Stereoselective Access to the Core Structure of Macroline-Type Indole Alkaloids: Total Synthesis of Macroline and Alstomicine

Article abstract of DOI:10.1021/acs.orglett.8b01921

Rapid synthesis of the pentacyclic core structure of macroline-type indole alkaloids, and its application in the total synthesis of macroline and alstomicine is described. The core structure was accomplished in a highly stereocontrolled manner via two key steps, Ireland-Claisen rearrangement and Pictet-Spengler cyclization, commencing from a readily available starting material l-tryptophan, which obviated the need of a particular chiral source as an external catalyst, reagent, or internal auxiliary.

Full text of DOI:10.1021/acs.orglett.8b01921

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Access to the Core Structure of Macroline-Type
Indole Alkaloids: Total Synthesis of Macroline and Alstomicine
Vilas D. Kadam,†,‡ Sridhara Shanmukha Rao B.,†,‡ S. K. Mahesh,† Mithun Chakraborty,†
S. Phani Babu Vemulapalli,§ Satya Narayana Dayaka,§ and Gangarajula Sudhakar*,†,‡
§
†Department of Organic Synthesis & Process Chemistry and Centre for NMR and Structural Chemistry, CSIR-Indian Institute of
Chemical Technology, Hyderabad-500007, India
‡Academy of Scientific & Innovative Research (AcSIR), New Delhi, India
S
* Supporting Information
ABSTRACT: Rapid synthesis of the pentacyclic core structure of macroline-type indole alkaloids, and its application in the
total synthesis of macroline and alstomicine is described. The core structure was accomplished in a highly stereocontrolled
manner via two key steps, Ireland−Claisen rearrangement and Pictet−Spengler cyclization, commencing from a readily available
starting material L-tryptophan, which obviated the need of a particular chiral source as an external catalyst, reagent, or internal
auxiliary.
ome plant families are affluent in alkaloids, of which the
Apocynaceae is a good example. The Apocynaceae family
S
has at least 150 genera and 1700 species and is distributed over a
tropical region of Central America, Africa, and Asia.1 Alstonia
macrophylla (family of Apocynaceae), one of the famous species
of the genus Alstonia, is commonly employed in traditional
medicine of Thailand for diverse applications.2 A drink prepared
from its leaves and stem bark is used to treat stomach aches and
for the putrefaction of urine.3 A recent report with biological and
pharmacological studies on A. macrophylla revealed that it
exhibits antimicrobial, antimalarial, antioxidant, antidiabetic,
anti-inflammatory, antidiarrheal, CNS depressant, antifertility,
and antiprotozoal activities.4
Plants of the genus Alstonia, well-known as a rich source of
novel alkaloids with an azabicyclo[3.3.1] substructure annelated
to an indole ring, churned out a variety of simple and complex
indole alkaloids such as macroline, sarpagine, and ajmaline.5 The
preponderance of macroline-type indole, bisindole (macroline-
macroline, macroline-sarpagine/ajmaline), and oxindole alka-
loids is an imperative feature of the genus Alstonia.5,6 Over the
period, pentacyclic macroline indole alkaloids were isolated
predominantly from this genus,7 for instance, alstonerine (1),7a
alstophylline (2),7a alstophyllal (3),7b alstonerinal (4),7c N4-
demethylalstonerine (5),7d N4-demethylalstonerinal (6),7d N1-
demethylalstophylline (7),7e N1-demethylalstophyllal (8),7e
alstohentine (9),7f macrocarpines A−C (10−12),7b talcarpine
(13),7b N4-methyl-N4,21-seco-talpinine (14),7b 19,20-dehydro-
10-methoxytalcarpine (15),7g anhydromacrosalhine-methine
(16),7h raumacline (17),7i N4-methylraumacline (18),7i and
alstolactones (19−20)7d,e (Figure 1).
Figure 1. Representative macroline indole alkaloids.
A tetracyclic indole base, macroline (21), has not yet been
found as such in nature, but it is believed that 21 is a likely
Received: June 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01921
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
biosynthetic precursor of various monomeric indole alkaloids (2,
3, and alstonisine)8−10 and bisindole alkaloids (villalstonine,
alstonisidine, macralstonine, and macralstonidine)11−13 and is a
degradation product of villastonine.14 Alstomicine (22),
structurally similar to 21 but without exomethylene, was isolated
by T. S. Kam from the leaf extracts of the Malayan species A.
macrophylla.7f This has structural features similar to the ring-
opened seco-macroline oxindole, alstonoxine A,15 and the ring-
opened derivative of 1.7f Additionally, it is a degradation
product,15 monomeric unit,7b,16 and proposed biosynthetic
precursor of several novel and bioactive alkaloids.17
rearrangement. In turn, 26 could be derived from the coupling
reaction between acid 27 and allylic alcohol having aldehyde
equivalent i.e., 28, shown in Figure 2.
The synthesis of 24 was begun with known acid 29,25 prepared
in two steps from the commercially available L-tryptophan. One-
carbon homologation of the acid 29 to 27 was achieved in two
steps (Scheme 1). First, treating 29 with Et3N, isobutyl
Scheme 1. Synthesis of Ireland−Claisen Rearrangement
Products 25
Given our interest in the total synthesis of bioactive natural
products from proposed biosynthetic pathways,18 we became
intrigued with the synthesis of macroline type indole alkaloids,
macroline (21) and alstomicine (22). These target molecules
21/22 could be amenable precursors in accessing a range of
indole alkaloids based on the proposed biosynthetic pathways.
Their fascinating and synthetically challenging structure with
four annulated rings, three contiguous asymmetric centers out of
four total, and to the best of our knowledge, thus far, no synthetic
attempts on22 alsoprompted us todevise asyntheticstrategy for
this indole alkaloid framework. Herein, we communicate an
expedient synthetic approach to the pentacyclic core 23, and its
application in the first total synthesis of alstomicine (22) and the
total synthesis of macroline (21).
Our synthetic plan is depicted in Figure 2, in which the
synthesis of macroline/alstomicine could be achieved from a
chloroformate and subsequent addition of diazomethane
provided the diazoketone intermediate. Subsequently, it was
treated with a catalytic amount of silver acetate to furnish the
homologated acid 27 in 81% yield. Next, the coupling of 27 with
allylic alcohol fragment 28A/28B26 using EDCI afforded the
requisite allylic ester 26A/26B in 77−78% yields, setting the
stage for crucial Ireland−Claisen rearrangement (ICR). Keeping
in mindthatthe stereochemical outcomeof ICRwouldrelyupon
on efficient control of the ketene acetal geometry, the allylic ester
26A was treated with LDA and TMSCl to provide the (E)-
trimethylsilyl ketene acetal.27 Then, stirring the reaction mixture
at rt for 3 days furnished an inseparable mixture of acids with
excellent diastereoselectivity (dr8:2, based onthe 1H NMR) that
was treated with an excess of diazomethane to result in separable
esters 25A and 25A′ (63% combined yield, 89% based on
recovery of 26A). Similarly, 26B under ICR reaction condition
provided an inseparable mixture of acids with improved
diastereoselectivity (dr 9:1), which upon reacting with diazo-
methane afforded separable 25B and 25B′ in a similar yield.
Complete stereochemistry of major compounds 25A and 25B
was established only after achieving 24 (Scheme 2). Here, we
proposed that the facile selectivity and minimization of steric
factors in chairlike transition state I (Scheme 1) account for the
formation of major diastereomer 25A and 25B in the Ireland−
Claisen rearrangement.28
Figure 2. Proposed retrosynthetic route for 21 and 22.
pentacyclic advanced intermediate 23 (introducing exomethy-
lene followed by a methyl group for 21 and the addition of
methyllithium for 22). An efficient synthetic route to access
pentacyclic core 23 would provide not only 21/22 but also a way
to obtain some other pentacyclic indole alkaloids, as shown in
Figure1. Weenvisionedthesynthesisof23from24withminimal
functional group transformations. Yoneda first reported a
tetracyclic core similar to 24, but it was devoid of the entire
functional crew.19 Then, it was significantly improved including
accessing in gram scale and was also employed in accomplishing
the elegant total syntheses of diverse monomeric as well as
dimeric indole alkaloids by continuous efforts from Cook’s
group.20 Also, some seminal and notable works on thistetracyclic
core were reported by Magnus,21 Balley,22 and others.23
Recently, biology-oriented synthesis of similar tetracyclic
scaffolds led to the discovery of a new class of Mycobacterium
protein tyrosine phosphate (MptpB) inhibitors.24 In our
approach, the C and D ring system of the tetracyclic core in 24
was devised from 25 by using Pictet−Spengler cyclization. The
challenging/critical stereochemistry in compound 25 was
envisioned from allylic ester 26 by using Ireland−Claisen
Toward the synthesis of 24, the O-silyl group of 25A was
deprotected using HF·pyridine to generate the primary hydroxyl
group 30 in 82% yield, which was oxidized to the corresponding
aldehyde 31 in 84% yield by using Dess−Martin periodinane
(Scheme 2). As per our plan, in one pot, 25B (the equivalent of
31) is expected to undergo a series of transformations, Boc and
acetal groups deprotection, followed by iminium ion formation
and Pictet−Spengler reaction. In this direction, upon treatment
B
DOI: 10.1021/acs.orglett.8b01921
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Letter
carried out to deliver aldehyde 36 in a yield of 63%. Subsequent
silyl ether deprotection using TBAF followed by oxidation of
resulted hemiacetal with TPAP furnished the six-membered
lactone 37 in 78% yield (2 steps). Next, the compelling Pictet−
Spengler reaction was carried out in the presence of TFA in
CH2Cl2. To our delight, the pentacyclic core 23 was obtained in
81%yieldandexclusively oneisomerlikelyviathetransitionstate
III, as shown in Scheme 3. The structure and relative
Scheme 2. Synthesis of 34 and Attempts To Oxidize the
Hydroxyl Group
Scheme 3. Synthesis of Pentacyclic Core 23
of25B/31withTFA,asanticipated,directlyprovidedthedesired
tetracyclic core 24 in 82% yield with complete diastereoselec-
tivity in favor of the desired isomer (Scheme 2). The structure
and relative stereochemistry of 24 was unequivocally established
by using incisive NMR studies such as 2D-NOESY and J-
coupling analysis, (Supporting Information, SI). We proposed
the plausible reaction mechanism for 24, as shown in Scheme 2,
where 25B on exposure to TFA would provide 31, and
subsequent Boc group deprotection would result in the
formation of incipient six-membered cyclic iminium ion II,
which would undergo Pictet−Spengler cyclization29 to give
tetracyclic 24.
Having enough quantity of 24 (achieved up to 10 g) in our
hand, we turned our attention toward functionalization of the
terminal olefin. In this direction, first, the ester 24 was reduced
with DIBAL-H to furnish primary alcohol 32, which was
protected as TBS ether to provide O-silyl protected alkene 33 in
91% yield (2 steps). Hydroboration was then carried out on
alkene 33 using BH3·THF followed by oxidation (H2O2 and
NaOH) to deliver the primary alcohol 34 in 65% yield.
Unfortunately, the alcohol 34 was found to be inert to the
oxidations; numerous attempts to oxidize either to an aldehyde
or carboxylic acid were unsuccessful. Mostly, we recovered the
starting material and found decomposition in some cases.
Standard oxidation reactions proved unrewarding.30 At this
point, we decided to oxidize the olefin in 33 to the corresponding
aldehyde by ozonolysis. Again, the reaction of alkene 33 with
ozone either in CH2Cl2 or MeOH was unsuccessful. Further
oxidation attempts on alkene 33 with OsO4 also ended up
dihydroxylation only on the indole ring (not shown). The highly
electron-rich nature of indole ring could be the leading cause of
decomposition on ozonolysis and OsO4-catalyzed dihydrox-
ylation.
stereochemistry of 23 were unequivocally assigned by using 1D
and 2D NMR analysis (SI). This core 23 possesses the same
stereoconfiguration at C(3), C(5), C(15), and C(16) as those in
the macroline class, which represents the majority of the isolated
indole alkaloids. An intermediate similar to 23 was reported from
entirely different routes; , moreover, accessing indole alkaloids
from these approaches requires additional protection/depro-
tection and functional group manipulations.31
Having achieved advanced core structure 23 in gram scale in a
very efficient manner, we have proceeded to complete the total
synthesis of 21 and 22, summarized in Scheme 4. First, macroline
Scheme 4. Total Synthesis of Macroline (21) and Alstomicine
(22)
(21) in 37% yield was achieved in a two-step sequence:
introducing exomethylene followed by the addition of
methyllithium.32 Finally, the much desired first total synthesis
of alstomicine (22) was accomplished in 72% yield on treating
pentacyclic core 23 with methyllithium.32b The spectral data of
With this unexpected roadblock toward the synthesis of
advanced intermediate, we surmised prefunctionalization of
olefin before the Pictet−Spengler cyclization. If successful, this
would simplify the process further in achieving the pentacyclic
core 23. Research in this direction, first, ester 25B was subjected
to DIBAL-H reduction to yield primary hydroxyl group that was
protected as TBS ether to provide 35 in 80% yield (two steps).
Then, a two-step reaction sequence (hydroboration/3 N NaOH,
H2O2, followed by Dess−Martin periodinane oxidation) was
synthesized 21 and 22 well matched with data reported in the
28
literature (SI). The specific rotation of macroline (21) [α]D
=
+17.7 (c 0.09, EtOH) resembled one reported in the literature,20j
28
25
[α]D = +18.9 (c 0.1, EtOH), but alstomicine (22) ([α]D
=
−15.0 (c 0.14, CHCl3)) differed to a great extent with the
reported value ([α]D = +74 (c 0.14, CHCl3)).7f
In conclusion, we have developed a practical synthetic route to
the advanced pentacyclic core and employed it in the total
C
DOI: 10.1021/acs.orglett.8b01921
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
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Corresponding Author
*E-mail: gsudhakar@iict.res.in.
ORCID
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Gangarajula Sudhakar: 0000-0003-3498-5584
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Science & Engineering Research Board (SERB),
India for National Post-Doctoral Fellowship (to M.C.) and
CSIR/UGC-India for Senior Research fellowships (to V.D.K.,
S.K.M., and S.S.R.B.). Thanks are also due to the Indo-French
Centre for Promotion of Advanced Research (IFCPAR, No.
5305-1) and CSIR (12th FYP-ORIGIN (CSC-0108)) for
financial support and Dr. B. Jagadeesh, Head, Analytical for 2D
NMR support. Manuscript number: IICT/Pubs./2018/186.
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