Synthesis of tryptophan derivatives via a palladium-catalyzed N-heteroannulation

Article abstract of DOI:10.1016/j.tetasy.2008.10.032

Tryptophan derivatives were prepared from 2-(2-nitrophenyl)-2-propen-1-yl substituted pyrazines, derived from Schoellkopf's chiral auxiliary, using a palladium-catalyzed, carbon monoxide-mediated reductive N-heteroannulation reaction. A diastereomeric ratio of products ranging from 4:1 to >30:1 was observed.

Full text of DOI:10.1016/j.tetasy.2008.10.032

Tetrahedron: Asymmetry 19 (2008) 2775–2783
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of tryptophan derivatives via a palladium-catalyzed
N-heteroannulation
*
Christopher A. Dacko, Novruz G. Akhmedov, Björn C. G. Söderberg
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Tryptophan derivatives were prepared from 2-(2-nitrophenyl)-2-propen-1-yl substituted pyrazines,
derived from Schöllkopf’s chiral auxiliary, using a palladium-catalyzed, carbon monoxide-mediated
reductive N-heteroannulation reaction. A diastereomeric ratio of products ranging from 4:1 to >30:1
was observed.
Received 3 September 2008
Accepted 21 October 2008
Available online 10 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
sponding tryptophan ester (Scheme 1). A drawback to this
methodology is the formation of regioisomers in some cases.
The second use of Schöllkopf’s chiral auxiliary in tryptophan
synthesis is the alkylation of the chiral 2,5-dihydro-3,6-dialkoxy-
5-(1-methylethyl)pyrazines with either 3-bromomethyl6- or 3-
N,N-dimethylaminomethyl7-indoles (Scheme 2). These reactions
afford tryptophan derivatives in high yields and diastereomeric ra-
tios (P30:1). Potential drawbacks to this route are the availability
of substituted indole electrophiles and the need to protect the
indole nitrogen.
We and others have developed a facile palladium-catalyzed,
carbon monoxide-mediated reductive N-heteroannulation of 1-
(2-nitrophenyl)-1-alkenes affording indole derivatives.8 Based on
this methodology, a novel and expedient route to optically active
tryptophan derivatives was envisioned using a building block also
derived from Schöllkopf’s chiral auxiliary. The goal was to develop
Tryptophan derivatives are important building blocks for the
synthesis of more complex indole alkaloids. Among several other
methods, tryptophan and a variety of functionalized tryptophan
derivatives can be prepared using two general strategies employ-
ing Schöllkopf’s chiral auxiliary. Based on Larock’s1 palladium-cat-
alyzed heteroannulation of alkynes and 2-halo-1-benzeneamines
to afford indoles, Cook et al. developed a methodology using 12
for the preparation of both
D- and L- tryptophan derivatives
(Scheme 1).3 Very high enantioselectivities (>99:1) have been
observed. Cook et al. have extensively used this reaction in the
total synthesis of mitragynine, 9-methoxygeissoschizol, 9-methoxy-
Nb-methylgeissoschizol,4 (+)-12-methoxy-Na-methylvellosimine,
(+)-12-methoxyaffinisine, and (ꢀ)-fuchsiaefoline.5 The chiral auxil-
iary is readily removed by treatment with HCl to give the corre-
OEt
OEt
N
N
NH2
CO2Et
N
OEt
N
I
OEt
TES
HCl
Pd(OAc)2, Na2CO3
LiCl, DMF, 77%
+
90%
N
N
NH2
TES
H
H
1
Scheme 1.
* Corresponding author. Tel.: +1 3042933534; fax: +1 3042934904.
E-mail address: bjorn.soderberg@mail.wvu.edu (B. C. G. Söderberg).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.032

2776
C. A. Dacko et al. / Tetrahedron: Asymmetry 19 (2008) 2775–2783
OEt
N
N
OEt
Br
OEt
N
+
N
91%
N
N
OEt
BOC
BOC
Scheme 2.
a short reaction sequence that would be useful for the preparation
tions in order to establish if the sequence was viable. Thus, com-
pound 4 was treated with bis(dibenzylidenacetone)palladium,
1,10-phenanthroline, and 1,3-bis(diphenylphosphino)propane
under 6 atm of carbon monoxide in DMF at 120 °C. The expected
tryptophan derivative 5 was isolated without any additional dete-
rioration of the isomer ratio (Scheme 3). It should be noted that the
reaction of 4 using our original, simpler, palladium diacetate-
triphenylphosphine catalyst system did not affect cyclization.10
In order to improve the isomer ratio of 4, we next turned our
attention to a catalyst system consisting of bis(dibenzylidene)pal-
ladium (5 mol %), triphenylphosphine (20 mol %), and copper
iodide (75 mol %) in DMF at ambient temperature.11 These
conditions gave a higher yield of 4 (64%) and only one diastereo-
mer was observed in the crude 1H NMR spectrum.
Reversing the polarity of the Kosugi–Migita–Stille cross-cou-
pling partners was next examined. The goal was to develop a more
flexible coupling partner to be used with an array of aromatic
halides. The bromine of the chiral auxiliary ent-312 was trans-
formed into a trimethyltin group using hexamethylditin in the
presence of a palladium catalyst (Scheme 4). Note that the enantio-
of novel amino acids related to tryptophan having either a
configuration. Herein we report the results of this study.
D- or L-
2. Results and discussion
Kosugi–Migita–Stille cross-coupling of 2-nitrophenyltributyltin
2
with (2S,5R)-2,5-dihydro-3,6-dimethoxy-2-(2-bromo-2-pro-
penyl)-5-(1-methylethyl)pyrazine 39 was initially examined. The
reaction of
3
using bis(acetonitrile)palladium dichloride
(5 mol %), triphenylarsine (10 mol %), and copper iodide
(10 mol %) in N-methylpyrrolidone at 80 °C gave the expected
product 4 (Scheme 3). However, an unacceptable amount of iso-
merization (4:1–10:1) of one of the chiral centers was observed.
The mechanism for the isomerization is unclear. However, the
isomerization appears to be thermally induced since heating a
sample of pure 4 in DMF at 120 °C for 12 h resulted in a 5:1 diaste-
reomeric mixture. Although poor selectivity was obtained in some
coupling reactions of 2 and 3, the isomeric mixture was subjected
to the previously reported reductive N-heteroannulation condi-
OMe
OMe
OMe
N
N
N
SnBu3
N
N
PdCl2(MeCN)2
AsPh3, CuI, NMP
N
+
OMe
OMe
NO2
OMe
Br
NO2
NO2
2
3
4 (10:1, 46%)
OMe
OMe
N
N
N
N
Pd(dba)2, 1,10-phenanthroline
dppp, CO (6 atm), 120 oC, DMF
OMe
OMe
N
N
H
H
5 (10:1, 53%)
Scheme 3.
OMe
OMe
N
OMe
N
N
N
Pd(dba)2, PPh3, Sn2Me6
iPr2NEt, PhH
Pd(dba)2, CuI
N
N
PPh3, DMF
I
OMe
OMe
OMe
Br
Me3Sn
NO2
NO2
ent-3
6 (80%)
ent-4 (58%, dr = 15:1)
Scheme 4.

C. A. Dacko et al. / Tetrahedron: Asymmetry 19 (2008) 2775–2783
2777
mer of 3 (compared to Scheme 3) was used in all the reactions
discussed below. Coupling of 6 with 2-nitro-1-iodobenzene gave
ent-4 in a 15:1 diastereomeric ratio.
for the indole product, the diastereoselectivity for hydroxyindole
32 was surprisingly high >30:1.
A number of annulation precursors were prepared via coupling
of 6 with halonitroarenes using the Pd(dba)2–PPh3–CuI conditions.
The results of these reactions are summarized in Table 1. In con-
trast to the reaction described in Scheme 3, no epimerization
was apparent in any of the coupling reactions (entries 2–11). Thus,
methoxy-, fluoro-, carbomethoxy-, and nitro-functionalized sub-
strates, in addition to a pyridine derivative, were obtained in 58–
82% yield (entries 1–7). We were unable to couple either 3-meth-
oxy-2-nitro-1-iodobenzene or 6-methoxy-2-nitro-1-iodobenzene
with 6. Only the homo-coupling product 7 and recovered aryl
iodide were isolated from the reaction mixtures (Scheme 5).13
The iodides were transformed instead into the corresponding tin
compounds 1414 and 15 using a related procedure as for the prep-
aration of 6 (Scheme 4). Kosugi–Migita–Stille cross-coupling of 14
and 15 with alkenylbromide ent-3 gave the expected products 16
and 17 (entries 8 and 9).
In addition to the tryptophan precursors, homotryptophan and
isotryptophan precursors 20 and 21 were prepared by the stereo-
selective alkylation of Schöllkof’s chiral auxilliary with 2-bromo-
4-iodo-1-butene and 1,3-dibromo-1-propene to give 18 and 19,
respectively (Scheme 6). The alkylation products were subse-
quently coupled with 2 to give 20 and 21 (Table 1, entries 10
and 11).
With a selection of substrates having both electron-withdraw-
ing and electron-donating substituents on the aromatic ring in
hand 8–13, 16–17, 20–21 (Table 1), the palladium-catalyzed N-
heteroannulation was next examined. The starting material was
completely consumed in all cases. Depending on the functional
group on the aromatic ring, a varying degree of isomerization
was observed for most substrates. The isopropyl groups of the ma-
jor and minor isomers were readily distinguished by 1H NMR. A
characteristic of the minor cis-isomers is the significant upfield
shift of the isopropyl methyl group resonances. One methyl group
resonates between 0.02 and 0.38 ppm while the other between
0.81 and 0.94 ppm in the 1H NMR spectra. The corresponding
methyl resonances for the major trans-isomers were observed at
0.61–0.66 and 0.91–1.00 ppm, respectively. This upfield shift can
be explained by a conformation wherein the isopropyl group is
shielded by the aromatic ring of the indole nucleus.15,16
3. Conclusion
In summary, we have developed a novel route to tryptophan
derivatives using two sequential palladium-catalyzed reactions, a
Kosugi–Migita–Stille cross-coupling and a carbon monoxide-med-
iated reductive N-heteroannulation. This reaction sequence may be
useful for the preparation of novel amino acids related to trypto-
phan having either D- or L-configuration.
4. Experimental
4.1. General procedures
NMR spectra were determined in CDCl3 at 600 MHz (1H NMR)
or 150 MHz (13C NMR). The chemical shifts are expressed in d val-
ues relative to Me4Si (0.0 ppm, 1H and 13C) or CDCl3 (77.0 ppm, 13C)
internal standards.
Tetrahydrofuran (THF) was distilled from sodium benzophe-
none ketyl prior to use. Hexanes and ethyl acetate were distilled
from calcium hydride. Chemicals prepared according to the litera-
ture procedures have been footnoted as first time used; anhydrous
benzene, DMF, NMP, and toluene and all other reagents were
obtained from commercial sources and used as received. All reac-
tions were performed under a nitrogen atmosphere in oven-dried
glassware unless stated otherwise. Solvents were removed from
reaction mixtures and products extracted on a rotary evaporator
at water aspirator pressure. Chromatography was performed on
Silica Gel 60 (40–63 lm, EMD).
4.1.1. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-methylethyl)-2-
(2-trimethylstannyl-2-propen-1-yl)pyrazine 6
To a solution of (2R,5S)-2-(2-bromo-2-propen-1-yl)-2,5-dihy-
dro-5-(1-methylethyl)-3,6-dimethoxypyrazine ent-312b (1.00 g,
3.30 mmol) in benzene (25 mL) at ambient temperature and under
an atmosphere of nitrogen were added diisopropylethylamine
(85 mg, 0.66 mmol) and hexamethylditin (2.16 g, 6.60 mmol), fol-
lowed by bis(dibenzylideneacetone)palladium (Pd(dba)2) (95 mg,
0.16 mmol) and triphenylphosphine (PPh3) (173 mg, 0.66 mmol).
The solution was heated for 24 h at 80 °C. The reaction mixture
was quenched by the addition of CuSO4 (satd-aqueous, 150 mL).
The reaction mixture was extracted with hexane (3 ꢁ 100 mL)
and the combined organic layers were washed with brine
(100 mL). The combined organic phases were dried over MgSO4, fil-
tered through Celite, and the solvents were removed under
reduced pressure. The resulting residue was purified by chroma-
tography (hexanes/EtOAc, 99:1) to afford 6 (1.01 g, 2.61 mmol,
80%) as a colorless oil. 1H NMR d 0.13 (s, 9H), 0.67 (d, J = 6.6 Hz,
3H), 1.03 (d, J = 6.6 Hz, 3H), 2.26 (dsept, J = 7.2, 3.6 Hz, 1H), 2.59
(dd, J = 13.2, 7.2 Hz, 1H), 2.83 (dd, J = 13.2, 7.2 Hz, 1H), 3.66 (s,
3H), 3.68 (s, 3H), 3.89 (t, J = 3.6 Hz, 1H), 4.05 (pent, J = 3.6 Hz,
1H), 5.25 (d, J = 3.0 Hz, 1H), 5.72 (d, J = 3.0 Hz, 1H); 13C NMR d
ꢀ8.8, 16.6, 19.1, 31.7, 44.3, 52.2, 52.4, 56.4, 60.7, 128.4, 151.7,
Good
yields
(78–88%)
and
diastereomeric
ratios
(dr = 12:1?30:1) were observed for three of the four possible
methoxy-substituted substrates (entries 2, 3 and 8). In contrast,
the more hindered compound 17 gave 29 with both a lower yield
(47%) and lower diastereomeric ratio (dr = 6:1, entry 9). The isom-
erization may occur before cyclization to give the indole. However,
isomerization was also observed by simply heating a sample of 23
(dr = 22:1) in DMF at 120 °C for 16 h resulting in a 7:1 diastereo-
meric mixture. Electron-withdrawing groups (–F, –CO2Me, and
–NO2) were also tolerated and gave the expected products (entries
4–6). However, the fluoro-substituted compound 10 gave 24 with a
significant amount of isomerization (dr = 4.5:1) although the reac-
tion proceeded in excellent yield. A very low yield of product was
obtained from cyclization of the nitro-substituted compound 12.
The starting material was completely consumed in the reaction;
however, no additional product was isolated.
Pyridine-derived substrate 13 smoothly gave aza-tryptophan
derivative 27 (entry 7). The homotryptophan derivative 30, the
one-carbon homolog of ent-5, was obtained from 20 in good yield
with a 15:1 diastereomeric ratio (entry 10). Finally, annulation of
21 gave the isotryptophan derivative 31 in low yield with almost
complete isomerization (entry 11). In addition, an incomplete
reduction forming an N-hydroxyindole 32 was also observed as a
minor product.17 Considering the high degree of isomerization
163.5, 163.7; IR (neat) 1220, 1692 cmꢀ1; ½a D25
¼ ꢀ12:0 (c 1.2,
ꢂ
CH2Cl2); HRMS (ESI) calcd for C15H29N2O2Sn (M+H+) 389.1251,
found 389.1246.
4.1.2. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-methylethyl)-2-
(2-(2-nitrophenyl)-2-propen-1-yl)pyrazine ent-4
To a solution of 6 (400 mg, 1.03 mmol) in DMF (10 mL) were
added 2-nitro-1-iodobenzene (214 mg, 0.861 mmol), Pd(dba)2
(25 mg, 0.043 mmol), and PPh3 (45 mg, 0.17 mmol). Next CuI
(123 mg, 0.646 mmol) was added in one portion and the reaction

2778
C. A. Dacko et al. / Tetrahedron: Asymmetry 19 (2008) 2775–2783
Table 1
Kosugi–Migita–Stille coupling and N-heteroannulation to give tryptophans
Entry
Halide
Tin reagent
Alkylation producta
Tryptophan derivative
OMe
OMe
OMe
R
N
N
N
1
2
I
1
N
N
N
R
R
NO2
OMe
OMe
OMe
Me3Sn
N
NO2
H
6
R = H
ent-4 (58%, dr = 15:1)
8 (68%)
9 (69%)
10 (61%)
11 (62%)
ent-5 (85%, dr = 15:1)
22 (70%, dr = 12:1)
23 (85%, dr = 22:1)
24 (84%, dr = 4.5:1)
25 (73%, dr = 10:1)
26 (12%, dr >30:1)
2
3
4
5
6
R = 4-OMe
R = 5-OMe
R = 4-F
R = 4-CO2Me
R = 4-NO2
b
12 (82%)
OMe
OMe
OMe
N
N
N
N
N
Cl
N
N
N
7
N
OMe
OMe
NO2
OMe
Me3Sn
N
H
NO2
13 (60%)
6
27 (79%, dr = 11:1)
OMe
OMe
OMe
N
N
R
1
N
SnMe3
NO2
N
R
N
8
N
R
OMe
OMe
2
OMe
N
Br
NO2
H
ent-3
R = 6-OMe, 14
16 (54%)
17 (70%)
28 (88%, dr > 30:1)
29 (47%, dr = 6:1)
9
R = 3-OMe, 15 (57%)c
MeO
N
MeO
N
OMe
N
N
SnBu3
N
N
OMe
OMe
10
NO2
Br
OMe
2
N
H
NO2
18
20 (73%)
30 (72%, dr = 16:1)
MeO
N
OMe
SnBu3
OMe
N
N
N
N
NO2
MeO
11
NO2
OMe
N
N
Br
OMe
R
21 (78%)
2
31 (R=H, 35%, dr = 1.2:1)
32 (R=OH, 11%, dr > 30:1)
19
a
Yield of isolated product and diastereomeric ratio in parentheses.
The corresponding bromide was used.
Prepared from the corresponding 1-iodo-compound and Me6Sn2.
b
c
mixture was stirred at ambient temperature for 26 h. The mixture
was diluted with Et2O (50 mL), washed with 10% aqueous NH4OH
(3 ꢁ 50 mL), H2O (50 mL), and brine (50 mL). The organic phase
was dried over MgSO4, filtered, and the solvents were removed

C. A. Dacko et al. / Tetrahedron: Asymmetry 19 (2008) 2775–2783
2779
OMe
OMe
N
OMe
N
I
Pd(dba)2, CuI
PPh3, DMF
+
N
N
N
NO2
OMe
N
OMe
Me3Sn
OMe
OMe
6
7 (22%)
Scheme 5.
OMe
OMe
OMe
N
N
N
1) BuLi, DMEU, THF
2)
1) BuLi, THF
N
N
N
I
2)
Br
Br
Br
OMe
Br
OMe
OMe
Br
19 (76%)
18 (31%)
Scheme 6.
under reduced pressure. The resulting oil was purified by chroma-
tography (hexanes/EtOAc, 97:3) to afford ent-4 [(2R,5S)/
(2S,5S) = 15:1, 173 mg, 0.500 mmol, 58%] as a yellow oil. 1H NMR
d 0.61 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 2.15 (dsept,
J = 6.6, 3.6 Hz, 1H), 2.84 (dd, J = 13.8, 6.0 Hz, 1H), 2.92 (dd,
J = 13.8, 6.0 Hz, 1H), 3.39 (s, 3H), 3.50 (s, 3H), 3.77 (t, J = 3.6 Hz,
1H), 4.06 (q, J = 6.0 Hz, 1H), 5.11 (s, 1H), 5.26 (s, 1H), 7.22 (d,
J = 7.2 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.90
(d, J = 8.4 Hz, 1H); 13C NMR d 16.6, 18.9, 31.9, 40.4, 51.9, 52.1,
55.1, 60.9, 118.6, 124.0, 127.8, 131.9, 132.6, 138.7, 144.2, 147.9,
(51 h), gave after extraction and chromatography (hexanes/EtOAc,
95:5) 8 (221 mg, 0.589 mmol, 68%) as a yellow oil. 1H NMR d 0.62
(d, J = 7.2 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 2.16 (dsept, J = 7.2, 3.6 Hz,
1H), 2.80 (dd, J = 13.8, 6.0 Hz, 1H), 2.89 (dd, J = 13.8, 6.0 Hz, 1H),
3.45 (s, 3H), 3.52 (s, 3H), 3.78 (t, J = 3.6 Hz, 1H), 3.85 (s, 3H), 4.04
(dt, J = 4.2, 2.4 Hz, 1H), 5.06 (d, J = 1.2 Hz, 1H), 5.21 (s, 1H), 7.03
(dd, J = 8.4, 2.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 3.0 Hz,
1H); 13C NMR d 16.6, 18.9, 31.9, 40.5, 52.0, 52.1, 55.0, 55.8, 60.8,
108.7, 118.1, 119.1, 131.0, 132.8, 143.9, 148.2, 158.9, 162.6,
163.1; IR (neat) 1220, 1528, 1692 cmꢀ1; ½a D25
¼ ꢀ20:2 (c 1.0,
ꢂ
162.5, 163.2; IR (neat) 1233, 1242, 1350, 1515, 1693 cmꢀ1
¼ ꢀ21:8 (c 1.2, CH2Cl2); HRMS (ESI) calcd for C18H24N3O4
(M+H+) 346.1767, found 346.1761.
;
CH2Cl2); HRMS (ESI) calcd for C19H26N3O5 (M+H+) 376.1873, found
376.1867.
½ ꢂ
a 2D5
4.1.5. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(2-(5-methoxy-2-
nitrophenyl)-2-propen-1-yl)-5-(1-methylethyl)pyrazine 9
Reaction of 3-iodo-4-nitro-1-methoxybenzene (240 mg,
0.861 mmol) with 6 (400 mg, 1.03 mmol) in the presence of
Pd(dba)2 (25 mg, 0.043 mmol), PPh3 (45 mg, 0.17 mmol), and CuI
(123 mg, 0.646 mmol) in DMF (10 mL), as described for ent-4
(43 h), gave after extraction and chromatography (hexanes/EtOAc,
95:5) 9 (224 mg, 0.597 mmol, 69%) as a yellow oil. 1H NMR d 0.63
(d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 2.18 (dsept, J = 6.6, 3.0 Hz,
1H), 2.86 (dd, J = 14.4, 6.0 Hz, 1H), 2.94 (dd, J = 14.4, 6.0 Hz, 1H),
3.45 (s, 3H), 3.52 (s, 3H), 3.79 (t, J = 3.6 Hz, 1H), 3.86 (s, 3H), 4.06
(dt, J = 4.2, 1.8 Hz, 1H), 5.09 (d, J = 1.8 Hz, 1H), 5.23 (d, J = 1.8 Hz,
1H), 6.65 (d, J = 3.0 Hz, 1H), 6.84 (dd, J = 9.6, 3.0 Hz, 1H), 8.02 (d,
J = 9.6 Hz, 1H); 13C NMR d 16.5, 18.8, 31.7, 40.3, 51.9, 52.0, 55.0,
55.7, 60.8, 112.9, 116.7, 117.5, 126.8, 140.6, 141.6, 145.2, 162.5,
4.1.3. Alternative method. (2S,5R)-2,5-Dihydro-3,6-dimethoxy-
5-(1-methylethyl)-2-(2-(2-nitrophenyl)-2-propen-1-yl)-
pyrazine 4
To a solution of (2S,5R)-2-(2-bromo-2-propen-1-yl))-2,5-dihy-
dro-5-(1-methylethyl)-3,6-dimethoxypyrazine
3 (310 mg, 1.02
mmol) in N-methylpyrrolidone (3 mL) were added tributyl-
(2-nitrophenyl)stannane (506 mg, 1.23 mmol), PdCl2(PhCN)2
(20 mg, 0.051 mmol), and AsPh3 (31 mg, 0.10 mmol). Next CuI
(19 mg, 0.10 mmol) was added and the reaction mixture was stir-
red at 80 °C for 3 days. The mixture was diluted with EtOAc
(20 mL), washed with 10% aqueous NH4OH (3 ꢁ 20 mL), H2O
(20 mL), and brine (20 mL). The organic phase was dried over
MgSO4, filtered, and the solvents were removed under reduced
pressure. The resulting oil was purified by chromatography (hex-
anes/EtOAc, 95:5) to afford
4
[(2S,5R/2R,5R) = 10:1, 162 mg,
162.7, 163.0; IR (neat) 1230, 1336, 1513, 1693 cmꢀ1
;
0.469 mmol, 46%] as a yellow oil. 1H NMR (partial data minor iso-
mer) d 0.72 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 3.10 (dd,
J = 14.4, 4.9 Hz, 2H), 3.50 (s, 3H), 3.62 (s, 3H), 5.10 (s, 1H), 5.30
(s, 1H).
½
a 2D5
ꢂ
¼ ꢀ17:5 (c 1.2, CH2Cl2); HRMS (ESI) calcd for C19H26N3O5
(M+H+) 376.1873, found 376.1867.
4.1.6. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(2-(4-fluoro-2-
nitrophenyl)-2-propen-1-yl)-5-(1-methylethyl)pyrazine 10
4.1.4. (2R,5S)-2,5-Dihydro-2-(2-(4-methoxy-2-nitrophenyl)-2-
propen-1-yl)-5-(1-methylethyl)-3,6-dimethoxy-pyrazine 8
Reaction of 1-iodo-4-methoxy-2-nitrobenzene (240 mg,
0.861 mmol) with 6 (400 mg, 1.03 mmol) in the presence of
Pd(dba)2 (25 mg, 0.043 mmol), PPh3 (45 mg, 0.17 mmol), and CuI
(123 mg, 0.646 mmol) in DMF (10 mL), as described for ent-4
Reaction
of
4-fluoro-1-iodo-2-nitrobenzene
(230 mg,
0.861 mmol) with 6 (400 mg, 1.03 mmol) in the presence of
Pd(PPh3)2Cl2 (30 mg, 0.043 mmol), PPh3 (23 mg, 0.86 mmol), and
CuI (123 mg, 0.646 mmol) in DMF (10 mL), as described for ent-4
(72 h), gave after extraction and chromatography (hexanes: EtOAc,
95:5) 10 (191 mg, 0.526 mmol, 61%) as a yellow oil. 1H NMR d 0.62

2780
C. A. Dacko et al. / Tetrahedron: Asymmetry 19 (2008) 2775–2783
(d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 2.17 (dsept, J = 6.6, 3.0 Hz,
1H), 2.81 (dd, J = 14.4, 6.0 Hz, 1H), 2.91 (dd, J = 14.4, 6.0 Hz, 1H),
3.44 (s, 3H), 3.52 (s, 3H), 3.79 (t, J = 4.2 Hz, 1H), 4.04 (dt, J = 4.2,
2.4 Hz, 1H), 5.09 (d, J = 1.8 Hz, 1H), 5.27 (d, J = 1.8 Hz, 1H), 7.21
(d, J = 2.4 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.64 (ddd, J = 8.4, 1.8,
0.6 Hz, 1H); 13C NMR d 16.6, 18.9, 31.9, 40.4, 52.0, 52.1, 55.0,
60.9, 111.6 (d, J = 26.3 Hz), 119.0, 119.8 (d, J = 20.7 Hz), 133.5 (d,
J = 7.1 Hz), 134.8 (d, J = 3.9 Hz), 143.3, 148.0 (d, J = 7.8 Hz), 161.0
(d, J = 249.3 Hz), 162.5, 163.3; IR (neat) 808, 1219, 1234, 1245,
4.1.10. Bis-2,3-((2R,5S)-2,5-dihydro-3,6-dimethoxy-5-
methylethyl-2-pyrazinylmethyl)-1,4-butadiene 712b
To a solution of 6 (370 mg, 0.956 mmol) in DMF (10 mL) was
added 1-iodo-3-methoxy-2-nitrobenzene (133 mg, 0.478 mmol),
Pd(dba)2 (14 mg, 0.024 mmol), PPh3 (25 mg, 0.096 mmol) and CuI
(68 mg, 0.36 mmol). The reaction was stirred at ambient tempera-
ture for 48 h. Next Et2O (30 mL) was added and the organic phase
was washed with NH4OH (10%, aq, 3 ꢁ 30 mL), H2O (30 mL), and
brine (30 mL). The organic phase was dried over MgSO4, filtered,
and the solvent was removed under reduced pressure. The result-
ing oil was purified by chromatography (hexanes/EtOAc, 95:5) to
afford 7 (47 mg, 0.10 mmol, 22%) as a yellow oil. 1H NMR d 0.65
(d, J = 6.6 Hz, 6H), 1.02 (d, J = 6.6 Hz, 6H), 2.23 (dsept, J = 7.2,
3.6 Hz, 2H), 2.46 (dd, J = 13.8, 7.2 Hz, 2H), 2.93 (dd, J = 13.8,
4.2 Hz, 2H), 3.62 (s, 6H), 3.66 (s, 6H), 3.83 (t, J = 3.6 Hz, 2H), 4.15
(pent, J = 3.6 Hz, 2H), 4.85 (s, 2H), 5.13 (d, J = 1.8 Hz, 2H); 13C
NMR d 16.5, 19.1, 31.4, 39.0, 52.0, 52.2, 55.3, 60.6, 115.1, 145.1,
1347, 1550, 1692 cmꢀ1; ½a D25
¼ ꢀ26:5 (c 1.4, CH2Cl2); HRMS (ESI)
ꢂ
calcd for C18H23FN3O4 (M+H+) 364.1673, found 364.1667.
4.1.7. Methyl 4-(1-((2R,5S)-2,5-dihydro-5-(1-methylethyl)-3,6-
dimethoxypyrazin-2-yl)prop-2-en-1-yl)-3-nitrobenzoate 11
Reaction
of
methyl
4-iodo-3-nitrobenzoate
(263 mg,
0.861 mmol) with 6 (400 mg, 1.03 mmol) in the presence of
Pd(dba)2 (25 mg, 0.043 mmol), PPh3 (45 mg, 0.17 mmol), and CuI
(123 mg, 0.646 mmol) in DMF (10 mL), as described for ent-4
(72 h), gave after extraction and chromatography (hexanes/EtOAc,
97:3) 11 (215 mg, 0.533 mmol, 62%) as a yellow oil. 1H NMR d 0.62
(d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 2.16 (dsept, J = 6.6, 3.0 Hz,
1H), 2.85 (dd, J = 13.8, 6.0 Hz, 1H), 2.95 (dd, J = 13.8, 6.0 Hz, 1H),
3.38 (s, 3H), 3.51 (s, 3H), 3.79 (t, J = 3.6 Hz, 1H), 3.96 (s, 3H), 4.06
(dt, J = 4.2, 2.4 Hz, 1H), 5.17 (s, 1H), 5.34 (s, 1H), 7.33 (d,
J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.54 (s, 1H); 13C NMR d
16.6, 18.9, 31.9, 40.2, 52.0, 52.1, 52.6, 55.0, 60.9, 119.6, 125.2,
130.0, 132.2, 133.0, 142.9, 143.5, 147.9, 162.4, 163.4, 164.9; IR
163.0, 163.2; IR (neat) 1011, 1194, 1232, 1693 cmꢀ1
;
½
a 2D5
ꢂ
¼ ꢀ50:8 (c 1.2, CH2Cl2); HRMS (ESI) calcd for C24H39N4O4
(M+H+) 447.2971, found 447.2966.
4.1.11. (3-Methoxy-2-nitrophenyl)trimethylstannane 15
To
a solution of 1-iodo-3-methoxy-2-nitrobenzene (1.57 g,
5.63 mmol) in toluene (25 mL) were added hexamethylditin
(2.03 g, 6.19 mmol), Pd(PPh3)2Cl2 (39 mg, 0.056 mmol), and PPh3
(30 mg, 0.11 mmol). The reaction mixture was heated at 80 °C
and stirred for 4 days. It was then diluted with EtOAc (50 mL)
and washed with 10% aqueous NH4OH (3 ꢁ 50 mL), H2O (50 mL),
and brine (50 mL). The organic phase was dried over MgSO4, fil-
tered, and the solvents were removed under reduced pressure.
The resulting oil was purified by chromatography (hexanes) to
afford 15 (1.02 g, 3.23 mmol, 57%) as a yellow oil.18 1H NMR d 0.33
(s, 9H), 3.92 (s, 3H), 7.03 (dd, J = 8.4, 1.2 Hz, 1H), 7.11 (dd, J = 7.2,
1.2 Hz, 1H), 7.43-7.47 (m, 1H); 13C NMR d ꢀ8.3, 56.3, 113.4,
(neat) 1113, 1240, 1283, 1532, 1692, 1729 cmꢀ1; ½a D25
¼ ꢀ8:1 (c
ꢂ
1.0, CH2Cl2); HRMS (ESI) calcd for C20H26N3O6 (M+H+) 404.1822,
found 404.1816.
4.1.8. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(2-(2,4-
dinitrophenyl)-2-propen-1-yl)-5-(1-methylethyl)pyrazine 12
Reaction of 1-bromo-2,4-dinitrobenzene (213 mg, 0.861 mmol)
with 6 (400 mg, 1.03 mmol) in the presence of Pd(dba)2 (25 mg,
0.043 mmol), PPh3 (45 mg, 0.17 mmol), and CuI (123 mg,
0.646 mmol) in DMF (10 mL), as described for ent-4 (72 h), gave
after extraction and chromatography (hexanes/EtOAc, 95:5) 12
(276 mg, 0.707 mmol, 82%) as a yellow oil. 1H NMR d 0.62 (d,
J = 7.2 Hz, 3H), 0.98 (d, J = 7.2 Hz, 3H), 2.16 (dsept, J = 6.6, 3.0 Hz,
1H), 2.84 (dd, J = 14.4, 6.0 Hz, 1H), 2.98 (dd, J = 14.4, 6.0 Hz, 1H),
3.39 (s, 3H), 3.54 (s, 3H), 3.80 (t, J = 4.2 Hz, 1H), 4.05 (dt, J = 4.2,
2.4 Hz, 1H), 5.21 (s, 1H), 5.41 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 8.34
(dd, J = 8.4 Hz, 2.4, 1H), 8.75 (d, J = 2.4 Hz, 1H); 13C NMR d 16.6,
18.9, 32.0, 40.3, 52.1, 52.2, 55.0, 61.0, 119.6, 120.6, 126.5, 133.2,
142.7, 144.9, 146.7, 147.8, 162.3, 163.7; IR (neat) 1237, 1350,
127.8, 132.4, 139.9, 146.2, 152.4; IR (neat) 775, 1269, 1519 cmꢀ1
.
4.1.12. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(2-(2-methoxy-6-
nitrophenyl)prop-2-en-1-yl)-5-(1-methylethyl)pyrazine 16
Reaction of (6-methoxy-2-nitrophenyl)trimethylstannane 148c
(470 mg, 1.49 mmol) with ent-3 (225 mg, 0.744 mmol) in the pres-
ence of Pd(dba)2 (21 mg, 0.037 mmol), PPh3 (39 mg, 0.15 mmol),
and CuI (106 mg, 0.558 mmol) in DMF (10 mL), as described for
ent-4 (36 h), gave after extraction and chromatography (hexanes/
EtOAc, 95:5) 16 (151 mg, 0.402 mmol, 54%) as a yellow oil. 1H
NMR d 0.68 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 2.17 (dsept,
J = 6.6, 3.0 Hz, 1H), 2.81 (br s, 1H), 2.97 (d, J = 12.0 Hz, 1H), 3.38
(s, 3H), 3.57 (s, 3H), 3.82 (s, 3H), 3.90 (t, J = 3.6 Hz, 1H), 4.17 (t,
J = 3.6 Hz, 1H), 5.05 (s, 1H), 5.43 (d, J = 1.2, 1H), 7.02 (dd, J = 7.8,
0.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.33 (dd, J = 7.8, 0.6 Hz, 1H);
13C NMR d 16.9, 18.9, 32.1, 40.6, 52.1, 52.2, 55.0, 56.2, 61.0,
114.0, 115.5, 119.2, 127.2, 127.9, 138.2, 150.1, 157.4, 163.1,
1529, 1691 cmꢀ1; ½a D25
¼ ꢀ4:3 (c 1.1, CH2Cl2); HRMS (ESI) calcd
ꢂ
for C18H23N4O6 (M+H+) 391.1618, found 391.1612.
4.1.9. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(2-(3-nitropyridin-
2-yl)prop-2-en-1-yl)-5-(1-methylethyl)pyrazine 13
Reaction of 2-chloro-3-nitropyridine (136 mg, 0.861 mmol)
with 6 (400 mg, 1.03 mmol) in the presence of Pd(dba)2 (25 mg,
0.043 mmol), PPh3 (45 mg, 0.17 mmol), and CuI (123 mg,
0.646 mmol) in DMF (10 mL), as described for ent-4 (24 h), gave
after extraction and chromatography (EtOAc) 13 (180 mg,
0.520 mmol, 60%) as an orange oil. 1H NMR d 0.63(d, J = 7.2 Hz,
3H), 0.99 (d, J = 7.2 Hz, 3H), 2.16 (dsept, J = 6.6, 3.0 Hz, 1H), 2.97
(dd, J = 13.8, 6.0 Hz, 1H), 3.17 (dd, J = 13.8, 6.0 Hz, 1H), 3.23 (s,
3H), 3.58 (s, 3H), 3.92 (t, J = 3.6 Hz, 1H), 4.19 (dt, J = 4.2, 2.4 Hz,
1H), 5.37 (s, 1H), 5.45 (s, 1H), 7.32 (dd, J = 8.4, 4.8 Hz, 1H), 8.06
(d, J = 8.4 Hz, 1H), 8.73 (dd, J = 4.8, 1.2 Hz, 1H); 13C NMR d 16.7,
18.9, 31.8, 39.3, 51.6, 52.1, 55.5, 60.9, 121.3, 121.9, 131.7, 142.7,
145.3, 151.6, 155.0, 162.2, 163.7; IR (neat) 732, 785, 1225, 1354,
163.2; IR (neat) 799, 1055, 1230, 1527, 1693 cmꢀ1; ½a D25
¼ ꢀ27:2
ꢂ
(c 1.0, CH2Cl2); HRMS (ESI) calcd for C19H26N3O5 (M+H+)
376.1873, found 376.1867.
4.1.13. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(2-(3-methoxy-2-
nitrophenyl)prop-2-en-1-yl)-5-(1-methylethyl)pyrazine 17
Reaction of 15 (142 mg, 0.449 mmol) with ent-3 (113 mg,
0.374 mmol) in the presence of Pd(dba)2 (11 mg, 0.019 mmol),
PPh3 (20 mg, 0.075 mmol), and CuI (53 mg, 0.28 mmol) in DMF
(10 mL), as described for ent-4 (72 h), gave after extraction and
chromatography (hexanes/EtOAc, 95:5) 17 (99 mg, 0.26 mmol,
70%) as a yellow oil. 1H NMR d 0.65 (d, J = 7.2 Hz, 3H), 1.00 (d,
J = 6.6 Hz, 3H), 2.19 (dsept, J = 7.2, 3.6 Hz, 1H), 2.71 (dd, J = 14.4,
7.2 Hz, 1H), 2.94 (dd, J = 13.2, 3.6 Hz, 1H), 3.46 (s, 3H), 3.58 (s,
3H), 3.87 (s, 3H), 3.92 (t, J = 3.6 Hz, 1H), 4.08 (dt, J = 4.2, 3.6 Hz,
1527, 1683 cmꢀ1; ½a D25
¼ þ4:8 (c 1.0, CH2Cl2); HRMS (ESI) calcd
ꢂ
for C17H23N4O4 (M+H+) 347.1719, found 347.1714.

C. A. Dacko et al. / Tetrahedron: Asymmetry 19 (2008) 2775–2783
2781
1H), 5.17 (d, J = 1.2 Hz, 1H), 5.24 (d, J = 0.6 Hz, 1H), 6.90 (t,
J = 7.8 Hz, 2H), 7.32 (t, J = 7.8 Hz, 1H); 13C NMR d 16.7, 18.9, 31.9,
40.7, 52.0, 52.1, 54.8, 56.4, 60.9, 110.9, 119.9, 121.5, 130.2, 136.8,
140.3, 141.0, 150.6, 162.7, 163.3; IR (neat) 1055, 1250, 1532,
3.65 (s, 3H), 3.67 (s, 3H), 3.92 (t, J = 3.6 Hz, 1H), 4.02 (dt, J = 4.2,
3.6 Hz, 1H), 4.99 (s, 1H), 5.19 (d, J = 1.2 Hz, 1H), 7.30 (d,
J = 7.8 Hz, 1H), 7.40 (t, J = 8.4Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.85
(d, J = 7.8 Hz, 1H); 13C NMR d 16.6, 19.0, 31.8, 31.9, 32.6, 52.3,
52.4, 54.8, 60.8, 114.4, 124.0, 127.9, 131.0, 132.4, 138.5, 146.9,
1693 cmꢀ1; ½a 2D5
¼ þ3:7 (c 1.0, CH2Cl2); HRMS (ESI) calcd for
ꢂ
C19H26N3O5 (M+H+) 376.1873, found 376.1867.
148.4, 163.5, 163.7; IR (neat) 1194, 1235, 1525, 1690 cmꢀ1
;
½
a 2D5
ꢂ
¼ þ4:8 (c 1.0, CH2Cl2); HRMS (ESI) calcd for C19H26N3O4
(M+H+) 360.1923, found 360.1918.
4.1.14. (2R,5S)-2-(3-Bromo-3-buten-1-yl)-2,5-dihydro-3,6-
dimethoxy-5-methylethylpyrazine 18
BuLi (1.91 mL, 4.77 mmol, 2.5 M in hexane) was added to a
ꢀ78 °C cold solution of (S)-2,5-dihydro-3,6-dimethoxy-2-methyl-
ethylpyrazine (800 mg, 4.34 mmol) and N,N0-dimethylethylene
urea (0.99 g, 8.7 mmol) in dry THF (40 mL) under a nitrogen atmo-
sphere. After 1 h, a solution of 2-bromo-4-iodo-1-butene (1.36 g,
5.21 mmol) in dry THF (10 mL) was added over 30 min. The reac-
tion mixture was allowed to warm to ambient temperature over-
night. The reaction was quenched with a 0.1 M phosphate buffer
(30 mL) and extracted with Et2O (3 ꢁ 30 mL). The combined
organic phases were dried over MgSO4, filtered, and the solvents
were removed under reduced pressure. The resulting oil was puri-
fied by chromatography (hexane/EtOAc 9:1) to afford 18 (419 mg,
1.32 mmol, 31%) as a pale yellow oil. 1H NMR d 0.70 (d, J = 7.2 Hz,
3H), 1.04 (d, J = 6.6 Hz, 3H), 1.86–1.92 (m, 1H), 2.19–2.17 (m, 1H),
2.25 (dsept, J = 7.2, 3.6 Hz, 1H), 2.42–2.52 (m, 2H), 3.69 (s, 3H), 3.71
(s, 3H), 3.94 (t, J = 3.0 Hz, 1H), 4.02 (dt, J = 7.2, 4.2 Hz, 1H), 5.39 (d,
J = 1.8 Hz, 1H), 5.57 (d, J = 1.8 Hz, 1H); 13C NMR d 16.7, 19.0, 31.9,
32.6, 37.1, 52.4, 52.5, 54.3, 60.9, 116.5, 134.3, 163.4, 163.8; IR
4.1.17. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-((2-nitrophenyl)-
2-propen-1-yl))-5-(1-methylethyl)pyrazine (E/Z) 21
Reaction of 2 (1.02 g, 2.47 mmol) with 19 (500 mg, 1.65 mmol)
in the presence of Pd(dba)2 (47 mg, 0.083 mmol), PPh3 (86 mg,
0.33 mmol), and CuI (236 mg, 1.24 mmol) in DMF (10 mL), as
described for ent-4 (48 h), gave after extraction and chromato-
graphy (hexanes/EtOAc, 9:1) 21 (444 mg, 1.29 mmol, 78%) as a yel-
low oil. Spectroscopic data from the E/Z-mixture: 1H NMR (Z-
isomer) d 0.68 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 7.2 Hz, 3H), 2.25
(dsept, J = 7.2, 3.6 Hz, 1H), 2.56 (dddd, J = 15.0, 7.2, 6.0, 1.8 Hz,
1H,), 2.66–2.79 (m, 1H, overlapped by 2H of E-isomer), 3.63 (s,
3H), 3.65 (s, 3H), 3.97 (t, J = 3.6 Hz, 1H), 4.08 (dt, J = 4.2, 1.8 Hz,
1H), 5.74 (dt, J = 7.8, 4.2 Hz, 1H), 6.80 (d, J = 12.0 Hz, 1H), 7.40
(dt, J = 8.4, 1.8, 1H), 7.49–7.52 (m, 1H, overlapped by 2H of E-iso-
mer), 7.56 (dt, J = 7.8, 1.2 Hz, 1H), 8.01 (dd, J = 6.6, 1.2 Hz, 1H). 1H
NMR (E-isomer) d 0.69 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H),
2.25 (dsept, J = 7.2, 3.6 Hz, 1H), 2.66–2.79 (m, 2H, overlapped by
1H of Z-isomer), 3.71 (s, 3H), 3.73 (s, 3H), 3.91 (t, J = 3.6 Hz, 1H),
4.18 (dt, J = 3.6, 1.8 Hz, 1H), 6.08 (dt, J = 7.8, 7.2 Hz, 1H), 6.89 (d,
J = 15.6 Hz, 1H), 7.33 (ddd, J = 8.4, 6.0, 3.0 Hz, 1H), 7.49–7.52 (m,
2H, overlapped by 1H of 1H of Z-isomer), 7.86 (d, J = 8.4 Hz, 1H);
13C NMR (both isomers) d 16.5, 16.6, 19.0, 31.8, 32.8, 37.9, 52.3,
52.4, 52.4, 52.5, 55.0, 55.3, 60.8, 60.9, 124.3, 124.4, 127.6, 127.6,
127.7, 128.1, 128.6, 129.6, 131.6, 132.0, 132.6, 132.8, 132.8,
133.1, 147.7, 148.1, 162.8, 162.9, 164.0, 164.2;19 IR (neat) 738,
(neat) 1194, 1234, 1690 cmꢀ1; ½a D25
¼ ꢀ2:3 (c 1.2, CH2Cl2); HRMS
ꢂ
(ESI) calcd for C13H22BrN2O2 (M+H+) 317.0865, found 317.0859.
4.1.15. (2R,5S)-2-(3-Bromo-2-propen-1-yl)-2,5-dihydro-3,6-
dimethoxy-5-methylethylpyrazine 19
At first BuLi (2.71 mL, 5.97 mmol, 2.2 M in cyclohexane) was
added dropwise to a ꢀ78 °C cold solution of (S)-2,5-dihydro-3,6-
dimethoxy-2-methylethylpyrazine (1.00 g, 5.43 mmol) in dry THF
(15 mL) under a nitrogen atmosphere. After stirring for 30 min, a
solution of 1,3-dibromo-1-propene (1.41 g, 7.06 mmol, 1:1 E/Z-
mixture) in THF (5 mL) was slowly added. After stirring for
90 min, the reaction was quenched with water (30 mL) and the
mixture was extracted with Et2O (3 ꢁ 30 mL). The combined
organic phases were dried (MgSO4), filtered, and the solvents were
removed under reduced pressure. The resulting oil was purified by
chromatography (hexane/EtOAc 95:5) to afford 19 (1.25 g,
4.12 mmol, 76%) as a yellow oil. Spectroscopic data from a 1:1 mix-
ture of Z:E-19: 1H NMR d 0.68 (d, J = 6.6 Hz, 3H), 0.69 (d, J = 6.6 Hz,
3H), 1.04 (d, J = 7.2 Hz, 6H), 2.25 (dsept, J = 6.6, 3.0 Hz, 2H), 2.46–
2.50 (m, 1H), 2.53–2.57 (m, 1H), 2.62 (dpent, J = 6.6, 1.2 Hz, 1H),
2.75–2.79 (m, 1H), 3.68 (s, 3H), 3.67 (s, 3H), 3.70 (s, 3H), 3.71 (s,
3H), 3.93–3.95 (m, 2H), 4.04–4.07 (m, 1H), 4.12–4.14 (m, 1H),
6.05–6.09 (m, 3H), 6.22–6.24 (m, 1H); 13C NMR d 16.6, 19.0, 31.8,
34.8, 37.4, 52.4, 52.5, 54.5, 54.8, 60.9, 106.7, 109.7, 130.7, 133.4,
162.5, 163.0, 164.1, 164.3 (6 peaks overlap); IR (neat) 1010,
1236, 1522, 1691 cmꢀ1; ½a D25
¼ ꢀ7:7 (c 1.0, CH2Cl2); HRMS (ESI)
ꢂ
calcd for C18H24N3O4 (M+H+) 346.1767, found 346.1761.
4.1.18. 3-(((2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-
methylethyl)pyrazin-2-yl)methyl)-1H-indole ent-520
At first, ent-4 (140 mg, 0.405 mmol), Pd(dba)2 (14 mg,
0.024 mmol), 1,3-bis-(diphenylphosphino)propane (dppp) (10 mg,
0.024 mmol),
and
1,10-phenanthroline
(phen)
(10 mg,
0.048 mmol) were dissolved in anhydrous DMF (3 mL) in
a
threaded ACE glass pressure tube. The tube was fitted with a pres-
sure head, and the solution was saturated with carbon monoxide
(four cycles of 6 atm of CO). The reaction mixture was heated at
120 °C (oil bath temperature) under CO (6 atm) for 18 h. Water
(10 mL) was added and the orange solution was extracted with
EtOAc (3 ꢁ 30 mL). The combined organic phases were dried over
MgSO4, filtered, and the solvent was removed under reduced pres-
sure. The resulting crude product was purified by chromatography
(hexanes/EtOAc, 8:2 then 1:1) to afford ent-5 [(2R,5S)/
(2S,5S) = 15:1, 108 mg, 0.345 mmol, 85%) as a yellow solid. mp
99–102 °C; 1H NMR d 0.62 (d, J = 7.2 Hz, 3H), 0.93 (d, J = 7.2 Hz,
3H), 2.14 (dsept, J = 7.2, 3.6 Hz, 1H), 3.29 (t, J = 3.6 Hz 2H), 3.37
(t, J = 3.6 Hz, 1H), 3.66 (s, 3H), 3.68 (s, 3H), 4.36 (q, J = 3.6 Hz,
1H), 6.89 (d, J = 1.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 7.13 (t,
J = 7.2 Hz, 1H), 7.26 (d, J = 7.2, 1H), 7.64 (d, J = 7.2 Hz, 1H), 8.03
(br s, 1H); 13C NMR d 16.5, 19.0, 29.5, 31.3, 52.1, 52.2, 56.7, 60.4,
110.7, 111.6, 118.9, 119.4, 121.6, 122.7, 128.4, 135.8, 163.0,
1235, 1691 cmꢀ1; ½a D25
¼ ꢀ14:4 (c 1.4, CH2Cl2); HRMS (ESI) calcd
ꢂ
for C12H20BrN2O2 (M+H+) 303.0708, found 303.0703.
4.1.16. (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(3-(2-
nitrophenyl)-3-buten-1-yl)-5-(1-methylethyl)pyrazine 20
Reaction of tributyl(2-nitrophenyl)stannane
2
(721 mg,
1.75 mmol) with 18 (370 mg, 1.17 mmol) in the presence of
Pd(dba)2 (34 mg, 0.058 mmol), PPh3 (61 mg, 0.23 mmol), and CuI
(167 mg, 0.877 mmol) in DMF (10 mL), as described for ent-4
(18 h), gave after extraction and chromatography (hexanes/EtOAc,
95:5) 20 (308 mg, 0.857 mmol, 73%) as a yellow oil. 1H NMR d 0.68
(d, J = 6.6 Hz, 3H), 1.03 (d, J = 7.2 Hz, 3H), 1.78–1.84 (m, 1H), 1.96–
2.02 (m, 1H), 2.24 (dsept, J = 6.6, 3.6 Hz, 1H), 2.30–2.39 (m, 2H),
163.7; IR (neat) 725, 1010, 1222, 1236, 1660, 1697 cmꢀ1
;
½
a 2D5
ꢂ
¼ ꢀ54:8 (c 1.3, CH2Cl2); HRMS (ESI) calcd for C18H24N3O2
(M+H+) 314.1869, found 314.1863. Partial data for the minor iso-
mer: 1H NMR d 0.12 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H),
3.71 (s, 3H).

2782
C. A. Dacko et al. / Tetrahedron: Asymmetry 19 (2008) 2775–2783
4.1.19. 3-(((2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-
4.1.22. Methyl 3-(((2R,5S)-2,5-dihydro-3,6-dimethoxy-5-(1-
methylethyl)-pyrazin-2-yl)methyl)-1H-indole-6-carboxylate 25
Reaction of 11 (87 mg, 0.22 mmol) in the presence of Pd(dba)2
(7.0 mg, 0.013 mmol), dppp (5.0 mg, 0.013 mmol), phen (5.0 mg,
0.026 mmol), and CO (6 atm) in DMF (3 mL), as described for ent-
5 (23 h), gave after chromatography (hexanes/EtOAc, 8:2 then
6:4) 25 [(2R,5S)/(2S,5S) = 10:1, 60 mg, 0.16 mmol, 73%] as a tan
solid. Mp 119–121 °C; 1H NMR d 0.61 (d, J = 6.6 Hz, 3H), 0.91 (d,
J = 7.2 Hz, 3H), 2.12 (dsept, J = 7.2, 3.0 Hz Hz, 1H), 3.29 (d,
J = 4.2 Hz, 2H), 3.34 (t, J = 3.6 Hz, 1H), 3.64 (s, 3H), 3.67 (s, 3H),
3.92 (s, 3H), 4.35 (q, J = 4.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.66
(d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.4, 1.2 Hz, 1H), 8.05 (s, 1H), 8.57
(br s, 1H); 13C NMR d 16.4, 18.9, 29.4, 31.4, 51.8, 52.2, 52.3, 56.6,
60.4, 112.1, 113.3, 119.0, 120.0, 123.3, 126.3, 132.0, 135.1, 162.8,
163.8, 168.3; IR (neat) 769, 1086, 1196, 1237, 1276, 1697,
methylethyl)-pyrazin-2-yl)methyl)-6-methoxy-1H-indole 22
Reaction of 8 (112 mg, 0.298 mmol) in the presence of Pd(dba)2
(10 mg, 0.018 mmol), dppp (7.0 mg, 0.018 mmol), phen (7.0 mg,
0.036 mmol), and CO (6 atm) in DMF (3 mL), as described for ent-
5 (26 h), gave after chromatography (hexanes/EtOAc, 8:2 then
6:4) 22 [(2R,5S)/(2S,5S) = 12:1, 71 mg, 0.21 mmol, 70%] as a yellow
solid. Mp 111–114 °C; 1H NMR d 0.61 (d, J = 6.6 Hz, 3H), 0.92 (d,
J = 7.2 Hz, 3H), 2.13 (dsept, J = 6.6, 3.0 Hz, 1H), 3.24 (d, J = 4.8 Hz,
2H), 3.36 (t, J = 3.0 Hz, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 3.82 (s, 3H),
4.33 (q, J = 4.2 Hz, 1H), 6.74 (dd, J = 8.4, 1.8 Hz, 1H), 6.76 (d,
J = 1.8 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H),
7.88 (br s, 1H); 13C NMR d 16.5, 19.0, 29.6, 31.3, 52.1, 52.2, 55.6,
56.8, 60.4, 94.2, 109.0, 111.6, 120.0, 121.4, 122.9, 136.4, 156.2,
163.0, 163.7; IR (neat) 780, 1027, 1157, 1224, 1693 cmꢀ1
;
½
a 2D5
ꢂ
¼ ꢀ44:6 (c 1.2, CH2Cl2); HRMS (ESI) calcd for C19H26N3O3
1710 cmꢀ1; ½a 2D5
¼ ꢀ43:1 (c 1.2, CH2Cl2); HRMS (ESI) calcd for
ꢂ
(M+H+) 344.1974, found 344.1969. Partial data of minor isomer:
1H NMR d 0.15 (d, J = 7.2 Hz, 3H), 0.85 (d, J = 7.2 Hz, 3H), 3.65 (s,
3H), 3.70 (s, 3H); 13C NMR d 30.0, 30.9, 52.0, 52.1, 57.2, 60.7,
108.9, 120.2, 121.6, 122.9.
C20H26N3O4 (M+H+) 372.1923, found 372.1918.
4.1.23. 3-(((2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-
methylethyl)-pyrazin-2-yl)methyl)-6-nitro-1H-indole 26
Reaction of 12 (165 mg, 0.423 mmol) in the presence of
Pd(dba)2 (15 mg, 0.025 mmol), dppp (11 mg, 0.025 mmol), phen
(10 mg, 0.051 mmol), and CO (6 atm) in DMF (3 mL), as described
for ent-5 (18 h), gave after chromatography (hexanes/EtOAc, 8:2
then 6:4) 26 (18 mg, 0.050 mmol, 12%) as a yellow oil. 1H NMR d
0.62 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 2.13 (dsept, J = 6.6,
3.6 Hz, 1H), 3.30 (d, J = 4.8 Hz, 2H), 3.39 (t, J = 3.6 Hz, 1H), 3.65 (s,
3H), 3.68 (s, 3H), 4.35 (q, J = 4.2 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H),
7.70 (d, J = 9.0 Hz, 1H), 7.98 (dd, J = 8.4, 1.8 Hz, 1H), 8.28 (d,
J = 1.8 Hz, 1H), 8.50 (br s, 1H); 13C NMR d 16.5, 18.9, 29.2, 31.5,
52.2, 52.3, 56.4, 60.6, 107.9, 113.2, 114.7, 119.5, 128.7, 133.1,
134.1, 143.2, 162.6, 164.0; IR (neat) 735, 1011, 1220, 1309, 1504,
4.1.20. 3-(((2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-
methylethyl)-pyrazin-2-yl)methyl)-5-methoxy-1H-indole 23
Reaction of 9 (145 mg, 0.386 mmol) in the presence of Pd(dba)2
(13 mg, 0.023 mmol), dppp (10 mg, 0.023 mmol), phen (9.0 mg,
0.046 mmol), and CO (6 atm) in DMF (3 mL), as described for ent-
5 (22 h), gave after chromatography (hexanes/EtOAc, 8:2 then
6:4) 23 [(2R,5S)/(2S,5S) = 22:1, 112 mg, 0.326 mmol, 85%] as a yel-
low oil. 1H NMR d 0.63 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H),
2.15 (dsept, J = 6.6, 3.6 Hz, 1H), 3.26 (d, J = 4.8 Hz, 2H), 3.40 (t,
J = 3.6 Hz, 1H), 3.67 (s, 3H), 3.70 (s, 3H), 3.86 (s, 3H), 4.36 (q,
J = 4.2 Hz, 1H), 6.80 (dd, J = 8.4, 1.8 Hz, 1H), 6.88 (d, J = 2.4 Hz,
1H), 7.10 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 7.95 (br s,
1H); 13C NMR d 16.4, 19.0, 29.5, 31.2, 52.2, 52.3, 55.9, 56.7, 60.4,
101.3, 111.3, 111.4, 111.9, 123.6, 128.8, 131.0, 153.7, 163.0,
1692 cmꢀ1; ½a 2D5
¼ ꢀ36:6 (c 1.3, CH2Cl2); HRMS (ESI) calcd for
ꢂ
C18H23N4O4 (M+H+) 359.1719, found 359.1714. Partial data for
minor isomer: 1H NMR
d 0.02 (d, J = 6.6 Hz, 3H), 0.81 (d,
J = 7.2 Hz, 3H), 3.66 (s, 3H), 3.70 (s, 3H), 3.93 (s, 3H), 7.14 (d,
J = 1.8 Hz, 1H), 8.03 (s, 1H), 8.50 (br s, 1H).
163.8; IR (neat) 794, 1012, 1232, 1435, 1692 cmꢀ1; ½a D25
¼ ꢀ49:5
ꢂ
(c 1.2, CH2Cl2); HRMS (ESI) calcd for C19H26N3O3 (M+H+)
344.1974, found 344.1969. Partial data for the minor isomer: 1H
NMR d 0.15 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 3.72 (s, 3H).
4.1.24. 3-(((2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-methyl-
ethyl)-pyrazin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine 27
Reaction of 13 (140 mg, 0.404 mmol) in the presence of
Pd(dba)2 (14 mg, 0.024 mmol), dppp (10 mg, 0.024 mmol), phen
(10 mg, 0.049 mmol), and CO (6 atm) in DMF (3 mL), as described
for ent-5 (18 h), gave after chromatography (hexanes/EtOAc, 8:2
then EtOAc) 27 [(2R,5S)/(2S,5S) = 11:1, 100 mg, 0.318 mmol, 79%]
as a tan solid. Mp 148–151 °C; 1H NMR d 0.64 (d, J = 7.2 Hz, 3H),
0.96 (d, J = 6.6 Hz, 3H), 2.18 (dsept, J = 6.6, 3.0 Hz, 1H), 3.27 (dd,
J = 14.4, 6.6 Hz, 1H), 3.53 (m, 2H), 3.63 (s, 3H), 3.66 (s, 3H), 4.40
(dt, J = 3.6, 3.0 Hz, 1H), 7.05 (dd, J = 8.4, 4.8 Hz, 1H), 7.28 (d,
J = 1.8 Hz, 1H), 7.60 (dd, J = 8.4, 1.2 Hz, 1H), 8.46 (dd, J = 4.2,
1.2 Hz, 1H), 8.84 (br s, 1H); 13C NMR d 16.6, 19.0, 28.4, 31.5, 52.2,
52.3, 56.4, 60.6, 112.7, 116.5, 118.0, 126.4, 128.6, 142.6, 145.9,
4.1.21. 6-Fluoro-3-(((2R,5S)-2,5-dihydro-3,6-dimethoxy-5-(1-
methylethyl)-pyrazin-2-yl)methyl)-1H-indole 24
Reaction of 10 (118 mg, 0.325 mmol) in the presence of
Pd(dba)2 (11 mg, 0.019 mmol), dppp (8.0 mg, 0.019 mmol), phen
(8.0 mg, 0.039 mmol), and CO (6 atm) in DMF (3 mL), as described
for ent-5 (21 h), gave after chromatography (hexanes/EtOAc, 8:2
then 6:4) 24 [(2R,5S)/(2S,5S) = 4.5:1, 90 mg, 0.27 mmol, 84%] as a
yellow oil. Spectroscopic data of (2R,5S)-24 from the mixture: 1H
NMR d 0.62 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 2.13 (dsept,
J = 6.6, 3.6 Hz, 1H), 3.25 (d, J = 4.2 Hz, 2H), 3.37 (t, J = 3.6 Hz, 1H),
3.65 (s, 3H), 3.67 (s, 3H), 4.34 (q, J = 4.2 Hz, 1H), 6.83 (dt, J = 9.6,
1.8 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 9.0, 1.8 Hz, 1H),
7.53 (dd, J = 8.4, 5.4 Hz, 1H), 8.03 (br s, 1H); 13C NMR d 16.5,
19.0, 29.5, 31.3, 52.1, 52.2, 56.7, 60.4, 97.0 (d, J = 25.6 Hz), 107.7
(d, J = 24.6 Hz), 111.8, 120.1 (d, J = 6.3 Hz), 122.9 (d, J = 3.9 Hz),
125.0, 135.6 (d, J = 12.0 Hz), 159.8 (d, J = 235.6 Hz), 162.9, 163.8;
163.5, 163.6; IR (neat) 765, 1012, 1220, 1695 cmꢀ1; ½a D25
¼ ꢀ23:2
ꢂ
(c 1.1, CH2Cl2); HRMS (ESI) calcd for C17H23N4O2 (M+H+)
315.1821, found 315.1816. Partial data for the minor isomer: 1H
NMR d 0.38 (d, J = 7.2 Hz, 3H), 0.94 (d, J = 7.2 Hz, 3H), 3.64 (s,
3H), 3.69 (s, 3H).
IR (neat) 799, 1012, 1140, 1194, 1220, 1692 cmꢀ1; ½a D25
¼ ꢀ41:8
ꢂ
(c 0.9, CH2Cl2); HRMS (ESI) calcd for C18H23FN3O2 (M+H+)
332.1774, found 332.1769. Partial data for the minor (2S,5S)-24
isomer: 1H NMR d 0.10 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H),
1.82 (dsept, J = 7.2, 3.6 Hz, 1H), 3.64 (s, 3H), 3.70 (s, 3H); 13C
NMR d 16.2, 19.4, 29.8, 31.1, 52.0, 52.2, 57.0, 60.7, 96.9 (d,
J = 25.6 Hz), 107.7 (d, J = 24.6 Hz), 112.6, 120.3 (d, J = 6.3 Hz),
123.1 (d, J = 4.0 Hz), 125.1, 135.7 (d, J = 12.0 Hz), 159.9 (d,
J = 235.6 Hz), 162.4, 163.2.
4.1.25. 3-(((2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-
methylethyl)-pyrazin-2-yl)methyl)-4-methoxy-1H-indole 28
Reaction of 16 (123 mg, 0.327 mmol) in the presence of
Pd(dba)2 (11 mg, 0.020 mmol), dppp (8 mg, 0.02 mmol), phen
(8 mg, 0.04 mmol), and CO (6 atm) in DMF (3 mL), as described
for ent-5 (23 h), gave after chromatography (hexanes/EtOAc, 8:2
then 1:1) 28 (99 mg, 0.29 mmol, 88%) as a yellow oil. 1H NMR d
0.66 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H), 2.21 (dsept, J = 7.2,

C. A. Dacko et al. / Tetrahedron: Asymmetry 19 (2008) 2775–2783
2783
3.6 Hz, 1H), 3.18 (ddd, J = 14.4, 7.2, 0.6 Hz, 1H), 3.59 (s, 3H), 3.61
(dd, J = 4.2, 0.6 Hz, 1H), 3.63 (t, J = 3.6 Hz, 1H), 3.69 (s, 3H), 3.91
(s, 3H), 4.36 (pent, J = 3.6 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H), 6.83 (d,
J = 1.8 Hz, 1H), 6.91 (dd, J = 7.8, 0.6 Hz, 1H), 7.04 (t, J = 8.4 Hz,
1H), 7.98 (br s, 1H); 13C NMR d 16.5, 19.1, 31.3, 31.4, 52.2, 52.3,
55.0, 57.1, 60.4, 99.3, 104.3, 112.6, 118.0, 121.4, 122.4, 137.6,
(s, 3H), 3.91 (t, J = 3.6 Hz, 1H), 4.24 (dt, J = 3.0, 1.8 Hz, 1H), 6.28
(d, J = 9.6 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H),
7.29 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H); 13C NMR d 16.7, 16.9, 19.0,
19.4, 31.0, 32.1, 32.8, 33.6, 52.4, 52.5, 52.6, 52.7, 55.9, 56.1, 60.7,
61.1, 100.7, 100.9, 110.4, 110.5, 119.3, 119.4, 119.8, 119.9, 120.9,
121.0, 128.3, 128.4, 135.9, 137.0, 137.1, 161.9, 162.5, 164.1,
155.0, 163.5, 164.2; IR (neat) 701, 1086, 1236, 1690 cmꢀ1
;
164.7; IR (neat) 732, 1229, 1243, 1688 cmꢀ1; ½a D25
¼ þ0:35 (c 1.0,
ꢂ
½
a 2D5
ꢂ
¼ ꢀ22:3 (c 1.0, CH2Cl2); HRMS (ESI) calcd for C19H26N3O3
CH2Cl2); HRMS (ESI) calcd for C18H24N3O2 (M+H+) 314.1869, found
314.1863. Spectroscopic data for 32: 1H NMR d 0.77 (d, J = 7.2 Hz,
3H), 0.99 (d, J = 6.6 Hz, 3H), 2.14 (dsept, J = 6.6, 3.0 Hz, 1H), 3.24
(dd, J = 14.4, 8.4 Hz, 1H), 3.65 (dd, J = 15.0, 3.6 Hz, 1H), 3.81 (s,
3H), 3.82 (s, 3H), 4.01 (t, J = 3.6 Hz, 1H), 4.15 (dt, J = 3.0, 1.8 Hz,
1H), 6.18 (s, 1H), 7.03 (t, J = 7.8 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H),
7.45 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 11.71 (br s, 1H);
13C NMR d 17.6, 19.0, 29.5, 32.9, 53.3, 53.6, 57.8, 62.4, 94.9,
108.1, 118.8, 120.0, 121.0, 123.1, 132.4, 133.8, 162.2, 168.5; IR
(M+H+) 344.1974, found 344.1969.
4.1.26. 3-(((2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-
methylethyl)-pyrazin-2-yl)methyl)-7-methoxy-1H-indole 29
Reaction of 17 (107 mg, 0.285 mmol) in the presence of Pd(dba)2
(10 mg, 0.017 mmol), dppp (7 mg, 0.02 mmol), phen (7 mg,
0.03 mmol), and CO (6 atm) in DMF (3 mL), as described for ent-5
(22 h), gave after chromatography (hexanes/EtOAc, 8:2) 29
[(2R,5S)/(2S,5S) = 6:1, 46.0 mg, 0.134 mmol, 47%] as a yellow oil.
1H NMR d 0.62 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 7.2 Hz, 3H), 2.13 (dsept,
J = 6.6, 3.0 Hz, 1H), 3.26 (d, J = 4.8 Hz, 2H), 3.37 (t, J = 3.6 Hz, 1H),
3.66 (s, 3H), 3.68 (s, 3H), 3.93 (s, 3H), 4.35 (q, J = 4.2 Hz, 1H), 6.59
(d, J = 7.2 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H),
7.24 (d, J = 8.4 Hz, 1H), 8.18 (br s, 1H); 13C NMR d 16.7, 19.2, 29.9,
31.5, 52.3, 52.5, 55.4, 55.5, 56.9, 60.6, 101.7, 112.5, 119.5, 122.5,
126.5, 130.0, 146.1, 163.2, 163.9; IR (neat) 729, 1013, 1048, 1225,
(neat) 1008, 1227, 1250, 1670 cmꢀ1; ½a D25
¼ ꢀ8:5 (c 1.2, CH2Cl2);
ꢂ
HRMS (ESI) calcd for C18H24N3O3 (M+H+) 330.1818, found
330.1812.
Acknowledgments
This work was supported by research grants from the National
Science Foundation (CHE 0611096). NSF-EPSCoR (Grant
#1002165R) is gratefully acknowledged for the funding of a
600 MHz Varian Inova NMR and a Thermo-Finnegan LTQ-FT Mass
Spectrometer and the NMR and MS facilities in the C. Eugene Ben-
nett Department of Chemistry at West Virginia University.
1259, 1693 cmꢀ1; ½a D25
¼ ꢀ25:2 (c 1.1, CH2Cl2); HRMS (ESI) calcd
ꢂ
for C19H26N3O3 (M+H+) 344.1974, found 344.1969.
4.1.27. 3-(2-((2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-
methylethyl)-pyrazin-2-yl)ethyl)-1H-indole 30
Reaction of 20 (138 mg, 0.384 mmol) in the presence of
Pd(dba)2 (13 mg, 0.023 mmol), dppp (9.0 mg, 0.02 mmol), phen
(9.0 mg, 0.05 mmol), and CO (6 atm) in DMF (3 mL), as described
for ent-5 (19 h), gave after chromatography (hexanes/EtOAc, 9:1)
30 [(2R,5S)/(2S,5S) = 16:1, 90.0 mg, 0.275 mmol, 72%) as a yellow
oil. 1H NMR d 0.74 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H),
2.10–2.16 (m, 1H), 2.24–2.33 (m, 2H), 2.72–2.84 (m, 2H), 3.70 (s,
3H), 3.75 (s, 3H), 4.01 (t, J = 3.6 Hz, 1H), 4.14 (dt, J = 4.8, 3.6 Hz,
1H), 6.98 (d, J = 1.8 Hz, 1H), 7.12 (dt, J = 7.8, 0.6 Hz, 1H), 7.19 (dt,
J = 7.2, 1.2 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H),
7.95 (br s, 1H); 13C NMR d 16.7, 19.0, 20.2, 31.8, 34.5, 52.3, 52.4,
55.1, 60.9, 111.0, 116.3, 119.0, 119.1, 121.1, 121.8, 127.6, 136.4,
References
1. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689–6690; (b) Larock,
R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652–7662.
2. Schöllkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl. 1981, 20, 793–795.
3. Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001,
66, 4525–4542.
4. Ma, J.; Yin, W.; Zhou, H.; Cook, J. M. Org. Lett. 2007, 9, 3491–3494.
5. (a) Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249–252; (b) Zhou, H.; Liao,
X.; Yin, W.; Ma, J.; Cook, J. M. J. Org. Chem. 2006, 71, 251–259; For related
compounds, see: (c) Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339–
3342.
6. For a recent example, see: Jain, H. D.; Zhang, C.; Zhou, S.; Zhou, H.; Ma, J.; Liu,
X.; Liao, X.; Deveau, A. M.; Dieckhaus, C. M.; Johnson, M. A.; Smith, K. S.;
Macdonald, T. L.; Kakeya, H.; Osada, H.; Cook, J. M. Bioorg. Med. Chem. 2008, 16,
4626–4651.
163.6, 163.9; IR (neat) 701, 1086, 1236, 1690 cmꢀ1; ½a D25
¼ ꢀ2:7
ꢂ
(c 0.8, CH2Cl2); HRMS (ESI) calcd for C19H26N3O2 (M+H+)
328.2025, found 328.2020. Partial data for minor isomer: 1H
NMR d 0.79 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 7.2 Hz, 3H), 3.71 (s,
3H), 3.76 (s, 3H), 7.02 (d, J = 1.8 Hz, 1H).
7. For a recent example, see: Okada, M.; Sato, I.; Cho, S. J.; Suzuki, Y.; Ojika, M.;
Dubnau, D.; Sakagami, Y. Biosci., Biotechnol., Biochem. 2004, 68, 2374–2387.
8. For some recent examples and references, see: (a) Clawson, R. W., Jr.;
Söderberg, B. C. G. Tetrahedron Lett. 2007, 48, 6019–6021; (b) Kuethe, J. T.;
Davies, I. W. Tetrahedron 2006, 62, 11381–11390; (c) Clawson, R. W., Jr.;
Deavers, R. E., III.; Akhmedov, N. G.; Söderberg, B. C. G. Tetrahedron 2006, 62,
10829–10834; (d) Davies, I. W.; Smitrovich, J. H.; Sidler, R.; Qu, C.; Gresham, V.;
Bazaral, C. Tetrahedron 2005, 61, 6425–6437; (e) Söderberg, B. C. G.; Hubbard, J.
W.; Rector, S. R.; O’Neil, S. N. Tetrahedron 2005, 61, 3637–3649.
9. Papageorgiou, C.; Florineth, A.; Mikol, V. J. Med. Chem. 1994, 37, 3674–3676.
10. Shriver, J. A.; Söderberg, B. C. J. Org. Chem. 1997, 62, 5838–5845.
11. Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359–5364.
4.1.28. 2-((2,5-Dihydro-3,6-dimethoxy-5-(1-methylethyl)-
pyrazin-2-yl)methyl)-1H-indole 31 and 2-(((2R,5S)-2,5-dihydro-
3,6-dimethoxy-5-(1-methylethyl)-pyrazin-2-yl)methyl)-1-
hydroxyindole 32
The reaction of 21 (217 mg, 0.628 mmol) in the presence of
Pd(dba)2 (22 mg, 0.038 mmol), dppp (16 mg, 0.038 mmol), phen
(15 mg, 0.075 mmol), and CO (6 atm) in DMF (3 mL), as described
for ent-5 (22 h), gave after chromatography (hexanes/EtOAc, 95:5
then 9:1) 31 [(2R,5S)/(2S,5S) = 1.2:1, 68 mg, 0.22 mmol, 35%] and
32 (22 mg, 0.067 mmol, 11%) both as a yellow oil. Spectroscopic
data of 31 from the isomer mixture: 1H NMR (minor) d 0.58 (d,
J = 7.2 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 2.23 (dsept, J = 6.6, 3.0 Hz,
1H), 2.91 (ddd, J = 14.4, 9.6, 0.6 Hz, 1H), 3.49 (dd, J = 14.4, 3.0 Hz,
1H), 3.76 (s, 3H), 3.83 (s, 3H), 4.00 (dd, J = 4.8, 3.6, 1H), 4.30
(ddd, J = 9.6, 4.8, 1.8 Hz, 1H), 6.28 (d, J = 9.6 Hz, 1H), 7.06 (t,
J = 7.8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H),
7.55 (s, 1H); 1H NMR (major) d 0.73 (d, J = 7.2 Hz, 3H), 1.03 (d,
J = 6.6 Hz, 3H), 2.23 (dsept, J = 6.6, 3.0 Hz, 1H), 3.03 (ddd, J = 14.4,
9.6, 0.6 Hz, 1H), 3.44 (dd, J = 14.4, 3.0 Hz, 1H), 3.77 (s, 3H), 3.82
12. ent-3 was prepared from L-valine in 5 steps: (a) Chen, J.; Corbin, S. P.; Holman,
N. J. Org. Process Res. Dev. 2005, 9, 185–187; (b) Møller, B. S.; Benneche, T.;
Undheim, K. Tetrahedron 1996, 52, 8807–8812.
13. Homocoupling of ent-3 has previously been reported, see Ref. 12b.
14. Scott, T. L.; Yu, X.; Gorugantula, S. P.; Carrero-Martinez, G.; Söderberg, B. C. G.
Tetrahedron 2006, 62, 10835–10842.
15. Siemion, I. Z.; Konopinska, D.; Klis, W. A. Roczniki Chem. 1975, 49, 781–789.
16. For related upfield shifts, see: (a) Pedras, M. S. C.; Biesenthal, C. J.
Phytochemistry 2001, 58, 905–909; (b) Caballero, E.; Avendano, C.; Menedez,
J. C. Tetrahedron: Asymmetry 1998, 9, 3025–3038.
17. (a) Incomplete reduction has been observed in some cases, see: Ref. 8d; (b)
Tollari, S.; Penoni, A.; Cenini, S. J. Mol. Catal. A: Chem. 2000, 152, 47–54.
18. This compound appears to be unstable and we were unable to obtain correct
combustion analyses or HRMS data.
19. One resonance not found.
20. A synthesis of compound 5 was published during our study. However, no
spectroscopical data was reported. Manabe, S.; Ito, Y. Synlett 2008, 880–
882.