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Asymmetric Allylic Alkylation

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Introduction

Palladium-catalyzed asymmetric allylic alkylation (AAA) has proven to be an exceptionally powerful method for the efficient construction of stereogenic centers. In sharp contrast to many other catalytic methods, AAA has the ability to form multiple types of bonds (C–C, C–O, C–S, C–N) with a single catalyst system.

C-2 symmetric diaminocyclohexyl (DACH) ligands in AAA

The Trost group at Stanford University has pioneered the use of C-2 symmetric diaminocyclohexyl (DACH) ligands in AAA, allowing for the rapid synthesis of a diverse range of chiral products with a limited number of chemical transformations. Reactions are typically high yielding, and excellent levels of enantioselectivity are observed.

DACH Table

References

1.
Trost BM, Fandrick DR. 2007. Aldrichimica Acta. 4059.
2.
Trost BM, Machacek MR, Aponick A. 2006. Predicting the Stereochemistry of Diphenylphosphino Benzoic Acid (DPPBA)-Based Palladium-Catalyzed Asymmetric Allylic Alkylation Reactions:  A Working Model. Acc. Chem. Res.. 39(10):747-760. https://doi.org/10.1021/ar040063c
3.
Trost BM. 2004. Asymmetric Allylic Alkylation, an Enabling Methodology. J. Org. Chem.. 69(18):5813-5837. https://doi.org/10.1021/jo0491004
4.
Trost BM, Crawley ML. 2003. Asymmetric Transition-Metal-Catalyzed Allylic Alkylations:  Applications in Total Synthesis. Chem. Rev.. 103(8):2921-2944. https://doi.org/10.1021/cr020027w
5.
Trost BM, Van Vranken DL. 1996. Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem. Rev.. 96(1):395-422. https://doi.org/10.1021/cr9409804
6.
Trost BM. 1996. Designing a Receptor for Molecular Recognition in a Catalytic Synthetic Reaction:  Allylic Alkylation. Acc. Chem. Res.. 29(8):355-364. https://doi.org/10.1021/ar9501129

Advantages

  • Atom-economical catalytic method
  • High yields and synthetically useful levels of enantiocontrol
  • Unparallelled ability to prepare chiral building blocks from simple precursors

Representative Applications

Pd-Catalyzed Asymmetric Allylic Alkylation: Carbon Nucleophiles

In early examples of this methodology, Trost and co-workers demonstrated that diesters are competent nucleophiles for the deracemization of cyclic allylic acetates, to afford chiral malonate derivatives. Since that time, soft carbon nucleophiles such as barbituric acid derivatives, β-keto esters, nitro compounds, and many others have been employed in AAA for assembly of tertiary and quaternary asymmetric centers.

Malonate Nucleophiles:

Malonate Nucleophiles 1
Malonate Nucleophiles 2

References

1.
Trost BM, Bunt RC. 1994. Asymmetric induction in allylic alkylations of 3-(acyloxy)cycloalkenes. J. Am. Chem. Soc.. 116(9):4089-4090. https://doi.org/10.1021/ja00088a059
2.
Helmchen G, Ernst M. A Novel Route to Iridoids: Enantioselective Syntheses of Isoiridomyrmecin and ?-Skytanthine. Synthesis. 2002(14 Special Issue): https://doi.org/10.1055/s-2002-34382
3.
Ernst M, Helmchen G. 2002. Angew. Chem., Int. Ed.. 4140-54. 10.1002/1521-3773(20021104)41:21<4054::AID-ANIE4054>3.0.CO;2-K
Malonate Nucleophiles2

References

1.
Trost BM, Fandrick DR, Dinh DC. 2005. Dynamic Kinetic Asymmetric Allylic Alkylations of Allenes. J. Am. Chem. Soc.. 127(41):14186-14187. https://doi.org/10.1021/ja0543705

Barbituric Acid Nucleophiles:

Barbituric Acid Nucleophiles

References

1.
Trost BM, Schroeder GM. 2000. Palladium-Catalyzed Asymmetric Allylic Alkylation of Barbituric Acid Derivatives:  Enantioselective Syntheses of Cyclopentobarbital and Pentobarbital. J. Org. Chem.. 65(5):1569-1573. https://doi.org/10.1021/jo991491c

β-Keto Ester Nucleophiles:

ß-Keto Ester Nucleophiles

References

1.
Trost BM, Radinov R, Grenzer EM. 1997. Asymmetric Alkylation of ?-Ketoesters. J. Am. Chem. Soc.. 119(33):7879-7880. https://doi.org/10.1021/ja971523i

Nitrosulfonyl Nucleophiles:

Nitrosulfonyl Nucleophiles 1

References

1.
Trost BM, Chupak LS, Lübbers T. 1998. Total Synthesis of (±)- and (+)-Valienamine via a Strategy Derived from New Palladium-Catalyzed Reactions. J. Am. Chem. Soc.. 120(8):1732-1740. https://doi.org/10.1021/ja973081g
Nitrosulfonyl Nucleophiles 1

References

Nitroalkane Nucleophiles:

Nitroalkane Nucleophiles 1

References

1.
Trost BM, Surivet JP. 2000. Angew. Chem., Int. Ed. 393122. https://doi.org/10.1002/1521-3773(20000901)39:17<3122::AID-ANIE3122>3.0.CO;2-8
Nitroalkane Nucleophiles 2

References

1.
Trost BM, Surivet JP. 2000. Angew. Chem., Int. Ed. 393122. https://doi.org/10.1002/1521-3773(20000901)39:17<3122::AID-ANIE3122>3.0.CO;2-8

Other Carbon Nucleophiles:

Other Carbon Nucleophiles 1

References

1.
Trost BM, Kallander LS. 1999. A Versatile Enantioselective Strategy Towardl-C-Nucleosides:  A Total Synthesis ofl-Showdomycin. J. Org. Chem.. 64(15):5427-5435. https://doi.org/10.1021/jo990195x
Other Carbon Nucleophiles 2

References

1.
Trost BM, Chisholm JD, Wrobleski ST, Jung M. 2002. Ruthenium-Catalyzed Alkene-Alkyne Coupling:  Synthesis of the Proposed Structure of Amphidinolide A. J. Am. Chem. Soc.. 124(42):12420-12421. https://doi.org/10.1021/ja027883+
Other Carbon Nucleophiles 3

References

1.
Trost BM, Dong L, Schroeder GM. 2005. Total Synthesis of (+)-Allocyathin B2. J. Am. Chem. Soc.. 127(9):2844-2845. https://doi.org/10.1021/ja0435586
2.
Trost BM, Dong L, Schroeder GM. 2005. Exploiting the Pd- and Ru-Catalyzed Cycloisomerizations:  Enantioselective Total Synthesis of (+)-Allocyathin B2. J. Am. Chem. Soc.. 127(29):10259-10268. https://doi.org/10.1021/ja051547m
3.
Trost BM, Pissot-Soldermann C, Chen I. 2005. A Short and Concise Asymmetric Synthesis of Hamigeran B. Chem. Eur. J.. 11(3):951-959. https://doi.org/10.1002/chem.200400558

Pd-Catalyzed Asymmetric Allylic Alkylation: Oxygen Nucleophiles

Carbon-oxygen bond-forming reactions using palladium-catalyzed asymmetric allylic alkylation have been well demonstrated in numerous natural product syntheses. Alcohols, carboxylates, and hydrogencarbonates have all been employed as O-nucleophiles.

Alcohol Nucleophiles:

Alcohol Nucleophiles Structure

References

1.
Lennon IC. 2004. Chimica Oggi; Chemistry Today.11.
Alcohol Nucleophiles Structure

References

1.
Fox ME, Lennon IC, Farina V. 2007. Catalytic asymmetric synthesis of ethyl (1R,2S)-dehydrocoronamate. Tetrahedron Letters. 48(6):945-948. https://doi.org/10.1016/j.tetlet.2006.12.025
Alcohol Nucleophiles 1

References

1.
Trost BM, McEachern EJ, Toste FD. 1998. A Two-Component Catalyst System for Asymmetric Allylic Alkylations with Alcohol Pronucleophiles. J. Am. Chem. Soc.. 120(48):12702-12703. https://doi.org/10.1021/ja983238k
Alcohol Nucleophiles 2

References

1.
Trost BM, Brown BS, McEachern EJ, Kuhn O. 2003. Asymmetric Synthesis of Oxygen Heterocycles via Pd-Catalyzed Dynamic Kinetic Asymmetric Transformations: Application to Nucleosides. Chem. Eur. J.. 9(18):4442-4451. https://doi.org/10.1002/chem.200304949
2.
Trost BM, Tang W, Schulte JL. 2000. Asymmetric Synthesis of Quaternary Centers. Total Synthesis of (?)-Malyngolide. Org. Lett.. 2(25):4013-4015. https://doi.org/10.1021/ol006599p
3.
Trost BM, Andersen NG. 2002. Utilization of Molybdenum- and Palladium-Catayzed Dynamic Kinetic Asymmetric Transformations for the Preparation of Tertiary and Quaternary Stereogenic Centers:  A Concise Synthesis of Tipranavir. J. Am. Chem. Soc.. 124(48):14320-14321. https://doi.org/10.1021/ja028497v
4.
Trost BM, Tang W. 2001. An Enantioselective Strategy to Macrocyclic Bisindolylmaleimides. An Efficient Formal Synthesis of LY 333531. Org. Lett.. 3(21):3409-3411. https://doi.org/10.1021/ol016666v
5.
Trost BM, Zhang T. 2006. Asymmetric Synthesis of ?-Substituted Aldehydes by Pd-Catalyzed Asymmetric Allylic Alkylation?Alkene Isomerization?Claisen Rearrangement. Org. Lett.. 8(26):6007-6010. https://doi.org/10.1021/ol0624878
Alcohol Nucleophiles 3

References

1.
Trost BM, Toste FD. 1999. Palladium-Catalyzed Kinetic and Dynamic Kinetic Asymmetric Transformation of 5-Acyloxy-2-(5H)-furanone. Enantioselective Synthesis of (?)-Aflatoxin B Lactone. J. Am. Chem. Soc.. 121(14):3543-3544. https://doi.org/10.1021/ja9844229
2.
Trost BM, Toste FD. 2003. Palladium Catalyzed Kinetic and Dynamic Kinetic Asymmetric Transformations of ?-Acyloxybutenolides. Enantioselective Total Synthesis of (+)-Aflatoxin B1and B2a. J. Am. Chem. Soc.. 125(10):3090-3100. https://doi.org/10.1021/ja020988s
3.
Trost BM, Crawley ML. 2002. 4-Aryloxybutenolides As ?Chiral Aldehyde? Equivalents:  An Efficient Enantioselective Synthesis of (+)-Brefeldin A. J. Am. Chem. Soc.. 124(32):9328-9329. https://doi.org/10.1021/ja026438b
4.
Trost BM, Crawley ML. 2004. A?Chiral Aldehyde? Equivalent as a Building Block Towards Biologically Active Targets. Chem. Eur. J.. 10(9):2237-2252. https://doi.org/10.1002/chem.200305634

Carboxylate Nucleophiles:

Carboxylate Nucleophiles 1

References

1.
Trost BM, Organ MG. 1994. Deracemization of Cyclic Allyl Esters. J. Am. Chem. Soc.. 116(22):10320-10321. https://doi.org/10.1021/ja00101a070
Carboxylate Nucleophiles 2

References

1.
Trost BM, Kondo Y. 1991. An asymmetric synthesis of (+)-phyllanthocin. Tetrahedron Letters. 32(13):1613-1616. https://doi.org/10.1016/s0040-4039(00)74285-7
carboxylate nucleophiles3

References

1.
Trost BM, Patterson DE, Hembre EJ. 1999. Dynamic Kinetic Asymmetric Transformations of Conduritol B Tetracarboxylates:  An Asymmetric Synthesis ofd-myo-Inositol 1,4,5-Trisphosphate. J. Am. Chem. Soc.. 121(46):10834-10835. https://doi.org/10.1021/ja992960v

Hydrogencarbonate Nucleophiles:

Hydrogencarbonate Nucleophiles 1

References

1.
Lüssem BJ, Gais H. 2003. Palladium-Catalyzed Deracemization of Allylic Carbonates in Water with Formation of Allylic Alcohols:  Hydrogen Carbonate Ion as Nucleophile in the Palladium-Catalyzed Allylic Substitution and Kinetic Resolution. J. Am. Chem. Soc.. 125(20):6066-6067. https://doi.org/10.1021/ja034109t
2.
Gais H, Bondarev O, Hetzer R. 2005. Palladium-catalyzed asymmetric synthesis of allylic alcohols from unsymmetrical and symmetrical racemic allylic carbonates featuring C?O-bond formation and dynamic kinetic resolution. Tetrahedron Letters. 46(37):6279-6283. https://doi.org/10.1016/j.tetlet.2005.07.044
Hydrogencarbonate Nucleophiles 2

References

1.
Trost BM, McEachern EJ. 1999. Inorganic Carbonates as Nucleophiles for the Asymmetric Synthesis of Vinylglycidols. J. Am. Chem. Soc.. 121(37):8649-8650. https://doi.org/10.1021/ja990783s
Hydrogencarbonate Nucleophiles 3

References

1.
Gais H, Bondarev O, Hetzer R. 2005. Palladium-catalyzed asymmetric synthesis of allylic alcohols from unsymmetrical and symmetrical racemic allylic carbonates featuring C?O-bond formation and dynamic kinetic resolution. Tetrahedron Letters. 46(37):6279-6283. https://doi.org/10.1016/j.tetlet.2005.07.044
2.
Dong Y, Teesdale-Spittle P, Hoberg JO. 2005. Regioselective palladium-catalyzed allylic alkylations. Tetrahedron Letters. 46(2):353-355. https://doi.org/10.1016/j.tetlet.2004.09.190

Pd-Catalyzed Asymmetric Allylic Alkylation: Nitrogen Nucleophiles

A formidable challenge in asymmetric synthesis is the stereocontrolled construction of carbon-nitrogen bonds. Nitrogen nucleophiles such as alkylamines, azides, amides, imides, and N-heterocycles have all been employed in asymmetric allylic alkylation reactions.

Alkylamines Nucleophiles:

Alkylamines Nucleophiles

References

1.
Trost BM, Krische MJ, Radinov R, Zanoni G. 1996. On Asymmetric Induction in Allylic Alkylation via Enantiotopic Facial Discrimination. J. Am. Chem. Soc.. 118(26):6297-6298. https://doi.org/10.1021/ja960649x

Azide Nucleophiles:

Azide Nucleophiles 1

References

1.
Trost BM, Pulley SR. 1995. Asymmetric Total Synthesis of (+)-Pancratistatin. J. Am. Chem. Soc.. 117(40):10143-10144. https://doi.org/10.1021/ja00145a038
Azide Nucleophiles 2

References

1.
Trost BM, Cook GR. 1996. An asymmetric synthesis (?)-epibatidine. Tetrahedron Letters. 37(42):7485-7488. https://doi.org/10.1016/0040-4039(96)01739-x

Sulfonamide Nucleophiles:

Sulfonamide Nucleophiles 1

References

1.
Ovaa H, van der Marel GA, van Boom JH, Stragies R, Blechert S. 2000. Asymmetric synthesis of indolizidine alkaloids by ring-closing?ring-opening metathesis. Chem. Commun..(16):1501-1502. https://doi.org/10.1039/b004106h
2.
Trost BM, Sorum MT. 2003. The Asymmetric Synthesis of (3S,4R,5S)-3-Amino-4,5-O-isopropylidenedioxycyclopentene. Org. Process Res. Dev.. 7(3):432-435. https://doi.org/10.1021/op025611l
Sulfonamide Nucleophiles 2

References

1.
Stragies R, Blechert S. 2000. Enantioselective Synthesis of Tetraponerines by Pd- and Ru-Catalyzed Domino Reactions. J. Am. Chem. Soc.. 122(40):9584-9591. https://doi.org/10.1021/ja001688i

Imide Nucleophiles:

Imide Nucleophiles 1

References

1.
Trost BM, Van Vranken DL. 1993. A general synthetic strategy toward aminocyclopentitol glycosidase inhibitors. Application of palladium catalysis to the synthesis of allosamizoline and mannostatin A. J. Am. Chem. Soc.. 115(2):444-458. https://doi.org/10.1021/ja00055a013
2.
Trost BM, Van Vranken DL, Bingel C. 1992. A modular approach for ligand design for asymmetric allylic alkylations via enantioselective palladium-catalyzed ionizations. J. Am. Chem. Soc.. 114(24):9327-9343. https://doi.org/10.1021/ja00050a013
3.
Trost BM, Patterson DE. 1998. Enhanced Enantioselectivity in the Desymmetrization of Meso-Biscarbamates. J. Org. Chem.. 63(4):1339-1341. https://doi.org/10.1021/jo971746r
Imide Nucleophiles 2

References

1.
Trost BM, Krueger AC, Bunt RC, Zambrano J. 1996. On the Question of Asymmetric Induction with Acyclic Allylic Substrates. An Asymmetric Synthesis of (+)-Polyoxamic Acid. J. Am. Chem. Soc.. 118(27):6520-6521. https://doi.org/10.1021/ja961061t
Imide Nucleophiles 3

References

1.
Trost BM, Bunt RC. 1994. Asymmetric induction in allylic alkylations of 3-(acyloxy)cycloalkenes. J. Am. Chem. Soc.. 116(9):4089-4090. https://doi.org/10.1021/ja00088a059
Imide Nucleophiles 4

References

1.
Trost BM, Bunt RC, Lemoine RC, Calkins TL. 2000. Dynamic Kinetic Asymmetric Transformation of Diene Monoepoxides:  A Practical Asymmetric Synthesis of Vinylglycinol, Vigabatrin, and Ethambutol. J. Am. Chem. Soc.. 122(25):5968-5976. https://doi.org/10.1021/ja000547d
2.
Trost BM, Lemoine RC. 1996. An asymmetric synthesis of vigabatrin. Tetrahedron Letters. 37(51):9161-9164. https://doi.org/10.1016/s0040-4039(96)02148-x
3.
Trost BM. 2003. Angew. Chem., Int. Ed. 425987.
4.
Trost BM, Horne DB, Woltering MJ. 2006. Palladium-Catalyzed DYKAT of Butadiene Monoepoxide: Enantioselective Total Synthesis of (+)-DMDP, (?)-Bulgecinine, and (+)-Broussonetine G. Chem. Eur. J.. 12(25):6607-6620. https://doi.org/10.1002/chem.200600202
Imide Nucleophiles 5

References

1.
Trost BM, Aponick A. 2006. Palladium-Catalyzed Asymmetric Allylic Alkylation ofmeso-anddl-1,2-Divinylethylene Carbonate. J. Am. Chem. Soc.. 128(12):3931-3933. https://doi.org/10.1021/ja0578348

Pd-Catalyzed Asymmetric Allylic Alkylation: Sulfur Nucleophiles

While not as extensively explored, certain sulfur nucleophiles are competent in the allylation reaction. In particular, sodium benzenesulfinate under goes alkylation to afford synthetically useful chiral sulfones.

Sulfur Nucleophiles 1

References

1.
Trost BM, Organ MG, O'Doherty GA. 1995. Asymmetric synthesis of allylic sulfones useful as asymmetric building blocks.. J. Am. Chem. Soc.. 117(38):9662-9670. https://doi.org/10.1021/ja00143a007
Sulfur Nucleophiles 2

References

1.
Trost BM, Crawley ML, Lee CB. 2000. ?-Acetoxysulfones as ?Chiral Aldehyde? Equivalents. J. Am. Chem. Soc.. 122(25):6120-6121. https://doi.org/10.1021/ja000627h

Asymmetric Allylic Alkylation: Molybdenum-catalyzed Reactions

The mechanism of molybdenum-catalyzed AAA reaction is presumed to be distinctly different from the analogous Pd-catalyzed reaction, and in some cases, levels regio-, enantio- and diastereoselectivity enhanced relative to the palladium-catalyzed reaction.

Asymmetric Allylic Alkylation: Molybdenum-catalyzed Reactions 1

References

1.
Trost BM, Zhang Y. 2006. Molybdenum-Catalyzed Asymmetric Allylation of 3-Alkyloxindoles:  Application to the Formal Total Synthesis of (?)-Physostigmine. J. Am. Chem. Soc.. 128(14):4590-4591. https://doi.org/10.1021/ja060560j
Asymmetric Allylic Alkylation: Molybdenum-catalyzed Reactions 2

References

1.
Trost BM, Dogra K. 2007. Synthesis of (-)-?9-trans-Tetrahydrocannabinol:  Stereocontrol via Mo-Catalyzed Asymmetric Allylic Alkylation Reaction. Org. Lett.. 9(5):861-863. https://doi.org/10.1021/ol063022k
Materials
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