Silylene transfer to α-keto esters and application to the synthesis of γ-lactones

Article abstract of DOI:10.1016/j.tet.2009.05.066

Disubstituted α-hydroxy acids have been synthesized by metal-catalyzed silylene transfer to α-keto esters. A range of substituents are tolerated in the transformation with the exception of branched groups at the vinylic position. The α-hydroxy acid produc

Full text of DOI:10.1016/j.tet.2009.05.066

Tetrahedron 65 (2009) 6447–6453
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Silylene transfer to
a
-keto esters and application to the synthesis of g-lactones
*
Brett E. Howard, K.A. Woerpel
Department of Chemistry, University of California, Irvine, CA 92697-2025, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 April 2009
Received in revised form 21 May 2009
Accepted 22 May 2009
Available online 29 May 2009
Disubstituted
a-hydroxy acids have been synthesized by metal-catalyzed silylene transfer to a-keto
esters. A range of substituents are tolerated in the transformation with the exception of branched groups
at the vinylic position. The
lactonization conditions.
a-hydroxy acid products can be converted into g-lactones using a variety of
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
aromatic groups (Table 1, entry 5). The synthetic utility of the re-
action could be enhanced by increasing the complexity of sub-
stituents at R1. Incorporation of a protected oxygen atom is
tolerated by the reaction conditions and provides an additional
handle that can be elaborated in later synthetic steps (Scheme 2).14
a
-Hydroxy acids are common structural motifs in nature.1,2
Several recent publications have featured natural products that
incorporate this moiety into their synthesis, including thapsigarin,
viridiofungin, zaragozic acid, and fukinolic acid (Scheme 1).3–6
Given the prevalence of
synthetic methods for their synthesis are desirable.7–13 We recently
reported the development of a method to obtain -hydroxy acids
Table 1
Silylene transfer to
a-hydroxy acids in small molecules, new
a
-keto esters with substitution at R1
t-Bu
t-Bu
a
Me
Me
i
Si
2
O
HO CO2H
R1
from simple
a
-keto esters utilizing metal-catalyzed silylene trans-
O
Ph
fer.14 In this paper we report the expanded scope and utility of this
methodology.
R1
AgOTs (10 mol %),
−25 °C, Tol
Ph
3a-e
O
1a-e
ii. HF•Pyr
HO2C OH
C7H15
CO2H
Entry
R1
Product
% Yield
dr
6
O
OH
1
2
3
4
5
Me
Et
i-Pr
t-Bu
Ph
3a
3b
3c
3d
3e
70
84
54
47
71
ꢀ97:3
ꢀ97:3
ꢀ97:3
ꢀ97:3
ꢀ97:3
O
NH
HO2C
viridiofungin A
Ph
O
Conditions:
a
-keto ester (1.0 equiv), silacyclopropane
2
(1.5 equiv), AgOTs
O
OH
OAc
(0.10 equiv), toluene, ꢁ25 ꢂC, 16 h. Then HF$Pyr (4.0 equiv), isolated yields.
Me
MeO2C
MeO2C
O
Ph
O
O
Me
i. 2, AgOTs (10 mol %),
−25 °C, Tol
HO CO2H
CO2Me
OH
Me
O
Me
ii. HF•Pyr
zaragozic acid C
a-Hydroxy acid containing natural products.
OBn O
OBn Ph
5
4
Scheme 1.
Ph
>98% ee
63%,
2. Results
80% diastereoselectivity
Scheme 2. Synthesis of
a
-hydroxy acids with branching at R1.
The silylene-mediated conversion of
a-hydroxy acids is general
for a range of substrates (Table 1). The highest yields were obtained
The mechanism for the conversion of
acids involves sequential pericyclic reactions. Initial generation of
a silacarbonyl ylide intermediate (7) is followed by a 6 electro-
cyclization and tandem Ireland–Claisen rearrangement (Scheme 3),
affording
-hydroxy acid products.14–20
a-keto esters to a-hydroxy
with linear
a
-keto esters (R1¼Et, Me) and substrates featuring
p
* Corresponding author. Tel.: þ1 949 824 4239; fax: þ1 949 824 9220.
E-mail address: kwoerpel@uci.edu (K.A. Woerpel).
a
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.066

6448
B.E. Howard, K.A. Woerpel / Tetrahedron 65 (2009) 6447–6453
i. 2, AgOTs
(10 mol %),
t-Bu
O
HO CO2H
OBn Me
t-Bu
Si
2
Me
Et
Me
O
4
Me −25 °C, Tol
O
1
O
1
10 mol % AgOTs
6π e-
O
R3
ii. HF•Pyr
6
O
R1
Et
R1
OBn O
R3
O
R2
4
O
18
17
50:50 dr, 72%
6
R2
7
6
Scheme 6. Competing chiral substituents at C1 and C4 lead to the formation of
diastereomers.
t-Bu
t-Bu
t-Bu
Si
O
t-Bu
t-Bu
t-Bu t-Bu
t-Bu
HO CO2H
Si
O
[3,3]
O
HF•Pyr
R2
Si
Si
O
O
R1
R3
O
R1
O
R3
Et O
O
6
6
R3
O
6
Me
4
Me
2
O
4
O
R1
R
4
Et
OBn
10
R2
H
BnO
Me
84-47 % yield
a-hydroxy acids.
Me
H
8
9
17a
17b
Scheme 3. Postulated mechanism for the formation of
Scheme 7. Two potential transition states for compound 17.
Functionalization at R2 (C4 of the Ireland–Claisen transition
state, Scheme 3) provided direct transfer of stereochemical in-
formation to the two newly formed chiral centers in the Ireland–
Claisen product (9). Substituents at this position have a preference
for being pseudo-equatorial in the transition state to avoid steric
congestion.19 Initial investigations employed a methyl group at R2
(11) as a single enantiomer; complete transfer of chirality was ob-
served (Scheme 4).14
Unfortunately, increasing the steric bulk at the C4 position (Et to
t-Bu, 19) does not improve the diastereomeric ratio of products
formed. Submitting a diastereomeric mixture of a-keto esters to
silylene transfer conditions (19a and 19b) led to the formation of
three products (20a, 20b, and 20c): two diastereomers of the
mismatched substrate and a single diastereomer from the matched
substrate, respectively (Scheme 8).22 This result indicates that
exocyclic stereocenters in the Ireland–Claisen transition state can
influence the product distribution as effectively as stereocenters on
the cyclic transition state.
O
i. 2, AgOTs (10 mol %),
n-Bu
−25 °C,Tol
HO CO2H
O
Me
Me
Me
ii. HF•Pyr
O
Me
11
n-Bu
O
O
2, AgOTs
12
Me
O
Me
Me
O
Me
(10 mol %),
>97% ee
77%, >97% ee
+
:
-25 °C, Tol
OBn O
t-Bu
OBn O
t-Bu
Scheme 4. Enantiopure a-keto esters bearing a chiral substituent on the allylic ester at
R2 (C4).
19b
19a
50
50
HO CO2H
Extending the substrate scope to include protected hydroxyl
groups at R2 did not impede the transformation. Reactions of
compounds 13 and 15 both led to enantiopure acids in good yields
upon exposure to the reaction conditions (Scheme 5).
HO2C OH
Me
HO CO2H
t-Bu Me
Me
t-Bu
+
+
OBn Me
OBn Me t-Bu
OBn Me
20a
20b
20c
O
OPMB
OTBS
HO2C OH
Me
2, AgOTs
O
(10 mol %),
25
:
25
: 50
Me
−25 °C, Tol
O
Scheme 8. Incorporation of
a
tert-butyl group at R2 does not change
OTBS
OPMB
14
diastereoselectivity.
13
Substitutions at R3 are generally well tolerated (Table 2).14
Substrates that feature branching at that position, however, do not
80%
2, AgOTs
O
OTBDPS
OPMB
HO CO2H
give rearrangement products (Schemes 9–11).
a
-Keto esters that
(10 mol %),
O
Me
Me
did not give
a-hydroxy acid products include terminally
−25 °C, Tol
O
OPMB
OTBDPS
16
Table 2
Silylene transfer to
15
a
-keto esters with substitution at R3
53%
O
i. 2, AgOTs (10 mol %),
HO CO2H
−25 °C, Tol
Scheme 5. Synthesis of enantiopure a-hydroxy acids.
O
R3
R1
R1
ii. HF•Pyr
R3
2a, f-i
Employing substitutions at both R1 and R2 led to the formation
of diastereomeric mixtures of -hydroxy acid products (Scheme 6).
O
1a, f-i
a
The formation of diastereomers is likely due to competing in-
teractions in the Ireland–Claisen transition state. Aligning the
benzyloxy group of 17 anti to the incipient carbon–carbon bond in
the transition state creates a syn-pentane like interaction between
the methyl groups at positions C1 and C6 (17a).21,22 This interaction
negates any favorable interactions gained by placing the ethyl
group at C4 equatorial, leading to the observed mixture of dia-
stereomers (Scheme 7).
Entry
R1
R3
Product
% Yield
dr
1
2
3
4
5
Me
Ph
Ph
Ph
Et
Ph
Me
n-Bu
CH2OTBDMS
(CH2)2OBn
2a
2f
2g
2h
2i
70
62
72
71
75
ꢀ97:3
ꢀ97:3
ꢀ97:3
ꢀ97:3
ꢀ97:3
Conditions:
a-keto ester (1.0 equiv), silacyclopropane 2 (1.5 equiv), AgOTs
(0.10 equiv), toluene, ꢁ25 ꢂC, 16 h, then HF$Pyr (4.0 equiv), isolated yields.

B.E. Howard, K.A. Woerpel / Tetrahedron 65 (2009) 6447–6453
6449
i. 2, AgOTs (10 mol %),
−25 °C, Tol
Access to a variety of lactones with differing functionality pro-
vided an opportunity to synthesize a range of compounds. Several
elaborations have led to differentiated products, including diol 29,
a potential precursor to the secondary marine metabolite (ꢁ)-del-
HO CO2H
Ph
O
O
O
Ph
ii. HF•Pyr, rt
O
O
21
22
esserine (Scheme 13). Utilization of a slightly modified a-keto ester
in the silylene transfer reaction could afford the natural product in
a few additional steps.28 Elaboration of the diol 29 to olefin 30 via
reductive elimination provides a potential handle for ring-closing
metathesis reactions (Scheme 13).29
Scheme 9. Substrates requiring dearomatization are not tolerated.
HO CO2H
Me
O
2, AgOTs (10 mol %),
−25 °C, Tol
Me
Ph
O
O
O
HO
O
HO
Me
O
Ph
O
Me
O
OMe
PPh3, I2, Imid,
CH2Cl2, reflux
O
O
Me
PMBO
Me
24
O
O
23
O
O
PMB
O
HO
Scheme 10.
a
-Keto esters with bulky substituents at R3 are not tolerated.
OH
H
OH
HO
29
30
95%
(−)-delesserine
i.2, AgOTs (10 mol %),
O
HO CO2H
Scheme 13. Elaboration of lactone products.
−25 °C, Tol
O
Me
Me
Ph
O
Ph
3. Experimental
ii. HF•Pyr, rt
Me Me
3.1. General remarks
26
25
Scheme 11. Terminally disubstituted alkenes are not tolerated.
Melting points were obtained using a Bu¨chi 510 melting point
apparatus and are reported uncorrected. Analytical thin layer
chromatography was performed on EMD Silica Gel 60 F254 pre-
coated plates. Liquid chromatography utilized force flow (flash
chromatography) of the indicated solvent system on Silacycle Sila-P
disubstituted allylic
a-keto ester 25 and substrates that would
require a dearomatization event (21). Branching at R3 may not be
tolerated because of the proximal silyl group in the Ireland–
Claisen transition state. Of all the positions available for sub-
stitution on the various substrates, R3 is the closest to the silyl
functionality.
silica gel (SiO2) 60 Å pore size, 40–63 mm mesh. Infrared spectros-
copy was performed on a Mattson Instruments FTIR, Galaxy Sys-
tem. High-resolution mass spectra were acquired on a Walters LCT
Premier and were obtained by peak matching. Microanalyses were
performed by Atlantic Microlabs, Atlanta, GA. 1H NMR and 13C NMR
spectra were recorded at 25 ꢂC at 400 and 100 MHz, and 500 and
125 MHz, respectively, using Bruker DRX 400 or DRX 500 spec-
trometer as indicated. These data are reported as follows: chemical
shift in parts per million from internal tetramethylsilane on the
Ultimately, the silylene transfer products feature a homoallylic
carboxylic acid that can be elaborated into a g-lactone by several
different lactonization conditions. Traditional iodolactonization
methods provided moderate to good yield of the desired lactone as
a mixture of diastereomers (Scheme 12, Table 3, entries 1–5).23–26
Use of N-bromosuccinimide led to slightly improved di-
astereomeric ratios and decreased yield. Asymmetric dihydroxy-
lation conditions yielded no product, but standard dihydroxylation
d
scale, multiciplity (br¼broad, s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet), coupling constants (Hz), and integration.
Silacyclopropanes were stored and manipulated in an Innovative
Technologies nitrogen-atmosphere dry box. All reactions were
performed under an atmosphere of nitrogen or argon in glassware
that had been flame-dried under vacuum prior to use. Solvents were
distilled or filtered before use. Compounds 1–5, 11, 12, 27a, 27b, and
27c, were synthesized according to previously published reports.
conditions provided the requisite product 28c as
a single
diastereomer.27 It is conceivable that the catalyst–ligand complex
in the asymmetric dihydroxylation is unable to accommodate the
sterically congested a-hydroxy acid substrates.
O
HO CO2H
O
R3
conditions
HO
R1
3.2. (S,E)-1-(tert-Butyldimethylsilyloxy)-5-(4-methoxy-
benzyloxy)pent-3-en-2-yl 2-oxopropanoate (13)
R1
R3
R2
R2
28a-e
X
27a-e
To a solution of (S,E)-1-(tert-butyldimethylsilyloxy)-5-(4-methoxy-
benzyloxy)pent-3-en-2-ol (0.520 g, 1.47 mmol) in benzene (30 mL)
were added pyruvic acid (0.164 mL, 2.36 mmol), triethylamine
(0.551 mL, 3.70 mmol), 4-dimethylaminopyridine (0.224 g,1.84 mmol),
and 2,4,6-trichlorobenzoylchloride (0.731 mL, 2.99 mmol). The re-
action mixture was then stirred for 16 h, diluted with 5% aqueous citric
acid, and extracted with EtOAc (3ꢃ25 mL). The organic layers were
combined, dried with Na2SO4, and concentrated in vacuo. The resultant
oil was purified by column chromatography (10:1 hexanes/EtOAc) to
Scheme 12. Silylene transfer products can be converted to g-lactones (Table 3).
Table 3
Lactonization conditions and results for the conversion of 27 to 28
Entry R1 R2
R3
X
Conditions
Product % Yield dr
1
2
3
4
5
6
7
8
9
Ph
H
H
I
I
I
NaHCO3, I2, CH3CN, 0 ꢂ
I2, CH3CN
KI, I2, THF, NaHCO3
C
C
28a
28b
28b
28c
28d
28e
28d
28d
28c
91
48
34
d
60:40
80:20
80:20
d
Me n-Bu Me
Me n-Bu Me
provide 13 (0.617 g, 99%) as a yellow oil: [
(400 MHz, CDCl3)
a]
2D38.2 (c 2.8, CHCl3); 1H NMR
Et n-Bu
Et n-Bu
Et n-Bu
Et n-Bu
Et n-Bu
Et n-Bu
H
H
H
H
H
H
OH H2O, t-BuOH, AD mix
NaHCO3, I2, CH3CN, 0 ꢂ
Br NBS, THF, 0 ꢂC
d
7.31–7.23 (m, 2H), 6.93 (d, J¼8.6, 2H), 6.01 (dt,
I
37
76
92
34
73
80:20
83:17
60:40
56:44
100:0
J¼15.6, 5.3,1H), 5.81 (dd, J¼15.7, 6.9,1H), 5.53 (dd, J¼12.1, 6.2,1H), 4.52
(s, 2H), 4.07 (d, J¼5.0, 2H), 3.90–3.76 (m, 5H), 2.52 (d, J¼5.4, 2H), 0.91 (s,
I
I
NIS, THF 0 ꢂC
Ti(Oi-Pr)4, NIS, CH2Cl2 ꢁ20 ꢂ
C
9H), 0.10 (t, J¼4.2, 6H); 13C NMR (100 MHz, CDCl3)
d 192.3, 167.3, 159.7,
OH OsO4, NMO, CH2Cl2
132.9,132.5,130.2,130.0,114.3, 77.4, 72.5, 69.6, 64.9, 55.7, 27.2, 26.2,18.7,

6450
B.E. Howard, K.A. Woerpel / Tetrahedron 65 (2009) 6447–6453
ꢁ4.98; IR (thin film) 3021, 2933, 1733, 1216, 755 cmꢁ1; HRMS (ESI) m/z
calcd for C22H34NaO6Si (MþNa)þ 445.2022, found 445.2022.
pyridine (0.25 mL) followed by Dess–Martin periodinane (0.330 g,
0.779 mmol). The reaction mixture was stirred for 16 h and then
diluted with saturated aqueous Na2SO3 and extracted with CH2Cl2
(3ꢃ15 mL). The organic layers were then combined, dried over
Na2SO4, and concentrated in vacuo. The crude oil was purified by
column chromatography (10:1 hexanes/EtOAc) to afford 17 (0.114 g,
3.3. (2R,3R,E)-6-(tert-Butyldimethylsilyloxy)-2-hydroxy-3-
((4-methoxybenzyloxy)methyl)-2-methylhex-4-enoic acid (14)
To 13 (0.318 g, 0.752 mmol) in toluene (10 mL) was added sila-
cyclopropane 2 (0.215 g, 1.09 mmol) and the reaction mixture was
then cooled to ꢁ25 ꢂC. After stirring for 0.5 h, silver tosylate
(0.021 g, 0.075 mmol) was added and the mixture was allowed to
warm to room temperature. Upon stirring for 3 h, the solution was
concentrated in vacuo and the resultant oil was purified by column
76%) as a yellow oil: [
CDCl3)
a]
23 16.0 (c 1.66, CHCl3); 1H NMR (400 MHz,
D
d
7.44–7.26 (m, 5H), 5.86 (dq, J¼13.1, 6.5, 1H), 5.58–5.42 (m,
1H), 5.33 (q, J¼6.9,1H), 4.73 (d, J¼11.5,1H), 4.63–4.50 (m, 2H), 2.05–
1.61 (m, 5H), 1.48 (d, J¼6.9, 3H), 0.95 (t, J¼7.4, 3H); 13C NMR
(100 MHz, CDCl3)
d 196.3, 162.8, 137.7, 131.6, 128.9, 128.6, 128.4,
79.50, 77.9, 73.0, 27.8, 18.2, 17.0, 9.9; IR (thin film) 2971, 2939, 2879,
1726, 1214 cmꢁ1; HRMS (ESI) m/z calcd for C17H22NaO4 (MþNa)þ
313.1416, found 313.1415. Anal. Calcd for C17H22O4: C, 70.32; H, 7.64.
Found: C, 70.14; H, 7.68.
chromatography (5:2 hexanes/EtOAc with 1% AcOH) to provide 14
23
(0.254 g, 80%) as a pale yellow oil: [
a
]
ꢁ12.7 (c 3.68, CHCl3); 1H
D
NMR (400 MHz, CDCl3)
d
7.24 (d, J¼8.6, 2H), 6.97–6.70 (m, 2H), 5.77
(t, J¼5.8, 2H), 4.42 (s, 2H), 4.23 (d, J¼3.5, 2H), 3.83 (d, J¼3.9, 3H),
3.61 (dd, J¼7.2, 5.5, 2H), 2.99–2.76 (m, 1H), 1.40 (s, 3H), 0.96 (d,
3.7. 1-(Benzyloxy)ethyl-2-hydroxy-3-methylhept-4-
enoic acid (18)
J¼2.6, 9H), 0.18–0.09 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 180.4,
159.7, 134.9, 129.9, 129.9, 129.9, 128.8, 126.1, 114.3, 76.3, 73.6, 71.4,
64.1, 55.6, 49.4, 27.7, 27.4, 26.4, 25.5, 18.8, ꢁ4.66, ꢁ4.68; IR (thin
film) 3434, 3018, 2933, 2859, 1770, 1722 cmꢁ1; HRMS (ESI) m/z
calcd for C22H36NaO6Si (MþNa)þ 447.2179, found 447.2169.
To 17 (0.150 g, 0.514 mmol) in toluene (5 mL) was added sila-
cyclopropane 2 (0.147 g, 0.745 mmol) and the reaction mixture was
cooled to ꢁ25 ꢂC. After stirring for 0.5 h, silver tosylate (0.014 g,
0.05 mmol) was added and the mixture was allowed to warm to
ambient temperature. Upon stirring for 2 h, the solution was con-
centrated in vacuo and the resultant oil was purified by column
chromatography (5:2 hexanes/EtOAc with 1% AcOH) to provide
a 1:1 mixture of diastereomers of 18 (0.108 g, 72%) as a pale yellow
3.4. (R,E)-5-(tert-Butyldiphenylsilyloxy)-1-(4-methoxy-
benzyloxy)pent-3-en-2-yl 2-oxopropanoate (15)
a
-Keto ester 15 was isolated as a yellow oil (1.15 g, 59%) using
23
a procedure identical to the one outlined in Section 3.3: [
a
]
ꢁ17.1
oil: 1H NMR (400 MHz, CDCl3)
d 7.40–7.14 (m, 5H), 5.60–5.49 (m,
D
(c 9.42, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.84–7.70 (m, 4H), 7.56–
2H), 4.73 (dd, J¼11.3, 5.8, 2H), 4.11–3.88 (m, 1H), 3.00–2.70 (m, 1H),
7.11 (m, 8H), 7.01–6.91 (m, 2H), 6.09–5.96 (m, 1H), 5.90 (ddt, J¼15.4,
7.0, 1.7, 1H), 5.77–5.65 (m, 1H), 4.62 (d, J¼5.0, 2H), 4.34 (ddd, J¼4.7,
3.8, 2.3, 2H), 3.88 (s, 3H), 3.71 (ddd, J¼14.7, 11.0, 5.7, 2H), 2.54 (s,
2.18–1.97 (m, 2H), 1.34 (d, J¼5.9, 3H), 1.04 (m, 6H); 13C NMR
(100 MHz, CDCl3)
d 177.1, 138.4, 135.1, 128.9, 128.8, 128.7, 128.5,
128.2, 83.0, 78.8, 72.0, 41.9, 26.0, 16.5, 15.3, 14.1, 13.1; IR (thin film)
3020, 2973, 1756, 1708, 1216 cmꢁ1; HRMS (ESI) m/z calcd for
C17H24NaO4 (MþNa)þ 315.1572, found 315.1572.
3H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 192.2, 160.3, 159.6,
136.6, 135.8, 135.3, 133.6, 132.8, 130.1, 130.1, 129.8, 129.8, 129.7,
128.0, 128.4, 128.0, 128.0, 123.2, 114.2, 75.6, 73.2, 71.0, 63.6, 55.5,
27.1, 27.0, 19.50; IR (thin film) 3016, 2933, 2858, 1735, 1581,
1513 cmꢁ1; HRMS (ESI) m/z calcd for C32H38NaO6Si (MþNa)þ
569.2335, found 569.2335.
3.8. (3R)-((E)-2,2-Dimethylhex-4-en-3-yl) 3-(benzyloxy)-
2-oxobutanoate (19)
To (ꢄ)(2S,3R)-((E)-2,2-dimethylhex-4-en-3-yl) 3-(benzyloxy)-2-
hydroxybutanoate (0.007 g, 0.02 mmol) in CH2Cl2 (1 mL) was added
pyridine (0.2 mL) followed by Dess–Martin periodinane (0.014 g,
0.032 mmol). The reaction mixture was stirred for 16 h and then di-
luted with saturated aqueous Na2SO3, extracted with CH2Cl2
(3ꢃ5 mL). The organic layers were then combined, dried over Na2SO4,
and concentrated in vacuo. The crude oil was purified by column
chromatography (10:1 hexanes/EtOAc) to afford 19 (0.069 g, 99%) as
3.5. (2S,3S,E)-3-((tert-Butyldiphenylsilyloxy)methyl)-2-
hydroxy-6-(4-methoxybenzyloxy)-2-methylhex-4-
enoic acid (16)
To 15 (0.188 g, 0.344 mmol) in toluene (5 mL) was added sila-
cyclopropane 2 (0.095 g, 0.48 mmol) and the reaction mixture was
cooled to ꢁ25 ꢂC. After stirring for 0.5 h, silver tosylate (0.009 g,
0.03 mmol) was added and the mixture was allowed to warm to
ambient temperature. After stirring for 2 h, the solution was con-
centrated in vacuo and the resultant oil was purified by column
a yellow oil: 1H NMR (500 MHz, CDCl3)
d 7.46–7.32 (m, 5H), 5.91–5.79
(m,1H), 5.61–5.46 (m,1H), 5.15 (t, J¼8.1,1H), 4.74 (d, J¼11.5, 1H), 4.65–
4.45 (m, 2H), 1.79–1.71 (m, 2H), 1.67–1.56 (m, 1H), 1.50 (d, J¼4.0, 3H),
chromatography (5:2 hexanes/EtOAc with 1% AcOH) to provide 16
0.98 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 196.2, 162.5, 137.2, 132.5,
23
(0.099 g, 53%) as a pale yellow oil: [
a
]
ꢁ0.7 (c 5.0, CHCl3); 1H NMR
128.5,128.1,128.0,125.3, 84.9, 72.6, 34.5, 29.8, 25.8,17.9,16.7; IR (thin
film) 3091, 3018, 2969, 1724, 1479 cmꢁ1; HRMS (ESI) m/z calcd for
C19H26NaO4 (MþNa)þ 341.1729, found 347.1738.
D
(400 MHz, CDCl3)
d
7.66 (d, J¼7.5, 4H), 7.54–7.31 (m, 6H), 7.27 (d,
J¼8.5, 2H), 6.89 (d, J¼8.5, 2H), 5.89 (dd, J¼15.5, 9.5, 1H), 5.74 (dt,
J¼15.5, 5.8, 1H), 4.46 (s, 2H), 4.02 (d, J¼5.6, 2H), 3.97–3.66 (m, 6H),
2.77 (dt, J¼9.1, 4.4, 1H), 1.42 (s, 3H), 1.06 (s, 10H); 13C NMR
3.9. 1-(Benzyloxy)ethyl-2-hydroxy-3,6,6-trimethylhept-
4-enoic acids (20a–c)
(100 MHz, CDCl3)
d 180.1, 159.5, 135.9, 135.8, 132.5, 132.4, 132.2,
130.5, 130.3, 129.7, 129.0, 128.1, 128.1, 114.1, 71.9, 70.3, 66.3, 55.5,
50.4, 27.0, 25.4, 19.3; IR (thin film) 3502, 2933, 2858, 1724,
1513 cmꢁ1; HRMS (ESI) m/z calcd for C32H40NaO6Si (MþNa)þ
571.2492, found 571.2505.
To 19 (0.0623 g, 0.196 mmol) in toluene (2 mL) was added 1,1-
di-tert-butyl-2,2-dimethylsilirane 2 (0.0587 g, 0.296 mmol) and the
reaction mixture was cooled to ꢁ25 ꢂC. After stirring for 0.5 h, silver
tosylate (0.006 g, 0.02 mmol) was added and the mixture was
allowed to warm to room temperature. After stirring for 12 h,
HF$Pyr (0.20 mL, 1.75 mmol) was added to the solution. The re-
action mixture was then diluted with saturated aqueous NaHCO3,
the organic layer was rinsed with saturated aqueous NaHCO3
(3ꢃ25 mL), the aqueous layers were then combined, and acidified
3.6. (R)-((S,E)-Hex-4-en-3-yl) 3-(benzyloxy)-2-
oxobutanoate (17)
To (2S,3R)-((S,E)-hex-4-en-3-yl) 3-(benzyloxy)-2-hydroxy-
butanoate (0.152 g, 0.520 mmol) in CH2Cl2 (10 mL) was added

B.E. Howard, K.A. Woerpel / Tetrahedron 65 (2009) 6447–6453
6451
with 1 M HCl (ca. 100 mL) until pH 2. After the desired pH was
reached, the aqueous layer was extracted with CH2Cl2 (3ꢃ25 mL),
the organic layers were combined, dried with Na2SO4, and con-
centrated to provide a 50:25:25 mixture of diastereomers of 20
(0.042 g, 67%) as a pale yellow oil. Major diastereomer: 1H NMR
164.3, 141.5, 135.3, 132.9, 130.4, 129.3, 117.8, 63.4, 26.2, 18.5; IR (thin
film) 2973, 2936, 2859, 1912, 1747 cmꢁ1; HRMS (ESI) m/z calcd for
C13H14NaO3 (MþNa)þ 241.0841, found 241.0842. Anal. Calcd for
C13H14O3: C, 71.54; H, 6.47. Found: C, 71.68; H, 6.64.
(400 MHz, CDCl3)
d 7.53–7.28 (m, 5H), 5.70–5.58 (m, 1H), 5.33 (m,
3.13. ( )-2-Ethyl-2-hydroxy-3-vinylheptanoic acid (27)
1H), 4.81–4.65 (m, 2H), 4.59–4.45 (m, 2H), 4.05–3.92 (m, 1H), 2.82–
2.74 (m, 1H), 1.32 ꢁ1.24 (m, 3H), 1.11–0.96 (m, 12H); 13C NMR
To (E)-oct-2-enyl 2-oxobutanoate (0.861 g, 4.34 mmol) in tolu-
ene (20 mL) was added silacyclopropane 2 (1.41 g, 6.30 mmol) and
the reaction mixture was cooled to ꢁ25 ꢂC. After stirring for 0.5 h,
silver tosylate (0.121 g, 0.434 mmol) was added and the mixture
was allowed to warm to room temperature. After stirring for 12 h,
HF$Pyr (0.50 mL, 4.4 mmol) was added to the solution. The reaction
mixture was then diluted with saturated aqueous NaHCO3, the
organic layer was rinsed with saturated aqueous NaHCO3
(3ꢃ45 mL), the aqueous layers were then combined, and acidified
with 1 M HCl (300 mL) until pH 2. After the desired pH was
reached, the aqueous layer was extracted with CH2Cl2 (3ꢃ50 mL),
the organic layers were combined, dried with Na2SO4, and con-
centrated to provide 27 (0.519 g, 60%) as a white powder: mp 57 ꢂC;
(100 MHz, CDCl3)
d 176.5, 144.89, 137.2, 129.2, 128.8, 128.3, 124.7,
81.2, 77.1, 72.5, 41.5, 33.6, 30.2, 16.1, 14.1; IR (thin film) 3551, 3020,
2962, 2865, 1756, 1710 cmꢁ1; HRMS (ESI) m/z calcd for C19H28NaO4
(MþNa)þ 343.1885, found 343.1882.
3.10. Furan-2-ylmethyl 2-oxo-2-phenylacetate (21)
To a solution of benzoylformic acid (0.500 g, 3.33 mmol) in
CH2Cl2 (25 mL) was added furfuryl alcohol (0.217 g, 2.22 mmol),
N,N-dimethylaminopyridine (0.026 g, 0.22 mmol), and dicyclo-
hexylcarbodiimide (0.687 g, 3.33 mmol). After stirring for 6 h, the
solution was filtered, diluted with saturated aqueous NaHCO3, and
extracted with CH2Cl2 (3ꢃ25 mL). The organic layers were com-
bined, dried with Na2SO4, and concentrated in vacuo. The resultant
oil was purified via column chromatography to give 21 (0.20 g, 45%)
1H NMR (400 MHz, CDCl3)
5.14 (d, J¼17.1, 1H), 2.37 (t, J¼10.3, 1H), 2.13–1.70 (m, 2H), 1.59–1.11
(m, 6H), 0.92 (m, 6H); 13C NMR (100 MHz, CDCl3)
181.5, 137.1,
d
5.81–5.54 (m, 1H), 5.25 (d, J¼10.1, 1H),
d
as a yellow oil: 1H NMR (400 MHz, CDCl3)
(t, J¼7.4, 1H), 7.60–7.47 (m, 3H), 6.59 (d, J¼2.6, 1H), 6.45 (s, 1H), 5.42
(s, 2H); 13C NMR (100 MHz, CDCl3)
186.2, 163.8, 148.5,144.2, 135.4,
132.8, 130.5, 129.3, 112.4, 111.2, 59.7; IR (thin film) 2955, 2877, 1736,
1689, 1451 cmꢁ1; HRMS (ESI) m/z calcd for C13H10NaO4 (MþNa)þ
253.0477, found 253.0470.
d
8.02 (d, J¼8.0, 2H), 7.69
119.2, 80.8, 52.2, 31.1, 29.8, 29.2, 22.8, 14.4, 8.16; IR (thin film) 3535,
3020, 2959, 1706, 1220 cmꢁ1; HRMS (ESI) m/z calcd for C11H20NaO3
(MþNa)þ 199.1334, found 199.1332. Anal. Calcd for C11H20O3: C,
65.97; H, 10.07. Found: C, 65.71; H, 9.96.
d
3.14. 3-Hydroxy-5-(iodomethyl)-3-phenyldihydrofuran-
2(3H)-one (28a)
3.11. (S,E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)allyl 2-oxo-
2-phenylacetate (23)
To (ꢄ)-2-hydroxy-2-phenylpent-4-enoic acid (0.023 g, 0.12 mmol)
in acetonitrile (3 mL) at 0 ꢂC was added NaHCO3 (0.030 g,
0.36 mmol) followed by iodine (0.091 g, 0.36 mmol). After stirring
for 16 h the reaction mixture was diluted with water, and extracted
with CH2Cl2 (3ꢃ15 mL). The organic layers were then combined,
dried with Na2SO4, and concentrated in vacuo. The crude mixture
was then purified via column chromatography (3:1 hexanes/EtOAc)
to afford a 3:2 mix of diastereomers of 28a (0.034 g, 91%) as a pale
To a solution of benzoylformic acid (0.500 g, 3.33 mmol) in
CH2Cl2 (25 mL) were added (S,E)-3-(2,2-dimethyl-1,3-dioxolan-4-
yl)prop-2-en-1-ol (0.351 g, 2.22 mmol), N,N-dimethylaminopyr-
idine (0.026 g, 0.22 mmol), and dicyclohexylcarbodiimide (0.687 g,
3.33 mmol). After stirring for 6 h, the solution was filtered, diluted
with saturated aqueous NaHCO3, and extracted with CH2Cl2
(3ꢃ25 mL). The organic layers were combined, dried with Na2SO4,
and concentrated in vacuo. The resultant oil was purified by column
oil. Major diastereomer: 1H NMR (500 MHz, CDCl3)
d 7.69–7.16 (m,
5H), 4.82–4.75 (m, 1H), 3.55–3.48 (m, 1H), 3.43–3.33 (m, 1H), 3.18
chromatography (5:1 hexanes/EtOAc) to give 23 (0.25 g, 39%) as
23
(s, 1H), 2.92 (m, 1H), 2.51 (dd, J¼13.1, 9.4, 1H); 13C NMR (125 MHz,
a yellow oil: [
a]
15.2 (c 1.77, CHCl3); 1H NMR (400 MHz, CDCl3)
D
CDCl3) d 177.0, 139.7, 129.3, 128.9, 125.4, 79.2, 76.1, 45.7, 6.3; IR (thin
d
8.02 (dt, J¼8.5, 1.5, 2H), 7.73–7.62 (m, 1H), 7.58–7.48 (m, 2H), 6.01
film) 3020, 2957, 1738, 1690 cmꢁ1; HRMS (ESI) m/z calcd for
C11H11INaO3 (MþNa)þ 340.9651, found 340.9651.
(ddd, J¼7.6, 6.3, 0.6, 1H), 5.92 (ddd, J¼15.5, 8.1, 3.8, 1H), 4.90 (d,
J¼5.8, 2H), 4.58 (q, J¼6.8, 1H), 4.14 (dd, J¼8.2, 6.3, 1H), 3.64 (dd,
J¼8.2, 7.4, 1H), 1.43 (d, J¼16.5, 6H); 13C NMR (100 MHz, CDCl3)
d
186.3, 163.7, 135.4, 134.0, 130.4, 129.3, 126.4, 110.00, 109.99, 76.3,
3.15. (3S,4R)-4-Butyl-3-hydroxy-5-(1-iodoethyl)-3-
methyldihydrofuran-2(3H)-one (28b)
69.6, 65.8, 27.0, 26.2; IR (thin film) 3020, 1739, 1691, 1527,
1220 cmꢁ1
;
HRMS (ESI) m/z calcd for C16H18NaO5 (MþNa)þ
313.1052, found 313.1046. Anal. Calcd for C16H18O5: C, 66.19; H,
6.25. Found: C, 66.41; H, 6.34.
To (2S,3R)-2-hydroxy-2-methyl-3-((E)-prop-1-enyl)heptanoic
acid (0.027 g, 0.14 mmol) in acetonitrile (3 mL) at 0 ꢂC was added
NaHCO3 (0.034 g, 0.040 mmol) followed by iodine (0.101 g,
0.401 mmol). The reaction mixture was stirred for 10 h, diluted
with H2O (3 mL), and extracted with CH2Cl2 (3ꢃ15 mL). The organic
layers were then combined, dried with Na2SO4, and concentrated in
vacuo. The crude mixture was then purified by column chroma-
tography (3:1 hexanes/EtOAc) to provide 28b (0.021 g, 48%) as a 4:1
mixture of diastereomers. Major diastereomer: 1H NMR (500 MHz,
3.12. 3-Methylbut-2-enyl 2-oxo-2-phenylacetate (25)
To benzoylformic acid (0.500 g, 3.33 mmol) in CH2Cl2 (25 mL)
were added 3-methyl-2-buten-1-ol (0.191 g, 2.22 mmol), N,N-
dimethylaminopyridine (0.026 g, 0.22 mmol), and dicyclohexyl-
carbodiimide (0.687 g, 3.33 mmol). After stirring for 6 h, the
solution was filtered, diluted with saturated aqueous NaHCO3, and
extracted with CH2Cl2 (3ꢃ25 mL). The organic layers were com-
bined, dried with NaSO4, and concentrated in vacuo. The resultant
oil was purified by column chromatography to give 25 (0.516 g,
CDCl3)
d
4.98 (dq, J¼12.3, 6.2, 1H), 3.96 (t, J¼10.4, 1H), 3.10 (s, 1H),
2.41 (dt, J¼9.1, 4.5, 1H), 1.81–1.69 (m, 3H), 1.66 (s, 1H), 1.63–1.51 (m,
3H), 1.48 (s, 3H), 1.46–1.34 (m, 2H), 0.98 (t, J¼7.3, 3H); 13C NMR
(125 MHz, CDCl3) d 175.7, 81.9, 73.8, 50.6, 33.3, 32.2, 30.5, 23.3, 22.9,
96%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
d
8.03 (d, J¼7.9, 2H),
21.4, 14.0; IR (thin film) 3020, 2958, 2876, 1734, 1690, 1215 cmꢁ1
;
7.67 (t, J¼7.4, 1H), 7.52 (t, J¼7.5, 2H), 5.49 (t, J¼6.9, 1H), 4.91 (d,
HRMS (ESI) m/z calcd for C11H19INaO3 (MþNa)þ 349.0277, found
J¼7.4, 2H), 1.81 (d, J¼6.1, 6H); 13C NMR (100 MHz, CDCl3)
d
186.9,
349.0269.

6452
B.E. Howard, K.A. Woerpel / Tetrahedron 65 (2009) 6447–6453
3.16. 4-Butyl-3-ethyl-3-hydroxy-5-(hydroxymethyl)-
dihydrofuran-2(3H)-one (28c)
MeOH 10:1) to give a 5:1 mixture of diastereomers of 29 (0.086 g,
50%) as a pale yellow oil. Major diastereomer: 1H NMR (400 MHz,
CDCl3)
d
7.25 (d, J¼8.4, 2H), 6.91 (d, J¼8.5, 2H), 5.04 (s, 1H), 4.78
To (ꢄ)-2-ethyl-2-hydroxy-3-vinylheptanoic acid (0.042 g,
0.19 mmol) in CH2Cl2 (5 mL) was added N-methylmorpholine-N-
oxide (0.037 g, 0.24 mmol) followed by OsO4 (2.5% in t-BuOH,
0.007 mL). The mixture was stirred for 56 h, diluted with Na2SO3,
and extracted with EtOAc (3ꢃ10 mL). The organic layers were
then combined, dried with Na2SO4, and concentrated in vacuo.
The resulting viscous oil was then purified via column chroma-
tography (1:1 hexanes/EtOAc) to provide 28c (0.040 g, 73%) as
(s, 1H), 4.45 (d, J¼6.5, 2H), 4.33 (d, J¼6.7, 1H), 3.98–3.37 (m, 7H),
2.79 (d, J¼5.8, 1H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
179.4, 159.8, 129.9, 128.8, 114.3, 80.5, 74.3, 73.5, 71.8, 67.2, 64.0,
55.7, 47.5, 19.4; IR (thin film) 3398, 3020, 2937, 1776, 1513 cmꢁ1
;
HRMS (ESI) m/z calcd for C16H22NaO7 (MþH)þ 349.1263, found
349.1267.
3.20. (3R,4S)-3-Hydroxy-4-((4-methoxybenzyloxy)methyl)-
3-methyl-5-vinyldihydrofuran-2(3H)-one (30)
a pale oil. 1H NMR (400 MHz, CDCl3)
d
4.14 (ddd, J¼9.7, 4.4, 2.2,
1H), 4.04 (d, J¼13.0, 1H), 3.72 (dd, J¼12.9, 4.2, 1H), 3.13 (s, 1H),
2.72–2.17 (m, 2H), 1.96–1.68 (m, 3H), 1.63 (d, J¼8.5, 1H), 1.55–
1.34 (m, 4H), 1.07 (t, J¼7.5, 3H), 0.97 (t, J¼7.1, 3H); 13C NMR
To a solution of 29 (0.19 g, 0.58 mmol) in THF (60 mL) were
added triphenylphosphine (0.46 g, 1.8 mmol), imidazole (0.24 g,
3.5 mmol), and iodine (0.44 g, 1.8 mmol). The reaction mixture
was heated to reflux for 2 h and then concentrated. The re-
sultant oil was taken up in MTBE (20 mL) and washed with
saturated aqueous NaHCO3, saturated aqueous Na2SO3, and
brine. The organic fraction was dried over Na2SO4 and concen-
trated in vacuo to provide a crude oil that was purified by col-
umn chromatography (1:1 hexanes/EtOAc) to give 30 as a yellow
(100 MHz, CDCl3)
d 178.7, 82.9, 78.1, 62.8, 46.6, 29.9, 26.1, 25.8,
23.3, 14.3, 7.6; IR (thin film) 3434, 3020, 2935, 1772, 1214 cmꢁ1
;
HRMS (ESI) m/z calcd for C11H20NaO4 (MþNa)þ 239.1259, found
239.1266.
3.17. 4-Butyl-3-ethyl-3-hydroxy-5-(iodomethyl)dihydro-
furan-2(3H)-one (28d)
oil (0.17 g, 95%): 1H NMR (400 MHz, CDCl3)
d 7.35–7.11 (m, 2H),
To a solution of (ꢄ)-2-ethyl-2-hydroxy-3-vinylheptanoic acid
(0.020 g, 0.10 mmol) in THF (3 mL) at 0 ꢂC was added N-iodo-
succinimide (0.024 g, 0.11 mmol). After stirring for 0.5 h, the
reaction mixture was concentrated in vacuo and the crude
mixture was purified by column chromatography to give 28d
(0.029 g, 92%) as a 3:1 mixture of diastereomers. Major dia-
6.90 (dd, J¼6.4, 4.9, 2H), 5.89 (ddd, J¼17.2, 10.4, 6.8, 1H), 5.40 (d,
J¼17.1, 1H), 5.32 (d, J¼10.4, 1H), 4.58 (dd, J¼9.7, 7.0, 1H), 4.52–
4.36 (m, 2H), 3.82 (s, 3H), 3.60 (d, J¼5.8, 2H), 2.81 (m, 1H), 2.51
(dt, J¼9.9, 5.8, 1H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
178.6, 159.6, 134.5, 129.6, 119.6, 114.1, 79.7, 74.9, 73.4, 65.4,
55.5, 52.0, 20.3; IR (thin film) 3440, 3020, 2935, 1778,
1513 cmꢁ1; HRMS (ESI) m/z calcd for C16H20NaO5 (MþNa)þ
315.1208, found 315.1204.
stereomer: 1H NMR (400 MHz, CDCl3)
d
3.95 (ddd, J¼9.2, 5.9, 3.3,
1H), 3.65 (dd, J¼11.4, 3.3, 1H), 3.36 (dd, J¼11.4, 5.9, 1H), 2.82 (s,
1H), 2.38 (td, J¼8.8, 5.4, 1H), 1.90–1.32 (m, 7H), 1.12 (t, J¼7.4, 1H),
1.06 (t, J¼7.5, 3H), 0.98 (t, J¼7.0, 3H); 13C NMR (100 MHz, CDCl3)
Acknowledgements
d
177.4, 128.8, 80.5, 78.4, 52.2, 29.7, 26.0, 23.3, 14.3, 7.5, 6.6; IR
(thin film) 3480, 2960, 2932, 2862, 1780 cmꢁ1; HRMS (ESI) m/z
calcd for C11H19INaO3 (MþNa)þ 349.0277, found 349.0268.
This research was supported by the National Institute of General
Medical Sciences of the National Institutes of Health (GM-54909).
K.A.W. thanks Amgen and Lilly for awards to support research. We
thank Dr. Phil Dennison (UCI) for assistance with NMR spectroscopy
and Dr. John Greaves and Ms. Shirin Sorooshian (UCI) for mass
spectrometry.
3.18. 5-(Bromomethyl)-4-butyl-3-ethyl-3-hydroxydi-
hydrofuran-2(3H)-one (28e)
To a solution of (ꢄ)-2-ethyl-2-hydroxy-3-vinylheptanoic acid
(0.020 g, 0.10 mmol) in THF (3 mL) at 0 ꢂC was added N-bromo-
succinimide (0.019 g, 0.11 mmol). After stirring for 0.5 h, the re-
action mixture was concentrated and the crude mixture was
purified by column chromatography (5:1 hexanes:EtOAc) to give
28e (0.021 g, 76%) as a 5:1 mixture of diastereomers. Major di-
References and notes
1. Coppola, G. M.; Schuster, H. F. Hydroxy Acids in Enantioselective Synthesis. Wiley-
VCH: Weinheim, 1997.
2. Hannessian, S. Total Synthesis of Natural Products. The Chiron Approach; Perga-
mon: New York, NY, 1983; Chapter 2.
3. Ball, M.; Andrews, S. P.; Wierschem, F.; Cleator, E.; Smith, M. D.; Ley, S. V. Org.
Lett. 2007, 9, 663–666.
4. Goldup, S. M.; Pilkington, C. J.; White, A. J. P.; Burton, A.; Barrett, A. G. M. J. Org.
Chem. 2006, 71, 6185–6191.
5. Bunte, J. O.; Cuzzupe, A. N.; Daly, A. M.; Rizzacasa, M. A. Angew. Chem., Int. Ed.
2006, 45, 6376–6380.
6. Queffe´lec, C.; Bailly, F.; Mbemba, G.; Mouscadet, J.-F.; Debyser, Z.; Witvrouw,
M.; Cotelle, P. Eur. J. Med. Chem. 2008, 43, 2268–2271.
7. Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E. L.; Dalley, N. K. Org. Lett. 2000,
2, 3035–3037.
astereomer: 1H NMR (400 MHz, CDCl3)
d
4.23 (d, J¼5.7, 1H), 3.80 (d,
J¼11.7, 1H), 3.55 (dd, J¼11.6, 5.4, 1H), 2.90 (s, 1H), 2.49 (d, J¼5.8, 1H),
1.90–1.34 (m, 8H), 1.07 (t, J¼7.3, 3H), 0.98 (t, J¼6.2, 3H); 13C NMR
(100 MHz, CDCl3)
d
177.6, 128.6, 80.5, 78.2, 50.1, 33.1, 29.8, 26.0,
23.3, 14.2, 7.5; IR (thin film) 3471, 3020, 2960, 2933, 2873,
1778 cmꢁ1; HRMS (ESI) m/z calcd for C11H20BrO3 (MþH)þ 279.0596,
found 279.0593.
8. Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2, 2165–2167.
9. He, L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000, 65, 7627–7633.
10. Jung, J. E.; Ho, H.; Kim, H. D. Tetrahedron Lett. 2000, 41, 1793–1796.
11. Nam, J.; Lee, S. K.; Park, Y. S. Tetrahedron 2003, 59, 2397–2401.
12. Tang, L.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2870–2871.
13. Yu, H.; Ballard, C. E.; Boyle, P. D.; Wang, B. Tetrahedron 2002, 58,
7663–7679.
14. Howard, B. E.; Woerpel, K. A. Org. Lett. 2007, 9, 4651–4653.
15. Driver, T. G.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9993–10002.
16. Heinicke, J.; Gehrhus, B. J. Organomet. Chem. 1992, 423, 13–21.
17. Ando, W.; Hagiwara, K.; Sekiguchi, A. Organometallics 1987, 6, 2270–2271.
18. Calad, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 2046–2047.
19. Hiersemann, M.; Nubbemeyer, U. The Claisen Rearrangement: Methods and
Applications; Wiley-VCH: Weinheim, 2007.
3.19. (3R,4S)-5-(1,2-Dihydroxyethyl)-3-hydroxy-4-
((4-methoxybenzyloxy)methyl)-3-methyldihydrofuran-
2(3H)-one (29)
To (2R,3R,E)-2,6-dihydroxy-3-((4-methoxybenzyloxy)methyl)-
2-methylhex-4-enoic acid (0.17 g, 0.53 mmol) in CH2Cl2 (10 mL)
was added N-methylmorpholine-N-oxide (0.084 g, 0.72 mmol)
followed by OsO4 (2.5% in t-BuOH, 0.13 mL). The mixture was stir-
red for 16 h, diluted with saturated aqueous Na2SO3, and then
extracted with CHCl3/i-PrOH (3:1, 3ꢃ15 mL). The organic layers
were combined, dried with Na2SO4, and concentrated in vacuo. The
resultant oil was purified by column chromatography (CHCl3/
20. Wood, J. L.; Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A. A.; Dietrich, H.-J.
J. Am. Chem. Soc. 1999, 121, 1748–1749.

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21. Yamazaki, T.; Shinohara, N.; Kitazume, T.; Sato, S. J. Org. Chem. 1995, 60,
8140–8141.
26. Pattarozzi, M.; Zonta, C.; Broxterman, Q. B.; Kaptein, B.; De Zorzi, R.; Randaccio,
L.; Scrimin, P.; Licini, G. Org. Lett. 2007, 9, 2365–2368.
22. Nubbemeyer, U. Synthesis 2003, 961–1008.
27. Trost, B. M.; Lee, C. J. Am. Chem. Soc. 2001, 123, 12191–12201.
28. Yvin, J. C.; Chevolot-Magueur, A. M.; Chevolot, L.; Lallemand, J.-Y.; Potier, P.
J. Am. Chem. Soc. 1982, 104, 4497–4498.
23. Singh, P.; Mittal, A.; Kaur, P.; Kumar, S. Tetrahedron 2006, 62, 1063–1068.
24. Bartlett, P. A.; Barstow, J. F. J. Org. Chem. 1982, 47, 3933–3941.
25. Liu, H.; Siegel, D. R.; Danishefsky, S. J. Org. Lett. 2006, 8, 423–425.
29. Garegg, P. J.; Samuelsson, B. Synthesis 1979, 469–470.