Enantioselective synthesis of fluorinated α-amino acids and derivatives in combination with ring-closing metathesis: Intramolecular π-stacking interactions as a source of stereocontrol

Article abstract of DOI:10.1021/ol016087q

(Equation presented) Hydride reduction of C=N bonds stereocontrolled by intramolecular π-stacking interactions of 1-naphthylsulfinyl and N-aryl groups, nonoxidative Pummerer rearrangement, and ring-closing metathesis are efficiently combined in a highly s

Full text of DOI:10.1021/ol016087q

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2621-2624
Enantioselective Synthesis of
Fluorinated r-Amino Acids and
Derivatives in Combination with
Ring-Closing Metathesis: Intramolecular
π-Stacking Interactions as a Source of
Stereocontrol
Santos Fustero,* Antonio Navarro, Bele´n Pina, Juan Garc´ıa Soler,
Ana Bartolome´, Amparo Asensio, Antonio Simo´n, Pierfrancesco Bravo,
Giovanni Fronza, Alessandro Volonterio, and Matteo Zanda
Departamento de Qu´ımica Orga´nica, Facultad de Farmacia, UniVersidad de Valencia,
E-46100 Burjassot (Valencia), Spain, and C.N.R.-Centro di Studio sulle Sostanze
Organiche Naturali and Dipartimento di Chimica del Politecnico, Via Mancinelli 7,
I-20131 Milano, Italy
santos.fustero@uV.es
Received May 9, 2001
ABSTRACT
Hydride reduction of CdN bonds stereocontrolled by intramolecular π-stacking interactions of 1-naphthylsulfinyl and N-aryl groups, nonoxidative
Pummerer rearrangement, and ring-closing metathesis are efficiently combined in a highly stereoselective entry to enantiomerically pure
cyclic and acyclic fluorinated â-amino alcohols and r-amino acid derivatives, respectively.
Attractive interactions between π-systems (π-stacking) play
a key role in diverse phenomena, including stabilization of
the helical structure of DNA, tertiary structures of proteins,
and complexation in host-guest systems.1 In asymmetric
synthesis, π-stacking interactions are gaining increasing
attention as a source of high stereoselectivity.2 We now report
a highly diastereoselective synthesis of cyclic and acyclic
fluorinated R-amino acids and derivatives,3 where intra-
molecular π-stacking interactions involving N-aryl and
1-naphthylsulfinyl groups were invoked to achieve stereo-
control with up to 98% de.
Fluorinated â-sulfinylamines 4, available from enantiopure
sulfinyl N-aryl imines (S)-Z-3 (Scheme 1),4 are suitable
starting materials for the synthesis of fluorinated alaninols
6 and the corresponding alanines 7.5 The key issue allowing
(3) For an overview of this field see: (a) Fluorine-containing Amino
Acids: Synthesis and Properties; Kukhar, V. P., Soloshonok, V. A., Eds.;
Wiley: Chichester, 1995. (b) Enantiocontrolled Synthesis of Fluoro-organic
Compounds; Soloshonok, V. A., Ed.; Wiley: Chichester, 1999.
(4) (a) Fustero, S.; Navarro, A.; Pina, B.; Asensio, A.; Bravo, P.;
Crucianelli, M.; Volonterio, A.; Zanda, M. J. Org. Chem. 1998, 63, 6210-
6219. (b) Bravo, P.; Cavicchio, G.; Crucianelli, M.; Markovsky, A. L.;
Volonterio, A.; Zanda, M. Synlett 1996, 887-889.
(1) (a) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112,
5525-5534 and references therein. (b) Doyon, J. B.; Jain, A. Org. Lett.
1999, 1, 183-185. (c) Edge-to-face aromatic interactions have also been
invoked in many examples of molecular recognition. See, for example:
Paliwal, S.; Greib, S.; Wilcox, C. S. J. Am. Chem. Soc. 1994, 116, 4497-
4498 and literature cited therein.
(5) Crucianelli, M.; Bravo, P.; Arnone, A.; Corradi, E.; Meille, S. V.;
Zanda, M. J. Org. Chem. 2000, 65, 2965-2971.
(2) Jones, G. B.; Chapman, B. J. Synthesis 1995, 475-497.
10.1021/ol016087q CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/25/2001

theory (DFT) calculations were carried out on representative
â-iminosulfoxides (R)-3b,c, all of them in both Z and E imino
configuration. This study brought two interesting features
to light (Table 2). First, Z imino tautomers are predicted to
Scheme 1a
Table 2. Energy Differencesa between the E and Z Imino
Tautomers of Optimized Structures of (R)-3b,c
method
∆E (E-Z)-3b
∆E (E-Z)-3c
HF/6-31G*
B3LYP/6-31G*//HF/6-31G*
B3LYP/6-31G*
1.73
1.26b
1.56
1.66
1.80b
2.20
.
a Energies in kcal mol-1 b Single-point calculations using the HF/6-31G*
geometry.
be more stable than those of the E configuration, regardless
of the computational method used. Second, and most
interestingly, calculations showed an almost parallel (face-
to-face)1c geometry between PMP and the 1-naphthyl rings
of (R)-Z-3b with an interplanar separation of 3.9-4.2 Å
(Figure 1), which strongly suggests the presence of an
attractive π-π interaction.
a (a) Bu4NBH4, MeOH, -70 °C. (b) CAN, CH3CN/H2O, rt, (>
90%). (c) ClCO2Bn, dioxane/aq K2CO3 50%, rt, (75-99%). (d) (i)
TFAA, CH3CN, sym-collidine, 0 °C; (ii) K2CO3 (10%); (iii) NaBH4,
H2O, (three steps, 70-90%). (e) RuO2‚xH2O/NaIO4, acetone/H2O,
rt, (65-70%).
this protocol to become synthetically useful was the develop-
ment of a highly efficient hydride reduction of the CdN bond
of 3 to 4. To this end, the influence of reaction conditions,
sulfinyl residue Ar, and imine substituent R1 on yields and
diastereoselectivity was carefully investigated. Use of
6
Bu4NBH4 as reducing agent, pure methanol or THF/
methanol as solvent, and in general, low temperatures (-70
°C) provided the best diastereocontrol. In fact, nearly
quantitative overall yields of 4a-j were obtained from 3a-
j, with overwhelming predominance of the syn-diastereomers
(dr ranging from 88:12 to 99:1) (Table 1). Apparently, the
arylsulfinyl group exerts a significant influence on stereo-
selectivity, and the de follows the order: 1-naphthyl (entries
2 and 4) > 2-naphthyl (entry 3) > p-Tol (entry 1). To find
some insights on the origin for the high syn-diastereoselec-
tivity, ab initio molecular orbital (MO) and density functional
Figure 1.
Theoretical predictions regarding the first point (geometry
of 3) are in full agreement with the spectroscopic data.4a
Satisfactorily, also the π-stacking predictions found support
Table 1. Synthesis of N-Aryl-â-sulfinylamines 4a-ja
entry
(S)-3
RF
Ar
R′
4
yield (%)b
syn:antic
1d
2d
3d
4
3a
3b
3c
3d
3e
3f
3g
3h
3i
CF3
CF3
CF3
CClF2
CHF2
CF3
CF3
CF3
p-MeC6H4
1-naphthyl
2-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
o-MeOC6H4
p-FC6H4
1-naphthyl
c-C6H11
p-MeOC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
>98
>98
>98
>98
>98
>98
>98
>98
33
88:12
99:1
94:6
99:1
91:9
97:3
98:2
99:1
66:34
99:1
5
6e
7e
8e
9e
CF3
10e,f
3j
CH2dCHCH2CF2
4j
>98
a Reaction time 30 min except for entries 9 (168 h) and 10 (5 h); Bu4NBH4 as reducing agent and methanol as solvent. b Isolated overall yields. c Determined
by 19F NMR of the crude reaction mixture. d Similar results have been obtained starting from (R)-3a (entry 1), (R)-3b (entry 2), or (R)-3c (entry 3). e THF/
MeOH as solvent. f See Scheme 2.
2622
Org. Lett., Vol. 3, No. 17, 2001

by NMR studies (ROESY) performed on (S)-Z-3b at 195 K
in CD3OD, which are the optimized reaction conditions. NOE
contacts among the four hydrogens of the PMP having nearly
the same chemical shift in CD3OD and all seven hydrogens
of the 1-naphthyl ring were clearly detected. Moreover, the
p-CH3O group showed selective NOE with the H-5,6,7 of
the naphthalene ring. Finally, the pro-S diastereotopic meth-
ylene hydrogen showed preferential contact with H-8 (peri
to the substituent) of the 1-naphthyl, while the pro-R showed
preferential contact with H-2 (ortho). These observations
suggest that the molecule is arranged in a preferred confor-
mation with the PMP and naphthyl rings close in the space.
The face-to-face π-stacking model predicted by the calcula-
tions is in good agreement with the experimental NOE data.
However, those data cannot exclude the occurrence of a
different interaction, such as edge-to-face stacking, which
would also bring at short distance some protons of the
aromatic rings.
reprotected with ClCO2Bn to afford syn-5b,d,e.10 Satisfac-
torily, the NOPR protocol afforded (R)-6a-c in good to
excellent yields. The final oxidation with RuO2‚xH2O/NaIO4
provided (R)-7a-c in fair yields.
This methodology has remarkable potential for the syn-
thesis of enantiomerically pure fluorinated amino-derivatives.
A new application combined with the ring-closing metathesis
(RCM)11,12 is demonstrated for the synthesis of the first
enantiomerically pure fluorinated cyclic â-amino alcohol
derivatives (10) featuring seven- and eight-membered rings
(Scheme 2).13
Scheme 2a
The stacking is likely to have a decisive influence on the
stereochemical outcome of the CdN bond reduction, because
the si face for RF ) CF3, CHF2 and the re face for RF )
CClF2 are exposed to the hydride attack, whereas the other
diastereoface is efficiently shielded (Figure 1).
The calculated geometry for the 2-naphthyl derivative (R)-
Z-3c predicts a less effective π-π interaction;7,8 in fact,
formation of syn-4c occurred with lower diastereoselectivity
(entry 3).
The influence of N-substituent R1 was also investigated.
A high degree of stereoselectivity was always obtained by
replacing PMP with aromatic groups having different electron
density, such as o-methoxyphenyl (3f, entry 6), p-fluoro-
phenyl (3g, entry 7), and 1-naphthyl (3h, entry 8). This minor
effect on diastereoselectivity and therefore on the stacking
stability suggests that either van der Waals or electrostatic
quadrupolar interactions7b involving 1-naphthylsulfinyl and
Ar rings could be responsible for the stacking, rather than a
charge-transfer that should be very sensitive to the ring
electron density. In addition, substitution of the N-aryl with
a N-cyclohexyl group, which cannot give stacking, featured
a dramatic drop of stereoselectivity (3i, entry 9).
With the enantiopure precursors syn-4 in hand, we
completed the synthesis of the target alaninols (R)-6a-c and
alanines (R)-7a-c9 (Scheme 1). Replacement of the 1-naph-
thylsulfinyl auxiliary by a hydroxyl was accomplished by
means of the “nonoxidative” Pummerer reaction (NOPR).5
To this end, the PMP groups of syn-4b,d,e were cleaved
oxidatively (CAN, 5 equiv), and then the amino groups were
a (a) (i) (S)-1a, LDA (2.0 equiv), THF, -78 °C to rt, 6 h, (80%);
(ii) Bu4NBH4, THF/MeOH, -70 °C to rt, 5 h, (>98%). (b), (c),
and (d) As in Scheme 1 [(R)-6d]. (e) PhCO2H, DCC, DMAP,
CH2Cl2, rt, 7 h (95%). (f) Br(CH2)nCHdCH2, NaH, DMF, 0 °C
[9a (n ) 1), 84%; 9b (n ) 2), 45%; 9c (n ) 3), 90%]. (g)
Cl2(PCy3)2RudCHPh (3-10 mol %), CH2Cl2 (0.01-0.005 M), rt,
[(R)-10a (n ) 1),75%; (R)-10b (n ) 2),87%].
The strategy consists of the diastereoselective reduction
of â-iminosulfoxide (S)-3j obtained by condensation reaction
of the hitherto unknown imidoyl chloride 2j14b and sulfoxide
(S)-1a14a to afford N-PMP â-aminosulfoxide syn-4j (entry
10, Table 1 and Scheme 2).
(10) The correct configuration assignments for these derivatives (syn-4
or syn-5) was unambiguously obtained by X-ray crystallographic analyses.
Because we were unable to obtain adequate single crystals for the major
diastereoisomer of 4 or 5, the relative stereochemistry of the new chiral
created center was determined by comparison with the X-ray structure of
the minor diastereoisomer anti-5e (RF ) CHF2, Ar ) 1-naphthyl, and R1
) p-MeOC6H4), which turns our to be (2R,SS)-5e. Full details of the X-ray
structure of (2R,SS)-5e will be published in a full account of this work.
(11) RCM has emerged as a prominent reaction for the synthesis of
medium- and large-sized rings from acyclic diene precursors. See, for
example: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (c) Morgan,
J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153-3155.
(12) RCM has been used to prepare a variety of nitrogen-containing
natural products including peptidomimetics: Phillips, A. J.; Abell, A. D.
Aldrichimica Acta 1999, 32, 75-89.
(13) For related systems, see: (a) Osipov, S. N.; Bruneau, Ch.; Picquet,
M.; Kolomiets, A. F.; Dixneuf, P. H. Chem. Commun. 1998, 2053-2054.
(b) Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.; Bruneau, Ch.; Dixneuf,
P. H. Synlett 2000, 1031-1033.
(6) (a) Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K. Tetrahedron
1993, 49, 11169-11182. (b) Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A. Ed.; Wiley: Chichester 1995; Vol. 7, pp 4722-
4724.
(7) For related examples, see: (a) Sakuraba, H.; Ushiki, S. Tetrahedron
Lett. 1990, 31, 5349-5352. (b) Heaton, N. J.; Bello, P.; Herrado´n, B.; del
Campo, A.; Jime´nez-Barbero, J. J. Am. Chem. Soc. 1998, 120, 9632-9645.
(8) π-Stacking between aromatic rings in protic solvents have been
described in the literature: (a) Kool, E. T.; Breslow, R. K. J. Am. Chem.
Soc. 1988, 110, 1596-1597. (b) Schumacher, D. P.; Clark, J. E.; Murphy,
B. L.; Fisher, P. A. J. Org. Chem. 1990, 55, 5291-5294.
(9) An efficient catalytic asymmetric synthesis of R-amino acids has been
very recently described. See: Abe, H.; Amii, H.; Uneyama, K. Org. Lett.
2001, 3, 313-315 and references therein.
Org. Lett., Vol. 3, No. 17, 2001
2623

Conversion into the N-Cbz derivative, followed by NOPR,
and O-protection furnished compound (R)-8. N-Alkylation
of (R)-8 with different alkenyl bromides gave oxazolidinones
(R)-9a-c,15 which in the presence of Grubb’s catalyst
(PCy3)2Cl2RudCHPh under high dilution conditions in dry
dichloromethane gave the cyclized derivatives (R)-10a,b with
good yields and high ee (>98%). The process works well
for seven- (n ) 1) and eight- (n ) 2) membered rings, yet
for nine-membered rings (n ) 3) dimerization and oligo-
merization products have been obtained instead.
Experiments are now underway to further exploit this
strategy.
Acknowledgment. The authors thank Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica (DGES PB97-0760-
C02-01 and PPQ2000-0824), M.U.R.S.T. COFIN (Rome)
and C.S.S.O.N. for financial support.
(14) For the preparation of enantiopure sulfoxides 1 and imidoyl halides
2, see: (a) Ferna´ndez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem.
1992, 57, 6789-6796. (b) Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda,
K. J. Org. Chem. 1993, 58, 32-36.
(15) Alternatively, (R)-9a-c can be directly obtained with slightly lower
yields by treatment of â-amino alcohol (R)-6d (RF ) CF2CH2CHdCH2)
with NaH followed by N-alkylation of the previously isolated N-unsubsti-
tuted oxazolidinone.
Supporting Information Available: Experimental pro-
cedures and analytical and spectroscopic data for compounds
2j and 4-10. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL016087Q
2624
Org. Lett., Vol. 3, No. 17, 2001