Synthesis of arylglycines via the D?tz benzannulation reaction

Article abstract of DOI:10.1016/j.tetlet.2005.10.105

Arylglycines are biologically active α-amino acids. Our approach toward the synthesis of arylglycines features the Do?tz benzannulation reaction between a variety of Fischer chromium carbene complexes 3 and alkyne 4. This leads to the formation of protect

Full text of DOI:10.1016/j.tetlet.2005.10.105

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 9039–9042
¨
Synthesis of arylglycines via the Dotz benzannulation reaction
*
´
Shon R. Pulley, Barbara Czako and Gregory D. Brown
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Received 27 August 2005; revised 20 October 2005; accepted 20 October 2005
Available online 8 November 2005
Abstract—Arylglycines are biologically active a-amino acids. Our approach toward the synthesis of arylglycines features the Do¨tz
benzannulation reaction between a variety of Fischer chromium carbene complexes 3 and alkyne 4. This leads to the formation of
protected arylglycinols 5, which can be transformed to the corresponding N-protected arylglycines.
Ó 2005 Elsevier Ltd. All rights reserved.
Arylglycines are an important class of nonproteinogenic
amino acids.1 They have been found to be potential ago-
nists and antagonists at the glutamate receptor of the
central nervous system.2,3 The arylglycine moiety also
occurs in several biologically active natural products.
Representative examples are the glycopeptide antibiot-
ics, such as vancomycin,4 ristocetin,5 and teicoplanin.6
Several members of the monocyclic b-lactam antibiotics,
known as nocardicins, also have the arylglycine moi-
ety.7,8 In addition to the naturally occurring arylgly-
cines, there are synthetic arylglycine containing
compounds; for example, synthetic D-arylglycines can
be found in the side chain of penicillins and
cephalosporins.9
All the known approaches for the synthesis of arylgly-
cines start out from an aromatic compound, which is
modified in the desired way to form the amino acid side-
chain. We have developed a novel strategy, where we
construct the aromatic portion of the molecules utilizing
the Do¨tz benzannulation reaction17 between a variety
Fischer chromium carbene complexes 3a–e and alkyne
4, which provides mild reaction conditions (Scheme 1).
The resulting protected arylglycinols 2a–e can be con-
verted to arylglycines by protecting group manipulation
followed by oxidation.
The a,b-unsaturated Fischer chromium carbene com-
plexes 3a–e used in the benzannulation were prepared
by modified literature procedures.18 Alkyne 4 was syn-
thesized from L-serine via GarnerÕsaldehyde.19
Due to the importance of the arylglycine structural
feature, several approaches were developed for their
synthesis.10 The most important methods include the
asymmetric Strecker synthesis,11 asymmetric alkylation
of electrophilic glycinates,12 asymmetric alkylation
of nucleophilic glycinates,13 asymmetric electrophilic
amination of enolates,14 asymmetric nucleophilic ami-
nation of a-substituted acids,15 and asymmetric
aminohydroxylation.16
The key Do¨tz benzannulation reaction between Fischer
chromium carbenes 3a–e and alkyne 4 was carried out
under both thermal and ultrasonic conditions (Table
1).20 While the thermal reaction gave moderate yields,
Keywords: Dotz benzannulation; Arylglycine.
*
Corresponding author at present address: Roy and Diana Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, PA19104-6323, USA. Tel.: +1 2155 734919; fax: +1
2155 737165; e-mail: barbarac@sas.upenn.edu
Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate
Center, Indianapolis, IN 46285, USA. Tel.: +1 317 433 6079.
Scheme 1. Synthetic strategy.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.105

9040
S. R. Pulley et al. / Tetrahedron Letters 46 (2005) 9039–9042
Table 1. Key step: The Do¨tz benzannulation reaction
a,b-Unsaturated chromium carbene complexes
Product
Thermal/ultrasonic %
65
87
51
66
69
85
67
53
83
59
the ultrasonic conditions afforded the formation of the
protected arylglycinols in good to excellent yields.
Subsequent protection of the hydroxyl group with MeI/
KOH in DMSO led to compounds 6a–e (Scheme 2).
Selective deprotection of the aminohydroxyl moiety
leading to the Boc-protected arylglycinols could not be
achieved. Under standard conditions, we obtained a
mixture of the partially and fully deprotected arylglyci-
nols. To avoid this problem, we decided to fully depro-
tect the arylglycinol derivatives using p-toluenesulfonic
acid or trifluoroacetic acid.
Scheme 2. Protection of the benzannulation product.
It is known in the literature that the benzyloxycarbonyl
(Cbz) group is often more favorable for the protection
of amines than the Boc group under oxidation condi-
tions due to its higher stability.21

S. R. Pulley et al. / Tetrahedron Letters 46 (2005) 9039–9042
9041
provides a convenient and mild approach for the synthe-
sis of electron rich arylglycine derivatives.
Acknowledgement
Financial support from the National Institutes of Health
and the University of Missouri-Columbia is gratefully
acknowledged.
Supplementary data
Scheme 3. Formation of N-protected arylglycinols.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.10.105.
For this reason, we decided to form the Cbz-protected
arylglycinols. This was accomplished by reacting the free
amines with benzyloxycarbonyloxy succinimide to form
compounds 7a–e (Scheme 3).
References and notes
Oxidation of arylglycinols to the corresponding arylgly-
cines is known to be problematic due to the sensitivity of
the structure. Indeed, we found this transformation very
challenging.
1. Williams, R. W.; Hendrix, J. A. Chem. Rev. 1992, 92, 889.
2. Watkins, J.; Collingridge, G. Trends Pharm. Sci. 1994, 15,
333.
3. Bedingfield, J. S.; Kemp, M. C.; Jane, D. E.; Tse, H. W.;
Roberts, P. J.; Watkins, J. Br. J. Pharmacol. 1995, 116,
3323.
4. McCormic, M. H.; Stark, W. M.; Pittenger, G. F.;
Pittenger, R. C.; McGuire, G. M. Antibiot. Annu. 1955–
1956, 9, 606.
5. Harris, C. M.; Kibby, J. J.; Fehlner, J. R.; Raabe, H. B.;
Barber, T. A.; Harrus, T. M. J. Am. Chem Soc. 1979, 101,
437.
6. Coronelly, C.; Bardone, M. R.; DePaoli, A.; Ferrari, P.;
Tuan, G.; Gallo, G. G. J. Antibiot. 1984, 37, 621.
7. Townsand, C. A.; Brown, A. M. J. Am. Chem. Soc. 1983,
105, 913.
8. Kamiya, T.; Hashimoto, M.; Nakaguchi, O.; Oku, T.
Tetrahedron 1979, 35, 323.
During the course of our studies, we have surveyed a
wide array of oxidation methods. Metal mediated oxida-
tions such as CrO3/H5IO6,22 RuCl3, H2O/HIO4,23 and
TPAP, NMO24 led to complete decomposition of the
starting arylglycinols, most probably due to the oxida-
tion of the electron rich aromatic ring. We have tried
several variants of the TEMPO oxidation,25 but TEM-
PO proved to be a capricious oxidant, which was not
reliable and the results were not reproducible. Swern
oxidation also led to the decomposition of the starting
material.26
9. Meijer, E. M.; Boesten, W. H. J.; Shoemaker, H. E.;
Balken, J. A. M. Studies in Organic Chemistry; Elsevier:
Amsterdam, 1985.
10. Williams, R. W.; Hendrix, J. A. Chem. Rev. 1992, 92, 889.
11. (a) Weinges, K.; Brune, G.; Droste, H. Liebigs Ann. Chem.
1980, 2, 212; (b) Weinges, K.; Koltz, K. P.; Droste, H.
Chem. Ber. 1980, 113, 722; (c) Weinges, K.; Brachmann,
H.; Stahnecker, P.; Rodewald, H.; Nixdorf, M.; Irngart-
inger, H. Liebigs Ann. Chem. 1985, 3, 566.
12. Schollkopf, U.; Guttner, S.; Anderskewitz, R.; Egert, E.;
Dyrbusch, M. Angew. Chem., Int. Ed. 1987, 26, 683.
13. Harwig, W.; Schollkopf, U. Liebigs Ann. Chem. 1982, 11,
1952.
14. (a) Oppoltzer, W.; Tamura, O. Tetrahedron Lett. 1990, 31,
991; (b) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc.
1997, 119, 6452.
For solving the oxidation problem, eventually we
decided to test a two-step sequence, applying Dess–Mar-
tin oxidation27 for the formation of aldehyde followed
by sodium chlorite oxidation.28 This method proved to
be viable and provided the desired N-Cbz-protected
arylglycines 8a–e with good yields (Scheme 4).29
In summary, we have developed a novel strategy for the
synthesis of arylglycines, where we constructed the aro-
matic skeleton via the Do¨tz benzannulation reaction.
Oxidation of the arylglycinol moiety was problematic,
but it could be achieved by Dess Martin oxidation fol-
lowed by sodium chlorite oxidation. The above method
15. (a) Evans, D. A.; Ellman, J. A.; Dorow, R. L. Tetrahedron
Lett. 1987, 28, 1123; (b) Evans, D. A.; Britton, T. C.;
Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112,
4011.
16. Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998,
120, 1207.
17. Do¨tz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644.
18. (a) Wulff, W. D.; Gilbertson, S. R. J. Am. Chem. Soc. 1985,
107, 503; (b) Aumann, R.; Fischer, E. O. Chem. Ber. 1968,
101, 945; (c) Aumann, R.; Heinen, H. Chem. Ber. 1987,
120, 5379; (d) Chan, T. H.; Mychajlowski, W.; Ong, B. S.;
Harpp, D. N. J. Org. Chem. 1978, 43, 1526; (e) Wulff, W.
D.; Bax, B. Tetrahedron 1993, 49, 5331; (f) Connor, J. A.;
Jones, E. M. J. Chem. Soc. A 1971, 21, 3368.
Scheme 4. Synthesis of N-protected arylglycines.

9042
S. R. Pulley et al. / Tetrahedron Letters 46 (2005) 9039–9042
19. (a) Garner, P.; Park, J. M. Synthesis 1991, 70, 18; (b)
Ohira, S. Synth. Commun. 1989, 19, 561.
20. Harrity, J. P. A.; Kerr, J. W.; Middlemiss, D. Tetrahedron
1993, 49, 5565.
21. Later in the synthesis the two-step oxidation involving a
Dess–Martin oxidation and NaClO2 oxidation of 7b, and
the N-Boc-protected derivative of the same compound was
compared. Indeed, the oxidation of the N-Cbz-protected
arylglycinol proceeded with higher yield (70% vs 43%).
22. Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.;
Grabowsky, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998,
39, 5323.
24. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625.
25. (a) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998,
120, 1207; (b) Leanna, M. R.; Sowin, T. J.; Morton, H. E.
Tetrahedron Lett. 1992, 5029.
26. (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem.
1978, 43, 2480; (b) Omura, K.; Swern, D. Tetrahedron
1978, 34, 1651.
27. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,
4155.
28. Bal, B. S.; Childers, W. E.; Pinnic, H. W. Tetrahedron
1981, 37, 2091.
23. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S. J. Org. Chem.
1981, 46, 3936.
29. For full characterization, the resulting acids were converted
to the corresponding methyl esters by diazomethane.