Total Synthesis of (+)-Sarcophytin

Article abstract of DOI:10.1002/anie.201711372

A total synthesis of the cembranoid (+)-sarcophytin is presented, featuring a Diels–Alder cycloaddition of an enone as the dienophile with an ester-derived dienoate. The study highlights a peculiar geometric preference for the Z dienoate to furnish the cy

Full text of DOI:10.1002/anie.201711372

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Accepted Article
Title: Total Synthesis of (+)-Sarcophytin
Authors: Erick Moran Carreira, Leonardo J. Nannini, and Suren J.
Nemat
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Total Synthesis of (+)-Sarcophytin
Leonardo J. Nannini, Suren J. Nemat and Erick M. Carreira*
Abstract A total synthesis of the cembranoid (+)-sarcophytin is
presented, featuring a Diels–Alder cycloaddition of an enone as
the dienophile with an ester derived dienoate. The study highlights
a peculiar geometric preference for the Z dienoate to furnish the
cycloadduct. The endgame involves a reaction cascade, including
lactone opening, alcohol oxidation and ketone epimerization to
complete an efficient synthesis. A salient feature of the synthesis
is the resulting reassignment of the absolute configuration,
correcting the previously reported nominal structure.
time generating the unsaturated ester 5. Tetracycle 6 suggests a
Diels–Alder cycloaddition reaction of ester 7, which may be
readily disconnected into two fragments (Scheme 1 B) of similar
complexity, leading to a highly convergent approach.[9,10]
Sarcophyton soft corals have been the subject of extensive
research due to the variety of cembranoid diterpenes produced
by these organisms, which have intrigued synthetic chemists for
decades.[ In 1998, Anjaneyulu and coworkers reported the
isolation of (+)-sarcophytin (1) from Sarcophyton elegans,
collected from the Indian Ocean at the Andaman and Nicobar
islands.[2] Herein, we describe a highly convergent synthesis of 1
as well as its enantiomer 4, relying on an intramolecular Diels–
Alder cycloaddition reaction. The synthesis of the natural product
commences from commercially available chiral pool building
blocks.[3] A salient feature of the crafted strategy is that it enables
access to the synthesis of both enantiomers. This led to the
assignment of the absolute configuration as shown for 4,
correcting the previously reported nominal structure 1.
1]
Numerous additional members of the sarcophytin family have
been recently isolated from a variety of species,[2,4] and their
primary biological function is believed to be chemical defense
against predators.[4a] The structures are characterized by a cis-
anti-cis dodecahydrophenanthrene core (see Scheme 1, 2).
Furthermore, these possess bridging hemiketals between a
tertiary C(10) alcohol and either C(3) or C(14) ketones. Among
them, chatancin (3), lacking ketone at C(3), was isolated from
Sarcophyton sp. off the coast of Okinawa in 1990.[5] While 3 has
captured the attention of different groups, including the seminal
works of Gössinger,[6] Deslongchamps[7] and Maimone,[8] no
synthetic work has been reported toward sarcophytin (1). Its
highly congested framework, along with the intriguing properties
of cembranoid natural products compelled us to embark on
synthetic investigations.
Scheme 1. A) Sarcophytin (1) and related cembranoids; B) retrosynthesis and
stereochemical analysis of the Diels–Alder reaction.
The cycloaddition involving tethered electron-deficient reaction
partners, namely an enone and a dienoate as shown for 7, sets
up a situation with little precedence.[11] The configuration at C(14)
would be critical for facial selectivity in the cycloaddition of 7,
controlling the C(4), C(5) and C(13) stereocenters, provided the
Diels–Alder reaction proceeded through an exo-transition
state.[11,12] The natural product bears a sp2-carbon at C(12),
consequently, this enables a priori the use of either E- or Z-
dienoates in 7. Considering that the center at C(1) in sarcophytin
might be susceptible to epimerization, either (R)- or (S)
diastereomer at C(1) may be employed. Collectively, the analysis
presented above reveals considerable flexibility in the strategy, as
there are a number of stereochemical options available for the
successful cycloaddition reaction of 7 to give 6.
Retrosynthetically, the C(11)–C(12) double bond in 4 would
suggest a transannular Diels–Alder reaction reminiscent of the
approach Deslongschamps employed in their total synthesis of
chatancin to construct the dodecahydrophenanthrene core from a
1
4-memberred macrocycle.[7] On the other hand, in our
retrosynthetic analysis a key issue to be examined was whether
transposition of the C(10)–C(11) double bond in 6 could be
employed as a handle for hydroxylation of C(10) while at the same
The synthesis commenced by conversion of (S)-(–)-citronellal
(
10) into isopulegone (11) by a procedure reported by Corey.[13]
[*]
L. J. Nannini, S. J. Nemat, Prof. E. M. Carreira
Laboratorium für Organische Chemie, ETH, Zurich, HCl H335
Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Isopulegone (11) was subsequently refluxed in aqueous HCl,[14]
undergoing an isomerization/retro-aldol-condensation reaction to
give desired enantiomerically pure (S)-3-methylcyclohexanone
Homepage: http://www.carreira.ethz.ch
(
12). We then explored the selective formation of vinyl triflate 13.
Supporting information for this article is given via a link at the end of
the document.
Unfortunately, sterically hindered lithium bases, such as LDA and
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LiTMP,[15] gave poor regioselectivity (13:14 = 2:1 and 3.4:1,
respectively). Inspired by the report of Antony and Maloney,[16] we
For the synthesis of the Z diene 18, we first synthesized enyne 17
by Negishi coupling with alkynyl zinc bromide 16.[18] Subsequent
saponification of the ethyl ester and hydrogenation with Lindlar’s
catalyst in the presence of quinoline afforded selectively the Z
dienoic acid fragment 18.
With a route to dienes 15 and 18 in hand and hydroxyenone 9
readily available,[9,10] a study of the Diels–Alder reaction was
conducted on (E,anti)-19 and (Z,anti)-19, possessing the (1R)-
configuration (Scheme 3) identical to that at C(1) in target 4.[19]
Unfortunately, no cycloaddition occurred upon heating (E,anti)-19
in DMSO at 150 °C, and at higher temperatures decomposition
was observed. By contrast, when (Z, anti)-19 was heated to
found that deprotonation of 12 with NaHMDS and 2 equivalents
of diglyme in t-BuOMe, followed by triflation with Comins’ reagent
yielded a 6:1 mixture of 13:14. With the desired vinyl triflate in
hand, we proceeded with the synthesis of E and Z dienoic acids
1
5 and 18, respectively. Heck reaction of 13 with methyl
acrylate,[17] followed by saponification yielded E dienoic acid 15 in
9% yield over two steps.
5
100 °C rapid intramolecular Diels–Alder was observed in 53%
yield to give (1R,12S)-20. The excitement over this promising
result, however, was dampened by the outcome of the
esterification of 18 with ent-9, affording (Z, anti)-19 in low yield
and (E,anti)-19 as side product.[20]
We then examined cycloaddition reactions of the
diastereomeric counterparts bearing (1S) configuration with
(
E,syn)- and (Z,syn)-19. These were accessible from 9 by
Mitsunobu coupling with 15 or 18, involving clean coupling without
the observation of dienoate E/Z-isomerization.
Dienoate (E,syn)-19 was found to be inert in the cycloaddition
reaction, consistent with the observations made for (E,anti)-19
discussed previously. However, heating ester (Z,syn)-19 at
1
00 °C in DMSO resulted in a rapid cycloaddition reaction to
afford tetracycle (1S,12S)-20 as a single diastereomer (NMR), in
6% yield (Scheme 3). As discussed below, X-ray
crystallographic analysis of an intermediate later in the sequence
7
(
21, Scheme 4) revealed that the cycloaddition had proceeded
through an exo arrangement.[
21]
Treatment of (1S,12S)-20 with m-CPBA afforded an
intermediate epoxide in a diastereoselective fashion (dr >10:1 by
NMR), which upon addition of DBU in the same pot led to clean
formation of unsaturated lactone 21. Subsequently, hydrolysis of
the lactone under aqueous alkaline conditions was explored.
Unfortunately, seco-acid 22 was only transiently observed under
various conditions, because it underwent rapid ring closure upon
work-up to furnish recovered lactone 21.
Scheme 2. Syntheses of acid fragment 15 and 18: a) PyH·ClCrO
b) HCl, H O, 120 °C, 54% (2 steps); c) NaN(SiMe , diglyme, tBuOMe, –78 °C,
min, then Comins’ reagent, –78 °C to rt, 62%; d) methyl acrylate,
Pd(PPh Cl (5 mol%), Et N, DMF, 80 °C, 78%; e) 10% NaOH (aq.), EtOH, 0 °C
to rt, 76%; f) ethyl propiolate, LDA, THF, –78°C; then ZnBr , –78 °C to 0 °C;
then 13, Pd(PPh , 0 °C to rt, 70%; g) 10% NaOH (aq.), EtOH, 0 °C to rt; h)
Lindlar’s catalyst, H , EtOAc, rt, 79% (2 steps).
3 2 2
, CH Cl , rt;
2
3 2
)
30
3
)
2
2
3
2
3 4
)
2
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Scheme 3. DCC coupling conditions: dicyclohexylcarbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), CH
2
Cl
2
. 0 °C to rt. Mitsunobu reaction conditions:
diisopropyl azodicarboxylate (DIAD), triphenylphosphine, THF, –78 °C to rt. Diels–Alder reaction conditions: DMSO (0.05 M), at the temperature shown.
Scheme 4. a) m-CPBA, NaHCO
3 2 2 3 2 2 2 8 2
, CH Cl , 0 °C to rt then diazabicycloundecane (DBU); b) RuCl ·nH O, K S O , KOH (1 M), H O:THF (10:1), 60 °C, 64% (2 steps);
c) TMS-diazomethane, PhH/MeOH (4:1), 0 °C to rt, 75%. Intermediates 21 and 23 are illustrated as their ORTEP representations with ellipsoids shown at 50 and
25% probability, respectively.
The majority of alcohol to ketone oxidations occurs under acidic
dienoate proved optimal in the cycloaddition. At the heart of the
retrosynthetic analysis is a disconnection approach that fully
forges strategic bonds (Diels–Alder cycloaddition) with
stereochemical variables (E- versus Z- diene) and the
susceptibility of C(1) towards epimerization to furnish an efficient
synthesis. Further studies on cembranoids natural products
synthesis are ongoing and will be reported as they become
available.
conditions, and these would inevitably lead to rapid cyclization of
seco acids to lactones. We thus turned our attention to oxidations
conducted under alkaline conditions, involving potassium
ruthenate (K
2
RuO
4
)
generated in situ upon treatment of
22]
RuCl ·nH O with K S O
3
2
2 2 8
in 1 M aqueous KOH.[ Gratifyingly,
under these reaction conditions, lactone opening/alcohol
oxidization was followed by in situ epimerization at C(1) and
hemiacetal formation to directly give 23 in 64% yield from 20.
Completion of the synthesis proceeded by esterification of acid 23
3 2
with Me SiCHN , furnishing (+)-sarcophytin (4), identical in all
respects with the data published for the natural product, including
positive optical rotation.
Experimental Section
Experimental Details.
Since the isolation of nominal sarcophytin (1),[2] there have been
doubts surrounding the absolute configuration originally
proposed.[7c,7d] The source of the skepticism stems from the fact
that the cis-anti-cis dodecahydrophenanthrene core in 1 bears an
enantiomeric relationship to that found in other secondary
metabolites of the same family, such as chatancin (3) at C(5), C(8),
C(10), and C(13).[2-4] Our initial planning stages targeted the
synthesis of nominal sarcophytin (1), as originally published by
the researchers who performed the isolation; the synthesis route
commenced with (R)-(–)-carvone and (R)-(+)-pulegone.[14]
Completion of the first synthesis of nominal (+)-sarcophytin (1)
furnished a final product, giving opposite negative specific optical
rotation thus affording (–)-sarcophytin. Therefore, the synthesis of
Acknowledgements
We thanks Dr. N. Trapp and M. Solar for X-ray crystallographic
analysis, and to Dr. M.-O. Ebert, R. Arnold, S. Burkhardt and R.
Frankenstein for NMR Measurements. We thank the Swiss
National Science Foundation (200020_152898) and ETH Zürich
for support.
Keywords: Diels–Alder • cembranoid • sarcophytin • potassium ruthenate •
natural product synthesis
4
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members of this class of natural products that have been fully
characterized.
In conclusion we have reported the synthesis and
configurational reassignment of (+)-sarcophytin. The convergent
approach relies on intramolecular Diels–Alder reaction of two
electron deficient partners. Interestingly, the Z-configured
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1
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L. J. Nannini, Suren J. Nemat, E. M.
Carreira*
Page No. – Page No.
Total Synthesis of (+)-Sarcophytin
A total synthesis of the cembranoid (+)-sarcophytin is presented, featuring a Diels–
Alder cycloaddition of an enone and Z-dienoate. A reaction cascade, including
lactone opening, alcohol oxidation and ketone epimerization completes an efficient
synthesis. Reassignment of the absolute configuration of the natural product,
corrects the previously reported nominal structure.
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