This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 7001--7003 7001

Cite this: Chem. Commun.,2013,49, 7001

Asymmetric Ti-crossed Claisen condensation:application to concise asymmetric total synthesis ofalternaric acid†‡

Ryohei Nagase,a Yumiko Oguni,a Satoko Ureshino,a Hiroaki Mura,a

Tomonori Misaki*b and Yoo Tanabe*a

Asymmetric Ti-crossed Claisen condensation utilizing the dioxane-

2,5-dione chiral template and its successful application to total

synthesis of chiral alternaric acid are described.

The chiral template methodology is a well-recognized strategy for thesynthesis of acyclic and multi-functionalized chiral building blocks.Seebach–Frater’s (1,3-dioxolan-4-ones),1 Schoellkopf’s (bis-L-lactim),2

Williams’ (morphorin-4-one),3 and Kellogg’s (oxathiolan-4-one)4

chiral template methodologies are representative methods that havebeen successfully applied for total synthesis of natural products andpharmaceuticals.

The crossed-Claisen ester condensation is a fundamental anduseful C–C bond forming reaction in organic syntheses.5 Ti-crossedClaisen condensations provide a variety of functionalized b-ketoesters6

and the asymmetric version is a highly anticipated extension. Here wedisclosed the first and efficient asymmetric crossed-Claisen condensa-tion mediated by the TiCl4–N-methylimidazole (NMI)–amine reagentto produce less accessible chiral building blocks, a-alkyl-a-hydroxy-b-ketoesters 4 (Scheme 1). The present method utilizes chiral templates,3-methyl-3-phenyl-1,4-dioxane-2,5-diones 2, which are readily preparedby cyclocondensation between commercially available (S)-atrolacticacid (1) and (�)-a-haloacid halides in good to excellent yield.7

To demonstrate the utility of the present method, we describesuccessful concise asymmetric total synthesis of chiral alternaricacid (Fig. 1),10 a natural product exhibiting phytotoxic and anti-fungal activities.

Diastereocontrolled Ti-crossed Claisen condensation of 2 withR1COCl was successfully performed to obtain various chiral acylatedprecursors 3 in good yield with excellent diastereoselectivity(Table 1). The salient features of the present reaction are as follows.

(i) Despite the difficulty in Claisen condensation using a,a-disubsti-tuted esters,5 all examples examined afforded successful results. (ii)Excellent anti-diastereoselectivity between Ph and R1CO groups wasrealized, probably due to a rational template effect, i.e. the Si-faceattack of Ti-enolate with an activated acylimidazolium intermediate11

predominates over Re-face attack, as depicted in Scheme 2. This resultis consistent with Seebach’s concept for the chiral template.1c

(iii) Terminal double bond, chloro-, and benzyloxy groups werecompatible. (iv) Optimization of the conditions revealed that morereactive linear acid chlorides used Bu3N as the amine (method A;entries 1–10), whereas less reactive a-branched acid chlorides usedsBu2NH (method B; entries 11–14). (v) With regard to the NMIactivator, 2-ethyl-N-methylimidazole was superior when linear acidchlorides were used, whereas N-methylimidazole matched with3,3-dimethylbutanoyl chloride and a-branched acid chlorides.This tendency is consistent with the outcome of the Ti-crossedClaisen condensation between simple esters and acid chlorides.6c

(vi) Ti-Claisen condensation using Seebach–Frater’s template, how-ever, failed to proceed due to the acid liability of the dioxolane moiety.

Simple and mild methanolysis of 3 using MeONa–MeOH at0–5 1C gave the desired product 4 in good yield with maintaining

Scheme 1

Fig. 1 Chiral alternaric acid.

a Department of Chemistry, School of Science and Technology,

Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.

E-mail: tanabe@kwansei.ac.jp; Fax: +81-79-565-9077; Tel: +81-79-565-8394b Graduate School of Material Science, University of Hyogo, 3-2-1, Kohto, Kamigori,

Hyogo 678-1297, Japan

† This paper is dedicated to Professor Teruaki Mukaiyama in celebration of the40th anniversary of the Mukaiyama aldol reaction.‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc43180k

Received 30th April 2013,Accepted 12th June 2013

DOI: 10.1039/c3cc43180k

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7002 Chem. Commun., 2013, 49, 7001--7003 This journal is c The Royal Society of Chemistry 2013

excellent enantiomeric excess and simultaneous recovery ofmethyl atrolactate 10 in >80% yield.

The present asymmetric Ti-Claisen condensation was applied tothe expeditious asymmetric total synthesis of chiral alternaric acid,8

a natural product with a unique structural scaffold possessing threecontiguous asymmetric centers. The first total and second formalsyntheses were accomplished by Ichihara’s group9 and Trost’sgroup,10 respectively.

Key chiral precursor 5 was readily prepared by the methanolysisof 3o in 49% yield from 2c (Scheme 3). A stereocomplementarymethod involving Tsuji–Trost allylation of 3p gave 3o0, followed bymethanolysis to produce 5 in slightly better yield (2 steps; 63%).Note that the allylation also proceeded with excellent anti-selectivity(>95% de) due to an expected template effect.

Trost pointed out that concise preparation of (2R,3R,4S)-synthon 6 is a crucial issue for the total synthesis of chiralalternaric acid (Scheme 4).10 Gratifyingly, anti-stereoselectivereduction of 5 using NaBH4–ZnCl2 gave the desired (3R)-diol 6with excellent diastereoselectivity (3R : 3S = >97 : 3). This type ofa,b-dihydroxyl ester comprises a useful chiral building block forthe synthesis of various natural products.12

Ene-type reaction between 6 and t-butyl 5-trimethylsilyl-4-pentynoate using an efficient CpRu(CH3CN)3

+PF6� catalyst13 pro-

ceeded smoothly to afford the desired regioselective vinylsilane adduct7 in 78% yield. Selective Cl3CCO– protection of the secondary hydroxylgroup in 7 giving 8 (99%), followed by deprotection of both t-Bu andTMS groups using CF3CO2H, afforded the core carboxylic acidsegment 9. Regioselective C-acylation of (R)-6-methyldihydro-2H-pyran-2,4(3H)-dione (10)9b,14 with 9 was successfully performed inassociation with the formation of 1,2-carbonate to obtain the pre-cursor 11 in 72% overall yield from 8. Finally, LiOH-promotedhydrolysis of methyl ester concurrent with deprotection of 1,2-carbo-nate in 11 successfully provided chiral alternaric acid in 55% yield.Compared with the previously reported syntheses, the presentmethod improved the efficiency and overall yield.

In conclusion, we have reported the first successful TiCl4-mediatedasymmetric crossed-Claisen condensation. The present method

Table 1 Asymmetric Ti-crossed Claisen condensation of chiral template 2 withacid chloridesa

Entry R1 Substrate R2 R Product Yieldb/%

1 2a Me Et 3a 742 2b Bu Et 3b 72

3 2a Me Et 3c 764 2b Bu Et 3d 73

5 2a Me H 3e 846 2b Bu H 3f 83

7 2a Me Et 3g 828 2b Bu Et 3h 79

9 2a Me Et 3i 6110 2b Bu Et 3j 61

11 2b Bu H 3k 7412 2c Allyl H 3l 58

13 2b Bu H 3m 7214 2cd Allyl H 3o 5415c 2d H H 3p 71

a Method A for entries 1–10 [R1COCl (1.4 equiv.), TiCl4 (2.5 equiv.),Bu3N (3.0 equiv.), �50 to �45 1C]. Method B for entries 11–14 [R1COCl(3.0 equiv.), TiCl4 (3.5 equiv.), sBu2NH (4.0 equiv.), 0–5 1C, 1 h, 20–25 1C,1 h]. b Isolated de was determined after methanolysis of 3 (see Table 2).c R1COCl (1.5 equiv.), TiCl4 (2.0 equiv.), iPr2NEt (2.5 equiv.), �50to �45 1C. d Antipodal (3R)-isomer was used (see Scheme 3).

Scheme 2

Scheme 3

Scheme 4

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produces less accessible chiral building blocks, a-alkyl-a-hydroxy-b-ketoesters, utilizing chiral templates, 3-methyl-3-phenyl-1,4-dioxane-2,5-diones. The present strategy was successfully applied to achieveconcise asymmetric total synthesis of chiral alternaric acid.

The typical procedure of Table 1 (entry 2): hexanoyl chloride (94 mg,0.70 mmol) was added to a stirred solution of (3S)-6-butyl-3-methyl-3-phenyl-1,4-dioxane-2,5-dione7 (131 mg, 0.50 mmol) and 2-ethyl-1-methy-limidazole (77 mg, 0.70 mmol) in CH2Cl2 (1.0 ml) at �50 to �45 1Cunder an Ar atmosphere, followed by stirring at the same temperaturefor 10 min. TiCl4 (138 mL, 1.25 mmol) and Bu3N (278 mg, 1.50 mmol)were successively added to the mixture, which was stirred at the sametemperature for 0.5 h. The mixture was quenched with water, whichwas extracted twice with Et2O. The combined organic phase waswashed with water, brine, dried (Na2SO4) and concentrated. Theobtained crude oil was purified by SiO2-column chromatography(hexane:AcOEt = 30:1) to give (3R,6S)-3-butyl-3-hexanoyl-6-methyl-6-phenyl-1,4-dioxane-2,5-dione (3b; 129 mg, 72%).

Colorless oil; [a]25D + 22.8 (c 1.04, CHCl3); 1H NMR (300 MHz,

CDCl3) d 0.73 (3H, t, J = 6.5 Hz), 0.90 (3H, t, J = 6.9 Hz), 1.04–1.38(8H, m), 1.57–1.69 (2H, m), 1.72–1.84 (1H, m), 1.89–2.02 (1H,m), 1.98 (3H, s), 2.56 (1H, dt, J = 7.2 Hz, Jgem = 18.6 Hz), 2.81(1H, dt, J = 7.2 Hz, Jgem = 18.6 Hz), 7.35–7.53 (5H, m); 13C NMR(75 MHz, CDCl3) d 13.4, 13.8, 22.2, 22.3, 22.9, 25.1, 28.5, 31.0,33.9, 37.6, 84.9, 91.0, 124.3, 129.2, 129.3, 139.0, 163.1, 166.1,200.0; IR (neat) 2959, 2934, 2872, 1761, 1269 cm�1; HRMS (ESI)calcd for C21H28O5 (M + Na+) 383.1834, found 383.1830.

The typical procedure of Table 2 (entry 2): NaOMe (1.0 M inMeOH, 0.27 mL, 0.27 mmol) was added to a stirred solution of 3b(195 mg, 0.54 mmol) in MeOH (1.0 mL) at 0–5 1C under an Aratmosphere, followed by stirring at the same temp. for 2 h. Themixture was quenched with water (5 mL), which was extracted twicewith ether. The combined organic phase was washed with water,brine, dried (Na2SO4) and concentrated. The obtained crude oil waspurified by SiO2-column chromatography (hexane–AcOEt = 15 : 1 -

10 : 1) to give the desired (2R)-methyl 2-butyl-2-hydroxy-3-oxooctanoate4b (109 mg, 82%) and (S)-methyl atrolactate (10) (91 mg, 93%).

Colorless oil; 97% ee [HPLC analysis of its phenylhydrazonederivative (flow rate: 0.50 ml min�1, solvent: hexane–2-propanol =95 : 5), tR (racemic) = 13.29 min and 15.69 min, tR (4b) = (13.31 min)];[a]23

D + 38.2 (c 1.03, CHCl3); 1H NMR (300 MHz, CDCl3) d 0.89 (t, 3H,J = 6.9 Hz), 0.90 (t, 3H, J = 6.9 Hz), 1.12–1.40 (m, 8H), 1.59 (quint, 2H,J = 7.2 Hz), 1.90 (ddd, 1H, J = 5.2, 10.7 Hz, Jgem = 14.1 Hz), 2.09(ddd, 1H, J = 4.8, 11.4 Hz, Jgem = 14.1 Hz), 2.51 (dt, 1H, J = 7.2 Hz,Jgem = 17.9 Hz), 2.69 (dt, 1H, J = 7.6 Hz, Jgem = 17.9 Hz), 3.79 (s, 3H),4.04–4.35 (br, 1H); 13C NMR (75 MHz, CDCl3) d 13.84, 22.35, 22.66,23.15, 25.24, 31.13, 35.14, 36.65, 53.19, 84.21, 171.61, 207.29; IR(neat) 3484, 2959, 2934, 1721, 1262, 1221 cm�1; HRMS (ESI) calcd forC13H24O4 (M + Na+) 267.1572, found 267.1579.

Notes and references1 (a) D. Seebach and R. Naef, Helv. Chim. Acta, 1981, 64, 2704; (b) G. Frater,

U. Muller and W. Gunther, Tetrahedron Lett., 1981, 22, 4221; (c) Review:D. Seebach, A. R. Sting and M. Hoffmann, Angew. Chem., Int. Ed. Engl.,1996, 35, 2708; (d) A recent example among many applications:A. Larivee, J. B. Unger, M. Thomas, C. Wirtz, C. Dubost, S. Handa andA. Furstner, Angew. Chem., Int. Ed., 2011, 50, 304; (e) Facile and robustpreparations: T. Misaki, S. Ureshino, R. Nagase, Y. Oguni and Y. Tanabe,Org. Process Res. Dev., 2006, 10, 500; ( f ) R. Nagase, Y. Oguni, T. Misakiand Y. Tanabe, Synthesis, 2006, 3915.

2 (a) U. Schoellkopf, W. Hartwig and U. Groth, Angew. Chem., Int. Ed.Engl., 1979, 91, 922. Recent examples: (b) Y. Chen, Y. Wu,P. Henklein, X. Li, K. P. Hofmann, K. Nakanishi and O. P. Ernst,Chem.�Eur. J., 2010, 16, 7389; (c) W. Li, W. Ye and S. W. Schneller,Tetrahedron, 2012, 68, 65.

3 (a) R. M. Williams and M. N. Im, J. Am. Chem. Soc., 1991, 113, 9276;(b) Recent examples: C. Song, S. Tapaneeyakorn, A. C. Murphy, C. Butts,A. Watts and C. L. Willis, J. Org. Chem., 2009, 74, 8980; (c) B. Hill,V. Ahmed, D. Bates and S. D. Taylor, J. Org. Chem., 2006, 71, 8190.

4 (a) B. Strijtveen and R. M. Kellogg, Tetrahedron, 1987, 43, 5039;(b) R. P. Hof and R. M. Kellogg, J. Chem. Soc., Perkin Trans. 1, 1995,1247; (c) Y. Tanabe, H. Yamamoto, M. Murakami, K. Yanagi,Y. Kubota, H. Okumura, Y. Sanemitsu and G. Suzukamo, J. Chem.Soc., Perkin Trans. 1, 1995, 935.

5 (a) M. B. Smith and J. March, Advanced Organic Chemistry, Wiley,New York, 6th edn, 2007, p. 1335 and 1452; (b) L. Kurti and B. Czako,Strategic Applications of Named Reactions in Organic Synthesis, Else-vier, Burlington, 2005, p. 86 and 138; (c) G. Zhou, D. Lim, F. Fangand D. M. Coltart, Synthesis, 2009, 3350; (d) Selected recent progress;Y. Nishimoto, A. Okita, M. Yasuda and A. Baba, Angew. Chem., Int.Ed., 2011, 50, 8623.

6 (a) Y. Tanabe, Bull. Chem. Soc. Jpn., 1989, 62, 1917; (b) S. N. Craneand E. J. Corey, Org. Lett., 2001, 3, 1395; (c) T. Misaki, R. Nagase,K. Matsumoto and Y. Tanabe, J. Am. Chem. Soc., 2005, 127, 2854;(d) A. Iida, S. Nakazawa, T. Okabayashi, A. Horii, T. Misaki andY. Tanabe, Org. Lett., 2006, 8, 5215; (e) Related Mannich reaction;T. Funatomi, S. Nakazawa, K. Matsumoto, R. Nagase and Y. Tanabe,Chem. Commun., 2008, 771.

7 R. Nagase, Y. Iida, M. Sugi, T. Misaki and Y. Tanabe, Synthesis, 2008, 3670.8 P. W. Brian, P. J. Curtis, H. G. Hemming, C. H. Unwin and J. M. Wright,

Nature, 1949, 164, 534.9 (a) H. Tabuchi and A. Ichihara, J. Chem. Soc., Perkin Trans. 1, 1994,

125; (b) H. Tabuchi, T. Hamamoto, S. Miki, T. Tejima and A. Ichihara,J. Org. Chem., 1994, 59, 4749.

10 B. M. Trost, G. D. Probst and A. Schoop, J. Am. Chem. Soc., 1998,120, 9228.

11 (a) K. Wakasugi, A. Iida, T. Misaki, Y. Nishii and Y. Tanabe, Adv.Synth. Catal., 2003, 345, 1209; (b) H. Nakatsuji, J. Morita, T. Misakiand Y. Tanabe, Adv. Synth. Catal., 2006, 348, 2057.

12 Asymmetric organocatalysis for preparing a-alkyl-a-hydroxy-b-keto-esters; T. Misaki, G. Takimoto and T. Sugimura, J. Am. Chem. Soc.,2010, 132, 6286. This method affords the diastereomeric diol isomerof 6. The utility of these compounds is cited therein.

13 (a) B. M. Trost, M. Machacek and M. J. Schnaderbeck, Org. Lett.,2000, 2, 1761; (b) B. M. Trost, M. U. Frederiksen and M. T. Rudd,Angew. Chem., Int. Ed., 2005, 44, 6630.

14 R. W. Hoffman and S. Dressely, Angew. Chem., Int. Ed. Engl., 1986,25, 189.

Table 2 Preparation of chiral a-alkyl-a-hydroxy-b-ketoesters 4 by methanolysisof 3a

Entry Substrate R1 R2 Product Yieldb/% eec/%

1 3a Me 4a 81 962 3b Bu 4b 82 97d

3 3c Me 4c 81 924 3d Bu 4d 82 92d

5 3e Me 4e 89 966 3f Bu 4f 78 93

7 3g Me 4g 69 988 3h Bu 4h 69 86

9 3i Me 4i 88 9110 3j Bu 4j 85 92

a ca. 80% of 10 were recovered. b Isolated. c Determined by HPLCanalyses of the benzoyl ester derivative unless otherwise noted. d Deter-mined by HPLC analyses of the phenylhydrazone derivatives.

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