Diastereoselective Reduction of a Chiral - American Chemical Society

chiral induction, the (R)-enantiomer of Alpine-Hydride was also tested ... (42) For a review of R-pinene-based borane reagents, including DIP- chlorid...
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Diastereoselective Reduction of a Chiral N-Boc-Protected δ-Amino-r,β-unsaturated γ-Keto Ester Phe-Gly Dipeptidomimetic Jon Våbenø,† Magnus Brisander,† Tore Lejon,‡ and Kristina Luthman*,†,§ Department of Medicinal Chemistry, Institute of Pharmacy and Department of Chemistry, University of Tromsø, N-9037 Tromsø, Norway, and Department of Chemistry, Medicinal Chemistry, Go¨ teborg University, SE-412 96 Go¨ teborg, Sweden [email protected] Received July 1, 2002

The readily available N-Boc-protected δ-amino R,β-unsaturated γ-keto ester 1 was diastereoselectively reduced to the corresponding alcohols 2 and 3, using boron- and aluminum-based reducing reagents. Reduction reactions were successful and resulted in anti/syn ratios of alcohols of >95:5 (80% yield), using LiAlH(O-t-Bu)3 in EtOH at -78 °C under chelation control, and 5:95 (98% yield), using NB-Enantride in THF at -78 °C under Felkin-Anh control. Introduction The syntheses of isomerically pure R-amino alcohols and R-amino alcohol esters have been studied extensively due to the versatility of these compounds as chiral starting materials.1-3 Several stereoselective reduction reactions have been reported for N-protected γ-amino-βketo esters (e.g. synthesis of statine and its analogues), both enzymatically4,5 and chemically.6-8 However, reductions of the corresponding δ-amino-γ-keto esters are considerably less studied, and little information is available in the literature.9 Structural differences such as the increased distance between carbonyl groups imply that these compounds offer other synthetic challenges. In our continuing studies on the synthesis and use of multifunctionalized Phe-Gly dipeptidomimetics,10-12 we have focused our interest on the diastereomeric alcohols 2 and 3 as useful starting materials. The alcohols can be obtained by reduction of the readily available R,β†

Department of Medicinal Chemistry, University of Tromsø. Department of Chemistry, University of Tromsø. Go¨teborg University. (1) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576. (2) For a review on preparation and reactions of R-amino aldehydes, ketones, aldimines, and ketimines, see: Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531-46. (3) For a review of diastereoselective synthesis of amino alcohols from chiral amino carbonyl compounds in general, see: Tramontini, M. Synthesis 1982, 8, 605-644. (4) Hashiguchi, S.; Kawada, A.; Natsugari, H. Synthesis 1992, 403408. (5) Raddatz, P.; Radunz, H. E.; Schneider, G.; Schwartz, H. Angew. Chem. 1988, 100, 414-15. (6) Dufour, M. N.; Jouin, P.; Poncet, J.; Pantaloni, A.; Castro, B. J. Chem. Soc., Perkin Trans. 1 1986, 11, 1895-9. (7) Harris, B. D.; Joullie, M. M. Tetrahedron 1988, 44, 3489-3500. (8) Maugras, I.; Poncet, J.; Jouin, P. Tetrahedron 1990, 46, 28072816. (9) Reductions of the methyl ester (see ref 10) and ethyl ester (see ref 16) derivatives have been described previously. (10) Berts, W.; Luthman, K. Tetrahedron 1999, 55, 13819-13830. (11) Jenmalm, A.; Berts, W.; Li, Y. L.; Luthman, K.; Cso¨regh, I.; Hacksell, U. J. Org. Chem. 1994, 59, 1139-1148. (12) Jenmalm, A.; Berts, W.; Luthman, K.; Cso¨regh, I.; Hacksell, U. J. Org. Chem. 1995, 60, 1026-1032. ‡ §

SCHEME 1

unsaturated keto ester derivative 1 (Scheme 1).13 Allylic alcohol derivatives, such as 2 and 3, have proven to be interesting as peptidomimetics that could be incorporated into peptides as replacements for hydrolyzable amide bonds,14,15 and they have also been successfully used, for example, in the stereospecific synthesis of fluoro derivatives via the corresponding unsaturated aziridines.10 When reducing the methyl ester analogue of 1 with NaBH4 in THF/MeOH, CeCl3 was needed as additive to increase the reactivity of the carbonyl group. We thereby achieved chemoselective ketone reduction and formation of the allylic alcohols in good yields.10 However, no diastereoselectivity was observed, although stereoselective reduction reactions using similar conditions had earlier been published.16,17 The purification and separation of the resulting mixture of alcohols was very time (13) The alcohols can be obtained also from ring opening of the corresponding epoxides; see ref 11 and references therein. (14) Kaltenbronn, J. S.; Hudspeth, J. P.; Lunney, E. A.; Michniewicz, B. M.; Nicolaides, E. D.; Repine, J. T.; Roark, W. H.; Stier, M. A.; Tinney, F. J.; Woo, P. K. W.; Essenburg, A. D. J. Med. Chem. 1990, 33, 838-845. (15) Urban, J.; Konvalinka, J.; Stehlikova, J.; Gregorova, E.; Majer, P.; Soucek, M.; Andreansky, M.; Fabry, M.; Strop, P. FEBS Lett. 1992, 298, 9-13. 10.1021/jo020442o CCC: $22.00 © 2002 American Chemical Society

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Selective Reduction of a Phe-Gly Dipeptidomimetic SCHEME 2a

FIGURE 1. Diastereoselective control in reductions of N-Bocprotected chiral R-amino ketones.

consuming, as flash chromatography on silica gel and recrystallizations had to be repeated several times before the pure stereoisomers could be isolated.10 To remove this bottleneck in an otherwise efficient reaction scheme, we have put considerable effort into finding reduction conditions that allow selective synthesis of the two diastereomeric alcohols in high yields and with high de. Two different modes of stereocontrol have been used to explain the stereochemical outcome of reduction reactions of R-amino ketone derivatives,18 i.e. chelation control and Felkin-Anh control.19,20 Chelation control has been used to explain the formation of the anti-diastereomer 2, whereas Felkin-Anh control is thought to result in formation of the syn-diastereomer 3, as depicted in Figure 1. Chelation control involves the coordination of a chelating atom (M), often boron or aluminum (from the reducing agent) or other ions (counterions or additives).21 In Felkin-Anh-controlled reactions, the incoming hydride species differentiates between the two faces of the carbonyl group due to stereoelectronic interactions with substituents close to the reacting center.22 Several reduction reactions stereoselectively producing R-amino alcohols have been published.23-25 However, from a mechanistic viewpoint, some diastereoselective (16) Litera, J.; Budesinsky, M.; Urban, J.; Soucek, M. Collect. Czech. Chem. Commun. 1998, 63, 231-244. (17) Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.; Zlatoidzky, P. J. Org. Chem. 1997, 62, 9348-9353. (18) For a summary, see: Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994; pp 876-880. (19) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9, 2199-2204. (20) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 9, 2205-2208. (21) For an overview of reduction of carbonyl groups with metal hydrides, see: Greeves, N. In Comprehensive organic synthesis: selectivity, strategy & efficiency in modern organic chemistry. Volume 8: Reduction, 1st ed.; Trost, B. M., Fleming, I., Eds.; Pergamon Press: 1991; Vol. 8, p 1-24, and references therein. (22) Calculations of the volumes of BocNHMe and PhCH2Me by MacroModel (Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440-67) version 7.0 gave values of 132.6 and 116.7 Å3, respectively, indicating that BocNH should be considered as Rlarge in the Felkin-Anh model, as shown in Figure 1. (23) Sengupta, S.; SenSarma, D. Tetrahedron: Asymmetry 1999, 10, 4633-4637. (24) Sengupta, S.; SenSarma, D. Tetrahedron Lett. 2001, 42, 485487. (25) Tao, J. H.; Hoffman, R. V. J. Org. Chem. 1997, 62, 6240-6244.

a Reagents and conditions: (a) LiCH PO(OMe) (3 equiv), THF, 2 2 -78 °C; (b) CHOCOO-t-Bu (5), LiCl, Et3N, CH3CN, 0 °C f rt.

reductions have given contradictory results, leading to a poor predictability of the outcome.26 In the present study, we have used the mechanistic implications outlined above in the selection of reducing agents to enable diastereoselective synthesis of either one of the two diastereomeric alcohols 2 and 3 by reduction of 1. Results and Discussion Synthesis of the Protected Amino Keto Ester 1. Several synthetic routes to amino ketones such as 1 have been published.10,16,27-30 The procedure employed in the present study started from Boc-protected L-phenylalanine methyl ester (Scheme 2), which was reacted with the anion of methyl dimethylphosphonate to produce the β-ketophosphonate 4. A Horner-Wadsworth-Emmons reaction of the phosphonate with tert-butyl glyoxylate31 in the presence of triethylamine and lithium chloride32 afforded the unsaturated ketone in good yield (73%). Synthesis of Allylic Alcohols 2 and 3 via Stereoselective Reduction of 1. A series of various chiral and achiral reducing agents (Table 1) and enzymes33 was evaluated in the stereoselective reduction reactions of 1. The diastereomeric ratio of alcohols 2 and 3 was analyzed by 1H NMR spectroscopy of the crude reaction mixtures, (26) Examples of low predictability in reduction reactions: Koskinen et al. got the Felkin-Anh product using NaBH4 in MeOH (chelating conditions) (Koskinen, A. M. P.; Koskinen, P. M. Tetrahedron Lett. 1993, 34, 6765-6768), Dondoni et al. observed the chelation product using L-Selectride in THF (Felkin-Anh conditions) (Dondoni, A.; Perrone, D.; Turturici, E. J. Org. Chem. 1999, 64, 5557-5564), and Rotella got the chelation product with NaBH4 in EtOH and with L-Selectride in THF (Rotella, D. P. Tetrahedron Lett. 1995, 36, 54535456). (27) Deziel, R.; Plante, R.; Caron, V.; Grenier, L.; LlinasBrunet, M.; Duceppe, J. S.; Malenfant, E.; Moss, N. J. Org. Chem. 1996, 61, 29012903. (28) Kim, B. H.; Chung, Y. J.; Ahn, H. J.; Ha, T. K. Bull. Korean Chem. Soc. 1996, 17, 401-404. (29) Saiah, M. K. E.; Pellicciari, R. Tetrahedron Lett. 1995, 36, 4497-4500. (30) Darkins, P.; McCarthy, N.; McKervey, M. A.; Ye, T. J. Chem. Soc., Chem. Commun. 1993, 1222-1223. (31) The tert-butyl glyoxylate was synthesized via an oxidative cleavage of di-tert-butyl tartrate, which was obtained by esterification of L-tartaric acid with a tert-butyl dicyclohexyl isourea derivative according to ref 45. See also the Experimental Section. (32) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-2186.

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Våbenø et al. TABLE 1. Results from Ketone Reductions of 1 Using Different Reducing Agents and Different Reaction Conditionsa entry

reagent

solvent

temp

time (min)

anti/syn (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

NaBH4, CeCl3 Zn(BH4)2 (S)-CBS, BH3‚THF (R)-CBS, BH3‚THF Na L-prolinate, BH3‚THFb Na D-prolinate, BH3‚THFb 6, BH3‚THF NaBH4 LiAlH(O-t-Bu)3 DIBALH DIBALH, ZnCl2 DIBALH, Ti(O-i-Pr)4 Superhydridec L-Selectride (R)-Alpine-Hydride (S)-Alpine-Hydrided NB-Enantridee

THF/MeOH (2:1) Et2O THF THF THF THF THF EtOH EtOH THF THF THF THF THF THF THF THF

rt -78f0 °C 0 °C 0 °C 0 °C 0 °C rt -78 °C -78 °C -78 °C -78 °C -78 °C -78 °C -78 °C -78 °C -78 °C -78 °C

15 300 30 30 30 30 480 120 120 60 150 60 60 120 60 60 60

53:47 68:32 68:32 67:33 74:26 63:37 60:40 68:32 >95:5 25:75 53:47 32:68 50:50 50:50 13:87 5:95 5:95

a Reaction conditions were screened with respect to reaction time, temperature, solvent, and amount of reducing agents in relation to ketone. Typical examples are presented in the table. b Using L- and D-proline + NaBH4 gave slightly poorer anti/syn ratios. c Also resulted in formation of an unknown byproduct, possibly the saturated alcohols. d Using CH2Cl2 as solvent reduced the anti/syn ratio to 42:58. e Using CH Cl as solvent reduced the anti/syn ratio to 37:63. 2 2

since the signals from the H-2 vinylic proton of 2 and 3 appeared as well-separated peaks (δ 6.08 and 5.98, respectively). These diagnostic signals in 1H NMR spectra were assigned by correlation to the corresponding methyl ester derivatives described earlier.10,11 The diastereomers were purified by recrystallization and/or HPLC (see the Experimental Section for details). Choice of Reducing Agents. Chelation Control. Many studies on stereoselective reductions have been performed on β-keto ester derivatives, which allow for efficient coordination of the two oxygen atoms to di- or trivalent metal ions. In 1, there is an unsaturated 1,4keto ester system in which the trans-double bond is expected to prevent all types of simultaneous coordination of the γ-keto ester carbonyl oxygens to metal ions. Instead, the carbamate oxygen or nitrogen atoms are expected to participate in such coordinations. However, O,O-chelation involving the carbonyl and carbamate oxygen will result in formation of a less favored sevenmembered ring; instead, O,N-chelation involving the carbamate nitrogen, resulting in a five-membered ring, seems more likely. In both cases the formation of the antiisomer of the alcohol (2) will be favored. NaBH4/CeCl3 in THF/MeOH at room temperature did not result in any stereoselectivity (entry 1, Table 1). Monovalent counterions such as Na+ or Li+ are not expected to produce stable chelates under these reaction conditions. However, using NaBH4 in EtOH at -78 °C resulted in an improved stereoselectivity (68:32) (entry 8, Table 1). Thus, it appears as if lowering of the temperature and/or using alcohols as solvents might improve the stability of the chelates. The addition of Lewis acids to the reaction medium has also been shown to improve the stability. Zn2+ ions have been successfully used to improve chelation of oxygen and nitrogen atoms,34 (33) Since successful enzymatic reductions of N-protected γ-aminoβ-keto esters using microorganisms have been reported (see refs 4 and 5), we tried both baker’s yeast and Pichia anomala (also known as Hansenula anomala) in reductions of 1. However, both reactions failed, as no alcohol product could be detected by NMR spectroscopy, probably as a result of the nonfavored distance between the two keto ester carbonyl groups in 1. Therefore, this route to alcohols 2 and 3 was not further explored.

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and therefore, reduction reactions using Zn(BH4)235 were explored. However, in our case, only a small improvement of the stereoselectivity was observed, even at -78 °C (entry 2, Table 1). To improve the chelation control, we tried several boron-containing chiral reducing reagents, e.g. Corey’s 2-methyl-CBS-oxazaborolidine (CBS),36 as well as BH3based prolinate37 and the D-valine derivative (R)-2-amino3-methyl-1,1-diphenylbutan-1-ol (6)38,39 (entries 3-7, Table

1). All these reagents predominantly gave the anti-isomer 2 with anti/syn ratios ranging from 60:40 to 74:26, indicating that boron is involved in the chelate. The chiral induction from the reducing agent was also explored by using the enantiomeric forms of the CBS and prolinate reducing agents, but none or only little improvement in the stereoselectivity was observed (entries 3-6, Table 1). During the course of our work, Hoffman et al. published their successful use of LiAlH(O-t-Bu)3 in EtOH at -78 °C as a highly selective reducing agent generating the chelation-controlled product.40 When using LiAlH(O-t-Bu)3 and the same conditions on 1 we obtained the highest stereoselectivity with almost exclusive formation of the anti-isomer 2 (entry 9, Table 1). The tert-butoxy groups on aluminum are readily exchangeable in EtOH, (34) Sengupta, S.; Das, D.; Mondal, S. Synlett 2001, 1464-1466. (35) Zn(BH4)2 was formed from ZnCl2 and NaBH4 according to ref 48. (36) For a review of enantioselective reduction of ketones, including oxazaborolidines, see: Singh, V. K. Synthesis 1992, 605-617, and references therein. (37) Umino, N.; Iwakuma, T.; Itoh, N. Chem. Pharm. Bull. 1979, 27, 1479-1481. (38) Itsuno, S.; Ito, K. J. Org. Chem. 1984, 49, 555-557. (39) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1985, 2039-44. (40) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002, 67, 1045-1056.

Selective Reduction of a Phe-Gly Dipeptidomimetic

and it is therefore difficult to define the reacting species under the reaction conditions used. This was to us a satisfactory result, as pure 2 could readily be obtained from the reaction mixture. Choice of Reducing Agents. Felkin-Anh Control. To facilitate a Felkin-Anh-controlled reaction, nonexchangeable ligands on boron or aluminum were needed. In addition, it was expected that a relatively bulky reagent would promote this mechanism.41 DIBALH reductions are known to mainly proceed from the less hindered face of the ketone. Results from reduction of 1 were encouraging but still not satisfying (entry 10, Table 1), and it was decided to investigate the effect of adding Lewis acids. On the basis of the fact that titanium readily coordinates both oxygen and nitrogen, as seen from the vast number of complexes published in the literature, it was decided to use titanium catalysts and zinc chloride. Both Lewis acids suppressed the Felkin-Anh control, and the results obtained (entries 11 and 12, Table 1) imply a competing chelation-controlled reaction. Interestingly, addition of ZnCl2 in reductions of 1 actually resulted in a small anti-preference, indicating that Zn is a more efficient chelator than Ti in this reaction. It is possible that the effect of Ti can be explained by a competing O,O-chelation between the carbonyl oxygens of the ketone and the carbamate groups. Instead of the aluminum-based reducing reagents, we turned to large boron-containing agents without readily exchangeable ligands. First, three neutral reagents were explored, 9-BBN-H, (-)-DIP chloride, and (+)-DIP bromide; all three derivatives are known to enantioselectively reduce prochiral ketones.42 For these reagents, ligand exchange/chelation is less likely and Felkin-Anh control is expected. However, these reducing agents showed low chemoselectivity and mainly resulted in reduction of the double bond instead of the keto function (results not shown). Therefore, we selected a series of LiBR3H reagents, i.e. negatively charged borohydrides, ranging in size from Superhydride (LiBEt3H) to the bulky pinene-based NBEnantride (entries 13-17, Table 1). The rather small Superhydride did not result in any stereoselectivity in the reduction (entry 13, Table 1). The NMR spectrum of the crude reaction mixture indicated byproduct formation, probably resulting from concomitant reduction of the double bond. The somewhat larger L-Selectride did not show any stereoselectivity either (entry 14, Table 1), indicating that the carbonyl group in 1 is quite accessible from both faces under nonchelating conditions. However, when increasing the bulk of the ligands on boron as in (S)-Alpine-Hydride or NB-Enantride, the stereoselectivity was considerably improved (entries 16 and 17, Table 1), giving ratios of 5:95. To test (41) Hoffman et al. used LiAlH(O-t-Bu)3 in THF at -5 °C on a substrate in which the N-carbamate protecting group had been replaced by the more sterically demanding N-trityl group to obtain Felkin-Anh control (the syn-isomer). However, in contrast to Hoffman et al., we wanted to use the same starting material for selective synthesis of both alcohol derivatives without changing protecting groups. Therefore we focused our efforts on finding reducing agents that favored the Felkin-Anh-controlled mechanism. (42) For a review of R-pinene-based borane reagents, including DIPchloride and Alpine-Hydride, see: Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500, 1-19, and references therein.

FIGURE 2. Proposed transition state indicating the involvement of THF.

whether the Felkin-Anh control could be influenced by chiral induction, the (R)-enantiomer of Alpine-Hydride was also tested (entry 15, Table 1). As can be seen, the (R)-enantiomer produced a lower stereoselectivity than the (S)-enantiomer, with an anti/syn ratio of 13:78, but the reduction still proceeds with Felkin-Anh control. The optimum size of the reducing agent to promote FelkinAnh control seems to level off at the size of AlpineHydride, as the larger NB-Enantride showed the same stereoselectivity of 5:95, but in better yield (60 and 98%, respectively). Despite the obvious structural similarities between these two reagents, there is an important difference apart from the size. Originally designed as an enantioselective reducing agent, NB-Enantride contains an ether oxygen atom, the presence of which, together with the lithium ion, has been shown to be important for the outcome of such reductions.43 The oxygen atom and lithium ion are predicted to be involved in a chelating transition state together with the carbonyl group. This is not the case with Alpine-Hydride, and it is therefore not expected that these two reagents should behave identically in this kind of reaction. Interestingly, it was also observed that when changing solvent from THF to CH2Cl2 in the (S)-Alpine-Hydride and NB-Enantride reductions, the stereoselectivity was dramatically reduced (from 5:95 to 42:58 and from 5:95 to 32:68, respectively). A possible explanation of these observations is that CH2Cl2 solvates the substrate to a lesser extent than THF and that the formation of an intramolecular hydrogen bond in 1, therefore, is more dominating in CH2Cl2 than in THF. This conformation resembles the effect of chelation control and leads to a less pronounced Felkin-Anh control in CH2Cl2. Thus, the favorable effect of using THF could be a result of both solvation of the substrate and possibly also by stabilizing the transition state in these reduction reactions, as depicted in Figure 2. Conclusions The readily available N-Boc-protected δ-amino-R,βunsaturated-γ-keto ester 1 could be diastereoselectively reduced to the corresponding allylic alcohols 2 and 3. The reduction reactions resulted in anti/syn ratios of alcohols of >95:5 (87% yield), using LiAlH(O-t-Bu)3 in EtOH at -78 °C, and 5:95 (98% yield), using NB-Enantride in THF at -78 °C. Chiral induction did not seem to play an important role in the reductions. The products were sufficiently pure to allow for a considerably simplified isolation procedure. Thus, mechanism-based selection of reducing agents allowed for the identification of reagents and conditions promoting either chelation-controlled or (43) Midland, M. M.; Kazubski, A.; Woodling, R. E. J. Org. Chem. 1991, 56, 1068-1074.

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Felkin-Anh-controlled reductions. This reasoning is expected to be highly useful in stereoselective reductions of keto ester derivatives other than 1.

Experimental Section General. 1H and 13C NMR spectra were recorded at 400 and 100 MHz, respectively. CDCl3 was used as NMR solvent, and chemical shifts are given relative to the solvent signal (δ 7.26 and 77.0, respectively). Thin-layer chromatography (TLC) was performed using silica gel (Silicagel 60 F254), with visualization by either UV detection or 5% phosphomolybdic acid hydrate (PMA) in EtOH, followed by heating. Flash chromatography was performed on silica gel (Silicagel 60 (0.040-0.063 mm)) under nitrogen pressure. THF was distilled from Na/ benzophenone ketyl. Other solvents were of analytical or synthetic grade and were used without further purification. Elemental analyses were done by Mikro Kemi AB, Uppsala, Sweden. Melting points are uncorrected. In HPLC, a UV detector operating at 254 nm was used. Analytical chromatography was performed on a LiChrosorb Si 60 (5 µm) 4 × 250 mm analytical column (flow rate 1.0 mL/min). Preparative chromatography was performed on a Prep Nova-Pak HR Silica 6 µm 60 Å 25 × 100 mm column (flow rate 6.0 mL/min). Dimethyl [(3S)-3-[N-(tert-Butoxycarbonyl)amino]-2oxo-4-phenylbutyl]phosphonate (4).44 n-Butyllithium (15% in n-hexane) (6.64 mL, 10.5 mmol) was added to a solution of dimethyl methyl phosphonate (1.15 mL, 10.7 mmol) in THF (10 mL) at -78 °C. The solution was stirred for 30 min at -78 °C. A solution of Boc-L-phenylalanine methyl ester (1.0 g, 3.6 mmol) in THF (7.5 mL) was added, and the reaction was stirred for 1 h at -78 °C. The reaction was quenched with 10% citric acid and partitioned between diethyl ether and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography [n-hexane/ CHCl3/MeOH (14:5:1)] afforded 723 mg (54%) of 4 as a white solid. For spectroscopical data on 4, see ref 27. Di-tert-butyl Tartrate. The method used was modified from ref 45. A mixture of DCC (10 g, 48.5 mmol), tert-butyl alcohol (5.6 mL, 58 mmol), and CuCl (200 mg, 2 mmol) was stirred at room temperature for 5 days. CH2Cl2 (70 mL) and L-tartaric acid (2.41 g, 16 mmol) were added. The reaction was stirred at room temperature for 28 h and then filtered through Celite. The filtrate was partitioned between CH2Cl2 and H2O. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography [diethyl ether: pentane (1:1)] afforded 801 mg (19%) of di-tert-butyl tartrate as a white solid. For spectroscopical data on di-tert-butyl tartrate, see ref 46. tert-Butyl Glyoxylate (5).47 Di-tert-butyl tartrate (1.5 g, 5.7 mmol) was dissolved in MeOH (30 mL), and a solution of NaIO4 (1.47 g, 6.9 mmol) in H2O (15 mL) was added. The reaction was stirred for 80 min at 0 °C. The reaction was partitioned between H2O and diethyl ether. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure to give 1.46 g (98%) of 5 as a colorless oil. The product was used as such in the synthesis of 1. tert-Butyl (5S)-5-[N-(tert-Butoxycarbonyl)amino]-4oxo-6-phenyl-(E)-2-hexenoate (1).44 Oven-dried LiCl (101 mg, 2.4 mmol) and Et3N (330 µL, 2.4 mmol) were added to a solution of phosphonate 4 (887 mg, 2.4 mmol) in acetonitrile (20 mL) at 0 °C. A solution of tert-butyl glyoxylate 5 (710 mg, 5.5 mmol) in acetonitrile (20 mL) was added. The reaction was stirred at 0 °C for 70 min and allowed to reach room temperature before quenching with 10% citric acid. The (44) Berts, W.; Luthman, K. Unpublished results. (45) Henry, R. A. J. Heterocycl. Chem. 1976, 13, 391-392. (46) Uray, G.; Lindner, W. Tetrahedron 1988, 44, 4357-4362. (47) Grinde, S. Master thesis: Design og syntese av dipeptidomimetika som ligand for transportmolekylet PepT1; University of Tromsø: Tromsø, 1999.

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reaction was extracted with diethyl ether, the organic phase was dried (MgSO4), and the solvent was removed under reduced pressure. Flash chromatography [diethyl ether:pentane (1:2)] afforded 1 (654 mg, 73%) as a light yellow solid: mp 68-70 °C; [R]D +7.7° (c 1, CHCl3); analytical HPLC: tR 5.41 min (1% EtOH in n-hexane); 1H NMR (CDCl3) δ 7.337.07 (m, 5H), 7.02 (d, 1H, J ) 15.7 Hz), 6.67 (d, 1H, J ) 15.7 Hz), 5.13 (br d, 1H), 4.82-4.75 (m, 1H), 3.16-2.95 (m, 2H), 1.49 (s, 9H), 1.40 (s, 9H). 13C NMR (CDCl3) δ 197.7, 164.3, 155.1, 135.6, 135.5, 134.4, 129.5 (2 C:s), 128.7 (2 C:s), 127.2, 82.2, 80.2, 59.6, 37.6, 28.3 (3 C:s), 28.0 (3 C:s). Anal. Calcd for C21H29NO5: C, 67.18; H, 7.79; N, 3.73. Found: C, 67.2; H, 7.8; N, 3.8. (The reaction also gave 103 mg (11%) of the cis-isomer (trans:cis 6.3:1)). (R)-(+)-2-Amino-3-methyl-1,1-diphenylbutan-1-ol (6). A solution of Boc-D-valine methyl ester (390 mg, 1.69 mmol) in diethyl ether (15 mL) was added to an ethereal solution of phenylmagnesium bromide [prepared from bromobenzene (1.42 mL, 13.49 mmol) and magnesium (328 mg, 13.49 mmol) in diethyl ether (15 mL)] at 0 °C. The reaction was stirred at room temperature for 4 h and thereafter quenched with saturated aqueous NH4Cl and extracted with diethyl ether. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography (CHCl3:MeOH 9:1) afforded 160 mg (27%) Boc-6 as a white solid. Deprotection. Boc-6 (160 mg) was dissolved in MeOH saturated with HCl(g) (15 mL) and stirred at room temperature overnight. Diethyl ether was added and the solvent was removed under reduced pressure. Because of incomplete deprotection, the crude product was extracted with aqueous NH3 and diethyl ether. The organic phase was dried (Na2SO4) and the solvent removed under reduced pressure. Flash chromatography [CHCl3:MeOH (9:1)] afforded 30 mg (26%) of 6 after evaporation. For spectroscopical data on 6, see ref 39. Chemical Reductions. The two diastereomeric alcohols 2 and 3 were synthesized by reduction of 1 with different reducing agents (Table 1). The anti/syn ratio was determined by NMR spectroscopy on the crude product mixture in order to avoid errors caused by fractionation of the alcohols during work up. When this was not possible due to interfering signals, the crude mixture was filtered through a short pad of silica gel before the ratio was determined by NMR spectroscopy. Care was taken so that this filtration did not cause any changes in the isomeric ratio. Where needed, the final purification of the alcohols was performed by flash chromatography [diethyl ether:pentane (1:2)]. The anti/syn ratio was increased by recrystallization of the mixture from EtOH/n-hexane before the final purification by preparative HPLC (1% EtOH in isohexane). Below the experimental procedures for the different reduction reactions are described. Only one procedure is given for reductions where enantiomeric forms of the reducing agent are used. Procedures for reductions resulting in low or no stereoselectivity (NaBH4/CeCl3,10 Superhydride, L-Selectride40) are omitted. tert-Butyl (4R,5S)-5-[N-(tert-butoxycarbonyl)amino]4-hydroxy-6-phenyl-(E)-2-hexenoate (2): white solid; mp 117-119 °C; [R]D -8.9° (c 1, CHCl3); analytical HPLC tR 13.61 min (2% EtOH in n-hexane); 1H NMR (CDCl3) δ 7.35-7.15 (m, 5H), 6.87 (dd, 1H, J ) 4.6, 15.6 Hz), 6.08 (dd, 1H, J ) 1.7, 15.6 Hz), 4.66 (br d, 1H), 4.41 (br s, 1H), 4.02 (br d, 1H), 3.83 (br s, 1H), 2.85-2.70 (m, 2H), 1.48 (s, 9H), 1.35 (s, 9H). 13C NMR (CDCl3) δ 165.7, 156.8, 144.8, 137.4, 129.2 (2 C:s), 128.7 (2 C:s), 126.8, 124.5, 80.7, 80.3, 73.5, 56.9, 36.2, 28.3 (3 C:s), 28.2 (3 C:s). Anal. Calcd for C21H31NO5: C, 66.82; H, 8.28; N, 3.71. Found: C, 67.2; H, 8.4; N, 3.7. tert-Butyl (4S,5S)-5-[N-(tert-butoxycarbonyl)amino]-4hydroxy-6-phenyl-(E)-2-hexenoate (3): white solid; mp 8991 °C; [R]D +1.9° (c 1, CHCl3); analytical HPLC tR 12.06 min (2% EtOH in n-hexane); 1H NMR (CDCl3) δ 7.33-7.16 (m, 5H), 6.80 (dd, 1H, J ) 4.2, 15.6 Hz), 5.98 (dd, 1H, J ) 1.8, 15.4 Hz), 5.00 (br d, 1H), 4.26 (br s, 1H), 3.80 (br d, 1H), 3.72 (br s, 1H), 3.06-2.82 (m, 2H), 1.44 (s, 9H), 1.37 (s, 9H). 13C NMR

Selective Reduction of a Phe-Gly Dipeptidomimetic (CDCl3) δ 165.9, 156.3, 146.9, 138.2, 129.3 (2 C:s), 128.6 (2 C:s), 126.6, 123.5, 80.6, 79.8, 71.0, 56.0, 37.6, 28.4 (3C:s), 28.2 (3 C:s). Anal. Calcd for C21H31NO5: C, 66.82; H, 8.28; N, 3.71. Found: C, 66.5; H, 8.2; N, 3.7. Reduction with Zn(BH4)2. Preparation of 0.5 M Zn(BH4)2 Solution.48 Zinc chloride (680 mg, 5 mmol) was added to a suspension of NaBH4 (378 mg, 10 mmol) in diethyl ether (10 mL). The reaction was stirred for 5 h at 0 °C and filtered through Celite, and the volume was adjusted to 10 mL with diethyl ether. The clear solution (0.5 M) was used immediately in the reduction of 1. Reduction. Zn(BH4)2 solution (0.5 M) (4.3 mL, 2.13 mmol) was added to a solution of 1 (200 mg, 0.53 mmol) in diethyl ether (12 mL) at -78 °C. The reaction was stirred at -78 °C for 100 min and allowed to reach room temperature. After 5 h, the reaction was quenched with 10% citric acid and the reaction partitioned between diethyl ether and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure to give 175 mg (87%) of a 68:32 mixture of 2 and 3. Reduction with (S)-CBS, BH3‚THF. (S)-CBS (1 M in toluene) (3 µL) and BH3‚THF (1 M) (16 µL) were added to a solution of 1 (10 mg, 0.027 mmol) in THF (1 mL) at 0 °C, and the reaction was stirred for 30 min. The reaction was quenched with 10% citric acid and partitioned between diethyl ether and H2O. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure to give a 68:32 mixture of 2 and 3. Reduction with Na D-Prolinate, BH3‚THF.37 BH3‚THF (1 M) (170 µL) was added to a solution of Na D-prolinate (23 mg, 0.17 mmol) in THF (5 mL) at 0 °C. A solution of 1 (58 mg, 0.15 mmol) in THF (10 mL) was added dropwise, and the reaction was stirred for 30 min. The reaction was quenched with H2O and the reaction partitioned between diethyl ether and H2O. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure to give 20 mg (34%) of a 63: 37 mixture of 2 and 3. Reduction with 6, BH3‚THF.38 BH3‚THF (1 M) (235 µL) was added dropwise to a stirred solution of 6 (30 mg, 0.12 mmol) in THF (5 mL) at -78 °C. The resulting solution was allowed to reach room temperature and stirring continued for 15 h. A solution of 1 (35 mg, 0.09 mmol) in THF (5 mL) was added, and the reaction was stirred for 8 h and then quenched with 10% citric acid. The reaction was partitioned between diethyl ether and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure to give 30 mg (85%) of a 60:40 mixture of 2 and 3. Reduction with NaBH4 in EtOH.40 A solution of 1 (50 mg, 0.13 mmol) in EtOH (2 mL) was added to NaBH4 (10 mg, 0.27 mmol) dissolved in EtOH (2 mL) at -78 °C. After 2 h, the solution was quenched with 10% citric acid, partitioned between ethyl acetate and H2O, and dried (MgSO4), and the solvent was removed under reduced pressure to give a 68:32 mixture of 2 and 3. (48) Crabbe´, P.; Garcı´a, G. A.; Rı´us, C. J. Chem. Soc., Perkin Trans. 1 1973, 810-816.

Reduction with LiAlH(O-t-Bu)3.40 LiAlH(OtBu)3 (135 mg, 0.53 mmol) was dissolved in EtOH (3 mL) at -78 °C, and a solution of 1 (100 mg, 0.27 mmol) in EtOH (4 mL) was added. After 2 h, the solution was quenched with 10% citric acid, partitioned between ethyl acetate and H2O, and dried (MgSO4), and the solvent was removed under reduced pressure to give 87 mg (87%) of a >95:5 mixture of 2 and 3. Reduction with DIBALH. DIBALH (1.2 M in toluene) (0.11 mL, 0.13 mmol) was added dropwise to a solution of 1 (45 mg, 0.12 mmol) in THF (6 mL) at -78 °C. The reaction was stirred for 1 h and quenched with water. The reaction was partitioned between diethyl ether and H2O and dried (MgSO4), and the solvent was removed under reduced pressure to give 18 mg (40%) of a 25:75 mixture of 2 and 3. Reduction with DIBALH, ZnCl2. DIBALH (1.2 M in toluene) (58 µL, 0.058 mmol) was added dropwise to a solution of 1 (20 mg, 0.053 mmol) and ZnCl2 (15 mg, 0.1 mmol) in THF (2 mL) at -78 °C. The reaction was stirred for 2.5 h and quenched with water. The reaction was partitioned between diethyl ether and H2O and dried (MgSO4), and the solvent was removed under reduced pressure to give a 53:47 mixture of 2 and 3. Reduction with DIBALH, Ti(O-i-Pr)4. DIBALH (1.2 M in toluene) (37 µL, 0.044 mmol) was added dropwise to a solution of 1 (15 mg, 0.04 mmol) and Ti(O-i-Pr)4 (13 µL, 0.044 mmol) in THF (2 mL) at -78 °C. The reaction was stirred for 1 h and quenched with water. The reaction was partitioned between diethyl ether and H2O and dried (MgSO4), and the solvent was removed under reduced pressure to give a 32:68 mixture of 2 and 3. Reduction with (S)-Alpine-Hydride. (S)-Alpine-Hydride (0.5 M in THF) (0.88 mL, 0.44 mmol) was added to a solution of 1 (150 mg, 0.4 mmol) in THF (10 mL) at -78 °C, and the reaction was stirred at -78 °C for 1 h. The reaction was quenched with 10% citric acid, partitioned between diethyl ether and brine, and dried (MgSO4), and the solvent was removed under reduced pressure. The residue was filtered through a short pad of silica and the solvent removed under reduced pressure to give 90 mg (60%) of a 5:95 mixture of 2 and 3. Reduction with NB-Enantride. NB-Enantride (0.5 M in THF) (293 µL, 0.15 mmol) was added to a solution of 1 (50 mg, 0.13 mmol) in THF (4 mL) at -78 °C, and the reaction was stirred at -78 °C for 1 h. The reaction was quenched with 10% citric acid, partitioned between diethyl ether and brine, and dried (MgSO4), and the solvent was removed under reduced pressure. The residue was filtered through a short pad of silica and the solvent removed under reduced pressure to give 49 mg (98%) of a 5:95 mixture of 2 and 3.

Acknowledgment. Financial support was obtained from the Norwegian Research Council (128256/420), the Swedish Science Research Council (621-2001-1431), and the Knut and Alice Wallenberg Foundation. We thank Kjell H. Halvorsen for excellent assistance in the synthetic work. JO020442O

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