Stereospecific Synthesis of (2S,4S,6S)-2-Amino-4,6-DihydroxypimelicAcid

Article abstract of DOI:10.1021/jo970307p

The Lewis acid catalyzed stereoselective carbonyl - ene-reaction between (2S,5S)-1-benzoyl-2-tertbutyl-3-methyl-5-(2-propenyl)imidazolidin-4-one (2) and anhydrous butyl glyoxylate was investigated with the aim to obtain highly functionalized amino acids. This reaction is assumed to proceed in a nonsynchronous fashion, giving rise to competing reactions within the time interval between the C-C bond formation and the proton migration step. Thus, a hypothesized dipolar intermediate could undergo two reaction pathways: besides conventional ene product 3, two further products 4 and 5 are obtained via nucleophilic attack involving two different neighboring carbamoyl groups. Acidic hydrolysis of both products afforded title compound 1. The absolute configuration of the two newly formed chiral centers was assigned by NMR measurements of lactone 4 and its rigid derivative 7. By varying the temperature (-20° to 25 °C) and the type of Lewis acid (SnCl₄, FeCl₃) the reaction can be directed to give either of the possible reaction products. A plausible reaction mechanism is proposed.

Full text of DOI:10.1021/jo970307p

4078
J . Org. Chem. 1997, 62, 4078-4081
Ster eosp ecific Syn th esis of
(2S,4S,6S)-2-Am in o-4,6-Dih yd r oxyp im elic Acid †
Michaela Mehlfu¨hrer, Klaus Thirring, and Heinz Berner*
Sandoz Forschungsinstitut, Brunnerstrasse 59, A-1235 Wien, Austria
Received February 18, 1997X
The Lewis acid catalyzed stereoselective carbonyl-ene-reaction between (2S,5S)-1-benzoyl-2-tert-
butyl-3-methyl-5-(2-propenyl)imidazolidin-4-one (2) and anhydrous butyl glyoxylate was investigated
with the aim to obtain highly functionalized amino acids. This reaction is assumed to proceed in
a nonsynchronous fashion, giving rise to competing reactions within the time interval between the
C-C bond formation and the proton migration step. Thus, a hypothesized dipolar intermediate
could undergo two reaction pathways: besides conventional ene product 3, two further products 4
and 5 are obtained via nucleophilic attack involving two different neighboring carbamoyl groups.
Acidic hydrolysis of both products afforded title compound 1. The absolute configuration of the
two newly formed chiral centers was assigned by NMR measurements of lactone 4 and its rigid
derivative 7. By varying the temperature (-20° to 25 °C) and the type of Lewis acid (SnCl4, FeCl3)
the reaction can be directed to give either of the possible reaction products. A plausible reaction
mechanism is proposed.
In tr od u ction
amounts of 3 and 5 were isolated after workup. Warming
up the reaction mixture from -20 °C to 25 °C with
subsequent hydrolysis furnishes 5 as the main product
along with 3 and minor amounts of 4. Catalyzing the
reaction with FeCl3 at 25 °C effects 3 almost exclusively.
Acidic hydrolysis of 4 as well as 5, followed by ion
exchange chromatography, yielded 2S,4S,6S-configured
amino acid 1. The use of 3% NH4OH (instead of 0.3%)
during the ion exchange procedure led to formation of
minor amounts of lactam 6. Lactone 4 was hydrolyzed
under mild basic conditions to give the N-benzoyl-
protected amino acid 8 without any detectable epimer-
ization.
Assign m en t of Con figu r a t ion (F igu r e 1 a n d
Sch em e 2). According to the proposed mechanism,
compounds 3, 4, and 5 should be formed via the same
configuration-determining transition state. Due to the
exo-arrangement of imidazolidinone 2 and butyl gly-
oxylate, all reaction products should have identical
S-configuration at the newly formed asymmetric centers
(γ- and ꢀ-carbons). This assumption could be verified by
spectroscopic investigations of 4 and its rigid derivative
7: a nuclear Overhauser effect of 3.2% between the R-
and the γ-protons, as well as comparable coupling pat-
terns of the â-protons of 4 with those of analogous
compounds,9 indicates cis configuration of the lactone
substituents. Therefore, we assigned an S configuration
to the γ-carbon based on the known S configuration of
the R-carbon. Reacting 4 with dimethoxypropane re-
sulted in a transesterification of the lactone moiety with
concomitant ring closure between γ- and ꢀ-hydroxy
groups to give the 1,3-dioxane derivative 7. According
to coupling patterns, 1,3-diaxial relationship of the γ- and
ꢀ-protons in 7 could be established, clearly indicating S
configuration for the ꢀ-carbon. Therefore, the 2S,4S,6S-
configuration assigned to 4 applies as well to amino acid
1. Acidic hydrolysis of 5 followed by ion exchange
chromatography afforded two compounds identical with
1 and 6, indicating an S-configuration for the γ- as well
as for the ꢀ-carbon of 5.
For the development of potent and effective immuno-
modulating compounds, considerable attention has been
focused on the synthesis of lipopeptides related to FK-
565.1-4 Most of these compounds containing the un-
altered R,R′-meso-diaminopimelyl residue are associated
with undesirable side effects which preclude their thera-
peutic use.5 Therefore, we were especially interested in
a stereospecific synthesis of the R-amino-γ,ꢀ-dihydroxy-
pimelic acid 1. Herein we describe the synthesis of amino
acid 1, bringing into focus the nucleophilicity of carbam-
oyl groups which interfere with the regular course of
hetero ene reactions. It is known that with peptidic
substrates this type of reaction occurs only stereoselec-
tively.2,3 However, by using Seebach’s imidazolidinone
26 as substrate, this type of reaction now proceeds in a
stereospecific fashion.
Resu lts
Syn th esis of Am in o Acid 1 (Sch em es 1 a n d 2). A
SnCl4-catalyzed carbonyl-ene-reaction of 5-(2-propenyl)-
imidazolidinone 26,7 and butyl glyoxylate8 furnished a
mixture of lactone 4, ene product 3, and rearranged ene
product 5. The reaction proceeds stereospecifically with-
out any detectable amounts of diastereoisomers. The
ratio of products 3, 4, and 5 depends on reaction condi-
tions such as type of Lewis acid, temperature, and time
(Table 1): at -20 °C mainly lactone 4 along with small
† This paper is dedicated to Professor D. Seebach on the occasion of
his 60th birthday.
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) Lederer, E. J . Med. Chem. 1980, 23, 819.
(2) Schneider, H.; Sigmund, G.; Schricker, B.; Thirring, K.; Berner,
H. J . Org. Chem. 1993, 58, 683.
(3) Frauer, A.; Mehlfu¨hrer, M.; Thirring, K.; Berner, H. J . Org.
Chem. 1994, 59, 4215.
(4) Mine, Y.; Yokota,Y.; Wakai,Y.; Fukuda, S.; Nishida, M.; Gotho,
S.; Kuwahara, S. J . Antibiot. 1983, 58, 683.
(5) For a detailed discussion see ref 2 and references cited therein.
(6) Fitzi, R.; Seebach, D. Angew. Chem. 1986, 98, 363.
(7) Mehlfu¨hrer, M.; Berner, H.; Thirring, K. J . Chem. Soc., Chem.
Commun. 1994, 1291.
(8) Anhydrous butyl glyoxylate was synthesized according to the
procedure of Hook, J . M. Synth. Commun. 1984, 14, 83.
(9) Matzinger, P.; Catalfono, Ph.; Eugster, C. H. Helv. Chim. Acta
1972, 55, 1478.
S0022-3263(97)00307-1 CCC: $14.00 © 1997 American Chemical Society

Synthesis of (2S,4S,6S)-2-Amino-4,6-dihydroxypimelic Acid
Sch em e 1
J . Org. Chem., Vol. 62, No. 12, 1997 4079
O
N
N
N
N
OH
H
N
N
O
O
O
O
O
O
O
O
OC4H9
O
H
Cl4Sn
2
OC4H9
5
H2O
N
N
N
(b)
O
O
N
a
N
N
O
O
(c)
O
+
c
O
N
N+
3
H
O–
+
O
H
b
O–
O
OC4H9
OH
b
O
O
OC4H9
A
B
O
OC4H9
O
O–
OC4H9
(e)
(a)
d
O
O
O–
E
N
N+
N
NH
O
O
(d)
O
O
H2O
N
OC4H9
O
O
O
4
OC4H9
OH
O
O
C
D
OC4H9
Sch em e 2
HO
O
OH OH
O
OH
H
N
H
α
γ
ε
RHN
O
α
O
H
H
O
H
H
1 R = H
8 R = COC6H5
γ
O
ε
O
H
H
O
OC4H9
O
O
O
N
OH
OC4H9
N
H
α
α
γ
ε
HN
OH
O
O
O
ε
γ
O
O
O
O
O
OC4H9
O
4
OC4H9
α
γ
ε
HN
5
O
O
7
O
HO
HN
OH
O
HO
6
Mech a n ist ic St u d ies (F igu r e 1 a n d Sch em e 1).
The mechanism of Lewis acid catalyzed ene reactions10
has been the subject of controversy and is usually
discussed in terms of a continuum from a concerted
pericyclic pathway to a stepwise, cationic process involv-
ing either a π-complex or a zwitterionic intermediate.11-13
In our case, the formation of lactone 4 and rearranged
ene product 5 strongly argues in favor of a zwitterionic
intermediate. Based on control experiments, a reason-
able mechanism for the SnCl4-mediated reaction can be
proposed. In the postulated chairlike transition state12,14
(12) Snider, B. B. Acc. Chem. Res. 1980, 13, 426.
(10) For review of the ene reaction: Oppolzer, W. Pure. Appl. Chem.
1981, 53, 1181.
(11) Stephenson, L. J . Org. Chem. 1981, 46, 2200.
(13) Mikami, K.; Shimizu, M. Chem.Rev. 1992, 92, 1021.
(14) Snider, B. B. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 1.

4080 J . Org. Chem., Vol. 62, No. 12, 1997
Mehlfu¨hrer et al.
Ta ble 1. P r od u ct Distr ibu tion of th e En e Rea ction
u n d er Differ en t Rea ction Con d ition s
N
N
products, % yield
N
N
O
no.
reaction conditionsa
SnCl4/25 °C/10 min
SnCl4/25 °C/3 h
SnCl4/-20 °C/3 h
SnCl4/-20 °C/1 h f 25 °C/3 h
FeCl3/25 °C/3 h
C(4)b
3
E(5)b Rb
O
O
O
1
2
3
4
5
47
5
75
6
28
35
14
20
78
5
40
2
58
2
20
20
9
16
17
O
OC4H9
O
O
Cl4Sn
H
O
H
Cl4Sn
OC4H9
3
a
All experiments were conducted with a ratio of substrate/
b
glyoxylic ester/Lewis acid as 1/3/4 in CH2Cl2. The corresponding
amounts of C and E present in a reaction mixture were determined
by HPLC analysis of 4 and 5 after acidic hydrolysis of drawn
samples. R represents the sum of undefined side and decomposi-
tion products.
O
H
N
H
N
O
H
N
H
N
O
Cl4Sn
O
SnCl
O
4 O
O
Exp er im en ta l Section
O
The general experimental procedures and the analytical
instruments employed have been described in detail.2 The
abbreviations CY (cyclohexane), TFA (trifluoro acetic acid), EE
(ethyl acetate), DIO (dioxane), and PTSA (p-toluenesulfonic
acid) were used.
Mea su r em en t of th e Rea ction P r ogr ess. A solution of
510 mg (4 mmol) of freshly distilled butyl glyoxylate,8 0.35 mL
(4 mmol) of SnCl4, and 300 mg (1 mmol) of (2S,5S)-1-benzoyl-
2-tert-butyl-3-methyl-5-(2-propenyl)imidazolidin-4-one7 in 30
mL of CH2Cl2 was kept at 25 °C (-20 °C) and periodically
drawn samples were analyzed by HPLC.
OC4H9
endo
OC4H9
exo
F igu r e 1.
a C-C bond is formed by a re-si interaction of the allylic
double bond and the glyoxylate carbonyl resulting in an
equilibrium of two bipolar intermediates A and B. For
the second step, three different pathways (a-c) can be
formulated: (a,c) the nucleophilic attack of the imid-
azolidinone- or benzoyl-carbonyl at the positive center of
A or B, leading to the iminolactone C or to the oxazine
E and (b) the transfer of the allylic proton to oxygen
leading to the ene product 3.
(2S,4S,6S)-2-Am in o-4,6-d ih yd r oxyh ep t a n ed ioic Acid
(1). (2S,4S,6S)-4,6-Dih yd r oxy-7-oxoa zep a n e-2-ca r boxylic
Acid (6). Meth od A. To a stirred solution of 360 mg (1.15
mmol) of 8 in a mixture of 10 mL of liquid NH3 and 5 mL of
ether was added in portions sufficient sodium to establish a
permanent blue coloration. The blue solution was stirred for
10 min, and the color was then discharged by addition of the
minimum amount of solid NH4Cl. After evaporation of the
NH3 under a stream of argon the solid residue was purified
by ion exchange chromatography (Dowex 50 X W8, 0.5%
NH4OH). Yield 176 mg (74%) of 1. Meth od B. A suspension
of 400 mg (0.9 mmol) 5 in 9 mL of 6 N HCl was heated in a
sealed tube at 120 °C for 3 h. After cooling, the reaction
mixture was diluted with water and extracted with EE. Ion
exchange chromatography on Dowex 50 X W8 (0.5% NH4OH)
afforded 150 mg (81%) of 1. Starting from lactone 4, amino
acid 1 can also be obtained in comparable yield (86%).
Meth od C. By using 3% NH4OH for the ion exchange
chromatography, lactam 6 could be isolated up to an yield of
15% besides amino acid 1: [R]20D -5.2° (c ) 0.5, H2O); 1H-NMR
The stable products 3-5 are not transformable into
each other under the conditions leading to their forma-
tion. Thus, A and B are common intermediates for these
products, indicating that the nucleophilic attack has to
occur prior to proton transfer. 4 is the main reaction
product at -20 °C together with small amounts of 3.
Upon warming to 25 °C, the postulated intermediate C
rearranges almost completely and irreversibly to 5,
assuming E as a possible intermediate. In addition,
small amounts of 3 again are formed (Table 1). As the
initial formation of 3 is favored over E, another pathway
from C to E besides the obvious (C f A f B f E) has to
be considered. Immediate rearragement of C to E is not
possible due to steric reasons; the most reasonable
intermediate is a highly reactive oxetane D generated
via pathway d. Thus, C and E can be assumed as the
kinetically and the thermodynamically controlled reac-
tion products, respectively.
(D2O) ABXY-System: (νA ) 1.93, νB ) 1.84, νX ) 4.13, νY
)
4.02, J AB ) 14.3, J AY ) 5.8, J AX ) 4.5, J BX ) 8.2, J BY ) 7.2
Hz), ABXY-System: (νA ) 1.82, νB ) 1.71, νX ) 3.44, νY ) 4.02,
J AB ) 14.3, J AX ) 4.2, J AY ) 9.8, J BX ) 9.2, J BY ) 3.0 Hz);
MS-FAB m/ e 207 (MH+, 10), 191 (36), 137 (44), 97 (100). Anal.
Calcd for C7H13NO6: C, 40.58; H, 6.32; N, 6.76. Found: C,
40.32; H, 6.16; N, 6.70. 6: 1H-NMR (D2O) ABXY-System: (νA
) 2.45, νB ) 1.47, νX ) 3.92, νY ) 4.13, J AB ) 13.3, J AY ) 4.3,
J AX) 10.5, J BY ) 11.3 Hz), ABXY-System: (νA ) 2.19, νB
)
The almost exclusive formation of ene product 3 in the
FeCl3-mediated reaction indicates a strong Lewis acid
dependency of the three pathways (a-c).
1.69, νX ) 4.35, νY ) 4.13, J AB ) 12.8, J AX ) 11.7, J AY ) 11.3,
J BX ) 2.2, J BY ) 4.0 Hz); 13C-NMR (D2O) 71.6, 68.2, 54.3, 43.2,
42.9. Anal. Calcd for C7H11NO5 C, 44.45; H, 5.86; N, 7.40.
Found: C, 44.57; H, 5.62; N, 7.48.
Discu ssion . These findings support the assumption
that the course of Lewis acid catalyzed carbonyl-ene-
reactions is characterized by very unsymmetrical transi-
tion states11,12,14 with C-C bond formation being almost
complete while C-H bond formation is just beginning.
Nucleophilic domains within the substrate (carbamoyl
oxygens) can interfere with the proton transfer step
which gives the above reaction pattern. This particular
property of Lewis acid catalyzed carbonyl-ene-reactions
could be potentially useful for stereocontrolled func-
tionalizations. In our case it was used to establish a
stereospecific, high yield synthesis of title compound 1.
5-(3-Ben zoyl-2(S)-ter t-bu tyl-1-m eth yl-5-oxoim id a zoli-
d in -4(S)-yl)-2(S)-h yd r oxyp en t-4-en oic Acid Bu tyl Ester
(3), 3-(4(S)-(Ben zoyla m in o)-5-oxo-tetr a h yd r ofu r a n -2(S)-
yl)-2(S)-h yd r oxyp r op ion ic Acid Bu tyl Ester (4), Ben zoic
Acid 3-(Bu toxyca r bon yl)-1-((2(R)-ter t-bu tyl-1-m eth yl-5-
oxoim id a zolid in -4(S)-yl)m eth yl)-3(S)-h yd r oxyp r op yl Es-
ter (5). To a -20 °C solution of 650 mg (5 mmol) of freshly
distilled butyl glyoxylate8 and 0.78 mL (6.6 mmol) of SnCl4 in
20 mL of CH2Cl2 was added dropwise via syringe a solution of
500 mg (1.7 mmol) of 2.7 The mixture was stirred for
additional 3 h and subsequently poured into a cooled solution
of 1 N HCl. After repeated extraction with CH2Cl2, the
combined extracts were washed with brine and evaporated to

Synthesis of (2S,4S,6S)-2-Amino-4,6-dihydroxypimelic Acid
J . Org. Chem., Vol. 62, No. 12, 1997 4081
dryness to give 650 mg of a mixture of 3-5. Chromatography
on silica gel (CY/DIO (2:1)) afforded 487 mg (75%) of 4, 106
mg (14%) of 3, and 14 mg (2%) of 5. Reaction conditions
determine the ratio of products 3-5 (Table 1). 3: [R]20D +106°
6(S)-(2(S)-(Ben zoyla m in o)-2(S)-(m et h oxyca r b on yl)-
et h yl)-2,2-d im et h yl[1,3]d ioxa n e-4(S)-ca r b oxylic Acid
Meth yl Ester (7). A solution of 120 mg (0.43 mmol) of 4 and
65 mg (0.34 mmol) of PTSA in 6 mL of dimethoxypropane was
heated under reflux for 5 h. After evaporation of the solvent
the reaction mixture was dissolved in EE and extracted with
NaHCO3. Chromatography on silica gel (CY/EE (3:2)) afforded
40 mg (30%) of 7. 1H-NMR (CDCl3) 7.42-7.80 (m, 5H), 7.50
(b, H), 3.78 (s, 6H), ABXY-System: (νA ) 2.13, νB ) 2.03, νX )
4.96, νY ) 4.13, J AB ) 14.6, J AY ) 2.5, J AX ) 5.9, J BX ) 3.9, J BY
) 10.0 Hz), ABXY-System: (νA ) 1.86, νB ) 1.62, νX ) 4.53, νY
1
(c ) 1.7, CH3OH); H-NMR (CDCl3) 7.39-7.57 (m, 5H), 5.70
(s, 1H), 5.30 (m, 1H), 4.91 (m, 1H), 4.65 (d, 1H, J ) 8.8 Hz),
4.14 (t, 2H, J ) 6.7 Hz), 3.68 (dd, 1H, J ) 3.5, 5.9 Hz), 3.08 (s,
3H), 2.08 (m, 2H), 1.61 (m, 2H), 1.36 (m, 2H), 1.09 (s, 9H),
0.94 (t, 3H); MS-FAB m/ e 431 (MH+, 58), 373 (100), 105 (43).
Anal. Calcd for C24H34N2O5: C, 66.95; H, 7.96; N, 6.51.
Found: C, 70.10; H, 7.90; N, 6.30. 4: [R]20 +17.4° (c ) 0.9,
D
1
) 4.13, J AB ) 13.1, J AX ) 2.8, J AY ) 2.6, J BX ) 12.1, J BY
)
CH3OH); H-NMR (CDCl3) 7.40-7.80 (m, 5H), 6.63 (d, 1H, J
11.8 Hz), 1.57-1.49 (m, 6H); MS-FAB m/ e 380 (MH+, 8), 364
(18), 322 (100). Anal. Calcd for C18H25NO7: C, 60.15; H, 6.34;
N, 3.69. Found: C, 59.92; H, 6.42; N, 3.47.
) 5.6 Hz), 4.24 (t, 2H), ABXY-System: (νA ) 3.1, νB ) 2.02, νX
) 4.76, νY ) 4.79, J AB ) 12.5, J AY ) 5.3, J AX ) 8.5, J BX ) 10.8,
J BY ) 10.7 Hz), ABXY-System: (νA ) 2.27, νB ) 2.23, νX
)
(2S ,4S ,6S )-2-(B e n z o y la m i n o )-4,6-d i h y d r o x y h e p -
ta n ed ioic Acid (8). A solution of 300 mg (0.86 mmol) of 4
and 810 mg (2.6 mmol) of Ba(OH)2 in 10 mL of CH3OH was
stirred at ambient temperature for 1.5 h. After adjustment
of the reaction mixture to pH 2.8 with DOWEX 50 X W8-H+,
the resin was filtered off and the solution lyophilized to afford
4.35, νY ) 4.79, J AB ) 14.5, J AX ) 6.4, J AY ) 6.4, J BX ) 5.3, J BY
) 5.3 Hz), 1.69 (m, 2H), 1.41 (m, 2H), 0.97 (t, 3H, J ) 7.3 Hz);
MS-FAB m/ e 350 (MH+, 56), 105 (100). Anal. Calcd for
C
18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.95; H,
6.78; N, 3.92. 5: 1H-NMR (CDCl3) 7.40-8.0 (m, 5H),
ABXY-System: (νA ) 2.31, νB ) 2.18, νX ) 4.30, νY ) 5.62, J AB
) 14.5, J AY ) 4.3, J AX ) 5.5, J BX ) 5.7, J BY ) 8.7 Hz), 4.05 (d,
1H, J ) 2.3 Hz), 3.98 (m, 2H), ABXY-System: (νA ) 2.27, νB
) 1.65, νX ) 3.60, νY ) 5.62, J AB ) 14.0, J AY ) 11.2, J AX ) 2.2,
J BX ) 2.2, J BY ) 10.4 Hz), 1.56 (m, 2H), 1.31 (m, 2H), 0.93 (s,
9H), 0.91 (t, 3H); MS-FAB m/ e 449 (MH+, 100), 391 (24), 327
(30), 155 (26). Anal. Calcd for C24H36N2O6: C, 64.26; H, 8.09;
N, 6.25. Found: C, 64.32; H, 7.90; N, 6.30.
230 mg (86%) of 8. [R]20 -7.3° (c ) 0.6, H2O); 1H-NMR
D
(CDCl3) 7.53 -7.85 (m, 5H), 4.60 (dd,1H, J ) 4.1, 9.4 Hz), 4.12
(dd, 1H, J ) 4.8, 8.6 Hz), 4.0 (m, 1H), 2.0-2.11 (m, 2H), 1.85-
1.99 (m, 2H); MS-FAB m/ e 311 (M+, 100), 293 (82). Anal.
Calcd for C14H17NO7: C, 54.02; H, 5.50; N, 4.50. Found: C,
54.18; H, 5.33; N, 4.67.
J O970307P