Scalable Formal Synthesis of (-)-Quinocarcin

Article abstract of DOI:10.1021/acs.orglett.9b01511

A scalable and unified strategy is described for the synthesis of (-)-quinocarcin, an important tetrahydroisoquinoline antitumor alkaloid. The strategy allows the practical formal synthesis of (-)-quinocarcin in 13 steps and 4.8% overall yield using N-pht

Full text of DOI:10.1021/acs.orglett.9b01511

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Scalable Formal Synthesis of (−)-Quinocarcin
Sheng-Long Fang,† Meng-Xue Jiang,‡,§ Shuo Zhang,† Yong-Jie Wu,† and Bing-Feng Shi*,†
†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
§International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
S
* Supporting Information
ABSTRACT: A scalable and unified strategy is described for the synthesis of (−)-quinocarcin, an important
tetrahydroisoquinoline antitumor alkaloid. The strategy allows the practical formal synthesis of (−)-quinocarcin in 13 steps
and 4.8% overall yield using N-phthaloyl-L-alanine as a chiral pool. It features the gram-scale and stereoselective synthesis of the
tetrahydroisoquinoline moiety (AB ring) via Pd-catalyzed C(sp3)−H arylation and Pictet−Spengler condensation and a Cu(I)-
catalyzed exo-selective [C + NC + CC] coupling reaction to generate the chiral pyrrolidine motif (D ring).
(−)-Quinocarcin is a potent antitumor antibiotic first isolated
from Streptomycse melanovinaceus by Takahashi and Tomita.1 It
belongs to an important subclass of the large family of
tetrahydroisoquinoline (THIQ) alkaloids.2 The main repre-
sentatives of this subclass are (−)-quinocarcin, DX-52-1,
quinocarcinol, tetrazomine, and lemonomycin, which share a
common tetracyclic THIQ-pyrrolidine core scaffold (I)
containing a THIQ as the AB ring and a chiral 3,8-
diazabicyclo[3.2.1]octane skeleton as the CD ring (Scheme
1).2 Quinocarcin exhibited remarkable antiproliferative activity
against lymphocytic leukemia.3 Its intricate polycyclic structure
and promising biological activities make quinocarcin an
attractive synthetic target.4,5 The first racemic total synthesis
of ( )-quinocarcin was reported by Fukuyama in 1988. Several
asymmetric syntheses of (−)-quinocarcin have been elegantly
demonstrated by the groups of Garner, Terashima, Myers,
Zhu, Stoltz, Fujii, and Ohno.5 Total syntheses of the racemic
form of the more stable quinocarcinol methyl ester and
quinocarcinamide have also been achieved.6 The THIQ
alkaloids hold great potential as anticancer agents and have
triggered ongoing synthetic endeavors, as exemplified by recent
achievements on the concise and practical total syntheses of
those families compounds by the groups of Stoltz and Ma.7
However, the medicinal applications have somehow been
restricted by their natural availability and synthetic efficiency
and scalability. Therefore, the development of a practical and
unified strategy to facilitate the convergent assembly of this
core tetracyclic scaffold (I) in sufficient quantity is highly
desirable. Undoubtedly, such a strategy might offer a great
opportunity to discover some new and promising anticancer
agents. As part of our continuous endeavors to promote
practical synthesis of natural products via C−H activation,8,9
we report herein a scalable synthesis of (−)-quinocarcin based
on the Pd(II)-catalyzed C(sp3)−H arylation, Pictet−Spengler
condensation, and CuI-catalyzed exo-selective asymmetric
multicomponent [C + NC + CC] coupling reaction.
Scheme 1. Quinocarcin Family Alkaloids Featuring a
Common Tetracyclic THIQ−Pyrrolidine Core Scaffold (I)
The key to the practical syntheses of quinocarcin family lies
in the development of a scalable and unified strategy to the
asymmetric construction of THIQ (AB ring) and pyrrolidine
(D ring). To date, the Pictet−Spengler condensation is one of
Received: April 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01511
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
the most popular strategies for the assembly of the THIQ
moiety. The pivotal point of this strategy relies on the use of
properly substituted chiral β-aryl-α-amino acids as general
precursors (6 + 7 → 3). Thus, the synthetic challenge shifted
to the stereoselective synthesis of β-aryl-α-amino acids. We
envisioned that our recently developed Pd-catalyzed mono-
arylation of β-methyl C−H of alanine could provide a practical
access to this general precursor (8e + 9 → 6).10,11 Different
from the conventional synthetic methods, this protocol uses
readily available L-alanine as a chiral pool and avoid the use of
expensive chiral auxiliaries or catalysts. For the D-ring featuring
a densely functionalized 4,5-trans-pyrrolidine, the asymmetric
1,3-dipolar cycloaddition has been recognized as an ideal
strategy.5a,b,12 In particular, we realized that a Cu(I)-catalyzed
exo-selective asymmetric multicomponent [C + NC + CC]
coupling reaction developed by Garner would be perfect for
setting up the three chiral centers of the D ring (3 + 4 + 5 →
2).13,14 Specifically, the 4,5-trans-pyrrolidine in 2 could be
synthesized by Cu(I)-catalyzed asymmetric coupling of
THIQ−aldehyde 3, methyl acrylate 5, and Oppolzer’s L-
glycylsultam 4 (XL = Oppolzer’s L-camphorsultam).13 The
quinocarcinol methyl ester 1, an advance intermediate in
Stoltz’s total synthesis of (−)-quinocarcin,5g could be obtained
from 2 by lactamization/ester cyclization. Our detailed
retrosynthetic analysis and envisions are shown in Scheme 2.
protecting groups (8a−e), we finally chose the use of 3-
iodophenyl benzoate 8e as the arylation reagent since it gave
the optimal results regarding both yield and scalability. Thus,
the arylation reaction was subjected to the following
conditions, that is, Pd(OAc)2 (10 mol %), AgBF4 (1.5
equiv), alanine derivative 9 (1.0 equiv) ,and 3-iodophenyl
benzoate 8e (1.2 equiv) in t-BuOH/DCE at 78 °C under N2
for 12 h, providing 10e in 82% yield on a 22.18 g scale. The
main advantage of this reaction is the robustness, which could
be repeated on a large scale. Removal of the 8-aminoquinoline
group and esterification of 10e was achieved in the presence of
TsOH in methanol, leading to the corresponding methyl ester
11 in 76% yield (9.88 g), with the benzoyl group
simultaneously removed. Bromination of 11 with DMSO/
HBr, an elegant procedure developed by Jiao and co-workers,
provided the desired bromination product 13 in 92% yield,
with 7% yield of 12.15 It is worth noting that 12 could be
reduced to 11 by hydrogenation over Pd on C in 99% yield.
The phthalimide group of 13 was removed in the presence of
ethylenediamine to afford the free amine 6 in 64% yield with
complete retention of chirality from alanine derivative 9 (9,
96% ee; 6, 97% ee). The Pictet−Spengler reaction of amido
phenol 6 with acetaldehyde 716 under mild acidic conditions
gave tetrahydroisoquinoline 14 in 69% yield (dr, 7:1).5f,17
Although attempts to improve the yield failed, we were glad
that THIQ 14 could be obtained in multigram scale (3.13 g).
It is worth noting that the multigram-scale synthesis of THIQ
14 could be achieved in five steps from alanine derivative 9.
Protecting the secondary amine as the N-tert-butoxycarbamate
gave 15 in 74% yield. Subsequent methylation of phenol 15
with TMSCHN2 afforded 16 in 95% yield. Treatment of 16
with LiBH4 led to the reduction of ester to primary alcohol,
providing 17 in 95% yield. THIQ−aldehyde 3 was obtained by
Dess−Martin oxidation in 93% yield.
Scheme 2. Retrosynthetic Analysis
With the key building block THIQ−aldehyde 3 secured,
efforts were directed toward the asymmetric synthesis of
functionalized pyrrolidine. The [C + NC + CC] coupling
reaction proceeded smoothly by combining THIQ−aldehyde
3, Oppolzer’s L-glycylsultam 4, and methyl acrylate 5 with
Cu(CH3CN)4PF6/dppb at room temperature, giving the
desired 4,5-trans-pyrrolidine 2 in 68% yield on a 1.22 g
scale.13 To ensure the scalability, a slightly modification of
Garner’s procedure was used with increased loading of copper
catalyst and bisphosphine (10 mol % Cu(CH3CN)4PF6 and 11
mol % dppb). The stereochemistry of the newly generated
pyrrolidine of 2 could not be clearly determined simply using
standard NMR techniques. The expected configurations were
tentatively assigned on the basis of Garner’s precedent13 and
later confirmed by correlation with an established intermediate
1.
Transesterification of the chiral sultam moiety to methyl
ester18 with concurrent removal of the N-Boc function from 2
were realized in a one-pot fashion to afford the desired 18 in
61% yield. Upon heating, the newly formed secondary amine
selectively condensed with esters to form lactams 19 in 96%
yield. We expected that the aryl bromide and the OBn
protecting group could potentially be removed under the same
conditions as that for the N-reductive methylation, by
judicious choice of reaction conditions. Indeed, simultaneous
deprotection and N-methylation of the unmasked amine was
realized under over Pd on C in the presence of aqueous
solution of formaldehyde,5f giving quinocarcinol methyl ester 1
in 86% yield on a 0.25 g scale. Compound 1 is an established
The combination of Pd-catalyzed C(sp3)−H arylation/Pictet−
Spengler condensation to construct the THIQ moiety (AB
ring) and a Cu(I)-catalyzed exo-selective [C + NC + CC]
coupling reaction to generate the chiral pyrrolidine motif (D
ring) might offer a unified strategy to access a diversity of
quinocarcin family compounds and elucidate their biological
activities.
Scalable synthesis of (−)-quinocarcin is shown in Scheme 3.
First, we focused our attention on the palladium-catalyzed
C(sp3)−H arylation reaction.10 We were delighted to find that
our previous protocol was quite robust, and several aryl iodides
were compatible with this protocol.10 After extensive
investigations of various 3-iodophenols bearing different
B
DOI: 10.1021/acs.orglett.9b01511
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Letter
Scheme 3. Scalable Formal Synthesis of Quinocarcin
precursor in Stoltz’s total synthesis of (−)-quinocarcin, and the
spectroscopic data are identical to those reported.5g
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bfshi@zju.edu.cn.
ORCID
In conclusion, a scalable formal synthesis of (−)-quinocarcin
has been achieved in 13 linear steps with 4.8% overall yield.
Pd(II)-catalyzed C(sp3)−H arylation has provided an efficient
and robust method to access the general precursor of THIQ
core. Subsequent scalable Pictet−Spengler condensation and
Cu(I)-catalyzed exo-selective asymmetric multicomponent [C
+ NC + CC] coupling reaction led to the success of practical
synthesis. We believe this approach would serve as a unified
strategy to facilitate the total synthesis of other natural
products containing the THIQ−pyrrolidine tetracyclic core
unit, such as tetrazomine, lemonomycin, and their analogues.
Related studies are currently underway in our laboratory.
Bing-Feng Shi: 0000-0003-0375-955X
Notes
The authors declare no competing financial interest.
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.
REFERENCES
■
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■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01511.
Experimental details and spectral data for all new
compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b01511
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