Metathesis studies to cyclic enol phosphonamidates

Article abstract of DOI:10.1016/j.jorganchem.2006.09.035

The development of cyclic, six membered enol phosphonamidates utilizing the ring-closing metathesis (RCM) reaction is discussed. Phosphonamidic monochloridates are generated and further functionalized to an array of acyclic, enol phosphonamidates. Subsequ

Full text of DOI:10.1016/j.jorganchem.2006.09.035

Journal of Organometallic Chemistry 691 (2006) 5307–5311
www.elsevier.com/locate/jorganchem
Metathesis studies to cyclic enol phosphonamidates
*
Stephen R. Sieck, Matthew D. McReynolds, Chad E. Schroeder, Paul R. Hanson
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045 7582, United States
Received 29 June 2006; received in revised form 6 September 2006; accepted 6 September 2006
Available online 24 September 2006
Abstract
The development of cyclic, six membered enol phosphonamidates utilizing the ring-closing metathesis (RCM) reaction is discussed.
Phosphonamidic monochloridates are generated and further functionalized to an array of acyclic, enol phosphonamidates. Subsequent
metathesis affords both desired RCM product and corresponding cross metathesis (CM) dimer. Efforts to optimize formation of desired
RCM product, while minimizing CM products are discussed, with interesting steric and electronic factors governing reactivity patterns.
This strategy allows for generation of cyclic enol phosphonamidates, with ultimate application to C(6)-substituted analogs of the anti-
cancer agent, cyclophosphamide.
Ó 2006 Elsevier B.V. All rights reserved.
Keywords: Metathesis; Enolphosphonamidate; Cyclophosphamide
Organophosphorus [1] compounds continue to be pop-
ular targets due to their ubiquity in biological systems [2]
and their potential to serve as novel pharmaceutical [3],
agricultural [4], and chemical agents [5]. Until 1996, gen-
eral methods to access phosphorus heterocycles (P-hetero-
cycles) employing transition metal-catalyzed processes
were primarily limited to Pd(0)-catalyzed protocols [6].
The advent of ring-closing metathesis [7] as a common syn-
thetic tool has led to numerous advances in the prepara-
tion of unique small molecules [8]. In particular, a
number of strained P-heterocycles has been reported utiliz-
ing ruthenium-based catalysts [(PCy3)2(Cl)2Ru@CHPh]
cat-A and [(ImesH2)(PCy3)–(Cl)2Ru@CHPh] cat-B [9]. A
number of noteworthy examples addressing olefinic substi-
tution patterns and thus expanding the scope of RCM
have emerged, including RCM with chlorine [10] and fluo-
rine-substituted olefins [11]. Recently, Shibasaki and co-
workers have carried out successful examples of RCM with
enol silanes employing Grubbs catalyst (cat-B) [12], while
RCM of various enol phosphates [13], and cross metathesis
(CM) of vinyl phosphonates [14] have also been achieved.
As part of our continued studies employing transition
metal-catalysis to new P-heterocycles, we herein report
the use of RCM en route to cyclic enol phosphonamidates,
with potential application to cyclophosphamide (CP)-like
analogs.
Among the more notable P-heterocycles displaying bio-
logical activity to emerge is cyclophosphamide (CP), a
widely used anti-cancer alkylating agent that requires acti-
vation in vivo (Fig. 1). The chemistry and pharmacology
of CP have been extensively studied and reviewed [15].
Cyclophosphamide is a prodrug and its cytotoxicity is
attributed to the formation of an aziridinium ion, which is
derived from release of a phosphoramide mustard; this
mustard is able to crosslink interstrand DNA. The byprod-
uct, acrolein, is also produced, though it does not contribute
to anti-cancer activity within CP. However, acrolein is
responsible for a number of undesired side effects associated
with CP, including hemorrhaggic cystitis [16]. A variety of
CP analogs have been developed with substitution at vari-
ous positions of the heterocycle. However, to-date, no ana-
log has shown the success of CP itself. With this in mind, we
set out to use RCM in the construction of a relatively unex-
plored class of CP-analogs displaying C(6)-substitution
[17].
*
Corresponding author.
E-mail address: phanson@ku.edu (P.R. Hanson).
0022-328X/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.09.035

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S.R. Sieck et al. / Journal of Organometallic Chemistry 691 (2006) 5307–5311
Cl
N
tems were slow, typically taking between 24 and 48 h com-
Cyclophosphamide
O
pared to 6 h for the methyl-substituted (R1 = Me) system.
In attempting to optimize this reaction, we examined a
number of factors, ranging from reaction concentration
(0.005–0.5 M), catalyst load (1–10 mol%), and solvent
(CH2Cl2, benzene, toluene). After surveying an array of
combinations it was found that 3 mol% of cat-B, run in
0.01 M CH2Cl2, gave optimal results.
H2N
P
N(CH2CH2Cl)2
Cl
O
OH
P
5
phosphoramide
mustard
1
6
O
P450
Site of oxidation
HN
O
3
4
H
Acrolein
Substitution at nitrogen was next probed. Thus
monochloridate 12 was generated using the previously
mentioned protocol. Subsequent O-alkylation with ace-
tophenone yielded acyclic enol phoshphonamidate 13.
Exposure of 13 to the optimized metathesis conditions,
resulted in exclusive CM product formation (14) (E/Z
97:3) (Scheme 3) with no desired cyclized product detected.
Thus the benzyl group at nitrogen seems to be essential to
inhibit dimer formation, presumably through a steric effect,
however the exact origin of this result is unclear.
In order to probe potential electronic effects, we next
turned our attention to metathesis studies containing pre-
cursors possessing substitution within the aromatic ring
(Table 1). Both electron withdrawing and donating groups
were examined in this study, with the reactions conve-
niently monitored using 31P NMR analysis [21]. Again in
order to accommodate late-stage introduction of the mus-
tard segment, we began this portion of our study by look-
ing at acyclic enol phosphonamidates possessing a labile
group at phosphorus (i.e., –Cl or –OPh, entries 1–6). As
shown in Table 1, metathesis of precursors containing a
para-substituted Cl- (entries 3 and 6) or MeO- (entries 2
and 5) aromatic ring led to an erosion of the RCM/CM
ratio. With these interesting results in hand we reexamined
the Me-substituted phosphonyl system. In stark contrast,
aromatic-substitution in these systems (entries 8–10)
resulted in a dramatic increase in conversion to the RCM
product. Both electron donating- (–OMe, entry 8) and elec-
tron withdrawing-substituted (–NO2, entry 10) [22] precur-
sors gave substantial increases in the RCM manifold. The
highest conversion occurred in entry 8 with 88% conversion
to the desired cyclic system.
Fig. 1. Cyclophosphamide.
We initially began our study with the phosphorylation
of allylbenzyl amine (1) using methylphosphonic dichloride
to afford monochloridate 2 (Scheme 1). Due to the ten-
dency of the monochloridate to undergo dimerization after
purification, 2 was immediately reacted with the potassium
enolate of acetophenone 3 to yield acyclic enol-phospho-
namidate 4. Subjection of 4 to olefin metathesis conditions
using Grubbs cat-B afforded target six-membered phos-
phonamidate 5 as the major product (64%), along with acy-
clic dimer [18] 6 (26%) resulting from olefin CM [19]. Not
surprisingly, no CM was seen between the enolic olefin
partners [20], but instead occurred only between two allylic
amine partners. To the best of our knowledge, this repre-
sents the first example of RCM on an enolphosphonami-
date-containing substrate.
In order to provide eventual late-stage introduction of
the mustard portion of CP, we explored the installation
of a labile group at phosphorus. Utilizing a variety of
P(V) dichlorides, successful generation of corresponding
mono chloridates (7a–c) was achieved in a straight-forward
manner (Scheme 2). Unlike 2, monochloridates 7a–c are
quite stable and can be stored for prolonged periods of
time. Subsequent O-phosphorylation with acetophenone
gave acyclic enol phosphonamidates 8a–c, which under-
went RCM (0.01 M) with cat-B to form the corresponding
RCM (9a–c) and CM (10a–c) products. Replacing
R1 = CH3 with other groups however, led to increased con-
version to the undesired CM product (10a–c) in all but one
case, which contrasts with the initial results outlined in
Scheme 1. Only the chloro-substituted phosphoryl acyclic
diene (8c) gave RCM product 9c as the major product
(albeit slightly). Furthermore, reaction times in these sys-
In order to further optimize this promising result we
reexamined our enol phosphonamidate systems utilizing
O
Me
N
O
Me
N
(ii) THF, –78 ˚C
KHMDS, HMPA, 93%
P
P
(i) MeP(O)Cl2
Cl
Ph
O
Ph
Ph
NH
OK
Et3N, DMAP,
CH2Cl2, 40 ˚C
94%
2
3
Ph
1
Ph
4
cat-B
(3 mol%)
CH2Cl2
@ 0.01M,
40 ˚C
O
Me
N
Ph
P
Me
O
O
Ph
Ph
O
N
P
+
P
N
O
Ph
Ph
O
Me
Ph
6, 26 %
5, 64%
Scheme 1.

S.R. Sieck et al. / Journal of Organometallic Chemistry 691 (2006) 5307–5311
R1
5309
R1
O
O
P
P
R1P(O)Cl2
THF, -78 ˚C
Ph
NH
Ph
N
O
Ph
N
Cl
KHMDS
PhCOCH3
Et3N, DMAP,
CH2Cl2, rt
Ph
a, R1= OPh
b, R1= Ph
c, R1= Cl
8a, 95%
8b, 81%
8c, 45%
7a, 95%
7b, 87%
7c, 87%
Ph
R1
O
O
R1
P
Ph
O
N
P
P
Ph
N
O
RCM
+
N
O
Ph
O
R1
Ph
Ph
10a, 56%a
10b, 40%a
10c, 44%a
9a, 30%a
9b, 18%a
9c, 45%a
a) % conversion calculated by 31P NMR analysis
Scheme 2.
O
OPh
N
PhOP(O)Cl2
Et3N, DMAP, CH2Cl2
Me
(i) KHMDS, THF
-78 oC
HN
P
Me
Cl
80%
O
11
85%
12
Ph
O
OPh
Me
N
OPh
O
O
P
Me
Ph
O
P
O
N
cat-B
P
N
Ph
PhO
O
CH2Cl2, reflux
14
100 %
Me
Ph
13
Scheme 3.
Table 1
Substitution effects
O
R1
O
R1
Bn
N
RCM
2nd Gen
P
Bn
P
Bn
O
N
O
N
R2
O
P
R1
O
2
+
CH2Cl2
reflux
24 h
RCM
CM
R2
R1
R2
Entry
R2
% RCM
% CM
SM
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
OPh
OPh
OPh
Me
Me
Me
Me
H
OMe
Cl
H
OMe
Cl
H
OMe
Cl
45
16
11
30
11
13
64
88
84
75
44
54
41
56
41
41
26
6
30
48
47
45
6
8
21
7
3
10
NO2

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S.R. Sieck et al. / Journal of Organometallic Chemistry 691 (2006) 5307–5311
Table 2
Sparging effects on RCM
References
O
R1
R1
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O
P
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(c) F. Mathey (Ed.), Phosphorous–Carbon Heterocyclic Chemistry:
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Me
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C6H5
C6H5
p-Cl–C6H5
3
20
3
82
39
75
17
42
2
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Acknowledgements
The authors thank the following funding agencies for
supporting our program. The Petroleum Research Fund
(PRF 42457-AC, administered by the American Chemical
Society), the DoD for a Breast Cancer Research Program
Predoctoral Fellowship (MDM) and NIH K-BRIN
(#P20 RR16475) for undergraduate support (CES). The
authors thank Dr. David Vander Velde and Sarah Neuens-
wander for assistance with NMR measurements and Dr.
Todd Williams for HRMS analysis.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.
2006.09.035.

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5311
[17] The byproduct of C(6) substituted CP analogs should produce the less
toxic cinnamyl aldehyde analogs.
[18] The CM product was obtained with >97:3 E/Z selectivity by 31P
NMR. The major E product was confirmed by 1H NMR.
[19] When the reaction is exposed to the first generation Grubbs catalyst
only trace amounts of CM product is observed.
[21] The progressof the reactionwas followedby TLC. After thecompletion
of the reaction, the crude reaction mixture was concentrated and 31P
NMR analysis was used to determine the conversion ratios.
[22] For a recent study of NO2 substituted CP analogs see: Y. Jiang, J.
Han, C. Yu, S.O. Vass, P.F. Searle, P. Browne, R.J. Knox, L. Hu, J.
Med. Chem. 49 (2006) 4333–4343.
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Chem. Soc. 125 (2003) 11360–11370.
[23] B. Nosse, A. Schall, W.B. Jeong, O. Reiser, Adv. Synth. Catal. 347
(2005) 1869–1874.