Stereospecific approach to the synthesis of ring-A oxygenated sarpagine indole alkaloids. Total synthesis of the dimeric indole alkaloid P -(+)-dispegatrine and six other monomeric indole alkaloids

Article abstract of DOI:10.1021/jo400469t

The first regio- and stereocontrolled total synthesis of the bisphenolic, bisquaternary alkaloid (+)-dispegatrine (1) has been accomplished in an overall yield of 8.3% (12 reaction vessels) from 5-methoxy-d-tryptophan ethyl ester (17). A crucial late-stage thallium(III) mediated intermolecular oxidative dehydrodimerization was employed in the formation of the C9-C9′ biaryl axis in 1. The complete stereocontrol observed in this key biaryl coupling step is due to the asymmetric induction by the natural sarpagine configuration of the monomer lochnerine (6) and was confirmed by both the Suzuki and the oxidative dehydrodimerization model studies on the tetrahydro β-carboline (35). The axial chirality of the lochnerine dimer (40) and in turn dispegatrine (1) was established by X-ray crystallography and was determined to be P(S). Additionally, the first total synthesis of the monomeric indole alkaloids (+)-spegatrine (2), (+)-10-methoxyvellosimine (5), (+)-lochnerine (6), lochvinerine (7), (+)-sarpagine (8), and (+)-lochneram (11) were also achieved via the common pentacyclic intermediate 16.

Full text of DOI:10.1021/jo400469t

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Article
Stereospecific Approach to the Synthesis of Ring-A Oxygenated
Sarpagine Indole Alkaloids. Total Synthesis of the Dimeric Indole
Alkaloid P-(+)-Dispegatrine and Six Other Monomeric Indole Alkaloids
Chitra Rahul Edwankar, Rahul Vinod Edwankar, Ojas Arvind Namjoshi, Xuebin Liao, and James M. Cook
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400469t • Publication Date (Web): 30 May 2013
Downloaded from http://pubs.acs.org on June 14, 2013
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Stereospecific Approach to the Synthesis of RingꢀA Oxygenated Sarpagine
Indole Alkaloids. Total Synthesis of the Dimeric Indole Alkaloid Pꢀ(+)ꢀ
Dispegatrine and Six Other Monomeric Indole Alkaloids
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†
†
†
†
Chitra R. Edwankar, Rahul V. Edwankar, Ojas A. Namjoshi, Xuebin Liao and James M.
*,†
Cook
†
Department of Chemistry & Biochemistry, University of WisconsinꢀMilwaukee, Milwaukee, WI
5
3201, USA
capncook@uwm.edu
TOC
Abstract
The first regioꢀ and stereocontrolled total synthesis of the bisphenolic, bisquaternary
alkaloid (+)ꢀdispegatrine (1) has been accomplished in an overall yield of 8.3% (12 reaction
vessels) from 5ꢀmethoxyꢀDꢀtryptophan ethyl ester (17). A crucial lateꢀstage thallium(III)
mediated intermolecular oxidative dehydrodimerization was employed in the formation of the
C9ꢀC9′ biaryl axis in 1. The complete stereocontrol observed in this key biaryl coupling step is
due to the asymmetric induction by the natural sarpagine configuration of the monomer
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lochnerine (6) and was confirmed by both the Suzuki and the oxidative dehydrodimerization
model studies on the tetrahydro βꢀcarboline (35). The axial chirality of the lochnerine dimer (40)
and in turn dispegatrine (1) was established by Xꢀray crystallography and was determined to be
P(S). Additionally, the first total synthesis of the monomeric indole alkaloids (+)ꢀspegatrine (2),
(+)ꢀ10ꢀmethoxyvellosimine (5), (+)ꢀlochnerine (6), lochvinerine (7), (+)ꢀsarpagine (8), and (+)ꢀ
lochneram (11) were also achieved via the common pentacyclic intermediate 16.
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INTRODUCTION
The sarpagine-macroline group is one of the largest groups of structurally related indole
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alkaloids isolated principally from the Apocynaceae plant family. More than 150 members of
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this group have been isolated to date, many of which exhibit interesting pharmacological
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,2
activities. Among them, bisindoles are of special significance because they exhibit more potent
3
bioactivity than their monomeric counterparts. However, a vast majority of these alkaloids have
been poorly evaluated due to paucity of material available for biological testing. The sarpagine-
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5
macroline bases are biogenetically related to the clinically important ajmaline alkaloids and
common to these three classes is the azabicyclo[3.3.1]nonane core, as illustrated in Figure 1.
6
In continuation of their efforts at the biologyꢀoriented synthesis (BIOS) of natural
product derived probes, Waldmann et al. targeted the sarpagine-macroline indole alkaloids
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which led to the cycloocta[b]indole core (I) as a starting point for library design. More than a
hundred tetracyclic analogues of this core, synthesized by a stereoselective solidꢀphase synthesis,
were investigated for their inhibitory activity in enzymatic assays with various tryrosine
phosphatases. The screen yielded an unprecedented class of potent inhibitors of Mycobacterium
protein tyrosine phosphatase B (MptpB) with IC50 values in low micromolar range (the most
potent MptpB inhibitor of the library has an IC value of 4.71±1.14 ꢁM). The MptpB inhibitory
5
0
activity of I seemed to be greatly influenced by the ‘S’ stereochemistry at C6 and C10 and by the
presence of a βꢀketoester moiety (see Figure 1). The N ꢀbenzyl group in I, containing: 1) an
b
oxygen atom either within the aromatic ring system or as a phenol substituent and 2) with m,pꢀ
disubstituted electron withdrawing groups were important, to potent MptpB inhibition. MptpA
and MptpB secreted by the causative organism of tuberculosis, Mycobacterium tuberculosis, are
known to selectively dephosphorylate human host proteins involved in interferonꢀγ signaling
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pathways thereby preventing the initiation of host defense mechanisms. The tetracyclic core (I)
of the sarpagine alkaloids thus may be considered as a promising target for the development of
new drug candidates against tuberculosis.
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N
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N
H
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14
H
H
19
sarpagine
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1
2
0
9
9
H
6
H
HO 6
H
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7
H 17
A
11
5
O
5
OH
B
C
1
1
16
15
1
13
1
7 16
N4
NH
N
4
N
N
21
OH
2
1
D
N
Me
3
R
15
1
Me
1
4
20
H
H
H14
20
19
H
H
azabicyclo[3.3.1] nonane
macroline O 19
18
(
tetracyclic core)
ajmaline
R = H/Me
18
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2
1
1
1
H
S
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12
9
O
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0
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5
6
N
R2
N
H
H S
8
CO Me
2
7
I
R = O atom containing phenyl groups/phenyl
2
groups containing m- and p-EWG groups
Figure 1. SAR of the cycloocta[b]indole framework (I) of the sarpagine-macroline and ajmaline
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related indole alkaloids active against MptpB. EWG: electron withdrawing group.
The dried roots and leaves of Rauwolfia verticillata (Lour.) or Lou Fu Mu have been used
in Chinese folk medicines for thousands of years as tranquilizers and more recently in the
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10
treatment of hypertension and hyperthyroidism. Illustrated in Figure 2 is (+)ꢀdispegatrine (1), a
bisquaternary, bisphenolic sarpagine alkaloid isolated from the waterꢀsoluble fraction of the root
of R. verticillata (Lour.) Baill var. hainanensis Tsiang along with the monomer (+)ꢀspegatrine
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(
2). Bisphenolic, bisquaternary indole alkaloids are very rare. Of the 300 or so dimeric indole
1
3
alkaloids isolated to date, the homodimer 1 and blumeanine (not shown) are the only two
dimers belonging to this class of alkaloids. Although dispegatrine (1) and its corresponding
monomer spegatrine (2) exhibit promising hypotensive activity, the affinities and activities of the
dimer 1 on both α1 and α2 adrenergic receptors was about an order of magnitude greater than
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e
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that of the monomer 2. The quaternary alkaloids verticillatine (3) and macrospegatrine (4)
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6
illustrated in Figure 2 are also known to exhibit promising antihypertensive activity.
H
H
HO
HO
H
H
OH
H
N
H
N
N
H
H
N
OH
H
NH
HH
N
1
1'
Cl
Cl
H
HO
N
O
9
'
2Cl
H
N
H
H
HO
H
H
H
H
O
H
H
2Cl
H
9
OH
H
H
H
H
OH
1
1
H
OH
O
H
(
+)-spegatrine (2)
(+)-verticillatine (3)
N
N
H
N
H
H
(
+)-dispegatrine (1)
N
H
H
H
(+)-macrospegatrine (4)
R1
MeO
MeO
R2
H
H
H
OH
OH
H
N
H
N
H
N
OH
R3
H
H
O
O
I
N
N
N
N
N
H
H
NH
H
H
H
Me
Me
OMe
H
H
H
H
H
H
H
5-8
N
H
(+)-lochneram (11)
(+)-lochnerine Nb-oxide (12)
H
O
H
5
6
7
R1 = OMe, R2 = H, R3 = CHO
+)-10-methoxyvellosimine
R1 = OMe, R2 = H, R3 = CH OH
(+)-lochnerine
R1 = OH, R2 = H, R3 = CH OH
+)-sarpagine
8 R1 = OMe, R2 = H, R3 = CH OAc
+)-O-acetylsarpagine
R1 = OMe, R2 = CH OH, R3 = H
OH
Me
H
(
HN
H
H
O
H
OH
H
2
H
O
H
N
N
N
N
2
N
H
Me
Me
H
OH
H
(
H
H
H
H
MeO
H
OH
2
H
15
)
(
+)-lumitinine E (
(
(
+)-perhentisine C (14)
9
2
N
lochvinerine
10 R1 = OH, R2 = CH OH, R3 = H
N
H
2
H
(
+)-episarpagine
(+)-perhentisine A (13)
Figure 2. RingꢀA oxygenated sarpagine (1ꢀ12) indole alkaloids and macroline-sarpagine (4, 13ꢀ
5) bisindole alkaloids.
A number of biogenetically related ringꢀA oxygenated monomeric alkaloids such as (+)ꢀ
1
1
7
18
19
20
10ꢀmethoxyvellosimine (5), (+)ꢀlochnerine (6), (+)ꢀsarpagine (7), Oꢀacetylsarpagine (8),
21
20
18c,22
(
+)ꢀlochvinerine (9), episarpagine (10), (+)ꢀlochneram (11)
and lochnerine N ꢀoxide
b
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(
12) have also been reported (Figure 2). Lochnerine (6), which itself has no antitumor activity,
when combined with vincristine or daunorubicin (not shown) at subcytotoxic concentrations
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induced complete inhibition of the vincristineꢀresistant P388 leukemic cells in vitro.
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Additionally, 6 is known to exhibit promising vasorelaxant actvity. Most recently, 6 and 7 were
found to be present in some of the new macroline-sarpagine bisindoles (13ꢀ15, Figure 2) isolated
2
6
from Alstonia angustifolia by Kam et al. The promising bioactivity of some of the members of
these ringꢀA oxygenated group of indole alkaloids combined with their complex architecture
made them very attractive targets.
The total synthesis of dispegatrine (1) and four other monomeric indole alkaloids was
recently reported via a general approach for the synthesis of ringꢀA oxygenated sarpagine
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alkaloids. Such a doubly convergent route could also be employed for the potential synthesis of
the complex bisindoles 4, 13ꢀ15; the biological activities of which have not yet been fully
investigated. In this report, the full details of the development of this general route including the
first total synthesis of alkaloids 9 and 11 are reported.
RESULTS AND DISCUSSION
Although dispegatrine (1) was isolated as a single atropodiastereomer and its structure
1
13
established on the basis of spectroscopic analysis ( H NMR, C NMR and mass spectrum
1
0
comparison to monomer 2), the apparent axial chirality at the C9ꢀC9′ biaryl axis in 1 was not
determined. The isolation chemists also reported a semisynthesis of 1 in an almost negligible
yield of 0.25% (Scheme 1), obtained by an oxidative phenolic dehydrodimerization of 2 in
1
0
aqueous ammonium acetate with K Fe(CN)6. Since only one atropodiastereomer was reportedly
3
formed, it can be assumed that the complete atropselectivity observed in this coupling is a result
of internal asymmetric induction by the natural sarpagine configuration of the monomer 2.
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Scheme 1. Partial Biomimetic Synthesis of (+)ꢀDispegatrine (1) by Yu et al.
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The retrosynthetic strategy was based on these reports (Scheme 2). A potentially
biomimetic intermolecular biaryl coupling could be employed to construct the C9ꢀC9′ bond in 1
via a nonꢀphenolic coupling of 6 or by a phenolic oxidative coupling of 7 or 2. In contrast to the
1
0
extremely low yield of phenolic coupling of 2, a nonꢀphenolic Scholl type oxidative coupling
2
7
of the methoxy analogue lochnerine (6) could be employed to this end. By performing such a
late stage biaryl coupling, one could not only avoid the potential formation of
atropodiastereomeric intermediates throughout the synthesis, but also take advantage of the
existing chiral centers in the sarpagine unit 6 for maximum stereoinduction. The 5ꢀmethoxyꢀDꢀ
(+)ꢀtryptophan ethyl ester 17 could be employed as the starting material and the chiral transfer
agent for the synthesis of the key pentacyclic framework 16 of the sarpagine alkaloids via the
28
asymmetric PictetꢀSpengler, which on further functionalization would result in the total
synthesis of the target alkaloids.
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Scheme 2. Retrosynthetic Analysis
H
H
H
N
N
H
0
1
2
3
4
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6
7
8
9
0
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2
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0
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7
8
9
0
1
1'
9'
2Cl
HO
RO
H
H
OR
OH
9
H
1
1
nonphenolic
coupling (R = Me)
N
N
H
H
H
OR
(+)-dispegatrine (1)
phenolic oxidative
coupling (R = H)
RO
MeO
9
H
O
OH
H
N
H
11
monomeric
alkaloids (5-12)
source of
stereocontrol
N
N
H
N
H
H
H
H
H
1
6
MeO
6
7
R = Me, (+)-lochnerine
R = H, (+)-sarpagine
H N
2
CO H
2
CO Et
2
NH2
N
H
L-valine
5-methoxy-D-(+)-tryptophan
ethyl ester (17)
Enantiospecific Synthesis of the 5ꢀMethoxyꢀDꢀ(+)ꢀTryptophan Ethyl Ester (17)
Although a number of synthetic routes to substituted tryptophans exist, principally
2
9
30
31
asymmetric hydrogenation, enzymatic synthesis, and more recently Negishi coupling;
attempts to execute these in a practical sense in the laboratory met with only limited success.
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Eventually, two approaches, the regiospecific bromination and the Larock heteroannulation
3
3
previously employed for the synthesis of 5ꢀmethoxyꢀDꢀtryptophan both utilizing the Schöllkopf
chiral auxiliary 18 were reinvestigated.
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Scheme 3. Synthesis of the PropargylꢀSubstituted Schöllkopf Chiral Auxiliary 19
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17
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The palladiumꢀcatalyzed heteroannulation of internal alkynes with oꢀiodoanilines
34
developed by Larock et al. has been successfully employed in this research group for the
synthesis of optically active 6ꢀ and 7ꢀmethoxy tryptophans on a multihundred gram scale which
in turn have resulted in the total synthesis of a number of alkoxy substituted sarpagine indole
35
alkaloids via the asymmetric PictetꢀSpengler reaction. Attempts to employ the Larock
heteroannulation for the synthesis of 17 under similar conditions, however, resulted in lower
3
2b,33
36
yields.
With the success reported in the synthesis of 4ꢀmethoxytryptophan via use of the
TMS substituted propargylic chiral auxiliary 19 (Scheme 3), it was decided to first test the effect
of this alkyne on the regioselectivity of the Larock heteroannulation. If successful, it would
provide a shorter and more efficient synthesis of 5ꢀmethoxytryptophan 17. Since both
regiospecific bromination and Larock heteroannulation employed the Schöllkopf chiral auxiliary,
large scale preparation (500 g) of the Schöllkopf chiral auxiliary 18 from Lꢀvaline and glycine,
37
based on the earlier procedure, was undertaken. The TMS protected chiral auxiliary 19 was
3
6
then prepared according to the modified procedure by Ma et al. in 96ꢀ100% de (Scheme 3).
Larock Heteroannulation
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. Larock Heteroannulation for the Synthesis of 5ꢀMethoxyꢀDꢀTryptophan Ethyl
Ester (17)
0
1
2
3
4
5
6
7
8
9
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1
2
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7
8
9
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2
3
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5
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9
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4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
In order to proceed with the Larock heteroannulation, oꢀiodoaniline 20 was first
3
8
synthesized based on a published procedure. The amino group in pꢀanisidine was protected
39
with a Boc group followed by a Snieckus ortho lithiation with 2.2 equivalents of tertꢀ
butyllithium at –78 °C. Initially, deprotonation of the NH moiety took place, after which the next
equivalent of tꢀbutyllithium provided the ortho lithiated species stabilized by the Boc group. This
process was quenched with diiodoethane to afford the desired Boc protected iodo aniline 20 in
86% yield. With the TMSꢀsubstituted alkyne 19 and the iodoaniline 20 in hand, the annulation
3
6
was carried out according to the recently developed conditions of Ma et al. Gratifyingly, in this
process the starting aniline 20 was consumed entirely on continued stirring for 36 hours and the
N ꢀH protected indoles 21a and 21b were obtained in a combined yield of 81% (Scheme 4).
a
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Hydrolysis of the Schöllkopf chiral auxiliary in 21a (separated by chromatographic separation)
with aqueous 2 N HCl in THF, accompanied by concomitant loss of the silyl group provided the
optically active 5ꢀmethoxyꢀDꢀtryptophan ethyl ester (17) in a single step in 86% yield. From a
practical point of view, this approach to the synthesis of 17 was disappointing. In spite of
replacement of the bulkier TESꢀsubstituted alkyne by the TMS alkyne 19, the regioselectivity of
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
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52
53
54
55
56
57
58
59
60
3
2
this method did not improve. For this reason the earlier regiospecific bromination route for the
preparation of N ꢀHꢀ5ꢀmethoxyꢀDꢀtryptophan ethyl ester (17) was employed. The success of this
a
sequence rested on the ability to scale up the first few steps to multihundred gram levels.
40
The commercially available 3ꢀmethylꢀ5ꢀmethoxyindole (23) was prepared on a 616 g
4
1
scale via the JappꢀKlingmann/Fischer indole protocol developed by Abramovitch and Shapiro
in two steps from pꢀanisidine (Scheme 5). Boc protection of the indole N ꢀH function in 23,
a
32,42
followed by allylic bromination
furnished the crude bromide 24 in greater than 90% yield,
which was directly alkylated with the anion of the Schöllkopf chiral auxiliary (18) at –78 °C to
provide the protected Dꢀtryptophan analogue 25 in 80% yield. Earlier, the Boc group was
32
removed in refluxing xylenes for 7 days; however, the much milder TMSOTf/2,6ꢀlutidine
4
3
system was found to be much more effective. Deprotection of the Boc group in 25 was
achieved on a 50 g scale at 0 °C in 12 hours to furnish the Schöllkopf analog 26 in 93% yield.
Hydrolysis of 26 under aqueous acidic conditions provided the desired optically active N ꢀHꢀ5ꢀ
a
methoxyꢀDꢀtryptophan ethyl ester (17) in 85% yield in greater than 98% ee.
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1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 5. Improved Regiospecfic Bromination Route for the Synthesis of 5ꢀMethoxy
Tryptophan Ethyl Ester (17) on a Large Scale
NaNO , aq HCl;
MeO
2
KOH, ethyl -
ethylacetoacetate;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeO
KOH, EtOH,
reflux, 1 h, 100%;
Me
EtOH/HCl, reflux,
Cu powder,
quinoline,
reflux, 2.5 h, 94%
NH2
N
74%
CO Et
2
H
p-anisidine (616 g)
22 (430 g)
MeO
MeO
(
Boc) O, DMAP,
MeCN, rt, 95%
2
Me
18, n-BuLi,
Br
NBS, AIBN,
cyclohexane,
reflux, > 90%
(50 g)
THF, -78 C,
80%
N
H
N
Boc
2
3 (158 g)
24
MeO
MeO
OEt
OEt
TMSOTf,
2
,6-lutidine,
N
N
DCM,
C - rt, 93%
N
N
N
N
0
Boc
H
OEt
OEt
26
2
5 (55 g)
2
N aq HCl, THF, 85%
17
(>98% ee)
Synthesis of the 5ꢀMethoxypentacyclic Ketone 16
Analogous to the parent system, the transformation of tryptophan 17 into the desired
trans-diester 28b (see Scheme 6) should follow the wellꢀdocumented trans transfer of chirality in
44
the asymmetric PictetꢀSpengler reaction in a straightforward fashion; however, this was not the
case. The electron rich character of the 5ꢀmethoxy indole in 17 facilitated the undesired Pictetꢀ
3
2a
Spengler reaction (with the benzaldehyde imine) as observed for the N ꢀmethyl series;
a
moreover, this 5ꢀmethoxyindole system 28 was not stable in trifluoroacetic acid (TFA)/CH Cl2
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for extended periods of time. Consequently, modifications were made analogous to the work of
3
2
Zhao et al. to carry out the PictetꢀSpengler cyclization and the decarboxylation reaction to
achieve optimum yields and very high diastereoselectivity. As illustrated in Scheme 6,
tryptophan 17, on treatment with benzaldehyde at room temperature, followed by sodium
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
borohydride reduction (at –10 °C) afforded the corresponding N ꢀbenzyltryptophan ethyl ester 27
b
in 93% yield. If the reaction was carried out at room temperature as in the parent system, a 1:1
mixture of 27 and the undesired PictetꢀSpengler product 1ꢀphenyl tetrahydro βꢀcarboline (not
Scheme 6. Synthesis of the 5ꢀMethoxytetracyclic Ketone 31
CO Me
2
MeO
OHC
PhCHO, EtOH,
CO Et
AcOH, CH Cl ,
2
2
2
Na SO , 0 °C, 5 h;
rt, 12 h;
2
4
17
HN
NaBH , -10 °C,
N
TFA, CH Cl ,
4
2
2
H
Ph
93%
4 d, 93%
(
29 g)
2
7 (21 g)
MeO
MeO
CO Et
2
NaH, MeOH
CO Et
2
Ph
toluene, reflux,
N
N
H
Ph
N
N
3
d, 88%
H
O
CO Me
29
2
trans-28b (10 g)
MeO
MeO
4
1
0% aq KOH,
,4-dioxane,
reflux, 48 h,
2%
H
H
OH
Ph
CO Me
O
N
N
N
H
N
8
H
H
2
H
Ph
30 (18 g)
31
5-methoxy tetracyclic ketone
32
shown) were observed as reported earlier by Zhao et al. However, PictetꢀSpengler reaction of
tryptophan derivative 27 with the aldehyde, methyl 3ꢀformylpropanoate, in AcOH/CH Cl2
2
afforded a mixture of transꢀ and cisꢀdiesters in nearly quantitative yield. If TFA/CH Cl was
2
2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
employed in this step in place of AcOH/CH Cl , decomposition of much of the N ꢀbenzyl
2
2
b
tryptophan 27 was observed. However, on completion of the PictetꢀSpengler reaction in acetic
acid, one equivalent of TFA was added to epimerize all of the cis isomer into the desired transꢀ
diester 28b in 93% yield. Dieckmann cyclization of 28b was followed by a base mediated
hydrolysis/decarboxylation sequence to provide the optically pure tetracyclic ketone 31 (Scheme
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
5
6
). Based on the work of Wang, under normal basic conditions, the δꢀlactam 29 was initially
formed. Then, in the presence of a large excess of sodium methoxide in refluxing toluene under
4
5
the same reaction conditions employed for the parent tryptophan system for an extended period
of time (72 hours), the desired Dieckmann product 30 was obtained in 88% yield (see Scheme 6).
The key to success in the Dieckmann cyclization is the controlled stirring rate and temperature
for 3 days. A base induced decarboxylation worked smoothly to provide the tetracyclic ketone 31
in 82% yield.
Scheme 7. Synthesis of the 5ꢀMethoxypentacyclic Ketone 16
Catalytic debenzylation of 31, under acidic conditions furnished the 10ꢀmethoxy N ꢀH
b
tetracyclic ketone 32 in 92% yield (Scheme 7). N ꢀalkylation of the secondary amine 32 with (Z)ꢀ
b
4
6
1ꢀbromoꢀ2ꢀiodoꢀ2ꢀbutene
under the conditions developed in Milwaukee (dry
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32,45
THF/K CO /reflux)
led to the formation of the desired product 33, but the reaction was very
2
3
sluggish, and led to a formation of a considerable amount of baseline impurities. Since
substitution by amines on bromides was clearly an S 2 type process and it is well known that the
N
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
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37
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39
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41
42
43
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45
46
47
48
49
50
51
52
53
54
55
56
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58
59
60
nucleophilic strength is dependent on the solvent employed in the S 2 reaction, it was decided to
N
increase the nucleophilicity of the amine 32 by employing a more polar aprotic solvent. Dry
acetonitrile proved to be the most suitable solvent for this process for the reaction went to
completion at room temperature to give 33 in 76% yield. Attempts to increase the yield by
adding more bromide were not successful. Initial attempts at executing the key enolate mediated
47
palladium catalyzed cyclization of ketone 33 under the modified conditions furnished the
desired pentacyclic ketone 16, albeit in lower yields (50%). The lower yields could be due to a
combination of the stronger base (tꢀBuONa) and the electron rich aromatic system in 33, which
led to a faster E2 elimination and formation of the unwanted acetylene byproduct (not shown)
before the oxidative addition of the vinyl iodide took place. This problem was circumvented by
subjecting the vinyl iodide 33 to the much milder conditions [PhOK/Pd(PPh ) ] of Bonjoch et
3
4
48
al. to furnish the desired pentacyclic ketone 16 in 73% yield.
The Regiospecific, Stereospecific Total Synthesis of (+)ꢀSpegatrine (2), (+)ꢀ10ꢀ
Methoxyvellosimine (5), (+)ꢀLochnerine (6), (+)ꢀSarpagine (7), (+)ꢀLochvinerine (11) and
(+)ꢀLochneram (11)
With the key Eꢀethylidene intermediate 16 in hand conversion into the desired αꢀ
aldehyde present in (+)ꢀ10ꢀmethoxyvellosimine (5) was accomplished by a Wittigꢀhydrolysisꢀ
epimerization sequence (Scheme 8). The one carbon homologation process was achieved by a
Wittig reaction, followed by acidic hydrolysis of the corresponding two steroisomeric enol
methyl ethers (not shown), to afford the theromodynamically stable αꢀaldehyde in 5 in 90%
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
yield. The aldehyde function of 5 was then reduced with sodium borohydride to provide (+)ꢀ
lochnerine (6). As illustrated in Scheme 8, demethylation of (+)ꢀlochnerine (6) was achieved
with 5 equivalents of BBr in dry CH Cl at –78 °C for 1 hour, after which the solution was
3
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
allowed to warm to room temperature and stirred for an additional 4 hours. Following work up,
(+)ꢀsarpagine (7) was obtained in 80% yield. Subsequent quaternization of the N ꢀnitrogen
b
function in 7 with excess methyl iodide provided the N ꢀmethiodide salt, which on stirring with
b
49
silver chloride in ethanol furnished (+)ꢀspegatrine chloride (2). Lochnerine (6) on Nbꢀ
methylation under similar conditions provided (+)ꢀlochneram (11) in 85% yield. The spectral
data for the synthetic 2, 5ꢀ7 and 11 were in good agreement with that reported for the natural
1
a
products and resulted in the first total synthesis of these alkaloids.
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Scheme 8. Completion of the Total Synthesis of (+)ꢀSpegatrine (2), (+)ꢀ10ꢀ
Methoxyvellosimine (5), (+)ꢀLochnerine (6), (+)ꢀSarpagine (7), and (+)ꢀLochneram (11)
MeO
MeO
H
O
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
H
N
H
N
CH OCH PPh Cl,
t-BuOK,
benzene/THF;
3
2
3
CHO
N
H
N
H
2
N aq HCl/THF,
55 °C, 90%
H
H
H
H
5
16
(+)-10-methoxyvellosimine
NaBH4 ,
EtOH, 0 °C,
90%
8
h
HO
MeO
H
H
OH
OH
H
N
H
N
BBr , CH Cl ,
3
2
2
-78 °C to rt,
N
H
N
H
80%
H
H
H
6
H
7
(+)-sarpagine
(+)-lochnerine
CH I (excess), MeOH, rt,
3
CH I (excess),
MeOH, rt, 24 h
3
8
5%
24 h; AgCl, MeOH, rt, 2 d
85%
HO
MeO
H
OH
Cl
H
H
N
OH
H
N
I
N
N
H
H
H
H
H
H
2
11
(+)-spegatrine
(+)-lochneram
In order to synthesize the βꢀalcohol at Cꢀ16 in lochvinerine (9), the chemoselective
50
hydroboration developed earlier was employed. Wittig reaction of the ketone 16 was then
carried out with triphenylphosphonium bromide in benzene in the presence of potassium tꢀ
butoxide to afford the diene 34 in 90% yield (Scheme 9). Analogous to earlier reports, the 9ꢀ
BBN reagent was chosen as the hydroborating agent to facilitate attack from the less hindered
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
50
face of the C16ꢀC17 double bond relative to the C19ꢀC20 site. Lochvinerine (9) was obtained
as the only detectable diastereomer after the hydroborationꢀoxidation sequence. The proton NMR
2
1
spectrum of 9 was in agreement with that of the natural product although some difference was
observed in chemical shifts of the reported and observed values of protons. This was mainly due
to the presence of methanol in the synthetic sample. The synthetic sample retained methanol
even after drying the compound under high vacuum for extended periods of time.
Scheme 9. Completion of the Total Synthesis of (+)ꢀLochvinerine (9)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeO
MeO
O
H
N
H
N
MePPh Br, t-BuOK,
3
benzene/THF,
92%
N
N
H
H
H
H
H
H
16
34
MeO
OH
H
N
H
9
-BBN, 0 °C to rt, 1.5 h;
NaBO 4H O,
3
2
N
0 °C to rt, 2 h,
75%
H
H
H
9
(+)-lochvinerine
Direct/Intermolecular Biaryl Coupling
The biaryl core is an important subunit found in a large number of natural products such
as alkaloids, coumarins, flavonoids, lignanes, polyketides tannins and terpenes. In particular,
axially chiral biaryls are important as chiral ligands in asymmetric synthesis. Because of their
interesting biological activity and complex architecture, natural and unnatural biaryls are
51
considered as attractive synthetic targets. For this reason considerable efforts have been made
in recent decades for the efficient asymmetric synthesis of biaryls both in the intramolecular and
5
1,52
the intermolecular mode and have been the subject of many reviews.
Particularly noteworthy
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51a
is the review by Bringmann et al. which focusses on enantioselective methods employed for
the total synthesis of complex biaryl natural products.
Within the area of intermolecular biaryl synthesis, the two most common approaches
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
52c
52,54
employed are: (1) oxidative coupling
and (2) reductive coupling such as Ullmann,
52,55
52,56
52,57
Suzuki,
Stille
or Cꢀ H activation
etc. Oxidative phenolic coupling is a powerful and
economical method for the synthesis of biaryl compounds and is especially suited to natural
5
8
product synthesis since many of the biosynthetic routes to biaryls involve such a coupling.
Although considerable progress has been made in carrying out the intramolecular oxidative
couplings, in the absence of activating groups, the position of the newly formed CꢀC bond is
determined by the electronic and steric preferences of the substrate and can lead to regioisomeric
5
2c,53c
reaction products in complex substrates especially in the intermolecular mode.
The coupling
mechanism is believed to involve either one twoꢀelectron or two oneꢀelectron oxidations to form
52c,59
an aryl–aryl coupled dimer through the ortho and/or para positions.
In the case of phenols
bearing no orthoꢀ and paraꢀsubstituents, the ortho-ortho, ortho-para and para-para coupling
reactions occur, giving rise to often unseparable mixtures. In some cases competing and/or
subsequent oxidation to form quinones occurs, either from the coupled product or from the
original substrate. Thus it is not always predictable which of the possible products will be formed
predominantly, consequently, thorough optimization of the oxidizing agent/reaction conditions is
required for successful transformations.
The Lewisꢀ acid catalyzed direct oxidative nonꢀphenolic coupling of two
6
0
unfunctionalized arenes or the Scholl reaction is one of the oldest CꢀC bond forming reactions
and has been extensively used for the intramolecular oxidative dehydrodimerization of branched
phenylene precursors to the corresponding polycyclic aromatic hydrocarbons (PAHs) such as
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5
5
5
5
5
5
5
5
6
61
triphenylenes, hexaꢀperiꢀhexabenzocoronenes (HBCs) etc.
and for the synthesis of
6
2
hexaalkoxytriphenylenes. Various strong acids (Brønsted acids/Lewis acids) and metal salts are
6
0
generally used in combination with an oxidant (O , KMnO , RNO ). Variants of the reaction
2
4
2
0
1
2
3
4
5
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9
0
1
2
3
4
5
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1
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4
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8
9
0
1
2
3
4
5
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7
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9
0
1
2
3
4
5
6
7
8
9
0
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64
3,
65
include oxidants such as: FeCl , CuCl , or Cu(OTf) with AlCl
Tl(O CCF ) /BF ꢂOEt
2 3 3 3 2,
3
2
2
66
67
68
III
Pb(OAc) /BF ꢂOEt ,
MoCl5,
SbCl5,
and (CF CO ) I C H
[phenyliodine(III)
4
3
2
3
2 2
6
5
6
9
bis(trifluoroacetate): PIFA]/BF ꢂOEt in CH Cl . Electrochemical oxidations of electronꢀrich
3
2
2
2
7
0
aryl compounds have been reported, but are not commonly used. Based on the observations of
7
1
King et al. the outcome of the Scholl reaction of substituted substrates follows the directing
group effects observed in electrophilic aromatic substitution. Alkoxy and alkyl groups are
effective o,pꢀ directors, whereas deactivating mꢀdirectors (e.g. NO ) suppress the reaction rate. A
2
variety of electronꢀrich substrates such as alkyl/alkoxy substituted aryl compounds have been
successfully dimerized using the above mentioned combinations. While a majority of these CꢀC
bond forming reactions are reported in the intramolecular mode, very few cases are reported in
the intermolecular mode, albeit in substrates with simpler systems, or in substrates with
substitution patterns such as to prevent side reactions.
Among the reductive coupling processes, the Suzuki reaction is the most widely used
method often affording good to high yields of the coupled products with predictable
5
5
regioselectivity. However, the advantages of employing preꢀactivated aryl components can be
offset by the requirement for their independent preparation in cases where multiple synthetic
steps are required, especially on a large scale. Also since no standard procedures are available,
each new catalyst and substrate requires time consuming optimization of the particular reaction
conditions.
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Reductive CouplingꢀModel Reaction
As per the retrosynthetic plan, both oxidative (phenolic and Schollꢀtype) or reductive
cross coupling could be employed to form the C9ꢀC9′ bond in 1. Although biomimetic oxidative
phenolic coupling still stands as a practical method for the synthesis of many biaryls, the
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1
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negligible yield obtained during the oxidative phenolic coupling of 2 by Lin et al. made it the
weakest method of choice. In order to avoid the potential problems associated with phenolic
oxidative couplings it was thus decided to employ a nonꢀphenolic coupling reaction for the
construction of the biaryl axis in 1. A nonꢀphenolic oxidative coupling of the sarpagine alkaloid
(
+)ꢀlochnerine (6), which contains all the chiral information required, could be attempted to this
end. The quaternary alkaloid lochneram (11) could also serve the same purpose but could affect
the isolation/purification process due to it polar nature. The nonꢀphenolic coupling could either
be a reductive crossꢀcoupling or a Scholl type direct oxidative coupling.
Taking into consideration the pros and cons of both types of coupling reactions, it was
decided to first study the biaryl coupling on a more robust model indole substrate. By doing so
one would be able to compare the results of both reactions on the same substrate and then select
the best method for coupling the sarpagine alkaloid 6. It would also give one a chance to study
the effect of oxidative dimerization conditions on the more sensitive 5ꢀmethoxy sarpagine
substrate, especially due to lack of literature precedent for such transformations. Additionally,
the supposition that the natural sarpagine framework was indispensable for complete asymmetric
induction in the formation of the biaryl axis could also be assessed. Tetrahydro βꢀcarboline 35,
the N ꢀmethyl analogue of 28b, was chosen as the model substrate for this purpose. In order to
a
perform any type of reductive coupling reaction (such as the Ullmann, Suzuki, Stille etc.) on 35,
it was necessary to first synthesize the corresponding aryl halide coupling partner.
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6
Synthesis of the Aryl Halide Coupling Partners 36a/37a
Due to the moderate reactivity of iodine, electrophilic iodination of aromatic compounds
requires the use of an appropriate oxidant for efficient transformation. Numerous methods
employing iodonium donating agents have been developed over the years; many of which
0
1
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2
employ harsh reaction conditions and longer reaction times. Initially, a milder method for
7
3
iodination with Nꢀiodosuccinimide (NIS) and catalytic TFA, reported by Colobert et al. was
employed for iodination of the model substrate 35. Although the reaction proceeded at room
temperature in acetonitirile, longer reaction times (16 hours) were required for complete
conversion of 35 and the regiosiosmers 36a and 36b were obtained in a combined yield of 80%
(Scheme 10). For synthesis of the corresponding aryl bromide, an NBS/TFA system provided the
7
4
optimum yield of the desired product 37a. Recently Moorthy et al. reported an expedient
protocol for iodination of a variety of electron rich and electronꢀpoor aromatic compounds using
an IBXꢀI redox couple. The high yields and very short reaction times were attributed to the
2
rapid generation of 4 equivalents of iodonium ions per equivalent of IBX, thereby increasing the
rate of the reaction even for electron poor substrates. As illustrated in Scheme 10, iodination of
the model substrate 35 under these conditions resulted in a much faster (8 hours) and a cleaner
reaction, with the desired product 36a formed in 82% yield. The regiochemistry of iodination in
36a was also confirmed by Xꢀray analysis (See SI).
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Scheme 10. Electrophilic Halogenation of 35
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36
37
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39
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48
49
50
51
52
53
54
55
56
57
58
59
60
Attempted Ullman Coupling Reaction
With the appropriate aromatic halides 36a and 37a in hand, the Ullmann reductive
54
coupling to form the C7ꢀC7′ bond was first investigated. Similar to other reductive coupling
processes, various protocols of the Ullmannꢀtype coupling procedures have been developed;
however, very few are suitable for atropselective synthesis of biaryls mainly due to the harsh
conditions (multiꢀhour reactions at temperatures >100 °C) required to obtain high yields of the
desired biaryl. Such harsher conditions could lead to racemization of the biaryls and are thus not
55e
useful.
Illustrated in Table 1 are the various attempts to perform the Cuꢀmediated Ullmann
coupling reaction of 36a and 37a. In spite of using up to 8 equivalents of activated Cuꢀpowder at
very high temperatures, either no conversion or complete decomposition of the starting materials
36a and 37a was observed (Table 1, entries 3ꢀ5). A copper(I)ꢀthiopheneꢀ2ꢀcarboxylate (CuTC)
7
5
protocol developed by Liebskind et al. was also tested on both the aryl iodide 36a and bromide
7a (Table 1, entries 2 and 6) but failed to provide the desired product. After the failure of the
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Ullmann reaction to dimerize the model substrate 36a/37a, the Suzuki reductive coupling
5
5
process was next attempted. To accomplish this, the aryl boronate ester coupling partner from
the corresponding aryl halide had to be prepared.
0
1
2
3
4
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8
9
0
1
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9
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2
3
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Table 1. Attempted CopperꢀMediated Ullmann Coupling Reaction of 36a and 37a
Entry
Reaction Conditions
Results
SM only
SM only
5
3b
1
.
Cu powder (2.5 equiv), DMF, 100 °C, 12 h
2.
3.
CuTC (3.0 equiv), Nꢀmethyl 2ꢀpyrrolidine, 70 °C, 72 h
Activated Cu powder (8 equiv), DMF, reflux, 72 h
SM only
SM only
4.
5.
6.
Activated Cu powder (8 equiv), Nꢀmethyl 2ꢀpyrrolidine,
sealed tube, sand bath, 140 °C, 26 h
Activated Cu powder (8 equiv), Nꢀmethyl 2ꢀpyrrolidine,
decomposition
decomposition
sealed tube, sand bath, 140 °C, 72 h
CuTC (8 equiv), Nꢀmethyl 2ꢀpyrrolidine, sealed tube, sand
bath, 140 °C, 26ꢀ72 h
CuTC: copper(I)ꢀthiopheneꢀ2ꢀcarboxylate; SM: Starting materials 36a or 37a
.
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Synthesis of the Aryl Boronic Ester Coupling Partner
The palladium catalyzed cross coupling reaction of (Bpin) with haloarenes developed by
2
5
5d,e
Miyaura et al.
provided a direct procedure for the synthesis of aryl boronic esters from aryl
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60
halides. Application of these borylation conditions in the system under study here furnished the
desired aryl boronate 39 in 55% yield, accompanied by a large amount of the
hydrodehaolgenation species 35 (Table 2, entry1). Performing the reaction at a lower temperature
with Pd(PPh ) as the catalyst, did decrease the amount of the byproduct 35 but also left some
3
4
starting material (36a) unreacted (as observed on TLC). Based on the initial findings of Masuda
76
77
78
et al. and reports by Buchwald et al. and Baudoin et al., it was found that a palladiumꢀ
catalyzed coupling of pinacolborane with aryl halides in presence of a tertiary amine as a base,
especially Et N, prevented the pinacolborane from acting as a hydride donor and thus avoided
3
formation of the undesirable ArꢀH byproduct (35 in this case). As illustrated in Table 2 (entries 3ꢀ
8), a careful optimization of the reaction by varying the palladium source and the ligand, finally
led to a combination of Pd(OAc) with the more electronꢀrich and bulkier ligand 2ꢀ
2
(dicyclohexylphosphanyl)biphenyl (DCPB) to provide 93% yield of the arylboronate 39 (Table
2, entry 8).
Table 2. Synthesis of the Aryl Boronic Ester Coupling Partner 39
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6
Boron
Source
Temp.
Solvent (Time)
a
b
c
d
Pd Source
Ligand
Base
Results
1
2
3
4
5
6
7
8
(Bpin)
2
Pd(dppf)Cl2
(10 mol %)
ꢀ
KOAc
KOAc
DMSO
DMSO
dioxane
dioxane
dioxane
dioxane
dioxane
100 °C
(10 h)
39(55%) +
35 (30%)
(
(
4 equiv)
e
0
1
2
3
4
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7
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9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
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0
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9
0
1
2
3
4
5
6
7
8
9
0
(Bpin)
Pd(PPh3)4
ꢀ
80 °C
(15 h)
36a + 39 + 35
2
4 equiv)
(
10 mol %)
e
HBpin
Pd(MeCN)
Cl2
DCPB
Et
Et
Et
Et
Et
N
N
N
N
N
110 °C
(3 h)
36a + 39
2
3
3
3
3
3
(3 equiv)
HBpin
(20 mol %)
(
5 mol %)
e
Pd(MeCN)
Cl2
DCPB
110 °C
(3 h)
36a +39
2
(
3 equiv)
(40 mol %)
(10 mol %)
e
HBpin
3 equiv)
Pd(MeCN)
Cl2
XPhos
100 °C
(3 h)
36a + 39 + 35
2
(
(20 mol %)
(
5 mol %)
HBpin
(3 equiv)
Pd(OAc)2
5 mol %)
DPEPhos
(10 mol %)
100 °C
(3 h)
39 (78%) +
35 (15%)
(
HBpin
3 equiv)
Pd(OAc)2
(5 mol %)
DCPB
110 °C
(3 h)
39 (80%) +
35 (10%)
(
(20 mol %)
HBpin
3 equiv)
Pd(OAc)2
DCPB
(20 mol %)
Et
N
dioxane 100 °C
(3 h)
39 (93%) +
35 (3%)
3
(
(
5 mol %)
a
b
(
Bpin) : Bis(pinacolato) diboron; HBpin: Pinacol borane; DCPB: 2ꢀ(Dicyclohexylphosphanyl)biphenyl; DPEPhos: Bis(2ꢀ
2
c
phenylphosphinophenyl)ether; XPhos: 2ꢀDicyclohexylphosphinoꢀ2′,4′,6′ꢀtriisopropylbiphenyl; 3 equiv of base was employed;
d
e
isolated yields; not separated.
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Suzuki –Miyaura Coupling (SMC)
Table 3. SuzukiꢀMiyaura Coupling (SMC) Reaction
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19
20
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22
23
24
25
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34
35
36
37
38
39
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45
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47
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49
50
51
52
53
54
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56
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58
59
60
Pd
Source
Temp. (°C)/
Time (h)
a,b
c,d
e,f
g
ArX
36a
37a
36a
36a
36a
36a
Ligand
Base
Solvent
Results
35 + 36a
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DCPB
DCPB
K PO4 dioxane:H O
100/24
100/24
100/24
100/24
100/24
100/24
2
3
K PO4 dioxane:H O
35 + 37a
3
2
DCPB
CsF
dioxane
35 + 36a
K PO4
XPhos
Tol:H O
35 + 36a
3
2
DavePhos
SPhos
K PO4
Tol:H O
35 + 36a
2
3
K PO4
Tol:H O
35 + 36a
3
2
3
8a (20%)+38b
(10%) + 35 (15%)
36a (13%)
7
36a
Pd(OAc)2
Pd(OAc)2
SPhos
K PO4
THF:H O
50/24
2
3
+
3
8a (37%) + 38b
18%) + 35 (20%)
8
36a
36a
SPhos
K PO4
THF:H O
50/48
3
2
(
9
Pd (dba)3
SPhos
K PO4
THF:H O
50/48
38a (38%) + 38b
19%) + 35 (20%)
2
3
2
(
a
b
c
5
mo % of Pd(OAc)2; 2.5 mol % of Pd (dba) ; Ligands: DCPB: 2ꢀ(Dicyclohexylphosphanyl)biphenyl; XPhos: 2ꢀ
2
3
Dicyclohexylphosphinoꢀ2′,4′,6′ꢀtriisopropylbiphenyl; DavePhos: 2ꢀDicyclohexylphosphinoꢀ2′ꢀ(N,Nꢀdimethylamino)biphenyl;
d
e
f
SPhos: 2ꢀDicyclohexylphosphinoꢀ2′,6′ꢀdimethoxybiphenyl; 20 mol % of ligand; 2 equiv. of K PO ; 8 equiv. of CsF;
3
4
g
solvent:H O/10:1.
2
With the appropriate aromatic halides (36a and 37a) and aryl boronate ester 39 in hand,
the Suzuki coupling reaction of these diꢀortho substituted coupling partners was next attempted.
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6
The synthesis of hindered biaryls via the Suzuki reaction, especially of substrates containing
large ortho substituents, and/or ortho, ortho' substituents has been shown to be a challenging
7
3,77
task.
The difficulty in such transformations can be increased in cases where the substrate has
0
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electronꢀdonating groups thereby slowing down the oxidativeꢀaddition process. More recently
the bulky and electronꢀrich, monodentate dialkylbiarylphospine ligands, synthesized by
7
7
Buchwald et al. were shown to improve the efficiency of such couplings. The superior activity
of the catalysts derived from the biarylphosphine ligands was attributed to a combination of
electronic and steric properties that enhanced the rates of oxidative addition, transmetalation, and
reductive elimination steps in the catalytic cycle.
Outlined in Table 3 are the different catalyst systems that were employed to carry out the
Suzukiꢀcoupling reactions of the aryl halides 36a and 37a with the boronate ester 39. Based on
79
the various synthetic applications
a general reaction system of Pd(OAc) /dialkylꢀ
2
biarylphospine ligand in a 1:4 ratio was employed with different solvents and bases (Table 3).
Initial couplings with 20 mol % of the DCPB, XPhos and DavePhos ligands, in presence of a
milder base (K PO ), resulted in mixtures of hydrodehaolgenation byproduct 35 and unreacted
3
4
starting material 36a/37a (Table 3, entries 1ꢀ5). Employment of the more efficient, electronꢀrich
7
9
and bulkier SPhos ligand also yielded similar result (Table 3, entry 6). It was possible that a
combination of basic reaction conditions at higher temperature was responsible for the extensive
hydrodehaolgenation. In order to circumvent this it was decided to employ THF as the coꢀ
solvent. The low boiling point and higher dielectric constant of THF provided a more
homogenous reaction medium at a lower temperature. This change reduced the excessive
hydrodehaolgenation taking place and a combined yield of 30% was obtained in favor of the
M(R)ꢀatropdiastereomer (Table 3, entry 7). Stirring the reaction mixture for a longer time led to
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complete conversion of the starting material 36a, and a 54% combined yield of the
atropodiastereomers was observed (Table 3, entry 8). Use of Pd (dba) also provided similar
2
3
results (Table 3, entry 9). At this point no further optimization was performed. Subsequently, the
more direct Schollꢀtype oxidative dehydrodimerization of the model substrate 35 was attempted.
Scholl Type Oxidative Dehdyrodimerizationꢀ Model Reaction
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
With samples of the atropdiastereomeric biaryls (38a and 38b) obtained from the Suzukiꢀ
Miyaura coupling on the model substrate 35 in hand, the desired products could now be
identified from a potential mixture of regioisomers which could arise during the oxidative
coupling of the model substrate. Since one was examining the effect of existing chiral centers on
the atropselectivity, it was decided to use achiral catalysts for this process. Of the various
protocols of the Scholl type oxidation discussed earlier, it was decided to carry out a hypervalent
69,80
iodine(III) mediated protocol developed by Kita et al.
and a thallium(III) mediated oxidative
6
5,81
dehydrodimerization approach developed by Taylor et al.
Both methods employ a
combination of a two electron oxidant and a Lewis acid (BF ꢂEt O) in polar aprotic solvents such
3
2
as CCl , CH Cl or MeCN, at temperatures ranging from –78 °C to room temperature. Although
4
2
2
6
9,82
hypervalent iodine(III) has been extensively used for intramolecular coupling reactions,
there
7
8a,83
has been little progress made in the intermolecular mode.
successfully employed intramolecularly for the synthesis of isoquinoline alkaloids, lignans
Thallium(III) has also been
8
4
85
8
6
87
and colchinol derivatives as well as aporphine alkaloids. Effective oxidative dimerizations of
88
89
2
ꢀsubstituted indoles, and indolocarbazoles by thallium(III) trifluoroacetate have also been
reported. The intermolecular oxidative dimerization of a polysubstituted indole core by Keller et
9
0
al. provided a suitable precedent for which to effect the oxidative dimerization in the system
under study here.
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