Ring-opening reactions of oxabicyclic alkene compounds: Enantioselective hydride and ethyl additions catalyzed by group 4 metals

Article abstract of DOI:10.1021/jo991429f

Titanium and zirconium catalysts selectively catalyze either the ethyl or hydride addition to [2.2.1] 4,5-bis(methoxymethyl)-7-oxabicycloheptene (6); the ring-opened products formed depend on catalyst, temperature, alkylaluminum reagent, and the concentration of alkylaluminum. Bis(neoisomen-thylindenyl)zirconium dichloride catalyzes the ethyl addition ring-opening of 6 to produce (1R,-2S,3S,6R)-2,3-bis(methoxymethl)-6-ethylcyclohex-4-enol (7) in 96% ee. Zirconium catalysts catalyze the ring-opening of [3.2.1] 2,4-dimethyl-3-(benzyloxy)-8-oxabicyclo-6-octene (7) when ethylmagnesium bromide is used as a reagent. Both hydride and ethyl addition products are obtained at all conditions studied. Bis(neoisomenthylindenyl)zirconium dichloride catalyzes the ethyl addition ring-opening of 7 to produce ( 1S,2A,3S,4S,4S,7s)-2,4-dimethyl-3-(benzyloxy)-7-ethyl-5-cydohexen-1-ol (8) in 48% ee.

Full text of DOI:10.1021/jo991429f

3
902
J . Org. Chem. 2000, 65, 3902-3909
Rin g-Op en in g Rea ction s of Oxa bicyclic Alk en e Com p ou n d s:
En a n tioselective Hyd r id e a n d Eth yl Ad d ition s Ca ta lyzed by Gr ou p
4
Meta ls
Dan B. Millward, Glenn Sammis, and Robert M. Waymouth*
Department of Chemistry, Stanford University, Stanford, California 94305-5080
Received September 10, 1999
Titanium and zirconium catalysts selectively catalyze either the ethyl or hydride addition to [2.2.1]
4
,5-bis(methoxymethyl)-7-oxabicycloheptene (6); the ring-opened products formed depend on catalyst,
temperature, alkylaluminum reagent, and the concentration of alkylaluminum. Bis(neoisomen-
thylindenyl)zirconium dichloride catalyzes the ethyl addition ring-opening of 6 to produce (1R,-
2
S,3S,6R)-2,3-bis(methoxymethyl)-6-ethylcyclohex-4-enol (7) in 96% ee. Zirconium catalysts catalyze
the ring-opening of [3.2.1] 2,4-dimethyl-3-(benzyloxy)-8-oxabicyclo-6-octene (7) when ethylmagne-
sium bromide is used as a reagent. Both hydride and ethyl addition products are obtained at all
conditions studied. Bis(neoisomenthylindenyl)zirconium dichloride catalyzes the ethyl addition ring-
opening of 7 to produce (1S,2R,3S,4S,7S)-2,4-dimethyl-3-(benzyloxy)-7-ethyl-5-cyclohexen-1-ol (8)
in 48% ee.
Desymmetrization can be a powerful method of access-
ing chiral molecules from achiral precursors.1 Meso
oxabicyclic compounds, which can be produced with
multiple chiral centers and high stereoselectivity through
Diels-Alder and [4 + 3] oxyallyl cation cyclization
reactions, are versatile precursors to molecules with high
degrees of stereocomplexity2 which can be converted to
valuable cyclic and straight chain synthetic intermedi-
ates.3
Transition metals are efficient catalysts in these ring-
opening reactions and can effect enantioselective ring-
opening reactions. Palladium complexes catalyze the
-4
,5
15
hydrostannylation of oxabicyclic compounds, and nickel
Lautens and co-workers have demonstrated that both
complexes have been shown to catalyze hydroalumination
alkyllithiums and cuprates serve as nucleophiles for the
as well as the addition of Grignards to oxabicyclo al-
2′ addition to oxabicycles (eq 1).3
,6-12
This approach
14,17
S
N
kenes.
Nickel compounds with chiral phosphine ligands
provides access to polypropionate natural products. A
synthetic route to a fragment of the macrolide rifamycin
S containing five contiguous stereocenters was developed
using this methodology.3 Hydride nucleophiles, either
directly from metal hydrides or indirectly from metal
alkyls are also effective.3
catalyze the hydride ring-opening reaction with excellent
enantioselectivity.1
4,16a
A palladium-binap catalyst pro-
motes ring-opening addition of a phenyl group in 96% ee
18
but in 13% yield; more recent results with alkylzinc
nucleophiles gave much better yields and ee’s from 67%
,13-16
16b
to 96%.
Zirconium catalysts have proven effective for the
enantioselective ring-opening of simple cyclic allyl ethers
(
1) Ho, T.-L. Symmetry: A Basis for Synthesis Design; J ohn Wiley
with >90% enantiomeric excess.1
9-22
These results, coupled
and Sons: New York, 1995; p 559.
(
(
(
(
(
2) Mann, J . Tetrahedron 1986, 42, 4611-4659.
3) Lautens, M. Synlett 1993, 177-184.
with the observation that zirconium benzyne complexes
23
mediate the ring-opening of benzooxanorbornene, sug-
4) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1-19.
5) Lautens, M.; Chiu, P. Top. Curr. Chem. 1997, 190, 1-85.
6) Lautens, M.; Gajda, C.; Chiu, P. J Chem. Soc., Chem. Commun.
gest that early transition metal complexes might also be
competent catalysts for the nucleophilic ring-opening of
oxabicycles. In light of recent reports that certain early
metal catalysts are competent for the stereoselective
1
993, 1193-1194.
7) Lautens, M.; Abdelaziz, A. S.; Lough, A. J . Org. Chem. 1990,
5, 5305-5306.
8) Lautens, M.; Smith, C. A.; Huboux, A. Abstr. Pap. Am. Chem.
Soc. 1990, 199, 342-ORGN.
9) Lautens, M.; Smith, A. C.; Abdelaziz, A. S.; Huboux, A. H.
Tetrahedron Lett. 1990, 31, 3253-3256.
(
5
(
24-27
polymerization and copolymerization of norbornenes,
(
(17) Lautens, M.; Ma, S. H. J . Org. Chem. 1996, 61, 7246-7247.
(18) Moinet, C.; Fiaud, J . C. Tetrahedron Lett. 1995, 36, 2051.
(19) Visser, M. S.; Harrity, J . P. A.; Hoveyda, A. H. J . Am. Chem.
Soc. 1996, 118, 3779-3780.
(20) Morken, J . P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H. J .
Am. Chem. Soc. 1994, 116, 3123-3124.
(21) Hoveyda, A. H.; Didiuk, M. T. Curr. Org. Chem. 1998, 2, 489-
526.
(
10) Lautens, M.; Belter, R. K. Tetrahedron Lett. 1992, 33, 2617-
2
620.
(
11) Lautens, M.; Belter, R. K.; Lough, A. J . J . Org. Chem. 1992,
5
7, 422-424.
(
(
(
12) Lautens, M.; Chiu, P. Tetrahedron Lett. 1993, 34, 773-776.
13) Lautens, M.; Chiu, P. Tetrahedron Lett. 1991, 32, 4827-4830.
14) Lautens, M.; Chiu, P.; Ma, S. H.; Rovis, T. J . Am. Chem. Soc.
1
995, 117, 532-533.
(22) Broene, R. D. In Comprehensive Organometallic Chemistry-II;
Abel, E. W., Stone, E. G. A., Wilkinson, G., Eds.; Pergamon: London,
1995; Vol. 12, pp 323-347.
(
15) Lautens, M.; Klute, W. Angew. Chem., Int. Ed. Engl. 1996, 35,
4
42-445.
(
16) (a) Lautens, M.; Rovis, T. J . Am. Chem. Soc. 1997, 119, 11090-
(23) Cuny, G. D.; Buchwald, S. L. Organometallics 1991, 10, 363-
1
2
1091. (b) Lautens, M.; Renaud, J .-L.; Hiebert, S. J . Am. Chem. Soc.
000, 122, 1804-1805.
365.
(24) McKnight, A. L. Thesis, Stanford University, 1997.
1
0.1021/jo991429f CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/08/2000

Ring-Opening Reactions of Oxabicyclic Alkenes
Ta ble 1. Ca ta lytic Rin g-Op en in g of 6a to 7 w ith Tr ieth yla lu m in u m
yieldb
J . Org. Chem., Vol. 65, No. 13, 2000 3903
%
entry
cat.
temp, °C
[Et3Al], M
isomer
7
8
[R]Dc
% ee
1
2
3
4
5
1
2
3
4
5
toluene
hexanes
hexanes
toluene
toluene
110
70
70
90-95
90-95
1.0
1.25
1.0
0.5
0.5
16
94
60
70
64
32
-
-
d
1R,2S,3S,6R
1S,2R,3R,6S
1R,2S,3S,6R
34
52
96
e
-49f
74
a
Conditions: [6] ) 0.5 M, [TEA] ) 1 M, [Zr], [Ti] ) 0.025 M. % Yield isolated by chromatography. c Polarimetry measured in CH2Cl2.
b
d
7% conversion by GC. c ) 3.3 mg/mL. f c ) 7.2 mg/mL
e
6
Ta ble 2. Ca ta lytic Rin g-Op en in g of 6a to 8.
b
entry
cat.
solvent
temp, °C
AlR3
[AlR3], M
yield, %
isomer
% ee
1
2
3
4
5
6
7
1
1
1
2
3
4
5
hexanes
toluene
hexanes
hexanes
hexanes
toluene
toluene
70
110
70
70
70
Et3Al
Et3Al
Pr3Al
Et3Al
Et3Al
2.5
2.5
1
2.5
2.5
1.0
0.75
85
99
88
57
80
30
47
-
-
-
-
-
-
17
17
0
c
1S,2R,3R
1S,2R,3R
-
i
d
110
110
Bu3Al
i
Bu3Al
a
Conditions: [6] ) 0.5 M, [Ti], [Zr] ) 0.025 M, 16-18 h. % Yield isolated by chromatography. c % ee determined from methoxymandelate
b
d
ester. % ee determined by chiral HPLC.
Treatment of 4,5-bis(methoxymethyl)-7-oxabicyclo-2-
heptene (6) with 2-5 equiv (1-2.5 M) of trialkylalumi-
num reagents (R Al) at 70-110 °C in the presence of 0.05
3
equiv of a titanium or zirconium catalyst yields the
cyclohexenols 7 and 8 upon hydrolytic workup (eq 2,
Table 1). No reaction was observed under these condi-
tions in the absence of a catalyst with up to 1.25 M Et
Al; however, 6 is slowly converted to 7 in refluxing
toluene in the presence of 2 M Et Al. The selectivity for
3
-
3
alkylation to give 7 versus hydride addition to give 8
depends on the catalyst, conditions and alkylaluminum
reagent (Tables 1 and 2).
F igu r e 1. Structures of catalyst precursors.
we initiated investigations on the stereospecific ring-
opening of oxabicycles with early transition metal com-
plexes. In this paper, we report our investigations on the
enantioselective nucleophilic ring-opening reactions of
oxanorbornenes and oxabicyclo[3.2.1]octanes.
Both the ethyl product 7 and the hydride product 8
are formed in refluxing toluene with titanocene dichloride
as the catalyst precursor in yields of 16% and 32%,
respectively (Table 1, entry 1). Yields obtained in hexanes
were from 60% to 94% with titanium catalysts 2 and 3,
although conversion was only 67% for 3 under these
conditions (entry 3). No deuterium was incorporated into
7 upon deuteriolytic workup of the reaction of 6 with
Resu lts
Five metallocenes were investigated for the ring-
opening of oxabicycles: Titanocene dichloride (Cp
, η-5,η-1-(tetramethylcyclopentadienyl)(dimethylsilyl)-
tert-butyl)amidotitanium dichloride (Cp*ATiCl ) 2, (+)-
η-5,η-1-(indenyl)(dimethylsilyl)(R-methylbenzyl)amido-
titanium dichloride ((+)-IndA*TiCl
) 3,28 bis(neomen-
thylindenyl)zirconium dichloride ((nmInd) ZrCl ) 4, and
bis(neoisomenthylindenyl)zirconium dichloride ((nimInd)
2 2
TiCl )
1
triethylaluminum and a catalytic amount of Cp*ATiCl
(eq 3).
2
(
2
2
2
2
2
-
ZrCl
2
) 5 (Figure 1). 2
9,30
(
25) Cherdron, H.; Brekner, M.-J .; Osan, F. Angew. Makromol.
Chem. 1994, 223, 121-133.
26) Harrington, B. A.; Crowther, D. J . J . Mol. Catal. A: Chem.
Careful temperature control is critical for the ring-
opening of 6 in the presence of the zirconocene catalysts.
In toluene at 90-95 °C, yields of 64-70% could be
obtained, but reaction temperatures below 90 °C led to
no conversion of substrate, while temperatures above 95
(
1
998, 128, 79-84.
(
27) Ruchatz, D.; Fink, G. Macromolecules 1998, 31, 4674-4680.
28) McKnight, A. L.; Masood, M. A.; Waymouth, R. M. Organome-
(
tallics 1997, 16, 2879-2885.
29) Knickmeier, M.; Erker, G.; Fox, T. J . Am. Chem. Soc. 1996,
18, 9623-9630.
30) Erker, G.; Aulbach, M.; Knickmeier, M.; Wingermuhle, D.;
Kruger, C.; Nolte, M.; Werner, S. J . Am. Chem. Soc. 1993, 115, 4590-
601.
(
1
°
C led to a mixture of products
(
The enantioselective ring opening of 6 with the chiral
titanocene 3 in hexanes at 70 °C gave (1R,2S,3S,6R)-7
4

3
904 J . Org. Chem., Vol. 65, No. 13, 2000
Millward et al.
Sch em e 1. Der iva tiza tion of 7 To Deter m in e
En a n tiom er ic Excess
sion had occurred after 18 h. Tripropylaluminum (1 M)
is an efficient hydride donor with titanocene dichloride,
1
00% conversion and 88% yield of 8 (determined by GC)
occurred after 24 h in refluxing hexanes.
In contrast to the titanium catalysts, the zirconocenes
are selective for delivery of an ethyl group to oxanor-
bornene 6, even at high Et
3
Al concentrations. However,
6
ring-opens with 0.05 equiv of optically active zir-
in 60% yield and 34% ee. Higher ee’s were obtained with
the zirconocene catalysts 4 and 5. Addition of Et Al to 6
in the presence of the neomenthylindenyl zirconocene 4
at 90-95 °C in toluene yields (1R,2S,3S,6R)-7 in 52% ee,
whereas the diastereomeric neoisomenthyl zirconocene
i
conocene and excess triisobutylaluminum ( Bu
8) upon hydrolysis (eq 7, Table 2).
3
Al) to give
3
(
5
yields the enantiomer (1R,2S,3S,6R)-7 in 64% yield and
9
6% ee (eq 4).
The yields are modest under these conditions, and the
enantioselectivity is low. The (1S,2R,3R) isomer of 8 was
formed in 17% enantiomeric excess when (nmInd) ZrCl
2
2
catalyst precursor was used; chiral HPLC was used to
determine the % ee from the 4-nitrobenzoate ester of 8.
Absolute stereochemistry was determined by comparing
the sign of optical rotation to (1S,2R,3R)-8 produced from
The enantioselectivities were determined from HPLC
analysis of the furanose nitrobenzoate ester 10 obtained
by ozonolysis of 7 (Scheme 1). The absolute stereochem-
istry of (1R,2S,3S,6R)-7 from (nimInd) ZrCl was deter-
2 2
mined from the circular dichroism spectrum of cyclohex-
2
IndA*TiCl .
Efforts to selectively introduce a methyl group by ring-
opening of 6 were unsuccessful. These included reacting
enone (2S,3S,6R)-11 obtained from the Swern oxidation
trimethylaluminum with 6 in the presence of Cp*ATiCl
or with (nmInd) ZrCl ; no product was seen in either case.
2
of 7 (eq 5).3
1-33
The absolute stereochemistry of the
2
2
products from other catalysts were established by com-
parison of the optical rotations or the HPLC traces of the
furanose esters of (1R,2S,3S,6R)-7.
To investigate the scope of the oxybicycle ring-opening
reactions, the [3.2.1]oxybicycle 2,4-dimethyl-3-(benzyl-
oxy)-8-oxabicyclo-6-octene (12) was also investigated.
Unlike the oxanorbornene substrate 6, the [3.2.1] bicycle
1
2 reacts with 2.2 equiv TEA in toluene at 90 °C in the
absence of a catalyst to give 2,4-dimethyl-3-(benzyloxy)-
7
8
-ethyl-5-cyclohexen-1-ol (13) in 42% isolated yield (eq
). Diethyl zinc will also ring-open 12 without a catalyst,
but more slowly than triethylaluminum. Substrate 12
does not react at all with ethylmagnesium bromide after
The selectivity of the titanium catalysts for ring-
opening to 7 or 8 depends on the concentration of the
6
h in refluxing hexanes and reacts only slightly in
refluxing toluene.
triethylaluminum. At concentrations [Et Al] ) 2.5 M, the
3
titanium catalysts selectively yield the hydride addition
product 8 in yields of 57-99% (Table 2). The enantiose-
lective ring-opening of 6 with the titanocene 3 gives
(1S,2R,3R)-8 in 80% yield but a low ee of 17%; the
absolute stereochemistry was determined from the (R)-
R-methoxymandelate ester (eq 6).34
No reaction was observed in the absence of a catalyst
under these conditions. Triisobutylaluminum can also be
used as a hydride donor with the titanium catalysts, but
the reactions proceed more slowly; less than 50% conver-
2 2
In the presence of (nmInd) ZrCl and triethylalumi-
num, 12 also ring-opens to 13 in 17% yield and 20% ee;
however, an unidentifiable compound was the major
product. A series of experiments with ethylmagnesium
bromide and zirconium catalysts were performed to
determine optimal conditions for the ring opening addi-
tion to 12 (eq 9, Table 3).
In all cases, both the ethyl and hydride addition
products 13 and 14 were formed in 50-67% combined
total yield; the relative amounts varied slightly with
solvent, catalyst, and temperature. Methylmagnesium
(
31) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
J ohn Wiley and Sons: New York, 1994; p 1267.
32) Moscowitz, A.; Mislow, K.; Glass, M. A. W.; Djerassi, C. J . Am.
Chem. Soc. 1962, 84, 1945-1955.
33) Mislow, K.; Glass, M. A. W.; Moscowitz, A.; Djerassi, C. J . Am.
Chem. Soc. 1961, 83, 2771-2772.
34) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
(
(
(
Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J . P. J . Org. Chem. 1986, 51, 2370-2374.

Ring-Opening Reactions of Oxabicyclic Alkenes
J . Org. Chem., Vol. 65, No. 13, 2000 3905
Ta ble 3. Zir con iu m -Ca ta lyzed Rin g-Op en in g Ad d ition s
room temperature to form a small amount of hydride
product 14 within 5 min; no ethyl product 13 is observed
initially. Upon heating to 110 °C, the reaction proceeds
rapidly (<30 min) to form 13 and 14 in a 1:1 ratio. To
compare rates of product formation, the reaction was
carried out at 67 °C and monitored at regular intervals.
Product 14 was formed in 7% yield after 10 min; this yield
remained constant for over 60 min and then began
increasing. Product 13 was formed more slowly but at a
more steady initial rate which decreased as formation of
product 14 began to increase again.
Deuteriolysis of the reaction of 12 with ethylmagne-
2 2
sium bromide and a catalytic amount of (nmInd) ZrCl
in toluene showed a 3-4:1 ratio of the monodeuterated
to undeuterated 13 (eq 11). The ratio varied with tem-
perature. The reaction of 12 with 2,2,2-(trideutero)-
ethylmagnesium bromide and a catalytic amount of
a
to 12
temp,
°C
entry
1
catalyst
solvent
13:14b % yieldc % ee
(nmInd)2ZrCl2 hexanes
70 2.9:1
13 - 40
4 - 17
6
1
NDe
-
d
2
3
4
(nmInd)2ZrCl2 THF
(nmInd)2ZrCl2 toluene
(nmInd)2ZrCl2 toluene
67
22
1:1
1:1
15
d
NDe
6
-
11
7
<30
55 2.9:1
13 - 35
4 - NDe
1
5
6
7
8
(nmInd)2ZrCl2 toluene
(nimInd)2ZrCl2 toluene
(nimInd)2ZrCl2 toluene
(nimInd)2ZrCl2 toluene
110 1:2
13 - 17
4 - 28
1:1.8 13 - 16
4 - 35
13 - 26
4 - 20
1:1.5 13 - 27
4 - 40
1
60
46
0
1
75 1.4:1
36
NDe
1
110
48
0
1
a
Conditions: [12] ) 0.5 M, [EtMgBr] ) 1.05 M, [Zr] ) 0.025
M. b Ratio determined by GC. % Yield isolated by chromatogra-
c
2 2
(nmInd) ZrCl in toluene afforded primarily dideuterated
phy. % Total Yield (13 + 14) measured by GC. e Not determined.
d
products 13a ,b, as well as trideuterated products 13c,d
2
in a relative ratio of four to one. Integration of the H
NMR spectrum of these products showed an equal
distribution of deuterium atoms at the methyl and
methylene positions (eq 12). In the presence of the same
Grignard reagent, deuterium is incorporated into the
allylic position adjacent to the alcohol of 14 (eq 13).
bromide failed to react with 12 in the presence of
(
nmInd)
2
ZrCl
2
after 24 h in toluene at 75 °C (less than
1
0% conversion, 5% unidentified product). The (nmInd) -
2
2
ZrCl catalyst precursor is more selective for (1R,2S,3R,-
4
R,7R)-13 in toluene at 55 °C or in refluxing hexanes
(entries 1 and 4), with approximately 3:1 preference as
measured by gas chromatography. However the enantio-
selectivity is no better than 6% enantiomeric excess
under these conditions. In refluxing toluene, the selectiv-
ity is reversed with the hydride product favored in a ratio
of 2:1. The enantioselectivity for the ethyl product 13
improves slightly to 11% enantiomeric excess, only 6%
ee for (1R,2S,3R,4R)-14 is seen at these conditions. The
reaction is sluggish in either refluxing tetrahydrofuran
or toluene at 22 °C; no more than 30% conversion occurs
after 24 h.
2 2
The (nimInd) ZrCl catalyst precursor also reacts with
1
2 and ethylmagnesium bromide to form both hydride
and ethyl addition product. No straightforward correla-
tion with reaction temperature was observed in this case,
although the relative ratio changed in each experiment
(
entries 6-8). Compound (1S,2R,3S,4S,7S)-13 in 48% ee
can be isolated in approximately 20% yield; compound
1
4 is formed racemically.
The hydride product 14 was formed more selectively
(
74% yield by GC, 53% isolated yield) with propylmag-
Discu ssion
nesium bromide and (nmInd) ZrCl ; no product corre-
2
2
sponding to a propyl addition could be isolated (eq 10).
The enantiomeric excess was not determined.
The catalytic ring-opening of bicycles with hydride
reagents has proven a powerful synthetic method; the
nickel-catalyzed ring-opening of oxabicycles with diisobu-
tylaluminum hydride proceeds in good yield with high
enantioselectivity.16 The corresponding nickel- and pal-
ladium-catalyzed ring-opening with delivery of an alkyl
group has also been reported.1
6b,17,18
In this paper we
report that early transition metal catalysts can be
effective for the alkylative ring-opening of oxabicycles in
good yields with moderate to excellent enantioselectivity.
The catalytic ring-opening of the oxanorbornene 6 with
1 M TEA in the presence of chiral zirconocenes of the
Monitoring the ring opening of 12 by GC reveals that
the (nmInd) ZrCl catalyst precursor reacts with 12 at
2 2

3
906 J . Org. Chem., Vol. 65, No. 13, 2000
Millward et al.
Erker type30 yields the substituted cyclohexanol 7 in 64-
ylmagnesium bromide lacks the product selectivity seen
in ring-openings of [2.2.1] oxabicyclo alkene 6 with
aluminum alkyls and zirconocenes; the enantioselectivity
is also uniformly lower. The catalytic ring opening of 12
with EtMgBr and zirconocenes 4 and 5 yields mixtures
of 13 and 14 in ratios of 1.4:1 to 1:1.8. The ratio of
products does not vary consistently with temperature.
The ratio of 13 to 14 can be altered from 3:1 to 1:2 by
7
0% yield and up to 96% ee. Both isomers can be
preferentially formed by choice of zirconocene. The
titanium catalysts also ring-open 6 in good yields; the
chiral catalyst precursor (+)-IndA*TiCl
2
produces the
(
1R,2S,3S,6R) isomer in 34% ee. For the ring-opening of
6
to 7, the zirconium catalysts afford similar yield with
improved enantioselectivity.
These results show that catalytic alkyl addition to a
2 2
increasing the temperature when (nmInd) ZrCl 4 is used
[
2.2.1] oxabicyclo alkene can afford cyclohexenol products
in good yield and excellent enantioselectivity when the
nimInd) ZrCl catalyst precursor is used. The scope of
as catalyst precursor. The combined yields range from
45 to 67%, and the enantioselectivity for both hydride
and ethyl addition with this catalyst is poor; a 12% ee of
(1R,2S,3R,4R,7R)-13 and a 7% ee of (1R,2S,3R,4R)-14 are
obtained. It is noteworthy that when TEA is used in place
of the Grignard, 13 is formed as a minor product but with
a 20% ee of (1R,2S,3R,4R,7R)-13. The alkylative ring
(
2
2
alkyl nucleophiles is currently limited only to ethyl
groups; attempts to ring-open 6 with 1 M tripropylalu-
minum in the presence of titanocene dichloride yielded
the hydride product 8 exclusively.
The titanium catalysts ring-open 6 with the delivery
of a hydride to give 8 at high concentrations (2.5 M) of
TEA; the yields range from 60 to 99%, but the enantio-
2
opening with (nimInd) ZrCl2 5 to give cycloheptenol 13
gave higher ee’s of 36-48%, but the selectivity is poor
and the yields low at 16-27%. Higher selectivities and
yields for hydride addition is possible with higher alky-
magnesiums such as PrMgBr, but no enantioselectivity
is observed in the formation of the hydride adduct 14.
The catalytic ring opening of [2.2.1] and [3.2.1] oxabi-
cycloalkenes with Grignard reagents can also be carried
out with nickel catalysts;17 to date, only achiral nickel
complexes have been reported with Grignards lacking
â-hydrogens. For the nickel catalysts, the selectivity for
selectivity with (+)-IndA*TiCl
2
is only 17% for the
1S,2R,3R) isomer (Table 2). The hydride product is also
(
exclusively obtained with 1 M tripropylaluminum and
titanocene dichloride.
In the presence of TIBA, the (nmInd)
precursor give the (1S,2R,3R) isomer of 8 in yields of 30-
7%. In contrast, the (nimInd) ZrCl produces racemic 8
Table 2). For the ring-opening of 6 to 8, the titanium
2 2
ZrCl catalyst
4
2
2
(
1
7
catalysts at high TEA concentrations give better yields
and similar stereoselectivity.
exo versus endo attack depends on the solvent. For the
zirconocene-catalyzed ring-opening reported here, we
observe only exo attack.
Although good yields of 8 can be obtained with the
titanium catalysts, the enantioselectivity is uniformly
poor and consistently lower than that observed in the
ethyl addition reactions; previously developed methods
with chiral nickel catalysis are more selective.16 Use of
the group 4 metal catalysts offers some measure of
convenience, as the hydride source is added all at once
rather than over the course of several hours via a syringe
pump.
Three plausible mechanisms can be envisaged for the
ring-opening of oxabicycles: Lewis acid-catalyzed S 2′
N
alkyl addition (eq 14), olefin insertion into a transition
metal alkyl (eq 15), and alkene reductive coupling
The catalytic ring-opening of [3.2.1] bicycles is also
possible with zirconocenes and alkylmagnesium reagents;
however, in these reactions we have been unable to find
N
conditions for the selective S 2′ addition of alkyl groups
to 12; in all cases we observe a mixture of the ethyl
adduct 13 and the hydride adduct 14. One of the
surprising differences in the [3.2.1] oxabicycle 12 relative
to the oxanorbornene 6 is the higher reactivity of 12 for
the uncatalyzed ring-opening reactions. Compound 6 is
unreactive with 2.5 equiv of triethylaluminum even in
refluxing toluene, whereas compound 12 reacts with 2.2
equiv of either triethylaluminum or diethyl zinc to
produce ethyl cycloheptenol compound 13. This was
somewhat unexpected, as the opposite trend occurs in
nickel-catalyzed ring-opening hydride addition to oxabi-
cyclic alkenes with DiBAl-H; the [2.2.1] oxabicyclo alkene
substrates ring-open at room temperature, whereas
through a metallacycle intermediate (Scheme 2). The
Lewis acid mechanism has been used to rationalize silyl
triflate-catalyzed enolate addition to an oxanorbornene.
3
5
Olefin insertion has been implicated in carbometalation
of R-olefins with group 4 metals with trialkyl aluminum
compounds.3 Alternatively, reductive coupling of R-ole-
fins with metal alkyls and group 4 metal catalysts has
6,37
also been postulated for the ethylmagnesation and ethyl-
alumination of olefins.1
9,20,38,39
This mechanism has also
[
3.2.1] oxabicyclo alkene substrates require elevated
1
4,16
temperatures to break the carbon-oxygen bond.
The
been proposed for the ring-opening of benzooxanorbor-
nene with a zirconocene benzyne complex.23
stability of oxabicycles to Grignard reagents is not well
understood but has been utilized in developing nickel-
catalyzed alkylative ring-opening methodology.17
For the catalytic ring-opening of the [3.2.1] bicycle 12,
we focused on the zirconocenes as the zirconocene com-
pounds were found to be superior in the ring-opening of
(35) Yamamoto, I.; Narasaka, K. Chem. Lett. 1995, 1129.
(
36) Kondakov, D. Y.; Negishi, E.-i. J . Am. Chem. Soc. 1996, 118,
577-1578.
37) Kondakov, D. Y.; Negishi, E.-i. J . Am. Chem. Soc. 1995, 117,
10771-10772.
38) Hoveyda, A. H.; Morken, J . P.; Houri, A. F.; Xu, Z. M. J . Am.
Chem. Soc. 1992, 114, 6692-6697.
39) Dawson, G.; Durrant, C. A.; Kirk, G. G.; Whitby, R. J .
Tetrahedron Lett. 1997, 38, 2335-2338.
1
(
(
6
, and we observed no uncatalyzed ring-opening of 12
ethylmagnesium reagents. The ring-opening of [3.2.1]
oxabicyclo alkene 12 with zirconium catalysts and eth-
(

Ring-Opening Reactions of Oxabicyclic Alkenes
J . Org. Chem., Vol. 65, No. 13, 2000 3907
Sch em e 2. P r op osed Red u ctive Cou p lin g
Mech a n ism for Tita n iu m - a n d
Zir con iu m -Ca ta lyzed Rin g-Op en in g Eth yl
Ad d ition s to Oxa bicyclo Alk en e Com p ou n d s
addition mechanisms is more difficult than in the ethyl
addition case. The hydrogen source in both mechanisms
is the metal alkyl reagent, so isotopic labeling does not
distinguish the two possibilities.
3
For the ring opening of 6 with Et Al, a reductive
coupling mechanism (Scheme 2) is plausible and consis-
tent with proposals for the ethylalumination of R-olefins
in the presence of zirconocenes.3
9,41
This mechanism
Al,
would account for the lack of reactivity of 6 with Me
3
but neither an olefin insertion mechanism nor a direct
nucleophilic attack via group 4 metal Lewis acid catalysis
can be ruled out on the basis of available data.
Isotopic labeling studies on the ring-opening of 12
implicate a metallacycle mechanism for this reaction. The
observation of the monodeuterio-13 upon deuteriolytic
workup the reaction of 12 with EtMgBr rules out direct
nucleophilic attack and olefin insertion mechanisms. In
addition the formation of di- and trideuterated products
1
3a -d with an equal distribution of deuterium atoms
between the methyl and methylene carbons strongly
implicates a metal ethylene adduct derived from the
magnesium alkyl as postulated in Scheme 2. Production
of the four products 13a -d is also consistent with the
metallacycle mechanism (Scheme 2), as isotopic effects
on the carbon-carbon bond-forming step are expected to
be minimal.38 The label should be found only at the
terminal carbon of the ethyl moiety in either Lewis acid
or olefin insertion mechanisms; so either mechanism
would produce only product 13c. The catalytic ring
As shown in eqs 14 and 15 and Scheme 2, only the
reductive coupling mechanism invokes an alkylmetal
species as a key intermediate after ring opening by
â-alkoxy elimination. Thus, deuteriolytic workup should
provide a signature for the reductive coupling mechanism
if transmetalation competes with â-hydride elimination
from intermediate 2A.
Two mechanisms can be envisaged for the ring-opening
of oxabicycles with delivery of a hydride: a Lewis acid-
catalyzed hydride addition via a â-hydride elimination
2 2
opening of 12 with triethylaluminum and (nmInd) ZrCl
yields 13 as a minor product, but the same enantiomer
of 13 as that obtained from the ethylmagnesium bromide
is observed, implicating a similar mechanism.
The nature of the metal alkyl appears to influence the
enantioselectivity; in the ring-opening of 12, reactions
with TEA produce 13 with higher % ee than those with
ethylmagesium bromide even though an uncatalyzed
TEA-induced ring-opening competes with the catalyzed
reaction. Furthermore, ring-opening of 6 with TEA has
much higher enantioselectivity than ring-opening of 12
with ethylmagnesium bromide. To a first approximation,
the substrates present the same 2,5-dihydrofuran “face”
to the zirconocene catalyst, although the substrates are
different. Together, these observations suggest that the
metal alkyls play a role in the transition state of the
stereochemistry-determining reductive coupling step.
Ring-opening deuteride addition to 12 with 2,2,2-
(eq 16) and olefin insertion into a transition metal
hydride (eq 17). The transition metal hydride can be
generated by prior â-hydride elimination from a transi-
tion metal alkyl.
2 2
trideuteroethylmagnesium bromide and (nmInd) ZrCl
places a deuterium atom at the allylic position adjacent
to the alcohol. This result clearly indicates the â-hydrogen
of the metal alkyl as the source of the hydride but does
not discriminate between a Lewis acid-catalyzed hydride
addition (eq 16) and an insertion mechanism (eq 17). The
fact that the ratio of hydride product 14 and ethyl product
1
3 change with conversion implicates different catalysts
Lewis acids can mediate hydride additions by metal
alkyls to double bonds; for example, triisobutylaluminum
reduces carbonyl groups through a â-hydride elimination
process analogous to the Meerwein-Ponndorf-Verley
reaction; it also exchanges isobutylene for other olefins
in a similar process.40 The metal alkyl serves as both
Lewis acid and reductant in these reactions. The inser-
tion of olefins into zirconocene metal hydrides is also well-
known. Discrimination between the two proposed hydride
for the two reactions.
The hydride and ethyl catalysts formed from IndA*TiCl
2
differ in their absolute stereoselectivity; the ethyl and
hydride are delivered to opposite enantiotopic alkene
carbon of 6. In contrast, the catalysts derived from
(nmInd)
2 2
ZrCl have the same absolute stereoselectivity.
This suggests that the nature of the catalytic species
(41) Dzhemilev, U. M.; Ibragimov, A. G.; Zolotarev, A. P.; Mus-
lukhov, R. R.; Tolstikov, G. A. Izv. Akad. Nauk SSSR, Ser. Khim. 1990,
12, 2831-2841.
(40) Winterfeldt, E. Synthesis 1975, 617-630.

3
908 J . Org. Chem., Vol. 65, No. 13, 2000
Millward et al.
varies not only by reaction type (ethyl or hydride) but
also by metal.
hydride to form the desired benzyloxy product. The product
was purified by flash column chromatography (4:1 hexane/
ethyl acetate eluent) to afford 2.9 g (17.1 mmol, 83% yield) of
1
substrate 12. H NMR: (CDCl
(
1
(
3
) δ 7.29-7.35 (m, 5H); 6.325
Exp er im en ta l Section
s, 2H); 4.425 (s, 2H); 4.4 (d, J ) 3 Hz, 2H); 3.534 (t, J ) 6 Hz,
1
3
H); 2.247-2.324 (m, 2H); 0.93 (d, J ) 7.2 Hz, 6H). C NMR:
Gen er a l. All manipulations involving air-sensitive com-
pounds were carried out under nitrogen in a glovebox or using
standard Schlenk line techniques. Hexanes were distilled from
lithium aluminum hydride, and tetrahydrofuran was distilled
from sodium/ benzophenone prior to use. Toluene was passed
through supported copper catalyst and alumina columns to
remove moisture and trace oxygen. All solvents were collected
and stored in Straus flasks (Kontes glassware). Alkyalumi-
nums (neat) were purchased from Aldrich and used as
received. Grignard reagents were either purchased from
Aldrich as solutions in tetrahydrofuran or prepared according
to literature procedure. Titanocene dichloride was purchased
from Aldrich and used as received. η-5-((tetramethyl)cyclo-
pentadienyl)(dimethylsilyl)(tert-butyl)amidotitanium dichlo-
3
CDCl ) δ 133.957; 128.161; 127.099; 126.902; 82.189; 80.201;
7
5.293; 38.826; 12.775.
Eth yl Rin g-Op en in g Rea ction of Oxa bicycle 6. Rep -
r esen ta tive P r oced u r e for Tita n iu m Ca ta lysts. In the
drybox, a 25 mL Schlenk flask was charged with 50 mg (0.136
2
mmol) of IndA*TiCl , 500 mg (2.71 mmol) of 6, and 10 mL of
hexanes. A 0.835 mL (6.78 mmol) portion of neat triethylalu-
minum was added to the reaction solution, and the flask was
fitted with a coldfinger condenser. The reaction flask was
attached to a Schlenk line and the solution was heated to
reflux with an oil bath. After 12 h, the solution was cooled to
0
°C. A 10 mL amount of a 10% HCl solution was added
dropwise (Th is qu en ch in g is extr em ely exoth er m ic -
exer cise gr ea t ca r e in a d d in g th e HCl solu tion ). The
products were extracted with 3 × 50 mL of diethyl ether, and
the combined organics were dried over magnesium sulfate.
After filtration, the solvents were removed on a rotary
evaporator. The cyclohexenol product 7 was obtained in 94%
yield (550 mg) in 95% purity (starting material was the only
impurity).
ride (Cp*ATiCl
benzyl)amidotitanium dichloride (IndA*TiCl
2
), (+)-η-5-(indenyl)(dimethylsilyl)(R-methyl-
28,42
2
),
and zir-
2
9,30
conocenes
were prepared according to the literature. All
other reagents were obtained commercially and used as
received unless otherwise noted.
Preparative chromatography was performed on silica gel 60,
0
.02-0.04 mm. GC analyses were obtained with an SE-30
Rep r esen ta tive P r oced u r e for Zir con iu m Ca ta lysts. In
the drybox, a 25 mL Schlenk flask was charged with 34 mg
column (30 mm × 0.32 mm i.d. × 0.25 µm coating) with an
1
13
FID detector. H and C NMR specta were obtained on Varian
Gemini-200 MHz, XL-400 MHz, and Unity Inova-500 MHz
spectrometers. FTIR were obtained as thin films on NaCl
plates. Chiral HPLC was performed with columns from
Chiralcel Technologies as noted.
2 2
(0.05 mmol) of (nmInd) Cl , 184 mg (2.71 mmol) of 6, and 2
mL of toluene. A 0.28 mL (2 mmol) portion of neat triethyl-
aluminum was added to the reaction solution and the flask
was fitted with a coldfinger condenser. The reaction flask was
attached to a Schlenk line and the solution was heated to
reflux with an oil bath. After 17 h, the solution was cooled to
Su bstr a te Syn th esis. P r ep a r a tion of 4,5-Bis(m eth oxy-
m eth yl)-7-oxa bicyclo-2-h ep ten e (6). This substrate was
0
°C. Ten milliliters of a 10% HCl solution was added dropwise
3
prepared by a modification of a literature procedure. Freshly
(Th is qu en ch in g is extr em ely exoth er m ic - exer cise
distilled furan (2.6 mL, 35.7 mmol) and freshly sublimed
mandelic anhydride (3.5 g, 35.7 mmol) were dissolved in ether
and stirred for several days. The crystalline, insoluble Diels-
Alder adduct was recovered by filtration in 64% yield (3.821
gr ea t ca r e in a d d in g th e HCl solu tion ). The products were
extracted with 3 × 15 mL of diethyl ether, and the combined
organics were dried over magnesium sulfate. After filtration,
the solvents were removed on a rotary evaporator. After flash
column chromatography with 1:1 hexane/diethyl ether, the
cyclohexenol product 7 was obtained in 70% yield (128 mg) in
g, 22.8 mmol). The product was characterized by NMR
1
spectroscopy. H NMR: (CDCl
(
3
) δ 6.580 (t, J ) 1 Hz, 2H), 5.465
t, J ) 1 Hz, 2H), 3.175 (s, 2H). The Diels-Alder adduct was
reduced to 4,5-bis(hydroxymethyl)-7-oxabicyclo-2-heptenediol
with 2.2 equiv of lithium aluminum hydride in tetrahydrofuran
9
5% purity (starting material was the only impurity). The
product was nonracemic: [R] ) -48.8°, c ) 0.33 in methylene
D
chloride.
and used without further purification after aqueous workup.
2
,3-Bis(m eth oxym eth yl)-7-eth yl-4-cycloh exen -1-ol (7).
1
H NMR: (CDCl
Hz, 4H); 1.95 (t, J ) 5 Hz, 2H). Methylation was carried out
3
) δ 6.389 (s, 2H); 4.685 (s, 2H); 3.805 (d, J )
1
H NMR: (CDCl ) δ 5.55-5.60 (m, 2H), 4.024 (d, J ) 10 Hz,
3
5
1
3
(
1
1
4
H), 3.7-3.85 (bm, J ) 10 Hz, 1H), 3.573 (d, J ) 7.8 Hz, 2H),
.449 (d, J ) 3 Hz, 2H), 3.383 (s, 3H), 3.376 (s, 3H), 2.5-2.5
by reacting the diol (2.07 g, 14.31 mmol) with (3.56 mL, 57.24
mol) iodomethane in methyl sulfoxide with potassium hydrox-
ide. The product 6 was purified by fractional vacuum distil-
lation as a pale yellow oil (1.87 g, 10.2 mmol). 1H NMR:
m, 1H), 2.331 (qd, J ) 7.8, 2 Hz, 1H), 1.92-2.0 (m, 1H), 1.2-
13
.8 (m, 2H), 0.992 (t, J ) 7.3 Hz, 3H). C NMR: (CDCl
3
) δ
30.953, 127.130, 73.177, 73.0737, 64.908, 58.854, 58.808,
(
2
CDCl
H); 3.345 (s, 6H); 3.305 (d, J ) 9.4 Hz, 2H); 1.881 (m, 2H).
P r ep a r a tion of 2,4-Dim eth yl-3-(ben zyloxy)-8-oxa bicy-
3
) δ 6.329 (s, 2H); 4.815 (s, 2H); 3.462 (dd, J ) 9.4, 5 Hz,
+
1.421, 36.338, 24.291, 11.546; MS 214 (M ). Anal. Calcd for
: C, 67.29; H, 10.28. Found: C, 67.10; H, 10.69.
Hydr ide Rin g-Open in g Reaction of Oxabicycle 6: Rep-
12 22 3
C H O
clo-6-octen e (12). This substrate was prepared according to
r esen ta tive P r oced u r e for Tita n iu m Ca ta lysts. In the
drybox, a 25 mL Schlenk flask was charged with 21.5 mg (0.05
3
literature procedure. A 5.4 g (35.5 mmol) quantity of 2,4-
dimethyl-8-oxabicyclo-6-octene-3-one was prepared by a [4 +
mmol) of IndA*TiCl , 184 mg (1 mmol) of 6, and 2 mL of
2
3
2
7
1
] oxyallyl cation cyclization.43 1H NMR: (CDCl
3
) δ 6.343 (s,
hexanes. A 0.7 mL (5 mmol) portion of neat triethylaluminum
was added to the reaction solution, and the flask was fitted
with a coldfinger condenser. The reaction flask was attached
to a Schlenk line, and the solution was heated to reflux with
an oil bath. After 12 h, the solution was cooled to 0 °C. Ten
milliliters of a 10% HCl solution was added dropwise (Th is
qu en ch in g is extr em ely exoth er m ic - exer cise gr ea t
ca r e in a d d in g th e HCl solu tion ). The products were
extracted with 3 × 15 mL of diethyl ether, and the combined
organics were dried over magnesium sulfate. After filtration,
the solvents were removed on a rotary evaporator. Flash
column chromatography with 3:2 hexanes/ethyl acetate as
eluent afforded the cyclohexenol product 7, 98.5% pure by GC
H); 4.852 (d, J ) 5 Hz, 2H); 2.77-2.84 (m, 2H); 0.968 (d, J )
1
3
.2 Hz, 6H). C NMR: (CDCl
3
) δ 133.578; 82.705; 50.312;
0.014. Reduction of this {3.2.1} oxabicyclic ketone with
diisobutylaluminum hydride in tetrahydrofuran at 0 °C se-
lectively produced the endo alcohol product upon workup.
Flash column chromatography with 1:1 hexane/ethyl acetate
as eluent afforded 2.54 g (20.6 mmol, 58% yield) of a white
1
crystalline solid. H NMR: (CDCl
3
) δ 6.526 (s, 2H); 4.48 (d,
J ) 3.4 Hz, 2H); 3.687 (dt, J ) 11.4, 6 Hz, 1H); 2.17-2.23 (m,
H); 1.535 (d, J ) 11.4 Hz, 1H); 0.98 (d, J ) 7.6 Hz, 6H). 13
NMR: (CDCl ) δ 136.355; 82.143; 72.797; 38.143; 12.851. The
alcohol product reacted with benzyl bromide and sodium
2
C
3
(
-
66% yield, 122 mg). The product was nonracemic: [R]
14.6°, c ) 0.5 in methylene chloride.
Rep r esen ta tive P r oced u r e for Zir con iu m Ca ta lysts. In
the drybox, a 25 mL Schlenk flask was charged with 35 mg
D
)
(
42) Shapiro, P. J .; Bunel, E.; Schaefer, W. P.; Bercaw, J . E.
Organometallics 1990, 9, 867-869.
43) Hoffmann, H. M. R. Org. Synth. 1978, 58, 17.
(

Ring-Opening Reactions of Oxabicyclic Alkenes
0.05 mmol) of (nmInd) Cl , 184 mg (1 mmol) of 6, and 2 mL
of toluene. A 0.5 mL (2 mmol) portion of neat triisobutylalu-
minum was added to the reaction solution, and the flask was
fitted with a coldfinger condenser. The reaction flask was
attached to a Schlenk line, and the solution was heated to
reflux with an oil bath. After 18 h, the solution was cooled to
J . Org. Chem., Vol. 65, No. 13, 2000 3909
(
2
2
R-methoxyphenylacetic acid to determine both enantiomeric
excess and absolute stereochemistry of compounds 8, 13, and
14.34 Compound 7 was unreactive with (R)-R-methoxyphenyl-
acetic acid, presumably due to the steric hindrance around the
secondary alcohol. The enantiomeric excesses of compound 7
produced by different catalysts was also determined by chiral
HPLC of the 4-nitrobenzyl ester derivative (chiralcel OD
column, 99.5:0.5 heptane/2-propanol). This ester was prepared
according to the literature from 4-nitrobenzoyl chloride, 4-(di-
methylamino)pyridine, and pyridine.44
0
°C. Ten milliliters of a 10% HCl solution was added dropwise.
The products were extracted with 3 × 15 mL of diethyl ether,
and the combined organics were dried over magnesium sulfate.
After filtration, the solvents were removed on a rotary
evaporator. Flash column chromatography with 1:1 hexanes/
ethyl acetate as eluent afforded the cyclohexenol product 7 in
Red u ctive Ozon olysis of 7 to F u r a n ose 9 a n d Ester
Der iva tive 10. A 215 mg (1 mmol) portion of 7 placed in a 50
mL round-bottom flask was dissolved in 25 mL of diethyl ether.
This solution was cooled to -25 °C, and a stream of ozone was
bubbled through it for 30 min. Dry oxygen was then bubbled
through the solution for 10 min. The solution was warmed to
3
0% yield (55 mg).
,3-Bis(m et h oxym et h yl)-4-cycloh exen -1-ol (8).14 1H
NMR: (CDCl ) δ 5.70 (m, 1H), 5.56 (m, 1H), 4.3 (d, J ) 10 Hz,
H), 3.92 (m, 1H), 3.56 (m, 2H), 3.37 (s, 3H), 3.37 (d, J ) 3.2
Hz, 2H), 3.36 (s, 3H), 2.61 (m, 1H), 2.4 (m, 1H), 2.31 (m, H),
2
3
1
0
°C, and 161 mg (4 mmol) lithium aluminum hydride was
1
3
2
6
3
.20 (m, 1H). C NMR: (CDCl ) δ 127.26, 126.24, 72.50, 72.36,
6.83, 59.23, 40.16, 37.55, 33.96.
added. The slurry was stirred overnight and then quenched
with saturated ammonium sulfate. The product was extracted
with 4 × 10 mL of ether. The combined organics were dried
over magnesium sulfate, concentrated, and purified by pipet
scale chromatography. The product 9 was recovered in 21%
Rin g-Op en in g Rea ction s of Oxa bicycle 12: Rep r esen -
ta tive P r oced u r e. A 25 mL Schlenk flask was charged with
.7 mL of 3.0 M ethylmagnesium bromide in diethyl ether.
0
The solvent was removed in vacuo for 1 or more hours; in all
cases the final pressure was below 100 milliTorr. The reaction
flask was taken to the drybox and charged with 34 mg of
13
yield (53 mg). The peak at 97.9 ppm in the C spectrum is
1
consistent only with the furanose structure. H NMR: (CDCl
3
)
δ 8.22 (dd, J ) 8.5, 1.7 Hz, 2H), (dt, J ) 9, 2 Hz, 2H), 5.20 (dd,
J ) 11.7, 4.8 Hz, 1H), 4.935 (d, J ) 11.7 Hz, 1H), 4.406 (d,
J ) 3 Hz, 1H), 4.395 (d, J ) 3 Hz, 1H), 4.147 (dd, J ) 6.8,4
Hz, 1H), 3.55-3.48 (m, 2H), 3.37-3.24 (m, 2H), 3.367 (s, 3H),
2 2
(nimInd) Cl , 244 mg of 12, and 2 mL of toluene. The flask
was fitted with a coldfinger condenser and adapted to a
Schlenk line where it was heated to 60 °C. The reaction was
stirred for 12 h and then cooled to room temperature and
quenched by careful addition of 10 mL of a 10% HCl solution.
The products were extracted with 3 × 15 mL of diethyl ether;
the organics were then dried over magnesium sulfate and dried
on a rotary evaporator. Flash column chromatography with
3
1
.307 (s, 3H), 2.6-2.5 (m, 1H), 2.4-2.3 (m, 1H), 1.8-1.7 (m,
H), 1.3-1.6 (m, 2H), 0.947 (t, J ) 7.5 Hz). 13C NMR: (CDCl
)
3
δ 11.637; 20.361; 42.103; 45.263; 47.095; 59.112; 59.081;
6
3.739; 68.686; 71.295; 84.419; 97.908. Selective esterification
of the primary alcohol to 10 with 4-nitrobenzoic acid was
performed with the acid chloride and 4-(dimethylamino)-
pyridine.
4
:1 hexane/ethyl acetate as eluent afforded 44 mg (16% yield)
of ethyl cycloheptenol 13 and 85 mg (35% yield) of hydride
cycloheptenol 14. Both compounds are white crystalline solids
when all traces of solvent are removed.
Oxid a tion of 7 to Cycloh exen on e 11. A two-neck 50 mL
round-bottomed flask fitted with a dropping funnel and a
2
,4-Dim et h yl-3-(b en zyloxy)-7-et h yl-5-cycloh exen -1-ol
1
nitrogen adapter was purged with N
4 µL of oxalyl chloride and 2 mL of CH
cooled to -78 °C. Dimethyl sulfoxide, 0.08 mL in 2 mL of CH
Cl , was added dropwise over 2 min. Compound 7, 120 mg from
(nimInd) ZrCl catalysis, was added in 2 mL of CH Cl . The
2
and then charged with
(
5
(
1
1
13): mp 70-71.5 °C. H NMR: (CDCl
3
) δ 7.25-7.35 (m, 5H),
5
2
2
Cl . The solution was
.41-5.51 (m, 2H) 4.639 (s, 2H), 3.680-3.686 (m, 1H), 3.565
2
-
t, J ) 2 Hz, 1H), 2.64-2.67 (m, 2H), 2.10-2.14 (m, 1H), 1.53-
.61 (m, 1H), 1.46-1.51 (m, 1H), 1.179 (d, J ) 6.4 Hz, 3H),
2
.168 (d, J ) 5.6 Hz, 3H), 0.959 (t, J ) 7.2 Hz, 3H). 13C NMR:
2
2
2
2
reaction was stirred 30 min at -78 °C, and then 1.0 mL of
triethylamine was added dropwise. The solution was warmed
to 22 °C and stirred 12 h. The reaction was quenched by
addition of water. The product was extracted with 3 × 20 mL
(
CDCl
3
) δ 139.345, 133.888, 130.032, 128.180, 127.169, 126.973,
8
1
7
4.144, 76.024, 74.850, 44.362, 43.264, 39.423, 24.505, 19.221,
7.204, 12.612; MS 274 (M ). Anal. Calcd for C18
8.79; H, 9.55. Found: C, 79.020; H, 9.91. Enantiomeric excess
+
26 2
H O : C,
2 2
of CH Cl ; organics were washed with 10% HCl, sodium
was determined by chiral HPLC (chiralcel AD column, 99:1
bicarbonate, and brine and then dried over magnesium sulfate.
heptane/2-propanol). For compound 13 formed with (nmInd)
in 6% ee, the optical rotation is [R] ) +9.7°, c ) 1.0 in CH
Cl
2
Cl
2
2
Flash chromatography on silica with 4:1 hexanes/ethyl acetate
D
-
1
afforded 22 mg (18% yield) of cyclohexenone product.
NMR: (CDCl
H
2
.
2
,4-Dim eth yl-3-(ben zyloxy)-5-cycloh exen -1-ol (14): mp
3
) δ 5.88 (m, 1H), 5.80 (m, 1H), 3.825 (dd, J )
1
10, 10 Hz, 1H), 3.463 (dd, J ) 10, 6 Hz, 1H), 3.356 (s, 3H),
3.2-3.2 (m, 2H), 3.215 (s, 3H), 2.9-3 (m, 2H), 2.8 (m, 1H),
4
(
3
(
(
1
3
O
0-44 °C. H NMR: (CDCl
m, 1H), 5.458 (ddd, J ) 13, 4.5, 2 Hz, 1H), 4.674 (s, 2H), 3.56-
.59 (m, 1H), 3.47-3.5 (m, 1H), 2.6-2.63 (m, 1H), 2.35-2.4
m, 2H), 1.81-1.86 (m, 1H), 1.217 (d, J ) 6.5 Hz, 3H), 1.201
d, J ) 6.8 Hz, 3H). C NMR: (CDCl
27.174, 125.456, 86.348, 75.524, 70.255, 49.981, 38.982,
7.420, 20.878, 17.618; MS 246 (M ). Anal. Calcd for C16
: C, 78.01; H, 9.00. Found: C, 77.74; H, 9.36.
Der iva tives of Rin g-Op en ed P r od u cts: Ester Der iva -
3
) δ 7.3-7.4 (M, 5H), 5.72-5.77
1
3
1.8-1.9 (m, 1H), 1.45-1.55 (m, 1H), 0.904 (t, J ) 7.5 Hz).
C
NMR: (CDCl ) δ 10.98, 22.44, 40.37, 49.88, 58.79, 58.97, 68.87,
3
1
3
) δ 136.268, 128.231,
68.90, 128.29, 130.14, 209.11. IR (NaCl plate) 2927 (m), 1719
(w), 1654 (s), 1530 (w), 1458 (w), 1274 (m), 1104 (s).
3
+
22
H -
J O991429F
2
tives of 8, 13, a n d 14. The literature procedure using N,N′-
dicyclohexyldiimide was followed in the esterification with (R)-
(44) Ireland, R. E.; Norbeck, D. W. J . Am. Chem. Soc. 1985, 107,
3279.