Stereoselection in the prins-pinacol synthesis of 2,2-disubstituted 4-acyltetrahydrofurans. Enantioselective synthesis of (-)-citreoviral.

Article abstract of DOI:10.1021/ol991315q

[reaction: see text] The condensation of allylic diols with unsymmetrical ketones proceeds with high stereoselection to form 2,2-disubstituted 4-acyltetrahydrofurans when the alpha-substituents of the ketone differ substantially in size. A Prins-pinacol c

Full text of DOI:10.1021/ol991315q

ORGANIC
LETTERS
2000
Vol. 2, No. 2
223-226
Stereoselection in the Prins-Pinacol
Synthesis of 2,2-Disubstituted
4-Acyltetrahydrofurans. Enantioselective
Synthesis of (−)-Citreoviral
Naoyuki Hanaki,† J. T. Link,‡ David W. C. MacMillan,§ Larry E. Overman,*
William G. Trankle,| and Julie A. Wurster
Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, IrVine, California 92697-2025
leoVerma@uci.edu
Received December 7, 1999
ABSTRACT
The condensation of allylic diols with unsymmetrical ketones proceeds with high stereoselection to form 2,2-disubstituted 4-acyltetrahydrofurans
when the r-substituents of the ketone differ substantially in size. A Prins-pinacol condensation of this type is the central strategic step in an
enantioselective synthesis of (−)-citreoviral.
(+)-Citreoviral (1) and the related polyene pyrone (-)-
citreoviridin (3) co-occur in Penicillum citreoViride.1 Citreo-
viridin is a potent neurotoxic mycotoxin because of its
specific inhibition of mitochondrial F1,F0-ATPase.2 These and
related mycotoxins3 have stimulated the development of
imaginative methods for preparing polysubstituted tetrahy-
drofurans, with total syntheses of citreoviridin (3) and
citreoviral (1) being achieved by several groups in both
racemic4 and optically active form.5
† Current address: Fuji Photo Film Co., Ltd., Ashigara Research
Laboratories, 210 Nakanuma, Minamiashigara-Shi, Kanagawa 250-0193,
Japan.
‡ Current address: Abbott Laboratories, Dept 47VAP-10 (Rm 305), 100
Abbott Park Road, Abbott Park, IL 60064-3500.
§ Current address: Department of Chemistry, University of California
Berkeley, Berkeley, CA 94720.
| Current address: Eli Lilly & Company, 1555 Kentucky Avenue, #4813,
Indianapolis, IN 46221.
Current address: Allergan, Inc., Chemical Sciences, 2525 Dupont
Drive, RD3D, Irvine, CA 92623-9534.
(1) (a) Sakabe, N.; Goto, T.; Hirata, Y. Tetrahedron 1977, 33, 3077-
3081. (b) Shizuri, Y.; Nishiyama, S.; Imai, D.; Yamamura, S.; Furukawa,
H.; Kawai, K.; Okada, N. Tetrahedron Lett. 1984, 25, 4771-4774.
(2) (a) Boyer, P. D.; Chance, B.; Ernster, L.; Mitchell, P.; Racker, E.;
Slater, E. C. Annu. ReV. Biochem. 1977, 46, 955-1026. (b) Mitchell, P.
FEBS Lett. 1977, 78, 1-20. (c) Chang, T.; Penefsky, H. S. J. Biol. Chem.
1974, 249, 1090-1098. (d) Muller, J. L. M.; Rosing, J.; Slater, E. C.
Biochim. Biophys. Acta 1977, 462, 422-437. (e) Gause, E. M.; Buck, M.
A.; Douglas, M. G. J. Biol. Chem. 1981, 256, 557-562.
(3) The synthesis of asteltoxin by Schreiber and Satake is an early notable
example: Schreiber, S. L.; Satake, K. J. Am. Chem. Soc. 1984, 106, 4186-
4188.
A wide variety of polysubstituted tetrahydrofurans can be
prepared by condensation of allylic diols with aldehydes or
ketones in a reaction sequence whose central step is a
pinacol-terminated Prins cyclization (Scheme 1).6,7 Recent
publications from these laboratories have illustrated the utility
of this strategy level reaction for preparing oxacyclic natural
10.1021/ol991315q CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/23/1999

diols 10 were anticipated to be readily available from (S)-
(-)-ethyl lactate.10
Scheme 1
For the approach adumbrated in Scheme 2 to be successful,
Prins-pinacol condensation of 10 and 11 must take place with
stereoselective incorporation of the ketone fragment. To gain
insight into stereochemical control elements in Prins-pinacol
reactions of unsymmetrical ketones, rearrangements of acetals
12 derived from 3,4-dimethyl-4-penten-2,3-diol11 and a series
of unsymmetrical ketones were investigated. Results are
summarized in Scheme 3.12 Stereoselection in the reaction
Scheme 3
products.8 Although the condensation of allylic diols 4 and
aldehydes (5, R6 ) H) has been employed to stereoselectively
assemble chiral tetrahydrofurans having substituents at each
ring carbon, we had not previously investigated stereoselec-
tion in the condensation of allylic diols with unsymmetrical
ketones. The opportunity to rectify this deficiency in our
understanding of the Prins-pinacol synthesis of tetrahydro-
furans and to examine the viability of introducing a hydroxyl
group at C3 of a 4-acyltetrahydrofuran by way of a silyl
surrogate9 led us to pursue the total synthesis of (-)-
citreoviral (2) by the strategy outlined in Scheme 2. The
of the series of methyl ketones increased approximately with
the size of the R1 substituent. Steric effects obviously play
the dominant role, with electronic effects being less impor-
tant. The preference for forming tetrahydrofuran 13 having
the larger C2 substituent on the â face is consistent with
this group preferentially occupying a pseudoequatorial posi-
tion in the Prins cyclization step (7 f 8, Scheme 1). We
concluded from this brief study that for 9 to be highly favored
in the pivotal Prins-pinacol conversion, the protecting group
of the 1-hydroxy-2-propanone component 11 would need to
be a large group. A tert-butyldiphenylsilyl (TBDPS) group
was chosen both for its steric size and its stability to Lewis
acids.
Scheme 2
Our synthesis of (-)-citreoviral begins with construction
of enantioenriched allylic diols 18 from (S)-3-(tert-butyl-
diphenylsiloxy)-2-butanone (16)10 and 1-(dimethylphenylsil-
yl)propyne (15).13 Using tantalum chemistry developed by
Takai and Utimoto,14 the tantalum alkyne complex derived
unnatural enantiomer 2 was targeted since this congener had
not been prepared previously and enantioenriched allylic
(4) (()-Citreoviridin: (a) Williams, D. R.; White, F. H. J. Org. Chem.
1987, 52, 5067-5079. (()-Citreoviral: (b) Williams, D. R.; White, F. H.
Tetrahedron Lett. 1985, 26, 2529-2532. (c) Bowden, M. C.; Patel, P.;
Pattenden, G. Tetrahedron Lett. 1985, 26, 4793-4796. (d) Bowden, M.
C.; Patel, P.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1991, 1947-
1950. (e) Begley, M. J.; Bowden, M. C.; Patel, P.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1991, 1951-1958. (f) Ebenezer, W.; Pattenden, G.
Tetrahedron Lett. 1992, 33, 4053-4056.
(5) (-)-Citreoviridin and (+)-citreoviral: (a) Nishiyama, S.; Shizuri, Y.;
Yamamura, S. Tetrahedron Lett. 1985, 26, 231-234. (b) Suh, H.; Wilcox,
C. S. J. Am. Chem. Soc. 1988, 110, 470-481. (c) Whang, K.; Venkataraman,
H.; Kim, Y. G.; Cha, J. K. J. Org. Chem. 1991, 56, 7174-7177.
(+)-Citreoviral: (d) Hatakeyama, S.; Matsui, Y.; Suzuki, M.; Sakurai, K.;
Takano, S. Tetrahedron Lett. 1985, 26, 6485-6488.
(7) For the original discovery of this route to tetrahydrofurans, see:
Martinet, P.; Mousset, G. Bull. Soc. Chim. Fr. 1970, 1071-1076.
(8) See, inter alia: (a) Grese, T. A.; Hutchinson, K. D.; Overman, L. E.
J. Org. Chem. 1993, 58, 2468-2477. (b) MacMillan, D. W. C.; Overman,
L. E. J. Am. Chem. Soc. 1995, 117, 10391-10392.
(9) Colvin, E. W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Heathcock, C. H., Eds.; Pergamon: Oxford, 1992; Vol. 7, pp 641-651.
(10) Overman, L. E.; Rishton, G. M. Organic Syntheses; Wiley: New
York, 1998; Collect. Vol. 9, pp 139-142.
(11) This diol was a 7:1 mixture of anti and syn isomers.6c
(12) Stereochemical assignments for tetrahydrofuran products 13 and 14
were secured by nOe experiments. Details are provided in Supporting
Information.
(6) For brief reviews, see: (a) Overman, L. E. Aldrichimica Acta 1995,
28, 107-120. (b) Overman, L. E. Acc. Chem. Res. 1992, 25, 352-359. (c)
Overman, L. E.; Rishton, G. M. Organic Syntheses; Wiley: New York,
1998; Collect. Vol. 9, pp 4-9.
(13) Available in 89% yield from silylation of 1-lithiopropyne: Meinke,
P. T.; Krafft, G. A.; Guram, A. J. Org. Chem. 1988, 53, 3632-3634.
(14) Kataoka, Y.; Miyai, J.; Oshima, K.; Takai, K.; Utimoto, K. J. Org.
Chem. 1992, 57, 1973-1981.
224
Org. Lett., Vol. 2, No. 2, 2000

from 15 was added to 16 and the vinyltantalum intermediate
was cleaved with aqueous NaOH to generate (E)-allylic diol
derivative 17 stereoselectively. Without purification, this
crude product was exposed to tetra-n-butylammonium fluo-
ride (TBAF) to provide allylic diol 18, a 6:1 mixture of allylic
alcohol epimers, in 82% overall yield from 16. Standard
silylation of 18 delivered bis(trimethylsilyl) derivative 19 in
essentially quantitative yield.
Disiloxy alkene 19 was condensed with dimethyl ketal 2015
in the presence of 0.1 equiv of trimethylsilyl triflate at -30
°C in CH2Cl2 in the expectation that ketal 21 would be
formed.16 To our surprise, these conditions generated nearly
equal amounts of 21 and the ultimately desired polysubsti-
tuted tetrahydrofuran 22. Separation of these products on
silica gel provided 22 in 47% yield and 21 in 41% yield.
Since acetal 21 was unchanged when exposed to 0.1 equiv
of trimethylsilyl triflate at -30 °C in CH2Cl2, 21 was not an
intermediate on the pathway to 22 under these conditions.17
However, 21 could be efficiently converted to 22 by exposure
to 1.2 equiv of SnCl4 at -78 °C in CH2Cl2.18,19 The sequence
summarized in Scheme 4 delivers polysubstituted tetra-
Our plan for preparing (-)-citreoviral from tetrahydrofuran
22 required introducing the C3 and C4 hydroxyl groups by
oxidation of the C-SiMe2Ph9,21 and C-COMe22 bonds,
processes that are well-established to proceed with retention
of configuration. After exhaustive attempts to activate the
C3 silyl functionality of 22 for oxidative cleavage by
conversion of the phenyl substituent to an electronegative
group failed,9,21 we turned to a procedure introduced by Taber
for activating dimethylphenylsilyl substituents for oxidation.23
The tert-butyldiphenylsilyl group of 22 was first dis-
charged with 48% aqueous HF in acetonitrile to give 23
(Scheme 5).24 To protect the ketone and simplify isolation
Scheme 5
Scheme 4
of subsequent intermediates, 23 was converted to bicyclic
acetal 24 by exposure to acidic methanol and trimethyl
orthoformate. Reduction of 24 with Li in ammonia, followed
by sequential reaction of the Birch reduction product with
TBAF and basic hydrogen peroxide generated alcohol 25
(mp 96-98 °C) in 62% yield.23 Protection of the secondary
alcohol of 25 as a benzoate, Baeyer-Villiger oxidation of
26 with trifluoroperacetic acid in CH2Cl225 and final basifi-
cation to pH 8.5 delivered diol 27 in 72% yield. Primary
acetate 28 was isolated also in 20% yield.
hydrofuran 22 in 67% overall yield and >95% ee from (S)-
siloxybutanone 16.20
The synthesis of (-)-citreoviral (2) was completed as
summarized in Scheme 6. Tetrapropylammonium perruth-
enate (TPAP)-catalyzed oxidation26 of 27 gave rise to lactone
(15) Nemoto, H.; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J. Org.
Chem. 1992, 57, 1707-1712.
(16) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357-1358.
(17) This result suggests that the R-alkoxycarbenium ion initially
generated16 from condensation of 19 with the more accessible secondary
trimethylsilyl ether group of 20 undergoes Prins cyclization faster than it
is trapped by the proximal tertiary trimethylsilyl ether.
(18) Hopkins, M. H.; Overman, L. E.; Rishton, G. M. J. Am. Chem.
Soc. 1991, 113, 5354-5365.
(19) A tetrahydrofuran product epimeric to 22 at C5 was not detected in
this reaction or in the initial condensation of 19 and 20.
(20) The enantiopurity of 22 was confirmed by HPLC analysis using a
Chiralcel OD column.
(21) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun.
1984, 29-31.
(22) Krow, G. R. Org. React. 1993, 43, 251-798.
(23) Taber, D. F.; Yet, L.; Bhamidipati, R. S. Tetrahedron Lett. 1995,
36, 351-354.
(24) At this point, the constitution of the tetrahydrofuran produced upon
Prins-pinacol rearrangement was rigorously established by single-crystal
X-ray analysis of the phenylcarbamate derivative.
(25) Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett
1990, 533-535.
(26) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13-19.
Org. Lett., Vol. 2, No. 2, 2000
225

is the first of the unnatural enantiomer of this natural product.
A notable feature of the synthesis is use of a Prins-pinacol
reaction to assemble highly functionalized tetrahydrofuran
intermediate 22 in 65% overall yield from (S)-(-)-ethyl
lactate. These studies extend the scope of the Prins-pinacol
synthesis of tetrahydrofurans by demonstrating that (a) 2,2-
disubstituted 4-acyltetrahydrofurans containing different C2
substituents can be formed with high stereoselection if the
R-carbons of the unsymmetrical ketone component differ
substantially in steric size and (b) 4-acyl-3-(dimethylphen-
ylsilyl)-tetrahydrofurans, which serve as precursors of 4-acyl-
3-hydroxytetrahydrofurans, can be accessed by Prins-pinacol
rearrangements of allylic diols containing an (E)-dimeth-
ylphenylsilyl substituent on the distal vinylic carbon.28,29
Scheme 6
Acknowledgment. This research was supported by a
Javits Neuroscience Investigator Award from NIH NINDS
(NS-12389). Merck, Pfizer, Roche Biosciences, and Smith-
Kline Beecham provided additional support. We particularly
thank Professors David Williams and Jin Cha for providing
samples of 32. NMR and mass spectra were determined using
instruments acquired with the assistance of NSF and NIH
shared instrumentation grants.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds
reported in Schemes 3-6. This material is available free of
charge via the Internet at http://pubs.acs.org.
29. Reduction of this intermediate with diisobutylaluminum
hydride (DIBALH) at -78 °C selectively generated lactol
30,5b without cleavage of the benzoate protecting group.
Wittig reaction of 30 with (carboethoxyethylidene)tri-
phenylphosphorane in refluxing benzene yielded a 4:1
mixture of E and Z R,â-unsaturated esters; separation of this
mixture on silica gel provided E isomer 31 in 51% yield.
Reduction of 31 with DIBALH at 0 °C f room temperature
gave allylic alcohol 32, which was identical in all respects
except optical rotation with an authentic sample.4b,5c Finally,
oxidation of 32 with barium manganate in refluxing benzene
OL991315Q
(27) Specific rotations at the sodium D line of +21.1 (c 2.5, CHCl3),5a
+18.7 (c 0.65, CHCl3)5b, and +23.3 (c 0.12, CHCl3),5c have been reported
for 1.
(28) This successful preparation of 4-acyl-3-(dimethylphenylsilyl)tet-
rahydrofurans demonstrates that pinacol rearrangements of 4-hydropyranyl
cations containing an equatorial dimethylphenylsilyl substituent at C3 (e.g.,
8, R3 ) SiPhMe2, Scheme 1) occur faster than â-silyl elimination to form
an alkene.29
(29) For other reports documenting the high rate of the pinacol
rearrangement step in Prins-pinacol rearrangements, see: (a) Minor, K. P.;
Overman, L. E. Tetrahedron 1997, 53, 8927-8940. (b) Pennington, L. D.;
Overman, L. E. Can. J. Chem. 2000, 78, in press.
furnished (-)-citreoviral (2), [R]23 -21 (c 0.6, CHCl3), in
D
46% overall yield from 31.27
The total synthesis of (-)-citreoviral (2) recorded herein
226
Org. Lett., Vol. 2, No. 2, 2000