Synthesis of rhazinicine by a metal-catalyzed C-H bond functionalization strategy

Article abstract of DOI:10.1002/anie.200705005

(Chemical Equation Presented) Iterative and regioselective metal-catalyzed C-H bondfunctionalization has been utilizedto develop a strategy for the first total synthesis of the pyrrole alkaloid rhazinicine (see scheme).

Full text of DOI:10.1002/anie.200705005

Communications
DOI: 10.1002/anie.200705005
À
C H Activation
À
Synthesis of Rhazinicine by a Metal-Catalyzed C H Bond
Functionalization Strategy**
Elizabeth M. Beck, Richard Hatley, and Matthew J. Gaunt*
The chemical synthesis of natural products has been revolu-
tionized by the development of metal-catalyzed coupling
reactions. As part of these advances the successful assembly
of complex molecules by cross-coupling tactics exploits the
reactivity of strategically installed metal-active functional
groups in the key bond-forming events.[1] The advance of
À
metal-catalyzed C Hactivation technology suggests that
similar transformations are possible without the need to
prefunctionalize the parent molecules.[2,3] There are many
methodological advances that highlight the potential efficacy
of these processes in synthesis. However, there are few
examples of the application of such catalytic tactics in total
synthesis, possibly because of complications with both the
harsh reaction conditions and the selectivity and stability
issues associated with the more complex substrates required
À
for these purposes. However, direct C Hfunctionalization
tactics could have an impact in streamlining natural product
synthesis, so development in this area represents an important
goal for synthetic chemists.[4] We report the first synthesis of
the pyrrole alkaloid rhazinicine (1) by using a short synthetic
strategy that demonstrates how iterative and regioselective
À
metal-catalyzed C Hbond functionalizations can positively
influence complex molecule assembly.
Molecules containing a diversely substituted pyrrole
nuclei embedded within
a complex architecture are
common among structures found in nature (Scheme 1).
Rhazinicine (1)[5a,b] is part of a family of natural products
(rhazinilams) that mimic the cellular effects of pacitaxel.[5c]
Although the total synthesis of rhazinicine is not known, the
related rhazinilam structure has inspired a number of
syntheses[4c–d,6] which showcased new methods for key bond
Scheme 1. Natural products with embedded pyrrole motifs and syn-
thesis strategy of rhazinicine (1). R1 =Boc or TIPS.
constructions and enabled structure-activity studies into its
biological properties.[5c,d] The striking feature of the rhazini-
lams is the embedded pyrrole unit that supports a tetrahy-
droindolizine ring system bearing a quaternary center, a
heterobiaryl unit, and a nine-membered lactam. In addition, 1
displays a pyrrole amide motif that is likely to affect the
reactivity and stability of the heteroarene core.
[*] E. M. Beck, Dr. M. J. Gaunt
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (+44)1223-336-362
E-mail: mjg32@cam.ac.uk
Homepage: http://www-gaunt.ch.cam.ac.uk/
The synthesis of a highly substituted pyrrole motif is often
beset by problems associated with regioselectivity, high
reactivity, and oxidative instability in the transformations
Dr. R. Hatley
Medicines Research Centre
GlaxoSmithKline
that will decorate the heteroarene nucleus. Towards this end,
Gunnels Wood Road, Stevenage, Herts, SG1 2NY (UK)
II
À
we recently reported an oxidative Pd -catalyzed C Halke-
nylation of pyrroles,[7b] wherein we were able to control the
regioselectivity depending on the characteristic of the pro-
tecting group on the N atom; the tert-butylcarboxy (Boc)
group directed alkenylation to C2 and the triisopropylsilyl
(TIPS) group directed alkenylation to C3 [Eq. (1)].
[**] We gratefully acknowledge GSK and EPSRC for studentships
(E.M.B.), the Royal Society for a University Research Fellowship
(M.J.G.), Philip & Patricia Brown for a Next Generation Fellowship
(M.J.G.), and the EPSRC Mass Spectrometry service (University of
Swansea). We are also grateful to Prof. Steven Ley for valuable
support.
In considering rhazinicine as our target molecule, we
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
À
questioned whether a metal-catalyzed C Hbond functional-
3004
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ization strategy could expedite the assembly of natural
products that contain a highly substituted pyrrole core
[Eq. (2)]. We envisioned that the key structural architecture
of 1 could be directly installed from a simple pyrrole nucleus
À
by a metal-catalyzed C Hbond arylation to produce the
heterobiaryl framework, and subsequent oxidative PdII-cata-
À
lyzed pyrrole C Hbond cyclization to form the indolizinone
structure [Eq. (3)]. This strategy would facilitate the elabo-
ration of the pyrrole nucleus in comparison to the conven-
tional metal-catalyzed cross-coupling reactions, and reinforce
À
the utility of catalytic C Hbond functionalization as a
powerful tactic in natural product synthesis.
For the synthesis of 1 [Eq. (2)], we were confident that we
could use our approach to control the site of arylation,
À
Scheme 2. Second step of the iterative pyrrole C H bond functionali-
zation strategy. Bz=benzoyl.
À
although it was not clear whether subsequent C Hbond
functionalizations could be similarly directed. Therefore, our
II
À
Pd -catalyzed C Halkenylation on 3c, it reacted predom-
À
initial investigation focused on the development of a C H
inantly at the C5 position to form 4c (9:1 C5:C2) presumably
because the C2 position is more sterically congested. Notably,
the nature of the aryl group at C3 did not influence the
selectivity (2-NO2Ph, Ph, and 4-NO2Ph gave the same C5
alkenylation products). Whereas this tactic provided a
straightforward method for a directed synthesis of 3,4- and
3,5-disubstituted pyrrole derivatives, it would not be amena-
ble for the assembly of the 2,3-disubstituted pyrrole motif of
1.
bond arylation reaction analogous to our previous alkenyla-
tion studies;[7b] however, despite our best attempts we were
unable to effect such a process suitable for rhazinicine (1).
Instead, we adopted the Ir -catalyzed C Hborylation,
developed by the groups of Smith–Malezcka and Hartwig–
Miyuara,[8] to furnish the desired pyrrole nucleus and then
performed a Suzuki coupling. When testing this strategy with
the Hartwig–Miyaura conditions[8b,c] (Table 1) we found that a
I
À
We therefore considered the installation of a temporary
blocking group for the C5 position. Upon closer examination
of other rhazinilam syntheses we noticed that in all cases the
route required the addition of a group to shield the C5
position of the pyrrole ring. Although not explicitly
explained, we propose that this step prevents competing
oxidative pyrrole dimerization reactions, which is in line with
our own observations regarding the behavior of these
heteroarenes. We installed a SiMe3 (TMS) group at C5 to
prevent the potential side reactions and to provide a handle
for controlling the selectivity of the reaction.
À
Table 1: Investigation of
a
regioselective one-pot C H arylation
process.[a]
Entry
R1
X
C3:C2
Product
Yield [%]
1
2
3
iPr3Si
iPr3Si
Boc
NO2
H
NO2
>99:1
>99:1
>99:1
3a
3b
3c
82
68
78
The TMS-protected pyrrole 2c underwent a one-pot IrI-
catalyzed borylation and Suzuki coupling to form the desired
pyrrole isomer with arylation at C3 (Scheme 3). Presumably,
[a] B2pin2 =bis(pinacolato)diboron; cod=cycloocta-1,5-diene; dtbpy=
2,6-di-tert-butyl-4-methylpyridine; S-Phos=2-dicyclohexylphosphino-
2’,6’-dimethoxy-1,1’-biphenyl; mw=microwave.
range of N-protected pyrroles underwent microwave-assisted
I
À
Ir -catalyzed C Hborylation, which was exclusively selective
for the C3 position of the pyrrole ring in the presence of both
N-Boc and N-TIPS groups. Moreover, the Suzuki coupling[9]
was performed as part of the same transformation by directly
adding the required components to the reaction mixture, thus
enabling the isolation of 3a–c in a single step from 2a–c in
excellent yield (Table 1).
À
Scheme 3. Iterative C H bond functionalization to 2,3-difunctionalized
pyrroles.
the SiMe3 group at C5 and the N-Boc motif cooperatively
directed borylation to C3, and hence, arylation to the C3
À
The next step in the model studies for an iterative
functionalization approach to rhazinicine (1), was to assess
position. In turn, C Hbond alkenylation is forced to the C2
position; it proceeded in good yield to form 4c, although the
reaction required higher temperatures because of the more
hindered nature of this position. This model iterative coupling
strategy now enables the formation of the 2,3-disubstituted
pyrrole isomer required for 1.
II
À
the selectivity of the subsequent Pd -catalyzed C Halkeny-
À
lation. The reaction with TIPS-protected pyrrole 3a led to C
Hbond alkenylation at the C4 position to give 4a, in
accordance with our hypothesis (Scheme 2).[7b] Boc-protected
pyrrole 3c could potentially react at either the C2 or the C5
position under these reaction conditions. When we tested the
Therefore, confident that we could control the function-
alization of pyrrole rings, we applied this tactic to our
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Communications
Scheme 4. The synthesis of rhazinicine. LHMDS=lithium hexamethyldisilazide; TSE=2-trimethylsilylethyl; TFA=trifluoroacetate.
synthesis of 1 and began with a one-pot microwave-assisted
In summary, we have completed the first total synthesis of
rhazinicine in 11 steps from commercial materials by using a
short synthetic strategy that demonstrates how iterative
I
À
Ir -catalyzed C Hborylation and Suzuki coupling on 2d,
which formed 3d in 78% yield as a single isomer (Scheme 4).
Removal of the Boc group under thermal conditions deliv-
ered 6 in excellent yield. With biaryl 6 in hand we turned our
attention to the development of a concise synthesis of the
remaining framework. The synthesis began with a Wittig
ethenylation of diester 7 that proceeded in good yield. Ester
hydrolysis (80% from 7) and subsequent treatment of the
crude diacid with Ac2O formed the eight-membered ring
anhydride 8 in situ. Subsequent reaction with 9 formed
monoester 10 in 55% yield over two steps as an inseparable
(but inconsequential) mixture of geometric alkene isomers.
Fragment union to deliver 11 was affected by the acylation of
the lithium pyrrolate anion of 6 with the acid chloride of 10 in
76% yield.
À
metal-catalyzed C Hbond functionalizations can positively
influence complex molecule assembly. The catalytic strategy
forms the key part of our synthesis wherein we have utilized a
I
À
one-pot Ir -catalyzed C Hborylation and Suzuki coupling
sequence, and developed an oxidative PdII-catalyzed pyrrole
À
C Hbond cyclization to rapidly deliver the natural product.
We are currently exploring the utility of these transformations
in other target syntheses and these results will be reported in
due course.
Received: October 29, 2007
Revised: January 5, 2008
Published online: March 12, 2008
With the full carbon skeleton in place we were set for the
key oxidative PdII-cyclization reaction that would assemble
the architecture of 1. By using conditions adapted from our
intermolecular alkenylation studies we found that when 11
was treated with 10 mol% Pd(TFA)2 catalyst and tBuOOBz
as the oxidant, the reaction formed (Æ )-12 in 53% yield,
installing the tetrahydroindolizine ring system and all quater-
nary carbon centers as a single regioisomer at the desired C2
position of the pyrrole unit.[10] Interestingly, the reaction
proceeded better with the more active Pd(TFA)2 catalyst than
with Pd(OAc)2, which is perhaps a reflection of the lower
reactivity of the sterically hindered C2 position of the pyrrole
ring. Notably, despite the potential pitfalls associated with
catalytic oxidative pyrrole reactions,[4g] the PdII-catalyzed
cyclization on this system successfully formed the embedded
heteroarene architecture in good yield for this delicate
transformation. The final steps involved hydrogenation of
the NO2 and alkene groups in (Æ )-12 and subsequent AlCl3
mediated cleavage of the 2-trimethylsilylethyl and SiMe3
groups to give the corresponding acid. When treated with
Mukaiyamaꢀs reagent, the acid underwent macrolactamiza-
tion to (Æ )-1 to complete the synthesis of rhazinicine.
Please note minor changes have been made to this manuscript since
its publication in Angewandte Chemie Early View. The Editor.
À
Keywords: C H activation · natural products · palladium
.
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