Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum

Article abstract of DOI:10.1002/anie.201510861

Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B-type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1-aza-perhydrocyclopentalene core, representing rings A and E of all calyciphylline B-type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4-conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2-carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines. The missing link? A concise and highly convergent total synthesis of isodaphlongamine H was accomplished in 24 linear steps. The molecule exhibited promising inhibitory activity against a panel of human cancer cell lines. PCC=pyridinium chlorochromate.

Full text of DOI:10.1002/anie.201510861

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International Edition: DOI: 10.1002/anie.201510861
German Edition: DOI: 10.1002/ange.201510861
Total Synthesis
Total Synthesis of Isodaphlongamine H: A Possible Biogenetic
Conundrum
Amit Kumar Chattopadhyay, Vu Linh Ly, Shashidhar Jakkepally, Gilles Berger, and
Stephen Hanessian*
Abstract: Herein we describe the first synthetic efforts toward
the total synthesis of isodaphlongamine H, a calyciphylline B-
type alkaloid. The strategy employs a chemoenzymatic process
for the preparation of a functionalized cyclopentanol with
a quaternary center. This molecule is elaborated to form an
enantiopure 1-aza-perhydrocyclopentalene core, representing
rings A and E of all calyciphylline B-type alkaloids. Further
transformations involve the formation of a cyclic enaminone,
1,4-conjugate addition with a cyclopentenyl subunit, and
intramolecular aldol cyclization to achieve a pentacyclic
intermediate, ultimately forming isodaphlongamine H in
a total of 24 steps from the commercially available compound
2-carbethoxycyclopentanone. Isodaphlongamine H exhibits
promising inhibitory activity against a panel of human
cancer cell lines.
was assigned by NMR spectroscopic analysis (Figure 1).[9] In
the same year, deoxycalyciphylline B (2) and deoxyisocalyci-
phylline B (3) were isolated from the stem of D. subverticil-
latum by Yue and Yang.[10] In 2009, Hao and co-workers
reported the isolation of daphlongamine H (4), a new caly-
ciphylline B-type alkaloid with an unprecedented C6/C7 cis-
ring junction, from the leaf extracts of the evergreen tree D.
longeracemosum Rosenth.[11] The structure and stereochem-
istry of daphlongamine H was proposed based on NMR
spectroscopy and its biogenetic relationship with deoxycaly-
ciphylline B, whose structure had been confirmed by X-ray
crystallography.[10] We now report the total synthesis of
isodaphlongamine H, the biogenetically related 5-epi isomer
of daphlongamine H (Figure 1).
T
he Daphniphyllum alkaloids are among the structurally
most diverse group of polyazacyclic natural products belong-
ing to a single genus of the family Daphniphyllaceae.[1] To
date, over 300 different structurally distinct alkaloids have
been isolated and characterized, representing complex poly-
azacyclic cage-like architectures. Besides their biological
activities,[1] their biosynthesis, starting with mevalonic acid
and proceeding via squalene dialdehyde to progressively
complex intermediates, is a fascinating example of the
ingenuity of nature. Following pioneering efforts by Suzuki,
Yamamura, and co-workers,[2] a unifying biosynthetic path-
way to prepare the Daphniphyllum alkaloids was proposed by
Heathcock and Ruggeri.[3] This seminal contribution paved
the way to the elegant total syntheses of several members of
this family by the Heathcock group.[4] Inspired by these
landmark feats in the total synthesis of complex Daphniphyl-
lum alkaloids, a number of groups have reported creative
approaches toward the synthesis of a variety of core
structures.[5] However, efforts toward the total synthesis of
other complex Daphniphyllum alkaloids have been sparse.
Only relatively recently have the total syntheses of daphma-
nidin E, daphenylline, and calyciphylline N been reported by
the groups of Carreira,[6] Li,[7] and Smith,[8] respectively.
In 2003, Kobayashi and Morita isolated calyciphylline B
(1) from the leaves of D. calycinum and the tentative structure
Figure 1. Representative calyciphylline B-type alkaloids and their
synthetic analogues.
The biosynthetic pathway proposed by Yue and Yang[10]
for deoxycalyciphylline B and deoxyisocalyciphylline B,
which differ only in the spatial disposition of the C5 methyl
group, presents a possible conundrum (Figure 2). Thus, it is
proposed that biosynthetic carbocation intermediate A,
harboring cis-oriented hydrogens at the C6 and C7 positions,
loses a hydrogen atom to give the neutral tetrasubstituted
olefin intermediate B, which would capture a proton in an
undefined process to give carbocation C, containing trans-
oriented hydrogens at the C6 and C7 positions. Lactone
formation with the appended propionic acid chain would
deliver deoxycalyciphylline B (2) and deoxyisocalyciphylli-
ne B (3).
[*] Dr. A. K. Chattopadhyay, V. L. Ly, Dr. S. Jakkepally, Dr. G. Berger,
Prof. Dr. S. Hanessian
Department of Chemistry, UniversitØ de MontrØal
Station Centre Ville, C.P. 6128, MontrØal, Qc, H3C 3J7 (Canada)
E-mail: stephen.hanessian@umontreal.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510861.
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Figure 3. Key synthetic steps toward daphlongamine H (4).
We commenced our synthetic efforts with 2-carbethoxy-
cyclopentanone (6) which was transformed to enantiopure
cyclopentanol 7 in two consecutive steps using a known
chemoenzymatic process[12] (Scheme 1). Swern oxidation of 7
provided b-ketoester 8 in 96% yield. A diastereoselective
alkylation of the corresponding Na enolate with triflate 9
prepared from d-lactic acid afforded a 1:1 inseparable
mixture of 10 in 41% yield.[13,14] Reduction of 10 was best
achieved under Luche conditions to give the corresponding
cyclopentanol as a single isomer after chromatographic
separation, which was then converted into diol 11 by
reduction of the ester with DIBAL-H. Bis-mesylation,
followed by selective monoazidation using Bu4NN3 in toluene
afforded 12 in 76% yield over two steps. Treatment of 12
Figure 2. Proposed biosynthetic pathway to deoxycalyciphylline B and
deoxyisocalyciphylline B[10] and the anticipated pathway to form
daphlongamine H (natural) and isodaphlongamine H (synthetic). The
structures of intermediates A–C were redrawn in the perspectives
shown to correspond to the drawing of the natural products. For the
original drawings, see Ref. [10].
We propose that daphlongamine H can result from the
direct C5 capture of the carbocation Awith the propionic acid
chain. Although not isolated from the extracts of the same
plant source as yet, one would also expect lactonization of
carbocation A to provide the 5-epi isomer, that is, isoda-
phlongamine H (5), in analogy with the isolation of deoxy-
calyciphylline B (2) and its 5-iso epimer (3). In this respect
our synthetic isodaphlongamine H could be the “missing”
fourth component in the biosynthetically related calyciphyl-
line B-type quartet of Daphniphyllum alkaloids.
The unique hexacyclic framework harboring an unprece-
dented C6/C7 cis-fused stereochemistry in the deoxycalyci-
phylline B family, as well as the intriguing biosynthetic
intermediates, encouraged us to undertake the total synthesis
of daphlongamine H (4) and its 5-epi isomer (5). We were also
cognizant that a strategy which would produce a common
advanced intermediate could also be applicable toward the
total synthesis of the biogenetically related deoxycalyciphyl-
line B (2) and deoxyisocalyciphylline B (3) (Figure 2). The
hexacyclic framework of daphlongamine H contains eight
stereogenic carbon atoms of which one is quaternary at the C8
position. A schematic representation of the key bond-forming
reactions is shown in Figure 3. We assumed that an enolate
alkylation and an intramolecular cyclization would be used to
access rings A and E. The central ring B could be generated
from a cyclic enaminone which would undergo 1,4-conjugate
addition with a cyclopentenyl organometallic subunit. Sub-
sequent intramolecular aldol cyclization of a keto aldehyde
would generate the pentacyclic framework harboring
rings A–E. Finally, a late-stage lactonization would provide
daphlongamine H and/or isodaphlongamine H.
Scheme 1. Synthesis of tricyclic enaminone 16. Reagents and condi-
tions: a) (COCl)2, (Me)2SO, CH2Cl2, Et3N, À78 to 08C, 96%;
b) NaHMDS, toluene, À78 to À40 to À788C, then 9, À78 to À408C,
41% yield (75% brsm), 1:1 mixture of diastereomers; c) NaBH4,
CeCl3·7H2O, MeOH, 08C, 43%; d) DIBAL-H, CH2Cl2, À788C, 69%;
e) MsCl, pyridine, DMAP, CH2Cl2, RT, 92%; f) Bu4NN3, toluene, RT,
83%; g) PPh3, THF, 1n aqueous NaOH, RT, then (Boc)2O, 91%;
h) DIBAL-H, CH2Cl2, À78 to À408C, 75%; i) Dess–Martin periodinane,
CH2Cl2, RT, 91%; j) Ethynyl MgBr, THF, 08C to RT; k) Dess–Martin
periodinane, CH2Cl2, RT, 85% (two steps); l) formic acid, NaI, RT, then
evaporated to dryness, then K2CO3, MeOH, RT, 80%. HMDS=
1,1,1,3,3,3-hexamethyldisilazane, THF=tetrahydrofuran, DIBAL-H=
diisobutylaluminum hydride, Ms=methane sulfonyl, DMAP=4-di-
methylaminopyridine, Boc=tert-butyl carbonyl; brsm=based on
recovered starting material.
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under Staudinger conditions led to the primary amine, which
underwent in situ intramolecular cyclization to give the aza-
octahydropentalene core unit 13 as the N-Boc derivative in
91% yield. DIBAL-H reduction of the ethyl ester, followed
by Dess–Martin oxidation of the corresponding alcohol,
afforded aldehyde 14 which was treated with ethynylmagne-
sium bromide, and the resulting alcohol was oxidized to ynone
15. Cyclization in the presence of formic acid, NaI and K2CO3
according to the procedure of Georg et al.[15] afforded the
cyclic enaminone 16 with an overall yield of 68% for the three
steps.
The synthesis of the cyclopentene subunit corresponding
to ring D started with the known enantiopure alcohol 18
(Scheme 2).[16] A Johnson–Claisen rearrangement in the
presence of catalytic propionic acid at 1458C led to the
homoallylic ester which was reduced with DIBAL-H, and the
resulting alcohol 19 was protected as the TBS ether 20 in
a maximum of 37% overall yield.
Scheme 2. Synthesis of the cyclopentene subunit. Reagents and con-
ditions: a) CH3C(OCH3)3, propionic acid, 1458C; b) DIBAL-H, CH2Cl2,
À78 to À408C, 25–40% (two steps); c) TBSCl, Et3N, CH2Cl2, RT, 93%.
TBS=tert-butyl dimethyl silyl.
Scheme 3. Synthesis of isodaphlongamine H. Reagents and condi-
tions: a) 20, nBuLi, Et2O, À788C; then CuBr·Me2S, BF3·Et2O, THF,
À788C, then 16, À788C to RT, 92%; b) (Æ)-CSA, CH2Cl2, MeOH, RT,
91%; c) PCC, CH2Cl2, RT, 65%; d) TBD, THF, RT, 90%; e) p-TSA, 1,1,2-
trichloroethane, 658C, 70%; f) L-Selectride, Et2O, À78 to À208C,
60%; g) MeLi, THF, À78 to +108C, 85%; h) 9-BBN, THF, RT; then
2n NaOH, H2O2, RT; i) PCC, CH2Cl2, RT, 65% (two steps). CSA=
camphorsulfonic acid, PCC=pyridinium chlorochromate, TBD=1,5,7-
triazabicyclo[4.4.0]dec-5-ene, p-TSA=p-toluenesulfonic acid, 9-
BBN=9-borabicyclo[3.3.1]nonane; L-Selectride=lithium tri-sec-butyl-
borohydride.
With the tricyclic enaminone 16 and cyclopentenyl iodide
20 in hand, we proceeded with the intended 1,4-conjugate
addition. Thus, treatment of the iodide 20 with nBuLi
generated the vinyllithium reagent 21, which was added to
the enaminone 16 in the presence of BF3·Et2O and
CuBr·Me2S, based on related precedents by Comins and co-
workers,[17] to give adduct 22 in 92% yield and 90% d.e.
(Scheme 3). Silyl deprotection to the alcohol 23 gave a single
diastereomer which was oxidized with PCC to the keto-
aldehyde intermediate 24 in 59% yield over two steps.
Following several trials with various bases, we found that
TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) led to intramolec-
ular aldol cyclization to give 25 in 90% yield.[18] A single
crystal X-ray structure analysis confirmed the stereochemis-
try of the cyclization product including the cis-orientation at
the B/C ring junction.[14,19] Treatment of 25 with p-TSA in
1,1,2-trichloroethane at 658C resulted in smooth elimination
to give the enone 26 which was subjected to conjugate
reduction with L-Selectride to afford the pentacyclic inter-
mediate 27 in 42% yield for two steps. Addition of MeLi
afforded exclusively the tertiary alcohol 28 whose structure
and stereochemistry were determined by X-ray crystallogra-
phy of the corresponding methiodide salt.[14,19] Considering
the cis-junction of rings B and C in 27, it is not surprising that
the trajectory of approach of the MeLi reagent toward the
carbonyl group favored the less hindered a-face. In view of
this result, we chose to complete the synthesis of isodaphlon-
gamine H (5). Thus, the allylic double bond in 28 was
hydroborated to the primary alcohol and the latter was
oxidized with PCC to the lactol which was further trans-
formed in situ to lactone 5. An X-ray crystal structure analysis
of 5 confirmed the absolute stereochemistry.[14,19] It is
interesting to note that in the crystal structure of deoxycaly-
ciphylline B, ring C adopts a boat conformation,[14] whereas
the crystal structure of our synthetic isodaphlongamine H (or
6-epi-deoxycalyciphylline B) shows a chair conformation
(Figure 4).[14] DFT calculations also suggest that isodaphlon-
gamine H is 3.3 kcalmolÀ1 more stable than deoxycalyciphyl-
line B.[14]
Considering the proposed biosynthetic pathway, it is
intriguing that intermediate A would preferentially give the
tetrasubstituted intermediate olefin B, which would be subject
to severe A1,3-strain only to reprotonate to C, then to cyclize
to deoxycalyciphylline B (2) and deoxyisocalyciphylline B
(3). In an attempt to reproduce the synthetic equivalent of the
proposed tetrasubstituted intermediate B in the biosynthetic
pathway[10] (Figure 2), we investigated the tertiary alcohol 28
under a variety of elimination reaction conditions. These led
exclusively to the exocyclic methylene product 29 (Scheme 4).
All attempts to isomerize it to the endocyclic pentacycle 30
corresponding to the intermediate B in the biosynthesis
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study. Based on the carbocation intermediate A proposed by
Yue, it seems highly probable that daphlongamine H and
isodaphlongamine H can be formed by direct lactonization.
The only biological activity in this unique family of
hexacyclic alkaloids has been reported for calyciphylline B
(IC50 = 12 mm against L1210 cells).[9] With the new synthetic
alkaloid isodaphlongamine H (5; 6-epi-deoxycalyciphylli-
ne B) in hand, we have obtained in vitro data on a panel of
NCI human cancer cell lines. Preliminary studies showed that
isodaphlongamine H exhibited good cytotoxicity against
HOP-92 (lung), SNB-75 (central nervous system),
MDA_MB-435 (melanoma), and UO-31 (renal) cell lines
with GI50 (50% growth inhibition) values of 38, 35, 48, and
43 mm respectively.[14] The natural product deoxycalyciphylli-
ne B, tested for the first time, was found to be only two times
more active than isodaphlongamine H.
In conclusion, we have reported a highly convergent total
synthesis of isodaphlongamine H accomplished in 24 linear
steps from the commercially available 2-carbethoxycyclo-
pentanone 6. Isodaphlongamine H, the 5-epi isomer of
daphlongamine H (the only cis-fused naturally occurring
Daphniphyllum alkaloid isolated to date among the calyci-
phylline B family), is believed to be the missing component in
this quartet of structurally unique hexacyclic alkaloids. Their
hitherto unreported antitumor activities against a variety of
cancer cell lines warrants further effort toward the total
synthesis of related congeners.
Acknowledgements
We thank Steven Cummings (McGill University) and Gabriel
Meilleur (UniversitØ de MontrØal) as undergraduate research
participants for Bakerꢀs yeast resolution experiments. We are
thankful to Dr. Michel Simard for X-ray crystallography and
to Dr. CØdric Malveau for high-resolution NMR studies. We
are also very grateful to Professor Yue for an X-ray quality
sample of deoxycalyciphylline B as a reference compound.
Anticancer activity was determined at the National Cancer
Institute (Washington, D.C.) for which we are highly appre-
ciative.
Figure 4. ORTEP diagrams of isodaphlongamine H and deoxycalyci-
phylline B.[19]
Keywords: alkaloids · deoxycalyciphylline B · enaminones ·
natural products · total synthesis
Scheme 4. Attempted synthesis of the tetrasubstituted intermediate B
reported by Yue and Yang (Ref. [10]). Reagents and conditions:
a) BF3·Et2O, CH2Cl2, 80%; or SOCl2, pyridine, THF, À50 to +108C,
85%; b) oxalic acid, toluene, 1158C; or p-TSA, 1,1,2-trichloroethane,
1158C.
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Received: November 23, 2015
Published online: January 14, 2016
Angew. Chem. Int. Ed. 2016, 55, 2577 –2581
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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