Memory of Chirality in Bromoalkyne Carbocyclization: Applications in

Letter Cite This: Org. Lett. 2019, 21, 292−295

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Memory of Chirality in Bromoalkyne Carbocyclization: Applications in Asymmetric Total Synthesis of Hasubanan Alkaloids Shenpeng Tan, Feng Li, Soojun Park, and Sanghee Kim* College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea

Org. Lett. 2019.21:292-295. Downloaded from pubs.acs.org by TULANE UNIV on 01/11/19. For personal use only.

S Supporting Information *

ABSTRACT: A transition-metal-free 5-exo-dig asymmetric cyclization of α-amino ester enolates onto bromoalkynes provided a product with excellent enantioselectivity via the memory of chirality concept. This strategy was applied to a concise total synthesis of (−)-runanine and a formal synthesis of (−)-8-demethoxyrunanine and (−)-cepharatine D.

T

he hasubanan alkaloids are a class of natural products sharing an aza[4.4.3]propellane core (Figure 1).1 More

Figure 2. Our previous application of memory of chirality. Figure 1. Representative hasubanan alkaloids.

could be obtained from the Cα-substituted proline 5 having an exocyclic alkene through a Friedel−Craft-type reaction (Scheme 1). Applying the MOC concept, we identified a conceivable asymmetric route for the synthesis of this cyclic amino ester 5 from the acyclic amino ester 7. This envisioned route involved carbocyclization of the axially chiral α-amino ester enolate 6 onto the pendant alkyne functionality.

than 40 members of this family have been reported to date. The primary synthetic challenge posed by these alkaloids is the construction of the tetracyclic framework having an α-tertiary amine moiety. Since hasubanonine (1) and its related metabolites were first synthesized in racemic form in the 1970s, numerous total and formal syntheses of hasubanan alkaloids have been reported.2,3 The first enantioselective total synthesis of a hasubanan alkaloid, (+)-cepharamine (3), was achieved in 1998 by the Schultz group utilizing the Birch alkylation of a chiral benzamide.4 In 2011, the Herzon group developed the efficient asymmetric entry to several hasubanan alkaloids including 1 and 2, employing a Corey’s CBScatalyzed enantioselective Diels−Alder reaction.5 In the same year, the Reisman group reported enantioselective total synthesis of (−)-8-demethoxyrunanine (4) using N-tertbutanesulfinamde chiral auxiliary for the asymmetric installation of α-tertiary amine moiety.6 As a part of our research program on the application of “memory of chirality” (MOC) to the asymmetric total synthesis of natural products,7 we have utilized the intramolecular aldol reaction (Figure 2, eq 1) and Michael addition (eq 2) of proline ester enolates to afford the bicyclic products with the correct stereochemical configurations required to proceed to the natural products. In this study, we envisioned that diverse structures of the hasubanan family of alkaloids © 2018 American Chemical Society

Scheme 1. Retrosynthetic Plan for Hasubanan Alkaloids

Received: November 22, 2018 Published: December 14, 2018 292

DOI: 10.1021/acs.orglett.8b03740 Org. Lett. 2019, 21, 292−295

Letter

Organic Letters

notable racemization (see the Supporting Information). We first examined the typical strong bases used for α-amino ester enolate generation, such as NaH, and KHMDS (entries 1 and 2). No desired reaction occurred with these bases. After other bases and conditions were screened, a promising result was obtained with a tert-butoxide base. When substrate 8a was treated with powdered KOtBu at 0 °C in DMF, the desired cyclized product 9a was rapidly (5 min) produced in 78% yield (entry 3). This reaction was stereoselective, and only the Zisomer was observed. Chiral HPLC analysis revealed, to our delight, that the enantiomeric excess of product 9a was 93%. This result indicated that MOC was well exerted during the reaction. The absolute stereochemistry of 9a, later confirmed by X-ray crystallography, indicated the retention of configuration at the α-carbon atom of the starting material.16 DMF was found to be the most suitable solvent among the various solvents studied. The reaction in other solvents was relatively slow, and the enantiomeric purity of the product was relatively low (entries 4 and 5). The reaction also occurred when NaOtBu was used. However, the reaction rate was slower than that with KOtBu, and the ee value of the product was lower (entries 6 vs 3). When using less basic LiOtBu, the reaction was considerably slower, and a large excess of base was required to complete the reaction. In this case, the product was obtained in only moderate yield (48%) and ee value (61%) (entry 7). The effect of the nitrogen protecting group on the enantioselectivity was briefly examined. Under the reaction conditions of KOtBu at 0 °C in DMF, the substrate 8b with a bulky Boc group underwent the reaction smoothly to furnish the cyclized product 9b in 81% yield with an excellent ee of 98% (entry 8), higher than that of substrate 8a with a benzoyl protecting group. Another widely used carbamate protecting group, the Cbz group, also gave product 9c with an excellent ee of 97% (entry 9). With the successful results of the asymmetric bromoalkyne carbocyclization, we returned to the total synthesis of hasubanan alkaloids. From the large number of members of this family, we first chose (−)-runanine (2)17 as a target for total synthesis. To date, there has been only one reported total synthesis strategy for 2.5 Our total synthesis of (−)-2 as shown in Scheme 2 began with the commercially available (R)-3,4dimethoxy-homophenylalanine (10, 98% ee). After esterification of the carboxyl group, the α-amino group was condensed with 2,4-dinitrobenzenesulfonyl (DNs) chloride to afford intermediate 11, which was a substrate for Fukuyama− Mitsunobu alkylation.18 The introduction of a homopropargyl group was achieved using Mitsunobu conditions with 4bromo-3-butyn-1-ol. A one-pot direct conversion of N-DNs to N-Boc was realized under mild conditions using thioglycolic acid, DIPEA, and Boc2O. The enantiomeric purity of the obtained MOC substrate 12 with N-Boc protecting group was 97% from chiral HPLC analysis. Subjecting 12 to the abovementioned carbocyclization conditions furnished the Cαfunctionalized proline 13 with 95% ee in a 79% yield. The degree of chirality preservation was excellent (98%). Removal of the Boc group and subsequent reductive amination with formaldehyde were accomplished in a one-pot fashion to provide N-methylated product 14 in high yield. For construction of the cyclohexenone ring of 2, we planned to use a Dieckmann-type condensation. To this end, we first focused on accessing the Dieckmann precursor 16 from 14 via a cross-coupling reaction of an exocyclic bromoalkene group

Several types of electrophilic groups have been shown to react with α-amino ester enolates via an MOC-based mechanism.8,9 However, although alkynes are versatile functional groups in organic synthesis,10 the use of alkynes as electrophilic partners for MOC reactions remains unexplored. Thus, we investigated the feasibility of alkyne MOC carbocyclization of α-amino ester enolates before total synthesis. In this Letter, we report the transition-metal-free asymmetric MOC cyclization of α-amino ester enolates onto bromoalkynes and the application of this reaction for the expedient total synthesis of hasubanan alkaloids. From the outset, we were aware that our envisioned MOC reaction would face some challenges. Previous examples of alkyne carbocyclization using a monocarbonyl enolate as the nucleophile are rare.11 In addition, the envisioned carbocyclization, similar to Conia-ene-related reactions, would be an unfavorable endothermic process because the initial enolate anion will be converted to a less stable vinyl carbanion. In Conia-ene-type reactions, this unfavorable thermodynamic profile was overcome in some cases by the application of Lewis acidic metals.12 However, this strategy is applicable only to substrates with β-dicarbonyl scaffolds. Haloalkynes are versatile functional groups with high reactivity.13 Because of the presence of a halogen atom, haloalkynes are more electrophilic in nature than alkynes and produce more stabilized vinyl carbanions after nucleophilic additions. The resulting vinyl halides are also versatile functional groups and can be employed for various crosscoupling reactions.14 Thus, instead of arduously searching for suitable reaction conditions for terminal or internal alkyne carbocyclization, we decided to employ haloalkynes as electrophilic partners for the envisioned MOC reaction. The feasibility of haloalkyne MOC carbocyclization was initially investigated with the model substrate 8a (Table 1). Table 1. Bromoalkyne MOC Carbocyclizationa

entry 1 2 3 4 5 6 7d 8e 9

8a 8a 8a 8a 8a 8a 8a 8b 8c

base

solvent

t (°C)

time (h)

yieldb (%)

eec (%)

NaH KHMDS KOtBu KOtBu KOtBu NaOtBu LiOtBu KOtBu KOtBu

THF THF DMF THF CH2Cl2 DMF DMF DMF DMF

66 −78 0 0 0 0 0 0 0

12 5 5 min 2 5 1.5 24 5 min 5 min

78 58 31 63 48 81 78

93 26 25 86 61 98 97

a

Reaction conditions: 8 (0.1 mmol) and base (1.5 equiv) in solvent (0.02 M). bIsolated yield. cThe ee values were determined by chiral HPLC. dLiOtBu (8.0 equiv) was used. eKOtBu (2.0 equiv) was used.

Although the Boc group is reported to be superior in the generation of dynamic axial chirality of amino ester enolates,9b,15 a benzoyl group was used as the protecting group on the nitrogen to avoid complications in determination of the enantioselectivity of the reaction. Substrate 8a (>99% ee) was prepared from L-alanine ester in three steps without 293

DOI: 10.1021/acs.orglett.8b03740 Org. Lett. 2019, 21, 292−295

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Organic Letters Scheme 2. Total Synthesis of (−)-Runanine (2)

Scheme 3. Formal Synthesis of (−)-8-Demethoxyrunanine (4) and (−)-Cepharatine D (21)

previously reported as the penultimate intermediate for the total synthesis of 4 and 21. In conclusion, identification of 5-exo-dig asymmetric cyclization of α-amino ester enolates onto bromoalkynes via memory of chirality provides an efficient route for total synthesis of hasubanan alkaloids. The enantioselective synthesis of (−)-runanine was achieved in only nine steps from the commercially available amino acid 10. This synthetic route also provided facile access to other hasubanan alkaloids, namely, (−)-8-demethoxyrunanine and its structurally related alkaloid (−)-cepharatine D. The mechanism and full scope of this MOC reaction and further application for the synthesis of other alkaloids are under investigation and will be reported in due course.

with an appropriate organometallic partner. However, these attempts were unsuccessful, possibly because of the steric hindrance imposed by the nearby quaternary center. To circumvent this problem, the bromoalkene group was first converted to stannyl alkene 15. The obtained 15 was coupled under Stille conditions with methoxyacetyl chloride to give exocyclic enone 16 in a modest overall yield. Before Dieckmann condensation, a Michael-type Friedel− Crafts reaction19 was performed using TfOH to yield 17 as the only regioisomer. A base-promoted Dieckmann ring closure of 17 yielded the tetracyclic system followed by etherification of a 1,3-diketone intermediate with TMS-diazomethane gave runanine (2) along with a minor amount of its regioisomer 2′ in a ratio of 2:1. We tentatively attribute this regioselectivity to the higher nucleophilicity of the C-8 oxygen compared to the C-6 oxygen based on the Fukui function calculations (see the Supporting Information for details). The regioisomer 2′ could be recycled by acid hydrolysis to give a 1,3-diketone intermediate, which was subjected again to the above etherification conditions. The spectral and optical rotation data for the synthetic (−)-runanine (2) were consistent with reported data.5,17 The Cα-functionalized proline 15 with exocyclic stannyl alkene was also useful for synthesis of other hasubanan and related alkaloids, such as (−)-8-demethoxyrunanine (4) and cepharatine D (21).20 Stille cross-coupling of 15 with acetyl chloride afforded enone 18 in a 70% yield (Scheme 3). The tetracyclic system was constructed via the above two-step sequence comprising acid-promoted Friedel−Crafts and basepromoted Dieckmann ring closure. Regioselective enol etherification of a crude 1,3-diketone intermediate with TiCl4 in methanol21 to give 19 followed by application of Stork− Danheiser enone synthesis22 delivered 20, which was

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03740. Experimental procedures and copies of spectra (PDF) Accession Codes

CCDC 1870763 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: + 44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sanghee Kim: 0000-0001-9125-9541 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Mid-Career Researcher Program (Grant NRF-2016R1A2A1A05005375) of the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP). 294

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(e) Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704. (15) Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J. Am. Chem. Soc. 1994, 116, 10809. (16) See the Supporting Information for details. (17) Zhi-Da, M.; Ge, L.; Guang-Xi, X.; Iinuma, M.; Tanaka, T.; Mizuno, M. Phytochemistry 1985, 24, 3084. (18) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. (b) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (19) Selected examples for the Michael-type Friedel−Crafts reaction: (a) Grundl, M. A.; Kaster, A.; Beaulieu, E. D.; Trauner, D. Org. Lett. 2006, 8, 5429. (b) Li, W.-D. Z.; Wang, X.-W. Org. Lett. 2007, 9, 1211. See also refs 5 and 6. (20) (a) Tomita, M.; Kozuka, M. Tetrahedron Lett. 1966, 7, 6229. (b) Wang, X.; Jin, H.; Li, Z.; Qin, G. Fitoterapia 2007, 78, 593. (21) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 2001, 57, 217. (22) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775.

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DOI: 10.1021/acs.orglett.8b03740 Org. Lett. 2019, 21, 292−295