1-Oxaspiro[4.4]nonan-6-ones. Synthetic access via oxonium ion technology, optical resolution, and conversion into enantiopure spirocyclic α,β-butenolides

Article abstract of DOI:10.1021/jo010026o

A general approach to the synthesis of enantiomerically pure spirocyclic α,β-butenolides is presented where the fundamental framework is rapidly elaborated by acid- or bromonium ion-induced rearrangement of the carbinol derived by addition of 2-lithio-4,5-dihydrofuran to cyclobutanone. Subsequent resolution of the resulting ketones by either sulfoximine or mandelate acetal technology has been applied effectively. The availability of these building blocks makes possible in turn the acquisition of the enantiomers of dihydrofurans typified by 17, 35, and 38 and lactones such as 25 and 31, as well as the targeted title compounds. Complementary reductions of the early intermediates provide the added advantage that the α- and β-stereoisomeric carbinol series can be obtained on demand. These capabilities have been coordinated to allow the crafting of any member of the series in relatively few steps.

Full text of DOI:10.1021/jo010026o

2828
J . Org. Chem. 2001, 66, 2828-2834
1-Oxa sp ir o[4.4]n on a n -6-on es. Syn th etic Access via Oxon iu m Ion
Tech n ology, Op tica l Resolu tion , a n d Con ver sion in to En a n tiop u r e
Sp ir ocyclic r,â-Bu ten olid es
Leo A. Paquette,* Dafydd R. Owen, Richard Todd Bibart, Christopher K. Seekamp,
Alexandra L. Kahane, J ames C. Lanter, and Miriam Alvarez Corral
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received J anuary 9, 2001
A general approach to the synthesis of enantiomerically pure spirocyclic R,â-butenolides is presented
where the fundamental framework is rapidly elaborated by acid- or bromonium ion-induced
rearrangement of the carbinol derived by addition of 2-lithio-4,5-dihydrofuran to cyclobutanone.
Subsequent resolution of the resulting ketones by either sulfoximine or mandelate acetal technology
has been applied effectively. The availability of these building blocks makes possible in turn the
acquisition of the enantiomers of dihydrofurans typified by 17, 35, and 38 and lactones such as 25
and 31, as well as the targeted title compounds. Complementary reductions of the early
intermediates provide the added advantage that the R- and â-stereoisomeric carbinol series can be
obtained on demand. These capabilities have been coordinated to allow the crafting of any member
of the series in relatively few steps.
In 1990, we reported the first examples of the oxonium
synthesis of spirocyclic bis-C,C-glycosides,7 furanose and
pyranose nucleosides,8 cis- and trans-theaspirone,9 dac-
tyloxene-B and -C,10 and (+)-grindelic acid.11 In most of
these studies, reliance was placed on double diastereo-
selection, the initial conjoining step involving optically
active reaction partners either singly or as matched pairs.
ion-initiated pinacolic ring expansion reaction.1 This
discovery, which constitutes an extension of the long
established Wagner-Meerwein2 and pinacolic rearrange-
ments,3 takes advantage of the fact that ketone adducts
of metalated vinyl ethers represented by 1 are amenable
under acid-catalyzed conditions to conversion to oxonium
ions such as 2. This first step triggers a subsequent 1,2-
shift under steric and stereoelectronic control, resulting
in diastereoselective ring expansion and spiro ketone
formation as exemplified by 3.4 The migratory aptitudes
Despite the latent potential of the parent oxa- and thia-
substituted spiro[4.4]nonan-6-ones as useful building
(7) (a) Paquette, L. A.; Dullweber, U.; Cowgill, L. D. Tetrahedron
Lett. 1993, 34, 8019. (b) Paquette, L. A.; Kinney, M. J .; Dullweber, U.
J . Org. Chem. 1997, 62, 1713.
(8) Paquette, L. A.; Brand, S.; Behrens, C. J . Org. Chem. 1999, 64,
2010.
(9) Paquette, L. A.; Lanter, J . C.; Wang, H.-L. J . Org. Chem. 1996,
61, 1119.
(10) (a) Paquette, L. A.; Lord, M. D.; Negri, J . T. Tetrahedron Lett.
1993, 34, 5693. (b) Lord, M. D.; Negri, J . T.; Paquette, L. A. J . Org.
Chem. 1995, 60, 191.
(11) (a) Paquette, L. A.; Wang, H.-L. Tetrahedron Lett. 1995, 34,
6005. (b) Paquette, L.A.; Wang, H.-L. J . Org. Chem. 1996, 61, 5352.
(12) Paquette, L. A. In Science at the Turn of the Millenium; Keinan,
E.; Shechter, I., Eds.; Wiley/VCH: New York, 2001, in press.
(13) Trost, B. M.; Mao, M. K.-T.; Balkovec, J . M.; Buhlmayer, P. J .
Am. Chem. Soc. 1986, 108, 4965.
(14) (a) Dimitroff, M.; Fallis, A. G. Tetrahedron Lett. 1998, 39, 2527.
(b) Paquette, L. A.; Lobben P. C. J . Am. Chem. Soc. 1996, 118, 1917.
(15) For a preliminary report from this laboratory, consult Paquette,
L. A.; Lanter, J . C.; Owen, D. R.; Fabris, F.; Bibart, R. T.; Corral, M.
A. Heterocycles 2001, 54, 49.
that come into play are predictably good,5 and the
differentiating elements that control product stereochem-
istry are reasonably well understood.6 As a consequence,
this process has seen serviceable application in the
(16) For representative examples, see: (a) Cram, D. J .; Steinberg,
H. J . Am. Chem. Soc. 1954, 76, 2753. (b) Hardegger, E.; Maeder, E.;
Semarne, H. M.; Cram, D. J . J . Am. Chem. Soc. 1959, 81, 2729. (c)
Gerlach, H. Helv. Chim. Acta 1968, 51, 1587. (d) Gerlach, H.; Mu¨ller,
W. Helv. Chim. Acta 1972, 55, 2277. (e) Gerlach, H.; Mu¨ller, W. Angew.
Chem., Int. Ed. Engl. 1972, 11, 1030. (f) Carruthers, W.; Orridge, A.
J . Chem. Soc., Perkin Trans. 1 1977, 2411. (g) Harada, N.; Ochiai, N.;
Takada, K.; Uda, H. J . Chem. Soc., Chem. Commun. 1977, 495. (h)
Harada, N.; Ai, T.; Uda, H. J . Chem. Soc., Chem. Commun. 1982, 232.
(i) Naemura, K.; Furutani, A. J . Chem. Soc., Perkin Trans. 1 1991,
2891. (j) Suemune, H.; Maeda, K.; Kato, K.; Sakai, K. J . Chem. Soc.,
Perkin Trans. 1 1994, 3441. (k) Nieman, J . A.; Parvez, M., Keay, B. A.
Tetrahedron: Asymmetry 1993, 4, 1973. (l) Nieman, J . A., Keay, B. A.
Tetrahedron: Asymmetry 1995, 6, 1575. (m) Nieman, J . A.; Keay, B.
A.; Kubicki, M.; Yang, D.; Rauk, A.; Tsankov, D.; Wieser, J . J . Org.
Chem. 1995, 60, 1918. (n) Nieman, J . A.; Keay, B. A. Synth. Commun.
1999, 29, 3829.
(1) Paquette, L. A.; Lawhorn, D. E.; Teleha, C. A. Heterocycles 1990,
30, 765.
(2) Molecular Rearrangements; de Mayo, P.; Ed.: Interscience
Publishers: New York, 1963; Part 1, Chapters 1 (Pocker, Y.), 3 (Berson,
J .), and 4 (Breslow, R.).
(3) Collins, C. J . Quart. Rev. (London) 1960, 14, 357.
(4) Paquette, L. A. Recent Res. Dev. Chem. Sci. 1997, 1, 1.
(5) Paquette, L. A.; Andrews, J . F. P.; Vanucci, C.; Lawhorn, D. E.;
Negri, J . T.; Rogers, R. D. J . Org. Chem. 1992, 57, 3956.
(6) Paquette, L. A.; Lanter, J . C.; J ohnston, J . N. J . Org. Chem. 1997,
62, 1702.
10.1021/jo010026o CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/22/2001

1-Oxaspiro[4.4]nonan-6-ones
J . Org. Chem., Vol. 66, No. 8, 2001 2829
blocks12,13 and molecular probes,14 no attention has
previously been directed to their acquisition in optically
active condition.15 That this concept has not been reduced
to practice contrasts with the frequency with which their
functionalized carbocyclic equivalents, the spiro[4.4]-
nonanes, have been resolved.16 These efforts have seem-
ingly been spurred on by the occurrence of the spirane
platform in nature (gloiosiphone A,17 fredericamycin,18
etc), by the applicability of designed derivatives to
asymmetric synthesis,19,20 and the like.
Sch em e 1
In an effort to remedy the deficiency existent in the
heterocyclic series, we have explored direct oxonium ion-
based routes to the 1-oxaspiro[4.4]nonan-4-one class,
established a notably feasible means for effecting their
optical resolution, unequivocally established absolute
configuration of the antipodes, and defined a selection
of regio- and stereocontrolled transformations within this
structural series.
Rin g Exp a n sion P r ocess. The addition of 2-lithio-
4,5-dihydrofuran (5)21a to cyclobutanone (4) in THF at
-78 °C provided the highly sensitive carbinol 6 in
excellent yield (Scheme 1). The elevated reactivity of 6
toward traces of acid precludes its attempted storage. The
fate of 6 in the presence of different acidic ion-exchange
resins was such as to give a preponderance of the racemic
spiro ketone 8 (45-87%) alongside variable quantities
of the highly crystalline 1,4-dioxanes 9 and 10 (0-14%
in a 1:1 ratio). Although dimerization in this fashion had
been observed in higher homologues,1 it was not antici-
pated at an appreciable level in the present example
because of very favorable strain release energetics in
oxonium ion 7. Since 8 and 9/10 do not interconvert under
the reaction conditions, they are evidently formed under
kinetic control. We speculate that the capture of inter-
mediate 7 by unrearranged 6 likely operates in the early
stages of this process when the concentration gradient
of the carbinol is high. However, the possibility cannot
be ruled out that the intermolecular reaction can compete
favorably as a consequence of multipoint coordinative
binding to the acidic resin.
electronic shift or a stepwise process with the identical
stereochemical alignment.6,7b The presence of a syn-
directed bromine atom in 12 can be projected to play
several obvious key roles. Of these, the more advanced
regioselective functionalization of the tetrahydrofuran
ring and the steric control potential for guiding nucleo-
philic attack at the carbonyl site were considered to be
the most serviceable.
Resolu tion Stu d ies a n d Absolu te Con figu r a tion a l
Assign m en ts. The structural features inherent to (()-
12 alluded to above prompted us initially to examine its
coupling to J ohnson’s (S)-(+)-sulfoximine22 for the pur-
pose of optical resolution. When the lithiated anion 13
was added to racemic 12 in THF at -78 °C, the three
chromatographically separable diastereomers 14, 15, and
16 were formed in a 2:1:1 ratio (Scheme 2). Determina-
tion of the stereochemical relationships present in major
adduct 14 was accomplished by X-ray crystallographic
analysis. Thermal activation of 14 by overnight heating
in xylene resulted in recovery of the chiral auxiliary and
smooth conversion to dextrorotatory 12, whose absolute
configuration could now be reliably depicted as shown.
Entirely comparable processing of 15 and 16 led to
formation of the enantiomeric bromo ketone (-)-12 in
both cases. The detailed stereochemistry of all three
compounds here involved was thereby directly elucidated.
Alternative initiation of the oxonium ion-promoted
rearrangement with N-bromosuccinimide requires the
presence of an acid scavenger to be effective, and propy-
lene oxide was found to serve well in this role.21b The
exclusive formation of (()-12 under conditions of proper
temperature control is consistent with initial formation
of bromonium ion 11, followed by the depicted concerted
(17) (a) Chen, J . L.; Moghaddam, M. F.; Gerwick, W. H. J . Nat. Prod.
1993, 56, 1205 (b) Paquette, L. A.; Sturino, C. F.; Doussot, P. J . Am.
Chem. Soc. 1996, 118, 9456. (c) Sturino, C. F.; Doussot, P.; Paquette,
L. A. Tetrahedron 1997, 53, 8913.
(18) (a) Pandey, R. C.; Toussaint, M. W.; Stroshane, R. M. Kalita,
C. C.; Aszalos, A. A.; Garretson, A. L.; Wei, T. T.; Byrne, K. M.;
Geoghegan, R. F. J r.; White, R. J . J . Antibiot. 1981, 34, 1389 (b) Kita,
Y.; Higuchi, K.; Yoshida, Y.; Iio, K. Kitagaki. S.; Akai, S.; Fujioka, H.
Angew. Chem., Int. Ed. 1999, 38, 683.
(19) (a) Nieman, J . A.; Keay, B. A. Tetrahedron: Asymmetry 1996,
7, 3521. (b) Keay, B. A.; Maddaford, S. P.; Cristofoli, W. A.; Andersen,
N. G.; Passafaro, M. S.; Wilson, N. S.; Nieman, J . A. Can. J . Chem.
1997, 75, 1163.
(20) (a) Chan, A. S. C.; Hu, W.; Pai, C.-C.; Lau, C.-P.; J iang, Y.; Mi,
A.; Yan, M.; Sun, J .; Lou, R.; Deng. J . J . Am. Chem. Soc. 1997, 119,
9570. (b) Seebach, D.; Beck, A. K.; Dahinden, R.; Hoffmann, M.;
Ku¨hnle, F. N. M. Croatica Chem. Acta 1996, 69, 459. (c) Srivastava,
N.; Mital, A.; Kumar, A. J . Chem. Soc., Chem. Commun. 1992, 493.
(21) (a) Paquette, L. A.; Oplinger, J . A. Tetrahedron 1989, 45, 107
and relevant references therein. (b) Koppenhoefer, B.; Lohmiller, K.;
Schurig, F. V. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; J ohn Wiley and Sons: Chichester, 1995; Volume
6, pp 4331-4336.
Beyond this, 16 was found to undergo dehydrobromi-
nation in the presence of DBU to furnish 18. Thermal
fragmentation of the latter delivered (+)-17, but with
lowered efficiency because of the thermal sensitivity of
this enone product. X-ray analysis of 18 provided the
necessary evidence to confirm the indicated configura-
tions. The lability to heat exhibited by 17 was also
(22) (a) J ohnson, C. R. Aldrichimica Acta 1985, 18, 3. (b) J ohnson,
C. R.; Zeller, J . R. J . Am. Chem. Soc. 1982, 104, 4021.

2830 J . Org. Chem., Vol. 66, No. 8, 2001
Paquette et al.
Sch em e 2
Sch em e 3
of mandelate acetals,24 this method failed in the present
circumstances. However, hydrolysis with lithium hydrox-
ide25 was uniformly advantageous and notably efficient
in returning the enantiopure spiro ketones quantita-
tively.
The structural assignment to 20 is based on direct
spectral comparison with the tetrahydrothiophene con-
gener for which crystallographic proof of structure is
available.26 Beyond this, the absolute configuration of
(+)-8 was independently derived by a chemical correla-
tion to be delineated below. The parallel conversion of
21 to (+)-8 and of 22 to (-)-8 holds similar relevance for
stereochemical assignment. In our view, the preferred
generation of acetals 20 and 22 stems from the avoidance
of nonbonded steric interactions involving the phenyl
substituent. These features are clearly apparent in
projections A and B, which depict additionally the
deshielding consequences on chemical shift when the
benzylic proton is projected above the tetrahydrofuranyl
oxygen atom.
manifested during the generation of its levorotatory
enantiomer by dehydrobromination of (+)-12 with DBU
in hot toluene.
The stereoselectivity with which 13 undergoes 1,2-
addition to (()-12 predominantly from the direction anti
to bromine can be viewed as a serviceable feature of the
chemistry of this spirocyclic ketone. Nonetheless, the
addition of 13 to (()-12 could not be forced beyond the
level of 45% conversion due presumably to competing
enolization. Our inability to resolve this dilemma despite
considerable experimentation prompted the search for an
improved method of resolution that would facilitate the
throughput of enantiomerically pure spirocyclic interme-
diates on a reasonable scale.
After a number of unproductive starts, recourse was
made to the acetalization of racemic 8 with (R)-(-)-
mandelic acid (19) under catalysis by scandium triflate23
(Scheme 3). Optimal conditions involving the use of a 13:1
solvent mixture of CH2Cl2 and acetonitrile under over-
night reflux in the presence of 4 Å molecular sieves to
remove the liberated water furnished a chromatographi-
cally separable mixture of 20, 21, and 22 (ratio of 3:1:4,
96% combined yield). Although acid-catalyzed metha-
nolysis has been touted as a means for the degradation
Ster eoselectivity of Ca r bon yl Gr ou p Red u ction .
The spirocyclic ketones 8, 12, and 17 constitute a subset
(24) Kellogg, R. M.; Hof, R. P. J . Org. Chem. 1996, 61, 3423.
(25) Bigi, F.; Bocelli, G.; Maggi, R.; Sartori, G. J . Org. Chem. 1999,
64, 5004.
(23) Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett.
1996, 839.
(26) Fabris, F.; Rogers, R. D. Unpublished results.

1-Oxaspiro[4.4]nonan-6-ones
Sch em e 4
J . Org. Chem., Vol. 66, No. 8, 2001 2831
Sch em e 5
Sch em e 6
Sch em e 7
of related structures that hold interest with regard to the
diastereofacial selectivity of nucleophilic attack at their
carbonyl groups. This general topic has been widely
scrutinized and diverse rationalizations have been of-
fered.27 The addition of methyllithium, methyl Gringnard
reagents, and several hydride sources to racemic 8 has
been independently explored by Dimitroff and Fallis.28
The Canadian group recognized that the controlling
factors operational in such reactions are subtle. Since our
purposes in the present context were preparative, clean
controlled conversion to the â- and R-carbinols on a
preparative scale was targeted. Recourse to Meerwein-
Ponndorf-Verley conditions was found to be particularly
well suited to the predominant formation of 23 in high
yield (â/R ) 85:15) (Scheme 4). No other reagent exam-
ined by us gave rise in useful amounts to the â-carbinol.
Following protection of the hydroxyl group in 23 as the
TBS derivative 24, the oxidation to lactone 25 was
examined. Ruthenium tetroxide29 gave 25 as the sole
product, thereby setting the stage for introduction of the
double bond as in 28. When attempts to introduce an
R-phenylselenenyl substituent into 25 were invariably
met with bisfunctionalization, advantage was taken of
this heightened nucleophilic reactivity for the generation
of 26 by comparable treatment with phenyl benzene-
thiosulfonate.30 With arrival at 26 in this manner, direct
conversion to 27 as a 1:1 diastereomeric mixture was
realized by reaction with ethylmagnesum bromide.13 The
Grignard reagent attacks at sulfur and cleanly produces
a solution of the enolate that is amenable to protonation
with delivery of the diastereomeric monosulfenylated
end-products in equivalent amounts. The route to 28 was
completed by formation of the sulfoxide and thermal
extrusion of phenylsulfenic acid.31 The levorotatory prop-
erties of 28 generated from (+)-8 in this manner correlate
perfectly with the optical rotations exhibited by 43 and
45 as synthesized in the sequel, thus establishing its
absolute configuration to be as shown.
The problem of generating the R-carbinol was resolved
when L-Selectride was discovered to produce 29 exclu-
sively in 96% yield (Scheme 5). As before, this carbinol
could be sequentially silylated and oxidized to give (+)-
31, a lactone previously reported in racemic form.13,32
In other studies, the serviceability of the PMB protect-
ing group is somewhat compromised in these RuO4-
promoted conversions because of concomitant oxidation
of the benzylic methylene group. The smooth transforma-
tion of 32 to 33 is illustrative of this chemistry (Scheme
6).
The stereoselectivity of the reduction of bromo ketone
12 is overwhelmingly controlled by the relative position
of the halogen atom. As a result, sodium borohydride can
be called upon to generate the â-carbinol 34 via approach
from the open R-surface (Scheme 7). A significant added
advantage associated with the bromine substituent is the
option that it offers for the introduction of a double bond
regioselectively by dehydrobromination. Dihydrofuran 35
is the sole product of the action on 34 of excess sodium
hydride and p-methoxybenzyl bromide in DMF (91%
yield). Thus, it is entirely feasible to protect the hydroxyl
group and bring about the loss of HBr in a single
(27) (a) Houk, K. N.; Paddon-Row: M. N.; Rondan, G. N.; Wu, Y.-
D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J . T.; Li, Y.; Loncharich, R.
J . Science 1986, 231, 1108. (b) Wu, Y.-D.; Tucker, J . A.; Houk, K. N. J .
Am. Chem. Soc. 1991, 113, 5018. (c) Wu, Y.; Houk, K. N.; J . Am. Chem.
Soc. 1993, 115, 10992. (d) Fraser, R. R.; Kong, F.; Stanciulescu, M.;
Wu, Y.-D.; Houk, K. N. J . Org. Chem. 1993, 58, 4431. (e) Gung, B. W.
Tetrahedron 1996, 52, 5263. (f) Fraser, R. R.; Faibish, N. C.; Kong, F.;
Bednarski, K. J . Org. Chem. 1997, 62, 6164.
(28) Dimitroff, M.; Fallis, A. G. Tetrahedron Lett. 1998, 39, 2531.
(29) Smith, A, B., III.; Scarborough, R. M. Synth. Commun. 1980,
10, 205.
(30) Takeuchi, K. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; J ohn Wiley and Sons: Chichester; 1995; Volume
6, pp 3957-3960.
(31) The phenylsulfenic acid subsequently enters into dimerization
and generates phenyl benzenethiosulfinate, an end-product that co-
elutes with 28. To skirt this difficult separation, the reaction mixture
was stirred with triphenylphosphine prior to workup in order to effect
reduction as recommended elsewhere [Horner, L.; Hoffmann, H.
Angew. Chem. 1956, 68, 473].
(32) The assignment defined earlier by Trost and co-workers13 as
(()-31 should be changed. Direct spectral comparisons show that the
intermediates prepared by them are in reality the anti diastereomers
25 and 26.

2832 J . Org. Chem., Vol. 66, No. 8, 2001
Paquette et al.
Sch em e 8
tive of the configuration of the RO-substituted carbon.
The general workability of this tactic is superior to other
alternatives starting from the lactone. Note that the
OPMB group survives this oxidative protocol quite well
(e.g., 35 f 43). The difficulties associated with the
phenylselenenylation-oxidation of 25 have already been
pointed out. While the less sterically congested features
of its invertomer 31 allow for reasonable control of the
monofunctionalization step,33 the efficiency with which
47 could be produced never exceeded 51%.
Sch em e 9
In a companion study, the â-OMOM derivative 45 was
deprotected and 46 so generated could be transformed
into the OPMB analogue 43 via the trichloroacetimidate
in a functional group exchange. This operation proved
to be difficult to reproduce, principally because of the
susceptibility of 46 to retrograde vinylogous aldol frag-
mentation.
Su m m a r y
The notable aspects of this synthetic exercise are
several in number. π-Facial diastereoselection in both
directions was realized during reduction of the parent
spiro ketone 8, with the Meerwein-Ponndorf-Verley
protocol delivering the â-carbinol and L-Selectide the
R-epimer. Alternative control of this important step can
be accomplished by reduction of readily available bromo
ketone 12 (â-specific) or dihydrofuranyl ketone 17 (R-
specific). The first of these regimens advances to the
butenolide level via the intermediate lactone, with in-
troduction of the double bond by way of R-substituted
organosulfur or selenium intermediates. Alternatively,
the presence of the bromine atom allows for the imple-
mentation of an elimination process and ultimate allylic
oxidation with high level regiocontrol. If preference is
given to overall yields, then the first option should be
viewed as the more serviceable synthetic entry.
Both 8 and 12 have been resolved and their absolute
configurations reliably defined. Many of the transforma-
tions reported herein have been carried out on enan-
tiopure samples of the numerous intermediates. The
ulterior motive of this aspect of the investigation was to
set a solid foundation for the synthesis of an entirely new
class of structurally restricted nucleosides whose unprec-
edented spirocyclic nature was contemplated to provide
several unique and interesting properties. Some of the
early progress realized in this arena will form the subject
of future submissions.
laboratory operation. It is, of course, also possible to effect
this overall structural change in stepwise fashion. The
formation of 36 and 37 can be realized with a somewhat
weaker base as a prelude to reaction with potassium tert-
butoxide. Advancement by way of either route does not
erode the configurational integrity of the vicinal stereo-
genic centers.
Further insight into reduction stereoselectivity was
realized by subjecting 17 to the action of lithium alumi-
num hydride. The presence of a double bond so modifies
the conformational and steric shielding within the spi-
rocyclic structure that nucleophilic attack syn to this site
of unsaturation is now overwhelmingly favored. The
isolated yield of 40 was consistently above the 90% level
(Scheme 8). Protection of the hydroxyl as in 41 and 42
proved expectedly to be a routine operation.
Allylic Oxid a tion . At this stage, the prospect of allylic
oxidation of the dihydrofurans occupied our attention.
When attempts to bring about this process by means of
selenium dioxide, pyridinium chlorochromate (PCC), or
N-bromosuccinimide under photochemical conditions were
to no avail, we developed a protocol involving the
combined action of PCC (5 equiv), chromium trioxide (5
equiv), and 3,5-dimethylpyrazole (10 equiv). As shown
in Scheme 9, conversion of the OCH2 residue to the
lactone segment of a spirocyclic R,â-butenolide occurs
regioselectively with very reasonable efficiency irrespec-
Exp er im en ta l Section
Gen er a l In for m a tion . THF and ether were distilled from
sodium benzophenone ketyl under nitrogen just prior to use.
For CH2Cl2, the drying agent was calcium hydride. Isopropyl
alcohol was freshly distilled from calcium oxide. All reactions
were performed under a nitrogen atmosphere. Analytical thin-
layer chromatography was carried out on E. Merck silica gel
60 F254 aluminum-backed plates. The 230-400 mesh size of
the same absorbent was utilized for all chromatographic
purifications. The organic extracts were dried over anhydrous
1
MgSO4 or Na2SO4. H and 13C NMR spectra were recorded at
the indicated field strengths. The high-resolution mass spectra
were recorded at The Ohio State University Campus Chemical
Instrumentation Center.
(()-1-Oxa sp ir o[4.4]n on a n -6-on e (8). A. Use of Dow ex-
50 for th e Rea r r a n gem en t of 6. A solution of 2,3-dihydro-
furan (9.0 mL, 0.12 mol) in dry THF (90 mL) was blanketed
with N2, cooled to -78 °C, and treated dropwise with tert-
(33) Hanessian, S.; Murray, P. J .; Sahoo, S. P. Tetrahedron Lett.
1985, 26, 5627.

1-Oxaspiro[4.4]nonan-6-ones
J . Org. Chem., Vol. 66, No. 8, 2001 2833
butyllithium (80 mL of 1.61 M in pentane, 0.13 mol). Upon
completion of the addition, the reaction mixture was stirred
at this temperature for 30 min, warmed to 0 °C for 1 h, and
returned to -78 °C, at which point cyclobutanone (7.5 mL, 0.10
mol) was introduced over 2 h by means of a syringe pump.
The reaction mixture was maintained at -78 °C for 6 h,
allowed to warm to room temperature overnight, returned to
-78 °C, and treated with a saturated aqueous solution of
NaHCO3 (115 mL). The separated aqueous phase was ex-
tracted with ether (3 × 25 mL), and the combined organic
layers were washed with brine, dried, and concentrated. The
resultant colorless oil (15.5 g) was dissolved in CH2Cl2 (1.25
L), treated with Dowex-50 (0.42 g), and stirred for 24 h prior
to filtration through a pad of Celite and solvent evaporation.
The residual light yellow oil/solid mixture was vacuum filtered
to remove the precipitated dimer. Washing with hexanes gave
9 and 10 as a 1:1 mixture (1.93 g, 14%): white powder, mp
178-188 °C; IR (CHCl3, cm-1) 1057; 1H NMR (300 MHz,
CDCl3) δ 4.15-4.06 (m, 2 H), 3.96-3.86 (m, 2 H), 2.47-1.68
(series of m, 18 H), 1.60-1.44 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 108.0, 107.6, 78.8, 77.4, 68.5, 68.3, 33.9, 33.1, 32.8,
32.2, 31.3, 31.1, 24.3, 24.0, 14.5, 14.3; EI MS m/z (M+) calcd
280.1675, obsd 280.1728. Anal. Calcd for C16H24O4: C, 68.55;
H, 8.63. Found: C, 68.45; H, 8.61.
6.1, 2.4 Hz, 1 H), 4.62 (dt, J ) 13.6, 2.0 Hz, 1 H), 4.55 (dt, J )
13.5, 2.0 Hz, 1 H), 3.38 (d, J ) 13.7 Hz, 1 H), 2.88 (d, J ) 13.7
Hz, 1 H), 2.87 (s, 3 H), 2.41-2.32 (m, 1 H), 2.28-2.15 (m, 1
H), 2.11-1.88 (m, 2 H), 1.68-1.57 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 138.5, 133.1, 129.5 (2C), 129.2, 129.1 (2C), 127.8,
100.9, 80.0, 75.4, 60.7, 33.9, 33.0, 28.8, 18.1; EI MS m/z (M+)
calcd 307.1242, obsd 307.1255. Anal. calcd for C16H21NO3S: C,
62.51; H, 6.89. Found: C, 62.47; H, 6.99.
(-)-1-Oxa sp ir o[4.4]n on -3-en -6-on e (17). A solution of (+)-
12 (1.33 g, 6.08 mmol) and DBU (9.13 g, 60.0 mmol) in toluene
(50 mL) was refluxed overnight under N2. The reaction mixture
was cooled, diluted with ether (200 mL), and washed with
saturated NH4Cl solution, 1 M NaHCO3 solution, and brine.
The organic phase was dried and carefully evaporated. The
residue was chromatographed on silica gel (elution with
hexanes/ethyl acetate 7:1) to afford 480 mg (57%) of 17 as a
colorless oil: IR (CHCl3, cm-1) 1748; 1H NMR (300 MHz, C6D6)
δ 5.58 (dt, J ) 6.1, 1.5 Hz, 1 H), 5.25 (dt, J ) 6.1, 2.4 Hz, 1 H),
4.64 (ddd, J ) 12.8, 2.4, 1.6 Hz, 1 H), 4.41 (dt, J ) 12.9, 1.9
Hz, 1 H), 1.98-1.69 (m, 3 H), 1.65-1.50 (m, 2 H), 1.33-1.19
(m, 1 H); 13C NMR (75 MHz, C6D6) δ 214.1, 129.5, 127.3, 94.2,
75.9, 35.4, 35.1, 18.3; EI MS m/z (M+) calcd 138.0681, obsd
138.0681.
Meer w ein -P on n d or f-Ver ley Red u ction of (+)-8. A
solution of (+)-8 (300 mg, 2.14 mmol) in isopropyl alcohol (2.5
mL) was treated with aluminum isopropoxide (310 mg, 1.51
mmol), refluxed for 1 h, and distilled at atmospheric pressure
until 1.5 mL of distillate was collected. The distillation flask
was cooled in ice and diluted with 40 mL of 1 M hydrochloric
acid. The products were extracted into ether (3 × 50 mL), and
the combined organic solutions were dried and concentrated.
The residue was chromatographed on silica gel (elution with
10:1 hexanes/ethyl acetate) to give 211 mg (70%) of (-)-23 and
46 mg (15%) of the epimeric carbinol (+)-29, independently
prepared below.
The oily fraction was purified by chromatography on silica
gel (elution with 8:1 hexanes/ethyl acetate) to furnish 6.31 g
(45%) of 8 as a clear, volatile, colorless oil: IR (CHCl3, cm-1
)
1
1744; H NMR (300 MHz, CDCl3) δ 3.90 (t, J ) 6.4 Hz, 2 H),
2.35-2.15 (m, 2 H), 2.15-1.60 (series of m, 8 H); 13C NMR (75
MHz, CDCl3) δ 218.3, 86.3, 68.6, 35.7, 35.0, 32.2, 25.8, 18.0;
EI MS m/z (M+) calcd 140.0837, obsd 140.0838.
A different synthetic approach to this ketone has been
reported.28
B. Use of Am ber lyst-15 a s th e Acid ic Ca ta lyst. A 18.0
mL (0.24 mol) sample of 2,3-dihydrofuran was metalated and
combined with cyclobutanone (15.0 mL, 0.20 mol) as described
above to leave 32 g of unpurified 6. This alcohol was dissolved
in CH2Cl2 (3 L), Amberlyst-15 (7.0 g) was introduced, and the
mixture was stirred for 2 h. The preceding workup afforded
24.34 g (87%) of 8 without any evidence for the formation of 9
and 10.
1
For (-)-23: colorless oil; IR (CHCl3, cm-1) 3534; H NMR
(300 MHz, CDCl3) δ 3.92 (dd, J ) 4.7, 1.4 Hz, 1 H), 3.80 (t, J
) 7.1 Hz, 2 H), 2.19-1.76 (series of m, 5 H), 1.72-1.63 (series
of m, 6 H); 13C NMR (75 MHz, CDCl3) δ 92.1, 77.1, 67.3, 31.7,
31.3, 29.3, 25.8, 19.2; [R]20 -4.8 (c 3.0, CHCl3).
D
The racemic form of this alcohol has been reported.28
For (+)-29: IR (CHCl3, cm-1) 3534; 1H NMR (300 MHz,
CDCl3) δ 3.71 (m, 2 H), 3.56 (t, J ) 7.0 Hz, 1 H), 2.87 (s, 1 H),
1.87-1.67 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 90.0, 76.5,
(()-4-Br om o-1-oxa sp ir o[4.4]n on a n -6-on e (12). A 15.3
mL (0.20 mol) sample of 2,3-dihydrofuran was metalated with
tert-butyllithium (80.0 mL of 1.7 M in pentane, 0.135 mol) in
the predescribed manner and reacted with 7.5 mL (0.10 mol)
of cyclobutanone to give 14.0 g of unpurified 6. This carbinol
(14.0 g, 0.10 mol) and propylene oxide (230 mL) were dissolved
in isopropyl alcohol (230 mL), cooled to -78 °C under N2, and
treated with N-bromosuccinimide (17.8 g, 0.10 mol) in one
portion. The reaction mixture was stirred overnight with
warming to room temperature. Concentration of the solution
followed by dilution with 300 mL of 2:1 ether/hexanes allowed
for the removal of succimide by filtration after standing for 1
h. The filtrate was washed with saturated NaHCO3 solution,
and the aqueous phase was back-extracted with ether. The
combined organic layers were washed with brine, dried, and
evaporated to give 21.0 g (96%) of diastereomerically pure 12
as a colorless oil: IR (CHCl3, cm-1) 1745; 1H NMR (300 MHz,
C6D6) δ 3.99 (ddd, J ) 9.3, 8.3, 4.0 Hz, 1 H), 3.48-3.36 (m, 2
H), 2.61-2.48 (m, 1 H), 1.93-1.66 (series of m, 5 H), 1.53-
1.43 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 215.0, 87.4, 66.9,
46.9, 37.0, 35.3, 33.7, 18.2; EI MS m/z (M+) calcd 217.9942,
obsd 217.9942. Anal. Calcd for C8H11BrO2: C, 43.86; H, 5.06.
Found: C, 44.02; H, 5.18.
Deh yd r obr om in a tion of 16. A solution of 16 (230 mg, 0.76
mmol) and DBU (0.92 g, 6.0 mmol) in toluene (50 mL) was
stirred under N2 at the reflux temperature overnight. The
reaction mixture was cooled, diluted with ether (200 mL), and
washed with saturated NH4Cl solution, 1 M NaHCO3 solution,
and brine prior to drying and solvent evaporation. The residue
was chromatographed on silica gel (elution with 1:1 hexanes/
ethyl acetate) to give 18 (170 mg, 82%) as a colorless crystalline
solid: mp 129-132 °C; IR (CHCl3, cm-1) 1446, 1246; 1H NMR
(300 MHz, CDCl3) δ 7.90-7.84 (m, 2 H), 7.64-7.52 (m, 3 H),
6.60 (br s, 1 H), 5.87 (dt, J ) 6.1, 1.5 Hz, 1 H), 5.59 (dt, J )
67.7, 34.7, 34.3, 31.6, 26.0, 19.3; [R]20 -3.4 (c 1.5, CHCl3).
D
The racemic form of this alcohol has been reported.28
Com p ou n d 25. To a vigorously stirred mixture of (-)-24
(2.60 g, 10.1 mmol), sodium periodate (8.64 g, 40.4 mmol),
carbon tetrachloride (30 mL), acetonitrile (25 mL), and water
(19 mL) was added ruthenium trichloride (640 mg, 3.0 mmol).
After 30 min, the reaction mixture was diluted with ether (100
mL) and filtered through a pad of silica gel (ether elution).
The filtrate was evaporated, and the residue was chromato-
graphed on silica gel (elution with 6:1 petroleum ether/ether)
to furnish 2.55 g (93%) of (-)-25 as a colorless oil: IR (CHCl3,
1
cm-1) 1765; H NMR (300 MHz, CDCl3) δ 4.00 (t, J ) 6.0 Hz,
1 H), 2.56-2.43 (m, 3 H), 1.98-1.63 (m, 6 H), 1.57-1.50 (m, 1
H), 0.84 (s, 9 H), 0.02 (s, 3 H), -0.03 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 177.0, 94.9, 77.4, 34.5, 31.6, 29.2, 26.9, 25.6
(3C), 18.8, 17.8, -4.7, -5.1; ES MS m/z (M + H)+ calcd
271.1729 obsd 271.1726; [R]20 -30.4 (c 1.10, CHCl3). Anal.
D
Calcd for C14H26O3Si: C, 62.18; H, 9.69. Found: C, 61.79; H,
9.26.
The racemic form of this lactone has previously been
incorrectly assigned.13,32
Com p ou n d 28. The diastereomers of 27 (3.60 g, 9.50 mmol)
were dissolved in CH2Cl2 (40 mL), cooled to -78 °C, treated
with m-chloroperbenzoic acid (2.07 g, 12.0 mmol), and warmed
to 0 °C for 2 h. Saturated NaHSO3 solution (100 mL) was
added, and the separated aqueous layer was extracted with
CH2Cl2 (150 mL). The organic phases were combined, dried,
and evaporated, leaving the sulfoxide, which was dissolved in
CCl4 (400 mL) containing calcium carbonate (3.17 g, 50 mmol).
This mixture was refluxed for 3 h, cooled, filtered, and
evaporated. The residue was dissolved in THF (200 mL),

2834 J . Org. Chem., Vol. 66, No. 8, 2001
Paquette et al.
triphenylphosphine (6.56 g, 25 mmol) was introduced, stirring
was maintained for 2 h, and the solvent was evaporated.
Chromatography of the residue on silica gel (elution with 20:1
petroleum ether/ether) afforded 2.23 g (87%) of (-)-28 as a
colorless oil: IR (neat, cm-1) 1766; 1H NMR (300 MHz, CDCl3)
δ 7.51 (d, J ) 5.7 Hz, 1 H), 6.06 (d, J ) 5.7 Hz, 1 H), 4.04 (dd,
J ) 4.8, 2.5 Hz, 1 H), 2.24-2.09 (m, 2 H), 1.98-1.91 (m, 2 H),
1.82-1.68 (m, 2 H), 0.86 (s, 9 H), 0.00 (s, 3 H), -0.01 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 172.4, 158.0, 121.0, 98.3, 80.6,
34.2, 33.0, 25.6 (3C), 21.6, 17.9, -4.7, -5.1; EI MS m/z (M+)
For 43: colorless oil; IR (neat, cm-1) 1769; 1H NMR (300
MHz, CDCl3) δ 7.60 (d, J ) 5.7 Hz, 1 H), 7.19-7.15 (m, 2 H),
6.88-6.84 (m, 2 H), 6.06 (d, J ) 5.7 Hz, 1 H), 4.44 (d, J ) 11.5
Hz, 1 H), 4.31 (d, J ) 11.5 Hz, 1 H), 3.87-3.84 (m, 1 H), 3.79
(s, 3 H), 2.20-2.11 (m, 2 H), 1.99-1.75 (m, 4 H); 13C NMR (75
MHz, CDCl3) δ 172.2, 159.3, 157.5, 129.7, 129.1 (2C) 121.0,
113.8 (2C), 97.5, 86.3, 71.1, 55.2, 33.9, 30.8, 30.5; EI MS m/z
(M+) calcd 274.1205, obsd 274.1180; [R]23 -223.8 (c 1.0,
D
CHCl3). Anal. Calcd for C16H18O4: C, 70.06; H, 6.61. Found:
C, 69.87; H, 6.74.
calcd 268.1495, obsd 268.1495; [R]20 -174.4 (c 0.47, CHCl3).
For 44: IR (CHCl3, cm-1) 1755, 1713; H NMR (300 MHz,
D
1
Anal. Calcd for C14H24O3Si: C, 62.64; H, 9.01. Found: C, 62.70;
H, 9.02.
CDCl3) δ 7.90 (d, J ) 9.0 Hz, 2 H), 7.33 (d, J ) 5.6 Hz, 1 H),
6.88 (d, J ) 9.0 Hz, 2 H), 6.01 (d, J ) 5.6 Hz, 1 H), 5.39 (dd,
J ) 8.1, 1.7 Hz, 1 H), 3.84 (s, 3 H), 2.40-1.63 (m, 6 H); 13C
NMR (75 MHz, CDCl3) δ 171.9, 165.7, 163.7, 155.7, 131.8 (2C),
122.2, 121.5, 113.8 (2C), 94.5, 75.1, 55.4, 32.6, 28.3, 19.1.
L-Selectr id e Red u ction of (+)-8. A N2-blanketed solution
of (+)-8 (0.25 g, 1.8 mmol) in dry THF (1.0 mL) was cooled to
-78 °C and treated dropwise with a solution of L-Selectride
in THF (5.4 mL of 1.0 M, 5.4 mmol), stirred at this temperature
for 1 h, and quenched with 3 M NaOH solution (10 mL) and
30% hydrogen peroxide (8 mL). The reaction mixture was
allowed to warm to 20 °C, transferred to a separatory funnel
with a CH2Cl2 rinse (15 mL), and neutralized to pH 7 by the
addition of 2 M sulfuric acid. The separated aqueous phase
was extracted with CH2Cl2 (4 × 15 mL), and the combined
organic layers were dried and concentrated. Purification of the
residue by chromatography on silica gel (elution with 7:1
hexanes/ethyl acetate) yielded (+)-29 as a colorless oil (0.24
Com p ou n d 47. Lithium hexamethyldisilazide (0.80 mL of
0.93 M in THF, 0.73 mmol) was cooled to -78 °C and treated
via cannula with a solution of (+)-31 (50 mg, 0.19 mmol) in
dry THF (5 mL). After 30 min, a solution of phenylselenenyl
bromide (2.0 mL of 0.25 M in THF, 0.5 mmol) was introduced.
After 1 h at this temperature, the reaction mixture was
quenched with 1 M hydrochloric acid (10 mL), and the
separated aqueous phase was extracted with ether (2 × 20
mL). The combined organic solutions were evaporated, and the
resulting selenide was dissolved in CH2Cl2 (10 mL), cooled to
0 °C, and treated with 30% hydrogen peroxide (15 mL). After
an hour of vigorous stirring, the separated aqueous layer was
extracted with CH2Cl2 (15 mL), and the combined organic
phases were washed with water (10 mL) and brine (10 mL)
prior to drying and evaporation. Purification of the residue
by chromatography on silica gel (elution with hexanes/ethyl
acetate 8:1) afforded 26 mg (51%) of (-)-47 as a colorless oil:
IR (CHCl3, cm-1) 1750; 1H NMR (300 MHz, C6D6) δ 6.23 (d, J
) 5.6 Hz, 1 H), 5.67 (d, J ) 5.6 Hz, 1 H), 3.53 (dd, J ) 7.1, 2.5
Hz, 1 H), 1.91-1.75 (m, 1 H), 1.70-1.48 (series of m, 2 H),
1.40-1.10 (series of m, 3 H), 0.89 (s, 9 H) -0.06 (s, 3 H), -0.09
(s, 3 H); 13C NMR (75 MHz, C6D6) δ 171.6, 155.4, 123.1, 94.7,
76.5, 32.3, 31.9, 26.2 (3C), 19.5, 18.6, -4.2, -4.4; EI MS m/z
(M+) calcd 268.1495, obsd 268.1501; [R]20D -91.1 (c 1.4, CHCl3).
1
g, 96%): IR (neat, cm-1) 3454; H NMR (300 MHz, CDCl3) δ
3.87-3.74 (m, 2 H), 3.62 (t, J ) 7.0 Hz, 1 H), 2.59 (s, 1 H),
1.99-1.41 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 91.0, 77.4,
68.7, 35.7, 35.3, 32.6, 27.0, 20.2; ES MS m/z (M + Na)+ calcd
165.0891, obsd 165.0887; [R]20 +3.4 (c 1.5, CHCl3).
D
The racemic form of 29 is a known compound.13,32
Com p ou n d 31. To a solution of (+)-30 (1.30 g, 5.06 mmol)
in CCl4 (19 mL), water (9.5 mL), and acetonitrile (15 mL) was
added sodium periodate (4.60 g, 21 mmol) and ruthenium
trichloride (0.23 g, 1.1 mmol). The reaction mixture was stirred
for 1.5 h, diluted with ether (10 mL), and filtered through a
pad of silica gel. Chromatographic purification on the same
adsorbent (elution with 11:1 hexanes/ethyl acetate afforded
(+)-31 as a colorless solid: mp 39.5-42.0 °C, (0.98 g, 71%); IR
(neat, cm-1) 1775; 1H NMR (300 MHz, CDCl3) δ 3.86 (dd, J )
7.9, 2.1 Hz, 1 H), 2.70 (dt, J ) 17.5, 10.2 Hz, 1 H), 2.49-2.39
(m, 1 H), 2.22-2.10 (m, 2 H), 2.04-1.57 (series of m, 6 H),
0.88 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 177.1, 92.7, 79.7, 33.5, 30.8, 29.5, 29.2, 25.7 (3C), 18.5,
17.9, -4.3, -5.1; EI MS m/z calcd 270.1651, obsd 270.1655;
Ack n ow led gm en t. D.R.O. was a GlaxoWellcome
Postdoctoral Fellow, 1998-1999; A.L.K. served as a
GAANN Fellow, 2000-2002; and M.A.C. was a Gradu-
ate Fellow of the Ministerio de Educacioˆn y Ciencia
(Spain) during 1998. The authors thank Dr. J udith
Gallucci (The Ohio State University) and Prof. Robin
Rogers (The University of Alabama) for their efforts in
obtaining the X-ray data, Dr. Robert Gold, Dean of the
College of Mathematical and Physical Sciences, for
financial support, and Prof. Barry Trost for kindly
providing his NMR spectra for 25 and 26 (corrected
formulations).
[R]20 +18.4 (c 1.18, CHCl3). Anal. Calcd for C14H26O3Si: C,
D
62.18; H, 9.69. Found: C, 62.11; H, 9.73.
This racemic lactone, prepared in a rather different manner,
has previously been incorrectly assigned.13,32
Allylic Oxid a tion of th e Sp ir od ih yd r ofu r a n s. Gen er a l
P r oced u r e. A mixture of pyridinium chlorochromate (16.06
g, 73 mmol), chromium trioxide (7.30 g, 73 mmol) and
powdered 3 Å molecular sieves (45.6 g) were suspended in CH2-
Cl2 (500 mL) and cooled to -25 °C. After 3,5-dimethypyrazole
(14.25 g, 146 mmol) had been added and stirring maintained
at this temperature for 30 min, (-)-35 (3.80 g, 14.6 mmol)
dissolved in CH2Cl2 (40 mL) was introduced. After 1 h at -20
°C, the reaction mixture was filtered through a pad of silica
gel (washing with ethyl acetate), the filtrate was concentrated,
and the residue was immediately chromatographed on silica
gel (elution with hexanes/ether 3:2) to give 2.6 g (65%) of (-)-
43 and 350 mg (8%) of 44.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for all compounds not described
in the printed format. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O010026O