3-(1-aminoalkyl)pyrazole- and 4,5-dihydropyrazole-5-carboxylic acids as peptide bond replacements

Article abstract of DOI:10.1055/s-0030-1259303

Orthogonally protected 3-(1-aminoalkyl)pyrazole- and 4,5-dihydropyrazole-5- carboxylic acids are prepared by 1,3-dipolar cycloaddition of α-aminonitrile imines with electron-deficient alkenes; the pyrazole is incorporated into pseudotri- and tetrapeptides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259303

LETTER
211
3-(1-Aminoalkyl)pyrazole- and 4,5-Dihydropyrazole-5-carboxylic Acids as
Peptide Bond Replacements
4
,5-Dihydropyraz
a
ole-5-carbo
y
xylic
A
cids
m
a
s
Peptide Bond Re
o
placements nd C. F. Jones,* Laura E. Seager, Mark R. J. Elsegood
Department of Chemistry, Loughborough University, Loughborough, Leics, LE11 3TU, UK
Fax +44(1509)223925; E-mail: r.c.f.jones@lboro.ac.uk
Received 19 August 2010
Dedicated to Professor Alberto Brandi on the occasion of his 60th birthday
N
N
O
n
Abstract: Orthogonally protected 3-(1-aminoalkyl)pyrazole- and
4,5-dihydropyrazole-5-carboxylic acids are prepared by 1,3-dipolar
cycloaddition of a-aminonitrile imines with electron-deficient al-
kenes; the pyrazole is incorporated into pseudotri- and tetrapeptides.
H
N
H
N
R2
N
H
R2
R1
1 n = 1, 2
O
R1
O
2
4
Key words: cycloaddition, dipole, heterocycles, amino acids, pep-
tide mimics
N
NR2
N
NR2
H
N
H
N
R1
R1
O
O
Peptides mediate many biological processes of potential
medicinal significance, however, the therapeutic use of
peptides can be compromised by metabolic instability and
bioavailability issues.1 Amide bond modification and the
introduction of conformational restraints into bioactive
peptides are established strategies in the search for new
receptor agonists or antagonists, or for new peptidase in-
hibitors.2 There is thus an ongoing quest for peptide mi-
metics (‘pseudopeptides’) incorporating both replacement
of important amide bonds and restriction of conformation-
al freedom relative to the native peptide. One focus of this
search is on molecules that enforce a reverse turn on a pre-
dominantly peptide chain.3 As part of a programme for the
incorporation of heterocycles into peptide mimetics as
backbone constraints, we have previously reported cyclic
amidines 1 (Figure 1) as amide bond replacements4 and 3-
(1-aminoalkyl)-4-carboxyisoxazoles 2 as pseudodipep-
tides that may be regarded as replacing a cis-amide bond.5
3
Figure 1
Ph
+N N–
Ph
N
N
BocHN
OR
BocHN
BocHN
CO2R
CO2R
R1
O
R1
or
NNHPh
Cl
(via aldehyde)
BocHN
CO2Me
R1
R1
5
Scheme 1 Synthetic strategy for synthesis of (dihydro)pyrazoles
zone or hydrazide; these routes were compared by the use
of alanine as the starting amino acid.
1
Examples of 1 (n = 1) show a turn conformation by H
VT-NMR studies,4a whilst for 2 a turn conformation has
been observed in the solid state.6 We now report on the
synthesis of orthogonally protected derivatives of pyra-
zoles 3 and their flexible incorporation into pseudopeptide
segments, and of 4,5-dihydropyrazoles 4. Pyrazoles have
been shown to possess a range of interesting biological
properties.7
The preferred hydrazone route commenced by reduction
of commercial N-tert-butoxycarbonyl-(S)-alanine methyl
ester (DIBAL-H, toluene, –78 °C) to afford 2-(tert-butoxy-
carbonylamino)propanal (93%) which was not further pu-
rified, but converted directly into its phenylhydrazone 6
(PhNHNH2·HCl, NaOAc, EtOH–H2O, 70 °C; Scheme 2),
isolated as a solid (81%) that was stable towards racemis-
ation.11 To form the nitrile imine, the hydrazone was C-
chlorinated using NCS (EtOAc, 60 °C, 1 h) or the com-
plex of NCS with dimethyl sulfide (DMS) (CH2Cl2, –78
°C to 20 °C over 3 h).12 The hydrazonoyl chloride 5 was
then treated without further purification under a range of
basic conditions to form the nitrile imine in situ, in the
presence of ethyl propenoate as a suitable dipolarophile.
Using direct NCS chlorination, the pseudodipeptide dihy-
dropyrazole 7 was isolated in 41% yield using KHCO3
and a few drops of water (70 °C, 20 h) as the basic medi-
um (method 1);13,14 almost the same yield (40%) was ob-
tained using Et3N as the base (method 2).15 Improvement
to 57% yield of 7 was found by employing NCS·DMS fol-
The synthetic strategy (Scheme 1) is related to that em-
ployed in our assembly of isoxazole pseudopeptides5 and
used extensively in our work on cyclic tricarbonyl natural
products.8 It involves the dipolar cycloaddition of a-ami-
no-1,3-dipoles, in this case nitrile imines, with suitable
electron-deficient alkenes as dipolarophiles.9,10 Synthesis
of the dipole began with a-amino acids and followed two
routes to the required hydrazonoyl chloride 5, via a hydra-
SYNLETT 2011, No. 2, pp 0211–0214
x
x.
x
x.
2
0
1
1
Advanced online publication: 05.01.2011
DOI: 10.1055/s-0030-1259303; Art ID: G25510ST
© Georg Thieme Verlag Stuttgart · New York

212
R. C. F. Jones et al.
LETTER
lowed by 0.1 M NaHCO3 solution and tetrahexylammoni-
um chloride as a phase-transfer agent (20 °C, 2 h; method
3).16 In this case the product was removed by filtration and
needed no further purification, whereas the other proto-
cols required chromatography. An attempt using silver ac-
etate as base (toluene, 20 °C, 20 h, method 4) after
chlorination with NCS·DMS, led to dihydropyrazole 7 in
only 25% yield.17
NNHPh
H
NNHPh
Cl
i, ii
CO2Me
iii
BocHN
BocHN
BocHN
6
5
NHNHPh
O
Figure 2 X-ray crystal structure of one diastereomer of dihydropy-
razole 7 (crystallographic numbering)
iv
vii
v, vi
BocHN
CO2H
BocHN
N
NPh
as dipolarophile. Using NCS chlorination of 6 and method
1 gave a 25% yield of pyrazole 9, improved to 40% using
NCS⋅DMS and method 3 (Scheme 3). Chiral-phase HPLC
of pyrazole 9 showed essentially one peak, indicating one
enantiomer, that is, the amino acid chiral centre retaining
its integrity. This conclusion was supported when the se-
quence was repeated with N-tert-butoxycarbonyl-(RS)-
alanine methyl ester (Scheme 3). Thus DIBAL-H reduc-
8
BocHN
CO2Et
7
Scheme 2 Dihydropyrazole synthesis. Reagents and conditions: (i)
DIBAL-H, toluene, –78 °C; (ii) PhNHNH2·HCl, NaOAc, EtOH–
H2O, 70 °C; (iii) NCS, EtOAc, 60 °C, 1 h, or NCS·DMS, CH2Cl2,
–78 °C to 20 °C over 3 h (see text); (iv) H2C=CHCO2Et; methods 1–
4 (see text): method 1, KHCO3 aq, 70 °C, 20 h; method 2, Et3N; me- tion (95%) and reaction with phenylhydrazine gave the ra-
thod 3, 0.1 M NaHCO3 solution, (C6H13)4NCl, 20 °C, 2 h; method 4,
AgOAc, toluene, 20 °C, 20 h; (v) HOBt, EDCI, DMF, 20 °C, 2 h; (vi)
PhNHNH2, DMF, 0 °C; (vii) CCl4–Ph3P, MeCN, 20 °C, 17 h.
cemic hydrazone 10 (88%) which underwent C-
chlorination and cycloaddition with methyl propynoate
using method 1 to give racemic pyrazole 11 (30%).
Chiral-phase HPLC examination of 11 revealed two peaks
in a 1:1 ratio, clearly showing that the two enantiomers
could be distinguished by HPLC if present.
The alternative hydrazide route to dipole precursor 5 be-
gan with N-tert-butoxycarbonyl-(S)-alanine which was
activated [N-hydroxybenzotriazole (HOBt), EDCI, DMF,
20 °C, 2 h] and then added to phenylhydrazine (DMF,
0 °C) to afford the hydrazide 8 (56%; Scheme 2).18 For-
mation of the hydrazonoyl chloride 5 was accomplished
using CCl4–Ph3P (MeCN, 20 °C, 17 h).19 Cycloaddition
was completed using the crude chloride in EtOAc, accord-
ing to method 1, to give dihydropyrazole 7 (31%). The hy-
drazide route proved less efficient and less technically
convenient than the hydrazone approach, so that all subse-
quent cycloadditions used hydrazonyl chlorides prepared
via the hydrazone. The N-benzyloxycarbonylalanine se-
ries failed to provide any cycloadduct in our hands, as did
the use of N-tert-butoxy- and N-benzyloxycarbonyl hy-
drazones, or the more electron-rich dipolarophile, prop-2-
en-1-ol.20
NNHPh
H
N
NPh
NPh
from N-Boc-(S)-
alanine
i, ii
or iii, iv
BocHN
BocHN
BocHN
CO2Me
methyl ester
6
9
NNHPh
N
from N-Boc-(RS)-
alanine
methyl ester
i, ii
BocHN
CO2Me
H
10
11
Scheme 3 Pyrazole synthesis. Reagents and conditions: (i) NCS,
EtOAc, 60 °C, 1 h; (ii) HC≡CCO2Me, method 1; (iii) NCS⋅DMS,
CH2Cl2, –78 °C to 20 °C over 3 h; (iv) HC≡CCO2Me, method 3 (see
text and Scheme 2).
The scope of the cycloaddition to generate dihydropyra-
zoles was briefly explored (Figure 3). In unoptimised re-
actions using hydrazone 6, NCS chlorination and dipole
generation by method 1, tert-butyl propenoate as dipo-
larophile afforded dihydropyrazole 12 (27%; raised to
32% using method 3), tert-butyl 2-methylpropenoate gave
13 (25%), and dimethyl fumarate led to the 4,5-trans-di-
ester mixture 14 (12%); the amide N,N-dimethylpropen-
amide gave the dihydropyrazole amide 15 (25%). All of
12–15 were still isolated as 1:1 diastereomer mixtures, de-
spite the larger dipolarophile steric requirement. The use
of propenamide dipolarophiles alerted us to the potential
The dihydropyrazole 7 was shown to be a 1:1 mixture of
two diastereomers, by chiral-phase HPLC. Unfortunately,
the two epimers could not be routinely preparatively sep-
arated, although on one occasion a sample selectively
crystallised to afford crystals of one diastereomer of suf-
ficient quality for an X-ray diffraction study.21 This con-
firmed the regiochemistry of the cycloaddition to be as
predicted, affording the 5-ethoxycarbonyl derivative
(Figure 2).
That the diastereomeric mixture was derived from C-5
and not from epimerization of the original alanine a-car-
bon centre, was demonstrated by using methyl propynoate
Synlett 2011, No. 2, 211–214 © Thieme Stuttgart · New York

LETTER
3-(1-Aminoalkyl)pyrazole-5-carboxylic Acids as Peptide Bond Replacements
213
for assembling a dihydropyrazole pseudotripeptide spectroscopy22 shows that an intramolecular H bond be-
wherein the C-terminal residue formed part of the dipo- tween centres marked *, as would be found if the mole-
larophile. Thus N-propenoyl-(S)-proline methyl ester was cule adopted a reverse turn conformation, is unlikely but
prepared and used as dipolarophile, giving cycloadduct 16 cannot be discounted without further study.
(28%); once again, no diastereomeric preference was ob-
served.
N
NPh
i
iii
BocHN
CO2Me
N
NPh
N
NPh
CO2t-Bu
13
NPh
CONMe2
BocHN
BocHN
BocHN
N
NPh
N
NPh
CO2Me
9
CO2t-Bu
BocHN
BocHN
–Cl+H3N
12
NPh
CO2H
N
N
N
20
22
BocHN
BocHN
iv
N
ii
CO2Me
15
N
NPh
NPh
CO2Me
CO2Me
NPh
14
O
N
NPh
CO2Me
CO2Me
HN
O
NH
BocHN
N
CO2Me
O
CO2Me
NHBoc
23
16
21
i
Figure 3
N
NPh
N
NPh
CO2H
The cycloaddition sequence was repeated with valine as
initial amino acid. Thus N-tert-butoxycarbonyl-(S)-valine
methyl ester was reduced and converted into the solid
phenylhydrazone 17 (DIBAL-H, toluene, –78 °C, 76%;
PhNHNH2·HCl, NaOAc, EtOH–H2O, 70 °C, 96%). Cy-
cloaddition via NCS chlorination and method 1, with eth-
yl propenoate as partner, afforded the dihydropyrazole 18
(20%; Figure 4). Glycine as initial amino acid via the
same sequence gave only a low yield (10%) of cycload-
duct 19.
ii
O
O
NH
HN
*
O
NH
*
CO2Me
NHBoc
25
NHBoc
24
Scheme 4 Synthesis of pseudopeptides from pyrazole 9. Reagents
and conditions: (i) 2 M NaOH aq, THF, 20 °C, 3 h; (ii) EDCI, Et2O,
20 °C, 16; (iii) TFA, CH2Cl2, 20 °C, 16 h; then 2 M HCl aq; (iv) Et3N;
then EDCI, CH2Cl2, 20 °C, 19 h.
We have thus demonstrated the assembly of pyrazole and
dihydropyrazole amino acids by nitrile imine cycloaddi-
tion, and the feasibility of their incorporation into
pseudopeptides. Further investigations of the conforma-
tional properties of the pseudopeptides are under way.
NNHPh
H
N
NPh
CO2Et
N
NPh
CO2Et
BocHN
BocHN
NHBoc
17
18
19
Figure 4
Acknowledgment
We thank Loughborough University (studentship to L.E.S.) and the
EPSRC National Mass Spectrometry Service Centre (Swansea) for
some high resolution MS data and the EPSRC National Crystallo-
graphy Service (Southampton) for diffraction data for compound 7.
To demonstrate the incorporation of the novel heterocy-
clic amino acids into pseudopeptide sequences
(Scheme 4), the (S)-pyrazole 9 was first treated with aque-
ous base (2 M NaOH aq, THF, 20 °C, 3 h) to afford the 5-
carboxylic acid 20 (97%), which was coupled to glycine
methyl ester (EDCI, Et2O, 20 °C, 16 h) to give the
pseudotripeptide 21 (46%). Alternatively, the N-terminus
of 9 was unmasked to leave the amine salt 22 (TFA,
CH2Cl2, 20 °C, 16 h; then 2 M HCl aq, 65%), which was
coupled to N-tert-butoxycarbonylglycine (Et3N; then ED-
CI, CH2Cl2, 20 °C, 19 h) to give another pseudotripeptide,
dihydropyrazole 23 (46%). Successive coupling at both
termini was achieved by hydrolysis of ester 23 (2 M
NaOH aq, THF, 20 °C, 3 h) to give acid 24 (70%), and
coupling to glycine methyl ester using the EDCI protocol
employed above with acid 20. This afforded the pseudo-
tetrapeptide 25 (33%). Preliminary investigation of com-
pound 25 by variable-temperature solution 1H NMR
References and Notes
(1) For example: (a) Leung, D.; Abbenante, G.; Fairlie, D. P.
J. Med. Chem. 2000, 43, 305. (b) Olson, G. L.; Bolin, D. R.;
Bonner, M. P.; Bös, M.; Cook, C. M.; Fry, D. C.; Graves,
B. J.; Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V. S.;
Rusiecki, V. K.; Sarabu, R.; Sepinwall, J.; Vincent, G. P.;
Voss, M. E. J. Med. Chem. 1993, 36, 3039.
(2) For example: (a) Wu, Y.-D.; Gellman, S. Acc. Chem. Res.
2008, 41, 1231; and following articles in this issue, pp. 1233-
1438. (b) Penke, B.; Tóth, G.; Váradi, G. In Amino Acids,
Peptides and Proteins, Vol. 36; Davies, J. S., Ed.; RSC
Publications: Cambridge, 2007, 131; and earlier volumes in
this series.
Synlett 2011, No. 2, 211–214 © Thieme Stuttgart · New York

214
R. C. F. Jones et al.
LETTER
(3) For a selection of leading references, see the following and
references therein: (a) Chakraborty, T. K.; Rao, K. S.; Kiran,
M. U.; Jagadeesh, B. Tetrahedron Lett. 2008, 49, 2228.
(b) Lesma, G.; Sacchetti, A.; Silvani, A. Tetrahedron Lett.
2008, 49, 1293. (c) Lomlim, L.; Einsiedel, J.; Heinemann, F.
W.; Meyer, K.; Gmeiner, P. J. Org. Chem. 2008, 73, 3608.
(4) (a) Jones, R. C. F.; Dickson, J. J. Peptide Sci. 2001, 7, 220.
(b) Jones, R. C. F.; Dickson, J. J. Peptide Sci. 2000, 6, 621.
(c) Jones, R. C. F.; Gilbert, I. H.; Rees, D. C.; Crockett,
A. K. Tetrahedron 1995, 51, 6315. (d) Jones, R. C. F.;
Crockett, A. K. Tetrahedron Lett. 1993, 34, 7459.
(5) Jones, R. C. F.; Hollis, S. J.; Iley, J. N. Tetrahedron:
Asymmetry 2000, 11, 3273.
(6) Pillainayagam, T. PhD Thesis; Loughborough University:
UK, 2005.
(7) See, for example: Elguero, J.; Goya, P.; Jagerovic, N.; Silva,
A. M. S. Targets in Heterocyclic Systems, Vol. 6; Attanasi,
O. A.; Spinelli, D., Eds.; Italian Society of Chemistry:
Rome, 2002, 52.
(8) For leading references, see: (a) Jones, R. C. F.; Choudhury,
A. K.; Iley, J. N.; Loizou, G.; Lumley, C.; McKee, V. Synlett
2010, 654. (b) Jones, R. C. F.; Pillainayagam, T. A. Synlett
2004, 2815.
(9) For our exploration with azomethine imines, see: Jones,
R. C. F.; Hollis, S. J.; Iley, J. N. ARKIVOC 2007, (v), 152.
(10) For a similar approach to 4,5-dihydroisoxazole peptide
mimetics, see: Chung, Y. J.; Ryu, E. J.; Keum, G.; Kim,
B. H. Bioorg. Med. Chem. 1996, 4, 209.
4.14 (2 H, q, J = 7.2 Hz, CH2CH3), 4.43 (1 H, m, CH3CH),
4.54, 4,57 (each 0.5 H, dd, J = 7.2, 12.4 Hz, CHCO2Et,
diastereomers 1 and 2), 5.00 (1 H, br s, NH), 6.78 (1 H, m,
ArH), 6.93 (2 H, m, ArH), 7.18 (2 H, m, ArH). 13C NMR
(100 MHz, CDCl3): d = 14.2, 21.1 (CH3) 28.2 [(CH3)3C],
40.15 (4-CH2), 46.1 (5-CH), 61.7 (OCH2), 113.0 (PhCH),
113.0, 119.7, 119.8, 129.0 (4 × CH), 129.1 (2 × C), 145.3
(CN), 171.2, 171.5 (2 × CO). MS (EI): m/z = 362 [MH+],
171 (12), 154 (24), 147 (19), 123 (21), 111 (28), 109 (35), 95
(54), 81 (54), 69 (85), 57 (100), 55 (99). HRMS (EI): m/z
calcd for C19H27N3O4: 362.2074 [MH+]; found 362.2073
[MH+]. Anal. Calcd (%) for C19H27N3O4: C, 63.1; H, 7.5; N,
11.6. Found: C, 62.6; H, 7.2; N, 11.8.
(15) Sharp, J. T. In Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A.; Pearson, W. H., Eds.; John Wiley and
Sons: Hoboken, 2003, 473.
(16) (a) Molteni, G.; Ponti, A.; Orlandi, M. New J. Chem. 2002,
26, 1340. (b) Broggini, G.; Molteni, G.; Orlandi, M.
J. Chem. Soc., Perkin Trans. 1 2000, 3742.
(17) (a) For a review of silver salts in pyrazole synthesis, see:
Molteni, G. ARKIVOC 2007, (ii), 224. (b) De Benassuti, L.;
Garanti, L.; Molteni, G. Tetrahedron 2004, 60, 4627.
(18) Zhang, X.; Breslav, M.; Grimm, J.; Guan, K.; Huang, A.;
Liu, F.; Maryanoff, C. A.; Palmer, D.; Patel, M.; Qian, Y.;
Shaw, C.; Sorgi, K.; Stefanick, S.; Xu, D. J. Org. Chem.
2002, 67, 9471.
(19) Sakamoto, T.; Kikugawa, Y. Chem. Pharm. Bull. 1988, 36,
(11) Cf. for a-amino-oximes: ref. 10. For a-amino
semicarbazides: Ito, A.; Takahashi, R.; Baba, Y. Chem.
Pharm. Bull. 1975, 23, 3081.
800.
(20) Cf. ref. 16a for a discussion on the reduced rate of nitrile
imine cycloadditions with electron-rich dipolarophiles and/
or electron-poor dipoles.
(12) Patel, H. V.; Vyas, K. A.; Pandey, S. P.; Fernandes, P. S.
Tetrahedron 1996, 52, 661.
(13) Bach, K.; El-Seedi, H.; Jensen, H.; Nielsen, H.; Thomsen, I.;
Torssell, K. Tetrahedron 1994, 50, 7543.
(21) Crystal Data for 7
C19H27N3O4, M = 361.44, monoclinic, a = 5.14990 (10),
b = 11.4316 (4), c = 16.8254 (6) Å, b = 96.320 (2),
U = 984.52 (5) Å3, T = 120 (2) K, space group P21, graphite
monochromated Mo Ka radiation, l = 0.71073 Å, Z = 2,
Dc = 1.219 g cm–3, F(000) = 388, colourless, dimensions
0.36 × 0.09 × 0.04 mm3, m = 0.086 mm–1, 3.02 < q < 28.19°,
11290 reflections measured, 2363 unique reflections,
Rint = 0.0376. The structure was solved by direct methods
and refined on F2. Friedel pairs were merged due to the lack
of any significant anomalous scattering. wR2 = 0.0833 (all
data, 244 parameters); R1 = 0.0351 [2223 data with F2 >
2s(F2)]. Crystallographic data (excluding structure factors)
for the structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. 787832. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or e-
mail: deposit@ccdc.cam.ac.uk).
(14) Typical Procedure for NCS Chlorination and Method 1
(S)-3-(1-tert-Butoxycarbonylaminoethyl)-2-phenyl-4,5-
dihydro-1H-pyrazole-5-carboxylic Acid Ethyl Ester (7)
To (S)-[1-methyl-2-(phenylhydrazono)ethyl]carbamic acid
tert-butyl ester (5, 1.24 g, 4.72 mmol) in EtOAc (15 mL) at
60 °C was added NCS (0.71 g, 5.35 mmol, 1.1 equiv) and the
mixture stirred for 1 h. Ethyl propenoate (0.918 g, 1.0 mL,
9.16 mmol, 1.9 equiv), KHCO3 (2.41 g, 23.97 mmol, 5.1
equiv) and a few drops of H2O were added and the mixture
stirred at 70 °C for 20 h. The mixture was then filtered and
the filtrate concentrated under reduced pressure to give a
dark orange oil, purified by column chromatography on
silica gel eluting with light PE–EtOAc (7:1, v/v) to yield the
title compound 7 (0.72 g, 41%) in an inseparable 1:1 mixture
of diastereomers, as an orange solid; mp 93–95 °C. IR
(CHCl3): nmax = 3354 (NH), 1599 (C=N), 1708 (C=O), 1168
(CO), 750 (PhCH) cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.16 (3 H, t, J = 7.2 Hz, CH2CH3), 1.35 (3 H, d, J = 7.0
Hz, CH3CH), 1.38 [9 H, s, C(CH3)3], 2.99 (1 H, dd, J = 7.2,
17.6 Hz, 4-CHH), 3.24 (1 H, dd, J = 12.4, 17.6 Hz, 4-CHH),
(22) For leading references, see: (a) Huck, B. R.; Fisk, J. D.;
Gellman, S. H. Org. Lett. 2000, 2, 2607. (b) Fisk, J. D.;
Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122,
5443.
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