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Duthaler-Hafner Reagent[edit]

History and Development:[edit]

Named after Andreas Hafner and Rudolf O. Duthaler, the Duthaler-Hafner reagent is a cyclopentadienyldialkoxyallyltitanium reagent first described in 1992, available in both enantiomeric forms capable of highly stereoselective allylation of aldehydes.[1] Though ƞ3-crotyl molybdenum complexes are capable of the same chemical transformation high enantioface differentiation, they tend to be sensitive, difficult to prepare, and display low solubility, slow reaction rates, while the sophisticated chiral auxiliaries hamper large-scale applications. Despite good results with simple aldehydes, the stereodifferentiation is often inadequate in the case of more complex, especially chiral, substrates.[2][3][4] Hafner and Duthaler believed that further improvements could be achieved for enantioselective alkylating reagents in their ease of preparation, solubility, reaction rate, and access to sophisticated chiral auxiliaries.[5], few moderately successful allyl-titanium reagents with chiral ligands have been reported so far.[6][7] This is astonishing, since high diastereocontrol has been observed for achiral allyl-titanates[8][9]. Furthermore, these organo-titanium reagents are low in toxicity and highly available.[10][11]

Duthaler-Hafner Catalyst
Names
IUPAC name
Chloro{[(4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl]bis(diphenylmethanolato-κO)(2-)}titanium(1+) 2,4-cyclopentadienide
Other names
(R,R)-DUTHALER-HAFNER
Identifiers
3D model (JSmol)
  • Cl[Rh-3]([P+](c0ccccc0)(c0ccccc0)c0ccccc0)([P+](c0ccccc0)(c0ccccc0)c0ccccc0)[P+](c0ccccc0)(c0ccccc0)c0ccccc0
Properties
C36H33ClO4Ti
Molar mass 612.96 g/mol
Appearance solid powder
Melting point 209 to 213 °C (408 to 415 °F; 482 to 486 K)
Structure
three legged piano stool
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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A variety of chiral cyclopentadienyldialkoxytitanium (IV) complexes were prepared and screened for enantioselective allyltitanation. These ligands were derivatives prepared from glucose, idose, allose, and xylose. Though the glucose-derived ligand showed the highest ee values (90% ee), it was only commercially available in the D form, restricting the enantioface discrimination to the "re"-side attack. However, particularly high ee values were observed when (TADDOL) ligands used. The marked influence on enantioselectivity is thought to be due to the steric bulk the phenyl substituents (Ph) exert on the carbinol group. Due to these promising findings and the ease of access to these ligands from the readily available natural (+)- or (-)-tartaric acid, Duthaler and Hafner further explored these catalysts.[1]

Preparation[edit]

These chiral monochlorotitanates are readily prepared from CpTiCl3 or Cp*TiCl3 and chiral tartaric acid 1,4-diols, readily available nontoxic materials in both enantiomeric forms. Treatment of the resultant chiral monochlorotitanates with the desired allyl gringard provides the allyltitanium catalyst.[1]

Insert Preparation Image Here:

Mechanism[edit]

Upon treatment of the allyltitanium reagent with the aldehyde, Si face attack of achiral aldehydes is preferred with the (R,R)-Duthaler-Hafner catalyst. Though the exact details of the mechanism are unclear, it is known that coordination of the aldehyde’s carbonyl to the metal center promotes occurs first which then promotes attack of the allyl olefin into the carbonyl.[12] A carbon-carbon bond then forms between the carbonyl of the aldehyde and carbon of the olefin farthest from the metal center. as well as bond breakage between the allyl carbon-Ti bond.[1][5][12] Treatment of the resulting intermediate with NH4F/H2O cleaves the Ti-O bond to release the desired product.[1]

Insert mechanism Image here: Caption: An allyl transfer occurs from the "si"-face of the aldehyde substrate to form a new stereocenter. In the case of branched olefins, the allyltransfer inevitably results in the anti-configuration.

Like other allyltitanation reactions, the method is thus restricted to the preparation of branched regioisomers with the anticonfiguration.[13] Irrespective of the geometry of the organometallic species used for the preparation of the allyl-titanate catalyst, the anti-product will always be obtained due to an observed rapid equilibration of the ƞ1-bound allyl-titanates to the most stable vans-isomer with titanium bound to the less substituted carbon.[1]


Insert Isomerization Image here:

Applications in Total Synthesis[edit]

In their synthesis of Epothilones A and B, Mulzer and Martin et al. utilized the Duthaler-Hafner reagent provided an alternative with >98% ee and a yield of 61%.[14] Previous routes towards this same intermediate devised by Nicalou et al. utilized Brown allylation with moderate ee values of ~84%.[15][16][17]

Epothilones A and B Image Here:

Caption:


Duthner-Hanfer's allylation played a significant role in the synthesis of a monomeric counterpart of marinomycin A, a 44-membered C2-symmetrical dimeric macrodiolide marine natural product with antitumor and antibiotic activity. (10.1021/ol070240k) Throughout this synthesis, Janine Cossy et. al. utilized the Duthner-Hanfer reagent to establish 3 of the 5 stereocenters with high ee and dr values and in moderate yields.[18][19]

Insert marinomycin A Image Here:

Caption:


In further work by Janine Cossy and coworkers, the Duthaler-Hafner reagent was again used to establish the sole chiral center in their synthesis of the marine natural product, (-)-mycothiazole. In their synthesis, the ability of the Duthaler-Hafner reagent to establish this stereocenter are directly compared with a chiral allylic borane, also generated from the addition of an allylmagnesium bromide to the corresponding (+)-chlorodiisopinocampheyl borane ((+)-DIPCl). The figure below shows that in this case, both the yield and %ee of the resultant chiral secondary alcohol were notably higher when using the allyltitanium complex.[20]

  1. ^ a b c d e f Hafner, Andreas; Duthaler, Rudolf O.; Marti, Roger; Rihs, Grety; Rothe-Streit, Petra; Schwarzenbach, Franz (1992). "Enantioselective syntheses with titanium carbohydrate complexes. Part 7. Enantioselective allyltitanation of aldehydes with cyclopentadienyldialkoxyallyltitanium complexes". Journal of The American Chemical Society. 117 (7): 2321–2336. doi:10.1021/ja00033a005.
  2. ^ Faller, J.W.; DiVerdi, M. J.; John, J. A. (March 4, 1991). "Diastereoselective synthesis of syn-β-methyl homoallyl alcohols with crotylmolybdenum complexes". Tetrahedron Letters. 32 (10): 1271-1274. doi:10.1016/S0040-4039(00)79643-2.
  3. ^ Faller, J. W.; John, J. A.; Mazzieri, M. R. (1989). "Controlling stereochemistry in crotyl additions to aldehydes with crotylmolybdenum complexes". Tetrahedron Letters. 30 (14): 1769-1772. doi:10.1016/S0040-4039(00)99575-3.
  4. ^ Faller, J. W.; Linebarrier, D. L. (March 1, 1989). "Enantioselective syntheses of secondary homoallyl alcohols with optically active .eta.3-allylmolybdenum complexes". Journal of The American Chemical Society. 111 (5): 1937–1939. doi:10.1021/ja00187a091.
  5. ^ a b Duthaler, Rudolf O.; Hafner, Andreas; Riediker, Martin (1990). "Asymmetric C-C-bond formation with titanium carbohydrate complexes" (PDF). Pure & Appl. Chem. 62 (4): 631-642. Catalyst Screening Image HERE
    A variety of sugar-derived ligands were screened for enantioselective allyltitanation of benzaldehyde; xylose acetonide, diacetone idose, diacetone glucose, and diacetone allose

    Caption: A variety of sugar-derived ligands were screened for enantioselective allyltitanation of benzaldehyde; xylose acetonide, diacetone idose, diacetone glucose, and diacetone allose.

    With the exception of the highly stereocontrolled addition of chiral allyl-groups<ref>"Hochenantioselektive Homoaldol-Addition mit chiralen N-Allylharnstoffen - Anwendung zur Synthese optisch reiner γ-Lactone". Angewandte Chemie. 23 (11): 898-899. November, 1984. doi:10.1002/anie.198408981. {{cite journal}}: Check date values in: |date= (help)

  6. ^ Collins, Scott; Kuntz, Bradley A.; Hong, Yaping (1989-08-01). "Additions of chiral allyltitanocenes to aldehydes: diastereoselective synthesis of homoallylic alcohols with a recyclable chiral transition metal reagent". The Journal of Organic Chemistry. 54 (17): 4154–4158. doi:10.1021/jo00278a031. ISSN 0022-3263.
  7. ^ Reetz, Manfred T.; Kyung, Suk Hun; Westermann, Juergen (1984-11-01). "Enantioselective Grignard-type addition of allyltitanium reagents having the center of chirality at titanium". Organometallics. 3 (11): 1716–1717. doi:10.1021/om00089a020. ISSN 0276-7333.
  8. ^ Seebach, Dieter; Widler, Leo (1982). "A case of highly diastereoselective addition to unsymmetrical ketones: lk-addition of (2-alkenyl)triphenoxytitanium derivatives". Helvetica Chimica Acta. 65 (7): 1972–1981. doi:10.1002/hlca.19820650704. ISSN 1522-2675.
  9. ^ Reetz, M. T.; Sauerwald, M. (1984-06-01). "Reversal of diastereoselectivity in the BF3-promoted addition of halobis(cyclopentadienyl)crotyltitanium compounds to aldehydes". The Journal of Organic Chemistry. 49 (12): 2292–2293. doi:10.1021/jo00186a045. ISSN 0022-3263.
  10. ^ T., Reetz, Manfred (1986). Organotitanium reagents in organic synthesis. Springer-Verlag. ISBN 978-3-642-70704-9. OCLC 704469446.{{cite book}}: CS1 maint: multiple names: authors list (link)
  11. ^ "Preparation of Ethers and Epoxides", Compendium of Organic Synthetic Methods, Hoboken, NJ, USA: John Wiley & Sons, Inc., pp. 204–217, 2006-11-22, ISBN 978-0-470-12596-0, retrieved 2021-06-15
  12. ^ a b Seebach, Dieter; Plattner, Dietmar A.; Beck, Albert K.; Wang, Yan Ming; Hunziker, Daniel; Petter, Walter (1992-11-11). "On the Mechanisms of Enantioselective Reactions Using ?,?,??,?? -Tetraaryl-1,3-dioxolane-4,5-dimethanol(TADDOL)-Derived Titanates: Differences betweenC2- andC1-symmetrical TADDOLs - facts, implications and generalizations". Helvetica Chimica Acta (in German). 75 (7): 2171–2209. doi:10.1002/hlca.19920750704. ISSN 0018-019X.
  13. ^ Marek, Ilan, ed. (2002-05-29). Titanium and Zirconium in Organic Synthesis (1 ed.). Wiley. doi:10.1002/3527600671. ISBN 978-3-527-30428-8.
  14. ^ Martin, Harry J.; Pojarliev, Peter; Kählig, Hanspeter; Mulzer, Johann (2001). "The 12,13-Diol Cyclization Approach for a Truly Stereocontrolled Total Synthesis of Epothilone B and the Synthesis of a Conformationally Restrained Analogue". Chemistry – A European Journal. 7 (10): 2261–2271. doi:10.1002/1521-3765(20010518)7:10<2261::AID-CHEM2261>3.0.CO;2-F. ISSN 1521-3765.
  15. ^ Inukai, Takashi; Yoshizawa, Ryo (1967-02-01). "Preparation of .beta.-oxo aldehydes by acylation of aldehyde enamines". The Journal of Organic Chemistry. 32 (2): 404–407. doi:10.1021/jo01288a032. ISSN 0022-3263.
  16. ^ Racherla, Uday S.; Brown, Herbert C. (1991-01). "Chiral synthesis via organoboranes. 27. Remarkably rapid and exceptionally enantioselective (approaching 100% ee) allylboration of representative aldehydes at -100.degree. under new, salt-free conditions". The Journal of Organic Chemistry. 56 (1): 401–404. doi:10.1021/jo00001a072. ISSN 0022-3263. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z. (1997-08-01). "Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy". Journal of the American Chemical Society. 119 (34): 7974–7991. doi:10.1021/ja971110h. ISSN 0002-7863.
  18. ^ Kwon, Hak Cheol; Kauffman, Christopher A.; Jensen, Paul R.; Fenical, William (2006-02-01). "Marinomycins A−D, Antitumor-Antibiotics of a New Structure Class from a Marine Actinomycete of the Recently Discovered Genus "Marinispora"". Journal of the American Chemical Society. 128 (5): 1622–1632. doi:10.1021/ja0558948. ISSN 0002-7863.
  19. ^ Amans, Dominique; Bellosta, Véronique; Cossy, Janine (2007-04-01). "An Efficient and Stereoselective Synthesis of the Monomeric Counterpart of Marinomycin A". Organic Letters. 9 (8): 1453–1456. doi:10.1021/ol070240k. ISSN 1523-7060.
  20. ^ Le Flohic, Alexandre; Meyer, Christophe; Cossy, Janine (2005-01-01). "Total Synthesis of (±)-Mycothiazole and Formal Enantioselective Approach". Organic Letters. 7 (2): 339–342. doi:10.1021/ol047603q. ISSN 1523-7060.
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