Enantioselective Model Synthesis and Progress toward the Putative Structure of Yuremamine

Article abstract of DOI:10.1021/acs.joc.6b01730

An enantioselective model synthesis of the 2,3-dihydro-1H-pyrrolo[1,2-a]indole core of the putative structure of yuremamine is reported in 39% overall yield and 96% ee over five steps. The model synthesis leverages enantioselective, rhodium-catalyzed hydroacylation of an N-vinylindole-2-carboxaldehyde as the key step in the installation of the stereochemical triad. An enantioselective synthesis of a densely functionalized dihydropyrroloindolone that maps onto the putative structure of yuremamine is demonstrated in 26% yield and 97% ee over eight steps.

Full text of DOI:10.1021/acs.joc.6b01730

Subscriber access provided by UNIVERSITY OF WISCONSIN MILWAUKEE
Article
An Enantioselective Model Synthesis and Progress
toward the Putative Structure of Yuremamine
Avipsa Ghosh, David T. Bainbridge, and Levi M. Stanley
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01730 • Publication Date (Web): 05 Aug 2016
Downloaded from http://pubs.acs.org on August 20, 2016
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 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
An Enantioselective Model Synthesis and Progress toward
the Putative Structure of Yuremamine
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
Avipsa Ghosh, David T. Bainbridge, and Levi M. Stanley*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
Email: lstanley@iastate.edu
ABSTRACT: An enantioselective model synthesis of the 2,3-dihydro-1H-pyrrolo[1,2-a]indole core of
the putative structure of yuremamine is reported in 39% overall yield and 96% ee over 5 steps. The
model synthesis leverages enantioselective, rhodium-catalyzed hydroacylation of an N-vinylindole-2-
carboxaldehyde as the key step in the installation of the stereochemical triad. An enantioselective syn-
thesis of a densely functionalized dihydropyrroloindolone that maps onto the putative structure of
yuremamine
is
demonstrated
in
26%
yield
and
97%
ee
over
8
steps.
INTRODUCTION
2,3-Dihydro-1H-pyrrolo[1,2-a]-indole and oxidized derivatives are recurring motifs in natural
products and drug candidates including the antimalarial flinderoles1 and isoborreverines,2 the antitumor
antibiotic mitomycin C,3 the PKC inhibitor JTT-0104 and isatisine A5 which exhibits antiviral activity.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
Yuremamine, a phytoindole alkaloid with hallucinogenic and psychoactive properties was isolated from
the stem bark of Mimosa hostilis in 2005 by Callaway and co-workers.6 The structure of yuremamine,
originally proposed to be the densely functionalized dihydropyrroloindole 1 with three contiguous stere-
ogenic centers, was recently revised to the flavonoidal indole 2 by Sperry and co-workers (Figure 1).7
NMe2
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
OH
NMe2
OH
O
N
OH
OH
N
H
HO
OH
OH
HO
1
2
OH
HO
HO
Originally proposed structure
Revised structure
Figure 1. Originally proposed structure and revised structure of yuremamine
The intriguing molecular architecture of 1 prompted numerous synthetic studies towards the pu-
tative structure since the isolation of yuremamine. While several synthetic strategies towards the dihy-
dropyrroloindole core of 1 have been developed by the Kerr, Shi, Dethe, Chen, France, You, Sperry and
Zu groups,8 the first racemic total synthesis was reported by the Iwasawa group in 2015.9 Despite these
synthetic efforts during the past decade, enantioselective total synthesis of 1 or synthetic approaches to
generate the chiral dihydropyrroloindole core with control of the absolute configuration of the stereo-
chemical triad have not been reported.
Scheme 1. Enantioselective Hydroacylation of N-Vinylindole-2-carboxadehydes to Access Chiral
Dihydropyrroloindolones
R2
R2
H
O
chiral, non-racemic
Rh catalyst
R1
O
R1
N
N
up to 99% yield
up to 99% ee
R3
R3
Compound 1 is a fundamentally challenging target due to the lack of well-established enantiose-
lective methods to generate chiral 2,3-dihydro-1H-pyrrolo[1,2-a]-indoles.10 The dihydropyrroloindole
2
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
core of 1 contains three contiguous stereogenic centers that must be formed in a stereocontrolled fash-
ion. Recently, we reported catalytic, intramolecular hydroacylations of N-vinylindole-2-
carboxaldehydes to form β-substituted dihydropyrroloindolones with high enantioselectivities that offer
the potential to address these challenges (Scheme 1).11 The enantioselective hydroacylation would ena-
ble control of the absolute configuration of one of the requisite stereogenic centers present in the dihy-
dropyrroloindole core. In addition, the ketone functionality present in the dihydropyrroloindolone prod-
uct of hydroacylation can serve as a synthetic handle to install the additional stereogenic centers with
precise control of the absolute and relative configuration of the stereochemical triad.
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
Herein, we report an enantioselective model synthesis of the 2,3-dihydro-1H-pyrrolo[1,2-
a]indole core of 1 utilizing enantioselective rhodium-catalyzed hydroacylation of an N-vinylindole-2-
carboxaldehyde as the key step for installation of the three contiguous stereogenic centers. We also re-
port an enantioselective synthesis of a functionalized chiral dihydropyrroloindolone that maps onto the
structure of 1.
RESULTS AND DISCUSSION
Scheme 2 illustrates the strategy we originally envisioned to complete an enantioselective syn-
thesis of 1. Installation of the stereochemical triad in 1 would be achieved by a sequence of hydrobora-
tion and oxidation occurring on the face of the olefin opposite to the aryl group attached to the stereo-
genic center in 3.12 Compound 3 would be synthesized by a sequence of Grignard addition to the chiral
dihydropyrroloindolone 4 followed by dehydration of the resulting tertiary alcohol to form the required
alkene. Based on our previous studies, we planned the synthesis of 4 from N-vinylindole-2-
carboxaldehyde 5 by an enantioselective, intramolecular rhodium-catalyzed hydroacylation reaction.11
Compound 5 would be generated by a palladium-catalyzed cross-coupling reaction of indole 7 and hy-
drazone 6.13 Indole 7 could be derived from 8 by direct installation of the ester functionality at the 2-
position of the indole followed by removal of the protecting group from the indole nitrogen.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
Scheme 2. Retrosynthetic Analysis for the Enantioselective Synthesis of Compound 1
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
We were aware that intermediate 3 may be susceptible to olefin isomerization that could race-
mize the stereogenic center set by enantioselective hydroacylation. To test our strategy to install the
three contiguous stereogenic centers in an enantioselective and diastereoselective fashion, we conducted
a model study starting from N-vinylindole-2-carboxaldehyde 9 (Scheme 3). Enantioselective hydroac-
ylation of 9 in the presence of 0.5 mol% of a Rh catalyst prepared in situ from [Rh(COD)Cl]2, (R)-MeO-
BIPHEP, and AgBF4 formed dihyropyrroloindolone 10 in 83% yield with 97% ee. Addition of phenyl-
magnesium bromide to 10 generated the tertiary alcohol 11 in 90% yield as a 6:1 mixture of diastere-
omers with complete retention of enantiomeric excess (97% ee). Subsequent dehydration of the result-
ing tertiary alcohol with Martin sulfurane generated (R)-1,3-diphenyl-3H-pyrrolo[1,2-a]indole 12.14
The carbon skeleton present in the dihydropyrroloindole core of 1 was established by immediate hy-
droboration of 12 followed by oxidation of the resulting alkylborane with basic hydrogen peroxide. Di-
hydropyrroloindole 13 was isolated as a 9:1 mixture of diastereomers in 52% yield over three steps
without significant loss of enantioselectivity (96% ee). Consistent with hydroboration and oxidations of
1,3-diarylcyclopent-1-enes, the hydroboration and oxidation of 12 preferentially occurs on the face of
4
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
the olefin opposite to the phenyl group attached to the stereogenic center.12 This sequence occurs to set a
stereochemical triad with both aryl groups trans to the hydroxyl group. The relative stereochemistry of
the dihydropyrroloindole core 13 was established by geminal carbon-proton spin coupling-constant
(2JC,H) values (J-based configuration analysis) and the dependence of these values on dihedral angles
(see Supporting Information for details).15
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
Scheme 3. Enantioselective Model Synthesis of the 2,3-Dihydro-1H-pyrrolo[1,2-a]indole Core of 1
[Rh(COD)Cl]2
(0.25 mol %)
(R)-MeO-BIPHEP
(0.5 mol %)
O
CHO
N
N
AgBF4 (0.5 mol %)
PhMgBr
1,4-dioxane
100 °C, 12 h
THF
65 °C, 16 h
9
10
83% yield, 97% ee
OH
N
N
Martin Sulfurane
CH2Cl2, rt, 1 h
11
12
90% yield, 97% ee
6:1 d.r.
N
1. BH3•THF
2. H2O2, aq NaOH
52% yield over
three steps
96% ee, 9:1 d.r.
OH
13
THF, 0 °C→rt
Encouraged by the results of our model synthesis, we initiated studies toward an enantioselective
synthesis of 1. Preliminary studies of the key hydroacylation step with N,N-dimethyltryptamine deriva-
tives were not encouraging, presumably due to coordination of the basic nitrogen in the N,N-
dimethyltryptamine derivative to the rhodium center. Thus, we conducted our studies starting from the
TBS ether of tryptophol 14. Scheme 4 illustrates the synthesis of indole 17 from the TBS ether of tryp-
tophol 14.16 The indole nitrogen in 14 was protected using benzenesulfonyl chloride in the presence of
tetrabutylammonium hydrogensulfate (TBAHS) to furnish 15 in 99% yield.17 We envisioned direct in-
stallation of an ester at the 2-position of indole via lithiation followed by quenching with an appropriate
electrophile. Interestingly, common lithiating agents such as n-BuLi, sec-BuLi, and tert-BuLi led to the
formation of complex mixtures of multiple products even with less than one equivalent of base.18 How-
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 21
ever, lithiation in the presence of freshly prepared lithium diisopropylamide (LDA) at -78 °C followed
by reaction with diethyl carbonate or ethyl chloroformate formed the desired ethyl indole-2-carboxylate
16 as the only product in 30-75% yield (Table 1, entries 1 and 2). The use of ethyl chloroformate as the
electrophile and increasing the reaction temperature improved the yield of the desired product to 90%
(Table 1, entry 3).
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
Scheme 4. Synthesis of Indole 17
Table 1. Identification of Reaction Conditions for Synthesis of Ester 16a
entry
electrophile
Temp
Yield
(°C)
(%)b
1
-78
-78
diethyl carbonate
30
2
75
ethyl chlorofor-
mate
3
-78→0
90
ethyl chlorofor-
mate
aReaction conditions: 15 (1.20 mmol, 1.00 equiv), LDA (1.20 mmol, 1.00 equiv), Electrophile (1.44
mmol, 1.20 equiv) and THF (7.0 mL). bIsolated yield of 16 after column chromatography.
6
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
With a suitable method to install the ester functionality, we attempted to remove the benzenesul-
1
2
fonyl protecting group in 16. Although many methods are established to accomplish similar transfor-
mations, the deprotection of 16 proved challenging.19 Deprotection in the presence of Na-Hg/Na2HPO4
led to incomplete conversion (60%) of 16 to indole 17.19a The reaction of 16 in presence of sodium tert-
butoxide in 1,4-dioxane was plagued by undesired transesterification and hydrolysis of the ester.19b
Deprotection of 16 in the presence of Cs2CO3 in a 2:1 mixture of THF:ethanol at room temperature led
to 99% conversion of 16 to 17 along with the formation of ethyl benzenesulfonate (eq 1).20 However,
the similar polarities of 17 and ethyl benzenesulfonate rendered isolation of pure 17 challenging by
standard chromatographic techniques. Conducting the reaction at reflux for 16 h led to the formation of
17 in 95% yield along with benzenesulfonic acid, which were easily separable by flash column chroma-
tography (eq 2). All the synthetic transformations shown in Scheme 4 are robust and were conducted in
multi-millimolar scale (up to 20 mmole).
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
Scheme 5 illustrates the enantioselective synthesis of the functionalized chiral dihydropyrroloin-
dolone 20. Palladium-catalyzed cross-coupling of 17 with hydrazone 6 generated ethyl N-vinylindole-2-
carboxylate 18 in 40% isolated yield. A sequence of DIBAL-H mediated reduction of 18 followed by
oxidation of the resulting crude alcohol with MnO2 furnished N-vinylindole-2-carboxaldehyde 19 in
84% yield over two steps. Enantioselective, intramolecular hydroacylation of 19 in the presence of a
catalyst generated in situ from [Rh(COD)Cl]2, (R)-MeO-BIPHEP, and AgBF4 formed dihyropyrroloin-
dolone 20 in 90% yield with 97% ee.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
Scheme 5. Synthesis of Dihydropyrroloindolone 20
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
Chiral dihydropyrroloindolone 20 is suitably functionalized to complete an enantioselective syn-
thesis of 1 based on the model synthesis illustrated in Scheme 2. However, we elected to terminate our
efforts toward 1 following the structural reassignment of yuremamine from a dihydropyrroloindole to a
flavonoidal indole.7
CONCLUSION
In conclusion, we have developed an enantioselective model synthesis of the 2,3-dihydro-1H-
pyrrolo[1,2-a]indole core present in the putative structure of yuremamine. The 2,3-dihydro-1H-
pyrrolo[1,2-a]indole core containing three contiguous stereogenic centers was synthesized in 39% over-
all yield and 96% ee in 5 steps. The catalytic protocol for enantioselective rhodium-catalyzed hydroac-
ylation of N-vinylindole-2-carboxaldehyde reported by our group was utilized in multi-milllimolar scale
as the key step for installation of the stereochemical triad. The ketone functionality present in the hy-
droacylation product served as a synthetic handle for the installation of additional stereocenters with
precise control of absolute and relative stereochemistry. Progress toward enantioselective synthesis of
the putative structure of yuremamine is reported, and the enantioselective synthesis of a densely func-
8
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
tionalized dihydropyrroloindolone core that maps onto this structure has been demonstrated in 26%
yield and 97% ee over 8 steps. The synthetic strategy is likely to be amenable to synthesis of other natu-
ral products containing a 2,3-dihydro-1H-pyrrolo[1,2-a]-indole core and highlights the utility of our hy-
droacylation protocol in the construction of complex molecular scaffolds.
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
EXPERIMENTAL SECTION
General Experimental Details
All air-sensitive procedures were conducted under inert atmosphere in a nitrogen-filled dry box
or by standard Schlenk techniques. All reactions were performed under an atmosphere of nitrogen un-
less otherwise stated. All glassware for moisture sensitive reactions was dried at 140 °C in an oven.
THF, DMF, CH2Cl2 and diethyl ether were degassed by purging with argon for 45 minutes and dried
with a solvent purification system by passing through a one-meter column of activated alumina. Flash
column chromatography was performed on SiliFlash® P60 silica gel (40-63µm, 60 Å) using hex-
anes/EtOAc or hexanes/ether mixtures. Reaction products were visualized on TLC by UV light or by
staining with KMnO4 or 2,4-dinitro-phenylhydrazine.
HRMS (ESI) analysis was performed on a QTOF spectrometer. Optical rotations were measured
on an automatic polarimeter. HPLC analyses were carried out on a HPLC system with Separations
Module and aUV/Vis dual wavelength detector. NMR spectra were acquired on 400 MHz and 600 MHz
NMR spectrometers. Chemical shifts are reported in ppm relative to a residual solvent peak (CDCl3 =
7.26 ppm for 1H and 77.16 ppm for 13C; C6D6 = 7.16 for 1H and 128.06 for 13C). Coupling constants are
reported in hertz.
Materials
N-Vinylindole-2-carboxaldehyde 9 was synthesized according to a literature procedure from
ethyl indole-2-carboxylate.11 3′,4′,5′-Trimethoxyacetophenone was synthesized from 3′,4′,5′-
trimethoxybenzoic acid according to a literature procedure.21 [Rh(COD)Cl]2, Pd2(dba)3, rac-BINAP,
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
(R)-MeO-BIPHEP, silver tetrafluoroborate were purchased from Strem Chemicals and used without fur-
1
2
3
ther purification.
4
5
6
7
Synthesis of (R)-3-Phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (10)11
8
9
In a nitrogen-filled glovebox, N-vinylindole-2-carboxaldehyde 9 (500 mg, 2.02 mmol, 1.00
equiv), [Rh(COD)Cl]2 (2.5 mg, 0.0050 mmol, 0.0025 equiv), (R)-MeO-BIPHEP (5.8 mg, 0.010 mmol,
0.0050 equiv), AgBF4 (1.9 mg, 0.010 mmol, 0.0050 equiv) and 1,4-dioxane (14.0 mL) were added to a
20 mL scintillation vial. The vial was sealed with a PTFE/silicone-lined septum cap and removed from
the glovebox. The reaction mixture was stirred at 100 °C in an oil bath for 12 h. The vial was removed
from the oil bath and allowed to cool to room temperature. The reaction mixture was filtered through a
short plug of silica gel (eluting with 100 mL of 3:2 hexane:EtOAc). The crude reaction mixture was
concentrated under reduced pressure. The mixture was purified by flash column chromatography (90:10
hexane:EtOAc) to give (R)-3-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one 10 as a light yellow sol-
id in 83% yield (415 mg, 1.68 mmol). The enantiomeric excess was determined by HPLC analysis (220
nm, 25 °C) tR 17.7 min (major); tR 21.1 min (minor) [Chiracel AD-H (0.46 cm x 25 cm) (from Daicel
Chemical Ind., Ltd.) hexane/i-PrOH, 95:5, 1.0 mL/min] to be 97%. [α]D24 = +232.2 (c 0.51, CHCl3). 1H
NMR (400 MHz, CDCl3) δ 3.07 (dd, J = 18.4, 4.0 Hz, 1H), 3.68 (dd, J = 18.4, 8.0 Hz, 1H), 5.74 (dd, J
= 8.0, 4.0 Hz, 1H), 6.93 – 6.95 (m, 1H), 7.11 – 7.21 (m, 5H), 7.32 – 7.39 (m, 3H), 7.77 – 7.79 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 50.4, 57.3, 99.3, 111.8, 121.7, 124.3, 125.4, 126.1, 128.6, 129.4, 132.6,
135.0, 136.3, 140.1, 192.2. HRMS (ESI): Calcd. for C17H14NO ([M+H]+): 248.1070, Found: 248.1069.
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
Synthesis of (1S,3R)-1,3-Diphenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ol (11)
A 3.0 M solution of phenylmagnesium bromide (0.67 mL, 2.0 mmol, 2.5 equiv) in diethyl ether
was added to a solution of (R)-3-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one 10 (200 mg, 0.808
mmol, 1.00 equiv) in THF (5.0 mL) under a nitrogen atmosphere. The reaction mixture was heated at 65
°C and stirred for 16 h. The mixture was cooled in an ice/water bath and then quenched with saturated
aqueous NH4Cl (20 mL). The organic layer was separated and the aqueous phase was extracted with
10
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
ether (3 × 30 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash column chromatography on silica gel
(85:15 hexane:EtOAc) to give (1S,3R)-1,3-diphenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ol 11 as a
yellow oil in 90% yield (237 mg, 0.728 mmol) as a 6.1:1 diastereomeric ratio. The enantiomeric excess
was determined by HPLC analysis (220 nm, 25 °C) tR 13.6 min [(1R,3R)]; tR 16.2 min [(1S,3S)], tR 20.5
min [(1S,3R)]; tR 36.3 min [(1R,3S)] [Chiracel AD-H (0.46 cm x 25 cm) (from Daicel Chemical Ind.,
Ltd.) hexane/i-PrOH, 93:7, 1.0 mL/min] to be 96% for the (1R,3R)-diastereomer and 97% for the
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
24
1
(1S,3R)-diastereomer. [α]D = +78.7 (c 0.25, CHCl3). H NMR (600 MHz, C6D6) δ 1.87 (s, 1H), 2.72
(dd, J = 13.3, 4.2 Hz, 1H), 2.95 (dd, J = 13.3, 8.1 Hz, 1H), 5.02 (dd, J = 8.1, 4.2 Hz, 1H), 6.27 (s, 1H),
6.88 – 6.96 (m, 3H), 7.02 – 7.03 (m, 3H), 7.06 (dd, J = 7.8, 7.8 Hz, 1H), 7.12 (dd, J = 7.8, 7.8 Hz, 1H),
13
7.17 – 7.21 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H). C NMR (151 MHz, C6D6) δ
57.6, 59.7, 78.7, 93.85, 111.3, 120.45, 122.0, 122.1, 126.1, 126.75, 127.7, 128.35, 128.5, 129.0, 132.85,
133.7, 141.3, 145.7, 148.8. HRMS (ESI): Calcd. for C23H20NO ([M+H]+): 326.1539, Found: 326.1546.
Synthesis of (1S,2R,3S)-1,3-Diphenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-ol (13)12, 14
Martin sulfurane22 (465 mg, 0.691 mmol, 1.50 equiv) was added to the solution of (1S,3R)-1,3-
diphenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ol 11 (150 mg, 0.461 mmol, 1.00 equiv) in CH2Cl2 (5.0
mL) under a nitrogen atmosphere. The reaction was stirred for 30 min at 23 °C. The reaction was
quenched with sat. aq NaHCO3 solution, extracted with EtOAc, and washed with 1 M NaOH (4x). The
organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude
product was immediately purified by flash column chromatography using silica gel, pre-treated with
0.1% triethylamine, (95:5 hexane:EtOAc) to give (R)-1,3-diphenyl-3H-pyrrolo[1,2-a]indole, 12 as a
bluish white solid (132 mg, 0.429 mmol).
After isolation, compound 12 (60.0 mg, 0.195 mmol) was immediately dissolved in anhydrous
.
THF (2.0 mL), cooled to 0 °C under a nitrogen atmosphere and a 1.0 M solution of BH3 THF (3.50 mL,
3.51 mmol, 18.0 equiv) was added. The reaction mixture was stirred at room temperature overnight. The
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
reaction mixture was then cooled to 0 °C and treated with 15% aqueous sodium hydroxide (0.25 mL)
and 30% hydrogen peroxide (0.50 mL). This mixture was stirred at room temperature for 2 hours and
extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, and con-
centrated under reduced pressure. The crude product was purified by flash column chromatography on
silica gel (80:20 hexane:EtOAc) to give (1S,2R,3S)-1,3-diphenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-
ol 13 as a yellow solid in 52% yield (35.6 mg, 0.109 mmol) over three steps as a 9:1 mixture of dia-
stereomers. The enantiomeric excess was determined by HPLC analysis (220 nm, 25 °C) tR 17.8 min
[(1R,2S,3S)]; tR 23.0 min [(1S,2R,3R)]; tR 28.3 min [(1S,2R,3S)]; tR 38.0 min [(1R,2S,3R)] [Chiracel AD-
H (0.46 cm x 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 95:5, 1.0 mL/min] to be 97%
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
24
for the (1R,2S,3S)-diastereomer and 96% for the (1S,2R,3S)-diastereomer. [α]D = +107.6 (c 0.23,
CHCl3). 1H NMR (600 MHz, C6D6) δ 1.37 (d, J = 6.1 Hz, 1H), 3.96 (m, 1H), 4.18 (d, J = 8.1 Hz, 1H),
4.63 (d, J = 7.2 Hz, 1H), 6.26 (s, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 7.05 – 7.09 (m,
5H), 7.22 (t, J = 7.6 Hz, 3H), 7.40 (d, J = 7.6 Hz, 3H), 7.68 (d, J = 7.9 Hz, 1H). 13C NMR (151 MHz,
C6D6) δ 52.7, 68.1, 91.5, 95.7, 111.2, 120.1, 121.2, 121.3, 127.5, 127.7, 128.35, 128.6, 129.96, 129.00,
129.2, 133.2, 138.5, 140.5, 143.2. HRMS (ESI): Calcd. for C23H20NO ([M+H]+): 326.1539, Found:
326.1535.
Synthesis of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole (14)16, 23
To a stirred solution of indole (11.0 g, 93.9 mmol, 1.00 equiv) in anhydrous diethyl ether (200
mL) at 0 °C, oxalyl chloride (9.50 mL, 113 mmol, 1.20 equiv) was added dropwise over 30 min. The
reaction mixture was stirred at the same temperature for 2 h. The resulting yellow crystals of 3-
indolylglyoxylyl chloride were filtered and washed with anhydrous diethyl ether.
3-Indolylglyoxylyl chloride (19.0 g, 91.5 mmol, 1.00 equiv) was refluxed for 30 min in a mix-
ture of ethanol (60 mL) and triethylamine (13.4 mL, 96.1 mmol, 1.05 equiv). The reaction mixture was
cooled to 0 °C and the solid ethyl indolylglyoxylate was isolated by filtration. The solid was washed
with cold diethyl ether, dried under reduced pressure and used directly for the next step.
12
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
A solution of ethyl indolylglyoxylate (18.0 g, 82.9 mmol, 1.00 equiv) in THF (100 mL) was
1
2
added dropwise to a suspension of LiAlH4 (11.6 g, 290 mmol, 3.50 equiv) in THF (300 mL) at 0 °C.
The reaction mixture was refluxed for 4 h, cooled to 0 °C and quenched with a saturated aqueous solu-
tion of potassium sodium tartrate (400 mL). The resulting solution was then filtered and washed with
EtOAc (500 mL). The combined organic extracts were dried over MgSO4 and the solvent was evapo-
rated under reduced pressure. The crude product was dried and used directly for the next step without
further purification.
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
To a cooled solution (0 °C) of tryptophol (12.4 g, 76.7 mmol, 1.00 equiv) and imidazole (11.6 g,
169 mmol, 2.20 equiv) in anhydrous DMF (120 mL), TBS-Cl (13.1 g, 84.3 mmol, 1.10 equiv) was add-
ed, and the reaction mixture was stirred for 16 h at room temperature. Ethyl acetate (250 mL) was then
added and the organic phase was washed with brine (200 mL). The organic phase was dried over
MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash col-
umn silica gel (98:2 hexane:EtOAc) to give 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole 14 as a
1
yellow solid in 81% yield over four steps (21.0 g, 76.2 mmol). H NMR (400 MHz, CDCl3) δ 0.05 (s,
6H), 0.93 (s, 9H), 3.02 (t, J = 7.4 Hz, 2H), 3.91 (t, J = 7.4 Hz, 2H), 7.04 (s, 1H), 7.13 (ddd, J = 7.8, 7.4,
1.2 Hz, 1H), 7.20 (ddd, J = 8.1, 7.4, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.96
(s, 1H). 13C NMR (101 MHz, CDCl3) δ -5.1, 18.5, 26.1, 29.1, 64.05, 111.2, 113.0, 118.95, 119.3, 121.9,
122.2, 127.7, 136.2.
Synthesis of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(phenylsulfonyl)-1H-indole (15)17
To a stirred mixture of 14 (6.00 g, 21.8 mmol, 1.00 equiv) and tetrabutylammonium hydro-
gensulfate (1.10 g, 3.30 mmol, 0.150 equiv) in toluene (90 mL) at 0 °C was added aq. NaOH (50 wt %,
90 mL) followed by benzenesulfonyl chloride (4.20 mL, 32.7 mmol, 1.50 equiv). The resulting suspen-
sion was allowed to warm to room temperature and vigorously stirred at this temperature for 15 h. The
reaction mixture was diluted with water (250 mL) and extracted with EtOAc (250 mL). The organic
layer was washed with water (250 mL) and brine (250 mL), dried over MgSO4 and concentrated under
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
reduced pressure. The crude product was purified by flash column silica gel (99:1 hexane:EtOAc) to
give 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(phenylsulfonyl)-1H-indole 15 as a white solid in 99%
yield (9.00 g, 21.6 mmol). 1H NMR (400 MHz, CDCl3) δ -0.02 (s, 6H), 0.87 (s, 9H), 2.88 (t, J = 6.7 Hz,
2H), 3.87 (t, J = 6.7 Hz, 2H), 7.22 – 7.25 (m, 1H), 7.29 – 7.33 (m, 1H), 7.40 – 7.44 (m, 3H), 7.49 – 7.53
1
2
3
4
5
6
7
8
9
13
(m, 2H), 7.87 (d, J = 7.5 Hz, 2H), 7.99 (d, J = 8.3 Hz, 1H). C NMR (101 MHz, CDCl3) δ -5.2, 18.4,
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
26.1, 28.7, 62.7, 113.8, 119.7, 120.45, 123.2, 123.6, 124.75, 126.85, 129.3, 131.4, 133.8, 135.2, 138.5.
HRMS (ESI): Calcd. for C22H29NO3SSiNa ([M+Na]+): 438.1530, Found: 438.1538.
Synthesis of ethyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(phenylsulfonyl)-1H-indole-2-
carboxylate (16)18
To a solution of lithium diisopropylamide (19.3 mmol, 1.00 equiv) prepared from diisopropyla-
mine (2.80 mL, 20.2 mmol, 1.05 equiv) and n-butyllithium (13.5 mL, 1.43 M in hexane; 19.3 mmol,
1.00 equiv) in dry THF (50 mL) under argon at -78 °C was added dropwise via syringe over 5 min a so-
lution of 15 (8.00 g, 19.3 mmol, 1.00 equiv) in dry THF (50 mL). The mixture was stirred for 1 h at -78
°C and then allowed to warm slowly to 0 °C over 3 h. The resulting solution was cooled to -78 °C and
treated with a solution of ethyl chloroformate (2.20 mL, 23.1 mmol, 1.20 equiv) in THF (10 mL). The
reaction mixture was stirred for 3 h at the same temperature and then warmed to room temperature
overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (100 mL) at 0
°C and extracted with diethyl ether (2 x 250 mL). The combined organic extracts were washed with wa-
ter (200 mL), brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash column chromatography on silica gel (95:5 hexane:ether) to give 3-
(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate 16 as a yellow oil in
1
90% yield (8.50 g, 17.4 mmol). H NMR (400 MHz, CDCl3) δ -0.10 (s, 6H), 0.79 (s, 9H), 1.41 (t, J =
7.2 Hz, 3H), 3.00 (t, J = 6.9 Hz, 2H), 3.78 (t, J = 6.9 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 7.22 – 7.28 (m,
13
1H), 7.35 – 7.43 (m, 3H), 7.46 – 7.58 (m, 2H), 7.89 (d, J = 7.4 Hz, 2H), 8.02 (d, J = 8.4 Hz, 1H). C
NMR (101 MHz, CDCl3) δ -5.4, 14.2, 18.4, 26.0, 28.4, 62.2, 63.1, 115.5, 121.3, 124.1, 126.9, 127.0,
14
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
127.3, 128.9, 129.1, 130.5, 133.8, 137.1, 137.7, 162.4. HRMS (ESI): Calcd. for C25H34NO5SSi
([M+H]+): 488.1921, Found: 488.1925.
1
2
3
4
5
6
7
8
NaOtBu-Mediated synthesis of ethyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-2-
carboxylate (17)19b
9
To a solution of 16 (0.500 g, 1.03 mmol, 1.00 equiv) in 1,4-dioxane (7.5 mL), NaOtBu (0.148 g,
1.54 mmol, 1.50 equiv) was added under nitrogen atmosphere. The reaction mixture was stirred at 80 °C
for 3 h, cooled to room temperature and filtered through a short plug of celite (eluting with 150 mL
EtOAc). The crude reaction mixture was concentrated under reduced pressure. The crude reaction prod-
uct obtained was a mixture of compounds 17, the corresponding tert-butyl ester and the corresponding
carboxylic acid. The crude mixture was purified by flash column chromatography on silica gel (90:10
hexane:ether) to give ethyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-2-carboxylate 17 as a
white solid in 20% yield (0.0710 g, 0.204 mmol). 1H NMR (400 MHz, CDCl3) δ -0.03 (s, 6H), 0.85 (s,
9H), 1.43 (t, J = 7.1 Hz, 3H), 3.36 (t, J = 7.3 Hz, 2H), 3.86 (t, J = 7.3 Hz, 2H), 4.43 (q, J = 7.1 Hz, 2H),
7.09 – 7.19 (m, 1H), 7.28 – 7.34 (m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 8.76 (s,
1H). 13C NMR (101 MHz, CDCl3) δ -5.2, 14.6, 18.5, 26.1, 28.8, 60.9, 63.8, 111.7, 120.2, 121.3, 121.4,
123.8, 125.7, 128.7, 135.9, 162.4. HRMS (ESI): Calcd. for C21H34NO3Si ([M+C2H5]+): 376.2302,
Found: 376.2308.
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
Cs2CO3-Mediated synthesis of ethyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-2-
carboxylate (17)
Ethyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-2-carboxylate 16 (10.0 g, 20.5 mmol,
1.00 equiv) was dissolved in a mixture of THF (150 mL) and EtOH (75 mL) at room temperature. Ce-
sium carbonate (20.4 g, 61.5 mmol, 3.00 equiv) was added to the clear solution. The resulting mixture
was stirred at reflux for 16 h, cooled and concentrated under reduced pressure. The mixture was treated
with water (200 mL) and extracted with diethyl ether (3 × 200 mL). The organic extracts were com-
bined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was pu-
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
rified by flash column chromatography on silica gel (90:10 hexane:ether) to give ethyl 3-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-1H-indole-2-carboxylate 17 as a white solid in 95% yield (6.80 g, 19.6
mmol). 1H NMR and 13C NMR spectra of the isolated product comply with the characterization data of
17 as reported above. HRMS (ESI): Calcd. for C21H34NO3Si ([M+C2H5]+): 376.2302, Found:
376.2311.
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
Synthesis of (E)-4-methyl-N'-(1-(3,4,5-trimethoxyphenyl)ethylidene)benzenesulfonohydrazide (6)13
1-(3,4,5-Trimethoxyphenyl)ethanone (10.0 g, 47.6 mmol, 1.00 equiv), p-toluenesulfonyl hydra-
zide (9.10 g, 47.6 mmol, 1.00 equiv) and dry methanol (120 mL) were charged in a round-bottom flask
equipped with a reflux condenser. The reaction mixture was heated to 60 °C and stirred for 1 h. The
mixture was cooled to 0 °C, and the product was collected by filtration on a Buchner funnel, washed
with diethyl ether, and then dried under reduced pressure to afford the pure product (E)-4-methyl-N-(1-
(3,4,5-trimethoxyphenyl)ethylidene)benzenesulfonohydrazide 6 as a light yellow solid in 61% yield
1
(11.0 g, 29.1 mmol). H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H), 2.41 (s, 3H), 3.85 (s, 3H), 3.86 (s,
6H), 6.86 (s, 2H), 7.31 (d, J = 8.2 Hz, 2H) 7.92 (d, J = 8.2 Hz, 2H), 8.35 (s, 1H). 13C NMR (101 MHz,
CDCl3) δ 13.8, 21.6, 56.1, 60.9, 103.8, 128.3, 129.5, 132.9, 135.4, 139.5, 144.3, 152.7, 152.9.
Synthesis of ethyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(1-(3,4,5-trimethoxyphenyl)vinyl)-1H-
indole-2-carboxylate (18)13
A 50 mL pressure reaction tube was charged with indole 17 (0.200 g, 0.575 mmol, 1.00 equiv),
N-tosylhydrazone 6 (0.327 g, 0.863 mmol, 1.50 equiv), iodobenzene (0.10 mL, 0.860 mmol, 1.50
equiv), Pd2(dba)3 (0.0527 g, 0.0575 mmol, 0.100 equiv), NaOtBu (0.155 g, 1.61 mmol, 2.80 equiv) and
CPME (25 mL). The flask was immersed in a preheated oil bath and stirred at 120 °C for 24 h. The
crude reaction mixture was allowed to cool to room temperature, EtOAc was added and stirred for 10
min. The reaction mixture was filtered through celite (eluting with 50 mL EtOAc) and the solvent was
evaporated under reduced pressure. The crude product was purified by flash column chromatography on
silica gel (80:20 hexane:ether) to give ethyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(1-(3,4,5-
16
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
trimethoxyphenyl)vinyl)-1H-indole-2-carboxylate 18 as a colorless oil in 40% yield (0.125 g, 0.232
mmol). 1H NMR (400 MHz, CDCl3) δ -0.02 (s, 6H), 0.86 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H), 3.35 (t, J =
7.3 Hz, 2H), 3.82 (s, 3H), 3.70 (s, 6H), 3.88 (t, J = 7.3 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 5.32 (s, 1H),
5.90 (s, 1H), 6.33 (s, 2H), 7.19 (ddd, J = 8.0, 6.6, 1.3 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.34 (d, J = 8.0 Hz,
1
2
3
4
5
6
7
8
9
13
1H), 7.77 (d, J = 8.0 Hz, 1H). C NMR (151 MHz, CDCl3) δ -5.2, 14.3, 18.5, 26.1, 29.1, 56.2, 60.7,
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
61.0, 64.0, 103.1, 111.1, 111.6, 120.9, 121.2, 122.8, 125.8, 126.8, 127.7, 133.6, 138.8, 139.3, 144.3,
153.3, 161.8. HRMS (ESI): Calcd. for C30H42NO6Si ([M+H]+): 540.2776, Found: 540.2772.
Synthesis of
3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(1-(3,4,5-trimethoxyphenyl)vinyl)-1H-
indole-2-carboxaldehyde (19)
A 1.0 M solution of DIBAL-H in toluene (0.83 mL, 0.83 mmol, 3.50 equiv) was added to a solu-
tion of 18 (125 mg, 0.239 mmol, 1.00 equiv) in anhydrous dichloromethane (1.0 mL) at –78 °C under a
nitrogen atmosphere. The resulting solution was stirred for 1 h at the same temperature. The mixture
was then quenched with saturated aqueous NH4Cl (10 mL). The organic layer was separated and the
aqueous phase was extracted with diethyl ether (3 × 10 mL). The organic layers were combined, dried
over MgSO4, filtered, and concentrated under reduced pressure. The crude alcohol was directly taken to
the next step without further purification.
Activated manganese dioxide (311 mg, 3.60 mmol, 15.0 equiv) was added to an acetonitrile (1.0
mL) solution of the crude alcohol (115 mg) in a round-bottom flask. The reaction mixture was stirred at
room temperature under a nitrogen atmosphere for 16 h. The reaction mixture was filtered through
celite, washed with a 1:1 mixture of hexane:EtOAc, and the filtrate was concentrated under reduced
pressure. The crude product was purified by flash column silica gel chromatography (80:20 hex-
ane:ether) to give 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(1-(3,4,5-trimethoxyphenyl)vinyl)-1H-
1
indole-2-carboxaldehyde 19 as colorless oil in 84% yield (96.0 mg, 0.200 mmol) over two steps. H
NMR (400 MHz, C6D6) δ -0.03 (s, 6H), 0.91 (s, 9H), 3.20 (s, 6H), 3.34 (t, J = 6.5 Hz, 2H), 3.76 (s, 3H),
3.89 (t, J = 6.5 Hz, 2H), 5.07 (s, 1H), 5.63 (s, 1H), 6.41 (s, 2H), 7.09 (ddd, J = 8.0, 7.0, 0.9 Hz, 1H),
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
7.20 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.70 (dt, J = 8.1, 0.9 Hz, 1H), 10.12 (s,
1H). 13C NMR (101 MHz, C6D6) δ -5.3, 18.5, 26.1, 28.25, 30.5, 55.75, 60.5, 63.9, 104.0, 111.9, 112.7,
121.5, 122.0, 125.9, 126.0, 127.4, 133.3, 133.4, 140.0, 140.7, 143.4, 154.4, 181.3. HRMS (ESI): Calcd.
for C28H38NO5Si ([M+H]+): 496.2514, Found: 496.2516.
1
2
3
4
5
6
7
8
9
Synthesis of (R)-9-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(3,4,5-trimethoxyphenyl)-2,3-dihydro-
1H-pyrrolo[1,2-a]indol-1-one (20)11
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
In a nitrogen-filled glovebox, 19 (20.0 mg, 0.0400 mmol, 1.00 equiv), [Rh(COD)Cl]2 (0.5 mg,
0.001 mmol, 0.025 equiv), (R)-MeO-BIPHEP (1.2 mg, 0.0020 mmol, 0.050 equiv), AgBF4 (0.4 mg,
0.002 mmol, 0.05 equiv) and THF (0.50 mL) were added to a 1-dram vial. The vial was sealed with a
PTFE/silicone-lined septum cap and removed from the glovebox. The reaction mixture was stirred at 60
°C in an oil bath for 12 h. The vial was removed from the oil bath and allowed to cool to room tempera-
ture. The reaction mixture was filtered through a short plug of silica gel (eluting with 20 mL of 3:2 hex-
anes:EtOAc). The crude reaction mixture was concentrated under reduced pressure. The crude reaction
mixture was purified by flash column silica gel chromatography (80:20 hexanes:ether) to give (R)-9-(2-
((tert-butyldimethylsilyl)oxy)ethyl)-3-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-
one 20 as a white solid in 90% yield (18.0 mg, 0.0360 mmol). The enantiomeric excess was determined
by HPLC analysis (254 nm, 25 °C) tR 14.3 min (minor); tR 17.3 min (major) [Chiracel AD-H (0.46 cm x
25
25 cm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 95:5, 1.0 mL/min] to be 97%. [α]D = -76.9
1
(c 0.52, CHCl3). H NMR (400 MHz, C6D6) δ 0.070 (s, 3H), 0.077 (s, 3H), 0.97 (s, 9H), 2.79 (dd, J =
18.2, 4.4 Hz, 1H), 3.09 (dd, J = 18.2, 8.0 Hz, 1H), 3.20 (s, 6H), 3.55 (t, J = 7.0 Hz, 2H), 3.78 (s, 3H),
4.18 (t, J = 7.0 Hz, 2H), 4.76 (dd, J = 8.0, 4.4 Hz, 1H), 6.14 (s, 2H), 6.95 (dd, J = 6.4, 2.6 Hz, 1H), 7.08
– 7.03 (m, 2H), 7.78 (dd, J = 6.1, 2.6 Hz, 1H). 13C NMR (101 MHz, C6D6) δ -5.1, 18.5, 26.2, 28.5, 30.5,
50.8, 55.8, 57.2, 60.5, 64.15, 103.5, 110.4, 112.0, 113.95, 121.2, 123.2, 125.5, 125.9, 128.1, 133.3,
134.0, 135.2, 136.0, 139.3, 154.8, 191.2. HRMS (ESI): Calcd. for C28H38NO5Si ([M+H]+): 496.2514,
Found: 496.2517.
18
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
SUPPORTING INFORMATION
1
2
3
4
5
6
7
8
The Supporting Information is available free of charge on the ACS Publications website. The Support-
ing Information includes discussion on stereochemical analysis of compound 13, NMR traces and
HPLC chromatograms for all new compounds (PDF).
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
ACKNOWLEDGMENT
We thank Iowa State University and National Science Foundation (CHE-CAREER 1353819) for
financial support of this work. We thank Dr. Sarah Cady and the Chemical Instrumentation Facility at
Iowa State University for helpful discussions and assistance with 2D NMR experiments. We thank Pro-
fessor Jason Chen (Iowa State University) for helpful discussions and suggestions.
REFERENCES
1.
Fernandez, L. S.; Buchanan, M. S.; Carroll, A. R.; Feng, Y. J.; Quinn, R. J.; Avery, V. M., Org.
Lett. 2009, 11, 329-332.
2.
(a) Pousset, J. L.; Cavé, A.; Chiaroni, A.; Riche, C., J. Chem. Soc., Chem. Commun. 1977, 261-
262; (b) Fernandez, L. S.; Sykes, M. L.; Andrews, K. T.; Avery, V. M., Int. J. Antimicrob. Agents
2010, 36, 275-279.
3.
4.
Wolkenberg, S. E.; Boger, D. L., Chem. Rev. 2002, 102, 2477-2496.
Sasase, T.; Yamada, H.; Sakoda, K.; Imagawa, N.; Abe, T.; Ito, M.; Sagawa, S.; Tanaka, M.;
Matsushita, M., Diabetes Obes and Metab 2005, 7, 586-594.
5.
6.
Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.; Zhang, X.-M.; Ma, Y.-B., Org.
Lett. 2007, 9, 4127-4129.
Vepsäläinen, J.; Auriola, S.; Tukiainen, M.; Ropponen, N.; Callaway, J., Planta Med. 2005, 71,
1053-1057.
7.
8.
Calvert, M. B.; Sperry, J., Chem. Commun. 2015, 51, 6202-6205.
(a) Johansen, M. B.; Kerr, M. A., Org. Lett. 2008, 10, 3497-3500; (b) Patil, D. V.; Cavitt, M. A.;
France, S., Org. Lett. 2011, 13, 5820-5823; (c) Chen, K.; Zhang, Z.; Wei, Y.; Shi, M., Chem.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
Commun. 2012, 48, 7696-7699; (d) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C.,
Angew. Chem. Int. Ed. 2009, 48, 5737-5740; (e) Liu, W.-B.; Zhang, X.; Dai, L.-X.; You, S.-L.,
Angew. Chem. Int. Ed. 2012, 51, 5183-5187; (f) Dethe, D. H.; Boda, R.; Das, S., Chem.
Commun. 2013, 49, 3260-3263; (g) Li, H.; Wang, Z.; Zu, L., RSC Adv. 2015, 5, 60962-60965;
(h) Calvert, M. B.; Sperry, J., Org. Biomol. Chem. 2016, 14, 5728-5743.
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
9.
Ohyama, T.; Uchida, M.; Kusama, H.; Iwasawa, N., Chem. Asian J. 2015, 10, 1850-1853.
(a) Cheng, H.-G.; Lu, L.-Q.; Wang, T.; Yang, Q.-Q.; Liu, X.-P.; Li, Y.; Deng, Q.-H.; Chen, J.-R.;
Xiao, W.-J., Angew. Chem. Int. Ed. 2013, 52, 3250-3254; (b) Wilson, R. M.; Thalji, R. K.;
Bergman, R. G.; Ellman, J. A., Org. Lett. 2006, 8, 1745-1747; (c) Thalji, R. K.; Ellman, J. A.;
Bergman, R. G., J. Am. Chem. Soc. 2004, 126, 7192-7193; (d) Schrader, T. O.; Johnson, B. R.;
Lopez, L.; Kasem, M.; Gharbaoui, T.; Sengupta, D.; Buzard, D.; Basmadjian, C.; Jones, R. M.,
Org. Lett. 2012, 14, 6306-6309; (e) Janssen-Müller, D.; Schedler, M.; Fleige, M.; Daniliuc, C.
G.; Glorius, F., Angew. Chem. Int. Ed. 2015, 54, 12492-12496; (f) Ni, Q.; Zhang, H.;
Grossmann, A.; Loh, C. C. J.; Merkens, C.; Enders, D., Angew. Chem. Int. Ed. 2013, 52, 13562-
13566; (g) Lu, H.; Lin, J.-B.; Liu, J.-Y.; Xu, P.-F., Chem. Eur. J. 2014, 20, 11659-11663; (h)
Bera, K.; Schneider, C., Chem. Eur. J. 2016, 22, 7074-7078; (i) Enders, D.; Greb, A.; Deckers,
K.; Selig, P.; Merkens, C., Chem. Eur. J. 2012, 18, 10226-10229.
10.
11.
12.
Ghosh, A.; Stanley, L. M., Chem. Commun. 2014, 50, 2765-2768.
Prashad, M.; Tomesch, J. C.; Wareing, J. R.; Larsen, D.; de Fex, H., Eur. J. Med. Chem. 1992,
27, 413-418.
13.
Roche, M.; Frison, G.; Brion, J.-D.; Provot, O.; Hamze, A.; Alami, M., J. Org. Chem. 2013, 78,
8485-8495.
14.
15.
Sparling, B. A.; Moslin, R. M.; Jamison, T. F., Org, Lett. 2008, 10, 1291-1294.
(a) Marquez, B. L.; Gerwick, W. H.; Thomas Williamson, R., Magn. Reson. Chem. 2001, 39,
499-530; (b) Oikawa, M.; Adachi, S.; Kusumoto, S., Org. Lett. 2005, 7, 661-664; (c) Matsumori,
N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana, K., J. Org. Chem. 1999, 64, 866-876; (d)
20
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
Schulte, J. r.; Lauterwein, J. r.; Klessinger, M.; Thiem, J., Magn. Reson. Chem. 2003, 41, 123-
130; (e) Bifulco, G.; Bassarello, C.; Riccio, R.; Gomez-Paloma, L., Org. Lett. 2004, 6, 1025-
1028; (f) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C., Tetrahedron 1980, 36, 2783-
2792.
1
2
3
4
5
6
7
8
9
16.
17.
Mancebo-Aracil, J.; Martín-Rodríguez, M.; Nájera, C.; Sansano, J. M.; Costa, P. R. R.; de Lima,
E. C.; Dias, A. G., Tetrahedron: Asymmetry 2012, 23, 1596-1606.
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
Che, Z.; Zhang, S.; Shao, Y.; Fan, L.; Xu, H.; Yu, X.; Zhi, X.; Yao, X.; Zhang, R., J. Agric. Food
Chem. 2013, 61, 5696-5705.
18.
19.
Saulnier, M. G.; Gribble, G. W., J. Org. Chem. 1982, 47, 757-761.
(a) Dethe, D. H.; Erande, R. D.; Ranjan, A., J. Am. Chem. Soc. 2011, 133, 2864-2867; (b) Viaud-
Massuard, M.-C.; Chaulet, C.; Croix, C.; Basset, J.; Pujol, M.-D., Synlett 2010, 2010, 1481-
1484; (c) Alonso, D. A.; Andersson, P. G., J. Org. Chem. 1998, 63, 9455-9461.
Bajwa, J. S.; Chen, G.-P.; Prasad, K.; Repič, O.; Blacklock, T. J., Tetrahedron Lett. 2006, 47,
6425-6427.
20.
21.
(a) Pierce, L. T.; Cahill, M. M.; McCarthy, F. O., Tetrahedron 2011, 67, 4601-4611; (b)
Fiandanese, V.; Marchese, G.; Martina, V.; Ronzini, L., Tetrahedron Lett. 1984, 25, 4805-4808.
Pooppanal, S., Synlett 2009, 2009, 850-851.
22.
23.
(a) Shaw, K. N. F.; McMillan, A.; Gudmundson, A. G.; Armstrong, M. D., J. Org. Chem. 1958,
23, 1171-1178; (b) Nogrady, T.; Doyle, T. W., Can. J. Chem. 1964, 42, 485-486.
21
ACS Paragon Plus Environment