2,5-disubstituted pyrrolidine

Kaiser and Muchowski (41) reduced A -(r-butoxycarbonyl) pyrroles to the corresponding pyrrolidines over 5% Pt-on-C at room temperature and atmospheric pressure. Under these conditions 0-benzyl groups are retained and 2,5-disubstituted pyrroles are reduced mainly or exclusively to thecis-2,5-disubstituted pyrrolidines. In some cases Pt-on-C proved superior to either Rh-on-C or PtO,. 

Interestingly, in the case of enantiomerically pure internal allenes, a diastereose-lective IH is observed (e.g.. Scheme 4-17), as shown by the catalytic hydrogenation of the Z/E mixture to give the trans-2,5-disubstituted pyrrolidine as a single compound. 

The reaction of nitrones with 3-butenylmagnesium bromide was used in the diastereoselective synthesis of cis -2,5-disubstituted pyrrolidines, arising from a Cope retro-elimination (Scheme 2.145) (Table 2.11) (201, 572). 

Significant decomposition prevented calculation of d.r. cNo 2,5-disubstituted pyrrolidine W-oxides were detected. 

Neutral aminyl radicals generated by anodic oxidation of lithium alkenyl amides undergo a stereoselective cyclization to cis-l-methyl-2,5-disubstituted pyrrolidines [249]. 

The cyclization of the lithium amide 29a to 2,5-disubstituted pyrrolidine shown in Scheme 17 is clearly a one-electron oxidation process. This suggests that the radical 29c is not an oxidizable species at the applied potential and thus... 

Other examples include the intramolecular radical cyclization of 3-bromoaIkyl-2(3fl)-oxazolones 192 and 196 with tributyltin hydride/azobisisobutyronitrile to give the pyrrolooxazolidinones 194,198, and 199. The 2,5-disubstituted pyrrolidine derivatives 195 are produced enantioselectively (Fig. 5.49). 

High asymmetric induction has been observed in some cyclizations to 2,5-disubstituted pyrrolidines. The selectivity in these cases appears to be a function of the nitrogen derivative used and the reaction conditions (equation 110 and Table 30). Cyclization of carbamate derivatives with mercury salts or I(col-... 

Table 30 Cyclization to 2,5-Disubstituted Pyrrolidine Derivatives (Equation 110)...

Aminyl radicals also can be generated via electrochemical oxidation of amide bases or O-substituted hydroxylamines. Suginome has studied radical cyclizations involving oxidations of lithium alkenylamides as a route to ccs-l-methyl-2,5-disubstituted pyrrolidines (85TL6085). Electrolysis of lithium alkenylamide 17a, generated from the amine and butyllithium at - 78°C, led to the formation of 18a, exclusively cis, in 52% yield (Scheme 4). The reactions require 0.25 M UC104 in THF HMPA (30 1) as the supporting electrolyte. A variety of 2-substituted amines were studied. 

The conjugate addition of CH3COSH to methacrylamides with chiral C2-symmetric nms -2,5-disubstituted pyrrolidines afforded the Michael addition products in excellent... 

The monocyclic 2,6-disubstituted piperidines have been considered as possible precursors for dendrobatid alkaloids containing piperidine rings, such as the histrionicotoxins, decahydroquinolines, and gephyrotoxins (see Ref. J). Similarly, the monocyclic 2,5-disubstituted pyrrolidines have been considered as possible precursors for dendrobatid alkaloids containing pyrrolidine rings, such as the pumiliotoxins, the indolizidines, and now the pyrrolizidines (see Ref. 5). It should be noted that 2,6-disubstituted piperidines and 2,5-disubstituted pyrrolidines occur only rarely in dendrobatid frogs, while in ants they appear as major venom constituents, along with pyrrolizidines and indolizidines. It has been proposed that the monocyclic piperidines and pyrrolidines may serve as biosynthetic precursors of the bicyclic alkaloids in ants 125,134). 

Disubstituted pyrrolidines from ants have insecticidal activity and, as venom constituents, presumably serve the ants in a defensive repellant function (149). Some also may have trail pheromone activity. Synthetic cis/rra/ij-pyrrolidine 197B acted as a noncompetitive blocker of nicotinic... 

The 2,5-disubstituted pyrrolidines (and pyrrolines) are well known as constituents of ant venoms, particularly ants of the myrmicine genera Solenopsis, Monomorium, and Megalomyrmex 158). More than 20 such compounds have been identified in myrmicine ants 134,149,158-161). These include the /rans-pyrrolidine 197B. Incidentally, all ant pyrrolidines so far detected are of the trans configuration. A trans-2-n-butyl-5-n-heptylpyrrolidine (cf. 225C) occurs in ants, but a 2,5-di-/i-butylpyrrolidine (cf. 183B) has not been reported. 

In dendrobatid frogs, pyrrolidines have been detected only in certain populations of Dendrobates histrionicus and Dendrobates pumilio (/). Pyrrolidine trans-iSH is the only pyrrolidine to occur as a major alkaloid, and it appears only in the most northern populations of Dendrobates histrionicus. In nondendrobatid frogs, 2,5-disubstituted pyrrolidines have not been detected. 

The most recent formal asymmetric synthesis of (+)-anatoxin-a was achieved through a highly diastereoselective [2+2] cycloaddition of dichloroketene with a chiral enol ether(63 Scheme 7.15) in order to reach the general stracture of 2,5-disubstituted pyrrolidine (66) for generating the acyliminum ion and getting the required bicycle skeleton (67) (Muniz et al. 2005). 

The second reported synthesis was by Martin and co-workers (Breimeman and Martin 2004 Brenneman, Machauer, and Martin 2004 Martin 2005). Fundamentally, this synthesis differs with respect to the previous one in the strategy for achieving the synthesis of the c/5-2,5-disubstituted pyrrolidine 71 (Scheme 7.17). The starting product in this case was the D-methyl pyroglutamate. 

A 2,5-disubstituted pyrrolidine was obtained by this method as a 1 1 mixture of cis- and tran.r-isomers. However, since diastereomeric or enantiomeric boronic esters can be easily prepared via asymmetric hydroboration, the control of the relative and absolute stereochemistry at C-2 and C-3 (ring numbering) should easily be achieved. Diisopinocampheylborane was employed in the first step, but exclusively with allyl bromide. 

Intramolecular Reactions 7.2.6.2.I. Preparation of Pyrrolidines 2,5-Disubstituted Pyrrolidines... 

Starting from 1-substituted 4-alkenylamines, pyrrolidines are directly obtained by intramolecular cyclization mediated by phenylselenenyl chloride or TV-phenylselenophthalimidc71,72. Treatment with phenylselenenyl chloride in dichloromethane at — 70 °C in the presence of trifluo-roacetic acid and silica gel, afforded 2,5-disubstituted pyrrolidines 1 in moderate yield through... 

Mercury-induced cyclization of 1-substituted 4-pentenylamines afforded 2,5-disubstituted pyrrolidines with high 1,3-asymmetric induction, the stereochemical outcome of the cyclization is determined by the reaction conditions75, 76. Treatment with mercury(II) chloride in tetrahy-drofuran/watcr (kinetic conditions) gave the iran.v-isomer as the major isomer in the reaction mixture. However, when mercury(ll) chloride in chloroform or mercury(II) chloride in tetrahy-drofuran were employed as electrophiles (thermodynamic conditions), the more stable s-iso-mer was obtained as the predominant component of the reaction mixture this result can be ascribed to a double A1 2 interaction76. 

The silver-catalyzed cyclization of A -substituted, 1-substitnted l-amino-4,5-dienes gave the corresponding 2,5-disubstituted pyrrolidine derivatives 6 in good yield. The intramolecular reaction was performed using silver tetrafluoroborate in dichloromethane at 20 °C. High 1,3-asymmetric induction was observed with the .s-2,5-disubstituted pyrrolidine derivative essentially the only product observed86,87- 216 218. -Substitution proved necessary for asymmetric induction. In fact, when the free amine underwent cyclization, only an equimolar mixture of cis- and franx-diastereomers was recovered. 

The mercuration of 1,5-hexadiene in the presence of aromatic amines, amides or carbamates is a suitable method for the preparation of 2,5-disubstituted pyrrolidines. The stereochemical outcome of this cyclization is strongly determined by the reaction conditions, 1,3-asymmetric induction depends on whether kinetic or thermodynamic control takes place. When mercury(II) acetate was allowed to react at — 20 °C in tetrahydrofuran with 1,5-hexadiene in the presence of an excess of arylamine (kinetic control), tra s-.V-substituted 2,5-dimethylpyrro-lidines 7 were the major product after reductive cleavage of the C —Hg bond88,89. 

When a bis-homoallylic amine containing a nucleophilic ester group 5 undergoes iodocycliza-tion, formation of a frara.v-2,5-disubstituted pyrrolidine ring is favored, followed by conversion of the iodoamine to an aziridine. The intramolecular capture of the intermediate aziridinium salt by participation of the proximate ester results in a net retention of carbon configuration and total stereoselectivity123. 

Reduction of 1,4-Diketones. Synthetic access to C2-symmetric 1,4-diols, useful building blocks for the preparation of chiral 2,5-disubstituted pyrrolidines and phospholanes, involves reduction of the parent 2-alkane-1,4-diones, or, even better, reduction of the related ( )-alk-2-ene-1,4-diones (11) (eq 7) or 2-alkyne-1,4-diones (12) (eq 8), followed by catalytic hydrogenation. ... 

In close relation to the work on acrylates derived from lactate, pantolactone and 2,5-disubstituted pyrrolidines (vide infra), A -acryloylproline benzyl ester (391) has t n studied as a chiral dienophile... 

Acylic syn-1,4-chloroacetates were used in a similar sulfonamide substitution-cyclization reaction for their transforaiation to stereodefined 2,5-disubstituted pyrrolidines (Scheme 8-24] [83]. Some of these 2,5-disiibstitiited pyrrolidines are ant venom pheromones and are also found in the skin of frogs. 

Scheme 8-24 Stereocontrolled synthesis of cis and trans 2,5-disubstituted pyrrolidines.

Lithium 1,2-dialkyl-1-(4-pentenyl)amide ions obtained from secondary pentenyla-mines may be anodically oxidized to form aminyl radicals which undergo cyclization to give regio- and stereoselectively c/5 -A/ -alkyl-2,5-disubstituted pyrrolidines [26] ... 

A few reactions of nitrogen compounds interesting from a stereochemical aspect have been reported. Tokuda and coworkers [372] reported the stereochemically clear result that lithium alkeynylamides undergo a highly stereoselective cyclization by anodic oxidation to give C75-1-methyl-2,5-disubstituted pyrrolidines in reasonable yields, as in Eq. (59). The cyclization seems to proceed via neutral amino radicals. 

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