Synthesis of Enantiopure Triols from Racemic Baylis-Hillman Adducts Using a Diastereoselective Peroxidation Reaction

Abstract

Using a chiral (−)-menthone auxiliary, enantiopure cyclic derivatives of Baylis-Hillman adducts were synthesized. A diastereoselective peroxidation reaction was used to introduce an oxygen atom and establish another stereocenter. The resulting products could be elaborated employing a one-flask reduction-acetylation protocol followed by a diastereoselective nucleophilic substitution reaction. Removal of the (−)-menthone auxiliary provided an enantiopure triol with a structure related to naturally occurring polyols.

Graphical Abstract

The structural motif consisting of a carbon chain bearing hydroxyl groups on consecutive carbon atoms recurs in many natural products. This motif, which defines carbohydrates, is also present in a number of biologically active compounds, such as (9S)-dihydroerythronolide A (1), which is a precursor to many common antibiotics, including erythromycin,¹ azithromycin,² and clarithromycin (Figure 1).³ Another natural product that contains this set of hydroxyl-bearing stereocenters, altersolanol A (2), displayed anticancer activity (Figure 1).⁴ The stereoselective synthesis of a tertiary hydroxyl group positioned between two secondary hydroxyl groups, as in compounds 1 and 2, has been particularly difficult. For example, establishing this stereochemical array in (9S)-dihydroerythronolide A (1) required lengthy synthetic routes.^5–9

Figure 1.

Biologically active compounds bearing hydroxyl groups on consecutive carbons.

In this Letter, we report a method for the synthesis of enantiomerically pure triols with the motif highlighted in 1 and 2 using racemic Baylis-Hillman adducts as the key starting materials (Scheme 1). The enantiomers of these adducts were resolved by forming an acetal with (−)-menthone (5).^10–14 The configuration at the tertiary hydroxyl group was established with a diastereoselective cobalt-catalyzed peroxidation reaction¹⁵ on the resulting acetal. A diastereoselective nucleophilic substitution reaction¹⁶ was used to extend the chain of carbon atoms and control the configuration of the remaining stereocenter, leading to enantiopure triols¹² with the relative stereochemistry found in 1 and 2.

Scheme 1.

General transformation from racemic Baylis-Hillman adducts to enantiopure triols.

The alkene hydration reaction required optimization. Initial studies were performed on lactone 6, which was prepared by the route illustrated in Scheme 2 (vide infra). It was anticipated that if the stereoselective peroxidation could be developed, the resulting peroxide could be reduced to the desired alcohol. Although the cobalt-catalyzed peroxidation of alkenes is generally not diastereoselective in simple systems,^17–22 similar cyclic Baylis-Hillman adduct derivatives have been used in stereoselective radical reactions.²³ Spiroacetal 6 reacted with high diastereoselectivity under conditions optimized for a related substrate¹⁵ (Table 1). With trifluorotoluene (PhCF₃) as the solvent and in the presence of Et₃SiH and molecular O₂, diastereoselectivity improved as the amount of PhSiH₃ was increased, likely by selective decomposition of the minor diastereomer of the silyl peroxide, anti-7.¹⁵ The yield of the major silyl peroxide syn-7 also decreased, however (entries 1–3). Switching the solvent to acetonitrile (MeCN) increased the yield of the major silyl peroxide syn-7 while maintaining high diastereoselectivity, even without PhSiH₃. Because the addition of 5 mol% of PhSiH₃ resulted in lower yields (entry 5), this additive was excluded from the optimal conditions (entry 4).

Scheme 2. Representative synthesis and peroxidation of enantiopure lactones.^a.

^aPeroxidation reaction conditions: alkene (15 or 16, 1 equiv), Et₃SiH (2 equiv), Co(thd)₂ (10 mol%) in MeCN (0.3 M) under a balloon of O₂, 3 h.

Table 1.

Optimization of the diastereoselective peroxidation reaction.

Entry	Solvent	PhSiH3 (mol%)	dr 7	Yield svn-7 (%)a	Yield 7a (%)a
1	PhCF3	0	94 : 6	63	10
2	PhCF3	5	97 : 3	66	11
3	PhCF3	10	98 : 2	57	12
4	MeCN	0	98 : 2	73	8
5	MeCN	5	99 : 1	68	7

^aYields obtained by ¹H NMR spectroscopy with mesitylene as the internal standard.

The purification method also required optimization. The use of Co(thd)₂ in cobalt-mediated peroxidation reactions results in the formation of significant quantities of cobalt-containing impurities that are difficult separate from the desired product.²⁴ The use of high surface-area silica (Davisil®-grade) was critical for the separation of the major silyl peroxide from the cobalt-containing impurities. After one purification, the product was isolated without residual cobalt-containing impurities, as evidenced by ¹H NMR spectroscopy and visual inspection of the resulting white solid. Purification using standard-grade silica gel also caused significant decomposition of the product,¹⁵ likely due to an acid-catalyzed²⁵ degradation pathway that formed methyl ketone 9.²⁶

The overall sequence employed for the preparation of enantiomerically pure products from racemic Baylis-Hillman adducts is demonstrated in Scheme 2 for a substrate that bears a side chain similar to those found in peroxide-containing natural products.²⁷ Ester 12, which was prepared from 3,5,5-trimethylhexanal (10) and methyl acrylate (11), was hydrolyzed to give the corresponding hydroxyacid 13 (dr 50 : 50). After recrystallization, a single diastereomer of hydroxyacid 13 was obtained in 33% yield. Silylation of hydroxyacid 13 with (Me₃Si)₂NH provided compound 14, which was immediately coupled to (−)-menthone (5) with catalytic trimethylsilyl trifluoromethanesulfonate (Me₃SiOTf).^10–13,28 The resulting diastereomeric lactones 15 and 16 were separated by flash chromatography.

Although the sequence was generally continued with the major lactone 16, the minor diastereomeric lactone 15 can also be used to prepare enantiomerically pure products. When lactones 15 and 16 were subjected separately to the optimized peroxidation conditions, the corresponding silyl peroxide products syn-17 and syn-18 were formed in similar diastereomeric ratios (Scheme 2). X-ray crystallographic analysis was used to establish the configuration of the major silyl peroxide product syn-18.²⁹ Comparison of the ¹H NMR spectra of the silyl peroxide products 17 and 18 showed that they shared the same relative configuration.²⁹ These experiments demonstrate that the configuration at the allylic stereocenter, not the menthone auxiliary, controlled the stereochemical outcome of the reaction. Torsional effects³⁰ during the addition of molecular O₂ to the planar, stabilized radical^31–32 likely dictate the stereochemical outcome.¹⁵

A range of Baylis-Hillman-derived alkenes underwent this peroxidation reaction with high diastereoselectivity (Scheme 3). The diastereoselectivity of the peroxidation depended upon the size of the alkyl side chain. The peroxidations of β-branched substrates, such as 6 and 16, occurred with the highest diastereomeric ratios (silyl peroxides 7 and 18, dr ≥98 : 2). The reactions of lactones with less substituted side chains, including lactones 20 and 21, occurred with slightly lower selectivity (silyl peroxides 23 and 24, dr = 94 : 6). The peroxidation of alkene 22, which bears an n-alkyl group, was the least selective (silyl peroxide 25, dr = 89 : 11). This trend suggests that the side chain may impede the approach of molecular O₂ to the radical intermediate.¹⁵

Scheme 3. Substrate scope of the diastereoselective peroxidation reaction.^a.

^aReaction conditions: alkene (6, 16, 20–22, 1 equiv), Et₃SiH (2 equiv), Co(thd)₂ (10 mol%) in MeCN (0.3 M) under a balloon of O₂, 3 h.

With two of the three stereogenic centers established, the next stage of the synthesis involved a nucleophilic substitution reaction. The success of this reaction was not assured because the unprotected hydroxyl group could complicate the substitution. One-flask reduction-acetylation³³ of the major silyl peroxylactone product (syn-7) with i-Bu₂AlH and Ac₂O resulted in the dioxane acetal 26. This reduction also converted the silylperoxy group into the desired hydroxyl group. The resulting acetal underwent nucleophilic substitution using allyltrimethylsilane and BF₃•OEt₂ to yield two products in a 91:9 ratio (Scheme 4). This result demonstrated that the acetal substitution reaction could be achieved in the presence of a free hydroxyl group.³⁴ The major product was initially assigned as the expected substitution product anti-29. NOE and long-range ¹H/¹³C correlation spectra (heteronuclear multiple bond correlation, HMBC), however, were not consistent with this connectivity. Instead, the ring-contracted product 28 was more consistent with the spectroscopic data. The minor component of the reaction mixture was not the diastereomer of 28. Its spectra indicate that it is the product of an annulation reaction, cis-fused tetrahydrofuran 28a.^35–40

Scheme 4. Allylation of reduced and acetylated acetal 26 and expected dioxanes 29.

^aYields obtained by ¹H NMR spectroscopy with mesitylene as the internal standard.

The formation of the observed products can be explained by considering the reaction mechanism (Scheme 5).⁴¹ Upon activation of the acetyl group, oxocarbenium ion 30 is formed. The nucleophile preferentially attacks from the bottom face to form a chair conformer (33).^30,42–43 A small amount of attack from the other face of oxocarbenium ion 30 leads to the formation of an unfavorable twist-chair (31). The β-silyl carbocation 31 is trapped by the hydroxyl group, forming the cis-fused tetrahydrofuran 32.

Scheme 5. Proposed reaction mechanism of the allylation of reduced and acetylated acetals.^a.

^aR^M refers to the menthone auxiliary.

The major allylation product 34, however, is not stable to the Lewis acid because it is destabilized by a 1,3-diaxial interaction between the allyl group and the axial C–C bond of the menthone auxiliary. To alleviate the syn-pentane-like interaction, the Lewis acid activates the oxygen atom that is farther from the isopropyl group on the menthone auxiliary, and is therefore less sterically hindered.^10–11,44 Acetal exchange leads to the favored ring-contracted product 36. Computational studies (ωB97XD/6–31G*) support this hypothesis: the dioxane with an axial allyl group, anti-29, was found to be 3.4 kcal/mol higher in energy than the diastereomer with an equatorial allyl group, syn-29 (Scheme 4). This difference in energy is comparable to the energy inherent to a syn-pentane interaction, which is evident in the three dimensional structure of dioxane anti-29 (Scheme 4).⁴⁵

The propensity to undergo rearrangement was even present in the starting lactone. Upon standing in MeCN over several weeks, alcohol 7a rearranged to acid 37 (Scheme 6). This rearrangement revealed that not only 1,3-diaxial interactions contribute to the tendency for these substrates to undergo ring contraction. This destabilizing effect may be stereoelectronic in origin, considering that hydrolysis of 1,3-dioxanes has been shown to be about 40 times faster than the hydrolysis of 1,3-dioxolanes due to improved orbital alignment during the protonation/elimination step.⁴⁶

Scheme 6.

Rearrangement of alcohol side product 7a.

The stereoselective addition and rearrangement reaction was general for the other substrates. In each case, the major product of the allylations of dioxanes 26 and 38–41 shared the same overall structure as the product shown in Scheme 4 (28 and 43–46, Scheme 7). Methallyltrimethylsilane (42) also reacted with the acetylated acetal 26 to form a single diastereomer of 1,3-dioxolane 47 without formation of a side product.

Scheme 7.

Substrate scope of nucleophilic additions.

The final step of the overall synthesis of triols involves a hydrolysis reaction, which was demonstrated on allylated dioxolanes 28 and 44.¹¹ Removal of the menthone auxiliary in acidic methanol yielded single stereoisomers of the triols 48 and 49 (Scheme 8).

Scheme 8. Hydrolysis of the menthone auxiliary.

^aThe low yield resulted from difficulty with purification. Details are provided as supporting information.

In summary, racemic Baylis-Hillman adducts were converted to enantiopure spirolactones using a (−)-menthone (5) auxiliary. These lactones were peroxidized diastereoselectively. The resulting silyl peroxides were subjected to a one-flask reduction-acetylation reaction. Diastereoselective nucleophilic substitution on the resulting acetylated spiroacetals, followed by removal of the (−)-menthone (5) auxiliary, yielded enantiopure triols that mirror substructures present in biologically active compounds.

Figure 2.

Methyl ketone decomposition product.