Total synthesis of (+)-galbulimima alkaloid 13 and (+)-himgaline

Article abstract of DOI:10.1021/ja0684996

The stereoselective syntheses of (+)-himgaline (1) and (+)-GB13 (2) are described. Important diastereoselective bond constructions include an intramolecular Diels-Alder reaction, an intramolecular Michael addition, and an intramolecular enamine aldol addi

Full text of DOI:10.1021/ja0684996

Published on Web 01/17/2007
Total Synthesis of (+)-Galbulimima Alkaloid 13 and (+)-Himgaline
David A. Evans* and Drew J. Adams
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received November 27, 2006; E-mail: evans@chemistry.harvard.edu
Scheme 1. Proposed Synthesis Plan
Himgaline (1) and galbulimima alkaloid 13 (2) (GB13) are two
members of a family of complex polycyclic alkaloids isolated from
Galbulimima belgraVeana, a rain forest tree native to Papua New
Guinea and northern Australia.1 Its bark has been used medicinally
by Papua New Guinean tribes,2 and himbacine (3) has attracted
attention from the medicinal3 and synthetic4 community as a result
of its potent muscarinic antagonist activity. However, it was the
molecular architecture of these structures that attracted our interest
as synthesis targets. We wish now to report the synthesis of ent-
galbulimima alkaloid 13 and ent-himgaline.
Scheme 2. Synthesis of the Functionalized Decalin Subunita
On the basis of Taylor’s postulated polyketide-derived biosyn-
thesis of these structures1c and informed by Baldwin’s biomimetic
approach to himbacine,4d we initiated a synthesis of ent-1 and ent-2
from a linear precursor. In addition to the racemic total synthesis
of GB13 published by Mander prior to the outset of this work,5a
two total syntheses of GB13 have been recently reported, including
one by Movassaghi.5b The other synthesis, by Chackalamannil, also
reported the successful conversion of GB13 to himgaline.5c,d
The synthesis plan is outlined in Scheme 1. We anticipated that
himgaline could be accessed from GB13 via conjugate addition of
the piperidine nitrogen into the proximal enone and subsequent
stereoselective ketone reduction. The GB13 [3.2.1] bicyclooctane
core was envisioned to arise from an intramolecular enamine aldol
addition, while the cyclopentanone synthon would be formed by a
stereoselective intramolecular Michael addition of the illustrated
â-ketoester. It was thought that such a Michael precursor could be
obtained by elaboration of the illustrated intramolecular Diels-
Alder cycloadduct.
The synthesis began with vinylogous Horner-Wadsworth-
Emmons (HWE) olefination6 of 6,6-dimethoxyhexanal7 with triethyl
4-phosphonocrotonate. This adduct was elaborated, in a routine
series of transformations, to the illustrated diene aldehyde 5 (Scheme
2). Following a second HWE olefination to incorporate the chiral
auxiliary,8 intramolecular Diels-Alder cycloaddition provided
trans-decalin 8 (81% yield) as a single diastereomer.9 The necessary
decalin oxygenation was installed at this stage by a highly
diastereoselective dihydroxylation and acetonide protection to give
9 in good yield. The chiral auxiliary then was converted to the
thioester, which was reduced with DIBAL-H to afford aldehyde
10 (88%, two steps).
a Conditions: (a) See Supporting Information; (b) (S)-6, LiClO4, i-Pr2NEt,
MeCN; (c) Me2AlCl, PhMe, -30 °C; (d) K2OsO4, NMO, acetone/pH 7
buffer; (e) dimethoxypropane, TsOH, acetone; (f) LiSEt, THF, 0 °C; (g)
DIBAL-H, PhMe, -90 °C.
alcohol, 12 was reduced (DIBAL-H) and deprotected (TBAF) to
afford the illustrated allylic alcohol 13a, which was then N-
benzylated.10 Both alcohols in 13b could be oxidized with Dess-
Martin periodinane,11 and the resulting aldehyde was selectively
engaged in a Roskamp reaction to install the â-ketoester necessary
for the planned Michael reaction.12 Although formation of the
â-ketoester could be monitored by 1H NMR spectroscopy, the
isolated product was enol ester 14, derived from conjugate addition
of the â-ketoester enol oxygen. This undesired process proved to
be reversible under basic conditions: a combination of lithium
methoxide and lithium perchlorate, conditions reported to provide
chelated â-ketoester anions,13 was employed to afford the desired
Michael adduct 15a in 62% over three steps. Although 15a was
obtained as a mixture of carboalkoxy diastereomers, decarboxylation
with Pd(PPh3)4 and morpholine revealed the desired cyclopentanone
15b as a single diastereomer, implying that the Michael reaction
had proceeded with high diastereoselection.
The transformation of acetonide 15b to triketone 16 was carried
out in the following manner: DBU-promoted elimination of the
acetonide afforded its derived allylic alcohol, which was hydroge-
nated over Pd(OH)2 on carbon with 9:1 selectivity for the desired
[3,2,0] cis ring fusion and concomitant N-benzyl cleavage. Oxida-
tion of the secondary alcohol with Dess-Martin periodinane
provided triketone 16 in 72% over three steps.
Elaboration of the trans-decalin synthon 10 to both (+)-GB13
and (+)-himgaline is presented in Scheme 3. The HWE olefination
of aldehyde 10 using the previously reported (R)-â-ketophosphonate
114e afforded the derived unsaturated ketone 12 (92%). Since
attempted deprotection of the silyl ether under a variety of
conditions led to irreversible conjugate addition of the liberated
9
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10.1021/ja0684996 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Himgaline and GB13 Synthesesa
a Conditions: (a) LiClO4, i-Pr2NEt, MeCN, 50 °C; (b) DIBAL-H, PhMe, -90 °C; (c) TBAF, HOAc, THF; (d) see Supporting Information; (e) DMP,
NaHCO3, CH2Cl2; (f) allyldiazoacetate, SnCl2; (g) LiOMe, LiClO4, Et2O, 0-23 °C; (h) Pd(PPh3)4, morpholine, THF; (i) DBU, PhH; (j) Pd(OH)2, H2, THF;
(k) DMP, NaHCO3, CH2Cl2; (l) 20% TFA/CH2Cl2, 0 °C, aq NaHCO3 workup; 4 Å MS, PhH; (m) HOAc, THF, 0-23 °C; (n) NaBH3CN, EtOH, 0 °C; (o)
DMP, NaHCO3, CH2Cl2; (p) benzyl chloroformate, Na2CO3, CH2Cl2/H2O, 0-23 °C; (q) IBX, TsOH‚H2O, DMSO/PhH, 65 °C; (r) TMSI, CH2Cl2, 0 °C;
HCl; NaOH, 23 °C; (s) HOAc, MeCN, 30 min; NaBH(OAc)3.
We next turned our attention to the intramolecular enamine aldol
addition. To our gratification, after deprotection of the amine under
acidic conditions, dehydration to the cyclic imine, and treatment
with excess acetic acid in THF, the desired addition took place to
give the aldol adduct isolated as its iminium ion 18. Interestingly, the
related structures depicted below failed to undergo the desired aldol
addition. Alcohols 17b and 17c were inert to a variety of reaction
conditions, highlighting the influence of the conformation of the
decalin on cyclopentanone reactivity. Enedione 17d appeared to
undergo conjugate addition in preference to the desired 1,2-addition.
from Amgen and Merck. Professor Lewis N. Mander is warmly
acknowledged for providing comparison samples of 1 and 2.
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.
References
(1) (a) Binns, S. V.; Dunstan, P. J.; Guise, G. B.; Holder, G. M.; Hollis, A.
F.; McCredie, R. S.; Pinhey, J. T.; Prgaer, R. H.; Rasmussen, M.; Ritchie,
E.; Taylor, W. C. Aust. J. Chem. 1965, 18, 569-573. (b) Mander, L. N.;
Prager, R. H.; Rasmussen, M.; Ritchie, E.; Taylor, W. C. Aust. J. Chem.
1967, 20, 1473-1491. (c) Mander, L. N.; Prager, R. H.; Rasmussen, M.;
Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1967, 20, 1705-1718.
(2) Thomas, B. Eleusis: J. Psychoact. Plants Compd. 1999, 3, 82-90.
(3) (a) Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.; McKinney, M. Bioorg.
Med. Chem. Lett. 1992, 2, 797-802. (b) Malaska, M. J.; Fauq, A. H.;
Kozikowski, A. P.; Aagaard, P. J.; McKinney, M. Bioorg. Med. Chem.
Lett. 1995, 5, 61-66.
(4) (a) Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995,
117, 9369-9370. (b) Chackalamannil, S.; Davies, R. J.; Aserom, T.;
Doller, D.; Leone, D. J. Am. Chem. Soc. 1996, 118, 9212-9213. (c)
Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetrahedron Lett.
1999, 40, 3399-3402. (d) Tchabanenko, K.; Adlington, R. M.; Cowley,
A. R.; Baldwin, J. E. Org. Lett. 2005, 7, 585-588. (e) Tchabanenko, K.;
Chesworth, R.; Parker, J. S.; Anand, N. K.; Russell, A. T.; Adlington, R.
M.; Baldwin, J. E. Tetrahedron 2005, 61, 11649-11656.
(5) (a) Mander, L. N.; McLachlan, M. M. J. Am. Chem. Soc. 2003, 125, 2400-
2401; McLachlan, M. M. Ph.D. Thesis, Research School of Chemistry,
Australian National University, 2002. (b) Movassaghi, M.; Hunt, D. K.;
Tjandra, M. J. Am. Chem. Soc. 2006, 128, 8126-8127. (c) Shah, U.;
Chackalamannil, S.; Ganguly, A. K.; Chelliah, M.; Kolutuchi, S.; Beuvich,
A.; McPhail, A. J. Am. Chem. Soc. 2006, 128, 12654-12655. (d)
References 5b and 5c led to a revision of the absolute stereochemical
assignments of 1 and 2. X-Ray crystal structures leading to the reassign-
ment of other galbulimima alkaloids were also recently disclosed: (e)
Willis, A. C.; O’Connor, P. D.; Taylor, W. C.; Mander, L. N. Aust. J.
Chem. 2006, 59, 629-632.
(6) Takacs, J. M.; Jaber, M. R.; Clement, F.; Walters, C. J. Org. Chem. 1998,
63, 6757-6760.
(7) Claus, R. E.; Schreiber, S. L. Organic Syntheses; Wiley & Sons: New
York, 1990; Collect. Vol. VII, pp 168-172.
(8) For preparation of (S)-6 and HWE procedure, see: Evans, D. A.; Miller,
S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559-7573.
(9) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110,
1238-1256.
(10) N-Benzylation was carried out in the interest of experiments conducted
in parallel with those shown. Although the synthesis has been completed
without N-benzylation, yields were optimized on N-benzylated material.
See Supporting Information.
Surprisingly, treatment of 18 with NaBH3CN reduced both the
iminium and the carbonyl moieties, even under pH 6 reaction
conditions, to give a 2:1 mixture of axial and equatorial alcohol
epimers. Oxidation of this mixture with Dess-Martin periodinane
provided dihydro-GB13 19a without affecting the hindered second-
ary amine. The amine was then protected using benzyl chlorofor-
mate14 and purified to give the carbamate 19b in 39% yield over
six steps (average yield, 85%). No undesired diastereomers were
isolated from this sequence. The necessary unsaturation was then
introduced using IBX (90%),5b,15 and the benzyl carbamate was
removed with TMSI to provide ent-GB13.5b Synthetic GB13
matched a natural sample spectroscopically and gave an optical
rotation of similar magnitude but opposite sign (ent-2, [R]20D +71.6
(c 0.2, CHCl3); 2, [R]20 -76 (c 1.0, CHCl3)).1a
D
The conversion of (+)-GB13 to (+)-himgaline began with the
conjugate addition of the piperidine nitrogen to the pendent enone,
which was facile in a variety of acidic media.1b,5c Eventually, it
was found to be convenient to perform the conjugate addition by
stirring (+)-GB13 in a 1:1 mixture of acetic acid and acetonitrile.
Subsequent addition of sodium triacetoxyborohydride initiated
directed hydride delivery to furnish ent-himgaline in 90% yield.16
Synthetic himgaline was spectroscopically identical to a natural
sample and gave an optical rotation of similar magnitude but
opposite sign (ent-1, [R]20 +80.0 (c 0.1, CHCl3); 1, [R]20 -84
(11) Dess, D. B; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(12) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258-3260.
(13) Raban, M.; Noe, E. A.; Yamamoto, G. J. Am. Chem. Soc. 1977, 99, 6527-
6531.
(14) The amine was also acylated with trifluoroacetic anhydride to intercept an
intermediate synthesized by Mander (ref 5a). See Supporting Information.
(15) Nicolau, K. C.; Montagnon, T.; Baran, P. S. J. Am. Chem. Soc. 2002,
124, 2245-2258.
(16) Chackalamannil performed the conjugate addition with scandium triflate
and hydrochloric acid prior to directed reduction (ref 5c).
D
D
(c 1.0, CHCl3)).1a
Acknowledgment. Support was provided by the National
Institutes of Health (GM-33328-20) and by unrestricted support
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