An Undergraduate Organic Synthesis, Spectroscopy, and Molecular Modeling Project Asymmetric Lewis Acid Catalyzed Diels-Alder Reaction of Menthyl Acrylate with Cyclopentadiene Moses ~ee,'Bonnie Garbiras, and Christopher Preti Furman University, Greenville, SC 29613 With the advent of affordable microcomputers and userfriendly programs molecular modeling has become a n important tool in chemical research by providingvaluahle insights into t h e structure and reactivity of compounds. ~ i c e n t l your department has established; compu~ationalmolecular modeline" classroomilahoratorv that is e a u i ~ o e d with nine CAChe Tektronix systems. As part of our continuing efforts in integrating the computer facility into our techniques of chemistry class, we have developed a project involving the synthesis of (2R)-(+)-2-hydroxymethyl-5-hicyclo[2.2.llheptene 3 by the Lewis acid catalyzed asymmetric Diels-Alder reaction of menthyl acrylate with cyclopentadiene. The racemic version of 3 also is prepared as a comparison to study the enantioselectivity of the preceding reaction. This project demonstrates a number of techniques commonly used in modern organic synthesis including chromatography (TLC a n d column), spectroscopy (FT-IR, 'H and 13C-NMR, GC-MS and polarimetry) and molecular modeling.
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Background on Asymmetric Diels-Alder Reactions In asymmetric [4+21 Diels-Alder reactions, dienophiles that contain a chiral auxiliary are commonly used (1).In such reactions one of the diastereomeric transition states has a lower energy leading to the creation of a n enantiomer predominantly (I).The thermal Diels-Alder reaction of menthyl acrylate with cyclopentadiene, followed by reduction, gives a n endo alcohol with low enantiomeric excess (e. e.) (2).However, the e. e. for this reaction can be enhanced dramatically by the use of a Lewis acid catalyst, such a s TiCl4, which stabilizes the s-trans conformation 'Author to whom all correspondence shold be addressed.
, menthyl
2, R = menthyl
5, R = methyl
4, R = Cb; methyl Figure 1. Synthesis of 2-hydroxymethyl-5-bicyclo[2.2.1]heptene3
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relative to t h e s-cis isomer by electronic effects andlor steric effects ( l b , 3). Synthesis of the Compounds Menthyl acrylate 1(41,as shown in Figure 1,reacts with cyclopentadiene and TiCI4to give the endo adduct 2 in 62% yield (5).The 'H-NMR spectrum of this compound given in Figure 2A shows two different sets of spectra for the (2s)(L)-menthyl and the (2R)-(L)-menthyl diastereomer. Integration of one of the olefinic hydrogens a t 5.87 ppm (major diastereomer) and 5.92 ppm (minor diastereomer) [see the insert i n Fig. 2Al provided the diastereomeric excess (d. e.) of t h e mixture to he 46M%, thus illustrating the diastereoselectivity of this reaction. The menthyl adduct 2 is reduced with LiAlH4 to give alcohol 3 in 57% yield ( 4 , 6). The structure of 3 is confirmed by spectroscopic analysesits 'H-NMR spectrum is depicted in Figure 2C. Similarly, reaction of methyl acrylate 4 with cyclopentadiene produces the racemic adduct 5 in 13% yield, whose 'H-NMR spectrum is shown in Figure 2B. Reduction of ester 5 with LiAlH4 also gives the racemic alcohol 3 in 95% yield. Optical Rotation and Asymmetric Induction The specific optical rotations of the chiral and the racemic alcohols 3 a t 578 n m and 22 "C are c12.1 and 0 ", respectively, thus demonstrating the diastereoselectivity of the Diels-Alder reaction and thence the enantioselective synthesis of alcohol 3. The (+) rotation of the chiral alcohol 3 confirms its (2R) absolute configuration (lc, 5).The e. e. of this alcohol is inferred to be identical to the above d. e. Molecular Modeling Studies Computer modeling studies are undertaken to provide a better understanding on the diastereofacial selectivity of the Diels-Alder reaction. The MM2 augmented force field energy minimized s-trans and s-cis acrylate:TiCI4 complexes a r e g e n e r a t e d on t h e CAChe Tektronix system. The s-trans conformer, whose structure is given in Figure 3, h a s a lower total energy (55.6512 kcal/mol) than its s-cis counterpart (61.7509 kcaWmo1). These data are i n agreement with ah initio calculations on Lewis acid complexed acrylates (3)and also with the X-ray struct u r e s of acrylate:TiCI4 (7a) a n d cinnamate ester:SnC14 (7b) complexes. As illustrated i n Figure 3, approach of the diene to the C(a)-re face of the strans acrylate:TiCI4 complex i s hindered by the isopropyl moiety of the chiral auxiliary. Consequently, the cycloaddition reaction progresses prefer-
entially via the C(a)-si face to produce a n adduct with the 2R absolute configuration. Experimental Procedure Diels-Alder Reaction of (L)-Menthyl Acrylate with Cyclopentadiene
A 1.6-mL (0.014 mol) portion of TiC14 was added using a glass syringe into 20 mL of dry CHzC12 (over molecular sieves 3A) in a 100-mL dried round-bottomed flask.
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Caution: 'ISQ liquid is highly toxic andmoisture sensitive. Aeornmercial 1.0 M TiC14 in CH& can be used.
A dried self-equalizing dropping funnel, equipped with a drying tube (drierite), containing 2.01 g (0.0095 moll of menthyl acrylate 1 (4) dissolved in 10 mL of dry CHzClz was attached to the flask. Upon cooling the reaction flask to -20 "C using a cryogenic finger in a C C 4 bath (or liquid
N2 in CCI,) the acrylate was added into the TiCI4 solution slowly. After 15 min, 2.0 mL (0.024 moll of freshly cracked cyclopentadiene in 10.0 mL of dry CH2C12was added into the funnel then slowly added into the reaction flask. After stirring a t -20PC for about 3 h, 20 mL of CH2C12and 20 mL of 2M HCI were added and the mixture was filtered. Discard the aqueous layer into a clearly labeled inorganic waste bottle. The CH2CI2 layer was separated using a separatory funnel, a n d i t was dried with anhydrous Na2S04then filtered. The filtrate was concentrated by rotary evaporation and the residue was purified by silica gel column chromatography (5% ethyl acetate:hexane). The desired fractions were combined and concentrated to give compound 2 as a clear colorless oil in 62% yield (1.63 g). TLC (20% ethyl acetate:bexane): Ri =0.47 (visualized by exposure to iodine vapor). IR (CHCla) v 2955,1723, 1633, 1456, 1405, 1271, 1198, 1046, 984 cm-'. 'H-NMR (CDC13, 300MHz) showed two sets of spectra: For the major dias-
Figure 2. 300 MHz 'H-NMR spectra of menthyl ester 2 (Part A), methyl ester 5 (Part B) and the optically active alcohol 3 (Part C)that were recorded on a Varian VXR 300s spectrometer. Volume 72 Number 4 April 1995
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tereomer S of some of the resolved signals 6.20 (dd., 3.0., 5.7. 1H). 5.87 (dd.. 2.7.. 5.4.. 1H). 4.58 (dt, 6.2, 12.3, I H ~ ;for the minor diastereomer 6.18, 5.92, and 4.60 ppm. Diels-Alder Reaction of Methyl Acrylate with Cyciopentadiene
The procedure was identical to that for the preparation of 2 except 4.8 mL of TiC14, 2.5 g of methyl acrylate, and 6.0 mL of cyclopentadiene were used, and a yield of 13% (0.59 g ) of compound 5 was obtained as a clear oil after purification by column chromatography. TLC (20% e t h y l a c e t a t e : h e x a n e ) RF0.44. IR (CHCld v 2950, 1733, 1435, 1355, 1308, 1196 cm-I. i ~ (CDC13) - 6 some ~ resolved ~ sig- ~ nals 6.19 (dd, 3.0, 5.7, l H ) , 5.93 (dd, 2.7, 5.7, lH), 3.67 (s, 3H). GC-MS (HP5890A, 12m x 0.2 mm Hp-1 cross-linked methyl silicone (film th~ckness:0.33 mm) capillary GC column retention time 7.40 min [152.05+1 (Mi, 1411. Preparation of ChiralAlcohol3
1.0 g (0.0036 moll of2 was dissolved in 50 mL of dry THF (over molecular sieves 3A) in a 250mL dried round-bottomed flask. 0.151 g (0.0040 mol) of LiAlH, was introduced to this mixture. A condenser equipped with a drying tube was attached to the flask then the reaction was refluxed gently for 6 h. Upon cooling the reaction to room temperature 0.15 mL of water, 0.15 mL of 15% sodium hydroxide, and 0.45 mL of water were added, then the suspension was filtered. The filtrate was dried with anhydrous Na2S04 then concentrated by rotary evaporation. The J residue was purified by silica ~ e column l chromatography (25% ethyl acetateThexane)to yield Fi!lure 3. MM2 energy minimized conformation of the s-trans menthyl acrylate:TiCl the chiral compound 3 as a clear and colorless complex. oil in 57% yield (0.25 g). TLC (20% ethyl acevan der Wads constants, tate:hexane): RI=0.14. IR (CHCIS)v 3344,2954,2868,1454, radius = 2.80 A, 1026 em-'. 'H-NMR (CDCl,) G 6.18 (dd, 2.7, 5.4, H5), 5.96 hardness factor E = 0.185 keallmol; (dd,2.7, H6) 3.40 (dd, 6.9, 10.5,H2'), 3.26 (dd, 9.0, 10.5, HZ'), bond lengths and 2.95 (br s, H I ) 2.81 (brs, H4),2.28(m, HZ), 1.82 (ddd, 3.9,9.3, stretch force constants far 7-0and Ti-CI are 2.05 A and 11.7, H3), 1.70 (br s, OH), 1.42 (ddd, 2.0,2.1,8.1, H7), 1.28 (br 4.40 rndynelk, and 2.31 and A 4.40 rndynel, respectively d, 8.1, H7), 0.52 (ddd, 2.4, 3.9, 11.4, H3). '%-NMR (CDC13, The bond angles and bonding constants for C=O-Ti, O75.4 MHz) S 137.34 (C6), 132.07 (C5),66.41(C2'), 49.49 ((231, 43.57 (Cl), 42.81 (C4), 41.66 (C21, 28.78 (C7). G G M S retenTi-0, GI-Ti-C1 and CI-Ti-CI were 121.4 ' a n d 0.550 mdyneNrad2, 180.0 " and 0.450 mdyne A/rad2, 90.0 " and tion time 9.22min [l23.05f 1(Mt, 11)l.Optical activity [a122sv8 0.450 mdyneA/rad2, and 180.0 and 0.450 mdyne A had2, = +12.1 "(CHCI3,c = 0.0382 g/mLj. Lit (5) [aIz2o= +67.7 (c = respectively. The torsional constants (kcallmol) vl and v2 0.718. ethanol). for O-C=O-Ti and =C-C=O-Ti were -0.27 and 10.0, and -0.27 and 10.0, respectively.
L
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Preparatfon of Racemic Alcohol 3
The procedure was identical to that used in the preced= 0 "(CHC13, c= 0.017 ing method. Optical activity [a122578 gimL). The spectral data were identical to those of the chiral alcohol. Molecular Modeling Studies
The desired s-cis and s-trans conformations of the acry1ate:Lewis acid complex, generated using the molecular editor on a CAChe system, resembled that of the X-ray structure of an acrylate:TiC14 complex (7a).The complexes were energy minimized using the augmented force field parameters available in a CAChe system using the conjugated gradient method with a convergence limit of 0.100 kcalimol. The parameters for d2sp3TXIV) were 380
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Acknowledgment The authors acknowledge the NSF-ILI, The Miliken Foundation, Furman University and Furman Chemistry alumni for providing the funds to establish the computation-molecular modeling ~IassroomAahoratory. Literature Cited As,vmmetric S w , h e # i ~ Momson. . J. D. Ed.: Academic Prers, Inc. Orlando. FL, 1985: Vol 1-5. ibi Opploeer WAngenr Chem. bil. Ed, E w i . 1984.23.876869 i c i P a q u e t k L . A. InAx.vmmetricS~,iihesir, Momson. J. D., Ed.;AendemicPresa. lnc.: Orlando. FL, 19RS: Vol.3, pp 456-101. la) Sauer. J.; f i d e l . J. Tetrohedinn Let,. 1966, 6359-6364. ibl Snuel: J.; Kredel. J. A,z#cu. Chem. l ~ r Ed. l En#;. L965.4.989. i c l Krrdel. J. P h D Dissertation; Unir of Munich, 1967. Loneharich.R. J.: Schwartz, T. R.; Houk. K. N. J. An. Chem. Soc. 1987. 109. 14-23. Farrncr R. E:Hamer, J. J. Org Cihnr. 1966,31,241&2419. Oppolcer W , Kulfh. M.. Reichlin. D.. Moffntt. F Xirnhndrnri Lett. 1981.22.254%254R. Oppoizcv, W.;Chapuii. C.: Bernardinelli. G.H d i . Chiai. Acln 1984, 67. 1397-1401. in, POII. T.: ~ e t t e r J. 0.: ~ e l m c h e n~, . ~ n pchrrn. r i I M ECI.E,W! 1985.24, 112114. ibl Lewis, F D.; Oxman. J. D.: Huffman. J. C.J. Am. Wem. So?. 1984. 106,
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