Asymmetric synthesis of 3-phenyl-2,3-methanophenylalanine developed by panning catalysts in a library format

Article abstract of DOI:10.1039/a805454a

Optimal catalysts for the key cyclopropanation step in a synthesis of the title compound were identified by screening libraries of metal complex-ligand combinations; the synthesis was completed, and a derivative of the final product was crystallized to es

Full text of DOI:10.1039/a805454a

Asymmetric synthesis of 3-phenyl-2,3-methanophenylalanine developed by
panning catalysts in a library format
Destardi Moye-Sherman, Mike B. Welch, Joe Reibenspies and Kevin Burgess*
Department of Chemistry, Texas A & M University, PO Box 300012, College Station, TX 77842-3012, USA.
E-mail: burgess@mail.chem.tamu.edu
Received (in Corvallis, OR, USA) 10th July 1998, Accepted 28th September 1998
Optimal catalysts for the key cyclopropanation step in a
synthesis of the title compound were identified by screening
libraries of metal complex–ligand combinations; the synthe-
sis was completed, and a derivative of the final product was
crystallized to establish its solid state conformation.
manually weighing and pipetting catalysts and reagents into 24
glass vials set in wells drilled in a cooled aluminium block.
Other papers from this laboratory describe the procedure used,10
but some critical points are given here. All manipulations prior
to the analysis were done in a glove box to maintain an inert
atmosphere. After the reactions were mostly complete (TLC),
the contents of each vial was manually filtered through a silica
plug, an internal standard was introduced, and the sample was
made up to a standard volume. The analysis was performed
using an HPLC instrument equipped with an autosampler and a
chiral column (Whelk-O SS , Regis Technologies). We estimate
this protocol is one or two orders of magnitude faster than a
conventional approach wherein a researcher would screen 2–3
reactions at a time.
Several generalities became apparent early in these investiga-
tions. First, the weighing errors with respect to the catalyst
precursors became significant if the reactions were performed on
10 mg of diazo compound. The test reactions on a plate format
were therefore performed on a 50 mg scale, and the important
oneswerecheckedonalargerscale. Second, pentaneappearedto
be the best solvent so this medium was used for all the latter
screens.However,thisprovidedastringenttestofreproducibility
in these experiments because the data obtained using relatively
insoluble catalyst precursors in this very apolar medium were
related to the degree of agitation. Small stirrers were used in each
well, but we were unable to arrange it so that they all spun
smoothly; consequently, some reproducibility issues arose.†
Nevertheless, the data obtained from the library screens did
indicate promising catalysts for further development.
Stereoisomers of 2,3-methanophenylalanine, ‘cyclo-Phe’, are
useful phenylalanine surrogates for syntheses of conformation-
ally constrained peptidomimetics.1 They impart very specific
steric perturbations at the C-terminal side or at the N-terminal
side, depending on the cyclo-Phe isomer selected.2 For some
applications, however, it would be desirable to introduce this
type of constraint at the N- and C-termini simultaneously.
Consequently, we set about an asymmetric synthesis of
3-phenyl-2,3-methanophenylalanine, ‘3-Ph-cyclo-Phe’.
H2N
CO2H
H2N
CO2H
H2N
CO2H
H2N
CO2H
Ph
Ph
Ph
Ph
constrains N-terminus
constrains C-terminus
stereoisomers of cyclo-Phe
H2N
Ph
CO2H H2N
CO2H
stereoisomers of 3-Ph-cyclo-Phe
constrain N- and C-termini simultaneously
Ph
Ph
Ph
Davies and co-workers have developed remarkably direct
and effective syntheses of cyclo-Phe stereoisomers that involve
enantio- and regio-selective cyclopropanations of phenyl-
ethene.3 Doyle and co-workers have also shown 1,2-diph-
enylethene is a good substrate for asymmetric cyclopropana-
tions using phenyl diazoacetate.4 While it was apparent that the
target compound identified above could be obtained using a
modification of this approach (Scheme 1), the ideal catalyst for
the cyclopropanation step was unknown. We therefore decided
to screen some options in a library format.5–9 This was done by
O
O
O
O
N
N
N
N
But
But
O
Ph
Ph
Ph
Ph
1
2
O
O
Ph
O
Ph
N
N
N
N
N
Ph
CO2Me
Ph
BocNH
Ph
CO2Me
Ph
Ph
CO2Me
i
ii
Pri
Pri
3
4
N2
Ph
CN
O
Rh
Rh
iii
O
O
Br
N
N
N
O
O
H
BocNH
Ph
CO2H
Ph
H
N
iv
Ph
Ph
SO2C6H4-4-R
NHPri
5
4
6 R = But, Rh2(S-TBSP)
O
Ph
Ph
7 R = C12H25, Rh2(S-DOSP)
Boc-3-Ph-cyclo-Phe
8
AgSbF6 (CuOTf)2•PhH
[RuCl2(C10H14)]2
Sc(OTf)3 Pd(NCMe)2Cl2
A
B
C
D
E
Scheme 1 Reagents and conditions: i, 1,1-diphenylethene (5 equiv.), Rh2(S-
TBSP)4 (1 mol%), 0 °C, 24 h (86%, 97% ee); ii, cat RuCl3, NaIO4, MeCN–
H2O, CCl4, 25 °C, 5 h then (PhO)2P(O)N3, NEt3, ButOH, reflux, 17 h (90%
for 2 steps); iii, LiOH, aq. MeOH, reflux, 4 h (86%); iv, PriNH2,
Me2NCFNMe2·PF6, CH2Cl2, PriNEt2, 0 °C, 30 min, then 50% TFA in
CH2Cl2, 0–25 °C, 45 min, then 4-BrC6H4CO2H, Me2NCFNMe2·PF6,
CH2Cl2, PriNEt2, 25 °C, 45 min (32% for 3 steps).
Several libraries of catalysts were screened to check solvent
effects, and metal–ligand combinations/ratios. This data, not
shown here, enabled us to bias the screening process in later
experiments. Consequently, Fig. 1 refers to a plate screen
performed in the latter part of this work.
Chem. Commun., 1998, 2377–2378
2377

Fig. 1 Enantioselectivity data obtained from a library screen (% yields inset
in columns). Reaction conditions: 1,2-diphenylethene (5 equiv.), metal (5
mol%), ligand:metal ratio = 1.5:1.0, pentane, 0 °C, 24 h.†
Fig. 2 Chem3D diagram of X-ray structure of 3-Ph-cyclo-Phe diamide.
Table 1 Data for catalyst systems tested in conventional waya
NIH for a predoctoral fellowship and TAMU for a Minority
Merit Fellowship. We would also like to thank Alex Porte and
Mark Powell for helpful discussions.
Catalyst
system
Entry
Metal/mol% Ee (%)b
Yield (%)c
1d
2d
3
1B
2A
2B
2C
2D
2D
4D
6
6
6
6
7
5.0
5.0
5.0
5.0
5.0
5.0
5.0
65e
24
3 (9)
62
2
23 (4)f
6 (14)f
Notes and references
4
> 98 (75)
> 98 (69 and 78) 10 (6 and 24)f
> 98
86 (75)
† Four experiments were repeated on the same plate to check reproducibility
in the same library; the worst correspondence of ee values was 26 vs. 6%,
and the best was 19 vs. 18%. Table 1 shows the data obtained from
experiments repeated on a larger scale, run in the conventional way. Five
data points correspond to experiments that were performed in the plate
format. The worst correspondence observed was for entry 5 (98 vs. 69% ee).
In all five cases the ees obtained when the reactions were repeated on a large
scale with efficient stirring were higher than those corresponding to the
plate format.
‡ Percent yield for each well measured vs. an internal standard (1-acena-
phthone): 1A = 12%; 1B = 23%; 1C = 8%; 2A = 18%; 2B = 4%; 2C =
14%; 2D = 6%; 3A = 12%; 3B = 27%; 3C = 2%; 3D = 24%; 4A = 41%;
4B = 13%; 4C = 1%; 4D = 16%; 5A = 29%; 5B = 66%; 5C = 1%; 5E
= 2%; catalyst 7 = 40%.
5
6d
7
8
9
10
11
12
a
1
9 (16)f
10
94
97
97
89
> 98
85
5.0
1.0
0.1
1.0
88
86
63
50
50 mg scale, pentane, 0 °C, 1,2-diphenylethene (5 equiv.), ligand:metal
= 1.5:1.0 for catalysts formed in situ. b Values in parentheses indicate data
obtained in library screen. Isolated yields unless otherwise indicated.
d Reaction run at 25 °C. e > 95% ee after one recrystallization. f Measured
c
vs. internal standard.
§ Both enantiomers of Rh2(TBSP)4 and of Rh2(DOSP)4 are commercially
available from Aldrich, but in each case one is more expensive than the
other.
Data given in Fig. 1 and Table 1 indicate that the Davies/
McKervey catalysts 6 and 7 were the most useful for the desired
transformation. Other combinations gave poor yields and/or
enantioselectivities except for the combination of copper triflate
with ligand 1. This gave product with a moderate enantiose-
lectivity and yield, and the product could be crystallized to
optical purity. This could be useful in some situations because
the latter system, and the Davies/McKervey catalysts 6 and 7,
gave opposite enantiomers of the product.§
The synthesis of Boc-protected 3-Ph-cyclo-Phe was com-
pleted as indicated in Scheme 1. Absolute configurations here
are assigned by extrapolation of Davies’ model for enantiose-
lective cyclopropanations with catalysts like 6 and 7,3,11 hence
this must be regarded as a prediction rather than an established
fact. Finally, a sample of this product was converted into
diamide 8, and single crystals of this material were formed for
X-ray diffraction; a Chem3D diagram of the molecular structure
is given in Fig. 2.¶ The observed o,y angles (87.7, 2152°) do
not correspond closely with any idealized turn structure. The
conformation seems to be governed by the phenyl rings
adopting orientations with their faces beneath the N- and C-
termini, with the N- and C-amide bonds in pseudo-parallel
arrangements below these. Further studies are planned to
elucidate less localized effects of 3-phenyl-cyclo-Phe on
secondary structures.
¶ Crystal data for 8: C26H25N2O2Br·1/2CH2Cl2, M = 519.8 amu, triclinic,
¯
P1, a = 12.423(3), b = 15.348(3), c = 16.332(3) Å, a = 63.02(2), b =
83.46(2), g = 67.87(2)°, V = 2564(1) Å3, Z = 2, T = 193(2) K, m = 1.35
mm21, l = 0.71073 Å, reflections measured: 5045, independent reflec-
tions: 4611, extinction coefficient = 0.0004(3), R(F) [I > 2s(I)] = 0.0865,
wR(F2) [I > 2s(I)] = 0.1118, S(F2) = 0.953. CCDC 182/1020.
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K. B. gratefully acknowledges support from NIH (GM50772
and DA06554) and The Robert A. Welch Foundation; and the
NIH for a Research Career Development Award, and The
Alfred P. Sloan Foundation for a fellowship. D. M. S. thanks
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Communication 8/05454A
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Chem Commun., 1998