Palladium-catalyzed stereospecific synthesis of 2,6-disubstituted tetrahydropyrans: 1,3-Chirality transfer by an intramolecular oxypalladation reaction

Article abstract of DOI:10.1021/jo060415o

PdCl₂(CH₃CN)₂ (10 mol %) catalyzed reactions of non-3-ene-2,8-diols 1 and 2 gave 2,6-disubstituted tetrahydropyrans 3 and 4 in excellent yields with high diastereoselectivities (>20:1). Intramolecular cyclizations of the h

Full text of DOI:10.1021/jo060415o

Palladium-Catalyzed Stereospecific Synthesis of 2,6-Disubstituted
Tetrahydropyrans: 1,3-Chirality Transfer by an Intramolecular
Oxypalladation Reaction
Nobuyuki Kawai, Jean-Marie Lagrange, Masashi Ohmi, and Jun’ichi Uenishi*
Kyoto Pharmaceutical UniVersity, Misasagi, Yamashina, Kyoto 607-8412, Japan
juenishi@mb.kyoto-phu.ac.jp
ReceiVed February 27, 2006
PdCl2(CH3CN)2 (10 mol %) catalyzed reactions of non-3-ene-2,8-diols 1 and 2 gave 2,6-disubstituted
tetrahydropyrans 3 and 4 in excellent yields with high diastereoselectivities (>20:1). Intramolecular
cyclizations of the hydroxy nucleophile to the chiral allylic alcohol take place efficiently under mild
conditions. A new stereogenic center is generated on the tetrahydropyran ring by 1,3-chirality transfer
from the chiral allylic alcohol via a syn-SN2′ type process. Cis tetrahydropyran 3E was formed from
syn-2,8-diols 1a and 2a, and trans tetrahydropyran 4E was formed from anti-2,8-diol 1b, stereospecifically.
Cis tetrahydropyran bearing a cis alkene 3Z was obtained from 2b at -40 °C, while 4E was formed from
2b in the presence of catalytic amount of water at -40 °C. The face selectivity of these cyclizations can
be rationalized by taking a favorable conformation of the intermediary Pd π-complex with allylic alcohols,
escaping the allylic strain and 1,3-diaxial interactions. A stereocontrolled synthesis of optically pure
2-alkenyl-6-methyltetrahydropyran 17 was achieved efficently in four steps from 6-silyloxy-1-heptyne
13 with an aldehyde and included asymmetric alkynylation, partial reduction of alkyne, deprotection of
the silyl group, and the stereospecific cyclization.
Introduction
biologically important natural products such as phorboxazole,1a
zampanolide,1b lasonolide,1c ratjadone,1d leucascandrolide,1e
swinholides,1f misakinolides,1g sorangicin A,1h scytophycins,1i
and laulimalide.1j The cis or trans configuration of the 2,6-
substituents on the hydropyran ring can affect the three-
dimensional molecular shape as well as the biological activity
in these natural products. Therefore, stereocontrolled synthesis
of 2,6-disubstituted tetra- and dihydropyrans is an important
task for the synthesis of these natural products.2 In fact,
considerable efforts have been devoted to the development of
efficient and stereoselective methods, including a hetero-Diels-
Alder reaction of dienes and aldehydes,3 an intramolecular
hetero-Michael-type reaction,4 an alkylation of oxonium ion,5
and others,6 some of which are shown in Figure 1.
The synthesis of substituted tetrahydropyrans remains a topic
of considerable interest due to the prevalence of these structures
in natural products and biologically active compounds. Tetra-
and dihydropyrans bearing substituents at the 2- and/or 6-posi-
tions on the ring are often observed in a large number of
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10.1021/jo060415o CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/18/2006
4530
J. Org. Chem. 2006, 71, 4530-4537

Synthesis of 2,6-Disubstituted Tetrahydropyrans
SCHEME 1. Synthesis of 2,6-Disubstituted
Tetrahydropyran by Intramolecular SN2′ Type Reaction
SCHEME 2
FIGURE 1. Synthesis of 2,6-disubstituted tetra- and dihydropyran
rings.
The stereochemistry of newly generated chiral centers has
been controlled by intermolecular and intramolecular reactions,
in which total conformational stability of the ring and stereo-
electronic effect of the hydropyran ring have been large factors
for the stereocontrol. Since strict stereocontrol ring-formation
is desired, we have designed a new stereocontrolled synthesis
of hydropyrans by an intramolecular SN2′ type reaction as
described in Scheme 1, in which an attack of oxygen nucleophile
onto the diastereotopic carbon of olefin in an exo trigonal
fashion results in the formation of a tetrahydropyran ring. A
stereospecific 1,3-chirality transfer might be expected in either
a syn-SN2′ or anti-SN2′ process intramolecularly. Although we
have examined ionic SN2′ cyclizations based on this idea,
unsatisfied stereoselective results have been obtained by anti-
SN2′ and SN1′ reactions.7 Therefore, we have started the study
of Pd-catalyzed tetrahydropyran synthesis.
A nucleophilic attack of heteroatoms on Pd π-complexes, as
well as π-allyl Pd complexes, is well-known in Pd-catalyzed
reactions,8 and PdII-promoted intramolecular ring formation
leading to oxygen heterocycles has been documented well.8,9
We have recently reported some PdII-catalyzed hydropyran
formation reactions10 in which intramolecular PdCl2-catalyzed
cyclization took place stereospecifically and gave 3,6-dihydro-
[2H]pyrans from ú-hydroxy-R,â,δ,ꢀ-unsaturated alcohol and
tetrahydropyrans from ú-hydroxy-R,â-unsaturated alcohols via
an SN2′-type reaction as shown in Scheme 2.
(3) Hetero-Diels-Alder cyclocondensation: (a) Danishefsky, S. J. Al-
drichim. Acta 1986, 19, 59-69. (b) Jorgensen, K. A. In Cycloaddition
Reactions in Organic Synthesis; Kobayashi, S., Jorgensen, K. A., Eds.;
Wiley-VCH: Weinheim, Germany, 2002; p 151. Recent examples: (c)
Anada, M.; Washio, T.; Shimada, N.; Kitagaki, S.; Nakajima, M.; Shiro,
M.; Hashimoto, S. Angew. Chem., Int. Ed. 2004, 43, 2665-2668. (d)
Lukesh, J. M.; Donaldson, W. A. Tetrahedron Lett., 2005, 46, 5529-5531.
(4) Recent hetero-Michael-type reactions leading to tetrahydropyran rings.
(a) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett.
2005, 7, 4125-4128. (b) Avery, T. D.; Caiazza, D.; Culbert, J. A.; Taylor,
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Chandrasekhar, S.; Prakash, S. J.; Shyamsunder, T. Tetrahedron Lett. 2005,
46, 6651-6653. (e) Joo, J. M.; Kwak, H. S.; Park, J. H.; Song, H. Y.; Lee,
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O.; De Brabander, J. K. Org. Lett. 2002, 4, 481-484.
(5) Recent C-C bond formaton reactions via oxonium cation leading to
trans tetrahydropyran rings. (a) Vitale, J. P.; Wolckenhauer, S. A.; Do, N.
M.; Rychnovsky, S. D. Org. Lett. 2005, 7, 3255-3258. (b) Rech, J. C.;
Floreancig, P. E. Org. Lett. 2005, 7, 5175-5178. (c) Dubost, C.; Marko, I.
E.; Bryants, J. Tetrahedron Lett. 2005, 46, 4005-4009. Recent syn and
anti SN2′ alkylation leading to hydropyran rings. (d) Gallagher, B. M., Jr.;
Zhao, H.; Pesant, M.; Fang, F. G. Tetrahedron Lett. 2005, 46, 923-926.
(e) Nakamura R.; Tanino, K.; Miyashita, M. Org. Lett. 2003, 5, 3579-
3582. (f) Bussolo, V. D.; Caselli, M.; Romano, M. R.; Pineschi, M.; Crotti,
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Fernandez, J.-C.; Fiol, S.; Fernandez-Forner, D.; Albericio, F. Tetrahedron
Lett. 2005, 46, 7271-7274.
(6) Recent intramolecular preparation of hydropyran: (a) Yang, C.-G.;
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C. H.; Keum, G.; Sohn, K. I.; Lee, D. H.; Lee, E. Tetrahedron Lett. 2005,
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2005, 7, 5509-5512. (d) Hayakawa, H.; Iida, K.; Miyazawa, M.; Miyashita,
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B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002, 124, 11102-
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S. J. Am. Chem. Soc. 2000, 122, 9836-9837.
In this paper, we report full accounts of the stereochemical
results in the PdII-catalyzed cyclization reactions of ú-hydroxy
allylic alcohols and a new stereospecific synthetic method for
2,6-disubstituted tetrahydropyrans.
Results and Discussion
Preparation of Non-3-ene-2,8-diols. Four optically pure non-
3-ene-2,8-diols, 1a, 1b, 2a, and 2b, that possess an E- or
Z-olefinic bonds with an R- or S-chiral center on the allylic
part were chosen as precursors for the cyclization. When these
diols are cyclized, four kinds of stereoisomeric tetrahydropyrans,
3E, 3Z, 4E, and 4Z, can be formed. These structures are shown
in Figure 2.
The synthesis of 1a,b and 2a,b is shown in Scheme 3. In our
previous communication, we used lipase-catalyzed kinetic
acetylation reactions for the preparation of ú-hydroxy and allylic
hydroxy chiral centers of 1a and 1b.10a In this study, we have
improved the method for preparation of ú-hydroxy chiral center
by using a ring-opening reaction of a chiral epoxide with a
Grignard reagent.
The addition of a copper reagent, generated from 4-bromo-
1-butene, to (S)-propylene oxide gave (S)-1-hepten-6-ol 511 in
(7) Uenishi, J.; Ohmi, M.; Matsui, K.; Iwano, M. Tetrahedron 2005, 61,
1971-1979.
(8) Hegedus, L. S. In Organometallics in Synthesis, 2nd ed.; Schlosser,
M., Ed.; John Wiley and Sons: New York, 2002; pp 1123-1217.
(9) Hosokawa, T.; Murahashi, S.-I. Intramolecular Oxypalladation. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-i., Ed.; John Wiley and Sons: New York, 2002; Vol. 2, pp 2169-2192.
(10) (a) Uenishi, J.; Ohmi, M.; Ueda, A. Tetrahedron: Asymmetry 2005,
16, 1299-1303. (b) Uenishi, J.; Ohmi, M. Angew. Chem., Int. Ed. 2005,
44, 2756-2760
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13505-13516.
J. Org. Chem, Vol. 71, No. 12, 2006 4531

Kawai et al.
SCHEME 3 a
a Reagents and conditions: (a) Mg, CuCN, THF, Et2O, 12 h, 0 °C (90%); (b) TBDMSCl, imidazole, DMF, 30 min, rt (85%); (c) O3, CH2Cl2, 1 h, -78
°C then Ph3P (90%); (d) CBr4, PPh3, NEt3, CH2Cl2, 15 h, 0 °C (89%); (e) n-BuLi, THF, -78 °C then acetaldehyde, 2 h, -78 to 0 °C (90%); (f) Red-al, THF,
reflux, 2 h (quant); (g) Cal, vinyl acetate, MS 4 Å, i-Pr2O, 1.5-12 h, rt (10: 45%, 9S: 48%, 11S: 39%, 12: 47%); (h) H2, Lindlar’s catalyst, 4 h, rt (95%);
(i) TBAF, THF, 41 h, rt; (j) K2CO3, MeOH, 2 h, rt (1a: 87% in 2 steps, 1b: 88%, 2a: 92%, 2b: 74% in 2 steps).
nyl bond with Red-al afforded (E)-allylic alcohol 9 in a quan-
titative yield. The diastereomeric alcohols 9 were subjected to
lipase-catalyzed kinetic acetylation by Candida antarctica lipase
(Cal) with vinyl acetate.13 An (R)-acetate 10 was obtained in
45% yield with >98% de, and (S)-alcohol 9S was recovered in
48% yield with >98% de. Desilylation of 10 with TBAF, fol-
lowed by methanolysis, gave diol 1a in 87% yield in two steps.
Diol 1b was obtained from 9S in 88% yield by treatment with
TBAF. For the preparation of 2a and 2b, hydrogenation of 8 in
the presence of Lindlar’s catalyst gave (Z)-allylic alcohol 11 in
95% yield. A Cal-catalyzed kinetic acetylation of alcohol 11
with vinyl acetate in a manner similar to that described above
gave (R)-acetate 12 in 39% yield with >98% de along with an
(S)-alcohol 11S in 47% yield with >98% de. Diol 2a was ob-
tained in 92% yield from 11S, and 2b was obtained in 74%
yield in two steps in the same manner as described for 1a and
1b.
FIGURE 2. (E)- and (Z)-non-3-ene-2,8-diols and (E)- and (Z)-6-
methyl-2-propenyltetraydropyrans.
Pd-Catalyzed Cyclizations. When diol 1a was treated with
10 mol % of PdCl2(MeCN)2 in THF at 0 °C for 5 min, cis-
(E)-tetrahydropyran 3E14 was obtained as a single stereoisomer
90% yield. After the protection of alcohol with TBDMSCl,
ozonolysis of the terminal olefin gave the aldehyde 612 in 77%
yield in two steps. Wittig reaction of 6 in the presence of
triethylamine gave 1,1-dibromo-1-alkene 7 in 89% yield. The
reaction of alkynyllithium, generated from 7 with 2 equiv of
BuLi, with acetaldehyde gave propargyl alcohol 8 in 92% yield
as a 1:1 diastereomeric mixture. A partial reduction of the alky-
(13) (a) Faber, K. Biotransformations in Organic Chemistry; Springer:
Berlin, Germany, 1992. (b) Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed.
Engl. 1989, 28, 695-707. (c) Klibanov, A. M. Acc. Chem. Res. 1990, 23,
114-120. (d) Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A.
Chem. ReV. 1992, 92, 1071-1140.
(12) Yu, M.; Alonso-Galicia, M.; Sun, C.-W.; Roman, R, J.; Ono, N.;
Hirano, H.; Ishimoto, T.; Reddy, Y. K.; Katipally, K. R.; Reddy, K. M.;
Gopal, V. R.; Yu, J.; Takhi, M.; Falck, J. R. Bioorg. Med. Chem. 2003, 11,
2803-2821.
(14) (a) Semmelhack, M. F.; Kim, C. R.; Dobler, W.; Meier, M.
Tetrahedron Lett. 1989, 30, 4925-4928. (b) Verner, E. J.; Cohen, T. J.
Am. Chem. Soc. 1992, 114, 375-377. (c) Arseniyadis, S.; Sartoretti, J.
Tetrahedron Lett. 1985, 26, 729-732.
4532 J. Org. Chem., Vol. 71, No. 12, 2006

Synthesis of 2,6-Disubstituted Tetrahydropyrans
SCHEME 4
SCHEME 5
FIGURE 3.
a single stereoisomer in 76% yield.15 In contrast, treatment of
2b with PdCl2(MeCN)2 under the same reaction conditions gave
a rather disappointing result. The expected trans-(E)-tetrahy-
dropyran 4E was obtained along with cis-(Z)-tetrahydropyran
3Z as a 1:1 mixture in a combined yield of 78%.15 The structure
of 3Z was identified by NOE experiments. When excess LiCl
was added in the reaction of 2b, cyclization did not occur. The
reaction rate became much slower below -70 °C. However,
when the reaction was conducted at -40 °C, cis-(Z)-tetrahy-
dropyran 3Z was obtained in 77% yield exclusively. More
surprisingly, when the reaction was performed in the presence
of 10 mol % of H2O at -40 °C, trans-(E)-tetrahydropyran 4E
was obtained as a single isomer in 72% yield. On the other
hand, the reaction in the presence of an excess of H2O (1 equiv
or more) gave a mixture of 3Z and 4E with moderate to poor
selectivity. An addition of 10 mol % of water for the reaction
of 2a at -40 °C gave 3E as a single stereoisomer in 72% yield.
The relative reaction rates of 1a, 1b, 2a, and 2b were examined.
When the reactions were conducted at -15 °C in THF in the
presence of 2.5 mol % of PdCl2(CH3CN)2, cyclizations of 1a
and 1b were complete in 40 and 70 min, respectively. On the
other hand, reactions of 2a and 2b were not completed even
after 3 h under the same conditions. Approximately 90% of 2a
and 70% of 2b were consumed to lead to the cyclized products
after 3 h. These results indicate that the relative rates are 1a >
1b . 2a > 2b. On the basis of the stereochemical outcome
and the relative rate studies, we should now consider the reaction
mechanism.
in 72% yield.15 Meanwhile, under the same conditions 1b gave
trans-(E)-tetrahydropyran 4E as a single isomer in 79% yield.15
The structures were confirmed by NOE experiments with H
1
NMR, and the relations are shown in Scheme 4. Although both
reactions seemed to proceed very smoothly in THF at 0 °C based
on the TLC analysis, the chemical yields of 3 and 4 after
isolation appeared to be less than the actual yields due to their
volatile characters. In fact, later as shown in Scheme 6, the
nonvolatile tetrahydropyran 17 was obtained in 95% yield in
the cyclization of 16. The results indicate that the 1,3-chirality
transfer from the chiral center of the starting allylic alcohol to
the newly generated chiral center on the tetrahydropyran ring
is perfectly controlled. In this conversion, a syn-SN2′ type
cyclization takes place stereospecifically in a 6-exo-trigonal
fashion promoted by a PdII catalyst.16,17
Mechanism and Origin of Stereoselectivity in Reactions
of PdII-Catalyzed Cyclization. The mechanism of oxypalla-
dation has been extensively studied.8,9,18 A chloride ion plays a
role for the stereocontrol in the intermolecular reactions.
However, we did not observed any chloride ion effect in the
intramolecular cyclization, and thus a reaction mechanism via
chloride intermediate in the above cyclizations has been
eliminated.18 On the basis of our experimental results, we can
propose its reaction mechanism as shown in Figure 3.
Under the same conditions, the cyclization of the (Z)-diol 2a
also proceeded smoothly to give cis-(E)-tetrahydropyran 3E as
(15) The quantitative conversion was observed in an NMR tube experi-
ment. Since products 3 and 4 are volatile liquids, some technical loss occurs
during the workup and purification process in the above scale of the reaction.
(16) Recent review of Pd-catalyzed reaction of alcohol. Muzart, J.
Tetrahedron 2005, 61, 5955-6008.
(17) Recent palladium-catalyzed ring formation of hydropyranes: (a)
Miyazawa, M.; Hirose, Y.; Narantsetseg, M.; Yokoyama, H.; Yamaguchi,
S.; Hirai, Y. Tetrahedron Lett. 2004, 45, 2883-2886. (b) Zacuto, M. J.;
Leighton, J. L. Org. Lett. 2005, 7, 5525-5527. (c) Blakemore, P. R.;
Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L.
A.; Wardrop, D. J.; White, J. D. J. Org. Chem. 2005, 70, 5449-5460. (d)
Hansen, E. C.; Lee, D. Tetrahedron Lett. 2004, 45, 7151-7155.
When a Pd π-complex is formed by a coordination of PdCl2
with the allylic alcohol, one of the π-faces of the olefinic bond
may be recognized with an assistance of the adjacent chiral
hydroxy group, which generates a π-complex I preferentially.
In this complex, Pd locates on the syn-face side to the hydroxy
(18) Henry, P. The Wacker Oxidation and Related Asymmetric Synthe-
ses. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-i., Ed.; John Wiley and Sons: New York, 2002; Vol. 2, pp
2119-2139.
J. Org. Chem, Vol. 71, No. 12, 2006 4533

Kawai et al.
FIGURE 4.
FIGURE 5.
group. This complex may be present in equilibrium with
complex II by a ligand exchange of the hydroxy function of
the ú-alcohol. A syn-attack of this hydroxy nucleophile onto
the electrophilic carbon in II occurs intramolecularly from the
same side of the Pd-complex in a 6-exo-trigonal fashion to give
a σ-Pd complex III.19 Subsequently, syn-elimination of PdCl-
(OH) generates tetrahydropyran bearing an (E)-olefinic sub-
stituent. In the catalytic cycle, PdCl(OH) may promote the
reaction by itself or regenerate PdCl2 by the reaction with HCl.
It should be noted that this PdII-catalyzed intramolecular
Heck-type reaction of allylic alcohol proceeds very smoothly
without any oxidant.
On the basis of the stereochemical outcome, plausible reaction
paths from 1a and 1b are proposed in Figure 4. For the
arrangement of the Pd complex in the reaction of 1a and 1b,
the initial π-complexes A and B from 1a and C and D from 1b
are available and could react. The conformations A and C lead
(19) The recent intramolecular syn-oxypalladation in 5-exo trigonal type
cyclization reaction via palladium(II) species, see: (a) Hayashi, T.;
Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126,
3036-3037. (b) Trend, R. M.; Ramtohul, Y. K.; Stoltz B. M. J. Am. Chem.
Soc. 2005, 127, 17778-17788.
4534 J. Org. Chem., Vol. 71, No. 12, 2006

Synthesis of 2,6-Disubstituted Tetrahydropyrans
SCHEME 6 a
3. Conclusion
We have described PdCl2-catalyzed stereospecific synthesis
of 2,6-substituted tetrahydropyrans in good yields with excellent
diastereoselectivities (>20:1). The important features of this
reaction are the following: (i) the face-selective formation of
the initial PdII π-complex can be controlled by the chiral center
of the allylic alcohol, (ii) elimination of PdCl(OH) regenerates
PdCl2 or itself promotes the catalytic cycle, (iii) the reaction
proceeds under mild conditions via a syn-SN2′ type process,
(iv) the stereochemistry of the product is perfectly controlled,
and (v) water plays an important role in the formation of 4E
from 2b. We have realized the asymmetric synthesis of cis 2,6-
substituted tetrahydropyran 17 from a hydroxyalkyne and an
aldehyde.
a Reagents and conditions: (a) Zn(OTf) 2, (+)-N-methylephedrine, Et3N,
toluene, rt, 3 h (96%); (b) Red-al, THF, reflux, 20 min (96%); (c) TBAF,
THF, rt, overnight (94%); (d) 10 mol % of PdCl2(CH3CN)2, THF, 0 °C, 35
min (95%).
Experimental Section
(5S)-5-(tert-Butyldimethylsilyloxy)-1-hexanal (6).12 To a solu-
tion of 511 (1.21 g, 10.6 mmol) and imidazole (1.46 g, 21.4 mmol)
in DMF (80 mL) was added TBDMSCl (2.42 g, 16.1 mmol) at 0
°C. The reaction mixture was stirred for 1 h at 0 °C and allowed
to warm to room temperature. The reaction mixture was quenched
with water and extracted with Et2O. The organic extracts were
washed with brine and dried (MgSO4). Evaporation of the solvent
and purification of the residue by column chromatography on silica
gel eluted with hexane gave (6S)-6-(tert-butyldimethylsilyloxy)-1-
heptene (2.07 g, 85%). After this compound (483 mg, 2.11 mmol)
was dissolved in CH2Cl2 (10 mL), a dilute stream of O3 in O2 was
bubbled into the solution at -78 °C until the colorless solution
became a persistent blue color. Then, PPh3 (1.11 g, 4.22 mmol)
was added, and the reaction was warmed to room temperature under
an Ar atmosphere. Evaporation of the solvent and purification of
the residue by column chromatography on silica gel eluted with
CH2Cl2 gave 6 (437 mg, 90%): colorless oil; [R]24D +18.0 (c 1.04,
CHCl3); Rf 0.65 (CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 9.76 (t,
1H, J ) 1.8 Hz), 3.78 (m, 1H), 2.43 (td, 2H, J ) 7.3, 1.8 Hz),
1.50-1.78 (m, 2H), 1.39-1.47 (m, 2H), 1.13 (d, 3H, J ) 6.1 Hz),
0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
to the 2,6-trans product 4E, whereas the conformations B and
D lead to the 2,6-cis product 3E. Although the π-complexes A
and D possess an unfavorable allylic strain in their conforma-
tions, the π-complexes B and C do not. Therefore, the
cyclization of 1a and 1b proceeds through the more likely
conformations B and C to give the cis-pyran 3E and the trans-
pyran 4Z, respectively, as a single product.
In the cyclization of (Z)-diol 2a, the favorable intermediate
F, void of the allylic strain in the two conformations E and F,
afforded 3E exclusively. On the other hand, as the stereochem-
ical results show, the mechanism is more complicated in the
reaction of 2b. The reaction at room temperature gave a mixture
of 3Z and 4E. Although the intermediate G is a conformation
void of the allylic strain, two pairs of severe 1,3-diaxial repulsive
interactions might be anticipated in the chair form. On the other
hand, the intermediate H has an allylic strain between the
terminal methyl group and the (Z)-substituent on the olefinic
bond. For this reason, no preferable conformation may be
present for the cyclization of 2b. The formation of 4E might
take place through a boat-form intermediate like I. Though the
effect of water in the preferential formation of 4E is not clear
yet, it might assist the boat conformation or any other
intermediate. For the formation of 3Z, it is interesting that low
temperature, in the absence of a trace of water, allows the
cyclization. We are not able to explain this phenomena rationally
at this stage.
(6S)-6-(tert-Butyldimethylsilyloxy)-1,1-dibromo-1-heptene (7).
To a solution of CBr4 (1.04 g, 3.14 mmol) in CH2Cl2 (3 mL) was
added dropwise a solution of PPh3 (1.65 g, 6.28 mmol) in CH2Cl2
(1 mL) at 0 °C. After the mixture was stirred for 15 min, NEt3
(1.76 mL, 12.6 mmol) was added, and the solution was stirred for
an additional 10 min. Then, a solution of 6 (362 mg, 1.57 mmol)
in CH2Cl2 (1 mL) was added, and the reaction mixture was stirred
for 10 h at room temperature. The mixture was quenched with a
saturated NaHCO3 solution and extracted 3 times (hexane). The
combined organic extracts were washed with brine and dried
(MgSO4). Evaporation of the solvent and purification of the residue
by column chromatography on silica gel eluted with hexane gave
General Synthesis of 2,6-Dialkyl-Substituted Tetrahydro-
pyran. The stereospecific ring formation might be useful for
the general synthesis of 2,6-disubstituted tetrahydropyrans.
Carreira’s asymmetric alkynylation of cyclohexanecarboxalde-
hyde with (S)-6-silyloxy-1-heptyne 1320 in the presence of (+)-
N-methylephedrine gave the (R)-propargyl alcohol 14 in 96%
yield with a 98:2 diastereomeric ratio.21 Partial reduction to
allylic alcohol by Red-al followed by deprotection of the silyl
group gave the diol 16 in 90% yield in 2 steps. Finally, treatment
of 16 with 10 mol % of PdCl2(CH3CN)2 gave the (Z,2S,6R)-
6-methyl-2-(2-cyclohexyl-1-ethenyl)tetrahydropyran 17 in 95%
yield. This reaction sequence presents a flexible and new
synthetic method for the synthesis 2,6-disubstituted tetrahydro-
pyrans.
7 (537 mg, 89%): colorless oil; [R]24 +8.7 (c 1.01, CHCl3); Rf
D
0.26 (hexane); 1H NMR (300 MHz, CDCl3) δ 6.38 (t, 1H, J ) 7.3
Hz), 3.78 (m, 1H), 2.06-2.17 (m, 2H), 1.37-1.54 (m, 4H), 1.12
(d, 3H, J ) 6.2 Hz), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 138.7, 88.6, 68.2, 38.9, 33.0, 25.9, 23.9, 23.8, 18.1, -4.4,
-4.7; IR (film, cm-1) 2928, 2857, 1623, 1462, 1373, 1254, 1188,
1139, 1096, 1036, 835, 774; MS (CI) m/z 385 (M + H+). HRMS
calcd for C13H27Br2OSi (M + H+) 385.0197, found m/z 385.0193.
(2S,8S)- and (2R,8S)-8-(tert-Butyldimethylsilyloxy)non-3-yn-
2-ol (8). To a solution of 7 (846 mg, 2.20 mmol) in THF (1.8 mL)
was added n-BuLi (1.68 mL of a 2.6 M solution in hexane, 4.37
mmol) at -78 °C. The mixture was stirred for 3 h before an addition
of freshly distilled acetaldehyde (3.67 mL, 65.7 mmol). The reaction
mixture was stirred for 0.5 h after removal of the cooling bath.
The mixture was quenched with water (80 mL) and extracted (Et2O).
The organic extract was washed with brine and dried (MgSO4).
Evaporation of the solvent and purification of the residue by column
chromatography on silica gel eluted with 15% Et2O in hexane gave
(20) Drian, C. L.; Greene, A. E. J. Am. Chem. Soc. 1982, 104, 5473-
5483.
(21) Carreira’s asymmetric addition reaction of alkyne to aldehyde.
Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806-1807.
J. Org. Chem, Vol. 71, No. 12, 2006 4535

Kawai et al.
8 (539 mg, 90%): colorless oil; Rf 0.72 (30% Et2O in hexane); 1H
NMR (300 MHz, CDCl3) δ 4.50 (qt, 1H, J ) 6.6, 1.8 Hz), 3.80
(m, 1H), 2.17-2.25 (m, 2H), 1.75 (s, 1H), 1.49-1.58 (m, 4H),
1.42 (d, 3H, J ) 6.6 Hz), 1.12 (d, 3H, J ) 6.2 Hz), 0.88 (s, 9H),
0.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 84.5, 82.4, 68.2, 58.6,
) 6.2 Hz), 0.88 (s, 9H), 0.04 (s, 3H), 0.04 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 170.2, 133.0, 129.4, 68.4, 67.0, 39.2, 27.7, 25.9,
25.7, 23.8, 21.3, 20.9, 18.1, -4.4, -4.8; IR (film, cm-1) 2930, 2858,
1739, 1462, 1371, 1243, 1133, 1087, 1041, 949, 836, 774; MS (CI)
m/z 315 (M + H+). HRMS calcd for C17H35O3Si (M + H+)
315.2355, found m/z 315.2360. The spectroscopic data of 9S and
11S are described in the synthesis of racemic mixtures above. The
38.7, 25.9, 24.8, 24.7, 23.7, 18.7, 18.1, -4.4, -4.7; IR (film, cm-1
)
3358, 2930, 2858, 2247, 1462, 1373, 1254, 1137, 1090, 899, 836,
774; MS (CI) m/z 271 (M + H+). HRMS calcd for C15H31O2Si (M
+ H+) 271.2093, found m/z 271.2089.
specific rotations are [R]27D +6.3 (c 1.00, CHCl3) for 9S and [R]26
D
+9.6 (c 1.11, CHCl3) for 11S.
(E,2S,8S)- and (E,2R,8S)-8-(tert-Butyldimethylsilyloxy)non-
3-en-2-ol (9). To a stirred solution of 8 (20 mg, 0.074 mmol) in
THF (1 mL) was added Red-Al (0.089 mL of a 65% solution in
toluene, 0.29 mmol) at 0 °C. The mixture was refluxed for 2 h and
quenched with water and extracted (ether). The organic extracts
was washed with brine and dried (MgSO4). Evaporation of the
solvent and purification of the residue by column chromatography
on silica gel eluted with 15% Et2O in hexane gave 9 (20.4 mg) in
quantitative yield: colorless oil; Rf 0.10 (10% EtOAc in hexane);
1H NMR (300 MHz, CDCl3) δ 5.62 (dt, 1H, J ) 15.4, 6.4 Hz),
5.49 (ddt, 1H, J ) 15.4, 6.2, 1.3 Hz), 4.25 (dq, 1H, J ) 6.4, 6.4
Hz), 3.77 (m, 1H), 1.97-2.04 (m, 2H), 1.31-1.49 (m, 4H), 1.25
(s, 1H), 1.24 (d, 3H, J ) 6.2 Hz), 1.10 (d, 3H, J ) 6.1 Hz), 0.88
(s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 134.3, 130.9,
68.9, 68.4, 39.1, 32.1, 25.9, 25.3, 23.8, 23.4, 18.1, -4.4, -4.7; IR
(film, cm-1) 3347, 2929, 2857, 1461, 1373, 1254, 1134, 1059, 968,
835, 774; MS (FAB) m/z 295 (M + Na+). HRMS calcd for
C15H32O2SiNa (M + Na+) 295.2069, found m/z 295.2076.
(Z,2S,8S)- and (Z,2R,8S)-8-(tert-Butyldimethylsilyloxy)non-
3-en-2-ol (11). To a solution of 8 (400 mg, 1.48 mmol) in a mixture
of EtOAc:pyridine:1-hexene (10:1:1, 1 mL) was added Lindlar’s
catalyst (5% of Pd, poisoned with lead, 40 mg). The reaction
mixture was stirred for 4 h under a H2 atmosphere and filtered
through a Celite pad. The filtrate was concentrated, and the residue
was purified by column chromatography on silica gel eluted with
50% Et2O in hexane gave 11 (384 mg, 95%): colorless oil; Rf 0.65
Preparation of 1b and 2a. To a solution of 9S or 11S (1.0
mmol) in THF (2 mL) was added TBAF (8.1 mL of a 1.0 M
solution in THF, 8.1 mmol) at room temperature. The reaction
mixture was stirred for 1-2 days and quenched with water, and
then extracted with EtOAc. The organic extracts was washed with
brine and dried (MgSO4). After evaporation of the solvent, the
residue was purified by column chromatography on silica gel eluted
with EtOAc to give 1b or 2a. 1b: 88%; colorless oil; [R]26D +1.4
1
(c 1.06, CHCl3); Rf 0.15 (40% EtOAc in hexane); H NMR (300
MHz, CDCl3) δ 5.61 (dt, 1H, J ) 15.4, 6.4 Hz), 5.50 (ddt, 1H, J
) 15.4, 6.2, 1.1 Hz), 4.24 (dq 1H, J ) 6.2, 6.2 Hz), 3.78 (m, 1H),
2.04 (m, 2H), 1.67 (s, 2H), 1.40-1.48 (m, 4H), 1.24 (d, 3H, J )
6.2 Hz), 1.17 (d, 3H, J ) 6.1 Hz); 13C NMR (75 MHz, CDCl3) δ
134.5, 130.5, 68.8, 67.9, 38.7, 32.0, 25.2, 23.5, 23.4; IR (film, cm-1
)
3337, 2968, 2930, 1455, 1371, 1129, 1063, 968, 938, 868; MS
(FAB) m/z 181 (M + Na+). HRMS calcd for C9H18O2Na (M +
Na+) 181.1204, found m/z 181.1198. 2a: 92%; colorless oil; [R]23
D
1
+4.3 (c 0.82, CHCl3); Rf 0.22 (90% Et2O in hexane); H NMR
(300 MHz, CDCl3) δ 5.37-5.48 (m, 2H), 4.63 (dq, 1H, J ) 7.5,
6.2 Hz), 3.80 (m, 1H), 2.12 (m, 2H), 1.52 (s, 2H), 1.39-1.50 (m,
4H), 1.24 (d, 3H, J ) 6.2 Hz), 1.19 (d, 3H, J ) 6.2 Hz); 13C NMR
(75 MHz, CDCl3) δ 134.1, 130.8, 67.9, 63.8, 38.7, 27.4, 25.7, 23.6,
23.5; IR (film, cm-1) 3336, 2967, 1656, 1457, 1371, 1314, 1181,
1110, 1058, 1012, 933, 826; MS (FAB) m/z 181 (M + Na+). HRMS
calcd for C9H18O2Na (M + Na+) 181.1204, found m/z 181.1211.
Preparation of 1a and 2b. Deprotections of the silyl group of
10 and 12 were performed by the same procedure described for
the desilylation of 9S and 11S except with 60% EtOAc in hexane
as an eluent for silica gel column chromatography. The intermediary
monoacetate from 10: colorless oil; [R]26D +66.7 (c 1.02, CHCl3);
1
(70% Et2O in hexane); H NMR (300 MHz, CDCl3) δ 5.41 (m,
2H), 4.64 (dqm, 1H, J ) 6.2, 1.1 Hz), 3.77 (m, 1H), 2.04-2.12
(m, 2H), 1.56 (s, 1H), 1.31-1.50 (m, 4H), 1.24 (d, 3H, J ) 6.4
Hz), 1.11 (d, 3H, J ) 6.0 Hz), 0.88 (s, 9H), 0.04 (s, 3H), 0.04 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 133.9, 133.8, 131.2, 122.0,
68.5 (11S) and 68.4 (11R), 63.9, 39.2, 27.6, 25.9, 25.8, 23.9 (11S),
and 23.8 (11R), 23.6, 18.1, -4.4, -4.7; IR (film, cm-1) 3349, 2929,
1656, 1462, 1373, 1254, 1188, 1135, 1032, 923, 836, 807, 774;
MS (CI) m/z 273 (M + H+). HRMS calcd for C15H33O2Si (M +
H+) 273.2250, found m/z 273.2254.
1
Rf 0.31 (30% EtOAc in hexane); H NMR (300 MHz, CDCl3) δ
5.54 (dt, 1H, J ) 15.4, 6.6 Hz), 5.40 (ddt, 1H, J ) 15.4, 6.8, 1.5
Hz), 5.24 (dq, 1H, J ) 6.4, 6.4 Hz), 3.73 (m, 1H), 1.98 (s, 3H),
1.94-2.07 (m, 3H), 1.31-1.49 (m, 4H), 1.23 (d, 3H, J ) 6.4),
1.12 (d, 3H, J ) 6.2 Hz); 13C NMR (75 MHz, CDCl3) δ 170.4,
132.9, 129.7, 71.1, 67.7, 38.6, 32.0, 25.0, 23.4, 21.3, 20.3; IR (film,
cm-1) 3419, 2932, 1735, 1372, 1242, 1041, 949; MS (CI) m/z 201
(M + H+). HRMS calcd for C11H21O3 (M + H+) 201.1491, found
m/z 201.1492. The intermediary monoacetate from 12: colorless
Lipase-Catalyzed Kinetic Acetylation of 9 and 11. To a
solution of 9 or 11 (3.0 mmol) in diisopropyl ether (50 mL) were
added MS 4 Å (592 mg), Cal (238 mg), and vinyl acetate (1.34
mL, 14.6 mmol) at room temperature. The mixture was stirred for
1.5 h and filtered through a Celite pad. After evaporation of the
solvent, the residue was purified by column chromatography on
silica gel eluted with 20% EtOAc in hexane for acetates 10 and 12
and with EtOAc for alcohols 9S and 11S. The physical and
spectroscopic data for 10 and 12 are described as follows. 10:
oil; [R]23 +6.9 (c 0.55, CHCl3); Rf 0.39 (70% Et2O in hexane);
D
1H NMR (300 MHz, CDCl3) δ 5.62 (dq, 1H, J ) 8.8, 6.4 Hz),
5.48 (dt, 1H, J ) 11.0, 7.5 Hz), 5.35 (ddt, 1H, J ) 11.6, 9.0, 1.5
Hz), 3.81 (m, 1H), 2.24 (m, 1H), 2.05 (m, 1H), 2.01 (s, 3H), 1.69
(s, 1H), 1.38-1.53 (m, 4H), 1.27 (d, 3H, J ) 6.4 Hz), 1.18 (d, 3H,
J ) 6.2 Hz); 13C NMR (75 MHz, CDCl3) δ 170.4, 132.8, 129.5,
67.5, 67.0, 38.6, 27.4, 25.6, 23.5, 21.4, 20.8; IR (film, cm-1) 3427,
2969, 2931, 1737, 1454, 1371, 1244, 1126, 1041, 949, 846; MS
(CI) m/z 201 (M + H+). HRMS calcd for C11H21O3 (M + H+)
201.1491, found m/z 201.1483. The monoacetates were hydrolyzed
by the following conditions: A mixture of monoacetate (1 mmol)
and K2CO3 (645 mg, 4.67 mmol) in methanol (11 mL) was stirred
for 2 h at room temperature. The mixture was quenched with a
saturated NH4Cl solution and extracted (EtOAc). The extract was
washed with brine and dried (MgSO4). After evaporation of the
solvent, the residue was purified by column chromatography on
silica gel eluted with EtOAc. 1a: 87% in 2 steps; colorless oil;
[R]25D +16.5 (c 1.05, CHCl3); Rf 0.13 (40% EtOAc in hexane); 1H
NMR (300 MHz, CDCl3) δ 5.63 (dt, 1H, J ) 15.4, 6.2 Hz), 5.51
(ddt, 1H, J ) 15.4, 6.2, 1.1 Hz), 4.25 (dq 1H, J ) 6.4, 6.2 Hz),
3.80 (qm, 1H, J ) 6.2 Hz), 2.04 (m, 2H), 1.51 (s, 2H), 1.36-1.50
colorless oil; [R]27 +53.5 (c 1.00, CHCl3); Rf 0.68 (20% EtOAc
D
in hexane); 1H NMR (300 MHz, CDCl3) δ 5.68 (dt, 1H, J ) 15.4,
6.4), 5.45 (ddt, 1H, J ) 15.4, 6.6, 1.5 Hz), 5.30 (dq, 1H, J ) 6.4,
6.4 Hz), 3.77 (m, 1H), 2.03 (s, 3H), 1.98-2.07 (m, 2H), 1.33-
1.50 (m, 4H), 1.28 (d, 3H, J ) 6.4 Hz), 1.11 (d, 3H, J ) 6.1 Hz),
0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 170.2,
133.1, 129.5, 71.0, 68.3, 39.0, 32.1, 25.8, 24.9, 23.7, 21.4, 20.3,
18.1, -4.4, -4.7; IR (film, cm-1) 2930, 2857, 1740, 1461, 1371,
1240, 1136, 1043, 968, 835, 774; MS (CI) m/z 315 (M + H+).
HRMS calcd for C17H35O3Si (M + H+) 315.2355, found m/z
315.2360. 12: colorless oil; [R]27D -0.76 (c 1.04, CHCl3); Rf 0.85
1
(60% Et2O in hexane); H NMR (300 MHz, CDCl3) δ 5.62 (dq,
1H, 8.4, 6.6 Hz), 5.47 (dt, 1H, J ) 10.6, 7.3 Hz), 5.36 (ddt, 1H, J
) 11.0, 8.8, 1.1 Hz), 3.77 (m, 1H), 2.03-2.17 (m, 2H), 2.01 (s,
3H), 1.34-1.47 (m, 4H), 1.27 (d, 3H, J ) 6.6 Hz), 1.11 (d, 3H, J
4536 J. Org. Chem., Vol. 71, No. 12, 2006

Synthesis of 2,6-Disubstituted Tetrahydropyrans
(m, 4H), 1.25 (d, 3H, J ) 6.2 Hz), 1.18 (d, 3H, J ) 6.1 Hz); 13C
NMR (75 MHz, CDCl3) δ 134.5, 130.6, 68.9, 68.0, 38.7, 32.0, 25.3,
23.5, 23.4; IR (film, cm-1) 3347, 2968, 2930, 1670, 1455, 1371,
1129, 1063, 968, 939, 869; MS (FAB) m/z 181 (M + Na+). HRMS
calcd for C9H18O2Na (M + Na+) 181.1204, found m/z 181.1210.
(M + H+) 339.2719, found m/z 339.2713. The enantiomeric purity
was deteremined by chiral HPLC after deriving the corresponding
benzoate with use of DAICEL CHIRALCEL OD-H. Eluent, hexane/
2-propanol (99/1); flow rate, 0.1 mL/min; detection, 254 nm;
retention time, 35.8 min (major R-isomer), 38.6 min (minor
S-isomer).
2b: 74% in 2 steps; colorless oil; [R]25 +16.5 (c 1.05, CHCl3);
D
1
Rf 0.13 (40% EtOAc in hexane); H NMR (300 MHz, CDCl3) δ
Preparation of 15. To a solution of 14 (37.5 mg, 0.11 mmol)
in THF (1.5 mL) was added Red-al (0.17 mL of a solution of 65%
in toluene, 0.55 mmol). The mixture was refluxed for 20 min,
quenched with a saturated NH4Cl solution, and then extracted
(Et2O). The extract was washed with brine and dried (MgSO4).
After evaporation of the solvent, the residue was purified by column
chromatography on silica gel eluted with 25% of Et2O in hexane
5.36-5.47 (m, 2H), 4.63 (dq, 1H, J ) 7.5, 6.2 Hz), 3.80 (m, 1H),
2.01-2.23 (m, 2H), 1.62 (s, 2H), 1.39-1.54 (m, 4H), 1.24 (d, 3H,
J ) 6.4 Hz), 1.18 (d, 3H, J ) 6.0 Hz); 13C NMR (75 MHz, CDCl3)
δ 134.1, 130.9, 68.0, 63.8, 38.5, 27.3, 25.8, 23.6, 23.5; IR (film,
cm-1) 3348, 2968, 2929, 1656, 1457, 1371, 1314, 1109, 1058, 1011,
929, 826; MS (FAB) m/z 181 (M + Na+). HRMS calcd for
C9H18O2Na (M + Na+) 181.1204, found m/z 181.1209.
to give 15 (36.1 mg, 96%): colorless oil; [R]23 +3.7 (c 0.52,
D
General Procedure of Pd-Catalyzed Cyclization of ú-Hydoxy-
R,â-unsaturated Alcohol. A mixture of alcohol 1 or 2 (1 mmol)
and PdCl2(CH3CN)2 (26.5 mg, 0.1 mmol) was stirred in THF (10
mL) at 0 °C for 5 min. The mixture was diluted with pentane, and
precipitates were removed by filtration through a Celite pad. After
removal of the solvent, the residue was purified by column
chromatography on silica gel eluted with 5% Et2O in pentane. The
physical and spectroscopic data for 3E, 4E, and 3Z are described
CHCl3) (96% de, based on the value obtained for 14); Rf 0.41 (25%
Et2O in hexane); 1H NMR (300 MHz, CDCl3) δ 5.60 (dt, 1H, J )
15.4, 6.4 Hz), 5.44 (ddt, 1H, J ) 15.4, 7.2, 1,1 Hz), 3.73-3.81
(m, 2H), 2.03 (q, 2H, J ) 6.6 Hz), 1.59-1.87 (m, 5H), 1.14-1.57
(m, 9H), 1.11 (d, 3H, J ) 6.1 Hz), 0.90-1.08 (m, 2H), 0.88 (s,
9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 132.8, 131.6,
77.6, 68.4, 43.7, 39.2, 32.2, 28.8, 28.7, 26.6, 26.2, 26.1, 25.9, 25.4,
23.8, 18.1, -4.4, -4.7; IR (film, cm-1) 3366, 2927, 2855, 1450,
1374, 1254, 1135, 1094, 1006, 892, 835, 774; MS (FAB) m/z 363
(M + Na+) . HRMS calcd for C20H40O2SiNa (M + Na+) 363.2695,
found m/z 363.2698.
as follows. 3E:14a,c colorless oil; [R]24 +13.6 (c 1.20, CHCl3); Rf
D
1
0.77 (10% Et2O in pentane); H NMR (300 MHz, CDCl3) δ 5.69
(dqd, 1H, J ) 15.4, 6.4, 0.9 Hz), 5.51 (ddq, 1H, J ) 15.4, 6.6, 1.5
Hz), 3.77 (ddm, 1H, J ) 11.3, 6.6 Hz), 3.48 (dqd, 1H, J ) 11.0,
6.2, 1.6 Hz), 1.82 (m, 1H), 1.68 (ddd, 3H, J ) 6.4, 1.5, 0.7 Hz),
1.46-1.60 (m, 3H), 1.25-1.35 (m, 2H), 1.19 (d, 3H, J ) 6.2 Hz);
13C NMR (75 MHz, CDCl3) δ 132.7, 126.7, 78.3, 73.7, 33.0, 31.4,
23.5, 22.2, 17.8; IR (film, cm-1) 2932, 1442, 1366, 1320, 1203,
Preparation of 16. To a solution of 15 (19.9 mg, 58.4 µmol) in
THF (0.1 mL) was added TBAF (0.47 mL of a 1.0 M solution in
THF, 0.47 mmol) at room temperature. The mixture was stirred
overnight, quenched with water, and then extracted (EtOAc). After
evaporation of the solvent, the residue was purified by column
chromatography on silica gel eluted with Et2O and gave 16 (12.4
1077, 1036, 963; MS (GC/MS) m/z 140. 4E:14c colorless oil; [R]23
D
1
mg, 94%): colorless oil; [R]20 +2.2 (c 0.83, CHCl3) (96% de,
+38.0 (c 2.00, CHCl3); Rf 0.70 (10% Et2O in pentane); H NMR
D
based on the value obtained for 14); Rf 0.46 (Et2O); 1H NMR (300
MHz, CDCl3) δ 5.66 (dt, 1H, J ) 15.2, 6.4 Hz), 5.46 (ddt, 1H, J
) 15.2, 7.2, 1.1 Hz), 3.75-3.83 (m, 2H), 2.06 (q, 2H, J ) 6.6
Hz), 1.64-1.88 (m, 4H), 1.03-1.60 (m, 10H), 1.19 (d, 3H, J )
6.2 Hz), 0.83-1.02 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 132.5,
131.9, 77.6, 68.0, 43.7, 38.8, 32.2, 28.8, 28.7, 26.5, 26.1, 26.0, 25.4,
23.5; IR (film, cm-1) 3366, 2925, 2853, 1667, 1450, 1374, 1308,
1124, 1005, 971, 910, 892, 842, 734; MS (FAB) m/z 249 (M +
Na+). HRMS calcd for C14H26O2Na (M + Na+) 249.1830, found
m/z 249.1835.
(300 MHz, CDCl3) δ 5.62-5.66 (m, 2H), 4.25-4.29 (m, 1H), 3.91
(dqd, 1H, J ) 7.5, 6.4, 2.8 Hz), 1.71 (dd, 3H, J ) 6.1, 1.3 Hz),
1.59-1.68 (m, 4H), 1.19-1.32 (s, 2H), 1.16 (d, 3H, J ) 6.4 Hz);
13C NMR (75 MHz, CDCl3) δ 131.4, 127.2, 71.9, 67.0, 32.1, 29.6,
20.4, 18.6, 17.9; IR (film, cm-1) 2930, 1444, 1378, 1260, 1038,
803; MS (GC/MS) m/z 140. 3Z:14b,c colorless oil; [R]24 -13.1 (c
D
0.35, CHCl3); Rf 0.60 (5% Et2O in pentane); 1H NMR (300 MHz,
CDCl3) δ 5.52 (dqd, 1H, J ) 11.0, 7.0, 1.1 Hz), 5.31 (ddq, 1H, J
) 11.0, 7.7, 1.8 Hz), 4.16 (ddd, 1H, J ) 11.0, 8.1, 2.2 Hz), 3.49
(dqd, 1H, J ) 11.0, 6.2, 1.8 Hz), 1.83 (m, 1H), 1.67 (dd, 3H, J )
6.6, 1.5 Hz), 1.49-1.59 (m, 3H), 1.21-1.37 (m, 2H), 1.18 (d, 3H,
J ) 6.2 Hz); 13C NMR (75 MHz, CDCl3) δ 132.1, 125.8, 73.8,
73.6, 33.0, 31.3, 23.6, 22.3, 13.4; IR (film, cm-1) 3022, 2932, 2856,
1443, 1365, 1307, 1203, 1183, 1158, 1075, 1049, 989, 961, 927,
875, 808; MS (GC/MS) m/z 140.
Pd-Catalyzed Cyclization of 16. To a solution of 16 (15 mg,
66 µmol) in THF (0.5 mL) at 0 °C was added a solution of
PdCl2(CH3CN)2 (1.7 mg, 10 mol %) in THF (0.5 mL). The mixture
was stirred for 35 min at 0 °C and diluted with pentane. After
filtration through a Celite pad, the filtrate was concentrated.
Purification of the residue by column chromatography on silica gel
eluted with 5% Et2O in pentane gave 17 (13.1 mg, 95%): colorless
Asymmetric Alkynylation: Preparation of 14. To a stirred
suspension of Zn(OTf)2 (73.6 mg, 0.202 mmol, predried overnight
at 125 °C under vacuum) and (+)-N-methylephedrine (39.6 mg,
0.221 mmol) in dry toluene (0.63 mL) was added Et3N (30.8 µL,
0.221 mmol) in one portion. After the white slurry was stirred at
room temperature for 3 h, alkyne 13 (50 mg, 0.221 mmol) was
added. The mixture was stirred for 30 min and quenched with
freshly distilled cyclohexanecarboxaldehyde (20.6 mg, 0.184 mmol).
After the mixture was stirred for 3 h at room temperature, a saturated
NH4Cl solution was added to the mixture, and it was extracted
(Et2O). The extract was washed with brine and dried (MgSO4).
After evaporation of the solvent, the residue was purified by column
chromatography on silica gel eluted with 25% of Et2O in hexane
oil; [R]20 -8.3° (c 0.60, CHCl3); Rf 0.61 (5% Et2O in pentane);
D
1H NMR (300 MHz, CDCl3) δ 5.65 (dd, 1H, J ) 16.1, 6.2 Hz),
5.47 (ddd, 1H, J ) 15.8, 6.4, 1.1 Hz), 3.82 (ddm, 1H, J ) 10.8,
6.2 Hz), 3.52 (dqd, 1H, J ) 11.0, 6.1, 1.8 Hz), 1.48-1.99 (m, 10H),
1.05-1.40 (m, 7H), 1.24 (d, 3H, J ) 6.1 Hz); 13C NMR (75 MHz,
CDCl3) δ 137.4, 128.9, 78.6, 73.6, 40.3, 33.1, 32.7, 31.7, 26.2,
26.1, 23.6, 22.3; IR (film, cm-1) 2925, 2851, 1448, 1366, 1306,
1260, 1201, 1084, 1038, 966, 886, 805; MS (EI) m/z 208 (M+).
HRMS calcd for C14H24O (M+) 208.1827, found m/z 208.1823.
Acknowledgment. This work was supported by Grant-in-
Aid for Scientific Research on Priority Areas 17035084 and in
part by the 21st COE Program from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
to give 14 (59.9 mg, 96%): colorless oil; [R]22 +10.7 (c 0.43,
D
1
CHCl3) (96% de); Rf 0.34 (25% Et2O in hexane); H NMR (300
MHz, CDCl3) δ 4,13 (dt, 1H, J ) 5.9, 2.0 Hz), 3.80 (m, 1H), 2.19-
2.24 (m, 2H), 1.43-1.86 (m, 11H), 1.12 (d, 3H, J ) 6.1 Hz), 1.03-
1.26 (m, 5H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 86.1, 80.3, 68.1, 67.4, 44.4, 38.8, 28.6, 28.1, 26.4, 25.9, 25.9,
25.0, 23.8, 18.8, 18.1, -4.4, -4.7; IR (film, cm-1) 3389, 2927,
2232, 1450, 1374, 1254, 1187, 1137, 1092, 1024, 893, 836, 774,
661; MS (FAB) m/z 339 (M + H+). HRMS calcd for C20H39O2Si
1
Supporting Information Available: Copies of the H and/or
13C NMR spectra for compounds 1a, 1b, 2a, 2b, 3E, 4E, 3Z, 7, 8,
9, 9S, 10, 11, 11S, 12, 14, 15, 16, and 17. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO060415O
J. Org. Chem, Vol. 71, No. 12, 2006 4537