Total syntheses of enantiomerically enriched R-(+)- And S-(-)-deplancheinef

Article abstract of DOI:10.1039/b503862f

Total syntheses of indoloquinolizidine alkaloid (±)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503862f

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A R T I C L E
Total syntheses of enantiomerically enriched R-(+)- and
S-(−)-deplancheine†
Nadiya Sydorenko, Craig A. Zificsak, Aleksey I. Gerasyuto and Richard P. Hsung*
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455.
E-mail: hsung@chem.umn.edu
Received 16th March 2005, Accepted 14th April 2005
First published as an Advance Article on the web 25th April 2005
Total syntheses of indoloquinolizidine alkaloid ( )-, R-(+)-, and S-(−)-deplancheine are described here. The
synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the
quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of
indoloquinolizidine alkaloids.
Introduction
Indole alkaloids have attracted strong interest from both
chemists and biologists for decades because of their diverse
medicinal properties.1–5 The core structure in many indole
alkaloids such as deplancheine (1, see Fig. 1),6 tangutorine
(2),7 geissoschizine (3),8 yohimbine (4), and reserpine (5),1–5,9–11
is an indolo[2,3-a]quinolizine or indoloquinolizidine (see 6 in
the box), in which the S-(−)-enantiomer of 6 is also a natural
product.12 R-(+)-Deplancheine (1), isolated from the New Cale-
donian plant Alstonia deplanchei van Heurck and Mueller Arg.
(stem and bark),5a is one of the simplest indoloquinolizidines.
It has subsequently been identified in a related plant Alstonia
undulata Guillaum5b–d and from the South American tree
Aspidosperma marcgravianum Woodson.5e
Scheme 1
We have communicated recently an application of this strategy
in a total synthesis of ( )-tangutorine (2).25,26 We wish to report
here full details related to total syntheses of ( )-, R-(+)-, and S-
(−)-deplancheine featuring an enantioselective intramolecular
formal aza-[3 + 3] cycloaddition reaction.
Results and discussion
As outlined in Scheme 2, ( )-deplancheine (1) can be derived
from the known pentacycle 10,14c in which the quinolizidine
CD-ring should be attainable via the intramolecular aza-[3 +
3] cycloaddition of vinylogous amide 11 that is tethered to an
a,b-unsaturated iminium ion. Vinylogous amide 11 could be
envisioned from condensing amino alcohol 12 with a b-diketone
equivalent followed by oxidation of the allyl alcohol moiety.
Amino alcohol 12 would be prepared from 2-bromo-tryptamine
13 via a cross-coupling process such as Heck-coupling with a
Fig. 1
Because of its simple structure, deplancheine (1) has become
an often synthesized natural product to demonstrate new
synthetic methodologies for the synthesis of indoloquinolizidine
alkaloids.13–15 Meyers’ synthesis15 of S-(−)-deplancheine (1)
firmly established its actual absolute configuration. Most syn-
theses of the indoloquinolizidine natural products have been
accomplished using the Pictet–Spengler cyclization.10,11,16–18
We became interested in deplancheine (1) because of our de-
velopment in a formal aza-[3 + 3] cycloaddition method.19–25 The
intramolecular variant of this annulation strategy using vinylo-
gous amides 7 tethered with an a,b-unsaturated iminium moiety
represents a novel and stereoselective approach toward the syn-
thesis of quinolizidines 8 or indoloquinolizidines 9 (Scheme 1).23
† Electronic supplementary information (ESI) available: experimental
1
procedures, H NMR spectra, and characterizations for all new com-
pounds. See http://www.rsc.org/suppdata/ob/b5/b503862f/
Scheme 2
2 1 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 4 0 – 2 1 4 4
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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suitable 3-carbon synthon, and the preparation of 13 would
commence with tryptamine 14. It is noteworthy that a Heck-
coupling27 could be employed for constructing the C2–C3
bond16–18 in place of the frequently used classic Pictet–Spengler
cyclization.
Our immediate problems were associated with finding a
suitable amino-protecting group for tryptamine 14 that would
survive the functionalization at C2 and the subsequent cross-
coupling reaction. As shown in Scheme 3, the first intermediate
targeted for this purpose was the 2-iodo-N,N-dibenzyl-N-
Boc-tryptamine 16. Reaction of tryptamine 14 with BnBr in
refluxing EtOH in the presence of K2CO3 afforded the known
dibenzylamine 15.28 After capping the indole nitrogen with
a Boc group, treatment of the doubly protected tryptamine
intermediate with t-BuLi followed by quenching with iodine
afforded the desired halogenated product 16 in 60% yield over 3
steps.
Scheme 4
25, obtained from hydroboration of propargyl silyl ether 17,37
afforded the desired vinyl indole 26 in good yield, albeit only on
very small scales (≤1 mmol).
Treatment of vinyl indole 26 with methyl hydrazine gave the
corresponding free amine, and the addition of the free amine
to 3-butyn-2-one in anhydrous CH2Cl2 afforded vinylogous
amide 27 but only in 25% overall yield from 26. Desilylation
using TBAF followed by oxidation with MnO2 furnished the
key precursor 29 for the formal aza-[3 + 3] cycloaddition in
90%. However, attempts at the key formal cycloaddition failed
using 29 because of both the small reaction scale and problems
stemming from the unprotected indole nitrogen.
The short supply in materials was caused by the poor isolated
yield (10–25%) obtained on larger reaction scales (≥2.5 mmol)
used for the Suzuki–Miyaura coupling of 24. This failure was
likely linked to the stability of vinyl catecholborane 25, which
slowly decomposed upon standing or during attempts to re-
purify it by chromatography or vacuum distillation.
The use of another coupling protocol became necessary and
Fukuyama’s27 Heck coupling protocol38 using acrylic acid esters
proved to be useful. In addition, we elected to reinstall a Boc
protecting group for the indole nitrogen to minimize potential
side reactions throughout the synthetic sequence.
As shown in Scheme 5, treatment of bromide 24 with Boc2O
in the presence of DMAP gave the Boc protected indole
intermediate, which was subjected to Fu and Littke’s39 improved
conditions: excess methyl acrylate and a 1 : 1 ratio of Pd catalyst
and the bulky Pt-Bu3 ligand. Phthalimido ester 30 was obtained
Scheme 3
With iodide 16 in hand, several coupling methods29 were
investigated. Initially, a Sonogashira coupling30 with propargyl
silyl ether 1731 was pursued (Scheme 3). Despite screening a large
number of conditions, the desired coupling product 18 was only
isolated in <5% yield at best, and the major by-product was
consistently the homo-coupled alkyne.
Consequently, both cis and trans isomers of vinyl stannane
19 were obtained via hydrostannylation32 of 17, and the trans
isomer could be readily separated from cis-19 using silica gel
column chromatography. The ensuing Stille coupling33 proved to
be effective using trans-19. The desired coupling product 20 was
isolated in good yield but with partial isomerization of the olefin.
Unfortunately, the subsequent reductive debenzylation could
not be accomplished without severe decompositions, including
reduction of the allylic ether. Dealkylation of one benzyl group
in 20 in exchange for a trichloroethoxycarbonyl (Troc) protecting
group did give 22.34 Further reductive removal of the Troc group
using Zn powder led to 23 in low yields, but attempts to remove
the remaining benzyl group also failed.
An alternative protection of the tryptamine amino group
was needed. Toward this goal, preparation of 2-bromo-N-
phthalimidotryptamine 24 was accomplished in 95% yield over
two steps from tryptamine 1435 (Scheme 4). The ensuing Suzuki–
Miyaura coupling36 of bromide 24 with vinyl catecholborane
Scheme 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 4 0 – 2 1 4 4
2 1 4 1

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in near quantitative yield. It was later found that the use of
Pd(PPh3)4 was also effective.
The treatment of ester 30 with methyl hydrazine succeeded in
cleavage of the phthalimido group, but addition to the acrylate
moiety was also observed, which had been a concern. An alter-
native deprotection of the phthalimide group followed Ganem’s
reductive sequence.40 Therefore, reduction of 30 with slightly
more than 3 equiv of DIBAL-H cleanly afforded hydroxyaminal
31. After aqueous workup to remove aluminium salts, further
reduction with NaBH4 afforded an amide intermediate, which
led to the free amine alcohol 32 upon treatment of the reduction
mixture with HOAc.
Attempts to purify amino alcohol 32 were not successful,
owing to the polarity of the product as well as the large amount
of undesirable salts within the reaction mixture. As such, the
intermediate amino alcohol 32 was only characterized after the
formation of a vinylogous amide such as 33 (see Scheme 6),
which was employed for the formal aza-[3 + 3] cycloaddition
reaction en route to ( )-tangutorine (2).25
Scheme 7
Scheme 6
For the synthesis of ( )-deplancheine (1), several reagents for
the formation of vinylogous amide were analyzed (Scheme 6).
The utility of four different amide precursors was screened: 3-
butyn-2-one,41 acetylacetaldehyde dimethyl acetal,42 4-methoxy-
3-buten-2-one,43 and acetylacetaldehyde sodium salt.44 The
formation of the vinylogous amide was equally effective, and the
use of 4-methoxy-3-buten-2-one was chosen based on its greatly
reduced cost and vinylogous amide 34 was isolated in 26%
overall yield starting from 30. It is noteworthy that vinylogous
1
amide 34 was distinctly in the Z-configuration, based on H
NMR coupling constants. In this configuration, a hydrogen
bond between the NH and the carbonyl can occur, which results
in a well-defined peak for the NH within the 1H NMR spectrum.
The key formal aza-[3 + 3] cycloaddition of vinylogous amide
35, obtained from the Mn2O oxidation of 34, was then examined
(Scheme 7). The use of piperidinium acetate salt proved to
be effective, leading to indoloquinolizidine tetracycle 36 after
hydrogenation in 35% yield over 3 steps. Simple treatment of
36 with a 1 : 1 mixture of TFA and CH2Cl2 gave the known
tetracycle 10, which matched that reported by Lounasmaa,14c
thereby completing a formal synthesis of ( )-deplancheine. To
complete the total synthesis, 10 was reduced using NaBH4 in
refluxing t-BuOH and MeOH13h to give ( )-deplancheine 1 in
67% yield. A minor isomer 37 was also found and was believed
to be the Z-isomer of ( )-deplancheine 1.
To complete the total syntheses of R-(+)-1 and S-(−)-1,
vinylogous amide 35 was subjected to an enantioselective aza-
[3 + 3] formal cycloaddition protocol45 using chiral amine salts
S-38 and S-39 (Scheme 8). Indoloquinolizidine S-36 was found
in 69% overall yield after hydrogenation with an er of 80 : 2046
in favor of the S-enantiomer. When using the chiral amine salt
Scheme 8
S-39, the ratio was only 68 : 32 also in favor of the S-enantiomer.
Removal of the Boc group followed by NaBH4 reduction gave
S-(−)-1 in 42% yield over two steps with the R : S ratio = 25 :
7546 and [a]D = −26◦ [c = 0.2, CHCl3] (an equivalent of 50%
23
◦
23
ee; lit.13a,15 [a]D = −52 [c = 1.0, CHCl3]).
When using the chiral amine salt R-38, the HPLC ratio was
69 : 31 in favor of R-36. Deprotection of the Boc group followed
by NaBH4 reduction gave R-(+)-1 in 83% overall yield with
[a]D = −19.6◦ [c = 0.2, CHCl3] (an equivalent of 38% ee;
23
◦
lit.13a,15 [a]D = +52 [c = 1.0, CHCl3]).
23
Conclusion
We have described here the total syntheses of the indoloquino-
lizidine natural products ( )-, R-(+)-, and S-(−)-deplancheine
2 1 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 4 0 – 2 1 4 4

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in 10 steps with an overall yield in the range of 1.4–2.7%.
The synthesis features an enatioselective intramolecular formal
aza-[3 + 3] cycloaddition reaction of a vinylogous amide to
furnish the quinolizidine CD-ring. This application serves to
introduce a new synthetic strategy for the synthesis of indole
alkaloids.
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Acknowledgements
RPH thanks NIH-NINDS [NS38049] for funding.
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 4 0 – 2 1 4 4
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2093.
46 Enantiomeric ratios were determined on an Agilent HPLC instru-
ment equipped with a Chiralcel OD column.
2 1 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 4 0 – 2 1 4 4