Asymmetric synthesis of the protoberberine alkaloid (s)-(-)-xylopinine using enantiopure sulfinimines

Article abstract of DOI:10.1021/jo010988v

A concise enantioselective synthesis of (S)-(-)-xylopinine (1) is described involving the addition of the laterally lithiated derivative of o-tolunitrile of 16 to enantiopure sulfinimine (+)-14. Treatment of the resulting cyano sulfinamide adduct (-)-17b with DIBAL-H accomplishes five operations in a single pot and furnishes the cyclic imine (+)-18 in good yield. Reduction and cyclization affords (S)-(-)-1. Alternatively basic hydrolysis of 17b,c gives isoquinolone 21 that is cyclized and reduced to give (S)-(-)-1.

Full text of DOI:10.1021/jo010988v

1290
J . Org. Chem. 2002, 67, 1290-1296
Asym m etr ic Syn th esis of th e P r otober ber in e Alk a loid
(S)-(-)-Xylop in in e Usin g En a n tiop u r e Su lfin im in es
Franklin A. Davis* and Pradyumna K. Mohanty
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
fdavis@astro.ocis.temple.edu
Received October 10, 2001
A concise enantioselective synthesis of (S)-(-)-xylopinine (1) is described involving the addition of
the laterally lithiated derivative of o-tolunitrile of 16 to enantiopure sulfinimine (+)-14. Treatment
of the resulting cyano sulfinamide adduct (-)-17b with DIBAL-H accomplishes five operations in
a single pot and furnishes the cyclic imine (+)-18 in good yield. Reduction and cyclization affords
(S)-(-)-1. Alternatively basic hydrolysis of 17b,c gives isoquinolone 21 that is cyclized and reduced
to give (S)-(-)-1.
Xylopinine (1) is a prototypical member of the proto-
berberines, a large family of naturally occurring alkaloids
characterized by a tetracyclic ring skeleton and an
isoquinoline core.1 Various alkoxy (methoxy, methylene-
dioxy) substitution patterns are found in the A- and
D-rings, and a stereogenic center at C(14) is present as
are alkyl and hydroxy groups at C(13). The protober-
berines play key roles as precursors in the biosynthesis
of many isoquinoline alkaloids such as rhoeadine, seco-
berbine, and benzo[c]phenanthridine.2 The various bio-
logical properties that have been attributed to this class
of alkaloids include antimicrobial, antileukemic, antitu-
mor, and antiinflammatory activities.Although several
racemic syntheses of the protoberberines have been
reported, the small number of asymmetric syntheses
undoubtedly reflects the lack of general methods to
prepare them in enantiopure form that have the desired
ring substitution patterns.3 Indeed the majority of these
asymmetric syntheses has been of (S)-(-)-xylopinine (1)
(Figure 1). Meyers reported two asymmetric synthesis
of (-)-1 employing his chiral formamidine anions4 and
chiral bicyclic lactam technologies.5 A chiral auxiliary
mediated Pictet-Spengler synthesis was used by Comins6
and by Czarnocki7 to prepare this alkaloid while Kamet-
ani employed a photochemical cyclization strategy with
an enantiomerically pure eneamide.8
F igu r e 1.
droisoquinolines, we have been examining the reactions
of laterally lithiated species 2 with enantiopure sulfin-
imines 3 (Scheme 1).9 Cyclization of the resulting sulfin-
amide 4 gives the isoquinolone 5 or cyclic imine 6, both
of which can be further elaborated to the tetrahydroiso-
quinonine 7. This methodology has the potential for
avoiding many of the limitations of the Bischler-Napi-
eralski and Pictet-Spengler protocols as well as provid-
ing isoquinolines with substitution patterns not easily
accessible by other means. In this context we reported
highly stereoselective asymmetric syntheses of (2R,4S)-
(-)-6-methoxy-N-methyl-3-phenyl-1,2,3,4-tetrahydroiso-
quinolin-4-ol (7, R ) 4-MeO, R1 ) R2 ) H, R3 ) Ph, R4 )
OH) using the laterally lithiated amide derived from
4-methoxy-N,N-diethyl-o-toluamide (2, X ) C(O)NEt2, R
) 4-MeO).10 However, when this protocol was applied to
the synthesis of trans-(1R,3R)-(-)-6,8-dimethoxy-1,3-
dimethyl-1,2,3,4-tetrahydroisoquinoline (7, R ) 6,8-di-
MeO, R1 ) R3 ) Me, R2 ) H), the isoquinoline segment
of the anti-HIV michellamines, it resulted in the forma-
tion of a complex mixture of sulfinamide 4 atropisomers.11
These atropisomers are caused by restricted rotation of
the N,N-diethylamide group, which prevents determina-
tion of the dr and eliminates the possibility of a obtaining
a diastereomerically pure product. Use of the laterally
lithiated o-tolylnitriles not only avoids this problem, but
As part of a program aimed at developing new strate-
gies for the asymmetric synthesis of biorelevant tetrahy-
(1) For a review see Bhakuni, D. S.; J ain, S. In The Alkaloids:
Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press: Or-
lando, FL, 1986; Vol. 28, pp 95-181.
(2) For reviews, see (a) Iwasa, K. In The Alkaloids: Chemistry and
Pharmacology; Cordell, G. A., Ed.; Academic Press: San Diego, CA,
1995; Vol 46, pp 273-346. (b) Hanaoka, M. In The Alkaloids: Chem-
istry and Pharmacology; Brossi, A., Ed.; Academic Press: Orlando, FL,
1988; Vol. 33, pp 141-222.
(3) For references to the asymmetric synthesis of other protober-
berine alkaloids, see (a) Matulenko, M. A.; Meyers, A. I. J . Org. Chem.
1996, 61, 573. (b) Pyne, S. G.; Dikie, B. J . Org. Chem. 1990, 55, 1932.
(c) Dean, R. T.; Rapoport, H. J . Org. Chem. 1978, 43, 4183.
(4) Meyers, A. I.; Boes, M.; Dickman, D. A. Angew. Chem., Int. Ed.
Engl. 1984, 23, 458.
(5) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1996, 61, 4607.
(6) Comins, D. L.; Thakker, P. M.; Baevsky, M. F.; Badawi, M. M.
Tetrahedron 1997, 53, 16327.
(7) Czarnocki, Z.; Arazny, Z. Heterocycles 1999, 51, 2871.
(8) Kametani, T.; Takagi, N.; Toyata, M.; Honda, T.; Fukumoto, K.
J . Chem. Soc., Perkin Trans. 1 1981, 2830.
(9) For a reviews on lateral lithiation reactions, see: (a) Clark, R.
D.; J ahangir, A. Org. React. 1995, 47, 5. (b) Snieckus, V. Chem. Rev.
1990, 90, 879.
(10) Davis, F. A.; Andemichael, Y. M. J . Org. Chem. 1999, 64, 8627.
(11) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y.
W. Org. Lett. 2000, 2, 3901.
10.1021/jo010988v CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/29/2002

Asymmetric Synthesis of (S)-(-)-Xylopinine
J . Org. Chem., Vol. 67, No. 4, 2002 1291
Sch em e 1
preparative TLC) were unsuccessful. Attempts to improve
the diastereoselectivity by varying the solvent, base, or
by the addition of additives had no effect on the diaster-
eomeric ratio (Table 1).
One of the advantages of our isoquinoline synthetic
strategy (Scheme 1) is that it offers many opportunities
to enhance the diastereomeric ratio and/or give chro-
matographically separable products by altering the reac-
tion partners, i.e., the sulfinyl auxiliary (R) or the
hydroxyl protecting group (PG) in sulfinimines 13-15.
Thus reaction of the laterally lithiated nitrile of 16 with
the O-tert-butyldimethylsilyl-protected sulfinimine (S)-
(+)-13b gave the corresponding sulfinamide (SS,S)-17b
in 68% yield with a slightly lower dr of 88:12 (76% de)
(Table 1: entry 8). Importantly, the diastereoisomers
were readily separable by flash chromatography. A
significantly improved dr of 98:2 (96% de) was observed
for the benzyl-protected 2-methoxynaphthylsulfinimine
(S)-(+)-14 affording the major diastereoisomer (SS,S)-
(-)-17c in 68% yield (Table 1, entry 9). With the tert-
butanesulfinimine (R)-(-)-15 the laterally lithiated nitrile
of 16 gave a complex mixture of products and the
corresponding sulfinamide was not detected (Table 1,
entry 10).
the corresponding sulfinamide 4 (X ) CN) can be
converted, in one pot, to the cyclic imine 6.11 As an
extension of this new protocol we describe a concise
stereoselective asymmetric synthesis of (S)-(-)-xylopinine
(1).
The major diastereoisomer is predicted to have the (S)-
configuration at the newly created chiral center in 17.
This assumption, confirmed in the synthesis of (S)-(-)-
1, is based on our mechanistic hypothesis11 wherein the
o-quinomethane structure derived from the nitrile anion
is chelated through the lithium cation to the sulfinyl
oxygen and approaches the Si-face of the sulfinimine via
six-membered chairlike transition state TS-1.
Resu lts a n d Discu ssion
Our synthesis begins with preparation of the requisite
sulfinimines 13-15 as outlined in Scheme 2. Com-
mercially available 3,4-dimethoxyphenethanol (8) was
protected either as the benzyl or TBDMS ethers 9 in
excellent yields. Refluxing of 9 with NBS in CHCl3
selectively furnished the desired bromides 10 in good
yield. Lithium halogen exchange was accomplished by
treating 10 with sec-BuLi at -78 °C, which was then
treated with dry DMF to give the protected aldehydes
11 in 82% yield. Sulfinimines 13-15 were prepared in
85-87% yield, as previously described,12 by reacting the
aldehydes with (S)-(-)-p-toluenesulfinamide (12a ),12 (S)-
(-)-2-methoxynaphthalenesulfinamide (12b)13 or (R)-(+)-
tert-butanesulfinamide (12c),14 in the presence of Ti-
(OEt)4.
Treatment of (SS,S)-(-)-17b with a slight excess of
DIBAL-H at 0 °C in toluene followed by hydrolysis with
3 N HCl resulted in the cyclic imine (S)-(+)-18 in 70%
isolated yield (Scheme 4). This accomplishes five opera-
tions in a single-pot. DIBAL-H reduces the nitrile to the
aldimine (operation 1), and then hydrolysis deprotects
TBDMS-ether (operation 2), converts the aldimine to the
aldehyde (operation 3), removes the sulfinyl group to give
the free amine (operation 4), which cyclizes to the imine
(operation 5). Reduction of (+)-18 with NaBH4 gave the
tetrahydroisoquinoline (S)-(+)-19 as the only detected
isomer in 85% yield. Cyclization was easily accomplished
by conversion of alcohol 19 into its tosylate 20 with TsCl
in pyridine solvent, isolation of the crude tosylate by
extraction into EtOAc, and treating with NaH. (S)-(-)-
Xylopinine (1) was isolated in 73% yield for the two steps.
The spectral properties of (S)-(-)-1 were consistent with
literature values and confirms its absolute configuration.
Synthesis of (S)-(-)-1 from (S)-(-)-8-oxoxylopine (23)
was also explored because of the possibility that the
corresponding laterally lithiated amide species could
provide access to diversely C(13)-substituted protober-
3,4-Dimethoxy-6-methylbenzonitrile (16), prepared from
the corresponding bromide and CuCN in 90% yield,11
reacts with LDA at -78 °C in THF to give the intensively
red-colored solution of the laterally lithiated o-tolylnitrile.
To this solution was added 1 equiv of sulfinimine (S)-
(+)-13a (PG ) Bn) (Scheme 3). After 0.5 h at -78 °C the
reaction mixture was quenched at this temperature with
1
aqueous NH4Cl. The de, readily determined by H NMR
on the crude reaction mixture, was an acceptable 80%.
However, all attempts to separate the diastereomeric
sulfinamides 17a by conventional chromatography (flash,
(12) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Faneli,
D. L.; Zhang, H. J . Org. Chem. 1999, 64, 1403. (b) Fanelli, D. L.;
Szewczyk, J . M.; Zhang, Y.; Reddy, G. V.; Burns, D. M. Davis, F. A.
Org. Synth. 1999, 77, 50.
(13) Davis, F. A.; Lee, T.; Zhang Z. Unpublished results. (S)-(-)-2-
Methoxynaphthalenesulfinamide (12b), mp 148-150 °C, [R]20 -81.2
D
(c 1.0, CHCl3) was prepared in the similar manner as (S)-(-)-12a in
85% yield. Full details will appear in due course.
(14) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J . A.
J . Org. Chem. 1999, 64, 1278.

1292 J . Org. Chem., Vol. 67, No. 4, 2002
Davis and Mohanty
Sch em e 2a
a
a : R ) (S)-(-)-p-tolyl, b: R ) (S)-(-)-2-methoxynaphthyl, c: R ) (R)-(+)-tert-butylsulfinyl.
Sch em e 3
molecular models suggest that steric constraints may
prevent the requisite planar conformation necessary for
formation of the o-quinomethane structure, i.e., TS-1.
In summary, concise asymmetric synthesis of naturally
occurring (S)-(-)-xylopinine (1) from readily available
sulfinimine derived cyclic imine (S)-(+)-18 and (S)-(-)-
8-oxoxylopine (23) is described. Application of this pro-
tocol (Scheme 1) to the enantioselective synthesis of other
protoberberine alkaloids is underway.
Exp er im en ta l Section
Gen er a l P r oced u r es. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). TLC
plates were visualized with UV, in an iodine chamber or with
phosphomolybdic acid, unless noted otherwise. Melting points
were recorded on a Mel-Temp apparatus and are uncorrected.
Optical rotations were measured on a Perkin-Elmer 341
polarimeter and IR spectra were recorded, using NaCl plates
or as KBr disks, on a Mattson 4020 FTIR polarimeter. 1H NMR
and 13C NMR spectra were recorded on a GE Omega 500,
operating at 500 and 125 MHz, respectively. HRMS were
performed in the Department of Chemistry, Drexel University,
Philadelphia, PA, using a Fissions ZAB HF double-focusing
mass spectrometer. Elemental analyses were performed in the
Department of Chemistry, University of Pennsylvania, Phila-
delphia, PA.
berines by reaction with electrophiles. Iinitial attempts
to hydrolyze the nitrile group in 17b,c under acidic
conditions failed. Although refluxing 17b in concentrated
HCl for 10 h removed the sulfinyl auxiliary, the desired
acid was not obtained, affording instead the amino nitrile.
Fortunately, heating 17b,c in aqueous MeOH with 4
equiv of LiOH for 8 h produced a 77-78% yield of 21a ,b.
For the TBDMS protected ether, 17b, the alcohol 21a was
obtained directly in 78% yield. Hydrogenation of 21b over
H2/Pd(OH)2 was necessary and furnished 21a in 96%
yield. The isoquinolone alcohol 21a was converted, as
before, into the tosylate 22, which was treated with NaH
to give (S)-(-)-23 in 75% overall yield for the two
operations.All attempts to generate the laterally lithiated
amide of (+)-23 by treatment with LDA failed and
starting material was recovered. Stronger bases such as
n-butyllithium are reported to prefer 1,2-addition at the
8-oxo group in 23 to give enamines.18 Inspection of
Dichloromethane was distilled over calcium hydride under
an inert atmosphere. THF and ether were freshly distilled
under nitrogen from a purple solution of sodium and ben-
zophenone ketyl. Unless stated otherwise, all reagents were
purchased from commercial sources and used without ad-
ditional purification.
2-Br om o-4,5-d im eth oxytolu en e. In a 250-mL two-necked
round-bottom flask equipped with a stirring bar and rubber
(15) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tatsuzawa, T.;
Tokuda, M.; Suginome, H. J . Org. Chem. 2000, 65, 7495.
(16) Charlton, J . L. Koh, K.; Ploarde, G. L. Can. J . Chem. 1990, 68,
2028,
(17) Luff, B. D. W. Perkin, W. H., J r.; Robinson, R. J . Chem. Soc.
1910, 97, 1131.
(18) Lenz, G. R. J . Org. Chem. 1974, 39, 2846.

Asymmetric Synthesis of (S)-(-)-Xylopinine
J . Org. Chem., Vol. 67, No. 4, 2002 1293
Ta ble 1. Rea ction of La ter ia l Lith ia ted o-Tolyln itr ile 16 w ith Su lfin im in es 13-15
entry
sulfinimine
conditions
THF, 0.5 h
THF, CuI 1:1 THF:EtO2
THF/DMPU
products
% yielda
dr (% de)b
1
2
3
(S)-(+)-13a
(SS,S)-(-)-17a
70
68
68
68
90:10 (80%)c
90:10 (80%)c
90:10 (80%)c
90:10 (80%)c
4
THF/Me3Al
5
toluene
no reaction
6
7
8
9
THF/sec-BuLi,TMEDA
THF/LiHMDS
THF, 0.5 h
THF, 0.5 h
THF, 0.5 h
complex mixture and 13a recovered
no reaction
(S)-(+)-13b
(S)-(+)-14
(R)-(-)-15
(SS,S)-(-)-17b
(SS,S)-(-)-17c
68
68
88:12 (76%)
98:2 (96%)
10
complex mixture of products
a
b
1
Isolated yield of pure major diastereoisomer. Determined from the H NMR of the crude reaction mixtures. c Could not be separated
by conventional chromatography.
Sch em e 4
Sch em e 5
septa under an argon atmosphere was placed 2.0 g (13.14
mmol) of 3,4-dimethoxytoluene (Aldrich) in CHCl3 (60 mL).
N-Bromosuccinamide, 2.38 g (13.40 mmol), was added under
an argon atmosphere, and the reaction mixture was refluxed
for 4 h. The organic phase was extracted with CHCl3 (2 × 30
mL), H2O (20 mL), dried (MgSO4), and concentrated. Purifica-
tion by silica gel column chromatography (hexane/EtOAc 50:
1) gave 3.29 g (85%) of an oil. Spectral properties are consistent
with literature values.16
solution was stirred for 30 min. At this time 1.95 mL (16.46
mmol) of benzyl bromide was added dropwise, and the reaction
mixture was stirred for 2 h. Cold H2O (5 mL) was added, the
solution was extracted with EtOAc (2 × 30 mL), dried (MgSO4),
and concentrated. Purification by silica gel column chroma-
tography (hexane/EtOAc 25:1) gave 4.12 g (91%) of an oil; IR
3,4-Dim eth oxy-6-m eth ylben zon itr ile (16). In a 250-mL
two-necked round-bottom flask equipped with a stirring bar
and rubber septa under an argon atmosphere was placed 2.0
g (8.65 mmol) of 2-bromo-4,5-dimethoxytoluene in DMF (40
mL). To the reaction mixture was added 1.16 g (12.97 mmol)
of CuCN, and the solution was stirred at 120 °C for 16 h and
cooled to room temperature, and H2O (30 mL) was added. The
organic phase was extracted with CHCl3 (2 × 30 mL) and
organic portion was washed with H2O (20 mL) and brine (20
mL), dried (MgSO4), and concentrated. Purification by silica
gel column chromatography (hexane/EtOAc 5:1) gave 1.38 g
(90%) of a white solid, mp 79-80 °C (lit.17 81 °C); IR (KBr)
1
(neat) 2935, 2857, 1516, 1028 cm-1; H NMR (CDCl3) δ 2.88
(t, J ) 6.9 Hz, 2 H), 3.68 (t, J ) 6.9 Hz, 2 H), 3.85, 3.86 (2 s,
6 H), 4.53 (s, 2 H), 6.77 (m, 3 H), 7.329 (m, 5 H); 13C NMR
(CDCl
3) δ 36.53, 56.34, 56.45, 72.00, 73.54, 111.78, 112.88,
121.39, 128.11, 128.19, 128.92, 129.94, 132.27, 148.06, 149.35.
Anal. Calcd for C17H20O3: C, 74.97, H 7.40. Found: C, 75.13;
H, 7.54.
1,2-Dim eth oxy-4-(2-ter t-bu tyld im eth ylsiloxyeth yl)ben -
zen e (9b). In
a 100-mL two-necked round-bottom flask
equipped with a stirring bar and rubber septa under an argon
atmosphere was placed 3.0 g (16.5 mmol) of 3,4-dimethoxy-
phenethyl alcohol (Aldrich) in DCM (50 mL) at 0 °C. Imidazole
(1.34 g, 19.75 mmol) and tert-butyldimethylsilyl chloride (2.72
g, 18.10 mmol) were added at 0 °C, and the reaction mixture
was stirred for 2 h. At this time the solution was extracted
with DCM (2 × 25 mL) and the organic phase was washed
with brine (20 mL), dried (MgSO4), and concentrated. Purifica-
tion by silica gel column chromatography (hexane/EtOAc 10:
1) gave 4.83 g (99%) of an oil; IR (neat) 2952, 2856, 1516, 1260,
1
2214 cm-1; H NMR (CDCl3) δ 2.48 (s, 1 H), 3.80, 3.86 (2 s, 6
H), 6.74, 6.99 (2 s, 2 H).
1,2-Dim eth oxy-4-(2-ben zyloxyeth yl)ben zen e (9a ). In a
100-mL two-necked round-bottom flask equipped with a stir-
ring bar and rubber septa under an argon atmosphere was
placed 3.0 g (16.46 mmol) of 3,4-dimethoxyphenethyl alcohol
(Aldrich) in THF (50 mL). To the solution was added 0.59 g
(24.69 mmol, 95% dry) of sodium hydride at 0 °C, and the

1294 J . Org. Chem., Vol. 67, No. 4, 2002
Davis and Mohanty
1031, 836 cm-1; 1H NMR (CDCl3) δ 0.00 (s, 6 H), 0.88 (s, 9 H),
2.78 (t, J ) 6.9 Hz, 2 H), 3.85, 3.86 (2 s, 6 H), 6.75 (m, 3 H);
13C NMR (CDCl3) δ -4.70, 18.98, 26.45, 39.83, 56.43, 56.56,
65.35, 111.78, 113.21, 121.64, 132.60, 148.08, 149.32. Anal.
Calcd for C16H28O3Si: C, 64.82; H, 9.52. Found: C, 64.70; H,
9.46.
110.68, 113.56, 127.45, 137.46, 147.75, 153.44, 190.13. Anal.
Calcd for C17H28O4Si: C, 62.92; H, 8.70. Found: C, 62.68; H,
8.69.
(S)-(+)-2-[(2-Ben zyloxyet h yl)-4,5-d im et h oxyb en zyli-
d in e]-p-tolu en esu lfin a m id e (13a ). Gen er a l Meth od . In a
100-mL two-necked round-bottom flask equipped with a stir-
ring bar and rubber septa under an argon atmosphere was
placed 1.0 g (3.33 mmol) of 11a in DCM (30 mL) at 0 °C. To
the reaction mixture were placed 0.568 g (3.36 mmol) of (S)-
(-)-p-toluenesulfinamide (12)12 and 2.79 mL (13.36 mmol) of
titanium(IV) ethoxide, and the reaction mixture was stirred
for 8 h. At this time H2O (1.5 mL) was added, and the organic
phase was filtered through Celite and concentrated. Purifica-
tion by flash chromatography (hexane/EtOAc 10:3) gave 1.26
g (87%) of a solid. mp 101-102 °C. [R]20D +97.2 (c 1.5, CHCl3);
1-Br om o-4,5-d im eth oxy-2-(2-ben zyloxyeth yl)ben zen e
(10a ). In a 100-mL two-necked round-bottom flask equipped
with a stirring bar and rubber septa under an argon atmo-
sphere was placed 4.0 g (14.69 mmol) of 9a in CHCl3 (60 mL),
and 2.66 g (14.98 mmol) of N-bromosuccinamide was added.
The reaction mixture was refluxed for 4 h, the organic phase
was extracted with DCM (50 mL) and H2O (30 mL), dried
(MgSO4), and concentrated. Purification by silica gel column
chromatography (hexane/EtOAc 30:1) gave 4.38 g (85%) of a
colorless oil; IR (neat) 2934, 2848, 1507, 1257, 1099 cm-1; H
IR (KBr) 1596, 1460 cm-1; H NMR (CDCl3) δ 2.39 (s, 3 H),
1
1
NMR (CDCl3) δ 3.00 (t, J ) 6.9 Hz, 2 H), 3.69 (t, J ) 6.9 Hz,
2 H), 3.82, 3.85 (2 s, 6 H), 4.55 (s, 2 H), 6.80, 7.00 (2 s, 2 H),
7.31 (m, 5 H); 13C NMR (CDCl3) δ 36.83, 56.66, 56.81, 70.35,
73.63, 114.45, 114.92, 116.07, 128.24, 128.27, 129.03, 130.92,
139.06, 148.78, 148.84. Anal. Calcd for C17H19BrO3: C, 58.13;
H, 5.45. Found: C, 58.35; H, 5.07.
3.22 (m, 2 H), 3.66 (t, J ) 6.6 Hz, 2 H), 3.88 (s, 6 H), 4.46 (s,
2 H), 6.76, 7.46 (2 s, 2 H), 7.28 (m, 7 H), 7.62 (d, J ) 8.1 Hz,
1 H), 8.98 (s, 1 H); 13C NMR (CDCl3) δ 21.37, 32.66, 55.92,
70.93, 72.91, 110.88, 113.27, 124.66, 124.76, 127.44, 128.17,
129.74, 135.46, 138.20, 141.51, 142.29, 147.71, 152.33, 158.15.
Anal. Calcd for C25H27NO4S: C, 68.62; H, 6.22; N 3.20.
Found: C 68.32, H 6.26; N 2.98.
1-Br om o-4,5-d im eth oxy-2-(2-ter t-bu tyld im eth ylsiloxy-
eth yl)ben zen e (10b). In a 100-mL two-necked round-bottom
flask equipped with a stirring bar and rubber septa under an
argon atmosphere was placed 2.2 g (10.79 mmol) of 9b in
CHCl3 (50 mL) and 1.95 g (6.11 mmol) of N-bromosuccinamide.
The reaction mixture was refluxed for 4 h, cooled to room
temperature, and extracted with DCM (2 × 20 mL). The
organic phase was washed with H2O (20 mL), dried (MgSO4),
and concentrated. Purification by silica gel column chroma-
tography (hexane/EtOAc 50:1) gave 3.16 (78%) of a colorless
oil; IR (neat) 2953, 2855, 1509, 1257, 1096, 836 cm-1; 1H NMR
(CDCl3) δ 0.01 (s, 6 H), 0.86 (s, 9 H), 2.88 (t, J ) 6.9 Hz, 2 H),
(S )-(+)-2-[(2-t er t -B u t y ld i m e t h y ls i lo x y e t h y l)-4,5-
d im eth oxyben zylid in e]-p-tolu en esu lfin a m id e (13b). Pu-
rification by flash chromatography (hexane/EtOAc 10:2) gave
0.81 g (85%) of a gum; [R]20 +40.8 (c 0.25, CHCl3), IR (neat)
D
2953, 2855, 1584, 1520, 1269 cm-1; H NMR (CDCl3) δ 0.08
1
(s, 6 H), 0.82 (s, 9 H), 2.39 (s, 3 H), 3.10 (m, 2 H), 3.79 (m, 2
H), 3.88, 3.91 (2 s, 6 H), 6.71, 7.47 (2 s, 2 H), 7.29, 7.63 (2 d,
J ) 8.1 Hz, 4 H), 8.94 (s, 1 H); 13C NMR (CDCl3) δ -4.91,
18.85, 22.01, 26.46, 36.18, 56.52, 56.58, 64.84, 111.33, 114.26,
125.36, 125.41, 130.39, 136.55, 142.15, 143.01, 148.35, 152.89,
158.81. Anal. Calcd for C24H35NO4SSi: C, 62.44; H, 7.64; N,
3.03. Found: C, 62.45; H, 7.76; N, 2.76.
3.79 (t, J ) 6.9 Hz, 2 H), 3.84 (s, 6 H), 6.78, 6.98 (2 s, 2 H), 13
C
NMR (CDCl3) δ -5.44, 18.22, 25.86, 39.20, 55.86, 56.06, 62.57,
114.16, 115.26, 130.37, 147.96. Anal. Calcd for C16H27BrO3Si:
C, 51.19; H, 7.25. Found: C, 51.39; H, 7.21.
(S)-(+)-2-[(2-Ben zyloxyet h yl)-4,5-d im et h oxyb en zyli-
d in e]-1-m eth oxyn a p h th a len esu lfin a m id e (14). Prepared
from (S)-(-)-2-methoxynaphthalenesulfinamide (12b)13 and
11a ; purification by flash chromatography (hexane/EtOAc 10:
4,5-Dim eth oxy-2-(ben zyloxyeth yl)ben za ld eh yd e (11a ).
In a 100-mL two-necked round-bottom flask equipped with a
stirring bar and rubber septa under an argon atmosphere was
placed 3.0 g (8.54 mmol) of 10a in THF (50 mL) at -78 °C. To
the reaction mixture was added dropwise 13.1 mL (1.3 M in
cyclohexane, 17.08 mmol) of sec-BuLi at -78 °C. The solution
was stirred for 45 min and 1.24 g (17.08 mmol) of DMF in
THF (2 mL) was added. After stirring for 15 min at -78 °C,
the reaction mixture was warmed to room temperature and
stirred for 2 h, and a saturated solution of NH4Cl (3 mL) was
added. The organic phase was extracted with Et2O (2 × 50
mL), dried (MgSO4), and concentrated. Purification by flash
chromatography (hexane/EtOAc 10:1) gave 2.10 g (82%) of a
gum; IR (neat) 2955, 2856, 1675, 1515 cm-1; 1H NMR (CDCl3)
δ 3.28 (t, J ) 6.9 Hz, 2 H), 3.70 (t, J ) 6.9 Hz, 2 H), 3.92 (s, 6
H), 4.49 (s, 2 H), 6.76, 7.37 (2 s, 2 H), 7.30 (m, 5 H), 10.19 (s,
1 H); 13C NMR (CDCl3) δ 32.70, 56.64, 56.71, 71.74, 73.07,
111.99, 114.18, 127.98, 128.16, 128.24, 129.00, 137.72, 138.82,
148.53, 154.22, 190.75. Anal. Calcd for C18H20O4: C, 71.98; H,
6.71. Found: C, 71.82; H, 6.90.
3) gave 1.44 g (86%) of a gum; [R]20 +63.2 (c 0.7, CHCl3); IR
D
(neat) 2935, 2854, 1568, 1506, 1271 cm-1; H NMR (CDCl3) δ
1
3.28 (m, 2 H), 3.70 (m, 2 H), 3.85, 3.89, 3.94 (3 s, 9 H), 4.45 (d,
J ) 3.5 Hz, 2 H), 6.70, 7.46 (2 s, 2 H), 7.61, 7.95, 8.65 (3 d, J
) 3.5 Hz, 3 H), 9.29 (s, 1 H); 13C (CDCl3) δ 32.68, 55.93, 71.19,
73.30, 110.79, 113.22, 113.46, 122.31, 122.48, 124.32, 124.85,
127.49, 127.92, 128.68, 129.29, 129.45, 131.38, 134.43, 134.97,
138.18, 147.73, 152.12, 157.17, 159.07. Anal. Calcd for C29H29
-
NO5S: C, 69.16; H, 5.80; N, 2.78. Found: C, 68.97; H, 5.81;
N, 2.87.
(R )-(-)-2-[(2-B e n zy lo x y e t h y l)-4,5-d im e t h o x y b e n -
zylid en e]-ter t-bu tylsu lfin a m id e (15). Prepared from (R)-
(+)-tert-butanesulfinamide (12c)14 and 11a ; purification by
flash chromatography (hexane/EtOAc 5:1) gave 0.23 g (85%)
of a gum; [R]20D -50.1 (c 0.6, CHCl3); IR(neat) 2934, 2871, 1583,
1514, 1280; 1NMR (CDCl3) δ 1.24 (s, 9 H), 2.68 (t, J ) 2.5 Hz,
2 H), 3.67 (m, 2 H), 3.90, 3.91 (2 s, 6 H), 4.48 (s, 2 H), 6.78,
7.47 (2 s, 2 H), 7.30 (m, 5 H), 8.71 (s, 1 H); 13C NMR (CDCl3)
δ 23.24, 33.43, 56.60, 56.66, 58.20, 71.68, 73.68, 111.69, 114.18,
125.57, 128.19, 129.00, 135.86, 138.91, 148.46, 152.86, 160.97.
Anal. Calcd for C22H29NO4S: C, 65.48; H, 7.24; N, 3.47.
Found: C, 65.31; H, 7.33; N, 3.32.
(SS,S)-(-)-N-[1-(2-(2-Ben zyloxyet h yl]-4,5-d im et h oxy-
ph en yl)-2-(2-cyan o-4,5-dim eth oxyph en yl]-p-tolu en esu lfin -
im id e (17a ). Gen er a l P r oced u r e. In a 100-mL two-necked
round-bottom flask equipped with a stirring bar and rubber
septa under an argon atmosphere was placed 1.49 mL (1.5 M
in THF, 2.24 mmol) of LDA in THF (25 mL) at -78 °C followed
by the dropwise addition of 0.20 g (1.12 mmol) of 3,4-
dimethoxy-6-methylbenzonitrile (16) in THF (2 mL). The
reaction mixture was stirred for 0.5 h, and 0.540 g (1.23 mmol)
of 13a in THF (2 mL) was added dropwise. After stirring for
0.5 h, saturated NH4Cl (5 mL) was added at -78 °C and the
solution was warmed to room temperature. The reaction
mixture was extracted with Et2O (2 × 30 mL), dried (MgSO4),
and concentrated. Purification by silica gel column chroma-
4,5-Dim et h oxy-2-(2-ter t-b u t yld im et h ylsilyoxyet h yl)-
ben za ld eh yd e (11b). In a 100-mL two-necked round-bottom
flask equipped with a stirring bar and rubber septa under an
argon atmosphere was place 3.0 g (7.99 mmol) of 10b in THF
(50 mL) at -78 °C. To the reaction mixture was added
dropwise 10.62 mL (15.98 mmol) of sec-BuLi at -78 °C, and
the solution was stirred for 45 min and 1.16 g (15.98 mmol) of
dry DMF in THF (2 mL) was added. After stirring for 15 min,
the reaction mixture was warmed to room temperature, stirred
for 2 h, and quenched with saturated NH4Cl (3 mL). The
organic phase was extracted with Et2O (2 × 25 mL), dried
(MgSO4), and concentrated. Purification by flash chromatog-
raphy (hexane/EtOAc 10:1) gave 2.12 g (82%) of a gum; IR
1
(neat) 2953, 2856, 1675, 1215 cm-1; H NMR (CDCl3) δ 0.07
(s, 6 H), 0.82 (s, 9 H), 3.16 (t, J ) 6.9 Hz, 2 H), 3.82 (t, J ) 6.9
Hz, 2 H), 3.91, 3.93 (2 s, 6 H), 6.74, 7.37 (2 s, 2 H), 10.18 (s, 1
H); 13C NMR (CDCl3) δ -5.58, 18.20, 25.79, 34.76, 55.95, 64.33,

Asymmetric Synthesis of (S)-(-)-Xylopinine
J . Org. Chem., Vol. 67, No. 4, 2002 1295
tography (hexane/EtOAc 5:1) gave 0.480 g (69%) of 17a as a
gum in de 80% that could not be separated. Major isomer: 1H
NMR (CDCl3) δ 2.33 (s, 3 H), 2.74 (m, 2 H), 3.36 (m, 4 H),
3.72, 3.76, 3.82, 3.86 (4 s, 12 H), 4.36 (s, 2 H), 4.47 (m, 1 H),
4.97 (m, 1 H), 6.51, 6.75, 6.84, 6.91 (4 s, 4 H), 7.22 (m, 7 H),
7.43 (d, J ) 8.5 Hz, 2 H). Minor isomer: 1H NMR (CDCl3) δ
2.38 (s, 3 H), 2.79 (m, 2 H), 3.46 (m, 4 H), 3.74, 3.77, 3.84,
3.89 (4 s, 12 H), 4.38 (s, 2 H), 4.51 (m, 1 H), 5.13 (m, 1 H),
6.49, 6.72, 6.82, 6.89 (4 s, 4 H), 7.23 (m, 7 H), 7.46 (d, J ) 8.5
Hz, 2 H).
56.56, 56.64, 56.71, 64.54, 109.47, 109.79, 112.40, 114.00,
126.80, 126.85, 132.17, 133.17, 148.12, 148.38, 148.44, 149.20.
HRMS Calcd for C21H27NO5 (M + H) 372.181. Found 372.1797.
(S)-(-)-Xylop in in e. In a 50-mL two-necked round-bottom
flask equipped with a stirring bar and rubber septa under an
argon atmosphere was placed 0.058 g (0.134 mmol) of 19 in
pyridine (10 mL) at 0 °C and 0.028 g (0.147 mmol) of
p-toluenesulfonyl chloride was added. The reaction mixture
was stirred for 6 h, sat. NaHCO3 (2 mL) was added, and the
organic phase was extracted with EtOAc (2 × 10 mL). The
organic phase was dried (MgSO4) and concentrated to give an
oil that was transferred to a 25-mL two-necked round-bottom
flask containing THF (10 mL). Sodium hydride (0.003 g, 95%
dry, 0.20 mmol, Aldrich) was added under argon atmosphere
at 0 °C, and the reaction mixture was stirred for 30 min. The
organic phase was extracted with EtOAc (2 × 10 mL) and H2O
(5 mL), dried (MgSO4), and concentrated. Purification by silica
gel column chromatography (hexane/EtOAc 10:3, the silica gel
was pretreated with 10% Et3N in n-hexane) gave 0.040 g (73%)
(SS,S)-(+)-N-[1-(2-(2-ter t-Bu tyld im eth ylsilyloxyeth yl)-
4,5-d im eth oxyp h en yl)-2-(2-cya n o-4,5-d im eth oxyp h en yl]-
p-tolu en esu lfin im id e (17b). Purification by silica gel column
chromatography (hexane/EtOAc 5:1) gave 1.39 g (68%) of 17b
as a gum; [R]20 +40.3 (c 0.3, CHCl3); IR (neat) 3295, 2935,
D
2218, 1598, 1465 cm-1; H NMR (CDCl3) δ 0.05 (s, 6 H), 0.82
1
(s, 6 H), 2.36 (s, 3 H), 2.61 (m, 2 H), 3.30-3.62 (m, 5 H), 3.81,
3.84, 3.85, 3.86 (4 s, 12 H), 4.44 (br s, 1 H), 4.91 (m, 1 H),
6.57, 6.75, 6.82, 6.92 (4 s, 4 H), 7.20, 7.48 (2 d, J ) 8.5 Hz, 4
H); 13C NMR (CDCl3) δ -4.68, 18.91, 21.96, 26.55, 36.00, 42.23,
54.41, 56.43, 56.71, 56.81, 64.54, 105.12, 110.86, 113.55,
113.93, 114.52, 119.10, 126.21, 129.98, 130.06, 130.99, 136.55,
142.00, 142.07, 148.28, 148.51, 148.93, 153.17. HRMS Calcd
for C35H42N2O6SSi (M+Na) 661.2756. Found 661.2763.
(SS,S)-(+)-N-[1-(2-(2-Ben zyloxyet h yl)-4,5-d im et h oxy-
ph en yl)-2-(2-cyan o-4,5-dim eth oxyph en yl]-1-m eth oxyn aph -
th a len esu lfin a m id e (17c). Purification by silica gel column
chromatography (hexane/EtOAc 5:1) gave 0.65 g (68%) of 17c
of a solid, mp 177-178 °C [lit.5 179-180 °C]; [R]20 -282.4 (c
D
0.7, CHCl3) [lit.5 -283.1 (c 0.36, CHCl3)]; IR (KBr) 2940, 1509
cm-1; 1H NMR (CDCl3) δ 2.65 (m, 2 H), 2.85 (dd, J ) 11.2, 3.6
Hz, 1 H), 3.15 (m, 2 H), 3.25 (dd, J ) 16, 3.7 Hz, 1 H), 3.67 (d,
J ) 14.7 Hz, 1 H), 3.85, 3.86, 3.87, 3.89 (4 s, 12 H), 3.94 (d, J
) 14.6 Hz, 1 H), 6.57, 6.62, 6.66, 6.74 (4 s, 4 H); 13C NMR
(CDCl3) δ 29.58, 36.95, 51.95, 56.50, 56.56, 56.60, 56.69, 58.78,
60.22, 109.16, 109.65, 112.01, 126.73, 126.81, 127.27, 130.19,
148.12, 148.20, 148.35. Analytical data were in agreement with
literature values.7
as a gum; [R]20 +35.2 (c 0.5, CHCl3); IR (neat) 3296, 2937,
D
2851, 2218, 1515 cm-1; 1H NMR (CDCl3) δ 2.88 (m, 2 H), 3.23
(dd, J ) 14, 6 Hz, 2 H), 3.38-3.57 (m, 3 H), 3.63, 3.90, 3.73,
3.87, 3.97 (5 s, 15 H), 4.42 (s, 2 H), 5.00 (m, 1 H), 6.01 (d, J )
4 Hz, 1 H), 6.66, 6.67, 6.68, 6.99 (4 s, 4 H), 7.30 (m, 5 H), 7.40
(m, 3 H), 7.79, 7.90, 8.22 (3 d, 3.5 Hz, 3 H); 13C NMR (CDCl3)
δ 33.23, 42.29, 54.10, 56.50, 56.58, 56.79, 57,49, 71.71, 73.57,
105.18, 110.16, 113.66, 113.89, 114.21, 119.13, 122.57, 125.18,
126.52, 128.17, 128.25, 128.53, 128.98, 129.08, 129.48, 129.95,
131.28, 131.91, 133.90, 136.80, 139.04, 148.22, 148.53, 148.99,
152.88, 155.94. HRMS Calcd for C39H40N2O7S (M + Na)
703.2453. Found: 703.2475.
(S)-(-)-3-[2-(2-Hyd r oxyeth yl)-4,5-d im eth oxy-3,4-d ih y-
d r o-2H-isoqu in olin -1-on e (21a ). In a 50-mL single-necked
round-bottom flask equipped with a stirring bar and condenser
was placed 0.45 g (0.70 mmol) of 17b in CH3OH (30 mL) and
H2O (5 mL). To the reaction mixture was added 0.067 g (2.80
mmol) of LiOH, and the solution was refluxed for 8 h. The
reaction mixture was concentrated, and the residue was
extracted with EtOAc (2 × 30 mL), dried (MgSO4), and
concentrated. Purification by flash chromatography on Et3N
pretreated silica gel (CH2Cl2/CH3OH 20:1) gave 0.211 g (78%)
of a gel; [R]20D -37.5 (c 0.2, CHCl3); IR (neat) 3403, 3328, 2954,
(S)-(+)-2-[2-(6,7-Dim eth oxy-3,4-d ih yd r oisoqu in olin -3-
yl)-4,5-d im eth oxyp h en yl]eth a n ol (18). In a 50-mL of two-
necked round-bottom flask equipped with a stirring bar and
rubber septa under an argon atmosphere was placed 0.25 g
(0.38 mmol) of 17b in toluene (20 mL) at 0 °C, and 1.0 mL (1
M in CH2Cl2, 0.53 mmol) of DIBAL-H was added. After stirring
for 2 h, 3 N HCl (5 mL) was added, the reaction mixture was
stirred for 15 min, and sat. NaHCO3 (20 mL) was added. After
10 min, the organic phase was extracted with EtOAc (2 × 20
mL), dried (MgSO4), and concentrated. Purification by flash
chromatography on silica gel (hexane/EtOAc 3:1) gave 0.1 g
1652, 1506, 1457 cm-1 1H NMR (CDCl3) δ 2.45 (br s, 1 H),
;
2.90 (m, 3 H), 3.19 (m,1 H), 3.83 (m, 2 H), 3.84, 3.86, 3.92,
3.94 (4 s, 12 H), 5.17, 5.19 (dd, J ) 13, 4 Hz, 1 H), 6.26 (br s,
1 H), 6.65, 6.70, 7.08, 7.57 (4 s, 4 H); 13C NMR (CDCl3) δ 35.60,
36.86, 52.63, 56.55, 56.69, 56.74, 56.82, 64.23, 109.99, 110.21,
110.76, 113.64, 121.39, 129.53, 131.91, 132.44, 148.62, 148.83,
149.30, 153.10, 167.42. HRMS Calcd for C21H25NO6 (M + Na)
410.1579. Found: 410.1585.
(S)-(-)-3-[2-(2-Ben zyloxyeth yl)-4,5-d im eth oxyp h en yl]-
6,7-d im et h oxy-3,4-d ih yd r o-2H-isoqu in olin -1-on e (21b ).
Purification by flash chromatography (hexane/EtOAc 5:20, the
silica gel was pretreated with 10% Et3N in n-hexane) gave
(70%) of 18 as a solid, mp 152-153 °C; [R]20 +42.6 (c 0.3,
D
CHCl3); IR (KBr) 3422, 1650 cm-1; H NMR (CDCl3) δ 2.88-
0.161 g (77%) of a gel. [R]20 -85.9 (c 1.1, CHCl3); IR (neat)
1
D
1
3.02 (m, 4 H), 3.77-3.80 (m, 2 H), 3.82, 3.88, 3.92, 3.93 (4 s,
12 H), 4.81-4.85 (m, 1 H), 6.71, 6.76, 6.86, 6.88 (4 s, 4 H),
8.28 (d, J ) 3 Hz, 1 H). 13C NMR (CDCl3) δ 32.96, 35.66, 56.60,
56.79, 56.85, 58.88, 64.51, 110.94, 111.30, 113.93, 121.64,
130.26, 130.53, 134.26, 148.10, 148.80, 148.90, 152.46, 159.95.
3326, 2936, 2853, 1662, 1515, 1267 cm-1; H NMR (CDCl3) δ
2.91 (m, 3 H), 3.18 (m, 1 H), 3.65 (t, J ) 7 Hz, 2 H), 3.87 (s, 6
H), 3.90, 3.96 (2 s, 6 H), 4.49 (s, 2 H), 5.11 (dd, J ) 13, 4 Hz,
1 H), 5.87 (br s, 1 H), 6.53, 6.71, 7.03, 7.29 (m, 5 H), 7.63 (4 s,
4 H); 13C NMR (CDCl3) δ 33.25, 37.25, 52.75, 56.58, 56.68,
56.77, 56.84, 74.74, 76.81, 109.71, 110.23, 110.81, 118.71,
121.49, 128.35, 129.05, 129.68, 131.86, 132.41, 138.67, 143.20,
148.64, 148.86, 153.09, 167.26. HRMS Calcd for C28H31NO6
(M+Na) 500.2049. Found: 500.2047.
HRMS Calcd for
372.1796.
C21H25NO5 (M + H) 372.1810. Found:
(S)-(+)-2-[2-(6,7-Dim eth oxy-1,2,3,4-tetr a h yd r oisoqu in o-
lin -3-yl)-4,5-d im eth oxyp h en yl]eth a n ol (19). In a 50-mL of
two-necked round-bottom flask equipped with a stirring bar
and rubber septa under an argon atmosphere was placed 0.080
g (0.21 mmol) of 18 in CH3OH (15 mL), and 0.008 g (0.21 mmol)
of NaBH4 was added at 0 °C. The reaction mixture was stirred
for 2 h at room temperature at which time H2O (0.5 mL) was
added, and the solution was concentrated. The residue was
extracted with EtOAc (2 × 10 mL), dried (MgSO4), and
concentrated. Purification by flash chromatography (CH2Cl2/
CH3OH 20:1, Et3N) gave 0.068 g (85%) of 19 as a solid, mp
(S)-(-)-3-[2-(2-H yd r oxyet h yl)-4,5-d im et h oxyp h en yl]-
6,7-d im eth oxy-3,4-d ih yd r o-2H-isoqu in olin -1-on e (21a ). In
a 50-mL of single-necked round-bottom flask equipped with a
stirring bar was placed 0.14 g (0.293 mmol) of 21b and 0.010
g of Pd(OH)2 in CH3OH (15 mL). The solution was stirred
under a hydrogen atmosphere (balloon) for 8 h, filtered through
Celite, and concentrated. Purification by silica gel flash
chromatography on Et3N pretreated silica gel (CH2Cl2/CH3-
OH 20:1,) gave 0.109 g (96%) of a gel, [R]20 -37.5 (c 0.2,
D
190 °C (dec); [R]20 +35.6 (c 0.3, CHCl3); IR (KBr) 3420, 3200,
CHCl3); IR (neat) 3403, 3328, 2954, 1652, 1506, 1457 cm-1
;
D
2935, 2860 cm-1; 1H NMR (CDCl3) δ 2.77-4.25 (m, 9 H), 3.81,
3.86, 3.87, 3.89 (4 s, 12 H), 4.81 (br s, 1 H), 6.55, 6.66, 6.77,
6.95 (4 s, 4 H); 13C NMR (CDCl3) δ 34.01, 36.08, 47.71, 52.92,
1H NMR (CDCl3) δ 2.45 (br s, 1 H), 2.90 (m, 3 H), 3.19 (m,1
H), 3.83 (m, 2 H), 3.84, 3.86, 3.92, 3.94 (4 s, 12 H), 5.17, 5.19
(dd, J ) 13, 4 Hz, 1 H), 6.25 (br s, 1 H), 6.65, 6.70, 7.08, 7.57

1296 J . Org. Chem., Vol. 67, No. 4, 2002
Davis and Mohanty
(4 s, 4 H); 13 C NMR (CDCl3) δ 35.60, 36.86, 52.63, 56.55, 56.69,
56.74, 56.82, 64.23, 109.99, 110.21, 110.76, 113.76, 121.39,
129.53, 132.44, 132.91, 148.62, 148.83, 149.30, 153.10, 167.42.
HRMS Calcd for C21H25NO6 (M + Na) 410.1579. Found:
410.1585.
NMR (CDCl3) δ 2.79-3.49 (m,5 H), 3.89, 3.90, 3.94, 3.95 (4 s,
12 H), 4.82-4.98 (m, 2 H), 6.69, 6.70, 6.72, 7.64 (4 s, 4 H); 13
C
NMR (CDCl3) δ 29.93, 38.36, 39.37, 55.95, 56.60, 56.73, 56.81,
77.20, 109.45, 109.84, 111.43, 112.14, 148.62, 148.67, 148.90,
152.57, 165.40. Analytical data were agreement with reported
values.18
(S)-(-)-2,3,10,11-Tetr am eth oxy-5,6,13,13a-tetr ah ydr oiso-
qu in o[3,2-a ]isoqu in olin -8-on e (23). In a 50-mL two-necked
round-bottom-flask equipped with stirring bar and rubber
septa under an argon atmosphere was placed 0.190 g (0.49
mmol) of 21a in pyridine (15 mL) at 0 °C was added. To the
reaction mixture was added 0.102 g (0.53 mmol) of p-toluene-
sulfonyl chloride, and the solution was stirred for 8 h, at which
time sat. NaHCO3 (2 mL) was added. The solution was
extracted with EtOAc (2 × 25 mL), dried (MgSO4), and
concentrated. The crude tosylate 22 was placed in a 50-mL
two-necked round-bottom flask equipped with a stirring bar
and rubber septa under an argon atmosphere in THF (15 mL).
To this solution, at 0 °C, was added 0.012 g (95% dry, 0.52
mmol) of sodium hydride, and the reaction mixture was stirred
for 30 min. At this time the organic phase was extracted with
EtOAc (2 × 25 mL) and H2O (5 mL), dried (MgSO4), and
concentrated. Purification by silica gel column chromatography
(hexane/EtOAc 10:2) gave 0.138 g (85%) of a solid, mp 185-
(S)-(-)-Xylop in in e (1). In a 50-mL two-necked round-
bottom flask equipped with a stirring bar and rubber septa
under an argon atmosphere was placed 0.075 g (0.20 mmol)
of 23 in THF (20 mL). To the reaction mixture was added 0.007
g (0.20 mmol) of LiAlH4 and the solution refluxed for 2 h. At
this time the reaction was cooled to 0 °C, and H2O (0.007 mL),
15% NaOH (0.007 mL), and H2O (0.02 mL) were added
successively. The organic phase was filtered through Celite
and concentrated, and the residue was purified by silica gel
flash chromatography (hexane/EtOAc 10:3, the silica gel was
pretreated with 10% Et3N in n-hexane) to give 0.054 g (75%)
of (-)-1.
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health (GM
51982).
186 °C [lit.6 187-188 °C], [R]20 -297.1 (c 0.42, CHCl3) [lit.6
D
-296.9 (c 0.95, CHCl3)]; IR(KBr): 1654, 1600, 1515 cm-1; H
J O010988V
1