Total synthesis of (±)-fasicularin via a 2-amidoacrolein cycloaddition

Article abstract of DOI:10.1021/ol016850g

(Equation Presented) The total synthesis of the cytotoxin fasicularin is described. The key steps include the following: (1) an intermolecular Diels-Alder cycloaddition of a 2-(triflamido)acrolein with the dioxolane ketal of trideca-1,3-dien-7-one to esta

Full text of DOI:10.1021/ol016850g

ORGANIC
LETTERS
2002
Vol. 4, No. 3
331-333
Total Synthesis of (±)-Fasicularin via a
2-Amidoacrolein Cycloaddition
Jun-Ho Maeng and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
rlf@chem.psu.edu
Received October 3, 2001
ABSTRACT
The total synthesis of the cytotoxin fasicularin is described. The key steps include the following: (1) an intermolecular Diels−Alder cycloaddition
of a 2-(triflamido)acrolein with the dioxolane ketal of trideca-1,3-dien-7-one to establish the trans-perhydroisoquinoline stereochemistry, (2) a
stereoelectronically controlled hydride addition to a N(1)−C(2) iminium ion to introduce the equatorial hexyl substituent, and (3) elaboration
of the pyrido ring by an internal aldol reaction.
Improved screening assays continue to uncover structurally
unique compounds possessing useful biological activities.
Fasicularin1 was recently isolated from a marine invertebrate,
the ascidian Nephteis fasicularis. The compound was dis-
covered using a yeast strain in which the RAD 52 gene had
been deleted, thus rendering the organism incapable of
recombination and repair of DNA double strand breaks.1a
Consequently, the yeast is sensitive to agents that produce
DNA damage by diverse mechanisms.2 Fasicularin was
subsequently shown to be cytotoxic to Vero cells (IC50 of
14 µg/mL).1a The structure was established primarily by
NMR spectroscopy and is quite similar to that of cylindricine
B3 and lepadiformine4 which have been isolated from the
ascidians ClaVelina cylindrica and C. lepadiformis, respec-
tively (Figure 1). We have recently reported a total synthesis
(1) The absolute configuration of fasicularin is unknown. For the isolation
and structural determination, see: (a) 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. For the first total synthesis, see: (b) Abe,
H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122, 4583. For the
synthesis of related azaspirocycles, see: (c) Fenster, M. D. B.; Patrick, B.
O.; Dake, G. R. Org. Lett. 2001, 3, 2109. (d) Bagley, M. C.; Oppolzer, W.
Tetrahedron: Asymmetry 2000, 11, 2625.
(2) For a related yeast bioassay, see: (a) Zhou, B.-N.; Hoch, J. M.;
Johnson, R. K.; Mattern, M. R.; Eng, W.-K.; Ma, J.; Hecht, S. M.; Newman,
D. J.; Kingston, D. G. I. J. Nat. Prod. 2000, 63, 1273. For a review of
yeast mutant bioassays, see: Perego, P.; Jimenez, G. S.; Gatti, L.; Howell,
S. B.; Zunino, F. Pharmacol. ReV. 2000, 52, 477.
(3) Cylindricine B is in equilibrium (2:3) via an aziridinium ion
intermediate with cylindricine A, which possesses a (chloromethyl)-
pyrrolidine ring instead of the chloropiperidine ring found in cylindrincine
B. For the isolation of these and other cylindricines, see: (a) Blackman, A.
J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White, A. H. Tetrahedron
1993, 49, 8645. (b) Li, C.; Blackman, A. J. Aust. J. Chem. 1994, 47, 1355.
Figure 1.
of lepadiformine4g that featured the construction of the trans-
perhydroisoquinoline substructure from a 2-amidoacrolein
Diels-Alder cycloadduct.5 Fasicularin also contains a trans-
perhydroisoquinoline, although the tricycle is composed of
a pyrido-quinoline rather than the pyrrolo-quinoline found
(c) Li, C.; Blackman, A. J. Aust. J. Chem. 1995, 48, 955. For total syntheses,
see: (d) Snider, B. B.; Liu, T. J. Org. Chem. 1997, 62, 5630. (e) Molander,
G. A.; Ro¨nn, M. J. Org. Chem. 1999, 64, 5183. (f) Liu, J. F.; Heathcock,
C. H. J. Org. Chem. 1999, 64, 8263.
10.1021/ol016850g CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/09/2002

in lepadiformine. We show herein that our amidoacrolein-
cycloaddition-based methodology can also facilitate the rapid
assembly of this novel tricyclic ring system in a total
synthesis of (()-fasicularin.
The 2-(triflamido)acrolein 6 was prepared using our
established protocol (Scheme 2). The N-benzylimine deriva-
Our retrosynthetic analysis is presented in Scheme 1. We
planned to introduce the sensitive thiocyanate6 functionality
Scheme 2
Scheme 1
tive of 1,3-dioxan-5-one (8)9 was converted to the corre-
sponding 5-(triflamido)-1,3-dioxin (Tf2O, NEt3), which was
then subjected to standard retrocycloaddition conditions to
afford the dienophile 6 and acetone. The key cycloaddition
reaction of amidoacrolein 6 with diene 710 was best ac-
complished using high-pressure conditions (12 kbar) and
afforded a single cycloadduct, triflamide 5, in excellent yield.
Reduction of aldehyde 5 with LiAlH4 and concomitant
removal of the trifluoromethanesulfonyl group8 proceeded
smoothly to the desired amino alcohol 9. Simultaneous
reduction of the cyclohexene double bond of amino alcohol
9 and hydrogenolysis of the N-benzyl substituent (H2, Pd/
C) provided an amino alcohol, which was directly subjected
to hydrolysis conditions to afford the expected oxazolidine
10. Subjection of oxazolidine 10 to NaBH4 in MeOH11 gave
rise to a single amino alcohol, compound 4, via stereocon-
trolled R/axial addition of hydride to an iminium ion
intermediate through a chair-chair conformer. The stereo-
chemical assignment for 4 was confirmed by X-ray crystal-
lography.
of fasicularin (1) at the conclusion of the synthesis by
displacement of an axial C(13) leaving group, in turn,
available by equatorial ketone reduction of the dihydro
derivative of enone 2. The pyrido ring of tricycle 2 might
arise from an internal aldol reaction of keto aldehyde 3. The
amino alcohol 4 is adequately functionalized for elaboration
to the keto aldehyde 3 and its C(2) hydrogen atom could be
derived from a stereoelectronically controlled hydride ad-
dition to the corresponding N(1)-C(2) iminium ion.7 The
iminium ion precursor, a C(10) primary amine, could be
prepared by two-stage reduction (1. LAH;8 2. H2/Pd) of
triflamide 5. Finally, on the basis of previous work in our
laboratories,4g,5 the 2-(triflamido)acrolein 6 was expected to
undergo a regio- and stereoselective (endo) cycloaddition
with diene 7 to afford the cycloadduct 5 possessing the
requisite stereochemistry for elaboration to the trans-per-
hydroisoquinoline 4.
Having established a viable route to the central C(2)
equatorially substituted trans-perhydroquinoline substructure
of fasicularin, we turned our attention to annulating the
remaining ring of the tricyclic system by the aforementioned
aldol-reaction-based strategy. To that end, we examined the
N-alkylation of amino alcohol 4 with bromoacetone or
equivalents, e.g., 3-iodo-2-methylpropene and 3-iodo-2-
(4) For isolation, see: (a) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist,
J. F.; Vercauteren, J.; Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35,
2691. For synthetic effort which led to a structural revision, see: (b) Werner,
K. M.; De los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem.
1999, 64, 686. (c) Werner, K. M.; De los Santos, J. M.; Weinreb, S. M.;
Shang, M. J. Org. Chem. 1999, 64, 4865. (c) Pearson, W. H.; Barta, N. S.;
Kampf, J. W. Tetrahedron Lett. 1997, 38, 3369. (e) Pearson, W. H.; Ren,
Y. J. Org. Chem. 1999, 64, 688. For total syntheses, see ref 1b and the
following: (f) Sun, P.; Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3, 3507.
(g) Greshock, T. J.; Funk, R. L. Org. Lett. 2001, 3, 3511.
(5) For the total synthesis of another novel tricyclic alkaloid (FR901483)
using this methodology, see: Funk, R. L.; Maeng, J. H. Org. Lett. 2001, 3,
1125.
(9) Prepared in two steps from tris(hydroxymethyl)aminomethane hy-
drochloride. Hoppe, D.; Schmincke, H.; Kleemann, H.-W. Tetrahedron
1989, 45, 687.
(10) Prepared from the known hepta-4,6-dienylnitrile (Grieco, P. A.;
Galatsis, P.; Spohn, R. F. Tetrahedron 1986, 42, 2847) and hexylmagnesium
bromide (2.5 equiv, Et2O, reflux, 1 h, 60%).
(6) The chemistry of thiocyanates has been reviewed, see: Erian, A.
W.; Sherif, S. M. Tetrahedron 1999, 55, 7957.
(7) (a) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289. (b) Deslongchamps,
P. Stereoelectronic Effects in Organic Chemistry; Pergamon Press: New
York, 1983; p 209.
(8) Tertiary triflamides can be efficiently desulfonylated, see: (a)
Hendrickson, J. B.; Bergeron, R.; Giga, A.; Sternbach, D. J. Am. Chem.
Soc. 1973, 95, 3412. (b) Hendrickson, J. B.; Bergeron, R.; Sternbach, D.
D. Tetrahedron 1975, 31, 2517.
(11) For selected reductions of oxazolidines, see: (a) McCarthy, J. R.;
Wiedeman, P. E.; Schuser, A. J.; Whitten, J. P.; Barbuch, R. J.; Huffman,
J. C. J. Org. Chem. 1985, 50, 3095. (b) Beulshausen, T.; Groth, U.;
Scho¨llkopf, U. Liebigs Ann. Chem. 1992, 523. (c) Farr, R. A.; Holland, A.
K.; Huber, E. W.; Peet, N. P.; Weintraub, P. M. Tetrahedron 1994, 50,
1033. (d) Hamdani, M.; Scholler, D.; Bouquant, J.; Feigenbaum, A.
Tetrahedron 1996, 52, 605.
332
Org. Lett., Vol. 4, No. 3, 2002

(methoxymethoxy)propene,12 but in all cases recovered only
starting material using a variety of solvents and reaction
conditions. We speculated that the nucleophilicity of the basic
nitrogen was compromised by an internal hydrogen bond as
well as the obvious steric factors. Accordingly, we investi-
gated the selective protection of the hydroxyl substituent.
Thus, acetylation of the amino alcohol 4 gave the desired
acetate 11 which underwent a smooth, albeit slow, alkylation
with 3-iodo-2-(methoxymethoxy)propene in the presence of
Hu¨nig’s base to furnish the desired tertiary amine 12 (76%)
and recovered starting material (20%) (Scheme 3). Trans-
to hydrolysis and/or aldol condensation15 conditions (TFA,
H2O, 1:1) to deliver the desired enone 2 in 74% yield for
the two steps. Although hydrogenation of the carbon-carbon
double bond of enone 2 was uneventful, the reduction of
the resulting ketone was not. Reduction with sodium boro-
hydride afforded a 1:1 mixture of ketone 13 and its C(13)
epimer, whereas lithium tri-sec-butylborohydride gave none
of the desired product. However, the diastereomeric ratio
was improved (5.3:1) upon reduction with lithium tri-tert-
butoxyaluminohydride to produce alcohol 13 as the major
isomer, whose spectral properties were identical with those
reported by Kibayashi.1b Alcohol 13 had been previously
converted to fasicularin in low yield [20%, due to competitive
formation of isothiocyante 15 (2%) and elimination product
16 (54%)] using a Mitsunobu procedure (HSCN,Ph3P,
DEAD, benzene, 40 °C, 72 h).1b However, in our hands only
trace amounts of fasicularin were observed. After consider-
able experimentation, we discovered that treatment of the
mesylate 14 with tetrabutylammonium thiocyanate16 in
toluene furnished fasicularin, albeit in poor yield (20%),
accompanied by the isothiocyanate 15 (12%) and the
elimination product 16 (28%). The spectral properties of our
racemic fasicularin (1) were in agreement with those previ-
ously reported.1a,b
Scheme 3
In summary, we have documented another example of
tricyclic alkaloid ring construction from a 2-(amido)acrolein
Diels-Alder cycloadduct by judicious choice of the nitrogen
acyl/sulfonyl and alkyl substituents. Additional applications
are underway and will be reported in due course.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM28663).
We thank Dr. Douglas R. Powell of the University of
Wisconsin for the X-ray crystallographic analysis of com-
pound 4. We thank Dr. Alan J. Freyer of GlaxoSmithKline
Pharmaceuticals for providing authentic spectra of fasicularin.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
esterification of acetate 12 gave an alcohol that could not
be cleanly oxidized to an aldehyde using many of the
standard reagents (PCC, Swern, Dess-Martin, IBX13).
Fortunately, the Corey-Kim14 protocol (NCS, DMS; NEt3)
cleanly gave an unstable aldehyde that was directly subjected
OL016850G
(14) (a) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586. For
another example where this oxidant was the only successful one, see:
Kuehne, M. E.; Bornmann, W. G.; Parsons, W. H.; Sitzer, T. D.; Blount,
J. F.; Zubieta, J. J. Org. Chem. 1988, 53, 3438.
(15) A related hydrolysis/aldol condensation using similar conditions to
prepare a 2H-1,6-dihydro-3-pyridinone substructure in the context of the
total synthesis of the 2,2,3-trialkyindoline vallesamidine has been reported,
see: Heathcock, C. H.; Norman, M. H.; Dickman, D. A. J. Org. Chem.
1990, 55, 798.
(12) (a) Janicki, S. A.; Fairgrieve, J. M.; Petillo, P. A. J. Org. Chem.
1998, 63, 3694. (b) The corresponding chloride has also been employed as
a chloroacetone equivalent, see: Gu, X.-P.; Nishida, N.; Ikeda, I.; Okahara,
M. J. Org. Chem. 1987, 52, 3192.
(13) A variety of amino alcohols have been oxidized with this reagent,
see: Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org.
Chem. 1995, 60, 7272.
(16) Spurlock, L. A.; Cox, G. W. J. Am. Chem. Soc. 1971, 93, 146.
Org. Lett., Vol. 4, No. 3, 2002
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