Facile synthesis of bis-α-aminoalkylphosphinates

Article abstract of DOI:10.1080/00397910600767330

Herein we report a facile synthesis of esters of bis-α- aminoalkylphosphinic acids obtained by an addition of Cbz-protected phosphinic analogues of amino acid methyl esters to an appropriate imine in refluxing benzene. Complete deprotection of the esters

Full text of DOI:10.1080/00397910600767330

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Facile Synthesis of
bis‐α‐Aminoalkylphosphinates
Marcin Drag a , Katarzyna Dlugosz a & Józef Oleksyszyn a
a Department of Chemistry , Wroclaw University of Technology , Wroclaw,
Poland
Published online: 16 Feb 2007.
To cite this article: Marcin Drag , Katarzyna Dlugosz & Józef Oleksyszyn (2006) Facile Synthesis of
bis‐α‐Aminoalkylphosphinates, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 36:19, 2787-2795, DOI: 10.1080/00397910600767330
To link to this article: http://dx.doi.org/10.1080/00397910600767330
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Synthetic Communicationsw, 36: 2787–2795, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600767330
Facile Synthesis of
bis-a-Aminoalkylphosphinates
´
Marcin Drag, Katarzyna Dlugosz, and Jozef Oleksyszyn
Department of Chemistry, Wroclaw University of Technology,
Wroclaw, Poland
Abstract: Herein we report a facile synthesis of esters of bis-a-aminoalkylphosphinic
acids obtained by an addition of Cbz-protected phosphinic analogues of amino acid
methyl esters to an appropriate imine in refluxing benzene. Complete deprotection of
the esters could be achieved in one step by the action of 30% HBr in acetic acid.
Keywords: Addition, imine, inhibitor, phosphinate
Phosphinates and phosphinates-drived pseudodipeptides are compounds that
have attracted considerable interest in recent years because of their interesting
and broad biological activity.[1] A special emphasis has been laid on the
synthesis of analogues, which could serve as inhibitors of Zn-metallopro-
teases, and have been recently reviewed by Dive et al. and Yiotakis et al.[2,3]
Recent data of the inhibition of aminopeptidase N (CD13) activity
resulting in the process of programmed cell death (apoptosis) of cancer
cells focused our interests on design of inhibitors of this Zn-containing ectoen-
zyme.[4] One of the promising group of the compounds seems to be bis-a-
aminoalkylphosphinates, which are structurally related to two well-known
families of inhibitors of aminopeptidase N (APN), namely phosphinic acids
(not specific toward APN) and hydroxamic acids (cause teratogenic effects)
(Scheme 1).[5,6]
Received in the U.K. August 16, 2005
Address correspondence to Marcin Drag, Department of Chemistry, Wroclaw
University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland.
E-mail: marcin.drag@pwr.wroc.pl
2787

2788
M. Drag, K. Dlugosz, and J. Oleksyszyn
Scheme 1. Structures of phosphinic and hydroxamic acid and their phosphinic
analogue 6.
The compounds 5 and 6 could be modified in two directions that should
result in better fit in the S1 and especially S10 –S20subsites of the APN. Such
additional interaction could be achieved by substitution of the amino group
(alkyl, aryl), even in combinatorial manner. bis-a-Aminoalkylphosphinates
are known in the literature, but the described methods of synthesis are
not general or the compounds were by-products obtained in very low
yields.[7–9] Moreover, the synthesis of the desired compounds usually was
multistep and tedious. The known biological activity of this compound was
determined only for a symmetrical derivative of phenylalanine, which after
additional modification served as a potent inhibitor of HIV protease.[10]
Herein we report a general synthetic approach to the methyl esters of bis-
a-aminoalkylphosphinic acids 5 starting from Cbz-protected phosphinic
analogues of amino acid methyl esters 4 available in a few steps according
to the procedures reported earlier.[11] Thus, an appropriate aldehyde reacts
with benzhydrylamine salt of phosphonous acid yielding 1, which is depro-
tected in 40% HBr, giving phosphinic analogue of amino acid 2. Subsequent
protection with a benzyloxycarbonyl group gave Cbz-protected phosphinic
acid 3, which was esterified to 4 by the action of methanol in presence of di-
cyclohyksylocarbodimide (DCC) and dimethylaminopiridine (DMAP) in
tetrahydrofurane (THF) (Scheme 2).[11,12]
In the final step, the desired methyl esters 5 were obtained by refluxing
Cbz-protected phosphinic analogue of amino acid methyl esters 4 with the
appropriate N-, di-, or triphenylmethylimine in dry benzene or toluene for
4–8 h. The reaction ratio strongly depends on the structure of the R2 and R3
substituents of the imine. In the case of the N-triphenylmethylamine-
derived imines with three bulky phenyl groups, the amount of the desired
product was from 50 to 85% (as determined by 31P NMR of the crude
reaction mixture). The longer reflux (up to 12 h) did not result in a better
addition rate. In the case of the reaction of Cbz-protected phosphinic

Scheme 2. Preparation of compounds 1–5.

2790
M. Drag, K. Dlugosz, and J. Oleksyszyn
analogue of leucine methyl ester 4 with N-(triphenylmethyl)-phenylmethani-
mine, we did not observe the formation of the product, which can be reason-
ably explained by the steric hindrance resulting from the bulky phenyl group.
The reflux of the reaction mixture for 4 days (each day for 8–10 h) gave no
trace of the desired product. The addition reaction was usually accompanied
by a side product (2–8%), namely Cbz-protected phosphinic acid, which
was removed by standard workup. In contrast to N-triphenylmethylimines,
application of the N-benzhydrylimines in all investigated reactions resulted
in almost quantitative (90–100%) addition to give the desired product after
6 h of reflux (Scheme 2).
GENERAL PROCEDURE FOR SYNTHESIS OF COMPOUNDS 5
In a round-bottom flask, 1.67 mmol of the appropriate Cbz-protected phosphi-
nic acid methyl ester 4 and 1.84 mmol (1.1 mol equivalent) of the appropriate
imine were dissolved in 3 ml of dry benzene. The reaction mixture was
refluxed 6–11 h. After that, 70 ml of EtOAc was added to the mixture, and
the organic phase was washed with 30 ml of 5%aqu. KHSO4, 30 ml of
water, and 30 ml of brine; dried (MgSO4); and evaporated in vacuo.
Column chromatography on silica gel (70–200 mesh: 90 g) using a
petroleum ether–AcOEt (1:1) gave the desired compound 5 (Table 1).
The isolated compounds 4 and 5 always contained up to 1–5% of mass of
1
DCU (N,N-dicyclohexylurea, omitted in the H NMR data), which remained
after the esterification of 3. Our attempts to eliminate this side product from 4
or 5 by several recrystallizations from dichloromethane or hexane/AcOEt
(1:1) and column chromatography of 4 and 5 were only partially successful.
Moreover, considering the sterical effects during addition, we observed
that the phosphinic substrate should be used as methyl ester. For example,
the benzyl ester of leucine or phenylglycine derivatives of 4 did not result
Table 1. Structural and synthetic data for compounds 5
Entry
R1
R2
R3
Time (h) Yield (%)
5a
5b
5c
5d
5e
5f
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
Ph
C(Ph)3
C(Ph)3
CH(Ph)2
CH(Ph)2
C(Ph)3
C(Ph)3
C(Ph)3
C(Ph)3
C(Ph)3
CH3
CH2CH2CH3
Ph
8
10
6
65
49
88
86
78
62
54
45
48
CH2CH (CH3)2
H
CH3
6
8
Ph
Ph
8
5g
5h
5i
CH2CH2CH3
CH2CH2Ph
CH2CH2Ph
11
10
10
Ph
CH2CH2Ph

bis-a-Aminoalkylphosphinates
2791
Scheme 3. An example of deprotection of compounds 5.
in any conversion of the substrate to the desired product (based on the exper-
iments with N-triphenylmethylimines).
The application of N-triphenylmethylimine or N-diphenylmethylimine
gives the choice of possibilities for deprotection conditions (acid hydrolysis
or hydrogenolysis), and that could be a convenient feature in future
derivations.
For total deprotection, the application of N-triphenylmethyl derivatives
appears to be more convenient and can be easily and fully deprotected
using 30% HBr/AcOH at room temperature for 1.5 h, giving bis-a-aminoalk-
ylphosphinic acids 6 in almost quantitative yield (Scheme 3). Unfortunately,
our efforts to deprotect N-diphenylmethyl derivative of 5d using aqueous
solutions of HBr (48%) or HCl (37%) in 1008C resulted in the cleavage of
the C-P bond.
DATA
5a: (yellowish semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 53.34 (s, 21%),
53.47 (s, 29%), 54.51 (s, 37%) and 55.60 (s, 13%); 1H NMR (CDCl3,
3
3
300.13 MHz) d: 0.63 (dd, 3H, JHP ¼ 16.6 Hz, JHH ¼ 6.9 Hz, PCHCH3,
one diastereomer), 0.74–0.98 (m, 9H, CH(CH2)2, PCHCH3), 1.07–1.51
[m, 3H, CH2CH(CH3)2], 2.91–3.16 (m, 1H, PCHCH3), 3.64
2
2
(d, JHP ¼ 9.8 Hz, OCH3, one diastereomer), 3.66 (d, JHP ¼ 9.7 Hz, OCH3,
one diastereomer), 3.71 (d, 2JHP ¼ 10.0 Hz, OCH3, one diastereomer), 3.80 (d,
2JHP ¼ 9.5 Hz, OCH3, one diastereomer), 4.06–4.50 (m, 1H, PCHCH2),
3
4.99–5.21 (m, 3H, CH2OCO, NH), 5.71 (d, 1H, JHH ¼ 10.0 Hz, NH),
7.18–7.54 (m, 20H, ArH); MW ¼ 584.7, MS (ESI) ¼ 608.6 (M þ Na)þ,
623.8 (M þ K)þ.
5b: (yellowish semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 53.81 and 53.87
(2xs, two overlapping resonance signals, 49%), 54.71 (s, 28%) and 56.12
1
(s, 25%); H NMR (CDCl3, 300.13 MHz) d: 0.45–1.04 [m, 9H, CH(CH3)2,
CH2CH3], 1.23–1.66 [m, 7H, CH2CH2CH3, CH2CH(CH3)2], 2.78–3.11
2
(m, 1H, PCHCH2), 3.57 (d, JHP ¼ 9.9 Hz, OCH3, one diastereomer), 3.66
2
2
(d, JHP ¼ 9.8 Hz, OCH3, one diastereomer), 3.72 (d, JHP ¼ 11.4 Hz,

2792
M. Drag, K. Dlugosz, and J. Oleksyszyn
OCH3, one diastereomer), 3.75 (d, 2JHP ¼ 9.6 Hz, OCH3), 4.12–4.67 (m, 1H,
PCHCH2CH), 4.89–5.19 (m, 3H, CH2OCO, NH), 5.62 (d, 1H, 3JHH ¼ 8.1 Hz,
NH), 7.15–7.53 (m, 20H, ArH); MW ¼ 612.7, MS (ESI) ¼ 635.7 (M þ Na)þ,
652.5 (M þ K)þ.
5c: (transparent semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 46.03 (s, 9%),
46.96 (s, 52%), 48.70 (s, 22%) and 49.35 (s, 17%); 1H NMR (CDCl3,
300.13 MHz) d: 0.88–1.04 [m, 6H, CH(CH3)2], 1.26–1.82 [m, 3H,
2
CH2CH(CH3)2], 2.86–3.13 (m, 1H, PCHCH2], 3.09 (d, JHP ¼ 9.7 Hz,
2
OCH3, one diastereomer), 3.32 (d, JHP ¼ 9.9 Hz, OCH3, one diastereomer),
2
2
3.68 (d, JHP ¼ 10.0 Hz, OCH3, one diastereomer), 3.69 (d, JHP ¼ 9.7 Hz,
3
OCH3, one diastereomer), 3.75 (d, 1H, JHH ¼ 13.9 Hz, NH), 4.13–4.52
(m, 1H, PCH), 4.63–4.66 (m, 1H, CHPh2), 4.86–5.21 (m, 2H, CH2OCO),
3
5.71 (d, 1H, JHH ¼ 8.3 Hz, NH), 7.18–7.41 (m, 20H, ArH); MW ¼ 570.7,
MS (ESI) ¼ 594.5 (M þ Na)þ, 610.5 (M þ K)þ.
5d: (transparent semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 51.49 (s, 31%),
53.75 (s, 14%), 55.20 (s, 31%) and 56.21 (s, 24%); 1H NMR (CDCl3,
300.13 MHz) d: 0.60–1.96 [m, 18H, 2xCH2CH(CH3)2], 2.91–3.12 (m, 1H,
2
PCHCH2), 3.62 (d, JHP ¼ 9.9 Hz, OCH3, one diastereomer), 3.64
2
2
(d, JHP ¼ 9.7 Hz, OCH3, one diastereomer), 3.67 (d, JHP ¼ 10.0 Hz,
2
OCH3, one diastereomer), 3.69 (d, JHP ¼ 9.4 Hz, OCH3), 4.02–4.44
(m, 1H, PCHCH2), 4.99–5.18 (m, 3H, CH2OCO, CHPh2), 7.17–7.38
(m, 17H, ArH, 2xNH); MW ¼ 550.7 MS (ESI) ¼ 551.4 (M)þ, 573.3
(M þ Na)þ, 589.6 (M þ K)þ.
5e: (beige semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 48.95 (s, 47%) and
49.81 (s, 53%); 1H NMR (CDCl3, 300.13 MHz) d: 2.25–2.73 (m, 2H,
2
CH2P), 3.31 (d, JHP ¼ 10.1 Hz, OCH3, one diastereomer), 3.59
2
(d, JHP ¼ 10.1 Hz, OCH3, one diastereomer), 5.04–5.15 (m, 2H,
CH2OCO), 5.28–5.40 (m, 1H, CHP), 6.0 and 6.2 (2xbs 1H, NH), 7.19–
7.44 (m, 26H, ArH, NH); MW ¼ 590.7, MS (ESI) ¼ 613.5 (M þ Na)þ,
629.2 (M þ K)þ.
5f: (white semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 50.06 (s, 30%), 50.91
and 51.14 (3xs, three overlapping resonance signals, 70%); 1H NMR (CDCl3,
300.13 MHz) d: 0.47 (dd, 3H, 3JHP ¼ 17.3 Hz, 3JHH ¼ 7.0 Hz, PCHCH3, one
3
3
diastereomer), 0.57 (dd, 3H, JHP ¼ 17.5 Hz, JHH ¼ 7.0 Hz, PCHCH3, one
dominant diastereomer and one minor hidden), 0.74 (dd, 3H,
3
3JHP ¼ 17.2 Hz, JHH ¼ 7.0 Hz, PCHCH3, one diastereomer), 2.95–3.13
2
(m, 1H, PCHCH3), 3.20 (d, JHP ¼ 9.1 Hz, OCH3, one diastereomer), 3.23
2
2
(d, JHP ¼ 9.7 Hz, OCH3, one diastereomer), 3.67 (d, JHP ¼ 9.8 Hz, OCH3,
2
one diastereomer), 3.70 (d, JHP ¼ 9.7 Hz, OCH3, one diastereomer),
5.03–5.32 (m, 3H, CH2OCO, PhCHP), 5.89–6.21 (4xbs 1H, NH),

bis-a-Aminoalkylphosphinates
2793
7.19–7.36 (m, 26H, ArH, NH); MW ¼ 604.7, MS (ESI) ¼ 628.3 (M þ Na)þ,
644.3 (M þ K)þ.
5g: (transparent semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 50.64 (s, 30%),
50.90 (s, 26%), 51.33 (s, 24%) and 51.48 (s, 20%); 1H NMR (CDCl3,
300.13 MHz) d: 0.44–0.54 (m, 3H, CH2CH3), 0.88–1.31 (m, 4H,
2
CH2CH2CH3), 2.81–3.12 (m, 1H, PCHCH2), 3.12 (d, JHP ¼ 9.9 Hz,
2
OCH3, one diastereomer), 3.18 (d, JHP ¼ 9.8 Hz, OCH3, one diastereomer),
2
2
3.59 (d, JHP ¼ 9.8 Hz, OCH3, one diastereomer), 3.64 (d, JHP ¼ 9.8 Hz,
OCH3), 5.00–5.25 (m, 3H, PCHPh, CH2OCO), 5.72–6.33 (4xbs, 1H, NH),
7.21–7.31 (m, 26H, ArH, NH); MW ¼ 632.7, MS (ESI) ¼ 656.7
(M þ Na)þ, 672.6 (M þ K)þ.
5h: (transparent semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 50.32 (s, 35%),
51.10 (s, 19%), 51.30 (s, 21%) and 51.52 (s, 25%); 1H NMR (CDCl3,
300.13 MHz) d: 0.85–2.58 (m, 4H, CH2CH2Ph), 2.89–3.12 (m, 1H, CHP),
2
2
3.12 (d, JHP ¼ 9.9 Hz, OCH3, one diastereomer), 3.28 (d, JHP ¼ 9.9 Hz,
2
OCH3, one diastereomer), 3.63 (d, JHP ¼ 9.9 Hz, OCH3, one diastereomer),
2
3.73 (d, JHP ¼ 9.7 Hz, OCH3, one diastereomer), 5.13–5.76 (m, 4H,
CbzNHCHP, CH2OCO, NH), 7.12–7.43 (m, 31H, ArH, NH); MW ¼ 694.3,
MS (ESI) ¼ 694.5 (M)þ, 716.8 (M þ Na)þ, 732.9 (M þ K)þ.
5i: (yellowish semisolid). 31P NMR (CDCl3, 121.5 MHz) d: 52.93 (s, 29%),
53.0 (s, 13%), 53.71 (s, 39%) and 55.60 (s, 19%); 1H NMR (CDCl3,
300.13 MHz) d: 0.86–2.68 (m, 8H, 2xCH2CH2Ph), 3.01–3.24 (m, 1H,
2
CHP), 3.55 (d, JHP ¼ 10.0 Hz, OCH3, one diastereomer), 3.64
2
2
(d, JHP ¼ 9.8 Hz, OCH3, one diastereomer), 3.76 (d, JHP ¼ 10.0 Hz,
2
OCH3, one diastereomer), 3.77 (d, JHP ¼ 9.6 Hz, OCH3, one diastereomer),
4.02–4.58 (m, 1H, CHP), 5.03–5.18 (m, 3H, CbzNHCHP, CH2OCO),
5.82–6.89 (4xbs, 1H, NH), 7.13–7.42 (m, 31H, ArH, NH); MW ¼ 722.9,
MS (ESI) ¼ 745.6 (M þ Na)þ.
PROCEDURE
Compound 5 (0.6 mmol) was reacted with 1 ml of 30% HBr/AcOH at rt for
1.5 h in the closed, round-bottomed flask. After this time, the volatile
products were removed in vacuo, and the residue was treated several times
with dry Et2O, which was decanted from the mixture. The remaining oil
was dissolved in 2 ml of MeOH, and the pH was adjusted to 6 by addition
of propylene oxide. Precipitation started immediately or after cooling the
mixture in a refrigerator. If the compound did not precipitate after 3 h, 2 ml
of dry Et2O was added to the mixture and the mixture was placed in the
refrigerator again. Filtration and washing with dry Et2O gave the desired
compound 6 in almost quantitative yield.

2794
M. Drag, K. Dlugosz, and J. Oleksyszyn
DATA
6f: (white powder). Yield 95%, mp ¼ 231.0–233.08C, 31P NMR (D2O,
121.5 MHz) d: 25.43 (s, 48%) and 25.49 (s, 52%); 1H NMR (D2O,
300.13 MHz) d: 0.63–0.68 (m, 3H, CH3), 1.09–1.45 (m, 4H, CH2CH2CH3),
2
3.18 (m, 1H, CH2CHP), 4.45 (d, 1H, JHP ¼ 8.8 Hz, diastereomeric), 4.50
2
(d, 1H, JHP ¼ 10.6 Hz, diastereomeric), 7.36 (m, 5H, ArH); 13C NMR
(D2O, 75.46 MHz) d: 12.64 (s, CH3, diastereomeric), 12.65 (s, CH3, diastereo-
meric), 18.71 (s, CH2CH3, diastereomeric), 18.84 (s, CH2CH3, diastereo-
meric), 29.70 (s, CH2CH2CH3, diastereomeric), 29.79 (s, CH2CH2CH3,
diastereomeric),
48.20
(d,
1JCP ¼ 98.3 Hz,
CH2CHP),
53.67
1
(d, JCP ¼ 93.1 Hz, PhCHP, 127.88 (s, ArH, diastereomeric), 127.93
(s, ArH, diastereomeric), 128.11 (s, ArH, diastereomeric), 128.17 (s, ArH, dia-
stereomeric), 129.47 (s, ArH, diastereomeric), 130.11 (s, ArH, diastereo-
meric), 131.34 (s, ArH); IR (KBr, n [cm21]) 1023.4 (s, P-OH), 1168.5
(s, P55O), 1608.8 (m, N-H), 2557.6–3054.6 (ms, C-H), 3247.1 (ms, N-H).
CONCLUSION
Summing up, we have presented a new and efficient route for the synthesis of
methyl esters of bis-a-aminoalkylphosphinic acids (patent applications:
P370097 (2004) and P373479 (2005)). Currently we are investigating the con-
ditions for selective deprotection of the compounds 5. Preliminary biological
experiments prove that some of the structures of 6 reveal very good inhibitory
activity toward APN (IC50 in the nanomolar range) as well as induction of
apoptosis in some human cancer cell lines. We have progressed in the
synthesis of diastereomers of bis-a-aminoalkylphosphinic acids 6 with the
desired configuration needed for detailed biological investigations.
ACKNOWLEDGMENT
We thank Waldemar Goldeman for the generous gift of the analytically pure
N-triphenylmethylimines. Marcin Drag is grateful to the Foundation for Polish
Science for the scholarship.
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