Applications of planar-chiral heterocycles in enantioselective catalysis: Cu(I)/bisazaferrocene-catalyzed asymmetric ring expansion of oxetanes to tetrahydrofurans

Article abstract of DOI:10.1016/S0040-4020(01)00082-5

A planar-chiral, C₂-symmetric bisazaferrocene ligand is shown to control the stereochemistry of Cu(I)-catalyzed ring expansions of oxetanes to tetrahydrofurans.

Full text of DOI:10.1016/S0040-4020(01)00082-5

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2621±2634
Applications of planar-chiral heterocycles in enantioselective
catalysis: Cu(I)/bisazaferrocene-catalyzed asymmetric ring
expansion of oxetanes to tetrahydrofurans
Michael M.-C. Lo and Gregory C. Fup
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Received 13 September 2000; revised 2 November 2000; accepted 6 November 2000
AbstractÐA planar-chiral, C2-symmetric bisazaferrocene ligand is shown to control the stereochemistry of Cu(I)-catalyzed ring expansions
of oxetanes to tetrahydrofurans. q 2001 Elsevier Science Ltd. All rights reserved.
As part of their seminal 1966 study of transition metal-cata-
lyzed enantioselective reactions, Nozaki and Noyori
reported that copper catalysts can effect the asymmetric
ring expansion of oxetanes to tetrahydrofurans (Eq. (1)),
although they did not determine the enantiomeric excess
of the products.1
lyzed cyclopropanation of ole®ns (Eq. (2)).4,5 Based on
these positive results, we decided to explore the possibility
that the same CuOTf/2 complex might also serve as an
effective catalyst for another reaction of diazo esters, the
asymmetric ring expansion of oxetanes to tetrahydrofurans.
In this paper, we describe our investigations in this area (Eq.
(3)).
ꢀ1†
Surprisingly, since this initial work, only Katsuki has
described further investigations of this interesting transfor-
mation.2,3 He has established that ring expansions catalyzed
by CuOTf in the presence of C2-symmetric bipyridine
ligands (e.g. 1) proceed with good stereoselectivity, and
he has utilized this process as a key step in the synthesis
of molecules such as trans-(1)-whisky lactone2b and (2)-
avenaciolide.2f
ꢀ2†
ꢀ3†
We have recently reported the application of C2-symmetric
bisazaferrocene 2 in a highly enantioselective Cu(I)-cata-
1. Results and discussion
Keywords: asymmetric synthesis; catalysis; copper and compounds; diazo
compounds; oxetanes.
Corresponding author. Tel.: 1617-253-2664; fax: 1617-253-7929;
e-mail: gcf@mit.edu
p
In an early study of the copper-catalyzed ring-expansion
process, we compared the selectivity of bisazaferrocene
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00082-5

2622
M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
Table 1. Asymmetric ring expansions catalyzed by CuOTf/2: Dependence
of selectivity on the diazo ester
in CH2Cl2 (10 min), without cleavage of the ring or epimeri-
zation.6
CuOTf/2 catalyzes the ring expansion of a range of 2-substi-
tuted oxetanes with good selectivity under our optimized
conditions (Table 2). Incorporation of an electron-with-
drawing substituent on the aromatic ring has no effect on
stereoselection (entry 1 vs entry 2). On the other hand,
incorporation of an electron-donating group leads to a
poor reaction, both in terms of stereoselectivity and yield
(entry 3), perhaps due to the ionization process illustrated in
Eq. (5). Naphthyl- and alkynyl-substituted oxetanes
undergo ring expansion with good stereoselection (entries
4 and 5).
Entry
OR
trans/cis
trans ee (%)
1
2
3
4
5
OEt
82:18
90:10
90:10
90:10
95:5
92
95
97
97
98
O-(d)-menthyl
O-(l)-menthyl
O-t-Bu
OCMeCy2
All data are the average of two runs.
ligand 2 with Katsuki's best bipyridine ligand (1). Under the
conditions that he had optimized for his catalyst system, we
found that our ligand furnishes nearly comparable stereo-
selection (Eq. (4)). In accord with the report of Katsuki, no
kinetic resolution of the oxetane is observed.
ꢀ5†
The ring expansions illustrated in Table 2 correspond to the
`matched' process, wherein the chiral catalyst and the
substrate are working in concert to preferentially generate
the trans diastereomer. When we employ the opposite
enantiomer of the catalyst, we produce the cis isomer with
good selectivity (Eq. (6)). Thus, the catalyst, not the
substrate, predominantly determines the con®guration of
the new stereocenter (Eq. (6) vs Table 2, entry 1).
ꢀ4†
We have optimized the reaction conditions for our ligand,
and we have found CuOTf to be the best copper source and
EtOAc to be the best solvent, among those that we have
examined. We have also determined that, as with CuOTf/
2-catalyzed cyclopropanations,4 the steric demand of the
diazo ester has a signi®cant impact on selectivityÐas the
bulk of the diazo ester increases, the stereoselection
increases (Table 1). Thus, whereas ethyl diazoacetate
affords 82:18 selectivity (entry 1), menthyl diazoacetates
and t-butyl diazoacetate furnish 90:10 selectivity (entries
2±4). Interestingly, the stereochemistry of the menthyl
subunit has essentially no impact on stereoselection (entry
2 vs entry 3). We obtain the highest selectivity with the most
hindered diazoester (RˆCMeCy2; entry 5). The CMeCy2
ester of the product tetrahydrofuran is readily converted
into the carboxylic acid through treatment with CF3CO2H
ꢀ6†
We have established that this observation is generalÐas
illustrated in Table 3, the cis, rather than the trans, tetra-
hydrofuran can be obtained in the ring-expansion process
simply by using the (S,S), rather than the (R,R), enantiomer
of bisazaferrocene ligand 2 (cf. Table 2). The stereoselection
Table 2. Asymmetric ring expansions catalyzed by CuOTf/2
Entry
R
Oxetane ee (%)
trans/cis
trans ee (%)
Yield (%)
1
2
3
4
5
Ph
99
97
98
99
99
95:5
94:6
75:25
86:14
89:11
98
98
69
91
97
74
81
29
75
64
4-(F3C)C6H4
4-(MeO)C6H4
1-Naphthyl
n-C7H15CuC
All data are the average of two runs. Yields are isolated yields. The yield for entry 1 includes both diastereomers.

M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
2623
Table 3. Asymmetric ring expansions catalyzed by CuOTf/2: Catalyst control of the newly generated stereocenter
Entry
R
Oxetane ee (%)
cis/trans
cis ee (%)
Yield (%)
1
2
3
4
5
Ph
99
97
98
99
99
84:16
86:14
58:42
85:15
84:16
95
95
82
95
94
74
52
20
72
60
4-(F3C)C6H4
4-(MeO)C6H4
1-Naphthyl
n-C7H15CuC
Yields are isolated yields. The yield for entry 1 includes both diastereomers.
appears to be largely independent of the nature of the
2-substituent, unless it is electron-rich (entry 3).
paraf®n oil, and oil-free KH was obtained after repeated
washing with pentane in a glove box, followed by drying
in vacuo. Ethyl diazoacetate was puri®ed by column
chromatography prior to use. Ligand 2,4 t-butyl diazo-
acetate,7 (d)-menthyl diazoacetate, (l)-menthyl diazo-
acetate,8 (^)-2-phenyloxetane,9 (40-tri¯uoromethylphenyl)-
tri-n-butylstannane,10 and methanesulfonyl azide11 were
synthesized according to literature procedures.
Hydrolysis of the ester generated in entry 5 of Table 3
furnishes the carboxylic acid that is an intermediate in the
Katsuki synthesis of (2)-avenaciolide.2f The stereoselec-
tivity that we obtain with bisazaferrocene ligand 2 (cis/
transˆ84:16, cis eeˆ94%) compares favorably with that
produced by bipyridine ligand 1 (cis/transˆ85:15, cis
eeˆ72%).2f
All reactions were carried out with magnetic stirring in
oven-dried glassware under an atmosphere of argon (mani-
fold) or under an atmosphere of nitrogen (Vaccum Atmos-
pheres glove box), unless otherwise noted. All reactions that
involve the preparation of substrates are unoptimized.
2. Conclusions
CuOTf/bisazaferrocene 2 serves as an effective catalyst for
the asymmetric ring expansion of oxetanes to tetrahydro-
furans. The catalyst controls the absolute stereochemistry of
the newly generated stereocenter and is capable of over-
riding the inherent preference of the substrate for formation
of the trans-2,3-disubstituted product. The level of stereo-
control compares favorably with other chiral catalysts that
have been developed for this reaction.
3.1.1. 10,10-Dicyclohexylethyl 2-diazo-3-oxobutanoate. In
a 100 mL round-bottom ¯ask equipped with a condenser,
1,1-dicyclohexylethanol12 (8.02 g, 38.1 mmol), DMAP
(0.461 g, 3.77 mmol), Et3N (0.386 g, 3.81 mmol), and
methanesulfonyl azide (6.04 g, 49.8 mmol) were mixed
and dissolved in MeCN (60 mL). The mixture was then
brought to re¯ux, and a solution of diketene (6.04 g,
49.8 mmol) in MeCN (15 mL) was added by syringe over
10 min. The deep-brown reaction mixture was cooled to
room temperature and stirred for another 12 h (TLC at
that time indicated that there was still some acetoacetate
ester). The reaction mixture was poured into Et2O/water.
The aqueous layer was extracted with Et2O (4£100 mL),
and the combined organic extracts were washed with 2 M
KOH and brine, dried (MgSO4), and concentrated to afford a
brown oil. The crude product was then dissolved in MeCN
(100 mL). Et3N (8.0 mL, 57 mmol) and then methanesul-
fonyl azide (7.18 g, 59.3 mmol) were added dropwise, and
the resulting mixture was stirred under air for 5 h, at which
time TLC indicated that there was no acetoacetate ester. The
reaction mixture was poured into Et2O/water. The aqueous
layer was extracted with Et2O, and the combined organic
extracts were washed with 2 M KOH and brine, dried
(MgSO4), and concentrated to afford an orange-yellow
3. Experimental
3.1. General
Analytical achiral GC analysis was performed on a J & W
Scienti®c DB-1701 column (0.25 mm£30 m). Analytical
chiral GC analysis was performed on either a Chiraldex
G-TA column (0.25 mm£20 m) or a Chiraldex B-PH
column (0.25 mm£20 m). Analytical chiral HPLC analysis
was performed on a Daicel Chiralcel OD or Chiralpak AD
column (4.6 mm£25 cm). Preparative achiral HPLC was
performed on an Alltech Econosphere Silica 10U column
(22 mm£250 mm).
Solvents were distilled under nitrogen from the indicated
drying agents: THF (sodium/benzophenone); Et2O (sodium/
benzophenone); CH2Cl2 (CaH2). Anhydrous MeCN and
EtOAc were obtained from Aldrich.
1
slurry. H NMR (500 MHz, CDCl3): d 1.0±1.3 (m, 11H),
1.48 (s, 3H), 1.6±2.0 (m, 11H), 2.45 (s, 3H).
3.1.2. 1,1-Dicyclohexylethyl diazoacetate. The unpuri®ed
product from the previous step was dissolved in MeOH
(100 mL). NaOMe (4.07 g, 75.3 mmol) was added batch-
wise to the stirred solution, turning the yellow-orange reac-
tion mixture to deep brown. After 12 h, TLC indicated that
there was no starting diazo ester. The reaction mixture was
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used as received. The following
reagents were distilled under reduced pressure from the
indicated drying agents: dicyclohexyl ketone (MgSO4);
diketene (CaH2). KH was purchased as a suspension in

2624
M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
diluted with water (200 mL) and saturated with NaCl.
Extraction with Et2O (4£200 mL) afforded a brown solu-
tion, which was then washed with brine, dried (MgSO4), and
concentrated to afford a yellow slurry. This crude product
was puri®ed by column chromatography (5/95 Et2O/
pentane), which afforded a bright-yellow liquid (7.76 g,
85% isolated yield based on 1,1-dicyclohexylethanol),
which slowly solidi®ed to a yellow solid upon storage at
3.1.5. 3-Chloro-1-(10-naphthyl)propan-1-one. 3-Chloro-
propionyl chloride (25.7 g, 0.240 mol) was added to a
suspension of AlCl3 (34.2 g, 0.257 mol) in CH2Cl2
(300 mL). The reaction mixture was cooled to 08C, and
then naphthalene (25.7 g, 0.201 mol) was added batchwise
over 15 min, resulting in the precipitation of a large quantity
of a white solid, which re-dissolved over 1 h. After 12 h
(total), the reaction mixture was poured onto ice, and the
resulting aqueous layer was extracted with CH2Cl2
(3£300 mL). The combined organic layers were washed
with saturated NaHCO3, dried (MgSO4), and concentrated
to afford an emerald-green liquid. The product was puri®ed
by column chromatography (5/20/75 Et2O/CH2Cl2/pen-
tane), which furnished a yellow oil (45.6 g, 100% yield).
1H NMR analysis showed a small amount of the 2-acyl
naphthalene (1-isomer/2-isomer,10:1). 1H NMR (500
MHz, CDCl3): d 3.51 (t, 2H, Jˆ6.6 Hz), 3.97 (t, 2H, Jˆ
6.6 Hz), 7.49 (dd, 1H, Jˆ7.3, 8.2 Hz), 7.53 (ddd, 1H,
Jˆ1.2, 6.9, 8.1 Hz), 7.59 (ddd, 1H, Jˆ1.4, 6.7, 8.7 Hz),
7.86 (d, 2H, Jˆ7.6 Hz), 7.99 (d, 1H, Jˆ8.2 Hz), 8.66 (d,
1H, Jˆ8.2 Hz). 13C NMR (126 MHz, CDCl3): d 39.3,
44.4, 124.5, 125.9, 126.8, 128.2, 128.4, 128.6, 130.2,
133.5, 134.1, 135.1, 200.6. IR (neat): 3050 (w), 2968
(w), 1682 (s), 1593 (m), 1573 (m), 1508 (s), 1337 (s),
1236 (s), 1099 (s), 944 (m), 801 (s), 776 (s) cm21. HRMS
(EI, m/z): Calcd for C13H11ClO: 218.0498 (M1). Found:
218.0495.
1
low temperature. H NMR (500 MHz, CDCl3): d 1.0±1.3
(m, 10H), 1.42 (s, 3H), 1.62±1.69 (m, 2H), 1.70±1.80 (m,
8H), 1.86 (tt, 2H, Jˆ2.9, 11.4 Hz), 4.60 (br, 1H). 13C NMR
(126 MHz, CDCl3): d 19.5, 26.6, 27.1, 27.7, 28.3, 45.1,
46.7, 91.8, 166.5. IR (KBr): 3136 (m), 2998 (m), 2955 (s),
2922 (s), 2850 (s), 2107 (s), 1693 (s), 1671 (s), 1450 (m),
1340 (s), 1244 (s), 1128 (m), 1050 (m), 997 (m), 737 (m)
cm21. mp 48±498C.
3.1.3. 3-Chloro-1-(40-tri¯uoromethylphenyl)propan-1-one.
A solution of P(t-Bu)3 (0.612 g, 3.02 mmol) in CH2Cl2
(30 mL) was added to a solution of Pd2(dba)3 (1.15 g,
1.26 mmol) in CH2Cl2 (20 mL).13 The reaction mixture
was cooled to 08C, and 3-chloropropionyl chloride (12.0
mL, 0.126 mol) was added, yielding an initially purple
solution that then turned brown. After 15 min, degassed
(40-tri¯uoromethylphenyl)tri-n-butylstannane (21.8 g, 50.1
mmol) was added to the reaction mixture, which was stirred
at 08C for 12 h and then at room temperature for an
additional 36 h. The reaction mixture was ®ltered through
a plug of silica (Et2O as the eluant), and the ®ltrate was
concentrated, affording a red liquid. The crude product
was puri®ed by column chromatography (2.5/97.5 Et2O/
pentane), which furnished the desired product as a yellow
liquid (7.79 g, 66% yield) that slowly solidi®ed to a white
3.1.6. (Non-1-ynyl)trimethylsilane. The title compound
was synthesized according to the procedure of Hanack and
Haûdentenfel for related alkynyltrimethylsilanes.15 The
crude product was distilled under reduced pressure (65±
688C, 0.6 Torr) to afford the product as a colorless liquid
(12.8 g, 90% yield). 1H NMR (500 MHz, CDCl3): d 0.14 (s,
9H), 0.88 (t, 3H, Jˆ6.9 Hz), 1.2±1.4 (m, 8H), 1.51 (qnt, 2H,
Jˆ7.3 Hz), 2.21 (t, 2H, Jˆ7.2 Hz). 13C NMR (126 MHz,
CDCl3): d 0.4, 14.3, 20.1, 22.8, 28.8, 29.0, 31.9, 84.4,
108.0. IR (neat): 2958 (s), 2931 (s), 2856 (s), 2176 (s),
1466 (m), 1249 (s), 1033 (m), 841 (s) cm21. HRMS (EI,
m/z): Calcd for C12H24Si: 181.1413 (M-CH31). Found:
181.1409.
1
solid upon standing at 08C. H NMR analysis showed a
small amount of an organotin impurity. 1H NMR (500
MHz, CDCl3): d 3.49 (t, 2H, Jˆ6.7 Hz), 3.94 (t, 2H, Jˆ
6.7 Hz), 7.76 (d, 2H, Jˆ8.9 Hz), 8.07 (d, 2H, Jˆ7.9 Hz).
13C NMR (126 MHz, CDCl3): d 38.4, 41.7, 123.7 (q,
3
1JC±Fˆ273 Hz), 126.0 (q, JC±Fˆ3.9 Hz), 128.6, 134.9 (q,
2JC±Fˆ32.6 Hz), 139.1, 195.9. IR (KBr): 1686 (s), 1513
(m), 1414 (m), 1326 (s), 1129 (s), 1067 (s), 853 (m), 834
(m), 714 (m), 653 (m) cm21. HRMS (EI, m/z): Calcd for
C10H8ClF3O: 236.0216 (M1). Found: 236.0211.
3.1.7. 1-Chlorododec-4-yn-3-one. A mixture of (non-1-
ynyl)trimethylsilane (12.7 g, 64.7 mmol) and 3-chloropro-
pionyl chloride (8.23 g, 64.8 mmol) was added over 10 min
to a stirred suspension of AlCl3 (9.50 g, 71.2 mmol) in
CH2Cl2 (150 mL) at 08C. The yellow suspension slowly
dissolved to form a brown solution. After the addition was
complete, the reaction mixture was allowed to warm to
room temperature and stirred for 1 h. The solution was
then poured into a mixture of ice and CH2Cl2. The aqueous
layer was extracted with CH2Cl2 (2£150 mL), and the
combined organic layers were washed with brine, dried
(MgSO4), and concentrated, to afford a brown liquid. The
crude product was puri®ed by column chromatography (30/
70!75/25 CHCl3/hexanes), which furnished the product as
a yellow oil (10.9 g, 68% yield). 1H NMR (500 MHz,
CDCl3): d 0.89 (t, 3H, Jˆ7.0 Hz), 1.2±1.5 (m, 8H), 1.59
(qnt, 2H, Jˆ7.3 Hz), 2.38 (t, 2H, Jˆ7.2 Hz), 3.01 (t, 2H,
Jˆ7.2 Hz), 3.79 (t, 2H, Jˆ6.7 Hz). 13C NMR (126 MHz,
C6D6): d 14.1, 19.1, 22.7, 27.7, 28.8, 28.9, 31.7, 38.0,
47.8, 80.4, 96.3, 184.0. IR (neat): 2929 (s), 2857 (m),
3.1.4.
3-Chloro-1-(40-methoxyphenyl)propan-1-one.
Anisole (13.5 mL, 0.124 mol) and then 3-chloropropionyl
chloride (12.5 mL, 0.131 mol) were added to a solution of
AlCl3 (20.0 g, 0.150 mol) in PhNO2 (150 mL). After 2 h,
TLC showed that no anisole remained. The reaction mixture
was quenched by pouring it into a mixture of ice and water
(300 mL). The resulting aqueous layer was extracted with
CH2Cl2 (4£300 mL), and the combined organic layers were
washed with a saturated Na2CO3 solution, dried (MgSO4),
and concentrated in vacuo (70±808C, 2 Torr) to afford a
mixture of a brown oil and a white solid. Recrystallization
of this crude product from Et2O/hexanes furnished the
desired product as pale-brown crystals (13.4 g, 55%
1
yield). H NMR (500 MHz, CDCl3): d 3.42 (t, 2H, Jˆ
6.9 Hz), 3.88 (s, 3H), 3.92 (t, 2H, Jˆ6.9 Hz), 6.95 (d, 2H,
Jˆ9.2 Hz), 7.95 (d, 2H, Jˆ8.9 Hz).14 13C NMR (126 MHz,
CDCl3): d 39.2, 41.1, 55.7, 114.1, 129.6, 130.6, 164.0,
195.4. HRMS (EI, m/z): Calcd for C10H11ClO2: 198.0448
(M1). Found: 198.0444.
2212 (m), 1678 (s), 1649 (m) cm21
.

M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
2625
3.2. Asymmetric reduction of g-chloroketones with DIP-
Cl: general procedure
purifying the 3,5-dinitrobenzoate ester derivative, and then
regenerating the alcohol (MeOH/catalytic NaHCO3). HPLC
analysis showed 97% ee. 1H NMR (500 MHz, C6D6): d 1.35
(dd, 1H, Jˆ1.2, 3.7 Hz), 1.87 (tdd, 1H, Jˆ4.7, 9.6, 14.5 Hz),
2.0 (m, 1H), 3.23 (ddd, 1H, Jˆ4.6, 5.8, 10.7 Hz), 3.63 (ddd,
1H, Jˆ4.7, 9.8, 10.5 Hz), 5.37 (td, 1H, Jˆ3.4, 9.2 Hz),
7.24±7.28 (m, 2H), 7.31 (ddd, 1H, Jˆ1.2, 6.7, 8.5 Hz),
7.50 (d, 1H, Jˆ7.0 Hz), 7.56 (d, 1H, Jˆ8.2 Hz), 7.65 (d,
1H, Jˆ8.5 Hz), 8.09 (d, 1H, Jˆ8.2 Hz). 13C NMR
(126 MHz, CDCl3): d 40.9, 42.5, 68.1, 122.9, 123.1,
125.7, 125.9, 126.5, 128.5, 129.2, 130.2, 134.0, 139.7. IR
(neat): 3382 (m, br), 3051 (w), 2962 (w), 1597 (w), 1511
(m), 1281 (m), 1070 (s), 801 (s), 778 (s) cm21. HRMS (EI,
m/z): Calcd for C13H13ClO: 220.0655 (M1). Found:
3.2.1. (R)-3-Chloro-1-(40-tri¯uoromethylphenyl)propan-
1-ol. A solution of (1)-DIP-Cl (2.67 g, 8.32 mmol) in
THF (15 mL) was added dropwise to a 2788C solution of
3-chloro-1-(40-tri¯uoromethylphenyl)propan-1-one (2.08 g,
8.81 mmol) in THF (10 mL). The reaction mixture was
warmed from 225 to 2308C and stirred for 48 h, at
which time the reaction mixture was quenched with
MeOH (2 mL), followed by saturated NH4Cl solution
(50 mL). The resulting aqueous layer was extracted with
Et2O (3£50 mL), and the combined organic layers were
added to HN(CH2CH2OH)2 (2.53 g, 24.1 mmol). A large
quantity of a white solid slowly precipitated. The solid
was removed by ®ltration, and the ®ltrate was concentrated
to a white slurry. The crude product was puri®ed by column
chromatography (4/96 Et2O/benzene), which furnished the
desired product as a colorless liquid (1.46 g, 67% yield). GC
analysis showed .98% ee. 1H NMR (500 MHz, CDCl3): d
2.08 (m, 1H), 2.12 (d, 1H, Jˆ3.7 Hz), 2.21 (tdd, 1H, Jˆ5.4,
8.9, 14.5 Hz), 3.58 (td, 1H, Jˆ5.7, 11.0 Hz), 3.78 (ddd, 1H,
Jˆ5.2, 8.5, 11.0 Hz), 5.05 (td, 1H, Jˆ4.0, 8.9 Hz), 7.50 (d,
220.0660. [a]20 ˆ1408 (cˆ0.64, CHCl3, 97% ee).
D
3.2.4. (R)-1-Chlorododec-4-yn-3-ol. Neat (R)-Alpine
Borane (11.5 mL, 42.2 mmol) was slowly added to 1-chloro-
dodec-4-yn-3-one (4.52 g, 21.1 mmol) at 2208C. The reac-
tion mixture was stirred at 215 to 2208C for 4 days and at
08C for 1 day. Then, the reaction mixture was diluted with
Et2O and quenched by the addition of acetaldehyde (2 mL).
Ethanolamine (,1.4 g) was then added to the stirring
mixture, and the resulting white precipitate was removed
by ®ltration. Concentration of the ®ltrate afforded the
crude product, which was puri®ed twice by column chroma-
tography (10/90 Et2O/pentane), resulting in an impure
yellow liquid (2.09 g, 46% yield). GC analysis showed
89% ee. In order to enhance the enantiomeric excess and
purify the product, the 3,5-dinitrobenzoate ester of the alco-
hol was synthesized. A suspension of 3,5-(O2N)2C6H3COCl
(3.34 g, 14.5 mmol) and DMAP (128 mg, 1.05 mmol) in
CH2Cl2 (20 mL) was added to a solution of the alcohol in
CH2Cl2 (50 mL). The resulting mixture was cooled to 08C,
and Et3N (2.0 mL, 14 mmol) was slowly added, resulting in
a change from a heterogeneous yellow suspension to a
brown solution. After 2 h, TLC showed no starting alcohol.
The reaction mixture was diluted with CH2Cl2 (300 mL),
washed with 1 M HCl and then a saturated NaHCO3
solution, dried (MgSO4), and concentrated, to afford a
yellow oil. Puri®cation by column chromatography
(5/95!10/90 Et2O/pentane) furnished the 3,5-dinitroben-
zoate as a pale-yellow solid (1.49 g, 37% overall yield
from the ketone). Recrystallization of this yellow solid
from Et2O/pentane afforded ®ne white needles (1.00 g),
which HPLC analysis showed was .99% ee. The ester
was then transesteri®ed back to the alcohol. The pure 3,5-
dinitrobenzoate (989 mg, 2.41 mmol) was dissolved in
15 mL MeOH/2 mL CH2Cl2. NaHCO3 (156 mg, 1.85
mmol) was added, and the reaction mixture was stirred at
room temperature. After 1 h, TLC showed no starting ester.
The reaction mixture was diluted with HCl (200 mL),
washed with 1 M HCl, dried (MgSO4), and concentrated,
to afford a white solid. This was puri®ed by column
chromatography (90/10 benzene/pentane), which furnished
the desired product as a colorless liquid (471 mg, 90%
yield). GC analysis con®rmed that the product is enantio-
2H, Jˆ8.2 Hz), 7.63 (d, 2H, Jˆ8.2 Hz). 13C NMR
1
(126 MHz, CDCl3): d 41.6, 41.6, 70.8, 124.3 (q, JC±F
ˆ
ˆ
3
2
272 Hz), 125.8 (q, JC±Fˆ3.8 Hz), 126.3, 130.3 (q, JC±F
32 Hz), 147.9. IR (neat): 3369 (m, br), 2967 (w), 2916 (w),
1621 (m), 1420 (m), 1327 (s), 1167 (s), 1127 (s), 1069 (s),
1017 (s), 840 (s) cm21. HRMS (EI, m/z): Calcd for
C10H10ClF3O: 238.0372 (M1). Found: 238.0367. [a]20
1158 (cˆ0.56, CHCl3, 98% ee).
ˆ
D
3.2.2. (R)-3-Chloro-1-(40-methoxyphenyl)propan-1-ol.
The general procedure was followed with 3-chloro-1-(40-
methoxyphenyl)propan-1-one as the substrate. The crude
product was ®rst puri®ed by column chromatography (25/
75 Et2O/pentane), followed by recrystallization (Et2O/
pentane, 2108C), which furnished a white, cotton-like
solid (618 mg, 24% yield). GC analysis of the acetate
derivative revealed .99% ee. A 1H NMR spectrum showed
that the product was still impure, but it was carried on to the
next step without further puri®cation. A pure sample of the
1
alcohol was obtained by repeating the recrystallization. H
NMR (500 MHz, CDCl3): d 1.90 (dd, 1H, Jˆ0.9, 3.4 Hz),
2.06 (m, 1H), 2.24 (tdd, 1H, Jˆ5.8, 8.2, 14.3 Hz), 3.54 (td,
1H, Jˆ6.0, 11.0 Hz), 3.72 (ddd, 1H, Jˆ5.7, 8.1, 10.8 Hz),
3.81 (s, 3H), 4.90 (ddd, 1H, Jˆ3.6, 4.7, 8.2 Hz), 6.90 (d, 2H,
Jˆ8.9 Hz), 7.29 (d, 2H, Jˆ8.5 Hz). 13C NMR (126 MHz,
CDCl3): d 41.5, 42.0, 55.5, 71.2, 114.2, 127.3, 136.0, 159.5.
IR (KBr): 3293 (m, br), 2960 (w), 2904 (w), 1612 (m), 1516
(m), 1288 (m), 1253 (s), 1179 (m), 1032 (m), 834 (m), 652
(m) cm21. HRMS (FAB, m/z): Calcd for C10H13ClO2:
200.0604 (M1). Found: 200.0608. Mp 59±608C. [a]20
1168 (cˆ1.03, CHCl3).
ˆ
D
3.2.3. (R)-3-Chloro-1-(10-naphthyl)propan-1-ol. The
general procedure was followed with 3-chloro-1-(10-
naphthyl)propan-1-one as the substrate. The crude product
was puri®ed by column chromatography (15/85 Et2O/
pentane), which furnished a yellow liquid (1.26 g, 39%
1
merically pure (.99% ee). H NMR (500 MHz, C6D6): d
0.89 (t, 3H, Jˆ7.2 Hz), 1.15±1.30 (m, 8H), 1.38 (qnt, 2H,
Jˆ7.2 Hz), 1.68 (d, 1H, Jˆ5.2 Hz), 1.86±2.00 (m, 2H), 2.02
(dt, 2H, Jˆ2.0, 7.1 Hz), 3.38 (td, 1H, Jˆ6.3, 10.8 Hz), 3.46
(ddd, 1H, Jˆ6.4, 7.3, 11.0 Hz), 4.44 (m, 1H). 13C NMR
(126 MHz, C6D6): d 14.7, 19.2, 23.4, 29.3, 29.5, 29.5,
1
yield). H NMR showed that the product was impure, but
it was carried on to the next step without further puri®cation.
An analytical sample was obtained by synthesizing and

2626
M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
32.4, 41.4, 41.4, 60.2, 81.4, 86.2. IR (neat): 3346 (m, br),
2930 (s), 2857 (s), 2228 (w), 1456 (m), 1285 (m), 1045 (m),
7.31 (d, 2H, Jˆ8.9 Hz). 13C NMR (126 MHz, C6D6): d
31.3, 54.8, 67.4, 82.4, 114.1, 127.0, 136.7, 159.8. IR
(KBr): 3059 (m), 2972 (m), 2881 (s), 1593 (m), 1508 (m),
662 (m) cm21. [a]20 ˆ23.18 (cˆ1.09, CHCl3).
D
1328 (m), 1048 (m), 977 (s), 927 (s), 800 (s), 781 (s) cm21
.
HRMS (EI, m/z): Calcd for C10H12O2: 164.0837 (M1).
3.3. Assignment of absolute con®guration of the alcohols
Found: 164.0840. Mp 48±498C. [a]20 ˆ11418 (cˆ1.04,
D
EtOH, 98% ee).
The absolute con®gurations of the 3-chloro-1-arylpropan-1-
ols obtained from (1)-DIP-Cl were assigned as (R), based
on the model proposed by Brown,16 and the 1-chlorododec-
4-yn-3-ol from (R)-Alpine Borane was assigned as (R),
based on the model proposed by Midland.17
3.4.4. (R)-2-(10-Naphthyl)oxetane. The general procedure
was followed with (R)-3-chloro-1-(10-naphthyl)propan-1-ol
as the substrate. The crude product was puri®ed by column
chromatography (1/4/95 Et3N/Et2O/pentane), which fur-
nished a white solid (695 mg, 70% yield; HPLC analysis:
97% ee). This was recrystallized from Et2O/pentane at
2358C to afford a crystalline white solid (438 mg; HPLC
3.4. Preparation of oxetanes: general procedure
3.4.1. (R)-2-Phenyloxetane. A solution of (R)-3-chloro-1-
phenylpropan-1-ol (943 mg, 5.53 mmol) in THF (8 mL)
was slowly added by syringe to a 08C suspension of KH
(290 mg, 7.24 mmol) in THF (70 mL). The reaction mixture
was then warmed to room temperature. After 15 h of
stirring, it was poured into a mixture of 200 mL Et2O/
100 mL H2O, and the aqueous layer was extracted with
Et2O (2£100 mL). The combined organic layers was
washed with brine, dried (K2CO3), and concentrated, to
afford a yellow liquid. Puri®cation by column chroma-
tography (1/4/96 Et3N/Et2O/pentane) furnished the desired
compound as a light-yellow liquid (564 mg, 76% yield). GC
analysis showed that the product is enantiomerically pure
1
analysis: .99% ee). H NMR (500 MHz, C6D6): d 2.18
(tdd, 1H, Jˆ7.3, 8.9, 10.7 Hz), 2.62 (dtd, 1H, Jˆ5.8, 8.2,
10.7 Hz), 4.32 (td, 1H, Jˆ5.8, 9.2 Hz), 4.52 (ddd, 1H,
Jˆ5.7, 7.5, 8.2 Hz), 6.22 (t, 1H, Jˆ7.6 Hz), 7.2±7.3 (m,
2H), 7.35±7.42 (m, 2H), 7.59 (d, 1H, Jˆ8.2 Hz), 7.66±
7.70 (m, 1H), 8.06 (td, 1H, Jˆ1.2, 7.0 Hz). 13C NMR
(126 MHz, C6D6): d 30.7, 68.5, 80.8, 122.2, 123.5, 126.1,
126.3, 126.4, 128.1, 129.5, 129.8, 134.5, 140.6. IR (KBr):
2999 (w), 2958 (m), 2882 (m), 1611 (m), 1514 (s), 1250 (s),
1034 (m), 957 (m), 832 (m) cm21. HRMS (FAB, m/z): Calcd
for C13H12O: 185.0966 (M1H1). Found: 185.0963. Mp 73±
748C. [a]20 ˆ12508 (cˆ1.05, EtOH).
D
(.99% ee). [a]20 ˆ11808 (cˆ1.52, EtOH).
D
3.4.5. (R)-2-(Non-10-ynyl)oxetane. The general procedure
was followed with (R)-1-chlorododec-4-yn-3-ol as the
substrate. The crude product was puri®ed by column
chromatography (1/4/95 Et3N/Et2O/pentane), which fur-
(S)-2-Phenyloxetane was prepared similarly from (S)-3-
chloro-1-phenylpropan-1-ol in 78% isolated yield. GC
analysis showed that the product is enantiomerically pure
(.99% ee).
1
nished a yellow liquid (149 mg, 38% yield). The H NMR
matched the literature data.2f 13C NMR (126 MHz, C6D6): d
14.7, 19.5, 23.3, 29.3, 29.5, 29.5, 30.5, 32.4, 68,4, 70.5,
81.9, 89.6. HRMS (EI, m/z): Calcd for C12H20O: 180.1514
3.4.2. (R)-2-(40-Tri¯uoromethylphenyl)oxetane. The
general procedure was followed with (R)-3-chloro-1-(40-
tri¯uoromethylphenyl)propan-1-ol as the substrate. The
crude product was puri®ed by column chromatography
(1/9/90 Et3N/Et2O/pentane), which furnished the desired
product as a colorless liquid (636 mg, 54% yield). GC
(M1). Found: 180.1511. [a]20 ˆ1928 (cˆ1.7, CHCl3). lit.2f
D
[a]20 ˆ133.38 (cˆ1.51, CHCl3).
D
1
3.5. Reaction in Eq. (4)
analysis showed 97% ee. H NMR (500 MHz, C6D6): d
1.97 (dddd, 1H, Jˆ7.0, 7.6, 9.1, 11.0 Hz), 2.33 (dtd, 1H,
Jˆ5.8, 8.2, 11.0 Hz), 4.19 (td, 1H, Jˆ5.8, 9.2 Hz), 4.38 (dt,
1H, Jˆ5.8, 7.9 Hz), 5.38 (t, 1H, Jˆ7.6 Hz), 7.10 (d, 2H,
Jˆ8.5 Hz), 7.37 (d, 2H, Jˆ8.2 Hz). 13C NMR (126 MHz,
A solution of (R,R)-2 (5.4 mg, 10 mmol) in CH2Cl2 (2 mL)
was added to CuOTf´0.5C6H6 (2.4 mg, 9.5 mmol) and stir-
red for 90 min. The resulting solution was ®ltered through
an acrodisc to afford an orange solution. Half of this solution
was transferred to a ¯ask containing (^)-2-phenyloxetane
(128 mg, 0.955 mmol), and CH2Cl2 was then added until the
total volume was 2.5 mL. A solution of t-butyl diazoacetate
(67.6 mg, 0.476 mmol) in CH2Cl2 (0.75 mL) was added to
the reaction mixture by a syringe pump over 45 min. After
one more hour, the reaction mixture was ®ltered through a
plug of silica gel (1% Et3N/Et2O as the eluant). GC analysis
showed that the product was a 55:45 trans/cis mixture and
that both diastereomeric products were formed in 71% ee.
The residual oxetane had an ee ,1%. The reaction was
repeated with (S,S)-2. GC analysis of the crude reaction
product revealed a 55:45 trans/cis mixture, with the trans
product formed in 71% ee and the cis product in 73% ee.
The residual starting oxetane had an ee ,1%. The 1H NMR
spectrum of the diastereomers matched the literature data.2c
1
C6D6): d 30.9, 68.2, 81.8, 125.4 (q, JC±Fˆ272 Hz), 125.7,
125.9 (q, 3JC±Fˆ3.9 Hz), 130.0 (q, 2JC±Fˆ32 Hz), 148.8. IR
(neat): 2965 (w), 2887 (w), 1619 (w), 1325 (s), 1165 (s),
1124 (s), 1067 (s), 983 (s), 838 (m) cm21. HRMS (EI, m/z):
Calcd for C10H9F3O: 202.0606 (M1). Found: 202.0609.
[a]20 ˆ11138 (cˆ2.64, EtOH, 97% ee).
D
3.4.3. (R)-2-(40-Methoxyphenyl)oxetane. The general
procedure was followed with (R)-3-chloro-1-(40-methoxy-
phenyl)propan-1-ol as the substrate. The crude product was
puri®ed by two column chromatographies (1/10/89 Et3N/
Et2O/pentane), which furnished the desired product as a
pale-yellow liquid that solidi®ed on standing to a white
solid (265 mg, 26% yield). HPLC analysis showed 98%
1
ee. H NMR (500 MHz, C6D6): d 2.28 (tdd, 1H, Jˆ7.6,
9.3, 10.8 Hz), 2.43 (dtd, 1H, Jˆ5.4, 8.0, 10.7 Hz), 3.30 (s,
3H), 4.32 (td, 1H, Jˆ5.7, 9.2 Hz), 4.47 (dt, 1H, Jˆ5.7,
8.0 Hz), 5.59 (t, 1H, Jˆ7.5 Hz), 6.83 (d, 2H, Jˆ8.5 Hz),
t-Butyl (2S,3R)-3-phenyltetrahydrofuran-2-carboxylate.

M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
2627
13C NMR (126 MHz, CDCl3): d 28.2, 35.1, 50.1, 69.6, 81.6,
84.0, 127.0, 127.5, 128.8, 142.1, 172.1.
3.6.3. Table 1, entry 3. Run 1: 91:9 trans/cis; trans
eeˆ97% ee (major enantiomer: 2S,3R). Run 2 (with (S,S)-
2, (S)-oxetane, (d)-menthyl diazoacetate): 90:10 trans/cis;
trans eeˆ97% ee (major enantiomer: 2R,3S).
t-Butyl (2S,3S)-3-phenyltetrahydrofuran-2-carboxylate.
13C NMR (126 MHz, C6D6): d 27.7, 31.8, 48.1, 68.9,
81.2, 81.8, 127.1, 128.4, 128.6, 139.5, 170.2.
(d)-Menthyl (2R,3S)-3-phenyltetrahydrofuran-2-carb-
1
oxylate. H NMR (500 MHz, C6D6): d 0.59 (dq, 1H, Jˆ
3.8, 12.7 Hz), 0.75 (d, 3H, Jˆ6.4 Hz), 0.79 (d, 3H, Jˆ
4.9 Hz), 0.80 (d, 3H, Jˆ4.6 Hz), 0.7±0.85 (m, 1H), 0.89
(q, 1H, Jˆ11.7 Hz), 1.1±1.2 (m, 1H), 1.26 (tdd, 1H, Jˆ
3.1, 11.0, 12.4 Hz), 1.36±1.44 (m, 2H), 1.71 (qd, 1H, Jˆ
7.8, 12.4 Hz), 1.93±2.08 (m, 3H), 3.56 (dt, 1H, Jˆ5.8,
7.6 Hz), 3.94 (dt, 1H, Jˆ4.3, 8.1 Hz), 4.08 (dt, 1H, Jˆ7.0,
8.2 Hz), 4.60 (d, 1H, Jˆ5.8 Hz), 4.93 (dt, 1H, Jˆ4.4,
10.9 Hz), 7.08 (tt, 1H, Jˆ1.8, 6.9 Hz), 7.09±7.15 (m, 4H).
13C NMR (126 MHz, C6D6): d 16.8, 21.2, 22.5, 23.9, 26.8,
31.8, 34.7, 35.5, 41.5, 47.5, 50.5, 69.8, 74.8, 84.5, 127.4,
127.9, 129.3, 143.0, 172.5. IR (neat): 3063 (w), 3029 (w),
2954 (s), 2870 (s), 1743 (s), 1604 (w), 1494 (m), 1455 (s),
1370 (m), 1264 (s), 1194 (s), 1100 (s), 986 (m), 758 (m), 700
(m) cm21. HRMS (FAB, m/z): Calcd for C21H30O3:
3.6. General procedureÐTable 1
A solution of (R,R)-2 (4.4 mg, 8.4 mmol) in EtOAc (2 mL)
was added to CuOTf´0.5C6H6 (1.8 mg, 7.2 mmol) and
stirred for 30 min. The catalyst solution was then ®ltered
through an acrodisc to afford an orange solution. Half of this
solution was transferred to a ¯ask containing (R)-2-phenyl-
oxetane (48.7 mg, 0.363 mmol), and EtOAc was added until
the total volume was 2.5 mL. The solution was stirred for
5 min in a water bath maintained at 208C, and then a solu-
tion of the diazo ester (0.48 mmol) in EtOAc (1 mL) was
added over 5 min to the reaction mixture. After 30 min, the
reaction mixture was ®ltered through a plug of silica gel
(Et2O as the eluant) to afford the crude product.
330.2195 (M1). Found: 330.2202. [a]20 ˆ2388 (cˆ1.10,
D
EtOH, .99.5% de).
3.6.1. Table 1, entry 1. Run 1: 81:19 trans/cis; trans
eeˆ91% ee (major enantiomer: 2S,3R). Run 2 (with (S,S)-
2, (S)-oxetane): 82:18 trans/cis; trans eeˆ92% ee (major
enantiomer: 2R,3S).
3.6.4. Table 1, entry 4. Run 1: 90:10 trans/cis; trans
eeˆ97% ee (major enantiomer: 2S,3R). Run 2 (with (S,S)-
2, (S)-oxetane): 90:10 trans/cis; trans eeˆ97% ee (major
enantiomer: 2R,3S).
Ethyl (2R,3S)-3-phenyltetrahydrofuran-2-carboxylate.
1H NMR (500 MHz, C6D6): d 0.85 (t, 3H, Jˆ7.2 Hz),
1.68 (qd, 1H, Jˆ7.8, 12.4 Hz), 1.99 (dtd, 1H, Jˆ4.6, 7.5,
12.2 Hz), 3.45 (dt, 1H, Jˆ6.0, 7.7 Hz), 3.90 (m, 3H), 4.02
(dt, 1H, Jˆ6.7, 8.2 Hz), 4.52 (d, 1H, Jˆ5.8 Hz), 7.00±7.06
(m, 1H), 7.08 (m, 4H). 13C NMR (126 MHz, CDCl3): d
14.4, 35.1, 49.8, 61.2, 69.7, 83.6, 127.1, 127.4, 128.9,
141.9, 172.9. IR (neat): 3030 (w), 2979 (m), 2878 (m),
1747 (s), 1603 (w), 1493 (w), 1455 (w), 1266 (m), 1192
(s), 1098 (s), 759 (m), 700 (s) cm21. HRMS (FAB, m/z):
Calcd for C13H16O3: 220.1099 (M1). Found: 220.1105.
3.6.5. Table 1, entry 5. Run 1: 95:5 trans/cis; trans
eeˆ98% ee (major enantiomer: 2S,3R). Run 2 (with (S,S)-
2, (S)-oxetane): 95:5 trans/cis; trans eeˆ98% (major enan-
tiomer: 2R,3S).
10,10-Dicyclohexylethyl (2R,3S)-3-phenyltetrahydrofuran-
2-carboxylate. H NMR (500 MHz, C6D6): d 0.9±1.2 (m,
1
10H), 1.43 (s, 3H), 1.5±1.8 (m, 11H), 1.85 (t qnt, 2H, Jˆ2.8,
11.6 Hz), 2.03 (dddd, 1H, Jˆ4.3, 6.7, 7.6, 11.9 Hz), 3.54 (dt,
1H, Jˆ6.4, 7.9 Hz), 3.93 (dt, 1H, Jˆ4.0, 8.1 Hz), 4.04 (dt,
1H, Jˆ6.7, 8.5 Hz), 4.51 (d, 1H, Jˆ6.4 Hz), 7.02±7.06 (m,
1H), 7.10± 7.16 (m, 4H). 13C NMR (125 MHz, C6D6): d
19.8, 27.2, 27.5, 27.6, 28.2, 28.2, 28.6, 28.7, 36.0, 45.5,
50.6, 69.8, 85.2, 91.1, 127.3, 128.0, 129.2, 142.9, 172.2.
IR (neat): 2929 (s), 2852 (s), 1742 (s), 1449 (s), 1190 (s),
1100 (s), 755 (m), 700 (s) cm21. HRMS (FAB, m/z):
Calcd for C25H36O3: 385.2743 (M1H1). Found: 385.2732.
[a]20 ˆ2998 (cˆ0.99, EtOH, 92% ee).
D
3.6.2. Table 1, entry 2. Run 1: 90:10 trans/cis; trans
eeˆ95% ee (major enantiomer: 2S,3R). Run 2 (with (S,S)-
2, (S)-oxetane, (l)-menthyl diazoacetate): 90:10 trans/cis;
trans eeˆ95% ee (major enantiomer: 2R,3S).
(l)-Menthyl (2R,3S)-3-phenyltetrahydrofuran-2-carboxyl-
[a]20 ˆ2638 (cˆ1.00, EtOH, 98% ee).
1
ate. H NMR (500 MHz, C6D6): d 0.58 (dq, 1H, Jˆ3.9,
D
12.7 Hz), 0.72 (d, 3H, Jˆ6.4 Hz), 0.76 (d, 3H, Jˆ4.9 Hz),
0.78 (d, 3H, Jˆ4.9 Hz), 0.75±0.82 (m, 1H), 0.86 (q, 1H,
Jˆ11.6 Hz), 1.08±1.18 (m, 1H), 1.21 (tdd, 1H, Jˆ3.1, 11.0,
12.3 Hz), 1.36±1.44 (m, 2H), 1.71 (ddd, 1H, Jˆ8.5, 12.2,
16.5 Hz), 1.77 (dtd, 1H, Jˆ2.8, 7.2, 14.4 Hz), 1.98±2.05 (m,
2H), 3.53 (dt, 1H, Jˆ6.6, 8.0 Hz), 3.94 (dt, 1H, Jˆ3.8,
8.0 Hz), 4.06 (dt, Jˆ6.6 Hz, 1H, 8.5), 4.58 (d, 1H, Jˆ
6.4 Hz), 4.85 (dt, 1H, Jˆ4.3, 10.8 Hz), 7.0±7.06 (m, 1H),
7.10±7.14 (m, 4H). 13C NMR (126 MHz, C6D6): d 16.6,
21.2, 22.4, 23.8, 26.5, 31.8, 34.7, 36.1, 41.4, 47.4, 51.0,
70.0, 74.9, 84.6, 127.4, 127.9, 129.3, 142.4, 172.8. IR
(neat): 3063 (w), 3029 (w), 2954 (s), 2870 (s), 1742 (s),
1604 (w), 1494 (m), 1455 (s), 1371 (m), 1265 (m), 1193
(s), 1099 (s), 986 (m), 758 (m), 700 (s) cm21. HRMS (FAB,
m/z): Calcd for C21H30O3: 330.2195 (M1). Found: 330.2205.
3.7. General procedureÐTables 2 and 3
A solution of (R,R)-2 (4.7 mg, 8.9 mmol) in EtOAc (1 mL)
was added to CuOTf´0.5C6H6 (1.9 mg, 7.5 mmol) and
stirred for 1 h. The catalyst solution was then ®ltered
through an acrodisc to afford an orange solution. Half of
this solution was added to a ¯ask containing the oxetane
(0.39 mmol), and EtOAc was added until the total volume
was 0.8 mL. The solution was stirred for 5 min in a water
bath maintained at 208C, and then a solution of the diazo-
acetate (170 mg, 0.62 mmol) in EtOAc (1 mL) was added to
the reaction mixture in four batches over 3 h. After one
additional hour, the reaction mixture was ®ltered through
a plug of silica gel (Et2O as the eluant).
[a]20 ˆ21358 (cˆ1.29, EtOH, 96% de).
D

2628
M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
3.7.1. Table 2, entry 1. Run 1 was carried out using (R)-
oxetane (77.1 mg, 0.575 mmol) and the diazoacetate
(208 mg, 0.746 mmol). 1,3-Diisopropylbenzene (111 mg,
0.685 mmol) was added to the crude product as an internal
NMR standard, and the NMR yield thus determined for the
trans tetrahydrofuran was 77% (C6D6). NMR analysis
showed that the product was a 95:5 trans/cis mixture. The
crude product was puri®ed by column chromatography
(5/95 Et2O/pentane), which afforded a mixture of trans
(98% ee, major enantiomer: 2S,3R) and cis (20% ee,
major enantiomer: 2R,3R) tetrahydrofurans (145 mg, 66%
yield) as colorless liquids. Run 2 was carried out similarly
with (S)-oxetane and (S,S)-2. NMR analysis showed that the
product was a 95:5 trans/cis mixture. Column chroma-
tography afforded a mixture of trans (98% ee, major
enantiomer: 2R,3S) and cis (22% ee, major enantiomer:
2S,3S) tetrahydrofurans (146 mg, 83% yield).
0.317 mmol) was added to the crude product as an internal
NMR standard, and the NMR yield thus determined for the
trans tetrahydrofuran was 32% (C6D6). NMR analysis
showed that the product was a 75:25 trans/cis mixture.
The crude product was puri®ed ®rst by column chroma-
tography (10/90 Et2O/pentane) and then by preparative
achiral HPLC (10/90 EtOAc/hexanes), which afforded the
trans tetrahydrofuran (25.9 mg, 26% yield, 68% ee, major
enantiomer: 2S,3R) and the cis tetrahydrofuran (53% ee,
major enantiomer: 2R,3R) as colorless liquids. Run 2 was
carried out similarly. NMR analysis revealed that the crude
product was a 76:24 trans/cis mixture and that the yield
of the trans tetrahydrofuran was 36%. Column chroma-
tography, followed by preparative achiral HPLC, afforded
the trans tetrahydrofuran (32.0 mg, 32% yield, 70% ee,
major enantiomer: 2S,3R) and the cis tetrahydrofuran
(52% ee, major enantiomer: 2R,3R).
3.7.2. Table 2, entry 2. Run 1 was carried out using (R)-
oxetane (78.1 mg, 0.386 mmol) and the diazoacetate
(172 mg, 0.617 mmol). 1,3-Diisopropylbenzene (69.4 mg,
0.428 mmol) was added to the crude product as an internal
NMR standard, and the NMR yield thus determined for the
trans tetrahydrofuran was 91% (C6D6). NMR analysis
showed that the product was a 94:6 trans/cis mixture. The
crude product was puri®ed ®rst by column chromatography
(10/90 EtOAc/hexanes), and then by preparative achiral
HPLC (15/85 EtOAc/hexanes), which afforded the trans
tetrahydrofuran (139 mg, 79% yield, 99% ee, major enan-
tiomer: 2S,3R) and the cis tetrahydrofuran (1% ee, major
enantiomer: 2S,3S) as colorless liquids. Run 2 was carried
out similarly. NMR analysis revealed that the crude product
was a 94:6 trans/cis mixture and that the yield of the trans
tetrahydrofuran was 89%. Column chromatography,
followed by preparative achiral HPLC, afforded the trans
tetrahydrofuran (171 mg, 82% yield, 98% ee, major enan-
tiomer: 2S,3R) and the cis tetrahydrofuran (6% ee, major
enantiomer: 2R,3R).
10,10-Dicyclohexylethyl (2S,3R)-3-(400-methoxyphenyl)te-
trahydrofuran-2-carboxylate. 1H NMR (500 MHz, C6D6):
d 0.95±1.2 (m, 10H), 1.45 (s, 3H), 1.55±1.61 (m, 2H),
1.63±1.94 (m, 11H), 2.04 (dddd, 1H, Jˆ4.0, 7.0, 7.6,
11.9 Hz), 3.31 (s, 3H), 3.54 (dt, 1H, Jˆ6.7, 8.1 Hz), 3.96
(dt, 1H, Jˆ3.8, 8.0 Hz), 4.06 (dt, 1H, Jˆ6.7, 8.5 Hz), 4.50
(d, 1H, Jˆ6.4 Hz), 6.76 (d, 2H, Jˆ8.8 Hz), 7.08 (d, 2H,
Jˆ8.5 Hz). 13C NMR (126 MHz, C6D6): d 19.8, 27.2,
27.2, 27.6, 27.6, 28.2, 28.3, 28.7, 28.7, 36.2, 45.5, 50.0,
55.1, 69.8, 85.4, 91.0, 114.7, 129.0, 134.6, 159.4, 172.3.
IR (neat): 2929 (s), 2852 (s), 1741 (s), 1613 (m), 1514 (s),
1448 (m), 1249 (s), 1180 (s), 1098 (s), 1036 (m), 827 (m)
cm21. HRMS (FAB, m/z): Calcd for C26H38O4: 453.2407
(M1K1). Found: 453.2417. [a]20 ˆ1438 (cˆ0.86, EtOH,
D
70% ee).
3.7.4. Table 2, entry 4. Run 1 was carried out using (R)-
oxetane (69.5 mg, 0.377 mmol) and the diazoacetate
(170 mg, 0.610 mmol). Anisole (81.1 mg, 0.750 mmol)
was added to the crude product as an internal NMR
standard, and the NMR yield thus determined for the trans
tetrahydrofuran was 74% (C6D6). NMR analysis showed
that the product was an 86:14 trans/cis mixture. The crude
product was puri®ed ®rst by column chromatography (10/90
Et2O/pentane) and then by preparative achiral HPLC (1/99
i-PrOH/hexanes), which afforded the trans tetrahydrofuran
(126 mg, 77% yield, 91% ee, major enantiomer: 2S,3R) and
the cis tetrahydrofuran (7% ee, major enantiomer: 2S,3S) as
colorless liquids. Run 2 was carried out similarly. NMR
analysis revealed that the crude product was an 86:14
trans/cis mixture and that the yield of the trans tetrahydro-
furan was 72% (C6D6). Column chromatography, followed
by preparative achiral HPLC, afforded the trans tetrahydro-
furan (146 mg, 73% yield, 91% ee, major enantiomer:
2S,3R) and the cis tetrahydrofuran (14% ee, major enan-
tiomer: 2S,3S).
10,10-Dicyclohexylethyl (2S,3R)-3-(400-tri¯uoromethyl-
phenyl)tetrahydrofuran-2-carboxylate. 1H NMR (500
MHz, C6D6): d 0.9±1.2 (m, 10H), 1.41 (s, 3H), 1.50±1.75
(m, 13H), 1.94 (dtd, 1H, Jˆ4.4, 7.5, 12.0 Hz), 3.40 (dt, 1H,
Jˆ6.4, 7.9 Hz), 3.86 (dt, 1H, Jˆ4.0, 8.1 Hz), 3.99 (dt, 1H,
Jˆ6.9, 8.3 Hz), 4.35 (d, 1H, Jˆ6.1 Hz), 6.93 (d, 2H, Jˆ
7.9 Hz), 7.31 (d, 2H, Jˆ7.9 Hz). 13C NMR (126 MHz,
CDCl3): d 19.3, 26.6, 26.7, 27.0, 27.0, 27.0, 27.6, 27.6,
28.1, 28.2, 35.8, 44.9, 44.9, 49.9, 69.5, 83.9, 92.3, 124.3
1
3
(q, JC±Fˆ272 Hz), 125.8 (q, JC±Fˆ3.8 Hz), 127.9, 129.4
2
(q, JC±Fˆ32.3 Hz), 146.3, 171.7. IR (neat): 2933 (s),
2854 (s), 1745 (s), 1620 (m), 1449 (s), 1327 (s), 1165 (s),
1124 (s), 1069 (s), 1017 (m), 834 (m) cm21. HRMS (FAB,
m/z): Calcd for C26H35F3O3: 452.2538 (M1). Found:
452.2546. [a]20 ˆ1528 (cˆ1.05, EtOH, 99% ee).
D
3.7.3. Table 2, entry 3. The general procedure was used to
prepare the catalyst solution. In a 4 mL vial, the (R)-oxetane
(39.0 mg, 0.238 mmol) and the diazoacetate (99.4 mg,
0.357 mmol) were dissolved in EtOAc (0.5 mL) and stirred
for 5 min in a water bath maintained at 208C. The catalyst
solution was added to the stirring reaction mixture, and after
1 h the reaction mixture was ®ltered through a plug of silica
with Et2O as the eluant. 1,3-Diisopropylbenzene (51.4 mg,
10,10-Dicyclohexylethyl (2S,3R)-3-(100-naphthyl)tetrahydro-
furan-2-carboxylate. H NMR (500 MHz, C6D6): d 0.8±
1
1.2 (m, 10H), 1.44 (s, 3H), 1.5±1.9 (m, 13H), 2.27 (tdd, 1H,
Jˆ6.6, 7.9, 13.1 Hz), 4.02 (dt, 1H, Jˆ5.8, 7.9 Hz), 4.24 (dt,
1H, Jˆ6.6, 8.0 Hz), 4.41 (td, 1H, Jˆ5.0, 8.2 Hz), 4.79 (d,
1H, Jˆ4.3 Hz), 7.23 (t, 1H, Jˆ7.6 Hz), 7.28 (ddd, 1H, Jˆ
1.2, 6.9, 8.1 Hz), 7.32 (d, 1H, Jˆ6.4 Hz), 7.37 (ddd, 1H,
Jˆ1.4, 6.9, 8.5 Hz), 7.55 (d, 1H, Jˆ8.2 Hz), 7.66 (d, 1H,

M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
2629
Jˆ7.9 Hz), 8.21 (d, 1H, Jˆ8.5 Hz). 13C NMR (126 MHz,
C6D6): d 19.4, 26.8, 26.8, 27.1, 27.2, 27.2, 27.8, 27.9, 28.3,
28.4, 34.0, 45.1, 45.1, 45.3, 69.3, 84.0, 90.9, 123.7, 123.8,
125.8, 125.8, 126.3, 127.7, 129.4, 132.3, 134.6, 138.7,
172.1. IR (neat): 3048 (m), 2926 (s), 2852 (s), 1738 (s),
1598 (m), 1512 (m), 1383 (s), 1279 (s), 1193 (s), 1106 (s),
1086 (s), 933 (m), 778 (s) cm21. HRMS (FAB, m/z): Calcd
(m, 2H), 1.5±1.7 (m, 9H), 1.73±1.9 (m, 2H), 2.29 (qd, 1H,
Jˆ8.7, 11.9 Hz), 3.27 (q, 1H, Jˆ8.1 Hz), 3.74 (q, 1H,
Jˆ7.8 Hz), 4.26 (dt, 1H, J ˆ3.7, 8.4), 4.58 (d, 1H, Jˆ
7.6 Hz), 7.05 (m, 1H), 7.14 (t, 2H, Jˆ7.6 Hz), 7.20 (d,
2H, Jˆ8.2 Hz). 13C NMR (126 MHz, C6D6): d 19.5, 27.2,
27.2, 27.6, 27.6, 27.7, 27.8, 28.2, 28.2, 28.6, 31.6, 45.3, 45.4,
48.6, 68.8, 83.0, 91.0, 127.4, 128.8, 129.2, 139.5, 170.6. IR
(neat): 2930 (s), 2852 (s), 1732 (s), 1449 (s), 1381 (m), 1243
(s), 1193 (s), 1101 (s), 1083 (s), 698 (s) cm21. HRMS (FAB,
m/z): Calcd for C25H36O3: 385.2743 (M1H1). Found:
for C29H38O3: 434.2828 (M1). Found: 434.2828. [a]20
132.88 (cˆ1.02, EtOH, 91% ee).
ˆ
D
3.7.5. Table 2, entry 5. Run 1 was carried out using (R)-
oxetane (46.3 mg, 0.257 mmol) and the diazoacetate
(108 mg, 0.386 mmol). 1,3-Diisopropylbenzene (23.2 mg,
0.143 mmol) was added to the crude product as an internal
NMR standard, and the NMR yield thus determined for the
trans tetrahydrofuran was 68% (C6D6). NMR analysis
showed that the product was an 87:13 trans/cis mixture.
The crude product was puri®ed by column chromatography
(4/96 Et2O/pentane), which afforded the trans tetrahydro-
furan (65.2 mg, 59% yield, 96% ee, major enantiomer:
2S,3R) and the cis tetrahydrofuran (17% ee, major enan-
tiomer: 2R,3R) as colorless liquids. Run 2 was carried out
similarly. NMR analysis revealed that the crude product was
a 90:10 trans/cis mixture and that the yield of the trans
tetrahydrofuran was 76% (C6D6). Column chromatography
afforded the trans tetrahydrofuran (135 mg, 69% yield, 97%
ee, major enantiomer: 2S,3R) and the cis tetrahydrofuran
(8% ee, major enantiomer: 2R,3R).
385.2735. [a]20 ˆ2448 (cˆ0.65, EtOH, 95% ee).
D
3.7.7. Table 3, entry 2. The reaction was carried out using
(R)-oxetane (32.5 mg, 0.161 mmol) and the diazoacetate
(70.8 mg, 0.254 mmol). 1,3-Diisopropylbenzene (32.9 mg,
0.203 mmol) was added to the crude product as an internal
NMR standard, and the NMR yield thus determined for the
cis tetrahydrofuran was 62% (C6D6). NMR analysis showed
that the product was an 86:14 cis/trans mixture. The crude
product was puri®ed ®rst by column chromatography (10/90
EtOAc/hexanes) and then by preparative achiral HPLC (15/
85 EtOAc/hexanes), which afforded the trans tetrahydro-
furan (17% ee, major enantiomer: 2R,3S) and the cis tetra-
hydrofuran (37.8 mg, 52% yield, 95% ee, major enantiomer:
2R,3R) as colorless liquids.
10,10-Dicyclohexylethyl (2R,3R)-3-(400-tri¯uoromethyl-
phenyl)tetrahydrofuran-2-carboxylate. 1H NMR (500
MHz, C6D6): d 0.63 (dq, 1H, Jˆ3.3, 12.3 Hz), 0.8±0.9
(m, 2H), 0.95±1.1 (m, 7H), 1.18 (s, 3H), 1.3±1.4 (m, 2H),
1.5±1.8 (m, 11H), 2.07 (qd, 1H, Jˆ8.4, 12.0 Hz), 3.10 (q,
1H, Jˆ7.9 Hz), 3.68 (q, 1H, Jˆ7.9 Hz), 4.17 (dt, 1H, Jˆ4.0,
8.4 Hz), 4.45 (d, 1H, Jˆ7.6 Hz), 7.05 (d, 2H, Jˆ7.9 Hz),
7.36 (d, 2H, Jˆ8.2 Hz). 13C NMR (126 MHz, C6D6): d 19.0,
10,10-Dicyclohexylethyl (2S,3R)-3-(non-100-ynyl)tetrahydro-
furan-2-carboxylate. 1H NMR (500 MHz, C6D6): d 0.89 (t,
3H, Jˆ7.0 Hz), 1.0±1.4 (m, 18H), 1.41 (m, 2H), 1.47 (s,
3H), 1.60 (m, 2H), 1.65±2.0 (m, 12H), 2.07 (dt, 2H, Jˆ2.3,
7.1 Hz), 3.30 (ttd, 1H, Jˆ2.0, 5.6, 9.7 Hz), 3.84 (m, 2H),
4.58 (d, 1H, Jˆ6.1 Hz). 13C NMR (126 MHz, C6D6): d 14.7,
19.5, 19.8, 23.4, 27.3, 27.3, 27.6, 27.6, 27.7, 28.3, 28.3,
28.8, 28.8, 29.5, 29.6, 29.6, 32.5, 34.7, 36.1, 45.5, 45.5,
69.3, 80.6, 83.0, 84.5, 91.4, 171.4. IR (neat): 2927 (s),
2853 (s), 1745 (s), 1449 (s), 1380 (m), 1283 (m), 1251
26.8, 26.8, 27.1, 27.1, 27.2, 27.2, 27.4, 27.8, 27.9, 28.2,
1
31.3, 44.9, 45.0, 47.8, 68.3, 82.3, 91.3, 125.0 (q, JC±F
ˆ
3
2
272 Hz), 125.4 (q, JC±Fˆ3.8 Hz), 129.2, 129.3 (q, JC±F
ˆ
32.2 Hz), 143.6, 169.7. IR (neat): 2932 (s), 2854 (s), 1733
(s), 1619 (m), 1449 (m), 1327 (s), 1165 (s), 1125 (s), 1070
(s), 849 (m) cm21. HRMS (FAB, m/z): Calcd for
(m), 1191 (s), 1098 (s) cm21. [a]20 ˆ1728 (cˆ1.11,
D
EtOH, 97% ee).
C26H35F3O3: 452.2538 (M1). Found: 452.2528. [a]20
2328 (cˆ0.62, EtOH, 95% ee).
ˆ
D
3.7.6. Table 3, entry 1. Run 1 was carried out using (R)-
oxetane (61.5 mg, 0.458 mmol) and the diazoacetate
(166 mg, 0.597 mmol). NMR analysis showed that the
product was an 84:16 cis/trans mixture. The crude product
was puri®ed by column chromatography (5/95 Et2O/pen-
tane), which afforded a mixture of trans (24% ee, major
enantiomer: 2R,3S) and cis (95% ee, major enantiomer:
2R,3R) tetrahydrofurans (120 mg, 68% yield) as colorless
liquids. Run 2 was carried out similarly with (S)-oxetane
and (R,R)-2. 1,3-Diisopropylbenzene (135 mg, 0.832
mmol) was added to the crude product as an internal
NMR standard, and the NMR yield thus determined for
the cis tetrahydrofuran was 74% (C6D6). NMR analysis
showed that the product was an 84:16 cis/trans mixture.
Column chromatography afforded a mixture of trans (23%
ee, major enantiomer: 2S,3R) and cis (95% ee, major enan-
tiomer: 2S,3S) tetrahydrofurans (181 mg, 81% yield).
3.7.8. Table 3, entry 3. The same procedure as for Table 2,
entry was followed, using (R)-oxetane (19.7 mg,
3
0.120 mmol) and the diazoacetate (50.3 mg, 0.181 mmol).
1,3-Diisopropylbenzene (18.3 mg, 0.113 mmol) was added
to the crude product as an internal NMR standard, and the
NMR yield thus determined for the cis tetrahydrofuran was
29% (C6D6). NMR analysis showed that the product was a
58:42 cis/trans mixture. The crude product was puri®ed ®rst
by column chromatography (10/90 Et2O/pentane) and
then by preparative achiral HPLC (10/90 EtOAc/hexanes),
which afforded the trans tetrahydrofuran (36% ee, major
enantiomer: 2S,3R) and the cis tetrahydrofuran (9.8 mg,
20% yield, 82% ee, major enantiomer: 2R,3R) as colorless
liquids.
10,10-Dicyclohexylethyl (2R,3R)-3-(400-methoxyphenyl)-
tetrahydrofuran-2-carboxylate. 1H NMR (500 MHz,
C6D6): d 0.73 (dq, 1H, Jˆ3.5, 12.5 Hz), 0.9±1.2 (m, 9H),
1.29 (s, 3H), 1.4±1.5 (m, 2H), 1.5±1.7 (m, 9H), 1.75±1.85
(m, 2H), 2.31 (qd, 1H, Jˆ8.7, 11.8 Hz), 3.28 (q, 1H, Jˆ
10,10-Dicyclohexylethyl (2R,3R)-3-phenyltetrahydrofuran-
2-carboxylate. 1H NMR (500 MHz, C6D6): d 0.71 (dq, 1H,
Jˆ3.4, 12.4 Hz), 0.86±1.16 (m, 9H), 1.24 (s, 3H), 1.4±1.5

2630
M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
Table 4. GC data (DB-1701)
Compound
Temperature (8C)
Carrier gas ¯ow (mL/min)
He, 1.0
trans tR (min)
cis tR (min)
130
180
130
33.2
31.2
He, 1.0
He, 1.0
47.7, 48.0
40.3
44.2, 44.8
39.3
9.2 Hz), 3.34 (s, 3H), 3.77 (q, 1H, Jˆ7.8 Hz), 4.29 (dt, 1H,
Jˆ3.7, 8.4 Hz), 4.59 (d, 1H, Jˆ7.6 Hz), 6.78 (d, 2H,
Jˆ8.5 Hz), 7.14 (d, 2H, Jˆ8.6 Hz). 13C NMR (126 MHz,
C6D6): d 19.5, 27.2, 27.2, 27.6, 27.6, 27.7, 27.8, 28.2, 28.2,
28.6, 31.8, 45.3, 45.5, 47.9, 55.1, 68.9, 83.1, 91.0, 114.3,
130.2, 131.4, 159.5, 170.8. IR (thin ®lm): 2929 (s), 2851 (s),
1733 (s), 1613 (w), 1514 (s), 1448 (m), 1248 (s), 1181 (m),
product was puri®ed ®rst by column chromatography (10/90
Et2O/pentane) and then by preparative achiral HPLC (1/99
i-PrOH/hexanes), which afforded the trans tetrahydrofuran
(18% ee, major enantiomer: 2R,3S) and the cis tetrahydro-
furan (49.9 mg, 72% yield, 95% ee, major enantiomer:
2R,3R) as colorless liquids.
1096 (m), 1073 (m), 1036 (m), 840 (w), 806 (w) cm21
.
HRMS (ESI, m/z): Calcd for C26H38O4: 437.2662
10,10-Dicyclohexylethyl
(2R,3R)-3-(100-naphthyl)tetra-
1
hydrofuran-2-carboxylate. H NMR (500 MHz, C6D6): d
0.11 (dq, 1H, Jˆ3.5, 12.5 Hz), 0.47 (dq, 1H, Jˆ3.2, 12.4 Hz),
0.7±1.1 (m, 10H), 1.02 (s, 3H), 1.1±1.2 (m, 1H), 1.35±1.6
(m, 8H), 1.69 (tt, 1H, Jˆ2.7, 11.9 Hz), 1.75±1.8 (m, 1H),
2.73 (tt, 1H, Jˆ9.0, 11.0 Hz), 3.86 (td, 1H, Jˆ7.6, 8.4 Hz),
4.00 (td, 1H, Jˆ7.3, 10.7 Hz), 4.41 (dt, 1H, Jˆ2.6, 8.2 Hz),
4.96 (d, 1H, Jˆ7.6 Hz), 7.22±7.34 (m, 3H), 7.52 (d, 1H,
Jˆ7.3 Hz), 7.54 (d, 1H, Jˆ8.2 Hz), 7.63 (d, 1H,
Jˆ7.9 Hz), 7.84 (d, 1H, Jˆ8.5 Hz). 13C NMR (126 MHz,
C6D6): d 19.5, 26.9, 27.1, 27.4, 27.4, 27.6, 27.7, 27.7, 28.1,
28.5, 30.2, 44.8, 45.1, 45.5, 68.6, 81.4, 90.5, 124.3, 125.0,
126.0, 126.1, 126.6, 128.3, 129.4, 133.7, 134.5, 134.7, 171.1.
IR (neat): 3045 (w), 2928 (s), 2852 (s), 1732 (s), 1447 (m),
1212 (m), 1192 (m), 1077 (m), 778 (m) cm21. HRMS (FAB,
m/z): Calcd for C29H38O3: 473.2458 (M1K1). Found:
(M1Na1). Found: 437.2649. [a]20 ˆ2338 (cˆ0.91,
D
EtOH, 82% ee).
3.7.9. Table 3, entry 4. The reaction was carried out using
(R)-oxetane (29.5 mg, 0.160 mmol) and the diazoacetate
(71.4 mg, 0.256 mmol). Anisole (28.1 mg, 0.260 mmol)
was added to the crude product as an internal NMR
standard, and the NMR yield thus determined for the cis
tetrahydrofuran was 70% (C6D6). NMR analysis showed
that the product was an 85:15 cis/trans mixture. The crude
Table 5. NMR data
Compound
Solvent
C6D6
d (trans)
d (cis)
473.2450. [a]20 ˆ21408 (cˆ0.60, EtOH, 95% ee).
D
4.51 (d)
4.58 (d)
3.7.10. Table 3, entry 5. The reaction was carried out using
(R)-oxetane (28.0 mg, 0.155 mmol) and the diazoacetate
(70.0 mg, 0.251 mmol). 1,3-Diisopropylbenzene (20.6 mg,
0.127 mmol) was added to the crude product as an internal
NMR standard, and the NMR yield thus determined for the
cis tetrahydrofuran was 62% (C6D6). NMR analysis showed
that the product was an 84:16 cis/trans mixture. The crude
product was puri®ed by column chromatography (4/96
Et2O/pentane), which afforded the trans tetrahydrofuran
(15% ee, major enantiomer: 2R,3S) and the cis tetrahydro-
furan (39.9 mg, 60% yield, 94% ee, major enantiomer:
2R,3R) as colorless liquids.
C6D6
4.35 (d)
4.45 (d)
4.59 (d)
C6D6
3.54 (dt)
[H on 5-position]
10,10-Dicyclohexylethyl
(2R,3R)-3-(non-100-ynyl)tetra-
1
hydrofuran-2-carboxylate. H NMR (500 MHz, C6D6): d
0.89 (t, 3H, Jˆ7.0 Hz), 1.1±1.4 (m, 18H), 1.49 (qnt, 2H,
Jˆ7.3 Hz), 1.60 (s, 3H), 1.61±2.2 (m, 14H), 2.14 (dt, 2H,
Jˆ2.1, 7.2 Hz), 2.95 (tq, 1H, Jˆ2.2, 7.9 Hz), 3.58 (q, 1H,
Jˆ7.5 Hz), 4.16 (dt, 1H, Jˆ4.9, 8.2 Hz), 4.45 (d, 1H, Jˆ
7.3 Hz). 13C NMR (126 MHz, C6D6): d 14.3, 19.4, 19.6,
23.0, 27.0, 27.0, 27.3, 27.4, 27.4, 27.9, 28.1, 28.3, 28.4,
29.3, 29.3, 32.1, 33.2, 34.6, 45.4, 45.5, 68.6, 77.9, 81.5,
84.1, 90.8, 170.2 IR (neat): 2927 (s), 2853 (s), 1732 (s),
C6D6
4.79 (d)
4.58 (d)
4.96 (d)
4.45 (d)
C6D6

M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
Table 6. Assay conditions for enantiomeric g-chloroalcohols
2631
Compound
Column
Conditions
Illustrat. con®g. tR (min)
Opposite con®g. tR (min)
GC Chiraldex B-PH
1208C, He, 1.0 mL/min
70.9
73.8
GC Chiraldex B-PH
HPLC Chiralcel OD
GC Chiraldex G-TA
1308C, H2, 1.0 mL/min
59.4
27.0
48.4
57.0
10.0
52.2
10% i-PrOH/hexanes
1.0 mL/min
1208C, H2, 1.0 mL/min
1449 (s), 1379 (m), 1300 (m), 1210 (m), 1097 (s) cm21
HRMS (FAB, m/z): Calcd for C28H46O3: 469.3084
.
(a) (J2,3)trans,(J2,3)cis;
(b) The ester group of the cis diastereomer is more
shielded than the ester group of the trans diastereomer;
(c) With the (R)-oxetane and the (R,R)-ligand, the trans
diastereomer is formed preferentially.
(M1K1). Found: 469.3068. [a]20 ˆ15.88 ^ 0.38 (cˆ
D
0.95, EtOH, 94% ee).
3.8. Assay of diastereoselectivity
3.10. Assay of enantioselectivity
Table 4 summarizes the GC (achiral) conditions for the
diastereomeric tetrahydrofurans.
The enantiomeric excess of the g-chloroalcohols was
assayed either directly or as the acetate derivative (Ac2O/
pyridine/Et3N in CH2Cl2). Table 6 summarizes the assay
conditions.
The diastereomeric ratios of the tetrahydrofurans that
cannot be analyzed by GC were determined by integration
of the 1H NMR spectra (delay timeˆ30 s). Table 5 lists the
peaks used for integration.
Table 7 summarizes the assay conditions for the
oxetanes.
3.9. Assignment of relative stereochemistry
The assignment for t-butyl 3-phenyltetrahydrofuran-2-
carboxylate is based on comparison with the NMR data of
Katsuki.2c The other assignments are based on analogy. It
appears that all of the diastereomers possess the following
properties:
The ee's of the tetrahydrofurans were assayed by one of
three methods:
(a) reduction to the alcohol (LiAlH4), followed by acetyl-
ation (Ac2O/pyridine);
Table 7. Assay conditions for enantiomeric oxetanes
Compound
Column
Conditions
Illustrat. con®g. tR (min)
Opposite con®g. tR (min)
GC Chiraldex G-TA
1208C, He, 1.5 mL/min
6.1
7.7
GC Chiraldex G-TA
HPLC Chiralcel OD
HPLC Chiralcel OD
1008C, He, 1.0 mL/min
7.8
14.1
18.9
8.4
13.2
8.4
1% i-PrOH/hexanes, 1.0 mL/min
3% i-PrOH/hexanes, 1.0 mL/min

2632
M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
Table 8. Assay conditions for enantiomeric tetrahydrofurans
Substrate
Column
Conditions
Illustrat. con®g. tR (min)
Opposite con®g. tR (min)
GC Chiraldex B-PH
1108C, H2, 2.0 mL/min
57.4
59.5
GC Chiraldex G-TA
GC Chiraldex G-TA
908C, He, 1.0 mL/min
908C, He, 1.0 mL/min
81.7
74.1
77.5
83.2
GC Chiraldex G-TA
HPLC Chiralcel OD
1208C, He, 0.5 mL/min
67.7
19.1
58.9
24.6
1% i-PrOH/hexanes, 1.0 mL/min
GC Chiraldex G-TA
HPLC Chiralcel OD
1208C, He, 0.5 mL/min
64.3
23.0
56.1
37.6
1% i-PrOH/hexanes, 1.0 mL/min
GC Chiraldex B-PH
GC Chiraldex B-PH
GC Chiraldex B-PH
GC Chiraldex B-PH
GC Chiraldex B-PH
1108C, He, 1.0 mL/min
1208C, H2, 1.0 mL/min
1208C, H2, 2.0 mL/min
1508C, He, 1.0 mL/min
1508C, He, 1.0 mL/min
68.3
41.6
70.4
44.0
50.1
51.3
134.0
131.8
138.0
135.6
GC Chiraldex G-TA
GC Chiraldex G-TA
GC Chiraldex G-TA
1308C, He, 1.0 mL/min
1308C, He, 1.0 mL/min
1308C, He, 1.0 mL/min
31.3
21.8
92.9
24.2
19.6
86.3

M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
2633
Table 8
(continued)
Substrate
Column
Conditions
Illustrat. con®g. tR (min)
Opposite con®g. tR (min)
GC Chiraldex G-TA
1308C, He, 1.0 mL/min
73.2
70.6
HPLC Chiralpak AD
HPLC Chiralpak AD
GC Chiraldex G-TA
1% EtOH/hexanes 1.0 mL/min
1% EtOH/hexanes 1.0 mL/min
1208C, He, 1.0 mL/min
19.6
21.6
15.2
27.4
92.3
110.4
GC Chiraldex G-TA
1208C, He, 1.0 mL/min
105.8
95.4
(b) reduction to the alcohol (LiAlH4), followed by
tri¯uoroacetylation ((CF3CO)2O);
Acknowledgements
(c) hydrolysis to the acid (CF3CO2H), followed by
methylation with TMSCHN2 (for tetrahydrofurans that
bear an ester derived from a tertiary alcohol).
Support has been provided by Boehringer-Ingelheim,
Bristol-Myers Squibb, Merck, the National Science Foun-
dation, Novartis, Pharmacia, and P®zer.
Table 8 summarizes the assay conditions for the tetrahydro-
furans.
References
1. (a) Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R.
Tetrahedron Lett. 1966, 5239±5244. (b) Nozaki, H.; Takaya,
H.; Moriuti, S.; Noyori, R. Tetrahedron 1968, 24, 3655±3669.
2. (a) Ito, K.; Katsuki, T. Chem. Lett. 1994, 1857±1860. (b) Ito,
K.; Yoshitake, M.; Katsuki, T. Chem. Lett. 1995, 1027±1028.
(c) Ito, K.; Yoshitake, M.; Katsuki, T. Heterocycles 1996, 42,
305±317. (d) Ito, K.; Yoshitake, M.; Katsuki, T. Tetrahedron
1996, 52, 3905±3920. (e) Ito, K.; Fukuda, T.; Katsuki, T.
Synlett 1997, 387±389. (f) Ito, K.; Fukuda, T.; Katsuki, T.
Heterocycles 1997, 46, 401±411.
3.11. Assignment of absolute con®guration
The sign of the optical rotation of the trans tetrahydrofuran
derived from the reaction of (S)-2-phenyloxetane and
t-butyl diazoacetate in the presence of (S,S)-2 is negative;
the absolute con®guration of the predominant enantiomer
of the trans tetrahydrofuran is therefore (2R,3S).2c The
absolute con®gurations of the other products (Table 1)
were assigned by correlation (reduction or hydrolysis of
the ester). The absolute con®gurations of the products
illustrated in Table 2 were assigned by analogy.
3. For a review of synthetic routes to tetrahydrofurans, see:
Boivin, T. L. B. Tetrahedron 1987, 43, 3309±3362.
4. Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 10270±
10271.
The sign of the optical rotation of the cis tetrahydrofuran
derived from the reaction of (S)-2-phenyloxetane and
t-butyl diazoacetate in the presence of (R,R)-2 is positive;
the absolute con®guration of the predominant enantiomer of
the cis tetrahydrofuran is therefore (2S,3S).2c The absolute
con®gurations of the products illustrated in Table 3 were
assigned by analogy.
5. (a) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62,
444±445. (b) Qiao, S.; Fu, G. C. J. Org. Chem. 1998, 63,
4168±4169. (c) Rios, R.; Liang, J.; Lo, M. M.-C.; Fu, G. C.
Chem. Commun. 2000, 377±378.
6. Cleavage of the CMeCy2 ester can also be effected with 1.2

2634
M. M.-C. Lo, G. C. Fu / Tetrahedron 57 (2001) 2621±2634
equivalents of TMSI at 08C. Use of a larger excess of TMSI
leads to the destruction of the THF ring.
Stille coupling (Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org.
Chem. 1983, 48, 4634±4642) was unsuccessful.
14. The 1H NMR data match all but one of the signals reported by
Ruotsalainen (Ruotsalainen, H. Suomen Kemistilehti B 1973,
46, 215±220). The discrepancy in the chemical shift of the
methoxy group is probably due to a typographical error in the
original report.
7. Regitz, M.; Hocker, J.; Liedhegener, A. Org. Synth. Coll.
1973, 5, 179±183.
8. Fritschi, H.; Leutenegger, U.; Pfaltz, A. Helv. Chim. Acta
1988, 71, 1553±1565.
9. Picard, P.; LeClercq, D.; Bats, J.-P.; Moulines, J. Synthesis
1981, 550±551.
15. Hanack, M.; Haûdentefel, J. R. Chem. Ber. 1982, 115, 764±
771.
10. Kozyrod, R. P.; Morgan, J.; Pinhey, J. T. Aust. J. Chem. 1985,
38, 1147±1153.
16. Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25,
16±24.
11. Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z.
J. Org. Chem. 1990, 55, 1959±1964.
17. Midland, M. M.; Tramontano, A.; Kazubski, A.; Graham,
R. S.; Tsai, D. J. S.; Cardin, D. B. Tetrahedron 1984, 40,
1371±1380.
12. The tertiary alcohol was prepared by the addition of MeMgBr
to dicyclohexyl ketone.
13. An attempt to employ Pd(Bn)(Cl)(PPh3)2 as the catalyst for the