Total Synthesis of (?)-Glaucocalyxin A

Article abstract of DOI:10.1002/anie.202005932

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃-mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (?)-glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.

Full text of DOI:10.1002/anie.202005932

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Accepted Article
Title: Total Synthesis of (−)-Glaucocalyxin A
Authors: Yanxing Jia, Jiuzhou Guo, Bo Li, Weihao Ma, and Mallesham
Pitchakuntla
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Total Synthesis of (−)-Glaucocalyxin A
Jiuzhou Guo, Bo Li, Weihao Ma, Mallesham Pitchakuntla, and Yanxing Jia*
Abstract: A practically useful method for the formation of the highly
oxygenated bicyclo[3.2.1]octane ring system by Mn(OAc)3-mediated
radical cyclization of alkynyl ketones has been developed, which
opens up a new avenue to the total synthesis of a number of highly
oxidized diterpenoids. Application of this method allows the first total
synthesis of (−)-glaucocalyxin A. Other salient features of the
synthesis include a highly enantioselective conjugate addition/
acylation cascade reaction, a Yamamoto aldol reaction, and an
intramolecular Diels-Alder reaction to assemble the A/B ring system.
tremendous challenges for chemical synthesis.[3d,3i,5] Furthermore,
it is difficult to introduce the C14-OH by employing the previously
reported strategies.[5,6] In the course of our investigation on the
total synthesis of structurally complex diterpenoids,[10] we are also
intrigued by the intricate molecular architecture of these 14-
oxygenated diterpenoids. We conceived an opposite sequence
for the formation of the ring system to the previously reported
approaches, and in our design the 14-oxygenated
bicyclo[3.2.1]octane system is formed at the early stage. Herein,
we report a practically useful method for the formation of the 14-
oxygenated bicyclo[3.2.1]octane system, which enables us to
achieve the first total synthesis of (−)-glaucocalyxin A (1).
The bicyclo[3.2.1]octane system is the basic subunit of many
important biologically active natural products, particularly of
compounds in a variety of diterpene families.[1] Accordingly, these
diterpenoids have attracted considerable attention from the
synthesis community over the past 50 years. A number of elegant
syntheses of some target molecules have been achieved based
on the evolution of strategies for constructing fused and bridged
ring systems.[1,2] And the bicyclo[3.2.1]octane system is generally
assembled either in the middle of or the late stage of the synthetic
strategy.[2-5]
Table 1: Condition optimization for the formation of the oxygenated
Bicyclo[3.2.1]octane System.[a]
Equiv. of
Mn(III)
Entry
Solvent
Temp. (°C )
Time
Yield[b]
1
2
3
4
5
6
7
8
6
6
EtOH/HOAc (9:1)
EtOH/HOAc (9:1)
HOAc
100 (heat)
100 (MW)
100 (MW)
100 (MW)
110 (MW)
110 (MW)
120 (MW)
125 (MW)
3 d
6 h
23%
27%
32%
40%
47%
58%
60%
60%
3
30 min
6 h
3
THF/HOAc (9:1)
THF
3
6 h
3
DCE
6 h
3
DCE
3 h
Figure 1. Diterpenoids possessing C14-oxygenated patterns.
2.5
DCE
3 h
[a] Reaction conditions: 7 (0.3 mmol), Mn(OAc)3, solvent (3 mL). [b] Isolated
yield. TMS = trimethylsilyl, THF = tetrahydrofuran, DCE = 1,2-dichloroethane.
Among these diterpenoids, about half contain 14(β)-
oxygenation patterns (Figure 1).[6,7] As shown, the 14-oxygenated
bicyclo[3.2.1]octane ring system contains four to five continuous
stereocenters. Some of these natural products, such as
glaucocalyxin A (1),[8] oridonin (3),[9] and grayanotoxin I (4),[7]
exhibit a variety of promising therapeutic properties and have
been used as leads in drug development. However, synthetic
efforts toward these diterpenoids have been especially limited,
perhaps because these highly oxygenated diterpenoids present
The Mn(OAc)3-mediated radical cyclization of alkynyl ketones
for the formation of the bicyclo[3.2.1]octane system developed by
Snider attracted our attention due to its short synthetic route and
readily available starting materials.[11] In order to verify the
feasibility, the alkynyl ketone 7 was prepared in two steps (See
SI) and subjected to Snider’s reaction conditions (Table 1, entry
1). The desired 8, a mixture of E/Z isomers, was obtained in only
23% yield. The low yield, long reaction time and the use of a large
excess of Mn(OAc)3 promoted us to optimize the reaction
conditions (Table 1). Microwave conditions can dramatically
reduce the reaction time (Table 1, entry 2). Unexpectedly, after a
variety of solvents were tested, DCE gave the highest yield (Table
1, entries 2-6). It is worth noting that HOAc and ethanol are the
most common solvents in Mn(OAc)3-mediated reactions, and the
use of DCE has not been reported.[11b] Further optimizations
[a]
J. Guo,[†] B. Li,[†] W. Ma, Dr. M. Pitchakuntla, and Prof. Y. Jia
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences,
Peking University,
Xue Yuan Rd. 38, Beijing 100191, China
E-mail: yanxingjia@pku.edu.cn
[†]
[b]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.202005932
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showed that the equivalence of Mn(OAc)3 can be reduced to 2.5
and the reaction temperature can be increased to 125 °C (Table
1, entries 7-8). Thus, the 14-oxygenated bicyclo[3.2.1]octane ring
system could be prepared in only three steps from commercially
available starting materials.
With this encouraging result, we selected glaucocalyxin A (1),[8]
a highly oxygenated ent-kaurene diterpenoid with promising
therapeutic properties, as the target molecule to prove our
concept. Retrosynthetically, we envisioned that 1 could be
generated from the tetracycle 9 via late-stage functional group
manipulations (Scheme 1). The key tetracycle 9 possessing the
kaurene skeleton could be assembled by an intramolecular Diels-
Alder (IMDA) reaction of 10. Accordingly, 10 could be prepared
from the 14-oxygenated bicyclo[3.2.1]octane compound 11 which
could be constructed by a Mn(OAc)3-mediated cyclization of 12.
In turn, 12 could be obtained from readily available compounds
13-15.
Scheme 1. Retrosynthetic analysis of glaucocalyxin
butyldimethylsilyl.
A (1). TBS = tert-
Scheme 2. Total synthesis of (−)-glaucocalyxin A (1). TFA = trifluoroacetic acid, DIBAL-H = diisobutylaluminium hydride, DMP = Dess-Martin periodinane, 2,6-DPP
= 2,6-diphenylphenol, TMP = 2,2,6,6-tetramethylpiperidine, DIPEA = N,N-diisopropylethylamine, MOM = methoxymethyl, TBAI = tetra-n-butylammonium iodide,
BHT = butylated hydroxytoluene, TBAF = tetra-n-butylammonium fluoride, DMAP = 4-dimethylaminopyridine, TASF = tris(dimethylamino)sulfanium.
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Our synthesis commenced with the scalable preparation of the
compound 10. Tetraene 10 was then subjected to intramolecular
chiral cyclization precursor 12 (Scheme 2). Baran had developed
Diels-Alder reaction to provide the desired tetracyclic silyl enol
a
highly enantioselective conjugate addition of 14 with
ether 23 as a single product in 97% yield. The high
cyclohexenone (13) by modification of Schmalz’ procedure.[12,13]
We thought that trapping the resulting enolate at the carbon
terminus could afford 16. After several trials, the stereoselective
conjugate addition−acylation cascade reaction with ethyl
cyanoformate (Mander’s reagent) proceeded smoothly to provide
16 as an inconsequential mixture of ketone and enol.
Diastereoselective alkylation of 16 with 15 provided the desired β-
ketoester 17. Selective removal of the allyl TMS group on 17 gave
cyclization precursor 12 in 85% yield. Oxidative cyclization of 12
under our optimized condition gave the desired 11 in 53% yield.
stereoselectivity observed may be attributed to a chair-like
conformation in the transition state. It is worthy to note that the
stereochemistry of C7-OH has a significant effect on the Diels-
Alder reaction.
The only thing left to assemble the ent-kaurene skeleton was
the introduction of the geminal dimethyl group at C4. In similar
structures, the methyl group was introduced by cyclopropanation
followed by opening the cyclopropane ring. However, attempts to
cyclopropanation of 23 failed.[16] We decided to employ a direct
methylation method with MeI and TBAF that is rarely used.[17]
After several trials, we found that treatment of 23 with high
concentrations of MeI and pre-dehydrated TBAF (dried with
LiAlH4) in 2-MeTHF afforded the desired product 9 in 86% yield.
Thus, we have successfully constructed the tetracyclic skeleton
of ent-kaurenoids.
Having
constructed
the
crucial
14-oxygenated
bicyclo[3.2.1]octane system 11, we turned our attention to the
Intramolecular Diels-Alder reaction (IMDA) to assemble the AB
rings. Desilylation of 11 with TFA afforded 18 in 73% yield.
Reduction of 18 with a variety of reducing agents afforded only
the undesired C14-α-OH. After a series of failures to invert the C-
14 configuration, we protected the alcohol with TBS and moved
the inversion to a later step. Reduction of 19 with DIBAL-H
followed by oxidation of the resulting alcohol with Dess-Martin
periodinance (DMP) afforded aldehyde 20. Vinylogous aldol
reaction of 20 according to the Yamamoto protocol provided the
desired product 21 and its C7-epimer (C7-epi-21) in 99%
combined yield as a mixture of two separable diastereoisomers
(dr = 3:1) in favour of 21.[14] The diastereo-selectivity could be
explained as depicted in Scheme 3. Firstly, the bulky aluminium
tris(2,6-diphenylphenoxide) (ATPH) coordinated to the aldehyde,
and two possible transition states (TS-1 & TS-2) could be
considered to lead to 21 and C7-epi-21, respectively. Due to the
enhanced steric repulsion between ATPH and isopropenyl group
in TS-2, the less hindered TS-1 should be favored, allowing the
formation of 21 as the main product.
With ketone 9 in hand, all that remained to complete the
synthesis of 1 was the inversion of C14 configuration and the
installation of the ketone group at C15. Attempts to remove the
TBS group of 9 resulted in decomposition of the starting material.
After several trials, we found that C3 ketone had a significant
effect on C14-OH desilylation. To overcome this issue, ketone 9
was selectively reduced to the corresponding alcohol which was
subsequently protected with Ac2O to provide the acetate 24.
Removal of the TBS group of 24 with TASF proceeded smoothly
to produce the corresponding alcohol which was then oxidized by
DMP to yield ketone 25.[18] Reduction of the ketone 25 with Li in
liquid NH3 gave the desired diol 26 in 73% yield.[19] The structure
of diol 26 was confirmed by X-ray crystallography analysis.[20]
Allylic oxidation with 4 equiv. of t-BuO2H (TBHP) in the presence
of 1 equiv of SeO2 provided the allylic alcohol 27 as the sole
stereoisomer, and its structure was confirmed by X-ray
crystallography analysis.[21] It was noteworthy that the amount of
SeO2 is critical to the reaction yield. Finally, chemoselective
oxidation of C3 and C15 hydroxyl groups followed by removal of
MOM protecting group provided 1 in 33% yield (3 steps). The
physical data of our synthesized (−)-glaucocalyxin A (1) was
identical to those reported in the literature.[8c]
In conclusion, we have developed a practically useful method
for the formation of the highly oxygenated bicyclo[3.2.1]octane
ring system by Mn(OAc)3-mediated oxidative cyclization of alkynyl
ketones. By application of this method, we have achieved the first
total synthesis of (−)-glaucocalyxin A (1). Our synthetic approach
offers the possibility for flexible and deep-seated structural
changes inaccessible by semi-synthesis. The present method
could also be applied to the synthesis of other natural products
containing the highly oxygenated bicyclo[3.2.1]octane system.
These studies are now in progress in our laboratory and will be
reported in due course.
Scheme 3. Proposed mechanism of vinylogous aldol condensation.
Acknowledgements
MOM protection of alcohol 21 followed by conversion of the
ester group to Weinreb amide yielded 22.[15] Treatment of amide
22 with excess MeMgBr followed by silyl enolization produced
This research was supported by the National Natural Science
Foundation of China (Nos. 21925101 and 21871013), the Drug
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Layout 2:
COMMUNICATION
Jiuzhou Guo, Bo Li, Weihao Ma,
Mallesham Pitchakuntla, and Yanxing
Jia*
Page No. – Page No.
Total Synthesis of (−)-Glaucocalyxin
A
The first total synthesis of (−)-glaucocalyxin A, a highly oxygenated ent-kaurene
diterpenoid, was achieved by using a Mn(OAc)3-mediated radical cyclization of
alkynyl ketones for the formation of the bicyclo[3.2.1]octane system.
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