Triarylaminium Radical Cation Promoted Coupling of Catharanthine with Vindoline: Diastereospecific Synthesis of Anhydrovinblastine and Reaction Scope

Article abstract of DOI:10.1021/jacs.9b06968

A new triarylaminium radical cation promoted coupling of catharanthine with vindoline is disclosed, enlisting tris(4-bromophenyl)aminium hexachlororantimonate (BAHA, 1.1 equiv) in aqueous 0.05 N HCl/trifluoroethanol (1-10:1) at room temperature (25 °C), that provides anhydrovinblastine in superb yield (85%) with complete control of the newly formed quaternary C16′ stereochemistry. A definition of the scope of aromatic substrates that participate with catharanthine in the BAHA-mediated diastereoselective coupling reaction and simplified indole substrates other than catharanthine that participate in the reaction are disclosed that identify the key structural features required for participation in the reaction, providing a generalized indole functionalization reaction that bears little structural relationship to catharanthine or vindoline.

Full text of DOI:10.1021/jacs.9b06968

Subscriber access provided by Duke University Libraries
Article
Triarylaminium Radical Cation Promoted Coupling
of Catharanthine with Vindoline: Diastereospecific
Synthesis of Anhydrovinblastine and Reaction Scope
Byron A. Boon, and Dale L. Boger
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06968 • Publication Date (Web): 23 Aug 2019
Downloaded from pubs.acs.org on August 23, 2019
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 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 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.
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
Journal of the American Chemical Society
Triarylaminium Radical Cation Promoted Coupling of Catharanthine with Vindoline:
Diastereospecific Synthesis of Anhydrovinblastine and Reaction Scope
1
2
3
4
Byron A. Boon and Dale L. Boger*
5
6
7
Department of Chemistry and The Skaggs Institute of Chemical Biology, 10550 N. Torrey Pines Road,
La Jolla, California 92037
8
9
Abstract. A new triarylaminium radical cation promoted coupling of catharanthine with vindoline is
disclosed, enlisting tris(4-bromophenyl)aminium hexachlororantimonate (BAHA, 1.1 equiv) in aqueous
0.05 N HCl/trifluoroethanol (1–10:1) at room temperature (25 °C), that provides anhydrovinblastine in
superb yield (85%) with complete control of the newly formed quaternary C16’ stereochemistry. A
definition of the scope of aromatic substrates that participate with catharanthine in the BAHA-mediated
diastereoselective coupling reaction and simplified indole substrates other than catharanthine that
participate in the reaction are disclosed that identify key structural features required for participation in
the reaction, providing a generalized indole functionalization reaction that bears little structural
relationship to catharanthine or vindoline.
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
INTRODUCTION
As a result of their clinical use as antitumor drugs, vinblastine (1) and vincristine (2) are the most widely
recognized members of the bis-indole Vinca alkaloids (Figure 1).1,2 They were originally isolated in
trace quantities from Cantharanthus roseus1 and their biological activity was among the first to be
shown to arise from targeting tubulin, resulting in disruption of microtubulin dynamics, inhibition of
microtubule formation, and mitotic block that is still regarded today as one of the more successful
oncology drug targets.3 We reported the total synthesis of vinblastine and its unnatural enantiomer in
studies that are complementary to earlier pioneering efforts.4-11 Our approach enlisted a powerful
biomimetic Fe(III)-promoted coupling of vindoline (3) with catharanthine (4) as a key step.12 When
combined with a subsequent in situ Fe(III)-promoted hydrogen atom transfer (HAT) oxidation reaction
that we developed for the introduction of the C20’ tertiary alcohol,11,13,14 this provided a remarkable two-
step, one-pot procedure for use in the synthesis of vinblastine that we additionally utilized in the total
synthesis of a series of related natural products, including vincristine (2),11 and in the preparation of an
extensive series of analogs (Figure 1).4d
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 16
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
Figure 1. Natural products and Fe(III)-promoted coupling.
Since its discovery by Kutney,12 insights into this coupling reaction have been disclosed although
there are mechanistic features of this reaction that are still not completely defined. The Fe(III)-promoted
coupling reaction is conducted in acidic aqueous solvent and exhibits a remarkable stereochemical
selectivity for formation of a quaternary center that produces exclusively the natural C16’ diastereomer
at 25 °C in yields as high as 90% (Figure 1). This stands in contrast to the alternative Polonovski
fragmentation5,6 (Figure 2), which is not nearly as diastereoselective. Although this reaction favors
formation of the natural C16’ stereochemistry at –40 °C (5:1), it provides mainly the opposite unnatural
C16’ stereochemistry at 0 or 25 °C (1:3).15 Moreover, solvent (H2O) or nucleophile (Cl–) trap of putative
reactive intermediates are not observed under the acidic aqueous conditions of the Fe(III)-promoted
reaction and catharanthine is recovered unchanged when subjected to the reaction conditions in the
absence of vindoline (2 h, NaBH4 workup).15,16 This indicates that the azabenzfulvene intermediate
central to the Polonovski fragmentation and related couplings may not be a subsequent (further
ACS Paragon Plus Environment

Page 3 of 16
Journal of the American Chemical Society
oxidized) participant in the Fe(III)-promoted coupling reaction. We have suggested that the Fe(III)-
mediated coupling reaction itself is radical mediated, involving reversible generation and subsequent
reaction of a persistent, charge-separated cation radical (Figure 2).16 Consistent with this proposal, we
were able to demonstrate that simple electron-deficient radicals cleanly and regioselectively add to
vindoline at the same C15 site. An intramolecular one-electron two-center bonding interaction between
the radical site alpha to the methyl ester and the iminium carbon in the fragmented radical cation B or
an electrophilic fully delocalized radical cation best formulated as C may impose a mechanistic as well
as conformational stereochemical control over the reaction in which the upper face of the radical is not
only sterically disfavored, but that requires the reaction to proceed with exclusive inversion of the
catharanthine C16’ stereochemistry, thus accounting for the diastereospecific nature of the coupling
reaction. Combined, this proposal suggests that the initial indole radical cation A and its fragmented
cation radical B or the delocalized radical cation C may possess a unique blend of stability, persistence,
electrophilic character, and conformational properties at room temperature to effectively react
selectively with vindoline.
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
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 16
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
Figure 2. BAHA-promoted single-electron oxidative coupling.
In addition to other Fe(III) salts (FeCl3, 90% > Fe2(SO4)3, 71% > Fe2(ox)3, 0%), we have shown
that additional oxidants (Mn(OAc)3, 79% and Ce(NH4)2(NO3)6, 51%) under near identical reaction
conditions also promote the coupling of catharanthine and vindoline to provide 5.16 In addition,
electrochemical,17 photochemical,18 and enzymatic19 coupling reactions have been described, and a
photoredox-catalyzed fragmentation of catharanthine has been reported.20 Herein, we disclose studies
on a new complementary triarylaminium radical cation promoted coupling reaction of catharanthine and
vindoline and initial studies on the scope of the reaction.
Triarylaminium radical cation salts have found use in a variety of transformations, including
protecting group manipulations (PMB ether, dithioacetal, and dithioketal deprotections), glycosidation
ACS Paragon Plus Environment

Page 5 of 16
Journal of the American Chemical Society
reactions of phenylseleno- and ethylthioglycosides, radical rearrangements, as well as a number of
radical cation mediated pericyclic reactions including [4+2],21 [2+2],22 and [3+2]23 cycloaddition
reactions.24 In addition, triarylaminium radical cation salts have been shown to oxidize a variety of
tertiary amines and electron rich aromatics.25 Based on this precedent, we anticipated that
triarylaminium radical cation salts might also promote the coupling of catharanthine and vindoline,
leading to the generation of anhydrovinblastine (5). If successful, this would constitute the first example
of the use of an organic oxidant for promoting the vindoline/catharanthine coupling reaction, provide a
useful alternative to inorganic oxidants, further clarify key elements of the reaction mechanism,
potentially expand the scope of such reactions, permit the use of more carefully tuned oxidants, and
further extend the synthetic utility of organic single-electron oxidants like BAHA.
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
Initial studies were directed at promoting the oxidative coupling of catharanthine with vindoline
using tris(4-bromophenyl)aminium hexachloroantimonate (BAHA, 6) as a stochiometric radical cation
oxidant. The use of organic solvents such as CH2Cl2, MeCN, EtOAc, CHCl3, and hexafluoroisopropanol
(HFIP) did not lead to productive coupling reactions in the presence of BAHA (Figure 3, entries 1-5).
However, the formation of anhydrovinblastine (5) was observed in a modest 18% yield in 2,2,2-
trifluoroethanol (TFE, entry 6). This notable discovery represented the first use of an organic single-
electron oxidant for promoting the coupling of catharanthine and vindoline, providing an alternative to
inorganic oxidants. Reactions conducted in water gave low yields of coupling product (7%, entry 7), but
the reaction yield improved to 45% in aqueous TFE (entry 8). Appreciable yields of 5 (46%) were
obtained when the reaction was conducted in aqueous 0.05 N HCl (entry 9) where it is thought
protonation of the tertiary amines protect their competitive oxidation. Significantly, a combined 0.05 N
aqueous HCl/TFE solvent system (10:1) afforded anhydrovinblastine in 83% yield, likely due to
increased solubility of the starting materials in the acidic, aqueous reaction media (entry 10). Mixed
solvent systems with higher ratios of HFIP or TFE to aqueous 0.05 N HCl provided similar reaction
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 16
yields (entries 11 and 12). Although not extensively investigated, use of alternative acids (H2SO4, TFA
vs HCl), while supporting the reaction, did not further improve the coupling reaction (entries 13 and 14).
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
Figure 3. Examination of reaction solvent.
Based on a proposed mechanism, we had anticipated the reaction to require 2 equiv of oxidant
for full conversion to product (Figure 2). Yet, the reaction of catharanthine with vindoline in the presence
of 1.1 equiv of BAHA (6) provided 5 in 85% yield (Figure 4, entry 1). With this observation, we came to
–
appreciate that the counterion SbCl6 , for which a variety of oxidation reactions are known,26 was acting
as a second milder oxidant responsible for the presumed oxidation of the subsequent vindoline addition
product that leads to the final aromatization. To confirm the effect of counterion and to further examine
alternative triarylaminium radical cations, we prepared a series of triarylaminium radical cation salts.
Salts 7 and 8 differ from BAHA in that they contain non-oxidizing BF4 and PF6 counterions.27 Reactions
–
–
conducted with 1.1 equiv of 7 or 8 gave low yields of coupling product, reflecting the integral
–
participation of the SbCl6 counterion (entries 3 and 5). In contrast to BAHA, yields nearly doubled when
2 equiv of oxidants 7 or 8 were employed (entries 4 and 6). These results are consistent with the
–
–
–
presumption that the BF4 and PF6 counterions are non-participatory counterions, whereas the SbCl6
ACS Paragon Plus Environment

Page 7 of 16
Journal of the American Chemical Society
counterion found in BAHA serves as a second mild oxidant to support the coupling reaction. Reaction
with 1.1 equiv of the less powerful oxidant 9, differing from BAHA (6) in the substitution of the aryl group
(Me vs Br) gave low yields of anhydrovinblastine (34%, entry 7), whereas increasing this oxidants
loading to 2 equiv increased the yield to 74% (entry 8). The efficient reactivity of BAHA (6) relative to
oxidant 9 may be attributed to the difference in oxidation potential of the tris(4-bromophenyl)aminium
radical cation in BAHA (6, E°' = +1.10 V vs SCE in MeCN) versus the tris(4-methylphenyl)aminium
group in oxidant 9 (E°' = +0.78 V vs SCE in MeCN).28 The combination of effective oxidation potential
and counterion established BAHA as the oxidant of choice for the remainder of the study.
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
Figure 4. Examination of the triarylaminium radical cation.
We turned our attention to the coupling reaction of catharanthine with substrates other than
vindoline. A variety of electron-rich aryl and heteroaromatic coupling partners were found to participate
in effective coupling reactions with catharanthine promoted by BAHA (Figure 5). Remarkably, each
reaction provided a single diastereomer (diastereospecific), matching the natural C16’ stereochemistry
of vinblastine. Each reaction is also regioselective favoring the site anticipated for electrophilic radical
addition or aromatic substitution of the catharanthine coupling partner. These results indicate that the
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 16
stereochemistry of the coupling reaction is controlled by catharanthine alone and that it is independent
of the structure of its reaction partner (e.g.; vindoline). Moreover and because BAHA and especially the
related reagents 7 and 8 produce the single-electron oxidation product as a free discrete radical cation
(i.e., C), there is no need to invoke an inner shell electron transfer or metal-bound intermediate in the
analogous reactions mediated by inorganic oxidants (e.g.; Fe(III), Mn(III), Ce(IV)) to account for the
remarkable stereochemical outcome of the reactions.16 The scope of the Polonovski fragmentation-
based coupling and related reactions that proceed through an azabenzfulvene has not been examined.
The limited examples that are reported display an analogous regioselectivity and a similar requirement
for electron-rich aromatic substrates, but the reactions exhibit a temperature-dependent stereochemical
outcome, producing predominately (e.g., 5:1) but not exclusively the natural C16’ stereochemistry at
low temperatures (e.g.; –40 °C) and the opposite unnatural C16’ stereochemistry at higher
temperatures (e.g.; 1:>3 at 0–25 oC °C).15 The diastereospecific nature of now both the BAHA as well
as the FeCl3 promoted reactions are analogous and involves exclusive inversion of the catharanthine
C16’ stereochemistry that we now can more confidently suggest occurs through requisite backside
attack on the electrophilic delocalized radical cation C. These reactions are now even more clearly
mechanistically distinguishable from the Polonovski fragmentation and related couplings where
temperature-dependent conformational features of the catharanthine-derived azabenfulvene controls
the variable reaction diastereoselectivity.15 Coupling reactions conducted with BAHA with the electron-
rich aromatics N,N-dimethylaniline (10b), 1,3-dimethoxybenzene (10c), and indole (10g) gave a single
product in high yield. Sterically hindered electron-rich aryl substrates also gave reaction products 10e
and 10f in excellent yield and diastereoselectivity. Moderate yields were observed with the coupling of
pyrrole (10h) and furan (10i). Highly electron-rich substrates such as 10a gave low yields due to
competing oxidative oligomerization reactions of the aryl substrate. Whereas strongly electron-rich
aromatic substrates were found to participate in the coupling reaction effectively, less electron-rich
substrates (e.g.; anisole), neutral aromatic substrates (benzene and thiophene), and electron-deficient
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
aromatic substrates (e.g.; methyl benzoate) failed to couple with catharanthine.
ACS Paragon Plus Environment

Page 9 of 16
Journal of the American Chemical Society
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
Figure 5. Catharanthine coupling with aromatic substrates.
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
A variety of substrates other than catharanthine were also examined for their coupling with
vindoline (Figure 6). Synthetic modification of the catharanthine C16 substituent provided a series of
substrates with alternative C16 electron-withdrawing groups (11a-c) as well the compound 11d with
simple C16 hydrogen substitution.29 Catharanthine derivatives with electron-withdrawing C16
substituents participated in effective BAHA-promoted coupling reactions with vindoline to provide 14a-
c (58-76%).29 In contrast, compound 11d, bearing no C16 substituent, provided a low yield (8%) of
coupling product 14d, indicating that electron-withdrawing C16 substituents are required to support the
coupling reaction, presumably stabilizing the radical cation intermediate (Figure 2). Like catharanthine,
each of these modified C16 catharanthine derivatives underwent coupling with vindoline with complete
diastereoselectivity. Substantially expanding the scope of the reactions, simplified indole derivatives 12
and 13, lacking the catharanthine bicyclic structure and tertiary amine, also underwent successful
coupling reactions with vindoline. With 12 and 13, the reaction products were formed as a mixture of
diastereomers, highlighting the role catharanthine plays in the substrate controlled diastereoselectivity.
Significantly, these results indicate that a single-electron indole oxidation is sufficient for the coupling
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 16
reaction to occur and that the oxidation reaction does not require the presence or participation of the
catharanthine tertiary amino group.16,30 In fact, it is thought that the use of the aqueous acidic reaction
conditions for the coupling reaction serves to protect the substrate tertiary amines from oxidation by
virtue of their protonation. Like catharanthine, the reactions of 12 and 13 are conducted at room
temperature in acidic aqueous solution (0.05 N aq HCl/CF3CH2OH) without competitive nucleophilic
solvent (H2O) or counter anion (Cl-–) participation, suggesting that the reactions are also unlikely to
proceed through an indole-derived azabenzfulvene derived from a second single-electron oxidation.
Since the reaction no longer requires the reduction of the catharanthine-derived iminium ion in the
reaction product, NaBH4 is no longer required for reductive workup of the reactions.31
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
Figure 6. BAHA-promoted coupling of vindoline with catharanthine derivatives and simpler indoles.
ACS Paragon Plus Environment

Page 11 of 16
Journal of the American Chemical Society
Finally, we examined the reaction of a simplified substrate (13) other than catharanthine with a
1
2
3
4
5
6
7
8
coupling partner other than vindoline (eq 1). The simplified indole 13 displayed the identical reactivity
observed with catharanthine itself, coupling with an electron-rich aromatic substrate (1 equiv) and
providing 17 as the only observed product in good yield (57%) under mild reaction conditions (1.1 equiv
9
o
BAHA, 2 h, 25 C) in the mixed reaction solvent system (1:1 aq 0.05 N HCl/TFE). Interestingly and
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
although not optimized or investigated in detail, this coupling also proceeded effectively (40%) in TFE
alone. Presumably this reflects in part the role aqueous acid plays in protonation protection of oxidizable
amines, which is not needed for this set of substrates. More broadly, it suggests this generalized
coupling reaction using BAHA as an organic oxidant, unlike the analogous FeCl3 mediated reactions,
can be utilized in the organic media alone where the latter is solubility limited. Significantly, these
combined studies define a generalization of the reaction to substrates that bear no close structural
resemblance to either catharanthine or vindoline, providing powerful new methodology for the synthesis
of indole-containing products structurally unrelated to vinblastine. Notably, the methodology represents
quaternary center generation adjacent to indole by a reaction mediated by BAHA and conducted at
room temperature.
CONCLUSIONS
A powerful new triarylaminium radical cation promoted coupling of catharanthine with vindoline is
disclosed that is conducted in aqueous 0.05 N HCl/TFE (2–10:1) at room temperature, enlisting BAHA
(1.1 equiv). The reaction provides anhydrovinblastine in excellent yield (85%) with complete
regioselectivity and diastereoselectivity for formation of the newly generated quaternary C16’
stereochemistry. The diastereospecific nature of now both the BAHA as well as the analogous FeCl3
promoted reactions, which proceed with exclusive inversion of the catharanthine C16’ stereochemistry,
is such that we can now more confidently conclude that they are mechanistically distinguishable from
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 16
and do not involve the same intermediates observed in the Polonovski fragmentation and related
couplings. Moreover, whereas temperature-dependent conformational features of the intermediate
catharanthine-derived azabenfulvene controls the condition-dependent diastereoselectivity of the latter,
the former displays characteristics of a diastereospecific reaction in which we suggest the
stereochemical outcome is mechanistically imposed by the requisite backside attack of vindoline on the
electrophilic delocalized radical cation C. An examination of alternative aromatic substrates other than
vindoline and simplified indole substrates other than catharanthine defined the scope of this
organoradical cation promoted reaction, identifying key structural features required for participation in
the reaction. This provided a generalized indole functionalization reaction and powerful new
methodology for the synthesis of indole-containing natural products as well expanded opportunities for
the preparation of previously inaccessible vinblastine analogs. Such extensions of the studies are in
progress and will be disclosed in due course.
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
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:10.1021/jacs.xxxxxxx.
Detailed experimental procedures and characterization data for all compounds. All new compounds
include 1H NMR, 13C NMR, HRMS, and optical rotation characterization. Details of the X-ray structure
determinations for 3’S-15 and 3’R-16. Copies of 1H NMR spectra provided (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: boger@scripps.edu
ORCID
Dale L. Boger: 0000-0002-3966-3317
Byron A. Boon: 0000-0002-3952-9708
Notes
The authors declare no competing financial interest.
ACKNOWLEGEMENTS
ACS Paragon Plus Environment

Page 13 of 16
Journal of the American Chemical Society
We are especially grateful to the National Institutes of Health for financial support of the studies
(CA042056, DLB). We thank Milan Gembicky of the Crystallography Facility at the University of
California, San Diego for X-ray structure determinations of 3’S-15 and 3’R-16.
1
2
3
4
5
REFERENCES
6
7
8
9
(1) (a) Noble, R. L.; Beer, C. T.; Cutts, J. H. Role of chance observations in chemotherapy: Vinca rosea.
Ann. N. Y. Acad. Sci. 1958, 76, 882-894. (b) Svoboda, G. H.; Neuss, N.; Gorman, M. Alkaloids of Vinca
rosea Linn. (Catharanthus roseus G. Don.) V. J. Am. Pharm. Assoc. Sci. Ed. 1959, 48, 659-666.
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
(2) The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic: San Diego, 1990; Vol. 37.
(3) Jordan, M. A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer 2004, 4,
253-265.
(4) (a) Kuehne, M. E.; Marko, I. Syntheses of vinblastine-type alkaloids. In The Alkaloids; Brossi, A.,
Suffness, M., Eds.; Academic: San Diego, 1990; Vol. 37, 77-131. (b) Potier, P. Synthesis of the
antitumor dimeric indole alkaloids from catharanthus species (vinblastine group). J. Nat. Prod. 1980,
43, 72-86. (c) Kutney, J. P. Plant cell culture combined with chemistry: A powerful route to complex
natural products. Acc. Chem. Res. 1993, 26, 559-566. (d) Sears, J. E.; Boger, D. L. Total synthesis of
vinblastine, related natural products, and key analogues and development of inspired methodology
suitable for the systematic study of their structure–function properties. Acc. Chem. Res. 2015, 48, 653-
662.
(5) Langlois, N.; Gueritte, F.; Langlois, Y.; Potier, P. Application of a modification of the Polonovski
reaction to the synthesis of vinblastine-type alkaloids. J. Am. Chem. Soc. 1976, 98, 7017-7024.
(6) Kutney, J. P.; Hibino, T.; Jahngen, E.; Okutani, T.; Ratcliffe, A. H.; Treasurywala, A. M.; Wunderly,
S. Total synthesis of indole and dihydroindole alkaloids. IX. Studies on the synthesis of bisindole
alkaloids in the vinblastine-vincristine series. The biogenetic approach. Helv. Chim. Acta 1976, 59,
2858-2882
(7) (a) Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. Enantioselective syntheses of vinblastine,
leurosidine, vincovaline and 20’-epi-vincovaline. J. Org. Chem. 1991, 56, 513-528. (b) Bornmann, W.
G.; Kuehne, M. E. A common intermediate providing syntheses of ψ-tabersonine, coronaridine,
iboxyphylline, ibophyllidine, vinamidine, and vinblastine. J. Org. Chem. 1992, 57, 1752-1760.
(8) (a) Magnus, P.; Mendoza, J. S.; Stamford, A.; Ladlow, M.; Willis, P. Synthesis of the antitumor
bisindole alkaloid vinblastine: Diastereoselectivity and solvent effect on the stereochemistry of the
crucial C-15–C-18’ bond. J. Am. Chem. Soc. 1990, 112, 8210-8212.
(9) (a) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T.
Stereocontrolled total synthesis of (+)-vinblastine. J. Am. Chem. Soc. 2002, 124, 2137-2139. (b)
Kuboyama, T.; Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Stereocontrolled total synthesis of (+)-
vincristine. Proc. Natl. Acad. Sci. USA 2004, 101, 11966-11970.
(10) (a) Zhang, Y.; Xue, Y.; Li, G.; Yuan, H.; Luo, T. Enantioselective synthesis of Iboga alkaloids and
vinblastine via rearrangements of quaternary ammoniums. Chem. Sci. 2016, 7, 5530-5536. (b) Wang,
N.; Liu, J.; Wang, C.; Bai, L.; Jiang, X. Asymmetric total syntheses of (−)-jerantinines A, C, and E, (−)-
16-methoxytabersonine, (−)-vindoline, and (+)-vinblastine. Org. Lett. 2018, 20, 292-295.
(11) (a) Ishikawa, H.; Colby, D. A.; Boger, D. L. Direct coupling of catharanthine and vindoline to provide
vinblastine:ꢀ Total synthesis of (+)- and ent-(–)-vinblastine. J. Am. Chem. Soc. 2008, 130, 420-421. (b)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 16
Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.; Rayl, T. J.; Hwang, I.; Boger, D. L. Total
synthesis of vinblastine, vincristine, related natural products, and key structural analogues. J. Am.
Chem. Soc. 2009, 131, 4904-4916.
1
2
3
4
5
6
7
8
9
(12) (a) Vukovic, J.; Goodbody, A. E.; Kutney, J. P.; Misawa, M. Production of 3', 4'-anhydrovinblastine:
a unique chemical synthesis. Tetrahedron 1988, 44, 325-331. (b) Szantay, C., Jr.; Balazs, M.; Bolcskei,
H.; Szantay, C. Synthesis of Vinca alkaloids and related compounds. Part LVI. 15′,20′-
Anhydrovinblastine borane complex. Structural investigations using NMR methods. Tetrahedron 1991,
47, 1265-1274. (c) Sundberg, R. J.; Hong, J.; Smith, S. Q.; Sabat, M.; Tabakovic, I. Synthesis and
oxidative fragmentation of catharanthine analogs. Comparison to the fragmentation-coupling of
catharanthine and vindoline. Tetrahedron 1998, 54, 6259-6292.
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
(13) (a) Leggans, E. K.; Barker, T. J.; Duncan, K. K.; Boger, D. L. Iron(III)/NaBH4-mediated additions to
unactivated alkenes: synthesis of novel 20'-vinblastine analogues. Org. Lett. 2012, 14, 1428–1431. (b)
Barker, T. J.; Boger, D. L. Fe(III)/NaBH4-mediated free radical hydrofluorination of unactivated alkenes.
J. Am. Chem. Soc. 2012, 134, 13588-13591.
(14) Crossley, S. W. M.; Martinez, R. M.; Obradors, C.; Shenvi, R. A. Mn, Fe, and Co-catalyzed radical
hydrofunctionalizations of olefins. Chem. Rev. 2016, 116, 8912-9000.
(15) Sundberg, R. J.; Gadamasetti, K. G.; Hunt, P. J. Mechanistic aspects of the formation of
anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline.
Spectroscopic observation and chemical reactions of intermediates. Tetrahedron 1992, 48, 277-296.
(16) Gotoh, H.; Sears, J. E.; Eschenmoser, A.; Boger, D. L. New insights into the mechanism and an
expanded scope of the Fe(III)-mediated vinblastine coupling reaction. J. Am. Chem. Soc. 2012, 134,
13240-13243.
(17) (a) Gunic, E.; Tabakovic, I.; Gasic, M. J. Electrochemical synthesis of anhydrovinblastine. J. Chem.
Soc., Chem. Commun. 1993, 1496-1497. (b) Tabakovic, I.; Gunic, E.; Juranic, I. Anodic fragmentation
of catharanthine and coupling with vindoline. Formation of anhydrovinblastine. J. Org. Chem. 1997, 62,
947-953.
(18) (a) Pennanen, S.; Huhtikangas, A. Photochemical one-pot synthesis of vinblastine and vincristine.
Photochem. Photobiol. 1990, 51, 515-518. (b) Hirata, K.; Duangteraprecha, S.; Morihara, E.; Honda,
M.; Akagi, T.; Nakae, M.; Katayama, H.; Miyamoto, K. Biomimetic one-pot synthesis of vinblastine:
NAD(P)H-mediated vinblastine synthesis from the product of FMN-mediated vindoline–catharanthine
coupling under near-ultraviolet light. Biotechnol. Lett 1997, 19, 53-57. (c) Duangteraprecha, S.; Hirata,
K.; Morihara, E.; Nakae, M.; Katayama, H.; Honda, M.; Miyamoto, K. Non-enzymic coupling of vindoline
and catharanthine to synthesize 3′,4′-anhydrovinblastine under irradiation with near-ultraviolet light. J.
Ferment. Bioeng. 1997, 83, 227-232.
(19) (a) Misawa, M.; Endo, T.; Goodbody, A.; Vukovic, J.; Chapplet, C.; Choi, L.; Kutney, J. P. Synthesis
of dimeric indole alkaloids by cell free extracts from cell suspension cultures of Catharanthus roseus.
Phytochemistry 1988, 27, 1355-1359. (b) Endo, T.; Goodbody, A.; Vukovic, J.; Misawa, M. Enzymes
from Catharanthus roseus cell suspension cultures that couple vindoline and catharanthine to form
3′,4′-anhydrovinblastine. Phytochemistry 1988, 27, 2147-2149. (c) Kutney, J. P.; Boulet, C. A.; Choi, L.
S. L.; Gustowski, W.; McHugh, M.; Nakano, J.; Nikaido, T.; Tsukamoto, H.; Hewitt, G. M.; Suen, R.
Alkaloid production in catharanthus roseus (L.) G. Don cell cultures. XIV. The role of unstable
dihydropyridinium intermediates in the biosynthesis of bisindole alkaloids. Heterocycles 1988, 27, 613-
620. (d) Kutney, J. P.; Boulet, C. A.; Choi, L. S. L.; Gustowski, W.; McHugh, M.; Nakano, J.; Nikaido,
T.; Tsukamoto, H.; Hewitt, G. M.; Suen, R. Alkaloid production in catharanthus roseus (L.) G. Don cell
ACS Paragon Plus Environment

Page 15 of 16
Journal of the American Chemical Society
cultures. XV. Synthesis of bisindole alkaloids by use of immobilized enzyme systems.
Heterocycles 1988, 27, 621-628.
1
2
3
4
5
6
(20) Beatty, J. W.; Stephenson, C. R. J. Synthesis of (-)-pseudotabersonine, (-)-pseudovincadifformine,
and (+)-coronaridine enabled by photoredox catalysis in flow. J. Am. Chem. Soc. 2014, 136, 10270-
10273.
7
(21) Bellville, D. J.; Wirth, D. W.; Bauld, N. L. Cation-radical catalyzed Diels-Alder reaction. J. Am.
Chem. Soc. 1981, 103, 718-720.
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
(22) Bauld, N. L.; Pabon, R. Cation radical catalyzed olefin cyclodimerization. J. Am. Chem. Soc. 1983,
105, 633-634.
(23) Takemoto, Y.; Furuse, S.-i.; Koike, H.; Ohra, T.; Iwata, C.; Ohishi, H. A diquinane synthesis using
a novel cation radical-mediated intramolecular [3+2] cycloaddition of cyclopropyl sulfides. Tetrahedron
Lett. 1995, 36, 4085-4088.
(24) Earle, M. J.; Vibert, A.; Jahn, U. Tris(4‐bromophenyl)aminium Hexachloroantimonate. In
Encyclopedia of Reagents for Organic Synthesis, Wiley, 2011. doi:10.1002/047084289X.rt397.pub2
(25) (a) Yueh, W.; Bauld, N. L. Mechanistic aspects of aminium salt-catalyzed Diels-Alder reactions:
The substrate ionization step. J. Phys. Org. Chem. 1996, 9, 529-538. (b) Jahn, U.; Aussieker, S.
Triarylaminium salt induced oxidative cyclizations of tertiary amines. Convenient access to 2-
substituted pyrrolidinium salts. Org. Lett. 1999, 1, 849-852.
(26) Cowell, G. W.; Ledwith, A.; White, A. C.; Woods, H. J. Electron-transfer oxidation of organic
compounds with hexachloroantimonate [SbCl6]– ion. J. Chem. Soc. B. 1970, 227-231.
(27) Connelly, N. G.; Geiger, W. E. Chemical redox agents for organometallic chemistry. Chem. Rev.
1996, 96, 877-910.
(28) Barham, J. P.; John, M. P.; Murphy, J. A. Contra-thermodynamic hydrogen atom abstraction in the
selective C–H functionalization of trialkylamine N-CH3 Groups. J. Am. Chem. Soc. 2016, 138, 15482-
15487.
(29) Tam, A.; Gotoh, H.; Robertson, W. M.; Boger, D. L. Catharanthine C16 substituent effects on the
biomimetic coupling with vindoline: preparation and evaluation of a key series of vinblastine analogues.
Bioorg. Med. Chem. Lett. 2010, 20, 6408-6410.
(30) Gotoh, H.; Duncan, K. K.; Robertson, W. M.; Boger, D. L. 10′-Fluorovinblastine and 10′-
fluorovincristine: synthesis of a key series of modified Vinca alkaloids. ACS Med. Chem. Lett. 2011, 2,
948-952.
(31) The structure and stereochemistry of the individual diastereomers of 15 and 16 were established
by X-ray crystallography: 3’S-15 (CCDC 1947271) was conducted with colorless crystals obtained from
slow vapor diffusion with MeOH/pentanes and 3’R-16 (CCDC 1947270) was conducted with colorless
crystals obtained from slow vapor diffusion with benzene/pentanes.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 16 of 16
TOC graphic
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
ACS Paragon Plus Environment