A mild, chemoselective protocol for the removal of thioketals and thioacetals mediated by Dess-Martin periodinane.

Article abstract of DOI:10.1021/ol027518n

[reaction: see text] This paper describes the development of a useful procedure for the removal of thioacetals and thioketals using Dess-Martin periodinane (DMP) reagent. In contrast to existing methods, this protocol offers general reactivity, compatibility with a wide range of functional groups, and convenient reaction times. Also discussed are chemoselectivity experiments involving functionalities that may be subject to oxidation by DMP, qualitative effects of substrate on hydrolysis rate, and direct thioacetal to acetal conversions.

Full text of DOI:10.1021/ol027518n

ORGANIC
LETTERS
2003
Vol. 5, No. 4
575-578
A Mild, Chemoselective Protocol for the
Removal of Thioketals and Thioacetals
Mediated by Dess−Martin Periodinane
Neil F. Langille, Les A. Dakin, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215
panek@chem.bu.edu
Received December 20, 2002
ABSTRACT
This paper describes the development of a useful procedure for the removal of thioacetals and thioketals using Dess−Martin periodinane
(DMP) reagent. In contrast to existing methods, this protocol offers general reactivity, compatibility with a wide range of functional groups,
and convenient reaction times. Also discussed are chemoselectivity experiments involving functionalities that may be subject to oxidation by
DMP, qualitative effects of substrate on hydrolysis rate, and direct thioacetal to acetal conversions.
Acetals and ketals are widely used as protecting groups for
carbonyl compounds due to their negligible susceptibility to
nucleophilic attack, ease of preparation, and stability to
reduction methods.1 Thioacetals and thioketals are particu-
larly attractive as carbonyl protecting groups in complex
molecule synthesis because of their added stability to acidic
conditions. Additionally, the lithium anions of 1,3-dithianes
have found utility as nucleophiles2 in alkylation and epoxide
ring-opening reactions, thereby providing an umpoloung3
approach to the synthesis of ketones or â-keto alcohols.
The use of cyclic thioacetals and thioketals in complex
molecule synthesis, however, is often impeded by the lack
of mild, general methods for their removal. Traditionally,
cyclic thioacetal or thioketal cleavage has mainly been
achieved through oxidative means or by the action of
mercury(II) salts.1a However, these methods frequently result
in competitive side reactions in the presence of olefins,
aromatic rings, groups that are readily oxidized, and acid-
sensitive functionalities.4 In 1989, Stork and Zhao reported
the removal of a series of 1,3-dithianes with bis(trifluoro-
acetoxy)iodobenzene (BTI).5,6 This reagent affords the
desired ketones, aldehydes, or acetals (in the presence of an
alcohol) in good yield with reaction times of less than 10
min. The use of BTI for dithiane cleavage has greatly
expanded the utility of these protecting groups. Indeed, in
applications involving complicated substrates, BTI is fre-
quently the reagent of choice.2c,7
As part of studies directed toward the synthesis of the
natural product leucascandrolide A, we required an efficient
method for the removal of a thioketal from the intermediate
1a (eq 1). In our hands, reaction of 1a with BTI resulted in
(4) Vedejs, E.; Fuchs, P. L. J. Org. Chem. 1971, 36, 366-367.
(5) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.
(6) For the original BTI report, see: Loudon, G. M.; Radhakrishna, A.
S.; Almond, M. R.; Blodgett, J. K.; Boutin, R. H. J. Org. Chem. 1984, 49,
4272-4276.
(7) For recent illustrative examples, see: (a) Nakatsuka, M.; Ragan, R.
A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J. Am.
Chem. Soc. 1990, 112, 5583-5601. (b) Chavez, D. E.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2001, 40, 3667-3670. (c) Paquette, L. A.; Duan,
M.; Kanetzki, I.; Kempmann, C. J. Am. Chem. Soc. 2002, 4257-4270.
(1) (a) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; pp 297-348.
(b) Cordes, E. H.; Bull, H. G. Chem. ReV. 1974, 74, 581-603.
(2) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1075-1077. (b) Page, P. C. B.; van Niel, M. B.; Prodger, J. C. Tetrahedron
1989, 45, 7643-7677. (c) Smith, A. B., III; Condon, S. M.; McCauley, J.
A. Acc. Chem. Res. 1998, 31, 35-46. (d) Liu, P.; Panek, J. S. Tetrahedron
Lett. 1998, 39, 6147-6150.
(3) Gro¨bel, B.-T.; Seebach, D. Synthesis 1977, 357-402.
10.1021/ol027518n CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/25/2003

70% yield of the desired ketone 2a in less than 5 min with
significant loss of silicon protecting group. Various amounts
(∼20%) of multiple olefin isomers were obtained as ad-
ditional side products.8 Increased reaction time (10 min)
resulted in larger amounts of undesired material.
using MeCN versus MeOH (entries 2 and 5), suggesting that
nucleophilic attack of methoxide onto the presumed car-
bocation electrophile effectively competes with or precedes
hydroxide attack. Interestingly, this observation indicates that
direct acetal formation from thioacetals under anhydrous
conditions may be possible. DMP reactivity in the presence
of methanol also indicates that chemoselective dethioacetal-
ization on substrates bearing hydroxyl groups may be
possible. Importantly, commercially available DMP is ef-
fective in this reaction, although it reacts more slowly than
freshly prepared DMP (entries 6 and 5, respectively).14
Accordingly, the use of two equivalents of DMP in an 8:1:1
CH3CN/CH2Cl2/H2O solvent mixture cleanly provides the
desired ketone in a convenient 2 h reaction period (entry 5).
To determine functional group compatibility and to
investigate chemoselectivity in this reaction, a series of
substrates were subjected to optimized deprotection condi-
tions. As illustrated in Table 2, this protocol provides smooth,
general removal of thioacetals and thioketals on substrates
containing many different functional groups, including
nitriles, esters, lactones, aldehydes, ethers, and olefins. The
desired ketones and aldehydes are synthesized in good to
excellent yield, with full conversion achieved in 0.5-18 h.
Although primary methoxymethyl ethers (1i), primary
TBDPS ethers (1p, 1a), and secondary TBS ethers (1p) are
stable to these slightly acidic conditions, primary TBS or
TES ethers (1n) are subject to hydrolysis, yielding the
hydroxy ketone as the major product. Additionally, acid-
promoted epimerization of a chiral center adjacent to an
emerging carbonyl in an aldehyde product has been observed
under these conditions (entry 13). In most cases, however,
no reaction with the functional groups illustrated is observed,
even after prolonged reaction times.15 It is also interesting
to note that both primary (1k, 1m) and secondary (1l)
hydroxyl groups are tolerated16 in this reaction without any
observable oxidation to the undesired aldehyde or ketone.17
Of principle interest to our current studies directed toward
the synthesis of leucascandrolide A, 1a is converted cleanly
to the desired R,â-unsaturated ketone 2a in 91% yield after
Concerned by the prospect of significant material loss
during scale-up procedures, we sought a more reliable
method for dithiane removal. Based on an examination of
the proposed mechanism for BTI-mediated dethioacetaliza-
tion,5 we postulated that Dess-Martin periodinane9 (DMP)
would affect the desired transformation in a milder manner.
Indeed, it is well established that DMP tolerates a myriad
of functional groups.10 Additionally, DMP is commercially
available.11 Despite the widespread use of DMP in oxidative
applications, there are no known reports of DMP-mediated
thioacetal or thioketal removal.12,13
To evaluate this possibility, a series of conditions were
investigated to affect the deprotection of 2-methyl-2-phenyl-
1,3-dithiane 1b. As shown in Table 1, clean conversion was
Table 1. Optimization of Thioketal Deprotection Conditions
entry equiv of DMP
solvent (8:1:1)
time (h) % convb
1
2
3
4
5
6
7
8
1.0
2.0
3.0
1.0
2.0
2.0d
2.0
2.0
MeOH/CH2Cl2/H2O
MeOH/CH2Cl2/H2O
MeOH/CH2Cl2/H2O
MeCN/CH2Cl2/H2O
MeCN/CH2Cl2/H2O
MeCN/CH2Cl2/H2O
H2O only
68
18
12
18
2
4
48
96
90
>95 (91c)
>95 (92c)
>95 (81c)
>95 (92c)
>95
(11) Aldrich catalog number 27,462-3 (Dess-Martin periodinane).
(12) A recent report of benzylic/allylic dithiane removal using o-
iodoxybenzoic acid (IBX) has come to our attention: Wu, Y.; Shen, X.;
Huang, J.-H.; Tang, C.-J.; Liu, H.-H.; Hu, Q. Tetrahedron Lett. 2002, 43,
6443-6445.
(13) A literature search of articles citing refs 5 and 9 resulted in nine
hits. Close inspection of the documents indicates that DMP oxidation has
never been reported on a dithiane-containing substrate.
>95
<50
THF/CH2Cl2/H2O
a All reactions run at room temperature, with 1.0 mmol of 1b, 0.2 M
solvent concentration. b Reflects percent conversion (measured by 1H NMR
analysis of crude mixture after removal of solvents). c Isolated yield of 2b
after column chromatography. d Reaction using commercially available DMP
(Aldrich).
(14) This trend appears to be general. All reported yields in this
publication are for DMP, freshly prepared as per ref 10a, and: Ireland, R.
E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(15) When the N-tosyl hydrazone of 1j was exposed to the conditions
outlined in Table 2, the hydrazone was removed in 20 min, leaving unreacted
thioacetal. For similar transformations using DMP, see: (a) Chaudhari, S.
S.; Akamanchi, K. G. Tetrahedron Lett. 1998, 39, 3209-3212. (b)
Chaudhari, S. S.; Akamanchi, K. G. Synthesis 1999, 760-764. (c) Bose,
D. B.; Narsaiah, A. V. Synth. Commun. 1999, 29, 937-941.
(16) Under these conditions, intramolecular attack of an unprotected
â-hydroxyl onto a stabilized allylic carbocation has been observed, resulting
in a mixture of heterocyclic compounds. This method is not recommended
for unprotected alcohols where formation of an epoxide, furan, or pyran is
possible.
generally achieved in polar solvents with the use of sto-
ichiometric or multiple equivalents of DMP. In these
experiments, a dramatic rate enhancement was observed
(8) Among multiple methods utilized, only BTI resulted in significant
conversion to desired compound 2a.
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(10) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287. (b) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-
7552. (c) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523-2584.
(17) In two separate experiments, treatment of 1k with 2 equiv and 8
equiv of DMP in 9:1 CH3CN/CH2Cl2 (0.2 M) under strictly anhydrous
conditions results in chemoselective conversion to aldehyde 2k after aqueous
workup, without observable alcohol oxidation.
576
Org. Lett., Vol. 5, No. 4, 2003

12 h (entry 15). Gratifyingly, no detectable loss of the
TBDPS ether or olefin isomerization occurs with the use of
DMP. These results suggest that this protocol may be useful
for late-stage formation of carbonyls in complex molecule
synthesis, including targets containing both alcohol and
ketone or aldehyde functionalities.
Table 2. Examination of Substrate Compatibility
In our preliminary studies, a significant increase in
hydrolysis rate was observed in unhindered substrates,
benzylic or allylic dithianes, and in thioketals versus thio-
acetals. Although this protocol provides desired product in
all cases examined, we felt that a brief analysis of the
contributing electronic factors affecting rate would provide
qualitative information regarding predictable reaction times.
Accordingly, DMP-mediated hydrolysis was performed on
a series of sterically similar cinnamaldehyde derived thio-
acetals and thioketals, and the reaction progress was closely
monitored. As shown in Table 3, a general increase in rate
Table 3. Effect of Substrate on Hydrolysis Rate
a Measured by 1H NMR analysis of crude material, after filtration through
a short MgSO4 column and solvent removal. b Starting material no longer
1
observable by H NMR. c Complete conversion achieved in less than 8 h.
is observed for more electron rich allylic substrates (1q, 1s)
and for thioketals (1q, 1r). Interestingly, the allylic substitu-
tion rate increase is similar in magnitude to that of the
thioketal effect. We postulate that a stabilization of the
carbocation in the R,â-unsaturated substrates provides a more
stable electrophile, thereby enhancing the rate of hydrolysis.
Importantly, the effects are cumulative, as shown in the rapid
dethioketalization of 1q, which reaches completion in less
than 30 min. These observations imply that in some cases
of unactivated thioacetals, DMP-mediated deprotection may
be sluggish.
a Reaction at room temperature, using 0.8-2.0 mmol of 1, 2 equiv of
DMP in 8:1:1 MeCN/CH2Cl2/H2O solvent mixture (0.2 M). b Isolated yield
after column chromatography. c >95% conversion to 2; yield reflects product
volatility. d Isolated yield of hydroxy ketone (desilylated product). e Product
epimerization observed by 1H NMR analysis (15:1 thioacetal f 5:1
aldehyde).
BTI-mediated thioacetal cleavage in the presence of an
alcohol is known to form the corresponding acetal directly.5
To determine if the analogous DMP-mediated transformation
Org. Lett., Vol. 5, No. 4, 2003
577

is effective, a series of thioacetals were treated with
anhydrous cleavage conditions as shown in Table 4. Interest-
be advantageous, or where an aldehyde functionality would
be problematic.
In summary, we have developed a convenient procedure
for the removal of thioacetals and thioketals mediated by
Dess-Martin periodinane reagent. This protocol possesses
enhanced functional group compatibility, displays milder yet
generally effective reactivity, and is especially useful for the
hydrolysis of more reactive allylic or benzylic dithianes. The
use of this reagent has facilitated the smooth deprotection
of the advanced leucascandrolide A thioketal intermediate
1a and should find general applicability in other complex
systems.18
Table 4. Conversion of Thioacetals to Acetals
Acknowledgment. This work has been financially sup-
ported by the National Institutes of Health (CA56304). We
are grateful to Merck, Inc., Pfizer, and Johnson & Johnson
for financial support of our program. J.S.P. is grateful to the
ACS for a 2002 Arthor C. Cope Scholar Award.
Supporting Information Available: General experimen-
tal procedures for thioacetal/thioketal formation, DMP-
mediated hydrolysis, and DMP-mediated direct acetal for-
mation. Spectroscopic characterization (IR, HRMS, [R]D, 1H
and 13C NMR data) of selected novel compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Reaction run at room temperature, using 2 equiv of DMP, 8:1:1 MeCN/
CH2Cl2/R′OH solvent (0.2 M). b Isolated yield after column chromatography.
c 2 equiv of DMP, 10 equiv of diol, 0.2 M CH2Cl2 solvent, rt.
OL027518N
(18) Representative Experimental Procedure. To a sample of 1b (210
mg, 1.0 mmol) in 5.0 mL of 8:1:1 MeCN/CH2Cl2/H2O (0.2 M) was added
424 mg of Dess-Martin periodinane (2.0 mmol) in one portion. The reaction
mixture was stirred at room temperature, exposed to air, for 2 h until
complete consumption of starting material as observed by TLC. The reaction
was quenched with 20 mL of 50% aq NaHCO3. The layers were separated,
and the aqueous layer was extracted 3× into 50 mL of CH2Cl2. The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated. Purification by flash chromatography (silica, 5%
EtOAc/hexanes) affords 112 mg (92%) of desired ketone 2b.
ingly, both cyclic and acyclic acetals are formed cleanly in
good yield, with reaction rate displaying similar trends as
the DMP/water-mediated process. Again, chemoselectivity
is demonstrated, as there is no involvement of a primary
alcohol (entry 2). This protocol should find general utility
in cases where a direct thioacetal to acetal conversion would
578
Org. Lett., Vol. 5, No. 4, 2003