cis-5-Amino-6-hydroxycyclohexadiene as a chiral building block: An asymmetric synthesis of (-)-swainsonine

Article abstract of DOI:10.1002/(SICI)1521-3765(19991105)5:11<3279::AID-CHEM3279>3.0.CO;2-4

A new asymmetric building block, cis-5-hydroxy-6-aminocyclohexa-1,3- diene in which the double bonds are differentiated as the Diels-Alder adduct with anthracene, is available in an enantiomerically pure form in three or four steps from anthracence and benzoquinone. The key step is a palladium- catalyzed desymmetrization of a meso-2-en-1,4-diol. It serves as a chiral precursor of the anticancer agent swainsonine. Diastereoselective dihydroxylation dictated by the dihydroanthracence unit sets the four stereogenic centers of swainsonine. The sequence then first creates the pyrrolidine ring followed by the piperidine ring. The effectiveness of the synthesis is evident from the overall yield of 15% for the 15-step protocol.

Full text of DOI:10.1002/(SICI)1521-3765(19991105)5:11<3279::AID-CHEM3279>3.0.CO;2-4

FULL PAPER
cis-5-Amino-6-hydroxycyclohexadiene as a Chiral Building Block:
An Asymmetric Synthesis of ( )-Swainsonine
Barry M. Trost* and Daniel E. Patterson[a]
Abstract: A new asymmetric building block, cis-5-hydroxy-6-aminocyclohexa-1,3-
diene in which the double bonds are differentiated as the Diels ± Alder adduct with
anthracene, is available in an enantiomerically pure form in three or four steps from
anthracence and benzoquinone. The key step is a palladium-catalyzed desymmetri-
zation of a meso-2-en-1,4-diol. It serves as a chiral precursor of the anticancer agent
swainsonine. Diastereoselective dihydroxylation dictated by the dihydroanthracence
unit sets the four stereogenic centers of swainsonine. The sequence then first creates
the pyrrolidine ring followed by the piperidine ring. The effectiveness of the synthesis
is evident from the overall yield of 15% for the 15-step protocol.
Keywords: alkaloids
synthesis ´ natural products ´ palla-
dium ´ swainsonine ´ total synthesis
´ asymmetric
Introduction
O
O
4
O
O
ent-4
NH HN
Asymmetric synthesis utilizing
NH HN
transition metal catalysis has
O
the advantage of providing
equivalent access to either
enantiomer of the product. Ex-
ploring the properties of both
O
PPh2
Ph2P
Ph2
P
O
O
PPh2
O
O
O
O
N
N
[(dba)3Pd2]•CHCl3
TsNH
NHTs
[(dba)3Pd2]•CHCl3
Ts
Ts
(C2H5)3N
(C2H5)3N
99% ee
99% ee
Scheme 1. Enantioselective synthesis of vinyloxazolidin-2-ones.
enantiomeric forms becomes
increasingly important. For ex-
This strategy was examined in the context of a synthesis of
the anticancer agent ( )-swainsonine (5). Polyhydroxylated
indolizidine alkaloids such as swainsonine have received
considerable attention because of their activity as glucosidase
inhibitors and because of their structural complexity.[7] These
ample, in the development of nucleoside analogues as anti-
HIV agents, the l-nucleosides sometimes are clinically
preferred over the ªnaturalº d-isomers because they have
lower toxicity.[1] We have been developing the utility of the
AAA (asymmetric allylic alkylation) reaction with palladium,
molybdenum, and tungsten catalysis.[2±4] Recently, we estab-
lished that the bis-urethanes of meso-2-ene-1-4-diols can be
cyclized to vinyloxazolidin-2-ones with near perfect enantio-
selectivity as shown in Scheme 1.[5] This reaction serves as the
equivalent of an asymmetric and regioselective cis-amino-
hydroxylation of a diene. We envisioned that an equivalent of
the oxazolidin-2-one 1, in which the double bonds were
differentiated as in 2, would be a useful asymmetric building
block. Using the method of Scheme 1, the achiral precursor
becomes diol 3 which derives in two steps from anthracene
and benzoquinone (Scheme 2).[6]
H
H
H
H
OH
NTs
O
O
O
O
HO
NTs
1
2
3
Scheme 2. The key intermediates.
compounds have shown anticancer, antiviral, and immunor-
egulatory properties. Swainsonine was first isolated from the
fungus Rhizoctonia leguminicola in 1973.[8] It has shown
activity as a potent inhibitor of both lysosomal a-mannosidase
and mannosidase II, and has been selected for clinical testing
[a] Prof. Dr. B. M. Trost, D. E. Patterson
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Fax: (‡1)650725-0002
E-mail: bmtrost@leland.stanford.edu
Chem. Eur. J. 1999, 5, No. 11
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3279

B. M. Trost and D. E. Patterson
FULL PAPER
as an anticancer drug.[9] Because of its biological importance,
swainsonine has been the focus of extensive synthetic effort.
Most of the syntheses reported to date use carbohydrate
starting materials,[10] but there have been four total syntheses
from achiral starting materials.[11] We report an effective
synthesis of ( )-swainsonine starting from achiral starting
materials that utilizes the palladium-catalyzed desymmetriza-
tion of meso-bis-carbamates.
[(dba)3Pd2]•CHCl3
OCONHTs
4
2
THF, DMSO
99% ee
OCONHTs
80%
6
Scheme 4. Synthesis of 2.
The present strategy for the synthesis of swainsonine is
shown in Scheme 3. Swainsonine is available from Avia a two-
carbon homologation followed by ring closure. Aldehyde A
could arise from B by a reductive ozonolysis followed by a
Mitsunobu cyclization and oxidation. Cyclohexene B was
proposed to arise from oxazolidinone 2 by diastereoselective
dihydroxylation followed by a retro Diels ± Alder reaction.
eocenters of swainsonine in the correct configuration. Pro-
tection of the diol as the acetonide 8 proceeded in 94% yield,
and basic hydrolysis of the oxazolidinone provided the desired
amino alcohol 9 in 96% yield. The protected double bond of 9
was unmasked by flash vacuum thermolysis (5008C,
0.05 mmHg, 91%). The ªdeblockingº can also be done at
the stage of oxazolidin-2-one 8, but the FVT yields were
lower. The choice of the alcohol protecting group is important
for the next stage of the synthesis. With many silyl ethers, after
ozonolysis and reductive work-up, they had a propensity to
migrate from the secondary alcohol to the neighboring
primary alcohol. For example, the TBDPS group extensively
migrated. We therefore turned to the MOM (methoxymethyl)
protecting group but were thwarted as a result to N-alkylation
competing with O-alkylation. A satisfactory solution was
found in the use of the triisopropylsilyl (TIPS) ether but even
here, the temperature during the reduction phase had to be
carefully controlled. The hydroxyl group of 10 was protected
as the TIPS ether in standard fashion to give cyclohexene 11 in
95% yield. Ozonolysis of 11 followed by treatment with
dimethyl sulfide gave the corresponding hemiaminal, which
could be isolated if desired. Normally, it was directly reduced
to the acyclic amino diol 12 with sodium borohydride in
methanol in 62% yield. Exposure of 12 to Mitsunobu
conditions closed the five-membered ring in 86%. There is
OP'
P'O
HO
OP
OH
H
H
N
O
NHTs
OP
2
OP
OH
TsN
OP
(-)-swainsonine 5
A
B
Scheme 3. Retrosynthesis of ( )-swainsonine.
The present synthesis uses the desymmetrization of diol 3
(readily available in two steps from anthracene and benzo-
quinone in 85% overall yield)[6] to set the stereochemistry of
the 1,2-amino alcohol functionality found in swainsonine.
Treatment of 3 with tosyl isocyanate (room temperature to
608C, THF) provided the desired bis-carbamate 6 in 90%
yield. Desymmetrization with [dba3Pd2] ´ CHCl3 (tris-diben-
zylideneacetone-bis-palladium, chloroform solvate) and chi-
ral ligand 4 afforded oxazolidinone 2 in 80% yield and >99%
ee (Scheme 4). The enantiomer-
ic excess was determined to be
>95% by chiral shift analysis,
and >99% by chiral HPLC
OH
O
analysis on the amino alco-
hol.[10] Because of the low sol-
a
b
2
O
OH
ubility of 6 in most organic
solvents, a mixed solvent sys-
tem of THF/DMSO (5:1) gave
7
8
O
NTs
O
NTs
O
O
the best results. The bis-carba-
mate may be formed in situ
from diol 3 and the chiral
O
O
O
c
d
e
O
O
O
palladium catalyst subsequently
HO
NHTs
O
HO
NHTs
TIPSO
NHTs
11
added, but the yield was lower
although the ee was still excel-
lent. It is best to recrystallize
the bis-carbamate for reprodu-
cible results.
With enantiopure oxazolidin-
2-one 2 in hand, its dihydrox-
ylation proceeded from the less
hindered face to give a single
diastereomer of diol 7 in 95%
yield (Scheme 5). Diol 7 con-
tains the four contiguous ster-
9
10
TIPSO
TIPSO
TIPSO
HO
O
O
H
H
f
g
h
O
HO
O
O
O
TsN
14
TsN
13
TsHN
12
OH
Scheme 5. Synthesis of fragment A (14). a) OsO4, NMO, CH2Cl2, RT, 12 h, 95%; b) 2,2-dimethoxypropane,
p-TsOH ´ H2O, acetone, RT, 2 h, 94%; c) K2CO3, MeOH/H2O (9:1), 608C, 1.5 h, 96%; d) FVT 5008C,
0.05 mmHg, 91%; e) TIPSOTf, 2,6-lutidine, CH2Cl2, RT, 3 h, 95%; f) O3, CH2Cl2, 788C, 15 min, then Me2S,
788C !RT, 2 h, then NaBH4, MeOH, 08C, 1 h, 62%; g) DIAD, Ph3P, THF, 08C, 45 min, 86%; h) Dess ± Martin
periodinane, NaHCO3, CH2Cl2, RT, 45 min, 98%.
3280
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Chem. Eur. J. 1999, 5, No. 11

Synthesis of ( )-Swainsonine
3279±3284
no need to protect the other primary alcohol since azetidine
formation is much less favorable than pyrrolidine formation.
Oxidation of the primary alcohol 13 with Dess ± Martin
periodinane afforded key aldehyde 14 nearly quantitatively.
Two routes were investigated for the synthesis of swainso-
nine from aldehyde 14. In route A, the six-membered ring of
swainsonine was envisioned to be closed by a 6-endo
palladium-catalyzed allylic amination. To investigate route
A (Scheme 6), aldehyde 14 was treated with vinylmagnesium
bromide in THF (95%). Conversion of the resulting mixture
of diastereomeric allyl alcohols 15 to the methyl carbonate
required use of a strong base such as n-butyllithium. Removal
of the toluenesulfonyl protecting group with sodium ± mer-
concomitant lactamization gave bicyclic lactam 20 in 72%
yield. The final two steps were similar to several previous
syntheses of swainsonine.[10, 15] Borane reduction went
smoothly in 95% yield to give protected swainsonine 21.
Acidic deprotection afforded ( )-swainsonine 5 in 88% yield.
Conclusion
( )-Swainsonine of >99% ee was synthesized in 15 steps
from achiral starting materials in 15% overall yield. The four
contiguous stereocenters were efficiently set from a palla-
dium-catalyzed desymmetrization of a meso-bis-carbamate
followed by a diasteroselective
dihydroxylation. Either isomer
of swainsonine is readily avail-
TIPSO
TIPSO
TIPSO
O
O
O
H
H
H
HO
b,c
able depending only on the
choice of the chiral ligand.
More generally, the adduct 2,
readily available enantiomeri-
cally pure in four steps (three
steps if urethane formation is
done in situ) should prove to be
a versatile synthon related to 1
a
O
O
O
14
O
O
N
N
TsN
16
17
15
Scheme 6. Route A: Attempted palladium-catalyzed allylic amination. a) Vinylmagnesium bromide, THF,
788C, 10 min, 95%; b) nBuLi, methyl chloroformate, THF, 788C, 15 min, 62%; c) 3% Na(Hg), Na2HPO4,
MeOH, RT, 30 min, 68%.
cury amalgam in methanol buffered with sodium dibasic
phosphate[12] effected a cyclization of the amine onto the
carbonate to form the bicyclic carbamate 16 directly in 69%
yield. All attempts to convert 15 into the desired allyl amine
17 using palladium catalysis however, were unsuccessful and
resulted in simply the epimerization of the starting material at
the carbamate chiral center, or decomposition. This result
suggests that the desired p-allyl palladium intermediate was
formed, but the desired decarboxylation and intramolecular
amination never occurred. Support for this interpretation
derives from the fact that use of an external nucleophile such
as p-methoxyphenol under otherwise identical conditions
does lead smoothly to alkylation of the phenol by the
vinylcarbamate 16.
Because of the inability to effect the cyclization of 16 to
form 17, route B was examined (Scheme 7). In route B,
olefination followed by lactamization would install the last
two carbons and close the ring. Horner± Wadsworth ± Em-
mons olefination[13] of aldehyde 14 provided the trans-enoate
18 in 90% yield, which was hydrogenated over platinum oxide
to afford ester 19 in 99% yield. Detosylation of 19 with
wherein each of the remaining double bonds can be selec-
tively and sequentially modified and with high diastereose-
lectivity.
Experimental Section
General methods: Reactions were generally conducted under a positive
pressure of dry argon or nitrogen in flame-dried glassware. THF was
distilled from sodium benzophenone ketyl. Methylene chloride and
acetonitrile were distilled from calcium hydride. Methanol and ethanol
were distilled from magnesium methoxide and magnesium ethoxide,
respectively. Acetone was distilled from calcium sulfate. Dimethyl sulf-
oxide was distilled at 608C at 0.1 mmHg. Common reagents and materials
were purchased from commercial sources and purified by distillation or
recrystallization. Anhydrous solvents and reaction mixtures were trans-
ferred by oven-dried syringe or cannula. Flash chromatography employed
ICN silica gel (Kieselgel 60, 230 ± 400 mesh), analytical TLC was per-
formed with 0.2 mm silica-coated glass plates (E. Merck, DC-Platten
Kieselgel 60 F254). Melting points were not corrected. Microanalyses were
performed by M-H-W Laboratories, Phoenix AZ.
Synthesis of oxazolidin-2-one (2): Toluenesulfonyl isocyanate (6.56 g,
33.3 mmol) was added to a slurry of diol 3[6] (5.0 g, 17.24 mmol) in THF
(38 mL). The resulting solution was stirred at room temperature for 30 min
and at 608C for 15 min. The resulting white slurry was cooled to 08C and
the solid was collected by filtration and dried to give bis-carbamate 6 as a
TIPSO
TIPSO
white solid (1:1.8 bis-carbamate/THF, 12.5 g, 90%). M.p. 230 ± 2328C
O
O
H
H
1
(THF); IR (neat) 3212, 2927, 1725, 1458, 1347, 1237, 1160 cm
;
1H NMR
a
c
b
O
O
14
(300 MHz, CDCl3/[D6]DMSO): d ˆ 7.98 (d, J ˆ 8.1 Hz, 4H), 7.75 (s, 2H),
7.38 (d, J ˆ 8.3 Hz, 4H), 7.15 (m, 4H), 7.07 (m, 4H), 5.09 (s, 2H), 4.75 (s,
2H), 4.25 (s, 2H), 2.72 (s, 2H), 2.46 (s, 6H); 13C NMR (50 MHz, CDCl3/
[D6]DMSO): d ˆ 149.2, 142.8, 142.3, 139.9, 135.2, 128.1, 126.1, 124.5, 124.3,
123.2, 122.4, 121.8, 69.6, 42.1, 38.8, 19.8. The compound was taken directly
to the next step.
TsN
TsN
EtO2C
EtO2C
18
19
TIPSO
TIPSO
O
O
O
H
N
H
e
d
O
5
DMSO (8 mL) was added to a slurry of the bis-carbamate 6 (7.85 g,
9.751 mmol) in THF (26 mL). An orange solution of [dba3Pd2] ´ CHCl3
(252 mg, 0.252 mmol) and ligand 4 (504 mg, 0.730 mmol) in THF (15 mL)
was then added in two portions. The resulting orange solution was stirred at
room temperature for 12 h. The reaction was diluted with methylene
chloride (100 mL), washed with water (100 mL), and concentrated.
Column chromatography on silica (25% petroleum ether/CH2Cl2) gave a
N
O
21
20
Scheme 7. Route B: Completion of the synthesis. a) Triethyl phosphono-
acetate, LiCl, DBU, CH3CN, RT, 2 h, 90%; b) PtO2, H2 (1 atm), EtOH, RT,
1.5 h, 99%; c) 3% Na(Hg), Na2HPO4, MeOH, RT, 3 h, 72%; d) BH3 ´
Me2S, THF, RT, 2 h, then EtOH, 95%; e) 6n HCl, THF, RT, 14 h, 88%.
Chem. Eur. J. 1999, 5, No. 11
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B. M. Trost and D. E. Patterson
FULL PAPER
white solid which was washed with 20% ethyl acetate/petroleum ether and
filtered to give 2 as a white solid (3.7 g, 80%)in >95% ee as determined by
1H NMR Eu(hfc)3 chiral shift experiment. [a]2D5 ˆ ‡76.3 (c ˆ 1.54 in
CH2Cl2); m.p. 250 ± 2528C (EtOAc/hexane); IR (neat): nÄ ˆ 3068, 3041,
CDCl3): d ˆ 7.78 (d, J ˆ 8.1 Hz, 2H), 7.26 (d, J ˆ 8.1 Hz, 2H), 5.99 (dd, J ˆ
4.9, 10.0 Hz, 1H), 5.89 (dd, J ˆ 3.4, 10.0 Hz, 1H), 5.64 (d, J ˆ 5.9 Hz, 1H),
4.54 (m, 1H), 4.33 (s, 1H), 4.25 (m, 1H), 3.24 (m, 1H), 3.17 (s, 1H), 2.38 (s,
3H), 1.25 (s, 3H), 1.00 (s, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 143.6,
136.4, 131.1, 129.6, 127.4, 126.7, 109.6, 73.3, 71.5, 64.9, 56.4, 27.1, 25.7, 21.4;
anal. calcd for C16H21NO5S: C 56.62, H 6.24 N 4.13; found: C 56.75, H 6.45,
N 4.24.
1
2926, 1780, 1596, 1458, 1364, 1316 cm 1; H NMR (300 MHz, CDCl3): d ˆ
7.81 (d, J ˆ 8.3 Hz, 2H), 7.29 (m, 5H), 7.10 (m, 3H), 6.95 (m, 2H), 5.91 (d,
J ˆ 10.3 Hz, 1H), 5.63 (d, J ˆ 10.5 Hz, 1H), 5.00 (t, J ˆ 7.3 Hz, 1H), 4.64 (m,
1H), 4.59 (s, 1H), 4.27 (s, 1H), 2.70 (m, 1H), 2.59 (m, 1H), 2.44 (s, 3H);
13C NMR (75 MHz, CDCl3): d ˆ 150.9, 145.3, 144.1, 143.0, 140.9, 140.2,
135.1, 133.7, 129.7, 128.3, 126.4, 126.3, 126.1, 126.0, 125.5, 124.0, 123.7, 123.0,
121.9, 73.9, 54.7, 49.7, 45.5, 38.0, 37.0, 21.7); anal. calcd for C28H23NO4S: C
71.62, H 4.94; found: C 71.86, H 5.08.
N-(5-Triisopropylsilyloxy-2,2-dimethyl-[3a,4,5,7a]-tetrahydro-benzo[1,3]-
dioxol-4-yl)-4-methyl-benzenesulfonamide (11): A solution of alcohol 10
(1.73 g, 5.10 mmol), triisopropylsilyl trifluoromethanesulfonate (1.7 mL,
6.32 mmol), and 2,6-lutidine (0.84 mL, 7.21 mmol) in methylene chloride
(20 mL) was stirred at room temperature for 3 h. The reaction was diluted
with methylene chloride (50 mL) washed with water (2 Â 25 mL), dried
(MgSO4), filtered and concentrated. Column chromatography on silica
(10% EtOAc/petroleum ether) gave the triisopropylsilyl ether 11 as a
Synthesis of diol (7): 4-Methylmorpholine-N-oxide (6 g, 51.17 mmol) was
added to a solution of oxazolidinone 2 (8.0 g, 17.05 mmol) and osmium
tetraoxide (1.08 mL, 4% solution in water, 0.17 mmol) in methylene
chloride (70 mL). The resulting solution was stirred at room temperature
overnight. Sodium sulfite (19 g) and water (40 mL) were added and the
solution was stirred 20 min. The reaction mixture was diluted with
methylene chloride (150 mL) and water (100 mL). The aqueous phase
was extracted with methylene choride (100 mL). The combined organic
extracts were dried (MgSO4), filtered, and concentrated. Filtration through
silica gel (45% EtOAc/petroleum ether) gave diol 7 as a white solid (8.01 g,
95%). [a]2D5 ˆ ‡55.1 (c ˆ 1.7 in CH2Cl2); m.p. 200 ± 2058C (EtOAc/hex-
ane); IR (neat): nÄ ˆ 3453, 3069, 2925, 1784, 1596, 1467, 1357 cm 1; 1H NMR
(300 MHz, CDCl3): d ˆ 7.84 (d, J ˆ 8.3 Hz, 2H), 7.33 (d, J ˆ 8.3 Hz, 2H),
7.27 (m, 4H), 7.09 (m, 4H), 4.93 (m, 1H), 4.43 (s, 1H), 4.40 (s, 1H), 4.24 (d,
J ˆ 8.1 Hz, 1H), 3.51 (m, 2H), 3.17 (brs, 1H), 2.52 (m, 2H), 2.45 (s, 3H),
2.38 (s, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 150.7, 146.0, 144.1, 143.4,
141.4, 140.4, 134.1, 129.9, 128.4, 126.3, 126.1, 126.0, 125.8, 124.6, 123.6, 123.1,
72.5, 69.2, 65.8, 62.1, 60.4, 46.3, 44.9, 39.8, 38.8, 21.7, 21.0, 15.2, 14.1; HRMS:
colorless oil (2.368 g, 95%). [a]D25
ˆ
83.0 (c ˆ 3.10 in CH2Cl2); IR (neat):
nÄ ˆ 3290, 1599, 1453, 1380, 1338 cm 1; 1H NMR (300 MHz, CDCl3): d ˆ 7.77
(d, J ˆ 8.1 Hz, 2H), 7.27 (d, J ˆ 8.1 Hz, 2H), 5.81 (m, 2H), 4.88 (d, J ˆ
5.1 Hz, 1H), 4.59 (m, 1H), 4.53 (t, J ˆ 6.4 Hz, 1H), 4.46 (m, 1H), 3.47 (q,
J ˆ 5.1 Hz, 1H), 2.39 (s, 3H), 1.30 (s, 3H), 1.16 (s, 3H), 0.95 (m, 21H);
13C NMR (75 MHz, CDCl3): d ˆ 143.4, 136.7, 130.9, 129.5, 127.4, 127.3,
109.4, 73.9, 71.3, 65.6, 56.3, 27.3, 26.0, 21.4, 17.9, 17.8, 12.2; anal. calcd for
C27H41NO5SSi: C 60.57, H 8.34 N 2.83; found: C 60.39, H 8.16, N 2.80.
N-[3-Hydroxy-1-(5-hydroxylmethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-2-tri-
isopropylsilyloxy-propyl]-4-methyl-benzenesulfonamide (12): Ozone was
bubbled through a solution of protected alcohol 11 (1.01 g, 2.07 mmol) in
methylene chloride (8 mL) at 78C for 15 min. Nitrogen was bubbled
through the solution for 5 min. Dimethyl sulfide (0.6 mL) was added and
the reaction was allowed to warm to room temperature. The reaction was
stirred at room temperature for 1 h and concentrated. Methanol (8 mL)
was added and the reaction was cooled to 08C and sodium borohydride
(171 mg, 4.51 mmol) was added slowly. The reaction was stirred at 08C for
1 h. The reaction was quenched with water and extracted with methylene
chloride (2 Â 50 mL). The combined organic extracts were dried (MgSO4),
filtered and concentrated. Column chromatography on silica (30% EtOAc/
‡
calcd for C28H25NO6S: 503.1402 [M] ; found: 503.1411.
Synthesis of acetonide (8): A solution of diol 7 (8.0 g, 16.19 mmol), 2,2-
dimethoxypropane (9 mL, 73.19 mmol) and p-toluenesulfonic acid mono-
hydrate (100 mg, 0.525 mmol) in acetone (90 mL) was stirred for 2 h. The
solution was concentrated and column chromatography on silica (25%
EtOAc/petroleum ether) gave 8 (7.8 g, 94%) as a white solid. [a]2D5 ˆ ‡67.6
petroleum ether) gave diol 12 as a colorless oil (680 mg, 62%). [a]D25
ˆ
6.7
(c ˆ 1.92 in CH2Cl2); m.p. 236 ± 2378C (EtOAc/hexane); IR (neat): nÄ ˆ
(c ˆ 2.61 in CH2Cl2); IR (neat): nÄ ˆ 3289, 1600, 1463, 1380, 1337, 1217,
1
1
2987, 2934, 1790, 1732, 1597, 1467, 1379, 1306 cm
;
1H NMR (300 MHz,
1164 cm
;
1H NMR (300 MHz, CDCl3): d ˆ 7.77 (d, J ˆ 8.3 Hz, 2H), 7.29
CDCl3): d ˆ 7.91 (d, J ˆ 8.4 Hz, 2H), 7.1 ± 7.4 (m, 7H), 7.0 ± 7.1 (m, 3H), 4.91
(t, J ˆ 6.4 Hz, 1H), 4.41 (s, 2H), 4.34 (dd, J ˆ 1.5, 6.4 Hz, 1H), 3.59 (dd, J ˆ
5.1, 7.3 Hz, 1H), 3.40 (dd, J ˆ 5.1, 1.5 Hz, 1H), 2.49 (m, 1H), 2.43 (s, 3H),
2.31 (m, 1H), 1.45 (s, 3H), 1.28 (s, 3H); 13C NMR (75 MHz, CDCl3): d ˆ
150.9, 145.8, 144.5, 142.1, 140.8, 140.4, 134.6, 129.8, 128.3, 126.8, 126.6, 126.1,
126.0, 125.9, 124.7, 124.0, 122.7, 108.2, 75.7, 75.6, 75.5, 60.7, 60.3, 46.4, 45.1,
39.4, 38.1, 28.0, 26.1, 21.6, 14.1; HRMS calcd for C31H29NO6S: 543.1715
(d, J ˆ 8.1 Hz, 2H), 5.15 (d, J ˆ 6.8 Hz, 1H), 4.41 (t, J ˆ 4.9 Hz, 1H), 4.16 (q,
J ˆ 6.6 Hz, 1H), 3.91 (m, 2H), 3.68 (dd, J ˆ 3.2, 12.2 Hz, 1H), 3.44 (m, 4H),
2.41 (s, 3H), 1.26 (s, 3H), 1.23 (s, 3H), 1.03 (m, 21H); 13C NMR (75 MHz,
CDCl3): d ˆ 143.5, 137.7, 129.5, 127.3, 107.7, 77.6, 75.3, 73.0, 62.9, 61.0, 52.1,
27.2, 24.9, 21.5, 18.0, 17.9, 12.6; HRMS calcd for C22H38NO7SSi: 488.2138
‡
[M iC3H7] ; found: 488.2140.
2-[2,2-Dimethyl-5-(toluene-4-sulfonyl)-tetrahydro-[1,3]dioxolo[4,5-c]pyr-
rol-4-yl]-2-triisopropylsilyloxy-ethanol (13): Triphenylphosphane (228 mg,
0.87 mmol) was slowly added at 08C to a solution of diol 12 (338 mg,
0.637 mmol mmol) and diisopropyl azodicarboxylate (DIAD, 0.193 mL,
0.98 mmol) in THF (5 mL). The resulting solution was stirred for 45 min.
The reaction was concentrated and column chromatography on silica (25%
‡
[M] ; found: 543.1726.
Synthesis of amino alcohol (9): A solution of 8 (4.0 g, 7.35 mmol) and
potassium carbonate (2.0 g, 14.5 mmol) in methanol/water (9:1 v/v 100 mL)
was heated to 608C for 1.5 h. Acetic acid (1 mL) was added and the
reaction was concentrated in vacuo. The resulting residue was diluted with
methylene chloride (100 mL) and water (50 mL). The aqueous layer was
extracted with methylene chloride (50 mL). The combined organic extracts
EtOAc/petroleum ether) gave 13 (281 mg, 86%) as a colorless oil. [a]D25
ˆ
59.8 (c ˆ 1.52 in CH2Cl2); IR (neat): nÄ ˆ 3541, 1464, 1382, 1346,
were dried and concentrated to give 9 as a white solid (3.65 g, 96%). [a]D25
ˆ
1216 cm
;
1H NMR (300 MHz, CDCl3): d ˆ 7.73 (d, J ˆ 8.3 Hz, 2H), 7.33
1
‡10.3 (c ˆ 1.53 in CH2Cl2); m.p. 185 ± 1508C (EtOAc/hexane); IR (neat):
(d, J ˆ 8.1 Hz, 2H), 4.53 (m, 1H), 4.14 (m, 2H), 4.03 (dd, J ˆ 6.0, 12.7 Hz,
1H), 3.77 (m, 2H), 3.62 (q, J ˆ 6.8 Hz, 1H), 3.17 (m, 1H), 3.03 (dd, J ˆ 8.6,
12.9 Hz, 1H), 2.44 (s, 3H), 1.43 (s, 3H), 1.18 (s, 3H), 1.08 (m, 21H);
13C NMR (75 MHz, CDCl3): d ˆ 144.6, 134.6, 130.2, 127.4, 113.4, 80.4, 77.6,
71.4, 63.6, 62.4, 52.7, 27.9, 25.3, 21.6, 18.2, 18.1, 12.7; anal. calcd for
C25H43NO6SSi: C 58.45, H 8.44, N 2.73; found: C 58.60, H 8.45, N 2.96.
1
nÄ ˆ 3529, 3278, 1466, 1326 cm 1; H NMR (300 MHz, CDCl3): d ˆ 7.73 (d,
J ˆ 8.1 Hz, 2H), 7.41 (m, 1H), 7.29 (m, 6H), 7.10 (m, 4H), 5.00 (d, J ˆ
7.1 Hz, 1H), 4.41 (s, 1H), 4.32 (s, 1H), 4.26 (s, 1H), 3.73 (t, J ˆ 6.4 Hz, 1H),
3.58 (m, 1H), 3.25 (t, J ˆ 7.6 Hz, 1H), 2.40 (s, 3H), 2.12 (m, 1H), 2.03 (m,
1H), 1.33 (s, 3H), 1.04 (s, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 144.3,
143.0, 142.6, 141.9, 141.8, 137.8, 129.2, 127.2, 126.4, 126.2, 125.9, 108.1, 78.5,
76.0, 73.7, 59.3, 46.6, 46.0, 44.4, 41.5, 27.8, 25.0, 21.3; HRMS calcd for
[2,2-Dimethyl-5-(toluene-4-sulfonyl)-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-
4]-yl-2-triisopropylsilyloxy-acetaldehyde (14): Dess ± Martin periodinane
(417 mg, 0.423 mmol) was added at 08C to a solution of alcohol 13 (440 mg,
0.858 mmol) and sodium bicarbonate (101 mg, 1.2 mmol) in methylene
chloride (8 mL). The resulting white slurry was stirred for 45 min at room
temperature. The reaction was concentrated, filtered through silica gel, and
‡
C30H31NO5S: 517.1923 [M] ; found: 517.1924.
N-(5-Hydroxy-2,2-dimethyl-[3a,4,5,7a]-tetrahydro-benzo[1,3]dioxol-4-yl)-
4-methyl-benzenesulfonamide (10): Alcohol 9 (500 mg, 0.965 mmol) was
subjected to flash vacuum thermolysis (5008C, 0.05 mmHg). Column
chromatography on silica (30 ± 60% EtOAc/petroleum ether) gave 10 as a
white solid (298 mg, 91%) in >99% ee as determined by HPLC (Chiralpak
AD column), elution time (flow rate 1 mLmin 1, 15% isopropyl alcohol in
concentrated to give aldehyde 14 (430 mg, 98%) as a colorless oil. [a]D25
ˆ
77.3 (c ˆ 4.19 in CH2Cl2); IR (neat): nÄ ˆ 2728, 1733, 1598, 1463, 1382,
1
1354 cm 1; H NMR (300 MHz, CDCl3): d ˆ 9.74 (d, J ˆ 1.5 Hz, 1H), 7.70
heptane, l ˆ 254 nm):
(
)-isomer: 13.25 min, (‡)-isomer: 14.73 min.
(d, J ˆ 8.3 Hz, 2H), 7.32 (d, J ˆ 8.1 Hz, 2H), 4.55 (dd, J ˆ 1.5, 5.9 Hz, 1H),
4.41 (q, J ˆ 6.8 Hz, 1H), 4.36 (q, J ˆ 6.6 Hz, 1H), 4.20 (q, J ˆ 6.6 Hz, 1H),
3.73 (dd, J ˆ 7.3, 12.9 Hz, 1H), 3.36 (dd, J ˆ 6.6, 13.2 Hz, 1H), 2.43 (s, 3H),
[a]2D5
ˆ
99.8 (c ˆ 1.50 in CH2Cl2); m.p. 138 ± 1418C (EtOAc/hexane); IR
1
(neat): nÄ ˆ 3312, 1599, 1455, 1430, 1375, 1334 cm
;
1H NMR (300 MHz,
3282
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0511-3282 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 11

Synthesis of ( )-Swainsonine
3279±3284
1.50 (s, 3H), 1.18 (s, 3H), 1.12 (m, 21H); 13C NMR (75 MHz, CDCl3): d ˆ
4.20 (m, 3H), 3.80 (dd, J ˆ 7.1, 12.7 Hz, 1H), 2.93 (dd, J ˆ 7.8, 12.7 Hz, 1H),
2.42 (s, 3H), 1.51 (s, 3H), 1.29 (t, J ˆ 7.1 Hz, 3H), 1.26 (s, 3H), 1.08 (m,
21H); 13C NMR (75 MHz, CDCl3): d ˆ 166.1, 147.8, 143.7, 136.4, 129.7,
127.4, 122.6, 114.4, 80.0, 78.5, 71.7, 65.7, 60.3, 52.5, 27.1, 25.0, 21.5, 18.1, 18.0,
202.7, 144.2, 134.5, 130.0, 127.5, 114.7, 79.4, 78.3, 77.7, 64.2, 53.2, 26.7, 24.9,
‡
21.6, 18.0, 12.3; HRMS calcd for C24H38NO6SSi: 496.2186 [M CH3] ;
found: 496.2200.
‡
14.2, 12.3; HRMS calcd for C26H40NO7SSi [M iC3H7] : 538.2295; found:
1-[2,2-Dimethyl-5-(toluene-4-sulfonyl)-tetrahydro-[1,3]dioxolo[4,5-c]pyr-
rol-4-yl]-1-triisopropylsilyloxy-but-3-en-2-ol (15): Vinylmagnesium bro-
mide (1.09 mL, 1m in THF, 1.09 mmol) was added to a solution of aldehyde
14 (430 mg, 0.841 mmol) in THF (8 mL) at 788C. After 10 min at 788C,
the reaction was quenched with wet diethyl ether and water. The reaction
was allowed to warm to room temperature and was diluted with diethyl
ether (50 mL) and saturated aqueous ammonium chloride (50 mL). The
organic layer was dried (MgSO4) and concentrated to give a 2.1:1 mixture
of diastereomers of vinyl alcohol 15 (425 mg, 95%) as a colorless oil. IR
(neat): nÄ ˆ 3508, 2944, 2867, 1351 cm 1; 1H NMR (300 MHz, CDCl3) major
diastereomer: d ˆ 7.65 (d, J ˆ 8.3 Hz, 2H), 7.32 (d, J ˆ 7.8 Hz, 2H), 6.00 (m,
1H), 5.45 (m, 1H), 5.23 (m, 1H), 4.4 ± 4.6 (m, 3H), 3.6 ± 3.9 (m, 4H), 3.20
(m, 1H), 2.43 (s, 3H), 1.48 (s, 3H), 1.20 (s, 3H), 1.14 (m, 21H); 13C NMR
(75 MHz, CDCl3) mixture of diastereomers: d ˆ 144.2, 138.9,137.1, 134.4,
130.1, 127.5, 127.4, 115.9, 115.0, 113.6, 80.9, 80.3, 77.9, 75.2, 74.1, 71.6, 63.7,
61.4, 53.0, 52.8, 27.7, 27.5, 25.2, 25.0, 21.5, 18.5, 18.4, 18.2, 18.1, 18.0, 13.4, 12.7,
538.2296.
Ethyl-4-[2,2-dimethyl-5-(toluene-4-sulfonyl)-tetrahydro-[1,3]dioxolo[4,5-
c]pyrrol-4-yl]-4-triisopropylsilyloxy-butyrate (19): A slurry of enoate 18
(266 mg, 0.457 mmol) and platinum oxide (6 mg, 0.023 mmol) in ethanol
(4 mL) was stirred under 1 atm of hydrogen for 1.5 h. The reaction was
filtered through celite and concentrated to give ester 19 as a colorless oil
(265 mg, 99%). [a]D25
ˆ
57.5 (c ˆ 1.62 in CH2Cl2); IR (neat): nÄ ˆ 1733,
1461, 1353 cm 1; 1H NMR (300 MHz, CDCl3): d ˆ 7.74 (d, J ˆ 8.3 Hz, 2H),
7.32 (d, J ˆ 7.8 Hz, 2H), 4.56 (t, J ˆ 6.4 Hz, 1H), 4.31 (q, J ˆ 6.4 Hz, 1H),
4.13 (q, J ˆ 7.1 Hz, 2H), 4.05 (t, J ˆ 6.6 Hz, 1H), 3.92 (q, J ˆ 6.8 Hz, 1H),
3.76 (dd, J ˆ 7.1, 13.2 Hz, 1H), 3.02 (dd, J ˆ 8.3, 12.9 Hz, 1H), 2.5 ± 2.7 (m,
2H), 2.44 (s, 3H), 2.19 (m, 1H), 2.02 (m, 1H), 1.45 (s, 3H), 1.26 (t, J ˆ
7.1 Hz, 3H), 1.20 (s, 3H), 1.10 (m, 21H); 13C NMR (75 MHz, CDCl3): d ˆ
173.8, 144.6, 135.7, 129.9, 127.4, 113.9, 80.4, 78.1, 70.2, 65.1, 60.2, 52.7, 29.9,
29.5, 27.4, 25.1, 21.5, 18.3, 18.0, 14.2, 12.9; anal. calcd for C29H49NO7SSi: C
59.66, H 8.46, N 2.40; found: C 59.80, H 8.53, N 2.63.
‡
12.3; HRMS calcd for C24H38NO6SSi [M iC3H7] : 496.2189; found:
496.2212.
[1S,2R,8R,8aR]-8-Triisopropylsilyloxy-1,2-(isopropylidenedioxy) indolizi-
din-5-one (20): Sodium dibasic phosphate (270 mg, 1.90 mmol) was added
to a solution of ester 19 (115 mg, 0.197 mmol) in methanol (0.7 mL),
followed by 3% sodium ± mercury amalgam (865 mg, 1.13 mmol). The
resulting slurry was stirred at room temperature for 3 h. The reaction was
poured into diethyl ether (25 mL) and water (25 mL). The aqueous layer
was extracted with ether (25 mL). The combined ether extracts were dried
(MgSO4), filtered and concentrated to give lactam 20 as a white solid
2,2-Dimethyl-4-triisopropylsilyloxy-5-vinyl-hexahydro-1,3,6-trioxa-[7-a]-
aza-cyclopenta[a]inden-7-one (16): n-Butyllithium (2.2 mL, 1.2m in hex-
ane, 2.62 mmol) was added to a solution of vinyl alcohol 15 (430 mg,
0.798 mmol) in THF (5 mL) at 788C. Methyl chloroformate (0.40 mL,
5.22 mmol) was added and the reaction was stirred at 788C for 15 min.
The reaction was quenched with wet diethyl ether and water. The reaction
was allowed to warm to RTand was diluted with diethyl ether (50 mL) and
saturated aqueous ammonium chloride (50 mL). The organic layer was
dried (MgSO4), concentrated, and filtered through silica to give the crude
methyl carbonate (295 mg, 62%) as a colorless oil which was used directly
in the next step.
(54 mg, 72%). [a]D25
ˆ
16.9 (c ˆ 1.98 in CH2Cl2); m.p. 76 ± 778C (EtOAc/
1
hexane); IR (neat): nÄ ˆ 2968, 2861, 1655, 1455, 1373, 1214 cm 1; H NMR
(300 MHz, CDCl3): d ˆ 4.69 (m, 2H), 4.28 (m, 1H), 4.12 (d, J ˆ 13.4 Hz,
1H), 3.28 (dd, J ˆ 2.9, 6.8 Hz, 1H), 3.06 (dd, 4.2, 13.7 Hz, 1H), 2.46 (dt, J ˆ
4.9, 17.4 Hz, 1H), 2.31 (m, 1H), 2.00 (m, 1H), 1.84 (m, 1H), 1.37 (s, 3H),
1.27 (s, 3H), 1.06 (s, 18H), 0.9 ± 1.2 (m, 3H); 13C NMR (75 MHz, CDCl3):
d ˆ 168.7, 111.6, 79.6, 77.4, 67.3, 65.8, 50.6, 30.7, 29.2, 26.4, 24.5, 17.9, 12.3;
3% Sodium ± mercury amalgam (177 mg, 0.231 mmol) was added to a
solution of the above methyl carbonate (23 mg, 0.0385 mmol) and sodium
dibasic phosphate (49.2 mg, 0.347 mmol) in methanol (0.5 mL). The
resulting slurry was stirred for 30 min. Water (5 mL) and diethyl ether
(5 mL) were added. The aqueous layer was extracted with diethyl ether
(2 Â 5 mL). The combined ether extracts were concentrated. Column
chromatography on silica (15% ethyl acetate/petroleum ether) gave 16 as a
‡
HRMS calcd for C17H30NO4SSi: [M iC3H7] : 340.1944; found: 340.1944.
[1S,2R,8R,8aR]-8-Triisopropylsilyloxy-1,2-(isopropylidenedioxy) indolizi-
dine (21): Borane/dimethyl sulfide complex (0.24 mL, 2m solution in THF,
0.48 mmol) was added at 08C to
a solution of lactam 20 (46 mg,
colorless oil (11 mg, 68%) of a 5:1 mixture of diastereomers. Major
1
0.120 mmol) in THF (2.5 mL). The reaction was stirred at 08C for 30 min
and at room temperature for 2 h. Ethanol (1.5 mL) was added (Caution:
hydrogen evolution), and the reaction was concentrated to a thick oil which
was redissolved in ethanol (3 mL) and refluxed for 2 h. Removal of solvent
diastereomer: IR (neat): nÄ ˆ 2926, 2868, 1720, 1426 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 5.96 (m, 1H), 5.55 (dt, J ˆ 1.3, 17.2 Hz, 1H), 5.52
(dt, J ˆ 1.1, 10.6 Hz, 1H), 4.74 (t, J ˆ 5.3 Hz, 1H), 4.69 (m, 1H), 4.48 (m,
1H), 4.19 (dd, J ˆ 7.9, 9.2 Hz, 1H), 4.10 (m, 1H), 3.41 (dd, J ˆ 3.8, 7.9 Hz,
1H), 3.22 (dd, J ˆ 5.1, 13.2 Hz, 1H), 1.43 (s, 3H), 1.30 (s, 3H), 1.08 (m,
21H); 13C NMR (75 MHz, CDCl3): d ˆ 152.5, 132.6, 120.1, 112.2, 80.9, 79.2,
78.5, 66.5, 66.0, 52.3, 26.3, 24.5, 18.1, 17.8, 12.8; HRMS calcd for
in vacuo gave 21 as a colorless oil (42 mg, 95%). [a]D25
ˆ
61.9 (c ˆ 1.93,
1
CH2Cl2); IR (neat): nÄ ˆ 2784, 1463, 1378, 1208, 1152 cm
;
1H NMR
(300 MHz, CDCl3): d ˆ 4.64 (t, J ˆ 4.6 Hz, 1H), 4.53 (t, J ˆ 4.6 Hz, 1H),
3.93 (m, 1H), 3.09 (d, J ˆ 10.7 Hz, 1H), 2.94 (bd, J ˆ 10.3 Hz, 1H), 2.04 (m,
2H), 1.80 (m, 1H), 1.61 (m, 3H), 1.45 (s, 3H), 1.27 (s, 3H), 1.22 (m, 1H),
1.07 (m, 21H); 13C NMR (75 MHz, CDCl3): d ˆ 110.5, 79.2, 77.7, 74.1, 68.2,
60.4, 51.8, 34.6, 25.9, 24.4, 24.1, 18.1, 12.6; HRMS calcd for C20H39NO3Si
‡
C21H37NO5Si [M] : 411.2441; found 411.2443; minor diastereomer: IR
(neat): nÄ ˆ 2942, 2868, 1715, 1431, 1217 cm 1; 1H NMR (300 MHz, CDCl3):
d ˆ 6.13 (ddd, J ˆ 3.4, 11.0, 17.6 Hz, 1H), 5.45 (d, J ˆ 25.4 Hz, 1H), 5.39 (d,
J ˆ 19.0 Hz, 1H), 4.83 (m, 1H), 4.65 (m, 2H), 4.48 (dd, J ˆ 5.1, 8.5 Hz, 1H),
4.04 (d, J ˆ 13.2 Hz, 1H), 3.30 (dd, J ˆ 2.8, 8.3 Hz, 1H), 3.23 (m, 1H), 1.43
(s, 3H), 1.30 (s, 3H), 1.10 (m, 21H); 13C NMR (75 MHz, CDCl3): d ˆ 151.3,
131.3, 118.3, 112.2, 79.6, 77.9, 64.5, 62.0, 52.8, 26.5, 24.6, 17.9, 12.3; HMRS:
‡
[M] : 369.2699; found: 369.2691.
[1S,2R,8R,8aR]-1,2,8-Trihydroxyindolizidine [( )swainsonine] (5): A sol-
ution of 21 (41 mg, 0.110 mmol) in THF (0.45 mL) was treated with 6n HCl
(0.45 mL) at room temperature for 14 h. The reaction was concentrated
and the residue was dissolved in methanol and ion-exchange resin (Dowex
1 Â 8 ± 50, HO , 2 g) was added and stirred for 15 min. The reaction was
filtered and concentrated to give ( )-swainsonine 5 as a white solid
‡
calcd for C20H34NO5Si: [M CH3] : 396.2206; found: 396.2207.
Ethyl-(E)-4-[2,2-dimethyl-5-(toluene-4-sulfonyl)-tetrahydro-[1,3]dioxolo-
[4,5-c]pyrrol-4-yl]-4-triisopropylsilyloxy-2-butenoate (18): DBU (0.079 mL,
0.527 mmol) and aldehyde 14 (270 mg, 0.527 mmol) were added to a slurry
of the triethyl phosphonoacetate (165 mg, 0.738 mmol) and lithium
chloride (31.3 mg, 0.738 mmol) in acetonitrile (5 mL). The resulting slurry
was stirred at room temperature for 2 h. The reaction was diluted with
diethyl ether (50 mL) and water (50 mL). The organic layer was concen-
trated and subsequent column chromatography on silica (15% EtOAc/
(16.8 mg, 88%). [a]D25
ˆ
74.9 (c ˆ 1.15 in MeOH) [lit.: [a]D25
ˆ
75.7 (c ˆ
2.33 in MeOH)][10]; m.p. 136 ± 1398C (lit.: m.p. 140 ± 1428C[16], 139 ±
1428C[10]), 141 ± 1438C[17]; IR (neat): nÄ ˆ 3340, 2931, 2855, 2802, 1654,
1
1330 cm
;
1H NMR (300 MHz, D2O): d ˆ 4.20 (ddd, J ˆ 2.8, 5.9, 8.0 Hz,
1H), 4.08 (dd, J ˆ 3.5, 5.8 Hz, 1H), 3.63 (td, J ˆ 4.6, 10.3 Hz, 1H), 2.73 (m,
2H), 2.46 (dd, J ˆ 8.1, 10.8 Hz, 1H), 1.86 (m, 3H), 1.53 (m, 1H), 1.30 (qt,
J ˆ 4.1, 13.2 Hz, 1H), 1.06 (qd, J ˆ 4.5, 12.3 Hz, 1H); 13C NMR (75 MHz,
D2O, MeOH internal standard): d ˆ 72.5, 69.3, 68.7, 65.9, 60.1, 51.4, 32.1,
petroleum ether) gave enoate 18 as a colorless oil (277 mg, 90%). [a]D25
29.3 (c ˆ 2.73 in CH2Cl2); IR (neat): nÄ ˆ 1720, 1463, 1359, 1270 cm
ˆ
1
;
1H NMR (300 MHz, CDCl3): d ˆ 7.70 (d, J ˆ 8.3 Hz, 2H), 7.28 (d, J ˆ
8.3 Hz, 2H), 7.07 (dd, J ˆ 6.4, 15.6 Hz, 1H), 5.89 (d, J ˆ 15.6 Hz, 1H),
4.77 (t, J ˆ 5.9 Hz, 1H), 4.71 (t, J ˆ 6.6 Hz, 1H), 4.34 (t, J ˆ 5.4 Hz, 1H),
‡
22.8; HRMS calcd for C8H15NO3 [M] : 173.1052; found: 173.1050. The
spectral data agree with those previously reported.[10, 15]
Chem. Eur. J. 1999, 5, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0511-3283 $ 17.50+.50/0
3283

B. M. Trost and D. E. Patterson
FULL PAPER
[9] a) A. D. Elbein, FASEB J. 1991, 5, 3055, and references therein;
b) I. C. di Bello, G. Fleet, S. K. Namgoong, K. I. Tadano, B. Win-
chester, Biochem. J. 1989, 259, 855, and references therein.
[10] W. H. Pearson, E. J. Hembre, J. Org. Chem. 1996, 61, 7217, and
references therein.
[11] a) J. A. Hunt, W. R. Roush, J. Org. Chem. 1997, 62, 1112; b) W.-S.
Zhou, W. G. Xie, Z.-H. Lu, X.-F. Pan, J. Chem. Soc. Perkin Trans. 1
1995, 2559; c) C. E. Adams, F. J. Walker, K. B. Sharpless, J. Org. Chem.
1985, 50, 420; d) F. Ferriera, C. Greck, J. P. Genet, Bull. Soc. Chim. Fr.
1997, 134, 615.
Acknowledgment
We thank the National Science Foundation and the National Institutes of
Health, General Medical Sciences, for their generous support of our
programs. D.E.P. was supported, in part, by a fellowship from the American
Chemical Society/Organic Division. Mass spectra were provided by the
Mass Spectrometry Facility at the University of California ± San Francisco
supported by the NIH Division of Research Resources.
[12] B. M. Trost, H. C. Arndt, P. E. Strege, T. R. Verhoeven, Tetrahedron
Lett. 1976, 3477.
[13] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune,
W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25, 2183.
[14] T. Hudlicky, M. G. Natchus, G. Sinai-Zingde, J. Org. Chem. 1987, 52,
4641.
[15] N. M. Carpenter, G. W. J. Fleet, I. C. di Bello, B. Winchester, L. E.
Fellows, R. J. Nash, Tetrahedron Lett. 1989, 30, 7261.
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Received: May 19, 1999 [F 1794]
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