Bispalladacycle-catalyzed bronsted acid/base-promoted asymmetric tandem azlactone formation-michael addition

Article abstract of DOI:10.1021/ja106088v

Cooperative activation by a soft bimetallic catalyst, a hard Bronsted acid, and a hard Bronsted base has allowed the formation of highly enantioenriched, diastereomerically pure masked α-amino acids with adjacent quaternary and tertiary stereocenters in a single reaction starting from racemic N-benzoylated amino acids. The products can, for example, be used to prepare bicyclic dipeptides.

Full text of DOI:10.1021/ja106088v

Published on Web 08/17/2010
Bispalladacycle-Catalyzed Brønsted Acid/Base-Promoted Asymmetric
Tandem Azlactone Formation-Michael Addition
Manuel Weber, Sascha Jautze, Wolfgang Frey, and Rene´ Peters*
Institut fu¨r Organische Chemie, UniVersita¨t Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received July 9, 2010; E-mail: rene.peters@oc.uni-stuttgart.de
Table 1. Investigation of the Solvent Effect
Abstract: Cooperative activation by a soft bimetallic catalyst, a
hard Brønsted acid, and a hard Brønsted base has allowed the
formation of highly enantioenriched, diastereomerically pure
masked R-amino acids with adjacent quaternary and tertiary
stereocenters in a single reaction starting from racemic N-
benzoylated amino acids. The products can, for example, be used
to prepare bicyclic dipeptides.
The catalytic asymmetric construction of quaternary stereocenters
has been intensively studied in the past decade and has reached a
high level of productivity for various reaction types.1 In contrast,
entry
solvent
conv. (%)a
yield (%)a
ee (%)b
for the simultaneous formation of adjacent quaternary and tertiary
stereocenters, only a limited number of highly diastereo- and
enantioselective protocols are available.1 Among those, direct
conjugate additions of R-carbonyl-stabilized nucleophiles to acti-
vated olefins2 are very attractive for C-C bond constructions
because of their atom economy and the versatility of the activating
functional groups.3 The step economy can be further increased by
the development of tandem processes, thus allowing the construction
of stereochemically complex and densely functionalized building
blocks employing simple starting materials.4 We present herein a
tandem process in which racemic N-benzoylated amino acids are
transformed in situ into azlactones [oxazol-5-(4H)-ones] that
undergo an enantio- and diastereoselective Michael addition to
enones triggered by a planar chiral bispalladacycle.
Azlactones in their role as masked and activated amino acid
fragments have recently been studied in different types of (orga-
no)catalytic asymmetric reactions.5-11 Their use is particularly
attractive for diversity-oriented synthesis because of the presence
of orthogonal nucleophilic and electrophilic reactive sites. Orga-
nocatalytic 1,4-additions of azlactones to enals using proline-derived
organocatalysts have been reported to proceed with moderate to
good diastereoselectivity and high enantioselectivity.12,13 Moreover,
organocatalytic protocols have lately been developed for highly
reactive Michael acceptors,14-18 whereas the use of the less
electrophilic enones has not been reported before.
1
2
3
4
5
diglyme
CH2Cl2
CH2Cl2 + 0.3 equiv of HOAc
HOAc
16
56
64
83
90
3
25
21
47
46
39
17
39
73
79
HOAc + 30 vol % Ac2O
a Determined by 1H NMR analysis using mesitylene as an internal
standard. b Determined by HPLC.
which also had a positive impact on the product yield (entry 4).
With acetic anhydride as the cosolvent (30 vol %), similar reactivity
with slightly improved enantioselectivity was observed (entry 5).
Various silver salts were subsequently evaluated for catalyst
activation (Table 2). AgOTs (entry 1) and AgOTf (entry 2) gave
similar results (79 and 78% ee, respectively). Catalysts with a
-
carboxylate or the noncoordinating BF4 counterion performed
slightly less well in terms of enantioselectivity (entries 3-5).
Table 2. Investigation of the Catalyst Activation
We recently showed that the bispalladacycle FBIP-Cl19-21 is
able to catalyze the asymmetric Michael addition of R-cyanoacetates
to vinyl ketones, generating a quaternary stereocenter.22 A bimetallic
activation mode23 had received validation by spectroscopic and
kinetic investigations. Utilizing similar reaction conditions for the
addition of azlactone 1a to ꢀ-substituted enone 2A (diglyme, room
temperature, activation of FBIP-Cl with AgOTs for chloride
exchange by the less Lewis basic tosylate) resulted in low
enantioselectivity (39% ee) and poor yield (3%; Table 1, entry 1).24
Using dichloromethane as the solvent resulted in more product
formation but poor enantioselectivity (entry 2), which could be
improved by using acetic acid as an additive (entry 3). However,
much higher enantioselectivity was attained in pure acetic acid,
entry
AgX
additive (mol %) conv. (%)a yield (%)a
dra
ee (%)b
1
2
3
4
5
6
7
AgOTs
AgOTf
AgOAc
AgO2CCF3
AgBF4
AgOTs
AgOTf
AgOAc
AgOTf
-
-
-
90
72
50
58
60
94
89
100
100
40
46
37
44
50
26
83
85
73
98
8
>98:2
96:4
79
78
70
72
74
78
78
78
79
31
-
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
-
-
NaOAc (4)
NaOAc (4)
NaOAc (4)
NaOAc (10)
NaOAc (4)
8
9c
10
a Determined by 1H NMR analysis using mesitylene as an internal
standard. b Determined by HPLC. c The reaction used 2 mol % FBIP-Cl
and 8 mol % AgOTf and was performed at 30 °C with 2 equiv of 2A.
9
12222 J. AM. CHEM. SOC. 2010, 132, 12222–12225
10.1021/ja106088v  2010 American Chemical Society

C O M M U N I C A T I O N S
An improvement of the product yield was achieved by addition
of catalytic amounts of NaOAc (entries 6-9). In contrast, poor
results were obtained in the presence of NaOAc when the catalyst
was not activated by a silver salt (entry 10).
Dienones can be used for a double Michael addition, as
exemplified for dibenzylidene acetone (2N, Scheme 2). Reaction
with N-benzoylglycine (5e) provided the spirocyclic product 7 with
excellent diastereo- and enantioselectivity.
Since the activated catalyst is stable toward acetic anhydride,
the in situ formation of azlactones by O-acylation of N-benzoylated
amino acids 5, generating mixed anhydrides 6 as intermediates,
was envisaged (Scheme 1).
Scheme 2. Double Michael Addition To Form Spirocyclic Product 7
Scheme 1. In Situ Azlactone Formation
Initially, we speculated that the soft bimetallic catalyst would
allow for a transition state 8 in which the azlactone would be
activated by enolization promoted by coordination of the N atom.
On the other side, the enone would be activated as an electrophile
by face-selective coordination of the olefinic double bond to the
carbophilic Lewis acid (Figure 1), similar to our previous
investigations with vinyl ketones and R-cyanoacetates.22 How-
ever, two facts seem to indicate that this mode of operation is
not valid in the present case: (1) useful yields and high
enantioselectivities were achieved only in the presence of acetic
acid as the solvent, suggesting that one component might be
activated by the Brønsted acid rather than by a PdII center; (2)
the expected face selectivity26 for the coordination of E-
configured olefins is not in agreement with the absolute
configuration of the products.27
Application of the reaction conditions optimized for the conjugate
addition of preformed azlactone 1a (see Table 2, entry 9) to a
tandem process (Table 3) resulted in an excellent yield and
diastereoselectivity for the formation of 3aA starting from racemic
N-benzoylalanine (5a), and the enantioselectivity was only slightly
affected (Table 3, entry 1). Changing the substituent R1 at the
enolizable R-C atom to a substituent with larger steric demand than
Me generally resulted in higher enantioselectivity (entries 2-16)
of up to 99% ee (entry 11). For the enone substituents R2 and R3,
the combinations aryl/alkyl (entries 1-5, 8-13, and 16), alkyl/
alkyl (entries 6, 7, and 15) and aryl/aryl (entry 14) were all well-
tolerated and provided good yields and high stereoselectivities.
Examination of various functional groups on aromatic R2 residues
revealed that electronic effects play only a minor role. Substrates
equipped with a π-donor substituent such as p-OMe or p-OH
(entries 3, 4, and 9), a π-acceptor substituent such as p-NO2 (entry
12), or σ-acceptor substituent such as o- or p-Cl (entries 10 and
11) as well as substrates with electron-rich heterocycles such as
2-furyl (entry 13) gave similar results in terms of yield and
enantioselectivity.25
Table 3. Domino Azlactone Formation-Michael Additiona
Figure 1. (left) Initially assumed activation mechanism and (right) modified
working model with a bidentate azlactone coordination mode.
Our modified working hypothesis involves coordination of the
bidentate azlactone to both Pd centers, which strongly activates
the azlactone for enolization.28 NaOAc likely acts as a base to
deprotonate the R-position, forming enolate 9,29 in which the Si
face is blocked by the ferrocene core while the Re face is accessible
for attack by the enone, which is activated by acetic acid (Figure
1). The diastereoselectivity can be explained by assuming that the
transition state adopts a staggered conformation about the develop-
ing C-C bond in which the energy is minimized by π interaction
of the electron-poor enone and the electron-rich enolate possessing
nucleophilic positions at C4 and C225 (Figure 1; see the Supporting
Information for the molecular orbitals involved). A bimetallic
activation mode was further confirmed by control experiments with
ferrocene monopalladacycles,30 which resulted in very low yields
for the conjugate addition product (e14%; see the Supporting
Information).
The synthetic utility of the reaction products was demonstrated
by nucleophilic ring opening of the conjugate addition products
3 (Scheme 3). Treatment with 1 M HCl for 3.5 h at 80 °C
provided R,R-disubstituted R-amino acid 10 as the hydrochloride
salt in good yield and almost diastereomerically pure form.
Quaternary R-amino acids have received considerable interest31
because they lead to unique folding when incorporated into
entry
3
R1
R2
R3
yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
3aA Me Ph
Me 95
Me 92
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
76
93
91
88
92
87
90
3bA Et
3bB Et
3bC Et
3bD Et
3bE Et
3bF Et
3cA n-Pr Ph
3cG n-Pr 4-MeOC6H4
3cH n-Pr 4-ClC6H4
Ph
3,4-(MeO)2C6H3 Me 81
e
4-HOC6H4
4-BrC6H4
Me
Me 43
Me 88
Et 92
Me 90
n-Pr
Me 89 (90)f >98:2
98 (97)f
96
98
99
98
96
9
Me 81
Me 85
Me 82
Me 76
Me 88
Ph 87
Me 64
Me 41
>98:2
>98:2
>98:2
>98:2
>98:2
98:2
10
11
12
13
3cI
n-Pr 2-ClC6H4
3cJ n-Pr 4-O2NC6H4
3cK n-Pr 2-furyl
14g 3cL n-Pr Ph
90
15
3cM n-Pr i-Pr
Ph
>98:2 >97
>98:2 81
16g 3dA Bn
a Reactions were performed with 0.27 mmol of 5 using 2.0 equiv of
2. b Yield of isolated product. c Determined by 1H NMR analysis.
d Determined by HPLC. e The OH group was acylated during the
reaction. f Data in parentheses were obtained in a run using 5.0 mmol of
5c and 1 mol % FBIP-Cl at 40 °C for 20 h. g Using 5 mol % FBIP-Cl,
20 mol % AgOTf, and 25 mol % NaOAc.
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C O M M U N I C A T I O N S
Scheme 3. Formation of Quaternary Amino Acid Derivatives
(5) Reviews: (a) Mosey, R. A.; Fisk, J. S.; Tepe, J. J. Tetrahedron: Asymmetry
2008, 19, 2755. (b) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. ReV.
2007, 36, 1432.
(6) [4 + 2] cycloaddition: Jiang, J.; Qing, J.; Gong, L.-Z. Chem.sEur. J. 2009,
15, 7031.
(7) Steglich reaction: (a) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
11532. (b) Shaw, S. A.; Alema´n, P.; Vedejs, E. J. Am. Chem. Soc. 2003,
125, 13368. (c) Shaw, S. A.; Alema´n, P.; Christy, J.; Kampf, J. W.; Va,
P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925. (d) Joannesse, C.;
Johnston, C. P.; Concello´n, C.; Simal, C.; Philp, D.; Smith, A. D. Angew.
Chem., Int. Ed. 2009, 48, 8914.
(8) Allylic alkylations: (a) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999,
121, 10727. (b) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124,
7256. (c) Trost, B. M.; Ja¨kel, C.; Plietker, B. J. Am. Chem. Soc. 2003,
125, 4438. (d) Uraguchi, D.; Asai, Y.; Ooi, T. Angew. Chem., Int. Ed.
2009, 48, 733.
(9) Nucleophilic ring opening: (a) Seebach, D.; Jaeschke, G.; Gottwald, K.;
Matsuda, K.; Formisano, R.; Chaplin, D. A.; Breuning, M.; Bringmann,
G. Tetrahedron 1997, 53, 7539. (b) Liang, J.; Ruble, J. C.; Fu, G. C. J.
Org. Chem. 1998, 63, 3154. (c) Berkessel, A.; Cleemann, F.; Mukherjee,
S.; Mu¨ller, T. N.; Lex, J. Angew. Chem., Int. Ed. 2005, 44, 807. (d) Yang,
X.; Lu, G.; Birman, V. B. Org. Lett. 2010, 12, 892.
(10) Mannich-type reactions: (a) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem.
Soc. 2008, 130, 14088. (b) Liu, X.; Deng, L.; Jiang, X. W.; Yan, W.; Liu,
C.; Wang, R. Org. Lett. 2010, 12, 876.
(11) Aldol-type additions: (a) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am.
Chem. Soc. 2009, 131, 3430. (b) Misaki, T.; Takimoto, G.; Sugimura, T.
J. Am. Chem. Soc. 2010, 132, 6286.
peptides as well as increased hydrophobicity and stability against
peptide degradation.31,32 Treatment of 3 with MeOH/TMSCl12
furnished proline derivative 11 as a single diastereomer with
one tertiary and two quaternary stereocenters. Unprotected
L-alanine gave direct access to bicyclic dipeptide 12, which also
contains two quaternary centers (56% yield over two steps from
racemic N-benzoylalanine)33,34 and was used to determine the
absolute configuration of the conjugate addition product 3aA
by X-ray crystal structure analysis (Scheme 3).35
In conclusion, we have reported the first catalytic asymmetric
conjugate addition of azlactones to enones. This task was ac-
complished by cooperative activation using a soft bimetallic catalyst,
a Brønsted acid, and a Brønsted base. Because of the robustness
of the FBIP catalyst toward acetic anhydride as a cosolvent in acetic
acid, a tandem azlactone formation-Michael addition was devel-
oped to generate in a single step diastereomerically pure and highly
enantioenriched masked amino acids with adjacent quaternary and
tertiary stereocenters starting from commercial racemic N-benzoyl
amino acids.
(12) Cabrera, S.; Reyes, E.; Alema´n, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen,
K. A. J. Am. Chem. Soc. 2008, 130, 12031.
(13) Hayashi, Y.; Obi, K.; Ohta, Y.; Okamura, D.; Ishikawa, H. Chem.sAsian
J. 2009, 4, 246.
(14) Nitroolefins: Alema´n, J.; Milelli, A.; Cabrera, S.; Reyes, E.; Jørgensen,
K. A. Chem.sEur. J. 2008, 14, 10958.
(15) Bis(phenylsulfonyl)ethylene: Alba, A.-N. R.; Companyo´, X.; Valero, G.;
Moyano, A.; Rios, R. Chem.sEur. J. 2010, 16, 5354.
(16) Acyl phosphonates: Jiang, H.; Paixa˜o, M. W.; Monge, D.; Jørgensen, K. A.
J. Am. Chem. Soc. 2010, 132, 2775.
(17) Acyl benzotriazoles: Uraguchi, D.; Ueki, Y.; Ooi, T. Science 2009, 326,
120.
(18) Maleimides: Alba, A.-N. R.; Valero, G.; Calbet, T.; Font-Bard´ıa, M.;
Moyano, A.; Rios, R. Chem.sEur. J. [Online early access]. DOI: 10.1002/
chem.201000239. Published Online: June 28, 2010.
(19) (a) Jautze, S.; Seiler, P.; Peters, R. Angew. Chem., Int. Ed. 2007, 46, 1260.
(b) Jautze, S.; Seiler, P.; Peters, R. Chem.sEur. J. 2008, 14, 1430. (c)
Jautze, S.; Diethelm, S.; Frey, W.; Peters, R. Organometallics 2009, 28,
2001.
(20) Recent reviews about palladacycles: (a) Djukic, J.-P.; Hijazi, A.; Flack,
H. D.; Bernardinelli, G. Chem. Soc. ReV. 2008, 37, 406. (b) Dupont, J.;
Pfeffer, M. Palladacycles; Wiley-VCH: Weinheim, Germany, 2008. (c)
Richards, C. J. In Chiral Ferrocenes in Asymmetric Catalysis; Dai, L.-X.,
Hou, X.-L., Eds.; Wiley-VCH, Weinheim, Germany, 2010; pp 337-368.
(21) First preparation of chiral ferrocenyl imidazolines: Peters, R.; Fischer, D. F.
Org. Lett. 2005, 7, 4137.
(22) Jautze, S.; Peters, R. Angew. Chem., Int. Ed. 2008, 47, 9284.
(23) Selected reviews about bimetallic catalysis: (a) van den Beuken, E. K.;
Feringa, B. L. Tetrahedron 1998, 54, 12985. (b) Shibasaki, M.; Kanai,
M.; Matsunaga, S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117.
(24) Selected recent applications of imidazolines as chiral ligands in asymmetric
catalysis: (a) Enthaler, S.; Hagemann, B.; Bhor, S.; Anilkumar, G.; Tse,
M. K.; Bitterlich, B.; Junge, K.; Erre, G.; Beller, M. AdV. Synth. Catal.
2007, 349, 853. (b) Nakamura, S.; Hyodo, K.; Nakamura, Y.; Shibata, N.;
Toru, T. AdV. Synth. Catal. 2008, 350, 1443. (c) Arai, T.; Yokoyama, N.
Angew. Chem., Int. Ed. 2008, 47, 4889. (d) Busacca, C. A.; Lorenz, J. C.;
Grinberg, N.; Haddad, N.; Lee, H.; Li, Z.; Liang, M.; Reeves, D.; Saha,
A.; Varsolona, R.; Senanayake, C. H. Org. Lett. 2008, 10, 341. (e) Review:
Liu, H.; Du, D.-M. AdV. Synth. Catal. 2009, 351, 489.
Acknowledgment. This work was financially supported by F.
Hoffmann-La Roche. We thank Dr. Martin Karpf (F. Hoffmann-
La Roche) for critical reading of this paper.
Supporting Information Available: General experimental infor-
mation, NMR spectra, HPLC data, and crystallographic data (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, Germany,
2005. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473. (c)
Trost, B. M.; Jiang, C. Synthesis 2006, 3, 369.
(2) Selected examples: (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
2003, 125, 11204. (b) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313. (c) Okino, T.; Hoashi,
Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127,
119. (d) Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli, A.; Locatelli, M.;
Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew. Chem., Int. Ed.
2006, 45, 4966. (e) Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M.
Nat. Chem. 2010, 2, 192.
(25) Although C2 versus C4 regioselectivity can be an issue for the reaction of
azlactones with electrophiles,16,17 C2 alkylation was not detected in any
case in the present studies.
(26) Fischer, D. F.; Barakat, A.; Xin, Z.-q.; Weiss, M. E.; Peters, R. Chem.sEur.
J. 2009, 15, 8722.
(27) Moreover, cyclic Z-configured enones such as cyclohexenone gave no
conjugate addition product at all, although activation of Z-configured olefins
with FBIP was previously found to be more efficient than for the
E-configured isomers.19b Similarly, Z-configured olefins were also found
to be the only reactive isomers with a Pt catalyst containing the same
ferrocene bisimidazoline backbone. See: Huang, H.; Peters, R. Angew.
Chem., Int. Ed. 2009, 48, 604.
(3) Selected recent reviews about asymmetric conjugate additions: (a) Christ-
offers, J.; Koripelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 1279. (b)
Alexakis, A.; Ba¨ckvall, J.-E.; Krause, N.; Pa`mies, O.; Die´guez, M. Chem.
ReV. 2008, 108, 2796. (c) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.;
Minnaard, A. J.; Feringa, B. L. Chem. ReV. 2008, 108, 2824. (d) Enders,
D.; Wang, C.; Liebich, J. X. Chem.sEur. J. 2009, 15, 11058. (e) Jautze,
S.; Peters, R. Synthesis 2010, 365.
(4) Reviews about catalytic asymmetric tandem reactions: (a) Enders, D.;
Grondal, C.; Huettl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (b)
Chapman, C. J.; Frost, C. G. Synthesis 2007, 1. (c) Pellissier, H. Tetrahedron
2006, 62, 2143.
(28) The O-acylated azlactones were present only in minute quantities, as
determined by GC-MS and NMR analyses.
(29) Acetate also binds to the activated catalyst (X ) OAc in Figure 1), as
determined by 1H NMR analysis.
(30) Ferrocenyl monoimidazoline palladacycles: see ref 26 and: (a) Peters, R.;
Xin, Z.-q.; Fischer, D. F.; Schweizer, W. B. Organometallics 2006, 25,
2917. (b) Weiss, M. E.; Fischer, D. F.; Xin, Z.-q.; Jautze, S.; Schweizer,
W. B.; Peters, R. Angew. Chem., Int. Ed. 2006, 45, 5694. (c) Fischer, D. F.;
Xin, Z.-q.; Peters, R. Angew. Chem., Int. Ed. 2007, 46, 7704. (d) Xin, Z.-
q.; Fischer, D. F.; Peters, R. Synlett 2008, 1495. (e) Peters, R.; Xin, Z.-q.;
Maier, F. Chem.sAsian J. 2010, 5, 1770.
9
12224 J. AM. CHEM. SOC. VOL. 132, NO. 35, 2010

C O M M U N I C A T I O N S
(31) (a) Vogt, H.; Bra¨se, S. Org. Biomol. Chem. 2007, 5, 406. (b) Cativiela, C.;
D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007, 18, 569.
(32) (a) Tanaka, M. Chem. Pharm. Bull. 2007, 55, 349. (b) Giannis, A.; Kolter,
T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (c) Khosla, M. C.;
Stachowiak, K.; Smeby, R. R.; Bumpus, F. M.; Piriou, F.; Lintner, K.;
Fermandjian, S. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 757.
constrained Val-Phe dipeptidomimetics was recently reported. See:
Gilleron, P.; Millet, R.; Domarkas, J.; Farce, A.; Houssin, R.; He´nichart,
J.-P. J. Pept. Sci. 2006, 12, 140.
(35) Supplementary crystallographic data for 12 have been deposited with the
Cambridge Crystallographic Data Centre (CCDC) under deposition number
CCDC 780031. These data are available from the CCDC at http://
www.ccdc.cam.ac.uk/products/csd/request/.
(33) For nucleophilic ring opening with O-protected amino acids and further
derivatization of azlactones, see refs 5, 8d, and 12.
(34) The synthesis of a structurally related bicyclic compound lacking quaternary
stereocenters (six steps, yield 2.7%) for the preparation of conformationally
JA106088V
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