole-2-carboxyaldehyde, bearing an unprotected indole nitrogen atom, required 2 eq. of enol ether to achieve the full conversion to 16, albeit in only 6:1 dr. Aromatic aldehydes, regardless of their steric or electronic properties, reacted very smoothly with 2a affording products 17-30 in good to excellent yields and excellent diastereoselectivities.

To further demonstrate the flexibility of this method, pivalaldehyde, 2-naphthaldehyde, methyl benzaldehyde-4-carboxylate, and 3,5-dibromobenzaldehyde were reacted with the silyl enol ether 2c yielding fluorinated ketones 31-34 respectively. Furthermore, benzaldehyde was also reacted with the silyl enol ether 2b, furnishing chlorinated heptyl ketone 35 (Table 3). Silyl enol ethers 2b and 2c showed similar good reactivity as 2a, albeit the corresponding products were afforded with slightly eroded diastereoselectivities.

Table 3.

Synthesis of β-siloxy-α-haloketones.

Yields of isolated ketones. Dr based on integration of the ¹H NMR signals of the crude reaction mixture.

Finally, we set out to establish if these halogenated, ketone-derived silyl enol ethers could be implemented into the one-pot sequential-aldol reaction^[14] and thus provide a rapid access to a new type of halogen-modified polyketide fragments. To demonstrate the utility of this protocol silyl enol ethers derived from chloro- and fluoroacetaldehyde,^[14j] as well as propanal^[14k] were chosen as partners in the first aldol step. To our delight, the one-pot sequential reaction of thus preformed anti-3-siloxy-2-functionalized aldehydes with 2a or 2c as second aldol-partners provided novel syn-syn-anti-configured 3,5-bissiloxy-2,4-bishaloketones 36-42 as well as a 3,5-bissiloxy-2-chloro-4-methylketone 43 in good to excellent yields and good to excellent diastereoselectivities (Table 4). The second aldol addition of (Z)-halo silyl enol ethers 2a/c to the mono-aldol intermediates is, as expected, Felkin-selective.^{[14j, 17]}

Table 4.

One-Pot Sequential Double-Aldol Reactions.

Reactions performed directly on crude mixtures of α,β-functionalized aldehydes. Yields of isolated ketones, yields given over two steps. Dr based on integration of the ¹H NMR signals of purified materials.

In summary, we have developed a remarkably general and highly anti-stereoselective Mukaiyama aldol reaction of tris(trimethylsilyl)silyl enol ethers derived from α-halogeneted ketones. Furthermore, we have successfully incorporated these silyl enol ethers into our one-pot sequential-aldol methodology which allows for a rapid, diastereoselective, and flexible construction of exotic polyketide-like fragments featuring four contiguous stereocenters. Overall, this methodology offers a step-economic access to a synthetically valuable and potentially pharmacophoric architectures, which are not easily accessible by other methods.