Asymmetric Total Synthesis of TAN-1085 Facilitated by Pd-Catalyzed Atroposelective C-H Olefination

Article abstract of DOI:10.1021/acs.orglett.9b01099

Asymmetric total synthesis of TAN-1085 via Pd-catalyzed atroposelective C-H olefination is described. This synthesis features the gram-scale construction of axially chiral biaryls in an enantiopure form employing the readily available l-tert-leucine as th

Full text of DOI:10.1021/acs.orglett.9b01099

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Total Synthesis of TAN-1085 Facilitated by Pd-
Catalyzed Atroposelective C−H Olefination
Jun Fan, Qi-Jun Yao, Yan-Hua Liu, Gang Liao, Shuo Zhang, and Bing-Feng Shi*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
S
* Supporting Information
ABSTRACT: Asymmetric total synthesis of TAN-1085 via Pd-catalyzed atroposelective C−H olefination is described. This
synthesis features the gram-scale construction of axially chiral biaryls in an enantiopure form employing the readily available L-
tert-leucine as the chiral transient auxiliary. The synthetic approach might provide a unified strategy for the total synthesis of
natural products containing trans-9,10-dihydrophenanthrene-9,10-diol motifs.
he trans-9,10-dihydrophenanthrene-9,10-diol scaffold (I)
is the core structural subunit of a wide range of
would offer a great opportunity to access related compounds
and elucidate their biological activities.
T
biologically active natural products, such as the anticancer
angucycline PD 116740 and TAN-1085,1a,b the cytotoxic
antibiotic FD 594,1c,d and the benanimicin and pradimicin
antibiotics (BPAs) (Scheme 1a).1e−h The significant biological
activity of these natural products as well as their unique
molecular architecture have triggered a number of synthetic
studies.2−6 The stereoselective and efficient construction of the
core structure of 9,10-dihydrophenanthrene with trans-vicinal
hydroxyl groups is particularly challenging and has been a
central topic of these synthetic efforts. In the seminal work by
Suzuki,3−6 a modified pinacol coupling that stereospecifically
transfers the biaryl axial chirality (II) to the pseudo-C2-
symmetric trans diols (I) was elegantly established as the key
step (Scheme 1a).3 Thereby, the synthetic challenge shifted to
the stereoselective synthesis of the axially chiral biaryldialde-
hydes (II), and several strategies were developed (Scheme 1b):
(a) a stereochemical-relay strategy involving two chirality
transfer steps (central-to-axial and then axial-to-axial) for the
synthesis of TAN-1085;4b (b) the Bringmann-type asymmetric
ring-opening reaction of the biaryl lactone with a chiral
nucleophile for the construction of the FD-594 aglycon;5b,7a,b
and (c) the introduction of a chiral auxiliary to enable an
optical resolution via chromatographic separation of the
resulting diastereomers for pradimicinone.6 However, these
previous endeavors suffered from the use of stoichiometric
chiral reagents, lengthy steps, and/or poor stereocontrol. We
envisioned that the development of a general method to
efficiently and stereoselectively construct the axially chiral
biaryldialdehydes followed by pinacol cyclization would
provide a unified strategy to greatly facilitate the total synthesis
of these natural products. Undoubtedly, such a unified strategy
In recent years, great efforts have been expanded to the
asymmetric synthesis of axially chiral biaryl skeletons.7,8 In
particular, asymmetric C−H activation has emerged as a
powerful tool to access the axial chirality.9,10 Recently, a
pioneering work of Pd-catalyzed enantioselective C(sp3)−H
functionalization to create point chirality by the use of tert-
leucine (Tle) as a transient directing group was developed by
the Yu group.10 Inspired by these elegant workd, we applied
this strategy to the highly atroposelective synthesis of axially
chiral biaryl aldehydes via asymmetric C−H functionaliza-
tions.11 We speculated that our previously developed Pd-
catalyzed atroposelective C−H olefination could streamline the
synthesis of trans-9,10-dihydrophenanthrene-9,10-diol11a since
the resulting olefins can be easily transferred to aldehydes.
Notably, despite the significant advance as well as the
promising prospect of enantioselective C−H activation in
organic synthesis,9 examples of using the enantioselective C−
H activation strategy to expedite the synthesis of natural
products were still rare.12−14 As part of our persistent pursuit
to promote concise synthesis of natural products via C−H
activation,11b herein, we report a novel approach that enables
the asymmetric total synthesis of TAN-1085 based on
palladium-catalyzed asymmetric C−H olefination (Scheme
1c).
Our retrosynthetic analysis for TAN-1085 is shown in
Scheme 2. The axially chiral biaryldialdehyde 1 would be the
crucial precursor for TAN-1085, which would undergo pinacol
Received: March 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01099
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyclization to form diol I stereoselectively.3−6 The formyl
group could be generated by oxidative cleavage of the double
bond in 2, which would be obtained via Pd-catalyzed
atroposelective C−H olefination of 3.11a 3 could be easily
accessed by Suzuki coupling of 4 and 5. Though promising as
it seemed, the direct subjection of 3 to the atroposelective C−
H olefination might be encountered with several challenges: (i)
the substrate 3 used in this reaction is extremely electron-rich,
and its compatibility with the oxidative conditions would be a
potential challenge; (ii) the vicinal methoxy group coupled
with the in situ formed imine group and the carboxylate of Tle
might act as a tridentate chelating group, which might
deactivate the palladium catalyst; (iii) whether benzyloxy and
methoxy substituents are sterically bulky enough to prevent
rotation about the biaryl axis;15 (iv) the scalability (gram scale)
of this reaction for further transformations would be another
challenge.
Scheme 1. Natural Products Containing trans-9,10-
Dihydrophenanthrene-9,10-diol Motifs and the Synthetic
Strategies
Our synthesis commenced with the preparation of building
blocks 4 and 5 (Scheme 3). A modified procedure was
Scheme 3. Syntheses of Fragments 4 and 5
developed for the preparation of compound 4 with high
efficiency and simplified operations on a multigram scale.16
Acetate protection of the free phenolic hydroxyl group of
commercially available 6, followed by treatment with N-
bromosuccinimide, afforded 7 in 63% yield upon recrystalliza-
tion.17 Allylation of 7 with but-3-enoic acid in the presence of
(NH4)2S2O8 and catalytic amount of AgNO316 and subsequent
deacylation and benzylation provided 8 in a 48% overall yield
for 3 steps on a 5.6 g scale. Napthoquinone 8 was transferred
to its dimethoxy benzyl form 9 in 82% yield. 9 was then
converted to the bromo-aldehyde 4 in 75% yield for 2 steps on
a 2.6 g scale.16 Overall, the coupling partner 4 was prepared in
a total yield of 19% over 9 steps on a multigram scale with one
recrystallization and three chromatography operations. Then,
we set out to prepare fragment 5 for Suzuki coupling. A
bismethoxymethyl (MOM) protected phenol was used in the
first total synthesis of TAN-1085 developed by Suzuki, and
subsequent three-step transformation of the MOM ether to
CO2 Me was needed, due to the incompatibility of CO2 Me
with the reaction conditions.4 Considering the mild reaction
conditions of our route, we decided to introduce CO2 Me at
the beginning to simplify the synthesis. Benzyl protection of
the phenolic hydroxyl of 10, followed by borylation under
Miyaura coupling conditions,18 afforded 5 in excellent yield.
Scheme 2. Retrosynthetic Analysis for TAN-1085
B
DOI: 10.1021/acs.orglett.9b01099
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
The sugar motif 13 was prepared according to literature
procedure.4,19
Table 1. Asymmetric C−H Olefination of 3
Suzuki coupling between 4 and 5 led to the formation of the
desired racemic biaryl 3 in 85% yield on a 1 g scale (Scheme
4). The reaction was better conducted in a sealed tube, and the
Scheme 4. Asymmetric Total Synthesis of TAN-1085
b
c
entry
oxidant (x equiv)
L-Tle (y equiv)
yield (%)
ee (%)
1
2
3
BQ (0.1)
BQ (0.2)
BQ (1)
AgOAc (4)
AgOAc (6)
Ag3PO4 (1.3)
Ag2SO4 (2)
Ag2CO3 (2)
Ag2CO3 (4)
0.2
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
30
41
47
46
44
35
34
51
75
90
>99
>99
>99
>99
>99
>99
>99
99
d
4
d
5
d
6
d
7
d
8
de
,
9
a
Reaction conditions: 3 (0.05 mmol), butyl acrylate (4.0 equiv),
Pd(OAc)2 (10 mol %), oxidant (x equiv), and L-Tle (y equiv) in
b
HFIP/HOAc (0.5 mL) at 60 °C under O2 for 72 h. Isolated yield.
c
d
e
The ee value was determined by HPLC. N2 instead of O2. 3 (1.2 g,
2.1 mmol) was used.
situ monoprotection with 3-methylbenzoyl chloride, gave 12 in
54% yield over two steps.4 Finally, TAN-1085 was obtained in
enantio- and diastereomerically pure form after glycosylation
and deprotection.4 The spectroscopic data of TAN-1085 were
in good agreement with that reported by Suzuki et al.4b
In conclusion, a concise total synthesis of TAN-1085 has
been achieved in 17 linear steps with 3% overall yield. The
route features a scalable, atroposelective axial-chirality
construction as a key step via Pd-catalyzed asymmetric C−H
olefination, which employs commercially available L-Tle as an
inexpensive, catalytic transient chiral auxiliary. We believe this
asymmetric synthetic strategy would serve as a unified strategy
to facilitate the total synthesis of other natural products
containing trans-9,10-dihydrophenanthrene-9,10-diol motifs,
and related works are currently underway in our lab.
reaction under reflux resulted in relatively lower yield. Then,
we focused our attention on the asymmetric C−H olefination
of 3. At the outset, 3 was directly subjected to our previously
reported conditions, that is Pd(OAc)2 (10 mol %), BQ (0.1
equiv), and L-Tle (0.2 equiv) in HFIP/HOAc (0.5 mL) at 60
°C under O2 for 72 h. However, (M)-2 was obtained in only
31% yield with 90% ee (Table 1, entry 1).20 Despite that an
unsatisfactory yield and ee were obtained, the reaction system
was relatively clean, and most unreacted starting material 3
could be recovered, indicating the robustness of 3 under the
oxidative and acidic conditions. Further optimization showed
that the equivalent of L-Tle was crucial for the enantiose-
lectivity, and the ee value was elevated to >99% when using 40
mol % of L-Tle (entry 2). Increasing the amount of BQ only
resulted in a little bit of improved yield (entry 3). Then we
screened different Ag salts as oxidants. Gratifyingly, when 4
equiv of Ag2CO3 was used, the reaction could be conducted on
a 1.2 g scale, and the desired product (M)-2 could be obtained
in 75% isolated yield with 99% ee (entry 9, (M)-2, 1.08 g).21
With gram-scale enantiopure 3 in hand, our attention was
turned to the oxidative cleavage of the double bond. Elevated
temperature and extended reaction time were required for the
complete conversion, and portionwise addition of K2OsO4 and
NaIO4 under 50 °C enabled the preparation of biaryldialde-
hyde 1 in high yield and ee (98%, 98% ee, 1.03 g). Hitherto,
we have succeeded in the gram-scale preparation of the key
axially chiral biaryldialdehyde precursor of TAN-1085 with
98% ee. Subsequently, treatment of 1 with SmI2, followed by in
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01099.
Experimental details and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bfshi@zju.edu.cn (B.-F. Shi).
ORCID
Yan-Hua Liu: 0000-0001-5524-4799
Bing-Feng Shi: 0000-0003-0375-955X
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b01099
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
Financial support from the NSFC (21572201, 21772170), the
National Basic Research Program of China (2015CB856600),
the Fundamental Research Funds for the Central Universities
(2018XZZX001-02), and Zhejiang Provincial NSFC
(LR17B020001) is gratefully acknowledged.
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(20) The absolute configuration of compound 2 was deduced from
previous studies (ref 11a) and confirmed by the optical rotation and
NMR spectra of the final product TAN-1085 (ref 4b).
(21) Consistent with our previous results (ref 11a) and Sternhell’s
investigations (ref 15), alkoxy groups are generally less sterically
bulky; therefore, rac-3 could undergo the atroposelective C−H
olefination through dynamic kinetic resolution.
E
DOI: 10.1021/acs.orglett.9b01099
Org. Lett. XXXX, XXX, XXX−XXX