Sodium borohydride reduction of carbamoyl azide function: A synthesis of N-protected N'-formyl-gem-diaminoalkyl derivatives

Article abstract of DOI:10.1002/ejoc.201300442

A simple, efficient two-step synthesis of N-protected N′-formyl-gem- diaminoalkyl derivatives is reported. The procedure involves the unprecedented reduction of the carbamoyl azide of α-N-Boc/Fmoc/Z-protected amino acids and dipeptides (Boc = tert-butoxycarbonyl, Fmoc = 9-fluorenylmethoxycarbonyl, Z = benzyloxycarbonyl) by treatment with NaBH₄ at room temperature. The reaction proceeds rapidly (45 min) without detectable epimerization (by HPLC-ESI-MS analysis) and is not influenced by the nature of the starting carbamoyl azide. The ¹H and ¹³C NMR analyses of the synthesized N-protected N′-formamides were carried out in [D ₆]DMSO. The spectra exhibited the presence of two rotameric forms in solution as a result of the restricted rotation around the N-CO formyl bond. The integration of the N-CH-N protons of the two isomers showed that the cis isomer (rotamer B) was the more abundant conformer by 60 to 78 %. The reported synthesis represents the potential value of carbamoyl azides as versatile chiral starting materials for many synthetic purposes. A simple two-step synthesis of N-protected N′-formyl-gem-diaminoalkyl derivatives is reported that employs the reduction of the carbamoyl azide of N-protected amino acids and N-protected dipeptide acids with NaBH₄. This racemization-free protocol is compatible with the most commonly used N-protecting groups. Copyright

Full text of DOI:10.1002/ejoc.201300442

FULL PAPER
DOI: 10.1002/ejoc.201300442
Sodium Borohydride Reduction of Carbamoyl Azide Function: A Synthesis of
N-Protected NЈ-Formyl-gem-diaminoalkyl Derivatives
Giancarlo Verardo*[a] and Andrea Gorassini[b]
Keywords: Synthetic methods / Amino acids / Peptides / Reduction / Protecting groups / NMR spectroscopy
A simple, efficient two-step synthesis of N-protected NЈ-
thesized N-protected NЈ-formamides were carried out in
formyl-gem-diaminoalkyl derivatives is reported. The pro- [D6]DMSO. The spectra exhibited the presence of two rotam-
cedure involves the unprecedented reduction of the carb-
amoyl azide of α-N-Boc/Fmoc/Z-protected amino acids and
dipeptides (Boc = tert-butoxycarbonyl, Fmoc = 9-fluorenyl-
methoxycarbonyl, Z = benzyloxycarbonyl) by treatment with
NaBH4 at room temperature. The reaction proceeds rapidly
(45 min) without detectable epimerization (by HPLC-ESI-MS
analysis) and is not influenced by the nature of the starting
carbamoyl azide. The 1H and 13C NMR analyses of the syn-
eric forms in solution as a result of the restricted rotation
around the N–CO formyl bond. The integration of the N–CH–
N protons of the two isomers showed that the cis isomer
(rotamer B) was the more abundant conformer by 60 to 78%.
The reported synthesis represents the potential value of
carbamoyl azides as versatile chiral starting materials for
many synthetic purposes.
esters,[17] ammonium formate,[18] trimethyl orthoformate,[19]
N-(diethylcarbamoyl)-N-methoxyformamide,[20] and N,N-
dimethylformamide in the presence of imidazole.[21] How-
ever, only two reports[22] describe the conversion of the
carboxyl component of N-protected amino acids into the
corresponding formamide (see Figure 1) with the retention
of configuration. These derivatives represent an interesting
alternative to the unstable asymmetric N-protected gem-di-
amines[23] that are particularly useful to the synthesis of
partially modified retro-inverso peptides.[24]
Introduction
Compounds that contain the N-formyl moiety are im-
portant derivatives and are employed as anti-inflamma-
tory,[1] anticancer,[1,2] immunogenic,[3] and antibacterial[4]
agents. Moreover, they have wide applications to heterocy-
clic[5] pharmaceuticals and organic synthesis. For example,
formamides are used as a catalyst in the enantioselective
hydrosilylation of C=N[6] and C=O[6i,6n,7] bonds as well as
in the asymmetric allylation[8] of carbonyl compounds.
Furthermore, they are useful starting materials in the syn-
theses of isocyanides,[5a,9] formamidines,[10] N-monomethyl-
amines,[11] and Vilsmeier reagents.[12] The formyl group is
also employed to protect the amino group in peptide syn-
thesis.[13]
A number of N-formylation methods have been reported
in recent years, and some of these can also be applied to
the amino group of α-amino acid derivatives. These include
the direct reaction of formic acid in the presence of ionic
liquids[14] or thiamine hydrochloride[15] or the employment
of activated formic acid by using 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide (EDCI).[16] Many other useful
formylating reagents have been reported such as formic acid
Figure 1. Conversion of N-protected amino acid into correspond-
ing formamide (PG = protecting group).
According to the most common procedure for the prepa-
ration of N,NЈ-diurethane gem-diamines, the synthesis of
these formamides involves a Curtius rearrangement to con-
vert the N-formyl protected α-amino acid azide into the
corresponding isocyanate. The subsequent alcoholysis of
[a] Department of Chemical Sciences and Technologies, University the obtained isocyanate affords the corresponding N-
formyl-NЈ-alkoxycarbonyl gem-diamine[13f] (see Scheme 1,
of Udine,
Via del Cotonificio 108, 33100 Udine, Italy
Route A). Sureshbabu and co-workers[22] have proposed an
Fax: +39-0432-558803
E-mail: giancarlo.verardo@uniud.it
alternative approach (see Scheme 1, Route B) by treating
the N-protected α-amino isocyanate with formic acid in the
presence of 4-dimethylaminopyridine (DMAP).
Recently, we reported the preparation of the carbamoyl
azides of α-N-protected amino acids,[25] and by studying
their reactivity,[26] we realized that this functional group can
Homepage: http://www.uniud.it
[b] Dipartimento di Storia e Tutela dei Beni Culturali, University
of Udine,
Palazzo Caiselli, Vicolo Florio 2, 33100 Udine, Italy
E-mail: andrea.gorassini@uniud.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300442.
Eur. J. Org. Chem. 2013, 5387–5397
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5387

G. Verardo, A. Gorassini
FULL PAPER
Scheme 1. General approaches to the synthesis of N-formyl-NЈ-protected asymmetric gem-diamines.
be considered a –N=C=O equivalent. Taking into account
However, under our experimental conditions, NaBH4 in
this acquired experience and that some authors have re- the presence of a large amount of water increased the pH[29]
ported the direct reduction of aryl and alkyl isocyanates and favored the hydrolysis of carbamoyl azide 1Zd into the
into the corresponding formamides[27] or N-methyl- corresponding amine 7, which in the presence of unreacted
amines,[27a,28] we now report our study of the reduction of 1Zd gave symmetrical urea 5 (see Scheme 3).[25]
the carbamoyl azide moiety with NaBH4.
Results and Discussion
In the present study, the carbamoyl azide of α-N-benzyl-
oxycarbonylphenylalanine (1Zd), which was obtained from
Z-Phe-OH (2Zd, Z = benzyloxycarbonyl) through the cor-
responding mixed anhydride 3Zd in the presence of a buff-
ered aqueous solution (KH2PO4/K2HPO4, pH ≈ 7) of
NaN3,[26] was used as the model substrate. The first ap-
proach involved the addition of powdered NaBH4
(3.5 equiv.) directly to the well-stirred final tetrahydrofuran
(THF)/water buffer biphasic mixture that contained the
prepared carbamoyl azide 1Zd (1.0 equiv.) at room tem-
perature. The ESI-MS analysis of the intact reaction mix-
ture showed the complete disappearance of 1Zd after 3 h
and the formation of the corresponding N-benzyloxycar-
bonyl-NЈ-formyl-gem-diamine 4Zd accompanied by sym-
metrical urea 5 in an approximate 70:30 ratio. It is interest-
Scheme 3.
To reduce as much as possible the contact of NaBH4
with water, the reaction was carried out as previously de-
scribed, but, instead, it was gently stirred. As expected, the
ing that the reduction of the carbamoyl azide function with
NaBH4 exclusively afforded N-formyl derivative 4Zd and
not N-methylamine 6 (see Scheme 2).
reaction was slower, and after 4 h, only 37% of 1Zd was
converted into N-formyl 4Zd. The symmetrical urea 5 was
absent. These preliminary results pointed out that the pres-
ence of water greatly affected the course of the reaction. In
fact, when the reduction was performed on the separated
organic phase (THF) that contained carbamoyl azide 1Zd
at room temperature, a lesser amount of NaBH4 (2.5 equiv.
with respect to 1Zd) was used, and the ESI-MS analysis
of the intact mixture showed that after 45 min, there was
complete conversion of 1Zd into the corresponding N-for-
myl derivative 4Zd. On the basis of these experimental find-
ings, the present protocol was successfully extended to other
N-Boc/Fmoc/Z-protected α-amino acids 2 (see Table 1).
The obtained results as well as some properties of the N-
protected NЈ-formyl-gem-diamines 4 prepared are reported
Scheme 2.
5388
in Table 2.
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Eur. J. Org. Chem. 2013, 5387–5397

Sodium Borohydride Reduction of Carbamoyl Azide Function
Table 1. Synthesis of formamides 4 derived from N-protected α-amino acids.[a]
1–4
PG[b]
R
1–4
PG[b]
R
Ba
Bb
Bc
Bd
Fa
Fb
Fc
Fd
Boc
Boc
Boc
Boc
Fmoc
Fmoc
Fmoc
Fmoc
CH3
Fe
Fmoc
Fmoc
Cbz
Cbz
Cbz
Cbz
Cbz
1H-indole-3-CH2
CH3S(CH2)2
CH3
(CH3)2CHCH2
PhCH2
1H-indole-3-CH2
NH2CO(CH2)2
(CH3)2CH
(CH3)2CHCH2
PhCH2
Ff
Za
Zc
Zd
Ze
Zg
CH3
(CH3)2CH
(CH3)2CHCH2
PhCH2
[a] Reagents and conditions: (a) N-methylmorpholine (NMM, 1.03 equiv.), THF, isobutyl chloroformate (IBCF, 1.10 equiv.), 10 min at
–15 °C; (b) KH2PO4 (0.50 equiv.), H2O and then KH2PO4 (5.00 equiv.), NaN3 (2.50 equiv.), H2O, 30 min at 0 °C and then 1.5 h at 45 °C;
(c) separation of the organic phase (THF) and then NaBH4 (2.50 equiv.), 45 min at room temp. [b] Boc = tert-butoxycarbonyl, Fmoc =
9-fluorenylmethoxycarbonyl, Cbz = benzyloxycarbonyl.
Table 2. Yields and properties of formamides 4 derived from N-protected α-amino acids.
Product[a]
Solvent for recrystallization
% Yield[b]
M.p. [°C]
[α]2D0 (c, solvent)
cis/trans[c]
Boc-gAla-CO-H (4Ba)
Boc-gVal-CO-H (4Bb)
Boc-gLeu-CO-H (4Bc)
Boc-gPhe-CO-H (4Bd)
Fmoc-gAla-CO-H (4Fa) toluene
Fmoc-gVal-CO-H (4Fb) CHCl3/hexane
Fmoc-gLeu-CO-H (4Fc) CHCl3/hexane
Fmoc-gPhe-CO-H (4Fd) toluene
Fmoc-gTrp-CO-H (4Fe) toluene
Fmoc-gMet-CO-H (4Ff) toluene
Cbz-gAla-CO-H (4Za)
Cbz-gLeu-CO-H (4Zc)
Cbz-gPhe-CO-H (4Zd)
Cbz-gTrp-CO-H (4Ze)
Cbz-gGln-CO-H (4Zg)
CHCl3/hexane
toluene
CHCl3/hexane
toluene
83
84
86
85
81
80
84
89
94
91
85
87
80
93
83
118–120
182–184
126–128
169–171
+7.02 (c = 0.6, MeOH)
+15.93 (c = 0.8, MeOH)
+4.84 (c = 0.8, MeOH)
+22.60 (c = 0.9, MeOH)
+38.81 (c = 0.3, MeOH)[d]
+19.10 (c = 0.7, MeOH)[e]
+29.92 (c = 0.5, MeOH)[f]
+5.54 (c = 0.9, DMSO)
+3.40 (c = 0.6, DMSO)
+19.90 (c = 0.4, MeOH)[g]
+14.84 (c = 0.3, DMSO)
+13.78 (c = 0.5, DMSO)
+4.71 (c = 0.4, DMSO)
+7.11 (c = 0.4, DMSO)
+5.69 (c = 0.5, DMSO)
60:40
65:35
66:34
67:33
66:34
66:34
73:27
68:32
68:32
66:34
60:40
64:36
61:39
60:40
60:40
212–214[d]
223–225[e]
184–186[f]
225–227 (dec)
238–240 (dec)
192–194[g]
143–145[h]
126–128[i]
192–194[j]
181–183
toluene
toluene
CHCl3/hexane
toluene
AcOEt/MeOH
184–186
1
[a] The g notation represents the gem-diamine derivative (see ref.[24n]). [b] Isolated yield. [c] Determined by H NMR integration of the
two distinct N–CH–N signals that are generated by the two rotamers (conformations of the two rotamers were defined as trans for
rotamer A and cis for rotamer B). [d] Ref.[22b] m.p. 178 °C, [α]2D4 = +1.22 [c = 0.9, dimethyl sulfoxide (DMSO)]. [e] Ref.[22b] m.p. 183 °C,
[α]2D4 = +1.00 (c = 1.0, DMSO). [f] Ref.[22b] m.p. 156 °C, [α]2D4 = –2.00 (c = 1.2, DMSO). [g] Ref.[22b] m.p. 165 °C, [α]2D4 = –1.62 (c = 1.3,
DMSO). [h] Ref.[22a] m.p. 132–33 °C. [i] Ref.[22a] m.p. 123–24 °C. [j] Ref.[22a] m.p. 174–75 °C.
With the aid of ESI-MS analysis, we observed that the (see Table 3, rotamer A), they appeared as a doublet (3Jab
rate of the reduction (45 min) was not influenced by the = 11.3–11.6 Hz) and a broad triplet (J = 10.1–10.3 Hz) in
nature of the α-N-protection and the amino acid side chain the δ range of 7.98–8.16 and 7.77–8.13 ppm, respectively.
that was present in the starting carbamoyl azide 1.
The assignments of the resonances were made on the basis
1
All the H and 13C NMR spectroscopic data of 4, which of the assumption that the trans proton-proton coupling
3
were recorded in [D6]DMSO, resulted in complex spectra, constant (i.e., Jab) was greater than that of the cis iso-
which was evidence of the presence of two rotameric forms mer.[30] Moreover, the carbamate NH resonance, which was
in solution as a result of the restricted rotation around the sometimes obscured by overlapping aromatic signals, ap-
N–CO formyl bond (see Table 3). (The conformations of peared as a broad singlet in the δ range 7.18–7.93 and 6.92–
the two rotamers were defined as trans for rotamer A and 7.70 ppm for the trans and cis isomer, respectively (see
cis for rotamer B) In particular, the 1H NMR spectra exhib- Table 3). Finally, the Hc proton, linked to the α-carbon of
ited a broad doublet (3Jbc = 7.3–9.4 Hz) and a doublet of the starting amino acid, appeared as a multiplet (J = 7.0–
doublets (3Jab = 1.6–1.8 Hz, 4Jac = 0.6–0.8 Hz) in the ranges 8.1 Hz) in the range from δ = 5.02 to 5.56 ppm for rot-
from δ = 7.93 to 8.38 ppm and δ = 7.89 to 8.00 ppm, which amer B and from δ = 4.44 to 5.26 ppm for rotamer A (see
were assigned to Hb and Ha, respectively, of the N-formyl Table 3). The ratio of the two isomers, as deduced from the
moiety of the cis isomer (see Table 3, rotamer B). When the integration of the two N–CH–N signals of 4, ranged from
Ha and Hb resonances of the trans isomer did not overlap 60:40 to 73:27 in favor of the cis isomer (see Table 2).
Eur. J. Org. Chem. 2013, 5387–5397
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5389

G. Verardo, A. Gorassini
FULL PAPER
1
Table 3. H NMR spectroscopic data of formamides 4 derived from N-protected α-amino acids.[a]
Product
δ NHbCOHa [J in Hz]
δ NHbCOHa [J in Hz]
cis trans
8.04, br. d 7.82, br. t
(7.6) (10.3)
7.93, br. d 7.77, br. t
(9.4) (10.2)
7.96, br. d 7.81, br. t
(9.1) (10.3)
8.23, br. d overlapped
(7.6)
8.18, br. d overlapped
(7.6)
δ NHCOO
δ N–CHc–N [J in Hz]
cis
trans
cis
trans
cis
trans
Boc-gAla-CO-H
(4Ba)
Boc-gVal-CO-H
(4Bb)
Boc-gLeu-CO-H
(4Bc)
Boc-gPhe-CO-H
(4Bd)
Fmoc-gAla-CO-H
(4Fa)
Fmoc-gVal-CO-H
(4Fb)
Fmoc-gLeu-CO-H
(4Fc)
Fmoc-gPhe-CO-H
(4Fd)
Fmoc-gTrp-CO-H
(4Fe)
Fmoc-gMet-CO-H
(4Ff)
Cbz-gAla-CO-H
(4Za)
Cbz-gLeu-CO-H
(4Zc)
Cbz-gPhe-CO-H
(4Zd)
Cbz-gTrp-CO-H
(4Ze)
Cbz-gGln-CO-H
(4Zg)
7.89, dd
(1.6, 0.8)
7.97, dd
(1.8, 0.6)
7.92, dd
(1.6, 0.6)
7.92, dd
(1.6, 0.6)
7.53, dd
(1.6, 0.6)
7.99, dd
(1.6, 0.6)
7.95, dd
(1.6, 0.6)
7.96, dd
(1.6, 0.6)
8.00, dd
(1.6, 0.6)
7.98, dd
(1.6, 0.6)
7.91, dd
(1.6, 0.8)
7.94, dd
(1.7, 0.8)
7.94, dd
(1.8, 0.8)
7.98, dd
(1.6, 0.8)
7.95, dd
(1.6, 0.6)
8.12, d
(11.5)
8.06, d
(11.5)
8.12, d
(11.5)
overlapped
7.06, br. s 7.26, br. s
6.92, br. s 7.18, br. s
6.98, br. s 7.25, br. s
overlapped 7.48, br. s
7.65, br. s 7.84, br. s
7.59, br. s overlapped
overlapped overlapped
overlapped overlapped
overlapped overlapped
7.59, br. s 7.79, br. s
7.66, br. s 7.85, br. s
7.60, br. s 7.83, br. s
7.54, br. s 7.78, br. s
7.70, br. s 7.93, br. s
7.65, br. s 7.85, br. s
5.29, sext
(7.0)
5.02, q
(8.1)
4.93, sext
(7.0)
4.44, q
(8.1)
5.29, quint
(7.7)
5.38, quint
(7.7)
4.79, quint
(7.9)
4.96, quint
(7.8)
overlapped
overlapped
overlapped
overlapped
overlapped
overlapped
5.38, sext
(7.0)
5.08, q
(8.1)
4.99, sext
(7.0)
4.50, q
(8.1)
overlapped overlapped
overlapped overlapped
5.37, quint
(7.6)
5.46, quint
(7.6)
4.86, quint
(7.6)
5.05, quint
(7.6)
8.32, br. d overlapped
(7.6)
8.30, br. d overlapped
(7.6)
8.21, br. d overlapped
(8.0)
8.23, br. d 7.99, br. t
5.41–5.73, m 4.95–5.24, m
5.38, quint
(7.3)
5.37, sext
(7.0)
4.96, quint
(7.3)
4.91–5.12, m
8.15, d
(11.6)
8.16, d
(11.6)
7.98, d
(11.3)
overlapped
(7.3)
8.22, br. d 7.99, br. t
(7.4) (10.2)
8.38, br. d 8.13, br. t
(7.8) (10.1)
(10.1)
5.38, quint
(7.6)
5.46, quint
(7.5)
5.56, quint
(7.5)
4.77–4.96, m
5.02–5.19, m
5.05–5.26, m
8.35, br. d overlapped
(7.6)
8.24, br. d overlapped
(7.3)
overlapped
5.27, quint
(7.6)
4.85, quint
(7.6)
[a] [D6]DMSO as solvent, δ values in ppm.
1
To support our assignments, we carried out two H-1H peared from the 1H NMR spectrum of Boc-gAla-CO-H
decoupling experiments on Boc-gAla-CO-H (4Ba) by irra- (4Ba). The two apparent sextets (δ = 4.93 and 5.29 ppm, J
diating the two apparent sextets (J = 7.0 Hz) that are gener- = 7.0 Hz), arising from the Hc proton of rotamer A and B
ated by the N–CH–N proton of rotamer A and B and are (Table 3), appeared as two quartets (J = 6.5 Hz) that were
centered at δ = 4.93 and 5.29 ppm, respectively (see centered at δ = 4.93 and 5.29 ppm, respectively. The absence
Table 3). The irradiation of the higher field multiplet (trans of the NHb proton also simplified the pattern of the formyl
isomer) collapsed the broad N–H formyl triplet (δ = proton. The doublet of doublets of the cis isomer became
7.82 ppm, J = 10.3 Hz) into a broad doublet centered at the a doublet centered at δ = 7.84 ppm with a coupling constant
same chemical shift (δ = 7.82 ppm) and with a coupling 4Jac = 0.6 Hz, and the doublet of the trans isomer collapsed
constant (J = 11.5 Hz) that is identical to that observed for into a singlet at δ = 8.04 ppm.
the corresponding formyl proton (doublet at δ = 8.12 ppm,
The 13C NMR spectra of 4 showed that larger differences
3Jab = 11.5 Hz, see Table 3). On the other hand, irradiation in the chemical shifts between the two isomers came from
of the lower field multiplet (cis isomer) caused the broad the N–CH–N and the formyl C=O carbons, with the trans
N–H formyl doublet (δ = 8.04 ppm, J = 7.6 Hz) to become isomer signals shifted downfield. In particular, the reso-
a broad singlet at the same frequency (see Table 3). More- nances of the N–CH–N carbons were in the range of δ =
3
over, the doublet of doublets (δ = 7.89 ppm, Jab = 1.6 Hz, 52.4–60.7 ppm for the cis isomer and δ = 56.1–65.6 ppm for
4Jac = 0.8 Hz), which was generated by the corresponding the trans isomer. The formyl C=O carbon signals ranged
formyl proton, collapsed to a doublet at the same chemical from δ = 159.7 to 160.3 ppm for the cis isomer and from δ
shift and with a coupling constant identical to the 3Jab that = 163.9 to 164.9 ppm for the trans isomer.
was observed for the doublet of doublets (see Table 3).
To test the generality of the present protocol, we ex-
Upon treatment with D2O, all the broad N–H signals disap- tended the reaction to some N-protected dipeptide acids 8
5390
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5387–5397

Sodium Borohydride Reduction of Carbamoyl Azide Function
(see Table 4). The critical steps in the overall reaction were found for all the crude reaction mixtures that were obtained
the synthesis of mixed anhydride 9 and its reaction with from
the
syntheses
of
N-protected
NЈ-form-
NaN3 through a Curtius rearrangement of the correspond- yl-gem-diaminoalkyl derivatives 12 and confirmed that the
ing acyl azide to lead to carbamoyl azide 10.[25] In fact, as present protocol proceeds with the retention of configura-
previously reported,[31] the ESI-MS analysis of the intact tion. The results and some properties of N-protected di-
mixture that was obtained after the synthesis of mixed an- peptidyl-NЈ-formamides 12 are reported in Table 5.
hydride 9 showed the complete conversion of 9 into the cor-
Also in this case, the complexity of the 1H and 13C NMR
responding 2,4-disubstituted-5(4H)-oxazolone 11, which spectra of 12 was evidence of the presence of the two rota-
was prone to racemization under basic conditions[32] (see mers A (trans isomer) and B (cis isomer), which resulted
Table 4).
from the restricted rotation around the N–CO formyl bond
Under our experimental conditions, the reaction of in the [D6]DMSO solution. Similar to the 1H NMR spectra
NaN3 with 11 occurred in the presence of aqueous of gem-diamines 4, when the formyl proton of the trans iso-
KH2PO4, which maintained the mixture at pH ≈ 7. More- mer (rotamer A) did not overlap with another resonance, it
over, with respect to the protocol for the syntheses of the appeared as a doublet (J = 11.2–11.5 Hz) that was centered
N-protected NЈ-formyl-gem-diamines 4, the reaction time from δ = 8.16 to 8.27 ppm, whereas that of the cis isomer
for the preparation of mixed anhydride 9 was reduced from (rotamer B) became a doublet (J = 1.2–1.4 Hz) in the range
10 to 5 min in this case, and the subsequent reaction of from δ = 7.91 to 8.10 ppm. These two doublets collapsed
oxazolone 11 with NaN3 was initially carried out at a lower into two singlets upon treatment with D2O. The integration
temperature (–15 °C).
of the two distinct N–CH–N signals, which were generated
To exclude any incursion of racemization under our ex- by the two rotamers, showed that the cis isomer was also
perimental conditions, Fmoc-l-Leu-l-gPhg-CO-H (12Fch) the more abundant isomer of the N-protected NЈ-formyl-
was prepared starting from Fmoc-l-Leu-l-Phg-OH (8Fch). gem-diaminoalkyl derivatives 12 (see Table 5, 65–78%).
The HPLC-ESI-MS profile of the intact reaction mixture
Despite the presence of the two isomers, all the 13C
was compared with that of the diastereoisomeric derivative NMR spectra of 12 exhibited a single set of peaks for the
Fmoc-l-Leu-dl-gPhg-CO-H (diast-12Fch) obtained em- carbons of the carbamate moiety. Otherwise, as expected,
ploying a 50:50 diastereoisomeric mixture of Fmoc-l-Leu- larger differences in the chemical shifts were observed for
dl-Phg-OH (diast-8Fch). The HPLC-ESI-MS analysis of the N–CH–N and C=O carbon signals. In particular, the
diast-12Fch showed two distinct peaks with retention times resonance of the N–CH–N carbon was in the range of δ =
(Rt) = 58.3 and 58.8 min with the same area, whereas that 50.8–55.7 ppm and 54.2–60.1 ppm for the cis and trans iso-
obtained from 12Fch exhibited only one peak at Rt = mer, respectively. The formyl and the amide C=O carbons
58.8 min. The analogous chromatographic behavior was of the cis isomer (rotamer B) appeared in the range of δ =
Table 4. Synthesis of formamides 12 derived from N-protected dipeptide acids.[a]
8–12
PG
R
R1
Bbe
Bcd
Fca
Fch
Fda
Zda
Zdd
Boc
Boc
Fmoc
Fmoc
Fmoc
Cbz
(CH3)2CH
(CH3)2CHCH2
(CH3)2CHCH2
(CH3)2CHCH2
PhCH2
PhCH2
PhCH2
1H-indole-3-CH2
PhCH2
CH3
Ph
CH3
CH3
PhCH2
Cbz
[a] Reagents and conditions: (a) NMM (1.03 equiv.), THF, IBCF (1.10 equiv.), 5 min at –15 °C; (b) KH2PO4 (0.50 equiv.), H2O and then
KH2PO4 (5.00 equiv.), NaN3 (2.50 equiv.), H2O, 15 min at –15 °C, then 15 min at 0 °C, and then 1.5 h at 45 °C; (c) separation of the
organic phase (THF) and then NaBH4 (2.50 equiv.), 45 min at room temp.
Eur. J. Org. Chem. 2013, 5387–5397
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5391

G. Verardo, A. Gorassini
FULL PAPER
Table 5. Yields and properties of formamides 12 derived from N-protected dipeptide acids.
Product
Solvent for recrystallization % Yield[a]
M.p. [°C]
[α]2D0 (c, solvent)
cis/trans[b]
Boc-Val-gTrp-CO-H (12Bbe)
Boc-Leu-gPhe-CO-H (12Bcd)
Fmoc-Leu-gAla-CO-H (12Fca)
Fmoc-Leu-gPhg-CO-H (12Fch)
Fmoc-Phe-gAla-CO-H (12Fda)
Cbz-Phe-gAla-CO-H (12Zda)
Cbz-Phe-gPhe-CO-H (12Zdd)
CHCl3/hexane
toluene
CHCl3/hexane
CHCl3/hexane
toluene/EtOAc
toluene
82
80
80
81
72
77
87
170–172
173–175
214–216
223–225
230–232
211–213[c]
232–234
–4.87 (c = 0.6, DMSO)
–8.81 (c = 0.2, DMSO)
+4.1 (c = 0.5, DMSO)
–3.75 (c = 0.3, DMSO)
+15.87 (c = 0.1, DMSO)
+26.67 (c = 0.4, DMSO)
+8.48 (c = 0.9, DMSO)
67:33
65:35
62:38
78:22
65:35
65:35
67:33
toluene
1
[a] Isolated yield. [b] Determined by H NMR integration of the two distinct N–CH–N signals that are generated by the two rotamers.
(Conformations of the two rotamers were defined to be trans for rotamer A and cis for rotamer B). [c] Ref.[22a] m.p. 158–60 °C.
terized by the term app (apparent), and this refers only to the ap-
pearance and may be an oversimplification. To assign the reso-
nances of the N–CH–NH–CO–H protons of the two isomers (rota-
159.9–160.4 ppm and 170.4–171.7 ppm, whereas for the
trans isomer (rotamer A), these signals shifted downfield to
a range from δ = 163.9 to 164.5 ppm and from δ = 171.0 to
172.3 ppm, respectively.
1
mers A and B), H-1H decoupling experiments were performed by
irradiating the corresponding N–CH–N proton at the center of its
signal. Optical rotations were measured in suitable solutions
(g/100 mL) at 20 °C with an AP-300 automatic polarimeter from
ATAGO. Elemental analyses were performed with a FlashEA 1112
Series CHNS-O elemental analyser. Melting points were deter-
mined with an automatic Mettler (Mod. FP61) melting point appa-
ratus.
Conclusions
In summary, we have developed a synthetic method for
the preparation of N-protected NЈ-formyl-gem-diamino-
alkyl derivatives 4 and 12 through the unprecedented re-
duction of the carbamoyl azide of N-protected α-amino ac-
ids and dipeptides with NaBH4. In contrast to other re-
ported methods, this simple, efficient, and racemization-free
protocol is compatible with the most commonly used N-
protecting groups (Boc, Fmoc, Cbz). The complexity exhib-
General Procedure for the Synthesis of Formamides 4 Derived from
N-Protected α-Amino Acids: N-methylmorpholine (0.28 mL,
2.58 mmol) was slowly added to a stirred solution of N-protected
α-amino acid 2 (2.50 mmol) in THF (20 mL). After 5 min, isobutyl
chloroformate (0.36 mL, 2.75 mmol) was slowly added to the reac-
tion mixture, which was cooled to –15 °C. The stirring was contin-
ued for 10 min at the same temperature. The reaction mixture was
subsequently warmed to 0 °C, and an aqueous solution of KH2PO4
(1.4 m, 0.89 mL, 1.25 mmol) was added in one portion followed,
after 5 min, by the addition of an aqueous solution of KH2PO4
(1.4 m, 8.93 mL, 12.50 mmol) and NaN3 (0.41 g, 6.25 mmol). After
30 min at 0 °C, the mixture was warmed to 45 °C, stirred for 1.5 h,
and then cooled to room temperature. The organic phase was sepa-
rated. Powdered NaBH4 (0.24 g, 6.25 mmol) was rapidly added to
the THF solution of carbamoyl azide 1 at room temperature with
vigorous stirring. After an additional 45 min, the THF was re-
moved under reduced pressure. The crude residue was dissolved in
AcOEt (80 mL), and the resulting solution was washed sequentially
with 5% HCl (10 mL), water (10 mL), 5% Na2CO3 (10 mL), water
(10 mL), and then a saturated brine solution (10 mL). The organic
layer was finally dried with Na2SO4. After filtration and evapora-
tion in vacuo of the solvent, the crude product was recrystallized
from suitable solvents to afford the N-protected NЈ-formyl-gem-
diaminoalkyl derivatives 4 in 80–94% overall yield (see Table 2).
1
ited by H and 13C NMR spectra of the N-protected NЈ-
formyl-gem-diaminoalkyl derivatives 4 and 12 highlighted
the presence of two rotamers in the [D6]DMSO solution,
with the cis isomer predominating. These compounds may
be useful building blocks in the syntheses of biologically
active compounds that contain an asymmetric gem-diamine
moiety, such as partially modified retro-inverso peptides.
Experimental Section
General Methods: N-protected dipeptide acids 8 were prepared by
a reported procedure.[31] All solvents and reagents were purchased
from Aldrich Chemical Company and used without further purifi-
cation. The reactions were monitored by ESI-MS in the positive
and negative ion modes with a Finnigan LXQ (linear trap) by dilut-
ing the intact reaction mixture with methanol and directly infusing
the resulting solution into the ion source with the aid of a syringe
pump. HPLC-ESI-MS analyses were performed with the same in-
strument coupled to a Dionex UltiMate 3000 RS Pump and
equipped with a Dionex UltiMate 3000 RS Autosampler. The LC
separations were performed with a Hypersil AA-ODS column
(200 mmϫ 2.1 mm, 5 mm) from Agilent Technologies that oper-
ated at 30 °C with a flow rate of 0.2 mL/min and a mobile phase
composed of water (A) and methanol (B). The proportion of sol-
vent B was linearly increased to 80% over a period of 50 min and
kept at this concentration until the end of the run. IR spectra were
obtained by the KBr technique for solids with a Bruker Vector 22
spectrophotometer and recorded in the range of 4000–400 cm–1.
The 1H and 13C NMR spectroscopic data were recorded in [D6]-
DMSO at 40 °C with a Bruker AC-F 200 spectrometer at 200 and
50 MHz, respectively. The NMR resonances are reported as δ val-
ues relative to TMS (0 ppm). Some 1H NMR multiplets are charac-
Boc-gAla-CO-H (4Ba): IR (KBr): ν = 3249, 2984, 1716, 1682, 1647,
˜
1532, 1397, 1367, 1324, 1245, 1157, 1140, 1111, 1052, 760,
615 cm–1. MS (ESI+): m/z = 211 [M + Na]+ Ǟ(MS2) 155, 111.
C8H16N2O3 (188.23): calcd. C 51.05, H 8.57, N 14.88; found C
1
51.10, H 8.55, N 14.85. Data for trans isomer: H NMR: δ = 1.24
(app t, J = 6.5 Hz, 3 H, CH3), 1.38 [s, 9 H, (CH3)3C], 4.93 (app
sext, J = 7.0 Hz, 1 H, gCH), 7.26 (br. s, 1 H, NHCOO), 7.82 (br.
t, J = 10.3 Hz, 1 H, NHCOH), 8.12 (d, J = 11.5 Hz, 1 H,
HCO) ppm. 13C NMR: δ = 20.6, 28.0, 56.1, 78.1, 154.4, 163.9 ppm.
1
Data for cis isomer: H NMR: δ = 1.24 (app t, J = 6.5 Hz, 3 H,
CH3), 1.38 [s, 9 H, (CH3)3C], 5.29 (app sext, J = 7.0 Hz, 1 H, gCH),
7.06 (br. s, 1 H, NHCOO), 7.89 (dd, J = 1.6, 0.8 Hz, 1 H, HCO),
8.04 (br. d, J = 7.6 Hz, 1 H, NHCOH) ppm. 13C NMR: δ = 20.8,
28.0, 52.4, 77.9, 154.0, 159.7 ppm.
5392
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Eur. J. Org. Chem. 2013, 5387–5397

Sodium Borohydride Reduction of Carbamoyl Azide Function
Boc-gVal-CO-H (4Bb): IR (KBr): ν = 3312, 2984, 2970, 2870, 1688, Fmoc-gVal-CO-H (4Fb): IR (KBr): ν = 3299, 2974, 2961, 1692,
˜
˜
1670, 1544, 1501, 1380, 1363, 1345, 1295, 1245, 1212, 1172, 1148,
1661, 1646, 1551, 1511, 1464, 1451, 1385, 1339, 1294, 1250, 1207,
1121, 1044, 1007, 711, 651 cm–1. MS (ESI+): m/z = 239 [M +
1018, 735 cm–1. MS (ESI+): m/z = 361 [M + Na]+ Ǟ(MS2) 316.
Na]+ Ǟ(MS2) 183, 139. C10H20N2O3 (216.28): calcd. C 55.53, H C20H22N2O3 (338.41): calcd. C 70.99, H 6.55, N 8.28; found C
1
9.32, N 12.95; found C 55.55, H 9.30, N 12.99. Data for trans 71.02, H 6.52, N 8.25. Data for trans isomer: H NMR: δ = 0.90
isomer: 1H NMR: δ = 0.86 and 0.89 [2 d, J = 6.2, 6.2 Hz, 6 H,
and 0.91 [2 d, J = 6.1, 6.1 Hz, 6 H, (CH3)2CH], 1.72–1.99 [m, 1 H,
(CH3)2CH], 1.39 [s, 9 H, (CH3)3C], 1.68–1.95 [m, 1 H, (CH3)2CH], (CH3)2CH], 4.15–4.38 (m, 3 H, CHCH2O), 4.50 (app q, J = 8.1 Hz,
4.44 (app q, J = 8.1 Hz, 1 H, gCH), 7.18 (br. s, 1 H, NHCOO),
7.77 (br. t, J = 10.5 Hz, 1 H, NHCOH), 8.06 (d, J = 11.5 Hz, 1 H,
1 H, gCH), 7.25–7.48 (m, 4 H, Ar), 7.65–7.77 (m, 2 H, Ar), 7.79–
7.96 (m, 4 H, Ar, NHCOH, NHCOO), 8.02–8.14 (m, 1 H,
HCO) ppm. 13C NMR: δ = 18.4, 18.7, 20.1, 31.0, 65.6, 78.1, 154.8, HCO) ppm. 13C NMR: δ = 18.6, 18.8, 31.0, 46.6, 66.0, 65.5, 120.0,
1
164.3 ppm. Data for cis isomer: H NMR: δ = 0.84 and 0.85 [2 d,
J = 6.8, 6.8 Hz, 6 H, (CH3)2CH], 1.38 [s, 9 H, (CH3)3C], 1.68–1.95
125.0, 127.0, 127.5, 140.6, 143.8, 155.6, 164.4 ppm. Data for cis
isomer: 1H NMR: δ = 0.85 and 0.86 [2 d, J = 6.7, 6.7 Hz, 6 H,
[m, 1 H, (CH3)2CH], 5.02 (app q, J = 8.1 Hz, 1 H, gCH), 6.92 (br. (CH3)2CH], 1.72–1.99 [m, 1 H, (CH3)2CH], 4.15–4.38 (m, 3 H,
s, 1 H, NHCOO), 7.93 (br. d, J = 9.4 Hz, 1 H, NHCOH), 7.97 (dd, CHCH2O), 5.08 (app q, J = 8.1 Hz, 1 H, gCH), 7.25–7.48 (m, 4
J = 1.8, 0.6 Hz, 1 H, HCO) ppm. 13C NMR: δ = 17.9, 18.0, 20.1, H, Ar), 7.59 (br. s, 1 H, NHCOO), 7.65–7.77 (m, 2 H, Ar), 7.79–
31.7, 60.6, 77.8, 154.5, 160.1 ppm.
7.96 (m, 2 H, Ar), 7.99 (dd, J = 1.6, 0.6 Hz, 1 H, HCO), 8.02–8.14
(m, 1 H, NHCOH) ppm. 13C NMR: δ = 18.0, 18.1, 31.7, 46.6, 60.7,
65.4, 120.0, 125.1, 127.0, 127.5, 140.6, 143.7, 155.1, 160.3 ppm.
Boc-gLeu-CO-H (4Bc): IR (KBr): ν = 3335, 3320, 2957, 1688, 1652,
˜
1545, 1502, 1394, 1367, 1290, 1234, 1213, 1157, 1144, 1061, 708,
636 cm–1. MS (ESI+): m/z = 253 [M + Na]+ Ǟ(MS2) 197, 153.
C11H22N2O3 (230.31): calcd. C 57.37, H 9.63, N 12.16; found C
Fmoc-gLeu-CO-H (4Fc): IR (KBr): ν = 3300, 2958, 2870, 1690,
˜
1660, 1549, 1508, 1464, 1449, 1386, 1284, 1266, 1228, 1207,
1
57.40, H 9.65, N 12.15. Data for trans isomer: H NMR: δ = 0.86
735 cm–1. MS (ESI+): m/z = 375 [M + Na]+ Ǟ(MS2) 330.
[d, J = 6.5 Hz, 6 H, (CH3)2CH], 1.39 [s, 9 H, (CH3)3C], 1.38–1.70 C21H24N2O3 (352.43): calcd. C 71.57, H 6.86, N 7.95; found C
1
(m, 3 H, CHCH2), 4.79 (app quint, J = 7.9 Hz, 1 H, gCH), 7.25
(br. s, 1 H, NHCOO), 7.81 (br. t, J = 10.3 Hz, 1 H, NHCOH), 8.12 [d, J = 5.9 Hz, 6 H, (CH3)2CH], 1.35–1.69 (m, 3 H, CHCH2), 4.15–
(d, J = 11.5 Hz, 1 H, HCO) ppm. 13C NMR: δ = 21.6, 22.0, 23.8,
4.41 (m, 3 H, CHCH2O), 4.86 (app quint, J = 7.6 Hz, 1 H, gCH),
71.60, H 6.81, N 7.97. Data for trans isomer: H NMR: δ = 0.87
28.0, 42.2, 58.4, 78.1, 154.1, 164.0 ppm. Data for cis isomer: 1H 7.25–7.48 (m, 4 H, Ar), 7.63–7.77 (m, 2 H, Ar), 7.83–7.93 (m, 3 H,
NMR: δ = 0.87 [d, J = 6.2 Hz, 6 H, (CH3)2CH], 1.38 [s, 9 H,
(CH3)3C], 1.38–1.70 (m, 3 H, CHCH2), 5.29 (app quint, J = 7.7 Hz,
Ar, NHCOO), 8.01–8.24 (m, 2 H, HCO, NHCOH) ppm. 13C
NMR: δ = 21.8, 22.0, 23.9, 42.1, 46.7, 58.7, 65.4, 120.0, 125.0,
1 H, gCH), 6.98 (br. s, 1 H, NHCOO), 7.92 (dd, J = 1.6, 0.6 Hz, 1 127.0, 127.6, 140.7, 143.8, 155.5, 164.3 ppm. Data for cis isomer:
H, HCO), 7.96 (br. d, J = 9.1 Hz, 1 H, NHCOH) ppm. 13C NMR:
δ = 21.9, 22.1, 24.0, 28.0, 43.3, 54.2, 77.8, 154.2, 159.8 ppm.
1H NMR: δ = 0.87 [d, J = 5.9 Hz, 6 H, (CH3)2CH], 1.35–1.69 (m,
3 H, CHCH2), 4.15–4.41 (m, 3 H, CHCH2O), 5.37 (app quint, J =
7.6 Hz, 1 H, gCH), 7.25–7.48 (m, 4 H, Ar), 7.63–7.77 (m, 3 H, Ar,
NHCOO), 7.83–7.93 (m, 2 H, Ar), 7.95 (dd, J = 1.6, 0.6 Hz, 1 H,
HCO), 8.01–8.24 (m, 1 H, NHCOH) ppm. 13C NMR: δ = 21.9,
22.2, 24.1, 43.2, 46.7, 54.4, 65.3, 120.0, 125.1, 127.0, 127.6, 140.7,
143.7, 154.9, 160.0 ppm.
Boc-gPhe-CO-H (4Bd): IR (KBr): ν = 3350, 3323, 2989, 1690,
˜
1664, 1540, 1496, 1391, 1366, 1297, 1220, 1171, 1009, 699 cm–1.
MS (ESI+): m/z = 287 [M + Na]+ Ǟ(MS2) 231, 187. C14H20N2O3
(264.32): calcd. C 63.62, H 7.63, N 10.60; found C 63.61, H 7.65,
N 10.57. Data for trans isomer: 1H NMR: δ = 1.37 [s, 9 H,
(CH3)3C], 2.76–3.02 (m, 2 H, CH2), 4.96 (app quint, J = 7.8 Hz, 1 Fmoc-gPhe-CO-H (4Fd): IR (KBr): ν = 3292, 3020, 1687, 1649,
˜
H, gCH), 7.12–7.35 (m, 5 H, Ar), 7.48 (br. s, 1 H, NHCOO), 7.93– 1552, 1509, 1465, 1451, 1439, 1396, 1349, 1295, 1265, 1229, 1050,
8.02 (m, 2 H, NHCOH) ppm. 13C NMR: δ = 28.0, 39.7, 61.4, 78.3, 1027, 735, 705 cm–1. MS (ESI+): m/z = 409 [M + Na]+ Ǟ(MS2)
126.2, 128.0, 129.3, 137.1, 154.2, 164.0 ppm. Data for cis isomer:
1H NMR: δ = 1.34 [s, 9 H, (CH3)3C], 2.76–3.02 (m, 2 H, CH2), C 74.56, H 5.78, N 7.27. Data for trans isomer: 1H NMR: δ =
5.38 (app quint, J = 7.7 Hz, 1 H, gCH), 7.12–7.35 (m, 6 H, Ar, 2.80–3.08 (m, 2 H, Ph-CH2), 4.12–4.40 (m, 3 H, CHCH2O), 5.05
364. C24H22N2O3 (386.45): calcd. C 74.59, H 5.74, N 7.25; found
NHCOO), 7.92 (dd, J = 1.6, 0.6 Hz, 1 H, HCO), 8.23 (br. d, J = (app quint, J = 7.6 Hz, 1 H, gCH), 7.15–7.49 (m, 9 H, Ar), 7.59–
7.6 Hz, 1 H, NHCOH) ppm. 13C NMR: δ = 28.0, 40.1, 57.2, 78.0,
126.1, 127.9, 129.1, 137.3, 154.5, 160.0 ppm.
7.75 (m, 2 H, Ar), 7.81–7.93 (m, 3 H, Ar, NHCOO), 7.99–8.17 (m,
2 H, NHCOH) ppm. 13C NMR: δ = 39.7, 46.5, 61.7, 64.4, 119.9,
124.9, 126.3, 126.9, 127.5, 128.1, 129.2, 137.0, 140.6, 143.6, 155.2,
Fmoc-gAla-CO-H (4Fa): IR (KBr): ν = 3296, 1696, 1655, 1544,
˜
1
164.9 ppm. Data for cis isomer: H NMR: δ = 2.80–3.08 (m, 2 H,
1504, 1445, 1385, 1343, 1264, 1222, 1203, 1105, 1083, 1058,
736 cm–1. MS (ESI+): m/z = 333 [M + Na]+ Ǟ(MS2) 288.
C18H18N2O3 (310.35): calcd. C 69.66, H 5.85, N 9.03; found C
Ph-CH2), 4.12–4.40 (m, 3 H, CHCH2O), 5.46 (app quint, J =
7.6 Hz, 1 H, gCH), 7.15–7.49 (m, 9 H, Ar), 7.59–7.75 (m, 3 H, Ar,
NHCOO), 7.81–7.93 (m, 2 H, Ar), 7.96 (dd, J = 1.6, 0.6 Hz, 1 H,
HCO), 8.32 (br. d, J = 7.6 Hz, 1 H, NHCOH) ppm. 13C NMR: δ
= 40.0, 46.5, 57.6, 65.4, 119.9, 125.0, 126.2, 126.9, 127.5, 128.0,
129.0, 137.2, 140.6, 143.7, 154.8, 160.1 ppm.
1
69.63, H 5.88, N 9.00. Data for trans isomer: H NMR: δ = 1.30
(d, J = 6.5 Hz, 3 H, CH3), 4.15–4.40 (m, 3 H, CHCH2O), 4.99 (app
sext, J = 7.0 Hz, 1 H, gCH), 7.27–7.48 (m, 4 H, Ar), 7.66–7.75 (m,
2 H, Ar), 7.84 (br. s, 1 H, NHCOO), 7.85–7.91 (m, 2 H, Ar), 7.95–
8.10 (m, 2 H, NHCOH) ppm. 13C NMR: δ = 20.5, 46.6, 56.4, 65.4, Fmoc-Trp-CO-H (4Fe): IR (KBr): ν = 3292, 3020, 1687, 1649, 1552,
˜
119.9, 124.9, 126.9, 127.4, 140.6, 143.7, 155.0, 163.9 ppm. Data for
1509, 1465, 1451, 1439, 1396, 1349, 1295, 1265, 1229, 1050, 1027,
cis isomer: 1H NMR: δ = 1.28 (d, J = 6.5 Hz, 3 H, CH3), 4.15–
735, 705 cm–1. MS (ESI+): m/z = 448 [M + Na]+ Ǟ(MS2) 403.
4.40 (m, 3 H, CHCH2O), 5.38 (app sext, J = 7.0 Hz, 1 H, gCH), C26H23N3O3 (425.49): calcd. C 73.39, H 5.45, N 9.88; found C
1
7.27–7.48 (m, 4 H, Ar), 7.65 (br. s, 1 H, NHCOO), 7.66–7.75 (m, 73.35, H 5.50, N 9.90. Data for trans isomer: H NMR: δ = 3.07
2 H, Ar), 7.85–7.91 (m, 2 H, Ar), 7.93 (dd, J = 1.6, 0.6 Hz, 1 H,
(app d, J = 7.0 Hz, 2 H, Ar-CH2), 4.06–4.43 (m, 3 H, CHCH2O),
HCO), 8.18 (br. d, J = 7.6 Hz, 1 H, NHCOH) ppm. 13C NMR: δ 4.95–5.24 (m, 1 H, gCH), 6.93–7.49 (m, 8 H, Ar), 7.55–7.76 (m, 4
= 20.7, 46.6, 52.7, 65.3, 119.9, 125.0, 126.9, 127.4, 140.6, 143.6,
154.6, 159.8 ppm.
H, Ar, NHCOO), 7.82–7.93 (m, 2 H, Ar), 8.04–8.16 (m, 2 H,
NHCOH), 10.81 (br. s, 1 H, Ar-NH) ppm. 13C NMR: δ = 30.1,
Eur. J. Org. Chem. 2013, 5387–5397
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5393

G. Verardo, A. Gorassini
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46.5, 61.0, 65.5, 109.4, 111.2, 118.0, 118.3, 119.9, 120.7, 123.9,
1187, 1047, 1014, 743, 696, 518 cm–1. MS (ESI+): m/z = 321 [M +
124.9, 126.9, 127.0, 127.4, 136.0, 140.6, 143.7, 155.2, 163.9 ppm.
Na]+ Ǟ(MS2) 276. C17H18N2O3 (298.34): calcd. C 68.44, H 6.08,
1
1
Data for cis isomer: H NMR: δ = 3.07 (app d, J = 7.0 Hz, 2 H, N 9.39; found C 68.43, H 6.10, N 9.35. Data for trans isomer: H
Ar-CH2), 4.06–4.43 (m, 3 H, CHCH2O), 5.41–5.73 (m, 1 H, gCH), NMR: δ = 2.79–3.05 (m, 2 H, gCHCH2), 5.02 (s, 2 H, OCH2),
6.93–7.49 (m, 9 H, Ar, NHCOO), 7.55–7.76 (m, 3 H, Ar), 7.82– 5.02–5.19 (m, 1 H, gCH), 7.14–7.43 (m, 10 H, Ar), 7.78 (br. s, 1 H,
7.93 (m, 2 H, Ar), 8.00 (dd, J = 1.6, 0.6 Hz, 1 H, HCO), 8.30 (br. NHCOO), 7.98 (d, J = 11.3 Hz, 1 H, HCO), 8.13 (br. t, J =
d, J = 7.6 Hz, 1 H, NHCOH), 10.77 (br. s, 1 H, Ar-NH) ppm. 13C
NMR: δ = 30.3, 46.5, 57.1, 65.4, 109.7, 111.3, 118.1, 118.2, 119.9,
120.7, 123.4, 125.0, 126.9, 127.3, 127.4, 136.0 140.5, 143.6, 154.9,
160.2 ppm.
10.1 Hz, 1 H, NHCOH) ppm. 13C NMR: δ = 39.7, 61.8, 65.4,
126.4, 127.5, 127.8, 128.2, 128.3, 129.3, 136.7, 137.8, 155.2,
1
164.1 ppm. Data for cis isomer: H NMR: δ = 2.79–3.05 (m, 2 H,
gCHCH2), 5.00 (s, 2 H, OCH2), 5.46 (app quint, J = 7.5 Hz, 1 H,
gCH), 7.14–7.43 (m, 10 H, Ar), 7.54 (br. s, 1 H, NHCOO), 7.94
(dd, J = 1.8, 0.8 Hz, 1 H, HCO), 8.38 (br. d, J = 7.8 Hz, 1 H,
NHCOH) ppm. 13C NMR: δ = 40.1, 57.6, 65.2, 126.3, 127.6, 127.7,
128.1, 128.3, 129.1, 136.9, 137.2, 154.8, 160.1 ppm.
Fmoc-gMet-CO-H (4Ff): IR (KBr): ν = 3298, 1695, 1645, 1549,
˜
1507, 1444, 1394, 1285, 1263, 1203, 1078, 1050, 736 cm–1. MS
(ESI+): m/z = 393 [M + Na]+ Ǟ(MS2) 348. C20H22N2O3S (370.47):
calcd. C 64.84, H 5.99, N 7.56, S 8.65; found C 64.87, H 5.98, N
1
7.58, S 8.62. Data for trans isomer: H NMR: δ = 1.80–1.98 (m, 2
Cbz-gTrp-CO-H (4Ze): IR (KBr): ν = 3435, 3319, 3295, 3062,
˜
H, gCHCH2), 2.04 (s, 3 H, SCH3), 2.44 (app t, J = 7.6 Hz, 2 H,
SCH2), 4.16–4.44 (m, 3 H, CHCH2O), 4.96 (app quint, J = 7.3 Hz,
1 H, gCH), 7.25–7.48 (m, 4 H, Ar), 7.64–7.76 (m, 2 H, Ar), 7.79
(br. s, 1 H, NHCOO), 7.83–7.92 (m, 2 H, Ar), 8.00–8.14 (m, 2 H,
NHCOH) ppm. 13C NMR: δ = 14.4, 29.1, 32.9, 46.6, 59.2, 65.4,
119.9, 124.9, 126.9, 127.5, 140.6, 143.7, 155.3, 164.2 ppm. Data for
3034, 2919, 2893, 1696, 1658, 1544, 1511, 1456, 1393, 1350, 1286,
1268, 1231, 1219, 1187, 1046, 1006, 968, 749, 733, 721, 701, 577,
510 cm–1. MS (ESI+): m/z = 360 [M + Na]+ Ǟ(MS2) 315.
C19H19N3O3 (337.38): calcd. C 67.64, H 5.68, N 12.45; found C
67.65, H 5.70, N 12.45. Data for trans isomer: 1H NMR: δ = 2.93–
3.17 (m, 2 H, Ar-CH2), 5.04 (s, 2 H, OCH2), 5.05–5.26 (m, 1 H,
gCH), 6.91–7.24 (m, 3 H, Ar), 7.24–7.44 (m, 6 H, Ar), 7.54–7.67
(m, 1 H, Ar), 7.93 (br. s, 1 H, NHCOO), 8.01–8.17 (m, 2 H,
NHCOH), 10.82 (br. s, 1 H, Ar-NH) ppm. 13C NMR: δ = 30.1,
61.1, 65.4, 109.4, 111.3, 118.0, 118.3, 120.8, 124.0, 127.1, 127.5,
127.8, 128.3, 136.0, 136.7, 155.2, 164.0 ppm. Data for cis isomer:
1H NMR: δ = 2.93–3.17 (m, 2 H, Ar-CH2), 5.01 (s, 2 H, OCH2),
5.56 (app quint, J = 7.5 Hz, 1 H, gCH), 6.91–7.24 (m, 3 H, Ar),
7.24–7.44 (m, 6 H, Ar), 7.54–7.67 (m, 1 H, Ar), 7.70 (br. s, 1 H,
NHCOO), 7.98 (dd, J = 1.6, 0.6 Hz, 1 H, HCO), 8.35 (br. d, J =
7.6 Hz, 1 H, NHCOH), 10.78 (br. s, 1 H, Ar-NH) ppm. 13C NMR:
δ = 30.4, 57.1, 65.2, 109.7, 111.2, 118.1, 118.2, 120.7, 123.5, 127.3,
127.6, 127.7, 128.2, 136.0, 136.9, 155.0, 160.3 ppm.
1
cis isomer: H NMR: δ = 1.80–1.98 (m, 2 H, gCHCH2), 2.04 (s, 3
H, SCH3), 2.44 (app t, J = 7.6 Hz, 2 H, SCH2), 4.16–4.44 (m, 3 H,
CHCH2O), 5.38 (app quint, J = 7.3 Hz, 1 H, gCH), 7.25–7.48 (m,
4 H, Ar), 7.59 (br. s, 1 H, NHCOO), 7.64–7.76 (m, 2 H, Ar), 7.83–
7.92 (m, 2 H, Ar), 7.98 (dd, J = 1.6, 0.6 Hz, 1 H, HCO), 8.21 (br.
d, J = 8.0 Hz, 1 H, NHCOH) ppm. 13C NMR: δ = 14.5, 29.0,
33.7, 46.6, 55.4, 65.3, 119.9, 125.0, 126.9, 127.5, 140.6, 143.6, 154.9,
160.1 ppm.
Cbz-gAla-CO-H (4Za): IR (KBr): ν = 3300, 2997, 1688, 1655,
˜
1551, 1505, 1457, 1394, 1344, 1315, 1265, 1219, 1167, 1096, 1058,
721, 699 cm–1. MS (ESI+): m/z = 245 [M + Na]+ Ǟ(MS2) 200.
C11H14N2O3 (222.24): calcd. C 59.45, H 6.35, N 12.60; found C
1
59.44, H 6.38, N 12.64. Data for trans isomer: H NMR: δ = 1.29
Cbz-gGln-CO-H (4Zg): IR (KBr): ν = 3435, 3396, 3317, 3285,
˜
(d, J = 6.5 Hz, 3 H, CH3), 4.91–5.12 (m, 3 H, OCH2, gCH), 7.24–
7.44 (m, 5 H, Ar), 7.85 (br. s, 1 H, NHCOO), 7.99 (br. t, J =
10.1 Hz, 1 H, NHCOH), 8.15 (d, J = 11.6 Hz, 1 H, HCO) ppm.
13C NMR: δ = 20.6, 56.5, 65.3, 127.7, 127.8, 128.3, 136.8, 155.1,
164.1 ppm. Data for cis isomer: 1H NMR: δ = 1.26 (d, J = 6.7 Hz,
3 H, CH3), 4.91–5.12 (m, 2 H, OCH2), 5.37 (app sext, J = 7.0 Hz,
1 H, gCH), 7.24–7.44 (m, 5 H, Ar), 7.66 (br. s, 1 H, NHCOO),
7.91 (dd, J = 1.6, 0.8 Hz, 1 H, HCO), 8.23 (br. d, J = 7.3 Hz, 1 H,
NHCOH) ppm. 13C NMR: δ = 20.8, 52.7, 65.2, 127.7, 127.8, 128.3,
136.9, 154.7, 159.9 ppm.
3209, 1690, 1661, 1635, 1553, 1519, 1455, 1411, 1386, 1341, 1285,
1265, 1242, 1228, 1187, 1068, 1055, 1012, 635, 578 cm–1. MS
(ESI+): m/z = 302 [M + Na]+ Ǟ(MS2) 257. C13H17N3O4 (279.30):
calcd. C 55.91, H 6.14, N 15.05; found C 55.93, H 6.11, N 15.01.
Data for trans isomer: 1H NMR: δ = 1.69–1.92 (m, 2 H,
CH2CH2CO), 2.02–2.20 (m, 2 H, CH2CH2CO), 4.85 (app quint, J
= 7.6 Hz, 1 H, gCH), 5.03 (s, 2 H, OCH2), 7.26 (br. s, 2 H, NH2),
7.30–7.40 (m, 5 H, Ar), 7.85 (br. s, 1 H, NHCOO), 7.98–8.14 (m,
2 H, NHCOH) ppm. 13C NMR: δ = 29.2, 30.7, 60.1, 65.4, 127.5,
127.8, 128.3, 136.8, 155.3, 164.2, 173.4 ppm. Data for cis isomer:
1H NMR: δ = 1.69–1.92 (m, 2 H, CH2CH2CO), 2.02–2.20 (m, 2
H, CH2CH2CO), 5.02 (s, 2 H, OCH2), 5.27 (app quint, J = 7.6 Hz,
1 H, gCH), 6.69 (br. s, 2 H, NH2), 7.30–7.40 (m, 5 H, Ar), 7.65
(br. s, 1 H, NHCOO), 7.95 (dd, J = 1.6, 0.6 Hz, 1 H, HCO), 8.24
(br. d, J = 7.3 Hz, 1 H, NHCOH) ppm. 13C NMR: δ = 30.0, 30.9,
56.0, 65.3, 127.6, 127.7, 128.2, 136.9, 154.9, 160.2, 173.5 ppm.
Cbz-gLeu-CO-H (4Zc): IR (KBr): ν = 3317, 3290, 2952, 1697,
˜
1659, 1551, 1508, 1464, 1390, 1285, 1265, 1231, 1217, 1062, 1001,
743, 697 cm–1. MS (ESI+): m/z = 287 [M + Na]+ Ǟ(MS2) 242.
C14H20N2O3 (264.32): calcd. C 63.62, H 7.63, N 10.60; found C
1
63.65, H 7.59, N 10.62. Data for trans isomer: H NMR: δ = 0.85
[d, J = 6.2 Hz, 6 H, (CH3)2CH], 1.38–1.70 [m, 3 H, CHCH2], 4.77–
4.96 (m, 1 H, gCH), 5.04 (s, 2 H, OCH2), 7.24–7.43 (m, 5 H, Ar),
7.83 (br. s, 1 H, NHCOO), 7.99 (br. t, J = 10.2 Hz, 1 H, NHCOH),
8.16 (d, J = 11.6 Hz, 1 H, HCO) ppm. 13C NMR: δ = 21.7, 22.0,
23.8, 42.1, 58.8, 65.4, 127.7, 127.8, 128.2, 136.8, 155.5, 164.2 ppm.
Data for cis isomer: 1H NMR: δ = 0.86 [d, J = 6.2 Hz, 6 H,
(CH3)2CH], 1.38–1.70 [m, 3 H, CHCH2], 5.03 (s, 2 H, OCH2), 5.38
(app quint, J = 7.6 Hz, 1 H, gCH), 7.24–7.43 (m, 5 H, Ar), 7.60
(br. s, 1 H, NHCOO), 7.94 (dd, J = 1.7, 0.8 Hz, 1 H, HCO), 8.22
(br. d, J = 7.4 Hz, 1 H, NHCOH) ppm. 13C NMR: δ = 21.9, 22.2,
24.0, 43.2, 54.5, 65.2, 127.7, 127.8, 128.2, 137.0, 154.9, 160.0 ppm.
General Procedure for the Synthesis of Formamides 12 Derived from
N-Protected Dipeptide Acids: N-methylmorpholine (0.28 mL,
2.58 mmol) was slowly added to a stirred solution of N-protected
dipeptide acid 8 (2.50 mmol) in THF (25 mL). After 5 min, isobutyl
chloroformate (0.36 mL, 2.75 mmol) was slowly added to the reac-
tion mixture, which was cooled to –15 °C. The stirring was contin-
ued for 5 min at the same temperature. After this time, an aqueous
solution of KH2PO4 (1.4 m, 0.89 mL, 1.25 mmol) was added in one
portion followed, after 5 min, by the addition of an aqueous solu-
tion of KH2PO4 (1.4 m, 8.93 mL, 12.50 mmol) and NaN3 (0.41 g,
6.25 mmol). After 15 min at –15 °C, the reaction mixture was
warmed to 0 °C, and after 15 min, it was warmed to 45 °C and then
Cbz-gPhe-CO-H (4Zd): IR (KBr): ν = 3318, 3290, 3062, 3033,
˜
2930, 1693, 1655, 1544, 1509, 1455, 1392, 1349, 1288, 1264, 1225,
5394
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5387–5397

Sodium Borohydride Reduction of Carbamoyl Azide Function
stirred for 1.5 h. The reaction mixture was then cooled to room
temperature, and the organic phase was separated. Powdered
NaBH4 (0.24 g, 6.25 mmol) was rapidly added to the THF solution
of carbamoyl azide 10 at room temperature with vigorous stirring.
After an additional 45 min, the THF was removed under reduced
pressure. The crude residue was dissolved in AcOEt (100 mL), and
the resulting solution was washed sequentially with 5% HCl
(15 mL), water (15 mL), 5% Na2CO3 (15 mL), water (15 mL), and
then a saturated brine solution (15 mL). The organic layer was fi-
nally dried with Na2SO4. After filtration and evaporation in vacuo
of the solvent, the crude product was recrystallized from suitable
solvents to afford the N-protected NЈ-formyl-gem-diaminoalkyl de-
rivatives 12 in 72–87% overall yield (see Table 5).
Na]+ Ǟ(MS2) 401, 375. C24H29N3O4 (423.51): calcd. C 68.07, H
6.90, N 9.92; found C 68.04, H 6.88, N 9.95. Data for trans isomer:
1H NMR: δ = 0.88 [app t, J = 5.9 Hz, 6 H, (CH3)2CH], 1.29 (app
t, J = 5.9 Hz, 3 H, gCHCH3), 1.36–1.52 (m, 2 H, CHCH2), 1.53–
1.74 [m, 1 H, (CH3)2CH], 3.93–4.13 (m, 1 H, *CHLeu), 4.14–4.41
(m, 3 H, CHCH2O), 5.21 (app sext, J = 7.6 Hz, 1 H, gCHAla),
7.22–7.49 (m, 5 H, Ar, NHCOO), 7.71 (app d, J = 6.5 Hz, 2 H,
Ar), 7.88 (app d, J = 7.0 Hz, 2 H, Ar), 8.04–8.23 (m, 2 H,
NHCOH), 8.30 (br. d, J = 7.0 Hz, 1 H, *CHLeuCONH) ppm. 13C
NMR: δ = 20.3, 21.3, 22.9, 24.0, 40.7, 46.6, 52.9 (br. signals), 54.2,
65.4, 119.9, 125.1, 126.8, 127.4, 140.6, 143.6, 143.8, 155.7 (br. sig-
nals), 164.0, 172.0 ppm. Data for cis isomer: 1H NMR: δ = 0.88
[app t, J = 5.9 Hz, 6 H, (CH3)2CH], 1.29 (app t, J = 5.9 Hz, 3 H,
gCHCH3), 1.36–1.52 (m, 2 H, CHCH2), 1.53–1.74 [m, 1 H, (CH3)2-
CH], 3.93–4.13 (m, 1 H, *CHLeu), 4.14–4.41 (m, 3 H, CHCH2O),
5.52 (app sext, J = 7.6 Hz, 1 H, gCHgAla), 7.22–7.49 (m, 5 H, Ar,
NHCOO), 7.71 (app d, J = 6.5 Hz, 2 H, Ar), 7.88 (app d, J =
7.0 Hz, 2 H, Ar), 7.92 (d, J = 1.2 Hz, 1 H, HCO), 8.04–8.23 (m, 2
H, NHCOH, *CHLeuCONH) ppm. 13C NMR: δ = 20.6, 21.3, 22.9,
24.0, 40.7, 46.6, 50.8, 52.9 (br. signals), 65.4, 119.9, 125.1, 126.8,
127.4, 140.6, 143.6, 143.8, 155.7 (br. signals), 159.9, 171.3 ppm.
Boc-Val-gTrp-CO-H (12Bbe): IR (KBr): ν = 3411, 3288, 2967,
˜
1667, 1547, 1509, 1457, 1411, 1387, 1366, 1244, 1168, 738 cm–1.
MS (ESI+): m/z = 425 [M + Na]+ Ǟ(MS2) 369, 325. C21H30N4O4
(402.49): calcd. C 62.67, H 7.51, N 13.92; found C 62.71, H 7.52,
1
N 13.87. Data for trans isomer: H NMR: δ = 0.74–0.84 [m, 6 H,
(CH3)2CH], 1.39 [s, 9 H, (CH3)3C], 1.75–2.00 [m, 1 H, (CH3)2CH],
2.97–3.11 (m, 2 H, Ar-CH2), 3.79 (app quint, J = 7.6 Hz, 1 H,
*CHVal), 5.33 (app quint, J = 7.3 Hz, 1 H, gCHTrp), 6.49 (br. d, J
= 7.0 Hz, 1 H, NHCOO), 6.92–7.23 (m, 3 H, Ar), 7.28–7.39 (m, 1
H, Ar), 7.53–7.66 (m, 1 H, Ar), 7.95–8.09 (m, 2 H, NHCOH), 8.40
(br. d, J = 7.0 Hz, 1 H, *CHValCONH), 10.80 (br. s, 1 H, Ar-
NH) ppm. 13C NMR: δ = 17.9, 18.9, 28.0, 29.9, 30.5, 58.7, 59.4
(br. signals), 78.0, 109.2, 111.3, 118.0, 118.3, 120.8, 123.8, 127.0,
136.0, 155.2 (br. signals), 164.1, 171.2 ppm. Data for cis isomer: 1H
NMR: δ = 0.74–0.84 [m, 6 H, (CH3)2CH], 1.39 [s, 9 H, (CH3)3C],
1.75–2.00 [m, 1 H, (CH3)2CH], 2.97–3.11 (m, 2 H, Ar-CH2), 3.79
(app quint, J = 7.6 Hz, 1 H, *CHVal), 5.68 (app quint, J = 7.3 Hz,
1 H, gCHTrp), 6.49 (br. d, J = 7.0 Hz, 1 H, NHCOO), 6.92–7.23
(m, 3 H, Ar), 7.28–7.39 (m, 1 H, Ar), 7.53–7.66 (m, 1 H, Ar), 7.94
(d, J = 1.4 Hz, 1 H, HCO), 8.15 (br. d, J = 8.0 Hz, 1 H, NHCOH),
8.30 (br. d, J = 7.6 Hz, 1 H, *CHValCONH), 10.76 (br. s, 1 H, Ar-
NH) ppm. 13C NMR: δ = 17.8, 19.0, 28.0, 30.2, 30.5, 55.1, 59.4
(br. signals), 78.0, 109.6, 111.2, 118.1, 118.2, 120.8, 123.3, 127.2,
136.0, 155.2 (br. signals), 160.4, 170.5 ppm.
Fmoc-Leu-gPhg-CO-H (12Fch): IR (KBr): ν = 3292, 2955, 2934,
˜
2844, 1683, 1659, 1643, 1542, 1516, 1450, 1397, 1322, 1283, 1265,
1244, 1208, 1128, 1030, 739, 697, 667 cm–1. MS (ESI+): m/z = 508
[M + Na]+ Ǟ(MS2) 463, 375. C29H31N3O4 (485.58): calcd. C 71.73,
H 6.43, N 8.65; found C 71.74, H 6.41, N 8.61. Data for trans
isomer: 1H NMR: δ = 0.88 [app t, J = 6.8 Hz, 6 H, (CH3)2CH],
1.34–1.73 (m, 3 H, CHCH2), 4.01–4.20 (m, 1 H, *CHLeu), 4.21–
4.40 (m, 3 H, CHCH2O), 6.31 (app t, J = 8.5 Hz, 1 H, gCHPhg),
7.23–7.50 (m, 10 H, Ar, NHCOO), 7.72 (app d, J = 7.0 Hz, 2 H,
Ar), 7.88 (app d, J = 6.8 Hz, 2 H, Ar), 8.27 (d, J = 11.2 Hz, 1 H,
HCO), 8.44 (br. t, J = 10.2 Hz, 1 H, NHCOH), 8.52–8.72 (m, 1 H,
*CHLeuCONH) ppm. 13C NMR: δ = 21.3, 22.8, 24.1, 40.6, 46.6,
53.1 (br. signals), 60.1, 65.5, 119.9, 125.1, 126.2, 126.9, 127.4, 127.8,
128.2, 139.0, 140.6, 143.6, 143.8, 155.7 (br. signals), 164.5,
172.2 ppm. Data for cis isomer: 1H NMR: δ = 0.88 [app t, J =
6.8 Hz, 6 H, (CH3)2CH], 1.34–1.73 (m, 3 H, CHCH2), 4.01–4.20
(m, 1 H, *CHLeu), 4.21–4.40 (m, 3 H, CHCH2O), 6.66 (app t, J =
8.2 Hz, 1 H, gCHPhg), 7.23–7.50 (m, 10 H, Ar, NHCOO), 7.72 (app
d, J = 7.0 Hz, 2 H, Ar), 7.88 (app d, J = 6.8 Hz, 2 H, Ar), 8.10 (d,
Boc-Leu-gPhe-CO-H (12Bcd): IR (KBr): ν = 3317, 2959, 2930,
˜
1686, 1666, 1549, 1530, 1510, 1389, 1368, 1275, 1251, 1231, 1173,
1158, 1073, 698, 664 cm–1. MS (ESI+): m/z
= 400 [M +
J
= 1.2 Hz, 1 H, HCO), 8.52–8.72 (m, 2 H, NHCOH,
Na]+ Ǟ(MS2) 344, 300. C20H31N3O4 (377.48): calcd. C 63.64, H
8.28, N 11.13; found C 63.62, H 8.29, N 11.15. Data for trans
isomer: 1H NMR: δ = 0.77–0.90 [m, 6 H, (CH3)2CH], 1.20–1.43
[m, 11 H, (CH3)3C, CHCH2], 1.44–1.64 [m, 1 H, (CH3)2CH], 2.82–
3.05 (m, 2 H, Ph-CH2), 3.91 (app q, J = 7.8 Hz, 1 H, *CHLeu), 5.24
(app quint, J = 7.9 Hz, 1 H, gCHPhe), 6.71 (br. d, J = 7.0 Hz, 1 H,
NHCOO), 7.14–7.32 (m, 5 H, Ar), 7.93–8.04 (m, 2 H, NHCOH),
8.30 (br. d, J = 7.9 Hz, 1 H, *CHLeuCONH) ppm. 13C NMR: δ =
21.4, 22.8, 24.1, 28.1, 39.8, 40.8, 52.7 (br. signals), 59.3, 77.9, 126.3,
128.1, 129.2, 136.8, 155.0 (br. signals), 164.0, 172.3 ppm. Data for
cis isomer: 1H NMR: δ = 0.77–0.90 [m, 6 H, (CH3)2CH], 1.20–1.43
[m, 11 H, (CH3)3C, CHCH2], 1.44–1.64 [m, 1 H, (CH3)2CH], 2.82–
3.05 (m, 2 H, Ph-CH2), 3.91 (app q, J = 7.8 Hz, 1 H, *CHLeu), 5.56
(app quint, J = 7.9 Hz, 1 H, gCHPhe), 6.71 (br. d, J = 7.0 Hz, 1 H,
NHCOO), 7.14–7.32 (m, 5 H, Ar), 7.91 (d, J = 1.4 Hz, 1 H, HCO),
8.07 (br. d, J = 7.9 Hz, 1 H, NHCOH), 8.30 (br. d, J = 7.9 Hz, 1
H, *CHLeuCONH) ppm. 13C NMR: δ = 21.4, 22.8, 24.1, 28.1, 39.1,
40.8, 52.7 (br. signals), 55.6, 77.9, 126.2, 128.0, 129.0, 137.0, 155.0
(br. signals), 160.2, 171.7 ppm.
*CHLeuCONH) ppm. 13C NMR: δ = 21.3, 22.8, 24.1, 40.6, 46.6,
53.1 (br. signals), 55.6, 65.5, 119.9, 125.1, 125.9, 126.9, 127.4, 127.5,
128.1, 139.8, 140.6, 143.6, 143.8, 155.7 (br. signals), 160.2,
171.5 ppm.
Fmoc-Phe-gAla-CO-H (12Fda): IR (KBr): ν = 3280, 2870, 1690,
˜
1673, 1652, 1566, 1540, 1521, 1450, 1392, 1287, 1262, 1249, 1223,
1126, 1086, 1035, 756, 740, 708, 666, 514 cm–1. MS (ESI+): m/z =
480 [M + Na]+ Ǟ(MS2) 435, 409. C27H27N3O4 (457.53): calcd. C
70.88, H 5.95, N 9.18; found C 70.91, H 5.99, N 9.16. Data for
trans isomer: 1H NMR: δ = 1.31 (app t, J = 6.5 Hz, 3 H, CH3),
2.78 and 3.00 (AB of ABX, J = 13.8, 10.3, 4.4 Hz, 2 H, Ph-CH2),
4.07–4.33 (m, 4 H, CHCH2O, *CHPhe), 5.24 (app sext, J = 7.0 Hz,
1 H, gCHAla), 7.12–7.50 (m, 10 H, Ar, NHCOO), 7.56–7.70 (m, 2
H, Ar), 7.86 (app d, J = 7.0 Hz, 2 H, Ar), 7.98 (br. t, J = 10.2 Hz,
1 H, NHCOH), 8.17 (d, J = 11.5 Hz, 1 H, HCO), 8.48 (br. d, J =
7.3 Hz, 1 H, *CHPheCONH) ppm. 13C NMR: δ = 20.4, 37.3, 46.5,
54.3, 55.8 (br. signals), 65.5, 119.9, 125.0, 126.1, 126.9, 127.4, 127.8,
129.1, 137.7, 140.5, 143.5, 143.6, 155.5 (br. signals), 164.0,
171.0 ppm. Data for cis isomer: 1H NMR: δ = 1.31 (app t, J =
Fmoc-Leu-gAla-CO-H (12Fca): IR (KBr): ν = 3267, 2955, 2873, 6.5 Hz, 3 H, CH3), 2.78 and 3.00 (AB of ABX, J = 13.8, 10.3,
˜
1687, 1667, 1567, 1540, 1520, 1466, 1450, 1387, 1269, 1247, 1224,
4.4 Hz, 2 H, Ph-CH2), 4.07–4.33 (m, 4 H, CHCH2O, *CHPhe), 5.55
(app sext, J = 7.0 Hz, 1 H, gCHAla), 7.12–7.50 (m, 10 H, Ar,
1134, 1114, 1035, 737 cm–1. MS (ESI+): m/z = 446 [M +
Eur. J. Org. Chem. 2013, 5387–5397
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5395

G. Verardo, A. Gorassini
FULL PAPER
Petit, M. V. Kalnins, T. M. H. Liu, E. G. Thomas, K. Parent,
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NHCOO), 7.56–7.70 (m, 2 H, Ar), 7.86 (app d, J = 7.0 Hz, 2 H,
Ar), 7.94 (d, J = 1.2 Hz, 1 H, HCO), 8.23 (br. d, J = 7.6 Hz, 1 H,
NHCOH), 8.30 (br. d, J = 7.3 Hz, 1 H, *CHPheCONH) ppm. 13C
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125.1, 126.0, 126.9, 127.4, 127.8, 129.1, 137.9, 140.5, 143.5, 143.6,
155.5 (br. signals), 159.9, 170.4 ppm.
[3]
[4]
Cbz-Phe-gAla-CO-H (12Zda): IR (KBr): ν = 3285, 3026, 1685,
˜
1668, 1645, 1556, 1535, 1518, 1454, 1395, 1315, 1297, 1258, 1217,
1131, 1083, 1042, 745, 695, 674, 520 cm–1. MS (ESI+): m/z = 392
[M + Na]+ Ǟ(MS2) 347, 321. C20H23N3O4 (369.42): calcd. C 65.03,
H 6.28, N 11.37; found C 65.00, H 6.30, N 11.34. Data for trans
isomer: 1H NMR: δ = 1.31 (app t, J = 6.3 Hz, 3 H, CH3), 2.73 and
2.99 (AB of ABX, J = 13.5, 10.6, 4.1 Hz, 2 H, Ph-CH2), 4.12–4.34
(m, 1 H, *CHPhe), 4.95 (s, 2 H, CH2O), 5.23 (app sext, J = 7.0 Hz,
1 H, gCHAla), 7.10–7.45 (m, 11 H, Ar, NHCOO), 7.99 (br. t, J =
10.1 Hz, 1 H, NHCOH), 8.16 (d, J = 11.5 Hz, 1 H, HCO), 8.48
(br. d, J = 7.0 Hz, 1 H, *CHPheCONH) ppm. 13C NMR: δ = 20.4,
37.3, 54.3, 55.8 (br. signals), 65.1, 126.1, 127.3, 127.5, 127.9, 128.1,
129.1, 136.9, 137.7, 155.7 (br. signals), 164.1, 171.1 ppm. Data for
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1
cis isomer: H NMR: δ = 1.31 (app t, J = 6.3 Hz, 3 H, CH3), 2.73
and 2.99 (AB of ABX, J = 13.5, 10.6, 4.1 Hz, 2 H, Ph-CH2), 4.12–
4.34 (m, 1 H, *CHPhe), 4.95 (s, 2 H, CH2O), 5.53 (app sext, J =
7.0 Hz, 1 H, gCHAla), 7.10–7.45 (m, 11 H, Ar, NHCOO), 7.94 (d,
J = 1.2 Hz, 1 H, HCO), 8.23 (br. d, J = 7.6 Hz, 1 H, NHCOH),
8.31 (br. d, J = 7.0 Hz, 1 H, *CHPheCONH) ppm. 13C NMR: δ =
20.6, 37.4, 51.0, 55.8 (br. signals), 65.1, 126.0, 127.3, 127.5, 127.9,
128.1, 129.1, 136.9, 137.9, 155.7 (br. signals), 160.0, 170.4 ppm.
[6]
Cbz-Phe-gPhe-CO-H (12Zdd): IR (KBr): ν = 3296, 3025, 1689,
˜
1664, 1647, 1556, 1535, 1515, 1497, 1455, 1392, 1309, 1256, 1220,
1088, 1074, 1042, 1026, 742, 700, 536, 519 cm–1. MS (ESI+): m/z
= 468 [M + Na]+ Ǟ(MS2) 423, 321. C26H27N3O4 (445.52): calcd.
C 70.10, H 6.11, N 9.43; found C 70.14, H 6.10, N 9.41. Data for
1
trans isomer: H NMR: δ = 2.63–3.05 (m, 4 H, 2 Ph-CH2), 4.14–
4.35 (m, 1 H, *CHPhe), 4.96 (s, 2 H, CH2O), 5.27 (app quint, J =
7.6 Hz, 1 H, gCHPhe), 7.12–7.42 (m, 16 H, Ar, NHCOO), 7.96–
8.06 (m,
2 H, NHCOH), 8.53 (br. d, J = 7.0 Hz, 1 H,
*CHPheCONH) ppm. 13C NMR: δ = 37.3 (br. signals), 40.1, 55.9
(br. signals), 59.5, 65.1, 126.0, 126.2, 127.2, 127.4, 127.8, 128.0,
128.1, 128.9, 129.2, 136.7, 136.9, 137.6, 155.5 (br. signals), 163.9,
1
171.0 ppm. Data for cis isomer: H NMR: δ = 2.63–3.05 (m, 4 H,
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Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all prepared com-
pounds.
Acknowledgments
The authors are grateful to Dr. P. Martinuzzi and Dr. S. Turco for
1
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Received: March 26, 2013
Published Online: July 5, 2013
Eur. J. Org. Chem. 2013, 5387–5397
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5397