Carbene cascades for the formation of bridged polycyclic rings

Article abstract of DOI:10.1016/j.tet.2014.03.060

A general strategy to synthesize bridged polycyclic molecules is presented. The synthesis is accomplished via a cascade reaction initiated by rhodium carbene formation. Subsequent intramolecular reaction with an alkyne is then followed by a transannular C-H bond insertion. A rationale for prediction of the major structural isomer that is formed is described and applied to a wide variety of substrates. This rationale is based on conformational and stereoelectronic considerations for the ring system in the substrate.

Full text of DOI:10.1016/j.tet.2014.03.060

Tetrahedron xxx (2014) 1e10
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Carbene cascades for the formation of bridged polycyclic rings
*
Santa Jansone-Popova, Phong Q. Le, Jeremy A. May
Department of Chemistry, University of Houston, 112 Fleming Building, Houston, TX 77204-5003, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A general strategy to synthesize bridged polycyclic molecules is presented. The synthesis is accomplished
via a cascade reaction initiated by rhodium carbene formation. Subsequent intramolecular reaction with
an alkyne is then followed by a transannular CeH bond insertion. A rationale for prediction of the major
structural isomer that is formed is described and applied to a wide variety of substrates. This rationale is
based on conformational and stereoelectronic considerations for the ring system in the substrate.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 20 January 2014
Received in revised form 6 March 2014
Accepted 7 March 2014
Available online xxx
Keywords:
Bridged rings
Cascade reactions
Carbene chemistry
CeH bond insertion
Alkynes
Caged rings
1. Introduction and background
products are isolable in only scarce quantities from natural sources.
Thus, a practical synthetic approach is needed to furnish the ma-
Examples abound of polycyclic natural products where
a bridged bicyclic core is fused with additional rings (Fig. 1). These
compounds routinely possess important biological activities that
are applicable to the study of biochemical pathways and the de-
velopment of new disease treatments. Many of these natural
terial to investigate the properties of these compounds. There has
been a significant effort to develop methods for the synthesis of
bridged bicycles. The variety of strategies developed to synthesize
different bridged rings includes ring formation via radical in-
termediates,1 enolate additions,2 pericyclic cycloadditions,3 and
Michael reaction cascades.4 However, each of these methods typi-
cally targets only one unique size and connectivity for the bridged
ring system. For example, the bicyclo[2.2.2]octane cores of tashir-
onin A (1) and maoecrystal V have been targeted with an intra-
molecular DielseAlder reaction.5 However, adenanthin (5) would
require a completely different strategy. A rapid, generalized ap-
proach to generate different bridged polycycles from common
starting points would increase synthetic utility, flexibility, and
efficiency.
We recently disclosed a generalized strategy to synthesize
bridged polycycles like 9 (Scheme 1).6 By altering the ring in 6,
a variety of bridged ring sizes may be formed with differing points
of connection. This cascade reaction approach to bridged polycycles
is initiated through catalytic diazo decomposition7 of an
a-diazo
carbonyl8 like 6 and terminates in a CeH bond insertion.9 Impor-
tantly, the CeH bond insertion allows for new CeC bond formation
without prefunctionalization of the carbocycle, allowing for greater
synthetic efficiency.10 The carbene cascade reaction proposed
herein forms multiple CeC bonds in a single reaction to further
increase efficiency. While bridged ring systems contain 17e23 kcal/
mol of ring strain relative to cyclohexane,11 the high reactivity of
the carbene intermediates allow the reaction to proceed.
Fig. 1. Bridged polycyclic natural products.
* Corresponding author. Tel.: þ1 832 842 8808; fax: þ1 713 743 2709; e-mail
address: jmay@uh.edu (J.A. May).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.060
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S. Jansone-Popova et al. / Tetrahedron xxx (2014) 1e10
Scheme 1. The carbene cascade and potential side reactions.
Also central to the cascade strategy is the intramolecular in-
a cascade reaction that terminates in CeH bond insertion to form
bridged polycycles.
sertion of a nearby alkyne to form a putative spirocyclic in-
termediate like 8. Such a process has precedent in work by Padwa,12
Hoye,13 and others14 (Scheme 2). In those examples, a carbene is
generated from a diazocompound, usually in the presence of
a transition metal catalyst that controls the carbene reactivity. This
initial carbene rapidly reacts with a nearby alkynyl group in-
tramolecularly to form a new carbene intermediate such as 14 or 17.
This new carbene can then proceed through additional reactions.
An intermolecular example has even been shown by Montgomery
with a Ni complex. However, little work had been reported on
The allylic metal carbenes 14 and 17, which would result from
a ‘carbene alkyne metathesis’12e from the initially formed carbene,
are useful hypothetical intermediates to consider and understand
these reactions. However, the actual mechanistic intermediates are
likely more complex. Hoye demonstrated this complexity with an
elegant study that compared diazoketone 25 and diazo enone 26
(Scheme 3).15 If the cascade sequence from 25 proceeded purely
through a metathesis reaction to form intermediate 29, both 25 and
26 would be expected to give the same product distribution. As can
Scheme 2. A few examples of carbene/alkyne cascade sequences.
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S. Jansone-Popova et al. / Tetrahedron xxx (2014) 1e10
3
Scheme 3. Hoye’s mechanistic study.
be seen in Scheme 3, however, quite different product distributions
were observed, implying that the intermediates are not accessed
identically from each diazoketone. One alternate pathway was
proposed to proceed through vinyl cation 30,15 which would ex-
plain the greater production of the trans isomer of olefin 32. 1,2-
Hydride migrations for metal carbenes like 29 generally have
a higher propensity to form cis olefins.16 Given the uncertainty of
the precise mechanistic intermediate in these alkynyl cascades, we
will use the term ‘carbenoid’ herein to denote the developing car-
bene character at the alkynyl carbon, even though there may not be
a fully formed carbene at that carbon. It should also be noted that
the expected cyclopropane, 1,2-hydride migration, and CeH bond
insertion products in Hoye’s study (31, 32, and 33, respectively) are
more pronounced when 29, the ‘carbene/alkyne metathesis prod-
uct,’ is the likely intermediate as generated from 26. None of the
CeH bond insertion product is obtained from diazoketone 25, fur-
ther supporting that the intermediates from 25 lack the strong
enone carbene character that would be exhibited by 29. To obtain
the desired CeH bond insertion for the cascade sequence in Scheme
1, the reactivity that would be manifested by intermediate 8 (and
not a vinyl cation like 30) is needed. Otherwise the bridged bicyclic
products could fail to form.
the properties of acceptor/donor carbenes, which show greater
insertion selectivity.21
The few applications to synthesize functionalized bridged bi-
cyclics using CeH bond insertions reported to date are diazoketone
studies by Wolff20a and Adams20bed to form bicyclo[3.2.1]octanes
35 from cyclohexyl and pyranyl diazoketones 34 in the context of
determining CeH bond insertion preferences (Scheme 4). Sona-
wane,22 Srikrishna,23 and Lee24 have provided examples of intra-
molecular CeH bond insertion to functionalize preformed bridged
bicyclics. Lee demonstrated how the inductive electron with-
drawing and hyperconjugative donating abilities of oxygen can be
independently observed in rigid polycyclic systems like 40. In the
same vein, the application of the sequence in Scheme 1 to the
synthesis of caged and bridged bicycles can be expected to show
altered selectivity patterns relative to established acyclic examples
because of the increased steric demands, ring strain, and rigidity in
the products. As shall be described herein, ring conformations in
particular must be assessed to enable predictions of reactivity.
A few potential complications of the proposed cascade in
Scheme 1 were worth contemplating at the outset of our endeavor.
The initial metal carbene in 7 could bypass the nearby alkyne and
directly insert into the ring, forming the fused bicycle 10a with an
angular alkynyl group (R¼CCSiMe3). Doyle observed this product
with a methyl in place of the alkyne (10b, R¼Me).25 Either of the
carbenoid intermediates 7 or 8 could react with a diazoester or
a second carbene intermolecularly to generate olefinic dimer
products like 11 or 12. Rearrangements of carbene intermediates
could also occur.26 These side reactions could be exacerbated by the
increased ring strain in the transition state to form bridged prod-
ucts 9 relative to monocyclic or fused bicyclics. On the other hand,
one side reaction that is unlikely to happen is insertion at a CeH
bond immediately adjacent to the point of attachment for the
spirocyclic rings in 8. Doing so would generate a highly strained 5-
4-5 fused ring system with a very distorted olefin. Consequently,
Doyle,17 Taber,18 Hashimoto,19 and others20 have reported
a number of experiments that describe the selectivity of CeH
bond insertion in intramolecular reactions to generate mono-
cycles and fused polycycles. In brief, the following trends are
observed: (A) five-membered ring formation is favored over
other ring sizes. (B) The rate of insertion is generally
R3CH>R2CH2[RCH3. (C) CeH bonds on an oxygenated or nitro-
genated carbon are the most reactive to insertion if proper orbital
alignment with the heteroatom lone pair is possible. (D) Allylic
and benzylic CeH bonds are preferred to unactivated hydrocar-
bons, and (E) CeH bonds close to electron withdrawing groups are
deactivated for insertion. Davies has noted and taken advantage of
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S. Jansone-Popova et al. / Tetrahedron xxx (2014) 1e10
Table 1
Analysis of reaction parameters
Entry Catalyst
(0.5 mol %)
AgOTf
Solvent
CH2Cl2
Rxn
concn (M)
time
Yield 9a
Yield
dimersa
1
0.01
No reaction
Trace
Trace
d
2
(CuOTf)2$PhH CH2Cl2
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
Trace
Trace
32%
24%
18%
41%
Trace
Trace
16%
5%
60%
23%
27%
trace
d
3
Cu(CH3CN)4PF6 CH2Cl2
4
5
6
7
8
9
10
11
12
13b
14
15c
16d
Rh2(OAc)4
Rh2(oct)4
Rh2(TPA)4
Rh2(TFA)4
Rh2(cap)4
Rh2(cap)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5 min 28%
5 min 50%
5 min 36%
5 min Trace
5 min
30 min
5 min 77%
5 min 46%
5 min 38%
5 min 55%
5 min 63%
d
e
d
ClCH2CH2Cl 0.005
Pentane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.005
0.005
0.01
0.005
0.005
2 h
30 min 85%
70%
a
Isolated yields.
b
c
Reaction run at 0 ꢀC.
Slow addition of 6 to Rh2(esp)2 in CH2Cl2 over 2 h.
Slow addition of 6 to Rh2(esp)2 and activated 4 A molecular sieves in CH2Cl2 over
d
ꢀ
30 min.
Scheme 4. CeH insertion with bridged rings.
e
Reaction at reflux.
productive reaction was observed with rhodium(II) dimers used as
catalysts. The simplest of these, Rh2(OAc)4 substantially improved
product formation to 28%, but also increased the formation of
olefinic dimers (entry 4). These dimers were a mixture of cis and
trans olefins derived from the coupling of the acetate carbon.
Rhodium complexes with a variety of steric and electronic differ-
ences were examined to find a combination that would favor the
formation of the bridged bicycle 9. The more lipophilic Rh2(oct)4
nearly doubled product formation (entry 5), but the sterically en-
a transannular insertion to generate a bridged ring would be the
only available option for intramolecular CeH bond insertion from 8.
2. Results and discussion
Carbocyclic alkynyl diazoesters like 6 were initially targeted to
probe the proposed cascade sequence with the thought that they
could be easily derived from cyclic ketones. Indeed, treatment of
trimethylsilylacetylene with n-BuLi generates a lithium acetylide
that adds to cyclopentanone in nearly quantitative yield
(Scheme 5).27 The resulting propargylic alcohol is then acetylated
with the tosylhydrazone of glyoxylic acid chloride in the presence
of dimethylaniline.28 Subsequent treatment with triethylamine
then converts the hydrazone to the requisite diazo group. Thus,
nearly all of the substrates in this manuscript were synthesized in
only two steps from cheap, commercially purchased ketones.
29
cumbered Rh2(TPA)4 behaved similarly to Rh2(OAc)4 (entry 6). A
catalyst with electron withdrawing TFA ligands provided only di-
mers as products (entry 7). A caprolactam-bridged Rh dimer was
catalytically ineffective in dichloromethane, even when refluxed
(entries 8 and 9). A breakthrough occurred when a catalyst origi-
nally developed for nitrene chemistry, Rh2(esp)2,30 allowed for the
formation of the bridged product 9 while minimizing the di-
merization observed (entry 10). The esp ligand has two substantial
differences from the other carboxylate ligands screened. Firstly,
a geminal dimethyl is found at the
a-carbon of the carboxylate.
Secondly, the ligand is bidentate, which is postulated to decrease
ligand dissociation. Both of these factors could be serving to protect
the carbenoid intermediate that is key to the cascade reaction.
Having identified a superior catalyst for bridged bicycle forma-
tion, we desired to know the impact other parameters of the re-
action had on the outcome. Solvent is known to have a significant
impact on carbene transformations,31 though the range of com-
patible solvents is somewhat limited. The use of dichloroethane,
which is similar in many ways to dichloromethane but has a higher
boiling point, diminished the formation of both 9 and dimeric
products (entry 11). A hydrocarbon solvent, which is also a common
alternative, showed increased dimerization at the expense of the
desired product (entry 12). When benzene was used, several
compounds derived from reaction with benzene were observed in
competition with 9. Lowering the temperature at which the
Scheme 5. Synthesizing alkynyl diazoesters.
Thermolyzing diazoester
6
resulted in nonspecific de-
composition. A variety of transition metal catalysts that are com-
monly used in diazo-initiated carbene reactions were then
examined. Silver(I) showed no reactivity (entry 1, Table 1), and Cu-
based catalysts fared little better (entries 2 and 3). A more
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S. Jansone-Popova et al. / Tetrahedron xxx (2014) 1e10
5
reaction occurred in CH2Cl2 also served to increase the formation of
dimers (entry 13). This result is not unexpected given the need for
enough thermal energy to adopt a transition state to form the
strained bridged bicycloheptane through CeH bond insertion. The
concentration of the reaction also affected the ratio of products
The reactivity of phenyl and vinyl diazoacetates in alkynyl cas-
cade reactions was demonstrated by Padwa.34 In that example the
resulting carbenoid from carbene/alkyne metathesis reacted with
the vinyl or aryl substituent in a 1,5-electrocyclization to form an
indene. To confirm that the introduction of the carbocycle in our
substrates did not alter this reactivity, we synthesized diazoester 44
(Scheme 6). Upon exposure to Rh(II), the alkyne insertion and 1,5-
electrocyclization took place as expected to form indene 45.
obtained. If the concentration was raised above 5 mM, dimer for-
mation increased (entry 14). These observations suggested that for
the desired alkyne insertion/CeH bond insertion cascade, a more
facile dimerization pathway had to be avoided. An obvious tech-
nique to do this was to slowly add the diazocompound to a solution
of the catalyst and thus maintain a very low concentration of re-
active species. Indeed, slow addition of 6 to Rh2(esp)2 greatly de-
creased the formation of dimers (entry 15). However, the long
introduction of 6 via syringe provided opportunity for exogenous
water to enter the system and increase the OH insertion products
observed to the detriment of the formation of 9. The addition of
activated molecular sieves suspended in the reaction resolved this
problem and provided the product 9 in the highest yield (entry 16).
Since these latter conditions are operationally more complex and
provide a modest 8% higher yield than the simple, single-portion
introduction of the starting material, all the subsequent experi-
ments were performed with the conditions found in entry 8 of
Table 1. We do note that as such, the reported yields below could be
easily improved in a straightforward manner using slow addition.
An obvious next step in this reaction discovery was the use of
enantioselective catalysts32 to transform the meso starting material
into enantioenriched product. We sampled several currently
available catalysts with chiral carboxylate ligands seeking pro-
ficiency in the transformation. These initial trials were made using
the reaction conditions found suitable for the use of Rh2(esp)2. The
phthalimido adamantyl acetate ligand PTAD showed a greatly de-
creased formation of product relative to Rh2(esp)2 with only a 31%
yield (Table 2, entry 1). However, it did provide the greatest
enantioenrichment at 23% ee. The cyclopropane-based BTPCP33 li-
gand and the proline-based DOSP ligand fared even worse (entries
2 and 3). Surprisingly, the DOSP relative 4-t-Bu-phenylsulfonyl
proline ligand (tBuSP) demonstrated the greatest product yield,
though the enantioinduction was noticeably less than the PTAD
catalyst (entry 4). A bidentate proline-based ligand, biTISP, was
hoped to be likely to replicate the efficacy of the esp ligand. Un-
fortunately, it provided the product 9 in the lowest yield of all of the
catalysts. The product that did form, however, was obtained with
21% ee. Because significant ligand redesign will be needed to im-
prove both the yield of product and the enantioinduction for this
cascade reaction, we turned our attention to the substrate scope of
the achiral catalyst Rh2(esp)2 before continuing with the asym-
metric transformation.
Scheme 6. The cascade with a phenyl diazoacetate.
The silyl group on the terminus of our initial substrate 6 proved
to be important for the effective formation of the bridged bicyclic
product 9. If a terminal alkyne were instead used, a mixture of 5-exo
and 6-endo alkyne cyclization products would be observed. Fortu-
nately, the silyl group in 9 or any of the other silyl alkane products
was easily removed through the use of Bu4NF to provide the
equivalent product to that derived from a terminal alkyne. If a more
robust silyl group was needed, TIPS could be used in lieu of TMS
(Table 3, entry 1). Aryl groups were also readily accommodated as
alkynyl substituents, with the sole problem occurring with a strong
resonance electron donor in the para position of the aromatic ring
(48c, R1¼OMe, entry 2). The starting material was consumed in the
reaction, but no well-defined product was observed. One hypoth-
esis for this phenomenon may be that the donating group greatly
stabilizes the intermediate carbenoid, rendering it insufficiently
Table 3
Alkynyl substituents
Table 2
Enantioselective catalysis
Entry
Catalyst
equiv
Timea
Yieldb
eec
1
2
3
4
5
Rh2(S-PTAD)4
Rh2(S-BTPCP)4
Rh2(S-DOSP)4
Rh2(S-tBuSP)4
Rh2(S-biTISP)2
0.3 mol %
0.3 mol %
0.3 mol %
0.6 mol %d
0.6 mol %d
1 h
1 h
1 h
12 h
12 h
31%
21%
19%
40%
10%
23%
6%
12%
16%
21%
a
Reaction stopped when 6 was consumed.
Isolated yields.
Measured by HPLC with chiral stationary phase.
b
c
d
Reaction started with 0.3 mol % and another 0.3 mol % added after 6 h.
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S. Jansone-Popova et al. / Tetrahedron xxx (2014) 1e10
Table 4
Effects of ring size
reactive to complete the reaction. A para-CF3 group or any number
of meta substituents were readily tolerated.
Alkyl substituents on the alkyne displayed differing reactivity.
The tert-butyl group found in the alkynyl diazoester 50 provided
opportunity for a 1,2-methyl migration to outcompete CeH bond
insertion and form the trimethylvinyl butenolide 51. Similarly,
a 1,2-hydride shift in the n-butyl group of ester 52 generated the
vinylbutenolide 53 as a mixture of cis and trans isomers. This oc-
curred even in pentane as a solvent, which has previously been
shown to discourage 1,2-migrations in carbene cascades.12o,p These
migrations in alkyl alkynes find robust precedent in Padwa’s work,
where similar migrations occur after carbene/alkyne cascade re-
actions.34 One note of interest is that the cis/trans ratios for 53 are
intermediate between those seen for 32 in Hoye’s study in Scheme
2. We may conclude that the early mechanistic steps in this cascade
process are closely related to those seen in previous examples of
the cascade.
Much of the most novel reactivity in this reaction was found in
the variation of the ring found between the alkyne and the diazo-
ester. Due to the ease of substrate synthesis, a number of permu-
tations of the original structure were readily available. A study on
the effects of ring sizes was performed early on to both establish the
scope of the reaction and define the effects of ring conformations
on product outcomes. Because of the conformational demands in
the transition state for CeH bond insertion to form a bridged
bicycloalkane, this analysis was deemed to be an important con-
sideration. As can be seen in Scheme 1, the final step of the cascade
sequence is a transannular CeH bond insertion from intermediate 8
(or its carbenoid mechanistic equivalent). The CeH bond that is
geometrically available for this insertion will be the most likely site
of CeC bond formation for the bridged bicycloalkane.
In the case of our study compound 6, insertion into either of the
CeH bonds highlighted in red in Table 4 provides bicyclo[2.2.1]
heptane 9, albeit as a racemic mixture (entry 1). However, in the
case of the cyclohexyl derivative, insertion into the CeH bond at
either of the 3-positions (see 54a) would form the bicyclo[3.2.1]
octane 55, but insertion at the 4-position would instead form
bicyclo[2.2.2]octane 56. Given our goal to be able to access a broad
selection of bridged ring sizes and connectivities, we need to be
able to access either of those products at will. Fortunately, with no
catalyst or substrate bias, the rates of insertion at those two posi-
tions occurred with a nearly statistical preference (entry 2). The
similarity between insertion rates at those sites will allow for bias
to be introduced either through substituents on the substrate or
through the future synthesis of catalysts with more controlling li-
gands. We note that the silyl-bearing carbon in 55 was found as
a mixture of a- and b-silyl diastereomers, but in all examples in
which an aryl-substituted alkyne was used only one diastereomer
was formed (see Table 6). The reason for the differences in dia-
stereoselectivity are difficult to fully rationalize given the uncertain
nature of the mechanistic intermediate formed from the metal
carbene reacting with the alkyne. A rigid transition state for the
formation of 47 and 49 where the transannular CeH bond insertion
occurs from the midplane of the ring is likely responsible for the
formation of only the endo diastereomer. Greater conformational
flexibility in the cyclohexane ring would allow for attack of the CeH
bond from either side, resulting in a mixture of diastereomers.
The use of seven- and eight-membered rings in the substrates
showed that there is more conformational bias in those systems.
Assuming that the carbenoid derived from the alkyne in cyclo-
heptyl substrate 57 must be in a pseudoaxial position for trans-
annular CeH bond insertion, a likely conformation is illustrated
with the most likely points of CeH bond insertion highlighted in
blue (entry 3). Indeed, the major product bicyclo[4.2.1]nonane 58 is
derived from insertion at those axially-displayed CeH bonds.
Similarly, the major product from the reaction of cyclooctyl
substrate 60 may be predicted. In this case, there are two somewhat
equivalent conformations that put the alkyne pseudoaxial and have
only 2 eclipsing interactions around the ring (entry 4). In the top
case, only one possibility presents itself for CeH bond insertion,
and in the lower case there are two non-equivalent CeH bonds that
appear as targets for insertion. The product distribution reflects this
with 5.5:1 preference for insertion into the red highlighted CeH
bonds to provide bicyclo[4.2.2]decane 61 as the major product.
Given the understanding of the conformations of variously sized
rings with substitution,11 this predictive ability is highly applicable
to design a synthesis of a complex bridged polycycle using this
strategy.
To further demonstrate the ability to predict reactivity based on
stereoelectronic and conformational considerations, we turned our
attention to cyclohexyl substrates with substituents at various
positions around the ring and with differing diastereomeric re-
lationships to the alkyne. Placing a methyl group in the ring’s 4-
position in a trans relationship to the alkyne as shown in 63
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S. Jansone-Popova et al. / Tetrahedron xxx (2014) 1e10
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(Table 5, entry 1) should activate the C4 CeH bond for insertion
given the greater reactivity of methines versus methylenes toward
Rh carbenes. Indeed, in contrast to the cyclohexyl substrate 54,
insertion occurred exclusively at the methine in the 4-position of
the ring to form only bicyclo[2.2.2]octane 64. On the other hand,
the diastereomeric methine in 65 places the CeH bond on the
opposite side of the ring to the developing carbenoid center (entry
2). Consequently, CeH bond insertion must occur at the methyl
CeH or at the methylene at the 3-position. Since methyl CeH bond
insertion is usually much slower than that for methylenes or
methines, bicyclo[3.2.1]octane 66 is now the exclusive product
formed. The trans 3-methylcyclohexyl or 3-phenylcyclohexyl sub-
strates 67a or 67b mirror the reactivity of 63, again producing the
predicted major methine insertion product in each case (entry 3).
However the diastereomeric 69 not only places the methine CeH
bond out of reach for the carbenoid center, but also requires an axial
orientation for the methyl in a transannular CeH bond insertion
(entry 4). In this case and for tetramethylcyclohexane 70 (entry 5),
no product is observed in the reaction. Surprisingly, a majority of
the starting material is recovered for these examples even after
refluxing in CH2Cl2 for several hours. Apparently, the catalyst is in
some way inactivated or sequestered by these substrates, possibly
by forming stable intermediates. With the methyl at the 2-position
on the ring and cis to the alkyne, reactivity is restored and an in-
teresting CeH bond insertion rate comparison is generated. The
carbene initially generated from the diazoester has the option of
either directly inserting into the CeH bond of the methine to form
lactone 73 or reacting with the alkyne. As can be seen by the
dominant formation of 72 and 74, reaction with the alkyne is
greatly favored over direct CeH bond insertion by the initial car-
bene, even though the final CeH bond insertion occurs at a meth-
ylene and not the methine. This ability to divert the reactivity of
a carbene through an alkyne insertion pathway has significant
implications to alter traditional orders of reactivity.
Heterocyclic rings displayed similar reactivity to the carbo-
cycles. For example, the pyranone-derived diazoesters 75 and 77
produced the oxabicyclo[3.2.1]octanes 76 and 78, where the final
CeH bond insertion only occurred at the carbon adjacent to the
oxygen (Table 6). Given oxygen’s ability to activate CeH bonds for
insertion if proper alignment is possible, these products were easily
anticipated. Notably, the phenylalkyne substrate 77 produced
a single product diasetereomer. Nitrogen-based heterocycles were
also functional for the transformation, as the N-Boc-piperidinone-
derived 79 provided the bridged azacycle 80.
Table 5
Substituent effects on CeH bond insertion
Table 6
Heterocyclic substrates
Diazoketones also proved viable for the formation of
cyclopentenone-fused bridged bicycloalkanes (entry 4). The diaz-
oketone 81 was synthesized in four steps from pyranone 86
through acetylide addition, trapping as the acetate, Lewis acid-
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8
S. Jansone-Popova et al. / Tetrahedron xxx (2014) 1e10
Table 7
Bridged bicyclic diazoesters
assisted displacement of the acetate by the appropriate silyl enol
ether,35 and diazotization36 (Scheme 7). When exposed to
Rh2(esp)2, ketone 81 rapidly formed enone 82. Since this oxacycle
was very prone to rearrangement (vide infra), a Luche reduction to
allylic alcohol 83 was carried out to characterize the bridged
product.
Scheme 7. Synthesis of diazoketone 81.
Substrates that would provide larger rings fused to the bridged
polycycle such as 84 were synthesized through propargylation of
the corresponding aldehyde or ketone with 1-chloro-2-phenyl-
acetylene.37 When exposed to the standard reaction conditions, the
anticipated bridged polycycle was indeed formed, though there
remains room for improvement (Table 6, entry 5). While bridged
rings 85 were the major products, numerous side products were
also seen.
products were obtained that could be structurally characterized.
Furthermore, this approach allows access to densely-functionalized
caged systems from more easily accessed bridged bicycles.
The products in Table 6 can undergo additional useful trans-
formations. The proton located in the
g-position relative to the
3. Conclusion
enone in 76 is fairly acidic (Scheme 8). It can be deprotonated in
This manuscript outlines a general approach for the synthesis
of bridged polycyclic compounds. A carbene cascade reaction
forms functionalized bridged bicyclics in only a few steps from
cyclic ketones. Importantly, the bridge connectivity in the final
product is predictable from conformational and stereoelectronic
effects that are well known. This predictability allows the cascade
to be applied the design of synthetic strategies for complex
polycyclic targets.
4. Experimental
4.1. General procedure A (Table 1, entry 9)
A flame-dried round-bottom flask was charged with the diaz-
oacetate (1.0 equiv) under an argon atmosphere. Anhydrous CH2Cl2
(to 0.005 M) was added. The reaction mixture was vigorously
stirred at room temperature while adding Rh2(esp)2 (0.5 mol %) in
one portion. After 5 min, the TLC analysis showed no starting ma-
terial. The reaction mixture was concentrated under reduced
pressure, and the residue was purified by flash column chroma-
tography on silica gel.
Scheme 8. Rearrangement of bridged oxacycles.
basic methanol or unbuffered Bu4NF. Elimination of the
may then occur, forming the fused bicycle 90. The oxyanion can
then add in an intramolecular Michael addition to the -un-
d-alkoxide
a
,b
4.2. General procedure B (Table 1, entry 15)
saturated carbonyl to form the propellane 91. The ring strain in-
herent in the bridged bicycle acts as the driving force for the
rearrangement. A phenyl group in place of the trimethylsilyl sub-
stituent (i.e., 78 or 82) makes this process even more facile.
Beginning the cascade sequence with bridged bicyclic alkynyl
diazoesters produced sterically congested caged polycycles. For ex-
ample, the camphor-derived esters 92a and 92b cleanly generated
the tetracycles 93a and 93b for silyl and methyl alkynes (Table 7).
Again, if a terminal alkyne was used, mixtures of 5-exo and 6-endo
ꢀ
A round-bottom flask charged with 4 A molecular sieves (w3 g/
mmol) was flame-dried under high vacuum. The flask was allowed
to cool to room temperature, and then it was purged with an argon
atmosphere. Rh2(esp)2 (0.5 mol %) was added, followed by anhy-
drous CH2Cl2 (to 0.005 M). Diazoacetate (1.0 equiv) dissolved in
anhydrous CH2Cl2 (0.1 M) was added dropwise slowly over 30 min
via syringe pump. After the addition, the TLC analysis showed no
starting material. The reaction mixture was concentrated under
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S. Jansone-Popova et al. / Tetrahedron xxx (2014) 1e10
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Acknowledgements
The authors are extremely grateful to Professor Huw Davies for
sharing samples of the Rh2(S-BTPCP)4 and Rh2(S-biTISP)2 rhodium
complexes. They also wish to thank the Welch Foundation
(_100000928) for funding this research effort (Grant E-1744).
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