A Counterion-Directed Approach to the Diels–Alder Paradigm: Cascade Synthesis of Tricyclic Fused Cyclopropanes

Article abstract of DOI:10.1002/anie.201608534

An approach to the intramolecular Diels–Alder reaction has led to a cascade synthesis of complex carbocycles composed of three fused rings and up to five stereocenters with complete stereocontrol. Computational analysis reveals that the reaction proceeds

Full text of DOI:10.1002/anie.201608534

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International Edition: DOI: 10.1002/anie.201608534
German Edition: DOI: 10.1002/ange.201608534
Cycloaddition
A Counterion-Directed Approach to the Diels–Alder Paradigm:
Cascade Synthesis of Tricyclic Fused Cyclopropanes
Emily Kiss, Craig D. Campbell, Russell W. Driver, John D. Jolliffe, Rosemary Lang,
Tetiana Sergeieva, Sergiy Okovytyy, Robert S. Paton,* and Martin D. Smith*
Abstract: An approach to the intramolecular Diels–Alder
reaction has led to a cascade synthesis of complex carbocycles
composed of three fused rings and up to five stereocenters with
complete stereocontrol. Computational analysis reveals that
the reaction proceeds by a Michael/Michael/cyclopropanation/
epimerization cascade in which size and coordination of the
counterion is key.
T
he intramolecular Diels–Alder reaction is a powerful tool
for the synthesis of complex frameworks bearing numerous
stereocenters from simple precursors.[1] This process can be
catalyzed by both Brønsted[2] and Lewis acids,[3] and secon-
dary amines.[4] Conceptually, these modes of activation rely
upon reducing the energy gap between the highest filled
molecular orbital (HOMO) of the diene and the lowest
unoccupied molecular orbital (LUMO) of the dienophile
through lowering of the LUMO. An alternative strategy to
reducing the energetic gap relies on elevating the energy of
the HOMO of the system, and this has been achieved through
Brønsted base[5] and secondary amine catalysis.[6] We rea-
soned that a related process could lead to the in situ
generation of a diene (2) by treatment of the vinyl ketone
1 under basic conditions and subsequent trapping by an
Figure 1. Phase-transfer-mediated intramolecular Diels–Alder-type pro-
cess. THF=tetrahydrofuran.
substituted with two electron-withdrawing groups. Substrate
8 was treated with tetrabutylammonium hydrogen sulfate
(TBAHS) and solid potassium hydroxide in toluene
(Scheme 1). This treatment resulted in cyclization to the
bicycle 9 (d.r. 4:1) in which the product bearing trans ster-
eochemistry across the ring junction predominates.[7]
alkene bearing
a suitable electron-withdrawing group.
(Figure 1). In this process, the counterion has the potential
to play a key role in directing both reactivity and stereose-
lectivity of the subsequent annulation process to give 3.
Herein we report that readily synthesized linear a-bromo
ester derivatives such as 4 and 5 can be selectively converted
into complex fused tricyclic cyclopropanes 6 and 7, respec-
tively, in a process that forges three carbon–carbon bonds and
up to five contiguous stereocenters with complete diastereo-
control. We also demonstrate that the diastereoselectivity of
the reaction can be reversed through judicious choice of
solvent and counterion. Our initial studies focused on the
cyclization of a substrate in which the dienophile was
Scheme 1. Reaction conditions: a) Substrate (0.17 mmol), TBAHS
(0.1 equiv), KOH (s, 4 equiv), toluene. The d.r. value was established
by 1H NMR analysis of the crude reaction mixture.
[*] Dr. E. Kiss, Dr. C. D. Campbell, Dr. R. W. Driver, J. D. Jolliffe, R. Lang,
Prof. Dr. R. S. Paton, Prof. Dr. M. D. Smith
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: robert.paton@chem.ox.ac.uk
This chemistry could exemplify a useful approach to the
synthesis of complex ring systems, and we rationalized that
variation of substituents on the dienophile could offer the
potential for the construction of quaternary all-carbon
centers. We reasoned that introduction of a halogen onto
the dienophile would enable a range of carbon–carbon bonds
to be made through metal-mediated coupling reactions. To
achieve this aim, the keto aldehyde 10 was treated with an in
situ generated brominated Still–Gennari reagent,[8] but rather
than the anticipated brominated E-olefin 11, we isolated the
5,5,3-tricycle 12 in moderate yield (40%) as a single diaste-
martin.smith@chem.ox.ac.uk
Homepage: http://msmith.chem.ox.ac.uk/
Dr. T. Sergeieva, Prof. Dr. S. Okovytyy
Department of Chemistry, Dnipropetrovsk National University
Dnipropetrovsk, 49010 (Ukraine)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201608534.
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with little variation in yield and with complete diastereose-
lectivity (> 20:1 d.r.). For substrates bearing a substituent at
the b-position of the enone, (16; R3 = m-FC6H4, 17; R3 = Ph,
18; R3 = p-CH3C6H4), tricycles bearing five contiguous ste-
reocenters can be generated as a single diastereomer (d.r.
> 20:1). Intriguingly, when 11 was treated with TBAHS and
solid KOH, cyclization to form a different 5,5,3-tricycle (19)
as a single diastereomer occurred.[7] To probe the generality of
this phenomenon, we examined the cyclization of a range of
substrates under these reaction conditions. The cascade
occurs smoothly to afford tricyclic products with four or five
stereocenters as a single diastereoisomer (19–25), but in all
cases the stereochemistry around the cyclopropane nucleus is
reversed relative to that observed when using NaH and THF.
Tricyclic products from the cascade processes can be
chemoselectively derivatized, with the ketone in 19 enabling
useful transformations (Scheme 3). Deprotonation using
Scheme 2. Reaction conditions: NaH (2 equiv), NBS (1 equiv), THF,
ethyl P,P-bis(2,2,2-trifluoroethyl)phosphonoacetate (1 equiv), RT. The
d.r. value was established H NMR analysis of the crude reaction
1
mixture. NBS=N-bromosuccinimide.
reoisomer (Scheme 2). We presume that the fused cyclo-
propane 12[7] arises from a base-promoted cyclization of the
intermediate 11.[9] To probe this possibility, an alternative
synthetic sequence was adopted in which the (E)-a-bromo-
acrylate could be isolated without initiating the cyclization
process. Treatment of 11 with NaH in THF afforded the same
tricycle 12 in 65% yield as a single diastereomer.
We examined the generality of this cascade process
through the generation of a range of substituted (E)-a-
bromoacrylates (5) and their treatment with NaH in THF at
room temperature (Table 1). The cascade reaction is success-
ful with substitution at both positions of the a,b-unsaturated
ketone. Alkyl and aryl groups (13 R2 = Me, 14 R2 = Et, 15
R2 = Ph) are smoothly incorporated into the tricyclic frame-
work to form contiguous all-carbon quaternary stereocenters
Table 1: Base-mediated cascade cyclizations of (E)-a-bromoacrylates.
Scheme 3. Diastereoselective derivatizations of the tricyclic scaffold.
1
The d.r. value was established H NMR analysis of the crude reaction
mixture.
sodium in EtOD mediates selective deuteration only at the
5,5-ring junction to yield 26. Tricycle 19 undergoes highly
chemo- and stereoselective Grignard addition (to give 27),
reduction (to give 28), and reductive amination to afford
amine 29. In all cases the nucleophile approaches from the
less hindered convex face of the system. Single-electron
reduction with sodium naphthalenide gave the cis-indanyl
framework 30 as the major diastereomer (d.r. 4:1).
The stereochemically distinct cyclization resulting from
different reaction conditions could potentially be explained
by: 1) interconversion between the two diastereoisomeric
tricyclic systems under the basic reaction conditions, 2) E/Z
isomerization of the bromoalkene prior to cyclization, or
3) the change of counterion (from sodium to ammonium)
changing the nature of the cyclization cascade. Treatment of
the diastereoisomeric cyclopropanes 12 and 9 under basic
reaction conditions (either NaH in THF or TBAHS and KOH
in toluene) did not lead to any change in diastereoisomeric
ratio, and cyclopropanes were recovered unchanged, thus
ruling out scenario 1. We reasoned that the stereochemical
difference observed under different reaction conditions could
reflect a stereospecific cyclization based on alkene geometry.
To investigate this, we examined the cyclization of the (Z)-a-
bromoacrylate 31 under both reaction conditions previously
Reaction conditions: a) Substrate (0.17 mmol) NaH (2 equiv), THF, RT.
b) substrate (0.17 mmol) KOH (2 equiv), TBAHS (0.1 equiv), RT. The
d.r. value was established H NMR analysis of the crude reaction
1
mixture. Yields are those of the isolated material.
2
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Scheme 4. Reaction conditions: a) Substrate (0.17 mmol), TBAHS
(0.1 equiv), KOH (s, 4 equiv), toluene. b) Substrate (0.17 mmol), NaH
(2 equiv), THF, RT. The d.r. value was established 1H NMR analysis of
the crude reaction mixture.
investigated (Scheme 4). The cyclopropane 19 was the only
product obtained upon treatment with NaH in THF (d.r.
> 20:1), and is consistent with a stereospecific ring closure
under these reaction conditions. However, treatment of 31
with TBAHS and KOH in toluene also led to formation of the
all-cis cyclopropane 19 as a single diastereoisomer.[10] This
outcome could be explained by interconversion of the E- and
Z-bromoacrylates under phase-transfer conditions. We
probed the potential for this interconversion under a range
of reaction conditions but did not observe any evidence of
a change in alkene geometry.[10]
To probe either a potential change in mechanism or
alkene geometry, we turned to quantum calculations. DFT
calculations at the M06-2X/6-311 ++ G(d,p) level were used
with an implicit (CPCM) description of the solvents used
experimentally.[11] The LANL08 uncontracted basis set/rela-
tivistic ECP was used for Br atoms.[12] This level of theory has
been successfully applied to study anionic cyclizations[13] and
for several model systems gave kinetic and thermodynamic
parameters within 1 kcalmolÀ1 of more expensive composite
ab initio CBS-Q//B3 calculations (see the Supporting Infor-
mation).[10] The cyclization was evaluated separately using
descriptions of toluene and THF solvation, thus giving
comparable results.
Figure 2. Formal [4+2] cyclization occurs by a stepwise Michael/
Michael process. CPCM-M062X/6–311+ +G(d,p) Grel(298 K),
R=CO2Me.
rization of the 5,5,3-fused products from 5,5-trans to the
observed 5,5-cis relative stereochemistry. The computations
predict that cis-57 will result from cyclization of the (Z)-a-
bromoacrylate, and was observed under all experimental
conditions studied.
The irreversible cyclization of the (E)-a-bromoacrylate is
predicted to form cis-51, which corresponds to the observed
À
product in THF. Since the first C C bond formation is
predicted to occur irreversibly, E to Z interconversion of the
starting material will be prevented, but why then is there
a switch in diastereoselectivity to form cis-57? We found that
We found a stepwise mechanism for the formal [4+2]
cyclization: the formation[14] of either diastereomer proceeds
via a stable intermediate enolate and is not concerted
(Figure 2). Two-dimensional scans of the potential energy
surface confirmed the absence of a concerted TS (see the
À
À
an exocyclic C C rotation (via TS 58) after the first C C bond
is formed, enables crossover to the diastereoisomeric path-
way. For the E substrate in toluene this rotation occurs faster
°
À1
À
(DDG = 2.4 kcalmol ) than the second C C bond-forming
Supporting Information). The first C C bond is formed
step. However, when a coordinating counterion (e.g. Na+) is
À
À
irreversibly (via TS 33 or 34) with a kinetically controlled
preference of 2.5 kcalmolÀ1 for the trans-diastereomer. This
step is the stereocontrolling step and is consistent with our
observations in Figure 1. The second, ring-closing step is
reversible and has no impact upon stereoselectivity. Consis-
tent with previous experiments and MP2 calculations, the cis-
fused bicyclic product 40 is more stable than the trans
diastereomer; since it is not observed, the stereoselectivity of
this reaction is kinetically controlled and product equilibra-
tion does not occur.[15,16]
present, the barrier for exocyclic C C rotation rises to
14.2 kcalmolÀ1, and is now higher than for the subsequent
À
C C bond-forming step. Under these reaction conditions the
reaction is stereospecific because free-rotation occurs more
slowly than the second cyclization step.
With the conclusion that the counterion plays a key role in
determining the ease of interconversion between trans-43 and
trans-44, we probed directly the effect that the counterion has
on diastereoselectivity (Table 2). We observed that increasing
solvent polarity favored 19, with a complete reversal in
diastereoselectivity for reactions in DMSO and DMF versus
those in THF. We considered that this could may reflect
solvation of the counterion by the dipolar aprotic solvent,
thus favoring crossover from trans-43 to trans-44. To probe
this further, we added ligands to complex the sodium
counterion. Addition of [2.2.1]cryptand in the presence of
NaH in THF led to a complete reversal of diastereoselectivity
from 12 to 19, and is consistent with sequestration of the
counterion, thus leading to rapid equilibration between trans-
43 and trans-44 via TS 58. Changing the size of the metal
We computed reaction pathways for the formation of
5,5,3-fused tricyclic systems from bromoacrylates (Figure 3).
As above, a trans-selective, stepwise cyclization operates for
both E and Z substrates. Based on the exergonicity of each
À
C C bond-forming step, these are predicted to occur irrever-
sibly, thus forming 5,6-adducts epimeric at the brominated
stereocenter (trans-47 and trans-53). The subsequent intra-
molecular enolate displacement of bromide is rapid and
irreversible via TS 49 and TS 55. There is a substantial
thermodynamic driving force (> 9 kcalmolÀ1) for the epime-
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Figure 3. The 5,5,3-fused tricyclic products are formed by stepwise [4+2] cycloaddition, irreversible enolate displacement of bromide, and
epimerization to the more stable cis-fused tricycle. CPCM-M062X/6-311+ +G(d,p)/LANL08 Grel(298 K), R=CO2Me.
supported by EPSRC (EP/I003398/1 and EP/K014668/1). We
acknowledge the Discovery Environment (XSEDE) sup-
ported by National Science Foundation grant number OCI-
1053575 in carrying out this work.
Table 2: Counterion, ligand, and solvent effects in cyclization of 5.
Keywords: cations · cycloadditions · diastereoselectivity ·
density-functional calculations · heterocycles
Solvent[a]
(d.r. 12:19)
Ligand[b]
THF
>95:5
none
>95:5
NaOH
>95:5
MeCN
40:60
15-C-5
71:29
KOH
DMF
DMSO
>5:95
[2.2.1]cryptand
>5:95
CsOH
>5:95
15-C-5*
60:40
RbOH
>95:5
(d.r. 12:19)
Base[c]
(d.r. 12:19)
>95:5
61:39
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[2] For reviews of enantioselective Brønsted acid catalysis, see:
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Akiyama, Chem. Rev. 2007, 107, 5744; c) J. Shen, C.-H. Tan, Org.
Biomol. Chem. 2008, 6, 3229.
Reaction conditions: [a] Substrate (0.17 mmol) NaH (2 equiv), solvent,
RT. [b] Substrate (0.17 mmol) NaH (2 equiv), THF, ligand (1 equiv).
* 2 equiv ligand used. [c] Substrate (0.17 mmol), base (2 equiv), THF,
RT. DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide.
[3] D. A. Evans, J. S. Johnson in Comprehensive Asymmetric
Catalysis, Vol. 3 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
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[4] A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
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[5] For early examples of Brønsted base mediated Diels–Alder
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counterion also has an effect consistent with the observations
above, with a larger counterion (Cs+) favoring the formation
of 19 as opposed to a smaller counterion (Na+).
We have demonstrated a robust synthetic method for the
generation of 5,5,3-fused tricyclic systems with excellent
diastereoselectivity. Computation and experiment have dem-
onstrated that the reaction proceeds by a stepwise Michael/
Michael/cyclopropanation/epimerization cascade, in which
the size and coordinating ability of the counterion is key to
diastereoselectivity.
[7] Stereochemistry was confirmed through x-ray crystallography of
2,4-dinitrophenylhydrazone
derivatives.
CCDC 1501147,
1501148, 1501149 and 1501150 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre.
Acknowledgments
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The European Research Council has provided financial
support (FP7/2007-2013)/ ERC grant agreement no. 259056.
We gratefully acknowledge the Diamond Light Source for an
award of instrument time on I19 (MT7768). This work was
4
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[14] Gibbs energies evaluated at 298.15 K, 1 molLÀ1. The quasi-
harmonic approximation was used, switching from RRHO to
Received: August 31, 2016
Published online: && &&, &&&&
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Communications
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Communications
Cycloaddition
E. Kiss, C. D. Campbell, R. W. Driver,
J. D. Jolliffe, R. Lang, T. Sergeieva,
S. Okovytyy, R. S. Paton,*
M. D. Smith*
&&&& — &&&&
Role play: An approach to the intramo-
lecular Diels–Alder reaction has led to
a cascade synthesis of complex carbo-
cycles composed of three fused rings and
up to five stereocenters with complete
stereocontrol. Computational analysis
reveals that the reaction proceeds by
a Michael/Michael/epimerization/cyclo-
propanation cascade in which size and
coordination of the achiral counterion
plays a key role in the stereochemical
outcome of the reaction.
A Counterion-Directed Approach to the
Diels–Alder Paradigm: Cascade Synthesis
of Tricyclic Fused Cyclopropanes
6
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