OXAZOLE, 2,2′,2′′-(2-METHYL-1-ETHANYL-2-YLIDENE)TRIS … 1

Oxazole, 2,2′′′,2′′′′′′-(2-methyl-1-ethanyl-2-ylidene)tris[4,5-dihydro-4-(1-methyl-ethyl)-], (4S,4′′′S,4′′′′′′S)

N

O

O

N

O

N

1

[458563-75-2] C21H35N3O3 (MW 377.52)InChI = 1/C21H35N3O3/c1-12(2)15-9-25-18(22-15)8-21(7,19

-23-16(10-26-19)13(3)4)20-24-17(11-27-20)14(5)6/h12-17H,8-11H2,1-7H3/t15-,16-,17-/m1/s1

InChIKey = ZLJMXDGDZUSSDE-BRWVUGGUBT

(chiral ligand for enantioselective metal-catalyzed reactions suchas copper-catalyzed Friedel–Crafts reaction of indoles with alkyli-dene malonates,1–5 Kinugasa reaction,6,7 and cobalt-catalyzed1,3-dipolar cycloaddition of nitrones to alkylidene malonates8)

Physical Data: [α]20D –47.2 (c 3.79, CHCl3).

Solubility: insoluble in H2O, soluble in common organic sol-vents.

Form Supplied in: colorless oil.Preparative Methods: pure enantiomer can be synthesized from

trimethyl 1,2,2-propanetricarboxylate and L-valinol in twosteps.9,10 It should be noted that an excess of amino alcoholis necessary to obtain satisfactory yield in the first step. 1 canalso be prepared by modular synthesis,4 i.e., deprotonation ofbisoxazoline by t-BuLi, followed by coupling with L-valinol de-rived 2-chloromethyl-2-oxazoline. Good yield can be achievedon a gram scale by the modular synthetic method. By the modi-fied approach, trisoxazolines bearing different substituents suchas compounds 2–5 are prepared in moderate to high yields.

Purification: trisoxazolines 1–5 can be purified by flash col-umn chromatography (silica gel/petroleum ether/EtOAc = 20/1to 1/1).

Handling, Storage, and Precaution: to prevent decomposition,stored at −20◦ C under nitrogen atmosphere.

N

O

O

N

O

N

iPr iPr

sBu

2

[862605-42-3]InChI = 1/C22H37N3O3/c1-8-15(6)18-12-26-19(23-18)9-22

(7,20-24-16(10-27-20)13(2)3)21-25-17(11-28-21)14(4)5/h13-18H,8-12H2,1-7H3/t15?,16-,17-,18-/m1/s1

InChIKey = ZTELCSAVBOCHJL-QSLYMNIHBH

N

O

O

N

O

N

But tBu

tBu

3

[862605-51-4]InChI = 1/C24H41N3O3/c1-21(2,3)15-12-28-18(25-15)11-24

(10,19-26-16(13-29-19)22(4,5)6)20-27-17(14-30-20)23(7,8)9/h15-17H,11-14H2,1-10H3/t15-,16-,17-/m1/s1

InChIKey = VFARSJRXDLJSDG-BRWVUGGUBR

N

O

O

N

O

N

sBu sBu

sBu

4

[668463-50-1]InChI = 1/C24H41N3O3/c1-8-15(4)18-12-28-21(25-18)11-24(7,

22-26-19(13-29-22)16(5)9-2)23-27-20(14-30-23)17(6)10-3/h15-20H,8-14H2,1-7H3/t15?,16?,17?,18-,19-,20-,24?/m1/s1

InChIKey = NNRXDOHSEMDAJV-QHRORSMPBX

N

O

O

N

O

N

Ph Ph

Ph

5

[668463-54-5]InChI = 1/C30H29N3O3/c1-30(28-32-25(19-35-28)22-13-7-3-8

-14-22,29-33-26(20-36-29)23-15-9-4-10-16-23)17-27-31-24(18-34-27)21-11-5-2-6-12-21/h2-16,24-26H,17-20H2,1H3/t24-,25-,26-/m0/s1

InChIKey = XXXJMHKHNMMDIN-GSDHBNREBM

Introduction. Compounds 1–5 are useful chiral ligandsin metal-catalyzed asymmetric C–C bond formation reactionssuch as Friedel–Crafts reaction of indoles with alkylidenemalonates,1–5 Kinugasa reaction,6,7 1,3-dipolar cycloaddition ofnitrones to alkylidene malonates,8 as well as Diels–Alderreactions.11

Friedel–Crafts Reaction of Inodoles with AlkylideneMalonates.1–5 Catalyst generated in situ from 1 and a CuII saltcan promote the reaction between indoles and alkylidene malo-nates with up to 97% ee in excellent yields in i-BuOH (eq 1).3 Thecatalyst is air-stable. Accordingly, the reaction can be carried outunder air in commercial alcohol without loss of ee, as compared

Avoid Skin Contact with All Reagents

2 OXAZOLE, 2,2′,2′′-(2-METHYL-1-ETHANYL-2-YLIDENE)TRIS …

with the reaction under N2. The reaction is highly solvent-dependent. Ester groups of alkylidene malonates have dramaticeffects on the enantioselectivity. Noticeably, a reversal ofenantioselectivity is observed by changing the solvent fromi-butanol to halogenated solvents such as 1,1,2,2-tetrachloroethane (TTCE).2,3 For example, with 1/Cu(OTf)2

(1.0/1.5) as the chiral catalyst, the Michael addition product(R-isomer) is obtained with 75% ee in TTCE at 0◦C (eq 2), whilethe same starting materials generate the S-enantiomer with 97%ee in iBuOH at −25◦C.

NH

PhCO2Bui

CO2Bui

NH

CH(CO2Bui)2Ph

+ 1/Cu(OTf)2 (1.2/1)

i-BuOH, –25 °Cair atmosphere

(1)

(S)-97% ee99% yield

NH

PhCO2Bui

CO2Bui

NH

CH(CO2Bui)2Ph

+ 1/Cu(OTf)2 (1/1.5)

TTCE, 0 °C, N2

(2)

(R)-75% ee73% yield

Under the same reaction conditions, CuII complexes withligands 2,4 4,3 and 53 combined with CuII furnish the desiredproducts with slightly poorer enantioselectivities than that of1/CuII.

Kinugasa Reaction.6,7 The Kinugasa reaction is a promisingprotocol to prepare β-lactams by copper-catalyzed cycloadditionof nitrones to terminal acetylenes. CuI is usually employed as thecatalyst, which requires the reaction to be carried out under strictlyoxygen-free conditions. Whereas, with ligand 1, Cu(ClO4)2·6H2Obecomes an effective catalyst. Thus, 1-ethynylbenzene reacts withnitrones to give cis-disubstituted β-lactams in moderate yieldswith 55–85% ee in the presence of 10 mol % of 1/CuII (eq 3).The reaction can be performed under air without loss of enan-tioselectivity because of the stability of CuII. Secondary bulkyamine give higher enantioselectivities and diastereoselectivitiesthan those of primary amines. Tertiary amines such as 2,2,6,6-tetramethylpiperidine (TMP) and diisopropylethylamine affordmuch higher diastereoselectivity but lower enantioselectivity than

PhN+

PhH

Ph O–

NO

Ph Ph

Ph

+Cu(ClO4)2·6H2O/1 (1/1.2)

dicyclohexylamine (1 equiv)

CH3CN, 0 °C

(3)

cis/trans 94/682% ee for cis-isomer, 56% yield

secondary amines. Under the screened conditions, dicyclohexy-lamine proves to be optimal. The cooperation between metal andligands has strong effects on the enantioselectivities and yields,with 4/CuII giving the highest enantioselectivity.

1,3-Dipolar Cycloaddition.8 The reaction of nitrones witholefinic dipolarophiles produces multisubstituted isoxazolidines.1/Co(ClO4)2·6H2O is an excellent catalyst for 1,3-dipolar cyclo-addition of nitrones to alkylidene malonates. It is noteworthy thatcis/trans-selectivities could be effectively switched by varyingreaction temperature. As a result, both enantiopure cis- andtrans-isoxazolidines could be prepared. For example, at 0 ◦C,trans-products are obtained with high diastereoselectivity andenantioselectivity of up to 98% ee; when the temperature isdecreased to −40 ◦C, cis-products are obtained as the major prod-ucts with good to high enantioselectivities (eq 4). A wide varietyof nitrones and alkylidene malonates are suitable substrates. Aryli-dene malonates usually give better selectivity. A mechanisticstudy shows that the reaction of N,C-diphenylnitrones withphenylidene malonates to form cis-isoxazolidines is reversible.

Ph

COOEt

COOEt

N+

PhH

Ph O–

N OPh

Ph

PhCOOEt

COOEt

N OPh

Ph

PhCOOEt

COOEt

+1/CoII

+

0 °C,

trans cis

trans/cis: 97/3, with 95% ee for trans-isomer; –40 °C, trans/cis: 11/89, with 93% ee for cis-isomer.

(4)

Diels–Alder Reaction.11 The chiral complex of 1/Cu(ClO4)2·6H2O generated in situ can promote Diels–Alder reaction ofcyclopentadiene with 2-oxazolidinone or ketoesters to givecycloaddition products. Moderate diasteroselectivities and enan-tioselectivities are achieved. Similar results are given by 4/Cu-(ClO4)2·6H2O. Enantioselectivity is poor when 5/Cu(ClO4)2·6H2O is used.

1. Zhou, J.; Tang, Y., J. Am. Chem. Soc. 2002, 124, 9030.

2. Zhou, J.; Ye, M.-C.; Tang, Y., J. Comb. Chem. 2004, 6, 301.

3. Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y., J. Org. Chem. 2004, 69,1309.

4. Ye, M.-C.; Li, B.; Zhou, J.; Sun, X.-L.; Tang, Y., J. Org. Chem. 2005,70, 6108.

5. Zhou, J.; Tang, Y., Chem. Soc. Rev. 2005, 34, 664.

6. Ye, M.-C., Zhou, J.; Huang, Z.-Z.; Tang, Y., Chem. Commun. 2003, 2554.

7. Ye, M.-C.; Zhou, J.; Tang, Y., J. Org. Chem. 2006, 71, 3576.

8. Huang, Z.-Z.; Kang, Y.-B.; Zhou, J.; Ye, M.-C.; Tang, Y., Org. Lett. 2004,6, 1677.

9. Kawasaki, K.; Katsuki, T., Tetrahedron 1997, 53, 6337.

10. Vorbruggen, H.; Krolikiewicz, K., Tetrahedron 1993, 49, 9353.

11. Zhou, J.; Tang, Y., Org. Biomol. Chem. 2004, 2, 429.

Xiu-Li Sun & Yong TangShanghai Institute of Organic Chemistry, Shanghai, China

A list of General Abbreviations appears on the front Endpapers