Total synthesis of the indole alkaloid (±)- and (+)-methyl N-decarbomethoxychanofruticosinate

Article abstract of DOI:10.1002/anie.201307788

All caged up: The first total synthesis of N- decarbomethoxychanofruticosinate (see figure) is achieved by using a SmI ₂-mediated intramolecular Reformatsky-like reaction to create the seven-membered ring, and an intramolecular oxidative coupling to install the caged and strained ring system. Copyright

Full text of DOI:10.1002/anie.201307788

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DOI: 10.1002/anie.201307788
Natural Product Synthesis
Total Synthesis of the Indole Alkaloid
(Æ)- and (+)-Methyl N-Decarbomethoxychanofruticosinate**
Yi Wei, Duo Zhao, and Dawei Ma*
Methyl N-decarbomethoxychanofruticosinate (1; Figure 1)[1]
belongs to a growing family of indole alkaloids with more
than twenty members, namely methyl chanofruticosinates[2–5]
(some of these members were also called kopreasins,[4b]
sinate alkaloids tested.[4b] Detailed investigations of the mode
of action and therapeutic potential of these alkaloids have
been very limited, however, and further studies must be
fueled by chemical synthesis. Structurally, methyl chanofru-
ticosinate alkaloids all contain a caged and strained hexacyclic
ring system, but are differentiated by their substituents at the
1-, 3-, 11-, 12-, 14-, and 15-positions. Other notable alkaloids
isolated from the Kopsia species include kopsinine,[7] kop-
sanone,[8] and kopsihainanine A.[9] During the past decades,
these natural products have received considerable attention
from the synthetic community.[10] However, none of methyl
chanofruticosinate alkaloids has been synthesized yet.
Herein, we report the first enantioselective total synthesis
of methyl N-decarbomethoxychanofruticosinate.
As outlined in Figure 2, we believed that the alkaloid
1 could be obtained by a diastereoselective attack on imine 2
with sodium cyanide and subsequent esterification. Building
Figure 1. Structures of methyl chanofruticosinate alkaloids and related
Kopsia alkaloids.
prunifolines,[2d] and flavisiamines[4a,c] by different isolation
groups). These alkaloids have been isolated from a variety of
Kopsia (Apocynaceae) species, which are widely distributed
in tropical Asia and have been historically used for the
treatment of diseases and symptoms like pharyngitis, tonsilli-
tis, rheumatoid arthritis,[6] and ulcerated noses in tertiary
syphilis.[3] Preliminary biological studies of these natural
products indicated that their existence is partially responsible
for the medicinal properties of the Kopsia (Apocynaceae)
species. For example, 1 has showed significant antitussive
activity in a citric acid induced guinea pig cough model, which
might be associated with the activation of d-opioid recep-
tors.[5] The same alkaloid also displayed relaxation activity
against phenylephrine-induced contractions of rat aortas, and
is the most potent agent among eleven methyl chanofrutico-
Figure 2. Retrosynthetic analysis of methyl N-decarbomethoxychano-
fruticosinate 1.
upon our recent successes in the syntheses of indoline
alkaloids through intramolecular oxidative coupling between
activated enolates and indoles,[11,12] we believed that 2 could
be assembled from the pentacyclic intermediate 3 through
a similar transformation. A SmI2-mediated cyclization[13]
could be used to construct the ketone 3 from the a-
bromoacetamide 4, which could be elaborated in either
racemic or enantioenriched form from the commercially
available 1,2,3,4-tetrahydro-4-oxocarbazole 5.
[*] Y. Wei, D. Zhao, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
E-mail: madw@mail.sioc.ac.cn
As depicted in Scheme 1, we started our synthesis by
protecting 5 using BnBr/NaH. Alkylation of the resultant
benzylation product 6 with ICH2CH2OTBS and subsequent
Michael addition with acrylonitrile provided the nitrile 7 in
45% overall yield. Reductive cyclization of 7 according to
Ergunꢀs procedure (nickel boride generated from NiCl2 and
[**] The authors are grateful to National Basic Research Program of
China (973 Program, grant 2010CB833200), Chinese Academy of
Sciences, and the National Natural Science Foundation of China
(grant 21132008 & 20921091) for their financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307788.
12988
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Scheme 2. Reagents and conditions: a) LiHMDS, THF, À788C,
30 min, then I2, À788C to RT, 35–78% yields; b) LiHMDS, THF, À78
to À408C, 30 min, then I2, À408C to RT, 77%; c) TMSCN, MeOH,
THF, 508C, 96%; d) K2CO3, H2O2, MeOH; e) HCl, MeOH, 45% yield
for 2 steps. HMDS=hexamethyldisilazide, TMS=trimethylsilyl.
Scheme 1. Reagents and conditions: a) BnBr, NaH, DMF, 83%;
b) LDA, ICH2CH2OTBS, THF, 65%; c) tBuOK, acrylonitrile, tBuOH,
THF, 70%; d) NiCl2·6H2O, NaBH4, NH2NH2·H2O, NaOH, EtOH;
e) Pd/C, H2, EtOH, 90% yield for 2 steps; f) 2-bromoacetyl chloride,
CH2Cl2, NaOH; g) HBr, THF; h) 0.05 mol% TPAP, NMO, CH2Cl2, 69%
yield for 3 steps; i) SmI2, THF, 78%; j) Na, liquid ammonia, THF,
tBuOH; k) BH3·THF; l) Py·SO3, DMSO, Et3N, CH2Cl2, 52% yield from
10a. DMSO=dimetylsulfoxide, DMF=N,N-dimethylformamide,
LDA=lithium diisopropylamide, NMO=N-methylmorpholine-N-oxide,
TBS=tert-butyldimetylsilyl, THF=tetrahydrofuran, TPAP=tetrapropyl-
ammonium perruthenate.
iodation is much faster than oxidation of the corresponding
anion to the radical at lower temperatures (ca. À788C). To
solve this problem, we decided to increase the reaction
temperatures before adding iodine. After some experimenta-
tion, we were pleased to find that if iodine was added at
À408C, the desired oxidative coupling product (Æ)-2[17] could
be obtained in 77% yield. No iodation product 12 was
observed in this case, thus indicating that reaction temper-
eature plays an essential role in differentiating reaction
pathways. Next, reaction of (Æ)-2 with hydrogen cyanide
(generated in situ from TMSCN and MeOH) provided the
amino nitrile (Æ)-13,[17] which was further treated with K2CO3
and hydrogen peroxide in methanol to afford the amide (Æ)-
14. Finally, treatment of (Æ)-14 with methanolic hydrochlo-
ride delivered the target molecule (Æ)-1, whose analytical
data were in agreement with those reported for natural
methyl N-decarbomethoxychanofruticosinate.[1] Its structure
was further confirmed by X-ray analysis.[17] Noteworthy is that
esterification of (Æ)-13 with methanolic hydrochloride and
hydrolysis of (Æ)-13 using either Ba(OH)2 or NaOH returned
(Æ)-2 as the single product, thus indicating that (Æ)-13 readily
undergoes cyanide elimination under both acidic and basic
conditions.
NaBH4 as the catalyst, hydrazine hydrate as the hydrogen
source)[14] delivered the imine 8, which was further reduced by
hydrogenation to afford the amine 9 stereoselectively. Next,
acylation of 9 with 2-bromoacetyl chloride produced the
corresponding amide, which was subjected to silyl ether
cleavage and Ley oxidation to produce the aldehyde 4a. The
stage was then set for an intramolecular Reformatsky-like
reaction to construct the seven-membered lactam. As we
expected, SmI2-mediated cyclization of 4a proceeded
smoothly at room temperature,[13] thus resulting in the b-
hydroxy lactam 10a in 78% yield as a mixture of two
diastereomers. After debenzylation of 10a with sodium and
liquid ammonia in THF/tBuOH to yield the lactam 11,[15]
selective reduction of the amide moiety was carried out with
borane to give the corresponding amino alcohol, which was
oxidized into (Æ)-3 under Parikh–Doering conditions in 52%
overall yield. The ketone (Æ)-3 was then ready for intra-
molecular oxidative coupling to install the caged, strained
ring system in the target molecule.
In the addition of hydrogen cyanide to (Æ)-2, only one
diastereomer was observed. This phenomenon could be
rationalized by the X-ray structure analysis of (Æ)-2
(Figure 3). A strong 1,3-diaxial interaction occurs if the
cyanide attacks the imine moiety from the Re face. Thus,
Our previous studies on intramolecular oxidative coupling
focused on using activated enolates.[11] Higuchi and co-
workers have recently demonstrated that oxidative coupling
between unactivated enolates and indoles is possible.[16]
Interestingly, under our previous reaction conditions
(2.2 equiv LiHMDS, À788C, then adding iodine),[11a,b] reac-
tion of (Æ)-3 produced the iodide 12 in 35% yield with about
50% conversion (Scheme 2). Increasing the amount of
LiHMDS to 4 equivalents gave complete conversion, but 12
was the single product (78% yield). This result indicated that
Figure 3. Stereochemical course in addition of hydrogen cyanide to the
imine (Æ)-2.
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nucleophilic attack from the Si face is favored and (Æ)-13 was
isolated as a single product.
steps (racemic) or 19 linear steps (enantioselective) from
commercially available 5. This route should allow the
assembly of the other members in methyl chanofruticosinate
family by tuning the substituents in carbazolones 5–7, and
therefore prompts the synthetic studies of these alkaloids and
their analogues, as well as their structure–activity relationship
investigations. Additionally, our observations during the
oxidative coupling of the indole moiety with activated and
unactivated enolates should serve as precedents for mecha-
nistic studies and further synthetic applications of this
strategy.
Very recently, the groups of Lupton[10i] and Shao[10j]
independently revealed that enantioselective palladium-cata-
lyzed decarboxylative allylation[18] of carbazolones could
produce enantioenriched carbazolones bearing a quaternary
carbon center. We envisioned that their products could be
perfectly applied to the asymmetric synthesis of 4. We
therefore attempted to develop an enantioselective synthesis
of N-decarbomethoxychanofruticosinate using this method-
ology. As outlined in Scheme 3, using the phosphine 15 as
a ligand, the carbazolone 16 was prepared from 5 in four steps
Received: September 4, 2013
Published online: November 20, 2013
Keywords: alkaloids · natural products · samarium ·
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strained molecules · total synthesis
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Scheme 3. Reagents and conditions: a) K2OsO4, NaIO4; b) NaBH4,
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d) NiCl2·6H2O, NaBH4, NH2NH2·H2O, NaOH, EtOH; e) Pd/C, H2,
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DMSO, Et3N, CH2Cl2, 74% yield for 2 steps; l) LiHMDS, THF, À78–
408C, 30 min, then I2, À408C to RT, 77%; m) TMSCN, MeOH, THF,
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in 48% overall yield and 94% ee. Oxidative cleavage of the
allyl group in 16, subsequent reduction with NaBH4, and
protection with TBSCl provided the silyl ether 17 in 91%
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genation of the resultant imine gave rise to 18, which was
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assembled by following a same procedure as shown in
Scheme 2.
In conclusion, we have accomplished the first total
synthesis of methyl N-decarbomethoxychanofruticosinate,
which features a SmI2-mediated intramolecular Reformat-
sky-like reaction to create its seven-membered ring and an
intramolecular oxidative coupling to install its caged and
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