of deoxyharringtonine (2).[12] By contrast, cephalotaxine (1)
itself was found to be biologically inactive.[13] The cytotoxic
properties of the Cephalotaxus esters arise from reversible
inhibition of protein synthesis[14] via induction of rapid
breakdown of the polyribosome, with concomitant release
of the polypeptide chain.[15] The remarkable antileukemia
activity of several Cephalotaxus esters spawned intense in-
vestigations into their therapeutic potential. Clinical studies
were first performed in the mid-1970s in China, where the
seeds of Cephalotaxus plants had long been used in tradi-
tional medicine. These results prompted Phase I clinical
evaluation of homoharringtonine (3) in the US in 1981,[16]
advancing to more recent phase II studies.[17] While difficul-
ties in production, coupled with its hematologic toxicity and
susceptibility to multidrug resistance (MDR),[18] have hin-
dered the development of 3, it is still viewed as a useful
drug for the treatment of chronic myeloid leukemia in com-
bination therapy.[17]
lidine core via 1,3-dipolar cycloaddition of azomethine
ylides derived from vinylogous amides; and 4) synthesis of
strained variants of advanced side chain intermediates to fa-
cilitate late-stage cephalotaxine acylation. Notably, the latter
three elements had not been applied to complex natural
product synthesis, yet ultimately played critical roles in the
non-racemic syntheses of the Cephalotaxus esters 2–5.
The success of these synthetic endeavors enabled exten-
sive cytotoxicity evaluation of several advanced natural and
non-natural compounds with an array of well established
human hematopoietic and solid tumor cell lines. Potent cyto-
toxicity was observed in several cell lines previously not
challenged with these alkaloids. Moreover, comparative cy-
totoxicity assays reveal the potential of synthetic structural
modification of this family of alkaloids to modulate suscepti-
bility to multi-drug resistance.
Cephalotaxine (1) has received considerable and enduring
attention in the arena of total synthesis. Several elegant syn-
theses of 1 have been reported over the past three decades.
The racemic approaches have embodied several key trans-
formations, including Nazarov cyclization,[19] photo-stimulat-
ed SRN1 cyclization,[20] Claisen rearrangement,[21,22] oxidative
ring contraction,[23] acylnitroso Diels–Alder cycloaddi-
tion,[24,25] transannular N-conjugate addition,[26,27] intramolec-
ular alkyne hydroamination,[28] and reductive ring expansion
of tetrahydrosioquinoline intermediates.[29,30] Non-racemic
routes have featured electrophilic aromatic substitution,[31]
Heck arylation,[32,33] Pummerer-electrophilic aromatic substi-
tution cascade,[34–36] and acid catalyzed ring expansion of cy-
clobutanol derivatives.[37]
On the other hand, the significance of the complex Ceph-
alotaxus esters (e.g., 2–5) extends beyond that of 1 on sever-
al levels, the most prominent being their exceedingly potent
antiproliferative properties. Moreover, the scarcity of these
complex ester derivatives from the natural source is far
more pronounced than that of 1; complex Cephalotaxus
esters are typically attainable in only <0.1% of the plant
dry weight. Thus, a principal goal in the work described
herein was the establishment of a synthetic approach to the
bioactive Cephalotaxus esters by a route completely distinct
from previous efforts.[38] Several key elements in the synthet-
Results andDiscussion
Dihydro[3]benzazepine construction via strain-release rear-
rangement: The first challenge addressed in the synthesis of
cephalotaxine (1) focused on construction of its seven-mem-
bered N-heterocycle. Strain-release [3,3]-sigmatropic rear-
rangements, in which a high energy three-membered ring is
incorporated into the 1,5-diene system of the substrate, have
been widely used for the construction of seven-membered
rings. Although the all-carbon divinyl cyclopropane rear-
rangement has received the most attention, the heterocyclic
epoxide-, thiirane-, and aziridine-containing variants are
also documented.[39] However, the aziridine-to-azepine ver-
sion of this transformation[40–46] has only been sporadically
used in target-directed synthesis. In this context, adaptation
to the synthesis of benzazepines and heterocyclic variants
thereof have focused on N-aryl-2-vinyl aziridines to form di-
hydro[1]benzazepines.[47–49]
However, the [3,3]-sigmatropic rearrangement of N-vinyl-
2-aryl aziridines to form dihydro[3]benzazepines, such as
that present in 1, had not been reported. Thus, investigations
into this reaction commenced with the synthesis of a few N-
vinyl-2-aryl aziridines (Scheme 1) via the condensation of
acetophenone derivatives 7/8/9 with hydroxylamine hydro-
chloride to provide the corresponding oximes (10/11/12) in
high yields (95/95/87%, respectively).[50] Each of these
oximes was exposed to LiAlH4 and iPr2NH at elevated tem-
peratures to induce reductive Neber rearrangement,[51] fur-
nishing the corresponding aziridines (13/14/15) in good
yields (76/74/88%), and providing a series of substituted 2-
aryl aziridines available for N-vinylation. This was most con-
veniently accomplished via addition-elimination with the
readily available alkene electrophile 3-chloro-2-cyclopente-
none (16), prepared in one step from the reaction of 1,3-cy-
clopentanedione with oxalyl chloride.[52] Condensation of
the two substrates 13 and 16 with expulsion of HCl provided
the vinyl aziridine 17 in moderate yield (58%). By compari-
son, coupling of aziridine 14 or 15 with chloroenone 16 pro-
ceeded with significantly diminished efficiency, resulting in
Figure 2.
ic strategy include (6, Figure 2): 1) introduction of the nitro-
gen atom via Neber rearrangement; 2) construction of the
benzazepine core via the strain-release rearrangement of N-
vinyl-2-aryl aziridines; 3) assembly of the spiro-fused pyrro-
4294
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4293 – 4306