Desymmetrization of 1,4-dien-3-ols and related compounds via Ueno-Stork radical cyclizations

Article abstract of DOI:10.1021/ol005613v

Desymmetrization of 1,4-dien-3-ols and related compounds via Ueno-Stork radical cyclizations is reported. The stereochemistry of the cyclization is controlled by the acetal center. Excellent stereocontrol at C(4) and C(5) of the newly formed tetrahydrofuran rings is observed. Use of a chiral auxiliary allows the preparation of enantiomerically pure material. The utility of this method has been demonstrated by achieving a short synthesis of (+)-eldanolide, the pheromone of the male African sugarcane stem borer Eldana saccharina.

Full text of DOI:10.1021/ol005613v

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1061-1064
Desymmetrization of 1,4-Dien-3-ols and
Related Compounds via Ueno−Stork
Radical Cyclizations
Fe´lix Villar, Olivier Equey, and Philippe Renaud*
UniVersite´ de Fribourg, Institut de Chimie Organique, Pe´rolles,
CH-1700 Fribourg, Switzerland
philippe.renaud@unifr.ch
Received February 2, 2000
ABSTRACT
Desymmetrization of 1,4-dien-3-ols and related compounds via Ueno−Stork radical cyclizations is reported. The stereochemistry of the cyclization
is controlled by the acetal center. Excellent stereocontrol at C(4) and C(5) of the newly formed tetrahydrofuran rings is observed. Use of a
chiral auxiliary allows the preparation of enantiomerically pure material. The utility of this method has been demonstrated by achieving a short
synthesis of (+)-eldanolide, the pheromone of the male African sugarcane stem borer Eldana saccharina.
Desymmetrization of 1,4-dien-3-ols such as 1,4-pentadien-
3-ol has been achieved in the past on the basis of epoxidation
and hydrosilylation reactions.1,2 This has led to efficient
preparation of useful chiral building blocks. Desymmetri-
zation reactions via formation of carbon-carbon bonds are
less developed. In this paper, we have investigated a novel
desymmetrization strategy on the basis of a regioselective
and diastereoselective formation of a carbon-carbon bond
according to Scheme 1. Our approach is taking advantage
Scheme 1
(1) For general reviews on desymmetrization reactions, see: Willis, M.
C. J. Chem. Soc., Perkin Trans. 1 1999, 1765-1784. Poss, C. S.; Schreiber,
S. L. Acc. Chem. Res. 1994, 27, 9-17. Magnuson, S. R. Tetrahedron 1995,
51, 2167-2213.
(2) For desymmetrization of 1,4-dien-3-ols and related compounds via
Sharpless epoxidation, see: Smith, D. B.; Wan, Z.; Schreiber, S. L.
Tetrahedron 1990, 46, 4793-4808. Ja¨ger, V.; Schro¨ter, D.; Koppenhoefer,
B. Tetrahedron 1991, 47, 2195-2210. Hatekeyama, S.; Sakurai, K.; Numata
H.; Ochi, N.; Takano, S. J. Am. Chem. Soc. 1988, 110, 5201-5203.
Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.;
Schreiber; S. L. J. Am. Chem. Soc. 1990, 112, 5583-5601. Okamoto, S.;
Kobayashi, Y.; Kato, H.; Hori, K.; Takahashi, T.; Tsuji, J.; Sato, F. J. Org.
Chem. 1988, 53, 5590-5592. Burke, S. D.; Buchanan, J. L.; Rovin, D. L.
Tetrahedron Lett. 1991, 32, 3961-3964. Belley, M. L.; Hill, B.; Mitenko,
M.; Scheigetz, J.; Zamboni, R. Synlett 1996, 92-94. Via hydrosilylation:
Tamao, K.; Tohma, T.; Inui, N.; Nakayama, O.; Ito, Y. Tetrahedron Lett.
1990, 31, 7333-7336.
of a group selective radical addition according to a concept
recently reported by Curran.3
The control of the selectivity of the process is achieved
by attaching the radical precursor to the alcohol moiety via
a haloacetalization process and by running a radical cycliza-
tion (Ueno-Stork reaction).4 Recently, we have demon-
(4) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M. J.
Am. Chem. Soc. 1982, 104, 5564-5566. Ueno, Y.; Chino, K.; Watanabe,
M.; Moriya, O.; Okawara, M. J. Chem. Soc., Perkin Trans. 1 1986, 1351-
1356. Stork, G.; Mook, R.; Biller, S. A.; Rychnovsky, S. D. J. Am. Chem.
Soc. 1983, 105, 3741-3742. Stork, G.; Sher, P. M.; Chen H-L. J. Am.
Chem. Soc. 1986, 108, 6384-6385. Stork, G. Bull. Chem Soc. Jpn. 1988,
61, 149-154. Stork, G. Bull. Soc. Chim. Fr. 1990, 127, 675-680.
(3) Curran, D. P.; Geib, S. J.; Lin, C.-H. Tetrahedron: Asymmetry 1994,
5, 199-202. Curran, D. P.; Qi, H.; DeMello, N. C. J. Am. Chem. Soc.
1994, 116, 8430-8431. Curran, D. P.; Lin, C.-H.; DeMello, N. C.;
Junggebauer, J. J. Am. Chem. Soc. 1994, 116, 8430-8431.
10.1021/ol005613v CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/25/2000

strated that the stereochemical outcome of this reaction could
be efficiently controlled from the temporary acetal center as
illustrated with the synthesis of 3-vinyl-γ-butyrolactone
(Scheme 2)5 and (()-botryodiplodin.6
Table 1. Radical Cyclizations According to Scheme 3
Scheme 2
Radical precursors were easily prepared from 1,4-penta-
dien-1-ol (1-4) and 1-methyl-2,5-cyclohexadien-4-one (5)
by haloacetalization with the suitable enol ethers. These
compounds were submitted to radical cyclization conditions
according to four different procedures (Scheme 3, methods
Scheme 3a
a Method A: Bu3SnH (Et3B, O2), -78 °C. Method B: Bu3SnH
(AIBN), 80 °C. Method C: (Bu3Sn)2 (AIBN), 10 °C. Method D:
Bu3SnCH2C(COOMe)dCH2 (AIBN), 80 °C.
A-D).7 Results are summarized in Table 1. Cyclization of
1 afforded the trisubstituted tetrahydrofuran 6 with total
diastereocontrol at -78 °C (entry 1). An important temper-
ature effect was observed in these systems. Running the same
reaction at 80 °C afforded the tetrahydrofuran in 86% ds8
(entry 2). When a gem-dimethyl group is introduced at
position 3 (numbering according to the tetrahydrofuran
moiety, see Scheme 3), a slightly lower diastereoselectivity
was observed (entries 3 and 4, 86% ds at -78 °C). When a
single substituent is present at position 3, the control of the
stereochemistry at the C3 center is rather low (entries 5 and
6) as predicted by the Beckwith-Houk radical cyclization
model9. Indeed, the alkoxy group at position 2 favors the trans
relative configuration and the substituent at position 4 favors
the cis configuration. This effect has already been noticed
in simple Ueno-Stork radical cyclizations controlled by the
a Only the major isomer is drawn. b The diasterereoselectivity is expressed
as % ds, see ref 8 for the definition. c The principal minor isomer is the
epimer at C(3).
acetal center.6 However, two out of the three newly formed
centers (C4 and C5) are created with high stereocontrol. The
cyclic radical precursor 5 gave also excellent level of
stereocontrol at low temperature (entry 7 and 8, >98% ds
at -78 °C). Interestingly, the reaction with (2-methoxycar-
(5) Villar, F.; Renaud, P. Tetrahedron Lett. 1998, 39, 8655-8658.
(6) Villar, F.; Andrey, O.; Renaud, P. Tetrahedron Lett. 1999, 40, 3375-
3378.
1062
Org. Lett., Vol. 2, No. 8, 2000

bonylpropenyl)tributylstannane afforded the R-alkylated bi-
cyclic ketone 11 with satisfactory diastereoselectivity (entry
9).
The stereochemical outcome of these reaction is rational-
ized by transition states of type A (chairlike) and B (boatlike)
for the open and the cyclic systems, respectively (Figure 1).
haloacetalization step is currently underway. Interestingly,
good stereocontrol are now routinely achieved with vinyl
ether derived from O-monomethylbinaphthol and (1R)-3-[N-
(3,5-dimethylphenyl)benzenesulfanamido]isoborneol.12 The
bromoacetal 13 (1:1 mixture of two diastereomers) was
submitted to cyclization conditions to afford 14 as a 1:1
mixture of two diastereoisomers; the cyclization process is
completely diastereoselective (ds > 98%) for each diaste-
reomer of 13. At this stage, the two diastereomers were
separated by flash chromatography, and (2S,4S,5R)-14 was
used for the rest of the synthesis. The γ-chain was modified
in a straightforward manner by hydroboration, Swern oxida-
tion, and Wittig reaction. Finally, hydrolysis of the acetal
15 furnished the lactol together with recovered (1R,2S)-2-
phenylcyclohexanol (62%). Oxidation of the lactol with PCC
gave enantiomerically pure (+)-eldanolide (optical purity
checked by gas chromatography on a chiral column, see
Supporting Information).
Figure 1. Model for the stereochemical outcome of radical
cyclizations starting from 1 (A) and 5 (B).
Finally, we have investigated a similar desymmetrization
process for 1,6-heptadien-4-ol. The bromoacetal 16, when
treated with Bu3SnH in the presence of triethylborane and
oxygen at -78 °C, gave 17, the product of a 6-exo-trig
cyclization, in 43% yield with complete stereocontrol
(Scheme 5). The moderate yield is due to the formation of
acyclic reduced product. The relative configuration was
deduced from the 1H NMR coupling constant, and the methyl
In these models, the systems adopt a conformation where
the anomeric effect at the acetal center is maximized.9,10
These simple models are supported by ab inito calculations
that will be reported in a forthcoming full paper.
The utility of this approach was demonstrated by the
preparation of the naturally occurring (+)-eldanolide, the
pheromone of the male African sugarcane stem borer Eldana
saccharina (Scheme 4).11 For this purpose, the bromoacetal
(7) Procedure A: A solution of the haloacetal (2.1 mmol) and Bu3SnH
(735 mg, 2.5 mmol) in toluene (52 mL) was cooled at -78 °C, and a 1 M
solution of Et3B in hexane (2.9 mL, 2.9 mmol) was added followed by air
(2.0 mL). The solution was kept at -78 °C for 3 h. A 1 M NaOH solution
(30 mL) was added, and the heterogeneous mixture was stirred for 2 h at
room temperature. The organic layer was washed with H2O, dried (MgSO4),
and evaporated under reduced pressure. The crude product was purified by
flash chromatography (hexane/Et2O). Procedure B: A solution of Bu3SnH
(735 mg, 2.52 mmol), AIBN (17 mg), and the haloacetal (2.1 mmol) in
benzene (20 mL) was heated under reflux. The reaction was followed by
TLC until all starting material disappeared. Workup as in procedure A.
Procedure C: A solution of the haloacetal (1 mmol) and (Bu3Sn)2 (58 mg,
0.1 mmol) in benzene (5 mL) was irradiated with a sun lamp at 10 °C until
all starting material disappeared (approximately 2 h). A KF aqueous solution
was added, and the mixture was stirred for 2 h. The organic layer was
washed with H2O, dried, and evaporated. The crude product was purified
by flash chromatography (hexane/Et2O). Procedure D: A solution of (2-
methoxycarbonylpropenyl)tributylstannane (1.55 g, 4 mmol), AIBN (4 mg),
and the haloacetal (0.5 mmol) in benzene (5.5 mL) was heated under reflux.
The reaction was monitored by TLC until all starting material disappeared.
Workup as in procedure A.
Scheme 4. Synthesis of (+)-Eldanolidea
(8) The diastereoselectivity is expressed as % ds, the percentage of a
certain diastereomer in a mixture of two or more diastereomers: Seebach,
D.; Imwinkelried, R.; Weber, T. In Modern Synthetic Methods 1986;
Scheffold, R., Ed.; Springer: Berlin, 1986; pp 125-259.
(9) For the Beckwith-Houk transition state model, see: (a) Beckwith,
A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-3941. (b) Spellmeyer,
D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959-974. For a discussion of
the stereochemistry in Ueno-Stork cyclization reactions controlled by the
acetal center, see refs 5 and 6 and: Beckwith, A. L. J.; Page, D. M. J. Org.
Chem. 1998, 63, 5144-5153.
a Key: (a) ethyl vinyl ether, Hg(OAc)2, 70%; (b) 1,4-pentadien-
3-ol, NBS, 75% (1:1 mixture of diastereomer); (c) Bu3SnH, Et3B,
O2, 85%, ds >98%; (d) chromatography; (e) 9-BBN then H2O2,
NaOH, 93%; (f) CO2Cl2, DMSO, 95%; (g) Ph3PC(CH3)2, 51%; (h)
HCl, H2O, 68% [(1R,2S)-2-phenylcyclohexanol recovered in 62%];
(i) PCC, Al2O3, 73%.
(10) The importance of the anomeric effect in Ueno-Stork radical
cyclization has already been studied by Fraser-Reid in carbohydrate
derivatives: Lopez, J.-C.; Gomez, A. M.; Fraser-Reid, B. J. Chem. Soc.,
Chem. Commun. 1994, 1533-1534. Lopez, J.-C.; Gomez, A. M.; Fraser-
Reid, B. Aust. J. Chem. 1995, 48, 333-352. Lopez, J.-C.; Fraser-Reid, B.
Chem. Commun. 1997, 2251-2257.
(11) Isolation: Vigneron, J.-P.; Me´ric, R.; Larcheveˆque, M.; Kunesch,
G.; Zagatti, P.; Gallois, M. Tetrahedron 1984, 40, 3521-3529. Synthesis
using a Ueno-Stork radical cyclization: Itoh, T.; Sakabe, K.; Kudo, K.;
Zagatti, P.; Renou, M. Tetrahedron Lett. 1998, 39, 4071-4074.
(12) Villar, F.; Renaud, P. Manuscript in preparation.
13 was prepared from (1R,2S)-2-phenylcyclohexanol via
mercury(II)-catalyzed transetherification and bromoacetal-
ization with 1,4-pentadien-3-ol. The haloacetalization step
is not stereoselective, the required diastereomerically pure
13 could be obtained after flash chromatography; however,
since the separation of the diastereomers is easier after the
cyclization reaction, the mixture of diastereomers was used
for the next step. A study of the stereochemistry of the
(13) Recently, Beckwith has observed a similar trans relationship in a
related 6-exo-cyclization reaction; see ref 10.
Org. Lett., Vol. 2, No. 8, 2000
1063

ization of chiral enol ethers, is under investigation and will
be reported in due course.
Scheme 5
Acknowledgment. This work was generously supported
by the Fonds National Suisse de la Recherche Scientifique
and by the Office Fe´de´ral de l’Education et de la Science as
part of the European COST D12 action. We thank Professor
T. Jenny for assistance in the attribution of the relative
configuration of 17 and Vale´ry Weber for optimizing critical
steps in the synthesis of (+)-eldanolide.
at position 4 is trans relative to the tert-butoxy group and
cis to the allyl group.13
In conclusion, we have demonstrated in this paper that
desymmetrization of 1,4-dien-3-ols and related compounds
via Ueno-Stork radical cyclization proceeds very efficiently.
Utilization of this approach for the synthesis of enantiomeri-
cally pure natural products has been demonstrated. A crucial
point for this strategy, i.e., the control of the relative
configuration at the acetal center during the bromoacetal-
Supporting Information Available: Experimental details
for all procedures including full characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Org. Lett., Vol. 2, No. 8, 2000