Design and Synthesis of a Taxoid Library
J . Org. Chem., Vol. 62, No. 17, 1997 6033
microreactor. The microreactors were washed thoroughly
according to the standard washing procedure and dried under
vacuum at room temperature for overnight.
1-IR. 1H NMR (500 MHz, CDCl3) δ 8.25-8.16 (m, 1 H),
8.10-8.03 (m, 2 H), 7.90 (d, J ) 8.3 Hz, 1 H), 7.84 (d, J ) 8.3
Hz, 1 H), 7.60-7.30 (m, 15 H), 6.88-6.85 (m, 2 H), 6.44 (s, 1
H), 6.30-6.27 (m, 1 H), 5.84 (dd, J ) 3.2 Hz, J ) 9.5 Hz, H),
5.75-5.65 (m, 2 H), 5.47 (d, J ) 3.6 Hz, 1 H), 5.00 (br d, J )
9.3 Hz, 1 H), 4.90-4.85 (m, 1 H), 4.30 (d, J ) 8.4 Hz, 1 H),
4.21 (d, J ) 8.4 Hz, 1 H), 4.01 (d, J ) 7.1 Hz, 1 H), 2.80-2.72
(m, 1 H), 2.60-1.20 (m, 8 H), 2.53 (s, 3 H), 2.45 (s, 3 H), 2.43
(s, 3 H), 2.08 (s, 3 H), 2.01 (s, 3 H), 1.90 (s, 3 H), 1.46 (s, 3 H),
1.25 (s, 3 H).
1-RF . 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J ) 7.6 Hz, 2
H), 8.05 (d, J ) 7.6 Hz, 2 H), 7.92 (d, J ) 7.6 Hz, 2 H), 7.65-
7.20 (m, 15 H), 6.90 (d, J ) 4.9 Hz, 1 H), 6.55 (br d, J ) 7.3
Hz, 1 H), 6.40 (s, 1 H), 6.32-6.28 (m, 1 H), 5.82 (dd, J ) 2.5
Hz, J ) 9.5 Hz, 1 H), 5.72-5.67 (m, 2 H), 5.00 (br d, J ) 8.5
Hz, 1 H), 4.80-4.76 (m, 1 H), 4.30 (d, J ) 8.3 Hz, 1 H), 4.21
(d, J ) 8.3 Hz, 1 H), 4.00 (d, J ) 7.0 Hz,1 H), 2.85-2.75 (m, 1
H), 2.55-1.00 (m, 8 H), 2.53 (s, 3 H), 2.38 (s, 3 H), 2.09 (s, 3
H), 2.03 (s, 3 H), 1.96 (s, 3 H), 1.48 (s, 3 H), 1.47 (s, 3 H).
1-MO. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J ) 4.5 Hz, 1
H), 8.07 (d, J ) 7.5 Hz, 2 H), 7.69 (d, J ) 7.5 Hz, 1 H), 7.58-
7.00 (m, 19 H), 6.28 (s, 1 H), 6.17-6.12 (m, 1 H), 5.68-5.60
(m, 2 H), 5.56 (dd, J ) 7.2 Hz, J ) 10.4 Hz, 1 H), 5.35 (d, J )
4.3 Hz,1 H), 4.87 (br d, J ) 9.5 Hz, 1 H), 4.67-4.62 (m, 1 H),
4.26 (d, J ) 8.4 Hz,1 H), 4.14 (d, J ) 8.4 Hz, 1 H), 3.89 (d, J
) 6.9 Hz, 1 H), 3.70-3.60 (m, 5 H), 2.60-1.00 (m, 9 H), 2.51
(s, 3 H), 2.40 (s, 3 H), 2.19 (s, 3 H), 2.08 (s, 3 H), 1.93 (s, 3 H),
1.47 (s, 3 H), 1.46 (s, 3 H).
Resin 7. The above microreactors were split into 20 groups
each containing 20 microreactors. Each group was encoded
with a unique rf code (Scheme 1) and subjected to coupling
with the corresponding carboxylic acid (R1, Scheme 1) under
the following conditions: carboxylic acid (0.1 M), DIEA (0.2
M), PyBOP (0.1 M), DMF (20 mL), room temperature, 2 h;
additional carboxylic acid and PyBOP (half the previous
amounts), room temperature, 2 h. The reactions were quenched
with methanol. The 20 groups of microreactors were kept
separate, washed according to the standard procedure, and
dried under vacuum at room temperature overnight to yield
the resin-bound amides 7.
Resin 8. The above microreactors were resplit into 20 new
groups by combining one microreactor from each of the
previous groups. Each of the 20 new groups was encoded with
a unique rf code. One group, corresponding to R2 ) H, was
set aside. Each of the remaining 19 groups was then subjected
to coupling with one of the second set of carboxylic acids (R2,
Scheme 1) under the following conditions: carboxylic acid (0.4
M), 4-DMAP (0.35 M), DIC (0.4 M), CH2Cl2 (20 mL), room
temperature, 24 h; additional carboxylic acid and DIC (half
the previous amounts), room temperature, 24 h. The reactions
were quenched by the addition of methanol. The microreactors
were pooled together, washed, and dried under vacuum to
afford the desired resin-bound taxoids 8.
Ta xoid Libr a r y 1. The above 400 microreactors were
distributed into 400 glass vials (8 mL capacity). The rf code
in each Microreactor was read, and the vial was labeled with
that code. AcOH/CF3CH2OH/CH2Cl2 (2:1:7, 2 mL) was then
added into each vial. The vials were sealed and shaken at
room temperature for 4 h. The microreactors were taken out
and rinsed with methanol (1 mL/microreactor) and CH2Cl2 1
mL/microreactor). The solutions in the vials were then slowly
evaporated in a SpeedVac under carefully controlled vacuum.
The residues were then redissolved in benzene (2 mL/vial),
frozen, and lyophilized to yield 400 powders with colors
ranging from white to brown. Part of the library (20 com-
1-P K. 1H NMR (500 MHz, CDCl3) δ 9.04 (br d, J ) 4.4 Hz,
1 H), 8.76-8.72 (m, 2 H), 8.64 (d, J ) 4.5 Hz, 1 H), 8.23 (d, J
) 7.7 Hz, 1 H), 8.16 (d, J ) 7.5 Hz, 2 H), 7.92-7.70 (m, 6 H),
7.60-7.20 (m, 10 H), 6.70-6.60 (m, 1 H), 6.44 (br s, 1 H), 6.36
(s, 1 H), 6.32-6.28 (m, 1 H), 6.08 (d, J ) 15.5 Hz, 1 H), 5.91
(dd, J ) 1.7 Hz, J ) 9.3 Hz, 1 H), 5.86 (dd, J ) 7.3 Hz, J )
10.3 Hz, 1 H), 5.72-5.68 (m, 2 H), 5.02 (d, J ) 8.9 Hz, 1 H),
4.73-4.66 (m, 1 H), 4.34 (d, J ) 8.4 Hz, 1 H), 4.26 (d, J ) 8.4
Hz, 1 H), 4.06 (d, J ) 7.0 Hz, 1 H), 2.85-2.74 (m, 1 H), 2.60-
1.10 (m, 8 H), 2.49 (s, 3 H), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.97 (s,
3 H), 1.47 (s, 3 H), 1.46 (s, 3 H).
1
pounds) were analyzed by mass spectrometry and/or H NMR
Ack n ow led gm en t. We thank Professor K. C. Nico-
laou, Mr. W. Ewing, and many other IRORI colleagues
for assistance and valuable discussions. Professor K.
C. Nicolaou is an advisor to IRORI Quantum Micro-
chemistry.
spectroscopy, and the structures were confirmed to be the
desired. Selective 1H NMR data (see Table 1 for purity.
Compounds are named using the rf codes in Scheme 1 in the
format of “1-R1R2”):
1-BU. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J ) 8.02 Hz,
2 H), 7.87-7.85 (m, 1 H), 7.62-7.50 (m, 2 H), 7.53-7.7.46 (m,
2 H), 7.40-7.25 (m, 4 H), 6.40 (d, J ) 7.5 Hz, 1 H), 6.32 (s, 1
H), 6.19 (m, 1 H), 5.70-5.68 (m, 2 H), 5.70-5.60 (m, 2 H), 5.53
(dd, J ) 7.2 Hz, J ) 10.3 Hz, 1 H), 5.30 (d, J ) 3.8 Hz, 1 H),
4.94 (br d, J ) 9.3 Hz, 1 H), 4.54-4.38 (m, 1 H), 4.29 (d, J )
8.4 Hz, 1 H), 4.18 (d, J ) 8.4 Hz, 1 H), 3.91 (d, J ) 7.0 Hz, 1
H), 2.80-0.80 (m, 29 H), 2.42 (s, 3 H), 2.13 (s, 3 H), 2.08 (s, 3
H), 1.97 (s, 3 H), 1.21 (s, 3 H), 1.15 (s, 3 H), 0.94 (s, 9 H).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
intermediates (4 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9708699