Highly diastereoselective synthetic route to enantiopure β2-amino acids and γ-amino alcohols using a fluorinated oxazolidine (Fox) as chiral auxiliary

Article abstract of DOI:10.1021/jo800562x

(Chemical Equation Presented) The alkylation reactions of an amide enolate derived from a trifluoromethylated oxazolidine (Fox) chiral auxiliary occur with a complete diastereoselectivity and in good yields with various electrophiles. This reaction provid

Full text of DOI:10.1021/jo800562x

a challenge to find a suitable chiral auxiliary which would
combine complete diastereoselectivity and good reactivity with
hindered halogenated compounds such as isobutyl and isopropyl
iodides. We recently reported the highly diastereoselective
alkylation of amides enolates using a trifluoromethylated
oxazolidine (Fox) as the chiral auxiliary.5 In the present paper,
we report now a new facet of the use of the Fox chiral auxiliary
for a straightforward synthetic route to various enantiopure ꢀ2-
amino acids and γ-amino alcohols through diastereoselective
alkylation of a unique chiral homoglycine precursor.
Highly Diastereoselective Synthetic Route to
Enantiopure ꢀ2-Amino Acids and γ-Amino
Alcohols Using a Fluorinated Oxazolidine (Fox)
as Chiral Auxiliary
Arnaud Tessier, Nour Lahmar, Julien Pytkowicz, and
Thierry Brigaud*
Laboratoire “Synthe`se Organique Se´lectiVe et Chimie
Organome´tallique” (SOSCO), UMR CNRS 8123,
UniVersite´ de Cergy-Pontoise, 5,
The starting N-ꢀ-aminopropanoyloxazolidine 3a was conve-
niently prepared from (R)-phenylglycinol and fluoral based
oxazolidines 1a,b6 in a two-step procedure. The one-pot
N-acylation/dehydrochlorination reaction of the 1a,b diastere-
omeric mixture with 3-chloropropanoylchloride in triethylamine
gave the corresponding trans- and cis-N-propenoyloxazolidines
2a and 2b in very good isolated yield after an easy silica gel
Mail Gay Lussac NeuVille sur Oise 95031,
Cergy-Pontoise Cedex, France
thierry.brigaud@u-cergy.fr
ReceiVed March 12, 2008
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The alkylation reactions of an amide enolate derived from a
trifluoromethylated oxazolidine (Fox) chiral auxiliary occur
with a complete diastereoselectivity and in good yields with
various electrophiles. This reaction provides a versatile and
straightforward strategy for the synthesis of ꢀ2-amino acids
and γ-amino alcohols in enantiopure form.
ꢀ2-Amino acids are finding an increasing interest because of
their biological properties.1 Moreover, their incorporation into
a peptide chain gives rise to the formation of well-defined
ꢀ-peptide secondary structures2 associated with specific biologi-
cal activities. For these reasons, several chiral auxiliary-based3
or catalytic asymmetric methods4 have recently been reported
for their preparation. From all of these strategies, it appears that
the stereoselective alkylation of a homoglycine-type precursor
would be one of the more versatile methods for the synthesis
of enantiomerically pure compounds, provided that the control
of the stereoselectivity is total to avoid tedious separations and
that the reaction is general. However, until now there has been
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3970 J. Org. Chem. 2008, 73, 3970–3973
10.1021/jo800562x CCC: $40.75 2008 American Chemical Society
Published on Web 04/18/2008

SCHEME 1. Synthesis of N-ꢀ-Aminopropanoyloxazolidines
3a,b
SCHEME 2. Benzylation Reaction with the cis-Fox Chiral
Auxiliary
of (S)-4a was present in the crude reaction mixture. The
alkylation with benzyl bromide, allyl bromide, and ethyl iodide
was also performed in good yield and with complete diaste-
reoselectivity (Table 1, entries 2-4). Interestingly, the reaction
with more hindered halogenated compounds such as isobutyl
iodide and isopropyl iodide giving rise to ꢀ2-homoleucine and
ꢀ2-homovaline precursors were also completely diastereoselec-
tive (Table 1, entries 5 and 6). However, longer reaction times,
higher temperature (-50 °C), and 4-8 equiv of electrophiles
were necessary for these reactions. To our knowledge, the direct
introduction of an isopropyl group has only previously been
reported by Davies et al. to occur in a very low yield (8%)
using the SuperQuat chiral auxiliary.3a,b Moreover, Lavielle et
al.3e reported that the enolate alkylation reaction with isobutyl
iodide failed using Oppolzer’s sultam chiral auxiliary, and these
authors had to use the more reactive triflate to succeed in
introducing the isobutyl side chain. Very recently, Davies et
al.3a and Karoyan et al.3c circumvented this difficulty by
diastereoselective conjugate addition of lithium amide or
Mannich-type reaction. Therefore, the completely diastereose-
lective direct introduction of isopropyl and isobutyl groups that
we are reporting now can be considered as a significant
improvement for the general synthesis of ꢀ2-amino acids.
As we had the cis-Fox precursor 3b in hand, we then decided
to investigate the performance of the cis chiral auxiliary in the
stereoselective benzylation reaction (Scheme 2). Using this chiral
auxiliary, the stereoselectivity of the benzylation was very low.
As we have previously reported,5 this is probably due to the
absence of pseudo-C2 symmetry of this chiral auxiliary.
Using the benzylated diastereomerically pure amide (R)-5a
as a representative substrate, we then performed the removal
of the Fox chiral auxiliary in order to obtain enantiopure ꢀ2-
homophenylalanine (R)-10 and the corresponding γ-amino
alcohol (R)-11. In both cases, these transformations were
conveniently achieved in a two-step procedure involving a
LiAlH4 reduction of (R)-5a followed by the oxidation or the
NaBH4 reduction of the intermediate amino aldehyde (Scheme
3). As the trans-Fox chiral auxiliary proved to be stable in
oxidation and NaBH4 reduction conditions, the mixture of amino
aldehyde and oxazolidine 1a was engaged in the next step
without purification. The ꢀ2-homophenylalanine (R)-10 and the
amino alcohol (R)-11 were then obtained in good isolated yield
after silica gel separation with a satisfactory recovery of the
trans-Fox chiral auxiliary.
TABLE 1. Alkylation of 3a
entry
RX
product
yielda (%)
deb (%)
1
2
3
4
5
6
MeIc
BnBrc
allylBrc
EtIc
(R)-4a
(R)-5a
(R)-6a
(R)-7a
(R)-8a
(R)-9a
84
86
82
80
51
51
>98
>98
>98
>98
>98
>98
iBuId
iPrIe
a Yield of pure isolated product. b One single diastereomer was detected
by 19F and 1H NMR spectroscopy analysis of the crude reaction mixture.
c Reactions conditions: 1.9 equiv of halogenated compound, 3 h, -78
°C. d Reaction conditions: 4 equiv of halogenated compound, 24 h, -50 °C.
e Reaction conditions: 8 equiv of halogenated compound, 36 h, -50 °C.
separation7 (Scheme 1). This procedure proved to be much more
efficient than the direct N-propenoylation of 1a,b with acryloyl
chloride leading mainly to polymerization. Both isolated trans-
and cis-oxazolidines 2a and 2b were then submitted to a Michael
addition of dibenzylamine to give the corresponding N-ꢀ-
aminopropanoyloxazolidine 3a and 3b in 87% and 75% yield,
respectively. Hence, the performance of both trans- and cis-
Fox chiral auxiliary will be compared for the diastereoselective
alkylation reaction.
As we anticipated that the highest diastereoselectivity would
be achieved with the substrate 3a bearing a trans-Fox chiral
auxiliary,5 the NaHMDS-promoted alkylation reaction of 3a was
performed using various halogenated electrophiles (Table 1).
Using this trans chiral auxiliary, all of the alkylation reactions
occurred with excellent diastereoselectivity. In all cases, only
one single diastereomer was detected by 19F or 1H NMR
spectroscopy or GC analysis of the crude reaction mixtures. The
complete diastereoselectivity of the methylation of 3a (Table
1, entry 1) was confirmed by epimerization of (R)-4a into (S)-
4a with sodium methylate proving that no measurable amount
The (R) configuration of 11 was assigned by the comparison
of its optical rotatory value with literature data.8 In order to
confirm the R configuration of 10 and to have a ꢀ2-amino acid
ready to use in peptide synthesis, (R)-10 was hydrogenolized
using Pearlman’s catalyst and protected with a Boc group to
afford the known N-Boc-ꢀ2-homophenylalanine (R)-12.9 The
comparison of its optical rotatory value with literature data
(7) The silica gel separation of trans- and cis-oxazolidines 2a and 2b was
very efficiently achieved because of a large Rf difference between the two
diastereomers (∆Rf ) 0.17, cyclohexane/ethyl acetate: 80/20).
(8) (a) Reference 4b. (b) Ibrahem, I.; Zhao, G.-L.; Co´rdova, A. Chem. Eur.
J. 2007, 13, 683–688.
(9) For the (R)-enantiomer, see ref3c, e. For the (S)-enantiomer, see ref 4a.
J. Org. Chem. Vol. 73, No. 10, 2008 3971

SCHEME 3. Transformation of (R)-5a into ꢀ2-Amino Acid
and γ-Amino Alcohol with Recovery of the Chiral Auxiliary
FIGURE 1. Postulated transition states, both leading to re face attack
of the enolate.
performed with hindered isobutyl and isopropyl iodides. Further
synthetic applications toward the synthesis of unnatural amino
acids synthesis are ongoing.
SCHEME 4. Derivatization of the Amino Acid (R)-10
Experimental Section
Typical Procedure for Alkylation Reactions: Synthesis of
(2S,4R)-2-Trifluoromethyl-4-phenyl-3-((2R)-3-N,N-dibenzyl-2-
methylaminopropanoyl)oxazolidine ((R)-4a). To a solution of the
amide 3a (0.532 g, 1.14 mmol) in THF (10 mL) was added
dropwise a NaHMDS (1.4 mL of 2 M solution in THF, 2.79 mmol)
at -78 °C under argon atmosphere. The resulting yellow solution
was stirred for 1.5 h, and the methyl iodide (396 mg, 2.79 mmol)
was added at this temperature. The mixture was stirred for 3 h at
-78 °C and hydrolyzed with a saturated solution of NH4Cl (15
mL). The aqueous layer was extracted successively with diethyl
ether (2 × 30 mL) and dichloromethane (30 mL). The combined
organic layers were dried over magnesium sulfate and evaporated
under reduced pressure. The crude mixture was purified by silica
gel chromatography (cyclohexane/ethyl acetate: 96/4) to give (R)-
4a (460 mg, 84%) as a white solid: [R]25D +19.8 (c 2.75, CHCl3);
1
mp ) 103 °C; Rf ) 0.35 (cyclohexane/ethyl acetate: 90/10); H
NMR (400 MHz, CDCl3) δ 1.13 (d, 3H, 3J ) 6.4 Hz), 1.92 (d, 1H,
confirmed its (R) configuration (Scheme 4). Finally, the enan-
tiopurity of (R)-12 was confirmed by formation of the (R)-
phenylethylamide derivative (R,R)-13, which was obtained as
a single diastereomer.10
The (R) configuration of the unique diastereomer is in good
agreement with a favored re face alkylation of the Z amide
enolate. To explain the excellent diastereoselectivity, we propose
the coexistence of two transition states presenting F · · ·Na or
π· · ·Na interactions (Figure 1).11 Due to the pseudo-C2 sym-
metry of the trans-Fox chiral auxiliary, both transition states
will give the same (R) diastereomer through re face alkylation
of the enolate.
2
2J ) 10.1 Hz), 2.45 (m, 2H), 2.72 (d, 2H, J ) 14.2 Hz), 3.09 (d,
2
2
2
2H, J )14.2 Hz), 4.05 (d, 1H, J ) 8.7 Hz), 4.68 (dd, 1H, J )
8.7 Hz, 3J ) 6.4 Hz), 4.99 (d, 1H, 3J ) 6.4 Hz), 6.13 (q, 1H, 3JH-F
) 5.0 Hz), 7.12-7.30 (m, 15H); 19F NMR (376.2 MHz, CDCl3) δ
-80.67 (d, 3 F, JH-F ) 5.0 Hz); 13C NMR (100.5 MHz, CDCl3)
3
δ 16.8, 37.9, 54.6, 57.9, 60.4, 76.5, 85.1 (q, CH, 2JC-F ) 38.3 Hz),
123.4 (q, C, 1JC-F ) 288.5 Hz), 125.5, 126.7, 128.1, 128.7, 129.6,
139.2, 141.9, 176.4; IR ν 3034, 2980-2798, 1661, 1281, 1227,
1178, 1147, 745, 700 cm-1; MS (EI) 481 (1), 405 (1), 391 (59),
286 (2), 210 (77), 174 (6), 118 (7), 91 (100). Anal. Calcd for
C28H29F3N2O2: C, 69.69; H, 6.06; N, 5.81. Found: C, 69.39; H,
6.10; N, 5.59.
In conclusion, we have developed a useful and straightforward
route to enantiopure ꢀ2-amino acids and γ-amino alcohols using
the trans-Fox chiral auxiliary. A key feature of this strategy is
that the diastereoselective alkylation step can even be efficiently
(2R)-2-Benzyl-3-(N,N-dibenzylamino)propanoic Acid ((R)-10).
LAH (0.135 g, 3.8 mmol) was added portionwise to a solution of
the amide (R)-5a (0.384 g, 0.68 mmol) in anhydrous diethyl ether
(8 mL) at -10 °C. The reaction was stirred for 2.5 h at this
temperature and was smoothly hydrolyzed at -10 °C with a
saturated NaCl solution. The mixture was extracted with diethyl
ether (2 × 20 mL) and dichloromethane (20 mL). The combined
organic layers were washed by a saturated ammonium chloride
solution and dried over anhydrous magnesium sulfate, and the
solvents were removed under reduced pressure. At this stage, the
intermediate aldehyde was characterized by 1H NMR and engaged
in the next step without further purification. To a solution of the
(10) In order to confirm the diastereomeric purity of (R,R)-13, the same 5 to
13 reaction sequence was performed from the (R)- and (S)-5b mixture giving a
(R,R)- and (S,R)-13 mixture. Comparison of the 1H and 13C NMR spectra clearly
established the complete diastereomeric purity of (R,R)-13.
(11) Sini, G.; Tessier, A.; Pytkowicz, J.; Brigaud, T. Chem. Eur. J. 2008,
14, 3363–3370.
(12) Litt value: [R]D -44.1 (c 0.14; MeOH, as hydrochloride salt). Chi, Y.;
Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804–6805.
3972 J. Org. Chem. Vol. 73, No. 10, 2008

crude material in terbutyl alcohol (16 mL) at room temperature
was added a 2 M solution of 2-methylbut-2-ene in tetrahydrofuran
(110 mL, 220 mmol), and a solution of sodium chlorite (NaClO2,
0.860 g, 9.5 mmol) and sodium dihydrogenophosphate monohydrate
(NaH2PO4, 1.18 g, 7.5 mmol) in water (10 mL). The yellow biphasic
mixture was vigorously stirred 1 h at room temperature and water
was added (50 mL). The mixture was extracted with a cyclohexane/
ethyl acetate mixture (9/1), dried over magnesium sulfate, and
concentrated under reduced pressure. The resulting crude material
was purified by flash chromatography (cyclohexane/ethyl acetate:
4.5/5.5) to yield oxazolidine 1a as a colorless oil (120 mg; 78%)
mL). The organic layer was extracted with dichloromethane (10
mL), dried over magnesium sulfate, and evaporated under reduced
pressure to give 616 mg of crude material which was purified by
flash chromatography (cyclohexane/ethyl acetate 9/1) to afford 1a
as a colorless oil (102 mg, 43%) and (R)-11 as a colorless oil (214
mg, 78%): [R]25D -37.9 (c 0.1; MeOH, as hydrochloride salt1); 1H
NMR (400 MHz, CDCl3) δ 2.24-2.37 (m, 3H), 2.44 (ddd, 1H, 2J
3
2
3
) 11.2 Hz, J ) 2.2 Hz), 2.56 (dd, 1H, J ) 12.3 Hz, J ) 10.5
Hz), 3.15 (d, 2H, 2J ) 13.2 Hz), 3.30 (dd, 1H, 2J ) 10.5 Hz, 3J )
2
3
8.2 Hz), 3.66 (ddd, 1H, J ) 10.5 Hz, J ) 2.2 Hz), 3.93 (d, 2H,
2J ) 13.2 Hz), 5.41 (broadband, 1H), 7.06-7.29 (m, 15H); 13C
NMR (100.5 MHz, CDCl3) δ 27.0, 36.5, 38.5, 58.9, 59.0, 68.4,
127.5, 128.5, 128.6, 129.0, 129.4, 137.8, 140.0; IR ν 2922, 1653,
and amino acid (R)-10 as a colorless oil (180 mg, 72%): [R]25
D
1
-56,4 (c 1; MeOH); H NMR (400 MHz, CDCl3) δ 2.53-2.56
1494, 1452, 1364, 1280 cm-1
.
(m, 2H), 2.71-2.73 (m, 2H), 3.21 (dd, 1H, 2J ) 14.2 Hz, 3J ) 3.6
2
2
Hz), 3.43 (d, 2H, J ) 13.2 Hz), 3.72 (d, 2H, J ) 13.2 Hz),
7.15-7.26 (m, 15H); 13C NMR (100.5 MHz, CDCl3) δ 26.7, 34.8,
41.9, 53.5, 57.2, 125.7, 126.2, 127.8, 128.3, 128.7, 129.3, 134.9,
Acknowledgment. We thank the French ministry of research
for awarding a research fellowship to A.T. and Central Glass
Company for financial support and the generous gift of
trifluoroacetaldehyde hemiacetal.
139.0, 175.6; IR ν 3027, 1708, 1602, 1494, 1453, 908, 732 cm-1
.
Anal. Calcd for C24H25NO2: C, 80.19; H, 7.01; N, 3.90. Found: C,
79.85; H, 6.97; N, 4.05.
(2R)-3-(N,N-Dibenzylamino-2-benzylpropan-1-ol ((R)-11). To
535 mg of a crude mixture of (2R)-2-benzyl-3-(N,N-dibenzylami-
no)propanal and (2S,4R)-2-trifluoromethyl-4-phenyloxazolidine 1a
in methanol (5 mL) was added sodium borohydride (41.6 mg, 1.1
mmol) at ambient temperature. The solution was stirred for 2 h at
ambient temperature and quenched by slow addition of water (5
Supporting Information Available: General experimental
methods, complete experimental procedures, and characteriza-
tion data for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO800562X
J. Org. Chem. Vol. 73, No. 10, 2008 3973