Construction of the Azacyclic Core of Tabernaemontanine-Related Alkaloids via Tandem Reformatsky-Aza-Claisen Rearrangement

Article abstract of DOI:10.1021/acs.joc.6b02648

A divergent synthetic methodology for a tabernaemontanine-related alkaloid was developed. The synthetic route features practical improvements in the Pictet-Spengler cyclization for the tetrahydro-β-carboline intermediate and an unprecedented tandem Reformatsky-aza-Claisen rearrangement to create the core carbon skeleton and stereochemistries of tabernaemontanine-related alkaloids.

Full text of DOI:10.1021/acs.joc.6b02648

Subscriber access provided by UNIV OF REGINA
Article
Construction of the Azacyclic Core of Tabernaemontanine-related
Alkaloids via Tandem Reformatsky-Aza Claisen Rearrangement
Young-Ger Suh, Changjin Lim, Jaehoon Sim, Jae Kyun Lee, Young-Joon Surh, and Seung-Mann Paek
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02648 • Publication Date (Web): 04 Jan 2017
Downloaded from http://pubs.acs.org on January 5, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Construction of the Azacyclic Core of Tabernaemontanine-related Alkaloids via Tandem
Reformatsky-Aza Claisen Rearrangement
,†
†
†
‡
§
,∥
YoungꢀGer Suh,* Changjin Lim, Jaehoon Sim, Jae Kyun Lee, YoungꢀJoon Surh, SeungꢀMann Paek,*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†
College of Pharmacy, Seoul National University, 1 Gwanakꢀro, Gwanakꢀgu, Seoul 151ꢀ742, Republic of Korea
NeuroꢀMedicine Center, Korea Institute of Science and Technology, PO Box 131, Seoul 130ꢀ650, Republic of
‡
Korea
§
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, 1
Gwanakꢀro, Gwanakꢀgu, Seoul 151ꢀ742, Republic of Korea
∥
College of Pharmacy, Research Institute of Pharmaceutical Science, Gyeongsang National University, Jinju
daero, Jinju, 660ꢀ751, Republic of Korea
Corresponding Authors
*
E mail: ygsuh@snu.ac.kr (Y.ꢀG. Suh)
*E mail: million@gnu.ac.kr (S.ꢀM. Paek)
Table of Contents
Abstract
A divergent synthetic methodology for tabernaemontanineꢀrelated alkaloid was developed. The synthetic route
features practical improvements in the PictetꢀSpengler cyclization for the tetrahydroꢀβꢀcarboline intermediate
and an unprecedented tandem Reformatskyꢀaza Claisen rearrangement to create the core carbon skeleton and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stereochemistries of tabernaemontanineꢀrelated alkaloids.
Introduction
Indole alkaloids constitute an important class of natural products because of their remarkable biological activity
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
and structural diversity. Historically, indole alkaloids, such as serotonin and melatonin, have received attention
2
as biologically important endogenous molecules used to elucidate the neuronal pathway. Other indole alkaloids,
such as vinblastine, vincristine, and sumatriptan, have been developed as blockbuster medicines to improve
3
human health.
Tabernaemontanineꢀrelated alkaloids, represented by tabernaemontanine (1), tabernaemontanol (2), vobasidine
C (3), and vobasinylꢀiboga bisindole alkaloid (4aꢀ4f), belong to this this alkaloid family (Figure 1). These
4
naturally isolated indole alkaloids are major components in members of the genus Tabernaemontana, and
tabernaemontanine (1) has been used in subtropical regions, including Africa, Polynesia, Southeast Asia, and
4a,5
southern China, to treat hypertension and prevent malaria and parasite infections.
Recently, 1 was also
6
reported to show promising apoptosisꢀinducing activity when used to treat human hepatoma HuHꢀ7 cells.
Despite its remarkable biological profiles, the pharmacological mechanism governing its activity remains poorly
understood.
From a structural standpoint, tabernaemontanineꢀrelated indole alkaloids have a challenging molecular
7
structure. This structure contains four contiguous stereocenters and an indoleꢀfused azecinone framework with
a formidable [5.1.3] bicyclic core. Notably, cyclically fused indole alkaloids have been synthesized using
strategies such as PictetꢀSpengler cyclizations, organocatalystꢀmediated reactions, and asymmetric ringꢀclosing
metatheses. Additionally, an elegant synthetic strategy for the related indole alkaloids was recently reported by
7
,8
the group of James M. Cook. With this synthetic need in mind, we commenced a synthetic study toward an
azacyclic core (5), which would be widely utilized for the synthesis of tabernaemontanineꢀrelated indole
alkaloids.
Figure 1. (ꢀ)ꢀTabernaemontanine and the related indole alkaloids
ACS Paragon Plus Environment

Page 3 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and Discussion
A retrosynthesis of 5 is depicted in Scheme 1. For a practical and efficient synthetic route, we designed the 10ꢀ
membered lactam 5 as a synthetic precursor to tabernaemontanineꢀrelated indole alkaloids in terms of carbon
skeleton, oxidation state, and substitution pattern. Transannulation of 5 utilizing a method such as allylic
9
alkylation and further functional manipulation including Wacker oxidation may be necessary to complete the
synthesis of tabernaemontanineꢀrelated indole alkaloids. To prepare 5, we pursued an aza Claisen rearrangement
1
0
(ACR) of the enol ether 4. We recently reported an efficient ACR to achieve the ring expansion of a mediumꢀ
11
sized lactam to generate a macrolactam. Employing this ring expansion methodology, we anticipated not only
the construction of the 10ꢀmembered azacycle skeleton but also the creation of stereogenic centers in a single
transformation. The enol ether 6 was considered to be accessible from the 1,3ꢀantiꢀsubstituted tetrahydroꢀβꢀ
carboline 7 through functional group interconversion and transꢀselective enol etherification reactions. In
addition, the same carbon and stereochemical frameworks are expected to readily convert 7 to the ACR
precursor 6. Finally, the synthesis of 7 was pursued from a modified PictetꢀSpengler cyclization of (L)ꢀ
1
2
tryptophan 8 that was reported by the groups of Massiot and Bailey.
Scheme 1. Synthetic strategy for the azacyclic core 5 of the tabernaemontanineꢀrelated indole alkaloids
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The synthesis of 7 commenced with a PictetꢀSpengler cyclization (Scheme 2). At first, Nꢀbenzyl tryptophan
1
3
12
methyl ester 9 was converted to 7 using the Bailey’s procedure. However, under the standard protocol
(
addition of methyl propiolate 10 followed by treatment of TFA in CHCl , 7 d), the reaction afforded only a
3
small amount of 7 with moderate diastereoselectivity (36 % yield, 3:1 d.r.). Although an excellent approach by
the groups Massiot and Bailey introduced methyl propiolate 10 as an efficient three carbon synthon for the
12
PictetꢀSpengler cyclization, low reactivity and diastereoselectivity in this procedure were also reported. We
observed that the amine addition to methyl propiolate 10 proceeded slowly after monitoring the reaction. Thus,
we carried out the reaction in MeOH because alcoholic solvents have been reported to accelerate the addition of
1
4
a heteroatom to a Michael acceptor. With this replacement, amine 9 was completely converted to 11 in 24 h. In
addition, an elevation in temperature accelerated the reaction (6 h) to achieve similar results to those in reactions
that proceeded at room temperature. However, CHCl was the best solvent during treatment of 11 with TFA to
3
generate 7 in situ because other solvents (MeOH, acetonitrile, tꢀBuOH, and THF) either hampered the CꢀC bond
forming step or promoted alcoholysis. Accordingly, we conducted the Michael addition step using MeOH,
3
which was evaporated and subsequently added CHCl to the residue for the CꢀC bond formation step. This
solvent exchange protocol afforded 7 in 90 % yield within 8 h. More importantly, lower temperature
dramatically improved the diastereoselectivity of 7. This improved facial selectivity is presumably derived from
a minimized steric interference of the transition state. As shown in Scheme 2, the cyclization appears to proceed
through the transition state 11-a rather than 11-b, which suffers from unfavorable steric interactions between the
carbomethoxy substituent of iminium moiety and the indole moiety as well as the carbomethoxy group of the
1
2d
side chain during cyclization. Subsequently, we obtained 7 in a highly efficient manner. Considering the
synthetic significance of the βꢀcarboline intermediate 7, our modified PictetꢀSpengler cyclization procedure
ACS Paragon Plus Environment

Page 5 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8
could be applied in the synthesis of related indole alkaloids.
Scheme 2. Improved PictetꢀSpengler cyclization
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
After the PictetꢀSpengler cyclization was optimized, functional group interconversions were conducted as
shown in Scheme 3. Boc protection of 7, followed by LAH reduction, afforded the Bocꢀprotected diol 12. Diol
12 could be obtained in more than 50 g using this procedure. Subsequently, selective silylation of 12 produced
the mono silyl ether 13, which was converted to the PMB ether 14 by PMB protection followed by TIPS
1
5
deprotection. Ley oxidation of alcohol 14 quantitatively afforded the corresponding aldehyde 15, which was
11,16
treated with DBU in the presence TBSCl to afford the transꢀenol ether 16 with high stereoselectivity.
Finally,
1
7
the debenzylation of 16 with the labile silyl enol ether intact was achieved using Pearlman’s catalyst, followed
by amidation to produce the desired butyryl amide 18 and the 2ꢀbromobutyryl amide 6 in high yields,
respectively.
Scheme 3. Functional group interconversion
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A pivotal ACR transformation of 18 (6) into the desired lactam 5 is summarized in Scheme 4. Initial attempts
for the conversion of 18 to 5 were not successful under various reaction conditions. Considering that enol ether
18 was left unreacted in most cases, αꢀdeprotonation of the amide appeared not to occur under the attempted
1
8
conditions. Thus, alternative procedures to generate the amide enolate were explored and the Reformatskyꢀ
type reaction was finally discovered for the facile ACR. Upon iPrMgCl treatment of 6, initial debromination in 1
1
9
h followed by ACR produced azacycle 5. Initial amide enolate generation induced by debromination and
spontaneous [3,3] sigmatropic rearrangement seemed to proceed. Treatment of 6 with iPrMgCl in refluxing
benzene and then trapping the resulting amide enolate with TBS induced facile ACR to produce lactam 5. The
20
structure was confirmed through an analysis of spectral data and Xꢀray crystallographic analysis (Figure 2).
To the best of our knowledge, we report the first synthetic application of the tandem Reformatskyꢀaza Claisen
2
1
rearrangement. More than 10 grams of lactam 5 were obtained from (L)ꢀtryptophan by our substantial
procedure.
Scheme 4. Tandem ReformatskyꢀACR of 6 and 18
ACS Paragon Plus Environment

Page 7 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OPMB
O
OPMB
N
ACR
HN
O
N
N
Boc
Boc
1
8
5
OTBS
OTBS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OPMB
OMgCl
OPMB iPrMgCl
O
TBSCl
OPMB
OTBS
N
N
N
N
N
N
Boc
Boc
Boc
Br
6
TBSO
TBSO
TBSO
Reformatsky type
unstable intermediate
TBS trap of amide enolate
OPMB
ACR
1%
OPMB
H
H
HN
O
N
N
OTBS
8
Boc
Boc
N
O
TBSO
TBS
5a
a
20
Absolute stereochemistry was determined by Xꢀray crystallographic analysis of 5
a
20
Figure 2. Xꢀray crystallographic structure of 5
a
Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of
arbitrary radii; Black = carbon, Red = oxygen, Blue = nitrogen, Orange = silicon
Conclusion
In conclusion, we achieved an efficient construction of the core structure of the tabernaemontanineꢀrelated
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
indole alkaloids. Our strategy features an advance in diastereoselective PictetꢀSpengler cyclization, and
development of the tandem Reformatskyꢀaza Claisen rearrangement. Additional efforts are underway to apply
our methodology to the total synthesis of biologically active tabernaemontanineꢀrelated indole alkaloids.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
General Experimental Procedure
Unless noted otherwise, all starting materials and reagents were obtained from commercial suppliers and were
used without further purification. Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone
ketyl. Dichloromethane, triethylamine, and pyridine were freshly distilled from calcium hydride. All solvents
used for the routine isolation of products and chromatography were reagent grade and glass distilled. Reaction
flasks were dried at 100 °C. Air and moisture sensitive reactions were performed under an argon atmosphere.
Flash column chromatography was performed using silica gel (230−400 mesh) with the indicated solvents.
Thinꢀlayer chromatography was performed using 0.25 mm silica gel plates. Optical rotations were measured
with a digital polarimeter at ambient temperature using a 100 mm cell of 2 mL capacity. Infrared spectra were
recorded on a FTꢀIR spectrometer. Mass spectra were obtained with a double focusing mass spectrometer
1
13
(
electrostatic analyzer and magnetic analyzer). H and C NMR spectra were recorded on a 300, 400, or 500
MHz spectrometers as solutions in deuteriochloroform (CDCl ) or tetradeuteromethanol (methanolꢀd ).
Chemical shifts are expressed in parts per million (ppm, δ) downfield from tetramethylsilane and are referenced
to the deuterated solvent (CDCl or CD OD, major solvent in a mixture of CDCl and CD OD). 1H NMR data
3
4
3
3
3
3
were reported in the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; dd, doublet of doublets;
br, broad; m, multiplet and/or multiple resonance), number of protons, and coupling constant in hertz (Hz).
(1R,3S)-methyl
2-benzyl-1-(2-methoxy-2-oxoethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-
carboxylate (7).
To a solution of benzyl amine 9 (2.0 g, 6.5 mmol) in MeOH (20 mL), methyl propiolate 10 (1.2 mL, 13.0 mmol)
was added and the reaction mixture was refluxed for 6 h. The reaction mixture was concentrated in vacuo. The
o
crude residue was dissolved in CHCl
stirred for 2 h, quenched with saturated NaHCO
layer was washed with brine, dried over MgSO , and concentrated in vacuo. The residue was purified by flash
3
(20 mL) and TFA (1.6 mL) was added at ꢀ40 C. The reaction mixture was
3
2 2
solution and extracted with CH Cl . The combined organic
4
column chromatography on silica gel (EtOAc: nꢀhexane = 1: 3) to afford 2.3 g (90%) of carboline 7 as a
ACS Paragon Plus Environment

Page 9 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
colorless oil. Recrystalization of 7 from a mixture of EtOAc and nꢀhexane (1: 5) afforded 7 as white solid with a
o
20
1
melting point of 138ꢀ141 C. [α]D –23.8 (c 0.48, CHCl ); HꢀNMR (CDCl , 400 MHz) δ 8.63 (s, 1H), 7.59 (d,
3
3
1
H, J = 7.8 Hz), 7.42 – 7.40 (m, 2H), 7.36 – 7.32 (m, 3H), 7.29 – 7.26 (m, 1H), 7.22 – 7.16 (m, 2H), 4.37 (dd,
H, J = 3.2, 9.6 Hz), 4.02 (dd, 1H, J = 4.8 Hz, 9.4 Hz), 3.93 (d, 1H, J = 14.0 Hz), 3.78 (s, 3H), 3.68 (s, 3H), 3.68
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
d, 1H, J = 14.0 Hz), 3.21 (dd, 1H, J = 9.6, 15.8 Hz), 3.09 (dd, 1H, J = 4.8 Hz, 16.0 Hz), 3.00 (dd, 1H, J = 4.0,
13
1
6.2 Hz), 2.83 (dd, 1H, J = 10.0, 16.2 Hz); CꢀNMR (CDCl
3
, 100 MHz) δ 173.4, 172.9, 139.1, 135.8, 133.6,
1
28.4, 128.2, 127.0, 126.5, 121.8, 119.3, 118.0, 111.0, 106.8, 57.5, 53.4, 52.1, 51.9, 51.8, 40.5, 21.0; IR (neat)
ꢀ
1
+
ν
max 3395, 3025, 2950, 2849, 1730, 1439, 1360 cm ; LRꢀMS (FAB+) m/z 393 (M+H ); HRꢀMS (FAB+) Calcd
+
for C H N O (M+H ): 393.1814, Found 393.1811.
23 25
2
4
(1R,3S)-tert-butyl 2-benzyl-1-(2-hydroxyethyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydropyrido[3,4-b]indole-
9
-carboxylate (12).
3 2
To a solution of carboline 7 (4.5 g, 11.0 mmol) in CH CN (20 mL), DMAP (140 mg, 1.1 mmol) and Boc O (3.0
mL, 14.0 mmol) were added. The reaction mixture was stirred for 10 min and quenched with saturated NH Cl
4
solution. The mixture was extracted with EtOAc and the combined organic layer was washed with brine, dried
over MgSO , and concentrated in vacuo. The crude product (5.3 g) was dissolved in THF (40 mL) and treated
4
o
with LAH (1.0 g, 27.0 mmol) at 0 C and stirred for 12h. The reaction mixture was quenched with H
2
O (1 mL),
10% NaOH (2 mL) and H O (3 mL). The mixture was dried over MgSO , and concentrated in vacuo. The
2
4
residue was purified by flash column chromatography on silica gel (EtOAc: nꢀhexane = 1: 1, 5% MeOH) to
o
20
afford 4.5 g (89% for 2 steps) of diol 12 as white solid with a melting point of 111ꢀ114 C. [α] +82.0 (c 0.27,
D
1
CHCl ); HꢀNMR (CDCl , 400 MHz) δ 8.24 (d, 1H, J = 8.1 Hz), 7.49 – 7.24 (m, 8H), 5.59 (br s, 1H), 4.45 (dd,
3
3
1
H, J = 3.2, 9.6 Hz), 4.05 (d, 1H, J = 13.0 Hz), 4.00 – 3.62 (m, 5H), 3.50 (t, 1H, J = 10.0 Hz), 3.30 (d, 1H, J =
3.0 Hz), 2.68 (dd, 1H, J = 4.8 Hz, 16.0 Hz), 2.55 (dd, 1H, J = 12.0, 16.0 Hz), 2.07 – 1.97 (m, 1H), 1.91 – 1.83
1
1
3
(
m, 1H), 1.43 (s, 9H); CꢀNMR (CDCl
3
, 100 MHz) δ 149.8, 138.7, 136.4, 135.1, 129.5, 128.8, 128.5, 127.3,
124.2, 122.7, 117.7, 115.8, 114.1, 83.7, 62.5, 62.2, 57.4, 52.6, 49.3, 33.8, 27.8, 19.5.; IR (neat) νmax 3363, 2929,
ꢀ
1
+
33 2 4
1729, 1647, 1539, 1456, 1368 cm ; LRꢀMS (FAB+) m/z 437 (M+H ); HRꢀMS (FAB+) Calcd for C26H N O
+
(M+H ): 437.2440, Found 437.2442.
(1R,3S)-tert-butyl 2-benzyl-3-(hydroxymethyl)-1-(2-(triisopropylsilyloxy)ethyl)-1,2,3,4-tetrahydropyrido
[3,4-b]indole-9-carboxylate (13).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2 2 2
To a solution of diol 12 (102 mg, 0.2 mmol) and iPr NEt (81 ꢁL, 0.5 mmol) in CH Cl (5 mL), TIPSOTf (70 ꢁL,
o
0.3 mmol) in CH
2
Cl
2
(1 mL) was added at 0 C for 5 min. After stirring for 1 h, the reaction mixture was
quenched with H
2
O and extracted with CH
2
Cl
2
. The combined organic layer was washed with brine, dried over
MgSO
4
, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
(
EtOAc: nꢀhexane = 1: 10) to afford 120 mg (87%) of ether 13 as a colorless oil. [α]D +24.7 (c 0.115, CHCl
3
);
1
HꢀNMR (CDCl
3
, 400 MHz) δ 8.26 (d, 1H, J = 8.1 Hz), 7.48 – 7.28 (m, 8H), 4.37 (dd, 1H, J = 4.4, 10.0 Hz),
3.97 (d, 1H, J = 11.0 Hz), 3.90 – 3.82 (m, 3H), 3.77 – 3.71 (m, 1H), 3.58 – 3.51 (m, 1H), 3.30 (d, 1H, J = 11.0
1
3
Hz), 2.94 (d, 1H, J = 7.5 Hz), 2.69 – 2.57 (m, 2H), 2.09 – 2.00 (m, 2H), 1.54 (s, 9H), 1.14 – 1.06 (m, 21H); Cꢀ
NMR (CDCl , 100 MHz) δ 149.8, 136.2, 136.5, 136.3, 129.1, 128.9, 128.3, 127.1, 124.0, 122.6, 117.7, 115.8,
3
113.9, 83.7, 61.9, 55.0, 52.5, 48.8, 35.9, 27.9, 19.5, 17.9, 17.6, 11.6; IR (neat) νmax 3438, 2940, 2865, 1730, 1456,
ꢀ
1
+
+
1
367 cm ; LRꢀMS (FAB+) m/z 593 (M+H ); HRꢀMS (FAB+) Calcd for C H N O Si (M+H ): 593.3775,
35 53 2 4
Found 593.3770.
(1R,3S)-tert-butyl 2-benzyl-1-(2-hydroxyethyl)-3-((4-methoxybenzyloxy)methyl)-1,2,3,4-tetrahydropyrido
3,4-b]indole-9-carboxylate (14).
[
To a solution of TIPS ether 13 (4.2 g, 7.1 mmol), TBAI (520 mg, 1.4 mmol) and PMBBr (3 mL, 21.0 mmol) in
o
DMF (15 mL), NaH (60% dispersion in mineral oil, 570 mg, 14.0 mmol) was added at 0 C. The reaction
mixture was stirred for 1 h at ambient temperature, quenched with H O and extracted with EtOAc. The
2
4
combined organic layer was washed with brine, dried over MgSO , and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc: nꢀhexane = 1: 20 to 1: 10) to afford an
inseperable mixture 5.1 g of PMB ether and unidentified side product. The crude PMB ether (5.1 g) was
dissolved in THF (30 mL) and treated with AcOH (2.1 mL, 36.0 mmol) and TBAF (1.0 M in THF, 21 mL, 21.0
mmol). After stirring for 7 d at the ambient temperature, the reaction mixture was quenched with saturated
NaHCO solution and extracted with EtOAc. The combined organic layer was washed with brine, dried over
3
MgSO
4
, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
2
0
(
EtOAc: nꢀhexane = 1: 2) to afford 3.2 g (81% for 2 steps) of alcohol 14 as a colorless oil. [α] +51.2 (c 0.31,
D
1
CHCl ); HꢀNMR (CDCl , 400 MHz) δ 8.23 (d, 1H, J = 8.1 Hz), 7.49 – 7.22 (m, 10H), 6.88 (d, 2H, J = 8.4 Hz),
3
3
5.27 (br s, 1H), 4.65 (d, 1H, J = 10.8 Hz), 4.55 (d, 1H, J = 10.8 Hz), 4.36 (dd, 1H, J = 2.8, 10.8 Hz), 3.97 – 3.90
(m, 2H), 3.82 – 3.72 (m, 1H), 3.77 (s, 3H), 3.68 – 3.61 (m, 2H), 3.46 (t, 1H, J = 10.4 Hz), 2.66 (dd, 1H, J = 4.8,
13
1
6.4 Hz), 2.59 (dd, 1H, J = 11.6, 16.0 Hz), 2.05 – 1.97 (m, 1H), 1.90 – 1.84 (m, 1H), 1.40 (s, 9H); CꢀNMR
ACS Paragon Plus Environment

Page 11 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(CDCl
3
, 100 MHz) δ 159.2, 149.8, 138.9, 136.4, 135.3, 129.9, 129.4, 128.9, 128.5, 128.4, 127.2, 124.2, 122.7,
1
1
5
17.7, 115.9, 114.0, 113.8, 83.7, 73.1, 69.8, 62.6, 57.8, 55.1, 50.5, 49.7, 34.1, 27.8, 19.7; IR (neat) νmax 2922,
ꢀ
1
+
+
725, 1512, 1455, 1365 cm ; LRꢀMS (FAB
57.3015, Found 557.3007.
41 2 5
+) m/z 557 (M+H ); HRꢀMS (FAB+) Calcd for C34H N O (M+H ):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1R,3S)-tert-butyl 2-benzyl-3-((4-methoxybenzyloxy)methyl)-1-(2-oxoethyl)-1,2,3,4-tetrahydropyrido[3,4-
b]indole-9-carboxylate (15).
To a solution of alcohol 14 (350 mg, 0.6 mmol) in CH
2
Cl
2
(40 mL), 4Å Molecular Sieve (350 mg), NMO (125
o
mg, 1.1 mmol) and TPAP (44 mg, 0.1 mmol) were added at 0 C and the mixture was stirred for 2 h at the
ambient temperature. The reaction mixture was filtered through silica gel and the combined organic layer was
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc: nꢀ
1
hexane= 1: 5 to 1: 3) to afford 342 mg (99%) of unstable aldehyde 15 as a colorless oil. HꢀNMR (CD
3
OD with
ca 10% of CDCl
.07 (d, 2H, J = 12.0 Hz), 6.19 – 6.87 (m, 2H), 4.92 – 4.84 (m, 1H), 4.61 (dd, 1H, J = 7.6, 15.8 Hz), 4.58 – 4.50
m, 2H), 3.98 (dd, 1H, J = 8.0, 15.8 Hz), 3.88 (s, 3H), 3.84 – 3.81 (m, 1H), 3.78 – 3.71 (m, 2H), 3.77 (d, 2H, J =
3
, 300 MHz) δ 9.82 (s, 1H), 8.15 – 8.11 (m, 1H), 7.85 (d, 2H, J = 12.0 Hz), 7.44 – 7.19 (m, 6H),
7
(
1
3
2
.0 Hz), 3.24 (dd, 1H, J = 6.4, 17.6 Hz), 2.66 – 2.62 (m, 2H), 2.01 – 1.90 (m, 1H), 1.47 – 1.45 (m, 9H); Cꢀ
, 100 MHz) δ 201.9, 190.6, 159.1, 149.8, 139.3, 136.1, 134.0, 131.9, 130.2, 129.2, 129.0, 128.2,
27.1, 124.3, 122.8, 118.0, 115.8, 115.7, 114.2, 113.7, 84.1, 72.8, 72.4, 55.4, 55.1, 52.9, 51.2, 50.4, 46.3, 27.7,
NMR (CDCl
3
1
2
ꢀ
1
+
0.4; IR (neat) νmax 1726, 1512, 1456, 1366, 1248 cm ; LRꢀMS (FAB+) m/z 554 (M+H ).
(1R,3S,E)-tert-butyl
2-benzyl-1-(2-(tert-butyldimethylsilyloxy)vinyl)-3-((4-methoxybenzyloxy)methyl)-
1,2,3,4-tetrahydropyrido[3,4-b]indole-9-carboxylate (16).
2 2
To a solution of aldehyde 15 (2.2 g, 4.0 mmol) and TBSCl (1.8 g, 12.0 mmol) in CH Cl (40 mL), DBU (1.2 mL,
8.0 mmol) was added under reflux. After stirring for 5 h at the same temperature, the reaction mixture was
cooled to room temperature, quenched with saturated NaHCO
3
solution, and extracted with CH
, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc: nꢀhexane= 1: 10 with 1% Et N) to afford 2.6 g
, 300 MHz) δ 8.21
d, 1H, J = 8.0 Hz), 7.45 – 7.07 (m, 10H), 6.85 (d, 2H, J = 8.2 Hz), 5.93 (dd, 1H, J = 1.5, 12.3 Hz), 5.11 (dd, 1H,
2 2
Cl . The
combined organic layer was washed with brine, dried over MgSO
4
3
2
0
1
3 3
(97%) of trans enol ether 16 as a colorless oil. [α] +16.7 (c 0.41, CHCl ); HꢀNMR (CDCl
D
(
J = 5.1, 12.3 Hz), 4.74 (d, 1H, J = 5.0 Hz), 4.51 (s, 2H), 3.90 (d, 1H, J = 14.0 Hz), 3.81 – 3.66 (m, 2H), 3.76 (s,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
3H), 3.42 (d, 1H, J = 14.0 Hz), 2.77 – 2.60 (m, 2H), 1.33 (s, 9H), 0.81 (s, 9H), 0.00 (s, 3H), 0.00 (s, 3H); Cꢀ
NMR (CDCl , 100 MHz) δ 159.1, 149.8, 143.7, 140.3, 136.4, 134.1, 130.4, 129.2, 129.1, 128.4, 128.1, 126.6,
23.8, 122.4, 117.8, 115.6, 115.5, 113.7, 112.3, 83.2, 72.7, 72.4, 55.3, 55.1, 50.6, 50.2, 27.7, 25.5, 21.0, 18.0; IR
3
1
ꢀ1
+
(
neat) νmax 2924, 1727, 1648, 1512, 1456 cm ; LRꢀMS (FAB+) m/z 669 (M+H ); HRꢀMS (FAB+) Calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
C
40
H
53
N
2
O
5
Si (M+H ): 669.3724, Found 669.3725.
(
1R,3S,E)-tert-butyl
1-(2-(tert-butyldimethylsilyloxy)vinyl)-3-((4-methoxybenzyloxy)methyl)-1,2,3,4-
tetrahydropyrido[3,4-b]indole-9-carboxylate (17).
2
To a solution of benzylamine 16 (1.6 g, 0.2 mmol) in EtOAc/MeOH (5 mL/ 5 mL), Pd(OH) /C (100 mg) was
added and the mixture was stirred under H
silica gel and the combined organic layer was concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc: nꢀhexane = 1: 3 to 1: 1 with 1% MeOH and Et N) to afford 1.2 g (87%)
of unstable enol ether 17 as a colorless oil. [α] ꢀ29.9 (c 0.23, CHCl ); HꢀNMR (CD OD, 300 MHz) δ 8.07 –
2
(balloon pressure) for 2 h. The reaction mixture was filtered through
3
2
0
1
D
3
3
8
.04 (m, 1H), 7.41 – 7.38 (m, 1H), 7.27 (d, 2H, J = 8.5 Hz), 7.28 – 7.15 (m, 2H), 6.86 (d, 2H, J = 8.5 Hz), 5.92
dd, 1H, J = 0.9, 12.0 Hz), 5.24 (dd, 1H, J = 6.3, 12.0 Hz), 5.15 – 5.13 (m, 2H), 4.48 (d, 1H, J = 2.0 Hz), 3.75 (s,
H), 3.61 (dd, 1H, J = 4.3, 9.6 Hz), 3.51 (dd, 1H, J = 6.9, 9.6 Hz), 3.37 – 3.36 (m, 1H), 2.78 (dd, 1H, J = 4.2,
(
3
1
3
16.2 Hz), 2.44 (dd, 1H, J = 11.0, 16.2 Hz), 1.61 (s, 9H), 0.81 (s, 9H), 0.00 (s, 3H), 0.00 (s, 3H); CꢀNMR
(CD OD, 100 MHz) δ 161.6, 151.9, 146.3, 138.3, 136.3, 132.3, 131.4, 131.0, 126.0, 24.5, 119.7, 17.5, 117.3,
3
1
15.6, 113.4, 85.7, 74.8, 56.4, 52.7, 48.1, 29.2, 26.8, 25.9, 19.8, ꢀ4.3 (2C); IR (neat) νmax 2928, 1729, 1649, 1513,
ꢀ
1
+
1
457, 1363 cm ; LRꢀMS (FAB+) m/z 579 (M+H ).
(
1R,3S)-tert-butyl 1-((E)-2-(tert-butyldimethylsilyloxy)vinyl)-2-butyryl-3-((4-methoxybenzyloxy)methyl)-
3
,4-dihydro-1H-pyrido[3,4-b]indole-9(2H)-carboxylate (18).
2 2 2
To a solution of amine 17 (22 mg, 38 ꢁmol) in CH Cl (2 mL) were added iPr NEt (23 ꢁL, 0.1 mmol) and nꢀ
o
butyryl chloride (10 ꢁL, 0.1 mmol) at 0 C and the mixture was warmed to ambient temperature. The reaction
mixture was stirred for 3 min, quenched with saturated NaHCO
combined organic layer was washed with brine, dried over Na SO , and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc: nꢀhexane = 1: 5, deactivated with 1% Et N) to
OD, 400
MHz, mixture of rotamers) δ 8.09 (d, 1H, J = 6.1 Hz), 7.42 (d, 1H, J = 7.2 Hz), 7.27 – 7.20 (m, 2H), 7.07 (br s,
3 2 2
solution, and extracted with CH Cl . The
2
4
3
2
0
1
afford 26 mg (100%) of butyryl amide 18 as a colorless oil. [α]D +5.66 (c 2.45, MeOH); HꢀNMR (CD
3
2
H), 6.72 (br s, 2H), 6.22 – 6.09 (m, 2H), 5.20 (br s, 1H), 4.42 ꢀ 4.26 (m, 3H), 3.69 (s, 3H), 3.54 (br s, 1H), 3.13
ACS Paragon Plus Environment

Page 13 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(br s, 2H), 2.82 (br s, 1H), 2.47 (m, 2H), 1.65 (s, 9H), 1.65 – 1.61 (m, 2H), 0.92 (t, 3H, J = 7.3 Hz), 0.80 (s, 9H),
1
3
0
1
5
1
6
3
.01 (s, 3H), 0.01 (s, 3H); CꢀNMR (CD OD, 100 MHz, mixture of rotamers) δ 177.0, 161.4, 151.9, 146.0,
38.3, 131.0, 126.3, 124.8, 120.0, 117.6, 116.1, 115.9, 115.7, 115.4, 114.8, 112.9, 112.3, 86.4, 74.3, 72.1, 56.4,
5.0, 54.4, 54.0, 38.4, 29.3, 26.8, 23.6, 20.8, 19.8, 14.9, ꢀ4.3, ꢀ4.3; IR (neat) νmax 2957, 1730, 1654, 1512, 1455,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ1
+
+
369, 1325, 1250 cm ; LRMS (FAB
+
) m/z 649 (M+H ); HRꢀMS (FAB
+
) Calcd for C37
H
53
N
2
O
6
Si (M+H ):
49.3673, Found 649.3688.
(1R,3S,E)-tert-butyl 2-(2-bromobutanoyl)-1-(2-(tert-butyldimethylsilyloxy)vinyl)-3-((4-methoxybenzyloxy)
methyl)-1,2,3,4-tetrahydropyrido[3,4-b]indole-9-carboxylate (6)
2 2 2
To a solution of amine 17 (390 mg, 0.8 mmol) in CH Cl (40 mL) were added iPr NEt (0.4 mL, 2.0 mmol) and
o
2ꢀbromobutyryl bromide (0.1 mL, 0.8 mmol) at 0 C and the mixture was warmed to ambient temperature. The
reaction mixture was stirred for 10 min, quenched with saturated NaHCO
3 2 2
solution, and extracted with CH Cl .
The combined organic layer was washed with brine, dried over Na SO , and concentrated in vacuo. The residue
2
4
3
was purified by flash column chromatography on silica gel (EtOAc: nꢀhexane = 1: 5, 1% Et N) to afford 400 mg
1
(
82%) of bromoamide 6 as a colorless oil. HꢀNMR (CD
3
OD, 400 MHz, mixture of rotamers and diastereomers)
δ 8.13 – 8.10 (m, 1H) 7.48 (d, 2H, J = 7.2 Hz), 7.32 – 7.23 (m, 2H), 7.10 (br s, 2H), 6.78 (d, 1H, J = 8.8 Hz),
6.76 (br s, 1H), 6.27 (d, 1H, J = 6.4 Hz), 6.26 – 6.15 (m, 1H), 5.23 (br s, 1H), 4.94 – 4.85 (m, 1H), 4.61 – 4.57
(m, 1H), 4.45 – 4.32 (m, 2H), 3.73 (s, 3H), 3.33 (br s, 1H), 3.13 – 3.09 (m, 2H), 2.90 – 2.87 (m, 1H), 2.02 (br s,
13
2
3
H), 1.69 – 1.68 (m, 9H), 0.97 (br s, 2H), 0.82 (s, 9H), 0.03 (br s, 6H); CꢀNMR (CD OD, 75 MHz, mixture of
rotamers and diastereomers) δ 175.5, 173.6, 172.4, 161.6, 160.8, 152.3, 152.0, 151.9, 147.1, 146.8, 145.8, 138.4,
37.9, 132.5, 131.8, 131.4, 131.3, 130.7, 130.4, 126.4, 126.2, 124.9, 120.1, 119.9, 118.3, 117.7, 115.5, 115.5,
11.6, 86.6, 86.5, 86.3, 74.6, 74.5, 74.4, 73.1, 71.2, 61.5, 61.0, 56.4, 56.0, 55.5, 54.9, 51.8, 50.9, 48.2, 47.9, 38.5,
7.3, 32.1, 31.3, 30.6, 29.3, 27.4, 27.1, 26.9, 24.9, 24.6, 23.5, 20.1, 19.9, 13.2, 13.1, ꢀ4.3, ꢀ4.4; IR (neat) νmax
1
1
3
ꢀ1
+
2932, 1731, 1657, 1513, 1456, 1367, 1250, 1142 cm ; LRꢀMS (FAB+) m/z 669 (M+H ); HRꢀMS (FAB+) Calcd
+
for C37
H52BrN
2
O
6
Si (M+H ): 727.2778, Found 727.2790.
(2S,5S,6R,E)-tert-butyl
6-(tert-butyldimethylsilyloxy)-5-ethyl-2-((4-methoxybenzyloxy)methyl)-4-oxo-
1,2,3,4,5,6-hexahydroazecino[5,4-b]indole-9-carboxylate (5).
To a solution of bromoamide 6 (340 mg, 0.5 mmol) in benzene (20 mL) was added iPrMgCl (0.6 mL, 2.0 M in
THF, 1.1 mmol) was added under reflux and then a solution of TBSCl (78 mg, 0.5 mmol) in benzene (1 mL)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was added immediately. After stirring for 5 h at the same temperature, the reaction mixture was cooled to room
temperature, quenched with H
brine, dried over MgSO , and concentrated in vacuo. The residue was purified by flash column chromatography
on silica gel (EtOAc: nꢀhexane= 1: 5 to 1: 1) to afford 250 mg (81%) of 10ꢀmembered lactam 5 as a colorless oil.
2
O, and extracted with EtOAc. The combined organic layer was washed with
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
20
D
Recrystallization of lactam 5 from MeOH afforded 5 as white solid with a melting point of 165ꢀ167 C. [α]
1
+
54.4 (c 0.57, CHCl
3
); HꢀNMR (CD
3
OD, 400 MHz) δ 7.76 (d, 1H, J = 7.8 Hz), 7.25 (d, 1H, 7.5 Hz), 7.14 –
6
.96 (m, 5H), 6.73 (d, 2H, J = 8.7 Hz), 6.36 (d, 1H, J = 16.6 Hz), 5.39 (dd, 1H, J = 9.0, 16.5 Hz), 4.33 (s, 2H),
3.94 (t, 1H, J = 9.6 Hz), 3.79 (t, 1H, J = 9.0 Hz), 3.70 – 3.66 (m, 1H), 3.62 (s, 3H), 3.30 – 3.21 (m, 1H), 3.03 (m,
H), 2.57 (d, 1H, J = 9.0 Hz), 1.85 (m, 1H), 1.61 – 1.51 (m, 2H), 1.50 (s, 9H), 0.76 (s, 9H), 0.71 (t, 3H, J = 7.8
1
1
3
Hz), 0.00 (s, 3H), ꢀ0.01 (s, 3H); CꢀNMR (CD
3
OD + 10% of CDCl
37.2, 132.2, 131.0, 125.5, 124.2, 122.1, 120.1, 119.4, 116.7, 115.3, 85.4, 78.3, 74.5, 73.3, 60.5, 57.5, 56.4, 29.3,
7.2, 27.1, 23.4, 22.6, 19.6, 13.7, ꢀ2.8, ꢀ3.7; IR (neat) νmax 3298, 228, 1739, 1645, 1514, 1456, 1365, 1323, 1249
3
, 100 MHz) δ 177.1, 161.2, 151.5, 142.0,
1
2
ꢀ1
+
+
cm ; LRMS (FAB
+) m/z 649 (M+H ); HRMS (FAB+) Calcd for C H N O Si (M+H ): 649.3673, Found
37 53 2 6
649.3678.
Acknowledgements
This work was supported by the National Research Foundation of Korea (NRF) grant for the Global Core
Research Center (GCRC) funded by the Korean government (MSIP) (No. 2011–0030001) and by the Basic
Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of
Science, ICT & Future Planning (NRFꢀ2016R1C1B2006699).
Supporting Information
1
13
H and C NMR spectra of all novel compounds as well as an Xꢀray crystallographic analysis of 5.
References
1) (a) Seigler, D. S. Plant Secondary Metabolism, Springer: New York, 2001. (b) Hibino, S.; Choshi, T. Nat.
(
Prod. Rep. 2002, 19, 148.
(2) (a) Sundberg, R. J.; katritzky, A. R.; MethꢀCohn, O.; Rees, c. S. Indoles Academic Press 1996. (b) Katzung,
th
B. G. Basic & Clinical Pharmacology 7 ed, Appleton & Lange 1997.
(3) Corey, E. J.; Czako, B.; Kurti, L. Molecules and medicine, John Wiley&Son, Inc. 2007.
ACS Paragon Plus Environment

Page 15 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(4) (a) Takayama, H.; Suda, S.; Chen, I.ꢀS.; Kitajima, M.; Aimi, N.; Sakai, S.ꢀi. Chem. Parm. Bull. 1994, 42(2),
280. (b) Girardot, M.; Gadea, A.; Deregnaucourt, C.; Deville, A.; Dubost, L.; Nay, B.; Macluk, A.; Rasoanalvo,
P.; Mambu, L. Eur. J. Org. Chem. 2012, 2816. (c) Sim, D. S. Y.; Chong, K. W.; Nge, C. E.; Low, Y. Y.; Sim, K.
S.; Kam, T. S. J. Nat. Prod. 2014, 77, 2504. (d) Ingkaninan, K.; Changwijit, K.; Suwanborirux, K. J. Pharm.
Pharmacol. 2006, 58, 847. (e) Sim, D. S. Y.; Teoh, W. Y.; Sim, K. S.; Lim, S. H.; Thomas, N. F.; Low, Y. Y.;
Kam, T. S. J. Nat. Prod. 2016, 79, 1048. (f) Zhang, B. J.; Teng, X. F.; Bao, M. F.; Zhong, X. H.; Ni, L.; Cai, X.
H. Phytochemistry 2015, 120, 46.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) (a) Perera, P.; Kanjanapothy, D.; Sandberg, F.; Verpoorte, R. J. Ethnopharmacol. 1985, 13(2), 165. (b) State
Administration of Traditional Chinese Medicine. In Zhonghua Bencao; Shanghai Science & Technology Press:
Shanghai, 1999; Vol. 18, pp 288.
(6) Mansoor, T. A.; Ramalho, R. M.; Mulhovo, S.; Rodrigues, C. M.; Ferreira, M. J. U. Bioorg. Med. Chem. Lett.,
2009, 19, 4255.
(7) For a total synthesis of related compounds. See, (a) Yang, J.; Rallapalli, S. K.; Cook, J. M. Tetrahedron Lett.
2010, 51, 815.
(8) For related approaches to synthesis of this skeleton, see (a) Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F. J.
Am. Chem. Soc., 2003, 125 (15), 4541. (b) Malcolmson, S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. R.;
Hoveyda, A. H. Nature 2008, 456, 933. (c) Rahman, M. T.; Deschamps, J. R.; Imler, G. H.; Schwabacher, A. W.;
Cook, J. M. Org. Lett. 2016, 18, 4174 and references cited therein.
(
9) For reviews of Wacker oxidation, see (a) Feringa, B. L. Transition Metals for Organic Synthesis 1998, 2, 307.
b) Jira, R. Applied Homogeneous Catalysis with Organometallic Compounds (2nd Edition) 2002, 1, 386.
(
(10) (a) Baldwin, J. E.; Walker, J. A. J. Chem. Soc. Chem. Comm. 1973, 117. (b) Greuter, H.; Lang, R. W.;
Romann, A. J. Tetrahedron Lett. 1988, 29(27), 3291. (c) Yang, Y.ꢀY.; Xu, J.; You, Z.ꢀW.; Xu, X.ꢀh.; Qiu, X.ꢀL.;
Qing, F.ꢀL. Org. Lett. 2007, 9(26), 5437.
(11) (a) Suh, Y.ꢀG.; Kim, S.ꢀA.; Jung, J.ꢀK.; Shin, D.ꢀY.; Min, K.ꢀH.; Koo, B.ꢀA.; Kim, H.ꢀS. Angew. Chem., Int.
Ed. 1999, 38(23), 3545. (b) Lee, Y.ꢀS.; Jung, J.ꢀW.; Kim, S.ꢀH.; Jung, J.ꢀK.; Paek, S.ꢀM.; Kim, N.ꢀJ.; Chang, D.ꢀ
J.; Lee, J.; Suh, Y.ꢀG. Org. Lett. 2010, 12, 2040. (c) Paek, S. M.; Kim, N. J.; Shin, D.; Jung, J. K.; Jung, J. W.;
Chang, D. J.; Moon, H.; Suh, Y. G. Chem. Eur. J. 2010, 16(15), 4623. . (d) Yun, H.; Kim, J.; Sim, J.; Lee, S.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Han, Y. T.; Chang, D.ꢀJ.; Kim, D.ꢀD.; Suh, Y.ꢀG. J. Org. Chem. 2012, 77(12), 5389. (e) Jang, J.; Jung, J.ꢀW.;
Ahn, J.; Sim, J.; Chang, D.ꢀJ.; Kim, D.ꢀD.; Suh, Y.ꢀG. Org. Biomol. Chem. 2012, 10, 5202. (f) Sim, J.; Yun, H.;
Jung, J.ꢀW.; Lee, S.; Kim, N.ꢀJ.; Suh, Y.ꢀG. Tetrahedron Lett. 2012, 53, 4813.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(12) (a) Vercauteren, J.; Lavaud, C.; Ley, J.; Massiot, G. J. Org. Chem. 1984, 49, 2278. (b) Bailey, P.;
Hollinshead, S.; Dauter, Z. J. Chem. Soc., Chem. Commun. 1985, 1507. (c) Bailey, P. D.; Hollinshead, S. P. J.
Chem. Soc., Chem. Commun., Perkin Transactions 1 1988, 4, 793. (d) Cox, E. D.; Cook, J. M. Chem. Rev. 1995,
95, 1797.
(13) Liu, X.; Wang, T.; Xu, Q.; Ma, C.; Cook, J. M. Tetrahedron Lett. 2000, 41, 6299.
(14) (a) Vercauteren, J.; Mangenot, C.; Nuzillard, J. M.; Guilhem, J. Tetrahedron 1999, 55(32), 9817. (b) Khan,
M. A.; Adams, H. Tetrahedron Lett. 1999, 40(29), 5389.
(15) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625.
(b) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13.
(
16) Guha, S. K.; Shibayama, A.; Abe, D.; Sakaguchi, Y.; Ukaji, Y.; Inomata, K. Bull. Chem. Soc. Jpn. 2004,
7, 2147 and references cited therein.
17) (a) Pearlman, W. M. Tetrahedron Lett. 1967, 17, 1663. (b) Jung, M. E.; Choi, Y. M. J. Org. Chem. 1991, 56,
729.
(18) Treatment of benzaldehyde to reaction mixture didn’t afford any aldol product.
7
(
6
(19) For similar utilization of iPrMgCl, see Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J.
Am. Chem. Soc. 2001, 123(20), 4834.
(20) CCDC 1509215 contains the supplementary crystallographic data for compound 5. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(21) (a) Ishihara, J.; Watanabe, Y.; Koyama, N.; Nishino, Y.; Takahashi, K.; Hatakeyama, S.. Tetrahedron 2011,
67, 3659. (b) Ishihara, J.; Tsuru, H.; Hatakeyama, S. J. Org. Chem. 2014, 79(12), 5908.
ACS Paragon Plus Environment