Total Syntheses of (+)-Marrubiin and (-)-Marrulibacetal

Article abstract of DOI:10.1021/acs.orglett.6b01602

A stereoselective total synthesis of (+)-marrubiin has been accomplished starting from a chiral building block via the CyNH₂-promoted Pauson-Khand reaction (PKR) followed by oxidative cleavage of the resultant cyclopentenone ring. Two successive oxidations and internal transacetalization culminated in the total synthesis of the antispasmodic labdane diterpenoid (-)-marrulibacetal.

Full text of DOI:10.1021/acs.orglett.6b01602

Letter
pubs.acs.org/OrgLett
Total Syntheses of (+)-Marrubiin and (−)-Marrulibacetal
Hiroyuki Yamakoshi, Yuki Sawayama, Yoshihiro Akahori, Marie Kato, and Seiichi Nakamura*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
S
* Supporting Information
ABSTRACT: A stereoselective total synthesis of (+)-marru-
biin has been accomplished starting from a chiral building
block via the CyNH2-promoted Pauson−Khand reaction
(PKR) followed by oxidative cleavage of the resultant
cyclopentenone ring. Two successive oxidations and internal
transacetalization culminated in the total synthesis of the
antispasmodic labdane diterpenoid (−)-marrulibacetal.
Scheme 1. Retrosynthetic Analysis of Marrulibacetal (1) and
Marrubiin (2)
n 2009, Borrelli and co-workers isolated and characterized a
Ilabdane diterpenoid marrulibacetal (1) from the aerial parts
of Marrubium globosum ssp. libanoticum, a medicinal plant used
as hypoglycemic, febrifuge, antispasmodic, and anti-inflamma-
tory drugs in Northern Lebanon.1 Due to its antispasmodic
effects in the isolated mouse ileum, this natural product is
considered to be the active ingredient of the herb. The
structure of 1 was determined on the basis of NMR
spectroscopic data. Since 1 was also obtained from Marrubium
deserti de Noe
́
that produces marrubiin (2),2,3 the bitter
principle of horehound, 1 is speculated to be biosynthesized
through oxidation of 2, though there is no evidence to support
this speculation.
and oxidative cleavage of the C−C bond at C6 were required,
together with the C5−C6 bond formation. We therefore
decided to utilize a Pauson−Khand reaction (PKR)/oxidative
cleavage sequence to achieve this transformation.
As part of our studies on the synthesis of biologically active
natural products, we have recently developed stereocontrolled
methods to access chiral building blocks for oxygenated
terpenoids by exploiting an Ireland−Claisen rearrangement.4
To demonstrate the synthetic utility of these building blocks,
we addressed the synthesis of 1 via its presumed biosynthetic
precursor 2.5
As outlined in Scheme 1, we planned to introduce the furan
moiety late in the synthesis, because the implementation of this
strategy would allow the incorporation of a variety of
substituents into a common, fully elaborated intermediate 3,6
which would be accessible from ester 5 through a chemo-
selective reduction. Comparison of the structure of lactone 5 to
that of chiral building block 7 revealed that, in addition to the
installation of a methyl group at C4 by an enolate alkylation
from the less-hindered diastereoface, both carboxylation at C4
While PKR7,8 has been utilized for the construction of a
dodecahydroacenaphthylene skeleton,9,10 there has been no
report on the formation of [6,6]-trans-fused compounds.
Therefore, we converted enyne 7 to the corresponding dicobalt
complex 8 (Co2(CO)8, CH2Cl2, 97% yield) and examined
several conditions to achieve the desired transformation (Table
1). Since initial attempts to carry out the intramolecular
reaction in refluxing MeCN resulted in decomplexation (entry
1), we were prompted to investigate the effect of promoters. As
expected, the desired tricyclic product 6 was obtained as a
single isomer when using NMO, a representative and well-
established promoter for PKR,11 in CH2Cl2 at room temper-
Received: June 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01602
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Having optimized the reaction conditions for PKR, we then
addressed the synthesis of 2 (Scheme 3). Since the formation of
Table 1. PKR of Dicobalt Complex 8
Scheme 3. Total Synthesis of (+)-Marrubiin
concn
(mM)
time
(h)
yield
(%)
entry additive
solvent
temp
a
1
2
3
4
none
MeCN
7
20
30
10
reflux
rt
0.5
2
0
a
NMO
CyNH2
CyNH2
CH2Cl2
23
(CH2Cl)2
(CH2Cl)2
reflux
reflux
2
71
97
1.5
a
Enyne 7 was obtained.
ature, although the yield (23%) suffered due to competitive
decomplexation (entry 2). The 4,5-cis-5,10-trans relationship
for the product 6 was unambiguously established by a NOESY
experiment (Figure 1). After considerable experimentation with
Figure 1. Relevant NOESY data for enone 6.
other promoters, we were gratified to find that cyclohexyl-
amine, the effectiveness of which was introduced by Sugihara
and Yamaguchi and co-workers,12 was a promoter of choice for
this transformation, providing enone 6 in 71% yield (entry 3).
The chemical yield was further improved to 97% by decreasing
the substrate concentration from 30 to 10 mM in order to
prevent intermolecular reaction (entry 4). With regard to the
reaction pathway of PKR, Magnus and Principe suggested a
working model in 1985,13 and results of quantum mechanical
studies were later reported by Nakamura and Yamanaka.14
Based on the results of density functional studies, it was
concluded that the stereochemistry of PKR is determined by
the irreversible olefin insertion step. In this case, it is speculated
that the reaction did not proceed through cis-fused chair−
chairlike TS B, which suffers from severe steric interaction
between C1−H and C8-Me (Scheme 2). No such nonbonded
destabilization was observed in trans-fused chair−boatlike TS A,
thus leading to the exclusive formation of isomer 6.
dicobalt complex 8 could be carried out in the same solvent as
that used for PKR, a convenient one-pot procedure was
devised: treatment of enyne 7 with Co2(CO)8 in (CH2Cl)2 at
room temperature was followed by addition of cyclohexyl-
amine, 11-fold dilution with (CH2Cl)2, and heating under
reflux. By utilizing this procedure, tricyclic enone 6 was
obtained in comparable (96%) yield. C-Alkylation of the
potassium enolate, generated from 6 with KHMDS in THF,
with MeI proceeded in a stereoselective manner to give enone
10 in 89% yield. At this stage, we were challenged with the task
of oxidative cleavage of the cyclopentenone moiety. In this
regard, RuCl3-catalyzed oxidation,15 a dihydroxylation/oxida-
tive cleavage sequence,16 or ozonolysis/oxidative workup17 is
employed in the literature. However, Ru-catalyzed oxidation of
enone 10 at room temperature resulted in the formation of a
complex mixture of products, whereas OsO4-catalyzed dihy-
droxylation did not proceed even at elevated temperatures.
While desired ketocarboxylic acid 12 was obtained by
ozonolysis of enone 10 with oxidative workup (O3, CH2Cl2,
−78 °C; NaOH, 30% aq H2O2), the reaction suffered from low
yield (33%) and reproducibility issues. Finally, the desired
transformation could be effected in 53% overall yield when
subjected to KMnO4-catalyzed oxidation in the presence of
NaIO4 and subsequent treatment of the resultant α-
ketocarboxylic acid 11 with activated carbon.18 Following the
Scheme 2. Stereochemical Course of PKR of 8
B
DOI: 10.1021/acs.orglett.6b01602
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Letter
literature precedent,5 ketocarboxylic acid 12 thus obtained was
converted into lactone 5 by a two-step sequence involving
reduction with NaBH4 and lactonization through a mixed
anhydride.
osmylated selectively over the trans-isomers trans-16 in aqueous
THF, providing a 1:1 diastereomeric mixture of cis-diols 17 and
18 in 61% yield. Alkene 16, recovered unchanged in 38% yield,
could be recycled back to a 2:1 mixture of isomers by
isomerization under acidic conditions (PPTS, EtOH, 90%
yield). Internal transacetalization of cis-diols 17 and 18 could be
attained with TsOH in undried benzene, providing (−)-marru-
libacetal (1) in 36% yield, along with its isomer 19 (38% yield)
and other two diastereomers (1:1, 18% combined yield).22
Synthetic compounds proved to be identical in all respects (1H
and 13C NMR, IR, HRMS, and optical rotations) to natural
products.1,23
In conclusion, total syntheses of both (+)-marrubiin and
(−)-marrulibacetal have been accomplished. The syntheses
illustrate the synthetic utility of chiral building blocks developed
in our laboratory for the synthesis of oxygenated terpenoids.
The synthesis will open entries into analogues for biological
investigations, leading to a useful structure−activity relation-
ship.
With the route to tricyclic lactone 5 secured, remaining
operations necessary for the synthesis of marrubiin involved
chemoselective reduction of the C11 ester functionality and
introduction of a furan moiety. The TMS ether at C9 was
deprotected by Bu4NF in THF at 0 °C in preparation for
hydroxyl-directed reduction. After a survey of reducing agents,
sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al)
proved to be the optimal reagent for this purpose. Thus,
Red-Al reduction of α-hydroxyester 13 in CH2Cl2 at −23 °C
followed by aqueous workup afforded a mixture of the
corresponding aldehyde and diol 15, which was reduced
again with Red-Al to give diol 15. This result can be
rationalized by assuming the formation of a five-membered
aluminate intermediate 14. Treatment of diol 15 with Ts-
imidazole and NaH afforded epoxide 3 in 84% yield for the
three-step sequence. Epoxide ring opening with (3-
furylmethyl)magnesium bromide6 in the presence of CuBr·
SMe2 in Et2O at −20 °C completed the total synthesis of (+)-2.
With optically active marrubiin in hand, we could then focus
on the conversion of (+)-2 to marrulibacetal (Scheme 4).
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.6b01602.
Scheme 4. Conversion of (+)-Marrubiin to
(−)-Marrulibacetal
Experimental procedures and full characterization data
for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: nakamura@phar.nagoya-cu.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported in part by the Platform Project for
Supporting in Drug Discovery and Life Science Research from
Japan Agency for Medical Research and Development
(AMED), and Shionogi Award in Synthetic Organic Chemistry,
Japan.
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DOI: 10.1021/acs.orglett.6b01602
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