Concise Total Synthesis of (?)-Affinisine Oxindole, (+)-Isoalstonisine, (+)-Alstofoline, (?)-Macrogentine, (+)-Na-Demethylalstonisine, (?)-Alstonoxine A, and (+)-Alstonisine

Article abstract of DOI:10.1002/chem.201703572

A highly enantio- and diastereoselective strategy to access any member of the sarpagine/macroline family of oxindole alkaloids via internal asymmetric induction was developed from readily available d-(+)-tryptophan. At the center of this approach was the diastereospecific generation of the spiro[pyrrolidine-3,3′-oxindole] moiety at an early stage via a tert-butyl hypochlorite-promoted oxidative rearrangement of a chiral tetrahydro-β-carboline derivative. This key branching point determined the spatial configuration at the C-7 spiro center to be entirely 7R or 7S. Other key stereospecific processes were the asymmetric Pictet–Spengler reaction and Dieckmann cyclization, which were scalable to the 600 and 150 gram levels, respectively. Execution of this approach resulted in first enantiospecific total synthesis of (+)-isoalstonisine and (?)-macrogentine from the chitosenine series (7R), as well as (+)-alstonisine, (+)-alstofoline, (?)-alstonoxine A and (+)-N_a-demethylalstonisine from the alstonisine series (7S).

Full text of DOI:10.1002/chem.201703572

A Journal of
Accepted Article
Title: Concise Total Synthesis of (-)-Affinisine Oxindole, (+)-
Isoalstonisine, (+)-Alstofoline, (-)-Macrogentine, (+)-Na-
Demethylalstonisine, (-)-Alstonoxine A and (+)-Alstonisine
Authors: Michael Rajesh Stephen, Md Toufiqur Rahman, V.V.N.
Phani Babu Tiruveedhula, German O. Fonseca, Jeffrey R.
Deschamps, and James M. Cook
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To be cited as: Chem. Eur. J. 10.1002/chem.201703572
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Chemistry - A European Journal
10.1002/chem.201703572
Concise Total Synthesis of (-)-Affinisine Oxindole, (+)-Isoalstonisine,
+)-Alstofoline, (-)-Macrogentine, (+)-N -Demethylalstonisine,
-)-Alstonoxine A, and (+)-Alstonisine
(
a
(
a
a
a
Michael Rajesh Stephen, M. Toufiqur Rahman, V.V.N. Phani Babu Tiruveedhula, German
a
b
a,
O. Fonseca, Jeffrey R. Deschamps, and James M. Cook *
aDepartment of Chemistry & Biochemistry, University of Wisconsin—Milwaukee, 3210
North Cramer Street, Milwaukee, Wisconsin 53211, United States
bCenter for Biomolecular Science and Engineering, Naval Research Laboratory, Code 6930,
Washington, DC 20375, United States
Abstract:
A highly enantio- and diastereoselective strategy to access any member of the
sarpagine/macroline family of oxindole alkaloids via internal asymmetric induction was
developed from readily available D-(+)-tryptophan. At the center of this approach was the
diastereospecific generation of the spiro[pyrrolidine-3,3'-oxindole] moiety at an early stage via
a tert-butyl hypochlorite-promoted oxidative rearrangement of a chiral tetrahydro-β-carboline
derivative. This key branching point determined the spatial configuration at the C-7 spiro center
to be entirely 7R or 7S. Other key stereospecific processes were the asymmetric Pictet-Spengler
reaction and Dieckmann cyclization, which were scalable to the 600 gram and 150 gram levels,
respectively. Execution of this approach resulted in first enantiospecific total synthesis of (+)-
isoalstonisine and (-)-macrogentine from the chitosenine series (7R), as well as (+)-alstonisine,
(
+)-alstofoline, (-)-alstonoxine A and (+)-N
7S).
a
-demethylalstonisine from the alstonisine series
(
Key words: Enantiospecific total synthesis; Sarpagine and Macroline; Spirooxindole
Alkaloids; Alstonisine and Chitosenine.
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Introduction
Oxindole alkaloids form an important group of monoterpene alkaloids that contain the
spirocyclic oxindole nucleus (see Figure 1, 1-11 for some examples).[1],[2] It is still not
clear whether oxindole alkaloids serve a specific function in plant species or are simply
present as indole alkaloid catabolites, but biogenetic considerations of Le Quesne
suggest that the indole alkaloid alstonerine (5) may serve as a precursor to alstonisine
(1
).[3] Oxindole alkaloids are often associated with significant pharmacological
[
4]
activity. The Gardneria oxindole alkaloids such as chitosenine (
exhibit short-lived inhibitory activity in vivo of ganglionic transmission in both rats and
rabbits.[4b] The spirocyclic oxindole
, prepared by Sakai and co-workers as an analogue
of
, has been employed in a formulation known to inhibit ulcers.[5] The bisindole
gardmultine (10), which was isolated from Gardneria multiflora, displayed antitumor
6) and alkaloid I (8)
9
8
activity.[5a, 6] The alkaloids
6 and 8 are the two monomeric bases that comprise the
structure of bisindole 10.[6]
Figure 1. Representative oxindole alklaloids
2
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A number of alkaloids from Alstonia angustifolia have been reported to possess potent
antimalarial activity;[4c-g] however, none of the Alstonia oxindoles 1-4 have been
evaluated biologically in detail because of the paucity of isolated material.
Alstonisine (1), the first reported macroline-related oxindole alkaloid, was isolated by
Elderfield and Gilman from Alstonia muelleriana Domin in 1972.[7] The original
structure and relative configuration of this alkaloid were established through single-
[
8]
crystal X-ray analysis by Nordman et al. However, the absolute configuration reported
for this molecule was chosen to agree with that deduced for ajmalicine and resulted in
an incorrect representation of the structure of alstonisine (1).[ The structures of
8]
alstonisine (
would on this basis, presumably, also be incorrect.[4c] The absolute configuration of
alstonisine ( ) was later determined by a biomimetic transformation of alstonisine (
into talpinine by Le Quesne et al. However, direct confirmation of the configuration
at the spirocenter had not been reported. After this initial report, alstonisine ( ) was also
1
) and N
b
-demethylalstophylline oxindole (3) illustrated by Wong et al.
1
1)
[
3]
1
found in the plant species, Alstonia angustifolia and A. macrophylla.[4c],[9] Other
macroline-related oxindole alkaloids have been isolated from A. macrophylla Wall,
including alstonal (
2
),[4c]
N
b
-demethylalstophylline oxindole (
3
),[10] and 16-hydroxy-N
-
b
demethylalstophylline oxindole (4).[ All of these macroline-related oxindole alkaloids
11]
1
-4 contain the 8-azabicyclo[3.2.1]nonane substructure represented in oxindole 12. The
structures of oxindole alkaloids and were determined by NOE spectroscopic
experiments and are believed to be correct, since they correlate well with previously
reported biogenetic proposals.[3, 10-11] The Gardneria alkaloids
11 also contain the
spirocyclic oxindole system present in 12, but the configuration at the spirocyclic C(7)
carbon atom is opposite [C-7(R)] to the proposed structure of alstonisine ( ). The
structure of gardmultine (10) was deduced by chemical and spectroscopic evidence[5a,
2
3
6
-
1
5
c]
and was confirmed by single-crystal X-ray analysis.[5b] The structure of alstonisine
(
1
) [especially the configuration at the spirocenter C(7)], however, had not been
unambiguously established previous to the report of Wearing et al. as mentioned
above.[2c, 8, 12]
The enantiospecific total synthesis of
1 via the asymmetric Pictet-Spengler reaction
was used to establish the absolute configuration of all chiral centers in (+)-alstonisine.
This was confirmed as C-7(S) by NOE spectroscopic experiments and further verified
by single-crystal X-ray analysis at low temperature with a Cu source.[2d] Once the
3
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structure and optical rotation were found to be the same as (+)-alstonisine from A.
muelleriana isolated by Elderfield, a sample of synthetic (2 mg) was admixed with a
sample of natural alstonisine (2 mg) from A. muelleriana, kindly provided by
1
1
1
3
Professor Le Quesne. The C NMR spectrum of this material contained only one set of
carbon signals, which were identical to those found in the spectrum of the natural
alkaloid (+)-alstonisine (1) from A. muelleriana. This confirmed unambiguously the
structure of
alstonisine reported by Nordman (X-ray crystallography) in 1963 was drawn incorrectly
and actually was the enantiomer of natural alstonisine ( ). In addition, the structures of
1 and the absolute configuration at C(7) as S. The original structure of
1
the two oxindoles in the report of Wong et al.[4c] were illustrated incorrectly. This work
stimulated interest in the synthesis of other macroline-related oxindole alkaloids in our
laboratory.
A general retrosynthetic strategy is depicted in Scheme 1. The common intermediate for
those oxindole alkaloids in the [C-7(S)]-series (the top of Scheme 1) would be the N
H-tetracyclic ketone oxindole (16). The later intermediate would arise from the tert-
butyl hypochlorite-promoted oxidation-rearrangement sequence of the important N -H-
b
-
b
tetracyclic ketone (15). The asymmetry of this tetrahydro-β-carboline would be
constructed by means of the modified Pictet-Spengler reaction followed by a
Dieckmann cyclization in a two-pot process from D(+)-tryptophan, as reported
earlier.[12a, 13] An analogous reasoning applies to those natural oxindole alkaloids in the
C-7(R)-series (bottom of Scheme 1). In this case, the N
oxindole (14) would be the common oxindole precursor. The presence of a bulky
protecting group on the N -nitrogen atom in the N -benzyl-tetracyclic ketone (13) is a
b
-benzyl-tetracyclic ketone
b
b
key structural feature that determines the diastereoselective generation of the (R)-
configuration at the C-7 spiro center during the oxidation-rearrangement reaction.[14]
Finally, although it was not part of the present study, it is important to mention two
features in regard to the generality of the approach proposed here: (1) the
sarpagine/macroline imino-ether alkaloids could also be accessed by the use of this
strategy given their closely-related chemical structure with the oxindole group; and (2)
those natural spirooxindole alkaloids bearing a substituted-benzene A-ring oxindole
moiety (the methoxyl group is the only type of substituent that has been found other
than hydrogen, to date, in this series) could be prepared through the proposed strategy
from the corresponding enantiopure methoxy-substituted tryptophan.[15]
4
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Scheme 1. Retrosynthetic strategy
Results and Discussion
The sarpagine-related (-)-affinisine oxindole was first isolated from the leaf extract of
Alstonia angustifolia var. latifolia by Kam et al. and its structure was assigned in
2
004.[16] The original structure and relative configuration of this alkaloid were
established via analysis by IR, UV/VIS, NMR, and mass spectroscopy.[16] The
configuration of the spirocyclic center was determined to be (S) from the NOE
interaction observed between H(9) and H(16) and the geometry of the C(19),C(20)-
double bond was determined to be (E) from the NOE interaction observed between the
H(18) (methyl group) and H(15) (Figure 3).[16] Unfortunately there was a typographical
5
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error on page 3052 of the Tetrahedron Letters, 2015, 56, 3052[17] which mislabelled the
configuration at C-7 as R; however, the synthesis of the correct stereochemistry 7S and
the properties of synthetic (˗)-affinisine oxindole (26) are in good agreement with the
structure reported by Kam et al.[18] The first enantiospecific total synthesis of (˗)-
affinisine oxindole (26), was carried out in 2015 (see Scheme 2 and later section),[17]
which confirmed the absolute configuration at C(7) and C(16) proposed by Kam et al.[18]
Later the absolute configuration of compounds 14
confirmed by X-ray crystallographic analysis (Figure 2).[14a] This stereospecific
approach provided entry into either the spirocyclic oxindole of the chitosenine-series
C-7(R)] or the opposite configuration at C(7) in the alstonisine-series 1-4 (Figure 1).
, 19, 20, and 23 were further
6
[
The utilization of this diastereomeric difference (synthetically) at C-7 is a key objective
of the present work.
Scheme 2: Total synthesis of affinisine oxindole (26 [
)
17]
6
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Figure 2. ORTEP drawing of 14, 19 (with CHCl solvent), 20 and 23 (Please see SI for
3
the X-crystal details)
The enantiospecific synthesis of alstonisine[2d] and affinisine oxindole[17] promoted
further interest in the synthesis of other spiro oxindole alkaloids diastereomeric at the
spiro juncture at C-7 via this strategy of internal asymmetric induction. Interestingly,
Yu et al.[12a] also demonstrated that when the N
-H, N
-benzoyl tetracyclic ketone (27
)
a
b
was employed in the oxidation-rearrangement process, N
b
-benzoyl oxindole (28), which
was structurally (7S) related to alstonisine, was diastereospecifically formed in 80%
yield (Scheme 2). This observation is of importance for the synthesis of other members
of the sarpagine/macroline oxindole alkaloids. Removal of the benzoyl group was
achieved in high yield under acidic conditions (6 N aq. HCl/reflux/40 hours, 80%
yield).[14a] This could also be carried out under basic conditions, if required.
The 100% diastereoselectivity obtained during these transformations was a result of the
difference in stereochemical attack of tert-butyl hypochlorite on the N
b
-benzyl versus
N
b
-H tetracyclic ketone. The N -benzyl group in the N -H, N -benzyl tetracyclic ketone
b
a
b
(
13), presumably, occupied the equatorial position (Scheme 3) and, therefore, blocked
one face of the 2,3-indole double bond.[14b] This promoted attack by the “Cl ” species
from the concave face of the molecule. In the subsequent pinacol-type rearrangement,
the migrating group must attack from the face opposite the C-Cl bond in (32) to provide
+
oxindole (14). Meanwhile, in the case of the N
was more hindered when compared to the N
tetrahydro- -carboline (15), the 2,3-indole double bond was presumably attacked from
the convex face to form oxindole (16), with the alstonisine (1) stereochemistry. In the
case of the N -benzoyl oxindole (28), it is believed that the planar character of the
C=O(N) amide bond rendered the position of the benzoyl moiety in a more planar
a
-H, N
b
-H ketone (15), the concave face
b
-benzyl ketone (13, Scheme 3). In the

b
conformation away from the double bond of the carboline system. Again, as in the N -
b
7
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H ketone (15) case, the concave face of the molecule would be the more hindered to
attack by tert-butyl hypochlorite (Scheme 3) which provided the 7(S) oxindole 16 [
.
12a,
1
2b]
Scheme 3. Proposed mechanism for the formation of the two diastereomeric
spirooxindoles
Finally, Yu et al.[12a] attempted to perform the tert-BuOCl oxidation on the
corresponding N
these conditions, presumably, because these N
undergo oxidation of the indole 2,3-double bond. Presumably, formation of the
indolenine intermediate iminium ion at the N -methyl position, similar to (30) in Scheme
, was too high in energy in this series under these conditions.[19]
To complete the synthesis of ( )-affinisine oxindole (26), ketone (19) was converted
a
-methyl derivatives of ketones (13) and (15) but these failed under
a
-methyl analogs would not readily
a
3

into the desired pentacyclic ketone (23) in 65% yield (Scheme 4) via an intramolecular
palladium-catalyzed enolate-mediated cross-coupling reaction, under the conditions
developed by Solé and Bonjoch et al. (10 mol%) Pd(PPh
3
)
4
/PhONa

3H O (2.5
2
equivalents) in THF (previously freeze-pump-thaw, 3-5 cycles, to remove all the oxygen
from the solution) at reflux for 2 hours.[20] The use of a weaker base than t-butoxide was
8
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thought to be of critical importance to gain access to the desired pentacyclic oxindole
23). The steric outcome of this reaction was again confirmed by X-ray analysis.
(
Especially important was the fact that no oxindole isomerization occurred during this
process (see SI). Gratifyingly, during studies on the total synthesis of isoalstonisine
described in later sections, it was found that the use of (40 mol%) of Pd
2
(dba) as a
3
palladium source with sodium bis(trimethylsilyl)amide [(NaHMDS, 2 equivalents) in
freeze-pump-thaw,THF] at room temperature (23 °C) significantly improved the yield
of the reaction to 80% of the pentacyclic ketone (23) after purification by
chromatography. This was the best yield we could obtain. The formation of the
privileged intermediate pentacyclic ketone 23 (80% yield) at room temperature via the
intramolecular enolate- mediated palladium cross coupling process is an important key
step in the total synthesis of affnisine oxindole (26) and of importance in alkaloid total
synthesis (Scheme 4). The reported palladium catalyst, Pd
2
(dba)
3
is a better air stable
.[21] The
catalyst and easier to handle than the previously reported catalyst, Pd(PPh
)
3 4
mild reaction conditions of this reaction at room temperature has the advantage of
limiting the possibility of an E2 elimination of the vinyl iodide. An increase from 65%
to 80% yield in a total synthesis which requires several steps is significant.
Scheme 4. The improved synthesis of pentacyclic ketone 23
The first example of such an important palladium-catalyzed coupling process involving
vinyl halides were reported by Piers et al.[22] in an alicyclic system at the beginning of
the 1990s, when he described the intramolecular alkenylation of ketone enolates and
then applied the reaction to the synthesis of the diterpenoid crinipellin B. Some years
later another example of this coupling process was reported in the heterocyclic series by
Wang et al. in the context of the total synthesis of the alkaloid (+)-vellosimine.[13c]
Bonjoch, Solé et al. reported their studies on the synthesis of nitrogen heterocycles by
the Pd(0)-catalyzed intramolecular coupling of amino-tethered vinyl halides and ketone
9
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enolates at about the same time.[20] Buchwald also described the intermolecular
vinylation of ketone enolates during this period.[23] The final steps in the first total
synthesis of (-)-affinisine oxindole have been reported.[17]
The first stereospecific total synthesis of the sarpagine-related (
)-affinisne oxindole
(
26) was successfully accomplished in 8 reaction vessels in a 10% overall yield from
commercially available D-(+)-tryptophan.[17] The H NMR (see SI Table 1) and C
1
13
NMR (see SI Table 2) spectral data, as well as the IR spectrum (dry film on KBr) 3375,
-
1
[16]
-1
1
711 cm [literature IR (dry film) 3384, 1712 cm were in excellent agreement with
the natural product.[16-17] In addition, the physical properties including the optical
rotation [ 66° (c 0.3, CHCl 70° (c 0.06, CHCl )]; and
]23 ) [literature[16] ]23
HRMS were in excellent agreement with those published by Kam et al.[16-17]
Finally, selected NOE NMR experiments were then carried out on synthetic (

D
=

3
[

D
=

3

)-
affinisine oxindole (26), as shown in Figure 3. NOE studies of the synthetic material
confirmed the configuration of the spirocyclic center, the configuration at C(16), and
the geometry of the C(19),C(20)-double bond to be the same as those reported by Kam
et al.[16],[18]
Figure 3. 1D NOE NMR data, C-7(S) series, (-)-affinisine oxindole (26
)
As further structural proof, the oxindole epimeric at C-7 [i.e., C-7(R)] of (

)-affinisine
oxindole (26) i.e., isoaffinisine oxindole was also synthesized in enantiospecific fashion
during these studies, and its structure was fully characterized and confirmed by X-ray
crystallography (see later section) which permitted the correlation of some of the same
signals to (-)-affinisine oxindole (26) here.[17]
1
0
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Enantionspecific total synthesis in the C-7(R) series, the oxindole alkaloid (+)-
isoalstonisine (35)
The successful first enantiospecific, diastereospecific total synthesis of the sarpagine
related C-7(
reported synthetic approach discussed in Scheme 1, prompted the extension of this
application to the synthesis of the C-7( ) series oxindole alkaloid (+)-isoalstonisine
35) also from commercially available D-(+)-tryptophan.
The macroline related oxindole alkaloid (+)-isoalstonisine (35) was first isolated
S) series ()-affinisine oxindole (26) from D-(+)-tryptophan, via the
R
(
from the ground leaves of the Malayan medicinal plant Alstonia angustifolia var.
latifolia in 2000 by Kam et al.[16, 24] It represented the first time that a C7-(R) series
sarpagine/macroline oxindole alkaloid was isolated from plants; [C7-(R) ()-
macrogentine (57, see later) was also isolated during this work]. The structure
elucidation by Kam et al. was performed on the basis of mass spectrometry; IR and UV
1
13
spectroscopic studies as well as H, C, and NOE NMR spectral techniques. In order to
confirm the assigned relative spatial arrangement of atoms in the structure of
isoalstonisine (35), computational studies were carried out by Kam et al. (MM2, CS
Chem3D Pro) in which the major and diagnostic differences in the observed NOE’s of
alstonisine (1, used for comparison) and isoalstonisine (35) were consistent with the
predicted distances in the energy minimized structures.[24] The configuration of the
spirocyclic center C-7 was, initially, incorrectly determined to be (S). Later, Kam et al.
corrected the C-7 configuration and labeled it (R).[18]
The synthetic route, which was envisaged in order to diastereospecifically
functionalize the C-15 position of the key oxindole intermediate (14, retrosynthetic
analysis in Scheme 1), was based on the successful stereospecific synthesis of (-)-
affinisine oxindole (26) during the course of these studies.[17]
Consequently, the chemistry described before for the preparation of (-)-affinisine
oxindole (26)[17] could be employed starting with the N
oxindole (14) instead of the ketone oxindole (16, compare Scheme 1 versus Scheme 5).
Thus, the E-ring in isoalstonisine (35) would be generated from tetracyclic oxindole (36
through a modified Wacker-oxidation sequence which would be followed by
regioselective removal of the N
-protecting group (R1).[25] In turn, oxindole (36) could
-H, N -benzyl tetracyclic ketone
a
b
)
b
be prepared with the execution of a base-promoted retro-Michael process on an N -alkyl
b
1
1
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quaternary ammonium salt of pentacyclic oxindole (37).[25],[26] The construction of the
-methyl ketone moiety in ( ) would be feasible from oxindole (38) by a highly

3
regiospecific (anti-Markovnikov), stereospecific (syn) hydroboration-oxidation
sequence to provide an alcohol which then could be oxidized by different
methods.[25],[26]
Scheme 5. Retrosynthetic analysis for (+)-isoalstonisine (35
)
It is important to note here that intermediate oxindole (38) is the [(R)-C-7] epimeric
isomer of the natural affinisine oxindole (26). Therefore, the synthesis of oxindole (38
)
would also contribute to the structural proof of affinisine oxindole (26). Finally, the
primary-hydroxy oxindole (38) would be prepared from tetracyclic ketone (14), and D-
(
+)-tryptophan as the initial starting material, by an analogous application of the
chemistry discussed in earlier sections. In agreement with the retrosynthetic analysis
depicted in Scheme 5, the N -methyl, N -allyl tetracyclic ketone oxindole (20), was
a
b
functionalized at the C-15 position in a stereospecific fashion through a modified
palladium-catalyzed enolate-driven cross-coupling reaction.[17, 20] The conditions of
which, were developed during these studies (Scheme 4 and 6).
Treatment of oxindole (20) with 40 mol% of Pd
2
(dba) , NaHMDS (2 equivalents) in
3
THF (freeze-pump-thaw, 3-5 cycles, to remove all the oxygen from the solution) at
ambient temperature (23 °C) for 8 hours provided the desired pentacyclic ketone
1
2
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oxindole (39), diastereospecifically and in high yield (80%). In a similar manner as the
preparation of [(S)-C-7] affinisine oxindole (26, Scheme 1) from oxindole (23),[ the
17]
a
N -methyl pentacyclic ketone (39) was also carried through a one-reaction-vessel (3
steps) homologation process of the carbonyl group at C-16 to give the C-17
functionalized aldehyde, which was subsequently reduced to the corresponding hydroxy
methyl moiety. This was easily executed by a successive Wittig-olefination reaction
with (methoxymethyl)triphenyl-phosphonium chloride and anhydrous tert-BuOK in dry
benzene. Then the mixture of stereoisomeric enol ethers (40) was hydrolyzed under
acidic conditions to afford the thermodynamically more stable α-epimeric aldehyde (41
)
as a single diastereomer. Finally, the crude aldehyde product (no purification was
required) was converted into its corresponding primary alcohol by reduction with
NaBH
4
in EtOH at room temperature to provide the [C-7(R)] (-)-isoaffinisine oxindole
(
38) in 70% overall yield from ketone 39 (Scheme 6).[17]
Scheme 6. Synthesis of (7R)-isoaffinisine oxindole (38)
The synthesis of oxindole (38) was of importance because the X-ray crystal structure
on this material served as additional proof of the correct stereochemical assignment of
(
-)-isoaffinisine oxindole as the epimer with the [(R)-C-7] spirocenter (see all ORTEP
drawings in the reference[14a] and in the SI).
In the next stage of the synthesis, directed toward the construction of 42, the primary
hydroxyl group of isoaffinisine oxindole (38) was protected with the bulky
1
3
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triisopropylsilyl moiety in 90% yield by reaction of oxindole (38) with triisopropylsilyl
trifluoromethanesulfonate (TIPSOTf, 1.6 equivalents) and 2,6-lutidine (2 equivalents)
in DCM at room temperature for 2 hours. The TIPS protecting group was used
successfully in the parent system for a similar transformation and had better stability
than smaller silyl groups such as TBDMS, as expected.[25, 27] The above protection with
a bulky group set the stage for the following hydroboration-oxidation sequence.
Therefore, the hydroboration process was executed on 42 in THF at ambient temperature
using a 9-fold excess of BH -DMS complex over 3 hours (Scheme 7).
3
Scheme 7. Synthesis of methyl ketone 44
After careful quenching of the reaction mixture with water at 0 °C, an aqueous solution
of NaOH (3 N) was added with stirring and this was followed by the addition of
hydrogen peroxide (H
2
2
O , 35% in water) in the usual fashion. The solution which
resulted was allowed to stir for 3 hours at 23 °C to provide a mixture of secondary
alcohols (43) which were easily purified through a very short column (wash column) to
remove highly polar material (also <5% tertiary alcohol had formed and was removed).
The diastereomeric mixture was inconsequential since they would be converted into the
corresponding methyl ketone in 44
Interestingly, the N -BH complex of oxindole (43) was never detected after the
hydroboration-oxidation protocol. This observation is consistent with the reactivity of
the N -nitrogen atom for in the oxindole system it is significantly lower than that of the
-nitrogen atom in the parent system due to steric hindrance, as was also observed
before in the N
-allylation of oxindoles.[14, 28] The diastereomeric mixture of secondary
.
b
3
b
N
b
b
alcohols (43) was then subjected to oxidation conditions to generate the corresponding
methyl ketone (44). Although many different oxidants were employed to execute this
1
4
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conversion with poor results,[14a] gratifyingly the use of 2 equivalents of organic-media
-
1
stable tetra-n-propylammoniumperruthenate (TPAP, [RuO
4
] , Ru-oxidation state: +7)
in dry DCM afforded the desired methyl ketone in a very clean, mild process at 23
C in 2 hours. The combined yield of the 1-reaction-vessel transformation from alkene
oxindole (42) into the corresponding -methyl ketone (44) was an acceptable 65%
Scheme 7). Interestingly, it was found that the blocking effect of the bulky TIPS
protecting group on the C-16 hydroxyl was greater on the oxindole system than that in
the parent (indole) case, since only the -diastereomer was observed at C-20, the
epimer was not detected. The high diastereospecificity occurred because the -face (top
[
29]
°

(

-

face) of the tertiary olefin was sterically more hindered than the
towards the borane addition to the double bond.
-face (bottom face)
Table 1. Retro-Michael reaction
Entry
Alkylation step
retro-Michael step
Result
1
R -X (eq.)
additive (eq.)
solvent/temp.
°C)/ 24 h
base (eq.)
solvent/temp
(°C)/30 min
(
1
2
3
4
5
6
7
Bn-Br (1.5)
Bn-Br (10)
Bn-Br (10)
Bn-Br (10)
Bn-Br (10)
Bn-Br (10)
Allyl-Br (10)
NaHCO
3
MeOH/64
MeOH/64
MeOH/64
MeOH/64
ACN/82
K
K
2
2
CO
CO
3
3
(2)
(2)
(20)
(2)
(2)
(2)
(2)
THF/66
THF/66
THF/66
THF/66
THF/66
THF/66
THF/66
decomposition
decomposition
decomposition
decomposition
decomposition
decomposition
decomposition
NaHCO
NaHCO
3
(10)
(10)
3
2 3
K CO
NaHCO
NaHCO
NaHCO
NaHCO
3
3
3
3
K
K
K
K
2
2
2
2
CO
3
CO
CO
CO
3
3
3
DMF/100
THF/66
(
(
(
10)/AgOTf
NaHCO
10)/AgOTf
NaHCO
10)/AgOTf
8
9
Allyl-Br (10)
Allyl-Br (10)
3
DMF/100
neat/70
K
K
2
2
CO
CO
3
3
(2)
(2)
THF/66
THF/66
decomposition
decomposition
3
1
0
Allyl-Br (10)
neat/70
K
2
CO
3
(2)
THF/66
decomposition,
2
0% (45)
1
1
Me-I
neat/70
t-BuOK (2)
THF/23
(46) 30%
1
2
Me-I
neat/70
NaHMDS (2)
THF/23
(46) 80%
1
5
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Table 2. Wacker-Cook oxidation[30] (termed the Wacker-Cook reaction by Moldanado)[30]
Entry
Catalyst
mol%)
Reoxidant/additiv
e
Solvent system
Temp
(°C)/
Result
(
time (h)
80/6
1
2
3
4
Na
Na
2
PdCl
PdCl
4
4
(40)
(40)
(40)
(40)
(40)
t-BuOOH (1.5 eq)/ AcOH/dioxane/H
NaOAc (1 eq) (1:3:3)
t-BuOOH (1.5 eq)/ AcOH/dioxane/H
NaOAc (1 eq) (1:3:3)
t-BuOOH (1.5 eq) AcOH/dioxane/H
1:3:3)
t-BuOOH (1.5 eq) AcOH/t-BuOH/H
2
2
2
O
O
O
decomposition
decomposition
decomposition
decomposition
2
80/2
80/6
80/6
Na
Na
Na
2
PdCl
2
PdCl
2
PdCl
4
4
4
(
2
O
(
1:3:3)
5
t-BuOOH (1.5 eq)
dioxane/H
2
O (6:1)
40/3
(47) 20%
6
Na
2
PdCl
4
(40) t-BuOOH (1.5 eq)
dioxane/H
2
O (6:1)
85/6
(47) 65%
With access to pentacyclic ketone (44), the next step rested on the ring-opening of 44
or 37 in Scheme 5) through a base-promoted retro-Michael reaction of an N -alkylated
quaternary ammonium salt of oxindole (44). Since natural isoalstonisine (35) possessed
an N -H functionalized nitrogen atom, it was advantageous to install an alkylating agent
that could be removed easily from the secondary N -nitrogen at a later stage. It was
known, however, that the steric access to the N -nitrogen position in these types of
sarpagine/ macroline oxindole systems was highly hindered.[14b, 28] Thus, initially, it was
decided to use benzyl bromide (b.p. = 201°C) to achieve the N -alkylation, which would
in turn leave an N
-benzyl functional group after the retro-Michael reaction.[31],[32],[33],[34]
(
b
b
b
b
b
b
The benzyl group would later be removed by known deprotection protocols (e.g.
reductive hydrogenation or radical debenzylation as seen before in related systems).
However, all attempts to execute this alkylation with either benzyl bromide or benzyl
iodide[14a] met with less than promising results and complex mixtures.[14a]
At this point it was decided to treat oxindole (44) with methyl iodide (b.p. = 42.4 °C),
which was successfully used for similar transformations in the parent system (indole).[25-
2
6]
In this vein, MeI was heated at 70 °C, neat, in the presence of oxindole (44, in a
sealed tube) for one day. After removal of the excess MeI under reduced pressure, the
1
6
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crude solid, which resulted, was dissolved in dry THF in the presence of 2 equivalents
of potassium tert-butoxide for 30 minutes at room temperature.
The desired ,-unsaturated methyl ketone (46, Table 1, entry 11) was detected albeit
in low yield (30%). The use of NaHMDS (2 equivalents) under similar conditions
improved the olefin yield to 80% (Table 1, entry 12). The next stage in the synthesis of
(+)-isoalstonisine (36) by the route depicted in Scheme 5, required the formation of a
carbon-oxygen bond that would close the E-ring of the molecule. To this end, a modified
Wacker-related process, used in the parent system by Liao et al. seemed promising. [25]
The execution of the intramolecular Wacker oxidation which worked in the Liao et al.
synthesis of (
complex mixtures of byproducts were recovered each time). Modification of these
reaction conditions: shorter reaction time (entry 2); removal of the NaOAc additive
entry 3); and use of tert-butanol instead of dioxane did not improve the outcome of the
reaction.
It was hypothesized that the acidic media was the cause of the problem, presumably
)-alstonerine (Table 2, entry 1) failed to provide the expected product
(
(
by promoting the equilibration of epimeric oxindoles at C-7, through a retro-Mannich
type of process, that was operational under these acidic reaction conditions.
Consequently, since the acidic media was not required for the transformation, it was
decided to remove the acetic acid and execute the protocol under neutral conditions.
Gratifyingly, the pentacyclic ketone oxindole (47) was found in the reaction mixture,
after heating at 40 °C for 3 hours, in 20% yield. The yield was later improved to 65%
by exposing the starting materials to a higher temperature (85 °C) and a longer reaction
time (6 hours).
Although the mechanism has not been studied in detail, a proposed one is shown in
Scheme 8.[25] It was believed that the process originally involved the fast and reversible
coordination of the Pd(II) species to the alkene much like the earlier work of Trost and
others. Under neutral conditions, the nucleophilic oxygen atom of the silyloxy
functional group would attack the Pd(II) olefin complex. This event would be followed
by cleavage of the silyl moiety in the presence of chloride ions; then
-hydride
elimination; and finally reductive elimination would provide the desired enone (47). The
Pd(0) was reoxidized to Pd(II) by tert-BuOOH (Scheme 8) analogous to the standard
conditions.
1
7
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Scheme 8. Possible mechanism for the formation 47
The best method found, to date, in the literature for the N-dealkylation of tertiary
amines was the one introduced by Olofson et al. which involved the use of the
inexpensive reagent  -
-chloroethyl chloroformate (ACE-Cl).[35] The cleavage of the
chloroethyl carbamate ester was carried out by simply heating it in methanol (addition
+
of H was not needed). Accordingly, N
b
-methyl pentacyclic oxindole (47) was exposed
to the conditions of Olofson et al. with 10 equivalents of ACE-Cl in 1,2-dichloroethane
4.6 mmol (47)/mL] at 85 °C for 24 hours. The ammonium salt which formed was then
treated with dry methanol at reflux for 5 hours. After basic work-up to neutralize the N
hydrochloride salt, the expected (+)-7R-isoalstonisine (35) was obtained in 80% yield
three steps in a 1-pot process, Scheme 9).
[
b
-
(
1
8
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Scheme 9. Synthesis of (+)-isoalstonisine (35)
1
13
The H NMR (see SI Table 3) and C NMR (see SI Table 4) spectral data of synthetic
-
1
(
+)-isoalstonisine (35), as well as the IR spectrum [dry film on KBr: 1701 cm ,
literature[24] IR (dry film) 1704 cm ] were in excellent agreement with that of the natural
-1
product.[24] In addition, the physical properties including the specific rotation {[
201° (c 0.15, CHCl = +207° (c 0.07, CHCl )]}, and HRMS were
), literature[24] ]23
in excellent agreement with those published by Kam et al.[24]

]23
=
D
+
3
[

D
3
Selected NOE-NMR experiments were then carried out on synthetic (+)-
isoalstonisine (35, Figure 4) and compared to those of Kam et al.[24] on natural
isoalstonisine and Wearing et al. on alstonisine.[14b] Irradiation of the diagnostic H-9
hydrogen-atom effected enhancement of H-15 by 20% and vice versa, in synthetic
alstonisine according to Wearing et al.[14b] Irradiation of H-9 in synthetic isoalstonisine
(
35) did not effect enhancement of H-15, thus confirming the correct assignment and
also that there was no epimerization at C-7 during the last step.
1
9
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Figure 4. NOE NMR, Isoalstonisine (35
)
Enantiospecific synthesis of (+)-alstonisine (1), (+)-N -demethylalstonisine (51), and (+)-
a
alstofoline (52)
The oxindole alkaloids (+)-N -demethylalstonisine (51) and (+)-alstofoline (52) were
a
first isolated by Kam and Choo et al. in 2000 from the Malayan Alstonia angustifolia
var. latifolia K. and G.[24] The initial report incorrectly named the source of the plant as
Alstonia macrophylla Wall but the authors then changed it in a later communication.[16]
The alkaloidal content of Alstonia macrophylla Wall was studied by Kam and Choo et
al. and appeared in published report in 2004.[36] The structures of these two oxindoles
were determined using NMR spectral techniques, UV, IR, optical-rotation and analysis
by mass spectroscopy. The corrected configuration at C-7, labeled (S), for both alkaloids
was reported by Kam et al. in a recent article.[18]
With isoalstonisine (35) and the C-7-epimerization conditions developed for the
tetracyclic oxindole system in hand,[14a, 37] it became of interest to explore the
isomerization of 7R-isoalstonisine (35) into 7S-alstonisine (
of the epimerization protocol in good yield would represent an improved route to this
important oxindole alkaloid alstonisine ( ). Accordingly, a pure synthetic sample of
isoalstonisine (35) was treated at 100-110 °C (in a sealed tube) in a dry pyridine-DCM
8:2) mixture for 60 hours. After separation and analysis of the mixture of diastereomers,
it was found that alstonisine ( ) was present in a gratifying 70% yield (Scheme 10). The
1). The successful execution
1
(
1
2
0
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C-7 epimeric isoalstonisine (35) was detected in 18% yield and the rest (12%) of the
material was a highly-polar unidentified mixture (baseline material on TLC analysis).
Scheme 10. C-7 epimerization
If the decomposition material was taken into account, the final mole ratio would be
(
35)/(1) = 4/1, approximately. On the other hand, heating alstonisine (1) in acetonitrile
at 80-85°C (in a sealed tube) in the presence of 3 equivalents of Hünig’s base (sodium
carbonate can be used in place of Hünig’s base) for 2 days gave, isoalstonisine (35) in
8
5% yield, and alstonisine (
1
) was recovered in 9% yield with 6% of decomposition,
)/(35) = 1/9.
The H NMR (see SI Table 5) and C NMR (see SI Table 6) spectral data of (+)-
the mol% of the mixture would be approximately (
1
1
13
-
1
[24]
alstonisine (
1), as well as the IR spectrum [dry film on KBr: 1701 cm , literature IR
-
1
(
dry film) 1704 cm ] are in excellent agreement with the literature. In addition, the
2
3
physical properties including the optical rotation {[

] D = +195° (c 0.2, EtOH),
2
3
[14b]
23
[7]
literature: [

] D = +197° (c 1.0, EtOH)
and [] D = +200° (c 1.0, EtOH) } and
HRMS were in excellent agreement with those published in the literature by Elderfield
et al. and Wearing et al.[7, 14b]
The transformation of (+)-alstonisine (1) into (+)- N -demethylalstonisine (51)
a
The 7S-series oxindole alkaloid (+)-N
the corresponding (+)-N -methyl alstonisine (
transformation that removed the N -methyl functional group. In a search of the literature,
a
-demethylalstonisine (51) could be obtained from
a
1
), presumably, through a chemical
a
attention was drawn to a communication by Hiemstra et al. on the total synthesis of (+)-
gelsedine,[38] in which the removal of a methyl group from an oxindole was readily
accomplished by using a procedure, which was known earlier for removal of an N-
methyl group from an indole system (by Nakatsuka et al.).[39] It was decided to make
2
1
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use of the conditions by Hiemstra et al. for the demethylation of alstonisine (
1
). A major
-H) in
souce of concern, however, was the presence of a secondary nitrogen atom (N
b
the molecule. The reaction of dibenzoyl peroxide with secondary amines to provide O-
benzoylhydroxylamines is well documented.[38]
Accordingly, a solution of alstonisine (
DCM was heated in a sealed tube for 24 hours at 85 °C (Scheme 11). After concentrating
the reaction mixture, a solution of saturated NH (g) in methanol was added and the
mixture was stirred for another 24 hours at ambient temperature to afford the expected
+)-N -demethylalstonisine (51) in moderate yield (65%). Attempts to increase the final
1) and 2 equivalents of dibenzoyl peroxide in
3
(
a
yield by increasing the number of peroxide equivalents had the opposite effect,
presumably for the reasons explained above, even though it could not be confirmed. A
proposed mechanism for the demethylation of these oxindoles has been
published.[14a],[38],[39]
Scheme 11. Synthesis of (+)-N
a
-demethylalstonisine(51)
1
13
The H NMR (see SI Table 7) and C NMR (see SI Table 8) spectral data and HRMS
for (+)-N
in the literature by Kam et al.[24] Selected NOE-NMR experiments were then carried out
on synthetic (+)-N -demethylalstonisine (51, Figure 5). Again, irradiation of the
a
-demethylalstonisine (51) were in excellent agreement with those published
a
diagnostic signal at the H-9 hydrogen atom effected enhancement of H-15 by 8% and
vice versa, thus, confirming the 7S configuration of the spirocenter.
Figure 5. NOE NMR, N -demethylalstonisine (51)
a
2
2
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The transformation of (+)-alstonisine (1) into (+)-alstofoline (52)
Several different methods for formylation of amines could be found in the literature.[40]
With all these precedents in mind, it was decided to employ conditions developed by
Hill et al., that used a simple alkyl formate as the source of the formyl group.[40f] The
reagent 2,2,2-trifluoroethyl formate (TFEF) can be used in a variety of reaction
manifolds depending on the presence of other additives.[40f] Consequently, when applied
to oxindole (
1, Scheme 12), it was found that the reaction of alstonisine (1) with 2,2,2-
trifluoroethyl formate (used as the solvent; either prepared (see SI) or from commercial
sources) at 65 °C for 24 hours generated the expected N
b
-formyl oxindole alstofoline
1
(
52) as a mixture of rotamers (in a 3:1 ratio, determined by H NMR spectroscopy) in
very high yield (90%). In order to reduce the amount of formate, a number of solvents
were screened. Using a concentrated solution of 1,2-dichloroethane and as low as 5
equivalents of the trifluoroformate on stirring for 24 hours provided the same final yield
of (+)-alstofoline (52, Scheme 12).
Scheme 12. Synthesis of (+)-alstofoline (52)
1
The H NMR (see SI Table 9) spectral data of (+)-alstofoline (52), as well as the IR
-
1
[24]
-1
spectrum [dry film on KBr: 1713 cm , literature IR (dry film) 1706 cm ] were in
good agreement with the natural product. In addition, the physical properties including
the optical rotation {[

]23
D
= +32° (c 0.10, CHCl
3
), literature[24]
[

]23
= +39° (c 0.21,
D
CHCl )]}, and HRMS were in good agreement with those published in the literature by
3
Kam et al.[24] The irradiation of the diagnostic H-9 hydrogen-atom effected
enhancement of H-15 by 10% and vice versa, thus, confirming the 7S configuration of
the spiro center (NOE-NMR) in (+)-alstofoline (52).
2
3
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The enantiospecific synthesis of ()-alstonoxine A (56) and ()-macrogentine (57)
The oxindole alkaloids ( )-alstonoxine A (56) and ( )-macrogentine (57) were both


isolated (by Kam et al.) from the stem-bark and leaf extract of a Malayan Alstonia
species: Alstonia angustifolia var. latifolia K. G, but they were not found in the related
Malayan Alstonia macrophylla.[16, 24, 36] The correct C-7 designation of configuration,
which is 7R for macrogentine (57) and 7S for alstonoxine A (56), was recently published
in a report in 2014.[18] The natural oxindole (
)-macrogentine (57) was the second
sarpagine/ macroline oxindole isolated, after isoalstonisine (35), to possess the 7R
configuration at the spirocenter.
The structural characterization of both alkaloids was done by Kam et al. whom
1
13
employed H, C, two-dimensional, and NOE NMR spectral techniques in conjunction
with optical rotation measurements as well as UV, IR spectroscopy, and mass
spectrometry. [16, 24, 36] Natural (
)-alstonoxine A (56) is an oxindole in which cleavage
of the E-ring has occurred. In a study on the alkaloid alstophylline (53), Kishi et al.
reported experimental conditions for the acidic hydrolysis of the E-ring in the indole
system (which Kam et al. also used for structural confirmation, Scheme 13).[24, 41]
Scheme 13. Acidic hydrolysis of E-ring[41]
Thus, when isoalstonisine (35) was heated at reflux in 2 N aqueous HCl for 24 hours,
cleavage of the E-ring was accomplished in 80% yield to provide (-)-isoalstonoxine A
[
55, C-7 epimer of alstonoxine A (56), Scheme 14].
Scheme 14. Synthesis of (-)-isoalstonoxine A (55
)
2
4
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It is important to add that isomerization at the C-7 spiro center was not detected. Laus
et al. observed that in acidic media the epimerization of oxindoles is remarkably slower
due to protonation at the N
opening of the E-ring is based on the studies of Kishi et al.[41] and is shown in Scheme
5.
b
-nitrogen atom.[37a, 42] The proposed mechanism for the
1
Scheme 15. Possible mechanism for the opening of the E-ring
Epimerization at C-7 of isoalstonoxine A (55) into the natural oxindole (
alstonoxine A (56)
)-
Since it was possible to achieve the hydrolysis of the E-ring in the C7-(R) series of (+)-
isoalstonisine (35) into the non-natural (-)-isoalstonoxine A (55) in high yield, attention
turned to access two more natural sarpagine/macroline oxindole alkaloids.
2
5
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Consequently, when oxindole (55) was treated under the conditions for epimerization
of the 7R-series to the 7S-series, e.g. pyridine-DCM (8:2) at 100-110 °C for 60 h, natural
)-alstonoxine A (56) was obtained in 81% isolated yield, accompanied by 18% of the
starting (-)-isoalstonoxine A (55). The mole ratio of 55 56 was 1:4 (Scheme 16). When
(

/
the reverse epimerization, e.g. 7S-series to 7R-series, was executed utilizing a pure
synthetic sample of alstonoxine A (56) in acetonitrile at 80-85 °C with 3 equivalents of
DIEA for 2 days, a mixture was reached in which the mole ratio was 1.8:1 [55
/56 =
6
4:36, Scheme 16] of (-)-isoalstonoxine A (55) and natural ( )-alstonoxine A (56).

Scheme 16. Epimerization at C-7
1
13
The H NMR (see SI Table 10) and C NMR (see SI Table 11) data for (

)-alstonoxine
-
1
[24]
A (56), as well as the IR spectrum [dry film on KBr: 3357, 3240, 1701 cm , literature
-
1
[24]
IR (dry film) 3390, 3288, 1694 cm ] were in agreement with the literature.
addition, the physical properties including the optical rotation value {[ 40.0° (c
]23
.15, CHCl 34° (c 0.19, CHCl )]}, and HRMS were in good
), literature[24] ]23
agreement with those published in the literature by Kam et al.[24] A number of selected
NMR-NOE experiments were then carried out on synthetic ( )-alstonoxine A (56). The
In

D
= 
0
3
[

D
=

3

diagnostic H-9 hydrogen-atom effected enhancement of H-15 by 5% and vice versa
when irradiated in an NOE NMR experiment, thus, confirming the 7S configuration of
the spiro center.
The diastereospecific synthesis of (
55)
)-macrogentine (57) from (-)-isoalstonoxine A
(
The oxindole alkaloid (-)-macrogentine (57) possesses a carbon skeleton in which rings
A, B, C, and D of the macroline oxindole system are essentially intact, however,
cleavage and rearrangement have occurred involving the E ring. More specifically, the
2
6
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E-ring is a 6-member oxazolidine with the 2-position of the oxazolidine system
substituted with a methyl group in the equatorial position.[24]
Oxazolidines can be synthesized by several routes with the direct route based on the
condensation of amino alcohols with either aldehydes or ketones. There are many
examples in the literature where amino alcohols are reacted with a ketone or aldehyde
to form a 2-mono substituted oxazolidine.[43] The most common procedure for the
formation of oxazolidines from amino alcohols involves the heating of the latter in the
presence of an excess of aldehyde and a dehydrating agent. Thus, when (-)-alstonoxine
A (56) was treated with 20 equivalents of acetaldehyde, in the presence of 2 equivalents
of anhydrous MgSO
4
in absolute ethanol at 80-85 °C (in a sealed tube) for 24 hours
Hitchcock et al. ), the oxazolidine E-ring formed in a 90% yield, as shown in Scheme
7. The use of other solvents failed to provide a high yield under the same conditions:
[
44]
(
1
in DCM or CHCl
3
(traces of product detected); in toluene or benzene (<20% yield).
was replaced with, molecular sieves it did not change the above
When the MgSO
4
results.
Scheme17. Synthesis of (-)-macrogentine (57)
As was expected from previous studies of molecular models, the newly formed C-21
stereocenter (2-position in the oxazolidine ring) had an S configuration with the methyl
group occupying the equatorial position of the 6-membered ring, as shown in Scheme
1
8. A proposed sequence of events, consistent with studies done by Wrackmeyer et
al.;[43g] Rizk et al.;[43h] Jones et al.;[43i] Neelakantan et al.;[43j, 43k]and Hagopian et al.,[43l]
is shown in Scheme 18. The stereospecific formation of the equatorial methyl group was
rationalized principally by the two unfavorable 1,3-diaxial interactions between the
methyl group and the protons at H-5 and H-17 in the epimeric oxindole (III, path a,
Scheme 18). Such steric interactions are not present in the equatorial epimer (IV).
Additionally, intermediate (I, Scheme 18) leading to intermediate (III), is more sterically
2
7
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Chemistry - A European Journal
10.1002/chem.201703572
hindered than intermediate (II) where the methyl group is located far away from the
hydroxy methyl moiety.
Scheme 18. Possible mechanism for the formation of (-)-macrogentine (57
)
This hypothesis was confirmed by NOE NMR studies in which irradiation of the methyl
group effected an increase in the H-14 signal by 13%; however, there was no
enhancement in the intensity of the signals at H-5 or H-17 signals (Figure 6). The proton
1
13
H NMR (see SI Table 12) spectral data and C NMR data (see SI Table 13) for (-)-
macrogentine (57) were in agreement with the literature.[24]
Figure 6. NOE NMR, (-)-macrogentine (57
)
2
8
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Chemistry - A European Journal
10.1002/chem.201703572
Conclusions
The (7R)-sarpagine/macroline related oxindole alkaloids (+)-isoalstonisine (35) and (
macrogentine (57) together with the (7S)-sarpagine/macroline related oxindole alkaloids
)-affinisine oxindole (27), ( )-alstonoxine A (56), (+)-alstonisine ( , second
generation total synthesis), (+)-N -demethylalstonisine (51) and (+)-alstofoline (52
)-
(


1
a
)
were synthesized in enantiospecific fashion; moreover, the key stereocenters at C(3) and
C(5) were established in >98% ee by the asymmetric Pictet-Spengler reaction. The
oxidation of the 2,3-indole double bond of the two different N
CH Ph or N -H) of the tetracyclic ketone gave either the C-(7)R or C-(7)S
stereochemistry respectively at the spiro junction in 100% de.
b
-substituted analogs (N
b
-
2
b
A highly enantio- and diastereoselective general strategy to access any member of the
sarpagine/macroline family of oxindole alkaloids was developed from cheap,
commercially-available and optically active D-(+)-tryptophan. This chiral-pool starting
material was manipulated through successive enantioselective reactions, using achiral
reagents, to obtain the desired target molecules. The built-in chirality in D-(+)-
tryptophan was used and expanded, via intramolecular asymmetric induction, to form
new enantio rich compounds. Although the routes were usually stereospecific any
diastereomeric byproducts enabled their facile separation by methods such as column
chromatography or crystallization. This only occurred in a few instances but was the
reason the chirality was built in from the beginning.
At the heart of this approach was the diastereospacific generation of the
spiro[pyrrolidine-3,3
-oxindole] moiety at an early stage of the route via a tert-butyl
hypochlorite-promoted oxidative rearrangement of chiral tetrahydro-

-carboline
derivatives. This key branching point determined the spatial configuration at the C-7
spiro center to be either 7R or 7S and on large scale. Other key enantiospecific initial
reactions were the asymmetric PictetSpengler and Dieckmann cyclization which were
scalable to the 600 and 150 gram levels, respectively. This early construction of the
spiro oxindole moiety furnished an important advantage for there was no need to
perform complex studies for every single target molecule at the end of the route which
involved the optimization of reaction conditions to the particular system under study,
e.g. finding the suitable oxindole-generating reaction or screening of chiral catalysts to
obtain the desired stereochemistry at C-7. On the other hand, it was well-known that
oxindoles at C-7 could equilibrate between 7R and 7S through a Mannich-retro-Mannich
2
9
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