Rapid, Stereochemically Flexible Synthesis of Polypropionates by “Super-Silyl”-Governed Aldol Cascades

The polypropionate motif is an important structural unit present in polyketide natural products, many of which are of great interest due to their wide range of biological activities.^[1] For instance, members of the erythromycin and rifamycin families have long been used as commercial antibiotics.^[2] The importance of these pharmaceutical agents, as well as the potential to discover new biologically active polypropionates, makes their efficient, stereoselective chemical synthesis an important ongoing challenge. The polypropionate structure is recognized by its characteristic carbon chain decorated with alternating methyl- and hydroxyl- groups. The numerous stereogenic centers allows for many possible stereochemical permutations. Even in the case of a simple dipropionate bearing four stereogenic centers, up to 16 diastereomers are possible. This structural complexity has inspired numerous methods for stereoselective synthesis.^[3] Of these methods, the aldol reaction is perhaps the most well studied and widely used in the synthesis of polypropionate natural products.^[4] Other methods include crotylation,^[5,6] epoxide opening,^[7] [2+2] cycloaddition,^[8] borylative aldehyde-diene coupling^[9] and reductive aldol addition.^[10]

While many of these methods have been developed to synthesize polypropionates with high enantio- and diastereo- control, the synthesis of complex polypropionates by these methods usually requires a great deal of steps. For instance, a conventional aldol synthesis of polypropionates begins with an aldol reaction of an ester enolate and an aldehyde (Scheme 1). In order to install a second propionate unit, the resulting β-hydroxyl must first be protected, and the ester reduced to the corresponding aldehyde oxidation state. As a result, in this route each carbon-carbon bond forming event requires numerous additional step-consuming protective group manipulations, redox adjustments, and purifications. Additionally, control of the stereochemistry in subsequent aldol reactions is often complicated.

Scheme 1.

Conventional aldol approach to polypropionates.

Recently, the efficiency of complex molecule synthesis has been evaluated by the concepts of redox economy,^[11] which strives to build molecules with minimal oxidation and reduction steps, and step economy,^[12] which emphasizes reactions that build complexity and avoid extraneous chemical steps. Under these considerations, a more efficient aldol route to polypropionates would be the aldehyde crossed-aldol reaction, in which the nucleophilic species is derived from an aldehyde rather than an ester. The product of the reaction is therefore also an aldehyde, circumventing the need for a redox adjustment. However, aldehyde crossed-aldol reactions,^[13] especially those employing metalloenolates^[14] and silyl enol ethers^[15] are uncommon, due to the instability of the product and side reactions. Toward this end, we have developed the aldol addition of the tris(trimethylsilyl)silyl “super silyl” enol ether of acetaldehyde with simple aldehydes (Scheme 2, X= H).^[16] The product of the reaction is a protected β-hydroxy aldehyde, and is stable yet suitable for nucleophilic addition. Careful choice of reaction conditions allowed for the controlled, stereoselective single, double and triple aldol reactions in a one-pot manner. Using this methodology, polyketides including the natural product EBC-23 were synthesized in a short sequence of steps, with minimal protecting group manipulations and functional group interconversions. The super silyl group plays a critical role in these polyaldol cascades, acting as both a reactive group and a stereodirecting group, allowing for high yields and diastereoselectivities. In this report, we describe our approach to the challenging polypropionate structure by stereoselective aldol cascades utilizing the silyl enol ethers derived from propionaldehyde (Scheme 2, X = CH₃).

Scheme 2.

Synthesis of polypropionates by one-pot aldol cascades using aldehyde-derived “super-silyl” enol ethers. Si =Si(TMS)₃

The first challenge was to develop a diastereoselective single aldol reaction between propionaldehyde derived silyl enol ethers and simple aldehydes. In preliminary experiments, we reported the stereoselective synthesis of the Z silyl enol ether 1Z and found that it reacted smoothly with simple aldehydes to generate 2,3-syn products in high diastereoselectivity.^[16a] We hypothesized that the unique steric and electronic properties of the super silyl group would allow for control of the 2,3- stereochemistry based on the enol ether geometry. The E silyl enol ether 1E was generated as a single diastereomer by iridium-catalyzed isomerization of the corresponding allyl silyl ether following Miyaura’s protocol.^[17] When treated with 0.1 mol% triflimide (HNTf₂) in CH₂Cl₂ at −78°C, 1E underwent smooth aldol addition with simple aldehydes (Table 1). Gratifyingly, the 2,3-anti adducts were obtained, complementing the syn-selective addition using 1Z. This remarkable stereospecific Z-syn, E-anti correlation is not usually observed in Mukaiyama-type aldol reactions. Rather, the diastereoselection is usually substrate controlled due to an open transition state.^[18]

Table 1.

Addition of propionaldehyde enol ethers to aldehydes.

Entry	Enol Ether	Substrate	Product	% yield	dr[a],[b]
1	1E	R1 = CH3	3a-anti	74	79:21
2	1E	n-Pent	3b-anti	87	87:13
3	1E	c-Hex	3c-anti	82	86:14
4	1E	(E)-PhCH=CH	3d-anti	58	97:3
5	1E	TMSC≡C	3e-anti	67	79:21
6	1E	Ph	3f-anti	76	96:4
7	1E	4-(OCH3)C6H4	3g-anti	54	93:7
8	1E	2-furyl	3h-anti	95	>97:3
9	1E	2-(Cl)C6H4	3i-anti	91	>97:3
10	1E	4-(NO2)C6H4	3j-anti	95	>97:3
11	2E	CH3	4a-anti	84	90:10
12	2E	n-Pent	4c-anti	66	96:4
13	2E	TMSC≡C	4e-anti	63	94:6
14	1Z			76	88:12
15	2E			79	>97:3
16	1Z			85	87:10:3
17[c]	2E			74	90:10
18	1Z			84	83:13:3:2 (er = 96:4)
19	1E			77	76:21:3
20	1Z			78	>97:3 (er = 99:1)

^[a]Ratio of detectable diastereomers by ¹H NMR integration of the crude reaction mixture.

^[b]Enantiomeric ratio of major diastereomer was determined by chiral HPLC.

^[c]Me₂AlNTf₂ (0.5 mol%) was used in place of HNTf₂. TES = trimethylsilyl; Tf = trifluoromethanesulfonyl; TIPS = triisopropylsilyl; Ts = p-toluenesulfonyl.

The anti-selective propionaldehyde aldol reaction displays a wide substrate scope with simple achiral aldehydes (Table 1, entries 1−13). Good yields and high anti-selectivity are obtained for linear and branched aliphatic aldehydes (entries 1−3), as well as unsaturated aldehydes (entries 4 and 5). Aromatic aldehydes of varying electronic and steric properties give excellent selectivity and good yields. The anti-selectivity of the reaction could be further improved by using the E enol ether of propionaldehyde bearing the larger tris(triethylsilyl)silyl “TES-type super silyl” group (entries 11−13, compared to entries 1−3). ^[19]

To further expand the scope of the reaction, and to examine its potential use in the synthesis of molecules of greater stereochemical complexity, we investigated the propionaldehyde aldol addition to chiral aldehydes (Table 1, entries 14−20).^[20] Reaction of 1Z with β-triisopropylsiloxy hexanal resulted in good yield and high selectivity (entry 14). After derivatization, the major diastereomer was found have 2,3,5- syn-syn stereochemistry, demonstrating 1,3-syn asymmetric induction. Use of 2E resulted in 2,3,5- anti-syn as a single diastereomer (entry 15). Aldehydes bearing a stereocenter in the α-position were also investigated (entries 16–20). Remarkably, in all cases the major product was 3,4-syn, following the Felkin model of stereocontrol.^[21] Both the challenging 2,3-syn, ^[22] and the 2,3-anti^[23] products can be obtained, even when aldehydes bearing similarly-sized alkyl groups were used (entries 18 and 19). Importantly, the use of enantiopure α-substituted chiral aldehydes led to products with high enantiopurity, indicating no substantial racemisation under the reaction conditions (entries 18, 20).

With highly selective syn and anti propionaldehyde aldol additions in hand, we turned our attention to multi-component aldol reactions for the one-pot synthesis of highly complex molecules.^[24] Our first goal was to see if a one-pot propionaldehyde/acetaldehyde cascade addition could be accomplished. Benzaldehyde was treated with 1E under standard conditions and monitored by TLC analysis. After the first aldol reaction was judged complete, acetaldehyde- derived enol ether 5 was added (Table 2, entry 1), to generate the double addition product in 67% yield and in excellent dr (95:5). The high diastereoselectivity indicates that the second addition step is nearly completely selective. The product was determined to have 2,3-syn stereochemistry, consistent with the Felkin model of 1,2- stereocontrol. Alternatively, the super silyl enol ether of acetone 6 could be employed as the second nucleophile, producing the methyl ketone double aldol adduct in high yield and selectivity on preparative scale (7.0 mmol) (Table 2, entry 2).

Table 2.

One-pot consecutive aldehyde crossed-aldol additions

Entry[a]	R1	Enol ether 1		Enol Ether 2		Product		% yield[b]	dr[c]
1	Ph		1E		5		7	67	95:5
2[d]	Ph		1E		6		8	86	96:4
3[e]	c-Hex		1Z		5		9	57[f]	–[g]
4	t-Bu		5		1Z		10	43[f]	–[g]
5	t-Bu		5		1E		11	45[f]	–[g]
6	c-Hex		1Z	——			12	63	81:13:2:4
7			1Z	——			13	72	94:4:1:1
8	CH3		1Z	——			14	47	95:5
9	BnOCH2		1Z	——			15	48	89:7:2:2
10	BnOCH2		1E	——			16	63	86:14
11			1E	——			17	74	97:3
12	Ph		1E	——			18	57	95:5
13	Ph		1E		1Z		19	92	89:7:4
14			1Z		1E		20	80	84:7:6:3

^[a]Reactions conducted at 0.30 mmol scale.

^[b]Combined isolated yield of all diastereomers.

^[c]Ratio of detectable diastereomers by ¹H NMR integration of the crude reaction mixture.

^[d]Reaction conducted at 7.0 mmol scale.

^[e]t-BuC≡CI (5 mol%) added with 5.

^[f]Yield shown of isolated single diastereomer after chromatography.

^[g]dr could not be determined by ¹H NMR analysis of the crude mixture.

Consecutive aldol additions to aliphatic aldehydes proved to be more challenging. Mono-aldol adducts varied greatly in reactivity, with small R groups displaying the highest reactivity. Use of HNTf₂ alone did not result in double aldol addition to more sterically demanding aldehydes. However, after optimization of reaction conditions, it was found that HNTf₂ or our previously developed carbon acid C₆F₅C(H)Tf₂^[25] promoted the acetaldehyde addition to propionaldehyde adducts when paired with 5 mol% tert-butyl iodoacetylene.^[16d] Still higher reactivity was observed with ≤0.5 mol% of Lewis acid AlMe₂NTf₂. Thus, under optimized reaction conditions, cyclohexane carboxaldehyde underwent propionaldehyde addition followed by double acetaldehyde addition to give the syn-syn-syn triple aldol product in one pot (entry 3). Alternatively, the order of silyl enol ether addition could be changed to give double acetaldehyde addition to pivalaldehyde followed by propionaldehyde addition (entries 4 and 5). Both 1Z and 1E gave triple aldol products 10 and 11, which were isolated after facile separation from their minor diastereomers in 43% and 45% yields, respectively.

We then turned our attention to consecutive propionaldehyde additions. Double aldol addition of 1Z with a range of aldehydes gave the 2,3,4,5-syn-syn-syn stereochemistry (entries 6−9). Interestingly, when acetaldehyde was used as a substrate, limiting the amount of 1Z to just 1.5 equivalents resulted in 48% yield of the syn-syn-syn double aldol adduct in excellent dr (95:5) along with 22% yield of the predominantly anti mono aldol adduct (dr = 85:15) (entry 8). When >1.5 equivalents was used, the yield of the double aldol product increased but the diastereomeric ratio of the product decreased. This observation can be explained by a kinetic resolution of diastereomers: the first aldol reaction is non-selective, resulting in a ~1:1 mixture of 3a-anti and 3a-syn. However, 3a-syn undergoes a selective second aldol addition more rapidly than 3a-anti.

Double propionaldehyde aldol addition of 1E to aldehydes was also possible (entries 10–12). Addition of 1E to alanine-derived (S)-N-benzyl-N-tosyl 2-amino-propanal^[26] (entry 11) showed excellent selectivity, producing predominantly one out of 16 possible diastereomers (dr = 97:3). After derivatization, the stereochemistry of 17 was determined by X-ray crystallographic analysis. Curiously, the anti-anti-anti-anti stereochemistry was obtained, indicating the first aldol addition takes place with anti-Felkin selectivity.^[27] The anti-anti-anti stereochemistry was also obtained by double addition of 1E to benzaldehyde and benzyloxy-acetaldehyde (entries 10 and 12).

Having generated double aldol products with 2,3,4,5- syn-syn-syn stereochemistry and 2,3,4,5- anti-anti-anti stereochemistry, we wondered if it would be possible to generate other stereotetrads with high diastereoselection by sequential addition of 1Z followed by 1E or vice versa. Gratifyingly, benzaldehyde underwent addition of 1E followed by 1Z in one pot in excellent yield (92%) and diastereoselectivity (dr = 89:7:4) (entry 13). After derivatization, product 19 was found to have 2,3,4,5- syn-syn-anti stereochemistry. Using 2-methyl butanal as a substrate, we reversed the order of addition (first 1Z then 1E), and obtained the 2,3,4,5,6-anti-syn-syn-syn product 20 in good yield (80%) and high selectivity (84:7:3:2).

In summary, we have developed a general propionaldehyde crossed-aldol reaction affording syn or anti aldol products with high diastereoselectivity and wide substrate scope. These aldol products can themselves undergo acetaldehyde- acetone-, and double-acetaldehyde aldol additions to rapidly assemble polyketide fragments in excellent step economy and without redox manipulations. Double-propionaldehyde aldol reactions were also developed, producing molecules with up to five contiguous stereogenic centers with high control of diastereoselectivity. The Z/E geometry of the silyl enol ether and the order of addition are convenient handles for controlling the stereochemistry of the product, making this method highly flexible. Overall, this report represents a highly efficient alternative to lengthy classical aldol syntheses of polypropionates.