Synthesis of the Tetracyclic ABCD Ring Domain of Calyciphylline A-Type Alkaloids via Reductive Radical Cyclizations

Article abstract of DOI:10.1021/acs.orglett.7b00035

A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps: the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group.

Full text of DOI:10.1021/acs.orglett.7b00035

Letter
pubs.acs.org/OrgLett
Synthesis of the Tetracyclic ABCD Ring Domain of Calyciphylline A-
Type Alkaloids via Reductive Radical Cyclizations
Guilhem Coussanes and Josep Bonjoch*
̀ ̀
Laboratori de Química Organica, Facultat de Farmacia, IBUB, Universitat de Barcelona, Av Joan XXIII s/n, 08028 Barcelona, Spain
*
S Supporting Information
ABSTRACT: A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a
cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps:
the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a
trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group.
1
he calyciphylline A-type alkaloids, which now number
bottom). The calyciphylline A-type alkaloids have been the
subject of intensive synthetic investigation since the isolation of
the first congener in 2003. However, no calyciphylline A-type
T
more than 30, constitute a group of architecturally complex
Daphniphyllum alkaloids. The majority of calyciphylline A-type
alkaloids are structurally characterized by a hexacyclic framework
6−6−5−7−5−5]. Some are F-seco derivatives (e.g., himalen-
sine A ) and bear up to nine stereogenic centers, including two
vicinal all-carbon quaternary centers (Figure 1, top).
2
9
natural product has been synthesized so far, despite several
10
11,12
[
reports of tri- and tetracyclic
fragments of these alkaloids.
3
Here we describe a synthesis of the [6−6−5−7] tetracyclic
system embedded in the structure of himalensine A and
13
daphiyunnine A. The essential features of the previous
syntheses of this azatetracyclic ring are outlined in Figure 2. In
After the classic foundational biomimetic methyl homoseco-
4
daphniphyllate synthesis by Heathcock, the synthetic efforts
toward Daphniphyllum alkaloids in the past decade have5
culminated in the total synthesis of daphmanidin E by Carreira,
6
calyciphylline N by Smith, and daphenylline, a 22-nor-
7
8
calyciphylline A-type alkaloid, by Li and Fukuyama (Figure 1,
Figure 2. Previous synthetic approaches and the current strategy to the
ABCD ring system of calyciphylline A-type alkaloids.
11
Hao−Wang’s approach, a [2 + 2] photocyclization was used to
generate the quaternary stereocenter at C5 from an elaborated
chiral pool derivative that established the configuration at C18. In
12
Li’s strategy, the AC ring was constructed by an intramolecular
Michael reaction, which also resulted in the formation of the
quaternary C5, while the stereochemistry at C18 was controlled
by a substrate-directed hydrogenation from an exocyclic double
bond.
Figure 1. Calyciphylline A-type alkaloids and synthesized structurally
related Daphniphyllum alkaloids.
Received: January 5, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00035
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Organic Letters
Letter
10a
The observation in our previous work that the stereo-
chemical course of the hydrogenation of an exocyclic methylene
at C18 is sensitive to subtle changes in substrate structure
prompted us to propose a synthetic plan in which the methyl
group is installed by an α-lactam alkylation. The synthetic
approach to the ABCD ring system of calyciphylline A-type
alkaloids (Scheme 1) involves a series of stepwise annelations
Scheme 2. Synthesis of the AC Octahydroindole Subunit
Scheme 1. Synthetic Approach
from 2-methyl-1,4-cyclohexanedione monoethylene acetal,
which preforms the carbocyclic A ring of the target. The crucial
steps of the synthesis are as follows: (i) closure of the pyrrolidine
C ring by a 5-endo-trig radical cyclization and generation of the
quaternary center at C5, (ii) closure of the D ring using an aldol
condensation, and (iii) elaboration of the B ring using a synthetic
methodology developed in our group for the synthesis of
14
morphan compounds based on the radical cyclization of
15
trichloroacetamides. The functionalization of the cyclized
tetracyclic compound allowed a stereocontrolled introduction of
the methyl group to achieve the targeted compound 1.
At the outset of this synthetic endeavor, it was perceived that
radical cyclization could serve as an effective means for the
construction of the C ring and generation of the all-carbon
quaternary center (Scheme 2). Treatment of ketone 5 with
benzylamine under Dean−Stark conditions afforded imine 6,
which was trapped with trichloroacetyl chloride to give enamide
Figure 3. X-ray structure of 3.
Starting from alkene 3, a low-catalyst-loading cross-metathesis
reaction with a Grubbs second-generation catalyst and CuI as an
24
7
. The trichloroacetamide was treated with Bu SnH/AIBN
additive afforded α,β-unsaturated aldehyde 10. The latter was
carefully hydrogenated to afford the corresponding aldehyde
(not shown), in which the acetal group was removed using an
aqueous solution of HCl in THF to afford keto aldehyde 11.
Aldol cyclization leading to the seven-membered ring was carried
out using p-toluenesulfonic acid in benzene at reflux. Thus, the D
ring was closed, enone 2 formed, and the ACD tricyclic ring
achieved. The ketone carbonyl group was protected using
3
(syringe pump addition) in refluxing benzene to give the 5-endo-
16
trig cyclization product, hydroindole 4, containing the all-
carbon quaternary center, in 77% yield (10 g scale).
17,18
The
success of this cyclization from a trichloroacetamide is due to the
electrophilicity of the carbamoyldichloromethyl radical and a
relatively low energy barrier for the rotation around both the
1
9
20
NCO amide and N-alkenyl bonds. Enamide 4 was allylated
using LHMDS and allyl bromide at −78 °C to diastereose-
lectively afford 8 in near-quantitative yield. The selectivity of the
allylation was controlled by the steric hindrance generated by the
neighboring methyl group. Reduction of the acyliminium
2
5
ethylene glycol in acetic medium, and as expected, a migration
of the double bond occurred, acetal 12 being isolated exclusively
(Scheme 3). Its stereochemistry was disclosed by NOE
experiments in which a strong interaction between the axially
located protons at H-8 (δ 2.96) and H-2 (δ 1.25) was observed.
Our next task was to construct the bridged piperidine ring for
the targeted polycyclic system.
2
1
generated from 8 using cyanoborohydride in acidic medium
22
selectively afforded cis-octahydroindole 3. The structure of 3
23
26,27
was unequivocally confirmed by X-ray analysis (Figure 3).
Initially, lactam 12 was
Notably, when enamide 4 was reduced before the allylation step,
giving octahydroindole 9, the installation of the allyl group was
unsuccessful under the reaction conditions used for the
transformation of 4 → 8, and the starting lactam 9 was
recovered. The withdrawing nature of the olefin in 4 may render
α-lactam hydrogen more acidic than in lactam 9.
debenzylated using sodium in liquid ammonia at −78 °C,
followed by reduction of secondary lactam 13 using LiAH to
4
afford secondary amine 14 in excellent overall yield (Scheme 4).
After exploring several approaches to achieve the final ring
28
closure, a radical cyclization proved fruitful. The trichlor-
oacetylation of 14 afforded 15, which was treated in acid medium
B
DOI: 10.1021/acs.orglett.7b00035
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Organic Letters
Letter
Scheme 3. Synthesis of the ACD Ring System
33% yield over three steps (70% yield for each of the three
separate chemical events from 18) (Scheme 5).
Scheme 5. Completion of the Synthesis of the [6−6−5−7]
Tetracyclic Core of Calyciphylline A-Type Alkaloids
Scheme 4. Synthesis of the ABCD Ring System
In summary, we have developed a synthetic route to the
tetracyclic core of calyciphylline A-type alkaloids (Figure 4). The
Figure 4. Stereoview of the ABCD ring system of calyciphylline A-type
alkaloids.
key steps involve a Bu SnH-mediated intramolecular 5-endo-trig
3
to regenerate the α,β-unsaturated ketone moiety (i.e., enone 16).
The required radical acceptor, enol acetate 17, was obtained by
treatment of 16 with p-toluenesulfonic acid and isopropenyl
and 6-exo-trig radical cyclization of trichloroacetamides to
construct the C and B rings and a ring-closing aldol condensation
in acidic conditions to build the D ring. The synthesis of
himalensine A and related calyciphylline A-type alkaloids using
this strategy will be pursued.
acetate. Reaction of enol acetate 17 with Bu SnH (3.2 equiv) and
3
AIBN under reaction conditions similar to those used for the
synthesis of 4 (see above) provided the morphan ring system in
29
1
8 in 82% overall yield (cyclization and reduction steps).
ASSOCIATED CONTENT
Supporting Information
■
During the course of the reaction, translocation of the radical
occurred at C10 to afford the more stable alkene.
*
S
In a crucial step to achieve valuable intermediates toward
calyciphylline A-type alkaloids, alkylation of lactam 18
diastereoselectively installed the methyl substituent, giving the
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00035.
Experimental procedures, spectroscopic and analytical
data, NMR spectra of new compounds (PDF)
30
same configuration as the targeted natural products. The
31
unpurified enol acetate 19 was deprotected using K CO in
2
3
MeOH. Unexpectedly, α-hydroxylated ketone 20 was isolated
instead of a ketone, and the configuration at the new stereogenic
quaternary center was unequivocally established from a NOESY
experiment, which revealed a correlation between OH and the
axially positioned proton at C-11. In order to improve the
conversion yield, the reaction was carried out under an oxygen
atmosphere and using dimethyl sulfide as a reductor of the
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: josep.bonjoch@ub.edu.
ORCID
Josep Bonjoch: 0000-0002-5551-6720
Notes
32
presumed hydroperoxide intermediate. Finally, the tertiary
alcohol in 20 was dehydrated using Burgess’ reagent to afford 1 in
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b00035
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Organic Letters
Letter
Ozdemir, A. D.; Willis, J.; Padwa, A. Org. Lett. 2004, 6, 917−920.
ACKNOWLEDGMENTS
■
(
f) Rose, M. D.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. J. Org.
Financial support for this research was provided by the FP7Marie
Curie Actions of the European Commission via the ITN
ECHONET Network (MCITN-2012-316379) and Spanish
MINECO (Project CTQ2013-41338-P).
Chem. 2007, 72, 538−549. (g) O’Connell, M.; Zeller, W.; Burgeson, J.;
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