Novel deprotection of SEM ethers: A very mild and selective method using magnesium bromide

Article abstract of DOI:10.1021/ol0057784

(Matrix presented) New lability and stability sequences have been established for multifunctional substrates containing SEM ether group(s) by a MgBr₂/Et₂O/ MeNO₂ deprotection protocol.

Full text of DOI:10.1021/ol0057784

ORGANIC
LETTERS
2
000
Vol. 2, No. 10
447-1450
Novel Deprotection of SEM Ethers: A
Very Mild and Selective Method Using
Magnesium Bromide
1
Alexandros Vakalopoulos and H. M. R. Hoffmann*
Department of Organic Chemistry, UniVersity of HannoVer, Schneiderberg 1 B,
D-30167 HannoVer, Germany
hoffmann@mbox.oci.uni-hannoVer.de
Received March 9, 2000
ABSTRACT
New lability and stability sequences have been established for multifunctional substrates containing SEM ether group(s) by a MgBr
2 2
/Et O/
MeNO deprotection protocol.
2
1
Since its introduction by Lipshutz in 1980, the trimethyl-
silylethoxymethyl (Me SiCH CH OCH ) or SEM group has
2
of SEM ethers. Using MgBr instead of the standard
conditions was not promising in donor solvents (Table 1).
3
2
2
2
joined the ranks of silyl protecting groups in organic
2
synthesis. A Beilstein on-line search (February 2000)
suggests there are more than 2000 SEM-protected ethers in
the literature.
Table 1. Monofunctionalized SEM Ether
There have been reports on the difficulty of removing the
2
b
SEM group which has in fact been characterized as “rugged”.
3
Typical deprotection conditions are TBAF in HMPA (or
nontoxic equivalents), and activated fluoride ion (CsF) at
elevated temperature. Other deprotection protocols have
been suggested. However, for the synthesis multifunction-
4
5
6
equiv of
MgBr2
time [h],
temp
solvent mixture
yield [%]
alized substrates, these conditions may be too vigorous and
destructive.7
6
6
Et2O/DME (6 equiv)
4, rt
4, rt
<5
insoluble precipitate
In the context of synthetic efforts in the polyketide field,
we had occasion to investigate the deprotection of a variety
Et2O/TMEDA (6 equiv)
<5
insoluble precipitate
(
(
1) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
2) (a) Greene, T. W.; Wuts, P. G. M.ProtectiVe Groups in Organic
Chemistry, 2nd ed.; Wiley: New York, 1991. (b) Kocienski, P. J. Protecting
Groups, 1st ed.; Thieme: Stuttgart, 1994. (c) Schelhaas, M.; Waldmann,
H. Angew. Chem. 1996, 108, 2192; Angew. Chem., Int. Ed. Engl. 1996, 35,
In the presence of DME and TMEDA, magnesium salts were
precipitated.
A variation of solvent is shown in Table 2. MgBr in
2
anhydrous ether gave not only the fully deprotected aldol 4
but to our surprise also small amounts of hemiacetal 5 (entry
2
056.
3) Kan, T.; Hashimoto, M.; Yanagiya, M. Shirahama, H. Tetrahedron
Lett. 1988, 29, 5417.
(
(4) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 7149.
5) (a) Ireland, R. E.; Norbeck, D. W. J. Am. Chem. Soc. 1985, 107,
(
4
), which survived under the mild experimental conditions.
3
279. (b) Suzuki, K.; Matsumoto, T.; Tomooka, K.; Matsumoto, K.;
Tsuchihashi, G.-I. Chem. Lett. 1987, 113.
Addition of nitromethane gave a clear improvement: The
1
0.1021/ol0057784 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/21/2000

Table 2. Deprotection of Masked Aldol
Table 4. Traditional vs New Deprotection Method
solvent
time [h],
yield of
entry
1
Lewis acid
mixture
temp [°C] 4 + 5 [%]
Pg
conditions
time [h] yield [%]
2 equiv of
MgBr2‚Et2O/2 equiv
of TBAF
THF/DMPU
(1:1)a
2, rt
2, rt
2, rt
0
TBS
TBS
TBS
TIPS
6 equiv of MgBr2/Et2O/MeNO2
10 equiv of MgBr2/Et2O/MeNO2
14 equiv of MgBr2/Et2O/MeNO2
14 equiv of MgBr /Et O/MeNO
2
16
10
5
40
74
87a
96
53
2
3
2 equiv of
DMF/MeOH
(2:1)a
0
5
2
2
MgBr2‚Et2O/2 equiv
of TBAF
insoluble
precipitate
0
TIPS 14 equiv of ZnBr /CH Cl /MeOH
5
2
2
2
a
ZnBr2 (14 equiv) in CH2Cl2/MeOH gives after 10 h the TBS-deprotected
product (72%).
4 equiv of
Et2O/MeOH
(8 equiv)
MgBr2‚Et2O
insoluble
precipitate
28 + 9
2
MeNO as a cosolvent. Presumably, deprotection is facilitated
4
5
5 equiv of
MgBr2‚Et2O
6 equiv of
Et2O
6, rt
6, rt
by interaction of magnesium cation with the additional
benzyloxygen heteroatom. The benzyloxy group also sur-
vived in a sterically hindered oxabicycle (entry 5). Methoxy
acetals are tolerated, which is of interest in carbohydrate
chemistry (entry 6). A free hydroxy group in a 1,3-
functionality distance slows deprotection (entry 7), although
a 1,6-distance is tolerated (entry 2). An excess of ni-
tromethane is not helpful (entry 7b), but changing to ZnBr
as Lewis acid is effective in this case (entry 7c). Furthermore,
double SEM deprotection was accomplished smoothly (entry
8).
Et2O/MeNO2
(12 equiv)
82 + 0
MgBr2‚Et2O
a
Molecular sieves (4 Å) present.
two-phase reaction mixture turned into a homogeneous
solution (entry 5). Encouraged by this finding, a variety of
differentially substituted alcohols were prepared and sub-
jected to the deprotection conditions (Table 3). Entry 4 shows
that it was possible to remove the SEM group even without
2
Table 3. Tolerance to Additional Functionality
1448
Org. Lett., Vol. 2, No. 10, 2000

Conventional desilylating conditions (TBAF, 0 °C) re-
moved the TBS group, leaving SEM intact as expected
Scheme 2. One-Pot Thioketalization-SEM Deprotection
(
Table 4). The new method allows preferential SEM depro-
tection under kinetic control to give the desired alcohol 9.
TIPS survived on deprotection with MgBr , but not with
ZnBr
2
2
.
Under conventional conditions (TBAF, THF) the terminal
O-silyl group in 11 is removed and the SEM group remains
intact (Table 5). Kinetically controlled reaction with MgBr
2
Table 5. Acetonide Tuning
We have applied the deprotecting protocol in the synthesis
of the northern C1-C16 segment 20 of 3-epi-bryostatins
(Scheme 3). The desired C16-OH group was liberated,
Scheme 3. Orthogonal Deprotection in Polyketide Total
Synthesis
equiv of MgBr2
6
time [h]
yield [%]
3
6
1
60
52a
1
1
2
4
81
a
The use of ZnBr2 (12 equiv) in CH2Cl2/MeOH gives after 6 h a complex
product mixture.
8
offers a turnaround of deprotection to afford 13, while the
acetonide survives. A selective double SEM deprotection
without compromising stereochemical integrity (see also
Table 3, entry 8) is illustrated in Scheme 1. Even sensitive
silylated cyanohydrin remained intact to give 15, while
traditional conditions (TBAF, DMPU) led to decomposition.
Treatment of SEM-protected aldols 16 and 18 with MgBr
2
and 1,3-propanedithiol allowed us to combine deprotection
with protection of the sensitive aldehyde group (Scheme 2).
leaving the three remaining O-silylated functions intact to
give masked polyketide 21.
In conclusion, a variety of functionalities are tolerated by
Scheme 1. Double Deprotection of O-Silylated Cyanohydrin
2
the MgBr deprotecting protocol including alcohols, esters,
benzyl groups, dithians, and methoxy acetals (Table 1). In
the presence of sensitive functionality such as acetonides,
TBS and TIPS ethers, and especially O-silylated cyanohy-
(
6) (a) HF/MeCN: White, J. D.; Kawasaki, M. J. Am. Chem. Soc. 1990,
1
1
12, 4991. (b) LiBF4/MeCN (T > 70 °C): Dittrich, K. Liebigs Ann. Chem.
990, 789. (c) BF3‚Et2O, deprotection of the related â-trimethylsilylethyl
ether group: Burke, S. D.; Pacofsky, G. J. Tetrahedron Lett. 1986, 27,
4
45. Jansson, K.; Frejd, T.; Kihlberg, J.; Magnusson, G. Tetrahedron Lett.
1986, 27, 753. (d) TFA: Schlessinger, R. H.; Poss, M. A.; Richardson, S.
J. Am. Chem. Soc. 1986, 108, 3112. (e) I2, hν: Karim, S.; Parmee, E. R.;
Thomas, E. J. Tetrahedron Lett. 1991, 32, 2269.
(7) In the synthesis of bicyclic systems related to taxol, the SEM ether
could not be removed and the [(p-methoxybenzyl)oxy]methyl (PMBM)
group was used instead: Zeng, Q.; Bailey S.; Wang, T.-Z.; Paquette, L. A.
J. Org. Chem. 1998, 63, 137.
Org. Lett., Vol. 2, No. 10, 2000
1449

9
drins, kinetically controlled deprotection is important and
feasible. Since the experimental conditions are very mild and
orthogonal to other deprotection strategies, modified SEM
linkers should also be useful in solid phase reactions and
combinatorial chemistry.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie for
their support and Ulrike Eggert for her help.
(
8) Representive Experimental Procedure. Synthesis of 13. MgBr2
140 mg, 0.76 mmol) was treated with 0.5 mL of anhydrous Et2O. After
dissolution of the solid, the resulting two phases were treated with MeNO2
(
(
(
85 µL, 1.52 mmol, ACROS, p.a., water < 0.5%). The resulting solution
one phase) was added to a stirred mixture of SEM ether 11 (40 mg, 0.054
OL0057784
mmol) in 0.5 mL of Et2O. The mixture was stirred for 1 h at room
temperature and then diluted with MTB ether and washed with water (20
mL). The aqueous layer was extracted with MTB ether (2 × 10 mL), the
combined organic layers were washed with brine (20 mL) and dried (Na2-
SO4), and the solvent was removed. The crude product was purified by
column chromatography (SiO2; MTB/PE, 1:10 f 1:3) to afford 13 (26 mg,
(CH3)2), 71.40 (3°, CHOH), 67.42 (3°, CH2CHOC(CH3)2)CH2), 65.72 (3°,
CHOC(CH3)2)CH2CH2OTPS), 59.62 (2°, CH2OTPS), 59.21 (3°, SCHS),
42.35 (4°, C(CH3)2), 39.26 (2°, CH2CH2OTPS), 36.66 (2°, CH(OH)CH2),
36.49 (2°, CHCH2CH), 31.50/31.39 (2°, SCH2CH2CH2S), 30.22 (1°, OC-
(CH3)2O), 26.57 (1°, SiPh2C(CH3)3), 26.38 (2°, SCH2CH2CH2S), 21.05 (1°,
OC(CH3)2O), 19.95/19.68 (1°, C(CH3)2), 19.18 (4°, SiPh2C(CH3)3); MS
8
1
1%), colorless oil: IR (CHCl3) ν 3672, 3482, 3072, 2996, 2932, 2900,
472, 1428, 1380, 1164, 1112, 956, 820 cm-1; 1H NMR (200 MHz, CDCl3)
+
+
δ 7.75-7.62 (m, 4 H, o-Ar-H), 7.44-7.31 (m, 6 H, Ar-H), 4.28 (s, 1 H,
SCHS), 4.24-3.99 (m, 3 H, CHOH, CH2CHO(C(CH3)2)CH2, CHOC-
m/z 603 (M + 1, 1.0), 602 (2.0, M ), 588 (2.7), 526 (2.4), 487 (12.4),
469 (3.5), 437 (2.6), 379 (1.4), 350 (4.9), 326 (7.0), 256 (21.4), 225 (12.0),
199 (30.7), 183 (10.2), 161 (10.8), 134 (11.3), 119 (100), 107 (8.7), 91
(
CH3)2)CH2CH2OTPS), 3.91-3.76 (m, 1 H, CH2OTPS), 3.75-3.61 (m, 1
+
H, CH2OTPS), 3.05-2.91 (bs, 1 H, OH), 2.90-2.82 (m, 4 H, SCH2-
CH2CH2S), 2.17-2.02 (m, 1 H, SCH2CH2CH2S), 1.95-1.51 (m, 7 H,
SCH2CH2CH2S, CH(OH)CH2, CHCH2CH, CH2CH2OTPS), 1.43/1.37 (s,
(13.0), 81 (5.9), 75 (5.0); HRMS calcd for C27H45O4S2Si1 (M - C6H5)
525.2317, found 525.2308.
(9) â-Silylethyl group as an anomeric linker in saccharide chemistry:
Weigelt, D.; Magnusson, G. Tetrahedron Lett. 1998, 39, 2839. For a general
review on linkers in solid phase organic synthesis, see: James, I. W.
Tetrahedron 1999, 55, 4855.
3
H, OC(CH3)2O), 1.05 (s, 9 H, SiPh2C(CH3)3), 1.08/1.02 (s, 6 H, C(CH3)2);
C NMR (50 MHz, CDCl3) δ 135.52/134.80 (3°, o-Ar-C), 135.36/133.90
4°, Ar-C), 129.54 (3°, p-Ar-C), 127.64 (3°, m-Ar-C), 98.73 (4°, CO2-
1
3
(
1450
Org. Lett., Vol. 2, No. 10, 2000