A novel synthesis of enantiopure octahydropyrrolo[3,4-b]pyrroles by intramolecular [3 + 2] dipolar cycloaddition on chiral perhydro-1,3-benzoxazines

Article abstract of DOI:10.1021/ol0261377

(Matrix presented) Condensation of N-substituted glycines with chiral 3-allyl-2-formyl perhydro-1,3-benzoxazines forms an azomethine ylide that cyclizes to give octahydropyrrolo[3,4-b]pyrrole derivatives. The [3 + 2] dipolar cycloadditions are stereoespec

Full text of DOI:10.1021/ol0261377

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2513-2516
A Novel Synthesis of Enantiopure
Octahydropyrrolo[3,4-b]pyrroles by
Intramolecular [3 + 2] Dipolar
Cycloaddition on Chiral
Perhydro-1,3-benzoxazines
Rafael Pedrosa,* Celia Andre´s,* Laura de las Heras, and Javier Nieto
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad de Valladolid,
Dr. Mergelina s/n, 47011-Valladolid, Spain
pedrosa@qo.uVa.es
Received May 6, 2002
ABSTRACT
Condensation of N-substituted glycines with chiral 3-allyl-2-formyl perhydro-1,3-benzoxazines forms an azomethine ylide that cyclizes to give
octahydropyrrolo[3,4-b]pyrrole derivatives. The [3 + 2] dipolar cycloadditions are stereoespecific leading to a single diastereoisomer. The
chemical yields are dependent on the reaction temperature and the presence or absence of a base.
The 1,3-dipolar cycloaddition reaction is one of the most
useful methods for the preparation of five-membered het-
erocycles, and consequently, it has been extensively studied.1
In particular, the reaction of azomethine ylides2 with alkenes
provides pyrrolidine ring systems that are the central skeleton
of numerous alkaloids3 and the core of physiologically active
compounds.4 The intramolecular version of this reaction
results in the formation of new fused or bridged nitrogen-
containing bicyclic systems and generally occurs with high
regio- and stereocontrol.5 This intramolecular reaction takes
place easily even with unactivated dipolarophiles such as
terminal alkenes, which do not react intermolecularly.6
Therefore, this powerful strategy has been extensively applied
toward the synthesis of complex molecules,7 including the
preparation of enantiopure substituted actahydropyrrolo[3,4-
b]pyrroles8 after chiral chromatographic separation of the
(5) Wade, P. A. In ComprehensiVe Organic Synthesis; Pergamon Press:
Oxford, 1991; Vol. 4, p 1111.
(6) (a) Smith, R.; Livinghouse, T. J. Org. Chem. 1989, 54, 1554. (b)
DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem. 1985, 50, 2309.
(7) For some recent examples, see: (a) Overman, L. E.; Tellew, J. E. J.
Org. Chem. 1996, 61, 8338. (b) Marx, M. A.; Grillot, A.-L.; Lover, C. T.;
Beaver, K. A.; Bartlett, P. A. J. Am. Chem. Soc. 1997, 119, 6153. (c) Nayyar,
N. K.; Hutchison, D. R.; Martinelli, M. J. J. Org. Chem. 1997, 62, 982. (d)
Vedejs, E.; Monahan, S. D. J. Org. Chem. 1997, 62, 4763. (e) Najdi, S.;
Park, K. H.; Olmstead, M. M.; Kurth, M. J. Tetrahedron Lett. 1998, 39,
1685. (f) Irie, O.; Samizu, K.; Henry, J. R.; Weinreb, S. M. J. Org. Chem.
1999, 64, 587. (g) Vedejs, E.; Piotrowski, D. W.; Tucci, F. C. J. Org. Chem.
2000, 65, 5498. (h) Pandey, G.; Sahoo, A. K.; Bagul, T. D. Org. Lett. 2000,
2, 2299. (i) Vedejs, E.; Klapers, A.; Naidu, B. N.; Piotrowski, D. W.; Tucci,
F. C. J. Am. Chem. Soc. 2000, 122, 5401. (j) Coldham, I.; Crapnell, K. M.;
Moseley, J. D.; Rabot, R. J. Chem. Soc., Perkin Trans. 1 2001, 1758. (k)
Novikov, M. S.; Khlebnikov, A. F.; Besidina, O. V.; Kastikov, R. R.
Tetrahedron Lett. 2001, 42, 533.
(1) (a) Carruthers, W. In Cycloaddition Reaction in Organic Synthesis;
Tetrahedron Organic Chemistry Series; Pergamon Press: Oxford, 1990;
Vol. 8, p 269. (b) Padwa, A. In ComprehensiVe Organic Synthesis;
Pergamon Press: Oxford, 1991; Vol. 4, p 1069.
(2) Tsuge, O.; Kanemasa, S. AdVances in Heterocyclic Chemistry 1989,
45, 231.
(3) Dictionary of Alkaloids; Southon, I. W., Buckingham, J., Eds.;
Chapman and Hall: New York, 1989.
(4) Li, Q.; Chu, D. T. W.; Claiborne, A.; Cooper, C. S.; Lee, C. M.;
Raye, K.; Berst, K. B.; Donner, P.; Wang, W.; Hasvold, L. Fung, A.; Ma,
Z.; Tufano, M.; Flamm, R.; Shen, L. L.; Baranowski, J.; Nilius, A.; Alder,
J.; Meulbroek, J.; Marsh, K.; Crowell, D. A.; Hui, Y.; Seif, L.; Melcher, L.
M.; Henry, R.; Spanton, S.; Faghih, R.; Klein, L. L.; Tanaka, S. K.; Plattner,
J. J. J. Med. Chem. 1996, 39, 3070.
(8) Russell, M. G. N.; Beer, M. S.; Stanton, J. A.; Sohal, B.; Mortishire-
Smith, R. J.; Castro, J. L. Bioorg. Med. Chem. Lett. 1999, 9, 2491.
10.1021/ol0261377 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/02/2002

racemate. Enantiopure pyrrolidines have been also obtained
in good de by cyclization of azomethine ylides, generated
in situ by decarboxylation, with alkenes bearing oxazolidi-
nones9 or (R)-phenethylamine derivatives10 as chiral auxil-
iaries. The intermolecular asymmetric cycloaddition is well
known,11,12 whereas the intramolecular version using a
removable chiral auxiliary or catalyst has been less studied.13
Scheme 1. Synthesis of Octahydropyrrolo[3,4-b]pyrroles by
Intramolecular [3 + 2] Dipolar Cycloaddition
Recently, we have exploited (-)-8-amino menthol,14
prepared from the easily accessible natural (+)-pulegone,
as a chiral environment and the source of the nitrogen atom
in diastereoselective cyclization processes leading to nitrogen
heterocycles.15,16 We now report the stereoespecific 1,3-
dipolar cycloadditions of nonstabilized azomethine ylides
with unactivated alkenes positioned on a chiral perhydro-
1,3-benzoxazine moiety.
The starting 3-allyl-2-formyl perhydro-1,3-benzoxazines
4a-d were prepared as single diastereoisomers in good
chemical yields from (-)-8-amino menthol in three steps as
summarized in Scheme 1. Condensation of the amino alcohol
with glycolaldehyde dimer at room temperature afforded
nearly quantitative 2-hydroxymethyl perhydro-1,3-benzox-
azine 2, which was transformed into N-allyl derivatives 3a-d
by alkylation with allyl-, crotyl-, methallyl-, and cinnamyl
bromides, respectively, in refluxing acetonitrile and potas-
sium carbonate.17 Swern oxidation18 of 3a-d yielded the
starting compounds 4a-d, respectively, in good yields (70-
74% from 1) as single diastereoisomers.
(9) (a) Ma, Z.; Chu, D. T. W.; Cooper, C. S.; Li, Q.; Fung, A. K. L.;
Wang, S.; Shen, L. L.; Flamm, R. K.; Nilius, A. M.; Alder, J. D.; Meulbroek,
J. A.; Or, Y. S. J. Med. Chem. 1999, 42, 4202. (b) Ma, Z.; Wang, S.; Cooper,
C. S.; Fung, A. K. L.; Lynch, J. K.; Plagge, F.; Chu, D. T. W.
Tetrahedron: Asymmetry 1997, 8, 883.
(10) Schrimpf, M. R.; Tietje, K. R.; Toupence, R. B.; Ji, J.; Basha, A.;
Bunnelle, W. H.; Daanen, J. F.; Pace, J. M.; Sippy, K. B. U.S. Patent PTC
Int. Appl. WO 01 81,347; Chem. Abstr. 2001, 135, 731.
(11) For a recent review of asymmetric 1,3-dipolar cycloaddition
reactions, see: Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863.
(12) For recent examples on intermolecular asymmetric 1,3-dipolar
cycloadditions involving azomethine ylides, see: (a) Fray, A. H.; Meyers,
A. I. J. Org. Chem. 1996, 61, 3362. (b) Kopach, M. E.; Fray, A. H.; Meyers,
A. I. J. Am. Chem. Soc. 1996, 118, 9876. (c) Wittlang, C.; Flo¨rke, V.; Risch,
N. Synthesis 1997, 1291. (d) Enders, D.; Meyer, I.; Runsink, J.; Raabe, G.
Tetrahedron 1998, 54, 10733. (e) Alker, D.; Harwood, L. H.; Williams, C.
E. Tetrahedron Lett. 1998, 39, 475. (f) Alker, D.; Hamblett, G.; Harwood,
L. H.; Robertson, S. M.; Watkin, D. J.; Williams, C. E. Tetrahedron 1998,
54, 6089. (g) Karlsson, S.; Han, F.; Ho¨gberg, H.-E.; Caldirola, P.
Tetrahedron: Asymmetry 1999, 10, 2605. (h) Pandey, G.; Laha, J. K.;
Mchanakrishnan, A. K. Tetrahedron Lett. 1999, 40, 6065. (i) Garner, P.;
Dogan, O.; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.; Zaniewki, R.
Tetrahedron 2001, 57, 71.
(13) For intramolecular asymmetric 1,3-dipolar cycloadditions of azome-
thine ylides, see: (a) Garner, P.; Sunitha, K.; Ho, W.-B-; Youngs, W. J.;
Kennedy, V. O.; Djebli, A. J. Org. Chem. 1989, 54, 2041. (b) Harwood, L.
M.; Lilley, I. A. Tetrahedron Lett. 1993, 34, 537. (c) Harwood, L. M.;
Kitchen, L. C. Tetrahedron Lett. 1993, 34, 6603. (d) Harwood, L. M.; Lilley,
A. I. Synlett 1996, 1010. (e) Garner, P.; Cox, P. B.; Anderson, J. T.;
Protasiewicz, J.; Zaniewki, R. J. Org. Chem. 1997, 62, 493. (f) Drew, M.
G. B.; Harwood, L. M.; Prince, D. W.; Choi, M. S.; Park, G. Tetrahedron
Lett. 2000, 41, 5077. (g) Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T. J.
Chem. Soc., Perkin Trans. 1 2001, 452.
The formation of the unstabilized azomethine ylides was
carried out by decarboxylative condensation of aldehydes
4a-d with N-substituted R-amino acids.19,20 Different reac-
tion conditions were initially tested on compound 4a (Table
1).
Condensation of 4a with N-benzyl glycine hydrochloride
in the presence of potassium carbonate provides, after
decarboxylation, the azomethine ylide, which cyclizes to
yield the cis adduct 5f as a single diastereomer but in low
yield. The change to triethylamine as a base only slightly
increases the yield of the desired adduct. In both reactions
(19) (a) Grigg, R.; Surendrakumar, S.; Thianpatanagul, S.; Vipond, D.
J. Chem. Soc., Chem. Commun. 1987, 47. (b) Grigg, R.; Idle, J.; McMeekin,
P.; Vipond, D. J. Chem. Soc., Chem. Commun. 1987, 49. (c) Grigg, R.;
Idle, J.; McMeekin, P.; Surendrakumar, S.; Vipond, D. J. Chem. Soc., Perkin
Trans. 1 1988, 2703. (d) Nyerges, M.; Bala´zs, L.; Ka´das, I.; Bitter, I.;
Ko¨vesdi, I.; To¨ke, L. Tetrahedron 1995, 51, 6783.
(14) Rassat, A.; Rey, P. Tetrahedron 1974, 30, 3315.
(15) Pedrosa, R.; Andre´s, C.; Iglesias, J. M.; Perez-Encabo, A. J. Am.
Chem. Soc. 2001, 123, 1817.
(16) (a) Pedrosa, R.; Andre´s, C.; Nieto, J. J. Org. Chem. 2002, 67, 782.
(b) Andre´s, C.; Duque-Soladana, J. P.; Pedrosa, R. J. Org. Chem. 1999,
64, 4273.
(17) Pedrosa, R.; Andre´s, C.; Nieto, J. J. Org. Chem. 2000, 65, 831.
(18) Tidwell, T. T. Org. React. 1990, 39, 297.
(20) For examples of intramolecular 1,3-dipolar cycloadditions of
azomethine ylides generated by the decarboxylative route, see: (a) Grigg,
R.; Savic, V.; Thronton-Pett, M. Tetrahedron 1997, 53, 10633. (b) Harling,
J. D.; Orlek, B. S. Tetrahedron 1998, 54, 14905. (c) Lovely, C. J.; Mahmud,
H. Tetrahedron Lett. 1999, 40, 2079. (d) Snider, B. B.; Ahn, Y.; Foxman,
B. M. Tetrahedron Lett. 1999, 40, 3339. (e) Snider, B. B.; Ahn, Y.; O’Hare,
S. M. Org. Lett. 2001, 3, 4217.
2514
Org. Lett., Vol. 4, No. 15, 2002

2-formyl-3-methallyl perhydro-1,3-benzoxazine 4c was trans-
formed into 5c in 90% yield. Nevertheless, under these
conditions the cinnamyl derivative 4d yielded 5d in only
56% yield, and it was necessary to increase the reaction
temperature to reflux and the reaction time to 6 h, using Et3N
as a base to achieve 5d in 76% yield (entries 12 and 13).
Table 1. Dipolar Cycloadditions of Compounds 4a-d
amino
acid
solvent
time
(min) productsa
entry compd
base
(T (°C))
1
2
3
4
4a
4a
4a
4a
N-Bn-Gly K2CO3 DMF (90)
N-Bn-Gly Et3N DMF (90)
N-Ph-Gly Et3N DMF (153)
60 5f (26),
6a (60)
60 5f (38),
6a (46)
300 5e (16),
6a (30)
120 5e (34),
6a (30)
It is noteworthy that the reaction for all the compounds
4a-d was stereospecific, leading to cis,syn-adducts 5a-f
as single diastereoisomers, and other diastereoisomers were
1
not detected on the H NMR of the reaction mixtures. The
relative stereochemistry of the tetracyclic compounds was
determined on the basis of NOESY and COSY experiments.
The values of the coupling constants between H3a and H6a
(8.4-8.9 Hz) point to a cis,syn relationship for the
cycloadducts.20e
N-Ph-Gly none
DMF (90)
5
6
4a
4a
N-Ph-Gly none
N-Me-Gly Et3N DMF (90)
PhCH3 (110) 120 5e (70)
60 5a (61),
6a (25)
60 5a (52),
6a (22)
45 5a (76),
6a (16)
7
8
4a
4a
N-Me-Gly Et3N DMF (153)
Interestingly, the signal for H6 appears as a singlet in the
1H NMR spectra for all the cyclization compounds, indicating
that it does not couple with the vicinal H6a. These data show
that the fusion of the oxazinine ring and the pyrrolidine was
established in a “cis” axial-equatorial fashion, and conse-
quently, the dihedral angle between H6 and H6a is near 90°.
M-Me-Gly none
DMF (153)
9
10
11
12
4a
4b
4c
4d
N-Me-Gly none
N-Me-Gly none
N-Me-Gly none
N-Me-Gly none
DMF (90)
DMF (90)
DMF (90)
DMF (90)
60 5a (94)
45 5b (78)
45 5c (90)
120 5d (56),
The absolute stereochemistry was determined by trans-
formation of 5d into 1-methyl-3-phenyl-5-tosyl octahydro-
pyrrolo[3,4-b]pyrrole 8. Cycloadduct 5d was reduced in 97%
yield with aluminum hydride in THF at -10 °C for 10 min
to 8-aminomenthol derivative 7. The elimination of the
menthol appendage was effected by oxidation of 7 with PCC
in the presence of sodium acetate at room temperature to
the 8-amino menthone derivative, which spontaneously
decomposed to give (+)-pulegone and the diazabicyclic
derivative. This compound was isolated as tosyl derivative
8 in 34% yield by treatment of the reaction mixture with
10% NaOH solution and tosyl chloride. The absolute
configuration of 8 was established as (3R,3aS,6aS) by X-ray
diffraction analysis (Figure 1), corroborating the absolute
configuration of 5d and the stereochemical outcome of the
[3 + 2] dipolar cycloaddition.
6d (18)
360 5d (76)
13
4d
N-Me-Gly Et3N DMF (153)
a Yields in parentheses refer to isolated and pure compounds.
the major product isolated was the 8-allylaminomenthol 6a,
resulting from the hydrolysis of 4a (entries 1 and 2 in Table
1).
The reaction of 4a with N-phenyl glycine in boiling DMF
for 5 h, in the presence of Et3N, yielded a complex reaction
mixture from which 5e and 6a were only isolated in 16 and
30%, respectively. When the reaction was carried out in DMF
at 90 °C for 2 h, in the absence of the base, the adduct 5e
was only isolated in 34%; however, the yield of the desired
cyclization product was improved to 70% when a mixture
of N-phenyl glycine and 4a was boiled in toluene for 2 h
under Dean-Stark conditions (entries 3-5).
The best results were obtained when N-methyl glycine was
used as a condensation amino acid for the formation of the
azomethine ylide. In this way, aldehyde 4a was condensed
with sarcosine (1.5 equiv), in the presence of Et3N (1.5
equiv), in DMF at 90° C for 1 h leading to 5a as a single
diastereoisomer in 61%. When the reaction was carried out
at reflux of the solvent, compound 5a was isolated in only
52% yield. In the absence of Et3N, cycloadduct 5a was
isolated in 76% yield after refluxing a mixture of 4a and
sarcosine for 45 min (entries 6-8). In all these reactions,
16-60% yields of 8-N-allylamino menthol 6a, resulting from
the hydrolysis of 4a, were isolated.
These results indicate that both an increase in the reaction
temperature and the presence of Et3N as a base decreased
the yield of the cyclized product. Then, a mixture of 4a and
sarcosine (1.5 equiv) was heated in DMF for 1 h at 90° C
leading to 5a in excellent yield (94%) as a single diastereo-
isomer. Under the same experimental conditions, 3-crotyl-
2-formyl derivative 4b yielded a single cycloadduct 5b in
78% after heating with sarcosine in DMF for 45 min, and
Figure 1. ORTEP diagram for compound 8.
The cis,syn stereochemistry of the cyclization products can
be only explained by accepting that the [3 + 2] dipolar
cycloaddition occurs with total diastereofacial selectivity
from the conformation shown in Scheme 2. In this confor-
mation, the allyl substituent attached to the nitrogen atom is
Org. Lett., Vol. 4, No. 15, 2002
2515

enantiopure nitrogen heterocycles. Efforts are currently
underway to optimize the reaction yield in both the cyclo-
addition and elimination of the chiral template.
Scheme 2. Proposed Stereochemistry of the Intermediate
Ylide in the Formation of 5a-f
Acknowledgment. We thank the Spanish Ministerio de
Ciencia y Tecnolog´ıa (DGICYT, Project PB98-0361) and
Junta de Castilla y Leo´n (Project VA040-01) for financial
support of this work.
Supporting Information Available: Copies of COSY
and NOESY experiments for 5d, full experimental proce-
dures and physical and spectroscopic data for all the
compounds, and X-ray crystal data, including atomic coor-
dinates, isotropic and anisotropic displacement parameters,
and a listing of bond angles and bond lengths. This material
is available free of charge via the Internet at http://pubs.acs.org.
in an “axial” arrangement, and the reaction occurs only in
an endo mode.
In summary, we have shown that the intramolecular [3 +
2] dipolar cycloaddition of nonstabilized azomethine ylides
with unactivated alkenes performed on a chiral perhydro-
1,3-benzoxazine template occurs with total regio- and
stereoselectivity and provides an efficient synthesis of
OL0261377
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Org. Lett., Vol. 4, No. 15, 2002