Synthesis of Orthogonally N-Protected, C-4 Functionalized Cyclic Guanidines from l -Serine

Article abstract of DOI:10.1055/s-0036-1589935

A straightforward and efficient preparation of five-membered cyclic guanidines bearing an ester, a hydroxymethyl or a Weinreb amide functional group at C-4 is described from l-serine. The novel synthetic route provides cyclic guanidines in which the three

Full text of DOI:10.1055/s-0036-1589935

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
D. R. C. Silva et al.
Letter
Synlett
Synthesis of Orthogonally N-Protected, C-4 Functionalized Cyclic
Guanidines from L-Serine
Diego R. C. Silvaa,b
O
Edmilson J. Mariab
Rosa M. Suárez Ordóñeza
Josiane Thierrya
O
(R = OMe), LiBH4
EtOH, 0 °C, 90%
OH
R
BocN
CbzN
BocN
CbzN
HO
OH
NPMB
NPMB
NH2
Kevin Cariou*a
Robert H. Dodd*a
R = OMe, 11 steps, 28%
R = N(Me)OMe, 13 steps, 24%
L-serine
orthogonally protected
a Institut de Chimie des Substances Naturelles, CNRS UPR 2301,
Univ. Paris-Sud, Univ. Paris-Saclay, 1 Avenue de la Terrasse,
91198 Gif-sur-Yvette, France
Kevin.cariou@cnrs.fr
Robert.dodd@cnrs.fr
b Universidade Estadual do Norte Fluminense Darcy Ribeiro,
Campos dos Goytacazes, RJ, CEP 28015620, Brazil
Received: 18.12.2016
Accepted after revision: 27.12.2016
Published online: 17.01.2017
NH
R
O
HN
NH
O
DOI: 10.1055/s-0036-1589935; Art ID: st-2016-d0700-l
OH
HN
HN
NH
NH2
OH
Abstract A straightforward and efficient preparation of five-mem-
bered cyclic guanidines bearing an ester, a hydroxymethyl or a Weinreb
amide functional group at C-4 is described from L-serine. The novel syn-
thetic route provides cyclic guanidines in which the three nitrogen at-
oms are orthogonally protected making them highly suitable for fur-
ther transformations into natural products or their analogues via the
introduced functional groups.
NH2
3 capreomycidine
1
2
L-enduracididine (R = H)
L-β-hydroxyenduracididine (R = OH)
Me
NH
O
N
N
OH
Me
Br
HN
NH NH2
Key words cyclic guanidine, amino acid, azide, orthogonal protec-
CO2H
tion, Weinreb amide
NH
3 tetrahydrolathyrin
N
H
4 trachycyladindole B
The cyclic guanidine motif is present in a wide range of
naturally occurring compounds,1 notably as a structural
unit of nonproteinogenic amino acids, examples of which
are enduracididine (1),2 its 3-hydroxy derivatives (2),3 cap-
reomycidine (3),4 tetrahydrolathyrin (4),5 or of alkaloids
such as trachycladindole B (5)6 and its derivatives (Figure
1). These amino acids have been isolated either in their free
form or as components of cyclic peptides. Thus, compound
1 is a structural unit of the cyclopeptide enduracidin2 and
of the recently described teixobactin,7 compound 2 of the
mannopeptimycins3 and compound 3 of capreomycins and
tuberactinomycins,8 all of which display antibiotic or anti-
fungal action. In terms of synthesis, formation of the cyclic
guanidine unit usually depends on the generation of a 1,2-
or 1,3-diamino motif which classically can then be cyclized
using cyanogen bromide, an inexpensive but highly toxic
reagent. Alternatively, one of the amino groups can be cou-
pled to a reactive isothiourea derivative which then under-
goes cyclization upon heating.9 Starting from a 1-hydroxyl-
2-(or 3-)-guanidine unit, a Mitsunobu-type cyclodehydra-
tion has also been used to prepare a five-(or six-)mem-
bered cyclic guanidine.10–12
Figure 1 Examples of natural products containing a C-4 substituted
cyclic guanidine structural unit
We have recently described the syntheses of both L-en-
duracididine (1)13 and tetrahydrolathyrin (4)14 by way of
prior iminoiodane-mediated aziridination of a common,
easily accessible starting material, L-allylglycine. Subse-
quent nucleophilic opening of the aziridine by azide (for en-
duracididine) or nitrile (for tetrahydrolathyrin) provided
the required diamino precursors after reduction. The lack of
diasteoselectivity in the aziridination step was, however, a
complicating factor in both cases.
It occurred to us that a more convergent way of synthe-
sizing cyclic guanidine-containing compounds, be they nat-
ural products, analogues thereof or in the context of drug
discovery, would consist of preparing a preformed cyclic
guanidine moiety bearing a functional group which could
thereafter be used to link another molecule (e.g., an amino
acid or an indole). Such a tactic was recently described by
us, whereby halogenated cyclic guanidines were obtained
in one step by halocyclization of unsaturated guanidines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
D. R. C. Silva et al.
Letter
Synlett
using a combination of lithium halides and Koser’s re-
agent.15 We now report herein the efficient preparation,
starting from L-serine, of 5-membered cyclic guanidines
functionalized at C-4 with an ester, a Weinreb amide or a
hydroxymethyl group and in which, moreover, the three
guanidine nitrogen atoms are orthogonally protected. The
possibility of accessing a mono-N-deprotected cyclic guani-
dine could be highly valuable, for example, for the introduc-
tion of different substituents on each nitrogen atom in the
context of a structure–activity relationship study of a par-
ticular bioactive molecule.
The success of our methodology was very much depen-
dent on the judicious choice of nitrogen-atom protecting
groups.16 Indeed, a frequently encountered problem in
working with partially N-protected cyclic guanidines is
scrambling of the protecting group(s)17 making characteri-
zation and purification of products difficult and lowering
yields. For our initial studies starting from L-serine methyl
ester (6), we thus chose to protect the amine function with
a p-methoxybenzyl (PMB) group not prone to migration but
easily removed under mild oxidizing conditions (Scheme
1). Additionally, the electron-rich nature of the group
should assist in the subsequent cyclization step. Thus, reac-
tion of 6 with p-methoxybenzaldehyde (7) in methanol in
the presence of triethylamine followed by sodium boro-
hydride promoted reduction of the resulting intermediate
imine provided the desired N-PMB serine methyl ester (8)
in 81% overall yield. Compound 8 in dichloromethane was
then treated at –78 °C with thionyl chloride in the presence
of pyridine to give the oxathiazolidine derivative 9. The lat-
ter was oxidized to the cyclic sulfamidate 10 in 77% overall
yield using catalytic ruthenium trichloride and sodium
metaperiodate in acetonitrile.18 Regioselective ring opening
of compound 10 in acetone was very efficiently achieved by
the action of aqueous sodium azide (Warning!) at room
temperature, furnishing methyl (2S)-3-azido-2-(p-me-
thoxybenzyl)aminopropanoate (11) in 85% yield.19
Transformation of azido derivative 11 into the orthogo-
nally N-protected cyclic guanidine 4-carboxylic ester 16 is
depicted in Scheme 2. Thus, the azido function of 11 was
first reduced to the primary amine 12 via a Staudinger reac-
tion using triphenylphosphine in aqueous dichlorometh-
ane. This amine was not purified but was reacted directly
with 1,3-bis(benzyloxycarbonyl)-2-methylisothiourea (13)
in the presence of triethylamine in dichloromethane.20 The
resulting guanidino derivative 14, obtained in 95% overall
yield over both steps, underwent cyclization when heated
for two days at 70 °C in acetonitrile, providing a 75% yield of
methyl 2-iminoimidazolidine-4-carboxylate 15.21 Finally,
treatment of compound 15 with excess Boc anhydride and
O
NCbz
O
O
HO
R
CbzHN
S
PPh3, CH2Cl2
H2O, rt
13
O
HN
N3
R
H2N
R
SOCl2, pyridine
CH2Cl2, –78 °C
1) 7, Et3N, MeOH, rt
CH2Cl2, Et3N,
0 °C to rt
NHPMB
NHPMB
HO
R
2) NaBH4, MeOH
0 °C to rt
NH2
11 R = OMe
25 R = N(Me)OMe
12 R = OMe
26 R = N(Me)OMe
O
6 R = OMe
21 R = N(Me)OMe
OMe
NCbz
O
R
MeCN
HN
MeO
NPMB
CbzHN
N
R
H
70 °C, 2 d
CbzN
8 R = OMe 81%
22 R = N(Me)OMe 91%
NHPMB
7
CHO
14 R = OMe 95% (2 steps)
27 R = N(Me)OMe 87% (2 steps)
15 R = OMe 75%
28 R = N(Me)OMe 74%
O
O
cat. RuCl3⋅3H2O
R
R
O
OH
O
LiBH4
BocN
CbzN
NaIO4, MeCN,
0 °C to rt
NPMB
S
NPMB
S
NPMB
O
O
EtOH, 0°C
O
O
9 R = OMe
23 R = N(Me)OMe
10 R = OMe 77% (2 steps)
24 R = N(Me)OMe 72% (2 steps)
17 90%
15
or
27
Boc2O, DMAP
MeCN, rt
R (16)
BocN
CbzN
NPMB
O
O
H2, 1 atm
PdO (cat.)
1) NaN3, acetone/H2O, rt
2) H2SO4, CH2Cl2, rt
10 or
24
OMe
N3
R
BocN
HN
16 R = OMe 73%
29 R = N(Me)OMe 84%
NPMB
NHPMB
MeOH, rt
11 R = OMe 85%
25 R = N(Me)OMe 68%
18 69%
Scheme 1 Preparation of the 2-amino-3-azido precursors for cyclic
Scheme 2 Preparation of the C-4 functionalized, N-protected five-
guanidine formation
membered cyclic guanidines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
D. R. C. Silva et al.
Letter
Synlett
DMAP in acetonitrile led to the targeted fully N-protected,
C-4 functionalized cyclic guanidine 16 in 73% yield. The lat-
ter could furthermore be transformed in 90% yield to the C-
4 hydroxymethyl derivative 17 by reduction of the ester
with lithium borohydride in ethanol at 0 °C. The orthogo-
nality of our design was illustrated by the selective removal
of the Cbz group of 16 by hydrogenolysis to give 18. Thus, it
is possible to go from 2,3-di-N-protected guanidine 15 to
tri-N-protected 16 and to 1,3-di-N-protected guanidine 18.
For the preparation of the Weinreb amide analogue of
the cyclic guanidine ester 16, the corresponding amide of L-
serine (i.e., compound 21) was first synthesized as shown in
Scheme 3. This two-step procedure consisted of EDCI-pro-
moted coupling of commercial N-Boc-L-serine (19) with
N,O-dimethylhydroxylamine in the presence of N-methyl-
morpholine (NMM) to give amide 20. Removal of the N-Boc
protecting group using trifluoroacetic acid in dichloro-
methane then provided 21 in 72% overall yield.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1589935.
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References and Notes
(1) (a) Berlinck, R. G. S. Nat. Prod. Rep. 1996, 13, 377. (b) Berlinck, R.
G. S.; Burtoloso, A. C. B.; Kossuga, M. H. Nat. Prod. Rep. 2008, 25,
919. (c) Berlinck, R. G. S.; Burtoloso, A. C. B.; Trindade-Silva, A.
E.; Romminger, S.; Morais, R. P.; Bandeira, K.; Mizuno, C. M. Nat.
Prod. Rep. 2010, 27, 1871. (d) Castagnolo, D.; Schenone, S.;
Botta, M. Chem. Rev. 2011, 111, 5247. (e) Berlinck, R. G. S.;
Trindade-Silva, A. E.; Santos, M. F. C. Nat. Prod. Rep. 2012, 29,
1382.
(2) (a) Hori, S.; Kameda, Y. J. Antibiot. 1968, 21, 665. (b) Higashide,
E.; Hatano, K.; Shibata, M.; Nakazawa, K. J. Antibiot. 1968, 21,
126. (c) Asai, M.; Muroi, M.; Sugita, N.; Kawashima, H.; Mizuno,
K.; Miyake, A. J. Antibiot. 1968, 21, 138.
(3) He, H.; Williamson, R. T.; Shen, B.; Graziani, E. I.; Yang, H. Y.;
Sakya, S. M.; Petersen, P. J.; Carter, G. T. J. Am. Chem. Soc. 2002,
124, 9729.
(4) Herr, E. B.; Haney, M. E.; Pittenger, G. E.; Higgins, C. E. Proc. Ind.
Acad. Sci. 1960, 69, 134.
O
O
TFA
MeONHMe
EDCI
CH Cl
OMe
2
2
21 96%
HO
N
HO
OH
rt
NMM, CH2Cl2
–15 °C
BocNH
Me
NHBoc
(5) Fellows, L. E.; Bell, E. A.; Lee, T. S.; Janzen, D. H. Phytochemistry
1979, 18, 1333.
(6) Capon, R. J.; Peng, C.; Dooms, C. Org. Biomol. Chem. 2008, 6,
2765.
20 75%
19
Scheme 3 Preparation of the Weinreb amide of L-serine
(7) Ling, L. L.; Schneider, T.; Peoples, A. J.; Spoering, A. L.; Engels, I.;
Conlon, B. P.; Mueller, A.; Schäberle, T. F.; Hughes, D. E.; Epstein,
S.; Jones, M.; Lazarides, L.; Steadman, V. A.; Cohen, D. R.; Felix, C.
R.; Fetterman, K. A.; Millett, W. P.; Nitti, A. G.; Zullo, A. M.; Chen,
C.; Lewis, K. Nature (London, U.K.) 2015, 517, 455.
(8) (a) Nomoto, S.; Teshima, T.; Wakamiya, T.; Shiba, T. Tetrahedron
1978, 34, 921. (b) Yoshioka, H.; Aoki, T.; Goko, H.; Nakatsu, K.;
Noda, T.; Sakakibara, H.; Take, T.; Nagata, A.; Abe, J. Tetrahedron
Lett. 1971, 23, 2043.
Application to 21 of the same reaction sequence used
for the preparation of cyclic guanidine 16 from L-serine
methyl ester (6) then allowed efficient access to optically
pure, N-protected cyclic guanidine derivative 29 having
now a Weinreb amide at the C-4 position suitable for fur-
ther transformations (Schemes 1 and 2).20,21
(9) Su, W. Synth. Commun. 1996, 26, 407.
In conclusion, esters 15, 16, and 18, primary alcohol 17
and Weinreb amide 29 represent five functionalized and
stereochemically defined cyclic guanidine derivatives
which can serve as starting materials for the synthesis of a
variety of natural products containing this five-membered
heterocyclic unit. An added feature of the synthetic strategy
presented here is that these key compounds can be ob-
tained with each nitrogen atom of the guanidine unit being
orthogonally protected allowing their selective deprotec-
tion and substitution in the context of a structure–activity
study (e.g., N-alkylation as in the trachycladindoles 5) or of
total synthesis (e.g., the mannopeptimycins).10b Such trans-
formations are the object of our ongoing studies.
(10) (a) Schwörer, C. J.; Oberthür, M. Eur. J. Org. Chem. 2009, 6129.
(b) Olivier, K. S.; Van Nieuwenhze, M. S. Org. Lett. 2010, 12,
1680.
(11) For other leading references dealing with the synthesis of cyclic
guanidine amino acids, see: (a) Fischer, S. N.; Schwörer, C. J.;
Oberthür, M. Synthesis 2014, 46, 2234. (b) Fuse, S.; Koinuma, H.;
Kimbara, A.; Izumikawa, M.; Mifune, Y.; He, H.; Shin-Ya, K.;
Takahashi, T.; Doi, T. J. Am. Chem. Soc. 2014, 136, 12011.
(c) Moeschwitzer, V. D.; Kariuki, B. M.; Redman, J. E. Tetrahe-
dron Lett. 2013, 54, 4526. (d) Craig, W.; Chen, J.; Richardson, D.;
Thorpe, R.; Yuan, Y. Org. Lett. 2015, 17, 4620. (e) Giltrap, A. M.;
Dowman, L. J.; Nagalingam, G.; Ochoa, J. L.; Linington, R. G.;
Britton, W. J.; Payne, R. J. Org. Lett. 2016, 18, 2788. (f) Wang, B.;
Liu, Y.; Jiao, R.; Feng, Y.; Li, Q.; Chen, C.; Liu, L.; He, G.; Chen, G. J.
Am. Chem. Soc. 2016, 138, 3926.
(12) DeMong, D. E.; Williams, R. M. Tetrahedron Lett. 2001, 42, 3529.
(13) Sanière, L.; Leman, L.; Bourguignon, J.-J.; Dauban, P.; Dodd, R. H.
Tetrahedron 2004, 60, 5889.
Acknowledgment
The authors are grateful to Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq, Brazil) for financial support, and
D.R.C.S is thankful to CAPES, Brazil for a scholarship. We thank the In-
stitut de Chimie des Substances Naturelles for financial and technical
support.
(14) Benohoud, M.; Leman, L.; Cardoso, S. H.; Retailleau, P.; Dauban,
P.; Thierry, J.; Dodd, R. H. J. Org. Chem. 2009, 74, 5331.
(15) Daniel, M.; Blanchard, F.; Nocquet-Thibault, S.; Cariou, K.; Dodd,
R. H. J. Org Chem. 2015, 80, 10624.
(16) Wuts, P. G. M.; Greene, T. W. Greene's Protective Groups in
Organic Synthesis, 4th ed.; John Wiley and Sons: Hoboken, 2006.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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D. R. C. Silva et al.
Letter
Synlett
(17) (a) Albrecht, C.; Barnes, S.; Böckemeier, H.; Davies, D.; Dennis,
M.; Evans, D. M.; Fletcher, M. D.; Jones, I.; Leitmann, V.; Murphy,
P. J.; Rowles, R.; Nash, R.; Stephenson, R. A.; Horton, P. N.;
Hursthouse, M. B. Tetrahedron Lett. 2008, 49, 185. (b) Davies, D.;
Fletcher, M. D.; Franken, H.; Hollinshead, J.; Kähm, K.; Murphy,
P. J.; Nash, R.; Potter, D. M. Tetrahedron Lett. 2010, 51, 6825.
(c) Al Shuhaib, Z.; Davies, D. H.; Dennis, M.; Evans, D. M.;
Fletcher, M. D.; Franken, H.; Hancock, P.; Hollinshead, J.; Jones,
I.; Kähm, K.; Murphy, P. J.; Nash, R.; Potter, D.; Rowles, R. Tetra-
hedron 2014, 70, 4412.
3.74–3.70 (m, 1 H, CH), 3.54 (s, 3 H, MeO), 3.51 (d, J = 12.8 Hz,
1H, CH2, PMB), 3.15 (s, 3 H, MeN), 3.20–3.10 (m, 1 H, CH2), 1.96
(br s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 163.8 (C), 158.9
(C), 156.1 (C), 153.7 (C), 137.0 (C), 135.0 (C), 131.8 (C), 130.4 (2
CH, PMB), 128.9 (CH, Cbz), 128.9 (CH, Cbz), 128.8 (CH, Cbz),
128.6 (CH, Cbz), 128.3 (CH Cbz), 128.1 (CH Cbz), 113.9 (2 CH
PMB), 68.3 (CH2, Cbz), 67.2 (CH2, Cbz), 61.8 (CH3 MeO), 55.7
(CHN), 55.5 (CH3, MeO), 51.4 (CH2), 43.3 (CH2), 32.5 (CH3, MeN).
HRMS: m/z calcd for C30H36N5O7 [M + H]+: 578.2609; found:
578.2618.
(18) Cobb, S. L.; Vederas, J. C. Org. Biomol. Chem. 2007, 5, 1031.
(19) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetrahedron: Asymme-
try 1990, 1, 881.
(20) Methyl (2S)-3-[2,3-Bis(benzyloxycarbonyl)guanidino]-2-(p-
methoxybenzylamino)propanoate (14)
(21) Methyl (4S)-2-(benzyloxycarbonylimino)-3-(p-methoxyben-
zyl)imidazolidine-4-carboxylate (15)
A solution of compound 14 (2.56 g, 4.6 mmol) in MeCN (25 mL)
was heated at 70 °C for 2 d. The reaction mixture was then
cooled to r.t., the solvent was removed under vacuum, and the
residue was purified by flash column chromatography on silica
gel (EtOAc–heptane, 1:1) to provide the cyclic guanidine 15 as a
To a solution of amine 12 (669 mg, 2.8 mmol) in CH2Cl2 (15 mL)
were successively added at r.t. 1,3-bis(benzyloxycarbonyl)-2-
methylisothiourea (13, 1.22 g, 3.4 mmol) and Et3N (0.93 mL, 6.7
mmol). The reaction mixture was stirred overnight, the solvent
was removed under vacuum, and the residue was purified by
flash column chromatography on silica gel (EtOAc–heptane,
40:60), providing compound 14 as a yellow oil (1.47 g, 95% yield
20
colorless oil (1.39 g, 75%); [α]D +25.7 (c 0.9, CHCl3). IR (neat):
ν
max = 3374, 2926, 1646, 1587, 1513, 1248, 1128, 1095, 799 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.95 (br s, 1 H, NH), 7.37 (d, J =
6.8 Hz, 2 H, Cbz), 7.31–7.21 (m, 3 H, Cbz), 7.10 (d, J = 8.6 Hz, 2 H,
CH, PMB), 6.78 (d, J = 8.6 Hz, 2 H, CH PMB), 5.16–5.05 (m, 3 H),
4.10–4.03 (m, 2 H,), 3.99 (dd, J = 10.0, 6.0 Hz, 1 H, CH2), 3.73 (s, 3
H, MeO), 3.67 (s, 3 H, MeO), 3.63 (dd, J = 10.0, 6.0 Hz, 1 H, CH2).
13C NMR (75 MHz, CDCl3): δ = 170.4 (C), 164.4 (C), 163.5 (C),
159.3 (C), 137.3 (C), 130.0 (2 CH, PMB), 128.3 (2 CH, Cbz), 128.2
(2 CH, Cbz), 127.7 (CH, Cbz), 114.1 (2 CH, PMB), 67.0 (CH2, Cbz),
56.4 (CHN), 55.3 (CH3, MeO), 52.7 (CH3, MeO), 46.2 (CH2), 44.5
(CH2). HRMS: m/z calcd for C21H24N3O5 [M + H]+: 398.1710;
found: 398.1711.
20
from 11); [α]D +5.5 (c 0.97, CHCl3). IR (neat): νmax = 3330,
1733, 1638, 1561, 1513, 1246, 1204, 1054, 698 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 11.7 (s, 1 H, NH), 8.82 (br s, 1 H, NH), 7.37
(m, 6 H, CH, Cbz), 7.30 (d, J = 7.5 Hz, 4 H, Cbz), 7.26 (d, J = 8.6 Hz,
2 H, CH, PMB), 6.80 (d, J = 8.6 Hz, 2 H, CH PMB), 5.19 (d, J = 1.7
Hz, 2 H, CH2, Cbz), 5.09 (s, 2 H, CH2), 3.90–3.79 (m, 1 H), 3.80 (d,
J = 12.8 Hz, 1 H, CH2, PMB), 3.76 (s, 3 H, MeO), 3.70 (s, 3 H, MeO),
3.64 (d, J = 12.8 Hz, 1 H, CH2, PMB), 3.64–3.37 (m, 2 H), 1.85 (br
s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 173.4 (C), 163.8 (C),
159.0 (C), 156.2 (C), 153.7 (C), 136.9 (C), 134.9 (C), 131.4 (C),
129.8 (2 CH, PMB), 129.0 (CH, Cbz), 128.9 (CH, Cbz), 128.8 (CH,
Cbz), 128.6 (CH, Cbz), 128.4 (CH, Cbz), 128.1 (CH, Cbz), 114.0 (2
CH, PMB), 68.4 (CH2, Cbz), 67.3 (CH2, Cbz), 58.8 (CH-N), 55.5
(CH3, MeO), 52.5 (CH3, MeO), 51.4 (CH2), 42.8 (CH2). HRMS: m/z
calcd for C29H33N4O7 [M + H]+: 549.2344; found: 549.2329.
N-Methoxy-N-methyl
(4S)-2-(benzyloxycarbonylimino)-3-
(p-methoxybenzyl)imidazolidine-4-carboxamide (28)
Treatment of compound 27 (0.6 mmol) as described above pro-
vided, after flash column chromatography of the crude product
on silica gel (EtOAc–heptane, 8:2), compound 28 as a colorless
20
oil (74%); [α]D +27.4 (c = 0.92, CHCl3). IR (neat): νmax = 3374,
2926, 1646, 1587, 1513, 1248, 1128, 1095, 799 cm–1 1H NMR
.
N-Methoxy-N-methyl
(2S)-3-[2,3-Bis(benzyloxycarbonyl)-
(300 MHz, CDCl3): δ = 7.94, (br s, 1 H, NH), 7.43–7.24 (m, 5 H,
CH, Cbz), 7.26 (d, J = 8.5 Hz, 2 H, CH, PMB), 6.81 (d, J = 8.5 Hz, 2
H, CH, PMB), 5.23 (d, J = 14.7 Hz, 1 H, CH2), 5.16 (d, J = 12.4, 2 H,
CH2), 5.10 (d, J = 12.4, 2 H, CH2), 4.27 (dd, J = 10.6 Hz, 6.5 Hz, 1 H,
CH), 3.98 (d, J = 14.7, 1 H, CH2), 3.81–3.73 (m, 1 H, CH2), 3.76 (s,
3 H, MeO), 3.46 (dd, J = 9.6 Hz, 6.6 Hz, 1 H, CH2), 3.35 (s, 3 H,
MeO), 3.14 (s, 3 H, MeN). 13C NMR (75 MHz, CDCl3): δ = 169.9
(C), 164.6 (C), 164.2 (C), 159.4 (C), 137.6 (C), 130.4 (2 CH, PMB),
128.5 (CH, Cbz), 128.3 (CH, Cbz), 127.8 (CH, Cbz), 114.2 (2 CH,
PMB), 67.1 (CH2, Cbz), 61.4 (CH3, MeO), 55.5 (CH3, MeO), 55.0
(CH-N), 45.9 (CH2), 44.6 (CH2), 29.9 (CH3, MeN). HRMS: m/z
calcd for C22H27N4O5 [M + H]+: 427.1976; found: 427.1984.
guanidino]-2-(p-methoxybenzylamino)propanamide (27)
Treatment of amine 26 (0.7 mmol) as described above provided,
after flash chromatography of the crude product on silica gel
(EtOAc–heptane, 6:4), compound 27 as a yellow oil (87% yield
20
from 25); [α]D –15.3 (c 1.12, CHCl3). IR (neat): νmax = 3330,
2931, 1732, 1638, 1563, 1512, 1245, 1204, 1052, 803, 746, 697
cm–1. 1H NMR (300 MHz, CDCl3): δ = 11.6 (br s, 1 H, NH), 8.85 (br
s, 1 H, NH), 7.40–7.24 (m, 10 H, CH, Cbz) 7.28 (d, J = 8.6 Hz, 2 H,
CH, PMB), 6.78 (d, J = 8.6 Hz, 2 H, CH, PMB), 5.24 (d, J = 12.2 Hz,
1 H, CH2, Cbz), 5.18 (d, J = 12.2 Hz, 1 H, CH2, Cbz), 5.10 (d, J = 12.4
Hz, 1 H, CH2), 5.05 (d, J = 12.4 Hz, 1 H, CH2), 3.89–3.81 (m, 1 H,
CH2), 3.79 (d, J = 13.0 Hz, 1 H, CH2, PMB), 3.75 (s, 3 H, MeO),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D