Aza-spirocyclization

Fig. 29 Ciufolini s synthesis of aza-spirocycles from para- and ort/io-phenolic sulfonamides and desymmetrization en route to the synthesis of a lepadiformine analogue...

In his approach toward the synthesis of the alkaloid himandrine [101, 102], Ciufolini applied his oxidative phenol (spiro)amidation reaction, using DIB in TFA, to the chiral dienyl sulfonamide 156 to generate the aza-spirocycle 157, which was then heated in added toluene (reflux) to furnish the entfo-Diels-Alder cycloadduct 158 as the major regioisomer. An epimerization occurred in situ to deliver the himandrine-like trani-decaline system 159 in a combined yield of 32%, together with the epimerized minor Diels-Alder regioisomer [101] (Fig. 39). 

Our synthesis commenced with metalating iodide 414, and addition of the ensuing alkyllithium to the enantiomeri-cally pure (5)-lactam 413 provided the ring-opened, Boc-protected amino ketone 412 in 61% yield (Scheme 12.104). A formic acid-induced aza-Prins cyclization afforded an inseparable diastereomeric mixture of aza-spirocycles 415 in which the allyl cation intermediate had been trapped by the formate anion. 

A third alkaloid of this type, chilocorine B (20), was isolated from C. cacti. In this molecule, NMR experiments showed that the 2-methylperhydro-9i -aza-phenalene and the 3,4-dimethyloctahydro-8b-azaacenaphtylene subunits are linked in a spirocyclic fashion. An X-ray diffraction analysis fully determined the structure and relative stereochemistry of this alkaloid [34]. 

Gallucci, J.C. (2004) Synthesis of l-aza-8-thiabicyclo[4.2.1]nona-2,4-diene 8,8-dioxide and its conversion to a strained spirocycle via photoinduced SO2-N bond cleavage. Organic Letters, 6, 1313-1315. 

In an approach to the gastrin receptor antagonist (+)-AG-041, the Iwabuchi group has prepared the nitrogen-substituted spirocycle 153 by means of an oxidative intermolecular aza-spiro-annulation (Scheme 38) [82], Accordingly, indole 151 was treated with dirhodium catalyst 152 in the presence of PHl(OAc)2 and MgO to afford spirocycle 153 in 70% yield and 96% ee. The deuterium labeling was necessary for successful implementation of the spirocyclization. 

The densely functionalized dispiro species 157 has been stitched together by Mondal and coworkers who choreographed a three-component azomethine ylide strategy for spirocyclization [83]. In the event, isatin 154, amino add (sarcosine 155), and the exocyclic a,p-unsaturated lactone (andrographolide 156) were combined to afford the aza-spirooxindole 157 in 60% yield (Scheme 39). 

Spiroproline derivatives are of interest in biological studies as an inhibitor and mechanistic probe of prolyl-4-hydroxylase. To develop potent inhibitors of angiotensinconverting enzyme (ACE), lipophilic and sterically hindered spiroproline derivatives have been substituted in the structural framework of peptides. In addition, spiroprolines could offer interesting scaffold precursors, particularly in synthesis of combinatorial libraries of peptides. Earlier synthetic efforts aimed at spiroproline analogs involved building the proline nucleus on the structural backbone of the alicyclic system followed by resolution. We decided to try to expand the potential of our synthesis of spirocyclic compounds to pro-line derivatives, with the hitherto unknown 2-aza-spiro[4.4]-nonane carboxylic acid (124) derivative as the target. 

An intramolecular aza-Piancatelli rearrangement that constructs a fully substituted carbon centre bearing a nitrogen atom and a spirocyclic ring system in a single operation has been catalysed by dysprosium (Ill)triflate. The azaspirocycles are formed exclusively as the irons diastereomer, consistent with a electrocyclization (Scheme 99). ... 

SCHEME 7.12 Spirocyclic l-oxa-9-aza-spiro[5.5]undecane scaffold library. 

Oxidative dearomatizations with introduction of nitrogen nucleophiles are rather rare in reports. Sorensen and co-workers describe the total synthesis of a powerful immunosuppressant (FR901483) by oxidative aza-spiroannulati(Hi with PIDA in HFIP followed by an intramolecular aldol addition (Scheme 12, top) [77]. Similar to Sorensen s procedure, Hrmda and co-workers completed the formal total synthesis of enantiopure (-)-TAN1251A by dearomatizing spirocyclization reaction of the enantiopure chiral phenol substrate with high stereocontrol at the diastereomeric spiro center [78]. 

Another interesting case of carbo-spirocyclization of phenolic substrates is that reported by Chabaud and GuUlou on the conversion of para-hydroxy acetanilides of type 133 into 1,2-aza/carbo-dispirodienones 134, using BTI in TFE at 0°C (Fig. 34) [92]. This is the first example of a synthesis of 1,2-dispirodienones via a X -iodane-mediated phenol dearomatization. 

The same year, Canesi s group reported an asymmetric s5mthesis of the levoro-tatory enantiomer of the Amaryllidaceae alkaloid fortucine [105]. The L-tyrosine-derived phenol 163 was treated with DIB in HFIP to induce an oxo-spirocyclization into the para-quinolic lactone 164, which was treated with methanolic KOH to mediate both the opening of the lactone unit and an aza-Michael addition of the amide onto the cyclohexa-2,5-dienone moiety in high yield and stereoselectivity. The resulting aza-bicyclic intermediate 165 was then converted in 11 steps into (-)-fortucine (Fig. 41). This first asymmetric synthesis of fortucine led to the correction of the absolute configuration of the natural (+)-fortucine [105]. 

Another domino application of an oxidative carbo-spirocyclization and an aza-Michael addition was developed by She and co-workers to construct the core skeleton of the Amaryllidaceae alkaloids tazettine and 6a-epipretazettine. In 2013, they disclosed their approach that requires the phenolic amide 185 as key precursor of the intended carbo-spirocyclization [112]. Both DIB and BTI were first used to mediate this oxidative para-para phenolic coupling reaction, but the more electrophilic Kita s p-oxoBTI reagent (see Fig. 4) in TFE gave higher yields. The addition of potassium hydroxide in the reaction mixture then promoted the aza-Michael addition to furnish the known tazettinone intermediate 187 in 72% yield as a single diastereomer (Fig. 46) [112]. 

Having highlighted the different stereoselective metal-mediated MBFT approaches to reach aza- or oxa-spirocyclic compounds, we now review the different strategies to build, in a step-economical manner, spiroacetal and aminal derivatives. As stated earlier, the last part of this chapter is dedicated to the organometallic stereoselective... 

The spiro-fused cyclopentenone 31 has been prepared by 3-aza-Cope rearrangement, intramolecular Mannich reaction, p-elimination reaction sequence from 30. A mixture of enamine stereoisomers in the initial condensation leads to a mixture of spirocyclic epimers in 31 (Scheme 5). ... 

NHCs have been used to promote reactions of enals with A -substimted isatini-mines ° ° and oxindole-derived a, -unsaturated imines to form spirocyclic y-lactam oxindoles. Asymmetric cross-aza-benzoin reactions of aliphatic aldehydes with A-Boc-protected aryl imines to form RCOCH(Ar)NHBoc have also been NHC catalysed. ... 

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