Stereocontrolled Construction of ABCD Tetracyclic Ring System with Vicinal All-Carbon Quaternary Stereogenic Centers of Calyciphylline A Type Alkaloids

Article abstract of DOI:10.1021/acs.orglett.8b01087

A unique approach to the synthesis of an ABCD tetracyclic core bearing the vicinal all-carbon quaternary stereogenic centers of the calyciphylline A type alkaloids is reported. The synthesis features two C-C bond formations at a sterically congested position: one is an intramolecular pinacol coupling to construct the central A ring; the other is a semipinacol rearrangement to construct a quaternary stereogenic center adjacent to another quaternary center.

Full text of DOI:10.1021/acs.orglett.8b01087

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereocontrolled Construction of ABCD Tetracyclic Ring System with
Vicinal All-Carbon Quaternary Stereogenic Centers of Calyciphylline
A Type Alkaloids
Yusuke Sasano,† Junpei Koyama,† Kaori Yoshikawa,† Naoki Kanoh,† Eunsang Kwon,‡
and Yoshiharu Iwabuchi*,†
‡
†Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, and Research and Analytical Center for Giant
Molecules, Graduate School of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: A unique approach to the synthesis of an ABCD tetracyclic core bearing the vicinal all-carbon quaternary
stereogenic centers of the calyciphylline A type alkaloids is reported. The synthesis features two C−C bond formations at a
sterically congested position: one is an intramolecular pinacol coupling to construct the central A ring; the other is a semipinacol
rearrangement to construct a quaternary stereogenic center adjacent to another quaternary center.
Daphniphyllum alkaloids, more than 300 species of which have
been isolated, have unique polycyclic fused ring systems that
are classified into 14 different structural types.1 One of these is
the calyciphylline A type, which possesses an unprecedented
fused penta- or hexacyclic ring system that contains more than
six stereogenic centers, some of which are vicinal all-carbon
quaternary stereogenic centers (Figure 1). A member of this
recently, four reports of the total syntheses of calyciphylline A
type alkaloids have been published.4,5 In this paper, we report a
unique approach to the synthesis of a common ABCD
tetracyclic structure bearing the vicinal all-carbon quaternary
stereogenic centers of calyciphylline A type alkaloids. Two
reactions have been employed for the construction of the C−C
bonds at a sterically congested position: SmI2-promoted
pinacol coupling to construct the central A ring and
semipinacol rearrangement to introduce an all-carbon quater-
nary stereogenic center adjacent to another quaternary center.
Our synthetic plan is shown in Scheme 1. We set the BCD
tricyclic lactam 7 as the platform for our feasibility study, the
Scheme 1. Synthetic Plan for Calyciphylline A Type
Alkaloids
Figure 1. Calyciphylline A type alkaloids.
class of alkaloids, namely, daphniyunnine D (2), exhibits
antitumor activity.2 However, further investigations into the
biological activities of this class of alkaloids have not been
carried out because of their poor availability in Nature. Owing
to their interesting biological effects and highly complex
structures, calyciphylline A type alkaloids have attracted the
interest of synthetic organic chemists; to date, more than 15
synthetic studies on these alkaloids have been reported.3 Very
Received: April 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01087
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
synthesis of which we previously reported as a synthetic
intermediate for other Daphniphyllum alkaloids, namely,
daphnicyclidins.6 (Note: The antipodes of natural products
were selected as the targets considering the ready availability of
the starting material, namely, (−)-8-phenylmenthol. The
synthetic studies of natural enantiomers of the natural products
are underway.) As a preliminary investigation, we examined C−
C bond formation at the C8 ketone of 7 to secure a synthetic
platform for the E-ring. As a result, it was proven that the
introduction of the C−C bond at this position is a formidable
challenge, likely due to the steric hindrance of this position
adjacent to the all-carbon quaternary stereogenic center:
Neither the attempted nucleophilic addition of an organo-
metallic reagent nor the transition-metal-catalyzed coupling of
the corresponding enol triflate gave us sufficient materials to
continue the synthesis. On the basis of these results, we
planned to adopt an intramolecular reductive radical coupling
of ketoaldehyde 8, which is readily obtainable from 7 and
allows the expedient construction of the A-ring of the
calyciphylline A type alkaloids.7 The subsequent construction
of the all-carbon quaternary stereogenic center at the C8
position adjacent to another quaternary stereogenic center at
the C5 position was anticipated as another challenge. We
envisaged that enone 10, potentially securable from diol 9 via a
conventional set of transformations, offered a possible platform
from where to achieve this demanding task: the cage-shaped
skeleton would govern 1,2-addition of an allyl group onto the
C1 ketone from the convex face and the resulting endo-alcohol
would direct syn-selective epoxidation to give epoxy alcohol 11,
setting up the subsequent Marson semipinacol rearrangement.8
Product 12 has a versatile allyl group at C8 and a hydroxy
group at the C9 position, which would serve as promising levers
for construction of the E- and F-rings.
Table 1. Intramolecular Pinacol Coupling
entry
1
conditions
results
Mg (5.0 equiv), TMSCl (5.0 equiv), DMF (0.03 M), no reaction
rt, 12 h
2
AIBN (20 mol %), Bu3SnH (1.5 equiv), benzene
(0.01 M), reflux, 16 h
15 (44%), 8
(47%)
3
4
SmI2 (5.0 equiv), THF (0.03 M), rt, 3 h
9 (71%)
SmI2 (5.0 equiv), HMPA (20 equiv), THF (0.03 M), 15 (62%)
rt, 1.5 h
5
SmI2 (5.0 equiv), LiCl (20 equiv), THF (0.03 M), rt, 15 (51%)
1.5 h
71% yield as a single diastereomer (entry 3: the stereochemistry
of 9 was not determined). HMPA and LiCl were examined as
additives for the SmI2-induced pinacol coupling; however, the
coupling product 9 was not obtained (entries 4 and 5).13 It is
likely that the strong oxophilicity of SmI2 forced the two
carbonyl groups into close proximity to one another to
promote the coupling reaction. The addition of HMPA and
LiCl might reduce the interaction between the SmI2 and the
carbonyl groups.
With tetracyclic compound 9 obtained, we focused our
efforts on installation of the quaternary stereogenic center at
the C8 position. Epoxy alcohol 11, the precursor of the
semipinacol rearrangement, was synthesized as shown below
(Scheme 3): The secondary alcohol of diol 9 was successfully
oxidized under 5-F-AZADO/NOx-catalyzed aerobic oxidation
to afford α-hydroxyketone 16 in 89% yield without cleavage of
the vicinal diol.14 Dehydration of α-hydroxyketone using
Martin sulfurane gave enone 10 and cyclopropane 17 in 75%
yield as a 4:1 inseparable mixture.15 The use of thionyl chloride
Our synthetic study began with an examination of the
construction of the ring A. The substrate for the intramolecular
pinacol coupling, ketoaldehyde 8, was synthesized from 76 in
84% yield in two steps, namely, by deprotection of the pivaloyl
group and mild oxidation of the resulting alcohol with Nor-
AZADO and DIAD (Scheme 2).9 In the case of using IBX for
Scheme 3. Synthesis of Epoxy Alcohol 11
Scheme 2. Synthesis of Ketoaldehyde 8
alcohol oxidation, the alcohol was excessively oxidized to the
corresponding carboxylic acid.10 Next, the key intramolecular
pinacol coupling was examined (Table 1). Mg induced no
reaction (entry 1).11 The use of AIBN and Bu3SnH did not lead
to the expected C−C bond formation between the two
carbonyl groups, but led to reduction of the aldehyde group
with recovery of the starting material (entry 2).12 Then, SmI2
was examined. Gratifyingly, tetracyclic diol 9 was obtained in
B
DOI: 10.1021/acs.orglett.8b01087
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Letter
in a pyridine solution gave enone 10 in lower (23%) yield
concomitant with a chloride, which is generated in 4% yield by
the substitution of the hydroxy group of 16 for a Cl group. The
spectral data of enone 10 were consistent with those of
Bonjoch’s product, whose synthesis was completely different
from ours.3d An allyl group was introduced onto the C1 ketone
using allylMgBr in the presence of CeCl3 to afford allylic
alcohol 18 in 69% yield, which was obtained as a single
diastereomer. Stereoselective epoxidation of allylic alcohol 18
with a vanadium catalyst afforded epoxy alcohol 11 in 79%
yield.
radical intermediate and the strong oxophilicity of the Sm ion.
The semipinacol rearrangement with LiBF4 in MeCN has
enabled the construction of the all-carbon quaternary stereo-
genic center adjacent to the other quaternary center. The final
product, 12, having allyl and hydroxy groups, could serve as a
synthetic scaffold for constructing the EF rings. Investigations
into the total synthesis of calyciphylline A type alkaloids are
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
With precursor 11 obtained, the key Marson semipinacol
rearrangement was examined (Table 2). The use of concd HCl
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01087.
Table 2. Semipinacol Rearrangement
Synthetic scheme for 7, detailed experimental proce-
dures, spectral data, and X-ray crystallographic data
(PDF)
Accession Codes
CCDC 1833117 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
temp
entry
1
acid (equiv)
solvent
(°C)
times
1 d
results
concd HCl
(1 drop)
CH2Cl2 rt
no reaction
2
3
4
TiCl4 (45)
CH2Cl2 −78
20 min unidentified
product
AUTHOR INFORMATION
BF3·OEt2 (2.0)
LiBF4 (2.0)
CH2Cl2 −78 to
2 h
12 (<63%)
■
rt
Corresponding Author
*E-mail: y-iwabuchi@m.tohoku.ac.jp.
ORCID
MeCN
60
11 h
12 (96%)
as the Brønsted acid induced no reaction (entry 1). Then,
several Lewis acids were examined. Although TiCl4 afforded an
unidentified product (entry 2), BF3·OEt2 afforded the desired
product 12 in moderate yield (entry 3). Eventually, it was
found that Lipshutz’s conditions using LiBF4 in MeCN
achieved a high yield of 12, which was obtained as a single
stereoisomer (entry 4).16 The stereochemistry of 12 was
verified by X-ray crystallographic analysis (Figure 2).
Naoki Kanoh: 0000-0002-4382-3715
Yoshiharu Iwabuchi: 0000-0002-0679-939X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysis” (No. 23105011) from MEXT,
Core to Core Program “Advanced Research Network for Asian
Cutting-Edge Organic Chemistry” from JSPS, Life Science
Research (Platform for Drug Discovery, Informatics, and
Structural Life Science) from Japan Agency for Medical
Research and Development (AMED), and Shionogi Award
(2013) in Synthetic Organic Chemistry, Japan. We thank Dr.
Shuhei Manabe (The Ohio State University) for helpful
discussions.
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Figure 2. ORTEP structure of 12.
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