Divergent Total Syntheses of Enmein-Type Natural Products: (?)-Enmein, (?)-Isodocarpin, and (?)-Sculponin R

Article abstract of DOI:10.1002/anie.201803709

Divergent total syntheses of the enmein-type natural products (?)-enmein, (?)-isodocarpin, and (?)-sculponin R have been achieved in a concise fashion. Key features of the strategy include 1) an efficient early-stage cage formation to control succeeding diastereoselectivity, 2) a one-pot acylation/akylation/lactonization to construct the C-ring and C8 quarternary center, 3) a reductive alkenylation approach to construct the enmain D/E rings and 4) a flexible route to allow divergent syntheses of three natural products.

Full text of DOI:10.1002/anie.201803709

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Title: Divergent Total Syntheses of Enmein-Type Natural Products: (-)-
Enmein, (-)-Isodocarpin and (-)-Sculponin R
Authors: Saiyong Pan, Sicong Chen, and Guangbin Dong
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10.1002/anie.201803709
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Divergent Total Syntheses of Enmein-Type Natural Products: (–)-
Enmein, (–)-Isodocarpin and (–)-Sculponin R
Saiyong Pan[a,b] Sicong Chen[a] and Guangbin Dong*[a,b]
Dedication ((optional))
Abstract: Divergent total syntheses of enmein-type natural products,
(–)-enmein, (–)-isodocarpin and (–)-sculponin R, have been achieved
in a concise fashion. Key features of the strategy include (a) an
efficient early-stage cage formation to control succeeding
diastereoselectivity, (b) an one-pot acylation/akylation/lactonization to
construct the C-ring and C8 quarternary center, (c) a reductive
alkenylation approach to construct enmain D/E rings and (d) a flexible
route to allow divergent syntheses of three natural products.
the different substitution patterns of the D/E rings.
The ent-kaurene diterpenoids, isolated from the isodon genus,
have been an important family of natural products that exhibit
rich biological activities and intriguing chemical structures.[1] Due
to the limited supply from natural sources, these diterpenoids
have attracted significant interests from the synthetic community
for efficient chemical synthesis (Figure 1a).[2,3] Among various
ent-kaurenoids, enmein (1) holds a unique position. It was the
first isodon family member that was investigated for biological
potency.[4] It is also the key compoent of enmei-so, namely “the
grass effective for prolonging human life”, which is a common
herbal medicine used in Asia.[5] Enmein was first isolated from I.
japonica in 1958,[6] and its structure was determined in 1966.[7]
Unlike a regular ent-kaurene, enmein exhibits a more oxidized
scaffold with C6,7 positions being cleaved, as well as a C1,7-
lactone–type skeleton. Until now, more than 90 enmein-type
natural products have been discovered, such as isodocarpin (2),
sculponin R (3), macrocalyxin A, isorothornin G, etc (Figure 1b).
Despite the great interest of this type of natural products from
both biological and synthetic prospects, there has been only one
relay synthesis of enmein by Fujita and coworkers in 1972,[8]
whereas 42 steps were used from intermediate 4 (Figure 1c).
Herein, we describe our efforts towards divergent total
syntheses of three enmein-type ent-kaurenoids: (–)-enmein, (–)-
isodocarpin and (–)-sculponin R.
Due to the distinct structure of enmein–type natural products,
the challenge for their synthesis is three-fold. First, they contain
various oxygen-based functional groups, such as free alcohols,
acetals or hemi-acetals, lactones and ketones, at different
oxidation levels. Thus, minimizing the use of protecting groups
(PGs) would not be trivial. Second, construction of the C8-10
stereocenters could be challenging as two of them are all-carbon
quarternary centers. Third, developing a divergent synthesis of
more than one natural product would require identification of a
common intermediate,[9] which might be complicated owing to
Figure 1. The isodon ent-kaurene diterpenoids.
To address these challenges, we conceived a strategy that is
depicted in Scheme 1. Advanced intermdiate 5 containing a
cyclohexenone ring was anticipated to serve as a common
intermediate to access enmein, isodocarpin and sculponin R in
similar numbers of steps. The enone moiety was envisioned to
provide a handle to contruct the E ring and introduce the C11
hydroxy group in sculponin R at a late stage. The C8
quarternary center in intermediate 5 can be established by a
consecutive acylation, alkylation and lactonization sequence
from intermediate 6. We postulated that building a cage ketal
saffold at an early stage would have two benefits: 1) it protects
both the C3 hydroxyl group and the hemi-acetal, thereby
reducing PG usages; and 2) the rigid cage structure would
facilitate subsequent diastereo-control for generating the C8 and
C9 centers. Cage compound 6 is expected to be eventually
prepared from a Diels–Alder adduct (7) through oxidation-state
adjustment and dearomatization.
[a]
[b]
Department of Chemistry
University of Chicago
5735 S Ellis Ave, Chicago, IL 60637 (USA)
E-mail: gbdong@uchicago.edu
Department of Chemistry
University of Texas at Austin
2506 Speedway STOP A5300, TX 78712 (USA)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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hypothesized that protection of the C1 hydroxyl group would
restrict the rotation of the C9-C10 bond, which would in turn
enhance the steric bias around the enone olefin. Indeed, TMS
protection of the C1 alcohol following by hydrogenation with
Pd/C afforded the C9 stereocenter with 4.8-8.7:1 dr. It is worthy
to mention that the reaction can be scaled up to a 10-gram scale.
Subsequently, enone 6 was synthesized using Newhouse’s
palladium-catalyzed
dehydrogenation
method,[12]
though
conventional two-step Saegusa oxidation also worked well. To
furnish the C8 quaternary center and δ-lactone, a one-pot α-
acylation/alkylation/lactonization was pursued. Treatment of
enone 6 with LiHMDS/Mander’s reagent[13] smoothly gave the β-
keto ester intermediate; however, the α-alkylation with 2,3-
dibromopropene proved to be a non-trivial challenge in this case
as the O-alkylation was found dominant under most alkylation
conditions. Ultimately, we found that, using NaH as the base and
HMPA:THF=1:5 as the mixed solvent, the C-alkylation became
the major reaction pathway (in a 6:1 ratio for C vs O-alkylation)
and excellent diasteroselectivity (>10:1) was observed. To our
delight, after removal of the TMS group with an acidic workup,
lactonization took place simultaneously to provide compound 5
as a white solid in 55% yield from enone 6. The structure and
stereochemistry of lactone 5 were unambiguously determined by
X-ray crystallography (Scheme 3).
With key intermediate 5 in hand, we turned our attention
towards divergent syntheses of sculponin R, isodocarpin and
enmein (Scheme 3). Vinylogous enol ether formation via
treatment with LiHMDS/TBSCl, followed by DMDO oxidation,
resulted in chemo- and diastereoselective[14] epoxidation at the
β,γ-olefin, which collapsed in situ to give the γ-hydroxyl enone.[15]
Subsequent one-pot acyl protection afforded ester 18 in 72%
yield. Notably, attempts with other allylic oxidation methods were
unfruitful for this transformation. Luche reduction of the enone
moiety, followed by the radical conditions at room temperature
trigered the 5-exo radical annulation to construct the [3.2.1]
scaffold;[3j,3k] Subject compound 19 under the Barton–McCombie
deoxygenation conditions promoted deoxygenation to eventually
afford compound 20 in 78% yield.[16] Allylic oxidation by selenium
dioxide followed by treatment with Dess–Martin periodinane
gave enone 21. Subsequent Mukaiyama hydration[17] followed by
deacetylation using Me3SnNMe2[18] completed the total synthesis
of sculponin R, which is spectroscopically identical to the natural
sample reported by Sun and coworkers.[19]
Scheme 1. Retro-synthetic analysis of enmein-type natural products.
The synthesis commenced with the Diels–Alder cycloaddition
between Danishefsky-type diene 8[10] and anhydride 9, each
prepared in three steps from commercially available chemicals
(Scheme 2). Upon refluxing the mixture in toluene for 15 hours,
followed by an acid workup, the bicyclic ketone product (10) was
isolated in 91% yield. Treatment of 10 with LiAlH4 led to
selective reduction of the bulkier carbonyl group in the
anhydride[11] as well as the ketone to afford lactone 11 in 90%
yield. It is noteworthy that the lactone moiety remained intact
even with prolonged reaction time or more LiAlH4, which is likely
due to the shielding effect by the arene ring. Subjecting lactone
11 to the Li/NH3 conditions promoted (a) the Birch reduction to
give the 1,4-diene, (b) reduction of the lactone to a hemi-acetal
and (c) removal of the benzyl PG. Upon workup with aqueous
HCl, the cyclohexenone moiety was afforded via enol ether
hydrolysis and olefin isomerization; concurrently, the caged
acetal was efficiently formed, which matches well with the
western hemisphere of sculponins R and M.
To synthesize enmein and isodocarpin, a distinct reductive
alkenylation approach was developed to build the D/E rings. L-
selectride reduction of 5 led to fomation of lithium enolate 22,
followed by palladium-catalyzed alkenylation[20]
,
smoothly
provided the [3.2.1] bicycle 23. An efficient reduction/Barton–
McCombie deoxygenation sequence was adopted to remove the
C14 oxygen, and, upon acidic workup in methanol, the cage
structure was opened to release alcohol 25 in 83% overall yield.
Compound 25 can serve as a common intermediate to prepare
enmein and isodocarpin through late-stage functional group
manipulations. Epimerization of the C3 hydroxyl group was
realized through Dess–Martin oxidation and then L-selectride
reduction. Finally, allylic oxidation followed by acid-mediated
acetal hydrolysis and silyl removal completed the total synthesis
of enmein (1). On the other hand, Barton–McCombie
deoxygenation of intermediate 25 removed the C3 hydroxyl
Scheme 2. Synthesis of key intermediate 5.
Direct hydrogenation of compound 13 under various
conditions resulted in nearly no diastereoselectivity, likely due to
that the cyclohexenone ring can undergo free rotation. We
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10.1002/anie.201803709
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Scheme 3. Divergent total syntheses of racemic enmein, isodocarpin and sculponin R.[22]
group. A similar allylic oxidatin/acetal hydrolysis protocol yielded
isodocarpin (2). The structures of synthetic enmein and
isodocarpin were further confirmed by X-ray crystallography
(Scheme 3).
and the major compound (29) was the desired isomer to access
the natural enantiomers of these natual products. Starting from
anhydride 29, a similar reduction and acid treatment sequence
was utilized to provide cage compound (+)-13, which is the
same intermediate employed in the racemic synthesis. Given the
relatively low cost of (S)-1-phenylethanol, this route provides a
rapid and inexpensive approach to access enantioenriched
synthetic intermediates. Following the identical synthetic routes
described in Schemes 2 and 3, syntheses of (–)-enmein, (–)-
isodocarpin and (–)-sculponin R were eventually achieved, of
which the optical rotation data match well with the reported ones
for the natural samples.[7,19,21]
In summary, syntheses of (–)-enmein, (–)-isodocarpin and (–)-
sculponin R have been achieved in a concise fashion. The key
features of the strategy include (a) an efficient early-stage cage
formation to control succeeding diastereoselectivity, (b) an one-
pot acylation/akylation/lactonization to construct the C-ring and
C8 quarternary center, (c) a reductive alkenylation approach to
construct enmain D/E rings and (d) a flexible route to allow
divergent syntheses of three natural products. We anticipate that
the practicality and conciseness of this strategy should have
important implications for preparing other ent-kaurene
diterpenoids. Investigation of the anticancer activity of these
natural products and their synthetic intermediates are ongoing.
Scheme 4. Syntheses of (–)-enmein, (–)-isodocarpin and (–)-sculponin R
To realize a practical route for the asymmetric syntheses of
these natural products, we conceived the idea of using chiral
diene 28, prepared from (S)-1-phenylethanol, to influence the
stereochemistry in the Diels–Alder reaction (Scheme 4). While
the diastereoselectivity obtained was not ideal, the two
diastereomers 29 and 30 can nevertheless be easily separated,
Acknowledgements
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10.1002/anie.201803709
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Financial support from American Cancer Society (RSG-14-155-
01-CDD) is acknowledged. We thank Mr. Ki-Young Yoon for X-
ray crystallography.
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Keywords: terpene • enmein • divergent synthesis • cage
formation• total synthesis
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COMMUNICATION
Saiyong Pan, Sicong Chen, Guangbin
Dong*
Page No. – Page No.
Divergent Total Syntheses of Enmein-
Type Natural Products: (–)-Enmein, (–
)-Isodocarpin and (–)-Sculponin R
Text for Table of Contents
Total syntheses of enmein-type natural products, (–)-enmein, (–)-
isodocarpin and (–)-sculponin R, have been achieved in a divergent and
concise fashion. The Common key intermediate contains a half-cage
structure.
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