Asymmetric, catalytic, vinylogous aldol reactions using pyrrole-based dienoxy silanes. Enantioselective synthesis of α,β-unsaturated γ-butyrolactam synthons

Article abstract of DOI:10.1016/j.tetlet.2009.02.181

A practical, catalytic and enantioselective vinylogous Mukaiyama aldol reaction between 2-silyloxypyrrole donors and aromatic or heteroaromatic aldehyde acceptors is described. Using an enantiopure bisphosphoramide catalyst in conjunction with SiCl_4<

Full text of DOI:10.1016/j.tetlet.2009.02.181

Tetrahedron Letters 50 (2009) 3428–3431
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Asymmetric, catalytic, vinylogous aldol reactions using pyrrole-based
dienoxy silanes. Enantioselective synthesis of a,b-unsaturated
c-butyrolactam synthons
a
a
b
a
a,
*
Claudio Curti a, , Andrea Sartori , Lucia Battistini , Gloria Rassu , Franca Zanardi , Giovanni Casiraghi
*
a Dipartimento Farmaceutico, Università degli Studi di Parma, Viale G. P. Usberti 27A, Parma I-43100, Italy
b Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, Li Punti, Sassari I-07040, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical, catalytic and enantioselective vinylogous Mukaiyama aldol reaction between 2-silyloxypyr-
role donors and aromatic or heteroaromatic aldehyde acceptors is described. Using an enantiopure
Received 15 January 2009
Revised 19 February 2009
Accepted 23 February 2009
Available online 27 February 2009
bisphosphoramide catalyst in conjunction with SiCl4, a variety of
-butyrolactam compounds were synthesized in high yields and with good to excellent levels of
site-, diastereo- and enantioselectivity.
a,b-unsaturated-d-hydroxylated
c
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Vinylogous aldol reaction
Lewis base catalysis
Pyrrole-based dienoxy silanes
Enantioselective synthesis
Saturated and unsaturated pyrrolidine and pyrroline entities
are enabling building blocks with which a variety of aminated nat-
ural and natural-like molecules and related frameworks can be
constructed.1 The design and development of asymmetric, catalytic
methodologies that lead to the assembly of N-containing com-
pounds in an enantio-enriched format therefore define a crucial
field of research in organic synthesis.2
Within this context, one area of investigation is focused on the
exploitation of enantiopure metal and metal-free catalysts to pro-
pel enantioselective vinylogous Mukaiyama aldol reactions
(VMAR) using heterocyclic dienoxy silanes for efficient access to
heteroatom-containing butenolide frameworks often found in
complex, multifunctional natural architectures.3,4
We began with the vinylogous coupling of TBS–pyrrole 2a to
aldehyde 3a (2.0:1.0 mol equiv ratio) in the presence of unpurified
commercial grade SiCl4 (1.1 mol equiv),7 enantiopure bisphospho-
ramide ligand (R,R)-1 (3.0 mol %) and DIPEA (10.0 mol %) in CH2Cl2
at ꢀ78 °C (entry 1), paralleling almost exactly the conditions Den-
mark exploited during his studies on catalytic, enantioselective
vinylogous aldol additions of ketone- and amide-derived silyl die-
nol ethers to various aldehydes.5 Here, the reaction went to com-
pletion in 20 h, with the expected aldol adduct 4a recovered in a
rather good 80% ee, as detected by chiral HPLC analysis (87% iso-
lated yield, >99% de). The rate of the uncatalyzed racemic reaction
was found to be considerable (roughly 21% substrate conversion in
the absence of enantiopure bisphosphoramide 1, under the same
reaction conditions, entry 2), indicating a significant acceleration
effect by the enantiopure ligand itself.
Indeed, several factors were found to increase the rate of the
catalyzed pathway relative to the background reaction. In particu-
lar, variation of the SiCl4 nature (purity, dilution and HCl content)
and the silyl diene substrate led to remarkable effects, providing
the bases for reaction optimization. Thus, for example, exposure
of a mixture of TBS–pyrrole 2a and 3a to neat, freshly refluxed
and redistilled SiCl4 under an argon atmosphere resulted in selec-
tive minimization of the racemic background pathway (entry 3),
with great acceleration of the corresponding enantiopure ligand-
assisted reaction (entry 4). Under such conditions (0.25 M in
CH2Cl2 on a 0.5 mmol scale), syn-configured unsaturated lactam
4a was obtained in a remarkable 97% isolated yield, with exquisite
Herein we disclose the results of our investigations highlighting
the ability of the Denmark’s bisphosphoramide/SiCl4 catalyst sys-
tem (1/SiCl4 complex)5,6 to guide a highly performing VMAR of
silyloxy pyrrole nucleophiles with aromatic and heteroaromatic
aldehydes that allow for preparation of a variety of
a,b-unsatu-
rated-d-hydroxylated -butyrolactam structures with very high
c
levels of site-, diastereo- and enantioselectivity.
The first phase of our investigation was aimed at optimizing
conditions for the VMAR between N-Boc-pyrroles 2a–c and benzal-
dehyde (3a) to give syn-configured lactam 4a (Table 1).
* Corresponding authors. Tel.: +39 0521 905079; fax: +39 0521 905006 (C.C.),
tel.: +39 0521 905080; fax: +39 0521 905006 (G.C.).
E-mail addresses: claudio.curti@unipr.it (C. Curti), giovanni.casiraghi@unipr.it
(G. Casiraghi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.181

C. Curti et al. / Tetrahedron Letters 50 (2009) 3428–3431
3429
Table 1
Optimizing 1/SiCl4-catalyzed enantioselective VMAR between 2-silyloxypyrroles 2a–c and benzaldehyde (3a) giving lactam syn-4aa
a
The reactions were carried out in the presence of pyrrole 2/aldehyde 3a (2.0/1.0 mol equiv), SiCl4 (1.1 mol equiv), DIPEA (10.0 mol %), with a substrate concentration of
0.25 M (0.5 mmol scale) in the indicated solvent, with a 20 h reaction time (unless otherwise stated). For details, see Supplementary data.
b
Based on 1H NMR analysis of the crude reaction product. Yield of isolated syn-4a in parentheses.
c
Determined by 1H NMR analysis of the crude reaction product.
d
Enantiomeric excess of syn-4a determined by chiral HPLC analysis.
Commercial grade neat SiCl4 used.
Refluxed and redistilled, HCl-free, neat SiCl4 used.
24 h reaction time.
e
f
g
levels of site-selectivity (
c
-attack only), diastereoselectivity (>99.5:
tiocontrol consistently performed with aldehyde substrates of var-
ied electronic and steric nature. Notably, the generality of the
reaction was also tested on a,b-unsaturated aldehydes such as cin-
0.5% dr) and enantioselectivity (>99% ee). Almost identical behav-
iour was also observed with larger pyrrole silyloxy substituents,
with TIPS–pyrrole 2b emerging as an equally performing donor
candidate (entry 5). Although in this instance the reaction rate
was slightly reduced (>99% substrate conversion after 24 h), both
yield and selectivity raised to nearly quantitative values for the
(5S,10S)-configured adduct syn-4a. On the other hand, when less
encumbered TES–pyrrole 2c was used as the donor component,
less brilliant results were obtained, with a significant erosion of
the yield, albeit with unaltered selectivity (entry 6). Finally, the
solvent effect was evaluated, under the optimal conditions of entry
4. Moving to toluene solvent, both yield and diastereoselectivity
decreased, while the use of THF still provided good results in terms
of yield and selectivity (entries 8 and 9).
On the bases of the positive outcome of the initial study, we
next investigated the bisphosphoramide 1/SiCl4-catalyzed VMAR
of a range of aldehyde substrates, with the results summarized in
entries 1–8 of Table 2. Due to the superior efficiency and selectivity
exhibited by redistilled, HCl-free SiCl4 in reaction involving ligand
1 and pyrrole nucleophile 2a, the reaction scope of the electrophilic
component was scrutinized by uniformly adopting the reaction
conditions of entry 4 in Table 1 (alias entry 1 in Table 2).
namaldehyde (3h), which proved to be a pertinent substrate in this
catalytic enantioselective VMAR reaction, giving rise to the corre-
sponding adduct 4h in high yield and with excellent syn/anti dia-
stereoselectivity. Regrettably, in this instance, significant erosion
of enantioselectivity was observed due to parasitic, concurrent
activation of the racemic pathway (85% substrate conversion in
the absence of ligand (R,R)-1, not shown).8
The relative 5,10-syn-configuration of the emerging benzalde-
hyde lactam adduct syn-4a was unambiguously assigned based
on comparison of the 1H and 13C NMR spectral data of our material
with those of the racemic counterpart previously reported by H.
Uno et al.9 There, the 1H–1H 3J5,1 coupling constant for the syn-con-
0
figured isomer (3J5,1 = 6.1 Hz) was especially diagnostic, when
0
compared to the smaller value for the corresponding 5,10-anti-con-
figured counterpart (3J5,1 = 2.4 Hz). On these bases, we confiden-
0
tially assigned the 5,10-relative syn stereodisposition to the
various lactam adducts 4b–h shown in Table 2, whose 1H–1H
3
0
J5,1 coupling constant values were invariably calculated in the
5.5–6.1 Hz range.
As for the absolute configuration assignment, we capitalized on
an empirical, never-contradicted rule according to which a high
Indeed, complete c-addition selectivity, good to excellent yields
of pure isolated adducts and high diastereo- and enantioselectivity
were generally observed in the reaction of 2a with a survey of aro-
matic and heteroaromatic aldehydes 3a–g. In all cases, the corre-
½
a D laevorotatory value pertains to 5S-configured unsaturated can-
ꢁ
didates of type 4, while a dextrorotatory ½a D
ꢁ
value is attributed to
5R-configured isomers.10 On these bases, we confidentially as-
signed a 5S,10S-configuration to major syn-isomers 4 (see optical
rotation values, Table 2) and a (5R,10S)-configuration to the minor
sponding syn-configured
a,b-unsaturated lactams 4a–g were the
sole or overwhelming isomers detected, with diastereo- and enan-

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C. Curti et al. / Tetrahedron Letters 50 (2009) 3428–3431
Table 2
Substrate scope for the 1/SiCl4-catalyzed VMAR between pyrrole diene 2a and aromatic and heteroaromatic aldehydes 3a–h leading to the corresponding lactam adducts 4a–ha
½ ꢁ
a 2D0
0 e
f
Entry
1
Substrate
Product
OH
Yieldb (%)
>99 (97)
drc (syn:anti)
eed (%)
>99
c
:
ac
3J5,1 (Hz)
>99.5:0.5
>99:1
6.1
–347.5
O
H
N
3a
Boc
syn-4a
OH
O
O
O
H
2
3
99 (96)
97 (92)
>99.5:0.5
>99.5:0.5
>99
>99:1
>99:1
6.0
5.8
–381.6
–340.3
N
OMe
OMe
Boc
3b
syn-4b
OH
O
H
96.2
N
F
F
Boc
O
3c
syn-4c
OH
O
H
4
5
82 (77)
92 (87)
84.0:16.0
>99.5:0.5
73.6
74.6
>99:1
>99:1
5.7
6.1
–278.3
–286.0
N
N
NO2
NO2
Boc
O
O
3d
syn-4d
OH
O
H
O
O
Boc
3e
syn-4e
OH
O
H
S
6
7
99 (93)
99 (85)
99 (94)
>99.0:1.0
>99.0:1.0
>99.0:1.0
88.4
99.0
45.1
>99:1
>99:1
>99:1
5.5
6.0
nd
–222.3
–280.0
–42.8
S
N
Boc
O
3f
syn-4f
OH
O
H
N
N
Boc
OH
O
O
3g
syn-4g
O
H
8
3h
Boc
syn-4h
a
The reactions were carried out in the presence of pyrrole 2a/aldehydes 3 (2.0/1.0 mol equiv), SiCl4 (1.1 mol equiv, refluxed and redistilled), DIPEA (10.0 mol %), with a
substrate concentration of 0.25 M (0.5 mmol scale) in CH2Cl2, with a 20 h reaction time. For details, see Supplementary data.
b
Based on 1H NMR analysis of the crude reaction product. Yield of isolated syn-4 in parentheses.
c
Determined by 1H NMR analysis of the crude reaction product.
d
Enantiomeric excess of syn-4 determined by chiral HPLC analysis.
e
Coupling constant value between the H5 and H10 protons of compounds syn-4 as determined by the respective 1H NMR spectra (CDCl3, 300 MHz).
f
Optical rotation values of compounds syn-4 (c 1.0 g/100 mL, EtOH).
epimeric counterparts.11,12 Decisive assessment of the absolute
configuration of compound syn-4a was performed by chemical
mers were equal in absolute value but opposite in sign
(½a 2D0
ꢁ
ꢀ 23:7 for 5 versus ½a D20
þ 23:1 for ent-5).
ꢁ
correlation to known
D
-glyceraldehyde-derived
a,b-unsaturated
In summary, we present a reasonably general and practical
methodology for catalytic, enantioselective, vinylogous aldol
reactions that involve TBS–pyrrole donors and aromatic or hetero-
aromatic aldehyde acceptors. The process proceeds efficiently
(77–97% isolated yields), with superb levels of site selectivity
lactam 6, whose identity had been firmly established by single
crystal X-ray analysis (5R,10S,20R absolute configuration).13 As
shown in Scheme 1, simple chemistry advanced syn-4a into car-
boxylic acid 5, while 6 was elaborated into ent-5 (the enantiomer
of 5). As expected, the optical rotation values of the two enantio-
(c-addition only), diastereoselectivity (84.0:16.0 to >99.5:0.5 dr)

C. Curti et al. / Tetrahedron Letters 50 (2009) 3428–3431
3431
References and notes
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L.; Rassu, G. Synlett 2009, in press.; See also: (b) Evans, D. A.; Kvꢀrnø, L.; Dunn,
T. B.; Beauchemin, A.; Raymer, B.; Mulder, J. A.; Olhava, E. J.; Juhl, M.;
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Scheme 1. Chemical correlation of compound syn-4a to known
derived lactam 6.
D-glyceraldehyde-
4. For related vinylogous Mukaiyama–Mannich and Mukaiyama–Michael
reactions, see: (a) Mandai, H.; Mandai, K.; Snapper, M. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2008, 130, 17961–17969; (b) Yang, H.; Kim, S. Synlett 2008, 555–
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Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2006, 45,
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6. Benaglia, M.; Guizzetti, S.; Pignataro, L. Coord. Chem. Rev. 2008, 252, 492–512.
7. Neat silicon tetrachloride purchased from Aldrich Chemical Company (2007–
2008 catalogue code 215120).
and enantioselectivity (73.6 to >99% ee for 5S,10S-configured
isomers).
Development of further vinylogous, enantioselective processes
involving heterocyclic dienoxy silane nucleophiles and aliphatic
aldehyde or imine substrates, and their application to synthesis
of natural and natural-like bioactive compounds are the focus of
ongoing studies.
8. Preliminary successful experiments using 2-methylpropanal showed that the
present enantioselective VMAR process could be extended to aliphatic
aldehydes.
Acknowledgements
9. Uno, H.;Nishihara,Y.;Mizobe,N.;Ono, N.Bull.Chem.Soc. Jpn. 1999, 72,1533–1539.
10. (a) Casiraghi, G.; Colombo, L.; Rassu, G.; Spanu, P.; Gasparri Fava, G.; Ferrari
Belicchi, M. Tetrahedron 1990, 46, 5807–5824; See also: (b) Cuiper, A. D.;
Brzostowska, M.; Gawronski, J. K.; Smeets, W. J. J.; Spek, A. L.; Hiemstra, H.;
Kellogg, R. M.; Feringa, B. L. J. Org. Chem. 1999, 64, 2567–2570.
11. Clean, base-promoted conversion (Et3N, CH2Cl2) of major isomer syn-4a into
the corresponding minor counterpart anti-4a proved their C5 epimeric
relationship.
This work was supported by Università di Parma. We thank the
Centro Interdipartimentale Misure ‘G. Casnati’ (Università di Par-
ma) for instrumental facilities.
Supplementary data
12. Heteroaromatic compounds syn-4e and syn-4f, in truth, are (5S,10R)-
configured, due to nominal change of the C10 absolute configuration
according to the Cahn–Ingold–Prelog priority rules.
Supplementary data (Experimental procedures and character-
ization data of compounds syn-4, 5 and ent-5) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.02.181.
13. Rassu, G.; Casiraghi, G.; Spanu, P.; Pinna, L.; Gasparri Fava, G.; Ferrari Belicchi,
M.; Pelosi, G. Tetrahedron: Asymmetry 1992, 3, 1035–1048.