Temperature- and time-dependent stereochemical control in thermally induced keto-ene cyclizations

Article abstract of DOI:10.1021/jo026525m

Reaction conditions determine the stereoselection in the intramolecular keto-ene reaction. The thermolysis of chiral 2-acyl-3-allyl-substituted 1,3-perhydrobenzoxazines derived from (-)-8-aminomenthol gives a mixture of only two cis-3-hydroxy-3,4-disubstituted pyrrolidine nuclei. The stereochemistry of the major diastereoisomer depends on both the temperature and the reaction time.

Full text of DOI:10.1021/jo026525m

Tem p er a tu r e- a n d Tim e-Dep en d en t Ster eoch em ica l Con tr ol in
Th er m a lly In d u ced Keto-En e Cycliza tion s
Rafael Pedrosa,* Celia Andre´s,* Carlos D. Roso´n, and Martina Vicente
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011-Valladolid, Spain
pedrosa@qo.uva.es
Received October 4, 2002
Reaction conditions determine the stereoselection in the intramolecular keto-ene reaction. The
thermolysis of chiral 2-acyl-3-allyl-substituted 1,3-perhydrobenzoxazines derived from (-)-8-
aminomenthol gives a mixture of only two cis-3-hydroxy-3,4-disubstituted pyrrolidine nuclei. The
stereochemistry of the major diastereoisomer depends on both the temperature and the reaction
time.
In tr od u ction
anols7 and type I carbonyl ene reactions on R-oxoesters
yielding cyclopentanol derivatives6 have been described.
As part of a project directed to the use of perhydro-
1,3-benzoxazines derived from (-)-8-aminomenthol as
chiral inductors in the synthesis of enantiopure nitrogen
heterocycles, we have demonstrated that these systems
are specially prone to participate in concerted,8 anionic,9
and radical10 mediated cyclizations when two substitu-
ents are placed in positions 2 and 3.
On the basis of these previous results, now we have
tested the carbonyl ene cyclization of 2-acyl-3-allyl-
substituted perhydro-1,3-benzoxazines, directed to the
synthesis of enantiopure 3-hydroxypyrrolidines.
The intramolecular ene reaction has been extensively
used in the formation of cyclic systems because it allows
the formation of a single carbon-carbon bond with
concomitant construction of two contiguous stereo-
centers.1 In addition, the relative stereochemistry in the
cyclization products is dependent on the ring size. The
cis adduct is the major product formed for cyclopentane
derivatives but the trans diastereoisomer predominates
in the formation of cyclohexanes. The absolute configu-
ration of both of them is also controlled by the presence
of stereocenters or chiral templates on the tether between
the ene and the enophile,2 or by the use of chiral Lewis
acids as promoters.3
Resu lts a n d Discu ssion
The interest of the type I carbonyl ene reaction lies in
the fact that macrocyclic alcohols4 and cyclohexanol1,5 and
cyclopentanol6 derivatives can be prepared in high yield
and diastereoselectivities. The Lewis acid or thermally
induced cyclizations of unsaturated aldehydes have been
profoundly studied, but there are no antecedents on the
intramolecular carbonyl ene reactions of unsaturated
ketones1,2 due to their low electrophilicity. In general, the
reaction is restricted to electron-deficient ketones which
cyclize to cyclohexanol or cyclopentanol derivatives, in
moderate yields, under Lewis acid mediated conditions.
Recently, intramolecular type II carbonyl ene reaction
on R,R′-alkoxy-disubstituted ketones leading to cyclohex-
The preparation of 2-formyl-3-prenyl derivative 3 was
attempted as summarize in Scheme 1. The 2-hydroxy-
methyl perhydro-1,3-benzoxazine 111 was alkylated by
reaction with prenyl bromide and potassium carbonate
in acetonitrile at reflux to give 2 in 91%. Swern oxidation
of 2 gave the formyl derivative 3, which cannot be isolated
because it immediately suffers the carbonyl ene reaction
to yield the cyclized compound 4 (85% after purification)
as a single enantiopure diastereoisomer. The absolute
stereochemistry of 4 was determined by X-ray crystal-
lography.12
The formation of the five-membered ring is very
interesting because there are few precedents on the
formation of cyclopentanols in Lewis acids13 or ther-
* Correspondence should be addressed to Prof. Rafael Pedrosa,
Universidad de Valladolid. Fax: Int + 983423013.
(1) Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 2, p 527.
(2) (a) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021. (b)
J ohnson, J . S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(3) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay,
S. N. J . Am. Chem. Soc. 1998, 120, 5824.
(4) Marshall, J . A.; Andersen, M. W. J . Org. Chem. 1993, 58, 3912.
(5) (a) Alcaide, B.; Pardo, C.; Rodr´ıguez-Ranera, C.; Rodr´ıguez-
Vicente, A. Org. Lett. 2001, 3, 4205. (b) Robertson, J .; O’Connor, G.;
Ringrose, C. L.; Middleton, D. S. Tetrahedron 2000, 56, 8321. (c)
Kocovsky, P.; Ahmed, G.; Srogl, J .; Malkov, A. V.; Steele, J . J . Org.
Chem. 1999, 64, 2765 and references therein.
(7) Cheung, C.-M.; Craig, D.; Todd, R. Synlett 2001, 1611.
(8) Pedrosa, R.; Andre´s, C.; Nieto, J . J . Org. Chem. 2002, 67, 782.
(9) Pedrosa, R.; Andre´s, C.; Iglesias, J . M.; Pe´rez-Encabo, A. J . Am.
Chem. Soc. 2001, 123, 1817.
(10) Andre´s, C.; Duque-Soladana, J . P.; Pedrosa, R. J . Org. Chem.
1999, 64, 4282.
(11) Pedrosa, R.; Andre´s, C.; de las Heras, L.; Nieto, J . Org. Lett.
2002, 4, 2513.
(12) See Supporting Information
(13) (a) Andersen, N. H.; Hadley, S. W.; Kelly, J . D.; Bacon, E. R. J .
Org. Chem. 1985, 50, 4144. (b) Paquette, L. A.; Annis, G. D. J . Am.
Chem. Soc. 1983, 105, 7358. (c) Snider, B. B.; Karras, M.; Price, R. T.;
Rodini, D. J . J . Org. Chem. 1982, 47, 4538.
(6) Hiersemann, M. Eur. J . Org. Chem. 2001, 483.
10.1021/jo026525m CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/29/2003
1852
J . Org. Chem. 2003, 68, 1852-1858

Stereochemical Control in Keto-Ene Cyclizations
SCHEME 1
SCHEME 2a
mally14 promoted processes, and the type I carbonyl ene
reaction failed when the tether between the formyl group
and the enophile takes part of a â-lactam system.5a The
stereochemical outcome in our system is also very notice-
able because the process is diastereospecific, leading to
only one of the two possible cis-disubstituted diastereo-
isomers formed in a concerted ene reaction.
Because of the easy reaction of 3 and the total control
of the stereoselection, we envisaged that the thermally
induced reaction could be extended to perhydro-1,3-
benzoxazines bearing different acyl substituents at C-2.
This methodology implies the participation of a ketonic
group as the enophile component, and provides a route
to the formation of a 3,4-disubstituted hydroxy pyrroli-
dine system with a quaternary stereocenter. To this end,
2-benzoyl and 2-isobutanoyl perhydro-1,3-benzoxazines
7a -c were prepared as summarized in Scheme 2.
2-Benzoyl derivatives 7a ,b were prepared from (-)-8-
aminomenthol, in two steps, by sequential condensation
with phenylglyoxal to 5 and alkylation with prenyl or
crotyl bromide and potassium carbonate in refluxing
acetonitrile, respectively. 7c was also obtained from the
amino alcohol and the hemiacetal of the ethyl glyoxylate
of 6 followed by alkylation with prenyl bromide to 8. This
compound was transformed15 into the Weinreb amide 9
by reaction with N,O-dimethyl hydroxylamine hydrochlo-
ride and isopropylmagnesium chloride. Compound 7c was
obtained (59% from 8) by treatment of 9 with isopropyl-
magnesium chloride.
a
Conditions: (i) HOCCOPh, CH2Cl2, rt, quant. (ii) HO(EtO)CH-
CO2Et, benzene, Dean-Stark, quant. (iii) Prenyl or crotyl bromide,
K2CO3, acetonitrile, rt or reflux, 7a (95%), 7b (88%), 8 (88%). (iv)
MeNHOMe, iPrMgCl, THF, -20 °C to room temperature. (v)
iPrMgCl, THF, rt, 7c (59% from 8).
SCHEME 3
Compounds 7a -c lead to mixtures of diastereomeric
3-hydroxypyrrolidines 10a -c and 11a -c under different
thermal conditions (Scheme 3). The results depend on
the experimental conditions and are collected in Table
1.
The results summarized in Table 1 are noteworthy.
Compounds 7a -c are N,O-acetals of R-formyl ketones,
and this is the first case of thermally induced type I
carbonyl ene reaction of this type of compounds leading
to cyclopentanol derivatives. This fact points to the
presence of vicinal oxygen and nitrogen substituents R
to the carbonyl group activating the ketone to participate
in the thermal reaction. As expected, N-prenyl-substi-
tuted compound 7a is more reactive than N-crotyl
derivative 7b. The former was totally transformed into
the cyclization compounds 10a and 11a after heating in
toluene at 150 °C for 3 h (entry 6), whereas 36% of
unreacted 7b was isolated after 18 h in the same
experimental conditions (entry 12).
The most surprising results refer to the stereochemical
outcome of the reactions. In this way, these thermal
carbonyl ene reactions are diastereoselective, giving a
mixture of cis-3,4-disubstituted pyrrolidine systems with
a cis fusion to the perhydro-1,3-benzoxazine nucleus.
These facts suggest that the reaction is a concerted
process that occurs when the ene component on the
nitrogen atom is axially oriented. In addition, the ratio
of diastereoisomers obtained is dependent on both the
reaction conditions and the nature of the substituents.
2-Benzoyl-3-crotyl perhydro-1,3-benzoxazine 7b yielded
mixtures of all-cis-10b and trans,cis-11b diastereoiso-
(14) White, J . D.; Somers, T. C. J . Am. Chem. Soc. 1987, 109, 4424.
(15) Williams, J . M.; J obson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J . J . Tetrahedron Lett. 1995, 36, 5461.
J . Org. Chem, Vol. 68, No. 5, 2003 1853

Pedrosa et al.
TABLE 1. In tr a m olecu la r Ca r bon yl En e Rea ction s of Com p ou n d s 7a -c
entry
substrate
R1
R2
reaction conditionsa
yieldb
products (ratio)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
7a
Ph
Me
170 °C, 1 h
170 °C, 2 h
170 °C, 3 h
170 °C, 8 h
88
86
88
85
80
84
85
20
40
50
80
40
70
88
50
10a , 11a (44:56)
10a , 11a (55:45)
10a , 11a (63:37)
10a , 11a (70:30)
10a , 11a (75:25)
10a , 11a (32:68)
10a , 11a (70:30)
10b, 11b (70:30)d
10b, 11b (75:25)e
10b, 11b (77:23)f
10b, 11b (88:12)
10b, 11b (72:28)g
10c, 11c (41:59)h
10c, 11c (50:50)
10ci
170 °C, 21 h
toluene, 150 °C, 3 h
xylene, reflux, 218 h
170 °C, 1h
toluene, reflux, 120 h
toluene, reflux, 240 h
xylene, reflux, 218 h
toluene, 150 °C, 18 h
170 °C, 3 h
7b
7c
Ph
H
i Pr
Me
170 °C, 8 h
170 °C, 18 h
a
b
The reactions, with or without solvent, were performed in a pressure tube. Yields refer to isolated compounds after column
chromatography. c Determined by 1H NMR of the reaction mixture. Extensive decomposition of 7b was observed. e 36% of 7b was
d
recovered. f 26% of 7b was recovered. 36% of 7b was recovered. 15% of 7c was recovered. 40% of decomposition products was formed.
g
h
i
mers in ratios which vary from 3:1 to 7:1 depending on
the experimental conditions, although it was necessary
to reflux a solution of 7b in xylene for 218 h to complete
the reaction. Compound 7b suffered extensive decompo-
sition with heating at 170 °C for 1 h (entry 8).
acetallic and hydroxylic protons for 11a -c, but a weak
(2%) nOe effect between the same protons for 10a -c.
These observations, corroborated by X-ray diffraction
analysis12 for 10c, indicate that in compounds 10a -c the
acetallic proton and the proton at C-4 are cis, and both
of them are trans to the OH at C-3. On the other hand,
for compounds 11a -c the acetallic proton and the OH
at C-3 are cis but both of them are trans with respect to
the proton at C-4.
Both the stereochemical outcome and the change in the
stereoselection depend on the experimental conditions,
and can be explained by accepting that the carbonyl-
ene cyclization in these compounds is a reversible pro-
cess16 (Scheme 4). The cyclization leading to the cis-3,4-
disubstituted pyrrolidine system occurs through the
unstrained17 endo transition states A and B which only
differ in the relative orientation of the diastereofaces of
the ene and enophile components.
The formation of diastereoisomers 11a and 11c was
favored, in low selectivity, under kinetic reaction condi-
tions because the chairlike18 transition state A is more
stable than B. This one suffers from steric repulsion
between the perhydro-1,3-benzoxazine nucleus and the
methyl group at R2. On the other hand, compounds 10a
and 10c should be more stable probably due to the
establishment of a hydrogen bond between the OH group
and the oxygen atom of the N,O-acetal, and consequently
were the major diastereoisomers formed under thermo-
dynamically controlled reactions.
By contrast, the formation of 10b as the major dias-
tereoisomer under any assayed experimental conditions
can be explained as a consequence of the lack of steric
interactions in the transition structure B (R2 ) H)
making compound 10b both kinetic and thermodynami-
cally favored. The isolation of the kinetic compound 4 as
a single diastereomer from the oxidation of 2 is a
consequence of the mild reaction conditions.
The behavior of 7a is quite different because it is more
reactive than 7b and the ratio of diastereoisomers
depends on the reaction conditions. The carbonyl ene
cyclization for 7a is a fast reaction giving quantitatively
a mixture (44:56) of diastereomeric adducts 10a :11a with
heating for 1 h at 170 °C. A mixture (32:68) of the same
diastereoisomers was formed after heating a solution of
7a in toluene at 150 °C in a sealed tube. The most
important and unprecedented feature of the reaction
refers to the change in the diastereoselection with the
reaction time. Thus, the ratio of diastereoisomers 10a :
11a varies when the reaction time increases (entries 1-5
in Table 1), changing from 44:56 after 1 h to 75:25 after
21 h of heating at 170 °C without solvent. Some decom-
position was observed for longer periods of heating. A
quite similar ratio (70:30, entry 7 in Table 1) of diaste-
reoisomers was obtained after a solution of 7a in xylene
was refluxed for 218 h.
Once isolated, compound 10a isomerized to a mixture
of 10a :11a (70:30) after being heated at 170 °C for 9 h,
and 11a also gave to the same equilibrium mixture under
the same experimental conditions. The same behavior
was observed for compound 7c, although it reacted more
slowly than 7a . Isobutanoyl derivative 7c was trans-
formed into a mixture of 10c and 11c (41:59, entry 13)
after 3 h at 170 °C, and quantitatively (entry 14) in an
equimolar mixture of the same diastereoisomers after
thermolysis for 8 h at the same temperature. Compound
10c was the only isomer isolated when 7c was thermo-
lyzed for 18 h, but only at 50% because extensive
decomposition products were observed after this period
of heating.
The stereochemistry of compounds 10a -c and 11a -c
was determined on the basis of nOe experiments. First,
a strong nOe effect was observed between the protons at
the acetallic and C-4 positions (pyrrolidine numbering)
for compounds 10a -c, but no nOe effect was observed
for the same protons in compounds 11a -c. Further
support of the assignment comes from nOe difference
spectra, showing a strong (7%) nOe effect between the
The major diastereoisomers 10a -c, once isolated, were
transformed into the enantiopure 3,4-disubstituted-3-
(16) (a) Warrington, J . M.; Yap, G. P. A.; Barriault, L. Org. Lett.
2000, 2, 663. (b) Ripoll, J . L.; Vale´e, Y. Synthesis 1993, 659.
(17) (a) Loncharich, R. J .; Houk, K. N. J . Am. Chem. Soc. 1987, 109,
6947. (b) Oppolzer, W.; Pfenninger, E.; Keller, K. Helv. Chim. Acta
1973, 56, 1807.
(18) Braddock, D. C.; Hii, K. K.; Brown, J . M. Angew. Chem., Int.
Ed. 1998, 37, 1720.
1854 J . Org. Chem., Vol. 68, No. 5, 2003

Stereochemical Control in Keto-Ene Cyclizations
SCHEME 4
by oxidation with PCC of 12a -c to 8-aminomentone
derivatives, which, without isolation, were transformed
into the final pyrrolidines 13a -c by elimination with
KOH and tosylation.
In summary, we have reported herein several note-
worthy features of the thermally induced intramolecular
carbonyl-ene reaction in 2-acyl-3-allyl-substituted 1,3-
perhydrobenzoxazines derived from (-)-8-aminomenthol.
Specially interesting and unreported facts follow: (1) the
participation of a ketone as an enophile under moderate
thermal conditions, giving the formation of five-mem-
bered rings; (2) the good stereoselection observed in the
cyclization process; (3) the reversibility of the reaction,
and consequently the dependence of the stereoselection
on both the structure of the starting compounds and the
experimental conditions; and (4) the cyclization products
that are easily transformed into enantiopure 3-hydroxy-
3,4-substituted pyrrolidines.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under argon
atmosphere, in oven-dried glassware. 1H NMR (300 MHz) and
13C NMR (75 MHz) spectra 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 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).
Syn th esis of (2S,4a S,7R,8a R)-[4,4,7-Tr im eth yl-3-(3-m e-
th ylbu t-2-en yl)octa h yd r oben zo[e][1,3]oxa zin -2-yl]m eth -
a n ol (2). A mixture of benzoxazine 111 (3.0 g, 14.1 mmol),
potassium carbonate (4.3 g, 31.0 mmol), and prenyl bromide
(28.2 mmol) in dry acetonitrile (8 mL) was heated in an oil
bath at 80-90 °C until the reaction was completed (TLC, 30
h). The reaction mixture was diluted with ethyl acetate, and
the solid was separated by filtration and washed with hot ethyl
acetate (3 × 25 mL). The solvents were evaporated under
vacuum and the residue was purified by flash chromatography
on silica gel, using hexanes-ethyl acetate 15:1 as eluent.
SCHEME 5a
Compound 2 was isolated as a colorless solid (91%), mp 64-
1
65 °C (from ethanol). [R]25 -46.9 (c 0.9, CHCl3). H NMR: δ
D
0.89-1.15 (m, 3H), 0.92 (d, 3H, J ) 6.5 Hz), 1.11 (s, 3H), 1.15
(s, 3H), 1.32-1.53 (m, 2H), 1.60-1.71 (m, 2H), 1.61 (d, 3H, J
) 0.7 Hz), 1.67 (d, 3H, J ) 1.3 Hz), 1.87-1.94 (m, 1H), 2.20
(br s, 1H), 3.02 (dd, 1H, J 1 ) 6.1 Hz, J 2 ) 17.1 Hz), 3.34 (dd,
1H, J 1 ) 6.1 Hz, J 2 ) 17.1 Hz), 3.46 (dt, 1H, J 1 ) 4.1 Hz, J 2
)
10.6 Hz), 3.55 (d, 2H, J ) 5.6 Hz), 4.55 (t, 1H, J ) 5.6 Hz),
5.17 (m, 1H, J 1 ) 1.3 Hz, J 2 ) 6.1 Hz). 13C NMR: δ 17.8 (CH3),
18.4 (CH3), 22.1 (CH3), 25.0 (CH2), 25.7 (CH3), 26.9 (CH3), 31.2
(CH), 34.8 (CH2), 41.0 (CH2), 41.2 (CH2), 47.6 (CH), 56.8 (C),
63.5 (CH2), 75.6 (CH), 87.1 (CH), 126.5 (CH), 130.4 (C). IR:
3300, 3060, 840 cm-1. CIMS (m/z, %): 282 (M + 1, 100%). Anal.
Calcd for C17H31NO2: C, 72.55; H, 11.10; N, 4.98. Found: C,
72.38; H, 11.39; N, 5.19.
Syn t h esis of (2S,4a S,7R,8a R)-P h en yl-(4,4,7-t r im et h -
ylocta h yd r oben zo[e][1,3]oxa zin -2-yl) Keton e (5). A mix-
ture of (-)-8-aminomenthol (2.5 g, 15 mmol) and phenylglyoxal
(2.01 g, 15 mmol) in dichloromethane (75 mL) was stirred for
24 h at room temperature. The solvent was removed under
vacuum, yielding quantitatively the perhydrobenzoxazine 5.
An analytical sample was recrystallized from EtOH. Colorless
a
Conditions: (i) AlH3, THF, -10 °C, 30 min. (ii) PCC, CH2Cl2,
rt. (iii) 2.5 M KOH, H2O, MeOH, THF (1:1:2), rt, 12 h, then TsCl,
DIPEA, EtOAc, rt, 36 h (13a , 39%; 13b, 45%; 13c, 42% from 10a -
c, respectively).
hydroxy pyrrolidines 13a -c as summarized in Scheme
5. Reductive ring opening of 10a -c with aluminum
hydride yielded 8-aminomenthols 12a -c. The elimina-
tion of the chiral moiety was achieved, in moderate yields,
solid, mp 69-70 °C (from ethanol). [R]25 -1.3 (c 1.1, CHCl3).
D
1H NMR: δ 0.92 (d, 3H, J ) 6.5 Hz), 0.95-1.15 (m, 4H), 1.19
(s, 3H), 1.21 (s, 3H), 1.45-1.55 (m, 1H), 1.69-1.72 (m, 2H),
J . Org. Chem, Vol. 68, No. 5, 2003 1855

Pedrosa et al.
1.93-1.97 (m, 1H), 2.38 (br s, 1H, NH), 3.69 (dt, 1H, J 1 ) 4.2
Hz, J 2 ) 10.4 Hz), 5.64 (s, 1H), 7.42-7.56 (m, 3H), 8.06 (d,
2H, J ) 7.9 Hz). 13C NMR: δ 19.5 (CH3), 22.2 (CH3), 25.5 (CH2),
29.6 (CH3), 31.4 (CH), 34.8 (CH2), 41.4 (CH2), 51.1 (C), 51.4
(CH), 75.9 (CH), 80.6 (CH), 128.4 (2CH), 129.3 (2CH), 133.5
(CH), 134.6 (C), 193.0 (CdO). IR: 3320, 1680, 1590, 790, 700
cm-1. Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87.
Found: C, 75.40; H, 8.79; N, 4.78.
3H), 1.21 (s, 3H), 1.27 (t, 3H, J ) 7.2 Hz), 1.30-1.53 (m, 2H),
1.56 (s, 3H), 1.64 (s, 3H), 1.60-1.75 (m, 3H), 1.95-2.02 (m,
1H), 3.22 (dd, 1H, J 1 ) 5.2 Hz, J 2 ) 7.0 Hz), 3.34 (dd, 1H, J 1
) 6.2 Hz, J 2 ) 7.0 Hz), 3.49 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.7
Hz), 4.13 (dq, 1H, J 1 ) 7.1 Hz, J 2 ) 10.8 Hz), 4.23 (dq, 1H, J 1
) 7.1 Hz, J 2 ) 10.7 Hz), 5.06 (s, 1H), 5.16-5.36 (m, 1H). 13C
NMR: δ 13.8 (CH3), 17.5 (CH3), 19.6 (CH3), 21.9 (CH3), 24.7
(CH2), 25.4 (CH3), 26.2 (CH3), 31.0 (CH), 34.6 (CH2), 40.8 (CH2),
42.4 (CH2), 45.6 (CH), 56.7 (C), 60.6 (CH2), 75.7 (CH), 85.3
(CH), 126.1 (CH), 129.8 (C), 168.5 (CdO). IR: 3080, 2920, 1740,
830 cm-1. CIMS (m/z, %): 324 (M + 1, 100%). Anal. Calcd for
C19H33NO3: C, 70.55; H, 10.28; N, 4.33. Found: C, 70.72; H,
10.09; N, 4.21.
Syn t h esis of (2S,4a S,7R,8a R)-4,4,7-Tr im et h yloct a -
h yd r oben zo[e][1,3]oxa zin e-2-ca r boxylic Acid Eth yl Ester
(6). A mixture of (-)-8-aminomenthol (5.01 g, 30 mmol) and
the hemiacetal of ethyl glyoxylate (4.44 g, 30 mmol) in benzene
(75 mL) was refluxed in a Dean-Stark trap for 24 h. The
solvent was removed under vacuum yielding quantitatively the
Syn th esis of (2S,4a S,7R,8a R)-4,4,7-Tr im eth yl-3-(3-m e-
th ylbu t-2-en yl)octa h yd r oben zo[e][1,3]-2-ca r boxylic Acid
Meth oxy Meth yl Am id e (9). This compound was prepared
by reaction of 8 with N,O-dimethyl hydroxylamine hydrochlo-
perhydrobenzoxazine 6. Colorless oil. [R]25 +20.22 (c 1.5,
D
1
CHCl3). H NMR: δ 0.85-1.05 (m, 2H), 0.87 (d, 3H, J ) 6.5
Hz), 1.06-1.16 (m, 2H), 1.06 (s, 3H), 1.09 (s, 3H), 1.26 (t, 3H,
J ) 7.2 Hz), 1.35-1.50 (m, 1H), 1.60-1.65 (m, 2H), 1.87-1.94
(m, 1H), 1.99 (br s, 1H), 3.46 (dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.5
Hz), 4.13 (q, 2H, J ) 7.1 Hz), 4.83 (s, 1H). 13C NMR: δ 13.9
(CH3), 19.2 (CH3), 22.1 (CH3), 25.3 (CH2), 29.4 (CH3), 31.2 (CH),
34.7 (CH2), 41.1 (CH2), 51.0 (C), 51.3 (CH), 61.5 (CH2), 75.5
ride as previously described.15 Colorless oil. [R]D 39.6 (c 0.6,
25
1
CHCl3). H NMR: δ 0.87-1.02 (m, 2H), 0.92 (d, 3H, J ) 6.5
Hz), 1.08-1.31 (m, 2H), 1.15 (s, 3H), 1.25 (s, 3H), 1.40-1.65
(m, 2H), 1.55 (s, 3H), 1.63 (s, 3H), 1.65-1.76 (m, 1H), 1.92-
2.02 (m, 1H), 3.13 (s, 3H), 3.15-3.36 (m, 1H), 3.40-3.80 (m,
2H), 3.81 (s, 3H), 5.17 (m, 1H), 5.62 (br s, 1H). 13C NMR: δ
17.6 (CH3), 21.1 (CH3), 22.1 (CH3), 24.8 (CH2), 25.6 (CH3), 26.6
(CH3), 31.3 (CH), 32.2 (CH3), 34.9 (CH2), 41.0 (CH2), 41.9 (CH2),
45.0 (CH), 57.3 (C), 61.5 (CH3), 76.6 (CH), 82.8 (CH), 126.6
(CH), 81.1 (CH), 168.2 (CdO). IR: 3320, 2920, 1740 cm-1
.
CIMS (m/z, %): 256 (M + 1, 100%). Anal. Calcd for C14H25
-
NO3: C, 65.85; H, 9.87; N, 5.49. Found: C, 66.08; H, 10.01; N,
5.31.
(CH), 129.5 (C), 169.9 (CdO). IR: 3080, 1640, 830 cm-1
.
Alk yla tion of 5 a n d 6. Gen er a l P r oced u r e. A mixture
of benzoxazine 5 or 6 (14.1 mmol), potassium carbonate (4.3
g, 31.0 mmol), and the corresponding allyl bromide (28.2 mmol)
in dry acetonitrile (8 mL) was heated in an oil bath at 80-90
°C until the reaction was completed (TLC, 30-80 h). The
reaction mixture was diluted with ethyl acetate, and the solid
was separated by filtration and washed with hot ethyl acetate
(3 × 25 mL). The solvents were evaporated under vacuum and
the residue was purified by flash chromatography on silica gel,
using hexanes-ethyl acetate 15:1 as eluent.
Syn t h esis of (2S,4a S,7R,8a R)-2-Met h yl-1-[4,4,7-t r i-
m et h yl-3-(3-m et h ylb u t -2-en yl)oct a h yd r ob en zo[e][1,3]-
oxa zin -2-ylp r op a n -1-on e (7c). To a cooled (0 °C) solution of
9 (6.24 mmol, 2.1 g) in anhydrous THF (200 mL) was added a
2 M solution (18.72 mmol, 9.36 mL) of isopropylmagnesium
chloride in Et2O and the mixture was stirred for 30 min. The
reaction mixture was quenched by addition of a saturated
solution of NH4Cl (200 mL). The aqueous phase was extracted
with Et2O (4 × 25 mL), and the organic phase was washed
with brine and dried over anhydrous MgSO4. After evaporation
of the solvents, the residue was recrystallized, giving to 7c
(59% from 8) as a colorless solid, mp 61-62 °C (from ethanol).
(2S,4aS,7R,8aR)-P h en yl-[4,4,7-tr im eth yl-3-(3-m eth ylbu t-
2-en yl)octa h yd r oben zo[e] [1,3]oxa zin -2-yl] Keton e (7a ).
Colorless solid (95%), mp 65-66 °C (from ethanol). [R]25D -16.6
1
[R]25 -82.1 (c 0.9, CHCl3). 1H NMR: δ 0.90-1.02 (m, 2H),
(c 1.2, CHCl3). H NMR: δ 0.93-1.03 (m, 2H), 0.94 (d, 3H, J
D
) 6.5 Hz), 1.18-1.29 (m, 1H), 1.19 (s, 3H), 1.27 (s, 3H), 1.37
(s, 3H), 1.39 (s, 3H), 1.43-1.76 (m, 4H), 2.01-2.05 (m, 1H),
3.19 (dd, 1H, J 1 ) 6.5 Hz, J 2 ) 16.6 Hz), 3.32 (dd, 1H, J 1 ) 6.5
Hz, J 2 ) 16.6 Hz), 3.57 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.4 Hz),
4.71 (m, 1H), 5.66 (s, 1H), 7.39 (t, 2H, J ) 7.2 Hz), 7.50 (t, 1H,
J ) 7.2 Hz), 8.20 (d, 2H, J ) 7.2 Hz). 13C NMR: δ 17.5 (CH3),
19.8 (CH3), 22.2 (CH3), 25.0 (CH2), 25.3 (CH3), 26.8 (CH3), 31.3
(CH), 34.9 (CH2), 41.3 (CH2), 42.3 (CH2), 46.2 (CH), 57.5 (C),
76.2 (CH), 88.7 (CH), 126.2 (CH), 127.8 (2CH), 129.2 (2CH),
130.8 (C), 132.7 (CH), 135.4 (C), 194.6 (CdO). IR: 3100, 1680,
1600, 1500, 830, 750, 690 cm-1. Anal. Calcd for C23H33NO2:
C, 77.70; H, 9.36; N, 3.94. Found: C, 77.39; H, 9.11; N, 4.00.
0.93 (d, 3H, J ) 6.5 Hz), 1.01 (d, 3H, J ) 6.9 Hz), 1.05-1.25
(m, 1H), 1.10 (d, 3H, J ) 6.9 Hz), 1.13 (s, 3H), 1.25 (s, 3H),
1.42-1.50 (m, 2H), 1.50 (s, 3H), 1.52-1.63 (m, 1H), 1.63 (d,
3H, J ) 1.3 Hz), 1.67-1.74 (m, 1H), 1.95-2.02 (m, 1H), 3.03
(dd, 1H, J 1 ) 6.1 Hz, J 2 ) 17.4 Hz), 3.10 (m, 1H, J ) 6.9 Hz),
3.26 (dd, 1H, J 1 ) 4.9 Hz, J 2 ) 17.4 Hz), 3.47 (dt, 1H, J 1 ) 4.0
Hz, J 2 ) 10.5 Hz), 5.13 (ddd, 1H, J 1 ) 1.3 Hz, J 2 ) 4.9 Hz, J 3
) 6.2 Hz), 5.15 (s, 1H). 13C NMR: δ 17.4 (CH3), 17.8 (CH3),
19.6 (CH3), 21.5 (CH3), 22.2 (CH3), 24.9 (CH2), 25.6 (CH3), 26.6
(CH3), 31.4 (CH), 35.0 (CH2), 36.3 (CH), 41.1 (CH2), 43.1 (CH2),
44.9 (CH), 57.2 (C), 76.3 (CH), 88.4 (CH), 126.8 (CH), 130.2
(C), 210.9 (CdO). IR: 3060, 1680, 830 cm-1. CIMS (m/z, %):
322 (M + 1, 100%). Anal. Calcd for C20H35NO2: C, 74.72; H,
10.97; N, 4.36. Found: C, 74.54; H, 10.78; N, 4.56.
Syn th esis of (1R,2R,4a S,7R,8a R,9a S)-2-Isop r op en yl-
4,4,7-tr im eth yldecah ydr o-9-oxa-3a-azacyclopen ta[b]n aph -
th a len -1-ol (4). To a cooled (-78 °C) solution of oxalyl chloride
(15 mmol, 1.9 g, 1.32 mL) in CH2Cl2 (32 mL) was slowly
dropped dimethyl sulfoxide (32 mmol, 2.5 g, 2.26 mL). After
15 min of stirring, a solution of 2 (12 mmol, 3.37 g) in CH2Cl2
(32 mL) was added and the mixture was stirred for 25 min
and triethylamine (45 mmol, 6.26 mL) was added. The stirred
mixture was allowed to reach rt, and then quenched by
addition of H2O (32 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 25 mL), and the organics were washed with
a solution of NaHCO3 and brine and dried over anhydrous
MgSO4. The solvent was evaporated, and the residue was
recrystallized giving to 4 as a colorless solid (85%), mp 118-
119 °C (from ethanol). [R]25D +6.85 (c 1.1, CHCl3). 1H NMR: δ
0.81-1.07 (m, 3H), 0.84 (d, 3H, J ) 6.5 Hz), 1.08 (s, 3H), 1.09
(s, 3H), 1.31-1.39 (m, 2H), 1.49-1.65 (m, 2H), 1.74 (s, 3H),
1.76-1.82 (m, 1H), 2.00 (br s, 1H, OH), 2.92-3.10 (m, 3H),
(2S ,4a S ,7R ,8a R )-(3-Bu t -2-e n yl-4,4,7-t r im e t h yloct a -
h yd r oben zo[e][1,3]oxa zin -2-yl)p h en yl Keton e (7b). Yel-
lowish oil (88%). [R]25D -18.0 (c 0.9, CHCl3). 1H NMR: δ 0.87-
1.05 (m, 2H), 0.93 (d, 3H, J ) 6.5 Hz), 1.12-1.32 (m, 1H), 1.19
(s, 3H), 1.27 (d, 3H, J ) 6.1 Hz), 1.37 (s, 3H), 1.39-1.57 (m,
2H), 1.61-1.73 (m, 2H), 1.99-2.04 (m, 1H), 3.16 (dd, 1H, J 1
)
5.2 Hz, J 2 ) 16.8 Hz), 3.31 (dd, 1H, J 1 ) 5.9 Hz, J 2 ) 16.8
Hz), 3.57 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.5 Hz), 4.99-5.20 (m,
2H), 5.71 (s, 1H), 7.37-7.52 (m, 3H), 8.17 (d, 2H, J ) 7.1 Hz).
13C NMR: δ 17.4 (CH3), 20.1 (CH3), 22.2 (CH3), 24.9 (CH2),
26.7 (CH3), 31.3 (CH), 34.9 (CH2), 41.2 (CH2), 46.1 (2CH), 57.7
(C), 76.2 (CH), 88.2 (CH), 125.8 (CH), 127.8 (2CH), 129.3
(2CH), 131.3 (CH), 132.8 (CH), 135.4 (C), 195.0 (CdO). IR:
3080, 1690, 1610, 1480, 1350, 980 cm-1. CIMS (m/z, %): 342
(M + 1, 100%). Anal. Calcd for C22H31NO2: C, 77.38; H, 9.15;
N, 4.10. Found: C, 77.54; H, 9.32; N, 3.91.
(2S,4aS,7R,8aR)-4,4,7-Tr im eth yl-3-(3-m eth ylbu t-2-en yl)-
octa h yd r oben zo[e][1,3]oxa zin e-2-ca r boxylic Acid Eth yl
25
1
Ester (8). Colorless oil (88%). [R]D -35.0 (c 1.1, CHCl3). H
NMR: δ 0.87-1.13 (m, 2H), 0.93 (d, 3H, J ) 6.5 Hz), 1.17 (s,
1856 J . Org. Chem., Vol. 68, No. 5, 2003

Stereochemical Control in Keto-Ene Cyclizations
1
3.36 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.5 Hz), 3.94 (br s, 1H), 4.62
(s, 1H), 4.81 (s, 1H), 4.93 (s, 1H). 13C NMR: δ 20.8 (CH3), 22.2
(CH3), 23.4 (CH3), 24.7 (CH2), 26.3 (CH3), 31.2 (CH), 35.0 (CH2),
41.4 (CH2), 43.7 (CH), 45.4 (CH2), 46.6 (CH), 52.9 (C), 74.5
(2CH), 91.5 (CH), 111.8 (CH2), 142.9 (C). IR: 3450, 3100, 2940,
1630, 880 cm-1. CIMS (m/z, %): 280 (M + 1, 100%). Anal.
Calcd for C17H29NO2: C, 73.07; H, 10.46; N, 5.01. Found: C,
73.31; H, 10.59; N, 5.20.
Keto-En e Cycliza tion s. Gen er a l P r oced u r e. A 5-mmol
sample of the corresponding compound 7a -c was introduce
in a pressure tube, under argon atmosphere, and heated as
pure or in the corresponding solvent (25 mL) at the temper-
ature and for the time indicated in Table 1. When the reactions
were finished, the reaction mixtures were purified by flash
chromatography or by recrystallization on the appropriate
solvents.
(from ethanol). [R]25 -98.1 (c 0.5, CHCl3). H NMR: δ 0.88-
D
1.09 (m, 3H), 0.89 (d, 3H, J ) 6.5 Hz), 1.17 (s, 3H), 1.18 (s,
3H), 1.29-1.54 (m, 2H), 1.57-1.62 (m, 1H), 1.67-1.73 (m, 1H),
1.77-1.84 (m, 1H), 2.91 (dd, 1H, J 1 ) 6.0 Hz, J 2 ) 9.1 Hz),
2.97 (s, 1H, OH), 3.31 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.4 Hz), 3.42
(dd, 1H, J 1 ) 9.1 Hz, J 2 ) 10.1 Hz), 3.52 (m, 1H), 4.55 (s, 1H),
5.00 (dd, 1H, J 1 ) 0.8 Hz, J 2 ) 17.2 Hz), 5.03 (dd, 1H, J 1 ) 0.8
Hz, J 2 ) 10.5 Hz), 5.93 (ddd, 1H, J 1 ) 7.9 Hz, J 2 ) 10.5, J 3
)
17.2 Hz), 7.21-7.34 (m, 3H), 7.63 (d, 2H, J ) 7.1 Hz). 13C
NMR: δ 22.3 (CH3), 22.4 (CH3), 24.8 (CH2), 26.1 (CH3), 31.2
(CH), 35.1 (CH2), 41.3 (CH2), 43.0 (CH), 48.0 (CH2), 48.7 (CH),
53.3 (C), 74.5 (CH), 82.3 (C), 92.6 (CH), 117.0 (CH2), 127.0
(CH), 127.3 (2CH), 127.4 (2CH), 135.9 (CH), 138.8 (C). IR:
3450, 1600, 1500, 920, 760, 690 cm-1. Anal. Calcd for C22H31
-
NO2: C, 77.38; H, 9.15; N, 4.10. Found: C, 77.02; H, 8.92; N,
4.12
(1S,2S,4aS,7R,8aR,9aS)-2-Isopr open yl-1-isopr opyl-4,4,7-
tr im eth yld eca h yd r o-9-oxa -3a -a za cyclop en ta [b]n a p h th a -
(1R,2S,4a S,7R,8a R,9a S)-2-Isop r op en yl-4,4,7-tr im eth yl-
1-p h en yld eca h yd r o-9-oxa -3a -a za cyclop en ta [b]n a p h th a -
len -1-ol (10a ). Yellow oil (60%, entry 5). [R]25 -25.7 (c)0.9,
len -1-ol (10c). Colorless solid (50%, entry 15), mp 64-65 °C
D
1
(from ethanol). [R]25 -44.3 (c 0.8, CHCl3). H NMR: δ 0.87-
1
D
CHCl3). H NMR: δ 0.86-0.99 (m, 2H), 0.91 (d, 3H, J ) 6.5
1.18 (m, 3H), 0.92 (d, 3H, J ) 6.5 Hz), 0.96 (d, 3H, J ) 7.3
Hz), 0.98 (d, 3H, J ) 7.0 Hz), 1.09 (s, 3H), 1.11 (s, 3H), 1.43-
1.56 (m, 2H), 1.57-1.61 (m, 1H), 1.70-1.75 (m, 1H), 1.78-
1.94 (m, 2H), 1.82 (s, 3H), 2.74 (t, 1H, J ) 8.3 Hz), 2.89 (t, 1H,
J ) 8.3 Hz), 3.09 (s, 1H, OH), 3.13 (t, 1H, J ) 8.3 Hz), 3.47
(dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.5 Hz), 4.47 (s, 1H), 4.86 (s, 1H),
4.93 (s, 1H). 13C NMR: δ 17.2 (CH3), 17.6 (CH3), 20.1 (CH3),
22.2 (CH3), 22.9 (CH3), 24.8 (CH2), 26.4 (CH3), 31.2 (CH), 35.0
(CH2), 36.3 (CH), 41.3 (CH2), 44.0 (CH), 48.3 (CH2), 48.9 (CH),
53.1 (C), 74.9 (CH), 81.9 (C), 87.1 (CH), 113.0 (CH2), 145.1 (C).
IR: 3540, 3060, 2920, 1630, 930 cm-1. CIMS (m/z, %): 322 (M
+ 1, 100%). Anal. Calcd for C20H35NO2: C, 74.72; H, 10.97; N,
4.36. Found: C, 74.89; H, 11.05; N, 4.18.
Hz), 1.02-1.14 (m, 1H), 1.16 (s, 3H), 1.20 (s, 3H), 1.46-1.51
(m, 2H), 1.60 (s, 3H), 1.60-1.64 (m, 1H), 1.70-1.72 (m, 1H),
1.85-1.88 (m, 1H), 2.94 (dd, 1H, J 1 ) 8.1 Hz, J 2 ) 9.1 Hz),
3.09 (dd, 1H, J 1 ) 8.1 Hz, J 2 ) 8.3 Hz), 3.36 (dd, 1H, J 1 ) 8.3
Hz, J 2 ) 9.1 Hz), 3.45 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.4 Hz), 3.73
(s, 1H, OH), 4.62 (s, 1H), 4.69 (s, 1H), 4.87 (s, 1H), 7.19-7.34
(m, 3H), 7.67 (dd, 2H, J 1 ) 1.4 Hz, J 2 ) 7.1 Hz). 13C NMR: δ
20.2 (CH3), 22.3 (CH3), 23.5 (CH3), 24.8 (CH2), 27.0 (CH3), 31.2
(CH), 35.0 (CH2), 41.2 (CH2), 44.5 (CH), 47.1 (CH2), 53.5 (C),
56.9 (CH), 75.0 (CH), 79.9 (C), 91.9 (CH), 111.3 (CH2), 124.7
(2CH), 126.4 (CH), 127.8 (2CH), 143.6 (C), 147.9 (C). IR: 3300,
1600, 1500, 1480, 900, 760, 690 cm-1. CIMS (m/z, %): 356 (M
+ 1, 100%). Anal. Calcd for C23H33NO2: C, 77.70; H, 9.36; N,
3.94. Found: C, 77.54; H, 9.52; N, 4.12.
(1S,2R,4a S,7R,8a R,9a S)-2-Isop r op en yl-4,4,7-tr im eth yl-
1-p h en yld eca h yd r o-9-oxa -3a -a za cyclop en ta [b]n a p h th a -
len -1-ol (11a ). Colorless solid (57%, entry 6), mp 75-76 °C
(from ethanol). [R]25D -116.2 (c 1.0, CHCl3). 1H NMR: δ 0.88-
1.09 (m, 2H), 0.89 (d, 3H, J ) 6.5 Hz), 1.16 (s, 3H), 1.18 (s,
3H), 1.38-1.48 (m, 1H), 1.48 (s, 3H), 1.48-1.61 (m, 3H), 1.69-
1.72 (m, 1H), 1.78-1.83 (m, 1H), 2.88 (br s, 1H), 3.08 (dd, 1H,
J 1 ) 6.3 Hz, J 2 ) 9.3 Hz), 3.28 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.3
Hz), 3.39 (dd, 1H, J 1 ) 9.3 Hz, J 2 ) 9.9 Hz), 3.54 (dd, 1H, J 1
) 6.3 Hz, J 2 ) 9.9 Hz), 4.46 (s, 1H), 4.84 (s, 1H), 4.89 (s, 1H),
7.23-7.33 (m, 3H), 7.69 (dd, 2H, J 1 ) 1.5 Hz, J 2 ) 7.1 Hz).
13C NMR: δ 20.0 (CH3), 22.3 (CH3), 23.9 (CH3), 24.8 (CH2),
26.3 (CH3), 31.3 (CH), 35.2 (CH2), 41.2 (CH2), 43.1 (CH), 46.7
(CH2), 51.5 (CH), 53.3 (C), 74.6 (CH), 81.5 (C), 93.3 (CH), 112.6
(CH2), 126.7 (CH), 127.2 (4CH), 139.9 (C), 143.0 (C). IR: 3350,
1600, 1480, 910, 760, 700 cm-1. Anal. Calcd for C23H33NO2:
C, 77.70; H, 9.36; N, 3.94. Found: C, 77.36; H, 9.10; N, 3.87.
(1R,2R,4aS,7R,8aR,9aS)-2-Isopr open yl-1-isopr opyl-4,4,7-
tr im eth yld eca h yd r o-9-oxa -3a -a za cyclop en ta [b]n a p h th a -
len e-1-ol (11c). Colorless oil (41%, entry 13). [R]25 -11.2 (c
D
1
0.9, CHCl3). H NMR: δ 0.87-1.04 (m, 2H), 0.88 (d, 3H, J )
6.5 Hz), 0.94 (d, 3H, J ) 6.8 Hz), 0.96 (d, 3H, J ) 6.8 Hz),
1.06 (s, 3H), 1.11 (s, 3H), 1.38-1.68 (m, 5H), 1.80-1.83 (m,
1H), 1.83 (s, 3H), 1.95 (hept, 1H, J ) 6.8 Hz), 2.07 (s, 1H, OH),
2.76 (dd, 1H, J 1 ) 6.0 Hz, J 2 ) 9.0 Hz), 2.95 (dd, 1H, J 1 ) 6.0
Hz, J 2 ) 10.1 Hz), 3.17 (dd, 1H, J 1 ) 9.0 Hz, J 2 ) 10.1 Hz),
3.28 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.4 Hz), 4.38 (s, 1H), 4.78 (s,
1H), 4.87 (s, 1H). 13C NMR: δ 16.7 (CH3), 18.4 (CH3), 21.8
(CH3), 22.2 (2CH3), 24.8 (CH2), 26.1 (CH3), 31.2 (CH), 32.0
(CH), 35.1 (CH2), 41.4 (CH2), 42.8 (CH), 49.0 (CH2), 50.1 (CH),
52.9 (C), 74.3 (CH), 84.1 (C), 92.2 (CH), 113.9 (CH2), 145.8 (C).
IR: 3520, 3060, 2920, 1630, 1450, 1380, 990, 880 cm-1. CIMS
(m/z, %): 322 (M + 1, 100%). Anal. Calcd for C20H35NO2: C,
74.72; H, 10.97; N, 4.36. Found: C, 74.58; H, 10.81; N, 4.22.
Syn th esis of Am in o Alcoh ols 12a -c. Gen er a l Meth od .
To a suspension of LiAlH4 (0.57 g, 15 mmol) in anhydrous THF
(40 mL) cooled to -10 °C was added, in portions, dry AlCl3
(0.67 g, 5 mmol). The mixture was stirred for 10 min, and a
solution of the corresponding adduct (3 mmol) in dry THF (20
mL) was slowly added. The reaction mixture was stirred fo 8
min at -10 °C and quenched by addition of H2O (4 mL). The
resulting mixture was filtered, the solid was washed with
EtOAc, and the organic layer was dried (MgSO4). The solvent
was eliminated under reduced pressure, and the residue was
chromatographed on silica gel with hexane/EtOAc 3/1 as
eluent.
(1R,2S,4a S,7R,8a R,9a S)-4,4,7-Tr im e t h yl-1-p h e n yl-2-
vin yld eca h yd r o-9-oxa -3a -a za cyclop en ta [b]n a p h th a len -
1-ol (10b). Colorless solid (70%, entry 11), mp 52-53 °C (from
ethanol). [R]25 -35.0 (c 1.0, CHCl3). 1H NMR: δ 0.85-1.02
D
(m, 2H), 0.90 (d, 3H, J ) 6.5 Hz), 1.06-1.16 (m, 1H), 1.12 (s,
3H), 1.16 (s, 3H), 1.39-1.48 (m, 2H), 1.57-1.69 (m, 2H), 1.86-
1.90 (m, 1H), 2.87 (q, 1H, J ) 8.4 Hz), 3.09 (t, 1H, J 1 ) 8.4
Hz), 3.15 (t, 1H, J 1 ) 8.4 Hz), 3.44 (dt, 1H, J 1 ) 4.1 Hz, J 2
10.5 Hz), 3.67 (s, 1H, OH), 4.67 (s, 1H), 4.86 (ddd, 1H, J 1
)
)
0.8 Hz, J 2 ) 1.8 Hz, J 2 ) 16.4 Hz), 5.00 (dd, 1H, J 1 ) 1.8 Hz,
J 2 ) 10.3 Hz), 5.91 (ddd, 1H, J 1 ) 8.4 Hz, J 2 ) 10.3, J 3 ) 16.4
Hz), 7.16-7.31 (m, 3H), 7.58 (d, 2H, J ) 8.0 Hz). 13C NMR: δ
19.0 (CH3), 22.2 (CH3), 24.8 (CH2), 26.7 (CH3), 31.2 (CH), 34.9
(CH2), 41.2 (CH2), 45.3 (CH), 48.8 (CH2), 53.6 (C), 53.9 (CH),
75.2 (CH), 80.4 (C), 91.2 (CH), 116.2 (CH2), 124.9 (2CH), 126.6
(CH), 127.8 (2CH), 136.1 (CH), 146.1 (C). IR: 3250, 1500, 930,
760, 690 cm-1. Anal. Calcd for C22H31NO2: C, 77.38; H, 9.15;
N, 4.10. Found: C, 77.16; H, 9.16; N, 4.49.
(3R,4S,1′S,2′R,4′R)-1-[1′-(2′-Hyd r oxy-4′-m eth ylcycloh ex-
yl)-1′-m eth yleth yl]-4-isop r op en yl-3-p h en ylp yr r olid in -3-
ol (12a ). Colorless solid, mp 78-79 °C (from hexane). [R]25
D
1
+9.3 (c 0.9, CHCl3). H NMR (333 K): δ 0.89 (d, 3H, J ) 6.5
Hz), 0.93-1.01 (m, 2H), 1.05 (s, 3H), 1.22 (s, 3H), 1.21-1.28
(m, 1H), 1.31 (s, 3H), 1.36-1.43 (m, 2H), 1.56-1.68 (m, 2H),
1.92-1.97 (m, 1H), 2.28 (s, 1H, OH), 3.07-3.19 (m, 4H), 3.36
(d, 1H, J ) 10.8 Hz), 3.67 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.2 Hz),
4.86 (s, 1H), 4.99 (s, 1H), 7.18-7.33 (m, 3H), 7.49 (d, 2H, J )
7.2 Hz), 8.40 (br s, 1H). 13C NMR (333 K): δ 17.1 (CH3), 21.4
(1S,2R,4a S,7R,8a R,9a S)-4,4,7-Tr im e t h yl-1-p h e n yl-2-
vin yld eca h yd r o-9-oxa -3a -a za cyclop en ta [b]n a p h th a len -
1-ol (11b). Colorless solid (11%, entry 10), mp 109-110 °C
J . Org. Chem, Vol. 68, No. 5, 2003 1857

Pedrosa et al.
(CH3), 21.9 (CH3), 24.2 (CH3), 25.6 (CH2), 31.0 (CH), 35.1 (CH2),
44.3 (CH2), 48.5 (CH2), 48.9 (CH), 56.3 (CH), 59.5 (C), 62.3
(CH2), 72.8 (CH), 79.2 (C), 113.8 (CH2), 125.0 (2CH), 126.7
(CH), 128.0 (2CH), 141.4 (C), 144.2 (C). IR: 3500, 3060, 1600,
1500, 900, 760, 690 cm-1. Anal. Calcd for C23H35NO2: C, 77.26;
H, 9.87; N, 3.73. Found: C, 77.48; H, 9.85; N, 3.70.
of the solvents the residues were purified by recrystallization
or flash chromatography.
(3R,4S)-4-Isop r op en yl-3-p h en yl-1-t osylp yr r olid in -3-
ol (13a ). Colorless solid (39% from 10a ), mp 90-91°C (from
pentane). [R]25D +24.7 (c 0.3, CHCl3). 1H NMR: δ 1.23 (s, 3H),
2.09 (s, 1H, OH), 2.46 (s, 3H), 3.15 (dd, 1H, J 1 ) 7.5 Hz, J 2
)
(3R,4S,1′S,2′R,4′R)-1-[1′-(2′-Hyd r oxy-4′-m eth ylcycloh ex-
yl)-1′-m eth yleth yl]-3-p h en yl-4-vin ylp yr r olid in -3-ol (12b).
11.4 Hz), 3.48 (dd, 1H, J 1 ) 9.5 Hz, J 2 ) 11.4 Hz), 3.61 (d, 1H,
J ) 11.2 Hz), 3.71 (d, 1H, J ) 11.2 Hz), 3.76 (dd, 1H, J 1 ) 7.5
Hz, J 2 ) 9.5 Hz), 4.74 (s, 1H), 4.98 (s, 1H), 7.25-7.37 (m, 7H),
7.77 (d, 2H, J ) 8.0 Hz). 13C NMR: δ 21.6 (CH3), 24.2 (CH3),
50.1 (CH2), 55.6 (CH), 62.8 (CH2), 79.8 (C), 114.7 (CH2), 125.0
(2CH), 127.5 (CH), 127.6 (2CH), 128.3 (2CH), 129.7 (2CH),
133.9 (C), 139.6 (C), 141.5 (C), 143.5 (Cd). IR: 3400, 3100,
1620, 1500, 1180, 900, 830 cm-1. CIMS (m/z, %): 358 (M + 1,
100%). Anal. Calcd for C20H23NO3S: C, 67.20; H, 6.49; N, 3.92.
Found: C, 66.97; H, 6.02; N, 4.10.
Colorless solid, mp 61-62 °C (from hexane). [R]25 -20.1 (c
D
1
1.0, CHCl3). H NMR (333 K): δ 0.87-1.01 (m, 2H), 0.89 (d,
3H, J ) 6.5 Hz), 1.04 (s, 3H), 1.21 (s, 3H), 1.25-1.36 (m, 1H),
1.37-1.47 (m, 2H), 1.55-1.69 (m, 2H), 1.88-1.96 (m, 1H),
2.05-2.40 (br s, 1H, OH), 3.00-3.15 (m, 4H), 3.32 (d, 1H, J )
10.9 Hz), 3.65 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.3 Hz), 5.02 (dd,
1H, J 1 ) 1.3 Hz, J 2 ) 17.2 Hz), 5.13 (dd, 1H, J 1 ) 1.3 Hz, J 2
) 10.8 Hz), 5.73 (ddd, 1H, J 1 ) 6.3 Hz, J 2 ) 10.8 Hz, J 3
)
17.2 Hz), 7.19-7.35 (m, 3H), 7.46 (d, 2H, J ) 7.3 Hz). 13C NMR
(333 K): δ 17.0 (CH3), 21.3 (CH3), 21.9 (CH3), 25.6 (CH2), 31.0
(CH), 35.1 (CH2), 44.3 (CH2), 48.8 (CH2), 49.0 (CH), 52.8 (CH),
59.5 (C), 61.3 (CH2), 72.8 (CH), 80.7 (C), 118.7 (CH2), 125.2
(2CH), 127.0 (CH), 128.1 (2CH), 133.0 (CH), 143.3 (C). IR:
3200, 3060, 1600, 1500, 900, 760, 690 cm-1. Anal. Calcd for
(3R,4S)-3-P h en yl-1-tosyl-4-vin ylp yr r olid in -3-ol (13b).
Yellowish oil (45% from 10b). [R]25 +4.6 (c 0.7, CHCl3). 1H
D
NMR: δ 2.01 (s, 1H, OH), 2.44 (s, 3H), 3.06-3.47 (m, 1H), 3.44
(dd, 1H, J 1 ) 9.5 Hz, J 2 ) 10.6 Hz), 3.59 (d, 1H, J ) 11.4 Hz),
3.66 (d, 1H, J ) 11.4 Hz), 3.73 (dd, 1H, J 1 ) 7.7 Hz, J 2 ) 9.5
Hz), 4.99 (d, 1H, J ) 17.4 Hz), 5.13 (d, 1H, J ) 10.7 Hz), 5.57
(ddd, 1H, J 1 ) 6.6 Hz, J 2 ) 10.7 Hz, J 3 ) 17.4 Hz), 7.25-7.36
(m, 7H), 7.76 (d, 2H, J ) 8.2 Hz). 13C NMR: δ 21.5 (CH3),
50.1 (CH2), 52.5 (CH), 61.9 (CH2), 81.1 (C), 120.1 (CH2), 125.1
(2CH), 127.5 (2CH), 127.7 (CH), 128.4 (2CH), 129.7 (2CH),
130.9 (CH), 134.0 (C), 140.5 (C), 143.6 (C). IR: 3380, 3100,
2960, 1620, 1500, 1180, 990, 830 cm-1. CIMS (m/z, %): 344
(M + 1, 100%). Anal. Calcd for C19H21NO3S: C, 66.45; H, 6.16;
N, 4.08. Found: C, 66.28; H, 6.32; N, 3.91.
C
22H33NO2: C, 76.92; H, 9.68; N, 4.08. Found: C, 77.01; H,
9.86; N, 3.77.
(3S,4S,1′S,2′R,4′R)-1-[1′-(2′-Hyd r oxy-4′-m eth ylcycloh ex-
yl)-1′-m eth yleth yl]-4-isop r op en yl-3-isop r op ylp yr r olid in -
1
3-ol (12c). Colorless oil. [R]25 -41.6 (c 0.9, CHCl3). H NMR
D
(333 K): δ 0.84-1.29 (m, 3H), 0.90 (d, 3H, J ) 6.5 Hz), 1.00
(d, 3H, J ) 6.9 Hz), 1.01 (d, 3H, J ) 6.9 Hz), 1.09 (s, 3H), 1.29
(s, 3H), 1.38-1.52 (m, 2H), 1.61-1.70 (m, 2H), 1.84 (hept, 1H,
J ) 6.9 Hz), 1.85 (s, 3H), 1.94-2.01 (m, 1H), 2.74 (dd, 1H, J 1
(3S,4S)-4-Isop r op en yl-3-isop r op yl-1-tosylp yr r olid in -3-
) 7.5 Hz, J 2 ) 11.2 Hz), 3.02-3.17 (m, 3H), 3.08 (dd, 1H, J 1
)
ol (13c). Colorless solid (42% from 10c), mp 139-140 °C (from
7.5 Hz, J 2 ) 9.4 Hz), 3.73 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.4 Hz),
4.93 (s, 1H), 5.03 (s, 1H). 13C NMR (333 K): δ 17.5 (CH3), 17.8
(CH3), 18.1 (CH3), 20.8 (CH3), 21.7 (CH3), 23.8 (CH3), 25.6
(CH2), 31.0 (CH), 34.6 (CH), 34.7 (CH2), 44.2 (CH2), 48.4 (CH),
49.7 (CH2), 50.2 (CH), 54.3 (CH2), 62.3 (C), 72.0 (CH), 81.6 (C),
115.0 (CH2), 141.4 (C). IR: 3300, 2940, 1630, 1450, 1370, 880
cm-1. CIMS (m/z, %): 324 (M + 1, 100%). Anal. Calcd for
1
hexane). [R]25 -4.8 (c 0.7, CHCl3). H NMR: δ 0.90 (d, 3H, J
D
) 6.9 Hz), 0.94 (d, 3H, J ) 6.9 Hz), 1.48 (d, 1H, J ) 0.8 Hz,
OH), 1.69 (hept, 1H, J ) 6.9 Hz), 1.78 (s, 3H), 2.43 (s, 3H),
2.72 (dd, 1H, J 1 ) 7.5 Hz, J 2 ) 11.0 Hz), 3.18 (d, 1H, J ) 10.8
Hz), 3.30 (dd, 1H, J 1 ) 9.3 Hz, J 2 ) 11.0 Hz), 3.39 (dd, 1H, J 1
) 0.8 Hz, J 2 ) 10.8 Hz), 3.51 (dd, 1H, J 1 ) 7.5 Hz, J 2 ) 9.3
Hz), 4.80 (s, 1H), 5.03 (s, 1H), 7.33 (d, 2H, J ) 8.2 Hz), 7.73
(d, 2H, J ) 8.2 Hz). 13C NMR: δ 17.5 (CH3), 18.0 (CH3), 21.5
(CH3), 24.3 (CH3), 34.3 (CH), 49.9 (CH), 50.9 (CH2), 55.3 (CH2),
82.4 (C), 115.2 (CH2), 127.4 (2CH), 129.6 (2CH), 133.8 (C),
C
20H37NO2: C, 74.25; H, 11.53; N, 4.33. Found: C, 74.12; H,
11.68; N, 4.19.
E lim in a t ion of t h e Men t h ol Ap p en d a ge. Gen er a l
Meth od . A solution of amino derivatives 12a -c (1.0 mmol)
and PCC (1.3 g, 6 mmol) in CH2Cl2 (40 mL) and 4 Å molecular
sieves (1 g) was stirred at room temperature until the oxidation
was finished (TCL, 6-8 h). The solvent was eliminated under
reduced pressure, the residue was dissolved in a 15% aqueous
solution of NaOH (25 mL), and the resulting solution was
extracted with EtOAc. The organic phase was washed with
brine and dried over anhydrous magnesium sulfate. The
solvents were eliminated under vacuum, the residue was taken
up in a 2.5 M solution (16 mL) of KOH in THF/MeOH/H2O
(2/1/1), and the solution was stirred at room temperature for
5-6 h. After elimination of the solvents under reduced
pressure, the residue was dissolved in 50 mL of CH2Cl2 and
washed with H2O. The organic layer was dried over MgSO4
and filtered, and the solvent was eliminated under vacuum to
give an oily residue that was treated with an excess of tosyl
chloride in diisopropylethylamine for 36 h. After elimination
140.4 (C), 143.4 (C). IR: 3400, 3100, 1620, 1160, 890, 820 cm-1
.
CIMS (m/z, %): 324 (M + 1, 100%). Anal. Calcd for C17H25
-
NO3S: C, 63.13; H, 7.79; N, 4.33. Found: C, 63.01; H, 7.96;
N, 4.17.
Ack n ow led gm en t. The authors thank the Spanish
Ministerio de Educacio´n y Cultura (DGICYT, Projects
PB98-0361 and BQU2002-01046) for financial support.
C.D.R. also thanks a predoctoral fellowship (FPU).
Su p p or tin g In for m a tion Ava ila ble: Ortep representa-
tion of X-ray structures of 4 and 10c, and 1H NMR and 13C
NMR for compounds 2-13. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O026525M
1858 J . Org. Chem., Vol. 68, No. 5, 2003