A general stereoselective enamine mediated alkylation of α-substituted aldehydes

Article abstract of DOI:10.1039/c2cc17482k

We herein present a general enamine-mediated α-alkylation of α-substituted aldehydes with carbenium ions for the stereoselective construction of quaternary stereogenic centers.

Full text of DOI:10.1039/c2cc17482k

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COMMUNICATION
A general stereoselective enamine mediated alkylation of a-substituted
aldehydesw
Andrea Gualandi, Diego Petruzziello, Enrico Emer and Pier Giorgio Cozzi*
Received 30th November 2011, Accepted 10th February 2012
DOI: 10.1039/c2cc17482k
We herein present a general enamine-mediated a-alkylation of
a-substituted aldehydes with carbenium ions for the stereo-
selective construction of quaternary stereogenic centers.
The formation of quaternary stereocenters in the synthesis of
complex molecules is a rather challenging transformation.1
Even more difficult is the control of their absolute and relative
configurations. In recent years, the development of new and
exciting methodologies in organocatalysis2 has furnished new
reactions for targeting the asymmetric formation of quaternary
stereogenic centers.3 All these new methodologies are appealing,
in that they offer excellent stereocontrol and operate under mild
operative conditions. It is also important to note that the use
of transition metals is, in general, avoided.4
Fig. 1 Stereoselective formylation for the preparation of quaternary
The direct asymmetric intermolecular a-alkylation of carbonyls
remains a difficult and hot topic in organocatalysis.5 The alkyla-
stereogenic centers.
tion of activated carbonyl substrates was developed by Merck
laboratories6 with the invention of a quite useful asymmetric
enantiopure alcohol has allowed the possibility of introducing
phase-transfer catalysis (PTC)7 that was employed for preparative
a quaternary center in a stereoselective fashion, starting from a
common precursor. The idea that we want to borrow to
purposes achieving high stereoselectivity. The quaternary cinchona
translate in the language of organocatalysis was to apply a
alkaloids employed at first as catalysts in asymmetric PTC were
general and a simple methodology for preparation of an
later replaced by more active and stereoselective catalysts
developed by Maruoka et al.8
Although some innovative strategies have been described,9 the
intermediate that, through practical and simple reactions,
can give the possibility to introduce many different groups
and to vary the chemistry.
development of a new general enamine-mediated a-alkylation of
a-substituted aldehydes has received scarcely any attention.9d,10
This idea can be simply pursued by the application of our
benzodithiol chemistry. In fact, the introduction of the benzo-
Recently, we have established the possibility of using stable
carbenium ions generated from alcohols in alkylation reactions10
dithiol (Fig. 1) in a stereoselective fashion can give the
in the presence of MacMillan catalysts.11 We have also
possibility to construct the desired quaternary stereogenic
center and to install many groups after lithiation and successive
performed enantioselective alkylation of aldehydes with 1,3-benzo-
dithiolylium tetrafluoroborate,12 a versatile synthon in organic
alkylation, or by reductive or oxidative cleavage of the
benzodithiol group.
chemistry. Herein we report the general and practical alkylation
Primary amines efficiently catalyzed Michael reactions with
of a-substituted aldehydes with the 1,3-benzodithiolylium ion.
a-substituted aldehydes.14 In order to find the optimal reaction
conditions, we started our preliminary investigation using
phenylpropionaldehyde 1a as a model substrate in the
presence of a commercially available 1,3-benzodithiolylium
tetrafluoroborate 2 and several aminoacids (such as L-tryptophan,
proline and others). Different primary amines and imidazolidi-
none were also tested, all giving disappointing results (see ESIw
for a complete table and all conditions screened). It is worth
mentioning that Melchiorre and Bartoli have provided evidence
that the catalysts derived from cinchona alkaloids (I–VII)15 were
compatible with the carbenium ion. We therefore investigated
Quite recently, Aggarwal and coworkers13 have presented a
general organometallic strategy for the preparation of stereogenic
centers. This outstanding procedure that starts with available
Dipartimento di Chimica ‘‘G. Ciamician’’ALMA MATER
STUDIORUM Universita` di Bologna, via Selmi 2, 40126 Bologna,
Italy. E-mail: piergiorgio.cozzi@unibo.it; Web: www.unibo.it;
Fax: +39-051-2099456; Tel: +39-051-2099511
w Electronic supplementary information (ESI) available: Optimization
of the reaction, general procedure for the synthesis of aldehydes 1b–l
and catalysts IV, V, complete analytical data for products 3a–l, 4a–7a.
See DOI: 10.1039/c2cc17482k
c
3614 Chem. Commun., 2012, 48, 3614–3616
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Table 1 Optimisation of reaction conditionsa
Entry Catalyst Additive
Solvent
Yieldb erc
1
2
3
4
5
6
7
8
I
II
(ꢀ)-CSA
(ꢀ)-CSA
(ꢀ)-CSA
(ꢀ)-CSA
(ꢀ)-CSA
(ꢀ)-CSA
(+)-CSA
(ꢀ)-CSA
(ꢀ)-CSA
(ꢀ)-CSA
(ꢀ)-CSA
(+)-CSA
PhCOOH
PTSA
CH3CN/H2O 90
CH3CN/H2O 84
CH3CN/H2O 84
CH3CN/H2O 85
CH3CN/H2O 86
CH3CN/H2O 87
CH3CN/H2O 68
CH3CN/H2O
92 : 8
89.5 : 10.5
90.5 : 9.5
90 : 10
84.5 : 15.5
11 : 89
21 : 79
nd
31.5 : 68.5
83 : 17
77.5 : 22.5
91 : 9
37 : 63
III
IV
V
VI
VII
VI
I
I
I
I
9
CH2Cl2
CH3CN
H2O
83
86
77
10
11
12
13
14
15
16
CH3CN/H2O 88
CH3CN/H2O 58
CH3CN/H2O 69
CH3CN/H2O 72
VI
VI
VI
VI
14 : 86
12 : 88
12.5 : 87.5
TfOH
N-Boc-D-Phe CH3CN/H2O 79
a
The reactions were carried out with 1 equiv. of 2, 3 equiv. of 1a in the
presence of 20 mol% of catalysts I–VII, 40 mol% of additive and with
2 equiv. of NaH2PO4 in 500 mL of solvent at 0 1C. b Determined by
1H NMR. c (R)-3a : (S)-3a ratio determined by HPLC (see ESI for details).
Scheme 1 Scope of the reaction with different a-substituted aldehydes.
The optimized reaction conditions were applied to a series of
aldehydes (Scheme 1). The hindrance of the starting aldehydes is
crucial in order to obtain the reaction. Ortho substituted alde-
hydes were not reactive under the optimized reaction conditions,
however a series of a-branched aldehydes were alkylated in good
yield and with good enantiomeric excess. Interestingly, moderate
enantiomeric excesses were obtained with a,a-dialkyl aldehydes
(3j–l). The absolute configuration of the newly formed quaternary
center was established by chemical correlation.
these primary amines and were pleased to find out that these
catalysts were able to transmit the chiral information in a
better way (Table 1). However, still the results were not useful,
a series of conditions, such as: solvent, temperature and
additive, were screened. Under the optimized conditions the
reactions were performed in a 1 : 1 mixture of CH3CN/H2O as
reaction solvent, at 0 1C, in the presence of NaH2PO4 as a
base. It is noteworthy that the solvent controls the enantio-
facial selectivity of the reaction (entry 9 vs. entry 10), as a
result of the delicate conformation of the cinchona alkaloid
framework.16 After testing several acidic additives able to
enhance both reactivity and selectivity, we have observed that
(ꢀ)-CSA as chiral acid17 gave the best results in terms of
stereoselectivity. We have also prepared and tested the
primary amines IV and V following the procedure developed
by Hintermann et al.,18 but the enantiomeric excess was not
increased.
The advantage of benzodithiol as a versatile and chame-
leonic synthetic group was fully explored in a series of
transformations performed on the derivative 3a with previous
protection of the alcoholic function as a benzyl ether. The
resulting 4a was treated with n-BuLi at 0 1C and alkylated with
MeI. Finally, by treatment with Ni-Raney19 compound 6a was
obtained without loss of enantiopurity, and the absolute
configuration of the product was determined.
We have applied our chemistry to the synthesis of a natural
product. Compound 4a can be straightforwardly transformed
c
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Scheme 2 Synthesis of (2R)-(+)-a-methyltropic acid from compound 4a.
in (2R)-(+)-a-methyltropic acid,20 by direct oxidation of the
benzodithiol to the corresponding acid and debenzylation of
the hydroxyl group (Scheme 2). In conclusion, we have
reported a simple and general methodology for the enamine-
mediated a-alkylation of a-substituted aldehydes, previously
an unresolved problem in organocatalysis. Synthetic work is in
progress towards the synthesis of more hindered carbenium
ions, in order to improve the stereoselection of this synthetic
methodology.
organophotoredox catalysis: (b) D. A. Nicewicz and D. W. C.
MacMillan, Science, 2008, 322, 77–80. For alkylation via an SN20-
type addition–elimination pathway with electron deficient allylic
halides: (c) E. Gomez-Bengoa, A. Landa, A. Lizarraga, A.
´
Mielgo, M. Oiarbide and C. Palomo, Chem. Sci., 2011, 2,
353–357. For SN1-type alkylation reactions: (d) A. R. Brown,
W.-H. Kuo and E. N. Jacobsen, J. Am. Chem. Soc., 2010, 132,
9286–9287; (e) P. G. Cozzi, F. Benfatti and L. Zoli, Angew. Chem.,
Int. Ed., 2009, 48, 1313–1316; (f) L. Zhang, L. Cui, X. Li, S. Luo and
J.-P. Cheng, Chem.–Eur. J., 2010, 16, 2045–2049; (g) G. Bergonzini,
S. Vera and P. Melchiorre, Angew. Chem., Int. Ed., 2010, 49,
9685–9688.
PRIN (Progetto Nazionale Stereoselezioni in Chimica Organica:
Metodologie ed Applicazioni), Bologna University, Fondazione
Del Monte, and the European Commission through the
project FP7-201431 (CATAFLU.OR) are acknowledged for
financial support.
10 Combination of a metal catalytic process and organocatalysts has
been used for allylation of a-branched aldehydes: Pd complexes:
(a) S. Mukherjee and B. List, J. Am. Chem. Soc., 2007, 129,
11336–11337. In(III): (b) M. G. Capdevila, F. Benfatti, L. Zoli,
M. Stenta and P. G. Cozzi, Chem.–Eur. J., 2010, 16, 11237–11241.
11 G. Lelais and D. W. C. MacMillan, Aldrichimica Acta, 2006, 39,
79–87.
12 A. Gualandi, E. Emer, M. Guiteras Capdevila and P. G. Cozzi,
Angew. Chem., Int. Ed., 2011, 50, 7842–7844.
13 R. P. Sonawane, V. Jheengut, C. Rabalakos, R. Larouche-
Gauthier, H. K. Scott and V. K. Aggarwal, Angew. Chem., Int.
Ed., 2011, 50, 3760–3763.
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c
3616 Chem. Commun., 2012, 48, 3614–3616
This journal is The Royal Society of Chemistry 2012