Enantioselective total synthesis of the kinesin motor protein inhibitor adociasulfate 1 [12]

Full text of DOI:10.1021/ja9934091

12206
J. Am. Chem. Soc. 1999, 121, 12206-12207
Enantioselective Total Synthesis of the Kinesin Motor
Protein Inhibitor Adociasulfate 1
Michael Bogensta¨tter, Anja Limberg, Larry E. Overman,* and
Adam L. Tomasi
Department of Chemistry, 516 Rowland Hall
UniVersity of California, IrVine
IrVine, California 92697-2025
ReceiVed September 20, 1999
nucleophilicity of the arene were borne out in early scouting
studies when treatment of 7 with a variety of Lewis acids under
a range of reaction conditions delivered only bi-, tri-, and
tetracyclic products and not the desired pentacycle 8. This failure
led us to examine the pivotal tetracyclization with a polyene
substrate containing an additional activating substituent at the 3′-
position of the arene, an approach that culminated in the total
synthesis of 1.
Utilizing the energy of ATP hydrolysis, the kinesin super family
of motor proteins is responsible for movement of cellular cargo
along microtubule tracks from the center of eukaryotic cells to
their periphery (anterograde transport).1 These proteins are
important targets for inhibition since they play a necessary role
in cell division2 and in vesicle and organelle transport.3 A family
of hexaprenoid hydroquinone sulfates, the adociasulfates (e.g.,
1-5), was isolated recently from extracts of the sea sponge
Haliclona (a.k.a. Adocia) sp. collected off Palau,4,5 and Queen-
sland, Australia.6 Adociasulfates 1 (1) and 2 (2) and congeners 3
and 4 inhibit members of the kinesin motor protein super family
in the low micromolar range and are the first kinesin inhibitors
identified that are not nucleotide analogues.4,5 Kinesin inhibition
by the most extensively investigated of these, 2, has been shown
to result from interfering with microtubule binding.4 Adociasul-
fates 1 (1) and 7 (5) have also been reported to be proton pump
inhibitors.6 Motivated by the opportunity to exploit the tools of
synthesis to enhance understanding of kinesin inhibition by the
adociasulfates, we undertook as our initial objective the total
synthesis of these novel hydroquinone bis-sulfates.
Geranylgeraniol cyclization substrate 19 was assembled from
the union of two geraniol-derived fragments, 14 and 13 (Scheme
1). The sulfone piece 14 was prepared according to literature
procedures,11 while allylic bromide 13 was accessed by initially
alkylating the lithium reagent derived from aryl bromide 9 with
silyl-protected allylic bromide 10.12 Discharge of the silyl-
protecting group of 11 and standard conversion to the allylic
bromide provided 13 in 56% overall yield from 9. Coupling of
the potassium salt of 14 with 13 furnished isomerically pure 15
in nearly quantitative yield.13 Desulfonylation of this intermediate
was initially problematic; for example, reduction of 15 with Na
(EtOH-THF) or Li (EtNH2) gave mixtures of tetraene stereo-
and regioisomers. Selectivity in the reduction of the allylic sulfone
was finally achieved by the method of Inomata14 by treating the
crude coupled product with LiEt3BH and Pd(dppp) at 0 °C to
furnish isomerically pure tetraene 16 on multigram scales in 64%
yield for the coupling and desulfonylation steps. It is notable in
this transformation, and not presaged in earlier publications, that
competing reduction of the allylic silyl ether functionality is
minimal when the reduction is conducted at 0 °C.15 The phenol
was reprotected and the silyl ether-protecting group was removed
with acidic methanol to provide 17. Sharpless asymmetric
epoxidation16 of 17 using the catalyst derived from (+)-diethyl
tartrate generated 18 (in 95% yield and 95% ee), which was
O-benzylated to give 19.
A variety of Lewis acids and cyclization conditions were
screened to induce polyene tetracyclization of 19 in CH2Cl2
(Scheme 2). Pentacycle 20 was produced in ∼10% yield using
BF3‚Et2O (-94 f -50 °C) or FeCl3‚6H2O (23 °C),17 whereas
MeAlCl2 (-90 f 0 °C), the Lewis acid reported optimal for
epoxide-initiated tetracyclizations terminated by enoxysilanes,8
gave only trace amounts (<5%) of 20. Of the Lewis acids
screened to date, Sc(OTf)3 (-90 f 0 °C) is optimal and provides
Hexacyclic hydroquinone 6 is a potential precursor of adocia-
sulfates 1-5. This intermediate contains nine stereogenic carbon
centers, of which eight are contiguous and four are quaternary.
Inspired by the pioneering investigations of Eschenmoser, Stork,
van Tamelen, Johnson, and Corey, we envisaged construction of
the bulk of this challenging stereochemical array in one step by
a cationic polyene cyclization.7 Recent notable success by the
Corey group in nonenzymatic epoxide-initiated polyene tetracy-
clizations8 suggested that 6 might be obtained by the cyclization
cascade shown in eq 1. From the outset we were mindful that
the two known epoxide-initiated polyene tetracyclizations featured
termination of the cationic cyclization by an enoxysilane,8 while
the proposed tetracyclization of 7 would require termination by
a significantly less-nucleophilic arene.9,10 Our concerns about the
(8) (a) Corey, E. J.; Luo, G.; Lin, L. S. J. Am. Chem. Soc. 1997, 119,
9927-9928. (b) Corey, E. J.; Luo, G.; Lin, L. S. Angew. Chem., Int. Ed.
1998, 37, 1126-1128.
(9) Kinetic investigations by Mayr and co-workers place the reactivity of
anisole and 1,3,5-trimethoxybenzene toward carbenium ion electrophiles 7
and 2 powers of 10 below that of 1-(trimethylsiloxy)cyclohexene.10
(10) (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-
957. (b) Burfeindt, J.; Patz, M.; Muller, M.; Mayr, H. J. Am. Chem. Soc.
1998, 120, 3629-3634.
(1) Hirokawa, N. Science 1998, 279, 519-526.
(2) (a) Walczak, C. E.; Mitchison, T. J. Cell 1996, 85, 943-946. (b)
Kashina, A. S.; Rogers, G. C.; Scholey, J. M. Biochim. Biophys. Acta 1997,
1357, 257-271.
(11) Chappe, B.; Musikas, H.; Marie, D.; Ourisson, G. Bull. Chem. Soc.
Jpn. 1988, 61, 141-148.
(12) Corey, E. J.; Tius, M. A.; Jagabandhu, D. J. Am. Chem. Soc. 1980,
102, 1742-1744.
(3) Sheetz, M. P. Cell Struct. Funct. 1996, 21, 369-373.
(4) Sakowicz, R.; Berdelis, M. S.; Ray, K.; Blackburn, C. L.; Hopmann,
C.; Faulkner, D. J.; Goldstein, L. S. B. Science 1998, 280, 292-295.
(5) Blackburn, C. L.; Hopmann, C.; Sakowicz, R.; Berdelis, M. S.;
Goldstein, L. S. B.; Faulkner, D. J. J. Org. Chem. 1999, 64, 5565-5570.
(6) Kalaitzis, J. A.; de Almeida Leone, P.; Harris, L.; Butler, M. S.; Ngo,
A.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64, 5571-5574.
(7) For a recent review, see: Sutherland, J. K. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3,
pp 341-377.
(13) Fujita, Y.; Ishiguro, M.; Onishi, T.; Nishida, T. Bull. Chem. Soc. Jpn.
1982, 55, 1325-1326.
(14) Mohri, M.; Kinoshita, H.; Inomata, K.; Kotake, H. Chem. Lett. 1985,
451-454.
(15) Hutchins, R. O.; Learn, K. J. Org. Chem. 1982, 47, 4380-4382.
(16) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(17) Sen, S. E.; Roach, S. L.; Smith, S. M.; Zhang, Y. z. Tetrahedron Lett.
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10.1021/ja9934091 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/14/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 51, 1999 12207
Scheme 1
of steric congestion surrounding the two carbons to be joined.21,22
We eventually found that this junction was best accomplished
by addition of (S)-cyclogeranyllithium 2323,24 to the aldehyde
formed from 22 by Dess-Martin oxidation.25 Adduct 24 was
produced as a single isomer, whose stereochemistry was incon-
sequential and not determined, in 79% yield for the two steps.
The congested steric environment surrounding C8 also compli-
cated removal of the hydroxyl group of 24, and many common
procedures for deoxygenation failed. The desired reduction was
finally achieved when a neat solution of xanthate derivative 25,26
n-Bu3SnH (100 equiv) and 2,2′-azobisisobutyronitrile (AIBN, 0.1
equiv) was warmed to 80 °C giving 26 in 78% yield from alcohol
24.
Preliminary survey experiments suggested that cleavage of an
acetate, rather than a silyl ether, from a hydrophilic hydroquinone
bis-sulfate precursor would simplify purification of the natural
product. Thus, the protecting group of the C10 alcohol was
changed to acetate.27 Next the phenolic methyl groups were
removed by oxidation to the quinone followed by reductive
workup to give hydroquinone 27 in 76% overall yield from 26.
Sulfation of 27 with excess SO3‚pyridine and pyridine for 14 h
at 23 °C provided bis-sulfate 28. The synthesis of adociasulfate
1 (1) was then completed by hydrolysis of 28 with a solution of
aqueous NaOH and MeOH (60 °C, 10 h), giving 1 in 67% yield
from 27. Synthetic adociasulfate 1 (1) was indistinguishable by
1H NMR, 13C NMR, HRMS, and reverse phase C-18 TLC
comparisons with an authentic sample. The optical rotation of
synthetic adociasulfate 1, [R]25D -30° (c ) 0.10), was the same
Scheme 2
sign as that reported for natural 1, [R]26 -34° (c ) 0.1)6 and
D
-15.0° (c ) 0.1).5
In conclusion, the first total synthesis of (-)-adociasulfate 1
was completed from commercially available geraniol and 2-hy-
droxy-5-methoxybenzaldehyde.28 In addition to establishing the
absolute configuration of the natural product, the synthesis
provides the first example of using an arene to terminate an
epoxide-initiated polyene tetracyclization. Tetracyclization to form
20 proceeded with a yield per ring of 62% (15% overall).
However, for this route to meet the challenge of providing a
practical synthetic entry to the adociasulfates, substantial improve-
ment in the yield of the critical polyene cyclization will be needed.
Acknowledgment. This research was supported by NIH Grant NS-
12389, graduate fellowships to A.L.T. from Pfizer and the ACS Organic
Division (supported by Merck Research Laboratories), and postdoctoral
fellowships to M.B. and A.L. from the Alexander von Humboldt
Foundation and Deutsche Forschungsgemeinschaft. We particularly thank
Professor D. John Faulkner and Dr. Christine Blackburn for a sample of
natural 1 and advice on its purification. NMR and mass spectra were
determined at UCI with instrumentation purchased with the assistance
of NSF and NIH shared instruments programs.
Supporting Information Available: Experimental procedures, spec-
troscopic and analytical data for new compounds described in Schemes
1 and 2, and 1H and 13C NMR spectra of synthetic and natural
adociasulfate 1 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA9934091
(19) Saa, J. M.; Dopico, M.; Martorell, G.; Garcia-Raso, A. J. Org. Chem.
1990, 55, 991-995.
(20) The authors have deposited coordinates for this compound with the
Cambridge Crystallographic Data Centre. The coordinates can be obtained,
on request, from the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, U.K.
20 in 15% yield.18 The secondary alcohol of 20 was protected as
a tert-butyldimethylsilyl (TBDMS) ether and the activating
allyloxy group was removed by a two-pot, three-step sequence
involving deallylation, triflation, and palladium-catalyzed reduc-
tion of the aryl triflate intermediate.19 The product, pentacycle
21, was obtained in 66% yield for the three steps. Hydrogenolysis
of the benzyl group then yielded crystalline alcohol 22.20
Next, the union of a cyclogeranyl fragment with 22 was
explored and found to be quite demanding due to the high degree
(21) For example, attempts to add 23 to tosyl or trisyl hydrazone derivatives
of 22 failed.22
(22) Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120, 8891-
8892.
(23) Made by conversion of (S)-R-cyclogeraniol24 (98% ee) to the corre-
sponding iodide (PPh3, I2, imidazole, benzene) followed by lithium-iodide
exchange using tert-butyllithium.
(24) Mori, K.; Amaike, M.; Itou, M. Tetrahedron 1993, 49, 1871-1878.
(25) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(26) Barton, D. H. R.; Dorchak, J.; Jaszberenyi, J. C. Tetrahedron 1992,
48, 7435-7446.
(27) (R)- and (S)-R-Methoxy-R-(trifluoromethyl)phenylacetyl derivatives
of the alcohol formed on desilylation were analyzed by 19F NMR.
(28) The synthetic sequence is 28 steps from either starting material.
(18) To our knowledge this is the first use of a lanthanide triflate to catalyze
a polyene cyclization.