Strain-release rearrangement of N-vinyl-2-arylaziridines. Total synthesis of the anti-leukemia alkaloid (-)-deoxyharringtonine

Article abstract of DOI:10.1021/ja063304f

Deoxyharringtonine (1) is among the most potent of the anti-leukemia alkaloids isolated from the Cephalotaxus genus. A convergent total synthesis of (-)-1 is reported, involving novel synthetic methods and strategies that include (1) the strain-release rearrangement of N-aryl-2-vinylaziridines for [3]benzazepine synthesis, (2) a vinylogous amide acylation-cycloaddition cascade for spiro-pyrrolidine construction, and (3) efficient acylation of the cephalotaxine core by α-(β-lactone)carboxylic acid derivatives to access the biologically active cephalotaxus esters. These innovations should allow rapid access not only to other Cephalotaxus alkaloids but also to non-natural analogues of potential therapeutic utility. Copyright

Full text of DOI:10.1021/ja063304f

Published on Web 07/20/2006
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
Received May 11, 2006; E-mail: gind@mskcc.org
Chart 1
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
Scheme 1 a
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 (-)-deoxyhar-
ringtonine (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
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-arylaziri-
dines 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
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%.
tion from tertiary vinylogous amide precursors.10 Thus, [3]benza-
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 f 7)7 and tautomerization to provide 8
(67%), an achiral version of the tetracyclic fragment within 2.
The establishment of this convergent approach to [3]benzazepine
construction permitted its application to the synthesis of (-)-
cephalotaxine (2, Scheme 2). Introduction of the â-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 â-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 aziri-
dines 11 ensued upon thermal activation (100 °C) to provide [3]-
benzazepine 12 (76%),9 the nonracemic tetracyclic core of (-)-2.
The vinylogous amide group in 12 allowed for application of a
variant of our recently disclosed approach to pyrrolidine construc-
zepine 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 PhSO2CHdCH2 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 di-
polarophile onto ylide 14, leading to the required C5 R configu-
ration.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 deoxy-
genation (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
† 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.
9
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J. AM. CHEM. SOC. 2006, 128, 10370-10371
10.1021/ja063304f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
hydrogenation and benzyl ester hydrogenolysis to yield the car-
boxylic acid 21 (99%). Activation of 21 with 2,4,6-Cl3C6H2COCl19
proceeded without rupture of the â-lactone, allowing for acylation
of 2 to afford ester 22 (81%). Methanolysis of the â-lactone in 22
concluded the synthesis of (-)-deoxyharringtonine (1, 76%).
The relative ease with which cephalotaxine (2) is acylated by
the â-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.
Acknowledgment. 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.
Supporting Information Available: Experimental details (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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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%). Trans-
esterification with acetal removal (BnOH) then provided the tertiary
alcohol 20 (88%). The hydroxy acid 20 was cyclized via the
Yamaguchi anhydride19 to provide the â-lactone, allowing for alkene
JA063304F
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