Towards the Sarpagine-Ajmaline-Macroline Family of Indole Alkaloids: Enantioselective Synthesis of an N-Demethyl Alstolactone Diastereomer

Article abstract of DOI:10.1002/chem.202000415

the strategy involving the use of functionalized tetrahydro-6H-cycloocta[b]indol-6-one is reported as a key intermediate for synthesis of members of the sarpagine-ajmaline-macroline family of monoterpene indole alkaloids. The desired tricycle was synthesized through the following key steps: 1) Evans’ syn-selective aldolization; 2) Liebeskind–Srogl cross-coupling using the phenylthiol ester of 3-chloropropanoic acid as a surrogate of acrylic thioester for the synthesis of 2,3-disubstituted indoles; and 3) ring-closing metathesis (RCM) for the formation of the eight-membered ring. An N-allylation followed by intramolecular 1,4-addition was planned for synthesis of the vobasine class of natural products. However, attempted cyclizations under a diverse set of conditions involving anionic, radical, and organopalladium/organonickel species failed to produce the bridged ring system. On the other hand, esterification of the pendant primary alcohol function with acetoacetic acid, followed by intramolecular Michael addition, afforded the desired tetracycle with excellent diastereoselectivity. Subsequent functional group manipulation and transannular cyclization of the amino alcohol afforded the N(1)-demethyl-3,5-diepi-alstolactone. We believe that the same synthetic route would afford the alstolactone should the amino alcohol with appropriate stereochemistry be used as the starting material.

Full text of DOI:10.1002/chem.202000415

A Journal of
Accepted Article
Title: Towards Sarpagine-Ajmaline-Macroline Family Indole Alkaloids:
Enantioselective Synthesis of N-Demethyl Alstolactone
Diastereomer
Authors: Dylan Dagoneau, Qian Wang, and Jieping Zhu
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To be cited as: Chem. Eur. J. 10.1002/chem.202000415
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10.1002/chem.202000415
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Towards Sarpagine-Ajmaline-Macroline Family Indole Alkaloids:
Enantioselective Synthesis of N-Demethyl Alstolactone
Diastereomer
Dylan Dagoneau, Qian Wang and Jieping Zhu*
Abstract: We report herein our strategy aiming at using the functionalized tetrahydro-6H-cycloocta[b]indol-6-one as a key
intermediate for the synthesis of sarpagine-ajmaline-macroline family of monoterpene indole alkaloids. The desired tricycle was
synthesized via following key steps: a) Evans’ syn-selective aldolization; b) Liebeskind-Srogl cross-coupling using phenylthiol ester of
3-chloropropanoic acid as a surrogate of acrylic thioester for the synthesis of 2,3-disubstituted indoles; c) ring-closing metathesis (RCM)
for the formation of the 8-membered ring. An N-allylation followed by intramolecular 1,4-addition was planned for the synthesis of
vobasine class of natural products. However, cyclization under a diverse set of conditions involving anionic, radical and
organopalladium/organonickel species failed to produce the bridged ring system. On the other hand, esterification of the pendent
primary alcohol with acetoacetic acid followed by intramolecular Michael addition afforded the desired tetracycle with an excellent
diastereoselectivity. Subsequent functional group manipulation and transannular cyclization of the amino alcohol afforded the N(1)-
demethyl-3,5-diepi-alstolactone. We believe that the same synthetic route would afford the alstolactone should the amino alcohol with
appropriate stereochemistry be used as a starting material.
HO
O
OH
7
Introduction
OH
COOMe
5
N
4N16
H
N
MeN
4
17
21
20
N
3
N
H
H
3
The sarpagine-ajmaline-macroline family of monoterpene indole
alkaloids comprises more than 300 members, including over 80
bisindoles. [1] Several of these natural products exhibit cytotoxicity
against various cancer cell lines and are capable of reversing the
multi-drug resistance.[2] Biosynthetically, sarpagine (1) is
produced by a reduction and decarboxylation sequence from
polyneuridine aldehyde which is in turn generated from 4,5-
dehydrogeissoschizine via an intramolecular Mannich reaction
15
HO
polyneuridine aldehyde
1 sarpagine
2 ajmaline
SBE
5
4
N
H
H
3
R
Me
Me
OH
O
N
N
N
N
O
H
N
H
H
16
Me
H
OH
MeOOC
(C5-C16 bond formation).[3] Ajmaline (2),
a
class Ia
6 vobasine
4,5-dehydrogeissoschizine
3 macroline
R = COOMe
antiarrthythmic agent widely used in the acute treatment of atrial
or ventricular tachycardia, is formed from polyneuridine aldehyde
via a key intramolecular aldol reaction. Sarpagine itself is in turn
a biogenetic precursor of a number of other natural products.
Thus, macroline (3) is proposed to be biosynthesized from
H
H
H
H
Me
H
O
O
O
O
N
N
N
Me
N
Me
H
H
H
H
sarpagine
derivative
via
a
sequence
of
N-
4 alstonerine
5 alstolactone
methylation/oxidation/retro-Michael addition. Although it has not
N
OH
OH
Me
O
been isolated from plants, macroline is believed to be a precursor
16
16
Me
[4]
N
N
N
of numerous other alkaloids such as alstonerine (4)
and
N
O
N
H
O
H
H
alstolactone (5).[5] Alternatively, cleavage of the C3-N4 bond of
sarpagan alkaloids affords another sub-family of natural products
represented by vobasine (6),[6] affinine (7), 16-epi-affinine (8) [7]
and amerovolficine (9).[8] The presence of a carbonyl or a hydroxy
group at C3 in vobasine (6) and its congeners renders this carbon
intrinsically electrophilic, prone to react with electron-rich aromatic
ring of other indole alkaloids. Indeed, vobasine (6) and its relatives
are main constituents of many dimeric indole alkaloids as
O
9 amerovolficine
8 16-epi-affinine
7 affinine
OMe
OMe
OMe
O
O
N
OH
O
O
Me
Me
N
H
N
H
MeO
N
N
N
H
H
H
MeO
H
HN
HN
HN
N
OHC
MeO2C
[a]
Dr. D. Dagoneau, Dr. Q. Wang, Dr. Jieping Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
École Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
N
MeO2C
N
OH
10 conodiparine
OH
12 conodirinine A
11 vobatricine
Homepage: http://lspn.epfl.ch
Scheme 1. The sarpagine-ajmaline-macroline family of indole alkaloids:
representative examples and biosynthesis.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.202000415
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exemplified by conodiparine (10),[9] vobatricine (11),[10] and
conodirinine A (12) (Scheme 1).[11]
O
The common structural feature of this family of indole
alkaloids is the presence of an 8-membered ring, either in its
native form or embedded in a bridged [3,3,1]bicyclic structure
(Scheme 2, highlighted in red). Total synthesis of this class of
natural products has attracted attention of synthetic chemists for
many years.[12] The representative approaches developed by
Tamelen,[13] Kutney,[14] Cook,[15] Martin,[16] Kuethe,[17] Kwon,[18]
Craig[19] and Gaich[20] are depicted in Scheme 2. As it is seen, all
these successful routes involved the stepwise construction of C
and D ring to reach the [3,3,1]bicyclic ring system.
OMe
C
C
NBn
NBn
N
N
Me
Me
COOMe
Martin
Cook
O
O
Ts
D
OEt
N
D
BnN
N
N
Me
I
Me
H
N
COOEt
FG1
Kuethe
Kwon
H
P
N
Me
H
FG2
H
H
OMe
O
C
Ts
ND
In connection with our research program dealing with the
indole alkaloids synthesis,[21] we became interested in the
sarpagine-ajmaline-macroline family of natural products. Keeping
in mind the literature precedents, we decided to explore a
completely different strategy aimed at using 6/5/8 fused tricycle
13 as a springboard to these alkaloids (Scheme 3a). Specifically,
N-alkylation of 13 by a suitably functionalized four carbon synthon
would afford 14 which, upon intramolecular Michael addition or
related transformations and functional group manipulation, would
afford vobasine (6), affinine (7) or epi-affinine (8) and
amerovolficine (9). On the other hand, O-alkylation followed by
cyclization of the resulting ether 15 would provide macroline-type
alkaloids such as alstonerine (4) [22] and alstolactone (5). Tricycle
13 would be accessible by intramolecular ring closing metathesis
of the corresponding diene 16 which could in turn be synthesized
by C-2 acylation of indole 17 (Scheme 3b). The latter was thought
to be synthesized from 18 by functional group interconversion
including a double SN2 reaction of the secondary alcohol in order
to obtain the desired relative stereochemistry between C5 and
C16 (monoterpene indole alkaloid numbering). The Evans’
aldolization between aldehyde 19 and imide 20 followed by
reduction was planned to reach 18. We report herein the
synthesis of the tricycle 13 and its subsequent conversion to a
stereoisomer of alstolactone. As it will be detailed below, should
the correct relative stereochemistry of the amino alcohol be
secured, the same strategy would lead us to the alstolactone 5.
N
E
N
O
D
Me
O
O
H
H
Craig
OH
Gaich
CN
H
N
N
O
N
H
N
H
H
H
O
Tamelen/Matin
Kutney
Scheme 2. The sarpagine-ajmaline-macroline family of alkaloids:
representative synthetic strategies: Formation of 6-membered ring via C-C bond
formation between two blue color coded carbons for the construction of
[3,3,1]bicycle.
N
OH
O
R
Me
Me
N
N
N
H
N
H
O
N
O
H
O
6 vobasine
R = COOMe
7 affinine
9 amerovolficine
8 16-epi-affinine
OP2
P1
P1HN
OP2
N
(a)
N
H
13
N
H
O
O
14
P1N
O
H
H
MeN
H
Me
N
MeN
H
H
H
N
O
H
Results and Discussion
O
O
H
H
N
H
O
O
Synthesis of 6/5/8 fused tricycle. Reaction of aldehyde 19,
freshly prepared by reduction of the corresponding Weinreb
amide with DIBAL,[23] with imide 20 (ee 99%)[24] under the
standard conditions developed by Evans[25] gave aldol 21 in 74%
yield with excellent syn-diastereoselectivity (Scheme 4).
Reduction of 21 with lithium borohydride[26] followed by treatment
of the resulting crude reaction mixture with TIPSCl afforded
chemoselectively the monoprotected silyl ether 22 in 84% overall
yield together with the recovered chiral oxazolidinone (78%). N-
Boc protection of 22 afforded 18 in 91% yield.
4 alstonerine
5 alstolactone
15
BocHN
16
OTIPS
5
OTIPS
NHBoc
13
N
Boc
N
O
Boc
16
17
(b)
O
O
5
OTIPS
O
OH
N
O
To reach amerovolficine (9), 1,3-amino alcohol 17 was
needed and a double SN2 process involving a sequence of
halogenation of the secondary alcohol 18 followed by
displacement of the resulting alkyl halide with azide was initially
pursued to convert 21 to 17. Unfortunately, halogenation of the
secondary alcohol 22 turned out to be problematic. Under a
variety of conditions, either decomposition of the substrate
+
N
Bn
H
N
Boc
18
19
20
Scheme 3. Proposed synthetic approach to sarpagine-ajmaline-macroline
family alkaloids.
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(PBr3/DIPEA, POCl3/pyridine or PCl3/pyridine) or unwanted
the desired coupling adduct 31 which underwent b-elimination
during the flash column chromatography (eluent containing Et3N)
to furnish directly the desired diene 32 in 90% yield on a multigram
scale. It is interesting to note that coupling of 29 with S-phenyl
elimination
processes
(CCl4 or
CBr4/PPh3,
Br2
or
I2/PPh3/imidazole) were observed and the desired product 23 was
never isolated (Scheme 4).[27] Similarly, only decomposition
occurred applying these conditions to the N-unprotected indole 22. prop-2-enethioate gave 32 in rather poor and unreproducible yield
Alternatively, mesylation of 18 (MsCl, Et3N) furnished the
mesylate 24 in excellent yield. Attempt to perform an SN2 reaction
of 24 with different sources of halides (TBAC, TBAB, LiCl or LiBr)
[28] failed to afford the substitution product 23. A complex mixture
containing the elimination products was instead obtained. Finally,
chlorination of 18 with thionyl chloride in the presence of pyridine
or 2,6-lutidine afforded 25 in high yields (89%). However, the
reaction occurred with retention of configuration instead of the
desired inversion process.[29] This was confirmed by converting
both the chloride 25 and mesylate 24 to the same alkyl azide 26.
We note that the reaction between tetrabutylammonium azide and
mesylate 24 proceeded much cleaner than that involving alkyl
chloride 25. Staudinger reduction of the crude azide 26 resulting
from mesylate 24 afforded 27 in 65% overall yield from alcohol 18.
due to the easy polymerization of this conjugated thioester. Diene
32 was then submitted to several ring-closing metathesis (RCM)
conditions.[33,34] Gratefully, the desired tricycle 33 was obtained in
85% yield when the reaction was performed in DCE at 80 °C in
the presence of Grubbs 2nd generation catalyst. It was important
to add the catalyst in 4 portions over a period of 30 h in order to
reach a complete and clean conversion, particularly on large scale.
BocHN
BocHN
OTIPS
Cl
OTIPS
30, b
a
28
SnBu3
N
Boc
N
Boc
O
29
31
BocHN
Bn
OTIPS
O
BocHN
O
OTIPS
O
a
O
N
N
O
c
O
+
N
H
OH
N
H
O
O
Bn
PhS
Cl
N
O
N
Boc
30
19
20 (ee 99%)
21
Boc
33
O
32
b,c
X
Scheme 5. Synthesis of 6/5/8 fused tricycle. Reagents and conditions: [a]
LiTMP, then n-Bu3SnCl, THF, -78 °C, 95%; [b] Pd2(dba)3 (10 mol%), AsPh3 (10
mol%), CuDPP, hexane/THF, RT, 90%; [c] Grubbs II (4 x 5 mol%), 1,2-DCE,
80 °C, 85%.
OH
N
d
OTIPS
X
N
OTIPS
R
Boc
22 R = H
18 R = Boc
23 X = Cl, or Br
e
f
Approach towards the affinine skeleton. A sequence of N-
allylation of 33 followed by intramolecular 1,4-addition was
envisaged to reach the affinine (7). Selective deprotection of the
C5-NHBoc without touching the indolyl N-Boc of 33 was
accomplished using modified Ohfune conditions (Scheme 6).[35]
Thus, stirring a CH2Cl2 solution of 33 with TBDMSOTf/lutidine
afforded the corresponding tert-butyldimethylsilyl carbamate
which, upon treatment with a solution of HCl in Et2O at 0 °C for 30
min, furnished the desired primary amine 34. N-Allylation of the
crude amine 34 with allyl bromide 35 in the presence of cesium
carbonate afforded the desired N-allyl amine 36 together with the
allyl carbamate 37. The latter appeared to be formed by
carbonylation of the amine with CO2 generated in situ from the
partial neutralization of Cs2CO3.[36] To avoid this side reaction,
other bases, particularly organic bases, were screened and
DIPEA was found to give the cleanest reaction leading to vinyl
iodide 36 in 69% overall yield from 33.
Cl
OMs
OTIPS
N
N
OTIPS
Boc
Boc
25
24
g
g
h
OTIPS
NHR
N
N3
N
OTIPS
Boc
26
27 R = H
28 R = Boc
Boc
i
Scheme 4. Synthesis of 1,3-amino alcohol involving the Evans aldolization as
a key step. Reagents and conditions: [a] n-Bu2BOTf, Et3N, CH2Cl2, -78 to 0 °C,
74%; [b] LiBH4, MeOH, THF, 0 °C; [c] TIPSCl, imidazole, CH2Cl2, RT, 84% in
two steps; [d] Boc2O, DMAP, CH2Cl2, RT, 91%; [e] MsCl, Et3N, CH2Cl2, RT; [f]
SOCl2, 2,6-lutidine, 1,2-DCE, RT; [g] n-Bu4NN3, MeCN, 65 °C from 24 or DMF,
85 °C from 25; [h] PPh3, THF/H2O, 40 °C, 65% from 18 via 24; 38% from 18 via
25; [i] Boc2O, CH2Cl2, 0 °C, 93%.
Since the relative and absolute configuration of compound
28 matches with that of the enantiomer of affinine (7),[30] we
decided to move forward our synthesis with 28 in order to test the
feasibility of our strategy. The deprotonation of the C-2 position of
indole 28 with LiTMP followed by trapping of the resulting lithiated
intermediate with electrophiles, such as acryloyl and crotonyl
chloride and their corresponding Weinreb amides provided a
With vinyl iodide 36 in hand, cyclization to the bridged ring
system of affinine was examined (Scheme 7). Attempts to
generate in situ the vinyllithium species by lithium/halogen
[37]
exchange (t-BuLi, THF, HMPA, TMSCl)
followed by
intramolecular 1,4-addition led to the decomposition of the
starting materials. Vinyl radical generated using AIBN/Bu3SnH[38]
[39]
or BEt3
as initiators also failed to cyclize leading to the
complex reaction mixture.
A
two-step sequence was
deiodinated compound 38 as an only isolable product. Transition
metal-catalyzed reactions also failed to produce the desired
product, although interesting polycycles were isolated. Thus,
Ni(0)-catalyzed cyclization afforded polycycle 39 in 42% yield[40]
while Pd(0)-catalyzed reductive Heck reaction under a variety of
subsequently developed for the C-2 acylation of 28 (Scheme 5).
Treatment of indole 28 with LiTMP followed by adding tributyltin
chloride afforded C-2 stannylated indole 29. The palladium-
catalyzed Liebeskind-Srogl coupling[31] between 29 and the
thioester 30 under our recently optimized conditions[32] provided
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conditions[41] afforded the Heck product 40 in up to 63% yield
together with 38 (see Table 1 in the Supporting Information)
complex LnM(0) would generate the vinylM(II)X species 41 which
may undergo transannular cyclization to hemiaminal 42. In the
case of Ni catalyst, intermediate Ni(II) species 42a might undergo
ligand exchange with the neighbouring hydroxy group to provide
43 which, upon reductive elimination, provided 39. With Pd
catalyst, the intermediate 42b would undergo the intramolecular
Heck reaction to afford 40 via the C(sp3)-Pd species 44.
I
BocHN
H2N
OTIPS
a
OTIPS
HN
OTIPS
35, b
N
N
Boc
O
O
Boc
Assuming that the hemiaminal intermediate 42 was
responsible for the formation of 39 and 40, it was decided to
methylate the secondary amine since the final natural product
affinine (7) contains the N-methyl group anyway. Reaction of 36
with an excess of formaldehyde in methanol in the presence of
NaBH3CN at room temperature gave the desired tertiary amine
45 in 89% yield (Figure 1). Submitting the latter to lithium /
halogen exchange (t-BuLi) led once again to decomposition.
Unfortunately, the deiodination product was the only isolated
product under a variety of radical-based or transition metal-based
conditions. It should be noted that partial deallylation of the
starting material was also observed when the reductive Heck
reaction was performed in the presence of Et3N at temperature
higher than 80 °C.
N
O
36
Boc
33
34
O
NH
OTIPS
O
Br
I
I
35
N
Boc
37
O
Scheme 6. Reagents and conditions: [a] TBDMSOTf, 2,6-lutidine, CH2Cl2, RT,
then 1 M HCl in Et2O, 0 °C; [b] DIPEA, DMF, RT, 69% from 33.
OTIPS
H
I
I
I
N
I
H
OTIPS
NH
O
NMe
N
NR
OTIPS
a
b
OTIPS
NH
OH
OTIPS
NH
Boc
39
OTIPS
H
N
Boc
N
Boc
O
N
Boc
N
O
N
H
O
N
Boc
O
O
38
46 R = H
47 R = Me
36
OH
N
45
48
Boc
40
Figure 1. Other substrates investigated for the cyclization.
Scheme 7. Reagents and conditions: [a] Ni(COD)2, Et3N, MeCN, RT, then
Et3SiH, 42%; [b] Pd(OAc)2, PPh3, HCOONa, DMF, 60 °C, 63%.
R
R
OTIPS
OTIPS
H
Me
Me
H
N
N
H
N
H
N
O
O
H
PdII
I
N
N
O
OH
N
Boc
40
N
Boc
OH
vobasidine B (49)
vobasidine D (50)
44
OTIPS
N
I
[M]II
NH
HN
I
route b
M = Pd
OTIPS
NH
OTIPS
M0
OTIPS
H
OTIPS
X
a
N
N
O
N
Boc
O
Boc
[M]II
I
H2N
OTIPS
51
53
N
Boc
OH
N
Boc
O
N
Boc
O
O
42a M = Ni
42b M = Pd
41a M = Ni
41b M = Pd
36
OTIPS
O
HN
HN
OTIPS
X
N
Boc
route a
M = Ni
O
b
34
OTIPS
H
N
OTIPS
H
N
N
O
N
Boc
O
Boc
52
54
NiII
O
N
O
N
Boc
Boc
39
43
Scheme 9. Attempted cyclization of enamine and enaminone aimed at
vobasidine B (49) and vobasidine D (50). Reagents and conditions: [a] n-
C3H7CHO, 4 Å MS, 1,2-DCE, RT; [b] MeCOCH=CHONa, AcOH, 4 Å MS, 1,2-
DCE, RT.
Scheme 8. Postulated reaction pathways leading to 39 and 40.
Possible reaction pathways leading to 39 and 40 are depicted
in Scheme 8. Oxidative addition of vinyl iodide to low valent metal
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To determine the impact of the bulky TIPS group on the
reaction outcome, compounds 46 and 47 were prepared from 36
and 45, respectively (THF, TBAF, AcOH). However, neither of
them underwent the desired cyclization under various conditions.
Compound 48 with a free indolyl NH, prepared by removal of the
N-Boc from 36 under acidic conditions (TFA), also failed to afford
the bridged ring system of the affinine skeleton.
desired cyclization to afford tetracycle 59. The reaction was highly
diastereoselective leading to an 8/6 cis-fused ring system as a
single diastereomer in 87% yield from 55. The relative
stereochemistry of the two newly formed stereocenters was
confirmed by ROESY analysis which highlighted the correlations
of H16/H15 and H16/H20. We note that the cyclization did not go
to completion with Na2CO3 and K2CO3 as bases even after
extended reaction time. Using stronger bases such as DBU, t-
BuOK or NaH led only to decomposition of the substrate.[46] The
1,3-ketolactone moiety of 59 was then converted to the desired
conjugated lactone 57 by triflation followed by Pd-catalyzed
reduction of the resulting enol triflate 60. The choice of the
reductant proved to be critical for the final geometry of the double
bond. For instance, triethylsilane[47] and methyl formate gave E/Z
ratio of 2/1 and 2.5/1, respectively. More promising results for the
generation of the desired (E)-isomer were obtained using
triethylammonium formate.[48] With equimolar amount of formic
acid and triethylamine, a 4/1 mixture (E/Z) was obtained but when
an excess of formic acid was employed, the ratio decreased to
3/1. Finally, using an excess of triethylamine, an excellent E/Z
ratio of 12/1 was obtained and the desired (E)-product 57 was
isolated in 72% yield over 2 steps. Since the geometry of enol
triflate was not determined, we hypothesized that in the presence
of an excess of base, the vinylpalladium triflate intermediate might
undergo the b-hydride elimination to afford an allene intermediate
which then was reduced stereoselectively to the E-alkene 57.
Knowing that the enamine and enaminone functions are found
in natural products such as vobasidine B (49) and vobasidine D
(50), imine 51 and enaminone 52 were prepared by condensation
of primary amine 34 with butanal and in situ generated
acetoacetaldehyde,[42] respectively (Scheme 9). The resulting
crude mixture, after removal of molecular sieves by filtration and
volatiles under vacuum, was submitted to intramolecular Michael
addition. Unfortunately, neither 53 nor 54 were isolated under a
variety of conditions varying the nature of Lewis acids, bases and
temperature.[43]
Approach towards the macroline skeleton. The difficulties
encountered in forming the desired bridged ring system of the
vobasine skeleton prompted us to investigate the macroline family
and more specifically the synthesis of alstolactone (5). As we
already had in hand the advanced tricyclic enone 33, we decided
to start our exploration from this intermediate although we were
aware of the fact that the relative stereochemistry of 33 did not
match the natural product and its cyclization would afford a
diastereomer of the natural product (cf Scheme 11). To reach this
goal, formation of a 8/6 cis-fused ring system and transannular
cyclization leading to aza-bridged [3,3,1] bicycle would have to be
accomplished.
BocHN
BocHN
OH
O
O
a
b
O
N
Boc
N
Boc
O
O
55
58
BocHN
Br
BocHN
OR
O
H
BocHN
O
BocHN
O
H
O
O
H
O
BocHN
O
O
b
15
16
d
c
20
X
H
O
OTf
H
H
N
Boc
Me
N
Boc
O
O
N
N
Boc
O
O
Boc
N
Boc
O
33 R = TIPS
55 R = H
59
60
a
56
57
RHN
O
H
H2N
O
H
O
O
g
f
Scheme 10. Attempted cyclization of enamine and enaminone aimed at
vobasidine B (49) and vobasidine D (50). Reagents and conditions: [a] TBAF,
AcOH, THF, RT; [b] (Z)-2-bromobut-2-enoic acid, EDCI, DMAP, DIPEA, RT,
87% from 33.
H
H
H
N
R
N
H
O
OH
62
57 R = Boc
61 R = H
e
HN
H
H
H2N
H
O
The synthesis of the required vinyl bromide 56 was
accomplished in a two-step sequence (Scheme 10). Removal of
the silyl protecting group from 33 (TBAF buffered with acetic acid)
followed by acylation of the resulting alcohol 55 with (Z)-2-
bromobut-2-enoic acid, synthesized in 3 steps from methyl
crotonate,[44] furnished the desired ester 56 in 87% yield over 2
steps. Unfortunately, submitting 56 to different cyclization
conditions led only to the decomposition of the starting material.
O
O
O
H
NH
N
H
N(1)-demethyl-3,5-diepi-
64
alstolactone (63)
Scheme 11. Synthesis of alstolactone skeleton (64). Reagents and conditions:
[a] MeCOCH2COOH, EDCI, DMAP, DIPEA, RT; [b] Cs2CO3, 4 Å MS, acetone,
55 °C, 87% from 33; [c] Cs2CO3, 4 Å MS, THF, RT then PhNTf2; [d] Pd(OAc)2
(20 mol%), PPh3 (50 mol%), HCOOH (5.0 equiv), Et3N (10 equiv), DMF, 60 °C,
2 steps; [e] BF3•Et2O, CH2Cl2, RT; [f] NaBH4, CeCl3, K2CO3,
MeOH/CHCl3, -40 °C, 77% over 2 steps; [g] TFE, 105 °C, 79%.
Intramolecular Michael addition using 1,3-ketoester as an
internal nucleophile turned out to be more rewarding which led to
a successful synthesis of alstolactone skeleton as shown in
Scheme 11. Esterification of alcohol 55 with acetoacetic acid,
freshly prepared by hydrolysis of tert-butyl acetoacetate under
acidic conditions (TFA),[45] furnished the ketoester 58. After
screening of various bases, it was found that heating to reflux an
acetone solution of 58 in the presence of Cs2CO3 triggered the
72% over
The double N-Boc deprotection by treating
dichloromethane solution of 57 with an excess of BF3•OEt2
afforded cleanly compound 61. The chemoselective reduction of
a
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10.1002/chem.202000415
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the ketone in the presence of a,b-unsaturated lactone was
Acknowledgements
attempted with sodium borohydride at low temperature (-40 °C).
[49]
However, the conversion was low and 1,4-reduction of the
Financial supports from EPFL (Switzerland) and Swiss National
Science Foundation (SNSF, N° 20020-169077) are gratefully
acknowledged.
conjugated lactone moiety became competitive when the reaction
was performed at higher temperature. Under the Luche
conditions[50] at -40 °C, complete consumption of the starting
material occurred after 4 h albeit with moderate yield due probably
to the instability of the resulting benzylic alcohol. Fortunately, by
adding a substoichiometric amount of potassium carbonate to
buffer the reaction media, the desired secondary alcohol 62 was
isolated in 77% yield. Although of no consequence, the reduction
turned out to be highly diastereoselective providing 62 as a single
diastereoisomer.
Keywords: Indole alkaloid • sarpagine • ring closing metathesis
(RCM) • transannular cyclization • asymmetric synthesis •
homogeneous catalyst
[1]
a) S. E. Lewis, Tetrahedron 2006, 62, 8665; b) M. D. Rahman, V. V. N.
P. B. Tiruveedhula, J. M. Cook, Molecules 2016, 21, 1525.
[2]
[3]
[4]
O. A. Namjoshi, J. M. Cook, Alkaloids Chem. Biol. 2016, 76, 63.
S. E. O’Connor, J. J. Maresh, Nat. Prod. Rep. 2006, 23, 532.
J. M. Cook, P. W. Le Quesne, R. C. Elderfield, J. C. S. Chem. Commun.
1969, 1306.
To accomplish the final transannular cyclization, an SN1
mechanism via dehydration of the benzylic alcohol 62 followed by
trapping the resulting azafulvenium species by the internal amine
nucleophile was a reasonable pathway to pursue. To our surprise,
this sequence has rarely been investigated although the reverse
reaction involving the opening of azabicyclo[3.3.1]nonane system
to the corresponding 8-membered ring is known.[51] Büchi and
coworkers reported in 1964 that such cyclization could proceed
by simple thermolysis of the substrate in refluxing xylene.[52]
However, submitting our substrate 62 in refluxing xylene gave,
after 12 h, a complex mixture from which the desired product is
identified in about 10% yield. Lowering the reaction temperature
by performing the reaction in refluxing toluene led to the recovery
of the starting material. As strong acid could not assist the desired
transformation due to the protonation of the amine nucleophile,
fluorinated solvents (HFIP with pka of 9.3 and TFE with pka of
12.4), were evaluated as promoters.[53] The optimum conditions
found consisted of heating a solution of 63 in TFE at 105 °C for
24 h. Under these conditions, the desired N(1)-demethyl-3,5-
diepi-alstolactone (63) was isolated in 79% yield (Scheme 11).
[5]
[6]
a) T.-S. Kam, Y. M. Choo, Phytochemistry 2004, 65, 603; b) S.-J. Tan,
J.-L. Lim, Y.-Y. Low, K.-S. Sim, S.-H. Lim, T.-S. Kam, J. Nat. Prod. 2014,
77, 2068.
Isolation: a) U. Renner, D. A. Prins, A. L. Burlingame, K. Biemann, Helv.
Chim. Acta. 1963, 46, 2186; b) M. P. Cava, S. K. Talapatra, J. A.
Weisbach, B. Douglas, G. O. Dudek, Tetrahedron Lett. 1963, 4, 53; c) D.
S.-Y. Sim, K.-W. Chong, C.-E. Nge, Y.-Y. Low, K.-S. Sim, T.-S. Kam, J.
Nat. Prod. 2014, 77, 2504.
[7]
[8]
[9]
Isolation: a) J. A. Weisbach, R. F. Raffauf, O. Ribeiro, E. Macko, B.
Douglas, J. Pharm. Sci. 1963, 52, 350; b) R. H. Burnell, J. D. Medina,
Can. J. Chem. 1971, 49, 307; c) J. Naranjo, M. Pinar, M. Hess, H. Schmid,
Helv. Chim. Acta. 1972, 55, 752; d) R. M. Braga, H. F. L. Filho, F. D. A.
M. Reis, Phytochem. 1984, 23, 175.
Isolation: a) J. A. Martinez, C. Gomez, T. Santana, H. Velez, Planta
Medica, 1989, 55, 283; b) X.-J. Hu, H.-P. He, H. Zhou, Y.-T. Di, X.-W.
Yang, X.-J. Hao, L.-Y. Kong, Helv. Chim. Acta 2006, 89, 1344; c) B.-J.
Zhang, L. Peng, Z.-K. Wu, M.-F. Bao, Y.-P. Liu, G.-G. Cheng, X.-D. Luo,
X.-H. Cai, J. Asian Nat. Prod. Res. 2013, 15, 1221.
T.-S. Kam, K.-M. Sim, H.-S. Pang, J. Nat. Prod. 2003, 66, 11.
[10] T.-S. Kam, K.-M. Sim, Helv. Chim. Acta. 2002, 85, 1027.
[11] T.-S. Kam, K.-M. Sim, Helv. Chim. Acta. 2003, 86, 122; b) M.-F. Bao, J.-
M. Yan, G.-G. Cheng, X.-Y. Li, Y.-P. Liu, Y. Li, X.-H. Cai, X.-D. Luo, J.
Nat. Prod. 2013, 76, 1406.
[12] C. K. G. Gerlinger, T. Gaich, Chem. Eur. J. 2019, 25, 10782.
[13] E. E. van Tamelen, L. K. Oliver, J. Am. Chem. Soc. 1970, 92, 2136.
[14] J. P. Kutney, G. K. Eigendorf, H, Matsue, A. Murai, K. Tanaka, W. L.
Sung, K. Wada, B. R. Worth, J. Am. Chem. Soc. 1978, 100, 938.
[15] a) P. Yu, T. Wang, J. Li, J. M. Cook, J. Org. Chem. 2000, 65, 3173; b) C.
R. Edwankar, R. V. Edwankar, J. R. Deschamps, J. M. Cook, Angew.
Chem. Int. Ed. 2012, 51, 11762; c) C. R. Edwankar, R. V. Edwankar, O.
A. Namjoshi, J. M. Cook, J. Org. Chem. 2013, 78, 6471 and references
cited therein.
[16] a) A. Dieters, K. Chen, C. T. Eary, S. F. Martin, J. Am. Chem. Soc. 2003,
125, 4541; b) C. E. Neipp, S. F. Martin, J. Org. Chem. 2003, 68, 8867.
[17] J. T. Kuethe, A. Wong, I. W. Davies, P. J. Reider, Tetrahedron 2002, 43,
3871.
[18] Y. S. Tran, O. Kwon, Org. Lett. 2005, 7, 4289.
[19] D. Craig, F. W. Goldberg, R. W. Pett, N. T. H. Thole, A. J. P. White, Chem.
Conclusion
In summary, we have developed an enantioselective
synthesis of functionalized tetrahydro-6H-cycloocta[b]indol-6-one
33 via a key ring-closing metathesis for the formation of 8-
membered ring. The tricycle 33 was designed as a key platform
on the way to the sarpagine-ajmaline-macroline family of
monoterpene indole alkaloids. An N-allylation followed by
intramolecular 1,4-addition was planned for the synthesis of
vobasine class of natural products. However, cyclization under a
diverse set of conditions involving the anionic, radical and
organopalladium/organonickel species failed to produce the
bridged ring system. On the other hand, esterification of the
pendent primary alcohol by acetoacetic acid followed by
intramolecular Michael addition afforded the desired tetracycle 59
with an excellent diastereoselectivity. Subsequent functional
group transformation and transannular cyclization of the amino
alcohol 62 afforded the N(1)-demethyl-3,5-diepi-alstolactone (63).
We believe that if the syn-amino alcohol 17, instead of the anti-
counterpart 28, were used, the same synthetic route would afford
the alstolactone (5).
Commun. 2013, 49, 9275.
[20] a) S. Krüger, T. Gaich, Angew. Chem. Int. Ed. 2015, 54, 315; b) H. W.
Rebmann, C. K. G. Gerlinger, T. Gaich, Chem. Eur. J. 2019, 25, 2704.
[21] a) Z. Xu, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2013, 52, 3272; b) Z.
Xu, Q. Wang, J. Zhu, J. Am. Chem. Soc. 2013, 135, 19127; c) T. Buyck,
Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2013, 51, 12714; d) O.
Wagnières, Z. Xu, Q. Wang, J. Zhu, J. Am. Chem. Soc. 2014, 136,
15102; e) J. B. Gualtierotti, D. Pasche, Q. Wang, J. Zhu, Angew. Chem.
Int. Ed. 2014, 52, 9926; f) Z. Xu, Q. Wang, J. Zhu, J. Am. Chem. Soc.
2015, 137, 6712; g) Z. Xu, X. Bao, Q. Wang, J. Zhu, Angew. Chem. Int.
Ed. 2015, 54, 14937; h) D. Dagoneau, Z. Xu, Q. Wang, J. Zhu, Angew.
Chem. Int. Ed. 2016, 55, 760; i) C. Piemontesi, Q. Wang, J. Zhu, Angew.
Chem. Int. Ed. 2016, 55, 6556; j) R. O. Torres-Ochoa, T. Buyck, Q. Wang,
J. Zhu, Angew. Chem. Int. Ed. 2018, 57, 5679; k) G. Li, C. Piemontesi,
Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2019, 58, 2870; l) for a review,
see: Z. Xu, Q. Wang, J. Zhu, Chem. Soc. Rev. 2018, 47, 7882.
[22] a) L. H. Zhang, J. M. Cook, J. Am. Chem. Soc. 1990, 112, 4088; b) P.
Yu, T. Wang, J. Li, J. M. Cook, J. Org. Chem. 2000, 65, 3173; c) J. Yang,
X. Z. Wearing, P. W. L. Quesne, J. R. Deschamps, J. M. Cook, J. Nat.
Prod. 2008, 71, 1431; d) D. Craig, F. W. Goldberg, R. W. Pett, N. T. H.
Tholen, A. J. P. White, Chem. Commun. 2013, 49, 9275.
Experimental Section
[23] A. Boumendjel, J. M. Nuzillard, G. Massiot Bull. Soc. Chim. Fr. 1990, 127,
645.
[24] a) J. R. Gage, D. A. Evans, Org. Synth. 1990, 68, 77; b) J. R. Gage, D.
A. Evans, Org. Synth. 1990, 68, 83.
For details of the synthetic procedures, physical and
spectroscopic data, copies of 1H, 13C NMR spectra of compounds,
see the Supporting Information.
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Full Paper
[25] D. A. Evans, E. B. Sjogren, J. Bartroli, R. L. Dow, Tetrahedron Lett. 1986,
27, 4957.
[26] K. Soai, A. Ookawa, J. Org. Chem. 1986, 51, 4000.
[27] a) R. Appel, Angew. Chem. Int. Ed. 1975, 14, 801; b) P. J. Garegg, Pure
Appl. Chem. 1984, 56, 845; c) P. J. Garegg, T. Regberg, J. Stawinski, R.
Strömberg, J. Chem. Soc. Perkin Trans. II 1987, 11, 271; d) R. M. Denton,
J. An, B. Adeniran, A. J. Blake, W. Lewis, A. M. Poulton, J. Org. Chem.
2011, 76, 6749.
[28] a) G. Cahiez, O. Gager, A. Moyeux, T. Delacroix, Adv. Synth. Catal. 2012,
354, 1519; b) G. Cahiez, N. Lefèvre, M. Poizat, A. Moyeux, Synthesis
2013, 45, 231.
[29] a) E. S. Lewis, C. E. Boozer, J. Am. Chem. Soc. 1952, 74, 308; b) D. J.
Cram, J. Am. Chem. Soc. 1953, 75, 332.
[30] Total Synthesis: J. Yang, S. K. Rallapalli, J. M. Cook, Tetrahedron Lett.
2010, 51, 815.
[31] a) L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122, 11260; b) H.
Yang, H. Li, R. Wittenberg, M. Egi, W. Huang, L. S. Liebeskind, J. Am.
Chem. Soc. 2007, 129, 1132; c) J. M. Villalobos, J. Srogl, L. S.
Liebeskind, J. Am. Chem. Soc. 2007, 129, 15734; d) For a review, see:
H. Prokopcová, C. O. Kappe, Angew. Chem. Int. Ed. 2009, 48, 2276.
[32] C. Piemontesi, Q. Wang, J. Zhu, J. Am. Chem. Soc. 2016, 138, 11148.
[33] O. M. Ogba, N. C. Warner, D. J. O’Leary, R. H. Grubbs, Chem. Soc. Rev.
2018, 47, 4510.
[34] a) M.-L. Bennasar, E. Zulaica, S. Tummers, Tetrahedron Lett. 2004, 45,
6283; b) M.-L. Bennasar, E. Zulaica, D. Solé, S. Alonso, Tetrahedron
2007, 63, 861.
[35] M. Sakaitani, Y. Ohfune, J. Am. Chem. Soc. 1990, 112, 1150.
[36] a) K. J. Butcher, Synlett 1994, 5, 825; b) D. Chaturvedi, Curr. Org. Chem.
2011, 15, 1593.
[37] W. Ren, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2014, 53, 1818.
[38] a) T. Wang, J. M. Cook, Org. Lett. 2000, 2, 2057; b) J. Yu, T. Wang, X.
Liu, J. Deschamps, J. Flippen-Anderson, X. Liao, J. M. Cook, J. Org.
Chem. 2003, 68, 7565.
[39] H. Takayama, F. Watanabe, M. Kitajima, N. Aimi, Tetrahedron Lett. 1997,
38, 5307.
[40] a) J. Bonjoch, D. Solé, S. García-Rubio, J. Bosch, J. Am. Chem. Soc.
1997, 119, 7230; b) S. Yu, O. M. Berner, J. M. Cook, J. Am. Chem. Soc.
2000, 122, 7827; c) M. Teng, W. Zi, D. Ma, Angew. Chem. Int. Ed. 2014,
53, 1814; d) W. Ren, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2016, 55,
3500.
[41] a) D. Solé, J. Bonjoch, S. García-Rubio, E. Peidró, J. Bosch, Chem. Eur.
J. 2000, 6, 655; b) A. B. Dounay, L. E. Overman, A. D. Wrobleski, J. Am.
Chem. Soc. 2005, 127, 10186; c) P. Gao, S. P. Cook, Org. Lett. 2012,
14, 3340.
[42] H. Qi, J. Zhang, J. Xu, Synthesis 2011, 43, 887.
[43] J. d’Angelo, D. Desmaële, F. Dumas, A. Guigant, Tetrahedron:
Asymmetry 1992, 3, 459.
[44] W. Li, J. Li, Z.-K. Wan, J. Wu, W. Massefski, Org. Lett. 2007, 9, 4607.
[45] S. Ohta, A. Tsujimura, M. Okamoto Chem. Pharm. Bull. 1981, 29, 2762.
[46] a) E. E. Kwan, J. R. Scheerer, D. A. Evans, J. Org. Chem. 2013, 78, 175;
b) M. C. Elliott, N. N. E. El Sayed, L.-L. Ooi, Tetrahedron Lett. 2007, 48,
4561; c) T. Boddaert, Y. Coquerel, J. Rodriguez, Chem. Eur. J. 2011, 17,
2048.
[47] Z. Iqbal, L.-C. Han, A. M. Soares-Sello, R. Nofiani, G. Thormann, A.
Zeeck, R. J. Cox, C. L. Willis, T. J. Simpson, Org. Biomol. Chem. 2018,
16, 5524.
[48] a) S. A. Ramachandran, R. K. Kharul, S. Marque, P. Soucy, F. Jacques,
R. Chenevert, P. Deslongchamps, J. Org. Chem. 2006, 71, 6149; b) C.
A. McGowan, A.-K. Schmieder, L. Roberts, M. F. Greaney, Org. Biomol.
Chem. 2007, 5, 1522.
[49] D. E. Ward, C. K. Rhee, Can. J. Chem. 1989, 67, 1206.
[50] a) J.-L. Luche, J. Am. Chem. Soc. 1978, 100, 2226; b) A. L. Gemal, J.-L.
Luche, J. Am. Chem. Soc. 1981, 103, 5454.
[51] a) J. P. Kutney, G. K. Eigendorf, H. Matsue, A. Murai, K. Tanaka, W. L.
Sung, K. Wada, B. R. Worth, J. Am. Chem. Soc. 1978, 100, 938; b) J.
Bonjoch, J.-C. Fernàndez, N. Valls, J. Org. Chem. 1998, 63, 7338.
[52] G. Büchi, R. E. Manning, S. A. Monti, J. Am. Chem. Soc. 1964, 86, 4631.
[53] J. P. Bégué, D. Bonnet-Delpon, B. Crousse, Synlett 2004, 1.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
O
O
O
Synthetic Methods
HN
H
H
N
O
H
O
Dylan Dagoneau, Qian Wang and Jieping
Zhu*__________ Page – Page
O
Bn
O
N
H
NH
+
O
O
HO
Towards Sarpagine-Ajmaline-Macroline
family Indole Alkaloids:
9.5% overall yield
PhS
Cl
Enantioselective Synthesis of
Alstolactone Diastereomer
Transannular cyclization was a key step for the formation of azabicyclo[3.3.1]nonane, a
common structural motif found in sarpagine-ajmaline-macroline family of natural products.
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