Enantioselective synthesis of spirocyclic aminochroman derivatives according to the CN(R,S) strategy

Article abstract of DOI:10.1021/jo026228h

Enantiomerically pure (3′R)- and (3′S)-3′,4′-dihydrospiro[piperidine-2,3′ (2′H)-benzopyran]s (R)-10 and (S)-10 were successfully synthesized according to the CN(R,S) methodology with the aim of serving as a pattern for the generation of related spirocyclic compounds. Two different synthetic pathways were studied starting from 2-cyano-6-phenyloxazolopiperidine (-)-2. One of them was selected and used for the preparation of amines (R)-17 and (S)-17 starting from (-)-2 and (+)-2, respectively. The enantiomeric purity of all final aminochroman derivatives was determinated by capillary electrophoresis using β-cyclodextrin as the chiral selector.

Full text of DOI:10.1021/jo026228h

En a n tioselective Syn th esis of Sp ir ocyclic Am in och r om a n
Der iva tives Accor d in g to th e CN(R,S) Str a tegy
Gre´goire Pave´,† J ean-Michel Le´ger,‡ Christian J arry,‡ Marie-Claude Viaud-Massuard,§ and
Ge´rald Guillaumet*,†
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite´ d’Orle´ans, BP 6759,
45067 Orle´ans Cedex 2, France, EA 2962 Pharmacochimie, UFR de Pharmacie, Universite´ Victor Segalen
Bordeaux 2, 33076 Bordeaux Cedex, France, and Groupe de Recherche en Chimie He´te´rocyclique et
The´rapeutique, EA 3247, UFR Sciences Pharmaceutiques, Universite´ de Tours, 31 avenue Monge,
37200 Tours, France
gerald.guillaumet@univ-orleans.fr
Received J uly 23, 2002
Enantiomerically pure (3′R)- and (3′S)-3′,4′-dihydrospiro[piperidine-2,3′(2′H)-benzopyran]s (R)-10
and (S)-10 were successfully synthesized according to the CN(R,S) methodology with the aim of
serving as a pattern for the generation of related spirocyclic compounds. Two different synthetic
pathways were studied starting from 2-cyano-6-phenyloxazolopiperidine (-)-2. One of them was
selected and used for the preparation of amines (R)-17 and (S)-17 starting from (-)-2 and (+)-2,
respectively. The enantiomeric purity of all final aminochroman derivatives was determinated by
capillary electrophoresis using â-cyclodextrin as the chiral selector.
In tr od u ction
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotrans-
mitter of the central nervous system that is involved in
many physiological and pathophysiological processes in
the brain. These processes are mediated by the specific
interaction of 5-HT with several different receptors.1,2 The
dysfunction of the serotoninergic system has been linked
to various behavioral problems involving memory,
thermoregulation, sleep, and sexual behavior. Moreover,
serotonin is also implicated in numerous neuropsychiatry
disorders such as anxiety, depression, schizophrenia, or
Alzheimer’s disease.3-5 Due to the role of 5-HT1A recep-
tors in anxiety and depression, the synthesis of 5-HT1A
agonists appears to be very attractive. In our laboratory,
previous works6-9 have led to new potential therapeutic
agents that demonstrated a good affinity and a high
selectivity for the 5-HT1A receptors. Among them, com-
pound 1b (S 22178) (Figure 1) showed an 8.8 nmol
F IGURE 1.
affinity toward this receptor.7 The synthesis of both
enantiomers of 1b was achieved for pharmacological
purposes.
At the present time, just one pathway leading only to
racemic 3-aminochroman derivatives has been described.7
To define an easy and enantioselective approach to this
type of compound, a model study was performed. The key
step of the synthetic pathway controls the stereochem-
istry of the spirocyclic center. It was generated using the
CN(R,S) method10 developed by Husson et al. from
2-cyano-6-phenyloxazolopiperidine (-)-2.11 Indeed, the
R-aminonitrile function of this chiral precursor could be
used to generate the required spirocyclic system. By this
approach, each enantiomer of target compound 1a was
synthesized in two different ways starting from (-)-2.
Finally, one pathway was selected and used to prepare
both enantiomers of the methoxylated derivative 1b
starting from isomers (-)-2 and (+)-2.
† Universite´ d’Orle´ans.
‡ Universite´ Victor Segalen Bordeaux 2.
§ Universite´ de Tours.
(1) Glennon, R. A. J . Med. Chem. 1987, 30, 1.
(2) Fozard, J . R. Trends Pharmacol. Sci. 1987, 8, 44.
(3) J ohnston, A.; File, S. E. Pharmacol., Biochem. Behav. 1986, 24,
1457.
(4) Eison, M. S. Psychopathology 1984, 17, 37.
(5) Peroutka, S. J .; Snyder, S. H. J . Pharmacol. Exp. Ther. 1981,
216, 142.
(6) Podona T.; Guardiola-Lemaˆıtre B.; Caignard D. H.; Adam G.;
Pfeiffer B.; Renard P.; Guillaumet G. J . Med. Chem. 1994, 37, 1779.
(7) Comoy C.; Marot C.; Podona T.; Baudin M. L.; Morin-Allory L.;
Guillaumet G.; Pfeiffer B.; Caignard D. H.; Renard P.; Rettori M. C.;
Adam G.; Guardiola-Lemaˆıtre B. J . Med. Chem. 1996, 39, 4285.
(8) Usse, S.; Guillaumet, G.; Viaud, M. C. J . Org. Chem. 2000, 65,
914.
Resu lts a n d Discu ssion
Syn th esis of Am in e (S)-12a . Compound 2 was found
to be a good candidate for triggering the asymmetric
(9) Usse, S.; Pave´, G.; Guillaumet, G.; Viaud-Massuard, M.-C.
Tetrahedron: Asymmetry 2001, 12, 1689.
(10) Husson, H.-P.; Royer, J . J . Chem. Soc. Rev. 1999, 28, 383 and
references therein.
10.1021/jo026228h CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/25/2003
J . Org. Chem. 2003, 68, 1401-1408
1401

Pave´ et al.
SCHEME 1
SCHEME 2
F IGURE 2. NOE connectivities on compound 7b.
that the hemiaminal 6a is an intermediate during the
reductive reaction of 5a to 7a . The absolute configuration
of 6a was deduced according to the literature.13 During
the reduction stage, the restricted imine is attacked by
the primary alcohol function on its accessible face. Hence,
only one isomer can be formed. The absolute configura-
1
tion of 7a was deduced from H NMR data of compound
synthesis of dihydrospiro[piperidine-2,3′(2′H)-benzo-
pyran] derivatives for an asymmetric synthesis by the
CN(R,S) method. The alkylation of the anion derived
from (-)-2 with 1-bromo-2-(chloromethoxy)benzene12 (3a )
(LDA, THF, -78 °C) led to the formation of 4a as a single
product. This compound was isolated in 62% yield after
flash chromatography (Scheme 1). Then compound 4a
was submitted to halogen/metal exchange using n-BuLi
in THF at -78 °C. The lithiated intermediate led to a
single isomer of imine 5a (91% yield). According to the
literature,13 the formation of this imine can be explained
by the intramolecular addition of the aryllithium species
onto the nitrile function followed by the attack of an
intermediate imine salt on the C-8a atom of the potential
iminium ion. The 1H NMR spectrum of 5a presents a
narrow triplet at δ 5.03 (J ) 2.1 Hz) assigned to the
bridgehead proton.
At this stage, only a reduction of 5a with sodium
cyanoborohydride at pH 3 (1 N HCl) gave satisfactory
results (Scheme 2). Initially, as described by Froelich et
al.,13 the reaction was conducted in methanol/THF (1:1),
giving a mixture of hemiaminal 6a and hemiacetal 7a ,
each one as a single isomer. A study of the solvent
influence gave interesting results. As depicted in Scheme
2, when the reaction was performed in refluxing THF for
4 h, only 6a was obtained in 80% yield. When the reaction
was performed in refluxing methanol for 36 h, only 7a
was obtained in 84% yield. Moreover, the hydrolysis of
6a in refluxing methanol performed in the presence of 1
N hydrochloric acid at pH 3 for 24 h gave 7a , indicating
7b. Indeed, the H-2b signal was inferred by the Karplus
theory: H-2a, δ 3.55 (dd, J cis ) 3.8 Hz, J gem ) 11.0 Hz);
H-2b, δ 4.28 (t, J trans ) 11.0 Hz, J gem ) 11.0 Hz); H-3, δ
3.93 (dd, J cis ) 3.8 Hz, J trans ) 11.0 Hz). Then, an NOE
experiment conducted on 7b indicated a relationship
between H-2b and OH (Figure 2). In addition, the NOE
experiment showed a connectivity between OH and
protons of the phenyl group. From these results, it was
possible to assign unambiguously the (3S,8aR,14bS)
absolute configuration for 7a , fixing the chirality of the
spiro center.
The next step consisted in reducing compounds 6a and
7a by the couple LiAlH4/AlCl3, in a suspension in THF.
This sequence gave compounds 8a and 9a in 99% and
88% yield, respectively (Scheme 3). As explained by
Husson et al.,13 the reduction of such compounds occurred
via a retention mechanism as proposed for ketals14 and
oxazolidines.15 Finally, diamine 10a and amino alcohol
11a were obtained by hydrogenolysis of the chiral ap-
pendage in 8a and 9a , in 96% and 97% yield, respectively.
The spatial group determined from the X-ray crystal
structure of 11a indicated that there is only one isomer.
This result can be used, in conjunction with the previous
NOE data, to establish the absolute configuration of 11a
and, consequently, absolute configuration of the related
compounds 9a , 9b, and 11b.
The reduction of the primary amine function of com-
pound 10a to its corresponding methylene was achieved
by hydroxylaminesulfonic acid (NH2OSO3H),16 in the
presence of 20% sodium hydroxide in ethanol at reflux
(11) Bonin, M.; Grierson, D. S.; Royer, J .; Husson, H.-P. Org. Synth.
1992, 70, 54.
(12) Compound 3a was synthesized starting from 2-bromophenol in
two steps in 70% overall yield using the same methodology as described
for 3b.
(13) Froelich, O.; Desos, P.; Bonin, M.; Quirion, J .-C.; Husson, H.-
P. J . Org. Chem. 1996, 61, 6700.
(14) Brewster, J . H. In Comprehensive Organic Chemistry; Trost B.
M., Flemming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8, p
211.
(15) Munchhof, M. J .; Meyer, A. I. J . Org. Chem. 1995, 60, 7084.
(16) Doldouras, G. A.; Kollonitsch, J . J . Am. Chem. Soc. 1978, 100,
341.
1402 J . Org. Chem., Vol. 68, No. 4, 2003

Synthesis of Spirocyclic Aminochroman Derivatives
SCHEME 3
SCHEME 4
SCHEME 6
SCHEME 5
with a mechanism described in the literature18 involving
the fact that the electrophile came on the more stable
enolate conformer bearing an equatorial phenyl group.
(Scheme 4). Hence, the amine (S)-12a was obtained in
moderate yield (26%).
To increase the accessibility to amine (S)-12a , the
alcohol function of 11a was reduced in corresponding
methylene by adding sodium borohydride in portions to
a solution of amino alcohol 11a in a mixture of TFA/CH2-
Cl2.17 After a basic treatment and subsequent purifica-
tion, amine (S)-12a was obtained in 65% yield. No
racemization was observed during the reduction of the
alcohol function. In this way, (3′S)-3′,4′-dihydrospiro-
[piperidine-2,3′(2′H)-benzopyran] ((S)-12a ) was synthe-
sized in six steps in 27% overall yield starting from the
nitrile (-)-2. The absolute configuration of (S)-12a was
deduced from its precursor 11a .
Syn th esis of Am in e (R)-12a . Complementary to the
previous work, the synthesis of the R enantiomer was
carried out with a different pathway, starting from the
same synthon (-)-2. To invert the spirocyclic stereogenic
center, we applied the method used for the synthesis of
pipecolic acid derivatives.18 Lactone 13 (7:3 epimeric
mixture, Scheme 5) was synthesized in two steps from
(-)-2 in 74% overall yield. The enolate of compound 13
(LDA, THF, -78 °C) was alkylated with 2-(tert-butyldim-
ethylsiloxy)benzyl bromide19 (14) to furnish only the
alkylated compound 15 in 44% yield. This compound
exhibited (4R,9aR) absolute configuration in accordance
Reduction of lactone 15 with a LiAlH4 suspension in
Et2O gave diol 16 in 86% yield (Scheme 6). The chiral
appendage in 16 was cleaved by hydrogenolysis (H2, Pd/
C, MeOH, HClaq) to furnish 17 in 78% yield. At this stage,
according to our synthetic pathway, the amino function
must be protected. Consequently, 17 reacted with Boc2O
in CH2Cl2 to afford 18 in 83% yield. The phenol function
was regenerated by Bu4NF in THF in 80% yield, and the
obtained diol 19 was engaged in a Mitsunobu reaction.
Cyclizated product 20 was thus obtained by using Ph3P
and DEAD in dry toluene in 85% yield. The synthesis
finished by cleavage of the protecting group by TFA in
CH2Cl2 to give (R)-12a in 72% yield. In this way (3′R)-
3′,4′-dihydrospiro[piperidine-2,3′(2′H)-benzopyran] ((R)-
12a ) was synthesized in nine steps in 8.8% overall yield
starting from (-)-2.
The absolute configuration of (S)-12a was unambigu-
ously determined from its optical rotation, opposite that
of (R)-12a . Enantiomeric purities of aminochromans (S)-
12a and (R)-12a were determinated by capillary electro-
phoresis using â-cyclodextrin as the chiral selector. Both
enantiomers (S)-12a and (R)-12a were obtained in 99.6%
and 99.3% enantiomeric purity, respectively.
Syn th esis of Am in es (S)-12b a n d (R)-12b. To obtain
both enantiomers of the compound 1b (S 22178), a
synthetic pathway should be selected. As described above,
amine (S)-12a was obtained in six steps in 27% overall
yield, whereas amine (R)-12a was synthesized in nine
steps in 8.8% overall yield. In both processes, nitrile (-)-2
was used as the starting material. By extrapolating these
results, it was supposed that amine (S)-12b could be so
obtained starting from (-)-2, and conversely (+)-2 could
(17) Gribble, G. W.; Lesse, R. M. Synthesis 1977, 172.
(18) Berrien, J .-F.; Royer, J .; Husson, H.-P. J . Org. Chem. 1994, 59,
3769.
(19) Stern, A. J .; Swenton, J . S. J . Org. Chem. 1989, 54, 2951.
(20) Sheldrick, G. M. In Crystallographic Computing 3; Sheldrick,
G. M., Kro¨ger, C., Goddard, R., Eds.; Oxford University Press: Oxford,
1985; p 175.
(21) Supplementary X-ray crystallographic data: University Chemi-
cal Lab, Cambridge Crystallographic Data Centre, Lensfield Rd.,
Cambridge, CB2 1EW, U.K. E-mail:
chemcrys.cam.ac.uk.
http:/www.deposit@
J . Org. Chem, Vol. 68, No. 4, 2003 1403

Pave´ et al.
SCHEME 7
SCHEME 8
SCHEME 9
furnish amine (R)-12b. Consequently, we investigated the
synthesis of both enantiomers of compound 1b (S 22178)-
with the first pathway starting from (-)-2 for (+)-S 22178
and (+)-2 for (-)-S 22178.
As depicted in Scheme 7, alkylating agent 3b used in
the first step was obtained starting from 3-methoxyphe-
nol. The phenol function was protected with a meth-
oxymethyl group to afford 21 in 83% yield. The bromi-
nation of 21 was performed by using n-BuLi and Br2C2Cl4
in Et2O, giving 22 in 87% yield. Phenol 23 was regener-
ated with 3 N hydrochloric acid in THF in 74% yield. The
phenolate (K2CO3, CH3CN) of 23 was reacted with
chloromethyl methyl sulfide to give thioacetal 24 in 71%
yield. Finally, compound 3b was obtained from thio
compound 24 by action of sulfuryl chloride in dichloro-
methane at -78 °C in 61% yield, after crystallization in
pentane.
As described for the generation of (S)-12b, the nitrile
(-)-2 was engaged in an anionic reaction using LDA in
THF at -78 °C. The obtained anion was alkylated by 3b
to give 4b as a single isomer. The synthetic pathway
described for (S)-12a was used to generate amine (S)-
12b. Compounds 4b, 5b, 7b, 9b, 11b, and (S)-12b were
obtained in similar yields compared to the generation of
(S)-12a . Thus, both enantiomers (S)-12b and (R)-12b
(Scheme 8) were synthesized starting from (-)-2 and
(+)-2 in 34% and 32% overall yield, respectively.
Determination of the enantiomeric excess of (S)-12b
and (R)-12b was performed by capillary electrophoresis
using â-cyclodextrin as the chiral selector. Amines (S)-
12b and (R)-12b were obtained in enantiomeric purity
higher than 99.5%.
and 8.8% overall yield, respectively. The former way was
used to generate amines (S)-12b and (R)-12b obtained
in 32% and 34% overall yield, respectively. The enantio-
meric purity of (S)-12a and (R)-12a was assessed by
capillary electrophoresis, showing an enantiomeric purity
superior to 99%. The same analytical procedure was
applied to (S)-12b and (R)-12b, indicating an enantio-
meric purity higher than 99.5%.
Exp er im en ta l Section
All air- and moisture-sensitive reactions were carried out
under an argon atmosphere. Anhydrous solvents (Et2O and
THF) were freshly distilled from sodium/benzophenone under
1
nitrogen prior to use. H and 13C NMR spectra were obtained
at 250.131 and 62.9 MHz, respectively. Chemical shifts (δ
values) were reported in parts per million (ppm) and coupling
constants (J values) in hertz. Carbon multiplicities have been
assigned by distortionless enhancement by polarization trans-
fer (DEPT) experiments. Infrared spectra were recorded using
NaCl film or KBr pellets. Mass spectroscopy (MS) was per-
formed by ion spray (IS). Optical rotations were determined
at rt and are referenced to the D-line of sodium. Melting points
(mp’s) were determinated in an open capillary tube and are
uncorrected. Analytical thin-layer chromatography was per-
formed on 60F254 silica gel precoated plates. Flash chroma-
tography was performed using silica gel 40-70 µm (230-400
mesh).
(3R,5S,8a R)-5-[(2-Br om op h en oxy)m et h yl]-3-p h en yl-
h e xa h yd r o-5H -[1,3]oxa zolo[3,2-a ]p yr id in e -5-ca r b on i-
tr ile (4a ). To a solution of nitrile (-)-2 (4 g., 17.5 mmol) in 50
mL of THF at -78 °C was added an LDA solution (2 M in
hexane, 18.3 mL, 35.0 mmol). After 30 min of stirring, HMPA
(8 mL, 35.0 mmol) and then 1-bromo-2-(chloromethoxy)-
benzene (3a ) (7.8 g, 35.0 mmol) in THF were added dropwise.
The mixture was stirred for 3 h and then hydrolyzed by a
saturated aq NH4Cl solution. The reaction was extracted with
CH2Cl2. Organic extracts were washed with water, dried over
MgSO4, and evaporated. The residue was purified by flash
chromatography (SiO2; petroleum ether/AcOEt, 98:2) to give
4a (colorless oil, 4.48 g, 62% yield): [R]20D ) -96 (c 1.0, CHCl3);
IR (film) 2222 cm-1; MS (IS) m/z 413 (M + 1, 79Br)+, 415 (M +
As depicted in Scheme 9, both enantiomers of 1a and
1b were synthesized according to the literature7 in 66%
and 76% yield starting from (S)-12a and (R)-12a , respec-
tively, and in 64% and 72% yield starting from (S)-12b
and (R)-12b, respectively.
Con clu sion
In this work was reported the efficient synthesis of both
enantiomers of compound 1b (S 22178). First, amines
(S)-12a and (R)-12a were synthesized as models, accord-
ing to the CN(R,S) method in two different ways in 27%
1404 J . Org. Chem., Vol. 68, No. 4, 2003

Synthesis of Spirocyclic Aminochroman Derivatives
1
1, 81Br)+; H NMR (CDCl3) δ 1.67-2.37 (m, 6H), 3.38 (d, 1H,
12.8 mmol) in THF (15 mL) at 0 °C was added a solution of
amino ether 6a (0.86 g, 2.5 mmol) in THF (15 mL). The
reaction mixture was stirred for 3 h at this temperature. A
solution of NaOH (10%) (0.5 mL) was added, followed by
addition of water (0.5 mL). After being stirred for 18 h, the
mixture was filtrated through a Celite pad and concentrated.
The residue was purified by flash chromatography (SiO2; CH2-
Cl2/MeOH, 95:5), affording 8a (0.85 g, 99%) as a white foam:
J ) 9.1 Hz), 3.71 (d, 1H, J ) 9.1 Hz), 3.78 (dd, 1H, J ) 7.9 Hz,
J ′ ) 4.9 Hz), 4.16 (dd, 1H, J ) 7.9 Hz, J ′ ) 4.9 Hz), 4.25 (dd,
1H, J ) 9.8 Hz, J ′ ) 2.8 Hz), 4.28 (t, 1H, J ) 7.9 Hz), 5.92
(dd, 1H, J ) 7.9 Hz, J ′ ) 1.2 Hz), 6.76 (td, 1H, J ) 7.9 Hz, J ′
) 1.2 Hz), 7.00 (td, 1H, J ) 7.9 Hz, J ′ ) 1.2 Hz), 7.17-7.44
(m, 5H), 7.46 (dd, 1H, J ) 7.9, J ′ ) 1.2 Hz); 13C NMR (CDCl3)
δ 18.9, 28.7, 32.6, 61.1, 61.6, 71.2, 73.7, 91.0, 111.2, 116.1,
121.6, 126.4, 127.0, 127.4, 127.8, 132.6, 141.7, 152.9. Anal.
Calcd for C21H21N2O2Br: C, 61.03; H, 5.12; N, 6.78; Br, 19.33.
Found: C, 61.15; H, 5.03; N, 6.87; Br, 19.01.
[R]20 ) -90 (c 1.0, CHCl3); IR (film) 3624-3126 cm-1; MS
D
(IS) m/z 339.5 (M + 1)+, 322.0 (M - NH2)+; H NMR (CDCl3)
1
δ 1.36-1.74 (m, 6H), 2.54-2.59 (m, 1H), 2.63 (br s, 2H), 3.05-
3.17 (m, 1H), 3.47 (dd, 1H, J ) 10.3 Hz, J ′ ) 4.5 Hz), 3.78 (d,
1H, J ) 11.3 Hz), 3.95 (t, 1H, J ) 10.3 Hz), 4.19 (d, 1H, J )
11.3 Hz), 4.44 (dd, 1H, J ) 10.3 Hz, J ′ ) 4.5 Hz), 4.77 (br s,
1H), 6.73 (d, 1H, J ) 7.6 Hz), 6.95 (t, 1H, J ) 7.6 Hz), 7.15 (t,
1H, J ) 7.6 Hz), 7.21-7.32 (m, 5H), 7.48 (d, 1H, J ) 7.6 Hz);
13C NMR (CDCl3) δ 22.8, 25.4, 31.6, 48.7, 54.3, 56.9, 62.7, 63.4,
64.0, 109.9, 120.3, 126.7, 126.8, 127.4, 127.8, 130.1, 146.0,
130.1. Anal. Calcd for C21H26N2O2: C, 74.53; H, 7.74; N, 8.28.
Found: C, 74.48; H,7.81; N, 8.45.
( 2 R ) -2 -[ ( 1 S ,1 2 S ) -1 0 -O x a -2 ,1 6 -d i a z a t e t r a c y c l o -
[10.3.1.03,12.04,9]h exa d eca -2,4(9),5,7-tetr a en -16-yl]-2-p h en -
yl-1-eth a n ol (5a ). To a solution of 4a (3.7 g, 8.9 mmol) in 40
mL of anhydrous Et2O at -78 °C was added dropwise 11.2
mL (17.9 mmol) of n-BuLi (1.6 M in hexane). After 2 h of
stirring, the reaction mixture was hydrolyzed, extracted with
AcOEt, and dried over MgSO4. After removal of the solvent
under reduced pressure, compound 5a was isolated by flash
chromatography (SiO2; petroleum ether/AcOEt, 7:3) as an
amorphous white solid (2.74 g, 91% yield): mp 73-75 °C; [R]20
(3′S,4′R)-[(1R)-2-Hydr oxy-1-ph en yleth yl]-4′-h ydoxy-3′,4′-
d ih yd r osp ir o[p ip er id in e-2,3′(2′H)-ben zop yr a n ] (9a ). Fol-
lowing the same procedure described for product 8a , 7a (1.2
g, 3.5 mmol) was reduced with a suspension of LiAlH4 (0.607
g, 16.0 mmol) and AlCl3 (2.14 g, 16.0 mmol) in THF (15 mL)
D
) -16 (c 1.0, CHCl3); IR (KBr) 3624-3122 cm-1; MS (IS) m/z
335.5 (M + 1)+; H NMR (CDCl3) δ 1.32-1.87 (m, 7H), 3.70-
1
3.74 (m, 2H), 3.99 (t, 1H, J ) 4.6 Hz), 4.06 (d, 1H, J ) 10.7
Hz), 4.21 (d, 1H, J ) 10.7 Hz), 5.03 (t, 1H, J ) 2.1 Hz), 6.93
(d, 1H, J ) 7.5 Hz), 7.04 (t, 1H, J ) 7.5 Hz), 7.29-7.48 (m,
6H), 8.03 (d, 1H, J ) 7.5 Hz); 13C NMR (CDCl3) δ 17.9, 20.7,
62.1, 65.7, 66.3, 74.0, 83.6, 116.7, 117.9, 122.2, 126.3, 128.4,
128.5, 129.2, 133.8, 140.4, 157.9, 168.1. Anal. Calcd for
at 0 °C to furnish 9a as a white foam (1.06 g, 88%): [R]20
)
D
-65 (c 1.0, CHCl3); IR (film) 3405 cm-1; MS (IS) m/z 340 (M +
1
1)+, 322.0 (M - OH)+; H NMR (CDCl3) δ 1.48-1.68 (m, 6H),
2.54-2.62 (m, 1H), 3.04-3.09 (m, 1H), 3.52 (dd, 1H, J ) 10.6
Hz, J ′ ) 4.6 Hz), 3.85-3.98 (m, 3H), 4.15 (d, 1H, J ) 11.6
Hz), 4.53 (dd, 1H, J ) 10.6, J ′ ) 4.6 Hz), 6.73 (dd, 1H, J ) 7.9
Hz, J ′ ) 0.9 Hz), 6.95 (td, 1H, J ) 7.9 Hz, J ′ ) 0.9 Hz), 7.11-
7.36 (m, 6H), 7.55 (d, 1H, J ) 7.9 Hz); 13C NMR (CDCl3) δ
19.8, 25.1, 25.3, 40.4, 26.8, 60.2, 61.4, 62.5, 66.2, 102.7, 109.9,
113.0, 126.4, 127.4, 128.4, 129.0, 129.2, 140.0, 155.9. Anal.
Calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C,
74.28; H, 7.48; N, 4.31.
(3′S,4′R)-4′-Am in o-3′,4′-d ih yd r osp ir o[p ip er id in e-2,3′-
(2′H)-ben zop yr a n ] (10a ). Hydrogenolysis of compound 8a
(0.96 g, 2.8 mmol) in MeOH (10 mL) in the presence of 2 drops
of HCl (37%) and 10% Pd/C (100 mg) for 4 h afforded a
compound which, after filtration and concentration, was
disolved in CH2Cl2 and washed by a saturated aq solution of
K2CO3. The purification was performed by flash chromatog-
raphy (SiO2; CH2Cl2/MeOH, 98:2). The diamine 10a (0.59 g,
96%) was obtained as a green oil: [R]20D ) -101 (c 1.0, CHCl3);
IR (film) 3684-3103 cm-1; MS (IS) m/z 219 (M + 1)+, 202 (M
- NH2)+; 1H NMR (CDCl3) δ 1.54-1.90 (m, 9H), 2.85-2.90
(m, 2H), 3.74 (br s, 1H), 4.05 (d, 1H, J ) 11.1 Hz), 4.21 (d, 1H,
J ) 11.1 Hz), 6.82 (d, 1H, J ) 7.9 Hz), 6.91 (t, 1H, J ) 7.9
Hz), 7.16 (t, 1H, J ) 7.9 Hz), 7.27 (d, 1H, J ) 7.9 Hz); 13C
NMR (CDCl3) δ 20.6, 26.5, 27.1, 41.6, 52.0, 54.7, 66.3, 116.8,
121.3, 127.3, 129.0, 130.4, 153.7. Anal. Calcd for C13H18N2O:
C, 71.53; H, 8.31; N, 12.83. Found: C, 71.48; H, 8.28; N, 12.99.
C
21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 75.39; H,
6.67; N, 8.51.
(3S,8a R,14b S)-3-P h en yl-2,3,5,6,7,8-h exa h yd r o-14b H -
ch r om en o[4,3-b]p yr id o[2,1-c][1,4]oxa zin -14b-a m in e (6a ).
To a solution of imine 5a (0.9 g, 2.7 mmol) in THF (20 mL)
acidified with 1 N aq HCl (pH 3) was added portionwise
NaBH3CN (0.186 g, 2.9 mmol). The reaction mixture was
maintained at pH 3, refluxed for 4 h, neutralized at pH 7 with
saturated aq NaHCO3, and extracted with CH2Cl2. The organic
layers were dried over MgSO4 and concentrated. The crude
product was purified by flash chromatography (SiO2; petroleum
ether/AcOEt, 7:3) to give 6a in 80% yield (0.72 g) as a white
foam: [R]20 ) -7 (c 1.0, CHCl3); IR (film) 3540-3113 cm-1
;
D
MS (IS) m/z 337.5 (M + 1)+, 320.0 (M - NH2)+; 1H NMR
(CDCl3) δ 1.50-1.80 (m, 6H), 2.30 (td, 1H, J ) 11.9 Hz, J ′ )
3.7 Hz), 2.56 (dt, 1H, J ) 11.9 Hz, J ′ ) 3.7 Hz), 2.60 (br s,
2H), 3.58-3.70 (m, 1H), 3.87-3.99 (m, 2H), 4.62 (d, 1H, J )
10.7 Hz), 4.95 (d, 1H, J ) 10.7 Hz), 6.83 (dd, 1H, J ) 8.0 Hz,
J ′ ) 0.9 Hz), 6.95 (td, 1H, J ) 8.0 Hz, J ′ ) 0.9 Hz), 7.28-7.38
(m, 5H), 7.21 (td, 1H, J ) 8.0 Hz, J ′ ) 0.9 Hz), 7.43 (dd, 1H,
J ) 8.0 Hz, J ′ ) 0.9 Hz); 13C NMR (CDCl3) δ 20.7, 26.0, 27.9,
45.8, 56.3, 60.0, 61.0, 66.4, 82.7, 116.9, 121.3, 125.6, 125.8,
127.9, 128.8, 129.7, 140.3, 152.4. Anal. Calcd for C21H24N2O2:
C, 74.97; H, 7.19; N, 8.33. Found: C, 75.03; H, 7.15; N, 8.45.
(3S,8a R,14b S)-3-P h en yl-2,3,5,6,7,8-h exa h yd r o-14b H -
ch r om en o[4,3-b]p yr id o[2,1-c][1,4]oxa zin -14b-ol (7a ). Re-
duction of 5a , in the manner described for the preparation of
6a , but using MeOH as solvent and 36 h for the reflux, affords
(3′S,4′R)-4′-Hyd r oxy-3′,4′-d ih yd r osp ir o[p ip er id in e-2,3′-
(2′H)-ben zop yr a n ] (11a ). Following the same procedure as
for product 10a , hydrogenolysis of 9a (0.50 g, 1.5 mmol)
afforded 11a (0.31 g, 97%) as a white solid: mp 122-123 °C;
7a in 84% yield: white foam; [R]20 ) -24 (c 1.0, CHCl3); IR
D
(film) 3524 cm-1; MS (IS) m/z 338 (M + 1)+, 320 (M - OH)+;
1H NMR (CDCl3) δ 1.40-1.83 (m, 7H), 2.28 (td, 1H, J ) 12.2
Hz, J ′ ) 3.3 Hz), 2.56-2.62 (m, 1H), 3.61-3.73 (m, 1H), 3.91-
4.03 (m, 2H), 4.44 (s, 1H), 4.62 (d, 1H, J ) 10.6 Hz), 4.96 (dd,
1H, J ) 10.6 Hz, J ′ ) 1.2 Hz), 6.81 (dd, 1H, J ) 7.6 Hz, J ′ )
0.9 Hz), 6.96 (td, 1H, J ) 7.6 Hz, J ′ ) 0.9 Hz), 7.16-7.49 (m,
6H), 7.63 (dd, 1H, J ) 7.6 Hz, J ′ ) 0.9 Hz); 13C NMR (CDCl3)
δ 20.5, 25.8, 27.5, 45.6, 56.5, 60.6, 60.8, 66.5, 92.9, 116.3, 121.1,
[R]20 ) -37 (c 1.0, CHCl3); IR (KBr) 3354, 3328-3003 cm-1
;
D
MS (IS) m/z 220 (M + 1)+, 202 (M - OH)+; H NMR (CDCl3)
δ 1.54-1.78 (m, 6H), 2.84-2.92 (m, 1H), 3.18-3.23 (m, 1H),
4.29 (d, 1H, J ) 11.6 Hz), 4.35 (d, 1H, J ) 11.6 Hz), 4.99 (s,
1H), 6.16 (br s, 2H), 6.79 (d, 1H, J ) 7.9 Hz), 6.94 (t, 1H, J )
1
7.9 Hz), 7.18 (t, 1H, J ) 7.9 Hz), 7.39 (d, 1H, J ) 7.9 Hz); 13
C
NMR (CDCl3) δ 18.6, 23.3, 23.6, 40.8, 55.2, 64.9, 69.0, 116.2,
121.7, 122.7, 129.2, 129.5, 152.9. Anal. Calcd for C13H17NO3:
C, 71.21; H, 7.81; N, 6.39. Found: C, 71.25; H, 7.79; N, 6.48.
124.0, 126.3, 128.1, 130.1, 139.4, 152.6. Anal. Calcd for C21H23
-
NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.81; H, 6.84; N,
4.30.
(3′S,4′R)-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-4′-a m in o-3′,4′-
d ih yd r osp ir o[p ip er id in e-2,3′(2′H)-ben zop yr a n ] (8a ). To a
suspension of LiAlH4 (0.485 mg, 12.8 mmol) and AlCl3 (1.7 g,
(3′S)-3′,4′-Dih yd r osp ir o[p ip er id in e-2,3′(2′H)-ben zop y-
r a n ] ((S)-12a ). The diamine 10a (0.1 g, 0.46 mmol) was
dissolved in a refluxing mixture of EtOH/NaOH (10%, 1:1, 4
mL). NH2OSO3H (1.0 g, 9.16 mmol) was added portionwise
over 30 min. After 3 h of stirring, the reaction was extracted
J . Org. Chem, Vol. 68, No. 4, 2003 1405

Pave´ et al.
with CH2Cl2 and dried over MgSO4. The crude product was
purified by flash chromatography (SiO2; CH2Cl2/MeOH, 98:2)
to furnish amine (S)-12a (0.024 mg, 26%) as a colorless oil:
g, 78%) was isolated as a green oil: [R]20 ) -8 (c 1.0, CHCl3);
D
IR (film) 3401-3088 cm-1; MS (IS) 336.5 (M + 1)+; H NMR
1
(CDCl3) δ 0.27 (s, 3H), 0.29 (s, 3H), 0.99 (s, 9H), 1.52-1.98
(m, 6H), 3.14-3.39 (m, 4H), 3.45 (d, 1H, J ) 12.5 Hz), 3.79 (d,
1H, J ) 12.5 Hz), 5.97 (br s, 2H), 6.84 (dd, 1H, J ) 7.9 Hz, J ′
) 1.2 Hz), 6.92 (td, 1H, J ) 7.9 Hz, J ′ ) 1.2 Hz), 7.13 (td, 1H,
J ) 7.9 Hz, J ′ ) 1.2 Hz), 7.29 (dd, 1H, J ) 7.9 Hz, J ′ ) 1.2
Hz); 13C NMR (CDCl3) δ -3.6, -3.5, 18.6, 18.7, 22.6, 26.2, 27.1,
30.0, 40.3, 61.5, 64.0, 119.7, 121.8, 125.4, 128.3, 132.7, 154.3.
Anal. Calcd for C19H33NO2Si: C, 68.01; H, 9.91; N, 4.17.
Found: C, 67.94; H, 9.87; N, 4.23.
[R]20 ) -37 (c 1.0, CHCl3); IR (film) 3684-3035 cm-1; MS
D
(IS) m/z 204 (M + 1)+; 1H NMR (CDCl3) δ 1.48-1.78 (m, 6H),
2.71 (d, 1H, J ) 16.4 Hz), 2.79-2.85 (m, 3H), 3.85 (d, 1H, J )
10.9 Hz), 4.09 (dd, 1H, J ) 10.9 Hz, J ′ ) 2.1 Hz), 6.81-6.89
(m, 2H), 7.02-7.13 (m, 2H); 13C NMR (CDCl3) δ 20.4, 26.4,
33.0, 36.6, 41.1, 48.4, 71.5, 116.5, 120.5, 120.9, 127.5, 130.6,
153.9. Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89.
Found: C, 76.74; H, 8.38; N, 6.93.
Red u ction of Am in o Alcoh ol 11a to Am in e (S)-12a . To
a suspension of the amino alcohol 11a (0.1 g, 0.4 mmol) and
NaBH4 (0.14 g, 4 mmol) in CH2Cl2 was added dropwise over
30 min 2 mL of TFA. The mixture was refluxed for 42 h and
then hydrolyzed by a solution of saturated K2CO3. Extraction
and flash chromatography (SiO2; CH2Cl2/MeOH, 98:2) gave
amine (S)-12a (0.06 g, 65%) with the same characteristics as
described above.
ter t-Bu tyl (2R)-2-(2-ter t-Bu tyld im eth ylsilyloxyben zyl)-
2-(h yd r oxym et h yl)t et r a h yd r o-1(2H )-p yr id in eca r b oxy-
la te (18). To a solution of amino alcohol 17 (0.152 g, 0.45
mmol) in CH2Cl2 (4 mL) in the presence of Et3N (0.13 mL, 0.90
mmol) was added 0.153 g (0.68 mmol) of Boc2O. The solution
was stirred for 72 h, then hydrolyzed, extracted by CH2Cl2,
and dried over MgSO4. Purification was achieved by flash
chromatography (SiO2; CH2Cl2/MeOH, 98:2) to furnish 18
(0.163 g, 83%) as a colorless oil: [R]20 ) +26 (c 1.0, CHCl3);
D
(4R,9aR)-9a-(2-ter t-Bu tyldim eth ylsiloxyben zyl)-4-ph en -
ylh exa h yd r op yr id o[2,1-c][1,4]oxa zin -1(6H)-on e (15). To a
solution of lactone 13 (0.51 g, 2.2 mmol) in 50 mL of THF at
-78 °C was added an LDA solution (2.2 mL, 4.4 mmol). After
30 min of stirring, HMPA (1.0 mL, 4.4 mmol) and then 2-(tert-
butyldimethylsiloxy)benzyl bromide (14) (1.55 g, 4.4 mmol) in
THF were added dropwise. The mixture was stirred for 3 h
and then hydrolyzed by a saturated aq NH4Cl solution. The
reaction was extracted with CH2Cl2, and the organic layers
were washed with water, dried over MgSO4, and evaporated.
The residue was purified by flash chromatography (SiO2;
petroleum ether/AcOEt, 98:2) to give 15 (colorless oil, 0.44 g,
IR (film) 3405-3105, 1736 cm-1; MS (IS) m/z 436.5 (M + 1)+;
1H NMR (CDCl3) δ 0.22 (s, 3H), 0.23 (s, 3H), 1.01 (s, 9H), 1.41
(s, 9H), 1.52-1.98 (m, 6H), 2.88-3.12 (m, 3H), 3.55 (dd, 1H, J
) 12.2 Hz, J ′ ) 7.0 Hz), 3.93-4.04 (m, 2H), 4.22 (br s, 1H),
6.79 (dd, 1H, J ) 7.6 Hz, J ′ ) 1.2 Hz), 6.83 (td, 1H, J ) 7.6
Hz, J ′ ) 1.2 Hz), 7.04 (dd, 1H, J ) 7.6 Hz, J ′ ) 1.2 Hz), 7.13
(dd, 1H, J ) 7.6 Hz, J ′ ) 1.2 Hz); 13C NMR (CDCl3) δ -3.9,
-3.8, 18.5, 18.9, 24.6, 26.1, 27.8, 28.6, 30.1, 32.7, 42.5, 63.8,
69.6, 80.2, 118.8, 121.3, 127.3, 128.4, 131.7, 154.3, 156.6. Anal.
Calcd for C24H41NO4Si: C, 66.16; H, 9.49; N, 3.21. Found: C,
66.45; H, 9.60; N, 3.25.
44%): [R]20 ) -61 (c 1.0, CHCl3); IR (film) 1731 cm-1; MS
ter t-Bu tyl (2R)-2-(2-Hyd r oxyben zyl)-2-(h yd r oxym eth -
yl)tetr a h yd r o-1(2H)-p yr id in eca r boxyla te (19). To a solu-
tion of alcohol 18 (0.2 g, 0.46 mmol) in CH2Cl2 (8 mL) was
added 0.92 mL (0.92 mmol) of a 1 M solution of Bu4NF in THF.
The solution was stirred for 4 h, then hydrolyzed, extracted
by CH2Cl2, and dried over MgSO4. Flash chromatography
(SiO2, CH2Cl2) gave diol 18 as a colorless oil (0.117 g, 80%):
D
(IS) m/z 452.5 (M + 1)+; H NMR (CDCl3) δ 0.25 (s, 3H), 0.26
1
(s, 3H), 1.01 (s, 9H), 1.40-1.85 (m, 6H), 2.41-2.49 (m, 1H),
2.65-2.76 (m, 1H), 3.18 (d, 1H, J ) 13.7 Hz), 3.56 (d, 1H, J )
13.7 Hz), 4.12 (dd, 1H, J ) 8.8 Hz, J ′ ) 3.6 Hz), 4.26-4.37 (m,
2H), 6.81-6.88 (m, 2H), 7.09-7.37 (m, 7H); 13C NMR (CDCl3)
δ -3.8, -3.4, 18.7, 22.3, 26.1, 26.9, 34.6, 38.3, 49.4, 64.2, 66.7,
74.8, 111.8, 120.2, 126.4, 126.7, 127.1, 127.5, 127.6, 129.7,
143.9, 158.5, 171.7. Anal. Calcd for C27H37NO3Si: C, 71.80;
H, 8.26; N, 3.10. Found: C, 71.98; H, 8.45; N, 3.15.
[R]20 ) +40 (c 1.0, CHCl3); IR (film) 3644-3105, 1756 cm-1
;
D
MS (IS) m/z 322 (M + 1)+; 1H NMR (CDCl3) δ 1.47 (s, 9H),
1.45-1.85 (m, 6H), 2.87 (d, 1H, J ) 14.0 Hz), 3.01-3.12 (m,
1H), 3.19 (dd, 1H, J ) 13.1 Hz, J ′ ) 11.3 Hz), 3.28 (d, 1H, J )
14.0 Hz), 3.77 (d, 1H, J ) 13.1 Hz), 4.04-4.11 (m, 1H), 6.79
(td, 1H, J ) 7.9 Hz, J ′ ) 1.2 Hz), 6.91 (dd, 1H, J ) 7.9 Hz, J ′
) 1.2 Hz), 7.09-7.17 (m, 2H), 7.88 (dd, 1H, J ) 11.3 Hz, J ′ )
1.8 Hz), 10.08 (s, 1H); 13C NMR (CDCl3) δ 20.1, 24.8, 28.5, 30.0,
31.1, 43.1, 63.7, 68.3, 81.5, 118.6, 119.6, 122.8, 128.6, 132.6,
156.8, 157.4. Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N,
4.36. Found: C, 67.48; H, 8.62; N, 4.41.
(2R)-2-[(2R)-2-(2-ter t-Bu tyld im eth ylsilyloxyben zyl)-2-
(h yd r oxym eth yl)tetr a h yd r o-1(2H)-p yr id in yl]-2-p h en yl-
1-eth a n ol (16). To a suspension of LiAlH4 (0.240 mg, 6.2
mmol) in Et2O (10 mL) at -10 °C was added a solution of
lactone 15 (0.56 g, 1.24 mmol) in Et2O (10 mL). The reaction
mixture was stirred for 3 h at rt. A solution of NaOH (10%)
(0.25 mL) was added, followed by addition of water (0.5 mL).
After being stirred for 4 h, the mixture was filtrated through
a Celite pad and concentrated. The crude product was purified
by flash chromatography (SiO2; CH2Cl2/MeOH, 95:5), affording
ter t-Bu tyl (3′R)-3′,4′-Dih yd r osp ir o[p ip er id in e-2,3′(2′H)-
ben zop yr a n ]ca r boxyla te (20). To a solution of diol 19 (0.055
g, 0.17 mmol) in dry toluene (5 mL) were added successively
Ph3P (0.055 g, 0.19 mmol) and DEAD (0.035 mL, 0.19 mmol).
After the solution was stirred at reflux for 18 h, the solvent
was evaporated, and the crude product was purified by flash
chromatography (SiO2; petroleum ether/AcOEt, 95:5) to furnish
benzopyran 20 (0.045 g, 85%) as a white solid: mp 75-77 °C;
16 (0.55 g, 98%) as a white foam: [R]20 ) -48 (c 1.0, CHCl3);
D
IR (film) 3688-3028 cm-1; MS (IS) m/z 456.5 (M + 1)+; 1H
NMR (CDCl3) δ 0.22 (s, 3H), 0.32 (s, 3H), 1.02 (s, 9H), 1.41-
1.84 (m, 6H), 2.82 (d, 1H, J ) 13.4 Hz), 2.83-2.89 (m, 1H),
2.91 (d, 1H, J ) 13.4 Hz), 3.19-3.23 (m, 1H), 3.68 (dd, 1H, J
) 10.6 Hz, J ′ ) 4.9 Hz), 3.72 (d, 1H, J ) 12.2 Hz), 3.92 (d, 1H,
J ) 12.2 Hz), 4.00 (t, 1H, J ) 10.6 Hz), 4.28 (br s, 2H), 4.85
(dd, 1H, J ) 10.6 Hz, J ′ ) 4.9 Hz), 6.84-6.94 (m, 2H), 7.08-
7.23 (m, 2H), 7.30-7.53 (m, 5H); 13C NMR (CDCl3) δ -3.8,
-3.4, 18.7, 20.9, 26.2, 27.2, 30.7, 31.5, 41.3, 61.0, 62.6, 62.7,
66.3, 119.4, 121.2, 127.1, 127.3, 128.3, 128.9, 129.2, 132.4,
140.3, 153.9. Anal. Calcd for C27H41NO3Si: C, 71.16; H, 9.07;
N, 3.07. Found: C, 71.23; H, 9.09; N, 3.11.
[R]20 ) -44 (c 1.0, CHCl3); IR (KBr) 1695 cm-1; MS (IS) m/ z
D
304 (M + 1)+; H NMR (CDCl3) δ 1.43 (s, 9H), 1.44-1.78 (m,
1
6H), 2.88 (dd, 1H, J ) 16.0 Hz, J ′ ) 2.2 Hz), 3.31-3.41 (m,
1H), 3.57 (d, 1H, J ) 16.2 Hz), 3.69-3.78 (m, 1H), 4.07 (dd,
1H, J ) 10.7 Hz, J ′ ) 2.5 Hz), 4.78 (d, 1H, J ) 10.7 Hz), 6.79-
6.89 (m, 2H), 7.02-7.11 (m, 2H); 13C NMR (CDCl3) δ 17.9, 23.9,
28.6, 29.8, 33.6, 41.6, 54.9, 70.8, 80.2, 116.6, 120.8, 121.7, 127.2,
130.2, 153.6, 155.5. Anal. Calcd for C18H25NO3: C, 71.26; H,
8.31; N, 4.62. Found: C, 71.19; H, 8.26; N, 4.65.
[(2R)-2-(2-ter t-Bu tyldim eth ylsilyloxyben zyl)h exah ydr o-
2-p yr id in yl]m eth a n ol (17). Hydrogenolysis of compound 16
(0.35 g, 0.77 mmol) in MeOH (15 mL) in the presence of 2 drops
of HCl (37%) and 10% Pd/C (40 mg) for 1 h afforded a
compound which, after filtration and concentration, was
disolved in CH2Cl2 and washed by a saturated aq solution of
K2CO3. The purification was performed by flash chromatog-
raphy (SiO2; CH2Cl2/MeOH, 95:5). The amino alcohol 17 (0.20
(3′R)-3′,4′-Dih yd r osp ir o[p ip er id in e-2,3′(2′H)-ben zop y-
r a n ] ((R)-12a ). To a solution of protected amine 20 (0.1 g, 0.33
mmol) in CH2Cl2 was added TFA (0.31 mL, 3.96 mmol), and
the mixture was stirred for 18 h. A saturated aq solution of
K2CO3 was then added, and the product was extracted by CH2-
Cl2 and dried over MgSO4. After concentration under reduced
1406 J . Org. Chem., Vol. 68, No. 4, 2003

Synthesis of Spirocyclic Aminochroman Derivatives
pressure, purification was performed by flash chromatography
(SiO2; CH2Cl2/MeOH, 98:2) to give amine (R)-12a (0.048 g,
72%) with the same characteristics as described for (S)-12a :
solid in 57% yield: mp 104-105 °C; [R]20 ) -116 (c 1.0,
D
CHCl3); IR (KBr) 2200 cm-1; MS (IS) m/z 443.5 (M + 1,
-
79
1
Br)+, 445.5 (M + 1, 81Br)+; H NMR (CDCl3) δ 1.61-2.48 (m,
6H), 3.36 (d, 1H, J ) 8.9 Hz), 3.71 (d, 1H, J ) 8.9 Hz), 3.75-
3.82 (m, 2H), 3.85 (s, 3H), 4,15 (dd, 1H, J ) 8.5 Hz, J ′ ) 4.9
Hz), 4.24 (dd, 1H, J ) 9.7 Hz, J ′ ) 2.1 Hz), 4.27 (t, 1H, J )
8.5 Hz), 5.59 (d, 1H, J ) 8.2 Hz), 6.49 (d, 1H, J ) 8.2 Hz),
6.96 (t, 1H, J ) 8.2 Hz), 7.17-7.48 (m, 5H); 13C NMR (CDCl3)
δ 18.6, 28.5, 32.3, 55.4, 60.9, 61.4, 71.3, 73.5, 90.8, 100.4, 103.7,
104.2, 116.0, 126.2, 126.8, 127.0, 127.7, 141.5, 154.0, 156.1.
[R]20 ) +37 (c 1.0, CHCl3).
D
1-Meth oxy-3-(m eth oxym eth oxy)ben zen e (21). To a so-
lution of 3-methoxyphenol (10 g, 80.5 mmol) in CH3CN (250
mL) was added under nitrogen at 0 °C dry K2CO3 (22 g, 161.0
mmol). After 15 min, 18-crown-6 (3 g, 21.7 mmol) and MOMCl
(7 mL, 92.2 mmol) were added. The mixture was stirred for
18 h at rt and then filtrated. The filtrate was evaporated under
reduced pressure and purified by flash chromatography (SiO2;
petroleum ether/AcOEt, 98:2), giving 21 as a colorless oil (11.3
(2R)-2-[(1S,12S)-5-Meth oxy-10-oxa-2,16-diazatetr acyclo-
[10.3.1.03,12.04,9]h exa d eca -2,4(9),5,7-tetr a en -16-yl]-2-p h en -
yl-1-eth a n ol (5b). Imine 5b was prepared from 4b (3.47 g,
7.8 mmol) in 84% yield as described for 5a to yield an
1
g, 83%): IR (film) 1283 cm-1; MS (IS) m/z 169 (M + 1)+; H
NMR (CDCl3) δ 3.47 (s, 3H), 3.78 (s, 3H), 5.15 (s, 2H), 6.56-
6.64 (m, 3H), 7.20 (t, 1H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 55.2,
55.9, 94.4, 102.6, 107.4, 108.3, 129.8, 158.4, 160.7.
amorphous white solid: mp 171-172 °C; [R]20 ) -40 (c 1.0,
D
CHCl3); IR (KBr) 3614-3002 cm-1; MS (IS) 365.5 (M + 1)+;
1H NMR (CDCl3) δ 1.34-1.87 (m, 7H), 3.72 (dd, 1H, J ) 10.9
Hz, J ′ ) 3.6 Hz), 3.79 (dd, 1H, J ) 10.9 Hz, J ′ ) 3.6 Hz), 3.91-
4.05 (m, 4H), 3.96 (s, 3H), 5.23 (t, 1H, J ) 2.1 Hz), 6.53 (d,
1H, J ) 7.6 Hz), 6,57 (d, 1H, J ) 7.6 Hz), 7.25-7.4 (m, 6H);
13C NMR (CDCl3) δ 16.4, 21.2, 21.6, 56.0, 61.3, 65.4, 66.5, 72.2,
83.2, 103.5, 109.5, 126.9, 127.6, 128.1, 128.4, 132.9, 140.3,
158.6, 160.0, 165.2.
2-Br om o-1-m eth oxy-3-(m eth oxym eth oxy)ben zen e (22).
To a solution of 21 (2 g, 11.9 mmol) in Et2O (40 mL) was added
dropwise n-BuLi (1.6 M in hexane, 8.8 mL, 14.3 mmol), and
the resulting solution was refluxed for 2 h. After the solution
was cooled at rt, 4.64 g (14.3 mmol) of Br2C2Cl4 was added in
portions, and the resulting mixture was stirred for 15 min.
The mixture was hydrolyzed and extracted by AcOEt. The
organic layers were dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography (SiO2; petroleum ether/AcOEt, 95:5) to furnish 22 as
a yellow oil (87%, 2.57 g): IR (film) 1258 cm-1; MS (IS) m/z
247 (M + 1, 79Br)+, 249 (M + 1, 81Br)+; 1H NMR (CDCl3) δ
3.52 (s, 3H), 3.90 (s, 3H), 5.25 (s, 2H), 6.61 (d, 1H, J ) 8.4
Hz), 6.80 (d, 1H, J ) 8.4 Hz), 7.21 (t, 1H, J ) 8.4 Hz); 13C
NMR (CDCl3) δ 56.4, 95.1, 102.4, 105.6, 108.5, 128.2, 155.0,
157.2.
2-Br om o-3-m eth oxyp h en ol (23). Compound 22 (5.94 g,
24 mmol) and 3 N HCl (50 mL) in THF (35 mL) were stirred
24 h at rt. A saturated solution of NaHCO3 was then added,
and the resulting solution was extracted by CH2Cl2 and dried
over MgSO4 before concentration. Purification by flash chro-
matography (SiO2; petroleum ether/AcOEt, 95:5) gave 3.6 g of
a tan solid (74%): mp 79-80 °C; IR (KBr) 3400 cm-1; MS m/z
(IS) 204 (M + 1)+; 1H NMR (CDCl3) δ 3.89 (s, 3H), 5.62 (s,
1H), 6.48 (d, 1H, J ) 8.3 Hz), 6.68 (d, 1H, J ) 8.3 Hz), 7.17 (t,
1H, J ) 8.3 Hz); 13C NMR (CDCl3) δ 56.3, 100.0, 103.6, 108.5,
128.6, 153.6, 156.5.
(3S,8a R,14bS)-5-Meth oxy-3-p h en yl-2,3,5,6,7,8-h exa h y-
d r o-14bH -ch r om en o[4,3-b]p yr id o[2,1-c][1,4]oxa zin -14b -
ol (7b). Reduction of 5b (0.94 g, 2.56 mmol) in the manner
described for the preparation of 7a afforded 7b in 96% yield:
amorphous white solid; mp 179-180 °C; [R]20 ) +2.5 (c 1.0,
D
CHCl3); IR (KBr) 3469 cm-1; MS (IS) m/z 368 (M + 1)+, 350
(M - OH)+; 1H NMR (CDCl3) δ 1.50-1.92 (m, 6H), 2.26-2.37
(m, 1H), 2.50-2.56 (m, 1H), 3.55 (dd, 1H, J ) 11.0 Hz, J ′ )
3.8 Hz), 3.92 (s, 3H), 3.93 (dd, 1H, J ) 11.0 Hz, J ′ ) 3.8 Hz),
4.28 (t, 1H, J ) 11.0 Hz), 4.66 (d, 1H, J ) 10.7 Hz), 4.79 (d,
1H, J ) 10.7 Hz), 5.89 (s, 1H), 6.51 (d, 2H, J ) 7.9 Hz), 7.14
(t, 1H, J ) 7.9 Hz), 7.21-7.39 (m, 5H); 13C NMR (CDCl3) δ
20.3, 25.4, 26.4, 44.8, 55.7, 55.9, 60.0, 60.4, 66.1, 94.6, 103.5,
110.3, 113.2, 127.3, 128.2, 129.4, 139.9, 154.3, 158.2.
(3′S,4′R)-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-4′-h yd oxy-5′-
m eth oxy-3′,4′-d ih ydr ospir o[p ip er idin e-2,3′(2′H)-ben zop y-
r a n ] (9b). Following the same procedure described for product
9a , 9b (1.07 g, 2.9 mmol) was reduced with a suspension of
LiAlH4 (0.50 mg, 13.1 mmol) in Et2O (15 mL) at 0 °C to furnish
9b (0.95 g) in 89% yield as an amorphous white solid: mp 70-
72 °C; [R]20 ) -91 (c 1.0, CHCl3); IR (KBr) 3588-3106 cm-1
;
2-B r o m o -1-m e t h o x y -3-[(m e t h y lt h io )m e t h o x y ]b e n -
zen e (24). Under nitrogen, 3.6 g (17.7 mmol) of phenol 23,
NaI (2.66 g, 17.7 mmol), and chloromethyl methyl sulfide (2.0
mL, 19.5 mmol) were added successively to a suspension of
NaH (60% in mineral oil, 1.42 g, 35.4 mmol) in DME (30 mL)
at 0 °C. The mixture was stirred at rt for 4 h, hydrolyzed, and
extracted by AcOEt. The organic layer was dried over MgSO4
and concentrated. The crude product was purified by flash
chromatography (SiO2; petroleum ether/AcOEt, 98:2) to give
24 as a yellow oil (3.3 g, 71%): IR (film) 1235 cm-1; MS (IS)
D
MS (IS) m/z 370 (M + 1)+, 352.0 (M - OH)+; 1H NMR (CDCl3)
δ 1.11-1.92 (m, 7H), 2.74-2.84 (m, 1H), 2.94-3.05 (m, 1H),
3.39 (sl, 1H), 3.43 (dd, 1H, J ) 10.3 Hz, J ′ ) 4.6 Hz), 3.88 (t,
1H, J ) 10.3 Hz), 3.89 (s, 3H), 4.09-4.20 (m, 2H), 4.51 (dd,
1H, J ) 10.3 Hz, J ′ ) 4.6 Hz), 6.49 (d, 1H, J ) 7.6 Hz), 6.53
(d, 1H, J ) 7.6 Hz), 7.15 (t, 1H, J ) 7.6 Hz), 7.27-7.39 (m,
5H); 13C NMR (CDCl3) δ 19.9, 24.8, 25.6, 40.4, 55.7, 26.9, 60.4,
61.2, 62.4, 66.2, 102.8, 109.9, 113.0, 127.8, 128.6, 129.0, 129.2,
140.0, 154.6, 159.3.
1
m/z 286 (M + Na)+; H NMR (CDCl3) δ 2.28 (s, 3H), 3.88 (s,
(3′S,4′R)-4′-Hyd oxy-5′-m eth oxy-3′,4′-d ih yd r osp ir o[p ip -
er id in e-2,3′(2′H)-ben zop yr a n ] (11b). Hydrogenolysis of com-
pound 9b (0.95 g, 2.6 mmol) was performed in MeOH (30 mL)
in the presence of 2 drops of HCl (37%) and 10% Pd/C (100
mg) for 4 h. After filtration and concentration, the residue was
dissolved in CH2Cl2 and washed by a saturated aq solution of
K2CO3. The purification was performed by flash chromatog-
raphy (SiO2; CH2Cl2/MeOH, 98:2) and afforded amino alcohol
3H), 5.22 (s, 2H), 6.59-6.64 (m, 2H), 7.21 (t, 1H, J ) 8.5 Hz);
13C NMR (CDCl3) δ 15.1, 56.8, 73.8, 103.4, 106.0, 108.4, 155.0,
157.7.
2-Br om o-1-(ch lor om eth oxy)-3-m eth oxyben zen e (3b).
To a solution of 24 (2.5 g, 0.95 mmol) in CH2Cl2 (35 mL) at
-78 °C was added dropwise SO2Cl2 (0.79 mL, 0.95 mmol) in
25 mL of CH2Cl2. After 1 h at -78 °C, CH2Cl2 was evaporated,
and the residue was crystallized in pentane to furnish 3b as
11b (0.58 g, 91%) as a white solid: mp 181-182°C; [R]20
)
D
-119 (c 1.0, CHCl3); IR (KBr) 3347, 3307-3003 cm-1; MS (IS)
a white solid (1.45 g, 61%): mp 57-58 °C; IR (KBr) 1240 cm-1
;
1
m/z 250 (M + 1)+, 232 (M - OH)+; H NMR (CDCl3) δ 1.55-
1H NMR (CDCl3) δ 3.91 (s, 3H), 5.92 (s, 2H), 6.70 (d, 1H, J )
8.5 Hz), 6.88 (d, 1H, J ) 8.5 Hz), 7.28 (t, 1H, J ) 8.5 Hz); 13
C
1.98 (m, 6H), 2.90-2.98 (m, 2H), 3.84 (s, 3H), 3.97 (d, 1H, J )
11.2 Hz), 4.18 (d, 1H, J ) 11.2 Hz), 4.89 (br s, 1H), 6.48 (d,
1H, J ) 11.6 Hz), 6.51 (d, 1H, J ) 11.6 Hz), 7.16 (t, 1H, J )
11.6 Hz); 13C NMR (CDCl3) δ 19.6, 24.9, 26.8, 41.1, 53.2, 55.7,
63.0, 66.1, 103.0, 109.9, 111.7, 129.9, 154.3, 159.4.
(3′S)-5′-Meth oxy-3′,4′-dih ydr ospir o[piper idin e-2,3′(2′H)-
ben zop yr a n ] ((S)-12b). Following the same procedure as
described for product (S)-12a , 11b (0.08 g, 0.3 mmol) was
NMR (CDCl3) δ 56.9, 74.4, 108.0, 110.3, 111.8, 128.8, 156.7,
160.4.
(3R,5S,8a R)-5-[(2-Br om o-3-m eth oxyp h en oxy)m eth yl]-
3-ph en ylh exah ydr o-5H-[1,3]oxazolo[3,2-a ]pyr idin e-5-car -
bon itr ile (4b). Alkylation of 3.16 g (13.8 mmol) of (-)-2 by
the bromo derivative 3b (7 g, 27.7 mmol) in the manner
described for the preparation of 4a afforded 4b as a yellow
J . Org. Chem, Vol. 68, No. 4, 2003 1407

Pave´ et al.
reduced with a suspension of NaBH4 (0.113 g, 3.1 mmol) in
49.3, 53.1, 70.8, 116.5, 120.7, 122.2, 127.1, 130.4, 154.1, 172.3.
Anal. Calcd for C26H36N2O3: C, 73.55; H, 8.55; N, 6.60.
Found: C, 73.48; H, 8.52; N, 6.67.
TFA (2 mL) and CH2Cl2 at 0 °C for 1.5 h to furnish (S)-12b
(0.069 g, 92%) as a colorless oil: [R]20 ) -46 (c 0.5, CHCl3);
D
IR (film) 3740-3040 cm-1; MS (IS) m/z 234 (M + 1)+; 1H NMR
(CDCl3) δ 1.61-1.78 (m, 6H), 2.66 (d, 1H, J ) 17.3 Hz), 2.92
(d, 1H, J ) 17.3 Hz), 2.92-3.05 (m, 2H), 3.80 (s, 3H), 3.89 (d,
1H, J ) 11.0 Hz), 4.11 (d, 1H, J ) 11.0 Hz), 5.37 (br s, 1H),
6.44 (d, 1H, J ) 8.5 Hz) 6.48 (d, 1H, J ) 8.5 Hz), 7.07 (t, 1H,
J ) 8.5 Hz); 13C NMR (CDCl3) δ 20.3, 26.5, 30.6, 33.3, 41.1,
48.0, 55.6, 71.7, 102.4, 109.3, 109.7, 127.1, 154.7, 158.7. Anal.
Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C,
72.02; H, 8.19; N, 6.07.
(3′S)-1-[4-(7,9-Dioxo-8-a za sp ir o[4.5]d eca n yl)b u t yl]-5′-
m eth oxo-3′,4′-d ih ydr ospir o[p ip er idin e-2,3′(2′H)-ben zop y-
r a n ] ((S)-1b). As described above, amine (S)-12b (0.05 g, 0.11
mmol) was alkylated by 8-(4-bromobutyl)-8-azaspiro[4.5]decane-
7,9-dione to furnish, after column chromatography (SiO2; CH2-
Cl2/MeOH, 95:5), (S)-1b as an oil (0.07 g) in 64% yield: [R]20
D
) +24 (c 1.3, CHCl3); IR (film) 1725 and 1673 cm-1; MS (IS)
m/z 455 (M + 1)+; 1H NMR (CDCl3) δ 1.34-1.78 (m, 18H),
2.31-2.39 (m, 1H), 2.46-2.2.56 (m, 1H), 2.57 (s, 4H), 2.60-
2.75 (m, 4H), 3.75 (t, 2H, J ) 7.3 Hz), 3.82 (s, 3H), 3.88 (d,
1H, J ) 10.3 Hz), 3.97 (d, 1H, J ) 10.3 Hz), 6.42 (d, 1H, J )
(3′S)-1-[4-(7,9-Dioxo-8-a za sp ir o[4.5]d eca n yl)bu tyl]-3′,4′-
d ih yd r osp ir o[p ip er id in e-2,3′(2′H)-ben zop yr a n ] ((S)-1a ).
To a solution of amine (S)-12a (0.05 g, 0.12 mmol) in dry CH3-
CN (3 mL) were added K2CO3 ( 0.084 g, 0.36 mmol), 8-(4-
bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (0.077 g, 0.17
mmol), and KI (catalytic amount), and the mixture was
refluxed for 18 h. After total consumption of starting material,
the mixture was hydrolyzed, and the crude product was
extracted with CH2Cl2 and dried over MgSO4. After column
chromatography (SiO2; CH2Cl2/MeOH, 95:5), (S)-1a was ob-
8.2 Hz), 6.74 (d, 1H, J ) 8.2 Hz), 7.04 (t, 1H, J ) 8.2 Hz); 13
C
NMR (CDCl3) δ 20.3, 24.2, 24.3, 25.5, 26.0, 27.2, 32.4, 37.6,
39.6, 45.0, 47.7, 49.4, 52.7, 55.5, 71.1, 102.1, 109.3, 111.1, 126.8,
128.7, 129.8, 154.9, 158.5, 172.3. Anal. Calcd for C27H38N2O4:
C, 71.34; H, 8.43; N, 6.16. Found: C, 71.37; H, 8.47; N, 6.23.
Ack n ow led gm en t. We are very grateful to Prof. M.
Dreux, Prof. P. Morin, and S. Zubrzycki (ICOA, Uni-
versite´ d’Orle´ans) for performing the capillary electro-
phoresis analyses.
tained as an oil (0.07 g) in 66% yield: [R]20 ) +34 (c 1.0,
D
CHCl3); IR (film) 1727 and 1682 cm-1; MS (IS) m/z 425.5 (M
1
+ 1)+; H NMR (CDCl3) δ 1.39-1.77 (m, 18H), 2.32-2.49 (m,
2H), 2.57 (s, 4H), 2.59-2.74 (m, 3H), 2.95 (d, 1H, J ) 16.4
Hz), 3.75 (t, 2H, J ) 7.3 Hz), 3.96 (dd, 1H, J ) 10.6 Hz, J ′ )
1.8 Hz), 4.02 (d, 1H, J ) 10.6 Hz), 6.79 (d, 1H, J ) 8.5 Hz),
6.86 (d, 1H, J ) 8.5 Hz), 7.04-7.09 (m, 2H).); 13C NMR (CDCl3)
δ 20.3, 24.3, 25.4, 25.9, 27.1, 30.4, 32.0, 37.6, 39.6, 45.0, 47.6,
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal struc-
ture data and ORTEP diagram of compound 9b. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O026228H
1408 J . Org. Chem., Vol. 68, No. 4, 2003