Addition of dimethyl phosphite to imines bearing the L -methionine moiety and its surprisingly poor chiral assistance

Article abstract of DOI:10.1002/hc.21029

The preparation of methyl 2-{[(dimethoxyphosphoryl)-methyl]-amino}-4- methyl- sulfanylbutyrates (3a-e) by the addition of dimethyl phosphite to 2-(methylidenamino)-4-methylsulfanylbutyric acid methyl esters (2a-e) is described. The nearly nonexisting dias

Full text of DOI:10.1002/hc.21029

Heteroatom Chemistry
Volume 00, Number 0, 2012
Addition of Dimethyl Phosphite to Imines
Bearing the L-Methionine Moiety and Its
Surprisingly Poor Chiral Assistance
Jarosław Lewkowski and Rafał Karpowicz
Department of Organic Chemistry, Faculty of Chemistry, University of Ło´dz´, 91-403 Ło´dz´, Poland
Received 5 March 2012; revised 19 April 2012
We have reported the formation of N-(1-meth-
ABSTRACT: The preparation of methyl 2-
oxycarbonyl-3-methylbutyl)- aminomethylphospho-
{[(dimethoxyphosphoryl)-methyl]-amino}-4-methyl-
nic acids, i.e., aminophosphonic systems derived
sulfanylbutyrates (3a–e) by the addition of
from l-leucine, where the diastereoselectivity var-
dimethyl phosphite to 2-(methylidenamino)-4-
ied from de = 14% up to de = 100% [7]. More-
methylsulfanylbutyric acid methyl esters (2a–e) is
over, we observed the self-separation of predom-
described. The nearly nonexisting diastereoselectivity,
inant diastereoisomers of studied leucine-derived
which was observed in all cases, is unexpected and
aminophosphonic acids.
astonishing in light of the fact that some other amino
Therefore, we wished to extend our studies on
acid esters, e.g., leucine, demonstrated very high
some other amino acid derivatives and we have cho-
stereoselectivity in similar reactions. The separa-
sen methionine in hope of obtaining similar or even
ꢀ
C
tion of formed diastereoisomers occurred.
2012
better results. To our surprise, methionine did not
turn out to be a good chiral auxiliary and we would
like to report our observations and reflections about
it.
Wiley Periodicals, Inc. Heteroatom Chem 00:1–4, 2012;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.21029
RESULTS AND DISCUSSION
INTRODUCTION
Imines 2a–d [8–11] have been prepared using a
previously published method [7] by simple mixing
of an aldehyde 1a–d with methionine methyl es-
ter hydrochloride in dichloromethane in the pres-
ence of triethylamine. They were isolated and used
for further conversions without previous purifica-
tion (Scheme 1).
Methyl 2-{[(dimethoxyphosphoryl)-methyl]-am-
ino}-4-methyl-sulfanylbutyrates (3a–d) were syn-
thesized by the reaction of 2-(methylidenamino)-
4-methyl-sulfanylbutyric acid methyl esters (2a–d)
with dimethyl phosphite in acetonitrile for 10 days,
where the mixture was refluxed during the day and
stirred at room temperature at night (Scheme 1).
Chromatography on silica gel with ethyl acetate: hex-
ane (4:1) obtained pure aminophosphonates 3a and
3c as a mixture of diastereoisomers, whereas for
The addition of dialkyl and diaryl phosphites to an
azomethine bond of chiral Schiff bases, such as
N-α-methylbenzylimines, has been described in sev-
eral papers [1–5]. Diastereoselectivity of reported re-
actions varied from 2:1 to 9:1 of a diastereoisomeric
ratio.
Mikołajczyk and co-workers invented an inter-
esting method for highly stereoselective synthesis
of aminophosphonic acids using the addition of
dialkyl phosphite anions to chiral sulfimines [6],
which achieved promising results.
Dedicated to Professor Henri-Jean Cristau on the occasion of
his 70th birthday.
Correspondence to: Jarosław Lewkowski; e-mail: jlewkow@
uni.lodz.pl.
c
ꢀ
2012 Wiley Periodicals, Inc.
1

2
Lewkowski and Karpowicz
SCHEME 1
TABLE 1 Results of Addition of Dimethyl Phosphite to 2-(Methylidenamino)-4-methylsulfanylbutyric Acid Methyl Esters (2a–d)
A Single Isomera
Compound
R
Y (%)
dr (de%)
31P NMR
31P NMR
α2D0
3a
3b
3c
3d
Ph
Ferrocenyl
2-Furyl
62
63
53
61
5:4 (11)
2:6 (50)
2:3 (20)
1:1 (0)
25.01, 24.99
24.11, 24.00
22.46, 22.42
23.27, 23.02
–
–
24.00
–
23.27
+164.5 (c = 0.1, CHCl3)
–
2-Thienyl
−0.82 (c = 1.14, CHCl3)
aSpectral data of separated diastereoisomer.
3b and 3d obtained separation of one of two di-
astereoisomers. Results are presented in Table 1.
Unfortunately, the addition of dimethyl phos-
phite to an azomethine bond of methionine-derived
imines turned out not to be significantly diastereose-
lective: the highest one, which occurred in a case of a
ferrocenyl derivative 3b (de = 50%), and the lowest,
practically null in a case of a thiophene derivative 3d.
Results are presented in Table 1. It is highly astonish-
ing, first because amino acids, i.e., proline, is a well-
known chiral auxiliary and catalyst in asymmetric
synthesis [12,13]. Moreover, valine is largely used as
a chiral auxiliary in the Schoellkopf reagent, the pre-
cursor for amino acid synthesis [14]. Studying a case
of phosphite addition to leucine analogues, diastere-
oselectivity was much higher, from de = 14% for the
thienyl derivative until de = 100% for the ferrocene
one [7]. Certainly, the tendency remained the same;
we noticed that in both cases, the highest stereoselec-
tivity occurred for ferrocene derivatives (vide supra),
less selectivity occurred for 2-furyl ones (de = 67%
for the leucine analogue [7] vs. de = 20% for the
methionine one), and dramatically less for 2-thienyl
derivatives (vide supra). Higher diastereoselectivity
of ferrocene derivatives has been discussed in light
of the Houk model [15], which provided the explana-
tion suggesting that “diastereoselection is reinforced
due to the stabilizing interaction between the phos-
phorus atom orbital and the ferrocenyl substituent”
[7, p. 328].
Such a low diastereoselectivity could also be
explained on the basis of the Houk model [15]. The
“normal” Houk action causes the formation of the
hydrogen bond between the hydrogen of dimethyl
phosphite and the nitrogen of the azomethine bond
from the side opposite to the methoxycarbonyl
substituent. The diastereoselection is weakened
by the formation of the hydrogen bond between
the hydrogen of dimethyl phosphite and sulfur of
the methionine ethylthiomethyl group from the
side of the methoxycarbonyl substituent, as it is
depicted in Scheme 2, which results in a very low
diastereoselectivity.
This
reaction
will
be
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Addition of Dimethyl Phosphite to Imines Bearing the L-Methionine Moiety and Its Surprisingly Poor Chiral Assistance
3
investigated in the future for some other amino
acids, such as valine or tert-leucine.
C(O) OCH3, 3H); 2.62–2.57 (m, CH2HCHSCH3,
1H); 2.46–2.42 (m, CH2HCHSCH3, 1H); 2.32–2.19
(m, CH2CH2SCH3, 2H); 2.16 (s, SCH3, 3H).
EXPERIMENTAL
2-(2-Thienylideneamino)-4-methylsulfanylbuty-
ric acid methyl ester (2d) [15]. Yield: 77%. 1H NMR
All solvents were routinely distilled and dried
prior to use. Aldehydes, methionine methyl ester
hydrochloride, and dimethyl phosphite (Aldrich,
Poznan´, Poland) were used as received. For column
chromatography, silica gel (Kiesegel 60 0.063–0.200
nm/70–230 mesh) from Aldrich was used. NMR spec-
tra were recorded on a Bruker Avance III appara-
tus (Bruker Biospin, Poznan´, Poland) working at
=
(600 MHz, CDCl3): δ 8.45 (s, CH N, 1H); 7.47 (dd,
4
5
3 J = 4.8 Hz and J = 1.2 Hz, Hthio, 1H); 7.41 (dd,
3 J = 3.6 Hz and J = 1.2 Hz, Hthio, 1H); 7.11 (dd,
4
3
3
4
3 J = 4.8 Hz and J = 3.6 Hz, Hthio, 1H); 4.20 (dd,
3 J = 8.4 Hz and 2 J = 4.8 Hz, CHmet, 1H); 3.77
(s, C(O) OCH3, 3H); 2.64–2.6 (m, CH2HCHSCH3,
1H); 2.5–2.45 (m, CH2HCHSCH3, 1H); 2.31–2.23
(m, CH2CH2SCH3, 2H); 2.12 (s, SCH3, 3H).
1
600 MHz for H NMR, 150 MHz for 13C NMR (with
TMS as an internal standard), and 243 MHz for 31P
NMR (with 85% H3PO4 as an external standard).
Methyl 2-{[(dimethoxyphosphoryl)-methyl]-ami-
no}-4-methyl-sulfanylbutyrates (3a–d)
2-(Methylidenamino)-4-methylsulfanylbutyric
Acid Methyl Esters (2a–d)
General method. Imine (2a–d) (2 mmol) was
dissolved in acetonitrile (30 mL), and dimethyl phos-
phite (2 mmol) was added. A mixture was refluxed
for 10 days, and then the solvent was evaporated in
vacuo; residue was dissolved in a small amount of
dichloromethane and washed three times with satu-
rated aqueous NaHCO3 (3 × 20 ml). An organic layer
was separated, dried, and filtered, and the solvent
was evaporated. Obtained crude aminophosphonate
was then chromatographed on silica gel with ethyl
acetate: hexane (4:1).
General procedure. To a solution of aldehyde
(2 mmol) in dichloromethane (30 mL), OMe-
methionine hydrochloride (2 mmol) in triethylamine
(2 mmol) was added and the solution was refluxed
for 5 days. Then the content of a flask was concen-
trated in vacuo up to/one third of the volume; hexane
was added and precipitated. Et3N·HCl was filtered
off to obtain dense oil of an imine.
2-(Benzenylideneamino)-4-methylsulfanylbutyric
Predominant diastereoisomers in the mixture
are denoted with an asterisk.
1
acid methyl ester (2a) [12]. Yield: 90%. H NMR
=
(600 MHz, CDCl3): δ 8.33 (s, CH N, 1H); 7.80–7.76
(m, ArH, 2H); 7.45–7.41 (m, ArH, 3H); 4.21 (dd,
2
3 J = 7.8 Hz and J = 5.6 Hz, CHmet, 1H); 3.75 (s,
Methyl 2-{[phenyl(dimethoxyphosphoryl)-methyl]-
amino}-4-methyl-sulfanylbutyrate (3a). Calcd for
C15H24NO5SP: C, 49.85; H, 6.69; N, 3.88. Found: C,
49.59; H, 6.51; N, 3.85.
C(O) OCH3, 3H); 2.66–2.35 (m, CH2CH2SCH3,
2H); 2.32–2.20 (m, CH2CH2SCH3, 2H); 2.09 (s,
SCH3, 3H).
Yield: 62%. 1H NMR (600 MHz, CDCl3): δ
2
7.43–7.29 (m, ArH, 5H); 4.15∗ (d, JPH = 18,6 Hz,
2-(Ferrocenylideneamino)-4-methylsulfanylbuty-
P CH N, 1H); 4.01 (d, 2 JPH = 20.4 Hz, P CH N,
1H); 3.78 and 3.51 (2d, 3 JPH = 10.8 Hz, P(O) OCH3,
3H); 3.69∗ and 3.46 (2s, C(O) OCH3, 3H); 3.67∗ and
3.64∗ (2d, 2 J = 10.8 Hz, P(O) OCH3, 3H); 3.49–
3.45∗ (m, CHmet, 1H); 3.25–3.20 (m, CHmet, 1H);
2.67–2.62∗ (m, CH2CH2SCH3met, 2H); 2.60–2.50 (m,
CH2CH2SCH3met, 2H); 2.09∗ and 2.04 (2s, SCH3,
3H); 1.93–1.80∗ (m, CH2CH2SCH3met, 2H). 31P NMR
(243 MHz, CDCl3): δ 25.01∗, 24.99.
ric acid methyl ester (2b) [13]. Yield: 95%. 1H NMR
=
(600 MHz, CDCl3): δ 8.20 (s, CH N, 1H); 4.73–4.72
(m, CpH, 1H); 4.67–4.66 (m, CpH, 1H); 4.41–4.39 (m,
CpH, 2H); 4.21 (s, CpH, 5H); 4.06 (dd, 3 J = 9.0 Hz and
2 J = 4.8 Hz, CHmet, 1H); 3.75 (s, C(O) OCH3, 3H);
2.61–2.57 (m, CH2HCHSCH3, 1H); 2.49–2.44 (m,
CH2HCHSCH3, 1H); 2.28–2.16 (m, CH2CH2SCH3,
2H); 2.10 (s, SCH3, 3H).
2-(2-Furylideneamino)-4-methylsulfanylbutyric
acid methyl ester (2c) [14]. Yield: 96%. 1H NMR
(600 MHz, CDCl3): δ 8.13 (s, CH=N, 1H); 7.55 (dd,
Methyl 2-{[ferrocenyl(dimethoxyphosphoryl)-
methyl] - amino} - 4 - methyl - sulfanyl-butyrate (3b).
Yield: 63%.
Isolated predominant diastereoisomer: Calcd for
C19H28NO5SPFe: C, 48.62; H, 6.01; N, 2.98. Found:
C, 48.29; H, 6.08; N, 2.75.
4
5
3 J = 1.8 Hz and J = 0.6 Hz, Hfur, 1H); 6.85 (dd,
4
3
3 J = 3.6 Hz and J = 0.6 Hz, Hfur, 1H); 6.50 (dd,
3
4
3 J = 3.6 Hz and J = 1.8 Hz, Hfur, 1H); 4.16 (dd,
2 J = 8.4 Hz and 3 J = 4.8 Hz, CHmet, 1H); 3.48 (s,
Heteroatom Chemistry DOI 10.1002/hc

4
Lewkowski and Karpowicz
3
1H NMR (600 MHz, CDCl3): δ 4.30 (s, CpH, 5H);
1H NMR (600 MHz, CDCl3): δ 7.27 (dd, JHH
=
4
5
4.27–4.25 (m, CpH, 1H); 4.21–4.19 (m, CpH, 2H);
4.18–4.16 (m, CpH, 1H); 3.79 (s, C(O) OCH3, 3H);
6.6 Hz and JHH = 1.8 Hz, Hthi, 1H); 7.12–7.11 (m,
3Hthi, 1H); 6.98 (dd, 3 JHH = 6.6 Hz and 3 JHH = 3,6 Hz,
2
2
3.74 (d, JHP = 18.4 Hz, P CH N, 1H); 3.67 (d,
4Hthi, 1H); 4,30 (d, JPH = 20,4 Hz, P CH N, 1H);
3
3
3 JPH = 10.8 Hz, P(O) OCH3, 3H); 3.60 (d, JPH
=
3,81 (d, JPH = 10,2 Hz, P(O) OCH3, 3H); 3,63 (d,
10,8 Hz, P(O) OCH3, 3H); 3.50–3.47 (m, CHNmet
,
3 JPH = 10,2 Hz, P(O) OCH3, 3H); 3.61 (dd, J =
6.0 and 7.2 Hz, CH–N, 1H); 3,57 (s, C(O) OCH3,
3H); 2,66–2.52 (m, CH2CH2SCH3, 2H); 2,11 (s, SCH3,
3H); 1.95–1.86 (m, CH2CH2SCH3, 2H). 31P NMR
(243 MHz, CDCl3): δ 23.27.
1H); 2.74–2.67 (m, CH2CH2SCH3, 2H); 2.15 (s,
SCH3, 3H); 1.27–1.23 (m, CH2CH2SCH3, 2H). 13
C
=
NMR (150 MHz, CDCl3): δ 175.39 (C O); 70.64 (d,
ferr
2 JPC = 10.5 Hz, Cqfeurart); 69.81 (C ); 68.79 (C5H5); 67.72
4,5
Second diastereoisomer: 1H NMR (600 MHz,
CDCl3): δ 7.34–7.32 (m, 5Hthi, 1H); 7.15–7.14 (m, 3Hthi,
(d, 3 JPC = 10.9 Hz, Cf2e,r3r); 58.68 (C(O)OCH3); 53.56 (d,
1 JPC = 160.7 Hz, PCN); 53.80 (d, 2 JPC = 7.1 Hz, POC);
52.76 (d, 2 JPC = 7.4 Hz, POC); 51.87 (CHC(O)); 34.06,
30.58 (CH2CH2); 15.49 (SCH3). 31P NMR (243 MHz,
CDCl3): δ 24.00.
1H); 6.98 (dd, 3 J = 4.8 Hz and 3 J = 3,6 Hz, Hthi,
4
2
1H); 4,51 (d, JPH = 18.6 Hz, P CH N, 1H); 3,84
3
3
(d, JPH = 10.8 Hz, P(O) OCH3, 3H); 3,75 (d, JPH
= 10.8 Hz, P(O) OCH3, 3H); 3.75 (s, C(O) OCH3,
3H); 3.34 (dd, J = 4.2 and 8.4 Hz, CH–N, 1H); 2,66–
2.52 (m, CH2CH2SCH3, 2H); 2,01 (s, SCH3, 3H); 1.95–
1.86 (m, CH2CH2SCH3, 2H). 31P NMR (243 MHz,
CDCl3): δ 23.02.
Second diastereoisomer: 1H NMR (600 MHz,
CDCl3): δ 4.29 (m, CpH, 5H); 4.25–4.24 (m, CpH,
1H); 4.22–4.21 (m, CpH, 1H); 4.19–4.18 (m, CpH,
2
2H); 3.80 (s, C(O) OCH3, 3H); 3.73 (d, JHP
3
= 15.6 Hz,
P CH N, 1H); 3.59 (d, JPH
=
10.8 Hz, P(O) OCH3, 3H); 3.49 (d, 3 JPH = 10.2 Hz,
P(O) OCH3, 3H); 3.53–3.50 (m, CHNmet, 1H);
2.73–2.64 (m, CH2CH2SCH3, 2H); 2.17 (s, SCH3,
3H); 2.09–2.02 (m, CH2CH2SCH3, 2H). 31P NMR
(243 MHz, CDCl3): δ 24.11.
REFERENCES
[1] Yuan, C.; Cui, S. Phosphorus Sulfur Silicon 1991, 55,
159–164.
[2] Głowiak, T.; Sawka-Dobrowolska, W.; Kowalik, J.;
Mastalerz, P.; Soroka, M.; ZoÒ, J. Tetrahedron Lett
1977, 45, 3965–3968.
[3] Skwarczyn´ski, M.; Kafarski, P. Synth Commun 1995,
25, 3565–3572.
[4] Sheiko, S.; Guliaiko, I.; Grushkun, E.; Kolodiazhnyi,
O. I. Phosphorus Sulfur Silicon 2002, 177, 2269–
2270.
[5] (a) Kachkovskii, G. A.; Andrushko, N. V.; Sheiko,
S. Yu.; Kolodiazhnyi, O. I. Russ J Gen Chem 2006,
75, 1735–1746; (b) Zh Obshch Khim 2006, 75, 1818–
1826.
[6] Mikołajczyk, M.; Łyz´wa, P.; Drabowicz, J. Tetrahe-
dron: Asymmetry 1997, 8, 3991–3996.
[7] Lewkowski, J.; Karpowicz, R. Heteroatom Chem
2010, 21, 326–331.
[8] Riera, X.; Lopez, C.; Caubet, A.; Moreno, V.; Solans,
X.; Font-Bardia, M. Eur J Inorg Chem 2001, 2135–
2141.
[9] Hess, A.; Sehnert, J.; Weyhermueller, T.; Metzler-
Nolte, N. Inorg Chem 2000, 39, 5437–5443.
[10] Grigg, R.; Sridharan, V.; Wang, J.; Xu, J. Tetrahedron
2000, 56, 8967–8976.
Methyl 2-{[2-furyl(dimethoxyphosphoryl)-methyl]-
amino}-4-methyl-sulfanylbutyrate (3c). Calcd for
C13H22NO6SP: C, 44.44; H, 6.31; N, 3.99. Found: C,
44.23; H, 6.21; N, 4.02.
1
Yield: 53%. H NMR (600 MHz, CDCl3): δ 7.43–
5
7,42∗ and 7.41–7.40 (2m, Hfur, 1H); 6.41–6.40∗ and
3
6.38–6.37 (2m, Hfur, 1H); 6.36–6.35∗ and 6.35–6.34
4
2
(2m, Hfur, 1H); 4.32 (d, JPH = 19.8 Hz, P CH N,
1H); 4.11∗ (d, 2 JPH = 22.8 Hz, P CH N, 1H); 3.83∗
and 3.73∗ (2d, JPH = 10.2 Hz, P(O) OCH3, 3H);
3
3
3.79 and 3.66 (2d, JPH = 10.8 Hz, P(O) OCH3,
3H); 3.70∗ and 3.55 (2s, C(O) OCH3, 3H); 3.47∗
(dd, 3 J = 7.2 Hz and 2 J
=
5.4 Hz, CHmet, 1H);
3.35 (dd, 3 J = 7.8 Hz and 2 J = 4.8 Hz, CHmet
,
1H); 2.67–2.51 (m, CH2CH2SCH3, 2H); 2.09 and
2.05∗ (2s, SCH3, 3H); 1.96–1.79 (m, CH2CH2SCH3,
2H);. 31P NMR (243 MHz, CDCl3):
22.42∗.
δ 22.46;
[11] Ankersmit, H. A.; Witte, P. T.; Kooijman, H.; Lakin,
M. T.; Spek, A. L.; Goubitz, K.; Vrieze, K.; van Koten,
G. Inorg Chem 1996, 35, 6053–6063.
[12] List, B. Tetrahedron 2002, 58, 5573–5587.
[13] List, B. Chem Commun 2006, 8, 819–824.
[14] Bull, S. D.; Davies, S. G.; Moss, W. O. Tetrahedron:
Asymmetry 1998, 9, 321–328.
Methyl 2-{[2-thienyl-(dimethoxyphosphoryl)-
methyl]-amino}-4-methyl-sulfanylbutyrate (3d). Yield:
61%.
Isolated diastereoisomer: Calcd for C13H22NO5
1
S2P• /2H2O: C, 41.48; H, 6.61; N, 3.72. Found: C,
[15] Houk, K. N.; Duh, H.-Y; Wu, Y.-D.; Moses, S. R. J Am
Chem Soc 1986, 108, 2154–2755.
41.21; H, 6.47; N, 4.01.
Heteroatom Chemistry DOI 10.1002/hc