Enantioselective Total Synthesis of Diocollettines A

Article abstract of DOI:10.1021/acs.orglett.9b01776

The first enantioselective total synthesis of diocollettines A was accomplished in only six steps from a known compound. A short and practical synthetic route was disclosed, featuring an intensive investigation of the stereoselective aldol reaction as a key step using an easily prepared aldehyde moiety and an enone derivative. The synthetic scheme also includes the efficient stereocontrolled construction of the tricyclic skeleton of diocollettines A by intramolecular acetal formation, stereoselective dihydroxylation, and intramolecular ether cyclization.

Full text of DOI:10.1021/acs.orglett.9b01776

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Total Synthesis of Diocollettines A
Yuichiro Kawamoto, Toyoharu Kobayashi, and Hisanaka Ito*
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
S
* Supporting Information
ABSTRACT: The first enantioselective total synthesis of diocollettines A was accomplished in only six steps from a known
compound. A short and practical synthetic route was disclosed, featuring an intensive investigation of the stereoselective aldol
reaction as a key step using an easily prepared aldehyde moiety and an enone derivative. The synthetic scheme also includes the
efficient stereocontrolled construction of the tricyclic skeleton of diocollettines A by intramolecular acetal formation,
stereoselective dihydroxylation, and intramolecular ether cyclization.
novel tricyclic diarylheptanoid derivative,1 diocollettine
(IC50 value >100 μM). To date, no total synthesis of
diocollettines A has been accomplished, and the structural
features of compound 1 provided our motivation for this
synthetic study. Here, we disclose a short and practical
synthetic route to 1 in only six steps from known compounds,
featuring an intensive investigation of the stereocontrolled
aldol reaction as a key step. Our total synthesis also involves
the efficient construction of the tricyclic skeleton of
diocollettines A by intramolecular acetal formation and
stereoselective dihydroxylation followed by intramolecular
ether cyclization.
A
A (1), along with known compound 2−6 was isolated by
Gao and co-workers in 2016 in their search for novel bioactive
compounds from the rhizomes Dioscorea collettii (Figure 1).2,3
Our retrosynthetic analysis for the total synthesis of
diocollettines A is shown in Scheme 1. From a retrosynthetic
perspective, the C ring of the core framework could be
constructed by stereoselective dihydroxylation of compound 7
and selective tosylation of the resultant primary alcohol
followed by ether cyclization. The A and B rings of compound
7 could be built by deprotection and subsequent intra-
molecular acetal formation of compound 8, which would in
turn be synthesized from aldehyde 9 and enone 10 using the
intermolecular aldol reaction in a stereoselective manner.
The synthesis commenced with the preparation of aldehyde
9 and enone 10, precursors for the key aldol reaction, as shown
in Scheme 2. The requisite aldehyde 9 was formed through a
three-step sequence involving asymmetric allylation, silylation
of the resultant alcohol, and oxidative cleavage of the double
bond. The asymmetric allylation was performed by employing
diisopinocampheylallylborane in 73% yield and 91% ee.4,5
After TBS protection, Lemieux−Johnson condition afforded
the desired aldehyde 14.6 Enones 16 and 17 were derived from
Figure 1. Chemical structures of compounds 1−6.
The structure of diocollettines A was elucidated by extensive
NMR spectroscopic analysis in addition to HR-ESI-MS
measurements. The absolute configuration of compound 1
was established by electronic circular dichroism (ECD) spectra
and X-ray single-crystal diffraction data. Compound 1
possesses a tricyclic skeleton with five stereogenic centers,
two tetrahydrofuran rings, and one tetrahydropyran ring fused
to construct a complicated heterocyclic structure.
Compounds 1−6 were evaluated for their cytotoxicity
against human lung cancer NCL-H460 cell lines.2 Compound
1 displayed moderate activity with an IC50 value of 20.15 μM,
while compound 4 showed the most potent activity with an
IC50 value of 0.23 μM. In contrast, compound 2 was less active
Received: May 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthetic Analysis of 1
Scheme 3. Attempts at Aldol Reaction Using Vinyl Lithium
Enolate
Scheme 2. Synthesis of Aldol Reaction Precursors
the resulting diastereoselectivity was almost the same. The
unsatisfactory outcome of the zinc enolate is because of
inadequate control of the geometric isomers, furnishing a
mixture of E/Z isomers. Therefore, a boron enolate was
employed to control the isomers.
Thus, enone 16 was directly subjected to the aldol
conditions using Cy2BCl and Et3N, which has been reported
to generate E-enolate selectively,8 followed by addition of
aldehyde 21. Regrettably, only starting material 16 was
recovered. This suggested that the boron enolate was not
produced from 16.
Therefore, compound 20, in which the double bond is
migrated to the terminal olefin, was synthesized via
deprotonation and protonation of enone 16 by treatment
with LHMDS and subsequent quenching by aqueous NH4Cl
(Scheme 4). The aldol reaction of the E boron enolate and
aldehyde 21 was performed to obtain adduct 22 in 91% yield
in an exclusively anti-selective fashion. However, the stereo-
chemical outcome regarding the 1,3-diol moiety was
unsatisfactory (undesired anti vs desired syn = 2:3). This
result encouraged us to add a metal additive to chelate the
carbonyl oxygen of the aldehyde and the MOM oxygen
depicted in Scheme 4. After many attempts including ZnCl2,
AlCl3, MgClO4, and ZnEt2, LiCl gave the best result, forming
anti and syn adducts in a 1:2 ratio. With access to
stereocontrolled aldol adduct 22 achieved, the next challenge
was to construct the AB rings. To accomplish this, cleavage of
the MOM groups followed by acetal cyclization was attempted
under several acidic conditions. However, all efforts (HCl,
TFA, TMSI,9 catechol boron bromide10) provided only
decomposition of the starting material. This failure to remove
the MOM groups prompted us to change the protective groups
(Scheme 5).
the alcohol 157 through protection with MOM and TBS
groups.
With the desired aldehyde 14 and enones 16 and 17 in
hand, we next focused on the key aldol reaction. At first, vinyl
lithium enolate generated from the enone 17 by LHMDS was
reacted with aldehyde 18 (racemic) to give the aldol adduct 19
in 77% yield (Scheme 3). The diastereoselectivity was very
poor, although the anti-aldol adducts were obtained as major
diastereomers. This low selectivity is probably due to the weak
chelation ability of lithium atom. Thus, zinc, which has a
strong chelation ability, was added to form a vinyl zinc enolate
after preparation of the vinyl lithium enolate. Unfortunately,
Having synthesized the requisite ketone 23 bearing a TBS-
protected primary alcohol and the desired aldehydes 24 or
2511 bearing a PMB- or SEM-protected secondary alcohol, the
aldol reaction was carried out again. The PMB or SEM group
was chosen not only because they could have the ability to
chelate the metal additive, and likewise the MOM group, but
B
DOI: 10.1021/acs.orglett.9b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Finally, we executed the aldol reaction utilizing only TBS
group (Scheme 7). Addition of the boron enolate generated
Scheme 4. Attempts at Aldol Reaction Using Vinyl Boron
Enolate
Scheme 7. Completion of Enantioselective Total Synthesis
Scheme 5. Failure To Remove MOM Groups
from 23 to aldehyde 14 with a secondary alcohol silylated by a
TBS group smoothly took place to produce adduct 27 in a
selective manner. Since the stereochemical control of the 1,3-
diol moiety was not satisfactory, some additives (ZnCl2, AlCl3,
LiCl) for chelation were employed as in the case of the MOM
group, but the selectivity was not improved. After HPLC
separation of the diastereomers, we turned our attention to
construction of the tricyclic skeleton. Treatment of 27 with 0.5
M H2SO4 triggered removal of the TBS groups followed by
intramolecular acetal cyclization to yield compound 7
possessing the AB rings. The stereochemistry of 7 was
confirmed by NOESY experiments (see the Supporting
Information). The phenyl group was located at the more
stable α face, the equatorial position. With the AB rings
constructed, the remaining task was to form the C ring in a
two-step procedure. Stereoselective dihydroxylation occurred
exclusively from the convex face to afford triol 28.
Furthermore, TsCl and Et3N induced the selective tosylation
of the primary alcohol, and the resultant tosylate was attacked
by the secondary alcohol to build the C ring, completing the
because they are easier to remove than the MOM group under
nonacidic conditions. However, the desired reaction did not
proceed (Scheme 6).
Scheme 6. Attempts at Aldol Reaction Using Other
Protective Groups
C
DOI: 10.1021/acs.orglett.9b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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1
total synthesis of the target molecule. Both the H and 13C
NMR spectra of synthetic diocollettines A (1) were identical
with those reported in the literature. The value of [α]D slightly
differs from the original one in the literature probably because
compound 12, which compound 1 was derived from, does not
have perfect ee (91% ee).
In conclusion, the first enantioselective total synthesis of
diocollettines A (1) was achieved in only six steps from the
known compound. The synthetic method involved a stereo-
controlled aldol reaction and efficient construction of the
tricyclic structure, including intramolecular acetal cyclization,
stereoselective dihydroxylation, and intramolecular ether
formation. This short and practical synthetic strategy could
be applied to structure and activity relationship studies of the
bioactive compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01776.
Experimental procedure, spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: itohisa@toyaku.ac.jp.
ORCID
Yuichiro Kawamoto: 0000-0003-1245-2090
Toyoharu Kobayashi: 0000-0002-7362-1129
Notes
The authors declare no competing financial interest.
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■
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D
DOI: 10.1021/acs.orglett.9b01776
Org. Lett. XXXX, XXX, XXX−XXX