Catalytic asymmetric ring opening of 2,3-substituted norbornenes with organometallic reagents: A new formal aza functionalization of cyclopentadiene

Article abstract of DOI:10.1021/ol050895q

(Chemical Equation Presented) An unprecedented regioselective and anti stereoselective asymmetric ring opening of 1,3-cyclopentadiene-heterodienophile cycloadducts, including also 2,3-diazabicyclo[2.2.1]heptenes, with hard alkylmetals and copper-phosphora

Full text of DOI:10.1021/ol050895q

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3605-3607
Catalytic Asymmetric Ring Opening of
2,3-Substituted Norbornenes with
Organometallic Reagents: A New
Formal Aza Functionalization of
Cyclopentadiene
Mauro Pineschi,* Federica Del Moro, Paolo Crotti, and Franco Macchia
Dipartimento di Chimica Bioorganica e Biofarmacia, UniVersita` di Pisa,
Via Bonanno 33, 56126 Pisa, Italy
pineschi@farm.unipi.it
Received April 22, 2005
ABSTRACT
An unprecedented regioselective and anti stereoselective asymmetric ring opening of 1,3-cyclopentadiene-heterodienophile cycloadducts,
including also 2,3-diazabicyclo[2.2.1]heptenes, with hard alkylmetals and copper phosphoramidite catalysts, is reported. The induced ring
opening, in conjunction with C C bond formation, gives a catalytic and practical access to new heterofunctionalized cyclopentenes in an
−
−
enantioenriched form (up to 86% ee).
Development of new methodologies for the preparation of
nonracemic chiral compounds by means of asymmetric
catalysis is of fundamental importance in synthetic organic
chemistry. Catalytic asymmetric transformations are espe-
cially valuable when the starting materials are easily acces-
sible and of low cost. For example, 3-aza-2-oxabicyclo-
[2.2.1]hept-5-enes 1a,b and 2,3-diazabicyclo[2.2.1]hept-5-
enes 2a-c (Figure 1) can be obtained in multigram amounts,
and azodicarboxylates, respectively.1,2 Acylnitroso-derived
Diels-Alder 1a,b possess several potential electrophilic sites3
but are most commonly elaborated through cleavage of the
N-O bond to form 1,4-aminocyclopentenols.4 A less com-
mon approach involves the cleavage of the C-O bond to
give hydroxamic acid, which is an important functionality
found in a variety of biologically active compounds.5
Symmetrical bi- and polycyclic hydrazines 2a-c have
been known for a long time,2 though there are very few
reports on their ring-opening reactions. Quite recently, a new
anti stereoselective palladium-catalyzed hydrazido arylation
of cyclic hydrazide to give novel hydrazino cyclopentenes,
albeit in racemic form, has been reported by Kaufmann et
al.6 Although, palladium-catalyzed asymmetric hydroaryla-
(1) Weinreb, S. M. In ComprehensiVe Organic Synthesis; Pergamon
Press: Oxford 1991; Vol. 5, pp 419-421.
(2) (a) Diels, O.; Blom, J. H.; Knoll, W. Justus Liebigs Ann. Chem. 1925,
443, 242-262. (b) Cookson, R. C.; Gilani, S. S. H.; Stevens, I. D. R.
Tetrahedron Lett. 1962, 14, 615-618.
(3) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317-1348 and
references therein.
Figure 1. 2,3-Heteronorbornenes 1 and 2 used as starting material
for asymmetric carbon-carbon bond formations.
(4) Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2,
3181-3183.
(5) Surman, M. D.; Miller, M. J. J. Org. Chem. 2001, 66, 2466-2469
and references therein.
in a very simple way, from the hetero Diels-Alder reaction
between cyclopentadiene with transient acylnitroso species
10.1021/ol050895q CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/19/2005

tions of norbornene are well documented,7 and huge efforts
have been devoted to the development of highly efficient
catalytic and enantioselective desymmetrization of 7-hetero-
atom-norbornene derivatives,8 no enantioselective addition
of carbon nucleophiles to norbornenes containing multiple
heteroatoms such as 1 and 2 has been described.9
Scheme 1. Regio- and Stereoselective Addition of Dialkylzinc
Reagents to 3-Aza-2-oxabicyclo[2.2.1]hept-5-enes
In our continuing interest in the development of new ring-
opening reactions of heterocyclic rings to give synthetically
useful enantiomerically enriched building blocks,10 we have
now found that readily available heteronorbornenes 1 and 2
can be opened with hard alkylmetals in the presence of
catalytic amounts of copper-phosphoramidite ligands.11
In a preliminary experiment, the addition of Me2Zn (2.0
equiv) to cycloadduct 1a in the presence of a catalytic amount
of Cu(OTf)2 (1.5 mol %) and phosphoramidite (R,R,R)-3a
(3.0 mol %) afforded the trans-1,2-hydroxamic acid 4b
cleanly with complete regioselectiVity and anti stereoselec-
tiVity (Table 1, entry 1).
Table 1. Regio- and Stereoselective Addition of Dialkylzinc
Reagents to (()-3-Aza-2-oxabicyclo[2.2.1]hept-5-enes 1a,ba
entry substrate R2 (equiv) time (conversion (%))b ee (%)c
better enantioselectivity (56% ee at 52% conversion) was
obtained with the use of Me2Zn (entry 3). When the kinetic
resolution reaction was carried out with diastereoisomeric
ligand (R,S,S)-3b,11a a very low enantioselectivity was
obtained (Table 1, entry 4). Similar results were obtained
with compound 1b containing an easily removable carbo-
benzyloxy (Cbz) protecting group on the nitrogen (Table 1,
entries 5-8).
On the basis of the encouraging results obtained with
racemic acyl nitrosoderived cycloadduct 1a,b, initial experi-
ments devoted to a challenging desymmetrization reaction
of symmetrical bicyclic hydrazines 2 were focused on the
use of dialkylzincs as the organometallic reagent. Unfortu-
nately, the copper phosphoramidite-catalyzed reaction of
dicarboxyethyl bicyclic hydrazine 2a with dialkylzinc re-
agents proved to be unsuccessful.
The more rigid, tri- or tetracyclic Diels-Alder adducts
2b and 2c of 1,3-cyclopentadiene with the cis-configured
dienophiles derived from 4-phenyl-1,2,4-triazolin-3,5-dione
and 2,3-phthalazine-1,4-dione, respectively, proved to be
more reactive (Scheme 2). With these substrates, the reaction
of Et2Zn in the presence of the copper-phosphoramidite
catalyst 3a afforded the corresponding trans-3,4-disubstituted
hydrazino cyclopentene derivatives 7a and 7c, albeit with
low yields and in almost racemic form (Table 2, entries 1
and 2). A low enantioselectivity (18%) was also obtained
with Bu2Zn (Table 2, entry 3).
1
2
3
4d
5
6
7d
8
1a
1a
1a
1a
1b
1b
1b
1b
Me (2.0)
Et (0.55)
Me (0.60)
Et (0.55)
Me (0.60)
Et (0.60)
Et (0.60)
Bu (0.60)
3 h (>96)
8 h (45)
3 h (52)
5 h (20)
2 h (46)
3 h (48)
3 h (42)
4 h (49)
44
56
8
58
53
30
37
a Reactions carried out with chiral ligand (R,R,R)-3a. For the typical
procedure, see Supporting Information. b Determined by 1H NMR of the
crude product. c Determined on adducts 4 by HPLC on a Daicel Chiralcel
OD-H column. For the determination of the absolute configuration of the
major enantiomer, see Supporting Information. d Reaction carried out with
diastereoisomeric ligand (R,S,S)-3b.
The copper-phosphoramidite catalyst efficiently promotes
the addition of the organometallic reagent on the double
bond, with cleavage of the C-O bond accompanied by allylic
rearrangement (path a, Scheme 1).12 When the reaction was
performed with Et2Zn (0.55 equiv) in accordance with a
kinetic resolution protocol, it was possible to obtain 4a with
a 44% ee at 45% conversion (Table 1, entry 2). A slighty
(6) Yao, M.-L.; Adiwidjaja, G.; Kaufmann, D. E. Angew. Chem., Int.
Ed. 2002, 41, 3375-3378.
(7) (a) Brunner, H.; Kramler, K. Synthesis 1991, 1121-1124. (b)
Namyslo, J. C.; Kaufmann, D. E. Eur. J. Org. Chem. 1998, 1997-2001.
(c) Brunel, J. M.; Hirlemann, M.-H.; Heumann, A.; Buono, G. Chem.
Commun. 2000, 1869-1870.
(8) For a review, see: Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem.
Res. 2003, 36, 48-58.
(9) For the unique example we know of a palladium-catalyzed asym-
metric ring-opening of diazabicycloheptenes with O-nucleophiles, proceed-
ing with a different regiochemistry and moderate enantioselectivity (up to
58% ee), see: Luna, A. P. L.; Cesario, M.; Bonin, M.; Micouin, L. Org.
Lett. 2003, 5, 4771-4774.
(10) For a recent review, see: Pineschi, M. New. J. Chem. 2004, 28,
657-665 and references therein.
(11) For overviews of phosphoramidites in catalytic asymmetric conjugate
additions, see: (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b)
Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236.
(12) Corresponding blank reactions performed without the use of
phosphoramidite ligands gave a mixture of products and a lower conversion.
Miller et al. have recently reported a ring opening of 3-aza-2-oxabicyclo-
[2.2.1]hept-5-enes of type 1 with Grignard reagents in combination with
catalytic amounts of CuCl2. However, the reaction is not completely regio-
and stereoselective, and the main product, racemic anti-1,2-hydroxamic acids
of type 4 (through path a, Scheme 2), were invariably obtained in a mixture
of ring-opened products of types 5 and 6 in which the attack of the
organometallic reagent had occurred at the bridgehead carbon atom (path
b, Scheme 2). See: Surman, M. D.; Mulvihill, M. J.; Miller, M. J. J. Org.
Chem. 2002, 67, 4115-4121.
3606
Org. Lett., Vol. 7, No. 17, 2005

new asymmetric formal hydrazido alkylation of cyclopen-
tadiene.16
Scheme 2. Enantioselective Desymmetrization of Polycyclic
Hydrazines 2b,c with Organometallic Reagents
Very interestingly, in the desymmetrization reaction of
diazabicyclic compounds 2b and 2c, the sense of chirality
of the amine part of the phosphoramidite proved to exhibit
a major influence on the stereochemical outcome of the
reaction. In fact, diastereoisomeric phosphoramidite ligand
(R,S,S)-3b afforded the opposite enantiomer of adduct 7d
(64% ee, entry 8) with respect to ligand (R,R,R)-3a.17 It
should be noted that this is an important exception to the
normal trend in which it is the binaphthol unit of the chiral
phosphoramidite ligand that imposes the absolute stereo-
chemistry of the conjugate adduct.11,14a
The nice results obtained with diazabicycloheptenes 2b,c
seem to indicate an evident dependence of the enantio-
selectivity on the nature of the aluminum organyl.18 The best
enantioselectivities were obtained with Me3Al, and by the
use of the more sterically demanding (i-Bu)3Al, a reversal
of the facial selectivity was even observed (Table 2, entry
10). These facts support the notion that the structure of the
active catalyst incorporates an AlR3-dependent substrate
binding pocket.19
Table 2. Desymmetrization of Polycyclic Hydrazines 2b,c with
Organometallic Reagents (R2-M)a
The present findings represent an unprecedented asym-
metric ring opening of norbornenes containing multiple
heteroatoms with hard alkylmetals. The induced ring opening,
in conjunction with C-C bond formation, gives for the first
time a catalytic and practical access to hetero-functionalized
alkyl cyclopentenes in an enantioenriched form.
no. substrate
R2-M
time (h) conversion (%)b ee (%)c
1
2
3
4
5
6
7
8d
9e
10e
2b
2c
2c
2b
2b
2c
2c
2c
2c
2c
Et2Zn
Et2Zn
Bu2Zn
Et3Al
Me3Al
Et3Al
Me3Al
Me3Al
(n-Pr)3Al
(i-Bu)3Al
24
6
38
22
3
0
6
34
18
4
1
4
4
4
20
20
>98
>98
94
>98
>98
>98
95
66(+)
80(+)
78(+)
86(+)
64(-)
54(+)
14(-)
Acknowledgment. This work was supported by Ministero
dell’Istruzione, dell’Universita` e della Ricerca (M.I.U.R.
Rome, P.R.I.N. 2004) and by the University of Pisa. The
authors thank Prof. Rita Menicagli for useful discussion about
organoaluminum reagents.
a Reactions entirely carried out at 0 °C with chiral ligand (R,R,R)-3a.20
For the general procedure, see Supporting Information. b Determined by
1H NMR of the crude mixture. c Determined by HPLC on a Daicel
Chiralpack AD-H. Sign of optical rotation reported in parantheses. d Reac-
tion carried out with diastereoisomeric ligand (R,S,S)-3b. e Reaction carried
out at up to room temperature.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL050895Q
(14) For the use of trialkyl aluminums with R,â-unsaturated carbonyl
compounds, see: (a) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem.,
Int. Ed. 2005, 44, 1376-1378. (b) Pineschi, M.; Del Moro, F.; Gini, F.;
Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004, 1244-1245. (c) Su,
L.; Li, X.; Chan, W. L.; Jia, X.; Chan, A. S. C. Tetrahedron: Asymmetry
2003, 14, 1865-1869. (d) Bennett, S. M.; Brown, S. M.; Muxworthy, J.
P.; Woodward, S. Tetrahedron Lett. 1999, 40, 1767-1770. (e) Dieguez,
M.; Deerenberg, S.; Pamies, O.; Claver, C.; van Leeuwen, P. W. N. M.;
Kamer, P. Tetrahedron: Asymmetry 2000, 11, 3161-3166. With vinyl
epoxides, see: (f) Equey, O.; Alexakis, A. Tetrahedron: Asymmetry 2004,
15, 1531-1536. With oxabicyclic alkenes, see: (g) Millward, D. B.;
Sammis, G.; Waymouth, R. M. J. Org. Chem. 2000, 65, 3902-3909.
(15) On the other hand, trialkylaluminums gave a complex mixture of
products when used with oxabicyclic compounds 1a,b and with bicyclic
hydrazine 2a.
(16) For a recent report on hydrohydrazination of simple alkenes, see:
Waser, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 32, 4099-4102.
(17) Some other phosphoramidite ligands that were employed gave lower
enantioselectivities (see Supporting Information).
(18) Substituted vinylic alane, readily available by hydroalumination of
1-hexyne, and freshly prepared AlPh3 proved to be only scarcely reactive
in our reaction conditions (<10% conversion after 18 h at 0 °C, data not
reported in Table 2).
Therefore, we decided to change the primary organo-
metallic reagent from the poorly reactive dialkylzinc reagents
to the more reactive organoaluminum reagents.
The copper-catalyzed conjugate addition of organoalumi-
num reagents to R,â-unsaturated carbonyl compounds is a
well-established, simple procedure for the transfer of hy-
drocarbon substituents.13 However, only a few examples of
enantioselective additions using trialkylaluminum reagents
have been reported, and bicyclic hydrazines have never been
considered as substrates for this reaction.14 To our delight,
with the use of trialkylaluminum, the corresponding opening
products 7 were obtained with high yields and good
enantioselectivities (Table 2, entries 4-7).15 In most cases,
it was possible to obtain adducts 7a-g in a pure state after
a simple washing of the crude mixtures with hexanes to get
rid of the chiral ligand. This reaction can be considered a
(19) Fraser, P. K.; Woodward, S. Chem. Eur. J. 2003, 9, 776-782.
(20) Reactions reported in Table 2 can be performed at -25 °C for 10-
18 h with only marginal variation of ee values.
(13) Westermann, J.; Nickisch, K. Angew. Chem., Int. Ed. 1993, 32,
1368-1370.
Org. Lett., Vol. 7, No. 17, 2005
3607