3-Aminopyrrolidines via ring rearrangement of 2-aminomethylazetidines. Synthesis of (-)-absouline

Article abstract of DOI:10.1021/ol052388e

(Chemical Equation Presented) A new entry to enantiopure 3-aminopyrrolidines was developed using a boron trifluoride-mediated rearrangement of 2-aminomethylazetidines. The method is quite general and produces rearranged products in good yield regardless o

Full text of DOI:10.1021/ol052388e

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5861-5864
3-Aminopyrrolidines via Ring
Rearrangement of
2-Aminomethylazetidines. Synthesis of
(−)-Absouline
Monica Vargas-Sanchez, Franc
Je´rome Marrot
¸ois Couty,* Gwilherm Evano,* Damien Prim, and
Laboratoire SIRCOB, UMR CNRS 8086, UniVersite´ de Versailles Saint Quentin en
YVelines, 45 aVenue des Etats-Unis, 78035 Versailles Cedex, France
couty@chimie.uVsq.fr; eVano@chimie.uVsq.fr
Received October 3, 2005
ABSTRACT
A new entry to enantiopure 3-aminopyrrolidines was developed using a boron trifluoride-mediated rearrangement of 2-aminomethylazetidines.
The method is quite general and produces rearranged products in good yield regardless of both substitution pattern and relative stereochemistry
of the starting material. A concise stereocontrolled synthesis of (−)-absouline was achieved on the basis of this new method.
3-Aminopyrrolidines are ubiquitous structural motifs that are
found in natural products1 such as absouline 11a and
pharmaceuticals displaying a broad spectrum of biological
activities ranging from antidepressant to analgesic, antiviral,
antibacterial, or antitumoral. Recent and well-known drugs
incorporating this skeleton include Moxifloxacin 2 (antibac-
terial),2 Nemonapride 3 (antipsychotic),3 or the influenza
neuraminidase inhibitor A-192558 4 (Figure 1).4 Acting as
chiral auxiliaries, 3-aminopyrrolidines have been found to
be especially efficient for the asymmetric addition of
organolithium reagents to aldehydes.5
derivatives,6 reduction of cyclic enamines,4,7 Mitsunobu
reaction of 4-hydroxy-proline derivatives,8 or asymmetric
A number of syntheses of 3-aminopyrrolidines have been
reported: they rely on, for example, cyclization of asparagine
(1) (a) Ikhiri, K.; Ahond, A.; Poupat, C.; Potier, P.; Pusset, J.; Se´venet,
T. J. Nat. Prod. 1987, 50, 626. (b) Neuner-Jehle, N.; Nesvadba, H.; Spiteller,
G. Monatsh. Chem. 1965, 96, 321.
(2) Barrett, J. F. Curr. Opin. InVest. Drugs 2000, 1, 45.
(3) Iwanami, S.; Takashima, M.; Hirata, Y.; Hasegawa, O.; Usuda, S. J.
Med. Chem. 1981, 24, 1224.
(4) Wang, W. T.; Chen, Y.; Wang, S.; Gentles, R.; Sowin, T.; Kati, W.;
Muchmore, S.; Giranda, V.; Stewart, K.; Sham, H.; Kempf, D.; Laver, W.
G. J. Med. Chem. 2001, 44, 1192.
(5) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. J. Org. Chem.
1998, 63, 8266.
Figure 1. Natural or biologically active 3-aminopyrrolidines.
10.1021/ol052388e CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/19/2005

conjugate additions to chiral bicyclic lactams.9 However,
these methods suffer limitations in terms of optical purity
of the products or scope or use not so readily available
starting materials. In our continuing efforts to expand the
utility of azetidine chemistry,10 we envisioned that the ring
rearrangement of 2-aminomethylazetidines 5 would yield
3-aminopyrrolidines 6 in a concise and especially straight-
forward fashion (Scheme 1). We therefore report in this
In considering methods to promote this rearrangement
starting from diamine 6a, we were initially interested in the
use of Brønsted acids. Therefore, diamine 6a was reacted
with 1 equiv of acid in refluxing toluene, but no conversion
was obtained (Table 1, entries 1 and 2). We next screened
Table 1. Evaluation of Acid Promoters and Solvents
Scheme 1. Preparation of 3-Aminopyrrolidines via Ring
Rearrangement of 2-Aminomethylazetidines
entry acid promoter
conditions
conversion (%)
1
2
3
4
5
6
7
8
APTS
TfOH
AlMe3
Ti(OiPr)4
TiCl4
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
toluene, reflux, 14 h
toluene, reflux, 14 h
CH2Cl2, reflux, 14 h
CH2Cl2, reflux, 14 h
CH2Cl2, reflux, 14 h
CH2Cl2, reflux, 14 h
toluene, reflux, 14 h
CH3CN, reflux, 14 h
0
0
0
0
6
communication a highly stereoselective approach to 3-amino-
pyrrolidines; the utility of this methodology is further
demonstrated in a straightforward asymmetric synthesis of
pyrrolizidine alkaloid (-)-absouline.
To explore the possibility of this rearrangement, we
prepared a series of diamines 6 using our addition/reduction
sequence11 from cyanoazetidines 7 (Scheme 2).12 Therefore,
11
54
>95
various Lewis acids in refluxing dichloromethane (Table 1,
entries 3-6). These studies established the requirement for
a strong Lewis acid to promote the reaction (TiCl4 or BF3‚
OEt2).16 Further improvement was found in replacing the
solvent with acetonitrile, which was found to be especially
suitable since it leads to a clean and complete reaction (Table
1, entry 8).
Scheme 2. Synthesis of Azetidinic Diamines
With a viable rearrangement procedure in hand, attention
was turned to the generality of the process and the reactivity
of a range of structurally diverse azetidinic diamines 6a-6l
was studied employing BF3‚OEt2 as an acid promoter in
refluxing acetonitrile. Results from those experiments are
represented in Table 2 and clearly show that polysubstituted
3-aminopyrrolidines are obtained as single diastereoisomers
in good to excellent yields in all cases. Interestingly, the
reaction is not substrate-dependent since neither the size of
the substituents (compare entries 5-9) nor the substitution
of the exocyclic amine (compare entries 2 and 12) have a
marked effect on reaction time or yield. An interesting feature
of this rearrangement, which is in contrast with most of the
ring rearrangement reactions involving nitrogen heterocycles,
by reacting 7 with either an organolithium or a Grignard
reagent followed by in situ reduction of the produced imine,
diamines 6, whose structures are represented in Table 2, were
obtained in good yields and excellent selectivities.13
With a set of 2-aminomethylazetidines in hand, we next
focused on the ring rearrangement. For this crucial step, we
anticipated that the strain release during the four- to five-
membered ring transformation would be a sufficient driving
force for the reaction, as previously documented in ring
expansion reactions.10b,14,15
(6) Maddaluno, J.; Corruble, A.; Leroux, V.; Ple´, G.; Duhamel, P.
Tetrahedron: Asymmetry 1992, 3, 1239.
(7) Lee, H.-S.; LePlae, P. R.; Porter, E. A.; Gellman, S. H. J. Org. Chem.
2001, 66, 3597.
(8) Rosen, T.; Chu, D. T. W.; Lice, I. M.; Fernandes, P. B.; Shen, L.;
Borodkin, S.; Pernet, A. G. J. Med. Chem. 1988, 31, 1586.
(9) Andres, C. J.; Lee, P. H.; Nguyen, T. H.; Meyers, A. I. J. Org. Chem.
1995, 60, 3189.
(10) (a) Couty, F.; Evano, G.; Prim, D. Mini-ReV. Org. Chem. 2004, 1,
133. (b) Couty, F.; Durrat, F.; Evano, G.; Prim, D. Tetrahedron Lett. 2004,
45, 7525. (c) Couty, F.; Durrat, F.; Evano, G. Synlett 2005, 1666.
(11) Couty, F.; Evano, G.; Prim, D.; Marrot, J. Eur. J. Org. Chem. 2004,
3893.
(12) Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymmetry 2002,
13, 297.
(15) For recent examples of ring rearrangement starting from azetidines,
see: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Salgado, N. R. J.
Org. Chem. 1999, 64, 9596. (b) Outurquin, F.; Pannecoucke, X.; Berthe,
B.; Paulmier, C. Eur. J. Org. Chem. 2002, 1007. (c) Couty, F.; Durrat, F.;
Prim, D. Tetrahedron Lett. 2003, 44, 5209. (d) Yoneda, R.; Sakamoto, Y.;
Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996, 52, 14563. (e)
O’Neil, I. A.; Potter, A. J. Chem. Commun. 1998, 1487. (f) Martorell, A.;
Inman, G. A.; Alper, H. J. Mol. Catal. A: Chem. 2003, 204, 91.
(16) BF3‚OEt2 is commonly used in Lewis acid-catalyzed ring openings
of aziridines. See: (a) Bodenan, J.; Chanet-Ray, J.; Vessiere, R. Synthesis
1992, 288. (b) Dauban, P.; Dodd, R. H. J. Org. Chem. 1997, 62, 4277. (c)
Cantrill, A. A.; Osborn, H. M. I.; Sweeney, J. Tetrahedron 1998, 54, 2181.
(d) McCoull, W.; Davis, F. A. Synthesis 2000, 1347. (e) Xiong, C.; Wang,
W.; Cai, C.; Hruby, V. J. J. Org. Chem. 2002, 67, 1399. (f) Concello´n, J.
M.; Riego, E. J. Org. Chem. 2003, 68, 6407. (g) Concello´n, J. M.; Riego,
E.; Sua´rez, R. J. Org. Chem. 2003, 68, 9242.
(13) See Supporting Information for more details.
(14) Hesse, M. Ring Enlargement in Organic Chemistry; VCH: Wein-
heim, Germany, 1991.
5862
Org. Lett., Vol. 7, No. 26, 2005

Table 2. 3-Aminopyrrolidines via Ring Rearrangement of 2-Aminomethylazetidines: Scope and Limitations
1
a Yield of isolated, pure product. b Determined by H NMR analysis of crude reaction mixtures. c Prepared by benzylation of the corresponding primary
amines 6a and 6b. See Supporting Information for details.
is that the relative stereochemistry of the substrate does not
have a pronounced influence on the efficiency of the reaction
since diastereoisomers 6a, 6b, 6c, and 6d all rearrange in
comparable yields (entries 1-4). More importantly, the
rearrangement proceeds in a complete stereospecific way,
and no epimerization at the reacting centers is observed.
To explain both the rearrangement itself and its stereo-
chemical outcome, we propose the mechanism depicted in
Scheme 3 inspired by related ring transformations.16f,g After
Scheme 3. Proposed Mechanism for the Rearrangement
Relative stereochemistry of the obtained 3-aminopyrroli-
dines was elucidated on the basis of NOE experiments.
Moreover, an X-ray structure of the N-Boc derivative of
pyrrolidine 5l confirmed the anti relationship of the substit-
uents at positions 4 and 5 of the pyrrolidine ring (Figure 2).
coordination of the azetidine nitrogen to the Lewis acid,
which results in an activation of the azetidine ring toward
nucleophiles, an intramolecular ring opening by nucleophilic
attack of the exocyclic amine with inversion of configuration
would afford the aziridinium salt 9. Migration of boron
trifluoride to the more basic cyclic amine followed by a
Figure 2. X-ray structure of N-Boc derivative of 5l. The structure
was obtained by reaction of 5l with Boc2O in AcOEt.
Org. Lett., Vol. 7, No. 26, 2005
5863

second intramolecular nucleophilic substitution within aziri-
dinium 10 would give, after hydrolysis, the 3-aminopyrroli-
dine product 5. All steps involved in this mechanism being
equilibrated, the driving force of the reaction is the formation
of the most stable pyrrolidine product which possesses a ring
strain by far smaller than the one of the azetidine starting
material or aziridine intermediates. Importantly, this mech-
anism can account for the stereochemistry of the product,
which can be rationalized by the inversion of configuration
occurring at each ring-opening/ring-closing step.
Scheme 4. Synthesis of (-)-Absouline
As an application of this methodology and to further
demonstrate its usefulness, a concise enantioselective route
to pyrrolizidine alkaloids absouline was developed. Ab-
souline (+)-1 as well as its Z stereoisomer (+)-isoabsouline
and their N-oxide derivatives were isolated in 1987 from New
Caledonian plants Hugonia oreogena and Hugonia penicil-
lanthemum and were shown to possess modest antiviral
activity.1a To date, one racemic17 and one asymmetric18
syntheses of absouline have been reported, the major
drawback of the latter being the low diastereoselectivity of
its key step.
Our synthesis started with cyanoazetidine 11, whose
preparation from (S)-R-methylbenzylamine was recently
reported.19 Addition of 3-benzyloxy-propyl lithium to 11
provided diamine 12 in gram quantities and high diastereo-
isomeric purity (Scheme 4). This set the stage for the key
rearrangement step: reaction of 12 with 1 equiv of boron
trifluoride in refluxing acetonitrile gave, in excellent yield
and selectivity, the desired 3-aminopyrrolidine possessing
all the carbon atoms necessary for elaboration of the
pyrrolizidine skeleton and the required stereochemistry.
Conversion of pyrrolidine 13 to absouline entailed formation
of the second ring system and installation of the side chain.
Therefore, the exocyclic amine in 13 was protected as a
carbamate, and both N- and O-benzyl-protecting groups were
cleaved by hydrogenolysis. Formation of the 1-amino-
pyrrolizidine skeleton was best effected using Appel’s
hydroxyl activation protocol, which gave the pyrrolizidine
core 15 in 76% yield.20 Finally, N-Boc deprotection followed
by DCC/DMAP-mediated coupling of the resulting amine
with (E)-para-methoxycinnamic gave (-)-absouline 1 as a
colorless solid whose spectroscopic data were identical to
those reported for the natural product.1a
In conclusion, we have developed a new rearrangement
that leads to the assembly of functionalized, enantiopure
3-aminopyrrolidines with high efficiency. The methodology
has been used as a key step in a stereocontrolled synthesis
of pyrrolizidine alkaloid absouline. Further development and
application of this ring expansion will be reported in due
course.
Acknowledgment. We gratefully acknowledge financial
support from CNRS. M.V.S. thanks CONACYT for a
graduate fellowship. We thank Dr. Christiane Poupat for a
gift of a sample of natural absouline and Prof. Huang Pei-
Qiang for sending us copies of 1H and 13C NMR spectra of
synthetic absouline and helpful comments. We are indebted
to Prof. James S. Panek for HRMS analyses.
Supporting Information Available: Spectroscopic data
and experimental procedures for all new compounds; copies
1
(17) Christine, C.; Ikhiri, K.; Ahond, A.; Al Mourabit, A.; Poupat, C.;
Potier, P. Tetrahedron 2000, 56, 1837.
(18) Tang, T.; Ruan, Y. P.; Ye, J. L.; Huang, P.-Q. Synlett 2005, 231.
(19) Couty, F.; Evano, G.; Vargas-Sanchez, M.; Bouzas, G. J. Org. Chem.
2005, 70, 9028.
of H and 13C NMR spectra for synthetic absouline. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) For asymmetric synthesis of 1-aminopyrrolizidine, see: Giri, N.;
Petrini, M.; Profeta, R. J. Org. Chem. 2004, 69, 7303.
OL052388E
5864
Org. Lett., Vol. 7, No. 26, 2005