Development of Biomimetic Synthesis of Propindilactone G?

Article abstract of DOI:10.1002/cjoc.202000293

The natural product propindilactone G is a complex Schisandra nortriterpenoid with a unique 5/5/7/6/5 pentacyclic framework. This full paper describes the development of concise biomimetic synthesis of propindilactone G from a known steroid lactone. The key C19-OH intermediate was synthesized via Breslow and Suárez radical remote C—H functionalizations. Wagner-Meerwein rearrangement was subsequently utilized for the expansion of the B ring. To invert the configuration of the C10 tertiary alcohol, an intramolecular peroxide cyclization catalyzed by BF₃·Et₂O was devised. The 5/5 fused lactone system was then assembled in a biomimetic transesterification/oxa-Michael addition sequence. Our work should provide experimental support for the proposed biosynthetic pathway and facilitate investigation of the biological activities of propindilactone G.

Full text of DOI:10.1002/cjoc.202000293

Nortriterpenoid, Biomimetic synthesis, Remote C—H
functionalization, Ring expansion, Cascade reaction
中
国 化 学
Development of Biomimetic Synthesis of Propindilactone G†
Yu Wang, Bo Chen, Xubiao He, and Jinghan Gui*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Cite this paper: Chin. J. Chem. 2020, 38, 1339—1352. DOI: 10.1002/cjoc.202000293
Summary of main observation and conclusion The natural product propindilactone G is a complex Schisandra nortriterpenoid with a unique 5/5/7/6/5
pentacyclic framework. This full paper describes the development of concise biomimetic synthesis of propindilactone G from a known steroid lactone.
The key C19-OH intermediate was synthesized via Breslow and Suárez radical remote C—H functionalizations. Wagner-Meerwein rearrangement was
subsequently utilized for the expansion of the B ring. To invert the configuration of the C10 tertiary alcohol, an intramolecular peroxide cyclization cata-
lyzed by BF3·Et2O was devised. The 5/5 fused lactone system was then assembled in a biomimetic transesterification/oxa-Michael addition sequence. Our
work should provide experimental support for the proposed biosynthetic pathway and facilitate investigation of the biological activities of propindilactone
G.
attracted great attention from synthetic chemists[3] and led to the
total syntheses of several members of this family.
Background and Originality Content
Propindilactone G (1, Figure 1) and related Schisandra
nortriterpenoids (3—7) are a large and abundant group of highly
Following the pioneering synthesis of schinortriterpenoid
schindilactone A[4a] by Yang[4] and co-workers in 2011, the elegant
oxidized polycyclic natural products isolated from plants of the
total syntheses of several other members were achieved in the
Schisandra genus, which can usually be divided into two genera,
past decade, including Yang’s total syntheses of propindilactone
Schisandra and Kadsura.[1] They are widely distributed throughout
East and Southeast Asia, with approximately 29 species in China.
In fact, Schisandra genus plants are widely employed in traditional
Chinese medicine to treat various diseases such as coughs, in-
somnia, and chronic dysentery.[2] The intriguing biological activi-
ties and complex structural diversity of schinortriterpenoids have
G[4b] (2015), 19-dehydroxyl arisandilactone A[4c] (2017), lancifodi-
lactone G acetate[4d] (2018), and pre-schisanartanin C[4e] (2019);
Li’s total syntheses[5] of rubriflordilactone A[5a] (2014), rubriflordi-
lactone B[5b] (2016), and pseudo-rubriflordilactone B[5c] (2019);
Anderson’s total syntheses[6] of rubriflordilactone A[6a,6b] (2015),
rubriflordilactone B[6c] (2019), and pseudo-rubriflordilactone B[6c]
(2019); Tang’s total syntheses[7] of schilancitrilactones B and C[7a]
(2015), schilancitrilactone A[7b] (2017), and schilancidilactones A
and B[7b] (2017); and Ding’s total synthesis of atrop-schiglautone
A[8] (2018).
Propindilactone G, which possesses a 29-carbon schiartane
skeleton, was isolated from the stems of Schisandra propinqua var.
propinqua by Sun and co-workers in 2008, alongside propindi-
lactones E, F, and H—J.[9] Structurally, propindilactone G is char-
acterized by a unique 5/5/7/6/5 fused ring framework and a bu-
tenolide side chain; hence, its synthesis poses an enormous chal-
lenge. In 2015, Yang and co-workers accomplished the first
asymmetric total synthesis of propindilactone G in 20 steps,[4b,10]
featuring several impressive transformations, including an asym-
metric Diels-Alder reaction and a ring expansion reaction to con-
struct the B ring, a Pauson-Khand reaction to build the D and E
rings, and an oxidative heterocoupling reaction to install the side
chain. It is worth mentioning that the stereochemistry of C17 was
also revised from the initially proposed C17α-H (2) to C17β-H (1)
during the synthesis.
Recently, we reported a strategy for the synthesis of propindi-
lactone G from a known steroid lactone,[11] which was largely in-
spired by a biogenetic proposal. In this article, we will detail the
synthesis more comprehensively.
Results and Discussion
Figure 1 Representative nortriterpenoids with unique 5-5-7 tricyclic ring
systems.
Our retrosynthetic analysis of propindilactone G was largely
inspired by the hypothetical biogenesis of schinortriterpenoids
*E-mail: guijh@sioc.ac.cn
For submission: https://mc.manuscriptcentral.com/cjoc
For articles: https://onlinelibrary.wiley.com/journal/16147065
† Dedicated to the 70th anniversary of Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences.
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Scheme 1 Biogenetic pathway and retrosynthetic analysis
proposed by Sun and co-workers (Scheme 1A).[1b] Biosynthetically,
the 5/5/7 fused ring system in 11 is thought to be produced via
the Baeyer-Villiger oxidation and dehydrogenation of the A ring of
cycloartane (8) to afford unsaturated lactone 9, C9—C10 cleavage
of 9 to give B-ring-expanded cycloheptanediol 10, and finally a
transesterification and oxa-Michael addition cascade (Scheme
1A).
Our retrosynthetic analysis of propindilactone G was based on
the above biosynthetic proposal and is outlined in Scheme 1B. We
envisioned that propindilactone G could be prepared by introduc-
ing the side chain onto aldehyde 12; its C16 ketone and C22 alde-
hyde groups could be accessed via the reduction and oxidation of
the right-hand lactone of 13. A biomimetic transesterification and
oxa-Michael addition cascade was envisaged for the construction
of the 5/5 fused ring system in 13 from unsaturated lactone 14.
Lactone 14 was expected to be synthesized through the Baeyer-
Villiger oxidation and dehydrogenation of diol 15, which could be
prepared via the Wagner-Meerwein rearrangement of 17 to pro-
vide 16, followed by Mukaiyama hydration. Finally, key intermedi-
ate 17 could be traced back to known lactone 18,[12] a product of
the degradation of commercially available tigogenin, via site-se-
lective C—H oxidation at C9 and C19.
Our synthesis of propindilactone G commenced with a six-step
synthesis of key C19 hydroxyl compound 17 via two remote C—H
radical functionalizations (Scheme 2). Mitsunobu reaction[13] of 18
with 3-iodobenzoic acid afforded 19 in 87% yield on a 20 g scale.
Subsequent Breslow remote C—H radical chlorination,[14] directed
by the C3α iodobenzoate, afforded a C9α chlorine intermediate
(not shown), which was transformed into acetate 20 on a 20 g
scale via treatment with potassium hydroxide in boiling methanol
followed by acetylation of the free C3 hydroxyl group.[15]
With a large-scale synthetic route to 20 in hand, we were
poised to investigate the second C—H radical functionalization to
produce 17. Directed C—H oxidation of the C19 methyl group is
generally achieved with the help of the C2β,[16] C6β,[17] or C11β[18]
hydroxyl group, because a six-membered transition state essential
for 1,5-hydrogen abstraction could be formed during this process.
To this end, we intended to install a C11β hydroxyl group by pre-
paring bromohydrin 21 or chlorohydrin 23 (Scheme 2). Bromohy-
droxylation of 20 with N-bromosuccinimide (NBS) and catalytic
HClO4 gave unstable bromohydrin 21, which could be transformed
into more stable chlorohydrin 23 via treatment with 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) in toluene to generate a C9,C11β
epoxide compound followed by regioselective opening of the
epoxide with anhydrous HCl using Ramírez’s protocol.[19] However,
this three-step sequence furnished 23 in only 52% overall yield
from 20 and the yield decreased dramatically when the bromohy-
droxylation reaction was performed on a large scale. Therefore,
we decided to investigate a protocol for direct olefin chlorohy-
droxylation[20] to furnish 23 in one step (Scheme 2). While rea-
gents such as Ca(ClO)2,[20a] N-chlorosuccinimide (NCS),[20b]
1,3-dichloro-5,5-dimethylhydantoin (DCDMH),[20c] and trichloro-
isocyanuric acid (TCCA)[20d] all resulted in low conversions or com-
plex reaction mixtures (Scheme 2, entries 1—4), we were de-
lighted to find that by switching the solvent from dioxane/H2O to
acetone/H2O[21] and lowering the temperature to –50 °C, 23 could
be obtained in 54% yield using TCCA as the chlorination reagent
(entry 5). Further screening of solvents revealed that a mixed
solvent of diglyme and H2O was the best, furnishing 23 in 62%
yield on a 5 g scale (entry 6). It is worth mentioning that a lower
temperature (–62 °C) was critical in ensuring a satisfactory yield
when the reaction was conducted on a 5 g scale.
With enough 21 and 23 in hand, we proceeded to investigate
the C—H oxidation of the C19 Me group to prepare key interme-
diate 17. Unfortunately, exposure of bromohydrin 21 to Suárez’s
conditions[22] ((diacetoxyiodo)benzene (DIB), I2, hv) led to the
formation of ketone 22 in 38% yield over two steps from 20, pos-
sibly through the elimination of hydrogen bromide via hydrogen
atom abstraction at C11 and subsequent bromine atom elimina-
tion.[23] However, to our delight, under the same conditions, re-
mote functionalization of chlorohydrin 23 proceeded smoothly to
produce tetrahydrofuran intermediate 24. Treatment of 24 with
activated Zn powder and aqueous NH4Cl in boiling dimethylfor-
mamide (DMF) led to the release of the C19 hydroxyl group and
the formation of the C9-C11 olefin, yielding desired compound 17
in 70% yield over two steps on an 8 g scale.
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Development of Biomimetic Synthesis of Propindilactone G
Chin. J. Chem.
Scheme 2 Synthesis of C19 hydroxyl compound 17
Scheme 3 Synthesis of cycloheptanol 28
tetrahydrofuran (THF) and H2O were the best (entries 2 and 3).
Similar results were obtained when a weaker organic base (Et3N)
and inorganic base (NaHCO3) were used instead of DBU (entries 4
and 5). Furthermore, we found that a higher yield could be ob-
tained when the reaction was conducted without a base (entry 6),
indicating that the byproduct, methanesulfonic acid, had no im-
pact on the rearrangement of 17. Finally, reducing the reaction
temperature and using t-BuOH/H2O as the solvent resulted in
higher yields (entries 7 and 8), although a longer reaction time
was required. A one-pot procedure was also developed and 28
could be obtained in 80% yield on a 4 g scale.
With access to alcohol 17 in only six steps, we began to inves-
tigate the key ring expansion for the seven-membered ring of
propindilactone
G
via the Wagner-Meerwein rearrangement
Mukaiyama hydration[26] of 28 resulted in the formation of di-
ol 29, whose structure was confirmed by X-ray crystallographic
analysis (Scheme 4A). Unfortunately, the stereochemistry of diol
29 at C10 was incorrect for propindilactone G. Therefore, the ste-
reoinversion of this tetrasubstituted stereocenter was required.
Initial attempts to invert the stereochemistry of the C10 tertiary
alcohol via intermolecular substitution were met with failure and
only elimination or decomposition was observed. However, we
surmised that the desired stereoinversion could be realized via
intramolecular capture of the C10 cation by a C3α hydroxyl or
carbonate group. To this end, alcohol 31 and carbonate 33 were
prepared (Scheme 4B); disappointingly, desired products 32 and
34 were not obtained despite attempts using various conditions
and only products derived from the elimination of the C10 hy-
droxyl group were observed.
(Scheme 3). Barton and co-workers observed that the deamina-
tion of a similar C19 homoallylic amine compound resulted in the
formation of the desired ring-expansion product;[24] however, the
stereochemistry of the newly formed C10 stereocenter was not
determined. Our preliminary work also showed that olefin regioi-
somers 25 possessing the 6/7/6 skeleton could be obtained in a
1.4 : 2.2 : 1.0 ratio and 78% combined yield by treating 17 with a
strong activating reagent, n-C4F9SO2F, and DBU in CH2Cl2 at 0 °C
(Scheme 3A), possibly via the elimination of C19, C1, and C5 pro-
tons from the same C10 cation intermediate, 27. We then at-
tempted to capture this unstable cation intermediate, hoping to
install a hydroxyl group at this position.
Alcohol 17 was mesylated to afford 26 in a quantitative yield,
and it was stable enough to isolate. To our delight, heating a solu-
tion of 26 in a mixed solvent of 1,2-dimethoxyethane (DME) and
H2O in the presence of DBU as a base afforded tertiary alcohol 28
in 50% yield, along with diene isomers 25 in 9% yield (Scheme 3B,
entry 1). Similar olefin side products were also observed during
Gademann’s biogenetic synthesis of icetexane natural products.[25]
Further screening of solvents revealed that mixed solvents of
In light of the above failure, we turned our attention to rear-
rangement product 28. We were curious as to whether a C9 per-
oxide group, accessible through Mukaiyama hydrosilylperoxida-
tion,[27] could engage in an intramolecular cyclization at C10 to
generate a bicyclo[4.2.1] endoperoxide compound to invert the
stereochemistry at C10. Interestingly, such a bicyclo[4.2.1]
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Scheme 4 Attempted installation of the correct tetrasubstituted C10
Table 1 Optimization of the hydrosilylperoxidation reaction
stereocenter
Table 2 Optimization of the intramolecular cyclization of 35
endoperoxide system has been found in triterpenoid natural
products schinalactone A[28] and pseudolarolide H.[29]
Our results for the optimization of the hydrosilylperoxidation
reaction are shown in Table 1. When 28 was reacted with Et3SiH
and Co(acac)2 in CH2Cl2 under an O2 atmosphere at room temper-
ature, only Mukaiyama-hydration-type products 29 and C9-epi-29
were obtained (Table 1, entry 1). Addition of 1.0 equiv of t-BuOOH
to the reaction system, which was expected to accelerate the
formation of Co(III) active species, completely suppressed the
reaction (entry 2). In stark contrast, replacing Co(acac)2 with
Co(thd)2,[30] a superior catalyst reported by O’Neill and co-workers
to be more effective in the hydrosilylperoxidation of cyclic alkenes,
resulted in a 56% yield of desired product 35 (entry 3). No reac-
tion was observed when bulkier silanes, such as Ph3SiH and
i-Pr3SiH (entries 4 and 5), were used instead of Et3SiH. However, a
higher yield of 35 and a lower yield of diols 29 and C9-epi-29 were
obtained at 0 °C (entry 6), indicating that a low reaction tempera-
ture could suppress peroxide reduction. Finally, we were delighted
to find that the yield could be further improved to 75% by using
Et2MeSiH. It is worth mentioning that the reaction yield dimin-
ished slightly on a large scale (entry 9), as 36 was obtained in 60%
yield on a 5.2 g scale (entry 10).
of Brønsted and Lewis acids revealed that BF3·Et2O was the opti-
mal catalyst, which ultimately led to an 88% yield of 37 (entries 5
and 6).
With the optimal conditions for peroxide 37 in hand, the
one-pot intramolecular cyclization of 36 and the global reduction
of the acetate and lactone moieties were carried out, generating
triol 38 in 76% yield on a 4.6 g scale (Scheme 5). Then, 38 was
reacted with 2,2-dimethoxypropane and PTSA to selectively pro-
tect the hydroxyl groups at C16 and C22, affording an acetonide
intermediate that was oxidized with Dess-Martin periodinane
(DMP) to furnish ketone 39 in 82% yield on a 2.5 g scale.
Next, we turned our attention to the dimethylation of ketone
39 to obtain 40, which proved to be difficult owing to competitive
formation of methyl enol ether byproducts 41 and 42. Among the
three bases screened, potassium hexamethyldisilazide (KHMDS)
afforded 40 in 24% yield (Scheme 5, entries 1—3). Addition of
HMPA (hexamethylphosphoramide) as a co-solvent increased the
yield dramatically (43%, entry 4). t-BuOK was also an effective
base, leading to a similar yield of 40 in a mixed solvent of t-BuOH
and HMPA (entry 5). Finally, we were delighted to find that the
yield could be further improved by adding a third solvent, toluene
(entry 6), and 40 could be obtained in 52% yield on a 1.1 g scale
when cyclohexane was used as a co-solvent (entry 7).
We then investigated the intramolecular cyclization reaction[31]
for the preparation of peroxide 37. We found that 35 remained
unchanged when treated with MsCl[32] in CH2Cl2 and desilylation
was observed when a stronger activating reagent, C4F9SO2F, was
used instead (Table 2, entries 1 and 2). However, in reactions with
p-toluenesulfonic acid (PTSA), we observed a dramatic solvent
effect. Polar solvents such as THF and DMF led only to the remov-
al of the silyl protecting group, while non-polar solvents like tolu-
ene led to desired peroxide 37 in 45% yield (entries 3 and 4). The
structure of 37 was unambiguously determined through X-ray
crystallographic analysis; therefore, we succeeded in inverting the
C10 tetrasubstituted stereocenter. Further screening of a variety
As illustrated in the retrosynthetic analysis (Scheme 1B), we
aimed to construct the 5/5 fused ring system of propindilactone G
through a biomimetic transesterification/oxa-Michael addition
cascade (Scheme 6). To this end, ketone 40 was treated with
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Development of Biomimetic Synthesis of Propindilactone G
Chin. J. Chem.
Scheme 5 Elaboration of acetate 36 to ketone 40
3-chloroperoxybenzoic acid (m-CPBA) in CH2Cl2 to effect the de-
sired Baeyer-Villiger rearrangement, producing lactone 43 in 46%
yield; a dramatic increase in yield (86%) was observed when the
reaction was performed in toluene. The peroxide in 43 was hy-
drogenated with 10% Pd/C in MeOH to afford a diol intermediate,
which underwent intramolecular transesterification and concom-
itant removal of the acetonide group to afford triol 44 in 76% yield.
From here, the only remaining step to access the skeleton of pro-
pindilactone G was the formation of the C—O bond in 44. To pre-
vent side reactions involving the free C16 and C22 hydroxyl groups,
44 was selectively acetylated to afford acetate 45. Unfortunately,
neither the dehydrogenation of the lactone nor the radical remote
C—H functionalization to give desired cyclization product 46 suc-
ceeded.
However, dehydrogenation of 43 with N-tert-butylbenzene-
sulfinimidoyl chloride[33] (Mukaiyama reagent) generated unsatu-
rated lactone 47 in 62% yield. Upon treatment with active zinc
powder and AcOH in CH2Cl2,[34] 47 smoothly gave diol intermedi-
ate 48, which underwent transesterification and oxa-Michael ad-
dition to afford 5/5 fused lactone 49. Deprotection of the ace-
tonide group in situ with the aid of PTSA and MeOH gave diol 50
in 84% yield. Subsequent Swern oxidation of 50 generated alde-
hyde 51 in 89% yield.
After developing a reliable route to key intermediate 51, we
turned our attention to the installation of the butenolide side
chain of propindilactone G as well as the C14-C15 olefin. To this
end, compound 53 bearing the same C16 ketone and C22 alde-
hyde groups as 51 was used as a model substrate (Scheme 7).
Aldehyde 53 was easily prepared in three steps from lactone 18
via the silylation of the C3 hydroxyl group and reduction of the
lactone to afford diol 52, followed by the Swern oxidation of the
resultant C16 and C22 hydroxyl groups. A vinylogous Mukaiyama
aldol reaction between aldehyde 53 and 3-methyl-2-(tert-butyl-
dimethylsilyloxy)furan[35] in the presence of TiCl4 produced bute-
nolide 54 in 72% yield.[36] However, the stereochemistry at C22
and C23 was opposite to that of propindilactone G. Fortunately,
the stereochemistry at C23 could be inverted by treating 54 with
Scheme 6 Successful construction of the core skeleton
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Scheme 7 Attempted installation of the side chain via Mukaiyama aldol
reaction
MeOH to generate 56 after 36 h in 60% yield. X-ray single-crystal
analysis of 56 revealed that the C22 stereocenter had been in-
verted successfully. However, the subsequent inversion of the C22
stereocenter via the Mitsunobu reaction was met with failure,
possibly because of the congestion around C22.
Inspired by the pioneering work of Yang and co-workers in
their total synthesis of propindilactone G, we attempted to install
the side chain through
a sequence involving the Horner-
Wadsworth-Emmons (HWE) reaction and dihydroxylation (Scheme
8). The HWE reaction of aldehyde 53 with phosphate 58[37] af-
forded unsaturated ester 59 with a trans-C24-C25 olefin in 77%
yield,[38] which was subjected to the Saegusa-Ito oxidation to
produce enone 60 in 62% yield. Owing to the opposite configura-
tion of C17 of 60 to that of propindilactone G, 60 was isomerized
using catalytic PTSA in toluene to afford 61 in 46% yield, while 52%
of starting material 60 was recovered. However, the subsequent
dihydroxylation of 61 failed to produce the desired C22-C23 diol
product, and products resulting from the dihydroxylation of the
C24-C25 olefin were observed instead. Speculating that the con-
figuration of the C24-C25 olefin might influence the dihydroxyla-
tion of the C22-C23 olefin, we decided to prepare enone 67 with a
cis-C24-C25 olefin. To this end, two-carbon homologation[39] of 53
with vinyl bromide 62[40] in the presence of t-BuLi and subsequent
acid hydrolysis were carried out, generating enal 63 in 60% yield.
The HWE reaction of enal 63 with phosphate 64 led to the for-
mation of cis-unsaturated ester 65,[41] which was transformed into
enone 67 through Saegusa-Ito oxidation[42] and C17 epimerization.
To our delight, Sharpless dihydroxylation[43] of 67 with concomi-
tant lactonization proceeded smoothly to generate desired lac-
tone 68 in 41% yield, along with 35% recovered 67. The structure
of 67 was confirmed by X-ray crystallographic analysis of its desi-
lylated analog, 69.
Having established a five-step synthetic sequence for the bu-
tenolide side chain of propindilactone G on model substrate 53,
we next focused our attention on completing the synthesis of
propindilactone G (Scheme 9). The two-carbon homologation of
51 using a zinc reagent derived from vinyl bromide 62 resulted in
incomplete conversion (Scheme 9B, entry 1).[44] Higher conversion
of 51 was achieved at the expense of a lower yield when the reac-
tion was conducted at a higher reaction temperature (entry 2).
DBU in toluene, possibly via enolization and protonation, to gen-
erate 55. To further confirm the stereochemistry of the butenolide
side chain, 55 was reacted with MeOH in the presence of catalytic
(±)-CSA (camphorsulfonic acid) for 2 h to afford the ketal interme-
diate in 81% yield, which was further desilylated using (±)-CSA in
Scheme 8 Installation of the side chain via Sharpless dihydroxylation
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Development of Biomimetic Synthesis of Propindilactone G
Chin. J. Chem.
Scheme 9 Completion of the synthesis of propindilactone G
higher conversion was observed and the resulting silyl enol ether
was treated with Pd(OAc)2 in dimethylsulfoxide (DMSO) to afford
enone 72 in 34% yield (entry 4). Further screening of solvents
revealed that a mixed solvent of DME and THF was optimal, af-
fording desired product 72 in 55% yield while 39% of starting ma-
terial 71 was recovered (entry 5).
With enone 72 in hand, all that remained to complete the
synthesis of propindilactone G was the epimerization of C17 and
asymmetric dihydroxylation of the C22-C23 olefin (Scheme 9). To
this end, 72 was isomerized with PTSA in toluene to afford 73 in
45% yield, which was subjected to the same Sharpless asymmetric
dihydroxylation reaction to afford 1 in 58% yield. The nuclear
magnetic resonance (NMR) spectroscopy and optical rotation data
of synthetic propindilactone G were in agreement with those re-
ported by Sun[9] and Yang.[4b]
Conclusions
In summary, the bioinspired synthesis of Schisandra nortriter-
penoid propindilactone G (1) was accomplished successfully from
known steroid lactone 18, representing the first biomimetic syn-
thesis of any member of the Schisandra nortriterpenoids. The
route illustrates how powerful radical remote functionalization
can be in oxidizing innate C—H bonds. A Wagner-Meerwein rear-
rangement was developed to achieve the ring expansion, trans-
forming the classic 6/6/6 fused ring system into the 6/7/6 fused
ring system. Because the stereochemistry of the newly formed
C10 tertiary alcohol was opposite to that of propindilactone G, a
silylperoxide was installed via Mukaiyama hydrosilylperoxidation,
and the C10 stereocenter was successfully inverted through sub-
sequent intramolecular peroxide cyclization. Finally, a biomimetic
transesterification/oxa-Michael addition cascade was employed to
assemble the 5/5 fused lactone and the synthesis of propindi-
lactone G was completed after the introduction of the butenolide
chain. Our work should enable in-depth understanding of the
proposed biogenetic origin of the schinortriterpenoid and facili-
tate further studies on the biological activities of propindilactone
G. Efforts to extend this biomimetic synthetic strategy to the syn-
theses of other schinortriterpenoids are currently ongoing and
will be reported in due course.
Experimental
All reactions utilizing air- or moisture-sensitive reagents were
carried out in flame-dried glassware under an argon atmosphere,
unless otherwise stated. Dry tetrahydrofuran (THF), dichlorometh-
ane (DCM), toluene (PhMe) and diethyl ether (Et2O) were ob-
tained by passing the HPLC grade or pre-dried solvents through
activated alumina columns. Tetrachloromethane (CCl4), 1,2-dichlo-
roethane (DCE), cyclohexane, t-BuOH, triethylamine (Et3N) and
hexamethylphosphoramide (HMPA) were distilled from CaH2.
Reagents were purchased at the highest commercial quality and
used without further purification, unless otherwise stated. Reac-
tions were magnetically stirred and monitored by thin layer
chromatography (TLC) with 0.15—0.2 mm pre-coated silica gel
(10—40 μm) plates, using UV light as the visualizing agent or eth-
anolic phosphomolybdic acid and heating as developing agents.
Flash chromatography was performed with silica gel (200—300
mesh) under pressure. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous material, unless other-
wise stated. NMR spectra were recorded on Bruker-400 and
Exclusion of the ZnMe2 additive from the reaction conditions re-
sulted in the decomposition of starting material 51 (entry 3). After
extensive solvent screening, we found that a mixed solvent of
ether and THF was better, and this led to a modest yield and ratio
(entry 4). Gratifyingly, 51 was fully converted when the reaction
was performed without ZnMe2, affording 70 in 59% yield after
treatment with 4% aq. HCl (entry 5). Subsequent Z-selective HWE
reaction of 70 with phosphate 64 gave 71 in 89% yield, which was
then converted to enone 72 via the dehydrogenation of the
C14—C15 bond (Scheme 9C). Initial direct oxidative dehydrogena-
tion attempts with (PhSeO)2O[45] led only to a complex reaction
mixture (entry 1). Fortunately, we found that Saegusa oxidation of
71 could afford 72 in 6% yield, along with 60% recovered starting
material. The low efficiency of the dehydrogenation was due to
the low conversion in the silyl enol ether formation when 70 was
treated with lithium hexamethyldisilazide (LHMDS) and trime-
thylsilyl chloride (TMSCl). Therefore, we focused on the optimiza-
tion of the Saegusa oxidation to improve the conversion of 70 to
the corresponding silyl enol ether. Disappointingly, the reaction
was inhibited when HMPA was added as a co-solvent (entry 3).
When LHMDS was replaced with lithium diisopropylamide (LDA),
1
Bruker-600 spectrometers. H NMR spectra were calibrated using
residual undeuterated solvent as an internal reference (CDCl3: δ
7.26; MeOH-d4: δ 3.31; C5D5N: δ 8.74) and 13C NMR spectra were
calibrated against the deuterated solvent peak (CDCl3: δ 77.2;
MeOH-d4: δ 49.0; C5D5N: δ 150.3). The following abbreviations
were used to explain multiplicities: s = singlet, d = doublet, t =
Chin. J. Chem. 2020, 38, 1339－1352
© 2020 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de
1345

Wang et al.
Comprehensive Report
triplet, q = quartet, m = multiplet, br = broad. IR spectra were
collected on Avatar 330 FT-IR spectrometer. Melting points were
determined on SGW X-4 microscopic melting point apparatus and
were uncorrected. Optical rotations were determined on JASCO
P-1030 Polarimeter in the solvent indicated. High-resolution mass
spectra were recorded on IonSpec 4.7 Tesla FTMS or Bruker Dal-
tonics, Inc. APEXIII 7.0 TESLA FTMS.
Synthesis of compound 22. To a solution of 20 (300 mg, 0.777
mmol, 1.0 equiv) in 1,4-dioxane and H2O (37 mL, 3.6 : 1) was
added a solution of 70% HClO4 (0.1 mL, 1.17 mmol, 1.5 equiv) in
2.9 mL H2O at room temperature. NBS (194 mg, 1.09 mmol, 1.4
equiv) was added slowly in 5 min at 0 oC and the resulting
reaction mixture was stirred at room temperature for another 1 h.
The reaction mixture was quenched with sat. aq. Na2S2O3 (10 mL),
and extracted with CH2Cl2 (3×20 mL). The combined organic layers
were washed with brine and dried over Na2SO4. Removal of the
solvent under reduced pressure afforded the crude product,
which was purified by flash chromatography (SiO2, 3 : 1 petroleum
ether : EtOAc) to provide compound 21.
To a solution of the bromohydrin 21 obtained above in 25 mL
dry cyclohexane was added DIB (490 mg, 1.52 mmol, 2.0 equiv)
and I2 (389 mg, 1.53 mmol, 2.0 equiv) at room temperature under
argon. The reaction mixture was heated to reflux by irradiation
with an infrared lamp (275 W) for 0.5 h. After cooled to room
temperature, the reaction was quenched with sat. aq. Na2S2O3 (15
mL) and extracted with EtOAc (3×15 mL). The combined organic
layers were washed with brine and dried over Na2SO4. Removal of
the solvent under reduced pressure afforded the crude product,
which was purified by flash chromatography (SiO2, 6 : 1→4 : 1
petroleum ether : EtOAc) to provide 22 (117 mg, 38% over 2 steps)
as a white solid.
with CH2Cl2 (3×10 mL). The combined organic layers were washed
with brine and dried over Na2SO4. Removal of the solvent under
reduced pressure afforded the crude product, which was purified
by flash chromatography (SiO2, 8 : 1 petroleum ether : acetone) to
provide 23 (313 mg, 87%) as a white solid.
o
74: mp: 191.9—193.5 C; TLC (petroleum ether : acetone, 4 :1
V/V): Rf = 0.43; [α]2D7 –8.6 (c 1.04, CHCl3); 1H NMR (400 MHz,
CDCl3) δ: 4.95 (t, J = 2.8 Hz, 1H), 4.86 (td, J = 7.8, 4.7 Hz, 1H), 3.40
(s, 1H), 2.58 (q, J = 7.6 Hz, 1H), 2.32 (dt, J = 13.9, 7.3 Hz, 1H), 2.17
(dd, J = 14.5, 2.6 Hz, 1H), 2.13—2.04 (m, 2H), 2.02 (s, 3H), 1.78 (d,
J = 7.8 Hz, 1H), 1.71—1.55 (m, 3H), 1.55—1.47 (m, 3H), 1.43 (dd,
J = 13.5, 4.8 Hz, 1H), 1.36—1.23 (m, 2H), 1.27 (d, J = 7.7 Hz, 3H),
1.23—1.15 (m, 2H), 1.15—1.07 (m, 2H), 0.93 (s, 6H); 13C NMR
(101 MHz, CDCl3) δ: 181.0, 170.5, 82.0, 69.4, 66.6, 60.3, 60.1, 55.5,
39.9, 39.5, 37.6, 37.0, 36.3, 33.9, 33.7, 33.2, 33.1, 28.5, 26.4, 25.5,
21.6, 18.0, 16.8, 14.5; IR (KBr) ν: 2929, 2867, 1768, 1732, 1375,
1246, 1189, 975 cm–1; HRMS (ESI, m/z): [M+Na]+ calcd for
C24H34O5Na, 425.2298; found, 425.2299.
Synthesis of compound 31. A solution of 26 (300 mg, 0.625
mmol, 1.0 equiv) and K2CO3 (518 mg, 3.75 mmol, 6.0 equiv) in 15
mL MeOH was stirred at room temperature for 14 h. Concentra-
tion under reduced pressure afforded the crude reaction mixture,
which was neutralized with 2.4 M aq. HCl to pH<7 and stirred at
room temperature for another 20 min. The aqueous layer was
extracted with EtOAc (3×10 mL) and the combined organic layers
were washed with brine and dried over Na2SO4. Removal of the
solvent under reduced pressure afforded the crude product,
which was purified by flash chromatography (SiO2, 2 : 1 → 1 : 1
petroleum ether : EtOAc) to provide 31 (180 mg, 66%) as a white
foam.
31: TLC (petroleum ether : EtOAc, 1 : 1 V/V): Rf = 0.21; [α]D25
–29.4 (c 2.30, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 5.42 (d, J = 6.3
Hz, 1H), 4.97 (td, J = 7.7, 4.3 Hz, 1H), 4.36 (d, J = 9.6 Hz, 1H), 4.29
(d, J = 9.6 Hz, 1H), 4.10 (br s, 1H), 2.91 (s, 3H), 2.61 (q, J = 7.5 Hz,
1H), 2.40 (dt, J = 14.2, 7.4 Hz, 1H), 2.32 (s, 1H), 2.13—2.03 (m, 2H),
2.02—1.92 (m, 3H), 1.91—1.71 (m, 4H), 1.71—1.46 (m, 4H),
1.41—1.28 (m, 3H), 1.30 (d, J = 7.6 Hz, 3H), 1.15—1.01 (m, 1H),
0.71 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 181.1, 140.5, 120.5,
83.0, 66.1, 65.6, 58.6, 52.6, 41.8, 40.3, 40.1, 37.8, 37.3, 36.6, 35.9,
35.9, 34.1, 32.9, 28.5, 27.8, 24.3, 17.9, 13.3; IR (KBr) ν: 3446, 2925,
1757, 1635, 1351, 1174, 947, 734 cm–1; HRMS (ESI, m/z): [M+H]+
calcd for C23H35O6S, 439.2149; found, 439.2149.
Synthesis of compound 33. To a solution of 31 (120 mg, 0.274
mmol, 1.0 equiv) and DMAP (4-dimeththylaminopyridine, 6.68 mg,
0.0548 mmol, 0.2 equiv) in 5 mL CH2Cl2 was added pyridine (66 μL,
0.822 mmol, 3.0 equiv) and ClCO2Me (43 μL, 0.548 mmol, 2.0
equiv). The reaction mixture was stirred at room temperature for
10 h, quenched with dilute aq. HCl, and extracted with CH2Cl2
(3×10 mL). The combined organic layers were washed with brine
and dried over Na2SO4. Removal of the solvent under reduced
pressure afforded the crude product, which was purified by flash
chromatography (SiO2, 2 : 1→1 : 1 petroleum ether : EtOAc) to
provide 33 (21 mg, 15%) as a colorless oil and recovered 31 (80
mg, 67%).
22: mp: 258.3—260.8 oC; TLC (petroleum ether : EtOAc, 3 : 1
V/V): Rf = 0.28; [α]2D7 –1.0 (c 1.14, CHCl3); 1H NMR (400 MHz, CDCl3)
δ: 5.01 (td, J = 7.7, 4.4 Hz, 1H), 4.96 (t, J = 2.9 Hz, 1H), 2.53 (q, J =
7.5 Hz, 1H), 2.38 (dt, J = 13.8, 7.3 Hz, 1H), 2.28 (d, J = 12.0 Hz, 1H),
2.23 (dt, J = 13.2, 3.4 Hz, 1H), 2.18 (d, J = 12.1 Hz, 1H), 2.06 (d, J =
7.5 Hz, 1H), 2.00 (s, 3H), 1.88—1.78 (m, 2H), 1.76 (d, J = 11.4 Hz,
1H), 1.73—1.60 (m, 3H), 1.56 (dd, J = 13.4, 4.4 Hz, 1H), 1.52—1.36
(m, 3H), 1.29 (d, J = 7.6 Hz, 3H), 1.24—1.09 (m, 4H), 0.99 (s, 3H),
0.67 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 208.7, 180.3, 170.5,
82.3, 69.7, 64.2, 57.6, 55.9, 54.1, 45.3, 39.8, 36.4, 35.9, 35.5, 32.6,
32.4, 32.3, 31.5, 27.4, 25.8, 21.5, 17.7, 14.7, 11.0; IR (KBr) ν: 2974,
2925, 1770, 1727, 1698, 1373, 1262, 1188 cm–1; HRMS (ESI, m/z):
[M+H]+ calcd for C24H35O5, 403.2479; found, 403.2477.
Synthesis of compound 23. To a solution of 20 (330 mg, 0.855
mmol, 1.0 equiv) in 1,4-dioxane and H2O (40 mL, 4 : 1) was added
a solution of 70% HClO4 (0.11 mL, 1.3 mmol, 1.5 equiv) in 3.2 mL
H2O at room temperature. NBS (213 mg, 1.20 mmol, 1.4 equiv)
was added slowly in 5 min at 0 °C and the resulting reaction
mixture was stirred at room temperature for another 0.5 h. The
reaction mixture was quenched with sat. aq. Na2S2O3 (15 mL), and
extracted with EtOAc (3×20 mL). The combined organic layers
were washed with brine and dried over Na2SO4. Removal of the
solvent under reduced pressure afforded the crude bromohydrin
21, which was used in the next step without further purification.
To a solution of the bromohydrin 21 obtained above in 30 mL
toluene was added DBU (0.5 mL, 3.42 mmol, 4.0 equiv) at room
temperature. The reaction mixture was stirred at room tempera-
ture for 0.5 h and concentrated in vacuo to provide the crude
residue. Purification by flash chromatography (SiO2, 12 : 1 → 10:1
petroleum ether : acetone) afforded the epoxide intermediate 74
(220 mg, 64% over 2 steps) as a white solid.
33: TLC (petroleum ether : EtOAc, 2 : 1 V/V): Rf = 0.39; [α]D25
–11.3 (c 0.12, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 5.43 (d, J = 5.8
Hz, 1H), 5.03—4.93 (m, 2H), 4.37 (d, J = 10.0 Hz, 1H), 4.32 (d, J =
9.4 Hz, 1H), 3.78 (s, 3H), 2.94 (s, 3H), 2.63 (q, J = 7.5 Hz, 1H), 2.42
(dt, J = 14.1, 7.3 Hz, 1H), 2.17—2.05 (m, 2H), 2.06—1.93 (m, 4H),
1.93—1.70 (m, 4H), 1.69—1.60 (m, 1H), 1.55—1.48 (m, 1H),
1.43—1.36 (m, 2H), 1.35—1.30 (m, 1H), 1.33 (d, J = 7.7 Hz, 3H),
1.25—1.19 (m, 1H), 1.18—1.04 (m, 1H), 0.73 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ: 181.0, 155.2, 140.1, 120.8, 83.0, 73.3, 65.8,
58.7, 54.8, 52.7, 41.5, 40.4, 40.1, 38.4, 37.4, 36.6, 35.8, 34.1, 33.1,
32.8, 27.6, 25.7, 24.9, 18.0, 13.3; IR (KBr) ν: 2917, 2854, 1738,
1732, 1274, 1261, 764, 749 cm–1; HRMS (ESI, m/z): [M+H]+ calcd
for C25H37O8S, 497.2204; found, 497.2204.
To a solution of the epoxide 74 (330 mg, 0.828 mmol, 1.0
equiv) obtained above in 50 mL CHCl3 was added HCl (0.7 mL, 4.0
M in 1,4-dioxane, 2.73 mmol, 3.3 equiv) at 0 oC. The reaction
o
mixture was stirred at 0 C for 40 min and quenched with H2O.
The organic layer was separated and aqueous layer was extracted
1346
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© 2020 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2020, 38, 1339－1352

Development of Biomimetic Synthesis of Propindilactone G
Chin. J. Chem.
Synthesis of compound 35, 29, C9-epi-29. To a solution of 28
(100 mg, 0.249 mmol, 1.0 equiv) and Co(thd)2 (31.8 mg, 0.0746
mmol, 0.3 equiv) in 10 mL dry DCE was added Et3SiH (120 μL,
0.747 mmol, 3.0 equiv) under O2 atmosphere (1 atm). The reac-
tion mixture was stirred at room temperature for 0.5 h and then
at 0 oC for 2 h under O2 (balloon). The reaction mixture was
quenched with sat. aq. NaHCO3 (10 mL) and extracted with CH2Cl2
(3×10 mL). The combined organic layers were washed with brine
and dried over Na2SO4. Removal of the solvent under reduced
pressure afforded the crude product, which was purified by flash
0.81 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 154.0, 100.6,
97.7, 86.8, 86.1, 71.9, 70.1, 58.8, 54.5, 50.4, 46.9, 45.2, 42.3, 40.6,
37.1, 34.8, 34.0, 33.3, 32.5, 31.4, 27.4, 27.2, 25.9, 23.8, 16.9, 12.7;
IR (KBr) ν: 2947, 2858, 1666, 1454, 1379, 1260, 1096, 808 cm–1;
HRMS (ESI, m/z): [M+Na]+ calcd for C26H40O5Na, 455.2768; found,
455.2765.
42: TLC (petroleum ether : EtOAc, 9 : 1 V/V): Rf = 0.57; [α]2D5 +5.2
(c 0.14, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 4.52 (q, J = 7.9 Hz, 1H),
3.80 (dd, J = 11.9, 5.7 Hz, 1H), 3.47 (s, 3H), 3.19 (t, J = 11.4 Hz, 1H),
2.56 (d, J = 12.0 Hz, 1H), 2.39—2.29 (m, 1H), 2.29—2.20 (m, 2H),
chromatography (SiO2, 7 : 1 → 4 : 1 → 1 : 2 petroleum ether:EtOAc) 2.20—2.10 (m, 2H), 2.09—1.95 (m, 2H), 1.97 (d, J = 11.9 Hz, 1H),
to provide compound 35 (91.0 mg, 67%) as a white solid, 29 and
C9-epi-29 (19.0 mg, 18%, 1.2 : 1) as a white foam.
1.94—1.77 (m, 3H), 1.70—1.59 (m, 3H), 1.57 (s, 3H), 1.46 (td, J =
11.7, 4.3 Hz, 1H), 1.39 (s, 3H), 1.32—1.17 (m, 5H), 1.27 (s, 3H),
0.85 (s, 3H), 0.81 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ:
147.6, 116.5, 100.6, 87.0, 86.2, 71.9, 70.1, 58.8, 56.4, 50.8, 46.8,
45.0, 44.8, 42.4, 37.1, 35.0, 33.9, 32.2, 31.4, 29.7, 27.7, 25.9, 23.7,
23.7, 16.9, 12.7, 12.6; IR (KBr) ν: 2934, 2855, 1454, 1377, 1260,
35: mp: 152.1—155.4 oC; TLC (petroleum ether : EtOAc, 2 : 1
V/V): Rf = 0.63; [α]2D5 –12.4 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ: 5.01 (t, J = 2.9 Hz, 1H), 4.95 (td, J = 7.7, 4.5 Hz, 1H), 2.57
(q, J = 7.6 Hz, 1H), 2.29 (d, J = 15.7 Hz, 1H), 2.23 (dt, J = 13.8, 7.1
Hz, 1H), 2.19—2.13 (m, 1H), 2.09—2.02 (m, 1H), 2.05 (s, 3H), 1.98
(dd, J = 14.0, 4.6 Hz, 1H), 1.89—1.81 (m, 1H), 1.85 (d, J = 7.4 Hz,
1H), 1.77 (d, J = 15.8 Hz, 1H), 1.80—1.63 (m, 3H), 1.59—1.51 (m,
2H), 1.47 (dd, J = 13.7, 4.8 Hz, 2H), 1.43—1.34 (m, 6H), 1.31 (d, J =
7.6 Hz, 3H), 1.11 (s, 1H), 1.00 (t, J = 7.9 Hz, 9H), 0.78 (s, 3H),
0.75—0.67 (m, 6H); 13C NMR (101 MHz, CDCl3) δ: 181.4, 170.8,
84.8, 82.7, 73.0, 69.8, 59.1, 53.2, 47.8, 45.2, 42.0, 40.3, 37.0, 36.3,
34.3, 34.2, 33.6, 33.4, 32.2, 27.4, 25.4, 21.6, 18.1, 13.4, 7.0, 4.1; IR
(KBr) ν: 3460, 2940, 2874, 1761, 1733, 1258, 1017, 745 cm–1;
HRMS (ESI, m/z): [M+H]+ calcd for C30H51O7Si, 551.3399; found,
551.3395.
1
1221, 1096, 802 cm– ; HRMS (ESI, m/z): [M+Na]+ calcd for
C27H42O5Na, 469.2924; found, 469.2919.
Synthesis of compound 44. A solution of 43 (117 mg, 0.253
mmol, 1.0 equiv) and 10% Pd/C (11.7 mg, 10% w/w) in 5 mL
MeOH was stirred at room temperature under 1 atm H2 for 80
min. The reaction mixture was filtered through celite and concen-
trated under reduced pressure to afford the crude product. Purifi-
cation by flash chromatography (SiO2, 3 :1 → 2:1 petroleum ether:
acetone) provided compound 44 (82.0 mg, 76%) as a white solid.
o
44: mp: 228.1—230.2 C; TLC (petroleum ether : acetone, 2 :1
V/V): Rf = 0.18; [α]2D5 –24.0 (c 0.42, CHCl3); 1H NMR (400 MHz,
CDCl3) δ: 4.40 (td, J = 7.6, 4.2 Hz, 1H), 3.69—3.53 (m, 2H), 3.06
(ddd, J = 13.3, 10.6, 8.4 Hz, 1H), 2.76—2.64 (m, 2H), 2.63—2.52
(m, 1H), 2.27—2.15 (m, 2H), 2.11 (d, J = 15.6 Hz, 1H), 1.94 (d, J =
15.8 Hz, 1H), 1.85—1.71 (m, 4H), 1.70—1.63 (m, 3H), 1.55—1.47
(m, 2H), 1.45—1.34 (m, 3H), 1.33—1.23 (m, 3H), 1.29 (s, 3H), 1.27
(s, 3H), 1.19—1.07 (m, 2H), 0.96 (d, J = 7.0 Hz, 3H), 0.91 (s, 3H);
13C NMR (101 MHz, CDCl3) δ: 177.8, 93.3, 74.2, 72.8, 72.6, 70.9,
C9-epi-29: mp: 147.5—150.3 oC; TLC (petroleum ether :EtOAc,
1
2 : 1 V/V): Rf = 0.18; [α]2D5 –45.3 (c 1.40, CHCl3); H NMR (400 MHz,
CDCl3) δ: 5.07—4.94 (m, 2H), 2.58 (q, J = 7.7 Hz, 1H), 2.37—2.27
(m, 1H), 2.27—2.15 (m, 1H), 2.05 (s, 3H), 1.99 (d, J = 14.9 Hz, 1H),
1.91 (d, J = 7.7 Hz, 1H), 1.91—1.87 (m, 1H), 1.87—1.80 (m, 1H),
1.79—1.66 (m, 5H), 1.65—1.42 (m, 8H), 1.39—1.33 (m, 1H),
1.33—1.18 (m, 3H), 1.31 (d, J = 7.6 Hz, 3H), 0.86 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ: 181.3, 170.8, 82.8, 78.6, 73.5, 70.0, 58.4, 52.0, 62.0, 55.8, 54.0, 47.3, 46.4, 43.2, 39.8, 35.7, 35.4, 32.6, 32.5, 32.5,
47.9, 44.3, 43.1, 42.1, 41.4, 36.7, 36.2, 35.1, 34.6, 33.0, 30.0, 28.4,
24.7, 21.7, 18.1, 14.1; IR (KBr) ν: 3391, 2933, 2873, 1769, 1731,
1242, 1020, 735 cm–1; HRMS (ESI, m/z): [M+Na]+ calcd for
C24H36O6Na, 551.3399; found, 551.3395.
29.7, 29.5, 27.5, 26.3, 16.9, 12.5; IR (KBr) ν: 3401, 2932, 2877,
1748, 1274, 1260, 764, 749 cm–1; HRMS (ESI, m/z): [M+Na]+ calcd
for C24H42O6Na, 447.2717; found, 447.2714.
Synthesis of compound 45. To a solution of 44 (50.0 mg,
0.118 mmol, 1.0 equiv) and DMAP (4.32 mg, 0.0354 mmol, 0.3
equiv) in 3 mL dry CH2Cl2 was added Et3N (82 μL, 0.589 mmol, 5.0
equiv) and Ac2O (39 μL, 0.413 mmol, 3.5 equiv) at room tempera-
ture. After stirring at the same temperature for 4.5 h, Ac2O (11 μL,
0.118 mmol, 1.0 equiv) was added and stirring was continued for
another 1 h at room temperature. Et3N (82 μL, 0.589 mmol, 5.0
equiv) and Ac2O (39 μL, 0.413 mmol, 3.5 equiv) were added and
stirring was continued for another 1 h at room temperature.
Finally, another portion of Et3N (82 μL, 0.589 mmol, 5.0 equiv) and
Ac2O (39 μL, 0.413 mmol, 3.5 equiv) were added and stirring was
continued for 1 h at room temperature. Solvent was removed
under reduced pressure and the resulting crude product was
purified by flash chromatography (SiO2, 3 : 1 petroleum ether :
acetone) to provide compound 45 (53.0 mg, 88%) as a white solid.
Synthesis of compound 40, 41, 42. To a solution of 39 (1.10 g,
2.63 mmol, 1.0 equiv) in t-BuOH/cyclohexane/HMPA (61.0 mL,
2.8 : 2.2 : 1) was added t-BuOK (1.0 M in THF, 7.9 mL, 7.89 mmol,
o
3.0 equiv) and MeI (0.49 mL, 7.89 mmol, 3.0 equiv) at 0 C. After
stirred at 0 oC for 25 min, t-BuOK (5.3 mL×2, 5.26 mmol×2, 2.0
equiv×2) and MeI (0.33 mL×2, 5.26 mmol×2, 2.0 equiv×2) were
added in two portions every 25 min. t-BuOK (2.6 mL, 2.63 mmol,
1.0 equiv) and MeI (0.16 mL, 2.63 mmol, 1.0 equiv) were added
and stirring was continued for another 25 min under the same
condition. Finally, another portion of t-BuOK (1.3 mL, 1.31 mmol,
0.5 equiv) and MeI (0.08 mL, 1.31 mmol, 0.5 equiv) were added
and stirring was continued for 25 min at 0 oC. The reaction
mixture was quenched with water (20 mL) and extracted with
EtOAc (3×40 mL). The combined organic layers were washed with
aq. NaCl (water/brine = 1 : 1, V/V, 30 mL) for 8 times and dried
over Na2SO4. Removal of the solvent under reduced pressure
afforded the crude product, which was purified by flash
chromatography (SiO2, 31 : 6 : 1 → 25 : 6 : 1 petroleum ether :
CH2Cl2 : EtOAc) to provide compound 40 (610 mg, 52%) as a white
solid, 41 and 42 (263 mg, 23%) as white foams.
o
45: mp: 200.3—202.4 C; TLC (petroleum ether : acetone, 3 :1
V/V): Rf = 0.32; [α]2D5 +23.6 (c 1.32, CHCl3); 1H NMR (400 MHz,
CDCl3) δ: 5.09 (td, J = 7.7, 4.2 Hz, 1H), 4.07 (dd, J = 10.7, 3.4 Hz,
1H), 3.65 (dd, J = 10.7, 6.8 Hz, 1H), 3.03 (ddd, J = 13.3, 10.7, 8.1 Hz,
1H), 2.77—2.63 (m, 1H), 2.66 (d, J = 8.5 Hz, 1H), 2.55 (ddd, J =
18.3, 10.7, 8.1 Hz, 1H), 2.35 (dt, J = 13.5, 7.7 Hz, 1H), 2.25—2.15
(m, 1H), 2.09 (d, J = 15.8 Hz, 1H), 2.031 (s, 3H), 2.025 (s, 3H), 1.97
41: TLC (petroleum ether : EtOAc, 9 : 1 V/V): Rf = 0.61; [α]2D5 +5.3
(c 0.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 4.52 (q, J = 8.0 Hz, 1H), (s, 1H), 1.95 (d, J = 14.7 Hz, 1H), 1.79—1.67 (m, 4H), 1.66—1.51
4.21 (s, 1H), 3.80 (dd, J = 11.9, 5.7 Hz, 1H), 3.47 (s, 3H), 3.19 (t, J =
10.8 Hz, 1H), 2.55 (d, J = 12.0 Hz, 1H), 2.41—2.27 (m, 2H),
2.19—2.10 (m, 2H), 2.08—1.88 (m, 5H), 1.87—1.75 (m, 2H),
1.70—1.60 (m, 2H), 1.56—1.52 (m, 1H), 1.47 (td, J = 11.7, 4.2 Hz,
1H), 1.39 (s, 3H), 1.35—1.16 (m, 5H), 1.27 (s, 3H), 0.86 (s, 3H),
(m, 4H), 1.45—1.30 (m, 4H), 1.28 (s, 3H), 1.25 (s, 3H), 1.23—1.14
(m, 1H), 1.09—0.99 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.86 (s, 3H);
13C NMR (101 MHz, CDCl3) δ: 177.5, 171.2, 170.8, 93.0, 74.9, 74.2,
72.7, 68.8, 55.7, 55.7, 54.0, 47.4, 46.4, 43.1, 39.8, 35.10, 35.08,
32.7, 32.3, 30.3, 29.6, 29.5, 27.4, 26.2, 21.4, 21.1, 16.6, 12.0; IR
Chin. J. Chem. 2020, 38, 1339－1352
© 2020 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de
1347

Wang et al.
Comprehensive Report
(KBr) ν: 3524, 3457, 2967, 2938, 1761, 1736, 1374, 1248 cm–1;
HRMS (ESI, m/z): [M+Na]+ calcd for C28H44O8Na, 531.2928; found,
531.2932.
CH2Cl2, 4.0 equiv) at –78 °C. After stirring at the same tempera-
ture for 10 min, 3-methyl-2-(tert-butyldimethylsilyloxy)furan (436
mg, 2.05 mmol, 3.0 equiv) was added. The reaction mixture was
stirred at –78 °C for 4 h and quenched with sat. aq. NaHCO3. The
aqueous layer was extracted with CH2Cl2 (3×10 mL) and the com-
bined organic layers were washed with brine, dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
chromatography (SiO2, 4 : 1 petroleum ether : EtOAc) to furnish
compound 54 (337 mg, 72%) as a white foam.
Synthesis of compound 52. To a solution of 18 (5.00 g, 14.5
mmol, 1.0 equiv), imidazole (2.95 g, 43.4 mmol, 3.0 equiv) and
DMAP (177 mg, 1.45 mmol, 0.1 equiv) in 40 mL CH2Cl2 was added
TBDPSCl (tert-butyldiphenylsilyl chloride, 7.7 mL, 28.9 mmol, 2.0
equiv) at room temperature. After stirred at the same tempera-
ture for 2.5 h, the reaction mixture was quenched with H2O and
extracted with CH2Cl2 (3×40 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash chromatography (SiO2,
20 : 1 petroleum ether : EtOAc) to furnish the silylated product
which was used in the next step without further purification.
To a solution of the silylated product obtained above in 80 mL
dry THF was added LiAlH4 (1.38 g, 36.3 mmol, 2.5 equiv) at room
temperature over 10 min. After stirred at room temperature for
70 min, the reaction mixture was quenched slowly with 1.4 mL
54: TLC (petroleum ether : EtOAc, 3 : 1 V/V): Rf = 0.39; 1H NMR
(400 MHz, CDCl3) δ: 7.70—7.65 (m, 4.37H), 7.44—7.34 (m, 6.31H),
7.07 (t, J = 1.6 Hz, 0.85H), 7.01 (t, J = 1.6 Hz, 0.15H), 5.00—4.97 (m,
0.17H), 4.96—4.91 (m, 0.88H), 4.29 (dd, J = 8.5, 3.8 Hz, 0.15H),
4.05 (dt, J = 5.3, 2.6 Hz, 0.85H), 3.63—3.54 (m, 1.10H), 3.49 (d, J =
5.4 Hz, 0.84H), 2.91 (s, 0.14H), 2.48 (td, J = 7.8, 3.1 Hz, 0.16H),
2.28—2.16 (m, 1.79H), 2.01—1.91 (m, 5.07H), 1.82—1.69 (m,
1.29H), 1.68—1.49 (m, 6.05H), 1.48—1.31 (m, 6.40H), 1.31—1.23
(m, 1.40H), 1.22—1.08 (m, 2.84H), 1.06—1.03 (m, 11.11H),
0.96—0.84 (m, 2.18H), 0.81 (s, 2.73H), 0.80—0.75 (m, 4.16H),
0.75—0.65 (m, 1.85H); 13C NMR (101 MHz, CDCl3) δ: 221.1, 174.2,
146.7, 146.6, 135.9, 135.02, 134.96, 134.9, 131.4, 130.9, 129.53,
129.50, 127.6, 127.54, 127.52, 116.6, 85.2, 82.9, 80.9, 77.5, 77.4,
77.2, 76.8, 73.7, 72.8, 72.7, 71.9, 66.1, 55.1, 54.2, 54.0, 50.7, 44.8,
44.7, 43.4, 42.9, 40.8, 39.0, 38.74, 38.71, 38.4, 38.3, 37.0, 36.8,
35.63, 35.61, 34.8, 34.5, 34.2, 33.7, 32.0, 31.8, 31.7, 28.6, 28.5,
27.1, 20.8, 19.3, 17.9, 14.3, 14.1, 13.3, 12.5, 12.4, 11.0, 10.9; IR
(KBr) ν: 3500, 2930, 2856, 1760, 1731, 1110, 1068, 740 cm–1;
HRMS (ESI, m/z): [M+Na]+ calcd for C43H58O5SiNa, 705.3946; found,
705.3947.
o
H2O, 1.4 mL 15% aq. NaOH and 4.2 mL H2O at 0 C. The reaction
mixture was filtered through celite and concentrated under
reduced pressure to afford the crude product which was purified
by flash chromatography (SiO2, 5 : 1 → 3 : 1 petroleum ether :
EtOAc) to provide compound 52 (6.90 g, 82% over 2 steps) as a
white foam.
52: TLC (petroleum ether : EtOAc, 2 : 1 V/V): Rf = 0.25; [α]D30
1
–7.9 (c 1.07, CHCl3); H NMR (400 MHz, CDCl3) δ: 7.71—7.63 (m,
4H), 7.44—7.31 (m, 6H), 4.35 (td, J = 7.7, 4.8 Hz, 1H), 3.64—3.50
(m, 3H), 3.31 (s, 1H), 2.49 (s, 1H), 2.23—2.12 (m, 2H), 1.89 (dt, J =
12.6, 3.4 Hz, 1H), 1.69—1.60 (m, 2H), 1.59—1.50 (m, 2H),
1.47—1.33 (m, 5H), 1.29—1.09 (m, 4H), 1.04 (s, 9H), 1.02—0.96
(m, 2H), 0.94 (d, J = 7.0 Hz, 3H), 0.89—0.84 (m, 1H), 0.87 (s, 3H),
0.82—0.77 (m, 1H), 0.79 (s, 3H), 0.73 (dd, J = 13.1, 4.2 Hz, 1H),
0.55—0.44 (m, 1H); 13C NMR (101 MHz, CDCl3) δ: 135.9, 135.0,
134.9, 129.49, 129.48, 127.53, 127.51, 72.9, 72.6, 70.6, 62.4, 54.3,
44.8, 43.0, 40.4, 38.4, 37.0, 35.6, 35.5, 35.1, 32.7, 32.1, 31.8, 28.7,
27.1, 21.0, 19.3, 17.1, 13.4, 12.5; IR (KBr) ν: 3300, 2930, 2855,
1111, 1067, 739, 701, 612 cm–1; HRMS (ESI, m/z): [M+Na]+ calcd
for C38H56O3SiNa, 611.3891; found, 611.3867.
Synthesis of compound 53. To a solution of (COCl)2 (1.9 mL,
23.1 mmol, 4.0 equiv) in 67 mL dry CH2Cl2 was added DMSO (2.4
mL, 34.7 mmol, 6 equiv) at –78 °C. After stirring at the same tem-
perature for 0.5 h, a solution of 23 (3.40 g, 5.78 mmol, 1.0 equiv)
in 44 mL CH2Cl2 was added and stirring was continued for 0.5 h at
–78 °C. Et3N (7.9 mL, 57.8 mmol, 10.0 equiv) was added and stir-
ring was continued for 1 h at –78 °C and 2 h at 0 °C. The reaction
mixture was quenched with sat. aq. NH4Cl and extracted with
CH2Cl2 (3×40 mL). The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash chromatography (SiO2, 25 : 1 → 15 : 1 petro-
leum ether : EtOAc) to furnish compound 53 (2.60 g, 78%) as a
white foam.
Synthesis of compound 55 (55 was in an equilibrium of
C16-ketone and hemiketal). A solution of 54 (30.0 mg, 0.0439
mmol, 1.0 equiv) and DBU (99 μL, 0.660 mmol, 15 equiv) in 2.5 mL
toluene was stirred at room temperature for 9 h. The reaction
mixture was quenched with sat. aq. NH4Cl and extracted with
EtOAc (3×10 mL). The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash chromatography (SiO2, 5 : 1 petroleum ether:
EtOAc) to furnish compound 55 (17.0 mg, 55%) as a white foam.
55: TLC (petroleum ether : EtOAc, 3 : 1 V/V): Rf = 0.46; 1H NMR
(400 MHz, CDCl3) δ: 7.70—7.63 (m, 4H), 7.44—7.33 (m, 6.78H),
7.31—7.28 (m, 0.21H), 5.08 (dt, J = 9.5, 1.9 Hz, 0.20H), 4.73 (dt, J =
9.3, 1.8 Hz, 0.78H), 4.41 (d, J = 4.2 Hz, 0.76H), 3.58 (dd, J = 9.4, 5.0
Hz, 0.20H), 3.64—3.53 (m, 0.99H), 3.50 (dd, J = 9.4, 3.9 Hz, 0.78H),
2.66 (s, 0.19H), 2.52—2.40 (m, 0.20H), 2.30—2.16 (m, 1.51H),
1.97—1.86 (m, 4.71H), 1.86—1.76 (m, 1.02H), 1.71—1.62 (m,
1.72H), 1.61—1.50 (m, 3.74H), 1.49—1.41 (tt, J = 9.2, 4.8 Hz,
2.97H), 1.40—1.30 (m, 1.73H), 1.30—1.23 (m, 2.00H), 1.22—1.13
(m, 2.01H), 1.09 (d, J = 7.2 Hz, 2.39H), 1.05 (s, 8.91H), 0.97—0.83
(m, 2.07H), 0.82 (s, 2.36H), 0.79 (s, 0.90H), 0.75 (s, 2.37H), 0.73 (s,
0.84H), 0.71—0.65 (m, 0.85H); 13C NMR (101 MHz, CDCl3) δ: 222.8,
174.2, 150.2, 149.8, 135.9, 135.0, 134.93, 134.89, 130.0, 129.6,
129.5, 127.53, 127.51, 117.0, 87.7, 80.6, 79.8, 77.5, 77.2, 76.8,
74.9, 72.7, 71.5, 69.2, 55.4, 54.3, 54.2, 50.7, 44.8, 43.7, 42.8, 41.8,
39.4, 38.9, 38.3, 37.9, 37.0, 36.8, 35.7, 35.6, 34.7, 34.50, 34.47,
32.9, 32.1, 31.7, 28.6, 28.4, 27.1, 20.7, 20.5, 19.2, 17.1, 15.7, 14.1,
13.9, 12.5, 12.4, 10.9, 10.8; IR (KBr) ν: 3456, 2930, 2856, 1764,
1449, 1111, 1064, 823 cm–1; HRMS (ESI, m/z): [M+Na]+ calcd for
C43H58O5SiNa, 705.3946; found, 705.3939.
53: TLC (petroleum ether : EtOAc, 2 : 1 V/V): Rf = 0.89; [α]D30
–74.3 (c 1.18, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 9.81 (d, J = 2.7
Hz, 1H), 7.75—7.63 (m, 4H), 7.45—7.31 (m, 6H), 3.66—3.51 (m,
1H), 2.59—2.46 (m, 1H), 2.37 (d, J = 9.7 Hz, 1H), 2.21 (dd, J = 18.6,
6.6 Hz, 1H), 1.99—1.89 (m, 1H), 1.81—1.69 (m, 1H), 1.69—1.61
(m, 1H), 1.61—1.42 (m, 8H), 1.42—1.32 (m, 2H), 1.26—1.17 (m,
2H), 1.07 (d, J = 7.1 Hz, 3H), 1.05 (s, 9H), 0.98—0.85 (m, 2H), 0.82
(s, 3H), 0.78—0.65 (m, 2H), 0.76 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ: 217.6, 203.6, 135.8, 134.8, 134.7, 129.45, 129.43, 127.5, 127.4,
72.6, 65.1, 53.9, 51.2, 44.6, 43.5, 42.2, 38.7, 38.2, 37.5, 36.7, 35.5,
34.4, 32.0, 31.6, 28.4, 27.0, 20.7, 19.2, 13.6, 13.1, 12.3; IR (KBr) ν:
2931, 2855, 1738, 1110, 1066, 823, 739, 702 cm–1; HRMS (ESI,
m/z): [M+Na]+ calcd for C38H52O3SiNa, 607.3578; found, 607.3558.
Synthesis of compound 54 (54 was in an equilibrium of C16-
ketone and hemiketal). To a solution of 53 (400 mg, 0.685 mmol,
1.0 equiv) in 24 mL CH2Cl2 was added TiCl4 (2.7 mL, 1.0 M in
Synthesis of compound 56. To a solution of 55 (64.0 mg,
0.0938 mmol, 1.0 equiv) in 6 mL MeOH was added (±)-CSA (2.18
mg, 0.00938 mmol, 0.1 equiv) at room temperature. After stirred
at the same temperature for 2 h, the reaction mixture was
quenched with sat. aq. NaHCO3. MeOH was removed under
reduced pressure, and the resulting residue was dissolved in H2O
and extracted with EtOAc (3×10 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash chromatography (SiO2,
1348
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© 2020 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2020, 38, 1339－1352

Development of Biomimetic Synthesis of Propindilactone G
Chin. J. Chem.
20 : 1 petroleum ether : EtOAc) to furnish the ketal intermediate
75 (53.0 mg, 81%) as a white foam.
30 mL EtOAc and washed twice with 10 mL H2O. The organic layer
was washed with brine and dried over Na2SO4. Removal of the
To a solution of the ketal 75 (53.0 mg, 0.0761 mmol, 1.0 equiv) solvent under reduced pressure afforded the crude product,
in 5 mL MeOH was added (±)-CSA (1.77 mg, 0.00761 mmol, 0.1
equiv) at room temperature. After stirred at room temperature
which was purified by flash chromatography (SiO2, 25 : 1 → 20 : 1
petroleum ether : EtOAc) to provide compound 60 (98.0 mg, 62%)
for 36 h, the reaction mixture was quenched with sat. aq. NaHCO3. as a white foam and recovered 59 (22.0 mg, 14%).
MeOH was removed under reduced pressure and the resulting
residue was dissolved in H2O and extracted with EtOAc (3×10 mL).
The combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash chromatography (SiO2, 3 : 1 petroleum ether : EtOAc) to fur-
nish compound 56 (21.0 mg, 60%) as a white solid.
60: TLC (petroleum ether : EtOAc, 10 : 1 V/V): Rf = 0.28; [α]D25
+117.0 (c 1.04, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.72—7.58 (m,
4H), 7.46—7.31 (m, 6H), 7.16 (d, J = 9.3 Hz, 1H), 6.46—6.14 (m,
2H), 5.69 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.65—3.46 (m, 1H),
2.92—2.73 (m, 1H), 2.43—2.24 (m, 1H), 2.12 (d, J = 4.3 Hz, 1H),
2.05—1.97 (m, 1H), 1.91 (s, 3H), 1.86—1.76 (m, 1H), 1.70—1.53
(m, 4H), 1.52—1.38 (m, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.34—1.21 (m,
7H), 1.13 (s, 3H), 1.05 (s, 9H), 0.95—0.84 (m, 1H), 0.87 (s, 3H),
0.83—0.70 (m, 2H); 13C NMR (101 MHz, CDCl3) δ: 208.1, 190.6,
168.7, 146.6, 138.7, 135.9, 134.9, 134.8, 129.59, 129.57, 127.59,
127.56, 125.4, 125.2, 124.3, 72.6, 64.6, 60.6, 54.7, 47.6, 44.1, 41.3,
38.2, 37.0, 36.5, 36.3, 36.1, 31.7, 29.7, 28.0, 27.1, 21.5, 21.2, 20.8,
19.3, 14.5, 12.7, 12.3; IR (KBr) ν: 3070, 2931, 2857, 1699, 1635,
1612, 1233, 1110 cm–1; HRMS (ESI, m/z): [M+H]+ calcd for
C45H61O4Si, 693.4334; found, 693.4321.
56: mp: 248.9—251.2 oC; TLC (petroleum ether : EtOAc, 3 : 1
V/V): Rf = 0.25; [α]2D5 –103.5 (c 1.43, CHCl3); 1H NMR (400 MHz,
CDCl3) δ: 7.29 (t, J = 1.6 Hz, 1H), 4.97 (dt, J = 9.6, 1.8 Hz, 1H), 3.85
(dd, J = 9.6, 8.0 Hz, 1H), 3.58 (tt, J = 10.6, 4.8 Hz, 1H), 3.27 (s, 3H),
2.52—2.38 (m, 1H), 2.11—1.98 (m, 1H), 1.93 (t, J = 1.7 Hz, 3H),
1.83 (d, J = 2.1 Hz, 1H), 1.87—1.75 (m, 1H), 1.71—1.36 (m, 8H),
1.29 (d, J = 7.3 Hz, 3H), 1.36—1.22 (m, 6H), 1.19—1.05 (m, 2H),
1.03—0.84 (m, 2H), 0.81 (s, 3H), 0.74 (s, 3H), 0.73—0.62 (m, 1H);
13C NMR (101 MHz, CDCl3) δ: 174.4, 150.2, 130.3, 120.4, 87.7,
79.5, 72.3, 71.3, 55.4, 54.4, 50.5, 44.9, 41.6, 38.5, 38.2, 37.0, 35.7,
35.0, 34.2, 33.9, 32.1, 31.6, 28.6, 20.7, 17.4, 13.6, 12.5, 10.9; IR
(KBr) ν: 3515, 3093, 2920, 1727, 1461, 1299, 891, 517 cm–1; HRMS
(ESI, m/z): [M+Na]+ calcd for C28H42O5Na, 481.2924; found,
481.2916.
Synthesis of compound 61. A solution of 60 (56.0 mg, 0.0809
mmol, 1.0 equiv) and PTSA (3.3 mg, 0.0162 mmol, 0.2 equiv) in
2.7 mL toluene was stirred at 110 oC for 0.5 h. The reaction
mixture was cooled to room temperature, quenched with sat. aq.
NaHCO3, and extracted with EtOAc (3×10 mL). The combined
organic layers were washed with brine and dried over Na2SO4.
Removal of the solvent under reduced pressure afforded the
crude product, which was purified by flash chromatography (SiO2,
25 : 1 petroleum ether : EtOAc) to provide compound 61 (26.0 mg,
46%) as a white foam and recovered 60 (29.0 mg, 52%).
Synthesis of compound 59. To a solution of 58 (678 mg, 2.57
mmol, 1.5 equiv) in 20 mL dry THF was added n-BuLi (1.3 mL, 1.9
M in hexane, 2.40 mmol, 1.4 equiv) at –78 °C. After stirring at
–78 °C for 0.5 h, a solution of 53 (1.00 g, 1.71 mmol, 1.0 equiv) in
20 mL dry THF was added and stirring was continued for 1 h at
–78 °C and 1 h at room temperature. The reaction mixture was
quenched with sat. aq. NH4Cl and extracted with EtOAc (3×40 mL).
The combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash chromatography (SiO2, 20 : 1 → 15 : 1 petroleum ether :
EtOAc) to furnish compound 59 (910 mg, 77%) as a white foam.
59: TLC (petroleum ether : EtOAc, 5 : 1 V/V): Rf = 0.75; [α]D30
–36.0 (c 1.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.68 (d, J = 7.1
61: TLC (petroleum ether : EtOAc, 6 : 1 V/V): Rf = 0.61; [α]D25
+125.1 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.71—7.62 (m,
4H), 7.46—7.31 (m, 6H), 7.14 (d, J = 10.8 Hz, 1H), 6.28 (dd, J = 15.3,
10.7 Hz, 1H), 6.16 (dd, J = 15.2, 7.6 Hz, 1H), 5.70 (d, J = 1.5 Hz, 1H),
4.19 (q, J = 7.1 Hz, 2H), 3.66—3.46 (m, 1H), 2.90—2.77 (m, 1H),
2.44—2.30 (m, 1H), 2.19 (d, J = 5.5 Hz, 1H), 1.91 (d, J = 1.4 Hz, 3H),
1.86—1.77 (m, 1H), 1.63—1.41 (m, 10H), 1.29 (t, J = 7.2 Hz, 3H),
1.32—1.25 (m, 4H), 1.22 (s, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.04 (s,
Hz, 4H), 7.45—7.33 (m, 6H), 7.17 (d, J = 9.6 Hz, 1H), 6.40—6.24 (m, 9H), 0.88 (s, 3H), 0.83—0.71 (m, 2H); 13C NMR (101 MHz, CDCl3) δ:
2H), 4.19 (q, J = 7.1 Hz, 2H), 3.65—3.52 (m, 1H), 2.66—2.55 (m,
208.6, 191.6, 168.7, 147.1, 138.6, 135.9, 134.9, 134.8, 129.61,
1H), 2.16 (dd, J = 18.3, 7.4 Hz, 1H), 1.98—1.89 (m, 1H), 1.92 (s, 3H), 129.59, 127.61, 127.59, 125.8, 124.5, 124.0, 72.6, 62.8, 60.6, 55.6,
1.87 (d, J = 5.6 Hz, 1H), 1.81—1.58 (m, 3H), 1.58—1.51 (m, 3H),
1.51—1.39 (m, 4H), 1.36—1.24 (m, 7H), 1.22—1.16 (m, 1H), 1.18
(d, J = 7.0 Hz, 3H), 1.05 (s, 9H), 0.96—0.85 (m, 2H), 0.82 (s, 3H),
0.74 (s, 3H), 0.71—0.64 (m, 1H); 13C NMR (101 MHz, CDCl3) δ:
217.7, 168.7, 147.4, 138.9, 135.9, 134.9, 134.8, 129.5, 127.5,
127.5, 125.2, 124.6, 72.8, 68.6, 60.5, 54.2, 50.8, 44.8, 43.3, 39.0,
38.8, 38.3, 36.8, 35.6, 35.0, 34.3, 32.2, 31.7, 28.5, 27.1, 20.9, 20.7,
19.2, 14.7, 14.5, 12.7, 12.4; IR (KBr) ν: 2930, 2855, 1737, 1703,
1635, 1107, 753, 702 cm–1; HRMS (ESI, m/z): [M+Na]+ calcd for
C45H62O4SiNa, 717.4310; found, 717.4281.
47.2, 44.2, 38.2, 37.0, 36.7, 36.4, 36.0, 35.6, 31.7, 29.7, 28.0, 27.1,
26.3, 21.0, 19.3, 18.4, 14.5, 12.8, 12.3; IR (KBr) ν: 3447, 2929,
2856, 1701, 1636, 1611, 797, 703 cm–1; HRMS (ESI, m/z): [M+H]+
calcd for C45H61O4Si, 693.4334; found, 693.4340.
Synthesis of compound 63. To a solution of vinyl bromide 62
(15.4 mg, 0.103 mmol, 2.0 equiv) in 0.4 mL dry THF was added
t-BuLi (1.3 M in pentane, 0.16 mL, 0.206 mmol, 4.0 equiv) drop-
wise. After the reaction mixture was stirred at –78 °C for 0.5 h,
ZnMe2 (1.0 M in toluene, 0.11 mL, 0.108 mmol, 2.1 equiv) was
added and stirring was continued for another 0.5 h at –78 °C. A
solution of aldehyde 53 (30.0 mg, 0.0514 mmol, 1.0 equiv) in 0.4
mL THF was added and the reaction mixture was stirred at –78 °C
for another 1 h before being quenched with 1 mL 2% aq. HCl. The
resulting mixture was stirred at room temperature for 0.5 h and
quenched with sat. aq. NaHCO3. The aqueous layer was extracted
with EtOAc (3×10 mL) and the combined organic layers were
washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by flash chromatography (SiO2, 10 : 1
petroleum ether : EtOAc) to furnish compound 63 (18.9 mg, 61%)
as a white foam.
Synthesis of compound 60. To a solution of 59 (159 mg, 0.229
mmol, 1.0 equiv) in 1.6 mL dry THF was added LHMDS (0.35 mL,
1.3 M in THF, 0.458 mmol, 2.0 equiv) dropwise at –78 °C. After
stirring at the same temperature for 1 h, TMSCl (87 μL, 0.687
mmol, 3.0 equiv) was added and stirring was continued for an-
other 0.5 h at –78 °C and 1 h at room temperature. The reaction
mixture was quenched with sat. aq. NaHCO3 and extracted with
EtOAc (3×10 mL). The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The resulting
silyl enol ether was used directly in the next step without further
purification.
63: TLC (petroleum ether : EtOAc, 3 : 1 V/V): Rf = 0.55; [α]D25
To a solution of the silyl enol ether obtained above in 11 mL
–63.5 (c 0.89, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 9.50 (d, J = 7.9
DMSO and 1 mL CH2Cl2 was added Pd(OAc)2 (61.5 mg, 0.275 mmol, Hz, 1H), 7.72—7.61 (m, 4H), 7.47—7.30 (m, 6H), 7.19 (dd, J = 15.7,
o
1.2 equiv) at room temperature. After stirred at 60 C for 1 h, the
reaction mixture was cooled to room temperature, diluted with
7.9 Hz, 1H), 6.06 (dd, J = 15.7, 7.9 Hz, 1H), 3.67—3.51 (m, 1H),
2.79—2.61 (m, 1H), 2.20 (dd, J = 18.5, 7.4 Hz, 1H), 2.01—1.87 (m,
Chin. J. Chem. 2020, 38, 1339－1352
© 2020 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de
1349

Wang et al.
Comprehensive Report
2H), 1.77 (dd, J = 18.5, 13.0 Hz, 1H), 1.69—1.52 (m, 5H),
1.48—1.28 (m, 6H), 1.20 (d, J = 7.0 Hz, 3H), 1.24—1.13 (m, 2H),
1.05 (s, 9H), 0.98—0.85 (m, 3H), 0.82 (s, 3H), 0.75 (s, 3H),
0.73—0.65 (m, 1H); 13C NMR (101 MHz, CDCl3) δ: 217.4, 194.6,
163.7, 135.9, 135.0, 134.9, 131.4, 129.5, 127.58, 127.56, 72.8,
68.4, 54.2, 50.9, 44.8, 43.3, 38.8, 38.7, 38.3, 36.8, 35.7, 34.6, 34.4,
32.2, 31.7, 28.5, 27.1, 20.7, 19.9, 19.3, 14.3, 12.5; IR (KBr) ν: 3070,
2931, 2855, 1738, 1670, 1110, 823, 703 cm–1; HRMS (ESI, m/z):
[M+H]+ calcd for C40H55O3Si, 611.3915; found, 611.3914.
1.28—1.24 (m, 2H), 1.12 (s, 3H), 1.04 (s, 9H), 0.95—0.89 (m, 1H),
0.87 (s, 3H), 0.82—0.70 (m, 2H); 13C NMR (101 MHz, CDCl3) δ:
208.4, 190.7, 167.9, 145.4, 141.1, 135.9, 134.9, 134.8, 129.61,
129.59, 127.61, 127.59, 127.1, 124.34, 124.28, 72.6, 64.7, 60.2,
54.8, 47.7, 44.1, 41.3, 38.2, 37.0, 36.5, 36.3, 35.8, 31.7, 29.7, 28.0,
27.1, 21.5, 21.4, 20.85, 20.80, 19.3, 14.5, 12.3; IR (KBr) ν: 3070,
2931, 2857, 1670, 1612, 1111, 824, 703 cm–1; HRMS (ESI, m/z):
[M+H]+ calcd for C45H61O4Si, 693.4334; found, 693.4331.
Synthesis of compound 67. A solution of 66 (110 mg, 0.159
mmol, 1.0 equiv) and PTSA (30.2 mg, 0.159 mmol, 1.0 equiv) in 5
mL toluene was stirred at 80 oC for 0.5 h. The reaction mixture
was cooled to room temperature, quenched with sat. aq. NaHCO3,
Synthesis of compound 65. To a solution of 18-crown-6 (2.16
g, 8.20 mmol, 5.0 equiv) in 38 mL dry THF was added KHMDS (2.3
mL, 1.0 M in THF, 2.29 mmol, 1.4 equiv) at –78 °C. After stirring at
–78 °C for 10 min, a solution of phosphate 64 (822 mg, 2.46 mmol, and extracted with EtOAc (3×10 mL). The combined organic layers
1.5 equiv) in 16 mL THF was added and stirring was continued for
another 0.5 h at –78 °C. A solution of 63 (1.0 g, 1.64 mmol, 1.0
equiv) in 60 mL THF was added and stirring was continued for
were washed with brine, dried over Na2SO4. Removal of the
solvent under reduced pressure afforded the crude product,
which was purified by flash chromatography (SiO2, 22 : 1
petroleum ether : EtOAc) to provide compound 67 (47.0 mg, 43%)
as a white foam and recovered 66 (52.0 mg, 47%).
o
another 1 h at –78 °C and 1 h at 0 C. The reaction mixture was
quenched with sat. aq. NH4Cl and extracted with EtOAc (3×50 mL).
The combined organic layers were washed with brine and dried
over Na2SO4. Removal of the solvent under reduced pressure af-
forded the crude product, which was purified by flash chromatog-
raphy (SiO2, 35 : 1 petroleum ether : EtOAc) to provide compound
65 (970 mg, 83%) as a white foam and isomer 59 (103 mg, 9%).
65: TLC (petroleum ether : EtOAc, 5 : 1 V/V): Rf = 0.50; [α]D25
–54.5 (c 1.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.73—7.63 (m,
4H), 7.46—7.30 (m, 6H), 7.09 (dd, J = 15.4, 11.1 Hz, 1H), 6.40 (d,
J = 11.1 Hz, 1H), 6.22 (dd, J = 15.4, 8.1 Hz, 1H), 4.20 (q, J = 7.1 Hz,
2H), 3.66—3.50 (m, 1H), 2.65—2.51 (m, 1H), 2.15 (dd, J = 18.3, 7.4
Hz, 1H), 1.93 (s, 3H), 1.86 (d, J = 5.4 Hz, 1H), 1.73 (dd, J = 18.2,
13.3 Hz, 1H), 1.67—1.38 (m, 8H), 1.31 (t, J = 7.1 Hz, 3H),
1.37—1.22 (m, 4H), 1.17 (d, J = 7.1 Hz, 3H), 1.21—1.11 (m, 2H),
1.05 (s, 9H), 0.96—0.83 (m, 2H), 0.81 (s, 3H), 0.74 (s, 3H),
0.77—0.62 (m, 2H); 13C NMR (101 MHz, CDCl3) δ: 217.9, 167.9,
146.3, 141.4, 135.9, 135.0, 134.9, 129.5, 127.57, 127.55, 126.4,
124.1, 72.8, 68.9, 60.2, 54.3, 50.9, 44.8, 43.3, 39.1, 38.8, 38.4,
36.8, 35.7, 34.6, 34.3, 32.2, 31.7, 28.5, 27.1, 21.0, 20.8, 20.7, 19.3,
14.7, 14.5, 12.4; IR (KBr) ν: 3070, 2931, 2856, 1738, 1705, 1110,
822, 756 cm–1; HRMS (ESI, m/z): [M+H]+ calcd for C45H63O4Si,
695.4490; found, 695.4489.
67: TLC (petroleum ether : EtOAc, 6 : 1 V/V): Rf = 0.55; [α]D25
+109.4 (c 1.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.73—7.59 (m,
4H), 7.48—7.32 (m, 6H), 7.07 (dd, J = 15.2, 11.3 Hz, 1H), 6.39 (d,
J = 11.1 Hz, 1H), 6.03 (dd, J = 15.3, 7.8 Hz, 1H), 5.69 (s, 1H), 4.20
(q, J = 7.1 Hz, 2H), 3.64—3.47 (m, 1H), 2.84—2.72 (m, 1H), 2.37 (t,
J = 9.3 Hz, 1H), 2.17 (d, J = 5.2 Hz, 1H), 1.93 (s, 3H), 1.87—1.74 (m,
2H), 1.67—1.56 (m, 3H), 1.55—1.49 (m, 1H), 1.49—1.40 (m, 4H),
1.31 (t, J = 7.1 Hz, 3H), 1.33—1.25 (m, 3H), 1.20 (s, 3H), 1.15 (d, J =
6.8 Hz, 3H), 1.05 (s, 9H), 0.93—0.85 (m, 1H), 0.87 (s, 3H),
0.82—0.70 (m, 2H); 13C NMR (101 MHz, CDCl3) δ: 209.0, 191.7,
167.9, 146.3, 141.0, 135.9, 134.85, 134.77, 129.59, 129.57, 127.58,
127.56, 126.0, 124.7, 124.0, 72.6, 62.6, 60.3, 55.5, 47.1, 44.2, 38.2,
37.0, 36.7, 36.4, 35.7, 35.1, 31.7, 29.7, 28.0, 27.1, 26.4, 20.9, 20.8,
19.3, 18.1, 14.4, 12.2; IR (KBr) ν: 3070, 2931, 2857, 1698, 1616,
1111, 823, 703 cm–1; HRMS (ESI, m/z): [M+H]+ calcd for C45H61O4Si,
693.4334; found, 693.4330.
Synthesis of compound 68. A solution of AD-mix-α (60.0 mg,
0.0434 mmol, 1.0 equiv), MeSO2NH2 (4.1 mg, 0.0434 mmol, 1.0
equiv) and K2OsO4·2H2O (1.6 mg, 0.00434 mmol, 0.1 equiv) in
t-BuOH and H2O (1 mL, 1 : 1, V/V) was stirred at room tempera-
ture for 10 min. 67 (30.0 mg, 0.0434 mmol, 1.0 equiv) was added
o
Synthesis of compound 66. To a solution of 65 (300 mg, 0.432
mmol, 1.0 equiv) in 3 mL dry THF was added LHMDS (0.66 mL, 1.3
M in THF, 0.864 mmol, 2.0 equiv) dropwise at –78 °C. After stirring
at the same temperature for 1 h, TMSCl (0.17 mL, 1.29 mmol, 3.0
equiv) was added and stirring was continued for another 0.5 h at
–78 °C and 1 h at room temperature. The reaction mixture was
at 0 C and stirring was continued for 12 h at the same tempera-
ture. The reaction mixture was quenched with sat. aq. Na2S2O3.
The aqueous layer was extracted with EtOAc (3×10 mL) and the
combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash chromatography (SiO2, 5 : 2 petroleum ether : EtOAc) to fur-
quenched with sat. aq. NaHCO3 and extracted with EtOAc (3×10 mL). nish compound 68 (12.0 mg, 41%) as a white foam and recovered
The combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The resulting silyl enol ether
was used directly in the next step without further purification.
To a solution of the silyl enol ether obtained above in 20 mL
67 (10.5 mg, 35%).
68: TLC (petroleum ether : EtOAc, 3 : 2 V/V): Rf = 0.48; [α]D25
1
+72.6 (c 0.93, CHCl3); H NMR (400 MHz, CDCl3) δ: 7.75—7.60 (m,
4H), 7.47—7.29 (m, 6H), 7.16—7.04 (m, 1H), 5.74 (d, J = 1.6 Hz,
DMSO and 5 mL CH2Cl2 was added Pd(OAc)2 (96.8 mg, 0.432 mmol, 1H), 5.00—4.94 (m, 1H), 4.54 (d, J = 5.2 Hz, 1H), 4.01—3.91 (m,
o
1.0 equiv) at room temperature. After stirred at 60 C for 1 h, the
reaction mixture was cooled to room temperature, diluted with
50 mL EtOAc and washed twice with 20 mL H2O. The organic layer
was washed with brine and dried over Na2SO4. Removal of the
solvent under reduced pressure afforded the crude product,
which was purified by flash chromatography (SiO2, 26 : 1
petroleum ether : EtOAc) to provide compound 66 (229 mg, 76%)
as a white foam.
1H), 3.62—3.50 (m, 1H), 2.76 (s, 1H), 2.47—2.34 (m, 1H),
2.18—2.05 (m, 1H), 1.93 (s, 3H), 1.87—1.79 (m, 1H), 1.70—1.59
(m, 4H), 1.52—1.41 (m, 5H), 1.32—1.25 (m, 4H), 1.21 (s, 3H), 1.04
(s, 9H), 0.94 (d, J = 7.0 Hz, 3H), 0.89 (s, 3H), 0.82—0.73 (m, 2H);
13C NMR (101 MHz, CDCl3) δ: 211.6, 195.5, 174.4, 147.2, 135.9,
134.84, 134.76, 130.8, 129.6, 127.60, 127.58, 123.8, 83.0, 74.5,
72.5, 57.7, 55.4, 46.6, 44.1, 38.1, 37.2, 37.0, 36.4, 34.1, 33.2, 31.7,
29.7, 27.9, 27.1, 26.4, 20.9, 19.2, 16.2, 12.3, 11.0; IR (KBr) ν: 3400,
2930, 2857, 1761, 1684, 1607, 740, 703 cm–1; HRMS (ESI, m/z):
[M+H]+ calcd for C43H57O5Si, 681.3970; found, 681.3967.
66: TLC (petroleum ether : EtOAc, 10 : 1 V/V): Rf = 0.35; [α]D25
1
+92.2 (c 0.71, CHCl3); H NMR (400 MHz, CDCl3) δ: 7.71—7.64 (m,
4H), 7.45—7.32 (m, 6H), 7.10 (dd, J = 15.2, 11.2 Hz, 1H), 6.39 (d,
J = 11.2 Hz, 1H), 6.10 (dd, J = 15.3, 8.1 Hz, 1H), 5.67 (d, J = 1.6 Hz,
1H), 4.20 (q, J = 7.1 Hz, 2H), 3.69—3.47 (m, 1H), 2.92—2.71 (m,
1H), 2.35 (t, J = 10.4 Hz, 1H), 2.10 (d, J = 4.1 Hz, 1H), 2.00 (d, J =
12.9 Hz, 1H), 1.92 (s, 3H), 1.86—1.76 (m, 1H), 1.69—1.35 (m, 8H),
1.30 (t, J = 7.2 Hz, 3H), 1.33—1.28 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H),
Synthesis of compound 69. To a solution of 68 (24.0 mg,
0.0347 mmol, 1.0 equiv) in 2.5 mL CH3CN was added 40% aq. HF
(36 μL, 0.694 mmol, 20.0 equiv) at room temperature. After
stirred at room temperature for 2 h, the reaction mixture was
quenched with sat. aq. NaHCO3 and extracted with CH2Cl2 (3×15
mL). The combined organic layers were washed with brine and
1350
www.cjc.wiley-vch.de
© 2020 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2020, 38, 1339－1352

Development of Biomimetic Synthesis of Propindilactone G
Chin. J. Chem.
dried over Na2SO4. Removal of the solvent under reduced
pressure afforded the crude product, which was purified by flash
chromatography (SiO2, 2 : 1 petroleum ether : EtOAc) to provide
compound 69 (15.0 mg, 97%) as a white solid.
Yao, M.; Zhang, X.; Xiao, W.-L.; Wang, J.-H.; Tian, P.; Sun, H.-D.; Puno,
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by chemical synthesis. J. Am. Chem. Soc. 2019, DOI: 10.1021/jacs.
9b09699.
o
69: mp: 241.3—242.5 C; TLC (EtOAc, V/V): Rf = 0.46; [α]D25
[6] (a) Goh, S. S.; Chaubet, G.; Gockel, B.; Cordonnier, M.-C. A.; Baars, H.;
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sandraceae nortriterpenoid rubriflordilactone A. Chem. Eur. J. 2017,
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1
+100.2 (c 0.77, CHCl3); H NMR (400 MHz, CDCl3) δ: 7.12 (s, 1H),
5.79 (s, 1H), 4.99 (brs, 1H), 4.53 (d, J = 5.3 Hz, 1H), 3.98 (q, J = 3.8
Hz, 1H), 3.67—3.54 (m, 1H), 2.80 (s, 1H), 2.47 (t, J = 10.8 Hz, 1H),
2.22—2.11 (m, 1H), 1.98—1.89 (m, 1H), 1.94 (s, 3H), 1.88—1.70
(m, 4H), 1.69—1.53 (m, 4H), 1.47—1.31 (m, 5H), 1.24 (s, 3H),
1.19—1.09 (m, 1H), 1.03 (dd, J = 13.2, 3.6 Hz, 1H), 0.99 (d, J = 7.0
Hz, 3H), 0.95—0.87 (m, 1H), 0.92 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ: 211.5, 195.2, 174.4, 147.2, 130.8, 123.9, 83.0, 74.5, 71.0,
57.7, 55.5, 46.6, 44.2, 37.9, 37.2, 37.0, 36.5, 34.2, 33.3, 31.4, 29.7,
27.9, 26.4, 21.0, 16.3, 12.3, 11.0; IR (KBr) ν: 3407, 2926, 2857,
1750, 1669, 1604, 1077, 736 cm–1; HRMS (ESI, m/z): [M+H]+ calcd
for C27H39O5, 443.2792; found, 443.2789.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.202000293.
Acknowledgement
Financial support was provided by the National Natural Sci-
ence Foundation of China (Nos. 21871289 and 21672245), the
Strategic Priority Research Program of the Chinese Academy of
Sciences (No. XDB20000000), CAS Key Laboratory of Synthetic
Chemistry of Natural Substances, and Shanghai Institute of Or-
ganic Chemistry.
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[11] Wang, Y.; Chen, B.; He, X.; Gui, J. Bioinspired synthesis of nortriter-
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Manuscript received: May 30, 2020
Manuscript revised: June 23, 2020
Manuscript accepted: June 24, 2020
Accepted manuscript online: June 26, 2020
Version of record online: XXXX, 2020
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