Asymmetric synthesis of propargylamides via 3,3′-disubstituted binaphthol-modified alkynylboronates

Article abstract of DOI:10.1021/ol0523087

(Chemical Equation Presented) Alkynylboronates derived from 3,3′-disubstituted-2,2′-binaphthols react with various N-acylimines to give the expected chiral propargylamides with up to 99% ee. This new methodology was applied to the first enantioselective s

Full text of DOI:10.1021/ol0523087

ORGANIC
LETTERS
2006
Vol. 8, No. 1
15-18
Asymmetric Synthesis of
Propargylamides via 3,3 -Disubstituted
′
Binaphthol-Modified Alkynylboronates
T. Robert Wu and J. Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, (GWC)2,
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario,
Canada N2L 3G1
jmchong@uwaterloo.ca
Received September 22, 2005
ABSTRACT
Alkynylboronates derived from 3,3
with up to 99% ee. This new methodology was applied to the first enantioselective synthesis of the antitubulin agent (
′
-disubstituted-2,2
′
-binaphthols react with various N-acylimines to give the expected chiral propargylamides
)-N-acetylcolchinol.
−
Stereochemically defined propargylamides are important as
synthetic intermediates for the preparation of natural prod-
ucts1 and biologically active compounds.2 Therefore, there
is considerable interest in the preparation of these amides.
Typical routes to prepare chiral propargylamides include
metal complex (Cu,3 Zn, and Zr4) catalyzed terminal alkyne
addition to achiral imines or the addition of alkynylmetallics
to imines bearing chiral auxiliaries.5 Protecting groups or
auxiliaries are then removed, and the intermediate propar-
gylamines are acylated to provide the desired propargyl-
amides.
However, to our knowledge, a method that provides
reliable and direct access to enantiomerically enriched
propargylamides via asymmetric synthesis has not been
reported.6
Recently, we found that 3,3′-disubstituted binaphthol-
modified alkynylboronates could deliver alkynyl groups onto
enones in a conjugate fashion with excellent yields (up to
99%) and enantioselectivities (up to >99% ee).7 Here we
report an asymmetric synthesis of N-protected propargyl-
amines by alkynylation of N-acylimines. We reasoned that
N-acylimines (1, Scheme 1), being structurally similar to
enones in that they also bear a carbonyl group conjugated
with a double bond (CdN instead of CdC), might also react
(1) For recent examples, see: (a) Trost, B. M.; Chung, C. K.; Pinkerton,
A. B. Angew. Chem., Int. Ed. 2004, 43, 4327-4329. (b) Davidson, M. H.;
McDonald, F. E. Org. Lett. 2004, 6, 1601-1603. (c) Brennan, C. J.;
Pattenden, G.; Rescourio, G. Tetrahedron Lett. 2003, 44, 8757-8760.
(2) Osipov, S. N.; Tsouker, P.; Hennig, L.; Bergur, K. Tetrahedron 2004,
60, 271-274.
(5) For representative examples, see: (a) Lettan, R. B.; Scheidt, K. A.
Org. Lett. 2005, 7, 3227-3230. (b) Bonanni, M.; Marradi, M.; Cicchi, S.;
Faggi, C.; Goti, A. Org. Lett. 2005, 7, 319-322. (c) Dondoni, A.; Perrone,
D. Tetrahedron 2003, 59, 4261-4273. (d) Fassler, R.; Frantz, D. E.; Oetiker,
J.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054-3056. (e) Feuvrie,
C.; Blanchet, J.; Bonin, M.; Micouin, L. Org. Lett. 2004, 6, 2333-2336.
(6) Recent examples of racemic syntheses of propargylamides: (a)
Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497-1499. (b) Black, D.
A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107-1110 and references therein.
(7) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc. 2000, 122,
1822-1823.
(3) For representative examples, see: (a) Knopfel, T. F.; Aschwanden,
P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed.
2004, 43, 5971-5973. (b) Gommermann, N.; Knochel, P. Chem. Commun.
2004, 2324-2325. (c) Wei, C.; Mague, J. T.; Li, C. J. Proc. Nat. Acad.
Sci. 2004, 5749-5754. (d) Benaglia, M.; Negri, D.; Dell’Anna, G.
Tetrahedron Lett. 2004, 45, 8705-8706.
(4) Travers, J. F.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2003, 5,
3273-3275.
10.1021/ol0523087 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/03/2005

among the three acylimines. The iodo-substituted binaphthol
2c, which is also the best ligand for catalytic conjugate
alkynylation of enones,9 gave excellent ee’s (Table 1, entries
3, 8, and 10). However, the yields were poor. In fact all
boronates with relatively strong electron-withdrawing groups
on the binaphthol rings gave poor yields (Table 1, entries
3-5, 8, and 10). This result may be rationalized by proposing
that, to deliver the alkynyl group via a 1,4-fashion, alkynyl
boronates must coordinate with the oxygen atom of the
acylimines (Scheme 2). Electron-withdrawing groups (I, CF3,
Scheme 1. Syntheses of N-Acylbenzaldimines
with alkynylboronates in a 1,4-addition manner to give chiral
propargyl amides.
Following Kupfer’s procedure,8 N-acylbenzaldimines (1a-
c) were synthesized in one pot from benzaldehyde quanti-
tatively (Scheme 1). Since 1a-c are very moisture-sensitive
compounds, they were used directly without further purifica-
tion.
Scheme 2. Alkynylation of N-Benzoylbenzaldimine with
Alkynylboronates
Upon treating 1a with binaphthol-modified alkynyl-
boronate 2a in CH2Cl2, the desired chiral propargylbenzamide
3a was obtained in 84% yield with 64% ee. Other solvents
(toluene, THF, ether) gave slightly lower selectivities. Further
investigation showed that when 3,3′-disubstitutedbinaphthols
were used in place of the parent binaphthol, additions to 1
were considerably more selective (Table 1).
Table 1. Alkynylation of N-Acylbenzaldimines with
Alkynylboronates
COOiPr) increase the Lewis acidity of boronates and thus
increase the possibility of boron coordinating with the
nitrogen atom of the acylimine, leading to poor yields. We
have no experimental evidence for this coordination, but it
is offered as a speculation as to why electron-withdrawing
groups have a major negative impact on reactions of
alkynylboronates with acylimines but not on the analogous
reactions with enones.9
Alkynylation of other N-acetylimines using 2f and 2h
proceeded smoothly to give products in high yields (Table
2). Excellent enantioselectivities (>90% ee) were observed
for all of the aromatic imines examined (Table 2, entries
1-6, 8, and 9) with highest selectivities (99% ee) noted for
aromatic groups that are ortho substituted (Table 2, entries
5 and 6). Similar to the results from our previous study on
allylboration,10 high yields but lower selectivity were found
with an alkenylimine (Table 2, entry 7). However, with a
larger alkenyl group, excellent selectivity was obtained
(Table 2, entry 10). Aliphatic acylimines were not examined
as the method of preparation used is applicable only to
nonenolizable aldehydes.8
reagent
entry
X
compd
R
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
H
Me
I
2a
2b
2c
2d
2e
2f
2g
2c
2f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OBn
OBn
CH3
CH3
84
85
30
<20
<20
82
84
40
90
33
64
67
80
75
ndc
80
80
80
40
94
92
CF3
COOiPr
Ph
4-MeOC6H4
I
Ph
I
10
11
2c
2f
Ph
75
a Isolated yields of purified products based on chiral boronates (acylimines
were generated in situ without isolation). b Determined by HPLC analysis
with a Chiralcel OD column. c Not determined.
The adduct 3k was prepared particularly to determine the
absolute configuration of the addition products. (S)-Boronate
(8) (a) Kupfer, R.; Meier, S.; Wurtwein, E.-U. Synthesis 1984, 688-
690. (b) Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang, T.-K. J. Org. Chem.
1983, 48, 289-294.
Among a variety of boronates, 3,3′-diarylbinaphthol-
modified boronates (2f, 2g) gave the best results in terms of
yield and selectivity. N-Acetylimine 1c gave the best ee’s
(9) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244-
3245.
(10) Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701-2704.
16
Org. Lett., Vol. 8, No. 1, 2006

as ZD6126, is useful in the treatment of cancer by selectively
disrupting tumor vasculature, leading to vessel occlusion and
extensive tumor necrosis.11 Racemic N-acetylcolchinol has
been prepared by total synthesis,12 but (-)-N-acetylcolchinol
has been previously obtained only by degradation of natural
colchicine.11,13
Table 2. Alkynylation of N-Acetylimines with 2f and 2h
The synthesis began with conversion of TBS protected
3-hydroxybenzaldehyde to its N-acetylimine. The crude imine
was treated with (R)-diphenylbinaphthol alkynylboronate 2i
to give the desired (R)-acetamide 4 in 72% yield and 94%
ee. (On the basis of the reaction model proposed, (R)-
diphenylbinaphthol should give the natural enantiomer of the
final product, whereas (S)-diphenylbinaphthol would give the
other enantiomer.) After hydrogenation over Pd/C, the
saturated compound (S)-5 was obtained in quantitative yield.
Finally, following Sawyer’s procedure,12 (S)-5 was trans-
formed into (-)-N-acetylcolchinol 6 by treatment with
(CF3COO)3Tl in the presence of freshly distilled BF3‚OEt2,
TFA, and TFAA in an unoptimized yield of 53%. This
material exibited an optical rotation of [R]20D -45.2 (c 0.6,
CHCl3), which is comparable to the literature value for (-)-
N-acetylcolchinol obtained from degradation of (-)-colchi-
cine (Scheme 3).13
entry
R
R′
compd yielda (%) eeb (%)
1
2
3
4
5
6
7
8
9
Ph
nC6H13
nC6H13
nC6H13
nC6H13
nC6H13
nC6H13
nC6H13
Ph
3c
3d
3e
3f
75
72
81
76
78
70
75
85
75
80
92
91
92
4-ClC6H4
4-MeOC6H4
4-MeC6H4
2-MeC6H4
1-naphthyl
PhCHdCH
Ph
92
3g
3h
3i
99
>99c
67
3j
92
4-BrC6H4
PhCHdC(CH3) Ph
Ph
3k
3l
91
93
10
a Isolated yields of purified products based on chiral boronates (acylimines
were generated in situ without isolation). b Determined by HPLC analysis
with a Chiralcel OD column. c The minor enantiomer was not detected by
HPLC analysis.
Scheme 3. Total Synthesis of (-)-N-Acetylcolchinol
2h produced propargyl amide 3k with S stereochemistry (X-
ray). This stereochemical result may be explained using a
cyclic six-membered chair transition state model similar to
that proposed by us for additions of the same alkynylboronate
reagents to enones (Figure 1).7 In this model, the larger or
In summary, we have shown that 3,3′-disubstituted bi-
naphthol-modified alkynylboronates can be used to prepare
chiral propargylamides in high yields and enantioselectivities.
This represents the first direct asymmetric synthesis of
propargylamides. We are currently investigating the catalytic
alkynylation of acylimines and other conjugate addition
Figure 1. Proposed model.
aryl group occupies an equatorial position in either of two
possible transition states. The 3- and 3′-substituents on the
binaphthol play an important role in destabilizing one of the
possible transition states. The nonbonded interactions be-
tween the 3-substituent (Ph) and the axial imine hydrogen
presumably favors B over A in the six-membered ring
transition state.
This methodology was applied to the first enantioselective
synthesis of (-)-N-acetylcolchinol 6. It has been reported
that the O-phosphate of (-)-N-acetylcolchinol 6, also known
(11) (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, 7247-7253. (b) Micheletti,
G.; Pli, M.; Borsotti, P.; Martinelli, M.; Imberti, B.; Taraboletti, G.; Giavazzi,
R. Cancer Res. 2003, 63, 1534-1537. (c) Bergemann, S.; Brecht, R.;
Buttner, F.; Guenard, D.; Gust, R.; Seitz, G.; Stubbs, M. T.; Thoret, S.
Bioorg. Med. Chem. 2003, 11, 1269-1281. (d) Vorogushin, A. V.; Predeus,
A. V.; Wulff, W. D.; Hansen, H. J. J. Org. Chem. 2003, 68, 5826-
5831.
(12) (()-6 was prepared in 71% yield using this method: (a) Sawyer, J.
S.; Macdonald, T. L. Tetrahedron Lett. 1988, 29, 4839-4842.
(13) Cech, J.; Santavy, F. Collect. Czech. Chem. Commun. 1949, 14,
532-539.
Org. Lett., Vol. 8, No. 1, 2006
17

acceptors, as well as applications of this methodology in total
synthesis. These results will be reported in due course.
Supporting Information Available: Experimental pro-
cedures, spectral data for propargylamides (3a-l, 4-6), and
X-ray data for 3k. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) for finan-
cial support and Dr. N. J. Taylor for X-ray diffraction studies.
OL0523087
18
Org. Lett., Vol. 8, No. 1, 2006