Synthesis of Bridged Cyclopentane Derivatives by Catalytic Decarbonylative Cycloaddition of Cyclobutanones and Olefins

Article abstract of DOI:10.1002/anie.201608158

Herein, we report an intramolecular rhodium-catalyzed decarbonylative coupling between cyclobutanones and alkenes that proceeds by C?C activation and provides a distinct approach to a diverse range of saturated bridged cyclopentane derivatives. In this reaction, cyclobutanones serve as cyclopropane surrogates, reacting in a formal (4+2?1) transformation. To demonstrate the efficacy of this method, it was applied in a concise synthesis of the antifungal drug Tolciclate.

Full text of DOI:10.1002/anie.201608158

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608158
German Edition: DOI: 10.1002/ange.201608158
À
C C Activation
Synthesis of Bridged Cyclopentane Derivatives by Catalytic
Decarbonylative Cycloaddition of Cyclobutanones and Olefins
Xuan Zhou, Haye Min Ko,* and Guangbin Dong*
Abstract: Herein, we report an intramolecular rhodium-
has been challenging owing to the lack of synthetic handles
catalyzed decarbonylative coupling between cyclobutanones
for ring closure. An ideal approach to construct saturated
cyclopentane rings would be a (3+2) cycloaddition between
simple cyclopropanes and olefins. Whereas activated cyclo-
propanes, including vinyl, methylene,[3] and donor–acceptor
cyclopropanes,[4] can effectively participate in various (3+2)
cycloadditions (Scheme 1a), the coupling between normal,
unactivated cyclopropanes and olefins has remained elusive
(Scheme 1b).[5]
À
and alkenes that proceeds by C C activation and provides
a distinct approach to a diverse range of saturated bridged
cyclopentane derivatives. In this reaction, cyclobutanones serve
as cyclopropane surrogates, reacting in a formal (4+2À1)
transformation. To demonstrate the efficacy of this method, it
was applied in a concise synthesis of the antifungal drug
Tolciclate.
C
yclopentanes are widely found in various bioactive natural
products, agrochemicals, and pharmaceuticals (Figure 1).[1] To
date, many robust methods, such as 1,3-zwitterion addition,
ring-closing metathesis, Pauson–Khand, and Nazarov reac-
tions, have been developed for preparing unsaturated or
oxygenated five-membered carbocycles.[2] However, the
direct synthesis of saturated, non-oxygenated cyclopentanes
À
Scheme 1. Cyclopentane formation by C C activation. EDG=electron-
donating group, EWG=electron-withdrawing group.
Stimulated by the aforementioned difficulties of directly
forming saturated cyclopentane rings, we considered using
cyclobutanones as cyclopropane surrogates in a catalytic
decarbonylation process. It was expected that the oxidative
Figure 1. Representative natural products and pharmaceuticals con-
taining bridged cyclopentanes.
À
addition of a transition metal into the cyclobutanone a-C C
bond followed by CO extrusion should lead to a similar
metallacyclobutane as the one that is obtained by direct
activation of a cyclopropane (Scheme 1c). Consequently,
a decarbonylative “cut and sew” sequence[6] between a cyclo-
butanone and an olefin can be imagined that proceeds
through olefin migratory insertion and reductive elimination,
and would enable the rapid synthesis of saturated non-
oxygenated cyclopentanes (Figure 2a). Herein, we describe
the development of a catalytic intramolecular decarbonyla-
tive coupling between cyclobutanones and alkenes for the
construction of saturated bridged cyclopentanes.
The challenges of this decarbonylative cut-and-sew pro-
cess are associated with two major side reactions: 1) decar-
bonylation of the cyclobutanone to give a cyclopropane,[7] and
2) the regular (4+2) cut-and-sew process[8] (Figure 2b).
Direct CO extrusion from cyclobutanones is known to be
[*] X. Zhou, H. M. Ko, G. Dong
Department of Chemistry, University of Texas at Austin
Austin, Texas, 78712 (USA)
X. Zhou, G. Dong
Department of Chemistry, University of Chicago
Chicago, Illinois, 60637 (USA)
E-mail: gbdong@uchicago.edu
H. M. Ko
Department of Bio-Nano Chemistry, Wonkwang University
460 Iksandae-ro, Iksan, Jeonbuk, 54538 (Republic of Korea)
E-mail: hayeminko@wku.ac.kr
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201608158.
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Table 1: Optimization of the decarbonylative cycloaddition between
cyclobutanones and olefins (selected results).
Entry [Rh]
Ligand (mol%)
T
Conv. Yield[a] [%]
[8C] [%]
2a
3a
1
2
3
4
5
6
7
8
[Rh(C2H4)2Cl]2 P(C6F5)3 (24)
[Rh(C2H4)2Cl]2 PPh3 (24)
[Rh(C2H4)2Cl]2 PCy3 (24)
[Rh(C2H4)2Cl]2 PCy3 (12)
[Rh(C2H4)2Cl]2 (t-Bu)3P (10)
[Rh(C2H4)2Cl]2 SPhos (12)
[Rh(C2H4)2Cl]2 XPhos (12)
160
160
160
160
60
20
70
33
6
8
28
18
0
44
48
63
65
55
50
49
0
53
8
42
14
0
32
27
30
32
44
45
40
0
Figure 2. Reactivity landscape of cyclobutanone activation.
160 100
160
160
160
160
160 100
160
82
76
95
99
fast and efficient with rhodium catalysts.[7] Thus, if olefin
insertion is slow, cyclopropane formation will dominate. On
the other hand, if the decarbonylation step is too slow,
regular, non-decarbonylative olefin insertion would compete
to give cyclohexanone side products.
[Rh(coe)2Cl]2
[Rh(coe)2Cl]2
[Rh(coe)2Cl]2
[Rh(coe)2Cl]2
[Rh(coe)2Cl]2
[Rh(coe)2Cl]2
[Rh(coe)2Cl]2
XPhos (12)
XPhos (10)
RuPhos (10)
DavePhos (10)
CyJohnPhos (10) 160
9
10
11
12
13
14
95
90
5
BrettPhos (10)
XPhos (10)
160
170 100
Our study began with cyclobutanone 1a[8e] as a model
substrate, and a range of mono- and bidentate phosphine
ligands were investigated (Table 1). The use of bidentate
ligands yielded cyclopropane 3a as the only observable
product. However, when electron-deficient monodentate
P(C6F5)3 was used, the desired (4+2À1) product (2a) was
isolated, albeit with cyclopropane 3a as the dominating
product (entry 1). Whereas changing to PPh3 resulted in low
conversion of the starting material (entry 2), a promising
result was obtained when electron-rich, bulky PCy3 was
employed as the ligand (entry 3). We hypothesized that bulky
monodentate ligands prevent the coordination of more than
one phosphine ligand, and that the resulting unsaturation of
the metal center should promote olefin coordination
(Figure 3).[9]
69
29
1
[a] Yields determined by H NMR analysis using mesitylene as the
internal standard. coe=cyclooctene, PCy3 =tricyclohexylphosphine,
Ts =para-toluenesulfonyl.
obtain the (4+2À1) bridged bicycle in 69% yield (entry 14),
which could be easily separated and purified.[11] The structure
of 2a was unambiguously determined by X-ray crystallo-
graphy.[12]
We then examined the substrate scope of the decarbon-
ylative alkene insertion (Table 2). First, cyclobutanones with
various substituents at the C3 position were found to be
suitable substrates for this reaction (entries 1–6). In partic-
ular, cyclobutanones bearing a hydrogen substituent at the C3
position (1 f) are known to undergo facile b-hydrogen
Figure 3. Ligand effect on the selectivity.
À
Encouraged by this discovery, more sterically hindered
ligands were tested. Whereas bulkier P(t-Bu)3 gave a complex
mixture of unidentifiable products (entry 5), Buchwaldꢀs
SPhos ligand[10] afforded bridged cyclopentane 2a as the
major product in 44% yield (entry 6). Further investigations
revealed that when more thermally stable [Rh(coe)2Cl]2 was
used as the precatalyst along with bulkier XPhos at 1608C, the
conversion of 1a reached 95%, and product 2a was formed in
63% yield (entry 8). Whereas it is challenging to completely
avoid cyclopropane formation, upon fine-tuning the metal/
ligand ratio and adjusting the reaction temperature (for more
details, see the Supporting Information), we were able to
elimination upon C C cleavage to give various ring-opening
products;[7,13] however, the desired bicycle (2 f) was still
isolated in 48% yield. It is likely that the bulky XPhos ligand
inhibited b-hydrogen elimination.[14] Not surprisingly, increas-
ing the steric hindrance of the olefin hampered the 2p inser-
tion, leading to larger quantities of the cyclopropane side
products. Nevertheless, a substrate containing a 1,1-disubsti-
tuted alkene (1g) still gave the decarbonylative cycloaddition
product in 58% yield.[15] When spirocyclic compound 1h
reacted under the standard conditions, the novel 5-6-5 fused/
bridged scaffold (2h) was isolated in 61% yield as a single
diastereomer. Changing the nitrogen protecting group from
2
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Table 2: Substrate scope.[a]
Entry
Substrate
Product
Yield
Entry
10[e]
Substrate
Product
Yield
[%][b]
[%][b]
67
86[f]
1
70[f,g]
2
3
4
5
68
67
65
56
11[e]
12[e]
13[e]
14[e]
80
83
80
82
6
48
58
61
63
15[e,h]
16[e,h]
17[e,h]
58
78
76
7[c]
8
9[d]
[a] Each reaction was run on 0.1 mmol scale in a sealed 8 mL vial, using 5 mol% [Rh(coe)2Cl]2 and 10 mol% XPhos in 1,4-dioxane (1.4 mL) at 1708C
for 72 h. [b] Yields of isolated products. For the yields of the corresponding cyclopropane and (4+2) side products, see the Supporting Information.
[c] A 4 mL vial was used. [d] Ns=2-nitrobenzenesulfonyl. [e] For entries 10–17, 40 mL vials were used. [f] Yield determined by 1H NMR spectroscopy
using mesitylene as the internal standard. [g] [Rh(coe)2Cl]2 (2.5 mol%) and XPhos (5 mol%). [h] 1,4-Dioxane (0.7 mL). Bn=benzyl, TBS=tert-
butyldimethylsilyl.
Ts to Ns (1i) did not significantly affect the reactivity
(entry 9).[16]
selectivity, and that by reducing the CO concentration, the
decarbonylative pathway could be accelerated. Indeed, upon
choosing a reaction vessel with a significantly larger gas
volume (switching from an 8 mL to a 40 mL vial), the desired
[2.2.1]bicycle (2j) was formed in 86% yield (entry 10).
Gratifyingly, the reaction with a 1,1-disubstituted alkene
(1k) also gave the corresponding product in high yield owing
to the more reactive arene linkage (entry 11). Furthermore,
many functional groups were tolerated (entries 12–17), which
shows promise for applications in complex molecule syn-
thesis.
Compared to substrates with nitrogen linkers, those with
an arene backbone (1j–1q) were found to be more reactive
towards cycloaddition. Instead of the cyclopropane forma-
tion, the (4+2) coupling (between the cyclobutanone and the
alkene) was found to be the major competing reaction
pathway.[8] For example, under the standard conditions,
substrate 1j produced an equal amount of the (4+2À1) and
(4+2) products in a total yield of 90%. We hypothesized that
the CO pressure would have a strong influence on the product
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As cyclopropane formation and regular (4+2) cut-and-
sew addition were the major side reactions, we asked
ourselves whether the (4+2À1) product originates from
a (3+2) cycloaddition between cyclopropane and olefin or
from decarbonylation of the (4+2) cyclohexanone product.
To gain more mechanistic insight, two control experiments
were conducted (Scheme 2). When cyclopropane 3a or (4+2)
product 4 was subjected to the standard decarbonylative
coupling conditions, product 2a was not formed. These
Scheme 4. Synthesis of Tolciclate.
was obtained in two steps from bridged intermediate 13
through demethylation and thiocarbamate formation
(Scheme 4).
Acknowledgements
This project was supported by the NIGMS (R01GM109054)
and the Welch Foundation (F 1781). G.D. is a Searle Scholar
and Sloan fellow. Johnson Matthey is acknowledged for the
donation of Rh salts. Prof. Dr. M. C. Young is thanked for
proofreading the manuscript. We also thank Dr. V. Lynch and
Dr. M. C. Young for X-ray structure determination.
Scheme 2. Control experiments.
observations suggest that 1) the cyclopropane formation and
the (4+2) cyclization are unlikely part of the catalytic cycle,
and that 2) product 2a should be directly formed from the
À
Keywords: C C activation · cycloaddition · cyclobutanones ·
À
cyclobutanone precursor through C C cleavage, CO de-
decarbonylation · rhodium catalysis
insertion, olefin migratory insertion, and reductive elimina-
tion, although the timing of the decarbonylation step remains
to be defined.
Furthermore, the decarbonylative cut-and-sew products
can be conveniently derivatized (Scheme 3). For example, the
N-tosyl group can be removed under mild conditions and
converted into an acetyl group. In addition, lactam 6 and
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À
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Scheme 3. Synthetic applications. brsm=based on recovered starting
material.
4
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Received: August 20, 2016
Published online: && &&, &&&&
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Communications
À
C C Activation
X. Zhou, H. M. Ko,*
G. Dong*
&&&& — &&&&
Synthesis of Bridged Cyclopentane
Derivatives by Catalytic Decarbonylative
Cycloaddition of Cyclobutanones and
Olefins
Decarbonylative “cut and sew”: An intra-
molecular decarbonylative coupling
between cyclobutanones and alkenes has
been developed that proceeds by rho-
vides a distinct approach to a diverse
range of saturated bridged cyclopen-
tanes. In this formal (4+2À1) transfor-
mation, cyclobutanones serve as cyclo-
propane surrogates.
À
dium-catalyzed C C activation and pro-
6
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