Total Synthesis of Psymberin (Irciniastatin A)

Article abstract of DOI:10.1021/acs.orglett.9b01113

A convergent, stereocontrolled total synthesis of psymberin, an architecturally complex marine antitumor agent, has been achieved in 27 steps from the known aldehyde 8. Highlights of this synthesis include a novel and efficient transannular Michael additi

Full text of DOI:10.1021/acs.orglett.9b01113

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Psymberin (Irciniastatin A)
Jie Yu, Mingze Yang, Yian Guo,* and Tao Ye*
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate
School, Xili, Nanshan District, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A convergent, stereocontrolled total synthesis of
psymberin, an architecturally complex marine antitumor agent, has
been achieved in 27 steps from the known aldehyde 8. Highlights of
this synthesis include a novel and efficient transannular Michael
addition/lactone reduction sequence to construct the highly
substituted 2,6-trans-tetrahydropyran, a diastereoselective IBr-induced
iodocarbonate cyclization to introduce the C17 stereogenic center, and
a Diels−Alder/aromatization reaction to install the highly substituted
aromatic ring.
n 2004, Crews and co-workers reported the isolation of
psymberin (1) (Figure 1) from the marine sponge
Scheme 1. Retrosynthetic Analysis of Psymberin
I
Psammocinia sp. collected from the waters of Papua New
Guinea.1 Independently, Pettit et al. reported the isolation of a
novel cytotoxic polyketide, irciniastatin A, from the extract of
Indo-Pacific marine sponge Ircinia ramosa.2 The first total
synthesis of psymberin, reported by De Brabander et al., not
only fully elucidated the structure but also confirmed
psymberin and irciniastatin A were structurally identical.3
Figure 1. Structure of psymberin (irciniastatin A) (1).
The architecturally intriguing and biologically potent yet
naturally scarce cytotoxin has spurred interest in the synthetic
community. To date, strategies for accomplishing the total,4
formal,5 or partial6 syntheses of psymberin have been reported
by several groups, and a comprehensive review7 of the current
state of this area was published by Bielitza et al. In connection
with our continuing interest in the synthesis of complex natural
products with promising biological activities,8 we embarked on
the development of an asymmetric total synthesis of
psymberin.
Structurally, psymberin is composed of a psymberic acid side
chain, a dihydroisocoumarin unit (DHIC), an N,O-hemiaminal
subunit, and a densely functionalized 2,6-trans-tetrahydropyran
(2,6-trans-THP) core. Retrosynthetic analysis of 1 (Scheme 1)
led us to an initial disconnection of the N,O-hemiaminal that
could be prepared from acid 2 and amide 3. The
dihydroisocoumarin motif was envisioned to be constructed
through Diels−Alder cyclization from a dienophilic alkyne 4,
which in turn would arise from 5, exploiting Brown asymmetric
crotylation followed by Bartlett iodine-induced carbonate
cyclization. Furthermore, it was envisaged that 2,6-trans-
tetrahydropyran moiety 5 could be derived from lactone 7
via a pivotal transannular oxa-Michael addition.
Received: March 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01113
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Our synthetic efforts commenced with the preparation of
psymberic acid (2) as outlined in Scheme 2. An organozinc
mixture (1.7:1) of 16 and 1711 in 92% yield. Undesired epimer
16 was readily converted into desired alcohol 17 in 85% yield
via a two-step sequence involving Swern oxidation12 and a
chelation-controlled reduction.13 Ozonolytic cleavage of the
terminal alkene in 17 gave rise to desired aldehyde 18 in 90%
yield, which was subsequently submitted to a Still−Gennari
modified HWE olefination14 with phosphonate 19. By
employing KHMDS as the base in combination with 18-
crown-6, the resultant cis-α,β-unsaturated ester underwent
concomitant transesterification to furnish unsaturated lactone
7 in 92% yield. It was hypothesized that acidic hydrolysis of the
pentylidene ketal protecting group afforded the corresponding
diol that could subsequently undergo an in situ transannular
oxa-Michael addition to give rise to cycloadduct 6. In the
event, treatment of lactone 7 with catalytic pyridinium p-
toluenesulfonate (PPTS) and water in toluene at 100 °C
provided 6 in 88% yield. As anticipated, careful examination of
NMR spectra of cycloadduct 6 allowed us to confirm the
stereochemistry. Furthermore, the facial selectivity of the
transannular oxa-Michael addition and the absolute and
relative configuration of cycloadduct 6 were confirmed by X-
ray crystallography of the corresponding p-nitrobenzoate
derivative. Carbinol 6 was then transformed into PMB ether
23 under acidic conditions, followed by reductive ring opening
with LiBH4 that furnished 2,6-trans-tetrahydropyranyl diol 5.
After successful construction of 2,6-trans-tetrahydropyran
(5) with the requisite stereochemistry, the stage was set for the
incorporation of the all-syn-oriented stereogenic centers at
C15−C17 (Scheme 4). Thus, treatment of diol 5 with
Scheme 2. Synthesis of Psymberic Acid 2
agent derived from 3-bromo-2-methylpropene underwent
chelation-controlled addition9 to commercially available
aldehyde 10 in the presence of SnCl2 to give rise to the
corresponding homoallylic alcohol 11 as a sole isomer in 87%
yield. Methylation of the homoallylic alcohol and subsequent
treatment of the methyl ether with p-toluenesulfonic acid in
methanol cleaved the acetonide moiety to afford diol 12 in
76% yield. This diol was subsequently converted into
monobenzoate 13 through a two-step sequence involving (1)
temporary protection of the primary alcohol as its TBS ether
and (2) benzoylation of the secondary hydroxyl group
followed by deprotection of the primary TBS ether under
acidic conditions. Alcohol 13 was converted into the
corresponding acid 2 in 70% overall yield by sequential
oxidation of the primary alcohol with Dess−Martin period-
inane, followed by Pinnick oxidation. The resulting carboxylic
acid (2) was then converted into the corresponding acid
chloride (14) that was sufficiently clean and could be used
directly in the coupling with fragment 3 (vide infra).
Scheme 4. Synthesis of Dienophile 29
The synthesis of 2,6-trans-tetrahydropyran commenced with
the known aldehyde 810 as shown in Scheme 3. Thus,
treatment of 8 with prenyl bromide and freshly activated zinc
powder under ultrasound sonication delivered a separable
Scheme 3. Synthesis of 2,6-trans-THP Derivative 5
triethylsilyl triflate and 2,6-lutidine led to the bis-silyl ether
(24) in 85% yield. Regioselective Swern oxidation15 of 24
proceeded without incident to afford aldehyde 25, which was
then subjected to Brown asymmetric crotylation,16 to furnish
the desired homoallylic alcohol 26 in 93% yield with excellent
diastereoselectivity. Next, we turned our attention to the
Bartlett iodine-induced carbonate cyclization17 as a means of
1,3-stereoinduction. Thus, treatment of homoallylic alcohol 26
with sodium bis(trimethylsilyl)amide followed by quenching
with Boc anhydride afforded the corresponding tert-butyl
carbonate 27 in 91% yield. tert-Butyl carbonate 27 was treated
with iodine monobromide in toluene at −78 °C, upon workup
with potassium carbonate in methanol to give rise to separable
diastereomers in a 5:1 ratio, with the desired epoxide (28)
isolated in 79% yield. Regioselective ring opening of epoxide
28 with lithium ethyl propiolate (THF, −78 °C) mediated by
B
DOI: 10.1021/acs.orglett.9b01113
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Organic Letters
Letter
BF3·Et2O led to alkynoate 4 in 54% yield. Subsequent bis-
silylation of 4 with triethylsilyl triflate and 2,6-lutidine
furnished silyl ether 29 in 67% yield.
compound 37 provided the primary alcohol, which was then
oxidized under Iwabuchi conditions,21 to afford acid 38 in 87%
yield over two steps. Treatment of acid 38 with ammonium
acetate and TBTU according to the protocol reported by
Pietruszka5b provided primary amide 39 in 81% yield. At this
stage, all of the protective groups in amide 39 were removed
upon exposure to B-bromocatechol borane in DCM. Treat-
ment of the crude product mixture with acetic anhydride gave
the corresponding peracetate 3 in 75% yield. This advanced
intermediate displayed spectral properties identical in all
respects to those previously reported by De Brabander.3,4h,5a
Employing a procedure developed by De Brabander,3,4h
tetraacetate 3 was eventually converted into psymberin (1).
Thus, 3 was treated with Meerwein’s reagent and poly(4-
vinylpyridine) (PVP) to provide an extremely moisture
sensitive imidate that was filtered, concentrated, condensed
with acid chloride 14, and subsequently subjected to reduction
with an ethanolic sodium borohydride solution to give rise to
peracetylated psymberin. Global deprotection of the acetyl
groups produced the crude product in a 2.5:1 diastereomeric
ratio, and psymberin (1) was isolated as the major product in
22% overall yield from 3 (Scheme 6).3,4h The specific rotation
and 1H and 13C NMR spectra of the synthetic sample of 1 are
in excellent agreement with the values reported for natural
psymberin.2,3,4h
Considering the requirement of stability to the harsh
conditions that would be required for the proposed Diels−
Alder reaction, cyclic diene 30, derived from dimedone,18
served as an effective diene in Diels−Alder reaction with
dienophilic alkyne 4 or 29. In the event, attempted Diels−
Alder reaction19 of alkyne 4 with diene 30 led to complex
mixtures. To our surprise and delight, heating dienophilic
alkyne 29 and diene 30 at 170 °C in a sealed tube for 3 days
resulted in the formation of the desired product 33 as a single
isomer in 64% yield (74% yield based on consumed 29).
Apparently, the transformation follows the designed cyclo-
addition with spontaneous fragmentation of the presumed
bicyclic intermediate 31 and extrusion of isobutylene and
subsequent cleavage of TMS ethers. Both phenolic groups in
33 were protected as their corresponding MOM ethers to give
rise to 34 in 83% yield. Next, regioselective bromination20 of
34 was effected with NBS in DCM/DMF to deliver 35 in
excellent yield. Lithium−bromide exchange of aryl bromide 35
upon treatment with n-BuLi at −100 °C followed by
quenching of the carbanion with methyl iodide furnished the
desired product 36 in 97% yield. TBAF-mediated removal of
the three triethylsilyl (TES) groups in 36 led to a facile
intramolecular transesterification with the ethyl ester to give
rise to the corresponding lactone ring of the dihydroisocou-
marin; reprotection of the two remaining free hydroxyl groups
as their TES ethers afforded 37 in 87% overall yield (Scheme
5).
Scheme 6. Completion of the Total Synthesis
With the two key fragments 14 and 37 in hand, the stage
was set for their union and elaboration into psymberin. In the
event, hydrogenolytic removal of the PMB group on
Scheme 5. Synthesis of Dihydroisocoumarin 37
In summary, the execution of a highly convergent strategy
has led to completion of the total synthesis of psymberin. Key
features of this synthesis include high levels of stereoselectivity
in a number of reactions, including a novel transannular
Michael addition/lactone reduction sequence for the con-
struction of the 2,6-trans-tetrahydropyran derivative, a
diastereoselective IBr-induced iodocarbonate cyclization, and
a Diels−Alder/aromatization reaction to install the highly
substituted aromatic system. As well as providing an avenue for
the preparation of the natural product, the synthesis would
provide access to analogues for further chemical biology
studies.
C
DOI: 10.1021/acs.orglett.9b01113
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Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01113.
■
S
Experimental details and data (PDF)
Accession Codes
CCDC 1899049 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yet@pkusz.edu.cn.
*E-mail: bryan_pku@qq.com.
ORCID
Yian Guo: 0000-0002-0341-6816
Tao Ye: 0000-0002-2780-9761
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the Shenzhen
Peacock Plan (KQTD2015071714043444), the National
Natural Science Foundation (21772009), the SZSTIC
(JCYJ20160527100424909, JCYJ20170818090017617,
JCYJ20170818090238288, and JSGG20170414114147358),
the GDNSF (2014B030301003), and the China Postdoctoral
Science Foundation (2018M641059 for Y.G.).
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