Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Aug 5.
Published in final edited form as: Tetrahedron Lett. 2015 Jun 17;56(32):4670–4673. doi: 10.1016/j.tetlet.2015.06.039

Synthesis and Exploration of Electronically Modified (R)-5,5-Dimethyl-(p-CF3)3-i-PrPHOX in Palladium-Catalyzed Enantio- and Diastereoselective Allylic Alkylation: A Practical Alternative to (R)-(p-CF3)3-t-BuPHOX

Robert A Craig II 1, Brian M Stoltz 1,*
PMCID: PMC4524747  NIHMSID: NIHMS705028  PMID: 26257445

Abstract

The synthesis of the novel electronically modified phosphinooxazoline (PHOX) ligand, (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX, is described. The utility of this PHOX ligand is explored in both enantio- and diastereoselective palladium-catalyzed allylic alkylations. These investigations prove (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX to be an effective and cost-efficient alternative to electronically modified PHOX ligands derived from the prohibitively expensive (R)-t-leucine.

Keywords: Allylic Alkylation, Diastereoselective, Enantioselective, Palladium-catalyzed, Phosphinooxazoline

Graphical abstract

graphic file with name nihms705028f8.jpg

1. Introduction

Phosphinooxazoline (PHOX) ligands, developed by Helmchen,1 Williams,2 and Pfaltz,3 have proven to be a privileged ligand scaffold in transition metal catalysis.4 PHOX ligands have found application in a variety of asymmetric transition metal-catalyzed transformations including asymmetric hydrogenation,5 azomethine ylide cycloadditions,6 intermolecular Heck couplings,7 and hydrosilylation8 as well as transition metal-catalyzed allylic substitution4,9 and protonation10 reactions. Our lab has extensively explored the utility of the PHOX ligand scaffold in the palladium-catalyzed enantioselective allylic alkylation of carbocyclic11 and heterocyclic12 substrates. These investigations have revealed electronically modified PHOX ligands (i.e. (S)-(p-CF3)3-t-BuPHOX ((S)-L1), Figure 1)13 can profoundly enhance the rate of reaction as well as yield, enantiomeric excess (ee) and/or diastereomeric ratio of a product containing an all-carbon quaternary center (e.g. use of (S)-L1 vs. (S)-L2 to construct lactam 2,12e cyclohexanone 4,13c cyclohexenone 6,13b and cyclohexanone diastereomers 9 and 10,14 Schemes 1A–1C and Scheme 2, respectively).

Figure 1.

Figure 1

Open in a new tab

Electronically Modified and Unmodified (S)-t-BuPHOX Ligands

Scheme 1.

Scheme 1

Open in a new tab

Comparison of Electronically Modified (S)-(p-CF3)3-t-BuPHOX ((S)-L1) and Unmodified (S)-t-BuPHOX ((S)-L2) in Intramolecular Palladium-Catalyzed Enantioselective Allylic Alkylation

Scheme 2.

Scheme 2

Open in a new tab

Comparison of Electronically Modified (S)-(p-CF3)3-t-BuPHOX ((S)-L1) and Unmodified (S)-t-BuPHOX ((S)-L2) in Diastereoselective Decarboxylative Alkylation Cascade

Most commonly, transition metal complexes employing tert-leucinol-derived PHOX ligands (e.g. (S)-L1 and (S)-L2˙, Figure 1) enable the formation of the corresponding products with the best enantiomeric and diastereomeric ratios. Although (R)-t-BuPHOX has been employed in natural product synthesis15 and explored in transition-metal catalyzed allylic alkylations,10a,16 these examples are quite rare considering the nearly prohibitive cost of the requisite starting material for ligand synthesis, (R)-t-leucine.17 Previously, 5,5-geminally disubstituted (R)-valine-derived PHOX ligands (e.g. (R)-L3 and (R)-L4, Figure 2) have been constructed as cost-effective alternatives to (R)-t-BuPHOX ((R)-L2).18 We sought to extend this precedent to the synthesis of electronically modified congener (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX ((R)-(p-CF3)3-i-PrPHOXMe2, (R)-L5, Figure 2) and explore its efficacy as a ligand in palladium-catalyzed enantio-and diastereoselective allylic alkylation reactions.

Figure 2.

Figure 2

Open in a new tab

5,5-Geminally Disubstituted (R)-Valine-Derived PHOX ligands

2. Results and discussion

2.1 Synthesis of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5)

Synthesis of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) was initiated with acid chloride 1119 and the hydrogen chloride salt of (R)-valine derivative 1218 (Scheme 3). Intermolecular coupling of acid chloride 11 and amino alcohol 12 in the presence of excess Et3N provides amide 13 in 79% yield. Intramolecular cyclization of amide 13 under acidic conditions furnishes oxazoline 14 in 87% yield. Completion of desired ligand (R)-L5 was accomplished over two steps, beginning with the copper-mediated coupling of phosphine oxide 15 with bromide 14 at elevated temperature.20 This procedure produces phosphine oxide 16 in 63% yield. Reduction of phosphine oxide 16 was subsequently accomplished in neat Ph2SiH2 at 140 °C over 48 hours, providing the desired ligand (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) in 81% yield in the final step of the synthetic sequence.

Scheme 3.

Scheme 3

Open in a new tab

Synthesis of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5)

2.2 Use of (R)-(p-CF3)3-i-PrPHOXMe2 in Palladium-Catalyzed Asymmetric Transformations

Application of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) was initially explored in the intermolecular palladium-catalyzed enantioselective allylic alkylation of silyl enol ether 17 with mesylate 18 (Scheme 4). Previously we disclosed the initial development and optimization of this transformation using (S)-t-BuPHOX ((S)-L2), which afforded chloroallylketone (S)-19 in 82% yield and 92% ee (entry 1).12d Substitution of (S)-L2 with the electronically modified (S)-(p-CF3)3-t-BuPHOX ((S)-L1) provided the product ((S)-19) in a slightly diminished 91% ee (entry 2). Switching the ligand to (S)-5,5-diphenyl-i-PrPHOX ((S)-L3) furnished chloroallylketone (S)-19 in 90% ee (entry 3). Moving into the opposite enantiomeric series, the use of (R)-5,5-dimethyl-i-PrPHOX ((R)-L4) provided chloroallylketone (R)-19 in a somewhat diminished 89% ee (entry 4) compared to the originally optimized reaction conditions (entry 1). Alternatively, we were pleased to find that (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) afforded chloroallylketone (R)-19 in the same 91% ee (entry 5) in the opposite enantiomeric series compared to the use of (S)-(p-CF3)3-t-BuPHOX (entry 2). It is noteworthy that the required reaction time and isolated yield of chloroallylketone 19 were independent of the ligand employed. Thus, (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) can allow access to the enantiomeric series of products to those afforded in reactions employing (S)-L1 without any loss in product ee in a cost-effective manner, being derived from (R)-valine, which is less than 2% of the cost of (R)-t-leucine.

Scheme 4.

Scheme 4

Open in a new tab

Ligand Comparison in Enantioselective Palladium-Catalyzed Intermolecular Allylic Alkylation.

The utility of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) was further demonstrated in the intermolecular palladium-catalyzed diastereoselective decarboxylative allylic alkylation of β-ketoester 20 with allyl electrophile 21 (Scheme 5).16a While the system displays an inherent selectivity for the formation of diastereomer 22 in a 2:1 ratio with diastereomer 23 when achiral PHOX ligand L6 was employed (entry 1),21 the use of (S)-t-BuPHOX ((S)-L2) can override this substrate bias, providing diastereomer 23 as the major product (entry 2). Comparatively, the use of (R)-t-BuPHOX ((R)-L2) reinforces the inherent selectivity, providing diastereomer 22 in a 12:1 ratio with minor diastereomer 23 in a combined 73% yield (entry 3). Pleasingly, the employment of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) further improved this transformation, furnishing an 18:1 mixture of products in favor of diastereomer 22 in an improved 85% combined yield (entry 4). These studies revealed that (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) was the optimal ligand for the highly diastereoselective formation of allylic alkylation product 22. Additionally, other research groups have found (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) to be a uniquely effective ligand for the palladium-catalyzed diastereoselective allylic alkylation of other carbocyclic substrates.22

Scheme 5.

Scheme 5

Open in a new tab

Diastereoselective Decarboxylative Allylic Alkylation Employing (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5).

3. Conclusion

Herein, we have disclosed the synthesis of a new, electronically modified phosphinooxazoline (PHOX) ligand, (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX ((R)-(p-CF3)3-i-PrPHOXMe2, (R)-L5). Derived from (R)-valine, this cost-effective alternative to (R)-(p-CF3)3-t-BuPHOX ((R)-L1) has proved effective in both palladium-catalyzed enantio- and diastereoselective allylic alkylations, furnishing the alkylation products in comparable ee and improved diastereomeric ratio. Efforts to further explore the utility of the readily available (R)-(p-CF3)3-i-PrPHOXMe2 ligand in palladium-catalyzed stereoselective transformations are currently underway.

Supplementary Material

Acknowledgements

The authors wish to thank the NIH-NIGMS (R01GM080269), Amgen, the Gordon and Betty Moore Foundation, and Caltech for financial support. R.A.C. gratefully acknowledges the support of this work provided by a fellowship from the National Cancer Institute of the National Institutes of Health under Award Number F31A17435.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Supplementary data

NMR spectra for new compounds (i.e., 13, 14, and (R)-L5) can be found in the supporting information, which is available online at: http://

References

  • 1.Sprinz J, Helmchen G. Tetrahedron Lett. 1993;34:1769–1772. [Google Scholar]
  • 2.Dawson GJ, Frost CG, Williams JMJ, Coote SJ. Tetrahedron Lett. 1993;34:3149–3150. [Google Scholar]
  • 3.Von Matt P, Pfaltz A. Angew. Chem. Int. Ed. Engl. 1993;32:566–568. [Google Scholar]
  • 4.a Carroll MP, Guiry PJ. Chem. Soc. Rev. 2014;43:819–833. doi: 10.1039/c3cs60302d. [DOI] [PubMed] [Google Scholar]; b Hargaden GC, Guiry PJ. Chem. Rev. 2009;109:2505–2550. doi: 10.1021/cr800400z. [DOI] [PubMed] [Google Scholar]; c McManus HA, Guiry PJ. Chem. Rev. 2004;104:4151–4202. doi: 10.1021/cr040642v. [DOI] [PubMed] [Google Scholar]; d Helmchen G, Pfaltz A. Acc. Chem. Res. 2000;33:336–345. doi: 10.1021/ar9900865. [DOI] [PubMed] [Google Scholar]; e Williams JM. Synlett. 1996:705–710. [Google Scholar]
  • 5.a Verendel JJ, Pàmies O, Diéguez M, Andersson PG. Chem. Rev. 2014;114:2130–2169. doi: 10.1021/cr400037u. [DOI] [PubMed] [Google Scholar]; b Braunstein P, Graiff C, Naud F, Pfaltz A, Tiripicchio A. Inorg. Chem. 2000;39:4468–4475. [Google Scholar]
  • 6.Stohler R, Wahl F, Pfaltz A. Synthesis. 2005:1431–1436. [Google Scholar]
  • 7.a Gilbertson SR, Fu Z. Org. Lett. 2001;3:161–164. doi: 10.1021/ol006747b. [DOI] [PubMed] [Google Scholar]; b Hashimoto Y, Horie Y, Hayashi M, Saigo K. Tetrahedron: Asymmetry. 2000;11:2205–2210. [Google Scholar]
  • 8.a Frölander A, Moberg C. Org. Lett. 2007;9:1371–1374. doi: 10.1021/ol0702730. [DOI] [PubMed] [Google Scholar]; b Sudo A, Yoshida H, Saigo K. Tetrahedron: Asymmetry. 1997;8:3205–3208. [Google Scholar]
  • 9.a Liu Y, Liniger M, McFadden RM, Roizen JL, Malette J, Reeves CM, Behenna DC, Seto M, Kim J, Mohr JT, Virgil SC, Stoltz BM. Beilstein J. Org. Chem. 2014;10:2501–2512. doi: 10.3762/bjoc.10.261. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Behenna DC, Mohr JT, Sherden NH, Marinescu SC, Harned AM, Tani K, Seto M, Ma S, Novák Z, Krout MR, McFadden RM, Roizen JL, Enquist JA, Jr, White DE, Levine SR, Petrova KV, Iwashita A, Virgil SC, Stoltz BM. Chem. Eur. J. 2011;17:14199–14223. doi: 10.1002/chem.201003383. [DOI] [PMC free article] [PubMed] [Google Scholar]; c García-Yebra C, Janssen JP, Rominger F, Helmchen G. Organometallics. 2004;23:5459–5470. [Google Scholar]
  • 10.a Doran R, Carroll MP, Akula R, Hogan BF, Martins M, Fanning S, Guiry PJ. Chem. Eur. J. 2014;20:15354–15359. doi: 10.1002/chem.201405246. [DOI] [PubMed] [Google Scholar]; b Carroll MP, Müller-Bunz H, Guiry PJ. Chem. Commun. 2012;48:11142–11144. doi: 10.1039/c2cc36452b. [DOI] [PubMed] [Google Scholar]; c Marinescu SC, Nishimata T, Mohr JT, Stoltz BM. Org. Lett. 2008;10:1039–1042. doi: 10.1021/ol702821j. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Mohr JT, Nishimata T, Behenna DC, Stoltz BM. J. Am. Chem. Soc. 2006;128:11348–11349. doi: 10.1021/ja063335a. [DOI] [PubMed] [Google Scholar]
  • 11.a Numajiri Y, Pritchett BP, Chiyoda K, Stoltz BM. J. Am. Chem. Soc. 2015;137:1040–1043. doi: 10.1021/ja512124c. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Reeves CM, Behenna DC, Stoltz BM. Org. Lett. 2014;16:2314–2317. doi: 10.1021/ol500355z. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Reeves CM, Eidamshaus C, Kim J, Stoltz BM. Angew. Chem. Int. Ed. 2013;52:6718–6721. doi: 10.1002/anie.201301815. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Enquist JA, Jr, Stoltz BM. Nature. 2008;453:1228–1231. doi: 10.1038/nature07046. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Mohr JT, Behenna DC, Harned AM, Stoltz BM. Angew. Chem. Int. Ed. 2005;44:6924–6927. doi: 10.1002/anie.200502018. [DOI] [PubMed] [Google Scholar]; f Behenna DC, Stoltz BM. J. Am. Chem. Soc. 2004;126:15044–15045. doi: 10.1021/ja044812x. [DOI] [PubMed] [Google Scholar]
  • 12.a Numajiri Y, Jiménez-Osés G, Wang B, Houk KN, Stoltz BM. Org. Lett. 2015;17:1082–1085. doi: 10.1021/ol503425t. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Korch KM, Eidamshaus C, Behenna DC, Nam S, Horne D, Stoltz BM. Angew. Chem. Int. Ed. 2015;54:179–183. doi: 10.1002/anie.201408609. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Bennett NB, Duquette DC, Kim J, Liu W-B, Marziale AN, Behenna DC, Virgil SC, Stoltz BM. Chem. Eur. J. 2013;19:4414–4418. doi: 10.1002/chem.201300030. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Craig RA, II, Roizen JL, Smith RC, Jones AC, Stoltz BM. Org. Lett. 2012;14:5716–5719. doi: 10.1021/ol3027297. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Behenna DC, Liu Y, Yurino T, Kim J, White DE, Virgil SC, Stoltz BM. Nature Chem. 2012;4:130–133. doi: 10.1038/nchem.1222. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Seto M, Roizen JL, Stoltz BM. Angew. Chem. Int. Ed. 2008;47:6873–6876. doi: 10.1002/anie.200801424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.a McDougal NT, Streuff J, Mukherjee H, Virgil SC, Stoltz BM. Tetrahedron Lett. 2010;51:5550–5554. doi: 10.1016/j.tetlet.2010.08.039. [DOI] [PMC free article] [PubMed] [Google Scholar]; b White DE, Stewart IC, Grubbs RH, Stoltz BM. J. Am. Chem. Soc. 2008;130:810–811. doi: 10.1021/ja710294k. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Tani K, Behenna DC, McFadden RM, Stoltz BM. Org. Lett. 2007;9:2529–2531. doi: 10.1021/ol070884s. [DOI] [PubMed] [Google Scholar]
  • 14.Streuff J, White DE, Virgil SC, Stoltz BM. Nature Chem. 2010;2:192–196. doi: 10.1038/nchem.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.a Day JJ, McFadden RM, Virgil SC, Kolding H, Alleva JL, Stoltz BM. Angew. Chem. Int. Ed. 2011;50:6814–6818. doi: 10.1002/anie.201101842. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Levine SR, Krout MR, Stoltz BM. Org. Lett. 2009;11:289–292. doi: 10.1021/ol802409h. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Petrova KV, Mohr JT, Stoltz BM. Org. Lett. 2009;11:293–295. doi: 10.1021/ol802410t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.a Liu W-B, Reeves CM, Virgil SC, Stoltz BM. J. Am. Chem. Soc. 2013;135:10626–10629. doi: 10.1021/ja4052075. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Fang X, Johannsen M, Yao S, Gathergood N, Hazell RG, Jørgensen KA. J. Org. Chem. 1999;64:4844–4849. doi: 10.1021/jo990238+. [DOI] [PubMed] [Google Scholar]
  • 17.The cost of (R)-t-leucine ranges between $350 and $400 per gram, depending on the size of the order from Sigma-Aldrich, as advertised on their sigmaaldrich.com, accessed 30 April, 2015. The synthesis of t-BuPHOX ligands, however, can be accomplished with ease on large scale, Mohr JT, Krout MR, Stoltz BM. Org. Synth. 2009;86:194–211. doi: 10.15227/orgsyn.086.0194.
  • 18.a Bélanger é, Pouliot M-F, Courtemanche M-A, Paquin J-F. J. Org. Chem. 2012;77:317–331. doi: 10.1021/jo2019653. [DOI] [PubMed] [Google Scholar]; b Bélanger é, Pouliot M-F, Paquin J-F. Org. Lett. 2009;11:2201–2204. doi: 10.1021/ol9005618. [DOI] [PubMed] [Google Scholar]
  • 19.Acid chloride 11 was synthesized in two steps from 2-bromo-5-(trifluoromethyl)benzonitrile by a known procedure, see: reference 13b.
  • 20.The procedure for the coupling of phosphine oxide 15 with oxazoline 14 and sequential reduction was adapted from reference 13a.
  • 21.Control experiments were performed using achiral PHOX ligand L6, bearing no substituent on the oxazoline ring, see reference 16a for full details.
  • 22.Professor Stephen F. Martin, University of Texas at Austin, personal communication.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

NIHMS705028-supplement.pdf (845KB, pdf)

RESOURCES