Total synthesis and absolute stereochemical assignment of (+)- and (-)-galbulimima alkaloid 13

Article abstract of DOI:10.1021/ja0626180

We describe the total synthesis of (+)- and (-)-galbulimima alkaloid 13. The absolute stereochemistry of natural (-)-galbulimima alkaloid 13 is revised to 2S. Sequential use of catalytic cross-coupling and cross-metathesis reactions followed by an intramo

Full text of DOI:10.1021/ja0626180

Published on Web 06/01/2006
Total Synthesis and Absolute Stereochemical Assignment of (+)- and
(-)-Galbulimima Alkaloid 13
Mohammad Movassaghi,* Diana K. Hunt, and Meiliana Tjandra
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received April 14, 2006; E-mail: movassag@mit.edu
The galbulimima alkaloids are a family of structurally fascinating
polycyclic compounds isolated from the bark of Galbulimima
belgraVeana, a tree native to northern Australia and Papua New
Guinea (Figure 1).1 The biological activity2 of himbacine (1), a
potential treatment for Alzheimer’s disease, has prompted several
inventive syntheses of 13 and an intriguing recent synthesis of (()-
galbulimima alkaloid 13 (GB 13, 2).4 Herein we describe the total
Figure 1. Representative galbulimima alkaloids.1a
synthesis of both (+)- and (-)-GB 13 (2), allowing revision of
their absolute stereochemical assignment.
Scheme 1. Retrosynthetic Analysis of (-)-Galbulimima Alkaloid
13
A compelling hypothesis by Mander, Ritchie, and Taylor in 1967
linked various galbulimima alkaloids to a common polyacetate-
derived precursor.1d Inspired by this theory, intrigued by the unique
structure of these alkaloids, and given the paucity of studies directed
at complex members possessing the fused CDE-ring system (i.e.,
2 and 3, Figure 1), we initiated our studies in this area. Guided by
our original biosynthetic hypothesis, we envisioned a strategic C5-
C20 bond disconnection to greatly simplify the structure of 2 to
the tetracyclic precursor 4 (Scheme 1). We expected to obtain the
imino ketone 4 from the unsaturated imine 5, in turn, prepared by
condensation of the iminium chloride 6 with aldehyde 7. Given
the uncertainty in the absolute stereochemistry of natural (-)-GB
13 (2), the coupling of the readily available (+)- or (-)-iminium
chloride 6 with (()-aldehyde 7 provided an expedient route to both
enantiomers of advanced intermediates and alkaloid 2.
An efficient synthesis of trans-decalin aldehyde 7 is outlined in
Scheme 2. Suzuki cross-coupling5 of readily available dibromide
86 and vinyl boronic acid 96 using thallium carbonate5c provided
cis-vinyl bromide7 10 in 75% yield. Subsequent copper-catalyzed
coupling of bromodiene 10 with oxazolidin-2-one afforded the
desired triene 11 in excellent yield8 and proved to be an effective
strategy for masking the C16 carbonyl. Conversion of the C20 silyl
ether of triene 11 to the C20 silyl enol ether gave tetraene 12
(Scheme 2). Selective functionalization of the C9-C10 alkene of
12 to the corresponding unsaturated aldehyde 13 (C9 E:Z, >20:1)
was achieved via an olefin cross-metathesis reaction with acrolein
using the 4,5-dihydroIMesCl2RudCH(o-iPrO)Ph9 catalyst. Heating
a solution of tetraenal 13 in toluene at 90 °C afforded the desired
trans-decalin aldehyde 7 in good yield (82%, >20:1, endo:exo).
Deprotonation of the (-)-iminium chloride 6 (>99% ee, Scheme
1)6 with nbutyllithium gave the corresponding lithiated enamine,10
which upon addition to a cold solution of aldehyde 7 provided the
corresponding â-hydroxy imines in 85% yield. Dehydration using
the Martin sulfurane reagent11 afforded the desired (7E)-R,â-
unsaturated imine 5 (Scheme 3) and the corresponding 2-epi-
enantiomer (not shown in Scheme 3) as an equal mixture of
inseparable diastereomers in 81% yield. The diastereomers were
chromatographically separated after the next two steps.
Scheme 2. Diastereoselective Synthesis of (()-Aldehyde 7a
a Conditions: (a) Pd(PPh3)4, Tl2CO3, THF, H2O, 23 °C, 75%; (b) CuI,
K2CO3, oxazolidin-2-one, (MeNHCH2)2, toluene, 110 °C, 95%; (c) (1)
TBAF, THF, 95%; (2) MnO2, CH2Cl2, 92%; (3) TBSOTf, Et3N, CH2Cl2,
-78 °C, 93%; (d) 4,5-dihydroIMesCl2RudCH(o-iPrO)Ph (10 mol %),
acrolein, CH2Cl2, 23 °C, 85%; (e) toluene, 90 °C, 82%, (g20:1, endo:exo).
AIBN, provided the desired tetracycle 16 along with the C2-epi-
enantiomer6 in 55% yield. Treatment of enol ether 16 with
triethylamine trihydrofluoride resulted in C5-C6 enamine addition
to the unmasked C20 carbonyl, directly providing the corresponding
pentacyclic imine. Removal of the volatiles under reduced pressure
and introduction of sodium borohydride resulted in diastereoselec-
tive C6 imine reduction, affording the corresponding stable pen-
tacyclic amine in a one-pot process (Scheme 3). Optically active
pentacyclic amine (-)-18 (36%) and the corresponding 2-epi-
enantiomer, amine (+)-19 (34%), were readily separated by flash
Diastereoselective introduction of the C21-C8 bond in tetracycle
16 was accomplished via a 5-exo-trig vinyl radical cyclization.12
Conversion of silyl enol ether 5 to the vinyl bromide 14 (Scheme
3, ∼1:1.5 mixture of C20 olefin isomers), followed by heating of
the crude vinyl bromide 14 with excess tributyltin hydride and
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10.1021/ja0626180 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Concise Synthesis of (-)-Galbulimima Alkaloid 13 (2)a
a Conditions: (a) nBuLi, THF, -78 °C, 5 min, 85%; (b) Martin sulfurane, benzene, 23 °C, 81%; (c) NBS, NaHCO3, THF, 0 °C; nBu3SnH, AIBN,
benzene, 60 f 90 °C, 55% (two steps); (d) Et3N‚(HF)3, THF, 23 °C; NaBH4, EtOH, 0 °C, 70% (two steps); (e) ClCO2Bn, Na2CO3, H2O, CH2Cl2, 65%; (f)
IBX, TsOH‚H2O, benzene, DMSO, 65 °C, 10 h, 80%; (g) TMSI, CH2Cl2, 0 °C; HCl; NaOH, 23 °C, 89%. For brevity, the corresponding ent-2-epi-isomer
of compounds 5 and 14-17 is not shown.6
Supporting Information Available: Experimental procedures,
spectroscopic data, and copies of 1H and 13C NMR spectra for all
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
column chromatography. Remarkably, formation of the C8 stereo-
center during the radical cyclization as well as the introduction of
the three contiguous stereocenters (C20, C5, and C6) in the
conversion of silyl enol ether 16 to pentacyclic amine (-)-18 occurs
with a high level of diastereoselection. To date, no other diaster-
eomers have been detected.
References
Introduction of the enone was accomplished by treatment of
N-vinyl carbamate (-)-20 with excess p-TsOH‚H2O and IBX in
benzene/DMSO at 65 °C for 10 h to provide carbamate (-)-21 in
80% yield.13 Subsequent deprotection of (-)-N-Cbz GB 13 (21)
with trimethylsilyl iodide (TMSI)14 followed by an aqueous workup
provided synthetic GB 13 (2) in 89% yield (Scheme 3). All
spectroscopic data for our enantiomerically enriched (-)-2 matched
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D
) -64 (c 0.06, CHCl3)), was consistent with that reported for the
natural enantiomer ([R] ) -84 (CHCl3)1b),6 unambiguously secur-
ing the absolute stereochemistry. Synthesis of (+)-GB 13 (ent-2,
[R]22 ) +66 (c 0.07, CHCl3)) using (+)-6 (>99% ee) via the
D
route described above confirmed our absolute stereochemical
assignment.6 Interestingly, intramolecular amine conjugate addition
at C19 was observed upon N-deprotection of 21 and acidic
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base treatment (1 N NaOHaq, 1 h).15 This facile cyclization supports
the hypothesis for the biosynthesis of himgaline (3) via sequential
conjugate addition and carbonyl reduction of 2.1c,6
We describe the first total synthesis of (+)- and (-)-GB 13 (2).
The absolute stereochemistry of natural (-)-2 is revised to 2S.
Noteworthy features of this chemistry include a vinyl radical
cyclization strategy to secure the C-ring and the successful execution
of our biomimetically inspired strategy for introduction of the CDE-
ring system in 2 (16 f 18, Scheme 3). Current efforts are directed
toward the synthesis of other members of this intriguing family of
natural alkaloids.
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Acknowledgment. M.M. is a Dale F. and Betty Ann Frey
Damon Runyon Scholar supported by the Damon Runyon Cancer
Research Foundation (DRS-39-04). M.M. is a Firmenich Assistant
Professor of Chemistry. We thank Professor R. G. Griffin and Dr.
T. Bielecki for use of a high field instrument at the MIT-Harvard
Center for Magnetic Resonance (EB-002026). We are grateful to
Professor L. N. Mander for a copy of the 1H NMR spectrum of 2.
We acknowledge financial support by NIH-NIGMS (GM074825).
1
(13) Monitoring of this transformation by H NMR spectroscopy revealed an
initial hydrolysis to the corresponding C16 ketone followed by oxidation
to the desired C16 enone; see: Nicolaou, K. C.; Zhong, Y.-L.; Baran, P.
S. J. Am. Chem. Soc. 2000, 122, 7596.
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(15) This addition occurs spontaneously for the 2-epi-diastereomer, giving 2-epi-
16-oxohimgaline. See Supporting Information for details.
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