Stereoselective formation and rearrangement of morpholinium ylides derived from copper carbenoids

Article abstract of DOI:10.1016/S0957-4166(03)00095-8

Amino diazoacetoacetates 4a-e and 7a,b were prepared from readily available amino alcohols and subjected to copper-catalyzed carbene-transfer reaction. Substrates 4c-e furnished the morpholin-2-ones 5c-e in good yield via the corresponding cyclic ammonium ylides, albeit with poor diastereoselectivity. Substrates 4a,b failed to provide the corresponding morpholinones, perhaps as a result of steric congestion. Cyclic substrates 7a,b underwent conversion to bicyclic morpholinones 8 and 9 in good yield and with moderate to good diastereoselectivity. This result is rationalized via control of the transiently stereogenic ammonium center of the intermediate bicyclic ylides.

Full text of DOI:10.1016/S0957-4166(03)00095-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 917–920
Stereoselective formation and rearrangement of morpholinium
ylides derived from copper carbenoids
Kevin W. Glaeske, B. N. Naidu and F. G. West*
Department of Chemistry, University of Utah, 315 S. 1400 East, Rm. 2020, Salt Lake City, UT 84112-0850, USA
Received 20 December 2002; accepted 21 January 2003
Abstract—Amino diazoacetoacetates 4a–e and 7a,b were prepared from readily available amino alcohols and subjected to
copper-catalyzed carbene-transfer reaction. Substrates 4c–e furnished the morpholin-2-ones 5c–e in good yield via the correspond-
ing cyclic ammonium ylides, albeit with poor diastereoselectivity. Substrates 4a,b failed to provide the corresponding morpholi-
nones, perhaps as a result of steric congestion. Cyclic substrates 7a,b underwent conversion to bicyclic morpholinones 8 and 9 in
good yield and with moderate to good diastereoselectivity. This result is rationalized via control of the transiently stereogenic
ammonium center of the intermediate bicyclic ylides. © 2003 Elsevier Science Ltd. All rights reserved.
Ammonium ylides are readily accessible from diazocar-
bonyl precursors and tertiary amines, and their subse-
quent rearrangement by a [1,2]- or [2,3]-shift of one of
the ammonium substitutents introduces functionality
adjacent to the nitrogen.1 We2 and others3 have shown
that this approach can be used for the construction of
amino acid derivatives. Formation of cyclic amino
esters such as morpholin-2-ones 12b or related azlac-
tones 23d is especially appealing (Scheme 1). Tethering
the diazoester metallocarbene precursor to the amine
trap maximizes the efficiency of ylide formation relative
to other normally competitive carbene processes, and
the resulting products are subject to selective processing
to reveal fully substituted amino acid derivatives. More-
over, the starting amino alcohols are readily available
and are easily converted into diazo ester substrates
using standard, high-yielding chemistry.
We have shown that cyclic ammonium salts of known
configuration at nitrogen undergo rearrangement with
good to excellent chirality transfer, involving migration
of benzyl or allylic groups in a facially selective man-
ner.5 Related studies involving catalytic generation and
rearrangement of spirocyclic ammonium ylides via
metallocarbene intermediates also demonstrated a high
Formation of racemic products is an obvious limitation
of this strategy and the power of this methodology
would be greatly leveraged if the new stereogenic center
could be formed with control of configuration.4 Estab-
lishing a particular configuration at the a position
would presumably require prior stereoselective quater-
nization at the ammonium nitrogen atom of the inter-
mediate ylide.
* Corresponding author. Current address: Department of Chemistry,
University of Alberta, W5-67 Gunning-Lemieux Chemistry Centre,
Edmonton, AB T6G 2G2, Canada. Tel.: 780-492-8187; fax: 780-
492-8231; e-mail: frederick.west@ualberta.ca
Scheme 1. Cyclic amino acid derivative via ammonium ylides.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00095-8

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K. W. Glaeske et al. / Tetrahedron: Asymmetry 14 (2003) 917–920
Given the modest selectivity and capricious reactivity
seen in these cases, the configuration of the major
diastereomers of 5d and 5e was not determined.
The low stereoselectivity seen with 4c–e was disappoint-
ing, and indicated that asymmetric centers in a flexible
intervening chain provided very little bias in favor of
one configuration at the ammonium nitrogen. On the
presumption that greater conformational rigidity
should be beneficial in this regard, we next examined
two cyclic cases (Scheme 4). N-Benzylthreonine methyl
ester was converted to oxazolidine 6a by treatment with
formaldehyde in the presence of p-toluenesulfonic acid.
Reduction to the primary alcohol and treatment as
before with diketene and MsN3 furnished diazoacetoac-
etate 7a. In a similar sequence, N-benzylprolinol9 was
converted to diazoacetoacetate 7b. When these sub-
strates were subjected to copper powder in refluxing
toluene, the corresponding fused bicyclic morpholones
8a,b and 9a,b were obtained in 57–67% yield.10 Both
cases showed significant stereoselectivity, especially 7b,
which provided a 4.5:1 ratio of diastereomers 8b and
9b. It was possible to obtain a crystalline sample of
minor diastereomer 9a suitable for X-ray diffraction
analysis,11 and it clearly showed an endo disposition for
the migrating benzyl group. The opposite configuration
at the quaternary carbon was therefore assigned to the
major isomer, and the structures of 8b and 9b were
assigned by analogy.
Scheme 2. Diastereoselective ylide formation via chiral diazo
esters.
Our rationale for the observed stereoselectivity in these
cases is based upon preferred attack by the metallocar-
bene intermediate from the b-face of the 5-membered
heterocycle (Scheme 5) to form ylides 10a and 10b. Two
factors should reinforce this bias. First, the amine
Scheme 3. Preparation and rearrangement of diazoacetoac-
etates 4a–e.
degree of N“C chirality transfer.6 Given this prece-
dent, we were interested in exploring the morpholinone
strategy using amino alcohols possessing a chiral back-
bone (Scheme 2). Such an approach would generate
morpholinium ylides subject to rearrangement as
before, but would rely on preexisting stereogenic cen-
ters to establish the ammonium stereocenter. Herein,
we describe our preliminary results in this study.
Our initial efforts focused on the use of acyclic
ethanolamine derivatives from the chiral pool possess-
ing one or two stereocenters. Thus, treatment of N,N-
dialkylphenylglycinols 3a,b, N-methyl-N-benzylalaninol
3c, N-methyl-N-benzylphenylalaninol 3d and N-
benzylephedrine7 3e with diketene followed by diazo-
transfer with MsN3 furnished substrates 4a–e in good
yield (Scheme 3). Diazoacetoacetates 4c–e underwent
efficient conversion to the corresponding morpholones
5c–e upon treatment with copper powder in refluxing
toluene, but with limited diastereoselectivity. Only the
ephedrine-derived substrate 4e showed any significant
stereoselectivity, suggesting that the presence of a single
stereocenter adjacent to nitrogen was insufficient to
effect selective quaternization of the amine.
Phenylglycinol derivatives 4a and 4b failed to yield any
of the desired morpholones 5a and 5b, perhaps as a
result of high steric demand near the amine nitrogen.8
Scheme 4. Preparation and rearrangement of diazoacetoac-
etates 7a,b.

K. W. Glaeske et al. / Tetrahedron: Asymmetry 14 (2003) 917–920
919
Acknowledgements
This work was supported by the Donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, and by the University of Utah
Research Foundation. The authors also thank Dr. Atta
Arif for assistance in obtaining X-ray crystallographic
data.
References
1. West, F. G.; Clark, J. S. In Nitrogen, Oxygen and Sulfur
Ylide Chemistry; Clark, J. S., Ed.; University Press
Oxford: Oxford, 2002; pp. 115–134.
2. (a) West, F. G.; Glaeske, K. W.; Naidu, B. N. Synthesis
1993, 977–980; (b) West, F. G.; Naidu, B. N. J. Org.
Chem. 1994, 59, 6051–6056.
3. (a) Zaragoza, F. Synlett 1995, 237–238; (b) Wright, D. L.;
Weekly, R. M.; Groff, R.; McMills, M. C. Tetrahedron
Lett. 1996, 37, 2165–2168; (c) Chelucci, G.; Saba, A.;
Valenti, R.; Bacchi, A. Tetrahedron: Asymmetry 2000, 11,
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2002, 4, 765–768; (e) Review: Zaragoza, F. Tetrahedron
1997, 53, 3425–3439.
4. Reviews of asymmetric approaches to unnatural amino
acid derivatives: (a) Willams, R. M. Synthesis of Optically
Active a-Amino Acids, Pergamon: Oxford, 1989; (b)
Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789–12854; (c)
Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517–3599; (d) Cativiela, C.; Diaz-
de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11,
645–732.
5. (a) Glaeske, K. W.; Arif, A. M.; West, F. G. Org. Lett.
1999, 1, 31–33. See also: (b) Pedrosa, R.; Andres, C.;
Delgado, M. Synlett 2000, 893–895; (c) Arbore, A. P. A.;
Cane-Honeysett, D. J.; Coldham, I.; Middleton, M. L.
Synlett 2000, 236–238; (d) Hanessian, S.; Mauduit, M.
Angew. Chem. Int. Ed. 2001, 40, 3810–3813.
6. (a) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994,
116, 8420–8421; (b) Clark, J. S.; Hodgson, P. B. Tetra-
hedron Lett. 1995, 36, 2519–2522; (c) Naidu, B. N.; West,
F. G. Tetrahedron, 1997, 53, 48, 16565–16574; (d) Beall,
L. S.; Padwa, A. Tetrahedron Lett. 1998, 39, 4159–4162;
(e) Padwa, A.; Beall, L. S.; Eidell, C. K.; Worsencroft, K.
J. J. Org. Chem. 2001, 66, 2414–2421; (f) Vanecko, J. A.;
West, F. G. Org. Lett. 2002, 4, 2813–2816; (g) see also
Refs 3a–c.
Scheme 5. Rationale for stereoselective rearrangement of
7a,b.
nitrogen should exist primarily in the invertomer that
places the benzyl group and the carbenoid side chain in
a trans arrangement, with the lone pair cis to the
carbenoid.12 Second, ring-closure to form the cis-fused
bicyclo[4.3.0]nonane ring system 10 should be kineti-
cally favored over closure to the less stable trans-fused
ylides 11. Formation of 8 and 9 then proceeds via N-C
benzyl homolysis and recombination at the adjacent
carbon.13 The major products 8 would result from
migration of the benzyl group along the bottom, exo
face of the bicyclic radical, in analogy to the earlier
monocyclic examples employing stepwise quaterniza-
tion/deprotonation.5a Minor products 9 could arise
from the trans-fused ylides 11, or more likely, via
diffusion of the radical pairs derived from ylides 10.
Since recombination after diffusion is likely to favor
approach of the benzyl group from the more accessible
exo face, the possibility that the observed selectivities
result entirely from this preference cannot be ruled out.
7. Tertiary ethanolamines 3a–e were readily prepared by
reductive amination of the corresponding secondary
amines with benzaldehyde and NaBH3CN/ZnCl2.
8. The congested steric environment of dibenzylamines has
been noted previously: (a) Reetz, M. T.; Drewes, M. W.;
Schmitz, A. Angew. Chem., Int. Ed. Engl. 1987, 26,
1141–1143; (b) Review: Reetz, M. T. Chem. Rev. 1999,
99, 1121–1162.
9. (a) Govindachari, T. R.; Rajagopalan, T. G.;
Viswanathan, N. J. Chem. Soc., Perkin Trans. 1 1974,
1161–1165; (b) Deur, C. J.; Miller, M. W.; Hegedus, L. S.
J. Org. Chem. 1996, 61, 2871–2876.
These preliminary studies have shown that morpholin-
2-ones with a quaternary center at C-3 can be formed
with useful stereoselectivity using readily available
amino acid-derived diazoacetoacetates. This process is
presumed to involve diastereoselective ammonium ylide
formation, followed by facially selective [1,2]-migration
of a benzyl group. Future efforts will include examina-
tion of the corresponding [2,3]-shift chemistry, and
elaboration of the bicyclic morpholones to acyclic a-
quaternary amino acid derivatives.

920
K. W. Glaeske et al. / Tetrahedron: Asymmetry 14 (2003) 917–920
10. Representative experimental procedures: Diazoacetoacetate
7b. Diketene (0.58 mL, 7.5 mmol) was added neat over a
period of 5 min to a 0°C solution of (S)-N-benzylprolinol
(2.65 g, 5.0 mmol) and Et3N (0.69 mL, 5.0 mmol) in 20
mL dry CH2Cl2. The reaction mixture was stirred at 0°C
for 3 h, then solvent and excess diketene were removed
under reduced pressure and the resulting orange liquid
was immediately dissolved in 20 mL CH3CN. To this
solution were added Et3N (0.69 mL, 5.0 mmol), H2O
(0.10 mL, 5.0 mmol) and MsN3 (0.56 mL, 6.5 mmol). The
reaction mixture was stirred at rt for 12 h, then most of
the solvent was removed and the residual oil was dis-
solved in Et2O (100 mL) and washed successively with 1
N NaOH (4×20 mL) and brine (25 mL). The organic
layer was dried (MgSO4), filtered and concentrated, and
the resulting yellow oil was purified by flash chromatog-
raphy (silica gel, 2 cm×15 cm column, 3:1 hexanes/
EtOAc) to give 1.16 g (77%) of 7b as a yellow oil:
[h]2D2=−43.4 (c=0.47, CH2Cl2); Rf 0.24 (7:3 hexanes/
hexanes/EtOAc) to afford 0.182 g (67%) of a 4.5:1 mix-
ture of 8b and 9b. Pure samples of each diastereomer 6b
could be obtained by iterative chromatography. 8b: white
solid (mp 103–105°C; [h]2D2=+62.8 (c=0.05, CH2Cl2); Rf
1
0.33 (7:3 hexanes/EtOAc); IR (KBr) 2977, 1731, cm−1; H
NMR (CDCl3, 300 MHz) l 7.29–7.20 (m, 5H), 4.28 (dd,
1H, J=10.0, 3.2 Hz), 4.04 (dd, 1H, J=10.5, 10.1 Hz),
3.43 (s, 2H), 3.13 (dt, 1H, J=8.6, 5.9 Hz), 2.78 (dt, 1H,
J=7.8, 5.3 Hz), 2.60–2.50 (m, 1H), 2.23 (s, 3H), 1.95–
1.63 (m, 4H); 13C NMR (CDCl3, 75 MHz) l 200.4, 168.3,
136.8, 130.3, 128.5, 126.8, 76.8, 75.3, 51.7, 45.0, 35.4,
27.1, 25.5, 23.4. Anal. calcd for C16H19NO3: C, 70.31; H,
7.01; N, 5.12. Found: C, 70.41; H, 7.07; N, 5.02%. 9b:
yellow oil; [h]2D2=−100.8 (c=0.03, CH2Cl2); Rf 0.31 (7:3
hexanes/EtOAc); IR (thin film) 2948, 1729, cm−1 1H
;
NMR (CDCl3, 300 MHz) l 7.29–7.14 (m, 5H), 4.06 (dd,
1H, J=10.2, 3.0 Hz), 3.36–3.26 (m, 1H), 3.22 (s, 2H),
3.18 (dt, 1H, J=8.1, 2.7 Hz), 3.07 (dd, 1H, J=10.2, 9.6
Hz), 2.65 (dt, 1H, J=8.4, 5.4 Hz), 2.20 (s, 3H), 2.05–1.81
(m, 4H); 13C NMR (CDCl3, 75 MHz) l 201.5, 169.1,
135.6, 130.4, 128.0, 126.9, 76.8, 72.5, 53.2, 45.6, 38.6,
28.6, 27.1, 23.5. Anal. calcd for C16H19NO3: C, 70.31; H,
7.01; N, 5.12. Found: C, 70.07; H, 6.95; N, 4.99%.
11. Crystallographic data (excluding structure factors) for
compound 9a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC 200163. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
12. Vedejs, E.; Arco, M. J.; Powell, D. W.; Renga, J. M.;
Singer, S. P. J. Org. Chem. 1978, 43, 4831–4837. See also
Refs 5a,c and 6a–f.
1
EtOAc); IR (thin film) 2962, 2139, 1718, 1660 cm−1; H
NMR (CDCl3, 300 MHz) l 7.29–7.20 (m, 5H), 4.22 (d,
1H, J=2.1 Hz), 4.19 (d, 1H, J=2.1 Hz), 4.01 (d, 1H,
J=13.2 Hz), 3.41 (d, 1H, J=13.2 Hz), 2.97–2.82 (m, 2H),
2.48 (s, 3H), 2.27 (dd, 1H, J=17.1, 8.4 Hz), 2.00–1.91 (m,
1H), 1.77–1.63 (m, 3H); 13C NMR (CDCl3, 75 MHz) l
189.6, 161.0, 139.1, 128.3, 127.9, 126.6, 76.0, 66.9, 61.7,
59.1, 54.2, 28.1, 28.0, 22.9. Anal. calcd for C16H19N3O3:
C, 63.77; H, 6.36; N, 13.94. Found: C, 63.89; H, 6.41; N,
13.79%. Morpholinones 8b and 9b. A solution of 7b (0.301
g, 1.0 mmol) in dry PhCH3 (20 mL) was added dropwise
via cannula to a refluxing suspension of copper powder
(32 mg, 0.5 mmol) in dry PhCH3 (50 mL) over a period
of 45 min. The addition flask was rinsed with PhCH3 (5
mL) and this solution was added to the reaction mixture.
After an additional 2 h at reflux, the reaction mixture was
cooled, concentrated and the residue was purified by flash
chromatography (silica gel, 4 cm×15 cm column, 7:3
13. The radical–pair mechanism for [1,2]-shifts of ammonium
ylides is well-established. See: Ollis, W. D.; Rey, M.;
Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1 1983,
1009–1027.