Enhancement of enantioselectivity by THF in asymmetric Mo-catalyzed olefin metathesis. Catalytic enantioselective synthesis of cyclic tertiary ethers and spirocycles

Article abstract of DOI:10.1021/ja020671s

Mo-catalyzed enantioselective rearrangement of achiral cyclopentenyl tertiary ethers to chiral cyclohexenyl tertiary ethers are reported. These olefin metathesis transformations proceed efficiently and with high levels of enantioselectivity. A noteworthy

Full text of DOI:10.1021/ja020671s

Published on Web 08/17/2002
Enhancement of Enantioselectivity by THF in Asymmetric
Mo-Catalyzed Olefin Metathesis. Catalytic Enantioselective
Synthesis of Cyclic Tertiary Ethers and Spirocycles
Xin Teng,† Dustin R. Cefalo,† Richard R. Schrock,‡ and Amir H. Hoveyda*,†
Contribution from the Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467, and Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
Received May 9, 2002
Abstract: Mo-catalyzed enantioselective rearrangement of achiral cyclopentenyl tertiary ethers to chiral
cyclohexenyl tertiary ethers are reported. These olefin metathesis transformations proceed efficiently and
with high levels of enantioselectivity. A noteworthy feature of these reactions is that added tetrahydrofuran
exerts a remarkably positive influence on the enantioselectivity of the metathesis-based rearrangement.
The first examples of catalytic asymmetric synthesis of spirocyclic structures by enantioselective olefin
metathesis are also disclosed.
of ketones5 or by kinetic resolution,6 are the desired products.
These latest studies have proved not to be a routine extension
Introduction
The availability of chiral catalysts for olefin metathesis has
allowed for efficient syntheses of an assortment of carbo- and
heterocycles that are not otherwise readily accessible in the
optically pure or enriched form.,1-3 One recent advance involves
the efficient and highly enantioselective rearrangement of achiral
cyclopentenyl ethers, such as 1, to unsaturated pyrans, repre-
sented by 2, through asymmetric metathesis catalyzed by 1-5
mol % chiral Mo complex 3 (eq 1).4 The utility of the catalytic
asymmetric method has been demonstrated through a concise
synthesis of the heterocyclic segment of the anti-HIV agent
tipranavir.4
of the previously reported class of rearrangements (e.g., 1f2),
as they have led to the uncovering of a remarkable additive
effect.7
In this paper, we disclose a new method for the asymmetric
synthesis of tertiary carbocyclic ethers by Mo-catalyzed olefin
metathesis, where the presence of tetrahydrofuran (THF) as an
(1) For Mo-catalyzed asymmetric ring-closing metathesis (ARCM), see: (a)
Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.; Schrock, R. R.
J. Am. Chem. Soc. 1998, 120, 4041-4042. (b) La, D. S.; Alexander, J. B.;
Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem.
Soc. 1998, 120, 9720-9721. (c) Zhu, S.; Cefalo, D. R.; La, D. S.; Jamieson,
J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc.
1999, 121, 8251-8259. (d) Weatherhead, G. S.; Houser, J. H.; Ford, J. G.;
Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000,
41, 9553-9559. (e) Kiely, A. F.; Jernelius, J.; A.; Schrock, R.; R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2002, 124, 2868-2869. (f) Dolman, S. J.; Sattely,
E. S.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991-
6997. For an overview of chiral Mo-based olefin metathesis catalysts, see:
(g) Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J. 2001, 7, 945-950.
(2) For Mo-catalyzed asymmetric ring-opening metathesis (AROM), see: (a)
La, D. S.; Ford, J. G.; Sattely, E. S.; Bonitatebus, P. J.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 11603-11604. (b) La, D.
S.; Sattely, E. S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2001, 123, 7767-7778. (c) Weatherhead, G. S.; Ford, J. G.; Alexanian,
E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 1828-
1829.
More recently, we have investigated another set of transfor-
mations, outlined by the conversion of I to II, where a
carbocyclic tertiary ether (versus a pyran heterocycle), chiral
molecules that cannot be prepared by asymmetric alkylations
* To whom correspondence should be addressed. E-mail: amir.hoveyda@
bc.edu.
† Boston College.
‡ Massachusetts Institute of Technology.
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J. AM. CHEM. SOC. 2002, 124, 10779-10784
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A R T I C L E S
Teng et al.
Scheme 1. Mo-Catalyzed Rearrangement of Achiral 4 to Chiral
additive leads to significantly enhanced levels of enantioselec-
tivity. In addition, we report the first examples of catalytic
asymmetric synthesis of various spirocyclic structures through
Mo-catalyzed tandem olefin metathesis (see IIIfIV).8
Tertiary Ether 5
Results and Discussion
(1) Catalytic Enantioselective Synthesis of Cyclohexenyl
Tertiary Ethers. We initially selected tertiary MOM (methoxy-
methyl) ether 4 as the substrate and examined its asymmetric
rearrangement to chiral tertiary ether 5 in the presence of a
variety of chiral Mo-based catalysts.9 These studies indicated
that the Lewis acidic dichloro-imido complex 6 is a desirable
catalyst. Such conditions deliver the desired product in 78% ee
(>98% conversion).
In searching for conditions that lead to improved enantiose-
lectivity, we examined the effect of various additives. This
approach was based on the assumption that association of a
Lewis base to the Lewis acidic Mo complex might alter the
equilibrium between syn and anti Mo-alkylidenes, each of
which may exhibit substantially different levels of reactivity
and give rise to varying degrees of enantioselectivity.10 More-
over, association of the Lewis base with the Mo center may
alter the steric environment of the catalyst’s chiral pocket, which
may in turn exert a positive influence on asymmetric induction.
The expectation that the transition metal system would ef-
ficiently associate with a Lewis basic additive is supported by
the fact that all binaphtholate-derived chiral Mo catalysts are
isolated as THF-bound complexes (see 3 and 6 in eq 1 and
Scheme 1).1c,9e Within this context, as illustrated in Scheme 1,
we have established that in the presence of 2 equiv of THF
(relative to 4), under otherwise identical conditions, tertiary ether
a Equivalents are relative to the amount of the substrate.
5 can be obtained in 85% ee (versus 78% ee).11 When the
amount of THF additive is increased to 10 equiv, 5 is isolated
in 92% ee and 93% yield after silica gel chromatography
(Scheme 1).12 Although reactions are faster and additive effects
are observed when the above transformation is performed at
22 and 50 °C, enantioselectivity levels are lower than that
obtained at 4 °C.13 Two important points merit mention: (1)
Rates of formation of tertiary cyclohexenyl ethers are not
significantly altered by the presence of THF. There is, however,
<5% conversion when reaction of 4 is attempted in pure THF
(even at 50 °C). (2) Similar additive effects are not observed in
the related processes represented by the transformation shown
in eq 1. This difference in the effect of added THF, the
mechanistic basis of which is not clear at the present time,
underlines the notion that formation of carbocyclic tertiary ethers
(e.g., 5) is not a simple extension of the earlier processes
affording chiral nonracemic dihydropyrans (e.g., eq 1).
(3) For reports on asymmetric Ru-catalyzed olefin metathesis, see the following.
(a) Ru-catalyzed ARCM: Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org.
Lett. 2001, 3, 3225-3228. (b) Ru-catalyzed AROM: Van Veldhuizen, J.
J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 4954-4955.
(4) Cefalo, D. R.; Kiely, A. F.; Wuchrer, M.; Jamieson, J. Y.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 3139-3140.
(5) For examples of catalytic enantioselective addition of carbon nucleophiles
to ketones, see: (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
445-446. (b) Casolari, S.; D_Addario, D.; Tagliavini, E. Org. Lett. 1999,
1, 1061-1063.
(6) For recent reviews of metal-catalyzed kinetic resolutions, see: (a) Hoveyda,
A. H.; Didiuk, M. T. Curr. Org. Chem. 1998, 2, 537-574. (b) Cook, G.
R. Curr. Org. Chem. 2000, 4, 869-885. (c) Keith, J. M.; Larrow, J. F.;
Jacobsen, E. N. AdV. Synth. Catal. 2001, 1, 5-26.
Screening of other additives suggests that the influence of
THF is likely due to its coordinative ability rather than alteration
of the polarity of the reaction medium. For example, 5 is
obtained in 80% ee in the presence of 10 equiv of Et2O or
dichloroethane. When catalyst 3 is used in the reaction of 4,
carbocycle 5 is formed in 45% ee. Consistent with the argument
that the high Lewis acidity of 6 is critical to the additive effect,
the addition of 10 equiv of THF does not increase the
enantioselectivity of the process catalyzed by 3. Remarkably,
when 5 equiv of 2,5-dimethyl THF is used (5 mol % 6), only
23% conversion is observed after 24 h and 5 is obtained in only
38% ee. With 10 equiv of 2,5-dimethyl THF, conversion is
reduced to <10% and the desired carbocycle is obtained in 27%
ee. It is plausible that coordination of the sterically bulky
additive inhibits substrate association to the Mo center, signifi-
(7) For a review on the effect of additives on asymmetric catalytic processes,
see: (a) Vogel, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 1570-1577. For additional recent examples, see: (b) Krueger,
C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284-
4285. (c) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 8180-8186. (d) Yamasaki, S.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 1256-1257. (e) Kobayashi, S.; Ishitani, H.; Yamashita,
Y.; Ueno, M.; Shimizu, H. Tetrahedron 2001, 57, 861-866. (f) Ribe, S.;
Wipf, P. Chem. Commun. 2001, 299-307, and references therein. (g) Deng,
H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2002, 41, 1009-1012.
(8) For reports on synthesis of spirocycles by tandem olefin metathesis (with
achiral catalysts), see: (a) Bassindale, M. J.; Hamley, P.; Leitner, A.;
Harrity, J. P. A. Tetrahedron Lett. 1999, 40, 3247-3250. (b) Wallace, D.
J.; Goodman, J. M.; Kennedy, D. J.; Davies, A.J.; Cowden, C. J.; Ashwood,
M. S.; Cottrell, I. F.; Dolling, U.-H.; Reider, P. J. Org. Lett. 2001, 3, 671-
674. (c) Wallace, D. J.; Bulger, P. G.; Kennedy, D. J.; Ashwood, M. S.;
Cottrell, I. F.; Dolling, U.-H. Synlett. 2001, 357-360.
(9) For details of catalyst screening, see the Supporting Information.
(10) (a) Schrock, R. R.; Crowe, W. E.; Bazan, G. C.; DiMare, M.; O’Regan,
M. B.; Schofield, M. H. Organometallics 1991, 10, 1832-1843. (b) Oskam,
J. H.; Schrock, R. R. J. Am. Chem. Soc. 1993, 115, 11831-11845. (c)
Alexander, J. B.; Schrock, R. R.; Davis, W. M.; Hultzsch, K. C.; Hoveyda,
A. H.; Houser, J. H. Organometallics 2000, 19, 3700-3715. (d) Tsang,
W. C.; Schrock, R. R.; Hoveyda, A. H. Organometallics 2001, 20, 5658-
5669. (e) Schrock, R. R.; Jamieson, J. Y.; Dolman, S. J.; Miller, S. A.;
Bonitatebus, P. J., Jr.; Hoveyda, A. H. Organometallics 2002, 21, 409-
417.
(11) For proof of absolute stereochemistry of the products reported herein, see
the Supporting Information.
(12) Levels of enantioselectivity are not further improved in the presence of 20
equiv of THF.
(13) At 22 °C, under otherwise identical conditions as shown in Scheme 1,
reaction of 4 is complete (>95% conversion) within 2 h and 5 is obtained
in 90% ee (2 h and 77% ee without THF). At 50 °C, the desired carbocycle
is obtained in 85% ee within 2 h (80% ee in the absence of THF).
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Enhanced Enantioselectivity in Olefin Metathesis
A R T I C L E S
Scheme 2. Use of Chiral Catalyst Prepared in Situ in the
Table 1. Mo-Catalyzed Enantioselective Rearrangement of
Protected Achiral Cyclopentenol to Cyclohexenyl Tertiary Ethersa
Enantioselective Synthesis of Tertiary Ethers
a THF present is equal to 12 equiv relative to the substrates.
to catalyze the enantioselective syntheses of MOM and tert-
butyldimethylsilyl (TBS) ethers 5 and 8, respectively. Levels
of selectivity are comparable to those attained by the isolated
complex (in the presence of THF additive).
(2) Catalytic Enantioselective Synthesis of Spirocycles.
Replacement of the ether protecting groups (e.g., MOM and
TBS ethers of substrates 5 and 8) with an alkenyl unit allows
for two tandem olefin metathesis reactions and generation of
nonracemic spirocyclic structures. As the results in Table 2
illustrate, depending on the olefin substitution and the size of
the unsaturated rings formed, various achiral cyclopentenyl
a Conditions: 5 mol % 6, C6H6, 4 °C, 24 h. b Conversions determined
1
by analysis of the 400 MHz H NMR spectra of the unpurified mixtures.
c Isolated yields after silica gel chromatography. d Determined by chiral GLC
(Betadex column for entries 1-2, CDGTA column for entries 3-6); see
the Supporting Information for details. nd ) not determined.
cantly reducing reactivity; the diminution in selectivity is more
difficult to explain.14
As the data in Table 1 illustrate, various carbocyclic tertiary
ethers can be synthesized by the Mo-catalyzed method ef-
ficiently and in 85-96% ee. In all cases, enhancement in
enantioselectivity is effected in the presence of 10 equiv of THF.
Particularly noteworthy is the reaction of silyl ether 7: whereas
8 is obtained in 58% ee in the absence of an additive (entry 1),
addition of THF (10 equiv) leads to the formation of the desired
product in 96% ee (94% isolated yield).
Table 2. Mo-Catalyzed Enantioselective Synthesis of Spirobicyclic
Ethersa
The present method puts forth an effective catalytic approach
to the synthesis of tertiary ethers (and the derived alcohols after
deprotection) that cannot be accessed by alkylations of the
corresponding ketones5 or through other catalytic or stoichio-
metric protocols.15 Another attractive feature of the method is
that the requisite catalyst can be prepared in situ16 without
isolation and characterization of the Lewis acidic chiral complex
6. Thus, as shown in Scheme 2, treatment of 13 with 1 equiv
of (R)-14 in THF at -40 °C and stirring at 22 °C for 24 h
affords a solution of chiral catalyst 6 that can be used directly
(14) It should be noted that all attempts to effect Mo-catalyzed ARCM of i to
5 (at 4, 22, 50, and 80 °C) proved unsuccessful (<20% ee); this is in contrast
to the related studies reported in ref 4 (see eq 1). In addition, <5%
conversion was observed in attempts to effect a similar reaction of the
more highly substituted diene ii. These findings, collectively, suggest that
reactions of 4 and related derivatives proceed through initial formation of
a terminal Mo alkylidene followed by an ARCM (versus AROM and a
subsequent RCM).
(15) For enantioselective synthesis of tertiary ethers and alcohols through Mo-
catalyzed olefin metathesis, see: (a) Hultzsch, K. C.; Jernelius, J. A.;
Hoveyda, A. H.; Schrock, R. R. Angew. Chem., Int. Ed. 2002, 41, 589-
593. (b) References 1e and 4.
(16) For in situ preparation of another chiral Mo-based metathesis catalyst,
see: Aeilts, S. L.; Cefalo, D. R.; Bonitatebus, P. J., Jr.; Houser, J. H.;
Hoveyda, A. H.; Schrock, R. R. Angew. Chem., Int. Ed. 2001, 40, 1452-
1456.
a Conditions: indicated mol % chiral Mo catalyst, 24 h. All reactions
carried out in C6H6, except that in entry 2 (in isooctane). All reactions carried
b
out at 22 °C, except entry 1 (50 °C). Conversions determined by analysis
c
of the 400 MHz 1H NMR spectra of the unpurified mixtures. Isolated yields
d
after silica gel chromatography. Determined by chiral GLC (CDGTA
e
column for all entries). The product mixture contains 55% of achiral 18.
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A R T I C L E S
Teng et al.
trienes can be catalytically converted to spiro-bicyclic ethers
efficiently and enantioselectively (62-88% ee). Catalytic reac-
tions afford optically enriched products with the same absolute
stereochemical sense as those observed in processes shown in
Scheme 1 and Table 1.
a larger fraction of the initial minor enantiomer undergoes a
second RCM, resulting in improved yield of the spirocycle but
diminished optical purity.
(5) The nonracemic vinylsilane 23 can be further function-
alized to a variety of compounds that are not otherwise easily
accessible. Conversion to spircocycle 29, shown in eq 2, is
illustrative. It should be noted that catalytic metathesis of triene
30 (eq 3) in the presence of a range of chiral Mo complexes
leads to the formation of 29 in <5% ee.
Several issues with regard to the data in Table 2 merit
mention:
(1) Enantioselective formation of spirocycle 16 (88% ee) is
accompanied by the generation of achiral 18 (55%). To
circumvent this complication, the related trisubstituted alkene
19 (92% E) was prepared and its asymmetric conversion to 16
was examined. These studies indicate that, with 19 as the
substrate, 16 can be obtained in 80% ee and 75% isolated yield,
with <10% of byproduct 18 formed.
Conclusions
The catalytic asymmetric reactions outlined herein should
prove to be of utility, as they deliver optically enriched products
that can be further functionalized but cannot be readily prepared
by alternative methods. The effect of added THF on the levels
of asymmetric induction is mechanistically and synthetically
intriguing and might be beneficial in a number of other Mo-
catalyzed enantioselective olefin metatheses.
Future studies will be directed toward the development of
additional Mo-catalyzed protocols for asymmetric synthesis of
synthetically versatile organic molecules, a comprehensive
examination of various additives, elucidation of the correspond-
ing mechanistic principles, and related applications in target-
oriented synthesis.
(2) Screening studies indicate that depending on the substrate,
different Mo complexes serve as the optimal chiral catalyst. Such
variations can arise from either a change in alkene substitution
(entries 1 and 2), the olefin substituent (entries 3 and 4), or the
size of the ring formed (entries 2, 3, and 5). Since it is not
unusual that the identity of the optimal chiral catalyst varies as
a function of structural modification within a substrate,17 the
results in Table 2 further underline the importance of the
modular character of this class of chiral catalysts.
Experimental Section
(3) Although complex 6 is used in the formation of spirocycle
21, added THF does not improve the level of enantioselectivity.
This observation suggests that the above-mentioned additive
effect depends on subtle mechanistic factors and its validity
should be determined on a case-by-case basis.
(1) General Methods. Infrared (IR) spectra are recorded on a
ThermoNicolet Avatar 210 spectrophotometer, Vmax (cm-1). Bands were
characterized as broad (br), strong (s), medium (m), and weak (w). 1H
NMR spectra are recorded on a Varian Unity INOVA 400 (400 MHz)
or Varian Gemini 2000 (400 MHz). Chemical shifts are reported in
parts per million from tetramethylsilane with the solvent resonance as
the internal standard (CDCl3; δ 7.26). Data are reported as follows:
chemical shift, multiplicity (s ) singlet, d ) doublet, t ) triplet, q )
quartet, br ) broad, m ) multiplet), coupling constants (Hz), and
integration. 13C NMR spectra are recorded on a Varian Unity INOVA
400 (100 MHz) or Varian Gemini 2000 (100 MHz) with complete
proton decoupling. Chemical shifts are reported in parts per million
from tetramethylsilane with the solvent resonance as the internal
standard (CDCl3; δ 77.0). Enantiomer ratios were determined by chiral
GLC analysis (Alltech Associates Chiraldex GTA column (30 m ×
0.25 mm)) or BETADEX 120 column (30 m × 0.25 mm)) in
comparison with authentic materials. Elemental analyses are performed
(4) When reactions of 22 and 26 are analyzed early, a mixture
of chiral monocyclic and bicyclic products are detected, where
the spircocycles are of higher enantiomeric purity than after
complete conversion. As an example, in the reaction of
vinylsilane 22 (entry 4, Table 2), after 30 min, the product
mixture contains equal amounts of spirocycle 23 and dihydro-
pyran 25 (versus 80% 23 and 20% 25 after 5 and 24 h).
Furthermore, this sample of 23 (after 30 min of reaction) is of
higher optical purity (92% ee versus 85% ee after 5 h). These
results imply that levels of enantioselectivity can be altered in
the course of the second RCM.18 That is, one enantiomer of
the initially formed monocyclic 25 is converted more rapidly
to 23 (partial kinetic resolution).6 Thus, as the reaction proceeds,
(18) For other examples where enantioselectivity is proposed to be influenced
in two steps (in a reaction after the irreversible step) of the catalytic cycle,
see: (a) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417-1419. (b) Zhang, W.; Lee, N. H.; Jacobsen, E. N. J. Am. Chem.
Soc. 1994, 116, 425-426, and references therein.
(17) Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. Chem. Eur. J. 1998, 4,
1885-1889.
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Enhanced Enantioselectivity in Olefin Metathesis
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by Robertson Microlit Laboratories (Madison, NJ). High-resolution
mass spectrometry is performed by the University of Illinois Mass
Spectrometry Laboratories (Urbana, IL). Absolute stereochemistry is
determined by optical rotation on a Rudolph Research Analytical
Autopol IV polarimeter.
CH2dCH), 3.24 (s, 3H, CH3O), 2.32 (ddt, J ) 14.8, 7.6, 1.6 Hz, 1H,
CH2CHdCH2), 2.25 (ddt, J ) 14.4, 7.2, 1.6 Hz, 1H, CH2CHdCH2),
2.20-1.92 (m, 4H, CH2CHdCHCH2), 1.76 (m, 1H, CHdCHCH2CH2),
1.64-1.55 (m, 1H, CH2CH2CHdCH). 13C NMR (100 MHz, CDCl3):
δ 133.9, 126.5, 124.2, 117.4, 74.2, 48.6, 39.4, 34.5, 29.7, 22.9. Anal.
Calcd for C10H16O: C, 78.90; H, 10.59. Found: C, 78.69; H, 10.22.
HRMS: Cacld for C10H17O (M + 1): 153.1279. Found: 153.1281.
GLC (CDGTA: column temperature ) 80 °C (isothermal); injector
and detector temperature ) 250 °C; inlet pressure ) 15 psi): tr(major)
) 13.1 min; tr(minor) ) 13.9 min.
(d) (S)-(1-Allylcyclohex-3-enyloxymethyl)benzene (12). IR
(neat): 3068(w), 3031(m), 2930(m), 2842(m), 1640(w), 1451(m), 1281-
(w), 1092(m), 1067(m), 922(m), 740(m), 702(m) cm-1. 1H NMR (400
MHz, CDCl3): δ 7.40-7.20 (m, 5H, C6H5), 5.94 (ddt, J ) 16.8, 9.6,
7.2 Hz, 1H, CH2dCH), 5.73-5.55 (m, 1H, CHdCH), 5.14-5.06 (m,
2H, CH2dCH), 4.50 (d, J ) 11.2 Hz, 1H, CH2O), 4.47 (d, J ) 11.2
Hz, 1H, CH2O), 2.42-1.96 (m, 6H, allylic-H), 1.86 (dt, J ) 13.2, 6.0
Hz, 1H, CHdCHCH2CH2), 1.69 (dt, J ) 13.2, 6.0 Hz, 1H, CHd
CHCH2CH2). 13C NMR (100 MHz, CDCl3): δ 139.6, 134.0, 128.2,
127.3, 127.1, 126.5, 124.2, 117.4, 74.8, 63.1, 40.2, 34.7, 30.4, 23.1.
Anal. Calcd for C16H20O: C, 84.16; H, 8.83. Found: C, 84.44; H, 8.59.
HRMS. Cacld for C16H20O: 228.1514. Found: 228.1515.
All reactions are conducted in oven- (135 °C) and flame-dried
glassware under an inert atmosphere of dry nitrogen. Solvents are
purified under a positive pressure of dry Ar by a modified Advanced
Chem Tech Purification system. Benzene and toluene were sparged
with argon and passed through activated copper and alumina columns.
Tetrahydrofuran and diethyl ether are also sparged with argon and
passed through activated alumina columns. Olefin-free pentane was
generated by stirring commercial grade pentane over concentrated
sulfuric acid for 24 h. The pentane is then poured over fresh
concentrated sulfuric acid. This process was repeated until the acid
layer remained colorless for 48 h. The pentane was subsequently
separated, washed with water, dried over Na2SO4, filtered, sparged with
nitrogen, and then passed through activated alumina and activated
copper columns, respectively. All handling of the Mo catalysts was
performed in a glovebox under inert atmosphere. All substrates were
vigorously dried by azeotropic distillation with anhydrous benzene (3×)
prior to use.
(2) Representative Procedure for Mo-Catalyzed Enantioselective
Synthesis of Cyclohexenyl Tertiary Ethers. To a solution of diene 7
(36.0 mg, 0.143 mmol) in benzene (1.44 mL) and THF (117 µL, 1.43
mmol) precooled at 4 °C was added Mo catalyst 6 (7.82 mg, 7.20 `ımol)
(in one portion). The reaction vessel was sealed with a Teflon cap,
and the solution was allowed to stir at 4 °C for 24 h. At this point, the
mixture was exposed to air and was then charged with MeOH (140
µL). Removal of the volatiles in vacuo followed by silica gel
chromatography (pentanes:diethyl ether, 50:1) afforded (S)-8 (34.0 mg,
0.137 mmol, 96% yield) as a colorless oil. Optical purity of the product
was established to be 96% ee by chiral GLC.
(3) Representative Procedure for Mo-Catalyzed Enantioselective
Synthesis of Spirocycles. A 10 mL round-bottom flask was charged
with triene 20 (20.0 mg, 0.10 mmol) and benzene (1 mL) in a glovebox
under an atmosphere of nitrogen. Chiral Mo catalyst 6 (10.2 mg, 9.37
µmol) was added in one portion at 22 °C. The flask was capped with
a septum and an 18 gauge needle inserted to vent the reaction to the
glovebox atmosphere. After 24 h, the solution was exposed to air and
MeOH (180 µL) was added. Removal of the volatiles in vacuo followed
by silica gel chromatography on silica gel (pentanes: diethyl ether 50:
1) afforded (R)-21 (13.6 mg, 0.083 mmol, 80% yield). Optical purity
of the product was established to be 83% ee by chiral GLC.
(a) (S)-4-Allyl-4-(methoxymethoxy)cyclohexene (5). IR (neat):
3068(w), 3024(m), 2923(s), 2848(m), 1640(w), 1451(m), 1155(w),
.
1105(m), 1036(s), 916(m), 658(m) cm-1 1H NMR (400 MHz,
(a) (S)-2-Methyl-6-oxaspiro[4.5]deca-2,8-diene (16). IR (neat):
3035(m), 2914(s), 2831(m), 1645(w), 1435(m), 1338(w), 1179(m),
1091(s), 1012(m), 833(m), 650(m) cm-1 1H NMR (400 MHz,
.
CDCl3): δ 5.89 (ddt, J ) 17.6, 10.4, 7.2 Hz, 1H, CH2dCH), 5.70-
5.54 (m, 2H, CHdCH), 5.11-5.00 (m, 2H, CH2dCH), 4.78 (d, J )
7.2 Hz, 1H, OCH2O), 4.72 (d, J ) 7.6 Hz, 1H, OCH2O), 3.37 (s, 3H,
OCH3), 2.44-1.96 (m, 6H, allylic-H), 1.80 (ddt, J ) 13.2, 1.2, 6.0
Hz, 1H, CHdCHCH2CH2), 1.64 (dddd, J ) 12.8, 6.8, 6.0, 1.2 Hz, 1H,
CHdCHCH2CH2). 13C NMR (100 MHz, CDCl3): δ 134.1, 126.3,
124.4, 117.6, 90.8, 76.0, 55.5, 42.0, 34.9, 30.9, 23.0. Anal. Calcd for
C11H16O2: C, 72.49; H, 9.95. Found: C, 72.38; H, 10.02. GLC
(CDGTA: column temperature ) 70 °C (isothermal); injector and
detector temperature ) 250 °C; inlet pressure ) 15 psi): tr(major) )
52.0 min; tr(minor) ) 54.9 min.
CDCl3): δ 5.83-5.75 (m, 1H, CHdCH), 5.72-5.65 (m, 1H, CHd
CH), 5.28-5.20 (m, 1H, CHdCCH3), 4.30-4.20 (m, 2H, CH2O),
2.64-2.45 (m, 2H, allylic-H), 2.30-2.15 (m, 4H, allylic-H), 1.71 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3): δ 137.8, 125.6, 123.6, 121.7,
81.1, 62.0, 48.2, 44.1, 35.9, 16.9. HRMS. Calcd for C10H14O: 150.1045.
Found: 150.1049. GLC (CDGTA: column temperature ) 80 °C
(isothermal); injector and detector temperature ) 250 °C; inlet pressure
) 15 psi): tr(major) ) 23.2 min; tr(minor) ) 22.5 min.
(b) (S)-9-Methyl-1-oxaspiro[5.5]undeca-3,8-diene (21). IR
(neat): 2919(m), 2930(m), 2827(m), 1446(m), 1180(w), 1090(m), 840-
1
(m), 658(m) cm-1. H NMR (400 MHz, CDCl3): δ 5.80-5.62 (m,
(b) (S)-(1-Allyl-cyclohex-3-enyloxy)-tert-butyldimethylsilane (8).
IR (neat): 3068(w), 3018(m), 2936(s), 2854(m), 1640(w), 1476(m),
2H, CHdCH), 5.30-5.22 (m, 1H, CH3CdCH), 4.24-4.08 (m, 2H,
CH2O), 2.20-1.82 (m, 7H, allylic-H, CH3CCH2CH2) 1.67 (s, 3H, CH3),
1.60-1.48 (m, 1H, CH3CCH2CH2). 13C NMR (100 MHz, CDCl3): δ
133.6, 125.4, 122.8, 118.1, 69.6, 60.8, 36.0, 34.0, 30.9, 27.5, 23.3. Anal.
Calcd for C11H16O: C, 80.44; H, 9.82. Found: C, 80.62; H, 9.85. GLC
(CDGTA: column temperature ) 80 °C (isothermal); injector and
detector temperature ) 250 °C; inlet pressure ) 15 psi): tr(major) )
39.2 min; tr(minor) ) 41.0 min.
1
1256(m), 1098(m), 922(m), 834(m), 771(m), 671(m) cm-1. H NMR
(400 MHz, CDCl3): δ 5.93 (ddt, J ) 16.8, 10.4, 7.2 Hz, 1H, CH2d
CH), 5.66-5.51 (m, 2H, CHdCH), 5.08-4.99 (m, 2H, CH2dCH),
2.31-1.92 (m, 6H, allylic-H), 1.70-1.55 (m, 2H, CHdCHCH2CH2),
0.86 (s, 9H, C(CH3)3), 0.09 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3). 13C
NMR (100 MHz, CDCl3): δ 135.1, 126.3, 124.9, 117.0, 73.4, 45.0,
38.4, 33.9, 25.9, 23.8, 18.3, -2.0, -2.1. Anal. Calcd for C15H28OSi:
C, 71.36; H, 11.18. Found: C, 71.61; H, 10.96. GLC (BETADEX:
column temperature ) 70 °C (isothermal); injector and detector
temperature ) 250 °C; inlet pressure ) 15 psi): tr(major) ) 197.6
min; tr(minor) ) 193.5 min.
(c) (R)-Trimethyl(1-oxaspiro[5.5]undeca-3,8-dien-9-yl)silane (23).
IR (neat): 3031(w), 2949(s), 2899(s), 2829(m), 1627(m), 1426(w),
1250(s), 1180(m), 1092(s), 1016(w), 941(w), 840(s), 752(m), 651(m)
1
cm-1. H NMR (400 MHz, CDCl3): δ 5.89-5.84 (m, 1H, olefin-H),
5.78-5.68 (m, 2H, olefin-H), 4.24-4.12 (m, 2H, CH2O), 2.28-1.80
(m, 7H, allylic-H, CH2CH2CO), 1.57-1.49 (m, 1H, CH2CH2CO), 0.04
(s, 9H, CH3). 13C NMR (100 MHz, CDCl3): δ 138.1, 132.4, 125.5,
122.7, 69.7, 60.7, 37.4, 33.7, 31.2, 24.5, -2.2. Anal. Calcd for C13H22-
OSi: C, 70.21; H, 9.79. Found: C, 69.99; H, 9.69. HRMS. Cacld for
C13H22OSi: 222.1440. Found: 222.1442. GLC (CDGTA: column
(c) (S)-4-But-3-enyl-4-methoxycyclopentene (10). IR (neat): 3068-
(w), 3031(m), 2974(m), 2930(s), 2829(m), 1640(w), 1451(m), 1180-
1
(w), 1080(m), 910(m), 740(w), 658(m) cm-1. H NMR (400 MHz,
CDCl3): δ 5.86 (ddt, J ) 16.8, 10.8, 7.2 Hz, 1H, CH2dCH), 5.72-
5.64 (m, 1H, CHdCH), 5.61-5.53 (m, 1H, CHdCH), 5.09 (ddt, J )
10.0, 2.4, 1.2 Hz, 1H, CH2dCH), 5.08 (ddt, J ) 17.2, 2.0, 1.6 Hz, 1H,
9
J. AM. CHEM. SOC. VOL. 124, NO. 36, 2002 10783

A R T I C L E S
Teng et al.
temperature ) 70 °C (isothermal); injector and detector temperature
) 250 °C; inlet pressure ) 25 psi): tr(major) ) 143.8 min; tr(minor)
) 141.4 min.
71.8, 60.8, 41.7, 35.6, 34.4, 34.2, 26.0, 21.6. HRMS. Calcd for
C12H18O: 178.1359. Found: 178.1358. GLC (CDGTA: column
temperature ) 90 °C (isothermal); injector and detector temperature
) 250 °C; inlet pressure ) 15 psi): tr(major) ) 38.6 min; tr(minor) )
40.3 min.
(d) (R)-9-Methyl-1-oxaspiro[5.6]dodeca-3,8-diene (27). IR
(neat): 3032(m), 2926(m), 2852(m), 1650(w), 1446(m), 1388(w), 1180-
(w), 1092(m), 1015(w), 850(m), 828(w), 656(m) cm-1. 1H NMR (400
MHz, CDCl3): δ 5.76-5.66 (m, 2H, CHdCH), 5.33 (t, J ) 6.8 Hz,
1H, CH3CdCH), 4.13-4.05 (m, 2H, CH2O), 2.32 (dd, J ) 14.8, 6.8
Hz, 1H, CH3CHdCHCH2), 2.22 (dd, J ) 14.8, 6.8 Hz, 1H, CH3CHd
CHCH2), 2.15 (ddd, J ) 15.2, 8.8, 2.8 Hz, 1H, allylic-H), 2.08 (ddd,
J ) 15.2, 8.4, 2.8 Hz, 1H, allylic-H), 2.00-1.94 (m, 2H, CH2(CH3)Cd
CHCH2), 1.81 (t, J ) 6.0 Hz, 2H, CH2CH2CCH3), 1.73 (s, 3H, CH3),
1.75-1.58 (m, 1H, CH3CCH2CH2CH2), 1.48-1.37 (m, 1H, CH3CCH2-
CH2CH2). 13C NMR (100 MHz, CDCl3): δ 141.8, 125.3, 122.9, 118.8,
Acknowledgment. This research was supported by the NIH
(Grant GM-59426) and the NSF (Grant CHE-0213009).
Supporting Information Available: Experimental procedures
and spectral and analytical data for all substrates and proof of
stereochemistry (PDF). This material is available free of charge
via the Internet at http://www.acs.pubs.org.
JA020671S
9
10784 J. AM. CHEM. SOC. VOL. 124, NO. 36, 2002