Very high stereoselectivity in organocatalyzed desymmetrizing aldol reactions of 3-substituted cyclobutanones

Article abstract of DOI:10.1039/c2ob25813g

N-Phenylsulfonyl (S)-proline catalyzes the direct aldol reaction of 3-substituted cyclobutanones and aryl aldehydes in good yield and with excellent diastereoselectivity and enantioselectivity. This desymmetrization process provides highly functionalized

Full text of DOI:10.1039/c2ob25813g

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PAPER
Very high stereoselectivity in organocatalyzed desymmetrizing aldol reactions
of 3-substituted cyclobutanones†
David J. Aitken,a Angela M. Bernard,b Francesca Capitta,a,b Angelo Frongia,*b Régis Guillot,a Jean Ollivier,a
Pier Paolo Piras,*b Francesco Seccib and Marco Spigab
Received 27th April 2012, Accepted 3rd May 2012
DOI: 10.1039/c2ob25813g
N-Phenylsulfonyl (S)-proline catalyzes the direct aldol reaction of 3-substituted cyclobutanones and aryl
aldehydes in good yield and with excellent diastereoselectivity and enantioselectivity. This
desymmetrization process provides highly functionalized cyclobutanones with control over three
contiguous stereogenic centers.
Introduction
Results and discussion
The development of easily applicable synthetic strategies for the
construction of carbon–carbon bonds with complete stereo-
chemical control remains an important challenge in organic syn-
thesis. Synthetic methods which rely on the use of cyclobutane-
based molecular building blocks are intrinsically appealing,
since these compounds are readily accessible and can undergo a
variety of ring fission or ring enlargement reactions as a result of
their inherent ring strain.1
The condensation of 3-phenylcyclobutanone 1a (in excess) and
4-nitrobenzaldehyde 2a was chosen as a model reaction for cata-
lyst screening and the results are summarized in Table 1.
(S)-Proline (I) was tested first in DMSO. The requisite aldol
product was obtained in modest yield (Table 1, entry 1) but with
high diastereoselectivity: only two of the four possible diastereo-
mers, designated 3aa and 3aa′, were observed, with the former
predominating. Furthermore, chiral HPLC analysis showed the
major diastereomer 3aa to be highly enantiomerically enriched.
When I was employed in dichloromethane (Table 1, entry 2), the
reaction yield decreased, but the stereoselectivity was even
higher: only one diastereomer 3aa was formed, with at least 99%
enantiomeric purity.
Cyclobutanones1 are particularly useful intermediates in the
synthesis of natural products and various complex organic mole-
cules.2 Despite significant recent advances in asymmetric orga-
nocatalysis,3 only a few applications have been made to
cyclobutanones, providing 2-substituted4 or 2,2-disubstituted5
derivatives. Organocatalyzed desymmetrization6,7 of prochiral
3-substituted cyclobutanones has been strictly limited to a
Baeyer–Villiger oxidation8 and a lactam-forming ring expansion
reaction.9 Organocatalyzed asymmetric aldol reactions of 3-sub-
stituted cyclobutanones, implying stereochemical control of
three contiguous stereocenters, represent an attractive but hitherto
unprecedented endeavour.
aLaboratoire de Synthèse Organique et Méthodologie, Institut de Chimie
Moléculaire et des Matériaux d’Orsay (ICMMO – CNRS UMR 8182),
Université Paris-Sud 11, 15 rue Georges Clemenceau, 91405 Orsay,
France
These results prompted the study of the model reaction using
other (S)-proline-derived catalysts, II–IV (Table 1).
Gratifyingly, the use of catalyst II (Table 1, entry 3) in
dichloromethane was entirely satisfactory: a good chemical yield
was combined with an excellent diastereomeric and enantiomeric
control in the formation of the major 3aa diastereomer. The
same reaction conducted with a lower molar excess of 1a
(Table 1, entry 4) diminished the yield and enantioselectivity
somewhat. Catalyst III (Table 1, entry 5) gave a slightly
improved chemical yield of the aldol adduct, but with a
bDipartimento di Scienze Chimiche, Università degli studi di Cagliari,
Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu,
I-09042, Monserrato, Cagliari, Italy. E-mail: afrongia@unica.it,
pppiras@unica.it
†Electronic supplementary information (ESI) available: Experimental
procedures, copies of NMR spectra, HPLC analyses, X-ray diffraction
data. CCDC reference numbers 752280 and 796934. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25813g
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diminished diastereoselectivity. Catalyst IV, used in conjunction
with a Brønsted acid, also provided an excellent yield of aldol,
but the stereoselectivity of the reaction was greatly reduced –
indeed, the second diastereomer 3aa′ became the major com-
ponent (Table 1, entry 6), with a poor enantiomeric excess (ee).
With the encouraging lead result using catalyst II in hand, we
retained the conditions used in entry 3 of Table 1 for a study of
the scope of the reaction. Organocatalyzed aldolisations of a
series of 3-substituted cyclobutanones 1 with a selection of alde-
hydes 2 were examined, and the results are shown in Table 2.
Firstly, the aldehyde scope was considered using 1a as the
representative cyclobutanone. Similarly to the reaction of 2a in
standard conditions (Table 2, entry 1), other aryl aldehydes
bearing an electron-withdrawing group in the para-position,
2b–2e, reacted with 1a to give good yields of the corresponding
aldols 3ab–3ae, with good-to-excellent diastereo- and enantio-
selectivities (Table 2, entries 2–5). At most, only very small
amounts of one other diastereomer (3ab′–3ae′) were detected.
An aldehyde with an electron-withdrawing group in the meta-
position also gave excellent selectivity (Table 2, entry 6),
but reactions involving aldehydes with substituents in the ortho-
position failed to proceed (Table 2, entries 7–8), presumably due
to steric hindrance. Less reactive aryl aldehydes (Table 2, entries
9–10) and an aliphatic aldehyde (Table 2, entry 11) also failed to
provide any aldol adduct.
Next, the substituent tolerance of cyclobutanone 1 was investi-
gated in a series of aldolisation experiments (Table 2, entries
12–16) using 2a as the aryl aldehyde. The reactions of 1b–1f
proceeded with uniform chemical yields to give the correspond-
ing aldol adducts 3ba–3fa. Once again, one diastereomer always
predominated, with dr values going up to 99 : 1, and in each
case, this diastereomer was obtained with high ee in the range
84% to >99%. The cyclobutanone substrate tolerance included
both aromatic and aliphatic chains at the 3-position. Some other
combinations of diversely substituted cyclobutanones and aryl
aldehydes completed the survey (Table 2, entries 17–19) and
confirmed the scope and high stereoselectivity of the reaction.
These organocatalyzed aldolisation reactions invariably pro-
vided one stereoisomer of the product 3 with excellent selec-
tivity. In order to establish the absolute configuration at the three
newly-formed stereocenters, the aldol product 3ba was trans-
formed by a Baeyer–Villiger oxidation (81% yield) into the crys-
talline lactone 4 (Scheme 1). Single crystal X-ray diffraction
analysis established the absolute configuration of compound 4 as
Table 1 Optimization of reaction conditions and catalyst screeninga
Entry Cat. Solvent Yield 3aab (%) drc 3aa:3aa′ ee 3aad (%)
1
2
I
I
II
II
III
IV
DMSO 31
CH2Cl2 10
CH2Cl2 71
CH2Cl2 61
CH2Cl2 80
CH2Cl2 92
82 : 18
99 : 1
98 : 2
98 : 2
78 : 22
37 : 63
96
99
99
93
99
26
3
4e
5
6f
a Cyclobutanone 1a (10 mmol), aldehyde 2a (0.5 mmol), catalysts I–IV
(20 mol%), solvent (2 mL), 96 h, room temperature. b Total yield of all
1
isomers of 3aa. c Determined by H NMR spectroscopic analysis of the
crude reaction mixture. d Determined by chiral HPLC analysis. e The
excess of 1a was halved (5 mmol instead of 10 mmol). f Benzoic acid
(20 mol%) was included in the reaction mixture.
Table 2 Asymmetric aldol reactions between 3-substituted cyclobutanones 1 and aldehydes 2a
Entry
R1
R2
Product
Yield 3b (%)
drc 3 : 3′
eed (%) 3 (major)
1
2
3
4
5
6
7
8
Ph–
Ph–
Ph–
Ph–
Ph–
Ph–
Ph–
Ph–
Ph–
Ph–
Ph–
4-Cl–C6H4–
4-Br–C6H4–
4-CH3–C6H4–
n-C6H13
PhCH2CH2–
4-Cl–C6H4–
4-NO2–C6H4–
4-CN–C6H4–
4-Cl C6H4–
4-F C6H4–
4-CF3 C6H4–
3-NO2–C6H4–
2-NO2 C6H4–
2,4-Cl2–C6H3–
Ph–
3aa
3ab
3ac
3ad
3ae
3af
—
—
—
—
—
3ba
3ca
3da
3ea
3fa
3be
3eb
3cb
71
76
64
66
51
51
0
0
0
0
0
77
63
74
70
60
70
60
64
98 : 2
97 : 3
98 : 2
96 : 4
98 : 2
99 : 1
—
—
—
—
—
89 : 11
96 : 4
93 : 7
98 : 2
99 : 1
90 : 10
98 : 2
96 : 4
99
98
84
81
91
95
—
—
—
—
—
97
89
83
>99
98
92
83
89
9
10
11
12
13
14
15
16
17
18
19
4-CH3–C6H4–
i-Pr–
4-NO2–C6H4–
4-NO2–C6H4–
4-NO2–C6H4–
4-NO2–C6H4–
4-NO2–C6H4–
4-CF3–C6H4–
4-CN–C6H4–
4-CN–C6H4–
–
n-C6H13
4-Br–C6H4–
–
a Cyclobutanone 1 (10 mmol), aldehyde 2 (0.5 mmol), catalyst II (20 mol%), CH2Cl2 (2 mL), 96 h, room temperature. b Total yield of all isomers of
3. c Determined by 1H NMR spectroscopic analysis of the crude reaction mixture. d Determined by chiral HPLC analysis.
5046 | Org. Biomol. Chem., 2012, 10, 5045–5048
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Scheme 1 Synthesis of the lactone 4.
Fig. 3 Proposed transition-state model leading to the predominant
aldol stereoisomer.
moiety of the aldehyde oriented away from the steric bulk (in the
equatorial position of the Zimmerman–Traxler six-membered
ring model).12 Two diastereomeric enamines are likely to
coexist; however, only one—designated the S,S-enamine, assum-
ing for the sake of argument that the 3-substituent has nomen-
clature priority—allows hydrogen bond-assisted approach of the
aldehyde to the unhindered face of the anti enamine. This model
leads to the preferred R,S,S configuration in the aldol product.
Conclusions
Fig. 1 X-Ray crystal structure of the lactone 4.
In conclusion, the II-catalyzed aldol reaction allows the desym-
metrization of 3-substituted cyclobutanones 1 to give aldol pro-
ducts 3 with unprecedented control of all three contiguous
stereocenters. The aldol adducts with trans ring substitution and
an anti aldol geometry are obtained with high enantioselectivity.
Given the value of functionalized cyclobutanones as building
blocks in organic synthesis, further studies of asymmetric orga-
nocatalyzed transformations of these substrates are an appealing
area for further developments.
Experimental
General procedure for the enantioselective organocatalyzed
aldol reactions
To a solution of aldehyde 2 (0.5 mmol) and 3-substituted
cyclobutanone 1 (10 mmol) in anhydrous CH2Cl2 (2 mL) was
added (2S)-N-(2-pyrrolidine-2-carbonyl)-benzenesulfonamide II
(0.05 mmol). The resulting mixture was stirred at room tempera-
ture for 96 h. The reaction was quenched with saturated aqueous
ammonium chloride (10 mL). The reaction mixture was extracted
with EtOAc (2 × 10 mL) and the combined organic layers were
dried over anhydrous Na2SO4. After removal of the solvent, the
residue was purified by flash column chromatography to give the
corresponding aldol product 3.
Fig. 2 X-Ray crystal structure of compound 3ba′.
R,S,S (Fig. 1).10 It was thus deduced that compound 3ba had the
same configuration and, by analogy, the R,S,S configuration was
attributed to each major stereoisomer of the suite of aldols 3.
Single crystal X-ray diffraction analysis of the minor diastereo-
mer from the same aldol reaction, 3ba′, was also carried out.
The crystal contained racemic material. The relative configur-
ation was established as that of a trans 2,3-cyclobutanone ring
substitution and a syn aldol geometry (Fig. 2).11
(See ESI† for details.)
On the basis of previous models for (S)-proline catalyzed
aldol reactions, supported by both experiments and DFT calcu-
lations,12 the stereochemical course of the reactions described
here can be rationalized in terms of the favoured transition state
model shown in Fig. 3. The lowest energy transition state for a
proline-type Brønsted acid mediated intermolecular aldol reac-
tion implicates Re attack on an anti enamine, with the aryl
Acknowledgements
Financial support from the MIUR, Rome, and by the University
of Cagliari (National Project “Stereoselezione in Sintesi Orga-
nica Metodologie ed Applicazioni”) and from CINMPIS, and
FIRB 2008 is gratefully acknowledged.
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10 CCDC 752280 contains the supplementary crystallographic data for com-
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11 CCDC 796934 contains the supplementary crystallographic data for com-
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