On the Selective Deprotection of Trityl Ethers

Full text of DOI:10.1021/jo9913255

J . Org. Chem. 2000, 65, 263-265
263
Sch em e 1. BCl1 Med ia ted Detr ityla tion
On th e Selective Dep r otection of Tr ityl
Eth er s
Graham B. J ones,* George Hynd, J ustin M. Wright, and
Anu Sharma
Bioorganic and Medicinal Chemistry Laboratories,
Department of Chemistry, Northeastern University,
Boston, Massachusetts 02115
Received August 19, 1999
In tr od u ction
methanolysis or B(OH)3 (6.8 ppm) on hydrolysis.10 Sub-
sequent optimization revealed that on a practical scale
deprotection is best conducted using dropwise addition
of 0.6 equiv of BCl3 at -30 °C with a concentration of
0.1 M. Encouraged by this finding, a variety of differen-
tially substituted alcohols were prepared and subjected
to the deprotection conditions (Table 1). Selective depro-
tection of primary trityl ethers is achieved in the presence
of either primary, secondary, or phenolic tert-butyldi-
methylsilyloxy (TBDMS) groups, the bulkier tert-butyl-
diphenylsilyloxy (TBDPS) group, the triethylsilyl (TES)
group, and the commonly used benzyloxy group (entries
1-5).11 In every case examined complete deprotection was
observed within 15 min, isolated yields are typically high
(even in the presence of delicate functionality), and
stereochemical integrity is maintained (entries 4 and 5).
Double deprotections are also rapid (entry 6), yet a
consistent and clear preference for detritylation is ob-
served even in the presence of primary TBDMS and
p-methoxybenzyl (PMB) ethers, making this a desirable
orthogonal set (entries 7-10). Numerous applications in
synthesis can be envisioned, and key substrates may
include saccharides and steroids, where stereochemical
integrity cannot be compromised (entries 11 and 12). The
ability of preformed dichloroalkoxyboranes to undergo
unmasking is noteworthy (entries 13 and 14) and sug-
gests that regioselectivity might even be exercised in the
selective deprotection of polyols using this strategy.
Unmasking of the trityl group in the presence of ap-
propriate electrophilic functionality may also allow for
the design of in situ cyclizations, as demonstrated by the
formation of the lactol (entry 15) on treatment with BCl3
followed by methanolysis.
The triphenylmethyl (trityl) protecting group has
enjoyed widespread use in contemporary organic synthe-
sis since its original applications in classic carbohydrate
chemistry.1 Its lipophilic nature renders it particularly
attractive for the protection of polar water soluble alco-
hols, including monosaccharides. A variety of methods
have been employed for its introduction, including trityl
triflate,2 tritylpyridinium fluoroborate,3 and the com-
mercially available trityl halides.4 Though the advent of
silicon based protecting groups has somewhat margin-
alized their use, syntheses involving combinations of
trityloxy, silyloxy, and other ethers offer the opportunity
for highly selective deprotective strategies. The identi-
fication of a mild yet expeditious method for removal of
the trityloxy protecting group thus formed the basis of
our investigation.
Resu lts a n d Discu ssion
Prompted by a need to selectively unmask the trityloxy
ethers of differentially protected diols,5 1,6-hexanediol
derivative 1 was prepared as a model substrate. Con-
ventional protocols using formic acid in ether6 and diethyl
aluminum chloride in methylene chloride7 were investi-
gated. Unsatisfactory results were obtained in both cases,
resulting in recovery of diol and a mixture of monodepro-
tected alcohols. On moving to a boron-based reagent,
however, addition of 1.0 equiv of boron trichloride yielded
smooth trityloxy deprotection within 10 min at -30 °C
(Scheme 1).8,9 Hydrolytic workup resulted in recovery of
near quantitative yields of trityl alcohol and the desired
alcohol 3. 11B NMR analysis confirmed the intermediacy
of alkoxyborane 2, with the replacement of the BCl3
signal (46.4 ppm) with a peak at 30.7 ppm (ROBCl2),
which is in turn converted to B(OCH3)3 (18.4 ppm) on
Analogous deprotections conducted with boron tribro-
mide resulted in rapid unmasking with marked loss in
selectivity, whereas boron trifluoride etherate was less
effective, resulting in recovery of substantial amounts of
starting material under standard conditions.12 Com-
mercially available solutions of BCl3 in methylene chlo-
ride, hexanes, heptanes, and xylene were equally effective
at inducing the deprotections. The ready availability of
these reagents, coupled with the high yields, speed, and
selective nature of deprotection, renders this strategy
* Corresponding author. Tel: 617/373-8619. Fax: 617/373-8795.
E-mail: grjones@lynx.neu.edu.
(1) Kocienski, P. J . Protecting Groups; Thieme-Verlag: Stuttgart,
1994.
(2) Hirama, M.; Noda, T.; Yasuda, S.; Ito, S. J . Am. Chem. Soc. 1991,
113, 1830.
(3) Seebach, D.; Chow, H.-F.; J ackson, R. F. W.; Sutter, M. A.;
Thaisrivongs, S.; Zimmerman, J . Liebigs Ann. Chem. 1986, 1281.
(4) Chaudhary, S. C.; Hernandez, O. Tetrahedron Lett. 1979, 20, 95.
(5) J ones, G. B.; Guzel, M.; Chapman, B. J . Tetrahedron: Asymmetry
1998, 9, 901.
(6) Bessodes, M.; Komiotis, D.; Antonakis, K. Tetrahedron Lett. 1986,
27, 579.
(7) Koster, H.; Sinha, N. D. Tetrahedron Lett. 1982, 23, 2641.
(8) J ones, G. B.; Chapman, B. J .; Huber, R. S.; Beaty, R. Tetrahe-
dron: Asymmetry 1994, 5, 1199.
(9) For related deprotections of trityl ethers using boron reagents,
see: Teranishi, K.; Goto, T. Bull. Chem. Soc. J pn. 1990, 63, 3132. Sum,
P. E.; Weiler, L. Can. J . Chem. 1978, 56, 2700.
(10) All values relative to BF3‚OEt2 (0.0 ppm). Webb, G. A. Ann.
Rep. NMR Spec. 1988, 20, 61.
(11) Congreve, M. S.; Davison, E. C.; Fuhry, M. A.; Holmes, A. B.;
Payne, A. N.; Robinson, R. A.; Ward, S. E. Synlett. 1993, 663; Williams,
D. R.; Brown, D. L.; Benbow, J . W. J . Am. Chem. Soc. 1989, 111, 1923.
(12) On the other hand, BF3‚OEt2/CH3OH was reported to induce
deprotection of the trityl ether derivative of
a glucopyranoside:
Rembold, H.; Schmidt, R. R. Carbohydrate Res. 1993, 246, 137.
10.1021/jo9913255 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/11/1999

264 J . Org. Chem., Vol. 65, No. 1, 2000
Notes
Ta ble 1. Selective Dep r otection sa
a
b
BCl3 (0.6 equiv)/-30 °C/0.1 M CH2Cl2/15 min. 0.9 equiv BCl3 used. c BCl3 (1.0 equiv) then CH3OH (1.0 equiv).
butyn-1-ol (500 mg, 2.71 mmol), and triethylamine (0.75 mL,
5.42 mmol) were dissolved in dry DMF (8 mL). The mixture was
stirred at 40 °C for 12 h. The solution was poured onto HCl (1%,
10 mL) and the resulting mixture extracted with ethyl acetate
(4 × 10 mL). The combined organic extracts were washed with
water (2 × 10 mL), NaHCO3 solution (saturated, 1 × 10 mL),
and brine (1 × 10 mL) and then concentrated in vacuo. The
residual oil was purified by SGC (9:1 hexane:diethyl ether),
affording 4-(1,1,1-triethylsilyl)-3-butynyl trityl ether as a white
advantageous for work involving diol and polyol manipu-
lation, particularly where a UV chromophore is desirable
in the molecule.
Exp er im en ta l Meth od s13
Melting points are uncorrected. NMR spectra were recorded
in CDCl3 with tetramethylsilane as the internal standard for
1H (300 MHz) or solvent as the internal standard for 13C (75
MHz). Reactions were performed in glassware which had been
oven dried (140 °C/12 h) and then flame-dried prior to use, under
an atmosphere of nitrogen. Methylene chloride was distilled from
P2O5. All reagents and solvents were commercial grade (Aldrich)
and purified according to established convention. Chromatog-
raphy (SGC) was performed on E. Merck 60H silica gel. Analyti-
cal TLC was performed on glass-backed 0.25 mm plates, with
anisaldehyde and phosphomolybdic acid for visualization. Sub-
strates were prepared from commercially available diols using
standard methods.5,14-16 Product identity was confirmed with
authentic (entry 1,15 2,17 8,18 1519) or commercial (entry 3, 6, 13)
material.
1
cyrstalline solid (1.02 g, 88%): mp 66 °C; H NMR 7.50 (d, 3H
J ) 7.2 Hz), 7.34-7.22 (m, 12H), 3.21 (t, 2H, J ) 6.8 Hz), 2.55
(t, 2H, J ) 6.8 Hz), 1.01 (t, 9H, J ) 8.1 Hz), 0.66-0.58 (m, 6H);
13C NMR 143.9, 128.6, 127.6, 126.8, 105.5, 86.4, 82.7, 61.7, 21.5,
7.6, 4.6. Anal. Calcd for C29H34OSi: C, 81.64; H, 8.03. Found:
C, 81.23; H, 8.02.
Gen er a l Dep r otection P r oced u r e. 3-P iva loylestr a d iol.
To a solution of 3-pivaloyl-17-trityloxyestradiol (82 mg, 0.137
mmol) in CH2Cl2 (5.0 mL) at -30 °C was added BCl3 (68 µL,
0.068 mmol, 1.0 M in CH2Cl2,) dropwise via syringe. After 30
min at -30 °C, the reaction was quenched by the addition of
anhydrous MeOH. The solution was poured onto a NaHCO3
solution (saturated, 5 mL), stirred for 5 min, and then extracted
with CH2Cl2 (5 × 5 mL). The organic phase was washed with
brine (2 × 5 mL), dried (MgSO4), and concentrated in vacuo.
The residual oil was purified by SGC (1:1, hexane:diethyl ether),
affording 3-pivaloylestradiol as white crystals (44 mg, 91%): mp
181-183 °C; 1H NMR 7.28 (d, 1H, J ) 8.7 Hz), 7.01 (dd, 1H,
J ) 2.4 Hz, 8.7 Hz), 6.77 (s, 1H), 3.71 (t, 1H, J ) 8.3 Hz), 2.85
(t, 2H, J ) 4.1 Hz), 2.35-1.17 (m, 23H), 0.77 (s, 3H); 13C NMR
177.1, 148.6, 137.9, 137.5, 126.1, 121.2, 118.3, 81.7, 50.0, 44.1,
43.2, 39.0, 38.5, 36.7, 30.5, 29.5 27.2, 27.0, 26.1, 23.1, 11.1; [R]D
) 42.3 (c ) 0.5, CHCl3). Anal. Calcd for C23H32O3: C, 77.49; H;
9.05. Found: C, 77.10; H; 9.01.
Gen er a l P r otection P r oced u r e. 4-(1,1,1-Tr ieth ylsilyl)-3-
bu tyn yl Tr ityl Eth er . Triphenylmethyl chloride (0.831 g, 2.98
mmol), DMAP (33 mg, 0.271 mmol), 4-(1,1,1-triethylsilyl)-3-
(13) J ones, G. B.; Wright, J . M.; Rush, T. M.; Plourde, G. W.; Kelton,
T. F.; Mathews, J . E.; Huber, R. S.; Davidson, J . P. J . Org. Chem. 1997,
62, 9379.
(14) J ones, G. B.; Huber, R. S.; Chapman, B. J . Tetrahedron:
Asymmetry 1997, 8, 1797.
(15) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1994, 35,
7565.
(16) Komiotis, D.; Currie, B. L.; LeBreton, G. C.; Venton, D. L. Synth.
Commun. 1993, 23, 531.
(17) Borjesson, L.; Csoregh, I.; Welch, C. J . J . Org. Chem. 1995, 60,
2989.
(18) deVries, E. F. J .; Brussee, J .; van der Gen, A. J . Org. Chem.
1994, 59, 7133.
The following were similarly produced.
2-(2-[1-(ter t-Bu tyl)-1,1-d im eth ylsilyl]oxyp h en oyl)-1-eth -
a n ol: colorless oil;15 1H NMR 7.16 (td, 1H, J ) 2.0, 7.5 Hz),
7.03 (dd, 1H, J ) 2.0, 8.0 Hz) 6.93 (dd, 1H, J ) 1.0, 8.0 Hz) 6.83
(td, 1H, J ) 1.5, 7.0 Hz) 3.94 (t, 2H, J ) 5.0 Hz), 2.90 (t, 2H,
(19) Woods, G. F., J r. Org. Synth. 1955, 3, 470.

Notes
J . Org. Chem., Vol. 65, No. 1, 2000 265
J ) 5.5 Hz), 0.93 (s, 9H), 0.10 (s, 6H); 13C NMR 155.8, 130.7,
128.2, 126.9, 120.0, 116.9, 65.8, 35.7, 25.8, 18.3, -5.7. Anal. Calcd
for C14H24O2Si: Found: C, 66.25; H; 9.32. Required: C, 66.61;
H; 9.58.
(4S)-4-{[1-(ter t-Bu tyl)-1,1-d ip h en ylsilyl]oxy}p en ta n -1-ol:
colorless oil; 1H NMR 7.7 (m, 6H), 7.4 (m, 9H), 3.91 (m, 1H),
3.57 (m, 2H), 1.51 (m, 4H), 1.1 (m, 12H); 13C NMR 135.9, 135.8,
134.6, 134.3, 129.6, 129.5, 127.5, 127.4, 69.3, 63.0, 35.5, 28.2,
27.0, 22.9, 19.2; IR (neat) 3368; [R]D ) -50.1 (c ) 0.051, MeOH).
Anal. Calcd for C21H30O2Si: C, 73.65; H; 8.83. Found: C, 73.79;
H; 8.64.
(9R)-9-{[1-(ter t-Bu tyl)-1,1-d im eth ylsilyl]oxy}d eca n -1-ol:
colorless oil; 1H NMR 3.75 (m, 1H), 3.62 (t, 2H, J ) 6.6 Hz),
1.6-1.2 (m, 14H), 1.10 (d, 3H, J ) 6 Hz), 0.88 (s, 9H), 0.03 (s,
6H); 13C NMR 68.7, 63.0, 39.7, 32.8, 29.6, 29.6, 29.4, 26.0, 25.8,
25.7, 23.8, 18.2, -4.4; IR (neat) 3339 (br) cm-1; MS (m/e) 287
(M+); [R]D ) +1.26 (c ) 0.5, CHCl3). Anal. Calcd for C16H36O2Si:
C, 66.60; H; 12.58. Found: C, 66.88; H; 12.46.
1,6-Bis{[1-(ter t-bu tyl)-1,1-d im eth ylsilyl]oxy}-2-h exa n ol:
colorless oil; 1H NMR 3.66-3.56 (m, 4H), 3.38 (dd, 1H, J ) 8.1
Hz, 10.5 Hz), 2.45 (d, 1H, J ) 2.4 Hz), 1.58-1.32 (m, 6H), 0.89
(s, 9H) 0.88 (s, 9H), 0.06 (s, 6H), 0.04 (s, 6H); 13C NMR 72.0,
67.4, 63.3, 33.1, 32.8, 26.2, 26.1, 22.2, 18.6, 18.6, -4.95, -5.02,
-5.08. Anal. Calcd for C18H42O3Si2. Found: C, 59.63; H; 11.95.
Required: C, 59.61; H; 11.67.
(2S,3S,4R,5S)-6-Met h oxy-3,4,5-t r is[(1,1,1-t r iet h ylsilyl)-
oxy]tetr a h yd r o-2H-2-p yr a n yl}m eth a n ol: colorless oil; 1H
NMR 4.61 (d, 1H, J ) 3.9 Hz), 3.82-3.40 (m, 6H), 3.31 (s, 3H),
0.99-0.92 (m, 27H), 0.74-0.59 (m, 18H); 13C NMR 100.0, 75.1,
74.3, 72.5, 72.0, 62.1, 54.7, 7.3, 7.1, 6.9, 5.6, 5.4, 5.2; [R]D ) 49.4
(c ) 0.8, CHCl3). Anal. Calcd for C25H56O6Si3: C, 55.92; H; 10.51.
Found: C, 56.14; H; 10.34.
5-(Tr ityloxy)p en ta n a l. Pyridinium chlorochromate (6.50 g,
30.16 mmol) was added slowly to a solution of 5-(trityloxy)-1-
pentanol16 (9.53 g, 27.42 mmol) and sodium acetate (2.24 g, 27.42
mmol) in CH2Cl2 (50 mL). The mixture was stirred at 30 °C for
12 h. The mixture was diluted with diethyl ether (150 mL),
filtered through a plug of silica gel, and then concentrated in
vacuo. SGC of the residue (19:1 hexane:ethyl acetate) gave
5-(trityloxy)pentanal (98%, 9.25 g) as a colorless oil; 1H NMR
9.74 (s, 1H), 7.22-7.44 (m, 15H), 3.08 (t, 2H, J ) 6.00 Hz), 2.40
(t, 2H), 1.67-1.74 (m, 4H); 13C NMR 202.6, 144.3, 128.6, 127.7,
126.9, 62.9, 43.6, 29.4, 28.3, 19.0; IR (neat) 1744 cm-1. Anal.
Calcd for C24H24O2: C, 83.69; H; 7.02. Found: C, 83.42; H; 6.94.
Tetr a h yd r o-2H-2-p yr a n ol. Boron trichloride (4.04 mL, 4.04
mmol, 1 M, CH2Cl2) was added to a solution of 5-(trityloxy)pen-
tanal (1.55 g, 4.49 mmol) in CH2Cl2 (30 mL) at -78 °C. The
mixture was stirred at -30 °C for 45 min and quenched by the
addition of dry MeOH. The mixture was then poured onto a
NaHCO3 solution (saturated, 10 mL) and extracted with CH2Cl2
(5 × 10 mL). The combined organic extracts were washed with
brine (2 × 10 mL) and concentrated in vacuo. The residual oil
was purified by gradient chromatography using deactivated
(Et3N) silica gel (7:3 through to 1:9 hexane:ethyl acetate) to
afford tetrahydro-2H-2-pyranol (330 mg, 75%) as a colorless oil,
spectroscopically identical with an authentic sample:19 1H NMR
4.87 (s, 1H), 3.98 (m, 1H), 3.53 (m, 1H), 2.94 (s, 1 H), 1.83 (m,
2H), 1.51 (m, 4H); 13C NMR 20.0, 24.9, 31.7, 63.6, 94.1.
1,6-Bis[(4-m eth oxyben zyl)oxy]-2-h exa n ol: colorless oil; 1H
NMR 7.26 (d, 4H, J ) 8.4 Hz), 6.88 (d, 2H, J ) 8.7 Hz), 6.87 (d,
2H, J ) 8.7 Hz), 4.47 (s, 2H), 4.42 (s, 2H), 3.80 (s, 3H), 3.79 (s,
3H), 3.49-3.40 (m, 4H), 3.28 (dd, 1H, J ) 7.9 Hz, 9.1 Hz), 1.68-
1.34 (m, 6H); 13C NMR 159.1, 158.9, 130.6, 130.0, 129.3, 129.2,
113.8, 113.7, 74.3, 73.0, 72.6, 70.3, 70.0, 55.3, 33.0, 29.8, 22.3.
Anal. Calcd for C22H30O5: C, 70.56; H; 8.07. Found: C, 70.34;
H; 8.05.
1-{[1-(ter t-Bu tyl)-1,1-d im eth ylsilyl]oxy}-6-[(4-m eth oxy-
b en zyl)oxy]-2-h exa n ol: colorless oil; 1H NMR 7.25 (d, 2H,
J ) 8.7 Hz), 6.87 (d, 2H, J ) 8.7 Hz), 4.48 (s, 2H), 3.80 (s, 3H),
3.60 (t, 2H, J ) 6.3 Hz), 3.47 (dd, 2H, J ) 3.3 Hz, J ) 9.6 Hz),
3.28 (dd, 1H, J ) 8.1 Hz, 9.6 Hz); 13C NMR 159.3, 130.2, 129.5,
114.0, 74.5, 73.2, 70.6, 63.3, 55.5, 33.2, 33.1, 26.3, 26.2, 22.1,
18.7, -4.9. Anal. Calcd for C20H36O4Si: C, 65.17; H; 9.75.
Found: C, 64.98; H; 9.84.
Ack n ow led gm en t. This work was supported by the
Petroleum Research Fund, Administered by the Ameri-
can Chemical Society (AC-33920), the National Institute
of General Medical Sciences (R01GM57123), and the
National Science Foundation (CHE-9700278). We thank
Timothy Snowden for conducting preliminary experi-
ments and Dr. Alex Kitaygorodskiy for assistance with
11B NMR analysis.
6-[(4-Meth oxyben zyl)oxy]-1,2-h exa n ed iol: colorless oil; 1H
NMR 7.25 (d, 2H, J ) 8.8 Hz), 6.87 (d, 2H, J ) 8.8 Hz), 4.48 (s,
2H), 3.80 (s, 3H), 3.64 (t, 2H, J ) 6.1 Hz), 3.47 (dd, 2H, J ) 2.8
Hz, 9.6 Hz), 3.29 (dd, 1H, J ) 7.8 Hz, 9.6 Hz); 13C NMR 159.4,
130.1, 129.6, 114.0, 74.5, 73.2, 70.5, 63.0, 55.5, 33.0, 32.9, 22.0;
HRMS calcd for C14H22O4 (M+) 254.1518, found 254.1518.
J O9913255