Nucleophilic openings of bicyclic β-lactones via acyl C-O and alkyl C-O cleavage: Catalytic, asymmetric synthesis of a versatile, carbocyclic nucleoside precursor and protected transpentacin

Article abstract of DOI:10.1016/S0040-4020(02)00703-2

A variety of carbocycle-fused β-lactones are accessible via the intramolecular catalytic, asymmetric nucleophile catalyzed aldol-lactonization reaction recently developed in our laboratory. These bicyclic β-lactones undergo facile ring cleavage under mild

Full text of DOI:10.1016/S0040-4020(02)00703-2

Tetrahedron 58 (2002) 7075–7080
Nucleophilic openings of bicyclic b-lactones via acyl C–O and
alkyl C–O cleavage: catalytic, asymmetric synthesis of a versatile,
carbocyclic nucleoside precursor and protected transpentacin
*
Yasuno Yokota, Guillermo S. Cortez and Daniel Romo
Department of Chemistry, Texas A&M University, P.O. Box 300012, College Station, TX 77842-3012, USA
Received 10 May 2002; accepted 23 May 2002
Abstract—A variety of carbocycle-fused b-lactones are accessible via the intramolecular catalytic, asymmetric nucleophile catalyzed aldol-
lactonization reaction recently developed in our laboratory. These bicyclic b-lactones undergo facile ring cleavage under mild conditions via
both acyl C–O and alkyl C–O bond cleavage. Cleavage of the acyl C–O bond with hydroxylamine nucleophiles proceeds at ambient
temperature and reductive cleavage is readily accomplished with aluminum and boron reducing agents. Alternatively, alkyl C–O cleavage
with various nucleophiles leads to a variety of trans-b-substituted cyclopentane carboxylic acids. The utility of these transformations is
demonstrated by the synthesis of protected (1S,2S )-transpentacin and a versatile diol for carbocyclic nucleoside synthesis. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
follow similar reactivity trends to those outlined above for
non-ring fused b-lactones. In this Symposia-in-Print, we
describe the synthesis of protected transpentacin, (1S,2S )-2-
aminocyclopentane-1-carboxylic acid and a versatile, car-
bocyclic nucleoside precursor. These syntheses demonstrate
the utility of ring cleavage of these versatile, chiral building
blocks.
b-Lactones are versatile synthetic intermediates, as they
undergo a variety of transformations in a stereospecific
fashion.1 The utility of b-lactones stems from their inherent
reactivity due to ring strain and their masked aldol
functionality. Thus, the asymmetric synthesis of these
useful heterocycles has experienced a renaissance in recent
years. In particular, b-lactones have emerged as targets of
opportunity for development of catalytic, asymmetric
methods.2 The ability to cleave b-lactones via either acyl
C–O or alkyl C–O cleavage further expands the repertoire
of these small rings to access a variety of functional arrays
(Fig. 1). In general, addition of soft nucleophiles leads to
alkyl C–O cleavage while hard nucleophiles promote acyl
C–O cleavage.1
2. Discussion
2.1. Acyl C–O cleavage of bicyclic b-lactones
We initially studied the acyl C–O cleavage mode of
bicyclic b-lactones 4a–c. As anticipated, ring opening of
bicyclic b-lactones with hydroxylamine nucleophiles
occurs under very mild conditions with exclusive cleavage
of the acyl C–O bond.4 Excess O-benzylhydroxylamine
(15–20 equiv.) was utilized to accelerate the ring cleavage
at 258C and the resulting hydroxamic acid derivatives 5a–c
were obtained as white solids (Scheme 1).4
We recently reported catalytic, asymmetric intramolecular
nucleophile catalyzed aldol-lactonization (NCAL) reactions
that allow access to a variety of carbocycle-fused b-lac-
tones.3 As a means to exploit the reactivity of these bicyclic
b-lactones, we have studied their behavior toward various
nucleophiles. In general, these novel, bicyclic systems
We also studied reductive opening of b-lactones 4a–b and 6
Figure 1. Dual reactivity of b-lactones toward nucleophilic ring cleavage.
Keywords: nucleophilic ring openings; bicyclic b-lactone; nucleophile catalyzed aldol-lactonization process.
*
Corresponding author. Tel.: þ1-979-845-2011; fax: þ1-979-845-4719; e-mail: romo@mail.chem.tamu.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00703-2

7076
Y. Yokota et al. / Tetrahedron 58 (2002) 7075–7080
nucleosides and serves as a key intermediate in the synthesis
of (2)-aristeromycin.5
2.2. Alkyl C–O cleavage of bicyclic b-lactones
The addition of nucleophiles to bicyclic-b-lactones leading
to alkyl-oxygen cleavage was also investigated. Using the
bicyclic-b-lactone 6, several nucleophiles were explored for
their reactivity towards alkyl-oxygen cleavage. In most
cases, nucleophilic ring opening proceeded at 508C in DMF
to deliver the trans-b-substituted carboxylic acids. How-
ever, the reactions were sluggish requiring .24 h to reach
completion. For example, addition of thiophenol leading to
the b-thiophenyl cyclopentane acid required 3 days. Use of
0.75 equiv. of Cs2CO3 greatly accelerated the nucleophilic
addition in the case of thiophenol, hydrocinnamic acid, and
N-Boc-cysteine ethyl ester.6 However, only low yields were
obtained in the latter case. In all cases, the nucleophilic
additions proceeded with a high degree of diastereo-
selectivity to give the trans substituted cyclopentanes
presumably via a SN2 process (Table 1).
Scheme 1.
Scheme 2.
(Scheme 2). Addition of di-isobutylaluminum hydride to
b-lactone 4a resulted in smooth reduction to the corre-
sponding diol 7a. On the other hand, reduction of the
dioxolane-containing b-lactone 6, even at low temperature
(2108C), with various aluminum-based reductants gave
small amounts of diol 7c accompanied by compounds in
which the dioxolane acetal had been cleaved competitively.
However, these by-products were greatly minimized by
using borane–dimethylsulfide complex as the reducing
agent leading to diol 7c in good yield. The borane reduction
also cleanly delivered diol 7b from b-lactone 4b. In most
cases, the diols obtained in this fashion did not require silica
gel purification.
To demonstrate the utility of this mode of b-lactone ring
cleavage, we targeted the synthesis of trans-2-amino
cyclopentane carboxylic acid, transpentacin, derivative 16.
2-Aminocyclopentanecarboxylic acids are constituents of
natural products, display a range of interesting biological
activities, and have recently been employed by Gellman to
prepare constrained b-peptides.7 Cispentacin, of unknown
configuration, is a constituent of the antibiotic amipurimi-
cin,8 while (1R,2S)-cispentacin, is an antifungal antibiotic
isolated from Bacillus cereus9 and Streptomyces setonii.10
Nucleophilic ring cleavage of b-lactone 4a with sodium
azide in DMF efficiently promoted b-cleavage to give azido
acid 14 (Scheme 4). Esterification followed by an azide
reduction/protection sequence delivered the known N-Boc-
protected b-amino acid ester 16, which confirmed the
stereochemistry and allowed assessment of enantiomeric
purity. Spectral data for amino ester 16 matched that
previously reported.11 The optical purity of ester 16 was
determined to be 89% as determined by comparative optical
rotation and this correlates well with the enantiomeric
excess of the starting b-lactone 4a (92% ee).
The utility of these bicyclic b-lactones was demonstrated by
the four-step conversion of bicyclic-b-lactone 6 into the
versatile carbocyclic nucleoside precursor 10 (Scheme 3).
Reductive cleavage of the b-lactone 6 as described above
gave the corresponding diol 7c, which was directly
subjected to aqueous acid. This resulted in hydrolysis of
the dioxolane and spontaneous b-elimination to deliver a,b-
unsaturated cyclopentenol 8. Protection of the hydroxyl
group as the trityl ether followed by a highly diastereoster-
eoselective 1,2-reduction of enone 13 with DIBAl-H
afforded the labile cyclopentenol 10. The latter compound
is the precursor to a number of antiviral carbocyclic
In conclusion, we have found that bicyclic b-lactones, in a
manner similar to their non-ring fused derivatives, readily
Scheme 3.

Y. Yokota et al. / Tetrahedron 58 (2002) 7075–7080
7077
Table 1. Nucleophilic ring cleavage of b-lactone 11 with various nucleophiles and esterification
Entry
Nucleophile
Rxn conditions
Compound no.
X
% Yield
1
2
NaN3
PhSH
24 h
Cs2CO3, 24 h
13a
13b
N3
SPh
76
81
3
Cs2CO3, 24 h
Cs2CO3, 24 h
13c
14
4
13d
58
resolution, double focusing, sectored (EB) mass spec-
trometer at the Center for Chemical Characterization and
Analysis (Texas A&M). IR spectra were recorded on a
1
Nicolet Impact 410DSP. H and 13C NMR spectra were
recorded on a Varian INOVA500 spectrometer or a Varian
VXR300 spectrometer and chemical shifts are reported in
ppm using tetramethylsilane (d 0.0) or residual CHCl3 (1H d
7.26, 13C d 77.0) as internal reference unless otherwise
noted. b-Lactones 4a–c by the NCAL method reported
previously.3
Scheme 4.
3.2. General procedure for preparation of hydroxamic
acid derivatives 5a–c
undergo both acyl C–O and alkyl C–O cleavage modes.
The availability of chiral carbocycle-fused b-lactones via
the NCAL process makes them versatile chiral building
blocks for synthesis. The resident b-lactone enables facile
functionalization, and thus these bicyclic b-lactones should
prove to be useful scaffolds for displaying functionality on a
carbocycle core. This concept was demonstrated by the ring
opening of b-lactones with azide, thiols, and carboxylate
nucleophiles. The utility of these bicyclic b-lactones was
further demonstrated by the synthesis of a versatile chiral
template for carbocyclic nucleoside synthesis and of a
protected transpentacin.
In a typical reaction, the b-lactone (ca. 5–10 mg,
1.0 equiv.) was treated with O-benzylhydroxylamine (15–
20 equiv.). To aid stirring of the resulting thick mixture,
anhydrous diethyl ether was added if needed. The clear
solution was stirred at room temperature until complete by
as monitored by TLC (24–30 h). The reaction mixture was
then poured into 1N HCl, and the aqueous layer was
extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, filtered and
concentrated to afford a white solid. Purification by flash
chromatography (40% EtOAc/hexanes) delivered the
hydroxamic acid derivatives as white solids (45–50%
yield).
3.2.1. 2-Hydroxy-N-(phenylmethoxy)-cyclopentane car-
boxyamide (5a). 48% yield. 1H NMR (500 MHz, CDCl3) d
8.2–8.30 (broad s, 1H), 7.28–7.40 (m, 5H), 4.93 (broad s,
2H), 4.32–4.43 (m, 1H), 2.30–2.40 (m, 1H), 1.60–2.10 (m,
6H); 13C NMR (75 MHz, CDCl3) d 148.7, 129.3, 128.9,
128.7, 78.3, 76.6, 74.2, 47.4, 34.4, 27.2, 21.9; FAB HRMS
calcd for C13H17O3N: 236.1287, found: 236.1277.
3. Experimental
3.1. General
All reactions were carried out under N2 in oven-dried
glassware unless noted otherwise. Methylene chloride was
distilled from CaH2 immediately prior to use. Tetrahydro-
furan and diethyl ether were distilled from sodium-
benzophenone ketyl radical immediately prior to use.
Other solvents used were also dried and distilled according
to standard procedures prior to use. Flash column chroma-
3.2.2. 4,4-Dimethyl-2-hydroxy-N-(phenylmethoxy)-
1
cyclopentane carboxyamide (5b). 50% yield. H NMR
(300 MHz, CDCl3) d 8.30 (broad s, 1H), 7.30–7.40 (m, 5H),
4.93 (broad s, 2H), 4.42 (broad s, 1H), 2.00 (t, J¼6.6 Hz,
1H), 1.52–1.70 (m, 4H), 1.18 (s, 3H), 0.98 (s, 3H);
FAB HRMS calcd for C15H21O3N: 264.1599, found:
264.1594.
˚
tography was done using Baxter S/P Silica Gel 60 A (23–
400 Mesh ASTM). Thin layer chromatography was done
using EM silica gel 60F glass plates (0.25 mm). Mass
spectra were obtained on a VG Analytical 70S high

7078
Y. Yokota et al. / Tetrahedron 58 (2002) 7075–7080
3.2.3. 2-Hydroxy-N-(phenylmethoxy)-cyclohexane car-
boxyamide (5c). 45% yield. 1H NMR (300 MHz, CDCl3) d
8.45 (broad s, 1H), 7.30–7.40 (m, 5H), 4.92 (broad s, 2H),
4.06–4.54 (m, 1H), 3.28 (broad s, 1H), 1.64–2.00 (m, 4H),
1.36–1.48 (m, 2H), 1.20–1.32 (m, 2H); FAB HRMS calcd
for C14H20O3N: 250.1443, found: 250.1454.
between saturated NH4Cl (20 mL) and EtOAc (20 mL). The
phases were separated, and the aqueous layer was extracted
with EtOAc (3£20 mL). The combined organic layers were
washed with brine, dried over MgSO4, filtered and
concentrated to afford a cloudy residue that was purified
by flash chromatography on SiO2 (3:7, Et2O/hexanes) to
provide trityl ether 9 (96.6 mg, 90% yield) as a colorless
residue that solidifies upon standing: Rf 0.68 (1:1,
EtOAc/hexanes); [a ]D25¼2178 (c 0.5, MeOH); IR (CHCl3)
3.2.4. (2)-trans-2-Hydroxcyclopentanemethanol (7a). A
solution of DIBAl-H (238 mL in 0.78 mL of CH2Cl2,
0.45 mmol) was added dropwise to a solution of b-lactone
(þ)-4a (53 mg, 0.47 mmol) in 5.3 mL of CH2Cl2 cooled to
08C. After stirring for 5 min, the solution was warmed to
258C and stirred for 1.0 h. The reaction mixture was then
cooled to 08C, diluted with 2.4 mL of ethyl acetate and
quenched with acetone (1.5 mL) and saturated Rochelle’s
salt (4.0 mL). The mixture was vigorously stirred at 258C
for 10 h. The layers were separated and the aqueous layer
was extracted with ethyl acetate (2£4 mL). The combined
organic layers were washed with brine (1£8 mL), dried over
MgSO4, filtered, and concentrated to give diol 7a as a
colorless oil (26.1 mg, 48% yield). Purification by flash
chromatography on SiO2 (100% EtOAc) gave an analyti-
cally pure sample: [a]D25¼233.08 (c 0.02, MeOH); lit.
[a ]2D5¼237.78 (c 0.68, MeOH). All other spectroscopic data
matched that previously reported.12
n
max 1709, 1601 cm21; 1H NMR (500 MHz, CDCl3) d 7.74
(dd, J¼2.4, 5.9 Hz, 1H), 7.38–7.42 (m, 7H), 7.28–7.33 (m,
8H), 6.22 (dd, J¼2.0, 5.4 Hz, 1H), 3.27 (dd, J¼5.9, 8.3 Hz,
1H), 3.20 (dddd, J¼1.9, 4.4, 8.3, 10.7 Hz, 1H), 3.12 (dd,
J¼6.3, 8.3 Hz, 1H), 2.46 (dd, J¼6.3, 18.6 Hz, 1H), 2.10 (dd,
J¼1.9, 18.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 209.5,
166.0, 143.7, 134.9, 128.6, 127.9, 127.1, 86.6, 65.2, 42.1,
38.0; FAB HRMS calcd for C25H24O2 [MþNa] 379.1674,
found 379.1670.
3.2.7. 4-Trityloxylmethyl-cyclopent-2-enol (10). Enone 9
(80.0 mg, 0.225 mmol) was dissolved in 11.5 mL of
anhydrous THF, cooled to 2788C, and treated with
240 mL of DIBAl-H (1.0 M in PhCH3, 0.234 mmol,
1.04 equiv.). After 30 min, an additional 0.70 equiv. of
DIBAl-H was added. After 20 min, the reaction mixture was
quenched by addition of 100 mL of water and 600 mg of
silica gel. The resulting slurry was allowed to warm to
ambient temperature and was stirred vigorously for 1 h. The
mixture was then filtered through a pad of anhydrous
Na2SO4, washing with EtOAc. The solvent was removed
3.2.5. (2)-4-Hydroxy (2)-methyl-2-cyclopenten-1-one
(8).
A
solution of (þ)-b-lactone (þ)-6 (101.8 mg,
0.598 mmol) in 6.0 mL of anhydrous THF was cooled to
08C and treated with 850 mL of neat BH3·DMS (15 equiv.,
8.97 mmol). After stirring for 18 h at 258C, excess borane
was quenched by careful addition of 5% Et3N in anhydrous
MeOH (8 mL). The solvents were removed under reduced
pressure to give a residue that was dissolved in 8 mL of 5%
Et3N/MeOH. The solvent was again removed, repeating this
operation a total of five times. The crude diol was dissolved
in 12.0 mL of THF and treated with 2.5 mL of 1.0N aq. HCl.
The yellow solution was stirred at 258C for 20 h, at which
point the reaction mixture was poured onto 10 mL of brine
and 20 mL of CH2Cl2. The phases were separated, and the
aqueous layer was extracted with CH2Cl2 (4£20 mL). The
organic phases were combined, and then washed with brine,
dried over MgSO4, filtered, and concentrated to afford a
light yellow residue that was purified by flash chromato-
graphy on SiO2 (EtOAc) to afford cyclopentenol 8 (34.2 mg,
51% yield for the two steps) as a colorless oil: Rf 0.45 (1:9,
MeOH/EtOAc); [a]2D5¼15.98 (c 0.34, MeOH); IR (CHCl3)
1
under reduced pressure to give a residue (.19:1 dr, H
NMR) that was purified by flash chromatography to afford
the desired cis-hydroxypentenol 10 (70 mg, 87% yield) as a
colorless oil that solidifies upon standing: Rf 0.63 (4:1,
Et2O/hexanes); [a ]D25¼266.38 (c 1.0, CHCl3); lit. [a ]2D5¼
1
272.18 (c 1.2, CHCl3);5 IR (CHCl3) nmax 3495 cm21; H
NMR (300 MHz, CDCl3) d 7.42–7.48 (m, 6H), 7.22–7.38
(m, 9H), 5.94–6.02 (m, 2H), 4.68–4.78 (m, 1H), 3.29
(dd, J¼4.7, 9.0 Hz, 1H), 3.07 (dd, J¼5.0, 9.0 Hz, 1H),
2.80–2.90 (m, 1H), 2.38 (ddd, J¼7.5, 8.6, 14.0 Hz, 1H),
2.12 (d, J¼8.7 Hz, 1H, OH), 1.44 (dt, J¼3.3, 14.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 143.8, 135.7, 134.8,
128.8, 127.8, 127.0, 86.9, 76.6, 65.9, 44.8, 37.4; FAB
HRMS calcd for C25H22O2 [MþNa] 377.1517, found
377.1517.
3.3. General procedure for preparation of trans-b-
substituted carboxylic acid esters 13a–d
1
nmax 3435 (broad), 1703, 1670 cm21; H NMR (300 MHz,
CDCl3) d 7.70 (dd, J¼2.4, 5.6 Hz, 1H), 6.22 (dd, J¼2.0,
5.6 Hz, 1H), AB of ABX (dA¼3.74, dB¼3.69, JAB
¼
In a typical reaction, b-lactone (1.0 equiv.) was dissolved in
DMF (,0.13 M). To this was added the nucleophile
(1.5 equiv.). In the case of hydrocinnamic acid, N-Boc-
cysteine ethyl ester, and benzenethiol, Cs2CO3 (0.75 equiv.
was also added), and the mixture was stirred at 508C for
24 h. The mixture was diluted with water (100 mL/1 mmol
b-lactone), carefully acidified with 1N HCl aqueous
solution to pH¼2. The phases were separated and the
aqueous solution was extracted with ether. The combined
organic layers were washed with water (50 mL), and dried
over MgSO4, filtered, and concentrated to afford an oil. The
crude acid was dissolved in ether (,5 mL) and treated with
0.25 M diazomethane in ether (3.0 equiv.). After 15 min,
excess diazomethane was quenched with glacial acetic acid
10.5 Hz, JAX¼6.1 Hz, JBX¼5.9 Hz, 2H), 3.12–3.22 (m,
1H), 2.47 (dd, J¼6.6, 18.9 Hz, 1H), 2.16 (dd, J¼2.1,
18.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 209.8, 165.5,
135.2, 64.4, 44.1, 37.6. Satisfactory HRMS could not be
obtained for this compound and may be due to the instability
noted for this enone.
3.2.6. 4-Trityloxymethyl-cyclopent-2-enone (9). A sol-
ution of alcohol 8 (34.0 mg, 0.303 mmol) in 3.40 mL of
anhydrous CH2Cl2 at ambient temperature was treated with
triphenylmethyl chloride (126.0 mg, 0.453 mmol), anhy-
drous pyridine (60 mL, 0.727 mmol) and a catalytic amount
of DMAP. After 18 h, the clear mixture was partitioned

Y. Yokota et al. / Tetrahedron 58 (2002) 7075–7080
7079
and the solvent was removed. Purification by flash
chromatography gave the esters as oils.
Et2O (5 mL). To this was added an ,0.25 M solution of
diazomethane in Et2O (30 mL, 7.50 mmol). After 15 min,
the reaction was quenched with a few drops of AcOH until
the yellow color disappeared and then the solvent was
removed under reduced pressure.
3.3.1. 1,4-Dioxaspiro[4.4]nonane-8-azido-7-carboxylic
acid, methyl ester (13a). Rf 0.59 (7:3, EtOAc/hexanes);
1
IR (CHCl3) nmax 3020, 2956, 2890, 2108, 1735 cm21; H
NMR (300 MHz, CDCl3) d 4.19 (q, J¼8.0 Hz, 1H), 3.87–
3.95 (m, 4H), 3.74 (s, 3H), 2.86–2.92 (m, 1H), 2.24–2.34
(m, 2H), 2.06–2.11 (m, 1H), 1.87–1.92 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 173.2, 113.8, 64.6, 64.5, 61.3, 52.2,
48.0, 41.7, 38.6; EI HRMS calcd for C9H13O4N3 [MþNa]
250.0804, found 250.0834.
The crude azide 15 was dissolved in MeOH (5 mL) and then
5% Pd/C (320 mg, 0.15 mmol) and (Boc)2O (0.65 g,
3.00 mmol) were added. The reaction mixture was placed
under a hydrogen atmosphere (1 atm, H2 balloon) and
stirred for 2 h. The reaction mixture was filtered through a
plug of Celite, washed with MeOH and concentrated to give
a white solid. The crude product was chromatographed to
give transpentacin derivative 16 (0.19 g, 54%) as a white
3.3.2. 1,4-Dioxaspiro[4.4]nonane-8-phenylthio-7-car-
boxylic acid, methyl ester (13b). Rf 0.65 (7:3, EtOAc/
hexanes); IR (CHCl3) nmax 3005, 2979, 2880, 1732, 1439,
1325 cm21; 1H NMR (300 MHz, CDCl3) d 77.20–7.44 (m,
5H), 3.84–3.95 (m, 5H), 3.60 (s, 3H), 2.90 (app q,
J¼9.0 Hz, 1H), 2.38–2.45 (m, 1H), 2.24–2.32 (m, 1H),
2.09–2.17 (m, 1H), 1.87–1.95 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 173.7, 133.7, 132.3, 128.8, 127.2,
115.0, 64.5, 64.5, 52.0, 48.8, 46.4, 43.4, 40.2; EI HRMS
calcd for C15H18O4S4 [MþLi] 301.1086, found 301.1058.
1
solid: Rf¼0.43 (hexane/EtOAc¼7:3); H NMR (300 MHz,
CDCl3) d 4.61 (s, 1H), 4.08 (m, 1H), 3.67 (s, 3H), 2.56 (q,
J¼7.8 Hz, 1H,), 1.60–2.20 (m, 6H), 1.44 (s, 9H). The
spectral data matched that previously reported in the
literature.
3.3.6. N-(tert-Butyloxycarbonyl)-trans-(1S,2S)-2-amino-
cyclopentanecarboxylic acid methyl ester 16. Compound
(1S,2S)-16 (40 mg, 49%) was prepared from (1R,2S)-4a
(35 mg, 0.36 mmol) according to the method described
above for the preparation of the racemate: [a ]2D5¼þ39.98 (c
1.2, CHCl3); lit. [a]2D5¼þ44.68 (c 1.2, CHCl3).10
3.3.3. S-[1,4-Dioxaspiro[4.4]nonane-7-carboxylate]-N-
[(1,1-dimethylethoxy)carbonyl]-L-cysteine dimethyl
ester (13c). Rf 0.67 (7:3, EtOAc/hexanes); IR (CHCl3)
1
nmax 2979, 2874, 1732, 1710 cm21; H NMR (500 MHz,
CDCl3) d 5.35 (m, 1H), 4.51 (m, 1H), 4.21 (app q,
J¼7.5 Hz, 2H), 3.84–3.94 (m, 4H), 3.73 (s, 3H), 3.47 (app
q, J¼8.5 Hz, 1H), 2.97–3.07 (m, 2H), 2.80–2.85 (m, 1H),
2.37–2.42 (m, 1H), 2.23–2.27 (m, 1H), 2.07–2.12 (m, 1H),
1.82–1.87 (m, 1H), 1.45 (s, 9H), 1,29 (t, J¼7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 173.7, 170.6, 155.5, 114.9, 80.3,
65.8, 64.6, 64.5, 61.8, 53.2, 52.2, 49.5, 44.1, 43.9, 40.2,
34.1, 28.4, 15.4, 14.2; ESI HRMS calcd for C19H31NO8S
[MþH] 434.1848, found 434.1861.
Acknowledgments
Support of this work by the NSF (CAREER Award CHE-
9624532 and 0104457), the Robert A. Welch Foundation
(A-1280), Zeneca and Pfizer is gratefully acknowledged.
D. R. is an Alfred P. Sloan Fellow and a Camille-Henry
Dreyfus Teacher-Scholar. The NSF (CHE-0077917) also
provided funds for purchase of NMR instrumentation. Dr
Shane Tichy and use of instrumentation in the
TAMU/LBMS Applications Laboratory are acknowledged.
3.3.4. 1,4-Dioxaspiro[4.4]nonane-8-dihydrocinnamoyl-7-
carboxylic acid, methyl ester (13d). IR (CHCl3) nmax
3026, 1733 cm21; 1H NMR (500 MHz, CDCl3) d 7.25–7.30
(m, 2H), 7.18–7.22 (m, 3H), 5.35 (app dt, J¼5.5, 8.0 Hz,
1H), 3.88–3.92 (m, 4H), 3.68 (s, 3H), 2.97 (ddd, J¼6.4, 9.7,
18.6 Hz, 1H), 2.93 (t, J¼7.8 Hz, 2H), 2.63 (app dt, J¼0.7,
7.5 Hz, 2H), 2.44 (ddd, J¼0.7, 8.2, 9.2 Hz, 1H), 2.22 (ddd,
J¼2.0, 8.8, 13.7 Hz, 1H), 2.08 (ddd, J¼1.1, 9.9, 13.5 Hz,
1H), 1.85 (d, J¼1.8, 5.5, 14.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 173.1, 172.2, 140.3, 128.4, 128.2,
126.2, 114.4, 74.3, 64.6, 64.4, 52.0, 47.9, 42.0, 38.2, 35.7,
30.8; ESI/TOF HRMS calcd for C18H22O6 [MþNa]
357.1314, found 357.1416.
References
1. For a general review of b-lactones, see: Pommier, A.; Pons,
J.-M. Synthesis 1993, 441.
2. (a) Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403.
(b) Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc.
1999, 121, 9742. (c) Evans, D. A.; Janey, J. M. Org. Lett. 2001,
3, 2125.
3. (a) Cortez, G. S.; Tennyson, R.; Romo, D. J. Am. Chem. Soc.
2001, 123, 7945. (b) Cortez, G. S.; Oh, S.-H.; Romo, D.
Synthesis 2001, 1731.
3.3.5. N-(tert-Butyloxycarbonyl)-trans-2-aminocyclo-
pentanecarboxylic acid methyl ester 16. NaN3 (0.98 g,
15.0 mmol) was added to a solution of cis-6-oxabicyclo-
[3.2.0]heptan-7-one 4a (150 mg, 1.50 mmol) in DMF
(10 mL). The mixture was stirred at 258C for 48 h. Water
(150 mL) was added and the pH was adjusted to ,8 with
saturated aq. NaHCO3 solution, and then extracted
with EtOAc. The aqueous solution was acidified to pH¼2
with 1N HCl solution, and then extracted with Et2O. The
combined Et2O layers were dried over MgSO4, filtered, and
concentrated to give azido acid 14, which was dissolved in
4. Yang, H. W.; Romo, D. J. Org. Chem. 1999, 64, 7657.
5. Alcohol (þ)-10 was employed in the synthesis of (þ)-
aristeromycin, the enantiomer of the natural product, see:
Roberts, S. M.; Shoberu, K. A. J. Chem. Soc., Perkin Trans. 1
1991, 2605.
6. Shao, H.; Wang, S. H. H.; Lee, C.-W.; Osapay, G.; Goodman,
M. J. Org. Chem. 1995, 60, 2956.
7. Barchi, J. J.; Huang, X.; Appella, D. H.; Christianson, L. A.;
Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122,
2711 and references cited.

7080
Y. Yokota et al. / Tetrahedron 58 (2002) 7075–7080
8. Goto, T.; Toya, Y.; Ohgi, T.; Kondo, T. Tetrahedron Lett.
1982, 23, 1271.
1. (b) Kawabata, K.; Inamaoto, Y.; Sakane, K. J. Antibiot.
1990, 43, 513.
˚
¨ ¨
11. Noteberg, D.; Branalt, J.; Kvarnstrom, I.; Classon, B.;
9. (a) Konishi, M.; Nishio, M.; Saitoh, T.; Miyaki, T.; Oki, T.;
Kawaguchi, H. J. Antibiot. 1989, 42, 1749. (b) Oki, T.; Hirano,
M.; Tomatsu, K.; Numata, K.; Kamei, H. J. Antibiot. 1989, 42,
1756.
´
Samuelsson, B.; Nillroth, U.; Danielson, H.; Karlden, A.;
Hallberg, A. Tetrahedron 1997, 53, 7975.
12. Inoguchi, K.; Fujie, N.; Yoshikawa, K.; Achiwa, K. Chem.
Pharm. Bull. 1992, 122, 7831.
10. (a) Iwamoto, T.; Tsujii, I.; Ezaki, M.; Fujie, A.; Hashimoto, S.;
Okuhara, M.; Kohsaka, M.; Imanaka, H. J. Antibiot. 1990, 43,