Total synthesis of amaminol A: Establishment of the absolute stereochemistry

Article abstract of DOI:10.1021/ol7022856

The first synthetic route to amaminol A with use of an organocatalytic intramolecular Diels-Alder reaction is reported. The absolute stereochemistry is proven with a crystallographic image of a cyclic carbamate of amaminol A.

Full text of DOI:10.1021/ol7022856

ORGANIC
LETTERS
2007
Vol. 9, No. 24
5043-5045
Total Synthesis of Amaminol A:
Establishment of the Absolute
Stereochemistry
Esa T. T. Kumpulainen,† Ari M. P. Koskinen,*,† and Kari Rissanen‡
Laboratory of Organic Chemistry, Helsinki UniVersity of Technology, P.O. Box 6100,
FI-02015 TKK, Espoo, Finland, and NanoScience Center, Department of Chemistry,
UniVersity of JyVa¨skyla¨, P.O. Box 35, FI-40014, JyVa¨skyla¨, Finland
ari.koskinen@hut.fi
Received September 19, 2007
ABSTRACT
The first synthetic route to amaminol A with use of an organocatalytic intramolecular Diels−Alder reaction is reported. The absolute
stereochemistry is proven with a crystallographic image of a cyclic carbamate of amaminol A.
Amaminols A (1) and B (2) are cytotoxic bicyclic aminoal-
cohols isolated in 1999 from an unidentified tunicate of the
family Polyclinidae (Figure 1),1 with an IC50 value of 2.1
and obscuraminols.7 The interesting trans-fused hexahydro-
indene substructure of amaminols has most likely been
formed in nature by an intramolecular Diels-Alder reaction
of a triene or tetraene, such as found from crucigasterin 277
(3) and obscuraminol A (4).8 No synthetic efforts toward
amaminols have been reported so far.
Our previous work9 on the total synthesis of amaminol A
(1) involved organocatalytic intramolecular Diels-Alder
reaction.10 A concurrent study on organocatalytic IMDA by
(2) (a) Thudichum, J. L. W. A Treatise on the Chemical Constitution of
the Brain, Bailliere, London, 1884, new ed.; Archon Books, Hamden, CT,
1962. (b) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075-
1091.
Figure 1. Structures of amaminols A (1) and B (2), crucigasterin
277 (3), and obscuraminol A (4).
(3) (a) Gulavita, N.; Scheuer, P. J. Org. Chem. 1989, 54, 366-369. (b)
Jime´nez, C.; Crews, C. J. Nat. Prod. 1990, 53, 978-982. (c) Ichihashi,
M.; Mori, K. Biosci. Biotechnol. Biochem. 2003, 67, 329-333. (d) Mori,
K.; Matsuda, H. Liebigs Ann. Chem. 1992, 131-137.
(4) Clark, R. J.; Garson, M. J.; Hooper, J. N. A. J. Nat. Prod. 2001, 64,
1568-1571.
µg/mL against P388 murine leukaemia cells. Their mode of
action is unknown, but they are structurally closely related
to aliphatic cytotoxic aminoalcohols such as sphingosines,2
xestoaminols,3 halaminols,4 leucettamols,5 crucigasterins,6
(5) Kong, F.; Faulkner, J. J. Org. Chem. 1993, 58, 970-971.
(6) Jares-Erijman, E.; Bapat, C.; Lithgow-Bertelloni, A.; Rinehart, K.;
Sakai, R. J. Org. Chem. 1993, 58, 5732-5737.
(7) Garrido, L.; Zub´ıa, E.; Ortega, M. J.; Naranjo, S.; Salva´, J.
Tetrahedron 2001, 57, 4579-4588.
† Helsinki University of Technology.
(8) For biosynthetic Diels-Alder reactions see: Stocking, E. M.;
Williams, R. M. Angew. Chem., Int. Ed. 2003, 42, 3078-3115.
(9) For the synthesis of a diastereomer of amaminol A see: Selka¨la¨, S.
Ph.D. Thesis, Helsinki University of Technology, Espoo, Finland, 2003.
‡ University of Jyva¨skyla¨. Contact this author for X-ray crystallography
only.
(1) Sata, N. U.; Fusetani, N. Tetrahedron Lett. 2000, 41, 489-492.
10.1021/ol7022856 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/23/2007

Macmillan and co-workers showed improved enantio- and
stereoselectivities and therefore we adopted these condi-
tions.11
Retrosynthetic analysis reveals a route based on three
consecutive olefinations (Scheme 1). The stereogenic center
11 with the phosphorane prepared from 8 followed by
DIBAL-H reduction gave 14C-aliphatic tetraene alcohol 12
initially in a 2:1 E:Z ratio, which was improved to 4:1 by
treatment with iodine.
Allylic alcohol 12 was initially oxidized with manganese
oxide in dichloromethane to the highly volatile and sensitive
aldehyde 7. Isolation of the aldehyde 7 was avoided by
conducting the oxidation in acetonitrile, filtering off the
mangane oxide, and continuing directly to the organocatalytic
intramolecular Diels-Alder step, adding a small amount of
water (2 v %), cooling to -20 °C, then adding the catalyst
13 and trifluoroacetic acid. This sequence of operations
yielded the desired bicyclo[4.3.0]nonane aldehyde 5 in
excellent enantioselectivity (98.1% ee). The organocatalytic
IMDA also effected kinetic purification when only (6E,11E,-
13E,15E)- and (6E,11E,13E,15Z)-geometrical isomers were
reacted.11c
Scheme 1. Retrosynthetic Analysis of Amaminol A (1)
Horner-Wadsworth-Emmons olefination between phos-
honate 614 and an aldehyde similar to 5 with potassium
carbonate in ethanol led to extensive epimerization (Scheme
3).9 We evaded this drawback by using conditions reported
Scheme 3. Synthesis of Amaminol A (1) and epi-Amaminol
A (18)
at C2 is derived from L-alanine and the C3 stereocenter was
envisaged to be formed through a diastereoselective 1,2-
reduction using the chirality derived from L-alanine. The rest
of the stereocenters in the C5-C18 unit were to be formed
in an enantioselective intramolecular Diels-Alder reaction
of the intermediate aldehyde 7. Obvious disconnections of
7 lead to the known phosphonium salt 8,12 protected
glutaraldehyde 9,13 and commercially available Wittig ylide
10.
Scheme 2. Synthesis of C5-C18 Unit 5
by D’Auria and co-workers.15 Phosphonate 6 and aldehyde
5 reacted with barium hydroxide16 to give 14 in moderate
yield (51%) without any epimerization.
(11) (a) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 11616-11617. (b) Jen, W. S. Ph.D. Thesis, California
Institute of Technology, Pasadena, CA, 2004. (c) Comparable yields have
been reported for similar sequences: see ref 11a for similar substrates of
Dess-Martin peridionane oxidation, 53%, IMDA, 39% (based on 47% yield
and 85% conversion), giving a total yield of 21% (over two steps).
(12) Gunatilaka, A. A. L.; Hirai, N.; Kingston, D. G. I. Tetrahedron Lett.
1983, 24, 5457-5460.
Ozonolysis of cyclopentene in methanol (Scheme 2)13 gave
the partially protected glutaraldehyde 9, which was converted
to the conjugated ester 11 with Wittig ylide 10 followed by
hydrolysis in good combined yield (88%) and geometrical
selectivity (E:Z, 20:1). A second Wittig reaction of aldehyde
(13) (a) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett. 1982,
23, 3867-3870. (b) Aurrecoechea, J. M.; Gil, J. H.; Lo´pez, B. Tetrahedron
2003, 59, 7111-7121.
(14) Chakravarty, P. K.; Greenlee, W. J.; Parsons, W. H.; Patchett, A.
A.; Combs, P.; Roth, A.; Busch, R. D.; Mellin, T. N. J. Med. Chem. 1989,
32, 1886-1890.
(10) Selka¨la¨, S. A.; Koskinen, A. M. P. Eur. J. Org. Chem. 2005, 1620-
1624.
5044
Org. Lett., Vol. 9, No. 24, 2007

Chemoselective 1,4-reduction of enones in the presence
of acidic NH-protons is a major challenge. Recent reports
on using in situ prepared copper hydride catalyst and
stoichiometric amounts of silanes as hydride source led us
to try such an approach.17 Most methods are based on
catalytic amounts of commercial Stryker’s reagent,17b,c
preformed catalytic complex,17d-f basic copper alkoxides,17a
or copper fluoride systems.17g,h Although many practical
methods have been introduced for asymmetric copper
catalysis, nonasymmetric methods have gained practically
no attention. Enone 14 has a high tendency for epimerization
and therefore we had to uncover a practical catalytic system
avoiding highly basic counterions (Scheme 3). We adopted
the Lee and Yun method for the preparation of Stryker’s
reagent18 employing the procedure in situ and using Me-
(OEt)2SiH as the hydride source.19 Ketone 15 was obtained
in excellent (90%) yield after workup.20
Scheme 4. Formation of Cyclic Carbamates 19 and 20
Most convincingly, we succeeded in crystallizing the cyclic
carbamate 19 and obtaining its crystal structure.22 For
additional proof we compared the original NMR spectra of
Boc-protected amaminol A (16) and cyclic carbamate 19 to
those we obtained and found them to be indistinguishable.
Initially, we could not match the spectra of our synthetic
amaminol A (1) to the originally reported spectra. Careful
examination of the original isolation procedure revealed that
the reported data are most likely for the corresponding
trifluoroacetic acid salts of natural amaminols. Accordingly,
after conversion of synthetic 1 to its corresponding TFA salt,
the NMR spectra of the synthetic and the natural product
matched.1
Reduction of ketone 15 with Li(OtBu)3AlH gave a
separable mixture of alcohols 16 and 17 in a 3:1 (syn:anti)
selectivity.21 Final removal of Boc-protection with trifluo-
roacetic acid gave either natural amaminol A (1) or epi-
amaminol A (18).
To verify the relative stereochemistries, the aminoalcohols
1 and 18 were converted to the cyclic carbamate analogues
19 and 20 with carbonyl diimidazole (Im2CO) (Scheme 4).22
In summary, we have accomplished the first total synthesis
of amaminol A (1) in 10 steps and 6.5% overall yield using
a route based on organocatalytic intramolecular Diels-Alder
reaction. We also developed an efficient practical method
for selective conjugate reduction of enones. Crystallographic
analysis of a derivate of amaminol A and synthetic correla-
tion of the stereochemistry derived from L-alanine proves
the relative and absolute stereochemistry of amaminols
beyond question. The synthesis of amaminol analogues is
currently in progress in our laboratory.
(15) (a) Zampella, A.; Sepe, V.; D’Orsi, R.; Bifulco, G.; Bassarello, C.;
D’Auria, M. V. Tetrahedron: Asymmetry 2003, 14, 1787-1798. (b) Shin,
Y.; Fournier, J.-H.; Balachandran, R.; Madiraju, C.; Raccor, B. S.; Zhu,
G.; Edler, M. C.; Harnel, E.; Day, B. W.; Curran, D. P. Org. Lett. 2005, 7,
2873-2876. (c) Alvarez-Ibarra, C.; Aras, S.; Ba˜no´n, G.; Ferna´ndez, M. J.;
Rodr´ıgues, M.; Sinisterra, V. J. Chem. Soc., Chem. Commun. 1987, 1509-
1511.
(16) Abdel-Magid, A. F.; Koskinen, A. M. P. Barium Hydroxide,
Electronic Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
A., Fuchs, P. L., Wipf, P., Crich, D., Eds.; John Wiley & Sons: Chichester,
UK, 2007.
(17) (a) Minireview, on chiral copper hydrides: Rendler, S.; Oestreich,
M. Angew. Chem., Int. Ed. 2007, 46, 498-504. (b) Lipshutz, B. H.; Keith,
J.; Papa, P.; Vivian, R. Tetrahedron Lett. 1998, 39, 4627-4630. (c) Lipshutz,
B. H.; Chrisman, W.; Noson, K.; Papa, P.; Sclafani, J A.; Vivian, E. W.;
Keith, J. M. Tetrahedron 2000, 56, 2779-2788. (d) Jurkauskas, V.; Sadighi,
J. P.; Buchwald, S. L. Org. Lett. 2003, 5, 2417-2420. (e) Yun, J.; Kim,
D.; Yun, H. Chem. Commun. 2005, 5181-5183. (f) Welle, A.; D´ıez-
Gonza´lez, S.; Tinant, B.; Nolan, S. P.; Riant, O. Org. Lett. 2006, 8, 6059-
6062. (g) Mori, A.; Fujita, A.; Kajiro, H.; Nishihara, Y.; Hiyama, T.
Tetrahedron 1999, 55, 4573-4582. (h) Courmarcel, J.; Mostefa¨ı, N.; Sirol,
S.; Choppin, S.; Riant, O. Isr. J. Chem. 2001, 41, 231-240.
(18) Lee, D.-W.; Yun, J. Tetrahedron Lett. 2005, 46, 2037-2039.
(19) When PMHS was used, overreduction to 16 and 17 was observed.
(20) Without acetic acid, extensive C2 epimerization was observed.
(21) (a) Koskinen, A. M. P.; Koskinen, P. M. Tetrahedron Lett. 1993,
34, 6765-6768. (b) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J.
Org. Chem. 2002, 67, 1045-1056. (c) Lindsay, K. B.; Skrydstrup, T. J.
Org. Chem. 2006, 71, 4766-4777. (d) Va˚benø, J.; Brisander, M.; Lejon,
T.; Luthman, K. J. Org. Chem, 2002, 67, 9186-9191. (e) Other reductants
(DIBAL-H, L-Selectride) were anti-selective except (S)-Alpine hydride,
which showed syn-selectity but major contamination of the product.
Acknowledgment. We thank professor Nobuhiro Fuset-
ani, Hokkaido University, and professor Shigeki Matsunaga,
University of Tokyo, for providing original spectra for
amaminols A (1) and B (2) and their derivatives. Dr. Jari
Koivisto, Helsinki University of Technology, is acknowl-
edged for his help in the NMR study. This work was
supported by The Graduate School of Organic Chemistry
and Chemical Biology and Helsinki University of Technol-
ogy.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL7022856
(22) See the Supporting Information.
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