The 2-Methylsulfonyl-3-phenyl-1-prop-2-enyloxycarbonyl (Mspoc)Amino-Protecting Group

Full text of DOI:10.1021/jo990541a

J . Org. Chem. 1999, 64, 8399-8401
8399
Sch em e 1
Th e 2-Meth ylsu lfon yl-3-p h en yl-1-p r op -2-
en yloxyca r bon yl (Msp oc)Am in o-P r otectin g
Gr ou p
Louis A. Carpino* and E. M. E. Mansour†
Department of Chemistry, University of Massachusetts,
Amherst, Massachusetts 01003-4510
Received March 29, 1999
Recently a new N-R-amino protecting group, the 1,1-
dioxobenzo[b]thiophene-2-ylmethyloxycarbonyl (Bsmoc)
residue 1, useful for peptide synthesis, was described.1
ments of methanesulfonyl chloride to â-methylstyrene
followed by elimination of hydrogen chloride and subse-
quent free radical bromination of the methyl group
(Scheme 1). This synthetic route, in contrast to that used
for the related Bsmoc system, does not involve a low-
valent, and therefore possibly unpleasant, sulfur inter-
mediate at any stage. Another difference appears to be
the greater ease with which the Mspoc acid fluorides are
obtainable in crystalline form, as contrasted to undefined
foams or amorphous materials. The stereochemistry of
5 and 6 was assigned on the basis of related reactions8
and the expected two-step process of trans addition
followed by trans elimination. For introduction of the
Mspoc residue, alcohol 8 was converted to the chlorofor-
mate and N-hydroxysuccinimide carbonate.
The Bsmoc and Mspoc groups, being â-substituted, are
similar in their lesser sensitivity toward premature
deblocking relative to the related 2-(tert-butylsulfonyl)-
2-propenoxycarbonyl (Bspoc) residue but differ from each
other regarding the byproducts formed upon piperidine-
induced deblocking. In the case of Bsmoc, the initial
Michael-like adduct quickly isomerized completely to the
final stable adduct, whereas in the case of Mspoc, an
equilibrium mixture of the two adducts resulted (eq 1, n
) 5). According to 1H NMR analysis the initial adduct 9
The key deblocking step in the case of amines protected
by the Bsmoc group involves the addition of a nucleophilic
reagent to the R,â-unsaturated sulfone system of 1 with
the consequent ejection of the carbamate anion. Among
the major advantages of such a process over systems for
which the deblocking step involves a classic â-elimination
process (e.g., the 2-(methylsulfonyl)ethoxycarbonyl, Msc,2
or 9-fluorenylmethyloxycarbonyl, Fmoc,3 systems) are
that (a) lower concentrations of piperidine or weaker
bases (e.g., morpholine) can be used for deblocking, thus
minimizing base-catalyzed side reactions, and (b) ap-
plication to the technique of rapid continuous solution
synthesis4 is greatly improved. Examples of peptide
assembly via both solid phase and rapid solution tech-
niques using these protecting groups have also been
presented.4
The Bsmoc residue was conceived in response to the
demonstration that the initially investigated protecting
group in this category, the 2-tert-butylsulfonyl-2-prope-
noxycarbonyl (Bspoc) residue 2, in certain cases suffered
premature deblocking by the amino group liberated
during the deblocking process.5 By affixing a substituent
at the â-position of 2, as in the Bsmoc residue 1, reactivity
at this position is moderated and such side reactions are
not observed. A second â-substituted system of this type,
the Mspoc residue 3, is described in this note.
Alcohol 8, key precursor of the 2-methylsulfonyl-3-
phenyl-1-prop-2-enyloxycarbonyl (Mspoc) residue, was
obtained from the corresponding allylic bromide 76 by
formate-catalyzed hydrolysis.7 The bromide was synthe-
sized according to the method of Doomes and Overton,6
which involves Cu(OAc)2-catalyzed addition of the ele-
predominated over 10 at the beginning (about 3/1), but
after 30 min the ratio changed to 1/1.6 and did not change
thereafter. Upon substitution of pyrrolidine for piperi-
dine, deblocking was both more rapid and more specific,
in that under conditions where the latter required 30 min
for complete deblocking the former was complete after
only 8 min. The initial adduct 9 (n ) 4) was only
fleetingly visible, and complete conversion to 10 (n ) 4)
occurred quickly. Thus for practical purposes, particularly
if quantitative UV tracking is desirable, it would be
preferable to adopt pyrrolidine for Mspoc deblocking.
As in the case of the Bsmoc residue, the Mspoc group
was shown to be sensitive to base-catalyzed mercaptan
† On leave of absence from the Department of Chemistry, Faculty
of Science, Alexandria University, Alexandria, Egypt.
(1) Carpino, L. A.; Philbin, M.; Ismail, M.; Truran, G. A.; Mansour,
E. M. E.; Iguchi, S.; Ionescu, D.; El-Faham, A.; Riemer, C.; Warrass,
R.; Weiss, M. S. J . Am. Chem. Soc. 1997, 119, 9915.
(2) Tesser, G. I.; Balvert-Geers, I. C. Int. J . Pept. Protein Res. 1975,
7, 295.
(3) Carpino, L. A. Acc. Chem. Res. 1987, 20, 401.
(4) Carpino, L. A.; Ismail, M.; Truran, G. A.; Mansour, E. M. E.;
Iguchi, S.; Ionescu, D.; El-Faham, A.; Riemer, C.; Warrass, R. J . Org.
Chem. 1999, 64, 4324.
(5) Carpino, L. A.; Philbin, M. J . Org. Chem. 1999, 64, 4315.
(6) Doomes, E.; Overton, B. M. J . Org. Chem. 1987, 52, 1544.
(7) Harris, M.; Bull, M. J . Synth. Commun. 1985, 15, 1225.
(8) (a) Kamigata, N.; Karushima, T.; Sawada, H.; Kobayashi, M.
Bull. Chem. Soc. J pn. 1984, 57, 1421. (b) Auvray, P.; Knochel, P.;
Normant, J . F. Tetrahedron 1988, 44, 6095.
10.1021/jo990541a CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/08/1999

8400 J . Org. Chem., Vol. 64, No. 22, 1999
Ta ble 1. Mod el Msp oc-Am in o Acid s a n d Acid F lu or id esa
Notes
a
Using the isolated acid fluorides described in this table, the pentapeptide leucine enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) was
assembled in good yield according to the method described for Bsmoc chemistry1,4 except that in these first runs deblocking was carried
out via 20% piperidine/DMF. Solvent was DMSO-d6 for acids and CDCl3 for acid fluorides. c IR (KBr) 1836 cm-1 (COF). The acid
fluorides were used as obtained and identified on the basis of their 1H NMR and IR spectra. e IR (KBr) 1833 cm-1 (COF). f IR (KBr) 1839
cm-1 (COF).
b
d
crystals: mp 74-76 °C; IR (KBr) 3543 (OH), 1628 (CdC), 1285,
1140 cm-1 (SO2); 1H NMR (CDCl3) δ 3.05 (t, 1), 3.15 (s, 3), 4.70
(d, 2), 7.50 (m, 5), 7.85 (s, 1). Anal. Calcd for C10H12O3S: C, 56.59;
H, 5.70. Found: C, 56.36; H, 5.82.
deblocking. For example, 3-mercapto-1,2-propanediol
caused rapid deblocking of the Mspoc derivative of
p-chloroaniline (Mspoc-PCA) in the presence of 10 mol
% of DIEA in CDCl3 (1H NMR test) to give an equimolar
mixture of p-chloroaniline and adduct 11. No thio adduct
analogous to 9 was observed.
(E)-2-(Meth ylsu lfon yl)-3-p h en yl-2-p r op en yl Ch lor ofor -
m a te. To a stirred solution of (E)-2-(methylsulfonyl)-3-phenyl-
2-propenyl alcohol 8 (8.5 g, 0.04 mol) in 50 mL of THF at 0 °C
was added in one portion 37.5 mL of phosgene. The reaction
mixture was stirred overnight at room temperature, and excess
phosgene and solvent were removed under reduced pressure
with the aid of a water aspirator. The crude material was
recrystallized from dichloromethane (DCM)-hexane to give 9.5
g (86.4%) of the chloroformate as colorless crystals: mp 118-
120 °C; IR (KBr) 1775 (CdO), 1632 (CdC), 1293, 1155 cm-1
(SO2); 1H NMR (CDCl3) δ 3.14 (s, 3), 5.35 (s, 2), 7.40 and 7.50
(m, 5), 8.10 (s, 1). Anal. Calcd for C11H11ClO4S: C, 48.09; H,
4.04; Cl, 12.91. Found: C, 47.98; H, 4.03; Cl, 13.10.
N-[(E)-2-(Meth ylsu lfon yl)-3-p h en yl-2-p r op en yloxyca r bo-
n yloxy]su ccin im id e. To a stirred solution of Mspoc-Cl (13.74
g, 50 mmol) in 150 mL of DCM was added 14.8 g of the
dicyclohexylamine salt of N-hydroxysuccinimide (50 mmol)
portionwise.9 The reaction mixture was stirred overnight and
filtered, and the precipitate was washed with DCM. The filtrate
was washed with 10% citric acid (100 mL), 10% NaHCO3 (100
mL), and water (100 mL). The organic layer was dried (MgSO4),
and the solvent was removed in vacuo to give the crude
succinimide ester, which was recrystallized from DCM-hexane
to give 13.24 g (75%) of the pure ester as white crystals: mp
152-154 °C (dec); IR (KBr) 1805, 1743 (CdO), 1295, 1141 cm-1
(SO2); 1H NMR (CDCl3 plus a few drops of DMSO-d6) δ 2.95 (s,
4), 3.20 (s, 3), 5.40 (s, 2), 7.55 (m, 5), 8.15 (s, 1). Anal. Calcd for
C15H15NO7S: C, 50.99; H, 4.28; N, 3.96. Found: C, 50.83; H,
4.30; N, 3.75.
In summary, this note describes a new amino pro-
tectant subject to deblocking via nucleophilic addition to
a Michael acceptor. Relative to the previously reported
Bspoc and Bsmoc residues, the Mspoc group is less
sensitive to premature deblocking than the former and
can be assembled from readily available materials with-
out recourse to low-valent sulfur intermediates.
Exp er im en ta l Section
(E)-3-(Meth ylsu lfon yl)-3-p h en yl-2-p r op en yl Alcoh ol (8).
(E)-3-Bromo-2-(methylsulfonyl)-1-phenyl-1-propene6 (25.6 g, 0.93
mol) and 15.82 g of sodium formate (0.23 mol) in 300 mL of
methanol were refluxed for 6 h. When the starting material had
disappeared (TLC) the mixture was allowed to cool and concen-
trated with the aid of a water aspirator. The residue was diluted
with water and extracted several times with 100-mL portions
of DCM. The organic layer was dried over MgSO4, the solvent
removed in vacuo, and the crude alcohol was recrystallized from
CHCl3-hexane to give 15.8 g (80.2%) of the pure alcohol as white
(9) Compare: Paquet, A. Can. J . Chem. 1982, 60, 976.

Notes
N-p -Ch lor op h en yl (E)-2-(Met h ylsu lfon yl)-3-p h en yl-2-
J . Org. Chem., Vol. 64, No. 22, 1999 8401
Ta ble 2. Cou r se of th e P ip er id in e-In d u ced Deblock in g
of Msp oc-P CA
p r op en yl Ca r ba m a te (Msp oc-P CA). To a stirred solution of
p-chloroaniline (1.16 g, 9.1 mmol) and DIEA (1.17 g, 9.1 mmol)
in 25 mL of DCM was added 2.5 g (9.1 mmol) of Mspoc-Cl
portionwise. After stirring at room temperature for 1.5 h, the
mixture was washed three times each with 10% HCl, 10%
NaHCO3, and water. After drying over MgSO4 the solvent was
removed in vacuo, and the residue was recrystallized from
MeOH to give 3.0 g (90%) of the urethane as white crystals: mp
178-180 °C; IR (KBr) 3322 (NH), 1696 (CdO), 1615 (CdC),
1291, 1141 cm-1 (SO2); 1H NMR (CDCl3 plus a few drops of
DMSO-d6) δ 3.20 (s, 3), 5.25 (s, 2), 7.25-7.65 (m, 9), 8.05 (s, 1),
9.25 (s, 1). Anal. Calcd for C17H16ClNO4S: C, 55.81; H, 4.41; N,
3.83. Found: C, 55.76; H, 4.46; N, 3.68.
Gen er a l P r oced u r e for th e P r ep a r a tion of Msp oc-Am in o
Acid s fr om Msp oc-OSu .9,10 To a stirred solution of an amino
acid (10 mmol) and NaHCO3 (25 mmol) in water (40 mL) was
added a solution of Mspoc-OSu (10 mmol) in acetone (50 mL).
After stirring for 3-5 h or overnight (TLC) the reaction mixture
was extracted with DCM to remove unreacted Mspoc-OSu. The
acetone was removed by means of a water aspirator. After
cooling, the reaction mixture was acidified with 10% HCl to
Congo red to give a white solid, which was filtered and washed
with water several times to give the crude Mspoc-AA-OH.
Recrystallization from a suitable solvent gave the pure acid. For
individual cases see Table 1.
time
(min)
Mspoc-PCA
(%)
PCA
(%)
6 (n ) 5)
7 (n ) 5)
(%)
(%)
0
8
15
25
30
100
23.8
9.1
3.4
0
0
0
0
76.2
90.9
96.6
100
57.2
57.9
41.4
38.5
19.0
33.0
55.2
61.5
Ta ble 3. Cou r se of th e P yr r olid in e-In d u ced Deblock in g
of Msp oc-P CA
time
(min)
Mspoc-PCA
(%)
PCA
(%)
6 (n ) 4)
7 (n ) 4)
(%)
(%)
0
8
15
20
30
100
0
0
0
0
0
100
100
100
100
0
0
66.7
81.8
100
100
33.3
18.2
0
0
Deblock in g of th e Msp oc Der iva tive of p-Ch lor oa n ilin e
(Msp oc-P CA) via P ip er id in e a n d P yr r olid in e. A solution of
0.0366 g (0.1 mmol) of Mspoc-PCA dissolved in 0.6 mL of CDCl3
containing a few drops of DMSO-d6 was prepared in an NMR
tube. The spectrum was taken before and after the addition of
0.017 g (0.2 mmol) of piperidine. The course of the reaction up
to a period of 30 min is shown in Table 2. A comparable run
using 0.2 mmol of pyrrolidine in place of piperidine gave the
results shown in Table 3.
Gen er a l P r oced u r e for th e P r ep a r a tion of Msp oc-Am in o
Acid F lu or id es.11 To a stirred solution of the Mspoc-amino acid
(2 mmol) in 5 mL of dry DCM and pyridine (2 mmol, 162 µL)
kept under a N2 atmosphere was added cyanuric fluoride (10
mmol, 900 µL) at room temperature. After 10-20 min
a
Finally, a similar run with 2 equiv of 3-mercapto-1,2-pro-
panediol and 10 mol % of DIEA substituted for the secondary
amine showed that after 20 min complete deblocking had
occurred and the only adduct visible in the NMR spectrum was
8. A similar run with threo-1,4-dimercapto-2,3-butanediol and
DIEA in DMSO-d6 showed complete deblocking after about 10
min. 2-Mercaptobenzothiazole/DIEA was relatively ineffective
as a deblocking agent, giving only partial deblocking after
several hours.
precipitate began to separate. After the reaction mixture was
stirred for 1 h, crushed ice was added along with 15 mL of
additional DCM. The organic layer was separated, and the
aqueous layer was extracted with 5 mL of DCM. The combined
organic layers were extracted with 10 mL of ice-cold water and
dried over MgSO4, and the solvent was evaporated in vacuo at
room temperature. The residue was recrystallized from a suit-
able solvent. For individual cases see Table 1. The two acid
fluoridesobtainedfrom Mspoc-phenylalanineandMspoc-O-tert-butyl-
tyrosine were obtained as crystalline solids and were therefore
easy to dry for long-term storage. In contrast, the corresponding
Bsmoc-derivatives of these two amino acid fluorides were often
obtained as foamy, amorphous materials that were difficult to
dry carefully.
Ack n ow led gm en t. We are indebted to the National
Science Foundation (NSF CHE-9003192), the National
Institutes of Health (GM-09706), and Research Corpo-
ration Technologies for support of this work. The
National Science Foundation is also thanked for grants
used to purchase the high-field NMR spectrometers
used in this research.
(10) The Bolin method could also be used. See: Bolin, D. R.; Syturu,
I.; Humeic, F.; Meienhofer, J . Int. J . Pept. Protein Res. 1983, 33, 353.
(11) Compare: (a) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H.-G.;
DeSelms, R. H. J . Am. Chem. Soc. 1990, 112, 9651. (b) Carpino, L. A.;
Mansour, E. M. E.; Sadat-Aalaee, D. J . Org. Chem. 1991, 56, 2611.
J O990541A