sign in sign up
<<
Home , Cyclic compound, Sodium borohydride

Laureates: awards and Honors, sCs FaLL Meeting 2011 CHIMIA 2012, 66, No. 4 233

doi:10.2533/chimia.2012.233 Chimia 66 (2012) 233–236 © Schweizerische Chemische Gesellschaft Alkaloids Synthesis via a Selective Cyclization of Aminocyclopropanes

Filippo De Simone§ and Jérôme Waser*

§SCS-DSM Award for best poster presentation

Abstract: The continuous progress in medicinal requires more versatile synthetic strategies for the generation of large libraries of active compounds and their analogues. As a result, the research for new effective cyclization and reactions is an essential task in organic chemistry. In 2008 we developed the first catalytic formal homo-Nazarov reaction starting from activated . Herein we report the extension of the catalytic formal homo-Nazarov cyclization to aminocyclopropanes. Highly diastereoselective cyclizations were obtained via an acyliminium intermediate generated through opening of the . An excellent control over the of either the C–C or C–N cyclization in the case of free as nucleophilic partners was achieved. The utility of the developed methodology was demonstrated by the generation of the polycyclic scaffolds of Aspidosperma and Gonioma natural products starting from a common intermediate. Based on this method, a formal total synthesis of the alkaloid aspidospermidine and the total synthesis of the alkaloid goniomitine are presented. Finally, the scope and limitations of our methodology are discussed on an extended range of vinyl-cyclopropyl with cyclic or acyclic carbamates, as well as as donor groups on the cyclopropane. Keywords: Activated cyclopropanes · Alkaloids · Heterocycles · Regioselectivity · Total synthesis

Introduction (Scheme 1).[2] Different from the concert- (Scheme 2). Indeed, the presence of a het- ed Nazarov cyclization, the cyclization of eroatom would assure a good stabilization Carbocyclic and heterocyclic scaffolds vinyl-cyclopropyl ketones proceeds via a of the formed carbocation, as demonstrat- play a key role in natural and pharmaceuti- stepwise process involving a carbocationic ed by the broad literature of donor–accep- cal compounds.[1] Rigidified ring systems intermediate III. tor cyclopropanes,[4] and would extend the assure a better stability and a well-defined In 2009, we reported the development range of structures accessible. In particu- tridimensional arrangement of functional of the first catalytic method for the homo- lar, the cyclohexylamines which could be groups allowing stronger and more se- Nazarov reaction of vinyl-cyclopropylke- obtained through the cyclization of ami- lective interactions with receptors or en- tones using a catalytic amount of a Brønsted nocyclopropanes can be found in several zymes. Consequently, the development of acid in acetonitrile.[3] Although the discov- natural alkaloids such as aspidospermidine new efficient processes for the synthesis ery of the new catalytic conditions for the (1), aspidofractinine (2), strychnine (3), of carbocycles and heterocycles is a fun- formal homo-Nazarov cyclization allowed vindoline (4), vindolinine (5), vinblastine damental task for an organic chemist. the application of our method to several (6) and vincristine (7) (Scheme 2). An ami- Starting from the Nazarov reaction, the unprecedented heterocyclic structures, the nocyclopropane could be used as precur- replacement of the double-bond by a cy- required presence of an aromatic group sor of an iminium intermediate in the for- clopropane could give access to larger ring to stabilize the carbocationic intermedi- mal homo-Nazarov cyclization. However, systems via a ‘homo-Nazarov’ cyclization ate still constituted a severe limitation in aminocyclopropanes with no electron- terms of scope. withdrawing groups are unstable and the We report herein the extension of the presence of an electron-withdrawing group methodology obtained replacing the aro- on the would be required to pre- matic stabilizing group by a heteroatom vent the opening of the cyclopropane ring.

Scheme 1. ANazarov Cyclization Mechanism of the Nazarov and formal O H OH conrotatory OH O ring closure homo-Nazarov reac- H tion. 1 2 1 2 R R R1 R2 R R R1 R2 *Correspondence: Prof. Dr. J. Waser I II H Ecole Polytechnique Fédérale de Lausanne Laboratory of Catalysis and BFormal Homo-Nazarov EPFL SB ISIC LCSO OLA BCH 4306 O LA OLA O 2 EDG R2 EDG R2 EDG R2 CH-1015 Lausanne EDG R H Tel.: +41 21 693 93 88 1 R1 R3 R R1 R1 Fax: +41 21 693 97 00 3 3 III R IV R LA R3 E-mail: [email protected] 234 CHIMIA 2012, 66, No. 4 Laureates: awards and Honors, sCs FaLL Meeting 2011

Scheme 2. Formal the more stable exo form 10a with cata- O OH O HA HA 1 1 1 homo-Nazarov cycli- lytic BF ·OEt . This isomerization, first X R X R X R 3 2 zation of aminocyclo- introduced by Grieco, was proposed to oc- R2 N propanes and alkaloid cur via a ketene iminium salt.[6] Ester 10a O N O N 3 2 natural products con- O R R2 R was then hydrolyzed to give a single dia- R3 R3 taining a cyclohexyl- stereoisomers of carboxylic acid 11. The H ring. O O choice of the right conditions to convert the H H H N N H H Et N sensitive cyclopropane 11 into the Weinreb H 12 in good yield was crucial. After N N a short screening of coupling reagents, we N Aspidospermidine (1) Aspidofractinine(2) Strychnine (3) selected 4-(4,6-dimethoxy-1,3,5-triazin- R HO CO Me H 2 2-yl)-4-methylmorpholinium chloride HO CO Me N OAc Me CO2Me 2 H H Et (DMTMM) since it allowed the formation N OAc N Me Et MeO of the amide 12 in good yield and without O N MeO MeO H further purification. With these encour- N N H N Et aging results in hand, we decided to syn- OH N thesize the free indole cyclization precur- Vindoline (4) Vindolinine (5) sor 14. The use of indole N-carboxylates R=Me: Vinblastine (6) R=CHO: Vincristine (7) pioneered by Katritzki[7] was considered the more appropriate choice. Indeed, the carboxy group presented the advantage to In this context, acylamino cyclopropanes afforded enamide 9 in good yield (Scheme direct selectively the lithiation on the C(2) represent a good compromise in terms of 3).[6] The benzyl-carbamoyl protecting position of indole and to protect the indole reactivity, since they are sufficiently elec- group was chosen due to its tolerance to- nitrogen at the same time. Furthermore, tron-rich to promote the ring opening and wards acidic conditions and its easy re- the obtained carboxy indole is labile and stabilize the formed cation as an acylimin- moval under mild conditions (for example underwent decarboxylation upon work ium species (I), but are stable enough to be via hydrogenation), as well as in order to up to give directly the unprotected prod- isolated (Scheme 2). obtain the desired electron-density on the uct. Nevertheless, the literature about this We propose herein the first utilization nitrogen. method included only examples with more of the catalytic formal homo-Nazarov cy- It was important to finely tune the prop- simple substrates. Using isolated and re- clization of aminocyclopropanes in the erties of the catalyst and the reaction time crystallized indole-N-carboxylic acid 13 synthesis of a . Based on in order to obtain reproducible yield for we were pleased to isolate the precursor this method, a formal total synthesis of the the of 9. On preparative 14 for the formal homo Nazarov cycliza- Aspidosperma alkaloid aspidospermidine scale, a diasteromeric mixture (1:1 dr) of tion in good yield. (1) is presented. cyclopropane ethyl esters 10a,b was ob- Surprisingly, when we attempted the Moreover, the versatility of our cycli- tained using copper (i) triflate and ethyl di- cyclization of 14 using our standard con- zation method is demonstrated by its suc- azoacetate in a reproducible 76% of yield. ditions for the formal homo-Nazarov re- cessful application in the total synthesis Endo ester 10b was then isomerized into action, two different compounds were of the natural alkaloid goniomitine (21), accomplished in 13 linear steps with an H Cbz Cbz Cbz Scheme 3. Synthesis a) BuLi, CbzCl Cu(I) cat, H overall yield of 11%. O N N O N O N of indole-substituted EtI, 67% N CHCO Et, BF3•Et2O Finally, the scope and limitations of our 2 2 cyclopropane 14. b) NaBH4 76% EtO 95% EtO Et Et Et methodology are investigated for a wide c) H2SO4 8993% overall 10a-b 10a range of vinyl-cyclopropyl ketones. dr: 1:1 NaOH 95% DMTMM Cbz N Cbz Cbz H MeNHOCH •HCl, H Formal Total Synthesis of O N 13 COOH O N 3 O N t 93% Aspidospermidine BuLi, LiCl O N HO HN Et Et Me Me Et 14 67% 12 11 When considering potential targets for the formal homo-Nazarov cyclization of aminocyclopropanes, we decided to at- Scheme 4. TsOH O O H Et H Et tempt first a synthesis of the Aspidosperma 20 mol % N H2,Pd/C HN Cyclization of cy- 14 N Cbz N CH CN Et H EtOH Et H clopropane 14 and alkaloid aspidospermidine (1). We select- 3 N N 74% O quant. O ed this alkaloid, isolated from the bark of H H determination of the N HN Aspidosperma quebracho blanco and other Cbz relative configuration cis-15 cis-16 cis-17 cis-18 of cis-17 and cis-18. species native of South America,[5] since it is the simplest natural product contain- ratio 1.6 :1 ing the tetracyclic scaffold also present in cis-17 cis-17 cis-18 many more complex alkaloids. A new con- 1 H H1 1 vergent approach to the total synthesis of a H b H c H H H2 2 Aspidosperma alkaloids would give access f H n H HN CH H m H2 d 3 l H1 o to a wide range of potentially bioactive nat- N H2 e H i ural compounds and synthetic analogues. h g H H Starting from commercially available O δ-valerolactam (8), a sequence of protec- Importantcorrelations NOESY: f a1 f n f o f e1 f m tion, alkylation, reduction and dehydration H -H ;H-H ;H-H ;H-H ;H-H . Laureates: awards and Honors, sCs FaLL Meeting 2011 CHIMIA 2012, 66, No. 4 235

isolated. NMR and X-ray analysis carried goniomitine scaffold cis-16 was obtained Moreover, in both the cyclization out after separation of the two cyclization with high yield and diastereoselectivity. mechanism, the regioisomers were ob- products and removal of the Cbz protect- One of the possible explanations for tainedaspurediastereoisomers.Qualitative ing group allowed the identification of the the observed selectivity could lie in the analysis of the possible transition states desired product cis-15 derived from the hard/soft properties of the generated enol suggested that a classical Fürst-Plattner attack on indole at the C(3) position and intermediates which allowed the selective stereocontrol could be the basis for the the compound cis-16 resulting from cy- formation of either the kinetic or the ther- high stereoselectivity observed for this clization on the N(1) position in a ratio modynamic product. When the aminocy- particular cyclization.[10] of 1.6:1 (Scheme 4). The isolation of free clopropane is activated with Cu(OTf) the 2 amine cis-17 accomplished the successful formed copper-bound enolate would have formal total synthesis of aspidospermi- a ‘soft’ character, which could favor the at- Total Synthesis of Goniomitine dine (1), since this intermediate had been tack of the acyl iminium on the softer C(3) reported in the synthesis by Wenkert and indole position. Proton-transfer and rearo- In order to finish the total synthesis of Hudlicky.[8] matization of the cyclization product lead goniomitine, we considered a more con- to the more stable thermodynamic product vergent approach starting from the cycli- cis-15. Moreover, the polar solvent is fun- zation precursor 19. Cyclopropane 19 was Selective Cyclization damental to stabilize the charged iminium obtained from the addition of a bislithiated intermediate so that the charge-controlled salt of TIPS-protected and N-carboxylated In order to improve the selectivity to- reaction with the nitrogen becomes slower tryptophol on Weinreb amide 12. wards C–C cyclization, we tested several compared with the attack from the carbon The indole 19 was then cyclized in combinations of acid catalysts and sol- atom. presence of catalytic p-toluenesulfonic vents (Scheme 5). We were pleased to note On the other hand, the use of TsOH acid in dichloromethane (Scheme 6). The that softer Lewis acid such as copper salts would generate a hard enol which could presence of the alkyl chain at C(3) had no increased dramatically the regioselectiv- lead to the attack of the iminium on the negative influence on the cyclization rate, ity toward the C–C cyclization allowing harder N(1) position of indole. The non- and the desired product 20 was obtained in the formation of the desired cyclic com- coordinating effect of methylene chloride, good yield as a pure diastereoisomer. pound cis-15 as a pure diastereoisomer would hence favor a fast charge-controlled The carbonyl group was then reduced in good yield. The N-cyclization product attack on the harder nitrogen. The formed with and the resulting cis-16 was also highly interesting, since intermediate, through deprotonation and acetylated in order to facilitate the it represented the tetracyclic core of go- tautomerization would yield the kinetic cleavage of the C–O bond. The acetate and niomitine (21). Considering the rarity of product cis-16. the benzyl carbamate were cleaved during this scaffold in nature, the few examples In order to confirm this hypothesis, hydrogenolysis and the deprotection of the of reported synthetic approaches[9] and the we analyzed the interconversion of the primary alcohol using TBAF finally gave absence of any information on its bioactiv- two cyclic compounds under the reaction goniomitine (21) in 77% overall yield from ity, we decided to optimize the cyclization conditions used to obtain the opposite re- 20. towards the formation of the N(1) cycliza- gioisomer. In presence of copper triflate in The total synthesis of goniomitine (21) tion product. During the screening of sev- acetonitrile, it was possible to convert the was accomplished in a linear sequence of eral different solvents we were delighted cyclic compound cis-16 into the regioiso- 13 steps with an overall yield of 11%.[11] to find a remarkable switch of selectivity mer cis-15, while no interconversion was This synthesis represents up to date the when p-toluenesulfonic acid was tested observed when cis-15 was submitted to p- most efficient way to obtain goniomitine in dichloromethane. The formation of the toluenesulfonic acid in dichloromethane. (21) as a racemic mixture. Moreover our convergent approach could be applied to introduce a broad structural diversity on Cbz Scheme 5. Regio- the indole and piperidine moiety. Catalyst Solvent cis-15 : cis-16 and diastereoselec- O N tive cyclization of TsOH CH3CN 1.6 :1 Cu(OTf) CH CN 7:1 aminocyclopropane HN Et 2 3 Scope Extension 14. TsOH CH2Cl2 1:21 14 With the optimized conditions for the regioselective cyclization in hand, we de- Cu(OTf)2 TsOH 80% 85% cided to synthesize a further series of sub- CH2Cl2,rt CH3CN, rt 15 min 15 min strates in order to extend the scope of this new reaction (Scheme 7). Modifications of H the hetero-aromatic part of the molecule N O Cu(OTf) 2 Cbz N Et were first considered. Using the conditions CH2Cl2,rt H N optimized for the cyclization of aminocy- H Et 48h clopropane 14, we were pleased to observe Cbz N O >90% a high yielding cyclization with a complete control on the regiochemistry for methoxy- cis-15 cis-16 indoles 22a and 22b. When pyran was used as nucleophile (23), the cyclization prod- Scheme 6. Total syn- Cbz uct 29 was obtained using p-toluenesulfon- Cbz N HN thesis of goniomitine N Et a) NaBH ;b)Ac O; Et O H 4 2 H (21). ic acid as catalyst in acetonitrile. TsOH, DCM N c) H2,Pd; d) TBAF N HN The scope was then extended to acy- Et 93% O 77% overall clic aminocyclopropanes (24 and 25) and OTIPS [12] OTIPS OH an oxycyclopropane (26). For N-methyl 19 20 (±)-Goniomitine(21) indole 24, cyclization was successful, but a 236 CHIMIA 2012, 66, No. 4 Laureates: awards and Honors, sCs FaLL Meeting 2011

O Scheme 7. Extension not limited to the formal homo-Nazarov O of the cyclization process, and further applications in other Et scope. type of cyclization or intermolecular an- 29 78% CbzN nulation reactions can be expected in the N [13] Cbz Et Me O future. TsOH, H N N CH3CN, R O rt Received: January 13, 2012 TsOH Cbz N 28a-b O Cbz Bn CH CN, rt N 86-92% 3 O TFA, 30 [1] J. Clardy, C. Walsh, Nature 2004, 432, 829. Me O 89% [2] a) W. S. Murphy, S. Wattanasin, Tetrahedron CH3CN, Cbz 23Et N rt Lett. 1980, 21, 1887; b) O. Tsuge, S. Kanemasa, O N T. Otsuka, T. Suzuki, Bull. Chem. Soc. Jpn. Cu(OTf) O Bn H 2 R 24 N N O CH Cl , X 1988, 61, 2897; c) F. De Simone, J. Waser, 2 2 HN R1 Cbz rt Et Chimia 2009, 63, 162. 22a-b 5 R R4 R3 2 [3] F. De Simone, J. Andres, R. Torosantucci, J. R H Et R O Cbz N O H Waser, Org. Lett. 2009, 11, 1023. R H O N N [4] a) H. U. Reissig, R. Zimmer, Chem. Rev. 2003, 27a-b Bn TsOH, 88-95% N 103, 1151; b) F. Gnad, O. Reiser, Chem. Rev. 26 CH CN, 25 Cbz 3 2003, 103, 1603; c) M. Yu, B. L. Pagenkopf, rt a R=4-OMe BF ·Et O, 3 2 Cu(OTf)2, Tetrahedron 2005, 61, 321; d) C. A. Carson, b R=5-OMe CH CH , HO 2 2 CH3CN, M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051; e) rt rt N F. De Simone, J. Waser, Synthesis 2009, 3353; O O O H f) T. P. Lebold, M. A. Kerr,. Pure Appl. Chem. N N O 31 2010, 82, 1797. 75% [5] G. Fraude, Berichte 1878, 11, 2189. 33 32 N [6] P. A. Grieco, M. D. Kaufman, J. Org. Chem. 65% Bn 70% Cbz 1999, 64, 7586. [7] A. R. Katritzky, K. Akutagawa, Tetrahedron Lett. 1985, 26, 5935. milder acid (TFA) had to be used to prevent eral successful applications in the synthe- [8] E. Wenkert, T. Hudlicky, J. Org. Chem. 1988, 53, 1953. formation of side products via hydrolysis sis of complex polycyclic scaffolds and the [9] a) C. Hashimoto, H. P. Husson, Tetrahedron and elimination to give a . In the total synthesis of natural products. Lett. 1988, 29, 4563; b) S. Takano, T. Sato, K. case of unprotected indole 25, cyclization In a broader sense, our method allowed Inomata, K. Ogasawara, J. Chem. Soc. Chem. on either C(3) or N(1) could be again ob- access to iminiums under mild conditions Commun. 1991, 462; c) G. Lewin, C. Schaeffer, tained in dependence on the choice of cata- based on the release of ring and Nat. Prod. Lett. 1995, 7, 227; d) G. Lewin, C. Schaeffer, P. H. Lambert, J. Org. Chem. lyst. Oxycyclopropane 26 gave N(1) cycli- cross polarization. When considering the 1995, 60, 3282; e) G. Lewin, C. Schaeffer, R. zation product 33 exclusively, but required utility of such reactive intermediate in the Hocquemiller, E. Jacoby, S. Leonce, A. Pierre, the use of a stronger Lewis acid. synthesis of complex structure, the formal G. Atassi, Heterocycles 2000, 53, 2353; f) C. L. homo-Nazarov cyclization is expected to Morales, B. L. Pagenkopf, Org. Lett. 2008, 10, 157; g) M. Mizutani, F. Inagaki, T. Nakanishi, be broadly applicable for the synthesis of C. Yanagihara, I. Tamai, C. Mukai, Org. Lett. Conclusion other natural and synthetic bioactive com- 2011, 13, 1796. pounds. Moreover, the development of [10] F. De Simone, J. Gertsch, J. Waser, Synlett In conclusion, we have developed the an asymmetric cyclopropanation method 2011, 589. first catalytic formal homo-Nazarov re- would allow an asymmetric entry into im- [11] F. De Simone, J. Gertsch, J. Waser, Angew. Chem. Int. Ed. 2010, 49, 5767. action and discovered also other types of portant building blocks for the synthesis of [12] F. De Simone, T. Saget, F. Benfatti, S. Almeida, cyclizations for donor–acceptor activated natural products. J. Waser, Chem. Eur J. 2011, 17, 14527. cyclopropanes. The versatility of our meth- The principle of cyclopropane activa- [13] a) F. De Nanteuil, J. Waser, Angew. Chem., odology has been showcased through sev- tion discovered in this project are certainly Int. Ed. 2011, 50, 12075. b) F. Benfatti, F. De Nanteuil, J. Waser, Org. Lett. 2012, 14, 386.