A Formal Construction of Fasicularin

Article abstract of DOI:10.1021/ol035566h

(Equation presented) Our synthetic approach toward fasicularin is presented. Key steps in this construction are a siloxy-epoxide semipinacol rearrangement, a B-alkyl Suzuki reaction and an intramolecular S_N2 reaction.

Full text of DOI:10.1021/ol035566h

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4313-4316
A Formal Construction of Fasicularin
Michae1l D. B. Fenster and Gregory R. Dake*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC V6T 1Z1, Canada
gdake@chem.ubc.ca
Received August 20, 2003
ABSTRACT
Our synthetic approach toward fasicularin is presented. Key steps in this construction are a siloxy-epoxide semipinacol rearrangement, a
B-alkyl Suzuki reaction and an intramolecular SN2 reaction.
Fasicularin (1) was isolated from the marine invertebrate
Nephteis fascularis in 1997 by Patil and co-workers (Figure
1).1 Its interesting tricyclic structure containing a spiro ring
compounds is its trans-1-azadecalin A-B ring system. In
addition, screening assays had found that 1 could induce
DNA damage through a currently unknown process. Fasicu-
larin was also shown to be cytotoxic to Vero cells (IC50 of
14 µg/mL).
Unsurprisingly, the appealing structure of 1 coupled with
its reported biological activities have made it, as well as 2
and 3, an attractive target for the synthetic organic com-
munity.3,4 Two previous total syntheses that produce 1 in
racemic form have been reported. Each used elegant cy-
cloaddition strategies to address the formation of the spiro
ring fusion of 1. The first construction from Kibayashi’s
laboratory utilized an acylnitroso Diels-Alder process,5 and
the second synthesis by Funk and Maeng produced the
precursor to the spiro center using a 2-amidoacrolein Diels-
Alder cycloadduct.6 Our interest in 1 stemmed from its
Figure 1. Fasicularin and related marine natural products.
(3) (a) The synthetic work on lepadiformine has been nicely sum-
marized: Weinreb, S. M. Acc. Chem. Res. 2003, 36, 59. See also: (b) Abe,
H.; Aoyagi, S.; Kibayashi, C. Angew. Chem., Int. Ed. Eng. 2002, 41, 3017.
(c) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337. (d)
Sun, P.; Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3, 3507. (e) Greshock, T.
J.; Funk, R. L. Org. Lett. 2001, 3, 3511. (f) Reference 5. (g) Abe, H.; Aoyogi,
S.; Kibayashi, C. Tetrahedron Lett. 2000, 41, 1205. (h) Werner, K. M.; De
los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1999, 64, 4865.
(i) Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688. (j) Werner, K.
M.; De los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1999,
64, 686. (k) Pearson, W. H.; Barta, N. S.; Kampf, J. W. Tetrahedron Lett.
1997, 38, 3369.
(4) For work on the cylindricines, see: (a) Liu, J. F.; Heathcock, C. H.
J. Org. Chem. 1999, 64, 8263. (b) Molander, G. A.; Ro¨nn, M. J. Org. Chem.
1999, 64, 5183. (c) Snider, B. B.; Liu, T. J. Org. Chem. 1997, 62, 5630.
(5) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122,
4583.
junction adjacent to nitrogen, is similar to other recently
isolated marine alkaloids such as lepadiformine (2) and the
cylindricines (e.g., cylindricine A and B, 3 and 4).2 The major
structural difference between fasicularin and the latter
(1) Patil, A. D.; Freyer, A. J.; Reichwein, R.; Carte, B.; Killmer, L. B.;
Faucette, L.; Johnson, R. K.; Faulkner, D. J. Tetrahedron Lett. 1997, 38,
363.
(2) (a) Lepadiformine: Biard, J. F.; Goyut, S.; Roussakis, C.; Verbist,
J. F.; Vercauteren, J.; Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35,
2691. (b) Cylindricines A and B: Blackman, A. J.; Li, C.; Hockless, D. C.
R.; Skelton, B. W.; White, A. H. Tetrahedron 1993, 49, 8645.
(6) Maeng, J.-H.; Funk, R. L. Org. Lett. 2002, 4, 331.
10.1021/ol035566h CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003

Scheme 1. Analysis of 1
spirocyclic center and the possibility of using a semipinacol
Our construction of the critical spirocyclic ketone inter-
mediate is presented in Scheme 2. Lactam 5, which can be
derived from L-glutamic acid (five steps) in multigram scales
using a slightly modified literature procedure,9 was protected
as its tert-butyldimethylsilyl ether 6 using standard condi-
tions. Sequential treatment of 6 with n-butyllithium followed
by p-toluenesulfonyl chloride in THF produced the N-p-
toluenesulfonyl imide 7 in 75% yield. The conversion of 7
into its enol trifluoromethanesulfonate (triflate) 8 using
potassium hexamethyldisilazane and N-(5-chloro-2-pyridyl)-
triflimide proceeded uneventfully.10 The vinylstannane re-
agent 9 was produced using a palladium(0)-catalyzed cross-
coupling between 8 and hexamethyldistannane.11 The
organomagnesium species generated from 9 ((a) 2.2 equiv
of methyllithium, (b) magnesium bromide etherate) could
add to cyclopentanone with a minimum of side reactions at
-100 °C. The cyclopentanol 10 was isolated in 89% yield
after workup and purification. Multigram batches could be
routinely processed through this sequence. Because the
attempted semipinacol reaction of 10 using protic acid failed,
a siloxy-epoxide rearrangement was used to generate the
desired spirocyclic ketone.7 To that end, the alkene in 10
was epoxidized by the action of dimethyldioxirane (DMDO)
in the presence of potassium carbonate to produce 11 as a
single diastereomer. This crude mixture was treated with
trimethylsilyl triflate and 2,6-lutidine to generate trimethyl-
silyl ether 12 (83%, over two steps). Treatment of 12 with
1 equiv of titanium tetrachloride in dichloromethane at -78
°C for 30 min resulted in smooth ring expansion to produce
cyclohexanone 13 in 96% yield after workup and purifica-
tion.7,12 The structure and stereochemistry of 13 was con-
firmed using X-ray crystallography.7 At this point, the
rearrangement for its construction.7,8
Our analysis of 1 is presented in Scheme 1. Similar to the
previous syntheses, we planned late stage introduction of the
thiocyanate unit using tricyclic amine a as an advanced
intermediate. Retro-annulation by cleavage of the N1-C2
bond and the C4-C5 bond produces the key spirocyclic
ketone intermediate b. Formation of the C4-C5 bond was
believed to be possible through a Pd(0)-catalyzed cross-
coupling reaction, and N-alkylation would serve to form the
N1-C2 bond. We planned to use a siloxy-epoxide rear-
rangement reaction of c to build the critical spirocyclic
intermediate b. Cyclopentanol c was thought to be derivable
from the known lactam 5.
Scheme 2. Construction of Azaspirocyclic Ketone 15a
(7) Fenster, M. D. B.; Patrick, B. O.; Dake, G. R. Org. Lett. 2001, 3,
2109.
(8) (a) Eom, K. D.; Raman, J. V.; Kim, H.; Cha, J. K. J. Am. Chem.
Soc. 2003, 125, 5415. (b) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew.
Chem., Int. Ed. 2001, 40, 4765. For reviews on the pinacol reaction, see:
(c) Rickborn, B. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, p 721. (d) Coveney,
D. J. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 3, p 777.
a (a) TBSCl, imidazole, DMF, rt, 92%; (b) nBuLi, TsCl, THF,
-78 °C, 75%; (c) KHMDS, Comins’ reagent, THF, -78 °C f rt,
76%; (d) Pd2dba3 (10 mol %), AsPh3 (40 mol %), Me6Sn2, THF,
rt, 7 h, 71%; (e) MeLi, -78 f 0 °C, 10 min, then MgBr2 at -78
°C, 30 min, then cyclopentanone at -100 °C f rt, 89%; (f) DMDO,
K2CO3, rt; (g) TMSOTf, 2,6-lutidine, THF, rt, 83% (over both
steps); (h) TiCl4, CH2Cl2, -78 °C, 30 min, 96%; (i) MsCl, DMAP,
CH2Cl2, rt, 87%; (j) DBU, toluene, reflux, 91%.
(9) Herdeis, C. Synthesis 1986, 232.
(10) Comins, D. L.; Dehghan, A. Tetrahedron Lett. 1992, 33, 6299.
(11) (a) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997,
62, 8131. (b) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.;
Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C.
K. J. Org. Chem. 1986, 51, 279.
4314
Org. Lett., Vol. 5, No. 23, 2003

hydroxy group at C11 (fasicularin numbering) was to be
removed. Because of difficulties in generating a xanthate
ester required for a Barton-McCombie deoxygenation, the
pseudoaxial alcohol functionality was ultimately removed
by an elimination-hydrogenation sequence. Conversion of
13 to methanesulfonate 14 (MsCl, DMAP, 87%) followed
by treatment with DBU in refluxing toluene produced alkene
15 in 91% isolated yield.
lowed by addition of water.15 To this intermediate was added
21 in conjunction with a Pd(0) catalyst system,16 which
resulted in the isolation of 22 in 84% yield. Dissolving metal
reduction smoothly deprotected both the toluenesulfonamide
and the p-methoxybenzyl ether to the corresponding amino-
alcohol 23. Diastereoselective reduction of the alkenes in
23 was best performed using 1 atm of hydrogen over rhodium
on carbon in ethanol to give the saturated amine 24 in 76%
yield with 10.5:1 diastereoselectivity at C5 favoring the
shown epimer. Cyclodehydration of 24 to 25 was effected
using Kibayashi’s conditions.17 Deprotection of the TBS ether
in 25 took place in 82% yield using TBAF with 4 Å
molecular sieves, a crucial additive. Omission of the sieves
resulted in decomposition. At this point the alcohol was
oxidized using TPAP-NMO to produce ketone 27, an
intermediate that was generated in racemic form by the Funk
group.6 The reduction of 27 using L-Selectride at -78 °C
The segment used for the annulation of the third ring of 1
was constructed in a straightforward manner as shown in
Scheme 3. Reduction of 1-trimethylsilyl-1-nonyne-3-one (16)
Scheme 3. Construction of Alkene 20a
Scheme 4. Construction of 1a
a (a) Catalyst Y (12 mol %), 2-propanol, rt, 94%, (>99% ee);
(b) p-methoxybenzyl trichloroacetimidate, PPTS (10 mol %),
CH2Cl2, 73%, (97% brsm); (c) TBAF, THF, 95%; (d) H2 (1 atm),
Pd/CaCO3 (Pb poisoned), EtOH, -6 °C, 93%.
using transfer hydrogenation conditions developed by Noyori
generated (S)-propargyl alcohol 17 (94% yield, 99% ee
(chiral GC)).13 The alcohol was protected as its PMB ether
(p-methoxybenzyl trichloroacetimidate, PPTS, 73%, (97%
based on recovered starting material)) and then desilylated
using tetrabutylammonium fluoride (TBAF) to give 19 in
95% yield. Hydrogenation of 19 over Lindlar’s catalyst
produced 20 in 93% yield.
A B-alkyl Suzuki cross-coupling reaction was planned to
connect fragments 20 and 15.14 Ketone 15 was converted to
its enol trifluoromethanesulfonate derivative 21 using stan-
dard conditions (KHMDS, PhN(Tf)2, 96%). Alkene 20 was
subjected to hydroboration conditions using 9-BBN-H fol-
a (a) KHMDS, PhNTf2, THF, -78 °C, 96%; (b) 9-BBN, THF,
rt, 1 h, then add H2O, rt, 1 h, then cannulate to a solution of 21,
PdCl2dppf‚CH2Cl2 (10 mol %), Ph3As (10 mol %), KBr, CsCO3,
DMF/THF/H2O, 60 °C, 14 h, 84%; (c) Li0, NH3/THF, -78 °C,
83%; (d) H2 (1 atm), Rh/C (20 mol %), EtOH, rt, 69%; (e) PPh3,
CBr4, Et3N, CH2Cl2, 0 °C f rt, 84%; (f) TBAF, 4 Å MS, THF, rt,
82%; (g) TPAP, NMO, 4 Å MS, CH2Cl2, rt, 79%; (h) Li
HB(sC4H9)3, THF, -40 °C, 67%; (i) MsCl, Et3N, DMAP, CH2Cl2,
0 °C, 84%; Bu4NSCN, toluene, 110 °C, 1 d.
(12) Siloxy-epoxide and related rearrangements: (a) Maruoka, K.;
Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazaki, M.; Tsuchihashi,
G.-i. J. Am. Chem. Soc. 1986, 108, 3827. (b) Shimazaki, M.; Itara, I.; Suzuki,
K.; Tsuchihashi, G.-i. Tetrahedron Lett. 1987, 28, 5891. (c) Maruoka, K.;
Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 6431. (d) Jung, M.
E.; D’Amico, D. C. J. Am. Chem. Soc. 1997, 119, 12150. (e) Marson, C.
M.; Walker, A. J.; Pickering, J.; Hobson, A. D.; Wrigglesworth, R.; Edge,
S. J. J. Org. Chem. 1993, 58, 5944. (f) Tu, Y. Q.; Sun, L. D.; Weng, P. Z.
J. Org. Chem. 1999, 64, 629. (g) Matsubara, S.; Yamamoto, H.; Oshima,
K. Angew. Chem., Int. Ed. Eng. 2002, 41, 2837.
generated a single desired diastereomeric alcohol 28 resulting
from “equatorial” attack of hydride. Conversion of 27 or 28
to 1 has been reported to be capricious and low-yielding,5,6
(13) (a) Matsumara, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738. (b) Haack, K. J.; Hashiguchi, S.; Fujii, A.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Eng. 1997, 36, 285.
(14) For reviews of the B-alkyl Suzuki reaction: (a) Chemler, S. R.;
Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. Eng. 2001, 40, 4544.
(b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
(15) (a) Kondo, K.; Sodeoka, M.; Shibasaki, M. Tetrahedron: Asymmetry
1995, 6, 2453. (b) Kondo, K.; Sodeoka, M.; Shibasaki, M. J. Org. Chem.
1995, 60, 4322.
(16) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014.
(17) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57, 2876.
Org. Lett., Vol. 5, No. 23, 2003
4315

and there was no exception in our case. Funk and Maeng,
after being unable to repeat the sequence of transformations
reported by Kibayashi to install the thiocyanate group,
disclosed a procedure to convert 28 to 1 in ∼20% yield. In
our hands, sequential treatment of this alcohol with the
conditions reported by Funk and Maeng ((a) MsCl, N(C2H5)3;
(b) Bu4NSCN, toluene, reflux) produced, as expected, a
mixture of several compounds. Signals attributable to 1 were
within a complex molecular setting. As our starting material
is derived from the chiral pool (L-glutamic acid), our
construction would produce one enantiomer of 1, but because
of the absence of either natural material or optical rotation
data, the absolute configuration of naturally occurring 1
cannot be established. This route does demonstrate the
viability of azaspirocycle formation using semipinacol reac-
tions in alkaloid synthesis. We are now extending this
methodology to the construction of other alkaloid natural
products.
1
observed in the H NMR spectrum of the crude reaction
mixture. Unfortunately, the low yield for the incorporation
of the thiocyanate coupled with difficulties in isolating and
purifying 1 from this mixture prevented us from obtaining
an analytically pure sample.18
In summary, our construction of fasicularin (or at least a
very late stage precursor to 1) has been presented. Our
strategy differs markedly from previous approaches as a
cycloaddition reaction was not used to install the critical
spirocyclic ring system. Rather, key steps in this synthetic
route are the use of a siloxy-epoxide rearrangement to
construct the spiro ring system and a B-alkyl Suzuki reaction
Acknowledgment. The authors thank the University of
British Columbia and the Natural Science and Engineering
Research Council (NSERC) of Canada for the financial
support of our programs. M.D.B.F. thanks the Gladys Estella
Laird Foundation for a Laird Fellowship and UBC for a
McDowell Award.
Supporting Information Available: Experimental pro-
cedures and characterization data for previously unreported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) A major difficulty in the final step is the detection and isolation of
fasicularin. The deactivation of silica (gel or chromatography plates) using
a 1% ammonium hydroxide wash is critical for the detection of the desired
compound. Funk, R., Penn State University, personal communication.
OL035566H
4316
Org. Lett., Vol. 5, No. 23, 2003