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-βlactam 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-βlactam and α-amino acid moieties, has been established.
P
Scheme 1. Remote Asymmetric Induction Reaction Using Vinylketene Silyl N,O-Acetal
lant glutamine synthetase is one of the essential enzymes of plant autotrophy and plays a crucial role in the assimilation 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 © 2017 American Chemical Society
group at the C2 position and isatin (8) (Scheme 3), C2-methylmissing vinylketene N,O-acetal 10, an acetate-type vinylketene N,O-acetal, gave the adducts in low yield with low stereoselectivity 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,Oacetal 3 and α-keto-β-lactam 6 is still challenging because not Received: March 18, 2017 Published: May 4, 2017 2530
DOI: 10.1021/acs.orglett.7b00814 Org. Lett. 2017, 19, 2530−2532
Letter
Organic Letters 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 accomplished as shown in Scheme 5. α,β-Unsaturated imide 12 was
Table 1. Vinylogous Mukaiyama Aldol Reaction with α-Ketoβ-lactam and Silyl Dienol Ether Possessing Chiral Auxiliary
Scheme 5. Stereoselective Synthesis of TβL (2)
entry
R
Si
Lewis acid
yield (%)
dra (12/5-epi-12)
1 2 3 4 5
H H Me Ph Ph
TBDPS 3a TBDPS 3a TBDPS 3b TBDPS 3 TBS 3c
TiCl4 SnCl4 SnCl4 SnCl4 SnCl4
95 94 94 97 95
1:2 10:1 5:1 >20:1 >20:1
a
Determined by 400 MHz 1H 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 stereoselectivity (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 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-ketoβ-lactam 6 approached from the upper face of 13. Accordingly,
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 2531
DOI: 10.1021/acs.orglett.7b00814 Org. Lett. 2017, 19, 2530−2532
Letter
Organic Letters
Experimental procedures, spectral data of compounds, and 1H and 13C NMR spectra (PDF)
Table 2. Hydrogenolysis of 19
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Seijiro Hosokawa: 0000-0002-8036-532X Notes entry 1 2 3 4 5 6
BnNH2·HCl (equiv)
time (h)
yield (%)
ratio (2/20/21)
1.2 3.0 5.0 5.0 10.0
3 3 3 3 12 12
77 78 73b 70b 85 85
48:20:32 85:15:
