Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents

Article abstract of DOI:10.1038/nchem.1917

Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH 2 Ca ‰ CCH 2 OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions - the homologous Diels-Alder and Diels-Alder cycloadditions - through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.

Full text of DOI:10.1038/nchem.1917

ARTICLES
PUBLISHED ONLINE: 13 APRIL 2014 | DOI: 10.1038/NCHEM.1917
Structural complexity through multicomponent
cycloaddition cascades enabled by dual-purpose,
reactivity regenerating 1,2,3-triene equivalents
Paul A. Wender , Dennis N. Fournogerakis†, Matthew S. Jeffreys†, Ryan V. Quiroz†, Fuyuhiko Inagaki
*
and Magnus Pfaffenbach
Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-
economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably
require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination
event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent
(TMSBO: TMSCH2C;CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [512]
cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this
intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate
that is readily intercepted in either a metal-catalysed or thermal [412] cycloaddition. TMSBO thus serves as an yne-to-
diene transmissive reagent coupling two powerful and convergent cycloadditions—the homologous Diels–Alder and Diels–
Alder cycloadditions—through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.
pre-eminent goal of synthesis is to produce targeted struc- readily polymerize, even at low temperatures (240 8C)20–23. Its reac-
tural complexity and thus functional value with step and tions with various reagents under a variety of reaction conditions
A
time economy in
a
green, if not ideal, fashion1–3
.
often provide polymeric materials. These problems also extend to
Multicomponent reactions provide a powerful means to achieve many other low-molecular-weight cumulenes, restricting their syn-
this end as they allow for the multiply convergent assembly of thetic utility. Control of chemoselectivity in the reactions of such
complex targets from two or more simple, often commercially avail- trienes poses an additional problem in their synthetic use, arising
able, fragments. Multicomponent processes rely on relaying or from the differing steric and electronic features of the component
regenerating reactivity such that the ‘product’ of each step is a reac- p-systems. 4-(Trimethylsilyl)but-2-yn-1-ol (TMSBO 2, Fig. 2) is a
tive ‘starting material’ for a subsequent bond-forming step until a potential butatriene equivalent that could circumvent all of these
termination event occurs4–10. Although in many multicomponent problems. It is an easily handled and prepared24–29 liquid at room
processes a single type of reactive intermediate (for example, a temperature, and would be expected to engage an ynophilic
cation, anion or radical) is regenerated with each step, the propa- partner exclusively at its 2,3-p bond. The resultant product would
gation of reactivity can also involve a change in reactive species or be poised for a relatively under-exploited vinylogous Peterson elim-
reagents. For example, in considering approaches to a new family ination30–37, thereby producing, in situ, a reactive diene for a sub-
of selective kinase inhibitors (Fig. 1, II), a subject of much current sequent [4 þ 2] cycloaddition (or other diene-initiated reaction).
clinical interest11, it occurred to us that access to designed, structu- Overall, TMSBO would serve as an yne-to-diene transmissive
rally simplified staurosporine-like 5-6-7 polycyclic targets incorpor- reagent, coupling two powerful and convergent cycloadditions
ating the critical activity determining functionality of the natural (the homologous Diels–Alder and Diels–Alder cycloadditions)
product lead could be realized in one operation by using 1,2,3-buta- through a vinylogous Peterson elimination, all effected in one syn-
triene (V) as a reactivity regenerating reagent (Fig. 1)12–15
According to this plan, butatriene would function as a two-carbon
ene component in an initiating rhodium-catalysed [5 þ 2] cyclo- Results and discussion
addition with a vinylcyclopropane (VCP), during which it would
.
thetic operation (Fig. 2).
To test whether TMSBO 2 (Fig. 2) could function as a butatriene
be transformed into a reactive four-carbon diene IV for a sub- equivalent in a [5 þ 2] cycloaddition, its reaction with commercially
38
sequent Diels–Alder or related cycloaddition. While the importance available VCP 1 in the presence of [(naph)Rh(COD)]SbF6
of butatriene equivalents has been recognized, equivalency is (2 mol%) was initially investigated. The reaction proceeded
achieved only through two or more reactions16–19. Here, we
describe a highly effective, regioselective butatriene (cumulene)
smoothly at room temperature, producing, after 6 h, a single
product in high yield. Significantly, this product proved not to be
equivalent that allows the realization of this single-flask the expected cycloadduct VII but rather the diene 3 resulting
multicomponent process.
from both a [5 þ 2] cycloaddition and vinylogous Peterson elimin-
Butatriene itself has found only limited use in synthesis, partly ation. The expected [5 þ 2] cycloadduct was not isolated or detected
due to difficulties in relation to its preparation, safe handling, phys-
by thin layer chromatography (TLC) analysis during the reaction,
ical properties (it is a gas at room temperature) and propensity to suggesting that it undergoes facile elimination at a rate comparable
Department of Chemistry, Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305-5080, USA, †These authors
contributed equally to this work. e-mail: wenderp@stanford.edu
*
448
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1917
ARTICLES
(TMSBOMe), was explored. Interestingly, in this case, NMR studies
suggest that not only does the cycloaddition reaction proceed less
rapidly, but additionally, the rate of elimination to form the diene
product is also slowed. The facility of the elimination with
TMSBO and the contrasting behaviour of TMSBOMe suggests a
steric effect in the Lewis acid activation stage of the 1,4-elimination
VIII or an unexplored cycloreversion of a zwitterion formed
through bond formation between the oxygen and silicon atoms
IX (Fig. 2). Mechanistic studies on these various pathways are in
progress and will be reported in due course.
H
H
N
N
O
O
O
FOS
N
N
O
H
O
N
NH
The above results establish that TMSBO is a superb substrate for
[5 þ 2] cycloadditions and serves as a highly effective butatriene
equivalent. These findings set the stage for numerous alkyne-to-
diene based reactions that would engage a third component, includ-
ing Diels–Alder cycloadditions and metal-catalysed variants, to
produce polycyclic products. Given the alkynophilic nature of the
[5 þ 2] cycloadditions, we next sought to determine whether the
initial [5 þ 2]/elimination process could be conducted in the pres-
ence of an alkene Diels–Alder dienophile. This proved to be
highly successful. As illustrated in Table 1, a variety of alkene
dienophiles can be mixed with TMSBO 2 and VCP 1 in the
presence of the Rh(I) catalyst to directly give the product of the
[5 þ 2] cycloaddition/elimination/[4 þ 2] cycloaddition sequence.
Maleate, fumarate and acrylate esters did not interfere with the cat-
alyst, initial cycloaddition and subsequent elimination, and could
therefore be added at the outset of the process, although heating
was required for completion of the final cycloaddition. In contrast,
4-phenyl-1,2,4-triazoline-3,5-dione did complex the catalyst, inter-
fering with the initial cycloaddition. However, by delaying its
addition until after the initial cycloaddition and elimination, the
three-component, one-flask process can be achieved in good yield.
In addition to alkenes, alkynes (abundantly available synthetic
building blocks) can also be used as a third component in the
II
Staurosporine (I)
[4 + 2]
H
N
H
N
O
O
O
O
X
X
X
X
III
III
[5 + 2]
1
4
3
1
2
3
4
2
V
Z
Z
VI
IV
Figure 1 | Retrosynthetic analysis of staurosporine analogues based on
butatriene-enabled cycloadditions. With the goal of step-economically
generating a library of simplified staurosporine analogues with selective
kinase inhibitory function (FOS, function-oriented synthesis), we envisaged a
1,2,3-butatriene (V) reacting first in a [5 þ 2] cycloaddition to provide a
1,3-diene ready for a subsequent [4 þ 2] cycloaddition.
to its rate of formation. An alternative mechanistic possibility in process. For this purpose, addition of the second alkyne is delayed
which TMSBO is first converted to butatriene was rendered unlikely until after the initial [5 þ 2] and elimination processes are complete.
by a control experiment indicating that TMSBO is unchanged after Significantly, both Diels–Alder [4 þ 2] cycloadditions and transition
multiple days under the reaction conditions in the absence of VCP metal-catalysed formal [4 þ 2] cycloadditions are possible. The
1. To further probe the mechanism of this transformation, the reac- former provide three component products in high yield (entries
tion of the methoxy derivative of TMSBO, TMSCH2C;CCH2OMe 5a–5g in Table 1, 8 in Table 2 and 10 in Table 3). Alkynes that do
TMS
R
R
2–5 mol%
[(naph)Rh(COD)]SbF6
R
R
O
O
+
+
O
1,2-dichloroethane;
H+
HO
Polycyclic products
1
2
Lewis acid promoted
elimination
Nu
Rh-catalysed/thermal
[4 + 2] cycloaddition
Rh-catalysed
[5 + 2] cycloaddition
TMS
O
HO LA
VIII
TMS
OH
O
O
O
Zwitterionic
cycloreversion
VII
3
Si
O
O
H
IX
Figure 2 | General depiction of the [512] cycloaddition/vinylogous Peterson elimination/[412] cycloaddition cascade and mechanistic possibilities.
The 1,2,3-butatriene equivalent, TMSBO, reacts under rhodium catalysis to give an intermediate cycloadduct. Under the reaction conditions, we observed the
spontaneous deprotection of the enol ether and an unexpectedly facile vinylogous Peterson elimination, giving directly the 1,3-diene we had envisaged in our
retrosynthetic analysis. The Peterson elimination presumably occurs by either a Lewis acid-promoted elimination or a zwitterionic cycloreversion. In the
presence of a suitable dienophile, a one-flask conversion to polycyclic products can be achieved.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1917
ARTICLES
Table 1 | [5 12]/Vinylogous Peterson/[412] adducts using VCP 1 and TMSBO 2.
TMS
2–5 mol%
[(naph)Rh(COD)]SbF6
R
R
R
*
*
O
O
+
+
1,2-dichloroethane;
H+
O
*
*
R
( * = new bonds)
HO
1
2
4, 5
Product
[4 + 2] time* Yield
Product
[4 + 2] time* Yield
Product
[4 + 2] time* Yield
(h)
(%)
(h)
(%)
(h)
(%)
From alkyne dienophiles
From alkyne dienophiles (continued)
From alkene dienophiles
O
TMS
96†
96†
92†
93†
60†
86†
O
O
6||
67†
88†
82†
4a
4b
4h
26
90
24
5a
O
O
O
16
19
O
O
O
OMe
6||
4i
4j
O
O
5b
5c
O
O
NH
OMe
O
O
O
OMe
OMe
F
24¶,
**
4c
4d
21
OMe
O
O
O
O
O
OMe
OMe
OMe
OMe
8‡
83†
92§
70¶,
53†,††
O
4k
21
5d
O
**
O
O
O
Br
OMe
88†
87§
24¶,
24¶
2
65†
O
O
21
O
O
18
22
O
O
**
4e
4f
4l
5e
5f
OMe
O
O
90†
86§
77†
3
4m
Boc
N
O
NHTs
N
N
78†
O
85§
76†
O
19
21
4g
4n
5g
O
N
Ph
O
Reactions were conducted at room temperature unless otherwise noted. *Unless otherwise noted, this time is the time required for only the [4 þ 2] portion of the reaction cascade; †2 mol%
[(naph)Rh(COD)]SbF6; ‡the [4 þ 2] cycloaddition was effected at 70 8C; §5 mol% [(naph)Rh(COD)]SbF6; ꢀthis time reflects the total time for both the [5 þ 2] and [4 þ 2] processes; }reaction run at
0.330 M; **the [4 þ 2] cycloaddition was effected at 100 8C; ††product is a 1.8:1 mixture of cis:trans esters starting from pure dimethyl maleate.
not react through a conventional Diels–Alder cycloaddition because cyclohexadienyl products or alternatively by starting with a
of a poor highest occupied molecular orbital (HOMO)—lowest higher-oxidation-level dienophile and effecting a double elimin-
unoccupied molecular orbital (LUMO) gap can be induced to ation after the cascade (Table 2). Finally, although our initial
react through an alternative, multistep metal-catalysed [4 þ 2] cyclo- focus was on the exploration of the viability of this one-operation
addition. In this case, the catalyst used in the [5 þ 2] cycloaddition is multicomponent process, we have also found that it can be extended
subsequently employed as a catalyst in the second [4 þ 2] cyclo- to variations in both the starting VCP and the reactivity transmissive
addition. For example, the addition of VCP 1 and TMSBO to a sol- reagent (Table 3). Thus, the substituted VCP 9 readily enters into
ution of the catalyst followed by addition of 3-phenylpropyne gives the sequence, producing polycycle 10 in one operation. Similarly,
the three-component product 4f in 90% yield. That the second cyclo- a methyl substituted butatriene equivalent 11 also reacts readily to
addition is Rh(I)-catalysed is supported by a control experiment in form products 12a and 12b, providing yet a further site
which diene 3 and 3-phenylpropyne are allowed to react in the for diversification.
absence of catalyst. No product is formed even after 2 days. A wide
Alkynes and dienes are among the most common and useful
range of electron-rich, electron-poor, internal and terminal alkynes building blocks in organic synthesis. In this study, we have shown
are accommodated in this sequence using either the thermal or how the versatile two-carbon p-reactivity of a suitably functiona-
metal-catalysed [4 þ 2] cycloaddition option (Table 1, entries 4a–4n). lized alkyne can be transformed through a metal-catalysed [5 þ 2]
In connection with our original interest in kinase inhibitors, we cycloaddition and vinylogous Peterson elimination into a cisoid
have also found that one can readily produce the corresponding diene capable of engaging a range of dienophiles in a conventional
arenyl core ring through oxidation of the initially formed Diels–Alder or metal-catalysed [4 þ 2] cycloaddition. Drawing on
450
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1917
ARTICLES
cycloadditions should prove useful in serially coupling other
cycloadditions including, for example, serial [4 þ 2]/[4 þ 2]
cycloadditions, [3 þ 2]/[4 þ 2] cycloadditions, [2 þ 2]/[4 þ 4]
cycloadditions and so on. Studies on these processes, on this strategy
for enhancing step economy through multipurpose designed
reagents and on the use of the serial [5 þ 2]/[4 þ 2] cycloadditions
to generate kinase inhibitor libraries are in progress.
Table 2 | Oxidative aromatization of reaction products.
R
R
[O]
O
O
R
R
4, 5
6–8
Product
Oxidant
Yield
O
Methods
General alkyne dienophile method. To an oven-dried or flame-dried vial was added
1.1 equiv. TMSBO 2 as a neat liquid followed by 1,2-dichloroethane (DCE, 0.162 M
with respect to VCP). To this solution was added 1 equiv. VCP 1 as a neat liquid,
and then 2–5 mol% [(naph)Rh(COD)]SbF6 in one portion. The reaction was stirred
for 6 h or until consumption of 1 could be observed by TLC. The second alkyne was
then added and the reaction monitored by TLC for consumption of the intermediate
diene. The reaction was quenched with dilute acid and the resulting products
purified via column chromatography. Results for these substrates are summarized
in Table 1.
OMe
OMe
97% from
4d
DDQ
6
7
8
O
O
O
5% KOH in
EtOH, air
82% from
O
O
5f
O
O
General alkene dienophile method. To an oven-dried vial was added 2 mol%
[(naph)Rh(COD)]SbF6, followed by DCE (0.165 or 0.330 M with respect to VCP, as
specified in Table 1). To this solution was added 1 equiv. VCP 1 as a neat liquid, 1.1
equiv. TMSBO 2 as a neat liquid, and then 1.3 equiv. of the corresponding alkene
dienophile (an exception was made for 4-phenyl-1,2,4-triazoline-3,5-dione as noted
above). The reaction was stirred for 6 h or until consumption of 1 could be observed
by TLC. Depending on the reactivity of the dienophile, the reaction was either
quenched, allowed to continue while stirring at room temperature, or heated to
100 8C as noted in Table 1. The reaction was then monitored by TLC for
consumption of the intermediate diene. The reaction was quenched with dilute acid
and the resulting products purified via column chromatography. Results for these
substrates are summarized in Table 1.
Pd/C
Acetone,
reflux
58%*
O
*The initial cycloadduct oxidizes readily and was thus converted directly to compound 8.
the benefit of performing four carbon–carbon bond-forming events
in one operation, the overall process translates three simple and
readily available building blocks into complex, polycyclic, added-
value products. Both activated and unactivated dienophiles can be
used in the second cycloaddition, allowing flexible access to highly
diversified polycycles. In the case of unactivated alkynes, the catalyst
used to effect the first ([5 þ 2]) cycloaddition is also used to effect
the second ([4 þ 2]) cycloaddition and possibly figures in facili-
tation of the intervening Peterson elimination. For conventional die-
nophiles, the second cycloaddition taps into the tremendous
breadth and versatility of the Diels–Alder reaction. More generally,
the key dual-purpose, dual-function reagent (TMSBO) and its con-
geners that enable these back-to-back complexity-increasing
Received 24 October 2013; accepted 5 March 2014;
published online 13 April 2014
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Acknowledgements
This research was supported by the National Science Foundation (NSF, CHE1265956) and
the National Institutes of Health (CA031841). Additional funding was provided by the NSF
Graduate Research Fellowship (R.V.Q.), an Abbott Laboratories Stanford Graduate
Fellowship (M.S.J.), Kanazawa University (F.I.) and the German Academic Exchange
Service (M.P.).
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Author contributions
P.A.W. conceived the study. F.I. and M.P. performed the initial syntheses of butynols and
evaluated the initial viability of [5 þ 2] and [5 þ 2]/[4 þ 2] reactions. D.N.F., M.S.J. and
R.V.Q. determined the substrate profile and performed the synthesis and characterization
of all reported compounds. M.S.J., R.V.Q. and P.A.W. wrote the paper. All authors
commented on the manuscript.
Additional information
Supplementary information and chemical compound information are available in
the online version of the paper. Reprints and permissions information is available online
at www.nature.com/reprints. Correspondence and requests for materials should be
addressed to P.A.W.
32. Angell, R., Parsons, P. J., Naylor, A. & Tyrrell, E. An extremely mild method for Competing financial interests
the construction of E-1,3-dienes. Synlett 1992, 599–600 (1992).
The authors declare no competing financial interests.
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