Enantioselective route to key intermediates in the synthesis of carbocyclic phosphoribosyltransferase transition state analogues

Article abstract of DOI:10.1016/S0040-4020(01)00968-1

The enantioselective preparation of key intermediates in the synthesis of transition state analogues of hypoxanthine-guanine phosphoribosyltransferase, (1S,2S,3R,4R)-4-acetoxymethyl-1-bromomethyl-2,3-isopropylidenedioxy-1- toluenesulfonamidocyclopentane (3a) and the 4-nitrobenzenesulfonamido analogue (3b), are described.

Full text of DOI:10.1016/S0040-4020(01)00968-1

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 9899±9909
Enantioselective route to key intermediates in the synthesis of
carbocyclic phosphoribosyltransferase transition state analogues
²
³
Mohammad Ahmadian, Naveen K. Khare, James M. Riordan, Anthony E. Klon§
and David W. Borhanip
Department of Organic Chemistry, Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, USA
Received 21May 2001; accepted 3 October 2001
AbstractÐThe enantioselective preparation of key intermediates in the synthesis of transition state analogues of hypoxanthine-guanine
phosphoribosyltransferase, /1S,2S,3R,4R)-4-acetoxymethyl-1-bromomethyl-2,3-isopropylidenedioxy-1-toluenesulfonamidocyclopentane
/3a) and the 4-nitrobenzenesulfonamido analogue /3b), are described. q 2001Elsevier Science Ltd. All rights reserved.
1. Introduction
Infection by T. gondii presents little threat to individuals
with a normal immune system.2 However, in immuno-
suppressed individuals, such as patients with Acquired
Immune De®ciency Syndrome /AIDS), recrudescence of
latent T. gondii cysts in the brain causes toxoplasmic
encephalitis.3 Disseminated toxoplasmosis is also a serious
complication of organ transplantation.
Parasitic protozoa cannot carry out the de novo synthesis of
purine nucleotides that are required for growth and
replication. Rather, they salvage pre-formed purine bases
from their hosts. A major purine salvage pathway is
controlled by the enzyme hypoxanthine-guanine phosphori-
bosyl transferase /HGPRT), which catalyzes the nucleo-
philic substitution of the pyrophosphate moiety of a-d-5-
phosphoribosyl-1-pyrophosphate /PRPP) by the N9 atom of
a purine base /Scheme 1). Since HGPRT is apparently
dispensable to mammalian metabolism, protozoal HGPRTs
have long been viewed as attractive targets for anti-
protozoal chemotherapy.1
Our approach has been to use the three-dimensional struc-
ture of T. gondii HGPRT to guide the design of improved
HGPRT inhibitors. Structural work carried out by us4±6 and
by others7±9 has provided many insights into both the overall
HGPRT catalytic mechanism as well as the mechanisms by
which protozoal HGPRTs are able, unlike the human
enzyme, to catalyze the ef®cient conversion of xanthine to
xanthosine 50-monophosphate.10 Nonetheless, it has been
clear since determination of the human HGPRT crystal
Our work has focused on Toxoplasma gondii, a pervasive
protozoan that infects as much as half of the population.
Scheme 1.
Keywords: HGPRT; transition state analogues; carbocyclic nucleosides; X-ray structure.
p Corresponding author. Present address: Abbott Bioresearch Center, Inc., 100 Research Drive, Worcester, MA 01605, USA. Tel.: 580-849-2944; fax: 508-
755-8361; e-mail: david.borhani@abbott.com.
²
Present address: Epoch Biosciences, Inc., 21720 - 23rd Dr. SE #150, Bothell, WA 98021, USA.
On leave from Chemistry Department, Lucknow University, Lucknow, India.
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
³
§
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00968-1

9900
M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
Scheme 2.
structure that signi®cant motion of a large active site loop
/loop II) accompanies catalysis by HGPRT.11 Despite
the ®ndings of recent reports of HGPRT crystal struc-
tures4,7±9 in which loop II is closed over an active site
occupied by a substrate and an unreactive substrate
analogue /e.g. PRPP and 9-deazaguanine), the true func-
tional role/s) of loop II closure remains unclear, in part
because all such HGPRT ternary complexes are bi-
substrate /analogue) complexes; they are not images
of the enzyme at the transition state. Indeed, the
enzyme still functions when loop II is deleted, albeit
at a much reduced rate,12 results consistent with loop
II playing a supporting but not critical role in the
precise positioning of substrates for catalysis and/or
transition-state stabilization.
2. Results and discussion
2.1. Retrosynthetic Analysis
As shown in Scheme 3, functional group simpli®cation
leads backwards from 2 to intermediate 4 /O5 phosphoryl-
ation, C9 pyrophosphonate construction, and conversion of
ªNº to a purine ring). Intermediate 4 in turn could be
accessed by a variety of routes. We considered spirohydan-
toin formation at C1. This method was used to prepare
carbocyclic analogues of the spironucleoside /1)-hydanto-
cidin.19 Bucherer±Bergs reaction of the cyclopentanone
provided the spirohydantoin /4, ±ªNº,XCH2± ˆ ±
NH/CO)NH/CO)±) with the incorrect stereochemistry
/albeit in high yield), however, and under Read reaction
conditions the stereochemically-correct aminonitrile was
formed in poor yield.19 Thus, we were interested in explor-
ing other synthetic routes /e.g. enolate chemistry, or open-
ing of an epoxide or azirdine ring) from the ole®n 5
/R2ˆOAc, H). Ole®n 5 is available as a single enantiomer
by lipase-catalyzed20 monoacetylation of the meso diol 6,21
which can be prepared by stereoselective OsO4-catalyzed
cis-dihydroxylation of norbornadiene ꢀ7).
To capture the essence of the catalytically-competent
HGPRT active site, therefore, we felt that it was essential
to trap the enzyme closer to the transition state 1 /Scheme
2). Thus, we set out to synthesize HGPRT transition state
/TS) analogues, ꢀ2). The TS analogues 2 mimic the purine
and ribose-50-phosphate aspects of the transition state,
whereas the labile PRPP pyrophosphate is replaced by a
non-hydrolyzable pyrophosphonate. It is also stabilized
against acid-catalyzed decomposition by substitution of
the ribose furanyl oxygen by a methylene group, a draw-
back of previously-reported analogues based on psico-
furanose.13±15 The target compounds 2 are distinct from
the pyrrolidine-based Immucillin nucleoside analogues16
and the carbocyclic analogue of PRPP,17,18 neither of
which encompass both HGPRT substrates in a single
molecule. We report here the enantioselective synthesis of
/1S,2S,3R,4R)-4-acetoxymethyl-1-bromomethyl-2,3-iso-
propylidenedioxy-1-toluenesulfonamidocyclopentane ꢀ3a)
and /1S,2S,3R,4R)-4-acetoxymethyl-1-bromomethyl-2,3-
isopropylidenedioxy-1-p-nitrobenzenesulfonamidocyclo-
pentane ꢀ3b), potential key intermediates toward the
synthesis of 2 that embody the correct carbon skeleton,
oxidation state, and relative and absolute stereochemistry
of the target.
2.2. Precursor Synthesis
The precursors for the synthesis of analogue 2 were
prepared as shown in Scheme 4. Following the route laid
out by Sakai and coworkers,21 OsO4-catalyzed cis-
dihydroxylation of norbornadiene followed by ketalization
furnished exo-5,6-isopropylidenedioxybicyclo[2.2.1]hept-
2-ene ꢀ8) along with a small amount of the bis-acetonide
9.22 Ozonolysis of 8 provided the meso-diol 6 in excellent
yield. The key desymmetrization of 6, namely the Pseudo-
monas ¯uorescens lipase /PFL)-catalyzed transesteri®cation
reaction of 6 and vinyl acetate, afforded the monoacetate
/1)-10a in .99% enantiomeric excess and 83% yield.21
The 19F NMR spectrum of the Mosher ester23,24 derivative
of /1)-10a, 10c, exhibited only one signal at 271.93 ppm
/referenced to CFCl3), whereas the Mosher ester of the
Scheme 3.

M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
9901
Scheme 4. /i) OsO4, NMNO; /ii) /CH3)CO, TsOH; /iii) O3; /iv) NaBH4; /v) CH2ˆCHOAc, P. ¯uorescens lipase; /vi) /1)-MTPA-Cl, pyridine; /vii) Ac2O,
pyridine; /viii) PCC; /ix) PDC, DMF, CH3OH; /x) PPh3, I2, pyridine; /xi) DBU; /xii) NaOCH3, MeOH; /xiii) Tf2O, BnOH, 2,6-di-t-butyl-4-methylpyridine.
Scheme 5. /i) AgNCO, I2; /ii) CH3OH, LiOCH3.
racemate, prepared by partial acetylation /Ac2O, pyridine)
of 6, exhibited two signals at 271.93 and 272.02 ppm. All
further work reported here was performed within the highly
enantiomerically-enriched series derived from /1)-10a.
accomplished in two steps by conversion to the iodide 13
followed by elimination of HI to yield 14a. Addition of
alkene 14a to a solution of INCO in CH2Cl2 at 2408C28,29
was followed by LiOH-catalyzed methanolysis; the de-
acetylated starting material /14b) was the only product
obtained. We anticipated that exchange of an acetyl protect-
ing group by a benzyl ether would provide the more
hydrolysis-resistant analogue /14c). Unexpectedly, reaction
of 14c with INCO under identical conditions did not result
in the incorporation of INCO, but rather provided the cyclic
ether 15 and the co-product benzyl carbamate 16 /Scheme
5). A straightforward mechanism for formation of 15 and 16
is shown in Scheme 5. Intramolecular capture of the inter-
mediate iodonium ion by the benzyl ether oxygen is
apparently more facile than intermolecular capture by
isocyanate.
2.3. Enolate Chemistry
Our ®rst approach to functionalization of C1centred on
enolate chemistry of the aldehyde 11,25 prepared by oxida-
tion of the monoacetate 10a /Scheme 4).26 Attempts to
incorporate an azide group at C1, adjacent to the carbonyl
group, by reaction of the enolate ion itself or its vinyl
trimethylsilyl ether derivative with p-toluenesulfonyl azide
failed. Since aldol condensation of 11 was likely the source
of dif®culty, we attempted a similar conversion on the
less-reactive methyl ester 12, prepared by oxidation of 11
with pyridinium dichromate in DMF in the presence of
methanol.27 However, in situ generation of the correspond-
ing enolate by several methods simply resulted in
decomposition of ester 12.
In contrast, reaction of alkene 14a with a solution of IN3 in
CH3CN32 yielded the isomeric iodo azides 17a and 17b
/Scheme 6). The IR spectra showed bands at 2105 cm21
,
characteristic of the organic azide functionality. The regio-
chemistry of the products was determined by examination of
their 13C NMR spectra. The chemical shifts observed for the
CH2X group /XˆI or N3) and the adjacent quaternary
2.4. Pseudohalogen Chemistry
Several reports indicate that the addition of iodine iso-
cyanate /INCO) or iodine azide /IN3) to simple alkenes
proceeds readily.28±31 The addition was postulated to
proceed through formation of an iodonium ion. We antici-
pated that reaction of a suitable exocyclic alkene /Scheme 4)
with INCO or IN3 should provide an iodonium ion, opening
of which would yield a transient tertiary carbenium ion at
C1that could be captured by azide or isocyanate.
Dehydration of alcohol 10a to an exo-ole®n /Scheme 4) was
Scheme 6. /i) ICl, NaN3, CH3CN.

9902
M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
of epoxide opening was con®rmed by conversion to its di-
and tribenzoyl derivatives 19a and 19b. Benzamide 19a had
a distinctive NMR spectrum consistent with a benzamide
benzoyl ester, not a benzimide tertiary alcohol.
Encouraged by these results, we turned our attention to the
conversion of alkene 14a to the corresponding epoxide.
Reaction with m-ClC6H4CO3H /m-CPBA)34 afforded a 4:1
mixture of the diasteromeric epoxides 20a and 20b /Scheme
8) which was separated by silica gel chromatography.35 The
stereochemistry of 20b was assigned by observation of 3%
nOe enhancement between the two oxirane ring protons and
the b-disposed protons on C2 and C5 /no nOe enhance-
ments were observed for 20a). The stereochemistry as
assigned is consistent with the major product 20a resulting
from attack of m-CPBA from the less-hindered b-face of the
alkene.
Scheme 7. /i) Et3Al, HN3; /ii) H2, 5% Pd/C; /iii) BzCl, pyridine; /iv)
PhIˆNTs, CuOTf; /v) Li2NiBr4 or NaN3, BF3´Et2O.
carbon of the major stereoisomer 17a, 62.8 and 56.8 ppm,
respectively, were consistent with the presence of a CH2N3,
not a CH2I, moiety. /The calculated 13C chemical shift for
the CH2I moiety of the regioisomer is ,10 ppm, in agree-
ment with experimental shifts observed for model
compounds.) The minor stereoisomer 17b exhibited similar
chemical shifts /60.6, 52.2 ppm). Thus, nucleophilic attack
of the azide ion occurred at the undesired, less hindered end
of the iodonium ion rather than at the desired, more hindered
tertiary position /C1).
Treatment of epoxide 20a with Et3Al/HN3 in toluene
provided azido alcohol 21 along with its deacetylated
analogue 22 in a 2:1ratio. Diol 22 was easily returned to
21 by acetylation /Ac2O, pyridine). Under these conditions
only the 4-hydroxymethyl group was acetylated, indicating
that the reaction had produced a tertiary alcohol. In addition,
catalytic hydrogenation of 21 followed by acetylation quan-
titatively provided the acetamide 23, which still possessed
one free /tertiary) hydroxyl group. Thus, in contrast to our
results with the model compound 1-oxaspiro[2,4]heptane as
well as literature reports, epoxide 20a reacted with Et3Al/
HN3 to afford the undesired primary azide 21. As
previously, nOe enhancement experiments on 21 led to a
clear assignment of the stereochemistry /b-hydroxyl
group). Under identical reaction conditions, the diastereo-
meric epoxide 20b did not react with Et3Al/HN3. Reaction
in the more polar solvent CH3CN afforded, however, the
azido triol 24 in poor yield, apparently resulting from
epoxide opening along with loss of the acetonide group. It
is likely that this occurs due to coordination of Et3Al by the
a-epoxide oxygen atom /i.e. syn to the acetonide).
The stereochemistry of the diastereomers 17a and 17b was
assigned on the basis of homonuclear nOe measurements.
Irradiation of the CH2N3 group in 17a resulted in a 2±3%
nOe enhancement of the C5 b proton with no effect on the a
proton. The converse was observed for 17b. De®nitive
identi®cation of the C5 a and b protons in each compound
was accomplished by observing the nOe enhancements of
these protons upon irradiation of the C3 proton or the
acetoxymethyl group protons /both b).
2.5. Epoxidation
A report of Mereyala et al.33 on the Et3Al-mediated addition
of HN3 to epoxides prompted us to examine this route to
introduce a nitrogen moiety at C1. This methodology has
been applied in a complex natural product synthesis with
good results.33 We ®rst tested the method with 1-oxa-
spiro[2,4]heptane. Reaction with Et3Al/HN3 provided the
expected azido alcohol, 1-azido-1-hydroxymethylcyclo-
pentane ꢀ18), in 58% yield /Scheme 7). The regiochemistry
This body of results on the addition of IN3 to the terminal
alkene 14a and of HN3 to the epoxides 20a and 20b led us to
conclude that molecular strain prevents the three-membered
ring intermediate in these reactions from opening to form
the /desired) tertiary carbenium ion at C1. Rather, formation
Scheme 8. /i) m-CPBA; /ii) Et3Al, HN3, toluene; /iii) Ac2O, pyridine; /iv) H2, 5% Pd/C; /v) Et3Al, HN3, CH3CN.

M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
9903
Scheme 9. /i) PhIˆNTs, CuOTf or PhIˆNSO2C6H4-4-NO2, Cu/CH3CN)41 ClO42; /ii) Li2NiBr4.
of compounds 17a, 17b, 21, 22, and 24 results from nucleo-
philic attack of azide ion on the more accessible exocyclic
atom of the three membered ring /iodonium ion inter-
mediate or activated oxirane ring, respectively) in each
case. Our observations are in accord with those made by
Griengl and co-workers on the opening of epoxides 20a
and 20b with acetate.35
target molecule /Scheme 9). Reaction of alkene 14a with
PhIˆNTs/CuOTf in CH3CN gave N-p-toluenesulfonyl-
/2S,3R,4R)-6-acetoxymethyl-4,5-isopropylidenedioxy-1-
azaspiro[2,4]heptane ꢀ28a) in 22% yield. Aziridine 28a
reacted with Li2NiBr4 to yield 3a. NMR and infrared spec-
troscopic analysis of 3a suggested that the aziridine ring had
been opened to provide the desired regioisomer. The struc-
ture of 3a was unequivocally con®rmed by determination of
its crystal structure. Slow evaporation of a solution of 3a in
CDCl3 provided crystals suitable for X-ray analysis. The
structure was determined with SHELX,38 and was re®ned
to an R-factor of 3.8%. An ORTEP view of the 3a structure
is shown in Fig. 1. The crystal structure con®rmed that the
regiochemistry of aziridine opening had indeed proceeded
in the desired direction, and also validated both the relative
and absolute stereochemistry of 3a. The yields in these last
two steps were dramatically improved by carrying out the
aziridination of alkene 14a with [/4-nitrobenzenesulfonyl)-
imino]-phenyliodinane,39 using Cu/CH3CN)4ClO4 as the
catalyst,40 to give 28b in 68% yield. Like 28a, aziridine
28b reacted with Li2NiBr4 to afford the bromide 3b in
94% yield.
2.6. Aziridination
An obvious tactical shift to surmount this barrier was incor-
poration of the requisite nitrogen atom prior to ring opening.
Thus, we hypothesized that nucleophilic opening of an
aziridine ring would leave the nitrogen at the tertiary carbon
C1and allow for further elaboration of the exocyclic
methylene group.
This idea was put to the test with methylene cyclohexane.
Reaction with [/4-toluenesulfonyl)imino]-phenyliodinane
/PhIˆNTs)36 catalyzed by copper/I) tri¯ate led to formation
of the desired N-p-toluenesulfonyl-1-azaspiro[2,5]octane
ꢀ25) in 73% yield /Scheme 7). Treatment of this aziridine
37
with Li2NiBr4 opened the aziridine ring to give the
primary bromide 26 in good yield. In addition, BF3´Et2O-
mediated reaction of the aziridine with NaN3 in DMF
provided the corresponding azido toluenesulfonamide 27.
3. Summary
We have described the enantiospeci®c synthesis of the
highly-functionalized cyclopentanes 3a and 3b. These
compounds possess the complete carbon skeleton and func-
tional group oxidation state of the target phosphoribosyl-
transferase transition state analogue inhibitor 2.
Completion of the synthesis of 2 by purine ring elaboration
and incorporation of the phosphate and pyrophosphonate
groups will be subject of our next report.
Encouraged by these results, we extended the method to our
4. Experimental
NMR spectra were recorded in CDCl3 on a Nicolet Model
NT 300NB spectrometer /300 MHz 1H frequency).
Chemical shifts are given in ppm relative to residual
CHCl3 /unless otherwise stated) at 7.26 ppm /for 1H
NMR) and 77.0 ppm /for 13C NMR). Coupling constants
are reported in Hz. The symbols s0, d0, t0 and q0 used for
13C NMR signals indicate zero, one, two, or three attached
hydrogens, respectively. 13C NMR chemical shifts were also
calculated using the Bruker SpecEdit program. Fast atom
bombardment /FAB) and electron-impact /EI) mass spectra
were recorded on a Varian/MAT 311A double-focusing
mass spectrometer. For FAB, the matrix was p-nitrobenzoic
acid /NBA), with or without added LiCl. High resolution
mass spectra were obtained on a Bruker Daltonics Bio-TOF
Figure 1. Crystal structure of key intermediate 3a. This thermal-ellipsoid
plot shows that the absolute and relative con®gurations at C2, C3, and C4
correspond to d-ribose, and that the relative con®guration at C1is as desired
for an HGPRT transition-state analogue. Figure prepared with ZORTEP.44

9904
M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
II ESI mass spectrometer. Optical rotations /one dm path
length) were obtained on a Rudolph precision polarimeter,
Model 80, and are reported at the NaD line /578 nm). Thin-
layer and column chromatography were performed with
silica gel. Unless stated otherwise, reaction mixtures were
dried with anhydrous Na2SO4, solvents were removed in
vacuo, and the residue was puri®ed by column chromato-
graphy.
Jˆ3.74), 4.25 /2H, app t, Jˆ2.4), 4.06 /2H, d, Jˆ5.9),
4.05 /2H, d, Jˆ6.0), 3.55 /6H, app t, JH-Fˆ1.2), 2.40 /4H,
m), 2.05 /3H, s), 2.04 /3H, s), 2.03 /2H, m), 1.47 /6H, s),
1.269 /3H, s), 1.267 /3H, s), 1.25 /2H, m). 19F NMR d
271.93 /s), 272.02 /s). From integration of the 19F NMR
signals of 10c,23 we estimated the enantiomeric excess of
/1)-10a to be .99%.
4.2. ꢀ1RS,2S,3R,4R)-4-Acetoxymethyl-2,3-isopropyl-
idenedioxycyclopentane-1-methanal ꢀ11)
4.1. ꢀ1S,2S,3R,4R)-4-Acetoxymethyl-2,3-isopropylidene-
dioxycyclopentane-1-methanol ꢀ10a), 1,4-diacetoxy-2,3-
isopropylidenedioxycyclopentane ꢀ10b), and the Mosher
ester derivatives ꢀ10c)
Monoacetate 10a /45 mg, 0.184 mmol) was stirred with
pyridinium chlorochromate /PCC, 80 mg, 0.37 mmol) in
CH2Cl2 /10 mL) on ice.26 After 3 h the mixture was warmed
to room temperature, and the progress of the reaction was
monitored by TLC until no starting material remained.
Diethyl ether /25 mL) was added, the mixture was ®ltered,
passed through a plug of Florisil and evaporated under
reduced pressure. A colorless oil containing a 3.2:1mixture
of /1R,2S,3R,4R)-4-acetoxymethyl-2,3-isopropylidenedioxy-
cyclopentane-1-methanal /11b)25 and the /1S,2S,3R,4R)-
diastereomer /11a) /40 mg, 90%) was obtained. Mass m/z
243 /M1H)1, 227 /M1H±CH4)1, 185 /M1H±C3H6O)1.
IR /neat) n 2987, 2939, 1742, 1455, 1382, 1377, 1235, 1212,
The asymmetric alcohol /1)-10a was prepared according to
Tanaka et al.21 by P. ¯uorescens lipase /PFL)-mediated
transesteri®cation of 6 in vinyl acetate. Diol 6 /5.0 g,
25 mmol) dissolved in vinyl acetate /50 ml) was stirred at
room temperature with a suspension of PFL /40 mg,
42.5 U/mg, Fluka 62321). The progress of the reaction
was monitored by TLC /CHCl3/CH3OH, 95:5). The reaction
was complete after 30 h. Vinyl acetate was evaporated
under reduced pressure and the residue was puri®ed by
column chromatography /CHCl3/CH3OH, 95:5) to provide
5.01g /83%) of / 1)-10a as a colorless, viscous oil /Lit. mp
42±438C21). Mass m/z 245 /M1H)1, 229 /M1H±CH4)1
187 /M1H±C3H6O)1; m/z 495 /2M1Li)1, 251/M 1Li)1,
1
1037 cm21. 11b: H NMR d 9.77 /1H, s), 4.94 /1H, dd,
Jˆ3.3, 6), 4.44 /1H, dd, Jˆ2.8, 6), 4.02 /1H, dd, Jˆ5.7,
11.3), 3.93 /1H, dd, Jˆ6.1, 11.3), 2.96 /1H, m), 2.48 /1H,
m), 2.36 /1H, m), 2.04 /3H, s), 1.86 /1H, dt, Jˆ5.9, 13.2),
1.50 /3H, s), 1.33 /3H, s). 11a: 1H NMR d 9.77 /1H, s), 5.0
/1H, t, Jˆ5.7), 4.52 /1H, d, Jˆ5.5), 4.34 /1H, m), 4.1 /1H,
m), 3.9 /1H, m), 2.87 /1H, m), 2.29 /1H, m), 2.08 /3H, s),
1.65 /1H, m), 1.42 /3H, s), 1.30 /3H, s). [a]2D0 ±9.48 /c 0.7,
MeOH).
1
245 /M1H)1. H NMR d 4.40 /1H, dd, Jˆ5.0, 7.0), 4.34
/1H, dd, Jˆ5.3, 7.0), 4.11 /2H, d, Jˆ6.4), 3.69 /1H, dd,
Jˆ5.9, 10.5), 3.63 /1H, dd, Jˆ6.6, 10.5), 2.4 /1H, m), 2.3
/1H, m), 2.08 /1H, m), 2.07 /3H, s), 1.50 /3H, s), 1.31 /3H,
s), 1.27 /1H, m). [a]D24 18.928 /c 1.02, CHCl3) /Lit. [a]2D4
18.558 /c 1.07, CHCl321)).
4.3. ꢀ1S,2S,3R,4R)-4-Acetoxymethyl-2,3-isopropylidene-
dioxycyclopentane-1-carboxylate methyl ester ꢀ12)
The reaction also provided 0.86 g /12%) of the meso-di-
acetate /^)-10b. Mass m/z 287 /M1H)1, 271/M 1H±
CH4)1, 229 /M1H±C3H6O)1; m/z 293 /M1Li)1, 287
/M1H)1, 271/M 1H±CH4)1, 277 /M1Li±CH4)1, 235
PDC /13.5 g, 36 mmol) was added to a solution of aldehyde
11 /1.43 g, 6 mmol) and CH3OH /1.5 mL, 36 mmol) in
DMF /20 mL).27 After stirring 20 h at room temperature
hexane /75 mL) and sat. aq. NaHCO3 /30 mL) were
added. The mixture was ®ltered through a Florasil plug,
dried and evaporated. The residue was distilled under
reduced pressure /bp 1058C, 0.25 torr) to obtain 705 mg
/43%) of ester 12. Mass m/z 279 /M1Li)1, 273 /M1H)1,
257 /M1H ± CH4)1, 21 5 /M1H ± C3H6O)1. IR /neat) n
2987, 2953, 1741, 1456, 1437, 1381, 1374, 1243, 1211,
1
/M1Li±C3H6O)1, 229 /M1H±C3H6O)1. H NMR d 4.34
/2H, dd, Jˆ1.1, 3.3), 4.12 /2H, dd, Jˆ6.6, 11), 4.07 /2H, dd,
Jˆ6.4, 11), 2.4 /2H, m), 2.10 /1H, dt, Jˆ7, 11) 2.07 /6H, s),
1.50 /3H, s), 1.30 /3H, s), 1.25 /1H, m).
The Mosher esters of /1)-10a and /^)-10a /obtained by
partial acetylation of 6 with Ac2O/pyridine) were prepared
by esteri®cation in pyridine/CCl4 with excess /S)-/1)-a-
methoxy-a-tri¯uoromethylphenylacetyl chloride24 and
were puri®ed by chromatography /CH2Cl2/MeOH, 99:1).
Mosher ester of /1)-10a, /1S,2S,3R,4R)-4-acetoxymethyl-
2,3-isopropylidenedioxycyclopentane-1-methanol /S)-a-
methoxy-a-tri¯uoromethylphenylacetate ꢀ10c): Mass m/z
461/M 1H)1, 445 /M1H±CH4)1, 403 /M1H±C3H6O)1,
1
1175, 1070, 1037, 865 cm21. H NMR d 4.85 /1H, dd,
Jˆ4.6, 6.6), 4.44 /1H, dd, Jˆ4.2, 6.8), 4.09 /1H, dd,
Jˆ6.15, 11.2), 4.04 /1H, dd, Jˆ6.4, 11.2), 3.71 /3H, s),
2.94 /1H, ddd, Jˆ4.6, 9.0, 16.9), 2.41 /1H, m), 2.32 /1H,
dd, Jˆ7.7, 13.2), 2.07 /3H, s), 1.80 /1H, dd, Jˆ9.0, 13.2),
1.50 /3H, s), 1.32 /3H, s). [a]2D0 ±25.58 /c 1.01, CHCl3).
HRMS Calcd for C13H20O6: m/z /M1H)1 273.1333,
/M1Na)1 295.1152; Found: m/z 273.1335, 295.1159.
1
401/M 1H±HOAc)1. H NMR d 7.53 /2H, m), 7.41/3H,
m), 4.43 /1H, dd, Jˆ5.5, 11.1), 4.32 /1H, dd, Jˆ6, 11.1),
4.29 /2H, app t, Jˆ3.7), 4.05 /2H, d, Jˆ6.0), 3.54 /3H, app
d, JH-Fˆ1.2), 2.40 /2H, m), 2.05 /3H, s), 2.03 /1H, m), 1.47
/3H, s), 1.27 /3H, s), 1.25 /1H, m). 19F NMR /564.7 MHz,
CDCl3, referenced to CFCl3) d ±71.93 /s). Mosher esters
of /^)-10a, /1SR,2SR,3RS,4RS)-4-acetoxymethyl-2,3-iso-
propylidenedioxycyclopentane-1-methanol /S)-a-methoxy-
4.4. ꢀ1S,2S,3R,4R)-4-Acetoxymethyl-1-iodomethyl-2,3-
isopropylidenedioxycyclopentane ꢀ13)
A mixture of Ph3P /8.38 g, 0.032 mol) and I2 /7.62 g,
0.030 mol) in anhydrous CH2Cl2 /100 mL) was stirred at
room temperature for one h.21 The brownish-red clear solu-
tion cooled to ±108C and a solution of alcohol 10a /4.88 g,
1
a-tri¯uoromethylphenylacetate: H NMR d 7.53 /4H, m),
7.41/6H, m), 4.43 /1H, dd, Jˆ5.5, 11.1), 4.37 /1H, d,
Jˆ5.7), 4.32 /2H, dd, Jˆ6.0, 11.1), 4.29 /2H, app t,

M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
9905
0.020 mol) in CH2Cl2 /25 mL) and pyridine /2.37 g,
0.030 mol) was added. The mixture stirred for 15 min, and
then 6 h at room temperature. The reaction mixture was
poured into 5% aq. Na2S2O3 /50 mL) and extracted with
Et2O /2 x 100 mL). The combined extracts were washed
with H2O, dried and evaporated. The residue was chroma-
tographed /20% EtOAc/hexanes, Rfˆ0.42) to obtain 6.76 g
/94%) of iodide 13. Mass m/z 355 /M1H)1, 339 /M1H±
CH4)1, 297 /M1H±C3H6O)1; m/z 361/M 1Li)1, 339
/M1H±CH4)1. IR /neat) n 2986, 2935, 1741, 1380, 1371,
mixture stirred for 30 min.41,42 Alcohol 14b /160 mg,
0.86 mmol) in CH2Cl2 /2 mL) was added slowly to the
reagent mixture, the reaction was stirred for 30 min, and
then warmed to room temperature and stirred for 1h.
Pyridine /300 mL) was added and the mixture was washed
with H2O /3 £ 5 mL), dried and evaporated. Chromato-
graphy of the residue /hexane/EtOAc, 90:10) gave benzyl
ether 14c /190 mg, 80%). Mass /ESI-MS) m/z 313 /M1K)1,
297 /M1Na)1, 292 /M1NH41)1, 275 /M1H)1, 21 7
/M1H±C3H6O)1, 91/PhCH )1. H NMR d 7.32 /5H, m),
2
1
1244, 1212, 1071, 1034 cm21. H NMR d 4.38 /1H, dd,
5.19 /1H, d, Jˆ1.3), 5.09 /1H, d, Jˆ1.3), 4.69 /1H, d, Jˆ6),
4.5 /1H, d, Jˆ6), 4.49 /2H, s), 3.27 /2H, d, Jˆ7.2), 2.78 /1H,
m), 2.45 /1H, m), 2.10 /1H, d, Jˆ15), 1.47 /3H, s), 1.32 /3H,
s). [a]2D0 25.058 /c 1.5, MeOH). HRMS Calcd for C17H22O3:
m/z /M1Na)1 297.1461; Found: m/z 297.1453.
Jˆ5.2, 7.0), 4.23 /1H, dd, Jˆ5.2, 7.0), 4.13 /1H, dd,
Jˆ6.4, 11), 4.09 /1H, dd, Jˆ6.0, 11), 3.38 /1H, dd, Jˆ5.0,
10), 3.24 /1H, dd, Jˆ6.8, 10), 3.39 /1H, m), 2.3±2.12 /2H,
m), 2.08 /3H, s), 1.5 /3H, s), 1.31 /3H, s), 1.37±1.24 /1H,
m). Anal. Calcd for C12H19IO4: C 40.69%, H 5.41%; Found:
C 40.79%, H 5.23%. [a]2D0219.28 /c 0.76, CHCl3).
4.7. ꢀ1R,4R,5R,6R)-1-Iodomethyl-5,6-isopropylidene-
dioxy-2-oxabicyclo[2.2.1]heptane ꢀ15) and N-benzyl
methyl carbamate ꢀ16)
4.5. ꢀ2S,3R,4R)-4-Acetoxymethyl-2,3-isopropylidene-
dioxy-1-methylenecyclopentane ꢀ14a)
Iodine /61mg 0.24 mmol) was added to a stirred suspension
of AgNCO /36 mg, 0.24 mmol) in anhydrous CH2Cl2
/5 mL) at 2408C.29 After 90 min a solution of benzyl
ether 14c /55 mg, 0.20 mmol) in CH2Cl2 /1mL) was
added and stirred an additional 90 min. The reaction
mixture was left at 2158C overnight, then allowed to
warm to room temperature. The solvent was evaporated
under reduced pressure, the residue was dissolved in
anhydrous methanol /2 mL) containing a catalytic amount
of LiOCH3, and the mixture was stirred at room temperature
overnight. The solvent was evaporated under reduced
pressure and the residue was puri®ed by preparative TLC
/hexane/EtOAc, 90:10) to give the cyclic ether 15 /42 mg,
67%) as a colorless oil. Mass /ESI-MS) m/z 311 /M1H)1.
IR /neat) n 2987, 2935, 1382, 1372, 1265, 1207, 1076,
A mixture of DBU /4.7 g, 30.2 mmol) and iodide 13 /5.38 g,
15.2 mmol) in anhydrous C6H6 /50 mL) was re¯uxed for
5 h.21 The mixture was cooled to room temperature and
then partitioned between aq. NH4Cl and Et2O /3 £
75 mL). The combined extracts were washed with 5% aq.
Na2S2O3 /25 mL) and water, and then dried and evaporated.
Distillation /bp 85±878C, 1mm Hg) yielded 2.70 g /77%)
of a colorless oil, alkene 14a. Mass m/z 227 /M1H)1, 21 1
/M1H±CH4)1, 169 /M1H±C3H6O)1; m/z 133 /M1Li)1.
IR /neat) n 2988, 2938, 1744, 1381, 1371, 1242, 1232, 1209,
1161, 1035, 873 cm21. 1H NMR d 5.23 /1H, d, Jˆ1.5), 5.11
/1H, app q, Jˆ1), 4.73 /1H, d, Jˆ5.6), 3.49 /1H, d, Jˆ5.6),
3.90 /1H, d, Jˆ1), 2.80 /1H, m), 2.44 /1H, q, Jˆ7.5), 2.04
/1H, m), 2.04 /3H, s), 1.48 /3H, s), 1.34 /3H, s). 13C NMR d
171.4 /s0), 148.5 /s0), 113.2 /t0), 110.7 /s0), 82.4 /d0), 81.6
/d0), 64.7 /t0), 42.8 /d0), 32.3 /t0), 26.6 /q0), 24.4 /q0), 20.9
/q0). [a]D20±124.88 /c 1.2, CHCl3). Anal. Calcd for
1
1048 cm21. H NMR d 4.39 /1H, d, Jˆ4.6), 4.00 /1H, dd,
Jˆ1.7, 5.5), 3.78 /1H, dd, Jˆ3.3, 7.9), 3.54 /1H, d, Jˆ11.2),
3.50 /1H, d, Jˆ11.2), 3.43 /1H, d, Jˆ7.9), 2.67 /1H, m),
1.94 /1H, d, Jˆ10.5), 1.55 /1H, m), 1.45 /3H, s), 1.31 /3H,
s). [a]2D0 245.28 /c 1.0, CHCl3). HRMS Calcd for
C10H15O3I: m/z /M1H)1 311.0139, /M1Na)1 332.9958;
Found: m/z 311.0135, 332.9969. The co-product benzyl car-
bamate 16 was isolated in 30% yield. Mass /ESI-MS) m/z
166 /M1H)1. IR /neat) n 3326 /br), 3062, 3030, 2948,
C12H18O4´/H2O)0.1:
62.84%, H 7.80%.
C 63.19%, H 8.04%; Found: C
4.6. ꢀ2S,3R,4R)-4-Methanol-2,3-isopropylidenedioxy-1-
methylenecyclopentane ꢀ14b) and ꢀ2S,3R,4R)-4-benzyl-
oxymethyl-2,3-isopropylidenedioxy-1-methylenecyclo-
pentane ꢀ14c)
1
2925, 1703, 1530, 1455, 1260 cm21. H NMR d 7.29 /5H,
m), 5.0 /1H, br s), 4.35 /2H, d, Jˆ6), 3.70 /3H, s).
Alkene 14a /345 mg, 1.5 mmol) and NaOCH3 /162 mg,
3 mmol) were stirred in anhydrous methanol /10 mL) at
room temperature for one h. The solvent was evaporated
under reduced pressure and the residue was chromato-
graphed /hexane/EtOAc, 80:20) to provide 270 mg /96%)
of alcohol 14b. Mass m/z 185 /M1H)1, 169 /M1H±CH4)1,
127 /M1H±C3H6O)1. 1H NMR d 5.22 /1H, d, Jˆ1.1), 5.1
/1H, app q, Jˆ1.1), 4.74 /1H, d, Jˆ5.5), 4.55 /1H, d,
Jˆ5.7), 3.50 /2H, m), 2.7 /1H, m), 2.30 /1H, m), 2.09
/1H, d, Jˆ15.6), 1.48 /3H, s), 1.38 /1H, t, Jˆ5.5) 1.34
/3H, s). [a]2D0 279.08 /c 1.0, CHCl3).
4.8. Reaction of ꢀ2S,3R,4R)-4-acetoxymethyl-2,3-iso-
propylidenedioxy-1-methylenecyclopentane ꢀ14a) with
IN3: ꢀ1R,2R,3R,4R)-4-Acetoxymethyl-1-azidomethyl-1-
iodo-2,3-isopropylidenedioxycyclopentane ꢀ17a) and
ꢀ1S,2R,3R,4R)-4-acetoxymethyl-1-azidomethyl-1-iodo-
2,3-isopropylidenedioxycyclopentane ꢀ17b)
Iodine monochloride /158 mg, 50 mL, 0.98 mmol) was
added slowly to a slurry of NaN3 /108 mg, 1.66 mmol) in
anhydrous CH3CN /4 mL) at 2308C.32 After 15 min a solu-
tion of alkene 14a /75 mg, 0.33 mmol) in CH3CN /1mL)
was added dropwise. The mixture allowed to warm to room
temperature and stirred overnight. The reaction was par-
titioned between H2O /10 mL) and Et2O /3£30 mL). The
combined extracts were washed with 5% aq. Na2S2O3 until a
clear, colorless solution was obtained. The organic layer
Tri¯uoromethanesulfonic anhydride /Tf2O, 490 mg,
1.74 mmol) was added to anhydrous CH2Cl2 /5 mL) under
N2. A solution of benzyl alcohol /188 mg, 1.74 mmol) and
2,6-di-t-butyl-4-methylpyridine /360 mg, 1.74 mmol) in
CH2Cl2 /2 mL) was added dropwise at 2708C and the

9906
M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
was washed with water, dried and concentrated. Chromato-
graphy /hexane/EtOAc, 80:20) provided the isomeric iodo
azides 17a and 17b in 67% yield as a 3.3:1mixture. 17a:
Mass m/z 396 /M1H)1, 380 /M1H±CH4)1, 338 /M1H±
C3H6O)1; m/z 402 /M1Li)1. IR /neat) n 2987, 2935, 2104,
8.02 /2H, d, Jˆ7), 7.74 /2H, dt, Jˆ1.5, 6.8), 7.58±7.38
/6H, m), 6.36 /1H, s), 4.64 /2H, s), 2.20 /2H, m), 2.01±
1.75 /6H, m); HRMS Calcd for C20H21O3N: m/z /M1H)1
324.1594; Found: m/z 324.1601] and N-benzoyl-1-benzami-
do-1-benzoyloxymethylcyclopentane ꢀ19b) /48.6 mg, 15%)
[Mass m/z 466 /M1K)1, 450 /M1Na)1, 445 /M1NH4)1,
1
1739, 1243, 1208 cm21. H NMR d 4.48 /1H, dd, Jˆ5.6,
1
7.8), 4.22 /1H, dd, Jˆ5.9, 11.2), 4.18 /1H, dd, Jˆ5.9, 11.2),
3.88 /2H, s), 3.69 /1H, d, Jˆ7.7), 2.93 /1H, m), 2.45 /1H,
dd, Jˆ6.4, 14.5), 2.09 /3H, s), 1.98 /1H, dd, Jˆ12, 14.5),
1.72 /3H, s), 1.33 /3H, s). 13C NMR d 170.8 /s0), 115.7 /s0),
83.4 /d0), 82.3 /d0), 64.5 /t0), 62.8 /t0), 56.8 /s0), 44.3 /t0),
43.3 /d0), 26.2 /q0), 25.6 /q0), 20.8 /q0). [a]2D0 ±34.58 /c 1.0,
CHCl3). 17b: Mass m/z 396 /M1H)1, 338 /M1H±
C3H6O)1. IR /neat) n 2987, 2935, 2105, 1742, 1232,
428 /M1H)1; H NMR d 7.99 /2H, d, Jˆ7), 7.49±7.05
/13H, m), 4.78 /2H, s), 2.6 /2H, m), 2.27 /2H, m), 1.82
/4H, m); HRMS Calcd for C27H25O4N: m/z /M1H)1
428.1856; Found: m/z 428.1861].
4.10. ꢀ3S,4R,5R,6R)-6-Acetoxymethyl-4,5-isopropyl-
idenedioxy-1-oxaspiro[2,4]heptane ꢀ20a) and ꢀ3R,4R,5R,
6R)-6-acetoxymethyl-4,5-isopropylidenedioxy-1-oxa-
spiro[2,4]heptane ꢀ20b)
1
1032 cm21. H NMR d 5.09 /1H, d, Jˆ5), 4.75 /1H, dd,
Jˆ2.4, 5.3), 4.51/1H, dd, Jˆ9.2, 11), 4.30 /1H, dd, Jˆ6.8,
11), 3.82 /1H, d, Jˆ13.4), 3.64 /1H, d, Jˆ13.2), 2.71 /1H,
dd, Jˆ9.9, 15.2), 2.50 /1H, m), 2.29 /1H, dd, Jˆ2.85, 15.2),
2.10 /3H, s), 1.45 /3H, s), 1.31 /3H, s). 13C NMR d 170.8
/s0), 112.7 /s0), 90.4 /d0) 84.6 /d0), 65.7 /t0), 60.6 /t0), 52.2
An aq. solution of NaHCO3 /0.5 M, 3 mL) was mixed with
alkene 14a /226 mg, 1mmol) in CH 2Cl2 /10 mL). Solid
m-CPBA /275 mg of 75% peracid, i.e. 207 mg, 1.2 mmol)
was slowly added in small portions, and the mixture was
stirred at room temperature overnight.34 The consumption of
peracid was tested with starch-iodide paper while the
consumption of the alkene was followed by TLC. When
both reactants were consumed, the two phases were
separated and the organic phase was washed with 1N
sodium hydroxide solution /15 mL), water /10 mL) and
dried. Chromatography /hexane/EtOAc, 80:20) provided
/3S,4R,5R,6R)-6-acetoxymethyl-4,5-isopropylidenedioxy-
0
/s0), 45.6 /d0), 43.1/t ), 27.0 /q0), 25.2 /q0), 20.9 /q0).
4.9. Reaction of 1-oxaspiro[2,4]heptane with Et3Al/HN3:
1-azido-1-hydroxymethylcyclopentane ꢀ18), 1-benzamido-
1-benzoyloxymethylcyclopentane ꢀ19a), and N-benzoyl-1-
benzamido-1-benzoyloxymethylcyclopentane ꢀ19b)
A solution of HN3 in C6H6 /1.4 M, 7.15 mL, 10 mmol) was
added with stirring to a solution of Et3Al in toluene
/5.25 mL of a 1.9 M solution; 10 mmol) under N2 at
2208C. The mixture was then brought to room tempera-
ture.33 The Et3Al/HN3 solution was added slowly to a
solution of 1-oxaspiro[2,4]heptane /400 mg, 4.08 mmol)
in toluene /2 mL) cooled to 2708C. The mixture was stirred
for 1h and then was warmed to room temperature. The
reaction mixture was poured into ice water and Et2O /25
and 60 mL) and mixed thoroughly. The ethereal solution
was dried, concentrated, and puri®ed by chromatography
/hexane/EtOAc, 80:20) to yield 1-azido-1-hydroxymethyl-
cyclopentane ꢀ18) /330 mg, 58%) as a colorless oil. Mass
/ESI-MS) m/z /molecular ion was not observed) 114
1-oxaspiro[2,4]heptane ꢀ20a) /192 mg, 79%) along with the
20a: Mass m/z
35
/3R,4R,5R,6R)-isomer 20b /51mg, 21%).
249 /M1Li)1, 243 /M1H)1, 227 /M1H±CH4)1, 185 /M±
C3H6O1H)1. IR /neat) n 2989, 2936, 1744, 1382, 1373,
1232, 1210, 1162, 1054, 1036, 878, 868 cm21. H NMR d
1
4.67 /1H, d, Jˆ5.7), 4.22 /1H, dd, Jˆ1.3, 5.7), 4.09 /2H, m),
2.99 /1H, d, Jˆ4.4), 2.86 /1H, d, Jˆ4.4), 2.63±2.50 /2H,
m), 2.09 /3H, s), 1.48 /3H, s), 1.32 /1H, d, Jˆ15), 1.31 /3H,
s). 13C NMR d 170.6 /s0), 110.7 /s0), 84.6 /d0), 82.5 /d0), 65.5
/s0), 64.7 /t0), 47.4 /t0), 43.5 /d0), 31.6 /t0), 26.4 /q0), 24.1
/q0), 20.9 /q0). [a]D20 ±58.18 /c 0.9, CHCl3). 20b: Mass m/z
249 /M1Li)1, 243 /M1H)1, 227 /M1H±CH4)1, 185 /M±
C3H6O1H)1. 1H NMR d 4.54 /1H, d, Jˆ5.5), 4.26 /1H, d,
Jˆ5.7), 4.04 /2H, m), 2.93 /1H, dd, Jˆ0.9, 5.3), 2.83 /1H, d,
Jˆ5.3), 2.59 /1H, m), 2.52 /1H, m), 2.08 /3H, s), 1.55 /3H,
s), 1.40 /1H, d, Jˆ12.3), 1.32 /3H, s). 103C NMR d 170.7 /s0),
111.4 /s0), 81.9 /d0), 80.2 /d0), 65.1/t ), 63.3 /s0), 54.4 /t0),
/M1H±N2)1, 1 1 3 /M±N)2 /negative mass detection). IR
2
/neat) n 3375, 2961, 2874, 2097, 1455, 1262, 1050 cm21. 1H
NMR d 3.59 /2H, d, Jˆ6.2), 2.33 /1H, br m), 1.8±1.6 /10H,
1
m). H NMR /300 MHz, DMSO-d6) d 5.21/1H, t, Jˆ5.5),
41.0 /d0), 30.4 /t0), 26.3 /q0), 24.2 /q0), 20.8 /q0). [a]2D0
±
58.78 /c 0.9, CHCl3). HRMS Calcd for C12H18O5: m/z
13
3.47 /2H, d, Jˆ5.5), 1.61 /10H, s). C NMR d 73.9 /s0),
68.4 /t0), 33.9 /t0), 24.2 /t0). HRMS Calcd for C6H11N3O: m/z
/M1H)1 243.1227; Found: m/z 243.1214.
/M1Na)1 164.0794; Found: m/z 164.0795.
1-Azido-1-hydroxymethylcyclopentane was reduced and
benzoylated as follows: 5% Pd/C /20 mg) was added to a
solution of ꢀ18) /110 mg, 0.78 mmol) in EtOAc /15 mL).
The mixture was placed under H2 at ambient pressure over-
night. The catalyst was removed by ®ltration and the solvent
was evaporated. The residue was dissolved in anhydrous
pyridine /2 mL), benzoyl chloride /545 mg, 450 mL,
3.8 mmol) was added, and the mixture was stirred at room
temperature overnight. The mixture was partitioned
between CH2Cl2 and H2O /50:10 mL), and the organic
layer was separated, dried and evaporated. Chromatography
/hexane/EtOAc, 80:20) provided 1-benzamido-1-benzoyl-
oxymethylcyclopentane ꢀ19a) /29.6 mg, 12%) [Mass m/z
4.11. ꢀ1S,2R,3R,4R)-4-Acetoxymethyl-1-azidomethyl-1-
hydroxy-2,3-isopropylidenedioxycyclopentane ꢀ21) and
ꢀ1S,2R,3R,4R)-4-hydroxymethyl-1-azidomethyl-1-
hydroxy-2,3-isopropylidenedioxycyclopentane ꢀ22)
A Et3Al/HN3 mixture prepared as above /1.9 mmol) was
added dropwise to a solution of epoxide 20a /196 mg,
0.8 mmol) in anhydrous toluene /4 mL) at 2708C. The
mixture stirred for 1h and then warmed slowly to room
temperature. The reaction progress was monitored by
TLC. When no starting material remained, the reaction
was poured on a mixture of ice water and Et2O /30 and
70 mL), and the organic layer was dried and evaporated.
Chromatography /CHCl3/EtOAc, 70:30) of the residue
1
362 /M1K)1, 346 /M1Na)1, 324 /M1H)1; H NMR d

M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
9907
yielded azido alcohol 21 /140 mg, 60%) and its 4-desacetyl
analogue 22 /65 mg, 33%) as colorless oils. 21: Mass m/z
286 /M1H)1, 270 /M1H±CH4)1, 228 /M1H±C3H6O)1.
IR /neat) n 3450 /br), 2990, 2940, 2105, 1741, 1719, 1383,
/t0), 46.3 /t0), 44.8 /d0), 36.6 /t0), 26.7 /q0), 24.3 /q0), 23.0
/q0), 21.0 /q0). [a]D20 ±87.78 /c 0.4, CHCl3). HRMS Calcd for
C14H23NO6: m/z /M1Na)1 324.1417; Found: m/z 324.1424.
1
1373, 1260, 1240, 1211, 1163, 1072, 1037, 871 cm21. H
4.13. ꢀ1R,2R,3R,4R)-4-Acetoxymethyl-1-azidomethyl-
1,2,3-trihydroxycyclopentane ꢀ24)
NMR d 4.61/1H, d, Jˆ5.6), 4.32 /1H, dd, Jˆ1.5, 5.6), 4.17
/2H, m), 3.66 /1H, d, Jˆ12.1), 3.40 /1H, d, Jˆ12.1), 2.61
/1H, d, Jˆ0.9), 2.41/1H, q, Jˆ8.4), 2.08 /3H, s), 2.02 /1H,
A Et3Al/HN3 mixture prepared as above /1.6 mmol) was
added dropwise to a solution of epoxide 20b /50 mg,
0.2 mmol) in anhydrous CH3CN /2 mL) at 2408C. The
mixture stirred 30 min, warmed slowly to room tempera-
ture, and allowed to proceed overnight. The reaction
progress was monitored by TLC. Workup followed by chro-
matography as before provided ,50% of recovered epoxide
20b. Additional chromatography /CHCl3/MeOH, 95:5)
yielded azido triol 24 /5 mg, 10%) as a colorless oil. Mass
m/z 252 /M1Li)1. IR /neat) n 3400 /br), 2105, 1732,
dd, Jˆ8.8, 13.8), 1.57 /1H, dd, Jˆ1.3, 13.8), 1.44 /3H, s),
13
0
1.30 /3H, s). C NMR d 171.1 /s0), 111.0 /s0), 86.1/d ),
83.7 /d0), 82.6 /s0), 66.1/t 0), 56.7 /t0), 44.8 /d0) 35.8 /t0), 26.6
/q0), 24.3 /q0), 20.9 /q0). HRMS Calcd for C14H23NO6: m/z
/M1H)1 286.1397, /M1Na)1 308.1217; Found: m/z
286.1386, 308.1220. 22: Mass m/z 244 /M1H)1, 228
/M1H±CH4)1. Mass m/z 250 /M1Li)1, 228 /M1H±
CH4)1. IR /neat) n 3350 /br), 2990, 2935, 2105, 1447,
1
1385, 1375, 1212, 1165, 1072, 1045 cm21. H NMR d
1
1252 cm21. H NMR d 4.15 /1H, dd, Jˆ5.5, 11.2), 4.06
4.89 /1H, br s), 4.73 /1H, d, Jˆ5.5), 4.32 /1H, dd, Jˆ1.3,
5.5), 3.92 /1H, br s), 3.85 /1H, dd, Jˆ4, 10.1), 3.68 /1H, dd,
Jˆ3.3, 10.1), 3.60 /1H, d, Jˆ12.3), 3.39 /1H, d, Jˆ12.3),
2.33 /1H, m), 2.21 /1H, dd, Jˆ9.9, 14.1), 1.65 /1H, d,
/1H, dd, Jˆ6.1, 11.2), 3.92 /1H, br s), 3.79 /1H, app d,
Jˆ6.1), 3.38 /2H, s), 3.04 /2H, br s), 2.49 /1H, m), 2.09
/3H, s), 2.05 /1H, dd, Jˆ8.5, 14), 1.56 /br s), 1.40 /1H, dd,
Jˆ8.9, 14). 1H NMR /300 MHz, DMSO-d6) d 4.79 /1H, d,
Jˆ6.4), 4.66 /1H, d, Jˆ6.6), 4.58 /1H, s), 4.08 /1H, dd,
Jˆ5.3, 11), 3.90 /1H, dd, Jˆ7, 11), 3.60 /1H, app q,
Jˆ6.5), 3.51/1H, app t, Jˆ6), 3.23 /1H, d, Jˆ12.5), 3.15
/1H, d, Jˆ12.5), 2.23 /1H, m), 2.0 /3H, s), 1.78 /1H, dd,
Jˆ8.8, 13.8), 1.24 /1H, dd, Jˆ9.9, 13.8).
1
Jˆ14.1), 144 /3H, s), 1.30 /3H, s). H NMR /300 MHz,
DMSO-d6) d 5.24 /1H, s), 4.81 /1H, s), 4.55 /1H, d,
Jˆ5.7), 4.21/1H, dd, Jˆ0.9, 5.5), 3.48 /1H, m), 3.38 /1H,
m), 3.32 /1H, d, Jˆ12.5), 3.21 /1H, d, Jˆ12.5), 2.03 /1H,
m), 1.85 /1H, dd, Jˆ9.0, 13.4), 1.33 /3H, s), 1.20 /3H, s).
13
0
C NMR d 110.7 /s0), 87.1/d ), 84.2 /d0), 82.3 /s0), 64.5
20
/t0), 56.1/t ), 46.7 /d0), 37.7 /t0), 26.7 /q0), 24.2 /q0). [a]D
±
0
87.58 /c 1.0, CHCl3). Diol 22 was converted back to acetate
21 in 98% yield by reaction with Ac2O/pyridine overnight at
room temperature.
4.14. N-4-Toluenesulfonyl-1-azaspiro[2,5]octane ꢀ25)
Methylene cyclohexane /144 mg, 1.5 mmol) was added
with stirring to CuOTf´0.5C6H6 /3.75 mg, 0.015 mmol) in
anhydrous CH3CN /2 mL) under N2. Solid [/4-toluene-
sulfonyl)imino]-phenyliodinane /112 mg, 0.3 mmol) was
added in one portion.36 After 1h, when all of the solid
was dissolved, the reaction mixture was ®ltered through a
silica plug, which was then washed with EtOAc /50 mL).
Evaporation of the solvent followed by chromatography
/hexane/EtOAc, 80:20) gave aziridine 25 /58.5 mg, 73%,
based on PhIˆNTs) as a colorless oil. Mass m/z 266
/M1H)1, 110 /M±Ts)1. IR /neat) n 2936, 2858, 1600,
1450, 1318, 1304, 1159, 1091, 943, 842, 817, 735, 722,
4.12. ꢀ1S,2R,3R,4R)-4-Acetoxymethyl-1-acetylamido-1-
hydroxy-2,3-isopropylidenedioxycyclopentane ꢀ23)
5% Pd/C /20 mg) was added to azido alcohol 21 /15 mg,
0.05 mmol) in EtOAc /10 mL) and the mixture was stirred
under H2 /1atm). The progress of the reaction was moni-
tored by TLC. When all the azido alcohol was consumed
/,12 h) the mixture was ®ltered and solvent was removed
1
to provide the crude amine: H NMR d 6.65 /1H, br d,
Jˆ12), 4.61 /1H, d, Jˆ5.7), 4.30 /1H, dd, Jˆ1.1, 5.5),
4.18 /2H, m), 3.1 /1H, br d, Jˆ12), 2.87 /br s), 2.38 /1H,
app q, Jˆ7), 2.07 /3H, s), 1.96 /1H, dd, Jˆ9, 14), 1.52 /1H,
dd, Jˆ0.9, 14), 1.43 /3H, s), 1.29 /3H, s). The crude amine
was mixed with anhydrous pyridine /1mL) and Ac 2O
/100 mL) and stirred at room temperature for 18 h. Excess
Ac2O was quenched with EtOH /1mL) and solvents were
evaporated. Chromatography /CHCl3/MeOH, 95:5) yielded
1 5 mg of23 /80%). Mass m/z 308 /M1Li)1. IR /neat) n
3350 /br), 2987, 2985, 1740, 1653, 1550, 1372, 1240, 1211,
1
567 cm21. H NMR d 7.83 /2H, d, Jˆ8.1), 7.31 /2H, d,
Jˆ8.1), 2.43 /3H, s), 2.40 /2H, s), 2.0±1.7 /6H, m), 1.5
/4H, m). Anal. Calcd for C14H19NO2S´/H2O)0.4: C 61.69%,
H 7.32%, N 5.14%; Found: C 61.35%, H 7.06%, N 5.26%.
4.15. 1-ꢀ4-Toluenesulfonyl)amido-1-bromomethyl-
cyclohexane ꢀ26)
1
37
1037 cm21. H NMR d 6.1/1H, br t, Jˆ5.3), 4.61/1H, d,
Li2NiBr4 /150 mL of ,0.4 M solution in THF, approx.
Jˆ5.7), 4.32 /1H, dd, Jˆ1.3, 5.5), 4.17 /2H, m), 3.72 /1H,
dd, Jˆ7, 14.3), 3.27 /1H, dd, Jˆ5.5, 14.3), 2.4 /1H, app q,
Jˆ7), 2.07 /3H, s), 2.05 /3H, s), 2.01/1H, dd, Jˆ9, 14), 1.57
0.06 mmol) was added to a solution of aziridine 25
/5.3 mg, 0.02 mmol) in anhydrous THF /0.5 mL) and the
mixture was stored at room temperature overnight. The
solvent was evaporated and the residue was puri®ed by
preparative TLC /hexane/EtOAc, 80:20) to yield the
primary bromide 26 /4 mg, 58%). Mass m/z 352 and 354
1
/1H, dd, Jˆ1.1, 14), 1.47 /3H, s), 1.30 /3H, s). H NMR
/300 MHz, DMSO-d6) d 7.65 /1H, t, Jˆ5.9), 4.99 /1H, s),
4.49 /1H, d, Jˆ5.3), 4.21/1H, d, Jˆ4.8), 4.13 /1H, dd,
Jˆ10, 11), 3.91 /1H, dd, Jˆ6.1, 11), 3.41 /1H, dd, Jˆ6.6,
13.6), 3.03 /1H, dd, Jˆ4.4, 13.6), 2.17 /1H, app q, Jˆ7),
2.01 /3H, s), 1.87 /1H, dd, Jˆ8.8, 13.6), 1.84 /3H, s), 1.46
/1H, Jˆ13.6), 1.35 /3H, s), 1.21 /3H, s). 13C NMR d 172.6
/s0), 171.0 /s0), 110.7 /s0), 86.6 /d0), 83.7 /d0), 83.4 /s0), 66.1
1
/M1Li)1, 346 and 347 /M1H)1. H NMR d 7.80 /2H, d,
Jˆ8.1), 7.29 /2H, d, Jˆ8.1), 4.53 /1H, br s), 3.56 /3H, s),
2.43 /3H, s), 1.9 and 1.5±1.2 /10H, several m). Anal. Calcd
for C14H20BrNO2S´/H2O)0.3: C 47.81%, H 5.90%, N 3.98%;
Found: C 47.69%, H 5.57%, N 3.85%.

9908
M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
4.16. 1-ꢀ4-Toluenesulfonyl)amido-1-azidomethylcyclo-
hexane ꢀ27)
50.69%, H 5.20%, N 6.56%; Found: C 50.75%, H 4.95%,
N 6.54%.
Sodium azide /0.045 mmol, 3 mg) and BF3´Et2O /6.4 mg,
0.045 mmol, 5.7 mL) were added to a solution of aziridine
25 /6.0 mg, 0.023 mmol) in anhydrous DMF /1mL). The
mixture was stirred at room temperature overnight. The
primary azide 27 was puri®ed by preparative TLC /hexane/
EtOAc, 80:20) yielding 3.0 mg /43%) of a colorless oil.
4.19. ꢀ1S,2S,3R,4R)-4-Acetoxymethyl-2,3-isopropyl-
idenedioxy-1-bromomethyl-1-toluenesulfonamido-
cyclopentane ꢀ3a)
Aziridine 28a /34 mg, 0.086 mmol) and Li2NiBr4 /0.5 ml of
,0.4 M THF solution, 0.2 mmol)37 were mixed in
anhydrous THF /0.2 ml) and kept at room temperature for
48 h. The solvent was evaporated and the residue was
puri®ed by preparative TLC /hexane/EtOAc, 80:20) to
yield the primary bromide 3a /12 mg, 30%) as a pale yellow
oil that eventually crystallized, mp 119±1218C. Mass m/z
1
Mass m/z 309 /M1H)1; m/z 315 /M1Li)1. H NMR d
7.79 /2H, d, Jˆ8.3), 7.30 /2H, d, Jˆ8.3), 4.4 /1H, br s,
D2O exchangeable), 3.41/2H, s), 2.43 /3H, s), 1.8 /2H,
m), 1.5±1.2 /8H, m). HRMS Calcd for C14H20N4O2S: m/z
/M1Na)1 331.1199; Found: m/z 331.1211.
1
482 & 484 /M1Li)1. H NMR d 7.82 /2H, app d, Jˆ8),
7.32 /2H, app d, Jˆ8), 5.23 /1H, br s, D2O exchangeable),
4.88 /1H, d, Jˆ 5.7), 4.38 /1H, dd, Jˆ2.2, 5.7), 4.13 /1H, dd,
Jˆ4, 11.2), 4.02 /1H, dd, Jˆ8.1, 11.2), 3.72 /1H, d, Jˆ11),
3.52 /1H, d, Jˆ11), 2.44 /3H, s), 2.33 /1H, m), 2.14 /1H, dd,
Jˆ8.8, 14.2), 2.09 /3H, s), 1.89 /1H, dd, Jˆ4.2, 14.3), 1.42
/3H, s), 1.27 /3H, s). [a]2D0 24.58 /c 0.3, CHCl3). HRMS
Calcd for C19H27O6NS32Br79: m/z 476.07425; Found: m/z
476.07434.
4.17. ꢀ4S,5R,6R)-N-p-Toluenesulfonyl-6-acetoxymethyl-
4,5-isopropylidenedioxy-1-azaspiro[2,4]heptane ꢀ28a)
Alkene 14a /113 mg, 0.5 mmol) was added with stirring to
CuOTf´0.5C6H6 /1.5 mg, 0.0055 mmol) in anhydrous
CH3CN /2 mL) under N2. Solid [/4-toluenesulfonyl)-
imino]-phenyliodinane /41mg, 0.11mmol) was added in
one portion and stirring was continued at room temperature.
The progress of the reaction was monitored by TLC. After
1h additional PhI ˆNTs /41mg) and CuOTf´0.5C 6H6
/3 mg) were added, the mixture was stirred at room
temperature for another hour, and then stored at 48C over-
night. The reaction mixture was ®ltered through a silica
plug, which was then washed with EtOAc /50 mL).
Evaporation of the solvent followed by chromatography
/hexane/EtOAc, 80:20) gave 78 mg of recovered alkene
14a along with 20 mg of the desired aziridine 28a /22%
based on PhIˆNTs; 33% based on 14a) as an oil. Mass
m/z 402 /M1Li)1. IR /neat) n 1742, 1600, 1455, 1372,
4.20. ꢀ1S,2S,3R,4R)-4-Acetoxymethyl-2,3-isopropyl-
idenedioxy-1-bromomethyl-1-ꢀ4-nitrobenzenesulfon-
amido)-cyclopentane ꢀ3b)
Aziridine 28b /100 mg, 0.23 mmol) and Li2NiBr4 /1.5 ml of
,0.4 M THF solution, 0.6 mmol) were mixed in anhydrous
THF /0.6 ml) and kept at room temperature for 48 h. The
residue was chromatographed /cyclohexane/EtOAc, 85:15)
to give 3b /112 mg, 94%) as a syrup. 1H NMR d 8.37 /2H,
m), 8.14 /2H, m), 5.96 /1H, s), 5.00 /1H, d, Jˆ5.8), 4.50
/1H, dd, Jˆ6.0, 2.1), 4.33 /1H, dd, Jˆ8.5, 11.4), 4.00 /1H,
dd, Jˆ6.8, 11.4), 3.69 /1H, d, Jˆ11.5), 3.53 /1H, d,
Jˆ11.5), 2.39 /1H, m), 2.16 /1H, dd, Jˆ8.5, 14.4), 2.13
/3H, s), 1.84 /1H, dd, Jˆ4.2, 14.3), 1.44 /3H, s), 1.30
/3H, s). [a]2D0 14.598 /c 1.02, CHCl3). Anal. Calcd for
C18H23BrN2O8S: C 42.61%, H 4.56%, N 5.52%; Found: C
42.84%, H 4.52%, N 5.56%.
1
1323, 1238, 1218, 1213, 1160, 1035, 710, 691 cm21. H
NMR d 7.82 /2H, d, Jˆ8.1), 7.33 /2H, d, Jˆ8.1), 4.87
/1H, d, Jˆ6), 4.65 /1H, d, Jˆ6), 4.22 /2H, m), 2.81/1H,
s), 2.55 /2H, m), 2.52 /1H, s), 2.44 /3H, s), 2.09 /3H, s), 1.95
13
/1H, m), 1.47 /3H, s), 1.32 /3H, s). C NMR d 170.9 /s0),
144.4 /s0), 137.0 /s0) 129.6 /d0), 127.6 /d0), 111.8 /s0), 82.1
0
/d0), 82.0 /d0), 64.1/t ), 56.9 /s0), 43.7 /d0), 36.2 /t0), 32.3
/t0), 26.7 /q0), 24.8 /q0), 21.6 /q0), 20.9 /q0). [a]2D0 ±65.58 /c
1.3, CHCl3). Anal. Calcd for C19H25NO6S: C 57.71%, H
6.37%, N 3.54%; Found: C 57.46%, H 6.48%, N 3.42%.
4.21. Crystal structure determination of 3a
Bromide 3a was crystallized by slow evaporation from
CDCl3. Diffraction data for a single pale yellow crystal
/0.42£0.16£0.14 mm) were collected at 173 K on a Bruker
SMART CCD-based area diffractometer /Mo Ka radiation,
4.18. ꢀ4S,5R,6R)-N-4-Nitrobenzenesulfonyl-6-acetoxy-
methyl-4,5-isopropylidenedioxy-1-azaspiro[2,4]heptane
ꢀ28b)
Ê
lˆ0.71073 A). Monoclinic, space group P21, aˆ10.5078
Ê
/7), bˆ9.3298 /6), cˆ10.7871 /7) A, bˆ92.3870 /10)8,
Ê 3
Alkene 14a /1.127 g, 5 mmol) and Cu/CH3CN)4´ClO4
/124 mg, 0.34 mmol) were dissolved in anhydrous CH3CN
/15 mL) containing activated 4A molecular sieves. Solid
[/4-nitrobenzene sulfonyl)imino]-phenyliodinane /3.043 g,
7.44 mmol)39 was added portionwise under Ar over a period
of 4 h, and the reaction mixture was stirred overnight.
Evaporation of the solvent followed by chromatography
/cyclohexane/EtOAc, 80:20) gave aziridine 28b /980 mg,
Vˆ1056.60 /12) A , Zˆ2, F/000)ˆ492. u and v scans,
uminˆ1.898, umaxˆ27.908, 6705 measured re¯ections, of
which 4249 were unique, 3922 . 2s, 258 parameters,
R1ˆ0.038, wR2ˆ0.0872, GOFˆ1.076 /Bijvoet pairs not
merged). Max./min. residual electron density 0.581/±
Ê 3
2
0.624 e /A . The positions of the Br and S atoms were
determined by visual inspection of the Patterson map; the
other non-hydrogen atoms were located in difference
Fourier maps /SHELXS-97).38 The structure was re®ned
against F2 for all observed re¯ections. Hydrogen atoms,
which were located in difference maps, were re®ned as
riding atoms at their calculated positions. The absolute
con®guration was determined unequivocally by re®nement,
1
64%) as a colorless oil. Mass m/z 453 /M1Li)1. H NMR
d 8.38 /2H, m), 8.14 /2H, m), 4.84 /1H, d, Jˆ5.9), 4.66 /1H,
d, Jˆ6.04), 4.23 /2H, m), 2.89 /1H, s), 2.57 /3H, m), 2.10
/3H, s), 1.98 /1H, m), 1.47 /3H, s), 1.33 /3H, s). [a]D20
63.388 /c 1.7, CHCl3). Anal. Calcd for C18H22N2O8S: C
±

M. Ahmadian et al. / Tetrahedron 57 +2001) 9899±9909
9909
15. Tatsuoka, T.; Imao, K.; Suzuki, K. Heterocycles 1986, 24,
2133±2136.
against the anomalous scattering data, of either enantiomer
of the initial Br/S two-atom model and subsequently the
complete molecule. The Flack parameter for the correct
enantiomer of the ®nal model was 0.026 /8).43 Crystallo-
graphic data /including structure factors) have been
deposited with the Cambridge Crystallographic Data Centre
/CCDC-133069).
16. Li, C. M.; Tyler, P. C.; Furneaux, R. H.; Kicska, G.; Xu, Y.;
Grubmeyer, C.; Girvin, M. E.; Schramm, V. L. Nature Struct.
Biol. 1999, 6, 582±587.
17. Parry, R. J.; Haridas, K. Tetrahedron Lett. 1993, 34, 7013±
7016.
18. Parry, R. J.; Burns, M. R.; Jiralerspong, S.; Alemany, L.
Tetrahedron 1997, 53, 7077±7088.
Acknowledgements
19. Sano, H.; Sugai, S. Tetrahedron 1995, 51, 4635±4646.
20. Xie, Z. F. Tetrahedron Asymmetry 1991, 2, 733±750.
21. Tanaka, M.; Yoshioka, M.; Sakai, K. Tetrahedron Asymmetry
1993, 4, 981±996.
We thank Drs John A. Secrist, III and John A. Montgomery
for useful suggestions on synthetic methodology, Mark
Richardson and Joan Bearden for analytical support, and
Rick Remy for literature searches. We are especially grate-
ful to Professor Robin D. Rogers and Dr Lillian Rogers for
assistance in the use of the Dept. of Chemistry X-ray facility
at the University of Alabama at Tuscaloosa. This work was
supported in part by NIH grant AI39952 /D. W. B.).
22. Sable, H. Z.; Katchian, H. Carbohydr. Res. 1967, 5, 109±117.
23. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc., 1973, 95, 51 2±
519.
24. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543±2549.
25. Mohar, B.; Stimac, A.; Kobe, J. Tetrahedron Asymmetry 1994,
5, 863±878.
26. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 31, 2647±
2650.
References
27. O'Connor, B.; Just, G. Tetrahedron Lett. 1987, 28, 3235±
3236.
1. Wang, C. C. J. Med. Chem. 1984, 27, 1 ±9.
2. Murray, H. W. Toxoplasmosis. In Harrison's Principles of
Internal Medicine; Wilson, J. D., Braunwald, E., Isselbacher,
K. J., Petersdorf, R. G., Martin, J. B., Fauci, A. S., Root, R. K.,
Eds.; McGraw-Hill: New York, 1991; pp. 795±799.
3. Tuazon, C. U. J. Antimicrob. Chemother. 1989, 23 Suppl A,
77±82.
28. Gebelein, C. G.; Rosen, S.; Swern, D. J. Org. Chem. 1969, 34,
1677±1679.
29. Gebelein, C. G. Chem. Ind. 1970, 57.
30. Grimwood, B. E.; Swern, D. J. Org. Chem. 1967, 32, 3665±
3667.
31. Hassner, A.; Hoblitt, R. P.; Heathcock, C.; Kropp, J. E.;
Lorber, M. J. Am. Chem. Soc. 1970, 92, 1326±1332.
32. Hassner, A.; Levy, L. A. J. Am. Chem. Soc. 1965, 87, 4203±
4204.
4. Heroux, A.; White, E. L.; Ross, L. J.; Kuzin, A. P.; Borhani,
D. W. Structure Fold. Des. 2000, 8, 1309±1318.
5. Heroux, A.; White, E. L.; Ross, L. J.; Davis, R. L.; Borhani,
D. W. Biochemistry 1999, 38, 14495±14506.
33. Mereyala, H. B.; Frei, B. Helv. Chim. Acta 1986, 69, 415±418.
34. Anderson, W. K.; Veysoglu, T. J. Org. Chem. 1973, 38, 2267±
2268.
6. Heroux, A.; White, E. L.; Ross, L. J.; Borhani, D. W.
Biochemistry 1999, 38, 14485±14494.
7. Focia, P. J.; Craig, S. P.; Eakin, A. E. Biochemistry 1998, 37,
17120±17127.
35. Marschner, C.; Penn, G.; Griengl, H. Tetrahedron 1993, 49,
5067±5078.
8. Shi, W.; Li, C. M.; Tyler, P. C.; Furneaux, R. H.; Cahill, S. M.;
Girvin, M. E.; Grubmeyer, C.; Schramm, V. L.; Almo, S. C.
Biochemistry 1999, 38, 9872±9880.
36. Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975,
361±362.
37. Dawe, R. D.; Molinski, T. F.; Turner, J. V. Tetrahedron Lett.
1984, 25, 2061±2064.
9. Shi, W.; Li, C. M.; Tyler, P. C.; Furneaux, R. H.; Grubmeyer,
C.; Schramm, V. L.; Almo, S. C. Nature Struct. Biol. 1999, 6,
588±593.
38. Sheldrick, G. M. SHELXS-96. Acta Crystallogr. 1996, 46,
467±473.
10. Pitera, J. W.; Munagala, N. R.; Wang, C. C.; Kollman, P. A.
Biochemistry 1999, 38, 10298±10306.
39. Sodergren, M. J.; Alonso, D. A.; Bedekar, A. V.; Andersson,
P. G. Tetrahedron Lett. 1997, 38, 6897±6900.
40. Israel, R. J.; Murray Jr, R. K. J. Org. Chem. 1985, 50, 1573±
1577.
11. Eads, J. C.; Scapin, G.; Xu, Y.; Grubmeyer, C.; Sacchettini,
J. C. Cell 1994, 78, 325±334.
12. Lee, C. C.; Medrano, J. F.; Craig, S. P.; Eakin, A. E. Biochim
Biophys Acta 2001, 1537, 63±70.
41. Berry, J. M.; Hall, L. D. Carbohydr. Res. 1976, 47, 307±310.
42. Lemieux, R. U.; Kondo, T. Carbohydr. Res. 1974, 35, C4±C6.
43. Flack, H. D. Acta Crystallogr. 1983, A39, 876±881.
44. Zsolnai, L., Huttner. G., ZORTEP, University of Heidelberg:
Heidelberg, 1994.
13. Elliott, R. D.; Niwas, S.; Riordan, J. M.; Montgomery, J. A.;
Secrist III, J. A. Nucleosides-Nucleotides 1992, 11, 97±119.
14. Tatsuoka, T.; Imao, K.; Suzuki, K. Heterocycles 1986, 24,
617±620.