Synthesis of bridged polycyclic ring systems via carbene cascades terminating in C-H bond insertion

Article abstract of DOI:10.1021/ja308305z

A carbene cascade reaction that constructs functionalized bridged bicyclic systems from alkynyl diazoesters is presented. The cascade proceeds through diazo decomposition, carbene/alkyne metathesis, and C-H bond insertion. The diazoesters are easily synth

Full text of DOI:10.1021/ja308305z

Communication
pubs.acs.org/JACS
Synthesis of Bridged Polycyclic Ring Systems via Carbene Cascades
Terminating in C−H Bond Insertion
Santa Jansone-Popova and Jeremy A. May*
Department of Chemistry, University of Houston, 136 Fleming Building, Houston, Texas 77204-5003, United States
S
* Supporting Information
Scheme 1. Carbene Cascade Reactions for Functionalized
Bridged Bicyclics
ABSTRACT: A carbene cascade reaction that constructs
functionalized bridged bicyclic systems from alkynyl
diazoesters is presented. The cascade proceeds through
diazo decomposition, carbene/alkyne metathesis, and C−
H bond insertion. The diazoesters are easily synthesized
from cyclic ketones. Substrate ring size and substitution
patterns control the connectivity and diastereomeric
preference found in the products.
unctionalized bridged bicycles are common structural
F
motifs in natural products, many of which have impressive
bioactivities (Figure 1). Strategies devised for the construction
of bridging rings include radical additions,1 enolate additions,2
cycloadditions,3 and multistep reaction cascades.4 Typically, a
bridgehead-functionalized bicyclo[n.2.1]alkanes (Scheme 1A).8
To access a greater variety of bridged polycycles, a cascade
reaction was conceived that would commence from alkynyl
diazoesters like 15 (Scheme 1B). These esters would be
conveniently synthesized from the appropriate cyclic ketone in
two steps. Upon exposure to the catalyst, a metal carbene 16
would be formed with concomitant loss of dinitrogen. The
adjacent alkyne can then insert into the carbene to generate a
butenolide ring and a new carbene 17. This carbene would then
insert into the δ-C−H bond to form bridged bicycle 18.
Few studies have been reported for C−H bond insertions in
the context of bridged bicycles,9 though many reports exist on
the selectivity for C−H bond insertion to form single or fused
rings.10 The increased steric demands and ring strain in the
formation of bridged bicyclic products can be expected to show
altered selectivity patterns relative to acyclic.11,12 While several
carbene8 and nitrene13 initiated cascades with alkynes have
been explored, few examples have been reported incorporating
C−H bond insertion as the final step. Thus, this application
also explores new territory in carbene/alkyne metathesis
cascades.
Figure 1. Examples of bridged polycyclic natural products.
given strategy only produces a particular bridged bicyclic
isomer. A strategy that predictably generates products varying
in ring size and points of connectivity from common, easily
accessed precursors is thus in demand. Herein is described a
general strategy to form functionalized bridged polycyclic
systems of varied size and structure via a cascade reaction5 that
is primed by the diazo functional group.6 The reaction proceeds
through initial rhodium-catalyzed diazo decomposition, for-
mation of a rhodium carbene, carbene/alkyne metathesis, and
C−H bond insertion to form multiple C−C bonds and a
strained bridged bicycle in a single reaction.
A few potential complications are worth noting. The initial
metal carbene in 16 could ignore the nearby alkyne and directly
insert into the ring, forming a fused bicycle 19.14 Either of the
carbene intermediates 16 and 17 could react intermolecularly
to generate olefinic dimers (20 and 21). These side reactions
could be exacerbated by the increased ring strain in the
transition state to form bridged product 18 relative to 19−21.11
Padwa designed a cascade reaction with a carbene/alkyne
Received: August 27, 2012
Published: October 19, 2012
metathesis followed by a 1,3-dipole cycloaddition7 to synthesize
© 2012 American Chemical Society
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Communication
Table 1. Reaction Optimization
Table 3. Ring Variations
a
b
Yields are from a single run of experiments run in parallel. TPA =
c
triphenylacetate. Rh2(esp)2 = Rh2(R,R,R′,R′-tetramethyl-1,3-benzene-
dipropionate).
Table 2. Alkyne Substituent Effects
a
b
Rh2(esp)2, CH2Cl2, 20 °C. Yields are averages of multiple trials.
c
d
Reaction at reflux. Yield based on NMR peak integration relative to
e
an internal standard. In pentane, 31 was obtained in 50% yield (cis/
trans 2:1)
Rearrangements of carbene intermediates could also occur.15
Finally, in larger rings (15, n ≥ 2) multiple possible sites of
insertion and conformational flexibility in the ring could lead to
mixtures of products.
a
The asterisk denotes the point of C−H insertion for the major
b
c
product. Rh2(esp)2, CH2Cl2, 20 °C. Yields are averages of multiple
d
trials. Yield based on NMR peak integration relative to an internal
standard. yield for two steps including desilylation.16
e
To avoid the last of these issues, our initial trials focused on
alkynyldiazoester 22 (Table 1), which is derived from
cyclopentanone.16 Our initial trial in dichloromethane using
Rh2(OAc)4 as a catalyst primarily produced carbene dimers, but
28% of the bicyclo[2.2.1]heptane 23 was also observed (entry
1). The relative stereochemistry of the product was determined
from 1D NOE experiments.16 This encouraging result led to an
examination of individual reaction parameters. While metals
other than rhodium did not efficiently provide 23,16 dirhodium-
(II) carboxylates generally produced the bridged bicycle in
isolable amounts (entries 1−3). Changing the solvent from
dichloromethane proved detrimental to product formation, as
afford mixtures of products derived from both 5-exo and 6-
endo alkyne insertion.19 Aryl alkynes generally provided
products cleanly. A p-CF3-C6H4-modified alkyne 24 was a
good substrate for bridged bicycle formation (entry 1). Aryl
alkynes with meta groups gave uniformly good yields
independent of the electronic nature of the substituent (entries
2−4). Silyl-substituted alkynes 28 provided bridged rings in
useful yields (entries 5 and 6). This result was pleasing as silyl
groups can subsequently be removed20 or oxidized.21 Aliphatic
alkynes produced more varied results. The n-butyl acetylene 30
showed that 1,2-hydride migration outcompeted C−H
insertion for bridged bicyclic formation (entry 7).22 More of
the cis isomer of alkene 31 was formed in pentane (50% yield,
2:1 cis/trans) than in dichloromethane (1:1.4 cis/trans), and
32 was not observed. For comparison, hydride migration was
suppressed in pentane for intramolecular C−H bond insertion
with an acyclic alkynyl substrate.22,23 Thus, the observation of
17
did increasing the concentration. Rh2(esp)2 uniquely
provided the product in excellent yield with only a small
amount of olefinic dimer formation (entry 3). This catalyst has
proven its effectiveness in a variety of applications where other
catalysts fared poorly.18
Next, the tolerance of various functional groups on the
alkyne was examined (Table 2). Terminal alkynes are known to
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Journal of the American Chemical Society
Communication
hydride migration in pentane illustrates an increased barrier to
C−H insertion that is likely due to the additional ring strain
introduced during the formation of the product. Lastly, a tert-
butyl-substituted alkyne 33 showed that a 1,2-methyl shift to
form butenolide spirocycle 34 is faster than C−H bond
insertion (entry 8).24
Scheme 2. Post-cascade Modifications
The variety of carbocycles and heterocycles that can be
incorporated in the cascade sequence demonstrates the power
of this strategy. The ring size and substituents of substrates
have a profound impact on the bridged bicycle that is produced.
While cyclopentane diazoester 22 produced bicyclo[2.2.1]-
heptane 23 as a single diastereomer (Table 1), cyclohexyl
diazoester 35 produced a mixture of bicyclo[2.2.2]octane 36
and both diastereomers of bicyclo[3.2.1]octane 37 (Table 3,
entry 1). The mixture of products observed likely arises from
the conformational flexibility of the cyclohexane.
The diastereomeric alkynyldiazoesters 38, 40, 42, 44, and 46
demonstrate how ring substituents can dictate selectivity. When
a methyl or phenyl group is anti relative to the alkyne (entries
2, 4, 5, and 6), the position with the substituent is more reactive
since a methine is more susceptible to C−H bond insertion
than a methylene.10 Thus, bicyclo[2.2.2]octane 39 was formed
as the major product from 38 and bicyclo[3.2.1]octane 43 was
formed from 42. With the alkyne syn to a 3- or 4-methyl group,
the C−H bond insertion at the methine is blocked. Insertion
could still occur at the 3-position of 40 in the presence of a 4-
methyl substituent, as it is disposed equatorially (60, Figure 2).
Both cycloheptanes and cyclooctanes showed noteworthy
insertion selectivity (entries 11 and 12). Diazoester 54
primarily formed the bicyclo[4.2.1]nonane core 55 in 65%
yield with moderate diastereoselectivity. Similarly, the cyclo-
octyl diazoester 57 generated the illustrated diastereomer of 58
in 56% yield, with another 11% of its constitutional isomer 59
isolated. Thus, the cyclooctyl ring showed the highest
diastereoselectivity of all the ring sizes greater than 5 tested
so far.
In conclusion, alkynyldiazoesters with cycloalkanes readily
form bridged polycyclic systems through the use of Rh2(esp)2.
Subsequent desilylation, hydrogenation, or rearrangement of
the bridged products proceeds without difficutly.16 The use of
diazoketones in the cascade reaction and application of this
strategy to the natural products in Figure 1 is underway.
ASSOCIATED CONTENT
* Supporting Information
Additional optimization data, experimental procedures, and
characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
jmay@uh.edu
■
Figure 2. Insertion conformations.
Notes
The authors declare no competing financial interest.
Thus, the bicyclo[3.2.1]octane 41 was the only product from
40 (Table 3, entry 3). For the 3-substitued 44, however, the
conformation 62 for C−H bond insertion to form the bridged
bicycle is higher in energy than 61 as it requires an axial methyl
group. Moreover, this group blocks any methylene C−H bond
insertion in 62, and consequently no bridged bicyclic product
was observed from 44. 46 would again contain an equatorial
methyl in the transition state, and insertion at the methylene
furthest from the methyl in the ring gave the major product 47.
If heteroatoms were present in the ring in the 4-position,
only the butenolide-fused bicyclo[3.2.1]octanes 51 and 53 were
produced (Table 3, entries 8−10). Not only is there no C−H
bond at the ring’s 4-position for insertion, but the 3-methylene
is activated for insertion by the heteroatoms. As seen for 51b,
aryl alkynes generally provide endo products exclusively. The 2-
oxabicyclo[3.2.1]octane 51a models a synthetic approach to the
synthesis of members of the aglain family of natural products
(see 1, Figure 1). The bridged heterocyclic product 51a
underwent further transformations to a key structural motif.
Buffered TBAF desilylated the bicycle to give butenolide 63
(Scheme 2). If 63 was treated with base, γ-elimination of the
alkoxide produced fused butenolide 64, and 1,4-addition of the
alkoxide then afforded propellane 65. If 51a was heated with
TBAF, 65, which is reminiscent of the core of brazilide A (2,
Figure 1), could be accessed directly. In fact, the transformation
of 50 to 65 was performed as a model system for the synthesis
of brazilide A that is underway.
ACKNOWLEDGMENTS
We thank the Welch foundation (Grant E-1744) and the
University of Houston for financial support of this work.
■
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