Recent progress in the synthesis of heterocyclic natural products by the Staudinger/intramolecular aza-Wittig reaction

A review of recent progress in the synthesis of heterocyclic natural products by the aza-Wittig method focusing on applications of the tandem Staudinger/intramolecular aza-Wittig reaction.


Introduction
The synthesis of heterocyclic natural products by the aza-Wittig method has been reviewed for the first time by us in 1997; 1 very recently and timely, Fresneda and Molina have reviewed the application of iminophosphorane-based methodologies for the synthesis of natural products. 2The utilization of the aza-Wittig method for the synthesis of heterocyclic natural products is spreading out to a variety of nitrogen heterocycles from simple alkaloids to complex functionalized natural products.In this mini review, emphasis will be placed on our results in this area, and in addition on related areas.Topics to be covered include recent examples of heterocyclic natural product syntheses by the aza-Wittig method focusing on the tandem Staudinger/intramolecular aza-Wittig reaction including quinazolinone annelation, benzodiazepinone synthesis, chemoselectivity in cyclization, synthesis of benzomalvins, and some selected examples of total syntheses of heterocyclic natural products based on the so-called Eguchi aza-Wittig protocol.

The aza-Wittig Reaction 1.1 The aza-Wittig reaction
The aza-Wittig reaction 3 is the nitrogen analog of the Wittig olefination process and involves the reaction of an iminophosphorane 4 with a carbonyl group.The reaction is useful in the synthesis of acyclic imines 5 and heterocumulenes, 3 and in the intramolecular formation of carbon-nitrogen double bonds in heterocyclic synthesis. 3Stability, basicity, and nucleophilicity of iminophosphoranes are mainly determined by the substituents at the nitrogen atom.General reactivity trends of N-and P-substituted series (R' and R", respectively) are summarized as follows: 1,3a,4 R'N=PPh 3 >> ArN=PPh 3 >> R'CON=PPh 3 ~ R'SO 2 N=PPh 3 R'N=P(R") 3 > R'N=P(Ar) 3 > R'N=P(OR") 3 > R'N=P(OPh) 3 Carbonyl groups of aldehydes, ketones, acid halides, and heterocumulenes are generally reactive. 1In the intramolecular version, amide, imide, and ester carbonyl groups are also reactive giving rise to imino-cyclization (see section 2). 3

Heterocyclic synthesis by the aza-Wittig reaction followed by various cyclizations
The intermolecular version has been utilized for various heterocyclic syntheses via initial imine formation followed by electrocyclization, cycloaddition, and nucleophilic cyclization etc. as developed by Molina (tandem aza-Wittig/cyclization strategy), 3d Saito (aza-Wittig/electrocyclization method), 6 and Wamhoff (three-component reaction) 3a (Scheme 1).Unique synthetic strategies with N-vinyliminophosphoranes by Nitta, 7 Palacios, 8 and benzotriazolyl derivatives by Katrizky 9 have also been developed demonstrating the maturity and excellent prospects of iminophosphorane-mediated syntheses.

Scheme 1
Since applications of the intermolecular aza-Wittig methodology to the synthesis of natural products have been included in previous reviews, 1,2 these examples are not discussed in the present mini review.

Routes to heterocyclic natural products by the intramolecular aza-Wittig reaction 2.1 The intramolecular aza-Wittig reaction
The intramolecular version of the aza-Wittig reaction (Scheme 2) provides a direct route to heterocyclic natural products.The reactivity depends on substituents Y and R' at the carbonyl group, and on Z and R" at the iminophosphorane; thus, a useful application has to consider (1) the ring size (formation of 5-7-membered rings >> 4-membered ring), (2) the carbonyl reactivity (COR, COAr, RCOOR, RCONRCOR >> RNCOR), (3) the substituents on P [PR" 3 > P(Ar) 3 > P(OR") 3 ], (4) the substituent on N (CH 2 , Ar, C=C, CO), ( 5) the ring strain: OS value ≤20 kcal/mol (the difference of heat of formation between unsaturated and saturated analogs).3b,c The ring closure to a non-cumulated sulfoxide via an intramolecular aza-Wittig type reaction to construct S=N linkage has been recently reported by Hemming. 10

Scheme 6
The quinazolinone annelation procedure described above by acylation of an amide group with 2-azidobenzoylchloride (1) followed by the Staudinger/intramolecular aza-Wittig tandem reaction is known as the Eguchi aza-Wittig protocol 2 after its successful application by Snider's group to the synthesis of the pyrazino[2,1-b]quinazoline scaffold in the fumiquinazolines, 20,21 and to the preparation of ardeemins by Danishefsky's group 22 (cf.section 2.6).

Synthesis of benzodiazepine derivatives by intramolecular aza-Wittig reactions
Acylation of α-amino esters 19 with 2-azidobenzoylchloride (1) gives the corresponding 2azidobenzoyl derivatives which, on treatment with phosphines, form iminophosphoranes 20 and cyclization products 21 via the tandem Staudinger/intramolecular aza-Wittig reaction, providing a simple route to 1,4-benzodiazepin-5-ones 21 (Scheme 7). 23The cyclization of N-substituted derivatives (R 1 ≠ H ) with TBP proceeds smoothly under very mild conditions; however, the reaction of N-unsubstituted amino acids 19 (R 1 = H ) is sluggish at room temperature leaving 20 unreacted and requiring elevated temperatures for completion of conversion.

Scheme 7
The successful application of this procedure to the synthesis of natural antibiotic DC-81 24b has been reported by Molina 24 and by Eguchi 23b (Scheme 8).DIBAL reduction of the readily available methyl 1-(2-azidobenzoyl)prolinate 22 to the aldehyde 23a and subsequent reaction with TPP at room temperature affords 24a, the O-benzyl derivative of DC81.23b Molina's group achieved an elegant synthesis of DC-81 24b from aldehyde 23b with TPP by consecutive Staudinger/intramolecular aza-Wittig reaction.

Scheme 8
Some other useful synthetic procedures for the synthesis of functionalized pyrrolo-[2,1-c]- [1,4]benzodiazepines (PBDs) have been developed thereafter by O'Neil's group and others, 25 but details of these studies are beyond the scope of this review.

Chemoselectivity of intramolecular aza-Wittig cyclizations
The chemoselectivity of bifunctional systems is important for the selective ring construction by intramolecular aza-Wittig reactions.The selective cyclization of methyl 1-(2-azidobenzoyl)-5oxo-L-prolinate 25a with TBP and TPP involves the ester carbonyl group rather than the imidoyl carbonyl group affording 26a selectively; but both 26a and 27a are formed with triethylphosphite (Scheme 9, Table 1); 26 product ratios 26/27 as determined by 1 H NMR spectra of the reaction mixture.The isolated 26a is sensitive to moisture and is converted quantitatively into 27a by treatment with a catalytic amount of conc.HCl in THF at r.t. for 3 h.The imidocarbonyl group of amide 25b is more reactive yielding 27b exclusively.The product ratio of 7-membered rings 26a,b versus 6-membered rings 27a,b depends on the carbonyl function and on the steric effect exerted by the substituents of the phosphorane reagents: 13b The bulkier TBP and TPP form predominantly 26a; the 6-membered 27a is formed preferentially with the smaller triethylphosphite.These results may be useful for the synthetic design of related heterocycles.

Synthesis of (-)-Benzomalvin A
We have successfully applied the intramolecular aza-Wittig method to the synthesis of the neurokinin receptor antagonists (-)-benzomalvin A 32 and B 34, which contain a 1,4-benzodiazepine ring and a 4-quinazolinone ring, and can be regarded as L-phenylalanine derivatives composed of two anthranilic acid moieties. 27Our synthesis utilized the 1,4-benzodiazepine synthesis as described above combined with the quinazolinone annelation reaction (Scheme 10).Amino acid ester 28 provided (-)-benzomalvin A 32 with 99.7% ee (based on HPLC analysis).

Scheme 13
The quinazolinone annelation method has been applied to piperazinedione 43 derived from L-tryptophan methyl ester by Danishefsky's group for the synthesis of ardeemin 44a and 5-Nacetylardeemin 44b, one of the most potent known agents for reversal of multiple drug resistance (MDR) 39 featuring a hexahydropyrrolo [2,3-b]indole scaffold substituted at the benzylic ring junction with the 1,1-dimethylallyl ("reverse-prenyl") group (Scheme 14). 22Acylation of 43 with KHMDS and 1 works well to give the corresponding imide in variable yields (50-80%); for technical reasons, on larger scale preparations the use of 2-azidobenzoic anhydride is preferred over the acid chloride 1. 22b The Staudinger/intramolecular aza-Wittig reaction of the imide product with TBP gave aredeemin 44a, which was acetylated to 5-N-acetylardeemin 44b (9 steps with 12.5% overall yield from bis(Boc)tryptophan methyl ester).

Scheme 14
A seco analogue of ardeemin has been synthesized by Menéndez' group also using the quinazolinone annelation method. 40 diverse library of benzodiazepine-quinazolinone alkaloids (the circumdatin family) has been prepared by Thomas with a polymer supported phosphine-mediated intramolecular aza-Wittig reaction as the key step, a novel modified Eguchi aza-Wittig protocol (Scheme 15). 41The multi-arrayed library generation strategy starts out from readily accessible benzodiazepinediones 45 and anthranilic acids, and all library members were purified by preparative reversed-phase HPLC, yielding 283 isolated pure products 46a,b and 47a,b from 384 individual reactions.

More applications of the intramolecular aza-Wittig method to the synthesis of heterocyclic natural products 3.1 Examples of total synthesis of heterocyclic natural products via cyclic imines by the tandem Staudinger/intramolecular aza-Wittig reaction
The intramolecular Staudinger/aza-Wittig reaction provides a simple and efficient method for the construction of 5-8-membered cyclic imines (cf.section 2.1) and has recently been utilized also for the synthesis of complex natural products as exemplified by 48-53 (Figure 1).In these total syntheses, the Staudinger/intramolecular aza-Wittig reaction is applied ingeniously for highly functionalized molecules as explained below.
Sha and coworkers used the intramolecular aza-Wittig imine formation reaction followed by NaBH 4 reduction to construct the pyrrolidine ring in the total synthesis of (-)-dendrobine 48 from 54 via 55 and 56 (Scheme 16). 42Direct reduction of the cyclic imine to the more stable pyrrolidine 56 is followed by methylation to afford (-)-dendrobine 48.
In the first synthesis of indoloquinoline alkaloid cryptotackiene 49, Fresneda, Molina and Delgado successfully applied the Staudinger/intramolecular aza-Wittig imine formation reaction to 3-(2-azidophenyl)-1-methylquinolin-2(1H)-one 57 with a sluggishly reacting carbonyl group (Scheme 17). 43Treatment of 57 with tri-(n-butyl)phosphine in o-xylene at room temperature followed by heating at reflux temperature for 24 h gives 49 in only 5% yield; treatment of 57 with trimethylphosphine at room temperature followed by heating in nitrobenzene at reflux for 24 h affords 49 in 24% yield; further improvement up to 40% yield is achieved by microwave irradiation (Scheme 17).

Scheme 17
Honda's group employed the intramolecular aza-Wittig imination reaction for construction of 6-membered imines in the enantioselective synthesis of the piperidine alkaloids (-)-anhydronupharamine 50a (Scheme 18). 44Treatment of the (-)-carvone-derived azide 58 with TPP in THF at room temperature, followed by heating at reflux gives imine 59, which without isolation upon reduction with NaBH 4 yields (-)-anhydronupharamine 50a as a single stereoisomer in 77% overall yield from 58.Since 50a is known to be converted into (-)-nupharamine 50b (Figure 1) on treatment with hydrochloric acid, 44c this synthesis constitutes its formal chiral synthesis.

Scheme 18
The antitumor antibiotic phloeodictine A1 51 has been synthesized by Snider's group (Scheme 19). 45The toluene solution of the unstable azide derived from 60 is subjected to a polymer supported Eguchi aza-Wittig reaction followed by a retro Diels-Alder reaction to prepare intermediate 61.The use of polystyrene-supported Ph 3 P prevents isomerization of 61 and facilitates purification of the product.Addition of 11-dodecenyl magnesium bromide followed by alkylation with 63 and deprotection completes an efficient synthesis of 51 (Scheme 19).
Many more heteroaromatic natural products have been synthesized by Molina and by other groups utilizing the aza-Wittig protocol in tandem reactions followed by electrocyclic ringclosure, heterocumulene-mediated annelation, intramolecular halide displacement methods.These topics are not discussed in this mini review (see references 1 and 2).

Scheme 23
Pyrazino[2,3-e[pyrido [1,2-a]diazepines 71 (6,9-diaza analogs of PBDs) have been prepared by us (Scheme 24). 51Condensation of 76 with t-butyldiphenylsilyl-protected (TBDPS) Lprolinol 80 gives 81, which is converted into iminophosphorane 82 by modified Kirsanov reaction followed by deprotection.Swern oxidation of the hydroxymethyl group of 82 generates the corresponding aldehyde (in situ), which by spontaneous intramolecular aza-Wittig cyclization followed by addition of alcohols affords the isolated products 71a,b.Utilizing the intramolecular aza-Wittig method many A-ring functionalized derivatives of PBD have been designed by O'Neil's group. 25These authors have applied this method to synthesize a B-ring modified PBD, benzodiazocine 72 as the first example of an 8-membered cyclic imine (Scheme 25). 52The requisite amide 83 is obtained from the reaction of 2-azidobenzoyl chloride (1) with O-protected homoprolinol.Hydrolysis of the carbonate followed by Dess-Martin oxidation yields the aldehyde 84 which, on treatment with TPP undergoes smooth cyclization to afford the pyrrolobenzodiazocine 72.Recently, Natsugari's group 54 has developed a highly efficient method for the synthesis of medium-sized lactams 86 by the intramolecular Staudinger/aza-Wittig protocol.The intramolecular aza-Wittig imino-cyclization reaction with the carbonyl group of pentafluorophenyl ωazido esters 85 followed by hydrolysis proceeds smoothly under high dilution conditions at room temperature affording 7-and 8-membered lactams 86a-d; conversion into 9-and 10-membered lactams 86e,f requires heating at 100 °C to obtain satisfactory yields (Scheme 24).This procedure has been applied to the synthesis of several analogs 87a of the potent γ-secretase inhibitor LY411575 87b (Scheme 26).

Scheme 9 Table 1 .
26emoselectivity of the Staudinger/aza-Wittig tandem reaction of 25a,b26In benzene or xylene, 1.1 equivalent of (R 1 )3P.b Yields were determined after conversion into a