Site-Specific Photochemical Desaturation Enables Divergent Syntheses of Illicium Sesquiterpenes

Article abstract of DOI:10.1021/jacs.1c00525

Desaturation of unactivated alkanes remains a challenging yet desirable strategy to make olefins. The Illicium sesquiterpenes usually possess highly oxygenated cage-like architectures, and some of them exhibit prominent neurotrophic effects. Here, we disclose a unique photochemical desaturation strategy for the efficient, highly stereocontrolled total syntheses of five Illicium sesquiterpenes from inexpensive (R)-pulegone, featuring a 13-step gram-scale synthesis of (-)-merrilactone A. The efficiency of the syntheses derives from an expedient construction of a tetracyclic framework via two annulations, a site-specific photoinduced single-step desaturation in a complex hydrocarbon system, and diverse oxygenation manipulations around the resultant olefin intermediate. This work highlights how late-stage desaturation can dramatically streamline the synthesis of complex terpenes and diverse non-natural analogues for establishing the structure-activity relationship and elucidating their molecular mechanisms of bioactivity.

Full text of DOI:10.1021/jacs.1c00525

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Article
Site-Specific Photochemical Desaturation Enables Divergent
Syntheses of Illicium Sesquiterpenes
Yang Shen, Linbin Li, Xiaoxia Xiao, Sihan Yang, Yuhui Hua, Yinglu Wang, Yun-wu Zhang,*
and Yandong Zhang*
Cite This: J. Am. Chem. Soc. 2021, 143, 3256−3263
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ABSTRACT: Desaturation of unactivated alkanes remains a
challenging yet desirable strategy to make olefins. The Illicium
sesquiterpenes usually possess highly oxygenated cage-like architec-
tures, and some of them exhibit prominent neurotrophic effects.
Here, we disclose a unique photochemical desaturation strategy for
the efficient, highly stereocontrolled total syntheses of five Illicium
sesquiterpenes from inexpensive (R)-pulegone, featuring a 13-step
gram-scale synthesis of (−)-merrilactone A. The efficiency of the
syntheses derives from an expedient construction of a tetracyclic
framework via two annulations, a site-specific photoinduced single-
step desaturation in a complex hydrocarbon system, and diverse oxygenation manipulations around the resultant olefin intermediate.
This work highlights how late-stage desaturation can dramatically streamline the synthesis of complex terpenes and diverse non-
natural analogues for establishing the structure−activity relationship and elucidating their molecular mechanisms of bioactivity.
of our knowledge, few applications to the natural product
synthesis have been reported to date. Sames et al. realized a
desaturation transformation in the total synthesis of
rhazinilam12 by employing an extraneous directing group and
a stoichiometric expensive platinum complex.
INTRODUCTION
■
Aliphatic desaturation is a vital oxidation process through
which nature generates functional molecules. For example, the
enzymatic desaturation of long-chain fatty acid derivatives is a
ubiquitous biotransformation that produces a variety of
unsaturated lipidic natural products with essential biological
functions.1 A similar transformation was also discovered in the
hepatic metabolism of the antiepileptic drug valproic acid (1)
(VPA)2 in which cytochrome P-450 catalyzed an oxidative
desaturation process to yield the potent hepatotoxin Δ4-VPA
(2) (Figure 1A).
In the realm of synthetic chemistry, however, the direct
desaturation of a unactivated alkyl motif to generate the
corresponding alkene functionality is still a formidable
challenge due to the high thermodynamic stability of the
parent alkane.3 Breslow’s pioneering biomimetic desaturation4
realized a site-selective double bond (C14−C15) formation (3
to 4), thus opening a possibility for the late-stage
functionalization of steroid skeletons (Figure 1B). This
achievement enlightened chemists on the strategic value of
the late-stage desaturation: two adjacent C−H bonds could be
conceived as a latent double bond, provided that they can be
activated when necessary in complex molecule synthesis.
Several approaches for aliphatic desaturation have been
developed, mainly employing active radicals5−9 or transition
metals.10,11 However, because of some significant limitations in
these methodological studies, such as poor substrate scope
(usually requiring preset directing groups or hydrogen
acceptors) and poor chemo- and regioselectivity, to the best
RESULTS AND DISCUSSION
■
Our interest in a desaturation reaction was ignited during the
syntheses of Illicium sesquiterpenes.13,14 The Illicium genus of
shrubs or trees, mostly distributed in eastern Asia and partially
in North America, is a rich source of structurally complex and
biologically intriguing sesquiterpenes.15−17 Most of them are
classified by carbon-skeleton features into three biosyntheti-
cally related categories: anislactone, seco-prezizaane, and allo-
cedrane type. To date, over 100 sesquiterpenes with diverse
oxygenation patterns have been discovered from this genus of
plants and display notable biological activities, including
antiviral, neurotoxic, and neurotrophic effects. Among them,
(−)-merrilactone A18 (7, Figure 1C) (anislactone type), which
exhibited prominent neurotrophic activities at remarkably low
concentrations (100 nM), has received the most attention
from the synthetic community with several creative syntheses
Received: January 15, 2021
Published: February 18, 2021
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Figure 1. Desaturation in nature and organic synthesis. (A) Biochemical desaturation of VPA with cytochrome P-450. (B) Biomimetic desaturation
in steroid synthesis pioneered by Breslow. (C) Desaturation−oxygenation strategy for chemical synthesis of Illicium sesquiterpenes.
reported.19−28 Although these sesquiterpenes hold the promise
for the treatment of neurodegenerative disorders associated
with Alzheimer’s and Parkinson’s diseases, most biological
studies are restricted to cell-culture-based assays due to low
natural product abundance and limited choices of synthetic
derivatives.29−33 Moreover, the molecular mechanism under-
lying the neurotrophic effect of Illicium sesquiterpenes remains
unclear. Here, we disclose a unique site-selective desaturation
strategy to access five anislatone-type Illicium sesquiterpenes
(7−11, Figure 1C) from inexpensive (R)-pulegone, including a
13-step synthesis of (−)-merrilactone A (7) on a gram scale.
The late-stage desaturation of a cyclopentanoid ring not only
enables expedient, protecting-group-free syntheses of these
natural products but also provides a synthetic platform to
prepare diverse derivatives for establishing the structure−
activity relationship and elucidating their molecular mecha-
nisms of bioactivity.
At the outset of our synthetic studies, structural relevance
among sesquiterpenes 7−11 (Figure 1C) convinced us that
these family natural products could be rapidly accessed from a
common intermediate. To take advantage of the various olefin
chemistries, compound 6, which bears the same carbon ring
skeleton with 7−11 but contains an unsaturated C-ring, was
selected as an entry point to this family. We envisioned that
(1) by following Fukuyama’s method,34 the epoxidation of the
C1−C2 double bond of 6 followed by intramolecular epoxide
opening by C7 hydroxyl group could furnish merrilactone A
(7); (2) a Markovnikov hydration of the alkenyl moiety would
deliver merrilactone B34 (8), which could be further converted
to anislactone B35 (9) via intramolecular transesterification and
then to anislactone A35 (10) through the epimerization at C7
stereocenter; and (3) majusanside36 (11), a sesquiterpene
glucoside, could be assembled through allylic C−H oxidation
after the inversion of C7 configuration and subsequent
incorporation of a glucose unit to the resulting alcohol 12.
Although either racemic or enantio-enriched 6 was also
selected as an advanced intermediate in previous synthetic
efforts toward merrilactone A, it took between 1627 and 29
steps22 to access 6, precluding their use in preparing analogues
in meaningful quantities. Here we provide a conceptually
different, scalable approach to 6.
In contrast to the elusive C−H oxygenation37−40 in
biosynthetic proposals,34 the derivatization through an olefin
intermediate would be much more doable in achieving chemo-
and stereoselectivity. We anticipated that the olefinic
compound 6 could be generated through site-selective
desaturation from dilactone 5. Our final-stage desaturation
strategy avoids the protection of the oxygenated functions of
C-ring in the early stages of the synthesis. The imposing
challenge associated with this strategy is the selective
functionalization of the C-ring in a complex hydrocarbon
system. To address these challenges, an efficient synthesis of 5
is necessary. The highly congested five-membered B-ring
comprising four contiguous quaternary centers has constituted
the critical challenge in the syntheses of related natural
products.19−28 We expected that the 15-carbon framework of 5
could arise through a series of annulations from the
inexpensive commodity chemical (R)-pulegone (13, $600/
kg). Overall, the site-selective desaturation is the key to achieve
a chiral pool approach41 to these family natural products.
The synthesis began with the transformation of (R)-
pulegone (13) into a suitable intermediate with C-ring
backbone functionality for the installation of the C9 quaternary
stereocenter and γ-lactone D-ring (Scheme 1). Sequential, one-
pot treatment of 13 with bromine and NaOEt provided ester
14 through dibromination followed by Favorskii ring
contraction and HBr elimination. Deprotonation of 14 with
potassium hexamethyldisilazide (KHMDS) and trapping of
resulting enolate from less hindered α-face with allyl iodide
furnished ester 15 as a single diastereomer in 94% yield. At this
stage, the C-ring bearing two consecutive stereocenters was
established in just two steps. Epoxidation of the electron-rich
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a
Scheme 1. Complete Synthetic Sequence for the Total Synthesis of (−)-Merrilactone A
a
Reagents and conditions: 1. Br2 (1.1 equiv), NaHCO3 (0.3 equiv), Et2O, −10 °C, 2 h; NaOEt (2.2 equiv), EtOH, 55 °C, 5 h, 90%. 2. KHMDS
(2.0 equiv), hexamethylphosphoric triamide (HMPA) (3.0 equiv), allyl iodide (2.0 equiv), tetrahydrofuran (THF), −78 °C, 1 h, 94%. 3. m-CPBA
(2.5 equiv), NaHCO3 (2.5 equiv), CH3CN, 0 °C; NaIO4 (5.0 equiv), RuCl3 (0.02 equiv), H2O, 12 h, 23 °C, 77%. 4. SOCl2 (1.5 equiv), Et3N (5.0
equiv), CH2Cl2, −78 °C, 1 h, 100%. 5. KHMDS (1.5 equiv), THF, 0 °C, 2 h; LiAlH4 (2.0 equiv), 0 °C, 2 h, 98%. 6. Dess−Martin periodinane
(DMP) (1.1 equiv), CH2Cl2, 0 °C, 1 h, 94%. 7. trimethylsilylethynylmagnesium chloride (1.2 equiv), THF, −78 to 23 °C, 30 min, 98%. 8. B2(pin)2
(1.1 equiv), Pd(OAc)2 (0.1 equiv), toluene/MeOH (5:1 v/v), 50 °C, 8 h; NaOH (4 M, 3.0 equiv), 30% aqueous H2O2 (30 equiv), THF, 0 °C, 1 h,
83%. 9. p-TsOH·H2O (1.0 equiv), CH3CN, 23 °C, 2 days, 96%. 10. N,N′-carbonyldiimidazole (CDI) (1.0 equiv), CH2Cl2, 23 °C, 1 h; PhSeSePh
(3.0 equiv), NaBH4 (3.0 equiv), N,N-dimethylformamide (DMF), 23 °C, 4 h, 80%. 11. AIBN (0.2 equiv), TTMSS (1.5 equiv), benzene, 80 °C, 8
h, 96%. 12. NBS (1.2 equiv), Ph2CO (0.1 equiv), HFIP, violet LED, 23 °C, 40 min, 82%. 13. m-CPBA (2.0 equiv), EtOAc,23 °C, 24 h; then p-
TsOH·H2O (1.0 equiv), EtOAc/MeOH (10:1), 23 °C, 24 h, 79%.
tetrasubstituted C4−C5 double bond with m-chloroperbenzoic
acid (m-CPBA) delivered β-epoxide 16 as a single diaster-
eomer, which underwent a double-bond oxidative cleavage−
epoxide opening lactonization cascade by in situ treatment with
RuCl3 and NaIO4 to generate lactone 18 in 77% overall yield.
The configuration of intermediate 16 was confirmed by the X-
ray structure of its derivative (see the Supporting Information).
We speculated that the excellent facial selectivity of the
epoxidation could be attributed to the favorable torsional
steering42the β-attack of the C4−C5 double bond by the
electrophile (m-CPBA) resulted in a less eclipsing interaction
in the transition state. Dehydration of 18 with SOCl2 and Et3N
afforded ester 19, which was then smoothly converted to
aldehyde 20 through a selective reduction of the hindered ester
group in the presence of a lactone group and subsequent
configuration at C7 while simultaneously setting the stage for
the key borylative cyclization. Interestingly, the replacement of
the Grignard reagent with the corresponding lithium reagent
only led to a decreased diastereomeric ratio (dr 3:1). To our
delight, Pd(OAc)2 catalyzed borylative cyclization of enyne 21
and bis(pinacolato)diboron [B2(pin)2]44 in a mixed solvent of
toluene and methanol (5:1 v/v) proceeded in good yield to
afford diol 22 after an oxidative work-up. The stereochemistry
of 22 was confirmed by X-ray crystallography. We found that
the free hydroxyl group at C7 was essential for inducing a
highly diastereoselective cyclization, probably through a
chelating transition state with palladium metal. Hydrolysis of
vinylsilane with p-toluenesulfonic acid (p-TsOH) and selective
formation of a selenocarbonate with primary alcohol (C14)
delivered the compound 23. Then, 23 underwent a 5-exo-trig
radical cyclization upon treatment with azobis-
(isobutyronitrile) (AIBN) and tris(trimethylsilyl)silane
(TTMSS) to form the lactone A-ring and the angular methyl
group (C8), providing the dilactone 5 in 96% yield. The
absolute stereochemistry of the key tetracyclic intermediate 5
was confirmed by X-ray crystallography (see the inset image,
Scheme 1), which also revealed that the tertiary C1−H bond is
oriented outward in a cage-like backbone and could be easily
oxidation.
43
́
Enlightened by the pioneering works of Cardenas and
Siegel,44 we envisioned that the central five-membered B-ring
could be constructed through a borylative cyclization of the
1,6-enyne precursor 21. First, the addition of freshly prepared
trimethylsilylethynylmagnesium chloride (1.2 equiv) to 20 at
−78 °C followed by warming to 23 °C delivered enyne 21 as a
single diastereomer in 98% yield, forging the correct
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accessed by reactants during the following C−H functionaliza-
tion process. At this stage, the tetracyclic framework of the
family natural products had been established in an efficient 11-
step sequence, and 5 could be prepared on a multigram scale.
With ample quantities of 5 available, our investigation then
focused on the pivotal desaturation step to generate the C1−
C2 double bond in the C-ring (Figure 2). To this end, we
initially designed a two-step desaturation sequence involving a
free-radical bromination and an HBr elimination, anticipating
the electron-rich tertiary C1−H of 5 could be selectively
substituted by a bromine atom. We found that treatment of 5
with excess N-bromosuccinimide (NBS, 4.0 equiv) and AIBN
(0.5 equiv) in refluxing CCl4 effected not only C1 bromination
but also the oxidation of secondary alcohol at C7,
consequently providing bromoketone 6′ (Figure 2A, entry
1). The structure of 6′ was determined by spectroscopic
analysis in conjunction with X-ray crystallography. Unfortu-
nately, decreasing the amounts of NBS and AIBN only led to a
complex product mixture with a low yield of 6′, and this may
be caused by the competitive reactions between C1−H and
C7−H. Density functional theory (DFT) calculations of C−H
bond dissociation energies (BDEs) of 5 (Figure 2B) also
revealed that BDEs of C1−H (88.6 kcal/mol) and C7−H
(85.4 kcal/mol) are close but much lower than those of other
C−H bonds.
To achieve a selective C1 bromination, the reactivity of C7−
H should be reduced, whereas that of C1−H is hard to be
tuned. Thus, we turned our sight to the solvent effect: a
hydrogen bond donor to the C7 hydroxyl group could reduce
the electron density of C7−H and simultaneously generate a
solvation shell to further increase the steric hindrance around
C7−H, thereby deactivating the C7−H toward an electrophilic
hydrogen abstraction. Hexafluoroisopropanol (HFIP), which
has recently found applications in a wide spectrum of
chemistry45,46 because of its unique physical and chemical
properties, well meets our expectations. To our surprise, the
irradiation of a solution of 5 in HFIP at room temperature with
UV light (312 nm) directly afforded the desired desaturation
product 6 in 42% NMR yield as the only product along with
some starting material recovered (Figure 2A, entry 2). To
completely consume the starting material, benzophenone47−49
(Ph2CO, 0.1 equiv) was used as a sustainable initiator instead.
Under such conditions, 6 was obtained in 42% NMR yield but
accompanied by some unidentified byproducts in prolonged
Figure 2. (A) Evaluation of radical desaturation conditions. Isolated
yield unless otherwise stated. See the Supporting Information for the
scale of each reaction. *NMR yield with triphenylmethane as an
internal standard. (B) BDEs in 5 calculated at the B3LYP/6-31G(d)
level (solvent = CCl4) (kcal/mol, 298 K). See the Supporting
Information for the calculated BDEs in the gas phase and in HFIP.
Scheme 2. Complete Synthetic Sequence for Total Syntheses of (+)-Merrilactone B, (−)-Anislactone B, (−)-Anislactone A,
a
and (−)-Majusanside
a
Reagents and conditions: 1. cobalt(II) acetylacetonate [Co(acac)2] (0.3 equiv), Ph(i-PrO)SiH2 (2.0 equiv), O2, THF, 23 °C, 8 h, 99%. 2. K2CO3,
MeOH, 23 °C, then HCl (1 M), 84%. 3. K2CO3, MeOH, 50 °C, then HCl (1 M), 99%. 4. DBU (3.0 equiv), LiBr (3.0 equiv), DMF, 80 °C, 82%. 5.
SeO2 (2.1 equiv), 1,4-dioxane, 100 °C, 18 h; NaBH4 (4.3 equiv), MeOH, 0 °C, 1 h, 95%. 6. PPh3AuOTf (0.5 equiv), 25 (2.0 equiv), 4 Å MS,
CH2Cl2, 0 °C, 30 min, 64%. 7. K2CO3, MeOH, 23 °C, 1 h, then Amberlyst 15 (H+ form), 74%.
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Figure 3. Evaluation of the neurotrophic activity of sesquiterpenes, intermediates, and derivatives. (A) Mouse primary neurons cultured for 16 h
were treated with indicated compounds at 0.1, 1.0, and 10 μM for 24 h. Neurons treated with ethanol (vehicle) were used as controls (CTRL).
Neurite lengths were measured and compared to those of controls (set as one arbitrary unit). (B) Representative images of mouse primary neurons
treated with various compounds at 1 μM. a: controls; b: (−)-merrilactone A (MA); c: 18; d: 19; e: 20; f: 21; g: 26; h: 27; i: (−)-jiadifenolide (Jia).
(C) Mouse primary neurons were treated with indicated compounds at 10 nM. Neurite lengths were compared to those of controls (set as one
arbitrary unit). (D) Representative images of neurons treated with various compounds at 10 nM. a′: controls; b′: 20; c′: 21; d′: 26; e′: 27; f′: Jia.
(E) Structures of compounds 26, 27, and Jia. Data represent mean SEM. Statistical analysis was conducted by using a nonparametric t test, n =
30 (from three independent experiments). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Scale bars: 20 μm.
reaction time (Figure 2A, entry 3). Note that oxidized product
6′ was not observed in these two experiments.
g). Note that MeOH (10 vol % of EtOAc) was added in the
second manipulation to prevent the possible acetylation of the
alcoholic product by EtOAc. Synthetic 1 was spectroscopically
identical with naturally obtained material.18 Our gram-scale
synthesis of 1 was achieved in 13 steps and 23% overall yield
from (R)-pulegone (13), fewer than the previous shortest
racemic synthesis by Zhai et al. (18 linear steps)27 and the
previous shortest asymmetric synthesis by Inoue et al. (31
steps).22 This synthesis also compares favorably with 0.004%
natural isolation yield.
The success of the desaturation of C-ring rendered fast
access for merrilactone A and opened entry to the other
anislactone-type Illicium sesquiterpenes (Scheme 2). In light of
the high similarity between the isomeric structures of
merrilactone B, anislactone B, and anislactone A, we assumed
that there might be thermodynamic equilibria between them.
DFT calculation results of the relative Gibbs free energies
revealed that anislactone A was more stable than anislactone B
by 3.56 kcal/mol, and the latter one was more stable than
merrilactone B by 1.15 kcal/mol, which suggested merrilactone
B could serve as a high-energy starting point of a kinetically
viable, thermodynamically “downhill” synthetic sequence. To
begin, Co-catalyzed Mukaiyama hydration25 of C1−C2 olefin
in 6 generated the desired tertiary alcohol, affording
(+)-merrilactone B (8) in a quantitative yield. Then by
treatment with K2CO3 in methanol followed by acidic work-
up, 8 was converted to (−)-anislactone B (9) in 84% yield
through an intramolecular transesterification. This conversion
could also occur when exposing 8 to an N-heterocyclic carbene
catalyst54 (see the Supporting Information). Finally, the
subjection of 9 to K2CO3 in refluxing methanol and
To improve this photochemical desaturation, less energetic
visible light was used to excite Ph2CO.50 To our great delight,
irradiation of a solution of 5 in HFIP with violet LED (390
nm) in the presence of 10 mol % Ph2CO and 1.2 equiv of NBS
afforded 6 in 76% isolated yield (Figure 2A, entry 4). The
increase of catalyst loading to 20 mol % gave a comparable
yield while shortening the reaction time to 1 h (Figure 2A,
entry 5). Furthermore, this procedure enabled a gram-scale
preparation of 6 (82% yield, Scheme 1). At this stage, we
achieved the most challenging transformation in the synthesis:
a mild photoinduced desaturation in a complex hydrocarbon
system. This success eliminated the protection manipulation of
the labile C7 alcohol, which usually occurred in the previous
synthetic efforts.19−28 The spectroscopic data of 6 are
consistent with those reported.34 Interestingly, masking the
C-7 alcohol as an acetate only led to the corresponding olefin
product with a moderate yield (see the Supporting Information
for more details). However, replacing HFIP with CH3CN
resulted in complex products. From a mechanistic point of
view, this unusual desaturation reaction might involve a
photoinduced halogenation followed by a photopromoted HBr
elimination,51 although the C1-brominated intermediate was
not captured. Meanwhile, two sequential hydrogen abstrac-
tions52 to generate a double bond is another possible pathway.
With the successful activation of the C-ring through a
photoinduced desaturation, our synthesis entered the final
oxygenation stage. A one-pot epoxidation of 6 with m-CPBA
and subsequent oxetane formation in the presence of p-TsOH
in EtOAc delivered (−)-merrilactone A (1) in 79% yield (1.28
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subsequent acidic work-up quantitatively delivered (−)-ani-
slactone A (10) probably through a retroaldol−aldol cascade.
Interestingly, direct subjection of merrilactone B (8) to K2CO3
in refluxing methanol only produced anislactone B (9) after
the acidic work-up, and no anislactone A (10) was observed.
The success of this thermodynamically driven synthetic
sequence might provide useful insights for the biosynthetic
proposal26,34 for this family of sesquiterpenes.
Furthermore, a concise synthesis of (−)-majusanside (11), a
sesquiterpene glucoside with antiviral bioactivity, was also
accomplished (Scheme 2). When the key intermediate 6 was
exposed to 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and
LiBr in DMF at 80 °C, an epimerization at C7 stereocenter
through a thermodynamically driven retroaldol−aldol cascade
(ΔG = −1.70 kcal/mol) proceeded smoothly to afford α-
alcohol 24 in 82% yield. Alcohol 12 was obtained in 95% yield
by one-pot SeO2-mediated allylic (C15) oxidation and further
reduction of the resulting aldehyde with NaBH4. Then by use
of Yu’s gold(I)-catalyzed glycosylation protocol,55 exposure of
aglycon 12 to 2,3,4,6-tetra-O-benzoyl-D-glucopyranosyl
orthohexynylbenzoate (25) and freshly prepared PPh3AuOTf
in CH2Cl2 followed by global debenzoylation with K2CO3 in
MeOH delivered (−)-majusanside (11) in 47% yield over two
steps. The synthetic samples of 8−11 exhibited spectroscopic
properties identical with those reported for the corresponding
natural products.34−36
The newly developed ring-construction sequence and
desaturation strategy allowed us to establish a small library
comprising 28 compounds with distinct structural features (see
the Supporting Information for synthetic details). We found
that five of them, 18, 20, 21, 26, and 27 (a propionate ester
derivative of merrilactone A, Figure 3E), showed much
stronger neurotrophic effects than merrilactone A at 0.1 μM
(Figure 3A,B). Among them, 20 and 21 with a much-simplified
scaffold, as well as 26, showed the comparable neurotrophic
effect to that of our synthetic (−)-jiadifenolide56 at 10 nM,
which is the known most potent neurotrophic molecule among
Illicium sesquiterpenes57 (Figure 3C−E). As a preliminary
study of the mechanism of action, nerve growth factor (NGF)
level change upon treatments with these compounds was
examined, and we found no significant increase of NGF
protein levels (Figure S12), implying that these compounds
promote neurite outgrowth through an NGF-independent
manner.
preparation of a diverse set of non-natural analogues, out of
which several highly potent small-molecule neurotrophic
agents were identified. Preliminary biological studies also
showed that some of these lead compounds could promote
neurite outgrowth, possibly through an NGF-independent
pathway. The synthetic strategy and the SAR information
described here will accelerate the chemical probe discovery to
further illuminate their mechanisms of action through more
sophisticated biological studies. Further investigation of the
newly developed photochemical desaturation reaction is
ongoing in our lab and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00525.
■
sı
Experimental procedures, characterization data, and
NMR spectra for all products; computed energies and
Cartesian coordinates of all the DFT-optimized
structures (PDF)
Accession Codes
CCDC 1881092−1881096 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Yandong Zhang − Department of Chemistry and Key
Laboratory of Chemical Biology of Fujian Province, iChEM,
College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen, Fujian 361005, China; orcid.org/
0000-0002-5558-9436; Phone: +86-592-2181902;
Email: ydzhang@ xmu.edu.cn
Yun-wu Zhang − Fujian Provincial Key Laboratory of
Neurodegenerative Disease and Aging Research, Institute of
Neuroscience, School of Medicine, Xiamen University,
Xiamen, Fujian 361102, China; orcid.org/0000-0002-
7152-7630; Phone: +86-592-2188528; Email: yunzhang@
xmu.edu.cn
Authors
CONCLUSIONS
Yang Shen − Department of Chemistry and Key Laboratory of
Chemical Biology of Fujian Province, iChEM, College of
Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, China
Linbin Li − Department of Chemistry and Key Laboratory of
Chemical Biology of Fujian Province, iChEM, College of
Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, China
Xiaoxia Xiao − Fujian Provincial Key Laboratory of
Neurodegenerative Disease and Aging Research, Institute of
Neuroscience, School of Medicine, Xiamen University,
Xiamen, Fujian 361102, China
Sihan Yang − Department of Chemistry and Key Laboratory
of Chemical Biology of Fujian Province, iChEM, College of
Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, China
■
In summary, we have developed a unique late-stage site-
selective desaturation strategy that enables the first chiral-pool
approach to these Illicium sesquiterpenoids, including a gram-
scale synthesis of (−)-merrilactone A (13 steps, 23% overall
yield), the first enantioselective total syntheses of (+)-merri-
lactone B (13 steps, 29% overall yield), (−)-anislactone B (14
steps, 25% overall yield), (−)-anislactone A (15 steps, 24%
overall yield), and (−)-majusanside (16 steps, 11% overall
yield). The efficiency of our approach derives from (a) the
development of a concise and scalable route to the tetracyclic
dilactone 5 with full stereochemical control starting from C1
stereocenter of (R)-pulegone, (b) a site-specific (C1−C2)
photochemical desaturation to generate olefin 6, and (c)
various oxygenation manipulations around the olefin and the
thermodynamically driven isomerization (from 8 to 9 to 10
and from 6 to 24). Furthermore, the desaturation strategy and
ring-construction sequence reported herein enabled the
Yuhui Hua − Department of Chemistry and Key Laboratory of
Chemical Biology of Fujian Province, iChEM, College of
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Article
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Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, China
Yinglu Wang − Department of Chemistry and Key Laboratory
of Chemical Biology of Fujian Province, iChEM, College of
Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00525
Author Contributions
Y.S., L.L., and X.X. contributed equally as first authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(22) Inoue, M.; Sato, T.; Hirama, M. Asymmetric Total Synthesis of
(−)-Merrilactone A: Use of a Bulky Protecting Group as Long-Range
Stereocontrolling Element. Angew. Chem., Int. Ed. 2006, 45, 4843−
4848.
Financial support from the National Natural Science
Foundation of China (Nos. 22071205, 21772164, and
21272194), National Key Research and Development Program
of China (2016YFC1305903 and 2018YFC2000400), and
PCSIRT is acknowledged. This work is dedicated to the 100th
anniversary of Xiamen University.
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( )-Merrilactone A via Catalytic Nazarov Cyclization. J. Am. Chem.
Soc. 2007, 129, 498−499.
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