Alkene metathesis approach to β-unsubstituted anti -allylic alcohols and their use in ene-yne metathesis

Article abstract of DOI:10.1021/jo202398q

The synthesis of β-unsubstituted, anti-allylic alcohols using a catalytic Evans aldol reaction conjoined with a relay-type ring-closing alkene metathesis is reported. The metathesis step serves to remove a β-alkenyl group, which facilitated the aldol step

Full text of DOI:10.1021/jo202398q

Note
pubs.acs.org/joc
Alkene Metathesis Approach to β-Unsubstituted Anti-Allylic Alcohols
and Their Use in Ene−Yne Metathesis
Joseph R. Clark, Jonathan M. French, and Steven T. Diver*
Department of Chemistry, University at Buffalo, the State University of New York, Buffalo, New York 14260, United States
S
* Supporting Information
ABSTRACT: The synthesis of β-unsubstituted, anti-allylic
alcohols using a catalytic Evans aldol reaction conjoined with a
relay-type ring-closing alkene metathesis is reported. The
metathesis step serves to remove a β-alkenyl group, which
facilitated the aldol step. The β-substituted enals serve as
acrolein surrogates. The products were employed in ene−yne
cross metathesis.
β-substituent bearing a pendant terminal olefin could
undergo a subsequent ring-closing metathesis (RCM) reac-
tion which would replace CHR with a CH2 group by extrud-
ing a cyclic alkene. Recent work suggests that alkenes bearing
allylic chiral centers should be broadly applicable in cross
metathesis chemistry.3
symmetric carbon−carbon bond formations mediated by
A
chiral auxiliaries have made a significant impact in organic
synthesis. Evans initially reported the use of N-acyloxazolidi-
nones for syn-diastereoselective aldol reactions with dialkyl-
boron and chlorotitanium enolates with high yields and
diastereoselectivities (eq 1).1 More recently Evans reported a
The approach to β-unsubstituted anti-aldols is envisioned in
Scheme 1. Anti-selective aldol bond construction via generated
Scheme 1. Two-Step, anti-Aldol/RCM Approach
highly diastereoselective anti-aldol reaction with chiral acyloxy-
azolidinones promoted by catalytic amounts of MgCl2 in the
presence of chlorotrimethylsilane and triethylamine.2 This
simple and practical procedure does not work for acrolein,
such that β-unsubstituted anti allylic alcohols cannot be
accessed by this catalytic aldol procedure. We required access
to both syn and anti aldols obtained by stereoselective aldol
reaction to evaluate diastereoselectivity in cross ene−yne
metathesis. In this report, we provide a simple method to
extend the catalytic Evans enolization conditions to access anti-
aldols for subsequent use in a metathesis reaction.
magnesium enolate should access the anti-aldol product
without competing polymerization of the enal reactant. In a
We sought a temporary β-substituent in the enal to suppress
undesired side reactions in the aldol reaction step. In our hands,
the Lewis acidic reaction conditions in eq 2 failed to deliver the
desired anti-aldol product using acrolein. We envisioned that a
Received: November 23, 2011
Published: December 22, 2011
© 2011 American Chemical Society
1599
dx.doi.org/10.1021/jo202398q | J. Org. Chem. 2012, 77, 1599−1604

The Journal of Organic Chemistry
Note
Table 1. Catalytic, Diastereoselective Aldol Reaction with β-Substituted Enals
entry
aldehyde (equiv)
MgCl2 (mol %)
% yield of 9
% yield of 10
recovered 1 (%)
1
2
3
4
7 (1.2)
8 (1.2)
8 (1.2)
8 (1.3)
10
20
20
20
26
27
54
74
a
92
a
>20:1 anti/syn (1H NMR spectroscopy); see text.
Table 2. RCM Removal of β-Substituent
entry
catalyst
ethylene (1 atm)
solvent
T (°C)
time (h)
isolated yield of 3 (%)
1
2
5
5
5
5
6
6
6
6
6
6
6
Y
DCE
40
40
60
60
40
60
60
60
60
60
60
12
12
12
12
12
12
12
12
12
3
56
61
10
7
N
N
Y
DCE
3
DCE
4
DCE
5
Y
DCE
69
62
12
83
46
77
74
6
Y
DCE
7
N
Y
DCE
8
PhCH3
PhCH3
PhCH3
PhCH3
9
N
Y
10
11
Y
6
second step, addition of Grubbs catalysts (5 or 6) would trigger
a ring-closing metathesis. This is similar to a relay ring-closing
metathesis (rRCM) which was conceived by Hoye4 specifically
to form ruthenium carbenes that are normally hard to make. In
the present case, the remote initiation site is used to remove the
β-substituent, which would have served its role as a blocking
group in the catalytic aldol step. The relay metathesis would
free the unsubstituted unsaturated aldol from its β-tether,
releasing cycloalkene 4 as a coproduct.
Two readily accessible aldehydes were employed as acrolein
surrogates in the diastereoselective anti-aldol reaction with
oxazolidinone 1 (eq 3). Aldehyde 7 was synthesized by the
procedure of Garcia-Gomez and Moreto.5 The allylic alcohol
precursor to 8 was made as described by Doyle et al.6 followed
by a PCC oxidation to access malonate 8, obtained as a 3:2
mixture of E/Z isomers. We found that aldehyde 7 did not
perform well in the diastereoselective anti-aldol reaction using
the standard Evans conditions (Table 1).2 Doubling the
concentration of MgCl2 did not lead to improved yields
(entry 2). This poor reactivity could be due to a Lewis acid
promoted γ-deprotonation/polymerization in the enal prior to
aldol reaction or due to debilitating coordination by the alkyl
ether. The malonate enal 8 gave improved yields of the anti-
aldol 10 (entries 3 and 4). The diastereomer ratio of aldol
product 10 was determined to be >20:1 anti/syn.7 Because of
the superior performance of aldehyde 8, it was used for the
remainder of the study.
To obtain the acrolein-derived anti-aldol 3, RCM was
performed on 10 using a catalytic amount of Grubbs’ catalysts 5
or 6. Treating 10 with the Grubbs' second-generation catalyst 5
resulted in cleavage of the β-substituent to give 4,4-
dicarboethoxycyclopentene (4) and alkene 3. Screening catalyst
and reaction conditions led to optimal reaction conditions with
yields up to 83% (Table 2). Temperature played a critical role
when using the Grubbs catalyst 5. In contrast to elevated
temperatures (entries 3 and 4), lower temperatures gave
increased product yields (entries 1 and 2). The presence of
ethylene did not seem to benefit reactions catalyzed by Grubbs’
catalyst 5. Using the Hoveyda−Grubbs complex 6 led to an
increase in yield (entries 5−11). Increasing the temperature to
60 °C and changing the solvent from 1,2 DCE to toluene
improved yield (entry 5 vs 8). At 60 °C, ethylene played a
crucial role in achieving higher yields with Hoveyda−Grubbs
complex 6 (entry 9 vs 8). Additionally, when Hoveyda−Grubbs
complex 6 in toluene was used at 60 °C, increasing the reaction
time from 3 h to overnight only had a slight effect on yield
(entry 10 vs 8). The byproduct 4 was isolated in entry 10
(using ethylene) in 79% yield. This illustrates that ethylene
does not directly cleave the Δ4,5 alkene by ethenolysis (vide
infra).8 The beneficial role of ethylene is most likely due to
1600
dx.doi.org/10.1021/jo202398q | J. Org. Chem. 2012, 77, 1599−1604

The Journal of Organic Chemistry
Note
improved efficiency of methylene transfer to the newly formed
alkylidene once the cyclopentene group is lost.9,10
prior to metathesis using an acyl transfer method introduced by
Olivo et al.14 (Scheme 3). This high yielding sequence provided
ethyl ester 13. To obtain the desired anti-aldol product, internal
alkene 13 was subjected to Hoveyda−Grubbs catalyst 6 and
60 psi of ethylene over 12 h, giving enantiopure allylic alcohol
14 in 78% isolated yield. Importantly, the enantiopure aldol 14
has the opposite absolute configuration to that of the products
obtained in Tables 1 and 2 using the N-acyloxazolidinones, illus-
trating that stereodivergence from S-phenylalanine is possible
through the aldol/RCM sequence.
The anti-aldols performed well in a “one-pot” β-linker
extrusion/cross ene−yne metathesis sequence. In a previous
study, we found that syn-aldols underwent efficient cross
metathesis at nearly equimolar ratio.3 We predicted that
functionalized anti-alkene 3 would display different reactivity
from that of the syn-diastereomer (not shown; see ref 3). To
test this hypothesis, a tandem one-pot reaction was developed
to remove the β-substituent and subsequently trigger the cross
ene−yne metathesis between alkene 3 with alkyne 15 (Scheme 4).
To our delight, functionalized diene 16 was obtained in 46%
yield, and 46% of the anti-alkene was recovered as well.15 Slow
addition of alkyne 15 using 10 mol % of 6 gave a higher
chemical yield of 16 (75%) in the one-pot procedure. Both
reactions resulted in complete consumption of the alkyne. For
the one-pot transformation, alkyne oligomerization appears to
be the major competing process.
We wondered whether the antipodal stereodyads could be
accessed using the aldol reaction between N-acyl thiazolidine-
thiones and β-cinnamaldehyde. The data in Table 2 showed
that the linker cleavage benefitted from ethylene; this suggested
that a direct cleavage of the linker using ethylene may be
possible. This would represent an additional strategy to cleaving
a β-blocking group. An earlier application of this concept was
demonstrated by Piscopio et al. in a cleavage/release strategy
for product removal from solid support.11 Here, we envisioned
using ruthenium carbenes to directly cleave the CC double
bond using ethylene without a ring-closing metathesis (Scheme 2).
Scheme 2. Attempted Route To Obtain Thiazolidinethione-
Derived anti-Aldol
Higher yielding access to 16 was achieved in a two-step
ethenolysis/cross ene−yne metathesis sequence (Scheme 5).
The anti-aldol product 17 can be synthesized via Evans’
procedure2 in 90% yield. Ethenolysis of 17 followed by removal
of ruthenium16 from the crude product gave 3 in 92% isolated
yield. Subsequent ene−yne metathesis cross-coupling3 of 3
(1.3 equiv) with 15 gave 16 as a mixture of two inseparable C7
diastereomers in 82% yield (Scheme 5).17 Ethenolysis of 17
under 1 atm of ethylene was not sufficient to give good conversion
Though the aldol proceeded uneventfully, attempts to cleave
the styrene to an unsubstituted alkene proved fruitless (cat. 6,
ethylene, 60 psi). Presumably, the thione moiety poisons the
Grubbs catalyst.12 Attempts to sequester the thione by use of
Lewis acids were unsuccessful.
Scheme 3. Route To Obtain the Thiazolidinethione-Derived
anti-Aldol
Scheme 5. Two-Step Ethenolysis/Cross Ene−Yne
Metathesis Sequence
Cleavage of the β-styrenyl group using ethenolysis proved
possible if the thiazolidinethione auxiliary was removed prior to
ethenolysis.13 The chiral auxiliary was cleaved to the ethyl ester
Scheme 4. An Efficient “One-Pot” Cleavage/Cross Ene−Yne Metathesis
1601
dx.doi.org/10.1021/jo202398q | J. Org. Chem. 2012, 77, 1599−1604

The Journal of Organic Chemistry
Note
to the desired product 3. It was found that 60 psi of ethylene was
necessary for complete ethenolysis of 17 to give 3.
In conclusion, two methods have been developed to access
anti-aldols formally derived from acrolein. The presence of a
removable β-substituent in the enal resulted in a high yielding
catalytic aldol step. Unmasking of the β-blocking group was
accomplished through a ring-closing metathesis triggered by a
pendant alkene. Alternatively, with β-styrenyl groups, direct
ethenolysis also worked well. Excellent yields were obtained
through either method, providing flexibility in the metathesis
cleavage step. The β-substituted aldols participate in cross ene−
yne metathesis which could be conducted consecutively or in
“one pot.” The ability to use anti-allylic alcohols successfully in
cross metathesis provides a catalytic method for cross coupling of
alkynes with stereochemically complex (and unprotected) alkenols.
Further use of anti-stereodyads in synthetic applications is ongoing
in our laboratories and will be reported in due course.
(S)-3-((2R,3R,E)-6-(Allyloxy)-3-hydroxy-2-methylhex-4-enoyl)-4-
benzyloxazolidin-2-one (9). Based on the Evans’ procedure.2 Into a dry
round-bottom flask were dissolved oxazolidinone 1 (0.462 g, 1.98 mmol),
MgCl2 (38 mg, 0.40 mmol), sodium hexafluoroantimonate (0.154 g,
0.59 mmol), triethylamine (0.55 mL, 3.96 mmol), aldehyde 7 (0.300 g,
2.38 mmol), and chlorotrimethylsilane (0.38 mL, 2.97 mmol) in 4 mL
of ethyl acetate, and the mixture was stirred at room temperature for
24 h. The cloudy yellow solution was filtered through a plug of silica
gel using diethyl ether as the eluent. The solution was concentrated in
vacuo (rotary evaporator), and 10 mL of methanol was added along
with two drops of trifluoroacetic acid. The solution was stirred at room
temperature for 30 min and concentrated in vacuo to give a clear
yellow/orange oil. The oil was purified by silica gel flash
chromatography using gradient elution (0−30% ethyl acetate in
petroleum ether) to provide analytically pure 9 as a colorless oil
(182 mg, 26% yield). Analytical TLC: Rf 0.31 (33% ethyl acetate
in petroleum ether). [α]22.5 +21.6 (c = 1.7, CHCl3). 1H NMR
EXPERIMENTAL SECTION
D
■
(500 MHz, CDCl3, ppm): δ 7.33 (t, J = 7.3 Hz, 2H), 7.29−7.26 (m,
1H), 7.24 (d, J = 7.8 Hz, 2H), 5.94−5.81 (m, 3H), 5.28 (d, J = 17.6
Hz, 1H), 5.18 (d, J = 10.3 Hz, 1H), 4.72−4.67 (m, 1H), 4.31 (q, J =
6.8 Hz, 1H), 4.22−4.15 (m, 2H), 4.00 (dd, J = 15.1, 4.0 Hz, 5H),
3.30 (dd, J = 13.7, 2.9 Hz, 1H), 2.80−2.74 (m, 2H), 1.21 (d, J = 6.8
Hz, 3H). 13C NMR (75 MHz, CDCl3, ppm): δ 176.2, 153.5, 135.2,
134.6, 132.6, 129.5, 129.4, 129.0, 127.3, 117.1, 75.0, 71.2, 69.8, 66.0,
55.5, 43.1, 37.8, 14.5. FT-IR (thin film, cm−1); 3477, 3085, 3027,
2970, 2909, 2852, 1785, 1695, 1454, 1381, 1205, 1111, 760. High-
resolution MS (EI+, m/z): molecular ion calcd for C20H25O5N
359.1727, found 359.1730, error 0.7 ppm.
General Information. Unless otherwise stated, reactions were
conducted with oven-dried glassware under an atmosphere of argon.
Solvents were dried by passage through alumina (dichloromethane) or
alumina and Q5 (toluene, benzene) and stored under argon. Dichloro-
ethane was dried over calcium hydride and distilled prior to use.
Grubbs’ ruthenium carbene complexes 5 and 6 were purchased or
obtained from commercial suppliers and used as received (unless
otherwise noted). The polar isocyanide KO2CCH2NC was prepared
and used for quenching metathesis reactions as reported.16 Ethylene
(polymer grade) was used without further purification. Flash column
chromatography was carried out on untreated silica gel 60 (230−
400 mesh) under air pressure. Thin-layer chromatography was performed
on glass-backed silica plates (F254, 250 μm thickness), visualized with UV
light or stained with iodine, ceric ammonium molybdate, or KMnO4 stains.
1H NMR spectra were recorded at 400 or 500 MHz, and 13C NMR spectra
were recorded at 75 MHz. Optical rotations were measured at the indicated
concentration and temperature using the sodium D line.
Diethyl 2-Allyl-2-((4R,5R,E)-6-((S)-4-benzyl-2-oxooxazolidin-3-yl)-
4-hydroxy-5-methyl-6-oxohex-2-enyl)malonate (10). Based on the
Evans’ procedure.2 Under argon, in a clean and dry round-bottom flask
were dissolved oxazolidinone 1 (0.700 g, 3.0 mmol), MgCl2 (38 mg,
0.40 mmol), sodium hexafluoroantimonate (0.233 g, 0.90 mmol),
triethylamine (0.84 mL, 6.0 mmol), aldehyde 8 (3:2 E/Z mixture, 1.02 g,
3.8 mmol), and chlorotrimethylsilane (0.57 mL, 4.5 mmol) in 7 mL of
ethyl acetate, and the mixture was stirred at room temperature for
24 h. The yellow and cloudy solution was filtered through a plug of
silica gel using diethyl ether as the eluent. The solution was con-
centrated in vacuo (rotary evaporator), and 15 mL of methanol was
added along with 2 drops of trifluoroacetic acid. The solution was
stirred at room temperature for 30 min and concentrated in vacuo to
give a yellow/orange and clear oil. The oil was purified by silica gel
flash chromatography using gradient elution (0−30% ethyl acetate in
petroleum ether) to provide analytically pure E-10 as a colorless oil
(1.38 g, 92% yield). Diastereomeric excess was determined after the
RCM step (below). Analytical TLC: Rf 0.50 (33% ethyl acetate in
petroleum ether). [α]22.5D +16.6 (c = 3.5, CHCl3). 1H NMR (500 MHz,
CDCl3, ppm): δ 7.34 (t, J = 6.8 Hz, 2H), 7.30−7.25 (m, 3H), 5.73−
5.62 (m, 3H), 5.18−5.11 (m, 2H), 4.75−4.68 (m, 1H), 4.26−4.18 (m,
7H), 3.94 (quintet, J = 6.8 Hz, 1H), 3.33 (dd, J = 13.7, 3.4 Hz, 1H),
2.80 (dd, J = 13.4, 9.3 Hz, 1H), 2.70−2.64 (m, 4H), 1.26 (t, J = 6.8 Hz,
6H), 1.17 (J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3, ppm):
δ 176.1, 170.6, 153.5, 134.9, 132.2, 129.5, 128.9, 127.6, 127.3, 119.3,
75.4, 66.1, 61.3, 57.3, 55.5, 43.2, 37.8, 35.2, 14.4, 14.1. FT-IR (thin
film, cm−1); 3513, 3386, 3059, 2977, 2924, 2867, 1779, 1726, 1448,
1391, 1293, 1211, 1100, 1027, 970, 920, 732, 700. High-resolution
Diethyl 2-Allyl-2-(4-oxobut-2-enyl)malonate (8). The 5,5-bis-
(carbethoxy)-cis-2,7-octadien-1-ol was prepared according to the
procedure developed by Doyle et al.6 The alcohol was subsequently
dissolved in 5 mL of dichloromethane (2.0 g, 7.4 mmol) and oxidized
via dropwise addition to stirred pyridinium chlorochromate (2.7 g,
12.6 mmol) in 10 mL of dichloromethane at room temperature. The
resulting dark orange slurry was stirred for 1 h until thin layer
chromatography revealed full conversion to the aldehyde. The crude
mixture was plug filtered through Celite/silica gel using 200 mL of
diethyl ether as the eluent. The solvent was concentrated in vacuo
(rotary evaporator) to obtain analytically pure 8 (3:2 E/Z mixture) as
a colorless oil (1.53 g, 77%). Analytical TLC: Rf 0.16 (5% ethyl acetate
1
in petroleum ether). H NMR (500 MHz, CDCl3, ppm): δ 10.05 (d,
J = 7.8 Hz, 0.6H), 9.51 (d, J = 7.8 Hz, 0.4H), 6.76 (dt, J = 15.6, 7.3 Hz,
0.4H), 6.53 (dt, J = 11.2, 8.3 Hz, 0.6H), 6.15 (dd, J = 15.6, 7.8 Hz,
0.4H), 6.07−6.03 (m, 0.6H), 5.69−5.61 (m, 1H), 5.18−5.13 (m, 2H),
4.26−4.17 (m, 4H), 3.17 (d, J = 8.1 Hz, 1.2H), 2.88 (d, J = 7.6 Hz,
0.8H), 2.71 (d, J = 7.3 Hz, 1.2H), 2.69 (d, J = 7.3 Hz, 0.8H), 1.27 (t,
J = 6.8 Hz, 6H). 13C NMR (75 MHz, CDCl3, ppm): δ 193.4, 190.5,
170.0, 152.0, 145.6, 135.8, 132.6, 131.5, 120.0, 61.7, 56.9, 37.6, 37.3,
35.9, 30.7, 14.1. FT-IR (thin film, cm−1): 3077, 2983, 2929, 2815,
2746, 1732, 1691, 1446, 1368, 1144, 1042, 927, 858. High-resolution
MS (EI+, m/z): molecular ion calcd for C14H20O5 268.1305, found
268.1308, error 1.0 ppm.
1602
dx.doi.org/10.1021/jo202398q | J. Org. Chem. 2012, 77, 1599−1604

The Journal of Organic Chemistry
Note
MS (EI+, m/z): molecular ion calcd for C27H35NO8 501.2381, found
501.2370, error 2.1 ppm.
(d, J = 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3, ppm): δ 175.2,
136.3, 131.8, 129.2, 128.3, 127.6, 126.3, 74.3, 60.5, 45.6, 13.9, 13.7. FT-
IR (thin film, cm−1) 3440, 2974, 1720, 1454, 1381, 1258, 1180, 1107,
1037. High-resolution MS (EI+, m/z): molecular ion calcd for C14H18O3
234.1250, found 234.1239, error 4.2 ppm.
(S)-4-Benzyl-3-((2R,3R)-3-hydroxy-2-methylpent-4-enoyl)-
oxazolidin-2-one (3). Procedure A: To an oven-dried 50 mL Schlenk
tube was added 10 (125.4 mg, 0.25 mmol) followed by the addition of
2.5 mL of toluene. The reaction was purged with one balloon of ethylene,
after which the Hoveyda−Blechert second-generation catalyst 6 (7.8 mg,
0.0125 mmol) was added. The reaction was kept under balloon
atmosphere of ethylene for 12 h and then quenched with the addition
of a methanolic solution of isocyanide KO2CCH2NC (8 mg, 0.063 mmol,
1 mL of MeOH). The reaction was concentrated in vacuo (rotary
evaporator) and purified using silica gel flash column chromatography
using a gradient elution (0−20% ethyl acetate in petroleum ether) to
afford 3 as a clear oil which solidified to a white solid upon standing
(60 mg, 83% yield).
(2S,3S,E)-Ethyl 3-Hydroxy-2-methyl-5-phenylpent-4-enoate (14).
Under argon, to an oven-dried pressure tube containing 50 mL of
freshly distilled DCE was added internal alkene 13 (900 mg, 3.84 mmol)
followed by the addition of Hoveyda−Blechert second-generation catalyst
6 (62.6 mg, 0.1 mmol). The reaction was pressurized to 60 psi and vented
three times. After the final venting, the reaction was repressurized to
60 psi ethylene and maintained at that pressure for the duration of the
reaction. After 12 h at room temperature, the reaction was judged
complete by TLC analysis, and the pressure tube was carefully vented.
The catalyst was quenched by the addition of a methanolic solution of
KO2CCH2NC (62 mg, 0.5 mmol, 2 mL of MeOH) then subsequently
concentrated in vacuo (rotary evaporator) and purified by silica gel flash
column chromatography using gradient elution (0−20% ethyl acetate in
Procedure B. To an oven-dried pressure tube containing 50 mL of
freshly distilled DCE was added the internal alkene 17 (366 mg,
1.0 mmol) followed by the addition of Hoveyda−Blechert second-
generation catalyst 6 (31.3 mg, 0.05 mmol). The reaction was
pressurized to 60 psi and vented (three cycles); after the final
series, the reaction was pressurized to 60 psi and maintained at that
pressure for the duration of the reaction. After 12 h, the reaction
was judged complete by TLC, the pressure tube was vented, and the
catalyst was quenched by the addition of a methanolic solution of
KO2CCH2NC (31 mg, 0.25 mmol, 1 mL of MeOH). The reaction
was concentrated in vacuo (rotary evaporator) and purified using
silica gel flash column chromatography using a gradient elution (0−
20% ethyl acetate in petroleum ether) to afford 3 as a white solid.
Mp: 73−75 °C (263 mg, 91% yield). Analytical TLC: Rf 0.56 (33%
petroleum ether) to afford 14 as a clear oil (474 mg, 78% yield). [α]22.5
D
1
−9.9 (c = 3.5, CHCl3). H NMR (500 MHz, CDCl3, ppm): δ 5.84 (m,
1H), 5.29 (d, J = 17.0 Hz, 1H), 5.20 (d, J = 10.5 Hz, 1H), 4.18 (q, J =
7.0 Hz, 2 H), 2.82 (d, J = 5.5 Hz, 1 H), 2.56 (quintet, J = 7.5 Hz, 1 H),
1.27 (t, J = 6.5 Hz, 3 H), 1.19 (d, J = 7.0 Hz, 3 H). 13C NMR (75 MHz,
CDCl3, ppm): δ 175.5, 138.1, 116.8, 74.7, 60.6, 45.1, 14.1, 13.9. FT-IR
(thin film, cm−1) 3424, 2978, 2929, 2880, 1728, 1462, 1377, 1254, 1197,
1037. High-resolution MS (EI+, m/z): molecular ion calcd for C8H14O3
158.0937, found 158.0934, error 2.0 ppm.
ethyl acetate in petroleum ether). [α]22.5 +40.5 (c = 3.0, CHCl3).
D
1H NMR (500 MHz, CDCl3, ppm): δ 7.35 (t, J = 7.3 Hz, 2H),
7.31−7.25 (m, 3H), 5.99−5.93 (m, 1H), 5.37 (d, J = 17.1 Hz, 1H),
5.27 (d, J = 10.7 Hz, 1H), 4.74−4.69 (m, 1H), 4.30, (q, J = 6.8 Hz,
1H), 4.24−4.17 (m, 2H), 4.02 (quintet, J = 6.8 Hz, 1H), 3.31 (dd, J =
13.7, 3.42 Hz, 1H), 2.82−2.76 (m, 2H), 1.25 (d, J = 6.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3, ppm): δ 176.3, 153.5, 138.4, 135.2, 129.5,
129.0, 127.4, 117.0, 75.8, 66.0, 55.5, 42.8, 37.8, 14.4. FT-IR (thin film,
cm−1); 3469, 3027, 2978, 2876, 1793, 1687, 1389, 1262, 1213, 115, 968.
High-resolution MS (EI+, m/z): molecular ion calcd for C16H19O4N
289.1308, found 289.1304, error 1.5 ppm.
(6R,7R,E)-8-((S)-4-Benzyl-2-oxooxazolidin-3-yl)-6-hydroxy-7-
methyl-3-methylene-8-oxooct-4-en-2-yl benzoate (16). Into an
oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar
and purged with argon were added successively a solution of 35.1 mg
of alkyne 15 (0.202 mmol, 1 equiv) dissolved in 1,2-dichloroethane, a
solution of 70 mg of alkene 3 (0.242 mmol, 1.2 equiv) dissolved in 1,2
dichloroethane, and 4 mL of additional 1,2 dichloroethane to achieve a
concentration of 0.04 M. To the solution was added 12.7 mg of
Hoveyda−Blechert second-generation catalyst 6 (0.0202 mmol, 10
mol %). The solution was stirred at 45 °C for 14 h, and the reaction
was judged to be complete by TLC analysis at that time. The reaction
was quenched by addition of a methanolic solution of KO2CCH2NC
(0.0606 mmol). The reaction was concentrated under reduced
pressure and the crude product was purified by silica gel flash
chromatography using gradient elution (0−30% ethyl acetate in
petroleum ether). Analytically pure 16 was obtained as a clear oil
(75 mg, 82% yield), containing all E-isomer and a 1:1 mixture of C7
epimers before and after purification. Analytical TLC: Rf 0.47 (33%
ethyl acetate in petroleum ether). 1H NMR (500 MHz, CDCl3, ppm):
δ 8.06−8.04 (m, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H),
7.33−7.24 (m, 3H), 7.20 (t, J = 7.8 Hz, 2H), 6.34 (d, J = 16.1, 4.4 Hz,
1H), 6.00−5.93 (m, 1H), 5.80 (q, J = 6.4 Hz, 1H), 5.33 (s, 0.5H), 5.31
(s, 0.5H), 5.21 (s, 0.5H), 5.18 (s, 0.5H), 4.69−4.64 (m, 1H), 4.36
(sextet, J = 6.3 Hz, 1H), 4.19−4.16 (m, 2H), 4.13−4.07 (m, 0.5H),
4.01 (quintet, J = 7.3 Hz, 0.5H), 3.30−3.25 (m, 1H), 2.81 (d, J =
7.3 Hz, 0.5H), 2.77 (dd, J = 7.3 Hz, 0.5H), 2.70 (dt, J = 9.8, 13.2 Hz,
1H), 1.53 (d, J = 6.3 Hz, 3H), 1.21−1.19 (m, 3H). 13C NMR (75 MHz,
CDCl3, ppm): δ 176.1, 165.6, 165.5, 153.5, 153.4, 145.5, 145.4, 135.4,
135.3 132.9, 130.9, 130.6, 130.4, 130.3, 129.5, 129.4, 128.9, 128.8,
128.4, 127.3, 127.2, 115.6, 115.3, 75.5, 75.3, 70.5, 70.3, 66.0, 55.5, 43.2,
42.9, 37.7, 37.6, 20.5, 20.4, 14.5, 14.4. FT-IR (thin film, cm−1): 3481,
Diastereomeric Excess Determination. After ring-closing meta-
thesis cleavage of 10, the diastereomeric excess of the anti-diastereomer
3 was determined by 1H NMR spectroscopy. The diastereomeric
excess of 3 (and indirectly of its progenitor 10) could be determined
by direct comparison to the syn-diastereomer, which we had previously
synthesized.3 Specifically, the major peak corresponding to the carbinol
methine of the anti-diastereomer, δ 4.72 ppm was integrated as
compared to the analogous proton in the syn-diastereomer, appearing
at δ 4.57 ppm. The integrated ratio of the major (anti) to minor (syn)
was 26.2:1.00, or >20:1 dr, >86% de. No other diastereomers were
1
detected by H NMR spectroscopy.
(2S,3S,E)-Ethyl 3-Hydroxy-2-methyl-5-phenylpent-4-enoate (13).
The procedure described by Olivo et al.14 afforded 13 as a clear and
1
colorless oil in 87% yield. [α]22.5 −11.6 (c = 3.5, CHCl3). H NMR
D
(400 MHz, CDCl3, ppm): δ 7.32 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 7.6
Hz, 2H), 7.22−7.18 (m, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.21 (dd, J =
7.2, 16.0 Hz, 1H), 4.36 (quintet, J = 7.2 Hz, 1H), 4.14 (q, J = 7.2, 2H),
3.24 (br s, 1H), 2.63 (t, J = 7.2 Hz, 1H), 1.21 (t, J = 7.2, 3H), 1.17
1603
dx.doi.org/10.1021/jo202398q | J. Org. Chem. 2012, 77, 1599−1604

The Journal of Organic Chemistry
Note
3072, 3027, 2974, 2925, 1781, 1704, 1450, 1389, 1274, 1209, 1111, 715.
High-resolution MS (EI+, m/z): molecular ion calcd for C27H29NO6
463.1989, found 463.1996, error 1.3 ppm.
Tetrahedron 1999, 55, 8249−8252. Role in depolymerization:
(e) Conrad, J. C.; Eelman, M. D.; Duarte Silva, J. A.; Monfette, S.;
Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2007,
129, 1024−1025. (f) Watson, M. D.; Wagener, K. B. J. Polym. Sci.,
Part A Polym. Chem. 1999, 37, 1857−1861.
(14) Osorio-Lozada, A.; Olivo, H. F. Org. Lett. 2008, 10, 617−620.
(15) An alternative is to conduct an ene−yne metathesis first and
then an Evans catalytic aldol reaction. However, the dienes iii cannot
be accessed by ene-yne metathesis directly and are expected to be
unstable with respect to polymerization under Lewis acid conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: diver@buffalo.edu.
■
(16) Galan, B. R.; Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister, J. B.;
Diver, S. T. Org. Lett. 2007, 9, 1203−1206.
(17) For a fatty esterethenolysis/ene−yne metathesis, see: Le Ravalec,
V.; Fischmeister, C.; Bruneau, C. Adv. Synth. Catal. 2009, 351, 1115−
1122.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-0848560) for financial support of this
work. We also thank Dr. Richard Pederson of Materia, Inc., for
supplying Grubbs’ catalysts.
REFERENCES
■
(1) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127−2129.
(2) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392−393.
(3) Clark, J. R.; Diver, S. T. Org. Lett. 2011, 13, 2896−2899.
(4) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210−10211.
(5) García-Gom
1359−1369.
(6) Doyle, M. P.; Peterson, C. S.; Protopopova, M. N.; Marnett, A. B.;
Parker, D. L.; Ene, D. G.; Lynch, V. J. Am. Chem. Soc. 1997, 119,
8826−8837.
́ ́
ez, G.; Moreto, J. M. Eur. J. Org. Chem. 2001, 2001,
(7) (a) At the aldol stage, the minor diastereomers could not be
unambiguously determined. The dr was therefore determined after the
RCM step (see the Experimental Section). In this way, the dr was
found to be >20:1 anti/syn. (b) As a comparison, Evans et al. report
diastereoselectivities with α- or β-substituted acroleins in the range of
16−21:1 anti/(all others combined), see ref 2.
(8) A reviewer suggested that ethylene may directly cleave the Δ4,5
bond to release diethyl diallylmalonate. The RCM of 10 was run to
partial conversion, quenched, and analyzed by GC. No diethyl
diallylmalonate was found. This supports the conclusion that the relay
RCM is initiating from the more reactive terminal alkene.
(9) For instance, ethylene helps speed up the slow step of an ene-yne
metathesis catalytic cycle, see: Giessert, A. J.; Brazis, N. J.; Diver, S. T.
Org. Lett. 2003, 5, 3819−3822.
(10) (a) The presence of ethylene is thought to assist catalysis and
limit decomposition by speeding up turnover of the alkylidene i to
product 3. The methylene ii would serve as a chain carrier and can
initiate with 10 to trigger ring-closing metathesis.
For decomposition of ruthenium carbenes due to allylic alcohols, see:
(b) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123−1125.
(11) Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett. 1997,
38, 7143−7146.
(12) The relay RCM using the thiazolidinethione also failed using the
conditions of Table 2, entry 10.
(13) For recent references on ethenolysis of internal alkenes, see:
(a) Han, C.; Yamano, Y.; Kita, M.; Takamura, H.; Uemura, D. Tetra-
hedron Lett. 2009, 50, 5280−5282. (b) Thomas, R. M.; Keitz, B. K.;
Champagne, T. M.; Grubbs, R. H. J. Am. Chem. Soc. 2011, 133, 7490−
7496. (c) Marinescu, S. C.; Levine, D. S.; Zhao, Y.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 11512−11514.
(d) Bykov, V. I.; Butenko, T. A.; Petrova, E. B.; Finkelshtein, E. S.
1604
dx.doi.org/10.1021/jo202398q | J. Org. Chem. 2012, 77, 1599−1604