[180475-25-6]  · C21H28N3OP  · (369.45)

(catalyst for asymmetric aldol additions of trichlorosilyl enolates to aldehydes,1 catalyst for asymmetric allylations and crotylations of allylic trichlorosilanes to aldehydes,2 catalyst for asymmetric ring opening of epoxides using silicon tetrachloride3)

Physical Data: mp 110 °C; [a]D22 +18.2 (c=1.3, CHCl3).

Solubility: soluble in most organic solvents except hydrocarbons.

Form Supplied in: white needles.

Preparative Methods: The enantiopure phosphoramide (S,S)-1a is prepared from treatment of (S,S)-N,-dimethyl-1,2-diphenyl-1,2-ethanediamine (5) with piperidinylphosphoric dichloride (6) and triethylamine (1).4 Synthesis of related phosphoramides is easily accomplished by substituting the desired diamine backbone in the former procedure. Recrystallization of phosphoramide (S,S)-1a from hexane followed by drying over P2O5 allows for isolation of analytically pure material. Enantiopure 1,2-diphenyl-1,2-ethanediamine (5) can be prepared from benzil and cyclohexanone according to the method of Pikul & Corey.5 Bis-formylation of the diamine with acetic formic anhydride followed by LiAlH4 reduction affords N,-dimethyldiamine 5. Alternatively, enantiopure 5 can be prepared directly from benzaldehyde and methylamine according to the method of Alexakis et al.6 Piperidinylphosphoric dichloride (6) is prepared from piperidine, triethylamine and phosphorous oxychloride according to the modified procedure of Peyronel et al.7

Handling, Storage, and Precautions: The phosphoramide is a stable, hygroscopic compound which is best stored in a dessicator or dry-box. Avoid prolonged exposure to air or moisture.


[4S-(4a,5b)]-1-(1,3-Dimethyl-2-oxido-4,5-diph-enyl-1,3,2-diazaphospholidine-2-yl)piperidine (1a) and its derivatives are an important class of phosphoramides which have seen much success as Lewis-basic catalysts for aldol additions,8 allylations,9 crotylations, and epoxide openings.10 The three nitrogen subunits of the phosphoramide provide the opportunity for a large number of structurally diverse analogs, allowing a wide spectrum of properties and shapes to be customized.11

Ester enolate aldol additions to aldehydes

Among the first examples of aldol additions employing chiral Lewis bases as catalysts were the additions of trichlorosilyl ketene acetals to aldehydes.12 Silyl ketene acetal 7 could be generated by metathesis of methyl tributylstannylacetate with SiCl4. Treatment of 7 with benzaldehyde and 10 mol % of a phosphoramide in CH2Cl2 at -78 °C afforded aldol products in good to high yields with moderate enantioselectivities for all phosphoramides employed. Reaction of 7 with pivalaldehyde provided aldol products in similar yields and with slightly improved enantioselectivities. The increase in stereoselection is presumably attributed to a less competent background reaction inherent with additions to more sterically encumbered aldehydes (2, Table 1).

Ketone enolate aldol additions to aldehydes

Addition of methyl ketone trichlorosilyl enolate 9 to benzaldehyde in the presence of catalytic amounts of phosphoramide (S,S)-1 affords aldol products in excellent yields.13 The level of enantioselectivity was found to be dependent upon the amount of (S,S)-1a used, with higher loadings providing better selectivities. A typical procedure involves equilibration of a solution of trichlorosilyl enolate and (S,S)-1a in CH2Cl2 at -78 °C followed by addition of aldehyde. Reactions are quenched upon completion by quickly pouring the cold reaction mixture into a rapidly stirring aqueous NaHCO3 solution placed in an ice bath. Alternatively, completed reactions may be quenched using a cold 1:1 mixture of a saturated aqueous KF solution and an aqueous 1 M KH2PO4 solution. In either case, rapid stirring of the cold quench mixture prevents acid-catalyzed b-elimination of the aldol products to give undesired a,b-unsaturated ketones (3, Table 2).

The generality of methyl ketone enolate additions to benzaldehyde was demonstrated by varying the spectator portion of the nucleophile.13 In all cases, high yields were achieved using as little as 5 mol % (S,S)-1a. The enantioselectivity of the process, however, was sensitive to the enolate structure with larger groups, such as t-butyl and phenyl (4, Table 3, entries 5 and 6), providing lower enantioselectivities. The success of a functionalized enolate (4, Table 3, entry 7) demonstrated the tolerance for oxygenated substituents in the phosphoramide-catalyzed aldol addition, whereby no deleterious effect was observed on either the yield or enantioselectivity as compared with unfunctionalized enolates.

The phosphoramide-catalyzed aldol addition was less sensitive to variations on the electrophile. Using 2-hexanone trichlorosilyl enolate 13 as an example aldol additions to various aldehydes affords aldol products in good to high yields and with excellent enantioselectivities, using as little as 5 mol % catalyst.13 Additions to branched aliphatic aldehydes, such as cyclohexanone and pivalaldehyde (5, Table 4, entries 5 and 6), were sluggish when using 5 mol % catalyst. However, increasing the catalyst loading to 10 mol % provides good yields of the aldol products after 6 h with excellent enantioselectivities.

Recently, the synthetic utility of phosphoramide-catalyzed aldol additions of trichlorosilyl enolates to aldehydes has been enhanced by the ability to generate the delicate trichlorosilyl enolates in situ.13 Treatment of the corresponding TMS enol ether with Hg(OAc)2 followed by addition of a solution phosphoramide and aldehyde afford aldol products in high yields over two steps without affecting stereoselectivities. This is exemplified by the addition of chiral a-oxygenated trichlorosilyl enolates to benzaldehyde. Using the (S)-lactate-derived methyl ketone enol ether 15, addition to benzaldehyde afforded aldol products in high diastereoselectivity for the matched-sense using (R,R)-1a.13,14 Although the reaction was compatible with various oxygen functionalities, the stereoselectivity was highly dependent upon the nature of the protecting group, with the OTBS group superior to both the benzyloxy or pivaloyl protecting groups (6, Table 5).

To further exemplify the dependence of the stereochemical course of chiral enolate additions catalyzed by phosphoramides, a detailed survey of additions to aldehydes using chiral b-hydroxyenolate 17 and 10 mol % of 1a was performed.15 Unlike additions of 15, diastereoselectivities of the resultant aldol products using 17 could be switched depending upon the configuration of the phosphoramide employed (7, Table 6).

The phosphoramide-catalyzed aldol addition of substituted enolates to aldehydes provides the opportunity to generate disubstituted aldol products with high stereoselectivity. The (S,S)-1a-catalyzed addition of cyclohexanone trichlorosilyl enolate 19 to aldehydes has been well studied and demonstrates good substrate generality.16 The aldol reactions of this E-enolate are rapid when 10 mol % of (S,S)-1a is used. Reactions are typically complete within 2 h affording anti-aldol products in high yields with excellent diastereo- and enantioselectivities. Although the typical procedure using methyl ketone enolates can be followed, higher diastereoselectivities may be achieved by slow addition of a solution of aldehyde to the mixture of enolate and catalyst in CH2Cl2 at -78 °C over several minutes.17 Remarkably, a dramatic switch in diastereoselectivity is observed when phosphoramide 1b (10 mol %) is employed as a catalyst (8, Table 7, entry 2). Although the level of enantioselectivity was modest, the change in diastereoselectivity demonstrates that small structural changes in the phosphoramide can have profound effects on the stereochemical course of the reaction. This is further exemplified through a systematic substitution of the internal (phospholidino) nitrogens (8, Table 7, entries 1 and 8), the external nitrogen (8, Table 7, entries 1 and 3-7),18,19 as well as changes to the electronic demand of the aryl substituent (8, Table 7, entries 1 and 9-11).20

In contrast to the E-enolates derived from cyclic ketones, addition of propiophenone trichlorosilyl enolate (Z)-21 to aldehydes requires longer reaction times and higher loadings of catalyst.16 Although the yields of the aldol products remain high, both the diastereo- and enantioselectivities are attenuated as compared to their E counterparts (9, Table 8).

Allylic additions to aldehydes

Although phosphoramide 1 is capable of promoting the addition of allyltrichlorosilane to aldehydes, the enantioselectivities were modest at best compared with the cyclohexyldiamine analogs 3.21 Preliminary results showed the allylations to be high yielding but giving only moderate enantioselectivities when using one equivalent of phosphoramide as a promoter. As observed in the stereoselective aldol additions with phosphoramides, subtle changes to the nitrogen substituents also dramatically affect the stereochemical course of allylations using allylic trichlorosilanes (10, Table 9, entries 7-9).22 Under optimized conditions, as few as 0.25 equivalents of phosphoramide may be used with little erosion in yield or stereoselectivity (10, Table 9, entries 3-5).

The phosphoramide-catalyzed allylic additions to aldehydes have also been extended to include stereoselective crotylations. When using geometrically defined 2-butenyltrichlorosilanes, additions to benzaldehyde afford homoallylic alcohols in good yields and excellent diastereoselectivity (11).21a Enantioselectivities, however, remain comparable to the results for allylic additions. Interestingly, the crotylation results suggest that addition proceeds through a cyclic transition structure.23

Epoxide openings using SiCl4

The binaphthyldiamine-derived phosphoramide (R)-4 is an effective catalyst for the opening of various epoxides with SiCl4 to afford chlorohydrins in high yields.24 The rate and stereoselectivity for the ring opening of meso-epoxides are extremely dependent upon the structure of the epoxide. In the examples shown for epoxycycloalkanes, only cyclohexene oxide [10 mol % (R)-4] affords a chlorohydrin in high yield and good enantioselectivity (12, Table 10, entry 2). In contrast, cyclopentene oxide and cyclooctene oxide give essentially racemic chlorohydrin (12, Table 10, entries 1 and 3) with cyclooctene oxide requiring more than 5 days for complete reaction. In comparison to the cyclic epoxides, the acyclic substrates afford chlorohydrins with increased enantioselectivities (12, Table 10, entries 4 and 5). In a typical procedure, a solution of epoxide in CH2Cl2 is added to a mixture of SiCl4 and phosphoramide at -78 °C in CH2Cl2. To avoid opening of epoxides by adventitious HCl,25 it is essential to maintain SiCl4 acid free.26

1. (a) Paterson, I.; Cowden C. J.; Wallace, D. J. In Modern Carbonyl Chemistry; Otera, J., Ed.: Wiley-VCH: Weinheim, 2000; Ch. 9. (b) Cowden, C. J.; Paterson, I., Org. React. 1997, 51, 1. (c) Heathcock, C. H.; Kim, B. M.; Williams, S. F.; Masamune, S.; Paterson, I.; Gennari, C. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Vol. 2, Pergamon Press: Oxford, 1991.
2. (a) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000, Ch.10. (b) Roush, W. R.; Chemler, C. R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000, Ch.11. (c) Stereoselective Synthesis, Methods of Organic Chemistry (Houben-Weyl); Edition E21; Helmchen, G.; Hoffmann, R.; Mulzer, J.; Schaumann, E., Eds.; Thieme: Stuttgart, 1996, Vol. 3, pp 1357-1602. (d) Yamamoto, Y.; Asao, N., Chem. Rev. 1993, 93, 2207.
3. (a) Erden I. In Comprehensive Heterocyclic Chemistry, 2nd edn; Padwa, A., Ed.; Pergamon Press: Oxford, 1996, Vol. 1A, Ch. 1.03. (b) Bartók, M.; Lang, K. L. In The Chemistry of Heterocyclic Compounds; Weissberger, A.; Taylor, E. C., Eds.; Wiley: New York, 1985; Vol. 42, Part 3, p 1. (c) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G., Tetrahedron 1983, 39, 2323.
4. Denmark, S. E.; Su, X.; Nishigaichi, Y.; Coe, D. M.; Wong, K.-T.; Winter, S. B. D.; Choi, J.-Y., J. Org. Chem. 1999, 64, 1958.
5. Pikul, S.; Corey, E. J., Org. Synth. 1991, 71, 22.
6. (a) Alexakis, A.; Aujard, I.; Mangeney, P., Synlett 1998, 873. (b) Alexakis, A.; Aujard, I.; Mangeney, P., Synlett 1998, 875.
7. Peyronel, J.-F.; Samuel, O.; Fiaud, J.-C., J. Org. Chem. 1987, 52, 5320.
8. Denmark, S. E.; Stavenger, R. A., Acc. Chem. Res. 2000, 33, 432.
9. (a) Iseki, K.; Kuroki, Y.; Takahashi, M.; Kobayashi, Y., Tetrahedron Lett. 1996, 37, 149. (b) Iseki, K.; Kuroki, Y.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y., Tetrahedron 1997, 53, 13. (c) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y., Tetrahedron Lett. 1998, 39, 67. (d) Hong, B.-C.; Hong, J.-H.; Tsai, Y.-C., Angew. Chem., Int. Ed. Engl. 1998, 37, 468.
10. For an additional example of Lewis-base catalyzed epoxide openings see: Tao, B.; Lo, M. M.-C.; Fu, G. C., J. Am. Chem. Soc. 2001, 123, 353.
11. (a) Ishihara, K.; Karumi, Y.; Kondo, S.; Yamamoto, H., J. Org. Chem. 1998, 63, 5692. (b) Verkade, J. G., Acc. Chem. Res. 1993, 26, 483.
12. Denmark, S. E.; Winter, S. B. D., Synlett 1997, 1087.
13. Denmark, S. E.; Stavenger, R. A., J. Am. Chem. Soc. 2000, 122, 8837.
14. Denmark, S. E.; Stavenger, R. A., J. Org. Chem. 1998, 63, 6524.
15. Denmark, S. E.; Fujimori, S., Synlett 2001, 1024.
16. Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.; Su, X., J. Am. Chem. Soc. 1999, 121, 4982.
17. For a discussion on the molecularity and mechanism of phosphoramide catalyzed aldol additions, see: (a) Denmark, S. E.; Su, X.; Nishigaichi, Y., J. Am. Chem. Soc. 1998, 120, 12990. (b) Denmark, S. E.; Pham, S. M., Helv. Chim. Acta 2000, 83, 1846. For solid state and solution structural studies of phosphoramide-tin complexes, see: (c) Denmark, S. E.; Su, X., Tetrahedron 1999, 55, 8727.
18. Wong, K.-T., unpublished results from these laboratories.
19. Nishigaichi, Y., unpublished results from these laboratories.
20. Su, X., unpublished results from these laboratories.
21. (a) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D., J. Org. Chem. 1994, 59, 6161. (b) Denmark, S. E.; Fu, J., J. Am. Chem. Soc. 2000, 122, 12021.
22. Coe, D. M., unpublished results from these laboratories.
23. Dimeric phosphoramides have recently been demonstrated to be superior to the monomeric versions for allylations and crotylations using allylic trichlorosilanes, see: reference 21b.
24. Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A., J. Org. Chem. 1998, 63, 2428.
25. Cross, A. D., Quart. Rev. Chem. Soc. 1960, 14, 317.
26. A report by Brunel, Legrand, Reymond and Buono describes the use of phosphonamide-type catalysts to achieve excellent enantioselectivities in the stereoselective ring opening of meso-epoxides with SiCl4. Recently, this group and others have been unable to verify the results by Buono et al., see: (a) Brunel, J. M.; Legrand, O.; Reymond, S.; Buono, G., Angew. Chem., Int. Ed. Engl. 2000, 39, 2554. (b) Denmark, S. E.; Wynn, T.; Jellerichs, B. G., Angew. Chem., Int. Ed. Engl. 2001, 40, 2255.

Scott E. Denmark & Son M. Pham

University of Illinois, Urbana, IL, USA

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