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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Angew Chem Int Ed Engl. Author manuscript; available in PMC 2011 January 1.
Published in final edited form as:
PMCID: PMC2995290

Gold(I)-Catalyzed Enantioselective Synthesis of Pyrazolidines, Isoxazolidines, and Tetrahydrooxazines**

The field of gold(I)-catalyzed addition of heteroatom nucleophiles to allenes[1] has recently expanded to include enantioselective synthesis of heterocyclic products.[2,3] Despite the growth in this area of research and the biological relevance of heterocycles containing multiple heteroatoms, the asymmetric addition of hydrazine and hydroxylamine nucleophiles to allenes has not yet been reported.[4] In 2007, our group reported the enantioselective hydroamination of allenes catalyzed by gold(I)-bis-p-nitrobenzoate complexes.[2a] We hypothesized that in addition to tosyl amines, gold(I)-bis-p-nitrobenzoate complexes would perform as efficient catalysts for the enantioselective addition of hydroxylamines and hydrazines to allenes. The heterocycles formed from these reactions, vinyl isoxazolidines[5] and pyrazolidines,[6] appear frequently in biologically important molecules.[7] In addition, these heterocycles serve as precursors to unnatural amino acid derivatives such as 5-oxaproline[7,8] as well as chiral allylic alcohols and 1,3-diamines.

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We began our studies with a mono-Boc protected homo-allenic hydrazine, easily synthesized in four steps from the homo-allenic alcohol. While unprotected amines are usually considered incompatible with cationic gold complexes, we hypothesized that the reduced Lewis basicity of the hydrazine would allow the use of an unprotected terminal amine. Indeed, upon treatment of 1a with (R)-xylyl-BINAP(AuOPNB)2 in nitromethane at 50 °C the desired product (2a) was formed, although in modest yield and low enantioselectivity (Table 1, entry 1). By simply adding a second protecting group, both the yield and enantiomeric excess of 2b were improved (entry 2). This result led us to theorize that sterically differentiating the protecting groups would be necessary to further improve the enantioselectivity. Indeed, utilizing a mesitylenesulfonyl protecting group on the terminal nitrogen raised the observed enantioselectivity to 80% ee (entry 3). A brief examination of chiral ligands revealed that DTBM-Segphos was optimal, yielding pyrazolidine 2c in 97% ee (entry 4). Similar to hydroamination with hydrazines, we found that although unprotected hydroxylamines were transformation into to the isoxazolidines in excellent conversion (>98%), low enantioselectivity (10% ee) was observed (entry 5). Upon treating N-Boc-protected hydroxylamine 1f with (R)-xylyl-BINAP(AuOPNB)2 the isoxazolidine 2f was formed in 93% yield and 93% ee (entry 7). Other protecting groups, such as CBz, significantly reduced the conversion to 8% (entry 6). Additionally, a polar, non-coordinating solvent such as nitromethane was effective, producing 2f in 98% conversion and 87% ee. However, non-polar solvents (benzene) and coordinating solvents (dioxane) completely eliminated catalyst activity.

Table 1
Hydroamination optimization.

While gold(I)-bis-p-nitrobenzoate complexes proved to be ineffective catalysts for the hydroalkoxylation of allenes (Table 2, entry 1), we hypothesized that employing a more non-coordinating counterion with a lower pKa would improve catalysis. Chiral silver sulfonate (S)-Ag(5) was synthesized in seven steps from (S)-BINOL.[9] Gratifyingly, upon treatment with 3 mol% dppm(AuCl)2 and 3 mol% (S)-Ag(5), isoxazolidine 4 was formed in quantitative conversion and 65% ee (entry 2). However, attempts to improve the enantioselectvity by matching the chiral counterion with chiral gold BINAP complexes were unsuccessful (entries 3 and 4). Both the matched and mismatched mixtures produced 4 with lower enantioselectivity (28% and 8% ee, respectively). Chiral silver phosphate (S)-Ag-TriP proved to be the key to enhancing the enantioselectivity to 97% ee (entry 5).

Table 2
Hydroalkoxylation optimization

We next sought to test the substrate scope of our optimized hydroamination conditions. Linear and cyclic alkyl substitutions were tolerated at the allene terminus in both the hydrazine and hydroxylamine hydroamination. For instance, methyl substituted substrates cyclized with excellent enantioselectivity (99% and 98%, entries 1 and 4, respectively). Cyclohexyl substituted allenes also reacted with high enantioselectivity (entries 3 and 6). Cyclopentyl substituted substrates 8 and 12 also provided pyrazolidine 9 and isoxazolidine 13 in good yield and slightly lower enantioselectivity (83% and 91%, entries 2 and 5). Furthermore, sterically challenging backbone substitutions were accomadated by heating gently (50 °C) in a polar, non-coordinating solvent (nitromethane). While substitution at the allenic position (entry 8) gave enhanced enantioselectivity (99%) with modest yield (73%), the homo-allenic position showed the reverse trend: modest enantioselectivity (63%) and excellent yield (94%).

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We also applied our hydroamination conditions to the formation of six-membered ring oxazine heterocycles. Gentle heating in a polar non-coordinating solvent was required to produce oxazines in good yield (63-85%). Substrates with backbone substitutions (entries 10 and 11) have higher yield than those without substitutions, presumably due to a Thorpe-Ingold effect. Also, both linear and cyclic alkyl substitutions were tolerated at the allene terminus providing the heterocycles with 89% ee in all cases.

The advantage of the increased nucleophilicity of hydroxylamines was demonstrated in the cyclization onto tetrasubstituted allenes. Nucleophilic additions to tetrasubstituted allenes is challenging; only a handful of substrates have been reported.[4a,10] While the use of a protecting group is normally beneficial to enantioselectivity (vide supra), in the case of addition to sterically encumbered substrates such protecting groups are detrimental to both the observed enantioselectivity and conversion (eq 2). Unprotected hydroxylamines, however, when treated with the same catalyst produce the desired product in quantitative conversion and 32% ee. Modifying the catalyst ligand to (R)-MeOBiPHEP further improved the enantioselectivity to 49%.

We were pleased to find that chiral silver salts used with gold(I) complexes catalyze the hydroalkoxylation of N-linked hydroxylamines with good to excellent enantioselectivity. Both cyclic and linear alkyl substitutions at the allene terminus were well tolerated, yielding the corresponding isomeric vinyl-isoxazolidines in good yield and high enantiomeric excess (Table 4, entries 1 and 2). Formation of oxazines proved to be more challenging, with the gold(I)-catalyzed reaction affording 31 in modest yield and 50% ee (entry 4).[11] However, both the yield and enantioselectivity were greatly improved by combining a chiral ligand with the chiral silver salt (94% yield and 87% ee, entry 5). Additionally, while good diasteroselectivity was observed for substituted substrates (entry 3), the corresponding enantioselectivities favor the minor diasteromer.

Table 4
Hydroxylamine hydroalkoxylation scope.

In conclusion, we have developed a series of enantioselective gold(I)-catalyzed hydroaminations and hydroalkoxylations of allenes with hydroxylamines and hydrazines. While chiral biarylphosphinegold(I)[12] are suitable catalysts for the enantioselective addition of nitrogen nucleophiles to allenes, the addition of oxygen nucleophiles requires the use of chiral anions. These complementary methods allow rapid access to chiral vinyl isoxolidines, oxazines, and differentially protected pyrazolidines.[13,14] Studies on the mechanism of enantioinduction in these transformations are ongoing in our laboratories.

Table 3
Hydrazine and hydroxylamine hydroamination scope.

Supplementary Material


supporting info


**We gratefully acknowledge NIHGMS (R01 GM073932-04S1), Bristol-Myers Squibb and Novartis for funding. R.L.L. thanks Novartis and Eli Lilly and J.Z.W thanks the Hertz Foundation for graduate fellowships. We thank Dr. Francesco Santoro for preliminary studies on the synthesis of silver biarylsulfonates. We are grateful Johnson Mathey for a generous donation of AuCl3 and to Takasago and Solvias for providing Segphos and MeOBiPHEP ligands, respectively

Supporting information for this article is available on the WWW under or from the author.


1. For examples of gold-catalyzed hydroamination of allenes, see: a. Krause N, Morita N. Org. Lett. 2004;6:4121–4123. [PubMed]; b. Nishina N, Yamamoto Y. Angew. Chem. Int. Ed. 2006;45:3314–3317. [PubMed]; c. Patil NT, Lutet LM, Nishina N, Yamamoto Y. Tetrahedron Lett. 2006;47:4749–4751.; d. Zhang Z, Liu C, Kinder RE, Han X, Qian H, Widenhoefer RA. J. Am. Chem. Soc. 2006;128:9066–9073. [PubMed]; e. Morita N, Krause N. Eur. J. Org. Chem. 2006:4634–4641.; For a recent review of gold(I)-catalyzed heterocyclic synthesis, see: Shen HC. Tetrahedron. 2008;64:3885–3903.
2. a. LaLonde RL, Sherry BD, Kang EJ, Toste FD. J. Am. Chem. Soc. 2007;129:2452–2453. [PubMed] b. Zhang Z, Bender CF, Widenhoefer RA. Org. Lett. 2007;9:2887–2889. [PubMed] c. Zhang Z, Bender CF, Widenhoefer RA. J. Am. Chem. Soc. 2007;129:14148–14149. For a dynamic kinetic resolution, see: [PubMed] e. Zhang Z, Widenhoefer RA. Angew. Chem. Int. Ed. 2007;46:283–285. For an Au(I)-catalyzed asymmetric hydroalkoxylation of allenes, see: [PubMed] f. Hamilton GL, Kang EJ, Mba M, Toste FD. Science. 2007;317:496–499. [PubMed] For a previous report of asymmetric hydroamination of allenes (maximum ee was 16%), see: Hoover JM, Peterson JR, Pikul JH, Johnson AR. Organometallics. 2004;23:4614–4620.;
3. For a review of recent developments in enantioselective gold catalysis, see: a. Widenhoefer RA. Chem. Eur. J. 2008;14:5382–5391. [PubMed]; For reviews of enantioselective hydroamination, see: b. Hultzsch KC. Org. Biomol. Chem. 2005;3:1819–1824. [PubMed]; c. Hultzsch KC. Adv. Synth. Catal. 2005;347:367–391.
4. For a racemic gold catalyzed synthesis of N-hydroxypyrrolines, dihydroisoxazoles and dihydro-1,2-oxazines, see: a. Winter C, Krause N. Angew. Chem. Int. Ed. 2009;48:6339–6342. [PubMed]; For a gold(I)-catalyzed addition of hydroxylamines to alkynes, see: b. Yeom H-S, Lee E-S, Shin S. Synlett. 2007:2292–2294.; For a silver catalyzed addition of hydroxylamines to allenes, see: c. Bates R, Nemeth J, Snell R. Synthesis. 2008;7:1033–10.
5. For selected enantioselective syntheses of isoxazolidines, see: a. Rios R, Ibrahem I, Wesely J, Zhao G-L, Cordova A. Tet. Lett. 2007;48(32):5701–5705.; b. Troisi L, De Lorenzis S, Fabio M, Rosato F, Granito C. Tet. Asymm. 2008;19:2246–2251.; c. Tokizana M, Sato K, Ohta T, Ito Y. Tet. Asymm. 2008;19:2519–2528.
6. For selected methods to synthesize pyrazolines and pyrazolidines, see: a. Whitlock GA, Carreira EM. J. Org. Chem. 1997;62:7916–7917. [PubMed]; b. Yamashita Y, Kobayashi S. J. Am. Chem. Soc. 2004;126:11279–11282. [PubMed]; c. Shintani R, Fu GC. J. Am. Chem. Soc. 2003;125:10778–10779. [PubMed]; d. Yang Q, Jiang X, Ma S. Chem. Eur. J. 2007;13:9310–9316. [PubMed]; e. Giampietro NC, Wolfe JP. J. Am. Chem. Soc. 2008;130:12907–12911. [PubMed]
7. For an isoxazoline artifical transcription activator, see: Buhrlage SJ, Brennan BB, Minter AR, Mapp AK. J. Am. Chem. Soc. 2005;127:12456–12457. [PubMed]
8. Vasella A, Voeffray R. J. Chem. Soc., Chem. Comm. 1981:97–98.
9. a. Hatano M, Maki T, Moriyama K, Arinobe M, Ishihara K. J. Am. Chem. Soc. 2008;130:16858–16860. [PubMed] b. Garcia-Garcia P, Lay F, Garcia-Garcia P, Rabalakos C, List B. Angew. Chem. Int. Ed. 2009;48:4363–4366. [PubMed]
10. For a single example of an intermolecular gold(I)-catalyzed addition of methyl carbamate to tetramethyl allene (61% yield), see: a. Kinder RE, Zhang Z, Widenhoefer RA. Org. Lett. 2008;10:3157–3159. [PubMed]; For a single example of an intermolecular gold(I)-catalyzed addition of indole to tetramethyl allene (56% yield), see: b. Toups K, Liu G, Widenhoefer RA. J. Organomet. Chem. 2009;694:571–575. [PubMed]
11. Use of 3 mol% dppm(AuCl)2, 6 mol% (S)-Ag(5), 0.1 M in Toluene, 23 °C, 18 h gave oxazine 27 in 60% yield and 34% ee.
12. a. Kleinbeck F, Toste FD. J. Am. Chem. Soc. 2009;131:9178–9179. [PubMed] b. Zhang Z, Lee SD, Widenhoefer RA. J. Am. Chem. Soc. 2009;131:5372–5373. [PubMed] c. Uemura M, Watson IDG, Katsukawa M, Toste FD. J. Am. Chem. Soc. 2009;131:3464–3465. [PubMed] d. Watson IDG, Ritter S, Toste FD. J. Am. Chem. Soc. 2009;131:2056–2057. [PubMed] e. Chao C-M, Vitale MR, Toullec PY, Genêt J-P, Michelet V. Chem – Eur. J. 2009;15:1319–1323. [PubMed]
13. The absolute configuration of 11 was assigned by oxidative cleavage, Boc deprotection, and Cbz protection to (S)-methyl-2-benzyloxycarbonyl-3-isoxazolidinecarboxylate (See Supporting Information). The absolute configurations of the remaining hydroamination products were assigned by analogy to 11.
14. For a representative procedure to cleave the N-O bond, see: Vasella A, Voeffray R, Pless J, Hugenin R. Helv, Chim. Acta. 1983;66:1241–1252.