Synthetic approaches to amino analogues of N-acetylcolchinol

Article abstract of DOI:10.1021/jo900632a

(Chemical Equation Presented) A straightforward synthesis of aminodibenzoxepines, new analogues of N-acetylcolchinol, is reported by using two different strategies. The first strategy involves a Grignard addition, a biaryl Suzuki-Miyaura coupling, and a H

Full text of DOI:10.1021/jo900632a

Synthetic Approaches to Amino Analogues of N-Acetylcolchinol
Virginie Colombel and Olivier Baudoin*
UniVersite´ Lyon 1, CNRS UMR5246, Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires,
43 BouleVard du 11 NoVembre 1918, 69622 Villeurbanne, France
oliVier.baudoin@uniV-lyon1.fr
ReceiVed March 25, 2009
A straightforward synthesis of aminodibenzoxepines, new analogues of N-acetylcolchinol, is reported by
using two different strategies. The first strategy involves a Grignard addition, a biaryl Suzuki-Miyaura
coupling, and a HF-mediated cyclodehydration as key steps. A second strategy, better adapted to the
synthesis of analogues bearing a benzylic substituent, was designed by inverting the order of the Grignard
addition and the biaryl coupling. This allowed the rapid and reliable production of a series of substituted
aminodibenzoxepines. A chelate model was proposed to account for the diastereoselectivity observed in
the Grignard addition step.
CHART 1
Introduction
Vascular-disrupting agents (VDAs) are promising anticancer
molecules which act by damaging existing tumor vasculature.1
Among VDAs, compounds that bind to tubulin at the colchicine
or vinblastin site and cause microtubule depolymerization
showed promising in vitro and in vivo activities.2 In particular,
two series of prodrugs of molecules that bind to the colchicine
site have undergone clinical trials (Chart 1): prodrugs of the
natural products combretastatin A-1 and A-4 (1-3) and the
allocolchicinoid ZD6126 (4), a prodrug of N-acetylcolchinol
(NAC, 5).3
Whereas the development of combretastatin analogues as
VDAs has been the subject of extensive research in the past
(1) (a) Thorpe, P. E. Clin. Cancer Res. 2004, 10, 415. (b) Don˜ate, F. Drugs
Future 2005, 30, 695. (c) Gaya, A. M.; Rustin, G. J. S. Clin. Oncol. 2005, 17,
277. (d) Tozer, G. M.; Kanthou, C.; Baguley, B. C. Nat. ReV. Cancer 2005, 5,
423. (e) Pilat, M. J.; LoRusso, P. M. J. Cell. Biochem. 2006, 99, 1021. (f) Lippert,
J. W., III. Bioorg. Med. Chem. 2007, 15, 605.
(2) Lee, R. M.; Gewirtz, D. A. Drug DeVelop. Res. 2008, 69, 352.
(3) (a) Davis, P. D.; Dougherty, G. J.; Blakey, D. C.; Galbraith, S. M.; Tozer,
G. M.; Holder, A. L.; Naylor, M. A.; Nolan, J.; Stratford, M. R. L.; Chaplin,
D. J.; Hill, S. A. Cancer Res. 2002, 62, 7247. (b) Micheletti, G.; Poli, M.; Borsotti,
P.; Martinelli, M.; Imberti, B.; Taraboletti, G.; Giavazzi, R. Cancer Res. 2003,
63, 1534.
(4) (a) Tozer, G. M.; Kanthou, C.; Parkins, C. S.; Hill, S. A. Int. J. Exp.
Pathol. 2002, 83, 21. (b) Nam, N.-H. Curr. Med. Chem. 2003, 10, 1697. (c)
Cirla, A.; Mann, J. Nat. Prod. Rep. 2003, 20, 558. (d) Tron, G. C.; Pirali, T.;
Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A. A. J. Med. Chem. 2006, 49,
3033.
few years,4 allocolchicinoid-type molecules have attracted much
less attention. This is probably due to synthetic issues, as
allocolchicinoids are less readily available than combretastatin
10.1021/jo900632a CCC: $40.75
Published on Web 05/07/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4329–4335 4329

Colombel and Baudoin
SCHEME 1
analogues. NAC (5) itself is derived from colchicine by
semisynthesis,5 a synthetic procedure that intrinsically delivers
a limited number of analogues.6,7 Short and efficient total
syntheses of allocolchicinoids that allow the introduction of a
variety of functional groups on different parts of the molecule
are therefore highly desirable in this context.8 We recently
reported on the racemic and enantioselective synthesis of
analogues of NAC having a heterocyclic medium ring (6).9 The
most active analogues (R1 ) H or Et, R2 ) Me, R3 ) H, X )
O, n ) 1) showed activity profiles similar to that of NAC in
various in vitro assays.9c To further increase the potency and
at the same time improve the bioavailability of these molecules,
we decided to synthesize the new aminodibenzoxepine ana-
logues 7. The amino group was chosen to improve the
bioavailability by analogy with combretastatin analogues.10 In
addition, preliminary molecular modeling studies11 indicated that
compounds 7 with benzylic substituents (R) of various size could
be well accommodated within the colchicine binding pocket of
tubulin.12
Our retrosynthetic analysis of the target aminodibenzoxepines
7 is depicted in Scheme 1. Following our previous reports,9 7
would arise from polyfunctionalized biphenyls 8 by deprotection
and cyclodehydration. Whereas dibenzoxepines such as 7 exist
as conformational mixtures of aR and aS atropisomers due to
the presence of the 7-membered bridging ring, biphenyls 8
contain two stereogenic elements, i.e., the benzylic stereocenter
and the biaryl axis, since there is a much higher rotational barrier
in a nonbridged triortho-substituted biaryl system.9,13 Biphenyls
8 would arise from iodides 9 by Suzuki-Miyaura coupling with
boronate 10 as previously described (route a). We have shown
that this coupling occurs with moderate to good atropo-
diastereoselectivity depending on the size of the R group (R )
alkyl).9,13,14 However, both diastereoisomers were converted to
the racemic dibenzoxepines (6, X ) O, n ) 1, Chart 1) by
cyclodehydration due to the absence of the stereogenic character
of the biaryl axis in these bridged biaryls. In turn, iodides 9
would arise from aldehyde 11 by Grignard reaction followed
by regioselective iodination. Even though this synthetic route
proved applicable to a number of allocolchicinoids 6, we were
concerned about the early introduction of the R benzylic
substituent, which is little compatible with diversity-oriented
synthesis purposes. In addition, we have shown that the yield
and diastereoselectivity of the biaryl coupling from iodoarenes
such as 9 rapidly decrease with increasing sizes of the R alkyl
group.9c We thus considered an alternative pathway (route b,
(5) (a) Cech, J.; Santavy, F. Collect. Czech. Chem. Commun. 1949, 14, 532.
(b) Dougherty, G. Angiogene Pharmaceuticals Ltd., patent WO 9902166, 1999.
(6) (a) Shi, Q.; Chen, K.; Morris-Natschke, S. L.; Lee, K.-H. Curr. Pharm.
Design 1998, 4, 219. (b) Baudoin, O.; Gue´ritte, F. In Studies in Natural Product
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The Netherlands, 2003;
Vol. 29, pp 355-417.
(7) Recent semi-syntheses: (a) Bergemann, S.; Brecht, R.; Bu¨ttner, F.;
Guénard, D.; Gust, R.; Seitz, G.; Stubbs, M. T.; Thoret, S. Bioorg. Med. Chem.
2003, 11, 1269. (b) Bu¨ttner, F.; Bergemann, S.; Gue´nard, D.; Gust, R.; Seitz,
G.; Thoret, S. Bioorg. Med. Chem. 2005, 13, 3497. (c) Nakagawa-Goto, K.;
Jung, M. K.; Hamel, E.; Wu, C.-C.; Bastow, K. F.; Brossi, A.; Ohta, S.; Lee,
K.-H. Heterocycles 2005, 65, 541.
(8) Recent total syntheses: (a) Vorogushin, A. V.; Wulff, W. D.; Hansen,
H.-J. J. Am. Chem. Soc. 2002, 124, 6512. (b) Vorogushin, A. V.; Predeus, A. V.;
Wulff, W. D.; Hansen, H.-J. J. Org. Chem. 2003, 68, 5826. (c) Vorogushin,
A. V.; Wulff, W. D.; Hansen, H.-J. J. Org. Chem. 2003, 68, 9618. (d) Leblanc,
M.; Fagnou, K. Org. Lett. 2005, 7, 2849. (e) Wu, T. R.; Chong, J. M. Org. Lett.
2006, 8, 15. (f) Besong, G.; Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle,
F. T. Org. Biomol. Chem. 2006, 4, 2193. (g) Seganish, W. M.; DeShong, P.
Org. Lett. 2006, 8, 3951. (h) Boyer, F.-D.; Hanna, I. Org. Lett. 2007, 9, 715. (i)
Broady, S. D.; Golden, M. D.; Leonard, J.; Muir, J. C.; Maudet, M. Tetrahedron
Lett. 2007, 48, 4627. (j) Djurdjevic, S.; Green, J. R. Org. Lett. 2007, 9, 5505.
(k) Vorogushin, A. V.; Wulff, W. D.; Hansen, H.-J. Tetrahedron 2008, 64, 949.
(l) Besong, G.; Billen, D.; Dager, I.; Kocienski, P.; Sliwinski, E.; Tai, L. R.;
Boyle, F. T. Tetrahedron 2008, 64, 4700. (m) Boyer, F.-D.; Le Goff, X.; Hanna,
I. J. Org. Chem. 2008, 73, 5163. (n) Boyer, F.-D.; Hanna, I. Eur. J. Org. Chem.
2008, 4938. (o) Nicolaus, N.; Strauss, S.; Neudo¨rfl, J.-M.; Prokop, A.; Schmalz,
H.-G. Org. Lett. 2009, 11, 341.
(10) Ohsumi, K.; Nakagawa, R.; Fukuda, Y.; Hatanaka, T.; Morinaga, Y.;
Nihei, Y.; Ohishi, K.; Suga, Y.; Akiyama, Y.; Tsuji, T. J. Med. Chem. 1998,
41, 3022.
(11) Joncour, A. Ph. D. Dissertation, University of Paris 11 Orsay, 2006.
(12) (a) Ravelli, R. B. G.; Gigant, B.; Curmi, P. A.; Jourdain, I.; Lachkar,
S.; Sobel, A.; Knossow, M. Nature 2004, 428, 198. (b) Nguyen, T. L.; McGrath,
C.; Hermone, A. R.; Burnett, J. C.; Zaharevitz, D. W.; Day, B. W.; Wipf, P.;
Hamel, E.; Gussio, R. J. Med. Chem. 2005, 48, 6107.
(9) (a) Joncour, A.; De´cor, A.; Thoret, S.; Chiaroni, A.; Baudoin, O. Angew.
Chem., Int. Ed. 2006, 45, 4149. (b) Joncour, A.; De´cor, A.; Liu, J.-M.; Tran
Huu Dau, M.-E.; Baudoin, O. Chem.sEur. J. 2007, 13, 5450. (c) Joncour, A.;
Liu, J.-M.; De´cor, A.; Thoret, S.; Wdzieczak-Bakala, J.; Bignon, J.; Baudoin,
O. ChemMedChem 2008, 3, 1731.
(13) Baudoin, O.; De´cor, A.; Cesario, M.; Gue´ritte, F. Synlett 2003, 2009.
(14) Review: (a) Baudoin, O. Eur. J. Org. Chem. 2005, 4223. For a related
method see: (b) Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5, 3281. (c) Broutin,
P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113. (d) Broutin, P.-E.; Colobert,
F. Org. Lett. 2005, 7, 3737.
4330 J. Org. Chem. Vol. 74, No. 11, 2009

Amino Analogues of N-Acetylcolchinol
SCHEME 2a
SCHEME 3a
a Reaction conditions: (a) AcCl, MeOH, reflux (99%); (b) CDI (2.0
equiv), Et3N (1.0 equiv), CH2Cl2, reflux (70%); (c) Boc2O (1.05 equiv),
Et3N (2.0 equiv), DMAP (0.1 equiv), THF, 20 °C (95%); (d) Cs2CO3 (0.5
equiv), MeOH, 20 °C (71%); (e) MeI (3.0 equiv), K2CO3 (3.0 equiv),
CH3CN, 20 °C (91%); (f) DIBALH (4.0 equiv), THF, -78 °C (73%); (g)
I2 (1.0 equiv), CF3CO2Ag (1.0 equiv), CHCl3, 0 °C (65%); (h) TPAP (0.02
equiv), NMO (1.5 equiv), CH2Cl2, 20 °C (96%); (i) MeMgBr (3.0 equiv),
THF, -78 °C (79%); (j) I2 (1.05 equiv), CF3CO2Ag (1.1 equiv), CHCl3, 0
°C (81%). CDI ) 1,1′-carbonyldiimidazole, TPAP ) tetrapropylammonium
perruthenate.
a Reaction conditions: (a) Pd(OAc)2 (5 mol %), S-Phos (10 mol %),
Ba(OH)2 ·8H2O (1.1 equiv), dioxane/H2O (9:1, c ) 0.3 M); (b) ClC(O)p-
NO2Ph (1.1 equiv), Et3N (3.0 equiv), DMAP (0.3 equiv), CH2Cl2, 0 °C
(48%); (c) TBAF (1.1 equiv), THF, 20 °C (53%).
Scheme 1) where biphenyl 8 would arise from aldehyde 12 by
Grignard addition, and 12 would be obtained by Suzuki-Miyaura
coupling of iodide 9a and boronate 10 followed by oxidation.
Moreover, this new route raised an interesting question on the
diastereoselectivity of the Grignard addition with regard to the
previous route a. In this paper, we report on the synthesis of
various aminodibenzoxepines 7 by route b, and address these
diastereoselectivity issues by comparison with route a.
FIGURE 1. Solution (left) and solid-state (right) structures of biaryls
8ba and 17 from NOESY experiments and X-ray diffraction analysis
(30% probability ellipsoids plot, most H atoms were omitted for clarity),
respectively.
Results and Discussion
1. Comparison of Pathways a and b. For the purpose of
comparing routes a and b (Scheme 1), the two iodoarene
precursors 9a and 9b (i.e., 9 with R ) Me) were synthesized
from the common primary alcohol precursor 16 (Scheme 2).
The synthesis commenced with the esterification of com-
mercially available carboxylic acid 13,15 followed by formation
of a cyclic carbamate with CDI, which gave ester 14 in 69%
overall yield. Ester 14 was converted to the orthogonally
functionalized phenol 15 by installation of a Boc group on the
carbamate nitrogen and selective cleavage of the cyclic car-
bamate with methanolic cesium carbonate (67% yield for two
steps).16 The methylation of phenol 15, followed by the
reduction of the ester group with DIBALH furnished the pivotal
alcohol 16 in 66% yield from 15 and 31% overall yield from
13. Iodide 9a was obtained in 65% yield by regioselective
iodination of 16 with use of I2/CF3CO2Ag.17 The competitive
oxidation of the primary alcohol could account for this
somewhat moderate yield. On the other hand, iodide 9b was
obtained in three steps, 61% overall yield from 16 by Ley’s
oxidation,18 reaction with methylmagnesium bromide, and
regioselective iodination.
First, route a (Scheme 1) was investigated with use of
iodoarene 9b. The cross-coupling of 9b and boronate 109 was
performed under conditions previously optimized in our labora-
tory, using Buchwald’s S-Phos19 as palladium ligand and barium
hydroxide as the base (Scheme 3).9 The two separable diaste-
reoisomeric biaryls 8ba and 8bb were isolated in 58% combined
1
yield, and H NMR analysis of the crude mixture allowed to
measure a 85:15 ratio of 8ba/8bb. The relative configuration
of 8ba and 8bb was ascribed to S,aR and R,aR, respectively,
by NOESY experiments (see Figure 1 for typical correlations
observed with 8ba). The level and sense of the diastereoselec-
tivity observed in the present biaryl coupling are in agreement
with those observed on analogous systems.9
To confirm the above stereochemical attribution, 8ba was
converted to p-nitrobenzoate 17 (Scheme 3), which furnished
(15) Hone, N. D.; Salter, J. I.; Reader, J. C. Tetrahedron Lett. 2003, 44,
8169.
(16) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185.
(17) Wilson, C. V.; Janssen, D. E. Organic Syntheses; J. Wiley & Sons:
New York, 1963; Collect. Vol. IV, p 547
(18) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625.
(19) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
J. Org. Chem. Vol. 74, No. 11, 2009 4331

Colombel and Baudoin
SCHEME 4a
a Reaction conditions: (a) Pd(OAc)2 (5 mol %), S-Phos (10 mol %), Ba(OH)2 ·8H2O (1.1 equiv), dioxane/H2O (9:1, c ) 0.5 M) (63%); (b) TPAP (0.02
equiv), NMO (3.0 equiv), CH2Cl2, 20 °C (75%); (c) BrMgR (3.0 equiv), THF, -78 °C (see Table 1); (d) aq HF, CH3CN, 20 °C (see Table 1); (e) 5% Pd/C,
H2 (1 atm), EtOH, 50 °C, 12 h (72% for 7f, 90% for 7g).
TABLE 1. Addition of Grignard Reagents (BrMgR) to Aldehyde
12 and Cyclodehydrationa
major product. Relative configurations were ascribed by NOESY
experiments in a similar manner to 8ba and 8bb and by
1
Grignard addition
cyclodehydration
comparison of H chemical shifts, which were very similar in
products yield (%)b
drc
product yield (%)d
the same series of diastereoisomers. The reaction diastereose-
lectivity proved remarkably similar regardless of the structure
of the Grignard reagent (entries 1-4). The addition of alkyl
entry
R
1
2
3
4
5
Me
CHdCH2
CH2sCHdCH2 8da, 8db
Ph
H
8ba, 8bb
8ca, 8cb
66
86
66
57
87:13
86:14
87:13
87:13
7b
7c
7d
7e
7a
66
70
88
67
79
n
Grignard reagents possessing a ꢀ-hydrogen (e.g., R ) Et, Pr)
8ea, 8eb
proved troublesome due to the formation of significant amounts
of the reduction product (8a). Thus, dibenzoxepines bearing
linear alkyl groups (7f,g) were obtained by a different approach
(vide infra).
a Reaction conditions: see Scheme 4. b Combined yield of isolated
diastereoisomers. c Measured by 1H NMR spectroscopic analysis of the
crude mixture. d Yield of isolated products.
By comparing the relative configuration of diastereoisomers
8ba and 8bb obtained by the two different synthetic routes
(Schemes 3 and 4), it appears that the diastereoselectivity is
comparable and in favor of the same major diastereoisomer
(8ba). This result is fortuitous, and it was checked that 8ba
and 8bb do not interconvert by atropisomerization below 100
°C, the temperature of the biaryl coupling, as it was observed
before on related biaryls.9 The stereochemical outcome of the
Suzuki-Miyaura coupling of iodide 9b and boronate 10 might
be explained by using the three-element model reported for
similar systems.9b In contrast, the diastereoselectivity of the
Grignard addition to aldehyde 12 deserves a more detailed
analysis. Diastereoselective additions of organometallic reagents
to o-biphenyl aldehydes have been reported before,20 but to the
best of our knowledge the stereoselectivity has never been
rationalized. The C(Ar)-C(O)H bond of compound 12 is
expected to adopt two favorable s-trans and s-cis conformations
(Scheme 5). In the absence of Grignard reagent, the s-trans
conformation should prevail due to the minimization of A1,3
allylic strain (model A).9b The attack of a Grignard reagent such
as MeMgBr should occur on the less hindered si face of the
aldehyde due to the steric repulsion by the silyl group. This
crystals suitable for X-ray diffraction analysis (Figure 1). In
the crystal, the two aryl rings adopt a nearly perpendicular
orientation (biaryl torsion angle: ca. 76°) and the C-H bond of
the benzylic stereocenter adopts an eclipsed A1,3 conformation,
which is probably a consequence of the minimization of allylic
strain. The S,aR relative configuration of the stereogenic center
and axis can be deduced from this structure, which is in
agreement with the NMR attribution.
Route b commenced with the cross-coupling of iodide 9a
with boronate 10 (Scheme 4) which, under the same conditions
as above with 9b and 10, provided biaryl 8a in 63% yield.
Oxidation of 8a with TPAP and NMO provided aldehyde 12
in 75% yield. The addition of excess methylmagnesium bromide
to 12 furnished a 87:13 diastereoisomeric mixture of 8ba and
8bb in 66% combined yield (Scheme 4, step c, and Table 1,
entry 1). The overall yield of the 8ba,8bb mixture from alcohol
16 was 35% via route a and 20% via route b. Thus route a is
slightly more efficient than route b for the synthesis of biaryls
8ba and 8bb, whereas both routes show an almost identical
diastereoselectivity (8ba/8bb).
2. Addition of Other Grignard Reagents. The addition of
other Grignard reagents to aldehyde 12 was next examined
(Table 1, entries 2-4). In all cases a mixture of S,aR and R,aR
diastereoisomers was obtained, with the former being again the
(20) (a) Uemura, M.; Daimon, A.; Hayashi, Y. J. Chem. Soc., Chem.
Commun. 1995, 1943. (b) Abe, H.; Takeda, S.; Fujita, T.; Nishioka, K.; Takeuchi,
Y.; Harayama, T. Tetrahedron Lett. 2004, 45, 2327. (c) Singidi, R. R.; RajanBabu,
T. V. Org. Lett. 2008, 10, 3351.
4332 J. Org. Chem. Vol. 74, No. 11, 2009

Amino Analogues of N-Acetylcolchinol
SCHEME 5. Proposed Models for the Grignard Addition to
Aldehyde 12
In contrast to their cyclodehydration precursors, substituted
dibenzoxepines 7b-g occur as conformational mixtures of two
interconverting atropisomers (Scheme 6), as evidenced by the
presence of exchange correlations on NOESY spectra. The ratio
of conformers ranged from 87:13 for 7c to 98:2 for 7b, and the
major conformer had the R,aR relative configuration as evi-
denced by long-distance correlations on NOESY spectra (see
Scheme 6 for 7b), and as observed before with other analogues.9
All dibenzoxepines 7a-g could be converted to the more
hydrosoluble hydrochlorides upon treatment with dry HCl in
diethyl ether. Biological evaluations of these new analogues of
N-acetylcolchinol analogues will be reported separately.
In conclusion, we reported a straightforward synthesis of new
aminodibenzoxepines using two different strategies. The first
strategy, in line with our previous reports, involved a Grignard
addition, a biaryl Suzuki-Miyaura coupling, and a cyclodehy-
dration as key steps. An alternative strategy was designed by
inverting the order of the Grignard addition and the biaryl
coupling, which allowed the rapid production of a series of
substituted dibenzoxepines 7a-g. A chelate model was proposed
to account for the diastereoselectivity observed in the Grignard
addition step. The target dibenzoxepines are potential analogues
of N-acetylcolchinol, and their evaluation as new vascular-
disrupting agents will be reported in due course.
would furnish the S,aS/R,aR diastereoisomer 8bb, which is the
minor diastereoisomer observed experimentally. Alternatively,
the s-cis conformation of 12 could be favored by chelation of
magnesium by the oxygen atoms of the aldehyde and of the
neighboring methoxy group (model B).21 Using this chelate
model, the attack of the Grignard reagent should occur this time
on the more accessible re face of the aldehyde, which would
give the major R,aS/S,aR diastereoisomer 8ba. Experimentally,
it was observed that an excess of Grignard reagent was necessary
for a complete conversion, which might be in favor of the
chelate model B.
3. Synthesis of Target Dibenzoxepines 7a-g. Dibenzox-
epine 7a, deprived of benzylic substituent (R), was first
synthesized from alcohol 8a (Scheme 4). Treating 8a with 50%
aq HF effected three operations in a single pot: cleavage of TES
and Boc groups and cyclodehydration to form the oxepine ring.
This process, which was developed before with a triisopropyl-
silyl ether instead of the Boc-carbamate,9c furnished 7a in 79%
yield (Table 1, entry 5). The same method was applied to obtain
dibenzoxepines 7b-e (Table 1, last column, entries 1-4). As
illustrated with 7b (Scheme 6), both S,aR and R,aR diastereoi-
somers of the same biaryl precursor (in this case 8ba and 8bb)
furnish the same dibenzoxepine upon treatment with aq HF,
since the cyclodehydration proceeds via the same carbocationic
intermediate 18 (Scheme 6).9 Thus, depending on the ease of
purification after the Grignard addition step, the diastereoiso-
meric mixture or the isolated diastereoisomers can be employed
in the cyclodehydration. For the sake of comparison, yields
indicated in Table 1 were obtained starting from the isolated
major S,aR diastereoisomers 8ba-8ea. These yields ranged from
66% for 8ba to 88% for 8da. Dibenzoxepines 7c and 7d were
then hydrogenated to give the ethyl and n-propyl-substituted
analogues 7f and 7g, respectively, in good yield (Scheme 4,
step e). Because the reaction of ethyl and n-propylmagnesium
bromide with aldehyde 12 failed to give the addition products,
this sequence provided a less direct but more reliable method
to obtain dibenzoxepines 7f,g.
Experimental Section
tert-Butyl [2-Hydroxymethyl-2′,3′,4′,5-tetramethoxy-6′-(trieth-
ylsilyloxymethyl)biphenyl-4-yl]carbamate (8a). A sealed tube was
charged with iodoarene 9a (3.00 g, 7.91 mmol), aryl boronate 10
(5.20 g, 11.9 mmol), Pd(OAc)2 (266 mg, 0.40 mmol), S-Phos (325
mg, 0.79 mmol), Ba(OH)2 ·8H2O (2.75 g, 8.7 mmol), and dioxane/
water (9:1; [9a] ) 0.5 M). The tube was sealed and placed in an
oil bath preheated at 100 °C and stirred for 2.5 h. After cooling to
room temperature, the reaction mixture was filtered through Celite
and MgSO4. The residue was purified by flash chromatography
(silica gel, cyclohexane/EtOAc 93:7) to give alcohol 8a as an oil
(2,79 g, 4.98 mmol, 63%). 1H NMR (300 MHz, CDCl3) δ 8.29 (s,
1H), 7.11 (s, 1H), 7.60 (s, 1H), 6.60 (s, 1H), 4.37 (d, J ) 13.5 Hz,
1H), 4.23 (d, J ) 13.5 Hz, 1H), 4.23 (s, 2H), 3.91 (s, 3H), 3.88 (s,
3H), 3.81 (s, 3H), 3.56 (s, 3H), 2.82 (s, 1H), 1.54 (s, 9H), 0.91 (t,
J ) 7.7 Hz, 9H), 0.56 (q, J ) 7.7 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 153.1, 152.8, 150.9, 146.9, 141.1, 135.2, 133.0, 128.7,
127.9, 125.3, 119.5, 117.7, 111.8, 106.9, 63.8, 62.5, 61.3, 61.2,
56.0 (2C), 28.5 (3C), 6.8 (3C), 4.4 (3C); IR (neat) ν 3439, 2925,
2874, 1729, 1491, 1048 cm-1; HRMS (ESI) calcd for C29H45-
NNaO8Si+ [(MNa+)] 586.2812, found 586.2813.
tert-Butyl [2-Formyl-2′,3′,4′-trimethoxy-6′-(triethylsilyloxymeth-
yl)biphenyl-4-yl]carbamate (12). Tetrapropylammonium perruth-
enate (3.74 mg, 0.011 mmol) and N-methylmorpholine N-oxide (187
mg, 1.59 mmol) were added to a solution of alcohol 8a (300 mg,
0.53 mmol) in CH2Cl2 at 20 °C, under argon. The mixture was
stirred at room temperature for 2 h. Water was added, then the
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with a 1 N aq solution of HCl, dried over
MgSO4, filtered, and evaporated under vacuum. The residue was
purified by filtration through a short pad of silica (cyclohexane/
EtOAc 85:15) to give aldehyde 12 as an oil (240 mg, 80%), which
1
was used directly in the next step. H NMR (300 MHz, CDCl3) δ
9.60 (s, 1H), 8.69 (s, 1H), 7.10 (s, 1H), 6.97 (s, 1H), 6.66 (s, 1H),
4.31 (d, J ) 12.9 Hz, 1H), 4.23 (d, J ) 12.9 Hz, 1H), 3.93 (s, 3H),
3.90 (s, 3H), 3.88 (s, 3H), 3.57 (s, 3H), 1.52 (s, 9H), 0.87 (t, J )
8.6 Hz, 9H), 0.52 (q, J ) 8.6 Hz, 6H); IR (neat) ν 3438, 1730,
1684, 1525, 1488, 1458 cm-1; HRMS (ESI) calcd for C29H43-
NNaO8Si+ [(MNa+)] 584.2656, found 584.2655.
(21) The coordination of magnesium by o-methoxy groups is involved in
Meyers’ oxazoline biaryl coupling method: (a) Meyers, A. I.; Nelson, T. D.;
Moorlag, H.; Rawson, D. J.; Meier, A. Tetrahedron 2004, 60, 4459. (b) Meyers,
A. I. J. Org. Chem. 2005, 70, 6137.
General Procedure for Grignard Addition to Aldehyde 12. A
solution of magnesium bromide was added dropwise to a solution
J. Org. Chem. Vol. 74, No. 11, 2009 4333

Colombel and Baudoin
SCHEME 6. Cyclodehydration of Biaryls 8ba and 8bb
of aldehyde 12 in THF at -78 °C, under argon. The mixture was
stirred at -78 °C and then allowed to warm to room temperature
for 1-5 h. A saturated aq solution of NH4Cl was added, and the
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
evaporated under vacuum. The resulting mixture was purified by
flash chromatography, using cyclohexane and ethyl acetate as the
eluents.
cautiously poured into a saturated aq solution of NaHCO3 and the
aqueous layer was extracted with EtOAc. The combined organic
layers were dried over MgSO4 and evaporated under vacuum. The
resulting mixture was purified by flash chromatography, using
cyclohexane and ethyl acetate as the eluents.
(()-2,9,10,11-Tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-3-
amine (7a). The cyclodehydratation of alcohol 8a was performed
according to the general procedure, starting from aq HF (1.13 mL)
and compound 8a (50 mg, 0.09 mmol) in CH3CN (5.7 mL). After
flash chromatography (silica gel, cyclohexane/EtOAc 3:1), com-
(()-tert-Butyl [2-(1-Hydroxyethyl)-2′,3′,4′,5-tetramethoxy-6′-(tri-
ethylsilyloxymethyl)biphenyl-4-yl]carbamate (8ba, 8bb). The ad-
dition of methylmagnesium bromide to aldehyde 12 was performed
according to the general procedure, starting from methylmagnesium
bromide (3 M in diethyl ether, 0.27 mL, 0.81 mmol) and aldehyde
12 (150 mg, 0.27 mmol) in THF (6 mL) at -78 °C for 5 h. After
flash chromatography (silica gel, cyclohexane/EtOAc 93:7 then 91:
9), alcohols 8ba and 8bb were isolated as colorless oils (total mass
101 mg, 66%, diastereoisomeric ratio 87:13). Major diastereoisomer
1
pound 7a was isolated as a colorless oil (23 mg, 79%). H NMR
(300 MHz, CDCl3) δ 7.20 (s, 1H), 6.76 (s, 1H), 6.75 (s, 1H), 4.35
(s, 1H), 4.07 (s, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.90 (s, 3H), 3.64
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.5, 150.5, 147.0, 142.7,
135.8, 131.5, 128.5, 127.2, 115.7, 111.7, 108.9, 67.7, 67.3, 61.3,
60.8, 56.2, 55.8; IR (neat) ν 3458, 2930, 1621, 1458, 1124 cm-1
;
HRMS (CI) calcd for C18H22NO5 [(MH+)] 332.1498, found
332.1495.
+
1
8ba: H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.10 (s, 1H),
7.03 (s, 1H), 6.55 (s, 1H), 4.45 (q, J ) 7.1 Hz, 1H), 4.03 (d, J )
13.3 Hz, 1H), 4.15 (d, J ) 13.3 Hz, 1H), 3.91 (s, 3H), 3.88 (s,
3H), 3.80 (s, 3H), 3.54 (s, 3H), 2.97 (s, 1H), 1.39 (d, J ) 7.1 Hz,
3H), 0.91 (t, J ) 7.7 Hz, 9H), 0.57 (q, J ) 7.7 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 153.1, 152.7, 150.5, 146.6, 140.9, 136.8, 135.4,
128.3, 127.6, 124.9, 115.3, 111.5, 106.3, 80.5, 66.7, 62.4, 61.3,
61.2, 56.0, 55.9, 28.5 (3C), 22.1, 6.9 (3C), 4.5 (3C); IR (neat) ν
3448, 2931, 1732, 1616, 1593, 1397 cm-1; HRMS (ESI) calcd for
C30H47NNaO8Si+ [(MNa+)] 600.2969, found 600.2968. Minor
diastereoisomer 8bb: 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H),
7.09 (s, 1H), 6.87 (s, 1H), 6.52 (s, 1H), 4.50 (q, J ) 6.6 Hz, 1H),
4.29 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.80 (s, 3H), 3.61 (s,
3H), 1.55 (s, 9H), 1.40 (d, J ) 6.6 Hz, 3H), 0.89 (t, J ) 8.1 Hz,
9H), 0.60 (q, J ) 8.1 Hz, 6H).
Compounds 8ba and 8bb were also obtained by Suzuki-Miyaura
coupling in the same manner as above for 8a, starting from
iodoarene 9b (120 mg, 0.30 mmol), aryl boronate 10 (200 mg, 0.46
mmol), Pd(OAc)2 (10 mg, 0.01 mmol), S-Phos (12 mg, 0.03 mmol),
Ba(OH)2 ·8H2O (106 mg, 0.33 mmol), and dioxane/water (9:1; [9b]
) 0.3 M). After flash chromatography (silica gel, cyclohexane/
EtOAc 93:7), alcohols 8ba and 8bb were isolated as oils (total
mass 101 mg, 58%, diastereomeric ratio 85:15).
(()-5-Ethyl-2,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]ox-
epin-3-amine (7f). To a solution of dibenzoxepine 7c (13 mg, 0.04
mmol) in EtOH at 20 °C under argon atmosphere was added Pd/C
(7.5 mg, 0.5 wt equiv). Then H2 was bubbled into the reaction
mixture for 5 min and the reaction mixture was stirred at 50 °C
under H2 atmosphere overnight. The reaction mixture was filtered
through a short pad of Celite and evaporated under reduced pressure.
The residue was purified by flash chromatography (silica gel,
cyclohexane/EtOAc 89:11) to give compound 7f as an oil (9.4 mg,
72%, conformer ratio 88:12). Major conformer: 1H NMR (300 MHz,
CDCl3) δ 7.14 (s, 1H), 6.81 (s, 1H), 6.74 (s, 1H), 4.36 (d, J )
11.2 Hz, 1H), 3.98-3.87 (m, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.89
(s, 3H), 3.66 (s, 3H), 1.97 (quint, J ) 7.6 Hz, 1H), 0.95 (t, J ) 7.6
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 152.6, 150.5, 146.5, 142.7,
135.7, 131.6, 129.8, 127.9, 127.1, 111.8, 111.6, 108.6, 74.5, 68.1,
60.6, 56.2, 56.2, 55.8, 31.1, 29.9; IR (neat) ν 3375, 2930, 1621,
1458, 1124 cm-1; HRMS (CI) calcd for C20H26NO5 [(MH+)]
+
360.1811, found 360.1812.
(()-5-Propyl-2,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]ox-
epin-3-amine (7g). Compound 7g was obtained in the same manner
as above for 7f, starting from dibenzoxepine 7d (16 mg, 0.04 mmol)
and Pd/C (8 mg) in EtOH (1 mL). After flash chromatography (silica
gel, cyclohexane/EtOAc 89:11), compound 7g was isolated as an
General Cyclodehydratation Procedure. An aq solution of HF
(48% to 51%) was added to a solution of compound 8 in CH3CN
at room temperature, and the mixture was stirred for 48 h. It was
1
oil (20 mg, 90%, conformer ratio 85:15). Major conformer: H
NMR (300 MHz, CDCl3) δ 7.13 (s, 1H), 6.82 (s, 1H), 6.74 (s,
4334 J. Org. Chem. Vol. 74, No. 11, 2009

Amino Analogues of N-Acetylcolchinol
1H), 4.34 (d, J ) 11.1 Hz, 1H), 4.00 (t, J ) 7.1 Hz, 1H), 3.96 (s,
3H), 3.95 (d, J ) 11.2 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.66 (s,
3H), 1.91 (q, J ) 7.6 Hz, 2H), 1.31 (m, J ) 7.6 Hz, 2H), 0.95 (t,
J ) 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 152.6, 150.4, 146.5,
142.6, 135.7, 131.6, 130.0, 127.8, 127.0, 111.8, 111.6, 108.6, 72.5,
68.0, 61.3, 56.0, 55.8, 55.8, 34.4, 19.9, 14.4; IR (neat) ν 3371,
2952, 2931, 2856 cm-1; HRMS (CI) calcd for C21H28NO5+ [(MH+)]
374.1967, found 374.1967.
acetate). We are also grateful to Dr. Erwann Jeanneau for
crystallographic data collection, structure solution, and refine-
ment and Dr. Denis Bouchu for mass spectrometry analyses.
Supporting Information Available: Full characterization of
all new compounds, detailed experimental procedures, copies
of NMR spectra for biaryl intermediates, and target dibenzox-
epines and X-ray crystal structure data (CIF) for compound 17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Ministe`re de l’Enseignement
Supe´rieur et de la Recherche (fellowship to V.C.), CNRS (ATIP
grant to O.B.), and Johnson Matthey PLC (loan of palladium
JO900632A
J. Org. Chem. Vol. 74, No. 11, 2009 4335