give different profiles, highlighting the importance of ac-
cessing single geometric isomers.11
Table 1. From Vinyl AA’s to Formyl AA’sa
Given this, it would be interesting to install such a trigger
at the R-carbon to probe its effectiveness in an AADC active
site. Yet, to our knowledge, no syntheses of quaternary,
R-(2′-fluoro)vinyl AA’s have yet been reported, though (E)-
and (Z)-R-(2′-fluoro)vinylglycine have been described by
McCarthy.12
A fluoromethylenation route related to McCarthy’s13 was
attractive, as protected R-formyl AA’s might be obtained
ozonolytically, from the corresponding quaternary, R-vinyl
AA’s. The latter were available, with appropriate protecting
groups, via a formal R-vinylation sequence that had been
developed earlier (Scheme 1).14 Furthermore, success in the
Scheme 1. Formal R-Vinylation of Amino Acids
a Procedure: Ozone was bubbled into a solution of the protected vinyl-
AA (4a-f) in CH2Cl2 at -78 °C, until a light blue color persisted. After
several minutes, oxygen was then bubbled through to remove excess ozone
(decolorizes). b Method A1: The crude ozonide was reduced with Me2S at
room temperature. Method A2: Ozonide reduction was carried out with
Zn, AcOH. c Isolated yields.
isomers.12 In considering the application of this chemistry
here, several key issues arose at the outset: (i) Would such
sterically encumbered aldehydes (5) be amenable to nucleo-
philic attack by 6? (ii) If so, would the intermediate â-al-
koxyphosphonates follow the desired HWE reaction mode
or fragment along a competing “retro-Claisen” mode (Scheme
2)? (iii) Would any such HWE products be formed as an
E/Z mixture as is typical for this chemistry?12
racemic series here would map onto an enantioselective
variant, starting from either L- or D-R-vinyl AA’s.15 Pleas-
ingly, the ozonolysis of vinylic AA’s (4) to formyl AA’s
(5) proceeded in good to excellent yield, across an array of
functionalized side chains (Table 1).
McCarthy had taken a Horner Wadsworth Emmons
(HWE) approach, condensing lithio diethyl R-fluoro-R-(phen-
ylsulfonyl)methylphosphonate (6) with the Garner aldehyde
to obtain an (E)/(Z) mixture of R-(2′-fluoro)vinylglycinol
(10) Silverman, R. B.; Bichler, K. A.; Leon, A. J. J. Am. Chem. Soc.
1996, 118, 1253-1261.
(11) For a related trigger bearing both E- and Z-configured fluorines,
see: Pan, Y.; Qiu, J.; Silverman, R. B. J. Med. Chem. 2003, 46, 5292-
5293.
Scheme 2. Competition between HWE and “Retro-Claisen”
Condensation Manifolds
(12) McCarthy, J. R.; Huber, E. W.; Le, T.-B.; Laskovics, F. M.;
Matthews, D. P. Tetrahedron 1996, 52, 45-58.
(13) For other examples of HWE-type condensations with 6, see: (a)
McCarthy, J. R.; Matthews, D. P.; Paolini, J. P. Org. Synth. 1995, 72, 216-
24. (b) Gross, R. S.; Mehdi, S.; McCarthy, J. R. Tetrahedron Lett. 1993,
34, 7197-7200. (c) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.;
Huber, E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S. J. Am.
Chem. Soc. 1991, 113, 7439-7440
(14) (a) Pedersen, M. L.; Berkowitz, D. B. J. Org. Chem. 1993, 58,
6966-6975. (b) Pedersen, M. L.; Berkowitz, D. B. Tetrahedron Lett. 1992,
33, 7315-7318. See also: (c) Columbo, L.; Di Giacomo, M.; Vinci, V.;
Columbo, M.; Manzoni, L.; Scolastico, C. Tetrahedron 2003, 59, 4501-
4513.
(15) For enantioselective syntheses of quaternary, R-vinyl AA’s, see:
(a) Ma, D.; Zhu, W. J. Org. Chem. 2001, 66, 348-350. (b) Berkowitz, D.
B.; McFadden, J. M.; Chisowa, E.; Semerad, C. L. J. Am. Chem. Soc. 2000,
122, 11031-11032. (c) Berkowitz, D. B.; McFadden, J. M.; Sloss, M. K.
J. Org. Chem. 2000, 65, 2907-2918. (d) Avenoza, A.; Cativiela, C.;
Corzana, F.; Peregrina, J. M.; Zurbano, M. M. J. Org. Chem. 1999, 64,
8220-8225. (e) Berkowitz, D. B.; Pumphrey, J. A.; Shen, Q. Tetrahedron
Lett. 1994, 35, 8743-8747 (f) Colson, P.-J.; Hegedus, L. S. J. Org. Chem.
1993, 58, 5918-5924. (g) Seebach, D.; Bu¨rger, H. M.; Schickli, C. P.
Liebigs Ann. Chim. 1991, 669-684. (h) Weber, T.; Aeschimann, R.;
Maetzke, T.; Seebach, D. HelV. Chim. Acta 1986, 69, 1365-1377. (i) Groth,
U.; Scho¨llkopf, U.; Chiang, Y.-C. Synthesis 1982, 864-866.
Should these issues be addressable, this synthetic strategy
would be redox-efficient in that the R-carboxyl group
oxidation state would be preserved throughout. This route
would also have the attractive feature of providing intermedi-
ate R-fluorovinylstannanes as potential vehicles for fluo-
rovinyl branch extension. Indeed, as can be seen from Table
1822
Org. Lett., Vol. 6, No. 11, 2004