Angewandte
Chemie
iodination. Atropo-diastereoselective Suzuki coupling with
boronate 6a followed by removal of the TES group on the
major diastereoisomer provided (S,aR)-7a in 54% yield
(entry 1). The stereochemically crucial dehydration of this
compound was first attempted under the same conditions as
the racemic mixture at 208C. This step gave 4a with 74% ee in
favor of the putative R,aR enantiomer. Gratifyingly,carrying
out the cyclization at À508C with trifluoroacetic acid (TFA)
in CH2Cl2 allowed almost complete conservation of the
optical purity (96% ee,86% yield). The R,aR absolute
configuration of the product was confirmed by the super-
imposition of its CD spectrum on that of an authentic sample
of (À)-NAC (3). Repeating the same reaction sequence from
enantiomeric (R)-5a (synthesized in 96% ee) furnished (S,
aS)-4a in 94% ee (entry 2). Introduction of another alkyl
group on the oxepine ring proved feasible,as illustrated by
the synthesis of the ethyl analogue (R,aR)-4b (entry 3). This
analogue was obtained with 95% ee from (S)-5b (98% ee).[11]
The dibenzazepine analogue (R,aR)-4c could be obtained
accordingly,starting from ( S)-5a and boronate 6b (entry 4).
In this case,a small loss of optical purity was observed
(88% ee),although the dehydration occurred at À788C.
Cleavage of the tert-butyloxycarbonyl (tBoc) group was
observed upon warming the reaction mixture to room
temperature. Finally,dibenzoxocine ( R,aR)-4d (eight-mem-
bered median ring) was synthesized with 96% ee from (S)-5a
and boronate 6c containing a homologated side chain. In this
case, L2 (S-Phos)[12] gave a better yield than L1 in the Suzuki
coupling. Compound 4d occurred as a single atropisomer in
solution,contrary to 4a,b,because of the presence of the
larger bridging ring,similar to stegane-type molecules. [3]
The stereoselectivity of the dehydrative cyclization of diol
functions as a stereochemical relay for the benzylic stereo-
center that is temporarily destroyed in intermediate A.
Additional evidence of a chiral carbocationic intermedi-
ate in the dehydrative cyclization was provided by the
reaction of the minor diastereoisomer (S,aS)-7e obtained in
a small amount after Suzuki coupling of (S)-5a with 6a and
deprotection (Scheme 3,path a). This reaction furnished
Scheme 3. Stereoconvergent syntheses of (S,aS)-4a.
(S,aS)-4a with 96% ee,most likely through the same carbo-
cationic intermediate (aS)-A as that formed from (R,aS)-7a
(path b). A third stereoconvergent pathway could be devised
for the synthesis of (S,aS)-4a (path c). When diol (S,aR)-7a,
which was previously converted into (R,aR)-4a with TFA
(Table 1,entry 1),was treated with (diethylamino)sulfur
trifluoride (DAST) in CH2Cl2 at À788C,( S,aS)-4a was
obtained as the major enantiomer in 44% ee. This result can
be best rationalized by the regioselective reaction of the
primary alcohol of 7a with DAST to give intermediate B,
followed by intramolecular SN2.[14] This reaction would
produce (S,aR)-4a,which interconverts into the more stable
atropisomer (S,aS)-4a. The loss of optical purity could be
ascribed either to incomplete regioselectivity in the reaction
of the diol with DAST or to a mixed SN2/SN1 mechanism.
The antimicrotubule activity of biaryls 4a–d was exam-
ined and compared to that of (À)-colchicine and (À)-NAC
(3). First,no activity was found for ( S,aS)-4a,as expected. The
IC50 values for the inhibition of the microtubule assembly for
the target compounds and the reference compounds were:
2.9(Æ0.7) mm for NAC (3); 8.2(Æ1.6) mm for colchicine;
12.3(Æ2.5) mm for (R, aR)-4a; 4.9(Æ0.4) mm for (R, aR)-4b;
11.1(Æ2.0) mm for (R, aR)-4d. Dibenzazepine (R,aR)-4c was
found to be inactive. Thus,all oxygen-containing analogues
were strong inhibitors of tubulin polymerization,with ( R,aR)-
4b being the most active (1.7 more active than colchi-
cine).[15]
(S,aR)-7a can be rationalized by the formation of chiral
+
benzylic cation (aR)-A,[13] in which the C H bond eclipses
À
the biaryl axis to minimize A1,3 allylic strain (Scheme 2). At
Scheme 2. Proposed cationic cyclization intermediate.
low temperature,this intermediate is configurationally stable
and trapped by the internal nucleophile,thus giving ( R,aR)-
4a with inversion of configuration at the benzylic stereocen-
ter. An atropisomerization barrier of 15 kcalmolÀ1 was
calculated for A (AM1 method),whereas the rotation barrier
+
À
of the C(Ar) C bond was significantly higher (22 kcal
molÀ1),as expected from conjugation with the aromatic
ring. This behavior indicates that the observed racemization
of (R,aR)-4a at higher temperatures might occur preferably
by atropisomerization. Overall,the biaryl axis,therefore,
In conclusion,we have reported a general and efficient
enantioselective synthesis of potent antimicrotubule biaryls
Angew. Chem. Int. Ed. 2006, 45, 4149 –4152
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4151