Facile synthesis of (-)-tabtoxinine-β-lactam and its (3′R)-isomer

Article abstract of DOI:10.1016/j.tetlet.2004.09.033

A concise and high yielding synthesis of (-)-tabtoxinine-β-lactam 1, the cause of tobacco wildfire disease, was achieved from l-serine. A concise and high yielding synthesis of (-)-tabtoxinine-β-lactam 1, the cause of tobacco wildfire disease, was achieve

Full text of DOI:10.1016/j.tetlet.2004.09.033

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8191–8194
Facile synthesis of (ꢀ)-tabtoxinine-b-lactam and its (30R)-isomer
Hiromasa Kiyota,* Takafumi Takai, Masatoshi Saitoh, Osamu Nakayama,
Takayuki Oritani and Shigefumi Kuwahara
Department of Applied Bioorganic Chemistry, Division of Bioscience and Biotechnology for Future Bioindustry,
Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Received 28 July 2004; revised 1 September 2004; accepted 3 September 2004
Available online 21 September 2004
Abstract—A concise and high yielding synthesis of (ꢀ)-tabtoxinine-b-lactam 1, the cause of tobacco wildfire disease, was achieved
from L-serine using a zinc-mediated coupling reaction, Sharpless asymmetric dihydroxylation and lactamization of N-OBn amide as
the key steps.
Ó 2004 Elsevier Ltd. All rights reserved.
NH
NH
2
Tobacco wildfire disease, caused by infection of Pseudo-
monas syringae pv. tabaci, has been the most serious pest
for tobacco.1 Several toxins and related compounds
were isolated from this bacteria and other Pseudomonas
sp.2 Tabtoxinine-b-lactam 1 was isolated as a phyto-
pathogenic compound2a,2b along with its precursor tab-
toxin 2. Compound 2 is hydrolyzed by host plant
aminopeptidase to give 1, which causes chlorosis by irre-
versible inactivation of glutamine synthetase.3 Recently,
the tabtoxin-resistance gene (ttr) was cloned and trans-
genic tobacco cultivars have been developed.4 In addi-
tion, a tabtoxin-resistant protein was characterized.5
Although 2 is available by fermentation (13mg/L),2b
subsequent conversion to 1 by hydrolysis of the amide
bond is complicated by concomitant isomerization to
isotabtoxin 3 (t1/2 = 24h at pH7.0).2b Several syntheses
of ( )-1,6a (ꢀ)-1,6b its analogs,7 28 and tabtoxinine-d-
lactam 49 have been reported to date, however these
not prove amenable to scale-up and further biological
tests of (ꢀ)-1 have yet to be conducted as a result. Here
we describe a short, efficient, and stereoselective synthe-
sis of both (ꢀ)-1 and its (30R)-isomer.
2
OH
OH
OH
H
N
HO
3'
O
NH
O
NH
HO
O
O
O
tabtoxinine-β-lactam [(–)-1]
tabtoxin (2)
lactamization
O
OH
NHZ
OH
HN
NH
2
H
X
BnO
N
R
O
Y
O
O
isotabtoxin (3: R = L-Thr)
tabtoxinine-δ-lactam (4: R = H)
A
asymmetric
reaction
metal-mediated
coupling
NHZ
NHZ
BnO
BnO
Y
+
X
O
R
O
R
B
C
D
Scheme 1. Related compounds and retrosynthetic analysis of (ꢀ)-1.
suitable asymmetric reactions of the double bond of B.
The carbon skeleton of B could be prepared from L-ser-
ine derivative C, and C4-fragment D.
Scheme 1 depicts our synthetic plan. b-Lactam forma-
tion can be achieved in many different ways; precursor
A could be (i) amino carboxylic acid (Y = OH,
X = NH2), (ii) amino ester (Y = OR, X = NH2), (iii)
amide (Y = NHR, X = leaving group), etc. The quater-
nary asymmetric center of A could be constructed by
The carbon framework was constructed as shown in
Scheme 2. Barton et al. reported a synthesis of 7a, how-
ever, the yield was only 34%.10 The synthesis started
from the known iodide 5,11b prepared from L-serine in
four steps. Using Baldwinꢀs radical coupling methodol-
ogy,11 this iodide was coupled with the known allylic
stannane 611a to give ester 7a in 61% yield. A variety
of conditions were tried, but the yield could not be im-
proved, so, we tried a zinc-mediated coupling reaction.12
*
Corresponding author. Tel.: +81 22 717 8785; fax: +81 22 717
8783; e-mail: kiyota@biochem.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.033

8192
H. Kiyota et al. / Tetrahedron Letters 45 (2004) 8191–8194
Table 2. Asymmetric dihydroxylationa
NHZ
NHZ
Bu3Sn
+
BnO
I
BnO
a
NHZ
NHZ
OH
OEt
O
AD-mix (α or β)
O
O
BnO
R
BnO
R
OR
O
5
7a: R = Et
7b: R = Me
6
t-BuOH/H O (2:1)
2
O
O
0˚C, 48 h
OH
olefin
diol (β)
b
c
9a: R = Et
9b: R = Me
Br
Entry Olefin (R)
AD-mix Diol Yield (%) deb (%)
OR
O
c
1
2
3
7a (CO2Et)
13a
13b
13a
84
88
78
6
38
23
NHZ
NHZ
c
b
a
BnO
ZnI
BnO
Br
TIPSO
O
O
4
5
11 (CH2OTIPS)
b
a
14b
14a
85
94
95
94
TIPSO
11
8
10
a Orientation of the hydroxy groups of 13 and 14 were attributed from
the final products (+)-1 and (ꢀ)-1, respectively.
Scheme 2. Synthesis of the carbon skeleton B: (a) AIBN, toluene, 65–
70°C (61%); (b) Zn, DMF, rt 20min; (c) CuCNÆ2LiCl, DMF (98% of
7a and 7b; 87% of 11).
b Diastereomeric excess (de) was determined by HPLC analysis using
Daicel CHIRALCELÒ OD column.
c OsO4 (cat), NMO (2equiv), MeCN/H2O (2:1).
The alkyl zinc iodide 8, prepared from 5 with active zinc,
was treated with allylic bromides 9a,12b,13 9b, and 10 to
afford 7a, 7b, and 11 in good yields, respectively.
amide of 18, derived from 13b (38% de), gave b-lactam
19,20 but the yield was only 30% (Scheme 3). Preliminal
study of deprotection of 19 afforded (+)-1 (38% de). We
then examined substitution conditions reported by Haaf
Construction of the asymmetric quaternary center was
achieved using Sharpless aminohydroxylation.14 As
shown in Table 1, a variety of nitrogen donors were used
to prepare amino alcohols 12a–c. The highest diastereo-
meric purity (81% de) was achieved for toluenesulfon-
amide (entry 5), however, the yield was only 40%
(accompanied by the corresponding diol) and further
conversion or deprotection of the N-Ts group failed.
and Ruchardt.21 Diol 170 was converted to 20; protec-
¨
tion of the tertiary hydroxy group was necessary to
avoid epoxy ring formation. Ring closure proceeded to
give b-lactam 21 in 80% yield.
We applied this method to the total synthesis (Scheme
4). Oxidation of the primary hydroxy group of 14b using
standard conditions (Dess–Martin, IBX,22 Swern oxida-
tion etc.) resulted in decomposition or low yields of the
aldehyde. This step was only successful with Aladroꢀs
TEMPO conditions,23 which gave carboxylic acid 22
in one pot. This was condensed with (benzyloxy)amine
to give benzyl hydroxamate and the silyl group was
removed to give diol 23. Tosylation proved troublesome:
23 underwent preferential N-tosylation at the hydroxa-
mate using either TsCl/Py or TsCl/Et3N. Fortunately,
mesylation was successful and the resulting monomesy-
late crystallized. A single recrystallization was sufficient
to give a diastereomerically pure sample.24 The tertiary
Next we tried a Sharpless asymmetric dihydroxylation
(Table 2).15 Diastereoselectivity was low using either
asymmetric catalyst (entries 1–3) for the a,b-unsaturated
ester 7a, but significantly higher for silyl ethers 11 (en-
tries 4 and 5).15b This may be due to the steric bulk of
the silicon group.
The next key step was closure of the b-lactam ring. Pre-
liminary studies using model compounds suggested that
condensation conditions from 15 to 17 including DCC,
MsCl/K2CO3,16 (PyS)2/Ph3P,17 sulfonamide/Ph3P18 or
the Mitsunobu reaction19 would fail. The magnesium
Table 1. Asymmetric aminohydroxylationa
OH
OH
OH
RNClNa, (DHQ) PHAL
NHZ
NHZ
NHR
OMe
2
NH
OH
OH
2
β-lactam
HO
K OsO (OH)
(1 mol%)
2
2
4
OBn
BnO
BnO
O
OH
O
NH
O
N
2
H
15
16
17
MeCN/H O (2:1)
2
O
O
NHZ
O
OMe
rt, 24 h
O
7b
12a-c
OH
OH
BnO
NH
2
a
b
Catalyst Product Yield deb
(+)-1
(38%de)
Entry N source (R)
NH
O
O
OEt
(%)
(%)
O
19
18 (38%de)
1
2
Bocc
4mol%
—
12a
12b
12c
53
38
69
11
OH
OH
OTMS
OTMS
n-C H
n-C H
Ts
n-C H
d
5
11
O
5
11
5
11
EtOCOc
4mol%
—
64
55
10
4
O
3
4
c
OBn
N
OBn
N
O
N
H
O
OBn
H
20
21
17'
5
6
Ts (chloramine T) 4mol%
—
40
64
81
5
Scheme 3. Model studies of b-lactam formation: (a) i. TMSCl, Et3N,
CH2Cl2, 0°C, 1h, ii. t-BuMgCl, THF/CH2Cl2; 0°C to rt, 12h, iii.
AcOH (30%); (b) H2, Pd/C, EtOH (quant); (c) i. TsCl, Py, ii. TMSOTf,
2,6-lutidine (88%); (d) NaH, THF (80%).
a Absolute configuration of the hydroxy group was not determined.
b Diastereomeric excess (de) was determined by HPLC analysis.
c These reagents were generated in situ.

H. Kiyota et al. / Tetrahedron Letters 45 (2004) 8191–8194
8193
NHZ
OTIPS
OH
This work was partially supported by a Grant-in-aid
for Scientific Research from Japan Society for the
Promotion of Science (No. 14760069), The Agricultural
Chemical Research Foundation, Intelligent Cosmos
Foundation and The Naito Foundation.
NHZ
OTIPS
OH
BnO
BnO
RO
BnO
BnO
a
b
O
O
O
O
OH
O
OH
14
β
(95%de)
22
NHZ
OH
NHZ
OMs
OH
TBSO
O
c
OBn
d
References and notes
OBn
N
N
O
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Genet. 1998, 97, 986–989.
H
H
23
24
(~100%de)
NHZ
NH
2
OTBS
N
OH
HO
e
O
NH
O
O
O
OBn
25: R = Bn
+ 26: R = H
tabtoxinine-β-lactam (1)
26
[α]
–24˚ (c 0.14, H O)
2
D
26
Dolle: [α]
–23.7˚ (c 0.30, H O)
2
D
NH
2
OH
26
[α]
+38˚ (c 0.09, H O)
2
D
HO
26
Dolle: [α]
+35.0˚
D
14α(94%de)
NH
(c 0.22, H O)
O
2
O
(3'R)-1
Scheme 4. Synthesis of (ꢀ)-1 and (+)-(30R)-1: (a) TEMPO, NaClO,
NaClO2, MeCN/H2O, rt, 12h (89%); (b) i. NH2OBnÆHCl, NaHCO3,
HOBt, EDCI, 0°C to rt, 12h (95%), ii. TBAF, THF; 0°C, 1h (86%);
(c) i. MsCl, Et3N, CHCl3, rt, 12h, ii. recrystallization (91%), iii.
TBSOTf, 2,6-lutidine, CH2Cl2, rt, 2h (88%); (d) KHMDS, THF, ꢀ78
to 0°C, 24h (59% of 25 and 11% of 26); (e) i. TBAF, THF, 0°C, ii. H2,
Raney-Ni, H2O–MeOH (1:2) (89% from 25 and 68% from 26).
5. (a) Liu, J.; Le, Y.; Ye, B.; Zhen, Y.; Zhu, C.; Shen, J.;
Zhang, R. Protein Expres. Purif. 2002, 24, 439–444; (b)
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Tang, H.; Zhang, R.; Joachimiak, A.; Liu, J.; Zhao, N.;
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hydroxy group was protected as a TBS ether to afford
24; a TMS group at this position was unable to with-
stand the conditions of the next step. b-Lactam forma-
tion was achieved using KHMDS to give 25, with
debenzylated acid 26 as a by-product. Use of NaH in-
creased the yield of 26.25 TBS deprotection of 25 and
26 followed by hydrogenolysis on Raney-Ni gave (ꢀ)-
1.26 The product was to be diastereomerically pure
and the value of specific optical rotation was in good
26
D
agreement with the literature value {½aꢁ ꢀ24 (c 0.14,
9. Lee, D. L.; Rapoport, H. J. Org. Chem. 1975, 40, 3491–
3495.
25
H2O), lit.6c ½aꢁ ꢀ23:7 (c 0.30, H2O)}. The overall yield
D
was 28% in 12 steps from 5 and 24% in 15 steps from L-
serine.
´
10. Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J.
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Commun. 1983, 944–945.
In a similar manner as described for (ꢀ)-1, (30R)-isomer
25
H2O), lit.6c ½aꢁ ꢀ38:0 (c 0.22, H2O)}. The overall yield
D
was 12% from 5.
25
(+)-(30R)-1 was synthesized from 14a {½aꢁ þ38 (c 0.09,
D
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64, 7579–7585; (b) Weigand, S.; Bruckner, R. Synthesis
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¨
In summary the stereoselective synthesis of (ꢀ)-tabtox-
inine-b-lactam (ꢀ)-1, a phytopathogenic compound of
tobacco wildfire disease, and its (+)-(30R)-isomer was
achieved using zinc-mediated coupling, Sharpless asym-
metric dihydroxylation, and b-lactam formation of
hydroxamate as the key steps.
13. Villieras, J.; Rambaud, M. Synthesis 1982, 924–926.
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Acknowledgements
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We thank Dr. Yoshifumi Itoh [Akita Research Institute
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H. Kiyota et al. / Tetrahedron Letters 45 (2004) 8191–8194
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1
24. Determined by H NMR analysis.
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26. Compound (ꢀ)-1: amorphous solid. IR mmax (KBr) cmꢀ1
:
3230 (s, O–H, N–H), 1740(s, C@O), 1620 (m), 1400 (m),
1
1200 (m), 940 (w), 790 (w). H NMR d (D2O, 300MHz):
1.65–2.08 (4H, m, H-10, H-20), 3.20 (1H, d, J = 6.6Hz,
H-4), 3.32 (1H, d, H-4), 3.68 (1H, t, H-20). 13C NMR
(D2O, 75MHz) d: 25.33, 30.75, 51.43, 54.93, 84.57, 174.29,
174.79. HRMS (FAB+) m/z: calcd for C7H13N2O4,
189.0875; found: 189.0879.
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