Efficient total synthesis of marine alkaloid (-)-nakadomarin A

Article abstract of DOI:10.1002/chem.201102101

Z's top: For the total synthesis of the marine alkaloid (-)-nakadomarin A, (-)-camphorsulfonic acid assisted, Z-selective, olefin RCM of a monoamine (less polar) rather than a diamine (more polar) was found to be highly practical for constructing the F ring. The ABCD-tetracyclic core was assembled through a novel efficacious PtCl₂-promoted cascade reaction sequence (see scheme).

Full text of DOI:10.1002/chem.201102101

COMMUNICATION
DOI: 10.1002/chem.201102101
Efficient Total Synthesis of Marine Alkaloid (ꢀ)-Nakadomarin A
Bin Cheng,[a] Fufang Wu,[a] Xiaobao Yang,[b] Yuedong Zhou,[a] Xiaolong Wan,[b] and
Hongbin Zhai*[b, c]
In 1997, Kobayashi and co-workers disclosed the isolation
of (ꢀ)-nakadomarin A (1, Scheme 1) from an Okinawan
marine sponge Amphimedon sp. Its unique 8/5/5/5/15/6 hex-
acyclic full-ring structure containing four stereogenic centers
and an imbedded furan was shown with extensive NMR
spectroscopic analyses including NOE and proton coupling
data.[1a] The biological properties of 1 range from prominent
cytotoxicity against murine lymphoma L1210 cells to out-
standing antimicrobial and CDK4 inhibitory activities.[1b]
Since 2003, elegant total and formal syntheses[2] of 1 have
been accomplished by the laboratories of Nishida,[2a,b]
Kerr,[2c] Dixon,[2d] Mukai,[2e] and Funk,[2f] and relevant syn-
thesis studies have been reported by an array of research
teams.[3] Having communicated a rapid construction of the
tetracyclic core (ABCD rings) of ent-1 by showcasing the
power of a PtII-promoted cascade reaction sequence,[3i] we
report herein a novel total synthesis of (ꢀ)-nakadomarin A
with higher practicality and efficiency. The synthesis fea-
tures: 1) the assembly of the tetracyclic core through the
PtCl2-catalyzed cascade cyclization strategy[3i] (4!3,
Scheme 1) followed by saturation[3i] of the C8=C9 double
bond (3!2), and 2) CSA-assisted[2d] Z-selective olefin ring-
closing metathesis (RCM; within 2!1) involving a mono-
amine precursor (17, Scheme 2) used to replace Dixonꢀs
more polar diamine substrate (19b)[2d] for the F ring genera-
tion. For the rest of our synthesis plan (Scheme 1), the
E ring can be forged by typical olefin RCM[2a–c,e] (within 2!
1) prior to the F ring formation. Enyne 4 can be obtained
through Sonogashira coupling of terminal alkyne 5 with io-
dofuran 7. While reductive amination of aldehyde 6 can be
implemented to form alkyne 5, furan 7 can be accessible
from cyclization/iodination of conjugated ynone 8 in the
presence of hydriodic acid. Finally, ketone 8 can be pre-
pared from 9 and 10.
The synthesis of disubstituted furan 7 is described in
Scheme 3. Propargyl alcohol THP ether[4] (9) was deproton-
ated and then treated with g-butyrolactone (10) in the pres-
ence of BF3·OEt2 to give ynone 8, treatment[5] of which with
hydriodic acid (3m) effected the desired cyclization/iodina-
tion to afford a mixture containing alcohol 11 and its THP
ether (generated due to THP migration). Subjecting the
above mixture to TsOH in MeOH led to 11 (52%, from 9)
as the sole product, which was silylated to furnish iodofuran
7 in 89% yield.
Scheme 1. Retrosynthetic analysis of (ꢀ)-nakadomarin A (1). R:
(CH2)3OTBDPS.
[a] Dr. B. Cheng, F. Wu, Y. Zhou
Hefei National Laboratory for Physical Science at Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei 230026 (P.R. China)
[b] Dr. X. Yang, X. Wan, Prof. Dr. H. Zhai
CAS Key Laboratory of Synthetic Chemistry
of Natural Substances and State Key Laboratory of Bioorganic
and Natural Products Chemistry
Unsaturated aldehyde 6[6] was converted into compound 5
(54%, overall yield) by stepwise[3i] reductive amination
(propargylamine.HCl, TEA, tBuOH, evaporation, NaBH4,
MeOH) followed by N-sulfonylation (BsCl, TEA, DCM).
Shanghai Institute of Organic Chemistry
Shanghai 200032 (P.R. China)
[c] Prof. Dr. H. Zhai
[PdACTHUNTGRNEUGN(PPh3)2Cl2]/CuI-catalyzed Sonogashira coupling of termi-
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (P.R. China)
nal alkyne 5 with furan 7 in degassed TEA/DMF at room
temperature gave rise to the key molecule 4 (87%), in
which the enecarbamate, alkyne and furan functionalities
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102101.
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Scheme 2. Synthesis of (ꢀ)-nakadomarin (1). Reagents and conditions: a) propargylamine.HCl, TEA, tBuOH, evaporation, NaBH4, MeOH; b) BsCl,
TEA, DCM, 54% (2 steps); c) 7, [PdACHTNURTGNE(UGN PPh3)2Cl2], CuI, TEA, DMF, 87%; d) PtCl2, MePh, 808C, 81%; e) BH3·SMe2, THF, H2O2, NaOH, 81%; f) NaH,
CS2, MeI, THF; g) Bu3SnH, AIBN, MePh, 94% (2 steps); h) DIBAL-H, DCM; i) Wittig, 74% (2 steps); j) ZnBr2, DCM; k) 5-hexenoyl chloride, TEA,
DMAP, DCM; l) TBAF, THF, 70% (3 steps); m) Grubbsꢀ second-generation catalyst (20 mol%), DCM, 508C; n) Swern; o) Wittig, 70% (3 steps);
p) Na, naphthalene, THF; q) 6-bromo-1-hexene, K2CO3, EtOH, 91% (2 steps); r) Grubbsꢀ first-generation catalyst (25 mol%), (ꢀ)-CSA, DCM, 508C, Z/
E about 2:1, 65% (E+Z), 31% (pure 18); s) Red-Al, MePh, 85%. R: (CH2)3OTBDPS; R’: (CH2)3OH; Bs: benzenesulfonyl chloride; TEA: triethyl-
ACHTUNGTRENNUNGamine; AIBN: azodiisobutyronitrile; TBAF: tetrabutylammonium fluoride; CSA: camphorsulfonic acid; Red-Al: sodium bis(2-methoxyethoxy)-
aluminum hydride.
2) reduction with TFA/Et3SiH,[3i] or 3) hydroboration fol-
lowed by protonation (with HBr or HOAc),[3i] 3 was subject-
ed to stereoselective hydroboration (BH3·SMe2) followed by
oxidation (H2O2, NaOH)[3i] to form alcohol 12 (81%), and
the C8 configuration was correctly established. Barton–
McCombie reaction[8] (Bu3SnH, AIBN, MePh) with prior
xanthate formation[9] (NaH, CS2, MeI, THF) generated tet-
racyclic core 2 (ABCD rings) in 94% overall yield.[3i]
Scheme 3. Synthesis of iodofuran 7. Reagents and conditions: a) BuLi,
BF3·Et2O, THF, 10; b) HI, MePh; c) TsOH, MeOH, 52% (3 steps);
d) TBDPSCl, Im, DMAP, DCM, 89%. TBDPSCl: tert-butyldiphenyl-
chlorosilane; Im: imidazole; THP: tetrahydropyranyl.
At this point, how to efficiently construct the E and
F rings in 1 became a central problem. Thus, compound 2
was transformed into dienol 14 in 52% overall yield after a
five-step reaction sequence: 1) partial reduction (DIBAL-H,
DCM) of the ester moiety to afford an aldehyde, 2) Wittig
reaction (MePPh3Br, tBuOK, THF) to produce the terminal
alkene 13, 3) Boc-deprotection (ZnBr2, DCM, reflux), 4) N-
acylation (5-hexenoyl chloride, TEA, DMAP, DCM), and
5) desilylation (TBAF, THF). Facile RCM of 14 (2 mm) took
place in the presence of Grubbsꢀ second-generation catalyst
(20 mol%) to give cleanly pentacycle 15 (ABCDE rings).
Swern oxidation[10] and Wittig olefination (MePPh3Br,
K2CO3, [18]crown-6, DCM)[11] to furnish terminal alkene 16
was achieved in 70% overall yield from 14. After desulfona-
tion (Na, naphthalene, THF) and N-alkylation (6-bromo-1-
hexene, K2CO3, EtOH), 16 was converted into bis(terminal
alkene) 17 in 91% overall yield. Inspired by Dixonꢀs obser-
are properly situated for a PtII-promoted cascade reaction
sequence originally developed by Dake.[7] By adopting our
modified procedure,[3i] treatment of 4 (introduced to the re-
action system via a syringe pump) with PtCl2 (20 mol%) in
toluene at 808C triggered the anticipated cascade reaction
sequence in a seemingly regiospecific (6-endo vs. 5-exo) and
stereospecific fashion. To our delight, tetracycle 3 was pro-
duced exclusively, and the yield reached 81%. The mecha-
nism for the process involves three steps and has been dis-
cussed elsewhere.[3i,7] No racemization was observed at C14.
Since saturation of the C8=C9 double bond within the
A ring could not be accomplished by: 1) hydrogenation,[3c,i]
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Chem. Eur. J. 2011, 17, 12569 – 12572

(ꢀ)-Nakadomarin A Total Synthesis
COMMUNICATION
Table 1. The Z/E selectivity and separability of the isomeric products from the RCM reactions of 17, 19a, and 19b.
RCM products
Data source
RCM type (Z/E ratio)
Z/E isomer separability
18/
18/
U
current work
Nishida[2i]
Kerr[2c]
Z selective (Z/E, 2:1)
regular (Z/E, 1:2)
regular (Z/E, 3:5)
regular (Z/E, 1:1.8)
regular (Z/E, 2:3)
regular (Z:E unavailable)
Z selective (Z/E, 63:37)
obtained by lactam reduction
obtained by lactam reduction
separable (SFC-HPLC)
inseparable
inseparable
separable (column chromatography)
separable (column chromatography)
separable (column chromatography)
separable (NP-HPLC)
inseparable
ent-18/ent-(24E)-18
20/(24E)-20
ent-20/ent-(24E)-20
ent-20/ent-(24E)-20
Nishida[2b]
Nishida[2a]
Kerr[2c]
1/
1/(24E)-1
ent-1/ent-(24E)-1
(24E)-1
Dixon[2d]
Nishida[2i]
Kerr[2c]
ACHTUNGTRENNUNG
inseparable
vation of amine protonation-assisted E/Z selectivity reversal
in a related investigation,[2d] we attempted treating 17
(0.5 mm) with Grubbsꢀ first-generation catalyst (25 mol%)
in the presence of (ꢀ)-camphorsulfonic acid (CSA,
200 mol%). The desired RCM proceeded smoothly while
the E/Z selectivity was reversed compared to the amine-free
lactam/amide substrates utilized by Nishida[2a,b] and Kerr.[2c]
Regular chromatographic purification resulted in a mix-
ture of 18 and its (24E)-isomer (65%, combined yield),
which upon semipreparative SFC-HPLC gave 18 in a pure
form in 31% (unoptimized) yield. Table 1 summarizes the
Z/E selectivity and separability of the isomeric products
from the RCM reactions. The substrate polarity is most
likely 19b>17>19a, and the trend should remain the same
for their RCM products. Dixon[2d] and we (in the current
C8=C9 double bond through
a
three-step protocol,
2) Grubbsꢀ second-generation catalyst-mediated RCM for
assembling the eight-membered ring, and 3) Grubbsꢀ first-
generation catalyst-promoted, (ꢀ)-CSA-assisted Z-selective
RCM of monoamine 17 instead of the more polar diamine
substrate (19b)[2d] for constructing the fifteen-membered
ring.
Acknowledgements
We are grateful for the generous financial support from the National
Basic Research Program of China (973 Program: 2010CB833200), “111”
Program of MOE, and NSFC (20625204, 20632030, 90713007, 20772141).
work) have separated 1/ACTHNUTRGENN(UG 24E)-1 and 18/ACHUTNGTREN(NNGU 24E)-18, respective-
Keywords: alkaloids · cascade reactions · monoamines ·
total synthesis · Z-selective RCM
ly, despite the related negative results by Nishida[2i] and
Kerr.[2c] Note that HPLC separation of 18 and (24E)-18
proved to be much more practical than that of 1 and (24E)-
1;[2a–d] this is consistent with compound polarity considera-
tions. To complete the total synthesis, 18 was reduced with
Red-Al in toluene to form (ꢀ)-nakadomarin A (1) in 85%
yield. The [a]2D1 of 1 was found to be ꢀ66.9 (c=0.28 in
MeOH); [a]D23 =ꢀ73.0 (c=0.08 in MeOH);[2b] [a]2D5 =ꢀ65.6
(c=0.66 in MeOH);[2d] [a]D =ꢀ72.7 (c=0.12 in MeOH);[2f]
(ent-1) [a]2D0 =ꢀ79.2 (c=0.12 in MeOH);[2a] (ent-1) [a]D =
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Received: July 8, 2011
Published online: September 29, 2011
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Chem. Eur. J. 2011, 17, 12569 – 12572