Diasteroselective cyclizations with enantiopure malonaldehyde monocycloacetals

Article abstract of DOI:10.1021/jo0057351

The synthesis of a series of enantiopure malonaldehyde monocycloacetals is described. Treatment of 8b with L-tryptophan methyl ester, 5-methoxytryptamine, and tryptamine, respectively, in the Pictet-Spengler condensation gave the corresponding enantiomerically pure key precursors 1-3 and 17-21 in only two steps. Using a chiral amino-diol successfully realized the kinetic resolution of racemic carbolines 23 and 24.

Full text of DOI:10.1021/jo0057351

22
J . Org. Chem. 2002, 67, 22-26
Dia ster oselective Cycliza tion s w ith En a n tiop u r e Ma lon a ld eh yd e
Mon ocycloa ceta ls
Lanrong Bi,† Ming Zhao,† Chao Wang,† Shiqi Peng,*,† and Ekkehard Winterfeldt‡
College of Pharmaceutical Sciences, Peking University, Beijing 100083, People’s Republic of China and
Institut fur Organische Chemie der Universitat Hannover,
Schneiderberg 1B, D-30167 Hannover, Germany
sqpeng@mail.bjmu.edu.cn
Received November 16, 2000
The synthesis of a series of enantiopure malonaldehyde monocycloacetals is described. Treatment
of 8b with L-tryptophan methyl ester, 5-methoxytryptamine, and tryptamine, respectively, in the
Pictet-Spengler condensation gave the corresponding enantiomerically pure key precursors 1-3
and 17-21 in only two steps. Using a chiral amino-diol successfully realized the kinetic resolution
of racemic carbolines 23 and 24.
In tr od u ction
optically pure malonaldehyde monocycloacetals as the
chiral director.
Enantiomerically pure indoloquinolizines 5, 6 and their
9-methoxy derivatives are interesting target compounds
because of their use as building blocks for the synthesis
of various indole and oxindole alkaloids with potential
biological activities.1 The development of efficient syn-
thetic methods for this type of chiral intermediates is
actively pursued worldwide. Unfortunately, the appar-
ently facile route to the enantiomers of these compounds
via decarboxylation of the corresponding 6-carboxylate
derivatives was unsuccessful. Thus, the preparation of
enantiomerically pure indoloquinolizine derivatives has
mainly been carried out by stepwise introduction of
functional groups into the indole ring. Moreover, careful
choice of parameters such as reaction sequence and
reaction condition is necessary to achieve the formation
of pure enantiomers in this class compounds. The opti-
cally pure ketones 5 and 6 were previously synthesized
in seven steps from L-tryptophan methyl ester starting
with a Pictet-Spengler condensation (Scheme 1).2
Consequently, our objective was to find a simple and
straightforward access to enantiomerically pure com-
pounds 3 and 4, the key intermediates in the preparation
of the enantiomers 5 and 6. We thus decided to utilize
the optically pure malonaldehyde monocycloacetals as an
advanced intermediate for the enantioselective synthesis,
since these compounds have been the subject of continu-
ing synthetic interest in our laboratory over the years.
In this area, we did also develop a new type of chiral
reagent derived from easily available natural amino
acids. Applying these tools, we herein report the synthe-
sis of the enantiomerically pure precursors 3, 4 and their
6-methoxy derivatives 21, 22 in only two steps utilizing
Resu lts a n d Discu ssion
We previously described a general method for the
synthesis of malonaldehyde monoacetals via transacetal-
ization or selective hydrolysis of 1,1,3,3-tetramethoxypro-
pane and its analogues.3 More recently, the scope of the
transacetalization of 1,1,3,3-tetramethoxypropane was
expanded to chiral amino-diol and 1,3-dioxacyclic dia-
stereomers, thus affording a versatile approach to the
optically pure malonaldehyde monocycloacetals4
For our initial studies we selected the mixed bisacetals
7 as starting material and the readily available diastero-
meric aldehyde 8 as the key intermediate (Scheme 2).
At 50 °C using oxalic acid and silica gel as the catalyst
the mixed bisacetals 7a -d were converted into the
expected aldehydes 8a -d in 80-85% yield. The relative
stereochemistry of all optically pure compounds could be
established on the basis of their spectroscopic param-
eters, especially those of 1HNMR, including NOESY
experiments.
The cis-2,5-disubstituted configurations of 8a , 8c, 8d
as well as the cis-2,5,6-trisubstituted configuration of 8b
were assigned by NOESY experiments and further
confirmed by thermal isomerizations. An NOE was
observed between the NH at 5-position and the CH2 at
2-position in each of 8a , 8c, 8d , and NOEs between the
NH at 5-position, the CH3 at 4-position, and the CH2 at
2-position in 8b were also observed. The optical purities
of 8b-d were confirmed by measurements with the chiral
shift reagent tris[3-(heptauoropropylhydroxymethylene)-
(+)-campthorato]europium(III). Since no line splitting
was observed, one can deduce that the products are
enantiomercially pure within the limits of detection by
1H NMR. None of the compounds investigated showed
any signs of configurational instability during the condi-
tions applied.
† Peking University.
‡ Institut fur Organische Chemie der Universitat Hannover.
(1) Lounasmaa, M.; Puhakka, M. Acta Chem. Scand., Ser. B 1978,
77, 216. Winterfeldt, E.; Gaskell, A. J .; Korth, T.; Radunz, H.;
Walkowiak, M. Chem. Ber. 1969, 102, 3558. Winterfeldt, E. Chem. Ber.
1975, 108, 248; Rackur, G.; Stahl, M.; Walkowiak, M.; Winterfeldt, E.
Chem. Ber. 1976, 109, 3817. Winterfeldt, E.; Radunz, H.; Korth, T.
Chem. Ber. 1968, 101, 3172. Peng, S.; Min, G.; Winterfeldt, E. Liebigs.
Ann. Chem. 1993, 137.
(3) Botteghi, C.; Soccolini, F. Synthesis 1985, 592. Tietze, L. F.;
Glusenkamp, K. H. W. holla, Angew. Chem. 1982, 94, 793. Peng, S.;
Winterfeldt, E. Liebigs Ann. Chem. 1989, 1045.
(4) Bi, L.; Zhao, M.; Wang, C.; Peng, S. Eur. J . Org. Chem. 2000,
2669.
(2) Peng, S.; Winterfeldt, E. Liebigs Ann. Chem. 1990, 313; Peng,
S.; Winterfeldt, E. Liebigs Ann. Chem. 1990, 319. Peng, S.; Zhang, L.;
Lai, M.; Winterfeldt, E. Liebigs Ann. Chem. 1990, 141.
10.1021/jo0057351 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/13/2001

Diasteroselective Cyclizations
J . Org. Chem., Vol. 67, No. 1, 2002 23
Sch em e 1. P r ep a r a tion of En a n tiom er ica lly P u r e In d oloqu in olizin es
Sch em e 2. P r ep a r a tion of Op tica lly P u r e
Ma lon a ld eh yd e Mon ocycloa ceta ls
methyl ester in a Pictet-Spengler condensation, the two
diastereomers 17 and 18 were obtained in 50% and 30%
yield, respectively. This has to be compared to the Pictet-
Spengler condensation of L-tryptophan methyl ester and
1,1,3,3-tetramethoxypropane, which gave a very similar
mixture of (cis)-1,3-disubstituted carboline (1) and (trans)-
1,3-disubstituted carboline (2) in 66% and 33% yield,
respectively. Next, the correlation between the chirality
of aldehyde 8b and the absolute configuration of cycliza-
tion products was investigated with 5-methoxytryptamine
replacing L-tryptophan methyl ester in the Pictet-
Spengler condensation. To our great satisfaction, under
the similar experimental conditions the Pictet-Spengler
condensation gave the (1R)-1-substituted carboline 19
stereospecifically. In the presence of methanol 19 was
subsequently converted into the expectant compound 21
in 89% yield. With tryptamine replacing L-tryptophan
methyl ester in the Pictet-Spengler condensation the
cyclization product without purification was treated with
methanol directly to provide the enantiomerically pure
3 in high yield (Scheme 4). In this case 8b was exclusively
favorable to the formation of C1 R-configuration, which
demonstrates the versatility of the new chiral director.
As a possible explanation for the configurational
outcome, one may assume auxiliary dependent face-
selectivity for the nucleophilic attack to the enamine-
doublebond in the generally accepted transition state (A)
of Pictet-Spengler cyclizations. The configuration gener-
ated this way would then uneventfully be carried through
to the final product (D) (see Figure 1).
To explore the configuration dependent reactivity of
the optically pure precursors and further identify the
configuration of the intermediates, 8b was then treated
with N-[2-hydroxy-1- (hydroxymethyl)ethyl]benzamide
(9), (1S,2R)-N-[2-hydroxy-1-(hydroxymethyl)propyl]benz-
amide (10), and (1S)-N-[3-hydroxy-1-(hydroxymethyl)-
propyl]benzamide (11), respectively. From all of these
reactions the corresponding malonaldehyde biscyclo-
acetals 12, 13, and 14 were satisfactorily obtained in 80-
89% yield (Scheme 3).
The study was then extended to the configurational
stability of the malonaldehyde biscycloacetals 12 and 13.
Stirring in chloroform at 45 °C for 2 h, 12 and 13 were
quantitatively converted into 15 and 16, respectively.
These transformations prove that 15 and 16 are ther-
modynamically more stable than 12 and 13, which means
that the acetalizations mentioned above are kinetically
controlled. The NOESY experiments of 12, 13, 15, and
16 gave NOEs between the CH3 at 4-position and the CH2
at 2-position, and also between the CH3 at 4-position and
the NH at 5-position in the (4-methyl-1,3-dioxan-5-yl)-
benzamide moiety only, suggesting the (2S,4R,5R)/
(2,5-trans) configuration for 12 and 15 and the (2S,4R,5R)/
(2S,4S,5S) configuration for 13 and 16. The NOESY
experiment of 14 gave NOEs between the CH3 at 4-posi-
tion and the CH2 at 2-position, between the CH3 at
4-position and the NH at 5-position in (4-methyl-1,3-
dioxan-5-yl)benzamide moiety, and between the CH2 at
2-position and the NH at 5-position in the (1,3-dioxan-
5-yl)benzamide moiety, indicating its (2S,4R,5R)/(2S,5R)
configuration.
Having noticed this remarkable directing effect of the
acetals formed from diol 10, we were encouraged to check
its options in transacetalization experiments. To our
delight the racemic 6-methoxycarboline 23 underwent a
As these results indicated optically active malonalde-
hyde monocycloacetals to be convenient chiral synthons,
we were encouraged to investigate their application for
an enantioseletive synthesis of the important precursors
3, 4, 21, and 22. On treatment of 8b with L-tryptophan
F igu r e 1. The possible mechanism of the enantiospecific
Pictet-Spengler condensation.

24 J . Org. Chem., Vol. 67, No. 1, 2002
Sch em e 3. Th e Ster eosp ecific Aceta liza tion of 8b
Bi et al.
Sch em e 4. Th e En a n tiosp ecific P ictet-Sp en gler Con d en sa tion of 8b
Sch em e 5. Th e Kn etic Resolu tion of Ra cem ic
highly enantioselective acetalization with only the cor-
responding R-configuration giving rise to the diastere-
omer 19. The unreacted enantiomer 22 was isolated
directly. In the presence of methanol 19 was converted
into the enantiomer 21.
Ca r bolin es Ba sed on th e Ster eosp ecific
Tr a n sa ceta liza tion
With the racemic carboline 24 replacing 23 the highly
enantioselective acetalisation with also only the corre-
sponding R-configuration giving rise to the diastereomer
20 which was not purified and treated with methanol
directly converting into the enantiomer 4. The unreacted
enantiomer 3 was isolated directly again (see Scheme 5).
The clear-cut kinetic resolution together with the
experiments described above disclose a high degree of
chiral recognition for diol 10 and its derivatives.
Con clu sion
In summary, we have developed a short and efficient
synthesis of enantiomerically pure alkaloid building
blocks from easily accessible enantiopure malonaldehyde
monocycloacetals. Our synthesis compares favorably in
terms of the use of the simple reagents and transforma-
tions with the previously reported syntheses. Studies on
applying the approach for other reactions and substrates
are in progress in our laboratory.

Diasteroselective Cyclizations
Exp er im en ta l Section
J . Org. Chem., Vol. 67, No. 1, 2002 25
was filtered, and the filtrate was evaporated to give a syrup
which was separated by chromatography CHCl3/CH3OH, 25:
1) to afford 477.0 mg (50%) of 17 as a colorless crystal and
286.0 mg (30%) of 18 as a colorless crystal. The compound 17
had the following properties. The properties for compound 18
are provided in the Supporting Information.
Meth yl (1R,3S,2′S,4′R,5′R)- 1-(5′-ben zoyla m in o-4′-m eth -
yl-1′,3′-d ioxa n e-2′-yl)-m eth yl-1,2,3,4-tetr a h yd r oca r bolin e-
3-ca r boxyla te (17): mp 96-97 °C. IR (KBr) 3465, 3457, 3396,
1705, 1640 cm-1; 1H NMR (CDCl3) δ 1.27 (d, J ) 6.6 Hz, 3H),
2.13 (dd, J ) 7.2 Hz, J ) 4.2 Hz, 2H), 2.41 (s, 1H, NH), 3.00
(dd, J ) 7.2 Hz, J ) 5.4 Hz, 1H), 3.10 (dd, J ) 7.2 Hz, J ) 5.4
Hz, 1H), 3.17 (s, 3H), 3.95 (t, J ) 6.0 Hz, 1H), 4.04 (d, J )
10.4 Hz, 2H), 4.08 (m, 1H), 4.15 (q, J ) 6.3 Hz, 1H), 4.50 (t, J
) 4.2 Hz, 1H), 4.98 (t, J ) 3.6 Hz, 1H), 6.92 (d, J ) 9.3 Hz,
1H), 7.11 (p, J ) 9.0 Hz, 2H), 7.26 (d, J ) 6.9 Hz, 1H), 7.46 (p,
J ) 6.6 Hz, 4H), 7.85 (d, J ) 7.2 Hz, 2H), 8.36 (s, 1H); FAB-
MS m/z 464 [M + H]+. [R]D -39.4° (c 0.018, CHCl3/CH3OH,
1:1). Anal. Calcd for C26H29N3O5: C, 67.36; H, 6.31; N, 9.07.
Found: C, 67.42; H, 6.36; N, 9.14.
Gen er a l. Melting points are uncorrected. Unless otherwise
stated, all reactions were run under a nitrogen atmosphere (1
bar). 1H NMR spectra were recorded at 300 or 500 MHz in
deuteriochloroform with tetramethylsilane as internal stan-
dard. Chromatography was performed with Qingdao silical gel
H. Optical rotations were determined at 20 °C.
Gen er a l P r oced u r e for P r ep a r in g Ma lon a ld eh yd e
Mon ocycloa ceta ls (8a -d ). The suspension of 0.16 mmol of
the mixed bisacetals 7a -d , 10.0 mg of oxalic acid, 10.0 mg of
silica gel, and 10.0 mL of chloroform was stirred at 50 °C for
48-60 h until TLC analysis (CHCl3/CH3OH, 40:1) indicated
complete disappearance of the starting materials 7a -d . The
reaction mixture was cooled, neutralized with sodium carbon-
ate, and filtered. The filtrate was evaporated to remove
chloroform. The residue was purified by chromatography
(CHCl3/CH3OH, 60:1) to yield the malonaldehyde monocyclo-
acetals 8a -d . The compound 8a had the following properties.
The properties for compounds 8b-d are provided in the
Supporting Information.
(1R,2′S,4′R,5′R)-1-(5′-Ben zoyla m in o-4′-m et h yl-1′,3′-d i-
oxan -2′-yl)m eth yl-6-m eth oxy-1,2,3,4-tetr ah ydr ocar bolin e-
3-ca r bolin e (19). To a solution of 391.4 mg (2.06 mmol) of
5-methoxytryptamine in 10.0 mL of chloroform were added
543.0 mg (2.06 mmol) of monocycloacetal 8b and 50.0 mg of
anhydrous sodium sulfate. The suspension was stirred at 60
°C for 80 h. The resultant was filtered, and the filtrate was
evaporated to give a syrup which was separated by chroma-
tography (CHCl3/CH3OH, 25:1) to afford 754.0 mg (86%) of 19,
as colorless crystals: mp 120-121 °C. IR (KBr) 3465, 3500,
3460, 1640, cm-1; 1H NMR (CDCl3) δ 1.25 (d, J ) 6.0 Hz, 3H),
2.22 (dd, J ) 6.6 Hz, J ) 3.5 Hz, 2H), 2.74 (s, 1H), 2.75 (t, J
) 4.2 Hz, 1H), 3.14 (t, J ) 5.8 Hz, 1H), 3.33 (t, J ) 4.2 Hz,
1H), 3.35 (t, J ) 5.8 Hz, 1H), 3.82 (s, 3H), 4.01 (d, J ) 10.8
Hz, 1H), 4.02 (m, J ) 6.0 Hz, 1H), 4.09 (d, J ) 6.6 Hz, 1H),
4.14 (m, 1H), 4.49 (t, J ) 5.7 Hz, 1H), 4.93 (t, J ) 5.7 Hz, 1H),
6.77 (d, J ) 9.0 Hz, 1H), 6.89 (d, J ) 4.5 Hz, 1H), 6.99 (d, J )
9.1 Hz, 1H), 7.16 (d, J ) 8.7 Hz, 1H), 7.41 (t, J ) 7.2 Hz, 2H),
7.50 (t, J ) 7.2 Hz, 1H), 7.81 (d, J ) 7.5 Hz, 2H), 8.62 (s, 1H);
FAB-MS m/z 436 [M + H]+. [R]D -24° (c 0.02, CHCl3/CH3OH,
1:1). Anal. Calcd for C25H29N3O4: C, 68.93; H, 6.72; N, 9.65.
Found: C, 69.01: H, 6.80; N, 9.70.
R a cem ic 1-(2′,2′-Dim et h oxyet h yl)-6-m et h oxy-1,2,3,4-
tetr a h yd r oca r bolin e 23. At room temperature the stirred
solution of 190.0 mg (1.00 mmol) of 5-methoxytryptamine and
164.0 mg (1.00 mmol) of 1,1,3,3-tetramethoxypropane in 10.0
mL of chloroform/methanol (1:1) was mixed with 40.0 mg of
hydrochloric acid. The suspension was stirred at room tem-
perature for 72 h, and then TLC analysis indicated complete
disappearance of the materials. The resultant was neutralized
with 100.0 mg of sodium carbonate and filtered, and the
filtrate was evaporated to give a syrup which was purified by
chromatography (CHCl3/CH3OH, 20:1) to afford 249.0 mg
(86%) of 23. The properties for compound 23 are provided in
the Supporting Information.
Th e Kin etic Resolu tion of Ra cem ic 1-(2′,2′-Dim eth oxy-
eth yl)-6-m eth oxy-1,2,3,4-tetr a h yd r oca r bolin e 23. To a
stirred solution of 190.0 mg (1.00 mmol) of racemic 23 and
104.5 mg (0.5 mmol) of (2S,3R)-2-benzoylamino-1,3-butanediol
(10) in 15.0 mL of chloroform was added 10.0 mg of PPTS.
The suspension was stirred at room temperature for 3 d, and
then TLC analysis indicated complete disppearance of (2S,3R)-
2-benzoylamino-1,3-butanediol. The reaction mixture was
washed with aqueous sodium chloride (10%, 10 mL × 3). The
chloroform phase was separated and dried with Na2SO4. After
evaporation, the residue was purified by chromatography
(CHCl3/CH3OH, 20:1) to afford 209.0 mg (48%) of 19 and 89.3
mg (47%) of 22. The compound 22 was obtained as a colorless
powder: mp 215-217 °C. IR (KBr) 3300, 3245 cm-1; 1H NMR
(CDCl3) δ 1.23 (s, 1H), 1.99 (t, J ) 4.6 Hz, 1H), 2.41 (t, J ) 7.2
Hz, 1 H), 2.78 (m, 2 H), 3.04 (m, J ) 11.7 Hz, 1H), 3.34 (m, J
) 11.0 Hz, 1H), 3.41 (s, 3H), 3.42 (s, 3H), 3.865 (s, 3H), 4.651
(dd, J ) 3.6 Hz, J ) 2.4 Hz, 1H), 4.18 (dd, J ) 7.2 Hz, J ) 3.6
Hz, 1H), 6.90 (dd, J ) 8.5 Hz, J ) 3.4 Hz, 1H), 6.93 (d, J ) 3.1
Hz, 1H), 7.23 (d, J ) 8.5 Hz, 1H), 8.71 (s, 1H); FAB-MS m/z
cis-N-(2-For m ylm eth yl-1,3-dioxan e-5-yl)ben zam ide (8a).
Compound 8a was obtained as a colorless syrup in 85% yield.
IR (film) 3305, 1760, 1630 cm-1; 1H NMR (CDCl3) δ 2.76 (d, J
) 2.4 Hz, 2H), 4.31 (d, J ) 4.8 Hz, 2H), 4.34 (d, J ) 4.5 Hz,
2H), 4.46 (m, J ) 2.7 Hz, 1H), 4.96 (t, J ) 4.5 Hz, 1H), 5.87
(d, J ) 7.5 Hz, 1H), 7.43 (t, J ) 6.9 Hz, 2H), 7.52 (t, J ) 6.0
Hz, 1H), 7.73 (d, J ) 6.9 Hz, 2H), 9.79 (t, J ) 1.8 Hz, 1H);
FAB-MS m/z 250 [M + H]. Anal. Calcd for C13H15NO4: C, 62.63;
H, 6.07; N, 5.62. Found: C, 62.69; H, 6.14; N, 5.68.
Gen er a l P r oced u r e for P r ep a r in g Ma lon a ld eh yd e Bis-
cycloa ceta ls (12-14). The suspensoion of 8b (263.0 mg, 0.10
mmol), 300 mg of anhydrous magnesium chloride, N-[2-
hydroxy-1-(hydroxymethyl)ethyl]benzamide (9, 195.0 mg, 0.10
mmol), or (1S,2R)-N-[2-hydroxy-1-(hydroxymethyl)propyl]ben-
zamide (10, 209.0 mg, 0.10 mmol), or (1S)-N-[3-hydroxy-1-
(hydroxymethyl)propyl]benzamide (11, 209.0 mg, 0.10 mmol),
and 10 mL of chloroform was stirred at room temperature for
8-10 h until TLC analysis (CHCl3/CH3OH, 40:1) indicated
complete disappearance of the starting materials. After filtra-
tion and evaporation, the residue was purified by chromatog-
raphy (CHCl3/CH3OH, 50:1) to provide the corresponding
malonaldehyde biscycloacetals 12, 13, and 14, respectively.
The compound 12 had the following properties. The properties
for compounds 13 and 14 are provided in the Supporting
Information.
N,N′-Met h ylen e[(2S,4R,5R)-4-m et h yl-1,3-d ioxa n -2,5-
d iyl][tr a n s-1,3-d ioxa n -2,5-d iyl]bisben za m id e (12). Com-
pound 12 was obtained as a colorless powder in 86% yield. IR
1
(KBr) 3547, 3450, 1635, 1626 cm-1; H NMR (CDCl3) δ 1.21
(d, J ) 6.6 Hz, 3H), 2.06 (t, J ) 5.7 Hz, 2H), 3.99 (d, J ) 9.9
Hz, 2H), 4.31 (d, J ) 5.7 Hz, 1H), 4.34 (d, J ) 4.8 Hz, 1H,),
4.68 (t, J ) 5.7 Hz, 1H), 4.84 (t, J ) 5.4 Hz, 1H), 5.71 (d, J )
8.4 Hz, 1H), 6.79 (d, J ) 9.9 Hz, 1H), 7.46 (t, J ) 7.2 Hz, 4H),
7.50 (t, J ) 7.2 Hz, 2H), 7.73 (d, J ) 7.4 Hz, 2H), 7.82 (d, J )
7.2 Hz, 2H); FAB-MS m/z 441 [M + H]+. Mp 183-186 °C. [R]D
+30.0 (c 0.02, CHCl3). Anal. Calcd for C24H28N2O6: C, 65.44;
H, 6.41; N, 6.36. Found: C, 65.56; H, 6.38; N, 6.15.
Con figu r a tion Con ver sion of 12 a n d 13. A solution of
the kinetically controlled product, 12 (220.0 mg, 0.50 mmol)
or 13 (227.0 mg, 0.50 mmol), concentrated hydrochloric acid
(0.02 mL), and chloroform (8.00 mL) was stirred at 45 °C for
10 h until TLC (CHCl3/CH3OH, 30:1) indicated complete
disappearance of 12 or 13. After neutralization, filtration, and
evaporation the residue was purified, and the thermodynami-
cally stable product 15 or 16 was obtained. The properties for
compounds 15 and 16 are provided in the Supporting Informa-
tion.
Meth yl (1R,3S,2′S,4′R,5′R)- a n d (1S,3S,2′S,4′R,5′R)- 1-
(5′-b en zoyla m in o-4′-m et h yl-1′,3′-d ioxa n e-2′-yl)m et h yl-
1,2,3,4-tetr a h yd r oca r bolin e-3-ca r boxyla te (17 a n d 18). To
a solution of 450.0 mg (2.06 mmol) of L-tryptophan methyl ester
in 10.0 mL of chloroform were added 543.0 mg (2.06 mmol) of
monocycloacetal 8b and 50.0 mg of anhydrous sodium sulfate.
The suspension was stirred at 60 °C for 60 h. The resultant

26 J . Org. Chem., Vol. 67, No. 1, 2002
Bi et al.
291 [M + H]+. [R]D -15.6° (c 0.92, CH3OH). Anal. Calcd for
C16 H22 N2O3: C, 66.17; H, 7.64; N, 9.65. Found: C, 66.12; H,
7.61; N, 9.58.
CH3OH, 20:1) analysis indicated complete disppearance of
(2S,3R)-2-benzoylamino-1,3-butanediol (10). The reaction mix-
ture was washed with aqueous sodium chloride (10%, 10 mL
× 3). The chloroform phase was separated and dried with Na2-
SO4. After evaporation the residue was purified by chroma-
tography (CHCl3/CH3OH, 20:1) to afford 186.4 mg (46%) of 20
and 122.3 mg (47%) of 4. The properties for compound 4 are
provided in the Supporting Information.
(1R)-1-(2,2-Dim et h oxyet h yl)-1,2,3,4-t et r a h yd r oca r b o-
lin e (3). To a stirred solution of 186.4 mg of 20 in 10.0 mL of
methanol was added 5.0 mg of 6 N hydrochloric acid. The
reaction mixture was stirred at room temperature until TLC
analysis (CHCl3/CH3OH, 20:1) indicated complete disappear-
ance of 20. The reaction mixture was neutralized with sodium
carbonate and filtered. The filtrate was evaporated to remove
methanol. The residue was purified by chromatography (CHCl3/
CH3OH, 20:1) to yield the 106.6 mg of (89%) 3. The properties
for compound 3 are provided in the Supporting Information.
Meth yl (1R,3S)- a n d (1S,3S)-1-(2′,2′-Dim eth oxyeth yl)-
1,2,3,4-tetr a h yd r oca r bolin e-3-ca r boxyla te (1 a n d 2). To
a stirred solution of 50.0 mg (0.11 mmol) of 17 or 18 in 10.0
mL of methanol was added 5.0 mg of 6 N hydrochloric acid.
The reaction mixture was stirred at room temperature for 12
h until TLC analysis (CHCl3/CH3OH, 20:1) indicated complete
disappearance of the starting materials. The reaction mixture
was neutralized with sodium carbonate and filtered. The
filtrate was evaporated to remove methanol. The residue was
purified by chromatography (CHCl3/CH3OH, 30:1) to yield the
31.3 mg (89%) of 1 or 30.0 mg (85%) of 2, respectively. The
properties for compound 1 and 2 are provided in the Support-
ing Information.
(1R,2′S,4′R,5′R)-1-(5′-Ben zoyla m in o-4′-m et h yl-1′,3′-d i-
oxa n e-2′-yl)m eth yl-1,2,3,4-tetr a h yd r oca r bolin e-3-ca r bo-
lin e (20). To a solution of 320.0 mg (2.00 mmol) of tryptamine
in 10.0 mL of chloroform were added 527.2 mg (2.00 mmol) of
monocycloacetal 8b and 50.0 mg of anhydrous sodium sulfate.
The suspension was stirred at 60 °C for 120 h. The resultant
was filtered, and the filtrate was evaporated to give a syrup
which was separated by chromatography (CHCl3/CH3OH, 20:
1) to afford 681.0 mg (84%) of crude 20, which was directly
used in next reaction without further purification.
(1R)-1-(2′,2′-Dim eth oxyeth yl)-6-m eth oxy-1,2,3,4-tetr ah y-
d r oca r bolin e (21). To a stirred solution of 209.0 mg (0.48
mmol) of 19 in 10.0 mL of methanol was added 5.0 mg of 6 N
hydrochloric acid. The reaction mixture was stirred at room
temperature until TLC analysis (CHCl3/CH3OH, 20:1) indi-
cated complete disappearance of 19. The reaction mixture was
neutralized with sodium carbonate and filtered. The filtrate
was evaporated to remove methanol. The residue was purified
by chromatography (CHCl3/CH3OH, 20:1) to yield 124.0 mg
(89%) of 21. The properties for compound 21 are provided in
the Supporting Information.
R a cem ic 1-(2,2-Dim et h oxyet h yl)-1,2,3,4-t et r a h yd r o-
ca r bolin e (24). The stirring solution of 31.2 mg (0.2 mmol)
of tryptamine in 5 mL of chloroform and 3 mL of methanol
was acidified with 80 mg of concentrated hydrochloric acid to
pH 2 at room temperature. To the solution 32.8 mg (0.2 mmol)
of 1,1,3,3-tetramethoxypropane was added. The reaction mix-
ture was stirred at room temperature for 45 h by which time
TLC analysis (CHCl3:CH3OH, 16:1) indicated complete disap-
pearance of tryptamine and neutralized with sodium carbon-
ate. After filtration and evaporation the residue was purified
by chromatograph CHCl3/CH3OH (30:1) furnished 39.0 mg
(75%) of 24, as colorless powder. The properties for compound
24 are provided in the Supporting Information.
Ack n ow led gm en t. The author Peng Shiqi wishes
to thank the National Natural Science Foundation and
the Key Reseach Project (G 1998051111) of China for
financial support.
Th e Kin etic Resolu tion of Ra cem ic 1-(2′,2′-Dim eth oxy-
eth yl)-1,2,3,4-tetr a h yd r oca r bolin e 24. To a stirred solution
of 260.3 mg (1.00 mmol) of racemic 24 and 104.5 mg (0.5 mmol)
of (2S,3R)-2-benzoylamino-1,3-butanediol (10) in 15.0 mL of
chloroform was added 10.0 mg of PPTS. The suspension was
stirred at room temperature for 3 d, and then TLC (CHCl3/
Su p p or tin g In for m a tion Ava ila ble: The characteriza-
tion data for compounds 1-24. This material is available free
of charge via the Internet at http/pubs.acs.org.
J O0057351