Synthesis of 1-oxaazulan-2-ones and furanotropones from troponoids: A reexamination and extension to colchicinoids

Article abstract of DOI:10.1016/S0040-4020(00)00106-X

Reactions of [3,5,7-²H₃]-2-tosyloxytropone (1b) in DMSO with enolates that, like sodium ethyl acetoacetate or sodium diethyl malonate, bear a leaving group, occur at C-7, followed by either sequential protonation at C- 2, 1,6-elimination, and intramolecular heterocyclization (to give 1- oxaazulan-2-ones), or sequential sulfinate loss and intramolecular heterocyclization (to give furanotropones). The latter is the exclusive route with enolates that, like sodium acetylacetonate, do not bear a leaving group. 9-Tosyloxyisocolchicide (15) behaves like 2-tosyloxytropone, giving the product 16 of C-11 attack, whereas 10-tosyloxycolchicide (17) resists attack at C-8 and only a very slow nucleophilic attack at C-10 by the enolate to give 18 is observed. Hydroxylic solvents do not allow any of these processes. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00106-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1917–1922
Synthesis of 1-Oxaazulan-2-ones and Furanotropones from
Troponoids: a Reexamination and Extension to Colchicinoids
a
b
c,*
Marino Cavazza, Graziano Guella and Francesco Pietra
a
Dipartimento di Chimica e Chimica Industriale, Universit a` di Pisa, via Risorgimento 35, I-56100, Pisa, Italy
b
Laboratorio di Chimica Bioorganica, Universit a` di Trento, I-38050 Povo-Trento, Italy
c
Centro Linceo Interdisciplinare B. Segre, via della Lungara 10, I-00165 Roma, Italy
Received 5 August 1999; revised 24 January 2000; accepted 3 February 2000
2
Abstract—Reactions of [3,5,7- H
3
]-2-tosyloxytropone (1b) in DMSO with enolates that, like sodium ethyl acetoacetate or sodium diethyl
malonate, bear a leaving group, occur at C-7, followed by either sequential protonation at C-2, 1,6-elimination, and intramolecular hetero-
cyclization (to give 1-oxaazulan-2-ones), or sequential sulfinate loss and intramolecular heterocyclization (to give furanotropones). The latter
is the exclusive route with enolates that, like sodium acetylacetonate, do not bear a leaving group. 9-Tosyloxyisocolchicide (15) behaves like
2
-tosyloxytropone, giving the product 16 of C-11 attack, whereas 10-tosyloxycolchicide (17) resists attack at C-8 and only a very slow
nucleophilic attack at C-10 by the enolate to give 18 is observed. Hydroxylic solvents do not allow any of these processes. ᭧ 2000 Published
by Elsevier Science Ltd. All rights reserved.
1
Simple troponoids have long found use as synthons, while
their condensation products with enolates that bear a leaving
group are a recent addition to this methodology, specifically2
adapted to the synthesis of guaianolides and octalactins.
The basic knowledge of these reactions of troponoids with
corresponding 1-oxaazulan-2-one 5 in fair yield as a single
product (Scheme 1). Detailed NMR and MS data (Experi-
mental) confirm the structure.
3
It should be noted that in absolute EtOH the reactions
3
3
enolates dates from the early 1970s, before which no
reportedly took a different course. Thus, 1a and diethyl
detailed study of the mechanism of the reactions of tropo-
noids with N- and O-nucleophiles had been carried out. In
addition, no extension of these reactions to colchicinoids
has appeared. The usefulness of these reactions in synthesis
could be amplified by a clarification of both these aspects,
which was the aim of this study.
malonate led to only traces of 5, while the major produc3t
was 8-hydroxy-3-carboethoxy-1-oxa-azulan-2-one (6).
With ethyl acetoacetate, 8-hydroxy-3-acetyl-1-oxaazulan-
2-one (7) was a by product (9%) in place of 3a, while the
4
3
major product (76%) was 2a.
Enolates that lack a leaving group had not been investigated
before in this context. Using acetyl acetonate in DMSO, we
have obtained furanotropone 4a in low yield from 1a.
Deuterium labeling shows that C-7 is attacked by the
enolate to give 4b. Both structures are fully supported by
NMR and MS data (Experimental).
Troponoid Series
The reactivity of 2-tosyloxytropone (1a) toward sodium
ethyl acetoacetate in DMSO was first studied, isolating the
1
-oxaazulan-2-one 2a and the furanotropone 3a, both in low
These observations can be fitted into the general reactivity
Scheme 2. As for the reaction by ethyl acetoacetate, it can
be conceived that intermediate 8, deriving from attack by
the enolate at C-7 of the substrate, can take either one of two
main pathways. Pathway a involves protonation at C-2 to
give intermediate 9, followed by the loss of toluensulfonic
acid (or deuterotoluensulfonic acid) to give intermediate 10
or 11. The latter only is stereochemically prone to intra-
molecular condensation to give 2a (or 2b). Pathway b
involves loss of sulfinate, followed by intramolecular
condensation at the acetyl moiety and loss of water to
give 3a (or 3b) via 13. No products from the putative
intermediate 14, which could result from the alternative
yields (Scheme 1). Detailed NMR and MS analysis (Experi-
mental) support structure 3a and confirm the assignment of
3
2
a. Deuterium labeling of 2-tosyloxytropone (1b) proves
that these reactions occur by C-7 attack of the enolate on the
troponoid, substantiating an early hypothesis from non-
3
labeled material.
Using diethyl malonate as an enolate we obtained the
Keywords: alkaloids; colchicinoids; furans; cyclisation; enolates; lactoni-
sation; regioselection; solvents and solvent effect.
*
Corresponding author. Tel.: ϩ39-0583-490282; fax: ϩ39-0583-490282;
e-mail: fpietra@discat.unipi.it
0
040–4020/00/$ - see front matter ᭧ 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00106-X

1
918
M. Cavazza et al. / Tetrahedron 56 (2000) 1917–1922
2
Scheme 1. Reactions of 2-tosyloxytropone (1a) or [3,5,7- H
DMSO, unless otherwise stated.
3
]-2-tosyloxytropone (1b) with sodium acetyl acetonate, ethyl acetoacetate, or diethyl malonate in
intramolecular condensation at the ester group, were
noticed. With diethyl malonate, unproductive inter-
mediates of type 10 are not formed, so a high yield of 5 is
obtained.
Colchicinoid Series
In view of the better yields of condensation products
obtained for troponoids with diethyl malonate, the latter
was chosen to explore the behavior of colchicinoids. 9-
Tosyloxyisocolchicide (15) behaves like 2-tosyloxytropone,
giving a single product, 16, which can be imagined to result
Finally, with acetyl acetonate the route a cannot take place
and only route b occurs, leading to 4a (or 4b).
Scheme 2. Proposed mechanism for the reaction of 2-tosyloxytropone (1a) with sodium ethyl acetoacetate.

M. Cavazza et al. / Tetrahedron 56 (2000) 1917–1922
1919
Scheme 3. Reactions of 9-tosyloxyisocolchicide (15) or 10-tosyloxycolchicide (17) or 10-chlorocolchicine (18) with sodium diethyl malonate in DMSO.
from C-11 attack by the enolate (Scheme 3). Structure 16 is
fully supported by MS and NMR data (Experimental), the
latter perfectly fitting deductions from the energy-
supported by NMR and MS data (Experimental), implies
attack by the enolate at C-10, in contrast with all the obser-
vations above for either the troponoids or colchicinoid 15.
Lack of formation of products from attack at C-8 by carbon
nucleophiles with 1-tosyloxycolchicide finds analogy in the
5
minimized structure (Fig. 1). Difficulties in small-scale
reactions in recovering products that are strongly adsorbed
by the chromatographic support, and formation of colchi-
ceine, account for the low yield of isolated 16.
6
behavior of this substrate toward either amines or
7
amidines. Such an inversion of reactivity may tentatively
be attributed to steric hindrance in the tetrahedral inter-
1
0-Tosyloxycolchicide (17) or, with better yields, 10-chloro-
mediate for attack at C-8, which overcomes an electronic
8
colchicide (18), also gave a single product, 19, albeit in
sluggish reactions where much of unreacted 17 or 18 were
recovered (Scheme 3). Structure 19, which is fully
preference. We have no evidence for radical anion routes.
Perspective
This work represents a rationalization, on the basis of novel
observations as to solvent directivity of the reaction course,
for annelation reactions of troponoids with enolates that
carry nucleofugic groups. Although yields have not been
optimized, these reactions proved applicable to isocolchici-
noids and colchicinoids, annelating a butenolide ring to the
cycloheptatrienone moiety, with transposition in the first
case and no transposition in the second one. These tetra-
cyclic products could hardly be obtained by current tech-
nologies. The colchicinoid framework is often endowed
9
with powerful biological activities, in particular hindering
the polymerization of tubulin, where the interaction sites
10
with colchicine are known. These points of contact are
altered drastically in compounds 16 and 19, while offering
new opportunities for interaction in the same critical region
that warrant biological assays to be carried out.
Experimental
General
All evaporations were carried out under reduced pressure.
Yields are given on reacted substrate. DMSO was dried on
Figure 1. Strain-energy minimized conformation for compound 16.

1
920
M. Cavazza et al. / Tetrahedron 56 (2000) 1917–1922
˚
3
A molecular sieves and was stored under N in Schlenk
Data of 2-methyl-3-ethoxycarbonyl-8H-cyclohepta[b]-
furan-8-one (3a). UV lmax(MeOH) nm/(log e) 350, 335,
2
tubes. TLC: Merck Kieselgel 60 F254 plates. Reversed-phase
HPLC: Spherisorb RP18, 8×250 mm, with 1:1 MeCN–
320, 310 series of sh, 297 (3.70), 258 (3.96). n
(Nujol)
max
Ϫ1
Ϫ1
H O, flux 3 mL min . IR: Perkin–Elmer 1725X FT-IR
1709, 1614, 1577, 1541, 1515 cm . d ((CD ) SO) 8.20 (1
2
H 3 2
spectrometer. UV: Perkin–Elmer Hitachi 200 spectro-
H, ddd, Jˆ0.6, 1.0, 11.2 Hz, 4-H), 7.47 (1 H, dddd, Jˆ0.6,
1.0, 8.6 Hz, 12.4, 6-H), 7.22 (ddd, Jˆ0.8, 8.6, 11.2 Hz,
5-H), 7.17 (1 H, tdd, Jˆ0.8, 1.0, 12.4 Hz, 7-H), 4.36 (2 H,
q, Jˆ7.0 Hz, CH CH ), 2.74 (3 H, s, CH -C2), 1.36 (3 H, t,
Ϫ1
Ϫ1
photometer; lmax in nm, in mol L cm . NMR: Varian
1
13
XL-300 spectrometer ( H 299.94 MHz, C 75.43 MHz)
operating under inverse detection, or, when indicated,
2
3
3
1
Varian Gemini BB200 spectrometer ( H 199.975 MHz and
Jˆ7.0 Hz, CH CH ); d (200 MHz, CDCl ) 8.35 (1 H, d,
2
3
H
3
1
3
C 50.289 MHz); d in ppm rel. to internal Me Si (ˆ0 ppm)
Jˆ11.1 Hz, 4-H), 7.34 (1 H, m, 6-H), 7.31 (1 H, m, 7-H),
7.10 (1 H, ddd, Jˆ11.1, 8.6, 1.0 Hz, 5-H), 4.42 (2 H, q,
Jˆ7.0 Hz, CH CH ), 2.82 (3 H, s, CH -C2), 1.43 (t,
4
1
13
and J in Hz; assignments from DEPT and H, C COSY.
The number of protons given for each H NMR signal often
1
2
3
3
results from decoupling and other techniques and not from
integration for non-first order spectra with protons of widely
different relaxation properties. MS (EI): Kratos MS80 with
home-built data system; m/z (rel.%).
Jˆ7.0 Hz, CH CH ). d ((CD ) CO) 175.37 (s, C-8),
2
3
C
3 2
164.92 (s, COO), 162.54 (s, C-2), 154.50 (s, C-8a), 138.46
(d, C-7), 136.42 (d, C-6), 129.98 (d, C-5), 129.59 (s, C-3a),
128.31 (d, C-4), 111.84 (s, C-3), 60.84 (t, CH CH ), 14.72
2
3
ϩ
(
(
[
[
q, CH -C2), 14.05 (q, CH CH ). m/z 232 (100, M ), 204
3 2 3
ϩ ϩ
44, [MϪCO] ), 187 (36, [MϪOEt] ), 175 (96,
General procedure for the reactions of enolates with
either troponoids or colchicinoids
ϩ
ϩ
MϪCOϪEt] ), 159 (40, [MϪCO Et] ), 131 (21,
2
ϩ
ϩ
MϪCOϪCO Et] ), 77 (31), 43 (48). HR-MS: M , found
2
ϩ
2
32.0735^0.001. C H O requires 232.0736).
13 12 4
To a stirred suspension of MeONa (ca. 2 mmol) in
dried DMSO (4 mL) at room temperature was added the
2
Reaction of [3,5,7- H ]-2-tosyloxytropone (1b) with
3
enolizable reagent, in a 1.2 molar excess under N , followed
2
sodium ethyl acetoacetate
by the troponoid or the colchicinoid (ca. 0.9 mmol), by
which the mixture turned immediately to orange-red in
color. The mixture was stirred for 30 min, unless otherwise
stated, and then it was acidified with dilute HCl (0.5 M,
Following the same procedure—with the same amounts of
reagents—as for the undeuterated compound, 2b and 3b
were obtained as semi-solids in similar yields.
5
mL) and was extracted with CHCl3 (10×3 mL). The
organic phase was washed three times with H O (5 mL),
2
2
Data of [5,7- H ]-3-acetyl-2H-cyclohepta[b]furan-2-one
2
separated, dried over Na SO , and evaporated. The
Ϫ1
2
4
(
2b). nmax (Nujol) 1734, 1653 cm . [Found: C 69.5; H
residue was subjected to TLC purification with Et O,
2
5
.1. C H D O requires C 69.47%, H 3.16%, D 2.10%].
11 6 2 3
unless otherwise stated. No optimization of yields was
performed.
dH (CDCl3, 200 MHz) 9.20 (1 H, br.s, 4-H), 7.57 (1 H,
br.s, 8-H), 7.42 (1 H, br.s, 6-H), 2.63 (3 H, s, COCH ). d
3
C
(
CDCl , 50 MHz) 194.9 (s, COCH ), 167.6 (s, C-2), 134.9
3
3
Reaction of 2-tosyloxytropone (1a) with sodium ethyl-
acetoacetate
(d, C-6), 131.7 (d, C-4), 120.1 (d, C-8), 30.1 (q, COCH ).
3
2
Data of [5,7- H ]-2-methyl-3-ethoxycarbonyl-8H-cyclo-
2
Ϫ1
Using MeONa (0.083 g, 1.54 mmol), ethyl acetoacetate
hepta[b]furan-8-one (3b).
[Found: C 66.8; H 6.0. C13
4.27%, D 1.71 %,]. d
4-H), 7.34 (1 H, br.s, 6-H), 4.42 (2 H, q, OCH
H, s, CH ), 1.43 (3 H, t, OCH CH ). d (CDCl
n
D
max (Nujol) 1710 cm .
O
2 4
(
0.20 mL, 1.6 mmol), and 1a (0.194 g, 0.7 mmol) in
H
10
requires C 66.67%, H
3
,11
DMSO (4 mL), we obtained 2a
2
(0.033 g, 0.175 mmol,
H
(CDCl3, 200 MHz) 8.35 (1 H, br.s,
CH ), 2.82 (3
, 50 MHz)
3
5%) as a yellow solid, mp 207–208ЊC, EtOH; lit. 208–
2
3
2
09ЊC; R 0.57, and 3a (0.022 g, 0.095 mmol, 13.5%) as a
3
2
3
C
3
f
colorless semi-solid, R 0.43.
175.4 (s, C-8), 165.0 (s, COO), 135.9 (d, C-6), 129.3 (d,
f
C-4), 61.0 (t, CH CH ), 15.2 (q, CH -C2), 14.4 (q, CH CH ).
2
3
3
2
3
Data of 3-acetyl-2H-cyclohepta[b]furan-2-one (2a). UV:
lmax(MeOH) nm/(log e) 416 (3.9), 271 (3.8), 247. nmax
Reaction of 2-tosyloxytropone (1a) with sodium acetyl-
acetonate
Ϫ1
(
Nujol) 1733, 1654, 1617, 1584, 1532, 1262 cm . dH
(CD ) CO) 9.13 (1 H, ddd, Jˆ0.6, 1.0,11.3 Hz, 4-H),
3
2
.91 (1 H, ddd, Jˆ1.1, 8.9, 11.3 Hz, 5-H), 7.83 (1 H,
Using MeONa (0.116 g, 2.15 mmol), acetylacetone
(0.26 mL, 2.53 mmol), and 1a (0.260 g, 0.94 mmol) in
DMSO (4 mL), we obtained 4a (0.025 g, 0.12 mmol,
0.0 Hz, 6-H), 2.88 (3 H, s, COCH ). d (CDCl ) 9.19 (1
13%) as a colorless semi-solid, R 0.12, besides an orange
3
H
3
f
H, d, 10.8 Hz, 4-H), 7.69 (1 H, dd, Jˆ10.8, 8.9 Hz, 5-H),
.57 (2 H, m, 7-H and 8-H), 7.42 (1 H, m, 6-H), 2.63 (3 H, s,
COCH ). d (CDCl ) 195.10 (s, COCH ), 167.53 (s, C-2),
colored, unidentified material (0.038 g), R 0.77.
f
7
Data of 2-methyl-3-acetyl-8H-cyclohepta[b]furan-8-one
(4a). UV lmax(MeOH) nm/(log e) 350, 335, 320, 310 series
3
C
3
3
159.12 (s, C-8a), 153.29 (s, C-3), 140.83 (d, C-5), 136.55 (d,
C-7), 135.00 (d, C-6), 131.76 (d, C-4), 120.09 (d, C-8),
of sh, 298 (3.70), 258 (3.96). n (Nujol) 1666, 1611, 1577,
max
ϩ
Ϫ1
1
1
03.57 (s, C-3a), 30.08 (q, COCH ). m/z 188 (36, M ),
1515 cm . dH ((CD ) CO) 8.33 (1 H, ddd, Jˆ0.8, 1.0,
3
3 2
ϩ
ϩ
73 (100, [MϪMe] ), 89 (23), 43 (23). HR-MS: M ,
11.3 Hz, 4-H), 7.15 (1 H, ddd, Jˆ0.8, 8.6, 11.3 Hz, 5-H),
ϩ
3
found 188.0473^0.005. C H O requires 188.0473);
7.42 (1 H, ddd, Jˆ1.0, 8.6, 12.4 Hz, 6-H), 7.16 (1 H, ddd,
1
1
8
ϩ
ϩ
3
[MϪMe] , found 173.0231^0.001. C H O requires
Jˆ0.8, 0.8, 12.4 Hz, 7-H), 2.87 (3 H, s, COCH ), 2.64 (s,
1
0
5
3
173.0239).
CH -C2). d (CDCl , 200 MHz) 8.40 (1 H, d, Jˆ11.1 Hz,
3
H
3

M. Cavazza et al. / Tetrahedron 56 (2000) 1917–1922
1921
4
-H), 7.36 (1 H, m, 6-H), 7.29 (1 H, m, 7-H), 7.07 (1 H, ddd,
Data of (S)-N-(5,6,7,11-tetrahydro-1,2,3-trimethoxy-12-
ethoxycarbonyl benzo[a]heptaleno[8,9-b]furan-11-one-
7-yl) acetamide (16). UV lmax(MeOH)/nm/(log e) 431,
264, 220 (4.5) (in EtOH the absorption maxima are shifted
to 433, 263, and 222 nm). CD l (De) (EtOH) 270 (ϩ11.3),
242 (ϩ4.2), 215 (Ϫ9.9). nmax (Nujol) 1756, 1751, 1650,
1582, 1516, 1467. d ((CD ) CO) 8.97 (1 H, s, 13-H), 7.98
Jˆ1.1, 8.6, 1.0 Hz, 5-H), 2.87 (3 H, s, COCH ), 2.63 (3 H, s,
3
CH -C2). d (CDCl , 50 MHz) 194.8 (s, COCH ), 173.4 (s,
3
C
3
3
C-8), 163.9 (s, C-2), 138.4 (d, C-7), 136.4 (d, C-6), 129.9 (d,
C-5), 128.9 (d, C-4), 31.5 (q, COCH ), 15.7 (q, CH -C2).
m/z 202 (76, M ), 187 (11, [MϪMe] ), 174 (14, [MϪCO] ),
3
3
ϩ
ϩ
ϩ
ϩ
ϩ
1
59 (100, [MϪMeCO] ), 131 (8, [MϪCOϪCOMe] , 43
H
3 2
ϩ
ϩ
3
(33); HR-MS: M found 202.0631^0.005. C H O
(1 H, br. d, Jˆ6.7 Hz, NH), 7.88 (1 H, d, Jˆ10.4 Hz, 9a-H),
7.63 (1 H, d, Jˆ10.4 Hz, 8-H), 6.82 (1 H, s, 4-H), 4.55 (1 H,
ddd, Jˆ4.1, 6.7, 12.8 Hz, 7-H), 4.27 (2 H, m, OCH CH ),
1
2
10
requires 202.0627.
2
3
3
.93 (3 H, s, CH O-C3), 3.90 (3 H, 3 H, s, CH O-C2), 3.71 (s,
3 3
3
.34 (1 H, ddd, Jˆ6.2, 12.8, 12.8 Hz, 5-H pro-R), 2.22 (1 H,
2
Reaction of [3,5,7- H ]-2-tosyloxytropone (1b) with
sodium ethylacetoacetate
3
CH O-C1), 2.66 (1 H, ddd, Jˆ2.1, 5.0,12.8 Hz, 5-H pro-S),
2
ddd, Jˆ6.2, 12.8, 12.8 Hz, 6-H pro-S), 1.99 (1 H, dddd,
Jˆ4.1, 5.0, 10.2,12.8 Hz, 6-H pro-R), 1.93 (3 H, s,
COCH ), 1.30 (3 H, t, Jˆ7.0 Hz, OCH CH ); NOE
Following the same procedure—with the same amounts of
reagents—as for the undeuterated analog, 4b was obtained
as a semi-solid in similar yield.
3
2
3
((CD ) CO): enhancements of 7% at 12-H on irradiation
3 2
CH O-C1, and vice versa; 9% at 4-H on irradiation at
3
2
CH O-C3; 4% at 4-H on irradiation at 5-H. d ((CD ) CO)
3
C
3 2
Data of [5,7- H ]-2-methyl-3-acetyl-8H-cyclohepta[b]-
2
Ϫ1
169.49 (s), 165.32 (s) 164.04 (s), 157.94 (s), 155.58 (s),
furan-8-one (4b). nmax (Nujol) 1667 cm . [Found: C
1
1
1
52.47 (s), 151.73 (s), 150.44 (s), 149.82 (s), 142.37 (s),
35.46 (s), 134.39 (d, C-13), 131.37 (d, C-9), 127.03 (s),
18.73 (d, C-8), 108.36 (d, C-4), 94.44 (s), 61.89 (q,
7
1.1; H 5.7. C H D O requires C 70.58%, H 3.92%, D
12 8 2 3
1
.96%]. dH (CDCl , 200 MHz) 8.40 (1 H, br.s, 4-H), 7.36
1 H, br.s, 6-H), 2.87 (3 H, s, COCH ), 2.63 (3 H, s, CH ).
3
(
3 3
CH O-C1), 61.18 (q, CH O-C2), 60.29 (t, OCH CH ),
3
3
2
3
5
6.37 (q, CH O-C3), 53.39 (d, C-7), 37.62 (t, C-5), 22.60
3
Reaction of 2-tosyloxytropone (1a) with sodium diethyl
malonate
(q, NHCOCH ), 14.66 (q, OCH CH ), while signals for C-6
3 2 3
ϩ
were buried under the solvent signals. m/z 481 (2, [M] ), 407
ϩ
ϩ
(
4, [MϪNH COMeϪMe] ), 368 (2), 28 (100); HR-MS: M
2
ϩ
Using MeONa (0.130 g, 2.4 mmol), diethyl malonate
found 481.1722^0.005. C H NO requires 481.1737).
26
27
8
(0.44 mL, 2.9 mmol) and 1a (0.298 g, 1.1 mmol) in
DMSO (4 mL), we obtained 5 (0.098 g, 0.45 mmol, 42%),
R 0.66 as a yellow crystalline solid, mp 129–130ЊC from
Reaction of 10-tosyloxycolchicide (17) or 10-chloro-
colchicide (18) with sodium diethyl malonate
f
3
Et O (lit. 129–130ЊC).
2
MeONa (0.021 g, 0.39 mmol) and diethyl malonate
0.100 mL, 0.66 mmol) were mixed with 17 (0.062 g,
0.11 mmol) in DMSO (2 mL) and the mixture was stirred
for 1 h. From the residue of work up, a TLC yellow spot at
Rf 0.64 was extracted and subjected to reversed-phase
HPLC, obtaining 19 (tR 6.3 min, 0.001 g, 0.0021 mmol,
Data of 3-ethoxycarbonyl-2H-cyclohepta[b]furan-2-one
(
(
(
5). UV lmax(MeOH) nm/(log e) 398 (3.9), 260, 247. n
max
Ϫ1
Nujol) 1764, 1689, 1654, 1587, 1531, 1270 cm . dH
(
(CD ) CO) 8.79 (1 H, ddd, Jˆ0.8, 1.0, 11.4 Hz, 4-H),
3
2
7
.82 (1 H, ddd, Jˆ1.1, 8.9,11.4 Hz, 5-H), 7.71 (1 H, dddd,
Jˆ0.8, 1.0, 9.4, 10.5 Hz, 7-H), 7.63 (dd, Jˆ1.4, 9.4 Hz,
1
8
0%) and unreacted 17 (t 9.0 min, 0.049 g, 0.088 mmol,
R
8
-H), 7.51 (1 H, dddd, Jˆ0.8, 1.4, 8.9, 10.5 Hz, 6-H),
0%). In a better procedure, 17 was replaced with 10-chloro-
4
.32 (2 H, q, CH CH ), 1.34 (3 H, t, CH CH ). d
2
3
2
3
C
12
colchicide (18); work up as above gave 19 (R 0.66,
f
(
(CD ) CO) 164.94 (s, COO), 163.87 (s, C-2), 159.32 (s,
3 2
0
0
.025 g, 0.052 mmol, 29%) and unreacted 18 (R 0.49,
.029 g, 0.072 mmol, 40%).
f
C-8a), 155.30 (s, C-3), 140.98 (d, C-5), 137.61 (d, C-7),
35.06 (d, C-6), 130.71 (d, C-4), 129.30 (s, C-3a), 120.06
d, C-8), 60.57 (t, CH CH ), 14.66 (q, CH CH ). m/z 218
1
(
(
2
3
2
3
ϩ
ϩ
ϩ
Data of (S)-N-(5,6,7,11a-tetrahydro-1,2,3-trimethoxy-11-
ethoxycarbonyl benzo[a]heptaleno[7,8-b]furan-10-one-
7-yl) acetamide (19). UV lmax(MeOH) nm/(log e) 425,
60, M ), 173 (100, [MϪOEt] ), 146 (97, [MϪCO Et] ),
9 (34), 63 (20). HR-MS: M found 218.0571^0.005.
2
ϩ
8
ϩ
4
C H O requires 218.0576.
12
10
2
2
63, 235 (4.4). CD l (De) (EtOH) 427 (Ϫ2.6), 330 (Ϫ3.6),
70 (ϩ1.7), 235 (ϩ7.6), 223 (Ϫ15.1). d ((CD ) CO) 8.66
H
3 2
Reaction of 9-tosyloxyisocolchicide (15) with sodium
diethyl malonate
(1 H, d, Jˆ11.8 Hz, 12-H), 7.80 (1 H, d, Jˆ11.8 Hz, 13-H),
7.78 (s, 8-H), 6.85 (1 H, s, 4-H), 4.56 (1 H, ddd, Jˆ4.1, 6.7,
1
2.8 Hz, 7-H), 4.32 (2 H, m, OCH CH ), 3.92 (3 H, s,
2 3
Using MeONa (0.033 g, 0.61 mmol), diethyl malonate
CH O-C3), 3.88 (3 H, s, CH O-C2), 3.66 (3 H, s, CH O-
3 3 3
(
(
(
0.130 mL, 0.86 mmol), and 9-tosyloxyisocolchicide
0.099 g, 0.18 mmol) in DMSO (2 mL), we obtained 16
0.011 g, 0.023 mmol, 12%) as a yellow semi-solid, Rf
C1), 2.66 (1 H, dddd, Jˆ2.1, 5.0, 12.8 Hz, 5-H pro-S), 2.36
(1 H, ddd, Jˆ6.2, 12.8, 12.8 Hz, 5-H pro-R), 2.22 (1 H, ddd,
Jˆ6.2, 12.8, 12.8 Hz, 6-H pro-S), 1.99 (1 H, dddd, Jˆ4.1,
0
.51. Eluting with CHCl /(CH ) CO 3:2, compound 15
5.0, 12.8 Hz, 6-H pro-R),1.97 (3 H, s, COCH ), 1.27 (3 H, t,
3
ϩ
3
3 2
was observed at R ˆ0.45, accompanied by much colchiceine
Jˆ7.0 Hz, OCH
2
CH
COMeϪMe] ), 368 (1), 207 (2), 28 (100).
2
), NH not detected. m/z 481 (3, [M] ),
3
ϩ
f
at R ˆ0.14. UV analysis of the reaction mixture, based on
407 (4, [MϪNH
f
ϩ
ϩ
molar absorption for isolated, pure 16, showed that the latter
HR-MS: M found 481.1719^0.005. C26H27NO requires
8
was formed in 50% yield.
481.1737).

1
922
M. Cavazza et al. / Tetrahedron 56 (2000) 1917–1922
MeO-C1 from the other side. For 16, the least-strain conformer
Acknowledgements
in the Fig. 1 was obtained by molecular mechanics calculations
using the MM3(96) computer program from QCPE, Indiana
University. In contrast, the computer program mmff94, as imple-
mented into PC Spartan Pro, either V. 1.0 or 1.0.1 from Wavefunc-
tion, Inc., Irvine, CA, in our hands gave unreliable outputs. In a
check with colchicine (Donaldson, W. A. Tetrahedron 1988, 44,
We thank A. Sterni for the MS spectra, and both MURST
Progetti di Interesse Nazionale) and CNR, Roma, for financial
support.
(
References
7
3
409–7412; Berg, U.; Bladh, H. Helv. Chim. Acta 1999, 82, 323–
25), mmff94 placed the NHAc group incorrectly into the pseudo-
1
2
. Ridgby, J. A. Tetrahedron 1999, 55, 4521–4538.
. Shimoma, F.; Kusaka, H.; Wada, K.; Azami, H.; Yasunami, M.;
axial position. Also bulkier groups, in place of NHAc, could not be
moved from the pseudoaxial to the pseudoequatorial position using
mmff94 under the ‘conformer distribution’ option.
Suzuki, T.; Hagiwara, H.; Ando, M. J. Org. Chem. 1998, 63, 920–
9
3
2
4
5
29.
6
2
7
8
. Cavazza, M.; Pietra, F. J. Chem. Soc., Perkin Trans. 1 1995,
657–2661.
. Cavazza, M.; Pietra, F. Tetrahedron 1998, 54, 14059–14064.
. It is interesting that, in contrast, C-8 of colchicine is involved in
. Nozoe, T.; Takase, K.; Kato, M.; Nogi, T. Tetrahedron 1971,
7, 6023–6035.
. Pietra, F. Acc. Chem. Res. 1979, 12, 132–138.
. The least-strain conformer of 16 (Fig. 1) proved helpful in
1
Diels–Alder cycloadditions with strained alkynes (Brecht, R.;
Haenel, F.; Seitz, G.; Frenzen, G.; Pilz, A.; Gu e´ nard, D. Eur. J.
Org. Chem. 1998, 2451–2460).
confirming the NMR assignments. Thus, the H NMR coupling
pattern in the segment C5–C7 matches the J values calculated
by Altona’s equation (Haasnoot, C. A. G.; De Leeuw, F. A. A.
M.; Altona, C. Tetrahedron 1980, 36, 2783–2792) for this con-
former; in particular, (i) a H5proS–C5–C6–H6proR dihedral
angle of 70Њ accounts for lack of a detectable coupling between
these two protons and (ii) a H5proR–C5–C6–H6proR dihedral
angle of 165Њ fits for the large coupling, Jˆ12.8 Hz, between
these two protons. Moreover, the conformer in the Fig. 1 accounts
for the observed NOE enhancements between 4-H and both
H5proS and MeO-C3 from one side, and between 13-H and
9
. Brossi, A.; Yeh, H. J. C.; Chrzanowska, M.; Wolf, J.; Hamel, E.;
Lin, C. M.; Quin, F.; Suffness, M.; Silverto J. Med. Res. Rev. 1988,
8
1
1
1
, 77–94.
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1. Nozoe, T.; Takase, K.; Nakazawa, T.; Fukuda, S. Tetrahedron
971, 27, 3357–3368.
12. Cavazza, M.; Pietra, F. Synth. Commun. 1997, 27, 3405–3413.