Iterative Organometallic Addition to Chiral Hydroxylated Cyclic Nitrones: Highly Stereoselective Syntheses of α,α′- and α,α-Substituted Hydroxypyrrolidines

Article abstract of DOI:10.1021/ol035798g

(Equation presented) Iteration of organometallic addition to chiral hydroxylated pyrroline N-oxides through an addition-oxidation-addition synthetic sequence allowed highly stereoselective double alkylation of pyrrolidine at C-2 or at C-2 and C-5 dependin

Full text of DOI:10.1021/ol035798g

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4235-4238
Iterative Organometallic Addition to
Chiral Hydroxylated Cyclic Nitrones:
Highly Stereoselective Syntheses of
r,r′- and r,r-Substituted
Hydroxypyrrolidines
,†
Andrea Goti,* Stefano Cicchi,† Vanni Mannucci,†,‡ Francesca Cardona,†
,‡
Francesco Guarna,† Pedro Merino,* and Tomas Tejero‡
Dipartimento di Chimica Organica “Ugo Schiff”, UniVersita` di Firenze,
Via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy, and Departamento de
Qu´ımica Orga´nica, ICMA, Facultad de Ciencias, UniVersidad de Zaragoza-CSIC,
E-50009 Zaragoza, Aragon, Spain
andrea.goti@unifi.it; pedro.merino@unizar.es
Received September 17, 2003
ABSTRACT
Iteration of organometallic addition to chiral hydroxylated pyrroline N-oxides through an addition-oxidation-addition synthetic sequence allowed
highly stereoselective double alkylation of pyrrolidine at C-2 or at C-2 and C-5 depending on the regioselectivity of the oxidation step. Application
of this methodology has been exemplified by the synthesis of the all-substituted pyrrolidine alkaloid (−)-codonopsinine and of proline-type
amino acid precursors possessing a quaternary stereogenic center, whose configuration can be controlled.
Suitably protected chiral mono- and dihydroxypyrroline
N-oxides of type 1 and 2 (and their enantiomers) have
emerged in the past decade as extremely useful intermediates
for the synthesis of chiral hydroxypyrrolidines and of more
complex bicyclic azaheterocycles, such as pyrrolizidines and
indolizidines.1
synthesis of pyrrolizidine and indolizidine alkaloids and
several unnatural analogues.1,2 Their reactivity as electro-
philes in organometallic additions has been much less
investigated.3 A detailed and systematic study is lacking,
albeit some sporadic examples of this reactivity have been
reported.4 Grignard reagents have been added to nitrones 1
for the synthesis of (-)-anisomycin,4a (+)-lentiginosine,4b
Particularly, the reactivity of 1 and 2 as 1,3-dipoles in
cycloaddition reactions has been exploited toward the
(2) For recent findings on related nitrones, see: (a) Cardona, F.; Faggi,
E.; Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron Lett. 2003, 44, 2315-
2318. (b) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003,
35-38. (c) Duff, F. J.; Vivien, V.; Wightman, R. H. Chem. Commun. 2000,
2127-2128. (d) Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48, 1337-
1342.
(3) For reviews of addition of organometal derivatives to nitrones, see:
(a) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (b) Enders, D.; Reinhold:
U. Tetrahedron: Asymmetry 1997, 8, 1895-1946. (c) Lombardo, M.;
Trombini, C. Synthesis 2000, 759-774. (d) Merino, P.; Franco, S.; Merchan,
F. L.; Tejero, T. Synlett 2000, 442-454. (e) Lombardo, M.; Trombini, C.
Curr. Org. Chem. 2002, 6, 695-713.
† Universita` di Firenze.
‡ Universidad de Zaragoza.
(1) (a) Cardona, F.; Goti, A.; Brandi, A. Org. Lett. 2003, 5, 1475-1478.
(b) Cordero, F. M.; Pisaneschi, F.; Gensini, M.; Goti, A.; Brandi, A. Eur.
J. Org. Chem. 2002, 1941-1951. (c) Socha, D.; Jurczak, M.; Frelek, J.;
Klimek, A.; Rabiczko, J.; Urban´czyk-Lipkowska, Z.; Suwin´ska, K.;
Chmielewski, M.; Cardona, F.; Goti, A.; Brandi, A. Tetrahedron: Asym-
metry 2001, 12, 3163-3172. (d) Goti, A.; Cacciarini, M.; Cardona, F.;
Cordero, F. M.; Brandi, A. Org. Lett. 2001, 3, 1367-1369. (e) Goti, A.;
Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A. Eur. J. Org.
Chem. 2000, 3633-3645 and references therein.
10.1021/ol035798g CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/09/2003

and biologically active tri- and tetrahydroxypyrrolidines.4c
Murahashi has carried out a carboxymethylation of nitrone
2 with a silyl ketene acetal on the route to Geissman-Waiss
lactone,4d and Reissig, Brandi, and co-workers have reported
the addition of an allenyllithium derivative to nitrones 1 and
2.4e Recently, we have reported a study on the addition of
metal cyanides to nitrones 1 and 2.5 Apart from the first
application, where the stereoselectivity of the addition was
poor,4a in all other cases substantial high and consistent anti
diastereoselectivity (>90%) of the addition has been
observed.4b-e,5 The stereocontrol is exerted by the vicinal
protected hydroxy group, with the organometallic derivative
attacking preferentially the opposite face.
The primary products of additions to nitrones are hydroxy-
lamines, which in turn are susceptible to undergo easy
oxidation to novel nitrones. Oxidation of the N-hydroxypyr-
rolidines 3 generated by a first organometallic addition to
nitrone 1 or 2 followed by a further addition might open the
way to pyrrolidines doubly substituted in the R-position(s)
(Scheme 1).6
Regarding the stereoselectivity of the organometallic addi-
tions, we expected a high preference for an anti attack with
respect to the vicinal alkoxy group, on the basis of the
previous findings.4,5 The second point is more critical and
was foreseen as being strongly dependent on the starting
nitrone. Indeed, on the basis of the few oxidations of
2-substituted 1-hydroxypyrrolidines to nitrones reported in
the literature,7 formation of keto nitrones 5 should be highly
preferred over their regioisomeric aldo nitrones 4 by oxida-
tion of hydroxylamines 3. On the other hand, we have
previously found that the presence of a heavily electro-
negative atom, as oxygen is, at C-3 has a strong influence
on regioselectivity, favoring the abstraction of the vicinal
anti proton.8 This effect does not work on hydroxylamine 3
(R2 ) H) derived from nitrone 2, which is expected therefore
to give mainly a keto nitrone of type 5. However, when
nitrone 1 is used, the two effects are working in opposite
directions, and hence the predominant one will control the
regioselectivity of the oxidation. Therefore, formation of
hydroxylamines 3 from the starting nitrones and of stereo-
isomers 6 and 7 from nitrones 4 and 5, respectively, was
anticipated.
These assumptions were preliminarily tested starting from
the L-tartaric acid derived nitrone (ent)-1,9 which was
subjected to the planned addition-oxidation-addition sequence
(Scheme 2). The first addition of PhMgBr occurred with
Scheme 1
Scheme 2
In this Letter we report the results on this iterative
organometallic addition approach starting from nitrones 1
and 2 (R1 ) tBu), including its applications to a novel
synthesis of the all-substituted pyrrolidine alkaloid (-)-
codonopsinine and to the stereocontrolled synthesis of
precursors of quaternary hydroxyproline-type amino acids.
From an examination of the strategy outlined in Scheme
1, two issues arise concerning the selectivity of the overall
process: (i) the diastereoselectivity connected with the two
addition steps; (ii) the regioselectivity of the oxidation step.
complete diastereoselectivity to give hydroxypyrrolidine 8
quantitatively. The subsequent oxidation, as expected, fur-
nished the two regioisomeric nitrones 9 and 10 with a scarce
60:40 selectivity in favor of the aldonitrone 9, which after
separation was reacted with lithium acetylide 11. Also this
(4) (a) Ballini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57,
1316-1318. (b) Giovannini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem.
1995, 60, 5706-5707. (c) Lombardo, M.; Fabbroni, S.; Trombini, C. J.
Org. Chem. 2001, 66, 1264-1268. (d) Ohtake, H.; Imada, Y.; Murahashi,
S.-I. Bull. Chem. Soc. Jpn. 1999, 72, 2737-2754. (e) Pulz, R.; Cicchi, S.;
Brandi, A.; Reissig, H.-U. Eur. J. Org. Chem. 2003, 1153-1156.
(5) Merino, P.; Tejero, T.; Revuelta, J.; Romero, P.; Cicchi, S.;
Mannucci, V.; Brandi, A.; Goti, A. Tetrahedron: Asymmetry 2003, 14, 367-
379.
(6) Disubstituted pyrroline N-oxides have been subjected to iterative
additions for the synthesis of nitroxides. See for example: (a) Keana, J. F.;
Lee, T. D.; Bernard, E. M. J. Am. Chem. Soc. 1976, 98, 3052-3053. (b)
Einhorn, J.; Einhorn, C.; Ratajczak, F.; Gautier-Luneau, I.; Pierre, J.-L. J.
Org. Chem. 1997, 62, 9385-9388.
(7) (a) Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett.
2001, 42, 6503-6505. (b) Cicchi, S.; Corsi, M.; Goti, A. J. Org. Chem.
1999, 64, 7243-7245. (c) Ali, Sk. A.; Hashmi, S. M. A.; Siddiqui, M. N.;
Wazeer, M. I. M. Tetrahedron 1996, 52, 14917-14928. (d) Ali, Sk. A.;
Wazeer, M. I. M. Tetrahedron 1993, 49, 4339-4354. (e) Murahashi, S.-I.;
Sun, J.; Kurosawa, H.; Imada, Y. Heterocycles 2000, 52, 557-562. (f)
Padwa, A.; Dent, W. H.; Schoffstall, A. M.; Yeske, P. E. J. Org. Chem.
1989, 54, 4430-4437.
(8) (a) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J. Org.
Chem. 1997, 62, 3119-3125. (b) Cicchi, S.; Goti, A.; Brandi, A. J. Org.
Chem. 1995, 60, 4743-4748.
(9) Cicchi, S.; Ho¨ld, I.; Brandi, A. J. Org. Chem. 1993, 58, 5274-5275.
4236
Org. Lett., Vol. 5, No. 22, 2003

addition turned out to be completely selective, with the
nucleophile entering from the opposite face with respect to
the vicinal tert-butoxy group, thus establishing the all-trans
stereochemistry of the resulting hydroxypyrrolidine 12. This
stereochemical pattern was unambiguously proved by X-ray
structural determination of the compound obtained by
desilylation of 12 followed by acetylation.
Scheme 3
Despite the low selectivity in the oxidation of 8, the
preferential formation of aldo nitrone 9 represents a confir-
mation of the previously observed effect furnished by the
vicinal alkoxy group,8 which is powerful enough to override
the otherwise favored formation of keto nitrone.7 The all-
trans stereochemical pattern of the final tetrasubstituted
hydroxypyrrolidine 12 suggests that this procedure is per-
fectly suited to be applied to the total synthesis of several
pyrrolidine alkaloids, such as (-)-codonopsine (13) and (-)-
codonopsinine (14), antibiotics extracted from Codonopsis
clematidea10,11 exhibiting hypotensive activity without effects
on CNS.12
Starting from D-tartaric acid derived nitrone 1 and using
MeMgBr and the Grignard reagent 18 as nucleophiles in the
above protocol, the hydroxypyrrolidine 19 was accessed,
again with complete control of the stereochemistry (Scheme
3). Methylation of 19 followed by N-O reductive cleavage
with Zn and catalytic In13 and final deprotection of the
hydroxy groups afforded the desired pyrrolidine alkaloid 14,
whose spectroscopic and analytical data were in agreement
with those reported in the literature.10-12 Several oxidants
were tested for achieving the best selectivity in favor of aldo
nitrone 16 from the hydroxylamine 15. Most of them gave
a quantitative yield of nitrones but with a moderate regio-
selectivity, with commercial MnO27a being the best perform-
ing (16/17 ) 70:30). For practical reasons, the mixture of
nitrones was directly reacted with the Grignard reagent 18
without separation. The reaction furnished the two hydroxy-
pyrrolidines 19 and 20, which could be better separated at
this stage. However, addition of 18 to a purified sample of
nitrone 16 afforded exclusively the hydroxylamine 19, whose
stereochemistry was ascertained by NOE experiments, in
87% yield. It is noteworthy that no diastereoisomer of 20
was observed, indicating also that the attack to keto nitrone
17 occurred with complete stereoselectivity, anti to the
vicinal tert-butoxy group.
This finding, together with the expected high preference
for oxidation to keto nitrones for hydroxylamines 3 when
derived from nitrone 2, opens the way to a selective and
stereocontrolled access to 2,2-disubstituted 3-hydroxypyr-
rolidines 7. This strategy was studied by using a metal
cyanide as one of the nucleophiles, to synthesize precursors
of hydroxyprolines and of chiral 1,2-diamines possessing a
quaternary stereogenic carbon atom. When the metal cyanide
was used as the first nucleophile, the process was efficient
and completely selective until the formation of a keto nitrone
of type 5 (R′ ) CN) but then was complicated by addition
of the second organometallic derivative at both nitrone and
cyano functionalities. However, a reversal in the order of
addition of the two nucleophiles resulted in a highly efficient
overall process, which straightforwardly afforded the desired
2-cyano hydroxypyrrolidines in a stereocontrolled way
(Scheme 4). Addition of PhMgBr to 28b followed by MnO2
oxidation gave quantitatively the keto nitrone 22. Thus,
oxidation of 21 occurs with complete regioselectivity, in
contrast to the analogous HgO oxidation of 2-phenyl-1-
hydroxypyrrolidine, which gave a 83:17 mixture of keto to
aldo nitrone.7c The addition of Me3SiCN to nitrone 22
proceeded sluggishly in the absence of a Lewis acid catalyst
(Table 1, entries 1 and 2). When 1 equiv of Et2AlCl and an
excess of cyanating reagent were used, the addition went
almost to completion in 2 h, affording the expected cyano-
hydroxypyrrolidine 23 as the major diastereoisomer (Table
1, entries 3 and 4). The solvent did not affect the reaction
substantially, albeit better yield and selectivity was obtained
in THF than in CH2Cl2. However, the diastereoselectivity
(10) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Yu. Khim. Prir.
Soedin. 1969, 5, 30-32.
(11) A synthesis of (-)-codonopsinine by alkylation of a L-xylose-
derived nitrone has been recently reported: see ref 2b. For other syntheses
of 13 and 14, see: (a) Haddad, M.; Larcheveˆque, M. Synlett 2003, 274-
276. (b) Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039-3042.
(c) Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996, 37, 5531-
5534. (d) Wang, C.-L. J.; Calabrese, J. C. J. Org. Chem. 1991, 56, 4341-
4343. (e) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52,
1956-1962.
(12) Khanov, M. T.; Sultanov, M. B.; Egorova, T. A. Farmakol.
AlkaloidoV Serdech. GlikoyidoV. 1971, 210-212.
(13) Cicchi, S.; Bonanni, M.; Cardona, F.; Revuelta, J.; Goti, A. Org.
Lett. 2003, 5, 1773-1776.
Org. Lett., Vol. 5, No. 22, 2003
4237

hydroxypyrrolidine 24. Indeed with Et2AlCN, albeit the
addition was slower and gave a more modest conversion, a
rewarding inversion of selectivity, up to 93:7, in favor of
cis CN-OtBu hydroxypyrrolidine 24 was found (Table 1,
entries 5-8). Any attempt to complete the reaction by longer
reaction time only led to extensive decomposition of the
starting materials. With Et2AlCN, the reaction showed a
strong solvent dependence. When carried out in CH2Cl2 it
went to a negligible extent only, whereas in THF with an
excess of reagent it took place satisfactorily. The different
mechanisms connected with the addition of Me3SiCN or Et2-
AlCN to nitrones are presumably responsible for the observed
inversion of selectivity.5 Addition of free cyanide, generated
from Et2AlCN when the reaction is quenched as observed
in our previous study,5 might also occur. With nitrone 22,
however, this possibility is negligible, since the direct
addition of free cyanide, under Murahashi conditions,4d
showed to be quite slow and 23 was obtained predominantly
(Table 1, entry 9). Anyway, the possibility of accessing both
diastereoisomers with remarkable selectivity simply by
changing the cyanating reagent is of great synthetic signifi-
cance. It is noteworthy that a quaternary carbon stereogenic
center can be created in a stereocontrolled manner from a
methylene unit. Compounds 23 and 24 can be considered
direct precursors of chiral 2-substituted hydroxyprolines and
of aminomethylpyrrolidines, which may find application in
peptidomimetics and catalysis, respectively.
In conclusion, the synthetic sequence involving nucleo-
philic addition-oxidation-nucleophilic addition to tartaric and
malic acids derived nitrones 1 and 2 has been studied
employing two different organometal derivatives. The pro-
cess allows high levels of diastereocontrol, as demonstrated
in the application to the syntheses of the fully substituted
pyrrolidine alkaloid (-)-codonopsinine and of 2,2-disubsti-
tuted 3-hydroxypyrrolidines. Studies are currently underway
in our laboratories in order to extend the range of substrates
and nucleophiles used and to devise other useful applications
in organic synthesis.
Scheme 4
of the reaction was not complete, and minor amounts of
product 24, deriving from syn-attack of cyano to the tert-
butoxy group, were also isolated.
Table 1. Addition of Metal Cyanides to Nitrone 22a
reagent
(equiv)
catalyst
(equiv)
conversion 23/24
entry
solvent
(%)b
ratio
1
2
3
4
5
6
7
8
9
Me3SiCN (3)
Me3SiCN (3)
CH2Cl2
THF
<10c,d
12c,d
95
95:5
95:5
92:8
Me3SiCN (3) Et2AlCl (1) THF
Me3SiCN (3) Et2AlCl (1) CH2Cl2
91
55
86:14
19:81
Et2AlCN (1)
Et2AlCN (1)
Et2AlCN (3)
Et2AlCN (3)
KCN (1.2)
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
0
57
13
15e
7:93
23:77
80:20
a All reactions were carried out at -20 °C for 2 h. b Based on integration
of 1H NMR spectra of the crude reaction mixtures. In all cases the chemical
yield was quantitative (100%) with respect to the reacted nitrone. c The
reaction was stopped after 2 weeks. d Further treatment with 5% methanolic
citric acid of the crude mixtures afforded free hydroxylamines. e The reaction
was carried out at room temperature for 1 h in the presence of 6 N HCl.
Acknowledgment. We thank MIUR, Italy (Cofin 2002),
MCYT, Spain, FEDER Program (Project CASANDRA,
BQU2001-2428), and the Government of Aragon (Project
P116-2001), Spain for financial support, MIUR and MCYT
for a bilateral exchange project (2000-2001). V.M. was a
Socrates/Erasmus (Firenze-Zaragoza) fellow.
This result is in contrast with the complete anti-selectivity
that we have observed in a previous study for the addition
of Me3SiCN to 1, 2, and other related nitrones.5 In the same
study it was found that reacting Et2AlCN with 2 resulted in
a less selective addition, still affording the anti-adduct as
the major diastereoisomer but with a low 1.5-2:1 diaste-
reoselection.5 We hoped therefore that switching to Et2AlCN
in the present case, where the additional phenyl at C-2
seemed to disfavor the anti attack more than the syn, might
result in a reversal of the stereoselectivity in favor of
Supporting Information Available: Experimental pro-
cedures and analytical and spectroscopical characterization
of compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL035798G
4238
Org. Lett., Vol. 5, No. 22, 2003