Synthesis of the four diastereoisomers of the N-terminal amino acids of nikkomycins via aminoalkylation with preformed ternary iminium salts

Article abstract of DOI:10.1515/znb-2004-0409

An efficient and convenient two step synthesis of each of the four possible diastereoisomers of the N-terminal amino acid component of nikkomycins is described. We first synthesized α-amino-β-oxo acids by aminoalkylation of ketones with iminium salts. The second step using Pearlman's catalyst gave directly nonnatural and natural precursors 13-16 of nikkomycins 1 which were easily separated by chromatography on silica gel.

Full text of DOI:10.1515/znb-2004-0409

Synthesis of the Four Diastereoisomers of the N-Terminal Amino Acids
of Nikkomycins via Aminoalkylation with Preformed Ternary Iminium
Salts*
Jeanne Delbos-Krampe, Nikolaus Risch, and Ulrich Fl o¨ rke
Department Chemie der Universit a¨ t Paderborn, Warburger Str. 100, D-33098 Paderborn, Germany
Reprint requests to Prof. Dr. N. Risch. Fax: +49(0)5251/603245;
E-mail: nr@chemie.uni-paderborn.de
Z. Naturforsch. 59b, 414 – 423 (2004); received January 13, 2004
Dedicated to Prof. Dr. Karsten Krohn on the occasion of his 60th birthday
An efficient and convenient two step synthesis of each of the four possible diastereoisomers of the
N-terminal amino acid component of nikkomycins is described. We first synthesized α-amino-β-oxo
acids by aminoalkylation of ketones with iminium salts. The second step using Pearlman’s catalyst
gave directly nonnatural and natural precursors 13 – 16 of nikkomycins 1 which were easily separated
by chromatography on silica gel.
Key words: Nikkomycins, Mannich Bases, Aminoalkylation, Lactones, 1,3-Amino Alcohols
Introduction
The 1,3-amino alcohol unit is quite common in nat-
ural products such as the nikkomycins 1, a group of nu-
cleoside peptide antibiotics produced by Streptomyces
tendae (Scheme 1) [1]. These structures are of interest
as potent chitin synthetase inhibitors and they exhibit
fungicidal, insecticidal and acaricidal activities [1 – 3].
In recent years, they have been the subject of inten-
sive studies focusing on their isolation, structural as-
signment, and pharmacological activity.
Several synthetic pathways for the synthesis of
the racemic or enantiomerically pure N-terminal side
chain of 1 and its derivates are described in the lit-
erature [1b, 1e, 4 – 10]. However, these approaches re-
quire quite a lot of reaction steps (4 to 7). We report a
racemic two step approach to N-terminal amino acid
units 2 using modern variants of the Mannich reac-
tion [11] to generate α-amino-γ-oxo acid esters 3 by
addition of either aliphatic ketones 4 or aromatic ke-
tones 5 to the iminium salt 6 (Scheme 2). The inter-
mediate 3 can be reduced and deprotected to yield the
desired 1,3-aminoalcohol unit 1.
*
(
1
Presented in part at the 6th Conference on Iminium Salts
ImSaT-6), Stimpfach-Rechenberg (Germany), September
6 – 18, 2003.
Scheme 1. Structure of nikkomycin B, Bx, J and X.
0
932–0776 / 04 / 0400–0414 $ 06.00 ꢀc 2004 Verlag der Zeitschrift f u¨ r Naturforschung, T u¨ bingen · http://znaturforsch.com
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J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
415
Scheme 2. Strategy for the synthesis of 1,3-aminoalcohol
unit 2 of the nikkomycins.
Fig. 1. Molecular structure of anti-10n showing 50% prob-
˚
◦
ability ellipsoids. Selected geometric parameters (A, ): O2-
C3 1.2006(18), O3-C6 1.2169(17), N1-C4 1.4722(17), C3-
C4 1.520(2), C4-C5 1.5343(19), C5-C6 1.525(2), C5-C13
1
.529(2); C14-N1-C21 111.14(12), C14-N1-C4 112.00(11),
C21-N1-C4 114.79(11), N1-C4-C3 111.69(12), N1-C4-C5
11.37(11), C3-C4-C5 113.22(11), C6-C5-C13 110.07(13),
1
C6-C5-C4 105.18(11), C13-C5-C4 111.39(11); C3-C4-C5-
C6 168.2(1), C3-C4-C5-C13 49.0(2), N1-C4-C3-O1 99.5(1),
N1-C4-C3-O2 −77.4(2).
Fig. 2. Molecular structure of syn-10n showing 50%
probability ellipsoids. Selected geometric parameters
˚
◦
(
A, ): O2-C3 1.196(7), O3-C6 1.218(7), N1-C4 1.474(7),
C3-C4 1.540(8), C4-C5 1.545(7), C5-C6 1.507(8), C5-C13
.548(7); C14-N1-C21 110.5(5), C14-N1-C4 113.7(5),
C21-N1-C4 114.5(5), N1-C4-C3 112.3(5), N1-C4-C5
11.1(5), C3-C4-C5 109.2(5), C6-C5-C13 108.0(5), C6-
Scheme 3. Preparation of the α-amino-γ-oxo acid esters 10.
◦
Reagents and conditions: a) Bt-H/HNR /toluene, 65 C, 5 h;
2
1
b) Lewis acid/THF, 1 h; c) THF.
1
Results and Discussion
C5-C4 110.1(6), C13-C5-C4 110.7(5); C3-C4-C5-C6
58.0(7), C3-C4-C5-C13 177.3(6), N1-C4-C3-O1 79.7(7),
N1-C4-C3-O2 −99.0(8).
Synthesis of the α-amino-γ-oxo acid esters
We previously demonstrated that iminium salts
9
generated in situ from ethyl glyoxylate 7, sec- lation of aromatic compounds [11d,13]. The iminium
ondary amines and 1-H-benzotriazoleaccording to Ka- salts 9 were produced by electrophilic attack of a Lewis
tritzky [12] are excellent reagents for the aminoalky- acid on the aminal 8 which in solution is in equilibrium
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J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
Table 1. Reaction of ketones 4 or 5 with aminals 8 to α-amino-γ-oxo acid esters 10.
Yield syn :
Ketone Aminal α-Amino-γ-oxo
Ketone Aminal α-Amino-γ-oxo
Yield syn :
Entry Product
Entry Product
4
or 5
8
acid esters 10
(%)
anti
4 or 5
8
acid esters 10
(%)
anti
1
2
10a
10b
4a
5a
8a
49
2 : 1
1
1
1
0
1
2
10j
10k
10l
5c
8b
96
2 : 1
8a
8a
8a
69
67
97
3 : 2
3 : 2
4 : 1
5d
8b
83
2 : 1
3
4
5
10c
10d
10e
5b
5c
5d
5e
4
8b
8c
8c
69
60
86
4 : 1
5 : 1
3 : 2
13 10m
1
1
1
1
1
4
5
6
7
8
10n
10o
10p
10q
10r
5a
8a
71
2 : 1
5b
5c
5d
5e
8c
8c
8c
8c
95
65
80
89
2 : 1
2 : 1
2 : 1
2 : 1
6
7
8
10f
10g
10h
5e
4
8a
8b
8b
51
47
33
2 : 1
3 : 1
2 : 1
5a
9
10i
5b
8b
60
3 : 2
with 8’ (Scheme 3). We have also shown that modified ily separated by crystallization. The relative configura-
ketone donors (enamines, imines) were reacted suc- tion of 10n was established by crystal structure deter-
cessfully with a lot of iminium salts. Herein, the suc- mination (Figures 1, 2). The comparison of the NMR
cess of a direct variant with unmodified ketone donors spectra of pure diastereomers with those of the mixture
is demonstrated. Ketones 4 and 5 were reacted with the of 10, combined with GC-analysis, allowed us to deter-
iminium salts 9 giving a good yield of the α-amino-γ- mine the ratio of anti- and syn-10. The β-aminoketones
oxo acid derivatives 3. Two diastereomers syn-10 and 10 were obtained in good to excellent yields. In all
anti-10 were generated by the aminoalkylation. The cases, the syn-compounds were the major products.
syn-10 compounds are precursors for the nikkomycin
Previously, we have demonstrated that addition
synthesis and anti-10 for the nonnatural products. The of enamines or imines to iminium salts gives anti-
best results were achieved using TiCl as Lewis acid in Mannich bases with excellent diastereoselectivities
4
THF. The yields and diastereoselectivities are listed in and good yields [11a]. However, using the protocol de-
Table 1. Variation of the solvent and temperature did scribed above, the reaction of imines or enamines did
not significantly improve the diastereoselectivities.
not give the β-aminoketones 10. Therefore, we devel-
In the following section we focussed our interest on oped another strategy for the selective synthesis of the
the Mannich bases anti- and syn-10n, which were eas- nonnatural derivatives of nikkomycins. The reaction of
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J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
417
Scheme 4. Diastereoselective preparation of the anti-α-
amino-γ-oxo acid esters 10.
aldehydes with secondary amines HNR , mediated by
2
NaI/Me SiCl/NEt quantitatively leads to the iminium
3
3
salts [11b, 14]. This methodology was applied to ethyl
glyoxylate 7 and dibenzylamine adding the enamines
Scheme 5. Preparation of the 1,3-amino alcohols 13-16.
1
1 and 12 to the solution (Scheme 4).
Inspite of the low yields of 10 (10 – 29%), this re- Conclusion
action is of special interest because of its excellent di-
astereoselectivity. Enamines 11 and 12 yield anti-10
This paper describes an efficient and convenient two
step synthesis of the N-terminal amino acid component
of nikkomycins. Each of the four possible diastereoiso-
mers is available in pure form by this procedure. It is
shown in the first step, that the aminoalkylation of ke-
tones with iminium salts 6 is an adapted method to pro-
(d. r. > 98 : 2). These products are intermediates for the
preparation of nonnatural derivatives of nikkomycins.
Synthesis of the 1,3-amino alcohols
A new one-pot approach was successfully devel- vide the α-amino-γ-oxo acid esters 3 which are potent
oped to establish the third stereogenic center. The si- precursors of nikkomycins. The NaI/Me SiCl/NEt -
3
3
multaneous reduction of the keto group, debenzylation mediated (“silylogous”) step selectively yields the key
and protection of the intermediate amino group as N- substance anti-10, whereas an easily separable mixture
Boc derivative of 10 efficiently gave the lactones 13 – of syn- and anti-10 is obtained with high yields using
1
6 (Scheme 5).
We used the reactive Pearlman’s catalyst (20%/ lyst gives directly nonnatural and natural precursors of
Pd(OH) /C) and H (1 atm) for this step. [15, 16]. nikkomycins. Additional work continues in our labora-
the aminal 8. The second step using Pearlman’s cata-
2
2
After debenzylation (TLC-control) the reaction mix- tory for an enantioselective approach to the N-terminal
ture was adjusted to pH = 8 by addition of NaOH to amino acid component of nikkomycins.
complete the formation of the lactones 13– 16. The
Mannich bases anti-10n were reacted to the cis,cis- Experimental Section
and trans,cis-lactones 13 and 14, respectively (13:14 =
General methods: 1H and 13C NMR: Bruker AMX
1
:1). Product syn-10n gave cis,trans- and trans,trans-
(
300 MHz) and (ARX 200 MHz), respectively; CDCl , int.
3
lactones 15 and 16 (15:16 = 1:1). The diastereoiso-
mers were easily separated by chromatography on sil-
ica gel. This strategy produces the 1,3-amino alco-
hol unit of nonnatural nikkomycins 13 – 15 and natural
nikkomycins 16 in one pot with high yields (88%). Al-
though no further transformation was carried out in 16,
however, it should be noted that closely related com-
1
3
standard: TMS. The multiplicities of the C signals were
assigned by CH correlation. The diastereomeric ratios were
13
determined from the C NMR spectra of the crude prod-
uct mixtures. In several cases, a complete assignment of the
H NMR spectra of compounds 10 was not possible (mix-
tures of diastereoisomers, overlapping multiplets). The sig-
nals for syn-10 (major product) are listed. – Elemental analy-
1
pounds have been transformed successfully to amino ses: Perkin Elmer Analysator 2400. – Melting Points: B u¨ chi
acid 2 [4a, 6, 7].
SMP 20 (uncorrected). – Column chromatography: Merck
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J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
silica gel 60 (70 – 230 mesh). – All solvents are purified and N(CH ) ), 39.73 (d, CHCH ), 51.06 (t, -CH -N-CH -),
2
5
3
2
2
dried in accordance with common procedures.
59.53 (t, CO CH CH ), 69.50 (d, NCH), 127.44, 127.87,
2 2 3
1
28.07, 128.09 (d, CHar), 135.91 (s, Car), 170.76, 203.29 (s,
C=O).
anti-10b: 13C NMR (50 MHz, CDCl ): δ = 14.24 (q,
Synthesis of α-Amino-γ-oxo acids 10
3
The reactions were conducted under argon. A solution
of ethyl glyoxylate aminal 6 (2 mmol) in anhydrous THF
CH CH ), 15.25 (q, CHCH ), 23.86, 25.60 (t, N(CH ) ),
2
3
3
2 5
3
8.72 (d, CHCH ), 51.06 (t, -CH -N-CH -), 59.60 (t,
3 2 2
◦
(
5 ml) was cooled to −78 C. TiCl (2 mmol, 0.22 ml) was
4
CO CH CH ), 71.93 (d, NCH), 127.44, 127.87, 128.07,
2
2
3
slowly added under stirring. After a reaction time of 1 h at
this temperature, the ketone 8 was added and the tempera-
ture was allowed to rise to ambient temperature. After stir-
ring overnight, HCl (6 N, 5 ml) was added and the mixture
1
–
1
28.09 (d, CHar), 137.69 (s, Car), 169.39, 203.01 (s, C=O).
GC-MS (80 eV): m/z (%) = 304(2) [M + 1] , 230(100),
98(2), 170(50), 124(13), 105(54), 77(11), 51(6), 41(15). –
+
Analysis. for C H NO (304.4): calcd. C 71.26, H 8.31,
1
8
25
3
was washed several times with Et O. Subsequently, the aque-
2
N 4.62; found C 71.11, H 8.39, N 4.55.
ous layer was adjusted to pH = 8 by the addition of NH3
(
25% NH : H O = 1 : 4) and the β-aminoketone was ex-
3 2
Ethyl 4-(4-methoxyphenyl)-3-methyl-4-oxo-2-(piperidin-1-
yl)-butanoate (10c)
tracted with CH Cl (3×50 ml). The combined organic lay-
2
2
ers were dried over Na SO and the solvent was removed in
2
4
vacuo. The compound 10 was purified by crystallisation or
used without further purification.
Yield 0.45 g (67%); two diastereomers (syn : anti = 3 : 2).
syn-10c: H NMR (200 MHz, CDCl3): δ = 1.11 (3H),
.23 (3H), 1.22 – 1.53 (m, 6H), 2.15 – 2.25 (m, 2H), 2.48 –
1
1
Ethyl 3-methyl-4-oxo-2-(piperidin-1-yl)-hexanoate (10a)
2.85 (m, 2H), 3.80 (s, 3H), 3.82 (1H), 3.94 (m, 1H), 4.12
1
3
(m, 2H), 6.85 – 8.0 (m, 4H). – C NMR (50 MHz, CDCl3):
Yield: 0.25 g (49%); two diastereomers (syn : anti = 2 : 1).
δ = 14.83 (q, CH CH ), 15.43 19 (q, CHCH ), 24.98, 27.13
2
3
3
1
syn-10a: H NMR (200 MHz, CDCl ): δ = 0.89 (t, 3H,
3
(t, N(CH ) ), 40.26 (d, CHCH ), 51.97 (t, -CH -N-CH -),
5
2 3 2 2
J = 7.2 Hz, CH CH ), 1.01 (d, 3H, J = 7.2 Hz, CHCH ),
2
3
3
55.84 (q, CH O), 60.63 (t, CO CH CH ), 70.41 (d, NCH),
3 2 2 3
1
6
2
2
.13 (t, 3H, J = 7.2 Hz, CO CH CH ), 1.22 – 1.51 (m,
2 2 3
114.18, 130.75, 130.89, 131.07 (d, CH ), 146.40, 163.84 (s,
ar
H, N(CH ) ), 2.15 – 2.27 (m, 2H, -CH -N-CH -), 2.27 –
2
5
2
2
C ), 172.03, 203.22 (s, C=O).
ar
.47 (m, 2H, CH CH ), 2.48 – 2.85 (m, 2H, -CH -N-CH -),
13
2
3
2
2
anti-10c: C NMR (50 MHz, CDCl ): δ = 15.03 (q,
CH CH ), 16.41 (q, CHCH ), 24.65, 26.43 (t, N(CH ) ),
3
.96 – 3.07 (m, 1H, CHCH ), 3.17 (d, 1H, J = 3.0 Hz,
3
2
3
3
2 5
13
NCH), 3.90 – 4.15 (m, 2H, CH CH ). – C NMR (50 MHz,
2
3
39.25 (d, CHCH ), 51.97 (t, -CH -N-CH -), 55.84 (q,
3 2 2
CH O), 60.63 (t, CO CH CH ), 72.50 (d, NCH), 114.18,
3 2 2 3
130.75, 130.89, 131.07 (d, CH ), 146.40, 163.84 (s, C ),
ar ar
CDCl ): δ = 7.28 (q, CH CH CO), 14.18 (q, CH CH ),
3
3
2
2
3
1
4.24 (q, CHCH ), 24.32, 26.44 (t, N(CH ) ), 34.71 (t,
3 2 5
COCH CH ), 44.38 (d, CHCH ), 50.98 (t, -CH -N-CH -),
2
3
3
2
2
170.80, 202.66 (s, C=O). – GC-MS (80 eV): m/z (%) =
5
9.62 (t, CO CH CH ), 69.03 (d, NCH), 171.06, 214.09 (s,
+
2
2
3
256(2) [M + 1] , 182(100), 170 (21), 142(8), 126(65),
10(8), 68(7), 58(13), 41(21). – Analysis for C H NO
C=O).
1
1
9
27
4
anti-10a: 13C NMR (50 MHz, CDCl ): δ = 7.22 (q,
3
(333.4): calcd. C 68.44, H 8.16, N 4.20; found C 68.26,
H 8.24, N 4.16.
CH CH CO), 13.67 (q, CH CH ), 14.34 (q, CHCH ),
3
2
2
3
3
2
4.20, 26.31 (t, N(CH ) ), 34.57 (t, COCH CH ), 44.83 (d,
5
2 2 3
CHCH ), 50.98 (t, -CH -N-CH -), 59.71 (t, CO CH CH ),
3
2
2
2
2
3
Ethyl 4-(4-hydroxyphenyl)-3-methyl-4-oxo-2-(piperidin-yl)-
butanoate (10d)
7
1.47 (d, NCH), 169.12, 212.79 (s, C=O). – GC-MS (80 eV):
+
m/z (%) =256(2) [M + 1] , 182(100), 170(21), 142(8),
Yield: 0.62 g (97%); two diastereomers (syn : anti = 4 : 1).
1
26(65), 110(8), 68(7), 58(13), 41(21). – Analysis for
1
syn-10d: H NMR (200 MHz, CDCl ): δ = 1.10 (3H),
C H NO (255.3): calcd. C 65.85, H 9.87, N 5.59; found
3
1
4
25
3
1
2
6
.23 (3H), 1.20 – 1.51 (m, 6H), 2.19 – 2.27 (m, 2H), 2.42 –
.79 (m, 2H), 3.80 (1H), 3.95 (m, 1H), 4.10 (m, 2H),
.90 – 7.95 (m, 4H). – C NMR (50 MHz, CDCl3):
C 65.66, H 8.90, N 5.56.
1
3
Ethyl 3-methyl-4-oxo-4-phenyl-2-(piperidin-1-yl)-butanoate
δ = 14.89 (q, CH CH ), 16.53 (q, CHCH ), 25.06, 26.01
2
3
3
(10b)
(
t, N(CH ) ), 40.21 (d, CHCH ), 51.96 (t, -CH -N-CH -),
2 3 2 2
5
Yield 0.42 g (69%); two diastereomers (syn : anti = 3 : 2).
60.79 (t, CO CH CH ), 70.44 (d, NCH), 115.30, 116.00,
2
2
3
1
syn-10b: H NMR (200 MHz, CDCl ): δ = 1.14 (3H), 126.48, 131.45(d, CHar), 139.16, 162.14 (s, Car), 172.48,
3
1
3
1
2
7
1
.25 (3H), 1.21 – 1.50 (m, 6H), 2.15 – 2.30 (m, 2H), 2.42 – 203.55 (s, C=O). anti-10d: C NMR (50 MHz, CDCl3):
.87 (m, 2H), 3.82 (1H), 3.94 (m, 1H), 4.10 (m, 2H), δ = 15.09 (q, CH CH ), 15.61 (q, CHCH ), 26.48, 27.21
2
3
3
.20 – 8.0 (m, 5H). – 13C NMR (50 MHz, CDCl ): δ = (t, N(CH ) ), 39.18 (d, CHCH ), 51.96 (t, -CH -N-CH -),
3
2 5
3
2
2
4.00 (q, CH CH ), 15.25 (q, CHCH ), 24.19, 26.34 (t, 60.79 (t, CO CH CH ), 72.48 (d, NCH), 115.30, 116.00,
2
3
3
2
2
3
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J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
419
1
2
26.47, 131.45(d, CHar), 139.16, 162.14 (s, Car), 172.48, δ = 8.06 (q, CH CH CO), 14.82 (q, CO CH CH ), 15.28
3
2
2
2
3
03.08 (s, C=O). Analysis for C H NO (319.4): calcd. (q, CHCH3), 35.56 (t, COCH CH ), 45.77 (d, CHCH ),
18
25
4
2
3
3
C 67.69, H 7.89, N 4.39; found C 67.78, H 7.80, N 4.51.
54.34 (t, NCH ), 60.74 (t, CO CH CH ) 63.65 (d, NCH),
2 2 2 3
1
20.27 (t, CH =CH-), 136.53 (d, CH =CH-), 172.92, 215.55
2 2
Ethyl 4-(4-acetoxyphenyl)-3-methyl-4-oxo-2-(piperidin-1-
yl)-butanoate (10e)
13
(s, C=O). anti-10g: C NMR (50 MHz, CDCl ): δ =
3
7
.85 (q, CH CH CO), 14.67 (q, CO CH CH ), 15.28 (q,
3 2 2 2 3
Yield 0.51 g (71%); two diastereomers (syn : anti = 2 : 1).
CHCH3), 35.56 (t, COCH2CH3), 46.10 (d, CHCH3), 53.98
1
syn-10e: H NMR (200 MHz, CDCl ): δ = 1.15 (3H), (t, NCH2), 60.74 (t, CO2CH2CH3), 63.36 (d, NCH), 120.02
3
1
(
4
.22 (3H), 1.22 – 1.55 (m, 6H), 2.11 (s, 3H), 2.15 – 2.25 (t, CH2=CH-), 136.05 (d, CH2=CH-), 170.90, 214.17 (s,
+
m, 2H), 2.48 – 2.80 (m, 2H), 3.83 (1H), 3.93 (m, 1H), C=O). – GC-MS (80 eV): m/z (%) = 268(100) [M + 1] ,
.05 (m, 2H), 7.20 – 8.0 (m, 4H). – 13C NMR (50 MHz, 194 (30), 134(5), 108(5). – Analysis for C15H25NO3 (267.4):
CDCl ): δ = 14.82 (q, CH CH ), 16.19 (q, CHCH ), 21.19 calcd. C 67.38, H 9.42, N 5.24; found C 67.49, H 9.30,
3
2
3
3
(
q, CH CO ), 25.63, 26.95 (t, N(CH ) ), 39.78 (d, CHCH ), N 5.13.
3 2 2 5 3
5
1.65 (t, -CH -N-CH -), 60.11 (t, CO CH CH ), 70.17 (d,
2 2 2 2 3
2
-Diallylamino-3-methyl-4-oxo-4-phenyl-butyric acid ethyl
NCH), 131.10 (d, CHar), 135.59 (s, Car), 139.21 (s, Car),
ester (10h)
1
54.55 (s, Car), 168.90, 171.41, 202.65 (s, C=O). anti-10e:
C NMR (50 MHz, CDCl ): δ = 15.15 (q, CH CH ),
1
3
3
2
3
Yield: 0.21 g (33%); two diastereomers (syn : anti = 2 : 1).
1
1
6.09 (q, CHCH ), 20.84 (q, CH CO ), 24.81, 26.40 (t,
syn-10h: H NMR (200 MHz, CDCl ): δ = 1.20 (d, 3H,
3
3
3
2
N(CH ) ), 39.40 (d, CHCH ), 51.65 (t, -CH -N-CH -), J = 6.7 Hz, CHCH ), 1.34 (t, 3H, J = 7.1 Hz, CH CH ),
2
5
3
2
2
3
2
3
6
1
1
3
9
0.60 (t, CO CH CH ), 72.30 (d, NCH), 130.78 (d, CHar), 3.05 (2H), 3.50 (2H), 3.82 (d, 1H, J = 10.7 Hz, NCH), 3.88 –
2 2 3
35.12 (s, Car), 138.79 (s, Car), 154.36 (s, Car), 168.90, 3.94 (m, 1H, CH CH), 4.25 (q, 2H, J = 7.1, CH CH ),
3
2
3
70.25, 202.36 (s, C=O). – GC-MS (80 eV): m/z (%) = 5.20 (m, 4H), 5.80 (m, 2H), 7.21 – 7.55 (m, 5 H). –
+
13
62(2) [M + 1] , 288(15), 246 (10), 170(18), 121(100),
C NMR (50 MHz, CDCl ): δ = 14.67 (q, CH CH ), 16.24
3 2 3
3(20), 65(25), 43(20). – Analysis for C H NO (361.4): (q, CHCH ), 41.04 (d, CHCH ), 54.49 (t, NCH ), 60.60
20
27
5
3
3
2
calcd. C 66.46, H 7.53, N 3.88; found C 66.31, H 7.75, (t, CO CH CH ), 64.15 (d, NCH), 117.91 (t, CH =CH-),
2
2
3
2
N 3.76.
ar ar
128.37, 128.96, 136.56 (d, CH ), 146.01 (s, C ), 172.54,
1
3
2
1
5
04.11 (s, C=O). anti-10h: C NMR (50 MHz, CDCl ): δ =
3
Ethyl 3-methyl-4-oxo-2-(piperidin-1-yl)-4-(pyridin-4-yl)-
butanoate (10f)
4.91 (q, CH CH ), 15.36 (q, CHCH ), 39.86 (d, CHCH ),
2
3
3
3
4.12 (t, NCH ), 60.60 (t, CO CH CH ), 65.86 (d, NCH),
2
2
2
3
Yield: 0.31 g (51%); two diastereomers (syn : anti = 2 : 1). 117.70 (t, CH2=CH-), 127.97, 128.63, 136.61 (d, CHar),
1
syn-10f: H NMR (200 MHz, CDCl ): δ = 1.17 (3H), 146.01 (s, Car), 170.98, 203.23 (s, C=O). – GC-MS (80 eV):
3
+
1
2
2
.28 (3H), 1.20 – 1.50 (m, 6H), 2.16 – 2.25 (m, 2H), 2.45 – m/z (%) = 316 (7) [M + 1] , 274(20), 242(72), 182(25),
.85 (m, 2H), 3.45 (m, 1H), 3.79 (1H), 4.10 (m, 2H), 7.95 (m, 105(100), 77(25), 49(29), 41(33). – Analysis for C19H25NO3
H), 8.90 (m, 2H). – 13C NMR (50 MHz, CDCl ): δ = 14.88 (315.4): calcd. C 72.35, H 7.99, N 4.44; found C 72.29,
3
(
q, CH CH ), 15.68 (q, CHCH ), 24.91, 25.95 (t, N(CH ) ), H 8.11, N 4.59.
2 3 3 2 5
4
1.00 (d, CHCH ), 51.84 (t, -CH -N-CH -), 60.72 (t,
3 2 2
2
-Diallylamino-4-(4-methoxyphenyl)-3-methyl-4-oxo-but-
CO CH CH ), 70.25 (d, NCH), 121.92 (d, CHar), 143.08
2
2
3
yric acid ethyl ester (10i)
(s, Car), 151.08 (d, CHar), 171.96, 203.83 (s, C=O). anti-
1
3
1
1
0f: C NMR (50 MHz, CDCl ): δ = 14.49 (q, CH CH ),
Yield: 0.41 g (60%); two diastereomers (syn : anti = 3 : 2).
3
2
3
1
5.07 (q, CHCH ), 24.44, 26.29 (t, N(CH ) ), 40.13 (d,
syn-10i: H NMR (200 MHz, CDCl ): δ = 1.17 (3H),
3
2 5
3
CHCH ), 51.84 (t, -CH -N-CH -), 61.37 (t, CO CH CH ), 1.31 (3H), 3.05 (2H), 3.50 (2H), 3.80 (s, 3H), 3.80 (1H),
3
2
2
2
2
3
7
2.99 (d, NCH), 121.83 (d, CHar), 143.57 (s, Car), 150.53 (d, 3.94 (1H), 4.25 (m, 2H), 5.20 (m, 4H), 5.80 (m, 2H), 6.90
1
3
CHar), 169.73, 203.74 (s, C=O). – Analysis for C H N O
– 7.85 (m, 4H). – C NMR (50 MHz, CDCl ): δ = 14.79
3
17
24
2
3
(304.4): calcd. C 67.08, H 7.95, N 9.20; found C 66.97, (q, CH CH ), 16.47 (q, CHCH ), 40.73 (d, CHCH ), 54.57
2 3 3 3
H 7.99, N 9.14.
(t, NCH ), 55.86 (q, OCH ), 60.61 (t, CO CH CH ), 64.24
2 3 2 2 3
(
d, NCH), 114.12 (d, CHar), 117.91 (t, CH =CH-), 131.02 (d,
2
2
-Diallylamino-3-methyl-4-oxo-hexanoic acid ethyl ester
CHar), 136.74 (d, CH =CH-), 163.77 (s, Car), 172.62, 202.59
(
2
3
(10g)
1
s, C=O). anti-10i: C NMR (50 MHz, CDCl ): δ = 15.00
3
Yield: 0.25 g (47%); two diastereomers (syn : anti = 3 : 1). (q, CH CH ), 15.59 (q, CHCH ), 39.55 (d, CHCH ), 54.21
syn-10g: H NMR (200 MHz, CDCl ): δ = 0.91 (t, (t, NCH ), 55.86 (q, OCH ), 60.61 (t, CO CH CH ), 65.81
H), 1.01 (d, 3H), 1.19 (t, 3H), 2.27 – 2.47 (m, 2H), 3.05 (d, NCH), 114.12 (d, CHar), 117.65 (t, CH =CH-), 130.80 (d,
2
3
3
3
1
3
2
3
2
2
3
3
2
(
(
1H), 3.29 (1H), 3.05 (2H), 3.50 (2H), 4.15 (m, 2H), 5.20 CHar), 136.30 (d, CH =CH-), 163.77 (s, Car), 171.38, 201.46
2
m, 4H), 5.80 (m, 2H). – 13C NMR (50 MHz, CDCl3): (s, C=O). – GC-MS (80 eV): m/z (%) = 345(100) [M + 1] ,
+
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2
20
J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
72(10) 182(50). – Analysis for C H NO (345.4): calcd. CH CH ), 15.82 (q, CHCH ), 41.49 (d, CHCH ), 54.09 (t,
20
27
4
2
3
3
3
C 69.54, H 7.88, N 4.05; found C 69.40, H 7.93, N 4.18.
NCH ), 60.93 (t, CO CH CH ), 64.20 (d, NCH), 118.14 (t,
2 2 2 3
CH =CH-), 121.48 (d, CHar), 136.39 (d, CH =CH-), 143.05
2
2
2
-Diallylamino-4-(4-hydroxyphenyl)-3-methyl-4-oxo-but-
(
s, Car), 151.16 (d, CHar), 172.84, 203.61 (s, C=O). anti-10l:
yric acid ethyl ester (10j)
13
C NMR (50 MHz, CDCl ): δ = 14.51 (q, CH CH ), 15.08
3
2
3
Yield: 0.64 g (96%); two diastereomers (syn : anti = 2 : 1). (q, CHCH3), 40.46 (d, CHCH3), 53.89 (t, NCH2), 60.97
syn-10j: H NMR (200 MHz, CDCl ): δ = 1.14 (3H), (t, CO2CH2CH3), 65.83 (d, NCH), 117.95 (t, CH2=CH-),
.33 (3H), 3.05 (2H), 3.50 (2H), 3.83 (1H), 3.98 (1H), 4.25 121.99 (d, CHar), 135.49 (d, CH2=CH-), 143.10 (s, Car),
1
3
1
(
m, 2H), 5.20 (m, 4H), 5.80 (m, 2H), 6.90 – 7.95 (m, 4H). – 151.10 (d, CHar), 171.28, 207.76 (s, C=O). – Analysis for
1
3
C NMR (50 MHz, CDCl ): δ = 14.75 (q, CH CH ), 16.69 C18H24N2O3 (316.4): calcd. C 68.33, H 7.65, N 8.85; found
3
2
3
(
q, CHCH ), 40.75 (d, CHCH ), 54.54 (t, N-CH -), 60.94 (t, C 68.24, H 7.73, N 8.71.
3 3 2
CO CH CH ), 64.26 (d, NCH), 115.31, 116.08 (d, CHar),
2
2
3
1
18.07 (t, CH =CH-), 126.49, 131.44 (d, CHar), 136.60 2-Dibenzylamino-3-methyl-4-oxo-hexanoic acid ethyl ester
2
(
d, CH =CH-), 139.14, 162.30 (s, Car), 173.18, 203.53 (s, (10m)
2
1
3
C=O). anti-10j: C NMR (50 MHz, CDCl ): δ = 14.99 (q,
3
Yield: 0.44 g (60%); two diastereomers (syn : anti = 5 : 1).
syn-10m: H NMR (200 MHz, CDCl ): δ = 0.91 (t, 3H),
.01 (d, 3H), 1.19 (t, 3H), 2.27 – 2.47 (m, 2H), 3.02 (1H),
CH CH ), 15.72 (q, CHCH ), 39.49 (d, CHCH ), 54.21 (t,
2
3
3
3
1
3
N-CH -), 60.80 (t, CO CH CH ), 65.90 (d, NCH), 115.31,
2
2
2
3
1
3
(
1
16.16 (d, CHar), 117.89 (t, CH =CH-), 126.49, 131.27
2
.27 (1H), 3.59 (2H), 4.01 (2H), 4.15 (m, 2H), 7.05 – 7.30
(
d, CHar), 136.14 (d, CH =CH-), 139.14, 162.37 (s, Car),
2
13
m, 10H). – C NMR (50 MHz, CDCl ): δ = 8.04 (q,
3
1
71.67, 202.59 (s, C=O). – Analysis for C H NO (331.4):
25
19 4
CH CH CO), 15.04 (q, CH CH ), 15.24 (q, CHCH ), 31.73
3
2
2
3
3
calcd. C 68.86, H 7.60, N 4.23; found C 68.76, H 7.54,
N 4.35.
(t, CO CH CH ), 45.39 (d, CHCH ), 55.50 (t, N-CH -),
2 2 3 3 2
6
0.97 (t, CO CH CH ), 62.93 (d, NCH), 125.47, 127.61,
2 2 3
4
-(4-Acetoxyphenyl)-2-diallylamino-3-methyl-4-oxo-butyric
128.67, 129.61 (d, CHar), 139.21 (s, Car), 172.03, 214.10
1
3
acid ethyl ester (10k)
(s, C=O). anti-10m: C NMR (50 MHz, CDCl3): δ = 7.81
(
q, CH CH CO), 13.81 (q, CH CH ), 14.61 (q, CHCH ),
3 2 2 3 3
Yield: 0.62 g (83%); two diastereomers (syn : anti = 2 : 1).
3
2.38 (t, CO CH CH ), 46.72 (d, CHCH ), 55.08 (t, N-
2 2 3 3
1
syn-10k: H NMR (200 MHz, CDCl ): δ = 1.18 (3H),
3
CH -), 60.71 (t, CO CH CH ), 64.63 (d, NCH), 125.47,
2
2
2
3
1
3
7
1
5
1
.32 (3H), 2.12 (s, 3H), 3.05 (2H), 3.50 (2H), 3.80 (1H),
.92 (1H), 4.20 (m, 2H), 5.20 (m, 4H), 5.80 (m, 2H),
127.61, 128.67, 129.61 (d, CHar), 139.21 (s, Car), 170.18,
2
+
11.86 (s, C=O). – GC-MS (80 eV): m/z (%) = 368(40) [M
1] , 294(100), 282(70), 146(10), 91(10). – Analysis for
.20 – 8.0 (m, 4H). – 13C NMR (50 MHz, CDCl ): δ =
3
+
4.70 (q, CH CH ), 16.62 (q, CHCH ), 40.66 (d, CHCH ),
2
3
3
3
C H NO (367.5): calcd. C 75.17, H 7.95, N 3.81; found
2
3
29
3
4.49 (t, NCH ), 60.78 (t, CO CH CH ), 64.21 (d, NCH),
2
2
2
3
C 75.10, H 7.91, N 3.87.
15.21, 115.93 (d, CHar), 117.96 (t, CH =CH-),126.34
2
(
d, CHar), 128.44 (s, Car), 131.36 (d, CHar), 136.59 (d,
2
-Dibenzylamino-3-methyl-4-oxo-4-phenyl-butyric acid
CH =CH-), 139.10 (s, Car), 162.31, 172.92, 203.30 (s, C=O).
anti-10k: C NMR (50 MHz, CDCl ): δ = 14.94 (q,
CH CH ), 15.63 (q, CHCH ), 38.97 (d, CHCH ), 54.16 (t,
2
ethyl ester (10n)
1
3
3
2
3
3
3
Yield: 0.71 g (86%); two diastereomers (syn : anti = 3 : 2).
◦
1
NCH ), 60.70 (t, CO CH CH ), 66.35 (d, NCH), 115.21,
syn-10n: M.p. 94 C. – H NMR (200 MHz, CDCl3):
16.01 (d, CHar), 117.76 (t, CH =CH-), 126.34 (d, CHar), δ = 1.20 (d, 3H, J = 6.7 Hz, CHCH ), 1.34 (t, 3H, J =
2
2
2
3
1
1
1
2
3
29.81 (s, Car), 131.18 (d, CHar), 136.14 (d, CH =CH-), 7.1 Hz, CH CH ), 3.59 (d, 2H, J = 13.4 Hz, -CH -N-CH -),
2
2
3
2
2
39.10 (s, Car), 162.36, 171.55, 202.34 (s, C=O). – GC- 3.82 (d, 1H, J = 10.7 Hz, NCH), 3.88 – 3.94 (m, 1H,
+
MS (80 eV): m/z (%) = 373(4) [M] , 332(100), 290(20), CH CH), 4.01 (d, 2H, J = 13.4 Hz, -CH -N-CH -), 7.21 –
2
C H NO (373.4): calcd. C 67.54, H 7.29, N 3.75; found 14.81 (q, CH CH ), 15.81 (q, CHCH ), 40.41 (d, CHCH ),
3
2
2
1
3
58(30), 182(25), 138(12), 121(17), 41(15). – Analysis for 7.94 (m, 15 H CH ). – C NMR (50 MHz, CDCl ): δ =
ar
3
2
1
27
5
2
3
3
3
C 67.59, H 7.21, N 3.66.
55.46 (t, N-CH -), 60.37 (t, CO CH CH ), 63.37 (d, NCH),
2 2 2 3
1
1
3
27.19, 128.26, 128.30, 128.50, 129.18, 132.84 (d, CHar),
2
-Diallylamino-3-methyl-4-oxo-4-(pyridin-4-yl)-butyric
36.14, 138.91 (s, Car), 171.74, 203.37 (s, C=O); IR (KBr):
acid ethyl ester (10l)
−1
062.4, 1725.9, 1673.9, 1180.2, 748.2, 698.7 cm . – GC-
+
Yield : 0.44 g (69%); two diastereomers (syn : anti = 4 : 1). MS (80 eV): m/z (%) = 414(5) [M - 1] , 342(100), 324(20),
1
◦
syn-10l: H NMR (200 MHz, CDCl ): δ = 1.19 (3H), 282(35), 105(35), 91(20), 77 (10). anti-10n: M.p. 86 C. –
3
1
1
(
(
.33 (3H), 3.52 (1H), 3.05 (2H), 3.50 (2H), 3.77 (1H), 4.24
H NMR (200 MHz, CDCl ): δ = 1.22 (d, 3H, J = 6.7 Hz,
3
m, 2H), 5.20 (m, 4H), 5.80 (m, 2H), 7.90 (m, 2H), 8.90 CHCH ), 1.44 (t, 3H, J = 7.1 Hz, CH CH ), 3.38 (d, 2H,
3 2 3
1
3
m, 2H). – C NMR (50 MHz, CDCl ): δ = 14.77 (q, J = 13.9 Hz, -CH -N-CH -), 3.93 (d, 1H, J = 10.9 Hz,
3
2
2
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J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
421
NCH), 3.96 (d, 2H, J = 13.9 Hz, -CH -N-CH -), 4.35 (q, 4-(4-Acetoxyphenyl)-2-dibenzylamino-3-methyl-4-oxo-but-
2
2
2
7
1
5
1
1
3
6
3
H, J = 7.1, CH CH ), 4.13 – 4.47 (d, 1H, CH CH), 7.21 – yric acid ethyl ester (10q)
2 3 3
13
.94 (m, 15 H CHar). – C NMR (50 MHz, CDCl ): δ =
3
Yield: 0.76 g (80%); two diastereomers (syn : anti = 2 : 1).
5.17 (q, CH CH ), 15.89 (q, CHCH ), 39.92 (d, CHCH ),
2
3
3
3
1
syn-10q: H NMR (200 MHz, CDCl ): δ = 1.17 (3H),
3
5.76 (t, N-CH -), 60.68 (t, CO CH CH ), 65.93 (d, NCH),
2
2
2
3
1
3
(
.32 (3H), 2.10 (s, 3H), 3.57 (2H), 3.83 (1H), 3.93 (1H),
.99 (2H), 4.20 (m, 2H), 7.05 – 7.30 (m, 10H), 7.20 – 8.0
27.40, 128.39, 128.61, 129.19, 129.31, 133.35 (d, CHar),
37.78, 138.93 (s, Car), 170.91, 201.75 (s, C=O). – IR (KBr):
058, 2983, 1726, 1682, 1448, 1286, 1182, 1149, 748, 715,
1
3
m, 4H). – C NMR (50 MHz, CDCl ): δ = 14.88 (q,
3
−1
+
CH2CH3), 16.20 (q, CHCH3), 21.35 (q, CH3CO2), 40.73
96 cm . – GC-MS (80 eV): m/z (%) = 414(15) [M - 1] ,
(
6
d, CHCH ), 55.87 (t, N-CH -), 60.79 (t, CO CH CH ),
3 2 2 2 3
42(100), 324(10), 282 (50), 105(55), 91(20). – Analysis for
3.83 (d, NCH), 122.11, 127.62, 129.22, 129.88, 130.27 (d,
CHar), 134.7, 139.25, 154.65 (s, Car), 169.13, 172.05, 202.54
C H NO (415.5): calcd. C 78.04, H 7.03, N 3.37; found
C 78.17, H 6.98, N 3.49.
2
7
29
3
◦
1
(s, C=O). anti-10q: M.p. 122 C – H NMR (200 MHz,
3
3
2
-Dibenzylamino-4-(4-methoxyphenyl)-3-methyl-4-oxo-but-
H, J = 7.1 Hz, CH CH ), 2.33 (s, 3H, CH CO ), 3.36 (d,
2 3 3 2
yric acid ethyl ester (10o)
NCH), 3.92 (d, 2H, J = 13.8 Hz, -CH -N-CH -), 4.10 dq,
2
2
Yield: 0.85 g (95%); two diastereomers (syn : anti = 2 : 1).
1
H, J = 6.6 Hz, J = 10.9 Hz, CH CH), 4.23 – 4.41 (m, 2H,
1
3
syn-10o: H NMR (200 MHz, CDCl ): δ = 1.18 (3H),
3
CH CH ), 7.01 – 7.29 (m, 12 H CHar), 7.97 (d, 2H, J =
2
3
1
(
.34 (3H), 3.59 (2H), 3.80 (s, 3H), 3.82 (1H), 3.94 (1H), 3.99
1
3
8
.7 Hz, CHar). – C NMR (50 MHz, CDCl ): δ = 15.09 (q,
3
2H), 4.25 (m, 2H), 6.85 – 8.0 (m, 4H), 7.05 – 7.30 (m, 10H).
CH CH ), 15.79 (q, CHCH ), 21.54 (q, CH CO ), 40.01 (d,
1
3
2
3
3
3
2
–
1
5
1
1
C NMR (50 MHz, CDCl ): δ = 14.97 (q, CH CH ),
3 2 3
CHCH ), 55.80 (t, N-CH -), 60.80 (t, CO CH CH ), 65.97
3
2
2
2
3
6.32 (q, CHCH ), 40.47 (d, CHCH ), 55.69 (t, N-CH -),
3
3
2
(
1
d, NCH), 122.35, 127.45, 128.44, 129.27, 130.19 (d, CHar),
35.15, 138.84, 154.72 (s, Car), 169.33, 170.90, 200.77 (s,
C=O). – IR (KBr): 2979, 1755, 1722, 1662, 1203, 1163, 744,
5.92 (q, OCH ), 60.75 (t, CO CH CH ), 63.86 (d, NCH),
3
2
2
3
14.15, 128.75, 129.66 (d, CHar), 139.00, 163.86 (s, Car),
72.10, 202.29 (s, C=O). anti-10o: 13C NMR (50 MHz,
−1
6
1
9
96 cm . – GC-MS (80 eV): m/z (%) = 474(35) [M +
CDCl ): δ = 15.14 (q, CH CH ), 16.53 (q, CHCH ), 39.49
3
2
3
3
+
] , 400(100), 382(50), 282(80), 163(10), 146(30), 121(60),
(
d, CHCH ), 55.76 (t, N-CH -), 55.92 (q, OCH ), 60.66 (t,
3 2 3
1(80), 65(20). – Analysis for C H NO (473.6): calcd.
2
9
31
5
CO CH CH ), 65.94 (d, NCH), 114.36, 128.37, 129.25 (d,
2
2
3
C 73.55, H 6.60, N 2.96; found C 73.69, H 6.67, N 2.90.
CHar), 139.41, 163.74 (s, Car), 170.98, 200.34 (s, C=O). –
+
GC-MS (80 eV): m/z (%) = 446(20) [M + 1] , 372(80),
2
-Dibenzylamino-3-methyl-4-oxo-4-(pyridin-4-yl)-butyric
3
54 (100), 282(55), 135(55), 91(40), 65(10). – Analysis for
acid ethyl ester (10r)
C H NO (445.5): calcd. C 75.48, H 7.01, N 3.14; found
2
8
31
4
Yield: 0.74 g (89%); two diastereomers (syn : anti = 2 : 1).
C 75.60, H 7.09, N 3.08.
1
syn-10r: H NMR (200 MHz, CDCl ): δ = 1.19 (3H),
3
1
4
.30 (3H), 3.52 (1H), 3.59 (2H), 3.79 (1H), 3.98 (2H),
.20 (m, 2H), 7.05 – 7.30 (m, 10H), 7.95 (m, 2H), 8.90
2
-Dibenzylamino-4-(4-hydroxyphenyl)-3-methyl-4-oxo-but-
yric acid ethyl ester (10p)
1
3
(m, 2H). – C NMR (50 MHz, CDCl ): δ = 14.57 (q,
3
Yield: 0.56 g (65%); two diastereomers (syn : anti = 2 : 1). CH2CH3), 14.71 (q, CHCH3), 41.27 (d, CHCH3), 56.05 (t,
1
N-CH -), 61.46 (t, CO CH CH ), 63.94 (d, NCH), 121.81,
2 2 2 3
syn-10p: H NMR (200 MHz, CDCl ): δ = 1.15 (3H),
3
122.96, 125.81, 127.62, 129.33 (d, CHar), 140.24, 143.62 (s,
1
4
–
1
6
1
.32 (3H), 3.59 (2H), 3.80 (1H), 3.95 (1H), 4.01 (2H),
.25 (m, 2H), 6.90 – 7.95 (m, 4H), 7.05 – 7.30 (m, 10H).
C NMR (50 MHz, CDCl ): δ = 14.97 (q, CH CH ),
6.80 (q, CHCH ), 40.54 (d, CHCH ), 55.91 (t, N-CH -),
Car), 151.16, (d, CHar), 172.47, 203.40 (s, C=O). anti-10r:
1
3
1
3
C NMR (50 MHz, CDCl ): δ = 15.01 (q, CH CH ), 15.17
3 2 3
3
2
3
(q, CHCH ), 40.90 (d, CHCH ), 55.95 (t, N-CH -), 61.19
3 3 2
3
3
2
(
t, CO CH CH ), 65.83 (d, NCH), 121.81, 122.96, 125.81,
2 2 3
1.06 (t, CO CH CH ), 63.93 (d, NCH), 115.42, 116.30,
2
2
3
1
27.81, 129.66 (d, CHar), 139.59, 143.13 (s, Car), 151.24, (d,
26.34, 127.71, 128.13, 128.23, 129.21, 129.36, 131.50 (d,
CHar), 138.94, 139.44, 162.96 (s, Car), 172.62, 203.35 (s,
C=O). anti-10p: C NMR (50 MHz, CDCl ): δ = 15.20 (q,
CH CH ), 16.11 (q, CHCH ), 39.41 (d, CHCH ), 55.69 (t,
CHar), 171.90, 201.22 (s, C=O). – Analysis for C H N O
6
28 2 3
2
1
3
(416.5): calcd. C 74.98, H 6.78, N 6.73; found C 74.92,
H 6.85, N 6.60.
3
2
3
3
3
N-CH -), 60.90 (t, CO CH CH ), 66.01 (d, NCH), 115.42,
2
2
2
3
NaI/Me SiCl/NEt -mediated one-pot synthesis of Mannich-
bases [14] 10
3
3
1
1
2
16.58, 126.34, 127.43, 128.29, 128.43, 129.21, 129.36,
31.50 (d, CHar), 139.36, 139.44, 163.17 (s, Car), 171.30,
01.3 (s, C=O). – Analysis for C H NO (431.5): calcd.
General procedure: To a solution of anhydrous NaI in dry
MeCN (5.5 mmol; c ≈ 1 mol/l) were added dibenzylamine
27
29
4
C 75.15, H 6.77, N 3.25; found C 75.09, H 6.81, N 3.14.
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4
22
J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
(
2.5 mmol), NEt (2.5 mmol) and Me SiCl (5.5 mmol). Af- CHN), 81.06 (s, C(CH ) ), 85.89 (d, CH-O-CO), 125.18,
3
3
3 3
ter stirring for 30 min at ambient temperature, ethyl gly- 128.82, 129.08, 129.30 (d, CHar), 138.49 (s, Car), 155.84,
oxylate (2.5 mmol) was given into the solution and stirring 175.42 (s, C=O); IR (KBr): 3357.4, 1781.9, 1708.6, 1513.8,
−
1
was continued for additional 30 min. The enamine or ketone 1162.9, 998.9 cm . – GC-MS (80 eV): m/z (%) = 236(20)
+
(
2.5 mmol) was added and the mixture was stirred for another [M – C H ] , 191(20), 147(30), 132(70), 115(30), 57(90),
4
7
6
0 min. Afterwards, the mixture was acidified with aqueous 49(100), 41(65). – Analysis for C H NO (291.3): calcd.
16
21 4
HCl (5 ml, 37% HCl : H O = 1 : 1) and stirred for 10 min. C 65.96, H 7.27, N 4.81; found C 66.09, H 7.39, N 4.62.
2
The organic layer was extracted with Et O (3×50 ml), dried
2
over Na SO and the solvent was finally removed in vacuo.
2
4
tert-Butyl (3S*,4S*,5R*)-4-methyl-2-oxo-5-phenyl-tetrahy-
drofuran-3-yl-carbamate (15)
Debenzylation of α-amino-γ-oxo acids 10
◦
Obtained from syn-10. Yield: 0.12 g (20%); m.p. 158 C.
H was bubbled through a solution of 10 (2 mmol, mixture – 1H NMR (200 MHz, CDCl ): δ = 0.85 (d, 3H, J =
2
3
of diastereomers or diastereomerically pure) in anhydrous 6.8 Hz, CHCH ), 1.45 (s, 9H, C(CH ) ), 2.77 – 2.91 (m,
3
3 3
EtOH (10 ml) in the presence of 20% Pd(OH) /C (20 mg) 1H, CHCH ), 4.15 – 4.31 (m, 1H, CHNHBoc), 4.98 (d, 1H,
2
3
and (Boc) O (2.5 mmol, 0.43 g) until the debenzylation was J = 7.6 Hz, NHBoc), 5.57 (d, 1H, J = 8.3 Hz, CH-O-
2
1
3
completed (TLC control). The solvent was removed in vacuo CO), 7.08 – 7.47 (m, 5 H CHar). – C NMR (50 MHz,
and 10 ml MeOH and 3 ml aqueous NaOH (1.5 g NaOH CDCl ): δ = 14.16 (q, CHCH ), 28.64 (q, C(CH ) ), 41.69
3
3
3 3
in 3 ml H O) were added. After stirring over night at am- (d, CHCH ), 54.92 (d, CHN), 81.06 (s, C(CH ) ), 82.56
2
3
3 3
bient temperature, the mixture was acidified with aqueous (d, CH-O-CO), 126.30, 128.93, 129.05 (d, CHar), 135.75 (s,
HCl to pH = 1. The catalyst was removed by filtration and Car), 156.06, 175.63 (s, C=O). – IR (KBr): 3342, 1784, 1696,
−
1
the organic layer was extracted with Et O (3×50 ml). After 1535, 1152, 991 cm . – GC-MS (80 eV) m/z (%) = 236(50)
2
+
drying over Na SO , the solvent was finally evaporated in [M - C H ] , 191(20), 147(30), 132(70), 115(20), 57(100),
2
4
4 7
vacuo. The crude residue provided the lactones respectively 49(40), 41(50). – Analysis for C H NO (291.3): calcd.
1
6
21
4
by column chromatography (n-hexane : ethyl acetate = 3 : 1). C 65.96, H 7.27, N 4.81; found C 66.12, H 7.17, N 4.89.
tert-Butyl (3R*,4S*,5R*)-4-methyl-2-oxo-5-phenyl-tetrahy-
tert-Butyl (3S*,4S*,5S*)-4-methyl-2-oxo-5-phenyl-tetrahy-
drofuran-3-yl-carbamate (13)
drofuran-3-yl-carbamate (16)
◦
◦
Obtained from anti-10. Yield: 0.14 g (24%); m.p. 149 C.
Obtained from syn-10. Yield: 0.13 g (22%); m.p. 143 C.
– 1
7
H NMR (200 MHz, CDCl ): δ = 0.56 (d, 3H, J = – 1H NMR (200 MHz, CDCl ): δ = 1.25 (d, 3H, J =
3
3
.3 Hz, CHCH ), 1.49 (s, 9H, C(CH ) ), 3.14 – 3.30 (m, 1H, 6.6 Hz, CHCH ), 1.51 (s, 9H, C(CH ) ), 2.27 – 2.48 (m,
3 3 3 3 3 3
CHCH ), 4.81 – 4.87 (m, 1H, CHNHBoc), 5.20 (brd, 1H, 1H, CHCH ), 4.10 – 4.37 (m, 1H, CHNHBoc), 4.92 (d,
3
3
NHBoc), 5.66 (d, 1H, J = 4.7 Hz, CH-O-CO), 7.23 – 7.47 1H, J = 10.1 Hz, CH-O-CO), 5.03 (brd, 1H, J = 7.3 Hz,
13
(
(
(
m, 5 H CHar). – 13C NMR (50 MHz, CDCl ): δ = 8.77 NHBoc), 7.16 – 7.50 (m, 5 H CHar). – C NMR (50 MHz,
3
q, CHCH ), 28.67 (q, C(CH ) ), 40.77 (d, CHCH ), 56.83 CDCl ): δ = 14.08 (q, CHCH ), 28.67 (q, C(CH ) ), 47.67
d, CHN), 81.01 (s, C(CH ) ), 81.78 (d, CH-O-CO), 125.51, (d, CHCH ), 58.27 (d, CHN), 81.07 (d, CH-O-CO), 85.25
3
3 3
3
3
3
3 3
3
3
3
1
28.55, 129.05 (d, CHar), 135.68 (s, Car), 155.78, 175.05 (s, (s, C(CH ) ), 126.93, 129.19, 129.55 (d, CHar), 136.87 (s,
3
3
−1
C=O). – IR (KBr): 3278, 1782, 1680, 1549, 1172, 976 cm
.
Car), 155.89, 174.71 (s, C=O). – IR (KBr): 3311, 1788,
+
−1
–
1
–
GC-MS (80 eV): m/z (%) = 236 (50) [M - C H ] , 1678, 1529, 1161, 997 cm . – GC-MS (80 eV): m/z (%) =
4
7
+
91(20), 147(30), 132(60), 115(20), 57(100), 49(40), 41(55). 236(80) [M - C H ] , 191(20), 147(20), 132(60), 115(20),
4
7
Analysis for C H NO (291.3): calcd. C 65.96, H 7.27, 57(100), 49(20), 41(60); Analysis for C H NO (291.3):
1
6
21
4
16 21
4
N 4.81; found C 65.84, H 7.32, N 4.75.
calcd. C 65.96, H 7.27, N 4.81; found C 65.86, H 7.35,
N 4.95.
tert-Butyl (3R*,4S*,5S*)-4-methyl-2-oxo-5-phenyl-tetrahy-
drofuran-3-yl-carbamate (14)
Crystal structure determinations of anti-10n and syn-10n
[17]
◦
Obtained from anti-10. Yield: 0.12 g (20%); m. p. 122 C;
1
H NMR (200 MHz, CDCl ): δ = 1.21 (d, 3H, J =
anti-10n: C H NO , Mr = 415.5; orthorhombic, space
3
27 29
3
7
.2 Hz, CHCH ), 1.48 (s, 9H, C(CH ) ), 2.87-3.05 (m, 1H, group Pccn (No 56); a = 18.039(3), b = 27.382(4), c =
3 3 3
˚
˚ 3
3
CHCH ), 4.49-4.56 (m, 1H, CHNHBoc), 4.86-5.02 (brd, 9.618(3) A, V = 4750.7(19) A ; Z = 8; Dc = 1.162 g/cm ;
1
H CHar). – C NMR (50 MHz, CDCl ): δ = 14.21 (q, diffractometer at 203(2) K; graphite monochromated Mo-Kα
3
−1
H, NHBoc), 5.35 (brs, 1H, CH-O-CO), 7.16 – 7.47 (m, 5 µ = 0.075 mm . Data were collected with a Bruker P4
1
3
3
CHCH ), 28.64 (q, C(CH ) ), 41.48 (d, CHCH ), 52.99 (d, radiation. Crystal dimensions 0.17 × 0.32 × 0.52 mm; scan
3
3 3
3
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J. Delbos-Krampe et al. · The Four Diastereoisomers of the N-Terminal Amino Acids of Nikkomycins
423
◦
−1
range 2.3 < Θ < 27.0 ; 0 < h < 23, −34 < k < 34, 0 < µ = 0.076 mm . Data collection as before. Crystal di-
l < 12; 10254 intensities of which 5190 were independent mensions 0.08 × 0.10 × 0.52 mm; scan range 2.8 < Θ <
◦
(
Rint = 0.031). Structure solution with direct methods. Full 25.0 ; 0 < h < 22, 0 < k < 12, −1 < l < 26; 4166 in-
3
matrix least squares refinement based on F and 281 parame- tensities of which 4145 were independent. Structure solu-
ters, all but hydrogen atoms refined anisotropically. H-atoms tion and refinement as before, 281 parameters. Refinement
were located from difference Fourier maps and refined with converged at R1 = 0.109 (I > 2σ(I)), wR2 = 0.161 (all
a riding model at idealized positions with Uiso = 1.2Uiso(C) data), max. (∆/σ) = 0.001, min/max height in final ∆F map
˚
3
and 1.5Uiso(Methyl-C). Refinement converged at R1 = 0.045 −0.22/0.25 e/A . Programs as before.
(
I > 2σ(I)), wR2 = 0.119 (all data), max. (∆/σ) = 0.001,
˚
3
min/max height in final ∆F map −0.15/0.14 e/A . Programs
Acknowledgements
used: SHELXTL V5 [17].
syn-10n: C H NO , Mr = 415.5; orthorhombic, space
Support of this work by the Fonds der Chemischen Indus-
2
7
29
3
group Pbca (No 61); a = 19.194(5), b = 10.909(5), c = trie and the Deutsche Forschungsgemeinschaft is gratefully
˚
˚ 3
3
acknowledged.
2
2.495(8) A, V = 4710(3) A ; Z = 8; Dc = 1.172 g/cm ;
[
1] a) H. Z a¨ hner, H. Holst, G. Zoebelein, A. Keckeisen,
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[
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[
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the structures reported in this paper have been de-
posited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-
169808 for anti-10n and CCDC-169809 for syn-10n.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (Fax: int. Code +44(1223)336-033; E-mail:
deposit@ccdc.cam.ac.uk).
9
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(
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