1. The Schmidt and Boyer Reactions Revisited: The Chemistry of Prof
The Schmidt and Boyer Reactions Revisited: The Chemistry of Prof. Jeffrey Aubé
Alexandre Lemire
Litterature Meeting
November 8th, 2004

2. Prof. Jeffrey Aubé University of Kansas Interim Chair, 2003 - present
Professor, 1996 – present
Associate Professor,
Assistant Professor,
Olin Petefish/Higuchi Award for Achievement in the Basic Sciences, 2001
Fellow, Japanese Society for the Promotion of Science, 1996
Phi Beta Kappa, honorary member, 1996
American Cyanamid Faculty Award in Organic Chemistry, 1993
Alfred P. Sloan Research Fellow,
Eli Lilly Grantee,
Department of Medicinal Chemistry School of Pharmacy University of Kansas Lawrence, Kansas Tel:
Fax:

3. Prof. Jeffrey Aubé 85 publications
NIS Postdoctoral fellow Yale U. (Prof. Danishefsky)
PhD Duke University 1984 (Durham, NC)
BSc U. of Miami 1980
Department of Medicinal Chemistry School of Pharmacy University of Kansas Lawrence, Kansas Tel:
Fax:

4. The Schmidt Reaction (1)
Name Reaction in Organic Chemistry, p
Schmidt, R. F. Ber. 1924, 57, 704.
Reviews: (a) Wolff, H. Org. React. 1946, 3, (b) Krow, G. R. Tetrahedron 1981, 37,

5. Mechanism?

6. The Schmidt Reaction (2)
The Merck Index, 12th Edition, p. ONR-82

7. The Schmidt Reaction (2)

8. Analogous Rearrangements

9. Reactions with Alkyl Azides

10. Reactions with Alkyl Azides
1 (a) Briggs, L. H. et al. J. Chem. Soc. 1942, (b) Smith, P. A. J. Am. Chem. Soc. 1948, 70,
2 Boyer, J. H. et al. J. Am. Chem. Soc. 1956, 78, Boyer, J. H.; Morgan, L. R., Jr. J. Am. Chem. Soc. 1959, 81,

11. Aubé and Milligan’s Discovery
Communication: J. Am. Chem. Soc. 1991, 113,
Full paper: J. Am. Chem. Soc. 1995, 117,

12. Aubé and Milligan’s Discovery

13. Questions to address Effects of ring size and tether length
Reaction conditions to effectively promote the process
Regiochemical rules to predict the product of the intramolecular Schmidt reaction
Stereochemistry (retention or inversion) at the migrating carbon

14. Effect of ring size and tether length
pyrrolizidine
quinolizidine
indolizidine
90% SM recovery after 1 h!
(stability of azide in TFA)

15. Effect of ring size and tether length
TiCl4 can help with recalcitrant substrates but not always

16. Effect of ring size and tether length
Results inconsistent with a mechanism implying a nitrene or nitrenium species:
given their high reactivity, their formation would be rate limiting and they would not be affected by
structural change near the carbonyl group 4 carbons away
The most readily accomplished ring-expansion reactions involved substrates containing 4 carbons between
the carbonyl group and the azido substitutent. The reaction proceeds through a presumably optimal six-membered
cyclic azidohydrin intermediate previously shown
Formation of the five-membered azidohydrin should be facile, but the reaction fails, presumably due to strain
encountered en route to the expected azetidine product
Ring expansion of aromatic ketones are less efficient:

17. nitrogen loss leads to four possible intermediates:
Regiochemistry
Theoritical and experimental insights support a mechanism were the proximal nitrogen atom of the aminodiazonium ion
intermediate has appreciable tetrahedral character in the transition state leading to product.
Chairlike azidohydrins are likely achieved when possible and migration of an antiperiplanar substituent during
nitrogen loss leads to four possible intermediates:

18. In the acyclic series, this would not be an issue anymore:
Regiochemistry
antiperiplanar C-C
bond migration
Only intermediate d has a pseudoaxial N2+ moiety, wich leads to bridged product. This intermediate might lead to an
higher energy transition state so the corresponding product is not observed
Another explanation is that the bridged bicyclic amide is not accessible because of the instability of the amide linkage
In the acyclic series, this would not be an issue anymore:

19. Regiochemistry: Acyclic Ketones
antiperiplanar C-C
bond migration
The population of azidohydrin type c would be expected to increase with smaller R1 substituents, like H

20. Regiochemistry: Acyclic Substrates
No azetidine formed, pyrrolidinone occurred only from aldehydes

21. Regiochemistry: Acyclic Substrates
Again, lactams only observed when aldehydes are reacted
Possibly because only H is small enough to permit path c discussed

22. Regiochemistry: Acyclic Aldehydes
Another mechanism could explain the formation of these lactams
H migration has been rarely observed, the elimination/tautomerization pathway is though to be favored

23. Stereochemistry of the Migrating Carbon
Note that we can deprotect the carbonyl group without triggering the intramolecular Schmidt reaction
Ring expansion occurred with retention of configuration, as known for the intermolecular process (HN3):

24. Stereochemistry of the Migrating Carbon
The classical Schmidt affords also the regioisomer and tetrazole byproduct
The major compound forms the lactam with identical ee

25. Stereochemistry of the Migrating Carbon: Enolizable Ketone
Little isomerization occurred with TFA for the trans ketone
Can be avoided using TiCl4/CH2Cl2

26. Stereochemistry of the Migrating Carbon

28. Ring Expansion of Alkyl Azides to Ketones
Boyer, J. H. et al. J. Am. Chem. Soc. 1956, 78,

29. Ring Expansion of Alkyl Azides to Ketones
Communication: J. Org. Chem. 1992, 57,
Full paper: J. Am. Chem. Soc. 2000, 122,
Follow up: J. Org. Chem. 2001, 66,

30. Ring Expansion of Alkyl Azides to Ketones

31. Ring Expansion of Alkyl Azides to Ketones
Reaction using BF3OEt2 or protic acids failed
Unindered cyclohexanones and cyclobutanone are successful
Unsymmetrical ketones gave mixtures of lactams
Only BnN3 and HexN3 reported

33. ???

34. ???

35. Use of TfOH: Mechanism

36. Use of TfOH

38. Ring Expansion of Hydroxy Azides to Ketones: The Boyer Reaction
Boyer, J. H. et al. J. Am. Chem. Soc. 1956, 78,
Boyer, J. H.; Morgan, L. R., Jr. J. Am. Chem. Soc. 1959, 81,

39. The Boyer Reaction Revisited by Aubé
Communication: J. Am. Chem. Soc. 1995, 117,
Follow up: J. Org. Chem. 1996, 61,
Full paper: Tetrahedron 1997, 53,
Related paper: J. Org. Chem. 2000, 65,

40. Mechanism
Mechanism originally proposed by Boyer

41. Mechanism
Mechanism seems more reasonable in light of relative easyness of intramolecular Schmidt reaction

42. Bronsted and Lewis Acid Survey

43. Azide Tether Length

44. Azide Tether Length 2 or 3 C between OH and N3 is optimal
Longer alkyl chain leads to transient formation of a seven or higher-membered ring system
This leads to the shift in mechanism shown above, to the original proposal of Boyer
These behave as simple alkyl azides

45. Mechanism

46. Symmetrical Ketones

47. Unsymmetrical Ketones

49. Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones: Desymetrization of meso-Ketones
Communication: Org. Lett. 1999, 1,
Full paper: J. Am. Chem. Soc. 2003, 125,
Follow up: J. Am. Chem. Soc. 2003, 125,
Theoritical studies: J. Org. Chem. 2004, 69,

50. Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones

51. Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones

52. Stereoselectivity
Every substituents in pseudoequatorial position exept N2+
Antiperiplanar bond to N2+ migrates

53. Deprotection of the Lactam
Destruction of the chiral auxiliairy

55. Use in Total Synthesis: Dendrobatid Alkaloid 251F
Isolation reported in 1992 from the skin of the Columbian dendrobatid poison frog Minyobates bombetes1
Skin extracts caused severe locomotor difficulties, muscle spasms and convulsions upon injection into mice
Pharmacological profile of the alkaloid is still unknown
First synthesized by Taber and You2
Cyclopenta[b]quinolizidine
7 stereogenic centers, 6 contiguous
1 Spande, T. F. et al. J. Nat. Prod. 1992, 55,
2 Taber, D. F.; You, K. K. J. Am. Chem. Soc. 1995, 117,

56. Retrosynthetic Analysis to Dendrobatid Alkaloid 251F
Communication: J. Am. Chem. Soc. 2002, 124,
Full paper: J. Am. Chem. Soc. 2004, 126,

57. Synthesis of the Bicyclic Enone
Diels-Alder: Evans, D. A. et al. J. Am. Chem. Soc. 1988, 110,
Metathesis: Grubbs, R. H. et al. J. Org. Chem. 1990, 55,

58. Diastereoselective Diels-Alder
Diels-Alder: Evans, D. A. et al. J. Am. Chem. Soc. 1988, 110,

59. Synthesis of the Bicyclic Enone

60. Synthesis of the Bicyclic Enone

61. Synthesis of the 4-C Side Chain Leading to the Third Ring

62. Installation of the 4-C Side Chain Leading to the Third Ring

63. Completion of the Synthesis
13 steps overall, 6.5% yield