Stereocontrolled approaches to (+)- and (-)-γ-trifluoromethyl-GABOB, a new hydroxymethylene (statine) dipeptide isostere

Article abstract of DOI:10.1016/S0957-4166(98)00397-8

Two efficient approaches to both enantiomers of syn-γ-trifluoromethyl γ-amino β-hydroxy butyric acid (γ-Tfm-GABOB) (10), a new hydroxymethylene (statine) dipeptide isostere, are described. One exploits the recently disclosed 'non-oxidative' Pummerer reaction, by means of which α-lithium alkyl sulfoxides are used as chiral α-hydroxyalkyl anion equivalents in the synthesis of β-amino alcohols. Trifluoropyruvaldehyde-N,S-ketal (R)-11, a novel stereochemically stable synthetic equivalent of α-amino trifluoropropanal, is used in the second approach.

Full text of DOI:10.1016/S0957-4166(98)00397-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3731–3735
Stereocontrolled approaches to (+)- and (−)-γ-trifluoromethyl-
GABOB, a new hydroxymethylene (statine) dipeptide isostere
Pierfrancesco Bravo,a Eleonora Corradi,b Cristina Pesenti,b Barbara Vergani,b Fiorenza Viani,a
Alessandro Volonterio b and Matteo Zanda b,∗
aC.N.R. - Centro di Studio sulle Sostanze Organiche Naturali, via Mancinelli 7, I-20131 Milano, Italy
bDipartimento di Chimica del Politecnico, via Mancinelli 7, I-20131 Milano, Italy
Received 14 September 1998; accepted 29 September 1998
Abstract
Two efficient approaches to both enantiomers of syn-γ-trifluoromethyl γ-amino β-hydroxy butyric acid (γ-
Tfm-GABOB) (10), a new hydroxymethylene (statine) dipeptide isostere, are described. One exploits the recently
disclosed ‘non-oxidative’ Pummerer reaction, by means of which α-lithium alkyl sulfoxides are used as chiral
α-hydroxyalkyl anion equivalents in the synthesis of β-amino alcohols. Trifluoropyruvaldehyde-N,S-ketal (R)-11,
a novel stereochemically stable synthetic equivalent of α-amino trifluoropropanal, is used in the second approach.
© 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Peptide isosteres are structural motifs in which a scissile amide bond has been replaced by a functional
group that mimics the peptide bond, but is incapable of hydrolytic cleavage. Many of them have
found important applications as efficient protease inhibitors, for example in the regulation of blood
pressure (renin inhibitors) and in AIDS therapy (HIV-protease inhibitors).1 Stereochemically defined
β-fluoroalkyl β-amino alcohols feature a great potential for the preparation of new lipophilic peptide
mimics, having improved properties as drugs, but the overwhelming difficulties connected with their
preparation have strongly limited their application in biomedicinal chemistry.2 In this paper we describe
two efficient approaches to both enantiomers of the orthogonally protected syn-γ-trifluoromethyl γ-
amino β-hydroxy butyric acid (γ-Tfm-GABOB) (10), a new hydroxymethylene (statine) dipeptide
isostere.
∗
Corresponding author. E-mail: zanda@dept.chem.polimi.it
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00397-8

3732
P. Bravo et al. / Tetrahedron: Asymmetry 9 (1998) 3731–3735
2. Results and discussion
2.1. (−)-γ-Tfm-GABOB 10: α-lithium sulfoxide (R)-1 as a chiral α-hydroxy γ-butenyl anion equivalent
The first approach to γ-Tfm-GABOB 10 (Scheme 1) takes advantage of a synergistic combination
of two methodologies we have developed recently: (1) the chiral sulfoxide stereocontrolled additions of
nucleophiles to fluorinated imines3 and (2) the ‘non-oxidative’ Pummerer reaction,4 that allows for a
one-pot SN2-type displacement of the sulfinyl auxiliary by a hydroxyl. Thus, easily available α-lithium
sulfoxides can be used as chiral α-hydroxyalkyl anion equivalents for preparing β-amino alcohols. In
this work, lithiated (R)-p-tolyl γ-butenyl sulfoxide 1 is used as a chiral α-hydroxy-γ-butenyl anion
equivalent with the N-p-methoxyphenyl (N-PMP) imine of fluoral 2, to achieve the synthesis of a syn
β-Tfm γ-amino β-hydroxy butyric acid unit.
Scheme 1. (i) CAN, CH3CN, H2O (66%). (ii) ClCOOCH2Ph, K2CO3 50%, dioxane (>98%). (iii) (CF3CO)2O, sym-collidine,
CH3CN. (iv) a. K2CO3/H2O up to pH 7; b. NaBH4, THF/H2O, 0°C (94%). (v) PhCOOH, DCC, DMAP (cat.), CH2Cl2 (92%).
(vi) KMnO4, H2SO4 3 N, acetone/H2O (89%)
A THF solution of lithium sulfoxide 1 (Scheme 1), prepared from (R)-p-tolyl γ-butenyl sulfoxide with
1.2 equiv. of LDA,5a–h was treated with a THF solution of trifluoro imine 2 at −70°C. The reaction
afforded two diastereomeric N-PMP β-amino sulfoxides (2R,3S,RS)-3 and (2S,3R,RS)-4 out of four
possible, in 1.0/2.75 d.r. and quantitative overall isolated yields.5i The preferential formation of the
diastereomer 4 might be explained by the fact that the lithiated butenyl sulfoxide 1 reacts mainly in the
anti-geometry, having p-tolyl and allyl groups trans with respect to the plane defined by the O–S–C–Li
bonds,5j through a Zimmerman–Traxler (aldol-type) transition state.5k,b
The mixture of diastereomeric sulfoxides 3 and 4 was treated with ceric ammonium nitrate (CAN)
(5 equiv.) in acetonitrile/water to cleave the N-PMP group, providing the free amino sulfoxide 5 in
diastereomerically pure form after flash chromatography (FC) (66%). The absolute stereochemistry of 5
was determined by X-ray diffraction.6 Compound 5 was reprotected as N-Cbz derivative 6 (quantitative),
then submitted to the ‘non-oxidative’ Pummerer reaction protocol.4 As expected, treatment of 6 with
trifluoroacetic anhydride (5 equiv.) and sym-collidine (3 equiv.) triggered an SN2 displacement of the
sulfinyl by a trifluoroacetoxy group, leading to the intermediate sulfenamide 7. One-pot treatment with
aqueous K2CO3 up to pH 7 and finally with an excess of NaBH4, provided the β-amino alcohol (2R,3S)-8

P. Bravo et al. / Tetrahedron: Asymmetry 9 (1998) 3731–3735
3733
(Scheme 1) in a very clean manner (94%),7 with overall stereoselectivity >98/2 (the other diastereomer
was not detected). Conversion of (2R,3S)-8 into the corresponding O-benzoate 9 (92%), and oxidative
cleavage of the double bond with KMnO4 (89%) delivered the targeted enantiopure γ-Tfm-GABOB
(−)-(3S,4R)-10, orthogonally protected and suitable for preparing new potential protease inhibitors via
coupling to other amino acids.
2.2. (+)-γ-Tfm-GABOB 10 from (R)-trifluoropyruvaldehyde N,S-ketal 11
The second approach to γ-Tfm-GABOB 10 exploits trifluoropyruvaldehyde N,S-ketal (R)-11, recently
prepared in our laboratories, as a new chiral and stereochemically stable synthetic equivalent of α-amino
trifluoropropanal (Scheme 2).8 Slow addition of a THF solution of (R)-11 (ee ca. 70%) to allylmagnesium
chloride in THF (3 equiv., −78°C, 1 min) produced the corresponding homoallylic alcohol syn-12 in
9/2 d.r. (85% overall isolated yield). The absolute stereochemistry of 12 was determined by X-ray
diffraction of an enantiomerically pure analytical sample obtained by crystallization from n-hexane.6a
Next, the thio derivative 12 was submitted to reductive desulfenylation with NaBH4/pyridine (0°C,
60 min),8b,c but disappointingly the diastereomeric β-amino alcohols (2S,3R)-8 and its (2R,3R)-epimer
were produced without stereocontrol (yield >98%). In order to improve the diastereoselectivity, 12 was
transformed into the corresponding phenylacetic ester 13 (yield >98%),8c,d which was submitted to
reductive desulfenylation affording the desired syn-derivative (2S,3R)-16 with good diastereoselectivity,
in a mixture with the diastereomer anti-(2R,3R)-15 (15:16=2:9, yield >98%). Compound 16 might
be directly transformed into the corresponding O-phenylacetoxy N-Cbz γ-Tfm-GABOB by oxidative
cleavage of the double bond. However, in order to confirm the stereochemistry at C-2 and to perform
a formal synthesis of the (+)-γ-Tfm-GABOB 10, the phenylacetate 16 was transformed into the β-
amino alcohol (2S,3R)-8, that is the enantiomer of (2R,3S)-8 prepared from the sulfoxide (R)-1 (see
Section 2.1, Scheme 1). Thus, methanolysis of the mixture of esters 15,16 afforded in quantitative yields
the corresponding diastereomeric β-amino alcohols, from which (2S,3R)-8 was obtained in pure form by
FC, without loss of enantiomeric purity with respect to the starting material (R)-11.
Scheme 2.
The protocol shown in Scheme 2 involves two fairly stereoselective asymmetric transformations: (1)
formation of the C-3 carbinolic centre of 12 by addition of allylmagnesium chloride to (R)-11, that
might be rationalized by the syn-selective chair-like transition state A (Fig. 1), involving sterically
controlled approach of the allylic nucleophile to the Re face of the carbonyl (Felkin–Anh);9,10 (2)
reductive desulfenylation of the thio derivative 13, which involves two steps:8b,c (a) generation of the
transient imine 14 (Scheme 2) by pyridine promoted elimination of p-thiocresol, (b) reduction of 14 by

3734
P. Bravo et al. / Tetrahedron: Asymmetry 9 (1998) 3731–3735
Figure 1.
NaBH4, that might be explained by the Felkin–Anh model B (Fig. 1), in which the phenylacetoxy group
plays the role of electronegative, ‘large’ substituent.9
In summary, we have described two alternative stereocontrolled entries to both enantiomers of the
orthogonally protected γ-Tfm-GABOB 10, a new hydroxymethylene (statine) dipeptide isostere now
available in gram-quantities. The synthesis of new potential protease inhibitors incorporating γ-Tfm-
GABOB is currently in progress.11
Acknowledgements
C.P., E.C. and B.V. thank Politecnico for a scholarship.
References
1. (a) Huff, J. R.; Darke, P. L. Inhibition of HIV protease: a strategy for the treatment of AIDS. In Anti-AIDS Drug
Development: Challenges, Strategies and Prospects; Mohan, P.; Baba, M., Eds; Harwood Academic Publishers, 1995;
pp. 93–116. (b) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699–1720. (c) Tao, J.; Hoffman, R. V. J. Org. Chem.
1997, 62, 6240–6244 and references cited therein. (d) Hoffman, R. V.; Tao, J. Tetrahedron Lett. 1998, 39, 4195–4198. (e)
Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 10419–10433.
2. (a) Bégué, J.-P.; Bonnet-Delpon, D. Trifluoromethylated amino alcohols: new synthetic approaches and medicinal targets.
In Biomedical Frontiers of Fluorine Chemistry; Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds; ACS Books, American
Chemical Society: Washington, DC, 1996; pp. 59–72. (b) Abouabdellah, A.; Bégué, J.-P.; Bonnet-Delpon, D.; Thanh Nga,
T. T. J. Org. Chem. 1997, 62, 8826–8833. (c) Ojima, I.; Slater, J. C.; Pera, P.; Veith, J. M.; Abouabdellah, A.; Bégué, J.-P.;
Bernacki, R. J. Bioorg. Med. Chem. Lett. 1997, 7, 133–138. (d) Marti, R. E.; Heinzer, J.; Seebach, D. Liebigs Ann. 1995,
1193–1215. (e) Beck, A. K.; Seebach, D. Chem. Ber. 1991, 124, 2897–2911.
3. Bravo, P.; Farina, A.; Kukhar, V. P.; Markovsky, A. L.; Meille, S. V.; Soloshonok, V. A.; Sorochinsky, A. E.; Viani, F.;
Zanda, M.; Zappalà, C. J. Org. Chem. 1997, 62, 3424–3425.
4. Bravo, P.; Zanda, M.; Zappalà, C. Tetrahedron Lett. 1996, 37, 6005–6006.
5. (a) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961–998. (b) Pyne, S. G.; Boche, G. J. Org. Chem. 1989, 54, 2663–2667.
(c) Chassaing, G.; Lett, R.; Marquet, A. Tetrahedron Lett. 1978, 19, 471–474. (d) Biellmann, J. F.; Vicens, J. J. Tetrahedron
Lett. 1974, 15, 2915–2918. (e) Williams, D. R.; Phillips, J. G.; White, F. H.; Huffman, J. C. Tetrahedron 1986, 42,
3003–3011. (f) Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277–297. (g) Tsuchihashi, G.; Iriuchijima, S.; Maniwa,
K. Tetrahedron Lett. 1973, 14, 3389–3392. (h) Ronan, B.; Marchalin, S.; Samuel, O.; Kagan, H. B. Tetrahedron Lett. 1989,
30, 6101–6104. (i) Attempts to improve the stereocontrol were made, however, changing the temperature of lithiation, the
use of more bulky bases such as lithium tetramethylpiperidide, or the use of toluene as solvent produced little or no changes
of diastereoselectivity. (j) This is in agreement with the few existing reports on additions of metallated alkyl sulfoxides
across the C–N double bonds of imines (see above, Refs. 5a–h), but in sharp contrast with the peculiar behaviour of α-
lithium benzyl p-tolyl sulfoxide, which was found to react with the imine 2 almost exclusively via the syn-geometry (Ref.
3). (k) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920–1923.
6. (a) Full data will be reported in a full paper. (b) The stereochemistry of the minor diastereomer 3 was determined as
follows. A mixture of sulfoxides 4 (having known stereochemistry) and 3 were deoxygenated with Me3SiCl/NaI providing
the corresponding sulfides, which proved to be enantiomers by NMR analysis (a single set of signals was detected). This
allowed us to assess that 3 has (2R,3S,RS)-stereochemistry.

P. Bravo et al. / Tetrahedron: Asymmetry 9 (1998) 3731–3735
3735
7. In order to confirm the stereochemistry of (2R,3S)-8, this compound was treated with NaH and PhCH2Br affording the
oxazolidinone 17 (93%), whose J2–3=3.6 Hz strongly suggests a trans pseudo-equatorial configuration, in full agreement
with the expected configuration.
8. (a) Volonterio, A.; Zanda, M.; Bravo, P.; Fronza, G.; Cavicchio, G.; Crucianelli, M. J. Org. Chem. 1997, 62, 8031–8040.
(b) Volonterio, A.; Bravo, P.; Capelli, S.; Meille, S. V.; Zanda, M. Tetrahedron Lett. 1997, 38, 1847–1850. (c) Volonterio,
A.; Vergani, B.; Crucianelli, M.; Zanda, M.; Bravo, P. J. Org. Chem. 1998, in press. (d) Transformation of N,S-ketals, like
12, into the corresponding phenylacetates followed by treatment with NaBH4/pyridine is an efficient strategy for obtaining
the corresponding desulfenylated derivatives, like 16, with syn-stereoselectivity: see Ref. 8c.
9. (a) Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9, 2199–2202. (b) Anh, N. G.; Eisenstein, O. Tetrahedron
Lett. 1976, 17, 155–158.
10. The stereoselectivity of this reaction is quite surprising, since all the reactions of (R)-11 with alkyl, vinyl and phenyl
Grignard reagents showed opposite stereocontrol, producing the corresponding anti-products, possibly originated from a
highly effective ‘chelation control’ (Ref. 8b,c). An opposite stereochemical outcome (chelation control) was also reported
for a wide range of reactions between N-monoprotected α-amino aldehydes and Grignard reagents, including allylic ones.
See for example: (a) Devant, R. M.; Radunz, H.-E. In Houben-Weyl: Methods in Organic Synthesis; Müller, E., Ed.; Thieme
Verlag: Stuttgart, 1995; Vol. E21b, pp. 1236–1239. (b) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149–164. (c)
Roush, W. R. In Comprehensive Organic Synthesis Vol. 2; Heathcock, C. H., Ed.; Pergamon Press: Oxford, 1991; pp.
1–54. (d) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293. For recent examples see: (e) Veeresha, G.; Datta,
A. Tetrahedron Lett. 1997, 38, 5223–5224. (f) Gryko, D.; Urbanczyk-Lipkowska, Z.; Jurczak, J. Tetrahedron: Asymmetry
1997, 8, 4059–4067. (g) Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1991, 56, 6939–6942. (h) Vara Prasad, J. V.
N.; Rich, D. H. Tetrahedron Lett. 1990, 31, 1803–1806. (i) Baker, W. R.; Pratt, J. K. Tetrahedron 1993, 49, 8739–8756. (j)
Ciapetti, P.; Falorni, M.; Taddei, M. Tetrahedron 1996, 52, 7379–7390. (k) Rübsam, F.; Seck, S.; Giannis, A. Tetrahedron
1997, 53, 2823–2834.
11. All new compounds have been characterized by means of 1H, 19F and 13C NMR, mass spectrometry and microanalyses.