Sequenced reactions with samarium(II) iodide. Tandem nucleophilic acyl substitution/ketyl-olefin coupling reactions

Article abstract of DOI:10.1021/ja952619k

Samarium(II) iodide has been employed to promote a tandem intramolecular nucleophilic acyl substitution/intramolecular ketyl-olefin coupling cyclization sequence, generating bicyclic, tricyclic, and spirocyclic ring systems in excellent yield and with high diastereoselectivity. This versatile reaction sequence allows entry to several different naturally occurring tricyclic systems containing the angular and linear triquinane framework.

Full text of DOI:10.1021/ja952619k

J. Am. Chem. Soc. 1996, 118, 4059-4071
4059
Sequenced Reactions with Samarium(II) Iodide. Tandem
Nucleophilic Acyl Substitution/Ketyl-Olefin Coupling
Reactions
Gary A. Molander* and Christina R. Harris
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309-0215
ReceiVed August 3, 1995X
Abstract: Samarium(II) iodide has been employed to promote a tandem intramolecular nucleophilic acyl substitution/
intramolecular ketyl-olefin coupling cyclization sequence, generating bicyclic, tricyclic, and spirocyclic ring systems
in excellent yield and with high diastereoselectivity. This versatile reaction sequence allows entry to several different
naturally occurring tricyclic systems containing the angular and linear triquinane framework.
Introduction
Applications of samarium(II) iodide (SmI2) to organic
chemistry have matured significantly since the first reported uses
of this reductant in organic chemistry in the early 1980s.1 The
reducing ability and therefore the chemoselectivity of this
reagent are largely solvent dependent and therefore adjustable.
This characteristic, combined with the high diastereoselectivities
associated with many SmI2-promoted reactions, makes it a
singularly effective reductant for promoting both individual and
sequential organic reactions.1,2
Previous research from this laboratory has demonstrated that
SmI2 promotes a variety of individual reduction reactions and
reductive coupling processes. Among them, nucleophilic acyl
substitution reactions of haloalkyl carboxylic acid derivatives3
and ketyl-olefin coupling reactions with both activated and
unactivated systems have been demonstrated.2b,c,4 Efforts
directed toward sequencing reactions with SmI2 have also proven
successful.1a For example, a tandem nucleophilic acyl substitu-
tion/Barbier-type coupling sequence leading to bicyclic and
tricyclic ring systems has been reported.2a As part of an ongoing
effort aimed at utilizing SmI2 in sequential reactions, this
Figure 1. Ring systems accessible through SmI2-induced sequential
reactions.
powerful ring-building strategy has been extended to include a
tandem nucleophilic acyl substitution/ketyl-olefin coupling
sequence. This concise transformation of simple acyclic
substrates to more complex carbocycles provides a unique entry
to a variety of bicyclic, tricyclic, and spirocyclic ring systems.
Included is an approach to both the angular and linear triquinane
ring systems found in the sesterterpenes pentalenene (1),
isocomene (2), and hirsutene (3).
Results and Discussion
At the outset, studies on the development of this sequential
process concentrated primarily on esters and lactones containing
both a tethered halide and a pendant olefin. A representative
example is shown in Scheme 1. The mechanism for this
sequential process likely involves initial generation of an
organosamarium species with subsequent nucleophilic acyl
substitution on the lactone carbonyl.3 Presumably, attack on
the lactone results in the formation of a tetrahedral intermediate
that collapses to liberate the ketone, which is poised for an
ensuing 5-exo radical cyclization reaction through its ketyl. The
resultant carbon-centered radical is rapidly reduced to an
organosamarium, generating the desired bicyclic product after
an aqueous workup. The major diastereomers in the exo
cyclizations are those with the developing radical center trans
to the alkoxy group. The formation of this isomer avoids
unfavorable stereoelectronic interactions in the radical cycliza-
tion.4
X Abstract published in AdVance ACS Abstracts, April 1, 1996.
(1) (a) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (b)
Molander, G. A. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New
York, 1994; Vol. 46, p 211. (c) Molander, G. A. Chem. ReV. 1992, 92, 29.
(d) Molander G. A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 1, Chapter 1.9. (e)
Soderquist, J. A. Aldrichim. Acta 1991, 24, 15. (f) Kagan, H. B. New J.
Chem. 1990, 14, 453. (g) Molander, G. A. In Chemistry of the Metal-
Carbon Bond: Hartley, F. R., Patai, S., Eds.; Wiley: New York, 1989;
Vol. 5, p 319. (h) Kagan, H. B.; Sasaki, M.; Collin, J. Pure Appl. Chem.
1988, 60, 1725.
(2) (a) Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1995, 117,
3705. (b) Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132.
(c) Molander, G. A.; Harring, L. S. J. Org. Chem. 1990, 55, 6171. (d)
Molander, G. A.; Kenny, C. J. Org. Chem. 1991, 56, 1439. (e) Takai, K.;
Nitta, K.; Fuimara, O.; Utimoto, K. J. Org. Chem. 1989, 54, 4732. (f)
Curran, D. P.; Fevig, T. L.; Totleben, M. J. Synlett. 1990, 773. (g) Curran,
D. P.; Wolin, R. L. Synlett 1991, 317. (h) Enholm, E. J.; Jiang, S.; Abboud,
K. J. Org. Chem. 1993, 58, 4061. (i) Yu, Y.; Lin, R.; Zhang, Y. Tetrahedron
Lett. 1993, 34, 4547. (j) Batey, R. A.; Motherwell, W. B. Tetrahedron
Lett. 1991, 32, 6649. (k) Enholm, E. J.; Trivellas, A. Tetrahedron Lett.
1994, 35, 1627. (l) Sasaki, M.; Collin, J.; Kagan, H. B. Tetrahedron Lett.
1988, 29, 6105. (m) Lannoye, G.; Cook, J. M. J. Org. Chem. 1988, 29,
171. (n) Lannoye, G.; Sambasivarao, K.; Wehrli, S.; Cook, J. M. J. Org.
Chem. 1988, 53, 2327. (o) Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. J.
Org. Chem. 1993, 58, 1458.
Initially, a series of olefinic esters was prepared to demon-
strate the scope and limitations of this sequential process.
Optimum reaction conditions for these substrates involved the
slow, dropwise addition of the substrate to a solution of 4.4
equiv of SmI2 in THF containing 5 equiv of hexamethylphos-
(3) (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.
(4) Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1989, 111, 8236.
S0002-7863(95)02619-9 CCC: $12.00 © 1996 American Chemical Society

4060 J. Am. Chem. Soc., Vol. 118, No. 17, 1996
Molander and Harris
Scheme 1
phoramide (HMPA)5 at 0 °C. The standard reaction conditions
did not involve the intentional addition of a proton source to
quench the final organosamarium intermediate. In general, these
reactions were complete after 30-45 min. Hence, the sequential
cyclization of the ethyl acetoacetate derived acetal 4 (eq 1)
The hydroxy ester 9 in eq 3 was generated as a single
diastereomer in high yield when the SmI2-promoted sequential
reaction with 8 was initiated and quenched at -40 °C.
Performing the reaction under standard reaction conditions
resulted in a substantial decrease in the yield of the desired
product. The lower yields can be ascribed to a retro-aldol
reaction which results in decomposition of the desired bicyclic
â-hydroxy ester at higher reaction temperatures or with prolonged
stirring.2a,4,6 The diester substrate 8 was prepared in two steps
by sequential alkylation of diethyl malonate with 4-bromo-1-
butene and then 1,3-diiodopropane.
Substrates with activating groups on the alkene were antici-
pated to provide higher yields of the tandem cyclization product
than substrates incorporating unactivated alkenes. The sequen-
tial cyclization depicted in eq 4 supports this supposition. The
provided the desired bicyclic alcohol, 5, in 70% yield as a single
diastereomer. Substrate 4 was prepared by successive alkylation
of ethyl acetoacetate with 4-bromo-1-butene and 1-chloro-3-
iodopropane, protection of the ketone as the ketal, and finally
reaction with NaI.
Subjecting the ethyl acetoacetate derived acetal 6 to the
standard reaction conditions provided a demonstration of the
ability to generate bicyclic products resulting from two sequen-
tial six-membered-ring-forming reactions (eq 2). The desired
desired bicyclic alcohol 11 was obtained in excellent yield as a
single diastereomer under the standard reaction conditions. The
substrate in eq 4 was prepared by alkylation of methyl
5-chlorovalerate with 4-iodo-1-(trimethylsilyl)-4-butyne, sub-
sequent Finkelstein reaction with NaI, and finally hydroboration/
protonation of the resultant iodoalkyne.
In the second phase of our investigations, efforts were directed
at the sequential cyclization process using lactone precursors.
The preparation of these substrates is outlined in Scheme 2.
Most of these substrates were prepared from the γ-lactone by
alkylation with either 1-chloro-3-iodopropane or 1-chloro-4-
iodobutane, followed by alkylation with either 4-bromo-1-butene
or an appropriate trimethylsilyl-substituted alkynyl halide.
bicyclio[3.3.0]decan-1-ol 7 was obtained in 73% yield as a 2:1
mixture of diastereomers epimeric at C-2. Substrate 6 was
prepared in a manner similar to that of 4 by successive alkylation
of ethyl 2-methylacetoacetate with 1-chloro-4-iodobutane and
then allyl bromide, acetal formation, and finally a Finkelstein
reaction with NaI to provide 6.
(5) (a) During the course of our investigations, a report appeared wherein
1,1,3,3-tetramethylguanidine (TMG) was found to be superior to additives
such as HMPA in its ability to facilitate aryl radical cyclizations by acting
as a strong ligand donor. Cabri, W.; Candiani, I.; Colombo, M.; Franzoi,
L.; Bedeschi, A. Tetrahedron Lett. 1995, 36, 949. In our hands, TMG
proved to be capable of promoting the present cyclizations, albeit providing
markedly decreased yields of the desired bicyclic products along with a
considerable amount of reduced ketone and a smaller amount of reduced
halide component. Consequently, all sequential cyclization reactions were
performed using 5 equiv of HMPA (relative to SmI2) as the cosolvent.
Inanaga, J.; Ujikawa, O.; Yamaguchi, M. Tetrahedron Lett. 1991, 32, 1737.
(b) Hou, Z.; Wakatsuki, Y. J. Chem. Soc., Chem. Commun. 1994, 1205.
(6) (a) Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem. Soc.
1987, 109, 453. (b) Heathcock, C. H. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 2,
Chapter 1.6.5.

Sequenced NAS/Ketyl-Olefin Coupling Reactions
J. Am. Chem. Soc., Vol. 118, No. 17, 1996 4061
Scheme 2
Scheme 3
Finally, a Finkelstein reaction with NaI and subsequent hy-
droboration of the resultant alkyne provided the requisite
substrates 15-c for the cyclization studies.
As indicated in eq 5, the yields in the SmI2 promoted
sequential process were markedly increased when the lactone
substrate contained an activated olefin (compare 15a with 15b).
reactions mediated by SmI2 have been reported.4,8 These studies
have established that successful ketyl-alkyne coupling requires
the use of an activating group on the terminus of the alkyne to
facilitate the coupling. Hence, the ester substrates (19a-d) in
eq 6 were prepared as outlined in Scheme 3 and subjected to
The lower yields generally observed in reactions of lactone
substrates with unactivated alkenes can be attributed in part to
an intramolecular hemiacetal-hydroxy ketone equilibrium
(Scheme 1) that undoubtedly hinders the desired ketyl-olefin
coupling reaction. Replacement of the unactivated olefin with
the more activating trimethylsilyl-substituted alkene (15b, eq
5, R ) TMS) lowers the π* orbital energy (LUMO) of the
alkene and establishes more effective overlap with the ketyl
radical anion SOMO.7 Any ketyl generated through the
pertinent equilibria would thus be more efficiently trapped by
the alkene, facilitating the cyclization. For the inherently slower
6-oxo ketyl-olefin cyclizations (15c, eq 5, R ) TMS) the
hemiacetal-hydroxy ketone equilibrium remains a problem even
with the activated olefinic substrate. Treatment of 15c (eq 5)
under either the standard sequential cyclization reaction condi-
tions or more vigorous conditions (SmI2/THF/HMPA heated at
reflux) provides only a complex mixture of products with no
apparent formation of the desired product. Ester substrates
which do not have this intramolecular hemiacetal-hydroxy
ketone equilibrium manifold available to them provide consis-
tently higher yields of the desired bicyclic products than do
lactones under the standard reaction conditions (eqs 1-4).
Having examined sequential reactions utilizing alkenes as the
ketyl acceptors in the final stage of the process, it seemed
appropriate to explore the use of alkynes as radical acceptors
as well. Both inter- and intramolecular ketyl-alkyne coupling
the standard sequential cyclization reaction conditions. The
tandem cyclization reactions culminating in a 5-exo ketyl-
alkyne coupling (eq 6, substrates 19a,c) each provided the
desired bicyclic alcohols (20a,c) as single diastereomers in
excellent yield. In contrast, those sequential cyclization reac-
tions terminating in a 6-exo mode (eq 6, substrates 19b,d)
provided bicyclic products (20b,d) which were isolated as
mixtures of diastereomers about the olefin.
The ketyl-alkyne coupling sequence also worked well with
lactone substrates terminating in a 5-exo mode, providing a
single diastereomer (21a) in excellent yield (eq 7).9 However,
a ketyl-alkyne coupling sequence terminating in a 6-exo fashion
(21b) provided only complex mixtures of intractable products
(14b, eq 7).
(8) (a) Inanaga, J.; Katsuki, J.; Ujikawa, O.; Yamaguchi, M. Tetrahedron
Lett. 1991, 32, 4921. (b) Shim, S. C.; Hwang, J.-T.; Kang, H.-Y.; Chang,
M. H. Tetrahedron Lett. 1990, 31, 4765.
(9) A report recently appeared demonstrating the silicon-directed ste-
reoselective syn addition of hydroxy groups to olefinic alkenylsilanes in
the presence of acid. Interestingly, the desired product in this cyclization
series was quantitatively transformed to the (trimethylsilyl)methyltetrahy-
dropyran in the NMR tube, as shown by 1H NMR in CDCl3 (proton NMR
1
spectrum of the (trimethylsilyl)methyltetrahydropyran-derived product H
NMR (400 MHz, CDCl3) δ 3.70 (dd, J ) 6.75, 11.99 Hz, 1H), 3.58 (dt, J
) 4.16, 12.27 Hz, 1H), 2.58 (2, 1H), 1.86 (m, 2H), 1.75-1.51 (m, 7H),
1.43 (m, 2H), 1.29 (dd, J ) 4.10, 12.93 Hz, 1H), 1.13 (d, J ) 14.84 Hz,
1H), 0.58 (d, J ) 14.83 Hz, 1H), 0.00 (s, 9H)). However, performing the
1H NMR measurement in benzene-d6 provided a spectrum of the desired
bicyclic diol. Miura, K.; Okajima, S.; Hondo, T.; Hosomi, A. Tetrahedron
Lett. 1995, 36, 1483.
(7) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.

4062 J. Am. Chem. Soc., Vol. 118, No. 17, 1996
Molander and Harris
Figure 2. Observed NOE’s from ketyl-alkyne cuyclization reaction.
Scheme 4
Confirmation of the stereochemistry about the alkenylsilane
was undertaken by examining the stereochemistry of the
cyclization product 23 derived from 7-(trimethylsilyl)-6-heptyn-
2-one (22, eq 8).8b Substrate 22 was prepared by alkylation of
methyl acetoacetate with 4-iodo-1-(trimethylsilyl)but-1-yne,
followed by subsequent LiCl-assisted decarboxylation to afford
the desired ketone 22. After the SmI2-promoted cyclization,
NOE difference experiments performed on 23 demonstrated that
the olefinic proton and methyl group were in close proximity
(Figure 2). Hence, irradiation of the singlet methyl group (δ
1.28) provided a 1.6% observed enhancement in the olefinic
proton with no concomitant enhancement at the singlet TMS
signal (δ 0.08). Irradiation of the olefinic proton (δ 5.56)
provided a 1.4% observed enhancement at the singlet methyl
group, further demonstrating that the methyl group and the
olefinic proton were sterically quite close. These analyses
confirm the stereochemistry of the product as depicted.
Further efforts were directed at determining the mechanism
of the ketyl-alkyne coupling. Presumably, the initial coupling
occurs through the ketyl of the intermediate ketone. However,
as depicted in Scheme 4, the resulting trimethylsilyl-substituted
alkenyl radical either could be quenched by hydrogen atom
abstraction from THF solvent or perhaps could be reduced
further to the alkenyl anion. A series of experiments were
performed to provide more insight into the mechanistic details
of this process.
Scheme 5
Thus, treatment of 19a (eq 6) under the standard sequential
cyclization reaction conditions but in the presence of 2.5 equiv
of D2O provided the desired bicyclic alcohol with approximately
45% deuterium incorporation on the alkene as determined by
1H NMR. The presence of deuterium in the final products
suggests the intermediacy of an alkenyl anion. Inanaga and
co-workers reported similar results during an intermolecular
carbonyl-alkyne reductive coupling reaction using aryl-
substituted alkynes.8a In their study, a nearly 1:1 mixture of
deuterated to protonated coupling product was observed when
CD3OD was employed as a trapping agent. The remaining
protonated material in their study was postulated to be derived
from hydrogen atom abstraction from another source, presum-
ably THF solvent. Hence, in an effort to determine if hydrogen
atom abstraction from THF solvent was indeed an operative
reaction manifold in our reaction sequence, the sequential
cyclization process was performed on 19a using THF-d8 as the
solvent under otherwise standard reaction conditions; i.e., no
intentional addition of a proton source. Isolation (81% yield)
and analysis of the resultant sequential cyclization product 20a
revealed no deuterium incorporation, as determined by both
2H NMR and by integration of the olefinic proton in question
hydrogen atom) still remains unclear. One additional experi-
ment was performed to determine if liberated alkoxide resulting
from seminal attack of the organosamarium reagent on the ester
functionality could serve as a potential hydrogen atom source
(perhaps by coordination to Sm(II) or Sm(III)). Thus, when
the ethyl-d5 ester of 19a was prepared and subjected to the
standard reaction conditions, no deuterium incorporation was
observed in the final product 20a (as determined by integration
1
of the appropriate signal in the H NMR), ruling out alkoxide
as a significant source of hydrogen atoms in this reaction
sequence. Further attempts to trap the alleged alkenyl anion
with electrophiles other than D2O met with failure, perhaps
attesting to the short-lived nature of the alkenyl anion that is
apparently generated. For example, performing the reaction in
the presence of acetone provided no product derived from attack
of the alkenyl anion on the carbonyl carbon of acetone.
The SmI2-promoted sequential process can be utilized to gain
access to ring systems other than fused bicycles. For example,
spirocycles can be generated as well. Thus, sequential cycliza-
tion of the cyclopentanecarboxylate ester 27 provided the desired
spirocyclic diol 28 in good yield as a single diastereomer (eq
9). The substrate cyclopentanecarboxylate was readily prepared
in four steps from cyclopentanecarboxylic acid, as depicted in
Scheme 5.
1
in the H NMR spectrum. Thus, it appears unlikely that the
nondeuterated material results from hydrogen atom abstraction
from THF solvent, although the source of the proton (or

Sequenced NAS/Ketyl-Olefin Coupling Reactions
J. Am. Chem. Soc., Vol. 118, No. 17, 1996 4063
Scheme 6
To demonstrate further the wide applicability of this sequen-
tial process, the method was applied to the synthesis of linear
and angular triquinane frameworks. Sequential cyclization of
the fused bicyclic lactone 31 provided the desired linear
triquinane framework 32 in good yield as a 6:1 mixture of
diastereomers epimeric at C-2 (eq 10). Amazingly, the derived
Scheme 7
product is formed even though it requires the formation of a
highly strained trans:anti:cis linear triquinane framework.10
Evidence for the stereochemical assignment made for this
cyclization product 32 is based in part on observation of the IR
spectra of both the major and minor diastereomeric products
isolated. Molecular models indicate that both diastereomers
(epimers at C-2) should exhibit considerable intramolecular
hydrogen bonding. Observation of the hydroxyl stretching
vibrations as seen in the IR spectrum of each diastereomer in
nonpolar CCl4 solvent performed at high dilution (0.04 M)
revealed a sharp “free hydroxyl” stretch (3617.7 and 3614.8
cm-1), intermolecular hydrogen bonding (3592.9/3550.1 cm-1),
and a broad shallow band at 3395.1/3404.4 cm-1 resulting from
intramolecular hydrogen bonding for both the major and minor
diastereomers, respectively. Molecular models of the potential
products resulting from reversible ketyl-olefin coupling (and/
or epimerization of the position R to the cyclopentanone
intermediate) to provide a cis:anti:cis or cis:syn:cis framework
do not have the potential for intramolecular hydrogen bonding,
thus supporting the stereochemical assignments and indicating
that the ketyl-olefin coupling process is irreversible. It deserves
note that formation of the desired product occurred in good yield
only when the substrate lactone was added slowly dropwise to
a SmI2/THF/HMPA mixture heated at reflux. Nevertheless, the
product formed is clearly the kinetic product of the reaction.
Substrate 31 was prepared from the known ethyl 2-oxocyclo-
pentane acetate as described previously (Scheme 6).2a
excellent yield. Unfortunately, attempts to extend this approach
to the one-carbon homologated substrate 37 were unsuccessful
(eq 12). The major product isolated under various reaction
Efforts directed toward the preparation of the angular
triquinane framework were also successful. Sequential cycliza-
tion of the cyclopentanoid substrate 35 (eq 11), prepared from
conditions was the bicyclic alkynyl ketone 38. Attempted ketyl
cyclizations on isolated 38 were also unproductive. Thus, when
38 was reacted with 2 equiv of SmI2 in THF/HMPA for 18 h
in the presence or absence of t-BuOH, the alcohol resulting from
reduction of the ketone was produced in yields of 48-60%,
and 40-50% of the starting material remained. No cyclized
material was detected.
ethyl 2-oxocyclopentanecarboxylate in four steps as described
previously (Scheme 7),2a provided a single tricyclic product in
Efforts directed at extending this protocol to incorporate
heterosubstituents R to the ester were only modestly rewarded.
Successful 5-exo ketyl-olefin cyclization in preference to
reductive elimination of an R-hetero substituent has been
(10) Fevig, T. L.; Elliot, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988,
110, 5064.

4064 J. Am. Chem. Soc., Vol. 118, No. 17, 1996
Molander and Harris
Scheme 8
either the initially generated carbon-centered radical species or
the further reduced carbon-centered anion generated in the
ketyl-olefin cyclization is quenched prematurely by either an
unidentified hydrogen atom source or protic acid source,
respectively. Performing the reaction by adding a proton source
(D2O) concurrently with the substrate (44) provided near-
quantitative deuterium incorporation (81% yield of the bicyclic
product) at the C-2 methyl, indicating that an organosamarium
is indeed formed and that H atom abstraction from another
source (i.e., THF solvent) is not a significant reaction manifold.
One potential protic acid source is the cyclopentanone or
cyclohexanone intermediate formed after initial nucleophilic acyl
substitution (Scheme 1). However, these intermediates were
excluded as a source of adventitious protons by performing the
cyclization sequence on 2-(3-butenyl)cyclopentanone exhaus-
tively deuterated at the positions R to the carbonyl. Thus,
performing the cyclization sequence on this deuterated substrate
provided no deuterium incorporation at the C-2 methyl group,
thus indicating that enolization of the intermediate cycloalkanone
is not a significant source of acidic protons in this sequence.
Another potential source of hydrogen atoms could be the
resultant ethoxide (or methoxide) or alkoxide coordinated with
Sm(II)/Sm(III), generated after the initial nucleophilic acyl
substitution. However, the sequential process carried out on
the deuterated ethyl ester (CD3CD2O) of 44 provided no
deuterium incorporation at the C-2 methyl, thus appearing to
rule out the resultant alkoxide as a potential hydrogen source.
reported.11 However, in systems with slower cyclization rates
(e.g., 6-exo cyclizations), R-hetero substituent extrusion ef-
fectively competes with the ketyl-olefin reductive coupling to
provide only low yields of the desired products. In the present
study, sequential cyclization of the dimethyl tartrate derived
substrate 40 (eq 13) provided the desired tricyclic product 42
1
Finally, Ashby and Welder13 have reported significant H
incorporation in reductions performed with LiAlD4. In that
communication, it was determined that the reaction vessel (i.e.,
1
Pyrex) could serve as a significant source of H incorporation
in reductions performed with LAD. Consequently, one cannot
rule out the possibility of the reaction vessel as a source of protic
acid.
In any event, with the requirement that the final, intermo-
lecular trapping could be accomplished only when the electro-
phile was present during the entire reaction sequence, successful
electrophiles were limited primarily to ketones that are not
competitively reduced to the alcohol under the reaction condi-
tions. Thus, when acetone was present during the entire reaction
sequence, bicyclic trapped materials were isolated in good yields
as single diastereomers (eq 14).
in 26% yield as a 6:1 mixture of diastereomers epimeric at C-3
under the standard reaction conditions. Attempts to enrich the
ketyl-olefin reaction manifold were partially successful when
the olefin was activated with a phenyl group. Hence, subjecting
the activated olefinic substrate 41 to standard reaction conditions
provided the desired tricyclic product 43 (eq 13) in markedly
increased yield (48%) as a 10:1 mixture of diastereomers
epimeric at C-3. The substrates in these cyclization events were
readily prepared from the dimethyl tartrate derived acetonide
by successive alkylation with allyl bromide and 1,4-diiodobutane
followed by ozonolysis and subsequent Wittig olefination
(Scheme 8).12
The SmI2-promoted intramolecular nucleophilic acyl substitu-
tion/ketyl-olefin cyclization sequence has been utilized to
convert a variety of suitable substrates to bicyclic, tricyclic, and
spirocyclic alcohols efficiently, in high yield and with excellent
diastereoselectivity. Substrates for these sequential processes
are readily prepared by classical alkylation chemistry in a
relatively few steps. The overall transformation represents an
effective means by which simple starting materials can be
converted to relatively complex products in a one-pot process.
Finally, we had hoped to trap the organosamarium species
generated after the ketyl-olefin cyclization with an electrophile
in order to extend the sequence of carbon-carbon bond-forming
reactions to three separate events. In our hands this could be
accomplished only when the electrophile was present during
the entire reaction sequence. As stated previously, under the
standard reaction conditions, in no instance was a proton source
(t-BuOH, MeOH, etc.) added deliberately until after the
complete consumption of the starting material. Apparently,
Experimental Section
(11) Maze´as, D.; Skrydstrup, T.; Beau, J.-M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 909. (b) dePouilly, P.; Che´nede´, A.; Mallet, J.-M.; Sinay¨,
P. Tetrahedron Lett. 1992, 33, 8065.
(12) (a) Naef, R.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1981, 20,
1030. (b) Ladner, W. Angew. Chem., Int. Ed. Engl. 1982, 21, 449. (c)
Tokunaga, Y.; Nagano, H.; Shiota, M. J. Chem. Soc., Perkin Trans. 1 1986,
581.
Reagents. Tetrahydrofuran (THF) was distilled immediately prior
to use from benzophenone ketyl under Ar. Samarium metal was
purchased from Cerac Inc., Milwaukee, WI, and was weighed and stored
(13) Ashby, E. C.; Welder, C. O. Tetrahedron Lett. 1995, 36, 7171.

Sequenced NAS/Ketyl-Olefin Coupling Reactions
J. Am. Chem. Soc., Vol. 118, No. 17, 1996 4065
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 the handling of air-sensitive reagents,14
and all reactions were carried out under argon.
Ethyl 2-acetyl-2-(3-chloropropyl)-5-hexenoate was prepared ac-
cording to the general procedure outlined for the preparation of 8 by
alkylation of ethyl 2-(3-butenyl)-acetoacetate15 with 1,3-dichloropropane
to afford the title compound in 81% yield after flash chromatography
with 4% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 5.74 (m, 1H),
4.98 (m, 2H), 4.18 (q, J ) 7.08 Hz, 2H), 3.50 (dt, J ) 6.10, 2.20 Hz,
2H), 2.12 (s, 3H), 2.03-1.78 (m, 6H), 1.56 (m, 2H), 1.24 (t, J ) 7.08
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.99, 137.25, 115.25, 62.62,
61.41, 44.79, 30.52, 28.56, 28.00, 27.18, 26.60 (2), 14.05.
Ethyl 2-Acetyl-2-(3-chloropropyl)-5-hexenoate, Ethylene Glycol
Acetal. A solution of ethyl 2-acetyl-2-(3-chloropropyl)-5-hexenoate
(3.05 g, 10.0 mmol) and ethylene glycol (1.24 g, 20.0 mmol) in 25
mL of benzene with catalytic p-toluenesulfonic acid was heated at reflux
for 18 h with azeotropic removal of water. After this period, the
reaction mixture was cooled to room temperature and the residual
solvent was removed in Vacuo. The resultant reaction mixture was
subjected to flash chromatography with 10% EtOAc/hexanes to afford
the title compound in 82% yield: 1H NMR (400 MHz, CDCl3) δ 5.79
(m, 1H), 4.97 (m, 2H), 4.15 (q, J ) 7.14 Hz, 2H), 3.92 (s, 4H), 3.53
(t, J ) 5.92 Hz, 2H), 2.10 (m, 1H), 1.96-1.67 (m, 7H), 1.34 (s, 3H),
1.25 (t, J ) 7.16 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.54,
138.78, 114.34, 118.86, 64.79, 64.69, 60.62, 56.97, 45.88, 30.18, 29.00,
28.26, 28.13, 21.28, 14.14.
Ethyl 2-acetyl-2-(3-iodopropyl)-5-hexenoate, ethylene glycol ac-
etal (4), was prepared from ethyl 2-acetyl-2-(3-chloropropyl)-5-
hexenoate, ethylene glycol acetal, according to the general procedure
outlined for the preparation of 15a to afford 4 in 96% yield after flash
chromatography with 8% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3)
δ 5.79 (m, 1H), 4.97 (m, 2H), 4.15 (q, J ) 7.19 Hz, 2H), 3.92 (s, 4H),
3.17 (t, J ) 6.47 Hz, 2H), 2.11 (m, 1H), 1.99-1.70 (m, 7H), 1.33 (s,
3H), 1.25 (t, J ) 7.13 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.53,
138.76, 114.38, 111.82, 64.82, 64.70, 60.66, 56.92, 31.84, 30.24, 29.01,
28.84, 21.31, 14.17, 7.75.
(1R*,2S*,5S)-5-Acetyl-2-methylbicyclo[3.3.0]octan-1-ol, ethylene
glycol acetal (5), was prepared from 4 according to the general
procedure outlined for the preparation of 16a to afford 5 as a single
diastereomer in 70% yield after flash chromatography with 10%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 3.97 (m, 4H), 2.80 (s,
1H), 2.17 (m, 1H), 1.81 (m, 2H), 1.70-1.51 (m, 5H), 1.41 (s, 3H),
1.27 (m, 2H), 1.05 (m, 1H), 0.95 (d, J ) 6.74 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 114.67, 92.53, 64.46, 64.20, 60.64, 46.58, 39.22, 36.33,
34.35, 29.29, 25.06, 20.59, 13.28; IR (CCl4) 3553.7 cm-1; HRMS calcd
for C13H22O3 226.1569, found 226.1560; LRMS (EI+) m/z 226 (65),
211 (100), 193 (31), 184 (25), 164 (55). Anal. Calcd for C13H22O3:
C, 68.99; H, 9.80. Found: C, 68.75; H, 9.84.
Ethyl 2-acetyl-2-(4-chlorobutyl)-2-methylhexanoate was prepared
according to the general procedure outlined for the preparation of 8 by
alkylation of ethyl 2-methylacetoacetate with 1-chloro-4-iodobutane to
afford the title compound in 71% yield after flash chromatography with
3% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 4.18 (q, J ) 7.10
Hz, 2H), 3.51 (t, J ) 6.59 Hz, 2H), 2.13 (s, 3H), 1.79 (m, 4H), 1.32 (s,
3H), 1.25 (t, J ) 7.10 Hz, 3H), 1.24 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 205.46, 172.83, 61.37, 59.48, 44.47, 33.49, 26.10, 21.51,
18.83, 14.08, 6.24.
the addition of the electrophile was complete, the reaction mixture was
maintained at -78 °C for 30 min and then warmed to room temperature.
TLC analysis at this time indicated the complete consumption of the
starting material. The reaction was quenched by the addition of
saturated aqueous NH4Cl. An aqueous workup followed by flash
chromatography with 3% EtOAc/hexanes provided the title compound
(0.88 g, 3.20 mmol) in 23% yield: 1H NMR (300 MHz, CDCl3) δ
5.75 (m, 1H), 4.98 (m, 2H), 4.16 (q, J ) 7.08 Hz, 2H), 3.51 (t, J )
6.35 Hz, 2H), 2.50 (dt, J ) 7.08, 3.18 Hz, 2H), 2.30 (m, 2H), 1.75 (m,
4H), 1.32 (s, 3H), 1.24 (t, J ) 7.08 Hz, 3H), 1.23 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 206.74, 172.87, 136.95, 115.37, 61.32, 59.29,
44.47, 37.59, 33.87, 32.67, 27.87, 21.50, 18.81, 14.05.
Ethyl 2-(4-chlorobutyl)-2-methyl-3-oxo-6-heptenoate, ethylene
glycol acetal, was prepared from ethyl 2-(4-chlorobutyl)-2-methyl-3-
oxo-6-heptenoate according to the general procedure outlined for the
preparation of 4 to afford the title compound in 72% yield after flash
chromatography with 5% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3)
δ 5.77 (m, 1H), 4.75 (m, 2H), 4.14 (m, 2H), 3.99 (m, 4H), 3.51 (t, J
) 6.59 Hz, 2H), 1.89 (m, 4H), 1.27 (m, 3H), 1.43 (m, 3H), 1.25 (t, J
) 6.59 Hz, 3H), 1.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.48,
138.47, 114.40, 113.92, 66.95, 66.88, 60.65, 56.09, 44.78, 34.98, 33.23,
33.15, 27.54, 22.31, 17.43, 14.17.
Ethyl 2-(4-iodobutyl)-2-methyl-3-oxo-6-heptenoate, ethylene gly-
col acetal (6), was prepared from ethyl 2-(4-chlorobutyl)-2-methyl-3-
oxo-6-heptenoate, ethylene glycol acetal, according to the general
procedure outlined for the preparation of 15a to afford 6 in 75% yield
after flash chromatography with 5% EtOAc/hexanes: 1H NMR (300
MHz, CDCl3) δ 5.77 (m, 1H), 4.96 (m, 2H), 4.14 (m, 2H), 4.00 (m,
4H), 3.16 (t, J ) 7.08 Hz, 2H), 1.93 (m, 4H), 1.78 (m, 3H), 1.40 (m,
3H), 1.26 (t, J ) 7.08 Hz, 3H), 1.18 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.38, 138.46, 114.39, 113.90, 66.94, 66.87, 60.67, 56.04,
34.97, 34.06, 32.88, 27.53, 25.92, 17.45, 14.22, 6.64.
(1R*,2R*/S*,6S*)-2,6-Dimethyl-5-oxabicyclo[4.4.0]decan-1-ol, eth-
ylene glycol acetal (7), was prepared from 6 according to the general
procedure outlined for the preparation of 16a to afford 7 as a 2:1 mixture
of diastereomers epimeric at C-2 in 73% combined yield: 1H NMR
(400 MHz, CDCl3) δ 3.91 (m, 4H), 3.26 (s, 1H), 2.08 (m, 1H), 1.94-
1.61 (m, 3H), 1.56-1.43 (m, 7H), 1.34-1.21 (m, 2H), 1.00 (s, 3H),
0.87 (d, J ) 7.74 Hz, 1.5H); 13C NMR (100 MHz, CDCl3) δ 114.54,
113.61, 75.47, 75.22, 65.21, 64.27, 64.19, 64.00, 46.25, 45.56, 37.04,
31.27, 31.16, 30.75, 30.06, 29.86, 29.81, 27.39, 27.17, 26.43, 22.35,
22.27, 21.31, 20.80, 20.28, 14.93, 14.81, 12.37; IR (CCl4) 3541.0 cm-1
;
HRMS calcd for C14H24O3 240.1725, found 240.1733; LRMS (EI+)
m/z 240 (12), 222 (16), 178 (21), 169 (18), 155 (17), 136 (34), 123
(98), 99 (100), 86 (26), 55 (22), 41 (36), 27 (19). Anal. Calcd for
C14H24O3: C, 69.96; H, 10.06. Found: C, 69.78; H, 10.24.
Diethyl 2-(3-butenyl)malonate was prepared by alkylation of diethyl
malonate with 4-bromo-1-butene according to the general procedure
outlined for the preparation of 8 to afford the title compound in 56%
yield after flash chromatography with 3% EtOAc/hexanes: 1H NMR
(400 MHz, CDCl3) δ 5.75 (m, 1H), 5.01 (m, 2H), 4.18 (q, J ) 7.12
Hz, 4H), 3.33 (t, J ) 7.14 Hz, 1H), 2.08 (m, 2H), 1.98 (m, 2H), 1.25
(t, J ) 7.14 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 169.41 (2), 136.88,
115.93, 61.30 (2), 51.19, 31.28, 27.82, 14.06 (2).
Diethyl 2-(3-Butenyl)-2-(3-iodopropyl)malonate (8). General
Procedure for the Alkylation of â-Dicarbonyl Substrates. 8 was
prepared from diethyl 2-(3-butenyl)malonate by alkylation with 1,3-
diiodopropane according to the following general procedure. Diethyl
2-(3-butenyl)malonate (5.06 g, 22.4 mmol) in 10 mL of dry DMF was
added dropwise via cannula to a stirred slurry of NaH (1.09 g of a
60% dispersion in mineral oil, 26.88 mmol) at 0 °C. After the addition
of the substrate was complete and the H2 evolution had ceased, the
reaction mixture was warmed to room temperature and stirred for 2 h.
After this period of time, the reaction mixture was cooled to 0 °C,
1,3-diiodopropane (9.94 g, 33.6 mmol) was added (neat), and the
reaction mixture was then warmed to room temperature and stirred for
2 h. The reaction mixture was then heated at 50 °C for 12 h before
being quenched at room temperature by the careful addition of saturated
aqueous NaHCO3 and subjected to an aqueous workup. Flash chro-
matography with 2% EtOAc/hexanes afforded 8 in 28% yield: 1H NMR
(400 MHz, CDCl3) δ 5.76 (m, 1H), 4.99 (m, 2H), 4.17 (q, J ) 7.14
Hz, 4H), 3.15 (t, J ) 6.73 Hz, 2H), 2.00-1.94 (m, 6H), 1.72 (m, 2H),
Ethyl 2-(4-Chlorobutyl)-2-methyl-3-oxo-6-heptenoate. Ethyl
2-acetyl-2-(4-chlorobutyl)-2-methylhexanoate (3.87 g, 14.2 mmol) was
added dropwise to a -78 °C solution of LDA (15.6 mmol). After the
addition of the substrate was complete, the reaction mixture was
maintained at -78 °C for 20-30 min before a solution of allyl bromide
(1.90 g, 15.6 mmol) in 3 mL of HMPA was added Via cannula. After
(14) Brown, H. C. Organic Syntheses Via Boranes; Wiley: New York,
1975.
(15) (a) Williams, R. H.; Lee, B. H. J. Am. Chem. Soc. 1986, 108, 6431.
(b) Williams, R. M.; Lee, B. H.; Miller, M. M.; Anderson, O. P. J. Am.
Chem. Soc. 1977, 89, 1073.

4066 J. Am. Chem. Soc., Vol. 118, No. 17, 1996
Molander and Harris
1.24 (t, J ) 7.18 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 171.22
(2), 137.38, 115.14, 61.26 (2), 56.67, 33.35, 31.79, 28.31 (2), 14.08
(2), 5.82.
1H), 1.86 (m, 1H), 1.78-1.53 (m, 5H); 13C NMR (100 MHz, CDCl3)
δ 178.29, 137.32, 115.38, 65.09, 45.31, 44.90, 34.83, 33.12, 32.41,
28.47, 27.41.
(1R*,4R*,5S*)-Ethyl 5-hydroxy-4-methylbicyclo[3.0.0]octanecarbox-
ylate (9) was prepared from 8 according to the general procedure
outlined for the preparation of 16a, except that the substrate 8 was
added as a 0.05 M solution in THF to a stirred solution of SmI2/HMPA
at -40 °C over a period of approximately 2 h. After this period of
time, TLC and GC analysis indicated that the starting material was
completely consumed, with concomitant formation of a single diaster-
omer. The reaction mixture was quenched at -40 °C and subjected to
an aqueous workup. Flash chromatography with 12% EtOAc/hexanes
afforded 9 as a clear, colorless oil in 74% yield: 1H NMR (400 MHz,
CDCl3) δ 4.13 (q, J ) 7.13 Hz, 2H), 2.57 (s, 1H), 2.47 (m, 1H), 2.21
(m, 1H), 1.98 (m, 1H), 1.73 (m, 2H), 1.66-1.48 (m, 4H), 1.39 (m,
1H), 1.26 (t, J ) 7.13 Hz, 3H), 1.17 (m, 1H), 0.98 (d, J ) 6.75 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 176.94, 93.82, 61.69, 60.68,
45.23, 37.97, 35.47, 35.35, 30.49, 24.78, 14.18, 13.20; IR (neat) 3500.3,
1704.3, 1454.6 cm-1; HRMS calcd for C12H20O3 212.1412, found
212.1418; LRMS (EI+) m/z 212 (31), 166 (98), 156 (99), 149 (36),
138 (84), 121 (82), 110 (96), 97 (41), 79 (28), 67 (30), 55 (33), 41
(64), 29 (48). Anal. Calcd for C12H20O3: C, 67.89; H, 9.50. Found:
C, 67.82; H, 9.69.
Dihydro-3-(3-chloropropyl)-3-(4-(trimethylsilyl)-3-butynyl)furan-
2(3H)one (13a) was prepared according to the general procedure for
the preparation of 12a by alkylation of 12a with 4-iodo-1-trimethylsilyl-
1-butyne17 to afford 13a in 45% yield as a clear yellow oil after flash
chromatography with 12% EtOAc/hexanes: 1H NMR (400 MHz,
CDCl3) δ 4.26 (ddd, J ) 2.91, 6.49, 9.63 Hz, 2H), 3.52 (t, J ) 5.68
Hz, 2H), 2.25 (m, 3H), 2.13 (m, 3H), 1.86 (m, 3H), 1.72 (m, 3H), 0.12
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.26, 105.58, 85.64, 65.07,
45.22, 44.74, 34.03, 32.67, 32.34, 27.31, 15.26, -0.03 (3).
Dihydro-3-(5-(trimethylsilyl)-4-pentynyl)furan-2(3H)-one was pre-
pared from γ-butyrolactone by alkylation with 1-iodo-5-(trimethylsilyl)-
4-pentyne15 according to the general procedure outlined for the
preparation of 12a to afford the title compound in 45% yield after flash
chromatography with 10% EtOAc/hexanes: 1H NMR (400 MHz,
CDCl3) δ 4.33 (dt, J ) 2.89, 8.81 Hz, 1H), 4.17 (dt, J ) 6.75, 9.37
Hz, 1H), 2.54 (m, 1H), 2.40 (m, 1H), 2.26 (t, J ) 7.16 Hz, 2H), 1.95
(m, 2H), 1.67-1.51 (m, 3H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 179.12, 106.41, 85.17, 66.43, 38.86, 29.56, 28.73, 26.33, 19.70, 0.10
(3).
Dihydro-3-(4-chlorobutyl)-3-(5-(trimethylsilyl)-4-pentynyl)furan-
2(3H)-one (13b) was prepared from dihydro-3-(5-(trimethylsilyl)-4-
pentynyl)furan-2(3H)-one by alkylation with 1-chloro-4-iodobutane to
afford 13b in 65% yield after flash chromatography with 8%
EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 4.24 (t, J ) 7.33 Hz,
2H), 3.53 (t, J ) 6.35 Hz, 2H), 2.22 (t, J ) 6.84 Hz, 2H), 2.15 (dt, J
) 7.08, 1.47 Hz, 2H), 1.79-1.40 (m, 10H), 0.13 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 180.77, 106.34, 85.26, 65.12, 45.64, 44.54, 34.92,
34.90, 32.59, 32.32, 23.48, 21.52, 20.08, 0.11 (3).
Methyl (5Z)-2-(3-iodopropyl)-6-(trimethylsilyl)-5-hexenoate (10)
was prepared according to the general procedure outlined for the
preparation of 15b by hydroboration of 19a to afford 10 in 81% yield
after flash chromatography with 3-4% EtOAc/hexanes: 1H NMR (400
MHz, CDCl3) δ 6.21 (m, 1H), 5.49 (d, J ) 13.98 Hz, 1H), 3.66 (s,
3H), 3.15 (t, J ) 6.86 Hz, 2H), 2.38 (m, 1H), 2.09 (m, 2H), 1.81-1.50
(m, 6H), 0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.91, 147.34,
130.07, 51.56, 44.24, 33.14, 32.31, 31.19, 31.14, 5.97, 0.13 (3).
(1R*,2S*,5S*)-2-((Trimethylsilyl)methyl)cyclo[3.3.0]octan-1-ol (11)
was prepared from 10 according to the general procedure outlined for
the preparation of 16a to afford 11 as a single diastereomer in 93%
yield after flash chromatography with 7% EtOAc/hexanes: 1H NMR
(400 MHz, CDCl3): δ 2.08 (m, 2H), 1.81 (m, 2H), 1.71 (m, 1H), 1.62
(m, 2H), 1.46 (t, J ) 7.23 Hz, 2H), 1.28 (s, 1H), 1.12 (m, 3H), 0.76
(dd, J ) 3.12, 14.38 Hz, 1H), 0.39 (dd, J ) 11.43, 14.42 Hz, 1H),
-0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 93.91, 50.54, 47.28,
36.54, 35.16, 32.18, 30.00, 25.60, 15.93, -0.84 (3); IR (CCl4) 3373.3
cm-1; HRMS calcd for C12H24OSi 212.1596, found 212.1605; LRMS
(EI+) m/z 212 (20), 197 (100), 183 (41), 169 (92), 75 (98). Anal. Calcd
for C12H24OSi: C, 67.86; H, 11.39. Found: C, 67.58; H, 11.69.
Dihydro-3-(chloropropyl)furan-2(3H)-one (12a). General Pro-
cedure for the Alkylation of Esters and Lactones.16 A 1.0 M solution
of γ-butyrolactone (1.72 g, 20.0 mmol) in THF was added dropwise
Via cannula over 1.0-1.5 h to a stirred solution of 22.0 mmol of LDA
at -78 °C. After the addition of the substrate was complete, the
reaction mixture was stirred an additional 20-30 min at -78 °C. After
this period of stirring, 1-chloro-3-iodopropane (4.90 g, 24.0 mmol) in
4.2 mL of HMPA was added slowly dropwise. After the addition of
the halide was complete, the reaction mixture was warmed to -30 °C
with continued stirring at reduced temperature overnight. After this
period, TLC/GC analysis revealed the near-complete consumption of
the starting material. The reaction mixture was quenched with saturated
aqueous NH4Cl. Aqueous workup followed by flash chromatography
(15% EtOAc/hexanes) afforded 2.30 g (14.2 mmol) of 12a as a clear
yellow oil in 71% yield after Kugelrohr distillation (ot 100-110 °C,
0.05 mmHg): 1H NMR (300 MHz, CDCl3) δ 4.34 (m, 1H), 4.18 (m,
1H), 3.55 (t, J ) 6.30 Hz, 2H), 2.53 (m, 1H), 2.40 (m, 1H), 2.03-1.79
(m, 4H), 1.63 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.92, 66.40,
44.40, 38.55, 30.10, 28.66, 27.70.
Dihydro-3-(3-iodopropyl)-3-(4-(trimethylsilyl)-3-butynyl)furan-
2(3H)-one (14a) was prepared from 13a according to the general
procedure outlined for the preparation of 15a to afford 14a in 90%
yield after flash chromatography with 12% EtOAc/hexanes: 1H NMR
(400 MHz, CDCl3) δ 4.26 (m, 2H), 3.15 (t, J ) 6.30 Hz, 2H), 2.29
(m, 3H), 2.13 (m, 1H), 1.78 (m, 6H), 0.12 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 179.92, 105.56, 85.64, 45.14, 36.20, 34.08, 32.32,
28.08, 15.26, 5.85, -0.02 (3).
Dihydro-3-(4-iodobutyl)-3-(5-(trimethylsilyl)-4-pentynyl)furan-
2(3H)-one (14b) was prepared from 13b according to the general
procedure outlined for the preparation of 15a to afford 14b in 90%
yield after flash chromatography with 8% EtOAc/hexanes: 1H NMR
(400 MHz, CDCl3) δ 4.24 (t, J ) 7.44 Hz, 2H), 3.17 (t, J ) 6.85 Hz,
2H), 2.22 (t, J ) 6.78 Hz, 2H), 2.14 (dt, J ) 7.02, 2.44 Hz, 2H), 1.81
(m, 2H), 1.72-1.49 (m, 7H), 1.34 (m, 1H), 0.13 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 180.72, 106.33, 85.26, 65.11, 45.59, 34.90, 34.47,
33.34, 32.34, 25.09, 23.48, 20.07, 6.22, 0.12 (3).
Dihydro-3-(3-butenyl)-3-(3-iodopropyl)furan-2(3H)-one (15a). So-
dium iodide (3.0 g, 20.0 mmol) was added to a stirred solution of
dihydro-3-(3-butenyl)-3-(3-chloropropyl)furan-2(3H)-one (0.43 g, 2.0
mmol) in 10 mL of acetone. The resultant solution was heated at reflux
for 12 h. After this period, the reaction mixture was cooled to room
temperature and the solvent was removed in Vacuo. The resultant
reaction mixture was diluted in ether, washed with saturated aqueous
sodium thiosulfate and brine, and then dried over MgSO4. The crude
product was purified by flash chromatography (10% EtOAc/hexanes)
to afford 15a as a clear yellow oil (0.59 g, 1.90 mmol) in 95% yield:
1H NMR (400 MHz, CDCl3) δ 5.75 (m, 1H), 5.01 (m, 2H), 4.25 (t, J
) 7.26 Hz, 2H), 3.16 (t, J ) 4.35 Hz, 2H), 2.15 (m, 3H), 2.05-1.63
(m, 7H); 13C NMR (100 MHz, CDCl3) δ 180.49, 137.30, 115.40, 65.09,
45.25, 36.66, 34.88, 32.41, 28.48, 28.20, 6.08.
Dihydro-3-(3-butenyl)-3-(3-chloropropyl)furan-2(3H)-one was pre-
pared according to the general alkylation procedure described for 12a
by alkylation of 12a with 4-bromo-1-butene. The crude product was
subjected to flash chromatography with 10% EtOAc/hexanes to afford
the desired olefinic lactone as a clear yellow liquid in 70% yield: 1H
NMR (400 MHz, CDCl3) δ 5.77 (m, 1H), 5.01 (m, 2H), 4.25 (t, J )
7.32 Hz, 2H), 3.53 (t, J ) 5.56 Hz, 2H), 2.21-2.10 (m, 3H), 2.04 (m,
Dihydro-3-(3-iodopropyl)-((3Z)-4-(trimethylsilyl)-3-butenyl)furan-
2(3H)-one (15b). General Procedure for the Preparation of (Z)-
(17) 4-Iodo-1-(trimethylsilyl)-1-butyne, 3-bromo-1-(trimethylsilyl)-1-pro-
pyne, and 5-iodo-1-(trimethylsilyl)-1-pentyne were prepared from 3-butyn-
1-ol, propargyl alcohol, and 4-pentyn-1-ol, respectively, according to the
following general procedures: (a) Overman, L. E.; Brown, M. J.; McCann
S. F. In Organic Synthesis; White, J. D., Ed.; Wiley: New York, 1989;
Collect. Vol. 68, p 182. (b) Miller, B. Synth. Commun. 1972, 2, 267.
(16) Hermann, J. L.; Schlessinger, R. H. J. Chem. Soc., Chem. Commun.
1973, 711.

Sequenced NAS/Ketyl-Olefin Coupling Reactions
J. Am. Chem. Soc., Vol. 118, No. 17, 1996 4067
Olefins from (Trimethylsilyl)alkynes.18 Substrate 14a (1.13 g, 3.0
mmol) in 5 mL of dry THF was added dropwise to a slurry of
dicyclohexylborane (3.3 mmol, 0.05 M in THF) at 0 °C. The resultant
reaction mixture was stirred for 2 h at 0 °C and then 1.5 h at room
temperature. During this time the initial white precipitate disappeared
and the reaction mixture became clear and colorless. After this period
of time, the reaction mixture was diluted with 0.76 mL of glacial acetic
acid and heated at 55-60 °C for several hours. The reaction mixture
was quenched by the careful addition of saturated aqueous NaHCO3.
After an aqueous workup, the crude product was dissolved in 10 mL
of THF and cooled to 0 °C, whereupon a solution of 0.70 mL of 3 N
NaOAc and 0.45 mL of 30% H2O2 was added slowly dropwise. The
reaction mixture was stirred at 0 °C for 1 h and at room temperature
for 1.5 h. The reaction mixture was quenched by the addition of H2O
and subjected to an aqueous workup. Flash chromatography with 10%
EtOAc/hexanes afforded 15d as a clear yellow oil (0.88 g, 2.31 mmol)
in 77% yield: 1H NMR (400 MHz, CDCl3) δ 6.19 (m, 1H), 5.51 (d, J
) 13.94 Hz, 1H), 4.25 (t, J ) 7.56 Hz, 2H), 3.16 (t, J ) 6.16 Hz, 2H),
2.22-2.06 (m, 4H), 1.91-1.53 (m, 6H), 0.10 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 180.30, 146.65, 130.46, 65.05, 45.30, 36.62, 35.58,
32.38, 28.20 (2), 5.96, -0.14 (3).
Dihydro-3-(4-iodobutyl)-3-((4Z)-5-(trimethylsilyl)-4-pentenyl)fu-
ran-2(3H)-one (15c) was prepared from 14b according to the general
procedure outlined for the preparation of 15b to afford 15c in 81%
yield after flash chromatography with 8% EtOAc/hexanes: 1H NMR
(300 MHz, CDCl3) δ 6.23 (m, 1H), 5.49 (d, J ) 13.92 Hz, 1H), 4.23
(t, J ) 7.08 Hz, 2H), 3.17 (t, J ) 6.83 Hz, 2H), 2.12 (m, 4H), 1.80 (m,
2H), 1.62-1.44 (m, 6H), 1.33 (m, 2H), 0.09 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 180.94, 147.78, 130.02, 65.13, 45.77, 35.59, 34.76,
33.39, 33.36, 32.19, 25.15, 25.15, 24.30, 6.32, 0.23 (3).
Ethyl 6-((tert-Butyldimethylsilyl)oxy)hexanoate (17a). General
Procedure for the Preparation of tert-Butyldimethylsilyl Ethers.19
Imidazole (17.0 g, 250.0 mmol) and tert-butyldimethylsilyl chloride
(18.1 g, 120.0 mmol) were added successively to a stirred solution of
ethyl 6-hydroxyhexanoate in 30 mL of DMF. The resultant reaction
mixture became slightly warm and was heated at 40-50 °C for 12 h.
The reaction was quenched by the addition of water and subjected to
an aqueous workup, extracting with pentane. Flash chromatography
with 5% EtOAc/hexanes afforded 17a (26.29 g, 96.0 mmol) in 96%
yield: 1H NMR (300 MHz, CDCl3) δ 4.10 (q, J ) 7.08 Hz, 2H), 3.58
(t, J ) 6.35 Hz, 2H), 2.28 (t, J ) 7.33 Hz, 2H), 1.62 (m, 2H), 1.51 (m,
2H), 1.35 (m, 2H), 1.23 (t, J ) 7.08 Hz, 3H), 0.87 (s, 9H), 0.02 (s,
6H); 13C NMR (100 MHz, CDCl3): δ 173.76, 62.96, 60.15, 34.36,
32.46, 25.94 (3), 25.42, 24.80, 18.33, 14.23, -5.20 (2).
Ethyl 2-(4-hydroxybutyl)-7-(trimethylsilyl)-6-heptynoate was pre-
pared from 17a according to the general procedure for the preparation
of 12a by alkylation of 17a with 5-iodo-1-(trimethylsilyl)-1-pentyne15
to afford the alkylated tert-butyldimethylsilyl ether of 17a (46% yield),
which was chromatographed through a short plug of silica gel to remove
the residual HMPA and then subjected to the following reaction
conditions. Removal of the primary tert-butyldimethylsilyl protecting
group was accomplished by stirring the protected alcohol in a 3:1:1
mixture of THF/AcOH/H2O at room temperature overnight. After this
period of time, the reaction mixture was diluted in 20 mL of brine and
subjected to an aqueous workup, extracting with ethyl acetate. Flash
chromatography with 35% EtOAc/hexanes afforded the title compound
in 39% overall yield from 17a: 1H NMR (300 MHz, CDCl3) δ 4.12
(q, J ) 7.32 Hz, 2H), 3.62 (q, J ) 6.34 Hz, 2H), 2.33 (m, 1H), 2.20
(t, J ) 7.08 Hz, 2H), 1.68-1.41 (m, 9H), 1.38-1.30 (m, 2H), 1.24 (t,
J ) 7.32 Hz, 3H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.05,
106.86, 84.84, 62.72, 60.19, 45.14, 32.60, 32.00, 31.41, 26.34, 23.56,
19.74, 14.35, 0.15 (3).
Ethyl 2-(4-((tert-butyldimethylsilyl)oxy)butyl)-6-(trimethylsilyl)-
5-hexynoate (18c) was prepared according to the general procedure
for the preparation of 12a by alkylation of 17a with 4-iodo-1-
(trimethylsilyl)-1-butyne15 to afford 18c in 20% yield after flash
chromatography with 3% EtOAc/hexanes: 1H NMR (300 MHz, CDCl3)
δ 4.10 (m, 2H), 3.58 (m, 2H), 2.28 (t, J ) 7.57 Hz, 2H), 2.21 (m, 1H),
1.62 (m, 2H), 1.49 (m, 4H), 1.35 (m, 2H), 1.23 (t, J ) 7.57 Hz, 3H),
0.86 (s, 9H), 0.12 (s, 6H), 0.02 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 173.76, 106.35, 85.25, 62.70, 62.89, 60.19, 44.50, 34.38, 32.64, 25.44
(3), 24.82, 23.52, 18.34, 14.30, 0.10 (2), -5.30 (3).
Methyl 2-(3-chloropropyl)-6-(trimethylsilyl)-5-hexynoate was pre-
pared according to the general procedure for the preparation of 12a by
alkylation of methyl 5-chlorovalerate with 4-iodo-1-(trimethylsilyl)-1-
butyne15 to afford the title compound in 45% yield after flash
chromatography with 8% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3)
δ 3.67 (s, 3H), 3.51 (t, J ) 6.30 Hz, 2H), 2.52 (m, 1H), 2.23 (m, 2H),
1.87 (m, 1H), 1.79-1.62 (m, 5H), 0.12 (s, 9H).
(1R*,2S*,5R*)-5-(2-Hydroxyethyl)-2-methylbicyclo[3.3.0]octan-
1-ol (16a). General Procedure for the SmI2-Induced Nucleophilic
Acyl Substitution/Ketyl-Olefin Coupling Reactions. Diiodomethane
(0.937 g, 3.50 mmol) was added to a vigorously stirred solution of Sm
(0.58 g, 3.89 mmol) in 25 mL of dry THF. The resultant blue-green
reaction mixture was stirred for 2.5 h at room temperature, and then
HMPA (3.0 mL) was added. The resultant deep purple solution was
stirred for 15 min at room temperature. The reaction mixture was
cooled to 0 °C, and substrate 15a (0.216 g, 0.70 mmol) was added
slowly dropwise over 2 h as a 0.05 M solution in THF. After the
substrate addition was complete, the reaction mixture was warmed to
room temperature and stirred an additional 30-45 min. TLC and GC
analysis at this time revealed the complete consumption of starting
material and the formation of a single diastereomeric product. The
reaction was quenched with saturated aqueous NaHCO3. Aqueous
workup followed by flash chromatography (25% EtOAc/hexanes)
afforded 16a as a clear colorless oil (0.080 g, 0.43 mmol) in 61%
yield: 1H NMR (400 MHz, CDCl3) δ 3.76 (t, J ) 7.33 Hz, 2H), 2.35
(s, 2H), 1.80 (m, 2H), 1.69 (t, J ) 6.33 Hz, 2H), 1.66-1.45 (m, 6H),
1.37 (m, 2H), 1.10 (m, 1H), 0.97 (d, J ) 6.72 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 91.14, 59.85, 53.14, 44.70, 41.04, 39.47, 36.59, 36.41,
30.05, 23.79, 13.59; IR (CCl4) 3635.3, 3466.0, 1032.6 cm-1; HRMS
calcd for C11H20O2 184.1463, found 184.1470; LRMS (EI+) m/z 184
(18), 141 (100), 128 (99), 109 (31), 97 (96), 81 (41), 67 (35), 55 (49),
41 (96). Anal. Calcd for C11H20O2: C, 71.70; H, 10.94. Found: C,
71.57; H, 10.89.
Methyl 2-(3-iodopropyl)-6-(trimethylsilyl)-5-hexynoate (19a) was
prepared from methyl 2-(3-chloropropyl)-6-(trimethylsilyl)-5-hexynoate
according to the general procedure outlined for the preparation of 15a
to afford 19a in 88% yield after flash chromatography with 4%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 3.15 (t,
J ) 6.76 Hz, 2H), 2.51 (m, 1H), 2.21 (m, 2H), 1.89-1.53 (m, 6H),
0.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.55, 105.89, 85.36,
51.67, 43.31, 32.67, 30.98, 30.76, 17.95, 5.80, 0.10 (3).
Methyl 2-(3-chloropropyl)-7-(trimethylsilyl)-6-heptynoate was
prepared according to the general procedure outlined for the preparation
of 12a by alkylation of methyl 5-chlorovalerate with 5-iodo-1-
(trimethylsilyl)-1-hexyne15 to afford the title compound in 61% yield
after flash chromatography with 3-4% EtOAc/hexanes: 1H NMR (300
MHz, CDCl3) δ 3.66 (s, 3H), 3.51 (t, J ) 5.86 Hz, 2H), 2.38 (m, 1H),
2.21 (t, J ) 7.08 Hz, 2H), 1.77-1.57 (m, 6H), 1.48 (m, 2H), 0.12 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 175.99, 106.62, 84.97, 51.56,
44.59, 44.31, 31.27, 30.28, 29.40, 26.19, 19.66, 0.12 (3).
(1R*,2S*,5R*)-5-(2-Hydroxyethyl)-2-((trimethylsilyl)methyl)bi-
cyclo[3.3.0]-octan-1-ol (16b) was prepared from 15b according to the
general procedure outlined for the preparation of 16a to afford 16b as
a single diastereomer in 92% yield after flash chromatography with
25% EtOAc/hexanes: mp 89.0-90.5 °C; 1H NMR (400 MHz, CDCl3)
δ 3.75 (t, J ) 6.43 Hz, 2H), 2.34 (s, 2H), 1.82-1.54 (m, 8H), 1.50-
1.33 (m, 4H), 1.02 (m, 1H), 0.78 (dd, J ) 3.07, 14.36 Hz, 1H), 0.41
(dd, J ) 11.38, 14.37 Hz, 1H), -0.01 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 92.01, 59.77, 52.27, 46.34, 41.08, 39.53, 36.91, 36.41, 29.92,
23.61, 16.16, -0.81 (3); IR (CCl4) 3252.5 cm-1; HRMS calcd for
C14H28O2Si 256.1859, found 256.1848; LRMS (EI+) m/z 256 (31), 238
(28), 223 (98), 211 (70), 193 (42), 169 (38), 128 (100), 73 (97). Anal.
Calcd for C14H28O2Si: C, 65.57; H, 11.00. Found: C, 65.23; H, 11.26.
Methyl 2-(3-iodopropyl)-7-(trimethylsilyl)-6-heptynoate (19b) was
prepared from methyl 2-(3-chloropropyl)-7-(trimethylsilyl)-6-heptynoate
according to the general procedure outlined for the preparation of 15a
to afford 19b in 84% yield after flash chromatography with 4%
(18) (a) Hoshi, M.; Masada, Y.; Arase, A. Chem. Lett. 1991, 251. (b)
Zweifel, G.; Polston, N. L. J. Am. Chem. Soc. 1970, 92, 4068.
(19) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.

4068 J. Am. Chem. Soc., Vol. 118, No. 17, 1996
Molander and Harris
EtOAc/hexanes: 1H NMR (300 MHz, CDCl3) δ 3.66 (s, 3H), 3.15 (t,
J ) 6.84 Hz, 2H), 2.88 (m, 1H), 2.21 (t, J ) 7.08 Hz, 2H), 1.81-1.45
(m, 8H), 0.13 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.96, 106.62,
84.99, 51.59, 44.05, 32.98, 31.26, 31.14, 26.21, 19.67, 5.96, 0.14 (3).
Ethyl 2-(4-bromobutyl)-6-(trimethylsilyl)-5-hexynoate (19c) was
prepared from 18c according to the general procedure for the preparation
of 19d by protecting group removal under acidic conditions (AcOH/
THF/H2O (3:1:1)) followed by bromination with CBr4/PPh3 to afford
19c in 40% yield from 18c: 1H NMR (400 MHz, CDCl3) δ 4.12 (q, J
) 7.06 Hz, 2H), 3.37 (m, 2H), 2.47 (m, 1H), 2.29 (t, J ) 7.39 Hz,
1H), 2.22 (q, J ) 7.23 Hz, 1H), 1.84 (m, 3H), 1.63 (m, 2H), 1.45 (m,
3H), 1.24 (m, 3H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.36,
106.12, 85.13, 60.32, 40.20, 33.37, 32.46, 31.03, 30.83, 25.75, 17.94,
14.29, 0.08 (3).
Ethyl 2-(4-Bromobutyl)-7-(trimethylsilyl)-6-heptynoate (19d).
General Procedure for the Preparation of Bromides from Alcohols.
CBr4 (3.3 g, 9.88 mmol) and PPh3 (2.70 g, 10.27 mmol) were added
successively to a solution of ethyl 2-(4-hydroxybutyl)-7-(trimethylsilyl)-
6-heptynoate (1.18 g, 3.95 mmol) dissolved in 20 mL of Et2O. The
resultant reaction mixture was stirred at room temperature for 18 h.
After this period of time, the reaction mixture was dilluted in pentane
and filtered through a plug of Celite to remove most of the phosphorus
salts. Flash chromatography of the resultant concentrated reaction
mixture with 5% EtOAc/hexanes afforded 19d (1.18 g, 3.27 mmol) in
83% yield: 1H NMR (400 MHz, CDCl3) δ 4.13 (q, J ) 7.14 Hz, 2H),
3.73 (t, J ) 6.72 Hz, 2H), 2.33 (m, 1H), 2.21 (t, J ) 7.08 Hz, 2H),
1.84 (m, 2H), 1.80-1.39 (m, 8H), 1.24 (t, J ) 7.08 Hz, 3H), 0.12 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 175.81, 106.77, 84.87, 60.23,
44.96, 33.45, 32.58, 31.38, 31.45, 26.27, 25.94, 19.71, 14.34, 0.14 (3).
(1R*,5S*)-2-((E)-(Trimethylsilyl)methylene)bicyclo[3.3.0]octan-
1-ol (20a) was prepared from 19a according to the general procedure
outlined for the preparation of 16a to afford 20a as a single diastereomer
in 85% yield after flash chromatography with 8% EtOAc/hexanes: 1H
NMR (400 MHz, CDCl3) δ 5.57 (m, 1H), 2.44 (m, 2H), 2.19 (m, 1H),
2.03 (m, 1H), 1.91 (m, 1H), 1.78-1.61 (m, 4H), 1.39-1.24 (m, 3H),
0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 167.78, 117.96, 91.22,
51.04, 40.91, 32.07, 31.36, 29.28, 25.26, -0.36 (3); IR (CCl4) 3354.2,
1631.6, 914.6 cm-1; HRMS calcd for C12H22OSi 210.1440, found
210.1444; LRMS (EI+) m/z 210 (8), 195 (48), 177 (54), 165 (38), 75
(100). Anal. Calcd for C12H22OSi: C, 68.51; H, 10.54. Found: C,
68.09; H, 10.29.
1H), 1.93 (m, 1H), 1.69-1.22 (m, 12H), 0.08 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 163.17, 118.59, 75.47, 73.19, 46.08, 44.75, 35.31,
32.32, 31.41, 29.08, 28.93, 28.71, 27.78, 27.56, 26.00, 22.12, 0.30,
0.28; IR (CCl4) 3445.7, 1611.1, 907.3 cm-1; HMRS calcd for C14H26-
OSi 238.1753, found 238.1754; LRMS (EI+) m/z 223 (28), 205 (100),
179 (53), 119 (90), 75 (99). Anal. Calcd for C14H26OSi: C, 70.52;
H, 10.99. Found: C, 70.82; H, 10.74.
(1R*,5R*)-5-(2-Hydroxyethyl)-2-((E)-(trimethylsilyl)methylene)-
bicyclo[3.3.0]octan-1-ol (21a) was prepared from 14a according to
the general procedure outlined for the preparation of 16a to afford 21a
as a single diastereomer in 81% yield after flash chromatography with
1
23% EtOAc/hexanes: mp 70-71 °C; H NMR (400 MHz, C6D6) δ
5.81 (m, 1H), 3.38 (m, 2H), 2.28 (m, 2H), 1.94 (m, 1H), 1.74 (m, 4H),
1.47 (m, 6H), 1.21 (m, 1H), 0.15 (s, 9H); 13C NMR (100 MHz, C6D6)
δ 168.17, 117.48, 90.54, 59.40, 53.52, 41.28, 38.42, 37.91, 34.17, 29.32,
22.77, -0.13 (3); IR (CCl4) 3630.8, 3600.0, 1438.5, 3292.3, 1623.1
cm-1; HRMS calcd for C14H26O2Si 254.1702, found 254.1694; LRMS
(EI+) m/z 221 (32), 192 (31), 165 (27), 120 (96), 105 (23), 91 (29), 75
(100). Anal. Calcd for C14H26O2Si: C, 66.09; H, 10.30. Found: C,
65.84; H, 10.53.
Methyl 2-acetyl-6-(trimethylsilyl)-5-hexynoate was prepared from
methyl acetoacetate according to the general procedure outlined for
the preparation of 8 to afford the title compound in 56% yield after
flash chromatography with 8% EtOAc/hexanes and Kugelrohr distil-
lation (ot 100-110 °C at 20 mmHg): 1H NMR (300 MHz, CDCl3) δ
3.73 (s, 3H), 2.26 (s, 3H), 2.13-1.99 (m, 5H), 0.13 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 202.68, 169.76, 105.05, 86.34, 57.68, 52.51, 29.57,
26.51, 17.76, 0.04 (3).
7-(Trimethylsilyl)-6-heptyn-2-one (22) was prepared according
to the general procedure.20 A solution of methyl 2-acetyl-6-(trimeth-
ylsilyl)-5-hexynoate (0.152 g, 0.63 mmol), LiCl (0.085 g, 2.0 mmol),
and H2O (0.03 g, 2.0 mmol) in 5 mL of HMPA was heated at 140 °C
for 6 h with vigorous stirring. TLC analysis of the reaction mixture
after this period of time showed complete consumption of starting
material with the formation of a single product. The reaction mixture
was cooled to room temperature and quenched with water. An aqueous
workup followed by flash chromatography with 7% EtOAc/hexanes
provided 22 (74.7 mg, 0.41 mmol) as a clear colorless oil in 65%
yield: 1H NMR (400 MHz, CDCl3) δ 2.55 (t, J ) 7.26 Hz, 2H), 2.24
(t, J ) 6.90 Hz, 2H), 2.14 (s, 3H), 1.75 (pent, J ) 7.06 Hz, 2H), 0.13
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 208.38, 106.31, 85.41, 42.16,
30.09, 22.39, 19.16, 0.14 (3).
1-Methyl-2-((E)-(trimethylsilyl)methylene)cyclopentan-1-ol (23)
was prepared according to the following general procedure. Substrate
22 (13.8 mg, 0.076 mmol) was added dropwise as a 0.05 M solution
in THF to a stirred solution of SmI2 (prepared from Sm (0.02 g, 0.21
mmol) and CH2I2 (0.051 g, 0.19 mmol) in 3 mL of dry THF) and
HMPA (0.20 mL) at 0 °C. After addition of the substrate was complete,
the reaction mixture was warmed to room temperature. TLC/GC
analysis at this time showed complete consumption of the starting
material for formation of a single product. The reaction mixture was
quenched with saturated aqueous NaHCO3 and subjected to an aqueous
workup. Flash chromatography with 8% EtOAc/hexanes and Kugelrohr
distillation (ot 100-110 °C at 15 mmHg) provided 23 in near-
quantitative yield: 1H NMR (300 MHz, CDCl3) δ 5.56 (t, J ) 2.44
Hz, 1H), 2.51 (m, 1H), 2.34 (m, 1H), 1.82-1.54 (m, 4H), 1.40 (s, 1H),
1.28 (s, 3H), 0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 167.26,
117.65, 79.42, 41.02, 30.89, 27.08, 21.53, -0.59 (3); IR (neat) 3353.8,
1633.6, 837.6 cm-1; HRMS calcd for C10H20OSi 184.1283, found
184.1278; LRMS (EI+) m/z 169 (19), 151 (58), 123 (8), 111 (14), 94
(21), 75 (100), 61 (12), 43 (32), 28 (16).
(1R*,6R*)-2-((Trimethylsilyl)methylene)bicyclo[4.3.0]nonan-1-
ol (20b) was prepared from 19b according to the general procedure
outlined for the preparation of 16a to afford 20b as a 4:1 mixture of E
and Z isomers in 61% combined yield after flash chromatography with
1
7% EtOAc/hexanes: mp 94-95 °C; H NMR (400 MHz, CDCl3) δ
5.62 (s, 1H), 2.56 (m, 1H), 2.06 (m, 3H), 1.82 (m, 3H), 1.69 (m, 2H),
1.37 (m, 2H), 1.26 (s, 1H), 1.19 (m, 2H), 0.09 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 160.97, 118.85, 84.69, 51.23, 36.40, 32.20, 31.25,
30.44, 26.95, 21.02, 0.28 (3); IR (CCl4) 3597.7, 1609.2, 1248.0, 866.5
cm-1; HRMS calcd for C13H23OSi (M - H)+ 223.1518, found 223.1521;
LRMS (EI+) m/z 206 (23), 191 (72), 151 (18), 134 (27), 119 (42), 106
(40), 91 (38), 75 (98), 59 (42). Anal. Calcd for C13H25OSi: C, 69.58;
H, 10.78. Found: C, 70.11; H, 10.72.
(1R*,6S*)-9-((E)-Trimethylsilyl)methylene)bicyclo[4.3.0]nonan-
1-ol (20c) was prepared from 19c according to the general procedure
outlined for the preparation of 16a to afford 20c as a single diastereomer
in 77% yield after flash chromatography with 8% EtOAc/hexanes: mp
1
57-58 °C; H NMR (400 MHz, CDCl3) δ 5.48 (t, J ) 2.47 Hz, 1H),
2.43 (m, 2H), 1.81 (m, 2H), 1.67 (m, 2H), 1.47 (m, 4H), 1.30 (s, 1H),
1.29 (m, 3H), 0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.53,
117.48, 80.09, 45.35, 33.77, 28.26, 26.52, 25.50, 22.97, 22.59, -0.51
(3); IR (CCl4) 3604.1, 3468.7, 1960.7, 1627.2, 844.3 cm-1; HRMS calcd
for C13H24OSi 224.1596, found 224.1588; LRMS (EI+) m/z 224 (11),
209 (61), 191 (100), 165 (89), 75 (98). Anal. Calcd for C13H24OSi:
C, 69.58; H, 10.78. Found: C, 70.04; H, 10.93.
3-((tert-Butyldimethylsilyl)oxy)propyl cyclopentanecarboxylate
(24) was prepared from cyclopentanecarboxylic acid and the tert-
butyldimethylsilyl ether of 1,3-propanediol21 according to the following
general procedure. 1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide
methiodide (EDCI; 5.77 g, 19.4 mmol) and a catalytic amount of DMAP
were added to a stirred solution of cyclopentanecarboxylic acid (1.71
g, 15.0 mmol) dissolved in 10 mL of CH2Cl2 and stirred at room
(1R*,6R*)-2-((Trimethylsilyl)methylene)bicyclo[4.4.0]decan-1-
ol (20d) was prepared from 19d according to the general procedure
outlined for the preparation of 16a to afford 20d as a 1:1 mixture of E
and Z isomers in 80% yield after flash chromatography with 5%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.53 (s, 0.5H), 5.28
(s, 0.5H), 2.49 (m, 1H), 2.34 (m, 1H), 2.13 (dt, J ) 13.31, 9.24 Hz,
(20) Bunce, R. A.; Dowdy, E. D.; Jones, P. B.; Holt, E. M. J. Org. Chem.
1993, 58, 7143.
(21) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.

Sequenced NAS/Ketyl-Olefin Coupling Reactions
J. Am. Chem. Soc., Vol. 118, No. 17, 1996 4069
temperature for 12 h. After this period of time the reaction mixture
was quenched with water and subjected to an aqueous workup to afford
24 in 84% yield after flash chromatography with 5% EtOAc/hexanes:
1H NMR (400 MHz, CDCl3) δ 4.13 (q, J ) 7.12 Hz, 2H), 3.56 (m,
2H), 2.51 (m, 1H), 2.40 (m, 1H), 2.24 (m, 1H), 1.92 (m, 4H), 1.63-
(1R*,4R*,5R*)-4-(3-Chloropropyl)-1-((E)-2-(trimethylsilyl)eth-
enyl)-2-oxabicyclo[3.3.0]octan-3-one (30) was prepared from 29
according to the general alkylation procedure outlined for the prepara-
tion of 12a to afford 30 in 40% yield after flash chromatography with
4% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.06 (d, J ) 18.81
Hz, 1H), 4.93 (d, J ) 18.82 Hz, 1H), 3.51 (m, 2H), 2.33 (m, 2H), 1.99
(m, 2H), 1.83 (m, 3H), 1.72 (m, 3H), 1.56 (m, 2H), 0.05 (s, 9H).
(1R*,4R*,5R*)-4-(3-Iodopropyl)-1-((E)-2-(trimethylsilyl)ethenyl)-
2-oxabicyclo[3.3.0]octan-3-one (31) was prepared from 30 according
to the general procedure outlined for the preparation of 15a to afford
31 in 95% yield after flash chromatography with 2-3% EtOAc/
hexanes: 1H NMR (400 MHz, CDCl3) δ 6.05 (d, J ) 18.82 Hz, 1H),
5.94 (d, J ) 18.82 Hz, 1H), 3.14 (m, 2H), 2.23 (m, 2H), 2.04-1.80
(m, 3H), 1.78-1.74 (m, 4H), 1.72-1.53 (m, 2H), 0.05 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 179.03, 146.66, 128.08, 95.70, 49.97, 48.08,
39.24, 34.56, 33.29, 31.01, 24.58, 5.66, -1.37 (3).
1.38 (m, 3H), 1.23 (t, J ) 7.11 Hz, 3H), 0.86 (s, 9H), 0.01 (s, 6H); 13
C
NMR (75 MHz, CDCl3) δ 215.02, 171.12, 63.02, 61.31, 60.18, 37.91,
32.78, 30.17, 28.19, 25.89 (3), 19.53, 18.25, 14.05, -5.39 (2).
3-Hydroxypropyl 1-(4-(trimethylsilyl)-3-butynyl)cyclopentane-
carboxylate (25) was prepared by alkylation of 24 with 4-iodo-1-
(trimethylsilyl)-1-butyne15 according to the general alkylation procedure
described for the preparation of 12a and subsequent deprotection of
the primary tert-butyldimethylsilyl ether under acidic conditions (AcOH/
THF/H2O, 3:1:1) to afford 25 in 45% yield (two steps) after flash
chromatography with 20% EtOAc/hexanes: 1H NMR (400 MHz,
CDCl3) δ 4.23 (t, J ) 6.07 Hz, 2H), 3.67 (m, 2H), 2.13 (m, 2H), 2.05
(m, 2H), 1.85 (m, 5H), 1.62 (m, 4H), 1.49 (m, 2H), 0.12 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 177.59, 106.86, 84.48, 61.31, 59.18, 53.78,
37.91, 35.92 (2), 31.82, 24.88 (2), 16.80, 0.09 (3).
3-Bromopropyl 1-(4-(trimethylsilyl)-3-butynyl)cyclopentanecar-
boxylate (26) was prepared from 25 according to the general bromi-
nation procedure described for the preparation of 19d to afford 26 in
65% yield after flash chromatography with 5% EtOAc/hexanes: 1H
NMR (400 MHz, CDCl3) δ 4.18 (t, J ) 6.01 Hz, 2H), 3.44 (t, J )
6.53 Hz, 2H), 2.20-2.04 (m, 6H), 1.87 (m, 2H), 1.62 (m, 4H), 1.49
(m, 2H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.87, 106.77,
84.49, 62.20, 53.78, 37.91 (2), 31.62, 29.35, 24.87 (2), 18.83, 0.09
(3).
3-Bromopropyl 1-((3Z)-4-(trimethylsilyl)-3-butenyl)cyclopentan-
ecarboxylate (27) was prepared by hydroboration of 26 according to
the general procedure outlined for the preparation of 15b to afford 27
in 77% yield after flash chromatography with 5% EtOAc/hexanes: 1H
NMR (300 MHz, CDCl3) δ 6.20 (dt, J ) 7.08, 14.16 Hz, 1H), 5.45
(dd, J ) 1.22, 13.9 Hz, 1H), 4.18 (t, J ) 6.10 Hz, 2H), 3.44 (t, J )
6.59 Hz, 2H), 2.09 (m, 6H), 1.65 (m, 6H), 1.49 (m, 2H), 0.07 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 177.32, 147.95, 129.35, 62.09, 54.09,
39.03, 36.05 (2), 30.20, 29.38, 24.91, 24.84 (2), 0.81 (3).
(1R*,2R*)-1-(3-Hydroxypropyl)-2-((trimethylsilyl)methyl)spiro-
[4.4]nonan-1-ol (28) was prepared from 27 according to the general
procedure outlined for the preparation of 16a to afford 28 in 73% yield
after flash chromatography with 25% EtOAc/hexanes: mp 88-89 °C;
1H NMR (400 MHz, CDCl3) δ 3.64 (m, 2H), 1.97 (m, 2H), 1.75-1.43
(m, 14H), 1.34 (m, 2H), 1.16 (m, 1H), 0.71 (d, J ) 14.08 Hz, 1H),
0.38 (m, 1H), -0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 85.64,
63.79, 57.28, 45.08, 36.83, 34.35, 33.74, 29.27, 28.68, 27.04, 25.25,
23.66, 20.25, -0.82 (3); IR (CCl4) 3637.7, 3625.8, 3318.4 cm-1; HRMS
calcd for C16H32O2Si 284.2172, found 284.2166 LRMS (EI+) m/z 284
(42), 253 (34), 209 (48), 188 (100), 175 (23), 167(16), 156 (15), 144
(13), 111 (17), 73 (99). Anal. Calcd for C16H32O2Si: C, 67.54; H,
11.34. Found: C, 67.58; H, 11.76.
(1R*,2RS*,3S*,7S*,8S*)-2-((Trimethylsilyl)methyl)tricyclo[6.3.03,7]-
undecan-1,3-diol (32) was prepared from 31 according to the general
procedure outlined for the preparation of 16a, except the substrate was
added as a 0.05 M solution in THF over a period of approximately 2.5
h to SmI2/HMPA heated at reflux, which afforded 32 as a 6:1 mixture
of diastereomers epimeric at C-2 in 58% combined yield. Major
1
diastereomer, high Rf: mp 91-92 °C; H NMR (400 MHz, CDCl3) δ
2.55 (s, 1H), 2.14 (m, 1H), 1.99 (m, 2H), 1.87-1.75 (m, 3H), 1.63-
1.49 (m, 6H), 1.44-1.30 (m, 4H), 0.70 (m, 2H), 0.02 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 99.39, 94.48, 59.47, 51.37, 49.49, 39.61, 32.52,
30.29, 26.95, 26.13, 22.82, 10.12, -0.74 (3); IR (CCl4) 3620.6, 3556.2,
1249.1, 875.1 cm-1; HRMS calcd for C15H28O2Si 268.1859, found
268.1859; LRMS (EI+) m/z 268 (2), 250 (19), 235 (100), 222 (52),
156 (100), 73 (85). Anal. Calcd for C15H28O2Si: C, 67.71; H, 10.51.
Found: C, 66.76; H, 10.21. Minor diastereomer, low Rf: mp 93-94
1
°C; H NMR (400 MHz, CDCl3) δ 2.90 (s, 1H), 2.17-1.93 (m, 3H),
1.88-1.65 (m, 5H), 1.62-1.33 (m, 6H), 1.23 (m, 2H), 0.54 (dd, J )
4.46, 15.21 Hz, 1H), 0.19 (dd, J ) 8.16, 15.21 Hz, 1H), 0.02 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 102.35, 97.76, 56.63, 52.75, 51.87,
37.25, 30.62, 29.58, 27.50, 26.59, 22.48, 13.86, -0.99 (3); IR (CCl4)
3614.8, 3553.8, 3404.5, 1549.8, 1249.7, 1004.1, 810.0 cm-1; HRMS
calcd for C15H27O2Si (M - H)+ 267.1781, found 267.1732; LRMS (EI+)
m/z 250 (31), 235 (98), 222 (95), 207 (43), 156 (100), 73 (92).
Ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-oxocyclopen-
tanecarboxylate (33) was prepared according to the general procedure
outlined for the preparation of 8 by alkylation of ethyl 2-oxocyclo-
pentanecarboxylate with the tert-butyldimethylsilyl-protected ether of
3-bromo-1-propanol to afford 33 in 64% yield after flash chromatog-
raphy with 3% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 4.13
(q, J ) 7.12 Hz, 2H), 3.56 (m, 2H), 2.51 (m, 1H), 2.40 (m, 1H), 2.24
(m, 1H), 1.92 (m, 4H), 1.63-1.38 (m, 3H), 1.23 (t, J ) 7.11 Hz, 3H),
0.86 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 215.02, 171.12,
63.02, 61.31, 60.18, 37.91, 32.78, 30.17, 28.19, 25.89 (3), 19.53, 18.26,
14.05, -5.39 (2); IR (neat) 1753.4, 1724.2 cm-1
.
(1R*,5R*)-1-((E)-2-(Trimethylsilyl)ethenyl)-2-oxabicyclo[3.3.0]-
octan-3-one (29) was prepared according to the following general
procedure.22 A solution of trans-(2-bromovinyl)trimethylsilane (2.15
g, 12.0 mmol) in 10 mL of dry THF was added slowly to a slurry of
magnetically stirred Mg turnings (0.35 g, 14.4 mmol) in 5 mL of dry
THF. After the addition was complete, the reaction mixture was heated
at reflux for 1 h and then cooled to -78 °C, whereupon the Grignard
reagent was treated with ethyl 2-oxocyclopentaneacetate2a (1.70 g, 10.0
mmol) in 10 mL of THF (added Via cannula to the -78 °C cooled
solution). The resultant solution was stirred at -78 °C for 30 min and
then warmed to room temperature. TLC analysis at this time showed
complete consumption of the starting material. The reaction mixture
was quenched by the careful addition of saturated aqueous NH4Cl. An
aqueous workup followed by flash chromatography with 12% EtOAc/
hexanes afforded 29 in 45% yield: 1H NMR (400 MHz, CDCl3) δ
6.02 (d, J ) 18.79 Hz, 1H), 5.96 (d, J ) 18.80 Hz, 1H), 2.76 (dd, J )
18.11, 9.55 Hz, 1H), 2.58 (m, 1H), 2.27 (dd, J ) 18.11, 1.86 Hz, 1H),
2.02 (m, 2H), 1.75 (m, 2H), 1.54 (m, 2H), 0.04 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 177.34, 145.38, 128.35, 97.29, 43.71, 38.80, 35.91,
33.96, 24.50, -1.41 (3).
(1R*,2R*)-Ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-hy-
droxy-2-(3-(trimethylsilyl)-2-propynyl)cyclopentanecarboxylate was
prepared according to the following general procedure.23 Unactivated
zinc metal (0.26 g, 4.0 mmol) was added to a vigorously stirred mixture
of 33 (0.89 g, 2.78 mmol) and 3-bromo-1-(trimethylsilyl)-1-propyne15
(0.76 g, 4.0 mmol) in 5 mL of DMF at room temperature. Following
the addition of the zinc metal, the reaction mixture became very warm
after approximately 15-20 min. The reaction mixture was stirred at
room temperature for 2 h after the exotherm had subsided. TLC
analysis at this time showed complete consumption of the starting
material. The reaction mixture was quenched by the careful addition
of saturated aqueous NH4Cl. An aqueous workup followed by flash
chromatography with 5% EtOAc/hexanes provided the title compound
(0.84 g, 1.90 mmol) in 70% yield: 1H NMR (400 MHz, CDCl3) δ
4.11 (m, 2H), 3.56 (m, 2H), 2.49 (d, J ) 16.9 Hz, 1H), 2.38 (d, J )
16.9 Hz, 1H), 2.23 (s, 1H), 2.20 (m, 1H), 1.95 (m, 2H), 1.87-1.68 (m,
3H), 1.49 (m, 2H), 1.25 (t, J ) 7.12 Hz, 2H), 1.23 (m, 3H), 0.86 (s,
9H), 0.14 (s, 9H), 0.02 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 175.18,
102.88, 88.03, 81.70, 63.44, 60.57, 59.87, 36.50, 30.93, 29.64, 28.96,
28.23, 25.89 (3), 18.73, 18.27, 14.15, -0.05 (3), -5.35 (2); IR (neat)
3530.1, 1723.5, 841.8 cm-1
(23) Shono, T.; Ishifune, M.; Kashimura, S. Chem. Lett. 1990, 449.
.
(22) Denmark, S. E.; Habermas, K.; Hite, G. A.; Jones, T. K. Tetrahedron
1986, 42, 2821.

4070 J. Am. Chem. Soc., Vol. 118, No. 17, 1996
Molander and Harris
(1R*,2R*)-Ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-((tert-
butyldimethylsilyl)oxy)-2-(3-(trimethylsilyl)-2-propynyl)cyclopen-
tanecarboxylate (34) was prepared according to the following general
procedure.24 2,6-Lutidine (0.33 g, 3.1 mmol) and tert-butyldimethylsilyl
triflate (0.66 g, 2.5 mmol) were added successively to a stirred mixture
of (1R*,2R*)-ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-hydroxy-
2-(3-(trimethylsilyl)-2-propynyl)cyclopentanecarboxylate (0.55 g, 1.25
mmol) in 2 mL of CH2Cl2 at 0 °C. The reaction mixture was stirred
for 1 h at 0 °C and then 12 h at room temperature. TLC analysis after
this period showed complete consumption of starting material and
formation of a single product. The reaction mixture was quenched by
the careful addition of a 1% HCl solution. An aqueous workup
followed by flash chromatography with 1-2% EtOAc/hexanes afforded
34 in 92% yield: 1H NMR (400 MHz, CDCl3) δ 4.08 (q, J ) 7.13 Hz,
2H), 3.54 (m, 2H), 2.52 (d, J ) 17.1 Hz, 1H), 2.35 (d, J ) 17.1 Hz,
1H), 2.17 (m, 1H), 2.06 (m, 2H), 1.79 (m, 1H), 1.66 (m, 4H), 1.46 (m,
2H), 1.23 (t, J ) 7.08 Hz, 3H), 0.88 (s, 9H), 0.86 (s, 9H), 0.18 (s, 6H),
0.12 (s, 9H), 0.01 (s, 6H).
consumption of the starting material. The reaction mixture was
quenched with saturated aqueous NH4Cl and filtered through a plug of
Celite to remove the metal salts. An aqueous workup followed by
flash chromatography with 6% EtOAc/hexanes afforded the desired
alcohol as a 55:1 mixture of diastereomers (capillary GC) in 65% yield.
The alcohol was then subjected to the general reaction conditions
described for the preparation of 34 to afford the title compound in 94%
yield after flash chromatography with 1-2% EtOAc/hexanes: 1H NMR
(300 MHz, CDCl3) δ 4.20 (m, 1H), 4.09 (m, 1H), 3.58 (t, J ) 6.35
Hz, 2H), 2.24 (m, 3H), 1.91-1.70 (m, 5H), 1.63-1.47 (m, 5H), 1.28
(t, J ) 7.08 Hz, 3H), 1.35-1.22 (m, 5H), 0.94 (s, 9H), 0.92 (s, 9H),
0.19 (s, 9H), 0.18 (s, 6H), 0.06 (s, 6H); 13C NMR (100 MHz, CDCl3):
δ 175.68, 107.27, 84.48, 78.68, 63.58, 60.07, 55.17, 33.04, 32.84, 28.94,
28.02 (3), 26.92 (3), 26.02, 25.93, 25.65, 23.94, 23.06, 22.65, 20.69,
20.43, 18.83, 18.29, 14.40, 0.16 (3), -1.11 (2).
(1R*,2R*)-Ethyl 2-(3-bromopropyl)-2-((tert-butyldimethylsilyl)-
oxy)-1-(5-(trimethylsilyl)-4-pentynyl)cyclohexanecarboxylate (37)
was prepared from (1R*,2R*)-ethyl 2-((tert-butyldimethylsilyl)oxy)-
2-(3-((tert-butyldimethylsilyl)oxy)propyl)-1-(5-(trimethylsilyl)-4-pen-
tynyl)cyclohexanecarboxylate according to the general procedure for
the preparation of 35 to afford 37 in 52% yield (two steps) after flash
chromatography with 1-2% EtOAc/hexanes: 1H NMR (300 MHz,
CDCl3) δ 4.18 (m, 1H), 4.06 (m, 1H), 3.33 (m, 2H), 2.18 (m, 2H),
1.97-1.71 (m, 8H), 1.57-1.37 (m, 4H), 1.24 (t, J ) 7.08 Hz, 2H),
1.22-1.11 (m, 5H), 0.90 (s, 9H), 0.12 (s, 6H), 0.12 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 175.59, 107.12, 84.56, 78.50, 60.25, 55.01, 35.59,
34.21, 33.43, 28.84, 27.93, 27.21, 25.98 (3), 23.84, 23.03, 20.64, 20.32,
18.82, 14.41, 0.14 (3), -1.04, -1.08.
(1R*,6R*)-6-((tert-Butyldimethylsilyl)oxy)-1-(5-(trimethylsilyl)-4-
pentynyl)bicyclo[4.4.0]decan-2-one (38) was prepared according to
the general procedure outlined for the preparation of 16a to afford the
title compound in 88% yield after flash chromatography with 4%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 2.37 (m, 1H), 2.23-
1.25 (m, 4H), 2.04-1.93 (m, 2H), 1.85 (m, 1H), 1.66 (m, 3H), 1.46-
1.34 (m, 7H), 1.25 (m, 2H), 0.91 (s, 9H), 0.13 (s, 9H), 0.11 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 213.52, 107.10, 84.82, 78.76, 58.92,
37.67, 36.07, 34.87, 26.77, 26.24 (3), 22.29, 22.21, 21.00, 20.43, 20.30,
18.84, 0.16 (3), -1.35, -2.00; HRMS calcd for C24H44O2Si2 420.2880,
found 420.2865; LRMS (EI+) m/z 420 (2), 363 (99), 289 (9), 273 (11),
251 (26), 197 (12), 171 (11), 147 (12), 73 (100).
(1R*,2R*)-Dimethyl 2,3-O-isopropylidene-2-(2-propenyl)tartrate
(39) was prepared from (-)-dimethyl 2,3-O-isopropylidene-L-tartrate
by alkylation with allyl bromide according to the general procedure
outlined for the preparation of 12a to afford 39 in 18% yield after flash
chromatography with 7% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3)
δ 5.74 (m, 1H), 5.08 (m, 2H), 4.98 (s, 1H), 3.79 (s, 3H), 3.78 (s, 3H),
2.56 (dd, J ) 13.97, 7.34 Hz, 1H), 2.43 (dd, J ) 13.93, 6.87 Hz, 1H),
1.60 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.89,
168.68, 131.19, 119.40, 112.63, 85.37, 79.41, 52.75, 52.57, 38.82, 27.45,
25.83.
(1R*,2R*)-Dimethyl 3-(4-iodobutyl)-2,3-O-isopropylidene-2-(2-
propenyl)tartrate (40) was prepared from 39 by alkylation with 1,4-
diiodobutane according to the general procedure outlined for the
preparation of 12a to afford 40 as a single diastereomer in 35% yield
after flash chromatography with 6% EtOAc/hexanes: 1H NMR (400
MHz, CDCl3) δ 5.70 (m, 1H), 5.09 (m, 2H), 3.82 (s, 3H), 3.76 (s, 3H),
3.11 (t, J ) 6.98 Hz, 2H), 2.65 (dd, J ) 8.09, 13.48 Hz, 1H), 2.42 (dd,
J ) 5.98, 13.48 Hz, 1H), 2.00 (m, 1H), 1.79 (pent, J ) 7.08 Hz, 2H),
1.65-1.54 (m, 2H), 1.58 (s, 3H), 1.55 (s, 3H), 1.21 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 170.58, 170.12, 131.37, 119.64, 112.56, 89.85,
89.51, 52.64, 52.42, 40.01, 34.45, 33.29, 29.03, 28.95, 25.16, 5.77.
(1R*,2R*)-Dimethyl 3-(4-Iodobutyl)-2,3-O-isopropylidene-2-((E)-
3-phenyl-2-propenyl)tartrate (41). Ozone was bubbled through a -78
°C cooled solution of 40 (0.685 g, 1.56 mmol) in 5 mL of 5:1 CH2-
Cl2/MeOH solvent with catalytic NaHCO3 until a blue color persisted.
Then, argon was bubbled through the blue reaction mixture until the
blue color was no longer apparent and DMS (1 mL) was added. The
reaction mixture was warmed to room temperature and stirred overnight.
After this period of time, the reaction mixture was filtered through a
plug of Celite and concentrated in Vacuo to afford the crude aldehyde.
The crude aldehyde was dissolved in 5 mL of dry THF and treated
with the Wittig reagent derived from benzyltriphenylphosphonium
(1R*,2R*)-Ethyl 1-(3-bromopropyl)-2-((tert-butyldimethylsilyl)-
oxy)-2-(3-(trimethylsilyl)-2-propynyl)cyclopentanecarboxylate (35)
was prepared from 34 according to the general procedure outlined for
the preparation of 19d by removal of the primary tert-butyldimethylsilyl
protecting group under acidic conditions (AcOH/THF/H2O, 3:1:1)
followed by bromination with CBr4/PPh3 to afford 35 in 77% yield
(two steps) after flash chromatography with 4% EtOAc/hexanes: 1H
NMR (400 MHz, CDCl3) δ 4.10 (m, 2H), 3.36 (m, 2H), 2.54 (d, J )
17.2 Hz, 1H), 2.35 (d, J ) 17.1 Hz, 1H), 2.21 (m, 2H), 2.04 (m, 1H),
1.83-1.59 (m, 7H), 1.25 (t, J ) 7.15 Hz, 3H), 0.90 (s, 9H), 0.19 (s,
6H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.03, 104.14, 87.47,
85.36, 61.72, 60.55, 36.68, 34.25, 31.86, 31.10, 29.74, 29.17, 25.98,
19.48 (3), 18.68, 14.15, -0.06 (3), -2.31, -2.42; IR (neat) 2178.0,
1722.9, 1462,9, 1249.3, 840.1 cm-1
.
(1R*,4S*,8S*)-4-((tert-Butyldimethylsilyl)oxy)-2-((E)-trimethylsilyl)-
methylene)tricyclo[6.3.04,8]undecan-1-ol (36) was prepared according
to the general procedure outlined for the preparation of 16a to afford
36 in 81% yield after flash chromatography with 5% EtOAc/hexanes:
1
mp 107-108 °C; H NMR (400 MHz, CDCl3) δ 5.53 (m, 1H), 2.61
(d, J ) 15.27 Hz, 1H), 2.42 (dd, J ) 15.27, 2.47 Hz, 1H), 2.33 (m,
1H), 1.82 (m, 4H), 1.67-1.44 (m, 7H), 1.26 (m, 1H), 0.87 (s, 9H),
0.08 (s, 9H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.22,
116.10, 89.32, 87.07, 64.94, 45.72, 43.53, 42.96, 35.11, 33.94, 25.82
(3), 34.18, 23.89, 18.12, -0.12 (3), -2.45, -2.52; IR (CCl4) 3600.1,
1633.5, 1471.4, 1248.9, 1082.4, 850.1, 836.6 cm-1; HRMS calcd for
C21H40O3Si2 380.2567, found 380.2563; LRMS (EI+) m/z 380 (12), 323
(51), 224 (23), 147 (21), 73 (60). Anal. Calcd for C21H40O2Si2: C,
66.25; H, 10.59. Found: C, 66.58; H, 10.65.
Ethyl 2-oxo-1-(5-(trimethylsilyl)-4-pentynyl)cyclohexanecarboxyl-
ate was prepared from ethyl 2-oxocyclohexanecarboxylate according
to the general procedure outlined for the preparation of 8 to afford the
title compound in 44% yield after flash chromatography with 7-8%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 4.18 (q, J ) 7.12 Hz,
2H), 2.48 (m, 1H), 2.43 (m, 2H), 1.19 (t, J ) 7.24 Hz, 2H), 1.96 (m,
1H), 1.91 (m, 1H), 1.76-1.53 (m, 4H), 1.48-1.39 (m, 3H), 1.24 (t, J
) 7.13 Hz, 3H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 207.83,
171.87, 106.83, 84.75, 61.19, 60.64, 41.03, 35.94 33.87, 27.57, 23.67,
22.48, 20.23, 14.16, 0.12 (3).
(1R*,2R*)-Ethyl 2-((tert-Butyldimethylsilyl)oxy-2-(3-((tert-butyl-
dimethylsilyl)oxy)propyl)-1-(5-(trimethylsilyl)-4-pentynyl)cyclohex-
anecarboxylate. The tert-butyldimethylsilyl ether of 3-bromo-1-
propanol (3.47 g, 13.7 mmol) in 10 mL of dry THF was added to a
slurry of Mg metal (0.50 g, 20.6 mmol) with vigorous stirring. After
the addition of the bromide was complete, the reaction mixture was
heated at reflux for 1 h. After this period, the dark gray solution was
cooled to -78 °C and a solution of ethyl 2-oxo-1-(5-(trimethylsilyl)-
4-pentynyl)cyclohexanecarboxylate (1.69 g, 5.48 mmol) in 5-10 mL
of dry THF was added dropwise Via cannula. After the addition of
the substrate was complete, the reaction mixture was warmed to room
temperature and then heated at reflux for 12 h. After this period of
time, TLC analysis of the crude reaction mixture showed complete
(24) Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.

Sequenced NAS/Ketyl-Olefin Coupling Reactions
J. Am. Chem. Soc., Vol. 118, No. 17, 1996 4071
chloride (1.52 g, 4.0 mmol) and n-butyllithium (4.1 mmol) at -78 °C.
After the addition of the substrate was completed, the reaction mixture
was warmed to room temperature. TLC at this period showed complete
consumption of starting material. The reaction was quenched by the
addition of saturated aqueous NH4Cl. An aqueous workup followed
by flash chromatography with 5% EtOAc/hexanes afforded the desired
compound 41 as a 4:1 mixture of diastereomeric products (E major) in
64% yield (two steps): 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 5H),
6.41 (d, J ) 15.86 Hz, 1H), 6.09 (m, 1H), 3.84 (s, 3H), 3.75 (s, 3H),
3.12 (t, J ) 6.97 Hz, 2H), 2.80 (dd, J ) 8.59, 13.70 Hz, 1H), 2.60 (dd,
J ) 5.74, 13.70 Hz, 1H), 2.20 (m, 1H), 1.80 (m, 2H), 1.64 (s, 3H),
1.63 (m, 2H), 1.58 (s, 3H), 1.21 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 170.64, 170.17, 136.90, 134.70, 128.39 (2), 127.44, 126.30 (2),
122.68, 112.65, 90.01, 89.54, 52.73, 52.54, 39.39, 34.51, 33.30, 29.08,
29.05, 25.19, 5.83.
(400 MHz, CDCl3) δ 3.21 (bs, 1H), 2.41 (bs, 1H), 2.15 (m, 1H), 2.08
(m, 2H), 1.87 (m, 1H), 1.69-1.55 (m, 4H), 1.45 (m, 2H), 1.32-1.17
(m, 3H), 1.26 (s, 6H), 1.02 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
91.64, 70.97, 50.99, 46.19, 42.92, 36.95, 35.04, 32.46, 32.10, 30.02,
28.11, 25.42; IR (neat) 3316.4 cm-1; LRMS (EI+) m/z 180 (31), 165
(17), 125 (42), 107 (46), 97 (49), 84 (100), 67 (29), 59 (72), 43 (86).
Anal. Calcd for C12H22O2: C, 72.68; H, 11.18. Found: C, 72.68; H,
11.24.
Ethyl 2-(3-butenyl)-6-((tert-butyldimethylsilyl)oxy)hexanoate was
prepared by alkylation of 17a with 4-bromo-1-butene according to the
general procedure outlined for the preparation of 12a to afford the title
compound in 42% yield after flash chromatography with 2%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.74 (m, 1H), 4.96
(m, 2H), 4.11 (q, J ) 7.14 Hz, 2H), 3.56 (t, J ) 6.51 Hz, 2H), 2.32
(m, 1H), 2.02 (m, 2H), 1.72-1.41 (m, 5H), 1.29 (m, 3H), 1.23 (t, J )
7.10 Hz, 3H), 0.86 (s, 9H), 0.01 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 176.21, 137.96, 114.98, 62.94, 60.03, 45.04, 32.70, 32.25, 31.57,
25.94 (3), 23.67, 18.33, 14.32, -5.20 (2).
Ethyl 2-(3-butenyl)-6-hydroxyhexanoate was prepared from ethyl
2-(3-butenyl)-6-((tert-butyldimethylsilyl)oxy)hexanoate by treatment
with a 3:1:1 mixture of THF/AcOH/H2O at room temperature overnight,
to afford the title compound in 94% crude yield: 1H NMR (400 MHz,
CDCl3) δ 5.75 (m, 1H), 4.98 (m, 2H), 4.12 (q, J ) 7.12 Hz, 2H), 3.62
(q, J ) 6.40 Hz, 2H), 2.35 (m, 1H), 2.01 (m, 2H), 1.76-1.60 (m, 2H),
1.58-1.42 (m, 5H), 1.32 (m, 2H), 1.24 (t, J ) 7.12 Hz, 3H).
(1R*,3R*,4S*,9R*)-Methyl 4-hydroxy-3,11,11-trimethyl-10,12-
dioxatricyclo[7.3.04,9]decanoate (42) was prepared from 40 according
to the general procedure outlined for the preparation of 16a to afford
42 as a 6:1 mixture of diastereomers in 26% yield after flash
chromatography with 7% EtOAc/hexanes (major diastereomer): 1H
NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 2.31 (d, J ) 2.59 Hz, 1H),
2.10 (m, 2H), 2.02 (m, 1H), 1.78 (m, 2H), 1.70 (m, 1H), 1.52 (m, 2H),
1.51 (s, 3H), 1.46 (s, 3H), 1.33-1.20 (m, 2H), 1.07 (m, 1H), 0.94 (d,
J ) 6.22 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.58, 111.40,
93.19, 90.72, 79.15, 52.56, 40.58, 39.89, 31.37, 28.53, 28.00, 27.20,
22.49, 19.29, 11.44; IR (CCl4) 3565.1, 1734.3, 1452.1, 1371.8 cm-1
;
Ethyl 2-(4-chlorobutyl)-5-hexenoate was prepared from ethyl 2-(3-
butenyl)-6-hydroxyhexanoate according to the general procedure
outlined for the preparation of 19d replacing CCl4 for CBr4 to afford
the title compound in 82% yield after flash chromatography with 2%
EtOAc/hexanes: 1H NMR (400 MHz, CDCl3) δ 5.72 (m, 1H), 4.97
(m, 2H), 4.13 (q, J ) 7.12 Hz, 2H), 3.50 (t, J ) 6.66 Hz, 2H), 2.34
(m, 1H), 2.02 (m, 2H), 1.74 (m, 2H), 1.51 (m, 2H), 1.43-1.38 (m,
4H), 1.24 (t, J ) 7.15 Hz, 3H).
Ethyl 2-(4-iodobutyl)-5-hexenoate (46) was prepared from ethyl
2-(4-chlorobutyl)-5-hexenoate according to the general procedure
outlined for the preparation of 15a to afford 46 in 96% yield after flash
chromatography with 2% EtOAc/hexanes: 1H NMR (400 MHz, CDCl3)
δ 5.75 (m, 1H), 4.97 (m, 2H), 4.13 (q, J ) 7.16 Hz, 2H), 3.15 (t, J )
6.97 Hz, 2H), 2.34 (m, 1H), 2.01 (m, 2H), 1.80 (m, 2H), 1.70 (m, 1H),
1.60 (m, 1H), 1.55-1.35 (m, 4H), 1.25 (t, J ) 7.16 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 175.90, 137.80, 115.12, 60.19, 44.78, 33.22, 31.53,
31.49, 31.18, 28.22, 14.35, 6.51.
HRMS calcd for C15H23O5 (M - H) 283.1164, found 283.1545; LRMS
(EI+) m/z 283 (6), 269 (96), 209 (68), 181 (39), 149 (100), 121 (46),
95 (26), 59 (36), 41 (79). Anal. Calcd for C15H24O5: C, 63.36; H,
8.51. Found: C, 63.74; H, 8.97.
(1R*,3R*,4S*,9R*)-Methyl 3-benzyl-4-hydroxy-11,11-dimethyl-
10,12-dioxatricyclo[7.3.04,9]decanoate (43) was prepared from 41 (E
isomer) according to the general procedure outlined for the preparation
of 16a to afford 43 as a 10:1 mixture of diastereomers in 48% combined
yield after flash chromatography with 6-7% EtOAc/hexanes, mp 81-
82 °C (major diastereomer): 1H NMR (300 MHz, CDCl3) δ 7.34-
7.20 (m, 5H), 2.84 (s, 3H), 3.03 (d, J ) 10.99 Hz, 2H), 2.49 (d, J )
2.44 Hz, 1H), 2.32 (m, 3H), 2.11 (m, 1H), 1.84 (m, 2H), 1.73 (m, 1H),
1.66-1.53 (m, 4H), 1.55 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.50, 141.25, 128.63 (2), 128.43 (2), 125.88, 111.52, 93.26,
90.37, 79.26, 52.69, 48.10, 38.54, 34.05, 31.25, 28.58, 28.11, 27.98,
22.49, 19.40; IR (CCl4) 3569.4, 3064.5, 3027.9, 1732.8, 1584.9, 1444.2
cm-1; HRMS calcd for C21H28O5 360.1937, found 360.1935; LRMS
(EI+) m/z 345 (100), 285 (68), 257 (46), 253 (13), 225 (64), 197 (21),
117 (19), 105 (16), 91 (98), 55 (24), 41 (34). Anal. Calcd for
C21H28O5: C, 69.98; H, 7.83. Found: C, 69.68; H, 8.13.
Methyl 2-(3-iodopropyl)-5-hexenoate (44) was prepared from
methyl 5-chlorovalerate (Aldrich) by alkylation with 4-bromo-1-butene
according to the general procedure for preparation of 12a. The crude
chloride obtained was chromatographed through a short plug of silica
to remove the HMPA and then subjected immediately to a Finkelstein
reaction with NaI to afford the title compound in 45% yield (two steps)
after flash chromatography with 2% EtOAc/hexanes: 1H NMR (400
MHz, CDCl3) δ 5.73 (m, 1H), 4.98 (m, 2H), 3.66 (s, 3H), 3.15 (t, J )
6.66 Hz, 2H), 2.37 (m, 1H), 2.02 (m, 2H), 1.83-1.51 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 176.06, 137.59, 115.28, 51.52, 43.92, 33.00,
31.44 (2), 31.15, 6.00.
(1R*,6R*,9R*)-9-(2-Hydroxy-2-methylpropyl)bicyclo[4.3.0]nonan-
1-ol (47) was prepared from 46 according to the general procedure
outlined for the preparation of 15b. However, an electrophile, acetone
(2.0 equiv), was added dropwise in THF with the substrate 46. The
product, 47, was obtained as a single diastereomer in 67% yield after
flash chromatography with 20% EtOAc/hexanes: 1H NMR (400 MHz,
CDCl3): δ 2.91 (s, 2H), 2.10 (m, 2H), 1.96 (m, 2H), 1.81 (m, 2H),
1.73-1.35 (m, 6H), 1.34-1.13 (m, 4H), 1.23 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 77.51, 70.96, 46.46, 44.87, 42.20, 31.92, 28.34, 28.19,
27.68, 24.17, 23.27, 20.94, 20.22; IR (neat) 3320.2 cm-1; LRMS (EI)
m/z 194 (34), 139 (23), 121 (54), 98 (100), 83 (33), 59 (57), 41 (67).
Anal. Calcd for C13H24O2: C, 73.55; H, 11.39. Found: C, 73.27; H,
11.30.
(1R*,2R*,5R*)-2-(2-Hydroxy-2-methylpropyl)bicyclo[3.3.0]octan-
1-ol (45) was prepared from 44 according to the general procedure
outlined for the preparation of 47 to afford 45 as a single diastereomer
in 66% yield after flash chromatography with 22-23% EtOAc/hexanes
and Kugelrohr distillation (ot 80-90 °C at 0.05 mmHg): 1H NMR
Acknowledgment. We wish to thank the National Institutes
of Health, which has provided generous financial support for
this research.
JA952619K