A Short Diastereoselective Synthesis of Enantiopure Highly Substituted Tetrahydroepoxyisoindolines

Article abstract of DOI:10.1021/jo991544q

Diastereoselective intramolecular Diels-Alder reaction on 3-allyl-2-furyl- or 3-furfuryl-2-vinyl-substituted chiral perhydro-1,3-benzoxazines derived from (-)-aminomenthol is described. The [4 + 2] cycloaddition is highly stereo- and regioselective leading to the thermodynamic adducts as major products. Reduction of the N,O-acetal, followed by elimination of the menthol appendage, allows both enantiomers of disubstituted epoxy tetrahydroisoindolines to be prepared. Nucleophilic ring opening of the N,O-moiety in the adducts by magnesium or aluminum derivatives, followed by elimination of the menthol, leads to the synthesis of enantiopure regioisomeric trisubstituted epoxy tetrahydroisoindolines with up to five stereocenters.

Full text of DOI:10.1021/jo991544q

J . Org. Chem. 2000, 65, 831-839
831
A Sh or t Dia ster eoselective Syn th esis of En a n tiop u r e High ly
Su bstitu ted Tetr a h yd r oep oxyisoin d olin es†
Rafael Pedrosa,* Celia Andre´s,* and J avier Nieto
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011 Valladolid, Spain
Received October 5, 1999
Diastereoselective intramolecular Diels-Alder reaction on 3-allyl-2-furyl- or 3-furfuryl-2-vinyl-
substituted chiral perhydro-1,3-benzoxazines derived from (-)-aminomenthol is described. The [4
+ 2] cycloaddition is highly stereo- and regioselective leading to the thermodynamic adducts as
major products. Reduction of the N,O-acetal, followed by elimination of the menthol appendage,
allows both enantiomers of disubstituted epoxy tetrahydroisoindolines to be prepared. Nucleophilic
ring opening of the N,O-moiety in the adducts by magnesium or aluminum derivatives, followed
by elimination of the menthol, leads to the synthesis of enantiopure regioisomeric trisubstituted
epoxy tetrahydroisoindolines with up to five stereocenters.
In tr od u ction
but the placement of the furan ring and the dienophile
into the same molecule can circumvent these problems
because it has been demonstrated that the intramolecular
reaction occurs at lower temperatures than its inter-
molecular counterpart.11 In this respect, the intra-
molecular Diels-Alder reaction of furyl-substituted R,â-
unsaturated amides has been reported,12 and even more
significantly, unactivated π bonds are often suitable
dienophiles for the internal cycloadditions.13
On the other hand, we have recently reported the
diastereoselective intramolecular [4 + 2] cycloaddition of
2-furyl substituted acrylamides derived from (-)-8-ami-
nomenthol to oxatricyclic adducts that can be further
elaborated to enantiomerically pure epoxy tetrahydroisoin-
dolines in excellent chemical yields.14 In conjunction with
these studies, we now report on the application of this
reaction, followed by nucleophilic ring opening of the N,O-
acetal15 in the perhydrobenzoxazine system, directed to
the diastereoselective synthesis of enantiopure 1- or
3-substituted epoxy tetrahydroisoindolines with up to five
stereocenters.
The application of the intramolecular Diels-Alder
reaction to the construction of aza-bicyclic compounds has
been practiced for more than 25 years,1,2 and interest in
this methodology has been reinforced during the past few
years.3 As such, syntheses of hydroquinolines,4 hydroin-
doles,5 hydroisoquinolines,6 hydroisoindoles,7 indoliz-
idines,8 and quinolizidines9 have been carried out by the
intramolecular [4 + 2] cycloaddition of different aza-
trienes.
The furan ring shows low reactivity toward unactivated
dienophiles, and the competing retro-Diels-Alder reac-
tion becomes a problem from a synthetic point of view,10
* Address correspondence to R. Pedrosa. Phone: Int + 34-983-
423211. Fax: Int + 983-423013. E-mail: pedrosa@qo.uva.es.
† Dedicated to Prof. Dr. Angel Alberola on occasion of his 70th
birthday.
(1) (a) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10. (b)
Oppolzer, W. Synthesis 1978, 793. (c) Oppolzer, W. Heterocycles 1980,
14, 1615. (d) Brieger, G.; Bennett, J . N. Chem. Rev. 1980, 80, 63.
(2) Craig, D. Chem. Soc. Rev. 1987, 16, 187.
(3) See for instance: Kappe, C. O.; Murphree, S. S.; Padwa, A.
Tetrahedron 1997, 53, 14179 and references therein.
(4) (a) Oppolzer, W.; Flaskamp, E. J . Am. Chem. Soc. 1977, 60, 204.
(b) Stork, G. Morgan J r., D. J . J . Am. Chem. Soc. 1979, 101, 7110. (c)
Keck, G. E.; Boden, E.; Sonnewald, V. Tetrahedron Lett. 1981, 22, 2615.
(d) Gallagher, T.; Magnus, P.; Huffman, J . C. J . Am. Chem. Soc. 1982,
104, 1140.
(5) (a) Martin, S. F.; Desai, S. R.; Phillips, G. W.; Miller, A. C. J .
Am. Chem. Soc. 1980, 102, 3294. (b) Martin, S. F.; Tu, C.; Kimura,
M.; Simonsen, S. H. J . Org. Chem. 1982, 47, 3634. (c) Padwa, A.;
Dimitroff, M.; Waterson, A. G.; Wu, T. J . Org. Chem. 1998, 63, 3986.
(d) Padwa, A.; Brodney, M. A.; Dimitroff, M. J . Org. Chem. 1998, 63,
5304.
(6) (a) Oppolzer, W.; Francotte, E,; Ba¨ttig, K. Helv. Chim. Acta 1981,
64, 478. (b) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum, A. G.;
Persichini, P. J ., III; Stabile, M. R.; Merola, J . S. J . Chem. Soc., Perkin
Trans. 1 1995, 2393, and references therein. (c) Leonard, J .; Fearnley,
S. P.; Hague, A. B.; Wong, G.; J ones, M. F. Tetrahedron Lett. 1997,
38, 3067.
(7) (a) Frater, G. Tetrahedron Lett. 1976, 4517. (b) Parker, K. A.;
Adamchuck, M. R. Tetrahedron Lett. 1978, 1689. (c) Pyne, S. G.;
Hensel, M. J .; Byrn, S. R.; McKenzie, A. T.; Fuchs, P. L. J . Am. Chem.
Soc. 1980, 102, 5960. (d) Mukaiyama, T.; Iwasana, N. Chem. Lett. 1981,
29. (e) Brettle, R.; J afri, I. A. J . Chem. Soc., Perkin Trans. 1 1983,
387. (f) Mellor, J . M.; Wagland, A. M. J . Chem. Soc., Perkin Trans. 1
1989, 997.
Retrosynthetic analysis (Figure 1) illustrates that both
enantiomers of 3- or 4-substituted epoxy tetrahydroisoin-
dolines (8 or ent-8) can be synthesized from the regio-
isomeric (-)-8-aminomenthol-derived perhydrobenzox-
azines 2 and 3, which differ in the position of the furan,
acting as diene, and the unactivated dienophile in the
heterocycle. Thermally induced cycloaddition of 2 and 3
(10) Lipshuts, B.Chem. Rev. 1986, 86, 795.
(11) (a) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J . Org. Chem.
1984, 49, 3427. (b) Klein, L. L. J . Org. Chem. 1985, 50, 1770. (c) J ung,
M. E.; Gervey, J . J . Am. Chem. Soc. 1989, 111, 5469.
(12) (a) J ung, M. E.; Street, L. J . J . Am. Chem. Soc. 1984, 106, 8327.
(b) Prajapati, D.; Sandhu, J . S. Heterocycles 1985, 23, 17. (c) Prajapati,
D.; Borthakur, D. R.; Sandhu, J . S. J . Chem. Soc., Perkin Trans. 1
1993, 1197. (d) Zylber, J .; Tubul, A.; Brun, P. Tetrahedron: Asymmetry.
1995, 6, 377.
(13) (a) Mance, A. D.; Sindler-Kulyk, M.; J akopcic, K.; Hergold-
Brundk, A.; Nagl, A. J . Heterocycl. Chem. 1997, 34, 1315. (b) Choony,
N.; Badabhoy, A.; Sammes, J . J . Chem. Soc., Chem. Commun. 1997,
513. (c). Choony, N.; Badabhoy, A.; Sammes, J . J . Chem. Soc., Perkin
Trans. 1 1998, 2017. (d) Andre´s, C.; Nieto, J .; Pedrosa, R.; Vicente, M.
J . Org. Chem. 1998, 63, 8570.
(8) Khatri, N. A.; Schmitthenner, H. F.; Shringarpure, J .; Weinreb,
S. M. J . Am. Chem. Soc. 1981, 103, 6387.
(9) Cheng, Y. S.; Fowler, F. W.; Lupo, A. T. J . Am. Chem. Soc. 1981,
103, 2090.
(14) Andre´s, C.; Maestro, G.; Nieto, J .; Pedrosa, R.; Garc´ıa-Granda,
S.; Pe´rez- Carren˜o, E. Tetrahedron Lett. 1997, 38, 1463.
(15) Andre´s, C.; Nieto, J .; Pedrosa, R.; Villaman˜a´n, N. J . Org. Chem.
1996, 61, 4130.
10.1021/jo991544q CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/14/2000

832 J . Org. Chem., Vol. 65, No. 3, 2000
Pedrosa et al.
Ta ble 1. Diels-Ald er Cycloa d d ition of
P er h yd r o-1,3-ben zoxa zin es 2a -d
reaction time yielda
oxazine R1
R2
(h)
(%)
products (ratio,%)b
2a
2b
2c
2d
H
Me
H
H
H
Me
Ph
120
240
160
300
93
4a (97), 4′a (3)
4b (97), 4′b (3)
4c (97), 4′c (3)
4d (100)
60c
80d
50e
H
a
Chemical yields of pure and isolated compounds. b Determined
by integration of the signals of 1H NMR spectra of the reaction
mixtures. c 35% of perhydrobenzoxazine 2b was recovered. 12%
d
of perhydrobenzoxazine 2c was recovered. e 37% of perhydroben-
zoxazine 2d was recovered.
The moderate chemical yield in intramolecular Diels-
Alder reaction of the furan diene (IMDAF) and substi-
tuted dienophiles is a well-documented fact in both
catalyzed16 and uncatalyzed17 processes and is a conse-
quence of the reversible character of the reaction. By
contrast, the reactions occurred with excellent, for com-
pounds 2a -c, or total, for compound 2d , stereofacial
discrimination. The absolute configuration of the cyclo-
adducts was assigned by transformation into the epoxy
isoindolines 8a -c and ent-8a -c (vide infra).
The change of the substituents at the starting perhy-
dro-1,3-benzoxazines would lead to obtain the enantio-
meric tetrahydroepoxyisoindolines. To this end, the
regioisomeric 2-vinyl-3-methylfurylperhydro-1,3-benzox-
azines 3a -d were prepared by condensation of 8-fur-
furylaminomenthol (12) with acrolein, methacrolein,
crotonaldehyde, and cinnamaldehyde, respectively, in
toluene at reflux (Scheme 1). As described for compounds
2a -d , compounds 3a ,b were totally transformed into a
mixture of cycloadducts 5a ,b and 5′a ,b , whereas 3c,d
give a mixture of cyclization products and unreacted
perhydrobenzoxazines (Table 2).
It is interesting to note that the chemical yields for the
cyclizations of 3a -d were better than those of 2a -d , but
the diastereoselection decreased, varying from moderate,
for 3c or 3d , to good, for 3a ,b. Nevertheless, the stereo-
chemistry of cycloadducts 5a -c and 5′a -c, determined
by correlation with ent-8a -c and 8a -c, respectively,
denoted that the IMDAF reaction followed the same
trend as that for their regioisomeric 2a -d counterpart.
In this respect, only exo cyclization took place, leading
to the thermodynamically more stable diastereoisomers
5a -d .
F igu r e 1.
was expected to give diastereomeric cycloadducts 4 and
5, respectively, which, after reductive ring opening to 6
and 7, followed by elimination of the menthol appendage
will lead to 8 and ent-8. This switch in selectivity, which
allows epoxytetrahydroisoindoline derivatives of opposite
absolute configuration to be produced, is seen to be a
consequence of changing the faces of both components
that participate in the reaction. In addition, the ring
opening of 4 and 5 by a nucleophile and elimination of
the menthol allow regioisomeric 1- and 3-substituted
epoxytetrahydroisoindoline derivatives 9 and 10 to be
prepared.
Resu lts a n d Discu ssion
The preparation of 3-allyl-2-furyl-substituted perhydro-
1,3-benzoxazines (2a -d ) was achieved by condensation
of (-)-8-allylaminomenthols 11a -d with furfural. In
turn, compounds 11a -d were synthesized by alkylation
of (-)-8-aminomenthol 1 with the corresponding allyl
bromide, and 12 was prepared, in two steps, by conden-
sation of 1 with furfural, followed by reduction of the
N-unsubstituted 2-furyl perhydro-1,3-benzoxazine with
sodium borohydride in methanol, at room temperature.
The condensation of 11a -d with furfural did not occur
under the standard conditions, even in the presence of
Lewis acids.15 Instead, the reactions took place after
heating a mixture of 11a -d and furfural (1.2 equiv) in
toluene at reflux. Under these conditions, it was not
possible to isolate perhydrobenzoxazine 2a because it was
totally transformed into a mixture of cycloadducts 4a and
4′a (97:3). On the contrary, Diels-Alder reaction of the
isolated allylic perhydrobenzoxazines 2b-d , with sub-
stituents at the dienophile, was not complete after
heating for long periods of time (Table 1).
After separation of the diastereoisomers by flash
chromatography, they were converted into the enan-
tiopure tetrahydroepoxyisoindolines 8 or ent-8 in two
steps (Scheme 2). Reductive ring opening of 4a -d with
a mixture of lithium aluminum hydride and aluminum
trichloride in THF led to the menthol derivatives 6a -d
in excellent chemical yields, whereas the same treatment
on 4′a -d yielded diastereoisomers 6′a -d . Cycloadduts
5a -d or 5′a -d were transformed into 6′a -d or 6a -d ,
respectively, by the same method. Elimination of the
menthol appendage was carried out by oxidation of 6 and
6′ with PCC to the corresponding aminomenthone de-
rivatives, which were not isolated, but immediately
subjected to elimination by treatment with a solution of
KOH in MeOH/ THF/ H2O to the known18 tetrahydro-
(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.

Synthesis of Tetrahydroepoxyisoindolines
J . Org. Chem., Vol. 65, No. 3, 2000 833
Sch em e 1
Sch em e 2
Ta ble 3. Red u ctive Rin g Op en in g of Cycloa d d u cts 4, 4′,
5, a n d 5′ a n d Elim in a tion of th e Men th ol Ap p en d a ge
aminomenthol tetrahydroepoxyisoindoline
entry cycloaddut
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a
4b
4c
4d
4′a
4′b
4′c
5a
6a (88)
6b (90)
6c (80)
6d (77)
6′a (83)
6′b (80)
6′c (91)
6′a (93)
6′b (88)
6′c (92)
6′d (90)
6a (92)
6b (78)
6c (82)
6d (84)
8a (72)
8b (73)
8c (66)
Ta ble 2. Diels-Ald er Cycloa d d ition of
P er h yd r o-1,3-ben zoxa zin es 3a -d
ent-8a (70)
ent-8b (67)
ent-8c (63)
ent-8a (65)
ent-8b (66)
ent-8c (70)
reaction time yielda
oxazine R1
R2
(h)
(%)
products (ratio,%)b
5b
5c
3a
3b
3c
3d
H
Me
H
H
H
Me
Ph
80
240
100
200
96
5a (90), 5′a (10)
5b (91), 5′b (9)
5c (77), 5′c (23)
5d (86), 5′d (14)
85
5d
5′a
5′b
5′c
5′d
80c
73d
8a (74)
8b (66)
8c (70)
H
a
Chemical yields of pure and isolated compounds. b Determined
by integration of the signals of 1H NMR spectra of the reaction
mixtures. c 13% of perhydrobenzoxazine 3c was recovered. 23%
d
of perhydrobenzoxazine 3d was recovered.
Sch em e 3
epoxyisoindolines 8a -c and ent-8a -c and (+)-pulegone
(Table 3).
It is noteworthy that all the aminomenthol derivatives
6 and 6′, and tetrahydro isoindolines 8a -c, and their
enantiomers showed high thermal stability, but the
isolation of both phenyl-substituted tetrahydroisoindo-
lines 8d or ent-8d was not possible because the oxida-
tion-elimination protocol on 6d and 6′d was followed by
a cycloreversion process13b,c leading to the cinnamyl
furfurylamine 13 as the only product (Scheme 3).
The stereochemistry of 4d , 5d , and 5′d was determined
by COSY and NOESY experiments, and the enantiomeric
relationship between the epoxyisoindolines obtained from
4a -c and 4′a -c, or from 5′a -c or 5a -c, allowed
(18) Andre´s, C.; Garc´ıa-Valverde, M.; Nieto, J .; Pedrosa, R. J . Org.
Chem. 1999, 64, 5230.

834 J . Org. Chem., Vol. 65, No. 3, 2000
Pedrosa et al.
Sch em e 4
Sch em e 5
establishment of not only the stereochemistry of the
cyclization products but also the stereochemical course
of the reaction. As expected, the facial discrimination in
the cycloadditions of 2a -d and 3a -d is imposed by the
size of the tether between diene and dienophile,19 the exo
adducts being the only diastereoisomers formed. On the
other hand, the formation of 4a -d as single or major
diastereoisomers from 2a -d is the result of the interac-
tion of the R-Si face of the dienophile toward the R-Si
face of the diene, demonstrating that the less polar
transition state A (Scheme 4) is favored over A′. Con-
versely, 5a -d , the major diastereoisomers formed from
3a -d , arise from the interaction of the R-Re face of the
diene and R-Re face of the dienophile, also via the less
polar transition state B. This facial discrimination, better
than for the corresponding acrylamide derivatives, is a
consequence of the thermodynamic control of the reac-
tion, wich is dictated by the experimental conditions14
(nonpolar solvent and high reaction temperature).
Taking into account the regiochemical relationship
between cycloadducts 4 and 5 and the easy stereoselec-
tive ring opening of the N,O-acetals in perhydro-1,3-
benzoxazine derivatives,15 the synthesis of regioisomeric
epoxytetrahydroisoindolines 9 and 10 was prepared by
nucleophilic ring opening of cycloadducts with organo-
metallics. To this end, 4a -d were treated with excess of
trimethylaluminum in toluene, at room temperature
(Scheme 5). Under these conditions, reaction was com-
pleted after 15-20 min leading to methyl derivatives
14a -d , in both excellent yields and diastereomeric excess
(Table 4).
After purification by flash chromatography, compounds
14a -d were transformed into the enantiopure 1-meth-
ylepoxytetrahydroisoindolines 9a -d by oxidation-elimi-
nation in good yield except for compound 14d . In this
case, (S)-N-cinnamyl-1-furylethylamine (40%), resulting
from the retro Diels-Alder reaction, was also isolated.
Surprisingly, the reaction of 5a with trimethylaluminum
under the above conditions gave 7a as a nearly equimolar
mixture of epimers at the newly created stereocenter.
Treatment of 5a -c with 4 equiv of methylmagnesium
iodide in diethyl ether, at room temperature, yielded in
excellent yield a mixture of epimeric aminomenthol
derivatives 7a -c and 7′a -c, in moderate de. The only
exception was the reaction of 5b (entry 7 in Table 4),
Ta ble 4. Rin g Op en in g of Cycloa d d u cts 4 a n d 5 by
Or ga n om eta llics a n d Elim in a tion of th e Men th ol
Ap p en d a ge
amino menthol
cyclo-
yielda productsb
epoxy-
entry adduct alkylmetal
(%)
(dr)
isoindolinea
1
2
4a
4b
Me3Al
Me3Al
97
95
14a (100)
14b (97)
14′b (3)
14c (97)
14′c (3)
14d (96)
14′d (4)
7a (49)
7′a (51)
7a (68)
7′a (32)
7b (100)
7c (75)
9a (80)
9b (68)
3
4
5
6
4c
4d
5a
5a
Me3Al
Me3Al
Me3Al
MeMgI
93
90
94
90
9c (72)
9d (42)
10a (76)
10′a (70)
10b (70)
10c (72)
10′c (68)
7
8
5b
5c
MeMgI
MeMgI
97
92
7′c (25)
Chemical yields of pure and isolated compounds. b Determined
a
by integration of the signals of 1H NMR spectra of the reaction
mixtures.
which gave 7b with total stereoselection. After separation
by flash chromatography, 7a -c and 7′a -c were indi-
vidually transformed by the oxidation-elimination se-
quence into enantiopure 3-methylepoxytetrahydroisoin-
dolines 10a -c and 10′a -c, respectively.
COSY and NOESY experiments allowed assignment
of the configuration of the newly stereocenter (C-1) as S
in compounds 9a -d , whereas the configuration at C-3
in the major stereoisomers 10a -c or minor ones 10′a -
c, arising from the opening of 5a -c was assigned as R
and S, respectively. These results indicated that the
nucleophilic ring opening of 4a -d with trimethylalumi-
num was highly stereoselective and that the reaction
occurred from the oxygen face of the heterocycle with
retention of the configuration. As expected, the opening
of the heterocycle by Grignard derivatives occurred
through the iminium ion,15,20 from the less hindered face,
leading to the inversion product as the major diastereo-
(19) J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224.

Synthesis of Tetrahydroepoxyisoindolines
J . Org. Chem., Vol. 65, No. 3, 2000 835
(50 mL) was added in portions sodium borohydride (2.28 g, 60
mmol) for 1.5 h. The reaction mixture was stirred at room
temperature for an additional 10 h and quenched by addition
of a saturated aqueous solution of NH4Cl (50 mL) at 0 °C. After
removal of the methanol in vacuo, the aqueous phase was
extracted four times with EtOAc. The organic layer was
washed with brine and dried over anhydrous Na2SO4. The
solvent was evaporated, and the residue was recrystallized
Sch em e 6
from hexane. Yield: 4.12 g, 82%. Colorless solid. Mp ) 70-71
1
°C (from hexane). [R]25 ) -26.6 (c ) 1.0, CH2Cl2). H NMR
D
(CDCl3): δ ) 0.87-1.08 (m, 3H), 0.91 (d, 3H, J ) 6.6 Hz), 1.16
(s, 3H), 1.17 (s, 3H), 1.34 (m, 1H), 1.42 (m, 1H), 1.60-1.71 (m,
2H), 1.95 (m,1H), 3.64 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.2 Hz),
3.75 (d, 1H, J ) 13.4 Hz), 3.84 (d, 1H, J ) 13.4 Hz), 6.18 (dd,
1H, J 1 ) 0.7 Hz, J 2 ) 3.1 Hz), 6.28 (dd, 1H, J 1 ) 1.8 Hz, J 2
)
isomer. The steric shielding of the R methyl group in the
methacrolein derivative 7b could explain the total ste-
reoselection observed in this case (Scheme 6).
3.1 Hz), 7.33 (dd, 1H, J 1 ) 0.7 Hz, J 2 ) 1.8 Hz),8.12-8.46 (br
s, 2H). 13C NMR (CDCl3): δ ) 21.6, 22.1, 25.8, 26.2, 31.0, 35.0,
38.6, 44.4, 49.6, 56.8, 72.4, 106.6, 110.2, 141.8, 153.2. IR (Nujol
dispersion): ν ) 3240, 1590 cm-1. MS (EI, 70 eV): m/z ) 251
(M+) (1), 81 (100). Anal. Calcd for C15H25NO2: C, 71.67; H,
10.02; N, 5.57. Found: C, 71.42; H, 10.31; N, 5.82.
In summary, a short and efficient way to both enan-
tiomers or regioisomers of enantiopure epoxyisoindolines,
with four or five stereocenters has been achieved in five
steps from (-)-8-aminomenthol. This methodology allows
the introduction of a variety of substituents on the
isoindoline nucleous and, combined with the transforma-
tions of the oxanorbornene moiety,21 opens a way to the
synthesis of complex structures.
Syn th esis of Octa h yd r o-1,3-ben zoxa zin es 2a -d a n d
Cycloa d d ition to 4a -d . A solution of furfural (2.4 g, 25
mmol) and the corresponding 8-allylaminomenthol 11a -d (10
mmol) in dry toluene (25 mL) was refluxed on a Dean-Stark
trap for 48-72h. The solvent and the excess of furfural were
eliminated in vacuo, and the residue was chromatographed
on silica gel using hexanes-EtOAc (3:1 for 4a -c and 8:1 for
4d ). Under these conditions, it was not possible to isolate 2a
because it was totally transformed into 4a ; the yields for the
reactions are given in Table 1.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under
argon atmosphere, in oven-dried glassware. 1H NMR (300
MHz) and 13C NMR (75 MHz) were registered in CDCl3 as
solvent, and TMS as internal standard, and chemical shifts
are given in ppm. Specific rotations were determined on a
digital polarimeter using a Na lamp, and concentration is given
in g per 100 mL. Melting points were obtained with open
capillary tubes and are uncorrected. Solvents were dried by
standard methods. TLC was performed on glass-backed plates
coated with silica gel 60 with an F254 indicator; the chromato-
grams were visualized under UV light and/or by staining with
a Ce/Mo reagent. Flash column chromatography was carried
out on silica gel 60 (230-240 mesh).
N-Meth acr yl-2r-(2-fu r yl)-4,4,7r-tr im eth yl-tr a n s-octah y-
d r o-1,3-ben zoxa zin e (2b). Colorless oil. [R]25 ) -24.9 (c )
D
1
2.8, CH2Cl2). H NMR (CDCl3): δ ) 0.80-0.91 (m, 2H), 0.84
(d, 3H, J ) 6.5 Hz), 1.02-1.16 (m, 1H), 1.03 (s, 3H), 1.14 (s,
3H), 1.35-1.52 (m, 2H), 1.42 (s, 3H), 1.53-1.63 (m, 2H), 1.87
(m, 1H), 2.87 (d, 1H, J ) 17.6 Hz), 3.17 (d, 1H, J ) 17.6 Hz),
3.49 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.5 Hz), 4.48 (d, 1H, J ) 0.8
Hz), 4.72 (d, 1H, J ) 0.8 Hz), 5.50 (s, 1H), 6.14 (dd, 1H, J 1
)
1.7 Hz, J 2 ) 3.3 Hz), 6.20 (dd, 1H, J 1 ) 0.8 Hz, J 2 ) 3.3 Hz),
7.18 (dd, 1H, J 1 ) 0.8 Hz, J 2 ) 1.7 Hz). 13C NMR (CDCl3): δ
) 19.0, 20.1, 22.1, 24.9, 26.4, 31.2, 34.8, 41.1, 46.1, 49.5, 56.7,
76.2, 83.7, 107.3, 109.2, 109.8, 141.1, 145.1, 152.7. IR (neat):
ν ) 3060, 1150 cm-1. Anal. Calcd for C19H29NO2: C, 75.21; H,
9.63; N, 4.62. Found: C, 75.51; H, 9.88; N, 4.45.
Syn th esis of 8-N-Meth a cr yla m in om en th ol (11b). This
compound was prepared as previously described22 for 11a , 11c,
and 11d starting from a mixture of (-)-aminomenthol (1.71
g, 10 mmol), anhydrous K2CO3 (1.66 g, 1.2 mmol), and
methacryl bromide (1.62 g, 1.2 mmol) in acetonitrile (70 mL).
N-Cr otyl-2r-(2-fu r yl)-4,4,7r-tr im eth yl-tr a n s-octah ydr o-
1,3-ben zoxa zin e (2c). Colorless oil. [R]25 ) -14.3 (c ) 3.4,
D
CH2Cl2). 1H NMR (CDCl3): δ ) 0.84-0.95 (m, 2H), 0.85 (d,
3H, J ) 6.5 Hz), 1.04-1.19 (m, 1H), 1.12 (s, 3H), 1.14 (s, 3H),
1.34-1.53 (m, 2H), 1.42 (dd, 3H, J 1 ) 1.3 Hz, J 2 ) 6.3 Hz),
1.53-1.64 (m, 2H), 1.88 (m, 1H), 2.83 (dd, 1H, J 1 ) 6.2 Hz, J 2
) 16.2 Hz), 3.16 (dd, 1H, J 1 ) 6.2 Hz, J 2 ) 16.2 Hz), 3.48 (dt,
1H, J 1 ) 4.1 Hz, J 2 ) 10.5 Hz), 4.97 (dq, 1H, J 1 ) 6.3 Hz, J 2
) 15.2 Hz), 5.12 (dtq, 1H, J 1 ) 1.3 Hz, J 2 ) 6.2 Hz, J 3 ) 15.2
Hz), 5.45 (s, 1H), 6.21 (dd, 1H, J 1 ) 1.8 Hz, J 2 ) 3.2 Hz), 6.26
(dd, 1H, J 1 ) 1.0 Hz, J 2 ) 3.2 Hz), 7.25 (dd, 1H, J 1 ) 1.0 Hz,
J 2 ) 1.8 Hz). 13C NMR (CDCl3): δ ) 17.5, 18.0, 22.0, 24.9,
26.8, 31.1, 34.8, 41.1, 46.1, 46.8, 56.9, 75.9, 83.3, 108.0, 109.8,
Colorless solid. Mp ) 72-73 °C (from hexane). [R]25 ) -17.6
D
1
(c ) 1.0, CH2Cl2). H NMR (CDCl3): δ ) 0.82-1.03 (m, 3H),
0.85 (d, 3H, J ) 5.6 Hz), 1.08 (s, 3H), 1.09 (s, 3H), 1.24 (m,
1H), 1.39 (m, 1H), 1.56-1.64 (m, 2H), 1.71 (s, 3H), 1.88 (m,
1H), 3.04 (d, 1H, J ) 13.3 Hz), 3.16 (d, 1H, J ) 13.3 Hz), 3.57
(dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.3 Hz), 4.75 (s, 1H), 4.81 (s, 1H),
5.30-5.42 (broad s, 2H). 13C NMR (CDCl3): δ ) 21.2, 21.5,
22.0, 25.7, 26.1, 30.9, 34.9, 44.4, 47.1, 49.7, 56.5, 72.4, 110.8,
143.5. IR (Nujol dispersion): ν ) 3220, 1185 cm-1. MS
(chemical ionization): m/z ) 226 (M+ + 1) (100). Anal. Calcd
for C14H27NO: C, 74.61; H, 12.08; N, 6.21. Found: C, 74.40;
H, 12.12; N, 6.02.
124.5, 131.5, 141.3, 152.2. IR (neat): ν ) 3060, 1150 cm-1
Anal. Calcd for C19H29NO2: C, 75.21; H, 9.63; N, 4.62. Found:
C, 75.47; H, 9.79; N, 4.80.
.
Syn th esis of 8-F u r fu r yla m in om en th ol (12). A mixture
of (-)-8-aminomenthol (8.55 g, 50 mmol), freshly distilled
furfural (5.76 g, 60 mmol), and 4 Å molecular sieves (3 g) in
anhydrous benzene (150 mL) was stirred at room temperature
for 40h. The reaction mixture was filtered through Celite, and
the solids were washed with benzene. The solvent was
evaporated in vacuo, and the residue was recrystallized from
pentane to give 2R-(2-furyl)-4,4,7R-trimethyl-trans-octahydro-
1,3-benzoxazine (11.95 g, 96%) as a colorless solid (mp 32-34
°C). To a solution of this compound (5 g, 20 mmol), in methanol
N-Cin n am yl-2r-(2-fu r yl)-4,4,7r-tr im eth yl-tr a n s-octah y-
d r o-1,3-ben zoxa zin e (2d ). Colorless oil. [R]25 ) -9.3 (c )
D
1
1.6, CH2Cl2). H NMR (CDCl3): δ ) 0.92-1.12 (m, 2H), 1.00
(d, 3H, J ) 6.5 Hz), 1.18-1.32 (m, 1H), 1.30 (s, 3H), 1.32 (s,
3H), 1.54 (m, 1H), 1.65 (m, 1H), 1.69-1.79 (m, 2H), 2.11 (m,
1H), 3.21 (dd, 1H, J 1 ) 5.3 Hz, J 2 ) 16.8 Hz), 3.53 (dd, 1H, J 1
) 4.9 Hz, J 2 ) 16.8 Hz), 3.67 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.5
Hz), 5.65 (s, 1H), 6.02-6.17 (m, 2H), 6.33 (dd, 1H, J 1 ) 1.8
Hz, J 2 ) 3.1 Hz), 6.45 (d, 1H, J ) 3.1 Hz), 7.18-7.34 (m, 6H).
13C NMR (CDCl3): δ ) 18.1, 22.2, 25.0, 26.9, 31.2, 34.8, 41.3,
46.6, 47.1, 57.2, 76.2, 83.5, 108.3, 110.0, 126.0 (2C), 126.6, 128.2
(2C), 128.6, 131.2, 137.5, 141.8, 149.3. IR (neat): ν ) 3015,
1150 cm-1. Anal. Calcd for C24H31NO2: C, 78.86; H, 8.55; N,
3.83. Found: C, 79.04; H, 8.81; N, 3.62.
(20) Wu, M. J .; Pridgen, L. N. J . Org. Chem. 1991, 56, 1340.
(21) Woo, S.; Keay, B. A. Synthesis 1996, 669.
(22) Andre´s, C.; Duque-Soladana, J . P.; Pedrosa, R. J . Org. Chem.
1999, 64, 4273.

836 J . Org. Chem., Vol. 65, No. 3, 2000
Pedrosa et al.
Cycloa d d u ct (4a ). Colorless solid. Mp ) 70-71 °C (from
hexane). [R]25D ) -69.9 (c ) 1.0, CH2Cl2). 1H NMR (CDCl3): δ
) 0.88-1.14 (m, 3H), 0.93 (d, 3H, J ) 6.5 Hz), 1.15 (s, 3H),
1.19 (s, 3H), 1.42-1.63 (m, 4H), 1.74 (m, 2H), 1.93 (m, 1H),
2.20 (m, 1H), 2.71 (dd, 1H, J 1 ) 5.8 Hz, J 2 ) 9.3 Hz), 3.32 (t,
1H, J ) 9.3 Hz), 3.53 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.5 Hz), 4.95
(s, 1H), 5.03 (dd, 1H, J 1 ) 1.4 Hz, J 2 ) 4.3 Hz), 6.24 (dd, 1H,
J 1 ) 1.4 Hz, J 2 ) 5.8 Hz), 6.56 (d, 1H, J ) 5.8 Hz). 13C NMR
(CDCl3): δ ) 20.3, 22.3, 24.8, 26.1, 31.3, 32.5, 35.1, 40.0, 41.6,
44.7, 48.5, 53.2, 75.0, 79.3, 84.9, 96.7, 134.5, 134.6. IR (Nujol
dispersion): ν ) 1600, 1100 cm-1. MS (EI, 70 eV): m/z ) 289
(M+) (4), 41 (100). Anal. Calcd for C18H27NO2: C, 74.70; H,
9.40; N, 4.84. Found: C, 75.01; H, 9.46; N, 4.71.
5.8 Hz), 6.71 (d, 1H, J ) 5.8 Hz), 7.04-7.20 (m, 5H). 13C NMR
(CDCl3): δ ) 20.2, 22.2, 24.7, 25.9, 31.2, 34.9, 41.4, 44.4, 48.4,
48.6, 52.2, 53.2, 75.0, 83.1, 84.9, 98.3, 126.4, 127.8, (2C), 128.0
(2C), 132.8, 135.3, 140.2. IR (neat): ν ) 3020, 1490 cm-1. MS
(EI, 70 eV): m/z ) 365 (M+) (1), 117 (100). Anal. Calcd for
C
24H31NO2: C, 78.86; H, 8.55; N, 3.83. Found: C, 78.61; H,
8.81; N, 4.01.
Syn th esis of Octa h yd r o-1,3-ben zoxa zin es 3a -d a n d
Cycloa d d ition to 5a -d . A solution of 8-furfurylaminomen-
thol 12 (2.11 g, 10 mmol) and acrolein, methacrolein, crotonal-
dehyde, or cinnamaldehyde (12 mmol) in anhydrous toluene
was refluxed for 96 h on a Dean-Stark trap. The solvent was
eliminated in vacuo, and the residue was subjected to flash
chromatography on silica gel using hexanes-EtOAc (5:1 for
5a , 5:1 for 5c, or 8:1 for 5d ) or EtOAc-CHCl3 1:40 (for 5b) as
eluents. Under these conditions, compounds 3a and 3b cannot
be isolated because they were totally transformed into the
corresponding cycloadducts. The yields for the reactions are
given in Table 2.
Cycloa d d u ct (4′a ). Yellow oil. [R]25D ) +16.7 (c ) 1.8, CH2-
1
Cl2). H NMR (CDCl3): δ ) 0.82-1.02 (m, 2H), 0.90 (d, 3H, J
) 6.6 Hz), 1.02-1.18 (m, 1H), 1.06 (s, 3H), 1.14 (s, 3H), 1.36-
1.52 (m, 2H), 1.46 (dd, 1H, J 1 ) 8.1 Hz, J 2 ) 11.3 Hz), 1.64
(m, 2H), 1.77 (dt, 1H, J 1 ) 4.4 Hz, J 2 ) 11.3 Hz), 1.87-2.00
(m, 2H), 2.88 (dd, 1H, J 1 ) 7.3 Hz, J 2 ) 8.7 Hz), 3.08 (t, 1H,
J ) 8.7 Hz), 3.48 (dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.5 Hz), 5.05 (s,
1H), 5.11 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.4 Hz), 6.29 (dd, 1H, J 1
) 1.6 Hz, J 2 ) 5.8 Hz), 6.45 (d, 1H, J ) 5.8 Hz). 13C NMR
(CDCl3): δ ) 14.9, 22.1, 24.8, 26.5, 31.2, 31.4, 34.8, 40.6, 41.2,
47.2, 48.1, 54.2, 75.9, 79.8, 83.8, 95.1, 134.7,135.8. IR (neat):
ν ) 1600, 1105 cm-1. Anal. Calcd for C18H27NO2: C, 74.70; H,
9.40; N, 4.84. Found: C, 74.52; H, 9.59; N, 4.96.
N-F u r fu r yl-2r-(1-p r op en yl)-4,4,7r-tr im eth yl-tr a n s-oc-
ta h yd r o-1,3-ben zoxa zin e (3c). Colorless oil. [R]25 ) -34.8
D
1
(c ) 0.6, CH2Cl2). H NMR (CDCl3): δ ) 0.88-1.00 (m, 2H),
0.92 (d, 3H, J ) 6.5 Hz), 1.00-1.20 (m, 2H), 1.11 (s, 3H), 1.17
(s, 3H), 1.38-1.53 (m, 2H), 1.63-1.75 (m,1H), 1.65 (dd, 3H,
J 1 ) 1.5 Hz, J 2 ) 6.5 Hz), 1.93 (m, 1H), 3.49 (dt, 1H, J 1 ) 4.1
Hz, J 2 ) 10.6 Hz), 3.61 (d, 1 H, J ) 17.1 Hz), 3.90 (d, 1H, J )
17.1 Hz), 4.96 (dd, 1H, J 1 ) 0.9 Hz, J 2 ) 5.5 Hz), 5.46 (ddq,
1H, J 1 ) 1.5 Hz, J 2 ) 5.5 Hz, J 3 ) 15.4 Hz), 5.83 (ddq, 1H, J 1
) 0.9 Hz, J 2 ) 6.5 Hz, J 3 ) 15.4 Hz), 6.03 (m, 1H), 6.27 (dd,
1H J 1 ) 1.9 Hz, J 2 ) 3.0 Hz), 7.29 (m, 1H). 13C NMR (CDCl3):
δ ) 17.8, 18.0, 22.2, 25.1, 26.9, 31.3, 34.9, 41.0, 41.3, 47.1, 56.8,
75.4, 87.7, 106.1, 110.0, 129.3, 130.8, 140.7, 157.0. IR (neat):
ν ) 1600, 1380 cm-1. Anal. Calcd for C19H29NO2: C, 75.21; H,
9.63; N, 4.62. Found: C, 75.52; H, 9.84; N, 4.45.
Cycloa d d u ct (4b). Colorless solid. Mp ) 67-68 °C (from
1
pentane). [R]25 ) -22.3 (c ) 1.1, CH2Cl2). H NMR (CDCl3):
D
δ ) 0.83-1.08 (m, 3H), 0.93 (d, 3H, J ) 6.6 Hz), 1.08-1.21
(m, 1H), 1.09 (s, 3H), 1.14 (s, 3H), 1.20 (s, 3H), 1.44-1.57 (m,
2H), 1.62 (m, 1H), 1.72 (m, 1H), 1.93 (m, 1H), 2.14 (dd, 1H, J 1
) 4.6 Hz, J 2 ) 11.2 Hz), 3.02 (d, 1H, J ) 9.3 Hz), 3.07 (d, 1H,
J ) 9.3 Hz), 3.50 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.4 Hz), 4.96 (dd,
1H, J 1 ) 1.6 Hz, J 2 ) 4.6 Hz), 5.02 (s, 1H), 6.31 (dd, 1H, J 1
)
1.6 Hz, J 2 ) 5.8 Hz), 6.55 (d, 1H, J ) 5.8 Hz). 13C NMR
(CDCl3): δ ) 20.7, 22.3, 24.8, 25.9, 27.6, 31.2, 35.1, 41.9, 42.1,
44.7, 46.4, 52.8, 57.6, 74.4, 79.1, 85.0, 97.4, 133.1, 134.6. IR
(Nujol dispersion): ν ) 3080, 1100 cm-1. MS (chemical
ionization): m/z ) 304 (M+ + 1) (74), 191 (100). Anal. Calcd
for C19H29NO2: C, 75.21; H, 9.63; N, 4.62. Found: C, 74.96;
H, 9.42; N, 4.78.
N-F u r fu r yl-2r-(1-cin n a m yl)-4,4,7r-tr im eth yl-tr a n s-oc-
ta h yd r o-1,3-ben zoxa zin e (3d ). Yellow oil. [R]25 ) -41.2 (c
D
) 2.8, CH2Cl2). 1H NMR (CDCl3): δ ) 0.85-1.03 (m, 2H), 0.94
(d, 3H, J ) 6.5 Hz), 1.08-1.39 (m, 1H), 1.19 (s, 3H), 1.21 (s,
3H), 1.40-1.60 (m, 2H), 1.64-1.76 (m, 2H), 1.99 (m, 1H), 3.56
(dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.5 Hz), 3.65 (d, 1H, J ) 16.9 Hz),
3.95 (d, 1H, J ) 16.9 Hz), 5.22 (dd, 1H, J 1 ) 0.9 Hz, J 2 ) 4.8
Hz), 6.02 (dd, 1H, J 1 ) 0.6 Hz, J 2 ) 3.1 Hz), 6.15 (dd, 1H, J 1
) 4.8 Hz, J 2 ) 16.1 Hz), 6.23 (dd, 1H, J 1 ) 1.8 Hz, J 2 ) 3.1
Hz), 6.72 (dd, 1H, J 1 ) 0.9 Hz, J 2 ) 16.1 Hz), 7.14-7.30 (m,
6H). 13C NMR (CDCl3): δ ) 18.9, 22.2, 25.0, 26.9, 31.3, 34.9,
41.0, 41.3, 46.6, 56.9, 75.6, 87.2, 106.3, 110.0, 126.6 (2C), 127.5,
128.3 (2C), 129.1, 132.0, 136.7, 140.9, 156.7. IR (neat): ν )
3020, 1595 cm-1. Anal. Calcd for C24H31NO2: C, 78.86; H, 8.55;
N, 3.83. Found: C, 78.52; H, 8.72; N, 4.01.
Cycloa d d u ct (4c). Colorless solid. Mp ) 80-81 °C (from
pentane). [R]25 ) -100.2 (c ) 1.0, CH2Cl2). 1H NMR (CDCl3):
D
δ ) 0.82-1.11 (m, 3H), 0.83 (d, 3H, J ) 7.0 Hz), 0.89 (d, 3H,
J ) 6.5 Hz), 1.13 (s, 3H), 1.15 (s, 3H), 1.41-1.52 (m, 2H), 1.60
(m,1H), 1.71 (m, 2H), 1.94 (m, 1H), 2.12 (m, 1H), 2.73 (dd, 1H,
J 1 ) 5.5 Hz, J 2 ) 9.2 Hz), 3.32 (t, 1H, J ) 9.2 Hz), 3.52 (dt,
1H, J 1 ) 4.1 Hz, J 2 ) 10.5 Hz), 4.77 (dd, 1H, J 1 ) 1.6 Hz, J 2
) 4.3 Hz), 4.90 (s, 1H), 6.22 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.8
Hz), 6.61 (d, 1H, J ) 5.8 Hz). 13C NMR (CDCl3): δ ) 17.3,
20.5, 22.3, 24.8, 26.0, 31.3, 35.1, 41.1, 41.6, 44.4, 48.2, 48.5,
53.1, 74.9, 82.6, 85.1, 97.7, 132.6, 135.6. IR (Nujol disper-
sion): ν ) 3060, 1110 cm-1. MS (EI, 70 eV): m/z ) 303 (M+)
(3), 55 (100). Anal. Calcd for C19H29NO2: C, 75.21; H, 9.63; N,
4.62. Found: C, 75.49; H, 9.78; N, 4.81.
Cycloa d d u ct 5a . Colorless solid. Mp ) 71-72 °C (from
1
pentane). [R]25 ) -26.7 (c ) 1.0, CH2Cl2). H NMR (CDCl3):
D
δ ) 0.89-1.07 (m, 2H), 0.93 (d, 3H, J ) 6.5 Hz), 0.95 (s, 3H),
1.10-1.17 (m, 1H), 1.16 (s, 3H), 1.26 (m,1H), 1.39-1.53 (m,
2H), 1.68-1.72 (m, 2H), 1.89-1.99 (m, 3H), 3.08 (d, 1H, J )
11.2 Hz), 3.37 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.5 Hz), 3.67 (d, 1H,
J ) 11.2 Hz), 4.14 (d, 1H, J ) 6.9 Hz), 5.01 (dd, 1H, J 1 ) 1.6
Hz, J 2 ) 4.3 Hz), 6.31 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.7 Hz), 6.41
(d, 1H, J ) 5.7 Hz). 13C NMR (CDCl3): δ ) 11.3, 22.1, 24.7,
26.6, 28.6, 31.4, 34.7, 41.4, 45.7, 48.3, 50.1, 54.7, 76.4, 79.7,
91.6, 92.6, 136.1, 136.6. IR (neat): ν ) 3070, 1560 cm-1. MS
(EI, 70 eV): m/z ) 289 (M+) (2), 81 (100). Anal. Calcd for
Cycloa d d u ct (4′c). Yellow oil. [R]25 ) +3.3 (c ) 1.1, CH2-
D
1
Cl2). H NMR (CDCl3): δ ) 0.84-1.20 (m, 3H), 0.86 (d, 3H, J
) 7.1 Hz), 0.96 (d, 3H, J ) 6.6 Hz), 1.05 (s, 3H), 1.14 (s, 3H),
1.31-1.50 (m, 3H), 1.50-1.72 (m, 2H), 1.96 (m, 1H), 2.19 (m,
1H), 2.93 (dd, 1H, J 1 ) 6.9 Hz, J 2 ) 8.7 Hz), 3.11 (t, 1H, J )
8.7 Hz), 3.46 (dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.5 Hz), 4.89 (dd, 1H,
J 1 ) 1.6 Hz, J 2 ) 4.3 Hz), 4.97 (s, 1H), 6.29 (dd, 1H, J 1 ) 1.6
Hz, J 2 ) 5.8 Hz), 6.53 (d, 1H, J ) 5.8 Hz). 13C NMR (CDCl3):
δ ) 14.6, 17.1, 22.1, 24.8, 26.5, 31.3, 34.7, 39.6, 41.1, 46.7, 48.1,
49.0, 54.3, 75.9, 83.2, 83.9, 95.9, 133.7, 135.8. IR (neat): ν )
3040, 1110 cm-1. Anal. Calcd for C19H29NO2: C, 75.21; H, 9.63;
N, 4.62. Found: C, 75.00; H, 9.85; N, 4.50.
C
18H27NO2: C, 74.70; H, 9.40; N, 4.84. Found: C, 74.49; H,
9.65; N, 4.81.
Cycloa d d u ct 5′a . Colorless solid. Mp ) 104-105 °C (from
hexane/EtOAc). [R]25 ) -57.7 (c ) 1.0, CH2Cl2). 1H NMR
D
(CDCl3): δ ) 0.89-1.03 (m, 2H), 0.91 (d, 3H, J ) 6.4 Hz),
1.07-1.27 (m, 2H), 1.17 (s, 3H), 1.20 (s, 3H), 1.40-1.51 (m,
2H), 1.58 (m, 1H), 1.69 (m, 1H), 1.84 (m, 1H), 1.98-2.09 (m,
Cycloa d d u ct (4d ). Yellowish oil. [R]25 ) -165.1 (c ) 1.3,
D
CH2Cl2). 1H NMR (CDCl3): δ ) 0.77-1.10 (m, 3H), 0.88 (d,
2H), 3.31 (d, 1H, J ) 10.9 Hz), 3.39 (dt, 1H, J 1 ) 4.2 Hz, J 2 )
3H, J ) 6.5 Hz), 1.10 (s, 3H), 1.16 (s, 3H), 1.38-1.45 (m, 2H),
10.3 Hz), 3.48 (d, 1H, J ) 10.9 Hz), 4.85 (d, 1H, J ) 4.4 Hz),
5.02 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.1 Hz), 6.22 (dd, 1H, J 1 ) 1.5
Hz, J 2 ) 5.7 Hz), 6.49 (d, 1H, J ) 5.7 Hz). 13C NMR (CDCl3):
δ ) 21.9, 22.2, 24.3, 24.8, 26.5, 31.1, 35.0, 41.4, 43.0, 47.5, 49.2,
53.7, 74.5, 79.2, 84.1, 94.6, 135.4, 138.1. IR (Nujol disper-
sion): ν ) 3090, 1330 cm-1. MS (EI, 70 eV): m/z ) 289 (M+)
1.56 (m, 1H), 1.66 (m, 1H), 1.89 (m, 1H), 2.41 (ddd, 1H, J 1
)
4.4 Hz, J 2 ) 5.3 Hz, J 3 ) 9.3 Hz), 2.85 (dd, 1H, J 1 ) 5.3 Hz, J 2
) 9.3 Hz), 3.32 (t, 1H, J ) 4.4 Hz), 3.38 (t, 1H, J ) 9.3 Hz),
3.49 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.5 Hz), 4.92 (s, 1H), 4.98 (dd,
1H, J 1 ) 1.6 Hz, J 2 ) 4.4 Hz), 6.08 (dd, 1H, J 1 ) 1.6 Hz, J 2
)

Synthesis of Tetrahydroepoxyisoindolines
J . Org. Chem., Vol. 65, No. 3, 2000 837
(15), 81 (100). Anal. Calcd for C18H27NO2: C, 74.70; H, 9.40;
N, 4.84. Found: C, 74.91; H, 9.29; N, 4.62.
1.54 (m, 2H), 1.60 (m, 1H), 1.62-1.71 (m, 1H), 1.90 (m, 1H),
2.28 (dd, 1H, J 1 ) 4.6 Hz, J 2 ) 4.8 Hz), 3.34 (d, 1H, J ) 10.8
Hz), 3.40 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.3 Hz), 3.53 (d, 1H, J )
10.8 Hz), 3.75 (dd, 1H, J 1 ) 4.4 Hz, J 2 ) 4.8 Hz), 4.93 (d, 1H,
J ) 4.6 Hz), 5.05 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.4 Hz), 6.14 (dd,
1H, J 1 ) 1.6 Hz, J 2 ) 5.6 Hz), 6.67 (d, 1H, J ) 5.6 Hz), 7.11-
7.27 (m, 5H). 13C NMR (CDCl3): δ ) 22.0, 22.2, 24.8, 26.5,
31.3, 35.0, 41.4, 42.9 (2C), 47.7, 53.7, 56.9, 74.6, 83.4, 83.7,
96.1, 126.3, 128.0 (2C), 128.1 (2C), 133.9, 138.6, 140.6. IR
(neat): ν ) 3040, 1330 cm-1. Anal. Calcd for C24H31NO2: C,
78.86; H, 8.55; N, 3.83. Found: C, 78.59; H, 8.41; N, 3.68.
Red u ctive Rin g Op en in g of 4a -d a n d 5a -d to 6a -d
a n d 6′a -d . Compounds 6a -d and 6′a -d were prepared by
reduction with LAH-AlCl3 in THF at -10 °C as previously
described.18 Compounds 6a -c and 6′a -c have been previously
described.18
Cycloa d d u ct 5b. Colorless solid. Mp ) 95-96 °C (from
1
hexane). [R]25 ) -24.53 (c ) 1.0, CH2Cl2). H NMR (CDCl3):
D
δ ) 0.87-0.95 (m, 3H), 0.90 (m, 3H), 0.91 (s, 3H), 0.92 (d, 3H,
J ) 6.6 Hz), 1.03-1.23 (m, 2H), 1.10 (s, 3H), 1.44 (m, 1H),
1.65-1.70 (m, 2H), 1.95 (m, 1H), 2.13 (dd, 1H, J 1 ) 4.7 Hz, J 2
) 11.5 Hz), 3.04, d, 1H, J ) 11.4 Hz), 3.34 (dt, 1H, J 1 ) 4.2
Hz, J 2 ) 10.5 Hz), 3.52 (d, 1H, J ) 11.4 Hz), 4.22 (s, 1H), 4.92
(dd, 1H, J 1 ) 1.2 Hz, J 2 ) 4.7 Hz), 6.37 (d, 1H, J ) 5.8 Hz),
6.38 (d, 1H, J ) 5.8 Hz). 13C NMR (CDCl3): δ ) 10.6, 17.3,
22.2, 24.7, 26.8, 31.4, 34.7, 37.2, 41.4, 44.5, 49.9, 50.6, 54.3,
76.1, 79.9, 93.4, 94.6, 134.6, 136.9. IR (Nujol dispersion): ν )
3060 cm-1. MS (EI, 70 eV): m/z ) 303 (M+,7), 81 (100). Anal.
Calcd for C19H29NO2: C, 75.21; H, 9.63; N, 4.62. Found: C,
75.43; H, 9.89; N, 4.79.
Cycloa d d u ct 5′b. Yellowish oil. [R]25 ) -10.9 (c ) 3.1,
D
(3a S,6R,7R,7a S)-N-(8-Men th olyl)-3a ,6-ep oxy-7-p h en yl-
3a ,6,7,7a -tetr a h yd r oisoin d olin e (6d ). Colorless solid. Mp
CH2Cl2). 1H NMR (CDCl3): δ ) 0.77-0.90 (m, 3H), 0.90 (d,
3H, J ) 6.5 Hz), 0.94 (s, 3H), 1.67 (m, 1H), 1.85 (m, 1H), 2.43
(dd, 1H, J 1 ) 4.7 Hz, J 2 ) 10.9 Hz), 3.30 (d, 1H, J ) 10.8 Hz),
3.37 (dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.4 Hz), 3.42 (d, 1H, J ) 10.8
Hz), 4.51 (s, 1H), 4.91 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.7 Hz), 6.34
(dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.6 Hz), 6.40 (d, 1H, J ) 5.6 Hz).
13C NMR (CDCl3): δ ) 21.6, 22.3, 24.3, 24.9, 26.4, 31.4, 33.9,
35.0, 41.5, 43.8, 47.2, 52.7, 53.3, 74.7, 79.2, 90.6, 96.2, 134.2
) 104-105 °C (from hexane). [R]25 ) +136.8 (c ) 1.0, CH2-
D
1
Cl2). H NMR (CDCl3): δ ) 0.89-1.11 (m, 3H), 0.93 (d, 3H, J
) 6.5 Hz), 1.02 (s, 3H), 1.21 (s, 3H), 1.34-1.54 (m, 2H), 1.54-
1.71 (m, 2H), 1.95 (m, 1H), 2.24 (m,1H), 2.55 (m, 1H), 3.04 (d,
1H, J ) 11.8 Hz), 3.33-3.39 (m, 2H), 3.66 (dt, 1H, J 1 ) 3.9
Hz, J 2 ) 10.3 Hz), 3.69 (m, 1H), 5.08 (dd, 1H, J 1 ) 1.4 Hz, J 2
) 4.4 Hz), 6.13 (dd, 1H, J 1 ) 1.4 Hz, J 2 ) 5.7 Hz), 6.60 (d, 1H,
(2C). IR (neat): ν ) 3080, 1190 cm-1. Anal. Calcd for C19H29
-
J ) 5.7 Hz), 7.07 (m, 2H), 7.16-7.27 (m, 3H), 8.59 (s, 1H). 13
C
NO2: C, 75.21; H, 9.63; N, 4.62. Found: C, 75.50; H, 9.40; N,
4.51.
NMR (CDCl3): δ ) 17.1, 21.9, 22.1, 25.5, 31.0, 35.0, 44.1, 47.4,
48.5, 48.9, 50.5, 51.2, 59.4, 73.0, 84.1, 96.6, 126.5, 127.9 (2C),
128.2 (2C), 134.6, 136.7, 139.7. IR (Nujol dispersion): ν ) 3100,
1320 cm-1. MS (chemical ionization): m/z ) 368 (M+ + 1) (100),
254 (52). Anal. Calcd for C24H33NO2: C, 78.43; H, 9.05; N, 3.81.
Found: C, 78.72; H, 8.91; N, 3.69.
Cycloa d d u ct 5c. Colorless solid. Mp ) 85-86 °C (from
pentane). [R]25 ) +8.8 (c ) 1.0, CH2Cl2). 1H NMR (CDCl3): δ
D
) 0.85-1.01 (m, 2H), 0.88 (d, 3H, J ) 7.1 Hz), 0.93 (d, 3H, J
) 6.5 Hz), 0.96 (s, 3H), 1.02-1.14 (m, 1H), 1.14 (s, 3H), 1.28
(m, 1H), 1.44 (m, 1H), 1.51 (dd, 1H, J 1 ) 3.4 Hz, J 2 ) 6.6 Hz),
1.61-1.74 (m, 2H), 1.96 (m, 1H), 2.33 (m, 1H), 3.00 (d, 1H, J
) 11.1 Hz), 3.35 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.6 Hz), 3.61 (d,
(3a R,6S,7S,7a R)-N-(8-Men th olyl)-3a ,6-ep oxy-7-p h en yl-
3a ,6,7,7a -tetr a h yd r oisoin d olin e (6′d ). Colorless solid. Mp
) 107-108 °C (from hexane). [R]25 ) -167.8 (c ) 1.0, CH2-
D
1H, J ) 11.1 Hz), 4.22 (d, 1H, J ) 6.6 Hz), 4.80 (dd, 1H, J 1
)
1
Cl2). H NMR (CDCl3): δ ) 0.79-1.08 (m, 3H), 0.89 (d, 3H, J
1.6 Hz, J 2 ) 4.3 Hz), 6.29 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.7 Hz),
6.50 (d, 1H, J ) 5.7 Hz). 13C NMR (CDCl3): δ ) 11.9, 17.0,
22.1, 24.7, 26.6, 31.4, 34.7, 36.9, 41.5, 46.0, 49.7, 54.5, 56.9,
76.1, 83.2, 91.1, 93.4, 134.4, 137.2. IR (Nujol dispersion): ν )
3030 cm-1. MS (EI, 70 eV): m/z ) 303 (M+) (2), 81 (100). Anal.
Calcd for C19H29NO2: C, 75.21; H, 9.63; N, 4.62. Found: C,
75.47; H, 9.69; N, 4.49.
) 6.5 Hz), 1.00 (s, 3H), 1.20 (s, 3H), 1.42 (m, 1H), 1.50-1.68
(m, 3H), 1.90 (m, 1H), 2.22 (m, 1H), 2.42 (m, 1H), 2.99 (d, 1H,
J ) 10.4 Hz), 3.32 (dd, 1H, J 1 ) 4.0 Hz, J 2 ) 4.4 Hz), 3.46-
3.61 (m, 2H), 3.65 (dt, 1H, J 1 ) 3.9 Hz, J 2 ) 10.2 Hz), 5.04
(dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.4 Hz), 6.12 (dd, 1H, J 1 ) 1.5 Hz,
J 2 ) 5.7 Hz), 6.55 (d, 1H, J ) 5.7 Hz), 7.04-7.28 (m, 5H), 8.29
(br s, 1H). 13C NMR (CDCl3): δ ) 17.8, 21.2, 22.0, 25.7, 30.9,
35.0, 44.2, 47.7, 48.4 (2C), 50.3, 50.9, 59.2, 72.7, 84.0, 96.1,
126.4, 127.9 (2C), 128.0 (2C), 134.4, 136.7, 139.4. IR (Nujol
dispersion): ν ) 3140, 1600 cm-1. MS (chemical ionization):
Cycloa d d u ct 5′c. Colorless oil. [R]25D ) -70.3 (c ) 0.6, CH2-
1
Cl2). H NMR (CDCl3): δ ) 0.82-1.01 (m, 2H), 0.85 (d, 3H, J
) 7.2 Hz), 0.91 (d, 3H, J ) 6.5 Hz), 1.05-1.28 (m, 2H), 1.16
(s, 3H), 1.20 (s, 3H), 1.44-1.53 (m, 2H), 1.58 (m, 1H), 1.71 (m,
1H), 1.85 (m, 1H), 2.47 (m, 1H), 3.24 (d, 1H, J ) 10.8 Hz),
3.40 (dt, 1H, J 1 ) 4.3 Hz, J 2 ) 10.4 Hz), 3.44 (d, 1H, J ) 10.8
Hz), 4.79 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.3 Hz), 4.89 (d, 1H, J )
4.7 Hz), 6.25 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.3 Hz), 6.56 (d, 1H,
J ) 5.7 Hz). 13C NMR (CDCl3): δ ) 17.0, 21.9, 22.2, 24.8, 26.5,
31.4, 31.9, 35.0, 41.4, 42.9, 47.8, 53.7, 57.5, 74.6, 82.8, 83.8,
95.5, 133.5, 138.9. IR (neat): ν ) 3060, 1330 cm-1. Anal. Calcd
for C19H29NO2: C, 75.21; H, 9.63; N, 4.62. Found: C, 75.52;
H, 9.80; N, 4.78.
m/z ) 368 (M+ + 1) (100), 254 (85). Anal. Calcd for C24H33
-
NO2: C, 78.43; H, 9.05; N, 3.81. Found: C, 78.67; H, 9.26; N,
3.71.
Rea ction of 5a -c w ith Meth ylm a gn esiu m Iod id e.
Syn th esis of 7a -c. To a solution of the corresponding adducts
5a -c (2.5 mmol) in diethyl ether (20 mL), under argon, was
slowly syringed a 0.5 M solution of methylmagnesium iodide
(20 mL, 10 mmol). After the addition was completed, the
reaction mixture was refluxed for 6 h and then cooled to 0 °C.
The reaction was quenched by addition, at 0 °C, of a saturated
NH4Cl solution (30 mL); the organic phase was decanted, and
the aqueous layer was extracted five times with EtOAc. The
organic extracts were washed with brine and dried over
anhydrous Na2SO4. The solvents were evaporated in vacuo,
and the residues were chromatographed on silica gel using
hexanes-EtOAc (3:1) for 7c or hexanes-EtOH (10:1) for 7a
and 7b as eluents.
Cycloa d d u ct 5d . Colorless solid. Mp ) 118-119 °C (from
hexane/EtOAc). [R]25 ) +141.2 (c ) 1.0, CH2Cl2). 1H NMR
D
(CDCl3): δ ) 0.83-0.98 (m, 2H), 0.91 (d, 3H, J ) 6.5 Hz),
1.00-1.12 (m, 1H), 1.02 (s, 3H), 1.19 (s, 3H), 1.22-1.33 (m,
1H), 1.40 (m, 1H), 1.65-1.71 (m, 2H), 1.92 (m, 1H), 2.29 (dd,
1H, J 1 ) 4.2 Hz, J 2 ) 6.4 Hz), 3.12 (d, 1H, J ) 11.2 Hz), 3.37
(dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.5 Hz), 3.58 (t, 1H, J ) 4.2 Hz),
3.72 (d, 1H, J ) 11.2 Hz), 4.39 (d, 1H, J ) 6.4 Hz), 5.15 (dd,
1H, J 1 ) 1.6 Hz, J 2 ) 4.2 Hz), 6.16 (dd, 1H, J 1 ) 1.6, J 2 ) 5.7
Hz), 6.57 (d, 1H, J ) 5.7 Hz), 7.10-7.25 (m, 5H). 13C NMR
(CDCl3): δ ) 12.1, 22.1, 24.7, 26.6, 31.4, 34.7, 41.4, 46.0, 48.0,
49.6, 54.7, 56.4, 76.2, 83.4, 91.4, 93.9, 126.3, 128.0 (2C), 128.1
(2C), 135.0, 137.0, 140.2. IR (Nujol dispersion): ν ) 3030, 1360
cm-1. MS (EI, 70 eV): m/z ) 365 (M+) (2), 81 (100). Anal. Calcd
for C24H31NO2: C, 78.86; H, 8.55; N, 3.83. Found: C, 79.08;
H, 8.32; N, 3.61.
(1R,3a S,6S,7a S)-N-(8-Men th olyl)-3a ,6-ep oxy-1-m eth yl-
3a ,6,7,7a -tetr a h yd r oisoin d olin e (7a ). Colorless solid. Mp )
92-93 °C (from hexane/EtOAc). [R]25 ) -4.7 (c ) 1.0, CH2-
D
1
Cl2). H NMR (CDCl3): δ ) 0.88-1.49 (m, 14H), 0.91 (d, 3H,
J ) 6.5 Hz), 1.50-1.90 (m, 4H), 1.92-2.04 (m, 2H), 3.04-3.18
broad, 1H), 3.21-3.45 (broad, 1H), 3.60-3.72 (m, 2H), 4.97
(dd, 1H, J 1 ) 1.4 Hz, J 2 ) 4.5 Hz), 6.31 (broad, 1H), 6.47
(broad, 1H), 8.70 (br s, 1H). 13C NMR (CDCl3): δ ) 14.0, 19.2,
19.8, 22.1, 23.9, 25.6, 31.0, 35.1, 43.9, 44.6, 48.1, 54.6, 58.8,
61.3, 72.8, 79.4, 95.2, 136.1, 137.6. IR (Nujol dispersion): ν )
Cycloa d d u t 5′d . Colorless oil. [R]25D ) -198.4 (c ) 0.9, CH2-
1
Cl2). H NMR (CDCl3): δ ) 0.86-1.00 (m, 2H), 0.92 (d, 3H, J
) 6.5 Hz), 1.12-1.27 (m, 1H), 1.18 (s, 3H), 1.20 (s, 3H), 1.37-
3110, 1050 cm-1. MS (chemical ionization): m/z ) 306 (M+
+

838 J . Org. Chem., Vol. 65, No. 3, 2000
Pedrosa et al.
1) (100), 192 (38). Anal. Calcd for C19H31NO2: C, 74.71; H,
10.23; N, 4.59. Found: C, 74.96; H, 10.08; N, 4.38.
J 1 )1.6 Hz, J 2 ) 4.5 Hz), 6.32 (d, 1H, J ) 5.8 Hz), 6.37 (dd,
1H, J 1 )1.6 Hz, J 2 ) 5.8 Hz), 8.63 (s, 1H). 13C NMR (CDCl3):
δ ) 18.9, 21.9, 22.1, 23.0, 25.4, 30.8, 31.0, 34.9, 38.8, 43.9, 48.6,
52.6, 52.9, 60.1, 72.8, 79.1, 98.4, 133.4, 136.4. IR (Nujol
dispersion): ν ) 3100, 1560 cm-1. MS (chemical ionization):
m/z ) 306 (M+ + 1) 100), 304 (22). Anal. Calcd for C19H31NO2:
C, 74.71; H, 10.23; N, 4.59. Found: C, 74.48; H, 10.08; N, 4.41.
(1S,3a S,6S,7a S)-N-(8-Men th olyl)-3a ,6-ep oxy-1-m eth yl-
3a ,6,7,7a -tetr a h yd r oisoin d olin e (7′a ). Colorless solid. Mp
) 98-99 °C (from pentane). [R]25 ) -44.9 (c ) 1.0, CH2Cl2).
D
1H NMR (CDCl3): δ ) 0.87-1.16 (m, 3H), 0.92 (d, 3H, J ) 6.5
Hz), 0.99 (s, 3H), 1.23 (s, 3H), 1.30 (d, 3H, J ) 5.9 Hz), 1.33-
1.50 (m, 3H), 1.55-1.78 (m, 4H), 1.92-1.97 (m, 1H), 2.85 (dq,
1H, J 1 ) 5.9 Hz, J 2 ) 8.7 Hz), 3.42 (d, 1H, J ) 13.2 Hz), 3.66
(d, 1H, J ) 13.2 Hz), 3.70 (dt, J 1 ) 4.0 Hz, J 2 ) 10.3 Hz), 5.00
(dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.4 Hz), 6.30 (d, 1H, J ) 5.8 Hz),
6.34 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 5.8 Hz), 9.10 (br s, 1H). 13C
NMR (CDCl3): δ ) 19.0, 22.1, 22.4, 24.0, 25.4, 31.0, 31.9, 35.1,
44.3, 49.7, 50.1, 52.0, 60.1, 61.6, 72.9, 79.5, 93.5, 134.9, 136.7.
IR (Nujol dispersion): ν ) 3080, 1170 cm-1. MS (chemical
ionization): m/z ) 306 (M+ + 1) (100), 192 (48). Anal. Calcd
for C19H31NO2: C, 74.71; H, 10.23; N, 4.59. Found: C, 74.49;
H, 10.42; N, 4.68.
(3S,3a R,6R,7a R)-N-(8-Men t h olyl)-3a ,6-ep oxy-3,7a -d i-
m eth yl-3a ,6,7,7a -tetr a h yd r oisoin d olin e (14b). Colorless
solid. Mp ) 134-135 °C (from hexane). [R]25 ) +29.9 (c )
D
1
1.1, CH2Cl2). H NMR (CDCl3): δ ) 0.83-1.04 (m, 4H), 0.84
(d, 3H, J ) 6.5 Hz), 0.92 (s, 3H), 0.97 (s, 3H), 1.20 (s, 3H),
1.32-1.40 (m, 1H), 1.35 (d, 3H, J ) 6.9 Hz), 1.50 (m, 2H), 1.59
(m, 1H), 1.86 (m, 1H), 1.98 (dd, 1H, J 1 ) 4.6 Hz, J 2 ) 11.0
Hz), 2.64 (d, 1H, J ) 8.4 Hz), 3.19 (d, 1H, J ) 8.4 Hz), 3.29 (q,
1H, J ) 6.8 Hz), 3.63 (dt, 1H, J 1 ) 3.9 Hz, J 2 ) 10.3 Hz), 4.82
(d, 1H, J ) 4.6 Hz), 6.32 (s, 2H), 8.53 (s, 1H). 13C NMR
(CDCl3): δ ) 18.7, 21.8, 22.3, 22.4, 23.1, 25.4, 30.7, 34.8, 39.6,
44.0, 46.3, 48.6, 53.3, 58.7, 60.1, 72.8, 79.0, 99.4, 132.6, 135.6.
IR (Nujol dispersion): ν ) 3120, 1630 cm-1. MS (chemical
ionization): m/z ) 320 (M+ + 1) (48), 206 (100). Anal. Calcd
for C20H33NO2: C, 75.19; H, 10.41; N, 4.38. Found: C, 75.42;
H, 10.32; N, 4.26.
(1R,3a S,6S,7a S)-N-(8-Men t h olyl)-3a ,6-ep oxy-1,7a -d i-
m eth yl-3a,6,7,7a-tetr ah ydr oisoin dolin e (7b). Colorless solid.
Mp ) 119-120 °C (from hexane). [R]25D ) -41.2 (c ) 1.0, CH2-
1
Cl2). H NMR (CDCl3): δ ) 0.87-1.23 (m, 7H), 0.91 (d, 3H, J
) 6.5 Hz), 1.09 (s, 3H), 1.29 (m, 6H), 1.32-1.50 (m, 1H), 1.58-
1.70 (m, 3H), 1.93-2.04 (m, 1H), 2.30 (m, 1H), 3.00-3.50
(broad, 3H), 3.64 (dt, 1H, J 1 ) 3.8 Hz, J 2 ) 10.3 Hz), 4.87 (dd,
1H, J 1 ) 1.3 Hz, J 2 ) 4.9 Hz), 6.33 (broad, 1H), 6.41 (m, 1H),
7.78 (br s, 1H). 13C NMR (CDCl3): δ ) 22.1 (4C), 26.1, 26.4,
31.1, 35.3 (2C), 37.4, 44.6, 48.3, 50.1, 60.1, 73.1, 79.0, 96.5,
(3S,3a R,6S,7S,7a R)-N-(8-Men th olyl)-3a ,6-ep oxy-3,7-d i-
m eth yl-3a ,6,7,7a -tetr a h yd r oisoin d olin e (14c). Colorless
solid. Mp ) 114-115 °C (from pentane). [R]25 ) -48.1 (c )
D
1
1.1, CH2Cl2). H NMR (CDCl3): δ ) 0.72-0.97 (m, 3H), 0.74
134.3, 137.4, 137.5. IR (Nujol dispersion): ν ) 3100, 1190 cm-1
.
(d, 3H, J ) 7.1 Hz), 0.84 (d, 3H, J ) 6.6 Hz), 0.92 (s, 3H), 1.18
(s, 3H), 1.28 (d, 3H, J ) 6.7 Hz), 1.37 (m, 1H), 1.50 (m, 3H),
1.62 (m, 1H), 1.85 (m, 1H), 2.08 (m, 1H), 2.41 (dd, 1H J 1 ) 8.8
MS (chemical ionization): m/z ) 320 (M+ + 1) (100), 318 (21).
Anal. Calcd for C20H33NO2: C, 75.19; H, 10.41; N, 4.38.
Found: C, 74.90; H, 10.32; N, 4.17.
Hz, J 2 ) 9.9 Hz), 3.25 (q, 1H, J ) 6.7 Hz), 3.53 (dd, 1H, J 1
)
7.7 Hz, J 2 ) 8.8 Hz), 3.62 (dt, 1H, J 1 ) 3.9 Hz, J 2 ) 10.3 Hz),
4.74 (dd, 1H, J 1 ) 1.7 Hz, J 2 ) 4.5 Hz), 6.28 (dd, 1H, J 1 ) 1.7
Hz, J 2 ) 5.9 Hz), 6.35 (d, 1H, J ) 5.9 Hz), 8.56 (s, 1H). 13C
NMR (CDCl3): δ ) 16.4, 19.0, 22.1, 22.3, 23.3, 25.6, 31.0, 25.1,
39.8, 44.1, 47.7, 48.9, 52.6, 53.5, 60.3, 73.0, 83.1, 99.7, 134.5,
134.8. IR (Nujol dispersion): ν ) 3120, 1610 cm-1. MS
(chemical ionization): m/z ) 320 (M+ + 1) (33), 166 (100). Anal.
Calcd for C20H33NO2: C, 75.19; H, 10.41; N, 4.38. Found: C,
75.37; H, 10.59; N, 4.49.
(1R,3a S,6S,7R,7a S)-N-(8-Men th olyl)-3a ,6-ep oxy-1,7-d i-
m eth yl-3a,6,7,7a-tetr ah ydr oisoin dolin e (7c). Colorless solid.
Mp ) 109-110 °C (from hexane). [R]25D ) +21.2 (c ) 1.0, CH2-
Cl2). 1H NMR (CDCl3): δ ) 0.80 (d, 3H, J ) 7.0 Hz), 0.83-
1.51 (m, 14H), 0.91 (d, 3H, J ) 6.5 Hz), 1.61 (m, 2H), 1.72 (m,
1H), 1.92 (m, 1H), 2.14 (broad, 1H), 2.96 (broad, 1H), 3.54-
3.78 (m, 3H), 4.77 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.5 Hz), 6,28 (m,
1H), 6.55 (broad, 1H), 8.63 (br s, 1H). 13C NMR (CDCl3): δ )
14.4, 17.1, 19.9, 22.1, 23.8, 25.6, 31.0, 33.6, 35.2, 44.0, 44.6,
48.1, 54.1, 56.4, 58.7, 72.8, 83.1, 96.4, 133.7, 138.8. IR (Nujol
dispersion): ν ) 3090 cm-1. MS (chemical ionization): m/z )
320 (M+ + 1) (100), 318 (22). Anal. Calcd for C20H33NO2: C,
75.19; H, 10.41; N, 4.38. Found: C, 75.38; H, 10.50; N, 4.51.
(1S,3a S,6S,7R,7a S)-N-(8-Men th olyl)-3a ,6-ep oxy-1,7-d i-
m eth yl-3a,6,7,7a-tetr ah ydr oisoin dolin e (7′c). Colorless solid.
(3S,3aR,6S,7S,7aR)-N-(8-Men th olyl)-3a,6-epoxy-3-m eth -
yl-7-p h en yl-3a ,6,7,7a -tetr a h yd r oisoin d olin e (14d ). Color-
1
less oil. [R]25 ) -163.2 (c ) 2.1, CH2Cl2). H NMR (CDCl3):
D
δ ) 0.77-1.00 (m, 3H), 0.83 (d, 3H, J ) 6.5 Hz), 0.98 (s, 3H),
1.22 (s, 3H), 1.27-1.38 (m, 1H), 1.35 (d, 3H, J ) 6.7 Hz), 1.48-
1.54 (m, 2H), 1.60 (m, 1H), 1.85 (m, 1H), 2.32 (m, 1H), 2.59
(dd, 1H, J 1 ) 9.1 Hz, J 2 ) 9.8 Hz), 3.32-3.38 (m, 2H), 3.59-
3.69 (m, 2H), 5.05 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.4 Hz), 6.07 (dd,
1H, J 1 ) 1.6 Hz, J 2 ) 5.8 Hz), 6.42 (d, 1H, J ) 5.8 Hz), 6.96-
7.20 (m, 5H), 8.45 (s, 1H). 13C NMR (CDCl3): δ ) 19.1, 22.1,
22.4, 23.4, 25.7, 31.0, 35.1, 44.1, 47.2, 49.0, 51.1, 53.2, 53.5,
60.5, 73.1, 83.5, 100.2, 126.4, 127.9 (2C), 128.1 (2C), 134.6,
135.1, 139.5. IR (neat): ν ) 3080, 1600 cm-1. MS (chemical
ionization): m/z ) 382 (M+ + 1) (100), 268 (84). Anal. Calcd
for C25H35NO2: C, 78.70; H, 9.25; N, 3.67. Found: C, 78.99;
H, 9.51; N, 3.58.
Mp ) 137-138 °C (from hexane). [R]25 ) -5.9 (c ) 1.0, CH2-
D
Cl2). 1H NMR (CDCl3): δ ) 0.85 (d, 3H, J ) 7.1 Hz), 0.91-
1.07 (m, 3H), 0.92 (d, 3H, J ) 6.5 Hz), 0.98 (s, 3H), 1.17-1.27
(m, 1H), 1.22 (s, 3H), 1.32 (d, 3H, J ) 5.9 Hz), 1.43 (m, 2H),
1.55 (m, 1H), 1.66 (m, 1H), 1.94 (m, 1H), 2.20 (m, 1H), 2.93
(dq, 1H, J 1 ) 5.9 Hz, J 2 ) 8.5 Hz), 3.33 (d, 1H, J ) 13.3 Hz),
3.62 (d, 1H, J ) 13.3 Hz), 3.69 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.3
Hz), 4.82 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.4 Hz), 6.31 (dd, 1H, J 1
) 1.6 Hz, J 2 ) 5.8 Hz), 6.39 (d, 1H, J ) 5.8 Hz), 9.05 (s, 1H).
13C NMR (CDCl3): δ ) 17.1, 18.9, 22.1, 22.4, 24.8, 25.4, 31.0,
35.1, 40.8, 44.3, 50.1, 50.2, 60.1, 60.6, 61.5, 72.9, 83.3, 94.5,
134.6, 136.1. IR (Nujol dispersion): ν ) 3080, 1070 cm-1. MS
(chemical ionization): m/z ) 320 (M+ + 1) (100), 318 (23). Anal.
Calcd for C20H33NO2: C, 75.19; H, 10.41; N, 4.38. Found: C,
74.92; H, 10.29; N, 4.36.
Elim in a tion of th e Men th ol Ap p en d a ge. Syn th esis of
th e F in a l Ep oxytetr a h yd r oisoin d olin es. The elimination
of the menthol appendage was carried out in two steps by
oxidation-elimination as previously described.22 The total
yields for both steps are summarized in Tables 3 and 4.
Compounds 8a -c and ent-8a -c have been previously de-
scribed.18
Rea ction of 4a -d w ith Tr im eth yla lu m in u m . Syn th esis
of 14a -d . Compounds 4a -d were reacted with Me3Al in
toluene at room temperature as previously described.15 The
yields are collected in Table 4.
(3S,3aR,6R,7aR)-3a,6-Epoxy-3-m eth yl-3a,6,7,7a-tetr ah y-
d r oisoin d olin e (9a ). Colorless oil. [R]25 ) -34.5 (c ) 1.2,
(3S,3a R,6R,7a R)-N-(8-Men th olyl)-3a ,6-ep oxy-3-m eth yl-
3a ,6,7,7a -tetr a h yd r oisoin d olin e (14a ). Colorless solid. Mp
D
1
CH2Cl2). H NMR (CDCl3): δ ) 1.27 (d, 3H, J ) 6.9 Hz), 1.36
) 118-119 °C (from hexane). [R]25 ) -10.6 (c ) 1.1, CH2-
(dd, 1H, J 1 )7.7 Hz, J 2 ) 11.5 Hz), 1.66 (ddd, 1H, J 1 ) 3.0 Hz,
J 2 ) 4.4 Hz, J 3 ) 11.5 Hz), 1.95 (ddt, 1H, J 1 )3.0 Hz, J 2 ) 7.7
Hz, J 3 ) 9.4 Hz), 2.57 (dd, 1H J 1 ) 9.4 Hz, J 2 ) 10.4 Hz), 3.25
(dd, 1H, J 1 ) 7.7 Hz, J 2 ) 10.4 Hz), 3.35 (s, 1H), 3.42 (q, 1H,
J ) 6.9 Hz), 4.96 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.4 Hz), 6.30 (dd,
1H, J 1 ) 1.5 Hz, J 2 ) 5.9 Hz), 6.34 (d, 1H, J ) 5.9 Hz). 13C
NMR (CDCl3): δ ) 19.2, 31.0, 43.2, 51.0, 53.5, 79.4, 100.6,
D
1
Cl2). H NMR (CDCl3): δ ) 0.85-1.08 (m, 3H), 0.91 (d, 3H, J
) 6.6 Hz), 1.00 (s, 3H), 1.27 (s, 3H), 1.32-1.46 (m, 2H), 1.37
(d, 3H, J ) 6.7 Hz), 1.47-1.64 (m,2H), 1.65-1.75 (m, 2H), 1.92
(m, 1H), 2.02 (m, 1H), 2.43 (dd, 1H, J 1 ) 8.8 Hz, J 2 ) 10.0
Hz), 3.40 (q, 1H, J ) 6.7 Hz), 3.52 (dd, 1H, J 1 ) 7.8 Hz, J 2
)
8.8 Hz), 3.69 (dt, 1H J 1 ) 3.9 Hz, J 2 ) 10.1 Hz), 4.98 (dd, 1H,

Synthesis of Tetrahydroepoxyisoindolines
J . Org. Chem., Vol. 65, No. 3, 2000 839
133.6, 136.5. IR (neat): ν ) 3300, 1050 cm-1. Anal. Calcd for
C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.78; H, 8.80;
N, 9.17.
1H, J 1 ) 6.5 Hz, J 2 ) 9.1 Hz), 3.28 (d, 1H, J ) 12.8 Hz), 3.53
(d, 1H, J ) 12.8 Hz), 5.04 (dd, 1H, J 1 ) 1.7 Hz, J 2 ) 4.4 Hz),
6.32 (dd, 1H, J 1 ) 1.7 Hz, J 2 ) 5.7 Hz), 6.42 (d, 1H, J ) 5.7
Hz). 13C NMR (CDCl3): δ ) 19.6, 29.3, 47.9, 52.1, 59.4, 80.2,
98.9, 136.0, 136.2. IR (neat): ν ) 3300, 1070 cm-1. Anal. Calcd
for C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.32; H,
8.46; N, 9.15.
(3S,3a R,6R,7a R)-3a ,6-ep oxy-3,7a -d im et h yl-3a ,6,7,7a -
tetr a h yd r o isoin d olin e (9b). Colorless oil. [R]25D ) +32.2 (c
) 1.5, CH2Cl2). 1H NMR (CDCl3): δ ) 0.85 (s, 3H), 0.86 (d,
1H J ) 11.3 Hz), 1.23 (d, 3H, J ) 7.0 Hz), 1.91 (dd, 1H, J 1
)
4.7 Hz, J 2 ) 11.3 Hz), 2.65 (s, 1H), 2.78 (d, 1H, J ) 9.9 Hz),
2.83 (d, 1H, J ) 9.9 Hz), 3.31 (q, 1H, J ) 7.0 Hz), 4.82 (d, 1H,
J ) 4.7 Hz), 6.22-6.30 (m, 2H). 13C NMR (CDCl3): δ ) 20.3,
22.5, 38.7, 49.3, 53.4, 58.2, 79.4, 101.1, 132.7, 135.7. IR
(neat): ν ) 3310, 1370 cm-1. Anal. Calcd for C10H15NO: C,
72.69; H, 9.15; N, 8.48. Found: C, 72.91; H, 8.96; N, 8.29.
(3S,3a R,6S,7S,7a R)-3a ,6-Ep oxy-3,7-d im eth yl-3a ,6,7,7a -
(1R,3a S,6S,7a S)-3a ,6-E p oxy-1,7a -d im et h yl-3a ,6,7,7a -
tetr a h yd r oisoin d olin e (10b). Colorless oil. [R]25 ) -55.1
D
1
(c ) 1.2, CH2Cl2). H NMR (CDCl3): δ ) 0.90 (s, 3H), 0.98 (d,
1H, J ) 11.8 Hz), 1.17 (d, 3H, J ) 6.7 Hz), 2.22 (dd, 1H, J 1
)
4.9 Hz, J 2 ) 11.8 Hz), 3.07 (q, 1H, J ) 6.7 Hz), 3.12 (d, 1H, J
) 13.2 Hz), 3.19 (s, 1H), 3.28 (d, 1H, J ) 13.2 Hz), 4.88 (dd,
1H, J 1 ) 1.5 Hz, J 2 ) 4.9 Hz), 6.40 (d, 1H, J ) 5.8 Hz), 6.48
(dd, 1H, J 1 ) 1.5 Hz, J 2 ) 5.8 Hz). 13C NMR (CDCl3): δ )
20.0, 27.3, 37.3, 46.5, 50.8, 61.8, 77.9, 99.7, 133.6, 137.4. IR
(neat): ν ) 3400, 1420 cm-1. Anal. Calcd for C10H15NO: C,
72,69; H, 9.15; N, 8.48. Found: C, 72.88; H, 9.01; N, 8.31.
(1R,3a S,6S,7R,7a S)-3a ,6-Ep oxy-1,7-d im eth yl-3a ,6,7,7a -
tetr a h yd r o isoin d olin e (9c). Colorless oil. [R]25 ) -80.7 (c
D
) 2.4, CH2Cl2). 1H NMR (CDCl3): δ ) 0.86 (d, 3H, J ) 7.1
Hz), 1.29 (d, 3H, J ) 6.9 Hz), 1.56 (ddd, 1H, J 1 ) 3.2 Hz, J 2
)
7.8 Hz, J 3 ) 8.8 Hz), 2.15 (m, 1H), 2.69 (dd, 1H, J 1 ) 8.8 Hz,
J 2 ) 10.7 Hz), 3.13 (s, 1H), 3.35 (dd, 1H, J 1 ) 7.8 Hz, J 2
)
10.7 Hz), 3.41 (q, 1H, J ) 6.9 Hz), 4.83 (dd, 1H, J 1 ) 1.6 Hz,
J 2 ) 4.4 Hz), 6.36 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.9 Hz), 6.50 (d,
1H, J ) 5.9 Hz). 13C NMR (CDCl3): δ ) 16.9, 19.0, 39.9, 50.6,
52.0, 54.1, 82.9, 101.8, 134.5, 134.9. IR (neat): ν ) 3320, 1375
cm-1. Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48.
Found: C, 72.45; H, 9.36; N, 8.59.
tetr a h yd r oisoin d olin e (10c). Colorless oil. [R]25 ) +66.9
D
1
(c ) 0.5, CH2Cl2). H NMR (CDCl3): δ ) 0.80 (d, 3H, J ) 7.0
Hz), 1.34 (d, 3H, J ) 7.0 Hz), 1.76 (dd, 1H, J 1 ) 3.9 Hz, J 2
)
8.6 Hz), 2.28 (m, 1H), 3.46 (d, 1H, J ) 13.2 Hz), 3.52 (d, 1H,
J ) 13.2 Hz), 3.91 (dq, 1H, J 1 ) 7.0 Hz, J 2 ) 8.6 Hz), 4.80 (dd,
1H, J 1 ) 1.5 Hz, J 2 ) 4.5 Hz), 6.33 (dd, 1H, J 1 ) 1.5 Hz, J 2
)
(3S ,3a R ,6S ,7S ,7a R )-3a ,6-E p oxy-3-m e t h yl-7-p h e n yl-
5.8 Hz), 6.46 (d, 1H, J ) 5.8 Hz), 7.47 (br s, 1H). 13C NMR
(CDCl3): δ ) 17.5, 18.5, 35.6, 48.4, 53.3, 55.7, 81.6, 99.9, 134.3,
3a ,6,7,7a -tetr a h yd r o isoin d olin e (9d ). Colorless oil. [R]25
D
) -200.3 (c ) 1.2, CH2Cl2). 1H NMR (CDCl3): δ ) 1.26 (d,
136.1. IR (neat): ν ) 3250, 1070 cm-1. Anal. Calcd for C10H15
-
3H, J ) 6.9 Hz), 2.22 (ddd, 1H, J 1 ) 3.9 Hz, J 2 ) 7.8 Hz, J 3
)
NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.47; H, 9.36; N,
8.59.
8.6 Hz), 2.75 (dd, 1H, J 1 ) 8.6 Hz, J 2 ) 10.7 Hz), 2.92 (s, 1H),
3.27 (dd, 1H, J 1 ) 3.9 Hz, J 2 ) 4.4 Hz), 3.34 (dd, 1H, J 1 ) 7.8
(1S,3a S,6S,7R,7a S)-3a ,6-Ep oxy-1,7-d im eth yl-3a ,6,7,7a -
Hz, J 2 ) 10.7 Hz), 3.40 (q, 1H, J ) 6.9 Hz), 5.00 (dd, 1H, J 1
)
tetr a h yd r o isoin d olin e (10′c). Colorless oil. [R]25 ) +23.9
D
1
1.6 Hz, J 2 ) 4.4 Hz), 6.12 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.9 Hz),
6.52 (d, 1H, J ) 5.9 Hz), 7.01-7.19 (m, 5H). 13C NMR
(CDCl3): δ ) 18.9, 50.8, 51.0, 52.0, 53.8, 83.3, 102.3, 126.4,
127.8 (2C), 128.0 (2C), 134.6, 134.7, 139.9. IR (neat): ν ) 3250,
1325 cm-1. Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N,
6.16. Found: C, 79.52; H, 7.51; N, 5.98.
(c ) 0.7, CH2Cl2). H NMR (CDCl3): δ ) 0.85 (d, 3H, J ) 7.1
Hz), 1.11 (dd, 1H, J 1 ) 3.2 Hz, J 2 ) 9.3 Hz), 1.28 (d, 3H, J )
6.3 Hz), 2.13 (m, 1H), 3.04 (dq, 1H, J 1 ) 76.3 Hz, J 2 ) 9.3 Hz),
3.24 (d, 1H, J ) 12.9 Hz), 3.57 (d, 1H, J ) 12.9 Hz), 4.07 (br
s, 1H), 4.86 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.3 Hz), 6.32 (dd, 1H,
J 1 ) 1.6 Hz, J 2 ) 5.8 Hz), 6.53 (d, 1H, J ) 5.8 Hz). 13C NMR
(CDCl3): δ ) 16.8, 19.3, 37.9, 47.8, 59.3, 60.3, 83.7, 99.4, 134.1,
(1R,3a S,6S,7a S)-3a ,6-Ep oxy-1-m eth yl-3a ,6,7,7a -tetr a h y-
d r oisoin d olin e (10a ). Colorless oil. [R]25 ) +17.0 (c ) 0.7,
136.8. IR (neat): ν ) 3350, 1080 cm-1. Anal. Calcd for C10H15
-
D
1
CH2Cl2). H NMR (CDCl3): δ ) 1.20 (d, 3H, J ) 7.0 Hz), 1.32
NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.41; H, 9.32; N,
8.69.
(dd, 1H, J 1 ) 8.4 Hz, J 2 ) 11.9 Hz), 1.85 (ddd, 1H, J 1 ) 3.6
Hz, J 2 ) 4.6 Hz, J 3 ) 11.9 Hz), 2.18 (ddd, 1H, J 1 ) 3.6 Hz, J 2
) 8.4 Hz, J 3 ) 8.7 Hz), 3.40 (d, 1H, J ) 13.5 Hz), 3.45 (d, 1H,
J ) 13.5 Hz), 3.71 (dq, 1H, J 1 ) 7.0 Hz, J 2 ) 8.7 Hz), 4.96 (dd,
1H, J 1 ) 1.5 Hz, J 2 ) 4.6 Hz), 6.05 (br s, 1H), 6.32 (dd, 1H, J 1
) 1.5 Hz, J 2 ) 5.8 Hz), 6.38 (d, 1H, J ) 5.8 Hz). 13C NMR
(CDCl3): δ ) 17.4, 27.9, 46.3 (2C), 54.0, 79.0, 97.2, 134.5, 137.1.
IR (neat): ν ) 3340, 1060 cm-1. Anal. Calcd for C9H13NO: C,
71.49; H, 8.67; N, 9.26. Found: C, 71.21; H, 8.89; N, 9.02.
(1S,3a S,6S,7a S)-3a ,6-Ep oxy-1-m eth yl-3a ,6,7,7a -tetr a h y-
Ack n ow led gm en t. The authors thank the Spanish
DGICYT (Project PB95-707) and J unta de Castilla y
Leo´n (VA79/99) for financial support of this work. J .N.
also thanks the Spanish MEC for a predoctoral fellow-
ship (FPU).
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
spectra for compounds 2b-d , 3c-d , 4a -d , 4′a -c, 5a -d , 5′a -
d , 6d , 6′d , 7a -c, 7′a -c, 9a -d , 10a -c, 10′a -c, 11b, 12, and
14a -d . This material is available free of charge via the
Internet at http://pubs.acs.org.
d r oisoin d olin e (10′a ). Colorless oil. [R]25 ) -23.7 (c ) 1.0,
D
1
CH2Cl2). H NMR (CDCl3): δ ) 1.19 (d, 3H, J ) 6.5 Hz), 1.35
(dd, 1H, J 1 ) 7.7 Hz, J 2 ) 11.2 Hz, J 3 ) 8.7 Hz), 1.46 (ddd,
1H, J 1 ) 2.8 Hz, J 2 ) 7.7 Hz, J 3 ) 9.1 Hz), 1.69 (ddd, 1H, J 1
) 2.8 Hz, J 2 ) 4.4 Hz, J 3 ) 11.2 Hz), 2.45 (s, 1H), 2.91 (dq,
J O991544Q