A stereoselective synthesis of (2S,4R)-δ-hydroxyleucine methyl ester: A component of cyclomarin A

Article abstract of DOI:10.1016/j.tetasy.2005.10.005

(2S,4R)-δ-Hydroxyleucine methyl ester, the N-demethyl analogue of an amino acid contained within the macrocycle of cyclomarin A, was successfully synthesized using Davis' asymmetric Strecker reaction.

Full text of DOI:10.1016/j.tetasy.2005.10.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3623–3627
A stereoselective synthesis of (2S,4R)-d-hydroxyleucine
methyl ester: a component of cyclomarin A
*
´
Darren B. Hansen, Mari-Lynn Starr, Nikolai Tolstoy and Madeleine M. Joullie
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA
Received 20 June 2005; revised 23 September 2005; accepted 4 October 2005
Available online 10 November 2005
Abstract—(2S,4R)-d-Hydroxyleucine methyl ester, the N-demethyl analogue of an amino acid contained within the macrocycle of
cyclomarin A, was successfully synthesized using DavisÕ asymmetric Strecker reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
arin A. En route to a total synthesis of cyclomarin
A, we herein report the synthesis of (2S,4R)-d-hydroxy-
leucine based on an EvansÕ asymmetric alkylation and
DavisÕ asymmetric Strecker reaction.
Cyclomarin A is a novel cyclic peptide isolated from a
estuarine actinomycete, cultured from a sediment sam-
ple collected in Mission Bay, CA1 (Fig. 1). Cyclomarin
A is cytotoxic toward cancer cells with a mean IC50 of
2.6 lM against a panel of human cancer cell lines. Of
greater interest is cyclomarin AÕs potent anti-inflamma-
tory both in vitro and in vivo. The structure of cyclo-
marin A was deduced using a variety of spectroscopic
methods. The number of non-coded amino acids
contained with cyclomarin A has attracted significant
attention from synthetic chemists2–5 culminating in the
synthesis of cyclomarin C6, a close congener of cyclom-
2. Results and discussion
Our goal was to develop a robust and general synthetic
method based on an asymmetric alkylation and an
asymmetric Strecker reaction. After examining a num-
ber of asymmetric alkylation conditions, we chose
EvansÕ oxazolidinone method. This method would com-
plement the route chosen by Wen et al. who used two
EvansÕ alkylations to set the stereochemistry of both
stereocenters.6 The required propionyl oxazolidinone 2
was synthesized from (S)-phenylalanine7,8 (Scheme 1).
N
O
O
O
O
H
O
O
N
HO
N
H
b
a
O
N
O
N
NH2
O
N
O
N
O
O
HO
O
Bn
Bn
HO
HN
OH
H
N
3
HN
2
1
O
O
(2S,4R) δ-Hydroxyleucine
MeO
c
Cyclomarin A
BnO
HO
Figure 1. Cyclomarin A and (2S,4R) d-hydroxyleucine 1.
5
4
*
Scheme 1. Reagents and conditions: (a) NaHMDS, allyl iodide, 77%;
Corresponding author. Tel.: +1 215 898 3158; fax: +1 215 573
(b) LiBH4, 88%; (c) NaH, BnBr, 74%.
9711; e-mail: mjoullie@sas.upenn.edu
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.005

3624
D. B. Hansen et al. / Tetrahedron: Asymmetry 16 (2005) 3623–3627
N
p-tolyl
Enolization, followed by the addition of allyl iodide gave
oxazolidinone 3 as the major diastereomer in greater
than 96% de. Removal of the chiral auxiliary was accom-
plished under reductive conditions to give alcohol 4,
which was subsequently protected as its benzyl ether 5.
O
S
a
BnO
BnO
O
8
7
H
p-tolyl
N
b
S
BnO
With intermediate 5 in hand, we set out to interconvert
the terminal alkene to the desired terminal aldehyde.
Exposure of 5 to ozone gave lower than expected yields
while further spectroscopic analysis showed that not
only had the terminal olefin been oxidized but the benzyl
ether had been oxidized to benzyl ester 6, a well docu-
mented side reaction of benzyl ethers to ozone.9,10 To
circumvent this problem a new method was employed,
a one pot dihydroxylation/periodate cleavage,11 provid-
ing the desired aldehyde 7 in good yield (Scheme 2).
O
CN
9
Scheme 3. Reagents and conditions: (a) (S)-(+)-p-toluenesulfinamide,
Ti(OEt)4, 84%; (b) Et2AlCN, iPrOH, 92% yield, 91% de.
H
NH2
p-tolyl
p-tolyl
N
a
BnO
BnO
S
BnO
BnO
CN
O
CN
10
With the Strecker aldehyde precursor in hand, we
reviewed a number of asymmetric Strecker conditions
and chose DavisÕ asymmetric Strecker reaction.12–14
This method uses a chiral N-sulfinimine as both a nitro-
gen source and chiral auxiliary. Condensation of an
enantiopure p-toluenesulfinamide with an aldehyde in
the presence of a dehydrating agent gives the desired
sulfinimine [thiooxime (S)-oxide]. The addition of
Et2AlCN gives an amino nitrile, while aqueous acid
cleaves the sulfinamide chiral auxiliary and hydrolyzes
the nitrile group to afford the amino acid (Fig. 2). Hav-
ing both aldehyde 7 and (S)-(+)-p-toluenesulfinamide in
hand, the two starting materials were condensed with
titanium ethoxide to give sulfinimine 8. The key Strecker
reaction was performed according to DavisÕ improved
conditions12 to afford the desired amino nitrile 9 in good
yield and diastereoselectivity (Scheme 3).
9
9
H
N
NH2
CO2Me
b
S
O
CN
1
Scheme 4. Reagents and conditions: (a) Et2O–HCl/H2O, 74%; (b)
methanol, HCl, 86%.
and basic conditions were attempted, but in our hands
none of the desired products could be isolated. The
milder conditions developed by Davis in his synthesis
of polyoxamic acid15 gave amino nitrile 10 (Scheme 4).
To our delight, exposure to methanolic hydrogen chlo-
ride overnight afforded 1 in good yield completing
the synthesis of the methyl ester of (2S,4R) d-
hydroxyleucine.
All that remained to complete the synthesis of d-OH-
Leu was to remove the sulfinyl chiral auxiliary and
hydrolyze the nitrile group. A variety of aqueous acidic
3. Conclusion
An efficient synthesis of (2S,4R) d-hydroxyleucine
methyl ester was accomplished in seven steps using a
combination of asymmetric alkylation and DavisÕ asym-
metric Strecker reaction. The approach is flexible and
should allow for the synthesis of similar amino acids.
O
a
O
BnO
BnO
BnO
BnO
5
6
b
O
4. Experimental
4.1. General
5
7
Scheme 2. Reagents and conditions: (a) O3, then DMS, 17%; (b)
K2[OsO2(OH)4], KIO4, 78%.
Reactions requiring air-sensitive manipulations were
conducted under an argon atmosphere. Methylene chlo-
ride was distilled from calcium hydride, tetrahydrofu-
ran, and diethyl ether were distilled from sodium/
benzophenone. Analytical TLC was performed on
0.25 mm E. silica gel 60 F254 plates. Silica gel (60, parti-
cle size 0.040–0.063 mm) was used for flash column
chromatography. NMR spectra were recorded on a
500 MHz spectrometer and calibrated by using residual
undeuterated solvent or TMS as an internal reference.
Chemical shifts (d) were measured in parts per million,
and coupling constants (J values) are in hertz (Hz).
p-Tolyl
H2N
O
R
O
Ti(OEt)4
R
N
p-Tolyl
S
S
O
H
H
H
R
NH2
Et2AlCN
R
p-Tolyl
3 N HCl
N
S
i-PrOH
CO2H
O
CN
Figure 2. DavisÕ asymmetric Strecker reaction.

D. B. Hansen et al. / Tetrahedron: Asymmetry 16 (2005) 3623–3627
3625
Infrared spectra (IR) were recorded on an FT-IR spec-
4.4. (R)-[(2-Methylpent-4-enyloxy)methyl]benzene 5
trometer. High-resolution mass spectra (HRMS) were
recorded using electrospray ionization (ESI). Optical
rotations were recorded on a polarimeter at the sodium
D line. Melting points were determined in an open cap-
illary tube and are uncorrected.
Alcohol 4 (6.00 g, 59.8 mmol) was slowly added to a sus-
pension of NaH (2.15 g, 89.7 mmol) in dry DMF
(100 mL) under argon. The reaction was cooled to
0 °C and benzyl bromide (8.5 mL, 72 mmol) added
dropwise. The reaction was allowed to warm to room
temperature and stirred overnight. The reaction was
cautiously quenched with water (30mL), and diluted
with additional water (100 mL). The aqueous layer
was extracted three times with Et2O and the organic lay-
ers combined and washed with water and brine, dried
over MgSO4, and reduced in vacuo. The residue was
purified by flash silica gel chromatography, eluting with
4.2. (S)-4-Benzyl-3-((R)-2-methylpent-4-enoyl)oxazoli-
din-2-one 3
Oxazolidinone 2 (22.16 g, 0.095 mol) was dissolved in
anhydrous THF (200 mL) under argon, and then cooled
to ꢀ78 °C. NaHMDS (1.0 M in THF, 100 mL, 0.10 mol)
was added dropwise and the reaction allowed to stir for
1 h at ꢀ78 °C. Allyl iodide (27 mL, 0.30 mol) was added
dropwise and the mixture allowed to stir at ꢀ78 °C for
6 h. The reaction was checked by TLC. When the start-
ing material was consumed, the reaction was quenched
at ꢀ78 °C with satd NH4Cl (250mL) and allowed to
warm to room temperature. The reaction mixture was
treated with H2O (500 mL) and Et2O (750mL). The
organic layer was separated, washed with brine, dried
over MgSO4, and reduced in vacuo. The residue was
purified by flash silica gel chromatography, eluting with
10% CH2Cl2/hexanes to give a pale oil (8.42 g, 74%
20
yield): ½aŠ ¼ ꢀ1:6 (c 1.2, CHCl3); TLC (5% EtOAc/
D
1
Hex), Rf = 0.56; H NMR (CDCl3, 500 MHz) d 7.34–
7.26 (m, 5H), 5.81–5.75 (m, 1H), 5.03–4.98 (m, 2H),
4.50(s, 1H), 3.35–3.26 (m, 2H), 2.25–2.20(m, 1H),
1.95–1.85 (m, 2H), 0.92 (d, J = 6.5, 3H); 13C NMR
(CDCl3, 125 MHz) d 138.8, 137.0, 128.3, 127.5, 127.4,
115.9, 75.3, 73.0, 38.0, 33.4, 16.8; IR (thin film) 3064
w, 2975 m, 2908 m, 2855 m, 1640 w, 1496 w, 1454 m,
1363 m, 1099 s, 944 m, 912 s, 735 m, 697 s; HRMS
(EI): m/z calcd for C13H18O 190.1357, found 190.1350.
25% Et2O/hexanes to give a pale oil (20.70 g, 80% yield):
20
½aŠ ¼ þ98:0 (c 0.9, CHCl3); TLC (20% EtOAc/Hex),
D
1
Rf = 0.40 H NMR (CDCl3, 500 MHz) d 7.34–7.21 (m,
5H), 5.87–5.79 (m, 1H), 5.12–5.05 (m, 2H), 4.70–4.66
(m, 1H), 4.21–4.14 (m, 2H), 3.87 (sext, J = 6.8, 1H),
3.29 (dd, J = 3.3, 13.4, 1H), 2.69 (dd, J = 9.9, 13.3,
1H), 2.53 (pent, J = 5.6, 1H), 2.24 (pent, J = 7.0, 1H),
1.19 (d, J = 6.9, 3H); 13C NMR (CDCl3, 125 MHz) d
176.5, 153.1, 135.4, 135.3, 129.4, 128.9, 127.3, 117.2,
66.0, 55.4, 38.1, 38.0, 37.2, 16.4; IR (thin film) 2977 w,
1779 s, 1698 s, 1454 m, 1386 s, 1934 m, 1242 m, 1210s,
1098 w, 703 m; HRMS (EI): m/z calcd for C16H19NO3-
NA 296.1262, found 296.1253.
4.5. (R)-Benzyl 2-methyl-4-oxobutanoate 6
Olefin 5 (1.04 g, 5.49 mmol) was dissolved in CH2Cl2
(22 mL) and cooled to ꢀ78 °C, ozone was bubbled into
the reaction until a pale blue color persisted, followed by
argon for 10min. The reaction was quenched with
dimethyl sulfide (4.0mL, 55 mmol) and allowed to warm
to room temperature and stirred overnight. The reaction
mixture was reduced in vacuo. The residue was purified
by flash silica gel chromatography, eluting with 10%
EtOAc/hexanes to give a pale oil (198 mg, 17% yield):
20
½aŠ ¼ þ0:7 (c 0.9, CHCl3); TLC (10% EtOAc/Hex),
D
4.3. (R)-2-Methylpent-4-en-1-ol 4
Rf = 0.34; 1H NMR (CDCl3, 500 MHz) d 9.83 (t,
J = 1.5, 1H), 8.02 (d, J = 7, 2H), 7.57 (d, J = 7.4, 1H),
7.45 (t, J = 8.0, 2H), 4.29 (q, J = 5.4, 1H), 4.17 (q,
J = 6.7, 1H), 2.65–2.61 (m, 2H), 2.43–2.41 (m, 1H),
1.11 (d, J = 6.8, 3H); 13C NMR (CDCl3, 125 MHz) d
201.2, 166.4, 133.1, 130.0, 129.6, 128.4, 68.8, 47.9,
28.0, 17.1; IR (thin film) 2965 m, 1720 br s, 1601 w,
1452 m, 1391 w, 1315 m, 1275 br s, 1177 m, 1112 s,
1070 m, 1026 m; HRMS (EI): m/z calcd for
C12H14O3Na 229.0841, found 229.0845.
Oxazolidinone 3 (19.20g, 69.6 mmol) was dissolved in
anhydrous Et2O (400 mL) under argon and cooled to
0 °C. Absolute ethanol (4.9 mL, 84 mmol) was added
followed by the dropwise addition of LiBH4 (2.0M in
THF, 41.7 mL, 84 mmol). The reaction was allowed to
warm to room temperature overnight under argon.
The reaction was quenched slowly with 1.0M NaOH
(400 mL) and allowed to stir until both layers were clear.
The aqueous layer was separated and extracted twice
with Et2O, all the organic layers were combined, washed
with brine, dried over MgSO4, and reduced in vacuo.
The residue was purified by flash silica gel chromatogra-
4.6. (R)-4-(Benzyloxy)-3-methylbutanal 7
Under mechanical stirring, olefin 5 (4.00 g, 21.0 mmol)
was dissolved in acetone (125 mL). The solution was
diluted with water (40mL), followed by addition of
phy, eluting with 25% Et2O/pentane to give a pale oil
20
(6.3 g, 88% yield): ½aŠ ¼ ꢀ1:8 (c 0.4, CHCl3); TLC
D
(20% EtOAc/Hex), Rf = 0.33; 1H NMR (CDCl3,
500 MHz) d 5.84–5.78 (m, 1H), 5.07–5.00 (m, 2H),
3.54–3.45 (m, 2H), 2.19–2.15 (m, 1H), 1.97–1.94 (m,
1H), 1.76–1.72 (m, 1H), 1.34 (br s, 1H), 0.93 (d,
J = 6.7, 3H); 13C NMR (CDCl3, 125 MHz) d 137.0,
116.1, 67.9, 37.9, 35.6, 16.4; IR (thin film) 3337 br,
3076 m, 2924 br s, 1640 s, 1458 s, 1381 m, 1104 m,
1044 s, 993 s, 911 s; HRMS (EI): m/z calcd for
C6H13O 101.0966, found 101.0960.
K2[OsO2(OH)4] (70mg, 0.21 mmol) and NaIO (9.89 g,
4
46.3 mmol). The reaction was complete after 6 h. The
mixture was collected by filtration and the remaining
salts washed twice with Et2O. The filtrate was diluted
with brine, the organic layer was separated, and the
remaining aqueous layer washed with Et2O. The organic
layers were combined, washed twice with satd Na2S2O3,
brine, dried over MgSO4, and reduced in vacuo. The res-
idue was purified by flash silica gel chromatography,

3626
D. B. Hansen et al. / Tetrahedron: Asymmetry 16 (2005) 3623–3627
20
D
eluting with 10% EtOAc/hexanes to give a pale oil
to give a pale oil (0.98 mg, 92% yield): ½aŠ ¼ þ10:7 (c
20
(3.11 g, 78% yield): ½aŠ ¼ þ8:9 (c 0.7, CHCl3); TLC
0.7, CHCl3); TLC (20% EtOAc/Hex), Rf = 0.11; 1H
NMR (CDCl3, 500 MHz) d 7.55 (d, J = 8.2, 2H),
7.37–7.28 (m, 7H), 5.65 (d, J = 7.2, 1H), 4.52 (q,
J = 8.2, 2H), 4.25 (q, J = 7.1, 1H), 3.47 (dd, J = 4.3,
9.4, 1H), 2.00–1.94 (m, 1H), 1.84–1.79 (m, 1H), 0.96
(d, J = 6.9, 3H); 13C NMR (CDCl3, 125 MHz) d
142.0, 139.6, 137.5, 129.8, 128.5, 127.9, 127.8, 126.0,
118.7, 74.8, 73.3, 40.1, 30.6, 21.3, 17.5; IR (thin film)
3192 br m, 2924 m, 1596 w, 1564 m, 1454 m, 1364 m,
1090 s, 1067 s, 813 m, 739 m, 699 m, cmꢀ1; HRMS
(EI): m/z calcd for C20H24O2N2SNa 379.1456, found
379.1452.
D
(5% EtOAc/Hex), Rf = 0.20; 1H NMR (CDCl3,
500 MHz) d 9.76 (t, J = 2.2, 1H), 7.36–7.26 (m, 5H),
4.49 (s, 2H), 3.42 (dd, J = 5.2, 9.1, 2H), 3.25 (dd,
J = 7.6, 9.1, 1H), 2.55 (ddd, J = 2.2, 6.3, 16.2, 1H),
2.45–2.40(m, 1H), 2.28 (ddd, J = 2.1, 6.9, 16.2, 1H),
0.99 (d, J = 6.8, 3H); 13C NMR (CDCl3, 125 MHz) d
202.3, 138.4, 128.2, 127.6, 127.5, 74.9, 73.0, 48.6, 29.1,
17.1; IR (thin film) 2930w, 2856 m, 2723 w, 1723 s,
1454 m, 1363 m, 1099 m, 1028 w, 738 m, 698 m; HRMS
(EI): m/z calcd for C12H16O2 192.1150, found 192.1156.
4.7. (Ss,3R)-(+)-4-(Benzyloxy)-3-methylbutylidene-p-
toluenesulfinamide 8
4.9. (2S,4R)-2-Amino-5-(benzyloxy)-4-methylpentane-
nitrile 10
Aldehyde 7 (2.34 g, 12.2 mmol) was added to a solution
of anhydrous CH2Cl2 (175 mL) and (S)-(+)-p-toluene-
sulfinamide (1.89 g, 12.2 mmol). After the slow addition
of Ti(OEt)4 (12.8 mL, 60.9 mmol), the reaction was
heated at reflux for 2 h, then cooled to 0 °C, followed
by the slow addition of water (250mL). The turbid mix-
ture was filtered through Celite, the Celite pad then
washed twice with CH2Cl2, and the organic layer sepa-
rated, dried over MgSO4 and reduced in vacuo. The res-
idue was purified by flash silica gel chromatography,
Nitrile 9 (178 mg, 0.80 mmol) was dissolved in 2.0 M
HCl in Et2O (5.0mL) and stirred under argon for
5 min, while a white precipitate formed. After the addi-
tion of a few drops of water, the reaction was allowed
to stir under argon overnight. The solvent was removed
under reduced pressure and quenched with satd K2CO3.
The aqueous layer was then extracted three times with
EtOAc. The organic layers were combined, washed with
brine, dried over MgSO4, and reduced in vacuo. The res-
idue was purified by flash silica gel chromatography,
eluting with 10% EtOAc/hexanes to give a pale oil
20
(3.33 g, 84% yield): ½aŠ ¼ þ37:0 (c 4.0, CHCl3); TLC
eluting with 10% EtOAc/hexanes to give a pale oil
D
20
(20% EtOAc/Hex), Rf = 0.30; 1H NMR (CDCl3,
500 MHz) d 8.25 (t, J = 5.1, 1H), 7.54 (d, J = 8.1, 2H),
7.34–7.25 (m, 7H), 4.44 (s, 2H), 3.36–3.33 (m, 1H),
3.28–3.25 (m, 1H), 2.67–2.26 (m, 1H), 2.39–2.23 (m,
4H), 2.25–2.23 (m, 1H), 0.96–0.93 (m, 3H); 13C NMR
(CDCl3, 125 MHz) d 166.4, 141.8, 141.5, 138.3, 129.6,
128.3, 127.5, 127.4 124.4, 74,7, 73.0, 40.0, 31.4, 21.3,
16.9; IR (thin film) 3029 w, 2957 m, 2871 m, 1619 s,
1494 m, 1454 m, 1363 m, 1097 s, 1073 s, 810 m, 738
m, 699 m; HRMS (EI): m/z calcd for C19H23O2N1SNa
352.1347, found 352.1354.
(113 mg, 74% yield): ½aŠ ¼ þ8:0 (c 0.6, CHCl3); TLC
D
(50% EtOAc/Hex), Rf = 0.18; 1H NMR (CDCl3,
500 MHz) d 7.37–7.26 (m, 5H), 4.50(s, 3H), 3.81 (t,
J = 7.4, 1H), 3.41–3.38 (m, 1H), 3.32–3.29 (m, 1H),
2.16–2.08 (m, 1H), 1.94–1.84 (m, 1H), 1.67–1.59 (m,
3H), 0.98 (d, J = 6.7, 3H); 13C NMR (CDCl3,
125 MHz) d 138.7, 128.8, 128.1, 128.0, 122.7, 75.6,
73.5, 42.2, 40.4, 30.8, 17.5; IR (thin film) 3380 w, 2956
w, 2859 m, 2358 s, 1455 m, 1363 m, 1095 s, cmꢀ1; HRMS
(CI): m/z calcd for C12H18ON 192.1388, found 192.1386.
4.10. (2S,4R)-Methyl 2-amino-5-(benzyloxy)-4-methyl-
pentanoate 1
4.8. (Ss,2S,4R)-(+)-N-(p-Toluenesulfinyl)-2-amino-5-
(benzyloxy)-4-methylpentanenitrile 9
Nitrile 9 (126 mg, 0.58 mmol) was dissolved in MeOH
(5.0mL) under argon and then cooled to 0 °C. HCl
gas was bubbled through the solution for 1 min. The
round-bottomed flask was then sealed and allowed to
stir overnight at room temperature. The reaction was
then slowly poured into satd NaHCO3 (50mL) and
more NaHCO3 added to keep the solution basic. The
aqueous layer was extracted three times with EtOAc,
the organic layers were combined, washed with brine,
dried over MgSO4, and reduced in vacuo. The residue
was purified by flash silica gel chromatography, eluting
Sulfinimine 8 (100 mg, 0.30 mmol) was dissolved in
anhydrous THF (15 mL) in a flame-dried, round-bot-
tomed flask, under argon and the solution cooled to
ꢀ78 °C. In a separate flame-dried round-bottomed flask,
THF (5 mL) was added, under argon, and cooled to
0 °C, Et2AlCN (1.0 M toluene, 0.45 mL, 0.45 mmol)
was added followed by iPrOH (0.02 mL, 0.30 mmol).
The reaction was allowed to stir at 0 °C for 10min
and then cannulated into the round-bottomed flask at
ꢀ78 °C and allowed to stir for 10min. It was warmed
to room temperature and stirred overnight. The reaction
was cooled to ꢀ78 °C, quenched with satd NH4Cl, and
warmed to room temperature. The reaction was filtered
through celite and the celite pad washed twice with
EtOAc. All the organic filtrates were combined, washed
with brine, dried over MgSO4, and reduced in vacuo.
The crude residue was examined 1H NMR (CDCl3,
500 MHz) to determine a 91% de by integration of the
methyl protons. The residue was purified by flash silica
gel chromatography, eluting with 20% EtOAc/hexanes
with 10% CH3CN/CH2Cl2 to give a yellow oil (79 mg,
20
86% yield): ½aŠ ¼ ꢀ36:0 (c 1.1, CHCl3); TLC (100%
D
EtOAc), Rf = 0.15; 1H NMR (CDCl3, 500 MHz) d
7.36–7.26 (m, 5H), 4.52–4.73 (m, 2H), 3.71 (s, 3H),
3.58 (t, J = 6.8, 1H), 3.34 (d, J = 6.0, 2H), 2.20–1.94
(m, 1H), 1.88–1.83 (m, 1H), 1.71 (br s, 2H), 1.46–1.40
(m, 1H), 0.99 (d, J = 6.8, 3H); 13C NMR (CDCl3,
125 MHz) d 176.6, 138.5, 128.3, 127.5, 127.5, 75.4,
73.0, 52.7, 51.9, 39.6, 30.4, 17.8; IR (thin film) 2928 m,
2854 m, 1736 s, 1454 m, 1363 w, 1200 m, 1172 m,

D. B. Hansen et al. / Tetrahedron: Asymmetry 16 (2005) 3623–3627
3627
´
4. Tarver, J. E.; Joullie, M. M. J. Org. Chem. 2004, 69, 815–
1095 m, 737 m, 698 m; HRMS (EI): m/z calcd for
C14H22O3N 252.1600, found 252.1611.
820.
´
5. Tarver, J. E.; Terranova, K. M.; Joullie, M. M. Tetra-
hedron 2004, 60, 10277–10284.
6. Wen, S. J.; Yao, Z. J. Org. Lett. 2004, 6, 2721–2724.
7. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83–91.
8. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77–82.
9. Hirama, M.; Shimizu, M. Synth. Commun. 1983, 13, 781–
786.
10. Smith, A. B., III; Nolen, E. G.; Shirai, R.; Blase, F. R.;
Ohta, M.; Chida, N.; Hartz, R. A.; Fitch, D. M.; Clark,
W. M.; Sprengeler, P. A. J. Org. Chem. 1995, 60, 7837–
7848.
Acknowledgments
We thank the NSF (CHEM-0130958) and the Univer-
sity of Pennsylvania for support. We also acknowledge
additional financial support in the form of an REU
undergraduate fellowship from the NSF to M.L.S.
11. Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S.
J. Org. Chem. 1956, 21, 478–479.
References
12. Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y. H.
J. Org. Chem. 1996, 61, 440–441.
13. Davis, F. A.; Zhang, Y. L.; Andemichael, Y.; Fang, T. A.;
Fanelli, D. L.; Zhang, H. M. J. Org. Chem. 1999, 64,
1403–1406.
1. Renner, M. K.; Shen, Y. C.; Cheng, X. C.; Jensen, P. R.;
Frankmoelle, W.; Kauffman, C. A.; Fenical, W.; Lobkov-
sky, E.; Clardy, J. J. Am. Chem. Soc. 1999, 121, 11273–
11276.
2. Sugiyama, H.; Shioiri, T.; Yokokawa, F. Tetrahedron
Lett. 2002, 43, 3489–3492.
14. Davis, F. A.; Zhou, P.; Chen, B. C. J. Chem. Soc. Rev.
1998, 27, 13–18.
3. Sugiyama, H.; Yokokawa, F.; Aoyama, T.; Shioiri, T.
Tetrahedron Lett. 2001, 42, 7277–7280.
15. Davis, F. A.; Prasad, K. R.; Carroll, P. J. J. Org. Chem.
2002, 67, 7802–7806.