Unified synthesis of (-)-folicanthine and (-)-ditryptophenaline enabled by a room temperature nickel-mediated reductive dimerization

Article abstract of DOI:10.1055/s-0033-1339126

A Ni·Phen-mediated reductive homocoupling of an optically active tertiary bromide has been efficiently achieved after the systematic screen of reaction conditions including ligands. This key step establishes sterically hindered vicinal quaternary stereocenters embedded in natural bispyrrolo[2,3-b]indoline alkaloids, thus enabling to realize the first asymmetric total synthesis of (-)-folicanthine via the detailed investigation of a challenging double decarboxylation. Notably, the concise synthesis of diketopiperazine alkaloid (-)-ditryptophenaline was also completed from the common dimeric intermediate. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339126

1908▌
SPECIAL TOPIC
sUpenciailftioepidc Synthesis of (–)-Folicanthine and (–)-Ditryptophenaline Enabled by a
Room Temperature Nickel-Mediated Reductive Dimerization
Concise Synthesis of (–)-Folicanthine and (–)-Ditryptophenaline
Long Luo, Jian-Jian Zhang, Wei-Jian Ling, Yong-Liang Shao, Ya-Wen Wang, Yu Peng*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912586; E-mail: pengyu@lzu.edu.cn
Received: 17.03.2014; Accepted after revision: 05.05.2014
chimonanthine and (±)-folicanthine. Surprisingly, the to-
Abstract: A Ni·Phen-mediated reductive homocoupling of an opti-
tal synthesis of (–)-folicanthine has not been reported yet,7
cally active tertiary bromide has been efficiently achieved after the
although significant progress8 has been made about asym-
metric construction of sterically hindered vicinal quater-
systematic screen of reaction conditions including ligands. This key
step establishes sterically hindered vicinal quaternary stereocenters
embedded in natural bispyrrolo[2,3-b]indoline alkaloids, thus en- nary stereocenters for the access to these two typical C3a–
C3a′-bispyrrolo[2,3-b]indoline alkaloids.9 Herein we
have extended this powerful method to the dimerization of
abling to realize the first asymmetric total synthesis of (–)-folican-
thine via the detailed investigation of a challenging double
decarboxylation. Notably, the concise synthesis of diketopiperazine
chiral tricyclic bromide (–)-1 by means of analogous
alkaloid (–)-ditryptophenaline was also completed from the com-
mon dimeric intermediate.
Ni·Phen catalysis in the presence of Zn dust as a stoichio-
metric reductant (Scheme 1, bottom), and the resulting
Key words: nickel catalysis, reductive homocoupling, dimeric al-
hexacyclic diester (–)-2 has been successfully converted
kaloids, total synthesis, vicinal quaternary stereocenters
into (–)-folicanthine (3). Starting from C2-symmetric (–)-
2 as a common precursor, the expeditious synthesis of
(–)-ditryptophenaline (4) that belongs to the dimeric dik-
Direct cross-coupling of halides has already emerged as a
etopiperazine (DKP) alkaloid10 is also accomplished. To
potentially advantageous method for the formation of C–
the best of our knowledge, this is the first catalytic synthe-
sis of (–)-(4) in terms of the construction of two all-carbon
quaternary carbons.
C bond. It can avoid some problems associated with pre-
formed organometallic reagents, therefore leading to gen-
erally excellent functional-group compatibility.
A
noteworthy advance is the nickel-catalyzed reductive cou-
pling of the challenging alkyl halides.1–5 Recently, Weix1
and Gong2 developed bi- and tridentate amine ligated
nickel-complex-catalyzed transformations toward the fac-
ile construction of C(sp3)–C(sp2) and C(sp3)–C(sp3) bonds
under reducing conditions. In particular, nickel/(R,R)-di-
phenyl-Box-catalyzed asymmetric reductive acyl cross-
coupling with secondary benzyl chlorides has been report-
ed by Reisman;3 Ni/Cy3P or Ni/Me3P-catalyzed reductive
carboxylation of benzyl (pseudo)halides with CO2 has
also been realized by Martin.4 More importantly, Weix1e
provided elegant mechanistic insight to this kind of cross-
electrophile couplings, which would enable rational im-
provement and reliable application of this strategy. Inde-
pendently, we5 have disclosed intermolecular and
unprecedented intramolecular reductive C–C and C–S
bond-forming reactions catalyzed by some nickel com-
plexes, which could be generated from bench stable and
easy-to-handle materials.
previous study: reductive dimerization of racemic tertiary bromide (ref. 6a)
CO2Et
N
Boc
N
EtO2C
Boc
N
Br
N
H
Zn
H
H
+
N
Ni•Bipy
(cat.)
N
H
H
Boc
CO2Et
N
N
N
N
(dl)
Boc
Boc
CO2Et
CO2Et
(meso)
X-ray
1:1
(dl)
this work: homocoupling of chiral tertiary bromide
Boc
N
Boc
N
H
Br
(–)-(3)
H
CO2Me
Zn
folicanthine
CO2Me
CO2Me
3a'
3a
H
N
N
H
H
Ni•Phen
(cat.)
Boc
Boc
(–)-(4)
ditryptophenaline
(–)-1
N
N
H
Boc
Boc
(–)-2
X-ray
However, the utility of these methods in the synthesis of
complex natural products remains elusive. In line with our
recent work on cross-coupling,5 we have already realized
the first Ni/Bipy-catalyzed reductive homocoupling of the
challenging racemic tertiary bromide (Scheme 1, top),6a
and further applied it to the versatile syntheses of both (±)-
Scheme 1 Comparison of reductive homocoupling
Esterification of natural L-tryptophan followed by the
double protection with di-tert-butyl dicarbonate provided
the bis-Boc-tryptophan methyl ester (+)-5 in 80% yield
(Scheme 2 and the experimental section). According to
the known protocol,11 the desired chiral tertiary bromide
(–)-1 with hexahydropyrroloindole scaffold12 can be pre-
pared in 91% yield and decagram scale. The key reductive
SYNTHESIS 2014, 46, 1908–1916
Advanced online publication: 21.05.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339126; Art ID: ss-2014-c0189-st
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Concise Synthesis of (–)-Folicanthine and (–)-Ditryptophenaline
1909
homocoupling was then investigated (Table 1), and the bidentate ligands such as 2,2′-isopropylidenebis(4-phe-
general procedure involved the subjection of (–)-1 into the nyl-2-oxazoline) (L4) showed deleterious effect on the re-
in situ generated nickel catalytic system at room tempera- action outcome (entry 5). Inspired by the preceding
ture. Ligand-free condition (Table 1, entry 1) resulted in utilization of tridentate nitrogen ligands in nickel-cata-
the almost exclusive formation of (+)-5 along with a trace lyzed homocoupling of primary and secondary bro-
of (–)-2, whereas the absence of either Zn or NiCl2 led to mides,13 we checked analogous 4′-(4-tolyl)-2,2′:6′,2′′-
quantitative recovery of the starting (–)-1 (not shown). terpyridine (L5, entry 6) and 2,6-(4-phenyl-2-oxazoli-
These control experiments indicated that the described di- nyl)pyridine (L6, entry 7), and disappointedly found that
merization event is a ligand-controlled reductive homo- even worse results were obtained. However, a little im-
coupling catalyzed by nickel. Thus, a series of ligands provement was indeed observed when NiCl2 was replaced
were next examined, and the 2,2′-bipyridine (L1) used by NiI2 and DMA was employed as the solvent (entries 8
successfully in the previous racemic setting6a was first and 9). Once the determination of these two reaction pa-
evaluated in MeCN (entry 2). Disappointedly, only 24% rameters was completed, a screen of other bidentate li-
yield of (–)-2 was obtained although the meso-dimer that gands besides 2,2′-bipyridine was conducted, and planar
would arise from the homocoupling of dl-1 could be ex- phenanthrolines14 proved to be beneficial (entries 10–16).
cluded. The diminished dimer could be ascribed to the When commercially available L7·H2O was used directly,
substantial formation of (+)-5 that may have resulted from (–)-2 was obtained in 38% yield; pleasingly, this dimer
facile fragmentation of (–)-1 with exo-methoxycarbonyl yield further increased to 50% when anhydrous L7 partic-
group at C2. Other 2,2′-bipyridines L2 and L3 did not ipated in the homocoupling (entry 10 vs 11). Replacement
bring any improvement (entries 3 and 4), whereas other of the ultimate reductant zinc by manganese resulted in
Scheme 2 Unified synthesis of (–)-folicanthine and (–)-ditryptophenaline. Reagents and conditions: (a) AcCl (3.5 equiv), MeOH, 0 °C to r.t.
then 50 °C, 5 h; then NaOH (10.0 equiv), n-Bu4NHSO4 (0.1 equiv), CH2Cl2, r.t.; then (Boc)2O (3.5 equiv), 0 °C to r.t., 24 h, 80%; (b) NBS (1.0
equiv), PPTs (1.0 equiv), CH2Cl2, 0 °C, 30 min, 91%; (c) Zn (1.2 equiv), NiCl2 (30 mol%), 1,10-phenanthroline (45 mol%), and pyridine–DMA,
25 °C, 10 h, 40%; (d) TMSI (8.0 equiv), MeCN, 0 °C to r.t., 30 min, 92%; (e) N-Boc-N-Me-L-Phe-OH (2.4 equiv), HATU (2.4 equiv), Et3N
(6.0 equiv), DMF, 0 °C, 77 h, 36% (41% brsm); (f) neat, 235 °C under vacuum, 30 min, 96%; (g) aq HCHO (6.0 equiv), NaBH(OAc)3 (6.0
equiv), r.t., MeCN, 30 min, 82%; (h) 5 M aq KOH, MeOH–THF, 0 °C to r.t., 3.5 h, then 2-mercaptopyridine N-oxide (3.0 equiv), DMAP (0.1
equiv), TCFH (3.0 equiv), Et3N (8.0 equiv), 6 h, then t-BuSH (24.0 equiv), hν, 2 h, 48%; (i) TMSOTf (20.0 equiv), 2,6-lutidine (20.0 equiv),
CH2Cl2, 0 °C, 30 min, then aq HCHO (20.0 equiv), NaBH(OAc)3 (20.0 equiv), r.t., MeCN, 1.5 h, 85%. HATU: N-[(Dimethylamino)-1H-1,2,3-
triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; TFCH: Chloro-N,N,N′,N′-tetramethylform-
amidinium hexafluorophosphate.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1908–1916

1910
L. Luo et al.
SPECIAL TOPIC
the almost identical dimerization yield (entry 12). The ter- whether this dimerization reaction has applicable poten-
tiary iodide, freshly prepared according to the procedure tial for practical synthesis or not. To our delight, dimeriza-
for (–)-1,15 afforded a slight decrease of (–)-2 (entry 13), tion with 10-fold scale relative to the standard procedure
presumably due to the labile nature of this tricyclic iodide. (Table 1, footnote a) still proceeded well, affording (–)-2
As shown in entry 14, the yield of (–)-2 dropped by 14% in 45% yield, albeit at a lower reaction rate (entry 20).
when the protocol with slow addition of (–)-1 in a dilute Slightly diminished yield of (–)-2 could be observed when
concentration was utilized. The comparison of solvents the dimerization reaction of (–)-1 was further scaled up to
identified DMA still as the superior choice (entries 15 and 3.5 g (entry 21). NiI2 loading can be lowered to 15 or 10
16). Some phenanthrolines with various substituents L8– mol% without a significant loss of dimerization efficiency
L10 were next surveyed (entries 17–19), and 2,9-dimeth- on gram scale (entries 22 and 23), but further lowering
yl-1,10-phenanthroline (neocuproine, L8) was found to nickel catalyst did resulted in the erosion of the dimeriza-
give similar result as that of parent ligand L7, whereas tion (entry 24). Nonetheless, the recovered (+)-5 could be
those ligands with substitution remote from the coordina- readily reconverted into (–)-1 that in turn could be sub-
tion center were detrimental to the dimerization. Finally, jected to the next round of reductive homocoupling. With
attempts to run this reductive homocoupling at large scale the above optimized conditions and recycle process in
with lower nickel catalyst loading were carried out to see hand, the sufficient supply of (–)-2 was then guaranteed.
Table 1 Optimization for Nickel-Catalyzed Reductive Dimerizationa
Boc
N
Boc
N
CO2Me
NHBoc
H
Br
Zn, NiX2
H
CO2Me
CO2Me
CO2Me
2
H
+
ligand
solvent
25 °C, 4 h
H
N
N
H
N
Boc
Boc
(–)-1
Boc
N
N
H
(+)-5
Boc
Boc
(–)-2
R
R
R3
R3
R2
R1
N
N
R2
O
O
N
L1 R = H
L2 R = OMe
L3 R = t-Bu
N
N
N
N
R1
Ph
Ph
L7 R1 = R2 = R3 = H
L6 Ph-Pybox
L8 R1 = Me, R2 = R3 = H
L9 R1 = H, R2 = R3 = Me
L10 R1 = R2 = H, R3 = Ph
N
N
N
O
O
L5 4'-tol-Terpy
N
N
Ph
Ph
L4 Ph-box
Entry
NiX2
Ligand (L)
Solvent
Yield (%)b
(–)-2
(–)-5
1
2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiI2
none
L1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMA
trace
24
16
18
3
90
61
65
62
80
71
82
53
48
47
28
3
L2
4
L3
5
L4
6
L5
12
3
7
L6
8
L1
31
36
38
50
9
L1
DMA
10
11
NiI2
L7·H2O
L7
DMA
NiI2
DMA
Synthesis 2014, 46, 1908–1916
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Concise Synthesis of (–)-Folicanthine and (–)-Ditryptophenaline
1911
Table 1 Optimization for Nickel-Catalyzed Reductive Dimerizationa (continued)
Boc
N
Boc
N
CO2Me
NHBoc
H
Br
Zn, NiX2
H
CO2Me
CO2Me
CO2Me
2
H
+
ligand
solvent
25 °C, 4 h
H
N
N
H
N
Boc
Boc
(–)-1
Boc
N
N
H
(+)-5
Boc
Boc
(–)-2
R
R
R3
R3
R2
R1
N
N
R2
O
O
N
L1 R = H
L2 R = OMe
L3 R = t-Bu
N
N
N
N
R1
Ph
Ph
L7 R1 = R2 = R3 = H
L6 Ph-Pybox
L8 R1 = Me, R2 = R3 = H
L9 R1 = H, R2 = R3 = Me
L10 R1 = R2 = H, R3 = Ph
N
N
N
O
O
L5 4'-tol-Terpy
N
N
Ph
Ph
L4 Ph-box
Entry
NiX2
Ligand (L)
Solvent
Yield (%)b
(–)-2
(–)-5
12c
13d
14e
15
NiI2
NiI2
NiI2
NiI2
NiI2
NiI2
NiI2
NiI2
NiI2
NiI2
NiI2
NiI2
NiI2
L7
L7
L7
L7
L7
L8
L9
L10
L7
L7
L7
L7
L7
DMA
DMA
DMA
DMF
MeCN
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
50
42
36
44
41
45
30
32
45
37
39
37
27
34
38
45
36
44
43
55
46
39
40
45
47
48
16
17
18
19
20f
21g
22h
23i
24j
a The reaction was conducted on a 0.3 mmol scale. A mixture of Zn (1.2 equiv), NiX2 (30 mol%), ligand (1.5 equiv relative to Ni), and pyridine
(1.0 mL) were employed for the generation of Ni·L at 55 °C, and then a solution of (–)-1 in solvent (1.0 mL) was added to the above nickel
complex dropwise at 25 °C. The resulting reaction mixture was stirred for 4 h, and subjected to the workup procedure.
b The yields were estimated by 1H NMR spectroscopic analysis with diethyl phthalate as an internal standard. Another by-product (ca. 10%)
resulted from direct reduction at C3a within (–)-1.
c Mn as the ultimate reductant.
d The corresponding tertiary iodide was employed.
e A solution of (–)-1 in solvent (3.0 mL) was added dropwise over a 3 h period.
f Scale: 3.0 mmol (1.5 g), DMA (3.0 mL), 10 h.
g Scale: 7.0 mmol (3.5 g), DMA (7.0 mL), 24 h.
h Scale: 3.0 mmol, NiI2 (15 mol%), 24 h.
i Scale: 1.5 mmol, NiI2 (10 mol%), 24 h.
j Scale: 1.5 mmol, NiI2 (5 mol%), 24 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1908–1916

1912
L. Luo et al.
SPECIAL TOPIC
Interestingly, Danishefsky and co-workers16 reported the precursor that was conveniently available in 82% yield
isolation of (–)-2, albeit as a by-product (10–15% yield) through permethylation of (–)-6 using formalin and sodi-
during their synthetic studies towards amauromine, and its um triacetoxyborohydride (Scheme 2). Subjection of (–)-
dimeric structure has been deduced by variable tempera- 9 into thermal or photochemical decarboxylation condi-
ture NMR experiments. In our hands, the expected C2- tion led to better yields (up to 16%, entries 3 and 4 vs 1)
symmetry was unambiguously confirmed by its single of (–)-folicanthine (3). The first synthetic sample of (–)-3
20
21.5
crystal X-ray analysis17 (Scheme 2 inset; selected H atoms {[α]D –331 (c 1.0, MeOH); Lit.20a [α]D
–364.4 (c
and Boc groups have been omitted for clarity). The suf- 2.043, MeOH)} demonstrated matched spectroscopic data
ficient amount of (–)-2 with the correct connection of with those published in the previous syntheses for dl and
vicinal quaternary stereocenters paved the way for its sub- (+)-3.6,8a–c Its structure was also unambiguously con-
sequent elaboration for the unified syntheses of (–)-di- firmed by X-ray crystallographic analysis17 using Cu-Kα
tryptophenaline (4) and (–)-folicanthine (3).
radiation, and the absolute configuration was accordingly
assigned as 3aS,8aR,3a′S,8a′R (Scheme 2 inset; selected H
atoms have been omitted for clarity). A two-fold increase
in the yield is still not satisfactory, thus the optimization
investigation was continued. While the direct decarboxyl-
ation via dicarboxylic acid chloride23 proved to be unfruit-
ful (entry 5), the protocol utilized in the related mono-
decarboxylation step by Baran and co-workers24 provided
(–)-3 in 30% yield (entry 6). The simplified procedure
with TCFH25 gave the almost identical result (entry 7).
Any further improvement was not obtained, since the di-
carboxylic acid derived from (–)-9 is somewhat soluble in
water and therefore the loss of some material is inevitable
during the aqueous workup. Gratifyingly, this procedure
with TCFH can be successfully applied to (–)-2, affording
(–)-8 in 48% overall yield that is fairly good as an essen-
tial three-step transformation (78% per step, entry 8 and
Scheme 2). Eventually, TMSOTf-mediated removal26 of
all the Boc groups in (–)-8 followed by reductive amina-
tion of unisolated N-demethylfolicanthine completed the
total synthesis of (–)-folicanthine (3) ultimately in a more
efficient route than that from (–)-6 mentioned above.
As a typical member of DKP alkaloid family, (–)-4 was
isolated from Aspergillus flavus cultures by Büchi and co-
workers18a and the absolute configuration of all eight chi-
ral centers in this molecule was determined as S.18b,c This
secondary metabolite was later identified as a weak inhib-
itor for the human neurokinin 1 receptor.18d Although the
pioneering18b (ca. 3% yield) and later some elegant
synthesis19a–c of (–)-4 has been reported, herein our ap-
proach featured the catalytic stereoselective construction
of vicinal quaternary stereocenters C3 and C3′. As shown
in Scheme 2 (bottom), the present end-game to (–)-4 is
straightforward: global cleavage of Boc protecting groups
in (–)-2 using iodotrimethylsilane delivered bis-ester (–)-
6 in 92% yield, which set the stage for the stepwise pep-
tide coupling for the formation of DKP moiety.10c Accord-
ingly, regioselective condensation of (–)-6 and L-
phenylanaline derivative followed by the pyrolysis of the
resulting amide (–)-7 under vacuum,19c eventually fur-
nished (–)-ditryptophenaline (4). Spectroscopic data of
synthetic (–)-4 {[α]D20 –286 (c 1.0, CH2Cl2); Lit.19b [α]D
–292 (c 0.97, CH2Cl2)} are consistent with those pub-
20
lished in the previous syntheses.19a–c It is noteworthy that In summary, the reductive homodimerization of chiral ter-
the late-stage formation of DKP is a beneficial route for tiary bromide (–)-1 mediated by a nickel complex ligated
the preservation of stereochemical integrity at C11 and to 1,10-phenanthroline could be secured in gram scale.
C15 since this cyclodipeptide moiety was found to be sen- The resulting C2 symmetric hexacycle (–)-2 bearing steri-
sitive toward base-promoted epimerization and autoxida- cally hindered vicinal all-carbon quaternary stereocenters,
tive decomposition, which has been accounted in the can be served as a common intermediate for the unified
distinct preassembly strategy before dimerization by syntheses of (–)-ditryptophenaline (4) and (–)-folican-
Movassaghi.19b
thine (3) via the preservation of methoxycarbonyl group
or not. Notably, these endeavors represent the first catalyt-
ic stereoselective syntheses of these two natural product
molecules.
The pursuit of (–)-folicanthine (3) that was isolated from
the leaves of Calycanthus floridus L. and C. occidenta-
lis,20 was then put on the agenda. However, the seemingly
simple and routine double decarboxylation21 of (–)-2 en
route to (–)-3, proved to be a challenging task. As shown
in Table 2, initial saponification of (–)-2 with aqueous
KOH and the ensuing Barton radical decarboxylation22 of
the resulting dicarboxylic acid failed to give any of N-Boc
carbamate (–)-8 (Table 2, entry 1). The omission of sensi-
tive dicarboxylic acid chloride intermediate, and therefore
the direct formation of thiohydroxamate ester by neutral
2-mercaptopyridine N-oxide and dicarboxylic acid, in-
deed provided (–)-8, albeit in only 8% yield under the ir-
radiation of 450 W Hg lamp (entry 2). It was hypothesized
that the overall efficiency of decarboxylation sequence
could be hampered by the steric hindrance of proximal
Boc groups. We thus explored the feasibility of (–)-9 as a
For product purification by flash column chromatography, silica gel
(200–300 mesh) and petroleum ether (PE; bp 60–90 °C) were used.
All solvents were purified and dried by standard techniques, and
distilled prior to use. Organic extracts were dried over Na2SO4 or
MgSO4, unless otherwise noted. Experiments were conducted under
an argon or N2 atmosphere in oven-dried or flame-dried glassware
with magnetic stirring, unless otherwise specified. NMR spectra
were recorded on 300 and 400 MHz instruments at r.t. All 1H chem-
ical shifts (δ) are reported relative to residual protic solvent (CHCl3:
δ = 7.26 ppm) or internal TMS (TMS: δ = 0.00 ppm), and all 13C
chemical shifts (δ) are reported relative to the solvent (CHCl3: δ =
77.00 ppm). High-resolution mass spectral data were measured with
electrospray ionization (ESI). IR spectra were recorded on an FT-IR
spectrophotometer. The X-ray diffraction studies were carried out
on a Bruker SMART Apex CCD area detector diffractometer
Synthesis 2014, 46, 1908–1916
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Concise Synthesis of (–)-Folicanthine and (–)-Ditryptophenaline
1913
Table 2 Double Decarboxylation Optimization
R
N
R
N
R
N
R
N
H
CO2Me
CO2Me
decarboxylation
H
H
H
H
N
R
N
N
R
N
H
R
R
(–)-9 R = Me
(–)-2 R = Boc
(–)-folicanthine (3) R = Me
(–)-8 R = Boc
Entry
1
Substrate
Conditions
Yield (%)a
(–)-2
5 M aq KOH, MeOH, 0 °C to r.t., 5 h;
0
(COCl)2 (4 equiv), DMF (1 drop), CH2Cl2, 0 °C to r.t., 2.5 h;
2-mercaptopyridine N-oxide sodium salt (3 equiv), (TMS)3SiH (10 equiv), AIBN (0.5 equiv), toluene,
80 °C, 1.5 h
2
(–)-2
5 M aq KOH, MeOH, 0 °C to r.t., 2.5 h;
8
2-mercaptopyridine N-oxide (4 equiv), DCC (3 equiv), DMAP (0.15 equiv), CH2Cl2, 0 °C to r.t., dark,
9 h;
t-BuSH (10 equiv), hν (450 W high-pressure Hg lamp), r.t., 3 h
3
4
(–)-9
(–)-9
5 M aq KOH, MeOH, 0 °C to r.t., 2.5 h; (COCl)2 (4 equiv), DMF (1 drop), CH2Cl2, 0 °C to r.t., 2 h; 16
2-mercaptopyridine N-oxide sodium salt (5 equiv), (TMS)3SiH (8 equiv), AIBN (0.5 equiv), toluene,
80 °C, 3 h
5 M aq KOH, MeOH, 0 °C to r.t., 1.5 h;
13
2-mercaptopyridine N-oxide (3 equiv), DCC (3.5 equiv), DMAP (0.2 equiv), CH2Cl2, 0 °C to r.t., dark,
9 h;
t-BuSH (40 equiv), hν (7 W LED), r.t., 10 h
5
6
(–)-9
(–)-9
5 M aq KOH, MeOH, 0 °C to r.t., 2 h;
(COCl)2 (10 equiv), DMF (1 drop), CH2Cl2, 0 °C to r.t., 2 h;
(TMS)3SiH (3 × 10 equiv), AIBN (3 × 1.5 equiv), toluene, 80 °C, 3 h
0
5 M aq KOH, MeOH, 0 °C to r.t., 1.5 h;
30
(COCl)2 (3.5 equiv), DMF (1 drop), CH2Cl2, 0 °C to r.t., 40 min;
2-mercaptopyridine N-oxide sodium salt (2.4 equiv), Et3N (2 equiv), CH2Cl2, 0 °C to r.t., dark, 0.5 h;
t-BuSH (40 equiv), hν (450 W high-pressure Hg lamp), r.t., 3 h
7
8
(–)-9
(–)-2
5 M aq KOH, MeOH, 0 °C to r.t., 2.5 h;
2-mercaptopyridine N-oxide (3 equiv), DMAP (0.2 equiv), TCFH (2.8 equiv), Et3N (8 equiv), THF,
0 °C, dark, 5 h;
31
48
t-BuSH (20 equiv), hν (450 W high-pressure Hg lamp), r.t., 3 h
5 M aq KOH, MeOH, 0 °C to r.t., 3.5 h;
2-mercaptopyridine N-oxide (3 equiv), DMAP (0.1 equiv), TCFH (3 equiv), Et3N (8 equiv), THF,
0 °C, dark, 6 h;
t-BuSH (20 equiv), hν (450 W high-pressure Hg lamp), r.t., 2 h
a Yield of isolated (–)-3 or (–)-8.
equipped with graphite-monochromated Cu-Kα radiation source
(λ = 1.54184 Å).
above L-tryptophan methyl ester (2.18 g, 10 mmol) in CH2Cl2 (40
mL) were added NaOH (4.0 g, 100 mmol, 10.0 equiv) and n-
Bu4NHSO4 (344 mg, 1 mmol, 0.1 equiv) portionwise at r.t. The re-
action system was cooled to 0 °C, and (Boc)2O (7.63 g, 35 mmol,
3.5 equiv) was added portionwise. The resulting mixture was then
allowed to warm to r.t. and stirred for 24 h. Eventually, the mixture
was diluted with CH2Cl2 (100 mL) and poured into a separatory fun-
nel that contained H2O (10 mL). The combined organic layers were
washed with H2O (3 × 20 mL) and brine (3 × 20 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
resulting L-Nα-Boc-Nβ-Boc-tryptophan methyl ester (+)-5 (3.8 g,
80%) could be used directly for further reactions; brown oil; Rf =
0.58 (PE–EtOAc, 2:1); [α]D21 +45 (c 2.0, CHCl3).
tert-Butyl (+)-(S)-3-[2-(tert-Butoxycarbonylamino)-3-methoxy-
3-oxopropyl]-1H-indole-1-carboxylate (5)16
AcCl (24.3 mL, 343 mmol, 3.5 equiv) was added dropwise to
MeOH (250 mL) under stirring at 0 °C. The stirring was continued
for 15 min followed by the addition of L-tryptophan (20 g, 98 mmol)
portionwise at 0 °C. The reaction mixture was allowed to warm to
r.t. slowly, then heated to 50 °C and stirred for 5 h. After the evap-
oration of MeOH, the residue was diluted with CH2Cl2 (150 mL)
and poured into a separatory funnel. The combined organic layers
were washed with aq NH3 (28%, 20 mL), H2O (20 mL) and brine (3
× 10 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The resulting pale yellow L-tryptophan methyl ester (18.8
g) could be used directly in the next step. To a stirred solution of the
1H NMR (400 MHz, CDCl3): δ = 8.11 (br, 1 H), 7.49 (d, J = 7.6 Hz,
1 H), 7.40 (s, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.23 (t, J = 7.6 Hz, 1
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1908–1916

1914
L. Luo et al.
SPECIAL TOPIC
H), 5.14 (d, J = 7.2 Hz, 1 H), 4.65 (d, J = 7.2 Hz, 1 H), 3.69 (s, 3 H),
3.27 (dd, J = 5.2, 14.8 Hz, 1 H), 3.18 (dd, J = 5.2, 14.8 Hz, 1 H),
1.67 (s, 9 H), 1.44 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.3, 155.0, 149.5, 135.3, 130.5,
124.4, 124.0, 122.5, 118.8, 115.2, 115.0, 83.6, 76.9, 53.6, 52.3, 28.2
(3 C), 28.1 (3 C), 27.7.
Dimethyl (–)-(2S,2′S,3aS,3′aS,8aR,8′aR)-2,2′,3,3′,8,8a,8′,8′a-
Octahydro-1H,1′H-3a,3′a-bipyrrolo[2,3-b]indole-2,2′-dicar-
boxylate (6)
To a stirred solution of (–)-2 (928 mg, 1.11 mmol) in MeCN (8 mL)
was added TMSI (1.3 mL, 8.8 mmol, 8.0 equiv) dropwise at 0 °C
over a 5 min period. The resulting mixture was allowed to warm to
r.t., stirred for 30 min, and then quenched with aq NaHCO3 (5 mL).
The mixture was diluted with CHCl3 (25 mL) and the combined or-
ganic layers were washed with H2O (3 × 5 mL), and brine (3 × 5
mL), dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash column chromatogra-
phy (PE–acetone, 1:2) on silica gel (basified with Et3N) to afford the
desired (–)-6 (443 mg, 92%) as a colorless solid; mp 181–182 °C;
Rf = 0.20 (PE–acetone, 1:1); [α]D20 –204 (c 0.5, CH2Cl2).
ESI-MS: m/z = 419.2 [M + H]+.
1,8-Di-tert-butyl 2-Methyl (–)-(2S,3aR,8aR)-3a-Bromo-3,3a-di-
hydropyrrolo[2,3-b]indole-1,2,8(2H,8aH)-tricarboxylate (1)27
To a stirred solution of the above (+)-5 (2.09 g, 5 mmol) in CH2Cl2
(60 mL) were added NBS (890 mg, 5 mmol, 1.0 equiv) and PPTs
(1.26 g, 5 mmol, 1.0 equiv) portionwise at 0 °C. After vigorous stir-
ring for 30 min, the resulting mixture was diluted with CH2Cl2 (100
mL) and poured into a separatory funnel containing H2O (10 mL).
The combined organic layers were washed with sat. aq Na2S2O3 (20
mL), H2O (3 × 15 mL), and brine (3 × 15 mL), dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (PE–EtOAc, 16:1)
on silica gel (basified with Et3N) to afford the desired tertiary ben-
zylic bromide (–)-1 (2.26 g, 91%) as a brown oil; Rf = 0.50 (PE–
EtOAc, 4:1); [α]D20 –148 (c 0.5, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.55 (br, 1 H), 7.36 (d, J = 7.6 Hz,
1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 6.40 (s, 1
H), 3.89 (dd, J = 6.4, 10.4 Hz, 1 H), 3.75 (s, 3 H), 3.21 (dd, J = 6.4,
12.4 Hz, 1 H), 2.82 (dd, J = 10.4, 12.4 Hz, 1 H), 1.59 (s, 9 H), 1.40
(br, 9 H).
13C NMR (100 MHz, CDCl3): δ (rotamers) = 171.4, 152.1 (2 C),
141.4, 132.8 (br), 130.5, 124.3 (br), 123.8, 118.6 (br), 83.7, 82.2,
81.4 (br), 59.6, 59.4, 52.3, 41.9 (br), 28.1 (6 C).
IR (film): 3434, 2252, 2126, 1658, 1053, 1027, 1007, 824, 762, 624
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 7.6 Hz, 2 H), 7.09 (t,
J = 7.6 Hz, 2 H), 6.75 (t, J = 7.6 Hz, 2 H), 6.60 (d, J = 7.6 Hz, 2 H),
4.84 (s, 2 H), 3.68 (s, 6 H), 3.56 (dd, J = 7.2, 9.2 Hz, 2 H), 2.41 (s,
2 H), 2.39 (d, J = 2.0 Hz, 2 H). Signal for NH was not detected.
13C NMR (100 MHz, CDCl3): δ = 173.7 (2 C), 151.1 (2 C), 129.3 (2
C), 129.0 (2 C), 124.9 (2 C), 118.7 (2 C), 109.4 (2 C), 80.9 (2 C),
63.9 (2 C), 59.5 (2 C), 52.1 (2 C), 42.1 (2 C).
HRMS (ESI): m/z [M + H]+ calcd for C24H27N4O4: 435.2027; found:
435.2031.
Dimethyl (–)-(2S,2′S,3aS,3′aS,8aS,8′aS)-1,1′-Bis{(S)-2-[tert-bu-
toxycarbonyl(methyl)amino]-3-phenylpropanoyl}-
2,2′,3,3′,8,8a,8′,8′a-octahydro-1H,1′H-3a,3′a-bipyrrolo[2,3-
b]indole-2,2′-dicarboxylate (7)
To a stirred solution of (–)-6 (36 mg, 0.081 mmol) in DMF (2.5 mL)
were added N-Boc-N-Me-L-Phe-OH28 (54 mg, 0.194 mmol, 2.4
equiv) and Et3N (68 μL, 0.486 mmol, 6.0 equiv) successively at
0 °C. After 10 min, HATU (76 mg, 0.194 mmol, 2.4 equiv) was
added slowly, and the resulting mixture was stirred for 80 h at 0 °C.
Then, the reaction mixture was carefully quenched with aq NH3
(28%, 2 mL), and the aqueous layer was extracted with CHCl3 (50
mL). The combined organic layers were washed with H2O (3 × 8
mL) and brine (3 × 5 mL), dried (Na2SO4), filtered, and concentrat-
ed under reduced pressure. The resulting residue was purified by
flash column chromatography (PE–acetone, 2:1) on silica gel (basi-
fied with Et3N) to afford the desired (–)-7 (28 mg, 36%) as a pale
yellow solid and the recovered (–)-6 (4 mg, 11%); mp 202–203 °C;
Rf = 0.67 (PE–acetone, 1:2); [α]D20 –222 (c 0.5, CH2Cl2).
ESI-MS: m/z = 497.1 [M + H]+.
1,1′,8,8′-Tetra-tert-butyl 2,2′-Dimethyl
(–)-(2S,2′S,3aS,3′aS,8aR,8′aR)-2,2′,3,3′-Tetrahydro-1H,1′H-
3a,3′a-bipyrrolo[2,3-b]indole-1,1′,2,2′,8,8′(8aH,8′aH)-hexacar-
boxylate (2)16
To a stirred slurry of Zn powder (234 mg, 3.6 mmol, 1.2 equiv) and
NiI2 (281 mg, 0.9 mmol, 0.3 equiv) in pyridine (2 mL) was added
1,10-phenanthroline (267 mg, 1.35 mmol, 0.45 equiv) at r.t. The
temperature then rose to 55 °C, and vigorous stirring was continued
for 15 min. The resulting black nickel(0) complex was cooled to r.t.,
and a solution of the bromide (–)-1 (1.5 g, 3 mmol) in degassed
DMA (3 mL) was added dropwise. After 10 h, the mixture was fil-
tered with a short plug of silica gel (elution with 50 mL of EtOAc),
and the combined organic layers were washed with H2O (3 × 15
mL) and brine (3 × 10 mL), dried (Na2SO4), filtered, and concen-
trated. The crude product was carefully purified by flash column
chromatography (PE–EtOAc, 16:1) on silica gel (basified with
Et3N) to afford 496 mg (40%) of (–)-2 as a white solid and 401 mg
(32%) of (–)-5. Product (–)-2 was dissolved in hexane–EtOAc (1:1)
and after 4 days, colorless single crystals were obtained by slow
evaporation of the solvent at r.t.; mp 194–195 °C; Rf = 0.21 (PE–
EtOAc, 4:1); [α]D19 –138 (c 0.5, CH2Cl2).
IR (film): 3284, 2926, 2854, 1746, 1663, 1608, 1479, 1453, 1382,
1367, 1320, 1257, 1201, 1158, 913, 857, 738, 623 cm–1.
NMR spectra showed complex rotamers mixture that were difficult
to characterize.
HRMS (ESI): m/z [M + Na]+ calcd for C54H64N6O10 + Na: 979.4576;
found: 979.4585.
(–)-Ditryptophenaline (4)
A 5 mL pear-shaped flask was charged with (–)-7 (9.0 mg, 0.0094
mmol), set-up under vacuum (6.7 × 10–2 Pa), and immersed in an oil
bath preheated to 235 °C for 30 min. The residue was cooled to r.t.,
then directly purified by flash column chromatography (PE–EtOAc,
1:5) on silica gel (basified with Et3N) to afford the desired (–)-di-
tryptophenaline (4; 6.3 mg, 96%) as white crystals; mp 198–199 °C;
Rf = 0.35 (EtOAc); [α]D20 –286 (c 1.0, CH2Cl2).
IR (film): 2982, 2933, 1759, 1715, 1631, 1482, 1460, 1396, 1366,
1335, 1258, 1159, 1015, 908, 854, 791, 755 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.30 (br, 2 H), 7.10 (t, J = 7.6 Hz,
2 H), 7.05 (d, J = 6.0 Hz, 2 H), 6.86 (t, J = 7.6 Hz, 2 H), 6.39 (br, 2
H), 3.79 (t, J = 8.0 Hz, 2 H), 3.71 (s, 6 H), 2.50 (br, 2 H), 2.38 (t, J =
11.2 Hz, 2 H), 1.61 (s, 18 H), 1.37 (br, 18 H).
13C NMR (100 MHz, CDCl3): δ (rotamers) = 172.4 (br, 2 C), 151.8
(4 C), 142.0 (2 C), 130.7 (br, 2 C), 129.2 (2 C), 124.0 (br, 2 C),
122.8 (br, 2 C), 116.8 (br, 2 C), 81.8 (2 C), 80.8 (br, 2 C), 79.0 (br,
2 C), 58.8 (2 C), 57.9 (br, 2 C), 52.1 (2 C), 35.5 (2 C), 28.3 (6 C),
28.1 (6 C).
HRMS (ESI): m/z [M + H]+ calcd for C44H59N4O12: 835.4124;
found: 835.4094.
IR (film): 3344, 2924, 2853, 1732, 1658, 1606, 1454, 1401, 1317,
1243, 1211, 1113, 1077, 745, 704, 619 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.56 (t, J = 7.2 Hz, 4 H), 7.50 (t,
J = 7.2 Hz, 2 H), 7.13 (d, J = 6.8 Hz, 4 H), 7.06 (td, J = 0.8, 7.6 Hz,
2 H), 6.96 (d, J = 7.2 Hz, 2 H), 6.69 (t, J = 7.2 Hz, 2 H), 6.55 (d, J =
8.0 Hz, 2 H), 4.80 (s, 2 H), 4.68 (br s, 2 H, NH), 4.26 (br s, 2 H),
3.66 (dd, J = 4.0, 12.0 Hz, 2 H), 3.52 (dd, J = 3.2, 14.4 Hz, 2 H),
Synthesis 2014, 46, 1908–1916
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Concise Synthesis of (–)-Folicanthine and (–)-Ditryptophenaline
1915
20
3.24 (dd, J = 4.4, 14.4 Hz, 2 H), 3.02 (s, 6 H), 2.01 (dd, J = 4.8, 12.4
Hz, 2 H), 1.56 (t, J = 12.4 Hz, 2 H).
solid; mp 225–226 °C; Rf = 0.76 (PE–EtOAc, 4:1); [α]D –213 (c
2.0, MeOH).
13C NMR (100 MHz, CDCl3): δ = 165.4 (2 C), 163.9 (2 C), 150.1 (2
C), 134.5 (2 C), 129.6 (2 C), 129.4 (4 C), 129.3 (4 C), 127.9 (2 C),
126.4 (2 C), 125.7 (2 C), 118.9 (2 C), 109.6 (2 C), 78.6 (2 C), 63.1
(2 C), 58.9 (2 C), 58.5 (2 C), 36.2 (2 C), 36.0 (2 C), 32.6 (2 C).
ESI-MS: m/z = 715.4 [M+ Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C42H41N6O4: 693.3184; found:
IR (film): 3046, 2959, 2928, 2858, 2792, 1602, 1492, 1463, 1427,
1380, 1347, 1325, 1299, 1254, 1211, 1159, 1124, 1040, 1022, 1021,
965, 927, 743, 725 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.33 (br, 2 H), 7.05 (t, J = 7.6 Hz,
2 H), 7.02 (d, J = 7.6 Hz, 2 H), 6.79 (t, J = 7.2 Hz, 2 H), 6.46 (br s,
2 H), 3.76 (dd, J = 7.6, 10.4 Hz, 2 H), 2.74 (td, J = 5.6, 10.8 Hz, 2
H), 2.25–2.11 (m, 4 H), 1.59 (s, 18 H), 1.50 (s, 18 H).
13C NMR (100 MHz, CDCl3): δ = 153.5 (2 C), 152.0 (2 C), 142.8 (2
C), 131.6 (2 C), 128.6 (2 C), 123.3 (2 C), 122.7 (2 C), 116.3 (br, 2
C), 81.5 (2 C), 80.4 (2 C), 78.4 (2 C), 60.5 (2 C), 45.0 (2 C), 33.8
(br, 2 C), 28.39 (6 C), 28.38 (6 C).
693.3192.
Dimethyl (–)-(2S,2′S,3aS,3′aS,8aR,8′aR)-1,1′,8,8′-Tetramethyl-
2,2′,3,3′,8,8a,8′,8′a-octahydro-1H,1′H-3a,3′a-bipyrrolo[2,3-
b]indole-2,2′-dicarboxylate (9)
To a stirred solution of (–)-6 (222 mg, 0.51 mmol) in MeCN (10
mL) were added HCHO (0.25 mL, 37% in H2O, 3.06 mmol, 6.0
equiv) and NaBH(OAc)3 (649 mg, 3.06 mmol, 6.0 equiv) sequen-
tially at r.t. The reaction mixture was stirred for 30 min, then
quenched with aq NH3 (28%, 20 mL). The mixture was diluted with
CHCl3 (15 mL) and the combined organic layers were washed with
H2O (3 × 5 mL) and brine (3 × 5 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resulting residue was pu-
rified by flash column chromatography (PE–acetone, 1:1) on silica
gel (basified with Et3N) to afford the desired (–)-9 (204 mg, 82%)
as colorless crystals; mp 211–213 °C; Rf = 0.40 (PE–acetone, 2:1);
[α]D20 –282 (c 0.5, CH2Cl2).
ESI-MS: m/z = 741.3 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C40H54N4O8 + Na: 741.3834;
found: 741.3859.
(–)-Folicanthine (3)
To a stirred solution of (–)-8 (45 mg, 0.0627 mmol) in CH2Cl2 (2.5
mL) were added TMSOTf (0.23 mL, 1.25 mmol, 20 equiv) and 2,6-
lutidine (0.14 mL, 1.25 mmol, 20 equiv) successively at 0 °C. The
reaction mixture was stirred for 30 min and then carefully quenched
with aq NH3 (28%, 1 mL). The mixture was diluted with CH2Cl2 (10
mL), and the aqueous layer was extracted with CH2Cl2 (10 × 10
mL). The combined organic layers were washed with brine (3 × 5
mL), dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The resulting white N-demethylfolicanthine could be used di-
rectly for the next step. Thus, HCHO (95 μL, 37% in H2O, 20 equiv)
and NaBH(OAc)3 (265 mg, 1.25 mmol, 20 equiv) were sequentially
added to a stirred solution of the above tetraamine in MeCN (5 mL)
at r.t. The reaction mixture was stirred for 1.5 h, and then carefully
quenched with aq NH3 (28%, 3 mL) at 0 °C. The mixture was dilut-
ed with CH2Cl2 (15 mL), and the aqueous layer was extracted with
CH2Cl2 (5 × 10 mL). The combined organic layers were washed
with brine (3 × 5 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
column chromatography (acetone–PE–Et3N, 4:1:0.1) on silica gel
to afford the desired (–)-folicanthine (3; 20 mg, 85%) as colorless
crystals. Product (–)-3 was dissolved in EtOAc and after 3 days, col-
orless single crystals were obtained by slow evaporation of the sol-
vent at r.t.; mp 178–179 °C; Rf = 0.45 (acetone–PE–Et3N, 4:1:0.1);
[α]D20 –331 (c 1.0, MeOH).
IR (film): 3355, 2923, 2853, 1745, 1602, 1461, 1371, 1264, 1111,
1065, 740 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.97 (br s, 2 H), 6.88 (br s, 2 H),
6.51 (br s, 2 H), 6.28 (br s, 2 H), 5.00 (s, 2 H), 3.68 (s, 6 H), 3.17
(dd, J = 5.6, 10.8 Hz, 2 H), 3.04 (s, 6 H), 2.46 (s, 6 H), 2.23 (br s, 4
H).
13C NMR (100 MHz, CDCl3): δ = 173.1 (2 C), 153.3 (2 C), 130.8 (2
C), 128.6 (2 C), 123.3 (br, 2 C), 117.0 (2 C), 106.5 (2 C), 91.2 (2 C),
63.6 (2 C), 60.9 (2 C), 51.8 (2 C), 40.6 (2 C), 36.8 (2 C), 34.1 (2 C).
HRMS (ESI): m/z [M + Na]+ calcd for C28H34N4 + Na: 513.2472;
found: 513.2478.
Tetra-tert-butyl (–)-(3aS,3′aS,8aR,8′aR)-2,2′,3,3′-Tetrahydro-
1H,1′H-3a,3′a-bipyrrolo[2,3-b]indole-1,1′,8,8′(8aH,8′aH)-tet-
racarboxylate (8)
To a stirred solution of (–)-2 (140 mg, 0.167 mmol) in MeOH (2
mL) and THF (1 mL) was added aq 5 M KOH (2 mL) at 0 °C, and
the vigorous stirring was continued for 5 min. The reaction mixture
was then stirred at r.t. for 3.5 h, then acidified with aq 1 M HCl to
pH 2 at 0 °C. The aqueous layer was extracted with CH2Cl2 (50
mL), and the combined organic layers were washed with brine (3 ×
5 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The resulting pale yellow carboxylic acid (almost quanti-
tative yield) could be used directly for the next step. Thus, 2-mer-
captopyridine N-oxide29 (65 mg, 0.51 mmol, 3.0 equiv), DMAP (2
mg, 0.017 mmol, 0.1 equiv), and TCFH (143 mg, 0.51 mmol, 3.0
equiv) were sequentially added to a solution of the above carboxylic
acid in degassed THF (2 mL) at 0 °C. The reaction flask was then
removed from the ice bath, covered in aluminum foil, and Et3N (137
mg, 1.36 mmol, 8.0 equiv) was added while re-cooling the mixture
back to 0 °C. After stirring for 6 h in the dark, t-BuSH (0.38 mL, 3.4
mmol, 20 equiv) was added, and the aluminum foil was removed.
The resulting suspension was warmed to r.t. and irradiated with a
450 W Hg lamp for 2 h. The mixture was diluted with CH2Cl2 (15
mL), and the combined organic layers were washed with H2O (3 ×
8 mL) and brine (3 × 5 mL), dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The resulting residue was purified by
flash column chromatography (PE–EtOAc, 15:1) on silica gel (ba-
sified with Et3N) to afford the desired (–)-8 (59 mg, 48%) as a white
1H NMR (300 MHz, CDCl3): δ = 6.97 (t, J = 7.2 Hz, 2 H), 6.91 (br
s, 2 H), 6.49 (t, J = 6.9 Hz, 2 H), 6.26 (d, J = 7.5 Hz, 2 H), 4.40 (br
s, 2 H), 3.00 (s, 6 H), 2.64 (br s, 2 H), 2.48–2.39 (m, 4 H), 2.41 (s,
6 H), 2.01–1.93 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 152.8 (2 C), 132.7 (2 C), 128.0 (2
C), 123.6 (2 C), 116.6 (2 C), 105.8 (2 C), 91.9 (2 C), 62.6 (2 C), 52.6
(2 C), 37.8 (2 C), 35.4 (2 C), 35.2 (2 C).
HRMS (ESI): m/z [M + H]+ calcd for C24H31N4: 375.2543; found:
375.2540.
Acknowledgment
This work was supported by NSFC (Nos. 21172096 and J1103307),
the Fundamental Research Funds for the Central Universities
(lzujbky-2013-ct02 and lzujbky-2014-59), Program for Changjiang
Scholars and Innovative Research Team in University (IRT1138),
and the ‘111’ Project of MoE.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1908–1916

1916
L. Luo et al.
SPECIAL TOPIC
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44, 447. (c) Ruiz-Sanchis, P.; Savina, S. A.; Albericio, F.;
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