Stereoselective Construction of the Methylcyclopentane Core of Peditithins B-H with Five Continuous Stereocenters

Article abstract of DOI:10.1021/acs.orglett.0c03615

A stereoselective construction of the methylcyclopentane core (3) of jatrophane diterpenoids peditithins B-H was achieved in 14 steps from commercially available d-(+)-ribono-1,4-lactone (9). The linear 5-ene-heptanal derived from 9 was cyclized to the five-membered ring by an intramolecular carbonyl ene reaction, and five continuous stereocenters on 3 were stereoselectively introduced via a successive substrate-controlled manner, involving diastereoselective 1,4-addition, MoOPH-induced hydroxylation, and stereospecific epoxidation.

Full text of DOI:10.1021/acs.orglett.0c03615

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Letter
Stereoselective Construction of the Methylcyclopentane Core of
Peditithins B−H with Five Continuous Stereocenters
Fu-Qiang Ni, Shu-Qi Wu, Wei Li, Qingjiang Li,* and Sheng Yin*
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ABSTRACT: A stereoselective construction of the methylcyclopentane core (3) of jatrophane diterpenoids peditithins B−H was
achieved in 14 steps from commercially available D-(+)-ribono-1,4-lactone (9). The linear 5-ene-heptanal derived from 9 was
cyclized to the five-membered ring by an intramolecular carbonyl ene reaction, and five continuous stereocenters on 3 were
stereoselectively introduced via a successive substrate-controlled manner, involving diastereoselective 1,4-addition, MoOPH-induced
hydroxylation, and stereospecific epoxidation.
In our continuing efforts toward discovering structurally
iterpenoids featuring a highly functionalized methylcy-
Dclopentane core (ring A) are mainly found in plants of intriguing and biologically significant metabolites from
Euphorbiaceae species,9 a series of new jatrophane diterpe-
the family Euphorbiaceae. So far, more than 900 of such
noids, peditithins B−H, were isolated from Pedilanthus
tithymaloides.10 These peditithins and their derivatives turned
out to be the most potent natural P-glycoprotein (Pgp)
inhibitors reported so far, exhibiting pronounced multidrug
resistance (MDR) reversal ability on adiamycin resistant
cancer cell lines in vitro and in vivo.10 Structurally, peditithins
B−H represent a group of complex jatrophane diterpenoids
(trans 5/12 ring system) containing a fully functionalized
methylcyclopentane core (ring A). The five continuous
stereocenters on ring A were considered as the essential
elements for the activity of this class. Thus, efficient
construction of this common motif not only constitutes a
synthetic pathway to a specific peditithin but also provides
access to a group of medicinally important jatrophane
analogues in future.
Euphorbiaceae diterpenoids, incorporating more than 10
scaffolds (Figure 1), have been isolated.1 Their fascinating
structures and significant biological activities have made this
class a promising feedstock in drug discovery, as exemplified by
picato2 (ingenane-type), resiniferatoxin3 (daphnane-type), and
prostratin4 (tigliane-type) in cancer or HIV therapy.
Spurred by their impressive structures and bioactivities, the
synthetic endeavors toward these Euphorbiaceae diterpenoids
have continued unabated over the past several decades, leading
to the elaborate chemical syntheses of several natural products
or their partial motifs.5 In these syntheses, the inaugural
construction of the common methylcyclopentane segment is
quite challenging, often involving lengthy and tedious synthetic
steps, especially when the five-membered ring was highly
functionalized. For instance, Rinner and co-workers reported
the synthesis of two diastereomeric cyclopentane segments via
a ring-closing metathesis (RCM) reaction of functionalized
1,6-diene using a precious Grubbs second-generation catalyst.6
Hiersemann et al. constructed the nonnatural 17-norjatro-
phane diterpene 3-propionyl-15-acetyl-17-norcharaciol
through the thermal intramolecular carbonyl ene reaction of
the activated enone substrate.7 Mulzer et al. synthesized the
cyclopentanyl vinyl triflate in a total yield of 1.8% in 18 steps
from a furfuryl alcohol.8 However, these efforts achieved the
synthesis of methylcyclopentane containing only three or four
stereocenters. So far, the synthesis involving five continuous
stereocenters has never been reported.
In this study, we designed a (1S,2S,3R,4S,5S)-3-methyl-1-
vinyl-6-oxabicyclo[3.1.0]hexane-2,4-diol derivative (3) as the
target, as it could serve as an advanced intermediate that
condenses with a series of alkenyl halides (2) by transition-
metal-mediated epoxide-opening reaction and subsequent
Received: October 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03615
© XXXX American Chemical Society
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of C2, and partial reduction of C1 to afford 7. Butenolide 8
would be obtained by deoxydehydration of the commercially
available D-(+)-ribono-1,4-lactone 9.
The synthesis of key linear intermediate 5 for subsequent
ring closure reaction is shown in Scheme 2. According to the
Scheme 2. Preparation of 5-Ene-heptanal 5
Figure 1. Some representative skeletons of methylcyclopentane-
containing Euphorbiaceae diterpenoids and the structures of
peditithins.
RCM reaction to generate the 5/12 ring skeleton of diverse
peditithins. As exemplified by the retrosynthetic analysis of
peditithin H (Scheme 1), 3 was envisaged to be prepared by
Scheme 1. Retrosynthetic Analysis of Peditithin H (1)
standard conditions reported by Toste,11 the methyltrioxo-
rhenium (MTO)-catalyzed deoxydehydration of commercially
available D-(+)-ribono-1,4-lactone 9 led to the desired
butenolide 10 on a gram scale in 70% yield. Protection of
the primary alcohol by using TBDPSCl/imidazole afforded 8
in 90% yield. Conjugate addition of Gilman reagent12
(CH3)2CuLi to α,β-unsaturated lactone 8 gave γ-lactone 11
as a single stereoisomer in 92% yield. Substrate-directed α-
hydroxylation of 11 with classic Davis reagent13 under various
base conditions led to 12 but in a poor yield and poor
stereoselectivity. Gratifyingly, Vedejs reagent,14 oxodiperox-
ymolybdenum (pyridine) (hexamethylphosphoric triamide)
(MoOPH), was proven to be effective for this transformation.
It is worth mentioning that the base played an important role
in the control of both yield and stereoselectivity in this
reaction, probably due to their different counterion effects.15
Among different bases, lithium hexamethyldisilazide
(LiHMDS) turned out to be the best, under which the desired
product 12a was smoothly afforded in 75% yield with a
diastereomeric ratio of 5:1. The resulting mixture could be
separated by column chromatography. DIBAL-H reduction of
lactone 12 gave hemiacetal 7 as inseparable diastereomers,
which further underwent an in situ Wittig olefination16 to
afford 6 in 72% yield as a 2.7:1 mixture of Z and E isomers.
Sequential protection of the allyl alcohol and C4-OH in 6 by
using TBSCl/imidazole and BzCl/Py, respectively, furnished
fully protected 14 in 83% overall yield. Selective removal of the
TBDPS group in 14 followed by Dess-Martin periodinane
C4-OH-induced stereospecific epoxidation of the diene
intermediate derived from homoallyl alcohol 4. The cyclo-
pentane core of 4 could be established by intramolecular
carbonyl ene reaction of the linear 5-ene-heptanal 5, which is
readily accessible from 6 through a selective protection and
oxidation sequence. The double bond on 6 could be formed by
an in situ Wittig olefination of hemiacetal 7. To introduce in a
stereocontrolled manner the substituents on C2 and C3 in 7,
butenolide 8 was used as the chiral template, which
successively underwent conjugate addition with lithium
dimethylcuprate, stereoselective MoOPH-induced oxidation
B
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(DMP) oxidation17 finally yielded linear 5-ene-heptanal 5 in
64% overall yield.
With enal 5 in hand, the stage is now set for the crucial
intramolecular carbonyl ene cyclization.7,18 To optimize the
reaction conditions, a variety of reaction parameters such as
the additive, solvent, and temperature were examined, and
some of the representative results are listed in Table 1. With
Thus, we realized that 1,5-epoxide 3 was the more suitable
building block, which could introduce the chiralities of both
C1 and C5 simultaniously in later synthesis of peditithins
(Scheme 1). As shown in Scheme 4, mesylation of 4 followed
Scheme 4. Synthesis of Epoxide 3 from 4
Table 1. Screening for Intramolecular Carbonyl Ene
a
Reaction of Unactivated 5-Ene-heptanal 5
b
entry
Lewis acid
solvent
temperature
yield
1
2
3
4
5
6
BF3·Et2O
BF3·Et2O
Et2AlCl
TMSOTf
ZnCl2
Et2AlCl
−
Et2O
0 °C to rt
−78 °C
0 °C to rt
0 °C
100 °C
100 °C
180−190 °C
NR
15%
NR
messy
messy
messy
47%
DCM
DCM
DCM
toluene
toluene
toluene
by heating with DBU in DMF generated diene 18 in 68% yield.
Removal of the benzoyl group in 18 employing NaOH in
CH3OH provided cyclopentanol 19 in quantitative yield,
which upon hydroxyl-induced chemoselective and stereo-
specific epoxidation with VO(acac)2 and tert-butyl hydro-
peroxide gave the desired methylcyclopentane core 3 with five
continuous stereocenters in 85% yield.20
Theoretically, the substrate-controlled manner from a chiral
starting material will warrant the correctness of all of the
chiralities in 3. However, to avoid the misassignment due to
some unexpected reaction pathways, we validate the structure
of 3 by two-dimensional NMR analysis combined with the
computational method. As shown in Figure 2, with the
c
7
a
General reaction conditions: 5 (0.1 mmol) in solvent (5 mL), Lewis
acid (1.0 equiv), under Ar. Isolated yield of 4. A sealed tube was
used.
b
c
Lewis acid BF3·Et2O as the promoter, no reaction occurred in
Et2O, while in dichloromethane, the desired homoallyl alcohol
4 was obtained in 15% yield as diastereoisomers. Other Lewis
acids such as Et2AlCl, TMSOTf, and ZnCl2 were found to be
ineffective for the cyclization. To our delight, 4 could be
directly generated at a higher temperature (180−190 °C) in
toluene (47% yield), without the addition of Lewis acid.
After the successful construction of the methylcyclopentane
ring, we initially designed a C1-OH intermediate 16 as the
alternative buiding block for 3 (Scheme 3). The C1-OH of 16
Scheme 3. Attempt to Introduce a Hydroxyl Group at the
C1 Position of Homoallyl Alcohol 4
Figure 2. Key NOE correlations of 3 and its two possible epoxy
isomers, 3a and 3b.
untouched stereochemistry of C-3 in hand, the strong NOE
correlations of H-2/Me-3, H-3/TBS, and H-4/H-3 suggested
that C2, C3, and C4 adopted 2S, 3R, and 4S configurations,
respectively. As the NOE signals regarding the epoxy area are
not helpful, two isomers, 3a and 3b, with different epoxy
orientations were predicted by gauge-independent atomic
1
orbital (GIAO) calculation of its H and 13C NMR chemical
shifts (see page S18 of the Supporting Information). The
experimental and calculated data were compared by the
improved probability DP4+ method,21 which showed a DP4+
probability score at 100% for β-oriented isomer 3a, indicating
that the absolute configuration of 3 was unambiguously
assigned as 1S,2S,3R,4S,5S.
In summary, the methylcyclopentane core containing five
consecutive stereocenters present in jatrophane diterpenoids
was first constructed in 14 steps via a facile and stereoselective
approach. This method may also be applicable to the
construction of a general class of a methylcyclopentane core
was supposed to be stereoselectively introduced by oxidation
of ketone 15. However, attempts to oxidize 4 to 15 under
various oxidation conditions were unsuccessful (see page S17
of the Supporting Information). Instead, a benzoyl-migrated
product 17 was isolated as the sole product in 70% yield under
Swern reaction conditions,19 which seemed to be formed from
the corresponding enol intermediate via ester exchange and
further oxidation.
C
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simple raw materials. The densely functionalized methylcyclo-
pentane core obtained in this study may not only serve as a
versatile building block for the synthesis of a specific peditithin
but also provide access to a group of medicinally important
jatrophane analogues in the future. These investigations are
continuing.
ASSOCIATED CONTENT
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■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03615.
Detailed experimental procedures, spectroscopic charac-
1
terization of all reported compounds, and H and 13C
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Qingjiang Li − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China;
orcid.org/0000-0001-5535-6993; Email: liqingj3@
mail.sysu.edu.cn
Sheng Yin − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China;
orcid.org/0000-0002-5678-6634; Email: yinsh2@
mail.sysu.edu.cn
Authors
Fu-Qiang Ni − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China
Shu-Qi Wu − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China
Wei Li − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China
(6) Lentsch, C.; Rinner, U. General Synthesis of Highly Function-
alized Cyclopentane Segments for the Preparation of Jatrophane
Diterpenes. Org. Lett. 2009, 11, 5326.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03615
̈
(7) (a) Helmboldt, H.; Kohler, D.; Hiersemann, M. Synthesis of the
Notes
Norjatrophane Diterpene (−)-15-Acetyl-3-propionyl-17-norcharaciol.
Org. Lett. 2006, 8, 1573. (b) Helmboldt, H.; Rehbein, J.; Hiersemann,
M. Enantioselective Synthesis of the C-14 to C-5 Cyclopentane
Segment of Jatrophane Diterpenes. Tetrahedron Lett. 2004, 45, 289.
(c) Schnabel, C.; Hiersemann, M. Total Synthesis of Jatrophane
Diterpenes from Euphorbia characias. Org. Lett. 2009, 11, 2555.
(d) Helmboldt, H.; Hiersemann, M. Synthetic Studies toward
Jatrophane Diterpenes from Euphorbia characias. Enantioselective
Synthesis of (−)-15-O-Acetyl-3-O-propionyl-17-norcharaciol. J. Org.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (81722042 and 81973195), the
Guangdong Basic and Applied Basic Research Foundation
(2019A1515011322), the Fundamental Research Funds for
the Central Universities (19ykpy124 and 20ykjc04), and the
Key-Area Research and Development Program of Guangdong
Province (2020B1111110003).
Chem. 2009, 74, 1698. (e) Schnabel, C.; Sterz, K.; Mu
Rehbein, J.; Wiese, M.; Hiersemann, M. Total Synthesis of Natural
and Non-Natural Δ5,6 12,13-Jatrophane Diterpenes and Their
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Δ
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