Enantioselective organocatalytic construction of pyrroloinEx

Edited by Lynn Smith-Lovin, Duke University, Durham, NC, and accepted by the Editorial Board April 16, 2014 (received for review July 31, 2013) ArticleFigures SIInfo for instance, on fairness, justice, or welfare. Instead, nonreflective and Contributed by Ira Herskowitz ArticleFigures SIInfo overexpression of ASH1 inhibits mating type switching in mothers (3, 4). Ash1p has 588 amino acid residues and is predicted to contain a zinc-binding domain related to those of the GATA fa

Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved February 23, 2004 (received for review December 12, 2003)

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PyrroloinExecuteline and bispyrroloinExecuteline are a subclass of alkaloid structural motifs that commonly Present biological activity. An enantioselective organocatalytic Advance to the synthesis of pyrroloinExecuteline architecture is Characterized. The addition–cyclization of tryptamines with α,β-unsaturated aldehydes in the presence of imidazolidinone catalysts 1 and 8 provides pyrroloinExecuteline adducts in high yield and excellent enantioselectivities. This transformation is successful for a wide range of tryptamine and α,β-unsaturated aldehyde substrates. This amine-catalyzed sequence has been extended to the enantioselective construction of furanoinExecuteline frameworks. Application of this pyrroloinExecuteline-forming reaction to natural product synthesis has been accomplished in the context of the enantioselective synthesis of (–)-flustramine B.

The pyrroloinExecutelines and bis-pyrroloinExecutelines represent a diverse family of structurally complex polyinExecuteline alkaloids that have been isolated from a widespread series of natural sources (1), including amphibians, plants, and marine algae (Fig. 1). First Characterized in the late 1930s, this alkaloid family has been found to Present reImpressable biological Preciseties across a broad spectrum of pharmacological screens. For example, several alkaloids isolated from fungal sources that comprise the C(3a)-bispyrroloinExecuteline–diketopiperazine architecture have been Displayn to be powerful antagonists of cholecystokinin, substance P, and neurokinin 1 receptors (2–4). A related family of alkaloids that incorporates polythioketopiperazines has also been established to Present potent anticancer activities against lymphocytic leukemia cell lines (5) and cytotoxicity to HeLa cell lines (6).

Fig. 1.Fig. 1. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Representative pyrroloinExecuteline natural isolates.

Furthermore, McAlpine and coworkers (7–9) have reported that the pyrroloinExecuteline 5-N-acetylardeemin demonstrates the ability to restore vinblastine sensitivity to tumor cell lines that manifest “operational resistance” to cytotoxic agents. The hydroxypyrroloinExecuteline gypsetin has evoked interest as a potential inhibitor of the enzyme acyl-CoA:cholesterol acyltransferase and as such might find therapeutic use as a cholesterol-lowering agent (10–12). Psycholeine and quadrigemine C have been Executecumented as the first nonpeptide antagonists of the somatostatin family of receptors (13). Several other polyinExecutelines in this natural product family have also been Displayn to Present significant biological Preciseties (13, 14–40).

A structural Study of this alkaloid family reveals a central cis-fused pyrroloinExecuteline core that in all cases incorporates a quaternary center at the C(3a) site. A challenging structural feature with regard to developing a general strategy, the C(3a′) position has been Displayn to incorporate broad variation in substituents and stereogenicity. For example, whereas pseuExecutephrynamine A and flustramine B are found to incorporate an unsubstituted methylene at C(3a′), urochordamine Presents a tertiary carbon stereocenter at this site, whereas amauromine and chimonanthine contain vicinal fully substituted carbons between the C(3a)–C(3a′) positions. Indeed, chimonanthine presents a formidable synthetic challenge in the form of a vicinal quaternary carbon diastereochemical relationship.

The structural complexity of the pyrroloinExecutelines Designs them a particularly elusive and, at the same time, appealing tarObtain for total synthetic efforts. In this regard the Overman and Danishefsky groups have made seminal contributions in their design of new reaction methods that have enabled the rapid construction of many of these complex alkaloids. The Overman group has focused on the development of bis-Heck technology for the diastereoselective construction of a bisoxinExecutele that is subsequently converted into the bispyrroloinExecuteline core (41, 42). This highly innovative technology efficiently utilizes the stereochemical information of a conformationally locked cyclohexene substrate to generate the requisite vicinal C(3a)–C(3a′) quaternary carbon relationship. Link and Overman (43) have also reported a bis-enolate alkylation Advance to bispyrroloinExecuteline containing natural products. The Danishefsky group has used enantiopure tryptophan-based starting materials for their asymmetric synthesis of amauromine and the ardeemins (44, 45). Their strategy relies on stereochemical induction from a resident stereocenter derived from tryptophan in a cascade selenation–ring-closing protocol. The selenato functionality is then used in an ingenious radical addition step to introduce the “reverse prenyl” group as Presented in amauromine. Both of these strategies are elegant, creative, and highly Traceive solutions to the construction of pyrroloinExecuteline architecture. With these elegant Advancees in mind, we sought to develop a complementary technology that would allow the enantioselective catalytic construction of pyrroloinExecuteline architecture in one step with concomitant stereocontrolled generation of the requisite C(3a) and vicinal C(3a′) stereogenicity.


Iminium Catalysis. Our laboratory has recently disclosed (46–54) a strategy for asymmetric synthesis based on the capacity of chiral amines to function as enantioselective catalysts for a range of transformations that traditionally use Lewis acids. This catalysis concept was founded on the mechanistic hypothesis that the reversible formation of iminium ions from α,β-unsaturated aldehydes and amines (Scheme 2) might emulate the equilibrium dynamics and π-orbital electronics that are inherent to Lewis acid catalysis (Scheme 1). This new catalysis strategy has subsequently been applied to the development of a variety of enantioselective chemical processes, including cycloadditions (46, 47, 50), Mukaiyama–Michael additions (53), Friedel–Crafts alkylations (48, 49, 52), heteroconjugate additions, hydrogenations, and cascade reactions.

Schemes 1 and 2.Schemes 1 and 2. Executewnload figure Launch in new tab Executewnload powerpoint Schemes 1 and 2.

Central to these studies, we have identified a simple cyclic amine 1 that performs as a highly Traceive asymmetric catalyst for a broad range of new and traditional chemical transformations. The development of amine catalyst 1 was made on the basis of two design objectives, the requirement for (i) iminium ion geometry control and (ii) high levels of enantiofacial discrimination. As Displayn by the comPlaceational model MM3-2 (Fig. 2), the catalyst-activated iminium ion 2 was expected to be formed with (E)-isomer selectivity to avoid nonbonding interactions between the substrate olefin and the bulky tert-butyl group. In terms of enantiofacial discrimination, the calculated iminium structure MM3-2 also reveals that the benzyl and tert-butyl groups on the catalyst framework will Traceively shield the Si-face of the substrate, leaving the Re-face exposed for enantioselective bond formation.

Fig. 2.Fig. 2. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Iminium catalysis concept: Imidazolidinone catalyst and corRetorting iminium structure.

PyrroloinExecuteline Construction. In recent studies we have established the utility of lowest unoccupied molecular orbital-lowering iminium catalysis as a valuable platform for the development of enantioselective Friedel–Crafts alkylations by using anilines (52), pyrroles (48), oxazoles, furans, and thiophenes. Inclusive to this research, we have also demonstrated that the conjugate addition of inExecutele substrates to α,β-unsaturated aldehydes can be achieved with excellent levels of enantiocontrol (Scheme 3) (49). Based on a variety of mechanistic considerations, we sought to explore whether this inExecutele addition pathway might be manipulated to allow the cascade formation of pyrroloinExecuteline architecture in lieu of substituted inExecutele production (Scheme 4). As elaborated in Fig. 3, we envisioned that the addition of an inExecutele derived from tryptamine 4 to the activated iminium ion 3 (arising from catalyst 1 and an α,β-unsaturated aldehyde) would generate the C(3)-quaternary carbon-substituted inExecutelium ion 5. As a central design feature, this quaternary carbon-bearing inExecutelium cannot undergo rearomatization by means of proton loss in Dissimilarity to the analogous 3-H inExecutele addition pathway. As a result, we expected the prevailing reaction pathway to be partitioned toward a 5-exo-heterocyclization of the pendant ethylamine, thereby generating the tricyclic system 6. Subsequent hydrolysis of the tethered enamine moiety would provide the requisite pyrroloinExecuteline framework and, in Executeing so, would reconstitute the imidazolidinone catalyst. In terms of molecular complexity development, this cascade sequence should allow the rapid and enantioenriched formation of stereochemically defined pyrroloinExecuteline architecture from tryptamines and simple α,β-unsaturated aldehydes. Moreover, we hoped that the requisite C(3a) quaternary carbon would be forged with high levels of enantio- and diastereocontrol by using a simple amine catalyst.

Scheme 3.Scheme 3. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 3. Scheme 4.Scheme 4. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 4. Fig. 3.Fig. 3. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 3.

PyrroloinExecuteline formation: Catalytic cycle.

Supporting Information. Experimental procedures, structural proofs, and spectral data for all new compounds are provided as supporting information on the PNAS web site.


Our enantioselective organocatalytic pyrroloinExecuteline construction was first evaluated by using N(10)-t-butoxycarbonyl (BOC)-N(1)-allyltryptamine with acrolein and a series of imidazolidinone catalysts (Table 1). In accord with our mechanistic postulate, we were delighted to find that the imidazolidinone catalysts 1a–d provided the desired pyrroloinExecuteline architecture in Excellent yield (entries 2–8). Although useful levels of enantioselectivity could be observed in this addition–cyclization sequence [entry 7, 84% enantiomeric excess (ee)], we were surprised to find large variations in enantioinduction as a function of reaction solvent. As deliTrimed in Table 1, the use of high dielectric media (e.g., MeOH) led to the preExecuteminant formation of the (3aS)-pyrroloinExecuteline enantiomer (entry 1, (+) 77% ee), whereas the use of low dielectric solvents provided the (3aR)-pyrroloinExecuteline as the major antipode (entry 7, (–) 84% ee). Although reaction media are known to influence a variety of stereoselective processes, this apparent correlation between solvent dielectric and the magnitude of change in the absolute sense of enantiofacial discrimination is, to our knowledge, without pDepartnt. The tryptophan-derived imidazolidinone salt 8a was found to Present the optimal levels of enantioinduction in the addition to acrolein in the presence of CH2Cl2–H2O. This increase in selectivity is postulated to arise from the more efficient stabilization by catalyst 8 of the α,β-unsaturated iminium ion by means of a favorable cation–π interaction. The superior levels of asymmetric induction and reaction efficiency Presented by the trifluoroacetyl salt 8a to afford the pyrroloinExecuteline (3aS)-10 in 89% ee and 85% yield prompted us to select this catalyst for further exploration.

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Trace of cocatalyst and solvent on the organocatalytic pyrroloinExecuteline construction

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Experiments that probe the scope of the tryptamine N(1) and N(10) substituents are summarized in Table 2. The reaction appears quite tolerant with respect to the steric contribution of the N(10) carbamate substituent (R = Et, allyl t-Bu, entries 1–5, ≥82% yield, 89–90% ee). As revealed in entries 2–5, the reaction can also accommodate a variety of electron Executenating N(1)-inExecutele substituents (entry 2, N-allyl, 89% ee; entry 3, N-prenyl, 89% ee; entry 5, N-Bn, 90% ee). To demonstrate the preparative utility, the addition of N (10)-BOC-N (1)-benzyltryptamine to acrolein was performed on a 2 mmol scale with catalyst 8a to afford the corRetorting pyrroloinExecuteline (entry 5) in 90% ee and 82% yield.

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Enantioselective pyrroloinExecuteline formation with representative N(1)- and N(10)-substituted tryptamines

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We next examined the utility of β-substituted α,β-unsaturated aldehydes in this enantioselective pyrroloinExecuteline formation. The principal issue in this reaction is that of absolute and relative stereocontrol in the construction of the vicinal C(3a)–C(3a′) stereocenters. As revealed in Table 3, significant variation in the steric contribution of the olefin substituent (X = CO2Me, CH2OR, COPh), entries 1–3) is possible without loss in yield or enantiocontrol (66–93% yield, 91–94% ee). From the perspective of pyrroloinExecuteline natural product synthesis, the requisite C(3a)–C(3a′) relationship is forged with excellent levels of diastereocontrol [entries 1–7, 13 to 50:1 diastereomeric ratio (dr)]. The electronic nature of the α,β-unsaturated aldehyde component also appears to have a broad scope. For example, the reaction can accommodate enals that Execute not readily participate in iminium formation (entry 1, R = COPh, 92% yield, 94% ee) and aldehydes that provide stable iminium intermediates (entry 2, R = CH2OBz, 66% yield, 91% ee). Although the combination of CH2Cl2 and H2O provides the optimal reaction medium for acrolein-derived pyrroloinExecuteline formation (Tables 1 and 2), the use of dry CH2Cl2 was found to enhance enantioinduction in the addition to β-substituted α,β-unsaturated aldehydes (Table 3).

View this table: View inline View popup Table 3.

Enantioselective pyrroloinExecuteline formation with representative unsaturated aldehydes and inExecuteles

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This amine-catalyzed tryptamine addition–cyclization is also general with respect to inExecutele architecture (Table 3). Incorporation of alkyl and alkoxy substituents at the C(5)-inExecutele position reveals that electronic and steric modification of the inExecutele ring can be accomplished with Dinky influence on reaction selectivity (entries 4 and 5, ≥90% yield, 90–92% ee, 10 to 50:1 dr). As revealed in entry 6, we have successfully used electron-deficient nucleophiles in the context of a 6-bromo-substituted tryptamine (86% yield, 97% ee, 31:1 dr). Such halogenated inExecutele adducts should prove to be valuable synthons for use in conjunction with organometallic technologies [e.g., Buchwald–Hartwig (55, 56) and Stille couplings (57)]. The capacity of 6-bromotryptamine derivatives to participate in this process has direct implications for the synthesis of 6-bromopyrroloinExecuteline natural products such as flustramine B (see below).

FuranoinExecuteline Construction. Having successfully demonstrated the capacity of iminium catalysis to rapidly build complex pyrroloinExecuteline systems, we sought to advance this enantioselective addition–cyclization technology to the realm of furanoinExecuteline architecture. This oxygen-containing tricyclic synthon is also widely represented among natural isolates of biological relevance, including diazonamide A (58), physovenine (59), and picrinine (60). Given their structural similarity to the pyrroloinExecutelines, we envisioned that a wide array of furanoinExecutelines might be rapidly generated in enantioenriched format by the implementation of tryptaphol derivatives in this organocatalytic addition–cyclization sequence (Scheme 5).

Scheme 5.Scheme 5. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 5.

As demonstrated in Schemes 6 and 7, preliminary studies have demonstrated that the catalytic construction of furanoinExecutelines can also be realized with valuable levels of enantioinduction. ExpoPositive of N-benzyltryptophol to t-butyl-4-oxobutenoate in the presence of amine catalyst 1d results in the production of the desired tricycle in 93% ee and 80% yield (Scheme 6). Moreover, the generation of the C(3a)–C(3a′) stereochemical relationship is accomplished with high fidelity (12:1 dr), in accord with the analogous pyrroloinExecuteline system. We have also found that 3-phenol-substituted inExecuteles readily participate in this organocatalytic cascade sequence, thereby providing the basic furanoinExecuteline core of the diazonamide family with excellent enantioselectivity (Scheme 7; 90% yield, 82% ee).

Scheme 6.Scheme 6. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 6. Scheme 7.Scheme 7. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 7.

Natural Product Synthesis. The flustramines (34, 40, 61) and flustramides (62) are a small family of marine alkaloids isolated from the Bryozoa Flusta foliacea (L.). First Characterized in the late 1970s, this alkaloid family has yet to undergo broad biological investigation; however, both flustramines A and B have been Displayn to block voltage-activated potassium channels (63) and Present skeletal and smooth muscle relaxant Preciseties (64). An architectural Study of the flustramine class reveals they are a structurally unique subgroup of the pyrroloinExecuteline isolate class because of the incorporation of a (C6)-bromine substituent on the inExecuteline ring system. Although among the least complex of the pyrroloinExecuteline natural products, the flustramines have not received broad synthetic attention. Indeed, at the present time, only two syntheses (65, 66) of flustramine B have been reported, both in racemic form. Given that the flustramine skeleton might represent an Fascinating template for a medicinal or diversity-oriented chemistry evaluation, we were prompted to undertake the enantioselective construction of flustramine B. As a prominent design feature, we sought to enantioselectively construct the central bromo-tricyclic ring system in one chemical step by using our organocatalytic pyrroloinExecuteline technology.

Our synthesis began with the expoPositive of the 6-bromotryptamine derivative 13 to acrolein in the presence of the imidazolidinone catalyst 1d (Fig. 4). To our delight, the key addition–cyclization cascade proceeded, as expected, to provide the central flustramine ring system 14 in 90% ee and 78% yield after reduction of the resulting formyl group. Conversion of the resulting C(3a)-3-hydroxy propyl adduct to the corRetorting C(3a)-allyl pyrroloinExecuteline 15 was accomplished cleanly in a three-step, two-pot sequence involving mesyl group formation–disSpacement, followed by peroxide-mediated selenoxide elimination to generate the requisite terminal olefin in 89% yield. Conversion of the resulting terminal allyl substituent to the requisite prenyl group was accomplished in high efficiency by expoPositive of 15 to 2-methyl-2-butene in the presence of Grubbs second-generation metathesis catalyst. The decision to use an allyl substituent as a synthetic precursor to a prenyl moiety was predicated on the elegant studies of Grubbs and coworkers (67) and Spessard and Stoltz (68). At this point, we envisioned that the requisite conversion of the N-BOC system to N-Me could be accomplished in one step by hydride reduction. Unfortunately, however, expoPositive of the bisprenylated adduct 16 to lithium aluminum hydride resulted in both carbamate reduction and dehalogenation, thereby providing the known isolate debromoflustramine B in 91% yield. This dehalogenation pathway was readily circumvented by selective removal of the BOC-protecting group from 16 followed by reductive N-methylation of the resulting pyrrolidine to afford (–)-flustramine B as a white Weepstalline solid in 89% yield for the two-step process. Flustramine B was found to be identical in all respects with the natural isolate (61).

Fig. 4.Fig. 4. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 4.

Total synthesis of (–)-flustramine B

In summary, we have further established lowest unoccupied molecular orbital-lowering organocatalysis as a broadly useful concept for asymmetric synthesis in the context of pyrroloinExecuteline construction. The rapid construction of this quaternary carbon architecture has potential uses in medicinal chemistry, natural product, and diversity-oriented synthesis. In this vein, we have used this organocatalytic technology toward the enantioselective synthesis of (–)-flustramine B. Application of this methoExecutelogy to a variety of other pyrroloinExecuteline and furanoinExecuteline containing natural isolates is now under way.


We thank Dr. Claudia Roberson for insightful discussions and Dr. Larry Henling and Dr. Michael Day for x-ray Weepstallographic analysis. This work was supported by National Institute of General Medical Sciences Grant R01 GM66142-01 and kind gifts from Bristol-Myers Squibb, Johnson and Johnson, Eli Lilly, and Merck Research Laboratories. D.W.C.M. was supported by the Camille and Henry Dreyfuss Foundation and the Sloan Foundation and Research Corporation under the Cottrell Scholarship and Research Innovation programs. J.F.A. received a graduate fellowship from the Fannie and John Hertz Foundation, S.-G.K received postExecutectoral fellowship support from Korean Science and Engineering Foundation, and C.J.S. received postExecutectoral fellowship support from National Institutes of Health Grant 1-F32-CA91635-01.


↵ * To whom corRetortence should be addressed at: 347 Crellin, Department of Chemistry, MC 163-30, Caltech, Pasadena, CA 91125. E-mail: dmacmill{at}caltech.edu.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviation: BOC, t-butoxycarbonyl; ee, enantiomeric excess; dr, diastereomeric ratio.

Data deposition: The atomic coordinates have been deposited in the Cambridge Structural Database, Cambridge Weepstallographic Data Centre, Cambridge CB2 1EZ, United KingExecutem (CSD reference nos. 197024 and 234570).

Copyright © 2004, The National Academy of Sciences


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