CR-trifluoro- and difluoropyruvaldehyde AT,S-ketals: Chiral synthetic equivalents of β-trifluoro and β-difluoro α-amino aldehydes

Article abstract of DOI:10.1021/jo980602p

A new, efficient, and stereoselective two-step approach to stereochemically defined chiral nonracemic γ-tri- and γ-difluoro β-amino alcohols (70% to >95% ee) is described, using tri- and difluoropyruvaldehyde W,S-ketals (R)-la,b as starting materials. Addition of Grignard reagents to (R)-l occurs with moderate to excellent anfi-stereocontrol, depending on the nature of the organomagnesium halides, providing the β-p-tolylthio β-benzyloxycarbonylamino secondary carbinols 5. The stereochemical outcome of these reactions can be rationalized by means of a chelated Cram's cyclic model, where the NCbz group is the chelating ligand and the p-tolylthio residue acts as the stereocontrolling "large" group. Reductive displacement of the 2-p-tolylthio substituent of 5 efficiently takes places by means of the NaBH₄pyridine system, probably via the corresponding intermediate transient imines 13, providing sulfur-free γ-tri- and γ-difluorinated β-amino alcohols 7 with high levels of anii-stereoselectivity. A considerable shift toward syra-stereoselectivity was obtained performing the reaction on the corresponding phenylacetates 8. Cleavage and reduction of the NHCbz moiety of 7 provided tri- and difluoro analogues of, respectively, norephedrine (11) and ephedrine (12).

Full text of DOI:10.1021/jo980602p

7236
J . Org. Chem. 1998, 63, 7236-7243
(R)-Tr iflu or o- a n d Diflu or op yr u va ld eh yd e N,S-Keta ls: Ch ir a l
Syn th etic Equ iva len ts of â-Tr iflu or o a n d â-Diflu or o r-Am in o
Ald eh yd es†
Alessandro Volonterio, Barbara Vergani, Marcello Crucianelli, and Matteo Zanda*
Dipartimento di Chimica del Politecnico, Via Mancinelli 7, I-20131 Milano, Italy
Pierfrancesco Bravo*
C.N.R.-Centro di Studio per le Sostanze Organiche Naturali, Via Mancinelli 7, I-20131 Milano, Italy
Received April 1, 1998
A new, efficient, and stereoselective two-step approach to stereochemically defined chiral nonracemic
γ-tri- and γ-difluoro â-amino alcohols (70% to >95% ee) is described, using tri- and difluoro-
pyruvaldehyde N,S-ketals (R)-1a ,b as starting materials. Addition of Grignard reagents to (R)-1
occurs with moderate to excellent anti-stereocontrol, depending on the nature of the organo-
magnesium halides, providing the â-p-tolylthio â-benzyloxycarbonylamino secondary carbinols 5.
The stereochemical outcome of these reactions can be rationalized by means of a chelated Cram’s
cyclic model, where the NCbz group is the chelating ligand and the p-tolylthio residue acts as the
stereocontrolling “large” group. Reductive displacement of the 2-p-tolylthio substituent of 5
efficiently takes places by means of the NaBH4/pyridine system, probably via the corresponding
intermediate transient imines 13, providing sulfur-free γ-tri- and γ-difluorinated â-amino alcohols
7 with high levels of anti-stereoselectivity. A considerable shift toward syn-stereoselectivity was
obtained performing the reaction on the corresponding phenylacetates 8. Cleavage and reduction
of the NHCbz moiety of 7 provided tri- and difluoro analogues of, respectively, norephedrine (11)
and ephedrine (12).
In tr od u ction
zymes, or living microorganisms, including the use of
fluorinating agents, which are barely stereospecific.6
Because of their biological importance, a huge number
of well-established methods have been developed for the
synthesis of stereochemically defined chiral â-amino
alcohols, according to two distinct general strategies: (1)
the introduction of amino alcohol entities without altering
the molecular carbon framework;7 (2) the construction of
the amino alcohol array by C-C bond interconnection
between two building blocks.8 One of the most direct
retrosynthetic analyses of the problem, belonging to the
second group of methods, leads to a chiral R-amino
aldehyde and an appropriate nucleophile R- (retrosyn-
thetic scheme).
Selective introduction of one or more fluorine atoms
in natural or synthetic organic molecules can lead to a
profound modification of their chemical and physical
properties, as well as a dramatic change in biological
activity.1 Nowadays, a number of efficient methods are
available to the chemist for the synthesis of fluorinated
molecules, thanks to the impressive development of new
mild and chemoselective fluorinating agents, to the
increasing commercial availability of novel fluorinated
building blocks, and to the disclosure of new synthetic
approaches to easily accessible fluorinated templates.2 On
the other hand, despite the great impact of the “stereo-
chemical factor” in modern medicinal chemistry3 and the
preminent position of fluorinated molecules in the bio-
medicinal and pharmaceutical field,4 asymmetric syn-
thesis in the area of fluoroorganic chemistry is still poorly
developed.5 This is true both for the classical diastereo-
selective synthesis via chiral auxiliaries as well as for
the enantioselective approach via chiral catalysts, en-
Since chiral nonracemic R-amino aldehydes feature a
reasonable configurational stability when treated with
nucleophiles and can be readily prepared from the
corresponding R-amino acids, this approach meets with
(4) (a) Welch, J . T.; Eswarakrischnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Biomedicinal Aspects of
Fluorine Chemistry; Filler, R., Kobayashi, Y., Eds.; Kodansha: Tokyo,
1982. (c) Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. M.,
Eds.; Elsevier: Amsterdam, 1993. (d) Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J . R., Welch, J . T., Eds.; American
Chemical Society: Washington, D.C., 1996.
* To whom correspondence should be addressed. Fax: (39-2) 2399
3080. E-mail: zanda@dept.chem.polimi.it.
† Presented in part at the 15th International Symposium on Fluorine
Chemistry, Vancouver, Canada, August 2-7, 1997.
(1) (a) Banks, R. E.; Tatlow, J . C.; Smart, B. E. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press:
New York, 1994. (b) O’Hagan, D.; Rzepa, H. S. J . Chem. Soc., Chem.
Commun. 1997, 645.
(2) (a) Fluoroorganic Chemistry: Synthetic Challenges and Biomedi-
cal Rewards; Resnati, G., Soloshonok, V. A., Eds.; Tetrahedron
Symposium-in-Print no. 58; Tetrahedron 1996, 52, 1-330. (b) Fluorine-
Containing Amino Acids: Synthesis and Properties; Kukhar, V. P.,
Soloshonok, V. A., Eds.; Wiley: Chichester, 1994.
(5) (a) Resnati, G. Tetrahedron 1993, 49, 9385. (b) Enantiocontrolled
Synthesis of Fluoro-Organic Compounds, Tetrahedron: Asymmetry
Special Issue, Guest Editors: T. Hayashi and V. A. Soloshonok,
Tetrahedron: Asymmetry, 1994, 5, 955-1126. (c) Enantiocontrolled
Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges
and Biomedicinal Targets; Soloshonok, V. A., Ed.; Wiley: Chichester,
scheduled to appear in 1998.
(6) For some recent successful stereoselective fluorinations: (a)
Enders, D.; Potthoff, M.; Raabe, G.; Runsink, J . Angew. Chem., Int.
Ed. Engl. 1997, 36, 2362. (b) Davis, F. A.; Kasu, P. V. N.; Sundarababu,
G.; Qi, H. J . Org. Chem. 1997, 62, 7546. For a review: (c) Davis, F. A.;
Qi, H.; Sundarababu, G. in the book of ref 5c, 1st Chapter.
(3) Casy, A. F. The Steric Factor in Medicinal Chemistry. Dissym-
metric Probes of Pharmacological Receptors; Plenum Press: New York,
1993.
S0022-3263(98)00602-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/19/1998

(R)-Fluoropyruvaldehyde N,S-Ketals
J . Org. Chem., Vol. 63, No. 21, 1998 7237
Retrosynthetic Scheme
the R-proton being strongly acidic due to the presence of
fluorine.12 Furthermore, the preparation of â-fluoro
R-amino aldehydes is very troublesome, given the lack
of readily available precursors and appropriate synthetic
methodologies. Trifluoro-, difluoro-, and chlorodifluoro-
pyruvaldehyde N,S-ketals (R)-1a -c (Retrosynthetic
Scheme) represent a new class of readily available,
versatile and stereochemically stable equivalents of chiral
nonracemic â-fluoro R-amino aldehydes, recently synthe-
sized in our laboratories. Substrates (R)-1 are non-
enolizable, and therefore optically stable, since the p-
tolylthio substituent creates a quaternary R-stereogenic
center. In a later stage of the synthetic sequence, the
p-tolylthio residue can be stereoselectively substituted by
a hydrogen atom, providing the targeted γ-fluoro â-amino
alcohol frameworks. The p-tolylthio group plays the key-
role of a removable auxiliary function which acts as the
main stereocontrolling group as well.13
great success in asymmetric synthesis.9,10 In contrast,
the same strategy has never been successfully applied
in the field of organofluorine chemistry for the stereo-
selective synthesis of γ-fluoro â-amino alcohols, a poorly
developed class of molecules with great potential in
biomedicinal chemistry.11 In fact, â-fluoro R-amino al-
dehydes are expected to have high proclivity toward
racemization even in a very weakly basic environment,
(7) Catalytic asymmetric aminohydroxylation: (a) Reddy, K. L.;
Sharpless, K. B. J . Am. Chem. Soc. 1998, 120, 1207 and references
therein. Ring opening of epoxides with nitrogen-centered nucleo-
philes: (b) Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. J .
Org. Chem. 1997, 62, 4970 and references therein. (c) Leighton, J . L.;
J acobsen, E. N. J . Org. Chem. 1996, 61, 389. (d) Nagamitsu, T.;
Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler, P. A.; Smith, A. B.,
III. J . Am. Chem. Soc. 1996, 118, 3584. (e) Righi, G.; Rumboldt, G.;
Bonini, C. J . Org. Chem. 1996, 61, 3557. Reduction of R-hydroxy/alkoxy
imines or oximes: (f) Meunier, N.; Veith, U.; J a¨ger, V. J . Chem. Soc.,
Chem. Commun. 1996, 331 and references therein. (g) Shimizu, M.;
Tsukamoto, K.; Fujisawa, T. Tetrahedron Lett. 1997, 38, 5193. (h)
Kreutz, O. C.; Moran, P. J . S.; Rodrigues, J . A. R. Tetrahedron:
Asymmetry 1997, 8, 2649. Reduction of R-amino ketones: (i) Hoffman,
R. V.; Tao, J . J . Org. Chem. 1997, 62, 2292. (j) Paleo, M. R.; Sardina,
F. J . Tetrahedron Lett. 1996, 37, 3403. Hydroboration/oxidation of
enamines: (k) Fisher, B. G.; Goralski, C. T.; Nicholson, L. W.; Hasha,
D. L.; Zakett, D.; Singaram, B. J . Org. Chem. 1995, 60, 2026 and
references therein. Azide opening of cyclic diol-derived carbonates: (l)
Chang, H.-T.; Sharpless, K. B. Tetrahedron Lett. 1996, 37, 3219.
Coniugate addition of O-nucleophiles to nitroalkenes: (m) Lucet, D.;
Toupet, L.; Le Gall, T.; Mioskowski, C. J . Org. Chem. 1997, 62, 2682
and references therein. (n) Enders, D.; Haertwig, A.; Raabe, G.;
Runsink, J . Angew. Chem., Int. Ed. Engl. 1996, 35, 2388.
(8) For a general review on the addition of nucleophiles to CdN
bonds: (a) Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997,
8, 1895. See also: (b) Gennari, C.; Vulpetti, A.; Donghi, M.; Mongelli,
N.; Vanotti, E. Angew. Chem., Int. Ed. Engl. 1996, 35, 1723. Henry
(nitroaldol) reaction: (c) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki,
T.; Itoh, N.; Shibasaki, M. J . Org. Chem. 1995, 60, 7388. Condensation
of allylamino-boranes with aldehydes: (d) Barrett, A. G. M.; Seefeld,
M. A.; White, A. J . P.; Williams, D. J . J . Org. Chem. 1996, 61, 2677.
(e) Alkylation of glycol aldehyde hydrazones: Enders, D.; Reinhold:
U. Liebigs Ann. 1996, 11.
(9) For a general review on R-amino aldehydes: (a) Devant, R. M.;
Radunz, H.-E. In Houben-Weyl: Methods in Organic Synthesis; Mu¨ller,
E., Ed.; Thieme Verlag: Stuttgart, 1995; Vol. E21b, pp 1236-1248.
For a review on N-monoprotected R-amino aldehydes: (b) J urczak, J .;
Golebiowski, A. Chem. Rev. 1989, 89, 149. For recent papers: (c)
Curran, T. T. J . Org. Chem. 1993, 58, 6360. (d) J urczak, J .; Pro-
kopowicz, P.; Golebiowski, A. Tetrahedron Lett. 1993, 34, 7107. (e)
Baker, W. R.; Pratt, J . K. Tetrahedron 1993, 49, 8739. (f) Blaskovich,
M. A.; Lajoie, G. A. J . Am. Chem. Soc. 1993, 115, 5021. (g) J ones, D.
M.; Nilsson, B.; Szelke, M. J . Org. Chem. 1993, 58, 2286. (h) Shioiri,
T.; Hayashi, K.; Hamada, Y. Tetrahedron 1993, 49, 1913. (i) Vedejs,
E.; Moss, W. O. J . Am. Chem. Soc. 1993, 115, 1607. (j) Parkes, K. E.
B.; Bushnell, D. J .; Crackett, P. H.; Dunsdon, S. J .; Freeman, A. C.;
Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin, J . A.; Merrett,
J . H.; Redshaw, S.; Spurden, W. C.; Thomas, G. J . J . Org. Chem. 1994,
59, 3656. (k) Kiyooka, S.; Shiomi, Y.; Kira, H.; Kaneko, Y.; Tanimori,
S. J . Org. Chem. 1994, 59, 1958. (l) Reetz, M. T.; Ro¨lfing, K.; Griebenow,
N. Tetrahedron Lett. 1994, 35, 1969. (m) Ciapetti, P.; Taddei, M.; Ulivi,
P. Tetrahedron Lett. 1994, 35, 3183. (n) Niel, G.; Roux, F.; Maisonnasse,
Y.; Maugras, I.; Poncet, J .; J ouin, P. J . Chem. Soc., Perkin Trans. 1
1994, 1275. (o) Dondoni, A.; Perrone, D.; Merino, P. J . Org. Chem. 1995,
60, 8074. (p) Palomo, C.; Miranda, J . C.; Cuevas, C.; Odriozola, J . M.
J . Chem. Soc., Chem. Commun. 1995, 1735. (q) Campbell, J . A.; Lee,
W. K.; Rapoport, H. J . Org. Chem. 1995, 60, 4602. (r) Ciapetti, P.;
Falorni, M.; Taddei, M. Tetrahedron 1996, 52, 7379. (s) Castejo´n, P.;
Moyano, A.; Perica`s, M. A.; Riera, A. Chem. Eur. J . 1996, 2, 1001. (t)
Ambroise, L.; J ackson, R. F. W. Tetrahedron Lett. 1996, 37, 2311. (u)
Bastiaans, H. M. M.; van der Baan, J . L.; Ottenheijm, H. C. J . J . Org.
Chem. 1997, 62, 3880. (v) Panek, J . S.; Liu, P. Tetrahedron Lett. 1997,
38, 5127. (w) Veeresha, G.; Datta, A. Tetrahedron Lett. 1997, 38, 5223.
(x) Gryko, D.; Urbanczyk-Lipkowska Z.; J urczak, J . Tetrahedron:
Asymmetry 1997, 8, 4059. (y) Ru¨bsam, F.; Seck, S.; Giannis, A.
Tetrahedron 1997, 53, 2823. (z) Braun, M.; Opdenbusch, K. Liebigs
Ann. 1997, 141. See also ref 12c and ref 13f.
In this paper we describe in detail the use of tri- and
difluoropyruvaldehyde N,S-ketals (R)-1a ,b, for the ste-
reoselective approach to biologically interesting fluoro-
(10) For a review on N,N-diprotected R-amino aldehydes: (a) Reetz,
M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531. For other
examples: (b) Bubert, C.; Reiser, O. Tetrahedron Lett. 1997, 38, 4985.
(c) Takikawa, H.; Maeda, T.; Seki, M.; Koshino, H.; Mori, K. J . Chem.
Soc., Perkin Trans. 1 1997, 97. (d) O’Brien, P.; Powell, H. R.; Raithby,
P. R.; Warren, S. J . Chem. Soc., Perkin Trans. 1 1997, 1031. (e) Gryko,
D.; Urbanczyk-Lipkowska, Z.; J urczak, J . Tetrahedron 1997, 53, 13373.
(f) Shimizu, M.; Wakioka, I.; Fujisawa, T. Tetrahedron Lett. 1997, 38,
6027. (g) Hanessian, S.; Park, H.; Yang, R. Y. Synlett 1997, 353 and
references therein. (h) La¨ıb, T.; Chastanet, J .; Zhu, J . Tetrahedron Lett.
1997, 38, 1771. (i) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno,
H.; Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N. J . Org.
Chem. 1997, 62, 999. (j) Gryko, D.; J urczak, J . Tetrahedron Lett. 1997,
38, 8275. (k) D’Aniello, F.; Falorni, M.; Mann, A.; Taddei, M. Tetra-
hedron: Asymmetry 1996, 7, 1217. (l) Dinh, T. Q.; Du, X.; Armstrong,
R. W. J . Org. Chem. 1996, 61, 6606. (m) Andre´s, J . M.; Barrio, R.;
Mart´ınez, M. A.; Pedrosa, R.; Pe´rez-Encabo, A. J . Org. Chem. 1996,
61, 4210. (n) Williams, L.; Zhang, Z.; Shao, F.; Carroll, P. J .; J oullie´,
M. M. Tetrahedron 1996, 52, 11673. (o) Gennari, C.; Pain, G.; Moresca,
D. J . Org. Chem. 1995, 60, 6248. (p) Marshall, J . A.; Seletsky, B. M.;
Coan, P. S. J . Org. Chem. 1994, 59, 5139. (q) Garner, P.; Park, J .-M.
Org. Synth. 1991, 70, 18.
(11) (a) Be´gue´, J .-P.; Bonnet-Delpon, D. in the book of ref 4d;
Chapter 4, pp 59-72. (b) Ojima, I.; Kuduk, S. D.; Slater, J . C.; Gimi,
R. H.; Sun, C. M.; Chakravarty, S.; Ourevitch, M.; Abouabdellah, A.;
Bonnet-Delpon, D.; Be´gue´, J .-P.; Veith, J . M.; Pera, P.; Bernacki, R. J .
in the book of ref 4d; Chapter 17, pp 228-243. (c) Marti, R. E.; Heinzer,
J .; Seebach, D. Liebigs Ann. 1995, 1193. (d) Beck, A. K.; Seebach, D.
Chem. Ber. 1991, 124, 2897. (e) Abouabdellah, A.; Be´gue´, J .-P.; Bonnet-
Delpon, D.; Thanh Nga, T. T. J . Org. Chem. 1997, 62, 8826. (f) Ojima,
I.; Slater, J . C.; Pera, P.; Veith, J . M.; Abouabdellah, A.; Be´gue´, J .-P.;
Bernacki, R. J . Bioorg. Med. Chem. Lett. 1997, 7, 133. (g) Bravo, P.;
Farina, A.; Kukhar, V. P.; Markovsky, A. L.; Meille, S. V.; Soloshonok,
V. A.; Sorochinsky, A. E.; Viani, F.; Zanda, M.; Zappala`, C. J . Org.
Chem. 1997, 62, 3424. (h) Uneyama, K.; Hao, J .; Amii, H. Tetrahedron
Lett. 1998, 39, 4079.
(12) (a) Konno, T.; Yamazaki, T.; Kitazume, T. Tetrahedron 1996,
52, 199. (b) Hedhli, A.; Baklouti, A.; Cambon, A. Tetrahedron Lett.
1994, 35, 6877. (c) Angert, H.; Czerwonka, R.; Reissig, H.-U. Liebigs
Ann. 1997, 2215.
(13) For some examples on the use of R-thio aldehydes in asymmetric
synthesis: (a) Eames, J .; de las Heras, M. A.; Warren, S. Tetrahedron
Lett. 1996, 37, 4077 and references therein. (b) Eames, J .; J ones, R.
V. H.; Warren, S. Tetrahedron Lett. 1996, 37, 4823. (c) Sato, T.; Otera,
J . Synlett 1995, 351. (d) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi,
P. G.; Consolandi, E. J . Org. Chem. 1992, 57, 456. (e) Shimagaki, M.;
Maeda, T.; Matsuzaki, Y.; Hori, I.; Nakata, T.; Oishi, T. Tetrahedron
Lett. 1984, 25, 4775 (f) Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.;
Crasto, C. F.; Schomer, W. W. J . Org. Chem. 1997, 62, 4293. (g) Enders
D.; Piva, O.; Burkamp, F. Tetrahedron 1996, 52, 2893. (h) Frye, S. V.;
Eliel, E. L. J . Am. Chem. Soc. 1988, 110, 484. (i) Annunziata, R.;
Cinquini, M.; Cozzi, F.; Fuchicello, A. Tetrahedron 1991, 47, 3853. (j)
Antolini, L.; Bellesia, F.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. Gazz.
Chim. Ital. 1997, 127, 11. (k) Watanabe, M.; Komota, M.; Nishimura,
M.; Araki, S.; Butsugan, Y. J . Chem. Soc., Perkin Trans. 1 1993, 2193;
corrigenda: J . Chem. Soc., Perkin Trans. 1 1993, 3177. (l) Brown, M.
D.; Witham, G. H. J . Chem. Soc., Perkin Trans. 1 1988, 817. (m)
Hoffmann, R. W.; Kemper, B. Tetrahedron Lett. 1980, 21, 4883. (n)
Shimagaki, M.; Takubo, H.; Oishi, T. Tetrahedron Lett. 1985, 26, 6235.

7238 J . Org. Chem., Vol. 63, No. 21, 1998
Volonterio et al.
Sch em e 1. P r ep a r a tion of F lu or op yr u va ld eh yd e
Sch em e 2. Rea ction of F lu or op yr u va ld eh yd e
N,S-Keta ls (R)-1
N,S-Keta ls (R)-1 w ith Gr ign a r d Rea gen ts
Ta ble 1. Rea ction of F lu or op yr u va ld eh yd e N,S-k eta ls
(R)-1 w ith Gr ign a r d Rea gen ts
entry product
X
R
RF
anti/ syna yields (%)b
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Cl CH3
Br CH2CH3
Br CHdCH2 CF3
Cl Ph
Cl CH3
Cl Ph
CF3
CF3
17:1
4:1
36:1
7:1
8:1
10:1
72
72
94
90
75
90
CF3
CHF2
CHF2
a
b
Determined by 1H and 19F NMR. Isolated overall yields of
the diastereoisomers anti- and syn-5.
organic molecules having a γ-tri- and γ-difluoro â-amino
alcohol unit, for example analogues of Ephedra alka-
loids.14 As a further matter of interest, the peculiar
reactivity of tri- and difluoropyruvaldehyde N,S-ketals
(R)-1a ,b toward Grignard reagents allowed us to compare
directly, for the first time, the relative stereodirecting
properties of an arylthio group, a monoprotected amino
group, and a fluoroalkyl group.
methods.19 Fluoropyruvaldehyde N,S-ketals (R)-1a -c
are now available with ee ranging from 82% (the trifluoro
derivative (R)-1a ) to 72% (the difluoropyruvaldehyde (R)-
1b).
Rea ction w ith Gr ign a r d r ea gen ts. Tr iflu or o De-
r iva tives. Addition of a THF solution of methylmag-
nesium chloride (3.0 equiv) to a solution of trifluoro-
pyruvaldehyde N,S-ketal (R)-1a , in the same solvent at
-78 °C, gave rise to a fast reaction, affording with high
diastereoselectivity (17:1) and good yields (72%) the
corresponding carbinol anti-5a (Scheme 2 and Table 1,
entry 1).20 Ethyl, vinyl-, and phenylmagnesium halides
(Scheme 2 and Table 1, entries 2-4) efficiently added to
the aldehyde (R)-1a , upon slow addition of a THF solution
of (R)-1a to the solution of Grignard reagent (3.0 equiv)
in the same solvent,21 producing the corresponding
carbinols anti-5 as major diastereomers. Ethylmag-
nesium bromide (Table 1, entry 2) added with moderate
facial diastereoselectivity, producing a 4:1 mixture of
isomers anti/ syn 5b. Vinylmagnesium bromide (Table
1, entry 3) produced the highest discrimination between
the two carbonylic diastereofaces of (R)-1a , leading to the
formation of the allylic alcohol anti-5c with ca. 95% de,
in almost quantitative yield. The reaction of (R)-1a with
phenylmagnesium chloride was of particular interest, as
the benzyl carbinols 5d are precursors of trifluoro
analogues of Ephedra alkaloids, molecules of remarkable
biological and pharmaceutical interest.11c,d Satisfactorily,
the reaction (Table 1, entry 4) occurred smoothly, as
usual, affording the desired products 5d in anti/ syn 7:1
ratio and 90% yield.
Resu lts
P r ep a r a tion of F lu or op yr u va ld eh yd e N,S-Keta ls.
Fluoropyruvaldehyde N,S-ketals (R)-1a -c (Scheme 1)
can be prepared in three steps from fluoroacetic esters,
which are commercially available and cheap fluorine
sources, and (R)-methyl p-tolyl sulfoxide, which is also
an easily available chiral building-block.15
Condensation of lithiated (R)-methyl p-tolyl sulfoxide
and fluoroacetic esters afforded high yields of the corre-
sponding R-fluoro R′-sulfinyl ketones (R)-2a -c,16 which
were transformed in good yields into geometrically
homogeneous cis-R-(fluoroalkyl)-â-sulfinyl enamines (R)-
3a -c by reaction with N-Cbz iminotriphenylphos-
phorane.17 A highly enantioselective tandem Pummerer
reaction/1,2-migration of the p-tolylthio group, which
produced in one-pot the target fluoropyruvaldehyde N,S-
ketals (R)-1a -c from the enamines (R)-3a -c, through
the intermediate imine (R)-4a -c, is the last step of the
sequence.18 This tandem reaction is operatively simple,
fast, and requires nonexotic and inexpensive reagents,
namely 1 equiv of trifluoroacetic anhydride, which pro-
motes the Pummerer rearrangement (step 1), and silica
gel or aqueous NaHCO3, which trigger the suprafacial
migration of the p-tolylthio residue to give the desired
fluoropyruvaldehyde N,S-ketals (R)-1a -c (step 2). Very
recently the enantioselectivity of the process has been
further improved and optimized by means of chemometric
The ee’s of the major anti â-amino alcohols 5a ,c were
checked by esterification with both enantiomers of R-phen-
ylpropionic acid (PPA), producing the corresponding
diastereomeric R-PPA esters (6a ,c).22 Careful examina-
(14) Volonterio, A.; Bravo, P.; Capelli, S.; Meille, S. V.; Zanda, M.
Tetrahedron Lett. 1997, 38, 1847.
(15) Bravo, P.; Crucianelli, M.; Fronza, G.; Zanda, M. Synlett 1996,
249.
(16) (a) Bravo, P.; Piovosi, E.; Resnati, G. Synthesis 1986, 579. (b)
Bravo, P.; Zanda, M. “Asymmetric Synthesis of Fluoro-Organic Com-
pounds via Chiral Sulfoxide Chemistry” in the book of ref 5c, Chapt.
4.
(17) (a) Bravo, P.; Crucianelli, M.; Zanda, M. Tetrahedron Lett. 1995,
36, 3043. (b) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S.
V.; Zanda, M.; Cavicchio, G.; Crucianelli, M. J . Org. Chem. 1996, 61,
3375; corrigenda: J . Org. Chem. 1996, 61, 9635.
(18) Volonterio, A.; Zanda, M.; Bravo, P.; Fronza, G.; Cavicchio, G.;
Crucianelli, M. J . Org. Chem. 1997, 62, 8031.
(19) Bjørsvik, H.-R.; Bravo, P.; Crucianelli, M.; Volonterio, A.; Zanda,
M. Tetrahedron: Asymmetry 1997, 8, 2817.
(20) In this paper, syn and anti descriptors refer to the relative
position of the amino and the hydroxy groups with respect to the
molecular carbon backbone.
(21) Inverse addition of THF solutions of ethyl, vinyl, and phenyl
Grignard reagents to (R)-1a in the same solvent invariably produced
low amounts of the corresponding carbinols 5b-d together with
partially racemized, unreacted starting pyruvaldehyde (R)-1a , even
after prolonged reaction time and heating to room temperature.
(22) (a) Helmchen, G.; Nill, G.; Flockerzi, D.; Schuhle W.; Youssef,
M. S. K. Angew. Chem., Int. Ed. Engl. 1979, 18, 62-63. (b) Bravo, P.;
Ganazzoli, F.; Resnati, G.; De Munari, S.; Albinati, A. J . Chem. Res.
1988, (S) 216, (M) 1701.

(R)-Fluoropyruvaldehyde N,S-Ketals
J . Org. Chem., Vol. 63, No. 21, 1998 7239
1
Sch em e 3. Ster eoselective Red u ctive
Desu lfen yla tion
tion of the corresponding crude reaction mixtures by H
and 19F NMR allowed us to assess that no loss of
enantiomeric purity had occurred during the addition of
methyl and vinyl Grignard reagents to (R)-1a . In fact,
the de of 6a ,c were almost identical to the ee of the
starting (R)-1a .
Absolute and relative stereochemistry of the major
methyl carbinol anti-5a was determined by X-ray dif-
fraction of its (+)-(S)-PPA ester 6a .14 Absolute (S)-
stereochemistry of the carbinolic center C-1 of the major
derivative anti-5c was determined by NMR analysis of
its (R)- and (S)-PPA esters 6c.22,23 Anti-(1S,2R) stereo-
chemistry was confidently assigned to the major dia-
stereoisomer of ethyl and phenyl derivatives 5b,d on the
basis of their 19F NMR spectra (stereochemistry of 5d was
later confirmed by chemical correlation, as shown below).
In fact, the 19F NMR signals of the trifluoromethyl groups
of the major diastereoisomers 5a -d were always ob-
served at lower fields than those of the minor dia-
stereomers (see Experimental Section and Supporting
Information). A similar trend has been already described
for the 19F NMR spectra of a closely related series of anti-
and syn-γ-trifluoro â-amino alcohols.11c,d
state, but, surprisingly, N,S-ketalic centers C-2 of 5e,f,
were found to be configurationally unstable in solution
of HPLC grade AcOEt at room temperature. For ex-
ample, in these conditions an anti/ syn 10:1 mixture of
5f epimerized completely overnight, producing a 1:1
mixture of diastereomers. In contrast, no epimerization
took place either in CHCl3 solution even after several
days at room temperature, or under reaction conditions
in the presence of the Grignard reagent. The latter point
was checked by performing two parallel reactions be-
tween (R)-1b and phenylmagnesium chloride, lasting,
respectively, 5 and 30 min, which produced the same 10:1
ratio of anti and syn diastereomers 5f (see Table 1, entry
6).
Ster eoselective Red u ctive Desu lfen yla tion . Pur-
suing the goal to obtain stereoselectively sulfur-free
γ-fluoro â-amino alcohols from the adducts 5d ,f, we
turned our attention to the problem of the stereocon-
trolled replacement of the p-tolylthio group with a
hydrogen atom.26 Inspection of the literature revealed
a report by Tsuchihashi and Ogura (1975) on the
reductive removal of a SCH3 group from racemic N,S-
ketals by means of a NaBH4/pyridine system.27 We
therefore decided to submit anti-5d to the same condi-
tions. The substrate was dissolved in pyridine, and 5
equiv of NaBH4 were added portionwise at 0 °C during 3
h, producing a 12:1 mixture of anti/ syn diastereomeric
N-Cbz γ-trifluoro â-amino alcohols 7a ,28 in 70% yield
(Scheme 3). With this excellent result in hand, we
repeated the protocol on the difluoro derivative anti-5f.
The reaction was very smooth, reaching completion in a
few minutes, delivering the desired N-Cbz γ-difluoro
3,3,3-Trifluoro-2-NHCbz-2-p-tolylthio alcohols 5a -d
are stable compounds, both chemically and optically: no
deterioration was detected after several months of stor-
age at 4 °C, as well as after a prolonged stay in chloro-
form or AcOEt solution at room temperature.
Diflu or o Der iva tives. Next, we examined the reac-
tivity of the difluoropyruvaldehyde N,S-ketal (R)-1b
toward Grignard reagents (Scheme 2, Table 1), to extend
the methodology to the synthesis of chiral nonracemic
γ-difluoro â-amino alcohols. Addition of a THF solution
of difluoropyruvaldehyde (R)-1b to a solution of methyl-
magnesium chloride (3.0 equiv) (Table 1, entry 5), in the
same solvent, at -78 °C, provided the corresponding
difluoro carbinol anti-5e, in 75% yield and 8:1 dr.
The reaction of difluoro pyruvaldehyde (R)-1b with
phenylmagnesium chloride (3.0 equiv) (Table 1, entry 6)
was of particular synthetic interest, since the product 5f
could be used as a synthetic intermediate for the syn-
thesis of difluoro analogues of Ephedra alkaloids. Sat-
isfactorily, the reaction proved to be a high yielding (90%)
and remarkably stereoselective process (10:1 anti/ syn).
In contrast with the trifluoro derivatives (entries 1-4,
Table 1), a partial loss of enantiomeric purity with respect
to the starting difluoro aldehyde (R)-1b was evidenced
by NMR analysis of anti-5f with the chiral shift reagent
Eu(hfc)3. Starting from a sample of difluoro aldehyde (R)-
1b with 61% ee, we obtained mixtures of diastereomeric
5f having 50% ee, independently of the reaction time.
This must be necessarily explained in terms of a partial
racemization occurring at the level of the starting dif-
luoropyruvaldehyde (R)-1b, catalyzed by the Grignard
reagents, in competition with the desired 1,2-addition
reaction.24,25
(25) The higher configurational and chemical stability featured by
the sp3 N,S-ketalic stereocenters C-2 of all trifluoro derivatives studied
in this work, with respect to the corresponding difluoro derivatives,
should be due to the stronger electron-withdrawing effect of the
trifluoromethyl group. For other examples of stable acyclic R-trifluo-
romethyl N,S-ketals see: Laduron, F.; Ates, C.; Viehe, H. G. Tetrahe-
dron Lett. 1996, 37, 5515.
In analogy with the corresponding trifluoro derivatives
5a -d , 3,3-difluoro-2-NHCbz-2-p-tolylthio alcohols 5e,f
are stable compounds, when stored in chemically pure
(26) Initial attempts to accomplish this transformation on the
trifluorobenzyl alcohol anti-5d by means of the classical hydrogenolysis
catalyzed by Raney-Ni produced very low yields of an almost equimolar
mixture of the corresponding sulfur-free diastereomeric N-Cbz â-amino
alcohols 7a .
(27) Ogura, K.; Yoshimura, I.; Katoh, N.; Tsuchihashi, G. Chem. Lett.
1975, 803.
(23) The δH of the CH)CH2 of (1S,2R,2′R)-6c resonates at higher
fields (5.76-5.95 ppm) with respect to the corresponding signal of
(1S,2R,2′S)-6c (5.84-6.03 ppm), because of the shielding effect exerted
by the phenyl ring of the PPA residue (see Supporting Information).
(24) Such racemization should occur by addition-elimination of
p-thiocresol from 1b, through the transient N-Cbz ketimine of difluo-
ropyruvaldehyde.
(28) anti-7a is a known compound: see ref 11 g.

7240 J . Org. Chem., Vol. 63, No. 21, 1998
Volonterio et al.
Sch em e 4. Syn th esis of F lu or in a ted Eph ed r a
â-amino alcohols 7b in anti/ syn 3:1 ratio and quantita-
tive yield.
Alk a loid s
To examine the effect of the hydroxyl on the diastereo-
selectivity of the reductive desulfenylation, as well as the
possibility of achieving inversion as the stereochemical
outcome of the process, for preparing γ-fluoro â-amino
alcohols of the syn series, we addressed the preparation
of the phenylacetic esters 8a ,b. High yields of these
compounds were obtained by treatment of the carbinols
anti-5d ,f with DCC/phenylacetic acid (Scheme 3). In
contrast, attempts to prepare the corresponding benzo-
ates, under the same conditions, were surprisingly
unsuccessful, the reaction being very slow.
Trifluoro ester anti-8a underwent desulfenylation with
NaBH4/pyridine under the conditions described for the
corresponding carbinol anti-5d , producing the desired
transformation with slightly higher yields, but with a
dramatic drop of diastereoselectivity. In fact, the dia-
stereomeric phenylacetoxy γ-trifluoro â-amino derivatives
9a were formed in 75% yield, as an almost equimolar
anti/ syn mixture. The same procedure, applied on the
difluoro ester anti-8b (Scheme 3), led to a clear-cut
inversion of diastereoselectivity, with respect to the
desulfenylation of the corresponding carbinol anti-5f.
Thus, the desired syn phenylacetoxy γ-difluoro â-NHCbz
derivative 9b was produced with 50% de, in quantitative
overall yield.
Stereochemistry of the diastereomeric difluorinated
phenylacetates 9b was determined by correlation with
the corresponding unprotected derivatives 7b (Scheme
3). Thus, esterification of anti-7b with phenylacetic acid/
DCC produced the minor diastereomer obtained by
desulfenylation of 8b. Ee’s of the major diastereomeric
γ-tri- and γ-difluoro â-amino alcohols 7a ,b were checked
by esterification with both enantiomers of PPA, leading
to the corresponding R-phenylpropionates (10a ,b), and
subsequent analysis of the crude reaction mixtures.
Starting from a sample of trifluoropyruvaldehyde (R)-
1a having 70% ee, N-Cbz trifluoronorephedrine anti-7a
was obtained with essentially the same degree of enan-
tiomeric purity. Starting from a difluoropyruvaldehyde
(R)-1b with 61% ee, N-Cbz difluoro norephedrine anti-
7b was obtained with 50% ee, owing to partial epimer-
ization of (R)-1b by action of phenylmagnesium chloride
(see above). Samples of N-Cbz difluoronorephedrine anti-
7b with ee > 95% were obtained easily by fractional
crystallization from diisopropyl ether.
Syn th esis of F lu or in a ted Eph ed r a -Alk a loid s. The
final step of the synthesis of the targeted fluorinated
Ephedra alkaloids was performed by means of simple
manipulations of the N-Cbz residue of trifluoro and
difluoro N-Cbz norephedrines 7a ,b (Scheme 4).
Trifluoronorephedrine anti-11a , having 70% ee, was
obtained from anti-7a in quantitative yield by hydro-
genolysis of the N-Cbz group with H2/Pd(OH)2. Trifluo-
roephedrine anti-12a (70% ee) was isolated in 86% yield
after reduction of the N-Cbz group with LiAlH4 in
refluxing THF. The same protocols, applied on enantio-
pure N-Cbz difluoronorephedrine anti-7b (ee > 95%),
produced difluoronorephedrine anti-11b (quantitative)
and difluoroephedrine anti-12b (25%) in enantiomerically
pure form.
recently reported from these laboratories.11g Further
evidence was obtained by comparison of the spectral
features of anti- and syn-11a with those reported by
Seebach for the racemic compounds.11c,d Trifluoronor-
pseudoephedrine syn-11a was obtained from a pure
sample of syn-7a (Scheme 4). As expected, the spectral
properties of both diastereomers anti- and syn-11a were
found to match those reported in the literature.
With the hope of confirming the stereochemistry of
both diastereomeric difluoro derivatives anti- and syn-
11b, a 3:1 mixture of these compounds was obtained by
hydrogenolysis of a mixture of anti and syn N-Cbz
difluoro derivatives 7b, having the same dr (Scheme 4).
Next, we compared the spectral properties of both dia-
stereomers 11b with the corresponding trifluoro deriva-
tives 11a , having known stereochemistry. Both the
major trifluoro and difluoro diastereomers 11a ,b were
found to feature a higher value of J H1-H2 with respect to
the minor diastereomers (Scheme 4), strongly suggesting
that the major diastereomer 11b should be difluoro-
norephedrine, having anti-(1S,2S) stereochemistry, where-
as the minor diastereomer should be difluoronorpseudo-
ephedrine syn-(1S,2R)-11b, in analogy with the triflu-
orinated derivatives 11a .
Discu ssion
Rea ction w ith Gr ign a r d Rea gen ts: A Mod el for
th e F a cia l Dia ster eoselectivity. On considering what
factors determine the stereochemical outcome of the
addition of Grignard reagents to fluoropyruvaldehydes
(R)-1, it should be noted (Scheme 2) that 3 equiv of
Grignard reagents are necessary for obtaining a complete
conversion of (R)-1 into the secondary carbinols 5. This
observation is in line with the literature reports on the
behavior of N-monoprotected R-amino aldehydes, which
are known to undergo removal of the acidic aminic proton
when submitted to reactions with basic nucleophiles.9a,b
The resulting salts are proposed to react with an excess
of nucleophile through a Cram’s cyclic five-membered
chelated structure,29 involving the counterion, the car-
bonylic oxygen, and the nitrogen in the R-position (Figure
1).
The absolute and relative stereochemistry of trifluo-
ronorephedrine anti-(1S,2S)-11a was assessed by com-
parison with a sample of the enantiomer anti-(1R,2R)-
11a , obtained through a different synthetic strategy,
(29) Cram, D. J .; Wilson, D. R. J . Am. Chem. Soc. 1963, 85, 1245.

(R)-Fluoropyruvaldehyde N,S-Ketals
J . Org. Chem., Vol. 63, No. 21, 1998 7241
F igu r e 1. Model for the facial diastereoselectivity of the
reaction of (R)-1 with Grignard reagents.
F igu r e 2. Model for the facial diastereoselectivity of the
reduction of the intermediate imines (S)-13.
Sch em e 5. Mech a n ism of th e Red u ctive
Desu lfen yla tion
5d ,f dissolved in pyridine, or Hunig’s base (see Support-
ing Information) at room temperature, underwent epimer-
ization of the ketalic center; (2) interconversion between
the diastereoisomers anti and syn-5f was clearly detected
by TLC analysis during the reaction, before the irrevers-
ible reductive desulfenylation took place; (3) reduction
of diastereomerically pure â-hydroxy ketals anti-5d ,f, as
well as of mixtures of syn/ anti isomers, afforded the same
degree of diastereoselectivity, when submitted to the
NaBH4/pyridine treatment, independent of the stereo-
chemistry of the starting materials (Scheme 5). By
analogy, the same process should be operating in the
reductive desulfenylation of phenylacetic esters 8a ,b.
The high level of anti selectivity featured by the CF3-
ketal 5d could be explained by means of the Felkin-Anh
model depicted in Figure 2A.32 The staggered position
should be occupied by the phenyl ring, and attack of the
hydride should therefore occur from the Re face of the
imine, with the hydroxyl acting as the “medium” group
and, obviously, the hydrogen as the “small” group.
Further stabilization of this conformation might derive
from hydrogen bonding involving the hydroxyl and the
iminic nitrogen, or the carbonyl oxygen of Cbz. The
major steric and electronic interactions should involve
the incoming hydride reducing species and the RF groups
attached to the azomethine function.32 This could rea-
sonably explain the fact that the substrate 5d undergoes
reductive desulfenylation with higher anti diastereo-
selectivity (12:1) than does 5f (3:1). In fact, the former
has RF ) CF3, which is known to be more electron-
withdrawing, and more sterically demanding owing to
Attack of the Grignard reagents to the Si face of the
carbonyl group of (R)-1 must therefore occur from the RF
group side, with the p-tolylthio group behaving as the
large substituent, which occupies the staggered position
(Figure 1). This hypothesis is also supported by the X-ray
diffraction of a single crystal of racemic difluoropyruv-
aldehyde 1b.30 Although it is clear that the situation of
1b in the solid state cannot be directly transferred to the
case of its magnesium salt dissolved in THF, it is worth
noting that the conformation of 1b in a crystal grown
from diisopropyl ether is very close to the conformation
represented in Figure 1. Finally, this picture is also
supported by the quite popular assumption that the
trifluoromethyl group should be “similar in size” to the
isopropyl group.31 Since some authors reported that an
arylthio residue is remarkably “larger” than the isopropyl
group,13d,e as a logical consequence, attack of the Grignard
reagents from the fluoroalkyl group side (Si face) of (R)-1
is expected to be strongly preferred over the attack from
the p-tolylthio group side (Re face), in agreement with
the experimental findings.
A Ra tion a le for th e Red u ctive Disp la cem en t of
th e p-Tolylth io Gr ou p . The mechanism of the dis-
placement of the p-tolylthio group by action of NaBH4 in
pyridine has been investigated in detail. The first step
of the process should be the elimination of p-thiocresol
from the N,S-ketalic center C-2 of anti-5d ,f, promoted
by pyridine, producing the corresponding transient N-Cbz
imines (S)-13 (Scheme 5), which, according to this
picture, should be the true reactive species toward
NaBH4.
its uniform fluorinated surface, than the residue RF
)
CHF2 of the latter.31
Transformation of the hydroxyl into a phenylacetoxy
residue should result in increasing electron-withdrawing
character and steric hindrance of this group, as well as
eliminating any hydrogen bonding. For these reasons,
the reactive conformation having the phenylacetoxy
group in staggered position (“large” residue) (Figure 2B)
should become competitive, leading to a considerable
increase of syn diastereoselectivity. This hypothesis
accounts for the observed lack of facial diastereocontrol
in the reductive desulfenylation of the phenylacetoxy
trifluoro derivative anti-8a (Scheme 3), and for the syn
facial diastereoselectivity (3:1) featured by the corre-
sponding difluorinated ester anti-8b.
This pathway is in agreement with several experimen-
tal observations: 1) diastereomerically pure anti-ketals
Con clu sion s
(30) Bravo, P.; Capelli, S.; Meille, S. V.; Zanda, M. Manuscript in
preparation.
The synthetic methodology described in this paper
(31) (a) Smart, B. E. in the book of ref 1a; Chapter 3, pp 80-81,
and references therein. See also ref 1b and 12a. For a discussion on
the stereolectronic effects of some perfluoroalkyl substituents in
asymmetric transformations see: (b) Schlosser, M.; Michel, D. Tetra-
hedron 1996, 52, 99. (c) Soloshonok, V. A.; Kacharov, A. D.; Avilov, D.
V.; Ishikawa, K.; Nagashima, N.; Hayashi, T. J . Org. Chem. 1997, 62,
3470. (d) Nagai, T.; Nishioka, G.; Koyama, M.; Ando, A.; Miki, T.;
Kumadaki, I. Chem. Pharm. Bull. 1991, 39, 233. (e) Ramachandran,
P. V.; Teodorovic, A. V.; Gong, B.; Brown, H. C. Tetrahedron: Asym-
metry 1994, 5, 1075 and refs therein.
demonstrates that fluoropyruvaldehyde N,S-ketals (R)-1
(32) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
9, 2199. (b) Anh, N. G.; Eisenstein, O. Tetrahedron Lett. 1976, 17, 155.
(c) Paddon-Row: M. N.; Rondan, N. G.; Houk, K. N. J . Am. Chem.
Soc. 1982, 104, 7162. (d) Wong, S. S.; Paddon-Row: M. N. J . Chem.
Soc., Chem. Commun. 1990, 456. (e) Bu¨rgi, H. B.; Dunitz, J . D.; Lehn,
J . M.; Wipf, G. Tetrahedron 1974, 30, 1563. (f) Evans, D. A.; Dart, M.
J .; Duffy, J . L.; Yang, M. G. J . Am. Chem. Soc. 1996, 118, 4322.

7242 J . Org. Chem., Vol. 63, No. 21, 1998
Volonterio et al.
141.7, 138.1, 135.3, 130.3, 128.8, 128.7, 122.7 (q, J ) 287 Hz),
120.7, 72.8 (q, J ) 28.9 Hz), 67.9, 21.4; MS (EI, 70 eV) m/ z
are useful chiral nonracemic electrophilic building blocks,
which can be used successfully for the stereoselective
synthesis of γ-fluoro â-amino alcohols of biological inter-
est. The N,S-ketalic stereocenter of (R)-1 is a stereogenic
masked electrophilic site, which effectively induces ste-
reocontrol in the 1,2-addition of Grignard reagents to the
carbonyl moiety. In a later stage of the synthetic
sequence the p-tolylthio group can be stereoselectively
replaced with a hydrogen, affording sulfur-free, stereo-
chemically defined γ-fluoro â-amino alcoholic units. The
whole process features high yields, cheap and nonexotic
reagents, operationally simple procedures, and mild
conditions. These considerations suggest that fluoro-
pyruvaldehyde N,S-ketals (R)-1 could find many further
useful applications in the field of asymmetric organo-
fluorine synthesis.
(%): 383 (M+, 8), 124 (35), 91 (100). Anal. Calcd for C18H16
-
NO3F3S: C, 56.39; H, 4.21; N, 3.65. Found: C, 56.49; H, 4.30;
N, 3.50.
2-[(Ben zyloxyca r b on yl)a m in o]-2-[(4-m et h ylp h en yl)-
su lfen yl]-3,3-d iflu or op r op a n a l (R)-1b (obtained from (R)-
(Z)-3b): yield 58%; [R]20D +280.8 (c 0.64, CHCl3), ee 62%; white
solid, the racemate could be crystallized from diisopropyl
ether: mp 81-82 °C; Rf (80:20 n-hexane/AcOEt) 0.67; 1H NMR
(CDCl3) δ 9.49 (1H, s), 7.48-7.32 (5H, m), 7.07 (2H, d, J ) 8
Hz), 6.95 (2H, d, J ) 8 Hz), 6.90 (1H, t, J ) 55 Hz), 5.64 (1H,
br s), 5.22 (1H, d, J ) 12 Hz), 4.98 (1H, d, J ) 12 Hz), 2.30
(3H, s); 19F NMR (CDCl3) δ -132.6 (1F, dd, J ) 55 and 290
Hz), -122.1 (1F, dd, J ) 55 and 290 Hz); 13C NMR (CDCl3) δ
183.2 (t, J ) 4 Hz), 153.7, 141.3, 137.9, 135.5, 130.2, 128.9,
121.2, 113.4 (dd, J ) 247.6 and 252.4 Hz), 73.2 (t, J ) 23 Hz),
67.6, 21.4; MS (EI, 70 eV) m/ z (%): 365 (M+, 4), 124 (35), 91
(100); FT IR (cm-1) 3372 (br), 1721 (br), 1494, 1245. Anal.
Calcd for C18H17NO3F2S: C, 59.17; H, 4.69; N, 3.83. Found:
C, 59.48; H, 4.85; N, 3.58.
Exp er im en ta l Section
Rea ction of (R)-1a ,b w ith Gr ign a r d Rea gen ts. The
synthesis of 5d is described as an example. To a cooled
solution (-78 °C) of phenylmagnesium chloride (993 µL of a 2
M solution in THF, 1.99 mmol) in dry THF (6 mL) was added
dropwise a solution of aldehyde (R)-1a (250 mg, 0.66 mmol)
in dry THF (2 mL) under nitrogen atmosphere. After 1 min
the reaction was quenched with a saturated aqueous solution
of NH4Cl, heated at room temperature, and extracted with
AcOEt. The collected organic phases were dried over anhy-
drous sodium sulfate and filtered, and the solvent was removed
in vacuo. The crude was purified by FC (85:15 hexane/AcOEt),
affording 273 mg (90%) of 5d .
(1S,2R)-2-[(Ben zyloxyca r b on yl)a m in o]-2-[(4-m et h yl-
p h e n yl)su lfe n yl]-3,3,3-t r iflu or o-1-p h e n ylp r op a n -1-ol
(5d ): Rf (8:2 n-hexane/AcOEt) 0.47; [R]20D -85.8 (c 0.3, CHCl3)
ee 73%; 1H NMR (CDCl3) δ 7.26-7.49 (12H, m), 7.08 (2H, d, J
) 7.8 Hz), 5.50 (1H, br d, J ) 3.1 Hz), 5.26 (1H, s), 5.13 (1H,
d, J ) 12.1 Hz), 5.07 (1H, d, J ) 12.1 Hz), 4.77 (1H, br m),
2.34 (3H, s); 13C NMR (CDCl3) δ 155.0, 140.9, 138.2, 137.5,
135.3, 129.9, 128.7, 128.66, 128.64, 128.5, 128.4, 127.9, 127.7,
124.4 (q, J ) 286.4 Hz), 75.5 (q, J ) 25.7 Hz), 74.8, 67.9, 21.3;
19F NMR (CDCl3) δ -69.2 (3F, s); MS (EI, 70 eV) m/ z (%):
584 (M+ + S-p-Tol, 3), 338 (M+ - S-p-Tol, 6), 230 (100), 153
(21); FT IR (cm-1) 3391, 3036, 1710, 1494, 1456.
Gen er a l Meth od s. 1H (400 or 250 MHz), 19F (235 MHz),
and 13C (100.6 or 62.8 MHz) NMR samples were prepared as
dilute solutions in the appropriate deuterated solvent. Chemi-
cal shifts (δ) are reported in parts per million (ppm) of the
applied field. Me4Si was used as internal standard (δH and
δC ) 0.00) for 1H and 13C nuclei, while C6F6 was used as
external standard (δF ) -162.90) for 19F nuclei. Ee’s have
been determined by 1H and 19F NMR analysis of pure samples
of the appropriate compounds, by using the chiral shift reagent
(+)-[Eu(hfc)3] in CDCl3 solution. Anhydrous THF was distilled
from sodium and benzophenone. Anhydrous CH2Cl2 was
distilled from calcium hydride. In all other cases commercially
available reagent-grade solvents were employed without pu-
rification. Grignard reagents were purchased from Sigma/
Aldrich Co. Reactions performed in dry solvents were carried
out in nitrogen atmosphere. Melting points are uncorrected
and were obtained on a capillary apparatus. Analytical thin-
layer chromatography (TLC) was routinely used to monitor
reactions. Plates precoated with E. Merck silica gel 60 F254 of
0.25 mm thickness were used. Merck silica gel 60 (230-400
ASTM mesh) was employed as a reagent [for the preparation
of (R)-1] and for flash column chromatography (FC). R-(Fluoro-
alkyl)-â-sulfinyl enamines (R)-3 were prepared according to
the procedure described in the literature.17
(1R,2R)-5d : Rf (8:2 n-hexane/AcOEt) 0.37; 1H NMR (CDCl3)
δ 7.26-7.49 (14H, m), 5.64 (1H, br d, J ) 2.7 Hz), 5.26 (1H,
s), 5.16 (1H, d, J ) 12.0 Hz), 5.05 (1H, d, J ) 12.0 Hz), 4.77
(1H, br m), 2.34 (3H, s); 19F NMR (CDCl3) δ -71.1 (3F, s).
Ester ifica tion w ith P h en yla cetic or P h en ylp r op ion ic
Acid . The synthesis of 8a is described as an example. To a
solution of 5d (139 mg, 0.3 mmol) in dry CH2Cl2 (5 mL) were
added neat phenylacetic acid (41 mg, 0.3 mmol) and then DCC
(62 mg, 0.3 mmol) and finally a catalytic amount of DMAP.
The mixture was kept at room temperature for 1 h. The
solution was diluted with Et2O and filtered, and the solvent
was removed under reduced pressure. The residue was
purified by FC (8:2 hexane/AcOEt), affording 154 mg (89%) of
8a .
F lu or op yr u va ld eh yd e N,S-k eta ls (R)-1. To a stirred
0.15 M solution of (R)-(Z)-3a (0.38 g, 1 mmol) in dry THF,
cooled at 0 °C, was added neat TFAA (1 mmol, 0.14 mL) via
syringe and left 1 min under stirring. TLC monitoring showed
the immediate disappearance of (R)-(Z)-3a , with the formation
of a unique spot at much higher Rf (0.45 in n-hexane/AcOEt
85:15). Silica gel (ca. 0.4 g) was added in one portion at 0 °C,
and the resulting mixture was vigorously stirred for 5 min at
the same temperature. Water (ca. 10 mL) was added at 0 °C,
and the phases were immediately separated. The aqueous
layer was extracted with AcOEt. The collected organic phases
were dried over anhydrous sodium sulfate and filtered, and
the solvent was removed under reduced pressure. FC of the
crude reaction mixture on a short silica gel column afforded
(1S,2R)-1-(O-P h en yla cet yl)-2-[(b en zyloxyca r b on yl)-
am ino]-2-[(4-m eth ylphenyl)sulfenyl]-3,3,3-tr ifluor o-1-ph en -
0.22 g (57%) of (R)-1a , [R]20 +138.6 (c 0.89, CHCl3) (ee 69%).
D
ylp r op a n -1-ol (8a ): Rf (8:2 n-hexane/AcOEt) 0.52; [R]20
For an improved procedure (both in terms of yield and
enantioselectivity) and a detailed chemometric study on the
factors influencing this reaction, see ref 19. Since that study
was performed when the present work was already in an
advanced stage, the samples of (R)-1a ,b used as starting
materials in the present work were usually prepared according
to the general procedure described above.
D
-114.0 (c 0.65, CHCl3) ee 79%; 1H NMR (CDCl3) δ 7.20-7.50
(17H, m), 7.02 (2H, d, J ) 8.0 Hz), 5.02 (1H, d, J ) 12.0 Hz),
4.82 (1H, d, J ) 12.0 Hz), 4.82 (1H, s), 3.61 (2H, s), 2.30 (3H,
s); 13C NMR (CDCl3) δ 168.7, 153.0, 141.2, 138.6, 135.7, 134.3,
133.4, 129.7, 129.6, 128.0, 127.6, 126.9, 124.5 (q, J ) 286.7
Hz), 123.0, 73.9, 72.1 (q, J ) 27.7 Hz), 67.2, 41.4, 21.3; 19F
NMR (CDCl3) δ -68.7 (3F, s); MS (EI, 70 eV) m/ z (%) 456
(M+ - S-p-Tol, 7), 124 (30), 91 (100); FT IR (cm-1) 3391, 3034,
1752 (br), 1496, 1242.
2-[(Ben zyloxyca r b on yl)a m in o]-2-[(4-m et h ylp h en yl)-
su lfen yl]-3,3,3-tr iflu or op r op a n a l (R)-1a : yellowish oil; Rf
(85:15 n-hexane/AcOEt) 0.45; 1H NMR (CDCl3) δ 9.37 (1H, q,
J ) 1.7 Hz), 7.43-7.32 (5H, m), 7.20 (2H, d, J ) 8 Hz), 7.01
(2H, d, J ) 8 Hz), 5.53 (1H, br s), 5.20 (1H, d, J ) 12 Hz), 5.07
(1H, d, J ) 12 Hz), 2.32 (3H, s); 19F NMR (CDCl3) δ -70.45 (q,
J ) 1.7 Hz); 13C NMR (CDCl3) δ 183.0 (q, J ) 1.8 Hz), 153.3,
Syn th esis of â-Am in o Alcoh ols 7a ,b a n d â-Am in o
Ester s 9a ,b. Reaction of 5d is described as an example. To
a cooled solution (0 °C) of 5d (290 mg, 0.64 mmol) in pyridine
(7 mL) was added portionwise NaBH4 (120 mg, 3.2 mmol), and

(R)-Fluoropyruvaldehyde N,S-Ketals
J . Org. Chem., Vol. 63, No. 21, 1998 7243
the mixture was kept under stirring 3 h, at the same
temperature. The reaction was quenched with 1 N aqueous
solution of HCl and extracted with AcOEt, the collected organic
phases were dried over anhydrous Na2SO4 and filtered, and
the solvent was removed in vacuo. FC of the crude (9:1
n-hexane/AcOEt) afforded 150 mg (70%) of 7a .
MS (EI, 70 eV) m/ z (%) 188 (M+ + 1, 10), 118 (19), 79 (55), 61
(100); FT IR (cm-1) 3370 (br), 2957 (br), 1561, 1522, 1385.
(1S,2R)-11b: Rf (7:3 n-hexane/AcOEt) 0.17; 1H NMR (CDCl3)
δ 7.3-7.45 (5H, m), 5.59 (1H, ddd, J ) 55.8, 56.6 and 3.5 Hz),
4.65 (1H, d, J ) 5.9 Hz), 3.08 (1H, dddd, J ) 3.5, 5.9, 7.2 and
17.3 Hz); 19F NMR (CDCl3) δ -127.7 (1H, ddd, J ) 284.8, 55.8
and 7.2 Hz), -135.3 (1F, ddd, J ) 284.8, 56.6 and 17.3 Hz).
Syn th esis of tr iflu or o- a n d d iflu or oep h ed r in e 12a ,b.
The synthesis of 12a is described as an example. To a solution
of 7a (45 mg, 0.13 mmol) in dry THF (2 mL) LiAlH4 (25 mg,
0.66 mmol) was added portionwise under nitrogen. The
mixture was refluxed for 7 h, quenched with water, and
extracted with AcOEt, the collected organic phases were dried
over anhydrous Na2SO4 and filtered, and the solvent was
removed in vacuo. FC of the crude (7:3 n-hexane/AcOEt)
afforded 25 mg (86%) of 12a . The same procedure was
performed for 12b (25%).
(1S,2S)-2-[(Ben zyloxyca r bon yl)a m in o]-3,3,3-tr iflu or o-
1-p h en ylp r op a n -1-ol (7a ): Rf (7:3 n-hexane/AcOEt) 0.49;
[R]20 +30.6 (c 0.67, CHCl3), +2.1 (c 0.5, acetone) ee 73.2%;
D
1H NMR (acetone-d6) δ 7.10-7.60 (10H, m), 6.79 (1H, d, J )
10.0 Hz), 5.03 (1H, dd, J ) 5.1 and 8.1 Hz), 5.00 (1H, d, J )
12.6 Hz), 4.95 (1H, d, J ) 5.1 Hz), 4.93 (1H, d, J ) 12.6 Hz),
4.60 (1H, m); 13C NMR (acetone-d6) 157.4, 142.6, 138.5, 129.8,
129.6, 129.5, 129.3, 128.9, 128.7, 127.1 (q, J ) 283.5), 73.4,
67.6, 59.2 (q, J ) 28.2 Hz); 19F NMR (acetone-d6) δ -67.4 (3F,
d, J ) 7.7 Hz); MS (EI, 70 eV) m/ z (%) 340 (M+, 4), 233 (29),
197 (29), 107 (73), 91 (100); FT IR (cm-1) 3310 (br), 1696, 1549,
1249.
(1S,2S)-2-(Meth ylam in o)-3,3,3-tr iflu or o-1-ph en ylpr opan -
(1S,2R)-7a: Rf (7:3 n-hexane/AcOEt) 0.54; 19F NMR (acetone-
d6) - 67.7 (3F, d, J ) 7.7 Hz).
Tr iflu or o- a n d Diflu or on or ep h ed r in e 11a ,b. The syn-
thesis of 11a is described as an example. A solution of 7a (100
mg, 0.29 mmol) in MeOH (6 mL) was stirred for 15 min in the
1-ol (12a ): Rf (6:4 n-hexane/AcOEt) 0.44; [R]20 +9.0 (c 0.79,
D
CHCl3) ee 74%; mp 173-177 °C dec (hydrochloride); 1H NMR
(CDCl3) δ 7.27-7.44 (5H, m), 4.96 (1H, d, J ) 5.1 Hz), 3.36
(1H, dq, J ) 5.1 and 7.4 Hz), 2.55 (3H, q, J ) 0.6 Hz); 13C
NMR (CDCl3) δ 128.6, 128.34, 128.32, 126.8, 125.9 (q, J )
presence of an excess of Pd(OH)2/C under
a dihydrogen
285.4 Hz), 71.0 (q, J ) 2.0 Hz), 66.2 (q, J ) 25.6 Hz), 35.7; 19
F
atmosphere. The solution was then filtered on a Celite pad,
and after evaporation of the solvent, the crude was purified
by FC (7:3 n-hexane/AcOEt), affording 59 mg (quantitative)
of 11a . The same procedure was applied for the synthesis of
11b (quantitative).
NMR (CDCl3) δ -70.7 (3F, d, J ) 7.4 Hz); MS (EI, 70 eV) m/ z
(%) 220 (M+ + 1, 100), 202 (22); FT IR (cm-1) 3364 (br), 3019,
2928, 1456, 1261.
(1S,2S)-2-(Meth yla m in o)-3,3-d iflu or o-1-p h en ylp r op a n -
1-ol (12b): Rf (6:4 n-hexane/AcOEt) 0.28; [R]20 +3.9 (c 0.70,
D
(1S,2S)-2-Am in o-3,3,3-t r iflu or o-1-p h en ylp r op a n -1-ol
MeOH), ee > 95%; mp 160-162 °C dec (hydrochloride); 1H
NMR (CDCl3) δ 7.27-7.46 (5H, m), 5.68 (1H, dt, J ) 3.7 and
55.3 Hz), 4.85 (1H, d, J ) 5.5 Hz), 3.03 (1H, m), 2.5 (3H, s);
19F NMR (CDCl3) δ -122.8 (1F, ddd, J ) 288.6, 55.3 and 7.0
Hz), -131.0 (1F, ddd, J ) 288.6, 55.3 and 16.8 Hz); MS (EI,
(11a ): Rf (7:3 n-hexane/AcOEt) 0.22; [R]20 +11.5 (c 1.053,
D
CHCl3) ee 70%; mp 196-198 °C dec (hydrochloride); 1H NMR
(CDCl3) δ 7.2-7.6 (5H, m), 4.93 (1H, d, J ) 5.5 Hz), 3.60 (1H,
dq, J ) 5.5 and 7.4 Hz), 2.72 (2H, br s); 13C NMR (CDCl3) δ
139.0, 128.62, 128.56, 127.0, 72.1, 58.5 (q, J ) 26.4 Hz), the
corresponding resonance of the CF3 group is obscured; 19F
NMR (CDCl3) δ -74.7 (3F, d, J ) 7.4 Hz); MS (EI, 70 eV)
m/ z (%) 206 (M+ + 1, 10), 185 (30), 107 (76), 79 (100); FT IR
(cm-1) 3380 (br), 2924, 1456, 1261.
70 eV) m/ z (%) 202 (M+ + 1, 20), 94 (100), 75 (52); FT IR (cm-1
3423 (broad), 1385.
)
Ackn owledgm en t. ConsiglioNazionale delle Ricerche
is gratefully acknowledged for financial support. Dr.
Alessandro Volonterio and Dr. Barbara Vergani thank
Politecnico di Milano for a scholarship.
(1S,2R)-11a: Rf (7:3 n-hexane/AcOEt) 0.22; 1H NMR (CDCl3)
δ 7.2-7.45 (5H, m), 4.94 (1H, d, J ) 3.9 Hz), 3.35 (1H, dq, J
) 7.5 and 3.9 Hz), 2.0 (2H, br s); 19F NMR (CDCl3) δ -75.7
(3F, d, J ) 7.5 Hz).
(1S ,2S )-2-Am in o-3,3-d iflu or o -1-p h e n y lp r op a n -1-ol
Su p p or tin g In for m a tion Ava ila ble: Full list of spectral
data of compounds 5a ,b,c,e,f, 6a ,c, 7b, 8b, 9a ,b, 10a ,b. Copies
of 1H, 19F, 13C NMR spectra of componds 5a -f, 6a , 7a ,b, 8a ,b,
9a ,b, 11a ,b, 12a ,b (53 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
(11b): Rf (7:3 n-hexane/AcOEt) 0.17; [R]20 +12.4 (c 1.00,
D
MeOH) ee > 95%; mp 212-215 °C dec (hydrochloride); 1H
NMR (CDCl3) δ 7.3-7.45 (5H, m), 5.82 (1H, dt, J ) 56.1 and
3.2 Hz), 4.69 (1H, d, J ) 7.0 Hz), 3.25 (1H, dddd, J ) 3.2, 6.7,
7.0 and 19.1 Hz); 13C NMR (CD3OD) δ 139.8, 130.0, 129.9,
127.7, 114.4 (t, J ) 243.2 Hz), 71.1, 58.2 (dd, J ) 18.5 and
22.2 Hz); 19F NMR (CDCl3) δ -127.7 (1F, ddd, J ) 284.5, 56.1
and 6.7 Hz), -135.3 (1F, ddd, J ) 284.5, 56.1 and 19.1 Hz);
J O980602P