Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO: Reaction development and application to the formal synthesis of (-)-galanthamine

Article abstract of DOI:10.1039/c6ob00660d

A Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO has been developed to synthesize functionalized 2-methylidene-3,4-cyclohexenones. The scope of this methodology has been investigated, showing that various functional groups can be tolera

Full text of DOI:10.1039/c6ob00660d

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Rh-catalysed [5 + 1] cycloaddition of
allenylcyclopropanes and CO: reaction
development and application to the formal
synthesis of (−)-galanthamine†
Cite this: DOI: 10.1039/c6ob00660d
Received 28th March 2016,
Accepted 13th May 2016
DOI: 10.1039/c6ob00660d
www.rsc.org/obc
Cheng-Hang Liu and Zhi-Xiang Yu*
A Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and Taber’s group deeply investigated such a reaction5 and applied
CO has been developed to synthesize functionalized 2-methyl- the methodology to the synthesis of several natural products.6
idene-3,4-cyclohexenones. The scope of this methodology has Recently we reported that Fe2(CO)9 could also mediate the [5 +
been investigated, showing that various functional groups can be 1] reaction of VCPs and CO without photoirradiation.7 Apart
tolerated. Both di- and tri-substituted allenylcyclopropanes can be from iron, other metal catalysts could also be used to catalyse
applied to this cycloaddition and the [5 + 1] cycloadducts with the or promote these transformations. In 2005, de Meijere
E configuration were obtained as the major products. In addition, reported the [5 + 1] reaction catalysed by Co2(CO)8 and [Rh
the present [5 + 1] cycloaddition reaction has been utilized as a (CO)2Cl]2,8 yet only limited substrates can be applied to this
key step in the formal synthesis of the natural product methodology. In 2012, our group reported the cationic Rh-cata-
(−)-galanthamine.
lysed [5 + 1] cycloaddition of VCPs and CO, which can use a
broad range of VCP substrates and gave good yields of [5 + 1]
cycloadducts.9 Despite the [5 + 1] cycloadditions involving
VCPs having been deeply investigated, there are few examples
involving the cycloadditions of allenylcyclopropanes (ACPs)10
and CO where ACPs act as the five-carbon unit (Scheme 1).
During the past few decades, transition-metal-catalysed
cycloadditions, which provide powerful approaches to syn-
thesize various sized ring compounds ranging from three- to
nine-membered rings, have attracted many researchers’ atten-
tion. These reactions usually take place under mild reaction
conditions and give high yields of cycloadducts of various
scaffolds. Among them, developing new metal-catalysed
cycloadditions to synthesize six-membered non-benzenoid
carbocycles is one of the most actively pursued research fields,
considering that six-membered non-benzenoid carbocycles are
the most ubiquitous ring skeletons in organic molecules.
Until now, many elegant transition-metal-catalysed cyclo-
additions,1 for example, the metal-catalysed [3 + 3], [4 + 2], [5 +
1], [2 + 2 + 2], [3 + 2 + 1], and [4 + 1 + 1] reactions, have been
developed for the synthesis of six-membered carbocycles.
Among them, the [5 + 1] reactions of vinylcyclopropanes
(VCPs) and CO to various functionalized cyclohexanones have
been under intensive investigations. As early as 1969, Sarel
reported the [5 + 1] reaction of 1,1-dicyclopropylethylene with
CO to generate a cyclohexanone product.2 They also discovered
that this reaction could be induced by photoirradiation for
VCPs with various functional groups.3,4 Soon after that,
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China. E-mail: yuzx@pku.edu.cn
†Electronic supplementary information (ESI) available: Experimental details and
NMR spectra of new compounds. See DOI: 10.1039/c6ob00660d
Scheme 1 Selected [5 + 1] reactions and the present investigated one.
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In 1995, Iwasawa’s group reported the synthesis of substi-
tuted hydroquinone using the Co-catalysed [5 + 1] strategy of
1-allenylcyclopropanols with CO (Scheme 1a).11 Several years
later, Murakami and Ito found that, Vaska’s complex IrCl(CO)
(PPh3)2 can catalyse the [5 + 1] reaction of ACPs and CO to
generate the functionalized 2-methylidene-3,4-cyclohexenones
(Scheme 1b).12 However, harsh reaction conditions were
needed (temperature was higher than 130 °C and 5 atm CO
was used), and the separation of the [5 + 1] cycloadducts was
resorted to using preparative thin layer chromatography, which
seriously restricted the application of this methodology in
large scale synthesis. Tang and co-workers elegantly developed
a Rh-catalysed tandem 1,3-acyloxy migration/[5 + 1] cyclo-
addition reaction to produce highly functionalized cyclohexa-
nones with alkoxy groups attaching the six-membered rings
(Scheme 1c).13 Tang and co-workers also showed in their syn-
thesis of the core of welwitindolinones C that Rh-catalyzed [5 +
1] cycloaddition directly using the trisubstituted ACP substrate
and CO (only one example) can give the [5 + 1] cycloadduct
(Scheme 1d).14
Table 1 Optimization of reaction conditions
Entry Catalyst
Solvent
Time [h] Yielda
1
2
3
4
5
6
7
8
[Rh(CO)2Cl]2 b
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
Dioxane
THF
DME
MeCN
DME
DME
DME
DME
2
2
3
3
2
72%
69%
No reaction
No reaction
68%
[Rh(CO)2Cl]2
[Rh(COD)2]BF4
Rh(CO)(PPh3)2Cl
[Rh(COE)2Cl]2
[Rh(COD)Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2 c
[Rh(CO)2Cl]2 d
[Rh(CO)2Cl]2 e
[Rh(CO)2Cl]2
2
2
65%
60%
9
10
3
58%
66%
77%
9
10
11
12
13
14
15
16
17
18
19
8
7
Low conversion
34%
3
3
68%
66%
f
[Rh(CO)2Cl]2 g
6
2
64%
81%
[Rh(CO)2Cl]2 g,h
[Rh(CO)2Cl]2
DME
DME
DME
2
2
71%
Trace
[Rh(CO)2Cl]2 + dpppg,i
Considering the existence of the 3,4-cyclohexenone skeleton
in many natural products and pharmaceuticals (Fig. 1)15 and
the importance of developing six-membered ring formation
reactions, together with inspiration from the seminal
discoveries of the Ir-catalysed [5 + 1] cycloaddition and Tang’s
synthesis of the core of welwitindolinones C, we were chal-
lenged to test whether a Rh complex catalysed [5 + 1] reaction
of ACPs and CO, which may have a broad substrate scope,
[Rh(CO)2Cl]2 + dppmg,i DME
2
No reaction
The reaction was performed in a 0.3 mmol scale and 3 mL solvent was
used. a Isolated yields. b 4 Å molecular sieves were added. c 80 °C. d 0.5
atm CO. e 0.2 M. f 2 mol% catalyst was used. g The substrate was dis-
solved in solution and added slowly (ca. 1 h). h 0.05 M. i 5 mol% ligand
was used.
reasonable reaction yields, and easy separation of the [5 + 1] effect on the reaction outcome (in contrast, our previous Rh-
cycloadducts, could be developed (Scheme 1e). Herein we catalysed [5 + 1] reaction of VCPs and CO was sensitive to the
report our success in developing this general [5 + 1] reaction of moisture in the reaction system)9 (Table 1, entry 2). We also
ACPs and CO and the application of this reaction to the asym- tested other rhodium catalysts, finding that no desired [5 + 1]
metric formal synthesis of (−)-galanthamine.
product was obtained using either [Rh(COD)2]BF4 or Rh(CO)
We first synthesized compound 1a and commenced our (PPh3)2Cl as the catalyst (Table 1, entries 3 and 4).16 Other
investigation. Treating substrate 1a with 5 mol% [Rh(CO)2Cl]2 dimeric Rh catalysts such as [Rh(COE)2Cl]2 and [Rh(COD)Cl]2
in toluene at 60 °C, the 2-alkylidene-3,4-cyclohexenone did not improve the reaction yields compared to [Rh(CO)2Cl]2
product 2a was isolated in 72% yield (Table 1, entry 1). This (Table 1, entries 5 and 6).
transformation showed good stereoselectivity, and only the
We then investigated how solvents affect the reaction
[5 + 1] product with the E configuration was observed. This results, finding that the [5 + 1] cycloaddition can take place in
was similar to Murakami and Ito’s Ir-catalysed cycloaddition, most commonly used solvents with the exception of MeCN, in
where product 2a was obtained in 28% yield (they did not moderate reaction yields (Table 1, entries 7–10). Among these
observe other geometric isomers in their reaction system by tested solvents, 1,2-dimethoxyethane (DME) turned out to be
1H NMR either). Adding 4 Å molecular sieves to the present the best one. In this case the [5 + 1] product 2a was obtained
reaction system did not improve the yield of the Rh-catalysed in 77% yield (Table 1, entry 10). Increasing either the reaction
[5 + 1] reaction, implying that water did not have a deleterious temperature (Table 1, entry 12) or concentration of the allenyl-
cyclopropane substrate (Table 1, entry 14) did not significantly
improve the reaction yield. Decreasing the CO pressure from 1
atm to 0.5 atm (Table 1, entry 13) did not affect the reaction
yield either. When we reduced the loading of the catalyst from
5 mol% to 2 mol%, only 64% product 2a could be isolated in
the [5 + 1] reaction.
We were still not satisfied with the [5 + 1] reaction’s yield
mentioned above and wanted to search for another approach
to get a higher yield of the desired [5 + 1] product. We hypo-
thesized that the yield of the [5 + 1] cycloadduct was due to the
Fig. 1 Natural products containing the 3,4-cyclohexenone skeleton.
competing side reactions of the ACP substrate, which is
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usually regarded as a very reactive species, in the reaction
system. Experimentally, several products with polarities
between the substrate 1a and the cyclohexanone product 2a
were observed by analytical TLC. We reasoned that some of
these unknown byproducts in the [5 + 1] reaction system may
come from the dimerization of ACP in the presence of the Rh
catalyst.17,18 Therefore, we tried to add a solution of substrate
1a in DME slowly (about 1 hour), with the help of a syringe
pump, to another solvent containing the catalyst at 60 °C
under 1 atm CO, with the hope that the Rh-catalysed or
mediated dimerization of 1a can be suppressed significantly
by this operation. A similar strategy has been used by Alexa-
Table 2 Scope of this Rh-catalysed [5 + 1] cycloaddition reaction
Entrya
Substrates
Time
Products and yieldsb
1
2
3
4
5
6
7
8
1a, R = Ph
1b, R = 4-BrPh
2 h
3 h
2 h
1.5 h
2 h
—
2a, 80%
2b, 86%
2c, 78%
2d, 56%
2e, 70%, 3e, 21%
Decomposed
Decomposed
2h + 3h, 66% (E/Z = 5.1 : 1)
2i, 64%, 3i, 12%
2j, 60%, 3j, 15%
Decomposed
nian in the nickel-catalysed [2
+ 2] cycloaddition of
1c, R = 4-MeOPh
1d, R = 2-thienyl
1e, R = CH2CH2Ph
1f, R = CH2OH
1g, R = CH2OTs
1h, R = CH2OTBS
1i, R = CH2OTBDPS
1j, R = CH2NMeTs
1k, R = CO2Et
ene–allenes.19 To our delight, the yield of product 2a can be
increased to 81% and formation of the side products can be
significantly suppressed, as judged by analytical TLC (Table 1,
entry 16).20 We also tried to decrease the concentration of the
substrate to further minimize the dimerization of ACP, but no
better result was obtained (Table 1, entry 17). Finally, we inves-
tigated whether adding a phosphine ligand to the [5 + 1] reac-
tion could further increase the reaction yield. Unfortunately,
adding either dppp or dppm to the reaction system gave much
lower yields.
—
2 h
2 h
2 h
2 h
9
10
11
12
13
1l, R1 = Ph, R2 = H
1m, R1 = H, R2 = Ph
—
—
Decomposed
Decomposed
Based on the results in Table 1, we chose the reaction con-
ditions of entry 16 in Table 1 as the optimal reaction con-
ditions and the scope of the target [5 + 1] cycloaddition was
presented in Table 2. We firstly investigated the influence of
the substitution patterns in the allene moiety of ACPs. Apart
from the phenyl used in the standard substrate, other aryl
groups such as 4-bromophenyl and 4-methoxyphenyl could
also be used and the corresponding [5 + 1] reaction yields were
high (Table 2, entries 2 and 3). Interestingly, in these [5 + 1]
reactions, only the products with the E configuration were
observed. Changing the phenyl group to the 2-thienyl group,
the corresponding [5 + 1] reaction gave a decreased reaction
yield, 56% (Table 2, entry 4). Furthermore, we found that re-
placing the aryl groups by an alkyl group such as the 2-phenyl-
ethyl group in ACPs, the [5 + 1] reaction of the resulting
substrate could also occur (Table 2, entry 5). It was found that
two geometric isomers of the [5 + 1] reaction of 1e, which can
be separated by flash column chromatography in 70% and
21% yields separately, were obtained. The ACP substrate 1f
14
15
1n
1o
2 h
2 h
2n, 90%
2o, 74%, 3o, 9%
16
17
1p
2 h
2 h
2p + 3p, 94% (E/Z = 1.7 : 1)
1q, R = CH2OBn
2q + 4q, 80% (2q : 4q = 4.3 : 1)
a The reaction was performed in a 0.3 mmol scale and 2 mL solution
of substrate was added slowly to another 1 mL solution of catalyst
with a free hydroxyl group was not a good substrate for the using a syringe pump. b Average yields of two runs.
[5 + 1] reaction and a complex mixture was obtained under the
optimized conditions (Table 2, entry 6). Protecting the hydroxyl
group in 1f by a Ts group, the resulting substrate 1g was still Z-cycloadducts (Table 2, entry 10). We also tried substrate 1k
not suitable for the [5 + 1] reaction (Table 2, entry 7) and with an ester group in the terminal position of the allene
decomposition of substrate 1g under the [5 + 1] reaction con- moiety, but only a complex mixture could be afforded, indicat-
ditions was observed. We reasoned that the OTs group in 1g ing that substrates with electron withdrawing groups attaching
was a good leaving group and this caused the decomposition the allene moieties were not good substrates (Table 2, entry
of the substrate during the [5 + 1] reaction. Fortunately, the 11).
hydroxyl group in 1f can be protected by the TBS or TBDPS
ACPs with terminal allenes, for example, 1l and 1m, were
group, and the resulting substrates 1h and 1i can undergo the synthesized and subjected to the optimal [5 + 1] reaction con-
[5 + 1] reactions to give both E and Z-cycloadducts (Table 2, ditions (Table 2, entries 12 and 13). We found that both 1l and
entries 8 and 9). Substrate 1j with an amine substituent was 1m failed to produce the desired [5 + 1] products, similar to
also a good substrate for the [5 + 1] reaction, giving both E and the Ir-catalysed [5 + 1] reaction of terminal ACPs.12 We
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reasoned that, in this case, the rhodium catalyst preferred to
coordinate at the allenic π-bond that is distal to the cyclopropyl
group.21 Consequently, cleavage of the cyclopropane ring in
ACPs becomes more difficult and many competing side reac-
tions18c could override the desired [5 + 1] reaction, leading to
the generation of complex mixtures for these terminal ACPs.
Under the standard [5 + 1] reaction conditions, trisubsti-
tuted ACPs were good substrates and the desired products
were obtained in high yields (Table 2, entries 14–16). For sub-
strate 1o with methyl and phenyl groups at the end of the
allenyl moiety of ACPs, a mixture of 2o and 3o was obtained.
This was different from Murakami and Ito’s report, where only
product 2o was isolated using Vaska’s complex. For substrate
1p, which had a methyl group at the internal allenyl position,
the [5 + 1] reaction could also occur, even though the E/Z ratio
of the desired products was relatively low (Table 2, entry 15).
We also investigated the selectivity of the cyclopropane ring
cleavage for substrate 1q with a substituent in the cyclopropyl
ring (Scheme 2), finding that the cyclopropane preferred to be
cleaved at the position opposite to the substitution at the
cyclopropane ring (bond “a” cleavage). As a result, product 2q
was the major product of the [5 + 1] reaction, which was
similar to Taber’s report using a Fe mediator.5a
To identify whether the ratio of the two isomers was deter-
mined by thermodynamics or kinetics, we resubjected 3i and 2i
to the reaction separately. No change of the configuration could
Scheme 3 Synthetic strategy and formal synthesis of (−)-galanthamine.
1
be observed from the H NMR spectra. This suggested that the
E/Z isomers did not equilibrate under the reaction conditions
and the ratio was controlled by kinetics (see the ESI† for details).
We also added PPh3 to the two isomers separately and
observed the transformations between 3i and 2i (Scheme 2).
The Z and E isomers could reach a thermodynamic equili-
brium and a ratio of 3.6 : 1 could be achieved after 36 h at
room temperature, both for 2i and 3i.
Finally, we want to apply this methodology to the synthesis of
natural products. (−)-Galanthamine (11)22,23 is an alkaloid iso-
lated from the bulb of the Amaryllidaceae family containing the
3,4-cyclohexenol skeleton (Scheme 2).24 It is a reversible and com-
petitive acetylcholine esterase inhibitor and has been used in the
early treatment of Alzheimer’s disease.25 The unique 3,4-cyclo-
hexenol skeleton in (−)-galanthamine, which is similar to our [5 +
1] adducts, and the pharmacodynamic effects of galanthamine,
promoted us to synthesize this drug using our [5 + 1] cyclo-
addition of allenylcyclopropanes and CO as the key step.
followed by a radical ring closing reaction or Heck reaction to
form the central five-membered ring in (−)-galanthamine. The
alcohol 5 could be achieved easily from the reduction of the
[5 + 1] cycloadduct 2h.
Presented in Scheme 3b is the formal synthesis of
(−)-galanthamine. The alcohol product 5 could be obtained in
79% yield with an ee value of 97% using the CBS reduction.27
Then alcohol 5 and phenol 6 underwent the Mitsunobu reac-
tion to form ether 7 in 86% yield. The TBS group was depro-
tected using TBAF and then the alcohol intermediate was
oxidized to aldehyde 8 by activated MnO2 in 86% yield over
two steps. The five-membered ring in the natural product
(−)-galanthamine was then formed using the radical ring
closing strategy in 60% yield.28 Finally, NaBH4 was applied to
reduce the aldehyde 9 to Brown’s intermediate 10 and there-
fore a formal asymmetric synthesis of (−)-galanthamine from
the [5 + 1] cycloadduct was realized.
In summary, we have developed a general Rh-catalysed [5 + 1]
cycloaddition of ACPs and CO to synthesize functionalized
2-methylidene-3,4-cyclohexenones, which are difficult to
obtain by using traditional methods. The scope of this
methodology has been investigated. When substrates with
aromatic groups attached to the allenyl moiety of ACPs were
applied to this method, only the [5 + 1] cycloadducts with the
E configuration were generated. In addition, various functional
groups could be tolerated in the ACP substrates. Importantly,
both di- and trisubstituted ACPs could be applied as the sub-
strates for the present [5 + 1] cycloaddition reaction. In
Our strategy toward (−)-galanthamine is presented in
Scheme 3a. (−)-Galanthamine can be synthesized by the
known procedures, from Brown’s intermediate 10 via Riley oxi-
dation and ring closing reaction.26 Intermediate 10 can be
afforded by the Mitsunobu reaction of alcohol 5 and phenol 6,
Scheme 2 Transformations between 3i and 2i.
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addition, the cycloadduct 2h has been applied in the formal
synthesis of the natural product (−)-galanthamine. Further
K. Sugikubo, F. Inagaki and C. Mukai, Eur. J. Org.
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Acknowledgements
We are indebted to the Natural Science Foundation of China
(21232001) and the National Basic Research Program of China-
973 Program (2011CB808600) for their generous financial
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for experimental assistance.
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26 V. Satcharoen, N. J. McLean, S. C. Kemp, N. P. Camp and
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