A stereoselective intramolecular Diels-Alder strategy for the tricyclo[9.3.1.03,8]pentadecane core of aromatic C-ring taxanes

Article abstract of DOI:10.1016/S0040-4039(03)01120-1

A stereoselective Lewis acid-catalyzed and chelation controlled intramolecular Diels-Alder entry into the tricyclo[9.3.1.0^3,8]pentadecane core of aromatic C-ring taxanes is described. The approach affords an efficient, high yield, access to aromatic C-ring taxanes variably functionalized at the C2, C4, C5, and C9 positions.

Full text of DOI:10.1016/S0040-4039(03)01120-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5129–5132
A stereoselective intramolecular Diels–Alder strategy for the
tricyclo[9.3.1.03,8]pentadecane core of aromatic C-ring taxanes
David V. Smil, Alain Laurent,† Nidejda S. Spassova‡ and Alex G. Fallis*
Centre for Research in Biopharmaceuticals, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario,
Canada K1N 6N5
Received 28 January 2003; accepted 22 April 2003
Abstract—A stereoselective Lewis acid-catalyzed and chelation controlled intramolecular Diels–Alder entry into the tri-
cyclo[9.3.1.03,8]pentadecane core of aromatic C-ring taxanes is described. The approach affords an efficient, high yield, access to
aromatic C-ring taxanes variably functionalized at the C2, C4, C5, and C9 positions. © 2003 Elsevier Science Ltd. All rights
reserved.
Paclitaxel 1 (Taxol®), Docetaxel 2 (Taxotere®) (Fig. 1)
and related taxane diterpenoids continue to elicit interna-
tional attention. This is a consequence of their proven
chemotherapeutic utility and their attraction as challeng-
ing synthetic targets.1 Six total syntheses of Taxol® have
been reported.2 Novel strategies continue to be developed
for construction of the unique taxane tricyclo[9.3.1.03,8]-
pentadecane nucleus, and the synthesis of structurally
simplified analogs. Consequently methods for the rapid
assembly of the core structure for the eventual prepara-
tion of improved therapeutic analogues are still required.
Despite the diminished cytotoxicity of aromatic C-ring
taxanes such as those prepared by Nicolaou (3a–c)3 and
Danishefsky (4a–b),4 structures in this class remain
attractive candidates for synthesis. In particular, the
multi-drug resistance (MDR) reversing activity of an
aromatic C-ring taxane observed by Kuwajima (5)5
warrants further study, and aromatic C-ring taxane
scaffolds with judiciously selected substituents posi-
tioned to accommodate current taxoid structure–activ-
ity relationship (SAR) data may show cyctotoxic
activity.6
Figure 1. Taxol®/Taxoetere® and biologically significant aromatic C-ring taxanes.
Keywords: taxanes; intramolecular Diels–Alder; Lewis acid; stereoselective.
* Corresponding author. Tel.: (613) 562-5732; fax: (613) 562-5170; e-mail: afallis@science.uottawa.ca
† Present Address: Delmar Chemicals Inc., 9321 Airlie St., 810 LaSalle, Quebec, Canada H8R 2B2.
‡ Present Address: Aegera Therapeutics, Inc., 810 Chemin du Golf, Ile-des-Soeurs, Quebec, Canada H3E 1A8.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01120-1

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D. V. Smil et al. / Tetrahedron Letters 44 (2003) 5129–5132
Several groups have reported the preparation of differ-
entially substituted aromatic C-ring taxanes as sim-
plified targets to demonstrate various B-ring
construction methods and subsequent functional group
manipulation.7 Shea8 and Malacria9 have described
efficient type II intramolecular Diels–Alder (IMDA)10
strategies to the AB-ring system. However, these routes
afford aromatic C-ring taxanes that are not readily
amenable for the introduction of therapeutically mean-
ingful substituents after ABC-ring assembly. We have
developed an extension of our ongoing taxane
research,11 that utilizes a concise AB-ring cycloaddition
protocol12 to highly oxygenated aromatic C-ring
taxanes.
oxygen, and to incorporate the requisite C4 and C5
oxygens into aryl bromide D (Scheme 1). It was antici-
pated, that addition of bromide D to C and subsequent
elaboration to triene B, would permit the Lewis acid
catalyzed and chelation controlled IMDA closure of the
AB-ring system to afford the aromatic C-ring taxane A
as a single diastereomer.
Diene aldehyde 6 (i.e. C) was readily prepared in multi-
gram quantities, and 45% overall yield as previously
reported from 2,3-dimethyl-2-butene (four steps,
45%).11 An established sequence (four steps, 86%)
afforded bromobenzaldehyde
9 from o-vanillin 7
(Scheme 2).14 The initial bromination of benzaldehyde 8
yielded 9, and acetate cleavage afforded bromophenol
10.
SAR data for Taxol® have established that the C2
benzoate and C4 acetate on the molecule’s ‘southern’
perimeter are crucial for activity. In contrast, the
‘northern’ perimeter substituents C7 hydroxyl and C10
acetate can be omitted without compromising efficacy.1
Although not essential, the C9 hydroxyl increases activ-
ity slightly, and acts as a handle for resolvable
derivatives3a or solubilizing groups.13 In addition,
Snyder suggested the C4ꢀC5 oxetane ring is not obliga-
tory but a replacement hydrogen bond acceptor is
desirable. In addition, the ‘structural stiffness’ imparted
in benzannulated skeletons is beneficial to ‘maintain
Taxol®-like protein polymerization activity’.6a
Protection of bromophenol 10 as its benzyl ether 11
was selected to allow the eventual facile deprotection
via hydrogenolysis following AB-ring closure to the
aromatic C-ring taxane core.2 Reduction of bromobenz-
aldehyde 11 gave the bromobenzyl alcohol 12b, which
was quantitatively protected as its triisopropylsilyl ether
to furnish aryl bromide 13b. The aryl bromide 13a was
prepared separately from 2-bromobenzyl alcohol 12a.
In order to establish the optimal conditions, the entire
synthetic sequence leading to the formation of aromatic
C-ring taxane 18a was performed initially with aryl
bromide 13a, and then repeated with aryl bromide 13b
to generate the aromatic C-ring taxane 18b (Scheme 3).
Lithium–halogen exchange enabled coupling of aryl
bromides 13a/b with diene aldehyde 6 (C, Scheme 1).
The resulting alcohols (not illustrated) were methylated
to provide intermediates 14a/b. Attempts to obtain
trienes 17a/b directly by coupling the diene aldehyde 6
Despite the elegance of previous syntheses, the diene
and aromatic C-ring components selected do not easily
allow installation of the critical substituents (or poten-
tial mimics) at the C4, C5, and C9 positions. In order
to address this deficiency and retain the advantage of
rapid cycloaddition AB-ring assembly, we elected to
employ diene aldehyde C as a source of the future C9
Scheme 1. Retrosynthetic strategy for differentially substituted aromatic C-ring taxanes
Scheme 2. Reagents and conditions: (a) Ac2O, DMAP (cat.), Et3N, CH2Cl2, rt, 2 h, 95%; (b) KBr, Br2, H2O, rt (22°C), 10 h, 98%;
(c) NaHCO3, MeOH/H2O (2:1), rt, 5 h, 96%; (d) BnCl, MeOH, K2CO3, 65°C, 5 h, 96%; (e) NaBH4, MeOH, rt, 2 h, 86%; (f)
TIPSCl, imidazole, CH2Cl2, rt, 18 h, 98%.

D. V. Smil et al. / Tetrahedron Letters 44 (2003) 5129–5132
5131
t
Scheme 3. Reagents and conditions: (a) (i) BuLi, THF, −78°C, 30 min (ii) 6, −78 to 0°C, 2 h, 76%; (b) NaH, MeI, THF, rt, 18
h, 95%; (c) TBAF, THF, rt, 2 h, 92%; (d) Dess–Martin periodinane, CH2Cl2, rt, 1 h, 89%; (e) CH2ꢁCHMgCl, Et2O, −78 to 0°C,
2 h, 97%; (f) Dess–Martin periodinane, CH2Cl2, rt, 1 h, 80%; (g) Et2AlCl, CH2Cl2, −78 to 0°C, 5 min, 72%.
and an aryl bromide substituted with the C1ꢀC2 alkene
dieneophile resulted in complex mixtures. Subsequent
deprotection of silyl ethers 14a/b with tetra-
butylammonium fluoride (TBAF) afforded benzyl alco-
hols 15a/b in 92% yield. Prolonged exposure of silyl
ether 14b to TBAF promoted the elimination of
methanol between the C9 and C10 positions, thus
deprotection was carefully monitored to minimize for-
mation of the undesired olefin. The benzyl alcohols
15a/b were readily oxidized to benzaldehydes 16a/b
using Dess–Martin periodinane. Subsequent generation
of the hydroxy-trienes (not illustrated) with vinyl mag-
nesium bromide followed by an additional oxidation of
the benzyl alcohols afforded the desired Diels–Alder
precursors 17a/b. Under conditions previously devel-
oped in the Fallis group,12 Lewis acid catalyzed and
chelation controlled IMDA cyclization of 17a/b
afforded aromatic C-ring taxanes 18a/b as single
diastereomers.
taxanes variably substituted at the C2, C4, C5, and C9
positions. This approach allowed the construction of a
single diastereomer of the substituted aromatic C ring
taxanes 18a/b19 in seven steps and greater than 40%
overall yield from the combination of diene aldehyde 6
and aryl bromides 13a/b. Additional investigations into
the stereoselective reduction of the C2 ketone, esterifi-
cation of the resulting C2 hydroxyl,1 and alteration
protecting group manipulation for the C4, C5, and C9
hydroxyls are in progress in order to access appropri-
ately functionalized, biologically active aromatic C-ring
taxanes.
Acknowledgements
We are grateful to the Canadian Breast Cancer
Research Initiative (CBCRI, NCI, Canada) for finan-
cial support of this research.
The stereochemistry of aromatic C-ring taxanes 18a/b
was assigned, as established earlier, based on the previ-
ously obtained crystal structure of a related AB-ring
compound prepared under identical Lewis acid cata-
lyzed IMDA conditions.12 The observed stereoselectiv-
ity arises from the chelation control provided by
complexation of the Lewis-acid between the C2 carb-
onyl and C9 methoxy substituents as illustrated in Box
A (R’s deleted for clarity). This geometric arrangement
mimics a ‘cycloheptene like’ ring and appears to be
particularly favorable, as this orientation may also be
partially stabilized by association with the aromatic
ring to facilitate achievement of the endo transition
state. Related chelation effects have been shown to
control the selectivity of both intermolecular15 and
intramolecular cycloadditions16 mediated by Lewis
acids. The aromatic C-ring taxanes 18a/b exist as the
endo atropoisomers based on the chemical shifts of the
three A-ring methyl groups (0.70, 1.09, 1.34 ppm for
18a and 0.82, 1.08, 1.32 ppm for 18b).17,18
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