Gold-catalyzed one-step construction of 2,3-dihydro-1H-pyrrolizines with an electron-withdrawing group in the 5-position: A formal synthesis of 7-methoxymitosene

Article abstract of DOI:10.1002/anie.201203678

What a ring formation! Bicyclic dihydropyrrolizines with an electron-withdrawing group (EWG) at the 5-position are formed in one step from linear azidoenynes under gold catalysis. This novel route involves the use of azide as a nitrene precursor, electronically-controlled regioselectivity, and the generation of destabilized 1-azapentadienium ions and their pericyclic reactions. This method was used for a formal synthesis of 7-methoxymitosene (see scheme).

Full text of DOI:10.1002/anie.201203678

Angewandte
Chemie
DOI: 10.1002/anie.201203678
Gold Catalysis
Gold-Catalyzed One-Step Construction of 2,3-Dihydro-1H-
Pyrrolizines with an Electron-Withdrawing group in the 5-position: A
Formal Synthesis of 7-Methoxymitosene**
Ze-Yi Yan, Yuanjing Xiao, and Liming Zhang*
2,3-Dihydro-1H-pyrrolizines form an important class of
bicyclic pyrroles. Among the many bioactive compounds
containing this structural motif are ketorolac, a nonsteroidal
anti-inflammatory drug, and 7-methoxyaziridinomitosene,
a mitosene that is more stable than mitomycin C but possesses
similar antitumor activities[1] (Scheme 1). Notably, both of
such as sulfoxide,[6a,7a] but to deliver a nitrene instead to the
tethered alkyne in a 5-endo-dig cyclization manner,[12] thus
yielding a reactive gold carbene (A; Scheme 2a) that
possesses umpolung reactivity at the normally nucleophilic
3-position of the indole. As azido groups can be easily
installed, the strategy of accessing a reactive a-imino gold
carbene using the combination of alkyne and azide is very
appealing. However, in the context of gold catalysis, only the
5-endo-dig cyclization of an azido group, acting as a nitrene
precursor, with an alkyne has so far been reported. We
reasoned that a 5-exo-dig cyclization would become feasible if
À
an electron-deficient C C double bond were to be attached to
the distal end of the alkyne (Scheme 2b) because: a) this
group could electronically bias the C-C triple bond so that the
alternative 6-endo-dig cyclization could be minimized;[13]
b) upon generation of the gold carbene intermediate B, a 4p
electrocyclic ring closure might occur to eventually afford the
2,3-dihydro-1H-pyrrolizine 2 with a desired electron-with-
drawing group at its 5-position. Notably, due to the weak
back-bonding capacity of gold,[14] a mesomeric form of B of
significant contribution is the 1-azapentadienium C,[5] which is
a conjugated cation[15] doubly destabilized by the imine
moiety and the EWG group. Since the enynyl azide 1 can
be assembled easily, for example, by the Sonogashira reaction,
this strategy would provide a convergent, two-step approach
to the biologically important 2,3-dihydro-1H-pyrrolizines
with EWGs at the 5-position.
Scheme 1. 2,3-Dihydro-1H-pyrrolizine, and bioactive compounds con-
taining a common motif that consists of this structure with an
additional electron-withdrawing group at its 5-position.
these compounds, as well many others,[2] contain an electron-
withdrawing group (EWG) at the 5-position of the dihydro-
pyrrolizine. Synthesis of this biologically important structural
motif from easy-to-assemble linear substrates in one step
would offer desirable synthetic convergence and flexibility
and perhaps improve overall efficiency, but to the best of our
knowledge there is only one example of such a synthesis and
this has limited scope.[3] Herein, we report a generally
applicable and efficient gold catalysis[4] that addresses this
need; moreover, this chemistry features the use of azides as
nitrene precursors, and electrocyclizations of destabilized 1-
azapentadienium intermediates.[5]
In line with our previous work[6] on the generation of a-
oxo gold carbenes by alkyne oxidation,[7] we have recently
reported results pertaining to the generation of their nitrogen
counterparts, that is, a-imino gold carbenes, by either intra-[8]
or intermolecular[9] delivery of a nitrene precursor to a C C
À
triple bond.[10] In the intramolecular case,[8] an azido group[11]
was employed in the same capacity as a nucleophilic oxidant
[*] Dr. Z.-Y. Yan, Dr. Y. Xiao, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry
University of California, Santa Barbara, CA (USA)
E-mail: zhang@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~zhang/index.html
[**] The authors thank NSF (CAREER CHE-0969157) and the China
Scholarship Council (Z.-Y.Y. and Y.X.) for generous financial support
and Sigma–Aldrich for the generous donation of [BrettPhosAuNTf2].
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203678.
Scheme 2. Azide as intramolecular nitrene precursor in gold catalysis:
our previous study and a new strategy.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
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We surmised that a ketone carbonyl group would be
a suitable electron-withdrawing group and, furthermore, that
having a cyclohexenone ring as the electron-deficient alkene
component would offer a product with the pyrrolo[1,2-
a]indole skeleton of mitosenes. Hence, cyclohexenone 3a
was chosen as the substrate for reaction development and
optimization (Table 1). 3a was readily prepared in 86% yield
by a Sonogashira coupling between 5-azidopent-1-yne and
5,5-dimethyl-3-iodocyclohex-2-en-1-one. Much to our delight,
[(Ph3P)AuNTf2] was a lot inferior under the same reaction
conditions (Table 1, entry 10), and neither KAuCl4 (Table 1,
entry 11) nor PtCl2 (Table 1, entry 12) were effective for this
transformation.
A major side reaction of this alkynyl azide substrate was
the Huisgen 1,3-dipolar cycloaddition.[19] When neat 3a was
stored over 6 days in the refrigerator, tiny amounts of polar
impurities were formed, and upon inspection of the 1H NMR
spectrum, we attributed their formations mainly to intermo-
lecular Huisgen reactions. In solution reactions at elevated
temperatures (Table 1, entries 7–12), the triazole 5a, formed
by the intramolecular cycloaddition, was detected in up to
14% yield (Table 1, entry 11). In the absence of any catalyst
(Table 1, entry 13), however, 5a was formed in a higher 17%
yield upon heating the reaction for a similar duration, thus
suggesting that this side reaction is most likely not catalyzed
by the gold catalysts but instead promoted by heating.
Interestingly, HNTf2 also promoted the formation of 5a but
did not promote the formation of 4a at all (Table 1, entry 14).
We also observed that the addition of 10 mol% of 5a to the
reaction mixture slowed the reaction rate substantially
(Table 1, entry 15); this result is consistent with the fact that
the basic triazole 5a could deactivate the [BrettPhosAuNTf2]
catalyst by coordination to the gold center.[20]
With the optimal conditions found (Table 1, entry 9) the
reaction scope was then examined (Scheme 3). To avoid
catalyst deactivation by the triazole impurities, all the
substrates were used straight after column purification. At
first, we focused on substrates deviating from 3a at the
cyclohexenone ring. To our delight, the substrate having no
methyl group and those with one methyl group at various
positions all gave the tricyclic pyrrole products (4b–4e) in
mostly good yields. Substituents a or b to the azido group
were readily tolerated, and the reaction yields were good to
excellent (4 f and 4g). In the case of a g-n-propyl group, the
intramolecular Huisgen cycloaddition was surprisingly facile.
The corresponding triazole 5h was formed in 32% yield
together with the desired 2,3-dihydro-1H-pyrrolizine 4h
(55% yield), even though the catalyst loading was 10 mol%
and the reaction time was 26 h. To our delight, the reaction
was dramatically improved when 15% of the catalyst was
used (Scheme 3, 4h). Notably, the reaction time was only 3 h.
This result is consistent with our previous observation that the
triazole side product hampers the gold catalysis, and suggests
that the gold catalysis is initially fast but then slows down
dramatically as the amount of the triazole builds up. The
linker can also be fused to a benzene ring, although 10% of
the catalyst was needed to obtain a decent yield of 4i because
of the competing Huisgen cycloaddition. The cyclohexenone
moiety could be replaced by other linear electron-deficient
alkenes. For example, pent-3-en-2-one can be used to deliver
the dihydropyrrolizine 4j in 76% yield, where an acetyl group
is installed at the 5-position. Similarly, a benzoyl group was
readily incorporated at the 5-position, and the product 4k was
formed in 81% yield. Interestingly, 4k is the decarboxylated
ketorolac.
the
anticipated
reaction
indeed
occurred
with
[(Ph3P)AuNTf2] as the catalyst[16] and in 1,2-dichloroethane
(DCE), and the expected cyclohexenone-fused 2,3-dihydro-
1H-pyrrolizine 4a was formed in 22% yield (Table 1, entry 1).
Despite the sluggishness of the reaction, we were encouraged
by the rather high yield (81%) based on the reaction
conversion. To speed up the reaction, we first tried a range
of other catalysts (Table 1, entries 2–5); the catalysts based on
bulky biphenylphosphine ligands (e.g., tBuXPhos and Brett-
Phos)[17] led to better yields and higher conversions at
ambient temperature (Table 1, entries 4 and 5). Further
increase of the phosphine ligand size (e.g., Me4tBuXPhos),[18]
however, led to a much lower conversion (Table 1, entry 6).
Although heating the reaction at 808C was not very helpful
when [tBuXPhosAuNTf2] was used (Table 1, entry 7), at the
same elevated temperature, the yield was improved with
[BrettPhosAuNTf2][17b] as the catalyst, and 4a was formed in
a satisfactory 69% yield, as determined by NMR spectrosco-
py (Table 1, entry 8). Screening the reaction solvents revealed
that toluene was better than DCE, and the yield was
improved to 96% (Table 1, entry 9). In comparison,
Table 1: Initial reaction development and optimization.[a]
Entry Catalyst
Conditions
t
4a
5a
conv.
[h] [%][b] [%][b] [%][b]
1
2
3
[(Ph3P)AuNTf2]
[IPrAuNTf2]
[(4-
(ClCH2)2, RT
(ClCH2)2, RT
(ClCH2)2, RT
28 22
28 29
28 30
–
–
–
27
41
37
CF3C4H4)3PAuNTf2]
[tBuXPhosAuNTf2]
[BrettPhosAuNTf2]
4
5
6
7
8
9
10
11
12
(ClCH2)2, RT
(ClCH2)2, RT
28 50
28 53
32 26
–
–
–
9
69
64
32
84
[Me4tBuXPhosAuNTf2] (ClCH2)2, RT
[tBuXPhosAuNTf2]
[BrettPhosAuNTf2]
[BrettPhosAuNTf2]
[(Ph3P)AuNTf2]
KAuCl4
(ClCH2)2, 808C 17 51
(ClCH2)2, 808C 17 69[c] 3[c]
96[c]
100
74
toluene, 808C
toluene, 808C
toluene, 808C
6
96[d]
18 37
19
–
15
14
13
3
45
49
PtCl2
toluene, 808C, 18 11
CO
13
14
-
toluene, 808C
toluene, 808C
toluene, 808C
18
18
8
0
–
30
17
56
33
82
HNTf2 (5 mol%)
15[e] [BrettPhosAuNTf2]
15[f] 49
[a] [3a]=0.05m. [b] Estimated by 1H NMR spectroscopy using dibro-
momethane as the internal reference. [c] 84%/2%/99% with base-
washed DCE. [d] Yield of the isolated product. [e] 10 mol% of 5a was
added to the reaction. [f] The amount formed during the reaction.
Tf =trifluoromethanesulfonyl.
As well as using ketones as the electron-withdrawing
groups, esters including a lactone could similarly control the
regioselectivity of the initial cyclization, and the yields were
2
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Table 2: Extension of the reaction to the formation of tetrahydroindoli-
zine.[a]
Entry Substrate Catalyst loading
t
7 (Yield [%]) 8 (Yield [%])
1
2
3
4
5
6
6a
6a
6a
6a
6a
6b
5%
0
19 h 7a (26)
28 h 7a (0)
2 min 7a (0)
8a (74)
8a (95)
8a (96)
0[b]
10%
15%
15%
10 h 7a (89/83[c]) 8a (11)
2 h
7a (94[c])
8a (<2)
8b (<2)
2.5 h 7b (91[c])
[a] The reactions were run in vial without exclusion of air and moisture;
[6]=0.2m. [b] HNTf2(1.1 equiv). [c] Yield of the isolated product.
much to our suprise. When the catalyst amount was increased
to 10 mol%, the desired tetrahydroindolizine 7a was isolated
in 83% yield, whereas the triazole 8a was formed in only 11%
(Table 2, entry 4). The reaction can be further improved by
using 15mol% of the catalyst (Table 2, entry 5). This trend is
consistent with our previous observation with 4h. These
optimized reaction conditions (Table 2, entry 5), when
applied to the substrate 6b, gave the corresponding tetrahy-
droindolizine 7b in an equally excellent yield (Table 2,
entry 6).
The ready access to the tricyclic pyrrolo[1,2-a]indole
skeleton of mitosenes through this chemistry offers a new
synthetic route to these biologically interesting compounds.
7-methoxymitosene was chosen as a target, and its synthesis
commenced from 4d.[21] After much experimentation, we
realized a one-step oxidative aromatization of its cyclohex-
enone ring by using a combination of TBSCl (3 equiv),
AgNTf2 (3 equiv), and Et3N in CH2Cl2. As the reaction was
run under dry air, oxygen was most likely the oxidant, which is
different from the known protocols where a metal oxidant
Scheme 3. Studies in the scope of the reaction. The reactions were run
in a vial without exclusion of air and moisture. Unless otherwise
noted, the amount of the triazole side product was typically less than
5%. [3]=0.1m. The yield of the isolated products are reported.
[a] 15% catalyst. [b] 10% of gold catalyst, and 28% of the correspond-
ing triazole was isolated. [c] [Cy-JohnPhosAuNTf2] as the catalyst.
[22]
such as MnO2 was needed. The resulting tricyclic indole 9
was then subjected to a regioselective Vilsmeier–Haack
reaction, delivering the aldehyde 10 in 82% yield. After
desilylation, phenol 11 was efficiently oxidized into the
indoloquinone 12 using oxygen as the oxidant and salcomine
as the catalyst. The requisite 7-methoxy group (mitosene
numbering) in 13 was then installed in one step by treating 12
with a solution of I2 and KOH in MeOH. As 13 has been
previously converted into 7-methoxymitosene in a three-step
sequence,[23] this route constitutes a formal synthesis of the 7-
methoxymitosene (Scheme 4).
In summary, we have developed a gold-catalyzed syn-
thesis of 2,3-dihydro-1H-pyrrolizines having electron-with-
drawing groups in the 5-postion, from linear azidoenynes. As
the substrates can be easily assembled by the Sonogashira
reaction, this reaction constitutes a two-step, convergent
approach to this subclass of dihydropyrrolizines of proven
medical importance. Mechanistically, the azido group acts as
a nitrene precursor, and in the presence of a gold catalyst, the
mostly good (Scheme 3, 4l–4n). The synthesis of 4n did not
go to completion, but the yields based on conversion were
high. By inspecting the yields for products 4j–4m it can be
seen that having R2 = H does not seem to affect the reaction.
To our delight, benzenesulfonyl group also turned out to be an
excellent EWG for this reaction; in both examples, the
expected dihydropyrrolizine products (4o and 4p) were
formed smoothly and in high yields.
Our initial attempt to extend the chemistry to the
substrate azidoenynone 6a, which possesses a four-carbon
À
linker between the C C triple bond and the azido group
resulted in a low yield of the expected tetrahydroindolizine 7a
(Table 2, entry 1). Instead, the triazole 8a was formed in 74%
yield, as determined by 1H NMR spectroscopy. This Huisgen
side reaction proceeded nearly quantitatively in the absence
of any gold catalyst either upon heating over an extended
time (Table 2, entry 2) or in just 2 minutes when HNTf2
(1.1 equiv) was added (Table 2, entry 3). This dramatic rate
acceleration resulting from the addition of a strong acid was
À
C C triple bond is transformed highly regioselectively into an
a-imino gold carbene. This intermediate, which is mesomeric
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Scheme 4. A formal synthesis of 7-methoxymitosene. Reagents and
conditions: a) TBSCl (3 equiv), AgNTf2 (3 equiv), Et3N (4 equiv),
molecular sieves (4 ꢀ), RT, dry air, 69%. b) (COCl)2 (1.2 equiv), DMF,
08C, 82%. c) LiOH (3 equiv), DMF, RT, 12 h, quantitative. d) Salco-
mine (10 mol%), O2, DMF, RT, 75%. e) I2 (4 equiv), KOH (8 equiv),
MeOH.
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to a destabilized 1-azapentadienium ion, undergoes apparent
electrocyclic ring closure to deliver the pyrrole ring. The
synthetic utility of this chemistry is demonstrated in a formal
synthesis of 7-methoxymitosene.
[13] For the enyne shown below, which lacks an EWG group, on the
alkene, the gold catalysis led to a low yield of the pyridine
product, the formation of which is attributed to an initial 6-endo-
dig cyclization. The expected tricyclic pyrrole was not detected.
Experimental Section
General procedure for the gold-catalyzed synthesis of dihydropyrro-
lizine: [BrettPhosAuNTf2] (5.1 mg, 0.005 mmol) was added to a solu-
tion of freshly prepared azidoalklyne 3 (0.10 mmol) in toluene
(1.0 mL) at room temperature. The reaction mixture in a vial was
stirred at 808C, and the progress of the reaction was monitored by
TLC. Upon completion, the mixture was concentrated under reduced
pressure, and the resulting residue was purified by silica gel flash
chromatography (eluant: ethyl actate/hexanes) to afford the desired
dihydropyrrolizine product.
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Published online: && &&, &&&&
Keywords: carbene · gold · homogeneous catalysis · mitosene ·
.
nitrene
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4
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Gold Catalysis
Z.-Y. Yan, Y. Xiao,
L. Zhang*
&&&& — &&&&
Gold-Catalyzed One-Step Construction of
2,3-Dihydro-1H-Pyrrolizines with an
Electron-Withdrawing group in the 5-
position: A Formal Synthesis of 7-
Methoxymitosene
What a ring formation! Bicyclic dihydro-
pyrrolizines with an electron-withdrawing
group (EWG) at the 5-position are formed
in one step from linear azidoenynes
under gold catalysis. This novel route
involves the use of azide as a nitrene
precursor, electronically-controlled regio-
selectivity, and the generation of desta-
bilized 1-azapentadienium ions and their
pericyclic reactions. This method was
used for a formal synthesis of 7-methox-
ymitosene (see scheme).
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!