1,3-Asymmetric induction: Highly enantioselective synthesis of α-amino acids via 2,5-trans disubstituted imidazolidin-4-ones

Article abstract of DOI:10.1016/0040-4039(91)85016-X

2,5-Trans imidazolidin-4-ones have been obtained from mercury promoted cyclisation of unsaturated amidals containing a stereogenic centre. A new enantioselective synthesis of α-amino acids has been devised.

Full text of DOI:10.1016/0040-4039(91)85016-X

Totrahe&on Letters, Vol.32, No.17. pp 1971-1974, 1991
Printed inGreatBritain
004(? 4039/91 $3(?(?+.(?0
Pergamon Press plc
1,3-ASYMMETRIC INDUCTION: HIGHLY ENANTIOSELECTIVE SYNTHESIS OF
o:.AMINO ACIDS VIA 2,5-TRANS DISUBSTITUTED IMIDAZOLID1N-4-ONES
Rosa Amoroso, Giuliana Cardillo * and Claudia Tomasini
Centro per 1o Studio della Fisica delle Macromolecole
Dipartimento di Chimica "G. Ciamician" ~ Universitd di Bologna
Via Selmi, 2 ~ 40126 Bologna - ITALY
Summary : 2,5-Trans imidazolidin-4-ones have been obtained from mercury promoted cyclisation of
unsaturated amidals containing a stereogenic centre. A new enantioselective synthesis of t~-amino acids has
been devised.
The synthetic usefulness of electrophilic cyclofunctionalisations of double bonds is principally due to
the high degree of stereoselectivity obtained when substituents are present on the tether. In fact substituent
interactions play an important role during the fomaation of the heterocycle, owing to 1,2 and 1,3 conformational
constraints in the transition state. Furthermore different results can be obtained whether kinetic or
thermodinamic conditions are employed 1.
In this field an important contribution to the synthesis of 2,5-trans and 2,5-cis disubstituted
tetrahydrofurans starting from ethers has been reported by Bartlett 2. A similar behaviour has been described by
Harding for the synthesis of 2,5-disubstituted pyrrolidines 3. Furthermore a high 1,3 asymmetric induction has
been reported for the halolactonisation of ~- and ~,[~-substituted-y,8-unsaturated amides, ascribed to a i,3
strain between the substituents 4
In order to prepare chiral aminoalcohols under high stereoconrrol, a total 1,3 asymmetric induction has
been recently reported in the intramolecular amidomercuration reaction of substrates containing an intraannular
N,O-acetal stereogenic centre 5 and in the cyclisation of chiral N-acylaminomethyl ether derivatives 6.
In this work we wish to report an enantioselective synthesis of c~-amino acids 7 through the 1,3
asymmetric induction of mercury mediated intramolecular cyclisation of amidals. With this aim a new chiral
synthon has been depicted, starting from ethyl glyoxylate and (S)-l-phenylcthylamine. We have previously
demonstrated the synthetic utility of the (S)-l-phenylethylamine in the preparation of polifunctionalised
compounds, due to the preferential conformation that the stereogenic centre assumes when a carbonyl group is
present in the ot position 8.
By treatment of c~-chloro-N-benzyloxycarbamoylglycine 9 with (S)-l-phenylethylamine 10 and
triethylamine in dichloromethane, the ethyl N-benzyloxy N' phenylethyl-l,l-diaminoacetates la and lb have
1971

1972
been obtained quantitative yield in 1 : 1 diastereoisomeric ratio. The two diastereoisomers have been separated
by silica gel chromatography (Scheme 1) 11.
H
Ph
•
Pb~N~[tNHCO2Bn
C02Et
CH2C12
Me CO2Et
flash
chromatography
N--H
H
' -
°
+
0
O ~ p h
O--'Nph
( S , R ) - l a
[~]D = -61-8° (C = 0.05 in CHCI3)
(S,S)-lb
[l~]D = -65.3° (c - 0.05 in CHCI3)
S c h e m e
1
The absolute configuration of the newly formed chiral centre was assigned on comparison of IH NMR
spectra of ( S , R ) - l a (Hr 4.75 ppm; OCHTCH3 4.18 ppm) and (S,S)-lb (Hs 5.10 ppm, O C H ) C H3 3.95
ppm), that show a difference in the chemical shifts that may be attributed to the phenyl group shielding 8. Due
to the NH and carbonyl groups interactions that influence the molecular conformations, the PCMODEL 12
shows a preferential conformation for each compound, that accounts for the IH NMR indications: in the
diastereoisomer (S,R)-la Hr is shielded by the phenyl of the amine residue; on the other hand in (S,S)-lb
the phenyl shields the hydrogens of the methylene of the ethyl group 13 (Scheme 1).
The N-benzyloxy aminal (S,R)-la was conver~ed into the corresponding acrylamide 2a in 95% yield
by addition of wiethylamine and acryloyl chloride in dichloromethane (Scheme 2).
Me I~'CO2Et
÷
cl " ~ ' ~
CrhCl~
Mo n/:co2Et
( S , R ) - l a
2a
[a]D -- -77.7° (C = 0.01 in CHCI3)
S c h e m e
2
The cyclisation of amidal 2a (Scheme 3) with mercuric triflouroacetate in dichloromethane afforded at
room temperature the organomercurial 3a in 2 hours. The reductive cleavage of the carbon-mercury bond was
perfortned in acetonitrile with sodium boron hydride at room temperature for 20 minutes under argon. A single
compound in 80% overall yield was obtained, as shown in GLC analysis and 13C NMR. Furthemaore, as a
result of hindered rotation of the carbamate group around the amide bond 14, the IH NMR spectrum is rather
complex and shows a 1 : 1 mixture ofrotamers 15.

1973
Hg(COzCF3)2 F 3 C O 2 C H ~ . - ~ P h NaBH4
Me
OF~Ph
(t equiv.)
CH3CN
~
X
.
~
-
P h~,~ N~NHC~)2Bn (I equiv.)
I~
~
"-_ x. ~H
~O2Et
~
H
~O2Et
Me FI/~CO2Et
CH2C12
H....~ph
H
H . _ ~ p h
Me (2R,5R,I'S)-4a
[et]D = -96.2° (c = 0.02 in CHCI3)
a
Me
2a
(2R,SR,I'S)-3a
S c h e m e
3
With the same procedure, the cyclisation of amidal 2b, obtained from compound ( S , S ) - l b and
acryloyl chloride, afforded, after reduction, the imidazolidin-4-one 4h in 75% overall yield as a single product
(Scheme 4).
Hg(COzCF3)2
O•
~ L - CO2Et
N(1aBeqHu4iv.)
p h , ~ N¢~NHCO2Bn (1 equiv.)
CH2C12
li-
Me
H CO2Et
Me
HgCO2CF3
Me
(2S,5S,1'S)-3b
(2S,5S,1'S)-4b
[ct]D = -16.6° (c = 0.01 in CHCI3)
2b
[CX]D = -108.6° (C = 0.02 in CHC13)
S c h e m e
4
The absolute configuration of the new stereogenic centre C-5 of the imidazolidin-4-ones 4a and 4b was
determined by comparison of the 4a and 4b 1H NMR spectra 15
Moreover the attribution was confirmed by hydrolysis of 4a in concentrated HCI and methanol (Scheme
5). A naixture of starting (S)-l-phenylethylamine bydrochloride and D-alanine hydrochloride was obtained. The
co-amino acid was characterised as its ethyl benzoyl derivative 6, for which [cq D value confirms the chiral
purity and the absolute configuration of 4a 16.
Me
.2~- 0 1 ~ Ph
Cl
NH3+
1. SOCI2/EtOH
2.
I N
X:
Et02C
NHCOPh
O
N
~
:
HCI/MeOH
HOOC
Me
(2R,5R,I'S)-4a
5
6
D - a l a n l n e
[a]D = + 7.71° (c = 0.0l in EtOH)
S c h e m e
5
In conclusion this work describes the complete 1,3 asymmetric induction obtained with the chiral
synthons l a and l b that allows to obtain exclusively the 2,5-trans imidazolidin-4-ones 4a and 4b. In fact
between the two possible transition states A and B, the 1,3 diaxialdike interaction disfavours the cis
configuration of B, favouring the more stable transition state A.

1974
H
H~ . N O ~ 2 g B C nO2CF3
H ~ N ~ - - ~~NHCO2Bn
"co2Et
M/'Ph
A
B
Moreover the synthons (S,R)-la and (S,S)-lb are inexpensive, easily prepared, and the chiral
auxiliary (S)-1-phenylethylamine is completely recovered after the hydrolysis of the heterocycle.
Acknowledgement
We thank Italian C.N.R. (Progetto Finalizzato 'Chimica Fine e Secondaria') for financial support.
References
1.
Bartlett P. A., in Asymmetric Synthesis, Morrison J. D., Ed.; Academic Press, New York, Vol. 3,
1984.
2.
3.
Rychnovsky S. D., Bartlett P. A. J. Am. Chem. Soc. 1981, 103, 3963.
(a) Harding K. E., Burks S. R. J. Org. Chem. 1984, 49, 40; (b) Harding, K. E., Mamaan T. H. J.
Org. Chem. 1984, 49, 2838.
Tamaru Y., Mizutani M., Furukawa Y., Kawamura S., Yoshida Z., Yanagi K., Minobe M. J. Am.
Chem. Soc. 1984, 106, 1079.
4.
5.
6.
7.
8.
Takacs J. M., Helle M. A., Yang L. Tetrahedron Lett. 1989, 30, 1777.
Harding K. E., Honingsworth D. R., Reibenspies J. Tetrahedron Lett. 1989, 30, 4775.
Amoroso R., Cardillo G., Tomasini C. Tetrahedron Lett. 1990, 44, 6413.
(a) Bongini A., Cardillo G., Orena M., Poral G., Sandfi S. Chemistry Lett. 1988, 87; (b) Cardillo
G., Orena M. Tetrahedron 1990, 46, 3321.
9.
Bernstein Z., Ben-Ishai D. Tetrahedron 1977, 33, 881.
10
(S)-l-Phenylethylamine was purchased by Janssen and distilled. The experimental [Ct]D value was -36°
(neat).
11
12.
All new compounds have been fully characterised by IR, 1H NMR, 13C NMR and high resolution MS.
PCMODEL, Serena Software, BOX 3076, Bloomington, IN 47402-3076.
13.
(S,R)-la: 300 MHz 1H NMR (CDC13) 8 (ppm) 1.26 (t, 3H, CH2CH~_), 1.35 (d, 3H, N-CH-CH2),
2.38 (bs, 1H, NH), 3.97 (q, 1H, N-CH-CH3), 4.18 (q, 2H, O.Q~2CH3), 4.75 (d, 1H, N-CH-N),
5.12 (s, 2H, OCH2Ph), 5.40 (d, 1H, NHCO2Bn), 7.35 (m, 10H, Ph~
(S,S)-lb: 300 MHz 1H NMR (CDCI3) 8 (ppm) 1.25 (t, 3H, CH2C~3_), 1.40 (d, 3H, N-CH-Q~_),
2.40 (bs, 1H, NH), 3.95 (q, 2H, OCH2CH3), 4.10 (q, 1H, N-CH-CH3), 5.10 (m, 3H, N-CH-N +
OCH2Ph), 5.50 (d, 1H, NHCO2Bn), 7.3-5 (m, 10H, Ph)
14.
15.
Hiemstra H., Fortgens H. P., Stegenga S., Speckamp W. N. Tetrahedron Lett. 1985, 26, 3151.
(2R,5R,I'S)-4a: 300 MHz 1H NMR (CDC13) 8 (ppm) 1.02 and 1.26 (t, 3H, J = 6.3 Hz,
O C H 2 C ~ ) , 1.48 and 1.57 (d, 3H, J = 7.0 Hz, OC-CH-C_Q_H_~), 1.52 and 1.55 (d, 3H, J = 7.3 Hz,
N-CH-~Jd3), 3.78 and 4.19 (q, 2H, J = 6.3 Hz, O~H.2CH3), 4.36 and 4.39 (q, 1H, J = 7.0 Hz,
OC-CH-CH3), 4.87 and 4.90 (s, 1H, N-CH-N), 5.08 (AB, 2H, CH2Ph), 5.48 and 5.51 (q, 1H,
J = 7.3 Hz, N-CH-CH3), 7.35 (m, 10H, Ph).
(2S,SS,I'S)-4b: 300 MHz IH NMR (CDCI3) 8 (ppm) 0.75 and 0.96 (t, 3H, J = 7.1 Hz,
OCH2CQ~_H ), 1.53 and 1.61 (d, 3H, J = 6.7 Hz, O C - C H - ~ _ ) , 1.72 and 1.73 (d, 3H, J = 7.1 Hz,
N-CH-C..Q_~H ), 3.14 and 3.47 (ABX3, 2H, J = 6.3 Hz, OCHgCH3), 4.38 and 4.42 (q, 1H, J = 6.7 Flz,
OC-CH-CH3), 5.10 (AB, 2H, CH2Ph), 5.29 and 5.32 (s,-1H, N-CH-N), 5.55 (q, 1H, J = 7.1 Hz,
N-CH-CH3), 7.35 (m, 10H, Ph).
16.
The [CqD value of ethyl benzoyl L-alanine is - 7.78° (c = 0.73 in EtOH): Andersen T. P., Ghattas A.-B.
A. G., Lawesson S.-O. Tetrahedron 1983, 39, 3419.
(Received in UK 21 December 1990)