Improved procedure for the reductive acetylation of acyclic esters and a new synthesis of ethers

Article abstract of DOI:10.1021/jo9914521

An optimized protocol for the DIBALH reductive acetylation of acyclic esters and diesters is described. This reductive acetylation procedure allows a wide variety of esters to be converted into the corresponding α-acetoxy ethers in good to excellent yields. It was found that, under mild acidic conditions, many α-acetoxy ethers can be further reduced to the corresponding ethers. This net two-step ester deoxygenation is an attractive alternative to the classical Williamson synthesis for certain ethers.

Full text of DOI:10.1021/jo9914521

J . Org. Chem. 2000, 65, 191-198
191
Im p r oved P r oced u r e for th e Red u ctive Acetyla tion of Acyclic
Ester s a n d a New Syn th esis of Eth er s
David J . Kopecky and Scott D. Rychnovsky*
Department of Chemistry, University of California, Irvine, California 92717-2025
Received September 14, 1999
An optimized protocol for the DIBALH reductive acetylation of acyclic esters and diesters is
described. This reductive acetylation procedure allows a wide variety of esters to be converted into
the corresponding R-acetoxy ethers in good to excellent yields. It was found that, under mild acidic
conditions, many R-acetoxy ethers can be further reduced to the corresponding ethers. This net
two-step ester deoxygenation is an attractive alternative to the classical Williamson synthesis for
certain ethers.
In tr od u ction
The reduction and in situ acetylation of esters was
developed in our laboratory several years ago to provide
access to unusual cyclic acetal structures.1 The general
strategy involved trapping of the aluminum hemiacetal
intermediate found in the reduction of an ester to an
aldehyde by diisobutylaluminum hydride (DIBALH).
Other groups had previously trapped the same type of
intermediate with a trimethylsilyl group.2 After some
exploration, we found that acetic anhydride, DMAP, and
pyridine led to efficient trapping to give R-acetoxy ethers
F igu r e 1. Original DIBALH reductive acetylation conditions
from the cyclic esters we had been studying.1 We were
surprised to find that the same conditions gave satisfac-
tory yields of the R-acetoxy ethers from acyclic esters.
The R-acetoxy ethers can be activated with a variety of
Lewis acids to give oxacarbenium ions. Thus, the syn-
thesis of R-acetoxy ethers from acyclic esters is a poten-
tially general route to new oxacarbenium ions. We have
used this strategy in a new entry to Prins cyclization
reactions.3 The reductive acetylation conditions were
initially developed for cyclic esters and did not work well
with some acyclic substrates. We have now optimized the
reaction for the reduction of acyclic esters, and the results
are reported below.
for lactones and some acyclic esters.
a 12 h period, an R-acetoxy ether of the general structure
3 was isolated. The reaction conditions described above
were found to be effective for the reductive acetylation
of cyclic esters and several acyclic esters, but further
studies in our laboratory have demonstrated that a
number of acyclic esters do not undergo efficient reduc-
tive acetylation under these conditions. In some cases,
incomplete conversion and/or overreduction predominate.
Clearly, there is a need for more versatile and structur-
ally tolerant DIBALH reductive acetylation conditions.
Several key reaction parameters were examined at the
outset. The exclusion of either DMAP or pyridine from
the acetylation step was shown to preclude the formation
of any R-acetoxy ether product (3). Also, the gradual
warming of the reaction mixture to 0 °C instead of -20
°C during the acetylation step had no effect upon the
reaction outcome. Thus, the reductive acetylation reac-
tions described below were all warmed to a final tem-
perature of 0 °C for the sake of convenience. It is critical
that the acetylation step be conducted at low temperature
(-78 °C) for an extended period of time (12-14 h) before
forcing the reaction to completion by warming to 0 °C. If
the acetylation is warmed to 0 °C too quickly, decomposi-
tion of the aluminum hemiacetal intermediate (2) pre-
dominates. Early optimization studies focused upon the
Resu lts a n d Discu ssion
Op tim iza tion Stu d ies. The original protocol for the
reductive acetylation of lactones and some acyclic esters
with DIBALH is shown in Figure 1.1 Treatment of an
ester of general structure 1 with a slight excess (1.1
equiv) of DIBALH in dichloromethane at -78 °C for 2 h
generated the proposed aluminum hemiacetal intermedi-
ate 2, which then underwent acylation at low tempera-
ture by the combined action of acetic anhydride, pyridine,
and a slight excess (1.1 equiv) of 4-(dimethylamino)-
pyridine (DMAP). After gradual warming to -20 °C over
(1) Dahanukar, V. H.; Rychnovsky, S. D. J . Org. Chem. 1996, 61,
8317-8320.
(2) (a) Kiyooka, S.; Shirouchi, M.; Kaneko, Y. Tetrahedron Lett. 1993,
34, 1491-1494. (b) Kiyooka, S.; Suzuki, K.; Shirouchi, M.; Kaneko,
Y.; Tanimori, S. Tetrahedron Lett. 1993, 34, 5729-5732. (c) Kiyooka,
S.; Shirouchi, M. J . Org. Chem. 1992, 57, 1-2. (d) Polt, R.; Peterson,
M. A.; Deyoung, L. J . Org. Chem. 1992, 57, 5469-5480. (e) Sames, D.;
Liu, Y. Q.; Deyoung, L.; Polt, R. J . Org. Chem. 1995, 60, 2153-2159.
(3) Rychnovsky, S. D.; Hu, Y. Q.; Ellsworth, B. Tetrahedron Lett.
1998, 39, 7271-7274.
10.1021/jo9914521 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/17/1999

192 J . Org. Chem., Vol. 65, No. 1, 2000
Kopecky and Rychnovsky
Ta ble 1. Effect of DIBALH Qu en ch on th e Red u ctive
Acetyla tion of Va ler a te Ester 4
Ta ble 2. Effect of DMAP on th e Red u ctive Acetyla tion
of Va ler a te Ester 4
yieldb (%)
entrya
equiv of DMAP
5
6
4
1
1.5
2.0
2.0
3.0
66
79
73
81
14
17
10
19
5
1
3
0
2
3c
4
yieldb (%)
entrya
quench (equiv)
5
6
7
recovered 4
a
For all entries, 2.0 equiv of DIBALH, 3.0 equiv of pyridine,
b
1
2
3
4
5
52
47
44
10
63
38
41
55
36
24
2
4
1
2
2
and 6.0 equiv of Ac2O were used. The products were not cleanly
separable by chromatography. Yields were determined by 1H NMR
and gas chromatographic analysis of partially purified mixtures.
c Toluene was used as the solvent.
HCO2Et (3)
AcOH (1.5)
MeOH (1.5)
H2O (1.5)
52
a
For all entries, 2.0 equiv of DIBALH, 3.0 equiv of pyridine,
the reaction leads to a heightened rate of aluminum
hemiacetal acylation versus aluminum hemiacetal break-
down. The use of >2 equiv of DMAP provided no
additional benefit to the reaction outcome (Table 2, entry
4). The effect of solvent choice upon the reductive
acetylation of 4 was also explored. For compound 4, as
well as a number of other acyclic esters examined,
toluene and dichloromethane proved to be equally effec-
tive reaction mediums, although overall yields tend to
be slightly lower in toluene solvent in most cases (for
example, see Table 2, entry 3). Other solvents such as
ether, tetrahydrofuran (THF), and mixtures of hexanes
and toluene were not as effective. The reductive acety-
lation of 4 in these solvents led to significantly dimin-
ished yields (30-62%) of 5 under conditions identical to
those described in Table 2.
b
1.1 equiv of DMAP, and 4.0 equiv of Ac2O were used. The
products were not cleanly separable by chromatography. Yields
were determined by 1H NMR and gas chromatographic analysis
of partially purified mixtures.
DIBALH reductive acetylation of valerate ester 4. We
chose ester 4 as a test substrate since it possesses
moderate complexity and is an acyclic precursor for a
Lewis acid-mediated Prins cyclization.3 Preliminary stud-
ies suggested that increasing the amount of reducing
agent and reducing the reaction time before the in situ
acetylation step minimized overreduction. Specifically, it
was determined that the reduction of ester 4 with a 2-fold
excess of DIBALH for 45 min at low temperature prior
to acetylation was optimal.
When 2.0 equiv of DIBALH was utilized, a full equiva-
lent of DIBALH was present in solution after complete
formation of the corresponding hemiacetal intermediate
of 4. This excess reagent may lead to complications in
the slow acylation step. A series of experiments examined
the effectiveness of in situ quenching of the excess
DIBALH for 30 min prior to acetylation (Table 1). Most
of the quenching agents tested led to diminished yields
of desired R-acetoxy ether 5 and increased yields of
acetylated overreduction product 6 (Table 1, entries 2-4).
Water was the sole quenching agent that partially
suppressed overreduction (entry 5), suggesting that the
presence of a small amount of ice in the -78 °C dichlo-
romethane solution before acetylation may be beneficial.
Another key variable that was independently examined
was the impact of DMAP stoichiometry upon product
yield. This study (Table 2) clearly suggested that the
addition of a larger excess of DMAP (2.0 equiv, Table 2,
entries 2-3) to the reaction increased product formation.4
This trend can be rationalized by considering the compet-
ing reaction rates: since DMAP catalyzes the acetylation
reaction, the presence of greater amounts of DMAP in
At this point, the efficacy of incorporating a DIBALH
quenching step prior to in situ acetylation was investi-
gated. Recall that water was effective in earlier studies
(Table 1), so in situ quenching with water was examined.
The effectiveness of an ethyl formate quench was also
explored. These quenching experiments establish that,
for both dichloromethane and toluene solvent, the in situ
quenching of excess DIBALH with either quenching
agent for 30 min prior to acetylation generates yields
(75-82%) of R-acetoxy ether 5 comparable to that of the
normal two-step protocol (79%, see Table 2, entry 2). The
inclusion of a DIBALH quenching step in the reductive
acetylation procedure was deemed unnecessary.
The optimization studies described above for valerate
ester 4 have established the need for several key modi-
fications of the original DIBALH reductive acetylation
conditions (Figure 1) when the starting ester substrate
is acyclic. These changes include increasing the DIBALH
stoichiometry (2.0 equiv) and reducing the duration of
the reduction before acetylation (45 min). Moreover, the
amounts of DMAP and acetic anhydride employed in the
acetylation step should be increased to 2.0 and 6.0 equiv,
respectively, and a gradual warming of the reaction to a
final temperature of 0 °C is preferred (Figure 2).
(4) It was necessary to increase the amount of acetic anhydride
employed when larger excesses of DMAP were used to ensure complete
acylation of the aluminum hemiacetal intermediate.

Reductive Acetylation of Acyclic Esters
J . Org. Chem., Vol. 65, No. 1, 2000 193
Ta ble 4. DIBALH Red u ctive Acetyla tion of Acyclic
Ester s
F igu r e 2. Optimized DIBALH reductive acetylation condi-
tions for acyclic esters.
Ta ble 3. DIBALH Red u ctive Acetyla tion of Acyclic
Ester s a n d La cton es
a
All entries were run in CH2Cl2 using 4.0 equiv of DIBALH,
6.0 equiv of pyridine, 4.0 equiv of DMAP, and 12.0 equiv of Ac2O
b
(reduction time ) 45 min). Reported yields are for chromato-
graphed products. c Diastereomeric ratios were determined by 1H
d
NMR analysis. Bis-acetal 27 was contaminated with a minor
amount of the corresponding monoacetal. The yield of 27 (75%)
and the yield of the corresponding monoacetal (3%) were deter-
mined by 1H NMR analysis of the product.
Sch em e 1
yield)1 illustrates the utility of the optimized conditions
for the reductive acetylation of lactones.
The improved DIBALH reductive acetylation protocol
also elicited facile conversion of acyclic diesters into the
corresponding bis R-acetoxy ethers (Table 4). The amounts
of all reagents used were doubled for diester substrates
relative to the standard reductive acetylation conditions
for esters, but the reduction time was not altered. Diethyl
malonate (26) and diethyl succinate (28) were trans-
formed into bis-acetals 27 and 29, respectively, in good
yields (60-75%, Table 4, entries 1-2). A minimal amount
of the mono-acetal byproduct was detected in the reduc-
tion of 26. Bis-reductive acetylation of neopentyl glycol-
derived diester 30 generated bis-acetal 31 in 66% yield
(Table 4, entry 3) along with a low yield (19%) of the
corresponding monoacetal.
a
All entries were run in CH2Cl2 using 2.0 equiv of DIBALH,
3.0 equiv of pyridine, 2.0 equiv of DMAP, and 6.0 equiv of Ac2O
b
(reduction time ) 45 min). Except for entry 1, all product yields
are after chromatography. c Diastereomeric ratios were deter-
mined by 1H NMR analysis. Acetal 5 was contaminated with the
d
corresponding overreduction product 6 (additional 17% yield). e A
modified workup procedure was employed.
Red u ctive Acetyla tion of Acyclic Ester s. The ap-
plicability of these optimized DIBALH reductive acety-
lation conditions to a series of acyclic substrates was
investigated (Table 3). In all cases, the R-acetoxy ether
products were isolated in good to excellent yields (78-
93%). The facile generation of hindered R-acetoxy ethers
such as neopentyl acetal 11 and tert-butyl acetal 19 is
remarkable (Table 3, entries 3 and 7), and the suppres-
sion of â-elimination in the formation of n-butyl acetal
21 is noteworthy (Table 3, entry 8). A substantial increase
in the yield of cyclic acetal 25 from macrolactone 24 under
the optimized reductive acetylation conditions (84%,
Table 3, entry 10) relative to the original protocol (72%
Several acyclic esters were problematic substrates. A
larger excess of DIBALH was required for the complete
conversion of benzyl-protected (S)-ethyl lactate5 (32) into
R-acetoxy ether 33 (Scheme 1). Competing aluminum
coordination by the benzyloxy group of 32 may account
(5) (a) Hasan, I.; Kishi, Y. Tetrahedron Lett. 1980, 21, 4229-4232.
(b) Stojanovic, A.; Renaud, P. Helv. Chim. Acta 1998, 81, 268-283. (c)
The enantiomeric excess of ester 32 was determined to be 71% by
optical rotation.

194 J . Org. Chem., Vol. 65, No. 1, 2000
Kopecky and Rychnovsky
Sch em e 2
Ta ble 5. DIBALH Red u ctive Acetyla tion of
3-P h en ylp r op yl Ester 34
Ta ble 6. BF 3‚OEt2/Et3SiH-Med ia ted Red u ction of
r-Acetoxy Eth er s to th e Cor r esp on d in g Eth er s
yieldb (%)
DIBALH
(equiv)
reduction
time
acetylation
conditionsa
entry
35
36
1
2
3
1.1
2.0
1.7
2 h
45 min
45 min
A
B
B
19
47
56
68
49
42
a
Conditions A: 3.0 equiv of pyridine, 1.1 equiv of DMAP, and
4.0 equiv of Ac2O. Conditions B: 3.0 equiv of pyridine, 2.0 equiv
of DMAP, and 6.0 equiv of Ac2O. Conditions B: 3.0 equiv of
b
pyridine, 2.0 equiv of DMAP, and 6.0 equiv of Ac2O. Compounds
35 and 36 were only partially separable by flash column chroma-
tography, thus product yields were calculated from both pure and
mixed fractions (ratios of products in mixed fractions determined
by 1H NMR).
Figu r e 3. Unsucessful acyclic ester substrates for the DIBALH
reductive acetylation reaction.
for the slow consumption of starting material in the
presence of only 2 equiv of DIBALH. 3-Phenylpropyl ester
34 was a poor substrate for the reductive acetylation
reaction under a variety of conditions examined (Table
5). A slight modification of the optimized protocol was
required to obtain a moderate yield (56%) of desired
R-acetoxy ether 35 (Table 5, entry 3). The original
reductive acetylation conditions were unable to suppress
the overreduction of ester 34 to any useful extent (Table
5. entry 1). The propensity of ester 34 to undergo facile
overreduction is surprising and cannot be easily rational-
ized since it possesses a structure similar to those of a
number of highly successful reductive acetylation sub-
strates described above (see Table 3, entries 4-7). Phenyl
ester 37 and (E)-cinnamate ester 38 failed to undergo
reductive acetylation under any conditions (Figure 3).
Exclusive overreduction occurred in both cases, presum-
ably due to the instability of the corresponding aluminum
hemiacetal intermediates.
Eth er Syn th esis. As an extension of the DIBALH
reductive acetylation methodology, a one-step transfor-
mation of R-acetoxy ethers into the corresponding ethers
has been developed. This new method is an alternative
to the popular Williamson reaction6 and provides easy
access to sterically congested ethers. The net deoxygen-
ation of acyclic esters has been achieved previously in
low to moderate yields by treatment of an ester with a
mixture of boron trifluoride etherate and either lithium
aluminum hydride or sodium borohydride.7 This trans-
formation has also been accomplished with manganese
acetyl complexes in the presence of triphenylsilane.8
Moreover, the conversion of acyclic thionoesters to ethers
a
General reaction conditions: 2.5 equiv of boron trifluoride
etherate and 2.5 equiv of triethylsilane were added to the acetal
in CH2Cl2 at -78 °C. b All product yields are after chromatography
or distillation. c 5 equiv each of boron trifluoride etherate and
d
triethylsilane were used. The reduction was performed at 0 °C.
by reductive desulfurization with either Raney nickel9
or organotin hydrides10 has been reported. Our procedure
entails treatment of an R-acetoxy ether 3, obtained by
DIBALH reductive acetylation of the corresponding ester,
with equimolar amounts of boron trifluoride etherate and
triethylsilane in dichloromethane at -78 °C for <30 min
to generate ether 40. The reaction is proposed to proceed
via oxacarbenium ion intermediate 39 (Scheme 2).
The reduction of a number of R-acetoxy ethers to the
corresponding ethers proceeded in excellent yields (83-
100%, Table 6). The synthesis of dineopentyl ether (41)
by our method (Table 6, entry 1) compares favorably to
a Williamson ether synthesis of the same material.11
Masada synthesizes 41 in 62% yield by combining sodium
(8) Mao, Z.; Gregg, B. T.; Cutler, A. R. J . Am. Chem. Soc. 1995, 117,
10139-10140.
(9) (a) Baxter, S. L.; Bradshaw, J . S. J . Org. Chem. 1981, 46, 831-
832. (b) Bradshaw, J . S.; J ones, B. A.; Gebhard, J . S. J . Org. Chem.
1983, 48, 1127-1128.
(10) (a) Nicolaou, K. C.; Sato, M.; Theodorakis, E. A.; Miller, N. D.
J . Chem. Soc., Chem. Commun. 1995, 1583-1585. (b) J ang, D. O.;
Song, S. H.; Cho, D. H. Tetrahedron 1999, 55, 3479-3488. (c) Nicolaou,
K. C.; McGarry, D. G.; Somers, P. K.; Veale, C. A.; Furst, G. T. J . Am.
Chem. Soc. 1987, 109, 2504-2506.
(11) (a) Gash, V. W. J . Org. Chem. 1972, 37, 2197-2201. (b) Davies,
R.; Hudec, J . J . Chem. Soc., Perkin Trans. 2 1973, 1395-1400. (c)
Masada, H.; Murotani, Y. Bull. Chem. Soc. J pn. 1979, 52, 1213-1214.
(6) For a brief summary of the Williamson reaction, see: Feuer, H.;
Hooz, J . In The Chemistry of the Ether Linkage; Patai, S., Ed.; J ohn
Wiley & Sons: New York, 1967; pp 446-448.
(7) Pettit, G. R.; Pitak, D. M. J . Org. Chem. 1962, 27, 2127-2130.

Reductive Acetylation of Acyclic Esters
J . Org. Chem., Vol. 65, No. 1, 2000 195
protocol has been shown to convert most of the examined
acyclic esters and diesters into the corresponding R-ace-
toxy ethers in good to excellent yields. These R-acetoxy
ethers can be further reduced to the corresponding ethers
under mild acidic conditions. This two-step ester deoxy-
genation protocol is an alternative to the classical Wil-
liamson ether synthesis and is particularly useful for the
synthesis of hindered ethers or polyethers.
Exp er im en ta l Section 14
P r ep a r a tion of r-Acetoxy Eth er s. Gen er a l P r oced u r e
for th e DIBALH Red u ctive Acetyla tion of Mon oester s.
The ester (1.0 mmol) was dissolved in dichloromethane (6 mL).
Upon cooling to -78 °C, DIBALH (1 M in hexanes, 2.0 mL,
2.0 mmol, 2.0 equiv) was added dropwise via syringe. After
45 min, the reaction was treated sequentially with pyridine
(243 µL, 3.0 mmol, 3.0 equiv) dropwise via syringe, a solution
of DMAP (244 mg, 2.0 mmol, 2.0 equiv) in dichloromethane (3
mL) dropwise via cannula, and acetic anhydride (566 µL, 6.0
mmol, 6.0 equiv) dropwise via syringe. The mixture was stirred
at -78 °C for 12-14 h, warmed to 0 °C, and stirred for an
additional 30 min, and then the reaction was quenched at 0
°C with saturated aqueous ammonium chloride (10 mL) and
saturated aqueous sodium potassium tartrate (7.5 mL). The
resultant mixture was warmed to room temperature and
stirred vigorously for 30 min or until layer separation was
complete. After extraction with dichloromethane (×4), the
combined dichloromethane extracts were washed with ice-
cooled 1 M sodium bisulfate (×2), saturated aqueous sodium
bicarbonate (×3), and brine (×1). After drying (anhydrous
sodium sulfate) and evaporation of dichloromethane, the
residue was purified by flash column chromatography on silica
gel or on silica gel previously deactivated with 2% triethyl-
amine/hexanes unless otherwise noted.
F igu r e 4. Possible oxacarbenium ion isomerization pathway
for the reduction of R-acetoxy ether 33.
metal and neopentyl alcohol at reflux, followed by
prolonged heating at 120 °C with neopentyl tosylate in
DMSO.11c By comparison, our two-step protocol for the
reduction of esters to ethers is mild and relatively
efficient. Our method was also excellent for the synthesis
of other hindered ethers, namely tert-butyl ether 43 and
novel diether 45 (Table 6, entries 3 and 5). Moreover, this
method provides an excellent route to macrocyclic ethers
such as 44 (Table 6, entry 4). Macrocycles containing one
or more ether linkages (crown ethers) are difficult to
access efficiently from acyclic precursors by a classical
Williamson approach.12 Not surprisingly, the reduction
failed for trifluoromethyl acetal 23 (Table 3), even at
elevated reaction temperatures. Stereoelectronic factors
play a role in this result; the R-trifluoromethyl group
strongly destabilizes oxacarbenium ion formation by an
inductive effect. This same effect is less pronounced in
the reduction of ethyl acetal 33, where the R-benzyloxy
substituent prevents facile oxacarbenium ion formation
at -78 °C but does not hinder reduction at 0 °C (Table
6, entry 6).
1-Bu tyl-2-oxo-3-(2-ph en ylpr opyl)-5-h exen yl Acetate (5).
According to the general procedure for the preparation of
R-acetoxy ethers described above, ester 4 (34.8 mg, 0.134
mmol) gave a crude mixture of 32.3 mg (79%, 0.106 mmol) of
5 and 4.9 mg (17%, 0.022 mmol) of acetate 6 as a light yellow
1
oil. H NMR analysis indicated that 5 was isolated as a 1.1:1
mixture of diastereomers. Data for pure 5: IR (mixture of
It is worth noting that the reduction of 33 to 46 is
expected to proceed through an oxacarbenium ion, and
a 1,2-hydride shift from the initially formed primary
oxacarbenium ion 47 can be envisioned that would
generate a more stable secondary oxacarbenium ion 48
(Figure 4). This pathway has been ruled out by examining
the optical purity of the starting material and product.
The optical purity of ester 32, precursor to R-acetoxy
ether 33, was found to be 71% ee by optical rotation.5
The optical purity of benzyl ether 46 was determined to
be 68% ee by hydrogenolysis and Mosher’s ester analy-
sis.13 The lack of significant epimerization upon conver-
sion of 33 to 46 is inconsistent with a 1,2-hydride shift
of the initial oxacarbenium ion to the achiral secondary
oxacarbenium ion. In this case reduction is faster than
cationic rearrangement, which is a useful feature in
oxacarbenium ion reactions.
1
isomers, neat) 1734, 1242 cm-1; H NMR (500 MHz, CDCl3,
mixture of isomers) δ 7.25-7.32 (m, 2 H), 7.15-7.21 (m, 3 H),
5.89-5.97 (m, 1 H), 5.72-5.87 (m, 1 H), 5.04-5.11 (m, 2 H),
3.60-3.71 (m, 1 H), 2.54-2.83 (m, 2 H), 2.26-2.36 (m, 2 H),
2.07 (s, 3 H, major isomer), 2.03 (s, 3 H, minor isomer), 1.73-
1.85 (m, 2 H), 1.64-1.74 (m, 2 H), 1.29-1.42 (m, 4 H), 0.91 (t,
J ) 6.7 Hz, 3 H); 13C NMR (125 MHz, CDCl3, mixture of
isomers) δ 171.1, 171.0, 142.2, 142.0, 134.6, 133.9, 128.4, 128.4,
128.3, 128.3, 125.9, 125.8, 117.8, 117.0, 98.5, 97.4, 78.6, 76.9,
39.3, 38.7, 36.1, 35.9, 34.7, 34.5, 31.7, 31.3, 29.7, 26.4, 26.3,
22.4, 21.5, 21.4, 14.0; MS (HREI-isobutane) calcd for C16H23O3
(M - C3H5) 263.1647, found 263.1646.
1-Ch lor om et h yl-2-oxo-3-(2-p h en ylp r op yl)-5-h exen yl
Aceta te (9). According to the general procedure for the
preparation of R-acetoxy ethers described above, ester 8 (36.2
mg, 0.143 mmol) gave a light yellow oil that was purified by
chromatography on silica gel (8% ethyl ether/hexanes) to give
1
39.0 mg (92%, 0.131 mmol) of 9 as a light yellow oil. H NMR
analysis indicated that 9 was isolated as a 1.1:1 mixture of
diastereomers: IR (mixture of isomers, neat) 1744, 1229 cm-1
;
Con clu sion s
1H NMR (500 MHz, CDCl3, mixture of isomers) δ 7.25-7.32
(m, 2 H), 7.16-7.22 (m, 3 H), 6.02 (dt, J ) 19.5 Hz, 5.2 Hz, 1
H), 5.76-5.87 (m, 1 H), 5.05-5.15 (m, 2 H), 3.71-3.79 (m, 1
H), 3.54-3.62 (m, 2 H), 2.53-2.82 (m, 2 H), 2.30-2.40 (m, 2
H), 2.10 (s, 3 H, minor isomer), 2.08 (s, 3 H, major isomer),
1.77-1.91 (m, 2 H); 13C NMR (125 MHz, CDCl3, mixture of
isomers) δ 170.7, 170.4, 141.9, 141.8, 134.1, 133.6, 128.5, 128.4,
128.3, 125.9, 125.9, 118.2, 117.4, 95.9, 94.8, 79.7, 78.1, 44.1,
By the systematic variation of key reaction parameters,
an improved procedure for the reductive acetylation of
acyclic esters with DIBALH has been developed. This
(12) For a review of crown ether synthesis, see: Laidler, D. A.;
Stoddart, J . F. In The Chemistry of Ethers, Crown Ethers, Hydroxyl
Groups and their Sulfur Analogues; Patai, S., Ed.; J ohn Wiley &
Sons: New York, 1980; pp 1-57.
(13) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(14) The general experimental procedure is included in the Sup-
porting Information.

196 J . Org. Chem., Vol. 65, No. 1, 2000
Kopecky and Rychnovsky
44.0, 39.1, 38.6, 35.9, 35.7, 31.6, 31.2, 21.2, 21.1; MS (HRCI-
isobutane) calcd for C13H16O3Cl (M - C3H5) 255.0788, found
255.0782. Anal. Calcd for C16H21O3Cl: C, 64.75; H, 7.13.
Found: C, 64.97; H, 7.21.
J ) 12.1 Hz, 1 H), 4.47 (d, J ) 12.1 Hz, 1 H), 3.65-3.71 (m, 1
H), 3.45-3.61 (m, 3 H), 2.05 (s, 3 H), 1.96-2.03 (m, 2 H), 1.47-
1.56 (m, 2 H), 1.30-1.39 (m, 2 H), 0.90 (t, J ) 7.4 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 170.8, 138.3, 128.4, 127.7, 127.6,
96.5, 73.0, 69.5, 65.6, 34.9, 31.6, 21.2, 19.2, 13.8; MS (HRCI-
isobutane) calcd for C14H21O3 (M - C2H3O) 237.1491, found
237.1493. Anal. Calcd for C16H24O4: C, 68.55; H, 8.63. Found:
C, 68.70; H, 8.95.
1-(2,2-Dim eth ylp r op oxy)-2,2-d im eth ylp r op yl Aceta te
(11). According to the general procedure for the preparation
of R-acetoxy ethers described above, ester 10 (850 mg, 4.93
mmol) gave a light yellow oil that was purified by chromatog-
raphy on deactivated silica gel (8% ethyl ether/hexanes) to give
930 mg (87%, 4.30 mmol) of 11 as a volatile light yellow oil:
IR (neat) 1740, 1246 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.54
(s, 1 H), 3.29 (d, J ) 8.7 Hz, 1 H), 3.08 (d, J ) 8.7 Hz, 1 H),
2.09 (s, 3 H), 0.93 (s, 9 H), 0.90 (s, 9 H); 13C NMR (100 MHz,
CDCl3) δ 171.3, 103.0, 79.9, 35.7, 32.0, 26.5, 24.5, 21.0; MS
(HRCI-isobutane) calcd for C12H24O3 (M+) 216.1725, found
216.1732.
1-(1-P h en ylet h oxy)-2,2,2-t r iflu or oet h yl Acet a t e (23).
According to the general procedure for the preparation of
R-acetoxy ethers described above, ester 22 (300 mg, 1.38 mmol)
gave a light yellow oil that was purified by chromatography
on silica gel (8% ethyl ether/hexanes) to give 336 mg (93%,
1.28 mmol) of 23 as a light yellow oil. 1H NMR analysis
indicated that 23 was isolated as a 2.2:1 mixture of diaster-
eomers: IR (mixture of isomers, neat) 1762, 1225 cm-1
NMR (400 MHz, CDCl3, mixture of isomers) δ 7.26-7.42 (m,
2 H), 6.22 (q, J HF ) 3.9 Hz, 1 H, major isomer), 5.88 (q, J HF
;
1H
1-P en toxy-3-p h en ylp r op yl Aceta te (13). According to the
general procedure for the preparation of R-acetoxy ethers
described above, ester 12 (250 mg, 1.13 mmol) gave a light
yellow oil that was purified by chromatography on silica gel
(8% ethyl ether/hexanes) to give 232 mg (78%, 0.88 mmol) of
13 as a colorless oil: IR (neat) 1738, 1240 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.24-7.31 (m, 2 H), 7.16-7.21 (m, 3 H), 5.83
(t, J ) 5.5 Hz, 1 H), 3.63-3.71 (m, 1 H), 3.43-3.51 (m, 1 H),
2.63-2.81 (m, 2 H), 2.06 (s, 3 H), 1.99-2.06 (m, 2 H), 1.55-
1.63 (m, 2 H), 1.30-1.37 (m, 4 H), 0.92 (t, J ) 6.3 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 170.9, 141.1, 128.4, 128.3, 126.0,
98.2, 69.6, 36.0, 30.3, 29.3, 28.2, 22.4, 21.2, 14.0. Anal. Calcd
for C16H24O3: C, 72.68; H, 9.16. Found: C, 72.64; H, 8.91.
1-Ben zyloxy-3-p h en ylp r op yl Aceta te (15). According to
the general procedure for the preparation of R-acetoxy ethers
described above, ester 14 (34.9 mg, 0.145 mmol) gave a yellow
oil that was purified by chromatography on silica gel (2% tert-
butylmethyl ether/hexanes grading to 5% tert-butylmethyl
ether/hexanes) to give 32.0 mg (78%, 0.113 mmol) of 15 as a
)
3.9 Hz, 1 H, minor isomer), 4.83 (q, J ) 6.5 Hz, 1 H, major
isomer), 4.82 (q, J ) 6.5 Hz, 1 H, minor isomer), 2.19 (s, 3 H,
minor isomer), 1.72 (s, 3 H, major isomer), 1.55 (d, J ) 6.5
Hz, 3 H, major isomer), 1.53 (d, J ) 6.5 Hz, 3 H, minor isomer);
13C NMR (125 MHz, CDCl3, mixture of isomers) δ 169.7, 169.2,
141.9, 140.6, 128.7, 128.6, 128.4, 128.0, 126.9, 126.2, 120.9 (q,
J CF ) 282 Hz), 89.7 (q, J CF ) 36 Hz), 88.3 (q, J CF ) 36 Hz),
80.7, 78.1, 23.7, 23.5, 20.6, 20.1. Anal. Calcd for C12H13O3F3:
C, 54.96; H, 5.00. Found: C, 54.77; H, 5.20.
2-Acetoxy-1-oxa cycloh exd eca n e (25). The general pro-
cedure for the preparation of R-acetoxy ethers described above
was carried out for lactone 24 (500 mg, 2.04 mmol) except that
a modified workup was performed: The reaction was quenched
at 0 °C with saturated aqueous ammonium chloride (21.5 mL)
and saturated aqueous sodium potassium tartrate (16.5 mL).
The resulting mixture was warmed to room temperature,
stirred vigorously for 4 h, and then saturated with sodium
chloride. After extraction with ethyl ether (×4), the combined
organic extracts were washed with ice-cooled 1 M sodium
bisulfate (×2), saturated aqueous sodium bicarbonate (×3),
and brine (×1). After drying (anhydrous sodium sulfate) and
evaporation of solvent, the resultant light yellow oil was
purified by flash column chromatography on silica gel (7%
ethyl ether/hexanes) to give 490 mg (84%, 1.72 mmol) of 25 as
a viscous colorless oil that partially solidified upon standing:
IR (neat) 1738, 1244 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.78
(dd, J ) 7.8 Hz, 3.1 Hz, 1 H), 3.75-3.81 (m, 1 H), 3.39-3.47
(m, 1 H), 2.07 (s, 3 H), 1.24-1.76 (m, 26 H); 13C NMR (100
MHz, CDCl3) δ 170.9, 99.2, 69.5, 34.1, 29.0, 27.2, 27.2, 27.1,
27.0, 26.6, 26.0, 26.0, 26.0, 25.7, 24.9, 23.0, 21.3; MS (HRCI-
isobutane) calcd for C17H32O3 (M+) 284.2351, found 284.2349.
Anal. Calcd for C17H32O3: C, 71.79; H, 11.34. Found: C, 71.57;
H, 11.16.
yellow oil: IR (neat) 1736, 1237 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 7.25-7.38 (m, 7 H), 7.14-7.22 (m, 2 H), 5.96 (dd, J
) 5.9 Hz, 5.0 Hz, 1 H), 4.73 (d, J ) 11.9 Hz, 1 H), 4.59 (d, J )
11.9 Hz, 1 H), 2.63-2.79 (m, 2 H), 2.04 (s, 3 H), 2.00-2.13 (m,
2 H); 13C NMR (125 MHz, CDCl3) δ 170.9, 141.1, 137.4, 128.5,
128.4, 127.9, 127.8, 126.0, 97.7, 71.4, 67.4, 36.0, 30.4, 21.2.
Anal. Calcd for C18H20O3: C, 76.03; H, 7.09. Found: C, 76.00;
H, 6.97.
1-(1-Meth yleth oxy)-3-p h en ylp r op yl Aceta te (17). Ac-
cording to the general procedure for the preparation of
R-acetoxy ethers described above, ester 16 (500 mg, 2.60 mmol)
gave a light yellow oil that was purified by chromatography
on deactivated silica gel (10% ethyl ether/hexanes) to give 547
mg (89%, 2.32 mmol) of 17 as a light yellow oil: IR (neat) 1736,
1
1243 cm-1; H NMR (400 MHz, CDCl3) δ 7.24-7.31 (m, 2 H),
7.15-7.22 (m, 3 H), 5.93 (t, J ) 5.5 Hz, 1 H), 3.97 (septet, J )
6.2 Hz, 1 H), 2.60-2.80 (m, 2 H), 2.06 (s, 3 H), 1.97-2.05 (m,
2 H), 1.18 (t, J ) 6.3 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ
171.0, 141.1, 128.4, 128.3, 126.0, 96.7, 71.2, 36.3, 30.4, 23.2,
21.9, 21.4. Anal. Calcd for C14H20O3: C, 71.16; H, 8.53.
Found: C, 71.07; H, 8.30.
(2S)-1-Eth oxy-2-ben zyloxyp r op yl Aceta te (33). Ester
325 (100 mg, 0.48 mmol) was dissolved in dichloromethane (4
mL). Upon cooling to -78 °C, DIBALH (1 M in hexanes, 1.44
mL, 1.44 mmol, 3.0 equiv) was added dropwise via syringe.
After 45 min, the solution was treated sequentially with
pyridine (175 µL, 2.16 mmol, 4.5 equiv) dropwise via syringe,
1-(1,1-Dim et h ylet h oxy)-3-p h en ylp r op yl Acet a t e (19).
According to the general procedure for the preparation of
R-acetoxy ethers described above, ester 18 (500 mg, 2.42 mmol)
gave a light yellow oil that was purified by chromatography
on deactivated silica gel (10% ethyl ether/hexanes) to give 543
mg (90%, 2.17 mmol) of 19 as a light yellow oil: IR (neat) 1731,
a
solution of DMAP (176 mg, 1.44 mmol, 3.0 equiv) in
dichloromethane (2.1 mL) dropwise via cannula, and acetic
anhydride (408 µL, 4.32 mmol, 9.0 equiv) dropwise via syringe.
The mixture was stirred at -78 °C for 14 h, warmed to 0 °C,
and stirred for an additional 30 min, and then the reaction
was quenched at 0 °C with saturated aqueous ammonium
chloride (7.5 mL) and saturated aqueous sodium potassium
tartrate (6 mL). The resultant mixture was warmed to room
temperature and stirred vigorously for 30 min. After extraction
with dichloromethane (×4), and the combined dichloromethane
extracts were washed with ice-cooled 1 M sodium bisulfate
(×2), saturated aqueous sodium bicarbonate (×3), and brine
(×1). After drying (anhydrous sodium sulfate) and evaporation
of dichloromethane, the resultant yellow oil was purified by
flash column chromatography on silica gel (10% ethyl ether/
hexanes) to give 115 mg (95%, 0.46 mmol) of 33 as a light
yellow oil. 1H NMR analysis indicated that 33 was isolated as
a 1.3:1 mixture of diastereomers: IR (mixture of isomers, neat)
1
1250 cm-1; H NMR (400 MHz, CDCl3) δ 7.24-7.32 (m, 2 H),
7.15-7.22 (m, 3 H), 6.09 (dd, J ) 6.5 Hz, 4.4 Hz, 1 H), 2.57-
2.78 (m, 2 H), 2.02 (s, 3 H), 1.91-2.05 (m, 2 H), 1.24 (s, 9 H);
13C NMR (100 MHz, CDCl3) δ 170.4, 141.2, 128.3, 128.3, 125.9,
93.8, 75.7, 37.0, 30.3, 28.3, 21.6. Anal. Calcd for C15H22O3: C,
71.97; H, 8.86. Found: C, 72.06; H, 8.69.
1-Bu toxy-3-ben zyloxyp r op yl Aceta te (21). According to
the general procedure for the preparation of R-acetoxy ethers
described above, ester 20 (34.6 mg, 0.146 mmol) gave a yellow
oil that was purified by chromatography on silica gel (8% ethyl
acetate/hexanes) to give 33.1 mg (81%, 0.118 mmol) of 21 as a
yellow oil: IR (neat) 1738, 1239 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 7.25-7.36 (m, 5 H), 6.00 (t, J ) 5.6 Hz, 1 H), 4.50 (d,

Reductive Acetylation of Acyclic Esters
1738, 1238 cm-1 1H NMR (500 MHz, CDCl3, mixture of
J . Org. Chem., Vol. 65, No. 1, 2000 197
;
indicated that 31 was isolated as a 1.9:1 mixture of diaster-
eomers: IR (mixture of isomers, neat) 1737, 1242; 1H NMR
(400 MHz, CDCl3, mixture of isomers) δ 5.51 (d, J ) 1.8 Hz, 2
H), 3.34 (dd, J ) 26.5 Hz, 8.7 Hz, 2 H), 3.19 (dd, J ) 20.1 Hz,
8.7 Hz, 2 H), 2.08 (s, 6 H, minor isomer), 2.07 (s, 6 H, major
isomer), 0.91 (s, 18 H), 0.87 (s, 6 H, major isomer), 0.87 (s, 6
H, minor isomer); 13C NMR (100 MHz, CDCl3, mixture of
isomers) δ 171.3, 102.8, 102.6, 74.9, 74.8, 36.1, 36.0, 35.7, 24.5,
24.5, 22.1, 22.0, 21.9, 21.0; MS (HRFAB) calcd for C19H36NaO6
isomers) δ 7.25-7.36 (m, 5 H), 5.89 (d, J ) 4.2 Hz, 1 H, minor
isomer), 5.80 (d, J ) 5.1 Hz, 1 H, major isomer), 4.55-4.70
(m, 2 H), 3.72-3.81 (m, 1 H), 3.53-3.66 (m, 2 H), 2.11 (s, 3 H,
minor isomer), 2.09 (s, 3 H, major isomer), 1.23 (d, J ) 6.5
Hz, 3 H), 1.21 (t, J ) 6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3,
mixture of isomers) δ 170.9, 138.5, 128.4, 127.8, 127.6, 127.6,
98.4, 97.5, 75.2, 75.0, 71.8, 71.7, 65.7, 21.2, 15.1, 14.7; MS
(HRCI-isobutane) calcd for C12H17O2 (M - C2H3O2) 192.1150,
found 192.1158. Anal. Calcd for C14H20O4: C, 66.65; H, 7.99.
Found: C, 67.02; H, 7.68.
(M
C
+ Na) 383.2410, found 383.2426. Anal. Calcd for
19H34O6: C, 63.66; H, 9.56. Found: C, 63.51; H, 10.00.
Gen er a l P r oced u r e for th e DIBALH Red u ctive Acety-
la tion of Diester s. The diester (1.0 mmol) was dissolved in
dichloromethane (12 mL). Upon cooling to -78 °C, DIBALH
(1 M in hexanes, 4.0 mL, 4.0 mmol, 4.0 equiv) was added
dropwise via syringe. After 45 min, the reaction was treated
sequentially with pyridine (486 µL, 6.0 mmol, 6.0 equiv)
dropwise via syringe, a solution of DMAP (488 mg, 4.0 mmol,
4.0 equiv) in dichloromethane (6 mL) dropwise via cannula,
and acetic anhydride (1.13 mL, 12.0 mmol, 12.0 equiv) drop-
wise via syringe. The mixture was stirred at -78 °C for 12-
14 h, warmed to 0 °C, and stirred for an additional 30 min,
and then the reaction was quenched at 0 °C with saturated
aqueous ammonium chloride (20 mL) and saturated aqueous
sodium potassium tartrate (15 mL). The resulting mixture was
warmed to room temperature and stirred vigorously for 30 min
or until layer separation was complete. After extraction with
dichloromethane (×4), the combined dichloromethane extracts
were washed with ice-cooled 1 M sodium bisulfate (×2),
saturated aqueous sodium bicarbonate (×3), and brine (×1).
After drying (anhydrous sodium sulfate) and evaporation of
dichloromethane, the residue was purified by flash column
chromatography on silica gel previously deactivated with 2%
triethylamine/hexanes.
1,3-Dia cetoxy-1,3-d ieth oxyp r op a n e (27). According to
the general procedure for the preparation of bis-R-acetoxy
ethers described above, diester 26 (160 mg, 1.00 mmol) gave
a yellow oil that was purified by chromatography on deacti-
vated silica gel (15% ethyl ether/hexanes) to give a mixture of
187 mg (75%, 0.75 mmol) of 27 and 7 mg (3%, 0.03 mmol) of
the corresponding mono-R-acetoxy ether as a yellow oil. 1H
NMR analysis indicated that 27 was isolated as a 1.9:1 mixture
of diastereomers. Data for pure 27: IR (mixture of isomers,
neat) 1739, 1233 cm-1; 1H NMR (400 MHz, CDCl3, mixture of
isomers) δ 5.94 (t, J ) 5.9 Hz, 2 H, minor isomer), 5.90 (t, J )
5.8 Hz, 2 H, major isomer), 3.67-3.77 (m, 2 H), 3.49-3.59 (m,
2 H), 2.09 (s, 6 H, major isomer), 2.07 (s, 6 H, minor isomer),
2.04-2.18 (m, 2 H), 1.20 (t, J ) 7.0 Hz, 6 H, minor isomer),
1.18 (t, J ) 7.0 Hz, 6 H, major isomer); 13C NMR (100 MHz,
CDCl3, mixture of isomers) δ 170.6, 94.8, 94.7, 65.2, 65.0, 39.7,
39.3, 21.1, 15.0, 14.9. Anal. Calcd for C11H20O6: C, 53.22; H,
8.12. Found: C, 53.25; H, 7.93.
P r ep a r a tion of Eth er s. Gen er a l P r oced u r e for th e
Syn th esis of Eth er s fr om r-Acetoxy Eth er s. The R-acetoxy
ether (1.0 mmol) was dissolved in dichloromethane (20 mL).
Upon cooling to -78 °C, triethylsilane (400 µL, 2.5 mmol, 2.5
equiv) was added via syringe. Boron trifluoride etherate (317
µL, 2.5 mmol, 2.5 equiv) was then added dropwise via syringe.
The reaction was stirred at -78 °C until complete by TLC
analysis (<30 min) and then was partitioned between pentane
(60 mL) and saturated aqueous sodium bicarbonate (60 mL).
The aqueous layer was extracted with additional pentane (×1).
The combined pentane extracts were dried (anhydrous sodium
sulfate). After evaporation of solvent, the residue was purified
by flash column chromatography on silica gel or by Kugelrohr
distillation.
1-(2,2-Dim eth ylp r op yl)-1-(2,2-d im eth ylp r op yl) Eth er
(41). According to the general procedure for the preparation
of ethers described above, R-acetoxy ether 11 (890 mg, 4.11
mmol) gave a light yellow oil that was purified by Kugelrohr
distillation (760 mmHg) to give 645 mg (99%, 4.07 mmol) of
41 as a clear oil: bp 135-137 °C. All spectral data for
compound 41 were identical to data reported previously.11c
1-(3-P h en ylp r op yl)-1-p en tyl Eth er (42). According to the
general procedure for the preparation of ethers described
above, R-acetoxy ether 13 (30.1 mg, 0.114 mmol) gave a light
yellow oil that was purified by chromatography (2% ethyl
ether/hexanes) to give 22.2 mg (95%, 0.108 mmol) of 42 as a
light yellow oil: IR (neat) 1114 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.25-7.31 (m, 2 H), 7.15-7.22 (m, 3 H), 3.42 (t, J )
6.4 Hz, 2 H), 3.40 (t, J ) 6.6 Hz, 2 H), 2.70 (t, J ) 7.5 Hz, 2
H), 1.85-1.94 (m, 2 H), 1.53-1.64 (m, 2 H), 1.29-1.39 (m, 4
H), 0.91 (t, J ) 7.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
142.1, 128.5, 128.3, 125.7, 71.0, 69.9, 32.4, 31.3, 29.5, 28.4, 22.5,
14.0; MS (HRCI-isobutane) calcd for C14H23O (M + H) 207.1749,
found 207.1741. Anal. Calcd for C14H22O: C, 81.49; H, 10.75.
Found: C, 81.69; H, 10.88.
1-(3-P h en ylp r op yl)-1-(1,1-d im et h ylet h yl) E t h er (43).
According to the general procedure for the preparation of
ethers described above, R-acetoxy ether 19 (136 mg, 0.54 mmol)
gave a light yellow oil that was purified by chromatography
(2% ethyl ether/hexanes) to give 86 mg (83%, 0.45 mmol) of
43 as a colorless oil: IR (neat) 1197, 1085 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.29-7.36 (m, 2 H), 7.19-7.28 (m, 3 H), 3.41
(t, J ) 6.4 Hz, 2 H), 2.74 (t, J ) 7.5 Hz, 2 H), 1.87-1.95 (m, 2
H), 1.25 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ 142.4, 128.5,
128.3, 125.7, 72.6, 60.8, 32.6, 32.2, 27.7; MS (HRCI-isobutane)
calcd for C13H20O (M+) 192.1514, found 192.1519. Anal. Calcd
for C13H20O: C, 81.20; H, 10.48. Found: C, 81.33; H, 10.49.
Oxa cycloh exa d eca n e (44). According to the general pro-
cedure for the preparation of ethers described above, R-acetoxy
ether 25 (136 mg, 0.54 mmol) gave a light yellow oil that was
purified by chromatography (2% ethyl ether/hexanes) to give
86 mg (83%, 0.45 mmol) of 44 as a colorless oil: IR (neat) 1120
1,4-Dia cetoxy-1,4-d ieth oxybu ta n e (29). According to the
general procedure for the preparation of bis-R-acetoxy ethers
described above, diester 28 (49.4 mg, 0.284 mmol) gave a
yellow oil that was purified by chromatography on deactivated
silica gel (10% ethyl acetate/hexanes) to give 44.3 mg (60%,
1
0.169 mmol) of 29 as a yellow oil. H NMR analysis indicated
that 29 was isolated as a 1.1:1 mixture of diastereomers: IR
(mixture of isomers, neat) 1738, 1239 cm-1; 1H NMR (500 MHz,
CDCl3, mixture of isomers) δ 5.85 (br m, 2 H), 3.66-3.76 (m,
2 H), 3.50-3.58 (m, 2 H), 2.08 (s, 6 H, minor isomer), 2.07 (s,
6 H, major isomer), 1.72-1.83 (m, 4 H), 1.95 (t, J ) 7.0 Hz, 6
H, minor isomer), 1.95 (t, J ) 7.0 Hz, 6 H, major isomer); 13
C
cm-1; H NMR (400 MHz, CDCl3) δ 3.42 (t, J ) 5.5 Hz, 4 H),
1
NMR (125 MHz, CDCl3, mixture of isomers) δ 170.9, 97.8, 97.7,
1.50-1.60 (m, 4 H), 1.39-1.49 (m, 4 H), 1.29-1.38 (m, 18 H);
13C NMR (100 MHz, CDCl3) δ 69.9, 29.4, 27.3, 27.1, 26.5, 26.2,
26.2, 25.3; MS (HRCI-isobutane) calcd for C15H31O (M + H)
227.2375, found 227.2365. Anal. Calcd for C15H30O: C, 79.58;
H, 13.36. Found: C, 79.73; H, 13.12.
65.0, 29.1, 29.1, 21.2, 15.0; MS (HRCI-isobutane) calcd for
C
10H19O4 (M - C2H3O2) 203.1283, found 203.1282. Anal. Calcd
for C12H22O6: C, 54.95; H, 8.45. Found: C, 54.82; H, 8.30.
1-(1-Acetoxy-2,2-d im eth ylp r op yloxy)-3-(1-a cetoxy-2,2-
d im eth ylp r op yloxy)-2,2-d im eth ylp r op a n e (31). According
to the general procedure for the preparation of bis-R-acetoxy
ethers described above, diester 30 (300 mg, 1.10 mmol) gave
a light yellow oil that was purified by chromatography on
deactivated silica gel (7% ethyl acetate/hexanes) to give 261
mg (66%, 0.72 mmol) of 31 as a colorless oil. 1H NMR analysis
1-(2,2-Dim eth ylp r op yloxy)-3-(2,2-d im eth ylp r op yloxy)-
2,2-d im eth ylp r op a n e (45). Bis-R-acetoxy ether 31 (95 mg,
0.26 mmol) was dissolved in dichloromethane (8 mL). Upon
cooling to -78 °C, triethylsilane (211 µL, 1.32 mmol, 5.0 equiv)
was added via syringe. Boron trifluoride etherate (167 µL, 1.32
mmol, 5.0 equiv) was then added dropwise via syringe. The

198 J . Org. Chem., Vol. 65, No. 1, 2000
Kopecky and Rychnovsky
mixture was stirred at -78 °C for 25 min, and then was
partitioned between pentane (35 mL) and saturated aqueous
sodium bicarbonate (35 mL). The aqueous layer was extracted
with additional pentane (x1). The combined pentane extracts
were dried (anhydrous sodium sulfate). Evaporation of solvent
gave a colorless oil which was purified by flash column
chromatography on silica gel (1% ethyl ether/pentane) to give
62 mg (96%, 0.25 mmol) of 45 as a colorless oil: IR (neat) 1116
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.15 (s, 4 H), 3.01 (s, 4 H),
0.89 (s, 18 H), 0.89 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ
81.7, 77.3, 36.8, 32.3, 26.8, 22.2; MS (HRCI-isobutane) calcd
for C15H33O2 (M + H) 245.2480, found 245.2486. Anal. Calcd
for C15H32O2: C, 73.71; H, 13.20. Found: C, 73.85; H, 12.97.
1-(2S)-(2-Ben zyloxyp r op yl)-1-et h yl E t h er (46). R-Ace-
toxy ether 33 (104 mg, 0.41 mmol) was dissolved in dichlo-
romethane (11.5 mL). Upon cooling to -78 °C, triethylsilane
(164 µL, 1.03 mmol, 2.5 equiv) was added via syringe. Boron
trifluoride etherate (130 µL, 1.03 mmol, 2.5 equiv) was then
added dropwise via syringe. The mixture was warmed to 0 °C
and stirred for 20 min, and then was partitioned between
pentane (60 mL) and saturated aqueous sodium bicarbonate
(60 mL). The aqueous layer was extracted with additional
pentane (×1). The combined pentane extracts were dried
(anhydrous sodium sulfate). Evaporation of solvent gave a light
yellow oil that was purified by flash column chromatography
on silica gel (15% ethyl ether/hexanes) to give 80 mg (100%,
0.41 mmol) of 46 as a light yellow oil. Hydrogenolysis of 46
(H2, 10% Pd/C, MeOH, room temperature) followed by com-
1
parative H NMR analysis of the (R)- and (S)-Mosher esters13
of the resultant alcohol indicated that 46 was isolated with
an enantiomeric excess of 68%. Data for 46: IR (neat) 1116
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.24-7.39 (m, 5 H), 4.63
(s, 2 H), 3.68-3.76 (m, 1 H), 3.49-3.56 (m, 3 H), 3.40 (dd, J )
10.1 Hz, 4.7 Hz, 1 H), 1.22 (t, J ) 7.0 Hz, 3 H), 1.21 (d J ) 6.3
Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 139.0, 128.3, 127.6,
127.4, 74.7, 74.0, 71.1, 66.7, 17.4, 15.3; MS (HRCI-isobutane)
calcd for C12H18O2 (M+) 194.1307, found 194.1299. Anal. Calcd
for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.03; H, 9.14.
Ack n ow led gm en t. Support has been provided by
the National Cancer Institute (CA-81635) and the
University of California, Irvine. We are grateful to
Alexandre J . Buckmelter for early work on the reductive
acetylation of compound 34.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details and procedures for the preparation of the ester
substrates are reported. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O9914521