Total synthesis of maoecrystal V: Early-stage C-H functionalization and lactone assembly by radical cyclization

Article abstract of DOI:10.1021/ja408231t

A total synthesis of the unusual ent-kaurane maoecrystal V is described. The synthesis strategy features a counterintuitive early disconnection of the lactone subunit to a polycyclic enol ether intermediate in order to preserve the central tetrahydrofuran ring until the beginning stages of the synthesis. This strategy enables an application of C-H functionalization at the early phase of the synthesis during the construction of a dihydrobenzofuran intermediate.

Full text of DOI:10.1021/ja408231t

Communication
pubs.acs.org/JACS
Total Synthesis of Maoecrystal V: Early-Stage C−H Functionalization
and Lactone Assembly by Radical Cyclization
Ping Lu, Zhenhua Gu,† and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93110-9510, United States
S
* Supporting Information
Scheme 1. Synthesis Design for Maoecrystal V
ABSTRACT: A total synthesis of the unusual ent-kaurane
maoecrystal V is described. The synthesis strategy features
a counterintuitive early disconnection of the lactone
subunit to a polycyclic enol ether intermediate in order
to preserve the central tetrahydrofuran ring until the
beginning stages of the synthesis. This strategy enables an
application of C−H functionalization at the early phase of
the synthesis during the construction of a dihydrobenzo-
furan intermediate.
mong many known ent-kauranoids,1 maoecrystal V stands
Aout for its atypical molecular architecture in this class of
natural products. Isolated and characterized by Sun and co-
workers in 2004,2 this unique C19 diterpenoid displayed potent
(IC50 = 20 ng/mL) and remarkably selective cytotoxicity
against HeLa cells. The pentacyclic framework of maoecrystal V
integrates three contiguous quaternary stereocenters (two all-
carbon), a bicyclo[2.2.2]octan-2-one subunit, and a strained
central tetrahydrofuran flanked by trans-fused six-membered
rings. Collectively, these structural characteristics amount to an
exquisite challenge for chemical synthesis. Numerous research
groups initiated programs directed at the synthesis of
maoecrystal V,3 identifying the construction of the quaternary
stereogenic centers as one of the main strategic goals and
developing many effective solutions. The successful completion
of the first total synthesis of maoecrystal V in racemic form,
reported by Yang and co-workers in 2010,4 relied on a concise
strategy centered on an intramolecular Diels−Alder reaction
(IMDA). The reaction enables a rapid assembly of the
bicyclooctanone and tetrahydrofuran ring systems in one
event, albeit with low facial selectivity for the diene counterpart.
The second of the two completed total syntheses of
( )-maoecrystal V reported to date was described by Peng
and Danishefsky in 2012.5 Other research groups have also
developed creative and efficient approaches based on IMDA
chemistry that is envisioned to precede tetrahydrofuran
formation.3
The strategic constrains of early THF installation suggested a
somewhat counterintuitive initial disassembly of the lactone
along the C7C8 bond (1⇒2, Scheme 1). We envisioned that
the target lactone subunit could be accessed from an
appropriately functionalized formate 2 (XH) by an intra-
molecular hydroformylation or radical cyclization of selenocar-
bonate (2, XSePh) onto the enol ether. The bicyclo[2.2.2]-
octanone is unraveled further by an IMDA disconnection (2⇒
3). The hydroxymethyl group at C10 used previously to deliver
the lactone carbonyl group is now refunctionalized to direct a
synthetic equivalent of ethylene for the IMDA reaction, thus
achieving the requisite facial selectivity. In our preliminary
investigations,8 we validated the efficiency of the IMDA
reaction and stability of the enol ether in the case of acrylate
and vinylsulfonate adducts 3a (YCO) and 3b (YSO2).
However, when faced with removal of the linking functional
groups, we found them to be less than ideal, necessitating
lengthy and cumbersome detours for their deletion. In search
for an alternative, we found that a silyl group serves the purpose
of enabling both an efficient [4 + 2] cycloaddition and an
effective tether removal.9 This modification provides a direct
path from 4 to 2. Further analysis led to functionalized
dihydrobenzofuran intermediate 5, which we planned to
prepare by a C−H-insertion process along the highlighted
C5C10 bond. In the long term, the C−H-insertion reaction
can potentially be carried out using asymmetric catalysis,10
Our strategy for the total synthesis of maoecrystal V has
emerged from the decision to pursue an early installation of the
central oxolane ring. We postulated that an early introduction
of the heterocycle would be beneficial for controlling
stereoselectivity in several key transformations. Conversely, its
construction late in the synthesis would carry undesired risks
due to its strained nature. Following this line of analysis, a plan
summarized in Scheme 1 was developed.
Received: August 8, 2013
© XXXX American Chemical Society
A
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Communication
paving the way for the enantioselective synthesis of maoecrystal
V.
As with other related substrates, the IMDA reaction occurred
cleanly upon heating a solution of 14 in toluene at 110 °C,
giving bicyclo[2.2.2]octane cycloadduct 15 in a nearly
quantitative yield. The enol ether within the ring system of
15 was found to be rather stable and generally suitable for
subsequent transformations.
Our next major goal was the appendage of the lactone ring.
We planned to accomplish this task by a rare formyl radical
endo-cyclization onto the enol ether double bond (Scheme
3a).17 This approach first required desilylation of 15, which was
The goal of initial studies was to define a synthetic path to
maoecrystal V in racemic form according to the aforemen-
tioned synthesis design. The preparation of the substrate for the
early C−H functionalization reaction began with alkylation of
sesamol using 3-(4-methoxybenzyloxy)-2,2-dimethyl-1-propa-
nol (6) in the presence of diisopropyl azodicarboxylate and
triphenylphosphine,11 which afforded aryl ether 7 in 79% yield
(Scheme 2). Its directed ortho-metalation with n-butyllithium in
Scheme 2
Scheme 3
THF, followed by transmetalation to the arylzinc reagent and
coupling with methyl chlorooxaloacetate, afforded α-keto ester
8,12 which was converted directly to α-diazoester 9.13 The
essential C−H-insertion was achieved by treatment of 9 with
rhodium acetate that provided the benzofuran product 10 in
74% yield and >10:1 diastereoselectivity in favor of the trans-
substituted isomer.14
Further elaboration included stereoselective installation of
the quaternary carbon center at C10 using zincate enolate
generated from 10 and benzyl chloromethyl ether (76% yield,
dr 9:1).15 Subsequent reduction of the ester group with lithium
aluminum hydride and opening of the formyl acetal of catechol
with methylmagnesium bromide,16 achieved upon heating in
benzene, afforded 13. Oxidation of the substituted phenol with
iodobenzene diacetate/EtOH and vinylsilylation of the primary
hydroxy group in the resulting protected ortho-quinone
intermediate provided the substrate for the intramolecular
Diels−Alder reaction (14) in high yield.
found to be rather challenging. The substrate for desilylation
reaction was accessed after an efficient reductive removal of the
gem-diethoxy substituents with samarium(II) iodide (90% yield,
Scheme 3b).18 Under extensively optimized reaction con-
ditions, the silyl group could be removed in a reproducible 50%
yield upon treatment with tetra-n-butylammonium fluoride in
B
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Journal of the American Chemical Society
Communication
DMPU at 0 °C for 1 h. The unusually high reactivity of the
trialkylsilyl ether is due to its position within the bicyclo[2.2.2]-
octanone ring system, and the presence of the carbonyl group is
essential for high reactivity. For example, when the carbonyl
group is replaced with a hydroxyl, the resulting compound is
substantially more resistant to desilylation.19
NOESY NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
zakarian@chem.ucsb.edu
After straightforward derivatization to selenocarbonate20 18,
our efforts concentrated on the lactone closure by radical
cyclization. Multiple attempts with tri-n-butyltin hydride as the
reagent using several initiators (AIBN, ACHN, V70) under a
variety of addition protocols and temperature regimes resulted
only in reduction to formate 23 (Scheme 3c), with none of the
desired lactone 19 observed. Clearly, the reaction of the initially
generated formyl radical with the hydrogen atom donor, n-
Bu3SnH,21 was too rapid relative to the desired cyclization (step
a, Scheme 3a). We hypothesized that using a less efficient
hydrogen atom donor would result in a more effective ring
closure. Tris(trimethylsilyl)silane ((Me3Si)3SiH) was the
reagent of choice.21 To our delight, slow addition of a mixture
of (Me3Si)3SiH and AIBN to a solution of phenylselenocar-
bonate 18 in benzene at 80 °C resulted in the successful
formation of lactone 19 (55% yield), along with a minor
amount of byproduct 24 resulting from radical fragmentation
(12%).22
Present Address
†Department of Chemistry, University of Science and
Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026,
China.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We dedicate this manuscript to Professor Larry E. Overman in
honor of his 70th birthday. Financial support for this work was
provided by the NSF (CHE-0836757), NIH (R01 GM077379),
and additional kind gifts from Amgen and Eli Lilly. We would
like to thank Professor Alexei Novikov (University of North
Dakota) for helpful discussions. Dr. Hongjun Zhou is thanked
for continued assistance with NMR spectroscopy. We are
grateful to Dr. James Pavlovich for performing the high-
resolution mass-spectroscopic analysis.
Formation of the last six-membered ring, the gem-dimethyl-
substituted cyclic enone, was required to complete the total
synthesis of maoecrystal V. Toward that goal, removal of the p-
methoxybenzyl group,23 oxidation of the exposed primary
hydroxyl with Dess-Martin periodinane (DMP),24 and the
Wittig methylenation25 delivered 20. Our synthetic studies
revealed that ketone 20 is the optimal substrate for the
introduction of the C17 methyl group, an operation that proved
to be difficult to achieve with any level of stereocontrol in the
previous total synthesis efforts. In this instance, addition of
iodomethane to the enolate derived from 20 and LiN(SiMe3)2
afforded the desired product as the major component in a 7:1
mixture of diastereomers (90% combined yield). After
debenzylation (DDQ, wet CH2Cl2, 50 °C, 12 h), the
diastereomers were separated, and the major isomer was
advanced to intermediate 22 by oxidation to the aldehyde with
DMP and chemoselective addition of vinylmagnesium bromide
in the presence of anhydrous cerium(III) chloride.26
Maoecrystal V was obtained in two additional steps, which
included ring-closing metathesis27 and oxidation to enone with
Dess-Martin periodinane.
In closing, a concise total synthesis of maoecrystal V has been
accomplished (24 steps, ∼1.5% overall yield from sesamol).
The strategic focus on the central strained tetrahydrofuran ring
resulted in an initial disassembly of the lactone ring to a
polycyclic enol ether. The enol ether was constructed by an
IMDA reaction of a tethered CH2CH2 equivalent with a 2,4-
cyclohexadienone fragment obtained by oxidative dearomatiza-
tion of a dihydrobenzofuran intermediate. This intermediate, in
turn, was prepared by an effective rhodium-catalyzed C−H
functionalization reaction which can potentially be modified to
access enantioenriched products using chiral rhodium cata-
lysts.10
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