Gold(I)-catalyzed cycloisomerization of 1,7- and 1,8-enynes: Application to the synthesis of a new allocolchicinoid

Article abstract of DOI:10.1021/jo800797c

(Chemical Equation Presented) Gold(I)-catalyzed cycloisomerization of 1,7- and 1,8-enyne propargylic acetates afforded cyclopropyl derivatives containing seven- and eight-membered rings, respectively. This reaction was used for the synthesis of a new allocolchicinoid having a cyclopropane ring fused to the B seven-membered ring at the C6-C7 positions.

Full text of DOI:10.1021/jo800797c

SCHEME 1
Gold(I)-Catalyzed Cycloisomerization of 1,7- and
1,8-Enynes: Application to the Synthesis of a New
Allocolchicinoid
Franc¸ois-Didier Boyer,† Xavier Le Goff,‡ and
Issam Hanna*,§
TABLE 1. Gold-Catalyzed Rearrangement of Propargylic
Acetates
Unite´ de Chimie Biologique, INRA, F-78026 Versailles,
France, Laboratoire He´te´roatomes et Coordination, CNRS
UMR 7653, and Laboratoire de Synthe`se Organique, CNRS
UMR 7652, Ecole Polytechnique, F-91128 Palaiseau, France
hanna@poly.polytechnique.fr
ReceiVed April 14, 2008
Gold(I)-catalyzed cycloisomerization of 1,7- and 1,8-enyne
propargylic acetates afforded cyclopropyl derivatives con-
taining seven- and eight-membered rings, respectively. This
reaction was used for the synthesis of a new allocolchicinoid
having a cyclopropane ring fused to the B seven-membered
ring at the C6-C7 positions.
Cycloisomerization of enynes in the presence of transition-
metal catalysts has played an important role in the preparation
of a variety of cyclic compounds.1 In particular, PtCl2- or Au(I)-
catalyzed cycloisomerization of enyne substrates bearing an ester
group at the propargylic position leads to bicyclic systems with
a fused cyclopropane ring, which upon hydrolysis furnishes a
cyclopropyl carbonyl derivative (Scheme 1).2 The overall result
of this squeletal rearrangement represents an attractive and less
hazardous equivalent to classical diazocarbonyl chemistry.3 Even
at the early stages of development, this methodology has already
been applied in the total syntheses of bicyclic sesquiterpenes
containing a cyclopropane subunit.4 However, while rearrange-
ment of 1,5- and 1,6-enynes is well-documented, rare examples
are known of such a reaction with 1,7- and 1,8-enyne substrates.5
We report here that polycyclic compounds in which the
cyclopropane ring is fused to seven- and eight-membered rings
can be readily obtained by cyclorearrangement of 1,7- and 1,8-
enynes, respectively. This methodology was applied to the
synthesis of a new class of allocolchicinoids.
Our work started with enyne propargylic acetate 1 (Table
1).6 Treatment of 1 with 5% of PtCl2 in toluene at 80 °C for
5 h gave tricyclic enol ester 4 in 53% yield along with allene
7 (7% yield) (Table 1, entry 1). This transformation could be
achieved under milder conditions using cationic gold complexes
† Unite´ de Chimie Biologique, INRA.
‡ Laboratoire He´te´roatomes et Coordination, CNRS.
§ Laboratoire de Synthe`se Organique, CNRS.
(1) For reviews, see: (a) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV.
2002, 102, 813. (b) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215. (c)
Zhang, Z.; Zhu, G.; Tong, X.; Wang, F.; Xie, X.; Wang, J.; Jiang, L. Curr. Org.
Chem. 2006, 10, 1457. (d) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed.
2007, 46, 3410. (e) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (f) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180.
(4) (a) Fu¨rstner, A.; Hannen, P. Chem. Commun. 2004, 2546. (b) Anjum,
S.; Marco-Contelles, J. Tetrahedron 2005, 61, 4793. (c) Fu¨rstner, A.; Hannen,
P. Chem.—Eur. J. 2006, 12, 3006. (d) Fehr, C.; Galindo, J. Angew. Chem., Int.
Ed. 2006, 45, 2901.
(2) For recent reviews, see: (a) Bruneau, C. Angew. Chem., Int. Ed. 2005,
44, 2328. (b) Marco-Contelles, J.; Soriano, E. Chem.—Eur. J. 2007, 13, 1350.
(c) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. For selected
examples, see: (d) Mainetti, E.; Mourie`s, V.; Fensterbank, L.; Malacria, M.;
Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132. (e) Mamane, V.;
Gress, T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (f) Harrak,
Y.; Blaszykowski, C.; Bernard, M.; Cariou, K.; Mainetti, E.; Mourie`s, V.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004, 126,
8656. (g) Marion, N.; de Fre´mont, P.; Stevens, E. D.; Fensterbank, L.; Malacria,
M.; Nolan, S. P. Chem. Commun. 2006, 2048.
(5) For examples of cycloisomerization of 1,7- and 1,8-enynes, see: (a)
Moreau, X.; Goddard, J.-P.; Mathieu, B.; Lemie`re, J.; Lopez-Romero, J. M.;
Mainetti, E.; Marion, N.; Mourie`s, V.; Thorimbert, S.; Fensterbank, L.; Malacria,
M. AdV. Synth. Catal. 2008, 350, 43. (b) Cabello, N.; Rodriguez, C.; Echavarren,
A. M. Synlett 2007, 1753, and ref 2d. (c) For an example of a gold-catalyzed
cycloisomerization of 1,9-enyne, see: Comer, E.; Rohan, E.; Deng, L.; Porco,
J. A. Org. Lett. 2007, 9, 2123.
(6) The preparation of propargylic acetates 1 and 3 is described in the
Supporting Information.
(7) (a) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133. (b)
Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614.
(3) For a review, see: Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385.
10.1021/jo800797c CCC: $40.75
Published on Web 06/06/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5163–5166 5163

SCHEME 2. Possible Reaction Pathways for
Gold-Catalyzed Rearrangement of Propargylic Acetates
FIGURE 1. Colchicine and allocolchicinoids.
exclusively, leading to the cycloheptyl derivative 5. For n ) 2
and 3, the strain incurred in forming eight- and nine-membered
rings presumably makes path a more difficult, allowing the
formation of allenyl acetates 7 and 9.10
We decided next to use the tricyclic structure 5 containig a
seven-membered ring for the synthesis of a new class of
allocolchicinoids. Allocolchicinoids are analogues of the im-
portant antimitotic (-)-colchicine 12, in which the tropolone
ring is replaced by a benzene ring (Figure 1). Like colchicine,
some allocolchicinoids also arrest mitosis by inhibiting tubulin
polymerization.11,12 Examples include natural allocolchicine 13,
N-acetylcolchinol 14, and its methyl ether which bind to tubulin
more strongly than colchicine itself. Total syntheses of 13 and
14 have been reported, and a number of syntheses of various
allocolchicinoids have also been described.13
Recently, we described the synthesis of allocolchicine 15,
analogue of 13, having the ester group at position C10.14,15 This
compound was found to be as active as natural allocolchicine
13.16 We report now the synthesis of a new allocolchicinoid
16, in which the acetamide function in 15 has been replaced by
a cyclopropane ring fused to the seven-membered ring at the
C6-C7 positions.
The retrosynthetic analysis is outlined in Scheme 3. Thus,
the target compound 16 could be prepared by a Diels-Alder/
aromatization sequence from diene 17. This intermediate can
be traced back to 18, which is formed by the Au(I) cycloi-
somerization reaction of enyne 2. This precursor was prepared
from aldehyde 19.15
As shown in Scheme 4, alkynylation of aldehyde 19 followed
by treatment of the resulting hydroxy ester with a catalytic
amount of TsOH in CH2Cl2 afforded lactone 20 in 61% overall
bearing the bis(trifluoromethanesulfonyl)imidate moiety.7 When
1 was treated with the biphenylphosphine-based catalyst 10 (1%)
in CH2Cl2 at room temperature, 4 was obtained in an improved
yield (78%) (Table 1, entry 2). Under these conditions, allene
7 was also isolated in 8% yield. In this skeletal reorganization,
enyne 1 was converted into a complex structure in which the
cyclopropane ring is fused to the eight-membered ring.5 The
use of the bulkier Au(I) catalyst 11 was found to be synthetically
less useful. Thus, treatment of enyne 1 with 11 gave allene
acetate 7 (16%), enol acetate 4 (60%), and a mixture of
unidentified products (Table 1, entry 3).
We next turned to the preparation of the tricyclic structure 5
containing a seven-membered ring. When propargylic acetate
2 was treated with 0.5% of catalyst 10, only the product of
cycloisomerization 5 was obtained in 90% yield (Table 1, entry
4). In this case, none of allene derivative 8 was isolated. By
sharp contrast, 1,9-enyne 3 (n ) 3)6 reacted rather sluggishly
under the same conditions (entry 5). In fact, to achieve the total
conversion of the starting enyne, further amounts of catalyst
10 (4%) were needed. Ultimately, the reaction gave a mixture
of products from which allenyl acetate 9 was isolated as the
major product in low yield (32%). Only 5% of cyclononane
derivative 6 was obtained.
To account for the formation of both enol esters and allenyl
acetates, a proposed mechanism is shown in Scheme 2. The
acetate group in the polarized metal-alkyne complex initially
formed can undergo either 1,2-O-acyl shift (path a)8 or 1,3-
acyl shift (path b) leading to a M-carbene A or to an allene B,
respectively. These complexes are poised for subsequent func-
tionalization: cyclopropanation of A leads to the tricyclic
derivative C, while B affords allene acetate D.9 The D/C ratio
strongly depends upon the cyclization efficiency, which is related
to ring size. For n ) 1, ring closure of intermediate A occurred
(10) Presumably, for the same reasons, 1,4-enynes (Scheme 1, n ) 0) do
not lead to the highly strained [2.1.0]bicyclic system. Instead, 2-cyclopentenones
are formed through the Rautenstrauch rearrangement. See: (a) Rautenstrauch,
V. J. Org. Chem. 1984, 49, 950. (b) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 5802.
(11) For reviews on the synthesis and biological activity of colchicine and
allo congeners, see: (a) Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed.
2004, 43, 3230. (b) Boye´, O.; Brossi, A. In The Alkaloids; Brossi, A., Cordell,
G. A., Eds.; Academic Press: New York, 1992; Vol. 41, p 125, and references
therein.
(12) For a review on microtubule-targeted drugs, see: Jordan, M. A.; Wilson,
L. Nat. ReV. Cancer 2004, 4, 253.
(13) For recent references, see: (a) Vorogushin, A. V.; Wulff, W. D.; Hansen,
H.-J. Tetrahedron 2008, 68, 949. (b) Besong, G.; Jarowski, K.; Kocienski, P. J.;
Sliwinski, E.; Boyle, F. T. Org. Biomol. Chem 2006, 4, 2193. (c) Leblanc, M.;
Fagnou, K. Org. Lett. 2005, 7, 2849. (d) Bu¨ttner, F.; Bergemann, S.; Gue´nard,
D.; Gust, R.; Seitz, G.; Thoret, S. Bioorg. Med. Chem. 2005, 13, 3497. (e) Wu,
T. R.; Chong, J. M. Org. Lett. 2006, 8, 15. (f) Vorogushin, A. V.; Predeus,
A. V.; Wulff, W. D.; Hansen, H.-J. J. Org. Chem. 2003, 64, 5826.
(14) The colchicine numbering has been used throughout this paper.
(15) Boyer, F.-D.; Hanna, I. Org. Lett. 2007, 9, 715.
(8) There is no general agreement on the respective order of 1,2-shift/
cyclopropanation. See for examples refs 2c and 4a and references cited therein.
(9) For examples of the formation of allenes as side products, see: Marion,
N.; Diez-Gonzalez, S.; de Fre´mont, P.; Noble, A. R.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2006, 45, 3647. ref 2c.
(16) Boyer, F.-D.; Dubois, J.; Hanna, I. Unpublished work.
5164 J. Org. Chem. Vol. 73, No. 13, 2008

SCHEME 3. Retrosynthetic Analysis
SCHEME 4. Preparation of Enyne 2
FIGURE 2. ORTEP drawing of compound 16. Only hydrogen atoms
of the cyclopropane ring are shown.
obtained as a white solid in 57% yield. On the basis of the results
reported in a previous work,15 we reasoned that [4 + 2]
cycloaddition of methyl ꢀ-nitroacrylate 2318 to 17 would occur
regioselectively, placing the ester group at the desired position.
Indeed, 23 readily reacted with diene 17 at room temperature,
affording cycloadduct 24 in quantitative yield (Scheme 5). The
elimination of nitrous acid using DBU and the subsequent
aromatization by DDQ furnished allocolchicinoid 16 in 68%
overall yield. This tetracyclic structure was assigned on the basis
of spectroscopic data, and the relative configuration at C-6 and
C-7 was determined by X-ray crystallographic analysis (Figure
2). As allocolchicinoids, this compound displays molecular
asymmetry resulting from a noncoplanar arrangement of rings
A and C. The X-ray data show that these rings are twisted with
a torsion angle of 45°.
In summary, we have achieved the synthesis of a new class
of allocolchicinoids using the Au-catalyzed cycloisomerization
reaction of 1,7-enyne propargylic acetate for the construction
of a seven-membered ring fused to a cyclopropane and a
Diels-Alder/aromatization sequence for the elaboration of the
aromatic ring C. Compound 16 will be subjected to a tubulin
binding assay in order to gain some indication of its ability to
function as antimitotic agent, and the results will be reported
in due course.
SCHEME 5. Synthesis of Allocolchicinoid 16
Experimental Section
Cycloisomerization of Enyne 2, Tricyclic Ketone 18: To a
solution of enyne propargylic acetate 1 (79 mg, 0.26 mmol) in dry
CH2Cl2 (1.5 mL) was added Au(I) catalyst 10 (1.5 mg, 0.75 mol
%). The mixture was stirred at room temperature for 2 h. After
addition of one drop of Et3N, the solvent was removed. To the
solution of the resulting residue in MeOH (3 mL) was added K2CO3
(7 mg), and the mixture was stirred for 2.5 h at room temperature.
The solvent was removed under reduce pressure, and the residue
was submitted to flash chromatography on silica gel (EtOAc/PE
1:4) to give ketone 18 (55 mg, 80% over 2 steps) as a white solid:
1
yield. This product was reduced to the corresponding lactol,
which was converted into enyne 21 using a Wittig reaction
followed by desilylation of the alkyne moiety. Subsequent
acylation of the resulting propargylic alcohol gave 2.
As seen above, enyne propargylic acetate 2 readily underwent
cycloisomerization, affording the tricyclic compound 5 (Table
1) which led after hydrolysis to cyclopropylketone 18 in 80%
yield over two steps (Scheme 5). Treatment of this ketone with
vinyllithium in ether/THF at -78 °C produced allylic alcohol
22 as a mixture of isomers in 58% yield along with 34% of
recovered starting material.17 When this mixture was heated at
100 °C in toluene in the presence of MgSO4, diene 17 was
mp 86-87 °C; H NMR δ ) 6.55 (s, 1 H), 3.87 (s, 3 H), 3.85 (s,
3 H), 3.84 (s, 3 H), 3.69 (d, J ) 13.2 Hz, 1 H), 3.48 (d, J ) 13.2
Hz, 1 H), 3.35 (dd, J ) 14.8, 6.0 Hz, 1 H), 2.87 (dd, J ) 14.8, 7.6
Hz, 1 H), 1.76-1.62 (m, 2 H), 1.35-1.30 (m, 1 H), 1.03 (q, J )
5.6 Hz, 1 H); 13C NMR δ ) 204.3 (C), 152.1 (C), 151.7 (C), 141.2
(C), 134.7 (C), 118.6 (C), 108.4 (CH), 61.5 (CH3), 60.9 (CH3),
56.0 (CH3), 38.7 (CH2), 34.4 (CH2), 26.9 (CH2), 20.2 (CH), 15.7
(17) Initial attempts to prepare 22 by treatment of ketone 18 with vinylmag-
nesium bromide at room temperature led to the desired alcohol in low yield
(24%) along with the reduction product of ketone 18.
(18) Methyl ꢀ-nitroacrylate was prepared according to the procedure described
by Pritchard et al.: Pritchard, R. G.; Stoodly, R. J.; Yuen, W.-H. Org. Biomol.
Chem. 2005, 3, 162.
J. Org. Chem. Vol. 73, No. 13, 2008 5165

(CH2); IR (CCl4) νmax 2998, 2937, 2869, 2840, 1740, 1690, 1595
cm-1; EI MS m/z (%) 262 (M+•) (100), 219 (M+• - Ac) (20); CI
MS (NH3) m/z (%) 280 (M+• + 18) (25), 263 (M+• + 1) (100);
HMRS (EI) m/z calcd for C15H18O4, 262.1205; found, 262.1219.
Cycloadduct 24. A solution of methyl ꢀ-nitroacrylate 23 (20
mg, 0.152 mmol, 5.2 equiv) and diene 17 (8 mg, 0.029 mmol) in
0.25 mL of CH2Cl2 was stirred at room temperature for 22 h. The
volatiles were removed by evaporation under reduced pressure, and
the residue was purified by chromatography on silica gel (EtOAc/
EP 1:9) to give 12 mg of 24 (0.029 mmol, 100%) as a mixture of
diastereoisomers unseparable by chromatography on silica gel.
CH2Cl2, and DDQ (10 mg, 44 µmol) was added. The solution was
stirred for 2 h at room temperature. The solvent was evaporated,
and the crude mixture was filtered through a layer of Al2O3 to give,
after solvent removal, 7 mg of ester 16 (19.7 µmol, 68% from diene
17) as a colorless oil which crystallized on cooling: mp 105-107
°C. Major atropoisomer: 1H NMR δ ) 8.09 (d, J ) 2.0 Hz, 1 H),
7.90 (dd, J ) 8.0, 2.0 Hz, 1 H), 7.57 (d, J ) 8.0 Hz, 1 H), 6.61 (s,
1 H), 3.934 (s, 3 H), 3.929 (s, 3 H), 3.91 (s, 3 H), 3.55 (s, 3 H),
3.89 (dd, J ) 13.6, 5.2 Hz, 1 H), 2.00-1.92 (m, 2 H), 1.27 (t, J )
3.7 Hz, 1 H), 1.04-1.00 (m, 1 H), 0.50 (q, J ) 5.0 Hz, 1 H); 13C
NMR δ ) 167.3 (C), 152.2 (C), 145.0 (C), 141.1 (C), 137.6 (C),
134.6 (C), 135.3 (C), 133.2 (CH), 132.8 (CH), 127.8 (CH), 127.6
(C), 124.5 (C), 106.7 (CH), 61.1 (CH3), 61.0 (CH3), 56.0 (CH3),
52.0 (CH3), 36.5 (CH2), 22.4 (CH), 16.5 (CH), 11.4 (CH2); IR
(CCl4) νmax 2997, 2933, 2854, 1724, 1596 cm-1; CI MS (NH3) m/z
(%) 372 (M• + 18) (100), 355 (M• + 1) (40), 323 (10); HMRS
(EI) m/z calcd for C21H22O5, 354.1467; found, 354.1453.
1
Major isomer: H NMR δ ) 6.35 (s, 1 H), 5.77-5.75 (m, 1 H),
5.35 (t, J ) 3.2 Hz, 1 H), 4.72-4.71 (br s, 1 H), 3.90 (s, 3 H),
3.84 (s, 6 H), 3.82-3.79 (m, 1 H), 3.20 (s, 3 H), 2.53 (dd, J )
14.0, 4.4 Hz, 1 H), 2.41 (dd, J ) 14.0, 11.6 Hz, 1 H), 2.16-2.12
(m, 1 H), 1.55-1.48 (m, 1 H), 1.28-1.16 (m, 2 H), 0.84-0.81
(m, 1 H), 0.49 (q, J ) 5.2 Hz, 1 H); 13C NMR δ ) 171.3 (C),
153.0 (C), 151.7 (C), 140.4 (C), 138.1 (C), 135.5 (C), 124.2 (CH),
122.5 (C), 108.4 (CH), 88.0 (CH), 60.8 (CH3), 60.7 (CH3), 55.9
(CH3), 51.8 (CH3), 41.1 (CH), 40.9 (CH), 34.9 (CH2), 23.1 (CH2),
19.9 (CH), 19.0 (CH), 12.0 (CH2).
Acknowledgment. We are grateful to Dr. F. Gagosz (Ecole
Polytechnique) for providing gold catalysts 10 and 11.
Allocolchicinoid 16. To a solution of 24 (12 mg, 29 µmol) in
THF (0.25 mL) was added two drops of DBU. The reaction mixture
was stirred for 2 h at room temperature under N2. The volatiles
were removed in vacuo, and the residue was filtered through a thin
plug of silica gel (EtOAc/PE 1:9) to give, after solvent evaporation,
10 mg of elimination product. This was dissolved in 0.25 mL of
Supporting Information Available: Experimental proce-
1
dures, characterization data, H and 13C NMR spectra for all
new compounds, and X-ray analysis of 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO800797C
5166 J. Org. Chem. Vol. 73, No. 13, 2008