Synthesis of the C3–C7 fragment of tylonolide by the γ-hydroxybutenolide approach

Tetrahedron Letters 57 (2016) 3929–3932

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Synthesis of the C3–C7 fragment of tylonolide by the c-hydroxybutenolide approach William H. Miles ⇑, Cassidy M. Madison, Michael L. Mastria, Pui-In Tang Department of Chemistry, Lafayette College, Easton, PA 18042, United States

a r t i c l e

i n f o

Article history: Received 15 June 2016 Revised 12 July 2016 Accepted 17 July 2016 Available online 18 July 2016

a b s t r a c t The seven-step synthesis of the C3–C7 fragment from 3-furanmethanol is described. The key step is an asymmetric aldol reaction of a c-hydroxybutenolide with the titanium enolate of an N-propionyloxazolidinone. The resulting lactone was reduced to give the C4–C6 stereotriad, with further selective reductions to differentiate the two termini and C20 as a protected acetal. Ó 2016 Elsevier Ltd. All rights reserved.

Keywords: Aldol c-Hydroxybutenolide Tylonolide Reduction Macrolide

Macrolide antibiotics are important human and veterinary medicines.1 Tylosin, a 16-membered macrolide first isolated from Streptomyces fradiae, is an antibiotic widely employed in the treatment of a variety of Gram-positive bacterial infections in animals.2 Many semi-synthetic compounds based on tylosin have also become commercially important veterinary medicines, including tilmicosin and tildipirosin.3 Other modifications of tylosin have led to compounds with anti-malarial activity and significant antibacterial activity against Gram-positive and Gram-negative bacteria.4 But the development of resistance by pathogens to macrolides and other commonly used antibiotics5 necessitates the discovery and development of new antibiotics. This goal is potentially achievable by the further modification of tylosin and also by the development of de novo synthetic strategies to the aglycone of tylosin, tylonolide (1; Fig. 1). The first syntheses of 1 appeared in the literature in the early 1980’s, relying on what have become standard tools of organic synthesis: efficient macrolactonizations, enantioselective aldol and related allylation reactions, and exploitation of the chiral pool.6 Since those initial syntheses, there continues to be interest in the synthesis of tylonolide and stereochemically-rich substructures of tylonolide.7 Our recent demonstration of the asymmetric aldol reaction of c-hydroxybutenolides employing either the titanium enolate of N-acyloxazolidinones or a substrate-controlled ketone enolate pointed to a new synthetic strategy for the construction

of polypropionate fragments of natural products.8,9 For example, this methodology readily allowed the synthesis of the all-syn stereopentads of the polypropionate moiety of etnangien. The reaction of asymmetric enolates and c-hydroxy-butenolides gives functionally-rich lactones, which has the potential to address other synthetic problems such as the C3–C7 fragment of tylonolide (Scheme 1). In considering the retrosynthesis of tylonolide, compound 2 is a potential intermediate, with the intact C4–C6 stereotriad, two differentiated termini at C3 and C7, and C20 in the proper oxidation state as a protected acetal (tylonolide numbering system). The asymmetric aldol reaction of c-hydroxybutenolide 3 with the enolate of N-propionyloxazolidinone 4 gives the critical syn-stereochemistry of C4 and C5, with the potential for further reductions to give 2. The challenge in extending this methodology is the manipulation of the functionally-rich lactone products, which we have successfully addressed with our seven-step synthesis of 2a from 3-furanmethanol.

O

7 HO

20 OH O

O

3

O

OH 1

⇑ Corresponding author. Tel.: +1 610 330 5221; fax: +1 610 330 5714. E-mail address: [email protected] (W.H. Miles). http://dx.doi.org/10.1016/j.tetlet.2016.07.060 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

Figure 1. Structure of tylonolide (1).

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W. H. Miles et al. / Tetrahedron Letters 57 (2016) 3929–3932 O

O O

O

O

Asymmetric alkylation

O

7

N

O

O

O

N OR

3. 3

3

O

O

2. ClTi(i-OPr) 3

OH HO

O

1. LDA

4

OH Mukaiyama aldol

6a (R = TBS; 72%) 6b (R = TBDPS; 77%)

Tylonolide (1)

O O

O

O

H2 O OR

OR

7

N

Rh/Al 2 O3 O

OR

O

20

OCH 3

O

O

O

+

N

7a (R = TBS; 82%) 7b (R = TBDPS; 55%)

O

HO 3

HO

2a (R=TBS) 2b (R=TBDPS)

3

Scheme 1. Retrosynthetic analysis of tylonolide.

O RO

O2 , DIPEA, rose bengal CH2Cl 2, -78 °C

5a (R = TBS) 5b (R = TBDPS)

Scheme 3. Synthesis of lactone 7.

4

HO

O

O

RO 3a (R = TBS; 78%) 3b (R = TBDPS; 72%)

Scheme 2. Synthesis of c-hydroxybutenolides 3.

The required c-hydroxybutenolides 3a and 3b have been previously prepared by the singlet oxygen oxidation of suitably substituted furans (Scheme 2).10,11 c-Hydroxybutenolide 3a has been synthesized by the singlet oxygen oxidation of 2-TMS-4-(CH2OTBS)furan (available in four steps from 3-furylmethanol);10 c-hydroxybutenolide 3b was prepared by the singlet oxygen oxidation of 3-(CH2OTBDPS)furan (5b).11 We pursued the direct synthesis of 3a and 3b from the corresponding 3-substituted furans 5a and 5b since it is highly advantageous to do this transformation in one step without resorting to placing activating groups on the furan ring, but the regioselectivity and the difficulty in scaling up the oxidations have been noted before in the literature.12 In our studies, we found an appreciable solvent effect on the regiochemistry for the reaction, with the regioselectivity (b-substituted vs. a-substituted-c-hydroxybutenolide) improved in going from MeOH to CH2Cl2. The oxidation of furan 5a and 5b in MeOH only gave 3–4:1 selectivity for the desired hydroxybutenolide 3a and 3b, respectively, while the oxidation of furan 5a and 5b in CH2Cl2 exhibited regioselectivity of approximately 8:1 (Scheme 2). The higher selectivity for the oxidation of 5b facilitated the further purification of 3b by recrystallization, which had not been feasible in the previous literature report in the synthesis of 3b, prepared by the authors by the oxidation of 5b in MeOH.11 The large scale (2 g) preparation of 3a and 3b gave them in 78% (95:5, 3a:iso3a) and 72% (94:6, 3b:iso-3b) yields, respectively. Although we were unable to fully separate the regioisomers in the oxidation of 5a or 5b, they were sufficiently pure for the next step in the synthesis. Using the protocol described in our earlier publication,8 the critical coupling of c-hydroxybutenolides 3 with the titanium enolate of 413 proceeded in good yields and high diastereoselectivity. One equivalent of the titanium enolate is consumed in an acid/base reaction with the c-hydroxybutenolide, and excess titanium enolate (3.3 equiv total) is necessary for the optimal conversion of the c-hydroxybutenolide 3 and good yields of 6. The addition of the titanium enolate of 4, generated according to Thorton’s procedure13a to either 3a or 3b, gave the desired lactones 6a (72% yield)

and 6b (77% yield), respectively, in greater than 96:4 dr after flash chromatography (Scheme 3). Despite the excess titanium enolate reagent, there was incomplete conversion of chydroxybutenolides 3 (5–10% of 3 observed in the crude reaction mixture), which could be resolved with longer reaction times or warmer reaction conditions but at a significant loss of yield. The reduction of unsaturated c-lactones would appear to be straightforward but previous studies have noted a subtle steric interplay between c-substituents and b-substituents on the alkenyl moiety of a,b-unsaturated-c-lactones.14 We looked at the reduction in some detail, optimizing the hydrogenation of 6a and 6b based on our previous studies of lactone 6c. We observed very high cis-selectivity for the reduction of 6c (>96:4, 7c:trans-7c) under standard conditions (Table 1; entries 1 and 2). Hydrogenations of 6a using Pd/C gave poor selectivity (entries 3 and 4) unlike the hydrogenation of 6c (entry 1). We saw a significant increase in selectivity using rhodium as a catalyst, with alumina as the

Table 1 Reduction of 6 O O

O

O O

O

O

O

N

O R

6a (R = CH 2OTBS) 6b (R = CH2OTBDPS) 6c (R = CH 3)

+

N

catalyst

O O

O

H2

O

O N

R

7a (R = CH2OTBS) 7b (R = CH2OTBDPS) 7c (R = CH3 )

O

R

trans-7a (R = CH2OTBS) trans-7b (R = CH2OTBDPS) trans-7c (R = CH3)

Entrya

Compd

Catalyst

Solvent

7:trans-7b

Yieldc (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14

6c 6c 6a 6a 6a 6a 6a 6a 6a 6a 6a 6a 6b 6b

10% Pd/C 5% Rh/Al2O3 10% Pd/C 10% Pd/C 5% Rh/C 5% Rh/Al2O3 5% Rh/Al2O3 5% Rh/Al2O3 5% Rh/Al2O3 5% Rh/Al2O3d 5% Rh/Al2O3 PtO 10% Pd/C 5% Rh/Al2O3

EtOH EtOH EtOH EtOAc EtOH EtOAc MeOH IPA EtOH EtOH Et2O MeOH EtOH EtOH

97:3 98:2 69:31 61:39 — 84:16 86:14 82:18 93:7 91: 9 89:11 85:15 59:41 76:24

88 85 70 72 0 78 65 78 72 82 79 40 26 36

a Std conditions: 0.24 mmol of 6, 10 mL of solvent, 50 mg of catalyst, 1–2 h under H2. b Ratio present in crude mixture. c Purified by flash chromatography. d Dried in vacuo at 130 °C for 16 h.

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W. H. Miles et al. / Tetrahedron Letters 57 (2016) 3929–3932

preferred support. The solvent was important for the selectivity in the hydrogenations of 6a with Rh/Al2O3, with EtOH (entries 9 and 10) and Et2O (entry 11) giving the highest selectivity, and other solvents giving slightly lower selectivity (entries 6–8). Reduction of 6a with Rh/C (entry 5), Pt/O (entry 12), [(PPh3)CuH]6 (Stryker’s reagent)15 and NiCl2/NaBH416 gave poor yields and/or selectivity. On a preparative scale, the reduction of 6a in EtOH using Rh/ Al2O3 as a catalyst gave the best yield and selectivity of 7a (82% yield; 97:3 dr after purification by flash chromatography). Reduction of 6b was plagued by the reduction of the phenyl ring of the TBDPS-protecting group (entries 13 and 14), which complicated the purification and optimization of the reaction. The stereochemical identification of 7a/trans-7a and 7b/trans-7b was based on the analogous compounds 7c/trans-7c, which were conclusively identified in our previous work.8 On first inspection, the c-substituent would appear to readily direct complexation of the metal catalyst to the face opposite the substituent to lead to cis-products, which is the case for unsaturated-c-lactones lacking b-substituents or a b-methyl substituent (conformation A in Scheme 4).14a But the hydrogenation of unsaturated c-lactones possessing b-substituents larger than a methyl group often lead to erosion of the cis-selectivity, in some cases to the selective formation of the trans-products.14 The origin of this change of selectivity in going from small (H or Me) to larger b-substituents has been ascribed to the adoption of a conformation that minimizes the steric interplay of the b- and c-substituents (conformation B in Scheme 4), thereby directing the metal catalyst to the same face as the c-substituent and leading to trans-products.14a These hydrogenation studies of 7 underscore the need to consider the steric demands of substituents in unsaturated b, c-disubstituted-c-lactones when planning a synthesis. The judicious choice of protecting groups and/or auxiliaries is necessary for a successful stereoselective reduction of the unsaturated c-lactone. The additional stereogenic centers of 7 may play a role in the selectivity but we do not have enough information to address their effect. The reduction of the lactone to the hemi-acetal followed by suitable protection, and reductive cleavage of the chiral auxiliary were the next tasks to give a suitable intermediate (2) for the further elaboration to tylonolide. Since c-lactone 7b, the precursor of 2b, was formed in lower yields with reproducibility issues, we pursued the synthesis of 2a via 7a. The c-lactone 7a was selectively reduced in the presence of the N-acyloxazolidinone with DIBAL to give lactol 8 (Scheme 5).17 Since isolation and purification of 8 lead to loss of yield, it was directly converted into methyl acetal 9 (71% yield of a 5:1 mixture of epimers, 2 steps) using MeOH in CH2Cl2 with CSA as a catalyst. With stronger acids such as TsOH, higher concentrations of CSA or methanol, or longer reaction times, the formation of the acetal was complicated by two side reactions: cleavage of the N-acyloxazolidinone to the methyl ester and deprotection of the TBS ether. Reduction of 9 using NaBH418 (or LiBH4) gave the desired product 2a in 77% yield (6:1 mixture of epimers).

OH O 7a

O

OCH 3 O

O

DIBAL

O

O

CH3 OH, CH2 Cl2 O

N

O OTBS

N

CSA 71% (2 steps)

OTBS

8

9 NaBH4

NaBH 4 THF/MeOH/H 2O 55%

THF/MeOH/H 2O

77% O OH

O

O CH3 OH

O

OTBS 10

OTBS 2a

Scheme 5. Synthesis of 2a and 10.

In an alternative approach, we explored the reductive cleavage of the chiral auxiliary of 7a, which was a successful approach for the synthetic manipulation of 7c, albeit in modest yields. The reduction of 7a with NaBH4 or LiBH4 also gave lactone 10 in modest yields due to an unidentified side reaction. We choose not to optimize this approach since the alternate cleavage protocol (7a ? 9 ? 2a) was preferable but this reaction illustrates the potential for cleaving the chiral auxiliary before chemically modifying the lactone derived from the c-hydroxybutenolide. In conclusion, the synthesis of 2a demonstrates the utility of employing functionally-rich lactones prepared by the reaction of an asymmetric enolate and c-hydroxybutenolides. The ability to reduce at either the chiral auxiliary or the lactone (originally derived from the c-hydroxybutenolide) provides different pathways to more diverse compounds. Future studies employing more complex asymmetric enolates and/or c-hydroxybutenolides hold potential for the synthesis of more complex natural products and will be the subject of future investigations. Acknowledgments Acknowledgement is made to the Donors of the American Chemical Society Petroleum Research Fund for support of this research. We also thank Bristol-Meyers Squibb for supporting P.I. with an Undergraduate Research Award in Organic Chemistry. We thank Professor Dasan Thamattoor of Colby College for obtaining the HRMS and Ugochukwu Okeibunor for his assistance on the hydrogenation studies of 6c. We gratefully acknowledge a grant from the Kresge Foundation for the purchase of a 400 MHz NMR spectrometer. Supplementary data Supplementary data (experimental procedures and NMR spectra) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.07.060. References and notes

O

O

M

M

O

O R

R' H

R H

M

M

A

B

cis

trans

R'

Scheme 4. Conformational analysis of the hydrogenation of 6.

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