Bicyclo[3.1.0]hexanes from sugar-derived diazo compounds and iodonium ylides. Diastereocontrol and synthetic applications

Article abstract of DOI:10.1016/S0040-4020(02)01002-5

The CuI and Rh₂(OAc)₄ catalyzed decomposition of ethyl 2-diazo-4,5-isopropylidenedioxy-3-oxo-6-heptenoate results in intramolecular cyclopropanation products with opposite diastereoselectivity. In contrast, decomposition of the respective iodonium ylide can proceed without catalysts to give the cyclopropanation products with diastereoselectivity unchangeable by the presence of CuI and Rh₂(OAc)₄, revealing thus, that in this particular case the reaction is an electrophilic addition of the iodonium center to the double bond. The synthetic importance of these reactions has been demonstrated by preparing a number of precursors of cyclopentyl, cyclopropyl and bicyclo[3.1.0]hexyl antiviral carbocyclic nucleosides.

Full text of DOI:10.1016/S0040-4020(02)01002-5

Tetrahedron 58 (2002) 8043–8053
Bicyclo[3.1.0]hexanes from sugar-derived diazo compounds and
iodonium ylides. Diastereocontrol and synthetic applications
*
John K. Gallos, Theocharis V. Koftis, Zoe S. Massen, Constantinos C. Dellios,
Ioannis T. Mourtzinos, Evdoxia Coutouli-Argyropoulou and Alexandros E. Koumbis
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54006, Greece
Received 6 June 2002; revised 23 July 2002; accepted 15 August 2002
Abstract—The CuI and Rh2(OAc)4 catalyzed decomposition of ethyl 2-diazo-4,5-isopropylidenedioxy-3-oxo-6-heptenoate results in
intramolecular cyclopropanation products with opposite diastereoselectivity. In contrast, decomposition of the respective iodonium ylide can
proceed without catalysts to give the cyclopropanation products with diastereoselectivity unchangeable by the presence of CuI and
Rh2(OAc)4, revealing thus, that in this particular case the reaction is an electrophilic addition of the iodonium center to the double bond. The
synthetic importance of these reactions has been demonstrated by preparing a number of precursors of cyclopentyl, cyclopropyl and
bicyclo[3.1.0]hexyl antiviral carbocyclic nucleosides. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Although there is little doubt about the mechanism of the
metal-catalyzed decomposition of diazo compounds, which
proceeds most probably via a metallo-carbenoid inter-
mediate,5 the mechanism of metal-initiated iodonium ylide
decomposition towards cyclopanation products is a field
of controversy. Moriarty et al.6 who first investigated
such CuCl-catalyzed intramolecular cyclopropanations of
iodonium ylides, have suggested a stepwise electrophilic
addition of the iodonium center to the double bond,
followed by reductive elimination of iodobenzene to afford
the cyclopropane ring. Recently, however, Mu¨ller et al.7
observed a substantial degree of asymmetric induction in
Cu-catalyzed intramolecular cyclopropanations of some
iodonium ylides, which is consistent with a carbenoid
mechanism.
Carbocyclic nucleosides have been widely studied as
potential antiviral and antitumor agents,1 and among them,
those with cyclopentyl, cyclopropyl or bicyclo[3.1.0]hexyl
sugar parts, such as aristeromycin (1),2 nucleoside A-5021
(2)3 and the nitrobenzylthioinosine analog of neplanocin C
3,4 exhibiting significant antiviral activity, have attracted
considerable attention (Fig. 1). It is most likely that the
sugar moiety of these and related nucleosides could be
prepared from hydroxylated bicyclo[3.1.0]hexane deriva-
tives 4 with the proper absolute configuration, as common
precursors. Nucleophilic opening of the cyclopropane ring
would lead to hydroxylated cyclopentanoids and therefore
to cyclopentyl nucleosides, whereas reduction of the
ketone and ester groups would give products, with the
bicyclo[3.1.0]hexane skeleton retained, which are precur-
sors of 3 and related nucleosides. Finally, glycolic cleavage
of the cyclopentane ring would result in precursors of
cyclopropyl nucleosides, such as 2. Furthermore, com-
pounds of the general structure 4 are potential precursors of
several classes of natural products and synthetic analogs
(prostanoids, cyclitols, aminocyclitols). It is, consequently,
highly desirable to synthesize bicyclo[3.1.0]hexanes 4, in
enantiomerically pure form and the intramolecular cyclo-
propanation of sugar derived chiral diazo compounds and
iodonium ylides is an attractive approach.
In this paper,8 we describe the diastereoselectivity of the
metal-catalyzed intramolecular cyclopropanations of some
chiral sugar derived unsaturated diazo compounds and
iodonium ylides. Furthermore, we have demonstrated their
synthetic potential by using the cyclopropanation products
to prepare the sugar part of some cyclopentyl, cyclopropyl
and bicyclo[3.1.0]hexyl carbocyclic nucleosides.
2. Results and discussion
Treatment of iodide 5 (Scheme 1), easily accessible from
D-ribose in two steps,9 with activated Zn in ethanol afforded
pentenal 6 in 95% yield.10 Because of the partial
epimerization to epi-6 (Fig. 2), upon standing or in the
chromatography column, this aldehyde was directly con-
verted to the ketoester 7 (76% yield), by slow addition of a
Keywords: diazo compounds; iodonium ylides; cyclopropanation;
nucleosides; carbohydrates; copper(I) iodide; rhodium(II) acetate.
*
Corresponding author. Fax: þ30-31-997679;
e-mail: igallos@chem.auth.gr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01002-5

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J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
products 10 and 11, which were easily separated chromato-
graphically (81%, 10/11¼4.5:1 diastereoisomeric ratio).
However, when Rh2(OAc)4 was employed as a catalyst,
diazo compound 8 was decomposed in 1.5 h to the same
cyclopropanation products, but with opposite diastereo-
selectivity (74%, 10/11¼1:3 diastereoisomeric ratio). Iodo-
nium ylide 9, in turn, was decomposed within 30 min, in
methylene chloride solution at 208C, under an argon
atmosphere, to give again 10 and 11, in moderate yield
and a slight preference of 11 (45% from 7, 10/11¼1:1.5
diastereoisomeric ratio). Surprisingly, both CuI and
Rh2(OAc)4 gave the same yield and diastereoselectivity,
and we also found that this reaction proceeds smoothly
even without the presence of any catalyst to give similar
results.
Figure 1.
It is worth mentioning that the enantiomers ent-10 and
ent-11 were prepared by the same reaction sequence,
starting from aldehyde ent-6, which is readily available
from the naturally abundant D-arabinose, via the protected
D-erythrose14 (Scheme 1), obviously with the same
diastereoselection outcome. From a synthetic point of
view, it is interesting that all isomers 10, ent-10, 11 and
ent-11 could be selectively built by starting from the proper
pentenal 6 or ent-6, preparing the right intermediate diazo
compound or iodonium ylide and choosing the appropriate
catalyst.
methylene chloride solution of 6 to ethyl diazoacetate11 at
08C, in the presence of dry SnCl2. These reaction conditions
should be strictly applied, since the presence of moisture
and elevated temperatures dramatically decrease the yield of
7, leading to the formation of a mixture of the two epoxides
20 as main products, the stereochemistry of which was not
completely assigned; epi-7 was also isolated (Fig. 2). Under
the above mentioned reaction conditions, the epimerization
of 7 was totally suppressed, whereas the epoxides 20 were
the normal side-products (yield ,10%).
Compound 7 was then converted to the diazo compound 8
(92%) and the respective iodonium ylide 9, by standard
procedures.12,13 The ylide, found to be unstable on
attempted isolation, was further used without charac-
terization. Refluxing of 8 in toluene with a 5% molar ratio
of CuI for 3 h, gave a mixture of the cyclopropanation
Applying an analogous pathway, diazo compound 16
was synthesized from 13, which in turn was prepared
from L-ribulose according to the literature,15 by Swern
oxidation and addition of the resulting unsaturated aldehyde
14 to ethyl diazoacetate, as discussed above to give the
ketoester 15 in 76% yield (68% overall). Further treatment
Scheme 1. Reagents and conditions: (i) N2CHCO2Et, SnCl2, CH2Cl2, 08C, 2 h. (ii) TsN3, Et3N, EtOH, 208C, 12 h. (iii) PhI(OAc)2, KOH (4 equiv.), EtOH,
258C, 30 min. (iv) CuI, toluene, reflux, 3 h for diazo compounds or CuI, CH2Cl2, 208C, N2, 30 min for iodonium ylides (for iodonium ylides see also text). (v)
Rh2(OAc)2, toluene, reflux, 1.5 h for diazo compounds or Rh2(OAc)2, CH2Cl2, 208C, N2, 30 min for iodonium ylides (for yields see text).

J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
8045
The variation of diastereoselectivities observed should
originate in the different reaction mechanisms followed by
diazo compounds and iodonium ylides, under the applied
conditions: the metal-catalyzed decomposition of diazo
compounds proceeds most probably via a metallo-carbenoid
intermediate,5 whereas the iodonium ylide decomposition
is, in our particular case, a stepwise electrophilic addition of
the iodonium center to the double bond, as proposed by
Moriarty,6 with possible formation of intermediates like I-1
or I-2 (Fig. 3). Further reductive elimination of iodobenzene
affords the cyclopropane ring. Since the decomposition
reaction of iodonium ylide is independent of the catalyst
used (or not), being completed at the same time (within
30 min) and giving the same results, regarding yields and
diastereoselectivity, it is apparent that the metal is not
coordinated with these intermediates. Furthermore, I-1
leading to the formation of 10, looks less favored compared
to I-2, because of the stronger interactions of the bulkier
iodophenyl group with one methyl of the acetonide group in
I-1 than the respective ones of the ethoxycarbonyl group
in I-2.
Figure 2.
of 15 with TsN3 and Et3N afforded 16 (90%). Unfortunately,
we failed to prepare the iodonium ylide 17, following the
known methods,15 possibly because the enolate generated
from 15 is sterically hindered, not allowing the approach of
the PhI(OAc)2 species and compound 15 was quantitatively
epimerized to 4-epi-15. Decomposition of 16 by Rh2(OAc)4
in refluxing toluene for 2.5 h, afforded compound 19
exclusively in 58% isolated yield, while the use of CuI or
CuCl as catalysts favored the formation of 18 (18/19¼2:1
and 1.7:1 diastereoisomeric ratios, respectively) in moderate
isolated yields (28 and 43%, respectively). The bulkier
Cu(OSO2CF3) also catalyzed the same reaction (54% yield),
favoring slightly the formation of 19 (diastereoisomeric
ratio 1:1.6). No reaction was observed when CuI was used
as a catalyst and the mixture was refluxed in lower boiling
point solvents (e.g. THF, methylene chloride).
Comparing the results reported by Moriarty6 and Mu¨ller7
with our present observations, it can be suggested that the
intramolecular cyclopropanations of iodonium ylides do not
follow a single and unified mechanism. Depending upon
the reaction conditions (solvent, temperature, catalyst)
and the nature of the substrate a stepwise electrophilic
addition of the iodonium center to the double bond or the
formation of metallo-carbenoid intermediate can occur. It
seems possible, that in our particular case the cis-geometry
of the dioxolane ring might be crucial, placing both the
double bond and the iodonium center in close proximity,
and thus favoring the stepwise mechanism.
The configurations of the newly formed stereocenters in
1
10, ent-10, 11, ent-11, 18, 19 were deduced from the H
NMR coupling constants and the observed NOE enhance-
ments. It has been demonstrated16 that the bicyclo[3.1.0]-
hexane system adopts boat-like conformations, with such
H4–C4–C5–H5 dihedral angles (Scheme 1), which result in
J4,5,0 and ,4 Hz, when the 4-H and 5-H have a trans- or
cis-disposition, respectively. In compound 10, the 4-H
signal appeared at d 5.04 as a ddd with J3,4¼8.0 Hz,
J4,5¼5.5 Hz and J4,6exo¼1.1 Hz, whereas in compound 11
the 4-H resonance appeared at d 4.30 as a dd with
J3,4¼4.9 Hz and J4,6exo¼1.6 Hz, data which match perfectly
with the assigned structures. Furthermore, the strong signal
enhancement of both 3-H and 5-H protons, when irradiating
the 4-H signal, unequivocally confirms the configuration
proposed.
Regarding the decomposition of diazo compounds, it is
generally accepted that the metallo-carbenoids inter-
mediately formed preserve their structural integrity during
the addition to the double bond.5 Thus, in the Rh2(OAc)4
catalyzed cyclopropanation of 8 the transition state TS-1
(R¼H) leading to the formation of 10, is destabilized by the
interactions of the bulk Rh(II) species with the acetonide
group, compared to those of the ethoxycarbonyl group in
TS-2 (R¼H). When CuI was the catalyst, the interactions of
the ethoxycarbonyl group in TS-2 (R¼H) with the acetonide
The structure discrimination of compounds 18 and 19 was
based on NOE experiments, since the 5-H is lacking and the
coupling constants could not be useful. For compound 18,
the 3-H and 4-H signals appeared at d 4.42 (d, J3,4¼8.2 Hz)
and 5.17 (dd, J3,4¼8.2 Hz and J4,6exo¼1.6 Hz), respectively,
while the 6-Hendo and 6-Hexo protons resonanced at d 1.87
(d, Jgem¼5.5 Hz) and 2.10 (dd, Jgem¼5.5 Hz and
J4,6exo¼1.6 Hz), respectively. Similarly, in compound 19,
the 3-H and 4-H signals appeared at d 4.81 (d, J3,4¼5.0 Hz)
and 4.34 (dd, J3,4¼5.0 Hz and J4,6exo¼1.6 Hz), respectively,
while the 6-Hendo and 6-Hexo protons resonanced at d 1.36
(d, Jgem¼6.0 Hz) and 2.20 (dd, Jgem¼6.0 Hz and
J4,6exo¼1.6 Hz), respectively. Whereas no appreciable
enhancement to the signals of 6-Hendo or 6-Hexo protons
appeared when irradiating the 3-H or 4-H signals in
compound 18, a strong signal enhancement of the 6endo-H
in compound 19 (d 1.29) was observed upon saturation of
both 3-H or 4-H protons, revealing thus indirectly the
configuration of the newly formed stereocenters in com-
pounds 18 and 19.
Figure 3.

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J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
group predominate over those of the smaller atom of Cu
with the acetonide. The TS-1 is further destabilized when
R¼CH2OBn, as in the case of decomposition of 16, by an
additional repulsion between the R and the CO2Et groups. It
is also possible that the Lewis acidic copper coordinates to
one of the acetonide oxygens, thus directing the stereo-
chemistry through TS-1. This pathway would not be open to
the coordinatively saturated rhodium carbenoid.
The hydroxylated bicyclo[3.1.0]hexane derivatives pre-
pared could serve as excellent precursors of carbocyclic
nucleosides. To demonstrate this possibility, compounds 10,
11 and 19 were further subjected to a number of synthetic
transformations.
Figure 4.
The reduction of 10 with NaBH4 or LiAlH4 was highly
stereoselective, affording compounds 21 and 22, respect-
ively, as the sole products, in good yields (Fig. 4). Similarly,
the protected tetrol 23 was stereoselectively prepared by
reduction of 11 with LiAlH4. Compound 21 was also
reduced to 22 upon treatment with LiAlH4 in high yield. The
configuration of the newly formed C-2 center was easily
deduced in all cases by NOE experiments and the coupling
constant between the 2-H and 3-H protons. For example,
the 2-H proton of compound 21 appeared at d 5.00 as a
doublet with J2,3¼6.8 Hz, a coupling constant, which
indicates a cis-disposition of the 2-H and 3-H protons,
taking into account the boat-like conformation of the
bicyclo[3.1.0]hexane system. In addition, irradiation of the
2-H proton caused a significant enhancement of the 3-H
signal, leaving little doubt about the configuration of the C-2
center.
and 29 is more sterically hindered than that of 27. In the last
case, this group adopting a trans-disposition to the all-cis
other substituents minimizes the steric interactions.
Cyclopropane nucleoside A-5021 (2)—recently reported by
Tsuji et al.3—and related nucleosides as well, could also be
accessible, using cyclopropanation products 10, ent-10, 11
and ent-11 as intermediates. Derivative 2, along with some
5-substituted uracil analogs,9 exhibits extraordinary activity
against HSV-1 and VZV, being superior and more selective
than acyclovir. It becomes evident when comparing the
structure of 2, 10, ent-10, 11 and ent-11, that the
configuration of the two chiral centers of the cyclopropane
ring of 2 matches to those of 10 or ent-11. Thus, the sugar
moiety of 2 could be prepared by conventional reduction,
deprotection and glycolic cleavage reactions.
The importance of these tetrols becomes evident when
comparing the structure of nucleoside 3 (Fig. 1) with that of
ent-22 (accessible from ent-10), which has the correct
configuration to be transformed into 3, apparently making
our method convenient for the synthesis of this type of
nucleoside.
Acetonide removal from the partially protected tetrol 22—
reduction product of 10 with LiAlH4—followed by trityla-
tion of the primary hydroxyl group (Scheme 3) afforded 34.
Attempted decarboxylations of compounds 10, 11 and 19
with preservation of the cyclopropane ring were less
successful. Thus, prolonged heating of 11 with DMSO/
H2O/NaCl17 at 1608C gave the desired ketone 24 (Fig. 4),
but only in 18% yield. On the contrary, compound 10, under
the same reaction conditions, underwent a further cyclo-
propane ring cleavage to give the cyclopentanone 25, also in
low yield (23%), whereas conventional hydrolysis of 19
with NaOH in THF/H2O afforded again low yields (25%) of
the acid 26.
In contrast, treatment of the cyclopropanation products 10,
11 and 19 with PhSH in t-BuOK/t-BuOH, led to
cyclopropane ring cleavage and formation of the b-keto
esters 27–29, respectively, in high yields (Scheme 2).
Subsequent decarboxylation of these b-keto esters afforded
good overall yields of cyclopentanoids 30–32, direct
precursors of cyclopentane nucleosides, as the thiophenyl
group can be easily transformed to a hydroxyl group via
a Pummerer oxidation.18 It is interesting to note that while
b-keto esters 28 and 29, exist exclusively as enols,
compound 27 is a keto/enol mixture (,2:3 ratio), apparently
because the ethoxycarbonyl group in the keto form of 28
Scheme 2. Reagents and conditions: (i) PhSH, t-BuOK, t-BuOH, 208C, 3–
12 h. (ii) DMSO, H2O, NaCl, 1608C, 5 h.

J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
8047
Scheme 3. Reagents and conditions: (i) LiAlH4, Et2O, 2108C, 30 min,
80%. (ii) HCl, H2O, THF, 208C, 30 min. (iii) TrCl, DMAP, Et3N, DMF,
208C, 24 h, 65% from 22. (iv) NaIO4, THF, H2O, 45 min then NaBH4,
MeOH, 30 min (twice), 55% overall. (v) BzCl, pyridine, 08C, 1 h. (vi)
HCO2H, Et2O, 208C, 20 min, 60% from 35. (vii) Ref. 3a.
Scheme 4. Reagents and conditions: (i) Zn, EtOH, reflux, 2 h. (ii)
N2CHCO2Et, 08C, 10 min, 65% from 39. (iii) TsN3, Et3N, EtOH, 208C,
10 h, 84%. (iv) PhI(OAc)2, KOH (4 equiv.), EtOH, 258C, 30 min.
where bicyclo[4.1.0]heptanes, like 44, were not possible to
be detected.
Further glycolic cleavage required prolonged stirring with
an excess of NaIO4, to afford low yields of 35 upon NaBH4
reduction, the mixture of polyols 37 and 38 being the main
products (Fig. 5). Evidently, the initially formed hydroxy-
bis-aldehydes exist predominantly as lactols, a structure
favored by the cis-disposition of these groups relative to the
cyclopropane ring, thus resisting the action of NaIO4.
Although bicyclo[4.1.0]heptanes have been previously
prepared by intramolecular cyclopropanation of metallo-
carbenoid intermediates,5 the tendency of the latter to form
five-membered rings might lead either to C–H insertion
reactions or to intermediate oxonium ylides by addition of
one oxygen of the benzyloxy groups to the carbenoid
carbon, which further decompose to several unidentified
products.
To overcome this problem, 34 was subjected to two
consecutive glycolic cleavage/NaBH4 reduction treatments,
to afford the desired compound 35, in good overall yield.
Conventional benzoylation of the two free hydroxyl groups
and detritylation gave the known compound 36, which can
be readily converted to the nucleoside A-5021 (2),
according to the literature.3a
3. Conclusion
In short, the diastereoselectivity of the metal-catalyzed
intramolecular cyclopropanations of erythro-2-diazo-4,5-
isopropylidenedioxy-3-oxo-6-heptenoate strongly depends
on the catalyst used. The endo product predominates when
CuI catalyzes the reaction, whereas Rh2(OAc)4 as a catalyst
favors the formation of the exo adduct. However, the
diastereoselectivity of the cyclopropanation of the respec-
tive iodonium ylides is independent of the catalyst used and
proceeds with similar results, even without the presence of
any catalyst. Our results are in accordance with the
mechanism suggested by Moriarty et al.6 which involves a
stepwise electrophilic addition of the iodonium center to the
double bond, followed by reductive elimination of iodo-
benzene to afford the cyclopropane ring. The synthetic
potential of these reactions was also demonstrated by
preparing precursors of carbocyclic nucleosides and by
developing a new synthesis of enantiopure antiviral
cyclopropane nucleoside A-5021.
In an attempt to extend the cyclopropanation methodology
into the synthesis of hydroxylated bicyclo[4.1.0]heptanes,
such as 44 (Scheme 4), the keto ester 41 was prepared by
addition of ethyl diazocetate to the chiral hexenal 40, easily
accessible from D-glucose.19 Iodide 39 was converted to 40
when treated with activated zinc in refluxing ethanol, and
was further used, without purification. To our surprise, ethyl
diazocetate added smoothly to 40 to give 41 in 65% yield,
without the presence of an SnCl2 catalyst. It is possible that
the hexenal 40 was contaminated by Zn2þ salts from the
previous reductive elimination step, which catalyzed the
reaction.
The keto ester was then easily converted to the respective
diazo compound 42 and iodonium ylide 43. As in the case of
9 and ent-9 (Scheme 1), the ylide 43, being unstable, was
prepared in situ and used in the next step without
purification. However, all attempts for catalytic decompo-
sition of 42 and 43 yielded a complex mixture of products,
4. Experimental
4.1. General
All reagents are commercially available and were used
without further purification. Solvents were dried by standard
methods. The progress of the reactions was checked by thin
layer chromatography (TLC) on Merck silica gel 60F254
glass plates (0.25 mm). The spots were visualized by heat
Figure 5.

8048
J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
staining with anisaldehyde in ethanol/sulfuric acid. Column
chromatography was performed with Merck silica gel 60
(0.063–0.200 mm). Optical rotations were determined at
room temperature on an A. Kru¨ss P3000 Automatic Digital
Polarimeter. Melting points were determined on a Kofler
hot-stage microscope and are uncorrected. Infrared spectra
were recorded on a Perkin–Elmer 297 spectrophotometer.
4.2.3. Ethyl (4R,5R)-6-[(benzyloxy)methyl]-4,5-isopro-
pylenedioxy-3-oxo-6-heptenoate (15). This compound
was obtained in 76% yield (68% from 13). [a]2D7¼,0.0
(c 0.3, CHCl3); IR (neat) 1730, 1710, 1640 cm21; 1H NMR
(CDCl3) d 1.24 (keto) and 1.31 (enol) (t, J¼7.0 Hz and
t, J¼7.0 Hz, total 3H), 1.41 (keto) and 1.51 (enol) (s and
s, total 3H), 1.61 (enol) and 1.67 (keto) (s and s, total 3H),
3.30 (keto) and 5.52 (enol) (d, J¼16.0 Hz and s, total 1H),
3.62 (keto) and 11.88 (enol) (d, J¼16.0 Hz and s, total 1H),
3.94 (keto) and 4.02 (enol) (d, J¼12.7 Hz and d, J¼13.1 Hz,
total 1H), 4.03 (keto) and 4.07 (enol) (d, J¼12.7 Hz and
d, J¼13.1 Hz, total 1H), 4.15 (keto) and 4.27 (enol)
(q, J¼7.0 Hz and q, J¼7.0 Hz, total 2H), 4.45 (d,
J¼12.0 Hz, 1H), 4.53 (d, J¼12.0 Hz, 1H), 4.60 (keto) and
4.65 (enol) (d, J¼8.0 Hz and d, J¼5.8 Hz, total 1H), 4.91
(enol) and 4.99 (keto) (d, J¼5.8 Hz and d, J¼8.0 Hz, total
1H), 5.29 (s, 1H), 5.44 (s, 1H), 7.34 (br s, 5H), (from
integration keto/enol ,9:1); 13C NMR (CDCl3) (keto form)
d 13.9, 24.4, 26.2, 47.3, 61.0, 70.8, 72.2, 77.1, 82.5, 110.2,
114.8, 127.6, 127.7, 128.3, 137.8, 139.7, 166.9, 202.7 and
(enol form) d 14.0, 25.1, 26.3, 60.1, 70.9, 72.1, 76.8, 77.4,
109.2, 114.9, 127.4, 127.5, 128.2, 138.0, 139.9, 140.0,
172.1, 174.1; MS m/z (%) 362 (Mþ, 71), 306 (31), 288 (32),
241 (43), 187 (100), 115 (93). Anal. calcd for C20H26O6: C,
66.28; H, 7.23. Found: C, 66.07; H, 6.96.
1
The H and 13C NMR spectra were recorded at 300 and
75 MHz, respectively, on a Bruker 300 AM spectrometer,
with tetramethylsilane (TMS) as internal standard. Mass
spectra were recorded under electron-impact (EI) conditions
at 70 eV on a VG TS-250 spectrometer and microanalyses
were performed on a Perkin–Elmer 2400-II Element
analyzer. High-resolution mass spectra (HRMS) were
obtained on a VG ZAB-ZSE mass spectrometer under
fast-atom bombardment (FAB) conditions with nitrobenzyl
alcohol (NBA) as the matrix or on an IONSPEC FTMS
spectrometer (matrix-assisted laser-desorption ionization,
MALDI) with 2,5-dihydroxybenzoic acid (DHB) as matrix.
4.2. General procedure for the synthesis of keto-esters 7,
ent-7 and 15
To a solution of aldehyde 6, ent-6 or 14 (prepared from
the appropriate precursor 5, 12 or 13 (10 mmol) according
to the literature procedure)10,14,15 in CH2Cl2 (35 mL),
anhydrous SnCl2 (190 mg, 1.0 mmol) was added. The
resulting mixture was cooled to 08C and N2CHCO2Et
(1.14 g, 10 mmol) was added dropwise during a period of
1 h under argon atmosphere and the mixture was stirred for
another 1 h at the same temperature. H2O (60 mL) was then
added, the organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3£60 mL). The combined
organic layers were dried over Na2SO4, the solvent was
removed on a rotary evaporator and the residue was
chromatographed on a column of silica gel with hexane/
ethyl acetate as the eluent to give keto esters 7, ent-7 or 15 as
pale yellow liquids.
4.3. General procedure for the synthesis of diazo
compounds 8, ent-8 and 16
To a solution of keto ester 7, ent-7 or 15 (10 mmol), in
absolute ethanol (60 mL) tosyl azide (2.366 g, 12 mmol)
and Et3N (13 mL) were added and the mixture was stirred at
room temperature for 12 h. The volatiles were then removed
on a rotary evaporator and the residue was chromatographed
on a column of silica gel with hexane/ethyl acetate as the
eluent to give diazo compounds 8, ent-8 or 16 as colorless
liquids.
4.3.1. Ethyl (4R,5R)-2-diazo-4,5-isopropylenedioxy-3-
oxo-6-heptenoate (8). This compound was obtained in
92% yield. [a]2D7¼þ55.7 (c 1.6, CHCl3); IR (neat) 2130,
4.2.1. Ethyl (4R,5R)-4,5-isopropylenedioxy-3-oxo-6-hep-
tenoate (7). This compound was obtained in 76% yield
(72% from 5). [a]2D7¼þ45.6 (c 1.6, CHCl3); IR (neat) 1740,
1
1705, 1610 cm21; H NMR (CDCl3) d 1.30 (t, J¼7.1 Hz,
3H), 1.43 (s, 3H), 1.65 (s, 3H), 4.28 (q, J¼7.1 Hz, 2H), 4.98
(dd as t, J¼7.7 Hz, 1H), 5.22 (d, J¼10.5 Hz, 1H), 5.37 (d,
J¼16.5 Hz, 1H), 5.61 (d, J¼7.7 Hz, 1H), 5.69 (ddd, J¼16.5,
10.5, 7.7 Hz, 1H); 13C NMR (CDCl3) d 14.3, 25.3, 26.7,
61.6, 78.8, 80.3, 110.6, 119.5, 132.6, 161.0, 188.0 (CvN2
not appeared); MS m/z (%) 268 (Mþ, 100), 253 (46), 211
(99), 127 (87); HRMS (m/z) calcd for C12H16N2O5 268.1059
(Mþ), found 268.1021.
1
1720, 1650 cm21; H NMR (CDCl3) d 1.26 (t, J¼7.3 Hz,
3H), 1.40 (s, 3H), 1.57 (enol) and 1.62 (keto) (s and s, total
3H), 3.35 (keto) and 5.47 (enol) (d, J¼16.5 Hz and s,
total 1H), 3.60 (keto) and 11.94 (enol) (d, J¼16.5 Hz and
s, total 1H), 4.17 (q, J¼7.3 Hz, 2H), 4.61 (keto) and 4.68
(enol) (d, J¼8.1 Hz and d, J¼7.3 Hz, total 1H), 4.79 (enol)
and 4.88 (keto) (dd as t, J¼7.3 Hz and dd as t, J¼8.1 Hz,
total 1H), 5.30 (m, 2H), 5.70 (m, 1H), (from integration
keto/enol ,5:1); 13C NMR (CDCl3) (keto form) d 13.7,
24.3, 26.3, 47.2, 60.8, 78.3, 82.5, 110.5, 118.7, 131.5, 166.5,
202.1 and (enol form) d 13.8, 24.6, 26.7, 59.9, 77.1, 79.0,
89.3, 109.6, 118.7, 132.5, 172.2, 173.0; MS m/z (%) 242
(Mþ, 46), 227 (26), 185 (100), 167 (19), 127 (79), 59 (63);
HRMS (m/z) calcd for C12H18O5 242.1154 (Mþ), found
242.1150.
4.3.2. Ethyl (4S,5S)-2-diazo-4,5-isopropylenedioxy-3-
oxo-6-heptenoate (ent-8). This compound was obtained
in 90% yield. [a]2D7¼255.7 (c 1.6, CHCl3) with spectra
identical to those of 8.
4.3.3. Ethyl (4R,5R)-2-diazo-6-[(benzyloxy)methyl]-4,5-
isopropylenedioxy-3-oxo-6-heptenoate (16). This com-
pound was obtained in 90% yield. [a]2D7¼236.3 (c 1.8,
CHCl3); IR (neat) 2120, 1700, 1650 cm21 1H NMR
;
(CDCl3) d 1.29 (t, J¼7.1 Hz, 3H), 1.41 (s, 3H), 1.63 (s,
3H), 3.91 (d, J¼13.8 Hz, 1H), 3.99 (d, J¼13.8 Hz, 1H), 4.24
(q, J¼7.1 Hz, 2H), 4.47 (s, 2H), 5.11 (d, J¼8.0 Hz, 1H),
4.2.2. Ethyl (4S,5S)-4,5-isopropylenedioxy-3-oxo-6-hep-
tenoate (ent-7). This compound was obtained in 75% yield
(69% from 12). [a]2D7¼245.3 (c 1.6, CHCl3) with spectra
identical to those of 7.

J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
8049
5.25 (s, 1H), 5.34 (s, 1H), 5.67 (d, J¼8.0 Hz, 1H), 7.3 (br
4.5. Decomposition of diazo compound 16
s, 5H); 13C NMR (CDCl3) d 14.3, 24.7, 26.0, 61.6, 69.3,
72.4, 79.1, 80.0, 110.0, 115.3, 127.5 (two overlapping
peaks), 128.3, 138.3, 141.3, 161.0, 187.7 (CvN2 not
appeared); MS m/z (%) 388 (Mþ, 100), 361 (10), 314
(15), 281 (31), 195 (100), 127 (74), 91 (62); HRMS (m/z)
calcd for C20H24N2O6 388.1634 (Mþ), found 388.1641.
Method A. To a well stirred solution of the diazo compound
16 (194 mg, 0.5 mmol) in toluene (5 mL) was added CuI
(6 mg) and the resultant mixture was refluxed for 5 h.
Evaporation of the solvent and subsequent column chroma-
tography on silica gel with hexane/ethyl acetate as the eluent
gave first 18 (33 mg, 18.5%), followed by the diastereo-
isomer 19 (17 mg, 9.5%), as colorless oils.
4.4. Decomposition of diazo compounds 8 and ent-8
Method B. To a well stirred solution of the diazo compound
16 (194 mg, 0.5 mmol) in toluene (5 mL) was added CuCl
(50 mg) and the resultant mixture was refluxed for 2 h.
Evaporation of the solvent and subsequent column chromato-
graphy on silica gel with hexane/ethyl acetate as the eluent
gave first 18 (48 mg, 27%), followed by the diastereoisomer
19 (29 mg, 16%).
Method A. To a well stirred solution of the diazo compound
8 or ent-8 (536 mg, 2 mmol) in toluene (20 mL) was added
CuI (20 mg) and the resultant mixture was refluxed for 3 h.
Evaporation of the solvent and subsequent column chroma-
tography on silica gel with hexane/ethyl acetate as the
eluent gave 10 or ent-10 at first (317 mg, 66%), followed by
the diastereoisomer 11 or ent-11 (72 mg, 15%) as colorless
oils.
Method C. To a well stirred solution of the diazo compound
16 (194 mg, 0.5 mmol) in toluene (5 mL) was added
Rh2(OAc)4 (3 mg) and the resultant mixture was refluxed
for 2.5 h. Evaporation of the solvent and subsequent column
chromatography on silica gel with hexane/ethyl acetate as
the eluent gave 19 (104 mg, 58%).
Method B. To a well stirred solution of the diazo compound
8 or ent-8 (536 mg, 2 mmol) in toluene (25 mL) was added
Rh2(OAc)4 (10 mg) and the resultant mixture was refluxed
for 1.5 h. Evaporation of the solvent and subsequent column
chromatography on silica gel with hexane/ethyl acetate as
the eluent gave 10 or ent-10 at first (90 mg, 19%), followed
by the diastereoisomer 11 or ent-11 (265 mg, 55%).
Method D. To a well stirred solution of the diazo compound
16 (194 mg, 0.5 mmol) in toluene (5 mL) was added
Cu(OSO2CF3) (0.5 mL of a 10% solution in CH3CN) and
the resultant mixture was refluxed for 5 h. Evaporation of
the solvent and subsequent column chromatography on
silica gel with hexane/ethyl acetate as the eluent gave first
18 (37 mg, 21%), followed by the diastereoisomer 19
(60 mg, 33%).
4.4.1. Ethyl (1R,3R,4R,5R)-3,4-isopropylenedioxy-2-oxo-
bicyclo[3.1.0]hexane-1-carboxylate (10). [a]2D7¼287.0
(c 1.0, CHCl3); IR (neat) 1755, 1725 cm21 1H NMR
;
(CDCl3) d 1.28 (t, J¼7.1 Hz, 3H), 1.31 (s, 3H), 1.51 (s, 3H),
1.81 (dd, J¼5.2, 5.0 Hz, 1H, 6-Hendo), 2.10 (ddd, J¼8.2, 5.0,
1.1 Hz, 1H, 6-Hexo), 2.76 (ddd, J¼8.2, 5.5, 5.2 Hz, 1H, 5-H),
4.21 (q, J¼7.1 Hz, 2H), 4.37 (d, J¼8.0 Hz, 1H, 3-H), 5.04
(ddd, J¼8.0, 5.5, 1.1 Hz, 1H, 4-H); 13C NMR (CDCl3) d
14.0, 20.5, 24.2, 25.6, 32.8, 41.7, 61.6, 73.5, 80.4, 114.8,
166.8, 199.5; MS m/z (%) 240 (Mþ, 100), 225 (21), 211
(23), 195 (22), 183 (22), 166 (14), 136 (55) 108 (58); HRMS
(m/z) calcd for C12H17O5 241.1076 (MþþH), found
241.1081.
4.5.1. Ethyl (1R,3R,4R,5R)-5-[(benzyloxy)methyl]-3,4-
isopropylenedioxy-2-oxobicyclo[3.1.0]hexane-1-carbox-
ylate (18). [a]2D7¼242.1 (c 1.0, CHCl3); IR (neat) 1750,
1
1710 cm21; H NMR (CDCl3) d 1.23 (t, J¼7.1 Hz, 3H),
1.32 (s, 3H), 1.51 (s, 3H), 1.87 (d, J¼5.5 Hz, 1H, 6-Hendo),
2.10 (dd, J¼5.5, 1.6 Hz, 1H, 6-Hexo), 3.47 (d, J¼10.5 Hz,
1H), 4.00 (d, J¼10.5 Hz, 1H), 4.17 (two dq as m, 2H), 4.42
(d, J¼8.2 Hz, 1H, 3-H), 4.45 (d, J¼11.5 Hz, 1H), 4.51
(d, J¼11.5 Hz, 1H), 5.17 (dd, J¼8.2, 1.6 Hz, 1H, 4-H), 7.3
(br s, 5H); 13C NMR (CDCl3) d 14.0, 22.5, 24.2, 25.7, 44.8,
45.7, 61.8, 68.1, 73.3, 75.6, 80.0, 114.8, 127.6, 127.8, 128.4,
137.6, 165.7, 205.8; MS m/z (%) 360 (Mþ, 14), 303 (9), 239
(23), 211 (31), 196 (41), 181 (31), 165 (24), 137 (22) 92
(100), 91 (73). Anal. calcd for C20H24O6: C, 66.65; H, 6.71.
Found: C, 66.74; H, 6.62.
4.4.2. Ethyl (1S,3R,4R,5S)-3,4-isopropylenedioxy-2-oxo-
bicyclo[3.1.0]hexane-1-carboxylate (11). [a]2D7¼276.3 (c
1.0, CHCl3); IR (neat) 1750, 1715 cm21; 1H NMR (CDCl3)
d 1.29 (t, J¼7.0 Hz, 3H), 1.29 (t, J¼5.5 Hz, 1H, 6-Hendo),
1.37 (s, 3H), 1.44 (s, 3H), 2.12 (ddd, J¼8.5, 5.5, 1.6 Hz, 1H,
6-Hexo), 2.87 (dd, J¼8.5, 5.5 Hz, 1H, 5-H), 4.23 (q,
J¼7.0 Hz, 2H), 4.30 (dd, J¼4.9, 1.6 Hz, 1H, 4-H), 4.73
(d, J¼4.9 Hz, 1H, 3-H); 13C NMR (CDCl3) d 13.9, 20.3,
25.5, 27.3, 35.4, 36.0, 61.4, 75.3, 79.2, 113.2, 166.9, 202.0;
MS m/z (%) 240 (Mþ, 100), 225 (41), 211 (6), 195 (7), 182
(25), 165 (11), 136 (39) 108 (32); HRMS (m/z) calcd for
C12H17O5 241.1076 (MþþH), found 241.1094.
4.5.2. Ethyl (1S,3R,4R,5S)-5-[(benzyloxy)methyl]-3,4-
isopropylenediooxy-2-oxobicyclo[3.1.0]hexane-1-car-
boxylate (19). [a]2D7¼227.2 (c 0.7, CHCl3); IR (neat) 1740,
1
1710 cm21; H NMR (CDCl3) d 1.21 (t, J¼7.0 Hz, 3H),
1.36 (d, J¼6.0 Hz, 1H), 1.40 (s, 3H), 1.43 (s, 3H), 2.20
(d, J¼6.0 Hz, 1H), 3.52 (d, J¼10.0 Hz, 1H), 4.13 (d,
J¼10.0 Hz, 1H), 4.16 (q, J¼7.0 Hz, 2H), 4.34 (dd, J¼5.0,
1.6 Hz, 1H, 4-H), 4.55 (d, J¼12.0 Hz, 1H), 4.60 (d,
J¼12.0 Hz, 1H), 4.81 (d, J¼5.0 Hz, 1H, 3-H), 7.3 (br s,
5H); 13C NMR (CDCl3) d 13.9, 22.5, 26.0, 27.6, 41.8, 44.1,
61.7, 66.4, 73.3, 76.5, 79.0, 113.6, 127.5, 127.7, 128.3,
137.8, 165.8, 203.1; MS m/z (%) 360 (Mþ, 74), 345 (17),
315 (22), 303 (74), 285 (56), 254 (91), 239 (83), 211 (41),
4.4.3. Ethyl (1S,3S,4S,5S)-3,4-isopropylenedioxy-2-oxo-
bicyclo[3.1.0]hexane-1-carboxylate (ent-10). [a]2D7¼þ84.5
(c 0.2, CHCl3).
4.4.4. Ethyl (1R,3S,4S,5R)-3,4-isopropylenedioxy-2-oxo-
bicyclo[3.1.0]hexane-1-carboxylate (ent-11). [a]2D7¼þ78.7
(c 1.0, CHCl3).

8050
J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
195 (82), 181 (74), 165 (34), 139 (52), 92 (100), 91 (75).
Anal. calcd for C20H24O6: C, 66.65; H, 6.71. Found: C,
66.34; H, 6.62.
From 21. To a solution of 21 (121 mg, 0.5 mmol) in dry
THF (10 mL) was added LiAlH4 (38 mg, 1 mmol) and the
mixture was stirred at 2108C for 30 min. A few drops of
H2O were added and the solids were filtered off and washed
with MeOH (3£10 mL). The solvent was evaporated and the
residue was chromatographed on silica gel with ethyl
acetate as the eluent to give 22 as colorless oil (38 mg,
76%).
4.6. General procedure for the preparation and
decomposition of iodonium ylides 9 and ent-9
To a cold stirred solution of keto ester 7 or ent-7 (242 mg,
1 mmol) in EtOH (5 mL) was added at 258C a solution of
KOH (224 mg, 4 mmol) in EtOH (5 mL) followed by
addition at the same temperature of a solution of PhI(OAc)2
(322 mg, 1 mmol) in EtOH (10 mL). The mixture was kept
at 258C for 30 min, then poured into H2O (20 mL),
extracted with CH2Cl2 (2£50 mL) and the organic layer
was dried over Na2SO4. The solution was concentrated to
10 mL and stirred at room temperature either with CuI
(10 mg) or Rh2(OAc)4 (5 mg) or without any catalyst for
30 min under argon atmosphere. Evaporation of the solvent
and subsequent column chromatography on silica gel with
hexane/ethyl acetate as the eluent gave in all cases first 10 or
ent-10 (43 mg, 18%), followed by 11 or ent-11 (65 mg,
27%).
4.6.3. (1R,2S,3R,4R,5S)-1-(Hydroxymethyl)-3,4-isopro-
pylenedioxybicyclo[3.1.0]hexane-2,3,4-triol (23). To a
solution of 11 (240 mg, 1 mmol) in dry THF (15 mL) was
added LiAlH4 (99 mg, 2.6 mmol) and the mixture was
stirred at 2108C for 30 min. A few drops of H2O were
added and the solids were filtered off and washed with
MeOH (3£20 mL). The solvent was evaporated and the
residue was chromatographed on silica gel with ethyl
acetate as the eluent to give 23 as colorless oil (82 mg,
82%). [a]2D7¼25.1 (c 0.5, CHCl3); H NMR (CDCl3) d
1
20.01 (dd, J¼6.1, 4.3 Hz, 1H), 0.67 (dd, J¼8.6, 6.1 Hz,
1H), 1.36 (s, 3H), 1.53 (s, 3H), 1.80 (dd, J¼8.6, 4.3 Hz, 1H),
2.91 (br s, 2H), 3.53 (d, J¼11.9 Hz, 1H), 4.00 (d,
J¼11.9 Hz, 1H), 4.07 (d, J¼5.8 Hz, 1H), 4.28 (dd, J¼5.8,
5.4 Hz, 1H), 4.64 (d, J¼5.4 Hz, 1H); 13C NMR (CDCl3) d
11.6, 24.5, 25.3, 26.0, 35.9, 64.7, 72.0, 80.4, 82.5, 112.8;
HRMS (m/z) calcd for C10H16NaO4 223.0941 (MþþNa),
found 223.0939.
4.6.1. Ethyl (1R,2S,3R,4R,5R)-2-hydroxy-3,4-isopropyl-
enedioxybicyclo[3.1.0]hexane-1-carboxylate (21). To a
solution of 10 (480 mg, 2 mmol) in absolute EtOH (30 mL)
was added NaBH4 (114 mg, 3 mmol) and the mixture was
stirred at 08C for 1 h. The volume of the mixture was
reduced to ,10 mL, H2O (20 mL) was added and then
extracted with CH2Cl2 (3£20 mL). The organic layer was
dried over Na2SO4, the solvent was removed on a rotary
evaporator and the residue was chromatographed on silica
gel with hexane/ethyl acetate as the eluent to give 21 as
colorless oil (329 mg, 68%). [a]2D7¼243.9 (c 1.0, CHCl3);
1H NMR (CDCl3) d 1.26 (t, J¼7.1 Hz, 3H), 1.30 (s, 3H),
1.52 (m, 2H, 6-H), 1.56 (s, 3H), 2.10 (ddd, J¼8.8, 5.4,
4.9 Hz, 1H, 5-H), 2.5 (br s, 1H, OH), 4.16 (two dq as m, 2H),
4.60 (dd as t, J¼6.8 Hz, 1H, 3-H), 4.87 (dd, J¼6.8, 5.4 Hz,
1H, 4-H), 5.00 (d, J¼6.8 Hz, 1H, 2-H); 13C NMR (CDCl3) d
14.2, 15.8, 24.6, 26.0, 32.5, 40.8, 61.0, 70.1, 79.2, 79.6,
113.0, 171.9; HRMS (m/z) calcd for C12H18NaO5 265.1046
(MþþNa), found 245.1054.
4.6.4. (1R,3R,4R,5S)-3,4-Isopropylenedioxy-bicyclo-
[3.1.0]hexan-2-one (24). To a solution of 11 (240 mg,
1 mmol) in DMSO (10 mL) were added NaCl (73 mg,
1.25 mmol) and H2O (2 drops) and the mixture was refluxed
for 5 h. H2O (50 mL) was added and the mixture was
extracted with CH2Cl2 (3£50 mL). The organic layer was
dried over Na2SO4, the solvent was removed on a rotary
evaporator and the residue was chromatographed on silica
gel with hexane/ethyl acetate as the eluent to give 24 as
white crystals (30 mg, 18%). Mp 70–718C (from Et2O/
hexane); [a]2D7¼2254.8 (c 0.05, CHCl3); IR (nujol)
1
1725 cm21; H NMR (CDCl3) d 0.92 (m, 1H, 6-Ha), 1.36
(s, 3H), 1.37 (m, 1H, 6-Hb), 1.45 (s, 3H), 2.04 (ddd, J¼9.0,
4.7, 4.3 Hz, 1H, 5-H), 2.43 (ddd, J¼8.7, 4.7, 4.0 Hz, 1H,
1-H), 4.24 (dd, J¼4.8, 1.8 Hz, 1H, 4-H), 4.79 (d, J¼4.8 Hz,
1H, 3-H); 13C NMR (CDCl3) d 12.3, 25.5, 25.6, 25.9, 27.3,
77.3, 77.7, 113.1, 209.3; MS m/z (%) 168 (Mþ, 22), 153
(60), 110 (63), 82 (100), 59 (17). Anal. calcd for C9H12O3:
C, 64.27; H, 7.19. Found: C, 64.38; H, 7.33.
4.6.2. (1S,2S,3R,4R,5R)-1-(Hydroxymethyl)-3,4-isopro-
pylenedioxybicyclo[3.1.0]hexane-2,3,4-triol (22). From
10. To a solution of 10 (480 mg, 2 mmol) in dry THF
(30 mL) was added LiAlH4 (198 mg, 5.2 mmol) and the
mixture was stirred at 2108C for 30 min. A few drops of
H2O were added and the solids were filtered off and washed
with MeOH (3£20 mL). The solvent was evaporated and the
residue was chromatographed on silica gel with ethyl
acetate as the eluent to give 22 as colorless oil (320 mg,
80%). [a]2D7¼27.2 (c 1.0, CHCl3); 1H NMR (CDCl3) d 0.66
(dd, J¼7.8, 4.5 Hz, 1H, 6-Ha), 1.20 (dd, J¼5.9, 4.5 Hz,
1H, 6-Hb), 1.30 (s, 3H), 1.55 (s, 3H), 1.62 (ddd, J¼7.8,
5.9, 4.0 Hz, 1H, 5-H), 3.05 (br s, 2H, two OH), 3.45 (d,
J¼11.7 Hz, 1H), 3.79 (d, J¼11.7 Hz, 1H), 4.55 (dd as t,
J¼6.8 Hz, 1H, 3-H), 4.61 (d, J¼6.8 Hz, 1H, 2-H), 4.88 (dd,
J¼6.8, 4.0 Hz, 1H, 4-H); 13C NMR (CDCl3) d 10.9, 24.5,
25.9, 26.1, 41.1, 65.1, 72.0, 79.2, 80.0, 112.3; HRMS (m/z)
calcd for C10H16NaO4 223.0941 (MþþNa), found
223.0935.
4.6.5. (2R,3R,4R)-4-(Chloromethyl)-2,3-isopropylene-
dioxycyclopentanone (25). To a solution of 10 (240 mg,
1 mmol) in DMSO (10 mL) were added NaCl (73 mg,
1.25 mmol) and H2O (2 drops) and the mixture was refluxed
for 5 h. H2O (50 mL) was added and the mixture was
extracted with CH2Cl2 (3£50 mL). The organic layer was
dried over Na2SO4, the solvent was removed on a rotary
evaporator and the residue was chromatographed on silica
gel with hexane/ethyl acetate as the eluent to give 25 as a
white foam (47 mg, 23%). [a]2D7¼2186.0 (c 0.05, CHCl3);
1
IR (nujol) 1740 cm21; H NMR (CDCl3) d 1.38 (s, 3H),
1.42 (s, 3H), 2.35 (dd, J¼18.2, 12.2 Hz, 1H), 2.47 (dd,
J¼18.2, 7.7 Hz, 1H), 2.62 (m, 1H), 3.69 (dd, J¼10.7,
6.9 Hz, 1H), 3.82 (dd, J¼10.7, 8.2 Hz, 1H), 4.29 (d,
J¼4.8 Hz, 1H), 4.85 (dd, J¼4.8, 4.3 Hz, 1H); 13C NMR

J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
8051
(CDCl3) d 25.1, 26.6, 38.0, 38.5, 43.5, 77.1, 80.4, 112.8,
212.1; MS m/z (%) 206 (Mþþ2, 18), 204 (Mþ, 55), 169
(22), 149 (27), 147 (80), 132 (15), 130 (45), 51 (100). Anal.
calcd for C9H13ClO3: C, 52.82; H, 6.40. Found: C, 53.01; H,
6.32.
(36), 186 (61), 141 (72), 123 (58), 81 (100). Anal. calcd for
C18H22O5S: C, 61.70; H, 6.33. Found: C, 61.90; H, 6.35.
4.7.2. Ethyl (3R,4R,5S)-3,4-isopropylenedioxy-2-oxo-5-
[(phenylthio)methyl]cyclopentanecarboxylate (28). This
compound was obtained in 71% yield as a colorless oil.
[a]2D7¼þ19.5 (c 0.6, CHCl3); IR (neat) 1710, 1660 cm21
;
4.6.6. (1S,3R,4R,5S)-5-[(Benzyloxy)methyl]-3,4-isopro-
pylenedioxy-2-oxobicyclo[3.1.0]hexane-1-carboxylic
acid (26). A mixture of 19 (180 mg, 0.5 mmol) in THF
(15 mL) and aqueous 0.1N NaOH (15 mL) was refluxed for
4 h and then carefully neutralized with dilute aqueous HCl.
H2O (50 mL) was added and the mixture was extracted with
CH2Cl2 (3£50 mL). The organic layer was dried over
Na2SO4, the solvent was removed on a rotary evaporator
and the residue was chromatographed on silica gel with
hexane/ethyl acetate as the eluent to give 24 as a white foam
(41.5 mg, 25%). [a]D27¼þ119.4 (c 0.07, CHCl3); IR
1H NMR (CDCl3) d 1.28 (t, J¼7.1 Hz, 3H), 1.36 (s, 3H),
1.42 (s, 3H), 2.97 (dd, J¼12.0, 7.4 Hz, 1H), 3.25 (dd, J¼7.4,
2.3 Hz, 1H), 3.35 (dd, J¼12.0, 2.3 Hz, 1H), 4.13 (q,
J¼7.1 Hz, 2H), 4.52 (d, J¼5.8 Hz, 1H), 5.11 (d,
J¼5.8 Hz, 1H), 7.18 (d, J¼7.5 Hz, 1H), 7.26 (t, J¼7.5 Hz,
2H), 7.35 (d, J¼7.5 Hz, 2H), 10.06 (br s, 1H); 13C NMR
(CDCl3) d 14.1, 25.4, 27.2, 36.8, 45.5, 60.5, 80.3, 80.7,
102.2, 111.3, 126.3, 128.8, 129.7, 136.0, 168.8, 171.2; MS
m/z (%) 350 (Mþ, 14), 349 (40), 334 (23), 292 (29), 275
(17), 229 (56), 181 (61), 140 (83), 125 (100), 108 (96). Anal.
calcd for C18H22O5S: C, 61.70; H, 6.33. Found: C, 61.84; H,
6.44.
1
(CHCl3) 1740, 1700 cm21; H NMR (CDCl3) d 1.40 (s,
3H), 1.42 (s, 3H), 1.87 (d, J¼5.2 Hz, 1H, 6-Ha), 2.43 (dd,
J¼5.2, 1.6 Hz, 1H, 6-Hb), 3.98 (d, J¼10.2 Hz, 1H), 4.15
(d, J¼10.2 Hz, 1H), 4.48 (dd, J¼5.0, 1.6 Hz, 1H, 4-H), 4.62
(s, 2H), 4.94 (d, J¼5.0 Hz, 1H, 3-H), 7.35 (br s, 5H); 13C
NMR (CDCl3) d 25.7, 27.3, 29.3, 39.1, 48.6, 65.5, 73.7,
76.2, 77.9, 114.5, 127.7, 127.8, 128.4, 137.9, 166.7, 202.2;
HRMS (m/z) calcd for C18H20NaO6 355.1152 (MþþNa),
found 355.1153.
4.7.3. Ethyl (2R,3R,4R)-2-[(benzyloxy)methyl]-3,4-iso-
propylenedioxy-5-oxo-2-[(phenylthio)methyl]-cyclopen-
tanecarboxylate (29). This compound was obtained in
94% yield as a colorless oil. [a]2D7¼þ37.6 (c 1.0, CHCl3);
IR (neat) 1705, 1655 cm21 1H NMR (CDCl3) d 1.12
;
(t, J¼7.0 Hz, 3H), 1.38 (s, 3H), 1.40 (s, 3H), 3.41 (d,
J¼13.6 Hz, 1H), 3.54 (d, J¼13.6 Hz, 1H), 3.67 (d,
J¼8.6 Hz, 1H), 3.83 (d, J¼8.6 Hz, 1H), 4.13 (q,
J¼7.1 Hz, 2H), 4.51 (d, J¼5.8 Hz, 1H), 4.57 (d,
J¼12.5 Hz, 1H), 4.59 (d, J¼12.5 Hz, 1H), 5.27 (d,
J¼5.8 Hz, 1H), 7.3 (m, 10H), 10.40 (br s, 1H); 13C NMR
(CDCl3) d 13.9, 25.9, 27.3, 41.1, 53.4, 60.3, 71.0, 73.3, 80.8,
81.7, 102.1, 111.4, 126.5, 127.4, 127.7, 128.2, 128.7, 130.6,
136.5, 138.6, 168.7, 173.0; MS m/z (%) 470 (Mþ, 5), 469
(17), 423 (7), 347 (43), 275 (86), 249 (68), 123 (100), 91
(37). Anal. calcd for C26H30O6S: C, 66.36; H, 6.23. Found:
C, 66.26; H, 6.45.
4.7. General procedure for the synthesis of compounds
27–29
To a solution of compound 10, 11 or 19, (1 mmol) in t-BuOH
(12 mL) were added t-BuOK (134 mg, 1.2 mmol), and
PhSH (121 mg, 1.1 mmol) and the mixture was stirred at
room temperature for 7 h (compound 10) or 3 h (compound
11) or 12 h (compound 19). The solution was quenched with
dilute aqueous HCl. H2O (50 mL) was added and the
mixture was extracted with CH2Cl2 (3£50 mL). The organic
layer was dried over Na2SO4, the solvent was removed on a
rotary evaporator and the residue was chromatographed on
silica gel with hexane/ethyl acetate as the eluent to give 27,
28 or 29.
4.8. General procedure for the synthesis of compounds
30–32
To a solution of compound 29, 28 or 29, (0.25 mmol) in
DMSO (5 mL) were added NaCl (20 mg, 0.5 mmol) and
H2O (1 drop) and the mixture was refluxed for 5 h. H2O
(50 mL) was added and the mixture was extracted with
CH2Cl2 (3£50 mL). The organic layer was dried over
Na2SO4, the solvent was removed on a rotary evaporator
and the residue was chromatographed on silica gel with
hexane/ethyl acetate as the eluent to give 30, 31 or 32.
4.7.1. Ethyl (3R,4R,5R)-3,4-isopropylenedioxy-2-oxo-5-
[(phenylthio)methyl]cyclopentanecarboxylate (27). This
compound was obtained in 77% yield as white crystals. Mp
57–598C (from Et2O/hexane); [a]2D7¼þ33.9 (c 0.8, CHCl3);
IR (nujol) 1760, 1715 cm21; 1H NMR (CDCl3) d 1.28 (keto)
and 1.35 (enol) (t, J¼7.5 Hz and t, J¼7.5 Hz, total 3H), 1.34
(keto) and 1.40 (enol) (s and s, total 3H), 1.42 (keto) and
1.46 (enol) (s and s, total 3H), 2.89–3.20 (keto/enol) and
10.32 (enol) (m and br s, total 3H), 3.43 (keto) and 3.71
(enol) (d; J¼12.0 Hz and d, J¼13.0 Hz, total 1H), 4.22
(keto) and 4.25 (enol) (q, J¼7.5 Hz, and q, J¼7.5 Hz, total
2H), 4.30 (keto) and 4.92 (enol) (d, J¼4.0 Hz and d,
J¼6.0 Hz, total 1H, 3-H), 4.81 (enol) and 4.87 (keto) (dd as
t, J¼6.0 Hz and dd as t, J¼4.0 Hz, total 1H, 4-H), 7.35 (m,
5H) (from integration keto/enol ,2:3); 13C NMR (CDCl3)
(keto/enol form) 14.1, 14.15, 24.8, 25.7, 26.7, 27.2, 30.6,
33.1, 38.9, 42.1, 55.8, 60.8, 61.9, 75.6, 76.4, 79.9, 80.3,
102.3, 112.0, 112.9, 125.4, 126.4, 128.2, 128.8, 129.0,
129.3, 135.4, 137.2, 167.8, 169.9, 171.4, 205.5; MS m/z (%)
350 (Mþ, 31), 335 (8), 292 (41), 274 (14), 241 (19), 227
4.8.1. (2R,3R,4R)-2,3-Isopropylenedioxy-4-[(phenyl-sul-
fanyl)methyl]cyclopentanone (30). This compound was
obtained in 78% yield as white crystals. Mp 84–858C (from
hexane); [a]2D7¼þ19.5 (c 0.6, CHCl3); IR (nujol)
1730 cm21 1H NMR (CDCl3) d 1.34 (s, 3H), 1.41 (s,
;
3H), 2.34–2.47 (m, 3H), 3.12 (dd, J¼13.0, 6.0 Hz, 1H),
3.29 (dd, J¼13.0, 6.5 Hz, 1H), 4.20 (d, J¼4.8 Hz, 1H), 4.79
(dd, J¼4.8, 4.2 Hz, 1H), 7.23 (d, J¼7.0 Hz, 1H), 7.31 (dd as
t, J¼8.0, 7.0 Hz, 2H), 7.39 (d, J¼8.0 Hz, 2H); 13C NMR
(CDCl3) d 25.1, 26.8, 34.3, 35.3, 39.1, 78.2, 80.3, 112.5,
126.5, 129.0, 129.9, 135.6, 212.9; MS m/z (%) 278 (Mþ,
24), 203 (10), 141 (18), 123 (100), 110 (52). Anal. calcd for
C15H18O3S: C, 64.72; H, 6.52. Found: C, 64.53; H, 6.40.

8052
J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
4.8.2. (2R,3R,4S)-2,3-Isopropylenedioxy-4-[(phenyl-sul-
fanyl)methyl]cyclopentanone (31). This compound was
obtained in 76% yield as a colorless oil. [a]2D7¼2117.0 (c
mixture was then extracted with CH2Cl2 (3£50 mL), the
organic layer was dried over Na2SO4, the solvent was
evaporated off on a rotary evaporator and the residue was
dissolved in dry EtOH (30 mL). NaBH4 (57 mg, 1.5 mmol)
was then added to this solution and the mixture was stirred
at room temperature for 30 min under argon atmosphere.
The solvent was then removed on a rotary evaporator and
the residue was treated again with NaIO4 and NaBH4
according to the procedures described above. Compound
35 was obtained as a colorless oil (103 mg, 55% overall)
by chromatographing the final residue on silica gel with
CH2Cl2/ethyl acetate as the eluent. [a]2D7¼227.7 (c 0.5,
1
0.3, CHCl3); IR (nujol) 1745 cm21; H NMR (CDCl3) d
1.33 (s, 3H), 1.42 (s, 3H), 2.27 (d, J¼18.0 Hz, 1H), 2.67 (m,
1H), 2.79 (dd, J¼18.0, 8.7 Hz, 1H), 2.91 (dd, J¼13.3,
6.3 Hz, 1H), 3.01 (dd, J¼13.3, 6.8 Hz, 1H), 4.32 (d,
J¼5.0 Hz, 1H), 4.67 (d, J¼5.0 Hz, 1H), 7.3 (m, 5H); 13C
NMR (CDCl3) d 24.8, 26.8, 37.0, 38.0, 39.5, 78.3, 81.1,
112.2, 127.0, 129.2, 130.3, 134.9, 212.9; MS m/z (%) 278
(Mþ, 100), 263 (15), 141 (77), 123 (93), 110 (99). Anal.
calcd for C15H18O3S: C, 64.72; H, 6.52. Found: C, 64.64; H,
6.58.
1
CHCl3); H NMR (CDCl3) d 0.35 (dd as t, J¼5.4 Hz, 1H),
0.56 (dd, J¼8.3, 5.4 Hz, 1H), 1.25 (br s, 1H), 1.30 (m,
1H), 1.65 (br, 1H), 3.02 (d, J¼9.8 Hz, 1H), 3.19 (d,
J¼9.8 Hz, 1H), 3.28 (d, J¼11.7 Hz, 1H), 3.32 (dd, J¼12.2,
5.4 Hz, 1H), 4.05 (dd, J¼12.2, 5.4 Hz, 1H), 4.15 (d,
J¼11.7 Hz, 1H), 7.30 (m, 9H), 7.46 (m, 6H); 13C NMR
(CDCl3) d 13.7, 24.8, 26.7, 63.6, 65.7, 70.9, 87.0, 127.2,
128.0, 128.6, 143.6; HRMS (m/z) calcd for C25H26NaO3
397.1774 (MþþNa), found 397.1774.
4.8.3. (2R,3R,4R)-4-[(Benzyloxy)methyl]-2,3-isopropyl-
enedioxy-4-[(phenylsulfanyl)methyl]-cyclopentanone
(32). This compound was obtained in 76% yield as a
colorless oil. [a]2D7¼253.0 (c 0.2, CHCl3); IR (nujol)
1745 cm21; 1H NMR (CDCl3) d 1.31 (s, 3H), 1.39 (s, 3H),
2.31 (d, J¼18.7 Hz, 1H), 2.42 (d, J¼18.7 Hz, 1H), 3.14
(d, J¼13.5 Hz, 1H), 3.21 (d, J¼13.5 Hz, 1H), 3.59 (d,
J¼9.1 Hz, 1H), 3.75 (d, J¼9.1 Hz, 1H), 4.41 (d, J¼5.2 Hz,
1H), 4.47 (s, 2H), 4.58 (d, J¼5.2 Hz, 1H), 7.3 (m, 10H); 13C
NMR (CDCl3) d 24.8, 26.7, 40.4, 42.8, 45.3, 71.6, 73.3,
79.5, 81.2, 112.2, 126.7, 127.5, 127.6, 128.3, 129.1, 129.8,
136.2, 138.2, 212.1; HRMS (m/z) calcd for C23H26NaO4S
421.1444 (MþþNa), found 421.1434.
4.9. [(1S,2R)-2-[(Benzoyloxy)methyl]-1-(hydroxy-
methyl)cyclopropyl]methyl benzoate (36)
Benzoyl chloride (56 mg, 0.4 mmol) was added to a solution
of 35 (75 mg, 0.2 mmol) in dry pyridine (10 mL) at 08C and
the mixture was stirred at the same temperature for 1 h.
Saturated aqueous NH4Cl was then added and the mixture
was extracted with CH2Cl2 (3£50 mL). The solvent was
removed, the residue was dissolved in HCO2H/Et2O 3:2
(20 mL) and the resultant mixture was stirred at 08C for
30 min. The mixture was diluted with H2O (20 mL) and
Et2O (20 mL), then neutralized by adding saturated Na2CO3
and extracted with CH2Cl2 (3£50 mL). The organic layer
was washed with H2O and dried over Na2SO4 to give after
evaporating the solvent and chromatographing the final
residue on silica gel with hexane/ethyl acetate as the eluent,
compound 35 as a colorless oil (41 mg, 60% overall) with
NMR data identical to those reported in the literature.3a
[a]2D7¼25.5 (c 0.2, CHCl3).
4.8.4. (1S,2S,3R,4R,5R)-1-[(Trityloxy)methyl]bicyclo-
[3.1.0]hexane-2,3,4-triol (34). To a solution of compound
22 (200 mg, 1 mmol) in THF (5 mL) was added aqueous 1N
HCl (5 mL) and the mixture was stirred at room temperature
for 15 min. The volatiles were then carefully evaporated off
on a rotary evaporator to afford pure tetrol 33 [1H NMR
(D2O) d 0.48 (dd as t, J¼6.6 Hz, 1H), 1.32 (dd as t,
J¼4.6 Hz, 1H), 1.58 (m, 1H), 3.27 (d, J¼11.7 Hz, 1H), 3.91
(dd, J¼6.4, 5.4 Hz, 1H), 3.92 (d, J¼11.7 Hz, 1H), 4.33 (dd,
J¼6.6, 5.4 Hz, 1H), 4.45 (d, J¼6.4 Hz, 1H); 13C NMR
(D2O) d 9.7, 26.7, 34.7, 64.1, 69.8, 71.4, 72.0] was dissolved
in dry DMF (10 mL). Dry Et3N (202 mg, 2 mmol), catalytic
DMAP (25 mg) and trityl chloride (306 mg, 1.1 mmol) were
then added to this solution and the resultant mixture was
stirred at room temperature for 24 h under argon atmos-
phere. The volatiles were then removed under reduced
pressure and the residue was chromatographed on silica gel
with CH2Cl2/MeOH 40:1 as the eluent to give 34 as a
colorless syrup (261 mg, 65%). [a]2D7¼219.5 (c 0.8,
CHCl3); 1H NMR (CDCl3) d 0.39 (dd, J¼8.2, 5.2 Hz,
1H), 1.35 (dd, J¼5.2, 4.2 Hz, 1H), 1.54 (ddd, J¼8.2, 5.4,
4.2 Hz, 1H), 1.6 (br, 3H), 3.14 (d, J¼9.8 Hz, 1H), 3.25 (d,
J¼9.8 Hz, 1H), 3.96 (dd as t, J¼5.4 Hz, 1H), 4.38 (dd,
J¼5.9, 5.4 Hz, 1H), 4.48 (d, J¼5.9 Hz, 1H), 7.27 (m, 9H),
7.43 (m, 6H); 13C NMR (CDCl3) d 9.9, 28.1, 34.2, 66.6,
69.8, 71.7, 73.8, 86.7, 127.1, 127.9, 128.6, 143.9; HRMS
(m/z) calcd for C26H26NaO4 425.1723 (MþþNa), found
425.1716.
4.9.1. Ethyl (4R,5S,6R)-4,5,6-tribenzyloxy-3-oxo-7-
octenoate (41). To a solution of 39 (574 mg, 1 mmol) in
95% EtOH (10 mL) activated Zn (654 mg, 10 mmol) was
added and the mixture was refluxed with vigorous stirring
under argon atmosphere until complete disappearance of 39
(,2 h). The mixture was cooled to room temperature, the
solids were filtered off and the solvent was evaporated to
give pure aldehyde 40. Ethyl diazoacetate (130 mg,
1.1 mmol) was added dropwise to this compound at 08C
with vigorous stirring under argon atmosphere. After 10 min
at the same temperature the mixture was chromatographed
on a column of silica gel with hexane/ethyl acetate as the
eluent, to give compound 41 as a colorless oil (328 mg,
65% overall). [a]2D7¼þ12.7 (c 1.0, CHCl3); IR (neat) 1740,
1715, 1640 cm21; 1H NMR (CDCl3) of the keto form d 1.20
(t, J¼6.9 Hz, 3H), 3.49 (d, J¼16.4 Hz, 1H), 3.65 (d,
J¼16.4 Hz, 1H), 3.79 (dd, J¼5.8, 3.8 Hz, 1H), 4.09 (q,
J¼6.9 Hz, 2H), 4.11 (m, 1H), 4.17–5.01 (m, 7H), 5.29 (m,
2H), 5.78 (m, 1H), 7.34 (br s, 15H); distinguishable peak for
the enol form d 11.93 (s), (from integration keto/enol
,20:1); 13C NMR (CDCl3) of the keto form d 14.1, 46.9,
4.8.5. {(1R,2R)-2-(Hydroxymethyl)-2-[(trityloxy)-
methyl]cyclopropyl}methanol (35). To a solution of
compound 34 (201 mg, 0.5 mmol) in THF/H2O 1:1
(20 mL) was added at 08C, NaIO4 (610 mg, 2.85 mmol),
the mixture was stirred at this temperature for 45 min and
then allowed to warm at room temperature. The resultant

J. K. Gallos et al. / Tetrahedron 58 (2002) 8043–8053
8053
4. Lee, K.; Cass, C.; Jacobson, K. A. Org. Lett. 2001, 3,
597–599.
61.1, 71.0, 73.4, 74.7, 80.6, 82.7, 85.3, 119.6, 127.6, 127.8,
127.9, 128.0, 128.1 (two peaks), 128.3, 128.4, 128.5, 134.8,
137.2, 137.7, 138.0, 167.8, 204.0; MS m/z (%) 502 (Mþ, 9),
431 (5), 395 (22), 357 (9), 266 (13), 249 (21), 197 (24), 181
(59), 105 (66), 91 (100), 77 (39), 65 (23). Anal. calcd for
C31H34O6: C, 74.08; H, 6.82. Found: C, 74.31; H, 6.72.
5. (a) Doyle, M. P. Acc. Chem. Res. 1986, 19, 348–356.
(b) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds.
Wiley: New York, 1998. (c) Ye, T.; McKervey, M. A.
Chem. Rev. 1994, 94, 1091–1160. (d) Brunner, H. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1183–1185. (e) Padwa, A.;
Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33,
1797–1815. (f) Doyle, M. P.; Protopopova, M. N.
Tetrahedron 1998, 54, 7919–7946. (g) Padwa, A.; Krumpe,
K. E. Tetrahedron 1992, 48, 5385–5453. (h) Singh, V. K.;
DattaGupta, A.; Sekar, G. Synthesis 1997, 137–149.
(i) Rasmussen, T.; Jensen, J. F.; Østergaard, N.; Tanner, D.;
Ziegler, T.; Norrby, P.-O. Chem. Eur. J. 2002, 8, 177–184.
6. (a) Moriarty, R. M.; Prakash, O.; Vaid, R. K.; Zhao, L. J. Am.
Chem. Soc. 1989, 111, 6443–6444. (b) Moriarty, R. M.;
Prakash, O.; Vaid, R. K.; Zhao, L. J. Am. Chem. Soc. 1990,
112, 1297. (c) Moriarty, R. M.; Kim, J.; Guo, L. Tetrahedron
Lett. 1993, 34, 4129–4132. (d) Moriarty, R. M.; May, E. J.;
Guo, L.; Prakash, O. Tetrahedron Lett. 1998, 39, 765–766.
(e) Varvoglis, A. The Organic Chemistry of Polycoordinated
Iodine. VCH: Weinheim, 1992.
4.9.2. Ethyl (4R,5S,6R)-2-diazo-4,5,6-tribenzyloxy-3-
oxo-7-octenoate (42). To a solution of keto ester 41
(502 mg, 1 mmol) in absolute ethanol (6 mL), tosyl azide
(260 mg, 1.3 mmol) and Et3N (1.3 mL) were added and the
mixture was stirred at room temperature for 10 h. The
volatiles were then removed on a rotary evaporator and
the residue was chromatographed on a column of silica
gel with hexane/ethyl acetate as the eluent to give
diazo compound 42 as a colorless oil (445 mg, 84%).
[a]2D7¼þ27.7 (c 1.0, CHCl3); IR (neat) 2125, 1700,
1
1665 cm21; H NMR (CDCl3) d 1.18 (t, J¼7.2 Hz, 3H),
3.91 (dd, J¼7.8, 2.5 Hz, 1H), 4.07 (q, J¼7.2 Hz, 1H), 4.10–
4.75 (m, 8H), 5.15 (m, 2H), 5.74 (m, 1H), 7.34 (br s, 15H);
13C NMR (CDCl3) d 14.3, 61.3, 70.9, 73.1, 74.3, 78.9, 82.8,
83.2, 119.7, 127.4, 127.7, 127.8 (two overlapping peaks),
128.0, 128.2, 128.3 (two overlapping peaks), 129.2, 134.7,
137.2, 138.2, 138.5, 160.8, 188.9 (CvN2 not appeared); MS
m/z (%) 500 (Mþ2N2, 25), 439 (44), 393 (75), 339 (51), 337
(29), 303 (44), 271 (40), 195 (32), 181 (100), 147 (66), 105
(31), 92 (83), 91 (63), 77 (28), 65 (55), 51 (6), 39 (21). Anal.
calcd for C31H32N2O6: C, 70.44; H, 6.10, N, 5.30. Found: C,
70.49; H, 6.23; N, 5.15.
´
7. (a) Mu¨ller, P.; Bolea, C. Synlett 2000, 826–828. (b) Mu¨ller, P.;
´
Bolea, C. Helv. Chim. Acta 2001, 84, 1093–1111.
8. For preliminary accounts of this work see: (a) Gallos, J. K.;
Koftis, T. V.; Koumbis, A. E. J. Chem. Soc., Perkin Trans. 1
1994, 611–612. (b) Gallos, J. K.; Massen, Z. S.; Koftis, T. V.;
Dellios, C. C. Tetrahedron Lett. 2001, 42, 7489–7491.
9. (a) Hill, J. M.; Hutchinson, E. J.; Le Grand, D. M.; Roberts,
S. M.; Thorpe, A. J.; Turner, N. J. J. Chem. Soc., Perkin Trans.
¨
1 1994, 1483–1487. (b) Palmer, A. M.; Jager, V. Eur. J. Org.
Chem. 2001, 1293–1308.
Acknowledgements
10. (a) Gallos, J. K.; Goga, E. G.; Koumbis, A. E. J. Chem. Soc.,
Perkin Trans. 1 1994, 613–614. (b) Paquette, L. A.; Bailey, S.
J. Org. Chem. 1995, 60, 7849–7856.
We are grateful to The Hellenic General Secretariat for
Research and Technology for financial support of this work
and to the ‘Leonidas Zervas’ Foundation for fellowships to
T. V. Koftis and C. C. Dellios.
11. Holquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54,
3258–3260.
12. Singh, A. J.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc.
1987, 109, 6187–6189.
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