Sequenced Reactions with Samarium(II) Iodide. Sequential Nucleophilic Acyl Substitution/Ketyl Olefin Coupling Reactions for the Preparation of Oxygen Heterocycles

Article abstract of DOI:10.1021/jo9700235

Samarium(II) iodide has been employed to promote a sequential intramolecular nucleophilic acyl substitution/intramolecular ketyl olefin coupling cyclization sequence to provide bicyclic, tricyclic, and spiro-fused oxygen heterocycles in excellent yield and with high diastereoselectivity.

Full text of DOI:10.1021/jo9700235

2944
J . Org. Chem. 1997, 62, 2944-2956
Sequ en ced Rea ction s w ith Sa m a r iu m (II) Iod id e. Sequ en tia l
Nu cleop h ilic Acyl Su bstitu tion /Ketyl Olefin Cou p lin g Rea ction s
for th e P r ep a r a tion of Oxygen Heter ocycles
Gary A. Molander* and Christina R. Harris
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received J anuary 2, 1997X
Samarium(II) iodide has been employed to promote a sequential intramolecular nucleophilic acyl
substitution/intramolecular ketyl olefin coupling cyclization sequence to provide bicyclic, tricyclic,
and spiro-fused oxygen heterocycles in excellent yield and with high diastereoselectivity.
In tr od u ction
substitution/Barbier-type coupling sequence leading to
bicyclic and tricyclic ring systems has been reported.6b
Additionally, a sequential nucleophilic acyl substitution/
ketyl olefin coupling sequence has been developed.6a
Since the initial development of samarium(II) iodide
(SmI2) as a reducing agent in the early 1980’s, its ability
to promote a variety of reductions and reductive coupling
processes has been overwhelming.1 Indeed, previous
research from this laboratory and others has demon-
strated SmI2 to be an excellent reagent for performing a
diverse array of reductive coupling processes. In each
of these reactions, SmI2 exhibits remarkable selectivity
because its reactivity can be modulated through the
addition of catalysts,1c,2 solvent additives,3 or through
other variations of the reaction conditions.4 It is the
ability to alter the reactivity of SmI2 that enhances the
applicability of this reagent in complex synthetic opera-
tions, thereby providing the potential to make a major
impact in many facets of synthetic chemistry.
Processes that generate multiple carbon-carbon or
carbon-heteroatom bonds in a sequence of events with-
out isolation of any intermediates represent a very
powerful means to increase molecular complexity dra-
matically in a single operation.5 Recent research from
this laboratory has been directed toward developing SmI2
into a useful reagent for such second-generation processes
by asserting its ability to perform sequential reactions
in both one- and two-electron processes, affording highly
functionalized products from relatively simple pre-
cursors.1a,6 For example, a sequential nucleophilic acyl
Both tetrahydrofurans and tetrahydropyrans are be-
coming increasingly recognized as a common structural
motif in many naturally occurring compounds.7 This
recognition, combined with our ongoing efforts aimed at
utilizing SmI2 in sequential processes, provided us with
the impetus to apply this powerful ring-building strategy
toward the generation of oxygen heterocycles. The
sequence to be investigated involved the transformation
of simple acyclic substrates to more complex heterocycles
through a sequential nucleophilic acyl substitution/ketyl
olefin coupling sequence, thus providing a unique entry
to a multitude of bicyclic, tricyclic, and spiro-fused oxygen
heterocycles. The problems associated with building
these ring systems have been generally recognized.8 The
stereoselective synthesis of highly functionalized oxygen
heterocycles by the protocol described herein posed a
significant challenge as well. One inherent difficulty
anticipated in constructing these heterocyclic systems
during a sequential SmI2-mediated process was the
potential for R-deoxygenation of the initial R-heterosub-
stituted carbonyl system or, more likely, deoxygenation
of the intermediate R-oxygenated ketone species.9 Al-
though it had been demonstrated repeatedly that SmI2
is capable of promoting the rapid deoxygenation of both
R-oxygenated ketones and esters (or lactones) even at
-78 °C, we found that in the desired sequential coupling
sequence the remarkable selectivity of SmI2 allowed the
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) (a) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307 and
references therein. (b) Molander, G. A.; Harris, C. R. In Encyclopedia
of Reagents for Organic Synthesis; Paquette, L. A., Ed.; J ohn Wiley &
Sons Ltd.: Chichester, England, 1995; Vol. 6, p 4428. (c) Girard, P.;
Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980, 102, 2693. (d)
Molander, G. A. Chem. Rev. 1992, 92, 29. (e) Sasaki, M.; Collin, J .;
Kagan, H. B. New J . Chem. 1992, 16, 89. (f) Soderquist, J . A.
Aldrichim. Acta 1991, 24, 15. (g) Molander, G. A. Org. React. 1994,
46, 211.
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4059-4071. (b) Molander, G. A.; Harris, C. R. J . Am. Chem. Soc. 1995,
117, 3705-3716. (c) Molander, G. A.; McKie, J . A. J . Org. Chem. 1992,
57, 3132. (d) Molander, G. A.; Kenny C. J . Org. Chem. 1991, 56, 1439.
(e) Molander, G. A.; Harring, L. S. J . Org. Chem. 1990, 55, 6172.
(7) (a) Dai, J .-R.; Hallock, Y. F.; Boyd, M. R. J . Nat. Prod. 1996, 59,
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S0022-3263(97)00023-6 CCC: $14.00 © 1997 American Chemical Society

Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2945
Sch em e 1
Sch em e 2a
formation of the desired multi-ring, highly functionalized
oxygen heterocycles while inducing little, if any, products
derived from reductive cleavage of the oxygen species R
to the ester or intermediate ketone.
Resu lts a n d Discu ssion
Initial studies on the development of this sequential
process concentrated primarily on ester functionalities
containing both a pendant olefin and halogen chain, with
one of these incorporating a remote oxygen ether func-
tionality. A representative example is shown in Scheme
1. The cyclization is believed to proceed through the
initial formation of an organosamarium species.6b,10
Presumably, attack of the organosamarium species on
the ester results in formation of a tetrahedral intermedi-
ate that collapses to liberate the cyclic ketone. The
resultant olefinic ketone may then undergo either a 5-exo
(n ) 0) or 6-exo (n ) 1) ketyl olefin coupling reaction.6a,c,d,11
The resultant carbon-centered radical is rapidly reduced
to an organosamarium species, generating the desired
bicyclic oxygen heterocycle after an aqueous workup. The
major diastereomers in both the 5-exo and 6-exo cycliza-
tions are those with the developing radical center trans
to the alkoxy group. The formation of this isomer avoids
unfavorable stereoelectronic interactions in the radical
cyclization.6c,11
a
Key: (a) NaH, allyl bromide, DMF; (b) LDA, 1-chloro-3-
iodopropane; (c) NaI, acetone.
Sch em e 3a
a
Key: (a) NaH, BrCH2C(Br)dCH2, DMF; (b) SOCl2, cat. HCl
(neat); then EtOH; (c) NaI, acetone, reflux.
phile provided suitable substrates for SmI2 chemistry.13
Scheme 3 outlines an alternative strategy to these
R-oxygenated substrates. As depicted in Scheme 3,
Williamson ether synthesis beginning with R-hydroxy-
butyrolactone and an appropriate electrophile provided
the desired allyloxy lactone. A one-pot lactone ring
opening/ester generation with SOCl2 (neat) followed by
the addition of ethanol provided the R-oxygenated sub-
strates. Finally, a Finkelstein reaction with NaI provided
the requisite substrates in relatively few steps.
Initially, a series of olefinic esters was prepared to
demonstrate the scope and limitations of this sequential
process. The R-oxygenated substrates in these systems
were prepared in one of two ways. A representative
example is depicted in Scheme 2. Thus, ethyl glycolate
was O-alkylated with an appropriate electrophile to
generate the allyloxy carboxylate.12 Subsequent alkyla-
tion of the resultant alkoxy ester with a second electro-
Optimum reaction conditions for these reactions in-
volved the dropwise addition of the substrate to a solution
of 4.4 equiv of SmI2 in THF containing 5 equiv of
hexamethylphosphoramide (HMPA) at 0 °C. The stan-
dard reaction conditions did not involve the intentional
addition of a proton source to quench the final organosa-
marium intermediate. In general, these reactions were
complete after 30-45 min.
In the event, cyclization of the R-oxygenated species
(3a -c, 8) provided the desired oxygen-containing het-
erocycles (7a -c, 9) in very good yield as single isomers
(1H NMR) in most cases (eqs 1 and 2). One obvious
challenge in these oxygenated systems was to acheive
both individual reactions without inducing reductive
cleavage of the oxygen heterosubstituent R to the carbo-
(9) (a) Yang, B. V.; Massa, M. A. J . Org. Chem. 1996, 61, 5149. (b)
Enholm, E. J .; Schreier, J . A. J . Org. Chem. 1995, 60, 1110. (c)
Hanessian, S.; Girard, C. Synlett 1994, 861. (d) Hanessian, S.; Girard,
C. Synlett 1994, 863. (e) Georg, G. I.; Cheruvallath, Z. S. J . Org. Chem.
1994, 59, 4015. (f) Linderman, R. J .; Cusack, K. P.; Kwochka, W. R.
Tetrahedron Lett. 1994, 35, 1477. (g) Enholm, E. J .; J iang, S.; Abboud,
K. J . Org. Chem. 1993, 58, 4061. (h) Enholm, E. J .; J iang, S.
Heterocycles 1992, 34, 2247. (i) Enholm, E. J .; J iang, S. Tetrahedron
Lett. 1992, 33, 6069. (j) Enholm, E. J .; J iang, S. Tetrahedron Lett. 1992,
33, 313. (k) Hanessian, S.; Girard, C.; Chiara, J . L. Tetrahedron Lett.
1992, 33, 573. (l) Inanaga, J .; Kafsuki, J .; Yamaguchi, M. Chem. Lett.
1991, 1025. (m) Kusuda, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron
Lett. 1989, 30, 2945. (n) Matsukawa, M.; Tabuchi, T.; Inanaga, J .;
Yamaguchi, M. Chem. Lett. 1987, 2101. (o) Otsubo, K.; Inanaga, J .;
Yamaguchi, M. Tetrahedron Lett. 1987, 28, 4437. (p) Molander, G. A.;
Hahn, G. J . Org. Chem. 1986, 51, 1135.
(10) (a) Molander, G. A.; McKie, J . A. J . Org. Chem. 1993, 58, 7216.
(b) Molander, G. A.; Shakya, S. R. J . Org. Chem. 1994, 59, 3445. (c)
Molander, G. A.; McKie, J . A. J . Org. Chem. 1991, 56, 4112. (d) Curran,
D. P.; Totleben, M. J . J . Am. Chem. Soc. 1992, 114, 6050.
(11) Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989, 111, 8236.
(12) Hart, D. J .; Hong, W.-P.; Hsu, L.-Y. J . Org. Chem. 1987, 52,
4665.
(13) Hermann, J . L.; Schlessinger, R. H. J . Chem. Soc., Chem.
Commun. 1973, 711.

2946 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and Harris
nyl. Surprisingly, only a very small amount of deoxy-
genated products (generally <5-10% of cyclopentanone/
cyclohexanone species) was detectable, although it has
been demonstrated repeatedly that SmI2 promotes the
rapid deoxygenation of both R-oxygenated ketones and
esters (or lactones) even at -78 °C.9 Apparently, the rate
of the SmI2-mediated organic halide reduction, nucleo-
philic acyl substitution, and the ensuing 5-exo ketyl olefin
coupling reaction are much more rapid than R-hetero-
atom extrusion under these reaction conditions.
Substrate 17 was prepared as depicted in Scheme 4
from methyl 5-chloropentanoate using a sequence initi-
ated by a Claisen condensation with propional, formation
of the mesylate, and generation of the enoate, 15, with
DBU.14 Finally, a Finkelstein reaction with NaI, ozo-
nolysis with a reductive workup, and subsequent ketal
generation with the trimethylsilyl ether of allyl alcohol
in the presence of catalytic TMSOTf provided the requi-
site bis(allyl) ketal, 17, in good overall yield.15
Unfortunately, substrates in which the terminating
cyclization event involved a 6-exo ketyl olefin coupling
reaction provided solely R-deoxygenated ketone products.
This observation implies that the rate of 6-exo ketyl olefin
coupling does not compete effectively with the R-hetero-
atom extrusion under these reaction conditions, and
therefore, only products resulting from R-heteroatom
cleavage of the intermediate cycloalkanone are generated.
Further investigation revealed the facility with which
strained bicyclic systems could be generated in good
yields and with high diastereoselectivity. For example,
sequential cyclization of substrates 10 and 6 afforded the
desired heterocycles 11 and 12, respectively, in good
yields (eqs 3 and 4).
A second class of substrates in this series contained a
â-substituted allylic ether functionality and pendant
halogen chain. Such substrates would each terminate
in a 6-exo ketyl olefin cyclization process. However, they
do not possess the problematic R-deoxygenation reaction
pathway, and hence, they were anticipated to work quite
well under the standard sequential SmI2 reaction condi-
tions. The allylic ether-functionalized substrates in this
series were prepared in one of two ways. One method
involved substrate preparation from the â-formyl ester
by Noyori-type ketalization as depicted in Scheme 5.
Thus, the â-formyl ester (20) was treated with the
trimethylsilyl ether of allyl alcohol (or propargyl alcohol)
in the presence of catalytic TMSOTf to provide the bis-
(allyloxy) [or bis(propargyloxy)] acetal 21 (or 23) in
excellent yield.11
Cyclization of the â-formyl ester-derived substrates 21
and 23 provided the desired hemiacetal products (22 and
24) in good yield and with high diastereoselectivity (eqs
7 and 8).
In an effort to probe further the ability of this reaction
sequence to generate highly sophisticated and strained
ring systems, substrates 13 and 17 (eqs 5 and 6) were
subjected to the SmI2-mediated sequential reaction con-
ditions. The cyclization event in eq 5 (performed on a
mixture of diastereomeric compounds 13) afforded the
strained tricyclic oxygenated ring systems in 14 contain-
ing an internal cyclobutane ring system as a 2:1 mixture
of diastereomeric products in 58% combined yield. When
the R-oxygenated species 17 in eq 6 was subjected to the
standard reaction conditions, the desired hemiketal 18
was generated as a mixture of the allyl and methyl ketals
in 57% combined yield as a single diastereomer. Appar-
ently, some transketalization (O-allyl to O-methyl) re-
sults from the liberated methoxy group during either the
reaction process or workup procedure.
The anticipated stereochemistry of these highly func-
tionalized molecules was verified by H NMR. Thus, H
NMR chemical shifts of the cyclized oxygen heterocycles
1
1
(14) Scolastico, C.; Banfi, L.; Bernardi, A.; Colombo, L.; Gennari, C.
J . Org. Chem. 1984, 49, 3784.
(15) Cossy, J .; Ranaivosata, J .-L.; Bellosta, V. Tetrahedron Lett.
1995, 36, 2067.

Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2947
Sch em e 4a
Sch em e 6a
a
Key: (a) NaBH4, MeOH; (b) CH2dCHCH2,OC(NH)CCl3,
BF3‚OEt2.
larger downfield shift observed for dihedral angles ap-
proaching 0°. Similarly, the solvent-induced chemical
shift difference of a methine group experiencing a 1,3-
diaxial interaction with a hydroxyl substituent is gener-
ally 0.20-0.40 ppm. As depicted in Figure 1, the
bridgehead methyl group in both systems experiences a
large downfield shift (0.31 ppm and 0.38 ppm for 22 and
24, respectively) indicating a cis-fused bicyclic ring
system. The results depicted in Figure 1 are also
consistent with the 1,3-diaxial orientation between the
acetal methine and the bridgehead hydroxyl group for
both 22 (0.21 ppm downfield shift in pyridine solvent
relative to the CDCl3 solvent spectrum) and 24 (0.38 ppm
downfield shift in pyridine solvent relative to the CDCl3
solvent). Finally, a 0.32 ppm shift downfield in the C2-
methine is indicative of a cis relationship between the
bridgehead hydroxyl and C2-methine in 22. Likewise,
the 0.54 ppm shift downfield observed for the olefinic
proton of 24 provides evidence for the E-stereochemistry
about the olefin as depicted in Figure 1.
a
Key: (a) LDA, propional, -78 °C; (b) MsCl, Et3N, DMAP; (c)
DBU, THF; (d) NaI, acetone; (e) O3; DMS; (f) TMSOCH2CHdCH2,
TMSOTf.
Sch em e 5a
a
Key: (a) LDA, MeI; (b) LDA, methyl formate; (c) NaI, acetone;
(d) CH2dCHCH2OTMS, TMSOTf.
Additional substrates were prepared from â-hydroxy
esters with allyl ether formation occurring via Schmidt-
type chemistry as outlined in Scheme 6. Initial attempts
to prepare these systems by O-alkylation of the corre-
sponding â-hydroxy esters under Williamson ether-type
conditions proved futile. Thus, as depicted in Scheme 6,
the formyl ester 20 was reduced with NaBH4 to provide
the â-hydroxy ester 25.17 Allyl ether formation was
accomplished via the Schmidt-type chemistry with the
trichloroacetimidate of allyl alcohol and catalytic TM-
SOTf or catalytic BF3‚OEt2 to provide 26.18 Cyclization
of the â-formyl ester-derived allylic ether 26 (eq 9)
generated the desired [4.3.0]oxabicyclic 27 in good yield
as an 11:1 mixture of diastereomers.
F igu r e 1. Interactions of the bridgehead hydroxyl group with
the bridgehead methyl, 1,3-diaxially substituted methine, and
vicinally substituted methine groups influencing solvent-
induced chemical shift differences (δpyr - δCDCl ) in compounds
3
22 and 24.
observed in d5-pyridine relative to those observed in
CDCl3 solvent (TMS internal standard) provided evidence
for the indicated cis ring fused stereochemistry at the
bridgehead of the oxabicyclo[4.3.0] systems, as well as
evidence for the stereochemistry about the methine/
hemiacetal position and the C-2 methyl of the cyclized
products (Figure 1).16 The protons about the bridgehead
hydroxyl groups experience a large deshielding effect in
these bridged bicyclic systems owing to coordination of
pyridine at the hydroxyl functionality, which influences
the chemical shift of protons positioned vicinally and 1,3-
diaxially to the bridgehead alcohol in both 22 and 24.
The extent of vicinal deshielding about the bridgehead
methyl group is a function of the dihedral angle of the
OCCCH3 unit, with the largest deshielding observed for
dihedral angles approaching 0°. Thus, the solvent-
induced chemical shift difference of a methyl (or methine)
group experiencing a vicinally oriented diaxial interaction
with a hydroxyl substituent ranges from approximately
0.0 ppm for a dihedral angle approaching 160-180° to
0.2-0.3 for a dihedral angle approaching 60° and an even
Likewise, it was discovered that the corresponding
â-keto esters would not provide the requisite bis(allyl)
ketals under several attempted reaction conditions.
Consequently, an alternative strategy to these systems
was sought. The overall strategy for this class of
substrates is demonstrated in Scheme 7. Thus, ethyl
2-oxo-cyclopentanecarboxylate was alkylated with the
TBS ether of 3-bromopropanol, and the resulting â-keto
ester was treated with MeMgBr to provide the desired
â-hydroxy ester 28 in nearly quantitative yield. Subse-
quently, treatment of 28 with the trichloroacetimidate
of allyl alcohol in the presence of catalytic TMSOTf or
catalytic BF3‚OEt2 provided the desired allyl ether in
(17) Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.;
Takeda, T.; Waldner, A.; Williard, P. G.; Zutter, V. J . Am. Chem. Soc.
1986, 108, 1039.
(16) Demarco, P. V.; Farkas, E.; Doddrell, D.; Mylari, B. L.; Wenkert,
E. J . Am. Chem. Soc. 1968, 90, 5480.
(18) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J . Chem. Soc., Perkin
Trans. 1 1985, 2247.

2948 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and Harris
Sch em e 7a
Sch em e 8a
a
Key: BrCH2CH2CH2OH, EDCI, CH2Cl2; (b) LDA, propional,
a
Key: Br(CH2)3OTBS, NaH, DMF, 60 °C; (b) MeMgBr, -78 °C;
-78 °C; (c) CH2dCHCH2OC(NH)CCl3, TMSOTf; (d) O3; DMS; (e)
Ph3PdCHPh, THF; (h) NaI, acetone.
(c) CH2dCHCH2OC(NH)CCl3, TMSOTf; (d) Amberlyst-15, EtOH;
(e) CBr4, PPh3, Et2O/CH3CN; (f) O3; DMS; (g) PhCHdPPh3; (h)
NaI, acetone.
establishes more effective overlap with the ketyl radical
anion SOMO.21 Consequently, any ketyl generated
through the pertinent equilibria would thus be more
efficiently trapped by the alkene, facilitating the cycliza-
tion. In most instances, it was also necessary to heat
the reaction mixture overnight in refluxing THF to
provide acceptable yields of the desired cyclized oxygen
heterocycles.
good yield.18 Removal of the TBS ether in these systems
was accomplished without lactonization by the use of
EtOH (protic solvent) and Amberlyst-15 resin.19 The
substrates could be further elaborated by subsequent
ozonolysis and Wittig reaction to provide the phenyl
substituted olefin in fair overall yield.17,20
Cyclization of the substrates thus prepared proceeded
in good yield and with excellent diastereoselectivity
provided that the olefin was activated with an electron-
withdrawing group (eqs 10-12). Without the activated
The anticipated stereochemistry of 32 was verified by
1
comparing the H NMR of 32 in pyridine-d5 and CDCl3.
The bridgehead hydroxyl group in 32 causes both the
bridgehead methyl group and vicinally substituted me-
thine to experience a large deshielding effect owing to
coordination of pyridine at the bridgehead hydroxyl
group, thus causing a substantial downfield shift of both
signals. Indeed, the bridgehead methyl 32 experiences
a downfield shift of 0.25 ppm and the vicinally substi-
tuted methine experiences a 0.33 ppm downfield shift,
all indicative of a cis relationship of the bridgehead
hydroxyl, bridgehead methyl, and the vicinally substi-
tuted methine. Additionally, the stereochemistry of the
cyclization product 32 in eq 10 was unambiguously
determined by single-crystal X-ray diffraction, thus
providing additional evidence for the predictability of the
ketyl olefin cyclization stereochemistry. The reaction in
eq 10 also provided a 35% yield of the spirocyclic
intermediate ketone in addition to the desired angular,
tricyclic oxygenated ring system.
The ability to prepare more elaborate spirocyclic ring
systems was further demonstrated by the reaction de-
picted in eq 13. Substrate 40 was prepared similarly to
olefin present in the substrate, little or no desired bicyclic
products were obtained, and the majority of the product
mixture contained merely cyclic ketone from the initial
intermediate or alcohol from reduction of the intermedi-
ate ketone. Replacement of the unactivated terminal
olefin with the more activating phenyl-substituted alkene
lowers the π* orbital energy (LUMO) of the alkene and
the above systems as illustrated in Scheme 8. Thus, the
desired ester 37 was prepared from cyclopentanecar-
boxylic acid under Mitsunobu-type reaction conditions.10b
The â-hydroxy ester functionality in 38 was prepared by
a Claisen condensation of the ester with propional. Then,
(19) Use of TBAF/THF provided a mixture of both the cyclized
lactone resulting from attack of the liberated primary alcohol on the
ester and a minor amount of the desired primary alcohol.
(20) Bunnelle, W. H.; Rafferty, M. A.; Hodges, S. L. J . Org. Chem.
1987, 52, 1603.
(21) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.

Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2949
a solution of LDA (33.0 mmol, 1 M in THF) cooled to -78 °C.
After the addition of the ester was complete, the reaction
mixture was stirred at -78 °C for an additional 30-40 min
before adding a solution of 1-chloro-3-iodopropane in 7.0 mL
of HMPA rapidly dropwise via cannula and warming the
reaction mixture to -30 °C. The reaction mixture was
maintained at -30 °C for 12 h and then quenched with
saturated aqueous NH4Cl and subjected to an aqueous workup.
Flash chromatography with 2-3% EtOAc/hexanes afforded 2
in 46% yield: 1H NMR (400 MHz, CDCl3) δ 5.88 (m, 1H), 5.23
(m, 2H), 4.17 (m, 3H), 3.88 (m, 2H), 3.54 (m, 2H), 1.89 (m,
4H), 1.28 (t, J ) 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.42, 133.92, 117.90, 77.25, 71.38, 60.92, 44.60, 30.21, 28.41,
14.24.
Dih yd r o-3-(2-p r op en yloxy)fu r a n -2(2H )-on e was pre-
pared from R-hydroxybutyrolactone by O-alkylation with allyl
bromide according to the general procedure for the preparation
of 1 to afford the desired allyl ether in 76% yield after flash
chromatography with 25% EtOAc/hexanes and Kugelrohr
distillation (ot 90-100 °C/10 mmHg): 1H NMR (400 MHz,
CDCl3) δ 5.89 (m, 1H), 5.24 (m, 2H), 4.37 (m, 2H), 4.18 (m,
3H), 2.48 (m, 1H), 2.25 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 174.60, 133.56, 118.32, 72.51, 71.22, 65.40, 29.81.
Eth yl 2-(2-Ch lor oeth yl)-3-oxa -5-h exen oa te. Gen er a l
P r oced u r e for On e-P ot La cton e Op en in g/Ha logen a tion /
Ester F or m a tion Rea ction s. Thionyl chloride (neat, 1.78
g, 15.0 mmol) and three drops of concd HCl were added neat
to dihydro-3-(2-propenyloxy)furan-2(2H)-one (0.44 g, 3.0 mmol)
in an argon-filled flask equipped with a drying tube and cooled
to 0 °C in an ice bath. After the addition was complete, the
ice bath was removed and the reaction mixture was stirred at
ambient temperature for 18 h. After this period of time, the
reaction mixture was cooled to 0 °C, absolute ethanol (20 mL)
was added cautiously in small portions, and the reaction
mixture was stirred for an additional 1 h at 0 °C and 4 h at
rt. Then, the reaction was quenched at 0 °C by careful addition
of a saturated aqueous NaHCO3 solution to afford the desired
ester in 94% yield (0.58 g, 2.82 mmol) after an aqueous workup
and flash chromatography with 5% EtOAc/hexanes: 1H NMR
(300 MHz, CDCl3) δ 5.89 (m, 1H), 5.22 (m, 2H), 4.17 (m, 2H),
4.10 (m, 1H), 3.93 (m, 1H), 3.68 (m, 1H), 3.68 (m, 2H), 2.15
(m, 2H), 1.28 (t, J ) 7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 172.26, 133.81, 118.12, 74.56, 71.81, 61.10, 40.70, 35.65,
14.21.
Eth yl 2-(2-iod oeth yl)-3-oxa -5-h exen oa te (3a ) was pre-
pared from ethyl 2-(2-chloroethyl)-3-oxa-5-hexenoate according
to the general procedure outlined for the preparation of 3b to
afford 3a in 92% yield after flash column chromatography with
5% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.90 (m,
1H), 5.24 (m, 2H), 4.19 (m, 3H), 3.94 (m, 2H), 3.28 (m, 2H),
2.19 (m, 2H), 1.27 (t, J ) 7.08 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.98, 133.85, 118.19, 77.49, 71.83, 61.12, 36.47,
14.22, 11.42.
ether formation under Schmidt-type reaction conditions
followed by ozonolysis with a reductive workup and
subsequent Wittig reaction provided the desired sub-
strate 40 after a Finkelstein reaction. Treatment of the
desired substrate under the standard sequential reaction
conditions provided the desired spirocycle 41 in fair yield
as a single diastereomer (eq 13).
The stereochemistry of 41 was verified by pyridine-d5
1H NMR studies that were consistent with the expected
1
cyclization stereochemistry. Thus, comparison of the H
NMR spectrum of 41 in CDCl3 and pyridine-d5 revealed
a 0.44 ppm shift in the C2-methine (indicative of a 1,3-
diaxial orientation of the C2-methine and hydoxyl group)
and no shift in the CH2 ethyl protons. This observation
is consistent with the stereochemistry depicted in 41 for
a cis relationship between the C2-methine and hydroxyl
functionality.
Con clu sion s
The SmI2-promoted intramolecular nucleophilic acyl
substitution/ketyl olefin cyclization sequence has been
utilized to convert a variety of suitable substrates to
bicyclic, tricyclic, and spiro-fused oxygen heterocycles
efficiently, in high yield, and with excellent diastereose-
lectivity. Substrates for these sequential processes are
readily prepared by classical alkylation chemistry in a
relatively few steps. The overall transformation repre-
sents an effective means by which simple starting
materials can be converted to highly sophisticated oxygen
heterocycles in a one-pot process. The remarkable se-
lectivity of SmI2 in these sequential reaction processes
allows formation of the desired bicyclic and tricyclic
products while inducing little, if any, products derived
from reductive cleavage of the heterosubstituents R to
the ester (or lactone) or the intermediate ketone.
Exp er im en ta l Section
Rea gen ts. Tetrahydrofuran (THF) was distilled immedi-
ately prior to use from benzophenone ketyl under Ar. Sa-
marium metal was purchased from Cerac Inc., Milwaukee, WI,
and was weighed and stored under an inert atmosphere.
CH2I2 was purchased from Aldrich Chemicals and was distilled
prior to use and stored under argon over copper turnings.
HMPA was purchased from either Aldrich or Sigma Chemicals
and was distilled from either Na(0) or CaH2 at 0.04 mmHg
and stored over 4 Å molecular sieves under Ar. Standard
benchtop techniques were employed for handling air-sensitive
reagents,22 and all reactions were carried out under argon.
Eth yl 3-Oxa -5-h exen oa te (1). Gen er a l P r oced u r e for
th e O-Alk yla tion of Alcoh ol Nu cleop h iles. Ethyl glycolate
(4.16 g, 40.0 mmol) was added neat to a stirred slurry of NaH
(1.76 g of a 60% dispersion in mineral oil, 44.0 mmol) in DMF
at 0 °C. The resultant reaction mixture was stirred at rt for
2 h and then cooled to 0 °C, whereupon allyl bromide (5.32 g,
44.0 mmol) was added via syringe. After the addition of the
electrophile, the reaction was allowed to come to rt and stir
for 2 h. After this period, the reaction was quenched by the
careful addition of saturated aqueous NH4Cl. The reaction
mixture was subjected to an aqueous workup. Shortpath
distillation afforded the desired product 1 in 88% yield: bp
Eth yl 2-(3-Iod op r op yl)-3-oxa -5-h exen oa te (3b). Gen -
er a l F in k elstein P r oced u r e. Compound 3b was prepared
from 2 according to the following general procedure. A solution
of 2 (0.56 g, 2.4 mmol) in 10 mL of acetone was heated at reflux
for 12 h with NaI (3.6 g, 24.0 mmol) to afford 3b in 95% yield
after an aqueous workup and flash chromatography with 5%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.88 (m, 1H),
5.23 (m, 2H), 4.18 (m, 3H), 3.88 (m, 2H), 3.20 (t, J ) 6.67 Hz,
2H), 1.89 (m, 4H), 1.28 (t, J ) 7.13 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 171.79, 134.74, 116.84, 77.38, 71.25, 60.47,
33.86, 29.64, 14.20, 5.87.
Eth yl 2-(4-ch lor obu tyl)-3-oxa -5-h exen oa te was prepared
according to the general procedure outlined for the preparation
of 2 by alkylation of 1 with 1-chloro-4-iodobutane to afford the
desired chloride in 24% yield after flash chromatography with
2-3% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 5.88 (m,
1H), 5.23 (m, 2H), 4.18 (m, 3H), 3.88 (m, 2H), 3.51 (t, J ) 6.63
Hz, 2H), 1.76 (m, 4H), 1.56 (m, 2H), 1.27 (t, J ) 7.14 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 172.72, 134.02, 117.86, 77.79,
71.42, 60.84, 44.68, 32.22, 32.17, 22.69, 14.26.
1
70-74 °C (20 mmHg); H NMR (300 MHz, CDCl3) δ 5.90 (m,
1H), 5.26 (m, 2H), 4.20 (q, J ) 7.08 Hz, 2H), 4.07 (m, 4H),
1.47 (t, J ) 7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.34,
133.72, 118.19, 72.34, 67.17, 60.82, 14.16.
Eth yl 2-(3-Ch lor op r op yl)-3-oxa -5-h exen oa te (2). Gen -
er a l P r oced u r e F or Alk yla t ion of E st er Nu cleop h iles.
Compound 2 was prepared according to the following general
procedure. Ethyl 3-oxa-5-hexenoate (1) (4.32 g, 30.0 mmol)
was added dropwise via cannula as a 1 M solution in THF to
Eth yl 2-(4-iod obu tyl)-3-oxa -5-h exen oa te (3c) was pre-
pared from ethyl 2-(4-chlorobutyl)-3-oxa-5-hexenoate according
to the general Finkelstein procedure outlined for the prepara-
tion of 3b to afford 3c in 74% yield after an aqueous workup
(22) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.

2950 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and Harris
and flash chromatography with 2% EtOAc/hexanes: 1H NMR
(300 MHz, CDCl3) δ 5.89 (m, 1H), 5.23 (m, 2H), 4.18 (m, 3H),
3.90 (m, 2H), 3.16 (t, J ) 7.08 Hz, 2H), 1.79 (m, 4H), 1.53 (m,
2H), 1.27 (t, J ) 7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.68, 134.02, 117.85, 77.74, 71.41, 60.84, 33.12, 31.79, 26.25,
14.28, 6.33.
Dih yd r o-3-[(2-b r om o-2-p r op e n yl)oxy]fu r a n -2(2H )-
on e (4) was prepared according to the general procedure
outlined for the preparation of 1 by O-alkylation of R-hydoxy-
butyrolactone with 2,3-dibromopropene to afford 4 in 66% yield
after flash chromatography with 18% EtOAc/hexanes: 1H
NMR (300 MHz, CDCl3) δ 5.97 (m, 1H), 5.67 (m, 1H), 4.42 (m,
3H), 4.25 (m, 2H), 2.52 (m, 1H), 2.32 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 174.55, 128.10, 119.29, 73.81, 72.33, 65.49,
29.68.
80 °C/0.1 mmHg). Major diastereomer: 1H NMR (300 MHz,
CDCl3) δ 4.07 (t, J ) 8.55 Hz, 1H), 3.64 (m, 1H), 3.40 (t, J )
9.40 Hz, 1H), 2.25 (m, 1H), 1.86 (m, 1H), 1.64-1.36 (m, 8H),
0.90 (d, J ) 6.84 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 80.36,
75.31, 71.87, 44.42, 28.35, 25.96, 20.69, 20.05, 9.31; IR
(CHCl3): 3886.0, 3690.0, 3607.3, 1087.9 cm-1; HRMS calcd for
C9H16O2 156.1150, found 156.1158; LRMS (EI+) m/ z 156 (13),
139 (10), 114 (86), 97 (34), 85 (48), 70 (100), 57 (78), 41 (77),
27 (52). Anal. Calcd for C9H16O2 C, 69.19; H, 10.32. Found:
C, 68.78; H, 10.53. Minor diastereomer: 1H NMR (300 MHz,
CDCl3) δ 4.09 (t, J ) 8.55 Hz, 1H), 3.70 (dd, J ) 5.61, 8.06
Hz, 1H), 3.53 (t, J ) 8.55 Hz, 1H), 2.25 (m, 1H), 1.86 (m, 1H),
1.64-1.36 (m, 8H), 0.95 (d, J ) 6.84 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 83.04, 78.30, 72.68, 37.86, 32.78, 29.54, 22.30,
22.13, 10.55.
Eth yl 6-[(ter t-bu tyld im eth ylsilyl)oxy]-3-oxa h exa n oa te
was prepared from ethyl glycolate by O-alkylation with tert-
butyldimethylsilyl-protected 3-bromo-1-propanol23 according to
the general procedure outlined for the preparation of 1 to afford
the desired TBS-protected alkoxy ester in 72% yield after flash
chromatography with 8% EtOAc/hexanes: 1H NMR (300 MHz,
CDCl3) δ 4.20 (q, J ) 7.33 Hz, 2H), 4.04 (s, 2H), 3.69 (t, J )
6.10 Hz, 2H), 3.60 (t, J ) 6.34 Hz, 2H), 1.81 (pent, J ) 6.10
Hz, 2H), 1.26 (t, J ) 7.08 Hz, 3H), 0.86 (s, 9H), 0.02 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 170.51, 68.59, 68.48, 60.75,
59.69, 32.72, 25.89 (3), 18.27, 14.18, -5.41 (2).
Eth yl 2-(3-bu ten yl)-3-oxa -6-[(ter t-bu tyld im eth ylsilyl)-
oxy]h exa n oa t e was prepared from ethyl 6-[(tert-butyldi-
methylsilyl)oxy]-3-oxahexanoate by alkylation with 4-bromo-
1-butene according to the general alkylation procedure for
preparation of 2 to afford the desired olefinic ester in 46% yield
after flash chromatography with 7% EtOAc/hexanes: 1H NMR
(400 MHz, CDCl3) δ 5.77 (m, 1H), 4.99 (m, 2H), 4.17 (m, 2H),
3.80 (t, J ) 6.41 Hz, 1H), 3.71-3.61 (m, 3H), 3.40 (m, 1H),
2.16 (m, 2H), 1.78 (m, 4H), 1.26 (t, J ) 7.17 Hz, 3H), 0.86 (s,
9H), 0.02 (s, 6H).
Eth yl 6-br om o-2-(3-bu ten yl)-3-oxa h exa n oa te was pre-
pared from ethyl 2-(3-butenyl)-3-oxa-6-[(tert-butyldimethylsi-
lyl)oxy]hexanoate according to the following general procedure.
To the ester (1.65 g, 5.0 mmol) dissolved in 10 mL of THF and
cooled to 0 °C in an ice bath was added dropwise 6 mL of a 1.0
M (in THF) solution of tetrabutylammonium fluoride (TBAF),
and the reaction mixture was allowed to warm to rt. TLC
analysis of the reaction mixture after warming to rt showed
complete consumption of the starting TBS ether. The reaction
mixture was concentrated in vacuo and flashed through a short
plug of silica gel with 50% EtOAc/hexanes to provide the
desired primary alcohol, which was subjected immediately to
halogenation according to the following procedure. The alcohol
was dissolved in 10 mL of Et2O, and then CBr4 (3.32 g, 10.0
mmol) and PPh3 (2.62 g, 10.0 mmol) were added successively,
and the reaction mixture was stirred overnight at ambient
temperature. After this period of time, the reaction mixture
was diluted with pentane, filtered through a short plug of
Celite to remove the resultant precipitate, concentrated in
vacuo, and subjected to flash chromatography with 10%
EtOAc/hexanes to afford the desired bromide (1.06 g, 3.80
mmol) in 76% yield (two steps): 1H NMR (400 MHz, CDCl3) δ
5.77 (m, 1H), 5.01 (m, 2H), 4.19 (m, 2H), 3.82 (m, 1H), 3.69
(m, 1H), 3.53 (m, 3H), 2.15 (m, 4H), 1.78 (m, 2H), 1.27 (t, J )
7.15 Hz, 3H).
Eth yl 5-br om o-2-(2-ch lor oeth yl)-3-oxa -5-h exen oa te (5)
was prepared from 4 according to the general procedure
outlined for the lactone ring opening/ester formation as
described for the preparation of ethyl 2-(2-chloroethyl)-3-oxa-
5-hexenoate to afford 5 in 95% yield after flash chromatogra-
phy with 5% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ
5.91 (m, 1H), 5.63 (m, 1H), 4.34-4.10 (m, 3H), 4.06 (m, 2H),
3.72 (m, 2H), 2.20 (m, 2H), 1.80 (t, J ) 7.08 Hz, 3H).
Eth yl 5-br om o-2-(2-iod oeth yl)-3-oxa -5-h exen oa te (6)
was prepared from 5 according to the general procedure
outlined for the preparation of 3b to afford 6 in 85% yield after
flash chromatography with 5% EtOAc/hexanes: 1H NMR (300
MHz, CDCl3) δ 5.91 (m, 1H), 5.63 (m, 1H), 4.36 (d, J ) 13.43
Hz, 1H), 4.20 (dq, J ) 1.46, 7.08 Hz, 2H), 4.04 (m, 2H), 3.33
(t, J ) 7.08 Hz, 2H), 2.25 (m, 2H), 1.28 (t, J ) 7.08 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 171.30, 128.37, 119.22, 77.66,
74.66, 61.35, 36.63, 14.21, 1.20.
(1R*,2S*,5S*)-2-Met h yl-4-oxa b icyclo[3.2.0]h ep t a n -1-
ol (7a ) was prepared from 3a according to the general
procedure outlined for the preparation of 7b to afford 7a as a
single diastereomeric product in 67% yield after flash chro-
matography with 35% EtOAc/hexanes: 1H NMR (300 MHz,
CDCl3) δ 4.33 (m, 1H), 4.12 (dd, J ) 4.15, 7.57 Hz, 1H), 3.53
(dd, J ) 9.52, 10.99 Hz, 1H), 2.24-2.05 (m, 3H), 1.79-1.69
(m, 2H), 1.58-1.45 (m, 1H), 0.98 (d, J ) 6.84 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 85.73, 83.61, 72.87, 42.68, 23.83, 18.50,
9.15; IR (neat) 3246.8 cm-1; HRMS calcd for C7H12O2 128.0887,
found 128.0837; LRMS (EI+) m/ z 128 (8), 113 (18), 100 (100),
85 (89), 67 (51), 57 (63), 43 (100), 29 (54). Anal. Calcd for
C7H12O2: C, 65.60; H, 9.44. Found: C, 65.38; H, 9.57.
(1R*,2S*,5S*)-2-Met h yl-4-oxa b icyclo[3.3.0]oct a n -1-ol
(7b). Gen er a l P r oced u r e for Sequ en ced Nu cleop h ilic
Acyl Su bstitu tion /Ketyl Olefin Cou p lin g Rea ction s Me-
d ia ted by Sm I2. Compound 7b was prepared from 3b
according to the following general procedure. Diiodomethane
(0.64 g, 2.39 mmol) was added to a vigorously stirred solution
of Sm metal (0.40 g, 2.66 mmol) in 20 mL of dry THF. The
resultant reaction mixture was stirred for 2 h at ambient
temperature, and then HMPA (2.1 mL) was added, and the
reaction mixture was cooled to 0 °C. Then, ethyl 2-(3-
iodopropyl)-3-oxa-5-hexenoate (3b) (0.156 g, 0.478 mmol) in
10 mL of dry THF was added dropwise via cannula over 2 h
to the 0 °C cooled solution. The reaction was monitored by
TLC and found to be complete after addition of the substrate
was complete. The reaction mixture was warmed to rt and
quenched with saturated aqueous NaHCO3 to afford 7b as a
single diastereomeric product in 83% yield after an aqueous
workup and flash chromatography with 22% EtOAc/hexanes:
1H NMR (400 MHz, CDCl3) δ 4.11 (dd, J ) 2.91, 6.01 Hz, 1H),
4.01 (t, J ) 8.41 Hz, 1H), 3.39 (t, J ) 8.97 Hz, 1H), 2.39 (m,
1H), 2.00 (m, 1H), 1.85 (m, 1H), 1.75 (m, 2H), 1.63 (m, 1H),
1.49 (m, 1H), 1.41 (s, 1H), 0.99 (d, J ) 6.88 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 90.92, 90.50, 74.13, 44.52, 33.79, 32.87,
24.98, 10.62; IR (neat) 3417.5 cm-1; HRMS calcd for C8H14O2
142.0994, found 142.0992; LRMS (EI+) m/ z 142 (2), 127 (10),
100 (100), 82 (46), 72 (51), 55 (48), 41 (98), 27 (78).
Eth yl 2-(3-bu ten yl)-6-iod o-3-oxa h exa n oa te (8) was pre-
pared from ethyl 6-bromo-2-(3-butenyl)-3-oxahexanoate ac-
cording to the general procedure outlined for the preparation
of 3 to afford 8 in 92% yield after flash chromatography with
10% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.78 (m,
1H), 5.01 (m, 2H), 4.19 (m, 2H), 3.81 (dd, J ) 5.65, 7.21 Hz,
1H), 3.63 (m, 1H), 3.39 (m, 1H), 3.30 (m, 2H), 2.19-2.03 (m,
4H), 1.78 (m, 2H), 1.28 (t, J ) 7.12 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 172.82, 137.36, 115.55, 78.41, 69.68, 60.68,
33.49, 32.11, 29.41, 14.28, 3.39.
(1R*,6S*,9R*)-9-Met h yl-5-oxa bicyclo[4.3.0]n on a n -1-ol
(9) was prepared from 8 according to the general procedure
outlined for the preparation of 7b to afford 9 as a single
(1R*,6S*,9S*)-9-Met h yl-7-oxa b icyclo[4.3.0]n on a n -1-ol
(7c) was prepared from 3c according to the general procedure
outlined for the preparation of 7b to afford 7c as a 7.3:1
mixture of diastereomeric products (epimeric at C9) in 76%
combined yield after an aqueous workup, flash chromatogra-
phy with 17% EtOAc/hexanes, and Kugelrohr distillation (ot
(23) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.

Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2951
diasteromeric product in 61% yield after flash chromatography
with 20% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 3.88
(m, 1H), 3.73 (m, 1H), 3.64 (m, 1H), 1.98-1.74 (m, 5H), 1.71-
1.59 (m, 4H), 1.36 (m, 1H), 1.00 (d, J ) 6.59 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 84.02, 76.21, 61.58, 42.26, 28.26, 26.69,
23.41, 21.20, 13.95; IR (neat) 3346.7 cm-1; HRMS calcd for
C9H16O2 156.1150, found 156.1131; LRMS (EI+) m/ z 156 (52),
114 (29), 100 (27), 86 (31), 71 (100), 55 (48), 43 (83), 27 (32).
Anal. Calcd for C9H16O2: C, 69.20; H, 10.32. Found: C, 68.97;
H, 10.57.
Dih yd r o-3-(2-p r op yn yloxy)fu r a n -2(2H )-on e was pre-
pared from R-hydroxybutyrolactone by O-alkylation with pro-
pargyl bromide according to the general alkylation procedure
given for the preparation of 1 to afford the propargyl ether in
72% yield after flash chromatography with 18% EtOAc/
hexanes: 1H NMR (300 MHz, CDCl3) δ 4.46 (dd, J ) 2.44,
13.67 Hz, 1H), 4.44-4.36 (m, 2H), 4.24 (m, 1H), 2.61-2.51 (m,
2H), 2.48 (t, J ) 2.44 Hz, 1H), 2.35-2.22 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 174.65, 78.52, 75.56, 71.70, 65.38, 57.44,
29.63.
Dih yd r o-3-[[(3-(tr im eth ylsilyl)-2-p r op yn yl]oxy]fu r a n -
2(2H)-on e was prepared according to the following general
procedure. Dihydro-3-(2-propynyloxy)furan-2(2H)-one (0.56 g,
4.0 mmol), dissolved in 5 mL of dry THF, was added dropwise
via cannula to a -78 °C cooled solution of LDA (4.4 mmol, 1
M in THF). The resultant reaction mixture was stirred for 5
min at reduced temperature, and then TMSCl (0.65 g, 6.0
mmol) was added rapidly. The reaction mixture was stirred
for an additional 15 min, and then the reaction was quenched
at -78 °C with saturated aqueous NH4Cl. The silylated
alkyne was obtained in 42% yield after an aqueous workup
and flash chromatography with 18% EtOAc/hexanes: 1H NMR
(300 MHz, CDCl3) δ 4.46 (d, J ) 5.13 Hz, 2H), 4.44 (m, 2H),
4.26 (m, 1H), 2.54 (m, 1H), 2.30 (m, 1H), 0.16 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 174.71, 100.11, 92.76, 71.56, 65.36, 58.31,
29.71, -0.26 (3).
Eth yl 2-(2-ch lor oeth yl)-2-oxa -6-(tr im eth ylsilyl)-5-h ex-
yn oa te was prepared from dihydro-3-[3-(trimethylsilyl)-2-
propynyl]oxy]furan-2(2H)-one according to the general lactone
ring opening/ester formation procedure outlined for the prepa-
ration of 5 to afford the desired ester in 70% yield after flash
chromatography with 15% EtOAc/hexanes: 1H NMR (300
MHz, CDCl3) δ 4.36 (d, J ) 16.4 Hz, 1H), 4.35 (m, 1H), 4.19
(d, J ) 16.1 Hz, 1H), 3.28 (t, J ) 7.08 Hz, 2H), 3.65 (m, 2H),
2.17 (m, 2H), 1.27 (t, J ) 7.08 Hz, 3H), 0.16 (s, 9H).
E t h yl 2-(2-iod oet h yl)-2-oxa -6-(t r im et h ylsilyl)-5-h ex-
yn oa te (10) was prepared from ethyl 2-(2-chloroethyl)-2-oxa-
6-(trimethylsilyl)-5-hexynoate according to the general proce-
dure outlined for the preparation of 3 to afford 10 in 70% yield
after flash chromatography with 10% EtOAc/hexanes: 1H
NMR (300 MHz, CDCl3) δ 4.36 (d, J ) 16.12 Hz, 1H), 4.34-
4.16 (m, 3H), 3.65 (m, 1H), 3.28 (t, J ) 7.08 Hz, 2H), 2.23 (m,
2H), 1.28 (t, J ) 7.08 Hz, 3H), 0.17 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 171.45, 100.42, 92.56, 73.48, 76.39, 61.25, 58.52,
36.66, 14.21, -0.19 (3).
(1R *,5S *,2E )-2-[(Tr im e t h ylsilyl)m e t h yle n e ]-4-oxa -
bicyclo[3.2.0]h ep ta n -1-ol (11) was prepared from 10 accord-
ing to the general procedure outlined for the preparation of
7b to afford 11 in 55% yield after flash chromatography with
20% EtOAc/hexanes and Kugelrohr distillation (ot 100-110
°C/0.5 mmHg); 1H NMR (300 MHz, CDCl3) δ 5.87 (t, J ) 2.44
Hz, 1H), 4.68 (dd, J ) 2.20, 14.41 Hz, 1H), 4.54 (dd, J ) 2.44,
14.16 Hz, 1H), 4.45 (m, 1H), 2.06-1.97 (m, 4H), 1.56 (m, 1H),
0.10 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 162.73, 121.19, 84.10,
81.90, 69.71, 28.46, 18.21, -0.80 (3); IR (neat) 3383.3, 1634.0,
838.3 cm-1; HRMS calcd for C10H17O2Si (M - H+) 197.0998,
found 197.0991; LRMS (EI+) m/ z 197 (61), 184 (74), 169 (100),
155 (96), 155 (96), 127 (32), 75 (100). Anal. Calcd for C10H18O2-
Si: C, 53.39; H, 7.24. Found: C, 53.34; H, 7.64.
70.50, 28.12, 18.27; IR (neat) 3418.0, 1668.1 cm-1; HRMS calcd
for C7H10O2 126.0681, found 126.0625; LRMS (EI) m/ z 125
(19), 111 (100), 98 (99), 69 (84), 41 (96), 27 (36).
(1R*,6S*,7R*)-7-[(2-Br om o-2-pr open yl)oxy]-9-oxabicyclo-
[4.3.0]n on -2-en e-8-on e was prepared from (1R*,6R*,7S*/R*)-
7-hydroxy-9-oxabicyclo[4.3.0]non-2-en-8-one24 according to the
following general procedure. The R-hydroxylactone (0.928 g,
6.03 mmol) in 5 mL of dry DMF was added dropwise to a
stirred, 0 °C, slurry of NaH (0.26 g of a 60% dispersion in
mineral oil, 6.6 mmol) in 10 mL of dry DMF. The reaction
mixture was maintained at 0 °C until H2 evolution had ceased
and substrate addition was complete. Then, the reaction
mixture was warmed to rt and allowed to stir for 2 h. After
this period of time, the reaction mixture was cooled to 0 °C,
and 2,3-dibromopropene (1.81 g, 9.04 mmol) was added neat.
The reaction mixture was warmed to rt and allowed to stir
for 12 h at ambient temperature. After this period of stirring,
the reaction mixture was quenched with saturated aqueous
NH4Cl and then subjected to an aqueous workup. Flash
chromatography with 8% EtOAc/hexanes afforded a mixture
of diastereomers epimeric at C-7 (1.21 g, 4.46 mmol) in 74%
yield: 1H NMR (400 MHz, CDCl3) δ 6.20 (m, 1H), 6.01 (m,
1H), 5.90 (m, 1H), 5.66 (m, 1H), 4.61 (m, 1H), 4.47 (m, 1H),
4.41 (m, 2H), 2.70 (m, 1H), 2.19 (m, 1H), 2.02-1.87 (m, 2H),
1.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.11, 136.22,
128.11, 121.66, 118.77, 76.59, 74.11, 70.98, 38.14, 23.11, 17.70.
(1R*,6S*,7S*)-7-[(2-Br om o-2-pr open yl)oxy]-9-oxabicyclo-
[4.3.0]n on -2-en e-8-on e: 1H NMR (400 MHz, CDCl3) δ 6.00
(m, 1H), 5.97 (m, 1H), 5.87 (m, 1H), 5.68 (m, 1H), 4.95 (m,
1H), 4.46 (m, 2H), 3.98 (d, J ) 7.93 Hz, 1H), 2.71 (m, 1H),
2.13 (m, 2H), 1.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
174.60, 133.08, 128.64, 124.02, 119.97, 74.34, 73.81, 73.77,
39.67, 21.01, 21.18.
Eth yl (1R*,2R*/S*)-5-br om o-2-(2-ch lor o-3-cycloh exen yl)-
3-oxa -5-h exen oa te (13) was prepared from a mixture of the
above bicyclic R-oxygenated lactones according to the general
lactone ring opening/esterification procedure outlined for the
preparation of 5 to afford an unseparable mixture of diaster-
eomeric 13 in 52% yield after flash chromatography with 3%
EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 5.96-5.68 (m,
3H), 5.62 (m, 1H), 4.82 (m, 0.34H), 4.56 (m, 0.66H), 4.23-4.18
(m, 3H), 4.08-3.81 (m, 2H), 2.64 (m, 0.66H), 2.43 (m, 0.34H),
2.15-1.86 (m, 3H), 1.71-1.42 (m, 1H), 1.29 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.93, 170.82, 130.88, 130.47, 130.14,
129.29, 128.95, 128.37, 128.08, 127.89, 119.04, 118.86, 80.98,
80.87, 78.35, 74.39, 74.36, 74.33, 61.18, 55.80, 55.00, 54.09,
45.78, 39.01, 37.73, 31.72, 31.08, 23.70, 23.55, 23.00, 19.83,
14.30, 14.22; HRMS calcd for C13H19BrClO2 (M + H+) 337.0206,
found 337.0156; LRMS (EI+) m/ z 301 (100), 265 (82), 257 (80),
222 (98), 200 (71).
(1R*,2S*/R*,7S*/R*,8R*)-9-Oxa -11-m et h ylen et r icyclo-
[6.3.02,7]u n d ec-3-en e-1-ol (14) was prepared from a diaster-
eomeric mixture of 13 according to the general procedure
outlined for the preparation of 7b to afford an inseparable 2:1
mixture of 14 in 58% combined yield after flash chromatog-
raphy with 25% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3)
δ 6.10 (m, 0.34H), 5.86 (m, 1H), 5.71 (m, 0.66H), 5.37 (t, J )
2.20 Hz, 0.34H), 5.17 (dt, J ) 2.69, 5.13 Hz, 1.66H), 4.72-
4.57 (m, 1.3H), 4.49-4.43 (m, 1.3H), 4.15 (d, J ) 2.44 Hz,
0.40H), 2.81 (m, 1H), 2.67 (m, 0.60H), 2.26-2.00 (m, 2.4H),
1.86-1.5 (m, 1H), 1.70-1.58 (m, 1H), 1.47-1.30 (m, 1H).
Major diastereomer: 13C NMR (100 MHz, CDCl3) δ 151.17,
129.41, 125.16, 108.15, 85.30, 84.39, 74.33, 39.22, 30.37, 22.26,
18.92. Minor diastereomer 13C NMR (100 MHz, CDCl3) δ
153.28, 132.05, 124.54, 107.63, 87.47, 82.62, 71.08, 38.14,
30.54, 21.43, 20.11; IR (neat) 3389.9, 3021.9, 1667.1, 1644.2
cm-1; HRMS calcd for C11H14O2 178.0994, found 178.1004;
LRMS (NH3) m/ z 178 (41), 161 (71), 149 (100), 131 (34), 121
(80), 115 (28), 109 (58).
Meth yl 3-Hydr oxy-2-(3-ch lor opr opyl)pen tan oate. Meth-
yl 5-chloropentanoate (6.02 g, 40.0 mmol) in 5 mL of dry THF
was added slowly dropwise to a -78 °C 1 M solution of LDA
(44.0 mmol). The reaction mixture was stirred at -78 °C for
0.5 h before propionaldehyde (2.90 g, 50 mmol) was added neat
(1R*,5S*)-2-Meth ylen e-4-oxa bicyclo[3.2.0]h ep ta n -1-ol
(12) was prepared from 6 according to the general procedure
outlined for the preparation of 7b to afford 25 in 69% yield
after flash chromatography with 35% EtOAc/hexanes and
Kugelrohr distillation (ot 100-110 °C/8 mmHg); 1H NMR (400
MHz, CDCl3) δ 5.34 (m, 1H), 5.15 (m, 1H), 4.61 (m, 1H), 4.46
(m, 1H), 2.16 (s, 1H), 2.10-2.03 (m, 3H), 1.63-1.56 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 154.43, 107.02, 85.05, 81.17,
(24) Lubineau, A.; Auge, J .; Grand, E.; Lubin, N. Tetrahedron 1994,
50, 10265.

2952 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and Harris
via cannula. The resultant reaction mixture was stirred at
-78 °C for 0.5 h and then quenched at -78 °C with saturated
aqueous NH4Cl. Kugelrohr distillation (ot 110-120 °C/0.05
mmHg) after an aqueous workup provided the desired â-hy-
droxy ester compound in 97% yield (8.07 g, 38.8 mmol): 1H
NMR (400 MHz, CDCl3) δ 3.70 (s, 3H), 3.58 (m, 1H), 3.52 (t, J
) 6.11 Hz, 2H), 2.46 (m, 1H), 2.30 (bs, 1H), 1.79 (m, 4H), 1.46
(m, 2H), 0.95 (m, 3H); 13C NMR (100 MHz, CDCl3), major, δ
175.50, 73.58, 51.69, 49.79, 44.41, 30.25, 28.32, 26.71, 10.00;
13C NMR (100 MHz, CDCl3), minor, δ 175.39, 73.38, 51.76,
49.95, 44.56, 30.59, 27.27, 24.32, 10.21.
6.69 Hz, 12.85H), 4.02 (m, 2H), 3.37 (m, 1H), 2.48 (bs, 1H),
2.30 (m, 1H), 1.98 (m, 1H), 1.88-1.78 (m, 3H), 1.61 (m, 2H),
1.00 (d, J ) 6.96 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.26,
115.90, 113.94, 87.66, 72.60, 64.59, 41.36, 32.53, 30.58, 21.54,
11.24; IR (neat) 3556.2, 1644.2, 1423.7 cm-1; HRMS calcd for
C11H18O3 198.1256, found 198.1253; LRMS (EI+) m/ z 198 (2),
181 (10), 157 (48), 140 (100), 115 (31), 97 (52), 55 (61), 41 (97).
(1R*,2S*,5R*)-2-Meth yl-4-oxa -5-m eth oxybicyclo[3.3.0]-
1
octa n -1-ol (18b): H NMR (400 MHz, CDCl3) δ 3.99 (t, J )
8.30 Hz, 1H), 3.35 (s, 3H), 3.36 (m, 1H), 2.42 (bs, 1H), 2.25
(m, 1H), 1.96 (m, 1H), 1.86-1.77 (m, 3H), 1.65-1.57 (m, 2H),
0.99 (d, J ) 6.96 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 114.10,
87.49, 72.54, 50.97, 41.40, 31.82, 30.75, 21.43, 11.25; IR (neat)
3550.6 cm-1; HRMS calcd for C9H16O3 172.1094, found 172.1091;
LRMS (EI+) m/ z 172 (11), 157 (15), 140 (100), 125 (34), 112
(68), 97 (94), 83 (99), 71 (74), 55 (83), 41 (95), 27 (41).
Meth yl 5-ch lor o-2-m eth ylp en ta n oa te (19) was prepared
according to the general procedure outlined for the preparation
of 3 by alkylation of methyl 5-chloropentanoate with methyl
iodide to afford 19 in 65% yield after flash chromatography
with 5% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 3.66
(s, 3H), 3.50 (t, J ) 6.35 Hz, 2H), 2.44 (m, 1H), 1.80-1.55 (m,
4H), 1.15 (d, J ) 7.08 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
176.70, 51.61, 44.68, 38.79, 30.30, 30.22, 17.14.
Meth yl 3-h ydr oxy-2-(3-ch lor opr opyl)pen tan oate, m eth -
a n esu lfon yl ester was prepared from methyl 3-hydroxy-2-
(3-chloropropyl)pentanoate according to the following general
procedure. To a solution of the alcohol (4.16 g, 20.0 mmol) in
30 of dry CH2Cl2 were added successively methanesulfonyl
chloride (2.52 g, 22.0 mmol) and triethylamine (2.23 g, 22.0
mmol). The resultant reaction mixture was stirred at 0 °C
for 0.5 h and then at rt for 2 h. The reaction mixture was
quenched with 0.1 N HCl after this period of stirring and
subjected to an aqueous workup to afford the desired mesylate
(5.60 g, 19.5 mmol) in 98% yield: 1H NMR (300 MHz, CDCl3)
δ 4.85 (m, 1H), 3.71 (s, 3H), 3.52 (m, 2H), 3.02 (s, 3H), 2.68-
2.84 (m, 1H), 1.83-1.71 (m, 6H), 0.99 (t, J ) 7.57 Hz, 3H); IR
(neat) 1731.8, 1455.5, 1337.9 cm-1
.
Meth yl 5-ch lor o-2-for m yl-2-m eth ylp en ta n oa te was pre-
pared according to the following general procedure. Methyl
5-chloro-2-methylpentanoate, 19 (1.65 g, 10.0 mmol), in 10 mL
of dry THF was added slowly dropwise via cannula to a -78
°C cooled solution of LDA (11.0 mmol, 1 M in THF). After the
addition of the ester was complete, the reaction mixture was
stirred for an additional 0.5 h, and then ethyl formate (0.89 g,
12.0 mmol) was added rapidly. The resultant reaction mixture
was stirred for 0.5 h at reduced temperature and then
quenched with saturated aqueous NH4Cl. The reaction mix-
ture was subjected to an aqueous workup followed by flash
chromatography with 15% EtOAc/hexanes to afford the desired
formyl ester in 60% yield after Kugelrohr distillation (ot 120-
140 °C/0.5 mmHg); 1H NMR (300 MHz, CDCl3) δ 9.67 (s, 1H),
3.75 (s, 3H), 3.51 (t, J ) 5.98 Hz, 2H), 2.01-1.68 (m, 4H), 1.31
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.85, 172.33, 57.15,
52.57, 44.58, 31.34, 27.46, 17.14.
Meth yl 2-for m yl-5-iod o-2-m eth ylp en ta n oa te (20) was
prepared from methyl 5-chloro-2-formyl-2-methylpentanoate
according to the general procedure outlined for the preparation
of 3 to afford 20 in 85% yield after flash chromatography with
12% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 9.66 (s,
1H), 3.75 (s, 3H), 3.14 (m, 2H), 1.96-1.75 (m, 4H), 1.30 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 198.78, 172.26, 57.06, 52.59,
34.82, 28.28, 17.18, 5.44.
Meth yl 2-F or m yl-5-iod o-2-m eth ylp en ta n oa te, Bis(2-
p r op en yloxy) Aceta l (21). Gen er a l P r oced u r e for th e
P r ep a r a tion of Bis(2-p r op en yloxy) Aceta ls. Trimethyl-
silyl triflate (TMSOTf) (86.0 mg, 0.38 mmol) was added via
syringe to a 0 °C cooled solution of 20 (0.28 g, 1.0 mmol) and
O-[(trimethylsilyl)allyl] ether (0.20 g, 1.5 mmol) in 3 mL of
dry CH2Cl2. The reaction mixture was stirred subsequently
for 1 h at 0 °C and then for 2 h at rt before adding successively
O-[(trimethylsilyl)allyl] ether (0.20 g, 1.5 mmol) and TMSOTf
(86.0 mg, 0.38 mmol). The reaction mixture was then stirred
for 18-24 h at rt before quenching with saturated aqueous
NaHCO3 and subjecting the reaction mixture to an aqueous
workup. Flash chromatography with 8% EtOAc/hexanes af-
forded the desired bis(allyloxy) hemiacetal 31 (0.36 g, 0.95
mmol) in 95% yield: 1H NMR (400 MHz, CDCl3) δ 5.84 (m,
2H), 5.30-5.11 (m, 4H), 4.66 (s, 1H), 4.23 (m, 2H), 4.04 (m,
2H), 3.65 (s, 3H), 3.11 (t, J ) 6.56 Hz, 2H), 1.78 (m, 2H), 1.61
(m, 2H), 1.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.91,
134.27, 134.20, 117.02, 116.32, 106.80, 71.50, 71.37, 52.09,
51.76, 36.16, 28.73, 15.24, 6.65.
(1R *,2S *,5 R *,6 R *)-5 -(2 -P r o p e n y l o x y )-4 -o x a -2 ,6-
d im eth ylbicyclo[4.3.0]n on a n -1-ol (22) was prepared ac-
cording to the general procedure outlined for the preparation
of 7b to afford 22 as a 17:1 mixture of diastereomeric products
in 71% combined yield (22, major diastereomer, 59% isolated
yield) after flash chromatography with 8% EtOAc/hexanes: 1H
NMR (400 MHz, CDCl3) δ 5.87 (dq, J ) 5.26, 15.77 Hz, 1H),
5.25 (dq, J ) 1.71, 17.39 Hz, 1H), 5.11 (dq, J ) 1.71, 10.44
Meth yl 2-(3-Ch lor opr opyl)-2-pen ten oate (15). The crude
mesylate ester, (5.60 g, 19.5 mmol), was taken up in 20 mL of
THF and cooled to 0 °C while DBU (3.3 g, 21.5 mmol) was
added via syringe. The resultant reaction mixture was stirred
at 0 °C for 1 h and then warmed to rt with continued stirring
for 12 h. The reaction mixture was quenched after this period
of time with saturated aqueous NH4Cl and subjected to an
aqueous workup. Flash chromatography with 2% EtOAc/
hexanes afforded the desired olefin 15 (3.12 g, 16.4 mmol) in
84% yield: 1H NMR (300 MHz, CDCl3) δ 6.79 (t, J ) 7.57 Hz,
1H), 3.71 (s, 3H), 3.50 (t, J ) 6.59 Hz, 2H), 2.42 (m, 2H), 2.21
(m, 2H), 1.86 (m, 2H), 1.04 (t, J ) 6.59 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 168.13, 145.68, 129.96, 51.68, 44.62, 31.96,
23.97, 21.90, 13.30.
Meth yl 2-(3-iodopr opyl)-2-pen ten oate was prepared from
15 according to the general procedure outlined for the prepa-
ration of 3 to afford the desired iodide in 91% yield after flash
column chromatography with 3% EtOAc/hexanes: 1H NMR
(400 MHz, CDCl3) δ 6.58 (t, J ) 7.55 Hz, 1H), 3.51 (s, 3H),
2.96 (t, J ) 6.86 Hz, 2H), 2.18 (m, 2H), 2.02 (m, 2H), 1.72 (m,
2H), 1.07 (t, J ) 6.86 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.10, 145.63, 129.79, 51.69, 33.01, 27.55, 22.03, 13.33, 6.36.
Meth yl 5-Iod o-2-oxop en ta n oa te (16). Gen er a l P r oce-
d u r e for Ozon olysis of Olefin s w ith Red u ctive Wor k u p .
Compound 16 was prepared from methyl 2-(3-iodopropyl)-2-
pentenoate according to the following general procedure.
Ozone was bubbled through a solution of the iodide (0.84 g,
3.0 mmol) in 10 mL of a 5:1 mixture of CH2Cl2/MeOH and
catalytic NaHCO3 until a blue color persisted. The reaction
mixture was then purged with argon for 5 min before adding
DMS (1.86 g, 30.0 mmol) and allowing the reaction mixture
to warm to rt and stir for 18 h. After this period of time, the
reaction mixture was concentrated in vacuo and subjected to
flash chromatography with 10% EtOAc/hexanes to afford 16
(0.50 g, 1.95 mmol) in 66% yield: 1H NMR (400 MHz, CDCl3)
δ 3.86 (s, 3H), 3.22 (t, J ) 6.67 Hz, 2H), 3.00 (t, J ) 6.96 Hz,
2H), 2.14 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 192.62,
161.03, 53.08, 39.93, 26.41, 5.06.
Meth yl 5-iod o-2-oxop en ta n oa te, d ia llyl k eta l (17) was
prepared from 16 according to the general procedure outlined
for the preparation of 21 to afford 17 in 72% yield after flash
chromatography with 4% EtOAc/hexanes: 1H NMR (400 MHz,
CDCl3) δ 5.90 (m, 2H), 5.33-5.15 (m, 4H), 4.01 (m, 4H), 3.78
(s, 3H), 3.15 (t, J ) 6.69 Hz, 2H), 2.03 (m, 2H), 1.77 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 169.21, 133.71 (2), 117.03 (2),
101.53 (2), 63.63, 52.52, 35.63, 27.38, 5.85.
(1R*,2S*,5R*)-2-Meth yl-4-oxa-5-(2-pr open yloxy)bicyclo-
[3.3.0]octa n -1-ol (18a ) was prepared from 17 according to the
general procedure outlined for the preparation of 7b to afford
18a and 18b in 57% combined yield after flash chromatogra-
phy with 10% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ
5.92 (m, 1H), 5.24 (m, 1H), 5.12 (m, 1H), 4.20 (ddt, J ) 1.61,

Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2953
Hz, 2H), 4.40 (s, 1H), 4.13 (ddt, J ) 13.53, 4.47, 1.61 Hz, 1H),
3.82 (ddt, J )15.01, 5.30, 1.53 Hz, 1H), 3.40-3.32 (m, 2H),
2.15 (m, 1H), 1.91 (m, 1H), 1.75-1.66 (m, 3H), 1.57 (m, 1H),
1.44 (m, 1H), 1.07 (s, 3H), 0.83 (d, J ) 6.82 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 134.61, 115.62, 105.11, 82.53, 68.17, 63.33,
48.95, 35.98, 33.87, 33.06, 20.56, 19.44, 10.86; IR (neat) 3345.0,
1640.6 cm-1; HRMS calcd for C13H22O3 226.1569, found
226.1542; LRMS (EI+) m/ z 226 (100), 185 (72), 122 (52), 109
(54), 98 (72), 69 (48), 55 (37), 41 (100). Anal. Calcd for
C13H22O3: C, 68.99; H, 9.80. Found: C, 69.24; H, 9.89.
Met h yl 2-for m yl-5-iod o-2-m et h ylp en t a n oa t e, b is(2-
p r op yn yloxy) a ceta l was prepared from 20 according to the
general procedure for the preparation of 21 (O-[(trimethylsilyl)-
propargyl] ether) to afford the desired bis(propargyloxy) acetal
in 96% yield after flash chromatography with 12% Et-
OAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 4.97 (s, 1H), 4.38
(m, 2H), 4.32 (m, 2H), 3.69 (s, 3H), 3.11 (t, J ) 5.86 Hz, 2H),
2.49 (t, J ) 2.44 Hz, 1H), 2.46 (t, J ) 2.44 Hz, 1H), 1.81-1.57
(m, 4H), 1.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.50,
104.81, 79.17, 79.12, 75.29, 74.98, 57.49, 57.03, 51.90, 51.65,
36.16, 28.59, 15.30, 6.42.
Met h yl 2-for m yl-5-iod o-2-m et h ylp en t a n oa t e, bis[[3-
(tr im eth ylsilyl)-2-p r op yn yl]oxy] a ceta l (23) was prepared
according to the general procedure outlined for the preparation
of dihydro-3-[[3-(trimethylsilyl)-2-propynyl]oxy]furan-2(2H)-
one except 2 equiv of LDA and 2 equiv of TMSCl were
employed to afford 23 in 47% yield after flash chromatography
with 5% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 4.94
(s, 1H), 4.44-4.24 (m, 4H), 3.69 (s, 3H), 3.11 (m, 2H), 1.82-
1.53 (m, 4H), 1.17 (s, 3H), 0.17 (s, 9H), 0.17 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 174.60, 104.56, 101.13, 101.01, 92.23,
91.92, 58.30, 57.72, 51.87, 51.68, 36.10, 28.70, 15.39, 6.39,
-0.17 (3), -0.22 (3).
(1R*,2E, 5R*,6R*)-6-Met h yl-4-oxa -2-[(t r im et h ylsilyl)-
m eth ylen e]-5-[[(3-(tr im eth ylsilyl)-2-pr opyn yl]oxy]bicyclo-
[4.3.0]n on a n -1-ol (24) was prepared according to the general
procedure outlined for the preparation of 7b to afford 24 as a
single diastereomeric product in 68% yield after flash chro-
matography with 6% EtOAc/hexanes: 1H NMR (300 MHz,
CDCl3) δ 5.77 (s, 1H), 4.60 (s, 1H), 4.33 (m, 1H), 4.20 (m, 2H),
2.33 (m, 1H), 1.78 (m, 3H), 1.54 (m, 2H), 1.41 (m, 1H), 1.21
(m, 1H), 0.99 (s, 3H), 0.12 (s, 9H), 0.12 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 154.82, 122.18, 103.96, 101.39, 91.25, 83.39,
62.07, 55.74, 52.14, 39.42, 33.20, 22.17, 19.23, 0.25 (3), -0.19
(3); IR (neat) 3499.9, 2177.3, 1620.8, 1614.5, 840.9 cm-1; HRMS
calcd for C19H34O3Si2 366.2047, found 366.2057; LRMS (EI+)
m/ z 366 (39), 351 (100), 336 (36), 321 (53), 305 (49), 239 (15),
195 (38), 98 (47), 73 (98). Anal. Calcd for C19H34O3Si2: C,
62.24; H, 9.35. Found: C, 62.49; H, 9.23.
Meth yl 2-(h yd r oxym eth yl)-5-iod o-2-m eth ylp en ta n oa te
(25) was prepared from 20 according to the following general
procedure. To a stirred solution of NaBH4 (0.13 g, 3.50 mmol)
in 5 mL of dry MeOH was added the substrate 20 (1.04 g, 3.82
mmol) dropwise in 2 mL of dry MeOH. The reaction mixture
was then warmed to rt and allowed to stir for 8 h at ambient
temperature. The reaction was quenched by the careful
addition of saturated aqueous NH4Cl. The desired alcohol 25
(1.04 g, 3.64 mmol) was obtained in 96% yield after an aqueous
workup and flash column chromatography with 25% Et-
OAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 3.70 (s, 3H), 3.64
(dd, J ) 7.23, 11.24 Hz, 1H), 3.53 (dd, J ) 6.16, 11.24 Hz,
1H), 3.13 (t, J ) 6.69 Hz, 2H), 2.25 (t, J ) 6.42 Hz, 1H), 1.81-
1.56 (m, 4H), 1.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.07,
68.08, 52.04, 47.28, 36.63, 28.51, 19.60, 6.30.
workup. Flash column chromatography with 4-5% EtOAc/
hexanes afforded the desired allyl ether 26 (0.605 g, 1.85 mmol)
in 51% yield: 1H NMR (400 MHz, CDCl3) δ 5.83 (m, 1H), 5.19
(m, 2H), 3.94 (d, J ) 5.62 Hz, 2H), 3.67 (s, 3H), 3.46 (d, J )
9.10 Hz, 1H), 3.39 (d, J ) 8.83 Hz, 1H), 3.12 (m, 2H), 1.74 (m,
3H), 1.55 (m, 1H), 1.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
176.04, 134.66, 116.80, 75.21, 72.27, 51.87, 46.76, 36.66, 28.70,
19.97, 6.52.
(1R*,2S*,6R*)-2,6-Dim eth yl-4-oxa bicyclo[4.3.0]n on a n -
1-ol (27) was prepared from 26 according to the general
procedure outlined for the preparation of 7b to afford 27 in
65% yield as an 11:1 mixture of diastereomeric products
epimeric at C-2. Major diastereomer: 1H NMR (400 MHz,
CDCl3) δ 3.75 (ddd, J ) 1.07, 5.09, 11.51 Hz, 1H), 3.38 (m,
1H), 3.14-3.02 (m, 2H), 2.01 (m, 1H), 1.92-1.51 (m, 5H), 1.27
(m, 1H), 1.13 (bs, 1H), 1.09 (s, 3H), 0.82 (d, J ) 6.69 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 83.02, 75.72, 72.09, 46.16, 36.46,
33.83, 30.73, 18.80, 17.83, 10.65; IR (neat) 3452.1 cm-1; HRMS
calcd for C10H18O2 170.1307, found 170.1316; LRMS (EI+) m/ z
170 (42), 128 (24), 111 (96), 97 (33), 84 (38), 69 (100), 55 (53),
41 (77), 28 (26). Anal. Calcd for C10H18O2: C, 70.55; H, 10.66.
Found: C, 70.14; H, 10.41.
Eth yl 2-Oxo-1-[3-[(ter t-bu tyld im eth ylsilyl)oxy]p r op yl]-
cyclop en t a n eca r boxyla t e. Gen er a l P r oced u r e for t h e
Alk yla tion of â-Keto Ester s a n d â-Keto La cton es. Ethyl
2-oxocyclopentanecarboxylate (6.25 g, 40.0 mmol) in 50 mL of
dry DMF was added neat via syringe to a 0 °C cooled slurry
of NaH (1.84 g of a 60% dispersion in mineral oil, 46.0 mmol),
and the resultant reaction mixture was stirred at 0 °C for 1 h
and then at rt for 2 h. Then, the resultant reaction mixture
was cooled to 0 °C, and the TBS ether of 3-bromo-1-propanol
was added (15.2 g, 60.0 mmol). The reaction mixture was
warmed to rt, heated for 18 h at 50-60 °C, and then quenched
after this period with saturated aqueous NH4Cl. The desired
alkylated keto ester (10.96 g, 30.1 mmol) was obtained in 75%
yield after an aqueous workup and flash chromatography with
4% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 4.13 (dq, J
) 2.14, 3.48 Hz, 2H), 3.57 (m, 2H), 2.50 (m, 1H), 2.38 (m, 1H),
2.22 (m, 1H), 2.02-1.84 (m, 4H), 1.60-1.38 (m, 3H), 1.22 (t, J
) 6.96 Hz, 3H), 0.86 (s, 9H), 0.01 (s, 3H), 0.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 214.93, 171.03, 63.01, 61.32, 60.18, 37.93,
32.79, 30.19, 28.21, 25.91 (3), 19.57, 18.29, 14.08, -5.34 (2).
Eth yl (1R*,2S*)-1-[3-[(ter t-Bu tyld im eth ylsilyl)oxy]p r o-
p yl]-2-h yd r oxy-2-m eth ylcyclop en ta n eca r boxyla te (28).
Gen er a l P r oced u r e for th e Ad d ition of Gr ign a r d Re-
a gen ts to â-Keto Ester s a n d â-Keto La cton es. Compound
28 was prepared from ethyl 2-oxo-1-[3-[(tert-butyldimethylsi-
lyl)oxy]propyl]cyclopentane carboxylate according to the fol-
lowing procedure. Methylmagnesium bromide (2.0 mL of a
3.0 M solution in Et2O, 6.0 mmol) was added to the â-keto ester
(1.83 g, 5.0 mmol) in 10 mL of dry THF cooled to -78 °C. The
resultant reaction mixture was stirred at -78 °C for 0.5 h and
then allowed to warm to rt. TLC analysis after reaching rt
revealed the complete consumption of the starting keto ester
and formation of a major, lower Rf product. The reaction
mixture was quenched at rt by the careful addition of saturated
aqueous NH4Cl. Flash chromatography with 10% EtOAc/
hexanes after an aqueous workup afforded 28 (1.55 g, 4.50
mmol) as a single diastereomeric product (1H NMR) in 90%
yield: 1H NMR (400 MHz, CDCl3) δ 4.14 (m, 2H), 3.58 (m,
2H), 2.11 (m, 1H), 1.98 (s, 1H), 1.95 (m, 1H), 1.84 (m, 1H),
1.76-1.62 (m, 4H), 1.55-1.36 (m, 2H), 1.26 (t, J ) 6.96 Hz,
3H), 1.22 (m, 1H), 1.19 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 175.73, 80.88, 63.34, 60.33, 59.44,
37.39, 29.21, 28.77, 28.07, 25.91 (3), 25.81, 18.29, 18.02, 14.30,
-5.30 (2).
Meth yl 2-(3-iod op r op yl)-2-m eth yl-4-oxo-6-h ep ten oa te
(26) was prepared from 25 according to the following general
procedure.25 To 25 (1.04 g, 3.64 mmol) in 3 mL of dry CH2Cl2
cooled to 0 °C in an ice bath was added successively the
trichloroacetimidate of allyl alcohol (0.80 mL of a 5 M solution
in hexanes, 4.0 mmol) followed by 30 µL of BF3‚OEt2. The
resultant reaction mixture was stirred at 0 °C for 1 h and then
warmed to rt and stirred at ambient temperature overnight.
The reaction mixture was quenched after this period with
saturated aqueous NaHCO3 and subjected to an aqueous
Eth yl (1R*,2S*)-1-[3-[(ter t-bu tyld im eth ylsilyl)oxy]p r o-
p yl]-2-m et h yl-2-(2-p r op en yloxy)cyclop en t a n eca r b oxyl-
a te (29) was prepared from 28 according to the general
procedure outlined for the preparation of 25 to afford 29 in
56% yield after flash chromatography with 2% EtOAc/hex-
anes: 1H NMR (400 MHz, CDCl3) δ 5.88 (m, 1H), 5.26 (m, 1H),
5.05 (m, 1H), 4.08 (m, 2H), 3.96-3.82 (m, 2H), 3.56 (m, 2H),
2.21 (m, 1H), 1.92 (m, 2H), 1.72-1.54 (m, 5H), 1.45-1.30 (m,
2H), 1.23 (t, J ) 6.96 Hz, 3H), 1.14 (s, 3H), 0.87 (s, 9H), 0.02
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 175.89, 136.12, 114.61,
(25) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J . Chem. Soc., Perkin
Trans. 1 1985, 2247.

2954 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and Harris
85.83, 63.83, 62.99, 61.55, 60.21, 35.01, 31.82, 29.82, 27.58,
25.97 (3), 19.92, 19.24, 18.35, 14.19, -5.26 (2).
7.38-7.18 (m, 5H), 6.58 (m, 0.3H), 6.51 (m, 0.67H), 6.25 (dt, J
) 5.36, 15.80 Hz, 0.30H), 5.79 (dt, J ) 11.78, 6.16 Hz, 0.67H),
4.22-4.00 (m, 4H), 3.19-3.13 (m, 2H), 2.18 (m, 1H), 2.00 (m,
2H), 1.76-1.54 (m, 7H), 1.25 (m, 3H), 1.15 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 175.51, 136.84, 130.30, 130.06, 128.67,
128.47, 128.17, 127.56, 127.31, 127.00, 126.32, 86.15, 62.69,
61.30, 61.18, 60.43, 60.40, 59.33, 34.83, 34.76, 32.71, 32.64,
32.02, 30.42, 30.33, 20.13, 20.10, 19.18, 14.24, 14.21, 7.34, 7.15;
LRMS (EI+) m/ z 439 (21), 426 (82), 382 (11), 339 (19), 323
(97), 249 (83), 197 (26), 133 (68), 117 (100), 91 (64), 77 (69), 55
(42), 43 (92), 29 (71).
E t h yl (1R*,2S*)-1-(3-H yd r oxyp r op yl)-2-m et h yl-2-(2-
p r op en yloxy)cyclop en ta n eca r boxyla te. Gen er a l P r oce-
d u r e for t h e R em ova l of t h e TBS P r ot ect in g Gr ou p .
Amberlyst-15 was added to a stirred solution of 29 (0.10 g,
0.26 mmol) in 2 mL of of absolute ethanol at ambient
temperature. After 3 h, TLC analysis of the reaction mixture
showed complete consumption of the starting TBS ether and
formation of a single, lower Rf product. The reaction mixture
was filtered through a plug of Celite and then concentrated
in vacuo. Flash chromatography with 25% EtOAc/hexanes
afforded the desired primary alcohol (0.07 g, 0.26 mmol) in
quantitative yield: 1H NMR (400 MHz, CDCl3) δ 5.87 (m, 1H),
5.25 (m, 1H), 5.07 (m, 1H), 4.10 (m, 2H), 3.88 (m, 2H), 3.60
(m, 2H), 2.21 (m, 1H), 1.96 (m, 2H), 1.74-1.47 (m, 6H), 1.37
(m, 2H), 1.24 (t, J ) 7.32 Hz, 3H), 1.15 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 175.90, 136.10, 114.78, 85.97, 63.47, 63.01,
61.58, 60.36, 34.82, 31.84, 29.24, 27.42, 20.03, 19.14, 14.19.
Eth yl (1R*,2S*)-1-(3-Br om op r op yl)-2-m eth yl-2-(2-p r o-
p en yloxy)cyclop en ta n eca r boxyla te (30). Gen er a l P r o-
ced u r e for th e P r ep a r a tion of Br om id es fr om Alcoh ols.
Compound 30 was prepared from ethyl (1R*,2S*)-1-(3-hydroxy-
propyl)-2-methyl-2-(2-propenyloxy)cyclopentanecarboxylate ac-
cording to the following general procedure. CBr4 (0.37 g, 1.12
mmol) and PPh3 (0.29 g, 1.12 mmol) were added to a solution
of the alcohol (0.25 g, 0.93 mmol) in 10 mL of dry ether. The
reaction mixture was allowed to stir overnight at ambient
temperature. After this period of stirring, the reaction mixture
was diluted with pentane, filtered through a short plug of
Celite, concentrated in vacuo, and then subjected to flash
column chromatography (2% EtOAc/hexanes) to afford the
desired bromide 30 (0.26 g, 0.77 mmol) in 83% yield: 1H NMR
(300 MHz, CDCl3) δ 5.94-5.82 (m, 1H), 5.26 (ddt, J ) 10.50,
19.04, 4.88 Hz, 1H), 5.08 (ddt, J ) 10.50, 3.66, 1.95 Hz, 1H),
4.11 (m, 2H), 3.89 (qtd, J ) 12.70, 4.88, 1.71 Hz, 2H), 3.37 (m,
2H), 2.17 (m, 1H), 2.00 (m, 2H), 1.80-1.55 (m, 7H), 1.25 (t, J
) 7.08 Hz, 3H), 1.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
175.54, 135.96, 114.75, 85.98, 62.89, 61.40, 60.40, 34.66, 34.20,
31.97, 30.33, 29.64, 20.09, 19.03, 14.18.
E t h yl (1R*,2S*)-1-(3-Br om op r op yl)-2-m et h yl-2-(2-for -
m yleth oxy)cyclop en ta n eca r boxyla te. Gen er a l P r oce-
d u r e for Ozon olysis w ith Red u ctive Wor k u p . This com-
pound was prepared from 30 according to the general proce-
dure outlined for the preparation of 16 to afford the desired
aldehyde (1.53 g, 4.56 mmol) in 100% yield after flash column
chromatography with 25-30% EtOAc/hexanes: 1H NMR (400
MHz, CDCl3) δ 9.71 (s, 1H), 4.18-4.09 (m, 2H), 3.98 (d, J )
17.40 Hz, 1H), 3.39 (m, 2H), 2.23 (m, 1H), 2.05 (m, 1H), 1.87
(m, 1H), 1.79-1.62 (m, 6H), 1.22 (m, 1H), 1.16 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 201.96, 175.06, 86.95, 68.65, 61.14, 60.04,
34.81, 35.05, 31.76, 30.28, 29.42, 19.75, 19.19, 14.19.
Eth yl (1R*,2S*)-1-(3-Iod op r op yl)-2-m eth yl-2-[(3-p h en -
yl-2(Z)-pr open yl)oxy]cyclopen tan ecar boxylate (31). Gen -
er a l Wittig Rea ction P r oced u r e. Compound 31 was pre-
pared from the above aldehyde according to the following
general procedure. n-Butyllithium (3.6 mL of a 1.6 M solution
in hexanes, 5.76 mmol) was added to a 0 °C solution of
benzyltriphenylphosphonium chloride (2.24 g, 5.76 mmol) in
20 mL of dry THF. The resultant dark red solution was
allowed to warm to rt and stir for 0.5 h before cooling to -78
°C. Then, the aldehyde (1.61 g, 4.80 mmol) was added in 10
mL of dry THF to the prepared Wittig reagent. The reaction
mixture was maintained at -78 °C until the substrate addition
was complete. After this period of time, the reaction mixture
was allowed to warm to rt. TLC analysis at this time revealed
the complete consumption of starting aldehyde and the forma-
tion of a single, higher Rf product. The reaction mixture was
quenched at rt with saturated aqueous NaHCO3 and subjected
to an aqueous workup. Flash column chromatography with
3% EtOAc/hexanes afforded the desired olefin as a mixture of
the bromide and chloride. The resultant mixture was taken
up in acetone and heated at reflux overnight with NaI (7.2 g,
48.0 mmol). The reaction mixture was then subjected to an
aqueous workup and flash column chromatography with 2%
EtOAc/hexanes to afford the desired iodide 31 (0.79 g, 1.73
mmol) in 36% yield (two steps): 1H NMR (400 MHz, CDCl3) δ
(1R *,2S *,5S *)-2-B e n zy l-5-m e t h y lt r ic y c lo [7.3.05 ,9 ]-
d od eca n -1-ol (32a ) was prepared from 31 (a 2:1 mixture of
Z and E olefin isomers, respectively) according to the general
procedure outlined for the preparation of 4 (except the reaction
mixture was heated at reflux for 12 h after the addition of the
substrate was complete) to afford 32a as a single diastereo-
meric product in 56% yield along with the uncyclized inter-
mediate (32b, 35% yield, a 2:1 mixture of E and Z olefin
isomers, respectively) after flash column chromatography with
8% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 7.70-7.64
(m, 5H), 4.19-4.06 (m, 2H), 3.42 (dd, J ) 13.65, 4.55 Hz, 1H),
3.20 (m, 1H), 2.78 (dd, J ) 13.39, 9.91 Hz, 1H), 2.67 (m, 1H),
2.42 (m, 1H), 2.23-2.03 (m, 8H), 1.95 (m, 1H), 1.83 (s, 3H),
1.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 140.50, 128.90
(2), 128.49 (2), 126.14, 81.26, 81.10, 66.89, 57.00, 45.77, 37.72,
37.45, 35.05, 33.86, 28.09, 26.82, 19.50, 18.19; IR (CCl4) 3614.2,
1542.9, 1494.8, 1455.6 cm-1; HRMS calcd for C19H26O2 286.1933,
found 286.1928; LRMS (EI+) m/ z 286 (21), 271 (100), 253 (13),
244 (62), 238 (31), 229 (22), 223 (13), 191 (97), 177 (23), 135
(28), 108 (95), 91 (94), 79 (23), 67 (17), 55 (28), 43 (26), 28 (18).
6-Meth yl-6-[(2E/Z)-3-p h en yl-2-p r op en yl)oxy]sp ir o[4.4]-
n on a n -1-on e (32b) (2:1 mixture of E and Z olefin isomers):
1H NMR (400 MHz, CDCl3) δ 7.37-7.18 (m, 5H), 6.58-6.49
(m, 1H), 6.26 (dt, J ) 15.80, 5.36 Hz, 0.67H), 5.76 (dt, J )
11.78, 6.16 Hz, 0.33H), 4.09-3.98 (m, 2H), 2.38-1.98 (m, 3H),
1.99-1.81 (m, 4H), 1.80-1.65 (m, 4H), 1.19 (m, 1H), 1.16 (s,
2H), 1.12 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 215.86, 137.11,
136.85, 130.47, 130.25, 129.92, 128.67, 128.48, 128.19, 127.86,
127.31, 127.03, 126.31, 86.55, 63.34, 63.19, 61.82, 58.48, 39.62,
39.59, 35.22, 35.14, 34.17, 32.25, 32.21, 20.32, 20.23, 19.31,
19.26, 17.38, 17.31; IR (neat) 1728.6, 1599.7, 1576.7, 1494.4
cm-1; HRMS calcd for C19H24O2 284.1776, found 284.1756;
LRMS (EI+) m/ z 284 (22), 266 (48), 223 (28), 199 (83), 167.100,
151 (21), 133 (18), 117 (98), 107 (9), 91 (19), 79 (8), 67 (9), 55
(11), 43 (17), 28 (8).
E t h yl 2-a cet yl-6-[(ter t-b u t yld im et h ylsilyl)oxy]-2-m e-
th ylh exa n oa te was prepared from ethyl 2-methylacetoacetate
according to the general procedure outlined for the preparation
of ethyl 2-oxo-1-[3-[(tert-butyldimethylsilyl)oxy]propyl]cyclo-
pentanecarboxylate to afford the desired â-keto ester in 52%
yield after flash column chromatography with 2-3% Et-
OAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 4.16 (q, J ) 7.23
Hz, 2H), 3.57 (t, J ) 6.43 Hz, 2H), 2.12 (s, 3H), 1.85 (m, 1H),
1.74 (m, 1H), 1.49 (m, 2H), 1.30 (s, 3H), 1.23 (t, J ) 7.23 Hz,
3H), 1.72 (m, 2H), 0.85 (s, 9H), 0.01 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 205.72, 173.02, 62.01, 61.18, 59.65, 34.52, 33.07,
26.09, 25.89 (3), 20.53, 18.71, 18.27, 14.03, -5.33 (2).
Eth yl 6-[(ter t-bu tyldim eth ylsilyl)oxy]-2-(2-h ydr oxypr o-
p yl)-2-m eth ylh exa n oa te was prepared from the above ethyl
2-acetyl-6-[(tert-butyldimethylsilyl)oxy]-2-methylhexanoate ac-
cording to the general procedure outlined for the preparation
of 28 to afford the desired tertiary alcohol (5.93 g, 17.1 mmol)
in 86% yield: 1H NMR (300 MHz, CDCl3) δ 4.16 (q, J ) 7.32
Hz, 2H), 3.61 (s, 1H), 3.57 (t, J ) 6.10 Hz, 2H), 2.08 (m, 1H),
1.57-1.33 (m, 4H), 1.28 (m, 1H), 1.27 (t, J ) 7.32 Hz, 3H),
1.15 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H), 0.86 (s, 9H), 0.01 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 177.69, 73.92, 62.83, 60.75,
53.64, 33.53, 33.35, 26.82, 25.91 (3), 23.94, 21.57, 18.29, 17.81,
14.21, -5.32 (2).
Eth yl 2-[4-[(ter t-bu tyld im eth ylsilyl)oxy]bu tyl]-4-oxa -
2,3,3-tr im eth yl-6-h epten oate was prepared from ethyl 6-[(tert-
butyldimethylsilyl)oxy]-2-(2-hydroxypropyl)-2-methylhex-
anoate according to the general procedure outlined for the
preparation of 26 to afford the desired allyl ether in 72% yield
after flash column chromatography with 2% EtOAc/hexanes:
1H NMR (300 MHz, CDCl3) δ 5.83 (m, 1H), 5.23 (m, 1H), 5.03

Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 62, No. 9, 1997 2955
(m, 1H), 4.09 (m, 2H), 3.86 (m, 2H), 3.56 (t, J ) 6.59 Hz, 2H),
1.92 (m, 1H), 1.51-1.44 (m, 2H), 1.42-1.31 (m, 2H), 1.25 (m,
4H), 1.20 (s, 3H), 1.18 (s, 3H), 1.17 (s, 3H), 0.86 (s, 9H), 0.01
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 175.68, 136.17, 114.26,
78.58, 63.08, 62.15, 60.04, 54.66, 33.81, 33.58, 25.93 (3), 21.70,
21.28, 20.93, 18.31, 17.04, 14.22, -5.30 (2).
Eth yl 2-(4-h yd r oxybu tyl)-4-oxa -2,3,3-tr im eth yl-6-h ep -
ten oa te was prepared from ethyl 2-[4-[(tert-butyldimethylsi-
lyl)oxy]butyl]-4-oxa-2,3,3-trimethyl-6-heptenoate according to
the general procedure outlined for the preparation of ethyl
(1R*,2S*)-1-(3-hydroxypropyl)-2-methyl-2-(2-propenyloxy)cy-
clopentanecarboxylate to afford the desired primary alcohol
in quantitative yield after flash column chromatography with
30% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 5.84 (ddt,
J ) 17.09, 10.50, 4.64 Hz, 1H), 5.23 (m, 1H), 5.03 (m, 1H),
4.09 (q, J ) 7.08 Hz, 2H), 3.86 (m, 2H), 3.62 (m, 2H), 1.98 (m,
1H), 1.59-1.49 (m, 2H), 1.43-1.32 (m, 2H), 1.24 (t, J ) 7.08
Hz, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18 (s, 3H), 1.15-0.89 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 175.77, 136.12, 114.31,
78.53, 62.69, 62.17, 60.18, 54.71, 33.40, 33.22, 21.53, 21.24,
20.93, 17.00, 14.21.
3-Acetyl-3-[3-[(ter t-bu tyldim eth ylsilyl)oxy]pr opyl]fu r an -
2(2H)-on e was prepared from 2-acetyl butyrolactone according
to the general procedure outlined for the preparation of ethyl
2-oxo-1-[3-[(t er t -bu t yld im et h yls ilyl)oxy]p r op yl]cyclo-
pentanecarboxylate to afford the desired â-keto lactone in 41%
yield after flash column chromatography with 15% EtOAc/
hexanes: 1H NMR (300 MHz, CDCl3) δ 4.27 (dt, J ) 3.17, 9.03
Hz, 1H), 4.13 (dt, J ) 7.08, 9.28 Hz, 1H), 3.63-3.55 (m, 2H),
2.91 (ddd, J ) 12.94, 7.08, 2.93 Hz, 1H), 2.32 (s, 3H), 2.26 (ddd,
J ) 4.88, 11.96, 14.16 Hz, 1H), 2.04-1.94 (m, 1H), 1.85-1.75
(m, 1H), 1.41-1.31 (m, 2H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 202.71, 175.50, 66.30, 62.08,
61.29, 31.56, 29.11, 28.19, 25.86 (3), 25.41, 18.23, -5.42 (2);
IR (neat) 1772.0, 1716.5, 830.0 cm-1
.
3-[3-[(t er t -B u t y ld im e t h y ls ily lo x y ]p r o p y l]-3-(2-h y -
d r oxyp r op yl)fu r a n -2(2H)-on e was prepared from 3-acetyl-
3-[3-[(tert-butyldimethylsilyl)oxy]propyl]furan-2(2H)-one ac-
cording to the general procedure outlined for the preparation
of ethyl 6-[(tert-butyldimethylsilyl)oxy]-2-(2-hydroxypropyl)-2-
methylhexanoate to afford the desired tertiary alcohol in 74%
yield after flash column chromatography with 20% EtO-
Ac/hexanes: 1H NMR (300 MHz, CDCl3) δ 4.24 (m, 2H), 3.64
(m, 1H), 3.54 (m, 1H), 3.01 (s, 1H), 2.33 (m, 1H), 2.17-1.99
(m, 2H), 1.62 (m, 1H), 1.47 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H),
0.86 (s, 9H), 0.02 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 181.79,
73.77, 65.81, 62.87, 53.68, 29.63, 29.37, 28.46, 26.71, 25.87 (3),
24.08, 18.26, -5.33, -5.38.
3-[[3-(ter t-Bu tyld im eth ylsilyl)oxy]pr op yl]-3-[5-(5-m eth -
yl-4-oxa -2-h exen yl)]fu r a n -2(2H)-on e was prepared from
[3-[3-[(tert-butyldimethylsilyl)oxy]propyl]-3-(2-hydroxypropyl)-
furan-2(2H)-one according to the general procedure outlined
for the preparation of 26 to afford the desired allyl ether in
72% yield after flash column chromatography with 8%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.82 (m, 1H),
5.19 (m, 1H), 5.04 (m, 1H), 4.22 (m, 1H), 3.89 (m, 2H), 3.63
(m, 1H), 3.54 (m, 1H), 2.62 (m, 1H), 2.10 (m, 1H), 1.71 (m,
1H), 1.55 (m, 2H), 1.43 (m, 1H), 1.35 (s, 3H), 1.22 (s, 3H), 0.86
(s, 9H), 0.02 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 179.92,
135.65, 114.99, 79.71, 65.81, 63.00, 62.28, 54.74, 29.77, 28.48,
28.36, 25.89 (3), 21.05, 19.83, 18.27, -5.30, -5.35.
3-(3-Hyd r oxyp r op yl)-3-[5-(5-m eth yl-4-oxa -2-h exen yl)]-
fu r a n -2(2H)-on e was prepared from 3-[3-[(tert-butyldimeth-
ylsilyl)oxy]propyl]-3-[5-(5-methyl-4-oxa-2-hexenyl)]furan-2(2H)-
one according to the general procedure outlined for the
preparation of ethyl (1R*,2S*)-1-(3-hydroxypropyl)-2-methyl-
2-(2-propenyloxy)cyclopentanecarboxylate to afford the desired
primary alcohol in 83% yield after flash column chromatog-
raphy with 50% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3)
δ 5.81 (m, 1H), 5.18 (m, 1H), 5.04 (m, 1H), 4.23 (m, 1H), 4.14
(m, 1H), 3.88 (m, 2H), 3.61 (m, 2H), 2.61 (m, 1H), 2.10 (m,
1H), 1.88 (m, 1H), 1.78 (m, 1H), 1.68-1.52 (m, 2H), 1.43 (m,
1H), 1.34 (s, 3H), 1.22 (s, 3H).
3-(3-Br om op r op yl)-3-[5-(5-m eth yl-4-oxa -2-h exen yl)]fu -
r a n -2(2H)-on e was prepared from 3-(3-hydroxypropyl)-3-[5-
(5-methyl-4-oxa-2-hexenyl)]furan-2(2H)-one according to the
general procedure outlined for the preparation of 30 to afford
the desired bromide in 100% yield after flash column chroma-
tography with 15% EtOAc/hexanes: 1H NMR (300 MHz,
CDCl3) δ 5.84 (m, 1H), 5.13 (m, 1H), 5.06 (m, 1H), 4.26-4.12
(m, 2H), 3.90 (m, 2H), 3.45 (m, 1H), 3.31 (m, 1H), 2.64 (m,
1H), 2.08 (m, 1H), 1.89-1.66 (m, 4H), 1.35 (s, 3H), 1.25 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 179.59, 135.49, 115.16, 79.64,
69.86, 62.32, 54.57, 33.44, 32.07, 28.47, 28.44, 20.99, 19.91.
3-(3-Br om op r op yl)-3-(4-m eth yl-3-oxa p en ta n oyl)fu r a n -
2(2H)-on e was prepared from 3-(3-bromopropyl)-3-[5-(5-meth-
yl-4-oxa-2-hexenyl)]furan-2(2H)-one according to the general
ozonolysis procedure outlined above to afford the desired
aldehyde in 100% yield after flash column chromatography
with 50% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 9.64
(s, 1H), 4.31 (m, 1H), 4.19 (m, 1H), 4.01 (s, 2H), 3.45 (m, 1H),
3.31 (m, 1H), 2.73 (m, 1H), 2.13 (m, 1H), 1.85 (m, 3H), 1.72
(m, 1H), 1.36 (s, 3H), 1.26 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 200.45, 179.16, 80.83, 67.92, 65.86, 54.37, 33.27, 32.13, 28.44,
28.30, 20.97, 19.99.
E t h yl 2-(4-b r om ob u t yl)-4-oxa -2,3,3-t r im et h yl-6-h ep -
ten oa te was prepared from ethyl 2-(4-hydroxybutyl)-4-oxa-
2,3,3-trimethyl-6-heptenoate according to the general proce-
dure outlined for the preparation of 30 to afford the desired
bromide in 73% yield after flash column chromatography with
2% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.84 (m,
1H), 5.23 (m, 1H), 5.03 (m, 1H), 4.10 (q, J ) 6.96 Hz, 2H),
3.86 (m, 2H), 3.38 (t, J ) 6.69 Hz, 2H), 1.95 (m, 1H), 1.83 (m,
2H), 1.42-1.35 (m, 2H), 1.23 (t, J ) 6.96 Hz, 3H), 1.19 (s, 3H),
1.19 (s, 3H), 1.18 (s, 3H), 1.12 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 175.49, 136.10, 114.36, 78.46, 62.19, 60.22, 54.56,
33.68, 33.44, 32.94, 24.09, 21.25, 20.94, 17.05, 14.23.
Eth yl 2-(4-br om obu tyl)-6-for m yl-4-oxa -2,3,3-tr im eth yl-
6-h exa n oa te was prepared from the above bromide, ethyl 2-(4-
bromobutyl)-4-oxa-2,3,3-trimethyl-6-heptenoate, according to
the general ozonolysis procedure described above to afford the
desired aldehyde in 98% yield after flash column chromatog-
raphy with 20% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3)
δ 9.66 (s, 1H), 4.13 (q, J ) 7.23 Hz, 2H), 3.90 (s, 2H), 3.39 (t,
J ) 6.69 Hz, 2H), 1.97 (m, 1H), 1.83 (m, 2H), 1.41 (m, 2H),
1.24 (t, J ) 7.23 Hz, 3H), 1.22 (s, 3H), 1.21 (s, 3H), 1.20 (s,
3H), 1.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 202.44,
175.06, 79.71, 68.08, 60.46, 54.35, 33.60, 33.30, 33.01, 23.98,
21.31, 21.05, 17.08, 14.26.
Eth yl 2-(4-iod obu tyl)-4-oxa -7-p h en yl-2,3,3-tr im eth yl-
6(Z)-h ep ten oa te (33) was prepared from the above aldehyde,
ethyl 2-(4-bromobutyl)-6-formyl-4-oxa-2,3,3-trimethyl-6-hex-
anoate, according to the general procedure outlined for the
preparation of 31 to afford 33 as a 2:1 mixture of Z and E
isomers, respectively, in 60% yield (two steps) after flash
column chromatography with 2-3% EtOAc/hexanes: 1H NMR
(400 MHz, CDCl3) δ 7.34-7.18 (m, 5H), 6.47 (d, J ) 12.05 Hz,
1H), 5.74 (dt, J ) 12.05, 6.16 Hz, 1H), 4.14-4.08 (m, 4H), 3.16
(t, J ) 6.96 Hz, 2H), 1.94 (m, 1H), 1.79 (m, 2H), 1.39 (m, 2H),
1.23 (t, J ) 7.23 Hz, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18 (s,
3H), 1.12 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 175.49,
136.92, 130.66, 129.97, 128.67 (2), 128.16, 126.95, 126.26,
78.73, 60.25, 58.79, 54.43, 34.18, 32.70, 26.42, 21.36, 21.07,
17.04, 14.29, 6.86; LRMS (EI+) m/ z 458 (5), 441 (16), 427 (19),
412 (22), 400 (100), 355 (83), 325 (52), 284 (30), 251 (40), 199
(18), 117 (73), 87 (64), 57 (73), 43 (100), 29 (65).
(1R*,2S*,6R*)-2-Ben zyl-4-oxa -5,5,6-t r im et h ylb icyclo-
[4.4.0]d eca n -1-ol (34) was prepared from 33 according to the
general procedure outlined for the preparation of 7b to afford
34 in 78% yield after flash column chromatography with 10%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 7.26-7.13 (m,
5H), 3.46 (m, 1H), 3.36 (m, 1H), 2.94 (d, J ) 10.44, 1H), 2.14
(m, 2H), 1.96 (m, 1H), 1.70-1.47 (m, 7H), 1.43 (s, 3H), 1.14 (s,
3H), 1.13 (m, 1H), 1.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
140.83, 128.87 (2), 128.24 (2), 78.63, 73.23, 42.96, 30.92, 27.84,
27.67, 21.81; IR (neat) 3564.5, 1455.9, 1372.9, 1090.6 cm-1
;
HRMS calcd for C19H27O2 (M - H+) 287.2011, found 287.1999;
LRMS (EI+) m/ z 287 (100), 273 (98), 270 (42), 255 (48), 112
(48), 91 (78), 71 (99), 55 (48), 41 (92), 27 (68). Anal. Calcd for
C19H28O2: C, 79.12; H, 9.78. Found: C, 78.96; H, 9.88.
3-(3-Iod op r op yl)-3-[5-(5-m et h yl-4-oxa -1-p h en yl-1(Z)-
h exen yl)]fu r a n -2(2H)-on e (35) was prepared from 3-(3-
bromopropyl)-3-[4-methyl-3-oxapentanoyl]furan-2(2H)-one ac-

2956 J . Org. Chem., Vol. 62, No. 9, 1997
Molander and Harris
cording to the general procedure outlined for the preparation
of 31 to afford 35 in 56% yield (two steps) as a 2:1 mixture of
Z and E isomers, respectively, after flash column chromatog-
raphy with 10% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3)
δ 7.83-7.64 (m, 5H), 6.99 (m, 1H), 6.66 (dt, J ) 5.62, 15.80
Hz, 0.3H), 6.19 (dt, J ) 6.43, 11.78 Hz, 0.67H), 4.70 (m, 1H),
4.62 (m, 2H), 4.54 (m, 1H), 3.71 (m, 1H), 3.56 (m, 1H), 3.12
(m, 1H), 2.55 (m, 1H), 2.75 (m, 3H), 2.12 (m, 1H), 1.88 (s, 2H),
1.83 (s, 2H), 1.78 (s, 1H), 1.73 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 179.56, 136.83, 136.64, 130.58, 129.69, 128.60, 128.48,
128.22, 127.45, 127.10, 126.97, 126.32, 79.84, 65.91, 62.17,
58.58, 54.48, 34.36, 34.31, 29.14, 29.11, 28.50, 21.10, 20.98,
20.21, 6.08; LRMS (EI+) m/ z 428 (100), 413 (13), 385 (19), 370
(9), 323 (11), 296 (68), 281 (97), 268 (10), 251 (14), 237 (12),
209 (13).
general procedure outlined for the preparation of 26 to afford
the desired allyl ether, 39, in 69% yield after flash column
chromatography with 2% EtOAc/hexanes: 1H NMR (400 MHz,
CDCl3) δ 5.89 (m, 1H), 5.23 (m, 1H), 5.11 (m, 1H), 4.19 (t, J )
5.89 Hz, 2H), 4.10 (dq, J ) 10.98, 5.35 Hz, 2H), 3.48 (dd, J )
8.57, 3.75 Hz, 1H), 3.45 (t, J ) 6.69 Hz, 2H), 2.19-2.13 (m,
2H), 2.10 (m, 1H), 1.95 (m, 1H), 1.74 (m, 1H), 1.64-1.39 (m,
7H), 0.95 (t, J ) 7.23 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
175.58, 135.11, 116.17, 85.18, 73.97, 62.13, 60.01, 33.92, 31.62,
30.64, 29.49, 25.89, 25.30, 25.21, 11.65.
3-Br om op r op yl 1-(1-eth yl-2-oxa -4-oxobu tyl)cyclop en -
ta n eca r boxyla te was prepared from 39 according to the
general ozonolysis procedure outlined above to afford the
desired aldehyde, which was subjected immediately to the
Wittig reaction conditions as below: 1H NMR (400 MHz,
CDCl3) δ 9.69 (s, 1H), 4.22-4.16 (m, 4H), 3.57 (m, 2H), 3.45
(t, J ) 6.69 Hz, 2H), 2.16 (m, 2H), 2.07 (m, 2H), 1.65-1.51 (m,
7H), 0.97 (t, J ) 7.50 Hz, 3H).
3-Iod op r op yl 1-(1-eth yl-2-oxa -5(Z)-p h en yl-4-p en ten yl)-
cyclop en ta n eca r boxyla te (40) was prepared from the above
aldehyde according to the general procedure outlined for the
preparation of 31 to afford 40 in 56% yield (from 39) after flash
column chromatography with 2% EtOAc/hexanes: 1H NMR
(400 MHz, CDCl3) δ 7.38-7.29 (m, 3H), 7.27 (m, 1H), 7.17 (m,
1H), 6.53 (d, J ) 11.8 Hz, 1H), 5.83 (dt, J ) 6.16, 11.8 Hz,
1H), 4.36 (ddq, J ) 1.61, 6.16, 12.60 Hz, 2H), 4.08 (t, J ) 6.16
Hz, 2H), 3.50 (dd, J ) 3.74, 8.03 Hz, 1H), 3.18 (t, J ) 6.96 Hz,
2H), 2.08 (m, 3H), 1.97 (m, 1H), 1.72 (m, 1H), 1.62-1.39 (m,
7H), 0.94 (t, J ) 7.50 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
178.26, 136.74, 130.62, 129.56, 128.72, 128.51, 128.20, 127.10,
126.46, 85.51, 69.76, 64.04, 59.96, 33.88, 32.23, 30.81, 25.85,
25.32, 25.24, 11.69, 1.64.
(2R*,5R*,6S*)-5-Ben zyl-2-eth yl-6-(3-h yd r oxyp r op yl)-3-
oxa sp ir o[5.4.0]d eca n -6-ol (41) was prepared from 40 ac-
cording to the general procedure outlined for the preparation
of 7b to afford 41 as a single diastereomer in 54% yield after
flash column chromatography with 40% EtOAc/hexanes: 1H
NMR (400 MHz, CDCl3) δ 3.82-3.73 (m, 3H), 3.57 (d, J ) 11.51
Hz, 1H), 3.46 (d, J ) 9.64 Hz, 1H), 2.81 (t, J ) 13.12 Hz, 1H),
2.65 (m, 1H), 2.07 (m, 2H), 1.91-1.79 (m, 7H), 1.72 (m, 2H),
1.64-1.43 (m, 8H), 1.36-1.21 (m, 3H), 1.00 (t, J ) 7.23 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 141.38, 129.26 (2), 128.35
(2), 125.97, 110.52, 83.21, 65.25, 63.47, 53.89, 44.95, 34.15,
31.23, 29.91, 29.34, 28.52, 26.59, 25.14, 23.41, 12.17; IR
(CHCl3) 3690.4, 3611.6, 3409.2, 1602.1, 1495.8 cm-1; HRMS
calcd for C21H32O3 332.2351, found 332.2372; LRMS (EI+) m/ z
332 (22), 314 (12), 285 (71), 273 (11), 255 (18), 205 (64), 165
(18), 110 (46), 91 (48). Anal. Calcd for C21H32O3: C, 75.86;
H, 9.70. Found: C, 75.46; H, 9.77.
(1R*,2S*,6R*)-2-Ben zyl-5,5-dim eth yl-6-(2-h ydr oxyeth yl)-
4-oxa bicyclo[4.3.0]n on a n -1-ol (36) was prepared from 35
according to the general procedure outlined for the preparation
of 7b (except the reaction mixture was heated at reflux for 12
h after addition of the substrate was complete) to afford 36 as
a 20:1 mixture of diastereomeric products in 54% yield after
flash column chromatography with 30% EtOAc/hexanes. Ma-
jor diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.27-7.20 (m,
5H), 4.11 (m, 1H), 3.81 (m, 1H), 3.48 (m, 1H), 3.37 (m, 1H),
3.11 (dd, J ) 3.21, 13.65 Hz, 1H), 2.42 (m, 1H), 2.21-2.03 (m,
3H), 2.14 (bs, 2H), 1.96-1.79 (m, 3H), 1.68-1.59 (m, 3H), 1.27
(s, 3H), 1.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.84,
128.79 (2), 128.35 (2), 125.87, 83.58, 77.90, 62.71, 59.78, 54.73,
45.12, 37.58, 36.06, 35.81, 33.82, 28.16, 24.71, 20.83; IR (neat)
3360.6, 3061.9, 3024.8, 1651.4, 1603.2, 1495.6, 1470.3 cm-1
;
HRMS calcd for C19H26O2 (M - H2O) 286.1933, found 286.1919;
LRMS (EI+) m/ z 286 (12), 216 (19), 198 (21), 137 (48), 110
(37), 110 (37), 91 (100), 79 (26), 67 (28), 55 (48), 43 (72). Anal.
Calcd for C19H28O3: C, 74.96; H, 9.27. Found: C, 74.49; H,
9.23.
3-Br om op r op yl Cyclop en ta n eca r boxyla te (37). Cyclo-
pentanecarboxylic acid (1.37 g, 12.0 mmol), EDCI (3.57 g, 12.0
mmol), 3-bromo-1-propanol (2.00 g, 14.4 mmol), and catalytic
DMAP were stirred together for 18 h at ambient temperature.
After this period of time, the reaction was quenched with
saturated aqueous NaHCO3 and subjected to an aqueous
workup. Flash column chromatography with 5% EtOAc/
hexanes afforded the desired ester 37 (2.46 g, 9.88 mmol) in
82% yield: 1H NMR (400 MHz, CDCl3) δ 4.18 (t, J ) 6.10 Hz,
2H), 3.44 (t, J ) 6.59 Hz, 2H), 2.70 (m, 1H), 2.15 (m, 2H), 1.88-
1.55 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 176.54, 61.90, 43.72
(2), 31.73, 29.96, 25.75 (2), 1.45.
3-Br om op r op yl 1-(1-h yd r oxyp r op yl)cyclop en ta n eca r -
boxyla te (38) was prepared from 37 according to the following
general procedure. The ester, 37 (2.32 g, 9.88 mmol), in 10
mL of dry THF was added dropwise via cannula to LDA (10.9
mmol) at -78 °C. After the addition of the ester was complete,
the reaction was stirred at reduced temperature for an
additional 0.5 h and then propionaldehyde (0.86 g, 14.82 mmol)
was added neat via syringe. The reaction mixture was
maintained at -78 °C for 0.5 h, and then quenched with
saturated aqueous NH4Cl. An aqueous workup followed by
flash column chromatography with 10% EtOAc/hexanes af-
forded the desired product, 38 (1.35 g, 4.61 mmol), in 47%
yield: 1H NMR (400 MHz, CDCl3) δ 4.23 (m, 2H), 3.43 (t, J )
6.35 Hz, 3H), 2.46 (d, J ) 8.55 Hz, 1H), 2.21-1.85 (m, 5H),
1.67-1.57 (m, 4H), 1.54-1.44 (m, 2H), 1.24 (m, 1H), 0.99 (t, J
) 7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.32, 78.57,
62.35, 59.00, 34.23, 33.06, 31.47, 29.23, 26.61, 25.94, 25.47,
Ack n ow led gm en t. The authors wish to thank Dr.
Bruce Noll for obtaining the X-ray crystal structure of
compound 32 and Betina Biolatto for the preparation
of (1R*,6R*,7S*/R*)-7-hydroxy-9-oxabicyclo[4.3.0]non-
2-en-8-one. This work was carried out with generous
support from the National Institutes of Health
(GM35249).
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra of compounds synthesized (148 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
11.27; IR (neat) 3491.9, 1725.7 cm-1
.
3-Br om op r op yl 1-(1-eth yl-2-oxa -4-p en ten yl)cyclop en -
ta n eca r boxyla te (39) was prepared from 38 according to the
J O9700235