M. A. Ornelas et al. / Tetrahedron Letters 52 (2011) 4760–4763
4763
Table 4
Tandem reductive amination/cyclization-SNAr reaction library
O
O
O
O
O
O
O
i
TBS
N
ii, iii
Ar
TBS
Ar
N
N
R1
R1
H2N
R1=
R1
X
O
O
N
N
N
S
N
N
e
f
d
No.
Ar
% ee
No.
Ar
N
% ee
No.
Ar
% ee
d: >99% ee
f: 95% ee
e: 99% ee
f: 58% ee
e: 91% ee
f: 73% ee
52
55
58
59
F
N
N
N
Cl
F
F
e: 94% ee
f: 78% ee
53
54
d: >99% ee
56
57
f: 63% ee
f: 62% ee
N
N
N
O
F
F
F
N
N
N
F
e: 99% ee
f: 84% ee
e: 94% ee
f: 79% ee
Cl
F
60
N
O
F
Reagents and conditions: (i) NaBH(OAc)3, DCM, rt; (ii) TBAF, THF/water, rt; (iii) Cs2CO3, MeCN, rt, 8 h.
The templates 33a–c were used for parallel synthesis involving
SNAr reactions with aryl fluorides or bromides. For the templates
bearing an O-TBS moiety on the right-hand side of the molecule,
the deprotection step was done using tetrabutyl ammonium fluo-
ride. The general reaction scheme and results for the chiral HPLC
analysis for these compounds are shown in the Table 3.
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
For the next round of synthesis; we were interested in exploring
both the left and right portions of the molecule simultaneously in a
full matrix fashion to allow us to explore both the best combinations
and to address the question of additivity for this series. For this pur-
pose, a tandem reductive amination/cyclization, SNAr reaction pro-
cedure was developed using the aryl halides and amines to give
products with the best calculated properties such as MW, c log D,
PSA, and docking scores. Table 4 summarizes the results obtained
from this library. From this data we observed the general trend seen
previously for the stepwise reactions regarding the reactivity of the
aryl halide; furthermore, the nature of the tail piece also had an ef-
fect on the erosion of the enantiomeric excess at the chiral center.
The products containing the right-hand pieces d and e showed bet-
ter ee values, whereas the moiety f -an oxygen bearing heterocycle-
showed decreased enantiopurity at the chiral center, presumably
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In conclusion, a method was developed to prepare alkoxy chiral
lactams under mild conditions starting from cheap, commercially
available (R)-pantolactone. In most cases the products were ob-
tained with general good ee (de) retention. The ee values for the
products were affected by the reactivity of the aryl halides and the
nature of the right-hand moiety. This method is amenable to parallel
synthesis and can be used to prepare diverse and highly substituted
chiral lactams with high enantiopurity that would not be accessible
by other methods, such as direct alkylation of the lactam ring.
13. HPLC analysis was carried out using a 150 Â 4.6 mm I-CH ChiralPakÒ column at
40 °C. Mobile phase A (MPA) was neat heptane while mobile phase B (MPB)
was a 1:1 methanol: ethanol mix. The gradient began at a 95:5 ratio of
MPA:MPB and was held at this level for 5 min before being increased to 30%
over 20 min at a flow rate of 2.5 mL/min. The method run-time was 30-min
with
quantization.
a
5-min re-equilibration. UV response at 254 nm was used for
injections were made directly from diluted ethanol
5 lL
solutions of approximately 1 mg/mL.
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17. After storage at 0 °C for 14 months, no decomposition of the aldehyde 32b was
observed by 1H NMR spectroscopy.
Acknowledgments
We would like to thank Jeff Elleraas for the SFC chiral purifica-
tions and Dr. Andy Myers for a very inspiring consulting session
and valuable feedback on the preparation of the manuscript.
18. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J.
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