Operationally simple and efficient workup procedure for TBAF-mediated desilylation: Application to halichondrin synthesis

Article abstract of DOI:10.1021/ol063113h

An operationally simple and efficient workup method for tetrabutylammonium fluoride (TBAF)-mediated t-butyldimethylsilyl (TBS) deprotection has been developed. The procedure includes addition of a sulfonic acid resin and calcium carbonate, followed by filtration and evaporation. This method eliminates the tedious aqueous-phase extraction process to remove excess TBAF and materials derived from TBAF, thereby making the protocol highly amenable to multiple TBS deprotections. Its efficiency and usefulness were demonstrated by using the transformation of 1 a to 3a in the halichondrin synthesis.

Full text of DOI:10.1021/ol063113h

ORGANIC
LETTERS
2007
Vol. 9, No. 4
723-726
Operationally Simple and Efficient
Workup Procedure for TBAF-Mediated
Desilylation: Application to Halichondrin
Synthesis
Yosuke Kaburagi and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received December 22, 2006
ABSTRACT
An operationally simple and efficient workup method for tetrabutylammonium fluoride (TBAF)-mediated t-butyldimethylsilyl (TBS) deprotection
has been developed. The procedure includes addition of a sulfonic acid resin and calcium carbonate, followed by filtration and evaporation.
This method eliminates the tedious aqueous-phase extraction process to remove excess TBAF and materials derived from TBAF, thereby
making the protocol highly amenable to multiple TBS deprotections. Its efficiency and usefulness were demonstrated by using the transformation
of 1a to 3a in the halichondrin synthesis.
The t-butyldimethylsilyl (TBS) group is one of the most
widely used protecting groups for alcohols, phenols, car-
boxylic acids, and amines because it is (1) easy to introduce,
(2) stable under various conditions, and (3) readily and
selectively cleaved under the fluoride-mediated, typically
tetrabutylammonium fluoride (TBAF), conditions.1,2 How-
ever, deprotection with TBAF often requires an excess
amount of the reagent, and an aqueous-phase extraction
protocol is commonly used to remove excess TBAF and
materials derived from TBAF. For the cases where depro-
tected products have a high water solubility, the protocol of
aqueous-phase extraction is not ideal. Despite this concern,
very limited TBAF workup methods are known to avoid an
aqueous-phase extraction. Thus, a TBAF workup with no
use of aqueous-phase extraction is potentially useful.
This need came to our attention for a slightly different
reason. In conjunction with the synthesis of marine natural
products halichondrins,3-7 we recently reported an ion-
exchange resin based device to achieve a complete conver-
sion of the enone 2a into the polycyclic ketal 3a in an
excellent chemical yield (Scheme 1).4d The enone 2a was in
turn obtained via TBAF deprotection of the penta-TBS enone
1a; this deprotection was accomplished in the presence of
7.5-10.0 equiv of TBAF (1.5-2.0 equiv of TBAF per TBS
ether), and 2a8 was isolated in a high yield by the standard
aqueous-phase extraction workup. However, tediously ex-
(1) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190-
6191.
(2) For example, see: Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups
in Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
10.1021/ol063113h CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/18/2007

nized the need of developing a nonaqueous workup method
of TBAF deprotection, not only because such a method
should eliminate the labor-intensive step but also because
such a method might allow us to achieve the conversion of
the enone 1a to the polycyclic ketal 3a without isolation of
the intermediate 2a. Herein, we report an operationally
simple, efficient, and versatile workup protocol for TBAF-
mediated desilylation.
Scheme 1. Transformation of 1a to 3a
Related to the current work, we noticed two relevant
methods known in the literature. First, Craig and Everhart
used sodium perchlorate, to remove excess TBAF as the
insoluble tetra-n-butylammonium perchlorate salt.9 Second,
Parlow, Vazquez, and Flynn reported the simultaneous use
of a calcium sulfonate resin with a sulfonic acid resin.10 We
appreciated an appealing future for both methods but, at the
same time, recognized some room for improvement.11
At the outset of our work, we envisioned the possibility
of removing the tetrabutylammonium cation with the use of
acidic ion-exchange resin. To test this possibility, we treated
TBAF in THF with excess sulfonic acid resin at room
temperature, removed the resin by filtration, and evaporated
1
the filtrate. A H NMR analysis of the residue showed that
only a small portion of TBAF was removed by this operation,
thereby suggesting that sulfonic acid resin alone cannot drive
eq 1 toward the right side (Scheme 2). On the basis of this
tensive extraction was required, to obtain 2a free from excess
TBAF and materials derived from TBAF. Thus, we recog-
(3) For the first isolation of the halichondrins from a marine sponge
Halichondria okadai Kadota, see: (a) Uemura, D.; Takahashi, K.; Yama-
moto, T.; Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chem.
Soc. 1985, 107, 4796-4798. (b) Hirata, Y.; Uemura, D. Pure Appl. Chem.
1986, 58, 701-710. For isolation of the halichondrins from different species
of sponges, see: (c) Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J. E.;
Dufresne, C.; Doubek, D. L.; Schmidt, J. M.; Cerny, R. L.; Hooper, J. N.
A.; Rutzler, K. C. J. Med. Chem. 1991, 34, 3339-3340. (d) Pettit, G. R.;
Tan, R.; Gao, F.; Williams, M. D.; Doubek, D. L.; Boyd, M. R.; Schmidt,
J. M.; Chapuis, J. C.; Hamel, E.; Bai, R.; Hooper, J. N. A.; Tackett, L. P.
J. Org. Chem. 1993, 58, 2538-2543. (e) Litaudon, M.; Hart, J. B.; Blunt,
J. W.; Lake, R. J.; Munro, M. H. G. Tetrahedron Lett. 1994, 35, 9435-
9438. (f) Litaudon, M.; Hickford, S. J. H.; Lill, R. E.; Lake, R. J.; Blunt,
J. W.; Munro, M. H. G. J. Org. Chem. 1997, 62, 1868-1871.
Scheme 2. Reaction of TBAF and Sulfonic Acid Resin in the
Absence (Eq 1) or Presence (Eq 2) of Calcium Carbonate
(4) For the synthetic work from this laboratory, see: (a) Aicher, T. D.;
Kishi, Y. Tetrahedron Lett. 1987, 28, 3463-3466. (b) Aicher, T. D.; Buszek,
K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Matelich, M. C.; Scola, P.
M.; Spero, D. M.; Yoon, S. K.; Kishi, Y. J. Am. Chem. Soc. 1992, 114,
3162-3164. (c) Choi, H.; Demeke, D.; Kang, F-A.; Kishi, Y.; Nakajima,
K.; Nowak, P.; Wan, Z.-K.; Xie, C. Pure Appl. Chem. 2003, 75, 1-17 and
the references cited therein. (d) Namba, K.; Kishi, Y. J. Am. Chem. Soc.
2004, 126, 7770-7771. (e) Namba, K.; Kishi, Y. J. Am. Chem. Soc. 2005,
127, 15382-15383 and references cited therein.
(5) For synthetic work by Salomon, Burke, and Yonemitsu, see: (a) Kim,
S.; Salomon, R. G. Tetrahedron Lett. 1989, 30, 6279-6782. (b) Cooper,
A. J.; Pan, W.; Salomon, R. G. Tetrahedron Lett. 1993, 34, 8193-8196
and the references cited therein. (c) Lambert, W. T.; Hanson, G. H.;
Benayoud, F.; Burke, S. D. J. Org. Chem. 2005, 70, 9382-9398 and the
references cited therein. (d) Horita, K.; Hachiya, S.; Nagasawa, M.; Hikota,
M.; Yonemitsu, O. Synlett 1994, 38-39. (e) Horita, K.; Nagasawa, M.;
Sakurai, Y.; Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1199-1216. (f)
Horita, K.; Nishibe, S.; Yonemitsu, O. Phytochem. Phytopharm. 2000, 386-
397 and the references cited therein.
observation, we focused on a method to remove liberated
HF from THF solution. Calcium carbonate (insoluble in
THF) seemed to be an attractive HF scavenger for the
following reasons: (1) the equilibrium should shift toward
the right side because formed CaF2 precipitates out from the
system (CaF2 is insoluble in THF) and (2) the products, i.e.,
CaF2 (insoluble in THF), water, and CO2, can be removed
by filtration and evaporation (see eq 2 in Scheme 2). To test
this possibility experimentally, we treated TBAF in THF in
(8) Compound 2 exists primarily as the intramolecular oxy-Michael
adducts shown below.
(6) For the mechanism of action, see: (a) Bai, R.; Paull, K. D.; Herald,
C. L.; Malspeis, L.; Pettit, G. R.; Hamel, E. J. Biol. Chem. 1991, 266,
15882-15889. (b) Hamel, E. Pharmacol. Ther. 1992, 55, 31-51. (c)
Dabydeen, D. A.; Burnett, J. C.; Bai, R.; Verdier-Pinard, P.; Hickford, S.
J. H.; Pettit, G. R.; Blunt, J. W.; Munro, M. H. G.; Gussio, R.; Hamel, E.
Mol. Pharmacol. 2006, 70, 1866-1875 and the references cited therein.
(d) Luduena, R. F.; Roach, M. C.; Prasad, V.; Pettit, G. R. Biochem.
Pharmacol. 1993, 45, 421-427.
(7) Recently, Jordan and co-workers reported that the primary antimitotic
mechanism of action of halichondrin analogue E7389 is suppression of
microtubule growth. For details, see: Jordan, M. A.; Kamath, K.; Manna,
T.; Okouneva, T.; Miller, H. P.; Davis, C.; Littlefield, B. A.; Wilson, L.
Mol. Cancer Ther. 2005, 4, 1086-1095.
(9) Craig, J. C.; Everhart, E. T. Synth. Commun. 1990, 20, 2147-2150.
(10) Parlow, J. J.; Vazquez, M. L.; Flynn, D. L. Bioorg. Med. Chem.
Lett. 1998, 8, 2391-2394.
(11) For instance, perchlorates are potentially hazardous, whereas calcium
sulfonate resin is not commercially available.
724
Org. Lett., Vol. 9, No. 4, 2007

the presence of calcium carbonate at room temperature,
removed the insoluble materials by filtration, and evaporated
the filtrate to dryness under reduced pressure. A H NMR
Table 1. Substrates Used to Test the Feasibility and Efficiency
of the TBAF Workup Protocola
1
analysis of the residue showed that more than 98% of TBAF
was removed via this simple operation. Among the sulfonic
acid resins tested,12 DOWEX 50WX8-400 was found to be
the most effective for this purpose.
Having demonstrated that a combination of sulfonic acid
resin and calcium carbonate can effectively remove TBAF
from THF solution, we then studied the effectiveness of this
workup method of TBAF-promoted TBS deprotection. The
anticipated overall transformation is depicted in Scheme 3.
Scheme 3. Overall Transformation
TBS ether is treated with excess TBAF, followed by addition
of DOWEX 50WX8-400 (H+ form, excess) and calcium
carbonate (powder, excess). The products formed in this
transformation are the desired alcohol, DOWEX 50WX8-
400 (n-Bu4N+ form), calcium fluoride, water, CO2, and
t-butyldimethylsilyl fluoride (TBSF). DOWEX 50WX8-400
(n-Bu4N+ form) and calcium fluoride, as well as excess
DOWEX 50WX8-400 (H+ form) and calcium carbonate, can
be removed by filtration, whereas water and TBSF can be
removed by evaporation. Thus, only the desired alcohol
should be left after filtration and evaporation.
To test the feasibility of this method, we selected seven
substrates that should furnish the deprotected products with
a broad range of polarity (Table 1). According to the general
procedure given below,13 deprotection and workup were
carried out. 1H NMR analysis revealed that the crude product
a Reaction conditions employed for desilylation: substrate (1 equiv),
TBAF (3-8 equiv), THF, rt or heat, 4-28 h; CaCO3, DOWEX 50WX8-
400 (used as supplied), MeOH, rt, 1 h. bBased on the weight obtained after
c
1
filtration and evaporation. Estimated from H NMR spectra of the crude
d
compound. Product was volatile.
thus obtained was the expected deprotected alcohol only
contaminated with a small amount of the TBAF-derived
materials. On the basis of the signal intensity in the 1H NMR
spectrum of the crude product, at least 99% of the TBAF-
derived materials was removed through this procedure for
all the cases. Interestingly, practically no TBS-derived
material was contaminated in the crude product. This
procedure thus proved effective for all the seven substrates
tested. In our view, this method offers an attractive option
to deal with water-soluble products for which a conventional
aqueous-phase workup is difficult to apply.
As mentioned earlier, we had one specific goal for this
developmental work. Thus, the penta-TBS enone 1a in the
halichondrin B series was subjected to TBAF-promoted TBS
removal in THF (TBAF: total of 10 equiv or 2.0 equiv per
TBS, room temperature, 49 h), followed by this workup
method, to furnish the crude desilylated enone 2a (126% of
the theoretical weight). Then, the crude product was directly
applied to the ion-exchange resin device,4d to give the crude
(12) Other sulfonic acid resins tested included Rexyn 101 and Amberlyst
15.
(13) General workup procedure for removal of TBAF residue (Table 1,
entry 1): A 10 mL flask containing a stirring bar was charged with substrate
(110 mg, 0.169 mmol). TBAF (1.0 M in THF, 1.35 mL, 1.35 mmol) was
added via syringe. After the solution was stirred at room temperature for 4
h (no SM nor partially deprotected intermediate detected by TLC), CaCO3
(280 mg), DOWEX 50WX8-400. (840 mg, used as supplied), and MeOH
(2.0 mL) were added. The suspension was stirred at room temperature for
1 h. All insoluble materials were removed by filtration through a pad of
Celite, and the filter cake was washed with MeOH thoroughly. The
combined filtrates were evaporated to dryness under reduced pressure to
give the crude product (36.3 mg, 111%) as a white solid. 1H NMR spectra
of the crude product showed that 99.3% of tetrabutylammonium salt was
removed by these operations.
Org. Lett., Vol. 9, No. 4, 2007
725

was also successfully applied to the transformation of the
penta-TBS enone 1b to the polycyclic ketal 3b in the E7389
series.14
Scheme 4. Application of This TBAF Workup Method to the
Advanced Synthetic Stage in Both the Halichondrin B and
E7389 Series
In summary, we developed an operationally simple and
efficient workup method for TBAF-promoted desilylations,
with the use of commercially available sulfonic acid resin
(used as supplied) and calcium carbonate. This method
eliminates the tedious aqueous-phase extraction protocol, to
remove excess TBAF and TBAF-derived materials. The
effectiveness and versatility of this method were demon-
strated for the seven examples shown in Table 1. The
usefulness of this method was further demonstrated by using
the transformation of 1a,b to 3a,b in the halichondrin
synthesis. We believe that this method offers an attractive
option to deal with water-soluble products for which a
conventional aqueous-phase workup is difficult to apply.
Acknowledgment. We are grateful to the National
Institutes of Health and Eisai Research Institute for generous
financial support.
Supporting Information Available: Experimental details
and 1H NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL063113H
(14) Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singer, L.
A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay, L.; Towle,
M. J.; Salvato, K. A.; Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B.
A.; Yu, M. J. Bioorg. Med. Chem. Lett. 2004, 14, 5551-5554.
ketal 3a (107% of the theoretical weight), which was passed
through a short plug of silica gel to furnish the pure ketal
3a in 96% overall yield from 1a (Scheme 4). This protocol
726
Org. Lett., Vol. 9, No. 4, 2007