Strain-driven direct cross-aldol and -ketol reactions of four-membered heterocyclic ketones

Article abstract of DOI:10.1021/acs.orglett.5b01002

Owing to the ring strain and α-heteroatom effect, the four-membered heterocyclic ketones can undergo direct cross-aldol and -ketol reactions without the need for preformed enol or "enolate-like" intermediates. Besides the organocatalyzed cross-ketol addition onto their highly active carbonyl group, their ability to act as a nucleophilic donor has also been explored. As a result, a number of discrete aldol adducts were synthesized and the distinct reactivities were successfully combined into a double-aldol one-pot reaction.

Full text of DOI:10.1021/acs.orglett.5b01002

Letter
pubs.acs.org/OrgLett
Strain-Driven Direct Cross-Aldol and -Ketol Reactions of Four-
Membered Heterocyclic Ketones
Zoltan Dobi, Tamas Holczbauer, and Tibor Soos*
́
́
́
Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1519 Budapest, Hungary
S
* Supporting Information
ABSTRACT: Owing to the ring strain and α-heteroatom effect, the
four-membered heterocyclic ketones can undergo direct cross-aldol and
-ketol reactions without the need for preformed enol or “enolate-like”
intermediates. Besides the organocatalyzed cross-ketol addition onto
their highly active carbonyl group, their ability to act as a nucleophilic
donor has also been explored. As a result, a number of discrete aldol
adducts were synthesized and the distinct reactivities were successfully combined into a double-aldol one-pot reaction.
n recent years, four-membered heterocycles have emerged as
I
prominent building blocks in drug discovery and develop-
ment.1 By including these structural motifs in drug candidates,
several pharmacological properties could be significantly altered,
among the most important of these was the capacity to improve
physicochemical and pharmacokinetic parameters.2 As a result,
there is a current drive to explore and broaden the synthetic
accessibility to this important class of molecules.3
Figure 1. Effect of the bond angle strain in 1a−d.
However, the effect of the ring strain on the chemical reactivity
is not versal as illustrated by the general base-catalyzed
enolization of cyclobutanone.8 The ring strain had only a
negligible effect on the rate constant of the enolization, as it was
similar to the value determined for acetone. Finally, the aldol
donor reactivity of 1a−d was expected to be further complicated
by the known effect of the α-heteroatom on carbonyl
enolization.9
While several strategies have been developed for the synthesis
of four-membered heterocycles, their construction remains far
from straightforward and facile, especially for medicinal
chemistry development. To circumvent this barrier, Carreira,
Rogers-Evans, Muller and co-workers have recently introduced
̈
1a,b azetidin-3-ones and oxetan-3-one (1c) into the synthetic
practice of medicinal chemistry as versatile synthetic modules
that can be easily attached onto molecular scaffolds or
transformed into new classes of spirocyclic ring systems.1a,d,4
Intrigued by the potential of four-membered heterocyclic
ketones 1a−d as practical synthetic modules in medicinal
chemistry, a study was initiated to investigate their organo-
catalytic aldol reactivity with a parallel purpose of generating
discrete building blocks. These inherently bifunctional molecules
1a−d were also envisaged as a linchpin element that can be
grown by aldol chemistry in two directions to form rigid
“polyketide-like” or “sugar-analog” fragments.5 The results of
these efforts are presented in this communication.
First, experiments were performed to ascertain if these strained
ketones are suitable electrophilic partners in selective cross-ketol
reactions. As an initial trial, the reaction of the 1-diphenylme-
thylazetidin-3-one (1a) with acetone was probed in the presence
of secondary amine catalysts (Table 1). Gratifyingly, the desired
cross-ketol product was observed as a sole product in the
presence of L-proline at rt, although with low conversion (Table
1, entry 1). To our delight, the employment of higher reaction
temperatures (70−110 °C) allowed a significant increase in yield
in neat acetone (Table 1, entries 2−4) without the formation of
either self-aldol products. Curiously, no aldol-condensation
product 3 was detected despite the harsh conditions. Above 110
°C, the conversion started to decrease due to the decomposition
of the catalyst (Table 1, entries 5−6). Although the L-proline
proved to be an efficient catalyst, the applied high temperature
would limit the general applicability of this reaction. Thus,
further screens for an improved catalyst were pursued.10 Finally,
we found that 20 mol % of pyrrolidine was an efficient promoter
of the cross-ketol formation at rt (Table 1, entry 7) while it
maintained the previously found exclusive selectivity in the cross-
ketol reaction. Lowering the catalyst load to 10 mol % resulted in
In most cases, the aldol reaction6 of nonequivalent aldehydes
and/or ketones is a formidable synthetic challenge on account of
(a) the need for preformed enolate or enolate-like species to
achieve selectivity, (b) undesired reactivity of aldehydes to
polymerize under basic conditions, (c) dehydration of the aldol
products, and (d) the equilibriums of ketol formation being
generally shifted toward the starting materials. Nevertheless, the
angle strain in 1a−d (Figure 1) was conceived to serve as a
handle to attain organocatalytic direct cross-aldol and -ketol
reactions. Prior studies on the carbocyclic analog have
established the enhanced reactivity of cyclobutanone in carbonyl
additions owing to the relief of strain during conversion of an sp2-
hybridized carbonyl carbon to an sp3-hybridized carbon.7
Received: April 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01002
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Catalyst Screening for Cross-Ketol Reaction of
Azetidinone 1a with Acetone
Scheme 1. Scope of Cross-Ketol Formation
cat. load
(mol %)
temp
conv
a
entry
catalyst
L-proline
(°C)
time
(%)
1
20
20
20
20
20
20
20
10
10
40
20
25
10 d
16 h
1 h
30
>99
66
b
2
L-proline
70
c
3
L-proline
100
c
4
L-proline
110
1 h
>99
85
c
5
L-proline
120
1 h
b
6
4-OH-L-proline
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
120
1 h
27
7
25
25
40
25
25
16 h
16 h
16 h
16 h
2 d
85
8
29
9
30
10
11
12
90
>99
d
20
25
16 h
78
a
b
1
Conversion was determined by H NMR. The reaction was carried
c
out in a sealed tube. The reaction was carried out in a microwave
reactor. Reaction conditions: 1a (0.5 mmol), acetone (1.0 mmol),
d
and pyrrolidine (0.1 mmol) in 0.5 mL of isopropanol.
a
b
a significant decrease of the conversion (Table 1, entry 8), which
could not be restored by applying a higher reaction temperature
(Table 1, entry 9). On the other hand, only a slight increase of
conversion was obtained when a 40 mol % catalyst load was
employed (Table 1, entry 10). Nevertheless, the reaction
proceeded to near full conversion after 2 days without the
formation of dehydration product 3 (Table 1, entry 11). A
subsequent brief survey of solvents identified isopropanol as a
viable alternative of acetone. This modification also allowed
reduction of excess acetone (1:20 vs 1:2).10
Isolated yields are shown. Reaction conditions: 1a−d (2.0 mmol),
nucleophile (15 equiv), pyrrolidine (20 mol %), 25 °C, 2 days.
c
Reaction conditions: 1a−d (2.0 mmol), nucleophile (2 equiv),
pyrrolidine (20 mol %), 25 °C, isopropanol (20 equiv), 2 days.
d
Reaction conditions: 1a−d (2.0 mmol), nucleophile (15 equiv), L-
e
proline (20 mol %), 80 °C, 24 h. Mixture of the 2 regioisomers; only
one of isomers was highlighted.
18). These experiments revealed that this cross-ketol reaction
works with cyclic or aliphatic methyl-ketones as nucleophiles and
even a slight structural modification or an increase of steric
demand of the nucleophile could result in a notable change in the
outcome. Nevertheless, it is worth mentioning the practical
utility of this organocatalytic approach; a previous attempt to
construct a N-benzyloxy analog of 8 opted for the Mukaiyama
aldol reaction with a markedly lower yield.11
These results indicate that the strain relief during ketol
formation drives not only the thermodynamics but also the
selectivity of the reaction. Thus, the strained 1a−d ketones
invariably act as an electrophile in these reactions of non-
equivalent enolizable ketones. As a second issue, these ketones
1a−d seem to have diminished reactivity as a nucleophile in the
aldol reaction compared to acetone, as the self-dimerization
ketol-product12 of 1a−d was not observed.
Intrigued by the tempered reactivity of 1a−d ketones via the
enol or enamine mechanism, we sought to explore their capacity
to act as a nucleophilic donor in aldol reactions. Of particular
relevance to our study were the recent organocatalytic
applications of cyclobutanone that suggested that this strained
ketone could be converted to a putative enamine species.13 With
this in mind, we embarked on studying the reaction of 1a−c with
a nonenolizable aldehyde, benzaldehyde, utilizing different
tertiary (DBU) and chiral primary and secondary amines as an
organocatalyst.10 Surprisingly, neither the oxetane-3-one (1c)
nor the N-Boc-azetidin-3-one (1b) showed any reactivity; only
the starting materials could be recovered (Scheme 2). Nonethe-
less, further test reactions disclosed that the desired aldol union is
indeed possible; however, the reaction of ketone 1a with
Having identified optimal reaction conditions for a cross-ketol
reaction, we next examined the scope of the electro- and
nucleophilic components (Scheme 1). Thus, the commercially
available four-membered heterocyclic ketones 1a−d were
reacted with cyclic and acyclic ketones. The acetone, cyclo-
hexanone and cyclopentanone generally reacted well and in the
catalytic cross-ketol protocol affording selectively the desired
products 2−13 in moderate to excellent yields. Notably, there
was a remarkable difference in the reactivity between the two
azetidinone substrates 1a,b; the Boc protected derivative 1b has
an augmented efficiency in the ketol formation. Using chiral
amines, no asymmetric induction was realized in the case of 7−
9.10 Moreover, thiethan-3-one (1d) proved to be the least
reactive electrophile in this series; only a moderate yield was
achieved with acetone (Scheme 1, 6) whereas no product
(Scheme 1, 10) was observed with cyclohexanone. The reactions
of acetone with 1a−d have been carried out also in isopropanol
using only a 2 molar excess of the nucleophilic component
(Scheme 1). The isolated yields generally proved to be lower, and
no product formation was observed in the reaction with 1d. Next,
acyclic ketones were explored to gauge the generality of cross-
ketol reactions. The butan-2-one showed lower catalytic capacity,
because pyrrolidine formed a stable enamine adduct with the
products. To overcome this limitation, L-proline was employed at
80 °C. As a result, the reactions furnished the inseparable mixture
of regioisomers that arose from two possible nucleophilic sites of
methyl-ethyl-ketone. The evaluation of the diethyl ketone and an
acetophenone derivative, however, afforded no reaction (14 and
B
DOI: 10.1021/acs.orglett.5b01002
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 2. Investigation of Cross-Aldol Reaction of 1a−e and
H−D Exchange
Scheme 3. Reaction Scope of Cross-Aldol Reaction of 1a
benzaldehyde proceeded without added amines, reinforcing the
previous finding of Masuda.12 Interestingly, no rate acceleration
was observed in the presence of more basic amines. We could
only isolate the anti aldol adduct 20a because the isolation of the
syn product was hampered by its tendency to undergo syn-anti
isomerization. Additionally, no aldol condensation product 19
was observed in the reaction suggesting the relative stability of
the aldol adduct owing to the ring strain. The observed aldol
reactivity could be rationalized by a self-activation mechanism by
the tertiary amine of 1a; therefore, hydrogen−deuterium
exchange studies (Scheme 2) and preliminary kinetic inves-
tigations10 have been performed. Somewhat astoundingly, there
was no detectable hydrogen−deuterium exchange in 1a when
CD3OD was applied; only the rapid formation of hemiacetal
occurred. The unexpected lack of H−D exchange suggested if the
H−D exchange via enol intermediate is operating at all that
process should be rather slow (compared to the acyclic analog).
To minimize the hemiacetal formation, the proton−deuterium
exchange experiment was conducted in d8-propan-2-ol (Scheme
2, IPA-d8). After 24 h, only one out of four α-hydrogens
exchanged at rt and no hemiacetal formation was observed.
Subsequent kinetic investigations suggested that the rate-
determining step is the formation of the zwitterionic
intermediate I and not the subsequent C−C bond formation.10
As revealed in a subsequent solvent screening,10 this unique
aldol coupling can be easily accomplished in a wide range of
solvents, among which the polar protic isopropanol proved to be
the optimal one. Accordingly, the role of the solvent is to
encourage the self-activation pathway14 via stabilizing the
zwitterionic intermediate I. Next, the capacity of 1a to participate
in cross-aldol and -ketol reactions was probed to investigate the
robustness and generality of the method. As highlighted in
Scheme 3, a series of aldehyde and ketone acceptors were able to
suppress the homodimerization reaction (21) and afforded high
yields of the desired products with low to modest diaster-
eoselectivities. Notably, one of the diastereomers could only be
isolated in pure form due to the rapid syn-anti isomerization
process. It is also important to note that byproducts deriving
from the dehydration of the aldol/ketol products were not
detected.
a
b
Isolated yields of diastereomers. The diastereomeric ratio in the
c
1
crude reaction product was determined by H NMR. Reactions were
run at 40 °C for 2 d. Reactions were run at 25 °C for 2 d. Reaction
was run at 80 °C for 16 h.
d
e
pyridine-aldehydes were suitable coupling partners at rt (23a,b−
24a,b). Nevertheless, the reaction afforded the desired cross-
aldol adducts (25a,b−27a,b) if bulky ortho-, meta-substituted or
electron-rich benzaldehydes were applied. Interestingly, a
selective cross-ketol reaction was realized to furnish 28a,b−30
when isatin or 1b,c was employed as an electrophile. At
moderately high temperature (80 °C) even double substitution
was achieved with the highly reactive p-nitro-benzaldehyde
(Scheme 3, 31). To our surprise, the highly reactive and
enolizable acetaldehyde was found to be amenable for cross-aldol
reaction. The formation of such a peculiar product (Scheme 3,
32a,b) was interpreted by the unique intramolecular activation
mode of 1a. Finally, this method was also found to be applicable
toward sterically more demanding, but still enolizable aliphatic
aldehyde (33a,b).
The above results prompted us to examine whether the two
reactivity profiles of strained ketone 1a can be combined together
to carry out an iterative aldol sequence (Scheme 4). Thus, upon
exposure to the reaction conditions of cross-ketol formation, the
isolated diastereomer of 20a proved to be a competent acceptor,
with the corresponding single diastereomer 34 isolated in a 69%
yield. As the X-ray structural determination indicates, the acetone
was added to the least hindered face of 20a.10 Accordingly, the
Scheme 4. Iterative Cross-Aldol and Cross-Ketol Reactions
As outlined in Scheme 3, efficiencies of the aldol reactions
were dependent on the reactivity of the acceptor. More
specifically, the reaction with the p-nitrobenzaldehyde went to
near full conversion to afford 22a,b after 2 days at rt, but with
benzaldehyde, more than 1 week was necessary to complete the
reaction, unless heated to 40 °C for 2 days. Thus, electron-poor
C
DOI: 10.1021/acs.orglett.5b01002
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(c) Burkhard, J. A.; Wuitschik, G.; Plancher, J.-M.; Rogers-Evans, M.;
Carreira, E. M. Org. Lett. 2013, 15, 4312. (d) Stepan, A. F.; Karki, K.;
McDonald, W. S.; Dorff, P. H.; Dutra, J. K.; DiRico, K. J.; Won, A.;
Subramanyam, C.; Efremov, I. V.; O’Donnell, C. J.; Nolan, C. E.; Becker,
S. L.; Pustilnik, L. R.; Sneed, B.; Sun, H.; Lu, Y.; Robshaw, A. E.; Riddell,
D.; O’Sullivan, T. J.; Sibley, E.; Capetta, S.; Atchison, K.; Hallgren, A. J.;
Miller, E.; Wood, A.; Obach, R. S. J. Med. Chem. 2011, 54, 7772.
(3) Recent examples: (a) Hodgson, D. M.; Mortimer, C. L.; McKenna,
J. M. Org. Lett. 2015, 17, 330. (b) Kern, N.; Felten, A.-S.; Weibel, J.-M.;
pyrrolidine catalyst did not facilitate the isomerization and/or the
retro-aldol reaction of 20a.
Since isopropanol proved to be a suitable solvent for both the
cross-ketol and -aldol reactions, the iterative double-aldol
sequence could be further streamlined. In a simple one-pot,
two-step procedure, we observed the formation of two
diastereomers (Scheme 4) with a moderate isolated yield.
Thus, the overall sense of diastereoselective induction was
unaltered in the second step and acetone functioned as a capping
agent for the first aldol step. The principal issue in this procedure,
however, is that no preformed enols were required to generate a
double-aldol product 35a,b.
In summary, we have documented that ring strain combined
with a unique α-heteroatom effect in four-membered hetero-
cyclic ketones can be exploited in the development of direct
cross-ketol and -aldol reactions providing several discrete
building blocks in an operationally simple manner. Significantly,
we have also demonstrated that azetidinone 1a can serve as a
linchpin element in an iterative double aldol sequence without
the need for preformed enols. We expect that the strain-directed
cross-aldol and -ketol reactions will provide a convenient
synthetic strategy to new classes of constrained building blocks.
Further investigation of the mechanism, scope, and limitations of
these reactions and the exploration of the altered reactivity of
four-membered heterocycles are underway.
Pale, P.; Blanc, A. Org. Lett. 2014, 16, 6104. (c) Barre,
Campagne, R.; Reymond, S.; Marin, J.; Ciapetti, P.; Brellier, M.;
Guerinot, A.; Cossy, J. Org. Lett. 2014, 16, 6160. (d) Zhang, H.-H.; Luo,
́
B.; Gonnard, L.;
́
Y.-C.; Wang, H.-P.; Chen, W.; Xu, P.-F. Org. Lett. 2014, 16, 4896.
(e) Hodgson, D. M.; Pearson, C. I.; Kazmi, M. Org. Lett. 2014, 16, 856.
(f) Davis, O. A.; Bull, J. A. Angew. Chem., Int. Ed. 2014, 53, 14230.
(g) Boyd, S.; Davies, C. D. Tetrahedron Lett. 2014, 55, 4117. (h) Morgan,
K. F.; Hollingsworth, I. A.; Bull, J. A. Chem. Commun. 2014, 50, 5203.
(i) Zhang, L. Acc. Chem. Res. 2014, 47, 877. (j) Ravelli, D.; Zoccolillo,
M.; Mella, M.; Fagnoni, M. Adv. Synth. Catal. 2014, 356, 2781.
(k) Takizawa, S.; Arteaga Arteaga, F.; Yoshida, Y.; Suzuki, M.; Sasai, H.
̌
Org. Lett. 2013, 15, 4142. (l) Selig, P.; Turockin, A.; Raven, W. Chem.
Commun. 2013, 49, 2930. (m) Maegawa, T.; Otake, K.; Hirosawa, K.;
Goto, A.; Fujioka, H. Org. Lett. 2012, 14, 4798. (n) Ye, L.; He, W.;
Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 3236. (o) Denis, J.-B.;
Masson, G.; Retailleau, P.; Zhu, J. Angew. Chem., Int. Ed. 2011, 50, 5356.
(4) (a) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Muller, K.;
̈
Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 3524. (b) Beasley, B. O.;
Alli-Balogun, A.; Clarkson, G. J.; Shipman, M. Tetrahedron Lett. 2014,
55, 541. (c) Allwood, D. M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V. J.
Org. Chem. 2014, 79, 328. (d) Geden, J. V.; Beasley, B. O.; Clarkson, G.
ASSOCIATED CONTENT
* Supporting Information
■
S
J.; Shipman, M. J. Org. Chem. 2013, 78, 12243. (e) Ruider, S. A.; Muller,
̈
S.; Carreira, E. M. Angew. Chem., Int. Ed. 2013, 52, 11908. (f) Burkhard,
J. A.; Tchitchanov, B. H.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50,
5379. (g) Meyers, M. J.; Muizebelt, I.; van Wiltenburg, J.; Brown, D. L.;
Thorarensen, A. Org. Lett. 2009, 11, 3523. (h) Alcaidea, B.; Almendrosb,
P.; Lunaa, A. Tetrahedron 2007, 63, 3102.
Experimental procedure, NMR spectra, and analytical data. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01002.
AUTHOR INFORMATION
Corresponding Author
(5) Selected examples: (a) Albert, B. J.; Yamamoto, H. Angew. Chem.,
■
Int. Ed. 2010, 49, 2747. (b) Lenagh-Snow, G. M. J.; Araujo, N.;
́
Jenkinson, S. F.; Martínez, F.; Shimada, Y.; Yu, C.-Y.; Kato, A.; Fleet, G.
*E-mail: soos.tibor@ttk.mta.hu.
Notes
W. J. Org. Lett. 2012, 14, 2142.
(6) (a) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858.
(b) Modern Aldol Reactions; ed. Mahrwald, R., Ed.; WILEY-VCH:
Weinheim, 2008.
The authors declare no competing financial interest.
(7) (a) Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221.
(b) Modelli, A.; Martin, H.-D. J. Phys. Chem. A 2002, 106, 7271.
(8) Cope, S. M.; Tailor, D.; Nagorski, R. W. J. Org. Chem. 2011, 76, 380.
(9) In conformationally constrained, α-heteroatom substituted
ketones, such as 3-pyrrolidinone, the enolization of ketones prefers to
be nonconjugated with the amino group. Garst, M. E.; Bonfiglio, J. N.;
Grudoski, D. A.; Marks, J. J. Org. Chem. 1980, 45, 2307.
ACKNOWLEDGMENTS
We are grateful for the financial support from Gedeon Richter
Plc. Financial support for the project was also provided by
■
Lendulet Program E-13/11/2010.
̈
REFERENCES
■
(10) For more details see the Supporting Information.
(1) (a) Carreira, E. M.; Fessard, T. C. Chem. Rev. 2014, 114, 8257.
(b) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev. 2014,
114, 8323. (c) Han, M.; Song, C.; Jeong, N.; Hahn, H.-G. ACS Med.
Chem. Lett. 2014, 5, 999. (d) Lowe, J. T.; Lee, M. D., IV; Akella, L. B.;
Davoine, E.; Donckele, E. J.; Durak, L.; Duvall, J. R.; Gerard, B.; Holson,
(11) The only example of analog cross-ketol reaction based on the
Mukaiyama aldol reaction Exelixis, Inc. Azetidines as MEK inhibitors for
treatment of proliferative diseases. WO2007/44515 A1, 2007; p 239.
(12) Morimoto, A.; Okutani, T.; Masuda, K. Chem. Pharm. Bull. 1973,
21, 228. They mentioned that ketol-dimerization to afford 12 was the
major side reaction during the synthesis of 1a. Additionally, they
reported the reaction of 1a with benzaldehyde.
́
E. B.; Joliton, A.; Kesavan, S.; Lemercier, B. C.; Liu, H.; Marie, J.-C.;
Mulrooney, C. A.; Muncipinto, G.; Welzel-O’Shea, M.; Panko, L. M.;
Rowley, A.; Suh, B.-C.; Thomas, M.; Wagner, F. F.; Wei, J.; Foley, M. A.;
Marcaurelle, L. A. J. Org. Chem. 2012, 77, 7187. (e) Wuitschik, G.;
Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-
(13) (a) Aitken, D. J.; Bernard, A. M.; Capitta, F.; Frongia, A.; Guillot,
R.; Ollivier, J.; Pira s, P. P.; Secci, F.; Spiga, M. Org. Biomol. Chem. 2012,
10, 5045. (b) Moles, F.; Guillena, G.; Naj
Asymmmetry 2014, 25, 1323.
́
era, C. Tetrahedron:
Evans, M.; Muller, K. J. Med. Chem. 2010, 53, 3227. (f) Burkhard, J. A.;
̈
Wuitschik, G.; Rogers-Evans, M.; Muller, K.; Carreira, E. M. Angew.
̈
(14) Recent examples for spontaneous aldol reaction of tropinone:
Lazny, R.; Nodzewska, A.; Tomczuk, I. Tetrahedron Lett. 2011, 52, 5680.
Interestingly, in these reactions, the syn-diastereomers were thermody-
namically favored.
Chem., Int. Ed. 2010, 49, 9052. (g) Wuitschik, G.; Rogers-Evans, M.;
Muller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira,
E. M. Angew. Chem., Int. Ed. 2006, 45, 7736. (h) Dejaegher, Y.; De
Kimpe, N. Chem. Rev. 2002, 102, 29.
̈
(2) Selected examples: (a) Skoda, E. M.; Sacher, J. R.; Kazancioglu, M.
Z.; Saha, J.; Wipf, P. ACS Med. Chem. Lett. 2014, 5, 900. (b) McLaughlin,
M.; Yazaki, R.; Fessard, T. C.; Carreira, E. M. Org. Lett. 2014, 16, 4070.
D
DOI: 10.1021/acs.orglett.5b01002
Org. Lett. XXXX, XXX, XXX−XXX