An efficient strategy for the synthesis of α,α'-cis and trans- disubstituted medium ring ethers

Article abstract of DOI:10.1055/s-2000-6268

An asymmetric alkylation-ring-closing metathesis strategy was developed for the construction of α,α'-disubstituted medium ring ethers. The approach features an asymmetric alkylation of highly functionalized α-alkoxy acyl oxazolidinones followed by ring closure effected by Grubbs' ruthenium catalyst. The relationship between diene conformation and the rate of ring- closure was examined.

Full text of DOI:10.1055/s-2000-6268

SPECIAL TOPIC
899
An Efficient Strategy for the Synthesis of a,a’-cis and trans-Disubstituted
Medium Ring Ethers
Michael T. Crimmins,* Kyle A. Emmitte
Venable and Kenan Laboratories of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA
Fax +1(919)9622388; E-mail: crimmins@email.unc.edu
Received 23 March 2000
Abstract: An asymmetric alkylation-ring-closing metathesis strat-
egy was developed for the construction of a,a’-disubstituted medi-
um ring ethers. The approach features an asymmetric alkylation of
highly functionalized a-alkoxy acyl oxazolidinones followed by
ring closure effected by Grubbs’ ruthenium catalyst. The relation-
ship between diene conformation and the rate of ring-closure was
examined.
Key words: asymmetric-alkylation, ring-closing metathesis, ma-
rine natural products, gauche effect, cyclic ethers, ruthenium
Medium ring ethers are a common structural feature of
many ladder ether marine toxins, as well as simpler me-
tabolites from Laurencia species. This diverse collection
of natural products often contains seven, eight, and nine
membered ring ethers.1 The challenge of efficient con-
struction of medium ring ethers has led to the develop-
ment of numerous strategies for their synthesis.2-5 The
Figure 1 Some naturally occurring a,a’-trans-disubstituted
medium ring ethers
vast majority of these approaches have focused on the
a,a’-cis-disubstitution pattern rather than a,a’-trans-di-
substituted medium ring ethers, despite their similar fre-
quency of occurrence. trans-Isoprelaurefucin (1),6 isolau-
refucin methyl ether (2),7 chlorofucin (3),8 bromofucin
1. NaN(SiMe3)2
(4),9 isolaureatin (5),10 and obtusenyne (6),8 for example,
Bn
BnO
I
XC
all contain a,a’-trans-disubstituted medium ring ethers
(Figure 1). Murai’s synthesis of obtusenyne (6)11 and our
own recent syntheses of prelaureatin and laurallene12 con-
stitute the only known syntheses of medium ring ether
natural products with the a,a’-trans-disubstitution ar-
rangement. The investigation of a versatile, general strat-
egy for the synthesis of both a,a’-cis and a,a’-trans-
disubstituted medium ring ethers is described here.
O
BnO
N
O
2. L4Ru=CHPh
H
O
O
H
H
8
O
O
7
Br
O
H
10 steps
OAc
H
(+)-laurencin 9
We recently published a total synthesis of the marine nat-
ural product (+)-laurencin (9), in which the key steps were
an asymmetric alkylation of the sodium enolate of substi-
tuted acyl oxazolidinone 7, followed by ring-closing met-
athesis of the resultant diene to give cyclic ether 8
(Scheme 1).2 Previous work in our laboratory has demon-
strated that an asymmetric aldol-ring-closing metathesis
strategy for the assembly of medium ring ethers was
equally adaptable to both the a,a’-cis and a,a’-trans-di-
substituted medium ring ethers.3,12 The asymmetric alky-
lation-ring-closing metathesis approach to cyclic ethers
also offered the potential for a similar adaptable strategy.
Scheme 1
constraints. For example diene 10, required for formation
of the a,a’-cis-disubstituted eight-membered ring, has a
low-energy conformation 10a which orients the oxygen
substituents gauche, positions the olefinic chains proxi-
mal, and allows the other two side chains to occupy pseu-
do-equatorial orientations (Figure 2). Significant rate
increases in ring-closing metathesis result, in comparison
to examples without vicinal oxygen substitution, thus al-
lowing for ring-closure without dimerization. For in-
stance, formation of oxocene 8 proceeds in 94% yield in
three hours with only 5 mole percent of Grubbs’ rutheni-
um catalyst ([(C6H11)3P]2Cl2Ru=CHPh).2 Diene 11, re-
We have found that by exploiting the known gauche effect
of 1,2-dioxygen substitution, medium ring-closure can be
accomplished without the use of cyclic conformational
Synthesis 2000, No. 6, 899–903 ISSN 0039-7881 © Thieme Stuttgart · New York

900
M. T. Crimmins, K. A. Emmitte
SPECIAL TOPIC
quired for formation of the a,a’-trans-disubstituted eight-
membered ring, also has a low-energy conformation 11a
with the oxygens gauche and the olefinic chains proximal;
however, one of the other two side chains must occupy a
pseudo-axial position for ring-closure to occur. The con-
formation 11b that positions both the ethyl and allyl
groups in pseudo-equatorial orientations should be more
favorable and result in a slower rate of ring-closure than
observed for 10.
H
H
H
H
Allyl
H
Et
Et
OAlkyl
OBn
O
BnO
R
O
OBn
R
H
H
10a
10
H
H
R
H
Et
O
O
OBn
H
11a
11b
H
Allyl
H
H
Et
OAlkyl
BnO
R
O
OBn
H
H
Figure 3 Low energy conformations of dienes 12 and 13 favoring
ring closure
H
Et
11
R
OBn
an 88% yield of cyclic ether 17 was isolated along with
11% of recovered diene 16. The metathesis rate for diene
16 was considerably slower than the rate of the diene to
produce the corresponding a,a’-cis-disubstituted eight-
membered ring system. The conformation of diene 16
which positions the olefinic chains favorably for ring-clo-
sure is destabilized somewhat by the pseudo-axial side
chain, slowing the metathesis. Nonetheless, it was demon-
strated that the desired a,a’-trans-disubstituted eight-
membered ring system could effectively be prepared uti-
lizing an asymmetric alkylation-ring-closing metathesis
approach.
Figure 2 Low energy conformations of dienes 10 and 11 favoring
ring closure
Diene 12, required for formation of the a,a’-trans-disub-
stituted seven-membered ring, has a low-energy confor-
mation 12a with the olefinic chains oriented in opposite
directions (Figure 3). For ring-closure to occur, one side
chain must be oriented in a pseudo-axial fashion, as is il-
lustrated in conformation 12b. Diene 13, required for for-
mation of the a,a’-cis-disubstituted seven-membered
ring, has two conformations of similar energy, 13a and
13b with psuedo-equatorial side-chains, one of which fa-
vors ring-closure. We set out to determine if the outlined
conformational effects would influence the rate of the
ring-closing metathesis reaction, particularly for the a,a’-
trans-disubstituted ethers.13
PivCl, NEt3
THF, Et2O
-78 to 0 °C
O
CO2H
Bn
BnO
Bn
O
N
78%
O
OBn
H
LiN
O
O
O
14
15
Our first target was the a,a’-trans-disubstituted eight-
membered ring 17 that comprises the oxocene core of iso-
laurefucin methyl ether (2), chlorofucin (3), and bromofu-
cin (4). Synthesis of D-4-oxocene 17 began with acid 14,
which was previously prepared for our (+)-laurencin syn-
thesis (Scheme 2).2 By attaching the antipode of the aux-
iliary used in the laurencin synthesis, the a,a’-trans cyclic
ether might be accessible. Treatment of the mixed pivalic
anhydride with lithiated (R)-(-)-4-benzyl-2-oxazolidino-
ne provided acyl oxazolidinone 15 in 78% yield. The so-
dium enolate of 15 was treated with excess allyl iodide at
-45 ºC to give 71% yield of diene 16. Upon exposure to
standard ring-closing metathesis conditions (5 mol% of
[(C6H11)3P]2Cl2Ru=CHPh, 0.005 M, CH2Cl2, 40 ºC, 8 h),
THF, PhMe
-78 to -45 °C
71%
NaN(SiMe3)2
I
O
Bn
Bn
5 mol %
L4Ru=CHPh
O
O
N
N
BnO
BnO
CH2Cl2, 40 °C
8 hours
88% (11% sm)
O
O
H
H
O
O
O
O
H
H
17
16
Scheme 2
Synthesis 2000, No. 6, 899–903 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
a,a’-cis and trans-Disubstituted Medium Ring Ethers
901
We next turned our attention to the a,a’-disubstituted sev-
en-membered ring systems which represent the core of
natural products such as trans-isoprelaurefucin (1). For
this synthesis, we began with the known chiral alcohol 18
(Scheme 3).14 The mixed pivalic anhydride of acid 19 was
treated separately with both antipodes of lithiated 4-ben-
zyl-2-oxazolidinone yielding acyl oxazolidinones 20 and
21. The sodium enolate of each acyl oxazolidinone was
treated with excess allyl iodide at -45 ºC to provide
dienes 22 and 23. In the case of diene 22, exposure to the
identical ring-closing metathesis conditions (5 mol% of
[(C6H11)3P]2Cl2Ru=CHPh, 0.005 M, CH2Cl2, 40 ºC, 8 h)
used for diene 16 gave a 49% yield of cyclic ether 24
along with 34% of recovered diene 22. In diene 22 the ap-
parent preference for the olefinic chains to orient in oppo-
site directions due to the destabilization of the
conformation with a pseudo-axial side chain has a pro-
found effect on the rate of ring-closure. The rate of ring
closure for this seven-membered ring is significantly
slower than any other examples of seven, eight, or nine-
membered ring formation in which there is a low-energy
gauche conformation with the olefinic chains proxi-
mal.2,3,12 Although the reaction was quite slow, the overall
yield of the desired product could be increased to >70%
after two recycles. In contrast, diene 23 underwent rapid
ring-closure (5 mol% of [(C6H11)3P]2Cl2Ru=CHPh, 0.005
M, CH2Cl2, 40 ºC, 2 h) to form cyclic ether 25 in 98%
yield in only two hours. This sequence clearly demon-
strates the importance of diene conformation on the rate of
the ring-closing metathesis reaction for cyclic ether for-
mation.
Bn
O
N
O
H
O
O
H
24
BnO
CH2Cl2
40 °C
49% (34% sm)
5 mol %
L4Ru=CHPh
8 hours
Bn
Bn
O
NaN(SiMe3)2
O
O
N
N
I
O
THF, PhMe
H
O
H
O
H
20
Bn
O
BnO
O
-78 to -45 °C
75%
22
BnO
PivCl, NEt3
THF, Et2O
-78 to 0 °C
70%
LiN
O
O
OBn
OBn
NaH, BrCH2CO2H
THF
O
CO2H
Bn
81%
OH
19
18
PivCl, NEt3
THF, Et2O
-78 to 0 °C
75%
LiN
O
O
Bn
Bn
NaN(SiMe3)2
O
N
O
N
I
O
THF, PhMe
O
O
H
H
O
H
-78 to -45 °C
BnO
O
O
23
21
BnO
70%
CH2Cl2
40 °C
98%
5 mol %
L4Ru=CHPh
2 hours
In conclusion, we have demonstrated that an asymmetric
alkylation-ring-closing metathesis strategy is effective for
the construction of both a,a’-cis and a,a’-trans-disubsti-
tuted medium-ring ethers. We have also shown that the
role of diene conformation with respect to the rate of ring-
closure is significant. These studies bode well for the syn-
thesis of marine natural products such as trans-isoprelau-
refucin (1), isolaurefucin methyl ether (2), chlorofucin
(3), and bromofucin (4), having already accessed the cy-
clic cores of these compounds. Current efforts are focused
on the expansion of this strategy to the synthesis of these
and other medium-ring ether containing natural products.
Bn
O
N
O
H
O
O
H
BnO
25
Scheme 3
(4R)-4-Benzyl-3-[2-((1R, 2R)-2-benzyloxy-1-ethylpent-4-en-
yloxy)acetyl]oxazolidin-2-one (15); Typical Procedure
To a solution of carboxylic acid 14 (3.98 g, 14.30 mmol) in Et2O (60
mL) was added Et3N (2.20 mL, 15.78 mmol) via a syringe, and the
mixture was cooled to -78 ºC. Pivaloyl chloride (1.80 mL, 14.61
mmol) was added dropwise via a syringe. After 5 min, the mixture
was warmed to 0 ºC, where it was stirred for 1 h and subsequently
recooled to -78 ºC. In a separate flask, (R)-(+)-4-benzyl-2-oxazoli-
dinone (2.54 g, 14.33 mmol) was dissolved in THF (25 mL) and
cooled to -78 ºC. BuLi (1.6 M in hexanes, 9.40 mL, 15.04 mmol)
was added dropwise via a syringe, and the mixture was stirred for
15 min. The lithiated oxazolidinone was added via a cannula to the
mixed anhydride, and the mixture stirred for an additional 10 min
before being warmed to 0 ºC, where stirring continued for 1 h. The
reaction was quenched by the addition of H2O and extracted twice
with EtOAc. The combined organic layers were washed with brine
and dried (Na2SO4). Concentration in vacuo and purification by
flash chromatography gave 4.87 g (78%) of acyl oxazolidinone 15;
[a]D25 -69.0 (c = 0.58, CH2Cl2).
IR spectra were obtained using a Perkin-Elmer 283 infrared spec-
trometer. 1H and 13C NMR spectra were recorded on a Bruker model
DRX 400 (1H at 400 MHz; 13C at 100 MHz). Optical rotations were
measured using a Perkin-Elmer 241 polarimeter. TLC was conduct-
ed on silica gel F254 TLC plates purchased from Scientific Adsor-
bents, Inc. Flash chromatography was carried out using silica gel
(32 to 63mm) purchased from Scientific Adsorbents, Inc. Et2O,
THF, and CH2Cl2 were dried by passing through a column of neutral
alumina under N2 immediately prior to use. Alkylamines were dis-
tilled from CaH2 immediately prior to use. All air and water sensi-
tive reactions were performed in flasks flame dried under a positive
flow of nitrogen and conducted under N2.
IR (film): n = 2925, 1780, 1720, 1390, 1260, 1130 cm-1.
Synthesis 2000, No. 6, 899–903 ISSN 0039-7881 © Thieme Stuttgart · New York

902
M. T. Crimmins, K. A. Emmitte
SPECIAL TOPIC
1H NMR (400 MHz, CDCl3): d = 7.37-7.13 (m, 10 H), 5.89 (ddt, 1
H, J = 17.2, 10.0, 7.0 Hz), 5.16-5.02 (m, 2 H), 4.81 (AB, 2 H,
JAB = 17.6 Hz, DnAB = 31.6 Hz), 4.60 (AB, 2 H, JAB = 11.8 Hz,
(4S)-4-Benzyl-3-{2-[(1R)-1-((1R)-1-benzyloxypropyl)but-3-en-
yloxy]acetyl}oxazolidin-2-one (20)
[a]D26 +42.9 (c = 0.79, CH2Cl2).
DnAB = 51.4 Hz), 4.40 (m, 1 H), 4.08 (dd, 1 H, J = 8.8, 2.8 Hz), 3.98
(dd, 1 H, J = 8.8, 8.8 Hz), 3.59 (m, 1 H), 3.39 (m, 1 H), 3.25 (dd, 1
H, J = 13.6, 3.2 Hz), 2.71 (dd, 1 H, J = 13.6, 9.6 Hz), 2.51 (m, 1 H),
2.27 (m, 1 H), 1.69 (m, 1 H), 1.55 (m, 1 H), 0.98 (t, 3 H, J = 7.4 Hz).
13C NMR (100 MHz, CDCl3): d = 10.2, 23.3, 34.5, 37.7, 54.6, 67.0,
71.4, 71.9, 80.9, 84.0, 117.1, 127.22, 127.24, 127.3, 128.2, 128.9,
129.4, 134.8, 135.1, 139.0, 153.3, 170.4.
IR (film): n = 2940, 1780, 1720, 1395, 1260, 1220 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.39-7.13 (m, 10 H), 5.94 (ddt, 1
H, J = 17.2, 10.0, 3.2 Hz), 5.15-5.02 (m, 2 H), 4.82 (s, 2 H), 4.63
(m, 1 H), 4.62 (AB, 2 H, JAB = 10.0 Hz, DnAB = 19.6 Hz), 4.21 (dd,
1 H, J = 8.4, 8.4 Hz), 4.17 (dd, 1 H, J = 9.2, 3.2 Hz), 3.57 (m, 1 H),
3.49 (m, 1 H), 3.27 (dd, 1 H, J = 13.2, 3.2 Hz), 2.80 (dd, 1 H,
J = 13.2, 9.6 Hz), 2.48 (m, 1 H), 2.33 (dt, 1 H, J = 14.4, 7.4 Hz),
1.72 (m, 1 H), 1.51 (m, 1 H), 0.97 (t, 3 H, J = 7.4 Hz).
(4R)-4-Benzyl-3-[(2S)-2-((1R, 2R)-2-benzyloxy-1-ethylpent-4-
enyloxy)pent-4-enoyl]oxazolidin-2-one (16); Typical Procedure
Into a flask fitted with a low-temperature thermometer was added
sodium bis(trimethylsilyl)amide (0.75 M in toluene/THF, 36.0 mL,
27.00 mmol). THF (20 mL) was added and the flask was cooled to
-78 ºC. Acyl oxazolidinone 15 (5.85 g, 13.37 mmol) in THF (35
mL) was added via a cannula at a rate to maintain the reaction tem-
perature below -60 ºC. After stirring for 30 min at -78 ºC, allyl io-
dide (6.10 mL, 66.71 mmol) was added via a syringe. After 10 min
the reaction was warmed to -45 ºC and stirred at that temperature
for 45 min. The reaction was quenched by the addition of aq sat.
NH4Cl and warmed to r.t. The solution was extracted twice with
Et2O. The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. Purification by flash chroma-
tography provided 4.50 g (71%) of diene 16; [a]D26 -102.4
(c = 0.84, CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 10.1, 22.8, 35.0, 37.7, 54.8, 67.1,
70.6, 72.7, 81.6, 82.0, 117.0, 127.4, 127.5, 127.8, 128.3, 129.0,
129.4, 135.0, 135.2, 138.8, 153.3, 170.4.
(4R)-4-Benzyl-3-{2-[(1R)-1-((1R)-1-benzyloxypropyl)but-3-
enyloxy]acetyl}oxazolidin-2-one (21)
[a]D26 -65.8 (c = 0.79, CH2Cl2).
IR (film): n = 2940, 1780, 1720, 1395, 1265, 1220 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.38-7.13 (m, 10 H), 5.93 (ddt,
1 H, J = 17.2, 10.0, 7.2 Hz), 5.15-5.03 (m, 2 H), 4.81 (AB, 2 H,
JAB = 18.0 Hz, DnAB = 21.2 Hz), 4.60 (AB, 2 H, JAB = 11.6 Hz,
DnAB = 14.4 Hz), 4.47 (m, 1 H), 4.11 (dd, 1 H, J = 9.2, 2.8 Hz), 4.04
(dd, 1 H, J = 8.6, 8.6 Hz), 3.57 (m, 1 H), 3.50 (m, 1 H), 3.26 (dd, 1
H, J = 13.6, 3.2 Hz), 2.73 (dd, 1 H, J = 13.6, 9.6 Hz), 2.46 (m, 1 H),
2.32 (dt, 1 H, J = 14.4, 7.6 Hz), 1.75 (m, 1 H), 1.51 (m, 1 H), 0.96
(t, 3 H, J = 7.4 Hz).
IR (film): n = 2920, 1780, 1710, 1390, 1210, 1105 cm-1.
13C NMR (100 MHz, CDCl3): d = 9.7, 22.7, 35.1, 37.7, 54.7, 67.0,
71.1, 72.3, 81.9, 82.3, 116.9, 127.3, 127.4, 128.2, 128.9, 129.4,
135.0, 135.2, 139.0, 153.3, 170.3.
1H NMR (400 MHz, CDCl3): d = 7.34-7.06 (m, 10 H), 5.97-5.80
(m, 2 H), 5.32 (dd, 1 H, J = 6.4, 4.8 Hz), 5.14-5.01 (m, 4 H), 4.49
(AB, 2 H, JAB = 12.6 Hz, DnAB = 80.2 Hz), 4.04 (m, 1 H), 3.78 (dd,
1 H, J = 9.0, 3.4 Hz), 3.50 (dt, 1 H, J = 7.6, 4.4 Hz), 3.38 (m, 1 H),
3.15 (dd, 1 H, J = 8.6, 8.6 Hz), 3.12 (dd, 1 H, J = 13.6, 3.2 Hz),
2.56-2.39 (m, 4 H), 2.17 (m, 1 H), 1.64 (m, 1 H), 1.48 (m, 1 H), 1.01
(t, 3 H, J = 7.4 Hz).
13C NMR (100 MHz, CDCl3): d = 10.6, 23.9, 33.8, 38.0, 38.5, 54.6,
66.2, 69.9, 79.4, 81.7, 84.6, 117.2, 118.1, 125.9, 126.9, 127.2,
128.3, 128.8, 129.3, 133.4, 134.1, 135.3, 139.4, 153.0, 172.3.
(4S)-4-Benzyl-3-{(2R)-2-[(1R)-1-((1R)-1-benzyloxypropyl)but-
3-enyloxy]pent-4-enoyl}oxazolidin-2-one (22)
[a]D26 +61.3 (c = 0.65, CH2Cl2).
IR (film): n = 2925, 1780, 1715, 1390, 1215, 1105 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.39-7.16 (m, 10 H), 6.02-5.82
(m, 2 H), 5.28 (dd, 1 H, J = 7.2, 4.8 Hz), 5.17-4.98 (m, 4 H), 4.65
(m, 1 H), 4.54 (AB, 2 H, JAB = 11.6 Hz, DnAB = 13.6 Hz), 4.18-4.08
(m, 2 H), 3.47 (dt, 1 H, J = 7.6, 4.4 Hz), 3.38 (dt, 1 H, J = 8.4, 4.0
Hz), 3.25 (dd, 1 H, J = 13.2, 3.2 Hz), 2.65 (dd, 1 H, J = 13.2, 10.0
Hz), 2.57-2.40 (m, 3 H), 2.25 (m, 1 H), 1.70 (m, 1 H), 1.47 (m, 1
H), 0.93 (t, 3 H, J = 7.4 Hz).
(4R)-4-Benzyl-3-[(2S, 7R, 8R)-7-benzyloxy-8-ethyl-3,6,7,8-
tetrahydro-2H-oxocine-2-carbonyl]oxazolidin-2-one (17);
Typical Procedure
Into a flask equipped with a reflux condenser was added diene 16
(0.326 g, 0.683 mmol) in CH2Cl2 (137 mL). N2 was bubbled
through the stirring solution for 20 min. The solution was heated to
reflux and (Cy3P)2Cl2Ru=CHPh (0.028 g, 0.034 mmol) was added
in one portion. The mixture was stirred at 40 ºC for 8 h and cooled
to r.t. The mixture was then stirred open to air overnight and con-
centrated in vacuo. Purification by flash chromatography provided
0.037 g (11%) of recovered diene 16 and 0.270 g (88%) of oxocene
17; [a]D24 -166.4 (c = 0.55, CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 10.4, 22.3, 34.9, 38.01, 38.03,
55.1, 66.7, 72.5, 76.6, 80.4, 81.4, 116.4, 118.3, 127.4, 127.5, 127.9,
128.3, 129.0, 129.4, 133.3, 135.1, 135.9, 138.8, 153.2, 172.7.
(4R)-4-Benzyl-3-{(2S)-2-[(1R)-1-((1R)-1-benzyloxypropyl)but-
3-enyloxy]pent-4-enoyl}oxazolidin-2-one (23)
[a]D26 -92.7 (c = 0.82, CH2Cl2).
IR (film): n = 2930, 1780, 1715, 1390, 1215, 1110 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.31-7.02 (m, 10 H), 5.89 (m, 2
H), 5.28 (dd, 1 H, J = 6.4, 4.8 Hz), 5.10-4.98 (m, 4 H), 4.45 (AB, 2
H, JAB = 12.2 Hz, DnAB = 43.2 Hz), 4.08 (m, 1 H), 3.80 (dd, 1 H,
J = 9.2, 3.2 Hz), 3.49 (m, 1 H), 3.42 (m, 1 H), 3.31 (dd, 1 H, J = 8.6,
8.6 Hz), 3.11 (dd, 1 H, J = 13.4, 3.2 Hz), 2.52-2.28 (m, 4 H), 2.21
(dt, 1 H, J = 14.4, 8.0 Hz), 1.72 (m, 1 H), 1.41 (m, 1 H), 0.88 (t, 3
H, J = 7.4 Hz).
13C NMR (100 MHz, CDCl3): d = 8.8, 21.8, 35.7, 38.0, 38.3, 54.7,
66.3, 70.4, 79.0, 82.3, 82.5, 116.9, 118.1, 126.3, 127.0, 127.2,
128.3, 128.8, 129.3, 133.4, 135.3, 135.5, 139.5, 153.0, 172.3.
IR (film): n = 2925, 1780, 1700, 1390, 1195, 1070 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.38-7.16 (m, 10 H), 5.97-5.86
(m, 2 H), 5.45 (dd, 1 H, J = 11.2, 3.2 Hz), 4.65 (m, 1 H), 4.60 (AB,
2 H, JAB = 12.4 Hz, DnAB = 107.6 Hz), 4.21 (dd, 1 H, J = 8.2, 8.2
Hz), 4.16 (dd, 1 H, J = 9.2, 2.8 Hz), 4.04 (dd, 1 H, J = 7.0, 7.0 Hz),
3.59 (d, 1 H, J = 6.4 Hz), 3.22 (dd, 1 H, J = 13.4, 3.4 Hz), 2.78 (dd,
1 H, J = 13.4, 9.4), 2.69-2.59 (m, 2 H), 2.40 (m, 1 H), 2.21 (dd, 1
H, J = 14.0, 5.6 Hz), 1.74-1.65 (m, 2 H), 0.67 (t, 3 H, J = 7.4 Hz).
13C NMR (100 MHz, CDCl3): d = 10.3, 26.0, 28.8, 29.2, 37.8, 55.0,
66.4, 70.9, 73.8, 77.9, 79.1, 127.4, 127.7, 128.2, 128.4, 128.9,
129.4, 130.0, 135.0, 138.3, 152.6, 173.0.
(4S)-4-Benzyl-3-[(2R, 7R)-7-((1R)-1-benzyloxypropyl)-2,3,6,7-
tetrahydrooxepine-2-carbonyl]oxazolidin-2-one (24)
[a]D26 +55.1 (c = 0.69, CH2Cl2).
IR (film): n = 2940, 1780, 1710, 1390, 1210, 1110 cm-1.
Synthesis 2000, No. 6, 899–903 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
a,a’-cis and trans-Disubstituted Medium Ring Ethers
903
1H NMR (400 MHz, CDCl3): d = 7.38-7.13 (m, 10 H), 5.77-5.63
(m, 3 H), 4.66-4.50 (m, 4 H), 4.11 (dd, 1 H, J = 9.2, 3.2 Hz), 4.06
(dd, 1 H, J = 8.4, 8.4 Hz), 3.43 (dt, 1 H, J = 8.4, 4.2 Hz), 3.22 (dd,
1 H, J = 13.4, 3.4 Hz), 2.78 (m, 1 H), 2.75 (dd, 1 H, J = 13.4, 9.4
Hz), 2.53 (m, 1 H), 2.45 (m, 1 H), 2.28 (m, 1 H), 1.67 (m, 1 H), 1.50
(m, 1 H), 0.96 (t, 3 H, J = 7.4 Hz).
(b) Masamune, T.; Murase, H.; Matsue, H.; Murai, A. Bull.
Chem. Soc. Jpn. 1979, 52, 135.
(c) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T.
J. Am. Chem. Soc. 1995, 117, 5958.
(d) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J.
A. Synlett 1996, 983.
(e) Krüger, J.; Hoffman, R. W. J. Am. Chem. Soc. 1997, 119,
7499.
(f) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J.
A. J. Org. Chem. 1998, 63, 9728.
(g) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall,
J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483.
(h) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345.
(i) Kotsuki, H. Synlett 1992, 97.
(j) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988,
110, 2248.
13C NMR (100 MHz, CDCl3): d = 10.6, 22.4, 30.1, 30.8, 37.8, 55.0,
66.5, 72.5, 74.0, 74.5, 82.8, 125.2, 127.4, 127.7, 128.2, 128.9,
129.4, 129.6, 135.0, 139.0, 152.7, 172.5.
(4R)-4-Benzyl-3-[(2S, 7R)-7-((1R)-1-benzyloxypropyl)-2,3,6,7-
tetrahydrooxepine-2-carbonyl]oxazolidin-2-one (25)
[a]D26 -57.3 (c = 0.56, CH2Cl2).
IR (film): n = 2940, 1790, 1715, 1390, 1205, 1110 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.38-7.13 (m, 10 H), 5.92-5.78
(m, 2 H), 4.97 (dd, 1 H, J = 10.4, 1.6 Hz), 4.62 (m, 1 H), 4.61 (AB,
2 H, JAB = 11.6 Hz, DnAB = 55.6 Hz), 4.19-4.11 (m, 2 H), 3.73 (ddd,
1 H, J = 10.2, 4.6, 2.0 Hz), 3.33 (m, 1 H), 3.26 (dd, 1 H, J = 13.2,
3.2 Hz), 2.78 (dd, 1 H, J = 13.2, 9.6 Hz), 2.62 (m, 1 H), 2.51-2.25
(m, 3 H), 1.62 (m, 1 H), 1.43 (m, 1 H), 0.92 (t, 3 H, J = 7.4 Hz).
13C NMR (100 MHz, CDCl3): d = 10.6, 22.8, 31.5, 33.2, 37.8, 55.3,
66.5, 72.6, 77.7, 81.1, 82.8, 127.3, 127.4, 127.8, 128.0, 128.2,
129.0, 129.4, 130.6, 135.1, 139.1, 152.7, 170.6.
For examples of medium ring ether synthesis via RCM, see:
Clark, J. S.; Hamelin O. Angew. Chem. Int. Ed. 2000, 39, 372,
and references cited therein.
(6) Kurosawa, E.; Fukuzawa, A.; Irie, T. Tetrahedron Lett. 1973,
42, 4135.
(7) de Nys, R.; Coll, J. C.; Carroll, A. R.; Bowden, B. F. Aust. J.
Chem. 1993, 46, 1073.
(8) Howard, B. M.; Schulte, G. R.; Fenical, W. Tetrahedron.
1980, 36, 1747.
(9) Coll, J. C.; Wright, A. D. Aust. J. Chem. 1989, 42, 1685.
(10) Ishihara, J.; Kanoh, N.; Fukuzawa, A.; Murai, A. Chem. Lett.
1994, 1563.
(11) Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.;
Honma, T.; Murai, A. J. Org. Chem. 1999, 64, 2616.
(12) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122,
in press.
Acknowledgement
Financial support of our program by the NIH is acknowledged with
thanks. We also thank the Burroughs-Wellcome Foundation for a
fellowship for K.A.E.
For other isolated observations on diastereomer effects on
rates of RCM, see:
Linderman, R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H. J. Am.
Chem. Soc. 1997, 119, 6919.
References
(1) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155.
Faulkner, D. J. Nat. Prod. Rep. 1998, 15, 113.
Faulkner, D. J. Nat. Prod. Rep. 1997, 14, 259.
Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75, and earlier
reviews in the same series.
Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 127.
(14) Mulzer, J.; Angermann, A.; Münch, W. Liebigs. Ann. Chem.
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(2) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029.
(3) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
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(4) (a) Masamune, T.; Matsue, H.; Murase, H. Bull. Chem. Soc.
Jpn. 1979, 52, 127.
Article Identifier:
1437-210X,E;2000,0,06,0899,0903,ftx,en;C02700SS.pdf
Synthesis 2000, No. 6, 899–903 ISSN 0039-7881 © Thieme Stuttgart · New York