Chiral template mediated diastereoselective intramolecular Diels-Alder reaction using furan as a diene. Toward the synthesis of enantiopure trisubstituted tetrahydroepoxyisoindolones

Article abstract of DOI:10.1021/jo0509509

Chiral precursors to the intramolecular Diels-Alder reaction using furan as a diene (IMDAF) have been prepared by diastereoselective addition of furyllithium to imines attached to perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol. The acylation of

Full text of DOI:10.1021/jo0509509

Chiral Template Mediated Diastereoselective Intramolecular
Diels-Alder Reaction Using Furan as a Diene. Toward the
Synthesis of Enantiopure Trisubstituted
Tetrahydroepoxyisoindolones
Rafael Pedrosa,* Sonia Sayalero, Martina Vicente, and Bernabe´ Casado
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/n, 47011-Valladolid, Spain
pedrosa@qo.uva.es
Received May 12, 2005
Chiral precursors to the intramolecular Diels-Alder reaction using furan as a diene (IMDAF) have
been prepared by diastereoselective addition of furyllithium to imines attached to perhydro-1,3-
benzoxazines derived from (-)-8-aminomenthol. The acylation of the furylamines with R,â-
unsaturated acyl chlorides and subsequent IMDAF reaction under thermal conditions provided
the corresponding cycloadducts as single diastereoisomers. The hydrolytic elimination of the chiral
template yielded enantiopure perhydroepoxyisoindolones with up to five stereocenters.
Introduction
between the two components6 on the selectivity of the
reaction are well documented, although the asymmetric
version has been less studied.
The placement of a nitrogen atom in the tether con-
necting the diene and dienophile, followed by IMDAF re-
action, allows for the construction of aza polyheterocycles
present in the skeleton of interesting alkaloids.7 In this
respect, we have prepared enantiopure epoxytetrahy-
droisoindolines8 and perhydroisoquinolines9 by IMDAF
reaction and benzoisoindoline derivatives10 by intramo-
lecular Diels-Alder reaction using styrene derivatives
Intramolecular Diels-Alder reaction using furan as a
diene (IMDAF) was described more than 20 years ago,1
but it continues to attract a lot of attention because it
allows for the regio- and stereocontrolled construction of
polycyclic complex structures, which are building blocks
for natural compounds.2,3
The effects of structural variations on both the furan
system4 and the dienophile5 and the size of the tether
* To whom correspondence should be addressed. Fax: 34 983 423
013.
(1) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Borden W. T.
Chem. Rev. 1989, 89, 1099. (c) Kappe, C. O.; Murphree, S. S.; Padwa,
A. Tetrahedron 1997, 53, 14179. (d) Keay, B. A.; Hunt, I. R. Adv.
Cycloaddit. 1999, 6, 173.
(2) (a) Warner, P. M. Chem. Rev. 1989, 89, 1067. (b) Thomas, E. J.
Acc. Chem. Res. 1991, 24, 229. (c) Fallis, A. G. Acc. Chem. Res. 1999,
32, 464. (d) Cycloaddition Reactions in Organic Synthesis; Kobayashi,
S., Jo¨rgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002.
(e) Suzuki, Y.; Takao, K. L.; Tadano, K. I. Stud. Nat. Prod. Chem. 2003,
29, 127.
(3) For some recent papers on IMDAF reaction see: (a) Claeys, S.;
Haver, V. D.; De Clercq, P. J.; Milanesio, M.; Viterbo, D. Eur J. Org.
Chem. 2002, 1051. (b) Richter, F.; Bauer, M.; Pe´rez, C.; Maichle-
Moessmer, C.; Maier, M. E. J. Org. Chem. 2002, 67, 2474. (c)
Wolkenberg, S. E.; Boger, D. L. J. Org. Chem. 2002, 67, 7361. (d)
Nicolaou, K.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668. (e) Fokas, D.; Patterson, J. E.;
Slobodkin, G.; Baldino, C. M. Tetrahedron Lett. 2003, 44, 5137. (f) Kato,
Y.; Miki, K.; Nishino, F.; Ohe, K.; Uemura, S. Org. Lett. 2003, 5, 2619.
(g) Namboothiri, I. N. N.; Ganesh, M.; Mobin, S. M.; Cojocaru, M. J.
Org. Chem. 2005, 70, 2235.
(4) (a) Choony, N.; Dadabhoy, A.; Sammes, P. G. Chem. Commun.
1997, 513. (b) Jung, M. E.; Kiankarimi, M. J. Org. Chem. 1998, 63,
2968. (c) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
63, 5304. (d) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.; Linch, S.
M. J. Org. Chem. 2002, 67, 3412.
(5) (a) Parker, K. A.; Adamchuk, M. R. Tetrahedron Lett. 1978, 19,
1689. (b) Roush, W. R. Comprehensive Organic Synthesis; Pergamon:
Oxford, 1991; Vol. 5, p 513.
(6) (a) Paulvannan, K.; Chen, T.; Jacobs, J. W. Synlett 1999, 1609.
(b) Padwa, A.; Reger, T. S. Can. J. Chem. 2000, 78, 749. (c) Jacobi, P.
A.; Li, Y. J. Am. Chem. Soc. 2001, 123, 9307. (d) Ghelfi, F.; Parsons,
A. F.; Tommasini, D.; Mucci, A. Eur. J. Org. Chem. 2001, 1845. (e)
Milkiewicz, K. L.; Neagu, I. B.; Parks, D. J.; Lu, T. Tetrahedron Lett.
2003, 44, 7431. (f) Crawford, K. R.; Bur, S. K.; Straub, C. S.; Padwa,
A. Org. Lett. 2003, 5, 3337. (g) Wang, Q.; Padwa, A. Org. Lett. 2004, 6,
2189.
(7) See for instance: (a) Saxton, J. E. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 1998; Vol. 51, p 1. (b) Chawla, A.;
Kapoor, V. In Alkaloids: Chemical and Biological Perspectives; Pelle-
tier, S. W., Ed.; Elsevier Science: New York, 1994; Vol. 9, p 85. (c)
Pilli, R. A.; de Oliveira, M. C. F. Nat. Prod. Rep. 2000, 17, 117.
10.1021/jo0509509 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/05/2005
J. Org. Chem. 2005, 70, 7273-7278
7273

Pedrosa et al.
SCHEME 1
FIGURE 1. Preferred conformation in CDCl3 solution for
imine 3.
matographic conditions tested. The N-benzylimine was
also prepared by condensation of 2 with benzylamine, but
their reaction with furyllithium yielded a very complex
mixture of compounds.
The absolute configuration of the created stereocenter
was assigned as S and later confirmed by X-ray diffrac-
tion analysis for the Diels-Alder cycloadducts. Interest-
ingly, the sense of the excellent 1,4-stereoinduction is
coincident with that previously described for 1,2-stere-
oinduction in related carbonyl derivatives13,14 and ex-
plained on the basis of the structure of the imines. In
fact, the preferred conformation of 3 in solution was
determined on the basis of NOE experiments. A strong
NOE effect (8.6%) was observed between the hydrogens
at the N,O-ketal position and the imine group (Figure
1).
The attack from the Re face of the imine group can be
rationalized by coordination of the hard lithium deriva-
tive to the harder oxygen atom13 or by the presence of
the benzyl group attached to the nitrogen atom, which
makes the Si face more encumbered to the approach of
the reagent.14
Amine 5 was subjected to acylation by treatment with
acryloyl chloride at 0 °C in the presence of triethylamine
using methylene chloride as solvent. The chromato-
graphic purification of the resulting amide must be done
on silica gel deactivated with triethylamine, but only a
modest yield was obtained because the product was
partially hydrolyzed. In addition, when the isolated
amide or the N-acylation mixture was allowed to stand
at room temperature, it partially evolved to the Diels-
Alder cycloadduct. On the basis of these facts, and trying
to improve the chemical yield of the intramolecular
Diels-Alder process, we studied the cyclization without
isolation of the intermediate amide. To this end, a
mixture of the amine 5, acryloyl chloride, and triethyl-
amine in methylene chloride was stirred at rt until
disappearance of the starting material (TLC), then the
mixture was heated in a sealed tube by immersion in a
bath at 50-60 °C, and the progress of the reaction was
monitored by TLC and 1H NMR. These experimental
conditions were used for the reactions of 5 and 6 with
acryloyl and methacryloyl chlorides, but in the reactions
with crotonoyl and cinnamoyl chlorides triethylamine
must be changed to pyridine, and elimination of the
excess of the base prior to the heating of the acylation
mixture was necessary. Interestingly, the rate of cycload-
dition of the methacryloyl derivatives was very slow, and
the yields of the final adducts for the p-methoxyphenyl
derivatives are higher than for the phenyl ones (Scheme
2 and Table 1). The moderate chemical yield for this
as dienes and perhydrobenzoxazines as chiral inductors
and as sources of the nitrogen atom in the final hetero-
cycle.
In this paper we summarize our results on the syn-
thesis of enantiopure perhydroisoindolones11 by diaster-
eoselective IMDAF reaction using perhydro-1,3-benzox-
azines as chiral templates. This approach differs from
that used until now because the perhydrobenzoxazine is
only used as a chiral inductor, and the (-)-8-aminomen-
thol is recovered in the final stage of the process.
The whole sequence of reactions requires the stereo-
selective preparation of furfurylamines and their trans-
formation into the corresponding R,â-unsaturated amides
to promote the IMDAF reaction. The template of the
chiral perhydrobenzoxazine will serve as a chiral inductor
in both the synthesis of amine derivatives and the
cycloaddition reaction.
Results and Discussion
The chiral furfurylamine derivatives 5 and 6 were
synthesized in three steps and excellent yield (>90%)
from (-)-8-N-benzylaminomenthol12 (1) (Scheme 1). The
condensation of 1 with o-phthalaldehyde in benzene for
16 h under Dean-Stark conditions provided the aldehyde
2 in 95% total yield, which was converted nearly quan-
titatively into 3 and 4 by reaction with aniline or
p-methoxyaniline in dry dichloromethane in the presence
of molecular sieves. Addition of a recently prepared 2.5
M solution of 2-furyllithium in THF to 3 or 4 at -30 °C,
using THF as solvent, afforded the desired furylamines
5 and 6 in 96% and 98% yields, respectively, as single
diastereomers. The chromatographic purification of fur-
ylamines on silica gel or alumina was unsuccessful also
if the silica gel was previously deactivated with triethyl-
amine. Compounds 5 and 6 decomposed under all chro-
(8) (a) Andre´s, C.; Maestro, G.; Nieto, J.; Pedrosa, R.; Garc´ıa-Granda,
S.; Pe´rez-Carren˜o, E. Tetrahedron Lett. 1997, 38, 1463. (b) Andre´s, C.;
Garc´ıa-Valverde, M.; Nieto, J.; Pedrosa, R. J. Org. Chem. 1999, 64,
5230. (c) Pedrosa, R.; Andre´s, C.; Nieto, J. J. Org. Chem. 2000, 65,
831.
(9) Andre´s, C.; Nieto, J.; Pedrosa, R.; Vicente, M. J. Org. Chem. 1998,
63, 8570.
(10) Pedrosa, R.; Andre´s, C.; Nieto, J. J. Org. Chem. 2002, 67, 782.
(11) Vedejs, E.; Campbell, J. B., Jr.; Gadwood, R. C.; Rodgers, J.
D.; Spear, K. L.; Watanabe, Y. J. Org. Chem. 1982, 47, 1534. (b) Kim,
B. M.; Guare, J. P. Heterocycles 1995, 41, 403. (c) Alvi, K. A.; Nair, B.;
Pu, H.; Ursino, R.; Gallo, C.; Mocek, U. J. Org. Chem. 1997, 62, 2148.
(12) Rassat, A.; Rey, P. Tetrahedron 1974, 30, 3315.
(13) Eliel, E. L.; Morris-Natschke, S. J. Am. Chem. Soc. 1984, 106,
2937.
(14) Eliel, E. L.; He, X.-C. J. Org. Chem. 1990, 55, 2114.
7274 J. Org. Chem., Vol. 70, No. 18, 2005

Diastereoselective IMDAF Reaction
SCHEME 2
SCHEME 3
TABLE 1. Synthesis of Intermediate Amides and
IMDAF Reactions to 7 and 8 (Scheme 2)
acyl
chloride
amide IMDAF
time (h) time (h) product (%)
yielda
entry compd
1
2
3
4
5
6
7
8
5
5
5
5
6
6
6
6
acryloyl
4
24
48
36
24
48
48
48
24
7a
7b
7c
7d
8a
8b
8c
8d
55
33
37
35
73
49
51
36
methacryloyl 115
crotonoyl
cinnamoyl
acryloyl
methacryloyl 120
crotonoyl
cinnamoyl
0.25
0.25
16
0.25
24
TABLE 2. Hydrogenation of Compounds 7 and 8 and
Hydrolysis to Lactams 15 and 16 (Scheme 3)
a Yields refer to isolated and purified compounds after column
chromatography and are calculated from amines 5 and 6.
hydrogenation
time
(days)
products
lactam
entry
compd
(yield, %)a
(yield, %)a
reaction is a well-documented fact in both catalyzed16 and
uncatalyzed17 processes and is a consequence of the
reversible character of the reaction.
1
2
7a
7a
7b
7c
7d
8a
8a
8b
8c
8d
2
2.5
16
5
20
2
5
5
12
19
11a (87)
15a (93)
15a (95)
15b (92)
15c (94)
15d (95)
16a (92)
16a (94)
16b (92)
16c (93)
16d (94)
11a (32), 12a (56)
12b (90)
3
4
11c (10), 12c (85)
In all cases, except for the reaction of 5 with acryloyl
chloride, isoindolone 9 (Ar ) Ph) or 10 (Ar ) PMP) was
isolated in 10-15% yield. Formation of these compounds
could be interpreted as a consequence of partial hydroly-
sis of 5 or 6, rapid oxidation, and intramolecular lactam-
ization. In addition, treatment of 5 in ethanol with dilute
hydrochloric acid (2%) at room temperature for 45 min,
in an open flask, provides the isoindolone 9 in excellent
yield.
5
12d (54)b,c
6
13a (85)
7
14a (86)
8
13b (44), 14b (33)c
13c (76), 14c (15)c
14d (90)
9
10
a Yields refer to isolated and purified compounds after column
chromatography. b The 1H NMR of the reaction mixture showed
40% lactam 15d in the mixture. c Compounds 12d, 14b, and 14c
could not be obtained in pure form from the reaction mixture.
Interestingly, in the described reaction conditions the
IMDAF reactions occurred with total facial selectivity,
providing the exo adducts as single diastereomers, and
traces of other cycloadducts were not detected in the 1H
NMR spectra of the reaction mixtures. The facial selec-
tivity is highly dependent on the solvent, and methylene
chloride favors the formation of the exo adducts.8,9 The
compounds were isolated and purified by flash chroma-
tography, and their stereochemistry was determined on
the basis of 1H and 13C NMR spectroscopy and later
confirmed by X-ray diffraction analysis (vide infra).
The transformation of the cycloadducts into the final
enantiopure perhydroisoindolones was achieved, in two
steps, with very good chemical yields (Scheme 3 and
Table 2). To this end, compounds 7 and 8 were subjected
to hydrogenation (H2, 1 atm, rt) using 10% Pd on carbon
as catalyst, and the reaction was monitored by TLC.
In these conditions, the hydrogenation of the double
bonds occurred very slowly, except for unsubstituted
derivatives 7a and 8a, and long periods of reaction were
necessary to obtain the saturated derivatives. The hy-
drogenation products depend on the reaction time. Un-
substituted cycloadduct 7a yielded the oxanorbornane
11a after 2 days of reaction but a mixture of 11a and
debenzylated derivative 12a (ca. 2:3) after 60 h of reaction
(entries 1 and 2 in Table 2). In the same way, 8a yielded
the hydrogenation product 13a or the hydrogenation-
debenzylation compound 14a after reaction for 2 or 5
days, respectively (entries 6 and 7). The control of the
hydrogenation-hydrogenolysis reaction is not easy, but
(15) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8,
1895. (b) Bloch, R. Chem. Rev. 1998, 98, 1407.
(16) Hunt, I. R.; Rauk, A.; Keay, B. A. J. Org. Chem. 1996, 61, 751
and references therein.
(17) Gschwend, H. W.; Hillman, M. J.; Kiss, B.; Rodebaugh, R. K.
J. Org. Chem. 1976, 41, 104.
J. Org. Chem, Vol. 70, No. 18, 2005 7275

Pedrosa et al.
SCHEME 4
compounds 11-14 or mixtures of benzylated and deben-
zylated products can be used in the next step of the
reaction without a problem because all of them gave the
final lactams by hydrolysis.
Surprisingly, hydrogenation of cycloadduct 7d gave the
debenzylated oxanorbornane 12d in moderate yield but
accompanied by a 40% yield of aldehyde 15d as a
consequence of partial hydrolysis of the perhydrobenzox-
azine moiety during the long period of reaction (entry 5).
The relative stereochemistry of hydrogenation products
was assigned by comparison of the coupling constants of
the protons at the oxanorbornane system with those
previously described for norbornane derivatives.18 Thus,
the value of the coupling constant (3J ) 4.9-5.5 Hz)
indicates a trans relationship between protons at C-5 and
C-6 and also for protons at C-6 and C-7 (3J ) 4.5-4.8
Hz) in compounds 11c and 12d. In addition, the absolute
stereochemistry was determined by X-ray diffraction
studies for compound 11a to be 1R,2S,5S,7S,19 which
confirms the total diastereoselectivity in both the addition
to the imine system and the exo IMDAF reaction.
Experimental Section
Adducts 11a-c and 12a-d or 13a-c and 14a-d were
converted into enantiopure lactams 15a-d and 16a-d,
respectively, by refluxing with dilute (2%) aqueous
alcoholic hydrochloric acid for 4-8 h (Scheme 3) in
excellent yields (Table 2). At this stage, the stereochem-
istry for compounds 15c and 16b19 was determined by
X-ray diffraction analysis, which is coincident with that
described for 11a. In these reactions the chiral adjuvant
(-)-8-aminomenthol was also recovered in 85-92% yield
after purification of the products.
The interest in the synthesis of these perhydroepoxy-
isoindolones lies in the possibility to obtain the enan-
tiopure N-unsubstituted derivatives, and to this end,
compounds 16a-c were subjected to deprotection. The
elimination of the p-methoxyphenyl substituent at the
nitrogen atom of these compounds was carried out by
treatment of a solution of 16a-c in acetonitrile with an
aqueous solution of ceric ammonium nitrate (CAN) at 0
°C (Scheme 4).20 Under these conditions compounds
17a-c were obtained in 98% yield, as a mixture (70:30)
of aldehydes and N,O-ketals, which were further reduced
with sodium borohydride to compounds 18a-c in excel-
lent yield (98%) (Scheme 4).
In summary, a novel totally diastereoselective synthe-
sis of enantiopure perhydroepoxyisoindolone derivatives
has been developed by IMDAF. This reaction provides a
facile method for the creation of densely functionalized
molecules with up to five stereocenters and predictable
regio- and stereochemistry. The starting compounds can
be easily prepared from (-)-N-benzyl-8-aminomenthol in
three steps, and a variety of different substituents can
be introduced into the heterocyclic nucleus depending on
the substitution of the double bond of the dienophile and
the nature of the group attached at the nitrogen atom of
the starting amine.
Synthesis of Cycloadducts 7a-d and 8a-d. General
Method. To a stirred solution of the amine 5 or 6 (0.96 mmol)
in dichloromethane (1.9 mL) at 0 °C were added triethylamine
or pyridine (1.5 mmol) and the corresponding acyl chloride (1.4
mmol). The mixture was stirred at rt until the disappearance
of the starting material (TLC), and then the mixture was
heated in a sealed tube by immersion in an oil bath at 50-60
°C for the time given in Table 1. When pyridine was used as
the base, the reaction mixture was filtered over silica gel
deactivated with 5% Et3N before heating. The Diels-Alder
adduct was purified by flash chromatography on silica gel (5%
Et3N, CH2Cl2, or hexanes-CH2Cl2).
(1R,2S,2′S,4a′S,5S,7S,7′R,8a′R)-2-[2-(N-Benzyl-4,′4,′,7′-
trimethyloctahydrobenzo[e][1,3]oxazin-2′-yl)phenyl]-3-
(4-methoxyphenyl)-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-
en-4-one (8a). Yield: 73%. Yellow solid. Mp: 102-104 °C
(from hexane). [R]23D ) +125.2 (c ) 0.9, CHCl3). 1H NMR (δ):
0.92 (s, 3H); 0.96 (d, 3H, J ) 6.5 Hz); 1.00-1.08 (m, 2H); 1.23
(q, 1H, J ) 11.7 Hz); 1.37 (s, 3H); 1.40-1.73 (m, 4H); 1.62 (dd,
1H, J1 ) 11.8 Hz, J2 ) 8.7 Hz); 1.99 (m, 1H); 2.32 (td, 1H, J1
) 11.8 Hz, J2 ) 4.3 Hz); 2.63 (dd, 1H, J1 ) 8.7 Hz, J2 ) 3.3
Hz); 3.56 (td, 1H, J1 ) 10.4 Hz, J2 ) 3.9 Hz); 3.70 (d, 1H, J )
16.9 Hz); 3.79 (s, 3H); 4.10 (d, 1H, J ) 16.9 Hz); 5.15 (dd, 1H,
J1 ) 4.3 Hz, J2 ) 1.5 Hz); 5.84 (d, 1H, J1 ) 5.8 Hz); 6.02 (s,
1H); 6.14 (s, 1H); 6.32 (dd, 1H, J1 ) 5.8 Hz, J2 ) 1.5 Hz); 6.68
(d, 2H, J ) 7.3 Hz); 6.77 (t, 2H, J ) 7.3 Hz); 6.81-6.93 (m,
1H); 6.84 (d, 2H, J ) 8.9 Hz); 7.25 (t, 2H, J ) 4.0 Hz); 7.37 (d,
2H, J ) 8.9 Hz); 7.40-7.45 (m, 1H); 7.74-7.77 (m, 1H). 13C
NMR (δ): 21.7; 22.3; 24.9; 28.2; 29.1; 31.4; 35.1; 41.5; 44.5;
45.5; 46.6; 55.4; 58.4; 63.7; 77.3; 79.3; 84.9; 93.0; 114.4 (2C);
124.4; 125.2; 126.2 (2C); 126.8 (2C); 127.5 (2C); 127.9; 128.2;
129.1; 131.4; 132.4; 133.7; 136.6; 137.8; 143.3; 157.7; 175.2.
IR (KBr): 3060; 3020; 1703; 1510; 769; 754; 722; 704 cm-1
.
Anal. Calcd for C39H44N2O4 (604.78): C, 77.45; H, 7.33; N, 4.63.
Found: C, 77.41; H, 7.55; N, 4.53.
(1R,2S,2′S,4a′S,5S,7S,7′R,8a′R)-2-[2-(N-Benzyl-4′,4′,7′-
trimethyloctahydrobenzo[e][1,3]oxazin-2′-yl)phenyl]-5-
methyl-3-(4-methoxyphenyl)-10-oxa-3-azatricyclo[5.2.1.01,5]-
dec-8-en-4-one (8b). Yield: 49%. Colorless solid. Mp: 92-
93 °C (from hexane). [R]23D ) +97.9 (c ) 1.2, CHCl3). 1H NMR
(δ): 0.80-1.06 (m, 1H); 0.95 (s, 3H); 0.97 (d, 3H, J ) 6.5 Hz);
1.06 (s, 3H); 1.15 (d, 1H, J ) 11.6 Hz); 1.23 (q, 1H, J ) 11.6
Hz); 1.36 (s, 3H); 1.42-1.76 (m, 5H); 1.99 (m, 1H); 2.59 (dd,
1H, J1 ) 11.6 Hz, J2 ) 4.7 Hz); 3.56 (td, 1H, J1 ) 10.5 Hz, J2
) 3.7 Hz); 3.65 (d, 1H, J ) 16.9 Hz); 3.80 (s, 3H); 4.07 (d, 1H,
J ) 16.9 Hz); 5.05 (dd, 1H, J1 ) 4.7 Hz, J2 ) 1.5 Hz); 6.05 (s,
1H); 6.09 (s, 1H); 6.11 (d, 1H, J ) 5.8 Hz); 6.40 (dd, 1H, J1 )
5.8 Hz, J2 ) 1.5 Hz); 6.68-6.70 (m, 2H); 6.78 (t, 2H, J ) 7.5
(18) Pretsch, E.; Bu¨hlmann, P.; Affolter, C. Structure Determination
of Organic Compounds, 3rd ed.; Springer-Verlag: Berlin, 2000.
(19) See the Supporting Information for the ORTEP representation
of the structures.
(20) (a) Gordon, H. K.; Balasubramanian, S. Org. Lett. 2001, 53. (b)
Kronental, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982, 47,
2765. (c) Fukuyama, T.; Frank, R. K.; Jewell, C. F. J. Am. Chem. Soc.
1980, 102, 2122.
7276 J. Org. Chem., Vol. 70, No. 18, 2005

Diastereoselective IMDAF Reaction
Hz); 6.83-6.92 (m, 1H); 6.85 (d, 2H, J ) 9.1 Hz); 7.14-7.23
(m, 2H); 7.45 (d, 2H, J ) 9.1 Hz); 7.43-7.48 (m, 1H); 7.74 (dd,
1H, J1 ) 6.9 Hz, J2 ) 2.2 Hz). 13C NMR (δ): 21.6; 22.3; 22.6;
24.9; 28.2; 31.4; 35.1; 38.8; 41.5; 44.9; 46.4; 52.6; 55.4; 58.4;
63.9; 77.1; 78.6; 84.7; 90.7; 114.3 (2C); 125.2; 125.7 (3C); 126.7
(2C); 127.5 (2C); 127.6 (2C); 129.1; 131.5; 131.7; 133.4; 135.7;
138.0; 143.4; 157.4; 178.1. IR (KBr): 3060; 3020; 1702; 1512;
770; 758; 721 cm-1. Anal. Calcd for C40H46N2O4 (618.80): C,
77.64; H, 7.49; N, 4.53. Found: C, 77.25; H, 7.26; N, 4.62.
(2C); 123.5 (2C); 126.5; 128.6; 131.3; 133.7; 134.4; 136.0; 139.1;
156.8; 175.2; 193.5. IR (KBr): 3060; 2953; 2872; 2749; 1696;
1600; 1576; 772; 748 cm-1. Anal. Calcd for C22H21NO4
(363.41): C, 72.71; H, 5.82; N, 3.85. Found: C, 72.80; H, 5.88;
N, 4.02.
(1R,2S,5S,7S)-2-[5-Methyl-3-(4-methoxyphenyl)-4-oxo-
10-oxa-3-azatricyclo[5.2.1.01,5]dec-2-yl]benzaldehyde (16b).
Yield: 92%. Colorless solid. Mp: 159-160 °C (from hexane).
[R]23 ) +1.4 (c ) 0.8, CHCl3). 1H NMR (δ): 0.83-0.90 (m,
D
1H); 1.35 (s, 3H); 1.44-1.58 (m, 3H); 1.94-1.96 (m, 1H); 2.45-
2.51 (m, 1H); 3.72 (s, 3H); 4.58 (t, 1H, J ) 5.3 Hz); 6.73 (s,
1H); 6.78 (d, 2H, J ) 9.1 Hz); 7.45 (d, 2H, J ) 9.1 Hz); 7.50-
7.57 (m, 3H); 7.91 (dd, 1H, J1 ) 5.7 Hz, J2 ) 2.0 Hz); 10.3 (s,
1H). 13C NMR (δ): 22.7; 24.8; 29.3; 46.2; 54.2; 55.3; 61.4; 76.2;
91.1; 114.0 (2C); 123.5 (2C); 127.5; 128.5; 131.7; 133.9; 134.0;
135.8; 139.1; 156.8; 178.7; 193.1. IR (KBr): 3060; 3016; 2925;
2853; 2767; 1691; 1602; 1573; 768; 752 cm-1. Anal. Calcd for
C23H23NO4 (377.43): C, 73.19; H, 6.14; N, 3.71. Found: C,
72.98; H, 5.98; N, 3.68.
(1R,2S,2′S,4a′S,5S,6S,7S,7′R,8a′R)-2-[2-(N-Benzyl-4′,4′,7′-
trimethyloctahydrobenzo[e][1,3]oxazin-2′-yl)phenyl]-6-
methyl-3-(4-methoxyphenyl)-10-oxa-3-azatricyclo[5.2.1.01,5]-
dec-8-en-4-one (8c). Yield: 51%. Yellow solid. Mp: 100-102
1
°C (from hexane). [R]23 ) +102.7 (c ) 1.0, CHCl3). H NMR
D
(δ): 0.93-1.08 (m, 1H); 0.94 (d, 3H, J ) 5.9 Hz); 0.97 (s, 6H);
1.17-1.29 (m, 2H); 1.37 (s, 3H); 1.45-1.59 (m, 1H); 1.61-1.75
(m, 3H); 1.99 (m, 1H); 2.12 (d, 1H, J ) 3.5 Hz); 2.70-2.75 (m,
1H); 3.57 (td, 1H, J1 ) 10.4 Hz, J2 ) 3.8 Hz); 3.67 (d, 1H, J )
16.9 Hz); 3.74 (s, 3H); 4.09 (d, 1H, J ) 16.9 Hz); 4.91 (d, 1H,
J ) 4.4 Hz); 5.92 (dd, 1H, J1 ) 5.9 Hz, J2 ) 1.2 Hz); 6.00 (s,
1H); 6.05 (s, 1H); 6.27 (d, 1H, J ) 5.9 Hz); 6.68-6.71 (m, 2H);
6.75-6.81 (m, 4H); 6.85-6.90 (m, 1H); 7.18-7.23 (m, 2H);
7.33-7.39 (m, 3H); 7.75-7.78 (m, 1H). 13C NMR (δ): 17.1; 21.7;
22.4; 24.9; 28.3; 31.4; 35.1; 37.7; 41.5; 44.5; 46.6; 53.2; 53.3;
58.5; 63.7; 77.4; 82.8; 84.9; 93.7; 114.4 (2C); 124.4; 125.3; 126.0
(2C); 126.9 (2C); 127.6 (2C); 127.9; 128.3; 129.1; 131.4; 133.5;
133.8; 134.8; 137.9; 143.3; 157.6. IR (KBr): 3063; 3020; 1703;
1510; 754; 741; 718 cm-1. Anal. Calcd for C40H46N2O4
(618.35): C, 77.64; H, 7.49; N, 4.53. Found: C, 77.71; H, 7.33;
N, 4.67.
(1R,2S,5S,6S,7S)-2-[6-Methyl-3-(4-methoxyphenyl)-4-
oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-2-yl]benzalde-
hyde (16c). Yield: 93%. Colorless solid. Mp: 136-137 °C
1
(from hexane). [R]23 ) +26.6 (c ) 0.7, CHCl3). H NMR (δ):
D
0.89-0.99 (m, 1H); 1.17 (d, 3H, J ) 7.0 Hz); 1.37-1.48 (m,
1H); 1.68-1.82 (m, 2H); 2.34 (d, 1H, J ) 4.8 Hz); 2.60-2.68
(m, 1H); 3.70 (s, 3H); 4.48 (t, 1H, J ) 4.4 Hz); 6.68 (s, 1H);
6.75 (d, 2H, J ) 9.0 Hz); 7.38 (d, 2H, J ) 9.0 Hz); 7.45 (d, 1H,
J ) 7.7 Hz); 7.50-7.61 (m, 2H); 7.88 (d, 1H, J ) 7.2 Hz); 10.2
(s, 1H). 13C NMR (δ): 15.8; 23.3; 28.8; 41.5; 55.2; 57.0; 61.1;
80.9; 90.1; 113.9 (2C); 123.3 (2C); 126.4; 128.6; 131.3; 133.7;
134.4; 135.9; 139.2; 156.6; 175.1; 193.4. IR (KBr): 3078; 2988;
(1R,2S,2′S,4a′S,5S,6S,7S,7′R,8a′R)-2-[2-(N-Benzyl-4′,4′,7′-
trimethyloctahydrobenzo[e][1,3]oxazin-2′-yl)phenyl]-6-
phenyl-3-(4-methoxyphenyl)-10-oxa-3-azatricyclo[5.2.1.01,5]-
dec-8-en-4-one (8d). Yield: 36%. Colorless solid. Mp: 98-
99 °C (from hexane). [R]23D ) +24.9 (c ) 1.0, CHCl3). 1H NMR
(δ): 0.95 (s, 3H); 0.96 (d, 3H, J ) 6.9 Hz); 0.95-1.04 (m, 1H);
1.12-1.36 (m, 2H); 1.39 (s, 3H); 1.43-1.73 (m, 4H); 1.99 (m,
1H); 2.89 (d, 1H, J ) 4.2 Hz); 3.57 (td, 1H, J1 ) 10.4 Hz, J2 )
3.8 Hz); 3.71 (d, 1H, J ) 16.9 Hz); 3.80 (s, 3H); 3.97 (t, 1H, J
) 4.2 Hz); 4.11 (d, 1H, J ) 16.9 Hz); 5.27 (dd, 1H, J1 ) 4.2
Hz, J2 ) 1.4 Hz); 6.01 (d, 1H, J ) 5.8 Hz); 6.04 (s, 1H); 6.17 (s,
1H); 6.22 (dd, 1H, J1 ) 5.8 Hz, J2 ) 1.4 Hz); 6.69-6.71 (m,
2H); 6.79 (t, 2H, J ) 7.5 Hz); 6.84 (d, 2H, J ) 9.0 Hz); 6.86-
6.94 (m, 1H); 7.11-7.14 (m, 2H); 7.16-7.28 (m, 5H); 7.41 (d,
2H, J ) 9.0 Hz); 7.38-7.44 (m, 1H); 7.76-7.79 (m, 1H). 13C
NMR (δ): 21.7; 22.3; 24.9; 28.2; 31.4; 35.1; 41.5; 44.6; 46.7;
48.3; 53.6; 55.4; 58.5; 63.8; 77.4; 83.0; 84.9; 94.2; 114.4 (2C);
124.4; 125.3; 126.0 (2C); 126.7; 126.9 (2C); 127.6 (2C); 128.0
(3C); 128.3 (2C); 128.4 (2C); 129.2; 131.3; 133.5; 133.6; 135.4;
139.0; 143.3; 157.6; 174.6. IR (KBr): 3060; 3030; 1702; 1636;
1513; 763; 716; 699; 668 cm-1. Anal. Calcd for C45H48N2O4
(680.87): C, 79.38; H, 7.11; N, 4.11. Found: C, 79.46; H, 6.93;
N, 4.29.
2963; 2926; 2876; 1698; 1672; 1601; 1576; 1513; 776 cm-1
.
Anal. Calcd for C23H23NO4 (377.43): C, 73.19; H, 6.14; N, 3.71.
Found: C, 73.02; H, 6.20; N, 3.57.
(1R,2S,5S,6S,7S)-2-[6-Phenyl-3-(4-methoxyphenyl)-4-
oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-2-yl]benzalde-
hyde (16d). Yield: 94%. Colorless solid. Mp: 90-91 °C (from
1
hexane). [R]23 ) -51.8 (c ) 0.9, CHCl3). H NMR (δ): 0.93-
D
1.01 (m, 1H); 1.49 (td, 1H, J1)11.9 Hz, J2 ) 5.0 Hz); 1.59-
1.76 (m, 2H); 3.10 (d, 1H, J ) 5.3 Hz); 3.71 (s, 3H); 3.91 (t,
1H, J ) 4.7 Hz); 4.89 (t, 1H, J ) 5.0 Hz); 6.77 (d, 2H, J ) 9.0
Hz); 6.81 (s, 1H); 7.19-7.41 (m, 5H); 7.43 (d, 2H, J ) 9.0 Hz);
7.46-7.64 (m, 3H); 7.89 (dd, 1H, J1 ) 5.9 Hz, J2 ) 1.6 Hz);
10.23 (s, 1H). 13C NMR (δ): 24.4; 28.9; 52.7; 54.7; 55.3; 61.3;
80.5; 90.5; 114.0 (2C); 123.4 (2C); 126.5; 126.6; 128.1 (2C);
128.5 (2C); 128.7; 131.3; 133.8; 134.5; 136.1; 138.5; 139.1;
156.7; 174.7; 193.5. IR (Nujol): 3060; 1694; 1600; 1576; 753;
701 cm-1. Anal. Calcd for C28H25NO4 (439.50): C, 76.52; H,
5.73; N, 3.19. Found: C, 76.26; H, 5.86; N, 2.98.
Elimination of the p-Methoxyphenyl Substituent with
CAN. Synthesis of Lactams 18a-c. General Method. To
a solution of the corresponding lactam 16 (1 mmol) in aceto-
nitrile (10.4 mL) at 0 °C was added dropwise a solution of CAN
(1.67 g, 3 mmol) in water (13.9 mL). The mixture was stirred
at rt until the reaction was complete (TLC, 30 min to 1 h).
Then the aqueous layer was extracted with CHCl3 (3 × 15 mL).
The combined organic layers were washed with brine, dried
over MgSO4, and concentrated under vacuum, giving a 98%
yield of colorless oils as 70:30 mixtures of aldehydes and N,O-
ketals 17a-c. The residue was dissolved in ethanol (15 mL),
and NaBH4 (1.5 mmol) was added slowly at 0 °C. The solution
was stirred at rt until the reduction was finished (TLC) and
quenched by addition of dilute (5%) hydrochloric acid. Ethanol
was eliminated under vacuum, and the aqueous layer was
extracted with EtOAc (3 × 15 mL). The organic layer was
washed with brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel using hexanes-
CH2Cl2 (4:1, v/v) as eluent.
Hydrolysis of Compounds 11-14 to 15a-d and 16a-
d. General Method. A solution of the perhydrobenzoxazine
(4 mmol) in ethanol (60 mL) and 2% aqueous hydrochloric acid
(30 mL) was refluxed until the hydrolysis was complete (TLC,
4-8 h). The aqueous layer was extracted with ethyl acetate
(3 × 60 mL), and the organic extracts were washed with brine
and dried (MgSO4). The aldehydes were purified by flash
chromatography on silica gel (deactivated with 5% Et3N) using
hexanes-EtOAc (3:1) as eluent.
(1R,2S,5S,7S)-2-[3-(4-Methoxyphenyl)-4-oxo-10-oxa-3-
azatricyclo[5.2.1.01,5]dec-2-yl]benzaldehyde (16a). Yield:
94%. Colorless solid. Mp: 65-66 °C (from hexane). [R]23
)
D
+42.0 (c ) 0.6, CHCl3). 1H NMR (δ): 0.95-1.03 (m, 1H), 1.40-
1.51 (m, 2H), 1.87-2.04 (m, 1H), 1.94 (dd, 1H, J1 ) 12.1 Hz,
J2 ) 9.5 Hz), 2.19-2.26 (m, 1H), 2.96 (dd, 1H, J1 ) 9.5 Hz, J2
) 4.3 Hz), 3.71 (s, 3H), 4.71 (t, 1H, J ) 5.1 Hz), 6.75 (s, 1H),
6.77 (d, 2H, J ) 9.1 Hz), 7.39 (d, 2H, J ) 9.1 Hz), 7.41-7.63
(m, 3H), 7.90 (dd, 1H, J1 ) 7.2 Hz, J2 ) 1.5 Hz), 10.22 (s, 1H).
13C NMR (δ): 28.3; 29.6; 35.7; 49.6; 55.3; 61.1; 76.9; 89.5; 113.9
(1R,2S,5S,7S)-2-(2-Hydroxymethylphenyl)-10-oxa-3-
azatricyclo[5.2.1.01,5]decan-4-one (18a). Yield: 98%. Color-
less solid. Mp: 194-195 °C (from ethanol). [R]23 ) +13.4 (c
D
) 0.4, EtOH/H2O (9:1)). 1H NMR (δ): 1.17-1.28 (m, 1H); 1.44-
J. Org. Chem, Vol. 70, No. 18, 2005 7277

Pedrosa et al.
1.54 (m, 2H); 1.88-1.95 (m, 1H); 1.93 (dd, 1H, J1 ) 12.0 Hz,
J2 ) 9.5 Hz); 2.12-2.13 (m, 1H); 2.46 (br s, 1H); 2.84 (dd, 1H,
J1 ) 9.5 Hz, J2 ) 4.6 Hz); 4.68 (t, 1H, J ) 4.9 Hz); 4.72 (dd,
1H, J1 ) 12.3 Hz, J2 ) 2.7 Hz); 4.88 (dd, 1H, J1 ) 12.3 Hz, J2
+10.8 (c ) 0.4, CHCl3). 1H NMR (δ): 1.06-1.28 (m, 1H); 1.14
(d, 3H, J ) 7.0 Hz); 1.44 (td, 1H, J1 ) 11.7 Hz, J2 ) 5.6 Hz);
1.64-1.80 (m, 2H); 2.19 (d, 1H, J ) 5.1 Hz); 2.46-2.52 (m,
1H); 2.77-2.86 (br s, 1H); 4.42 (t, 1H, J ) 4.8 Hz); 4.67 (d,
1H, J ) 12.3 Hz); 4.83 (d, 1H, J ) 12.3 Hz); 5.24 (d, 1H, J )
1.5 Hz); 6.20 (br s, 1H); 7.20-7.41 (m, 4H). 13C NMR (δ): 15.7;
23.2; 29.5; 41.1; 55.3; 55.8; 62.9; 80.9; 93.9; 125.9; 128.2; 128.6;
129.4; 137.1; 137.8; 178.1. IR (KBr): 3432 (br); 2971; 1677;
1560; 766 cm-1. Anal. Calcd for C16H19NO3 (273.33): C, 70.31;
H, 7.01; N, 5.12. Found: C, 70.48; H, 7.19; N, 4.98.
) 2.7 Hz); 5.36 (s, 1H); 6.09 (br s, 1H); 7.28-7.44 (m, 4H). 13
C
NMR (CDCl3/acetone-d6, δ): 28.8; 29.4; 34.9; 47.7; 55.4; 62.3;
76.7; 92.9; 125.7; 127.9; 128.0; 128.9; 136.8; 138.2; 178.0. IR
(KBr): 3260 (br); 2990; 2940; 1680; 1610; 770; 720 cm-1. Anal.
Calcd for C15H17NO3 (259.30): C, 69.48; H, 6.61; N, 5.40.
Found: C, 69.33; H, 6.44; N, 5.34.
(1R,2S,5S,7S)-2-(2-Hydroxymethylphenyl)-5-methyl-
10-oxa-3-azatricyclo[5.2.1.01,5]decan-4-one (18b). Yield:
Acknowledgment. We thank the Spanish Minister-
io de Educacio´n y Ciencia (DGI, Project BQU2002-
01046) and Junta de Castilla y Leo´n (Project VA042/
03) for financial support. We also thank Dr. A. Pe´rez-
Encabo for the determination of the X-ray structures.
98%. Colorless solid. Mp: 88-89 °C (from ethanol). [R]23
)
D
1
+22.0 (c ) 0.2, CHCl3). H NMR (δ): 1.31 (s, 3H); 1.37-1.52
(m, 4H); 1.84-1.93 (m, 1H); 2.26-2.31 (m, 1H); 3.00 (br s, 1H);
4.50 (t, 1H, J ) 5.3 Hz); 4.65 (d, 1H, J ) 12.4 Hz); 4.90 (d, 1H,
J ) 12.4 Hz); 5.34 (d, 1H, J ) 0.8 Hz); 6.33 (br s, 1H); 7.30-
7.34 (m, 2H); 7.43-7.47 (m, 2H). 13C NMR (δ): 22.6; 25.3; 29.0;
45.0; 52.0; 56.1; 62.2; 76.3; 94.3; 125.8; 128.0; 128.2; 129.6;
Supporting Information Available: General experimen-
tal methods and physical and spectral characteristics for
compounds 2-7a-d and 9-15a-d and copies of 1H NMR and
13C NMR spectra for compounds 2-18. This material is
available free of charge via the Internet at http://pubs.acs.org.
136.1; 138.4; 181.5. IR (KBr): 3397 (br); 2972; 1686; 772 cm-1
.
Anal. Calcd for C16H19NO3 (273.33): C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.22; H, 6.95; N, 5.02.
(1R,2S,5S,6S,7S)-2-(2-Hydroxymethylphenyl)-6-meth-
yl-10-oxa-3-azatricyclo[5.2.1.01,5]decan-4-one (18c). Yield:
98%. Colorless solid. Mp: 162-163°C (from ethanol). [R]23
)
JO0509509
D
7278 J. Org. Chem., Vol. 70, No. 18, 2005