A Concise Total Synthesis of (?)-Berkelic Acid

Article abstract of DOI:10.1002/anie.202014660

Reported here is a concise total synthesis of (?)-berkelic acid in eight linear steps. This synthesis features a Catellani reaction/oxa-Michael cascade for the construction of the isochroman scaffold, a one-pot deprotection/spiroacetalization operation for the formation of the tetracyclic core structure, and a late-stage Ni-catalyzed reductive coupling for the introduction of the lateral chain. Notably, four stereocenters are established from a single existing chiral center with excellent stereocontrol during the deprotection/spiroacetalization process. Stereocontrol of the intriguing deprotection/spiroacetalization process is supported by DFT calculations.

Full text of DOI:10.1002/anie.202014660

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Accepted Article
Title: A Concise Total Synthesis of (–)-Berkelic Acid
Authors: Qianghui Zhou, Hong-Gang Cheng, Zhenjie Yang, Ruiming
Chen, Liming Cao, Qiang Wei, Wen-Yan Tong, Qingqing
Wang, Chenggui Wu, and Shuanglin Qu
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A Concise Total Synthesis of (–)-Berkelic Acid
Hong-Gang Cheng1†, Zhenjie Yang1†, Ruiming Chen1, Liming Cao1, Wen-Yan Tong,3 Qiang Wei1,
Qingqing Wang1, Chenggui Wu1, Shuanglin Qu*3 and Qianghui Zhou*1,2
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
Abstract: Herein, we report a concise total synthesis of (–)-
berkelic acid in eight linear steps. This synthesis features a
Catellani reaction/oxa-Michael cascade for the construction of the
isochroman scaffold, a one-pot deprotection/spiroacetalization
operation for the formation of tetracyclic core structure, and a late-
stage Ni-catalyzed reductive coupling for the introduction of the
lateral chain. Notably, four stereocenters are established from a
single existing chiral center with excellent stereocontrol during the
deprotection/spiroacetalization process. Stereocontrol of the
intriguing deprotection/spiroacetalization process is supported by
DFT calculations.
(–)-Berkelic acid (1, Figure 1A) was isolated in 2006 by Stierle[1]
and co-workers from an extremophilic Penicillium species
collected from the Berkeley Pit Lake in Butte, Montana (USA).
This compound was reported to display selectivity against the
human ovarian cancer cell line OVCAR-3 (GI50 91 nm), as well as
Figure 1. The structure of (–)-berkelic acid and planned synthetic tools for
(–)-berkelic acid synthesis.
a moderate inhibitory activity against the matrix metalloproteinase
MMP-3 (1.87 μM) and the cysteine protease caspase-1 (98 μM).
The structure of (–)-berkelic acid features a unique tetracyclic
stereochemistry of C22. In 2010, the Fürstner group also
isochroman/chroman spiroketal structure, a pentasubstituted
accomplished the total synthesis of (–)-berkelic acid, using a
phenyl ring with a free hydroxyl group and six stereogenic centers,
deprotection/Michael addition/spiroacetali-zation cascade to
including one quaternary carbon center. Owing to the distinctive
construct the tetracyclic core.[2b] In 2012, Fañanás, Rodríguez and
molecular architecture, promising biological activities[8] as well as
co-workers developed a scalable route involving a Ag-catalyzed
the limited natural accessibility,[1] (–)-berkelic acid has attracted
double cycloisomerizations/formal [4+2]-cycloaddition sequence
substantial attention from the synthetic community.[2-7]
to access (–)-berkelic acid. However, the diastereoselectivity of
In 2008, Fürstner and co-workers completed the synthesis of
this route was only moderate.[5] Aside from these total synthesis
the methyl ester variant of (+)-berkelic acid, and revised the
works, several other formal syntheses of (–)-berkelic acid have
assignment of the relative stereochemistry at C18 and C19.[2a]
also been reported by the groups of Pettus[6] and Brimble[7]. While
Soon after, Snider[3b] and co-workers reported the first total
these studies constitute great progress, there is still room for
synthesis of (–)-berkelic acid, featuring an oxa-Pictet–Spengler
improving the synthetic efficiency, for example, higher
reaction for the construction of the tetracyclic core. In the same
diastereoselectivity control[3b,5] and finding more efficient methods
year, a bio-inspired approach was developed by De Brabander
to install the lateral chain[2-5]
.
and
co-workers,[4]
using
a
Ag-catalyzed
cascade
Recently, nickel-catalyzed reductive coupling has become a
versatile strategy in organic synthesis for forging new carbon-
carbon bonds.[9] For example, in 2012, the Weix group[9f] reported
the direct synthesis of functionalized dialkyl ketones via a nickel-
catalyzed reductive coupling of carboxylic acid chlorides with alkyl
iodides (Figure 1B). We imagined this may be an ideal method for
the lage-stage installation of the lateral chain of (–)-berkelic acid.
In 2018, our group developed an efficient three-component one-
pot procedure for the assembly of isochroman scaffolds,[10] which
is enabled by a Catellani reaction[11] followed by an oxa-Michael
addition. Readily available aryl iodides, epoxides and electron-
poor olefins are utilized as the reactants (Figure 1C). As such, we
envisioned this method would enable a highly convergent strategy
for the construction of the highly functionalized isochroman core
structure of berkelic acid. Inspired by these two synthetic
methodologies, we herein report a concise total synthesis of (–)-
berkelic acid, featuring the formation of the key isochroman
scaffold through the Catellani reaction/oxa-Michael cascade, the
dearomatization/cycloisomerization/cycloaddition
sequence as the key step. Both of these reports confirmed the
structure reassignments made by the Fürstner group, establishing
the absolute configuration of (–)-berkelic acid, including the
[*]
Prof. Dr. H.-G. Cheng, Z. Yang, R. Chen, L. Cao, Q. Wei, Q. Wang,
C. Wu, Prof. Dr. Q. Zhou
Sauvage Center for Molecular Sciences, Engineering Research
Center of Organosilicon Compounds & Materials (Ministry of
Education), College of Chemistry and Molecular Sciences, Wuhan
University, Wuhan, 430072 (China), E-mail: qhzhou@whu.edu.cn
Prof. Dr. Q. Zhou
The Institute for Advanced Studies, Wuhan University, Wuhan,
430072 (China)
W.-Y. Tong, Prof. Dr. S. Qu
College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China. E-mail: squ@hnu.edu.cn
These authors contributed equally to this work.
Supplementary information for this article is given via a link at the end
of the document.
[†]
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10.1002/anie.202014660
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construction of tetracyclic core structure via
deprotection/spiroacetalization operation, and introduction of the
lateral chain by a late-stage Ni-catalyzed reductive coupling.
a
one-pot
the desired racemic enone 9 in 60% yield (1.19 g, 90% yield brsm).
Alternatively, 9 could be directly obtained from ester 11 in 47%
yield, via a tandem procedure involving β-keto phosphonate
formation and in situ HWE olefination.[15]
Scheme 2. Retrosynthetic analysis of (–)-berkelic acid (1). Reagents and
conditions: a) methyl 2-(diethoxyphosphoryl)propanoate, nBuLi, THF, -78 oC
to 0 oC; b) H2, Pd/C, MeOH, RT; c) iPrMgCl, N-methoxymethylamine
hydrochloride, THF, RT; d) vinyl-magnesium bromide, THF, 0 oC; e) LDA,
MePO(OMe)2, (CH2O)n, THF, 0 oC. brsm: based on recovered starting
material. THF = tetrahydrofuran. RT = room temperature. LDA = lithium
diisopropylamide.
With substantial quantities of building blocks 7, 8 and (rac)-9
in hand, we then turned our attention to examine the key Catellani
reaction to access the pentasubstituted aromatic intermediate 13.
First, 7, 8 and 9 were subjected to our previously developed
reaction conditions: 10 mol% of Pd(OAc)2, 24 mol% of XPhos and
Scheme 1. Retrosynthetic analysis of (–)-berkelic acid (1).
A retrosynthetic analysis of (–)-berkelic acid is depicted in
Scheme 1. Inspired by the emerging field of Ni-catalyzed
reductive coupling as a powerful tool for the assembly of
ketones,[9f-k,9o-q] we envisaged a late-stage Ni-catalyzed reductive
coupling of Fürstner’s iodide 3[2,5] with non-racemic acid chloride
2 for the installation of the lateral chain. For the synthesis of 2, an
enzyme-catalyzed hydrolysis of the prochiral diester 5, referring
to Björkling’s work[12] could be adopted. Iodide 3 can be derived
from the corresponding alcohol 4,[2,5] which can be obtained via
o
0.5 equivalent of NBE-CO2K in NMP at 60 C under an argon
atmosphere.[10] The desired product 13 was obtained as an
inseparable diastereoisomeric mixture in 26% yield, along with
substantial quantities of direct Heck coupling side-product (13′) of
7 and 9 (Table 1, entry 1). Increasing the loading of NBE-CO2K to
1.0 equivalent could effectively reduce the direct Heck coupling
side product and improve the yield of 13 to 38% yield (Table 1,
entry 2). However, further increasing the loading of NBE-CO2K (to
1.5 equivalent) had a deleterious effect (Table 1, entry 3).
Therefore, we sought to increase the loading of the Pd catalyst.
Gratifyingly, the yield of 13 could be significantly improved to 70%
when 15 mol% of Pd(OAc)2 and 36 mol% of XPhos were used in
an
acid-catalyzed
deprotection/spiroacetalization[2,7]
of
isochroman 6. For construction of the key isochroman
intermediate 6, we imagined combining the known aryl iodide 7,[10]
optically pure epoxide 8[13] and a single enantiomer of enone 9 in
a Catellani reaction/oxa-Michael addition sequence.[10] Though
promising as it seemed, we were aware that this synthetic
strategy may encounter several challenges: (i) the late-stage Ni-
catalyzed reductive coupling might be problematic, owing to the
highly functionalized coupling partner 3; (ii) two new chiral centers
will be generated during the deprotection/spiroacetalization
procedure through desymmetrization, and control of the
stereochemistry throughout this process will be a difficult task; (iii)
the Catellani reaction/oxa-Michael cascade could prove difficult to
achieve since the stereogenic centre of enone 9 is theoretically
labile under the basic reaction conditions.
Table 1: Optimization of the Catellani reaction to synthesize arene 13
We began our synthesis with the preparation of building
blocks 7, 8 and (rac)-9 to test the key three-component Catellani
reaction. 7[10] and 8[13] are known compounds and were prepared
on gram scales according to reported procedures.[14] As shown in
Scheme 2, the synthesis of (rac)-9 was achieved on a gram scale
in four conventional steps, from commercially available 2,2-
dimethyl-1,3-dioxan-5-one (10). First, a Horner–Wadsworth–
Emmons (HWE) reaction with 10 followed by a catalytic
hydrogenation provided ester 11 in 89% overall yield. Treatment
of 11 with N-methoxymethylamine hydrochloride in the presence
of iPrMgCl at room temperature gave Weinreb amide 12 in 92%
yield. Finally, addition of vinylmagnesium bromide to 12 afforded
[a] Reactions were performed on a 0.1 mmol scale. [b] Isolated yield. [c]
Reaction was performed on a 1.2 mmol scale. [d] Reaction was performed on
a 5.4 mmol scale. NMP = N-methyl-2-pyrrolidinone.
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10.1002/anie.202014660
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the presence of 1.0 equivalent of NBE-CO2K (Table 1, entry 4).
Notably, this reaction is scalable, the reaction efficiency remained
good on 1.2 mmol and 5.4 mmol scale operations (Table 1, entries
5-6), and the latter was able to afford 2.46 grams of 13 (Table 1,
entry 6).
acidic media (p-toluenesulfonic acid in methanol) in a “one pot”
operation, triggered the in situ spiroacetalization and afforded the
key tetracyclic intermediate 4 as the major diastereomer (87%
yield, d.r. > 10:1). It is noteworthy that, in this transformation, the
three new chiral centers (C17, C18, and C19) were established
through spiroacetalization (C17), dynamic kinetic resolution (C18)
and desymmetrization (C19). More importantly, when the 1,3-
trans diastereomer 14b was subjected to identical reaction
conditions, the same diastereomer of 4 was obtained as the major
product (77%, d.r. > 10:1). Notably, in this case, four new chiral
centers (C15, C17, C18 and C19) were established through
isomerization (trans to cis), spiroacetalization, dynamic kinetic
resolution and desymmetrization. It is noteworthy that the above
spiroacetalization
step
was
finished
alongside
a
desymmetrization process, and two new chiral centers were
generated. The observed experimental results demonstrate
excellent diastereocontrol of this challenging process. Additionally,
the observed dynamic kinetic resolution of the C18 stereocenter
in 14a and 14b evidently indicates that the preparation of
enantiopure enone 9 (Scheme 1) is not necessary, since the
stereo-information of the four newly established chiral centers in
4 are all generated from the C9 stereocenter.
To rationalize this intriguing transformation, we propose the
reaction mechanism depicted in Scheme 3B. After global
deprotection of 14a and 14b, the free phenol groups condense
with the C17 carbonyl group to form the tricyclic cationic
intermediates 9,15-cis-15a, 9,15-cis-15b and 9,15-trans-15,
respectively. Epimerization of the alpha position of the ketone in
9,15-cis-15a results in an equilibrium with 9,15-cis-15b. Then,
these rigid tricyclic intermediates undergo a facile retro-oxa-
Michael addition reaction to form the thermodynamically favored
chromenylium intermediate 16. This intermediate links 9,15-cis-
and 9,15-trans-15 and constitutes the equilibriums among them.
We assume that 9,15-cis-15b is the most stable tricyclic
intermediate, since it corresponds to the major product 4. Thus,
9,15-cis-15b undergoes a desymmetrization process involving
the nucleophilic attack by one of the two hydroxy groups to the
C17 cationic carbonyl to form the stable and isolable tetracyclic
product 4 (Scheme 3B). We believe the stereochemistry of this
desymmetrization process is controlled by the preferential
conformation of 9,15-cis-15b, and the two newly generated chiral
centers were established in a stereospecific manner. Remarkably,
the common intermediate 16 enables good relay of stereo
information from the C9 stereocenter to the four new chiral
centers.
In order to support this assumption, we carried out density
functional theory (DFT) calculations (Scheme 3C).[16] As expected,
9,15-cis-15b is the most thermodynamically stable among these
four tricyclic isomers. For instance, 9,15-cis-15b is more stable
than 9,15-cis-15a and 9,15-trans-15b by 3.5 and 5.8 kcal/mol,
respectively. Thus, 9,15-cis-15b is the predominant isomer which
can lead to product and can be accumulated from 9,15-cis-15a
through epimerization or from 9,15-trans-15 through a retro-oxa-
Michael addition and oxa-Michael addition reactions via 16a and
16b (The conversion of 15 to 16 may undergo through an enol
ether intermediate[17]). The equilibrium towards 9,15-cis-15b
could be driven by the following reaction to form the more stable
product 4. According to the optimized geometry of 9,15-cis-15b
(Scheme 3C), the hydroxyl group on the bottom face is very close
Scheme 3. (A) Synthesis of key tetracyclic intermediate 4: a) Cs2CO3,
CH3CN, 60 oC, 1 h; b) Pd/C, H2, MeOH, 0.5 h; TsOH·H2O, 12 h. (B)
Proposed reaction mechanism. (C) Computational study. Energies refer to
Gibbs free energy activation barriers (in kcal/mol) calculated using M06-
2X/def2-TZVPP-SMD(MeOH)//B3LYP-D3(BJ)/def2-SVP. DKR = dynamic
kinetic resolution. TsOH·H2O = p-Toluenesulfonic acid monohydrate.
With an efficient approach to the pentasubstituted arene 13
established, we next focused on the synthesis of tetracyclic core
intermediate 4 (Scheme 3A). To better understand the details of
this process, a stepwise operation was initially conducted.
Treatment of 13 with Cs2CO3 in CH3CN at 60 oC triggered the oxa-
Michael reaction to generate two diastereomers of 14: 9,15-cis-
isochroman 14a and 9,15-trans-isochroman 14b, which can be
readily separated on silica gel chromatography. To our surprise,
subjecting 14a to sequential deprotection of the benzyl group
through catalytic hydrogenation and the acetonide group in an
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to the C17 cationic carbonyl group (the C-O distance is 2.203 Å,
indicating a favorable electrostatic interaction), which took the
exclusive role for the nucleophilic attack. Therefore, the stereo-
configurations of the two new chiral centers were established as
18S/19R. These calculations agree with the experimental results.
through the selective saponification of the methyl benzoate of 17
in the presence of (Bu3Sn)2O, following reported procedures.[4-5]
The NMR spectra and optical rotation of both (–)-berkelic acid
methyl ester 17 and (–)-berkelic acid are in agreement with those
previously reported (see SI for the corresponding comparisons).
Table 2. Optimization of Ni-catalyzed reductive coupling of iodide 3 and acyl
chloride 2.
Scheme 4. Total synthesis of (–)-berkelic acid (1). Reagents and
conditions: a) Pd(OAc)2, XPhos, NBE-CO2K, NMP, 60 oC, 12 h; Cs2CO3,
11 h; b) Pd/C, H2, MeOH, 0.5 h; TsOH·H2O, 12 h; c) I2, PPh3, imidazole,
DCM, 3 h; d) 2, NiCl2(dme), dmbpy, Mn, DMA, 0 oC, 5-10 h; e) (Bu3Sn)2O,
toluene, 115 oC, 8 h. DCM = dichloromehane. dme = dimethoxyethane.
dmbpy = 4,4'-dimethyl-2,2'-bipyridine. DMA = N,N-dimethylacetamide.
[a] Isolated yield. [b] Based on recovered 3.
In conclusion, we have accomplished a concise total synthesis
of (–)-berkelic acid (1) in eight linear steps starting from
commercially available reagents. This synthesis features a three-
component Catellani reaction/oxa-Michael cascade for the
Having demonstrated the feasibility of the stepwise synthesis
of isochroman scaffold, we then attempted the one-pot procedure.
As shown in Scheme 4, after the completion of the three-
component Catellani reaction (monitored by TLC), Cs2CO3 was
directly added into the reaction mixture and stirred at the same
temperature for an additional 11 hours. Consistent with the
stepwise experiments, the desired isochroman intermediate 14
was obtained as a 1.2:1 diastereo mixture of 9,15-cis-14a and
9,15-trans-14b in 67% combined yield. The isochroman mixture
of 14 was then subjected to the deprotection/spiroacetalization
assembly
of
isochroman
scaffold,
a
one-pot
deprotection/spiroacetalization to construct the tetracyclic core
structure, and a late-stage Ni-catalyzed reductive coupling to
introduce the lateral chain. Notably, four stereocenters are
established from one existing chiral center with excellent
stereocontrol during the deprotection/spiroacetalization process.
Initial DFT calculations support our proposed mechanism to
rationalize
the
intriguing
stereocontrol
of
the
protocol to provide
4
in
a
good yield and excellent
deprotection/spiroacetalization process. We believe this highly
efficient stereochemical-relay strategy may have broader
implications for asymmetric syntheses.
diastereoselectivity (69%, d.r. > 10:1). Treatment of 4 with PPh3
and I2 in DCM gave Fürstner’s iodide 3[2] in 86% yield. At this
stage, we focused on the late-stage reductive coupling to
introduce the lateral chain. Initially, 3 reacted with acyl chloride 2
(70% ee)[12,18] under Weix’s conditions (NiCl2(dme) and dtbpy (L1)
Acknowledgements
in the presence of Mn in DMA at 0 C)[9f]. The desired coupling
o
product, (–)-berkelic acid methyl ester 17 was obtained in 25%
yield, along with the de-iodination side product S6 and an
unidentified byproduct (Table 2, entry 1). When dmbpy (L2) was
used as the ligand, the yield of 17 was significantly improved to
47% (Table 2, entry 2). Optimization by increasing the catalyst
loading to 15 mol% proved ineffective (Table 2, entry 3). Further
optimization by performing the reaction at room temperature or -
5 oC and -10 oC all led to unsatisfactory results (Table 2, entries
4-6). Thus, the reaction conditions of entry 2 (Table 2) was fixed
as the best conditions for synthesizing 17, and about 50 mg of the
pure sample can be obtained in one operation.[19] The extremely
mild reaction conditions and excellent function group tolerance
ensured the success of this impressive late-stage Ni-catalyzed
reductive coupling. Finally, (–)-berkelic acid (1) was accessed
We are grateful to the National Natural Science Foundation of
China (Grants 21871213, 21801193 and 22071189), the start-up
funding from Wuhan University for financial support. We thank
Profs. C.-J. Li (McGill University), H. Xu (Brandies University), H.
Ding (Zhejiang University) and G. Yin (Wuhan University) for
helpful discussions, Dr. W. Reid (J-STAR Research Inc., US) for
assistance with the preparation of the manuscript, and Dr. S. Liu
(Wuhan University) for assistance with NMR spectroscopy.
Keywords: (–)-berkelic acid • Catellani reaction •
spiroacetalization • reductive coupling • total synthesis
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[8] The recent bioactivity studies of (–)-berkelic acid (see refs. 3c, 4b and 5c)
are inconsistent with the originally reported ones (see ref. 1), which
deserves further systematic studies.
[13] S. Blechert, P. Dewi-Wülfing, J. Gebauer, Synlett 2006, 0487-0489.
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supplementary information (SI) for details.
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[16] DFT calculations were performed by Gaussian program under the level of
M06-2X/def2-TZVPP-SMD(MeOH)//B3LYP-D3(BJ)/def2-SVP. See SI for
computational details.
[17] For related calculation results, please see SI for details.
[18] Chiral acyl chloride 2 is readily prepared through the enzymatic hydrolysis
of the known prochiral diester 5 (referring to Björkling’s work (ref. 11)) and
a following reaction with SOCl2. See SI for experimental details.
[19] The 22R-diastereomer of (–)-bekelic acid methyl ester 17 and other
diastereoisomers were also formed through this reductive coupling
protocol (detected by crude 1H NMR and HRMS). However, we failed to
obtain the pure sample for characterization owing to the contamination of
some unidentified impurities with a similar polarity.
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Hong-Gang Cheng1†, Zhenjie Yang1†,
Ruiming Chen1, Liming Cao1, Wen-Yan
Tong,3 Qiang Wei1, Qingqing Wang1,
Chenggui Wu1, Shuanglin Qu*3 and
Qianghui Zhou*1,2
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A Concise Total Synthesis of (–)-
Berkelic Acid
A concise total synthesis of (–)-berkelic acid in eight linear steps was developed. This
synthesis features a Catellani reaction/oxa-Michael cascade for the construction of
the isochroman scaffold, a one-pot deprotection/spiroacetalization operation for the
formation of tetracyclic core structure, and a late-stage Ni-catalyzed reductive
coupling for the introduction of the lateral chain.
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