Multicomponent assembly processes for the synthesis of diverse yohimbine and corynanthe alkaloid analogues

Article abstract of DOI:10.1021/co400055b

A strategy involving a Mannich-type multicomponent assembly process followed by a 1,3-dipolar cycloaddition has been developed for the rapid and efficient construction of parent heterocyclic scaffolds bearing indole and isoxazolidine rings. These key intermediates were then readily elaborated using well-established protocols for refunctionalization and cross-coupling to access a diverse 180-member library of novel pentacyclic and tetracyclic compounds related to the Yohimbine and Corynanthe alkaloids. Several other new multicomponent assembly processes were developed to access dihydro-β- carboline-fused benzodiazepines, pyrimidinediones, and rutaecarpine derivatives.

Full text of DOI:10.1021/co400055b

Research Article
pubs.acs.org/acscombsci
Multicomponent Assembly Processes for the Synthesis of Diverse
Yohimbine and Corynanthe Alkaloid Analogues
Brett A. Granger, Zhiqian Wang, Kyosuke Kaneda, Zhenglai Fang, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The Texas Institute for Drug and Diagnostic Development, The University of Texas
at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: A strategy involving a Mannich-type multi-
component assembly process followed by a 1,3-dipolar
cycloaddition has been developed for the rapid and efficient
construction of parent heterocyclic scaffolds bearing indole
and isoxazolidine rings. These key intermediates were then
readily elaborated using well-established protocols for refunc-
tionalization and cross-coupling to access a diverse 180-member
library of novel pentacyclic and tetracyclic compounds related
to the Yohimbine and Corynanthe alkaloids. Several other new
multicomponent assembly processes were developed to access dihydro-β-carboline-fused benzodiazepines, pyrimidinediones, and
rutaecarpine derivatives.
KEYWORDS: combinatorial chemistry, dipolar cycloaddition, heterocycle, Mannich, multicomponent reaction
pyridazine, norbenzomorphan, 2-aryl piperidine, and tetrahy-
droisoquinoline scaffolds.9,10 More recently we reported a use-
ful extension of this general approach to DOS for the facile
synthesis of compounds containing the octahydroindolo[2,3-a]-
quinolizine-2-amine scaffold.11 We herein report the application
of this strategy to the rapid synthesis of a 180-member library of
these compounds, many of which possess substitution patterns
that were heretofore unknown.
INTRODUCTION
■
The discovery of small molecules that potently and selectively
modulate biological targets is a critical endeavor that enables
fundamental studies of complex systems using temporal
biological probes and that generates potential drug leads to
treat medical abnormalities. Once a promising lead compound
is identified, its physiochemical properties may be fine-tuned
through selective modification of functional groups and sub-
stituents. In this context, others have developed useful
strategies for the preparation of small molecule libraries toward
the goal of identifying compounds that display potent activity
toward known targets via high throughput screening (HTS).1
The Yohimbine and Corynanthe alkaloids, of which yohimbine
(1), tetrahydroalstonine (2), and geissoschizine (3) are typical
members (Figure 1), are well documented to elicit a wide array
of useful biological effects.2 Accordingly, analogues of these
compounds are attractive targets for creating unique libraries
for HTS. The related octahydroindolo[2,3-a]quinolizine-2-amine
scaffold (4) is also present in compounds that exhibit various
important biological activities as exemplified by compounds such
as the derived amide 5 and the sulfonamide 6, both of which are
potent α2-adrenoceptor antagonists.3
During the course of developing concise syntheses of 2 and
3,4 we discovered a novel Mannich-type multicomponent assembly
process (MCAP) that inspired the subsequent development of a
number of three- and four-component MCAPs that generate highly
functionalized intermediates. The combination of these MCAPs in
tandem with various ring closing reactions that are enabled by
selective pairing of resident functional groups has led to a powerful
strategy for the diversity oriented synthesis (DOS) of a broad array
of unique heterocycles5 comprising the benzodiazepine,6 benzox-
azocine,7 benzazocine, isoindolinone,8 tetrahydrobenzonaphtheridine,
RESULTS AND DISCUSSION
■
In close analogy with our syntheses of 2 and 3,4 the first step
toward creating a novel library of compounds possessing the
yohimboid and corynantheoid skeletons involved the reaction
of the readily available dihydro-β-carbolines 7−912 with trans-
crotonyl chloride and silyl enol ether 1013 to form the aldehydes
11−13 (Scheme 1). When compounds 11−13 were condensed
with N-methylhydroxylamine in toluene, the intermediate nitrone
that was formed underwent an intramolecular 1,3-dipolar cyclo-
addition with the crotonamide moiety to furnish isoxazolidines
14−16 in 43−60% yield over the two steps. The relative
stereochemistry resident in 14−16 was confirmed by single
crystal X-ray analysis of a compound derived from 16 (vide
infra). Reduction of the lactam moiety in 14 with lithium
aluminum hydride provided amine 17 in 98% yield.
Having prepared the nor-bromo scaffolds 14 and 17, we
envisioned that N,O-bond cleavage followed by nitrogen
functionalization would lead to the generation of an initial
collection of small molecules (Scheme 2). In the event, reaction
Received: April 18, 2013
Revised: May 21, 2013
Published: May 22, 2013
© 2013 American Chemical Society
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Research Article
Figure 1. Natural products and compounds containing the octahydroindolo[2,3-a] quinolizine scaffold.
Scheme 1. Synthesis of Isoxazolidine Scaffolds 14−17
Scheme 2. N,O-Bond Cleavage and N-Functionalization
Figure 2. N-Functionalizing reagents.
of isoxazolidines 14 and 17 with nickel boride in methanol14
delivered amines 18 and 19 in 68% and 64% yields,
respectively. The secondary amine functionality resident in 18
and 19 was an obvious point for diversification, and the reac-
tion of these intermediates with a series of N-functionalizing
reagents 20 under standard conditions gave chemsets 21 and
Conditions: (a) 20{1−11}, Et3N, CH2Cl2; (b) 20{12−14}, Et3N,
CH2Cl2; (c) 20{15−24}, CH2Cl2; (d) 20{25−28}, CH2Cl2; (e)
20{29−31}, MeCN, 82 °C; then NaBH3CN, AcOH, rt; (f) 20{32−
33}, Na2CO3, THF/H2O.
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Table 1. Preparation of 21 and 22 via N-Functionalization
entry
N-functionalizing reagent
product
yield (%)
1
2
20{1}
21{1}
53
89
99
87
57
82
77
85
58
92
75
94
49
89
59
57
64
53
81
83
57
56
98
92
93
91
65
57
60
75
82
89
88
99
90
73
57
81
72
20{3}
21{3}
3
20{5}
21{5}
4
20{8}
21{8}
5
20{12}
20{16}
20{17}
20{18}
20{20}
20{21}
20{23}
20{24}
20{26}
20{32}
20{33}
20{35}
20{36}
20{3}
21{12}
21{16}
21{17}
21{18}
21{20}
21{21}
21{23}
21{24}
21{26}
21{32}
21{33}
21{35}
21{36}
22{3}
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
Figure 3. Boronic acids.
Table 2. Preparation of Chemset 24
20{5}
22{5}
entry
boronic acid
product
yield (%)
20{10}
20{13}
20{14}
20{15}
20{16}
20{17}
20{18}
20{20}
20{21}
20{22}
20{23}
20{24}
20{26}
20{27}
20{28}
20{29}
20{31}
20{34}
20{35}
20{36}
22{10}
22{13}
22{14}
22{15}
22{16}
22{17}
22{18}
22{20}
22{21}
22{22}
22{23}
22{24}
22{26}
22{27}
22{28}
22{29}
22{31}
22{34}
22{35}
22{36}
1
2
3
4
5
6
7
8
9
23{1}
23{2}
23{3}
23{4}
23{5}
23{6}
23{11}
23{13}
23{14}
24{1}
24{2}
24{3}
24{4}
24{5}
24{6}
24{11}
24{13}
24{14}
90
92
71
44
85
66
58
56
91
quantities. When 18 and 19 were treated with aldehydes, the
initially formed cyclic N,O-acetals, which were sufficiently stable
for isolation, underwent reduction by the action of sodium
cyanoborohydride in refluxing acetonitrile to furnish N-alkylated
amino derivatives.
The aryl bromide moiety in the halogenated scaffolds 15 and
16 could be exploited in Suzuki15 cross-coupling reactions, allow-
ing for the creation of novel products possessing substitution
patterns at the 5- and 8-positions that were not otherwise
accessible. Accordingly, coupling of 15 with boronic acids 23
provided biaryl chemset 24 (Scheme 3, Figure 3, Table 2). To
generate compounds that could be used to explore SAR, electron
neutral 23{1−3}, electron deficient 23{4−10}, and electron rich
23{11−14} boronic acids with varying substitution patterns were
used as inputs.
Scission of the N,O-bond in 24{1} and 24{5}, followed by
reaction of the intermediate amino alcohol moiety with N-
functionalizing agents 20 led to the formation of chemset 26
(Scheme 4, Figure 2, Table 3). In analogous fashion, chemset
29 was prepared after reduction of the lactam moiety of 24{1}
22 (Figure 2, Table 1). A wide array of N-functionalizing
reagents was selected that included alkyl, aryl, and heteroaryl
acid chlorides, sulfonyl chlorides, isocyanates, isothiocyanates,
aldehydes, and chloroformates with varying electronic proper-
ties to generate a set of compounds that would enable an
exploration of structure−activity relationships (SAR) for any
actives that were identified during screening. Notably, these
transformations were highly selective for reaction at the amino
group. On the rare occasions that the undesired O-function-
alized products were detected, they were formed in only trace
Scheme 3. Preparation of Biaryl Chemset 24 via Suzuki Coupling
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Scheme 4. Preparation of the 5-Substituted Library via Lactam Reduction, N,O-Bond Cleavage, and N-Functionalization
Conditions: (a) 20{1−11}, Et3N, CH2Cl2; (b) 20{12−14}, Et3N, CH2Cl2; (c) 20{15−24}, CH2Cl2; (d) 20{25−28}, CH2Cl2; (e) 20{29−31},
MeCN, 82 °C; then NaBH3CN, AcOH, rt; (f) 20{32−33}, Na2CO3, THF/H2O.
Table 3. Preparation of Chemsets 26 and 29
Table 4. Preparation of Chemset 30
entry amino alcohol N-functionalizing reagent
product
yield (%)
entry
boronic acid
product
yield (%)
1
2
25{1}
25{1}
25{1}
25{1}
25{1}
25{1}
25{1}
25{1}
25{1}
25{5}
25{5}
25{5}
25{5}
28{1}
28{1}
28{1}
28{1}
28{1}
28{14}
28{14}
20{2}
26{1,2}
98
93
58
57
93
77
48
68
51
85
99
99
83
78
85
74
41
72
55
72
1
2
23{1}
23{2}
23{3}
23{4}
23{5}
23{6}
23{7}
23{8}
23{9}
23{10}
23{12}
23{13}
23{14}
30{1}
30{2}
30{3}
30{4}
30{5}
30{6}
30{7}
30{8}
30{9}
30{10}
30{12}
30{13}
30{14}
68
99
64
98
81
76
62
77
67
83
98
83
87
20{3}
26{1,3}
3
20{4}
26{1,4}
3
4
20{13}
20{17}
20{18}
20{26}
20{30}
20{36}
20{1}
26{1,13}
26{1,17}
26{1,18}
26{1,26}
26{1,30}
26{1,36}
26{5,1}
4
5
5
6
6
7
7
8
8
9
9
10
11
12
13
14
15
16
17
18
19
20
10
11
12
13
20{15}
20{25}
20{35}
20{2}
26{5,15}
26{5,25}
26{5,35}
29{1,2}
20{3}
29{1,3}
by X-ray crystallography, thereby confirming our initial
assignment of relative stereochemistry.
20{10}
20{18}
20{30}
20{3}
29{1,10}
29{1,18}
29{1,30}
29{14,3}
29{14,15}
Nickel boride mediated N,O-bond cleavage of 30{1}, 30{3},
and 30{14} provided the corresponding amino alcohols, which
were subjected to N-functionalization by reagents 20 to afford
chemset 32 (Scheme 6, Figure 2, Table 5). After reduction of
lactams 30 with lithium aluminum hydride, analogous
chemistry allowed for the preparation of chemset 35 from
amines 33.
20{15}
and 24{13} with the complex of alane with N,N-dimethylethyl-
amine.
The 8-bromo scaffold 16 was also readily diversified via
Suzuki reactions to provide chemset 30 (Scheme 5, Figure 3,
Table 4). We determined the structure for compound 30{12}
We have previously reported the development of several
novel MCAPs for the synthesis of fused-tetrahydroisoquinoline
scaffolds,9 and it occurred to us that we might apply this
Scheme 5. Preparation of Biaryl Chemset 30 via Suzuki Coupling
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Scheme 6. Preparation of the 8-Substituted Library via Lactam Reduction, N,O-Bond Cleavage, and N-Functionalization
Conditions: (a) 20{1−11}, Et3N, CH2Cl2; (b) 20{12−14}, Et3N, CH2Cl2; (c) 20{15−24}, CH2Cl2; (d) 20{25−28}, CH2Cl2; (e) 20{29−31},
MeCN, 82 °C; then NaBH3CN, AcOH, rt; (f) 20{32−33}, Na2CO3, THF/H2O.
Scheme 7. Preparation of Scaffolds via Novel MCAP Chemistry
chemistry to the synthesis of unique scaffolds derived from 9.
Compounds containing the pyrimidinedione ring exemplified
in 39 are known to exhibit hypotensive, diuretic, and antianoxic
effects.16 In initial experiments toward accessing this hetero-
cyclic systems, 9 was allowed to react with the silyl ketene
acetal 3617 in the presence of a substoichiometric amount of
TMSOTf. The putative intermediate amino ester 37 was then
treated with phenylisocyanate to give the pyrimidinedione 39,
presumably by cyclization of 38 (Scheme 7).9a However, when
we recently returned to this reaction to prepare a compound
library derived from this scaffold, only small amounts of 39
were isolated, and varying amounts of the amino ester and urea
ester derived from protodesilylation of 37 and 38, respectively,
were observed instead. After some experimentation, we found
that adding TBAF to the reaction mixture was necessary to
effect complete cyclization, and 39 was then reproducibly
obtained in 45% overall yield from 9. This useful procedure
provides convenient access to pyrimidinediones from 9 in one-
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Table 5. Preparation of Chemsets 32 and 35
entry amino alcohol N-functionalizing reagent
product
yield (%)
entry amino alcohol N-functionalizing reagent
product
yield (%)
1
2
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{1}
31{3}
31{3}
31{3}
31{3}
31{3}
31{3}
31{3}
31{3}
31{14}
31{14}
31{14}
31{14}
31{14}
31{14}
31{14}
20{1}
20{3}
32{1,1}
32{1,3}
99
87
98
99
98
99
92
98
99
97
89
94
97
98
99
92
89
94
99
95
87
85
91
81
78
72
85
80
81
87
79
99
85
89
95
89
89
83
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
31{14}
31{14}
31{14}
31{14}
31{14}
34{1}
34{1}
34{1}
34{1}
34{1}
34{1}
34{1}
34{1}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{3}
34{14}
34{14}
34{14}
34{14}
34{14}
34{14}
34{14}
34{14}
34{14}
20{18}
20{19}
20{26}
20{35}
20{36}
20{3}
32{14,18}
32{14,19}
32{14,26}
32{14,35}
32{14,36}
35{1,3}
72
85
89
82
70
90
63
76
78
70
76
79
65
78
79
78
95
59
79
77
82
86
87
86
74
87
68
72
91
61
78
60
46
93
85
85
80
3
20{5}
32{1,5}
4
20{6}
32{1,6}
5
6
7
20{8}
20{9}
32{1,8}
32{1,9}
20{10}
20{11}
20{13}
20{15}
20{16}
20{17}
20{18}
20{19}
20{22}
20{24}
20{25}
20{26}
20{27}
20{28}
20{30}
20{35}
20{36}
20{3}
32{1,10}
32{1,11}
32{1,13}
32{1,15}
32{1,16}
32{1,17}
32{1,18}
32{1,19}
32{1,22}
32{1,24}
32{1,25}
32{1,26}
32{1,27}
32{1,28}
32{1,30}
32{1,35}
32{1,36}
32{3,3}
20{5}
35{1,5}
8
9
20{17}
20{18}
20{26}
20{27}
20{28}
20{30}
20{2}
35{1,17}
35{1,18}
35{1,26}
35{1,27}
35{1,28}
35{1,30}
35{3,2}
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
20{3}
35{3,3}
20{5}
35{3,5}
20{6}
35{3,6}
20{7}
35{3,7}
20{9}
35{3,9}
20{15}
20{17}
20{18}
20{19}
20{26}
20{27}
20{28}
20{35}
20{36}
20{3}
35{3,15}
35{3,17}
35{3,18}
35{3,19}
35{3,26}
35{3,27}
35{3,28}
35{3,35}
35{3,36}
35{14,3}
35{14,5}
35{14,6}
35{14,9}
35{14,17}
35{14,18}
35{14,19}
35{14,26}
35{14,27}
20{5}
32{3,5}
20{15}
20{16}
20{17}
20{18}
20{19}
20{22}
20{1}
32{3,15}
32{3,16}
32{3,17}
32{3,18}
32{3,19}
32{3,22}
32{14,1}
32{14,3}
32{14,5}
32{14,9}
32{14,15}
32{14,16}
32{14,17}
20{5}
20{6}
20{9}
20{3}
20{17}
20{18}
20{19}
20{26}
20{27}
20{5}
20{9}
20{15}
20{16}
20{17}
pot procedure that represents a marked improvement upon
known methods to such compounds.18
inhibit serine protease24 and to bind to the benzodiazepine
receptor.25 We thus decided to fuse this scaffold to the 8-
bromo-3,4-dihydro-β-carboline scaffold (9) to provide a novel
set of compounds that might be screened. In the event,
sequential treatment of 9 with TMSOTf, ethynylmagnesium
bromide, and the acid chloride 40 afforded an intermediate
amide that underwent cyclization via an intramolecular 1,3-
dipolar cycloaddition upon warming to room temperature to
generate the novel benzodiazepine 43 in 63% yield. Further
elaboration of 43 by cross-coupling reactions may also be
readily envisioned.
The quinazolinocarboline alkaloid rutaecarpine (41) was
isolated from Evodia Rutaecarpa in 1915,19 and this compound
together with a number of its derivatives displays a wide array
of biological activities.20 We thus envisioned that compounds
related to 41 having substituents on the indole ring might be
attractive compounds for screening. In previous work, we
discovered that reaction of the hydrochloride salt of 7 with
o-azidobenzoyl chloride (40) provided a novel entry to 41,9a so
we queried whether this chemistry might also be applied to
bromo-substituted analogues of 41. To establish the underlying
feasibility of this approach to rutaecarpine derivatives, imine 9
and o-azidobenzoyl chloride (40) were heated in refluxing 1,2-
dichloroethane to furnish 42, which is known as a selective
COX-2 inhibitor,21 in 63% yield. Derivatives prepared from 42
via cross-coupling chemistry may exhibit novel biological activities.
The 1,5-benzodiazepin-2-one scaffold present in 43 is found
in compounds that bind to various targets including the
interleukin-1β converting enzyme (ICE)22 and voltage-gated
potassium channels.23 Moreover, triazolo-fused benzodiazepine
scaffolds are present in compounds that have been reported to
BIOLOGICAL ACTIVITY
■
High throughput biological screening of the 180-member
library of Yohimbine and Corynanthe alkaloid analogues through
the NIH Molecular Library Probe Production Center Network
(MLPCN) and the National Institute of Mental Health’s
(NIMH) Psychoactive Drug Screening Program (PDSP) is
currently underway in hopes of identifying compounds with
useful biological activities for further development. Notably,
compound 17 was found to promote the differentiation of
acute myeloid leukemia cells,26 and is an agonist of mouse
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serotonin receptor 2A,27 which may have implications in the
treatment of schizophrenia, depression, and drug addic-
tion.28−30 Additionally compound 32{1,22} is a human trace
amine associated receptor 1 (hTAAR1) antagonist.31
(a) Brown, R. T. In Indoles; Saxton, J. E., Ed.; Wiley-Interscience: New
York, 1983. (b) Szantay, C.; Blasko, C.; Honty, K.; Dornyei, G. In The
́ ́
̈
Alkaloids, Chemistry and Physiology; Brossi, A., Ed.; Academic Press:
New York, 1986. (c) Lounasmaa, M.; Tolvanen, A. In Monoterpenoid
Indole Alkaloids; Saxton, J. E., Ed.; Wiley-Interscience: New York,
1994.
SUMMARY
■
(3) (a) Klioze, S. S.; Ehrgott, F. J., Jr.; Wilker, J. C.; Woodward, D. L.;
Repke, D. B. Synthesis and Antihypertensive Activity of 2-Benzamido-
1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizines. J. Med. Chem.
1979, 22, 1497−1504. (b) Clark, R. D.; Repke, D. B.; Berger, J.;
Nelson, J. T.; Kilpatrick, A. T.; Brown, C. M.; MacKinnon, A. C.;
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We have prepared a 180-member library of Yohimbine and
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features an MCAP followed by a 1,3-dipolar cycloaddition to
generate functionalized scaffolds that were readily diversified
using several well established reactions for refunctionalization
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These compounds have been submitted to the NIH Molecular
Libraries Small Molecule Repository (MLSMR) for distribution
to HTS centers within the Molecular Libraries Probe
Production Centers Network (MLPCN) and biological screen-
ing is currently underway. Further applications of novel MCAPs
are in progress, and the results of these investigations will be
reported in due course.
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of Multicomponent Reactions for the Synthesis of Diverse
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Scaffolds via Tandem Additions to Imine Derivatives and Ring-
forming reactions. Tetrahedron 2009, 65, 6454−6469. (c) Donald, J.
R.; Granger, B. A.; Hardy, S.; Sahn, J. J.; Martin, S. F. Applications of
Multicomponent Assembly Processes to the Facile Synthesis of
Diversely Functionalized Nitrogen Heterocycles. Heterocycles 2012, 84,
1089−1112.
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1,2,3-Triazole-fused 1,4-Benzodiazepine Scaffolds. Org. Lett. 2011, 13,
852−855. (b) Donald, J. R.; Wood, R. R.; Martin, S. F. Application of a
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectral data for all new compounds,
full characterization data for representative compounds, LCMS
data for representative compounds, and tabulated physiochem-
ical properties for representative compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: sfmartin@mail.utexas.edu.
Funding
We thank the National Institutes of Health (GM 86192 and
GM 25439) and the Robert A. Welch Foundation (F-0652) for
their generous support of this work.
■
(7) Sahn, J. J.; Martin, S. F. Facile Syntheses of Substituted,
Conformationally-constrained Benzoxazocines and Benzazocines via
Sequential Multicomponent Assembly and Cyclization. Tetrahedron
Lett. 2011, 52, 6855−6858.
Notes
The authors declare no competing financial interest.
(8) (a) Sahn, J. J.; Su, J. Y.; Martin, S. F. Facile and Unified Approach
to Skeletally Diverse, Privileged Scaffolds. Org. Lett. 2011, 13, 2590−
2593. (b) Sahn, J. J.; Martin, S. F. Expedient Synthesis of
Norbenzomorphan Library via Multicomponent Assembly Process
Coupled with Ring-Closing Reactions. ACS Combi. Sci. 2012, 14, 496−
502.
(9) (a) Granger, B. A.; Kaneda, K.; Martin, S. F. Multicomponent
Assembly Strategies for the Synthesis of Diverse Tetrahydroisoquino-
line Scaffolds. Org. Lett. 2011, 13, 4542−4545. (b) Granger, B. A.;
Kaneda, K.; Martin, S. F. Libraries of 2,3,4,6,7,11b-hexahydro-1H-
pyrido[2,1-a]isoquinoline-2-amine Derivatives via a Multicomponent
Assembly Process/1,3-Dipolar Cycloaddition Strategy. ACS Comb. Sci.
2012, 14, 75−79.
(10) (a) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Privileged
Structures for Library Design and Drug Discovery. Curr. Opin. Chem.
Biol. 2010, 14, 347−361. (b) Horton, D. A.; Bourne, G. T.; Smythe,
M. L. The Combinatorial Synthesis of Bicyclic Privileged Structures or
Privileged Substructures. Chem. Rev. 2003, 103, 893−930.
(11) Wang, Z.; Kaneda, K.; Fang, Z.; Martin, S. F. Diversity Oriented
Synthesis: Concise Entry to Novel Derivatives of Yohimbine and
Corynanthe Alkaloids. Tetrahedron Lett. 2012, 53, 477−479.
(12) Glennon, R. A.; Grella, B.; Tyacke, R. J.; Lau, A.; Westaway, J.;
Hudson, A. L. Binding of β-Carbolines at Imidazoline I2 Receptors: A
Structure-Affinity Investigation. Bioorg. Med. Chem. Lett. 2004, 14,
999−1002.
ACKNOWLEDGMENTS
■
We thank Dr. Karin Keller (The University of Texas at Austin)
for her assistance with LCMS experiments and Dr. Vincent
Lynch (The University of Texas at Austin) for performing X-
ray crystallography.
DEDICATION
■
This paper is dedicated to Professor Robert Williams on the
occasion of his 60th birthday.
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