Synthesis and resolution of β2,2-HBin, the first enantiomerically stable β-amino acid with chirality only due to axial dissymmetry

Article abstract of DOI:10.1016/S0957-4166(01)00435-9

The first gem-disubstituted β^2,2-amino acid possessing only axial chirality, was synthesized by bis-alkylation of methyl or ethyl cyanoacetate with both racemic and enantiomerically pure (R)-2,2′-bis-(bromomethyl)-1,1′-binaphthyl, followed by N

Full text of DOI:10.1016/S0957-4166(01)00435-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2571–2580
Synthesis and resolution of b2,2-HBin, the first enantiomerically
stable b-amino acid with chirality only due to axial dissymmetry
Anne Gaucher, Yohan Zuliani, Daniel Cabaret, Michel Wakselman and Jean-Paul Mazaleyrat*
SIRCOB, University of Versailles, F-78000 Versailles, France
Received 6 September 2001; accepted 5 October 2001
Abstract—The first gem-disubstituted b2,2-amino acid possessing only axial chirality, was synthesized by bis-alkylation of methyl
or ethyl cyanoacetate with both racemic and enantiomerically pure (R)-2,2%-bis-(bromomethyl)-1,1%-binaphthyl, followed by
NaBH4/CoCl2 reduction of the cyano group, treatment of the resulting amino esters with Boc2O and finally saponification of the
ester function, to afford the C- and/or N-protected derivatives of 2%,1%:1,2;1%%,2%%:3,4-dinaphthcyclohepta-1,3-diene-6-aminomethyl-
6-carboxylic acid: (RS)- and (R)-X-b2,2-HBin-OR (X=Boc; H) (R=Me, Et or H). For the medium-scale resolution of b2,2-HBin,
the racemic amino esters (RS)-H-b2,2-HBin-OR (R=Me, Et) were treated with benzoic anhydride and the resulting derivatives
(RS)-Bz-b2,2-HBin-OR were saponified. The obtained (RS)-Bz-b2,2-HBin-OH was coupled with
L
-phenylalanine cyclohexylamide
by the EDC/HOBt method to afford the dipeptide diastereoisomers Bz-(R)-Bin-
L
-Phe-NH-C6H11 and Bz-(S)-Bin- -Phe-NH-
L
C6H11, which were separated by chromatography. Complete hydrolysis under acidic conditions, followed by esterification of the
resulting free amino acid enantiomers, N-protection and saponification, led to the enantiomerically pure derivatives (R)- and
(S)-X-b2,2-HBin-OR (X=Boc; H) (R=Me, H). © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
oligomers of a-amino acids and Ca,a-disubstituted
glycines: 3.613 (a) and 310 helices.7
The field of b-peptides has attracted considerable inter-
est in the past few years1,2 following the extensive
studies of Seebach,1–5 Gellman1,6 and other groups,1
who have shown that b-peptides may adopt stable
secondary structures of an even greater variety than
their a-peptide counterparts. Besides parallel and
antiparallel sheet structures, two turn motifs and at
least two new stable helical conformations: 314 and 2.512
helices,1–6 have been discovered in oligomers of b-
amino acids, different in nature from those adopted by
In previous studies, we have shown that the Ca,a-disub-
stituted glycines Bip and Bin8 possessing only axial
chirality, behave as helix inducers in short-chain pep-
tides.9 In connection with this, we found it interesting
to synthesize b2,2-HBip and b2,2-HBin (Fig. 1),10 which
are b-analogues of Bip and Bin. However, although
conformational analysis of the homopeptides Boc-(b2,2
-
HBip)n-OMe suggested the concomitant occurrence of
intramolecularly H-bonded forms of different ring size
Figure 1. Structure of the axially dissymmetric b2,2-HBip and b2,2-HBin residues.
* Corresponding author. E-mail: jean-paul.mazaleyrat@chimie.uvsq.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00435-9

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A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
in these oligomers, precise structural information could
not be obtained, presumably because of the conforma-
tional lability of the b2,2-HBip residue.11
thyl-substituted 3-amino-2,2-dimethylpropanoic acid
(homo-aminoisobutyric acid: b2,2-HAib),14 or a di-
naphtho-1-aminomethyl-cycloheptane carboxylic acid
related to the 1-aminomethylcycloalkane carboxylic
acid series b2,2-HAcnc previously investigated by See-
bach et al.4 It is also the first i-amino acid with chirality
only due to axial dissymmetry. Furthermore, in contrast
to b2,2-HBip, it is expected to be conformationally
stable even at high temperatures, according to the
known very high conformational stability of 2,2%-
bis(methylene)-substituted-1,1%-binaphthyls.15
Since the folding patterns of peptides based on the
corresponding axially chiral and conformationally rigid
b
2,2-HBin residue could probably be more easily investi-
gated, both in the solid state (because of expected
higher crystallinity) and in solution (where simpler FT-
1
IR and H NMR absorption spectra are expected) we
targeted the synthesis of both enantiomers of b2,2-HBin
in enantiomerically pure form. Herein, we report (i) the
direct preparation of a sample of protected (R)-b2,2
-
HBin from the known enantiomerically pure (R)-2,2%-
bis(bromomethyl)-1,1%-binaphthyl, allowing the
2. Results and discussion
determination of both its absolute configuration and its
2.1. Direct synthesis of C- and N-protected derivatives
of (R,S)-b2,2-HBin and (R)-b2,2-HBin
maximum specific rotation10 and (ii) the resolution of
racemic b2,2-HBin using
L-phenylalanine cyclohexyl-
amide as chiral auxiliary, according to the method
proposed for the a-amino acids by Obrecht et al.12 and
previously applied by us in the successful resolution of
the Bin residue,13 allowing access to relatively large
quantities of both enantiomers. The preparation of
other enantiopure or achiral geminally disubstituted
As in the previously observed bis-alkylation of benzyli-
dene derivatives of glycine esters,5 a,a-bis-alkylation of
the active methylene of ethyl or methyl cyano-acetate in
DMF/K2CO3 at 20°C, using both racemic (RS)- and
enantiomerically pure (R)-2,2%-bis(bromomethyl)-1,1%-
binaphthyl,16 as the alkylating agent, readily furnished
the cyanoesters (RS)-1a (94%), (RS)-1b (91%) and (R)-
1a (79%) with [h]25456=−358 (c 0.3; MeOH) (Fig. 2) in
b-amino acids has been recently reviewed.2 The b2,2
-
HBin residue may be regarded as either a 1,1%-binaph-
Figure 2. Synthetic scheme for the preparation of the a,a-disubstituted-b-aminoacid derivatives (RS)- and (R)-b2,2-HBin 2–7 (only
the R configuration of the binaphthyl unit is represented). (i) EtOOC–CH2–CN or MeOOC–CH2–CN, DMF, K2CO3; (ii) NaBH4,
CoCl2, MeOH; (iii) Boc2O, CH3CN; (iv) 1N NaOH, MeOH, 80°C; (v) TFA:CH2Cl2 1:1; (vi) Bz2O, CH3CN.

A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
2573
2.2. Resolution of (RS)-b2,2-Hbin
excellent yields. The cobalt(II)-assisted selective reduc-
tion method of nitriles in the presence of an ester
function,17 was applied to the gem-cyanoesters 1a and
1b which, upon treatment with sodium borohydride (10
equiv.) and cobalt(II) chloride (2 equiv.) in methanol at
room temperature, gave the amino esters H-b2,2-HBin-
OEt (R,S)-2a (53%), (R)-2a (59%) with [h]25456=−297 (c
0.2; MeOH) and H-b2,2-HBin-OMe (RS)-2b (67%). The
harshly acidic workup necessary for decomposition of
the Co2B complexes is probably responsible for the
relatively low chemical yields. The alternative Raney-Ni
reduction method has been reported to work efficiently
for similar gem-cyanoesters.4a
We decided to follow Obrecht’s resolution conditions12
as closely as possible because they have previously been
demonstrated to be efficient in the resolution of the
corresponding a,a-disubstituted a-amino acid, Bin.13
Therefore, a benzoyl group was chosen for protection
of the amino function of the racemic amino esters
(RS)-2a and (RS)-2b, which were treated with benzoic
anhydride Bz2O in acetonitrile at room temperature, to
give Bz-b2,2-HBin-OEt (RS)-6a (92%) and Bz-b2,2
-
HBin-OMe (RS)-6b (86%) (Fig. 2). Saponification of
the ester function of (RS)-6a and (RS)-6b in aqueous
1N NaOH/MeOH at ca. 80°C, afforded the N-pro-
tected amino acid Bz-b2,2-HBin-OH (RS)-7 (96%). This
The N-Boc-protected derivatives were synthesized in
two steps from the C-protected derivatives 2a and 2b,
which were first treated with di-tert-butyl dicarbonate
in acetonitrile at room temperature18 to give the fully
protected compounds Boc-b2,2-HBin-OEt (RS)-3a
(89%), (R)-3a (63%) with [h]25456=−178 (c 0.2; MeOH)
and Boc-b2,2-HBin-OMe (RS)-3b (93%). Saponification
of the ester function of 3a and/or 3b, performed in
aqueous 1N NaOH/MeOH at ca. 80°C, a relatively
high temperature often required for a,a-disubstituted-
amino esters,4a,8b afforded the N-Boc protected amino
acids Boc-b2,2-HBin-OH (R,S)-4 (98%) and (R)-4 (99%)
with [h]25456=−153 (c 0.2; MeOH). Finally, cleavage of
the Boc group of samples of 4 in TFA/CH2Cl2 (1:1) at
room temperature led to the free amino acid tri-
fluoroacetates H-b2,2-HBin-OH.CF3COOH (RS)-5
(62%) and (R)-5 (57%) with [h]25456=−255 (c 0.2;
MeOH).
compound was coupled with
L-phenylalanine cyclo-
hexylamide, prepared as previously described,12 by
using the EDC/HOBt method in CH2Cl2/THF at room
temperature, to give a 1:1 mixture of diastereoisomeric
dipeptides Bz-(R)-b2,2-HBin-
L
-Phe-NH-C6H11 (R,S)-8
and Bz-(S)-b2,2-HBin-
L
-Phe-NH-C6H11 (S,S)-8 (Fig. 3)
in 78% yield after chromatography. However, in con-
trast to the case of Bin, where the corresponding (RS)-
dipeptide diastereoisomer could be easily separated by
crystallization because of its high crystallinity from
ethyl acetate,13 attempts at the separation of (R,S)-8
and (S,S)-8 by crystallization were unsuccessful, as only
an amorphous white solid consisting of a mixture of
isomers could be obtained. Fortunately, these two
diastereoisomers, which presented distinct spots of close
Rf on analytical TLC, could be separated by HPLC on
silica gel (conventional column chromatography or
preparative TLC was only successful on very small
scale), leading to pure (R,S)-8 with [h]25456=−11 (c 0.1;
Figure 3. Resolution of (RS)-b2,2-HBin. (i) H-
L-Phe-NH-C6H11, EDC, HOBt, CH2Cl2/THF, rt; (ii) 1. 35% aq. HCl (10
M)/dioxane (1:1 vol./vol.), 110°C, 6–8 days. 2. MeOH/98% H2SO4 (cat.), reflux, 3 days; (iii) Boc2O, CH3CN; (iv) 1N NaOH,
MeOH, 80°C.

2574
A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
MeOH) in 95% yield19 and (S,S)-8 with [h]25456=+141 (c
0.15; MeOH) in 56% yield.19 The absolute configuration
of the binaphthyl unit in the two diastereoisomers was
established according to the further recovery of (R)-2b,
(R)-3b and (R)-4 from (R,S)-8 and of (S)-2b, (S)-3b
and (S)-4 from the acidic hydrolysis of (S,S)-8 (vide
infra).
worthy that splitting of NMR signals of the two
diastereoisomers occurred in spite of the b position of
the chiral carbon atom of the Mosher’s reagent. The
very high enantiomeric purity of the recovered samples
of (R)-2b and (S)-2b demonstrates the expected absence
of racemization of the 2,2%-substituted-1,1%-binaphthyl
unit,15 also previously observed for the corresponding
Bin derivatives,13 under the rather drastic experimental
conditions of hydrolysis of the dipeptides (R,S)-8 and
(S,S)-8.
Acid hydrolysis of (R,S)-8 and (S,S)-8 was performed
in a 1:1 mixture of 10N aqueous HCl and dioxane at
110°C for several days, which effected cleavage of all
the amide functions in a single step. The resulting free
amino acids H-b2,2-HBin-OH·HCl (R)-5 and (S)-5,
respectively, were not purified but directly esterified in
refluxing methanol/H2SO4 to the corresponding amino
esters H-b2,2-HBin-OMe (R)-2b (68%,19 crude) and (S)-
2b (75%,19 crude). Again, it was found more convenient
to complete to a chromatographic purification only
after the next step of N-protection by a tert-butyloxy-
carbonyl (Boc) group. Therefore, these crude amino
esters were treated with an excess of Boc2O in acetoni-
trile at room temperature and the crude reaction prod-
ucts purified by column chromatography to afford the
corresponding Boc-b2,2-HBin-OMe (R)-3b (69%) with
[h]25546=−180 (c 0.2; MeOH) and (S)-3b (65%) with
[h]25546=+179 (c 0.2; MeOH). From these analytically
pure fully protected derivatives, it was easy, when
required, to either hydrolyze the Boc protecting group
with TFA/CH2Cl2 (1:1) at room temperature back to
In conclusion, the present medium scale resolution of
the readily available racemic b2,2-HBin residue to afford
both of its enantiomers in enantiomerically pure form
(or nearly so) and in ca. 30% overall yield,19 has shown
that the efficient method of Obrecht et al.12 for resolu-
tion of a,a-disubstituted a-amino acids, using L-phenyl-
alanine cyclohexylamide as resolving agent, can be
extended not only to a-amino acids with axial chirality
instead of stereogenicity at the a-carbon,13 but also to
axially dissymmetric a,a-disubstituted b-amino acids.
As emphasized earlier, b2,2-HBin is the lead of a new
class of axially chiral b-amino acids, potentially useful
for the synthesis of new catalysts and new conforma-
tionally constrained peptides with atropisomerism. The
synthesis of b-peptides based on (S)- or (R)-b2,2-HBin
with a view to their conformational analysis is currently
in progress. Interesting initial targets are the homopep-
tides (b2,2-HBin)n in connection with the corresponding
the crude but analytically pure free amino esters H-b2,2
-
series of b2,2-HAcnc4 and (b2,2-HBip)n
previously
11
HBin-OMe (R)-2b (98%) with [h]25456=−289 (c 0.1;
MeOH) and (S)-2b (99%) with [h]25456=+299 (c 0.1;
MeOH), or to proceed to saponification of the ester
function in aqueous 1N NaOH/MeOH at ca. 80°C, to
afford the analytically pure crude N-Boc protected
amino acids Boc-b2,2-HBin-OH (R)-4 (94%) with
[h]25546=−200 (c 0.2; MeOH) and (S)-4 (73%) with
[h]25546=+215 (c 0.2; MeOH).
investigated, as well as the cyclopeptides c[b2,2-HBin]n
as potential inducers of new chiral tubular struc-
tures.5,22
3. Experimental
3.1. General
As already pointed out, the absolute configuration of
the b2,2-HBin derivatives 2b, 3b and 4 resulting from
resolution was readily established by comparison of the
signs of their optical rotation with those of the deriva-
tives of (R)-configuration resulting from direct synthe-
sis. In the same manner, the enantiomeric purity of the
(R)- and (S)-enantiomers obtained by resolution was
shown to be very high, according to the observed
absolute values of their specific rotations, which were
similar to the ones of the corresponding enantiomeri-
cally pure samples resulting from direct synthesis. A
more precise determination of the enantiomeric excess
of the resolved H-b2,2-HBin-OMe (R)-2b and (S)-2b
enantiomers was performed, both by HPLC on b-
cyclodextrin-bonded phases or after derivatization with
Racemic and enantiomerically pure 2,2%-bis(bromo-
methyl)-1,1%-binaphthyl,16 as well as
L-phenylalanine
cyclohexylamide,12 were prepared as previously des-
cribed. (−)-(S)-a-Methoxy-a-trifluoromethyl-a-phenyl-
acetic acid (99+%) was purchased from Aldrich. Melt-
ing points were determined with a temperature rise of
3°C/min and are uncorrected. 1H and 13C NMR spectra
were recorded at 300 and 77 MHz, respectively, the
solvent CDCl3, DMSO-d6, or CD3OD being used as
internal standard (l=7.27, 2.51 or 3.31 ppm, respec-
tively, for 1H and 77.0, 39.5 or 49.0 ppm for 13C).
Splitting patterns are abbreviated as follows: (s) singlet,
(d) doublet, (t) triplet, (q) quartet, (m) multiplet. The
optical rotations were measured with an accuracy of
0.3%, in a 1 dm thermostated cell. Analytical thin-layer
chromatography (TLC) and preparative column chro-
matography were performed on Kieselgel F 254 and on
Kieselgel 60 (0.040–0.063 mm) (Merck), respectively,
with the following eluent systems: CH2Cl2 (I); 2.5%
MeOH–97.5% CH2Cl2 (II); 3% MeOH–97% CH2Cl2
(III);5% MeOH–95% CH2Cl2 (IV); 10% MeOH–90%
CH2Cl2 (V); 30% Et2O–70% pentane (VI); 15% Et2O–
85% CH2Cl2 (VII); 1% AcOEt–99% CH2Cl2 (VIII), 50%
Et2O–50% CH2Cl2 (IX). UV light (254 nm) allowed
1-fluoro-2,4-dinitrophenyl-5-L
-alanine amide,20 and by
1H/19F NMR after treatment of an aliquot of both
samples with (−)-(S)-a-methoxy-a-trifluoromethyl-a-
phenyl-acetic acid anhydride, resulting from reaction of
the Mosher’s acid21 with a half-equiv. of EDC,8b which
led to the diastereoisomeric amido esters (S)-
Ph(OCH3)(CF3)C-CO-(R)-b2,2-HBin-OMe with >98%
d.e. from (R)-2b and (S)-Ph(OCH3)(CF3)C-CO-(S)-
b
2,2-HBin-OMe with >97% d.e. from (S)-2b. It is note-

A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
2575
visualization of the spots after TLC runs for all com-
3.4. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
aminomethyl-6-carboxylic acid ethyl ester (RS)-2a and
(R)-2a
pounds, even at low concentration. HPLC was per-
formed with a Gilson chromatograph equipped with a
SPD-6A Shimadzu UV spectrophotometer and a C-R
5A Shimadzu integrator, using a Merck lobar column,
size C (440-37), pre-packed with lichroprep Si 60, 40–63
mm.
To a solution of cyanoester (RS)-1a (8.29 g; 21.20
mmol) and cobaltous chloride hexahydrate (10.08 g;
42.40 mmol) in 99% MeOH (350 mL) and THF (120
mL), was added NaBH4 (8.04 g; 212 mmol) in portions.
Evolution of hydrogen gas was observed as well as the
formation of a black precipitate. When the addition
was complete, stirring was continued for 2 h at rt. HCl
(2 M, 70 mL) was then poured in the reaction mixture
in order to dissolve the black precipitate. After removal
of MeOH and THF, the aqueous layer was made
alkaline by addition of concentrated NH4OH and then
extracted with diethylether (4×200 mL). The combined
extracts were washed with saturated sodium chloride
solution, dried (MgSO4), filtered and evaporated in
vacuo. The crude product was chromatographed on a
4.5×30 cm column of silica gel with eluent IV to give
pure (RS)-2a as a white solid (4.46 g, 53%) of. Mp=
113.7°C. Rf=0.3 (IV). 1H NMR (CDCl3): 7.95–7.15 [m,
12H, ArH], 4.20 [m, 2H, OCH2], 3.16 and 2.21 [d,d,
J=12.9, 2H, CH2 b], 2.84 [m, 4H, CH2 b% and CH2-N],
1.43 (s, 2H, NH2), 1.28 (t, J=7.1, 3H CH3]. 13C NMR
(CDCl3): 175.3 (CꢀO), 135.9, 135.1, 134.5, 133.9, 132.9,
132.8, 131.9, 131.7 (CAr), 128.4, 128.2, 128.1, 128.0,
127.9, 127.2, 127.1, 125.7, 125.6, 125.1, 124.9 (CHAr),
60.8 (OCH2), 51.9 (Ca), 48.0 (CH2N), 38.6 (CH2 b),
36.3 (CH2 b%), 14.4 (CH3). Anal. C27H25NO2·0.3H2O:
calcd C, 80.89; H, 6.43; N, 3.49; found C, 81.04; H,
6.51; N, 3.41%.
3.2. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
cyano-6-carboxylic acid ethyl ester (RS)-1a and (R)-1a
A mixture of (R,S)-2,2%-bis(bromomethyl)-1,1%-bina-
phthyl16 (4.40 g; 10 mmol), ethylcyanoacetate (1.28 mL;
12 mmol) and anhydrous potassium carbonate (3.31 g;
24 mmol), in DMF (20 mL) was magnetically stirred at
room temperature for 16 h. The reaction mixture was
then poured into water and extracted with diethyl ether
(150 mL), the organic layer was washed with water
(5×20 mL), dried (MgSO4), filtered and evaporated in
vacuo. The resulting white solid was chromatographed
on a 50×3 cm column of silica gel with eluent (I) to give
pure (RS)-1a as a white solid (3.70 g, 94%). Mp=
1
164.4°C. Rf=0.5 (I). H NMR (CDCl3): 8.03–7.24 [m,
12H, ArH], 4.31 [m, 2H, OCH2], 3.44 and 2.93 [d,d,
J=13.4, 2H, CH2 b], 3.18 and 3.08 [d,d, J=13.6, 2H,
CH2 b%], 1.37 [t, J=7.2, 3H, CH3]. 13C NMR (CDCl3):
167.5 (CꢀO), 134.5, 134.2, 133.5, 133.3, 132.1, 131.8,
131.6, 131.5 (CAr), 129.0, 128.4, 128.3, 128.0, 127.5,
127.1, 127.0, 126.1, 126.0, 125.7, (CHAr), 119.4 (CꢁN),
63.0 (OCH2), 52.9 (Ca), 39.3 (CH2 b), 38.9 (CH2 b%),
14.0 (CH3). Anal. C27H21NO2: calcd C 82.84, H 5.41, N
3.58; found C 83.03, H 5.61, N 3.43%.
(R)-1a was prepared in the same way as (RS)-1a from
(R)-2,2%-bis(bromomethyl)-1,1%-binaphthyl16 (2.20 g; 5
mmol), ethylcyanoacetate (0.64 mL; 6 mmol) and anhy-
drous potassium carbonate (1.65 g; 12 mmol), in DMF
(10 mL) afforded, after column chromatography (SiO2;
eluent I), (R)-1a as a white solid (1.55 g, 79%). Mp=
146.7°C. [h]25589=−300; [h]25578=−314; [h]52546=−358;
[h]24536=−577; [h]32655=−297 (c 0.3; MeOH). Anal.
C27H21NO2: calcd C, 82.84; H, 5.41; N, 3.58; found C,
82.97; H, 5.51; N, 3.38%.
(R)-2a was prepared in the same way as (RS)-2a start-
ing from (R)-1a (1.44 g; 3.69 mmol), using cobaltous
chloride hexahydrate (1.76 g; 7.38 mmol), NaBH4 (1.39
g; 36.90 mmol) and a mixture of 99% MeOH (100 mL)
and THF (30 mL) to afford (R)-2a as a white solid
25
(0.594 g, 59%). Mp=104.8°C. [h]25859=−248; [h]
=
578
−261; [h]25546=−297; [h]42356=−458; [h]23655=−60 (c 0.205;
MeOH). Anal. C27H21NO2 calcd C, 81.99; H, 6.37; N,
3.54; found C, 81.01; H, 6.51; N, 3.41%.
3.3. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
cyano-6-carboxylic acid methyl ester (RS)-1b
3.5. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
aminomethyl-6-carboxylic acid methyl ester (RS)-2b
Prepared in the same way as (RS)-1a using (R,S)-2,2%-
bis(bromomethyl)-1,1%-binaphthyl (4.40 g; 10 mmol),
methylcyanoacetate (1.06 mL; 12 mmol), anhydrous
potassium carbonate (3.31 g; 24 mmol), and DMF (10
mL) to afford, after column chromatography (SiO2;
eluent VI), (RS)-1b as a white solid (3.43 g, 91%).
Mp=205.2°C. Rf=0.7 (I). 1H NMR (CDCl3): 8.03–
7.24 [m, 12H, ArH], 3.86 [s, 3H, OCH3], 3.43 and 2.93
[d,d, J=13.6, 2H, CH2 b], 3.18 and 3.07 [d,d, J=13.4,
2H, CH2 b%]. 13C NMR (CDCl3): 168.0 (CꢀO), 134.5,
134.3, 133.5, 133.3, 131.9, 131.8, 131.6, 131.5 (CAr),
129.0, 128.51, 128.47, 128.43, 128.3, 127.9, 127.5, 127.1,
127.0, 126.1, 126.0, 125.8 (CHAr), 119.3 (CꢁN), 53.7
(OCH3), 52.9 (Ca), 39.3 (CH2b), 39.0 (CH2b%). Anal.
C26H19NO2·0.2H2O: calcd C, 81.91; H, 5.13; N, 3.67;
found C, 82.09; H, 5.29; N, 3.69%.
Prepared in the same way as (RS)-2a starting from
(RS)-1b (2.50 g; 6.65 mmol), cobaltous chloride hex-
ahydrate (3.15 g; 13.30 mmol), NaBH4 (2.0 g; 53 mmol)
and a mixture of 99% MeOH (40 mL) and THF (10
mL) to afford after column chromatography (SiO2;
eluent IV), (RS)-2b as a white solid (1.68 g, 67%).
1
Mp=90.2°C. Rf=0.15 (IV). H NMR (CDCl3): 8.05–
7.15 [m, 12H, ArH], 3.71 [s, 3H, OCH3], 3.16 and 2.21
[d,d, J=13.2, 2H, CH2 b], 2.85 [m, 4H, CH2N and CH2
b%], 1.56 (s, 2H, NH2]. 13C NMR (CDCl3): 175.9 (CꢀO),
135.8, 135.0, 134.5, 133.8, 132.8, 132.7, 131.8, 131.7
(CAr), 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.2,
127.1, 125.8, 125.6, 125.1, 125.0 (CHAr), 61.0 (Ca),
51.9 (OCH3), 47.9 (CH2N), 38.7 (CH2 b), 36.2 (CH2 b%).
Anal. C26H23NO2·0.2H2O: calcd C, 81.09; H, 6.12; N,
3.63; found C, 80.99; H, 6.33; N, 3.53%.

2576
A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
3.6. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
N-tert-butyloxycarbonylaminomethyl-6-carboxylic acid
ethyl ester (RS)-3a and (R)-3a
solubilized in ethyl acetate, the organic solution was
washed with 5% NaHCO3 then with water, dried
(MgSO4), filtered and evaporated in vacuo. The residue
was chromatographed on a 4.5×35 cm column of silica
gel with eluent II to give 6.57 g (92%) of pure (R,S)-6a
To a solution of (R,S)-2a (0.395 g; 1.0 mmol) in
acetonitrile (10 mL) was added di-tert-butyl dicarbon-
ate (0.436 g; 2.0 mmol). The solution was stirred at rt
overnight and evaporated in vacuo. The residue was
directly chromatographed on a 4.5×35 cm column of
silica gel with eluent I to afford pure (RS)-3a as a white
solid (0.442 g, 89%). Mp=105.1°C. Rf=0.1 (I). 1H
NMR (CDCl3): 7.96–7.21 [m, 12H, ArH], 4.86 (m, 1H,
NH) 4.16 [dq, J=1.7 and 7.2, 2H, OCH2], 3.31 [m, 2H,
CH2N], 3.08 and 2.31 [d,d, J=13.2, 2H, CH2 b], 2.86
and 2.76 [d,d, J=13.60, 2H, CH2 b%], 1.45 [s, 9H, CH3
Boc], 1.28 (t, J=7, 2H CH3]. 13C NMR (CDCl3): 175.0
1
as a white solid. Mp=181.0°C. Rf=0.7 (II). H NMR
(CDCl3): 8.05–7.15 [m, 17H, ArH], 6.72 (m, 1H, NH)
4.22 [q, J=7.2, 2H, OCH2], 3.79 [dd, J=6.8 and 13.6,
1H, CHN], 3.52 [dd, J=5.3 and 13.6, 1H, CHN], 3.12
and 2.44 [d,d, J=13.2, 2H, CH2 b], 2.94 and 2.85 [d,d,
J=13.60, 2H, CH2 b%], 1.27 [t, J=7.2, 3H, CH3]. 13C
NMR (CDCl3): 175.5 (CꢀO), 167.3 (N-C6 ꢀO), 135.1,
134.4 134.2, 134.0, 133.0, 131.7, 131.6, 131.5, (CAr),
128.6, 128.4, 128.3, 128.1, 127.8,127.2, 127.1, 125.7,
125.6, 125.2, 125.1 (CHAr), 61.2 (OCH2), 58.7 (Ca),
44.4 (CH2N), 38.8 (CH2 b), 36.7 (CH2 b%), 14.2 (CH3).
Anal. C34H29NO3·0.5H2O: calcd C, 80.29; H, 5.95; N,
2.75; found C, 80.52; H, 6.08; N, 2.83%.
(CꢀO), 155.8 (N-C6 ꢀO), 135.4, 134.4, 133.9, 132.9, 132.8,
131.7, (CAr), 128.6, 128.2, 128.1, 127.8, 127.2, 127.1,
125.7, 125.6, 125.1, 125.0 (CHAr), 79.4 (O-C), 61.2
(OCH2), 59.1 (Ca), 45.6 (CH2N), 38.5 (CH2 b), 36.5
(CH2 b%), 28.3 (CH3 Boc), 14.2 (CH3). Anal.
C32H33NO4: calcd C, 77.55; H, 6.71; N, 2.83; found C,
77.42; H, 6.78,; N, 2.67%.
3.9. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
N-benzoylaminomethyl-6-carboxylic acid methyl ester
(RS)-6b
Prepared in the same way as (RS)-6a from the amino
ester (RS)-2b (0.768 g; 2.02 mmol) and benzoic anhy-
dride (0.910 g; 4.04 mmol) in acetonitrile (20 mL) to
afford, after column chromatography (SiO2; eluent I),
(RS)-6b as a white solid (0.840 g, 86%). Mp=90.3°C.
Rf=0.21 (I). 1H NMR (CDCl3): 8.38–7.22 [m, 17H,
ArH], 6.84 (m, 1H, NH), 3.86 [dd, J=6.8 and 13.6, 1H,
CHN], 3.75 [s, 3H, OCH3], 3.56 [dd, J=5.3 and 13.6,
1H, CHN], 3.17 and 2.47 [d,d, J=13.2, 2H, CH2 b],
2.98 and 2.90 [d,d, J=13.60, 2H, CH2 b%]. 13C NMR
(R)-3a was prepared in the same way as (RS)-3a start-
ing from (R)-2a (0.500 g; 1.26 mmol) and di-tert-butyl
dicarbonate (0.550 g; 2.52 mmol) in acetonitrile (13
mL) to afford, after column chromatography (SiO2;
eluent I), as a white solid (0.435 g, 63%). Mp=120.0°C.
[h]25589=−148; [h]52758=−155; [h]25546=−178; [h]24536=−255;
[h]23565=+135 (c 0.2; MeOH). Anal. C32H33NO4: calcd C,
77.55; H, 6.71; N, 2.83; found C, 77.02; H, 6.91; N,
2.71%.
(CDCl3): 175.9 (CꢀO), 167.7 (N-C6 ꢀO), 135.1, 134.3
3.7. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
N-tert-butyloxycarbonylaminomethyl-6-carboxylic acid
methyl ester (RS)-3b
134.2, 134.0, 133.4, 132.9, 132.8, 131.65, 131.64, 131.5,
(CAr), 128.55, 128.52, 128.3, 128.2, 128.1, 127.9, 127.8,
127.1, 127.0, 126.9, 125.7, 125.6, 125.1, 125.0 (CHAr),
58.8 (Ca), 52.3 (OCH3), 44.5 (CH2N), 38.7 (CH2 b),
36.6 (CH2 b%). Anal. C33H27NO3·1.2H2O: calcd C,
78.14; H, 5.84; N, 2.76; found C, 78.02; H, 5.52; N,
2.26%.
Prepared in the same way as (R,S)-3a from the
aminoester (R,S)-2b (0.250 g; 0.65 mmol) and di-tert-
butyl dicarbonate (0.287 g; 1.31 mmol) in acetonitrile (7
mL). Yield 0.293 g (93%) after column chromatography
(SiO2; eluent I), as a white solid. Mp=187.3°C. Rf=
3.10. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
N-tert-butyloxycarbonylaminomethyl-6-carboxylic acid
(RS)-4 and (R)-4
1
0.22 (I). H NMR (CDCl3): 7.92–7.12 [m, 12H, ArH],
4.83 (m, 1H, NH), 3.62 (s, 3H, OCH3), 3.25 [m, 2H,
CH2N], 3.03 and 2.24 [d,d, J=13.2, 2H, CH2 b], 2.80
and 2.72 [d,d, J=13.60, 2H, CH2 b%], 1.39 [s, 9H, CH3
A suspension of (RS)-3a (0.360 g, 0.73 mmol) in
MeOH (40 mL) and 1N NaOH (20 mL) was stirred at
80°C for 4 h. The resulting clear solution was allowed
to cool to rt, acidified by addition of an excess of 0.5 M
HCl and extracted with diethylether. The ethereal solu-
tion was washed twice with water, dried (MgSO4),
filtered and evaporated in vacuo to give pure (RS)-4 as
a white solid (0.335 g, 98%). Mp=172.2°C. Rf=0.11
Boc]. 13C NMR (CDCl3): 175.4 (CꢀO), 155.7 (N-C
6 ꢀO),
135.3, 134.3, 133.9, 132.9, 132.8, 131.7, 131.6 (CAr),
128.5, 128.2, 128.1, 127.9, 127.1, 127.0, 125.6, 125.5,
125.1, 125.0 (CHAr), 79.4 (O-C), 59.2 (Ca), 52.1
(OCH3), 45.6 (CH2N), 38.5 (CH2 b), 36.4 (CH2 b%), 27.3
(CH3 Boc). Anal. C31H31NO4·0.5H2O: calcd C, 75.89;
H, 6.57; N, 2.82; found C, 75.77; H, 6.54; N, 2.69%.
1
(IV). H NMR (CDCl3): 8.02–7.21 [m, 12H, ArH], 6.34
3.8. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
N-benzoylaminomethyl-6-carboxylic acid ethyl ester
(RS)-6a
[s broad, 1H, OH], 4.97 [m, 1H, NH], 3.37 [m, 2H,
CH2N], 3.10 and 2.35 [d,d, J=13.6, 2H, CH2 b], 2.88
and 2.80 [d,d, J=13.8, 2H, CH2 b%], 1.43 [s, 9H, CH3
Boc]. 13C NMR (CDCl3): 180.9 (CꢀO), 156.1 (N-C
6 ꢀO),
To a solution of (RS)-2a (5.64 g; 14.29 mmol) in
acetonitrile (140 mL) was added benzoic anhydride
(6.46 g; 28.58 mmol). The solution was stirred at rt
overnight and evaporated in vacuo. The residue was
135.5, 134.4, 133.9, 132.9, 132.8, 131.7, 131.6 (CAr),
128.6, 128.2, 127.9, 127.1, 125.6, 125.5, 125.1, 124.9
(CHAr), 79.9 (O-C), 59.2 (Ca), 45.9 (CH2N), 38.3 (CH2
b), 36.6 (CH2 b%), 28.3 (CH3 Boc). Anal. C30H29NO4·

A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
2577
0.25H2O: calcd C, 76.31; H, 6.29; N, 2.96; found C, 76.35;
H, 6.56; N, 2.76%.
benzotriazole) (3.09 g; 22.9 mmol) in CH2Cl2 (160 mL)
and THF (160 mL) was added dropwise at 0°C, a solu-
tion of EDC (N-ethyl-N%-dimethylaminopropylcarbodi-
imide hydrochloride) (3.76 g; 19.6 mmol) in CH2Cl2 (80
mL). The solution was allowed to warm to rt and stirred
overnight. The solvents were evaporated in vacuo and the
residue was dissolved in EtOAc (900 mL). The solution
was successively extracted with 0.5N HCl (3×200 mL),
H2O (2×200 mL), 5% NaHCO3 (3×250 mL), H2O (3×250
mL), then dried (MgSO4), filtered and evaporated in
vacuo. The residue was chromatographed on a 4.5×40 cm
column of silica gel with eluent (V) to give 8.77 g (78%)
of a 1:1 mixture of diastereomers (R,S)-8 and (S,S)-8.
Attempts for crystallization of this mixture in EtOAc was
unsuccessful: no crystals deposited even from highly con-
centrated solutions and evaporation to dryness led to an
amorphous white solid. 7.5 g of the mixture of
diastereomers (R,S)-8 and (S,S)-8 were separated by
HPLC using eluent (VII) for (R,S)-8 and eluent (IX) for
(S,S)-8 to give pure (R,S)-8 (3.62 g, 95%) and pure (S,S)-
8 (2.12 g, 56%).
(R)-4 was prepared in the same way as (RS)-4 by sapon-
ification of (R)-3a (0.22 g, 0.44 mmol) in MeOH (20 mL)
and 1 M NaOH (16 mL) at 80°C for 5 h to afford (R)-4
as a white solid (0.206 g, 99%). Mp=250–270°C
(decomp. at solid state before melting). [h]25859=−129;
[h]25578=−134; [h]52456=−153; [h]24536=−225; [h]23565=+71 (c
0.2; MeOH). Anal. C30H29NO4·1.6 H2O: calcd C, 72.59;
H, 6.54; N, 2.82; found C, 72.59; H, 6.51; N, 2.73%.
3.11. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
N-benzoylaminomethyl-6-carboxylic acid (RS)-7
(RS)-7 was prepared in the same way as (RS)-4: by
saponification of (RS)-6b (6.50 g, 13 mmol) in MeOH
(350 mL) and 1 M NaOH (150 mL) at 80°C for 4 h. Yield
5.89 g (96%) as a white solid. Mp=181°C. Rf=0.3 (IV).
1H NMR (CDCl3): 8.05–7.19 [m, 17H, ArH], 7.02 (t, J=
6.2, 1H, NH), 6.75 [s broad, 1H, OH], 3.84 [dd, J=6.2
and 13.6, 1H, CHN], 3.46 [dd, J=6.2 and 13.6, 1H,
CHN], 3.19 and 2.36 [d,d, J=13.2, 2H, CH2 b], 2.86 [s,
2H, CH2 b%]. 13C NMR (DMSO-d6): 175.5 (CꢀO), 166.9
Bz-(R)-b2,2-HBin-
Mp=169–171°C. Rf=0.34 (VII). 1H NMR (CDCl3):
8.01–7.82 [m, 6H, ArH], 7.70 [m ( -like), 1H, ArH], 7.48–
-like),
L
-Phe-NH-C6H11 (R,S)-8: white solid.
(N-C
6
ꢀO), 135.9, 135.6, 134.7, 133.6, 133.2, 132.5, 132.4,
D
131.2, 131.1, 131.0, (CAr), 128.9, 128.4, 128.2, 127.8,
127.4, 126.3, 125.9, 125.1 (CHAr), 58.9 (Ca), 44.5
(CH2N), 37.9 (CH2 b), 36.4 (CH2 b%). Anal.
C33H27NO3·1.4H2O: calcd C, 77.37; H, 5.64; N, 2.82;
found C, 77.32; H, 5.61; N, 2.09%.
7.04 [m, 14H, ArH and NH b2,2-HBin], 6.95 [m (
D
2H, ArH], 6.26 [d, J=7.7, 1H, NH Phe], 6.07 [d, J=8.1,
1H, NHC6H11], 4.54 [m, 1H, CHa Phe], 3.77 [dd, J=7.2
and 13.8, 1H, NCH6 b b
2,2-HBin], 3.67 [m, 1H,
CHcyclohexyl], 3.45 [dd, J=5.1 and 13.8, 1H, NCH6 -
b b2,2
HBin], 2.99 [dd, J=6.6 and 13.6, 1H, CHb Phe], 2.85 [dd,
J=8.8 and 13.6, 1H, CHb Phe], 2.83 and 2.49 [d,d, J=
13.6, 2H, CH2b b2,2-HBin], 2.70 and 2.64 [d,d, J=13.2,
2H, CH2b% b2,2-HBin], 1.86–0.89 [m, 10H, 5 CH2cyclohexyl].
13C NMR (CDCl3): 175.9, 170.0, 167.4 (CꢀO Phe, CꢀO
3.12. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
aminomethyl-6-carboxylic acid, trifluoroacetate (RS)-5
and (R)-5
To a cold solution of (RS)-4 (0.056 g, 0.12 mmol) in
CH2Cl2 (0.5 mL) was added TFA (0.5 mL). The solution
was stirred at rt for 2 h and evaporated in vacuo. The
resulting solid was repeatedly triturated with diethylether
and the mixture evaporated in vacuo, to afford pure
(RS)-5 as a white solid (0.36 g, 62%). Mp=196.4°C. Rf=
b
2,2-HBin, CꢀO Bz), 136.2, 134.5, 134.3, 134.2, 133.9,
132.9, 132.8, 131.8, 131.6, 131.4, 128.9, 128.8, 128.6,
128.4, 128.37, 128.31, 128.2, 127.3, 127.25, 127.2, 127.0,
126.9, 125.8, 125.6, 125.3, 125.1 (CAr and CHAr), 58.8
(Ca b2,2-HBin), 54.9 (Ca Phe), 48.5 (CHcyclohexyl), 44.9
(NCH2b b2,2-HBin), 39.2 (CH2b b2,2-HBin), 38.0 (CH2b
Phe), 36.7 (CH2b% b2,2-HBin), 32.8, 32.6, 25.3, 24.7
(CH2cyclohexyl). [h]25859=−9; [h]25758=−11; [h]25456=−11;
[h]42356=−70; [h]32655=+705 (c 0.10; MeOH). Anal.
C47H45N3O3·0.5H2O: calcd C, 79.63; H, 6.54; N, 5.93;
found C, 79.71; H, 6.62; N, 5.84%.
1
0.1 (I). H NMR (CD3OD): 8.01–7.21 [m, 12H, ArH],
3.31 [m, 2H, CH2N], 3.15 and 2.33 [m,7H, CH2 b, CH2 b%
and NH3 ]. 13C NMR (CD3OD): 174.7 (CꢀO), 136.1,
+
135.9, 135.0, 134.7, 133.3, 133.0, (CAr), 129.7, 129.6,
129.5, 129.3, 129.1, 128.1, 127.9, 127.2, 126.9, 126.7,
126.5 (CHAr), 54.9 (Ca), 45.6 (CH2N), 39.9 (CH2 b), 39.1
(CH2 b%). Anal. C27H22F3NO4·1.1H2O: calcd C, 64.69; H,
4.87; N, 2.79; found C, 64.76; H, 4.88; N, 2.81%.
Bz-(S)-b2,2-HBin-
Mp=176–178°C°C. Rf=0.24 (VII). H NMR (CDCl3):
L
-Phe-NH-C6H11 (S,S)-8: White solid.
1
8.05–7.85 [m, 6H, ArH], 7.71 [m (D-like), 1H, ArH], 7.51–
(R)-5 was obtained in the same way as (RS)-5 starting
from (R)-4 (0.034 g, 0.0.73 mmol) and TFA (0.5 mL) in
7.20 [m, 11H, ArH and NH b2,2-HBin], 7.09–6.90 [m, 5H,
ArH], 6.23 [d, J=7.2, 1H, NH Phe], 5.56 [d, J=8.1, 1H,
NHC6H11], 4.56 [m, 1H, Ha Phe], 3.83 [dd, J=7.1 and
13.5, 1H, NCHb b2,2-HBin], 3.63 [m, 1H, CHcyclohexyl],
CH2Cl2 (0.5 mL) to afford (R)-5 as a white solid (0.020 g,
25
57%). Mp=209.3°C. Rf=0 (I). [h]25859=−212; [h]
=
578
−221; [h]25546=−255; [h]42356=−401; [h]23655=−146 (c 0.2;
MeOH). Anal. C27H22F3NO4·1.2H2O: calcd C, 64.46; H,
4.88; N, 2.78; found C, 64.34; H, 4.77; N, 2.81%.
3.43 [dd, J=4.8 and 13.5, 1H, NCH6
b b2,2-HBin], 3.45
and 2.96 [d,d, J=13.2, 2H, CH2b b2,2-HBin], 3.06 [dd,
J=5.5 and 13.5, 1H, CHb Phe], 2.85 [dd, J=8.1 and 13.5,
1H, CHb Phe], 2.81 and 2.62 [d,d, J=12.7, 2H, CH2b%
3.13. Coupling of (RS)-7 with
cyclohexylamide
L
-phenylalanine
b
2,2-HBin], 1.86–0.78 [m, 10H, 5 CH2cyclohexyl]. 13C NMR
(CDCl3): 175.1, 169.3, 167.5 (CꢀO Phe, CꢀO b2,2-HBin,
CꢀO Bz), 135.8, 135.7, 135.0, 134.3, 134.2, 134.1, 133.6,
133.0, 132.9, 131.7, 131.6, 131.4, 129.0, 128.6, 128.44,
128.4, 128.3, 128.26, 128.2, 127.8, 127.2, 127.1, 127.0,
To a solution of (RS)-7 (7.6 g; 16.1 mmol), H-
L-Phe-
NHC6H1112 (5.63 g; 22.9 mmol) and HOBt (N-hydroxy-

2578
A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
125.8, 125.7, 125.3, 125.2 (CAr and CHAr), 58.9 (Ca
[h]23565=−126 (c 0.2; MeOH). Anal. C31H31NO4·0.3H2O:
calcd C, 76.45; H, 6.54; N, 2.87; found C, 76.54; H,
6.51; N, 2.58%.
b
2,2-HBin), 54.8 (Ca Phe), 48.5 (CHC5H10), 45.0
(NCH2b b2,2-HBin), 38.5 (CH2b b2,2-HBin), 38.2 (CH2b
Phe), 36.4 (CH2b% b2,2-HBin), 32.8, 32.6, 25.3, 24.7
(CH2 C5H10). [h]25589=+122; [h]25758=+128; [h]25456=+141;
[h]24536=+211; [h]32655=−20 (c 0.15; MeOH). Anal.
C47H45N3O3: calcd C, 80.65; H, 6.48; N, 6.00; found C,
80.08; H, 6.62; N, 5.75%.
3.15. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
aminomethyl-6-carboxylic acid methyl ester (R)-2b and
(S)-2b
To a cold (0°C) solution of (R)-3b (0.24 g; 0.5 mmol) in
CH2Cl2 (0.5 mL) was added TFA (0.5 mL). The solu-
tion was stirred at rt for 3 h and evaporated in vacuo.
The residue was solubilized in EtOAc (100 mL) and 5%
NaHCO3 (10 mL). the organic layer was extracted with
NaHCO3 (2×10 mL), dried (MgSO4), filtered and evap-
3.14. Acidic hydrolysis of (R,S)-8 and (S,S)-8.
2%,1%:1,2;1%%,2%%:3,4-dinaphthcyclohepta-1,3-diene-6-N-tert-
butyloxycarbonylaminomethyl-6-carboxylic acid methyl
ester (R)-3b and (S)-3b
To a solution of (R,S)-8 (3.55 g; 5.07 mmol) in dioxane
(40 mL) was added 35% (10N) HCl (40 mL), resulting
in the formation of a strong white precipitate. The
mixture was magnetically stirred at 110°C and the
precipitate gradually disappeared to give a clear pale
yellow solution after ca. 20 h. The solution was stirred
at 110°C for 6 days, then evaporated to dryness in
vacuo at 80°C. Water (ca. 20 mL) was added to the
residue and the mixture was evaporated again in vacuo,
this operation being repeated several times, to give
crude (R)-H-b2,2-HBin-OH·HCl as a solid. The crude
solid was esterified in refluxing MeOH (100 mL) con-
taining 98% H2SO4 (2 mL) for 4 days. the solution was
then concentrated in vacuo at 30°C to ca. 10 mL and
crushed ice (100 mL) then water (50 mL) were added to
the stirred mixture, followed by small portions of solid
NaHCO3 up to a large excess. The basic aqueous phase
was extracted with ether (150 mL), the organic phase
was washed with water (3×20 mL), dried (MgSO4),
filtered and evaporated in vacuo to give 1.32 g (68.0%)
of crude H-b2,2-HBin-OMe (R)-2b which was used in
the next step without further purification. This crude
amino ester (1.29 g; 3.4 mmol) was treated with di-tert-
butyl dicarbonate (1.63 g; 7.48 mmol) in acetonitrile (75
mL) in the same experimental conditions of reaction
and work-up as for the synthesis of (R,S)-3a, to give
1.214 g (69%) of pure Boc-b2,2-HBin-OMe (R)-3b after
column chromatography (SiO2; eluent VIII), as a white
solid. Mp=114–116°C. [h]25589=−151; [h]25758=−159;
[h]25546=−180; [h]42356=−266; [h]23565=−123 (c 0.21;
MeOH). Anal. C31H31NO4·1.5H2O: calcd C, 74.84; H,
6.89; N, 2.81; found C, 74.58; H, 6.35; N, 2.47%.
orated in vacuo to give pure (R)-2b as a white solid
25
(0.188 g; 98%). Mp=97.7°C. [h]25859=−236; [h]
=
578
−253; [h]25546=−289; [h]42356=−448; [h]23655=−13 (c 0.1;
MeOH). Anal. C26H23NO2·0.3H2O: calcd C, 80.72; H,
6.15; N, 3.62; found C, 80.85; H, 6.34; N, 3.39.
Treatment of (S)-3b (0.241 g; 0.5 mmol) in exactly the
same manner gave pure (S)-2b as a white solid (0.190 g;
99%). Mp=101.1°C. [h]25859=+258; [h]52758=+265;
[h]25546=+299; [h]24356=+462; [h]23655=+68 (c 0.1; MeOH).
Anal. C26H23NO2·0.2H2O: calcd C, 81.00; H, 6.11; N,
3.63; found C, 81.07; H, 6.21; N, 3.35%.
3.16. Coupling of (R)-2b and (S)-2b with (−)-(S)-a-
methoxy-a-trifluoromethyl-a-phenylacetic acid
To a solution of (−)-(S)-a-methoxy-a-trifluoromethyl-a-
phenyl-acetic acid (0.019 g; 0.08 mmol) in acetonitrile
(2 mL) was added EDC (0.0078 g; 0.04 mmol). After
stirring at rt for 1 h the clear colorless solution of the
resulting MTPA anhydride was divided in two portions
of 1 mL each, which were respectively added to samples
of (S)-2b (0.0031 g; 0.008 mmol) and (R)-2b (0.0030 g;
0.008 mmol). The resulting clear colorless solutions
were stirred at rt overnight and the solvent was
removed in vacuo. After addition of ether (10 mL) the
organic phases were successively extracted with 5%
NaHCO3 (2×2 mL), then water (2×2 mL), dried
(MgSO4), filtered and evaporated in vacuo. The
residues were chromatographed on preparative TLC
plates of silica gel with eluent (I), care being taken not
to exercise a mechanical separation of one of the
diastereoisomers over the other. From (R)-2b was
obtained amido ester (S)-Ph(OCH3)(CF3)C-CO-(R)-
In the same manner, to a solution of (S,S)-8 (2.06 g;
2.94 mmol) in dioxane (24 mL) was added HCl (35%,
10 N, 24 mL). The mixture was magnetically stirred at
110°C, resulting in the slow disparition of the initially
formed white precipitate to give a clear pale yellow
solution. After 6 days at 110°C, the solution was evap-
b
2,2-HBin-OMe with >98% d.e.: 1H NMR (CDCl3):
7.95–7.20 [m, 18H, ArH and NH], 3.74 [dd, J=7.7 and
13.5, 1H, NCHb], 3.67 [s (99.3%), 3H, OCH3 b2,2
-
HBin], 3.63 [s (0.7%), OCH3 b2,2-HBin of the (S,S)-iso-
mer], 3.43 [m, 3H, OCH3 MTPA], 3.32 [dd, J=5.3 and
13.5, 1H, NCHb], 3.99 and 2.39 [d,d, J=13.1, 2H,
CH2b], 2.90 and 2.77 [dd, J=13.7, 2H, CH2b%]. 19F
NMR (CDCl3): −69.24 [s (99%), CF3], −69.29 [s (1%),
CF3 of the (S,S) isomer]. 13C NMR (CDCl3): 175.4,
166.4 (CꢀO b2,2-HBin, CꢀO MTPA), 134.9, 134.3,
134.0, 133.0, 132.9, 132.3, 131.7, 131.6, 129.4, 128.5,
128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7, 127.2,
127.0, 125.7, 125.2 (CAr and CHAr, 83.5 (CF3), 59.0
(Ca), 55.0 (OCH3 MTPA), 52.6 (OCH3 b2,2-HBin), 44.0
(CH2N), 38.9 (CH2b), 36.3 (CH2b%). The amido ester
orated to dryness in vacuo, to give crude (S)-H-b2,2
-
HBin-OH·HCl as a solid. The crude solid was treated
exactly as above: esterification in refluxing MeOH with
98% H2SO4 led after work-up to crude H-b2,2-HBin-
OMe (S)-2b (0.845 g, 75%), which was directly treated
with di-tert-butyl dicarbonate (1.08 g; 4.94 mmol) in
acetonitrile (45 mL), to give pure Boc-b2,2-HBin-OMe
(S)-3b after column chromatography (SiO2; eluent
VIII), as a white solid (0.888 g, 65%). Mp=116–119°C.
[h]25589=+155; [h]52758=+159; [h]25546=+179; [h]24536=+261;

A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
2579
was obtained from (S)-2b (S)-Ph(OCH3)(CF3)C-CO-
1996, 79, 2043–2066; (c) Matthews, J. L.; Overhand, M.;
Ku¨hnle, F. N. M.; Ciceri, P. E.; Seebach, D. Liebigs
Ann./Recueil 1997, 1371–1379; (d) Hintermann, T.; See-
bach, D. Chimia 1997, 51, 244–247; (e) Seebach, D.;
Abele, S.; Gademann, K.; Guichard, G.; Hintermann, T.;
Jaun, B.; Matthews, J. L.; Schreiber, J. V.; Oberer, L.;
Hommel, U.; Widmer, H. Helv. Chim. Acta 1998, 81,
932–982; (f) Abele, S.; Guichard, G.; Seebach, D. Helv.
Chim. Acta 1998, 81, 2141–2156; (g) Abele, S.; Vogtli, K.;
Seebach, D. Helv. Chim. Acta 1999, 82, 1539–1558; (h)
Seebach, D.; Abele, S.; Gademann, K.; Jaun, B. Angew.
Chem., Int. Ed. 1999, 38, 1595–1598; (i) Seebach, D.;
Boog, A.; Schweizer, W. B. Eur. J. Org. Chem. 1999,
335–360; (j) Seebach, D.; Schreiber, J. V.; Abele, S.;
Daura, X.; van Gunsteren, W. F. Helv. Chim. Acta 2000,
83, 34–57; (k) Seebach, D.; Jacobi, A.; Rueping, M.;
Gademann, K.; Ernst, M.; Jaun, B. Helv. Chim. Acta
2000, 83, 2115–2139; (l) Schreiber, J. V.; Seebach, D.
Helv. Chim. Acta 2000, 83, 3139–3152; (m) Bo¨hm, A.;
Seebach, D. Helv. Chim. Acta 2000, 83, 3262–3278; (n)
Seebach, D.; Schreiber, J. V.; Arvidsson, P. I.; Fracken-
pohl, J. Helv. Chim. Acta 2001, 84, 271–279; (o) Daura,
X.; Gademann, K.; Scha¨fer, H.; Jaun, B.; Seebach, D.;
van Gunsteren, W. F. J. Am. Chem. Soc. 2001, 123,
2393–2404; (p) Arvidsson, P. I.; Rueping, M.; Seebach,
D. J. Chem. Soc., Chem. Commun. 2001, 649–650.
1
(S)-b2,2-HBin-OMe with >97% de: H NMR (CDCl3):
7.93–7.21 [m, 18H, ArH and NH], 3.73 [dd, J=7.6 and
13.5, 1H, NCHb], 3.67 [s (1.4%), OCH3 b2,2-HBin of
the (S,R) isomer], 3.63 [s (98.6%), 3H, OCH3 b2,2
-
HBin], 3.42 [m, 3H, OCH3 MTPA], 3.37 [dd, J=5.5
and 13.5, 1H, NCHb], 3.06 and 2.36 [d,d, J=13.2, 2H,
CH2b], 2.88 and 2.70 [d,d, J=13.4, 2H, CH2b%]. 19F
NMR (CDCl3): −69.24 [s (>98%), CF3], −69.29 [s (<
2%), CF3 of the (S,R) isomer]. 13C NMR (CDCl3):
175.3, 166.5 (CꢀO b2,2-HBin, CꢀO MTPA), 134.9,
134.3, 134.0, 133.9, 132.9, 132.8, 132.3, 131.7, 129.4,
128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.8, 127.5,
127.1, 127.0, 125.8, 128.7, 125.2, 125.1 (CAr and
CHAr), 83.9 (CF3), 59.1 (Ca), 55.0 (OCH3 MTPA),
52.3 (OCH3 b2,2-HBin), 38.6 (CH2b), 36.7 (CH2b%).
3.17. 2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-diene-6-
N-tert-butyloxycarbony-
L-aminomethyl-6-carboxylic
acid (R)-4 and (S)-4
Saponification of (R)-3b (1.19 g; 2.49 mmol) in MeOH
(50 mL) and 1 M NaOH (25 mL) at 80°C for 4 h, in the
same experimental conditions of reaction and work-up
as for the synthesis of (R,S)-4, gave pure (R)-4 as a
white solid (1.09 g, 94%). Mp=270–290°C (decomp. at
solid state before melting). [h]25589=−168; [h]25758=−173;
[h]25546=−200; [h]24356=−299; [h]23655=+62 (c 0.2; MeOH).
Anal. C30H29NO4·H2O: calcd C, 74.20; H, 6.43; N, 2.88;
found C, 74.16; H, 6.01; N, 2.59%.
4. (a) Seebach, D.; Abele, S.; Sifferlen, T.; Hanggi, M.;
Gruner, S.; Seiler, P. Helv. Chim. Acta 1998, 81, 2218–
2243; (b) Abele, S.; Seiler, P.; Seebach, D. Helv. Chim.
Acta 1999, 82, 1559–1571; (c) Seebach, D.; Sifferlen, T.;
Mathieu, P. A.; Ha¨ne, A. M.; Krell, C. M.; Bierbaum, D.
J.; Abele, S. Helv. Chim. Acta 2000, 83, 2849–2864.
5. (a) Seebach, D.; Matthews, J. L.; Meden, A.; Wessels, T.;
Baerlocher, C.; McCusker, L. B. Helv. Chim. Acta 1997,
80, 173–182; (b) Gademann, K.; Seebach, D. Helv. Chim.
Acta 1999, 82, 957–962; (c) Gademann, K.; Ernst, M.;
Seebach, D.; Hoyer, D. Helv. Chim. Acta 2000, 83, 16–33;
(d) Le, H. C.; Hintermann, T.; Wessels, T.; Gan, Z.;
Seebach, D.; Ernst, R. R. Helv. Chim. Acta 2001, 84,
208–221.
(S)-4 was also prepared in the same way as (R,S)-4, by
saponification of (S)-3b (0.87 g, 1.80 mmol) in MeOH
(50 mL) and 1 M NaOH (25 mL) at 80°C for 4 h to
afford (S)-4 as a white solid (0.62 g, 73%). Mp=290–
25
310°C (decomp. at solid state before melting). [h]
=
=
589
25
+183; [h]25578=+188; [h]52456=+215; [h]24356=+321; [h]
365
−68 (c 0.2; MeOH). Anal. C30H29NO4·H2O: calcd C,
76.18; H, 6.31; N, 2.96; found C, 76.21; H, 6.37; N,
2.69%.
6. (a) Appella, D. H.; Christianson, L. A.; Klein, D. A.;
Powell, D. R.; Huang, X.; Barchi, Jr., J. J.; Gellman, S.
H. Nature 1997, 387, 381–384; (b) Appella, D. H.; Chris-
tianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H.
J. Am. Chem. Soc. 1996, 118, 13071–13072; (c)
Krauthauser, S.; Christianson, L. A.; Powell, D. R.;
Gellman, S. H. J. Am. Chem. Soc. 1997, 119, 11719–
11720; (d) Applequist, J.; Bode, K. A.; Appella, D. H.;
Christianson, L. A.; Gellman, S. H. J. Am. Chem. Soc.
1998, 120, 4891–4892; (e) Chung, Y. J.; Christianson, L.
A.; Stanger, H. E.; Powell, D. R.; Gellman, S. H. J. Am.
Chem. Soc. 1998, 120, 10555–10556; (f) Appella, D. H.;
Barchi, J. J.; Durell, S. R.; Gellman, S. H. J. Am. Chem.
Soc. 1999, 121, 2309–2310; (g) Huck, B. R.; Langenham,
J. M.; Gellman, S. H. Org. Lett. 1999, 1, 1717–1720; (h)
Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell,
D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121,
6206–6212; (i) Appella, D. H.; Christianson, L. A.; Klein,
D. A.; Richards, M. R.; Powell, D. R.; Gellman, S. H. J.
Am. Chem. Soc. 1999, 121, 7574–7581; (j) Barchi, Jr., J.
J.; Huang, X.; Appella, D. H.; Christianson, L. A.;
Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 2000,
122, 2711–2718; (k) Chung, Y. J.; Huck, B. R.; Christian-
References
1. Highlighted in recent reviews: (a) Chem. Eng. News 1999,
41–44; (b) DeGrado, W. F.; Schneider, J. P.; Hamuro, Y.
J. Peptide Res. 1999, 54, 206–217; (c) Koert, U. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1836–1387; (d) Iverson, B.
L. Nature 1997, 385, 113–115; (e) Borman, S. Chem. Eng.
News 1997, 32–35; (f) Seebach, D.; Matthews, J. L. J.
Chem. Soc., Chem. Commun. 1997, 2015–2022; (g) Gell-
man, S. H. Acc. Chem. Res. 1998, 31, 173–180; (h)
Gademann, K.; Hintermann, T.; Schreiber, J. V. Curr.
Med. Chem. 1999, 6, 905–925; (i) Wu, Y.-D.; Wang,
D.-P. J. Am. Chem. Soc. 1999, 121, 9352–9362; (j) Hart-
gerink, J. D.; Clark, T. D.; Ghadiri, M. R. Chem. Eur. J.
1998, 4, 1367–1372; (k) DeGrado, W. F.; Schneider, J. P.;
Hamuro, Y. J. Peptide Res. 1999, 54, 206–217.
2. Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1–15.
3. (a) Seebach, D.; Overhand, M.; Ku¨hnle, F. N. M.; Marti-
noni, B.; Oberer, L.; Hommel, U.; Widmer, H. Helv.
Chim. Acta 1996, 79, 913–941; (b) Seebach, D.; Ciceri, P.
E.; Overhand, M.; Jaun, B.; Rigo, D. Helv. Chim. Acta

2580
A. Gaucher et al. / Tetrahedron: Asymmetry 12 (2001) 2571–2580
son, L. A.; Stanger, H. E.; Krautha¨user, S.; Powell, D.
Budapest, 1999; pp. 376–377; (b) Gaucher, A.; Waksel-
man, M.; Mazaleyrat, J. P.; Crisma, M.; Formaggio, F.;
Toniolo, C. Tetrahedron 2000, 56, 1715–1723.
12. (a) Obrecht, D.; Spiegler, C.; Scho¨nholzer, P.; Mu¨ller, K.;
Heimgartner, H.; Stierli, F. Helv. Chim. Acta 1992, 75,
1666–1696; (b) Obrecht, D.; Bohdal, U.; Broger, C.; Bur,
D.; Lehmann, C.; Ruffieux, R.; Scho¨nholzer, P.; Spiegler,
C.; Mu¨ller, K. Helv. Chim. Acta 1995, 78, 563–580.
13. Mazaleyrat, J.-P.; Boutboul, A.; Lebars, Y.; Gaucher, A.;
Wakselman, M. Tetrahedron: Asymmetry 1998, 9, 2701–
2713.
14. Drey, C. N. C.; Ridge, R. J. J. Chem. Soc., Perkin Trans.
1 1981, 2468–2471.
15. (a) Hall, D. M.; Turner, E. E. J. Chem. Soc. 1955,
1242–1251; (b) Dixon, W.; Harris, M. M.; Mazengo, R.
Z. J. Chem. Soc. (B) 1971, 775–778.
R.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122, 3995–
4004; (l) Appella, D. H.; LePlae, P. R.; Raguse, T. L.;
Gellman, S. H. J. Org. Chem. 2000, 65, 4766–4769; (m)
Wang, X.; Espinosa, J. F.; Gellman, S. H. J. Am. Chem.
Soc. 2000, 122, 4821–4822; (n) Huck, B. R.; Fisk, J. D.;
Gellman, S. H. Org. Lett. 2000, 2, 2607–2610.
7. For some recent reviews on a,a-disubstituted glycines,
see: (a) Karle, I. L. Acc. Chem. Res. 1999, 32, 693–701;
(b) Benedetti, E. Biopolymers 1996, 40, 3–44; (c) Karle, I.
L. Biopolymers 1996, 40, 157–180; (d) Toniolo, C.;
Crisma, M.; Formaggio, F.; Benedetti, E.; Santini, A.;
Iacovino, R.; Saviano, M.; Di Blasio, B.; Pedone, C.;
Kamphuis, J. Biopolymers 1996, 40, 519–522.
8. (a) Mazaleyrat, J.-P.; Gaucher, A.; Wakselman, M.; Tch-
ertanov, L.; Guilhem, J. Tetrahedron Lett. 1996, 37,
&
2971–2974; (b) Mazaleyrat, J.-P.; Gaucher, A.; Savrda, J.;
16. (a) Maigrot, N.; Mazaleyrat, J.-P. Synthesis 1985, 1,
317–320; (b) Mazaleyrat, J.-P.; Wakselman, M. J. Org.
Chem. 1996, 61, 2695–2698.
Wakselman, M. Tetrahedron: Asymmetry 1997, 8, 619–
631.
9. (a) Mazaleyrat, J.-P.; Gaucher, A.; Wakselman, M.;
Toniolo, C.; Crisma, M.; Formaggio, F. In Peptides 1996;
Ramage, R.; Epton, R., Eds.; Mayflower Scientific, 1998;
pp. 623–624; (b) Formaggio, F.; Crisma, M.; Toniolo, C.;
Mazaleyrat, J.-P.; Wakselman, M. In Peptides 1998;
Bajusz, S.; Hudecz, F., Eds.; Akade´miai Kiado:
Budapest, 1999; pp. 352–353; (c) Formaggio, F.; Crisma,
M.; Toniolo, C.; Tchertanov, L.; Guilhem, J.; Maza-
leyrat, J. P.; Gaucher, A.; Wakselman, M. Tetrahedron
2000, 56, 8721–8734; (d) Formaggio, F.; Peggion, C.;
Crisma, M.; Toniolo, C.; Tchertanov, L.; Guilhem, J.;
Mazaleyrat, J. P.; Goubard, Y.; Gaucher, A.; Waksel-
man, M. Helv. Chim. Acta 2001, 84, 481–501.
10. Preliminary communication concerning this study:
Gaucher, A.; Bintein, F.; Wakselman, M.; Mazaleyrat,
J.-P. Tetrahedron Lett. 1998, 39, 575–578.
11. (a) Gaucher, A.; Mazaleyrat, J.-P.; Wakselman, M.;
Toniolo, C.; Crisma, M.; Formaggio, F. In Peptides 1998;
Bajusz, S.; Hudecz, F., Eds.; Akademiai Kiado:
17. (a) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763–780
and references cited therein; (b) Satoh, T.; Suzuki, S.
Tetrahedron Lett. 1969, 52, 4555–4558; (c) Heinzman, S.
W.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 6801–6802;
(d) Osby, J. O.; Heinzman, S. W.; Ganem, B. J. Am.
Chem. Soc. 1986, 108, 67–72.
18. (a) Kemp, D. S.; Curran, T. P. J. Org. Chem. 1988, 53,
5729–5731; (b) Kemp, D. S.; Carey, R. I. J. Org. Chem.
1989, 54, 3640–3646.
19. Yield based on the half amount of the starting racemic
compound.
20. Torok, G.; Peter, A.; Gaucher, A.; Wakselman, M.;
Mazaleyrat, J.-P.; Armstrong, D. W. J. Chromatogr. A
1999, 846, 83–91.
21. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543–2549.
22. Clark, T. D.; Buehler, L. K.; Ghadiri, M. R. J. Am.
Chem. Soc. 1998, 120, 651–656.