1,3-Asymmetric induction via 1,5-hydrogen atom translocation reactions. Highly enantioselective synthesis of β-substituted β-amino acids

Full text of DOI:10.1021/ja961484v

J. Am. Chem. Soc. 1996, 118, 8727-8728
8727
Scheme 1
1,3-Asymmetric Induction via 1,5-Hydrogen Atom
Translocation Reactions. Highly Enantioselective
Synthesis of â-Substituted â-Amino Acids
F. Beaulieu, J. Arora, U. Veith, N. J. Taylor,
B. J. Chapell, and V. Snieckus*
The Guelph-Waterloo Centre for
Graduate Work in Chemistry, UniVersity of Waterloo
Waterloo, Ontario, N2L 3G1, Canada
ReceiVed May 3, 1996
Since the introduction of the 1,5-hydrogen atom translocation
as a new mechanistic concept in radical processes,1 eminent
accomplishments by Curran2a and De Mesmaeker,2b among
others,2c-f have demonstrated its considerable scope and ap-
plication for synthetic methodology. As part of our efforts in
this active area,1c,3 we report on the highly (>95:5) diastereo-
selective transformation of racemic and enantiomerically pure
N-(o-bromo- and -iodobenzoyl)-2-tert-butyl-perhydropyrimidi-
nones 1a,b with electron-deficient alkenes into substituted
products 3a-c (Scheme 1). This aryl to R-amidoyl 1,5-radical
translocation,4 tailored for the first time for 1,3-asymmetric
induction,5 offers a new general route for the synthesis of
unusually functionalized optically active â-substituted â-amino
acids6a such as 7, 8 which are of considerable current interest
as bioactive natural and unnatural entities and as precursors for
â-lactams.6b
Racemic N-o-bromobenzoylperhydropyrimidinone 1a and the
corresponding iodo analogue 1b were prepared7 from â-alanine
in four steps according to the Juaristi-Seebach protocol for the
debromo derivative,8a while enantiomerically pure 1a was
obtained from L-asparagine by a route used for the preparation
of other enantiopure perhydropyrimidinones.8b-11 While 1H and
13C NMR spectra of the pyrimidinones 1a,b displayed high
complexity due to restricted rotation about the amide N-CO
and Ar-CO bonds,1c,3 X-ray crystallographic analysis12 of
enantiomerically pure (-)-1a (Figure 1) showed the heterocyclic
ring in a sofa-like conformation with a quasi axial tert-butyl
group, similar to that described for the debromo analogue and
related derivatives.13 Thus, in the solid state, the equatorial and
axial R-amidoyl hydrogens are located 3.30 and 4.65 Å,
respectively, from the bromo atom, and the tert-butyl group
strongly shields the â-face of the molecule.
To probe the efficacy of the 1,5-hydrogen atom transfer,
pyrimidinone 1a was subjected to tin deuteride/AIBN conditions
to afford deuterated products 5 and 6 (Scheme 2) (89% yield,
53% d1 by MS) in a 7:3 ratio14 which is in good agreement
with corresponding rotamer populations as determined by
variable temperature NMR.15
The results of electrophilic olefin-trapping experiments are
summarized in Table 1. Using standard tin hydride conditions
(11) Hydrogenation of known (S)-2-tert-butyl-1-carbobenzyloxy-2,3-
dihydro-4(1H)-pyrimidinone9a at 35 bar hydrogen pressure over Pd-C at
room temperature gave the saturated 2-tert-butylperhydropyrimidinone in
89% yield. After benzoylation (o-bromobenzoyl chloride/NEt3/THF) fol-
lowed by N-methylation (Me2SO4/NaH/THF), (-)-1a was obtained in 57%
yield after recrystallization. In the preparation of potassium (6S)-2-tert-
butyl-4-pyrimidinone-6-carboxylate from L-asparagine and pivaldehyde,
Juaristi and co-workers report a 86:14 cis:trans isomeric mixture which is
retained upon benzoylation. Acidic workup precipitated the pure cis isomer
(74% yield) (Juaristi, E.; Quintana, D.; Balderas, M.; Garc´ıa-Pe´rez, E.
Submitted for publication in Tetrahedron: Asymmetry. We are grateful to
Dr. Juaristi for providing us with a copy of this manuscript prior to
publication). On the other hand, Konopelski reported the formation only of
the cis isomer which, upon CbzCl treatment and HCl workup, furnished
(2S,6S)-1-Cbz-6-carboxypyrimidinone.9a In the overall conversion of as-
paragine into this product, we detected (NMR) and isolated only the cis
isomer.
(12) Crystal data for (-)-1a, C16H21BrN2O2, Mr ) 353.26, monoclinic,
P21, a ) 8.041(1) Å, b ) 7.495(1) Å, c ) 14.109(2) Å, â ) 99.85(1)°,V
) 837.8(3) Å3, Z ) 2, Dc ) 1.400 g/cm3, µ (Mo KR) ) 24.59 cm-1, F(000)
) 364, T ) 295 K. Data were collected on a Siemens P4 diffractometer
with Mo KR radiation (λ ) 0.71073 Å). 3130 reflections were measured
giving 2914 independent reflections (1457 Friedel pairs). The structure was
solved using Patterson and Fourier routines (SHELXTL Ver.4.2/IRIS) and
refined by full-matrix least-squares on F resulting in final R, wR, and GoF
(for 2288 data with F > 4.0σ(F)) of 0.0367, 0.0260, and 1.78, respectively,
for solution using the S model (for solution of the R model, final R, and
wR values were 0.0675 and 0.0642, respectively).
* Fax: 519-746-5884. E-mail: snieckus@buli.uwaterloo.ca.
(1) (a) Beckwith, A. L. J.; Ingold, K. U. In Rearrangements in the Ground
and Excited States; de Mayo, P., Ed.; Academic: New York, 1980; Vol. 1,
p 161. (b) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem. Soc.
1988, 110, 5900-5902. (c) Snieckus, V.; Cuevas, J.-C.; Sloan, C. P.; Liu,
H.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896-898.
(2) (a) Curran, D. P.; Xu, J. J. Am. Chem. Soc. 1996, 118, 3142-3147
and references cited therein. (b) Denenmark, D.; Winkler, T.; Waldner, A.;
De Mesmaeker, A. Tetrahedron Lett. 1992, 33, 3613-3616. (c) Crich, D.;
Sun, S.; Brunckova, J. J. Org. Chem. 1996, 61, 605-615 and references
cited therein. See also: (d) Booth, S. E.; Benneche, T.; Undheim, K.
Tetrahedron 1995, 51, 3665-3674. (e) Ikeda, M.; Akamatsu, S.; Kugo,
Y.; Sato, T. Heterocycles 1996, 42, 155-158. (f) Gimisis, T.; Chatgilialoglu,
C. J. Org. Chem. 1996, 61, 1908-1909.
(3) Beaulieu, F. Ph.D. Thesis, University of Waterloo, 1994. Arora, J.
M.Sc. Thesis, University of Waterloo, 1995.
(4) For an alternative method of generating R-amidoyl radicals via 1,5-
hydrogen atom translocation, see: Esker, J. L.; Newcomb, M. Tetrahedron
Lett. 1992, 33, 5913-5916. Esker, J. L.; Newcomb, M. J. Org. Chem. 1994,
59, 2779-2786. For radical C-C bond formation by photoinduced electron
transfer in R-silyl carbamates, see: Meggers, E.; Steckhan, E.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2137-2139. Pandey, G.; Reddy,
G. D.; Chakrabarti, D. J. Chem. Soc., Perkin Trans. 1 1996, 219-224.
(5) For 1,2-asymmetric induction via radical intervention, see: Curran,
D. P.; Abraham, A. C. Tetrahedron 1993, 49, 4821-4840.
(6) (a) Review: Cole, D. C. Tetrahedron 1994, 50, 9517-9582. (b)
Georg, G. I. The Organic Chemistry of â-Lactams; VCH: New York, 1993.
(7) â-Alanine was converted into its N-methylamide, which was con-
densed with pivaldehyde to give the Schiff base. Treatment with 2-bromo/
iodobenzoic anhydride in Tol at reflux gave heterocycles 1a and 1b in 31%
and 21% overall yield, respectively.
(13) Seebach, D.; Lamatsch, B.; Amstutz, R.; Beck, A. K.; Dobler, M.;
Egli, M.; Fitzi, R.; Gautschi, M.; Herrado´n, B.; Hidber, P. C.; Irwin, J. J.;
Locher, R.; Maestro, M.; Maetzke, T.; Mourin˜o, A.; Pfammatter, E.; Plattner,
D. A.; Schickli, C.; Schweizer, W. B.; Seiler, P.; Stucky, G.; Petter, W.;
Escalante, J.; Juaristi, E.; Quintana, D.; Miravitlles, C.; Molins, E. HelV.
Chim. Acta 1992, 75, 913-934.
(8) (a) Juaristi, E.; Quintana, D.; Lamatsch, B.; Seebach, D. J. Org. Chem.
1991, 56, 2553-2557. (b) For the synthesis of â-alkyl-â-amino acids by
metalation/electrophile quench from dihydropyrimidinones, see: Chu, K.
S.; Konopelski, J. P. Tetrahedron 1993, 49, 9183-9190.
2
(14) Determined by integration of the H NMR spectra (30.7 MHz).
1
(15) The H NMR spectrum of 1a in CDCl3 or DMSO-d6 exhibits four
resonances for the tert-butyl group at 20 °C (for details, see supporting
information). We believe that the split in the major and minor resonances,
e.g. at 20 °C, is due to restricted rotation about the Ar-C(O) bond, and the
major and minor resonances themselves, e.g. at 60 °C, are due to the Z:E
amide isomerization of (O)C-N bond. At 80 °C, the integration of the
major and the minor peaks correspond to a ratio of 7:3. Overall coalescence
is observed at 100 °C (∆Gq ) 18.7 kcal/mol).
(9) (a) Chu, K. S.; Negrete, G. R.; Konopelski, J. P.; Lakner, F. J.; Woo,
N.-T.; Olmstead, M. M. J. Am. Chem. Soc. 1992, 114, 1800-1812. (b)
Lakner, F. J.; Chu, K. S.; Negrete, G. R.; Konopelski, J. P. Org. Synth.
1995, 73, 201-214.
(10) Juaristi, E.; Quintana, D. Tetrahedron: Asymmetry 1992, 3, 723-
726.
S0002-7863(96)01484-9 CCC: $12.00 © 1996 American Chemical Society

8728 J. Am. Chem. Soc., Vol. 118, No. 36, 1996
Communications to the Editor
Table 2. 1,5-Hydrogen Atom Transfer in Optically Active
N-(o-Bromobenzoyl)-tert-butylpyrimidinone (-)-1a using the
Catalytically Tin Hydride Methoda
addition product
Y
yield, %b ee, % reduction (4), %b
3a
3b
3c
CO2Me
CN
SO2Ph
56
59
50
97
97
98
10
20
41
a Bu3SnCl (0.1 equiv)/NaCNBH3 (2 equiv)/AIBN (cat)/alkene (5
equiv)/t-BuOH/reflux. b All yields refer to isolated and purified (chro-
matographed) materials. By 1H NMR spectroscopy all crude products
showed the presence of only one isomer (dr >95:5); ee’s were measured
on the single pure isomers 3a-c, obtained by flash chromatography.
Scheme 3
Figure 1.
Scheme 2
Table 1. R-Amidoyl Functionalization of Racemic
Perhydropyrimidinones 1a and 1b
obtained in acceptable yields (similar to the racemic series) and
high enantiomeric purity (Table 2).17
addition product
(yield, %)b
reduction (4)
X
conditionsa
Y
(yield, %)b
To demonstrate the utility of the 1,5-hydrogen atom trans-
location for the synthesis of optically active â-amino acids,
compounds 3a-c were treated under acid-catalyzed conditions8a
followed by purification by acidic ion-exchange resin to afford
3-aminoadipic acid 718 and the δ-sulfonyl-substituted analogue
8 in 45-80% yields (Scheme 3).19
In summary, a new highly diastereoselective transformation,
1 f 3, mediated by 1,5-hydrogen atom translocation (2), has
been uncovered. Its generality and application to the synthesis
of â-substituted â-amino acids 7, 8 has been demonstrated. The
broader conceptualization of this 1,3-asymmetric induction
radical process and its application in the design and construction
of optically active, biologically important natural and unnatural
â-amino acids and â-lactams may be anticipated.
Br
Br
I
Br
I
Br
I
A
B
B
B
B
B
B
3a (53)
3a (62)
3a (63)
3b (64)
3b (42)
3c (40)
3c (27)
CO2Me
CO2Me
CO2Me
CN
CN
SO2Ph
SO2Ph
41
16
34
21
57
48
70
a A: Bu3SnH (2 equiv)/AIBN (cat)/alkene (5 equiv)/PhH/reflux
(standard conditions). B: Bu3SnCl (0.1 equiv)/NaCNBH3 (2 equiv)/
AIBN (cat)/alkene (5 equiv)/t-BuOH/reflux. b All yields refer to isolated
and purified (chromatographed) materials. In all cases, 1H NMR spectra
of crude materials showed the presence of only one isomer (dr > 95:
5).
in the presence of methyl acrylate,1c the bromoperhydropyri-
midinone 1a cleanly furnished a mixture of addition product
3a (53% yield, >90% diastereoselectivity) and reduced material
4 (41%). By the application of the catalytic tin method,16 the
yield of the addition product 3a (62%) was improved and the
amount of reduction product 4 (16%) was considerably de-
creased. In the presence of acrylonitrile and phenyl vinyl
sulfone as acceptor olefins, the radical interception products 3b
and 3c were obtained from 1a in 64% and 40% yields,
respectively, together with 21% and 48% reduced material 4.
Trapping the R-amidoyl radical derived from the iodo compound
1b with these alkenes led to predominant amounts of 4. The
substantial difference in amounts of reduction product between
the iodo and the bromo derivatives is not understood and needs
further investigation.
Acknowledgment. Dedicated to Nelson Leonard with respect for
his scientific achievements and his exuberance for chemistry and life.
We are grateful to NSERC Canada and Monsanto for support under
the Industrial Research Chair award.
Supporting Information Available: Detailed description of ex-
perimental procedures for the preparation and reactions of 1, 3a-c, 4,
1
7, 8; H-NMR spectra of 1a, 3a-c, 7, 8, and X-ray data of 1a (26
pages). See any current masthead page for ordering and internet access
instructions.
JA961484V
(17) An (S,S)-Whelk-O1 chiral column was used. Enantiomeric purity
assays were completed with both racemic and enantioenriched materials
and repeated at least once in order to ensure accuracy of the method used.
For details, see supporting information.
When optically active (-)-1a was subjected to the catalytic
tin hydride conditions, the substituted products 3a-c were
(18) Obtained from Sigma/Aldrich as the racemate.
(19) For the synthesis and biological properties of amino sulfonic acids,
see e.g.: Braghiroli, D.; Mussati, E.; Di Bella, M.; Saladini, M. Tetrahe-
dron: Asymmetry 1996, 7, 831-836 and references cited therein.
(16) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303-304.