Synthesis of 4-deacetyl-1-dimethylsilyl-7-triethylsilylbaccatin III

Article abstract of DOI:10.1021/jo802598m

A one-pot trisilylation step to protect three hydroxyl groups of baccatin III (1), followed by hydride ester cleavage and base hydrolysis of a triethylsilyl ether at C13, provides efficient access to a key intermediate 9 (top path). This route removes two

Full text of DOI:10.1021/jo802598m

Synthesis of 4-Deacetyl-1-dimethylsilyl-
7-triethylsilylbaccatin III
Mark E. Ondari† and Kevin D. Walker*,†,‡
FIGURE 1. Paclitaxel (Taxol).
Department of Chemistry and Department of Biochemistry
and Molecular Biology, Michigan State UniVersity,
East Lansing, Michigan 48824
The various next generation analogs are usually derived from
the natural product, baccatin III (1). Silyl ethers are routinely
employed to protect the hydroxyl groups during the semisyn-
thesis of modified taxanes; removal of these silyl groups
typically requires reaction with acids, bases, or fluorides.8,10-13
Unfortunately, these reagents generally lack regiospecificity
when multiple silyl ethers are present, and accordingly, produc-
tion yields of the target compound are reduced. Therefore,
regioselective acylation of taxoids largely necessitates calculated
and often redundant silylation chemistry.8,10-14 By implement-
ing a one-pot process along with a regiospecific desilylation
step, we demonstrate a more efficient synthetic route to make
the key precursor 4-deacetyl-1-dimethylsilyl-7-triethylsilyl-
baccatin III (9), which potentially could be used to construct
new generation paclitaxel compounds.
walke284@msu.edu
ReceiVed NoVember 23, 2008
The basis of the synthetic procedure described herein was
encouraged from our several attempts to convert 1 to 13-acetyl-
4-deacetylbaccatin III (6) (used as a product standard in our
previous study).15 The conversion of 1 to 4 was successful,
following a described procedure;16 however, our attempts to
deacetylate compound 4 at C4 with sodium bis(2-methoxy-
ethoxy)aluminum hydride (Red-Al) reagent to acquire interme-
diate 5 (Scheme 1) were confounded by migration of the silyl
group at C1.17 Alternatively, a previously described synthesis
in which the 4-acetyl and trimethylsilyl (TMS) groups were
removed from 8 to produce 9 (Scheme 2)18 was considered
potentially suitable for the synthesis of 6.
A one-pot trisilylation step to protect three hydroxyl groups
of baccatin III (1), followed by hydride ester cleavage and
base hydrolysis of a triethylsilyl ether at C13, provides
efficient access to a key intermediate 9 (top path). This route
removes two steps from a previously established reaction
sequence to 9 (bottom path). In principle, inclusion of the
truncated reaction sequence into widely utilized semisynthetic
routes to next generation Taxol (paclitaxel) compounds could
conceivably shorten the overall process.
This latter four-step synthesis started from baccatin III (1),
which was capped at the secondary hydroxyl of C7 by
employing triethylsilyl chloride (TES-Cl) to make 2, followed
by separate TMS (trimethylsilyl) and DMS (dimethylsilyl)
protection steps at the C13 and C1 hydroxyls to produce
intermediates 7 and 8, respectively. Following the hydride
reduction of 8, after a typical quench time (<5 min), the yield
of 9 was recovered at 58%. This deacetylation mechanism is
purportedly directed by coordination of the aluminum hydride
Structure-activity studies have shown that the various ester
and amide groups of the antineoplastic drug paclitaxel (Taxol)1
(Figure 1) define the pharmacophore.2-6 Strategic exchange of
the acyl groups on the paclitaxel structure by synthetic methods
has improved drug pharmacokinetics.7-9
† Department of Chemistry.
‡ Department of Biochemistry and Molecular Biology.
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2186 J. Org. Chem. 2009, 74, 2186–2188
10.1021/jo802598m CCC: $40.75 2009 American Chemical Society
Published on Web 01/29/2009

SCHEME 1. Attempted Synthesis of 6
SCHEME 3. Putative 13-O-Desilylation Reaction Conditions
To Make Compound 9a
a (a) Red-Al, THF, 3 h, then aq Na tartrate (pH 8.5), 5 min; (b) aq Na
tartrate (pH 8.5), 3 h; (c) Red-Al, THF, 3 h, then aq Na tartrate (pH 8.5),
5 min; (d) Red-Al, THF, 3 h, then water (pH 5.6), 3 h; (e) Red-Al, THF,
0°C, 3 h, then NaOH solution (pH 8.5), 3 h; (f) Red-Al, THF, 3 h, then aq
Na tartrate (pH 8.5), 3 h.
broadly used to make 4-deacetyltaxanes.11 However, hydride
reduction has also been described for the cleavage of silyl
ethers.20 Knowledge of the correct reaction process aided our
efforts to optimize the deprotection of 10 to make 9 via
intermediate 11. Therefore, we systematically assessed whether
the silyl group at the C13 hydroxyl of 10 was analogously
removed by hydride reduction upon treatment with Red-Al or
by some other process. The mode of this desilylation has not
been described in previous work and has only been generally
explained as occurring during reaction workup.18
SCHEME 2. Parallel Synthetic Routes to a Key Precursor
of Next Generation Taxoidsa
Several reaction conditions were tested to assess how the
regioselective deprotection was promoted (Scheme 3). To obtain
compound 11, a solution of 10 in THF at 0 °C was added to
Red-Al (5 equiv from a 3.5 M solution in toluene) and stirred
for 3 h. The reaction was quenched with saturated Na tartrate
solution (1 mL, pH 8.5) for 5-10 min, and compound 11 was
then tested under various desilylation reaction conditions as
follows. After treatment of 11 with Red-Al for 3 h, the reaction
was quenched for 3 h with a NaOH solution (pH 8.5) or with
acidic water (pH 5.6) instead of with the typical sodium tartrate
solution. Neither of these alternative conditions converted 11
to the 13-desilylated product 9, as assessed by ESI-MS analysis,
suggesting that pH-buffering by the quench solvent was
necessary. In brief, the only process suitable to regioselectively
deprotect 11 was sequential treatment with Red-Al followed
by long-term treatment with basic sodium tartrate solution. The
tartrate buffer alone did not deprotect 11, indicating that it was
necessary to add Red-Al to the reaction pot in a prior step.
In conclusion, our modified method for the conversion of 1
to 9 (Scheme 2; steps e and f) removes two synthetic steps from
the previously described reaction sequence (Scheme 2; steps
a-d).18 The condensed synthetic pathway employs a commonly
used hydride-deacetylation step but more significantly invokes
removal of a more recalcitrant triethylsilyl group (compared to
a TMS group of 8)18 from the 13-hydroxyl of 10.
a (a) TES-Cl, pyradine, 61% yield; (b) TMS-Cl, imidazole, DMF; (c)
DMS-Cl, imidazole, DMF, 87% yield after steps a and b; (d) Red-Al, THF,
then sat. Na tartrate in water (pH 8.5) for 10 min, 58% yield; (e) TES-Cl,
imidazole, then add DMS-Cl in one pot, 65% yield; (f) Red-Al, THF, then
sat. Na tartrate in water (pH 8.5), 3 h, 70% yield (steps e and f not fully
optimized).
with the proximate oxygen of the 4(5)-oxetane of 10 (or 8) to
promote regioselective ester cleavage.19
In the present study, we demonstrate a method to shorten
this previously described 13-O-desilylation route to 9 from four
to two steps. Our procedure advanced directly from 1 to 10 by
adding DMS-Cl to the reaction mixture to protect the tertiary
hydroxyl at C1. The latter reaction was performed in the same
reaction pot in which the hydroxyls at C7 and C13 were first
protected as TES ethers, using excess TES-Cl. The trisilylated
product 10 was isolated and treated with aluminum hydride
reagent to selectively remove the C4 acetate. Final quenching
with the Na tartrate solution (<5 min) resulted in clean
conversion of 10 to the transient intermediate 4-deacetyl-1-
DMS-7,13-bis(TES)-baccatin III (11) (Scheme 2), but less than
2.5% conversion to 9 was evident by ESI-MS analysis.
Surprisingly, by extending the tartrate reaction to >3 h, ∼70%
of this intermediate was converted to 9. Notably, C13 depro-
tection was not observed prior to C4-deacetylation.
Whereas the synthesis described herein is relatively straight-
forward, it nevertheless has not been described in methods
within the compendium of literature pertaining to semisynthe-
sizing taxane analogs. Foreseeably, the application of this one-
pot trisilylation and reductive ester cleavage steps to acquire
compound 9 can be extended toward synthesizing the plethora
of paclitaxel analogs that bear alternative acyloxy moieties or
alkylcarbonate groups at C4 and/or C13 and are currently
deployed in bioactivity tests.8,21,22 Consequently, the routes to
these next generation taxanes would be effectively shortened,
The cleavage of the C4 acetate of the 4-acetoxy-4(20),5-
oxetane taxoids by reaction with Red-Al, described herein, is
(19) Chen, S.-H.; Wei, J.-M.; Long, B. H.; Fairchild, C. A.; Carboni, J.;
Mamber, S. W.; Rose, W. C.; Johnston, K.; Casazza, A. M.; et al. Biorg. Med.
Chem. Lett. 1995, 5, 2741–2746.
(20) Patel, P.; Chang, C.-T.; Kang, N.; Lee, G.-J.; Powell, W. S.; Rokach, J.
Tetrahedron Lett. 2007, 48, 5289–5292.
J. Org. Chem. Vol. 74, No. 5, 2009 2187

Synthesis of 11. The synthesis of 11 was identical to that of 9,
except that during the quenching step with Na tartrate solution (pH
8.5) the mixture was stirred for 5 min instead of 3 h. The crude
product mixture containing 11 was worked up and purified by PTLC
(20:80 (v/v) EtOAc in hexane) similarly to the procedure described
for 9 to give 4-deacetyl-1-DMS-7,13-bis(TES)-baccatin III (11)
(53% yield, >97% pure by 1H NMR), m/z 831.3 (M + H+), 853.3
starting from 1, by eliminating redundant silyl group manipula-
tions, reducing the use of reagents, and minimizing the number
of workup and purification steps. In addition, taxane compounds
derived via 9 could also be used as substrates in the ongoing
biosynthetic studies on paclitaxel in Taxus cell cultures.
1
(M + Na+). H NMR (300 MHz, CDCl3) δ: -0.3 (d, J ) 3 Hz,
Experimental Section
CH3Si(H)CH3), 0.0 (d, J ) 3 Hz, CH3Si(H)CH3), 0.5 (m,
CH3CH2Si-O), 0.6 (m, CH3CH2Si-O), 0.8 (m, CH3CH2Si-O),
0.9 (m, CH3CH2Si-O) 1.1 (s, CH3-16), 1.2 (s, CH3-17), 1.5 (s,
CH3-19), 2.0 (m, 6ꢀ), 2.1 (s, CH3-18), 2.2 (s, OC(O)CH3 at 10ꢀ),
2.3 (m, 6R), 2.4-2.8 (m, 14R, ꢀ), 3.5 (d, J ) 6 Hz, 3R), 3.6 (bs,
OH-4R), 4.1 (m, 7R), 4.2 (dd, J ) 9 Hz, J ) 9 Hz, 20R, 20ꢀ), 4.6
(m, H-Si(CH3)2), 4.6-4.7 (m, 5R, 13R), 5.6 (d, J ) 6 Hz, 2ꢀ), 6.4
(s, 10R), 7.4 (t, J ) 6 Hz), 7.5 (t, J ) 6 Hz), 8.0 (d, J ) 6 Hz)
[m-H, p-H, o-H of OBz, respectively].
Rate of TES Ether Hydrolysis of 11 at C13. To a solution of
1-DMS-7,13-bis(TES)-baccatin III (10) (160 mg, 0.183 mmol) in
THF (3 mL) at 0 °C was added Red-Al (250 µL, 1.26 mmol)
dropwise within 1 min. After 2 h, 2 mL of saturated Na tartrate (2
mL, pH 8.5) was added slowly within 1 min; the reaction mixture
was stirred at 0 °C for another 3 h, during which time 250-µL
aliquots were removed from the reaction mixture every 15 min
within the first hour and then every 30 min. Each sample was
immediately quenched for 5 min with Na tartrate (pH 8.5), and the
products in each aliquot were separately extracted into 500 µL of
EtOAc. A 50-µL aliquot of the organic extract was diluted with
250 µL of acetonitrile and analyzed by ESI-MS.
Assessment of the Conditions that Promote Regioselective
13-O-Desilylation of 14. For each of the following experiments
20 mg (0.024 mmol) of 4-deacetyl-1-DMS-7,13-bis(TES)-baccatin
III (11) was used. Scheme 3, step b: to a solution of 11 in THF (2
mL) at 0 °C was added saturated Na tartrate (1 mL) dropwise for
5 min. The reaction was monitored by drawing 250-µL aliquots
every 30 min for 3 h. Scheme 3, step c: to a solution of 11 in THF
(2 mL) at 0 °C was added Red-Al (5 µL, 0.025 mmol), and 250-
µL aliquots were removed from the reaction every 30 min for 3 h.
Saturated Na tartrate (pH 8.5) was added dropwise within 5 min,
and EtOAc (2 mL) was added immediately to extract the products,
which were analyzed by ESI-MS as described. Scheme 3, step d:
to a solution of 11 in THF (2 mL) at 0 °C was added Red-Al (5
µL, 0.025 mmol), and 250-µL aliquots were withdrawn every 30
min for 3 h, after which, water (2 mL, pH 5.6) was added slowly
within 1 min, and 250-µL aliquots were removed from the reaction
vessel every 30 min for 3 h. Scheme 3, step e: to a solution of 11
in THF (2 mL) was added Red-Al (5 µL, 0.025 mmol) at 0 °C,
and aliquots were withdrawn every 30 min for 3 h, after which
NaOH (1 mL, pH 8.6) was added, and again aliquots were
withdrawn every 30 min for 3 h.
Synthesis of 9. To a solution of 1-DMS-7,13-bis(TES)baccatin
III (48 mg, 0.082 mmol) in THF (2 mL) was added Red-Al (80
µL, 3.5 µM solution in toluene) dropwise over 5 min at 0 °C. The
reaction was stirred for 40 min and quenched with 1 mL of saturated
Na tartrate solution (pH 8.5), and the reaction mixture was stirred
for 3 h. The solution containing crude product was diluted with
EtOAc (20 mL), washed with an equal amount of water, and dried
(Na2SO4). The organic layer was removed under vacuum, and the
crude product was purified by PTLC (20:80 (v/v) EtOAc in hexane)
to give 4-deacetyl-1-DMS-7-TES-baccatin III (9) (70% yield, >99%
pure by 1H NMR). The product was characterized by ESI-MS
1
(positive ion mode), m/z 717.3 (M + H+), 739.3 (M + Na+). H
NMR (300 MHz, CDCl3) δ: -0.4 (d, J ) 3 Hz, CH3Si(H)CH3),
0.0 (d, J ) 3 Hz, CH3Si(H)CH3), 0.5 (m, CH3CH2Si-O), 0.9 (m,
CH3CH2Si-O), 1.0 (s, CH3-16), 1.2 (s, CH3-17), 1.6 (s, CH3-19),
2.08 (s, CH3-18), 2.13 (s, OC(O)CH3 at 10ꢀ), 2.2 (s, OC(O)CH3 at
4R), 2.3 (m, 6R, ꢀ), 2.6 (m, 14R, ꢀ), 3.3 (d, J ) 6 Hz, 3R), 4.0
(dd, J ) 6 Hz, J ) 6 Hz, 7R), 4.2 (dd, J ) 9 Hz, J ) 9 Hz, 20R,
20ꢀ), 4.6 (m, H-Si(CH3)2), 4.7 (dd, J ) 3 Hz, J ) 3 Hz, 5R), 4.9
(m, 13R), 5.6 (d, J ) 6 Hz, 2ꢀ), 6.38 (s, 10R), 7.4 (t, J ) 6 Hz),
7.5 (t, J ) 6 Hz), 8.0 (d, J ) 6 Hz) [m-H, p-H, o-H of OBz,
respectively].
Synthesis of 10. To a solution of baccatin III (1) (50 mg, 0.085
mmol) in DMF (3 mL) was added imidazole (70 mg, 1.02 mmol)
and TES-Cl (285 µL, 1.7 mmol), and the reaction mixture was
stirred at 45 °C. After 3 h the reaction was judged to be complete
by TLC monitoring. The reaction flask was cooled to 0 °C, after
which DMS-Cl (190 µL, 1.7 mmol) was added, and the reaction
was stirred at 0 °C for 2 h. The reaction was warmed to room
temperature over 2 h, quenched by adding water (20 mL), and
diluted with EtOAc (50 mL). The organic fraction was washed with
saturated brine and water (20 mL × 3 each), dried over Na2SO4,
and purified by PTLC (20% EtOAc in hexanes) to obtain 48 mg of
1-DMS-7,13-bis(TES)baccatin III (10) (∼70% isolated yield and
1
>99% by H NMR). The identity of the compound was verified
by ESI-MS (positive ion mode), m/z 873.3 (M + H+), 895.3 (M +
Na+). 1H NMR (300 MHz, CDCl3) δ: -0.3 (d, J ) 3 Hz,
CH3Si(H)CH3), 0.0 (d, J ) 3 Hz, CH3Si(H)CH3), 0.5 (m,
CH3CH2Si-O), 0.6 (m, CH3CH2Si-O), 0.9 (m, CH3CH2Si-O),
0.98 (m, CH3CH2Si-O) 1.01 (s, CH3-16), 1.1 (s, CH3-17), 1.6
(s, CH3-19), 2.0 (s, CH3-18), 2.1 (s, OC(O)CH3 at 10ꢀ), 2.2 (s,
OC(O)CH3 at 4R), 2.3 (m, 6R, ꢀ), 2.4 (m, 14R, ꢀ), 3.8 (d, J ) 6
Hz, 3R), 4.2 (dd, J ) 9 Hz, J ) 9 Hz, 20R, 20ꢀ), 4.4 (dd, J ) 6
Hz, J ) 6 Hz, 5R), 4.5 (m, H-Si(CH3)2), 4.9 (m, 7R, 13R), 5.7 (d,
J ) 6 Hz, 2ꢀ), 6.4 (s, 10R), 7.4 (t, J ) 6 Hz), 7.5 (t, J ) 6 Hz),
8.0 (d, J ) 6 Hz) [m-H, p-H, o-H of OBz, respectively].
Acknowledgment. This work was supported by the MSU
College of Natural Science and by the Michigan Agricultural
Experiment Station. We thank Irosha Nawarathne for her
generous technical assistance.
1
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Supporting Information Available: Copies of H NMR
spectra for compounds 9, 10, and 11. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO802598M
2188 J. Org. Chem. Vol. 74, No. 5, 2009