Iminophosphorane-mediated synthesis of cyclic guanidines: Application to the synthesis of a simplified NA22598A1 analogue

Article abstract of DOI:10.1055/s-2008-1078279

Reaction of Cbz-protected β-amino azides with bis(diphenylphosphino) butane and tosyl isocyanate provides differentially substituted 2-iminoimidazolidines in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078279

LETTER
2339
Iminophosphorane-Mediated Synthesis of Cyclic Guanidines: Application to
the Synthesis of a Simplified NA22598A1 Analogue
I
minophospho
t
rane-M
e
e
diated Sy
f
o
a
f
Cyclic
G
u
n
anidines o M. Nalli,a Guy J. Clarkson,a Alison S. Franklin,b Graziella Bellone,c Michael Shipman*a
a
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
Fax +44(24765)24112; E-mail: m.shipman@warwick.ac.uk
b
c
Department of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK
Department of Clinical Physiopathology, Università di Torino, Via Genova 3, 10126 Torino, Italy
Received 31 March 2008
suitably substituted b-amino azide 2 with an isocyanate in
the presence of a phosphine. Mechanistically, one can
imagine that this process entails the following sequence of
reactions: (i) Staudinger-type reaction of the azide with
the phosphine to generate iminophosphorane 4; (ii) aza-
Wittig reaction of 4 with the added isocyanate to produce
carbodiimide 5; (iii) ring closure by the proximal amine to
yield the 2-iminoimidazolidine ring (Scheme 1). As a
number of methods exist for the synthesis of organic
azides,5 and a variety of isocyanates are commercially
available, this strategy appears to offer a simple and flex-
ible route to differentially substituted 2-iminoimida-
zolidines. Molina et al. have made heteroaromatic
systems such as 2-aminoimidazoles using a similar ap-
proach.6
Abstract: Reaction of Cbz-protected b-amino azides with
bis(diphenylphosphino)butane and tosyl isocyanate provides differ-
entially substituted 2-iminoimidazolidines in good yields.
Key words: antitumor agents, azides, cyclizations, heterocycles,
stereoselective synthesis
In 1997, the novel antitumour compound NA22598A1 (1)
was isolated by Kuwahara and co-workers from Strepto-
myces sp. NA22598 (FERM P-14686).1 This molecule se-
lectively inhibits the anchorage-independent growth of
human colon cancer DLD-1 cells by arresting the cell cy-
cle at the G1 phase and suppressing cyclin D1 synthesis.2
The molecular structure of this natural product consists of
a simple dipeptide unit linked through an amide bond to a
functionalised decanoic acid. Unusually, this latter por-
tion of the molecule contains a selectively carbamoylated
cyclic guanidine (2-iminoimidazolidine) at its terminus
(Figure 1).3 The stereochemistry of NA22598A1 is yet to
be fully resolved. This fact, combined with its important
antitumour properties, make it an attractive target for total
synthesis. In this Letter, we describe studies directed to-
wards the preparation of differentially substituted 2-imi-
noimidazolidines, and the application of this new
methodology to the synthesis of a structurally simplified
analogue of NA22598A1.
NY
1. PR3
2. YN=C=O
N3
R2
– N2
XHN
R1
XN
R1
NH
R2
2
3
PR3
NY
PR3
YN=C=O
– OPR3
XHN
R1
N
N
XHN
R1
R2
R2
4
5
where R1, R2 = H, alkyl, aryl; X = CO2Bn, CONH2, etc.; Y = Ts, Bn, etc.
O
Scheme 1 Planned route to 2-iminoimidazolidines
NH2
OH
HN
HN
NH2
O
N
H
N
CO2H
The feasibility of the approach was established using sim-
ple b-amino azide 6.7 Treatment of this azide with triphen-
ylphosphine for two hours at room temperature in diethyl
ether, and subsequent addition of one equivalent of tosyl
isocyanate provided 7 in 40% yield after chromatography.
When the reaction solvent was changed to CH2Cl2, the
yield improved to 55%. 31P NMR studies conducted on
closely related systems revealed that iminophosphorane
formation was rather slow and incomplete after two hours.
This observation led us to extend the length of time 6 was
reacted with PPh3 to 22 hours prior to addition of the iso-
cyanate. Under these conditions, 7 was produced in an im-
proved 68% yield. Although not a major issue in this
particular example, the removal of triphenylphosphine
oxide from the 2-iminoimidazolidine proved difficult
with more highly polar products (e.g. 16). To circumvent
N
H
OH
NH2
O
NA22598A1 (1)
Figure 1 Structure of NA22598A1
One of the key challenges associated with the preparation
of NA22598A1 and related structures concerns the instal-
lation of a differentially substituted 2-iminoimidazoli-
dine.4 Compounds of this type (e.g. 3) might be con-
veniently prepared under mild conditions by reaction of a
SYNLETT 2008, No. 15, pp 2339–2341
Advanced online publication: 21.08.2008
DOI: 10.1055/s-2008-1078279; Art ID: D10408ST
© Georg Thieme Verlag Stuttgart · New York
1
5
.0
9
.2
0
0
8

2340
S. M. Nalli et al.
LETTER
this problem, 0.5 equivalents of bis(diphenylphosphi- acid (R)-12, which was then coupled with a slight excess
no)butane (DPPB) was used as phosphine.8 Under these of 14 (made by deprotection of 1314 using TFA) to give 15
optimised conditions, 7 could be readily isolated in 71% in 84% yield from (R)-11. Gratifyingly, treatment of 15
yield (Scheme 2).9,10
under our optimised conditions for 2-iminoimidazolidine
formation, produced differentially substituted cyclic
guanidine 16 in 56% yield. Clearly, the reaction proceeds
well even in the presence of a variety of other potential nu-
cleophiles. Global deprotection of the tosyl, Cbz and ben-
zyl ester groups of 16 was achieved by dissolving metal
reduction. Although this reaction was very clean, the iso-
lation of 17 completely free of ammonium salts was made
difficult because of its zwitterionic character. After col-
umn chromatography 17 was isolated in ca. 57% yield
along with small quantities of CF3CO2NH4 arising from
the workup and purification protocol.15
NTs
NH
1. DPPB, CH2Cl2, 22 h
2. TsNCO, –20 °C to r.t., 22 h
N3
CbzN
CbzHN
71%
6
7
Scheme 2 Optimised conditions for 2-iminoimidazolidine forma-
tion
X-ray crystallography performed on a single crystal of 2-
iminoimidazolidine 7 grown from CH2Cl2–Et2O con-
firmed its structure (Figure 2).11 In the solid state, this cy-
clic guanidine exists in the depicted tautomeric form with
the Cbz and the tosyl groups anti to one another.
O
OH
O
a,b
TBDPSO
OMe
89%
OMe
(S)-9, 87% ee
7
7
8
c–f
75%
CbzHN
N3
O
CbzHN
TBDPSO
O
g–i
OR
OMe
7
76%
7
(R)-11 (R = Me)
(R)-12 (R = H)
(R)-10
j
CbzHN
O
l
H
N
N3
CO2Bn
84%
from 11
N
H
7
O
15
H
N
CO2Bn
XHN
m
56%
O
Figure 2 Solid-state structure of 7 with thermal ellipsoids drawn at
50% probability
TsN
HN
Cbz
13 (X = Boc)
14 (X = H)
k
O
N
H
N
CO2Bn
N
H
With suitable conditions for cyclic guanidine formation
established, we sought to use it to prepare NA22598A1 an-
alogues. In the first instance, we chose to make 17, by way
of azide 15, in which the dipeptide unit (L-ala-L-val) was
retained but the diol, diamine and carbamoyl substituent
were omitted. Biological evaluation of 17 might be ex-
pected to provide some initial insights into structure–ac-
tivity relationships. To avoid the preparation of mixtures
of stereoisomers, we arbitrarily chose to make 17 with the
9R stereochemistry in the first instance.
7
O
16
HN
HN
O
NH
R
n
H
N
CO2H
N
7
H
O
17
Scheme
3
Reagents and conditions: (a) K2OsO4·2H2O,
(DHQ)2AQN, K3Fe(CN)6, K2CO3, NaHCO3, H2O–t-BuOH (1:1), –20
°C, 2 d, 97%; (b) TBDPSCl, imidazole, DMF, 19 h, r.t., 92%; (c)
MsCl, Et3N, CH2Cl2, 0 °C, 3 h, 95%; (d) NaN3, DMF, 80 °C, 19 h,
88%; (e) H2, 10% Pd/C, MeOH, 24 h, 96%; (f) CbzCl, Na2CO3, THF–
H2O (1:1), 0 °C, 94%; (g) TBAF, THF, 0 °C → r.t., 2 h, 93%; (h)
MsCl, Et3N, CH2Cl2, 0 °C, 3 h, 83%; (i) NaN3, DMF, 80 °C, 19 h,
99%; (j) LiOH, MeOH–H2O (1:1), 24 h, 94%; (k) TFA, CH2Cl2, 0 °C
→ r.t., 16 h, 99%; (l) HOBt, EDC·HCl, Et3N, 19 h, r.t., 89%; (m)
DPPB, CH2Cl2, 22 h then TsNCO, –20 °C → r.t., 22 h, 56%; (n) Na
(40 equiv), NH3–THF (5:2), –70 °C → 30 °C, 2 h, ca. 57% (see text).
The synthesis of 17 began with Sharpless asymmetric di-
hydroxylation (AD) of methyl dec-9-enoate (8) using the
hydroquinine
(anthraquinone-1,4-diyl)
diether
[(DHQ)2AQN] ligand and monosilylation of the resulting
diol. This sequence provided (S)-9 in 89% yield and 87%
ee (Scheme 3).12 The sense of asymmetric induction in the
AD reaction was deduced by analogy to related literature
examples.13 (S)-9 was transformed into (R)-11 via (R)-10
using a high yielding sequence of reactions that inverted
the stereogenic centre. Hydrolysis of ester (R)-11 by treat-
ment with LiOH in methanol and water gave carboxylic
Using an anchorage-independent growth assay, the effect
of 17 on colon cancer DLD-1 cells was evaluated. No sig-
nificant decrease in cell growth was observed against con-
trol at several time points up to 120 hours using inhibitor
Synlett 2008, No. 15, 2339–2341 © Thieme Stuttgart · New York

LETTER
Iminophosphorane-Mediated Synthesis of Cyclic Guanidines
2341
see: O’Neil, I. A.; Thompson, S.; Murray, C. L.; Kalindjian,
S. B. Tetrahedron Lett. 1998, 39, 7787.
concentrations up to 1 mg/mL. Since NA22598A1 com-
pletely inhibits cell growth under these conditions,2 our
data indicate that one or more of the omitted functional
groups on the decanoic acid chain are essential for activi-
ty. Alternatively, 17 may possess the wrong stereochem-
istry at C-9 in relation to the natural product.
(9) Representative Procedure: To a solution of 6 (0.20 g, 0.91
mmol) in anhyd CH2Cl2 (10 mL) under nitrogen was added
DPPB (0.213 g, 0.50 mmol). The reaction mixture was
stirred at r.t. for 22 h, cooled to –20 °C and tosyl isocyanate
(144 mL, 0.94 mmol) was slowly added. The reaction
mixture was allowed to warm to r.t. and stirred for 22 h.
Removal of the solvent in vacuo and subsequent column
chromatography (8% EtOAc in CH2Cl2) gave 7 (0.24 g,
71%) as a white solid.
To conclude, a new mild methodology for the synthesis
of unsymmetrically substituted 2-iminoimidazolidines
has been devised. It has been shown to be suitable for the
preparation of simplified analogues of NA22598A1. Work
to fully define the scope of this reaction and to apply it to
the synthesis of other NA22598A1 derivatives will be the
subject of future studies.
(10) Selected Spectroscopic Data: 7: mp 152–153 ºC (from
CH2Cl2–Et2O). 1H NMR (400 MHz, CDCl3): d = 7.81 (d, J =
8.3 Hz, 2 H, ArH), 7.71 (s, 1 H, NH), 7.29–7.37 (m, 5 H,
ArH), 7.22 (d, J = 8.3 Hz, 2 H, ArH), 5.25 (s, 2 H, OCH2Ph),
3.90–3.95 (m, 2 H), 3.60–3.65 (m, 2 H), 2.40 (s, 3 H, Me).
13C NMR (100.5 MHz, CDCl3): d = 154.1 (C), 150.8 (C),
142.6 (C), 139.7 (C), 135.1 (C), 129.3 (CH), 128.6 (CH),
128.3 (CH), 128.0 (CH), 126.3 (CH), 68.5 (CH2), 43.9
(CH2), 39.9 (CH2), 21.5 (Me). IR (neat): 3315, 2919, 1753,
1621 cm–1. MS (FAB+): m/z = 374 [M + H+], 330. HRMS
(FAB+): m/z [M + H+] calcd for C18H20N3O4S: 374.1175;
found: 374.1179. 16: [a]D24 47 (c = 1.2, EtOH). 1H NMR
(400 MHz, CDCl3): d = 7.67–7.69 (m, 3 H, 2 × ArH, NH),
7.27–7.33 (m, 10 H, ArH), 7.21–7.25 (m, 3 H, 2 × ArH, NH),
6.54 (br s, 1 H, NH), 5.19 (d, J = 12.3 Hz, 1 H, OCHHPh),
5.11 (d, J = 12.3 Hz, 1 H, OCHHPh), 5.09 (d, J = 12.3 Hz, 1
H, OCHHPh), 5.02 (d, J = 12.3 Hz, 1 H, OCHHPh), 4.53–
4.61 (m, 1 H, a-CH Ala), 4.43 (dd, J = 5.0, 8.5, Hz, 1 H, a-
CH Val), 4.16–4.19 (m, 1 H, H-9), 3.56 (t, J = 9.4 Hz, 1 H,
H-10), 3.22 (d, J = 10.8 Hz, 1 H, H-10¢), 2.28 (s, 3 H, Me),
2.03–2.10 (m, 3 H, H-2, b-CH Val), 1.58–1.70 (m, 1 H, H-
8), 1.42–1.55 (m, 3 H, H-8¢, 2 × H-3), 1.25 (d, J = 7.0 Hz, 3
H, b-Me Ala), 1.05–1.20 (m, 8 H, 2 × H-4, 2 × H-5, 2 × H-6,
2 × H-7), 0.81 (d, J = 6.8 Hz, 3 H, g-Me Val), 0.78 (d, J = 6.8
Hz, 3 H, g-Me Val). 13C NMR (100.5 MHz, CDCl3): d =
173.1 (C), 172.8 (C), 171.5 (C), 153.7 (C), 150.9 (C), 142.5
(C), 139.8 (C), 135.4 (C), 135.1 (C), 129.3 (CH), 128.6
(CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.0 (CH),
126.2 (CH), 68.4 (CH2), 66.9 (CH2), 57.4 (CH), 56.0 (CH),
48.6 (CH), 45.2 (CH2), 36.4 (CH2), 33.0 (CH2), 30.9 (CH),
29.1 (CH2), 29.0 (CH2), 25.5 (CH2), 24.2 (CH2), 21.5 (Me),
19.1 (Me), 18.3 (Me), 17.7 (Me). IR (neat): 3400, 3281,
3061, 2925, 2885, 1717, 1631, 1616, 1541 cm–1. MS
(FAB+): m/z = 776 [M + H+], 338. HRMS (FAB+): m/z [M +
H+] calcd for C41H54N5O8S: 776.3693; found: 776.3692.
(11) This data has been deposited at the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK. Deposition number: CCDC 679310.
(12) The enantiomers were separated by analytical HPLC on a
chiralpak OD-H column (3% IPA in n-hexanes, flow rate =
0.5 mL/min, l = 245 nm); tR [(S)-9] = 12.5 min, tR [(R)-9] =
14.8 min.
Acknowledgment
The University of Warwick is gratefully acknowledged for financial
support. We are indebted to EPSRC (EP/C007999/1) for the provi-
sion of mass spectrometers.
References and Notes
(1) (a) Kuwahara, A.; Nishikiori, T.; Shimada, N.; Nakagawa,
T.; Fukazawa, H.; Mizuno, S.; Uehara, Y. J. Antibiot. 1997,
50, 712. (b) Nishikiori, T.; Kuwahara, A.; Uehara, Y.;
Fukazawa, S.; Mizuno, S. Jpn. Kokai Tokkyo Koho, Jpn.
Patent, JP 09048791, 1997.
(2) Kawada, M.; Kuwahara, A.; Nishikiori, T.; Mizuno, S.;
Uehara, Y. Exp. Cell Res. 1999, 249, 240.
(3) Recently, K01-0509 B and guadinomines A–C were
isolated. These compounds all possess a carbamoylated 2-
iminoimidazolidine. Moreover, guadinomine B is strikingly
similar to NA22598A1, see: Tsuchiya, S.; Sunazuka, T.;
Hirose, T.; Mori, R.; Tanaka, T.; Iwatsuki, M.; Omura, S.
Org. Lett. 2006, 8, 5577; and references therein.
(4) For other recent approaches to 2-iminoimidazolidines, see:
(a) Dardonville, C.; Goya, P.; Rozas, I.; Alsasua, A.; Martín,
M. I.; Borrego, M. J. Bioorg. Med. Chem. 2000, 8, 1567.
(b) Isobe, T.; Fukuda, K.; Yamaguchi, K.; Seki, H.;
Tokunaga, T.; Ishikawa, T. J. Org. Chem. 2000, 65, 7779.
(c) Matosiuk, D.; Fidecka, S.; Antkiewicz-Michaluk, L.;
Dybala, I.; Koziol, A. E. Eur. J. Med. Chem. 2001, 36, 783.
(d) Dennis, M.; Hall, L. M.; Murphy, P. J.; Thornhill, A. J.;
Nash, R.; Winters, A. L.; Hursthouse, M. B.; Light, M. E.;
Horton, P. Tetrahedron Lett. 2003, 44, 3075. (e) Abou-
Jneid, R.; Ghoulami, S.; Martin, M.-T.; Dau, E. T. H.;
Travert, N.; Al-Mourabit, A. Org. Lett. 2004, 6, 3933.
(f) Sanière, L.; Leman, L.; Bourguignon, J.-J.; Dauban, P.;
Dodd, R. H. Tetrahedron 2004, 60, 5889. (g) Kim, M.;
Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett. 2006,
8, 1073.
(5) For a review, see: Bräse, S.; Gil, C.; Knepper, K.;
Zimmermann, V. Angew. Chem. Int. Ed. 2005, 44, 5188.
(6) (a) Molina, P.; Conesa, C.; Velasco, D. Synthesis 1996,
1459. (b) See also: Palacios, F.; Alonso, C.; Aparicio, D.;
Rubiales, G.; de los Santos, J. M. Tetrahedron 2007, 63,
523.
(7) Cooper, R. G.; Etheridge, C. J.; Stewart, L.; Marshall, J.;
Rudginsky, S.; Cheng, S. H.; Miller, A. D. Chem. Eur. J.
1998, 4, 137; and references therein.
(13) For example, see: Hodgkinson, T. J.; Shipman, M. Synthesis
1998, 1141; and references cited therein.
(14) Synthesised by coupling commercially available N-Boc-L-
alanine with L-valine benzyl ester (EDC, HOBt, Et3N,
CH2Cl2, 16 h, 90%).
(15) This contamination arises from the fact that solid NH4Cl is
used to quench the dissolving metal reduction and TFA is
used as a co-solvent in the subsequent purification by silica
gel chromatography. The effective molarity of 17 in D2O,
from which the yield could be estimated, was determined by
adding known quantities of 1,4-dioxane to the sample and
subsequent quantification of the dioxane/17 ratio by 1H
NMR integration.
(8) Bis(diphenylphosphino)ethane has been used to address
similar problems in Staudinger and Mitsunobu reactions,
Synlett 2008, No. 15, 2339–2341 © Thieme Stuttgart · New York

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