An alternative synthesis of (+)‐sesbanimide A

Abstract

Abstract. D-( + )-xylose has been converted to ( + )-sesbanimide A in sixteen steps. The synthetic scheme involves an unusual tricyclic siiylated derivative (9a) of the monobenzoylated product of the earlier described glutarimide intermediate (7). Compound 9a is a pivotal intermediate for the construction of ring C of ( + )-sesbanimide A.The alkaloid ( + )-sesbanimide A (12; Scheme 1) is one of the antileukemic constituents of the extracts of the seeds of Sesbania drumondii'. Syntheses of both ( + )-and ( -)-sesbanimide A have been reported from this2J-d and other laboratories''-k. A salient problem in all the reported syntheses is the selective protection of the secondary hydroxy group in diol intermediate 7. In our previous work2a,b this was achieved by a sequence of two steps involving acetalization with 3,4-dimethoxybenzaldehyde, followed by reductive ring opening of the actal function, to yield the C(5')-substituted 3,4-dimethoxybenzyl ether. Direct protection as a silyl ether, of the C(5')-hydroxyl function in derivatives of 7 in which the primary hydroxy had been derivatized, has been ~l a i m e d~' -~.~, though, in our opinion, without firm structural evidence. In our own work, we have shown that the silylation product of alcohol 8 is in fact the tricyclic lactam 9a2c,d. This structure is based upon detailed NMR studies and X-ray crystallographic analysis. We now describe in detail the total synthesis of ( + )-sesbanimide A via the crucial intermediate 9a. provided benzoate 8 in very good yield (94%). Attempted silylation of the free hydroxy group of 8 with tert-butyldiphenylsilyl triflate** led to a product whose structure was established as 9a. Of special relevance to the structure assignment of 9a were: (i) the presence of one ester carbonyl (1718 crn-') and one amide carbonyl(l668 cm-I), and the absence of the glutarimide carbonyls in the IR spectrum; (ii) a quarternary carbon at 6 101 ppm, in the I3C NMR spectrum, which has been assigned to the unique carbon (C-9), that is bonded to two oxygens and a nitrogen atom; (iii) the spatial proximity of C(7)-H to one of the C(12) protons and to N(1O)-H, as revealed by Nuclear Overhauser difference experiments and (iv) the X-ray structure' (Figure 1) of the alcohol 9b, obtained upon debenzoylation of 9a, by reduction with DIBAH*. The formation of 9a from 8 under the usual silylation conditions, presumably proceeds via attack of the C(5')-hydroxyl group on the C(2)-carbonyl function, which is activated by coordination with the silyl triflate or by addition of the same hydroxyl to the corresponding C(2)-0-silyl imino-ether", formed in the initial step of the reaction. In both cases the product (9a) possesses the 1 R,9S configuration at the newly created asymmetric centres. It should be noted that while operation of the aforementioned mechanism is, in principle also allowed at the C(6)-carbonyl, steric constraints, apparently, favour the ring closure leading to 9a, rather than a cyclisation to the isomeric 1S,9R tricyclic system 9c. The origin of this anomalous ...

Functional Group Variation in tert‐Butyldiphenylsilanes (TBDPS): Syntheses, Reactivities, and Effects on the Intermolecular Interaction Pattern in the Molecular Crystalline State

“…n-Butyllithium (2.5 M solution in hexane, Merck KGaA), phenyllithium (1.9 M solution in dibutyl ether, Merck KGaA), dichlorodiphenylsilane (98 %, Merck KGaA), pyrrolidine (99 %, Merck KGaA), and triethylamine (99 %, Merck KGaA) were used without further purification. tert-Butylchlorodiphenylsilane (2), [1e,30] tert-butyltriphenylsilane (3), [31] and tert-butylmethoxydiphenylsilane (4) [30,32] have been reported previously. Benzened 6 used for NMR spectroscopy was dried over Na/K amalgam.…”

“…Synthesis of t BuPh 3 Si (3) : According to a modified procedure, [31] phenyllithium (3.8 mL of a 1.9 M solution in dibutyl ether, 7.3 mmol) was added dropwise to a solution of compound 2 (2.00 g, 7.3 mmol) in hexane (20 mL) at room temperature with stirring. The reaction mixture was then heated at reflux for 12 h. After cooling down to room temperature, the mixture was filtered through a fritted column layered with Celite® and the remaining solid washed with hexane (2×10 ml).…”

Reactivity of Aziridinomitosene Derivatives Related to FK317 in the Presence of Protic Nucleophiles

“…24 In principle, desilylation might be possible using nucleophilic “silaphiles” without resorting to acidic conditions that destroy the sensitive aziridinomitosene core. 19,25–27 Accordingly, the t -butyldiphenylsilyl (TBDPS) group was installed by treating 7 with 1 equiv of freshly prepared TBDPS triflate (TBDPSOTf) 28 and Hünig’s base to provide 30 (Scheme 3) after workup with a basic buffer solution (pH 10). A similar experiment using TIPSOTf/Hünig’s base did not give acceptable conversion, and the N- TIPS aziridinomitosene was not sufficiently stable for purification.…”

“…Plans were adjusted to exploit the apparent correlation between better stability and solubility observed for aziridinomitosenes containing the bulky, hydrophobic N -trityl group ( 9 or 29 ) compared to N–H aziridines ( 7 or 28 ) by replacing the N -trityl group with a bulky N -silyl group . In principle, desilylation might be possible using nucleophilic “silaphiles” without resorting to acidic conditions that destroy the sensitive aziridinomitosene core. ,− Accordingly, the t -butyldiphenylsilyl (TBDPS) group was installed by treating 7 with 1 equiv of freshly prepared TBDPS triflate (TBDPSOTf) and Hünig’s base to provide 30 (Scheme ) after workup with a basic buffer solution (pH 10). A similar experiment using TIPSOTf/Hünig’s base did not give acceptable conversion, and the N- TIPS aziridinomitosene was not sufficiently stable for purification.…”

“…To a solution of 7 in 1.9 mL CH 2 Cl 2 was added i -Pr 2 EtN (0.02 mL, 0.14 mmol). The solution was cooled to −78 °C and TBDPSOTF as a solution in CH 2 Cl 2 (0.62 M, 0.16 mL, 0.096 mmol) was added dropwise via syringe (1 drop/5 s). After 30 min at −78 °C, the mixture was poured into pH 9.6 carbonate buffer, extracted 3 x with CH 2 Cl 2 (10 mL), and the combined organic phases were washed with brine and dried over Na 2 SO 4 .…”