Stereoselective Mannich-Type Reaction of an Acyclic Ketimine with a Substituted Chlorotitanium Enolate: Efficient Approach to D-erythro-α-Trifluoromethyl-β-hydroxyaspartic Units

Full text of DOI:10.1021/jo9909397

J . Org. Chem. 1999, 64, 8731-8735
8731
Sch em e 1
Ster eoselective Ma n n ich -Typ e Rea ction of
a n Acyclic Ketim in e w ith a Su bstitu ted
Ch lor otita n iu m En ola te: Efficien t
Ap p r oa ch to D-er yth r o-r-Tr iflu or om eth yl-
â-h yd r oxya sp a r tic Un its
Pierfrancesco Bravo,† Santos Fustero,‡
Maurizia Guidetti,§ Alessandro Volonterio,§ and
Matteo Zanda*,§,1
Mannich-type reaction of the chlorotitanium enolate of
(R-benzyloxy)acetyl 2-oxazolidinone (S)-19,10 with the
N-Cbz-imine of ethyl trifluoropyruvate 2a 11 (Scheme 2).
Our choice to use the 2-oxazolidinone ring system as a
chiral auxiliary was driven by its well-established ap-
plication in synthesis, by its high versatility and ready
C.N.R. - C.S.S.O.N., via Mancinelli 7, I-20131 Milano, Italy,
Departamento de Quı´mica Orga´nica, Facultad de Farmacia,
Universidad de Valencia, 46100-Burjassot (Valencia),
Spain, and Dipartimento di Chimica del Politecnico di
Milano, via Mancinelli 7, I-20131 Milano, Italy
(7) For some reviews: (a) Bloch, R. Chem. Rev. (Washington, D.C.)
1998, 98, 1407. (b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895. To our knowledge, the few existing examples are limited
to stereoselective aldol reactions of acyclic N-sulfinylketimines with
enolates of acetate: (c) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J . Org.
Chem. 1992, 57, 6387. (d) Tang, T. P.; Ellman, J . A. J . Org. Chem.
1999, 64, 12. For leading references on asymmetric condensations of
enolates with aldimines, see: (e) Abrahams, I.; Motevalli, M.; Robinson,
A. J .; Wyatt, P. B. Tetrahedron 1994, 50, 12755. (f) Annunziata, R.;
Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron Lett.
1993, 34, 6921. (g) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi,
F.; Ponzini, F.; Raimondi, L. Tetrahedron 1994, 50, 2939. (h) Annun-
ziata, R.; Benaglia, M.; Chiovato, A.; Cinquini, M.; Cozzi, F. Tetrahe-
dron 1995, 51, 10025. (i) Annunziata, R.; Benaglia, M.; Cinquini, M.;
Cozzi, F.; Raimondi, L. Tetrahedron 1994, 50, 5821. (j) Annunziata,
R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron
1994, 50, 9471. (k) Boger, D. L.; Honda, T. Tetrahedron Lett. 1993,
34, 1567. (l) Gennari, C.; Vulpetti, A.; Pain, G. Tetrahedron 1997, 53,
5909. (m) Vaccaro, W. D.; Sher, R.; Davis, H. R., J r. Bioorg. Med. Chem.
Lett. 1998, 8, 35. (n) Fujisawa, T.; Ichikawa, M.; Ukaji, Y.; Shimizu,
M. Tetrahedron Lett. 1993, 34, 1307. (o) Evans, D. A.; Morrissey, M.
M.; Dorow, R. L. J . Am. Chem. Soc. 1985, 107, 4346. (p) van der Steen,
F. H.; Kleijn, H.; Britovsek, G. J . P.; J astrzebski, J . T. B. H.; van Koten,
G. J . Org. Chem. 1992, 57, 3906. (q) Corey, E. J .; Decicco, C. P.;
Newbold, R. C. Tetrahedron Lett. 1991, 32, 5287. (r) Gennari, C.;
Venturini, I.; Gislon, G.; Schimperna, G. Tetrahedron Lett. 1987, 28,
227. (s) Hart, D. J .; Lee, C.-S. J . Am. Chem. Soc. 1986, 108, 6054.
(8) (a) Bravo, P.; Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron
Lett. 1998, 39, 7771. (b) Ishii, A.; Miyamoto, F.; Higashiyama, K.;
Mikami, K. Tetrahedron Lett. 1998, 39, 1199. (c) Sewald, N.; Seymour,
L. C.; Burger, K.; Osipov, S. N.; Kolomiets, A. F.; Fokin, A. V.
Tetrahedron: Asymmetry 1994, 5, 1051. (d) Zanda, M.; Bravo, P.;
Volonterio, A. In Asymmetric Fluoro-Organic Chemistry: Synthesis,
Applications, and Future Directions; Ramachandran, P. V., Ed.;
American Chemical Society Symposium Series; American Chemical
Society: Washington, DC, 1999; in press.
Received J une 9, 1999
The sequence Arg-Gly-Asp (RGD) mediates binding of
fibrinogen to its platelet receptors GP IIb/IIIa,2 which
represents a contributing factor in the platelet-mediated
thrombus formation. Enormous interest has been devoted
to the discovery of RGD analogues for an antithrombotic
therapy.3 In connection with a program for the synthesis
of new RGD peptide mimetics incorporating R-trifluo-
romethyl (Tfm) R-amino acids,4,5 as conformational modi-
fiers, we needed to synthesize nonracemic R-Tfm-â-
hydroxyaspartic acid units A in a stereoselective and
effective manner.6 Assembly of the chiral enolate B with
the imine C was envisaged as a potentially convenient
entry to A (Scheme 1).
This goal presented several stimulating challenges.
First, to our knowledge no method has yet been reported
for the synthesis of nonracemic units A. Second, very
few examples of stereoselective addition of enolates to
acyclic ketimines are extant in the literature, none of
them involving substituted enolates.7 Finally, the ste-
reocontrolled synthesis of organofluorine compounds
bearing a quaternary carbon is a mostly unresolved
problem.8
Here, we disclose the synthesis of D-erythro-R-Tfm-â-
hydroxyaspartic units, exploiting a highly stereoselective
* To whom correspondence should be addressed. Fax: +39-2-
23993080. E-mail: zanda@dept.chem.polimi.it.
(9) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127.
† C.N.R. - C.S.S.O.N..
(10) (a) Evans, D. A.; Gage, J . R.; Leighton, J . L.; Kim, A. S. J . Org.
Chem. 1992, 57, 1961 and references therein. For leading references
on aldol reactions involving R-alkoxy-acetyloxazolidinones, see: (b)
Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc. 1988, 110,
2506. (c) Keck, G. E.; Palani, A.; McHardy, S. F. J . Org. Chem. 1994,
59, 3113. (d) Batchelor, M. J .; Gillespie, R. J .; Golec, J . M. C.;
Hedgecock, C. J . R.; J ones, S. D.; Murdoch, R. Tetrahedron 1994, 50,
809. (e) Fuhry, M. A. M.; Holmes, A. B.; Marshall, D. R. J . Chem. Soc.,
Perkin Trans. 1 1993, 2743. (f) J ones, T. K.; Reamer, R. A.; Desmond,
R.; Mills, S. G. J . Am. Chem. Soc. 1990, 112, 2998. (g) Evans, D. A.;
Kaldor, S. V.; J ones, T. K.; Clardy, J .; Stout, T. J . J . Am. Chem. Soc.
1990, 112, 7001. (h) Piscopio, A. D.; Minowa, N.; Chakraborty, T. K.;
Koide, K.; Bertinato, P.; Nicolaou, K. C. J . Chem. Soc., Chem. Commun.
1993, 617. (i) Ku, T. W.; Kondrad, K. H.; Gleason, J . G. J . Org. Chem.
1989, 54, 3487. (j) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1984, 753.
(k) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T. Tetrahedron 1997,
53, 2421. (l) Andrus, M. B.; Schreiber, S. L. J . Am. Chem. Soc. 1993,
115, 10420. (m) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem.
Soc. 1992, 114, 9434. (n) Evans, D. A.; Barrow, J . C.; Leighton, J . L.;
Robichaud, A. J .; Sefkow, M. J . Am. Chem. Soc. 1994, 116, 12111. (o)
Loubinoux, B.; Sinnes, J .-L.; O′Sullivan, A. C.; Winkler, T. Helv. Chim.
Acta 1995, 78, 122. (p) Martin, S. F.; Dodge, J . A.; Burgess, L. E.;
Limberakis, C.; Hartmann, M. Tetrahedron 1996, 52, 3229. (q) Hulin,
B.; Newton, L. S.; Lewis, D. M.; Genereux, P. E.; Gibbs, E. M.; Clark,
D. A. J . Med. Chem. 1996, 39, 3897. (r) Roush, W. R.; Marron, T. G.;
Pfeifer, L. A. J . Org. Chem. 1997, 62, 474. (s) Crimmins, M. T.; Choy,
A. L. J . Org. Chem. 1997, 62, 7548.
‡ Universidad de Valencia.
§ Politecnico di Milano.
(1) Current address: Universite´ Louis Pasteur de Strasbourg,
Laboratoire de Synthe`se Bioorganique, Faculte´ de Pharmacie, 74 Route
du Rhin, 67401 Illkirch-Graffenstaden, France. Fax: +33-3-88678891.
E-mail: zanda@bioorga.u-strasbg.fr.
(2) Samanen, J .; Ali, F.; Romoff, T.; Calvo, R.; Sorenson, E.; Vasko,
J .; Storer, B.; Berry, D.; Bennett, D.; Strohsacker, M.; Powers, D.;
Stadel, J .; Nichols, A. J . Med. Chem. 1991, 34, 3114.
(3) See, for example: McDowell, R. S.; Gadek, T. R. J . Am. Chem.
Soc. 1992, 114, 9245.
(4) Dal Pozzo, A.; Muzi, L.; Moroni, M.; Rondanin, R.; de Castiglione,
R.; Bravo, P.; Zanda, M. Tetrahedron 1998, 54, 6019.
(5) (a) Fluorine-containing Amino Acids: Synthesis and Properties;
Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, 1994. (b)
Koksch, B.; Sewald, N.; J akubke, H.-D.; Burger, K. In Biomedical
Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J . R., Welch, J .
T., Eds.; American Chemical Society: Washington, DC, 1996; pp 42-
58.
(6) It is worth noting that the D-erythro-R-Tfm-â-hydroxyaspartic
unit A can be also envisaged as a suitable precursor of the polar head
of the 2-Tfm-analogue of natural sphingosine, the structural unit
common to most natural sphingolipids. For a review, see: Koskinen,
P. M.; Koskinen, A. M. P. Synthesis 1998, 1075. Efforts directed toward
the total synthesis of D-erythro-2-Tfm-sphingosine are presently in
progress.
10.1021/jo9909397 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

8732 J . Org. Chem., Vol. 64, No. 23, 1999
Notes
Sch em e 2
F igu r e 1. HF/6-31G*-optimized structures of (Z)- and (E)-
2b.
variation of the diastereomeric ratio (3:5:4:6 ) 91:9:0:0,
70%).
To understand the source of the high, and rather
unexpected, stereoselectivity for this Mannich-type reac-
tion, we investigated the geometry of the imine 2a . As
1
judged by H and 19F NMR spectroscopy (CDCl3, rt), 2a
exists as a single geometric isomer, probably the ther-
modynamic one, since imines derived from fluorinated
ketones can interconvert rapidly at ambient tempera-
tures.18 However, for the same reason, the presence of a
single set of signals could be due to a fast equilibrium
between E and Z forms or to an accidental overlap of the
signals. The exceeding reactivity of 2a precluded the use
of analytical techniques such as TLC or HPLC. Thus, we
decided to evaluate the relative energies of the Z and E
isomers of N-Cbz-imines of trifluoropyruvate performing
ab initio MO calculations. The methyl ester 2b was used
as a model.
The structures (Z)-2b and (E)-2b were fully optimized
by Hartree-Fock calculations with the 6-31G* basis set.19
The optimized structures are shown in Figure 1. The Z
isomer was calculated to be 10.3 kcal mol-1 less stable
than the E isomer,20 which adopts a slightly nonplanar
s-cis conformation, featuring a significant twisting of the
N-Cbz carbonyl with respect to the CO2Me group. This
twisting is probably caused by the electrostatic repulsion
between the carbonyl oxygen lone pairs. Imines 2a ,b
should therefore exist only as (E)-geometric isomers,
having the stereoelectronically demanding CF3 trans with
respect to the Cbz.
The TS leading to the major adduct 3 should involve
electrophilic addition of (E)-2a from its Si-face to the
unhindered Si-face of the (Z)-chlorotitanium enolate of
(S)-1. The Evans facial diastereoselectivity of the title
reaction strongly suggests that titanium is not coordi-
nated to the oxazolidinone carbonyl at the time of the
electrophilic attack. On the other hand, the total anti
simple diastereoselection provides evidence for efficient
coordination of the electrophile (E)-2a . Thus, the stere-
ochemical outcome might be rationalized using the model
D featuring complexation of both the spatially close
availability in both enantiomeric forms from unexpensive
parent amino acids.12 The strongly electrophilic imine 2a
was prepared in situ by Staudinger reaction of the
iminophosphorane Ph3PdNCbz13 with 1 equiv of com-
mercial ethyl trifluoropyruvate and used without remov-
ing the coproduct Ph3PO.
In an effort to obtain a stereoselective C-C bond
formation, we initially explored the lithium enolate of 1.
Unfortunately, a 65:35 mixture of “non-Evans”-anti and
-syn adducts 5 and 6, respectively, was produced in
modest yields (47%).14 Even more disappointingly, and
somewhat surprisingly, repeated attempts to form and
react a boron enolate of 1 (Bu2BOTf-i-Pr2NEt-CH2Cl2),
a tin (IV) enolate (SnCl4-i-Pr2NEt-CH2Cl2), or a tin(II)
enolate [Sn(OTf)2-Et3N-CH2Cl2] did not lead to any
adduct 3-6.
Finally, we investigated the chlorotitanium enolate of
1 [TiCl4 (1 equiv), i-Pr2NEt, CH2Cl2, -30 °C]. Satisfac-
torily, the “Evans”-anti adduct 3 and the minor “non-
Evans” anti-5 were produced in a 91:9 ratio (88% overall
isolated yield) after 2 h at 0 °C, while syn-4,6 were not
detected at all in the crude mixture.15 The use of Et3N
instead of i-Pr2NEt afforded lower stereoselectivity (3:5:
4:6 ) 79:21:0:0, 70%). Next, we examined the use of 2
equiv of TiCl4, since its stoichiometry has been reported
to exert remarkable influence in related processes.16 In
this case, the identical ratio 3:5:4:6 ) 91:9:0:0 was
obtained, although in much lower yields (ca. 30%).
Precomplexation of the imine 2a with 1 equiv of TiCl4
afforded yields lower than 5%.17 Ph3PO, which is present
in the reaction environment using in situ generated imine
2a , has no effect on the stereoselectivity. In fact, the use
of Ph3PO-free imine 2a , obtained by selective extraction
in boiling n-hexane, did not produce any detectable
(18) Osipov, S. N.; Kolomiets, A. F.; Fokin, A. V. Russ. Chem. Rev.
1992, 61, 798.
(11) (a) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.;
Kukhar, V. P.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5,
2009.
(12) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 77-91.
(13) Kricheldorf, H. R. Synthesis 1972, 695.
(14) The low yields were due to partial decomposition of lithium
enolate of 1, probably via fragmentation into R-benzyloxyketene and
the corresponding deacylated N-lithium 2-oxazolidinone.
(15) Diastereomeric ratios established by 19F NMR and HPLC.
(16) See, for example: (a) Walker, M. A.; Heathcock, C. H. J . Org.
Chem. 1991, 56, 5747. (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.
J . Am. Chem. Soc. 1997, 119, 7883.
(19) Gaussian 94, Revision C.3: Frisch, M. J .; Schlegel, G. W.;
Trucks, H. B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman,
J . R.; Keith, T.; Petersson, G. A.; Montgomery, J . A.; Raghavachari,
K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;
Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.; Challacombe, N.;
Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andre´s, J . L.,
Replogle, E. S.; Gomperts, R.; Mart´ın, R. L.; Fox, D. J .; Binkley, J . S.;
Defrees, D. J .; Baker, J .; Stewart, J . J . P.; Head-Gordon, M.; Gonza´lez,
C.; Pople, J . A. Gaussian Inc., Pittsburgh, PA, 1995.
(20) The preferential anti geometry of the N-substituent with respect
to the fluorinated rest in 2 has been already observed in related
structures. See, for example: Fustero, S.; Navarro, A.; Pina, B.;
Asensio, A.; Bravo, P.; Crucianelli, M.; Volonterio, A.; Zanda, M. J .
Org. Chem. 1998, 63, 6210.
(17) The byproducts formed by TiCl4 precomplexation of 2 were not
investigated.

Notes
J . Org. Chem., Vol. 64, No. 23, 1999 8733
Sch em e 3
Sch em e 4
carbonyl oxygens of (E)-2a by titanium, within its
expanded coordination sphere.
and protic solvents (EtOH and/or H2O) was used for this
purpose.24 In contrast, the conventional reagents LiAlH4
or LiBH4 produced low chemoselectivity and/or low yields
of the desired oxazolidinone-free products (Scheme 4).
Thus, treatment of 3 with 16 equiv of NaBH4 in a mixture
of THF/H2O 3:1 at -20 °C for ca. 2 h afforded the
diastereomerically pure carbinol D-erythro-9 in excellent
yields, without affecting the COOEt. The chiral auxiliary
(S)-4-Bn-2-oxazolidinone was recovered quantitatively.
D-Erythro-R-Tfm-R-NHCbz-γ-lactone 10 was quantita-
tively prepared by cyclization of 9. Selective transforma-
tion of 9 into the corresponding primary tosylate, followed
by intramolecular cyclization (n-BuLi, -78 °C, rt), pro-
duced a high yield of the azetidine 11.
The cyclic carbamate 12 was prepared from 3 by one-
pot reductive oxazolidinone cleavage/COOEt reduction/
intramolecular cyclization, achieved with 5 equiv of
NaBH4 in a mixture of THF/H2O 3:1 + 5% EtOH.
Esterification of 12 with (+)-(S)-R-methoxyphenylacetic
acid provided a compound suitable for X-ray diffraction,
which allowed us to establish the absolute configuration
of 3 and derivatives.25
Imine nitrogen is believed to be not involved in the
coordination, because of its exceedingly poor Lewis basic-
ity.21 This theory is supported by the literature. In fact,
Iseki and Kobayashi reported that aldol reactions of
boron and titanium acyloxazolidinone enolates with
fluoral and hexafluoroacetone, which do not undergo
coordination, take place with totally reverse non-Evans
facial selectivity and moderate anti simple selectivity.22
Aldol adduct 3 is a versatile intermediate for the
synthesis of D-erythro-R-Tfm-â-hydroxyaspartic acid 8
(Scheme 3) and several derivatives (Scheme 4).
The acyloxazolidinone imide bond was hydrolyzed in
exocyclic fashion with LiOOH23 to provide protected
R-Tfm-â-hydroxy-aspartate 7 (Scheme 3). Simultaneous
catalytic hydrogenolysis of both N-Cbz and O-Bn groups
delivered the target R-Tfm derivative 8.
To prepare reduced derivatives of 8 from 3, we have
developed a new epimerization-free, chemoselective, and
fine-tunable method for the exocyclic reductive removal
of the 2-oxazolidinone ring. NaBH4 in a mixture of THF
The diol D-erythro-13 was obtained from 3 upon reduc-
tive oxazolidinone cleavage/COOEt reduction (8 equiv of
NaBH4, absolute EtOH, 0 °C, 5.5 h). The minor aldol
adduct 5 was analogously treated, providing the enan-
tiomer L-erythro-13, that allowed us to assess the ster-
eochemistry of 5. By action of NaH, D-erythro-13 provided
the carbamate 12 as well (quantitative).
In summary, a rare example of stereoselective Man-
nich-type reaction of a ketimine with a substituted
enolate has been disclosed, optimized and exploited for
the synthesis of enantiomerically pure, densely function-
alized D-erythro-R-trifluoromethyl-â-hydroxy-aspartic units.
(21) Three strongly electron-withdrawing groups, namely CF3,
COOEt, and COOBn, attached to the CdN bond render the nitrogen
lone pair unavailable to coordination by Lewis acids and the imine
carbon strongly electrophilic: see ref 18.
(22) (a) Iseki, K.; Oishi, S.; Taguchi, T.; Kobayashi, Y. Tetrahedron
Lett. 1993, 34, 8147. (b) Makino, Y.; Iseki, K.; Fujii, K.; Oishi, S.;
Hirano, T.; Kobayashi, Y. Tetrahedron Lett. 1995, 36, 8147. Those
reactions were proposed to take place via open TS involving chelated
acyloxazolidinone enolates. It is worth noting that almost identical non-
Evans-anti stereocontrol was described for the reactions of lithium,
boron, and titanium enolates of chiral acyloxazolidinones with several
fluorine-free pyruvic esters: (c) J acobson, I. C.; Reddy, G. P. Tetrahe-
dron Lett. 1996, 37, 8263. For the sake of comparison, ethyl trifluo-
ropyruvate E was also reacted with the chlorotitanium enolate of 1,
using the identical optimized conditions found for the parent imine
2a .
Exp er im en ta l Section
For general experimental information see ref 20.
Syn th esis of Im in e 2a . To a solution of Ph3PdNCbz13 (440
mg, 1.07 mmol) in dry THF (6 mL) was added a solution of ethyl
trifluoropyruvate E (190 mg, 1.12 mmol) in dry THF (2 mL) at
room temperature, under nitrogen. The solution was warmed
at 50 °C for 10 min and then stirred at room temperature for 2
h; finally, the solvent was removed in vacuo.
2-Ben zyloxyca r bon ylim in o-3,3,3-tr iflu or op r op ion ic a cid
eth yl ester (2a ): 1H NMR (CDCl3) δ 7.70-7.34 (5H, m), 5.33
As expected, the reaction afforded a mixture of two diastereomeric
adducts F (whose stereochemistry has not been determined yet) with
low stereocontrol (66:34 ratio, 85%). For very recent impressive
progress in the field of enantiocontrolled aldol reactions of pyruvates
see: (d) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. V. J .
Am. Chem. Soc. 1999, 121, 686.
(24) To our knowledge, the use of NaBH4 to achieve reductive
removal of 2-oxazolidinone rings from N-acyloxazolidinones had not
been reported yet in the literature. However, while this manuscript
was in preparation, a paper describing the use of NaBH4 in THF/water
for achieving the same transformation appeared: Prashad, M.; Har,
D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998, 39, 7067.
(25) X-ray data will be published separately.
(23) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141.

8734 J . Org. Chem., Vol. 64, No. 23, 1999
Notes
(2H, s), 4.31 (2H, q, J ) 7.15 Hz), 1.31 (3H, t, J ) 7.15 Hz); 19
F
Na2SO3, warmed to room temperature, and extracted twice with
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Purification by FC
(from 1:1 hexane/AcOEt to 1:1 hexane/AcOEt + 1% AcOH)
afforded 162 mg of 7 (76%) and quantitative recovery of the
oxazolidinone.
NMR (CDCl3) δ - 71.4 (s); 13C NMR (CDCl3) δ 167.7, 154.6,
135.1, 132.0, 128.6, 121.4 (q, J ) 287.6 Hz), 69.6, 64.3, 13.7.
Ma n n ich -Typ e Rea ction w ith TiCl4. To a cooled solution
of 1 (87 mg, 0.27 mmol) in dry CH2Cl2 (1.5 mL) was added a 1
M solution of TiCl4 in CH2Cl2 (0.27 mL, 0.27 mmol) at - 30 °C
under nitrogen atmosphere. After 10 min, Hunig’s base (0.09
mL, 0.54 mmol) was added, and the resulting dark purple
solution was stirred at the same temperature for 1 h. Then, a
solution of crude 2a (85 mg, 0.28 mmol) in dry CH2Cl2 (1 mL)
was added via cannula. The solution was slowly warmed to 0
°C, and after 3 h, the reaction was quenched with saturated
aqueous NaHCO3, filtered on a Celite pad, and extracted with
CH2Cl2. The collected organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (FC) (75:25 hexane/AcOEt) afforded 148 mg of
pure diastereoisomers 3 and 5 in a 91:9 ratio (88% overall yield).
Ma n n ich -Typ e Rea ction w ith LDA. To a cooled solution
of 1 (221 mg, 0.68 mmol) in dry THF (2 mL) was added a 1.5 M
solution of LDA in THF (0.48 mL, 0.71 mmol) at -78 °C under
nitrogen atmosphere. After 15 min, a solution of 2a (215 mg,
0.71 mmol) in dry THF (2 mL) was added at the same temper-
ature. After 1 h, the solution was quenched with saturated
aqueous NH4Cl and extracted with AcOEt. The collected organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. Purification by FC (95:5 benzene/AcOEt) af-
forded 201 mg of a 65:35 mixture of diastereoisomers 5 and 6
(47% overall yield).
(2R,3S)-3-Ben zyloxy-2-b en zyloxyca r b on yla m in o-2-t r i-
flu or om eth ylsu ccin ic a cid 1-eth yl ester (7): Rf (1:1 hexane/
AcOEt + 1% of AcOH) 0.21; [R]20 -17.2 (c 0.98, CHCl3); 1H
D
NMR (CDCl3) δ 7.40-7.14 (10H, m), 6.38 (1H, br s), 5.10 (2H,
s), 4.77 (1H, d, J ) 11.0 Hz), 4.60 (1H, s), 4.49 (1H, d, J ) 11.0
Hz), 4.20 (2H, m), 2.36 (1H, s), 1.20 (3H, t, J ) 7.1 Hz); 19F NMR
(CDCl3) δ -70.4 (3F, s); 13C NMR (CDCl3) δ 171.8, 163.4, 154.1,
135.6, 135.5, 129.0, 128.5, 128.4, 128.3, 128.0, 123.4 (q, J ) 288.5
Hz), 74.1, 70.2, 67.7, 66.4 (q, J ) 28.6 Hz), 63.1, 13.6; FT IR
(cm-1) 2926, 1748, 1506; HRMS (FAB) calcd for (M+ + 1)
C
22H23F3NO7 470.1427, found 470.1428.
Syn th esis of 8. To a stirred solution of 7 (158 mg, 0.34 mmol)
in absolute MeOH (6 mL) was added a catalytic amount of Pd-
(OH)2/C, and the slurry was vigorously stirred for 2 h at room
temperature, under dihydrogen atmosphere. Pd(OH)2/C was
removed by filtration on a Celite pad, and the solution was
concentrated in vacuo. The crude was washed with CH2Cl2,
affording 72 mg (87%) of 8 as a white solid.
(2R,3S)-2-Am in o-3-h yd r oxy-2-t r iflu or om et h ylsu ccin ic
a cid 1-eth yl ester (8): Rf (8:1:1 t-BuOH/AcOH/H2O) 0.40; [R]20
D
+15.6 (c 0.65, MeOH); 1H NMR (CD3OD) δ 4.30 (2H, q, J ) 7.0
Hz), 3.31 (1H, br s), 1.30 (3H, t, J ) 7.0 Hz); 19F NMR (CD3OD)
δ -71.1 (3F, s); 13C NMR (CD3OD) δ 172.4, 166.0, 124.8 (q, J )
285.8 Hz), 72.3, 68.3 (q, J ) 26.6 Hz), 64.5, 14.0; MS (EI, 70 eV)
(2R,3S)-4-[(4S)-4-Ben zyl-2-oxooxa zolid in -3-yl]-3-b en zy-
loxy-2-ben zyloxyca r bon yla m in o-4-oxo-2-tr iflu or om eth yl-
bu tyr ic a cid eth yl ester (3): Rf (7:3 hexane/AcOEt) 0.38; [R]20
m/z 246 (M+ + 1, 100), 200 (14), 170 (53), 142 (32); FT IR (cm-1
)
2954, 2855, 1762, 1655.
D
1
+11.2 (c 0.96, CHCl3); H NMR (CDCl3) δ 7.38-7.13 (15H, m),
6.37 (1H, s), 6.03 (1H, s), 5.16 (1H, d, J ) 12.1 Hz), 5.01 (1H, d,
J ) 12.1 Hz), 4.66 (1H, d, J ) 11.4 Hz), 4.65 (1H, m), 4.48 (1H,
d, J ) 11.4 Hz), 4.12 (2H, q, J ) 7.1 Hz), 4.10 (2H, m), 3.12 (1H,
dd, J ) 13.4, 3.7 Hz), 2.42 (1H, dd, J ) 13.4, 10.1 Hz), 1.26 (3H,
t, J ) 7.1 Hz); 19F NMR (CDCl3) δ - 69.5 (3F, s); 13C NMR
(CDCl3) δ 167.5, 164.2, 154.3, 153.5, 135.6, 134.9, 129.2, 129.0,
128.7, 128.55, 128.50, 128.4, 128.1, 128.0, 127.4, 125.2, 123.3
(q, J ) 288.9 Hz), 77.2, 73.7, 73.2, 67.4 (q, J ) 27.6 Hz), 67.0,
63.4, 55.8, 38.0, 13.4; MS (EI, 70 eV) m/z 629 (M+, 7), 431 (11),
304 (14), 181 (29), 91 (100); FT IR (cm-1) 3422, 1784, 1738, 1502;
HRMS (FAB) calcd for (M+ + 1) C32H32F3N2O8 629.2111, found
629.2113.
Syn th esis of (+)-9. To a suspension of NaBH4 (223 mg, 5.90
mmol) in a 3:1 mixture of THF/H2O (4 mL) was added a solution
of 3 (370 mg, 0.59 mmol) in THF (1.9 mL) dropwise at - 20 °C.
After 25 min, 3 equiv of solid NaBH4 was added at -20 °C,
followed by other 3 equiv after 1 h at the same temperature.
The reaction was quenched with saturated aqueous NH4Cl,
warmed to room temperature, and extracted with AcOEt. The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. Purification by FC (7:3
hexane/AcOEt) afforded 233 mg of (+)-9 (87%) and the quantita-
tive recovery of the oxazolidinone. The same procedure was
applied for the synthesis of the enantiomer (-)-9 starting from
5 (83% yield and quantitative recovery of the oxazolidinone).
(+)-(2R,3S)-3-Ben zyloxy-2-b en zyloxyca r b on yla m in o-4-
h yd r oxy-2-tr iflu or om eth ylbu tyr ic a cid eth yl ester (9): Rf
(2S,3R)-4-[(4S)-4-Ben zyl-2-oxooxa zolid in -3-yl]-3-b en zy-
loxy-2-ben zyloxyca r bon yla m in o-4-oxo-2-tr iflu or om eth yl-
bu tyr ic a cid eth yl ester (5): Rf (7:3 hexane/AcOEt) 0.45; [R]20
D
+24.0 (c 0.87, CHCl3); H NMR (CDCl3) δ 7.40-7.16 (15H, m),
(8:2 hexane/AcOEt) 0.22; [R]20 +3.0 (c 1.05, CHCl3); 1H NMR
1
D
6.47 (1H, s), 5.81 (1H,s), 5.15 (1H, d, J ) 12.5 Hz), 5.04 (1H, d,
J ) 12.5 Hz), 4.77 (1H, d, J ) 11.5 Hz), 4.70 (1H, m), 4.44 (1H,
d, J ) 11.5 Hz), 4.17 (2H, m), 4.02 (1H, dd, J ) 8.8, 1.9 Hz),
3.80 (1H, dd, J ) 8.8 Hz both), 3.46 (1H, dd, J ) 13.8, 3.1 Hz),
2.48 (1H,dd, J ) 13.8, 11.1 Hz), 1.30 (3H, t, J ) 7.1 Hz); 19F
NMR (CDCl3) δ - 69.7 (3F, s); 13C NMR (CDCl3) δ 167.2, 164.0,
154.5, 153.0, 135.7, 129.6, 129.4, 128.9, 128.6, 128.56, 128.47,
128.39, 128.1, 128.0, 127.2, 127.0, 123.4 (q, J ) 288.5 Hz), 74.1,
72.4, 66.7, 63.4, 55.8, 36.6, 29.7, 13.6, CF3 signal is obscured
due to its low intensity.
(CDCl3) δ 7.37-7.13 (10H, m), 6.28 (1H, s), 5.13 (1H, d, J ) 12.1
Hz), 5.06 (1H, d, J ) 12.1 Hz), 4.67 (1H, d, J ) 11.1 Hz), 4.60
(1H, d, J ) 11.1 Hz), 4.23 (3H, m), 3.84 (1H, dd, J ) 12.0, 6.1
Hz), 3.74 (1H, dd, J ) 12.0, 5.0 Hz), 2.15 (1H, br s), 1.25 (3H, t,
J ) 7.1 Hz); 19F NMR (CDCl3) δ - 68.7 (3F, s); 13C NMR (CDCl3)
δ 164.7, 154.4, 136.8, 135.8, 128.6, 128.5, 128.3, 128.0, 123.9 (q,
J ) 288.5 Hz), 78.7, 74.3, 67.6 (q, J ) 26.8 Hz), 67.4, 63.0, 61.2,
13.8; MS (EI, 70 eV) m/z 456 (M+ + 1, 11), 410 (27), 274 (87),
181 (23), 91 (100); FT IR (cm-1) 3468, 1751, 1703, 1460; HRMS
(FAB) calcd for (M+ + 1) C22H25F3NO6 456.1634, found 456.1635.
(-)-(2S,3R)-3-Ben zyloxy-2-b en zyloxyca r b on yla m in o-4-
(2R,3R)-4-[(4S)-4-Ben zyl-2-oxooxa zolid in -3-yl]-3-ben zy-
loxy-2-ben zyloxyca r bon yla m in o-4-oxo-2-tr iflu or om eth yl-
h yd r oxy-2-tr iflu or om eth ylbu tyr ic a cid eth yl ester 9: [R]20
D
bu tyr ic a cid eth yl ester (6): Rf (7:3 hexane/AcOEt) 0.30; [R]20
-2.7 (c 0.75, CHCl3); Rf, 1H, 13C, 19F NMR, MS, and FT IR
D
+ 26.9 (c 0.39, CHCl3); 1H NMR (CDCl3) δ 7.38-7.11 (15H, m),
6.76 (1H, s), 6.12 (1H, s), 5.17 (1H, d, J ) 12.2 Hz), 5.10 (1H, d,
J ) 12.2 Hz), 4.80 (1H, d, J ) 11.8 Hz), 4.52 (1H, d, J ) 11.8
Hz), 4.32 (3H, m), 4.03 (1H, dd, J ) 9.1, 3.3 Hz), 3.90 (1H, dd,
J ) 9.1 Hz both), 3.24 (1H, dd, J ) 13.3, 3.1 Hz), 2.46 (1H, dd,
J ) 13.3, 10.2 Hz), 1.27 (3H, t, J ) 6.9 Hz); 19F NMR (CDCl3) δ
-69.2 (3F, s); 13C NMR (CDCl3) δ 167.9, 163.2, 154.4, 153.2,
136.2, 134.6, 130.9, 129.3, 129.0, 128.7, 128.5, 128.33, 128.29,
128.24, 128.21, 127.4, 123.3 (q, J ) 288.9 Hz), 74.4, 73.2, 67.3,
66.6, 63.0, 55.3, 42.0, 37.3, 13.8, CF3 signal is obscured due to
its low intensity.
spectra matched those of (+)-9.
Syn th esis of 10. To a solution of (+)-9 (23 mg, 0.05 mmol)
in MeOH (0.5 mL) was added a catalytic amount of saturated
aqueous NaHCO3, and the resulting solution was stirred at room
temperature for 10 min. The reaction was quenched with
saturated aqueous NH4Cl and extracted with AcOEt. The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. Purification by FC (85:15
hexane/AcOEt) allowed quantitative recovery of the lactone 10
(21 mg).
(4S,3R)-(4-Ben zyloxy-2-oxo-3-t r iflu or om et h ylt et r a h y-
d r ofu r a n -3-yl)ca r ba m ic a cid ben zyl ester (10): Rf (8:2
Syn th esis of 7. To a cooled solution of 3 (286 mg, 0.45 mmol)
in a 4:1 mixture of THF/H2O (5 mL) was added a 30% (in weight)
aqueous solution of H2O2 (0.19 mL, 1.82 mmol) at 0 °C under
nitrogen atmosphere, followed by solid LiOH (11 mg, 0.45 mmol).
After 90 min, the reaction was quenched with saturated aqueous
hexane/AcOEt) 0.42; [R]20 -1.2 (c 1.29, CHCl3); 1H NMR
D
(CDCl3) δ 7.37-7.22 (10H, m), 5.55 (1H, br s), 5.14 (1H, d, J )
12.3 Hz), 5.07 (1H, d, J ) 12.3 Hz), 4.65 (1H, d, J ) 11.3 Hz),
4.60 (1H, m), 4.51 (1H, d, J ) 11.3 Hz), 4.47 (1H, dd, J ) 10.0,

Notes
J . Org. Chem., Vol. 64, No. 23, 1999 8735
5.6 Hz), 4.27 (1H, m); 19F NMR (CDCl3) δ -75.0 (3F, s); 13C NMR
(CDCl3) δ 154.7, 136.3, 129.8, 128.7, 128.6, 128.5, 128.4, 128.3,
127.9, 122.8 (q, J ) 285.8 Hz), 72.3, 73.5, 71.7, 69.3, 68.0, CF3
signal is obscured due to its low intensity; MS (EI, 70 eV) m/z
410 (M+, 1), 274 (27), 196 (6), 91 (100); FT IR (cm-1) 2926, 1799,
1729; HRMS (FAB) calcd for (M+ + 1) C20H19F3NO5 410.1215,
found 410.1228.
Syn th esis of 11. To a solution of 9 (97 mg, 0.21 mmol) in
dry CH2Cl2 (3.5 mL) were added triethylamine (0.033 mL, 0.23
mmol) and solid TsCl (48.7 mg, 0.25 mmol) at room temperature
under nitrogen atmosphere. After 14 h, the solution was
quenched with water and extracted with CH2Cl2. The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Purification by FC (8:2 hexane/AcOEt)
afforded 110 mg of O-tosylate (85%). To a solution of O-tosylate
(28 mg, 0.05 mmol) in dry THF (0.5 mL) was added dropwise a
2.5 M solution of n-BuLi in hexane (0.02 mL, 0.05 mmol) at -
78 °C and under nitrogen atmosphere. The mixture was slowly
warmed until 0 °C. After 4 h, the reaction was quenched with
saturated aqueous NH4Cl, warmed to room temperature, and
extracted with AcOEt. The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo.
Purification by FC (8:2 hexane/AcOEt) afforded 20 mg of 11
(85%).
(2R,3R)-3-Ben zyloxy-2-tr iflu or om eth yla zetid in e-1,2-d i-
ca r boxylic a cid 1-ben zyl ester 2-eth yl ester (11): Rf (8:2
hexane/ethyl acetate) 0.45; [R]20D -34.6 (c 0.97, CHCl3); 1H NMR
(CDCl3) δ 7.44-7.29 (10H, m), 5.30 (1H, d J ) 12.0 Hz), 5.23
(1H, d J ) 12.0 Hz), 4.70 (1H, d J ) 11.7 Hz), 4.65 (1H, d J )
11.7 Hz), 4.32-4.25 (4H, m), 3.96 (1H, dd J ) 13.2, 2.8 Hz), 1.29
(3H, t J ) 7.2 Hz); 19F NMR (CDCl3) δ -72.0 (3F, s); 13C NMR
(CDCl3) δ 167.8, 153.8, 136.8, 135.8, 128.5, 128.4, 128.3, 128.1,
127.8, 123.3 (q, J ) 284.8 Hz), 72.3, 69.9, 69.1, 68.6 (q, J ) 26.8
Hz), 65.1, 63.1, 13.9; MS (EI, 70 eV) m/z 437 (M+, 9), 212 (19),
181 (26), 91 (100); FT IR (cm-1) 1752, 1677, 1401; HRMS (FAB)
calcd for (M+ + 1) C22H23F3NO5 438.1528, found 438.1524.
Syn th esis of 12 fr om 3. To a cooled solution of 3 (194 mg,
0.31 mmol) in a 3:1 mixture of THF/H2O was added solid NaBH4
(35 mg, 0.93 mmol) at 0 °C. After 1 h, another 2 equiv of solid
NaBH4 (23 mg) was added. After 4 h, the solution was diluted
with EtOH (1 mL) and stirred for 30 min at room temperature.
The reaction was quenched by carefully adding saturated
aqueous NH4Cl and extracted with AcOEt. The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. Purification by FC (1:1 hexane/AcOEt) afforded
65 mg of 12 (69%) and quantitative recovery of the oxazolidinone.
(4S)-4-[(1S)-1-Ben zyloxy-2-h yd r oxyeth yl)]-4-tr iflu or om -
66.7, 65.2 (q, J ) 28.7 Hz), 60.5; MS (EI, 70 eV) m/z 611 (2M+,
19), 396 (M+ + CH2Ph, 27), 306 (M+ + 1, 14), 91 (100); FT IR
(cm-1) 3278, 1761. HRMS (FAB) calcd for (M+ + 1) C13H15F3-
NO4 306.0953, found 306.0964.
Syn th esis of 13. To a solution of 3 (614 mg, 0.98 mmol) in
dry EtOH (9.8 mL) was added 5 equiv of solid NaBH4 (185 mg)
at 0 °C. The reaction appeared very slow by TLC monitoring.
Thus, after 3 h another 3 equiv of solid NaBH4 (111 mg) was
added at the same temperature. After 5 h, the reaction was
quenched by adding carefully saturated aqueous NH4Cl (gas
evolution), warmed to room temperature, and extracted with
AcOEt. The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Purification by FC
(1:1 hexane/AcOEt) afforded 295 mg of 13 (73%) and the
quantitative recovery of the oxazolidinone.
(1S,2S)-(2-Ben zyloxy-3-h yd r oxy-1-h yd r oxym eth yl-1-tr i-
flu or om eth ylp r op yl)ca r ba m ic a cid ben zyl ester (13): Rf
(6:4 hexane/ethyl acetate) 0.42; [R]20 +15.7 (c 1.02, CHCl3); 1H
D
NMR (CDCl3) δ 7.38-7.28 (10H, m), 5.84 (1H, br s), 5.13 (1H, d
J ) 12.3 Hz), 5.07 (1H, d J ) 12.3 Hz), 4.64 (1H, d J ) 11.2 Hz),
4.58 (1H, d J ) 11.2 Hz), 4.10-3.82 (3H, m), 3.72 (1H, dd J )
11.4, 2.7 Hz), 2.70 (2H, br signal); 19F NMR (CDCl3) δ - 75.9
(3F, s); 13C NMR (CDCl3) δ 156.3, 136.7, 135.5, 128.65, 128.59,
128.51, 128.3, 128.2, 125.5 (q, J ) 289.4 Hz), 78.9, 73.5, 67.6,
63.8 (q, J ) 25.0 Hz), 60.2, 59.5; MS (EI, 70 eV) m/z 307 (M+
-
OCH2Ph, 1), 289 (45), 246 (21), 91 (100); FT IR (cm-1) 3409, 1720,
1510, 1455.
Syn th esis of 12 fr om 13. To a suspension of NaH (80% in
weight, 18 mg, 0.58 mmol) in dry THF (1 mL) was added a
solution of 13 (142 mg, 0.34 mmol) in a 3:1 mixture of dry THF/
DMF (4 mL) dropwise at 0 °C under nitrogen atmosphere. After
20 min, the reaction was quenched with water, warmed to room
temperature, and extracted with AcOEt. The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. Purification by FC (1:1 hexane/AcOEt) afforded
104 mg of 12 (quantitative).
Ack n ow led gm en t . We thank MURST COFIN
(Rome) and CSSON for financial support. This work was
partially supported by the Direccio´n General de Inves-
tigacio´n Cient´ıfica y Te´cnica (DGES, PB97-0760-C02-
01). Dr. Amparo Asensio is gratefully acknowledged for
her assistance in ab initio calculations. We are grateful
to Dr. Arnaud Gissot for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Copies of optimized
structures at the HF/6-31G* level for compounds (Z)- and (E)-
2b and copies of 1H, 13C and 19F NMR spectra of (2R,3S)-3,
(2R,3S)-7, (2R,3S)-8, (2R,3S)-9, (3R,4S)-10, (2R,3R)-11, 12, and
(1S,2S)-13. This material is available free of charge via the
Internet at http://pubs.acs.org.
eth yloxa zolid in -2-on e (12): Rf (1:1 hexane/AcOEt) 0.30; [R]20
D
-22.1 (c 1.06, CHCl3); 1H NMR (CDCl3) δ 7.42-7.28 (5H, m),
6.85 (1H, br s), 4.71 (1H, d, J ) 11.3 Hz), 4.65 (1H, d, J ) 11.3
Hz), 4.61 (1H, d, J ) 9.8 Hz), 4.44 (1H, d, J ) 9.8 Hz), 3.92 (1H,
m), 3.77 (1H, dd, J ) 16.8, 3.7 Hz), 3.76 (1H, m), 1.79 (1H, br s);
19F NMR (CDCl3) δ - 78.4 (3F, s); 13C NMR (CDCl3) δ 158.8,
136.6, 128.7, 128.4, 128.1, 124.7 (q, J ) 285.8 Hz), 77.9, 74.1,
J O9909397