Stereoselectivity of intramolecular SN′ cyclizations of alkyllithium reagents on methoxy alkenes

Article abstract of DOI:10.1021/jo052166u

The cyclization of alkyllithium reagents onto methoxy alkenes has been investigated. The alkyllithium reagent was generated by reductive lithiation of an alkyl nitrile. In an unbiased substrate, a methoxy leaving group attached to a stereogenic secondary

Full text of DOI:10.1021/jo052166u

Stereoselectivity of Intramolecular SN′ Cyclizations of Alkyllithium
Reagents on Methoxy Alkenes
Thomas E. La Cruz and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
ReceiVed October 17, 2005
The cyclization of alkyllithium reagents onto methoxy alkenes has been investigated. The alkyllithium
reagent was generated by reductive lithiation of an alkyl nitrile. In an unbiased substrate, a methoxy
leaving group attached to a stereogenic secondary carbon atom led to the cyclization product with high
optical purity. The configuration of the product demonstrated that the cyclization had proceeded with
high syn-SN′ selectivity. Previously we have shown that 2-lithiotetrahydropyran reagents cyclize to form
spirocycles with the alkene cis to the pyran oxygen. Substrates were prepared to evaluate the importance
of the configuration of the secondary allyl methyl ether against the R-alkoxy alkyllithium configuration.
In the matched case (cyano acetal 38), a very selective cyclization ensued. In the mismatched case (cyano
acetal 39), the spiro ether selectivity dominated. The syn-SN′ selectivity overcame the normal E selectivity
in the cyclization and accounted for the major product, Z-alkene 45. Thus the stereochemical preference
in these alkyllithium cyclizations is dominated by the spiroether effect, followed by the syn-SN′ selectivity
and finally the preference for E-alkene formation.
Introduction
alkenes. These SN′ cyclizations of organolithium species were
first studied systematically by the Broka and Chamberlin
groups.4 Since then other groups reported successful SN′
cyclization reactions using a variety of allyl ethers as the leaving
group,5 but fundamental questions about the preference for the
syn or anti addition of the organolithium species still remained.
Cyclizations onto allylic acetates show syn-SN′ selectivity
with soft nucleophiles such as malonates.6 The selectivity with
alkyllithium cyclizations is more confusing. Both the syn- and
The SN′ carbon-carbon bond forming cyclization reaction
of an alkyllithium species onto an allylic ether can be a valuable
tool in synthetic organic chemistry.1 Although the earliest
example of an alkyllithium cyclization involved displacement
of an alkoxy group,2 the 5-exo-trig cyclization of a carbon-
lithium bond into an unactivated alkene attracted more attention
and has been investigated more often. Both the mechanism and
the synthetic applications of the carbolithiation-cyclization
reaction have been comprehensively investigated by Bailey.3
However, the cyclization was found to be efficient only with
unactivated terminal alkenes, or electron deficient alkenes.
Alkyllithium cyclizations onto allyl ethers have a wider scope
and more potential utility than cyclizations onto unactivated
(3) (a) Bailey, W. F.; Patricia, J. J.; DelGobbo, V. C.; Jarret, R. M.;
Okarma, P. J. J. Org. Chem. 1985, 50, 1999-2000. (b) Bailey, W. F.;
Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.; Rossi, K.; Thiel, Y.; Wiberg,
K. B. J. Am. Chem. Soc. 1991, 113, 5720-5727. (c) Bailey, W. F.;
Khanolkar, A. D.; Gavaskar, K. V. J. Am. Chem. Soc. 1992, 114, 8053-
8060.
(4) (a) Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H.
J. Am. Chem. Soc. 1988, 110, 4788-4796. (b) Broka, C. A.; Lee, W. J.;
Shen, T. J. Org. Chem. 1988, 53, 1336-1338. (c) Broka, C. A.; Shen, T J.
Am. Chem. Soc. 1989, 111, 2981-2984.
(5) (a) Coldham, I.; Lang-Anderson, M. M. S.; Rathmell, R.; Snowden,
D. J. Tetrahedron Lett. 1997, 38, 7621-7624. (b) Tomooka, K.; Komine,
N.; Nakai, T. Tetrahedron Lett. 1997, 38, 8939-8942. (c) Bailey, W. F.;
Tao, Y. Tetrahedron Lett. 1997, 38, 6157-6158.
(1) (a) Review: Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002,
646, 59-67. (b) Woltering, M. J.; Frohlich, R.; Hoppe, D. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1764-1766. (c) Deng, K.; Bensari, A.; Cohen, T.
J. Am. Chem. Soc. 2002, 124, 12106-12107. (d) Yus, M.; Ortiz, R.; Huerta,
F. F. Tetrahedron 2003, 59, 8525-8542.
(2) Farnum, D. G.; Monego, T. Tetrahedron Lett. 1983, 24, 1361-1364.
10.1021/jo052166u CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/11/2006
1068
J. Org. Chem. 2006, 71, 1068-1073

Alkyllithium SN′ Cyclizations
SCHEME 1. The SN′ Cyclization of Methyl Allyl Ethers Is Syn Selective
SCHEME 2. Spiroannulation of Primary Allyl Methyl
Ethers
anti-SN′ cyclization reactions of alkoxy alkenes with organo-
lithium reagents have been reported. However, the preference
for syn or anti addition in an unbiased system has not been
investigated. Examples by Farnum2 and Lautens7 support the
view that syn-SN′ cyclization predominates, but their substrates
were structurally biased to give solely the syn-SN′ product.
Intermolecular SN2′ reactions have been investigated and in
some cases found to prefer syn-SN2′ substitution, but the
substrates are sterically biased and the conclusions may not be
general.8 Conversely, Stille showed that SN′ cyclization pref-
erentially generates E-alkenes with 10:1 to 20:1 selectivity,9 but
he assumed in his work that anti-SN′ cyclization of an organo-
lithium species was favored by analogy to cuprate additions.10
Stille’s substrate, which could only react in an anti-SN′ fashion,
cyclized efficiently.11 Both syn and anti cyclizations are possible
depending on the structural constraints of the cyclization
precursor, but which mode is preferred?
We have reported the cyclization of an unbiased substrate in
an intramolecular SN′ alkyllithium cyclization reaction.11 The
optically pure acyclic cyclization precursor 1 was prepared and
subjected to reductive lithiation by treatment with lithium di-
tert-butylbiphenylide (LiDBB) (Scheme 1).12 It was observed
that the syn-SN′ pathway predominated over the anti pathway
with a 20:1 preference.11 In accordance with Stille’s observation,
the E-alkene was found to be the major product of the
cyclization reaction. The experiment presented in Scheme 1
provided the first unbiased measure of syn- or anti-SN′ selectivity
in alkyllithium cyclizations, and set the stage for the further
development of this type of annulation reaction.
found that for each SN′ spiroannulation reaction of primary allyl
methyl ethers, the diastereomer with the alkene chain cis to the
pyran oxygen atom was formed exclusively (Scheme 2).13 In
an unbiased case, the stereochemistry at the methoxy-substituted
carbon controlled the configuration at the newly formed
stereogenic center (Scheme 1), but in the spiro ether cyclizations,
the configuration was dictated by the oxygen present in the ring.
Scheme 2 illustrates our proposal for the transition state that
leads to selective spiro ether formation, with strong lithium
coordination to the ring oxygen dictating the approach of the
alkene.13 In a related observation, Cohen has shown that
proximate alkoxylithium groups accelerate alkene cyclization
reactions.1c If both selectivity elements, spiro ether selectivity
and syn-SN′ selectivity, were combined in a single substrate,
which would predominate? Setting these two directing effects
against each other provides a criterion to measure the strength
and reliability of these stereochemical interactions that will be
useful in the design of new reactions.
The R-alkoxy alkyllithium spiroannulation reaction of primary
alkoxy alkenes has been investigated in our laboratories.13 We
(6) Ba¨ckvall, J. E.; Vågberg, J. O.; Geneˆt, J. P. J. Chem. Soc., Chem.
Commun. 1987, 159-160.
We set out to investigate the dependability of the spiroether
effect and the SN′ syn selectivity as outlined in Scheme 3. The
SN′ cyclization of an organolithium species onto a stereogenic
methoxy alkene derived from optically pure cyclic acetals was
investigated both to study the stereoselectivity and to broaden
the scope of SN′ alkyllithium cyclization reactions. Since the
syn-SN′ pathway is intrinsically preferred,11 substrate 9 is a
matched case in which the interaction of the lithium and ring
oxygen moieties and the parallel alignment of the carbon-
lithium bond with the alkene favor diastereomer 11. A proposed
transition state geometry is illustrated with structure 10. Cy-
clization of 9 is expected to take place with high diastereo-
(7) Lautens, M.; Kumanovic, S. J. Am. Chem. Soc. 1995, 117, 1954-
64.
(8) (a) Arjona, O.; de Dios, A.; de la Pradilla, R. F.; Plumet, J.; Viso, A.
J. Org. Chem. 1994, 59, 3906-3916. (b) Smith, A. B.; Pitram, S. M.; Gaunt,
M. J.; Kozmin, S. A. J. Am. Chem. Soc. 2002, 124, 14516-14517.
(9) (a) Harms, A. E.; Stille, J. R.; Taylor, S. K. Organometallics 1994,
13, 1456-1464. (b) Bailey, W. F.; Zarcone, L. M. J. Chirality 2002, 14,
163-165.
(10) (a) Magid, R. M. Tetrahedron 1980, 36, 1901-1930. (b) Gendreau,
Y.; Normant, J. F. Tetrahedron 1979, 35, 1517-1521. (c) Corey, E. J.;
Boaz, N. W. Tetrahedron Lett. 1984, 25, 3059-3062. (d) Paquette, L. A.;
Stirling, C. J. M. Tetrahedron 1992, 48, 7383-7423.
(11) La Cruz, T. E.; Rychnovsky, S. D. Chem. Commun. 2004, 2, 168-
169.
(12) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924-1930. (b) Buckmelter, A. J.; Powers, J. P.; Rychnovsky, S. D. J.
Am. Chem. Soc. 1998, 120, 5589-5590. (c) Rychnovsky, S. D.; Hata, T.;
Kim, A. I.; Buckmelter, A. J. Org. Lett. 2001, 3, 807-810.
(13) (a) Rychnovsky, S. D.; Takaoka, L. R. Angew. Chem., Int. Ed. 2003,
42, 818-820. (b) Takaoka, L. R.; Buckmelter, A. J.; LaCruz, T. E.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 528-529.
J. Org. Chem, Vol. 71, No. 3, 2006 1069

La Cruz and Rychnovsky
SCHEME 3. SN′ Cyclization of Diastereomeric Allyl Methyl Ethers
SCHEME 4. Synthesis of Optically Active Alkyl Iodide 26
selectivity. Cyclic acetal 12 is a mismatched case, making the
outcome of the cyclization reaction difficult to predict. If the
syn-SN′ selectivity takes priority, then 16 or 17 would result
depending on the importance of Li-O interaction versus E/Z
selectivity. If syn to anti selectivity is modest and E-selectivity
is important then 18 would be expected to predominate.
Cyclization of these substrates will weigh the relative importance
of syn-SN′ cyclizations, the spiroether effect, and E/Z selectivity
against each other. The outcome of these experiments will
answer fundamental questions about stereoselectivity in alkyl-
lithium spiroannulation reactions.
alcohol 22 in 81% yield, and 97% ee.15 Reduction of 22 with
RedAl gave the E-alkene 23 in 90% yield, which was then
methylated to give methyl allyl ether 24 in 95% yield.16 Removal
of the silyl group generated alcohol 25, which was then
converted to optically active alkyl iodide 26 in 97% yield.17
The same optically active methyl allyl ether 26 was used for
the initial studies of the SN′ cyclization and the more compre-
hensive alkyllithium cyclizations described herein.
Synthesis of the optically active acetals, as outlined in Scheme
5, began with â-keto ester 27 prepared by the method of
(14) Dussault, P. H.; Eary C. T.; Woller K. R. J. Org. Chem. 1999, 64,
1789-1797.
(15) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285-288. (b) Fujii, A.; Haack,
K.-J.; Hashiguchi, S.; Ikariya, T.; Matsumura, K.; Noyori, R. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 288-290.
(16) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738-8739. (b) Ishiyama, H.; Takemura, T.; Tsuda,
M.; Kobayashi, J.-I. Tetrahedron, 1999, 55, 4583-4594.
(17) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979,
978-980.
Results
Synthesis of optically active allylic ether 26, as outlined in
Scheme 4, began with the addition of the lithium anion of TIPS
ether 20 to Weinreb amide 19, derived from commercially
available 4-phenylbutanoic acid, to give the alkynyl ketone 21
in 95% yield.14 Asymmetric reduction of ketone 21 with
Noyori’s hydrogen-transfer catalyst gave the desired propargyl
1070 J. Org. Chem., Vol. 71, No. 3, 2006

Alkyllithium SN′ Cyclizations
SCHEME 5. Synthesis of Optically Active Cyclic Acetals
SCHEME 6. Alkylation of Acetals
SCHEME 7. Initial Attempts for the Reductive Cyclization
of Cyano Acetal 38
Roskamp.18 Asymmetric hydrogenation of â-keto ester 27, with
Noyori’s ruthenium BINAP catalyst, provided the desired (S)-
â-hydroxy ester 28 in 78% yield and 97% ee.19 The secondary
alcohol was protected as the TMS ether and the resulting ester
29 was then reduced to aldehyde 30. Aldehyde 30 was treated
first with TMSCN, to generate a cyanohydrin, then acetylalde-
hyde and CSA to give a mixture of cis and trans acetals 31 and
32 (78% yield) in 1:1.1 ratio, respectively.20 Minor diastereomers
related to 31 and 32, which have the methyl substituent in the
axial position at C2, were present as 3-5% of the total
diastereomeric mixture. Although acetals 31 and 32 could be
separated by silica gel chromatography, it was found that the
minor diastereomers bearing the methyl substituent in the axial
position could not be separated from the major diastereomers.
Fortunately, this minor impurity did not introduce any compli-
cations when the diastereomeric mixture was taken to the next
step of the reaction sequence. The mixture comprised of acetals
31 and 32 was treated with lithium diisopropylamide and alkyl
iodide 26 (Scheme 6) to afford the “matched” cyclization
precursor 38 in 84% yield as a single diastereomer.21 Repeating
this route along with the substitution of (S)-BINAP by (R)-
BINAP in the hydrogenation stage of the synthetic sequence
led to the formation of acetals 36 and 37. By using the same
procedure, the “mismatched” cyclization precursor 39 was
synthesized in 92% yield by alkylating the mixture of acetals
36 and 37 with iodide 26.21 With the successful synthesis of
the desired optically active cyclization precursors, the reductive
cyclizations could be investigated.
was treated with 4 equiv of LiDBB at -78 °C and the reaction
1
mixture was placed in a -40 °C bath for 1.5 h. The H NMR
spectrum of the crude reaction mixture revealed that the reduced
acetal 40 was the major product of the reaction (Scheme 7).
This experiment indicates that the SN′ cyclization of secondary
methoxy alkenes to form a spiro compound takes place more
slowly than that of primary methoxy alkenes. When the
temperature of the reaction was maintained at -78 °C for an
extended period of time (12 h), using THF as the solvent, the
desired cyclized product 41 was isolated in 54% yield. However,
a significant amount of acetal 40 was still detected. Evidently,
proton abstraction from THF by the organolithium species is
competitive with the cyclization pathway. The reaction was
repeated with a 1:1 THF/hexanes solvent mixture to reduce the
rate of THF deprotonation,22 and these conditions afforded the
best yield, 74%, of the cyclization product 41 (Scheme 8).
Cyclization precursor 39 was subjected to the identical reaction
conditions to produce the cyclization products in a combined
72% yield. The use of low temperatures, extended reaction
times, and a THF/hexanes solvent system led to good yields in
the reductive cyclization of nitriles 38 and 39 (Scheme 8).
The product distributions in the reductive cyclization reactions
are presented in Scheme 8. Cyclization of the matched acetal
38 gave rise to spirocycle 41 with >98:2 E/Z selectivity. The
coupling constant between the vinylic protons was found to be
15.4 Hz, consistent with an E-alkene geometry. The chemical
shifts of the allylic proton and allylic carbon of acetal 41 were
found to be δ 2.74 and 46.5 ppm, respectively. Furthermore,
the configuration of the newly formed allylic stereocenter of
41 was determined by nOe measurements as illustrated in Figure
1. The olefin geometry, in conjunction with the configuration
of the newly formed allylic center, leads to the conclusion that
the cyclization of the matched acetal 38 occurs by a syn-SN′
mechanism with excellent selectivity.
Initial attempts to cyclize nitrile 38 began with the procedure
successfully used in other spiroacetal cyclizations.13 Nitrile 38
(18) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258-
3260.
(19) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856-
5858.
(20) (a) Rychnovsky, S. D.; Zeller, S.; Skalitzky, D. J.; Griesgraber, G.
J. Org. Chem. 1990, 55, 5550-5551. (b) Rychnovsky, S. D.; Griesgraber,
G. J. Org. Chem. 1992, 57, 1559-1563. (c) Sinz, C. J.; Rychnovsky, S. D.
Top. Curr. Chem. 2001, 216, 51-92.
(21) The minor axial methyl isomers apparently do not alkylate efficiently
under these conditions, and were not observed in the alkylation products
38 or 39.
(22) Rychnovsky, S. D.; Mickus, D. E. Tetrahedron Lett. 1989, 30,
3011-3014.
J. Org. Chem, Vol. 71, No. 3, 2006 1071

La Cruz and Rychnovsky
SCHEME 8. Olefin Geometry and Configuration of the Allylic Stereocenter
Cyclization of the mismatched acetal 39 gave an inseparable
mixture of E and Z olefin isomers 44 and 45 in an 15:85 ratio.
The coupling constants of the vinylic protons of the major
isomer 45 were found to be ca. 10.5 Hz, consistent with a
Z-alkene assignment. The chemical shifts of the allylic proton
and carbon atoms of 45 were found to be δ 2.91 and 41.0 ppm,
respectively. The configuration of the newly formed allylic
center of 45 was determined to have the alkene cis to the ring
oxygen by nOe measurements, as illustrated in Figure 1. Thus,
the syn-SN′ cyclization predominates for the mismatched case
in moderate selectivity.
ethers, however, react more slowly and proton abstraction from
THF by the very basic R-alkoxy organolithium reagent appears
to be a competing pathway. This decomposition pathway can
be attenuated by generating the organolithium species in a
THF-hexanes solvent mixture. The optimized SN′ cyclization
of secondary methoxy alkenes is an efficient process.
Cyclization of both matched and mismatched acetals gave
exclusively products with the alkene chain cis to the ring oxygen,
in good agreement with the stereochemical outcome of the SN′
cyclization of organolithiums derived from THP systems.13
Cyclization of the matched cyano acetal 38 gave spiro product
41 with high diastereoselectivity, whereas cyclization of the
mismatched cyano acetal 39 gave a mixture of two isomeric
products, 44 and 45, with identical C7 configurations. The spiro
ether effect, resulting in an alkene cis to the ring oxygen,
dominated the stereoselectivity.
The cyclizations were completely stereoselective with respect
to the previously observed spiro ether preference. Cyclization
of the matched acetal 38 gave rise to predominantly one product,
1
acetal 41, as determined by H NMR and 13C NMR analysis.
Cyclization of the mismatched substrate 39, however, gave a
mixture of two inseparable geometric isomers that complicated
the H NMR spectrum of the product, making it difficult to
A syn-SN′ addition takes priority over anti-SN′ addition in
the cyclization of the mismatched substrate 39. The preference
for syn selectivity and the spiroether effect led to formation of
the normally disfavored Z-alkene as the major isomer 45, while
the E-alkene 44 was formed as the minor isomer. The spiroether
selectivity dominated in the formation of minor stereoisomer
44, and an anti-SN′ transition state led to the E-alkene geometry.
The dominant effect in these R-alkoxy alkyllithium cyclizations
is the spiroether preference for an alkene cis to the ring oxygen
(e.g., structure 7, Scheme 2). The preference for the syn-SN′
cyclization (e.g., structure 2, Scheme 1) is secondary, followed
by the preference for E-alkene formation previously identified
by Stille.9
1
unambiguously determine if the epimer at C7 was formed. The
products of each cyclization reaction were hydrogenated to give
enantiomeric acetals 43 and 46 as single diastereomers. The
structures of these saturated products are illustrated in Scheme
8. These experiments confirm that the minor isomer for the
mismatched cyclization, E-alkene 44, has the same C7 config-
uration as the major isomer, Z-alkene 45. The epimer at C7
was not a significant product in the cyclization of either nitrile
38 or 39.
Discussion
Organolithium reagents derived from cyano acetals 38 and
39 cyclize onto secondary methoxy alkenes in an SN′ fashion
and generate novel spiro compounds with two new stereogenic
centers. The methyl ether is a robust functional group that can
be installed at an early stage of a synthetic sequence.9a Primary
allyl methyl ethers are more reactive than simple alkenes in
the reductive cyclization reactions. Secondary allyl methyl
Conclusion
The stereoselectivity of the intramolecular SN′ cyclization of
an organolithium species derived from optically pure cyclic
acetals was investigated. The cyclization event generated a spiro
compound and simultaneously set two new stereogenic centers.
Cyclization of the matched cyano acetal 38 followed the
spiroether effect and the syn-SN′ mode to give one predominant
product with excellent E-selectivity. Cyclization of the mis-
matched cyano acetal 39 gave a mixture of stereoisomers
comprised of predominately the syn-SN′ product with the
Z-alkene accompanied by the minor anti-SN′ cyclization product
with an E-alkene geometry. In each case the spiroether effect,
with strong lithium coordination to the ring oxygen dictating
the approach of the alkene, dominated the selectivity and led
FIGURE 1. nOe measurements for major products 41 and 45.
1072 J. Org. Chem., Vol. 71, No. 3, 2006

Alkyllithium SN′ Cyclizations
Spirocycle 41. Acetal 38 (40.0 mg, 0.087 mmol) was dissolved
in 0.87 mL of 1:1 THF/hexanes. To this solution was added 0.1
mg of 1,10-phenanthroline, then the solution was cooled to -78
°C and titrated with n-BuLi (1.6 M in hexanes) to a brown-red
endpoint to remove any trace of water. A solution of LiDBB (0.87
mL, 0.35 mmol), precooled to -78 °C, was introduced into the
reaction vessel, and the resulting dark green mixture was allowed
to stir at -78 °C for 12 h. The excess LiDBB was then quenched
with 2 mL of MeOH, and the mixture was diluted with 5 mL of
water. The aqueous phase was extracted with pentane (2 × 10 mL),
then combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (20% Et2O/
pentane) to give 26.0 mg of the cyclized product 41 (>98:2 E/Z,
74% yield) as a slightly yellow oil: Rf 0.50 (10% Et2O/pentane);
to the formation of a spiro ring with a single configuration at
the spiro center and the adjacent allylic center. These experi-
ments will be useful for predicting the stereochemical outcome
of more complex alkyllithium cyclizations.
Experimental Section23
Mismatched Cyclization Precursor 39. To a 0 °C solution of
diisopropylamine (0.0920 mL, 0.655 mmol) in THF (2.18 mL) was
added n-butyllithium (1.6 M in hexanes, 0.405 mL, 0.648 mmol)
dropwise over a 5 min period. The solution was stirred at 0 °C for
0.5 h and then cooled to -78 °C. A solution of acetals 36 and 37
(0.150 g, 0.649 mmol) in 1 mL of THF was added to the reaction
mixture, and the resulting yellow solution was allowed to stir for
1 h at -78 °C. A solution of (R)-(9-iodo-4-methoxynon-5-enyl)-
benzene (26) (0.116 g, 0.324 mmol) in THF (1.00 mL) was
introduced into the reaction vessel and stirring was continued at
-78 °C for 15 h. The excess anion was quenched with a saturated
aqueous solution of NH4Cl (1 mL), the mixture was washed with
water (5 mL), and the aqueous layer was extracted with pentane (3
× 10 mL). The combined organic layers were washed with saturated
NaHCO3(aq) (2 × 5 mL) and brine (2 × 10 mL), dried over
anhydrous MgSO4, filtered, and concentrated under reduced pres-
sure. The resulting oil was purified by silica gel chromatography
(20% Et2O/pentane) to give 0.138 g (92% yield) of the desired
compound as a colorless oil: Rf 0.56 (20% Et2O/pentane); [R]D
+43 (c 0.48, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.28 (m, 4H),
7.18 (m, 6H), 5.58 (dt, 1H, J ) 15.2, 6.6 Hz), 5.29 (dd, 1H, J )
15.4, 8.1 Hz), 5.07 (q, 1H, J ) 5.1 Hz), 3.89 (m, 1H), 3.48 (m,
1H), 3.23 (s, 3H), 2.82 (ddd, 1H, J ) 14.1, 10.0, 5.4 Hz), 2.67 (m,
1H), 2.62 (t, 2H, J ) 7.1 Hz), 2.12 (m, 2H), 1.92-1.60 (m, 10H),
1.54-1.48 (m, 2H), 1.38 (d, 3H, J ) 5.1 Hz) ppm; 13C NMR (125
MHz, CDCl3) δ 142.5, 141.3, 132.7, 131.6, 128.5, 128.4, 128.3,
128.2, 126.0, 125.7, 119.0, 96.5, 82.3, 74.1, 72.8, 55.9, 40.0, 39.3,
37.0, 35.9, 35.2, 31.7, 31.0, 27.3, 22.8, 20.7 ppm; IR (neat) 2930,
1603, 1495, 1453, 1333, 1140 cm-1; HRMS (CI/ammonia) m/z
calcd for C30H40NO3 [M ]+ 461.2930, found 461.2916.
Matched Cyclization Precursor 38. Synthesis of acetal 38 was
accomplished by following the same experimental protocol that was
used for the preparation of acetal 39. The diastereomeric mixture
comprised of acetals 31 and 32 (0.278 g, 1.20 mmol) was alkylated
with alkyl iodide 26 (0.216 g, 0.602 mmol), which gave the desired
matched cyclization precursor 38 in 84% yield: Rf 0.56 (20% Et2O/
pentane); [R]D -30 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.28 (m, 4H), 7.18 (m, 6H), 5.58 (dt, 1H, J ) 15.3, 6.6 Hz), 5.29
(dd, 1H, J ) 15.5, 8.1 Hz), 5.07 (q, 1H, J ) 4.8 Hz), 3.88 (m,
1H), 3.47 (m, 1H), 3.23 (s, 3H), 2.81 (ddd, 1H, J ) 14.2, 10.2, 5.5
Hz), 2.68 (m, 1H), 2.61 (t, 2H, J ) 7.1 Hz), 2.12 (m, 2H), 1.91-
1.60 (m, 10H), 1.54-1.48 (m, 2H), 1.38 (d, 3H, J ) 5.0 Hz) ppm;
13C NMR (125 MHz, CDCl3) δ 142.5, 141.3, 132.7, 131.6, 128.5,
128.4, 128.3, 128.2, 126.0, 125.7, 119.0, 96.5, 82.3, 74.1, 72.8,
55.9, 39.9, 39.3, 37.0, 35.9, 35.2, 31.7, 31.1, 27.4, 22.8, 20.7 ppm;
IR (neat) 2928, 1603, 1496, 1454, 1378, 1143 cm-1; HRMS (CI/
ammonia) m/z calcd for C30H40NO3 [M ]+ 461.2930, found
461.2919.
1
[R]D -79 (c 0.96, CHCl3); H NMR (500 MHz, CDCl3) δ 7.31
(m, 4H), 7.20 (m, 6H), 5.51 (dd, 1H, J ) 15.3, 9.3 Hz), 5.41 (dt,
1H, J ) 15.2, 6.6 Hz), 4.82 (q, 1H, J ) 5.0 Hz), 3.77 (m, 1H),
2.80 (ddd, 1H, J ) 14.1, 9.8, 5.6 Hz), 2.72 (m, 2H), 2.62 (t, 2H,
J ) 7.6), 2.06 (q, 2H, J ) 6.9 Hz), 1.99-1.83 (m, 3H), 1.75-1.63
(m, 4H), 1.62-1.48 (m, 3H), 1.46 (m, 2H), 1.26 (d, 3H, J ) 5.1
Hz) ppm; 13C NMR (125 MHz, CDCl3) δ 142.5, 142.0, 131.6,
129.8, 128.5, 128.4, 128.3, 128.2, 125.8, 125.7, 94.8, 83.3, 72.4,
46.5, 40.7, 39.5, 37.6, 35.4, 32.1, 31.4 (2C), 31.3, 21.3, 19.2 ppm;
IR (neat) 2936, 1604, 1496, 1454, 1328, 1135 cm-1; HRMS (CI/
ammonia) m/z calcd for C28H36O2 [M]+ 404.2715, found 404.2718.
Spirocycle 45. Acetal 39 (30.0 mg, 0.065 mmol) was cyclized
by using the same experimental protocol that was developed for
the cyclization of acetal 38. Cyclic acetals 44 and 45 were isolated
as an inseparable mixture of geometric isomers (15:85 E/Z,
respectively) (18.0 mg, 72% overall yield) as a slightly yellow oil:
Major isomer 45: Rf 0.50 (10% Et2O/pentane); 1H NMR (500 MHz,
CDCl3) δ 7.29 (m, 4H), 7.19 (m, 6H), 5.53 (app. t, 1H, J ) 10.8
Hz), 5.35 (dt, 1H, J ) 10.3, 6.8 Hz), 4.64 (q, 1H, J ) 5.1), 3.65
(m, 1H), 2.91 (m, 1H), 2.78 (ddd, 1H, J ) 13.8, 9.7, 5.6 Hz), 2.68
(ddd, 1H, J ) 13.8, 9.3, 6.8 Hz), 2.62 (ddd, 2H, J ) 7.5, 7.5, 3.2
Hz), 2.10-1.95 (m, 3H), 1.88 (m, 2H), 1.74-1.61 (m, 6H), 1.50
(m, 3H), 1.25 (d, 3H, J ) 5.1 Hz) ppm; 13C NMR (125 MHz,
CDCl3) δ 142.4, 142.0, 131.4, 128.5, 128.4, 128.3, 128.2, 128.0,
125.8, 125.7, 95.2, 83.6, 72.4, 41.0, 40.9, 40.0, 37.6, 35.5, 32.1,
31.4, 31.3, 26.9, 21.3, 19.8 ppm; IR (neat) 2936, 1603, 1496, 1454,
1330, 1134 cm-1; HRMS (ESI) calcd for C28H36O2Na [M + Na]+
427.2613, found 427.2618.
Acknowledgment. The National Institutes of Health
(GM65388) provided support for this project. Novartis Phar-
maceuticals is gratefully acknowledged for fellowship support
to T.E.L.
Supporting Information Available: Experimental details for
the preparation of the cyclization substrates and the characterization
and correlation of the products as well as proton and 13C NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) The general experimental information may be found in the Sup-
porting Information.
JO052166U
J. Org. Chem, Vol. 71, No. 3, 2006 1073