Strain-Release Rearrangement of N-Vinyl-2-Arylaziridines. Total Synthesis of the Anti-Leukemia Alkaloid (–)-Deoxyharringtonine

doi:10.1021/ja063304f

J Am Chem Soc. Author manuscript; available in PMC 2008 December 27.

Published in final edited form as:

J Am Chem Soc. 2006 August 16; 128(32): 10370–10371.

doi: 10.1021/ja063304f

PMCID: PMC2610334

NIHMSID: NIHMS82036

Strain-Release Rearrangement of N-Vinyl-2-Arylaziridines. Total Synthesis of the Anti-Leukemia Alkaloid (–)-Deoxyharringtonine

Joseph D. Eckelbarger, Jeremy T. Wilmot, and David Y. Gin^†

Department of Chemistry, University of Illinois, Urbana, Illinois 61801

^† Address correspondence to Department of Molecular Pharmacology and Chemistry, The Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail: gind/at/mskcc.org

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The cephalotaxus esters constitute a family of remarkably potent anti-leukemia alkaloids from the Cephalotaxus genus.¹ Several of these alkaloids, including deoxyharringtonine (1, Chart 1), exhibit acute toxicity toward P388 and L1210 leukemia cells with IC₅₀ values in the ng/mL range.¹ The bulk of the multistep synthetic efforts toward these targets have involved innovative routes to cephalotaxine (2),² the most abundant constituent of this family of alkaloids. However, 2, itself, is biologically inactive, and the difficulties associated with acylation of its hindered C3-hydroxyl with sterically demanding carboxyl derivatives, such as that in 1, have been noted.¹^,³ We report the total synthesis of (–)-deoxyharringtonine (1), employing novel synthetic strategies not only for the preparation of the [3]benzazepine and the spiro-fused pyrrolidine substructures present in cephalotaxine (2), but also for hindered acyl chain synthesis and attachment to 2 for efficient access to the biologically relevant and rare cephalotaxus esters.⁴

Chart 1

Strain-release [3,3]-rearrangements of N-aryl-2-vinylaziridines to generate [1]benzazepines are documented;⁵ however, to our knowledge, successful [3,3]-rearrangements of N-vinyl-2-arylaziridines to form [3]benzazepines, such as that present in 2, have not been reported. The feasibility of this reaction was assessed in a model investigation (Scheme 1) commencing with the conversion of 3,4-methylenedioxyacetophenone (3) to aziridine 4 via the sequential steps of oxime formation (HONH₃Cl, NaOH, 87%) and reductive Neber rearrangement (LiAlH₄, HN(CHMe₂)₂, 88%).⁶ Treatment of aziridine 4 with 3-chloro-2-cyclopentenone under basic conditions afforded the benzylic chloride 5 (64%), likely the result of conjugate addition–elimination followed by chloride-mediated aziridine opening. The key N-aryl-2-vinylaziridine was regenerated in situ (Cs₂CO₃, 1,4-dioxane) and underwent sequential thermal rearrangement (100 °C, 6 → 7)⁷ and tautomerization to provide 8 (67%), an achiral version of the tetracyclic fragment within 2.

Scheme 1 ^a

^a Reagents and conditions: (a) HONH₃Cl, NaOH, EtOH, H₂O, 80 °C, 87%; (b) LiAlH₄, HN(CHMe₂)₂, THF, 60 °C, 88%; (c) 3-chloro-2-cyclopentenone, Et₃N, THF, 60 °C, 64%; (d) Cs₂CO₃, 1,4-dioxane, 100 °C, 67%.

The establishment of this convergent approach to [3]benzazepine construction permitted its application to the synthesis of (–)-cephalotaxine (2, Scheme 2). Introduction of the β-chloro substituent on (S,S)-4,5-dihydroxycyclopent-2-enone isopropylidene acetal (9)⁸ was accomplished in a four-step sequence involving (1) Luche reduction of the enone to afford the (R)-allylic alcohol, (2) chloroselenenylation of the alkene (73%, two steps), (3) selenide oxidation–elimination to generate the corresponding vinyl chloride (91%), and (4) Dess-Martin periodinane (DMP) oxidation of the allylic alcohol to provide the β-chloroenone 10 (98%). Conjugate addition–elimination of 10 with racemic aziridine 4 provided N-vinyl-2-arylaziridine 11 (85%) as a 1:1 mixture of benzylic diastereomers. Smooth [3,3]-rearrangement of the epimeric aziridines 11 ensued upon thermal activation (100 °C) to provide [3]-benzazepine 12 (76%),⁹ the nonracemic tetracyclic core of (–)-2.

Scheme 2 ^a

^a Reagents and conditions: (a) NaBH₄, CeCl₃, MeOH, 23 °C; (b) PhSeCl, CH₂Cl₂, 23 °C, 73% (2 steps); (c) m-CPBA, CH₂Cl₂, 23 °C; Et₃N, 40 °C, 91%; (d) DMP, THF, 23 °C, 98%; (e) 4, Et₃N, THF, 23 °C, 85%; (f) (more ...)

The vinylogous amide group in 12 allowed for application of a variant of our recently disclosed approach to pyrrolidine construction from tertiary vinylogous amide precursors.¹⁰ Thus, [3]benzazepine 12 was N-alkylated with Me₃SiCH₂I (75%) to generate the tertiary vinylogous amide 13, which permitted selective carbonyl O-acylation (pivaloyl triflate) followed by C-desilylation (TBAT)¹¹ to produce the transient nonstabilized azomethine ylide 14. The presence of PhSO₂CH=CH₂ led to stereo- and regioselective dipolar cycloaddition to form the spiro-pyrrolidine 15 (77%). Notably, X-ray analysis of 15 confirmed that the cycloaddition proceeded via an apparent contra-steric face-selective approach of the dipolarophile onto ylide 14, leading to the required C5 R configuration.¹²

Further functional group interconversions in the synthesis of (–)-2 involved SmI₂-mediated reductive desulfonylation (74%)¹³ and exchange of the C3 enol ester in 15 to its enol benzyl carbonate counterpart 16 (85%, two steps). Manipulation of the C1–C2 oxidation states in 16 was then accomplished by isopropylidene removal followed by sequential Yb(OTf)₃-mediated selective C1-O-acylation (Boc₂O)¹⁴ and C2 oxidation (IBX) to form the corresponding C2 ketone (50%, two steps). Subsequent C1 deoxygenation (CrCl₂) and benzyl carbonate hydrogenolysis provided the enol 17 (42%, two steps), which allowed for its two-step conversion to (–)-(2) via C2 enol ether formation (55%) and stereoselective C3 reduction (95%).^2h

Incorporation of preformed acyl chains of bioactive cephalotaxus esters onto 2 has proven to be challenging on two fronts. Typically, protracted synthetic routes to these chiral acyl fragments are required,¹⁵ and their direct attachment to the C3–OH of 2 is often inefficient, if not prohibitive.³^,¹⁶ Thus, a short nonracemic synthesis of the acyl chain of (–)-1 was developed (Scheme 3), commencing with acetal derivatization of d-malic acid (18) with Me₃CHO to afford [1,3]dioxolanone 19 (82%).¹⁷ The C2′ stereocenter in the acyl chain was established via double deprotonation of 19 followed by diastereoselective C2′ alkylation¹⁸ with prenyl bromide to provide the corresponding C2′-R-[1,3]dioxolanone (66%). Transesterification with acetal removal (BnOH) then provided the tertiary alcohol 20 (88%). The hydroxy acid 20 was cyclized via the Yamaguchi anhydride¹⁹ to provide the β-lactone, allowing for alkene hydrogenation and benzyl ester hydrogenolysis to yield the carboxylic acid 21 (99%). Activation of 21 with 2,4,6-Cl₃C₆H₂COCl¹⁹ proceeded without rupture of the β-lactone, allowing for acylation of 2 to afford ester 22 (81%). Methanolysis of the β-lactone in 22 concluded the synthesis of (–)-deoxyharringtonine (1, 76%).

Scheme 3 ^a

^a Reagents and conditions: (a) TMSCl, TMS₂NH, CH₂Cl₂, 23 °C; Me₃CCHO, Me₃SiOTf, CH₂Cl₂, −25 °C, 82%; (b) LHMDS, Me₂C=CHCH₂Br, THF, −78 °C, 66%; (c) NaH, BnOH, THF, 0 °C; 88%; (d) 2,4,6-Cl₃C₆H₂COCl, DMAP, (more ...)

The relative ease with which cephalotaxine (2) is acylated by the β-lactone 21 highlights this approach for the synthesis of the anti-leukemia cephalotaxus esters. This, in conjunction with novel strategies for N-heterocycle synthesis that include the rearrangement of an N-vinyl-2-arylaziridine and a vinylogous amide acylation–cycloaddition cascade, should allow rapid access to other related structures of potential therapeutic utility.

Supplementary Material

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Acknowledgments

This research was supported by the NIH-NIGMS (GM67659), Merck, Pfizer, Eli Lilly, and Abbott. A Procter & Gamble graduate fellowship to J.D.E. is acknowledged.

References

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