Synthesis of the all-syn C35–C39 stereopentad of etnangien by the γ-hydroxybutenolide approach

Tetrahedron Letters 56 (2015) 2303–2306

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Synthesis of the all-syn C35–C39 stereopentad of etnangien by the c-hydroxybutenolide approach William H. Miles ⇑, Steven T. Jones, Jason S. George, Pui-In Tang, Meghan D. Hayward Department of Chemistry, Lafayette College, Easton, PA 18042, United States

a r t i c l e

i n f o

Article history: Received 23 February 2015 Revised 5 March 2015 Accepted 10 March 2015 Available online 17 March 2015 Keywords: Etnangien c-Hydroxybutenolide Titanium enolate Luche reduction Aldol

a b s t r a c t The synthesis of the all-syn C35–C39 stereopentad of etnangien has been achieved using the asymmetric aldol reaction of a c-hydroxybutenolide (5-hydroxy-4-methylfuran-2(5H)-one) as the key step in the five-step synthesis. The reaction of the titanium enolate of (S)-4-isopropyl-3-propionyl-2-oxazolidinone with 5-hydroxy-4-methylfuran-2(5H)-one gave good yields and diastereoselectivity of corresponding lactone, which was converted into a lactone with an all-syn stereotriad. Ó 2015 Elsevier Ltd. All rights reserved.

Etnangien is a polyketide macrolide isolated from two strains of myxobacterium Sorangium cellulosum, So ce750 and So ce1045 (Fig. 1).1,2 It is a powerful antibiotic that acts against a broad range of Gram-positive bacteria in both in vitro and in vivo assays.1 Etnangien and its corresponding methyl ester join the rifamycins as inhibitors of bacterial RNA polymerase, a promising yet underutilized approach in antibiotic therapy.3 The low mammalian cell cytotoxicity of etnangien has prompted a multi-faceted scientific investigation of etnangien’s potential as a therapeutic agent.1,2,4–9 The total synthesis of etnangien was accomplished by Menche in 2009.6 One of the biggest challenges in the synthesis of etnangien is the construction of the stereochemically-rich polypropionate fragment of the macrocyclic moiety.4,10 Our retrosynthetic analysis of etnangien envisions an olefination reaction between C32 and C33, a Mukaiyama aldol reaction to establish the stereochemistry at C40, and a macrolactonization (Scheme 1). Lactone 1, which has the imbedded all-syn C35–C39 stereopentad, is potentially available by the substrate-controlled aldol reaction of c-hydroxybutenolide 211 with ethyl ketone 312,13 and appropriate reduction reactions. The employment of c-hydroxybutenolides as substrates in the asymmetric aldol reaction14,15 has very little precedent, limited to Nagoa’s seminal studies of the reaction of tin(II) enolates of 3-acetyl-4(S)-isopropyl-1,3-thiazolidine-2-thione with c-hydroxybutenolides.14a Herein, we report the successful development of ⇑ 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.2015.03.042 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

39

HO 35

OH

OH

O

O

OH

O 5 OH OMe

OH

OH etnangien Figure 1. Structure of etnangien.

the asymmetric aldol reaction employing c-hydroxybutenolide 2 and its application to the synthesis of lactone 1.16 The previous studies in the reaction of the titanium enolate of 313,17 with aldehydes were the starting point for our own studies. Since c-hydroxybutenolides are inherently acidic, the key to the successful asymmetric aldol reaction between the titanium enolate of 3 with c-hydroxybutenolide 2 was in generating the appropriate conjugate base of 2. Unlike Nagoa’s studies of the tin enolates of 3-acetyl-4(S)-isopropyl-1,3-thiazolidine-2-thione,14a in which 1.5 equiv of the c-hydroxybutenolide were used per equivalent of enolate, one equivalent of the titanium enolate of 3 fully consumed one equivalent of 2 in an acid/base reaction. The addition of 2–3 equiv of the titanium enolate of 3 per equivalent of 2 gave complex mixtures that contained an appreciable amount of the

2304

W. H. Miles et al. / Tetrahedron Letters 56 (2015) 2303–2306

39

HO 35

O OH Mukaiyama aldol

OH

O

O

O

O

macrolactonization

OBn

OH

OH

O olefination

OH 1. DIPEA

OMe

3

2

5

OH

1. (i-PrO)TiCl3

2. Cl2Ti(i-PrO)2

2. DIPEA

OH (i-PrO)Cln O O

O

Cl(i-PrO)2TiO

Ti

OBn

H

O

O O

O

O

O

O

OBn 2. H+

+ 35

OH

39

O 1

2

O

O

3

OBn

Scheme 1. Retrosynthetic analysis of etnangien.

desired lactone 4. The addition of the titanium enolate of 3 to the sodium or lithium salt of 2 or the conjugate base of 2 generated by the addition of DIPEA led to mostly recovered starting materials. These results suggested a strategy of generating the conjugate base of 2 from (i-PrO)4 x TiClx, with amines serving as a base. Attempts to generate the conjugate base of 2 employing TiCl4 led to a significant isomerization of 2 to give the corresponding E-acid of 2. The reactions of the conjugate base of 2, generated by the addition of DIPEA and TiCl(i-PrO)3, with the titanium enolate of 3 gave fair yields of 4 (50–55%) and good diastereoselectivity (>90:10 dr) but were plagued by the incomplete conversion of ketone 3. The optimal conditions for generating the conjugate base of 2 employed DIPEA as the base followed by the addition of TiCl2(i-PrO)2, with careful control of the temperature so as to insure complete formation of the conjugate base but with minimal isomerization (Scheme 2). When this conjugate base of 2 reacted with the titanium enolate of 3 generated from TiCl3(i-PrO)/ DIPEA,17 lactone 4 was obtained in 67% yield (81% yield based on recovered 3) and greater than 94:6 dr with less than 10% recovered yield of 3.18 Three reductions are necessary to secure the fourth and fifth stereogenic centers, and to deprotect the benzyl ether (Scheme 3). The reduction of the alkenyl moiety of the unsaturated lactone was complicated by the lack of diastereoselectivity in the reduction as well as reduction of the aromatic ring of the benzyl group by several catalyst systems. Of the catalysts screened, Rh/ alumina in diethyl ether gave the best diastereoselectivity (7:1, 5:trans-5) with the least (<10%) hydrogenation of the benzyl group.19 Hydrogenolysis (1 atm H2, Pearlman’s catalyst) of the benzyl ether of 5 gave alcohol 6 (59% yield, two steps). Unexpectedly, the conversion of 6 to 7 was relatively unselective under a variety of standard conditions known to effect the syn-reduction of b-hydroxyketones.20 For example, the reduction of 6 with reagents such as Zn(BH4), catecholborane, BH3
C5H5N/TiCl4, etc., gave good to excellent yields of the desired alcohol but in only 1:1 to 3:1 dr. The solution to this problem was the counterintuitive use of the Luche reduction (NaBH4/CeCl3
H2O),21 which is not known to favor syn-reduction of b-hydroxyketones. The reduction proceeded with increasing selectivity with more bulky alcohol solvents (MeOH, EtOH, IPA; 3:1, 6:1, 13:1 dr), although the reaction rate slowed and conversion of the starting material suffered. The use of water as a co-solvent (5%) in IPA was advantageous for both insuring

4 Scheme 2. Reaction of titanium enolate of 3 with 2 to give 4 (81% yield based on recovered 3; 94:6 dr).

O

O O

O

OBn

O

O

a

4

OBn

b

5

O

O O

O

OH

OH

O

c

6

OH

d

7 O O

O

O

1 Scheme 3. Reagents and conditions: (a) H2, Rh/alumina; (b) H2, Pearlman’s catalyst, 59%, 98:2 dr (two steps); (c) NaBH4, CeCl3
7H2O, IPA/H2O, 79%, 93:7 dr; (d) (CH3)2C(OCH3)2, H+, 74%.

complete conversion of 6 to 7 and reproducible diastereoselectivity (79% yield, 13:1 dr). Diol 7 was readily converted into the acetonide 1 by the reaction with 2,2-dimethoxypropane using phosphomolybdic acid as a catalyst (74% yield). We also examined an alternative approach to synthesizing synpolypropionate fragments employing the well-known and extensively employed enolates of N-acyloxazolidinones.22 We were able to achieve good yields and diastereoselectivity in the reaction of the titanium enolate of 8 with 2 by using either one as the limiting reagent (Scheme 4). The addition of three equivalents of the titanium enolate of 8 (LDA/TiCl(i-OPr)3; Thornton’s conditions23) to 2 gave lactone 9 in 68% yield and 98:2 dr (dr of the crude product was 92:8).24 As in the case for the reaction of the titanium enolate

W. H. Miles et al. / Tetrahedron Letters 56 (2015) 2303–2306

O O O

O

O +

O c

a

N

O

O

2

N

or b

8

2305

further work is necessary to understand the source of diastereoselectivity in the Luche reduction of sterically congested lactone 6 (it is highly unlikely that the selectivity results from a chelation-controlled process), the conditions developed in this study may offer a useful modification of a very practical reaction. These studies and further applications of the asymmetric aldol reaction of c-hydroxybutenolides will be reported in due course.

9 O O

O

Acknowledgments

O

O d

OH

O

N

O

10

11

Scheme 4. Reagents and conditions: (a) 8, LDA, TiCl(i-OPr)3; 2, 68%, 98:2 dr (b) 8, TiCl4, DIPEA; TiCl(i-OPr)3; 2, DIPEA, TiCl3(i-OPr); 69%, 98:2 dr (c) H2, Rh/alumina, 63% (dr 98:2) (d) Zn(BH4)2 (2.0 mol equiv), MeOH (2.0 mol equiv), 50%.

of 3, the composition of the conjugate base was critical in achieving high diastereoselectivity and complete conversion when using 8 as the limiting reagent. The conjugate base of 2, prepared by the reaction of 2 with DIPEA and TiCl3(i-OPr), reacted with the titanium enolate of 8, prepared by the addition of TiCl4 and DIPEA to 8,25 gave lactone 9 in 69% yield and 98:2 dr (dr of the crude product was 85:15). The unsaturated lactone was reduced with H2 using Rh/alumina catalysis to give the saturated lactone 10 in 63% yield, establishing the third chiral center as in the transformation of 4 to 5. The cleavage of the chiral auxiliary is complicated by the reactivity of the c-lactone, but the literature precedent for such a reduction has been noted.26 The careful reaction of LiBH4 (2 mol equiv; 2 mol equiv of MeOH, 42 °C?0 °C)27 with 10 cleaved the chiral auxiliary with minimal reduction of the c-lactone to give 11 (50% yield). Longer reaction times and/or higher temperatures gave significant amounts of the triol formed by the further reduction of 11. Compound 11 has been previously prepared by the microbial Baeyer–Villiger of prochiral (3a,4b,5a)4-hydroxy-3,5-dimethylcyclohexanone.28 The proposed transition states for the reaction of the titanium enolates of 3 and 8 with the conjugate base of 2 are depicted in Figure 2 and based on the previous proposals for the asymmetric aldol reaction of these reagents with aldehydes.13,23 The dominant feature of both transition states is internal chelation of the enolate reagent: the oxygen of the benzyl ether in A and the carbonyl group of the oxazolidinone in B. The potential for chiral enolates to react with k-hydroxybutenolides29,30 with high diastereoselectivity offers an opportunity to synthesize functionally-rich lactones that are readily amenable to further reactions. Coupled with the hydrogenation of the alkenyl moiety of the unsaturated lactone, the synthesis of all-synstereotriads and stereopentads has been demonstrated. Although

LnTi Bn H

O LnTi

H CO2TiLn

O LnTi

O H

O

O O

H

O O

H N O

A

B

Figure 2. Transition states for the reaction of the titanium enolate of 3 and 8 with the conjugate base of 2 (A and B, respectively).

Acknowledgement is made to the Donors of the American Chemical Society Petroleum Research Fund for partial support of this research. We also thank Lafayette College’s Academic Research Committee for financial support and 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. We gratefully acknowledge a grant from the Kresge Foundation for the purchase 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.2015.03.042. References and notes 1. Irschik, H.; Schummer, D.; Höfle, G.; Reichenbach, H.; Steinmetz, H.; Jansen, R. J. Nat. Prod. 2007, 70, 1060–1063; Höfle, G.; Reichenbach, H.; Irschik, H.; Schummer, D. DE 19630980 B4, 1998. 2. Menche, D.; Arikan, F.; Perlova, O.; Horstmann, N.; Ahlbrecht, W.; Wenzel, S. C.; Jansen, R.; Irschik, H.; Muller, R. J. Am. Chem. Soc. 2008, 130, 14234–14243. 3. Mariani, R.; Maffioli, S. I. Curr. Med. Chem. 2009, 16, 430–454. 4. Li, J.; Menche, D. Synthesis 2009, 2293–2315. 5. Kretschmer, M.; Menche, D. Synlett 2010, 2989–3007. 6. Li, P. F.; Li, J.; Arikan, F.; Ahlbrecht, W.; Dieckmann, M.; Men che, D. J. Am. Chem. Soc. 2009, 131, 11678–11679; Li, P.; Li, J.; Arikan, F.; Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Org. Chem. 2010, 75, 2429–2444. 7. Arikan, F.; Li, J.; Menche, D. Org. Lett. 2008, 10, 3521–3524. 8. Altendorfer, M.; Raja, A.; Sasse, F.; Irschik, H.; Menche, D. Org. Biomol. Chem. 2013, 11, 2116–2139. 9. Sabitha, G.; Yadagiri, K.; Bhikshapathi, M.; Chandrashekhar, G.; Yadav, J. S. Tetrahedron: Asymmetry 2010, 21, 2524–2529. 10. Ward, D. E. In Modern Methods in Stereoselective Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinhem, Germany, 2013; pp 377–429. 11. Bourguignon, J. J.; Wermuth, C. G. J. Org. Chem. 1981, 46, 4889–4894. 12. Paterson, I.; Lister, M. A.; Ryan, G. R. Tetrahedron Lett. 1991, 32, 1749–1752. 13. Solsona, J. G.; Nebot, J.; Romea, P.; Urpi, F. J. Org. Chem. 2005, 70, 6533–6536. 14. For the aldol and related reactions of k-hydroxybutenolides, see: (a) Nagao, Y.; Dai, W. M.; Ochiai, M.; Shiro, M. J. Org. Chem. 1989, 54, 5211–5217; (b) Yuste, F.; Sanchezobregon, R. J. Org. Chem. 1982, 47, 3665–3668; (c) Yuste, F.; Vergel, H.; Barrios, H.; Ortiz, B.; Sanchezobregon, R. Org. Prep. Proceed. Int. 1988, 20, 173–177; (d) Zhang, J.; Blazecka, P. G.; Berven, H.; Belmont, D. Tetrahedron Lett. 2003, 44, 5579–5582; (e) Zhang, J.; Das Sarma, K.; Curran, T. T.; Belmont, D. T.; Davidson, J. G. J. Org. Chem. 2005, 70, 5890–5895. 15. For the aldol reactions of the closely related 3-hydroxyisobenzofuran-1(3H)ones, see: (a) Donati, C.; Prager, R.; Weber, B. Aust. J. Chem. 1989, 42, 787–795; (b) Pahari, P.; Senapati, B.; Mal, D. Tetrahedron Lett. 2004, 45, 5109–5112; (c) Mal, D.; Pahari, P.; De, S. R. Tetrahedron 2007, 63, 11781–11792. 16. For a review of the synthetic applications of k-hydroxybutenolides, see: Miles, W. H. Curr. Org. Synth. 2014, 11, 244–267. 17. Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215–8216. 18. Procedure for the synthesis of lactone 4: To a solution of 3 (2.230 g, 10.8 mmol) in CH2Cl2 (30 mL) at 78 °C was added dropwise over 5 min a solution of TiCl3(i-PrO) [11.2 mmol; prepared by the addition Ti(i-PrO)4 (0.83 mL, 0.80 g, 2.8 mmol) to TiCl4 (0.93 mL, 1.60 g, 8.4 mmol) in CH2Cl2 (10 mL)]. After stirring for 2 min, DIPEA (1.92 mL, 1.42 g, 11.0 mmol) was added over five min and stirred for an additional 25 min at 78 °C. The conjugate base of 2 was prepared by the addition of DIPEA (2.44 mL, 1.81 g, 14.0 mmol) to a solution of 2 (1.48 g, 13.0 mmol) in CH2Cl2 (10 mL) at 42 °C; after further stirring for 5 min, a solution of TiCl2(i-PrO)2 [14.0 mmol; prepared by the addition of Ti(iPrO)4 (2.07 mL, 1.99 g, 6.99 mmol) to TiCl4 (0.77 mL, 1.32 g, 7.0 mmol) in CH2Cl2 (3 mL)] was added over 5 min. The conjugate base of 2 was stirred at 42 °C for 1 h, warmed to 0 °C for 15 min, and then cooled down again to 42 °C. The conjugate base of 2 was added to the enolate solution of 3 at

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19.

20. 21. 22. 23. 24.

W. H. Miles et al. / Tetrahedron Letters 56 (2015) 2303–2306

78 °C over 5 min by cannula. After stirring at 78 °C for 3 h, the reaction mixture was poured into a mixture of saturated NH4Cl (150 mL) and 1 M HCl (10 mL), and stirred for 4 h. Two phases were transferred to a separatory funnel with CH2Cl2 (100 mL), separated, and the aqueous phase was extracted with CH2Cl2 (2  30 mL). The combined organic extracts were washed successively with water (2  200 mL), 10% Na2CO3 (100 mL) and brine (200 mL). The organic phase was dried over Na2SO4 and the volatiles were removed on the rotary evaporator. The crude product (94:6 dr) was purified by column chromatography (20%?30% EtOAc–hexanes) to give 4 (2.151 g, 67% yield (81% yield based on recovered 3); 98:2 dr) as a white solid: mp, 54–56 °C. [a]22 D 53.5 (c 1.0, CH2Cl2); IR (CH2Cl2) 1762, 1715, 1646, 1600 cm 1; 1H NMR (CDCl3, 400 MHz) d 7.34–7.24 (m, 5H), 5.77 (app pentet, J = 1.5, 1H), 5.29 (br d, J = 4.8, 1H), 4.45 (AB, J = 11.7 Hz, 1H), 4.43 (AB, J = 11.7 Hz, 1H), 3.61 (t, J = 8.8 Hz, 1H), 3.50 (dd, J = 5.1, 8.8 Hz, 1H), 3.18 (m, 1H), 2.88 (dq, J = 4.8, 7.3 Hz, 1H), 1.90 (br s, 3H), 1.13 (d, J = 7.3 Hz, 3H), 1.06 (d, J = 7.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 212.8, 172.9, 167.9, 137.8, 128.5, 127.9, 127.7, 117.9, 83.4, 73.5, 73.4, 48.3, 44.0, 14.4, 13.7, 10.2; HRMS (DART-TOF) calcd for C18H23O4 [M+1]+ 303.1596, found 303.1607. The diastereoselective reduction of substituted butenolides is often executed with supported ruthenium catalysis: Hanessian, S.; Murray, P. J. Tetrahedron 1987, 43, 5055–5072. We observed diastereoselectivity as high as 13:1 dr with some lots of Ru/alumina catalysts, but we were unable to reproduce this diastereoselectivity consistently. Bode, S. E.; Wolberg, M.; Muller, M. Synthesis 2006, 557–588. Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227. Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109–1127. Nerz-stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56, 2489–2498. Procedure for the synthesis of lactone 8 employing excess enolate: To a solution of 8 (3.60 mL, 3.96 g, 22.0 mmol) in THF (40 mL) at 78 °C was added dropwise over 5 min a solution of LDA (16 mL, 1.5 M in cyclohexane, 24 mmol). After stirring for 30 min at 78 °C, TiCl(i-PrO)3 (10.0 mL, 41.7 mmol) was added over 15 min at 78 °C and the reaction mixture was warmed to 42 °C for 1 h. After

25. 26. 27. 28. 29.

30.

cooling to 78 °C, a solution of 2 (0.863 g, 7.56 mmol) in THF (15 mL) was added to the reaction mixture over 10 min. The reaction mixture was warmed to 42 °C and stirred for an additional 1 h. The reaction mixture was poured into a solution of saturated NH4Cl (300 mL) and 1 M HCl (25 mL) and vigorously stirred for 2 h. The reaction mixture was extracted with ethyl acetate (3  250 mL), the combined organic phases washed with brine, dried over Na2SO4, and concentrated on the rotary evaporator. The crude product (92:8 dr) was purified by column chromatography (toluene?50% Et2O– toluene) to give recovered 8 (2.448 g, 57% recovery) and 9 (1.440 g, 68% yield; 98:2 dr) as a white solid: mp, 163–164 °C. [a]22 D +109.2 (c 1.0, CH2Cl2); IR (CH2Cl2) 1770, 1713, 1646 cm 1; 1H NMR (CDCl3, 400 MHz) d 5.87 (m, 1H), 5.33 (br s, 1H), 4.55 (dt, J = 4.0, 8.4 Hz, 1H), 4.35 (t, J = 9.0 Hz, 1H), 4.26 (dd, J = 3.7, 9.2 Hz, 1H), 4.07 (dq, J = 2.6, 7.0 Hz, 1H), 2.35 (d of septet, J = 4.0, 7.0 Hz, 1H), 2.12 (br s, 3H), 0.93 (d, J = 7.2 Hz, 3H), 0.91 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 172.8, 172.0, 166.7, 154.4, 118.3, 84.0, 64.1, 58.5, 39.6, 28.6, 17.9, 15.0, 13.8, 7.6; HRMS (DART-TOF) calcd for C14H20NO5 [M+1]+ 282.1341, found 282.1334. Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpí, F. J. Am. Chem. Soc. 1991, 113, 1047–1049. Xu, Q. Q.; Zhao, Q.; Shan, G. S.; Yang, X. C.; Shi, Q. Y.; Lei, X. S. Tetrahedron 2013, 69, 10739–10746. Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000–4005. Mihovilovic, M. D.; Rudroff, F.; Grotzl, B.; Stanetty, P. Eur. J. Org. Chem. 2005, 809–816. The reaction of the titanium enolate of 8 with c-hydroxybutenolides (b-H, bCH(CH3)2, or b-CH2OTBS) gave good yields with good diastereoselectivity of the corresponding lactones. The N-propionyloxazolidinone derived from (1S,2R)norephedrine gave lower diastereoselectivity in its reaction with 2 (dr 4:1). Unlike Nagoa’s studies14a of the reaction of tin(II) enolates of 3-acetyl-4(S)isopropyl-1,3-thiazolidine-2-thione, our preliminary investigations into the reactions of the tin (or boron) enolates of 8 with 2 have led to recovered starting materials or complex mixtures.