A selective intramolecular transacylation of taxoids accompanying with the oxetane ring opening

Article abstract of DOI:10.1248/cpb.60.415

A selective intramolecular transacylation from C-4 to C-5 of taxoids, which occurred simultaneously with the oxetane D-ring opening and was promoted by TiCl₄, was presented. The optimal condition was found to be treatment of substrates in doubl

Full text of DOI:10.1248/cpb.60.415

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March 2012
Note
Chem. Pharm. Bull. 60(3) 415 418 (2012)
415
A Selective Intramolecular Transacylation of Taxoids Accompanying
with the Oxetane Ring Opening
,a,b
,b
Feng Gao,* Min Yu,a Qiao-Hong Chen,b and Feng-Peng Wang*
a Department of Chinese Traditional Herbal, Agronomy College, Sichuan Agricultural University; No. 221, Huimin
b
Road, Wenjiang Region, Chengdu 611130, P.R. China: and Department of Chemistry of Medicinal Natural Products,
West China College of Pharmacy, Sichuan University; No. 17, Duan 3, Renmin Nan Road, Chengdu 610041, P.R.
China. Received November 20, 2011; accepted December 12, 2011; published online December 15, 2011
A selective intramolecular transacylation from C-4 to C-5 of taxoids, which occurred simultaneously
with the oxetane D-ring opening and was promoted by TiCl4, was presented. The optimal condition was
found to be treatment of substrates in double dose of dichloromethane (per mg of substrate dissolved in 2mL
°
DCM) with 1eq of TiCl4 at 25 C for 10min.
Key words taxane; paclitaxel; titanium tetrachloride; D-ring opening; transacylation
The diterpenoid natural product paclitaxel (Fig. 1) was these D-ring modified analogues greatly enriched the struc-
initially isolated by Wall and Wani from Taxus brevifolia and ture–activity relationships of paclitaxel.
led to the discovery of a new biochemical mechanism.1,2) Its
To search for novel D-ring modified analogues of paclitaxel,
mechanism of action as a promoter of tubulin assembly has we need an intermediate with an acetoxy group at the C-5 po-
provided the basis of the extensive mechanism-based devel- sition, which is the minor product from the above-mentioned
opment of anticancer agents. As two of the most effective D-ring opening process.14) Therefore, we revisited the Lewis
drugs for the treatment of cancer, paclitaxel and its analogue acid-promoted oxetane D-ring opening and hoped to search
docetaxel (Fig. 1) are now used, either as single agents or in for an unusual and selective transacylation from C-4 to C-5.
combination with other drug, for the treatment of ovarian can- In this note, we wish to report our observed results in this
cer, breast cancer, and non-small-cell lung cancer.
regard.
The oxetane D-ring is one of the unusual features of the
paclitaxel structure, and it plays a significant role in pacli-
Results and Discussion
We began our exploitation with BF3·OEt3 as a Lewis acid
3)
’
taxel s unique activity. A characteristic reaction of the ox-
etane D-ring of paclitaxel is its opening promoted by Lewis because BF3·OEt3 is the most common Lewis acid that was
acid, which is accompanied by intramolecular transacylations used to promote the D-ring opening of taxoids. Our initial
(Chart 1).4) The related mechanism was proposed as follows: experiment demonstrated that the treatment of an derivative
i) an orthoester between C-4, C-5, and C-20 may be formed (3) of 10-deacetyl Baccatin III (10-DBA, 6) with BF3·OEt3 at
°
promoted by Lewis acid; and ii) this orthoester may be hy- −15 C generated 4 with a C-20 acetoxy group in 65% yield,
drolyzed to afford the C-5 and C-20 acetoxy derivatives, with as well as trace amount of our desired product 5 (10%) (Entry
C-20 acetoxy derivative as the major product.4) This interest- 1, Table 1). Next, we examined the effect of the reaction con-
ing reaction not only furnished the D-ring opening analogue ditions (such as amount of Lewis acid, reaction time, reaction
of paclitaxel, but also acted as a conventional approach to temperature, and concentration of reaction mixture) on the
—
13)
other D-ring modified analogues.5
The biological data of selectivity of the transacylation from C-4 to C-5 (Table 1).
Significantly, it was found that the yield of C-5 acetoxy prod-
uct 5 was increased from 10 to 25% when the reaction was
performed in a highly diluted reaction mixture (Entry 4).
Most importantly, this result encouraged us to further ex-
ploit the possibility to increase the yield of the expected prod-
uct 5 by examining various Lewis acids, including BF3·OEt3,
SnCl4, AlCl3, and TiCl4 (Table 1). It was observed: i) that em-
ployment of SnCl4 as a Lewis acid in combination with diluted
reaction mixture led to slightly improved selectivity for the
transacylation from C-4 to C-5 (Entry 9); ii) that AlCl3 is not
a good Lewis acid for this reaction in consideration of both
Fig. 1. Structures of Paclitaxel and Docetaxel
Chart 1. Conventional D-Ring Opening of Taxoids
*To whom correspondence should be addressed. e-mail: gaofeng@sicau.edu.cn; wfp@scu.edu.cn
© 2012 The Pharmaceutical Society of Japan

416
Vol. 60, No. 3
Table 1. Lewis Acid-Promoted Intramolecular Transacylation and D-Ring Opening of 3
Amount of
Entry
Lewis acid
Reaction temperature
Reaction time
Yield % for 4
Yield % for 5
dichloromethanea)
°
1
2
BF3·Et2O (1eq)
BF3·Et2O (1eq)
BF3·Et2O (2eq)
BF3·Et2O (1eq)
BF3·Et2O (1eq)
SnCl4 (1eq)
SnCl4 (2eq)
SnCl4 (1eq)
SnCl4 (1eq)
SnCl4 (1eq)
AlCl3 (1eq)
AlCl3 (2eq)
AlCl3 (1eq)
TiCl4 (1eq)
−15 C
10min
30min
10min
10min
10min
30min
30min
30min
30min
10min
30min
30min
30min
10min
30min
30min
30min
10min
1mL/mg
1mL/mg
1mL/mg
4mL/mg
2mL/mg
1mL/mg
1mL/mg
2mL/mg
2mL/mg
2mL/mg
2mL/mg
2mL/mg
2mL/mg
2mL/mg
1mL/mg
2mL/mg
2mL/mg
4mL/mg
65
50
50
65
35
35
30
35
45
15
20
20
10
0
10
8
°
−15 C
°
0 C
3
5
°
4
−15 C
25
5
°
25 C
5
°
6
−15 C
30
20
35
45
15
5
°
−15 C
°
−15 C
°
0 C
°
25 C
°
0 C
°
0 C
7
8
9
10
11
12
13
14
15
16
17
18
5
°
25 C
2
°
25 C
93
45
35
60
93
°
TiCl4 (1eq)
25 C
15
45
25
0
°
0 C
°
25 C
°
25 C
TiCl4 (1eq)
TiCl4 (2eq)
TiCl4 (1eq)
a) 1mL/mg means that 1mL of dichloromethane was used for per mg of substrate.
total yield and selectivity (Entry 11); and iii) that TiCl4 was for 10min (Chart 2). The selective transacylation from C-4 to
established as an optimal Lewis acid, which might provide C-5 also proceeded smoothly in this case to furnish the D-ring
an excellent selectivity and yield (Entries 14, 18). It is worth opening products 7, 8 and 9, respectively. This indicated that
noting that a highly diluted reaction mixture and a relatively both protected and unprotected hydroxyl groups are perfectly
higher reaction temperature are very beneficial to the selec- compatible with the aforementioned reaction conditions.
tivity when using TiCl4 as Lewis acid. However, enhance-
In conclusion, we have developed a regioselective D-ring
ment of the amount of TiCl4 from 1 to 2eq is detrimental to opening reaction, in which the acetyl group at C-4 could be
the selectivity (Entry 17). To this end, treatment of a highly selectively transferred to C-5 in an excellent yield while the
diluted solution of 3 in double dose of dichloromethane (per D-ring opening. This reaction is applicable for various taxoids
mg of substrate dissolved in 2mL DCM) with 1eq of TiCl4 at including paclitaxel and docetaxel and highly tolerated to
°
25 C for 10min was found to be the optimal condition for the the free hydroxyl groups, which suggested that this selective
simultaneous ring-D opening and selective transacylation from reaction is particularly useful in the ring D-modifications of
C-4 to C-5.
taxoids.
1
The major differences in the H-NMR spectra of 4 and
5 (Table 2) occurred at C-5 and C-20, and these differences
are consistent with the assignment of the acetoxy group at
Experimental
General 1H- and 13C-spectra were recorded on a Varian
C-20 for 4 and at C-5 for 5. Specifically, the chemical shift Unity INOVA 400/54NMR spectrometer in CDCl3 with tetra-
of the C-20 protons in 4 downshifted from 4.08/3.59 in 5 to methylsilane (TMS) as the internal standard. Chemical shifts
4.52/4.41, indicating that the acetoxy group was transformed are given as δ value and are referenced to residual solvent
to C-20 in 4. Similarly, the chemical shift of the C-5 proton proton carbon pick. Mass spectra were obtained on a VG
in 5 downshifted from 3.79 in 4 to 5.32, suggesting the trans- Auto spec 3000 or on a Finnigan MAT 90 instrument. Optical
acylation at C-5.
rotations were measured on a Perkin-Elmer 341. Silica gel H
At this point, we paid our attention to the evaluation of (Qingdao Sea Chemical Factory, Qingdao, P.R. China) was
the applicability of this selective transacylation while the used for column chromatography. Spots on TLC (silica gel
D-ring opening. Accordingly, 10-DAB (6), Paclitaxel (1) and G) were detected with H2SO4–EtOH. Commercially available
Docetaxel (2) possessing free hydroxyl groups was treated reagents and solvents were used without further purification.
°
with TiCl4 (1eq) in DCM (2mL per mg of substrate) at 25 C
Preparation of the D-Opening Derivate 5 To a stirred

March 2012
417
Table 2. NMR Spectroscopic Data for Compounds 4 and 5
4
5
No.
1H-NMR
13C-NMR
1H-NMR
—
13C-NMR
—
1
2
90.2 s
72.1 d
43.4 d
75.4 s
81.1 d
30.6 t
90.1 s
72.1 d
45.3 d
74.0 s
81.7 d
30.0 t
4.23 d (4.4)
3.74 d (4.4)
4.24 d (4.8)
3
3.50 d (4.8)
—
—
4
5
3.79 t (2.8)
5.32 t (2.8)
6
1.85 m, 2.24 m
2.00 m, 2.12 m
7
5.44 dd (11.2, 4.4)
71.4 d
59.1 s
5.20 dd (11.6, 4.8)
71.6 d
59.0 s
201.9 s
78.0 d
132.0 s
143.8 s
71.3 d
32.7 t
—
—
8
—
—
9
202.0 s
78.3 d
132.0 s
144.2 s
69.8 d
32.5 t
10
11
12
13
14
6.48 s
6.44 s
—
—
—
—
5.72 dd (10.0, 2.4)
3.13 dd (15.6, 4.0)
2.64 dd (15.6, 10.0)
—
5.82 dd (8.4, 5.6)
3.13 dd (15.2, 5.6)
2.64 dd (15.2, 10.0)
—
15
16
17
18
19
20
40.6 s
18.8 q
27.1 q
16.6 q
12.7 q
64.7 t
41.1 s
19.5 q
26.0 q
16.1 q
12.7 q
62.9 t
1.15 s
1.15 s
1.22 s
1.28 s
2.29 s
2.31 s
1.35 s
1.29 s
4.52 ABq (12.0)
4.41 ABq (12.0)
—
4.08 ABq (9.2)
3.59 ABq (9.2)
—
OCOO
151.8 s
27.7 q
151.9 s
27.6 q
1.44, 1.47, 1.50, s
—
1.44, 1.47, 1.49, s
—
82.8 s
83.0 s
—
—
170.5 s
20.7 q
171.0 s
21.3 q
2.13 s
2.34 s
Chart 2. TiCl4-Mediated D-Ring Opening and Transacylation of 10-DAB, Paclitaxel and Docetaxel
solution of compound 3 (100mg, 0.13mmol) in CH2Cl2
Preparation of the D-Opening 10-DAB Derivate 7 To a
°
(200mL) at 25 C, 1M TiCl4 (in CH2Cl2) 0.13mL was added. stirred solution of 10-DAB (6, 103mg, 0.19mmol) in CH2Cl2
°
°
The reaction mixture was stirred at 25 C for 10min, then sat- (206mL) at 25 C, 1M TiCl4 (in CH2Cl2) 0.19mL was added.
°
urated K2CO3 and water were added to quench this reaction. The reaction mixture was stirred at 25 C for 10min, then
The organic phase was washed with water, dried over Na2SO4 saturated K2CO3 and water were added to quench this reac-
and evaporated under reduced pressure. The residue was puri- tion. The organic phase was washed with water, dried over
fied on silica gel (cyclohexane/acetone 6:1) to yield compound Na2SO4 and evaporated under reduced pressure. The residue
5 (96mg, 93%) as an amorphous powder. [α]D25 −13.2 (c=2.0, was purified on silica gel (petroleum ether/acetone 3:1) to
CHCl3), MS (electrospray ionization (ESI), MeOH) m/z 785 yield compound 7 (68mg, 66%) as an amorphous powder.
25
[M+H]+; HR-ESI-MS: 785.3502 (M+H+, C38H57O17, Calcd
785.3517);
Characterization data of compound 7 : [α]D −16.6 (c=0.9,
“
”
1
—
CHCl3), H-NMR (400MHz, CDCl3+CD3OD) δ: 7.39 7.88

418
Vol. 60, No. 3
(5H, m), 5.30 (1H, d J=6.4Hz), 5.21 (1H, brs), 5.16 (1H, brs), (1H, m), 4.12 (1H, ABq), 3.85 (1H, ABq), 2.12, (1H, s), 1.63
4.16 (1H, ABq, J=9.2Hz), 3.67 (1H, ABq, J=9.2Hz), 3.98 (3H, s), 1.44 (9H, s), 1.15 (3H, s), 1.13 (3H, s), 0.86 (3H, s).
(1H, d, J=6.4Hz), 2.15 (3H, s), 1.99 (3H, s), 1.13 (3H, s), 1.05 13C-NMR (CDCl3, 100MHz) δ: 200.1, 176.4, 161.9, 160.0,
(3H, s), 1.00 (3H, s). 13C-NMR (CDCl3+CD3OD, 100MHz) 139.5, 127.9, 124.3, 122.7, 121.5, 119.6, 119.6, 119.5, 99.9, 99.6,
δ: 202.3, 170.9, 168.3, 152.8, 152.3, 147.8, 147.8, 129.9, 129.9, 73.7, 68.7, 68.2, 66.2, 66.1, 65.4, 61.3, 59.5, 59.5, 59.5, 59.2,
90.3, 83.7, 80.8, 79.3, 77.2, 76.1, 73.7, 66.9, 58.0, 44.2, 40.8, 50.2, 40.1, 39.9, 39.6, 39.4, 39.2, 34.7, 29.6, 29.4, 23.8, 23.3,
35.5, 33.8, 27.5, 25.4, 22.4, 20.6, 19.9, 15.7, 10.7. MS (ESI, 21.0, 20.9, 20.7, 18.6, 17.9, 17.6, 17.0, 14.0, 11.9. MS (ESI,
MeOH) m/z 563 [M+H]+; HR-ESI-MS: 563.2471 (M+H+, MeOH) m/z 826 [M+H]+; HR-ESI-MS: 826.3613 (M+H+,
C29H39O11, Calcd 563.2492).
C43H56NO15, Calcd 826.3650).
Preparation of the D-Opening Paclitaxel Derivate 8 To
a stirred solution of paclitaxel (1, 142mg, 0.17mmol) in
Acknowledgments We are grateful to the National
°
CH2Cl2 (300mL) at 25 C, 1M TiCl4 (in CH2Cl2) 0.17mL was Natural Science Foundation of China (No. 30873147 and
°
added. The reaction mixture was stirred at 25 C for 10min, No. 81001383) and the Doctoral Foundation of Ministry of
then saturated K2CO3 and water were added to quench this re- Education, China (No. 20105103120009).
action. The organic phase was washed with water, dried over
Na2SO4 and evaporated under reduced pressure. The residue
was purified on silica gel (petroleum ether/acetone 3:1) to
yield compound 8 (104mg, 73%) as an amorphous powder.
References
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—
“
”
Characterization data of compound 8 : [α]D +235.2 (c=1.0,
(1979).
1
—
CHCl3), H-NMR (400MHz, CDCl3) δ: 7.17 8.05 (15H, m),
6.58 (1H, s), 6.00 (1H, dd, J1=9.6Hz, J2=3.2Hz), 5.92 (1H, d,
J=9.2Hz), 5.56 (1H, d, J=5.6Hz), 4.70 (1H, s), 4.50 (1H, m),
4.13 (1H, s), 4.02 (1H, ABq), 3.71 (1H, ABq), 3.04 (1H, dd,
J1=12.0Hz, J2=4.4Hz), 2.21, (1H, s), 2.08 (3H, s), 1.63 (3H,
s), 1.24 (3H, s), 1.13 (3H, s), 1.11 (3H, s). 13C-NMR (CDCl3,
100MHz) δ: 203.6, 188.6, 171.5, 170.6, 169.6, 167.4, 166.8,
140.3, 138.7, 134.9, 134.1, 133.1, 131.8, 130.0, 128.8, 128.8,
128.7, 128.6, 128.6,128.2, 128.0, 126.9, 126.9, 126.6, 126.6,
77.3, 75.4, 75.2, 74.4, 73.6, 73.2, 71.8, 68.5, 64.1, 60.3, 54.6,
45.7, 42.4, 42.4, 35.0, 31.5, 27.8, 20.7, 19.9, 18.8, 16.2, 10.6.
MS (ESI, MeOH) m/z 873 [M+H]+; HR-ESI-MS: 872.3453
(M+H+, C47H54NO15, Calcd 872.3493).
—
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689 705 (2003).
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Preparation of the D-Opening Docetaxel Derivate 9
To a stirred solution of Docetaxel (2, 86mg, 0.11mmol) in
—
Himes R. H., Wang M., Snyder J. P., J. Org. Chem., 66, 3321 3329
(2001).
10) Mercklé L., Dubois J., Place E., Thoret S., Guéritte F., Guénard
°
CH2Cl2 (206mL) at 25 C, 1M TiCl4 (in CH2Cl2) 0.11mL was
°
added. The reaction mixture was stirred at 25 C for 10min,
—
D., Poupat C., Ahond A., Potier P., J. Org. Chem., 66, 5058 5065
then saturated K2CO3 and water were added to quench this
reaction. The organic phase was washed with water, dried
over Na2SO4 and evaporated under reduced pressure. The resi-
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to yield compound 9 (59mg, 69%) as an amorphous powder.
25
“
”
Characterization data of compound 9 : [α]D +142.5 (c=0.8,
1
—
CH3OH), H-NMR (400MHz, CDCl3) δ: 7.27 8.12 (10H, m),
6.18 (1H, d, J=9.6Hz), 6.05 (1H, m), 5.59 (1H, d, J=5.2Hz),
5.55 (1H, brs), 5.39 (1H, brd, J=8.0Hz), 4.58 (1H, brs), 4.40
—
—
Biomol. Chem., 10, 361 366 (2012).