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Asymmetric Synthesis of -Alkyl--aminocarboxylic Acids by Alkylation of 1-chiral-Substituted 2-Imidazolin-5-ones.

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[140] J . Rosenthal, S. Winstein. unpublished results cited by P. Warner in
Pbl.
[141] L. A . Paquette. H . C . Berk, C . R . Degenhardt, G . D. Ewing, J. Am.
Chem. SOC.99, 4764 (1977).
[1421 Compare the more general conclusions of M . J . Goldstein, R . Hoflmann,
J. Am. Chem. SOC.93, 6193 (1971).
[I431 L. N . Domelsmith, K . N . Houk, C . R . Degenhardt, L. A . Paquette,
J. Am. Chem. SOC.100, 100 (1978).
[I441 P. Radlick, S. Winstein, J. Am. Chem. SOC.85, 345 (1963); K . Untch,
ibid. 85, 345 (1963); W . R . Roth, Justus Liebigs Ann. Chem. 671,
10 (1964).
[145] R . B. Woodward, 7: Fukunaga, R . C . Kelly, J. Am. Chem. SOC.86,
3162 (1964); I . T. Jacobson, Acta Chem. Scand. 21, 2235 (1967); C.
Mercier, P. Soucy, W Rosen, P. Deslongchamps, Synth. Commun. 3,
161 (1973); M . J . Wyuraft, L. A . Paquette, Tetrahedron Lett. 1974,
2433.
[146] A . de Meijere, D . Kaufmann, 0 . Schallner, Angew. Chem. 83, 404
(1971); Angew. Chem. Int. Ed. Engl. 10, 417 (1971).
[147] W R . Roth, W P. Bang, P. Gobel, R . L. Sass, R . B. Turner, A . P.
Tu, J. Am. Chem. SOC.86, 3178 (1964).
[148] J . Aihara, J. Am. Chem. SOC.98, 2750 (1976).
11491 P. BischoJ R . Gleiter, E. Heilbronner, Helv. Chim. Acta 53, 1425
( 1970).
[150] J . C . Bunzli, D . C. Frost, L. Weiler, Tetrahedron Lett. 1973, 1159;
P. Bischoj; D. Bosse, R . Gleiter, M . J . Kuklu, A . de Meijere, L. A .
Paquette, Chem. Ber. 108, 1218 (1975).
[151] E. D . Stevens, J . D . Kramer, L. A . Paquette, J. Org. Chem. 41, 2266
(1976).
[I521 E. Heilbronner, R . Gleiter, 7: Hoshi, A . de Meijere, Helv. Chim. Acta
56, 1594 (1973).
[153] R . W Thies, M . Gasie, D . Whalen, J . B. Grutzner, M . Sukui. B. Johnson,
W Winsrein, J. Am. Chem. SOC. 94, 2262 (1972); R . W Thies, M .
Sakui, D. Whalen, S. Winstein, ibid. 94, 2270 ( 1 972).
[154] R . S . Boikess, S . Winstein, J. Am. Chem. SOC.85, 343 (1963).
M . R . Dertj', L. A . Paquerte, Tetrahedron Lett. 1977, 347.
[156] H . Prinzbuch, 1/: Wessely, H . Fritz, Tetrahedron Lett. 1976, 2765.
[155]
[157] M . J . Goldstein, S . Natowsky, E. Heilbronner, I! Hornung, Helv. Chim.
Acta 56, 294 (1973); G. Bieri, E. Heilbronner, M . J . Goldsrein, R .
S . Leight, M . S. Lipton, Tetrahedron Lett. 1975, 581.
[158] H . E. Simmons, 7: Fukunaga, J. Am. Chem. SOC.89, 5208 (1967);
R . Hofmann, A . Imamura, G . D . Zeiss, ibid. 89. 521 5 (1967); A. Tajiri,
7: Nakajima, Tetrahedron 27, 6089 (1971); M . F . Semmelhuck, J .
S . Foos, S . Katz, J. Am. Chem. SOC.95, 7325 (1973); M . D. Gordon,
7: Fukunaga, H . E . Simmons, ibid. 98, 8401 (1976).
[159] J . A. Berson, L. Salem, J. Am. Chem. Soc. 94. 8918 (1972).
C 0 M MU N I CAT1 0 N S
Asymmetric Synthesis of a-Alkyl-a-aminocarboxylic
Acids by Alkylation of 1-chiral-Substituted 2-Imidazolin-lones['l
By Ulrich Schollkopf, Hans Heinrich Hausberg, Inga Hoppe,
Marcos Segal, and U d o Reiterr]
Owing to the immensely important role played by optically
active amino acids in pure and applied chemistry, asymmetric
amino acid synthesis has attracted especial interest. Of preparative importance, however, are only those methods which
[*] Prof. Dr. U. Schollkopf, Dr. H.-H. Hausberg, Dr. I. Hoppe, Dipl.-Chem.
M. Segal, Dip1.-Chem. U. Reiter
Organisch-chemisches Institut der Universitat
Tammannstr. 2, D-3400 Gottingen (Germany)
Angew. Chem. Int. Ed. Engl. 17 (1978) No. 2
a) are relatively easy to carry out with good chemical yields,
b) give high optical yields, and c) enable recovery of the
chiral auxiliary agent[".
We wish to report an asymmetric synthesis of a-alkyl-aamino acids ( 1 I ) , which in many cases satisfies these requirem e n t ~ [ ~The
! 4-metalated 4-alkyl-1-[(S)-l-phenylethyl]-2-imidazolin-5-ones (76) or their tautomers (8) are alkylated with
RZ-Hal ( 9 ) and the resulting 4,4-disubstituted imidazolinones
(10) hydrolyzed to the amino acids ( I I). After the hydrolysis
the (S)-I-phenylethylamine (2) used for the synthesis of (7),
can be recovered. In the case of alkylating agents (9) with
large R2 groups, e.g. benzyl halides, the asymmetric induction at C-4 of (10) is almost 100%; it decreases with
decreasing size of R2 (cf. Table 1). The stereoselectivity
of the reaction can be determined 'H-NMR spectroscopically at the stage of the imidazolinone ( 1 0) (usually at 60 MHz
and without shift reagents), preferably by observing the doublet
of the methyl protons of the phenylethyl moiety, which shows
different chemical shifts in the two diastereomers. An induction
of >95 % (cf. Table 1) is assumed if only one diastereomer
is recognizable in the NMR spectrum.
The 2-imidazolin-5-ones ( 7 a ) are obtained either from the
(S)-a-aminoN-phenylethylcarboxamides with or tho form ate^[^^
or, better, by base-induced cyclization of the (S)-N-phenylethyl-2-isocyanoalkanamides ( 3 ) - ( 4 ) .
Isolation of the
imidazolinone ( 7 a) is, however, unnecessary. Reaction of
the amides ( 3 ) to (4)-prepared
from methyl 2-isocyanoalkanoate ( 1 ) and (S)-1-phenylethylamine (2)-with one equivalent of a metalating agent (M-base such as butyllithium,
potassium tert-butoxide, sodium hydroxide etc.) leads to the
4-metalated imidazolinones (7b) in situ. The cyclization
( 6 ) -++(7b) proceeds apparently rapidly, so that the same
results can be achieved with this (more convenient) in situ
method [Method A, cf. Table t ] as when starting from ( 7 a ) .
In some experiments we used (S)-N-phenylethylisocyanoacetamide ( 5 ) as starting compound. Twofold metalation
117
of (5) with two equivalents of butyllithium and subsequent
reaction with R'-Hal afforded the intermediate (6), M =Li,
which cyclized to (7b)*(8), from which (10) was finally
obtained by reaction with R2-Hal [Method B, cf. Table 11.
In order to achieve the highest possible optical yield via this
route it would seem advisable to first incorporate the smaller
substituents as R'-Hal [cf. in Table 1 e . g . (JUa) with (JOo),
(JUj) with ( J U p ) ] . As expected the preferred configuration
at C-4 of (10) changes if the sequence of incorporation of
R' and R2 is changed [cf. in Table 1 e . g . (JUa) with ( l o o ) ,
( J o n )with ( J o t ) , (101) with (JUq)].
Hydrolysis of the 4,4-disubstituted imidazolinones (1 0)
necessitates more or less drastic conditions, depending on
the nature of R' and RZ. In principle, the hydrolysis can
be carried out under acid or alkaline conditions. Thus,
e. g., we obtained (S)-a-methylphenylalanine (I J a ) by acid
hydrolysis [from (IUa)][5], but later found out that alkaline
hydrolysis (with K O H in ethanol/water, glycol/water etc.) was
more suitabler6! The amino acids ( I I ) have been characterized
by way of their (readily crystallizing) N-acetyl derivatives
( I 2)[61.
With (S)-configuration of the I-phenylethyl group ( L * b a s
revealed by the synthesis of the configuratively known @)-amethylphenylalanine[31 (J I a) and (S)-a-methyl-DOPA[61the configuration shown in formulas (10) and (I I ) is induced
[S when RZ has priority over R', otherwise R ] . The following
model concept explains this finding: in the most favorable
conformation for (8) the hydrogen atom in the ring plane
of the heterocycle is oriented towards the oxygen atomL7',
which+omplexed with metal atom and solvent-is the "largest" neighbor. Methyl and phenyl groups lie below and above
the diastereotopic heterocyclic plane [cf. ( 1 3 ) ] ; for steric reasons RZ preferably enters at that side which bears the smaller
methyl group. Accordingly, the degree of induction depends
on the size of the entering group R2 [cf. in Table 1 e.g.
( 3 ) . R' = CH,
( 4 ) j R' = CHzCcjH,
( 5 ) , R' = H
( l o ) : L" = (S)-1-Phenylethyl
R',R2 s e e Table 1
NHX
CBH5
( l l ) ,X = H
(121, X = A c
(JOo) with ( I o n ) ] , and not on that of the stationary substituents R' [cf. in Table 1 (JOa), (10i)-(10n)]18J.
Experimental
(S)-N-phenylethyl-2-isocyanoalkanamides
(3)-(5): (S)-1phenylethylamine (2) (12.1 g, 0.1 mol) and ( I ) (0.1 mol) are
Table 1. Synthesized 2-imidazolin-5-ones (10) and N-acetylamino acids (12).
R'
Method [a]
(10)
Yield [b]
[%]
A
B
[fl
A [dl
A
A
A
A
A
B
B
B
B
B
B
A
A
A
A
A
A
60
86
90
84
87
80
87
88
85
75
77
78
67
72
89
86
62
72
75
87
112)
Optical
yield [b]
>95,90 [d]
100
66
72 [5]
> 95
> 95
> 95
> 95
> 95
95
90
90
95
95
100
20
43
65
55, 50 [d]
31
100
Config.
(c. Solvent) [c]
[a];'
4.7"
M.p. r C ]
(1.05, 1~ HCI) [el
S
S
-
S
-28.8"
(2.0, CHaOH) [gl
- 4.4" ( I .O, I N HC1) [h] [S]
-91.38" (1.08, CHIOH)
- 92.31' (1.62, CH30H)
(1.0, CH30H)
-37.5"
(1.0, DMF)
- 69.5"
- 77.6" (1.0, CH30H)
- 1 9 . 0 1 ~ (1.875, CH30H)
(1.665, CHIOH)
-21.8"
- 12.9" (1.419, CH3OH)
222
212
224
244
239
223-225
264-265
238-240
-
199-200
S
S
S
S
S
S
S
S
S
R
S
R
R
R
849" (1.46, CH30H)
S
R
S
S
If not otherwise stated, with butyllithium as M-base and bromides as (9)
Determined on crude product.
If not otherwise stated, optically pure.
With potassium tert-butoxide.
For ( i i a ) . Ref. [3]: -4.5" (1.0, I N HCI).
[fl A F y Mpkosza, with veratryl chloride, 50 %. NaOH, TEBA, CHzCIz, 25--40°C
[g] 55 A ee; optically pure (12bj. -52" (2.0, C H 3 0 H ) [6].
[h] For (1 1c ) .
[i] With iodide.
[a]
[b]
[c]
rdl
[ej
118
Angew. Chem. Inr. Ed. Engl. 17 (1978) N o . 2
mixed together with 0.1 g p-toluenesulfonic acid with stirring.
(3): 11.3g (0.1 mol) (I a), 12h at room temperature, 30min
at 100°C; crystallization from methanol or chromatography
on alumina with ether; 16.4 g (81 %) (3), m.p. 89 "C. ( 4 ) : 18.9 g
(0.1mol) (I b), 12 h a t 6 0 T , then methanol removed in uacuo;
26.5g (95 %) ( 4 ) , m.p. 135-136°C (from isopropanol). ( 5 ) :
9.9g (0.1 mol) (I c), 12 h at 30-35°C without catalyst, otherwise as in the case of ( 4 ) ; 15g (80 %) ( 5 ) , m.p. 122-123°C
(from ethyl acetate).
2-Imidazolin-5-ones ( 7 a ) : To a solution of (3) or ( 4 ) in
tetrahydrofuran at - 60°C is added 1 equivalent of butyllithium or potassium tert-butoxide and the stirred mixture
warmed to -2O"C, neutralized with glacial acetic acid,
and worked up in the usual way. ( 7 a ) , R1=CH3: b.p.
105"C/10-3 torr (with enol form). ( 7 a ) , R' =CH2C6H5:used
as crude product (no enol form detectable). ( 7 a ) , R ' = H :
not preparable, unstable.
2-Imidazolin-5-ones (10): Method A: To a solution of
(3) (3.03g, 15mmol) in 20ml dry tetrahydrofuran at
- 60°C is added 15 mmol butyllithium (dropwise) (9.4 ml of
a 1.6 M solution in hexane) or 15 mmol potassium tert-butoxide. A solution of 15 mmol R'-Hal (9) in ca. lOml tetrahydrofuran is added dropwise at - 60°C to the solution of ( 7 b ) e ( 8 ) .
The mixture is allowed to warm to room temperature, the
solvent removed in uacuo, and the residue taken up in 20ml
CH2C12.The solution is washed with 2 x 20ml water, dried
over magnesium sulfate, and worked up in the usual way
(cf. Table l).-In the case of ( 4 ) , 0.84 g (3 mmol) in 15 ml
THF is metalated with 3mmol BuLi at -78°C. For the
cyclization (6) -+ (7) the solution is allowed to warm to room
temperature. It is then cooled to -70°C and treated with
3mmol (9). After 3 h at room temperature the solution is
neutralized with glacial acetic acid, the solvent removed,
and the residue worked up in the usual way.-Method
B:
20mmol butyllithium (13 ml of a 1.5 M solution in hexane) is
added dropwise at - 78 "C to a solution of ( 5 ) (1.9g, 10 mmol)
in 25 ml THF. The mixture is stirred for lOmin, treated with a
solution of 10mmol RI-Hal in 10ml THF, and then,allowed to
warm to 10°C. Finally, lOmmol(9) in lOml T H F is added
and the whole stirred for ca. 2 h. Work-up as in Method A.
Amino acids (11) and (12): A mixture of 2 g of ( l o ) ,
20ml ethanol, 10ml water and 2 g KOH (if need be, glycol
+
The solution is then evaporated down at lo-* torr and (12)
isolated by recrystallization from ethanol or ethanol/water.
Received: June 9, 1976 [Z 871 IE]
revised: October 12, 1977
German version: Angew. Chem. 90, 136 (1978)
Publication delayed at authors' request
Asymmetric Syntheses via Heterocyclic Intermediates, Part 1.
For known methods, some of which, however, do not fulfill all these
requirements, cf. H . B. Kagan, 7: P . Dang, J. Am. Chem. SOC.94, 6429
(1972); W S. Knowles, M . J . Saback, B. D . Vineyard, D . J . Weinkauff,
ibid. 97, 2567 (1975); E. J. Corey, R . J . McCaully, H . S . Sachdeu, ibid. 92,
2476 (1970); B. W Bycrof, G . L. Lee, J. Chem. SOC.Chem. Commun.
1975, 988: S. Yamada, 7: Oguri, 7: Shioiri, ibid. 1976, 136; U . Schmidt, E.
bhler, Angew. Chem. 88, 54 (1976): Angew. Chem. Int. Ed. Engl. 15,
42 (1976).
For a Strecker synthesis of a-methyl-a-amino acids, which proceeds
with high optical yield via an asymmetric rearrangement of the second
kind, but in which the chiral reagent is destroyed, cf. K . Weinges, G.
Graab, D . Nagel, B. Stemmle, Chem. Ber. 104, 3594 (1971): K . Weinges,
K . Cries, B. Stemmle, W Schrank, ibid. 110, 2098 (1977).
W Boll, H . 4 . M a y , BASF AG, private communication.
H:H. Hausberg, Dissertation, Universitat Gottingen 1976.
W Boll, BASF AG, private communication.
According to an X-ray structure analysis the hydrogen atom of the
1-phenylethyl group in ( 1 O a ) lies in the plane of the heterocycle
and points towards the oxygen; moreover, the benzyl group inserted at
C-4 is located on the same side as the methyl group of the phenylethyl
moiety,itsphenyl ringislocatednear thecarbonyl group: W Saenger, MaxPlanck-Institut fur Experimentelle Medizin, Gottingen, private communication.
If a methyl group is inserted at C-2 in ( 7 b ) * ( a ) , the extent of induction
is drastically reduced.
The Coz(CO)8/Ph3P-CatalyzedReaction of Aldehydes
with Hydrosilane and Carbon Monoxide"]
By Yoshio Seki, Shinji Murai, and Noboru Sonodup]
We recently reported that olefind'] and cyclic ethers13' give
enol silyl ethers and silyl-protected hydroxyaldehydes, respectively, when allowed to react with a hydrosilane and carbon
monoxide in the presence of C O ~ ( C O ) ~ .
We now wish to report the new catalyzed reaction of aldehydes with HSiR3 and CO to give 1,2-bis(siloxy)olefins (I).
0
RtfH + 2 HSiEt,Me
Cat.
+ CO
MeE t2SiOHOSiEt2Me
R
H
(1)
Table 1. Physical properties of some silyl-protected 1,2-enediols ( I ) .
R
(1 a )
(1 b)
( 1 c)
(1 d )
n-Hexyl
n-Propyl
Cyclohexyl
Et2MeSiO(CH2)4
IR [a1
B. p.
["C/torr]
v (C=C) [cm-'1
'H-NMR [b]
6 (HC=C, s)
12&123/0.5
130-1 50/25
140--1 SOjO.8
155-1 65/0.4
1685
1685
1685
1685
5.44 and
5.44 and
5.48 and
5.44 and
5.90
5.92
5.78
5.92
[a] Without solvent.
[b] In CC14. The signals at higher fields correspond to ( Z ) isomers and those at lower field to ( E ) isomers.
or triglycol instead of ethanol) is boiled under reflux until
completion of hydrolysis (up to 20 h). Water is then added,
if necessary after removal of the ethanol, and the solution
extracted twice with CH2C12 [separation of (2)]. Further
work-up depends upon the properties of (11). On acidification
of the aqueous phase with 6~ HCI, (11) often precipitates.
In other cases the aqueous phase is neutralized and evaporated
down in uacuo. The crude product (contaminated with KCI)
can be used for the acylation: A solution of (11) (1 g) in
dimethylformamide (10 ml) is treated with 2-equivalents of
acetic anhydride and the mixture heated for 1 h at 90°C.
Angew. Chem. Int. Ed. Engl. 17 ( 1 978) N o . 2
Reaction of n-heptanal with diethyl(methy1)silane(threefold
excess w.r.t. aldehyde) and carbon monoxide in the presence
of C O ~ ( C Oand
) ~ triphenylphosphane gave a mixture of (E)and (Z)-1,2-bis[diethyl(methyl)siloxy]-l-octenes (I a ) in 66 %
yield (cf. Table 1). The use of Ph3P as a cocatalyst is necessary
[*] Y. Seki, Prof. Dr. S . Murai ['I, Prof. Dr. N. Sonoda
Department of Petroleum Chemistry, Faculty of Engineering, Osaka
University
Suita, Osaka 565 (Japan)
['I Author to whom correspondence should be addressed.
119
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