Enantioselective Synthesis of α-Methylene-β-hydroxy Carboxylic Acid Derivatives via a Diastereoselective Aldol-β-Elimination Sequence: Application to the C(15)–C(21) Fragment of Tedanolide C

Abstract

An enantioselective synthesis of α-methylene-β-hydroxy carboxylic acid derivatives via a highly diastereoselective, one-pot syn-aldol and β-elimination sequence utilizing the chiral β-(phenylselenyl)propionyl imide 15 is described. This new method, which constitutes an alternative to the Baylis-Hillman reaction, has been applied to the synthesis of the C(15)-C(21) fragment of tedanolide C.

Tedanolide C (1) is the newest member of a family of marine natural products which include tedanolide (2), 13-deoxytedanolide (3) and the candidaspongiolides (4, Figure 1).^1–4 Tedanolide C was isolated from a Papua New Guinea marine sponge of the Ircinia species, and its structure and relative stereochemistry were assigned by NMR methods in conjunction with molecular modeling and DFT calculations. Tedanolide C displays an IC₅₀ value of 0.057 µg/mL (95 nM) against HCT-116 cells (colorectal cancer cell line), and also arrests growth of HCT-116 cells in the S-phase after 24 h exposure at 0.2 µg/mL. It has been suggested that tedanolide C, like 13-deoxytedanolide (3), may be a protein synthesis inhibitor.¹

Figure 1.

Family of tedanolide natural products

In planning a synthesis of tedanolide C (1), we elected to target the enantiomeric structure 5 (Scheme 1). The C(10)–C(23) fragment has been identified as the key pharmacophoric unit of 13-deoxytedanolide,⁵ but the stereochemistry of the corresponding fragment has been given the enantiomeric configuration (except for the epoxide) in the proposed structure of tedanolide C (1);¹ the absolute configuration of tedanolide C has not been assigned. Therefore, we selected the enantiomeric stucture 5 as the synthetic target in anticipation that this will lead to the biologically active, naturally occuring enantiomer.

Scheme 1.

Retrosynthetic anaylsis of the C(15)–C(23) fragment of tedanolide C (synthetic target 5).

Our retrosynthetic analysis (Scheme 1) of target 5 focuses on the formation of the tertiary hydroxy group at C(16) by a dihydroxylation reaction of alkene 7. In order to synthesize 7, we considered using the Baylis-Hillman reaction between epoxyaldehyde 8 and methyl acrylate (9).^6,7 However, this reaction failed (Scheme 1), presumably because the valuable, synthetically advanced aldehyde intermediate 8 could not be used in large excess—as is generally required for bimolecular Baylis-Hillman reactions.^6,7

We therefore considered the possibility of using an aldol reaction to prepare Baylis-Hillman type products in an enantioselective fashion.⁸ Specifically, we anticipated that an acyl oxazolidinone like 10, equiped with a leaving group at C(3) of the propionyl fragment, would be a suitable substrate for a boron-mediated Evans syn-aldol reaction (Scheme 2).⁹ This approach would have the advantage that both the masked Michael acceptor 10 and the aldehyde could be used in stoichiometric amounts.

Scheme 2.

Rationale of applying aldol chemisty for the preparation of Baylis-Hillman type products.

As additional design criteria, the leaving group “X” in 10 was required to be stable under the aldol reaction conditions but to undergo β-elimination during reaction work-up. We anticipated that the phenylselenyl group, as in 15, would satisfy these criteria.⁸ Accordingly, acyl oxazolidinone 15 was synthesized in high yield by 1,4-addition of PhSeH to known acryloyl imide 14 and subsequent re-crystallization.¹⁰

Oxazolidinone 15 was readily converted into the corresponding boron enolate upon treatment with Bu₂BOTf and NEt₃ under standard conditions (c = 0.2 M in CH₂Cl₂, −78 °C).^9a Addition of isobutyraldehyde to the enolate solution at −78 °C to promote the aldol reaction (6 h at up to 0 °C), followed by oxidative workup with H₂O₂ and pyridine at 0 °C resulted in the oxidation of the phenylselenide to the selenoxide which underwent a subsequent β-elimination to give the allylic alcohol 13a in 81% yield.

A wide variety of aldehydes are compatible with this methodology (Table 1). Simple aliphatic aldehydes such as isobutyraldehyde and propionaldehyde gave α-methylene-β-hydroxy imides 13a and 13b in 81–93% yield (entries 1, 2). Use of the stereochemically demanding pivaldehyde as substrate gave product 13c in 56% yield after conversion to the TBS ether (entry 3).

Table 1.

Synthesis of α-methylene-β-hydroxy acyl oxazolidinones 13a–i via an aldol-elimination sequence^a

entry	aldehyde		product b,c	yield d
1		13a		81%
2		13b		93%
3		13c		56%e
4		13d		86%
5		13e		86%
6		13f		84%
7		13g		88%
8		13h		88%
9		13i		76%

^aGeneral procedure for the aldol-elimination sequence: Formation of the boron enolate from imide 15 (1.0 equiv), Bu₂BOTf (1.2 equiv) and NEt₃(1.8 equiv) in CH₂Cl₂(c = 0.2 M) at −78 °C; addition of aldehyde (1.1 equiv) at −78 °C; oxidation of the aldol product in CH₂Cl₂ and pyridine (2.0 equiv) at 0 °C with H₂O₂ (approx. 3–5 equiv); all products were isolated by column chromatography;

^bXp = (4S)-(4-benzyloxazolidinone)-5-yl;

^cdr >20:1;

^dIsolated yields of the indicated products;

^e13a was isolated after protection as the TBS ether.

Various aromatic aldehydes were excellent substrates: aldol-elimination reactions of benzaldehyde, 2-furaldehyde, 4-methylthiazole-5-carboxaldehyde and 3-pyridinecarboxaldehyde gave products 13d (86%), 13e (86%), 13f (84%), and 13g (88%), respectively (entries 4 – 7). Due to the mild oxidative work-up conditions, pyridine-N-oxide formation was not observed in the latter case.

Finally, the silyl-protected α-hydroxyaldehyde 16¹¹ gave 13h in 88% yield (entry 8). In addition, α,β-unsaturated aldehydes such as 17¹² could also be used as substrate (76% yield; entry 9); unsaturated aldehydes are typically avoided in Baylis-Hillman reactions.⁶ The only substrate that worked poorly in our hands was acrolein, which gave a multitude of side products that were difficult to separate (data not shown). In all cases, the isolated allylic alcohols 13a–13i were obtained as single diasteromers.

We expected from the outset that acyl oxazolidinone 15 would undergo aldol reaction via the corresponding Z(O)-boron-enolate 11 (X = SePh) and provide syn-aldol products prior to oxidative workup. This was confirmed in the case of aldol 18, which was isolated from an aldol reaction of 15 and isobutryraldehyde following mild basic (but non-oxidative) work-up. Treatment of 18 with LiBH₄ and protection of the resulting 1,3-diol gave p-methoxyphenyl (PMP) acetal 19. The H_a–H_b coupling constant of 19 (³J = 1.9 Hz) as well as ¹H NOE data provide the basis for this assignment (Scheme 3).

Scheme 3.

Stereochemical assignments

The absolute configuration of aldol 18 was determined independently via the advanced Mosher ester method,¹³ as well as by reduction of the derived allylic alcohol 13a to the known diol 20 upon treatment with NaBH₄ in the presence of CeCl₃ .7H₂O.^14,15

Application of this new methodology to the synthesis of the C(15)–C(21) fragment 27 of tedanolide C is presented in Scheme 4. Aldehyde 8 was synthesized starting from the known aldehyde 21. Thus, standard Wittig reaction of 21 with Ph₃P=CHCO₂Et followed by DIBAL reduction of the ester provided allylic alcohol 22 (80%). Subjection of 22 to the Sharpless asymmetric epoxidation conditions¹⁶ followed by a Parikh-Doering oxidation of epoxyalcohol 23 provided the epoxyaldehyde 8 in 79% yield from 22. Use of epoxyaldehyde 8 as the substrate for aldol reaction with 15, followed by oxidative workup, provided allylic alcohol 24 in 79% yield with > 20:1 distereoselectivity. Treatment of 24 with NaBH₄ and CeCl₃.7H₂O^14b and subsequent protection of the bis-allylic alcohol 25 with 2 equiv of TESCl gave the bis-silyl ether 26 in 91% yield for the two steps. Finally, asymmetric dihydroxylation of 26 by using Sharpless’ AD-mix β¹⁷ gave diol 27 (75%, 95% b.r.s.m.) as the major component of a 4.5:1 mixture of diastereomers.^18,19

Scheme 4.

Synthesis of the C(15)–C(21) fragment 27 of tedanolide C

In summary, we developed an efficient and highly stereoselective procedure for synthesis of α-methylene-β-hydroxy acyl oxazolidinones - so-called Baylis-Hillman adducts - via an enantioselective syn-aldol/β-elimination sequence using β-(phenylselenyl)propionyl imide 15 as the key reagent. This method allows for the use of 15 and the aldehyde reaction partner in stoichiometric amounts—which is not possible in conventional Baylis-Hillman reactions. This new sequence has been applied to the synthesis of the C(15)–C(21) fragment 27 of tedanolide C (target structure 5). Further elaborations of 27 towards tedanolide C will be reported in due course.