A novel approach to the solid-phase synthesis of peptides with a tetrazole at the C-terminus

Article abstract of DOI:10.1055/s-2007-986661

Peptidomimetics containing a C-terminal tetrazole can be easily prepared using modifications to traditional peptide synthesis protocols. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-986661

LETTER
2643
A Novel Approach to the Solid-Phase Synthesis of Peptides with a Tetrazole at
the C-Terminus
Solid-Phase Sy
a
nthesis of
rPeptides
a
with
a
Tetr
h
azole at the C-Term
J
inus . Gunn,a Alison Baker,b Richard D. Bertram,c Stuart L. Warriner*a
a
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
Fax +44(113)3436565; E-mail: s.l.warriner@leeds.ac.uk
b
c
Centre for Plant Sciences, University of Leeds, Leeds, LS2 9JT, UK
Infineum UK Ltd., PO Box 1, Milton Hill, Abingdon, Oxfordshire, OX13 6BB, UK
Received 17 July 2007
standard approach to peptide assembly requires attach-
ment of the peptide to the solid support via the C-terminal
carboxylic acid. Reported approaches to C-terminal tetra-
zolyl peptides have employed solution-phase couplings12
which we found to be very inefficient giving poor yields
and difficult purifications. Hallberg has employed in-
verted N-to-C peptide assembly on solid phase to prepare
tetrazole-containing protease inhibitors;5 however, this
methodology risks epimerization of the C-terminal resi-
due during activation to give byproducts which are diffi-
cult to separate. We reasoned that if the tetrazole could
provide a linkage to the solid support that was stable to
peptide synthesis conditions, then assembly of the target
sequences would be much more easily achieved.
Abstract: Peptidomimetics containing a C-terminal tetrazole can
be easily prepared using modifications to traditional peptide syn-
thesis protocols.
Key words: bioorganic chemistry, peptides, peptidomimetics,
solid-phase synthesis, tetrazole
Tetrazoles have long been recognized as classical carbox-
ylic acid isosteres.1 The acidity of the tetrazole has been
found to correspond well to that of the carboxyl group,2
and it often exhibits greater metabolic stability.3 Tetra-
zole-containing compounds have been explored, amongst
others, as antibacterial,4 antiviral,5 and antiarrhythmic
agents.6
As part of a study towards the development of novel in-
hibitors of peroxisomal protein trafficking we designed C-
terminally modified analogues of the pentapeptide
YQSKL (1), a well-studied ligand of the peroxisomal pro-
tein import receptor PEX5.7 Our targets included those
containing a C-terminal tetrazole equivalent of a range of
amino acids (2a–d, Figure 1). Fmoc-protected tetrazole
derivatives of leucine, tyrosine, phenylalanine, and cyclo-
hexylalanine were synthesized using variations of
literature procedures. Following conversion of the com-
mercially available Fmoc-protected amino acids into the
respective amides,8 dehydration with cyanuric chloride9
gave the nitrile. The protocol of Sharpless10 gave a good
conversion of the nitrile to the tetrazole for the leucine
derivative; however, some optimization of the solvent
system was required in order to prepare the tyrosine,
phenylalanine, and cyclohexylalanine analogues as the
precursors were insoluble in the recommended iso-
propanol–water mixture. Changing the solvent to a mix-
ture of THF and water (10:1) went some way to address
the problem, giving a solvent in which both the nitrile and
the sodium azide were soluble and enabling the prepara-
tion of Fmoc-protected amino tetrazoles 3a–d.11
OH
OH
O
O
H
H
N
N
H2N
N
H
N
H
CO2H
O
O
1
H2N
OH
O
NH2
OH
O
O
O
R
H
H
N
N
N
H2N
N
N
N
H
H
HN
O
N
H2N
O
NH2
2a R = i-Bu
2b R = CH2(4-OH-C6H4)
2c R = Bn
2d R = CH2Cy
Figure 1 YQSKL 1 and tetrazole-containing peptidomimetic
targets 2.
We were delighted to observe that the Fmoc-protected
amino tetrazole was easily coupled to 2-chlorotrityl
chloride polystyrene resin under basic conditions13 and
that the trityl tetrazole linkage proved to be stable to stan-
dard peptide coupling procedures. The loaded resin was
subjected to standard Fmoc deprotection using piperidine
followed by chain extension to couple the remainder of
the residues in the pentapeptide sequence, (lysine, serine,
glutamine, and tyrosine). A cleavage cocktail of TFA
With the required tetrazole building blocks in hand we
needed to assemble the target peptidomimetics. Prepara-
tion of the naturally occurring sequence 1 is easily per-
formed using solid-phase peptide synthesis. However, the
SYNLETT 2007, No. 17, pp 2643–2646
1
6
.1
0
.
2
0
0
7
Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986661; Art ID: D21207ST
© Georg Thieme Verlag Stuttgart · New York

2644
S. J. Gunn et al.
LETTER
N
R
N
N
b
a
N
+
Cl
Cl
N
FmocHN
3a R = i-Bu
N
R
Cl
HN
N
FmocHN
3b R = CH2(4-Ot-Bu-C6H4)
3c R = Bn
3d R = CH2Cy
OH
O
OH
O
R
H
H
N
N
N
N
N
N
H2N
N
H
N
c, b, d, b, e, b, f, b
N
g
H
2a–d
N
N
O
O
N
R
Cl
H2N
Ph
Cl
H2N
O
2a R = i-Bu
2b R = CH2(4-OH-C6H4)
2c R = Bn
NH2
2d R = CH2Cy
Scheme 1 Reagents and conditions: (a) DIPEA, CH2Cl2; (b) piperidine, DMF; (c) Fmoc-Lys(Boc)-OH (5 equiv), 2-(6-chloro-1H-benzotriazo-
le-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU, 4.9 equiv), HOBt (5 equiv), DIPEA (10 equiv); (d) Fmoc-Ser(t-Bu)-OH (5
equiv), HCTU (4.9 eqiuv), HOBt (5 equiv), DIPEA (10 equiv); (e) Fmoc-Gln(Trt)-OH (5 equiv), HCTU (4.9 equiv), HOBt (5 equiv), DIPEA
(10 equiv); (f) Fmoc-Tyr(t-Bu)-OH (5 equiv), HCTU (4.9 equiv), HOBt (5 equiv), DIPEA (10 equiv); (g) TFA, i-Pr3SiH, H2O.
References and Notes
Table 1 Preparation of Fmoc-Protected Amino Tetrazoles and their
Conversion into Pentapeptides
(1) (a) Morley, J. S. J. Chem. Soc. C 1969, 809. (b) Patani, G.
A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147.
(2) McManus, J. M.; Herbst, R. M. J. Org. Chem. 1959, 24,
1643.
(3) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra,
R. K. Prog. Med. Chem. 1980, 17, 151.
(4) Stone, G. W.; Zhang, Q.; Castillo, R.; Doppalapudi, V. R.;
Bueno, A. R.; Lee, J. Y.; Li, Q.; Sergeeva, M.; Khambatta,
G.; Georgopapadakou, N. H. Antimicrob. Agents
Chemother. 2004, 48, 477.
(5) Johansson, A.; Poliakov, A.; Åkerblom, E.; Wiklund, K.;
Lindeberg, G.; Winiwarter, S.; Danielson, U. H.;
Samuelsson, B.; Hallberg, A. Bioorg. Med. Chem. 2003, 11,
2551.
(6) Wu, S. D.; Fluxe, A.; Sheffer, J.; Janusz, J. M.; Blass, B. E.;
White, R.; Jackson, C.; Hedges, R.; Murawsky, M.; Fang,
B.; Fadayel, G. M.; Hare, M.; Djandjighian, L. Bioorg. Med.
Chem. Lett. 2006, 16, 6213.
Yields (%)
Fmoc-protected amino Acid to Amide to Nitrile to Tetrazole to
acid
amide
nitrile
tetrazole peptidec
leucine
91
72
63a
40b
34b
36b
96
79
95
78
tyrosine
91
75
phenylalanine
cyclohexylalanine
90
78
96
81
a Solvent: i-PrOH–H2O.
b Solvent: THF–H2O.
c Yield of isolated 2 starting from 3. Typically, approximately 10 mg
of peptide were prepared.
(7) (a) Gatto, G. J.; Maynard, E. L.; Guerrerio, A. L.;
Geisbrecht, B. V.; Gould, S. J.; Berg, J. M. Biochemistry
2003, 42, 1660. (b) Gatto, G. J.; Geisbrecht, B. V.; Gould, S.
J.; Berg, J. M. Nat. Struct. Biol. 2000, 7, 1091.
containing 2.5% triisopropyl silane and 2.5% water gave
efficient cleavage of the peptidomimetics from the resin
and simultaneous global deprotection of the side chains to
yield pentapeptides with a tetrazole moiety at the C-termi-
nus in excellent purity and isolated yield (Scheme 1,
Table 1).14
(8) Pozdnev, V. F. Tetrahedron Lett. 1995, 36, 7115.
(9) Maetz, P.; Rodriguez, M. Tetrahedron Lett. 1997, 38, 4221.
(10) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525.
(11) Analytical Data of the Fmoc-Protected Tetrazoles
Compound 3a: mp 175–177 °C; Rf = 0.8 (EtOAc); [a]D –32
(c 1, MeOH). IR (solid): nmax = 3308, 2961, 1682, 1532
cm–1. 1H NMR (500 MHz, CD3OD): d = 0.85 (3 H, d, J = 6.6
Hz, Ld1), 0.87 (3 H, d, J 6.6 Hz, Ld2), 1.54 (1 H, m, Lg), 1.69
(1 H, m, Lb1), 1.75 (1 H, m, Lb2), 4.10 (1 H, t, J = 6.5 Hz,
CH), 4.27 (1 H, dd, J = 10.5, 6.5 Hz CH2a), 4.38 (1 H, dd,
J = 10.4, 6.8 Hz, CH2b), 4.96 (1 H, dd, J = 5.6, 9.8 Hz, La),
7.18 (2 H, t, J = 7.4 Hz, FmocAr2), 7.28 (2 H, t, J = 7.4 Hz,
FmocAr3), 7.54 (2 H, t, J = 7.6 Hz, FmocAr1), 7.68 (2 H, d,
J = 7.5 Hz, FmocAr4). 13C NMR (75 MHz, CD3OD): d = 22.2
(Ld), 23.5 (Ld), 26.0 (Lg), 43.5 (La), 43.5 (Lb), 46.4 (CH2),
68.1 (CH), 121.2 (FmocAr1), 126.4 (FmocAr2), 128.4
In summary, we have demonstrated that peptides contain-
ing a C-terminal tetrazole function can be easily prepared
on solid phase by using the tetrazole as a point of attach-
ment. The procedure is simple to perform and provides
rapid access to this interesting range of peptidomimetics.
Acknowledgment
We are grateful to the EPSRC and Infineum for funding.
(FmocAr3), 129.1 (FmocAr4), 142.9 (FmocAr5), 145.4 (FmocAr6
)
Synlett 2007, No. 17, 2643–2646 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of Peptides with a Tetrazole at the C-Terminus
2645
158.6 (CO), 160.5 (Ltetrazole). MS (ES): m/z calcd for
(6 × 1 mL, 2 min), i-PrOH (3 × 1 mL, 5 min) and hexane
(4 × 1 mL, 2 min), sucked dry in air (10 min) then dried in
vacuo, over KOH (16 h) and stored at 5 °C. The loaded resin
was subject to standard Fmoc solid-phase peptide synthesis
conditions: Couplings were performed with a solution of the
amino acid to be coupled (5 equiv), HOBt (5 equiv), HCTU
(4.9 equiv), and DIPEA (10 equiv) in DMF for 60 min and
Fmoc deprotection was performed using a solution of 20%
piperidine in DMF. Cleavage from the resin and side-chain
deprotection was effected with TFA containing 2.5%
triisopropyl silane and 2.5% H2O. Peptides were purified by
preparative HPLC where necessary (with the exception of
2a; all the other peptides were single peaks by HPLC
following cleavage from the resin, and could be used without
further purification).
C21H22N5O2: 376.1779; found [M – H]–: 376.1773.
Compound 3b: mp 97 °C; Rf = 0.13 (10% MeOH in CH2Cl2);
[a]D –32 (c 2, DMF). IR (solid): nmax = 3308, 2976, 2763,
1679 cm–1. 1H NMR (500 MHz, CD3OD): d = 1.10 (9 H, s,
t-Bu), 3.06 (1 H, m, Yb1), 3.22 (1 H, m, Yb2), 3.98 (1 H, t,
J = 7.0 Hz, CH), 4.10 (1 H, m, CH2a), 4.20 (1 H, m, CH2b),
5.11 (1 H, t, J = 6.0 Hz, Ya), 6.72 (2 H, d, J = 8.1 Hz, YAr1),
7.00 (2 H, d, J, = 8.1 Hz, YAr2), 7.18 (2 H, t, J = 7.2 Hz,
FmocAr2), 7.27 (2 H, t, J = 7.3 Hz, FmocAr3), 7.48 (2 H, t,
J 8.1 Hz, FmocAr1), 7.67 (2 H, d, J = 7.4 Hz, FmocAr4). 13
C
NMR (75 MHz, CDCl3): d = 29.2 (CMe3), 38.2 (Yb), 47.5
(CH), 56.3 (Ya), 67.5 (CH2), 78.9 (OCt-Bu), 121.2
(FmocAr1), 125.5 (FmocAr2), 126.5 (YAr1), 128.4 (YArCH2),
129.1 (FmocAr3), 131.2 (FmocAr4), 133.3 (YAr2), 142.9
(FmocAr5), 145.5 (FmocAr6), 155.7 (YArOt-Bu), 158.4 (CO),
159.8 (Ytetrazole). MS (ES): m/z calcd for C28H28N5O3:
482.2198; found [M – H]–: 482.2180.
Compound 3c: mp 186–190 °C; Rf = 0.43 (20% MeOH in
CH2Cl2); [a]D –28 (c 1, DMF). IR (solid): nmax = 3316, 2899,
2469, 1680 cm–1. 1H NMR (500 MHz, DMSO-d6): d = 3.19
(1 H, dd, J = 10.3,13.6 Hz, Fb1), 3.30 (1 H, dd, J = 6.0,13.6,
Fb2), 4.16–4.25 (3 H, m, CH2, CH), 5.14 (1 H, t, J = 6.3 Hz,
Fa), 7.19–7.31 (7 H, m, FAr, FmocAr2), 7.42 (2 H, t, J = 7.4
Hz, FmocAr3), 7.63 (2 H, d, J = 5.3 Hz, FmocAr1), 7.89 (2 H,
d, J = 7.5 Hz, FmocAr4). 13C NMR (75 MHz, DMSO-d6): d =
38.7 (Fb), 46.9 (CH), 56.4 (Fa), 66.1 (CH2), 120.5 (FmocAr1),
125.7 (FmocAr2), 126.9 (FAr1), 127.4 (FAr2), 128.0 (FAr3),
128.6 (FmocAr3), 129.6 (FmocAr4), 137.5 (FAr-CH2), 141.0
(FmocAr5), 144.1 (FmocAr6), 156.0 (CO), 156.6 (Ftetrazole). MS
(ES): m/z calcd for C24H20N5O2: 410.1622; found [M – H]–:
410.1633.
Compound 2a: 1H NMR (500 MHz, D2O): d = 0.89 (3 H, d,
J = 6.6 Hz, Ld1), 0.94 (3 H, d, J = 6.6 Hz, Ld2), 1.26–1.41 (2
H, m, Kg), 1.55–1.68 (3 H, m, Lg, Kd), 1.70–1.87 (3 H, m,
Kb1, Lb1, Kb2,), 1.94 (1 H, m, Qb1), 2.04 (1 H, m, Qb2), 2.31
(2 H, at, J = 7.6 Hz, Qg), 2.94 (2 H, at, J = 7.6 Hz, Ke), 3.11
(1 H, dd, J = 5.6, 14.2 Hz, Yb1), 3.13 (1 H, dd, J = 5.0, 14.2
Hz, Yb2), 3.83 (1 H, dd, J = 5.8, 11.4 Hz, Sb1), 3.88 (1 H, dd,
J = 5.9, 11.4 Hz, Sb2) 4.22 (1 H, t, J = 7.3 Hz, Ya), 4.34 (1
H, t, J = 7.2 Hz, Ka), 4.38 (2 H, m, Sa, Qa), 5.33 (1 H, dd,
J = 6.0, 9.6 Hz, La), 6.85 (2 H, d, J = 8.4 Hz, YAr1), 7.12
(2 H, d, J = 8.4 Hz, YAr2). 13C NMR (125 MHz, D2O): d =
21.2 (Ld1), 22.2 (Ld2), 22.3 (Kg), 24.6 (Lg), 26.6 (Kd), 27.7
(Qb), 30.7 (Kb), 31.3 (Qg), 36.4 (Yb), 39.6 (Ke), 41.3 (Lb),
43.6 (La), 53.1 (Qa), 54.0 (Ka), 54.7 (Ya), 56.0 (Sa), 61.5
(Sb), 116.2 (YAr1), 125.7 (YArCH), 131.2 (YAr2), 155.6
(YArOH), 158.6 (Ltetrazole), 169.3 (Yco), 172.0 (Sco), 172.5
(Qco), 173.8 (Kco), 178.2 (QCONH2). MS (ES): m/z calcd for
C29H46N11O7: 660.3587; found [M – H]–: 660.3601.
Compound 3d: mp 178–181 °C. Rf = 0.32 (20% MeOH in
CH2Cl2); [a]D +3 (c 0.5, DMF). IR (solid): nmax = 3291,
3041, 2924, 2851, 1704 cm–1. 1H NMR (500 MHz,
DMSO-d6): d = 0.79–1.02 (2 H, m, Cha), 1.07–1.23 (4 H, m,
Cha), 1.30 (1 H, m, Chag), 1.56–1.87 (6 H, m, Cha, Chab),
4.28 (2 H, m, CH2), 4.39 (1 H, m, CH), 5.00 (1 H, dd, J = 7.5,
15.2 Hz, Chaa), 7.33 (2 H, t, J = 6.8 Hz, FmocAr2), 7.43 (2 H,
t, J = 8.6 Hz, FmocAr3), 7.72 (2 H, t, J = 8.9 Hz, FmocAr1),
7.90 (2 H, d, J = 8.1 Hz, FmocAr4). 13C NMR (75 MHz,
DMSO-d6): d = 25.9 (Cha), 26.1 (Cha), 26.3 (Cha), 32.0
(Cha), 33.2 (Chag), 33.7 (Chab), 47.0 (CH), 52.5 (Chaa),
66.0 (CH2), 120.5 (FmocAr1), 125.6 (FmocAr2), 127.4
(FmocAr3), 128.0 (FmocAr4), 141.1 (FmocAr5), 144.0
(FmocAr6), 156.2 (CO), 158.7 (Chatetrazole). MS (ES): m/z
calcd for C24H26N5O2: 416.2092; found [M – H]–: 416.2086.
(12) Rönn, R.; Gossas, T.; Sabnis, Y. A.; Daoud, H.; Åkerblom,
E.; Danielson, U. H.; Sandström, A. Bioorg. Med. Chem.
2007, 15, 4057.
Compound 2b: 1H NMR (500 MHz, D2O): d = 1.15–1.23 (2
H, m, Kg), 1.57–1.61 (4 H, m, Kd, Kb1, Kb2), 1.90 (1 H, m,
Qb1), 2.01 (1 H, m, Qb2), 2.30 (2 H, t, J = 7.5 Hz, Qg), 2.91
(2 H, t, J = 7.5 Hz, Ke), 3.11 (2 H, d, J = 7.0 Hz, Y5b), 3.21
(1 H, dd, J = 9.4, 14.0 Hz, Y1b1), 3.32 (1 H, dd, J = 6.5, 14.0
Hz, Y1b2), 3.75 (1 H, dd, J = 5.8, 11.4 Hz, Sb1), 3.85 (1 H,
dd, J = 5.8, 11.3 Hz, Sb2), 4.19–4.27 (2 H, m, Y1a, Ka), 4.36
(2 H, m, Sa, Qa), 5.49 (1 H, t, J = 6.5 Hz, Y5a), 6.82 (2 H,
d, J = 8.3 Hz, Y1Ar1), 6.84 (2 H, d, J = 8.3 Hz, Y5Ar1), 7.08
(2 H, d, J = 8.4 Hz, Y1Ar1), 7.11 (2 H, d, J = 8.4 Hz, Y5Ar1).
13C NMR (125 MHz, D2O): d = 24.7 (Kg), 29.1 (Kd), 30.2
(Qb), 33.2 (Kb), 33.7 (Qg), 38.9 (Yb), 40.1 (Yb), 42.0 (Ke),
49.0 (Y5a), 55.5 (Qa), 56.6 (Ka), 57.2 (Y1a), 58.4 (Sa), 63.9
(Sb), 118.4 (Y1Ar1), 118.7 (Y5Ar1), 128.2 (Y1Ar-CH), 130.6
(Y5Ar-CH), 133.5 (Y1Ar2), 133.7 (Y5Ar2), 157.4 (Y1ArOH),
158.0 (Y5ArOH), 160.6 (Y5tetrazole) 171.8 (Yco), 174.4 (Sco),
174.9 (Qco), 176.1 (Kco), 180.6 (QCONH2). MS (ES): m/z
calcd for C32H46N11O8: 712.3525; found [M + H]+:
(13) A substoichiometric quantity of tetrazole was loaded relative
to the theoretical loading of the resin. The success of loading
was determined by isolation of the target peptide. Yields are
calculated from the starting quantity of 3 employed in the
loading reaction.
712.3538.
Compound 2c: 1H NMR (500 MHz, D2O): d = 1.15–1.29 (2
H, m, Kg), 1.56–1.66 (4 H, m, Kd, Kb1, Kb2), 1.94 (1 H, m,
Qb1), 2.02 (1 H, m, Qb2), 2.30 (2 H, t, J = 7.5 Hz, Qg), 2.91
(2 H, t, J = 7.5 Hz, Ke), 3.13 (2 H, d, J = 6.7 Hz, Yb), 3.30
(1 H, dd, J = 9.9, 13.6 Hz, Fb1), 3.40 (1 H, dd, J = 7.2, 13.6
Hz, Fb2), 3.76 (1 H, dd, J = 6.4, 11.2 Hz, Sb1), 3.87 (1 H, dd,
J = 6.0, 11.2 Hz, Sb2), 4.23 (1 H, t, J = 7.3 Hz, Ya), 4.28 (1
H, t, J = 7.0 Hz, Ka), 4.35–4.40 (2 H, m, Sa, Qa), 5.55 (1 H,
t, J = 7.9 Hz, Fa), 6.87 (2 H, d, J = 8.2 Hz, YAr1), 7.13 (2 H,
d, J = 7.9 Hz, YAr2), 7.23 (2 H, d, J = 6.4 Hz, FAr1), 7.30–7.38
(3 H, m, FAr2, FAr3). 13C NMR (125 MHz, D2O): d = 24.7
(Kg), 29.0 (Kd), 30.1 (Qb), 33.2 (Kb), 33.7 (Qg), 38.8 (Yb),
41.1 (Fb), 41.9 (Ke), 49.1 (Fa), 55.5 (Qa), 56.5 (Ka), 57.1
(Ya), 58.3 (Sa), 63.9 (Sb), 118.7 (YAr2) 128.2 (YArCH2),
130.1 (FAr3), 131.6 (FAr2), 132.1 (FAr1), 133.6 (YAr1), 138.8
(14) Typical Procedure
2-Chlorotrityl chloride resin (Novabiochem, 100–200 mesh,
100 mg, 1.4 mmol/g loading) was suspended in CH2Cl2 (1
mL) and agitated (30 min), then drained. A solution of
Fmoc-amino tetrazole (0.08 mmol) and DIPEA (78.2 mL,
0.47 mmol) in DMF (1 mL) was added and the mixture
agitated (4 h). The solution was removed and the resin was
washed (DMF, 2 × 1 mL, 2 min) and then treated with a
solution of CH2Cl2–MeOH–DIPEA (80:15:5, 2 × 1 mL, 5
min) and then was washed again (DMF, 3 × 1 mL, 2 min).
The Fmoc group was removed (25% piperidine in DMF,
2 × 1 mL, 2 min). Finally, the resin was washed with DMF
Synlett 2007, No. 17, 2643–2646 © Thieme Stuttgart · New York

2646
S. J. Gunn et al.
LETTER
(FArCH2), 158.0 (YArOH), 161.0 (Ftetrazole), 171.7 (Yco), 174.3
(Sco), 174.9 (Kco), 176.0 (Qco), 180.6 (QCONH2). MS (ES):
m/z calcd for C32H46N11O7: 696.3576; found [M + H]+:
696.3587.
dd, J = 6.4, 8.2 Hz, Ka), 4.37–4.41 (2 H, m, Sa, Qa), 5.36 (1
H, dd, J = 6.4, 9.5 Hz, Chaa), 6.85 (2 H, d, J = 8.5 Hz, YAr1),
7.12 (2 H, d, J = 8.2 Hz, YAr2). 13C NMR (125 MHz, D2O):
d = 24.8 (Kg), 28.5 (Cha), 28.6 (Cha), 28.8 (Cha), 29.1 (Kd),
30.2 (Qb), 33.1 (Kb), 33.7 (Qg), 34.5 (Cha), 35.6 (Cha),
36.4 (Chag), 38.8 (Yb), 42.0 (Ke), 42.3 (Chab), 45.4 (Chaa),
55.5 (Qa), 56.4 (Ka), 57.1 (Ya), 58.5 (Sa), 63.9 (Sb), 118.7
(YAr2), 128.2 (YArCH2), 133.7 (YAr1), 158.0 (YArOH), 161.3
(Chatetrazole), 171.6 (YCO), 174.4 (SCO), 174.9 (KCO), 176.2
(QCO), 180.6 (QCONH2). MS (ES): m/z calcd for C32H51N11O7:
702.4046; found [M + H]+: 702.4048.
Compound 2d: 1H NMR (500 MHz, D2O): d = 0.89–1.04 (2
H, m, Cha), 1.16 (4 H, m, Cha), 1.23–1.31 (1 H, m, Cha),
1.32–1.42 (3 H, m, Kg, Chag), 1.57–1.72 (6 H, m, Cha, Kd),
1.75 (2 H, m, Kb1, Chab1), 1.84 (2 H, m, Kb2, Chab2), 1.94
(1 H, m, Qb1), 2.04 (1 H, m, Qb2), 2.32 (2 H, t, J = 7.6 Hz,
Qg), 2.94 (2 H, t, J = 8.1 Hz, Ke), 3.12 (2 H, d, J = 7.3 Hz,
Yb), 3.83 (1 H, dd, J = 5.7, 11.3 Hz, Sb1), 3.90 (1 H, dd, J =
5.7, 11.3 Hz, Sb2), 4.22 (1 H, t, J = 7.2 Hz, Ya), 4.33 (1 H,
Synlett 2007, No. 17, 2643–2646 © Thieme Stuttgart · New York

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