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Asymmetric Synthesis of -Amino--nitrocarboxylic Esters by the Bislactim Ether Method.

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T,ihlr I . Activdtioii parameters for the stereoselectivity of H-transfer to the
iinyl radical 5b.
H - Ilonor
AH'((E)-4b)AH'((a-4b)
[kJ/mol]
AS'((E)-4b)ASc((.Z-4b)
[Jmol ' K - ' I
Temperalure
I'Cl
c-C,.H,,HgH
BuSnH
C.C,,H<?
2.5i0.2
4.6k 1.5
I 1 . 7 i 1.0
1.2 20.5
7 is
28 ? 1.3
- 20-80
0- 84
120-260
reactivity of the H-donor. It increases from 2.5 (cyclohexylmercury hydride) to 4.6 (tributyltin hydride) to 11.7 kJ/
mol (cyclohexane). At the same time, the rate of H-transfer
in this series decreases by about a factor of
HXc-c6H11
'&
<H-Donor
'~3~5
-'tjHl
1
C6H5
(Z)- 4 b
5b
( E ) -4b
Apparently, the differences in the steric shielding have
greater influence on the activation enthalpies the less reactive the H-donor is, because the distance between the reactants is smaller in the later transition states.''] Since the difference in the activation entropies in the same series also
increases from 1.2 to 7 to 28 J/rnol-' K - ' , the compensation of the activation enthalpies and activation entropies
leads to an isoselective temperature,f61which lies between
60 and 80°C (Fig. I). In this temperature range the Hdonors mentioned here react with the same selectivity. In
the case of cyclohexane the entropy effects are so large
that above 140°C the isomer (E)-4b is the major product.
Thus, at 0°C the ratio ( 9 - 4 b :(E)-4b is 78:22 with
Bu,SnH as donor, whereas at 260°C with cyclohexane as
H-donor the selectivity (29 : 7 1) is reversed.[']
These investigations on the vinyl radical 5b show how
the stereoselectivities of radical reactions can be steered by
varying the H-donors (radical trapping agents) and the
reaction temperature.
Received: January 13, 1987 [Z 2045 1 9
German version: Angew Chem. Y9 (1987) 478
[ I ] R. Giese, Anyew Chem. Y7 (1985) 5 8 5 : Angen,. Chem. In,. Ed. Eiigl. 24
(1985) 853: Radicab in Organic S.vnthecir. Pergamon Press, Oxford
1986.
121 R Giese. S. Lachhein, Angen, Chem. 94 (1982) 7 8 0 ; Angew. Clzem. Int.
Ed. Engl. 21 (1982) 768: B. Giese, G. Kretzschmar, Chem Ber. 117 (1984)
3175.
131 T h e phenyl suhstituent enforces s p hybridization at the radical center: R.
M. Kochik, J. A. Kampmeier, J . Am. Chem. Soc. YO (1968) 6733; J. E.
Rennett, J. A. Howard, C/iem. P h ~ tLett Y (1971) 460: L. Bonazzola, S.
Fenistein, R. Marx, Mol. Phys 22 (1971) 689.
I41 T h e rate coefficients for H-transfer to alkyl radicals for cyclohexylmercury hydride, tributyltin hydride. and cyclohexane have been reported to
he about lo', 10" a n d I L mol- ' s - I, respectively at 20°C: B. Giese, G.
Kretzschmar, Cliem. Ber. 117 (1984) 3160; C. Chatgilialoglu, K. U. Ingold, J. C. Scaiano, J Am. Clzem. Soc. If13 (1981) 7739: D. J. Roddy, E
W. R. Steacie, Can J Chem. 3Y (1961) 13.
[ S ] Later transition states are required by the Hammond postulate for slower
reactions: G. S. Hammond, J . Am. Chem. So< 77 (1955) 334
161 R. Giese, Anyen Chem. 89 (1977) 162; Angew. Clzem. Inf Ed. Engl. 16
(1977) 125; Acc. C h n . Re.s. 17 (1984) 438.
[7] For the experimental procedure with cyclohexane see J Hartmanns, K.
Klenke, J. 0. Metzger. Chem Ber. 119 (1986) 488. Control experiments'
\how that an isomerization (Z)-4b-(E)-4b is not apparent u p to 260°C.
Asymmetric Synthesis of
a-Amino-y-nitrocarboxylic Esters by the
Bislactim Ether Method**
By Ulrich SchollkopJ* Wulf'Kiihnle, Ernst Egert. * and
Michael Dyrbusck
Dedicated to Professor Hans Paulsen on the occasion of
his 65th birthday
Optically active y-nitro-a-amino acids are attracting attention lately because of their potential biological activity
and there usefulness as building blocks for modified oligopeptides. Moreover, they are suitable as starting compounds for the synthesis of further unusual amino acids,
since the nitro group can be reduced to an amino group'
or converted into a carbonyl group by the Nef reaction." 'I
So far, however, no method for the asymmetric synthesis
of this class of compounds has been reported in the literature. We now describe here an asymmetric synthesis for
the methyl a-amino-y-nitrocarboxylates 7 starting from
the titanium derivative 3 of the (commercially available[41)
bislactim ether 1 of cyclo(-L-Val-Gly) and the nitroolefins
4 . Intermediates of the synthesis are the adducts 5, which,
in the case of the (E)-nitroolefins 4a-c, are formed with
high asymmetric induction with respect to the two stereocenters (C-2 and C-1') (Table 1). Surprising is not only the
[*] Prof. Dr. U. Schollkopf, DiplLChem. W. Kuhnle
lnstitut fur Organische Chemie der Universitrit
Tammannstrasse 2, D-3400 Gottingen ( F R G )
I
I
'
I
10311 I K - ' ~
-
Dr. E. Egert, M. Dyrbusch
lnstitut fur Anorganische Chemie der Universitiit
Tammannstrasse 4, D-3400 Gottingen (FRG)
I
'
Fig. I . Temperature drpendrnce 01 the \iurcoxleciiiit) lor H-transfer to the
vinyl radical 5b by c-C,,H,?. Bu:SnH, a n d c-C,,H,,HgH as H-donors.
480
0 VCH V e d u g r ~ e ~ e l l d z anzhH.
fi
0-6940 Weinheim. I987
['*I
Asymmetric Syntheses bia Heterocyclic Intermediates, Part 34.-Part
33: U. Schollkopf, J. Bardenhagen, Liehigs Ann. Chem. 1987. 393
0.~70-0833/87/0505-f~480S 02.50'0
Angen,. Chem. Int. Ed. Engl. 26
119871 No.
C
eric ratio (Table I ) was determined by capillary gas-chromatography'"] (with and without combined GC/MS) and/
o r by Iff- and "C-NMR spectroscopy (Table 2).
Hydrolysis of the adducts 5 to methyl L-valinate 6 and
the methyl (2R,3S)-2-amino-4-nitrobutanoates 7 (Table 2),
the target compounds, was accomplished under such mild
conditions (0.1 N HC1, room temperature, tetrahydrofuran
(THF) as cosolvent) that the nitro group remained intact.
However, on attempting to hydrolyze the ester 7a to the
amino acid under acidic conditions (4 N HCI) a Nef reaction took place. An example has been described in the literatureC2'for an alkaline ester hydrolysis ( I N NaOH) in
which the nitro group remained intact. As shown by an ex-
2 , M = Li
3, M = Ti[N(C2H5)213
1
( 2 R, 1 $S)- 5
Table I . Synthesis of the diastereomeric compounds 5
5
R'
R'
Yield [%I; diastereomers [a]
with 3 [c]
with 2 [d]
B.p. [b]
[ "C/
0.01 torr]
7
a
b
c
d
(HI
('#,H.
[el
CHt
H
H
H
<'HI
80
140
Y4-9S[fI
80
5 1 ; 9 7 . 4 . 0 . 8 : 1 .0.8
57: 9 4 : 2.7 : 3.3 : 60:9Y : - : I : -
-
81;86.-:10:4
78; 45 : 38 . 1 I : 6
52:49 : 4 1 : 6 : 4
80: 98 : 2 [gl
Table 2 S o m e physical data of 5 and 7. ' H - a n d " C - N M R : 6 values
(CDCI,). B.P.: Kugelrohr: [a];:':
c = 2.0: ethanol.
[a] T h r mtio (2R,I'S):(2R,I'R):(2S,l'S):(2S,I'R) is given: the 1'-configuration in the case of (2S)-isomers is arbitrary. A dash means no longer clearly
recognizable. [b] (Kugelrohr). [c] C C Capillary. [d] Mean value of a capillary
GC analysis and a " C - N M R analysis. [el R ' =3,4-methylenedioxyphenyl. [fl
M.p.: purified b y low-pressure chromatography [silica gel, etherlpetroleum
ether ( I - 5 ) ) [gl (2R) :(2S).
5 a : 'H-NMR:0.70, 1 . 0 4 ( 2 d , J = 7 H z : 6 H , C H ( C H I ) , ) , 1 . 1 3 ( d , J = 7 H z : 3 H ,
C H I o n C-I,), 2.04-2.50 (dsp, J , = 3 Hz, J 1 = 7 Hz; 1 H , C H I C H
( m ; I H , I'-H),3.68,3.73(2~:6H,OCH,),3.98,3.99(2dd,'J=3.
Hz; 2 H , 2-H, 5-H), 4.13 ( d d , J,,,3=11 Hz,J,,,=8 Hz; A part of ABX, I H,
2'-H), 4.34 (dd, J B , , = I I Hz, J,,,=6 Hz; B part of ABX, I H, 2 ' - H ) . - - ' ' C N M R : 14.25 ( C H 2 on C-I,), 1659, 18.89 (CH(CHI)?), 31.88 (CH(CH,),),
3601 (C-I,), 52.48, 52.57 (OCH,). 57.79, 60.84 IC-2. C-S), 78.51 1CH:NO.).
161.42, 164.81 (C-3, C-6)
high stereoselectivity with which the two stereocenters are
simultaneously formed, but also the finding that nitroolefins 4 react in satisfactory yields with the azaenolate 3 (or
2). SET processes between the nitro group and the azaenolate were to be expected, because 3 affords a relatively stable "diazapentadienyl radical". The 2,2-dimethyl-substituted nitroolefin 4d does not react with 3 however, but
does so-and with high induction-with the lithium com-
5b: ' H - N M R : 0.62. 0.94 (2d, J = 7 Hz: 6 H . CH(CH,jIj, 204-2.30 (dhp,
J,=3.5 Hz.J:=7 Hz: I H , CH(CH,),),3.54 (dd. ' J , = 3 . 8 H z , J - = 3 5 H z : I H,
5-H), 3.73. 3.16 ( 2 s : 6 H , OCH,), 4.16 (ddd, J \ \ = 6 Hz. J i , \ = 9 Hz. J , = 3 5
Hz; X part of ABX, I H, l'-H), 4.30 (dd. ' J , = 3 . 8 Hz. J 2 = 3 . 5 HI: I H. 2-H),
4 . 7 4 ( d d , J , , , , = 6 H r : A p a r l o f A B X , lH.?'-H).485(dd,J,,,,=I2 H z . J , , = 9
Hz; R part of ABX, I H. 2'-H). 7.3-7.37 ( m : S H , phenyl-H).- " C - N M R :
46.YO (C-1'). I.? 72. 52.72
16.22. 19.01 (CH(CH,),), 31 53 (CH(C
(OCH,), 58.45, 60 57 (C-2, C - 5 ) , 78.33
NO?). 127.8, 128 23. 1223.44.
128.54, 128.57, 137.23 (phenyl-Cj, 160.91. 165.28 (C-3. C-6i
pound 2.I5l
The C-Z/C-S-truns configuration of the main components of 5 follows from the (in the bislactim ether system
typical) ~ ~ U ~ ~ - ~ J ~ . ~ ,coupling
~ , . ~ - Nconstants
MR
of ca.
4 Hz, and from the fact that 1'-aryl compounds show a
high-field shift of the cis-H-5, which is attributed to the
"aryl-i nside" preferred conformation ("folded" conformation). The (l'S)-configuration was determined, by way of
example on 5c, by an X-ray structure analysis (Fig. I),
which concomitantly confirmed the NMR-spectroscopically identified "folded" conformation. The diastereom-
5 ~ ' .H - N M R : 0.64, 0.Y9 (2d. 5=7 Hz: 6 H . C'H(CHt)2). 2.08 3.32 (dbp,
J = 3 . 5 Hz, J=7 Hz: I H, CH(CHIj:). 3.70(dd. ' J , = 3 . 5 Hz, J ? = 3 . 5 Hz: I H.
5-H), 3.76, 3.78 (2s: 6 H , OCH,), 4.10 (ddd. J \ \ = 3 5 Hz, Jt,,=9.5 HI.
J , = 3 . 5 Hz: X part of ABX, I H. I',H), 4.26 (dd. ' J , = 3 . 5 Hz. J 2 = 3 . 5 Hz: I H.
2-H), 4.64 (dd, J , H =13 Hz, J,,=6 Hz: A part of ABX, I H. 2'-H). 4.73 (dd.
JAB=
13 Hz. J,,,=9.5 Hz: B part of ABX, I H, 2'-H). 5 96 I s :
6.6-6.95 (m: 3 H, aryl-H) - W N M R : 16.48, 18.92 ( C H ( C
(CH(CH,),), 45.48 (C-1'). 52.76. 52.52 (OCH,). 57.18, 6 0 3 4 ((--2
(CHZNO.), 101 08 (CH.0,). IOS.lO, 108.88, 122.07, 128.Y3, 147 23. 147.49
(Aryl-C), 160.46. 165.00 (C-3, C-6)
5d: ' H - N M R : 0.67, 1.08 (2d. J = 6 Hz; 6 H , CH(CH,),), 1.01. 1.20 ( 2 s : 6 H .
C H I a n C-1'). 2.1-2.5 (dsp, J , = 3 Hz. J1=6 Hz; I H, CH(CH,),). 3.69, 3.72
(2s: 6 H . OCH,), 3.90 (dd, J , = 3 Hz, J 1 = 3 Hz: I H, 5-H), 4.13 (d. 5 - 3 Hz:
1 H. 2-H), 4.40. 4.61 (2d, J,,H= I I Hz; AB spectrum. 2 H . 2'-H).- "C-NMR:
16.37, 19.19 (CH(CH2),), 21.39, 22.91 ( C H I a n C-I,), 31.06 ( C H ( C H
(C-I,), 52.34, 52.70 (OCH,), 60.45. 61.10 (C-2. C-5). 84.03 ( C H I N O I ) , 161.68.
164.75 (C-3. C-6)
7 a . (2R,3S): yield 78%: B.p.=6O"C/O.O01 torr; [a]?:'=
-40.7'~: ' H - N M R :
1.06 (d, J=6.5 Hz; 3 H . CH-CH,), 2.66 (5. br: 2 H . NH.), 2.4-3.1 ( m : I H.
3 - H ) , 3 . 4 2 ( d , J = 6 . 5 H ~ ; IH.2-H),3.76(~:3H,OCH,),4.31 (dd,J,,,,=IZ Hz,
J , x = 8 Hz; A part of ABX, I H, 4-H), 4.64 (dd. J,,+,=I2 Hz, J l l \ = 6 . 5 Hz:
B-Teil von ABX, I H,4-H).--"C-NMR: 14.59 (CH-CH,), 36.63 (C-3). 52.25
(OCH,), 57.02 (C-2), 78.25 (C-4). 174.54 (C-I)
7c: (2R,3S): yield 47%; not distilled: [a];:'=
-8.0"; ' H - N M R : 1 6 2 (s, br:
2 H , NH:), 3.59 ( s : 3 H , OCH>), 3.63 (d, J = 7 . 5 Hz: I H , 2 ~ H ) .3.73 ( d d d ,
J,,=8.5 Hz, JI,,=5.5 Hz, J,,"=7.5 Hz; X part of ABX, I H, 3 - H ) , 4 . 7 0 ( d d .
J A B 10.3
= Hz, J,,,=8.5 Hz: A part of ABX, I H, 4-H), 5.05 (dd, J,,,= 10.3
H z , J H X = 5 . 5 H z : B p a r t o f A B X , lH,4-H),S.Y3(s:2H.CH.O:),6.6-6.8(m:
3 H , aryl).-"C-NMR: 47.50 (C-3), 52.15 (OCH,). 57.90 (C-2). 77.35 (C-4).
101.26(CH2O1), 108.10. 108.54, 121.52, 130.07, 147.42, 148.01 (aryl-C), 173.98
(C-I)
Fig. I ('rystal structure 01 (5,$,2R,I'S)-5c [ I I]. Remarkable is the "arylinside" conformation ("folded" conformation). 0 atoms dotted, N atoms
hatched
7d: (2R): yield 41'!h: B.p. 65"C/0.001 torr: [a];:'=
- L4O: ' H - N M R . 1.08,
1.16 (2s: 6 H , CH,), 1.70 (s: br; 2 H , NH?), 3.54 (s; I H , 2-H), 3.77 ( s : 3 H .
OCH.,), 4.33 (d, J,,s= I I Hz: A of AB. I H, 4-H), 4.73 (d, J,,"= 1 I Hz: R of
AB, I H. 4-H)
[4] Merck-Schuchardt, Frankfurter Str. 250, D-6100 Darmstadt (FRG), MS
Info 85-14.
151 As a rule, organolithium compounds are more reactive but less selective
than organotitanium. Cf. M. T. Reetz: Organotilanium Reagents in Organic Synthesis. Springer, Berlin 1986.
[6] Carlo-Erba-Fractovap 2300, Chrompack-WCOT-CP-SIL-5CB
column,
50 m, 0.22 mm diameter, hydrogen.
(71 See also [I].
[8] U. Schollkopf, U. Groth, C. Deng, Angew. Chem. 93 (1981) 793; Angew.
Chem. In!. Ed. Engl. 20 (1981) 798.
[9] M. T. Reetz, R. Urz, T. Schuster, Synthesis 1983. 540.
[lo] All the compounds 5 and 7 gave satisfactory elemental analyses.
[ I l l 9:Space group P2,2,2,, a=732.6(1), b=964.5(1). c=2712.5(2) pm,
V=1.916 nm', Z=4, p=O.O8 m m - ' (MoKn); crystal dimensions
0.5 x 0.4 x 0.3 mm', 4538 measured intensities, 28,,,, = 50", 2367 symmetry independent reflections with IFI>3uF used for the structure solution
(direct methods) and refinement; C, N, and 0 atoms refined anisotropically, H atoms located by differential electron density determination
and refined with a riding model, R=0.073, R,=0.062, w - ' = a :
0.0005 F2). Further details of the crystal structure investigation are available on request from the Fachinformationszentrum Energie, Physik,
Mathematik GmbH, D-7514 Eggenstein-Leopoldshafen2 on quoting the
depository number CSD-52 299, the names of the authors, and the journal citation.
ploratory hydrogenation experiment (Pd/C) with 7a here, as usual[',*I-the nitro group of 7 can be reduced to
an amino group. Hence, the bislactim ether method also
affords access to optically active a,y-diamino acids (NH2
instead of NOz in compounds of type 7), which, as analogues of GABA, are of interest as potential enzyme inhibitors."]
Experimen taI
Compounds 5 : The bislactim ether 1 [4, 81 was lithiated to 2 [S] (1.1 equivalents of butyllithium, -78"C, 10 min. 8 mL of T H F per mmol of I).-Experiments with 2: The solution of 2 was treated at -78°C with the solution of
one equivalent of 4 in T H F (10 mL per mmol of 4). After I2 hours' stirring
the mixture was treated with 1.1 equivalents of acetic acid and allowed to
warm to room temperature. Water (30 mL per mmol of 4) was then added
arid the mixture extracted with ether. The ether extract (containing 5 ) was
dried over MgS04 and the ether removed under vacuum. 5 was isolated from
the residue by Kugelrohr distillation (Table I).-Experiments with 3 : 1
(0.42g. 3.0mmol) was lithiated to 2. The solution of CITi[N(C2H,)Z], [9]
(3.15 mmol) in hexane (ca. 3.5 mL) was then added to 2 and, after 45 min,
the mixture was forced under pressure (with argon) into a solution of 4 (3.0
mmol) in T H F (30 mL). After 12 hours' stirring the mixture was treated with
3.2 mmol of acetic acid and then worked-up as described above [lo].
+
Compounds 7 : The solution of 5 (3.0 mmol) in T H F (2 mL) was treated with
60 mL of 0.1 N HCI and the resulting suspension stirred at room temperature
until complete dissolution (ca. 24-80 h). After saturation with NaCl and subsequent addition of 20 mL of ether, concentrated ammonia was added to the
stirred mixture until a pH of 9 was reached. The phases were then separated;
the aqueous phase was extracted with 4 x 20 mL of ether and, after drying the
extract over MgSOl the solvent was removed under vacuum. Methyl L-valinate 6 was then removed by evaporation at 3O0C/O.01 torr in a Kugelrohr
apparatus and 7 isolated from the resulting residue by Kugelrohr distillation
(0.01 torr); 7c was purified by low-pressure chromatography (silica gel, eth-
Synthesis of Valienamine""
By Richard R . Schmidt* and Arnim Kohn
Valienamine 1 has interesting biological properties.
Aside from its inhibitory action towards a-glucosides['.21it
exhibits antibiotic activity.l2] Much more important, how-
(OH
0
o
\B
BzlO
z
l
o
q
BzlO
OMe
x
%
BzlO
Y
Y
40: X = H, Y = OAc
4b: X = OAC, Y = H
3a: X = H. Y = OH
3b: X = OH. Y = H
RO
fl
- -
+
i BzlO
- -
NHR
BzlO
-
Bz'
h B BzlO
z L
H N-TOS
7
Bzl = CsH5CH2;
O
e
(9B
BzlO
z
l
BzlO
O
qX
OBzl
6
1 : R = H-
2: R = Ac J
j
Bzl;z)x
CN
5a: X = H, Y = OH
5b: X = OH, Y = H
Bz = C6H5C0
Scheme 1. Synthesis of valienamine, I , from methyl a-D-glucopyranoside, a) Six steps, see text and [lo]: b) EtSH/MeOH, HCI; Ac20,
pyridine (86%); c) Me&-CN, SnCL, CH&, 0°C (85%); d) DIBAH, CH2CIZ/petroleum ether, -70°C to toom temperature (RT)
(78%); e) LiAIH,, tetrahydrofuran, 0 ° C to RT (85%): f) BzCN, CH,CN/NEt,, - 15°C (73%): g) PPh,, DEAD, toluene, RT (79%); h)
chloramine T, BTAC, CH2CI?, RT (78%); i) NH,(liq.), Na, -70°C (58%); j) AczO, pyridine (quantitative).
er. RF=0.16). When prepared via 3 the crude compounds 7 were isomerically pure ("C-NMR, C G C and CGC/MS; 'H-NMR with Eu(hfc), [lo]).
Received: January 16, 1987 [Z 2048 IE]
German version: Angew. Chem. 99 (1987) 480
[ I ] For examples of the diastereoselective reaction of lithium enolates with
nitroolefins and for the hydrogenation and Nef reaction of nitro compounds see: G. Calderi, D. Seebach, Helu. Chim. Acta 68 (1985) 1592,
and references cited therein.
121 For the synthesis and modification of methyl 2-amino-44trobutanoate
(the only compound of type 7 described hitherto) see Z. Prochazka, J.
Smolikova, P. Malon, K. Jost, Colieet. Czech. Chem. Comm. 46 (1981)
2935.
[3] For a review of the Nef reaction cf. W. E. Noland, Chem. Rev. 55 (1955)
137.
482
0 VCH Verlagsgesellschaji mbH. 0-6940 Weinheim. 1987
ever, is its occurrence as central building block of several
complex aminoglycoside antibiotics, such as, e.g., the valid a m y c i n ~ , [and
~ ] a series of pseudooligosaccharidic a-glucosidase inhibitors, including a c a r b ~ s e . [ ' . ~ l
The synthesis of valienamine described by Paulsen and
Heiker leads from (+)-quebrachitol via several steps to op[*] Prof. Dr. R. R. Schmidt, Dipl.-Chem. A. Kohn
Fakultiit fur Chemie der Universitiit
Postfach 5560, D-7750 Konstanz (FRG)
[**I
a-Glucosidase Inhibitors. Part 4. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.-Part 3: 141.
0570-0833/87/0505-0482 .$ 02.50/0
Angew. Chem. Int. Ed. Engl. 26 (1987) No. 5
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