Simple synthesis of variously N-protected α-aminomethanesulfinate salts

Full text of DOI:10.1021/jo9516648

5648
J . Org. Chem. 1996, 61, 5648-5649
Sim p le Syn th esis of Va r iou sly N-P r otected
r-Am in om eth a n esu lfin a te Sa lts
Fre´de´ric J . M. Dujols and Michel E. Mulliez
Institut de Chimie Mole´culaire, Universite´ Paul Sabatier,
118 Route de Narbonne, 31062 Toulouse Cedex, France
Received September 11, 1995
The synthesis of R-sulfonopeptides (chain of R-amino-
sulfonic acid residues linked to each other by a sulfon-
amide bond) and particularly of the sulfonamide transi-
tion state analogs (intercalation of an R-amino sulfonic
acid residue in a peptide chain) has remained an elusive
goal.1 We considered this in the context of the overac-
tivation of the sulfonyl group of N-protected R-amino acid
intermediate 2 deriving from 1. â-elimination of SO2Cl
was favored over the coupling that would lead to 3,
amines acting merely as bases, not as nucleophiles
(Figure 1). To circumvent this, we first took an intramo-
lecular approach,2,3 since stabilization by cyclization of
2 could be faster than â-elimination. Though we suc-
ceeded in an attempt using an ureyl group in 2 (Y )
RNHCO), it was not complete.4
F igu r e 1.
An intermolecular synthetic route, avoiding sulfonyl
activation of 2, exploits an Umpolung reaction, i.e.,
electrophilic amination of the corresponding sulfinates
4 with O-sulfonylated (or phosphor(n)ylated) hydroxy-
lamine derivatives 5 (Figure 1). These previously un-
known key compounds 4 were obtained only recently,
first with Y protecting groups of the sulfonyl type, in a
Mannich-like reaction. Coupling (Figure 2, top), in a
basic aqueous medium, occurs readily between R-hydroxy
sulfinates5 such as rongalite 6, and sulfonamides 7 (Y )
mesyl, tosyl).6 Unfortunately the generalization of this
reaction with amino derivatives YNH2 7 other than
sulfonamides is difficult. This is mainly due to the very
basic conditions used. Only benzhydryl, ureyl, and
probably diphenylphosphinyl protecting groups can be
easily introduced.7 Common protecting groups such as
Cbz, Boc, phthaloyl, and benzoyl are not tolerated.
In the course of this latter study,7 we observed that,
with excess ammonia, sodium8 methanesulfinate (8) was
formed and trapped with phenyl isocyanate.7 In this
paper, we present the generalization of this coupling
reaction. It allows the easy introduction of the common
protecting groups, which was impossible or very difficult
to achieve with the previous method. The results of the
study of this coupling reaction 8 f 4 and 10 (Figure 2;
bottom) are displayed in Table 1.
F igu r e 2.
Schotten-Baumann conditions; dioxane is used in order
to solubilize, at least partially, the acylating reagents 9.
Solvents must be degassed because of the sensitivity to
oxidation of some of these sulfinates (particularly the
phthaloyl derivative 4c). Extra base is added when acidic
components arising from the X moiety of YX reagents
912-18 are released because is acidic media the ammonium
(9) Toyle, J . In The Chemistry of Sulfinic Acids Esters and Their
Derivatives; Patai, S., Ed.; J ohn Wiley and Sons: New York, 1991; pp
469-470.
(10) Electrophilic amination is advantageously performed directly
on the sodium salts 4, in water, the resulting insoluble sulfonamide
derivatives 3 being easily separated by filtration (Mulliez, M. Unpub-
lished results). For example, 4a leads to the known 3 (R′ ) H):
Etienne, A.; Le Berre, A.; Lonchambon, G.; Lochey, G.; Cucumel, B.
Bull. Soc. Chim. Soc. Fr. 1974, 580. Gilmore, W. F.; Yeih, M. M.;
Smith, R. B. J . Org. Chem. 1986, 43, 4784.
(11) This is the case with HOSu but not with HCl. Therefore,
introduction of the protecting group via the chloride is restricted to
the sodium salt 4.
(12) Frankel, M.; Ladkany, D.; Gilon, C.; Wolman, Y. Tetrahedron
Lett. 1966, 4765.
(13) Wu¨nsch, E.; Graf, W.; Keller, O.; Wersin, G. Synthesis 1986,
958.
(14) Moroder, L.; Halett, A.; Wu¨nsch, E.; Keller, O.; Wersin, G.
Hoppe-Seyler’s Z. Physiol. Chem. 1976, 357, 1651.
(15) Nefkens, G. H. L.; Tesser, G. I.; Nivard, R. J . F. Rec. Trav. Chim.
Pays-Bas 1960, 79, 688.
(16) Richardson, A. G.; Pierce, J . S.; Reid, E. E. J . Am. Chem. Soc.
1952, 74, 4011. The oxalyl group can repetitively be used successively
Resu lts a n d Discu ssion
Since sulfinate 8 can be obtained (just prepared) only
in aqueous solution, the reaction is performed under
(1) Gennari, C.; Salom, B.; Potenza, D.; Williams, A. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2067 and references cited therein.
(2) Mulliez, M. Tetrahedron 1981, 37, 2021.
(3) Garrigues, B.; Mulliez, M. Synthesis 1988, 810.
(4) Garrigues, B.; Mulliez, M. Phosphorus, Sulfur Silicon 1991, 57,
203.
as a protecting and an activating group: Mulliez, M.; Royer, J .
Tetrahedron 1984, 40, 5143.
(17) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 351.
(18) Ramage, R.; Hopton, D.; Parott, M. J .; Kenner, G. W.; Moore,
G. A. J . Chem. Soc., Perkin Trans. 1984, 1357.
(5) Mulliez, M.; Naudy, C. Tetrahedron 1993, 49, 2469.
(6) Mulliez, M.; Naudy, C. Tetrahedron 1994, 50, 5401.
(7) Leurquin, F.; Mulliez, M. Phosphorus, Sulfur Silicon 1994, 92,
201.
(19) The pH of the reaction mixture must be kept at ∼7-8, the value
of the roughly estimated pKa of the ammonium form of 8: lower than
for glycinate (9.6), as the SO2- group is more electron attracting than
COO- and higher than for R-aminomethanesulfonate (5.7: Lacoste,
(8) Previously,6 we observed that with the zinc salt attack is
dramatically diverted on the sulfur atom, probably as a result of
complexation of nitrogen with the zinc cation. With the sodium salt
one cannot exclude such an attack followed by fast transfer to nitrogen.
-
R. G.; Martell, A. E. J . Am. Chem. Soc. 1955, 77, 5512) as -SO2 is
-
less electron attracting than -SO3
.
S0022-3263(95)01664-1 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 16, 1996 5649
Ta ble 1. Stu d y of th e Cou p lin g of r-Am in om eth a n e Su lfin a te 8 w ith Va r iou s Acyla tin g Rea gen t 9 YX. Syn th eses of
-
N-P r otected r-Am in om eth a n eSu lfin a tes YNH CH2SO2 4 a n d 10
acylating
reagentsa
YX (9)
yieldb
yield (%)
leading
ref
time of
completion
isolated
compds
(%) of Na of DCHA recrystallizn
δCH2CDCl3
mp (°C) (CD3SOCD3)
exptl condns
salt 4
salt 10
solvent
Z-OSu (9a )12
12
H2O-dioxane (1:1) +
0.5 equiv of Na2CO3
H2O-dioxane (1:1)
H2O-dioxane (1:1)
H2O-dioxane (1:1)
H2O-dioxane (1:1)
1 h
10a
100
80
H2O
142-145 3.6 (3.13)
Z-benzotriazolyl (9a ′)13
Boc-O-Boc (9b)14
13
14
15
17
7 days 10a + Z-NH2
24 h
48 h
24 h
50
100
60
30
40
48
17
CHCl3-AcOEt id.
id.
10b
10c
ClCH2CH2Cl 102-104c 3.56 (3.14)
Pht-NCOOEt (9c)15
Bz-imidazolyl (9d )17
EtOH
iPrOH
193-196 4.14
160-165 3.95
10d + PhCO2H‚
DCHA (13)
60
a
Z ) PhCH2OCO; -OSu ) N-(hydroxysuccinimidyl); Boc ) Me3COCO; Pht ) o-OCC6H4CO-; Bz ) PhCO; DCHA ) H2N(C6H11)2.
Isolated after concentration to dryness of the extracted (CHCl3) aqueous layer or estimated using 1H NMR and standards. c Adduct
b
with 0.25 ClCH2CH2Cl.
group is unreactive19 and sulfinates are unstable.9 The
pH of the reaction mixture must be kept above ∼5 at
completion of the reaction, and the products can only be
isolated as salts. The sodium salts 4, being very water
soluble, are easily separated from organic byproducts by
extraction and are obtained (see 4b) in a fairly pure state
by concentration to dryness.10 It is wiser, however, to
crystallize the compounds as dicyclohexylammonium
salts, which, due to the very hydrophobic cation, are less
soluble in water than in chloroform, and they can be
extracted selectively using this latter solvent, provided
that the dicyclohexylammonium salt formed with the X-
group (arising from 9) is more soluble in water than the
salt 10.11 In some cases, particularly 10b and 10d , the
dicyclohexylammonium salts 10 form rather stable ad-
ducts with solvents.
The identity of the products 4 and 10 was established
by their conversion into their sulfonamide derivatives 310
and by conventional means: elemental analysis and IR
and NMR (both 13C and 1H) spectroscopy. Using this
latter technique, it is worth mentioning the deshielding
effect, as expected, on the RCH2 of the acyl protecting
substituents (compared to δ 3.18 for 87) and the same
specific shielding effect (∆δ ∼0.5 ppm) of DMSO as
observed with sulfonates.3
chloroform (3 × ∼20 g). To the aqueous alkaline phase was
added a water (11 g) solution of citric acid (0.67 g, 3.5 mmol)
and dicyclohexylamine (1.8 g, 10 mmol). The immediately
precipitated oil was extracted with chloroform (3 × ∼20 g) and
the product 10a crystallized and isolated (3.3 g, 80% yield): IR
ν 3160, 2600-2400, 1703 cm-1; 1H NMR (CDCl3) δ 1.2-1.7 (m),
2.9 (m), 3.06 (d, J ) 7.45 Hz, 2H), 5.07 (s, 2H), 5.74 (br s, 1H),
7.27 (s, 5H), 8.9 (br s, 2H); 13C (CDCl3) δ 24.6, 25.1, 29.1, 52.9,
66.75, 67.4, 127.97, 128.4, 136.6, 153.3. Anal. Calcd for C21H34
-
N2O4S: C, 61.43; H, 8.35; N, 6.82. Found: C, 61.95; H, 8.51; N,
6.90.
Boc Der iva tives 4b a n d 10b. The sodium salt 4b was
obtained after concentration of the aqueous alkaline phase to
1
dryness until constant weight. It was proved by H NMR to be
dihydrated after addition of a known quantity of sodium acetate
as a standard: IR ν 3441, 3333, 3256, 1678 cm-1; 1H NMR (D2O)
δ 1.45 (s, 9H), 3.57 (s, 2H); 13C NMR (D2O) δ 30.3, 69.5, 84.3,
160.1, identical to the values given in ref 7.
The dicyclohexylammonium salt, 10b, soluble in water, was
extracted with chloroform. The concentrated extracts were
taken up in THF, filtered from some small insoluble material,
concentrated to dryness, and crystallized from 1,2-dichloroethane
at -30 °C: IR ν 3200, 2700-2400, 1699 cm-1; 1H NMR (CDCl3)
δ 1.42 (s, 9H), 3.56 (d, J ) 6.45 Hz, 2H), 3.71 (s, 1H), 5.33 (br s,
1H).
P h th a loyl Der iva tive 10c. Commercial (Aldrich) 9c was
satisfactorily recrystallized from acetonitrile. Crystallization
under argon of the product 10c from the yellow aqueous phase
took several days at 4 °C: IR ν 2700-2400, 1715 cm-1; 1H NMR
(CDCl3) δ 4.14 (s, 2H), 7.74 (br s, 4H); 13C NMR (CDCl3) δ 63.78,
123.1, 132.2, 133.9, 167.4. Anal. Calcd for C21H30N2O4S: C,
62.04; H, 7.43; N, 6.89. Found: C, 61.91; H, 7.56; N, 6.80.
Ben zoyl Der iva tive 10d . The reaction was performed with
a 50% excess of 8 versus 9d (Lancaster), and at completion the
pH was still above ∼10. The hydrolysis salt 13 first was
separated by selective crystallization in MeOH (3.5 g for a 10
mmol residue of coupling), 23% yield: mp 199-200 °C (metha-
nol); IR ν 2700-2400, 1624 cm-1. Anal. Calcd for C19H19NO2:
C, 75.2; H, 9.63; N, 4.61. Found: C, 75.08; H, 9.72; N, 4.55.
Cocrystallization of the aminolysis product 10d with ∼0.5
equiv of protic solvents was observed: with ethanol, mp 138-
140 °C; with 2-propanol, mp 138-142 °C. Long drying (∼1
month) at room temperature under reduced pressure (∼10 mm)
in the presence of P2O5 was necessary in order to remove it: IR
ν 3329, 2700-2400, 1639 cm-1; 1H NMR (CDCl3) δ 3.95 (d, J )
7 Hz, 2H), 6.66 (br s merged with +H2N DCHA, 1H); 13C NMR
(CDCl3) δ 66.2, 127.3, 128.4, 131.5, 134.1, 168.1.
Con clu sion s
The described procedure (Figure 2, bottom) provides
chemists with a choice20 of N-protecting groups for the
class of glycine analogs 4 and 10. Work is in progress
that deals with its generalization using CR-substituted
R-aminosulfinates.
Exp er im en ta l Section
The reactions were performed under argon and with degassed
solvents, as described previously.5,6 Melting points were deter-
mined with capillaries and are uncorrected. IR spectra were
recorded as Nujol mulls on CaF2 or NaCl disks. 1H, 13C (J
modulated), and 31P NMR spectra were obtained, respectively,
at 80.13, 20.15, and 32.44 MHz. Signals arising from the
dicyclohexylammonium cation, with no significant change from
one salt to another, are given once (for 10a ).
N-(Ben zyloxyca r bon yl)-r-a m in om eth a n esu lfin a te, Di-
cycloh exyla m m on iu m Sa lt (10a ). Illu str a tive P r oced u r e.
To a freshly prepared solution of 87 (6.65 g, 0.5 mmol/g, 13.3
mmol) were added 9a (recrystallized from 2-propanol) (2.53 g,
10 mmol) and Na2CO3 (0.53 g, 5 mmol) with water (20 g) and
dioxane (20 g). After 1 h, the resulting solution was concentrated
to ∼20 g, diluted with water (∼20 g), and extracted with
Ack n ow led gm en t. We thank Mrs. A. Colomer for
recording the IR spectra and Dr. D. Houalla for directing
us to ref 1 soon after its publication.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra for the sulfonates derived from 10b and 10c and
hydrolysis products (o-EtOCONHC6H4CO2H‚DCHA (11),
PhNHCOCO2H‚DCHA (12), and PhCO2H‚DCHA (13) (10
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(20) This choice should be extended by using reagents 9 with proper
leaving groups. These can lead both to rate enhancement and to more
selective aminolysis, avoiding the two side reactions observed: am-
monolysis, as with 9′a , resulting of the decomposition of 8, and
hydrolysis as observed partially with 9d and completely with ethyl
oxanilate16 9e and diphenylphosphinyl chloride18 9f.
J O9516648