A concise and straightforward approach to total synthesis of (+)-Strictifolione and formal synthesis of Cryptofolione via a unified strategy

Article abstract of DOI:10.1080/00397911.2019.1580373

We describe a concise and straightforward approach to the total syntheses of (+)-Strictifolione and Cryptofolione in the longest linear sequences of four steps and six steps from 3-phenyl propanal and trans-cinnamaldehyde, respectively. The route utilized a titanium tetraisopropoxide/(R)-[1,1'-binaphthalene]-2,2'-diol catalyzed Mukaiyama aldol reaction, indium(0)-promoted Barbier reaction, and olefin cross-metathesis as the key reactions.

Full text of DOI:10.1080/00397911.2019.1580373

Synthetic Communications
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A concise and straightforward approach to total
synthesis of (+)-Strictifolione and formal synthesis
of Cryptofolione via a unified strategy
Xiaotong Li, Gaopeng Wang, Zhibin Zhang, Na Wu, Qianqian Yang,
Shuangping Huang & Xiaoji Wang
To cite this article: Xiaotong Li, Gaopeng Wang, Zhibin Zhang, Na Wu, Qianqian Yang,
Shuangping Huang & Xiaoji Wang (2019): A concise and straightforward approach to total
synthesis of (+)-Strictifolione and formal synthesis of Cryptofolione via a unified strategy, Synthetic
Communications, DOI: 10.1080/00397911.2019.1580373
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https://doi.org/10.1080/00397911.2019.1580373
A concise and straightforward approach to total synthesis
of (þ)-Strictifolione and formal synthesis of Cryptofolione
via a unified strategy
a
a
a
c
b
ꢀ
ꢀ
ꢀ
Xiaotong Li , Gaopeng Wang , Zhibin Zhang , Na Wu , Qianqian Yang ,
Shuangping Huanga, and Xiaoji Wangb
b
aSchool of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, China; School of
c
Life Science, Jiangxi Science and Technology Normal University, Nanchang, China; School of Chemistry
and Pharmaceutical Sciences, Key Laboratory for the Chemistry and Molecular Engineering of Medicinal
Resources, Guangxi Normal University, Guilin, China
ABSTRACT
ARTICLE HISTORY
Received 10 December 2018
We describe a concise and straightforward approach to the total syn-
theses of (þ)-Strictifolione and Cryptofolione in the longest linear
sequences of four steps and six steps from 3-phenyl propanal and
trans-cinnamaldehyde, respectively. The route utilized a titanium tet-
raisopropoxide/(R)-[1,1’-binaphthalene]-2,2’-diol catalyzed Mukaiyama
aldol reaction, indium(0)-promoted Barbier reaction, and olefin cross-
metathesis as the key reactions.
KEYWORDS
Strictifolione; Cryptofolione;
total synthesis; Barbier
reaction; olefin
cross-metathesis
GRAPHICAL ABSTRACT
Introduction
The potential Michael acceptor, a,b-unsaturated d-lactone (also named 5,6-dihydro-
a-pyrone) is found in many natural products possessing useful pharmacological proper-
ties, such as anti-inflammatory, antiproliferative and anticancer activity.[1] The related
natural products include Strictifolione, Cryptofolione, Lactone monoalcohol,[2]
Kurzilactone,[3] Passifloricin A,[4] Tarchonanthuslactone[5] (Figure 1). (þ)-Strictifolione
CONTACT Shuangping Huang
185544590@qq.com
School of Pharmacy, Jiangxi Science and Technology Normal
University, Nanchang, China.
ꢀ
These three authors contributed equally to this work.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher's website
ß 2019 Taylor & Francis Group, LLC

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X. LI ET AL.
Figure 1. Example of natural products possessing a,b-unsaturated d-lactone.
was isolated by Aimi et al. from the stem bark of Cryptocaria strictifolia which is indi-
genous to the Indonesian tropical rainforest.[6] The relative stereochemistry of
Strictifolione’s structure was elucidated based on the spectroscopic method and the
absolute configuration of the three chiral centers was established by Aimi’s group in
2002 through its first total synthesis.[7a] Cryptofolione was isolated from Cryptocarya
latifolia, C. myrtifolia and C. alba[8]and its structure was determined through an asym-
metric total synthesis in 2005.[9a] Cryptofolione showed interesting bioactivity, such as
reducing the number of Trypanosoma cruzi trypanosomastigotes by 77% at 250 lg/mL,
demonstrating cytotoxicity in both macrophages and T. cruzi amastigotes, and display-
ing inhibitory effects on the promastigote form of Leishmania species
amongst others.[10]
As two typical members of this class of natural products containing an
a,b-unsaturated d-lactone moiety, syn- or anti-1,3-diol or 1,3,5-triol and a lipophilic
subunit, (þ)-Strictifolione and Cryptofolione attracted considerable interests in their
total syntheses. Over the past decade, many efforts have been made towards the total
syntheses of Strictifolione[7] and Cryptofolione[9]. Strictifolione has almost the same
structure as Cryptofolione except for the saturated bond at C70-C80; both have a 1,3-
anti diol unit connecting the C-6 substituent of the a,b-unsaturated d-lactone moiety
with a double bond. Most of the published synthetic routes for Strictifolione and
Cryptofolione involved scission of the unsaturated bond at C10-C20 utilizing a conver-
gent strategy. For the construction of stereogenic centers, many and varied protocols
were employed, such as chiral pool syntheses,[7e] enantioselective allyltitanation,[7b]
enzymatic reduction,[7j] asymmetric acetate aldol reaction[9f] and so on. Curiously, there
is no synthetic report of these two molecules using a unified synthetic strategy. The
shortest approach was explored by Hanson, who recently applied a three-pot process to
accomplish a modular approach toward (þ)-Strictifolione and the related natural pro-
ducts.[7k] As a part of our research aimed at developing a concise synthesis of natural
products possessing an a,b-unsaturated d-lactone,[11] we decided to devise a unified,
concise and efficient route to (þ)-Strictifolione and Cryptofolione. It appears that the

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Scheme 1. Retrosynthetic analysis of Strictifolione and Cryptofolione.
Scheme 2. Synthetic route of intermediate 1-S. Reagents and conditions: (a) TiCl4, DIPEA, CH2Cl2,
ꢁ78 ꢂC, 84% (d.r. ¼ 2.5:1); (b) DIBAL-H, CH2Cl2, ꢁ78 ꢂC.
key to a shorter total synthesis is fewer synthetic steps towards the fragments.
Therefore, here we describe a concise and practical total synthesis of (þ)-Strictifolione
and Cryptofolione through rapid preparation of two fragments.
Results and discussion
Our retrosynthetic analysis is shown in Scheme 1. (þ)-Strictifolione and Cryptofolione
were disconnected into two similar fragments, 1-S/1-C and 2, via a cross-metathesis
reaction. For the fragment 1-S/1-C, the 1,3-anti-diol was assumed to be obtained via an
In (0) promoted Barbier allylation from aldehyde 3-S/3-C,[12] which would be readily
prepared from aldehyde 5-S/5-C using a Crimmins modified Evans aldol reaction.[13]
Another known building block 2[7f,h,j], was devised to be readily prepared from
d-hydroxyl b-keto ester 4, in which the chiral hydroxyl might be achieved employing an
asymmetric Muakiyama aldol reaction.[9e,14]
As shown in Scheme 2, we began our synthesis of (þ)-Strictifolione with the prepar-
ation of fragment 1-S, using commercially available 3-phenyl propanol 5-S. 3-phenyl
propanol was subjected to a Crimmins modified Evans aldol reaction when treated with
compound 7 in the presence of TiCl4 and DIPEA to give 8 in a yield of 84% (dr =
2.5:1). Alcohol 8 then needed to be reduced to b-hydroxyl aldehyde 3-S. The presumed
instability of 3-S was evident, so the crude 3-S was immediately subjected to the subse-
quent Barbier reaction.

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X. LI ET AL.
Table 1. Optimization of Barbier reaction.
Entry
Solvent
H2O
THF/H2O (1:1)
THF/H2O (10:1)
THF
Time (h)
Anti: syna
Yield (%)b
1
2
3
4
72
72
72
72
1:1
6:1
3:1
–
60
55
50
Trace
adr value was determined by NMR spectra.
bCombined yield based on isolation by column chromatography from compound 8.
Scheme 3. Synthesis of intermediate 2. Reagents and conditions: (a) Ti(OiPr)4, (R)-BINOL, THF, -78 ꢂC,
83%, 96% ee; (b) NaBH4, MeOH, 0 ꢂC, 85%; (c) PPTS, benzene, reflux, 95%; (d) MsCl, Et3N, CH2Cl2,
0 ꢂC, 80%; (e) PPTS, toluene, reflux, 90%.
Following Li’s protocol,[12a] we first attempted the allylation in water, however,
we only obtained the 1,3-diol 1-S in 60% after 72 h with no diastereoselectivity (entry 1
in Table 1). This disappointing ratio impelled us to optimize this transformation.
As shown in Table 1, by simply adjusting the ratio of solvent (water to THF), we
found the desired 1-S was obtained in 55% over two steps with the dr ratio of 6:1
(anti: syn) when using THF/H2O (1:1) as the solvent mixture (entry 2). However,
increasing the ratio of THF only resulted in poor diastereoselectivity (entry 3) and yield
(entry 4).
Synthesis of fragment 2 started from acrylaldehyde 6. Retrosynthetically, the chiral
hydroxyl was installed through Mukaiyama aldol reaction. Thus, the addition of acrylal-
dehyde 6 to Chan’s diene in the presence of Ti(OiPr)4/(R)-BINOL and molecular sieves
ꢂ
in THF at ꢁ78 C afforded d-hydroxyl b-keto ester 4 smoothly in 83% yield with 96%
ee value (Scheme 3). Considering the requirement for a b-hydroxyl, the intermediate 4
was then subjected to reduction with NaBH4 to furnish diol 10 in 85% without deter-
mination of dr value. Cyclization of 10 with PPTS in refluxing benzene smoothly
afforded lactone 11 in a yield of 95%. The compound 11 was subsequently treated with
ꢂ
MsCl and triethylamine in DCM at 0 C to give fragment 2 via a one-pot process in
80% yield. At higher temperature, the desired fragment 2 was able to be prepared from
10 directly.[15] Thus, lactone 2 was obtained from diol 10 in 90% by refluxing
in toluene.
With fragment 1-S and 2 in hand, we conducted the cross-metathesis coupling of
two fragments. Following the known procedure,[7j] the olefin cross-metathesis reaction

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Scheme 4. Synthesis of (þ)-Strictifolione. Reagents and conditions: (a) Grubbs’ 2nd CH2Cl2,
50 ꢂC, 80%.
Scheme 5. Synthetic route of intermediate 1-C. Reagents and conditions: (a) see ref. [9f]; (b) DIBAL-H,
CH2Cl2; (c) In powder, 3-bromoprop-1-ene, THF: H2O = 1:1, 75% (d.r. = 4:1) over two steps;
ꢂ
ꢂ
(d) p-TsOH, CH2Cl2, 2,2- dimethoxypropane, 0 C, 5.5 h; (e) 4N HCl, MeCN, 0 C, 93%.
of 1-S and 2 in the presence of Grubbs’ second generation catalyst furnished
(þ)-Strictifolione (Scheme 4).
The same synthetic sequence described above was applied to Cryptofolione by replac-
ing 3-phenyl propanol with trans-cinnamaldehyde. As depicted in Scheme 5, Crimmins
modified Evans aldol reaction of cinnamaldehyde and compound 7 easily gave alcohol
12 following Yadav’s procedure.[9f] The prepared 12 was subjected to a DIBAL-H
reduction to prepare aldehyde 3-C, and then, without purification, the crude of alde-
hyde 3-C was subjected to the In (0)-promoted Barbier reaction in THF/H2O (10:1) to
afford anti-diol 1-C in 75% yield over two steps with moderate diastereoselectivity (dr =
4:1). 1-C was too difficult to be separated efficiently from its diastereoisomer. However,
when they were subjected to protection with 2,2-dimethoxypropane, 1-C would be
obtained in 20% accompanied by the protected diol mixtures 130. 130 were then treated
with 4 N HCl gave the free diols, which then performed the above kinetic resolution.
After three kinetic resolutions, we could obtain about one half of 1-C (48%) from the
mixture of the diastereoisomers.
An attempt to conduct the cross-metathesis reaction of compound 1-C with fragment 2
failed, therefore, the hydroxyls of 1-C were subsequently protected with 2,2-dimethoxypropane

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X. LI ET AL.
Scheme 6. Formal synthesis of Cryptofolione. Reagents and conditions: (a) p-TsOH, CH2Cl2, 2,2-dime-
thoxy-propane, 0 ꢂC, overnight, 83%.
to give the intermediate 13, previously reported as a fragment, which was coupled with lactone
2 to easily furnish Cryptofolione via a CM reaction (Scheme 6).[9c] The physical and spectral
data (1H, 13C) of compound 13 from our lab were in agreement with those reported in
the literature.
Conclusion
Thus, we have successfully achieved the total synthesis of (þ)-Strictifolione and formal
synthesis of Cryptofolione via a unified strategy. To the best of our knowledge, the pre-
sent synthetic route represents the shortest route to these two molecules. We separated
the target into two fragments, and the linear route was only 4 steps and 6 steps for
(þ)-Strictifolione and Cryptofolione respectively. This synthetic approach provides an
alternative route to these natural products of similar structure.
Experimental
All air and water sensitive reactions were carried out under a nitrogen atmosphere with
dry solvents under anhydrous conditions unless otherwise noted. All the chemicals were
purchased commercially and used without further purification. Anhydrous THF and
was distilled from sodium-benzophenone, toluene was distilled from sodium, and
dichloromethane was distilled from calcium hydride. Reactions were monitored by thin-
layer chromatography (TLC) carried out on 0.25 mm silica gel plates (60F-254) that
were analyzed by staining with KMnO4 (200 mL H2O of 1.5 g KMnO4, 10 g K2CO3
and 1.25 mL of 10% aqueous NaOH), fluorescence upon 254 nm irradiation or by stain-
ing with anisaldehyde (450 mL of 95% EtOH, 25 mL of conc.H2SO4, 15 mL of acetic
acid, and 25 mL of anisaldehyde). Silica gel (60, particle size 0.040–0.063 mm) was used
for flash chromatography. IR spectra were obtained using FT-IR Spectrometer. NMR
spectra were recorded on either a 300 (1H: 300 MHz, 13C: 75 MHz), 400 (1H: 400 MHz,
13C: 100 MHz), or 500 (1H: 500 MHz, 13C: 125 MHz). The following abbreviations were
used to explain the multiplicities: s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet;
b: broad. High-resolution mass spectra were obtained from a MALDI-TOF mass
spectrometer.
(3S,5S)-1-phenyloct-7-ene-3,5-diol (1-S)
To a stirred mixture of 8 (0.2 g, 0.52 mmol) in THF (5 mL) was added DIBAL-H
ꢂ
ꢂ
(1.5 mmol, 1.5 mL, 1 M in toluene) dropwise at ꢁ78 C. After stirring at ꢁ78 C for
0.5 hour, the reaction was quenched by addition of a saturated potassium sodium tar-
trate aqueous solution (20 mL), and the aqueous phase was extracted with ethyl acetate

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SYNTHETIC COMMUNICATIONSV
7
(50 mL ꢃ 3). The combined organic extracts were washed with brine, dried over
Na2SO4, filtered and concentrated and gave a yellow oil as the crude product 3-S.
Without further purification, the crude 3-S was used in the next reaction.
To a stirred solution of crude 3-S in THF/H2O (vol/vol = 1:1, 5 mL) was added
Indium powder (72 mg, 0.62 mmol) and allyl bromide (70 lL, 0.75 mmol). The result-
ing mixture was stirred at room temperature till the aldehyde 3-S was consumed. Then
the reaction was diluted by addition of ethyl acetate (5 mL), and the aqueous phase was
extracted with ethyl acetate (5 mL ꢃ 2). The combined organic extracts were washed
with brine, dried over Na2SO4, filtered and concentrated. Silica gel flash column chro-
matography (hexanes/ethyl acetate = 5:1) of the residue gave a yellow oil (0.063 g, 0.29
mmol, 55% (d.r. = 6:1)) as the product 1-S.
1
[a]2D5 = þ4.23 (c = 1.0, CHCl3); H NMR (300 MHz, CDCl3) d 7.34 – 7.14 (m, 5H),
5.88 – 5.72 (m, 1H), 5.16 (d, J = 1.0 Hz, 1H), 5.14 – 5.09 (m, 1H), 4.06 – 3.92 (m, 2H),
2.73 (dddd, J = 34.3, 13.7, 9.6, 6.3 Hz, 2H), 2.31 – 2.22 (m, 2H), 1.92 – 1.72 (m, 2H),
1.69 – 1.63 (m, 2H); 13C NMR (75 MHz, CDCl3) d 142.09, 134.61, 128.55, 128.52,
125.99, 118.54, 68.93, 68.37, 42.12, 41.99, 39.15, 32.32; IR: 3347, 1641, 1496, 1454;
HRMS: m/z calcd. for C14H20NaO2 [M þ Na]þ 243.1356, found 243.1356.
1
Full experimental detail and H and 13C NMR spectra, HPLC traces can be found via
the Supplementary Content section of this article’s Web page.
Funding
We thank the National Science Foundation of China [21062088, 21562020, and 21462004], the
Science and Technology Plan Project of Jiangxi Province [No. 20151BBG70028, 20142BBE50006]
and State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources
[CMEMR2014-A04] for the funding support.
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