An Unusual Acyliminium Cyclization and Other Drawbacks during an Attempted Synthesis of a Chiral Primary α‐Phosphinoalkanamine

Abstract

Studies towards the synthesis of a chiral primary a-phosphinoalkanamine la are reported. 0-Activated, N-carbamate-protected phenylalaninol 3a did not undergo S, reaction with KPPh, : instead, after N-dcprotonation, intramolecular substitution led to formation of the aziridine derivative 5a (Sdirmne 2). N-Phthalimido-protected, 0-activated phenylaloninol 3b also underwent an intramolecular process on treatment with KPPh,, i.c., an unusual aryl-acyliminium cyclization furnishing the (epoxymethano)isoindolo[l,2-cr]isoquinolinone 7 (Schcinc~ 3). In it reaction with KPPh,, the N,N-dibenzyl-protected and activated phenylalaninol3d finally yielded the intermolecular S, reaction product 2a (Schemr4). However, debenzylation by catalytic hydrogenation turned out to be iinpossible.Introduction. ~ Asymmetric C,C-bond-forming reactions are of great significance for the synthesis of optically active compounds, and towards this goal, the application of chiral transition-metal catalysts has become a flourishing field of research. Chelating phosphine ligands are particularly suited for the coordination to late transition metals due to their n-acceptor character, and the preparation of chiral representatives from the readily available starting materials of the chiral pool is an attractive and popular strategy. For example, Kumada and coworkers [I] have introduced the N,N-dimethyl-cc-phosphinoalkanamines ( = p-(dimethy1amino)alkylphosphines) of the general type 1 (Scheme I ) , which originate from natural cc-amino acids, and which have been shown to be highly efficient ligands for catalytic asymmetric Grignard cross-coupling reactions applying Ni" or Pd" [2]. In our eyes, the synthesis of analogues like l a bearing a primary-amine function seemed to be also an attractive goal. The latter ligands were planned to be applied in our projects on transition-metal-catalyzed Michael reactions [3]. Moreover, the presence of the primary amino group should also allow an application as a chiral auxiliary, e g . , after amide or aminocarbene complex [4] formation. A retrosynthetic

Cyclizations of N-Acyliminium Ions

“…There is a large body of practical synthetic chemistry involving cyclic N -acyliminium ions that contain additional heteroatoms. − A notable example is the hydantoin-based N -acyliminium ion cyclization illustrated in eq 108 . In the bromination of the 5-phenyl derivative 326 ( n = 2), the tricyclic product 327 forms spontaneously in 90% yield; there is no need for a Lewis acid such as tin(IV) chloride to generate the requisite N -acyliminium ion.…”

“…An intriguing N -acyliminium cyclization is found in the treatment of 352 with potassium diphenylphosphide, which yields polycycle 353 (eq 119) …”

“…An intriguing N-acyliminium cyclization is found in the treatment of 352 with potassium diphenylphosphide, which yields polycycle 353 (eq 119). 434 This reaction probably proceeds as follows: the phosphide adds to the imide to generate a transient R-oxidophosphine, which is rapidly trapped by intramolecular alkylation on oxygen to give an oxazolidine intermediate that dissociates to a cyclic alkoxy N-acyliminium species, which cyclizes onto the phenyl group to give 353. The high yield of 353 is remarkable, especially given the absence of acidic reagents.…”

An enantioselective, modular, and general route to the cytochalasins: Synthesis of L-696,474 and cytochalasin B

“…Retrosynthetic modification of 6 permits the implementation of an alternative DielsAlder disconnection. material N,N-dibenzyl phenylalanal (7), derived from the Lamino acid in three steps, as reported (80%) (31,32). Intermolecular HWE condensation of 7 with diethyl 3-oxo-2-butylphosphonate (14) (33) in the presence of barium hydroxide at 23°C (34) provided the expected trans-␣,␤-unsaturated ketone with 99:1 trans͞cis selectivity and 98% enantiomeric excess [HPLC analysis, Chiracel OD-H column (Daicel, Fort Lee, NJ), 87% yield; Scheme 1].…”