Synthesis of (-)-tabtoxinine-β-lactam, the phytotoxin of tobacco wildfire disease

Article abstract of DOI:10.1055/s-2007-983785

Synthesis of (-)-tabtoxinine-β-lactam and its (3R)-isomer, the cause of tobacco wildfire disease, was achieved from L-serine using a zinc-mediated coupling reaction, Sharpless asymmetric dihydroxylation and lactamization of β-mesyloxy benzylhydroxamate amide as the key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983785

PAPER
2471
Synthesis of (–)-Tabtoxinine-b-lactam, the Phytotoxin of Tobacco Wildfire
Disease
S
ynthesis of (–)-T
a
i
btoxin
r
ine-
b
-lac
o
tam masa Kiyota,* Takafumi Takai, Yasuharu Shimasaki, Masatoshi Saitoh, Osamu Nakayama, Tomoko Takada,
Shigefumi Kuwahara
Department of Applied Bioorganic Chemistry, Division of Bioscience & Biotechnology for Future Bioindustry, Graduate School of
Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Fax +81(22)7178785; E-mail: kiyota@biochem.tohoku.ac.jp
Received 5 March 2007; revised 8 May 2007
This paper is dedicated to the memory of Dr. Takeyoshi Sugiyama who passed away in 1999 at 53 years of age.
O
NH2
OH
Abstract: Synthesis of (–)-tabtoxinine-b-lactam and its (3R)-iso-
mer, the cause of tobacco wildfire disease, was achieved from L-
serine using a zinc-mediated coupling reaction, Sharpless asymmet-
ric dihydroxylation and lactamization of b-mesyloxy benzylhy-
droxamate amide as the key steps.
NH2
HN
OH
OH
t1/2
OH
H
N
H
N
R
R
pH 7.0, 5 d
pH 4.5, 15 min
O
NH
O
HO
O
HO
O
O
Key words: tabtoxinine-b-lactam, b-lactam, amino acids, total syn-
thesis, natural products
tabtoxin
2
3
R = Me
R = H
isotabtoxin
4
5
R = Me
R = H
[Ser2]-tabtoxin
[Ser2]-isotabtoxin
(inactive)
(inactive)
O
Wildfire disease, caused by infection of Pseudomonas sy-
ringae pv. tabaci, has been the most serious pest for to-
bacco since the early twentieth century.1 A phytotoxic
compound, tabtoxin, was isolated from the
phytopathogen2 and its structure was finally established
by Stewart as 2 (Figure 1).3 Tabtoxin (2) and its serine ho-
mologue 34 were later found to be inactive precursors of
the true toxin, tabtoxinine-b-lactam (TbL, 1)5 which is
produced by host plant peptidases6 and causes chlorosis
by irreversible inactivation of the host plant glutamine
synthetase (GS).7 Although 2 is available by fermentation
(13 mg/L),3 hydrolysis of the amide bond is complicated
by isomerization to stable isotabtoxins (4 and 5) or tabtox-
inine-d-lactam (6) (t1/2 = 24 h at pH 7.0 and 15 min at pH
4.5). TbL is expected to be a selective pesticide because
the tabtoxin resistance gene (ttr) has been cloned8 and a
tabtoxin-resistant protein (TTR) was characterized.9
Thus, an effective synthetic procedure for the synthesis of
TbL has been desired. In addition to synthetic studies10 of
( )-1,11a (–)-1,11b its analogues,12 213 and tabtoxinine-d-
lactam 4,14 we have reported a short and efficient synthe-
sis of (–)-1 and (3R)-1 as a preliminary communication.15
Herein we describe details for the synthesis of the latter
two compounds.
OH
NH2
HN
HO
NH2
OH
4'
2'
3
4
HO
3'
1'
host plant
peptidase
O
NH
2
O
1
O
tabtoxinine-β-lactam (TβL)
tabtoxinine-δ-lactam
1
6
(active)
(inactive)
Figure 1 Tabtoxinine-b-lactam and related compounds
C and the C4-fragment D (Y = metal and Z = halogen, or
vise versa).
Scheme 2 shows the coupling reaction. L-Serine was con-
verted into the known iodide 7 (= C,17b four steps, 79%
yield), which was coupled with allylic stannane 817a using
Baldwin’s radical methodology17 to give 9 ( = B) in 61%
yield. Barton et al. also reported a synthesis of 9 by a de-
carboxylative coupling reaction.18 We then tried an alter-
native method using a zinc-mediated coupling reaction.19
Thus, the iodide 7 was treated with active zinc in order to
generate alkyl zinc iodide 10, which reacted with the al-
asymmetric
lactamization
BnO
NHCbz
X
NHCbz
Our synthetic plan is depicted in Scheme 1. We selected
an intramolecular SN2 reaction of the amide anion A for
the key b-lactam ring closure. The chirality of the tertiary
oxygen function could be constructed by Sharpless
dihydroxylation16 of the double bond of B. Such a carbon
framework would be easily accessible using a metal-me-
diated coupling reaction between the L-serine derivative
reaction
PO
BnO
R
TβL 1
O
O
O
N
P
A
B
metal-mediated
coupling
NHCbz
BnO
Y
R
L-serine
+
Z
O
SYNTHESIS 2007, No. 16, pp 2471–2480
x
x.
x
x
.
2
0
0
7
C
D
Advanced online publication: 12.07.2007
Scheme 1 Retrosynthetic analysis of 1
DOI: 10.1055/s-2007-983785; Art ID: F04707SS
© Georg Thieme Verlag Stuttgart · New York

2472
H. Kiyota et al.
PAPER
O
NHCbz
Table 1 Asymmetric Dihydroxylation
BnO
I
a
NHCbz
NHCbz
+
Bu3Sn
OEt
OH
R
AD-mix (α or β)
BnO
R
BnO
O
NHCbz
O
7
8
t-BuOH–H2O (2:1)
0 °C, 48 h
BnO
O
O
b
OEt
OH
olefin
diol (β)
O
O
NHCbz
Entry Olefin (R)
1
AD-mix Diola
Yield (%) deb (%)
9
BnO
ZnI
+
Br
c
OEt
b
–
14a
14b
99
88
6
O
2
9
b
38
11
10
(CO2Et)
+
NHCbz
3
4
a
b
14a
78
85
23
95
BnO
b
Br
OR
OR
13a
(CH2OTIPS)
15ab
13a R = TIPS
O
R = TBS
13b
13c
12a–c
R = TBDPS
5
6
a
b
15aa
15bb
94
94
94
90
Scheme 2 Synthesis of the carbon skeleton B: a) AIBN, toluene,
70 °C (61%); b) i. Zn, DMF, r.t., 20 min; ii. bromide, CuCN·2LiCl,
DMF [9 (98%), 13a (87%), 13b (85%), 13c (80%)].
13b
(CH2OTBS)
7
8
a
b
15ba
15cb
72
35
90
87
lylic bromides 1119b,20 to afford 9 in 98% yield. In a simi-
lar procedure, coupling with silyl ethers 12a,21 12b22 and
12c23 gave 13a, 13b and 13c, respectively.
13c
(CH2OTBDPS)
9
b
a
15cb
15ca
75
58
82
68
Construction of the tertiary hydroxy group was achieved
by Sharpless asymmetric dihydroxylation (Table 1).16 Al-
though diastereoselectivities were low for the a,b-unsat-
urated ester 9 (entries 1–3), results for silyl ethers 13a–c
(entries 4–7) were satisfactory (90–95% de).16b This may
be due to the steric bulk of the silicon group. The yield of
15cb was only 35% because of the low solubility of 13c
(entry 8), however, higher temperature resulted in loss of
diastereomeric purities (entry 9 and 10).
10
a Orientation of the hydroxy group was attributed from the final prod-
uct (–)-1.
b Diastereomeric excess (de) was determined by HPLC analysis using
a Daicel CHIRALCEL® OD column.
c Reaction conditions: OsO4 (cat.), NMO (2 equiv), MeCN–H2O
(2:1).
The key b-lactam ring formation step was studied using
Haaf and Rüchardt’s conditions.24 In preliminary studies
(Scheme 3), the exo-olefin of 1625 was dihydroxylated to
17 and the ethoxy group was substituted with amine to
give amide 18. The primary hydroxy group was tosylated
to 19 and the tertiary hydroxy was protected with a tri-
methylsilyl (TMS) group, giving 20; protection of the ter-
tiary hydroxy group was necessary in order to avoid
epoxy ring formation. Ring closure proceeded to give the
b-lactam 21 in 80% yield when sodium hydride was used
as base.
NHCbz
olefin
NHCbz
OH
AD-mix (α or β)
BnO
R
BnO
R
t-BuOH–H2O (2:1)
0 °C, 48 h
O
O
OH
diol (β)
OH
OH
OR
OTs
a
c
O
OEt
O
R
O
NH
OBn
Scheme 4 shows the total synthesis of 1. 2,2,6,6-Tetra-
methylpiperidine N-oxyl (TEMPO) oxidation26 of the pri-
mary hydroxy group of 15ab afforded carboxylic acid
24b, which was condensed with (benzyloxy)amine to give
benzyl hydroxamate 25b. The triisopropylsilyl (TIPS)
group was then removed to give diol 26b. Selective tosy-
lation proved troublesome since preferential N-tosylation
at the hydroxamate occurred using tosyl chloride with ei-
ther pyridine or triethylamine. Instead, mesylation was
successful and the resulting monomesylate 27b fortunate-
ly crystallized. The minor a-diastereomer was removed
by a single recrystallization to give a stereochemically
pure sample. The tertiary hydroxy group was protected as
a tert-butyldimethylsilyl (TBS) ether to afford 28b; a tri-
19 R = H
20 R = TMS
16
17 R = OEt
18 R = NHOBn
d
b
OR
OH
e
g
N
N
O
OBn
O
H
21 R = TMS
22 R = H
23
f
Scheme 3 Model studies of b-lactam formation: a) K2OsO2(OH)4,
K3Fe(CN)6, K2CO3, t-BuOH–H2O (91%); b) NH2OBn·HCl, AlMe3,
PhMe (58%); c) TsCl, pyridine (quant.); d) TMSOTf, 2,6-lutidine,
CH2Cl2 (88%); e) NaH, THF (80%); f) AcOH–THF–H2O (1:2:2), r.t.
(quant.); g) H2, Raney-Ni, MeOH (54%).
Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Tabtoxinine-b-lactam
2473
methylsilyl (TMS) group at this position was unable to toxinine-b-lactam [(–)-1], was achieved in 15 steps, 24%
withstand the conditions of the next step. The diastereo- overall yield from L-serine, using zinc-mediated coupling,
meric purity (~100% de) was determined by HPLC anal- Sharpless asymmetric dihydroxylation and b-lactam for-
ysis of 28b. b-Lactam formation was achieved using mation from the protected hydroxamate as key steps.
potassium hexamethyldisilazide (KHMDS) to afford 29b,
with debenzylated acid 30b as a by-product. Use of sodi-
Melting points are uncorrected. Elemental analysis was carried out
um hydride increased the yield of 29b. Deprotection of the
TBS group of 29b and 30b followed by hydrogenolysis on
Raney-Ni gave (–)-1. The specific optical rotation was
found to be in good agreement with the literature value
with a Perkin–Elmer 2400II CHN analyzer. Optical rotation values
were recorded on a Horiba SEPA 300 polarimeter. HPLC was per-
formed with a Hitachi L-6000 pump and a Hitachi L-4200 UV-Vis
detector. IR spectra were recorded by a Jasco Report-100 infrared
spectrometer. FT-IR spectra were recorded on a Jasco 4100 infrared
26
25
{[a]D –24 (c 0.14, H2O); lit.11c [a]D –23.7 (c 0.30,
H2O)}. The overall yield was 28% in 12 steps from 7 and
24% in 15 steps from L-serine.
1
spectrometer. H- and 13C NMR spectra were recorded on Varian
Gemini 2000 (300 MHz for 1H and 75 MHz for 13C), Varian Unity
Inova 500 (500 MHz for 1H and 125 MHz for 13C) and Varian Unity
Inova 600 (150 MHz for 13C) spectrometers using TMS as an inter-
nal standard. EI and FAB mass spectra were recorded with a Jeol
JMS–700 spectrometer using m-nitrobenzyl alcohol (NOBA) as
matrix (FAB). Merck silica gel 60 (70–230 mesh) was used for col-
umn chromatography.
In a similar manner as described for (–)-1, the (3R)-iso-
25
mer, (+)-(3R)-1, was synthesized from 15aa {[a]D +38
25
(c 0.09, H2O); lit.11c [a]D +35.0 (c 0.22, H2O)}.27 The
overall yield was 11% from 7.
In conclusion, the stereoselective synthesis of a phyto-
pathogenic compound of tobacco wildfire disease (–)-tab-
1-Benzyl 6-Ethyl (S)-2-Benzyloxycarbonylamino-5-methylene-
hexanedioate (9): Tin Coupling
A solution of iodide 7 (8.05 g, 18.5 mmol), 8 (14.9 g, 37.0 mmol,
2.0 equiv) and AIBN (0.60 g) in anhyd toluene (220 mL) was stirred
at 70 °C for 3 h. After the reaction mixture was cooled to r.t., KF
(6.4 g) was added and the resulting suspension was stirred for 1 d.
The mixture was filtered through a Celite pad and the filtrate was
concentrated in vacuo. The residue was purified by chromatography
on silica gel (hexane–EtOAc, 10:1→5:1) to give 9 (4.82 g, 11.3
mmol, 61%) as a colorless oil.
NHCbz
NHCbz
OH
OH
BnO
a
BnO
1
3
2
4
OTIPS
OTIPS
5
6
O
O
OH
O
R
15aβ (95% de)
24β R = OH
R = NHOBn
b
25β
NHCbz
NHCbz
OH
OTBS
c
BnO
d
e
BnO
Zinc Coupling
OR
OBn
OMs
OBn
A suspension of Zn powder (7.18 g, 110 mgatom, 6.0 equiv) and
1,2-dibromoethane (1.0 g, 5.5 mmol, 0.3 equiv) in DMF (20 mL)
was stirred at 60 °C for 30 min under nitrogen. TMSCl (0.060 g,
0.55 mmol, 0.03 equiv) was added and the mixture was stirred at
60 °C for a further 30 min. Iodide 7 (8.05 g, 18.3 mmol) in DMF (16
mL) was added dropwise and the mixture was stirred at 60 °C for 10
min. The mixture was cooled to –55 °C and a solution of
CuCN·2LiCl (3.19 g, 18.3 mmol 1.0 equiv) in DMF (16 mL) was
added at –55 °C. The mixture was warmed to 0 °C and stirred for 10
min then again cooled to –55 °C and bromide 11 (4.11 g, 21.4
mmol, 1.2 equiv) was added. After stirring for 6 h, unreacted Zn was
filtered through a Celite pad, sat. aq NH4Cl (20 mL) was added to
the filtrate and the mixture was extracted into EtOAc (3 × 100 mL).
The combined organic layer was washed with brine (10 mL), dried
with Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (hexane–EtOAc, 5:1) to
give 9.
O
O
O
N
H
O
N
H
26β R = H
27β
28β
R = Ms (~100% de)
NHCbz
NHCbz
OTBS
OH
N
4'
2'
RO
BnO
f
g
4
3'
1'
3
O
N
O
2
1
O
O
OBn
OBn
29β: R = Bn
30β: R = H
31β
+
NH2
OH
HO
h
[α]D26 –24° (c 0.14, H2O)
O
NH
Dolle: [α]D25 –23.7°
O
The spectroscopic data were in good agreement with those report-
ed.18
(c 0.30, H2O)
tabtoxinine-β-lactam 1
25
Similarly:
Yield: 7.66 g, 18.0 mmol (98%); colorless oil; [a]D +4.9 (c 1.4,
NH2
CHCl3), [a]D25 –16 (c 0.82, MeOH) [Lit.18 –17.9 (c 1.6, MeOH)].
OH
[α]2D6+ 38° (c 0.09, H2O)
HO
IR (film): 3340 (s, OH), 1710 (s, C=O), 1630 (m), 1520 (s), 1190
(s), 1050 (s), 700 (s) cm–1.
Dolle: [α]D26 +35.0°
15aα (94% de)
O
NH
(c 0.22, H2O)
O
1H NMR (CDCl3, 500 MHz): d = 1.26 (3 H, t, J = 7.0 Hz, CH2CH3),
1.85 (1 H, m, H-3), 2.05 (1 H, m, H-3), 2.28–2.38 (2 H, m, H-4),
4.17 (2 H, q, J = 7.0 Hz, CH2CH3), 4.44 (1 H, m, H-2), 5.11 (2 H, s,
CH2Ph), 5.17 (2 H, m, CH2Ph), 5.37 (1 H, d, J = 8.3 Hz, NH), 5.51
(1 H, s, H-6), 6.15 (1 H, s, H-6), 7.23–7.37 (10 H, m, ArH).
(3R)-1 (~100% de)
Scheme 4 Synthesis of (–)-1 and (+)-(3R)-1: a) TEMPO, NaClO,
NaClO2, MeCN–H2O, r.t., 12 h (89%); b) NH2OBn·HCl, NaHCO3,
HOBt, EDCI, 0 °C→r.t., 12 h (95%); c) TBAF, THF; 0 °C, 1 h (86%);
d) i. MsCl, Et3N, CHCl3, r.t., 12 h; ii. recrystallization (91%); e)
TBSOTf, 2,6-lutidine, CH2Cl2, r.t., 2 h (88%); f) KHMDS, THF,
–78→0 °C, 24 h [(29b (59%) and 30b (11%)]; g) TBAF, THF; 0 °C;
h) H2, Raney-Ni, H2O–MeOH (1:2) (89% from 29b and 68% from 30b).
1-Benzyl 6-Ethyl (2S,5RS)-2-Benzyloxycarbonylamino-5-hy-
droxy-6-hydroxymethylhexanedioate (14a)
A solution of 9 (2.50 g, 5.88 mmol), K2OsO2(OH)4 (22 mg, 0.060
mmol) and NMO (2.1 g, 18 mmol) in t-BuOH–H2O (1:1, 66 mL)
Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York

2474
H. Kiyota et al.
PAPER
was stirred at 20 °C for 20 h. Sodium bisulfate (3.0 g) was added
and the reaction mixture was stirred for a further 30 min then ex-
tracted with EtOAc (3 × 30 mL). The combined organic layers were
washed with aq HCl (1 M, 1 × 20 mL) and brine (1 × 10 mL), dried
with MgSO4 and concentrated in vacuo. The residue was purified by
chromatography on silica gel (hexane–EtOAc, 5:1) to give 14a.
CH2Ph), 5.15 (1 H, d, J = 12.3 Hz, CHHPh), 5.20 (1 H, d, J = 12.3
Hz, CHHPh), 5.30 (1 H, pseudo d, J = 7.6 Hz, NH), 7.3–7.4 (10 H,
m, ArH).
13C NMR (CDCl3, 75 MHz): d = 11.84, 17.57, 17.88, 28.07, 30.82,
53.73 (C-2), 65.86, 66.98, 67.13, 109.29 (H2C=), 128.18, 128.24,
128.38, 128.56, 128.59, 128.69, 135.37, 136.32, 147.09 (C2C=),
155.97 (NHC=O), 172.37 (C-1).
Yield: 2.67 g, 5.82 mmol (99.0%); colorless oil; 6% de.
IR (film): 3350 (s, OH), 1720 (s, C=O), 1520 (s), 1210 (s), 1050 (s)
cm–1.
MS (FAB): m/z = 91, 181, 322, 496, 540 [M + H]+.
HRMS–FAB: m/z [M + H]+ calcd for C28H41O5Si: 540.3145; found:
1H NMR (CDCl3, 300 MHz): d = 1.22–1.26 (6 H, 2 × t, J = 7.1 Hz,
2 × CH2CH3), 1.4–1.9 (3 H, m, H-3, H-4), 1.9–2.2 (2 H, m, H-3,
OH), 3.50–3.57 (2 H, m, H-6, OH), 3.70 (1 H, m, H-6), 4.22 (2 H,
q, J = 7.1 Hz, CH2CH3), 4.40 (1 H, br m, H-2), 5.10 (2 H, s, PhCH2),
5.16 (2 H, s, PhCH2), 5.37 (1 H, br m, NH), 7.3–7.4 (1 H, m, ArH).
540.3149.
Benzyl (S)-2-Benzyloxycarbonylamino-5-tert-butyldimethyl-
silyloxymethyl-5-hexenoate (13b)
Yield: 85%; colorless oil; [a]D28 +2.6 (c 0.63, CHCl3).
MS (FAB): m/z = 91, 181, 263, 326, 416 [M + H – OEt]+, 460 [M +
1H NMR (CDCl3, 300 MHz): d = 0.038 (6 H, s, Me2Si), 89 (9 H, m,
t-Bu), 1.82 (1 H, m), 1.95–2.10 (3 H, m), 4.00 (2 H, s, CH2OSi),
4.44 (1 H, m, H-2), 4.78 (2 H, s, H-6), 4.78 (1 H, m), 5.03 (1 H, d,
J = 1.4 Hz, H-6), 5.10 (2 H, s, CH2Ph), 5.14 (1 H, d, J = 12.4 Hz,
CHHPh), 5.20 (1 H, d, J = 12.4 Hz, CHHPh), 5.32 (1 H, pseudo d,
J = 7.7 Hz, NH), 7.28–7.38 (10 H, m, ArH).
13C NMR (CDCl3, 125 MHz): d = –5.43 (MeSi), 18.32, 25.86
[(CH3)3C], 28.14 and 30.84 (C-3 and C-4), 53.72 (C-2), 65.72,
66.99, 67.16, 109.60 (C=CH2), 128.10, 128.17, 128.31, 128.48,
128.51, 128.61, 135.22, 136.19, 146.91 (C=CH2), 155.82
(NHC=O), 172.18 (C-1).
H]+.
HRMS–FAB: m/z [M + H]+ calcd for C24H30NO8: 460.1971; found:
460.1974.
1-Bromo-2-tert-butyldiphenylsilyloxymethyl-2-propene (12c)
To a solution of 2-tert-butyldiphenylsilyloxymethyl-2-propen-1-ol
(2.9 g, 8.9 mmol) in CH2Cl2 (30 mL) were added CBr4 (4.45 g, 13.4
mmol) and PPh3 (2.81 g, 10.7 mmol) at 0 °C. The mixture was
stirred for 10 min then quenched with sat. aq NaHCO3 (10 mL) and
extracted with EtOAc (1 × 40 mL). The combined extract was
washed with brine (1 × 10 mL), dried with MgSO4, and concentrat-
ed in vacuo. The residue was purified by chromatography on silica
gel (hexane) to give 12c.
MS (FAB): m/z = 73, 91, 181, 322, 440, 498 [M + H]+.
HRMS–FAB: m/z [M + H]+ calcd for C28H41O5Si: 498.2676; found:
498.2679.
Yield: 3.5 g, 9.0 mmol (quant.); colorless oil.
1H NMR (CDCl3, 300 MHz): d = 1.07 (9 H, s, t-Bu), 4.03 (2 H, s),
4.31 (2 H, pseudo t, J = 1.7 Hz), 5.29 (1 H, m), 5.31 (1 H, q, J = 1.7
Hz), 5.30 (1 H, pseudo d, J = 7.6 Hz, NH), 7.3–7.5 (6 H, m, ArH),
7.65–7.72 (4 H, m, ArH).
MS (EI): m/z = 91, 251, 261, 263, 331, 333, 389 [M + H]+.
HRMS (EI): m/z [M + H]+ calcd for C20H26BrOSi: 389.0936; found:
Benzyl (S)-2-Benzyloxycarbonylamino-5-tert-butyldiphenyl-
silyloxymethyl-5-hexenoate (13c)
Yield: 80%; colorless oil; [a]D24 +4.8 (c 0.65, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 1.0–1.4 (9 H, m, t-Bu), 1.76 (1 H,
m), 1.90–2.08 (3 H, m), 4.03 (2 H, s, CH2OSi), 4.41 (1 H, m, H-2),
4.82 (1 H, s), 5.09 (1 H, s), 5.12–5.18 (3 H, m), 5.24 (1 H, pseudo
d, J = 7.7 Hz, NH), 7.2–7.5 (16 H, m, ArH), 7.6–7.7 (4 H, m, ArH).
389.0933.
13C NMR (CDCl3, 125 MHz): d = 19.21, 26.73, 26.78, 28.14, 30.83,
53.68, 66.20, 67.05, 109.60, 127.61, 127.66, 127.70, 128.13,
128.50, 129.64, 129.69, 133.43, 133.45, 135.19, 135.41, 135.51,
136.16, 146.48, 155.79, 172.13, 65.72, 66.99, 67.16, 109.60
(C=CH2), 128.10, 128.17, 128.31, 128.48, 128.51, 128.61, 135.22,
136.19, 146.91 (C=CH2), 155.82 (NHC=O), 172.18 (C-1).
MS (FAB): m/z = 91, 135, 199, 322, 564, 622 [M + H]+.
HRMS–FAB: m/z [M + H]+ calcd for C38H44O5NSi: 622.2989;
Benzyl (S)-2-Benzyloxycarbonylamino-5-triisopropylsilyl-
oxymethyl-5-hexenoate (13a)
A suspension of Zn powder (4.8 g, 73.4 mgatom) and 1,2-dibromo-
ethane (0.315 mL, 3.66 mmol) in DMF (13 mL) was stirred at 60 °C
for 30 min under nitrogen. TMSCl (0.093 mL, 0.073 mmol) was
added and the mixture was stirred at 60 °C for further 30 min. A so-
lution of iodide 7 (5.35 g, 12.2 mmol) in DMF (11.5 mL) was added
dropwise and, after stirring at 60 °C for 10 min, the mixture was
cooled to –55 °C and a solution of CuCN (1.09 g, 12.2 mmol) and
LiCl (1.03 g, 24.3 mmol) in DMF (11.5 mL) was added. The mix-
ture was warmed to 0 °C and stirred for 10 min then the mixture was
again cooled to –55 °C and bromide 12a (5.60 g, 18.2 mmol) was
added. The mixture was stirred for 12 h then unreacted Zn was fil-
tered through a Celite pad and the filtrate was quenched with sat. aq
NH4Cl (15 mL). The mixture was extracted with EtOAc (3 × 100
mL) and the combined organic layer was washed with brine (1 × 10
mL), dried with Na2SO4 and concentrated in vacuo. The residue was
purified by chromatography on silica gel (hexane–EtOAc, 5:1) to
give 13a.
found: 622.2991.
Benzyl (2S,5R)-2-Benzyloxycarbonylamino-5-triisopropyl-
silyloxymethyl-5,6-dihydroxyhexanoate (15ab)
AD-mix b (5.19 g) in H2O (15 mL) and t-BuOH (15 mL) was stirred
at r.t. for 10 min and then cooled to 0 °C. A solution of 13a (2.00 g,
3.71 mmol) in H2O (3.5 mL) and t-BuOH (3.5 mL) was added at
0 °C and the mixture was stirred at 0 °C for 3 d. After quenching
with Na2SO3 (5.6 g) the reaction was allowed to come to r.t. and the
mixture was extracted with EtOAc (3 × 100 mL). The combined or-
ganic layers were washed with brine (10 mL), dried with MgSO4
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane–EtOAc, 3:1) to give 15ab.
The de was determined by HPLC using a Daicel Chiralcel® column
[OD (4.6 × 250 mm), i-PrOH–hexane (1:15), 0.3 mL/min; 25 °C;
detection, 254 nm; tR 80.8 min (15ab, 95%) and 87.4 min (15aa,
2.5%)].
28
Yield: 5.70 g, 10.6 mmol (87%); colorless oil; [a]D –8.9 (c 5.3,
EtOH).
IR (film): 3330 (br s), 1730 (br s, C=O), 1670 (w), 1450 (s), 880
(m), 695 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.96–1.13 [21 H, m, Si(i-Pr)3],
1.82 (1 H, m), 1.87–2.5 (3 H, m), 4.08 (2 H, s, SiOCH2), 4.44 (1 H,
m, H-2), 4.79 (1 H, s, H-6), 5.09 (1 H, m, H-6), 5.11 (2 H, s,
Yield: 0.301 g, 0.566 mmol (94%); colorless oil; [a]D26 –8.7 (c 3.2,
EtOH); 95% de.
Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Tabtoxinine-b-lactam
2475
IR (film): 3400 (br s), 1720 (br s, C=O), 1450 (s), 880 (m), 695 (s)
cm–1.
Benzyl (2S,5R)-2-Benzyloxycarbonylamino-5-tert-butyldiphe-
nylsilyloxymethyl-5,6-dihydroxyhexanoate (15cb)
The de was determined by HPLC using a Daicel Chiralcel® column
[OD (4.6 × 250 mm), i-PrOH–hexane (1:10), 0.5 mL/min; 15 °C;
detection, 254 nm; tR 40.0 min (15ca, 9%) and 46.0 min (15cb,
91%)].
1H NMR (CDCl3, 300 MHz): d = 0.95–1.2 [21 H, m, Si(i-Pr)3], 1.45
(2 H, m), 1.78 (1 H, m), 1.98 (1 H, m), 2.28 (1 H, m, 6-OH), 2.87
(1 H, s, 5-OH), 3.41 (1 H, dd, J = 11.0, 6.9 Hz, H-6), 3.52 (1 H, dd,
J = 11.3, 4.7 Hz, H-6), 3.54 (1 H, d, J = 9.6 Hz, SiOCH2), 3.64 (1 H,
d, J = 9.6 Hz, SiOCH2), 4.43 (1 H, m, H-2), 5.10 (2 H, s, CH2Ph),
5.17 (2 H, s, CH2Ph), 5.45 (1 H, pseudo d, J = 8.8 Hz, NH), 7.28–
7.4 (10 H, m, ArH).
13C NMR (CDCl3, 150 MHz): d = 11.72, 17.89, 17.90, 26.32, 29.21,
53.98, 66.34, 67.02, 67.20, 67.57, 73.14, 128.11, 128.18, 128.36,
128.48, 128.51, 128.60, 135.22, 136.16, 156.02 (NHC=O), 172.12
(C-1).
Yield: 75%; colorless oil; [a]D25 +17 (c 0.065, CHCl3); 82% de.
1H NMR (CDCl3, 300 MHz): d = 1.05 (9 H, s, t-Bu), 1.70 (1 H, m),
1.82–2.10 (3 H, m), 2.73 (1 H, s, OH), 3.39 (1 H, dd, J = 7.1, 11.3
Hz), 3.46–3.58 (3 H, m), 4.39 (1 H, m, H-2), 5.0–5.16 (4 H, m,
CH2Ph), 5.38 (1 H, pseudo d, J = 8.0 Hz, NH), 7.22–7.48 (16 H, m,
ArH), 7.60–7.66 (4 H, m, ArH).
MS–FAB: m/z = 91, 135, 199, 230, 320, 656 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C38H46O7NSi: 656.3044;
MS (FAB): m/z = 91, 230, 320, 530, 574 [M + H]+.
HRMS–FAB: m/z [M + H]+ calcd for C31H48O7NSi: 574.3200;
found: 656.3040.
found: 574.3205.
(2S,5S)-Isomer (15ca)
(2S,5S)-Isomer (15aa)
Yield: 58%; colorless oil; [a]D25 +1.9 (c 0.26, CHCl3); 68% de.
In the same manner as described above, using AD-mix a (7.26 g),
13a (2.80 g, 5.19 mmol) was converted into 15aa. The de was de-
termined by HPLC using a Daicel Chiralcel® column [OD
(4.6 × 250 mm), i-PrOH–hexane (1:15), 0.3 mL/min; 25 °C; detec-
tion, 254 nm; tR 73.7 min (15ab, 3%) and 79.9 min (15aa, 97%)].
Yield: 2.80 g, 4.88 mmol (94%); colorless oil; [a]D23 –8.5 (c 0.83,
EtOH); 94% de.
1H NMR (CDCl3, 300 MHz): d = 1.09 (9 H, s, t-Bu), 1.72 (1 H, m),
1.82–1.89 (3 H, m), 2.68 (1 H, s, OH), 3.40 (1 H, m), 3.45–3.58
(3 H, m), 4.39 (1 H, m, H-2), 5.0–5.17 (4 H, m, CH2Ph), 5.38 (1 H,
m), 7.22–7.48 (16 H, m, ArH), 7.60–7.66 (4 H, m, ArH).
HRMS (FAB): m/z [M + H]+ calcd for C38H46O7NSi: 656.3044;
found: 656.3052.
1H NMR (CDCl3, 300 MHz): d = 0.95–1.2 [21 H, m, Si(i-Pr)3],
1.35–1.55 (2 H, m), 1.79 (1 H, m), 1.98 (1 H, m), 2.25 (1 H, m, 6-
OH), 2.79 (1 H, s, 5-OH), 3.42 (1 H, dd, J = 11.0, 7.1 Hz, H-6), 3.51
(1 H, m, H-6), 3.54 (1 H, d, J = 9.6 Hz, SiOCH2), 3.63 (1 H, d,
J = 9.6 Hz, SiOCH2), 4.42 (1 H, m, H-2), 5.10 (2 H, s, CH2Ph), 5.14
(1 H, d, J = 10.4 Hz, CH2Ph), 5.20 (1 H, d, J = 10.4 Hz, CH2Ph),
5.45 (1 H, pseudo d, J = 7.5 Hz, NH), 7.28–7.4 (10 H, m, ArH).
( )-Ethyl 2-Hydroxy-2-hydroxymethylheptanoate (17)
A mixture of 16 (2.00 g, 11.7 mmol), K2CO3 (4.86 g, 35.2 mmol),
K3Fe(CN)6 (11.6 g, 35.2 mmol) and K2OsO2(OH)4 (17.2 mg,
0.0468 mmol) in H2O (40 mL) and t-BuOH (40 mL) was stirred at
r.t. for 12 h. To this mixture was then added Na2SO3 (1.8 g) and the
mixture was warmed to r.t. and extracted into EtOAc (3 × 80 mL).
The combined organic layer was washed with aq sat. NH4Cl (1 × 15
mL) and brine (1 × 10 mL), dried with MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography on sil-
ica gel (hexane–EtOAc, 3:1) to give 17.
HRMS (FAB): m/z [M + H]+ calcd for C31H48O7NSi: 574.3200;
found: 574.3207.
Benzyl (2S,5R)-2-Benzyloxycarbonylamino-5-tert-butyldimeth-
ylsilyloxymethyl-5,6-dihydroxyhexanoate (15bb)
The de was determined by HPLC using a Daicel Chiralcel® column
[OD (4.6 × 250 mm), i-PrOH–hexane (1:15), 0.5 mL/min; 25 °C;
detection, 254 nm; tR 52.7 min (15bb, 95%) and 58.1 min (15ba,
5%)].
Yield: 2.18 g, 10.6 mmol (91%); colorless oil.
IR (film): 3450 (m, OH), 1725 (s, C=O), 1255 (s), 1210 (s), 1150
(s), 1080 (s), 1050 (s), 1020 (s), 915 (m), 755 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.87 (3 H, t, J = 6.9 Hz, H-7), 1.10
(1 H, m), 1.20–1.34 (4 H, m), 1.32 (3 H, t, J = 7.1 Hz,
CO2CH2CH3), 1.46 (1 H, m, H-3), 1.59 (2 H, m), 2.12 (1 H, pseudo
dd, J = 3.2, 9.3 Hz, CH2OH), 3.53 (1 H, s, 2C-OH), 3.60 (1 H, dd,
J = 3.8, 11.3 Hz, CHHOH), 3.79 (1 H, ddd, J = 11.3, 9.9, 1.1 Hz,
CHHOH), 4.28 (2 H, m, CO2CH2CH3).
Yield: 94%; colorless oil; [a]D26 +3.9 (c 0.76, CHCl3); 90% de.
1H NMR (CDCl3, 300 MHz): d = 0.058 (6 H, s, SiMe2), 0.88 (9 H,
s, t-Bu), 1.43 (1 H, m), 1.78 (1 H, m), 1.96 (1 H, m), 2.21 (1 H, m),
2.77 (1 H, s, OH), 3.3–3.6 (4 H, m, H-6, SiOCH2), 4.43 (1 H, m, H-
2), 5.10 (2 H, s, CH2Ph), 5.15 (1 H, d, J = 12.4 Hz, CHHPh), 5.20
(1 H, d, J = 12.4 Hz, CHHPh), 5.32 (1 H, pseudo d, J = 8.2 Hz,
NH), 7.3–7.38 (10 H, m, ArH).
MS–FAB: m/z = 73, 91, 230, 446, 532 [M + H]+, 554 [M + Na]+.
HRMS (FAB): m/z [M + Na]+ calcd for C28H41O7NSiNa: 554.2550;
HRMS (EI): m/z [M + H]+ calcd for C10H21O4: 205.1539; found:
205.1441.
( )-N-Benzyloxy-2-hydroxy-2-hydroxymethylheptanamide (18)
To a solution of NH2OBn·HCl (5.48 g, 36.6 mmol) in toluene (80
mL) was added AlMe3 in toluene (1.02 M, 48.8 mL, 49.8 mmol) at
0 °C under N2. The solution was warmed to 20 °C and stirred for 1
h, then, after warming to 50 °C, 17 (2.23 g, 10.9 mmol) was added
and the mixture was stirred at 50 °C for 12 h. The mixture was
quenched with aq HCl (5%, 20 mL), extracted into EtOAc (6 × 100
mL) and the combined organic layer was dried with MgSO4 and
concentrated in vacuo. The residue was recrystallized (EtOAc–hex-
ane) and further purified by column chromatography on silica gel
(hexane–EtOAc, 1:1) to give 18.
found: 554.2555.
(2S,5S)-Isomer (15ba)
Yield: 72%; colorless oil; [a]D26 +2.0 (c 0.56, CHCl3); 90% de.
1H NMR (CDCl3, 300 MHz): d = 0.058 (6 H, s, SiMe2), 0.88 (9 H,
s, t-Bu), 1.45 (2 H, m), 1.78 (1 H, m), 1.96 (1 H, m), 2.29 (1 H, s,
OH), 2.72 (1 H, s, OH), 3.36–3.55 (4 H, m, H-6, SiOCH2), 4.42
(1 H, m, H-2), 5.10 (2 H, s, CH2Ph), 5.10–5.25 (2 H, m, CH2Ph),
5.48 (1 H, pseudo d, J = 7.1 Hz, NH), 7.3–7.4 (10 H, m, ArH).
Yield: 1.78 g, 6.33 mmol (58%); colorless solid; mp 98.0–98.6 °C.
IR (film): 3370 (s, NH), 3300 (s, OH), 1655 (s, C=O), 1060 (s), 740
(s), 700 (s) cm–1.
HRMS (FAB): m/z [M + Na]+ calcd for C28H41O7NSiNa: 554.2550;
found: 554.2550.
Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York

2476
H. Kiyota et al.
PAPER
1H NMR (CDCl3, 300 MHz): d = 0.87 (3 H, t, J = 6.9 Hz, H-7),
1.14–1.34 (4 H, m), 1.43 (2 H, m), 1.67 (2 H, m), 2.81 (1 H, s, OH),
3.26 (1 H, s, OH), 3.39 (1 H, dd, J = 11.0, 6.0 Hz, CHHOH), 3.97
(1 H, dd, J = 11.0, 5.2 Hz, CHHOH), 4.88 (1 H, d, J = 11.1 Hz,
CHHPh), 4.94 (1 H, d, J = 11.1 Hz, CHHPh), 7.30–7.45 (5 H, m,
ArH), 9.18 (1 H, s, NHOBn).
was purified by column chromatography on silica gel (hexane–
EtOAc, 6:1) to give 21.
Yield: 175 mg, 0.552 mmol (80%); colorless oil.
IR (film): 1770 (s, C=O), 1450 (m), 1250 (s), 1200 (s), 990 (s), 840
(s), 750 (m), 690 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.14 (9 H, s, SiMe3), 0.88 (3 H, t,
J = 6.9 Hz, H-5¢), 1.19–1.73 (8 H, m), 3.23 (1 H, d, J = 4.4 Hz, H-
4), 3.26 (1 H, d, J = 4.4 Hz, H-4), 4.94 (1 H, d, J = 11.3 Hz, CHH-
Ph), 4.99 (1 H, d, J = 11.3 Hz, CHHPh), 7.36–7.44 (5 H, ArH).
HRMS (EI): m/z [M + H]+ calcd for C15H24O4N: 282.1705; found:
282.1705.
( )-N-Benzyloxy-2-hydroxy-2-(p-toluenesulfonyloxymeth-
yl)heptanamide (19)
MS–FAB: m/z = 73, 91, 147, 228, 281, 336 [M + H]+.
To a solution of 18 (1.00 g, 3.55 mmol) in pyridine (10 mL) was
added TsCl (1.01 g, 5.30 mmol) and the mixture was stirred at r.t.
for 10 h. Aq HCl (1 M, 40 mL, 40 mmol) was added at 0 °C and the
mixture was extracted into EtOAc (3 × 5 mL). The combined or-
ganic layer was washed with aq sat. NaHCO3 (2 × 15 mL) and H2O
(1 × 5 mL), dried with Na2SO4 and concentrated in vacuo. The res-
idue was purified by column chromatography on silica gel (hexane–
EtOAc, 3:1) to give 19.
HRMS (FAB): m/z [M + H]+ calcd for C18H30O3NSi: 336.1995;
found: 336.1998.
( )-1-Benzyloxy-3-hydroxy-3-pentyl-2-azetidinone (22)
A solution of 21 (75.0 mg, 0.224 mmol) in H2O (0.50 mL), THF
(0.50 mL) and AcOH (0.25 mL) was stirred at r.t. for 3 h. The mix-
ture was extracted into EtOAc (3 × 15 mL) and the combined organ-
ic layer was dried with Na2SO4 and concentrated in vacuo to give
22.
Yield: 1.54 g, 3.54 mmol (quant.); colorless oil.
IR (film): 3300 (m), 1730 (m), 1660 (s, C=O), 1590 (w), 1170 (s),
810 (m) cm–1.
Yield: 59.0 mg, 0.224 mmol (quant.); colorless oil.
FT-IR (ATR, Zn–Se): 3350 (m, OH), 1753 (s, C=O), 956 (m), 747
(s), 697 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.88 (3 H, t, J = 6.9 Hz, H-5¢),
1.20–1.48 (6 H, m), 1.58–1.80 (2 H, m), 2.94 (1 H, br, OH), 3.26
(1 H, d, J = 4.7 Hz, H-4), 3.32 (1 H, d, J = 4.7 Hz, H-4), 4.97 (2 H,
s, CH2Ph), 7.37–7.43 (5 H, ArH).
1H NMR (CDCl3, 300 MHz): d = 0.85 (3 H, t, J = 6.9 Hz, H-7),
1.16–1.37 (6 H, m, H-4, H-5, H-6), 1.48 (1 H, m, H-3), 1.70 (1 H,
m, H-3), 2.45 (3 H, s, PhCH3), 3.15 (1 H, d, J = 4.4 Hz, 2C-OH),
4.05 (1 H, d, J = 10.2 Hz, CHHOTs), 4.23 (1 H, d, J = 10.2 Hz,
CHHOTs), 4.870 (1 H, d, J = 11.3 Hz, CHHPh), 4.874 (1 H, d,
J = 11.3 Hz, CHHPh), 7.30–7.43 (7 H, ArH), 7.77 (2 H, d, J = 8.2
Hz, ArH), 9.11 (1 H, s, NHOBn).
MS–FAB: m/z = 91, 236, 264 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C15H22O3N, 264.1600;
HRMS (EI): m/z [M + H]+: calcd for C22H30O6NS: 436.1794; found:
found: 264.1599.
436.1797.
( )-3-Hydroxy-3-pentyl-2-azetidinone (23)
( )-N-Benzyloxy-2-p-toluenesulfonyloxymethyl-2-trimethyl-
silyloxyheptanamide (20)
To a suspension of Raney-Ni (10 mg) in MeOH (3.0 mL) was added
a solution of 22 (59.0 mg, 0.224 mmol) in MeOH (2.0 mL). The
mixture was stirred at r.t. under H2 for 12 h then the mixture was fil-
tered through a Celite pad and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane–
EtOAc, 2:1) to give 23.
To a mixture of 19 (1.37 g, 3.15 mmol) and 2,6-lutidine (1.47 mL,
12.6 mmol) in CH2Cl2 (20 mL) was added TMSOTf (1.71 mL, 9.45
mmol) at 0 °C under N2. The solution was warmed to r.t. and stirred
for 12 h. After H2O (2 mL) was added at 0 °C, the mixture was ex-
tracted into EtOAc (3 × 30 mL) and the combined organic layer was
washed with brine (1 × 3 mL), dried with Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography on
neutral silica gel (hexane–EtOAc, 5:1) to give 20.
Yield: 19.0 mg, 0.121 mmol (54%); colorless needles; mp 81–
81.5 °C.
IR (film): 3380 (s), 3220 (m), 3160 (m), 1710 (s, C=O), 1685 (s,
C=O), 1470 (m), 1185 (m), 1150 (m), 1140 (m), 800 (m), 700 (m)
cm–1.
1H NMR (CD3OD, 300 MHz): d = 0.92 (3 H, t, J = 6.7 Hz, H-5¢),
1.29–1.58 (6 H, m), 1.65–1.80 (2 H, m), 3.17 (1 H, d, J = 5.8 Hz, H-
4), 3.32 (1 H, d, J = 5.8 Hz, H-4).
Yield: 1.40 g, 2.76 mmol (88%); colorless oil.
IR (film): 3390 (m), 1690 (s, C=O), 1600 (m), 1255 (s), 1180 (s),
1170 (s), 980 (m), 850 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.12 (9 H, s, SiMe3), 0.84 (3 H, t,
J = 6.9 Hz, H-7), 1.10–1.33 (6 H, m), 1.40 (1 H, m, H-3), 1.68 (1 H,
m, H-3), 2.43 (3 H, s, PhCH3), 4.13 (1 H, d, J = 9.9 Hz, CHHOTs),
4.13 (1 H, d, J = 9.9 Hz, CHHOTs), 4.80 (1 H, d, J = 11.3 Hz,
CHHPh), 4.86 (1 H, d, J = 11.3 Hz, CHHPh), 7.33–7.42 (7 H,
ArH), 7.77 (2 H, d, J = 8.5 Hz, ArH), 8.91 (1 H, s, NHOBn).
Anal. Calcd for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C,
61.11; H, 10.03; N, 9.04.
1-Benzyl Hydrogen (2S,5S)-2-Benzyloxycarbonylamino-
5-hydroxy-5-[(triisopropylsilyloxy)methyl]hexanedioate (24b)
To a mixture of 15ab (0.410 g, 0.715 mmol), TEMPO (15.4 mg,
0.0986 mmol, 0.14 equiv) and sodium phosphate buffer (4.7 mL,
0.67 M, pH 6.7) in MeCN (10 mL) were added, simultaneously, aq
NaClO2 (0.422 g, 80% in 3.0 mL H2O) and bleach (5%, 0.20 mL) at
r.t. After stirring overnight, H2O (0.5 mL) was added at 0 °C and the
pH was adjusted to 8.0 with 0.5 N NaOH. The reaction was
quenched with aq Na2SO3 (0.43 g in 8.8 mL H2O) and the mixture
was extracted into Et2O (3 × 30 mL). The combined organic layer
was dried with MgSO4, concentrated in vacuo and the residue was
purified by column chromatography on silica gel (hexane–EtOAc,
1:1) to give 24b.
MS–FAB: m/z = 73, 91, 508 [M + H]+, 530 [M + Na]+.
HRMS (FAB): m/z [M + H]+ calcd for C25H38O6NSiS: 508.2189;
found: 508.2193.
( )-1-Benzyloxy-3-pentyl-3-trimethylsilyloxy-2-azetidinone
(21)
To a suspension of NaH (60%, 31 mg, 0.775 mmol, washed with
hexane) in THF (5.0 mL), was added a solution of 20 (330 mg,
0.650 mmol) in THF (5.0 mL) at 0 °C under N2. After stirring for 12
h, the mixture was diluted with Et2O (15 mL), filtered through a
Celite pad and the filtrate was concentrated in vacuo. The residue
Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Tabtoxinine-b-lactam
2477
Yield: 0.374 g, 0.636 mmol (89%); colorless oil; [a]D24 –11 (c 1.7,
EtOH).
Yield: 1.69 g, 2.44 mmol (76%); colorless oil; [a]D23 +6.8 (c 0.50,
EtOH).
IR (film): 3600–2400 (br s, COOH), 3520 (m), 3340 (br s, OH),
1730 (br s, C=O), 1460 (s), 880 (s), 695 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.96–1.13 [21 H, m, Si(i-Pr)3],
1.46–1.60 (2 H, m), 1.76 (1 H, m), 1.99 (1 H, m), 3.49 (1 H, s, OH),
3.50 (1 H, d, J = 8.8 Hz, H-6), 3.91 (1 H, d, J = 8.8 Hz, H-6), 4.39
(1 H, br m, H-2), 4.83 (1 H, d, J = 11.5 Hz, NOCHH), 4.90 (1 H, d,
J = 11.5 Hz, NOCHH), 5.08 (1 H, m, PhCH2) 5.10 (1 H, m,
PhCH2), 5.24 (1 H, br d, J = 8.3 Hz, BnONH), 7.24–7.40 (15 H, s,
ArH), 9.10 (1 H, s, NHOBn).
1H NMR (CDCl3, 300 MHz): d = 0.90–1.20 [21 H, m, Si(i-Pr)3],
1.60 (2 H, m), 1.74–1.99 (3 H, m), 3.60 (1 H, d, J = 9.1 Hz,
SiOCH), 3.92 (1 H, d, J = 9.1 Hz, SiOCH), 4.41 (1 H, m, H-2), 5.08
(2 H, s, CH2Ph), 5.15 (2 H, s, CH2Ph), 5.46 (1 H, br, NH), 7.20–7.4
(10 H, m, ArH).
13C NMR (CDCl3, 75 MHz): d = 11.65, 17.66, 26.32, 29.87, 53.70,
66.97, 67.14, 68.86, 77.96, 128.08, 128.15, 128.28, 128.43, 128.51,
128.60, 135.29, 136.24, 156.14 (NHC=O), 172.14, 177.92.
HRMS (FAB): m/z [M + H]+ calcd for C38H53O8N2Si: 693.3571;
found: 693.3572.
Benzyl (2S,5S)-5-Benzyloxycarbamoyl-2-benzyloxycarbonyl-
amino-5,6-dihydroxyhexanoate (26b)
MS–FAB: m/z = 152, 173, 478, 586 [M – H]–.
HRMS (FAB): m/z [M – H]– calcd for C31H44O8NSi: 586.2836;
A solution of 25b (1.56 mg, 2.25 mmol) and aq HF (48%, 8.5 mL)
in MeCN (30 mL) was stirred at r.t. for 12 h. After dilution with aq
sat. NaHCO3 (10 mL) at 0 °C, the mixture was extracted into EtOAc
(3 × 20 mL). The combined organic layer was dried with Na2SO4,
concentrated in vacuo and the residue was purified by column chro-
matography on silica gel (hexane–EtOAc, 1:2) to give 26b.
found: 586.2838.
(2S,5R)-Isomer (24a)
Synthesized from 15aa (2.42 g, 4.22 mmol) in the same manner as
described above.
23
Yield: 1.04g, 1.94 mmol (86%); colorless solid; mp 127.5–
Yield: 2.19 g, 3.73 mmol (88%); amorphous solid; [a]D +8.6 (c
128.0 °C; [a]D24 –20 (c 1.0, MeOH).
0.50, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 0.90–1.20 [21 H, m, Si(i-Pr)3],
1.71 (1 H, m), 1.80–2.00 (2 H, m), 2.11 (1 H, m), 3.72 (1 H, d,
J = 9.3 Hz, SiOCH), 3.95 (1 H, d, J = 9.3 Hz, SiOCH), 4.30 (1 H,
m, H-2), 5.08 (2 H, s, CH2Ph), 5.17 (2 H, s, CH2Ph), 5.0–5.2 (1 H,
overlapped, NH), 7.20–7.45 (10 H, m, ArH).
HRMS (FAB): m/z [M + H]+ calcd for C31H46O8NSi: 588.2992;
found: 588.2986.
IR (KBr): 3450 (s), 3370 (s), 3270 (s), 3050 (w), 3025 (w), 1730 (s,
C=O), 1670 (s), 1650 (s), 1535 (s), 740 (m), 695 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.4–1.9 (4 H, m, H-3, H-4), 2.44
(1 H, br s, 6-OH), 3.37 (1 H, dd, J = 10.5, 7.3 Hz, H-6), 3.51 (1 H,
br s, OH), 3.78 (1 H, br dd, J = 10.5, 5.5 Hz, H-6), 4.39 (1 H, br m,
H-2), 4.84 (2 H, m, CH2Ph), 5.05 (2 H, m, PhCH2), 5.15 (2 H, m,
PhCH2), 5.41 (1 H, br d, J = 7.7 Hz, BnONH), 7.3–7.44 (15 H, s,
ArH), 9.14 (1 H, br s, NHOBn).
13C NMR (CD3OD, 75 MHz): d = 26.44, 32.65, 55.70, 67.72, 67.95,
68.45, 79.21, 79.46, 128.97, 129.16, 129.37, 129.41, 129.56,
129.63, 129.72, 129.78, 130.64, 136.88, 137.36, 138.30, 158.80,
173.25, 173.85.
MS–FAB: m/z = 91, 136, 154, 537 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C29H33O8N2: 537.2237;
Benzyl (2S,5S)-5-Benzyloxycarbamoyl-2-benzyloxycarbonyl-
amino-5-hydroxy-6-triisopropylsilyloxyhexanoate (25b)
A mixture of 24b (0.534 g, 0.909 mmol), NH2OBn·HCl (0.290 g,
1.82 mmol, 2.0 equiv), NaHCO3 (0.153 g, 1.82 mmol), HOBt
(0.246 g, 1.82 mmol, 2.0 equiv) and EDCI (0.349 g, 1.82 mmol, 2.0
equiv) in DMF (3.5 mL) and CH2Cl2 (10 mL) was stirred at r.t. un-
der N2 for 12 h. The mixture was cooled to 0 °C, H2O (5 mL) was
added and the resulting mixture was extracted into EtOAc (3 × 20
mL). The combined organic layer was washed with sat. aq NH4Cl
(1 × 5 mL) and brine (1 × 5 mL), dried with anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel (hexane–EtOAc, 4:1) to give 25b.
found: 537.2242.
(2S,5R)-Isomer (26a)
In the same manner as described above, 25a (1.44 g, 2.08 mmol)
was converted into 26a.
Yield: 0.597 g, 0.862 mmol (95%); colorless oil; [a]D26 –18 (c 3.0,
EtOH).
Yield: 1.09 g, 2.03 mmol (98%); colorless solid; [a]D23 –1.3 (c 0.91,
MeOH).
IR (film): 3500 (m), 3320 (br s), 1700 (br s, C=O), 1460 (s), 880
(m), 695 (s) cm–1.
1H NMR (CDCl3, 300 MHz): 1.4–1.6 (2 H, m), 1.6–2.05 (2 H, m),
3.20 (1 H, br s, OH), 3.34 (1 H, d, J = 11.3 Hz, H-6), 3.74 (1 H, br
d, J = 11.3 Hz, H-6), 4.15 (1 H, br s, OH), 4.40 (1 H, m, H-2), 4.76
(1 H, d, J = 11.0 Hz, CH2Ph), 4.80 (1 H, d, J = 11.0 Hz, CH2Ph),
5.07 (2 H, m, PhCH2), 5.14 (2 H, m, PhCH2), 5.57 (1 H, br d, J = 8.0
Hz, BnONH), 7.2–7.4 (15 H, s, ArH), 9.35 (1 H, br s, NHOBn).
1H NMR (CDCl3, 300 MHz): d = 0.96–1.1 [21 H, m, Si(i-Pr)3], 1.53
(1 H, m), 1.74–1.84 (2 H, m), 3.41 (1 H, s, OH), 3.49 (1 H, d,
J = 9.3 Hz, H-6), 3.91 (1 H, d, J = 9.3 Hz, H-6), 4.40 (1 H, br m, H-
2), 4.82 (1 H, d, J = 11.3 Hz, NOCHH), 4.90 (1 H, d, J = 11.3 Hz,
NOCHH), 5.092 (1 H, m, PhCH2), 5.096 (2 H, m, PhCH2), 5.28
(1 H, br d, J = 8.0 Hz, BnONH), 7.24–7.40 (15 H, s, ArH), 9.09
(1 H, s, NHOBn).
HRMS (FAB): m/z [M + H]+ calcd for C29H33O8N2: 537.2237;
found: 537.2241.
Benzyl (2S,5S)-5-Benzyloxycarbamoyl-2-benzyloxycarbonyl-
amino-5-hydroxy-6-methylsulfonyloxyhexanoate (27b)
A solution of 26b (0.165 g, 0.308 mmol) and MsCl (36 mL, 1.5
equiv) in pyridine (5 mL) was stirred at r.t. under N2 for 6 h. H2O (3
mL) was added at 0 °C and the mixture was extracted into EtOAc
(3 × 15 mL). The combined organic layer was washed with aq sat.
NH4Cl (1 × 5 mL) and H2O (1 × 5 mL), dried over anhyd Na2SO4
and concentrated in vacuo. The residue was recrystallized (hexane–
EtOAc), purified further by column chromatography on silica gel
(hexane–EtOAc, 1:1) and again recrystallized (hexane–EtOAc) to
give 27b.
13C NMR (CDCl3, 75 MHz): d = 11.56, 17.68, 26.28, 31.34, 53.64,
66.97, 67.16, 67.37, 78.38, 128.14–129.20, 135.15, 136.28, 155.96
(NHC=O), 170.98, 172.02.
MS–FAB: m/z = 91, 181, 214, 390, 480, 559, 649, 693 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C38H53O8N2Si: 693.3571;
found: 693.3572.
(2S,5R)-Isomer (25a)
In the same manner as described above, 24a (1.89 g, 3.22 mmol)
was converted into 25a.
Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York

2478
H. Kiyota et al.
PAPER
Yield: 0.169 g, 0.275 mmol (89%); colorless powder; mp 117.5–
128.78, 128.97, 129.07, 134.54, 134.86, 136.05, 155.64, 167.92,
171.27.
118.0 °C; [a]D24 +3.8 (c 1.2, CHCl3).
IR (KBr): 3350 (s), 3150 (m), 3050 (w), 3025 (w), 1730 (s, C=O),
1705 (s), 1665 (s), 1355 (s), 1175 (s), 950 (m), 740 (m), 695 (s)
cm–1.
MS–FAB: m/z = 73, 91, 181, 671, 729 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C36H49O10N2SiS: 729.2877;
found: 729.2877.
1H NMR (CDCl3, 300 MHz): d = 1.56 (1 H, m), 1.74–1.90 (3 H, m),
2.97 (3 H, s, SCH3), 3.65 (1 H, s, OH), 4.13 (1 H, d, J = 11.0 Hz,
CHHOMs), 4.37 (1 H, d, J = 10.7 Hz, CHHOMs), 4.42 (1 H, m, H-
2), 4.87 (2 H, s, NOCH2Ph), 5.08 (2 H, s, CH2Ph), 5.13 (1 H, d,
J = 12.1 Hz, CHHPh), 5.20 (1 H, d, J = 12.9 Hz, CHHPh), 5.42
(1 H, d, J = 7.4 Hz, NH), 7.26–7.42 (15 H, m, ArH), 9.16 (1 H, s,
NHOBn).
13C NMR (CDCl3, 150 MHz): d = 14.08, 14.11, 22.59, 25.86, 30.78,
31.52, 37.21, 53.50, 60.40, 67.12, 67.34, 73.64, 76.62, 78.39,
128.08, 128.21, 128.32, 128.49, 128.51, 128.54, 128.60, 128.85,
129.32, 134.59, 135.00, 135.93, 156.12, 168.40, 171.76.
(2S,5R)-Isomer (28a)
In the same manner as described above, 27a (744 mg, 1.21 mmol)
was converted into 28a. The de was determined by HPLC using a
Daicel Chiralcel® column [OD (4.6 × 250 mm), i-PrOH–hexane
(1:4), 0.5 mL/min; 25 °C; detection, 254 nm; tR 25.5 min].
Yield: 871 mg, 1.19 mmol (98%); colorless oil; [a]D24 +5.0 (c 0.22,
CHCl3); ~100% de.
1H NMR (CDCl3, 300 MHz): d = 0.034 (3 H, s, SiMe), 0.10 (3 H, s,
SiMe), 0.67 (9 H, s, t-Bu), 1.48 (1 H, m), 1.7–2.05 (3 H, m), 2.96
(3 H, s, SMe), 3.98 (1 H, d, J = 10.2 Hz, H-6), 4.33 (1 H, d, J = 10.2
Hz, H-6), 4.3–4.4 (1 H, m, H-2), 4.84 (2 H, s, NOCH2Ph), 5.09
(2 H, s, CH2Ph), 5.16 (2 H, s, CH2Ph), 5.47 (1 H, d, J = 8.2 Hz,
NH), 7.30–7.42 (15 H, m, ArH), 8.80 (1 H, s, NHOBn).
MS–FAB: m/z = 91, 181, 571, 615 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C30H35O10N2S: 615.2012;
found: 615.2012.
HRMS (FAB): m/z [M + H]+ calcd for C36H49O10N2SiS: 729.2877;
(2S,5R)-Isomer (27a)
found: 729.2880.
In the same manner as described above, 26a (1.09 g, 2.03 mmol)
was converted into 27a.
(3S,3¢S)-1-Benzyloxy-3-(3¢-benzyloxycarbonyl-3¢-benzyloxy-
carbonylaminopropyl)-3-tert-butyldimethylsilyloxy-2-azetidi-
none (29b) and (3S,3¢S)-1-Benzyloxy-3-(3¢-benzyloxycarbonyl-
amino-3¢-carboxypropyl)-3-tert-butyldimethylsilyloxy-2-azet-
idinone (30b)
To a solution of 28b (64.1 mg, 0.0879 mmol) in anhyd THF (1.3
mL) was added a solution of KHMDS (0.5 M, 0.21 mL, 0.105
mmol) in toluene at –78 °C and the resulting mixture was stirred for
12 h while the temperature of the solution gradually raised to 0 °C.
The mixture was quenched with sat. aq NH4Cl (2 mL) and extracted
into EtOAc (3 × 5 mL). The extract was dried with MgSO4, concen-
trated in vacuo and the residue was purified by column chromatog-
raphy on silica gel (hexane–EtOAc–AcOH, 2:1:0→0:20:1) to give
29b and 30b.
Yield: 756 mg, 1.23 mmol (59%); colorless powder; mp 136–
137.5 °C; [a]D24 –3.0 (c 0.30, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 1.48–1.70 (2 H, m), 1.92 (1 H, m),
2.03 (1 H, m), 2.98 (3 H, s, SCH3), 4.11 (1 H, d, J = 10.7 Hz,
CHHOMs), 4.32 (1 H, d, J = 10.7 Hz, CHHOMs), 4.53 (1 H, m, H-
2), 4.75 (1 H, s, OH), 4.83 (1 H, d, J = 11.0 Hz, NOCHHPh), 4.88
(1 H, d, J = 11.0 Hz, NOCHHPh), 5.11 (2 H, s, CH2Ph), 5.17 (2 H,
s, CH2Ph), 5.52 (1 H, d, J = 8.0 Hz, NH), 7.26–7.42 (15 H, m, ArH),
9.21 (1 H, s, NHOBn).
HRMS (FAB): m/z [M + H]+ calcd for C30H35O10N2S: 615.2012;
found: 615.2014.
Benzyl (2S,5S)-5-Benzyloxycarbamoyl-2-benzyloxycarbonyl-
amino-5-tert-butyldimethylsilyloxy-6-methylsulfonyloxyhex-
anoate (28b)
29b
26
Yield: 33.0 mg, 0.0521 mmol (59%); colorless oil; [a]D +14 (c
0.64, CHCl3).
To a mixture of 27b (61.0 mg, 99.2 mmol) and 2,6-lutidine (46 mL,
4.0 equiv) in CH2Cl2 (1.2 mL) was added TBSOTf (45 mL, 2.0
equiv) at 0 °C. The solution was warmed to r.t. and stirred over-
night. H2O (1 mL) was added at 0 °C and the mixture was extracted
into EtOAc (3 × 10 mL). The combined organic layer was washed
with aq sat. NaHCO3 (1 × 3 mL) and H2O (1 × 2 mL), dried over
anhyd Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (hexane–EtOAc, 2:1) to
give 28b. The de was determined by HPLC using a Daicel Chiral-
cel® column [OD (4.6 × 250 mm), i-PrOH–hexane (1:4), 0.5 mL/
min; 25 °C; detection, 254 nm; tR 27.7 min].
1H NMR (CDCl3, 300 MHz): d = 0.040 (3 H, s, SiMe), 0.092 (3 H,
s, SiMe), 0.81 (9 H, s, t-Bu), 1.48–1.8 (3 H, m), 2.06 (1 H, m), 3.11
(1 H, d, J = 4.6 Hz, H-4), 3.15 (1 H, d, J = 4.6 Hz, H-4), 4.37 (1 H,
m, H-3¢), 4.89 (1 H, d, J = 11.3 Hz, NOCHHPh), 4.95 (1 H, d,
J = 11.3 Hz, NOCHHPh), 5.10 (2 H, s, CH2Ph), 5.14 (1 H, d,
J = 12.3 Hz, CH2Ph), 5.16 (1 H, d, J = 12.3 Hz, CH2Ph), 5.26 (1 H,
d, J = 8.3 Hz, NH), 7.26–7.41 (15 H, m, ArH).
13C NMR (CDCl3, 75 MHz): –3.91, –3.82, 17.78, 25.40, 27.04,
31.82, 53.60, 60.55, 67.02, 67.24, 81.67, 128.20, 128.28, 128.41,
128.62, 128.73, 129.15, 135.01, 135.20, 136.23, 155.86, 165.27,
171.91.
Yield: 52.4 mg, 71.9 mmol (72%); colorless oil; [a]D22 –6.8 (c 2.2,
CHCl3); ~100% de.
MS–FAB: m/z = 73, 91, 429, 473, 633 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C35H45O7N2Si: 633.2996;
IR (film): 3400 (s), 3350 (br s), 3150 (w), 3050 (m), 3025 (m),
1740–1680 (br s), 740 (m), 695 (s).
found: 633.2999.
1H NMR (CDCl3, 300 MHz): d = 0.029 (3 H, s, SiMe), 0.099 (3 H,
s, SiMe), 0.67 (9 H, s, t-Bu), 1.48 (1 H, m), 1.68–1.91 (3 H, m), 2.98
(3 H, s, SMe), 4.03 (1 H, d, J = 10.2 Hz, H-6), 4.33 (1 H, d, J = 10.7
Hz, H-6), 4.36 (1 H, m, H-2), 4.82 (1 H, d, J = 11.8 Hz, NOCHH-
Ph), 4.88 (1 H, d, J = 11.8 Hz, NOCHHPh), 5.10 (2 H, s, CH2Ph),
5.18 (2 H, s, CH2Ph), 5.32 (1 H, d, J = 8.8 Hz, NH), 7.30–7.42
(15 H, m, ArH), 8.80 (1 H, s, NHOBn).
13C NMR (CDCl3, 125 MHz): d = –3.04, –2.90, 14.07, 14.14, 18.05,
20.99, 22.59, 25.60, 26.61, 31.29, 31.54, 36.84, 53.24, 60.32, 67.02,
67.40, 72.81, 78.30, 80.43, 128.09, 128.18, 128.48, 128.61, 128.63,
30b
Yield: 5.5 mg, 0.0101 mmol (11%); colorless oil.
1H NMR (CDCl3, 300 MHz): d = 0.050 (3 H, s, SiMe), 0.103 (3 H,
s, SiMe), 0.83 (9 H, s, t-Bu), 1.56–1.87 (3 H, m), 2.10 (1 H, m), 3.19
(1 H, d, J = 4.4 Hz, H-4), 3.23 (1 H, d, J = 4.4 Hz, H-4), 4.31 (1 H,
m, H-3¢), 4.91 (1 H, d, J = 11.5 Hz, NOCHHPh), 4.96 (1 H, d,
J = 11.5 Hz, NOCHHPh), 5.02–5.18 (2 H, m, CH2Ph), 5.41 (1 H, d,
J = 7.7 Hz, NH), 7.26–7.41 (10 H, m, ArH).
Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Tabtoxinine-b-lactam
2479
MS–FAB: m/z = 73, 91, 339, 383, 543 [M + H]+, 565 [M + Na]+.
h then the mixture was filtered, concentrated in vacuo and lyo-
philized to give 1.
HRMS (FAB): m/z [M + H]+ calcd for C28H39O7N2Si: 543.2527;
26
found: 543.2533.
Yield: 17.0 mg (quant.); colorless amorphous solid; [a]D –24 (c
0.14, H2O) {Lit.11c [a]D25 –23.7 (c 0.30, H2O)}.
(3R,3¢S)-Isomer (29a)
In the same manner as described above, 28a (844 mg, 1.16 mmol)
was converted into 29a.
Yield: 528 mg, 0.834 mmol (72%); colorless oil; [a]D26 –12 (c 0.50,
CHCl3).
1H NMR (CDCl3, 300 MHz): d = 0.04 (3 H, s, SiMe), 0.08 (3 H, s,
SiMe), 0.81 (9 H, s, t-Bu), 1.62 (1 H, m), 1.75–1.95 (2 H, m), 2.1
(1 H, m), 3.14 (1 H, d, J = 5 Hz, H-4), 3.18 (1 H, d, J = 5 Hz, H-4),
4.37 (1 H, m, H-2), 4.90 (1 H, d, J = 12 Hz, NOCHHPh), 4.96 (1 H,
d, J = 12 Hz, NOCHHPh), 5.12 (2 H, s, CH2Ph), 5.16 (2 H, s,
CH2Ph), 5.26 (1 H, d, J = 8.8 Hz, NH), 7.26–7.41 (15 H, m, ArH).
IR (KBr): 3230 (s, OH, NH), 1740 (s, C=O), 1620 (m), 1400 (m),
1200 (m), 940 (w), 790 (w) cm–1.
1H NMR (D2O, 300 MHz): d = 1.65–2.08 (4 H, m, H-1¢, H-2¢), 3.20
(1 H, d, J = 6.6 Hz, H-4), 3.32 (1 H, d, J = 6.6 Hz, H-4), 3.68 (1 H,
t, H-3¢).
13C NMR (D2O, 75 MHz): 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.
3-epi-Tabtoxinine-b-lactam [(3R)-1]
HRMS (FAB): m/z [M + H]+ calcd for C35H45O7N2Si: 633.2996;
found: 633.3000.
In the same manner as described above, 31a (220 mg, 0.348 mmol)
was converted into (3R)-1.
Yield: 95.0 mg, 0.183 mmol (53%); colorless oil; [a]D26 +38 (c 0.09,
(3S,3¢S)-1-Benzyloxy-3-(3¢-benzyloxycarbonyl-3¢-benzyloxy-
carbonylaminopropyl)-3-hydroxy-2-azetidinone (31b)
To a solution of 29b (50.0 mg, 92.1 mmol) in THF (1 mL) was added
TBAF in THF (1 M, 111 mL, 1.2 equiv) at 0 °C under argon and the
mixture was stirred for 1 h at 0 °C. After dilution with Et2O (5 mL),
the reaction was quenched with aq sat. NH4Cl (1 mL) and extracted
into EtOAc (3 × 10 mL). The combined organic layer was dried
with MgSO4, concentrated in vacuo and the residue was purified by
column chromatography on silica gel (hexane–EtOAc–AcOH,
5:15:1) to give 31b.
H2O) {Lit.11c [a]D26 +35.0 (c 0.22, H2O)}.
1H NMR (D2O, 500 MHz): d = 1.6–2.1 (4 H, m, H-1¢, H-2¢), 3.41
(1 H, d, J = 5.9 Hz, H-4), 3.53 (1 H, d, J = 5.9 Hz, H-4), 3.80 (1 H,
m, H-3¢).
HRMS (FAB): m/z [M + H]+ calcd for C7H13N2O4: 189.0875;
found: 189.0878.
Acknowledgment
Yield: 38.6 mg, 90.1 mmol (98%); colorless oil; [a]D26 –7.4 (c 0.26,
CHCl3).
We thank Dr. Yoshifumi Ito [Tohoku University, Japan] for acade-
mic assistance. This work was partially supported by a Grant-in-aid
for Scientific Research from Japan Society for the Promotion of
Science (No. 14760069 & 17580092), The Agricultural Chemical
Research Foundation, Intelligent Cosmos Foundation and The
Naito Foundation.
1H NMR (CDCl3, 300 MHz): d = 1.55–1.90 (3 H, m), 2.02 (1 H, m),
3.12 (1 H, d, J = 4.4 Hz, H-4), 3.29 (1 H, d, J = 4.7 Hz, H-4), 4.27
(1 H, m, OH), 4.40 (1 H, m, H-3¢), 4.89 (1 H, d, J = 11.3 Hz,
NOCHHPh), 4.93 (1 H, d, J = 11.8 Hz, NOCHHPh), 5.08 (2 H, s,
CH2Ph), 5.14 (2 H, s, CH2Ph), 5.61 (1 H, d, J = 8.0 Hz, NH), 7.25–
7.40 (15 H, m, ArH).
References
13C NMR (CDCl3, 75 MHz): d = 27.4, 29.6, 30.0, 53.6, 59.8, 67.2,
67.3, 77.8, 80.3, 128.27, 128.32, 128.47, 128.62, 128.65, 128.75,
128.78, 129.25, 129.35, 134.8, 135.2, 136.1, 156.3, 165.8, 171.9.
MS–FAB: m/z = 91, 136, 154, 307, 519 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C29H31O7N2: 519.2131;
(1) Wolf, F. A.; Foster, A. C. Science 1917, 46, 361.
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(3R,3¢S)-Isomer (31a)
In the same manner as described above, 29a (160 mg, 0.252 mmol)
was converted into 31a.
Yield: 125 mg, 0.241 mmol (96%); colorless oil; [a]D24 –7.5 (c 0.10,
CHCl3).
1H NMR (CDCl3, 300 MHz): d = 1.71 (2 H, t, J = 7.3 Hz), 1.85
(1 H, m), 1.97 (1 H, m), 2.02 (1 H, m), 3.11 (1 H, d, J = 4.7 Hz, H-
4), 3.27 (1 H, d, J = 4.7 Hz, H-4), 3.76 (1 H, m, OH), 4.46 (1 H, m,
H-3¢), 4.90 (1 H, d, J = 11.3 Hz, NOCHHPh), 4.95 (1 H, d, J = 11.8
Hz, NOCHHPh), 5.10 (2 H, s, CH2Ph), 5.15 (2 H, s, CH2Ph), 5.55
(1 H, d, J = 7.7 Hz, NH), 7.25–7.40 (15 H, m, ArH).
HRMS (FAB): m/z [M + H]+ calcd for C29H31O7N2: 519.2131;
found: 519.2136.
Tabtoxinine-b-lactam [(3S,3¢S)-3-(3¢-Amino-3¢-carboxypropyl)-
3-hydroxy-2-azetidinone] (1)
To a solution of 31b (38.6 mg, 90.1 mmol) in H2O (0.2 mL) and
MeOH (0.2 mL) was added Raney-Ni (washed with aq 1 M HCl just
before use). The suspension was stirred at r.t. under hydrogen for 2
Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York

2480
H. Kiyota et al.
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25.13, 32.62, 46.31, 53.84, 75.36, 176.86.
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Synthesis 2007, No. 16, 2471–2480 © Thieme Stuttgart · New York