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M. A. Massa et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1625–1628
Most of the target compounds were easily assembled
from three simple components: an appropriately sub-
stituted benzaldehyde, 3-phenoxyaniline, and commer-
cially available 1,1,1-trifluoro-2,3-epoxypropane, of
unspecified enantiomeric composition (Scheme 1).5
Reductive amination of the benzaldehydes with 3-phe-
noxyaniline provided the secondary amines needed for
the epoxide ring opening reactions. By using Yb(OTf)3
as a catalyst6 the amine reactions with this volatile
epoxide were facilitated so that they could be performed
at lower temperature and near stoichiometry (Scheme 1,
route a). The indicated regioisomers were the only pro-
ducts detected prior to workup.
from the same commercial source, resulting in final
products as an unequal mixture of enantiomers.5 All
final products had satisfactory H NMR, HR-MS, and
microanalyses,9 and the biological evaluations were
performed on the resulting enantiomeric mixtures.
1
Several analogues of 1a were prepared in which the TFE
group was replaced in order to explore the SAR at this
position. The resulting compounds were initially asses-
sed in a buffered in vitro transfer assay (Table 1).10
Compounds having comparable potency to 1a in this
assay were also evaluated in the presence of human
serum to determine their IC50 (Table 2).11 The serum
transfer assay is presumably more representative of
their activity in the desired target tissue, human blood.
Examples of the various methods used to prepare the
substituted benzaldehydes are illustrated in Scheme 2.
The 3-(2-furyl)benzaldehydes (3a–d) were prepared from
the corresponding 3-bromobenzaldehydes by Stille cou-
pling7 with 2-(tributylstannyl)furan. Suzuki coupling8 of
the boronic acid with 2-bromopyridines allowed the pre-
paration of various 3-(2-pyridyl)benzaldehydes (3e–g).
Similarly, 2-bromopyrimidine underwentSuzuki cou-
pling to give 3-(2-pyrimidinyl)benzaldehyde, 3h. In order
to prepare 3-(1-methylpyrrol-2-yl)benzaldehyde, 3i, 2-
lithio-1-methylpyrrole was prepared in situ and then
coupled with 3-bromobenzaldehyde using Pd(II).
Since no structural data exists for CETP with or with-
out bound substrates, the rationale for changes made to
the TFE group came from molecular modeling insights.
Ab initio calculations with Gaussian 9412 predicthtat
the TFE group preferred a nearly perpendicular (ꢀ90ꢁ)
orientation to the phenyl ring in PhOCF2CF2H.13 In
contrast, PhOEt was predicted to adopt a more co-pla-
nar orientation. As a possible mimic of the TFE spatial
interaction, 2-phenyl furan was also modeled and was
shown to have a similar, energetically favorable, out of
plane orientation with a smaller torsion angle (ꢀ30ꢁ)
(Fig. 1).14,15 Substitutions in the 4-position of the benzyl
ring combined with the 2-furyl ring were explored to
provide a more perpendicular torsion angle.
In the cases where R=pyridyl in compound 4, t he
epoxide reaction proceeded poorly, possibly due to
competition from the basic nitrogen in the pyridine ring.
This difficulty was avoided if the epoxide was first
opened with the aniline to give intermediate 5 followed
by reductive amination with the appropriately sub-
stituted pyridyl-benzaldehyde (Scheme 1, route b).
The resulting 2-furyl substitution product, 2a, displayed
submicromolar activity as a CETP inhibitor. However,
the introduction of additional substituents at the 4-
position of the benzylic group led to decreased potency
as the size of the substituent increased (IC50
R=H<F<CH3<N-morpholino). All of the 2-pyridyl
substitutions (2e–g) showed significantloss of poetncy.
Since the least basic compound, 2g, exhibited the most
potency in this series, it is likely that substituents with
hydrogen-bond accepting character are disfavored at
this position. In addition, comparison of 2e, 2m, and 2n
as the 2-, 3-, and 4-pyridyl substituents showed the 4-
pyridyl, 2n, to be the most potent suggesting that a basic
An alternative, more convergent method utilized the
(tertiaryamino)propanol, 6, having a 3-bromo sub-
stituent on the benzylic group. Intermediate 6 under-
went Pd-catalyzed cross-coupling with aryl Grignard
reagents or heteroaryl stannanes to give the desired final
products (Scheme 1, route c).
All of the amino alcohol products were obtained from
the ring opening of 1,1,1-trifluoro-2,3-epoxypropane
Scheme 1. Synthesis of trifluoro-3-(tertiaryamino)-2-propanols. Reaction conditions: (a) 3-phenoxyaniline, NaBH(OAc)3, AcOH, 1,2-dichloro-
ethane, rt; (b) 1,1,1-trifluoroepoxypropane, Yb(CF3SO3)3, CH3CN, 50 ꢁC, 2 h; (c) 1,1,1-trifluoroepoxypropane, neat, 100 ꢁC, 18 h; (d) 3,
NaBH(OAc)3, AcOH, 1,2-dichloroethane, rt; (e) ArMgBr, Pd(PPh3)4, THF, reflux, 18 h or HetSnBu3, Pd(PPh3)2Cl2, dioxane, reflux, 18 h. R and
R0 defined in Table 1.