Trimethylsilyl trifluoromethanesulfonate (TMSOTf) assisted facile deprotection of N,O-acetonides

Article abstract of DOI:10.1021/jo7021923

(Chemical Equation Presented) Employing TMSOTf as an easily available reagent, we have developed a mild and efficient method for the deprotection of both terminal and internal N,O-acetonide functionalities. Various regularly used protecting groups and com

Full text of DOI:10.1021/jo7021923

SCHEME 1
Trimethylsilyl Trifluoromethanesulfonate
(TMSOTf) Assisted Facile Deprotection of
N,O-Acetonides
Kevin W. C. Poon, Kimberly M. Lovell,
Kendra N. Dresner, and Apurba Datta*
Department of Medicinal Chemistry, The UniVersity of Kansas,
1251 Wescoe Hall DriVe, Lawrence, Kansas 66045
bru¨ggen protocol),4 we found that, in addition to the desired
nucleobase incorporation, the Lewis acidic reaction condition
has also resulted in clean cleavage of the acetonide protection
to form the corresponding nucleoside derivative 3 in high yield.
It is worth mentioning that the only known instances of
acetonide functionality cleavage in the presence of silyl triflates
have been reported by Rychnovsky and co-workers during the
early 1990s.5,6 In their studies aimed at “protecting group
interconversion”, acetonides derived from 1,2- or 1,3-terminal
diols on treatment with TMSOTf or TESOTf in the presence
of Hu¨nig’s base were found to regioselectively rearrange to
acetonide-cleaved products, with concomitant reprotection of
the resulting primary hydroxy group as its silylether and the
secondary hydroxy group as an isopropenyl ether. Interestingly,
internal acetonides remained unaffected under the above condi-
tions, thereby also providing an efficient protocol to differentiate
terminal acetonides from internal ones (Figure 1).6
adutta@ku.edu
ReceiVed October 9, 2007
Employing TMSOTf as an easily available reagent, we have
developed a mild and efficient method for the deprotection
of both terminal and internal N,O-acetonide functionalities.
Various regularly used protecting groups and common
organic functional moieties were found to be unaffected by
the described reaction conditions. In a few representative
examples, the present method was also extended to deprotect
acetonides obtained from 1,2-, and 1,3-terminal diols. The
acetonide deprotection protocol described herein is expected
to be a useful addition to the presently available methods
for performing the above transformation.
Isopropylidene ketal (acetonide) formation is among the most
frequently used protocols for the simultaneous protection of 1,2-
or 1,3-diols and aminoalcohols.1 Consequently, development of
methods for such acetonide-forming reactions and selective
removal of these protecting groups continues to be an active
area of research.1-3 The classical methods for both the formation
and deprotection of acetonides generally involve the presence
of either a protic or a Lewis acid catalyst.1 In recent unrelated
research in our laboratory, while attempting a nucleoside-
forming reaction involving the C4′-N,O-acetonide-containing
glycosyl donor 1 (Scheme 1) and bis-silylated thymine (2), in
the presence of an excess of TMSOTf as the activator (Vor-
FIGURE 1. Rychnovsky’s acetonide interconversion protocol.5b
To the best of our knowledge, there have been no reports on
N,O-acetonide deprotection utilizing silyl triflates. Intrigued by
the observation from our nucleoside-forming reaction above
(Scheme 1) and Rychnovsky’s studies on diol acetonides, we
decided to further investigate the possibility of TMSOTf-assisted
deprotection of N,O-acetonides. The details of the studies
undertaken are reported herein.
In an initial reaction, the L-serinol-derived N,O-acetonide 4a
(Scheme 2) was treated with 2 equiv of TMSOTf, and the
reaction mixture was stirred at 0 °C for 2 h. Subsequent
quenching of the reaction by the addition of an aqueous saturated
sodium bicarbonate solution followed by column chromato-
graphic purification of the crude product provided the desired
(1) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in
Organic Synthesis, 4th ed.; John Wiley & Sons: New Jersey, 2007.
(2) For some recent studies on the deprotection of O,O-acetonides, see:
(a) Coste, G.; Gerber-Lemaire, S. Tetrahedron Lett. 2006, 47, 671-674.
(b) Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Reddy, N. M.; Yadav,
J. S. J. Mol. Catal. A 2005, 238, 229-232. (c) Reddy, S. M.; Reddy, Y.
V.; Venkateswarlu, Y. Tetrahedron Lett. 2005, 46, 7439-7441. (d) Yadav,
J. S.; Satyanarayana, M.; Raghavendra, S.; Balanarsaiah, E. Tetrahedron
Lett. 2005, 46, 8745-8748. (e) Chari, M. A.; Syamasundar, K. Synthesis
2005, 708-710 and references therein.
(4) For a review, see: Vorbru¨ggen, H.; Ruh-Pohlenz, C. Org. React.
2000, 55, 1-630.
(5) (a) Rychnovsky, S. D.; Kim, J. Tetrahedron Lett. 1991, 32, 7219-
7222. (b) Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116,
1753-1765.
(3) For some recent reports on the deprotection of N,O-acetonides, see:
(a) Cong, X.; Hu, F.; Liu, K.-G.; Liao, Q.-J.; Yao, Z.-J. J. Org. Chem.
2005, 70, 4514-4516. (b) Shaikh, N. S.; Bhor, S. S.; Gajare, A. S.;
Deshpande, V. H.; Wakharkar, R. D. Tetrahedron Lett. 2004, 45, 5395-
5398 and references therein.
(6) We are thankful to one of the reviewers of this manuscript for bringing
to our attention the following publication, observing the cleavage of an
O,O-acetonide (albeit as a minor reaction), presumably by TMSOTf.
Procopiou, P. A.; Lynn, S. M.; Roberts, A. D. Tetrahedron 1999, 55, 3649-
3656.
10.1021/jo7021923 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/13/2007
752
J. Org. Chem. 2008, 73, 752-755

TABLE 1. TMSOTf-Assisted Deprotection of N,O-Acetonides
SCHEME 2
acetonide-deprotected aminoalcohol 5a in good yield. The acetyl
protecting group of 4a was found to be stable to the above
reaction conditions.
A probable mechanistic pathway for the observed acetonide
cleavage is proposed in Scheme 3.7 Initial complexation of the
oxazolidine ring oxygen and/or the carbamoyl oxygen by the
Lewis acidic TMSOTf results in the formation of the activated
cationic species I and/or II and their subsequent rearranged
products III/IV. Aqueous workup of the reaction mixture then
leads to the acetonide-deprotected product 5 (Scheme 3). Unlike
in Rychnovsky’s method,5 the absence of any base in the
reaction presumably prevents the base-induced rearrangement
of the activated acetonide, thereby avoiding the enol ether (as
in Figure 1) formation.
SCHEME 3
acetonides were also subjected to successful deprotection
employing the present acetonide cleavage protocol (Table 1).
Thus, the aminodiol derivative 7 could be easily obtained by
deprotection of the corresponding acetonide 6. More interest-
ingly, the internal N,O-acetonide protection of the substrates 8
and 10 could also be efficiently cleaved to provide the
corresponding aminoalcohol derivatives 9 and 11, respectively
(Table 1). The deprotections were equally facile with both the
cis-8- and trans-10-substituted acetonides. It is worth noting
that both the ester functionality and the stereochemical integrity
of 10 remained unaffected under the acetonide deprotection
conditions. When extended toward deprotection of the acetonide
functionalities as present in the chiral R,â-unsaturated lactones
12 and 14, the desired aminoalcohols 13 and 15 were obtained
in very high yields. The strategically functionalized lactones
12 and 14 are routinely used as key synthetic intermediates in
several ongoing research projects in our group. In our hands,
the present deprotection protocol was found to be more efficient
and better yielding compared to some of the literature reported
acetonide deprotection methods (e.g., aq AcOH, HCO2H, PTSA/
MeOH, DOWEX (H+) resin/MeOH, etc.) previously employed
by us to perform the same transformation. One of the limitations
of the present method is the instability of the N-Boc functionality
to TMSOTf, thus the method is not suitable for substrates
containing N-Boc-protected N,O-acetonides.14
With an aim to explore the compatibility of the present
acetonide cleavage protocol with other commonly used protect-
ing groups, variously protected N,O-acetonides were then
subjected to the above TMS-assisted deprotection reaction. Thus,
the benzyl ether moiety of 4b (Scheme 2) was found to be
unaffected by the described reaction conditions, providing the
corresponding N-Cbz-aminoalcohol derivative 5b in high yield.
On the other hand, the tert-butyldimethylsilyl (TBDMS) ether
functionality of the acetonide 4c was found to be unstable to
the above conditions, leading to cleavage of both the N,O-
acetonide and TBDMS ether linkages to form the amino diol
5c in high yield. The observed desilylation reaction is not
completely unexpected, as TBDMS ethers are known to be
deprotected by TMSOTf.1,9 In contrast, the tert-butyldiphenyl-
silyl (TBDPS) protecting group of the N,O-acetonide 4d was
found to be stable to TMSOTf, and the desired acetonide-
deprotected product 5d was obtained in 85% yield (Scheme 2).
In further exploration of the method, several other N,O-
(10) Khalaf, J. K.; Datta, A. J. Org. Chem. 2004, 69, 387-390.
(11) Evans, D. A.; Hu, E.; Tedrow, J. S. Org. Lett. 2001, 3, 3133-
3136.
(7) We thank one of the reviewers of this manuscript for suggesting an
alternative mechanistic pathway (via the formation of II and IV, Scheme
3) leading to the observed acetonide cleavage.
(8) Delle Monache, G.; Di Giovanni, M. C.; Maggio, F.; Misiti, D.;
Zappia, G. Synthesis 1995, 1155-1158.
(9) (a) Hunter, R.; Hinz, W.; Richards, P. Tetrahedron Lett. 1999, 40,
3643-3646. (b) Bou, V.; Vilarrasa, J. Tetrahedron Lett. 1990, 31, 567-
568.
(12) Bhaket, P.; Stauffer, C. S.; Datta, A. J. Org. Chem. 2004, 69, 8594-
8601.
(13) Bhaket, P.; Morris, K.; Stauffer, C. S.; Datta, A. Org. Lett. 2005,
7, 875-876.
(14) For examples of Boc deprotection (in N-Boc compounds) with
TMSOTf and TBDMSOTF, see ref 1.
(15) Labelle, M.; Morton, H. E.; Guindon, Y.; Springer, J. P. J. Am.
Chem. Soc. 1988, 110, 4533-4540.
J. Org. Chem, Vol. 73, No. 2, 2008 753

TABLE 2. Studies on TMSOTf-Assisted Deprotection of
O,O-Acetonides
(10 mL), dried over Na2SO4, and concentrated under vacuum, and
the residue was purified by flash chromatography (EtOAc/hexanes
) 3/2 to 4/1) to yield pure 3 (870 mg, 82%) as a foamy semisolid:
[R]25D -4.0 (c 1, CHCl3); IR (neat) broad 3306, 1751, 1747, 1693
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.90 (s, 3H), 2.09 (s, 6H),
2.65 (br s, 1H, exchangeable with D2O), 3.70-3.78 (m, 1H), 3.92-
4.0 (m, 1H), 4.05-4.22 (m, 1H), 4.31-4.39 (m, 1H), 5.13-5.14
(m, 2H), 5.34-5.37 (m, 1H), 5.48-5.51 (m, 1H), 5.63 (br s, 1H),
5.79 (d, J ) 5.5 Hz, 1H), 7.08 (s, 1H), 7.33-7.46 (m, 5H), 8.37
(s, 1H); 13C NMR (125.8 MHz, CDCl3) δ 12.8, 20.8, 20.9, 53.9,
61.8, 67.5, 71.2, 72.9, 81.9, 89.4, 112.3, 128.5, 128.6, 128.9, 136.6,
137.1, 151.2, 157.1, 164.2, 170.3, 170.5; HRMS (m/z) calcd for
C23H28N3O10 (M + H) 506.1775, found 506.1764.
General Procedure for TMSOTF-Assisted Acetonide Depro-
tection. To a stirred, ice-cold solution of the acetonide derivative
in anhydrous CH2Cl2 (10% solution w/v) under an inert atmosphere
was added TMSOTf (2 equiv) through a syringe. The resulting
solution was stirred at the same temperature for the specified time
(TLC monitoring), followed by quenching the reaction by addition
of a saturated aqueous NaHCO3 solution. After stirring the mixture
for 5 min, the organic layer was separated and the aqueous layer
was saturated with solid NaCl and extracted with CH2Cl2 (three
times). The combined organic layers were dried over anhydrous
Na2SO4. Concentration of the solvent under reduced pressure and
column chromatographic purification of the residue provided the
pure acetonide-cleaved product.
Having successfully demonstrated the TMSOTf-assisted
deprotection of various N,O-acetonides, we decided to inves-
tigate the feasibility of the above protocol in the deprotection
of O,O-acetonides. Accordingly, in a subsequent study, a
representative set of 1,2- and 1,3-diol-derived O,O-acetonides
16, 18, and 20 (Table 2) was subjected to deprotection in the
presence of TMSOTf. Thus, the 1,2-diol acetonide 16 on
treatment with TMSOTf under similar conditions as described
earlier provided the corresponding free diol 17 (Table 2) in 90%
yield. The reaction was equally successful when extended to
the corresponding 1,3-diol-derived acetonide 18, resulting in
the deprotected 1,3-diol 19 in good yield. However, in confor-
mity with Rychnovsky’s observations,5 the acetonide 20, derived
from two secondary hydroxyl groups, failed to undergo ac-
etonide deprotection under the above conditions.
1
Compound 4d. Colorless oil; [R]D -20.7 (c 0.56, CHCl3); H
NMR (CDCl3, 400 MHz, mixture of rotamers) δ 7.70-7.62 (m,
4H), 7.47-7.21 (m, 11H), 5.19-4.96 (m, 2H), 4.26-3.81 (3m, 4H),
3.69-3.55 (m, 1H), 1.57-1.15 (4s, 6H), 1.09 and 1.06 (2s, 9H);
13C NMR (CDCl3, 125.7 MHz, mixture of rotamers) δ 152.9, 152.2,
136.2, 135.6, 135.5, 133.6, 133.4, 133.3, 129.8, 128.5, 128.1, 128.0,
127.9, 127.8, 127.7, 94.3, 93.9, 67.2, 66.5, 65.4, 65.1, 62.9, 62.3,
58.9, 58.1, 27.4, 26.9, 26.8, 26.5, 24.6, 23.1, 19.3, 19.2; HRMS
(ESI, m/z) calcd for C30H38NO4Si (M + H+) 504.2570, found
504.2548.
The structures and stereochemical purity (as applicable) of
all the products obtained during the present studies were
confirmed by their spectral and analytical data and by com-
parison with known compounds wherever available.
Compound 5d. Low-melting solid; [R]D 1.8 (c 1.02, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 7.53-7.50 (m, 4H), 7.35-7.22 (m,
11H), 5.20 (br s, 1H), 4.99 (s, 2H), 3.74-3.59 (m, 5H), 2.12 (br s,
1H), 0.95 (s, 9H); 13C NMR (CDCl3, 125.7 MHz) δ 156.5, 136.4,
135.5, 132.7, 130.0, 128.6, 128.2, 128.1, 127.9, 66.9, 64.1, 63.4,
53.3, 26.9, 19.2; HRMS (ESI, m/z) calcd for C27H34NO4Si (M +
H+) 464.2257, found 464.2278.
Compound 8. Colorless liquid; [R]D -11.4 (c 0.51, CHCl3); 1H
NMR (CDCl3, 400 MHz, mixture of rotamers) δ 7.43-7.35 (m,
5H), 7.05-6.99 (m, 2H), 6.81-6.78 (m, 2H), 5.78-5.72 (m, 1H),
5.20-5.14 (m, 4H), 4.36 (br s, 1H), 3.93 (br s, 1H), 3.80 (s, 3H),
3.05-3.01 (m, 2H), 1.68 and 1.63 (2s, 3H), 1.29 and 1.20 (2s, 3H);
13C NMR (CDCl3, 125.7 MHz, mixture of rotamers) δ 158.3, 152.3,
136.9, 136.4, 131.0, 130.6, 129.1, 128.6, 128.2, 117.7, 113.8, 95.7,
95.3, 79.2, 78.7, 67.0, 63.4, 63.0, 55.2, 37.7, 35.1, 29.1, 27.2, 26.5,
25.0; HRMS MS (ESI, m/z) calcd for C23H28NO4 (M + H+)
382.2018, found 382.2023.
In conclusion, employing TMSOTf as an easily available
reagent, we have developed a mild and efficient method for
the deprotection of both terminal and internal N,O-acetonide
functionalities. A variety of other types of protecting groups
and common functional moieties were found to be unaffected
by the described reaction conditions, thereby adding to the utility
of the method. Complementary to the terminal O,O-acetonide
deprotection method as developed by Rychnovsky, in a few
selected examples, the present method was also found to
deprotect acetonides formed from 1,2- and 1,3-terminal diols.
We hope that the acetonide deprotection protocol described
herein will prove to be a useful addition to the literature methods
for acetonide deprotection and will also provide an alternative
protocol to the known methods.
Compound 9. White solid; mp 117-118 °C; [R]D 58.3 (c 1.01,
1
CHCl3); H NMR (CDCl3, 500 MHz) δ 7.27-7.23 (m, 5H), 7.07
(d, J ) 10 Hz, 2H), 6.75 (d, J ) 10 Hz, 2H), 5.84-5.77 (m, 1H),
5.19 (d, J ) 17 Hz, 1H), 5.10 (d, J ) 10.5 Hz, 1H), 5.11-4.96
(m, 3H), 4.06 (s, 1H), 3.79 (d, J ) 5 Hz, 1H), 3.71 (s, 3H), 2.84-
2.24 (m, 2H), 2.04 (s, 1H); 13C NMR (CDCl3, 125.7 MHz) δ 158.3,
156.5, 138.2, 136.5, 130.3, 130.0, 128.5, 128.1, 127.9, 116.3, 114.0,
72.4, 66.7, 56.4, 55.3, 37.1; HRMS (ESI, m/z) calcd for C20H24-
NO4Na (M + Na+) 364.1525, found 364.1542.
Compound 15. White solid; mp 85-87 °C; [R]D -40.7 (c 1.00,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.26-7.24 (m, 5H), 6.86-
6.83 (m, 1H), 5.94 (d, J ) 9.5 Hz, 1H), 5.53 (d, J ) 8.5 Hz, 1H),
5.04 (s, 2H), 4.50-4.45 (m, 1H), 4.0 (d, J ) 10.5 Hz, 1H), 3.85
(br s, 1H), 3.68 (d, J ) 10 Hz, 1H), 2.56-2.36 (m, 3H); 13C NMR
(CDCl3, 125.7 MHz) δ 163.8, 156.4, 145.8, 136.1, 128.6, 128.3,
Experimental Section
Compound 3. To a solution of the triacetate 112 (1 g, 2.09 mmol)
in anhydrous (CH2Cl)2 (25 mL) were added sequentially bis-
(trimethylsilyl)thymine (1.41 g, 5.21 mmol, 2.5 equiv) and TMSOTf
(1.9 mL, 10.43 mmol, 5 equiv). After stirring at room temperature
for 2 h, the reaction was quenched by the addition of saturated
aqueous NaHCO3 solution (10 mL). The organic layer was
separated, and the aqueous layer was extracted with CHCl3 (3 ×
10 mL). The combined organic extracts were washed with brine
(16) Bovicelli, P.; Sanetti, A.; Lupattelli, P. Tetrahedron 1996, 52,
10969-10978 and references therein.
754 J. Org. Chem., Vol. 73, No. 2, 2008

128.1, 121.0, 67.2, 60.5, 55.0, 54.4, 26.5; HRMS (ESI, m/z) calcd
for C15H18NO5 (M + H+) 292.1185, found 292.1174.
Supporting Information Available: General experimental
procedure and copies of NMR spectra (1H and 13C) of all the new
compounds synthesized. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Institute of
General Medical Sciences (KU-CMLD, P50 GM-069663) for
financial support of this research.
JO7021923
J. Org. Chem, Vol. 73, No. 2, 2008 755