Exploiting the palladium[0]-catalysed Ullmann cross-coupling reaction in natural products chemistry: Application to a total synthesis of the alkaloid (±)-aspidospermidine

Article abstract of DOI:10.1039/b415977b

The application of Ullmann cross-coupling reaction for the synthesis of the alkaloid (±)-aspidospermidine was studied. The initial step associated with the second stage of the synthesis of aspidospermidine involved the Pd[0]-catalyzed Ullmann cross-coupli

Full text of DOI:10.1039/b415977b

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C O M M U N I C A T I O N
Exploiting the palladium[0]-catalysed Ullmann cross-coupling
reaction in natural products chemistry: application to a total
synthesis of the alkaloid ( )-aspidospermidine
Martin G. Banwell* and David W. Lupton
Research School of Chemistry, Institute of Advanced Studies, The Australian National
University, Canberra, ACT 0200, Australia. E-mail: mgb@rsc.anu.edu.au
Received 19th October 2004, Accepted 15th November 2004
First published as an Advance Article on the web 7th December 2004
Azide 14, available through the title cross-coupling process,
has been converted, via the ring-fused aziridine 15, into the
alkaloid aspidospermidine.
We have recently disclosed a two-step process for the per-
paration of indoles that involves the initial palladium[0]-
catalysed Ullmann cross-coupling of o-nitrohalobenzenes with
readily available a-halo-enones or -enals.1 The resulting a-(o-
nitrophenyl)enones or -enals then engage in a simple reductive
cyclisation reaction to deliver the target indoles.2 We are now
seeking to exploit such chemistry in the development of a total
synthesis of the structurally complex and clinically significant
indole–indoline binary alkaloid vinblastine (1),3 a compound
that had eluded de novo total synthesis until recently.4 As
part of such endeavours, we have recently shown5 that the
micro-organism Pseudomonas putida BGXM1 can convert m-
ethyltoluene into the metabolite 2, a compound incorporating
key elements associated with the C-ring of compound 1. Herein
we outline complementary work that has culminated in the
synthesis of the racemic modification of the alkaloid aspidosper-
midine (3),6 a compound embodying the ABCDE-ring system
associated with vinblastine. This study serves to highlight the
synthetic utility of a-(o-nitrophenyl)enones available through the
title cross-coupling process as well as the likelihood of being able
to exploit compound 2 in developing a synthesis of vinblastine.
Scheme 1 Reagents and conditions: (i) EtMgBr (2 mol equiv.), THF,
18 ◦C, 3 h then 10% aq. HCl, 0 ◦C, 14 h; (ii) NaBH4 (1 mol equiv.),
MeOH, 0→18 ◦C, 3 h; (iii) Ac2O (2 mol equiv.), DMAP (cat.), pyridine,
0→18 ◦C, 10 h; (iv) LDA (1.2 mol equiv.), TBDMS–Cl (1.3 mol equiv.),
THF, −78→66 ◦C, 6 h then MeOH, 18 ◦C, 14 h; (v) LiAlH4 (7 mol
equiv.), THF, 0→18 ◦◦C, 4 h; (vi) TEMPO (cat.), PhI(OAc)2 (1.1 mol
=
equiv.), CH2Cl2, 18 C, 5 h; (vii) Ph3P C(H)OMe (1.1 mol equiv.),
THF, −78→18 ◦C, 3 h; (viii) 1 : 10 v/v 10% aq. HCl–THF, 0 ◦C, 3 h;
(ix) NaBH4 (1 mol equiv.), MeOH, 0→18 ◦C, 3 h; (x) Ac2O (2 mol
equiv.), DMAP (cat.), pyridine, 0→18 ◦C, 10 h; (xi) Cr(CO)6 (0.5 mol
equiv.), 70% t-BuOOH (3.0 mol equiv.), MeCN, 82 ◦C, 14 h; (xii) I2
(4 mol equiv.), 1 : 1 v/v CCl4–pyridine, 18 ◦C, 12 h.
the allylic acetate 68 in 96% yield over the two steps. The
ketene acetal obtained by treating compound 6 with LDA then
tert-butyldimethylsilyl chloride (TBDMS–Cl) engaged in an
Ireland–Claisen rearrangement9 reaction on heating in refluxing
THF and, after workup, the cyclohexene acetic acid 710 was
obtained (62%). Acid 7 was reduced to the corresponding
alcohol 811 (96%) using lithium aluminium hydride (LAH) and
the latter then oxidised to the corresponding aldehyde using the
protocol of Margarita et al.12 Reaction of this aldehyde with
(methoxymethylene)triphenylphosphorane, generated in situ by
treating the corresponding phosphonium salt with sodium
hexamethyldisilazide, afforded a 1 : 1 mixture of the E- and
Z-isomers of the alkenyl ether 9 in 92% over these two steps.
The synthesis of the a-iodocyclohexenone required for the
Pd[0]-catalysed Ullmann cross-coupling reaction is shown in
Scheme 1. Thus, commercially available 3-ethoxycyclohexenone
(4) was treated with ethylmagnesium bromide and the result-
ing tertiary-alcohol subjected to an acidic work-up. In this
manner the previously reported enone 57 was obtained in 89%
yield. Subjection of the last compound to 1,2-reduction using
sodium borohydride gave the expected allylic alcohol which was
immediately acetylated under standard conditions to provide
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 3 – 2 1 5
2 1 3
©

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Acid-catalysed hydrolysis of the last compound and reduction
of the resulting aldehyde with sodium borohydride then afforded
the higher homologue, 10 (84% from 9), of alcohol 8. The
readily derived acetate was then subjected to allylic oxidation
using Cr(CO)6–t-BuOOH13 to give enone 11 (65% from 10).
Subjectionof compound 11 to the versatilea-iodination protocol
of Johnson and coworkers14 finally gave the target halide 12 in
quantitative yield.
from this material proved a good match, in all respects, with
those reported previously by Wenkert and Hudlicky6g who have
described a two-step method for the conversion of compound
17 into aspidospermidine (3). However, we followed the slightly
longer but higher yielding procedure (Scheme 3) described by
Toczko and Heathcock6r in completing the present synthesis of
( )-aspidospermidine. Thus, reaction of piperidine 17 with a-
chloroacetyl chloride afforded the a-chloroamide 186r (69%) that
was, in turn, converted into the corresponding a-iodoamide 196r
under Finkelstein conditions. Treatment of this last compound
with silver(I) triflate then gave the lactam 206r which was reduced
with LAH to give ( )-aspidospermidine (3) (47% yield from
amide 18). The spectral data derived from this material matched
those reported6n,r for the natural product.
The initial step associated with the second stage (Scheme 2)
of our synthesis of aspidospermidine involved the pivotal Pd[0]-
catalysed Ullmann cross-coupling of a-iodoenone 12 with o-
iodonitrobenzene. This was achieved in DMSO at 70 ◦C using 5 g
atom equiv. of copper powder and Pd2(dba)2 as catalyst. In this
manner compound 13 was obtained in 75% yield. In anticipation
of carrying out an intramolecular 1,3-dipolar cycloaddition
reaction of the type recently reported by Guo and Schultz,15
acetate 13 was hydrolysed to the corresponding alcohol and the
readily derived mesylate reacted with sodium azide in DMF at
67 ◦C to give compound 14 in 87% yield over these three steps.
Heating a benzene solution of azide 14 at ca. 75 ◦C for three days
then afforded the ring-fused aziridine 15 in 72% yield. The tria-
zoline arising from 1,3-dipolar cycloaddition of the azide moiety
within substrate 14 to the tethered a-(o-nitroaryl)enone unit is
undoubtedly the immediate precursor to product 15 although it
could not be isolated from the reaction mixture.16 After much
experimentation we established that regioselective cleavage of
aziridine 15 could be achieved by treating this compound with
an ethereal solution of HCl in CH2Cl2. The resulting and rather
unstable hydrochloride salt of a-chloroketone 16, which was
obtained as a single diastereoisomer, was immediately subjected
to reduction with titanium trichloride·3THF in the presence
of ammonium◦acetate. In this manner the crystalline indole 17
(mp 172–177 C; lit.6g mp 180–182 ◦C) was obtained in 46%
yield over the two steps. The physical and spectral data derived
Scheme 3 Reagents and conditions: (i) a-chloroacetyl chloride (1.1 mol
equiv.), Et3N (1.1 mol equiv.), CH2Cl2, 0→18 ◦C, 2 h; (ii) NaI (10 mol
equiv.), acetone, 56 ◦C, 2 h; (iii) AgOTf (2 mol equiv.), THF, 18 ◦C, 0.5 h;
(iv) LAH (4 mol equiv.), THF, 18→66 ◦C, 2 h.
The S-enantiomer of compound 8 is readily available11 in 96%
ee so the present work also constitutes a formal total synthesis
of the unnatural or (−)-enantiomer of aspidospermidine. Since
R-8 will almost certainly be available by closely related means,
the chemistry presented here should also allow access to the
naturally occurring enantiomeric forms of various Aspidosperma
alkaloids.
Notes and references
1 M. G. Banwell, B. D. Kelly, O. J. Kokas and D. W. Lupton, Org. Lett.,
2003, 5, 2497.
2 Analogous protocols utilising b-halo-enones or -enals have been
applied to the preparation of quinolines; M. G. Banwell, D. W.
Lupton, X. Ma, J. Renner and M. O. Sydnes, Org. Lett., 2004, 6,
2741.
3 Antitumor Bisindole Alkaloids from Catharanthus roseus (L.), The
Alkaloids, Vol. 37, ed. A. Brossi and M. Suffness, Academic Press,
San Diego, CA, 1990.
4 (a) S. Yokoshima, T. Ueda, S. Kobayashi, A. Sato, T. Kuboyama, H.
Tokuyama and T. Fukuyama, J. Am. Chem. Soc., 2002, 124, 2137; for
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5 M. G. Banwell, A. J. Edwards, D. W. Lupton and G. Whited,
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6 For previously reported total syntheses of aspidospermidine see;
(a) G. Stork and J. E. Dolfini, J. Am. Chem. Soc., 1963, 85, 2872;
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Scheme 2 Reagents and conditions: (i) o-nitroiodobenzene (2 mol
equiv.), Cu (5 g atom equiv.), Pd2(dba)3 (cat.), DMSO, 70 ◦C, 5 h; (ii) 1 :
4 v/v 1 M aq. K2CO3–MeOH, 18 ◦C, 16 h; (iii) MsCl (1.2 mol equiv.),
Et3N (1.2 mol equiv.), Et2O, 0→18 ◦C, 2 h; (iv) NaN3 (3 mol equiv.),
DMF, 67 ◦C, 3 h; (v) C6H6, 75 ◦C, 3 d; (vi) 1 M HCl in Et2O (2.4 mol
equiv.), CH2Cl2, −15 ◦C, 1.5 h; (vii) TiCl3·3THF (10 mol equiv.) in 1 : 2 :
2 v/v/v H2O–2.5 M aq. NH4OAc–acetone, 18 ◦C, 0.33 h.
2 1 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 3 – 2 1 5

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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 3 – 2 1 5
2 1 5