Rhodium-Catalyzed Stereoselective Intramolecular Tandem Reaction of Vinyloxiranes with Alkynes: Atom- and Step-Economical Synthesis of Multifunctional Mono-, Bi-, and Tricyclic Compounds

Article abstract of DOI:10.1021/acscatal.6b03399

Skeletal diversity in diversity-oriented synthesis has proven to be especially challenging. A rhodium-catalyzed intramolecular tandem reaction of vinyloxirane-alkynes leading to four structurally distinct classes of mono-, bi-, and tricyclic carbocycles and heterocycles was developed. [Rh(NBD)₂]⁺BF₄^- is identified to be an efficient catalyst for these transformations. Using this highly efficient catalyst, hetero-[5 + 2] cycloadditions, tandem hetero-[5 + 2] cycloaddition/Claisen rearrangements, and subsequent cyclopropane ring-opening reactions of vinyloxiranes with monoalkynes afford 2,5-dihydrooxepins, tetrasubstituted vinylcyclopropanes, and multifunctional five-membered rings, respectively, under mild conditions with high stereoselectivity and yield. Moreover, hetero-[5 + 2] cycloaddition/Claisen rearrangement/[5 + 2] cycloaddition reactions of vinyloxiranes with diynes for step-economical construction of linearly fused 5-7-5 tricyclic skeletons has also been developed. The complete transfer of chirality from readily available vinyloxiranes to the corresponding products provides a highly efficient and practical access to these chiral cyclic compounds.

Full text of DOI:10.1021/acscatal.6b03399

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Article
Rhodium-Catalyzed Stereoselective Intramolecular Tandem
Reaction of Vinyl Oxiranes with Alkynes: Atom- and Step-Economic
Synthesis of Multifunctional Mono-, Bi- and Tri-Cyclic Compounds
Jian-Jun Feng, and Junliang Zhang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03399 • Publication Date (Web): 13 Jan 2017
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ACS Catalysis
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Rhodium-Catalyzed Stereoselective Intramolecular Tandem
Reaction of Vinyl Oxiranes with Alkynes: Atom- and Step-
Economic Synthesis of Multifunctional Mono-, Bi- and Tri-
Cyclic Compounds
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JianꢀJun Feng* and Junliang Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering,
East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062, P. R. China.
ABSTRACT: Skeletal diversity in diversityꢀoriented synthesis has proven to be especially challenging. A rhodiumꢀcatalyzed inꢀ
tramolecular tandem reaction of vinyl oxiraneꢀalkynes leading to four structurally distinct classes of monoꢀ, biꢀ and triꢀcyclic carꢀ
bocycles and heterocycles was developed. [Rh(NBD)2]+ BF4ꢀ is identified to be efficient catalyst for these transformations. Using
this highly efficient catalyst, heteroꢀ[5+2] cycloadditions, tandem heteroꢀ[5+2] cycloaddition/Claisen rearrangement and subseꢀ
quent cyclopropane ring opening reactions of vinylic oxiranes with monoꢀalkynes afford 2,5ꢀdihydrooxepins, tetrasubstituted vinylꢀ
cyclopropanes and multifunctional fiveꢀmembered rings, respectively, under mild conditions with high stereoselectivity and yield.
Moreover, heteroꢀ[5+2] cycloaddition/Claisen rearrangement/[5+2] cycloaddition reaction of vinylic oxiranes with diynes for stepꢀ
economic construction of linearly fused 5ꢀ7ꢀ5 tricyclic skeletons has also been developed. The complete transfer of chirality from
readily available vinylic oxiranes to the corresponding products provides a highly efficient and practical access to these chiral cyꢀ
clic compounds.
KEYWORDS: Rhodium, tandem reaction, vinylic oxirane, alkyne, diversityꢀoriented synthesis, chirality transfer
1. INTRODUCTION
The design or discovery of new versatile building blocks is of
preeminent importance to the realization of the diversityꢀ
oriented synthesis (DOS).1 Cyclopropanes, cyclopentenes, 2,3ꢀ
dihydroꢀ1Hꢀpyrroles, 2,3ꢀdihydrofurans, oxepines and linearly
fused 5ꢀ7ꢀ5 tricyclic skeletons are ubiquitous structural motifs
found in an array of natural products and pharmaceuticals with
diverse biological and medicinal properties (Figure 1).2 Thereꢀ
fore, the development of highly efficient synthetic methods to
access these skeletons has been intensively pursued by synꢀ
thetic community.3 However, the widely applied approaches
for construction of these threeꢀ, fiveꢀ and sevenꢀmembered
carbocycles and heterocycles require building each ring indeꢀ
pendently from different building blocks. Thus, the developꢀ
Figure 1. Representative biologically active threeꢀ, fiveꢀ and sevꢀ
enꢀmembered carbocycles and heterocycles.
ment of an ideal method for construction of these diverse scafꢀ
folds from a common building block in an atomꢀ and stepꢀ
Trost,9 Louie,10 Fürstner11 have realized the [5+2] cycloaddiꢀ
economic fashion is extremely interesting and highly desiraꢀ
ble.4
tions of VCPs and alkynes by using different transitionꢀmetal
catalysts. [5+2+1],12 [5+1],13 [5+1+2+1]14 cycloadditions have
Modern transition metalꢀcatalyzed cycloaddition reactions
also been developed for constructing different cyclic systems
in which VCPs serving as fiveꢀcarbon synthons. The VCP
motif can also act as an activated cyclopropane ring (threeꢀ
carbon synthon) to undergo [3+x] cycloadditions, Tsuji,15a
Trost,15bꢀc Yu,15dꢀi and others15jꢀm have done seminal work on
this kind of cycloadditions. The significance of the VCPs has
been highlighted in the synthesis of several natural products
by using [5+x] and [3+x] cycloadditions.7c,16
represent powerful tools enabling quick and efficient access to
monoꢀ, biꢀ and tricyclic structures from relatively simple startꢀ
ing materials.5 In particular, using smallꢀring compounds as
cycloaddition partners brings opportunities for developing
novel reactions that complement to or surpass traditional cyꢀ
cloadditons.6,7 Among them, vinylcyclopropanes (VCPs) repꢀ
resent an important subclass of activated cyclopropane derivaꢀ
tives with rich cycloaddition chemistry.7 For example,
Wender’s group pioneered the development of Rhꢀcatalyzed
[5+2] cycloadditions of VCPs and πꢀsystems for synthesis of
sevenꢀmembered rings.8 Subsequently, the research groups of
Due to the inherent reactivity of their constrained ring sysꢀ
tem, cyclopropane and oxirane derivatives constitute valuable
building blocks for organic synthesis.17 In contrast to VCPs,
vinyl oxiranes18, one of versatile synthons of oxirane derivaꢀ
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tives, have and continue to serve as attractive ringꢀexpansion [5+2]cycloaddition/Claisen rearrangement/[5+2] cycloaddition
motifs in metalꢀcatalyzed [3+2] cycloadditions,19 epoxide carꢀ
bonylation20 and substitution reactions.21 Recently, an elegant
system for copperꢀcatalyzed rearrangement of vinylic oxiranes
to 2,5ꢀdihydrofurans has been developed by Njardarson
group.22 However, there has been no report about utilizing
vinyl oxiranes as a hetero fiveꢀatom partner in cycloaddition
reaction until we reported an atomꢀeconomic route to multiꢀ
substituted VCPs relying upon a new synthetic application of
vinylic oxiranes in a rhodiumꢀcatalyzed intramolecular heteroꢀ
[5+2] cycloaddition/Claisen rearrangement reaction.23 Altꢀ
hough many fiveꢀcarbon components have been developed,8m,
reaction of vinyl oxiranes with diynes for construction of 5ꢀ7ꢀ
5 tricyclic compounds in one step (Scheme 1d). In addition,
enantioselective synthesis of these compounds from optically
pure vinyl oxiranes via a chirality transfer process was
achieved and mechanistic studies have also been investigated.
Of note, while other catalystꢀselective synthesis systems are
known,26 we know few being capable of delivering the level of
skeletal diversity by simply varying the reaction temperature
and using a single catalyst.
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2. RESULTS AND DISCUSSION
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-
2.1 [Rh(NBD)2]+BF4 catalyzed hetero-[5+2] cycloaddi-
24
cyclopropylimines had been the only heteroatomꢀcontaining
tion and tandem hetero-[5+2] cycloaddition/Claisen rear-
rangement reaction of vinyl oxiranes with mono-alkynes
fiveꢀatom component in Rhꢀcatalyzed heteroꢀ[5+2] cycloaddiꢀ
tion prior to our study.25a,b Considering that the product of
heteroꢀ[5+2] cycloaddition/Claisen rearrangement reaction is
the multifunctional VCPs and the rich chemistry of VCPs,7,8
we became interested in whether vinylic oxiraneꢀalkynes 1
could be used as a common precursor to build structurally
distinct compounds and tuning the selectivity by the subtle
choice of catalyst and modification of the substrate.
Oxepine derivatives represent a ubiquitous class of oxygenꢀ
containing heterocycles with wide occurrence in numerous
biologically active natural products and pharmaceuticals, such
as Lobatrienetriol, Zoapatanol, and Stellettasterenol (Figure
1).2 However, relative to reactions that establish fiveꢀ and sixꢀ
membered oxygenꢀheterocycles, the development of efficient
methodology for construction of oxepine skeletons is often
much more difficult because of the unfavorable entropic facꢀ
tors and transannular interactions.27
Scheme 1. Diversity-Oriented Synthesis of Three-, Five
and Seven-Membered Rings from Vinyl Oxirane-Alkynes
-
Table 1. [Rh(NBD)2]+BF4 -Catalyzed Hetero-[5+2] Cy-
cloaddition Reactiona
yield
entry
1c
substrate
product
(%)b
72
2a
1a
1b
1c
2c
3d
75
56
65
2b
7c
4 d
7d
1d
In previous examples,23 we found that RhCl(IPr)(COD)
/AgSbF6 bearing a strong σꢀdonating IPr ligand can catalyze
the heteroꢀ[5+2] cycloaddition/Claisen rearrangement reaction
a
ꢀ
Conditions A: 1 (0.2 mmol), [Rh(NBD)2]+BF4 (5 mol%), in
CH2Cl2 (0.08 M) at 0 oC. b Isolated yield. c The reaction was run at
o
o
d
at 60ꢀ84 C. Because the Claisen rearrangement of 2 to 3 is a
20 C. the corresponding heteroꢀ[5+2] cycloadduct was treated
rapid process under thermal conditions, it is very hard to obꢀ
tain the heteroꢀ[5+2] cycloadducts 2. With respect to substrate
scope, the alkyne moiety of 1 was limited to internal alkyne.
In this article, we demonstrate the details of the development
of this heteroꢀ[5+2] cycloaddition/Claisen rearrangement reacꢀ
tion and expansion of its substrate scope to both trimethylsilyl
alkyne and terminal alkynes by using [Rh(NBD)2]+BF4ꢀas the
catalyst (Scheme 1b). Furthermore, We also found that
[Rh(NBD)2]+BF4ꢀ is an efficient catalyst for catalyzing this
reaction at room temperature, which give an opportunity to
obtain the heteroꢀ[5+2] cycloaddition product, i.e. 2,5ꢀ
dihydrooxepin 2 (Scheme 1a). We also disclose two new
[Rh(NBD)2]+BF4ꢀcatalyzed cascade reactions: 1) heteroꢀ[5+2]
cycloaddition/Claisen rearrangement/cyclopropane ring openꢀ
ing reaction of vinyl oxiranes with monoꢀalkynes leading to
multifunctional five membered rings (Scheme 1c); 2) heteroꢀ
with 10 % Pd/C and H2 (1atm).
During our investigation of Rh(I)ꢀcatalyzed cycloadddiꢀ
tions of vinylaziridines with πꢀsystems,28 we found that the
cationic rhodium(I) complex [Rh(NBD)2]+BF4ꢀ is a convenient
and highly effective catalyst for the intramolecular heteroꢀ
[5+2] cycloaddition of vinylaziridines and a wide range of
terminal and internal alkynes. Atom analogy suggests that
vinyl oxiraneꢀalkynes could be analogously activated by
[Rh(NBD)2]+BF4ꢀ to generate fused oxepine derivatives. Altꢀ
hough this assumption was first validated by us in 2011, the
use of firstꢀgeneration catalyst (RhCl(IPr)(COD)/AgSbF6)
makes it very hard to intercept of heteroꢀ[5+2] cycloadducts 2,
due to the rapid Claisen rearrangement of 2 to vinylcycloproꢀ
pane derivative 3 under thermal conditions. For example, subꢀ
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ACS Catalysis
Claisen rearrangement reaction could occur even at room temꢀ
strate 1a in presence of 5 mol% of RhCl(IPr)(COD)/AgSbF6 in
DCE for 4 h at 84 oC, gave only 9% NMR yield of the heteroꢀ
perature (Table 2). Both internal (entries 1ꢀ10, 14) and termiꢀ
nal alkynes (entries 11ꢀ13) were compatible to afford the corꢀ
responding vinylcyclopropane products 3, which have demonꢀ
strated a broad substrate scope in current reaction (entry 11
versus 12). Dramatic improvements were also observed for
other substrates, when using [Rh(NBD)2]+ BF4ꢀ as the catalyst.
For example, moderate yield was obtained for substrate 1g
under conditions C (RhCl(IPr)(COD)/AgSbF6). By contrast,
product 3g was isolated in 72% yield under conditions B (enꢀ
try 3 versus 4). What’s more, the treatment of 1h (R1 = TMS)
with [Rh(NBD)2]+BF4ꢀ can also furnish the corresponding
product in 64% yield. Whereas, 1h decomposed quickly under
the catalysis of RhCl(IPr)(COD)/AgSbF6 (entry 5 versus 6).
Substrate 1s was prepared to test the limitation of the present
reaction. Under conditions B, no reaction occurred, and the
starting material was recovered (Figure 2).
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5
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[5+2] cycloadduct 2a with the further Claisen rearrangement
products 3a and 6a in 83% total NMR yield (eq 1).23 Moreoꢀ
ver, the previous tandem heteroꢀ[5+2] cycloaddition/Claisen
rearrangement reaction of vinyl oxiranes with monoꢀalkynes
under the catalysis of RhCl(IPr)(COD)/AgSbF6 is limited to
internal alkynes. Thus, the development of the secondꢀ
generation catalyst to broaden the substrate scope under mild
reaction conditions and intercept the heteroꢀ[5+2] cycloadduct
is highly desirable.
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To our delight, as depicted in Table 1, subjection of 1a and
1b to the mixture of 5 mol% [Rh(NBD)2]+BF4ꢀ in CH2Cl2 at 20
oC afforded the desired products 2a and 2b in 72% and 75%
yields, respectively (Table 1, entries 1 and 2). It was found
that 2,5ꢀdihydrooxepin products were not stable at room temꢀ
perature for prolonged reaction time, because of the enol ether
In order to gain insight into above transformations, cisꢀ
oxirane substrate 1t was also prepared. It is noteworthy that
substrate 1t in presence of 5 mol% [Rh(NBD)2]+BF4ꢀ in DCE
o
for 1 h at 75 C gave a more stable heteroꢀ[5+2] cycloadduct
2t in 72% NMR yield together with a 8% NMR yield of 3t (eq
2). Moreover, 2t could rearrange to 3t as a single diastereomer
upon heating in the absence of the Rh catalyst (eq 3). Besides
these, enantioenriched substrate (R,R)ꢀ1d (92% ee) was preꢀ
pared from the corresponding chiral epoxide 8, which was
easily accessed by asymmetric Shi expoxidation of ethyl sorbꢀ
ate.29 Surprisingly, both diꢀ and tetraꢀsubstituted alkene moieꢀ
ties of the corresponding heteroꢀ[5+2] cycloadducts could be
hydrogenated under the Pd/C, H2 conditions, affording the
corresponding (+)ꢀ7d, possessing four chiral stereocenters,
with 94% ee as a single diastereomer (eq 4). The absolute conꢀ
figuration of (+)ꢀ7d was determined by Xꢀray analysis (Figure
2).30 Complete transfer of chirality in heteroꢀ[5+2] cycloaddiꢀ
tion/Claisen rearrangement reaction of 1d under conditions B
to access multiꢀsubstituted VCPs was also observed (eq 5).
moiety. To facilitate easy characterization, the heteroꢀ[5+2]
cycloadducts 2c and 2d were further treated with 10 % Pd/C
and H2, delivering the fully saturated oxepanes 7c and 7d in
acceptable yield over two steps (Table 1, entries 3 and 4).
Table 2. [Rh(NBD)2]+BF4 -Catalyzed Tandem Hetero-[5+2]
-
Cycloaddition/Claisen Rearrangement Reactiona
R4
R1
R4
R4
R4
R1
O
5 mol% [Rh(NBD)2]+BF4
DCE / RT
-
X
H
X
O
H
R3
R2
R3
3
R2
1
entry
X
R1/R2/R3/R4 (1)
t (h) yield
(%)b
1
C(CO2Me)2 Ph/Ph/H/H (1e)
5
7
7
5
2
5
7
3e (92)
2
C(CO2Me)2 4ꢀMeOC6H4/Ph/H/H(1f)
C(CO2Me)2 4ꢀClC6H4/Ph/H/H (1g)
C(CO2Me)2 4ꢀClC6H4/Ph/H/H (1g)
C(CO2Me)2 TMS/Ph/H/H (1h)
C(CO2Me)2 TMS/Ph/H/H (1h)
3f (89)
3g (72)
3g (50)
3h (64)
3h (<5)
3i (82)
3
4c
5
6c
7
NNs
NTs
NTs
NTs
NTs
NTs
NTs
O
Ph/Ph/H/H (1i)
Ph/CH2OTBS/H/H (1j)
Me/Ph/H/H (1k)
Me/Me/H/H (1d)
H/Ph/H/H (1l)
8
1.5 3j (80)
9
1
2
2
4
4
5
3k (88)
3d (86)
3l (60)
3l (<5)
3m (45)
10
11d
12c,d
13d
14
H/Ph/H/H (1l)
H/Ph/H/Me (1m)
Ph/Ph/H (1n)
3n (83)
a Conditions B: 1 (0.2 mmol), 5 mol% [Rh(NBD)2]+BF4 , DCE
ꢀ
(0.08 M), 20 C. b isolated product. c Conditions C: 5 mol%
o
RhCl(IPr)(COD)/AgSbF6 (1:1), DCE (0.08 M), 75 oC; 10
d
mol% catalyst was used.
Unfortunately, the interception of heteroꢀ[5+2] cycloadꢀ
duct 2 is still quite challenging even using the secondꢀ
generation catalyst [Rh(NBD)2]+ BF4ꢀ and the subsequent
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Figure 2. Substrate 1s and crystal structure of compound (+)ꢀ7d
1
and 4d.
2
3
4
2.2 Tandem hetero-[5+2] cycloaddition/Claisen rear-
rangement/cyclopropane ring opening reaction.
After running the reaction of 1e at rt for 21 hours under the
catalysis of [Rh(NBD)2]+BF4ꢀ, 6% NMR yield of cyclopentene
derivative 4e was observed, which was derived from the ringꢀ
opening of 3e in the presence of rhodium catalyst (Table 3,
entry 1 and eq 6). Given that five membered rings are ubiquiꢀ
tous in organic molecules and tandem reactions involved
VCPs are relatively rare,8k,l a systemic screening of the cataꢀ
lysts and conditions for realizing the tandem heteroꢀ[5+2] cyꢀ
cloaddition/Claisen rearrangement/cyclopropane ring opening
reaction was carried out. Under the conditions C described in
Table 2, no any five membered ring product 4e was detected
(Table 3, entry 3). In contrast, the treatment of 1e with 5 mol%
[Rh(NBD)2]+BF4ꢀ in DCE at 75 oC for 5 h furnished 4e in 91%
NMR yield. Other cationic rhodium catalysts were also examꢀ
ined, but did not give better result (entries 4ꢀ5). Different solꢀ
vents (entries 6ꢀ8) were tested and 1,4ꢀdioxane was also found
to be a suitable solvent.
5
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7
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With the optimal reaction conditions in hand, we next exꢀ
amined the scope of this tandem reaction by variation of the
substitution patterns on alkyne and epoxide moieties (Table 4).
Table 4. Rh(I)-Catalyzed Tandem Hetero-[5+2] Cycloaddi-
tion/Claisen Rearrangement/Cyclopropane Ring-Opening
Reactiona
Table 3. Optimization of Reaction Conditionsa
entry
substrate
product
yield(%)b
1
2
3
4
1e, R = Ph
4e, R = Ph
90
time yield(%)d
1f, R = 4ꢀMeOC6H4
1g, R = 4ꢀClC6H4
4f, R = 4ꢀMeOC6H4
4g, R = 4ꢀClC6H4
86
77
entry
catalyst (mol%)
solvent
(h)
4e 3e
ꢀ
1b
2
3c
[Rh(NBD)2] +BF4
[Rh(NBD)2] +BF4
DCE
DCE
DCE
DCE
21
6
85
0
93
86
71
41
ꢀ
5.0
2.0
8.0
91
0
1c
4c
4o
RhCl(IPr)(COD)/AgSbF6
[Rh(η6ꢀ
94
0
5c
6
4
80
C10H8)(COD)]+SbF6
ꢀ
ꢀ
[Rh(COD)2] +BF4
DCE
5.0
52 24
1o
1b
5
O
Me
ꢀ
6e
[Rh(NBD)2] +BF4
[Rh(NBD)2] +BF4
Toluene 5.0
Dioxane 5.0
0
67
0
Me
ꢀ
7
91
CO2Me
MeO2C
ꢀ
[Rh(NBD)2] +BF4
MeOH f
5.0
69 13
4b
8
a
7
Unless otherwise noted, the reaction was performed with 0.2
o
b
mmol of 1e and 5 mol% of catalyst in 2.5 mL DCE at 75 C.
Reaction was run at RT. c Rh to AgSbF6 = 1:1. d NMR yield with
CH2Br2 as an internal standard. e 30% 1a was recovered. f 0.1 mL
MeOH in 2.5 mL DCE.
1h
1i
4h
4i
8
85
81
92
93
9
4p
4k
4d
1p
1k
1d
10
11
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12
1
94
2
3
4
5
6
7
8
9
10
4q
4n
1q
1n
1r
13c
61
14c
40
4r
a
ꢀ
Reaction conditions: 1 (0.2 mmol), [Rh(NBD)2]+BF4 (5
mol%) in DCE (2.5 mL) at 75 oC. b Isolated yield. c the reaction
was carried out as follow: RhCl(IPr)(COD)/AgSbF6 (5 mol%),
The plausible mechanism for the formation of five memꢀ
bered ring 4 was presumably originated from the oxidative
addition of 3 affords the Rh(III) intermediate followed by βꢀH
elimination and reductive elimination. With this in mind, we
wondered whether we can intercept this Rh(III) intermediate A
by another alkyne or not. If it works, one step construction of
multifunctional fused 5ꢀ7ꢀ5 tricyclic skeleton 10 from a readiꢀ
ly available linear starting materials could be realized (Scheme
2). This stepꢀ,31a,b atomꢀ32 and timeꢀ31c economical approach
precludes the challenging synthesis of multisubstituted vinylꢀ
cyclopropanes with high diastereoselectivities and enantioseꢀ
lectivities. The major challenge for this route is to identify the
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20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
60 or 75 C, 3 h then [Rh(NBD)2]+BF4 (5 mol%), 75 C, 6 h,
o
ꢀ
o
DCE (3 mL).
Variation of the substituent with different electron nature of
the aryl ring on the alkyne moiety showed that the electron
rich ones would give higher yields than those with electronꢀ
deficient ones (Table 4, entries 1ꢀ3). Besides the substituted
phenyl, methylꢀ and trimethylsilyl alkyne could be compatible
with this reaction (entries 4ꢀ7). The present transformation is
tolerant of tether incorporating sulfonamide functionality to
afford 81ꢀ94% yield of the corresponding 2,3ꢀdihydropyrroles
that commonly appear in natural alkaloids and biologically
relevant compounds (entries 8ꢀ12). The structure of the 2,3ꢀ
dihydropyrrole 4d was unambiguously assigned by the Xꢀray
analysis (Figure 2).30 Moreover, it should be noted that 1q
with trisubstituted alkene reacts cleanly to afford the desired
product 4q as a single diastereomer (entry 12). However, Subꢀ
strates 1n or 1r with an oxygen linker yielded the correspondꢀ
ing product 4 in poor yield using [Rh(NBD)2]+BF4ꢀ as catalyst.
But it can be improved to moderate to good yield by oneꢀpot
operation and a stepwise addition of RhCl(IPr)(COD)/AgSbF6
and [Rh(NBD)2]+BF4ꢀ (entries 13 and 14).
Scheme 3. [5+2] Cycloaddition of 3u
Importantly, a complete chirality transfer was observed in
the present tandem process, providing a new and rapid method
for the synthesis of multifunctional fiveꢀmembered carbocyꢀ
cles and heterocycles in an enantioselective manner (eq 7 and
8).
Table 5. Optimization of Reaction Conditionsa
2.3 Tandem hetero-[5+2] cycloaddition/Claisen rear-
rangement/[5+2] cycloaddition reaction of vinyl oxiranes
with diynes.
Tricyclic and polycyclic carbocycles and heterocycles are
widely found in biologically active natural and unnatural
products, such as the linearly fused 5ꢀ7ꢀ5 tricyclic skeletons of
the Calyciphylline A class alkaloids (Figure 1).2f Owing to the
diversity of biological functions and pharmacological activiꢀ
ties coupled with complex structural features, these multifuncꢀ
tional 5ꢀ7ꢀ5 tricyclic compounds have attracted much attention
as targets for total synthesis. Previous approaches for conꢀ
struction of these challenging 5ꢀ7ꢀ5 tricyclic scaffolds have
focused on building each ring step by step2e or building one
ring first and then the other two rings in one step.9aꢀc The deꢀ
sign of new cycloaddition reactions and reaction sequences
that enable the construction these 5ꢀ7ꢀ5 tricyclic skeletons in
one step offer decisive advantages in developing stepꢀ and
atomꢀeconomical synthesis.
yield(%)d
entry
catalyst (5 mol%)
T(oC)
t (h)
3u 5a
1b
2b
3b,f
4c
5b,c
6
RhCl(IPr)(COD)/AgSbF6
RhCl(IMes)(COD)/AgSbF6
NHCRh/AgSbF6
80
80
80
80
80
3.5
3.5
5.0
7.0
7.0
4.0
4.0
99
95
43
ꢀe
0
0
0
0
0
0
0
[Rh(CO)2Cl]2
(PPh3)3RhCl/AgSbF6
[Rh(η6ꢀC10H8)(COD)]+SbF6 30
37
99
25
ꢀ
7
[Rh(dnCOT)(MeCN)2]+
30
ꢀ
SbF6
Scheme 2. Constructions of the Linearly Fused 5-7-5 Tri-
cyclic Systems
ꢀ
8c
9b
[Cp*Ru(MeCN)3] +PF6
50
30
7.0
1.0
29
99
0
0
[Rh(COD)Cl]2/AgSbF6
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a
10
11c
12
13
14
15c
16
[Rh(COD)Cl]2
[Rh(COD)2]+BF4
[Rh(NBD)dppe]+BF4
80
80
30
30
60
60
80
13
ꢀg
0
0
ꢀg
0
Unless otherwise noted, the reaction was performed with 0.12
b
1
2
3
4
5
6
7
ꢀ
mmol of 9a and 5 mol% of catalyst in 3.0 mL DCE. Rh to
9.0
2.5
3.5
97
ꢀg
c
d
1
AgSbF6 = 1:1. Using 10 mol% catalyst. Determined by H
ꢀ
NMR analysis using CH2Br2 as the internal reference. eComplex
f
ꢀ
[Rh(NBD)2]+BF4
99
mixture.
NHCRh = Bromo(cyclooctadiene)[1ꢀ(benzyloxy)ꢀ3ꢀ
benzylꢀ4,5ꢀdimethylimidazolylidene]rhodium. g no reaction.
ꢀ
[Rh(NBD)2]+BF4
28.0 17 77
ꢀ
[Rh(NBD)2]+BF4
4.5
9.0
0
0
94
94
ꢀ
[Rh(NBD)2]+BF4
8
9
Table 6. Exploration of Substrate Scopea,b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
MeO
Cl
OMe
Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
TsN
TsN
NTs
NTs
O
O
TsN
TsN
NTs
NTs
TsN
NTs
TsN
NTs
9a
9b
(8%/10 h)
9c
9d
9e
9f
D
D
D
D
D
D
(5%/9 h)
(8%/10 h)
(8%/11 h)
(8%/12 h)
(8%/10 h)
O
O
H
Ph
TsN
Ph
TsN
H
H
O
O
O
O
Cl
MeO
Ph
TsN
Ph
TsN
H
H
H
H
NTs
NTs
H
NTs
TsN
NTs
TsN
NTs
NTs
H
H
H
H
Ph
H
Ph
Ph
Cl
OMe
5a (90% yield)
5b (88% yield)
5c (91% yield)
5d (82% yield)
5e (84% yield)
5f (51% yield)
Me
Me
Me
Ph
Me
Ph
Ph
Ph
TMS
Ph
Ph
Me
O
O
O
O
O
O
MeO2C
MeO2C
CO2Me TsN
CO2Me
CO2Me
CO2Me
O
CO2Me MeO2C
CO2Me
MeO2C
NTs
TsN
NTs
NsN
NNs
9g
D
9h
D
9i
9j
9k
9l
D
(8%/10 h)d
E
D
E
(10%/11 h)
(10%/14 h)
(8%/10 h)
O
O
H
O
H
O
H
O
H
O
TMS
TsN
Ph
NsN
Me
Ph
TsN
Ph
Me
H
H
H
H
H
H
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C
MeO2C
NTs
NNs
O
NTs
H
H
Ph
Ph
Me
5i
+
Me
Me
Ph
5g (63% yield)
5h (85% yield)
5j
+
5k
5l
+
O
+
H
H
H
H
H
H
Me
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
TsN
O
MeO2C
MeO2C
NTs
Me
O
10i
Me
O
Me
O
H
Me
Ph
Ph
Ph
10j
10k
11l
5i+10i (50%)
5i : 10i = 1.0:4.0c
5j+10j (64%)
5j : 10j = 1.0:1.0c
5k+10k (60%)
5k : 10k= 1.2:1.0c
5l+11l (75%)
5l : 11l = 1.6:1.0c
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
O
MeO2C
MeO2C
O
CO2Me MeO2C
CO2Me
NTs MeO2C
NTs
CO2Me
CO2Me
O
O
O
NTs
MeO2C
MeO2C
9m
D
9n
(5%/9.5 h)
9o
(10%/10 h)e
9p
9q
9r
D
D
E
D
D
(5%/4 h)
(8%/14 h)
(5%/7 h)
O
H
O
O
O
H
O
O
H
Ph
Ph
Ph
Ph
O
Ph
Ph
H
H
H
H
H
H
MeO2C
CO2Me
CO2Me
MeO2C
MeO2C
MeO2C
MeO2C
CO2Me
CO2Me
NTs
NTs
O
O
NTs
O
MeO2C
H
H
H
Ph
Ph
H
Ph
Ph
5q (51% yield)
Ph
5m (72% yield)
5n (88% yield)
5o (41% yield)
5p (71% yield)
5r (78% yield)
Conditions D: 9 (0.12 mmol), [Rh(NBD)2]+BF4 (5ꢀ10 mol%), DCE (0.04 M), 80 oC; Conditions E: 9 (0.12 mmol),
a
ꢀ
RhCl(IPr)(COD)/AgSbF6 (5 mol%), 60 or 80 oC, 4ꢀ10 h then [Rh(NBD)2]+BF4ꢀ (5 mol%), 80 oC, 10 h, DCE. b Yield of the isolated prodꢀ
uct. c Determined by H NMR analysis of the crude product. The reaction was run at RT for 4 h then at 75 C for 10 h. e The reaction
1
d
o
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was run at 65 oC
1
2
3
4
5
6
7
8
9
catalyst system which must be compatible with substrates,
heteroꢀ[5+2] cycloaddition/Claisen rearrangement and [5+2]
cycloaddition reaction into a sequential, oneꢀpot process by
using conditions E smoothly produced the corresponding
products in moderate yields.
intermediates and also exhibit reaction sequence selectivity to
avoid the competing isomerization of the vinyl oxiranes,22,33 [2
+ 2 + 2] cycloadditions of alkynes34 and the reaction described
in section 2.2 of this article. Furthermore, the [5+2] cycloaddiꢀ
tion of tetrasubstituted vinylcyclopropaneꢀalkynes 3 in which
the cyclopropane bearing a carbonyl group have rarely been
studied with Rh catalysts and are unreactive substrates for Ruꢀ
catalyzed [5+2] cycloaddition.9b,c Thus, a variety of catalysts
were examined to achieve the [5+2] cycloaddition of 3u (see
SIꢀTable 1 in the Supporting Information). However, no [5+2]
cycloadduct was detected in presence of commonly used rhoꢀ
dium and ruthenium catalysts in literatures (Scheme 3). Gratiꢀ
fyingly, treatment of 3u with 10 mol% [Rh(CO)2Cl]2 in toluꢀ
After the successful transfer of chirality in the above reacꢀ
tion (section 2.1 and 2.2), we then investigate chirality transfer
in the more challenging tandem heteroꢀ[5+2] cycloaddiꢀ
tion/Claisen rearrangement/[5+2] cycloaddition reaction of
vinyl oxiranes with diynes. This transformation delivers the
formation of four new carbonꢀcarbon bonds, two new carbonꢀ
hetero bonds, three chiral stereogenic centers containing one
quaternary center and three rings in one single step. In order to
be able to synthesize chiral fused 5ꢀ7ꢀ5 tricyclic products steꢀ
reospecifically in a stepꢀeconomic fashion, it is mandatory to
develop a general route of the enantioenriched vinyl oxiraneꢀ
diyne substrates. The Shi asymmetric monoexpoxidation of
conjugated dienes could successfully deliver optically pure
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
ene for 17 h at 80 C gave 5ꢀ7ꢀ5 tricyclic product 5a in 58%
NMR yield favoring regioselective cleavage of the less substiꢀ
tuted cyclopropane bond of 3u, rather than the product 10
described in Scheme 2. Notably, the NMR yield of the [5+2]
cycloaddition of 3u could be improved to 98% using
[Rh(NBD)2]+BF4ꢀ.
Scheme 4. Converting One Common Precursor to Five
Enantioenriched Vinylic Oxiranes-Diynes
To simplify the procedure, an ideal way to build the triꢀ
cyclic skeleton that would be to mediate both heteroꢀ[5+2]
cycloaddition/Claisen rearrangement reaction and [5+2] cyꢀ
cloaddition by a cascade catalyst system. A series of Rh and
Ru catalysts was tested but failed to realize this idea (Table 5,
entries 1ꢀ12). When we carried out the reaction in the presence
of 5 mol% [Rh(NBD)2]+BF4ꢀ at 30 oC, 3u was also obtained in
99% NMR yield (entry 13). To our delight, elevating the temꢀ
o
perature to 60 C provided 5a as a single stereoisomer in 77%
NMR yield together with a 17% NMR yield of 3u (Table 5,
entry 14). Both increasing the catalyst loading and raising the
temperature significantly improved the yield of 5a to 94%
(Table 5, entries 15 and 16). Interestingly, [Rh(COD)2]+BF4ꢀ
containing a COD ligand failed to catalyze this reaction (Taꢀ
ble 5, entry 11).
vinyloxiranesꢀdiynes 9.29 Enantioenriched substrates 9m, 9n
and 9p-9u were rapidly prepared from readily available
(2E,4E)ꢀhexaꢀ2,4ꢀdieneꢀ1,6ꢀdiol 12 or (2E,4E)ꢀ1,6ꢀdibromoꢀ
hexaꢀ2,4ꢀdiene in just two or three steps (please see Supportꢀ
ing Information for details). For example, as depicted in
Scheme 4, Compounds 14 and 15 were synthesized by Wilꢀ
liamson etherification reaction of 12 with 13, then 15 reacted
with the corresponding functionalized alkynes to generate
diynes 16 or 17. Shi asymmetric monoexpoxidation of 14, 16
and 17 finally gave the enantioenriched vinyl oxiraneꢀdiynes
9p, 9q, 9s, 9r and 9t. According to this synthetic route, stratꢀ
ing from one common precursor 12, five optically pure vinyl
oxiraneꢀdiynes were efficiently synthesized.
Under the optimal reaction conditions, a series of vinyl
oxiraneꢀdiyne substrates 9 were tested under the optimized
reaction conditions D (Table 6). It was found that a variety of
tethers (nitrogenꢀ, oxygenꢀ, and gemꢀdiester) could be compatꢀ
ible, delivering 5ꢀ7ꢀ5 heteroꢀ and carbotricyclic skeletons
(substrates 9a, 9h, 9m, 9n, 9q and 9r). Both internal and terꢀ
minal alkynes were compatible to afford 5ꢀ7ꢀ5 tricyclic scafꢀ
folds (9f and 9o). The alkyne substitution could be either an
aromatic (9aꢀ9e) or alkyl group (9i). A substrate (9g) bearing a
trimethylsilyl alkyne was also successfully converted to the
desired product. Notably, when R1 and R2 substituents of 9 are
aromatic group, the reactions provided 5 as a single regioisoꢀ
mer and diastereoisomer favoring regioselective cleavage of
the less substituted cyclopropane bond of 3, suggesting that
the steric effect is the dominant factor. Compound 9i bearing
methyl group on R1 and R2 gave 5i and 10i in a ratio of 1:4,
whereas substrate 9l with methyl group on R1 and phenyl
group on R2 afforded 5l in reasonable 45% yield and 30%
yield of 11l which arises from the isomerization of the olefin
to form a more stable 1,3ꢀdiene. For substrates 9j, 9k, and 9p
either some complex mixture or only trace amount of the 5ꢀ7ꢀ5
tricyclic products was observed under conditions D probably
owing to the cationic and Lewis acidic rhodium catalyst inꢀ
duced isomerization of the epoxide. In order to address this
issue, an alternative strategy was developed. Coupling the
Table 7. Stereospecific Tandem Hetero-[5+2] Cycloaddi-
tion/Claisen Rearrangement/[5+2] Cycloadditiona,b
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60
2.5 Mechanistic consideration.
With the aid of DFT calculation, two general mechanisms
of transition metalꢀcatalyzed [5+2] cycloadditions of VCPs
and πꢀsystem have been proposed. Houk and Wender showed
that Rh(I)ꢀcatalyzed [5+2] reactions usually involve the forꢀ
mation of a metallacyclohexene intermediate, which can then
be intercepted by various cycloaddition components.35 Recentꢀ
ly Houk and Trost found that the mechanism involving an
initial eneꢀyne oxidative cyclization to form a metallacycloꢀ
pentene intermediate followed by cyclopropane cleavage and
reductive elimination is favored in Ru(II) catalytic system.9d
a
The reaction was carried out under the conditions D or E as
b
those described in Table 6. Yield of the isolated product.
X = C(CO2Me)2
Based on the above suggestion and the chirality transfer
experiment, we proposed the mechanism shown in Scheme 6
for the rhodiumꢀcatalyzed tandem reaction involving heteroꢀ
[5+2] cycloaddition of vinyl oxiranes with alkynes. In cycle I,
the rhodium complex πꢀfacial selectivity coordination to eneꢀ
yne moieties of the optically pure (S,S)ꢀ1 would give diastereꢀ
omeric metallacyclopentenes A-II or B-II formed by oxidative
cyclometalation of the 1,6ꢀenyne moiety. The subsequent forꢀ
mation of a Zꢀolefin in A-IV and B-IV requires a syn alignꢀ
ment of the protons Hb and Hc along the CꢀC bond, which is
achieved through rotation around the HbꢀCꢀCꢀHc bond to give
A-III and B-III. However, only the conformation of A-III
allows the CꢀO bond in the epoxide moiety to properly overlap
with the CꢀRh bond as required for concerted ring expansion
to afford the rhodium species A-IV. Then, reductive eliminaꢀ
tion of C(sp2)ꢀRhꢀO bond25f from A-IV produces the 2,5ꢀ
dihydrooxepin (S,R)ꢀ2 and regenerates the rhodium catalyst.
The observed highly efficient chirality transfer is thus a conꢀ
sequence of the reversibility of the initial mechanistic steps
and the influence of the substituent on a later step, putatively
involving irreversible cleavage of the CꢀO bond. Finally, the
2,5ꢀdihydrooxepins 2 undergo a subsequent stereospecific
Claisen rearrangement to afford the VCPs (R,R,R)ꢀ3. In cycle
II, metallacyclohexene intermediate Int-C could be derived
from the cleavage of bond a in (R,R,R)ꢀ3, then it underwent βꢀ
H elimination and reductive elimination to afford product (R)ꢀ
4. By contrast, in cycle III, Int-E could be originated from
regioselective cleavage of the less substituted cyclopropane
bond b in (R,R,R)ꢀ3 owing to the steric effect. Then it was
intercepted by an alkyne to generate Int-F. Finally, reductive
elimination would afford the desired 5ꢀ7ꢀ5 tricyclic products
and regenerate the rhodium (I) catalyst. It is noteworthy that
the cleavage of the more substituted cyclopropane bond a is
also possible. Compound 9r and 9u in Table 7 bearing phenyl
group on R2 gave 5r and 5u respectively as a single diastereꢀ
omer, whereas substrate 9k and 9j in Table 6 with methyl
group on R2 afforded the desired product (5k and 5j) and the
With the optically pure substrates 9 in hand, a series of tanꢀ
dem heteroꢀ[5+2] cycloaddition/Claisen rearrangement/[5+2]
cycloaddition reaction were carried out. Under conditions D,
[Rh(NBD)2]+BF4ꢀ catalyzed tandem reaction of enantioenꢀ
riched 9m, 9r, 9t, 9n delivered 5ꢀ7ꢀ5 tricyclic products with
excellent chirality transfer. Under condition E, a complete
transfer of chirality was obtained for 9p and 9s. By contrast,
the efficiency of the chirality transfer was found to be lower
for substrates 9q and 9u.
It is noteworthy that this stereospecific tandem reaction is
easy to scaleꢀup. A gramꢀscale reaction of 1.2 g of (S,S)ꢀ9a
(96% ee) was subjected to the current reaction conditions,
affording the corresponding (R,R,R)ꢀ5a in 90% yield. The
absolute configuration of product (R,R,R)ꢀ5a was determined
by Xꢀray analysis (the stereochemistry of the other 5ꢀ7ꢀ5 tricyꢀ
clic products was then assigned accordingly).30 To demonꢀ
strate the potential synthetic utility of this protocol, the diaꢀ
stereoselective epoxidation of the tetrasubstituted double bond
in (R, R, R)ꢀ5a was accomplished with mꢀCPBA. Alternativeꢀ
ly, the selective functionalization of the disubstituted double
bond was realized by dihydroxylation with K2OsO4ꢀ
2H2O/NMO, providing the corresponding 19 in 50% yield
with 98% ee. The preservation of the enantiomeric excess in
19 demonstrated complete chirality transfer in the present tanꢀ
dem heteroꢀ[5+2] cycloaddition/Claisen rearrangement/[5 + 2]
cycloaddition reaction (Scheme 5).
Scheme 5. Scale Up Reaction and Functionalization of
(R,R,R)-5a
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Supporting Information
regioisomer (10k and 10j), respectively. Based on the above
1
2
3
4
5
6
Experimental details, characterization data and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
experiments and eq 1, we believe that the cleavage of the cyꢀ
clopropane bond a or b is a reversible process. Although the
exact reason for the regioselective CꢀC cleavage remains unꢀ
clear at this stage, both the another alkyne (YCH2C≡CR2) in 9
and the steric hindrance of the cyclopropane moiety play a
central role on the regioselectvity of the current reaction.8dꢀe
AUTHOR INFORMATION
Corresponding Author
7
8
9
Scheme 6. Proposed Mechanism
*Eꢀmail: jjfeng@chem.ecnu.edu.cn;
*Eꢀmail: jlzhang@chem.ecnu.edu.cn
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
We grateful to the funding support from Shanghai Sailing Proꢀ
gram (15YF1403600), NSFC (21602062, 21373088, 21425205),
Ministry of Education (IRTꢀ16R25).
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Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am. Chem. Soc. 2004,
126, 14095ꢀ14104. (d) Burke, M. D.; Schreiber, S. L. Angew. Chem.
Int. Ed. 2004, 43, 46ꢀ58.
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Q.; Brouard, I.; Diaz, M. T.; Rico, M.; Rodriquez, R.; Rodriquez, R.
M.; Perez, R.; Perez, R. L.; Martin, J. D. Tetrahedron 2002, 58, 1921ꢀ
1942. (b) Edrada, R. A.; Proksch, P.; Wray, V.; Witte, L.; van Ofꢀ
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3. CONCLUSION
In summary, relying upon a new synthetic application of a
vinyl oxirane as a heteroatomꢀcontaining fiveꢀatom component
in Rh(I)ꢀcatalyzed cycloaddition reactions, four catalytic sysꢀ
tems were developed: heteroꢀ[5+2] cycloaddition, heteroꢀ
[5+2] cycloaddition/Claisen rearrangement reaction and hetꢀ
eroꢀ[5+2] cycloaddition/Claisen rearrangement/cyclopropane
ring opening reaction of vinylic oxiranes with monoꢀalkynes
leading to multifunctional sevenꢀ, threeꢀ and five membered
rings respectively; heteroꢀ[5+2] cycloaddition/Claisen rearꢀ
rangement/[5+2] cycloaddition reaction of vinyl oxiraneꢀ
diynes for the construction of the linearly fused 5ꢀ7ꢀ5 tricyclic
skeletons in a stepꢀ, atomꢀeconomical fashion from readily
available starting materials has also been demonstrated. In
most cases, the catalyst [Rh(NBD)2]+BF4ꢀ is more efficient
than the previous catalyst RhCl(IPr)(COD)/AgSbF6. All the
reactions were highly regioselective and diastereoselective,
affording the corresponding product under mild conditions
over a broad range of substrates with excellent functional
group tolerance. In addition, the complete chirality transfer
was observed for all the above reactions. Functionalization of
the products and mechanistic consideration have also been
investigated. Of note, the wellꢀdesigned tandem reactions to
form four structurally diverse products from a common vinyl
oxiraneꢀalkyne precursor give rapid access of molecular diverꢀ
sity.
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