Stereoselective Synthesis of Tabtoxinine-β-lactam by Using the Vinylogous Mukaiyama Aldol Reaction with Acetate-Type Vinylketene Silyl N,O-Acetal and α-Keto-β-lactam

Article abstract of DOI:10.1021/acs.orglett.7b00814

Stereoselective total synthesis of tabtoxinine-β-lactam has been achieved. The vinylogous Mukaiyama aldol reaction with vinylketene silyl N,O-acetal and α-keto-β-lactam proceeded to afford the adduct possessing a TβL-skeleton with a tert-alcohol in high yield and stereoselectivity. Stereoselective introduction of the amino group has been accomplished by azidation at the α position of the imide followed by hydrogenolysis. A straightforward method to achieve the potent inhibitor of glutamine synthetase, possessing both α-hydroxy-β-lactam and α-amino acid moieties, has been established.

Full text of DOI:10.1021/acs.orglett.7b00814

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Tabtoxinine-β-lactam by Using the
Vinylogous Mukaiyama Aldol Reaction with Acetate-Type
Vinylketene Silyl N,O‑Acetal and α‑Keto-β-lactam
Hirotaka Ejima, Fumihiro Wakita, Ryo Imamura, Takuya Kato, and Seijiro Hosokawa*
Department of Applied Chemistry, Faculty of Science and Engineering, Waseda University 3-4-1 Ohkubo, Shinjuku-ku, Tokyo
169-8555, Japan
S
* Supporting Information
ABSTRACT: Stereoselective total synthesis of tabtoxinine-β-
lactam has been achieved. The vinylogous Mukaiyama aldol
reaction with vinylketene silyl N,O-acetal and α-keto-β-lactam
proceeded to afford the adduct possessing a TβL-skeleton with a
tert-alcohol in high yield and stereoselectivity. Stereoselective
introduction of the amino group has been accomplished by
azidation at the α position of the imide followed by
hydrogenolysis. A straightforward method to achieve the potent
inhibitor of glutamine synthetase, possessing both α-hydroxy-β-
lactam and α-amino acid moieties, has been established.
lant glutamine synthetase is one of the essential enzymes of
plant autotrophy and plays a crucial role in the assimilation
Scheme 1. Remote Asymmetric Induction Reaction Using
Vinylketene Silyl N,O-Acetal
P
and reassimilation of ammonia derived from a wide variety of
metabolic processes.1 It catalyzes the incorporation of ammonia
into glutamate to generate glutamine.2 Tabtoxin (1, Figure 1)
Scheme 2. Synthetic Plan of TβL (2)
Figure 1. Structures of tabtoxin (1) and tabtoxinine β-lactam (TβL, 2).
has been isolated as a phytotoxic compound from Pseudomonas
tabaci, the phytopathogen of widefire disease of tabacco.3
Tabtoxin (1) is inactive itself, however, it undergoes hydrolysis
by host plant aminopeptidase to convert to tabtoxinine-β-lactam
(TβL, 2), an inhibitor of glutamine synthetase.4 Therefore, TβL
has been expected to be a selective pesticide and synthetic
studies on TβL have been reported.5 Herein, we present a
stereoselective synthesis of TβL by a remote asymmetric
induction reaction.
Recently, we have developed the remote asymmetric
induction reaction using vinylketene silyl N,O-acetal 3 (Scheme
1).6 The vinylogous Mukaiyama aldol reaction produced
TBDPS-attaching adduct 4 in high stereoselectivity.
To face the synthesis of TβL (2), we planned to apply this
reaction to construct α-hydroxy-β-lactam (Scheme 2). TβL (2)
would be derived from α,β-unsaturated imide 5, which might be
synthesized by the vinylogous Mukaiyama aldol reaction using
α-keto-β-lactam 6 and vinylketene N,O-acetal 3. Although we
have accomplished the stereoselective vinylogous Mukaiyama
aldol reaction with vinylketene N,O-acetal 7 possessing a methyl
group at the C2 position and isatin (8) (Scheme 3), C2-methyl-
missing vinylketene N,O-acetal 10, an acetate-type vinylketene
N,O-acetal, gave the adducts in low yield with low stereo-
selectivity because the stability and the direction of extension of
the diene of 10 were different from those of 7.7 Therefore, the
stereoselective reaction between acetate-type vinylketene N,O-
acetal 3 and α-keto-β-lactam 6 is still challenging because not
Received: March 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00814
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Vinylogous Mukaiyama Aldol Reactions Using
Vinylketene Silyl N,O-Acetals 7 and 10 with Isatin (8)
Scheme 4. Proposed Mechanism of the Reaction with 3 and 6
in the Presence of SnCl4
only the direction of extension of the diene but also the manner
of stereocontrol were different between 3 and 7.6
Based on these backgrounds, the vinylogous Mukaiyama aldol
reaction with vinylketene N,O-acetal 3 and α-keto-β-lactam 68
was examined (Table 1).9 At first, TBDPS ether 3a was reacted
E-isomer 13 reacted with α-keto-β-lactam 6 via the transition
state 14 to give 5S-isomer 12.
After the stereoselective reaction between 3 and 6 was
established, stereoselective synthesis of TβL (2) was accom-
plished as shown in Scheme 5. α,β-Unsaturated imide 12 was
Table 1. Vinylogous Mukaiyama Aldol Reaction with α-Keto-
β-lactam and Silyl Dienol Ether Possessing Chiral Auxiliary
Scheme 5. Stereoselective Synthesis of TβL (2)
a
entry
R
Si
Lewis acid yield (%) dr (12/5-epi-12)
1
2
3
4
5
H
TBDPS 3a
TBDPS 3a
TBDPS 3b
TBDPS 3
TBS 3c
TiCl4
SnCl4
SnCl4
SnCl4
SnCl4
95
94
94
97
95
1:2
10:1
H
Me
Ph
Ph
5:1
>20:1
>20:1
a
1
Determined by 400 MHz H NMR.
with 6 in the presence of TiCl4 which was used for the reaction
in Scheme 3. The reaction proceeded to give adduct 12a in high
yield, but the stereoselectivity was low (Table 1, entry 1). When
SnCl4 was employed as a Lewis acid, the reaction with 3a
afforded 12a with high stereoselectivity (entry 2). Silyl dienol
ether 3b possessing the methyl groups at the C5′ position
produced adducts in high yield but with moderate stereo-
selectivity (entry 3). On the other hand, the reaction with 5′,5′-
diphenyloxazolidone derivative 3 proceeded in the presence of
SnCl4 to give adduct 12 possessing unprotected tertiary alcohol
in excellent yield with excellent stereoselectivity (entry 4). The
corresponding TBS ether 3c also worked very well to afford
tertiary alcohol 12 in high yield and excellent selectivity (entry
5). Therefore, the conditions shown in entry 4 using TBDPS
ether 3 were employed in our synthesis of TβL.10
submitted to hydrogenation to give saturated imide 15, of which
the tert-alcohol was protected as benzyloxymethyl ether 16.
Compound 16 was treated with potassium bis(trimethylsilyl)-
amide (KHMDS), and the resulting enolate was reacted with
2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) to provide
azide 17 with high stereoselectivity.11 The p-methoxybenzyl
group on the β-lactam and the chiral auxiliary were removed by
using cerium ammonium nitrate and Ti(OBn)4 prepared from
benzyl alcohol and titanium tetraisopropoxide,12 respectively.
With benzyl ester 19 in hand,13 simultaneous hydrogenolysis of
The stereoselective reaction using 3 proceeded as shown in
Scheme 4. SnCl4 isomerized Z-enol ether 3 to the more reactive
E-enol ether 13 as reported previously.6 Since one of the phenyl
groups of TBDPS covered the lower face of 13 as 13a,6 α-keto-
β-lactam 6 approached from the upper face of 13. Accordingly,
B
DOI: 10.1021/acs.orglett.7b00814
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Experimental procedures, spectral data of compounds,
and 1H and 13C NMR spectra (PDF)
Table 2. Hydrogenolysis of 19
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: seijiro@waseda.jp.
ORCID
Seijiro Hosokawa: 0000-0002-8036-532X
Notes
a
The authors declare no competing financial interest.
entry
BnNH2·HCl (equiv)
time (h) yield (%)
ratio (2/20/21)
1
2
3
4
5
6
3
3
77
78
73
70
85
85
48:20:32
85:15:<1
95:05:<1
97:03:<1
95:05:<1
95:05:<1
ACKNOWLEDGMENTS
■
1.2
3.0
b
b
We are grateful for financial support to The Kurata Memorial
Hitachi Science and Technology Foundation, The Naito
Foundation, and The Sumitomo Foundation.
3
5.0
3
5.0
12
12
10.0
REFERENCES
a
b
1
■
Determined by 400 MHz H NMR. Partially remaining BnOCH2O
group was observed by H NMR.
1
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smoothly; however, N-methylated byproducts 20 and 21 were
produced (Table 2, entry 1). Under these conditions, the
resulting amine underwent the reductive alkylation with
formaldehyde, which was generated by hydrogenolysis of the
benzyloxymethyl ether. After examination of several reaction
conditions, benzylammonium chloride (BnNH2·HCl) was
found to be effective in suppressing N-methylation of the
resulting amine (entries 2 and 3). Although BnNH2·HCl reacted
with formaldehyde to prevent N-methylation, the yield of 2
decreased because the hydrogenolysis slowed and a part of
benzyloxymethyl group remained (entries 3 and 4). The
problem was solved by extending the reaction time, and the
desired 2 was obtained in good yield (entry 5). Employing large
excess amount (10 equiv) of BnNH2·HCl did not change the
yield or ratio (entry 6). Spectral data of 2 were identical with
those of TβL reported in literature.5f Therefore, we accom-
plished to establish an efficient route to synthesize tabtoxinine-
β-lactam (2) in a stereoselective manner.
In conclusion, a stereoselective synthesis of tabtoxinine-β-
lactam (2) has been accomplished. The vinylogous Mukaiyama
aldol reaction with vinylketene silyl N,O-acetal 3 and α-keto-β-
lactam 6 proceeded to afford the adduct possessing TβL-
skeleton with a tert-alcohol in high yield and stereoselectivity.
The subsequent manipulation including the stereoselective
azidation and the simultaneous hydrogenolysis of the azide, the
benzyl ester, and the benzyloxymethyl moieties gave TβL.
Addition of benzylammonium chloride in the hydrogenolysis
suppressed the formation of N-methylated products. This
procedure is a straightforward method to the potent inhibitor
of glutamine synthetase possessing α-hydroxy-β-lactam and α-
amino acid moieties.
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dihydroxy-β-lactam. Therefore, a solution of 6 in CH2Cl2 was dried
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̃
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00814.
X-ray data for compound 15 (CIF)
C
DOI: 10.1021/acs.orglett.7b00814
Org. Lett. XXXX, XXX, XXX−XXX