Oxabicyclo[3.2.1]octenes in organic synthesis: Direct ring opening of oxabicyclo[3.2.1] ring systems with diisobutylaluminum hydride and a silyl ketene acetal - synthesis of the chiral C(19)-C(26) and C(27)-C(32) fragments of scytophycin C

Article abstract of DOI:10.1021/ol010253c

Chemical equation presented An efficient strategy for transforming meso-oxabicyclo[3.2.1]octenone 1 into optically active intermediates for macrolide synthesis has been developed. The direct bridgehead opening of optically active oxabicyclo[3.2.1]octene d

Full text of DOI:10.1021/ol010253c

ORGANIC
LETTERS
2002
Vol. 4, No. 2
245-248
Oxabicyclo[3.2.1]octenes in Organic
Synthesis: Direct Ring Opening of
Oxabicyclo[3.2.1] Ring Systems with
Diisobutylaluminum Hydride and a Silyl
Ketene AcetalsSynthesis of the Chiral
C(19)−C(26) and C(27)−C(32) Fragments
of Scytophycin C
Kevin W. Hunt and Paul A. Grieco*
Department of Chemistry and Biochemistry, Montana State UniVersity,
Bozeman, Montana 59717
grieco@chemistry.montana.edu
Received November 1, 2001
ABSTRACT
An efficient strategy for transforming meso-oxabicyclo[3.2.1]octenone 1 into optically active intermediates for macrolide synthesis has been
developed. The direct bridgehead opening of optically active oxabicyclo[3.2.1]octene derivative 2 with hydride or a silyl ketene acetal utilizing
the highly polar medium lithium perchlorate in diethyl ether resulted in highly functionalized cycloheptenones, which were transformed into
the C(19)−C(26) and C(27)−C(32) fragments of Scytophycin C.
We recently disclosed a procedure1 for the direct bridgehead
opening of activated oxabicyclic molecules employing silyl
ketene acetals in the highly polar medium 4.0 M lithium
perchlorate-diethyl ether (LPDE)2[eq 1]. We now wish to
disclose (1) the desymmetrization of the starting oxabicyclo-
[3.2.1]octenone 1 via enantioselective deprotonation [eq 2],
(2) the direct bridgehead opening of the oxa bridge of 2
employing diisobutylaluminum hydride3 leading to the direct
formation of cycloheptenone 4 [eq 3], (3) the use of 4 in the
construction of the C(27)-C(32) fragment 7 of Scytophycin
C (5),4 and (4) the transformation of optically active 3 into
the C(19)-C(26) subunit 6 of 5. In contrast to the use of
rigid oxabicyclo[3.2.1]octenes as stereocontrol vehicles for
the preparation of the acyclic fragments of 5 as detailed
(3) For the complementary SN2′ opening of oxabicyclo[3.2.1]octenes
employing diisobutylaluminum hydride see: Lautens, M.; Chiu, P.; Colucci,
J. T. Angew. Chem., Int. Ed. Engl. 1993, 32, 281.
(1) Hunt, K. W.; Grieco, P. A. Org. Lett. 2001, 3, 481.
(2) For the use of highly polar media to promote organic reactions, see:
Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc. 1990, 112,
4595. Grieco, P. A. Aldrichimica Acta 1991, 24, 59. Grieco, P. A. Organic
Chemistry in Lithium Perchlorate/Diethyl Ether. In Organic Chemistry: Its
Language and Its State of the Art; Kisakurek, V., Ed.; VCH: Basel, 1993;
p 133.
(4) (a) For the total synthesis of Scytophycin C, see: Paterson, I.; Watson,
C.; Kap-Sun, Y.; Wallace, P. A.; Ward, R. A. J. Org. Chem. 1997, 62,
452. Paterson, I.; Watson, C.; Kap-Sun, Y.; Wallace, P. A.; Ward, R. A.
Tetrahedron 1998, 54, 11935; 11955. (b) For previous synthetic studies,
see: Grieco, P. A.; Speake, J. D.; Yeo, S. K.; Miyashita, M. Tetrahedron
Lett. 1998, 39, 1125. Grieco, P. A.; Speake, J. A. Tetrahedron Lett. 1998,
39, 1275. (c) Roush, W. R.; Dilley, G. J. Tetrahedron Lett. 1999, 40, 4955.
10.1021/ol010253c CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/04/2002

The synthetic strategy for accessing the C(27)-C(32)
fragment 7 of Scytophycin C required bridgehead addition
of hydride to enol silane 2. Initially, 2 was treated with a
variety of silanes (triethyl, triphenyl, triethoxy, chlorodi-
phenyl) in concentrated solutions of LPDE (3.0-5.0 M) at
ambient temperature.8 In all cases studied, only recovered
starting material was detected by TLC and 1H NMR analysis.
Use of traditional Lewis acids (BF3‚OEt2, TiCl4) resulted in
hydrolysis of the enol silane to provide meso ketone 1.
Finally, it was found that addition of diisobutylaluminum
hydride (DIBALH) to enol silane 2 in 5.0 M LPDE provided
the â-hydroxy cycloheptenone 4 in 65% yield (eq 3).9 The
stereochemistry of the eventual stereogenic center at C(30)
is a result of an axial-like protonation of the intermediate
aluminum enolate (cf. eq 3) upon aqueous workup. It is
important to note that exposure of enol silane 2 to 5.0 M
LPDE in the absence of DIBALH for 24 h returns 2 without
any loss of optical activity.
With the hydride opened product 4 in hand, the stage was
set for determining and increasing the enantiomeric excess.
Although conversion of 4 into the corresponding Mosher
ester10 clearly revealed by 1H NMR analysis that the
enantiopurity of 4 was 75% ee, the resulting diastereomeric
esters were not readily separable. After surveying a series
of mandelic acid derivatives, it was found that coupling
(DCC, cat. DMAP, CH2Cl2, 0 °C) of 4 with (S)-O-
methylmandelic acid (10) provided a 7:1 mixture of esters
11a and 11b, respectively, in excellent yield (eq 4). Chro-
below, previous efforts in this area have employed asym-
metric crotylboration,4 boron-mediated aldol reactions,4a
methyl ketone aldol reactions,4a,c and methylation of γ,δ-
epoxy acrylates employing trimethylaluminum.4b
matography of the mixture on silica gel provided 11a, [R]25
D
-164 (c 1.3, CHCl3), in 83% isolated yield in 98% de. The
absolute configuration of each ester was initially deduced11
by comparing the chemical shifts of the olefinic proton and
the methine proton adjacent to the carbon bearing the (S)-
O-methylmandelate present in 11a and 11b.
The synthetic studies commenced with desymmetrizing
ketone 1 via enantioselective deprotonation.5 Thus, depro-
tonation of 1 with the homochiral lithium amide base 8,
derived from [R-(R*,R*)]-(+)-bis(R-methylbenzyl)amine (9),
in tetrahydrofuran containing HMPA and tert-butyldimethyl-
silyl chloride (TBSCl) at -78 °C for 24 h provided (97%)
optically active enol silane 2. The enantiomeric purity of
the desymmetrized material was found to be 75% ee (vide
infra).6 In contrast to previous work,7 the use of HMPA and
the exclusion of lithium chloride proved crucial to the yield
and enantioselectivity of the reaction.
Stereoselective reduction of 11a with lithium tri-tert-butoxy-
aluminum hydride, followed by methylation of the resulting
hydroxyl group under solvent-free conditions,4a provided
methyl ether 12 in 77% yield (Scheme 1). As the O-methyl-
mandelate had served its dual purpose as a resolving agent
and a protecting group, it was removed with lithium alumi-
num hydride. Conversion of 13 into ester-aldehyde 14 was
(5) Koga, K. Pure Appl. Chem. 1994, 66, 1487. Cox, P. J.; Simpkins,
N. S. Tetrahedron: Asymmetry 1991, 2, 1.
246
Org. Lett., Vol. 4, No. 2, 2002

-114 (c 3.9, CHCl3), could be obtained in 63% isolated
yield, 96% de, after chromatography on silica gel.13
Scheme 1
One-pot saponification and iodolactonization of 16a,
followed by selective formation (PhO(CS)Cl, DMAP) of the
thionocarbonate of the least hindered hydroxyl group,
affected by sequential Ley oxidation,12 dihydroxylation of
the crude enone, and exhaustive oxidative cleavage. Chemo-
selective reduction of the aldehyde, protection of the resulting
primary alcohol as a TIPS ether, and reduction of the ester
gave rise to the known alcohol 7, [R]25D -2.0 (c 2.0, CHCl3),
Scheme 2
lit.4a [R]25 -1.9 (c 2.0, CHCl3), in 78% overall yield.
D
Construction of the C(19)-C(26) fragment of Scytophycin
C required treatment of enol silane 2 (75% ee) with 2.0 equiv
of 1-methoxy-1-(tert-butyldimethylsiloxy)-ethylene in 4.0 M
LPDE at 0 °C [eq 1]. Exposure of the crude product to tetra-
n-butylammonium fluoride (HOAc, THF) provided keto-ester
15 in 83% overall yield. Coupling of 15 with (S)-O-
methylmandelic acid (10) provided an inseparable 7:1
mixture of diastereomers in quantitative yield. Stereoselective
reduction of the ketone carbonyl with lithium tri-tert-
butoxyaluminum hydride [eq 5] provided (95%) alcohols 16a
and 16b in a ratio of 7:1, respectively. Thus, 16a, [R]25
D
(6) Interestingly, application of the Simpkins-Koga protocol to bicyclo-
[3.2.1]octenone i employing [S-(R*,R*)]-(-)-bis(R-methylbenzyl)amine
provided the chiral lithium enolate ii possessing the assigned absolute
configuration [see: Nowakowski, M.; Hoffman, H. M. R. Tetrahedron Lett.
1997, 38, 1001].
(7) Bunn, B. J.; Cox, P. J.; Simpkins, N. S. Tetrahedron 1993, 49, 207.
Majewski, M.; Lazny, R.; Nowak, P. Tetrahedron Lett. 1995, 36, 5465.
(8) For the deoxygenation of allylic alcohols employing Et3SiH/LPDE,
see: Wustrow, D. J.; Smith, W. J., III; Wise, L. D. Tetrahedron Lett. 1994,
35, 61.
(9) A solution of 2 (11.5 g, 43.2 mmol) in 5.0 M LPDE (216 mL, 0.2 M
in substrate) was cooled to 0 °C under argon. A solution of DIBALH in
toluene (86.4 mL of a 1.0 M solution in toluene, 2.0 equiv) was added
over 5 min. The reaction was allowed to warm to ambient temperature and
stirred for 20 h. The reaction was cooled to 0 °C and quenched with saturated
aqueous potassium sodium tartrate solution, and the product was extracted
with diethyl ether. The combined organic layers were dried over MgSO4,
filtered, concentrated in vacuo, and purified on silica gel. Elution with 25%
ethyl acetate-hexanes provided 5.64 g (65%) of 4.
Org. Lett., Vol. 4, No. 2, 2002
247

provided iodolactone 17 in 70% overall yield. Radical-
induced syn elimination14 of 17 (Scheme 2) followed by an
acidic workup and reduction of the olefin afforded the
saturated lactone 18 in 60% overall yield. Methylation of
the dianion-derived lactone 18, followed by sequential
protection of the hydroxyl group as a PMB ether and
reduction of the lactone carbonyl, gave way to diol 19.
Silylation of the primary hydroxyl group and subsequent
oxidation12 of the secondary hydroxyl group gave rise to
ketone 20, which upon desilylation provided hemiketal 21.
Direct subjection of 21 to Baeyer-Villiger oxidation15,16
followed by exposure of the resulting lactones to potassium
carbonate in allyl alcohol gave rise to allyl ester 22.
Tritylation of the primary hydroxyl and protection of the
secondary hydroxyl as a triethylsilyl ether generated the
C(19)-C(26) fragment 6, [R]25 -4.7 (c 1.6, CHCl3).
D
In summary, desymmetrization of oxabicyclo[3.2.1]-
octenone 1 employing [R-(R*,R*)]-(+)-bis(R-methylbenzyl)-
amidolithium 8 provides access to (-)-silyl enol ether 2,
which is capable of undergoing direct bridgehead ring
opening with diisobutylaluminum hydride and a silyl ketene
acetal affording cycloheptenones 4 and 15, respectively,
which constitute useful substrates for the elaboration of
acyclic molecule fragments rich in stereogenic centers.
(10) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(11) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M. J. Org. Chem. 1986, 51, 2370.
(12) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625. Griffith, W. P.; Ley, S. V. Aldrichimica
Acta 1990, 23, 13.
(13) Repetitive purification of the remaining (32%) material provided
additional 16a (ca. 20%).
(14) Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFrees, S. A.;
Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. J. Am. Chem.
Soc. 1990, 112, 3040.
Acknowledgment. This investigation was supported by
a Public Health Service research grant from the National
Institute of General Medical Sciences (GM 33605).
Supporting Information Available: 1H and 13C NMR
spectra for 2, 4, 6, 7, 11-20, and 22. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Hunt, K. W.; Grieco, P. A. Org. Lett. 2000, 2, 1717.
(16) Attempts to perform the Baeyer-Villiger oxidation on ketone 20
met with no success.
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