Aminal-pyrrolidine organocatalysts - Highly efficient and modular catalysts for α-functionalization of carbonyl compounds

Article abstract of DOI:10.1002/ejoc.200901283

The substitution of the 4-position of hydroxyproline by a phenol group, together with an aminal on the 2-position, gave a synergistic effect leading to two powerful complementary organocatalysts. They show excellent enantiocontrol in the α-functionalization of a wide range of linear/ branched aldehydes and ketones, including Michael additions to ethenediyl disulfones or nitrostyrene and α-amination. We obtained ees up to 98.5 % with low catalyst loadings (down to 1 mol-%). As a proof of efficiency, TOFs of up to 1000 h^-1 could be obtained.

Full text of DOI:10.1002/ejoc.200901283

FULL PAPER
DOI: 10.1002/ejoc.200901283
Aminal–Pyrrolidine Organocatalysts – Highly Efficient and Modular Catalysts
for α-Functionalization of Carbonyl Compounds
Adrien Quintard,[a] Sébastien Belot,[a] Estelle Marchal,[a] and Alexandre Alexakis*[a]
Keywords: Asymmetric catalysis / Organocatalysis / Michael addition / Enamine / Pyrrolidine
The substitution of the 4-position of hydroxyproline by a
phenol group, together with an aminal on the 2-position,
gave a synergistic effect leading to two powerful comple-
mentary organocatalysts. They show excellent enantiocon-
trol in the α-functionalization of a wide range of linear/
branched aldehydes and ketones, including Michael ad-
ditions to ethenediyl disulfones or nitrostyrene and α-amin-
ation. We obtained ees up to 98.5% with low catalyst load-
ings (down to 1 mol-%). As a proof of efficiency, TOFs of up
to 1000 h–1 could be obtained.
have shown widespread application but still need further
development in order to obtain increased reactivity or lower
Introduction
Enamine catalysis has recently emerged as a method of catalyst loading, allowing organocatalysis to be a viable in-
choice for the α-functionalization of carbonyl com- dustrial process. This explains the need for a continuous
pounds.[1] An ever-increasing number of new reactions have effort towards the design of more efficient catalysts.
been developed during the last decade, leading researchers
In order to imagine a new catalyst, many different pa-
to design more efficient catalysts. This is notably the case rameters have to be taken into account, such as the basicity/
for the Michael addition, where the addition to nitro olefins acidity of the active site, the presence of a hydrogen donor,
has in particular been extensively studied. Rarely has a re- solubility, availability, and the possibility of recycling.
search area been so heavily investigated, leading to the de- Given these numerous factors, diarylprolinol silyl ethers
sign of powerful catalytic systems in such a short period.[2] have emerged as powerful catalysts for the α-functionaliza-
This activity is mainly due to the novelty of the area, the tion of aldehydes. Designed on the basis of a strong steric
opportunity to obtain useful synthons by new activation hindrance on the 2-position of the pyrrolidine ring, they are
modes and in few steps, and mostly to the mild experimen- able to promote high enantioselectivity in numerous reac-
tal conditions, which do not require particular equipment tions. Indeed, they favor the exclusive formation of the (E)-
such as Schlenk tubes or a glove box. Among enamine cata- enamine, while totally shielding the upper face of the
lysts, some of them have been found to be more general formed enamine.[6] Inspired by these results and by the fact
such as proline,[3] MacMillan’s oxazolidinones,[4] or the that the presence of an extra amine on the pyrrolidine sub-
widely used diarylprolinol silyl ethers.[5] These catalysts stituent led to high reactivity,[1m,2c] we recently briefly re
Figure 1. Aminal structure and proposed new aminal–pyrrolidine catalysts.
ported the design of a new catalyst incorporating an aminal
[a] Department of Organic Chemistry, University of Geneva,
on the pyrrolidine. The goal was to bring increased steric
hindrance as close as possible to the catalytic site. Indeed,
in the aminal structure, the nitrogen atoms are stereogenic
(Figure 1).[7] The substituents on each nitrogen atom adopt
Quai Ernest Ansermet 30, 1211 Geneva, Switzerland
Fax: +41-22-379-32-15
E-mail: alexandre.alexakis@unige.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901283.
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A. Quintard, S. Belot, E. Marchal, A. Alexakis
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a trans configuration relative to the substituent on the adja- (Scheme 1).[9] The protected Cbz-prolinal as well as the ob-
cent carbon atoms. Thus, the chiral information of the di- tained catalysts were stable to prolonged storage without
amine backbone is transferred closer to the catalytic site. any loss of enantioselectivity. Boc-protected proline could
Furthermore, since various diamines can be incorporated at not be a starting point due to the harsh acidic conditions
a late stage of the synthesis, these catalysts contain another needed for the deprotection, leading to aminal decomposi-
interesting property. They are highly modular and tunable, tion.
We then tested these seven catalysts in the Michael ad-
dition of isovaleraldehyde to an ethene-1,1-diyl disulfone
(Scheme 2). This reaction, developed in our group, led to
interesting gem-disulfone adducts.[10] The obtained Michael
adducts are highly useful synthons due to the versatility of
the sulfonyl group. This reaction can thus be considered as
a formal alkylation of aldehydes. We previously achieved
moderate yields and enantiocontrol using bipyrrolidine or
bimorpholine derivatives.[11] Only recently did Palomo and
co-workers, Lu and co-workers and our group report simul-
taneously the successful use of diarylprolinol silyl ethers in
this reaction.[12]
and by just changing the diamine substituent, totally dif-
ferent properties can be obtained. These catalysts gave
moderate to good results in the Michael addition to nitro
olefins or ethenediyl disulfones.[8]
Herein, we wish to present further improvement of these
catalysts by the introduction of a 4-phenoxy group on the
pyrrolidine ring. The addition of a bulky substituent at the
4-position led to better control of the steric hindrance on
the upper face of the enamine. Thus, the obtained catalysts
gave impressive reactivity and selectivity for the α-function-
alization of various carbonyl compounds, such as linear and
α-branched aldehydes and cyclohexanone.
All the aminals 4a–g cleanly catalyzed the reaction in less
than 2 h. As expected, the influence of the stereochemistry
of the aminal was crucial in terms of selectivity. Impres-
sively, the enantioselectivity varied from 77% ee to 43% ee
from aminal diastereoisomers 4a to 4c, respectively. Replac-
Results and Discussion
Preliminary Results Using Proline Derivatives
In a preliminary investigation,[8] we prepared catalysts ing the methyl group by a bulkier isopropyl group on the
4a–g in four steps from protected Cbz--proline nitrogen atoms in catalyst 4d did not improve the selectivity
Scheme 1. Synthesis of proline-based aminal–pyrrolidine catalysts. MS = molecular sieves.
Scheme 2. Catalyst screening in the addition of isovaleraldehyde to ethenediyl disulfones.
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Aminal–Pyrrolidine Organocatalysts
of the reaction (76% ee). These results suggest that it is not hydroxyproline, we easily obtained OBn-protected 11 in five
the substituent on the nitrogen atom but the phenyl group steps, but all attempts to deprotect the hydroxy group failed
of the backbone that interacts in the transition state with (Scheme 3A). Turning to the acetoxy protecting group al-
catalyst 4a or 4d. This is consistent with the importance of lowed the synthesis of catalyst 14 by a six-step procedure
the aminal configuration. Using an achiral diamine also (Scheme 3B). Unfortunately, when performing the catalytic
gave good results. Catalyst 4e, substituted by a phenyl group test reaction, we observed no improvement of enantio-
on the nitrogen atoms, gave the same enantioselectivity selectivity, compared to that of proline catalyst 4e (76% ee).
(76% ee) as that given by catalyst 4a, whereas the addition This suggested that the free hydroxy group did not activate
of a benzyl or substituted aryl group lowers the enantio- the electrophile at all.
selectivity for catalysts 4f and 4g.
By using benzyl-protected catalyst 11, we observed a dra-
matic drop to 40% ee. This result was really important,
since it showed that the 4-position substituent of the pyr-
rolidine ring interacted with the electrophile, lowering the
enantioselectivity. This can be considered the mismatched
Aminal–Hydroxypyrrolidine Catalysts
These good results in this challenging transformation case, since the two substituents of the pyrrolidine ring influ-
motivated us to pursue catalyst improvements. We first enced the nucleophilic attack in a negative fashion.
thought to introduce a free hydroxy group on the pyrrol-
We thus envisaged that changing the stereochemistry of
idine ring to activate the electrophile, as recently described this 4-pyrrolidine carbon center would create a synergistic
by Palomo and co-workers.[2g] Starting from Cbz-protected effect leading to the matched case. Indeed, the aminal
Scheme 3. Synthesis and use of (4R)-hydroxypyrrolidine derivatives. MS = molecular sieves.
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A. Quintard, S. Belot, E. Marchal, A. Alexakis
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Scheme 4. Synthesis and use of 4-substituted aminal–pyrrolidine organocatalysts. MS = molecular sieves.
would favor the (E)-anti enamine, while the two bulky even be lowered to –25 °C using catalyst 17a. The results
groups would interact together to force the electrophile to using a broad range of various linear and branched alde-
approach from the opposite face of the enamine (Figure 1). hydes are summarized in Scheme 5.
We easily synthesized this new family of 4-substituted ami-
Satisfyingly, we obtained high yields and the same high
nal–pyrrolidine catalysts in five steps (Scheme 4). A Mitsu- enantioselectivities (95–96% ee) using different linear alde-
nobu reaction using phenol allowed for the inversion of the hydes 5a–e. We directly reduced these product aldehydes to
configuration at C-4 of the pyrrolidine.[13]
the corresponding alcohols to prevent any racemization
The first screening, by the addition to ethene-1,1-diyl dis- during the purification process. More-substituted isovaler-
ulfones, confirmed our hypothesis. We obtained impres- aldehyde led to the highest 98% ee using either catalyst 17a
sively high enantioselectivity (94% ee) at room temperature or 17b. We obtained the more-substituted adduct 7g in only
using catalyst 17a or 17b, compared to the 77% ee obtained 73% ee using catalyst 17a. But, due to the modularity of
using the unsubstituted catalyst 4a. This result clearly the catalysts, 17b gave an encouraging 97% ee in this reac-
showed that the two bulky groups of the enamine interacted tion. We obtained even more interesting results in the for-
together to strongly enhance the enantioselectivity, while mation of quaternary carbon centers. Indeed, catalyst 17a
keeping high reactivity. We obtained a quantitative yield gave an impressive 73% or 83% ee in the formation of ad-
without any purification using catalyst 17a, whereas catalyst duct 7h or 7i, respectively. These are the highest enantio-
17b gave a small amount (Ͻ10%) of the homo-aldol prod- selectivities reported to date for such a challenging reaction,
uct. Diastereomeric 17c did not give any increase in much higher than the 47 and 64% ee observed with a di-
enantioselectivity compared to the unsubstituted 4c. This phenylprolinol silyl ether.[12a] In the case of 7h, catalyst 17b
clearly indicated that the addition of a bulky group at the did efficiently catalyze the reaction but in very poor 16% ee.
4-position was not sufficient to induce higher enantio- All these results on sulfone 6 are among the best reported to
selectivity. This had already been shown by List and co- date in terms of catalyst loading and enantioselection. They
workers, who had incorporated an OTBS group on the 4- highlight the great potential of aminal–pyrrolidine catalysts
position of a diarylprolinol silyl ether without any improve- in the addition to ethene-1,1-diyl disulfones. Furthermore,
ment in enantioselectivity.[14] Indeed, a synergistic effect be- they show substantial complementarity of the catalysts,
tween the two substituents is needed, indicating that the confirming our hypothesis of catalysts modularity.
two bulky groups interact.
The introduction of the allyl moiety in substrate 7b is
highly interesting due to further possible derivatization of
the C=C bond. To demonstrate the utility of this reaction,
we cyclized adduct 7b into its furan derivative using various
Organocatalytic Addition to Ethenediyl Disulfones
The good results obtained with catalyst 17a,b led us to activation modes (Scheme 6). Cyclization using PhSeCl
decrease the amount of catalyst to 5 mol-% and the number gave a moderate yield and no diastereocontrol on the cy-
of equivalents of aldehyde to two. The temperature could clized product. To overcome this problem, we decided to
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Aminal–Pyrrolidine Organocatalysts
Scheme 5. Addition of linear and branched aldehydes to ethene-1,1-diyl disulfone catalysed by 17a and 17b. chex = cyclohexyl.
use cheaper iodine instead of selenium.[15] The iodocycli-
Recently, we disclosed the use of the very inexpensive
zation proceeded satisfyingly, giving rise to adduct 19 in ethene-1,2-diyl disulfone 22 as an alternative to ethene-1,1-
88% yield and 4:1 syn diastereoselectivity. This adduct, with diyl disulfone 6. This ethenediyl disulfone gave an unprece-
its halogen atom and gem-disulfone moiety, seems a valu- dented [1,2] sulfone shift, leading to the corresponding gem-
able synthon for further transformations.
disulfone. Most catalysts were inefficient in this reaction,
The good results obtained on sulfone 6 prompted us to and only aminal catalyst 4a catalyzed the reaction in 82%
turn our attention to other ethene-1,1-diyl disulfones, no- ee for the formation of adduct 7f and 69% ee for 23.[16]
tably to the use of β-substituted disulfone 20 (Scheme 7).
We were pleased to find that catalyst 17a performed
This sulfone had shown a tendency to easily decompose, much better in this challenging transformation, giving the
thus lowering the yields, while the control of diastereoselec- best results ever obtained (Scheme 8). In contrast, catalyst
tivity remained difficult.[12] Gratifyingly, catalyst 17a gave 17b did not catalyze this particular transformation. Using
impressively high yields and reactivities in this transforma- catalyst 17a, we observed a high 94% ee and 88% yield for
tion, while maintaining good levels of diastereoselectivity. the formation of 7f, much higher than previously reported.
The observed ees (87–92%) were good but slightly lower More interestingly, catalyst 17a also catalyzed the addition
than the one obtained using diphenylprolinol silyl ether; of cyclohexanone; we obtained 76% ee of the clean adduct
however, the reactivity of 17a was much higher.
23 with 91% conversion after 6 h. This good result indi-
Scheme 6. Access to furans 18 and 19.
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A. Quintard, S. Belot, E. Marchal, A. Alexakis
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that is the addition to nitro olefins (Table 1). As for ethene-
diyl disulfones, the introduction of a free hydroxy group on
the pyrrolidine ring, as in catalyst 14, did not activate the
electrophile, giving rise to a poor 68% ee (Table 1, Entry 1).
The results obtained using catalyst 17a (Table 1, Entry 2)
were quite disappointing. Indeed, the 4-phenoxy group did
not seem to interact with the electrophile, giving only mod-
erate enantiocontrol. Encouragingly, catalyst 17b showed
again a complementary reactivity to catalyst 17a. It ef-
ficiently catalyzed the reaction of propionaldehyde or bu-
tyraldehyde with nitrostyrene with good diastereoselectivity
and moderate to good enantioselectivity (Table 1, Entries 3
and 4). The less-hindered propionaldehyde gave rise to a
good 91% ee, whereas bulkier butyraldehyde gave lower
85% ee for the same reaction.
Scheme 7. Addition of linear aldehydes to substituted ethenediyl
disulfone 20 catalyzed by 17a.
cated that the substitution on the pyrrolidine ring in cata-
lyst 17a did not block the formation of the more-substituted
ketone enamine and still provided good enantioselectivity.
This experiment extends the possible range of application
of aminal–pyrrolidines from linear/β-branched aldehydes to
ketones.
Organocatalytic C–N Bond Formation
Since our aminal–pyrrolidine catalysts were efficient in a
wide range of conjugate additions, we wondered if they
could be applied to other α-functionalizations of carbonyl
groups, notably for the formation of C–heteroatom bonds.
This would considerably enhance the scope of our catalyst
and its potential as a general organocatalyst.
We thus focused our attention on the direct α-amination
of aldehydes, creating a new C–N bond. This methodology,
leading to interesting building blocks, had been reported
separately by Jørgensen and co-workers and List using pro-
line as the catalyst with good to excellent enantioselectivi-
ties.[17] Under the conditions developed using diphenylproli-
nol silyl ether, we were pleased to see that our catalyst per-
formed well in this heterofunctionalization. The results are
summarized in Table 2.
Using only 1 mol-% of catalyst 17a, we obtained ex-
tremely high reactivities and good enantioselectivities (89–
93% ee) with aldehydes 5f and 5b (Table 2, Entries 1 and
3). The obtained enantioselectivities were in the range of
those obtained using -proline or diphenylprolinol silyl
ethers. In the case of pentenal 5b, the reaction was complete
after 4 min (as indicated by the disappearance of the
Scheme 8. Organocatalyzed addition to ethene-1,2-diyl disulfone 22
and subsequent [1,2] sulfone shift.
Organocatalytic Addition to Nitrostyrene
Besides ethenediyl disulfones, we were interested to know DEAD yellow color)! This high reactivity and enantio-
if our catalyst was also efficient in the benchmark reaction, selectivity, at such a low catalyst loading, constitutes a
Table 1. Organocatalyzed addition to nitrostyrene.
Entry[a]
Catalyst
R (product)
T [h]
Conversion (yield) [%][b]
dr (syn/anti)[b]
ee[c] [%]
1
2
3
14
17a
17b
Et (25k)
Et (25k)
Et (25k)
7
36
22
100
100
100
(82)
100
(85)
73:23
78:22
88:12
68
75
85
4
17b
Me (25j)
22
91:9
91
1
[a] Reactions were performed on 0.2 mmol of nitrostyrene in 0.8 mL of CHCl3 using 2 mmol of aldehyde. [b] Determined by H NMR
spectroscopy. Isolated yields shown in parentheses. [c] Determined by superfluid chromatography or chiral GC analysis.
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Aminal–Pyrrolidine Organocatalysts
Table 2. Organocatalyzed α-amination of aldehydes.
Entry[a]
Catalyst (mol-%)
R (product)
T [min]
Yield [%]
ee [%][b]
1
2
3
4
5
17a (1)
17b (1)
17a (1)
17b (1)
17a (0.5)
iPr (27f)
iPr (27f)
allyl (25b)
allyl (25b)
allyl (25b)
10
16
4
25
45
60
240
80
83
76
75
93
89
89
81
n.d.
–
68
50[c]
61[c]
90[c]
67
6
7
17a (10)
17b (10)
tBu (25g)
tBu (25g)
38
96
[a] Reactions were performed on 0.25 mmol of DEAD in 0.25 mL of CH2Cl2 using 1.5 equiv. of aldehyde. [b] Determined by chiral GC
analysis. [c] Conversions.
unique example of high turnover frequency (TOF) in en-
amine catalysis (TOF Ͼ 600–1000 h–1). A high TOF and
turnover number (TON) are crucial characteristics for the
future development of enamine catalysis from an industrial
point of view. When we further decreased the catalyst load-
ing to 0.5 mol-%, we obtained a partial conversion, indicat-
ing that further reaction condition optimization is necessary
(Table 2, Entry 5). Catalyst 17b also gave good reactivities
but slightly lower enantioselectivities on aldehydes 5f and
5b (Table 2, Entries 2 and 4). In contrast, using highly hin-
dered aldehyde 5g, catalyst 17b gave much better results
than 17a (Table 2, Entries 6 and 7). We obtained an impres-
sive 96% ee in this transformation, but full conversion re-
quired 10 mol-% of catalyst.
Stereochemical Outcome
The transition state in the various organocatalytic reac-
tions of aldehydes using either 17a or 17b can be rational-
ized by analogy to diphenylprolinol silyl ethers.[6] The abso-
Scheme 9. Proposed transition state using aminal–pyrrolidine cata-
lute configuration of the adducts obtained led us to postu-
late that high enantioselectivity came from steric control in
the transition state (Scheme 9). Among the two possible (E)
enamines, the (E)-anti one is favored due to the bulkiness
of the aminal moiety. The presence of the two bulky groups
lysts.
Conclusions
We have disclosed the synthesis and use of highly ef-
at the 2- and 4-position of the pyrrolidine ring creates a ficient aminal–pyrrolidine organocatalysts. A careful design
strong steric hindrance on the upper face of the enamine, of the pyrrolidine substituents led to a considerable increase
thus avoiding the attack of the electrophile from this Re in enantioselectivity. A cooperative effect between the bulky
face. With the lower face being less exposed, the electrophile aminal on the 2-position of the pyrrolidine ring and a phen-
can approach from this Si face affording the observed en- oxy group on the 4-position led to two different catalysts,
antiomer. The same analysis can be performed on cyclo- giving high reactivity and some of the highest enantio-
hexanone, where the (E)-syn enamine is favored. This steric selectivities ever observed in the α-functionalization of a
interaction is strong enough to allow good enantio- wide range of carbonyl compounds. We obtained ees up to
selectivity, regardless of the nature of the electrophile.
98.5% in the addition of linear and branched aldehydes or
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A. Quintard, S. Belot, E. Marchal, A. Alexakis
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ture was extracted with CH2Cl2 (3ϫ3 mL), the combined organic
layers were dried with Na2SO4, and evaporation of the solvent led
to the crude compound. If needed, purification by flash chromatog-
raphy using a cyclohexane/ethyl acetate mixture afforded the corre-
sponding Michael adduct.
a ketone to ethene-1,1- or -1,2-diyl disulfone, nitrostyrene,
and diethyl azodicarboxylate. The modularity of the cata-
lyst, introduced by the aminal portion, induces totally dif-
ferent properties in the new catalysts, giving rise to two
complementary catalysts (17a and 17b) and to a broad ap-
plicability. Furthermore, low catalyst loadings and some of
the highest TOFs ever obtained in enamine catalysis were
observed with high enantioselectivities. This last factor is
highly important, and further developments are necessary
before these enamine catalysis reactions can be applied on
an industrial scale. This substitution on the 4-position can
also be considered as the starting point for an efficient so-
lid-phase version of these catalysts.[18]
(R)-2-[2,2-Bis(phenylsulfonyl)ethyl]pent-4-enal (7e): 181 mg from
0.5 mmol of starting sulfone. Yield 92%. The ee was determined
by SFC (Chiralcel OJ column, 2 mL/min, 200 bar, MeOH 5%–2–
2–25%, 30 °C), tR = 8.6 and 9.5 min. [α]2D0 = –25.3 (CHCl3, c = 1.1,
96% ee). 1H NMR (300 MHz, CDCl3): δ = 1.92–2.21 (m, 6 H,
alkyl), 3.37–3.43 (m, 1 H, CH2O), 3.61–3.66 (m, 1 H, CH2O), 4.96–
5.12 (m, 3 H, CH=CH), 5.58–5.67 (m, 1 H, CHSO2), 7.51–7.69 (m,
6 H, Ph), 7.90–7.96 (m, 4 H, Ph) ppm. 13C NMR (100 MHz,
CDCl3): δ = 27.9 (CH2), 36.2 (CH2), 38.5 (CH), 65.5 (CH2), 81.3
(CH), 117.5 (CH2), 129.1 (CH), 129.6 (CH), 134.6 (CH), 135.5
(CH), 137.6 (Cquat.) ppm. MS ESI: m/z = 395.0 [M + H]+. HRMS
ESI [M + H]+ calcd. for C19H22O5S2 395.0981; found 395.0996.
Experimental Section
(S)-2-Isopropyl-4,4-bis(phenylsulfonyl)butanal (7f): 76 mg. Yield
96%. The ee was determined by chiral SFC (Chiralcel OJ column,
2 mL/min, 200 bar, MeOH 10%–2–1–25%, 30 °C, tR = 4.5 and
6.20 min). 1H NMR (400 MHz, CDCl3): δ = 0.94 (d, J = 6.8 Hz, 3
H, Me), 0.99 (d, J = 7.1 Hz, 3 H, Me), 2.11–2.17 (m, 2 H, CH2),
2.47–2.54 (m, 1 H, OH), 2.90–2.94 (m, 1 H, CHCO), 4.68–4.71 (dd,
J = 9.1, 3.1 Hz, 1 H, CHSO2), 7.53–7.60 (m, 4 H, Ph), 7.67–7.73
(m, 2 H, Ph), 7.88–7.96 (m, 4 H, Ph), 9.59 (s, 1 H, CHO) ppm.
Spectroscopic data are in agreement with those in the literature.[11a]
1
General Remarks: H (400 MHz or 300 MHz) and 13C (100 MHz)
NMR spectra were recorded with a Bruker 400 FT or a Bruker
300 FT NMR spectrometer in CDCl3, and chemical shifts (δ) are
given in ppm relative to residual CHCl3. Multiplicity is indicated
as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), dd (doublet of doublet), dt (doublet of triplet), ddd (doublet
of doublet of doublet), and br. s (broad singlet). Coupling con-
stants are reported in Hertz [Hz]. Mass spectra (MS) were obtained
by ESI and HRMS-ESI. Optical rotations were recorded with a
Perkin–Elmer 241 polarimeter at 20 °C in a 10 cm cell in CHCl3.
[α]2D9 values are given in 10–1 degcm2 g–1 (c is given in g/100 mL).
IR spectra were recorded in an NaCl cell with a Perkin–Elmer
Spectrum One IR spectrometer. The ee values were determined by
chiral-SFC measurements with a Berger SFC instrument with the
stated column or chiral GC analysis. Gradient programs are de-
scribed as follows: initial methanol concentration (%) – initial time
[min] – percent gradient of methanol (%/min) – final methanol con-
centration (%); retention times (tR) are given in min. Flash
chromatography was performed using silica gel 60 Å. If needed,
THF and CH2Cl2 were dried by filtration through alumina (acti-
vated at 350 °C under nitrogen for 12 h). All the organocatalyzed
reactions were conducted in nondried solvents. Unless otherwise
specified, products were purchased directly from commercial
sources.
(2R,3S)-2-Methyl-3-phenyl-4,4-bis(phenylsulfonyl)butanal
(21j):
36 mg from 0.1 mmol of starting material. Yield 81%. The ee was
determined by SFC on the isolated major diastereomer (Chiralcel
IC column, 2 mL/min, 200 bar, MeOH 10%–2–2–25%, 30 °C), tR
1
= 15.7 and 16.4 min. H NMR (300 MHz, CDCl3): δ = 0.75 (d, J
= 6.6 Hz, 3 H, Me), 2.22–2.25 (m, 1 H, OH), 3.13–3.18 (m, 1 H,
CHMe), 3.60–3.68 (m, 1 H, CHPh), 3.86 (dd, J = 9.2, 1.6 Hz,
CH2OH), 4.14–4.19 (m, 1 H, CH2OH), 5.76 (s, 1 H, CHSO2), 7.26–
7.55 (m, 15 H, Ph) ppm. Spectroscopic data are in agreement with
those in the literature.[12c]
(S)-2-[2,2-Bis(phenylsulfonyl)ethyl]cyclohexanone (23): The ee was
determined by SFC (Chiralcel OJ column, 2 mL/min, 200 bar,
1
MeOH 5%–2–2–25%, 30 °C), tR = 8.55 and 12.37 min. H NMR
(300 MHz, CDCl3): δ = 1.25–1.30 (m, 1 H, cyclohexanone), 1.62–
2.10 (m, 8 H, cyclohexanone), 2.28–2.57 [m, 4 H, CH2CO and
CH2(CHSO2)], 3.03–3.09 (m, 1 H, CHCO), 4.97 (dd, J = 9.3,
3.6 Hz, 1 H, CHSO2), 7.53–7.69 (m, 6 H, Ph), 7.87–7.96 (m, 4 H,
Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.0 (CH2), 26.5
(CH2), 27.8 (CH2), 34.8 (CH2), 42.9 (CH2), 47.3 (CH), 80.7 (CH),
129.0 (CH), 129.3 (CH), 129.7 (CH), 134.4 (Cquat.) ppm. Spectro-
scopic data are in agreement with those in the literature.[12d]
General Procedure for the Michael Addition to Ethene-1,1-diyl Di-
sulfones or Ethene-1,2-diyl Disulfones: To a solution of the aminal–
pyrrolidine catalyst in the solvent (0.4 mL, CHCl3 for 6 and 20,
toluene or DMF for 22), at the appropriate temperature, were
added successively the carbonyl compound (0.4 mmol, 2 equiv. for
linear aldehydes and 6, 5 equiv. for α-branched aldehydes and cy-
clohexanone, and 10 equiv. for the addition to 20) and the ethene-
Procedure for Iodocyclization. Synthesis of (2S,4R)-4-[2,2-Bis(phen-
diyl disulfone (0.2 mmol, 1 equiv.). The mixture was stirred at the ylsulfonyl)ethyl]-2-(iodomethyl)tetrahydrofuran (19): Adapted from
indicated temperature. Reactions were monitored by TLC. When
the reaction was complete, the reaction mixture was brought to
0 °C, ethanol (1.5 mL) was added, followed by the slow addition
of NaBH4 (1.5 equiv. per aldehyde equivalent). The mixture was
stirred at 0 °C for 30 min. Aqueous HCl (1 , 3 mL) was then
added, the organic layer was extracted with CH2Cl2 (3ϫ4 mL) and
dried with sodium sulfate, and the solvent was evaporated. Purifica-
tion by flash chromatography using a cyclohexane/ethyl acetate
mixture afforded the corresponding Michael adduct. In the case of
disulfone 20, the excess aldehyde was removed by evaporation prior
to reduction. In the case of aldehydes 5f–i and cyclohexanone, the
compounds were not reduced to the alcohols. To these reaction
mixtures was added saturated aqueous NH4Cl (2 mL), and the mix-
a known procedure.[15] To a solution of the alcohol (58 mg,
0.15 mmol) in CH2Cl2/saturated aqueous NaHCO3 (1:1, 1.5 mL)
in a round-bottomed flask protected from light, was added iodine
(89 mg, 0.35 mmol). The solution was then stirred at room tem-
perature for 7 h, and aqueous Na2S2O5 (3 mL) was slowly added.
The aqueous layer was extracted with CH2Cl2 (3ϫ4 mL), the com-
bined organic layers were dried with MgSO4 and filtered, and the
solvent was evaporated. The expected compound (69 mg,
0.13 mmol) was obtained as a 4:1 mixture of diastereoisomers after
simple filtration through a small plug of silica using diethyl ether
1
as the eluent. Yield 88%. H NMR (400 MHz, CDCl3): δ = 1.06–
1.11 [m, 1 H (major diastereomer, alkyl)], 1.79–1.81 (m, 1 H, minor
diastereomer, alkyl), 2.19–2.26 (m, 3 H, alkyl), 2.63–2.79 (m, 1 H,
934
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Eur. J. Org. Chem. 2010, 927–936

Aminal–Pyrrolidine Organocatalysts
f) H. Pellissier, Tetrahedron 2007, 63, 9267; for a special issue
on different aspects of organocatalysis, see: g) Chem. Rev. 2007,
107, 5413; for selected reviews of enamine catalysis, see: h)
D. W. C. MacMillan, Nature 2008, 455, 304; i) B. List, Acc.
Chem. Res. 2004, 37, 548; j) B. List, Chem. Commun. 2006,
819; k) A. Erkkila, I. Majander, P. M. Pihko, Chem. Rev. 2007,
107, 5416; l) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List,
Chem. Rev. 2007, 107, 5471; m) P. Melchiorre, M. Marigo, A.
Carlone, G. Bartoli, Angew. Chem. Int. Ed. 2008, 47, 6138; n)
S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; o) S. Sulzer-
Mossé, A. Alexakis, Chem. Commun. 2007, 3123; p) D. Almasi,
D. A. Alonso, C. Najera, Tetrahedron: Asymmetry 2007, 18,
299; q) J. L. Vicario, B. Dolores, L. Carrillo, Synthesis 2007,
2065; r) S. Bertelsen, K. A. Jørgensen, Chem. Soc. Rev. 2009,
38, 2178.
For selected articles on the enamine-catalyzed, asymmetric
conjugate addition of aldehydes and ketones to nitro olefins,
see: a) B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3,
2423; b) J. M. Betancort, C. F. Barbas III, Org. Lett. 2001, 3,
3737; c) A. Alexakis, O. Andrey, Org. Lett. 2002, 4, 3611; d)
D. Enders, A. Seki, Synlett 2002, 26; e) O. Andrey, A. Alexakis,
A. Tomassini, G. Bernardinelli, Adv. Synth. Catal. 2004, 346,
1147; f) W. Wang, J. Wang, H. Li, Angew. Chem. Int. Ed. 2005,
44, 1369; g) C. Palomo, S. Vera, A. Mielgo, E. Gómez-Bengoa,
Angew. Chem. Int. Ed. 2006, 45, 5984; h) J. Wang, H. Li, B.
Lou, L. Zu, H. Guo, W. Wang, Chem. Eur. J. 2006, 12, 4321;
i) E. Reyes, J. L. Vicario, D. Badia, L. Carillo, Org. Lett. 2006,
8, 6135; j) H. Huang, E. N. Jacobsen, J. Am. Chem. Soc. 2006,
128, 7170; k) M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew.
Chem. Int. Ed. 2006, 45, 6366; l) D. Enders, M. R. M. Hüttl,
C. Grondal, G. Raabe, Nature 2006, 441, 861; m) T. Mandal,
C.-G. Zhao, Tetrahedron Lett. 2007, 48, 5803; n) S. H.
McCooey, S. J. Connon, Org. Lett. 2007, 9, 599; o) M. Wiesner,
J. D. Revell, H. Wennemers, Angew. Chem. Int. Ed. 2008, 47,
1871; p) S. Belot, A. Massaro, A. Tenti, A. Mordini, A.
Alexakis, Org. Lett. 2008, 10, 4557; q) S. Belot, S. Sulzer-
Mosse, S. Kehrli, A. Alexakis, Chem. Commun. 2008, 4694; r)
Y. Hayashi, T. Itoh, M. Ohkubo, H. Ishikawa, Angew. Chem.
Int. Ed. 2008, 47, 4722; s) Y. Chi, L. Guo, N. A. Kopf, S. H.
Gellman, J. Am. Chem. Soc. 2008, 130, 5608; t) M. Wiesner,
J. D. Revell, S. Tonazzi, H. Wennemers, J. Am. Chem. Soc.
2008, 130, 5610; u) S. Zhu, S. Yu, D. Ma, Angew. Chem. Int.
Ed. 2008, 47, 545; v) D. Bonne, L. Salat, J.-P. Dulcère, J. Rodri-
guez, Org. Lett. 2008, 10, 5409; w) D.-Q. Xu, A.-B. Xia, S.-P.
Luo, J. Tang, S. Zhang, J.-R. Jiang, Z.-Y. Lu, Angew. Chem.
Int. Ed. 2009, 48, 3821; x) J. M. Betancort, K. Sakthivel, R.
Thayumanavan, C. F. Barbas III, Tetrahedron Lett. 2001, 42,
4441.
alkyl), 3.11–3.21 (m, 2 H, CH2I), 3.35 (dd, CHO, J = 6.0, 2.8 Hz,
1 H, minor diastereomer), 3.43 (t, CHO, J = 7.6 Hz, 1 H, major
diastereomer), 3.87–4.01 (m, 2 H, CH2O), 4.32 (t, J = 6 Hz, 1 H,
CHSO2), 7.56–7.73 (m, 6 H, Ph), 7.92–7.95 (m, 4 H, Ph) ppm. 13C
NMR (100 MHz, CDCl3): δ = 9.8 (CH2), 29.2 (CH2), 37.9 (CH),
38.5 (CH2), 73.0 (CH2), 78.7 (CH), 82.5 (CH), 129.3 (CH), 129.7
(CH), 134.9 (CH), 137.5 (Cquat.) ppm. MS ESI: m/z = 521.3 [M +
H]+. HRMS calcd. for C19H22N3O5S2I 520.9947; found 520.9965.
General Procedure for the Michael Addition to Nitrostyrene: To a
solution of the aldehyde (2 mmol) and nitrostyrene (0.2 mmol) in
CHCl3 (0.8 mL) was added the appropriate amount of catalyst, and
the reaction mixture was stirred at room temperature. The reaction
was monitored by TLC. After the reaction was complete, aqueous
NH4Cl (2 mL) was added, and the mixture was extracted with
CH2Cl2 (3ϫ2 mL). The combined organic layers were dried with
Na2SO4 and filtered, and the solvents were evaporated. The crude
material was purified by chromatography on silica gel using cyclo-
hexane/ethyl acetate (8:2) as the eluent.
[2]
(2R)-2-Methyl-4-nitro-3-phenylbutanal (25j): 35 mg, yield 85%. The
ee was determined by SFC [Chiralpak OD-H, 2 mL/min, 200 bar,
MeOH 2%–6–1–15%, 30 °C, tR = 7.1 (2S,3R) and 7.6 (2R,3S)
1
min]. H NMR (400 MHz, CDCl3): δ = 1.02 (d, J = 7.2 Hz, 3 H,
Me), 2.75–2.84 (m, 1 H, CHMe), 3.83 (dt, J = 9.4, 5.6 Hz, 1 H,
CHPh), 4.70 (dd, J = 12.8, 9.4 Hz, 1 H, CH2NO2), 4.82 (dd, J =
12.8, 5.4 Hz, 1 H, CH2NO2), 7.17–7.21 (m, 2 H, Ph), 7.28–7.40 (m,
3 H, Ph), 9.73 (s, 1 H, CHO) ppm. Spectroscopic data are in agree-
ment with those in the literature.[19]
General Procedure for the α-Amination of Aldehydes: To a stirred
solution of diethyl azodicarboxylate (0.25 mmol) and the corre-
sponding aldehyde (0.375 mmol) in CH2Cl2 (0.25 mL) was added
the aminal–pyrrolidine catalyst, and the solution was stirred at
room temperature until the yellow color disappeared. MeOH
(0.6 mL) was then added, followed by the slow addition (exother-
mic) of NaBH4 (3 equiv.). The reaction mixture was then stirred at
room temperature for 30 min before aqueous NaOH (0.5 ,
2.5 mL) was added. After 2 h of stirring at room temperature, the
solvent was evaporated. The residue was suspended in water
(3 mL), and the mixture was extracted with CH2Cl2 (3ϫ20 mL).
The combined organic layers were then dried with Na2SO4 and
filtered, and the solvent was evaporated. In most cases, the prod-
ucts were of sufficient purity without further silica gel chromatog-
raphy.
[3]
For the pioneering use of -proline as a catalyst, see: a) U.
Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. Engl. 1971,
10, 496; b) Z. G. Hajos, R. Parrich, J. Org. Chem. 1974, 39,
1615; c) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem.
Soc. 2000, 122, 2395; for a review of the aldol reaction, see: d)
G. Guillena, D. J. Ramon, Tetrahedron: Asymmetry 2006, 17,
1465.
For pioneering results and highlights, see: a) N. A. Paras,
D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123, 4370; b) G.
Lelais, D. W. C. MacMillan, Aldrichim. Acta 2006, 39, 79–87.
For leading examples and highlights, see: a) M. Marigo, T. C.
Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew. Chem. Int.
Ed. 2005, 44, 794; b) M. Marigo, D. Fielenbach, A. Braunton,
A. Kjoersgaard, K. A. Jørgensen, Angew. Chem. Int. Ed. 2005,
44, 3703; c) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, An-
gew. Chem. Int. Ed. 2005, 44, 4212; d) J. Franzen, M. Marigo,
D. Fielenbach, T. C. Wabnitz, A. Kjaersgaard, K. A.
Jørgensen, J. Am. Chem. Soc. 2005, 127, 18296; e) C. Palomo,
A. Mielgo, Angew. Chem. Int. Ed. 2006, 45, 7876; f) A. Mielgo,
C. Palomo, Chem. Asian J. 2008, 3, 922.
Ethyl (S)-4-Isopropyl-2-oxooxazolidin-3-ylcarbamate (27f): 45 mg,
yield 83%. The ee was determined by GC [Chirasil Dex Cβ column,
150 °C for 30 min, 1 °C/min to 170 °C, then holding for 5 min, tR
= 43.2 (S) and 45.3 (R) min]. 1H NMR (400 MHz, CDCl3): δ =
0.93 (t, J = 2.4 Hz, 6 H, CH3), 1.28 (t, J = 6.8 Hz, 3 H, CH3),
2.02–2.06 (m, 1 H, CHMe), 3.91–4.09 (m, 2 H, CH2CO2), 4.18–
4.24 (m, 3 H, CH2O and CHN), 4.38–4.41 (m, 1 H, CH2O), 6.77
(br. s, 1 H, NH) ppm. Spectroscopic data are in agreement with
those in the literature.[17]
[4]
[5]
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures and catalyst synthesis.
[1] For selected general reviews on organocatalysis, see: a) P. I.
Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43, 5138; b)
G. Guillena, D. J. Ramon, Tetrahedron: Asymmetry 2006, 17,
1465; c) M. J. Gaunt, C. C. C. Johansson, A. Mc Nally, N. T.
Vo, Drug Discovery Today 2007, 12, 8; d) R. M. De Figueiredo,
M. Christmann, Eur. J. Org. Chem. 2007, 2575; e) P. I. Dalko,
Enantioselective Organocatalysis, Wiley-VCH, Weinheim, 2007;
[6]
P. Diner, A. Kjaersgaard, M. A. Lie, K. A. Jørgensen, Chem.
Eur. J. 2008, 14, 122.
Eur. J. Org. Chem. 2010, 927–936
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
935

A. Quintard, S. Belot, E. Marchal, A. Alexakis
FULL PAPER
[7] a) For reviews of aminals, see: A. Alexakis, P. Mangeney, “Chi-
ral Aminals in Asymmetric Synthesis” in Advanced Asymmetric
Synthesis (Ed.: G. R. Stephenson), Springer, London, 1996; b)
A. Alexakis, P. Mangeney, N. Lensen, J.-P. Tranchier, R. Gos-
mini, S. Rausou, Pure Appl. Chem. 1996, 68, 531.
[8] A. Quintard, C. Bournaud, A. Alexakis, Chem. Eur. J. 2008,
14, 7504.
[9] For aminal formation on N-tritylprolinal, see: J. Bejjani, F.
Chemla, M. Audouin, J. Org. Chem. 2003, 68, 9747.
[10] For selected reviews, see: a) N. S. Simpkins, Sulphones in Or-
ganic Synthesis, Pergamon Press, Oxford, 1993; b) C. Najera,
M. Yus, Tetrahedron 1999, 55, 10547; c) E. N. Prilezhaeva,
Russ. Chem. Rev. 2000, 69, 367.
a primary amine catalyst, see: d) Q. Zhu, L. Cheng, Y. Lu,
Chem. Commun. 2008, 6315.
[13]
For examples of 4-phenoxy-substituted pyrrolidine catalysts
used in aldol reactions, see: a) J. Huang, X. Zhang, D. W. Arm-
strong, Angew. Chem. Int. Ed. 2007, 46, 9073; b) S.-p. Zhang,
X.-k. Fu, S.-d. Fu, Tetrahedron Lett. 2009, 50, 1173.
P. Garcia-Garcia, A. Ladepeche, R. Halder, B. List, Angew.
Chem. Int. Ed. 2008, 47, 4719.
For an iodocyclization precedent, see: M. Tredwell, J. A. R.
Luft, M. Schuler, K. Tenza, K. N. Houk, V. Gouverneur, An-
gew. Chem. Int. Ed. 2008, 47, 357.
[14]
[15]
[16]
A. Quintard, A. Alexakis, Chem. Eur. J. 2009, 15, 11109.
[17] a) A. Bogevig, K. Juhl, N. Kumaragurubaran, W. Zhuang,
K. A. Jørgensen, Angew. Chem. Int. Ed. 2002, 41, 1790; b) B.
List, J. Am. Chem. Soc. 2002, 124, 5656; c) N. Dalhin, A. Boge-
vig, H. Adolfsson, Adv. Synth. Catal. 2004, 346, 1101; see also
ref.[5d]; d) after first submission of this manuscript, an interest-
ing article appeared on the amination of aldehydes using 5 mol-
% of catalyst: P.-M. Liu, C. Chang, R. J. Reddy, Y.-F. Ting, H.-
H. Kuan, K. Chen, Eur. J. Org. Chem. 2010, 42–46.
[18] For a review of solid-phase, proline catalysts, see: M. Grutta-
dauria, F. Giacalone, R. Noto, Chem. Soc. Rev. 2008, 37, 1666.
[19] J. M. Betancort, C. F. Barbas III, Org. Lett. 2001, 3, 3737.
Received: November 9, 2009
[11] For pioneering findings, see: a) S. Mossé, A. Alexakis, Org.
Lett. 2005, 7, 4361; for the use of bimorpholine derivatives, see:
b) S. Mossé, M. Laars, K. Kriis, T. Kanger, A. Alexakis, Org.
Lett. 2006, 8, 2559.
[12] a) S. Sulzer-Mossé, A. Alexakis, J. Mareda, G. Bollot, G.
Bernardinelli, Y. Filinchuk, Chem. Eur. J. 2009, 15, 3204; b) Q.
Zhu, Y. Lu, Org. Lett. 2008, 10, 4803; c) A. Landa, M. Mae-
stro, C. Masdeu, A. Puente, S. Vera, M. Oiarbide, C. Palomo,
Chem. Eur. J. 2009, 15, 1562. The Lu and Palomo groups re-
ported the same addition to β-substituted ethenediyl disulfones
using diphenylprolinol silyl ether but with opposite enantio-
induction and much different yields and levels of diastereocon-
trol; for the addition of cyclohexanone derivatives catalyzed by
Published Online: December 18, 2009
936
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 927–936