Metal Coordination Controlled and Bifunctional H-Bonded Catalysis in Stereoselective Intramolecular Aldol Cyclizations toward Carbocyclic Tertiary β-Ketols

Article abstract of DOI:10.1002/ejoc.201700437

The principle of bifunctional catalysis is shown in the highly regio- and stereoselective intramolecular aldolization of 2-methyl-1,3-cyclopentanedione, C2-substituted with a methyl ethyl ketone group, to provide [3.2.1]-bicyclooctanol diones in the presence of catalytic amounts of either LiBr and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). Mechanistic investigations corroborated by DFT calculations show that LiBr engages in a bifunctional coordination of two carbonyl moieties and leads to the preorganization of the reactive enolate intermediate for a base-mediated intramolecular aldol cyclization. On the other hand, TBD catalysis of the triketone substrate proceeds through a bifunctional H-bonded mechanism to give the same aldol product as the major diastereomer. The LiBr and TBD-catalyzed highly stereocontrolled intramolecular aldol cyclizations can be extended to other di- and triketones to give carbocyclic and carbobicyclic products as single diastereomers.

Full text of DOI:10.1002/ejoc.201700437

A Journal of
Accepted Article
Title: Metal Coordination-controlled and Bifunctional H-bonded
Catalysis in Stereoselective Intramolecular Aldol Cyclizations
toward Carbocyclic Tertiary β-Ketols
Authors: Stephen Hanessian, Bin Chen, and Gilles Berger
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700437
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10.1002/ejoc.201700437
European Journal of Organic Chemistry
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Metal Coordination-controlled and Bifunctional H-bonded
Catalysis in Stereoselective Intramolecular Aldol Cyclizations
toward Carbocyclic Tertiary β-Ketols
Bin Chen,[a] Gilles Berger[a,b] and Stephen Hanessian*[a]
Abstract: The principle of bifunctional catalysis is shown in the
highly regio- and stereoselective intramolecular aldolization of 2-
methyl-1,3-cyclopentanedione harboring a C-2 methyl ethyl ketone
appendage, to provide [3.2.1]-bicyclooctanol diones in the presence
of catalytic amounts of either LiBr and DBU, or 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD). Mechanistic investigations
corroborated by DFT calculations show that LiBr engages in a
bifunctional coordination of the two carbonyl moieties and leads to
the pre-organization of the reactive enolate intermediate for a base-
mediated intramolecular aldol cyclization. On the other hand, TBD-
catalysis of the same triketone substrate proceeds through a
bifunctional H-bonded mechanism to give the same aldol product as
the major diastereomer. The LiBr and TBD-catalyzed highly
stereocontrolled intramolecular aldol cyclizations can be extended to
other di- and tri-ketones to give carbocyclic and carbobicyclic
products as single diastereomers.
activation leading to intramolecular aldol cyclization under
catalytic conditions. In the first of these, we hypothesized that
pre-coordination of the triketone 1 with a neutral salt such as a
lithium halide[12] would orient one of the carbonyl groups of the
1,3-cyclopentanedione ring and the carbonyl group in the
extended chain of triketone 1 in a parallel mode, which in the
presence of a non-nucleophilic base, would proceed to the
enolate 7, then undergo intramolecular aldolization to give 6 as
the major product (Scheme 1A). In the second case, we
envisaged that in the presence of a bicyclic guanidine such as
TBD[13] triketone 1 would be transformed to the enol 8 via a
bifunctional H-bonded intermediate which would also
preferentially lead to 6 (Scheme 1B).
While the intramolecular version of the aldol cyclization
reaction of carbonyl compounds has been known for many
years,[1] a paradigm shift in the field was realized by seminal
independent contributions from scientists at Hoffmann-LaRoche
and Schering AG over 40 years ago. In particular, Hajos and
Parrish[2] demonstrated the feasibility of a proline-catalyzed
asymmetric intramolecular aldol reaction of a prochiral triketone
leading to the corresponding enantiomerically enriched
perhydroindanedione core structure harboring
a
β-ketol
functionality (Scheme 1). This remarkable asymmetric metal-free
bond-forming reaction[3,4] was a prelude for what is now known
as organocatalysis.[5,6] The translation of this technology to
intermolecular aldol condensations was another timely
development in the field.[7] Extensive mechanistic and theoretical
studies have validated the proposed enamine mechanism for the
Hajos-Parrish-Sauer-Eder-Wiechert reaction, wherein triketone 1
is converted to a perhydroindanedione β-ketol 3 in 97% ee.[2,8,9]
New mechanistic insights have also been advanced based on
the formation of discreet intermediates.[10,11] Racemic 3 is
obtained in the presence of piperidinium acetate in ether, also
proceeding by an enamine mechanism.[2] Importantly, two
Scheme 1. A. Proline-catalyzed β-ketol formation from triketone 1; B.
Proposed bifunctional pathways to β-ketol 6 from triketone 1.
diastereomeric [3.2.1]-bicyclooctanedione β-ketols
5 and 6
In this communication, we provide comprehensive
experimental and theoretical evidence that such bifunctional
metal-coordinated and H-bonded cooperative catalysis in
intramolecular aldol reactions are indeed operative.
where formed via an alternative intramolecular aldol pathway
when the same reaction was conducted in water (Scheme 1).[2]
The prerequisite parallel alignment of two of the three carbonyl
groups en-route to the formation of β-ketols 5 and/or 6 via
enolate 4, prompted us to consider new modes of carbonyl
Treatment of 1 with diazabicycloundecene (DBU, 1 equiv.)
[14,15]
at room temperature for 24 h led to a mixture of β-ketol
compounds 3, 5, and 6 in quasi-equal amounts. However, using
catalytic amounts (5 mol % each in THF) of DBU and LiBr at -
40 °C afforded 6 with high selectivity and 88% isolated yield.
Catalytic DBU and LiCl also generated 6 in good yield. However,
switching to MgBr2 or MgBr2·Et2O, led to trace amounts of 6 with
recovery of starting triketone 1.[16] These experiments validated
the critical role of lithium bromide in the selective formation of
the axial β-ketol 6 (see SI for details).
[a]
[b]
Dr. Bin Chen, Dr. G. Berger, Prof. Dr. S. Hanessian
Department of Chemistry, Université de Montréal
Station Centre-Ville, C.P. 6128, Montreal, QC, H3C 3J7, Canada
E-mail: stephen.hanessian@umontreal.ca
Dr. G. Berger
Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry
Université Libre de Bruxelles
Campus Plaine CP205/5, Université Libre de Bruxelles, Bd du
Triomphe, 1050 Brussels, Belgium
We also studied a series of bases with different pKa values
o
as catalysts with and without LiBr at -40 C (see SI for details).
Supporting information for this article is given via a link at the end of
the document.
Only traces of 6 were formed with relatively weaker bases such
as Et3N and LiBr. Excellent yields of 6 were obtained with
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10.1002/ejoc.201700437
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piperidine (pKa = 14.3 in THF) and other bases, but only in the
presence of LiBr. With the bicyclic Eschenmoser amidine,[17]
formation of 6 was significantly enhanced in the presence of 5
Table 1. Aldol reactions with benzyl triketone 11.
mol%
LiBr.
In
the
presence
of
N-methyl-1,5,7-
triazabicyclo[4.4.0]dec-5-ene (N-MeTBD, pKa = 18.6),[14] an
excellent yield of 6 was obtained, but only when 5 mol% LiBr
was added. On the other hand, using 5 mol% of the more basic
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, pKa = 21.0) gave 6 in
89% yield in the absence of added LiBr. Intrigued by the distinct
preference and high yield in the formation of the axial β-ketol
product 6 using catalytic amounts of bases, with and without
LiBr, we carried out the cyclization reaction of the triketone 1 in
the presence of 5 mol% of sparteine,[18] at -40 oC with and
without LiBr as catalysts, but no reaction was observed. Upon
adding 5 mol% of DBU to the mixture, 6 was obtained in 88%
isolated yield, regardless of the order of addition. Unfortunately,
the product was racemic.
Yield, %
Entry
Additive
TBD
T, °C
-40
-40
-40
-40
-78
12
33[b]
40[b]
-
13
-
14
1
2
3
4
5
-
-
-
TBD, LiBr
DBU
-
83
-
DBU, LiBr
DBU
16
-
81
82
-
The guanidine-based bifunctional catalysis[19] was
extended to the intramolecular aldolization of the
cyclohexanedione analog 9 with and without LiBr to give the
corresponding β-ketol 10 in high yields (Scheme 2). In the case
of the benzyl triketone 11 and catalytic TBD, the yield of the
All reactions were run with 0.14 mmol triketone in 1 mL THF for 72 h. [a]
Isolated yield. [b] Reaction did not complete and significant amounts of
starting material were recovered.
The formation of 6 in high yield in the presence of catalytic
DBU and LiBr is attributed to a conformational pre-organization
whereby the carbonyl groups of the side-chain and the
cyclopentanedione are favorably aligned due to a bidentate
coordination with the oxophilic LiBr (Scheme 3).
Scheme 2. Intramolecular aldol reactions with triketone 9.
bicyclic product 12 was modest, even with addition of LiBr.
(Table 1, entries 1 and 2). On the other hand, treatment of 11
with 5 mol% DBU at -40 °C led to the diastereomeric β-ketol
product 13 in excellent yield (Table 1, entry 3). Under the same
conditions, the catalytic DBU/LiBr combination gave 12 and 14
in 16% and 81% yields respectively. Curiously, catalytic DBU by
itself also gave 14, albeit at -78 °C (Table 1, entries 4 and 5).
The formation of the [3.2.1]bicyclooctane β-ketols 5 and 6
has been scarcely studied since the initial report by Hajos and
Parrish in 1974. Dauben and Bunce[20] reported formation of 6
under 15 bar in the presence of Et3N and acetonitrile at 20 °C. In
an effort to obtain enantioselective intramolecular aldolization,
Shibasaki and coworkers[21] reported the formation of 6 in 52%
ee and 60% yield (THF, -52 °C, 6 days) in the presence of
catalytic amounts of an ytterbium dialkoxide originally prepared
from (R,R)-tartaric acid. Davies and coworkers[22] investigated
the asymmetric synthesis of 6 from 1 in the presence of
(1’R,2’S)-5-(2’-aminocyclopentan-1’-yl) tetrazole as a catalyst,
however, the product obtained in 67% yield was racemic.
Mahrwald and coworkers tested a tetranuclear BINOL-titanium
complex catalyst,[23] to give racemic 6 in 44% yield.
Scheme 3. Proposed catalytic cycle in the LiBr pre-coordination model. The
Li-coordinated endocyclic enolate as calculated from DFT is depicted in the
center; showing the pre-organization by Li, which brings the HOMO (red/blue)
located on the enolate and the carbonyl LUMO (yellow/purple) close together.
Abstraction of a proton by DBU leads to the corresponding
endocyclic lithium enolate, which undergoes cyclization to 6.
Indirect evidence for this proposal is provided by 13C NMR
spectra of 1 in the presence of increasing quantities of LiBr in
THF-d8 and observing appropriate shifts (see SI). The failure of
the reaction to occur with catalytic DBU alone at -40 °C, attests
to the existence of a prior cooperative effect involving LiBr which
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10.1002/ejoc.201700437
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COMMUNICATION
also activates the adjacent carbon atom towards enolization with
DBU. A similar mechanism could be operative in the presence of
the Eschenmoser amidine acting as a base, although the
conversion was more efficient with added LiBr. (see SI for
details). It is noteworthy that the use of THF as solvent is
another important factor most likely due to the coordination of
the carbonyl groups of the triketone 1 with a LiBr-THF complex.
When MeOH was used as solvent, the major product was the
equatorial β-ketol 5, presumably due to the solvation of triketone
1 in MeOH, thus preventing coordination with LiBr.
DFT calculations conducted at the ωB97x-D/def2-TZVP
level of theory for the LiBr-catalyzed reactions support these
findings and highlight the formation of a complex between 1 and
LiBr (1LiBr). This results in a stabilization energy of about 2
kcal.mol-1 while forming a pre-organized reactive intermediate,
which is followed by proton abstraction and enolization with a
strong preference (5 kcal.mol-1) for the formation of the
endocyclic enolate (Figure 1). Activation barriers to the transition
states (TS) leading to 6 and 3 are found around 10 kcal.mol-1,
with a ΔΔGǂ of 1.2 kcal.mol-1 favoring the formation of β-ketol 6
(Figure 1).
Figure 2. Transition states and free energies for the non-catalyzed reaction, in
THF at 298 K, resulting from both conformations of endocyclic enolization (TSA
and TSB) and exocyclic enolization (TSC). Side-chain enolization is disfavored
and the preferred reaction pathway involves the equatorial conformation of the
exocyclic ketone leading to the β-ketol 5.
Since the equatorial β-ketol 5 is the kinetic product for the
non-catalyzed
reaction,
it
could
transform
to
the
thermodynamically-preferred axial product 6 by a retro-aldol
reaction. However, β-ketol 5 was stable under the same reaction
conditions (5 mol% DBU and LiBr at -40 °C for 24 h), and was
converted to 6 only upon warming to room temperature. Thus,
the thermodynamically stable ketol 6 is produced directly from
starting triketone 1. With strong bases, such as N-methyl TBD, a
significant lithium effect is observed when comparing the product
distribution in the presence of 5 mol% of N-methyl TBD when β-
ketol 6 was obtained in 5% yield at -40 °C for 24 h. In contrast,
inclusion of 5 mol% LiBr led to the formation of 6 in 88% yield
(see SI for details).
A different mechanism can be suggested for the catalytic
action of a cyclic guanidine like TBD (Scheme 1). Enolization
could also lead to a favorable alignment of the enol and the side-
chain carbonyl bridged by TBD. We propose that catalysis is
occurring through a bifunctional H-bonded mechanism, since
there was no yield difference in the presence or absence of LiBr.
A dual role of TBD, acting as a proton donor and acceptor is
most likely taking place in the intramolecular aldol reaction of
triketone 1 leading to β-ketol 6.
Figure 1. Free energy profile for the LiBr-catalyzed reaction using DBU as
base, in THF at 233 K. Reaction pathway undergoing enolization on the 5-
membered ring is represented in blue, while the enolization occurring in the
side-chain is drawn in black.
The newly forming C-C bond length is significantly shorter
for the most stable transition structure (2.13 Å versus 2.23 Å).
The overall free energy of the reaction for both pathways
remains positive, which is experimentally observed as products
kept in THF tend to revert to 1, and is in accordance with
previous DFT studies.[8e,13a] Therefore, when Li is used to
conformationally lock the exo- and endocyclic carbonyl groups to
be aligned parallel to each other, β-ketol 6 is produced
kinetically as the endocyclic enolate and the subsequent
transition structures are favored, even though β-ketol 3 resulting
from exocyclic enolization is thermodynamically preferred.
Without the addition of LiBr, the endocyclic enolate is still
favored but the absence of any pre-organization and parallel
alignment of the C-O bonds leads to the equatorial β-ketol 5,
with a 3 kcal.mol-1 preference with respect to the axial β-ketol 6
(Figure 2).
Figure 3. Free energy profile for the TBD-catalyzed reaction of 1 in THF at 233
K leading to β-ketol 6. Reaction pathway undergoing enolization on the 5-
membered ring is represented in blue, while the enolization occuring in the
side-chain is drawn in black.
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DFT optimization led to the formation of stable adducts
involving bifunctional H-bonding (H-bond lengths between 1.7
and 2.1 Å) with an activation energy for the C-C bond formation
in the same range as for the LiBr-catalyzed reaction (Figure 3).
In this case, however, the activation energy was slightly higher,
13.4 and 14.6 kcal/mol-1 respectively for the endocyclic enolate
and the side-chain enolate pathways. The C-C distance at the
stationary saddle point is also shorter for the preferred TS, which
leads to product 6 (TSTBD1). The axial β-ketol 6 is therefore
produced due to a favored enolization and transition state. In a
related isolated example, Baati, Himo and coworkers[13] have
studied the intramolecular aldol reaction of an acyclic keto
aldehyde catalyzed by TBD through DFT calculations and
proposed a proton shuttling general base mechanism. We have
recently used the presently described TBD-catalyzed
intramolecular aldol cyclization reaction in a critical key step
toward the total synthesis of isodaphlongamine H.[24] To the best
of our knowledge, the intramolecular TBD-catalyzed aldol
reaction of a triketone such as 1 has not been previously
reported[25] and offers distinct advantages.
DBU, addition of 5 mol% LiBr, led to a 74% yield of a single
diastereomer 16 (Table 2, entries 1 and 2) The same product
was also formed in the presence of 5 mol% TBD (Table 2, entry
3). These results provide good support for our proposed lithium
pre-organization and bifunctional H-bonded mechanisms in
these stereoselective intramolecular aldol cyclizations to β-ketols.
Table 2. Intramolecular aldol reaction of diketone 15.
Entry
Additive (5mol%)
DBU
T, °C
-40
Yield, %[a]
No reaction
74
1
2
3
DBU, LiBr
TBD
-40
-40
85
The proposed LiBr pre-coordination and bifunctional H-
bonding mechanisms can also explain the diastereoselectivities
in the reactions of benzyl triketone 11. When LiBr is added, pre-
organization leads to a favored chair conformation with the
phenyl group occupying the equatorial position to give β-ketol 14
(Figure 4).
The reactions were run with 0.14 mmol triketone in 1 mL THF for 12 h.
[a] Isolated yield.
In conclusion, we have shown that the combination of 5
mol% DBU/LiBr forms an excellent catalyst duo, combining
oxophilicity and basicity to effect highly stereoselective
intramolecular aldol cyclizations of 1,5-diketones in monocyclic
and acyclic substrates, affording diastereomeric carbocyclic, and
bicyclic β-hydroxy ketones. Remarkably, these reactions take
place at temperatures as low as -78 °C. DFT calculations
confirms the formation of spatially pre-organized and Li-
coordinated 1,5-enolate/carbonyl intermediates which then
undergo cyclization. The same intramolecular aldol cyclizations
can be achieved in the presence of 5 mole% TBD as a catalyst,
proceeding via
a
donor-acceptor bifunctional H-bonded
cooperative mechanism that engages an enol and a carbonyl
group simultaneously. High-level DFT calculations support this
pathway and account for the formation of the axial β-ketols
resulting from the conformation lock and the kinetically-favored
endocyclic enolization. Extensions to other 1,5-diketones and
the prospects of asymmetric induction using chiral non-racemic
amidines and guanidines are in progress.
Figure 4. Proposed coordination transition states for the reaction of benzyl
triketone 11 in THF.
This is further predicted by the optimization of both TSs (TS13
and TS14) leading to 13 and 14 in which ΔΔGǂ is found around 7
kcal.mol-1 in favor of the equatorial conformation of the phenyl
ring. Catalysis in the presence of DBU alone appears to be
temperature dependent, leading to 14 at -78 °C, possibly
Experimental Section
Copies of 1H and 13C NMR spectra of new compounds, computational
details and chemistry procedures can be found in the provided
supporting information. CCDC 1468933, 1468934, 1468935, 1468936
and 1468937 contain the supplementary crystallographic data for this
paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
through an H-bonded enol intermediate similar to
a Li-
coordination (Figure 4). At higher temperatures (Table 1, entry
3) the diastereomeric 13 was favored, with minimal retro-aldol
formation. Unfortunately, these results could not be rationalized
based on DFT calculations.
Finally, based on these experimental observations and
mechanistic studies, we were curious to see if the LiBr/DBU dual
catalyst combination could also be operative via bidentate
coordination in the case of the acyclic benzyl diketone 15 (Table
2). Although no reaction occurred in the presence of 5 mol%
Acknowledgements
We thank NSERC for financial support. G. Berger acknowledges
the ULB/VUB high performance computing center.
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[12] For selected uses of Li salts involving carbonyl compounds, see: [a]
Leverett, C. A.; Purohit, V. C.; Romo, D. Angew. Chem. Int. Ed. 2010, 49,
9479; [b] Hasaninejad, A.; Zare,, A.; Mohammadizedeh, R. M.; Shekouly, M.
Green Chem. Lett. 2010, 3, 143; [c] Mojtahedi, M. M. Akbarzadeh, E.; Sharif,
R.; Abaee, M. S. Org Lett. 2007, 9, 2791; [d] Zhu, C. Shen, X.; Nelson, S. G. J.
Am. Chem. Soc. 2004, 126, 5352; [e] Maiti, G. Kundu, P.; Guin, C.
Tetrahedron Lett. 2003, 44, 2757; f. Firouzabadi, H.; Iranpoor, N. Karimi, B.
Synthesis 1999, 58; [g] Seebach, D. Thaler, A.; Beck,A, K. Helv. Chim. Acta
1989, 72, 857; [h] Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. D.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183; [i]
Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000, 65,
4745.
[13] For a precedent related to keto aldehydes see: [a] Hammar, P.; Ghobril,
C.; Antheaume, C.; Wagner, A.; Baati, R.; Himo, F. J. Org. Chem. 2010, 75,
4728; [b] Ghobril, C.; Sabot, C.; Mioskowski, C.; Baati, R. Eur. J. Org. Chem.
2008, 4104.
[14] For relevant reviews, see: [a] Taylor, J. E.; Bull, S. D.; Williams, J. M. S.
Chem. Soc. Rev. 2012, 41, 2109; [b] Fu, X.-J.; Tan, C.-H. Chem. Comm. 2011,
47, 8210; [c] Leow, D.; Tan, C.-H. Chem. Asian J. 2009, 4, 488; [d] Coles, M.
Chem. Comm. 2009, 3659.
[15] Ishikawa, T. Superbases for Organic Syntheses: Guanidines, Amidines,
Phosphazenes and Related Organocatalysts, Wiley, Chippenham 2009.
[16] For selected uses of inorganic magnesium salts in aldol reactions, see: [a]
Abaee, M. S.; Sharfi, R.; Mojtahedi, M. Org. Lett. 2005, 7, 5893; [b] Wei, H.-
X.; Jasoni, R. L.; Shao, H.; Hu, J.; Paré, P. W. Tetrahedron 2004, 60, 11829;
[c] Wei, H.-X.;; Li, K.; Zhang, Q.; Jasoni, R. L.; Hu, J.; Paré, P. W. Helv. Chim.
Acta 2004, 87, 2354; [d] Swiss, K. A.; Choi, W.-B.; Liotta, D. C.; Abdel-Magid,
A. F.; Maryanoff, C. A. J. Org. Chem. 1991, 56, 5978; [e] Mansour, T. S.
Synth. Comm. 1988, 18, 727.
Keywords: Organocatalysis • Intramolecular aldol • Bifunctional
catalysis • DFT • β-Ketol
[1] For intramolecular aldol reactions, see Mahrwald, R. Modern Aldol
Reactions. Wiley- VCH, Weinheim, 2004.
[2] [a] Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1612; [b] Hajos, Z.
G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
[3] Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. 1971, 10, 469
[4] For an early example of an intramolecular catalytic asymmetric aldol
reaction, see:
[a] Yamada, S.; Hiroi, K.; Achiwa, K. Tetrahedron Lett. 1969, 4233; [b]
Yamada, S.; Otami, G. Tetrahedron Lett. 1969, 4237.
[5] See for example: [a] Jacobsen, E. N.; MacMillan, D. W. C. Proc. Natl. Acad.
Sci. USA, 2010, 107, 20618; [b] Lelais, G.; MacMillan, D. W. C. Aldrichim.
Acta 2006, 39, 79; [c] MacMillan, D. W. C. Nature 2008, 455, 304; [d] Ahrendt,
K. A.; Broths. C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4235.
[6] For excellent monographs and reviews, see: [a] Recent Advances in
Organocatalysis, Karame, I; Srour, H [Eds.]; Intech, 2016; [b] Comprehensive
Enantioselective Organocatalysis: Catalysts, Reactions, and Applications,
Dalko, P. I [Ed.]; Vol, 1-3, Wiley-VCH, Weinheim, 2013; [c] Asymmetric
Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric
Synthesis. Berkessel, A.; Groger, H. [Eds.], Wiley-VCH, Weinheim, 2004. For
a review summarizing recent contributions, see: Ricci, A. M.; ISRN Organic
Chemistry, 2014, 1-29.
[7] [a] List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000, 122,
2395; for authoritative reviews, see: [b] List, B.; Tetrahedron, 2002, 58, 2481;
[c] List, B. Synlett 2011, 1675; [d] Barbas, C. F. III; Angew. Chem Int. Ed. 2008,
47, 42; [d] Cordova, A.; Notz, W.; Barbas, C. F. III. J. Org. Chem. 2002, 67,
301.
[17] Heinzer, F.; Soukup, M.; Eschenmoser, A. Helv. Chim. Acta 1978, 61,
2851.
[8] [a] Bahmayar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273; [b]
Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A, 2002, 106, 5115; [c]
Bahmayar, S. Houk, K. N.; Martin, H-J; List, B. J. Am. Chem. Soc. 2003, 125,
2475; [d] Allemand, C.; Gordillo, R,; Clemente, F. R.; Cheong, P. H-Y.; Houk,
K.N. Acc. Chem. Res. 2004, 37, 558; [e] Clemente, F. R.; Houk, K. N. Angew.
Chem. Int. Ed. 2004, 43, 5766; [f] Bahmayar, S.; Houk, K. N. J. Am. Chem.
Soc, 2001, 123, 9922. For a recent confirmation of the original Houk model,
see: [g] Armstrong, A.; Boto, R. A.; Dingwall, P. Contreras-Garcia, J. Harvey,
M. J; Mason, N. J. Rzepa, H. S. Chem. Sci. 2014, 5, 2057.
[9] [a] Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386; [b] Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F. III. J. Am. Chem. Soc. 2001, 123, 5260; see
also: [c] Brown, K. L.; Damon, L.; Dunitz, J. D.; Eschenmoser, A.; Hobi, R.;
Kratky, C. Helv. Chim. Acta 1978, 61, 3108.
[10] [a] Klussmann, H.; Iwamura, H; Matthew, S. P.; Wells, D. H. Jr.; Pandya,
U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621; [b] Hayashi, Y.;
Matsuzawaq, M.; Yamaguchi, S.; Yonehara, S.; Matsumoto, Y. Shoji, M;
Hashizume, D. Koshino, H. Angew. Chem. Int. Ed. 2006, 45, 4593.
[11] Seebach, D.; Beck, A. K.; Badine, D. M.; Limbach, M; Eschenmoser, A.;
Treasurywala,. A. M.; Hobi, R.; Prikossovich, W.; Linder, B. Helv. Chim. Acta
2007, 90, 425.
[18] For a review, see: [a] Hoppe, D.; Hense, T. Angew. Chem. Int. Ed. 1997,
36, 2282; see also: [b] O’Brien, P. Chem. Comm. 2008, 655.
[19] Maji, B.; Stephenson, D. S.; Mayr, H. ChemCatChem. 2012, 4, 993
[20] Dauben, W. G.; Bunce, R. A. J. Org. Chem. 1983, 48, 4642.
[21] Sasai, H.; Szuki, T.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114,
4418.
[22] Davies, S. G.; Russel, A. J.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E.
Org. Biomol. Chem. 2007, 5, 3190.
[23] Schetter, B.; Ziemer, B.; Schnakenburg, G.; Mahrwald, R. J. Org. Chem.
2010, 75, 4728.
[24] Chattopadhyay, A. K.; Ly, V.-L.; Jakkepally, S.; Berger, G.; Hanessian, S.
Angew. Chem. Int. Ed. 2016, 55, 2577.
[25] A large number of catalytic reactions with chiral and achiral cyclic
guanidines involving Brønsted bases and ion-pair mechanisms have been
reported. See for example: [a] Goldberg, M.; Sartakov, D.; Bats, J. W.; Bolte,
M.; Göbel, M. W. Beilstein J. Org. Chem. 2016, 12, 1870; [b] Alvarez-Casao,
Y.; Marques-Lopez, E.; Herrera, R. D. Symmetry 2011, 3, 220.
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10.1002/ejoc.201700437
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
Ménage à trois (ou quatre).
Bin Chen, Gilles Berger and
Stephen Hanessian*
The
oxophilic
or
LiBr/DBU
bicyclic
combination
a
Page No. – Page No.
guanidine such as TBD are
excellent catalysts for the
activation of carbonyl groups in
acyclic and carbocyclic 1,5-
diketo compounds, generating
energetically favored metal (Li)
Metal Coordination-controlled
and Bifunctional H-bonded
Cooperative Catalysis in
Stereoselective Intramolecular
Aldol Cyclizations toward
Carbocyclic Tertiary β-Ketols
and
H-bonded
in
(TBD)
which
intermediates
a
carbonyl group and an enol(ate)
are exquisitely aligned to
undergo
intramolecular
aldolization
conformationally
leading
to
and
stereochemically distinct beta-
ketols.
This article is protected by copyright. All rights reserved.