Synthesis of a Chiral Spiranic Aminochroman Derivative from L-Proline

Full text of DOI:10.1021/jo991089y

914
J . Org. Chem. 2000, 65, 914-917
Ch a r t 1
Syn th esis of a Ch ir a l Sp ir a n ic
Am in och r om a n Der iva tive fr om L-P r olin e
Ste´phanie Usse, Ge´rald Guillaumet, and
Marie-Claude Viaud*
Institut de Chimie Organique et Analytique associe´
au CNRS, Universite´ d’Orle´ans, B.P. 6759,
45067 Orleans Cedex 2, France
Sch em e 1
Received J uly 7, 1999
In tr od u ction
Serotonin or 5-hydroxytryptamine (5-HT) is a neu-
rotransmitter of the nervous central system1,2 and has a
strong influence at the physiological and pathophysi-
ological levels. It has been linked to various behavioral
problems involving memory, thermoregulation, sleep, and
sexual behavior, and it is also implicated in numerous
neuropsychiatry disorders such as anxiety, schizophrenia,
or Alzheimer’s disease.3-5 At first, only four mains types
of serotoninergic receptors were defined, i.e., the 5-HT1,
5-HT2, and 5-HT3 in 19866 and 5-HT4 in 1988.7 Recently,
three new classes of receptors, the 5-HT5, 5-HT6, and
5-HT7,8 were described. Among all of these classes, some
have been subdivided such as 5-HT1, which includes six
subtypes such as the 5-HT1A receptor.7
Sch em e 2
The synthesis of 5-HT1A agonists appear to be very
attractive due to their role in anxiety and depression
behavioral disorders. In our laboratory, previous work9,10
has led to new therapeutic agents that demonstrate very
good affinity and high selectivity for the 5-HT1A receptor.
Among them, the compound (+)-S 21552 (Chart 1) is a
good candidate for a clinical development.10
At the present time, only a racemic synthesis of this
3-aminochroman has been described. Each enantiomer
could be resolved using optically pure 1,1′-binaphthyl-
2,2′-diyl hydrogen phosphate as chiral agent for enan-
tioselective resolution.11 The high cost of resolving agent
prompted us to devise a chiral synthesis of this ami-
nochroman derivative using the commercially available
L-proline.
Resu lts a n d Discu ssion
* To whom correspondence should be addressed. Present address:
UFR Sciences Pharmaceutiques, Laboratoire Chimie Organique, 31
Avenue Monge, 37200 Tours, France. Tel: 33 247 36 72 27. Fax: 33
247 36 72 29. E-mail: mcviaud@univ-tours.fr.
(1) Glennon, R. A. J . Med. Chem. 1987, 30, 1-12.
(2) Fozard, J . R. Trends Pharmacol. Sci. 1987, 8, 44-45.
(3) J ohnston, A.; File, S. E. Pharmacol. Biochem. Behav. 1986, 24,
1457-1470.
The retrosynthetic pathway of this synthesis is il-
lustrated in Scheme 1. The first reaction, which is the
key step in our synthetic pathway, involves R-alkylation
of oxazolidinone 1 with 2-methoxy-6-methoxymethoxy-
benzaldehyde 212 using Seebach’s methodology.13
Treatment of oxazolidinone 1, prepared from L-pro-
line,13 with lithium diisopropylamide at -78 °C followed
by the addition of the benzaldehyde 2 at same temper-
ature gave a diastereosomeric mixture of alcohols 3 (ratio
3/1) in 72% yield (Scheme 2).
(4) Eison, M. S. Psychopathology 1984, 17, 37-44.
(5) Peroutka, S. J .; Snyder, S. H. J . Pharmacol. Exp. Ther. 1981,
216, 142-148.
(6) Saxena, P. R.; Ferrari, M. D. Trends Pharmacol. Sci. 1989, 10,
200-204.
(7) Clarke, D. E.; Craig, D. A.; Fozard, J . R. Trends Pharmacol. Sci.
1989, 10, 385-386.
The next step in our sequence focused on deoxygen-
ation of the hydroxyl group of 3. Our first attempt used
the Barton-McCombie reaction,14 which met with failure.
(8) Gerhardt, C. C.; Van Heerikhuizen, H. Eur. J . Pharmacology
1997, 334, 1-23.
(9) Podona, T.; Guardiola-Lemaˆıtre, B.; Caignard, D. H.; Adam, G.;
Pfeiffer, B.; Renard, P.; Guillaumet, G. J . Med. Chem. 1994, 37, 1779-
1793.
(10) 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,
4285-4298.
(11) J acques, J .; Fourquey, C.; Viterbo, R. Tetrahedron Lett. 1971,
48, 4617-4620.
(12) Narasimhan, N. S.; Mali, R. S.; Barve, M. V. Synthesis 1979,
906-909.
(13) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J . Am. Chem.
Soc. 1983, 105, 5390-5398.
(14) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
10.1021/jo991089y CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/10/2000

Notes
J . Org. Chem., Vol. 65, No. 3, 2000 915
Sch em e 3
Sch em e 4
Sch em e 5
The next approach involved replacement of the hydroxyl
group with iodide followed by reduction. The introduction
of iodide (Scheme 2) was achieved using Garreg’s meth-
odology15 by reacting compound 3 with triphenylphos-
phine, imidazole, and iodine in a mixture toluene/aceto-
nitrile at room temperature to furnish 4 in 75% yield.
Compound 4 was shown to be a diastereomeric mixture.
The removal of iodine proved to be very difficult, and
a number of reduction procedures were examined. Sev-
eral standard procedures using zinc in acetic acid or
lithium aluminum hydride in diethyl ether were unsuc-
cessful, and both led to degradation products. Likewise,
catalytic hydrogenation of 4 using Pd/C in methyl alcohol
quantitatively cleaved the MOM group and led to re-
placement of the iodo substituent with a methoxy group.
To avoid the formation of this compound, the hydrogena-
tion was carried out in dioxane but only degradation
products were obtained. Finally, the reduction of the
organic halide 4 was accomplished using samarium(II)
iodide16 in tetrahydrofuran in the presence of hexameth-
ylphosphoramide (Scheme 3) to afford the desired com-
pound 5 in 76% yield.
We explored several chemical procedures to hydrolyze
the oxazolidinone moiety of 5 and found that Amberlyst
XN-1010 in a mixture of hydrochloric acid and methyl
alcohol (Scheme 3) was one of the more promising. This
reaction mixture led to the corresponding methyl ester
6, as the main product, in 69% yield.
Finally, the best procedure for the hydrolysis of chiral
oxazolidinone 5 employed a suspension of silica gel in a
mixture of methyl alcohol and water according to the
conditions described by J ohnson et al.17 but instead under
reflux as depicted in Scheme 3. The amino acid 7 was
obtained in 97% yield.
The strategy we followed to complete the synthesis is
outlined in Scheme 4. Acid 7 was used as starting
material. The carboxylic acid function was first reduced
to the corresponding primary alcohol with borane-
tetrahydrofuran complex18 in tetrahydrofuran at room
temperature. To avoid the formation of aziridine, the
amino group was protected using di-tert-butyl dicarbon-
ate in anhydrous tetrahydrofuran at room temperature
to provide the expected compound 8 in 71% overall yield.
Cleavage of methoxymethoxy group occurred in methyl
alcohol either with hydrochloric acid or with Amberlyst
to give compound 9 in low or moderate yield, whereas
bromotrimethylsilane19 in methylene chloride at -30 °C
provided 9 in very good yield.
Scheme 5 illustrates the synthesis of final derivative
11, which was obtained in two steps from 9 in 98% yield.
Ring closure of 9 by the Mitsunobu reaction20 using
triphenylphosphine and diethyl azodicarboxylate in an-
hydrous diethyl ether at room temperature provided a
quantitative yield of the pyran 10, which in turn was
hydrolyzed with trifluoroacetic acid in methylene chloride
to furnish 11 in 98% yield.
The enantiomeric purity of the aminochroman 11 was
determined by capillary electrophoresis using anionic
sulfated-â-cyclodextrins as chiral selector.21 An alterna-
tive route used chiral high-performance liquid chroma-
tography (Chiralpak). In these two cases, we obtained
the desired enantiomer with an enantiomeric excess of
99.7%.
(18) Kimura, T.; Takase, Y.; Hayashi, K.; Tanaka, H.; Ohtsuka, I.;
Saeki, T.; Kogushi, M.; Yamada, T.; Fujimori, T.; Saitou, I.; Akasaka,
K. J . Med. Chem. 1993, 36, 1630-1640.
(15) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Chem. Commun.
1979, 979-980.
(19) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett.
1984, 25, 2515-2518.
(16) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485-1486.
(20) Mitsunobu, O. Synthesis 1981, 1-28.
(17) Genin, M. J .; Baures, P. W.; J ohnson, R. L. Tetrahedron Lett.
1994, 35, 4967-4968.
(21) Morin, P.; Dreux, M.; Usse, S.; Viaud, M. C.; Guillaumet, G.
Electrophoresis 1999, 20, 2630-2637.

916 J . Org. Chem., Vol. 65, No. 3, 2000
Notes
(3CH3), 25.4 (CH2), 30.1 (CH), 36.0 (C), 37.6 (CH2), 54.7 (CH3),
56.1 (CH3), 57.7 (CH2), 75.9 (C), 94.4 (CH2), 104.3 (CH), 105.3
(CH), 106.0 (CH), 116.7 (C), 129.6 (CH), 154.4 (C), 159.7 (C),
171.3 (C); minor isomer, 24.3 (3CH3), 25.4 (CH2), 29.9 (CH), 36.0
(C), 37.7 (CH2), 55.9 (CH3), 56.7 (CH3), 57.7 (CH2), 75.9 (C), 94.0
(CH2), 104.0 (CH), 104.3 (CH), 107.2 (CH), 116.4 (C), 129.6 (CH),
156.8 (C), 157.8 (C), 171.3 (C). MS (IS): m/z ) 490 (M + 1). Anal.
Calcd for C20H28INO5: C, 49.09, H, 5.77, N, 2.86. Found: C, 49.29,
H, 5.61, N, 2.65.
In conclusion, the synthesis of (2R)-5′-methoxy-3′,4′-
dihydrospiro[pyrrolidine-2,3′(2′H)-benzopyran] was ac-
complished starting with the naturally occurring L-pro-
line. It took 10 steps with an overall yield of approximately
18%. The key step of the synthetic sequence concerned
the alkylation of the L-proline derivative 1 according to
Seebach’s strategy. This synthetic sequence proved to be
highly stereoselective, and the final compound 11 was
obtained with an enantiomeric excess of 99.7%.
(3R,7aR)-3-ter t-Bu tyl-7a-[2-m eth oxy-6-(m eth oxym eth oxy)-
ben zyl]p er h yd r op yr r olo[1,2-c][1,3]oxa zol-1-on e (5). Under
an argon atmosphere, 1 mL of HMPA and 1.1 mL of 2-propanol
were added to 500 mg (1.02 mmol) of iodo derivatives 4 dissolved
in anhydrous THF (5 mL). The mixture was degassed during
30 min, and 26 mL (2.55 mmol) of samarium iodide, 0.1 M
solution in THF, was added. After 5 min, the solvent was
removed under vacuum, and the residue was purified by flash
chromatography (eluent: petroleum ether/EtOAc, 9/1) to give
desired compound 5 (564 mg, 76%) as a white solid. Mp: 61-62
Exp er im en ta l Section
All air- and moisture-sensitive reactions were carried out
under an argon atmosphere. Anhydrous solvents (diethyl ether
and tetrahydrofuran) were freshly distilled from sodium/ben-
zophenone under nitrogen prior to use. 1H and 13C NMR spectra
were recorded at 250.131 and 62.9 MHz, respectively. Carbon
multiplicities have been assigned by distortionless enhancement
by polarization transfer (DEPT) experiments. Infrared spectra
were recorded using NaCl film or KBr pellet techniques. Mass
spectra (MS) were recorded by ion spray (IS). Melting points
were determined in open capillary tube and are uncorrected.
Analytical thin-layer chromatography was performed on Merck
60F254 silica gel precoated plates. Flash chromatography was
performed using silica gel Merck 40-70 µm (230-400 mesh).
For the diastereoisomers of 4 only, signals are different in the
NMR spectra for each isomer.
(3R,7a R)-3-(ter t-Bu t yl)-7a -[1-h yd r oxy-1-[2-m et h oxy-6-
m eth oxym eth oxyp h en yl]m eth yl]p er h yd r op yr r olo[1,2-c]-
[1,3]oxa zol-1-on e (3). Under an argon atmosphere, a solution
of 1.2 g (6.6 mmol) of oxazolone (1)13 in anhydrous THF (30 mL)
was cooled to -78 °C, and then 4.3 mL (17.7 mmol) of LDA, 2 M
solution in hexane, was slowly added. After 45 min, 1.73 g (8.5
mmol) of aldehyde 2 was added. The mixture was stirred during
40 min at -78 °C and then allowed to warm to room temperature
and stirred during 18 h. After evaporation, the crude product
was hydrolyzed by 25 mL of saturated NH4Cl solution and
extracted with EtOAc. The organic layers were dried over
MgSO4, concentrated, and purified by flash chromatography
(eluent: petroleum ether/EtOAc, 9/1) to give a mixture of the
desired alcohols 3 (1.78 g, 72%) as a white solid. IR (KBr): ν
cm-1 3522-3242 (O-H), 1773 (CdO). NMR 1H (CDCl3): δ ppm
0.77 (s, 9H), 1.69-2.05 (m, 3H), 2.39-2.61 (m, 1H), 2.68-2.91
(m, 1H), 2.98-3.16 (m, 1H), 3.49 (s, 3H), 3.84 (s, 3H), 4.13 (s,
1H), 4.71 (d, 1H, J ) 9.3 Hz), 5.16 (s, 2H), 5.47 (d, 1H, J ) 9.3
Hz), 6.59 (d, 1H, J ) 8.5 Hz), 6.81 (d, 1H, J ) 8.5 Hz), 7.17 (t,
1H, J ) 8.5 Hz). NMR 13C (CDCl3): δ ppm 24.1 (3CH3), 24.9
(CH2), 33.6 (CH2), 35.9 (C), 55.5 (CH3), 56.2 (CH3), 57.0 (CH2),
72.5 (CH), 78.2 (C), 95.2 (CH2), 103.8 (CH), 104.9 (CH), 107.7
(CH), 116.4 (C), 129.3 (CH), 155.4 (C), 158.8 (C), 175.4 (C). MS
(IS): m/z ) 380 (M + 1). Anal. Calcd for C20H29NO6: C, 63.31, H,
7.70, N, 3.69. Found: C, 63.13, H, 7.81, N, 3.53.
(3R,7a R)-3-(ter t-Bu tyl)-7a -[1-iod o-1-[2-m eth oxy-6-m eth -
oxym et h oxyp h en yl]m et h yl]p er h yd r op yr r olo[1,2-c][1,3]-
oxa zol-1-on e (4). Under an argon atmosphere, 840 mg (2.21
mmol) of alcohols 3 was dissolved in a mixture of toluene (10
mL) and acetonitrile (5 mL). The mixture was cooled to 0 °C,
and 1.7 g (6.48 mmol) of Ph3P, 890 mg (13.07 mmol) of imidazole
and 1.7 g (6.70 mmol) of iodine were added. The mixture was
allowed to room temperature and stirred during 18 h. After
evaporation, the residue was hydrolyzed and extracted with CH2-
Cl2. The organic layers were combined and dried over MgSO4,
concentrated, and purified by flash chromatography (eluent:
petroleum ether/EtOAc, 9/1) to give desired iodine compounds
4 (810 mg, 75%) as a yellow solid. IR (KBr): ν cm-1 1781 (CdO).
NMR 1H (CDCl3): δ ppm major isomer, 0.96 (s, 9H), 1.46-1.72
(m, 1H), 1.75-1.91 (m, 1H), 2.11-2.27 (m, 1H), 2.51-2.68 (m,
1H), 2.68-2.81 (m, 1H), 3.18-3.34 (m, 1H), 3.46 (s, 3H), 3.88
(s, 3H), 4.12 (s, 1H), 5.14 (s, 2H), 6.32 (s, 1H), 6.56 (d, 1H, J )
8.5 Hz), 6.66 (d, 1H, J ) 8.5 Hz), 7.19 (t, 1H, J ) 8.5 Hz); minor
isomer, 0.96 (s, 9H), 1.46-1.72 (m, 1H), 1.75-1.91 (m, 1H), 2.11-
2.27 (m, 1H), 2.51-2.68 (m, 1H), 2.68-2.81 (m, 1H), 3.18-3.34
(m, 1H), 3.58 (s, 3H), 3.77 (s, 3H), 4.12 (s, 1H), 5.14 (s, 2H), 6.32
(s, 1H), 6.47 (d, 1H, J ) 8.5 Hz), 6.77 (d, 1H, J ) 8.5 Hz), 7.18
(t, 1H, J ) 8.5 Hz). NMR 13C (CDCl3): δ ppm major isomer, 24.3
1
°C. IR (KBr): ν cm-1 1767 (CdO). NMR H (CDCl3): δ ppm 0.85
(s, 9H), 1.64-1.95 (m, 3H), 2.08-2.22 (m, 1H), 2.64-2.76 (m,
1H), 2.95-3.08 (m, 1H), 3.15 (d, 1H, J ) 13.3 Hz), 3.22 (d, 1H,
J ) 13.3 Hz), 3.47 (s, 3H), 3.78 (s, 3H), 4.18 (s, 1H), 5.14 (s, 2H),
6.54 (d, 1H, J ) 8.2 Hz), 6.75 (d, 1H, J ) 8.2 Hz), 7.13 (t, 1H, J
) 8.2 Hz). NMR 13C (CDCl3): δ ppm 23.6 (3CH3), 24.9 (CH2),
29.6 (CH2), 35.7 (CH2), 36.1 (C), 55.2 (CH3), 56.0 (CH3), 57.8
(CH2), 72.6 (C), 94.7 (CH2), 104.9 (CH), 105.5 (CH), 106.6 (CH),
114.4 (C), 128.0 (CH), 157.1 (C), 159.2 (C), 177.5 (C). MS (IS):
m/z ) 364 (M + 1). [R]20 ) -5 (c 1.1, CHCl3). Anal. Calcd for
D
C20H29NO5: C, 66.09; H, 8.04; N, 3.85. Found: C, 66.22; H, 7.85;
N, 3.67.
Meth yl (2R)-2-(2-Hydr oxy-6-m eth oxyben zyl)pyr r olidin e-
2-ca r boxyla te (6). Under an argon atmosphere, 130 mg of
Amberlyst XN-1010 and 1 mL of HCl 6 N were added to 130 mg
(0.358 mmol) of oxazolidinone (5) dissolved in MeOH (6 mL).
The mixture was stirred during 48 h at room temperature and
neutralized with saturated NaHCO3 solution. After hydrolysis,
Amberlyst was filtered off and the mixture washed with CH2-
Cl2. After extraction of the aqueous layer with CH2Cl2, the
organic layers were dried over MgSO4 and evaporated to give
crude ester 6 (66 mg, 69%) as a yellow oil. IR (NaCl): ν cm-1
3500-3000 (NH, OH), 1732 (CdO). NMR 1H (CDCl3): δ ppm
1.41-1.73 (m, 2H), 1.82-2.00 (m, 1H), 2.02-2.20 (m, 1H), 2.75-
2.91 (m, 1H), 2.91-3.02 (m, 1H), 3.08 (d, 1H, J ) 13.9 Hz), 3.30
(d, 1H, J ) 13.9 Hz), 3.78 (s, 3H), 3.79 (s, 3H), 4.29 (s, 1H), 6.39
(d, 1H, J ) 8.2 Hz), 6.54 (d, 1H, J ) 8.2 Hz), 7.06 (t, 1H, J ) 8.2
Hz), 10.68 (s, 1H). NMR 13C (CDCl3): δ ppm 26.3 (CH2), 33.5
(CH2), 34.0 (CH2), 46.4 (CH2), 52.7 (CH3), 55.5 (CH3), 70.7 (C),
101.6 (CH), 111.0 (CH), 112.2 (C), 128.3 (CH), 158.7 (2C), 176.8
(C). MS (IS): m/z ) 266 (M + 1).
(2R)-2-[2-Meth oxy-6-(m eth oxym eth oxy)ben zyl]p yr r oli-
d in e-2-ca r boxylic Acid (7). To a solution of 578 mg (1.59
mmol) of oxazolidinone 5 in a mixture MeOH/H2O (6/1, 7 mL)
was added 720 mg of silica gel 200-400 mesh, 60 Å. The mixture
was heated during 62 h, and solvents were evaporated. The
purification was made by flash chromatography (eluent: CH2-
Cl2/MeOH, 95/5 and 8/2) to give desired compound 7 (454 mg,
97%) as a white foam. Mp: 175-176 °C. IR (KBr): ν cm-1 3660-
3040 (NH, OH), 1622 (CdO). NMR 1H (CDCl3): δ ppm 1.54-
1.71 (m, 1H), 1.75-2.03 (m, 2H), 2.36-2.53 (m, 1H), 2.79-2.97
(m, 1H), 3.26 (d, 1H, J ) 14.5 Hz), 3.47 (s, 1H), 3.49 (s, 3H),
3.55-3.69 (m, 1H), 3.81 (d, 1H, J ) 14.5 Hz), 3.92 (s, 3H), 5.27
(d, 1H, J ) 6.9 Hz), 5.34 (d, 1H, J ) 6.9 Hz), 6.66 (d, 1H, J )
8.3 Hz), 6.86 (d, 1H, J ) 8.3 Hz), 7.26 (t, 1H, J ) 8.3 Hz), 7.53
(br s, 1H). NMR 13C (CDCl3): δ ppm 24.1 (CH2), 28.3 (CH2), 32.9
(CH2), 46.7 (CH2), 56.1 (CH3), 56.3 (CH3), 74.8 (C), 94.6 (CH2),
104.8 (CH), 107.3 (CH), 113.0 (C), 128.9 (CH), 156.5 (C), 158.3
(C), 174.3 (C). MS (IS): m/z ) 296 (M + 1). [R]20 ) -43 (c 1.0,
D
CHCl3). Anal. Calcd for C15H21NO5: C, 61.00; H, 7.17; N, 4.74.
Found: C, 61.29; H, 7.33; N, 4.59.
ter t-Bu tyl (2R)-2-(Hydr oxym eth yl)-2-[2-m eth oxy-6-(m eth -
oxym eth oxy)ben zyl]p yr r olid in e-1-ca r boxyla te (8). Under
an argon atmosphere, 3.1 mL (3.08 mmol) of BH3‚THF, 1 M in
THF, was slowly added to a suspension of 454 mg (1.54 mmol)
of amino acid 7 in anhydrous THF (8 mL). The mixture was
stirred during 18 h at room temperature, and 2.7 mL of MeOH
was added. After evaporation, the residue was hydrolyzed by

Notes
J . Org. Chem., Vol. 65, No. 3, 2000 917
2.7 mL of a solution of 20% KOH and extracted with CH2Cl2.
The organic layers were dried over MgSO4 and concentrated.
The crude amino alcohol was engaged in the next step without
further purification. IR (NaCl): ν cm-1 3686-3050 (NH, OH).
6.58 (d, 1H, J ) 8.2 Hz), 7.10 (t, 1H, J ) 8.2 Hz). NMR 13C
(CDCl3): δ ppm 21.4 (CH2), 24.7 (CH2), 28.4 (3CH3), 33.2 (CH2),
48.9 (CH2), 55.2 (CH3), 67.6 (CH2), 69.3 (C), 80.9 (C), 101.6 (CH),
110.9 (CH), 112.1 (C), 128.1 (CH), 156.9 (C), 158.0 (C), 159.4
1
NMR H (CDCl3): δ ppm 1.55-1.80 (m, 4H), 2.80-3.02 (m, 2H),
(C). MS (IS): m/z ) 338 (M + 1). [R]20 ) -21 (c 1.1, CHCl3).
D
2.88 (d, 1H, J ) 13.7 Hz), 2.97 (d, 1H, J ) 13.7 Hz), 3.19 (br s,
2H), 3.26 (d, 1H, J ) 10.9 Hz), 3.32 (d, 1H, J ) 10.9 Hz), 3.49
(s, 3H), 3.83 (s, 3H), 5.19 (s, 2H), 6.60 (d, 1H, J ) 8.2 Hz), 6.78
(d, 1H, J ) 8.2 Hz), 7.15 (t, 1H, J ) 8.2 Hz). NMR 13C (CDCl3):
δ ppm 25.8 (CH2), 29.8 (CH2), 33.1 (CH2), 46.3 (CH2), 55.6 (CH3),
56.3 (CH3), 67.0 (C), 67.3 (CH2), 94.8 (CH2), 104.6 (CH), 107.1
(CH), 115.6 (C), 127.7 (CH), 156.5 (C), 158.6 (C). MS (IS): m/z )
282 (M + 1).
Anal. Calcd for C18H27NO5: C, 64.07; H, 8.06; N, 4.15. Found: C,
64.26; H, 8.29; N, 3.99.
(2R)-1-ter t-Bu toxycar bon yl-5′-m eth oxy-3′,4′-dih ydr ospir o-
[p yr r olid in e-2,3′(2′H)-ben zop yr a n ] (10). Under an argon
atmosphere, 126 mg (0.48 mmol) of Ph3P and 75 µL (0.48 mmol)
of diethyl azodicarboxylate were added to a solution of 135 mg
(0.40 mmol) of diol 9 in anhydrous Et2O (4 mL). The mixture
was stirred during 18 h at room temperature, and after evapora-
tion, the residue was purified by flash chromatography (eluent:
petroleum ether/EtOAc, 98/2 then 95/5) to give desired compound
10 (128 mg, quantitative) as a white solid. Mp: 100-101 °C. IR
Under an argon atmosphere, 386 mg of the crude amino
alcohol was dissolved in anhydrous THF (7 mL), and 350 µL
(1.50 mmol) of di-tert-butyl dicarbonate was added. The mixture
was stirred at room temperature during 1 h, hydrolyzed, and
extracted with CH2Cl2. The organic layers were dried over
MgSO4, concentrated, and purified by flash chromatography
(eluent: petroleum ether/EtOAc, 8/2) to lead to carbamate 8 (400
mg, 68% overall yield for two steps) as a colorless oil. IR (NaCl):
ν cm-1 3710-3130 (OH), 1674 (CdO). NMR 1H (CDCl3): δ ppm
1.40-1.75 (m, 2H), 1.49 (s, 9H), 1.75-2.10 (m, 2H), 2.98-3.27
(m, 4H), 3.48 (s, 3H), 3.40-3.72 (m, 2H), 3.72-4.00 (m, 4H), 5.17
(s, 2H), 6.56 (d, 1H, J ) 8.2 Hz), 6.76 (d, 1H, J ) 8.2 Hz), 7.13
(t, 1H, J ) 8.2 Hz). NMR 13C (CDCl3): δ ppm 21.7 (CH2), 26.3
(CH2), 28.7 (3CH3), 33.9 (CH2), 48.7 (CH2), 55.7 (CH3), 56.1 (CH3),
68.5 (C), 71.1 (CH2), 79.3 (C), 94.8 (CH2), 104.4 (CH), 107.1 (CH),
116.6 (C), 127.5 (CH), 155.8 (C), 157.0 (C), 159.2 (C). MS (IS):
1
(KBr): ν cm-1 1681 (CdO). NMR H (DMSO-d6 at 80 °C): δ ppm
1.40 (s, 9H), 1.55-1.68 (m, 1H), 1.77 (q, 2H, J ) 6.7 Hz), 1,87-
2.02 (m, 1H), 2.40-2.55 (m, 1H), 3.26-3.56 (m, 3H), 3.70-3.82
(m, 1H), 3.76 (s, 3H), 4.40 (d, 1H, J ) 9.9 Hz), 6.42 (d, 1H, J )
8.2 Hz), 6.51 (d, 1H, J ) 8.2 Hz), 7.03 (t, 1H, J ) 8.2 Hz). NMR
13C (DMSO-d6 at 80 °C): δ ppm 20.6 (CH2), 27.7 (3CH3), 28.6
(CH2), 35.6 (CH2), 47.7 (CH2), 55.0 (CH3), 58.4 (C), 69.0 (CH2),
78.4 (C), 102.3 (CH), 108.5 (CH), 109.8 (C), 126.4 (CH), 152.6
(C), 153.7 (C), 157.6 (C). MS (IS): m/z ) 320 (M + 1). [R]20
)
D
-21 (c 1.0, CHCl3). Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89;
N, 4.38. Found: C, 67.90; H, 7.69; N, 4.53.
(2R)-5′-Meth oxy-3′,4′-d ih yd r osp ir o[p yr r olid in e-2,3′(2′H)-
ben zop yr a n ] (11). Under an argon atmosphere, 280 µL (3.3
mmol) of trifluoroacetic acid dissolved in CH2Cl2 (2 mL) was
transferred to a cold solution of 110 mg (0.33 mmol) of protected
amine 10 in CH2Cl2 (2 mL). The mixture was allowed to warm
to room temperature, stirred for 4 h, and hydrolyzed by a
saturated NaHCO3 solution. After extraction of the aqueous
layer with CH2Cl2, the organic layers were dried over MgSO4,
concentrated, and then purified by flash chromatography (eluent:
CH2Cl2/MeOH, 9/1) to give desired amine 11 (70 mg, 98%) as a
yellow oil. IR (NaCl): ν cm-1 3330 (NH). NMR 1H (CDCl3): δ ppm
1.53-1.98 (m, 4H), 2.36 (s, 1H), 2.67 (s, 2H), 2.92-3.19 (m, 2H),
3.80 (s, 3H), 3.82 (s, 2H), 6.42 (d, 1H, J ) 8.2 Hz), 6.50 (d, 1H,
J ) 8.2 Hz), 7.06 (t, 1H, J ) 8.2 Hz). NMR 13C (CDCl3): δ ppm
25.7 (CH2), 33.4 (CH2), 34.8 (CH2), 46.3 (CH2), 55.5 (CH3), 57.4
(C), 72.3 (CH2), 102.1 (CH), 109.3 (CH), 110.4 (C), 127.2 (CH),
154.8 (C), 158.3 (C). MS (IS): m/z ) 220 (M + 1). [R]20D ) +10 (c
0.9, CHCl3). Anal. Calcd for C13H17NO2: C, 71.20; H, 7.81; N,
6.39. Found: C, 70.97; H, 8.03; N, 6.21.
m/z ) 382 (M + 1). [R]20 ) +63 (c 1.1, CHCl3). Anal. Calcd for
D
C
20H31NO6: C, 62.97; H, 8.19; N, 3.67. Found: C, 62.77; H, 8.01;
N, 3.43.
ter t-Bu t yl (2R)-2-(2-H yd r oxy-6-m et h oxyb en zyl)-2-(h y-
d r oxym eth yl)p yr r olid in e-1-ca r boxyla te (9). Under an argon
atmosphere, 100 mg (0.26 mmol) of carbamate 8 was dissolved
in CH2Cl2 (4 mL). The mixture was cooled to -30 °C, and 140
µL (1.05 mmol) of bromotrimethylsilane was added. The solution
was stirred during 2 h at -30 °C and then hydrolyzed. The
mixture was allowed to room temperature and the aqueous layer
was extracted with CH2Cl2. The organic layers were dried over
MgSO4, and after concentration, the residue was purified by
flash chromatography (eluent: petroleum ether/EtOAc, 9/1) to
give diol 9 (78 mg, 89%) as a white solid. Mp: 133-134 °C. IR
1
(KBr): ν cm-1 3740-3000 (OH), 1646 (CdO). NMR H (CDCl3 +
D2O): δ ppm 1.09-1.34 (m, 1H), 1.48 (s, 9H), 1.66-1.87 (m, 2H),
2.12-2.38 (m, 1H), 2.97 (d, 1H, J ) 14.1 Hz), 3.34 (d, 1H, J )
14.1 Hz), 3.27-3.43 (m, 1H), 3.46 (d, 1H, J ) 12.5 Hz), 3.62 (d,
1H, J ) 12.5 Hz), 3.57-3.73 (m, 1H), 6.42 (d, 1H, J ) 8.2 Hz),
J O991089Y