A short stereoselective preparation of dienamides from cyclobutene compounds. Application in the synthesis of a new cyclohexene nucleoside

Article abstract of DOI:10.1021/jo001467v

A short stereoselective synthesis of N-acylamino-1,3-dienes was developed starting from the cyclobutene lactani 8, which was obtained from 2-hydroxypyridine by a photochemical electrocyclic reaction. The tert-butoxycarbonyl derivative 17 was prepared to facilitate nucleophilic attacks to the Carbonyl group, and the subsequent thermal ring opening provided dienes 18-21. One of these (20) was used in the synthesis of the cyclohexene nucleoside 30. A Diels-Alder reaction between diene 20 and maleic anhydride provided the endo-cycloadduct 22a. Three additional steps yielded amine 26. Construction of the uracil moiety afforded intermediate 29. Cyclization and removal of the protecting groups occurred in one step in the presence of ammonia, giving the target molecule 30. Diene 20 also underwent [4 + 2] cycloaddition with methyl acrylate to provide predominantly the endo-product 23a, regioselectively.

Full text of DOI:10.1021/jo001467v

J . Org. Chem. 2001, 66, 583-588
583
A Sh or t Ster eoselective P r ep a r a tion of Dien a m id es fr om
Cyclobu ten e Com p ou n d s. Ap p lica tion in th e Syn th esis of a New
Cycloh exen e Nu cleosid e
Noe¨lle Gauvry and Franc¸ois Huet*
Laboratoire de Synthe`se Organique, UMR CNRS 6011, Faculte´ des Sciences, Universite´ du Maine,
Avenue Olivier Messiaen, F-72085 Le Mans Cedex 9, France
fhuet@univ-lemans.fr
Received October 11, 2000
A short stereoselective synthesis of N-acylamino-1,3-dienes was developed starting from the
cyclobutene lactam 8, which was obtained from 2-hydroxypyridine by a photochemical electrocyclic
reaction. The tert-butoxycarbonyl derivative 17 was prepared to facilitate nucleophilic attacks to
the carbonyl group, and the subsequent thermal ring opening provided dienes 18-21. One of these
(20) was used in the synthesis of the cyclohexene nucleoside 30. A Diels-Alder reaction between
diene 20 and maleic anhydride provided the endo-cycloadduct 22a . Three additional steps yielded
amine 26. Construction of the uracil moiety afforded intermediate 29. Cyclization and removal of
the protecting groups occurred in one step in the presence of ammonia, giving the target molecule
30. Diene 20 also underwent [4 + 2] cycloaddition with methyl acrylate to provide predominantly
the endo-product 23a , regioselectively.
Sch em e 1
In tr od u ction
The use of N-acylamino-1,3-dienes in Diels-Alder
reactions has become popular, especially in connection
with alkaloid synthesis.1 The first general method for the
preparation of dienamides, described by Oppolzer and co-
workers,2 involves the acylation of vinylimines in the
presence of a tertiary amine. A second useful approach
to these dienes, based on the Curtius rearrangement of
dienoic acid azides, was reported by Overman et al.3 In
these literature methods, the C-4 carbon is often substi-
tuted by an alkyl or an aryl group.
Herein we present our results on the synthesis of diene
carbamates bearing different functionalities at C-4. Our
strategy employs cyclobutenes as precursors and allows
stereoselective preparation of either (Z,E) or (E,E) dienes.
The formation of dienes by thermal opening of cy-
clobutenes is a long established route,4a but it suffers
from several limitations. For instance, the method is
efficient only if the starting cyclobutenes are easily
available and if the thermal opening gives a single isomer
of the possible dienes. Moreover, this diene must be stable
at the temperature required for the opening. When the
starting unsymmetrical cyclobutene compound contains
two cis-substituents at the allylic position (1), both (Z,E)-
products 2 and 3 are usually obtained.4b,c However, recent
theoretical studies from Houk’s group5 and experimental
work from our laboratory6 have shown that nitrogen
substituents have a strong outward rotation preference
and thus provide excellent stereochemical control (Scheme
1). A subsequent isomerization into (E,E)-products has
been observed upon standing in several cases.
Such bifunctional (Z,E)- or (E,E)-dienes have found
several applications as a diene moiety7 and in annulation
reactions.8 We planed to investigate their use in the
preparation of substituted cyclohexene compounds via a
Diels-Alder reaction in the course of the synthesis of
* To whom correspondence should be addressed. Tel: 33 2 43 83 33
38. Fax: 33 2 43 83 39 02.
(1) For reviews, see: (a) Petrzilka, M.; Grayson, J . I. Synthesis 1981,
753-786. (b) Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421-452.
(2) (a) Oppolzer, W.; Fro¨stl, W. Helv. Chim. Acta 1975, 58, 587-
589. (b) Oppolzer, W.; Fro¨stl, W.; Weber, H. P. Helv. Chim. Acta 1975,
58, 590-595. (c) Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron
Lett. 1979, 981-984.
(3) (a) Overman, L. E.; Taylor, G. F.; J essup, P. Tetrahedron Lett.
1976, 3089-3092. (b) Overman, L. E.; Taylor, G. F.; Petty, C. B.;
J essup, P. J . J . Org. Chem. 1978, 43, 2164-2167. (c) Overman, L. E.;
Taylor, G. F.; Houk, K. N.; Domelsmith, L. N. J . Am. Chem. Soc. 1978,
100, 3182-3189. (d) Overman, L.; J essup, P. J . J . Am. Chem. Soc. 1978,
100, 5179-5185.
(4) (a) Durst, T.; Breau, L. Cyclobutene Ring Opening Reactions.
In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.;
Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 675-
697. (b) Trost, B. M.; Mc Dougal, P. G. J . Org. Chem. 1984, 49, 458-
468. (c) Binns, F.; Hayes, R.; Hodgetts, K. J .; Saengchantara, S. T.;
Wallace, T. W.; Wallis, C. J . Tetrahedron 1996, 52, 3631-3658 and
references therein.
(5) Niwayama, S.; Kallel, E. A.; Spellmeyer, D. C.; Sheu, C.; Houk,
K. N. J . Org. Chem. 1996, 61, 2813-2825.
(6) (a) Gourdel-Martin, M.-E.; Huet, F. J . Org. Chem. 1997, 62,
2166-2172. (b) Gourdel-Martin, M.-E.; Huet, F. Tetrahedron Lett.
1996, 37, 7745-7748.
(7) Shimasaki, H.; Kagechika, H.; Fukasawa, H.; Kawachi, E.;
Shudo, K. Chem. Pharm. Bull. 1995, 43, 100-107.
(8) (a) Koike, T.; Tanabe, M.; Takeuchi, N.; Tobinaga S. Chem.
Pharm. Bull. 1997, 45, 27-31. (b) Koike, T.; Tanabe, M.; Takeuchi,
N.; Tobinaga, S. Chem. Pharm. Bull. 1997, 45, 243-248.
10.1021/jo001467v CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/23/2000

584 J . Org. Chem., Vol. 66, No. 2, 2001
Gauvry and Huet
and its phosphorylated analogue 11b.11c The syntheses
of 11 started from cyclohexadiene and involved either the
corresponding monoepoxide,11a,b or the 1,4-trans-cyclo-
hexenediol11c as intermediates. In the case of 10a ,b the
key step in one of the sequences10a was a cycloaddition
between cyclohexadiene and chlorosulfonyl isocyanate.
In another report, a 1,2-disubstituted product 12 was
prepared from phthalic anhydride.12 Cis- and trans-1,3-
disubstituted products13 and several trisubstituted
products11b,14,15 such as enantiomerically pure 13 and 14
have also been prepared. The synthesis of 13 was
achieved via an enzymatic resolution of trans-4,5-bis-
(hydroxymethyl)cyclohexene,14 and 14 was obtained from
R-(-)-carvone.15 Cyclohexene compounds substituted at
the vinylic position have also been described.11a,16
The main advantages of the strategy we envisaged,
based on a Diels-Alder reaction, include the short
synthetic route and the possibility of introducing several
substituents cis to the base moiety in one step via endo
selectivity.
Resu lts a n d Discu ssion
F igu r e 1. Cyclohexenyl nucleoside analogues.
Access to Dien es. The starting lactam 8 was obtained
from the commercially available 2-hydroxypyridine 9, in
aqueous solution, by the photochemical method previ-
ously described by Dilling.9 However, this reaction must
be carried out under very dilute conditions (10-3 M) and
several days of irradiation in order to provide high yields
(88%). Under these conditions, the scale of the reaction
is too small for preparative purposes. We found that the
scale could be increased with only a modest reduction in
the yield. As compound 9 is inexpensive, this lowered
yield is tolerable. Performing the reaction at a concentra-
tion of 4.7 × 10-2 M provided lactam 8 in an acceptable
46% yield, providing approximately 2.1 g of product on
average per run with our photochemical apparatus. When
the concentration was increased to 5.2 × 10-2 M, the yield
decreased further to 30% providing only 1.50 g of lactam
8. Under these conditions, the formation of [4 + 4]
products becomes competitive.17
Sch em e 2
cyclohexene nucleosides 4 (Scheme 2). In this case the
dienophile should bear one or two substituents, R1 and
R2, which can be converted to OH or CH2OH groups
afterward. In our early experiments, with these dienes,
the nitrogen-substituted cyclobutenes were prepared via
a Hofmann rearrangement.6a The synthetic route could
be shortened by using a cyclobutene already bearing a
nitrogen atom at the allylic position. A potentially
interesting compound, from this point of view, was lactam
8, which is available in one step, through a photochemical
electrocyclic reaction, from 2-hydroxypyridine 9.9
The synthesis of nucleoside analogues as potential
antiviral and anticancer agents is a very active field of
research. In this area, several interesting results have
been obtained in the preparation of cyclohexene nucleo-
sides during the past few years (Figure 1). To the best of
our knowledge, although several methods have been used
for the syntheses of these compounds, only a few of them
allow for the introduction of the nitrogen at an early
stage. Considerable effort in this area has been devoted
to homocarbovir 10,10 the cyclohexenyl nucleoside 11a ,11a,b
We had previously synthesized (Z,E)-diene 18,6b as a
single isomer, by the thermal opening of cyclobutene 16,
available in 60% overall yield6a from 1518 in five steps
(Scheme 3). The new experiments with lactam 8 show
(11) (a) Arango, J . H.; Geer, A.; Rodriguez, J .; Young, P. E.; Scheiner,
P. Nucleosides Nucleotides 1993, 12, 773-784. (b) Ramesh, K.; Wolfe,
M. S.; Lee, Y.; Vander Velde, D.; Borchardt, R. T. J . Org. Chem. 1992,
57, 5861-5868. (c) Pe´rez-Pe´rez, M.-J .; Rozenski, J .; Busson, R.;
Herdewijn, P. J . Org. Chem. 1995, 60, 1531-1537.
(12) Von Langen, D. J .; Tolman, R. L. Tetrahedron: Asymmetry
1997, 8, 677-681.
(13) (a) Konkel, M. J .; Vince, R. Nucleosides Nucleotides 1995, 14,
2061-2077. (b) Konkel, M. J .; Vince R. Tetrahedron 1996, 52, 8969-
8978.
(14) Rosenquist, A.; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J .
Org. Chem. 1996, 61, 6282-6288.
(15) Wang, J .; Herdewijn, P. J . Org. Chem. 1999, 64, 7820-7827.
(16) Maurinsh, Y.; Schraml, J .; De Winter, H.; Blaton, N.; Peeters,
O.; Lescrinier, E.; Rozenski, J .; Van Aerschot, A.; De Clercq, E.; Busson,
R.; Herdewijn, P. J . Org. Chem. 1997, 62, 2861-2871.
(17) For examples of [4 + 4] dimerization of 2-pyridones, see: (a)
Paquette, L. A.; Slomp, G. J . Am. Chem. Soc. 1963, 85, 765-769. (b)
Taylor, E. C.; Kan, R. O. J . Am. Chem. Soc. 1963, 85, 776-784. (c)
Sieburth, S. McN.; Hiel, G.; Lin, C.-H.; Kuan, D. P. J . Org. Chem. 1994,
59, 80-87.
(18) (a) Brauman, J . I.; Archie, W. C., J r. J . Am. Chem. Soc. 1972,
94, 4262-4265. (b) Bloomfield, J . J .; Owsley, D. C. Org. Photochem.
Synth. 1976, 2, 36-40. (c) Binns, F.; Hayes, R.; Ingham, S.; Saengchan-
tara, S. T.; Turner, R. W.; Wallace, T. W. Tetrahedron 1992, 48, 515-
530. (d) Gauvry, N.; Comoy, C.; Lescop, C.; Huet, F. Synthesis 1999,
574-576.
(9) Dilling, W. L. Org. Photochem. Synth. 1976, 2, 5-6.
(10) (a) Konkel, M. J .; Vince, R. Tetrahedron 1996, 52, 799-808.
(b) Katagiri, N.; Ito, Y.; Shiraishi, T.; Maruyama, T.; Sato, Y.; Kaneko,
C. Nucleosides Nucleotides 1996, 15, 631-647. (c) Olivo, H. F.; Yu, J .
J . Chem. Soc., Perkin Trans. 1 1998, 391-392.

Dienamides from Cyclobutene Compounds
J . Org. Chem., Vol. 66, No. 2, 2001 585
Sch em e 3a
F igu r e 2. Significant coupling constants and NOE enhance-
ments.
by isomerization to the more stable diene 20 in the basic
reaction medium, a type of isomerization for which there
is precedent.20 This is supported by several observations.
Treatment of diene 21 with LiOH in MeOH afforded
diene 20 in less than 1 h. When the ring-opening reaction
of 17 was run in a neutral medium, under the experi-
mental conditions of Palomo et al.,21 in the presence of
sodium azide, the expected (Z,E)-diene 21 was formed,
but it could not be isolated and quickly gave degradation
products. On the other hand, esterification of acid 19
under mild conditions with diazomethane afforded diene
21 in a stable form.
1
The dienes in this paper were identified by H NMR
spectroscopy (Figure 2). Coupling constants between H-4
and H-5 for 18 and 20, albeit moderate, were consistent
with those observed for trans-relationships in similar
nitrogen compounds.6b,7 NOE experiments confirmed
these assignments for both compounds. In the cases of
19 and 21, one of the coupling constants could not be
measured due to overlapping signals. However, as 20 was
undoubtedly identified, the structure of its isomer 21,
with an expected (Z,E)-structure, was deduced from the
lower J 2-3. Compound 19 also exhibited a moderate
coupling constant between H-2 and H-3. Moreover, the
formation of diene 21 from esterification of acid 19 was
consistent with these results.
a
Reagents and conditions: (a) Boc2O, DMAP, Et3N, CH2Cl2; (b)
NaBH4, MeOH, -20 °C; (c) toluene, reflux, 10 min; (d) LiOH, H2O,
THF; (e) LiOH, MeOH; (f) NaN3, MeOH, DMF; (g) CH2N2, Et2O.
Cycloa d d ition s a n d Selectivities. We attempted to
carry out Diels-Alder reactions with these dienes. Nu-
merous attempts to cyclize diene 18, or derivatives of 18
in which both hydrogen atoms were replaced by methyl
or benzyl groups, and maleic anhydride, without a
catalyst, or in the presence of Lewis acids (AlCl3, ZnCl2,
SnCl4, TiCl4), failed to give the expected products due to
rapid degradation of the dienes. In contrast, diene 20
reacted readily to provide a single product in 92% yield.
This product was clearly identified as the endo-adduct
22a from NOE experiments (Scheme 4). Moreover, analy-
sis of the coupling constants confirmed this identification
and showed that the predominant conformation of adduct
22a was folded rather than extended.22 Of the main
expected conformations of 22a and the exo-isomer 22b,
the small J 2-3 and J 4-5 coupling constants, in agreement
with a pseudoaxial position for H-2 and H-5, were
consistent only with conformations A or D. However the
that this compound is an excellent precursor to several
dienes provided that it is first converted into the tert-
butoxycarbonyl derivative 17 to facilitate the nucleophilic
additions.6a,19 Reaction with sodium borohydride led to a
1:1 mixture of cyclobutene 16 and diene 18, which was
completely converted to diene 18 by briefly heating the
mixture. This diene was therefore easily obtained by a
short synthetic route. The reaction of cyclobutene 17 with
lithium hydroxide provided (Z,E)-diene 19. The facile
thermal opening of the cyclobutene intermediate is not
surprising and was probably due to the presence, in this
case, of two substituents with complementary preferences
for the conrotatory mode.4c,5,6b The nucleophilic attack of
methanol to cyclobutene 17, under basic conditions, also
afforded a diene via a thermally unstable cyclobutene
compound. However, in this case, the product was the
(E,E)-isomer 20. One possible explanation for this result
is isomerization of the cis-cyclobutene intermediate to the
trans-compound, under base catalysis, prior to ring
opening. However, a more likely explanation is the
formation of diene 21 as the primary product followed
(20) Prokof’ev, E. P.; Krasnaya, Zh. A.; Kucherov, V. K. Izv. Akad.
Nauk. SSSR, Ser. Khim. 1972, 10, 2218-2225.
(21) Palomo, C.; Aizpurua, J . M.; Cuevas, C.; Mielgo, A.; Galarza,
R. Tetrahedron Lett. 1995, 36, 9027-9030.
(22) See for instance (a) Danishefsky, S.; Yan, C. F.; Singh, R. K.;
Gammill, R. B.; McCurry, P. M.; Fritsch, N.; Clardy, J . J . Am. Chem.
Soc. 1979, 101, 7001-7008. (b) Maddaluno, J .; Gaonac’h, O.; Marcual,
A.; Toupet, L.; Giessner-Prettre, C. J . Org. Chem. 1996, 61, 5290-
5306.
(19) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.

586 J . Org. Chem., Vol. 66, No. 2, 2001
Gauvry and Huet
Sch em e 4
Sch em e 5
Sch em e 6a
moderate J 1-2 and J 5-6 coupling constants were not
consistent with the trans-diaxial relationships present
in D.
The reaction of diene 20 with excess methyl acrylate
in toluene provided a mixture of two adducts 23a and
23b in a 90:10 ratio, respectively (Scheme 5). In both
isomers, H-1, which was easily assigned by decoupling
from NH, was coupled with proton H-6, adjacent to a
methoxycarbonyl group. NOE experiments showed that
the major product was the endo-isomer, and the large
J 5′-4 and J 5′-6 coupling constants showed that the pre-
dominant conformer was F . Thus, the cycloaddition
occurred with complete regioselectivity and with high
endo-selectivity.
Syn th esis of th e Nu cleosid e An a logu e 30. The
reduction of 22a , followed by benzoylation, provided
compound 25 in moderate yield (Scheme 6). Several
attempts under different experimental conditions failed
to improve the yield. Removal of the amine protecting
group yielded amine 26. To avoid an internal acyl
transfer, transforming amine 26 to amide 27, which
occurred upon standing, amine 26 was immediately
treated with isocyanate 2823 to give compound 29.
Finally, cyclization and removal of the protecting group
from compound 29 occurred in one step, providing the
cyclohexene nucleoside analogue 30. This compound is
the first cyclohexene nucleoside analogue with four
substituents in an all cis-relationship.
a
Reagents and conditions: (a) LiAlH4, THF, reflux; (b) BzCl,
pyridine, CH2Cl2; (c) TFA, CH2Cl2; (d) upon standing; (e) benzene;
(f) NH3, MeOH.
In conclusion, several diene carbamates were synthe-
sized by a short and selective route. Two examples of
(23) Shaw, G.; Warrener, R. N. J . Chem. Soc. 1958, 153-161.

Dienamides from Cyclobutene Compounds
J . Org. Chem., Vol. 66, No. 2, 2001 587
7.0 Hz), 4.24 (m, 2H, CH2), 1.48 (s, 9H, CH3); 13C NMR (CDCl3)
δ 152.6, 129.1, 128.8, 124.9, 105.4, 79.8, 58.4, 28.2; HRMS calcd
for (C10H17NO3) 199.1208, found 199.1207.
Diels-Alder reactions with one of these dienes provided
cycloadducts in high yields with good selectivity. Thus,
several cyclohexene derivatives were efficiently obtained
from a cyclobutene. The synthesis of the novel cyclohex-
ene nucleoside 30 illustrates the utility of these dienes.
(2Z,4E)-5-(ter t-Bu toxyca r bon yla m in o)p en ta -2,4-d ien o-
ic Acid (19). Solid LiOH (0.37 g, 15.40 mmol) was added to a
solution of compound 17 (1.00 g, 5.12 mmol) in THF (20 mL)
and water (15 mL). The mixture was stirred at room temper-
ature for 16 h, and the solvent was removed in vacuo. The
aqueous layer was acidified with acetic acid to pH 4 and
extracted with EtOAc. The combined extracts were washed
with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by recrystallization (MeOH) to give
compound 19 (0.96 g, 88%) as colorless crystals: mp 175-179
Exp er im en ta l Section
Gen er a l. All moisture-sensitive reactions were carried out
in oven-dried glassware (110 °C) under a nitrogen atmosphere.
Commercially available reagents and solvents were purified
and dried, when necessary, by standard methods just prior to
use. IR spectra were scanned on a FT infrared spectropho-
1
°C (dec); IR (KBr) 3500, 1698, 1629 cm-1; H NMR (DMSO-
1
tometer. All melting points are uncorrected. H and 13C NMR
d6) δ 11.82 (s, 1H, OH), 9.86 (br s, 1H, NH), 7.05-6.92 (m,
2H, H-4 and H-5), 6.64 (dd, 1H, H-3, J ) 10.8, 10.8 Hz), 5.29
(d, 1H, H-2, J ) 10.8 Hz), 1.43 (s, 9H, (CH3)3); 13C NMR
(DMSO-d6) δ 167.8, 152.4, 144.8, 137.3, 111.9, 106.9, 80.1, 27.8.
Anal. Calcd for C10H15O4N: C, 56.33; H, 7.09; N, 6.57. Found:
C, 56.11; H, 6.81; N, 6.42.
spectra were recorded at 400 and 100.6 MHz, respectively.
Chemical shifts are reported in ppm downfield from TMS
which was used as an internal reference. Multiplicities in the
13C spectra were determined by DEPT experiments, and
numerous assignments were obtained by 13C/1H HETCOR
experiments. Ratios in mixtures of isomers were calculated
from 1H NMR. Elemental analyses were obtained from the
Service de Microanalyze, CNRS ICSN, Gif-sur-Yvette. High-
resolution mass measurements were performed at the CRM-
PO, Rennes.
(2E,4E)-5-(ter t-Bu toxyca r bon yla m in o)p en ta -2,4-d ien o-
ic Acid Meth yl Ester (20). Solid LiOH (0.92 g, 38.40 mmol)
was added to a solution of compound 17 (2.50 g, 12.81 mmol)
in dry MeOH (80 mL). The mixture was stirred at room
temperature for 3 h, and the solvent was removed in vacuo.
The residue was dissolved in EtOAc, washed with H2O and
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by recrystallization (Et2O/petroleum, 2:3)
to afford compound 20 (2.27 g, 78%) as yellow crystals: mp
2-Aza bicyclo[2.2.0]h ex-5-en -3-on e (8). Compound 8 was
prepared according to the procedure described by Dilling.9 A
solution of 2-hydroxypyridine (4.50 g, 47.32 mmol) in H2O (2.9
L) was internally irradiated (Mazda, MAF 400 W) at 25-28
°C for 62 h. The water was removed in vacuo, and the residue
was purified by sublimation (80 °C, 20-30 mmHg) to give the
title compound (2.09 g, 46%) as colorless crystals: mp 67-68
123-125 °C; IR (KBr) 1712, 1639 cm-1 1H NMR (CDCl3) δ
;
7.29 (dd, 1H, H-3, J ) 15.2, 11.8 Hz), 7.05 (m, 1H, H-5, J )
11.8, 11.8 Hz), 5.80 (br d, 1H, NH, J ) 11.8 Hz), 5.73 (dd, 1H,
H-4, J ) 11.8, 11.8 Hz), 5.71 (d, 1H, H-2, J ) 15.2 Hz), 3.73
(s, 3H, OCH3), 1.49 (s, 9H, (CH3)3); 13C NMR (CDCl3) δ 167.9,
152.0, 144.2, 135.0, 115.8, 107.6, 81.7, 51.3, 28.1. Anal. Calcd
for C11H17O4N: C, 58.14; H, 7.54; N, 6.16. Found: C, 58.21;
H, 7.41; N, 6.14.
°C (lit.9 mp 68-69 °C); IR (KBr) 3212, 1720, 1540 cm-1 1H
;
NMR (CDCl3) δ 6.65 (dd, 1H, H-6, J ) 2.5, 2.5 Hz), 6.54 (dd,
1H, H-5, J ) 2.5, 1.0 Hz), 6.35 (br s, 1H, NH), 4.44 (dd, 1H,
H-1, J ) 2.5, 2.5 Hz), 4.17 (m, 1H, H-4).
N-ter t-Bu toxyca r bon yl-2-a za bicyclo[2.2.0]h ex-5-en -3-
on e (17). Et3N (3.25 mL, 23.32 mmol), Boc2O (10.19 g, 46.68
mmol), and DMAP (2.85 g, 23.33 mmol) were added to a cooled
(0 °C) solution of lactam 8 (3.70 g, 38.91 mmol) in CH2Cl2 (75
mL). The reaction mixture was stirred at room temperature
for 2 h and then diluted with CH2Cl2 (25 mL). The solution
was washed with cool 1 M solution of HCl and then with H2O
and dried over MgSO4. The solvent was evaporated in vacuo
to give compound 17 (7.59 g, 100%) as a pale yellow oil (1H
NMR estimated purity >98%) which was immediately used
in the next step (degradation was observed in the course of
column chromatography on silica gel or after storing at -18
°C for 1 week): IR (KBr) 1803, 1716 cm-1; 1H NMR (CDCl3) δ
6.64 (dd, 1H, H-5, J ) 2.5, 1.5 Hz), 6.58 (ddd, 1H, H-6, J )
2.5, 2.5, 1.0 Hz), 4.65 (dd, 1H, H-1, J ) 2.7, 2.5 Hz), 4.14 (ddd,
1H, H-4, J ) 2.7, 1.5, 1.0 Hz), 1.46 (s, 9H, (CH3)3); 13C NMR
(CDCl3) δ 165.9, 149.0, 141.7, 140.3, 83.0, 56.8, 52.5, 27.8;
HRMS calcd for [(C10H13NO3) - OC4H9]+ 122.0242, found
122.0256.
(1S*,2R*)-N-ter t-Bu toxyca r bon yl-(2-h yd r oxym eth ylcy-
clobu t-3-en yl)a m in e (16) a n d (2Z,4E)-5-(ter t-Bu toxyca r -
bon yla m in o)p en ta -2,4-d ien ol (18). NaBH4 (4.42 g, 0.12 mol)
was added to a solution of compound 17 (7.60 g, 38.93 mmol)
in dry methanol (350 mL) at -20 °C. The mixture was stirred
at -20 °C for 1 h. A solution of 1 M HCl (40 mL) was then
added dropwise while the temperature was slowly allowed to
warm to 20 °C, and then the solvents were evaporated to
dryness (without heating). The residue was dissolved in CH2-
Cl2 and washed with brine. The aqueous layers were extracted
with CH2Cl2, and the combined extracts were dried (MgSO4)
and concentrated. The residue was purified by flash chroma-
tography (silica gel, CH2Cl2/Et2O, 4:1) to afford a mixture of
compounds 166a and 18 (5.90 g, 76%) in a 1:1 ratio as a pale
yellow solid. This mixture was refluxed in toluene for 10 min
to totally convert cyclobutene 16 into diene 18, isolated as a
yellow oil: IR (KBr) 3400-3200, 1695 cm-1; 1H NMR (CDCl3)
δ 6.76 (br dd, 1H, H-5, J ) 12.3, 12.3 Hz), 6.61 (br d, 1H, NH,
J ) 12.3 Hz), 6.05 (dd, 1H, H-3, J ) 10.9, 10.9 Hz), 5.89 (br
dd, 1H, H-4, J ) 12.3, 10.9 Hz), 5.45 (td, 1H, H-2, J ) 10.9,
(2Z,4E)-5-(ter t-Bu toxyca r bon yla m in o)p en ta -2,4-d ien o-
ic Acid Meth yl Ester (21). Meth od A. NaN3 (17 mg, 0.26
mmol) and MeOH (12 µL, 0.30 mmol) were successively added
to a solution of compound 17 (50 mg, 0.25 mmol) in dry DMF
(0.5 mL). The reaction mixture was stirred at room tempera-
ture for 16 h and diluted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and concentrated in
vacuo to give compound 21 (52 mg, 90%) as an orange oil
(unstable). Meth od B. A solution of diazomethane (from
diazald (260 mg, 1.21 mmol)) in Et2O (15 mL) was added
dropwise to a cooled (0 °C) suspension of acid 19 (200 mg, 0.93
mmol) in Et2O (5 mL). Excess of diazomethane was destroyed
by addition of acetic acid, and the mixture was concentrated
in vacuo to afford compound 21 (203 mg, 95%) as an orange
1
oil: IR (neat) 1708, 1668 cm-1; H NMR (CDCl3) δ 7.06-7.00
(m, 2H, H-4 and H-5), 6.90 (m, 1H, NH), 6.56 (m, 1H, H-3),
5.49 (d, 1H, H-2, J ) 11.1 Hz), 3.71 (s, 3H, OCH3), 1.49 (s, 9H,
(CH3)3); 13C NMR (CDCl3) δ 163.3, 152.2, 144.7, 136.3, 111.6,
107.0, 83.5, 50.9, 28.0; HRMS calcd for (C11H17NO4) 227.1158,
found 227.1156.
(1S*,2R*,5S*,6S*)-2-ter t-Bu toxyca r bon yla m in o-4-m eth -
oxycar bon yl-8-oxabicyclo[4.3.0]n on -3-en e-7,9-dion e (22a).
A solution of diene 20 (1.90 g, 8.36 mmol) and maleic
anhydride (0.90 g, 9.18 mmol) in dry CHCl3 (50 mL) was
1
refluxed for 24 h. The solvent was evaporated in vacuo. A H
NMR spectrum of the crude product indicated an endo-adduct
as the sole product. The residue was purified by recrystalli-
zation (EtOAc/toluene, 1:1) to give compound 22a (2.50 g, 92%)
as yellow crystals: mp 177-179 °C; IR (KBr) 1845, 1783, 1731,
1687 cm-1 1H NMR (CDCl3) δ 6.45 (ddd, 1H, H-4, J ) 9.7,
;
2.7, 2.7 Hz), 5.95 (ddd, 1H, H-3, J ) 9.7, 2.6, 2.6 Hz), 5.63 (d,
1H, NH, J ) 10.5 Hz), 4.46 (m, 1H, H-2), 3.98 (dd, 1H, H-6, J
) 10.0, 6.3 Hz), 3.86 (s, 3H, OCH3), 3.71 (dd, 1H, H-1, J )
10.0, 7.1 Hz), 3.25 (m, 1H, H-5), 1.48 (s, 9H, (CH3)3); 13C NMR
(CDCl3) δ 170.8, 170.6, 169.5, 155.2, 132.3, 127.0, 80.6, 52.8,
46.5, 43.2, 42.5, 39.6, 28.3. Anal. Calcd for C15H19O7N: C,
55.38; H, 5.89; N, 4.31. Found: C, 55.43; H, 5.65; N, 4.36.
(1R*,4R*,6S*)-N-ter t-Bu toxyca r bon yl-(4,6-d im eth oxy-

588 J . Org. Chem., Vol. 66, No. 2, 2001
Gauvry and Huet
ca r b on ylcycloh ex-2-en yl)a m in e (23a ) a n d It s (6R*)-
Isom er (23b). A solution of diene 20 (150 mg, 0.66 mmol),
methyl acrylate (0.75 mL, 6.60 mmol), and a trace of hydro-
quinone in toluene (2 mL) was heated in a sealed tube at 100
°C for 72 h. The reaction mixture was concentrated in vacuo.
The residue was purified by chromatography (silica gel,
cyclohexane/EtOAc, 4:1) to yield a mixture of adduct 23a and
23b (125 mg, 60%) in a 90:10 ratio as a colorless oil: IR (neat)
C6H5), 5.95 (m, 1H, H-2 or H-3), 5.74 (m, 1H, H-2 or H-3), 4.89
(dd, 1H, H-7, J ) 11.0, 8.7 Hz), 4.81 (dd, 1H, H-8, J ) 11.9,
3.8 Hz), 4.67 (dd, 1H, H-7′, J ) 11.0, 6.5 Hz), 4.53-4.42 (m,
3H, H-8′, H-9 and H-9′), 3.66 (m, 1H, H-1), 2.96 (m, 1H, H-4),
2.69 (m, 1H, H-5), 2.42 (m, 1H, H-6), 1.45 (br s, 2H, NH2); 13
C
NMR (CDCl3) δ 168.2, 168.1, 168.0, 134.7, 134.6, 134.5, 134.0,
131.9, 131.7, 131.6, 131.3, 131.2, 130.1, 130.0, 127.8, 67.5, 66.5,
64.0, 47.6, 43.4, 41.8, 36.9; HRMS calcd for C30H29NO6
499.1995, found 499.1998.
1
1716, 1705, cm-1; H NMR (CDCl3) major isomer 23a δ 5.95
(m, 1H, H-2), 5.86 (m, 1H, H-3), 4.69 (br d, 1H, NH, J ) 9.0
Hz), 4.58 (m, 1H, H-1), 3.71 (s, 3H, CH3), 3.68 (s, 3H, CH3),
3.12 (m, 1H, H-4), 2.76 (m, 1H, H-6), 2.19 (m, 1H, H-5), 1.94
(m, 1H, H-5′), 1.42 (s, 9H, (CH3)3), minor isomer 23b (partially
hidden by the major compound) δ 5.95-5.75 (m, 2H, H-2 and
H-3), 4.70-4.47 (m, 2H, NH and H-1), 3.70 (s, 3H, CH3), 3.69
(s, 3H, CH3), 3.23 (m, 1H, H-4), 2.76 (m, 1H, H-6), 2.19 (m,
1H, H-5), 1.94 (m, 1H, H-5′), 1.43 (s, 9H, (CH3)3); 13C NMR
(CDCl3) major isomer 23a δ 173.2, 172.9, 154.7, 128.2, 127.5,
79.6, 52.1, 51.8, 45.0, 42.9, 41.0, 28.2, 22.6, minor isomer 23b
(partially hidden by the major compound) δ 173.2, 172.9,
154.74, 129.2, 127.0, 79.6, 52.8, 52.1, 45.8, 43.3, 41.6, 28.2, 24.0;
HRMS calcd for [(C15H23NO6) + H - C4H9]+ 257.0895, found
257.0894.
(1R*,4S*,5S*,6S*)-N-ter t-Bu toxyca r bon yl[4,5,6-tr is(h y-
d r oxym eth yl)cycloh ex-2-en yl]a m in e (24). A solution of
adduct 22a (1.90 g, 5.84 mmol) in dry THF (15 mL) was added
dropwise to a cooled (0 °C) suspension of LiAlH4 (0.70 g, 0.17
mol) in dry THF (35 mL). The reaction mixture was refluxed
for 16 h and then cooled to -5 °C. A saturated solution of Na2-
SO4 (1.5 mL) was carefully added and, after addition of Et2O,
the suspension was stirred at room temperature for 15 min.
The precipitate was removed by filtration and washed with
THF and Et2O. The combined filtrates were concentrated in
vacuo, and the residue was dissolved in CH2Cl2. The solution
was dried over MgSO4, and the solvent was removed under
vacuum to give compound 24 (0.50 g, 78% crude) as a pale
yellow oil used in the next step without purification: IR (neat)
3600-3100, 1681 cm-1; 1H NMR (CDCl3) δ 5.81 (m, 1H, H-2),
5.72 (m, 1H, H-3), 5.56 (d, 1H, NH, J ) 16.4 Hz), 4.34 (m, 1H,
H-1), 3.84-3.50 (m, 9H, CH2 and OH), 2.61 (m, 1H, H-4), 2.14
(m, 1H, H-6), 1.96 (m, 1H, H-5), 1.45 (s, 9H, (CH3)3); 13C NMR
(CDCl3) δ 157.6, 130.8, 128.0, 80.2, 63.7, 62.6, 59.2, 44.0, 43.8,
41.7, 38.4, 28.3; HRMS calcd for C14H25NO5 287.1733, found
287.1729.
(1R *,4S *,5S *,6S *)-N -t er t -Bu t oxyca r b on yl[4,5,6-t r is-
(ben zoxym eth yl)cycloh ex-2-en yl]am in e (25). Pyridine (4.00
mL, 40.0 mmol) and benzoyl chloride (4.50 mL, 40.0 mmol)
were successively added to a cooled (0 °C) solution of crude
compound 24 (1.25 g, 4.35 mmol) in dry CH2Cl2. The reaction
mixture was stirred at room temperature for 16 h and diluted
with CH2Cl2. The solution was washed with 1 M aqueous HCl,
water, 10% NaHCO3, and brine. The aqueous layers were
extracted with CH2Cl2. The combined extracts were dried over
MgSO4 and concentrated in vacuo. The residue was purified
by chromatography (silica gel, CH2Cl2 then CH2Cl2/EtOAc, 95:
5) to afford compound 25 (1.33 g, 51%) as a colorless oil: IR
(neat) 1718, 1602 cm-1; 1H NMR (CDCl3) δ 8.12-7.94 (m, 6H,
C6H5), 7.63-7.32 (m, 9H, C6H5), 5.87 (m, 2H, H-2 and H-3),
4.70-4.53 (m, 6H, H-1, NH and CH2), 4.44 (m, 2H, CH2), 2.98
(m, 1H, H-4), 2.78 (m, 1H, H-5 or H-6), 2.64 (m, 1H, H-5 or
H-6), 1.36 (s, 9H, (CH3)3); 13C NMR (CDCl3) δ 171.2, 166.4,
166.3, 155.4, 133.5, 133.1, 133.0, 132.9, 130.1, 129.8, 129.7,
129.51, 129.49, 129.0, 128.4, 128.32, 128.28, 128.0, 79.8, 65.3,
(1R *,4S *,5S *,6S *)-N -[4,5-Bis(b e n zoxym e t h yl)-6-h y-
d r oxym eth ylcycloh ex-2-en yl]ben za m id e (27). If compound
26 was not rapidly used in the next step, it rearranged to give
compound 27: IR (neat) 3400-3200, 1714, 1643 cm-1; 1H NMR
(CDCl3) δ 8.06-7.26 (m, 15H, C6H5), 6.23 (d, 1H, NH, J ) 8.5
Hz), 6.03 (m, 2H, H-2 and H-3), 4.98 (m, 1H, H-1), 4.55 (dd,
1H, H-8, J ) 11.8, 5.0 Hz), 4.53-4.42 (m, 3H, H-9, H-9′ and
OH), 4.26 (dd, 1H, H-8′, J ) 11.8, 6.3 Hz), 3.87 (dd, 1H, H-7,
J ) 11.2, 11.2 Hz), 3.69 (dd, 1H, H-7′, J ) 11.2, 3.9 Hz), 3.09
(m, 1H, H-4), 2.60 (m, 1H, H-5), 2.43 (m, 1H, H-6); 13C NMR
(CDCl3) δ 169.0, 166.4, 166.3, 133.4, 133.2, 133.0, 132.0, 130.5,
129.7, 129.6, 129.5, 129.3, 128.7, 128.6, 128.4, 127.5, 126.9,
65.2, 62.4, 61.9, 44.7, 44.4, 39.9, 34.6.
(1R*,4S*,5S*,6S*)-[4,5,6-Tr is(ben zoxym eth yl)cycloh ex-
2-en yl]-3-(3-m eth oxya cr yloyl)u r ea (29). Thionyl chloride
(0.15 mL) was added to a solution of 3-methoxyacrylic acid
(120 mg, 1.20 mmol) in dry CH2Cl2 (1 mL). The reaction
mixture was refluxed for 3 h and concentrated to dryness. The
residue was dissolved in dry benzene, and AgOCN (0.31 g, 2.1
mmol) was added. The suspension was refluxed for 30 min to
afford 28 and cooled to 0 °C, and the supernatant liquor was
added to amine 26 (300 mg, 0.60 mmol). The mixture was
stirred at room temperature for 20 h and concentrated in
vacuo. The residue was purified by chromatography (silica gel,
cyclohexane/EtOAc, 1:1) to give compound 29 (263 mg, 70%)
as a white solid: mp 56-59 °C; IR (KBr) 1720, 1673 cm-1; 1H
NMR (CDCl3) δ 9.75 (s, 1H, NH), 9.01 (d, 1H, NH, J ) 9.8
Hz), 8.05-7.93 (m, 6H, C6H5), 7.55-7.29 (m, 10H, C6H5 and
H-3′′), 5.95 (m, 1H, H-2′ or H-3′), 5.88 (m, 1H, H-2′ or H-3′),
5.25 (d, 1H, H-2′′, J ) 12.3 Hz), 4.87 (m, 1H, H-1′), 4.79-4.48
(m, 6H, CH2), 3.62 (s, 3H, CH3), 2.99 (m, 1H, H-4′), 2.81 (m,
1H, H-5′ or H-6′), 2.70 (m, 1H, H-5′ or H-6′); 13C NMR (CDCl3)
δ 168.0, 166.27, 166.25, 166.20, 163.6, 155.1, 132.94, 132.86,
132.8, 130.1, 129.9, 129.8, 129.6, 129.5, 128.5, 128.3, 128.2,
128.1, 97.3, 65.3, 63.8, 61.6, 57.7, 44.1, 40.4, 39.4, 34.1; HRMS
calcd for [(C35H34N2O9) + H]+ 627.2343, found 627.2348.
(1R*,4S*,5S*,6S*)-1-[4,5,6-Tr is(h ydr oxym eth yl)cycloh ex-
2-en yl]u r a cil (30). A solution of compound 29 (100 mg, 0.16
mmol) in NH4OH 20% (1.5 mL) and MeOH (1.5 mL) was
heated in a sealed tube at 85 °C for 48 h. The mixture was
concentrated in vacuo, and the residue was purified by
chromatography (silica gel, CH2Cl2/MeOH, 9:1) to give com-
pound 30 (29 mg, 67%) as a yellow oil: IR 3500-3200, 1710,
1
1695 cm-1; H NMR (DMSO-d6) δ 11.14 (br s, 1H, NH), 7.38
(d, 1H, H-6, J ) 7.9 Hz), 6.14 (m, 1H, H-2′ or H-3′), 5.85 (m,
1H, H-2′ or H-3′), 5.48 (d, 1H, H-5, J ) 7.9 Hz), 5.07 (m, 1H,
H-1′), 3.56-3.19 (m, 9H, CH2 and OH), 2.38 (m, 2H, H-4′ and
H-6′), 2.12 (m, 1H, H-5′); 13C NMR (CD3OD) δ 168.3, 155.1,
146.6, 137.3, 127.1, 103.3, 64.9, 64.1, 61.1, 58.7, 42.6, 42.5, 42.4;
HRMS calcd for C13H18N2O5 282.1215, found 282.1216.
Ack n ow led gm en t. We thank Rhoˆne-Poulenc Rorer
Company for financial support and for evaluation of the
antitumor properties, Dr. M. Zucco (R.-P. R.) for useful
discussions, one of the referees and Dr. Simon Woo
(AstraZeneca R&D Montreal) for assistance with the
English language, and the local section of Sarthe of the
Ligue Nationale contre le Cancer for a fellowship to N.G.
63.7, 61.7, 45.4, 40.5, 39.2, 34.0, 28.2; HRMS calcd for [(C35H37
-
NO8) - C4H9 - CO2C6H5] 421.1519, found 421.1529.
(1R*,4S*,5S*,6S*)-[4,5,6-Tr is(ben zoxym eth yl)cycloh ex-
2-en yl]a m in e (26). Trifluoroacetic acid (5 mL) was added to
a solution of compound 25 (500 mg, 0.83 mmol) in CH2Cl2 (5
mL). The reaction mixture was stirred at room temperature
for 1.5 h and then cooled to 0 °C. A 20% NaOH solution was
carefully added until pH 10, and the mixture was extracted
with CH2Cl2. The combined extracts were dried over K2CO3,
and the solvent was removed under reduced pressure to give
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 16-21, 22a , 23-27, 29, and 30, and several NOE
spectra of 18, 20, 22a , and 23a . This material is available free
of charge via the Internet at http://pubs.acs.org.
1
26 (371 mg, 89%) as a colorless oil: IR (neat) 1727 cm-1; H
NMR (CDCl3) δ 8.06-7.94 (m, 6H, C6H5), 7.59-7.28 (m, 9H,
J O001467V