Total Synthesis of the Hamigerans

Article abstract of DOI:10.1002/anie.201604070

The first total synthesis of hamigerans D, G, L, and N–Q has been accomplished. A convergent approach was used to build the basic tricarbocyclic ring system bearing a 5-6-6 structure. A sequence of oxidative cleavage, homologation, and ring regeneration provided access to the 5-7-6 skeleton of hamigeran G. Based on the biogenetic hypothesis, elegant and highly efficient biomimetic transformations of hamigeran G into hamigerans D, N–Q, and L were achieved.

Full text of DOI:10.1002/anie.201604070

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604070
German Edition: DOI: 10.1002/ange.201604070
Natural Product Synthesis
Total Synthesis of the Hamigerans
Xiaojun Li, Dongsheng Xue, Cheng Wang, and Shuanhu Gao*
Abstract: The first total synthesis of hamigerans D, G, L, and
N–Q has been accomplished. A convergent approach was used
to build the basic tricarbocyclic ring system bearing a 5-6-6
structure. A sequence of oxidative cleavage, homologation, and
ring regeneration provided access to the 5-7-6 skeleton of
hamigeran G. Based on the biogenetic hypothesis, elegant and
highly efficient biomimetic transformations of hamigeran G
into hamigerans D, N–Q, and L were achieved.
virus in vitro without showing any significant cytotoxicity.[1]
Hamigeran G (6) inhibits growth of the P388 tumor cell line
as well as the HL-60 promyelocytic leukemia cell line (IC50
8 mm).[2a] We have noticed that Hamigerans and gukulenins
(Figure 1), a small group of marine tetraterpenoids from the
Korean sponge Phorbas gukulensis, have similar structural
features.[3] Gukulenins contain unusual bis(tropolone) frag-
ments, and gukulenins A (12) and B (13) inhibit growth of
human colon, renal, pharynx, and stomach cancer cell lines
with nanomolar IC50 values.
The unique structures and potent biological potential of
hamigerans have attracted considerable attention from syn-
thetic chemists.[4] Many synthetic studies have been reported,
including those by the groups of Nicolaou,[5] Clive,[6] Trost,[7]
Taber,[8] Stoltz,[9] Lau,[10] Jiang,[11] Miesch,[12] Xie and Zhou,[13]
and others.[14] These synthetic endeavors have focused mainly
on 2, while to the best of our knowledge, the more challenging
total syntheses of hamigerans and gukulenins containing
seven-membered rings have not been reported. Herein we
report the first total synthesis of hamigeran G (6) and its
biomimetic transformation into hamigerans L (4), D (7), and
N–Q (8–11).
H
amigerans belong to a family of halogenated natural
products isolated from the poecilosclerid sponge Hamigera
tarangaensis and were discovered by Cambie and co-workers
in 2000 (Figure 1).[1] More recent investigation of the same
Most hamigerans contain 5-6-6 or 5-7-6 fused tricarbo-
cyclic rings, also known as A-B-C rings (Scheme 1), which
include a cyclopentane ring (A ring) with three stereogenic
centers as well as a polysubstituted aromatic ring (C ring).
Careful structural analysis has shown that the major structural
differences among hamigerans are in the size and function-
alization of the B ring. Oxidative cleavage of the B ring of the
Figure 1. Hamigerans and gukulenins.
sponge by Northcote and co-workers led to the isolation of
several new hamigerans, particularly the nitrogenous con-
geners hamigeran D (7) and N–Q (8–11).[2] To date, over 30
hamigerans have been discovered and identified, and most of
them show interesting biological activities. Notably, hamiger-
an B (2) completely inhibits replication of herpes and polio-
[*] X. Li, D. Xue, C. Wang, Prof. Dr. S. Gao
Shanghai Key Laboratory of Green Chemistry and Chemical Pro-
cesses, School of Chemistry and Molecular Engineering
East China Normal University
3663N Zhongshan Road, Shanghai 200062 (China)
E-mail: shgao@chem.ecnu.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604070.
Scheme 1. Structural and retrosynthetic analysis. FG=functional
group.
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tricycle leads to formation of 5-6 structures (A-C rings), which
are the basic skeletons of hamigerans E (3) and L (4).
Northcote hypothesized that condensing 6 with various amino
acids should generate 7 and 8–11, which contain a benzoxazine
ring (D ring).[2b] Gukulenins and hamigerans share a similar
basic skeleton (A-B rings) and differ primarily in the aromatic
tropolone C ring.
Based on this structural analysis, we postulated that
hamigerans and gukulenins could be synthesized from the
same intermediate 15 with the basic 5-6-6 structure (A-B-C
ring; Scheme 1). Appropriate ring-opening or ring-expansion
reactions could regulate the size of the B or C ring, thus
affording related natural products. Based on this hypothesis,
we cleaved 15 to give the fragments 16 (A ring) and 17
(C ring), and used Suzuki–Miyaura cross-coupling and
McMurry coupling to construct the central B ring.
benzyl group and subsequent PCC oxidation furnished the
ketone 24, which was efficiently converted into 16. The
aryltriflate 25 was derived from 2,6-dimethoxy-4-methylbenz-
aldehyde in two steps[19] and then transformed into the
pinacol boronate 17 by Miyauraꢀs protocol[18] involving
palladium-catalyzed borylation with bis(pinacolato)diboron.
With both coupling components in hand, we explored the
palladium-catalyzed Suzuki–Miyaura cross-coupling reaction
(Scheme 3).[20] Treating 16 and 17 with PdCl2(dppf)·CH2Cl2 in
Our synthesis commenced with the syntheses of the
coupling fragments vinyl triflate 16 and arylboronate 17
(Scheme 2). The starting material was (R)-piperitone (18),
Scheme 3. Attempt at the B ring expansion. DME=1,2-dimethoxy-
ethane, DMSO=dimethylsulfoxide.
the presence of K2CO3 in DMSO produced the desired
coupling products 26 and 27 as a mixture of two rotamers in
excellent yield. Removal of the ketal groups of both rotamers
generated dialdehyde intermediates, which were converted,
by McMurry coupling, into the cyclized compound 28 in 67%
yield over two steps. The compound 28 contains the basic 5-6-
6 tricarbocyclic skeleton and was considered to be a common
intermediate for the divergent synthesis of hamigerans. We
speculated that olefin cyclopropanation on the B ring and
subsequent ring opening would form a molecule with a 5-7-6
structure. Reacting 28 with dibromocarbene smoothly deliv-
ered the gem-dibromocyclopropane 29 in 50% yield, and
subsequent treatment with AgNO3, AgOAc, or other silver
salts led to electrophilic ring opening in 29, thus generating 30
and then the allylic carbocation 31. We reasoned that this
carbocation could be intermolecularly trapped by water to
form the hydroxylated products 32 or 33 (Scheme 3; path-
way a). Instead, the undesired compounds 34 and 35 were
produced by an intramolecular reaction with the electron-rich
olefin (Scheme 3; pathway b).[21]
Scheme 2. Preparation of the two coupling components. DCM=di-
chloromethane, dppf=1,1’-bis(diphenylphosphanyl)ferrocene, LDA=
lithium diisopropylamide, PCC=pyridinium chlorochromate, TMS=tri-
methylsilyl, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran.
which contains an isopropyl group,[15] and was efficiently
converted into the epoxide 19 through a previously described
two-step procedure.[16] Protecting the hydroxy group of 19 as
benzyl ether gave the compound 20, after which ring
contraction was achieved using acid-promoted semipinacol
rearrangement, thus generating the cyclopentane A ring.[17]
Extensive screening of reaction conditions using various
Lewis and Brønsted acids showed that the reaction could be
promoted using a catalytic amount (10 mol%) of trifluoro-
methanesulfonic acid, thus providing the aldehyde 21, having
a quaternary carbon atom (C9), as a single diastereomer.
Adding 1,2-bis(trimethylsiloxy)ethane to the reaction mix-
ture directly protected the aldehyde group as a dioxolane,
thus affording 22 in 79% yield over two steps. Removal of the
Therefore we revised our strategy for generating the
seven-membered B ring, thus opting for a sequence of
oxidative cleavage, homologation, and ring regeneration
=
(Scheme 4). The C10 C11 bond in the B ring of 28 was
2
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Scheme 4. Total synthesis of 6. X-ray structures are shown. Thermal ellipsoids shown at 50% probability.[24] DMP=Dess–Martin periodinane,
NMO=4-methyl-morpholin-4-oxide, PTSA=p-toluenesulfonic acid, Py=pyridine.
selectively dihydroxylated and the resulting diol was pro-
tected as acetates, thus affording 37. High-pressure hydro-
the reactivity of 6 with various amino acids. As predicted,
heating a solution of 6 with l-phenylalanine in 2-methyl-
tetrahydrofuran at 808C generated 8 and its 18-epi isomer in
a ratio of 2.4:1 in 55% yield (Scheme 5). We proposed that
=
genation of the tetrasubstituted olefin (C5 C6) and hydrol-
ysis of the acetates gave the desired product 38 as a single
diastereomer with cis-fused stereochemistry, which was con-
firmed by X-ray analysis. Oxidative cleavage of the diol in 38
using sodium periodate produced the dialdehyde 39, in which
the aldehyde at C9 could be selectively protected as a ketal.
One-carbon homologation of the resulting monoaldehyde
was achieved through methylmagnesium bromide addition
followed by Dess–Martin oxidation, thus yielding the com-
pound 40 after removal of the ketal group. Intramolecular
aldol reaction under basic conditions generated a b-hydroxy
ketone (41a and 41b, d.r. = 5:1) with a seven-membered
B ring. The relative stereochemistry of 41a was confirmed by
X-ray analysis. PTSA-mediated dehydration of 41a and 41b
smoothly provided the enone 42. Hydrogenation of this enone
followed by methoxy group removal using BBr3 afforded the
ketone 43 in 95% yield over two steps.[22] Various brominating
reagents were tested for their ability to achieve regioselective
o-bromination of the phenol 43, including NBS/iPr2NH,
tetrabutylammonium tribromide, and pyrrolidone hydrotri-
bromide. Pyridinium tribromide (py·HBr3) was found to work
best, thus providing the monobrominated product in excellent
yield. Finally, selenium dioxide oxidation in the presence of
catalytic acetic acid[23,10,14a] led to introduction of the 1,2-
Scheme 5. Biomimetic transformation of 6 into 8 and its 18-epi isomer.
condensing 6 with l-phenylalanine gave the imine intermedi-
ate 44, which underwent tautomerization and a key decar-
boxylation to generate 45 with higher oxidation state.
Subsequent 6p electrocyclization of 45 generated the ben-
zoxazine D ring and furnished the desired products.
We then showed that 6 can serve as a common biogenetic
precursor for synthesizing 7, 9–11, and their 18-epi isomers by
reacting 6 with appropriate amino acids as described above
for l-phenylalanine (Scheme 6). We predict that this strategy
will allow preparation of benzoxazine-containing hamigerans
and their derivatives, some of which may be isolated from
natural sources in the future. In addition, we were able to
transform 6 into hamigeran L (4) through a three-step
1
diketone moiety, thus completing the total synthesis of 6. H
and 13C NMR spectra as well as HRMS data for synthetic (À)-
6 were in agreement with published data for the natural
product.[2a] Hamigeran G (6) was found to exist as an
equilibrium mixture of twist-chair and twist-boat conformers,
fully consistent with observations by Northcote and co-
workers.[2a]
Naturally occurring 7 and N–Q (8–11), as well as their 18-
epi isomers contain the basic skeleton (A-B-C ring) of 6 with
an unusual benzoxazine D ring. Northcote and co-workers
proposed that these molecules could be viewed as hybrids of
amino acids and 6.[2b] To test this hypothesis, we investigated
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Scheme 6. Divergent synthesis of hamigerans. Reagents and condi-
tions: a) d-alanine, 2-Me-THF, 808C, d.r.=1.6:1 at C18, 50%(78%
brsm); b) dl-leucine, 2-Me-THF, 808C, d.r.=1.4:1 at C18, 60% (65%
brsm); c) l-valine, 2-MeTHF, 808C, d.r.=3.9:1 at C18, 43%(57%
brsm); d) l-isoleucine, 2-MeTHF, 808C, d.r.=1.8:1 at C18, 56% (60%
brsm); e) MOMCl, K2CO3, DMF, 08C; f) H2O2, NaOH, 1,4-dioxane,
08C; g) HCl, H2SO4, THF, RT, 34% (3 steps). brsm=based on
recovered starting material, DMF=N,N-dimethylformamide, MOM=
methoxymethyl.
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sequence involving phenol group protection, oxidative cleav-
age of the diketone, and deprotection.
In summary, we have accomplished the first total synthesis
of hamigerans L (4), G (6), D (7), and N–Q (8–11). A
convergent synthetic strategy was developed based on the
versatile common intermediate 28. Our results suggest that
benzoxazine-containing 7 and 8–11 may derive from naturally
occurring amino acids and 6. We believe that this biomimetic
approach should enable the synthesis of a variety of
hamigerans and their derivatives, thus facilitating biological
studies of these promising natural products. We are currently
studying the total synthesis of the gukulenins.
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Acknowledgments
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1 mLminÀ1, 230 nm).
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We thank the National Natural Science Foundation of China
(21272076, 21422203), National Young Top-notch Talent
Support Program, the Qi Ming Xing Foundation of Shanghai
Ministry of Science and Technology (14QA1401400), and the
program for professor of special appointment (Eastern
Scholar) at Shanghai institutions of higher learning and
Program for Changjiang Scholars and Innovative Research
Team in University (PCSIRT) for generous financial support.
Keywords: biomimetic synthesis · cross-couplings ·
heterocycles · natural products · total synthesis
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4
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tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
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[22] The ketone 43 exists as an equilibrium mixture of two con-
formers at a ratio of 1.9:1.
Received: April 27, 2016
[23] N. Rabjohn, Org. React. 1976, 24, 261.
Published online: && &&, &&&&
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Communications
Natural Product Synthesis
X. Li, D. Xue, C. Wang,
S. Gao*
&&&& — &&&&
Total Synthesis of the Hamigerans
The hammer: The total synthesis of
hamigerans D, G, L, and N–Q has been
accomplished from a common inter-
mediate bearing the basic 5-6-6 structure.
A sequence of oxidative cleavage, homo-
logation, and ring regeneration provided
access to the 5-7-6 skeleton of hamiger-
an G which was transformed into hami-
gerans D, N–Q, and L efficiently based on
a biomimetic hypothesis.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!