2H-Azirine 3-phosphonates: a new class of chiral iminodienophiles. Asymmetric synthesis of quaternary piperidine phosphonates.

Article abstract of DOI:10.1021/ol017289p

[reaction: see text] Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphonates and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts that on hydrogenation afford the first examples of enantiopure quaternary pip

Full text of DOI:10.1021/ol017289p

ORGANIC
LETTERS
2002
Vol. 4, No. 4
655-658
2H-Azirine 3-Phosphonates: A New
Class of Chiral Iminodienophiles.
Asymmetric Synthesis of Quaternary
Piperidine Phosphonates
Franklin A. Davis,* Yongzhong Wu, Hongxing Yan, Kavirayani R. Prasad, and
William McCoull
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@astro.ocis.temple.edu
Received December 21, 2001
ABSTRACT
Diels−Alder reactions of enantiomerically enriched 2H-azirine 3-phosphonates and dienes stereoselectively furnish optically pure, bicyclic
aziridine adducts that on hydrogenation afford the first examples of enantiopure quaternary piperidine phosphonates.
The theoretical, mechanistic, and synthetic chemistry of 2H-
azirines, the smallest unsaturated nitrogen heterocycles, has
Scheme 1
been extensively explored.1 Activated by the high ring strain,
the C-N π-bond and nitrogen lone pair participate in a wide
variety of reactions with electrophiles and nucleophiles,
including cycloaddition reactions. Although simple 2H-
azirines are more reactive than acyclic imines, which are
generally poor dienophiles, they only participate in Diels-
Alder reactions with highly reactive dienes.2 Studies by
Gilchrist and co-workers, however, have shown that activated
azirine 3-carboxylate 2 (R* ) (N,N-diethylsulfamoyl)-
2H-azirines such as 1 are effective iminodienophiles and can
participate in a variety of cycloaddition reactions (Scheme
1).3 These additions were observed to be highly regio- and
stereoselective and were consistent with endo addition of
the azirine to the diene. Because of the remoteness of the
auxiliary from the azirine three-membered ring, in chiral 2H-
isoboronyl) this azirine displays poor diastereoselectivities
in cycloaddition reactions.4 Methods for the asymmetric
synthesis of 1 have not been reported.
Recently we disclosed the first asymmetric synthesis of
2H-azirine 3-phosphonate (R)-(+)-3 by Swern oxidation of
the corresponding NH-aziridine phosphonate (Scheme 1).5,6
2H-Azirine 3-phosphonate 3 is the major product, which was
unexpected because similar oxidations of NH-aziridine
carboxylates afford the 2H-azirine 2-carboxylate exclusively.7
(1) For reviews on the chemistry of azirines, see: (a) Padwa, A.;
Woolhouse, A. D. In ComprehensiVe Heterocyclic Chemistry; Lowowski,
W., Ed; Pergamon Press: Oxford, 1984; Vol. 7, Chapter 5, p 47. (b) Pearson,
W. H.; Lian, B. W.; Bergmeier, S. C.; Padwa, A. ComprehensiVe
Heterocyclic Chemistry II; Pergamon Press: Oxford, 1996; Chapter 1, p 1;
(c) Nair, V. In Heterocyclic Compounds; Hassner, A., Ed.; John Wiley &
Sons: New York, 1983; Chapter 2, p 215. (d) Fowler, F. W. In AdVances
in Heterocyclic Chemistry; Academic Press: New York, 1971; p 45.
(2) For a review, see: Anderson, D. J.; Hassner, A. Synthesis 1975, 483.
(3) For a review, see: Gilchrist, T. L. Aldrichimica Acta 2001, 34, 51.
(4) Alves, M. J.; Bickley, J. F.; Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1, 1999, 1399.
(5) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249.
(6) For the asymmetric synthesis of 2H-azirine 2-phosphonates (up to
52% ee) using the Neber reaction, see: Palacios, F.; de Retana, A. M. O.;
Gil, J. I. Tetrahedron Lett. 2000, 41, 5363.
10.1021/ol017289p CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/01/2002

We attributed this finding to the fact that the acidifying effect
of a C-2 carboxylate ester is much less than the phosphonate
ester: the former cannot easily stabilize a pyramidal R-anion
on an aziridine ring.5 We have found that 2H-azirine
3-phosphonates, a new class of chiral iminodienophiles,
undergo the Diels-Alder reaction with a variety of dienes
and that the adducts are useful precursors of novel enan-
tiopure R-amino phosphonates. R-Amino phosphonates are
important surrogates of R-amino acids and as such exhibit a
range of biological activities.8
Synthesis of 2H-Azirine 3-Phosphonates. Treatment of
dimethyl chloromethylphosphonate (5)9 (2 equiv) and the
anisaldehyde- or the benzaldehyde-derived sulfinimines (S)-
(+)-4a or (S)-(+)-4b10 (1 equiv) with n-butyllithium (2.1
equiv) at -78 °C afforded R-chloro-â-amino adducts
(SS,1S,2R)-(+)-6 (Scheme 2). Flash chromatography gave
equiv of n-BuLi at -78 to rt. The absolute stereochemistry
of these aziridines was based on analogy to (R)-(+)-3,5 and
the cis relationship of the C-2 and C-3 substituents was
assigned by the coupling constant of 7.5 Hz.5,12
The sulfinyl auxiliary in N-sulfinyl aziridines is normally
easily removed under acidic conditions with TFA/MeOH.5,12
Indeed NH-aziridine (-)-8b was obtained in 71% yield using
this protocol. However, application of these conditions to
7a led to decomposition, undoubtedly related to the activating
effect of the p-methoxy group, which results in ring-opening
reactions. The sulfinyl group in 7a,b was readily removed,
without ring-opening, on reaction with 2 equiv of MeMgBr
to afforded methyl p-toluenesulfoxide and NH-aziridines 8a
and 8b in 71-79% yield (Scheme 2).
Swern oxidation [DMSO/(COCl)2 and then Et3N] of (-)-
8a and (-)-8b at -78 °C to rt gave the corresponding 2H-
azirine 3-phophonates (2R)-(+)-9 and 2H-azirine 2-phos-
phonate (2S)-(+)-10 (Scheme 3). The major azirines (+)-9
Scheme 2
Scheme 3
were isolated in 68-72% yield and are characterized by the
C-2 proton at δ 3.1 ppm in the 1H NMR and the absorption
1
at δ 3.9 ppm in the 31P NMR. In the minor isomer the H
and 31P NMR absorptions appear at δ 2.1 and 25.5 ppm,
respectively. 2H-Azirine 3-phophonates (2R)-(+)-9 can be
stored in solution (benzene or toluene) for several days
without decomposition. As neat liquids they decompose in
less than a day and are sensitive to moisture. By contrast
(2S)-(-)-10a was stable for several months.
Cycloaddition Reactions. Diels-Alder reactions were
conducted by stirring 100 equiv of 2,3-dimethylbutadiene
or trans-piperylene with (2R)-(+)-9 for 2-4 days at rt
(Scheme 4). Bicyclic aziridines 11a,b and 12 were isolated
(+)-6a and (+)-6b in 51 and 58% isolated yields, respec-
tively.11 Minor amounts, 10 to 15%, of the other R-chloro-
â-amino isomers were detected by H NMR, but were not
isolated. The R-chloro-â-amino adducts 6 were readily
transformed into the corresponding aziridines (SS,2S,3R)-
(-)-7a,b, in excellent yield (82-85%), by reaction with 1.1
1
(7) Gentilucci, L.; Grijzen, Y.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1995, 36, 4665.
(8) For reviews: (a) Kafarski, P.; Lejczak, B. Phosphorus Sulfur Silicon
1991, 63, 193. (b) Seto, H.; Kuzuyama, T. Nat. Prod. Rep. 1999, 16, 589.
(c) Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological
ActiVity; Kukhar, V. P.; Hudson, H. R., Eds.; Wiley: Chichester, UK, 2000.
(9) For a method to prepare 5, see: Savignac, P.; Petrova, J.; Dreux,
M.; Coutrot, P. Synthesis 1975, 535.
Scheme 4
(10) (a) Davis, F. A.; Zhang, Y.; Andemichael Y.; Fang, T.; Fanelli, D.
L.; Zhang, H., J. Org. Chem. 1999, 64, 1403. (b) Fanelli, D. L.; Szewczyk,
J. M.; Zhang, Y.; Reddy, G. W.; Burns, D. M.; Davis, F. A. Org. Synth.
1999, 77, 50.
(11) We have found it easier to work with dimethyl phosphonate
analogues of aziridine phosphonates rather than the diethyl derivatives 3.
Not only is the diastereoselectivity for the addition of the dimethyl
chloromethylphosphonate anion to the sulfinimine better (dr 72:28 (other
isomers) vs 59:41 for 3) but the products are more easily separated by
chromatography and give simpler NMR spectra.
656
Org. Lett., Vol. 4, No. 4, 2002

as single stereoisomers by flash chromatography in 89-98%
yields. The reaction of (2R)-(+)-9b and 5 equiv of 1-meth-
oxy-3-trimethylsilyloxybuta-1,3-diene (Danishefsky’s diene)
at rt required only 8 h and afforded 13 as a single isomer in
>90% yield. Isolation consisted of passing the reaction
mixture through a short plug of silica gel; longer contact
times resulted in decomposition. This material was sensitive
to moisture and could only be stored for a few days at -10
°C. It is interesting to note that the reaction time for 1 and
this diene was only 15 min,4 suggesting that 2H-azirine
3-carboxylates are more reactive as iminodienophiles than
9. The likely cause for this effect is the greater steric bulk
of the tetrahedral phosphonate group vs the smaller, planar
carboxylate group.
Scheme 5
The stereochemistry of adducts 11-13 was established by
COSY, NOESY, and NOE experiments and was consistent
with exclusive addition of the diene to the less hindered face
of the azirine. In 11a,b, 12, and 13 the H-7 proton appears
as a doublet in the narrow range of δ 3.12-3.27 ppm,
indicative of shielding by the C-C double bond and coupling
with the phosphorus atom (JPH ) 6 Hz). Irradiation of H-7
in 11b resulted in enhancement of the signals for the C-3
and C-4 methyl groups. The assigned regiochemistry of the
unsymmetrical adducts is supported by the C-5 carbon
chemical shifts in 12 and 13 appearing at δ 22.1 and 27.4
ppm, respectively, and coupled with the phosphorus atom
(JPC ) 11 Hz). A COSY spectrum of 12 reveals cross-ring
coupling between H-2 and H-5. Gilchrist observed similar
stereoselective addition of dienes to azirines 1 and 2.4,13
Hydrogenation of Aziridine Adducts. Catalytic hydro-
genation of aryl C-3 aziridines 2-carboxylates and 2-phos-
phonates results in aziridine ring-opening at the C-3-N bond
to furnish R-amino acids12,14 and R-amino phosphonates,
respectively.5,15 Comparable ring-opening of aziridine adducts
11-13 would afford novel, enantiopure R-amino phospho-
nates. Thus catalytic hydrogenation of 11a,b for 2 h (Pd/C/
H2balloon pressure) resulted in two products. The major
products, isolated in 47-49% yield, were identified as
quaternary piperidine phosphonates (2S)-(-)-14a,b, which
resulted from the expected cleavage of the C-7-N bond in
11 (Scheme 5). In each case the 3,4 carbon-carbon double
bond remained intact. The minor products, obtained in 28%
and 13% yield, respectively, were identified as pyridines
15a,b. That the pyridines are derived from 14 was confirmed
by hydrogenolysis of 14a,b to 15 in 64-66% yield. In THF
solvent (-)-11a gave 14 exclusively. Cleavage of a carbon-
phosphorus bond is rare, and to the best of our knowledge
reductive elimination of phosphite under these conditions has
not been described.16,17 Aromatization of the intermediate
piperidine enimine, resulting from 1,2-elimination of HP-
(O)(OMe)2 from 14, must be particularly facile under the
reductive conditions. The piperidines and pyridines had
HRMS and spectral properties consistent with their structures.
Hydrogenation of (-)-12 for 2 h in MeOH resulted in
reduction of the C-C double bond, affording the bicyclic
aziridine (2S,7R)-(-)-16 in 40% isolated yield along with a
complex mixture of products that could not be identified
(Scheme 6). If the hydrogenation of (-)-12 is carried out in
Scheme 6
THF for 6 h, piperidine phosphonate (2S,6R)-(+)-17 was
isolated in 81% yield. That this material results from cleavage
of the C-7-N bond in (-)-16 was demonstrated by the
hydrogenation of 16 to 17. Interestingly, when the bicyclic
aziridine (-)-16 was hydrogenated for 16 h in MeOH, cis-
2-(p-methoxybenzyl)-6-methylpiperidine (18) was obtained
exclusively in 75% yield.18 Products were identified by their
HRMS and had spectral properties consistent with their
structures.
(12) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y.
J. Org. Chem. 1999, 64, 7559.
(13) (a) Bhullar, P.; Gilchrist, T. L.; Maddocks, P. Synthesis 1997, 271.
(b) Alves, M. J.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998, 299.
(14) (a) Davis, F. A.; Liang, C.-H.; Liu, H. J. Org. Chem. 1997, 62,
3796. (b) Davis, F. A.; Zhang, Y.; Rao, A.; Zhang, Z. Tetrahedron 2001,
57, 6345.
(15) Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 1999, 1, 1053.
(16) Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley: New
York, 2000.
The reason the C-C double bond was hydrogenated in
12 but was not in 11 is unclear but may be related to greater
steric hindrance in the latter adduct. We suggest that
(18) Piperidine imines (H2/Pd-C) are stereoselectively reduced to 2,6-
cis-piperidines. See: Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001,
3, 759.
(17) For an example of C-P bond cleavage, see: Berkowitz, D. B.; Bose,
M.; Asher, N. G. Org. Lett. 2001, 3, 2009.
Org. Lett., Vol. 4, No. 4, 2002
657

characterized by HRMS and had spectral properties consis-
tent with its structure. Unfortunately, catalytic hydrogenation
(Pd/C, THF) of 19 resulted in decomposition.
Scheme 7
In summary, enantiomerically enriched 2H-azirine 3-phos-
phonates, a new class of chiral iminodienophiles, afford
bicyclic aziridine Diels-Alder adducts in good to excellent
yields. Hydrogenation of these bicyclic aziridine adducts
results in a ring-opening that affords the first examples of
optically pure quaternary piperidine phosphonates. Continued
hydrogenation of these materials gives pyridines and pip-
eridines.
piperidine 18 results from elimination of methyl phosphite
from 17, as was observed in the formation of pyridines 15,
to furnish an intermediate imine that is stereoselectively
reduced.18 Indeed, hydrogenation of 17 gave 18 (Scheme 6).
We further speculate that the palladium catalyst associates
with the nitrogen and phosphorus atoms, which promotes
1,2-elimination of dimethyl phosphite, to furnish an inter-
mediate imine that was not detected.
Hydrogenolysis of 13 under the standard protocol resulted
in decomposition with a variety of different catalyst [Pd/C,
Pd(OH)2, Pd/BaSO4] and solvent (MeOH, THF, DCM)
combinations. However, exposure to silica gel in CHCl3 for
3 days afforded the ketone (2S,6S,7R)-(+)-19 as a single
isomer in 51% yield (Scheme 7). The aziridine ketone was
isolated by chromatography and proved to be stable for
several weeks at -10 °C, in contrast to 13. This ketone was
Acknowledgment. We thank Professors David R. Dalton
and Scott McN. Sieburth, Temple University, for helpful
discussion. This work was supported by grants from the
National Institutes of Health (GM57870) and the National
Science Foundation.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL017289P
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Org. Lett., Vol. 4, No. 4, 2002