Strategies for the synthesis of enantiomerically pure medium-sized carbocycles from carbohydrates

Article abstract of DOI:10.1081/CAR-120004333

A series of strategies (the Pauson-Khand reaction and the 1,3-dipolar cycloaddition reaction) have been analyzed in order to develop new and original synthetic protocols for the synthesis of enantiomerically pure medium-sized carbocycles. The intramolecular Pauson-Khand reaction on dideoxy-3,4:5,6-bis-O-(1-methylethylidene)-D/L-glycero-D-gluco-non-1-en-8- ynitol (4) is a low yielding, but highly stereoselective acyclic enyne precursor 1,2-procedure for the synthesis of bicyclo[5.3.0]decanones of type 5. In the second approach ("the nitrone route"), the intramolecular nitrone cycloaddition of precursors 14 and 19 derived from D-mannose has afforded the corresponding 9-oxa-8-azabicyclo[5.3.0]decanes as a mixture of trans fused isomers, in a critically dependent reaction of a pre-existing isopropylidene group which entropically favors the approach of the reactive species; this is the first documented example of a. 1,3-dipolar cycloaddition in 7-alkenyl nitrones.

Full text of DOI:10.1081/CAR-120004333

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: http://www.tandfonline.com/loi/lcar20
STRATEGIES FOR THE SYNTHESIS OF
ENANTIOMERICALLY PURE MEDIUM-SIZED
CARBOCYCLES FROM CARBOHYDRATES
José Marco-Contelles & Elsa de Opazo
To cite this article: José Marco-Contelles & Elsa de Opazo (2002) STRATEGIES FOR
THE SYNTHESIS OF ENANTIOMERICALLY PURE MEDIUM-SIZED CARBOCYCLES FROM
CARBOHYDRATES, Journal of Carbohydrate Chemistry, 21:3, 201-218
To link to this article: http://dx.doi.org/10.1081/CAR-120004333
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J. CARBOHYDRATE CHEMISTRY, 21(3), 201–218 (2002)
STRATEGIES FOR THE SYNTHESIS
OF ENANTIOMERICALLY PURE
MEDIUM-SIZED CARBOCYCLES
FROM CARBOHYDRATES
*
Jose´ Marco-Contelles and Elsa de Opazo
Laboratorio de Radicales Libres (CSIC), C/ Juan de la Cierva 3;
28006 Madrid, Spain
ABSTRACT
A series of strategies (the Pauson–Khand reaction and the 1,3-dipolar
cycloaddition reaction) have been analyzed in order to develop new and
original synthetic protocols for the synthesis of enantiomerically pure
medium-sized carbocycles. The intramolecular Pauson–Khand reaction
on dideoxy-3,4:5,6-bis-O-(1-methylethylidene)-D/L-glycero-D-gluco-non-
1-en-8-ynitol (4) is a low yielding, but highly stereoselective acyclic
enyne precursor 1,2-procedure for the synthesis of bicyclo[5.3.0]de-
canones of type 5. In the second approach (‘‘the nitrone route’’), the
intramolecular nitrone cycloaddition of precursors 14 and 19 derived from
D-mannose has afforded the corresponding 9-oxa-8-azabicyclo[5.3.0]de-
canes as a mixture of trans fused isomers, in a critically dependent reac-
tion of a pre-existing isopropylidene group which entropically favors the
approach of the reactive species; this is the first documented example of a
1,3-dipolar cycloaddition in 7-alkenyl nitrones.
Key Words: Carbohydrates; Medium-sized carbocycles; Carbocycliza-
tion; Pauson-Khand reaction; 1,3 Dipolar cycloaddition reaction; Nitrones
*
Corresponding author. Fax: +3491-564-4853; E-mail: iqoc21@iqog.csic.es
201
Copyright D 2002 by Marcel Dekker, Inc.
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202
MARCO-CONTELLES AND DE OPAZO
INTRODUCTION
The synthesis of medium-sized rings, notably seven and eight-membered ring
systems, has been usually hampered by entropic/enthalpic factors and transannular
interactions between the methylene groups.[1a–1c] These are serious limiting factors
which have usually resulted in low chemical yields of the desired products.[2a–2c]
Although some solutions to this formidable challenge have been advanced using cyc-
loaddition or annulation strategies,[3] the cyclization approach for the synthesis of these
structures still remains a partially unsolved problem.[4a–4g] In view of these difficulties,
we reasoned that chiral, highly functionalized precursors derived from carbohydrates
could probably be excellent substrates in order to test the viability of these strategies
for the preparation of chiral, densely functionalized medium-sized rings. In fact, it is
now well recognized that carbohydrates form a large mass of readily available,
enantiomerically pure, cheap starting materials with a plethora of stereocenters which
can be easily modulated in suitable conformational and configurational terms for the
synthesis of natural products.[5]
In this paper we want to disclose the full details of our recent efforts on the
synthesis of seven-membered ring systems. We have particularly directed our attention
to the Pauson–Khand (PK) reaction[6a–6c] and to the 1,3-dipolar cycloaddition (1,3-
DC)[7] strategies. We have applied them to selected carbohydrate precursors in order to
investigate their scope, synthetic potential and limitations for the synthesis of seven-
membered ring systems. These synthetic efforts, due to the growing number of natural
compounds of this type with attractive biological/pharmacological activity,[8] pre-
sumably will be useful for a rational design directed to the synthesis of some members
of this family of molecules. A particularly important point in these reactions has been
the stereochemical outcome in the formation of new stereocenters.
RESULTS AND DISCUSSION
The Pauson–Khand Approach
In order to test the viability of the PK reaction for the synthesis of [5.3.0]fused
bicyclo decanones of type 5 in a single step, we prepared the conveniently substituted
acyclic enyne precursor 1,2-dideoxy-3,4:5,6-bis-O-(1-methylethylidene)-D/L-glycero-D-
gluco-non-1-en-8-ynitol (4) (Scheme 1).
The 5,7-fused structural motif is found in the hydrazulene skeleton present in the
guaianolide and pseudoguaianolide type of natural products.[9a,9b,10] Usual major stra-
tegies for the synthesis of bicyclo[5.3.0]decane structures rely on annulation stra-
tegies.[11a,11b] The PK approach for this purpose has been described, but until now the
reported results have not been very encouraging. Thus, the intermolecular PK reaction
of cycloheptene with differently substituted acetylenes has been studied, giving poor
chemical yields of the desired products.[12] Schore has developed a method based on
the fragmentation of the PK products resulting from the reaction of acetylenes with
bicyclo [3.2.0]hept-6-enes.[13] More recently, in a study of the PK reaction of a,o-
allenynes Cazes has reported the synthesis of some 6,6(1H)azulenedicarboxylic acid
derivatives.[14] Finally, others have described the intramolecular PK on 3-(prop-2-

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ENANTIOMERICALLY PURE MEDIUM-SIZED CARBOCYCLES
203
Scheme 1. Pauson–Khand reaction on precursor 4. Reagents: (a) Ph3P = CH2, THF, À 20ꢀC
(84%); (b) DMSO, DCC, CF3CO2H, rt, toluene (73%); (c) Ethynylmagnesium bromide, THF, 0ꢀC
(83%); (d) i. Co2(CO)8, ii. NMO. H2O, CH2Cl2, rt (14%); (e) Ac2O, Py, rt (90%).
ynylsulfanyl)cycloheptene with notable success; subsequent desulfuration gave the
desired bicyclo[5.3.0]decane framework. Note that in this case the convenient and
astute tactic needs a preformed cycloheptene ring template, a fact which limits the
scope of this method.[15] In summary, to the best of our knowledge the intramolecular
PK reaction of non-1-en-8-ynes has not been studied.[15b,15c] Prompted by this fact and
desiring convenient precursors for the synthesis of the chiral, highly functionalized
bicyclo[5.3.0]decanones present in most of the natural perhydroazulene class of ses-
quiterpenoids and in accordance with our project, we prepared compound 4 from the
readily available starting material 1,[16] derived from D-glucose, in a straightforward
manner (Scheme 1). Compound 4 was isolated as an unseparable 3:2 mixture of anti
and syn isomers in 83% yield. We have tentatively assigned the anti stereochemistry to
the major isomer, in agreement with similar results from literature;[17a,17b] this as-
signment has been unequivocally demonstrated in the ‘‘cyclic’’ derivative (see below).
The conventional protocol for the PK reaction applied to the mixture of isomers 4,
using chemical decomposition with N-N-oxide (NMO)[18] of the intermediate cobalt-
complex, afforded a 14% yield of a single product 5, which showed analytical and
spectroscopic data in good agreement with those expected for the normal PK product.
Additional proof was obtained from acetate 6, prepared by standard conditions from
alcohol 5 in 90% yield. From the structural point of view, particularly diagnostic were
the vicinal coupling constants for protons H-10a and H-10b (10.1 Hz in 5, and 10.4 Hz
in 6) (see Scheme. 1), a series of values which clearly point out that these protons are
trans, showing that the PK reaction has taken place to give exclusively the exo[19]
product. Regarding the stereochemistry at carbon C-7, a strong NOE effect between
protons H-6a and H-7 (5: J6a,7 =2.9 Hz; 6: J6a,7 =2.4 Hz) led us to conclude that the
configuration at this carbon is R. This would imply that only the major anti isomer in
product 4 has survived the PK reaction conditions, affording the only observed and
isolated adduct. The other epimer probably was decomposed during the cobalt-complex
intermediate transformation.
In Scheme 2 we show a possible mechanism for this PK transformation. In
agreement with the model proposed by Magnus,[20] the preferred intermediate complex
should be in a chair-like conformation with most of the substituents in pseudoequatorial

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204
MARCO-CONTELLES AND DE OPAZO
Scheme 2. Postulated transition state for the carbocyclization of the cobalt complex from
precursor 4.
orientations affording the observed exo-5 product. In support of this model the observed
coupling constant between protons H-2 and H-3 in compound 4-anti is J2,3 =8.1 Hz, a
value which places these protons in a preferred trans 1,3-parallel arrangement. In
summary, the first PK of a non-1-en 8-yne has been described, using a sugar
derivative as starting material, giving highly stereospecific exo bicyclo[5.3.0]dodeca-
nones in low yield. However, this is balanced by the simple access to the desired
target molecules and the ready availability of the intermediates.
The Nitrone Route
The Intramolecular Olefin–Nitrone Cycloaddition (INC) reaction[21] is one of the
best known and exploited 1,3-DC processes.[7] Since the pioneer work of LeBel[22] this
reaction has been largely used for the synthesis of a variety of carbocyclic or
heterocyclic systems in racemic or enantiomerically pure form. The majority of the
described intramolecular 1,3-DC reactions are those in which the alkene part is linked
to the carbon atom of the nitrone. In these cases bicyclic compounds of type [l.3.0] or
[l.2.1] and containing isoxazolidine moieties have been observed. In this context the
carbohydrate area[23] has been a particularly active domain, and different types of 5- or
6-alkenyl nitrones have been synthesized and submitted to 1,3-DC giving good yields
of the resulting isoxazolidines, whose nature and stereoselectivity were dependent on
the structure of the substrate.[24] However, in spite of these efforts, we were surprised
to see that, at least to the best of our knowledge, 7-alkenyl nitrones have not yet been
tested in the 1,3-DC.[25] This was very interesting for our purposes and prompted us to
synthesize the INC precursors 14 and 19 (Scheme 3).[26]
These precursors have been obtained from D-mannose via the known di-O-benzyl
derivative 7[27] (Scheme 3). After acetal mediated acid hydrolysis, a mixture of the
tetrol 8 and diol 9 was isolated. Both molecules were transformed following parallel
synthetic sequences: 1) silylation at C-6; 2) O-protection at C2-, C-4 and C-5 (or at C-2
as O-methyl ethers); 3) desilylation; 4) oxidation; and 5) nitrone formation. All new
compounds showed analytical and spectroscopic data in good agreement with these
structures. With the desired precursors in our hands we checked the key INC reaction.
Not surprisingly compound 14 was reluctant to undergo the 1,3-DC reaction, and it was
recovered unchanged after heating a solution of this material in chlorobenzene for an
extended period of time. We were pleased to see that precursor 19, under the same
conditions, afforded a mixture of isoxazoliodines 20 and 21 in 50% yield, as a 3:2
mixture of isomers (Scheme 4), which we were unable to separate. The spectroscopic

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ENANTIOMERICALLY PURE MEDIUM-SIZED CARBOCYCLES
205
Scheme 3. Synthesis of precursors (14 and 19) for the INC reaction. Reagents: (a) Ref. [29]; (b)
AcOH/H2O (4:1), rt (8: 78%; 9: 20%); (c) ClSitBuPh2, Py, DMAP, 0ꢀC (for 8 to 10: 83%), (for 9 to
15: 99%); (d) NaH, IMe, Bu4NI, THF, 0ꢀC (for 10 to 11: 60%), (for 15 to 16: 74%); (e) Bu4NF,
THF, rt (for 11 to 12: 93%; for 16 to 17: 92%); (f) PCC, CH2Cl2, NaAcO, rt, molecular sieves (for
12 to 13: 85%; for 17 to 18: 93%); (g) PhCH2NHOH.HCl, Py, CH2Cl2, reflux (for 13 to 14: 74%;
for 18 to 19: 65%).
analysis of this mixture was difficult, as most of the signals were overlapping, and this
fact complicated the structural determination. However, after a detailed 1H and 13C
NMR analysis and complementary experiments (1H-1H COSY, HMQC, NOESY) it was
soon evident that the reaction proceeded to give the corresponding bicyclic isoxazo-
lidines as a mixture of only trans isomers at carbons C-3a and C-9a. In fact, the
absence of any signal around 26.0 ppm in the 13C NMR spectrum excluded the al-
ternative compounds with a methylene in the bridge position. Conversely, we have
found and identified specific and diagnostic signals for major isomer 20 [(d) 44.5 (C-
3a), 67.7 (C-9a); 3.80 (t, J3,3a =J3,3’ = 7.4 Hz, 1 H, H-3), 3.53 (dd, J3,3’ = 7.4 Hz,

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206
MARCO-CONTELLES AND DE OPAZO
J3’,3a =10.7 Hz, 1 H, H-3’), 2.69 (dt, J3,3a =7.4 Hz, J3’,3a =J9a,3a = 10.7 Hz, 1 H, H-3a)]
and for the minor isomer 21 [(d) 42.4 (C-3a), 67.5 (C-9a); 4.07 (t, J3,3’ =J3a,3’ = 7.6 Hz,
1 H, H-3’), 3.68 (dd, J3,3a =10.9 Hz, J3,3’ = 7.6 Hz, 1 H, H-3), 3.62 (d, J9,9a = 10.1 Hz, 1
H, H-9), 3.14 (br t, J9.,9a =J9a,3a = 10.1 Hz, 1 H, H-9a)] that strongly support the
absolute configuration at the newly formed stereocenters. These data (particularly the
vicinal coupling constants of J3a,9a) coupled to the absence of an NOE effect between
the protons at the carbon atoms C-3a and C-9a, led us to tentatively conclude that
compounds 20 and 21 are the trans isomers at these carbons.[28] An inspection of
molecular models supported these assumptions.
In Scheme 4 we show a simple and possible rationale in order to explain the
stereochemical outcome of this INC reaction. As shown, for the transition states leading
to the carbocyclic products we propose a boat-like conformation, slightly preferred in
terms of steric interactions, and a chair-like conformation with the alkene and the
nitrone termini of the reaction in pseudoequatorial orientations to give the major and
minor, 20 and 21 isomers, respectively. Note also that in this conformation the nitrone
and the carbon of the dipolarophile are at convenient distance for the reaction to take
place. In addition, and due to the forcing experimental conditions, we have assumed
that only the E nitrone is operative in the reaction medium.[29] An interesting point also
Scheme 4. INC of nitrone 19 in chlorobenzene at 130ꢀC.

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ENANTIOMERICALLY PURE MEDIUM-SIZED CARBOCYCLES
207
to comment upon is the unsuccessful attempt to promote the INC in nitrone 14. This is
a nice example of the difficulties found in preparing seven-membered ring systems due
to entropic factors. Compared with the success in nitrone 19, it is clear that the
presence of an external functional moiety, the isopropylidene group here, overrides
other negative factors, and presumably influences the reacting partners by reducing the
conformational freedom of the molecule. Examples of the benefit of the isopropylidene
group, or other similar templates,[30] are known and have been used in our laboratory
very recently.[31a–31c]
In summary, we have shown that the INC reaction of 7-alkenyl nitrone (19)
derived from D-mannose is possible, gives a moderate yield of the expected 9-oxa-8-
azabicyclo[5.3.0]decane derivatives as a mixture of trans fused isomers. In addition, we
have found that this reaction is critically dependent on a pre-existing isopropylidene
group that favors the approach of the termini of the reacting partners.
EXPERIMENTAL
General Methods. Reactions were monitored by TLC using precoated silica gel
aluminum plates containing a fluorescent indicator (Merck, 5539). Detection was done
by UV (254 nm) followed by charring with sulfuric-acetic acid spray, 1% aqueous
potassium permanganate solution or 0.5% phosphomolybdic acid in 95% EtOH. An-
hydrous Na2SO4 was used to dry organic solutions during work-ups, and the removal
of solvents was carried out under vacuum with a rotary evaporator. Flash column
chromatography was performed using silica gel 60 (230–400 mesh, Merck) and hex-
ane/ethyl acetate mixtures as eluent unless otherwise stated. 1H NMR spectra were
recorded with a Varian VXR-300(400)S spectrometer, using tetramethylsilane as
internal standard and 13C NMR spectra were recorded with a Bruker WP-200-SY.
Values with (*) can be interchanged. The MS spectra were recorded in a Hewlett
Packard MDS 5973 or in a Hewlett Packard MSD 1100 (for the electrospray expe-
riments, positive mode) spectrometer.
General Procedure (GP) for Grignard Addition. To a solution of the aldehyde in
dry THF (1 M) under argon at 0ꢀC, the Grignard reagent (4 equiv, 0.5 M in THF) was
added, and the mixture was stirred for 1 h. Then, an aqueous saturated solution of
ammonium chloride was added, and the mixture was extracted with ethyl acetate
several times. The organic phase was washed with brine, dried, concentrated and the
residue submitted to chromatography to give the corresponding alcohols as a mixture of
syn amd anti products.
General Procedure (GP) for Oxidation with PCC. To a suspension of the alcohol
sodium acetate (0.3 equiv), powdered molecular sieves and PCC (2 equiv) were added.
The mixture was stirred at rt for 4 h. Then, the reaction was filtered over Celite, and
the filtrate was concentrated. The residue was submitted to chromatography.
General Procedure (GP) for Silylation Reactions. The compound was dissolved in
dry pyridine (0.12 M) and cooled to 0ꢀC. Then 4-dimethylaminopyridine (0.1 equiv)
and t-butyldiphenylsilyl chloride (1 equiv) were added under argon. The mixture was

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MARCO-CONTELLES AND DE OPAZO
stirred at rt for 24 h. The solvent was removed, the residue was taken up in ethyl
acetate and washed with brine. The organic phase was dried, filtered and concentrated.
The residue was submitted to chromatography.
General Procedure (GP) for Desilylation Reactions. The compound was dissolved in
dry THF (0.14 M) and treated with tetrabutylammonium fluoride (3 equiv) at rt for 24 h.
The solvent was evaporated, and the residue was submitted to chromatography.
General Procedure (GP) for the Synthesis of Nitrones. A 0.1 M solution of the
aldehyde, N-benzylhydroxylamine hydrochloride (3.1 equiv) and pyridine (3.5 equiv)
in CH2Cl2 was refluxed for 12 h. The solvent was eliminated, the residue was diluted
with ethyl acetate, washed with brine, the organic phase was dried, filtered and con-
centrated, and the residue was submitted to chromatography.
General Procedure (GP) for Acetylation. The compound was treated with a mixture
of acetic anhydride/pyridine (1/1, v/v) at rt overnight. The solvent was evaporated, and
the residue was submitted to chromatography.
General Procedure (GP) for Acetal Hydrolysis. The compound was dissolved in a
mixture of AcOH/H2O (7:3) at rt until complete reaction (18–24 h). The solvent was
evaporated, and the residue was submitted to chromatography.
General Procedure (GP) for O-alkylation (Benzylations or Methylation). The
compound, dissolved in dry THF (0.2 M), under argon and at 0ꢀC, was treated with
sodium hydride (1.5 equiv, 60% dispersion in oil), a catalytic amount of tetrabutyl-
ammonium iodide and benzyl bromide or methyl iodide (1.1 equiv). After stirring at rt
for 15 h, the reaction was complete, and some drops of AcOH were added. Then the
mass was filtered over Celite. The filtrate was concentrated, diluted with water, ex-
tracted with CH2Cl2 several times and washed with brine. The organic layer was dried
and filtered. The filtrate was concentrated and chromatographed.
1,2-Dideoxy-3,4:5,6-bis-(1-O-methylethylidene)-D-gluco-hept-1-enitol (2). To a sus-
pension of hemiacetal 1[16] (1.15 g, 4.41 mmol) and triphenylphosphonium bromide
(4.91 g, 13.7 mmol, 2 equiv) in dry THF (7 mL), cooled at À 20ꢀC, under argon,
n-BuLi (5.5 mL, 8.8 mmol, 1.6 M in hexane) was slowly added. The mixture was
stirred at rt for 2 h and quenched with an aqueous saturated solution of ammonium
chloride. Then, the mixture was diluted with methylene chloride, washed with an
aqueous saturated solution of sodium bicarbonate, brine, dried, filtered and concen-
trated. The residue was submitted to flash chromatography (hexane/ethyl acetate: 7/3)
25
to give compound 2 (960 mg, 84%): oil; [a]D À 12 (c 0.23, CHCl3); IR (film) n 3460
1
(OH), 2986, 2936 1380, 1216, 1050 cmÀ1; H NMR (300 MHz, CDCl3) d 5.79 (ddd,
J1,2 =17.3 Hz, J1’,2 = 10.1 Hz, J2,3 =7.6 Hz, 1 H, H-2), 5.41 (dm, J1,2 = 17.3 Hz, 1 H, H-
1), 5.28 (dm, J1’,2 = 10.1 Hz, 1 H, H-1’), 4.45 (dd, J3,4 =8.6 Hz, J2,3 = 7.6 Hz, 1 H, H-3),
4.23 (dt, J6,7 =J6,7’ = 5.2 Hz, J5,6 = 6.7 Hz, 1 H, H-6), 4.05 (dd, J5,6 =6.7 Hz, J4,5 =1.7
Hz, 1 H, H-5), 3.76 (t, J6,7 = J7,OH =5.2 Hz, 2 H, H-7), 3.68 (dd, J3,4 = 8.6 Hz, J4,5 =1.7
Hz, 1 H, H-4), 2.84 (t, J7,OH = 5.2 Hz, 1 H, OH), 1.50, 1.42 (2 s), 1.35 [4 s,
2Â OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) d 134.4 (C-2), 120.1 (C-1), 109.8, 108.8

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ENANTIOMERICALLY PURE MEDIUM-SIZED CARBOCYCLES
209
[2 C, 2 Â OC(CH3)2O], 79.3 (C-3), 78.2 (C-6), 77.2 (C-4), 73.3 (C-5), 61.3 (C-7), 27.1,
26.8, 26.4, 25.5 [4 C, 2 Â OC(CH3)2O]; MS (70 eV) m/z 243 (M + À 15, 12), 141 (5),
127 (21), 113 (10), 98 (36), 69 (52), 43 (100).
Anal. Calcd for C13H22O5: C, 60.45; H, 8.58. Found: C, 60.30; H, 8.81.
6,7-Dideoxy-2,3:4,5-bis-(1-O-methylethylidene)-L-manno-hept-6-enose (3). To a
solution of alcohol 2 (122 mg, 0.47 mmol), DMSO (0.8 mL, 11.0 mmol, 23.5 equiv),
DCC (293 mg, 1.4 mmo, 3 equiv), pyridine (0.04 mL, 0.47 mL, 1 equiv) in dry toluene
(1.6 mL, 0.3 M), trifluoroacetic acid (0.02 mL, 0.23 mmol, 0.5 equiv) was added. The
mixture was stirred at rt for 1.5 h. Then, ethyl acetate was added, and the precipitated
dicyclohexylurea was eliminated by filtration. The filtrate was washed with brine,
dried, concentrated, and the residue was submitted to chromatography (hexane/ethyl
1
acetate, 91/9) to give aldehyde 3 (84 mg, 73%) as an oil: H NMR (300 MHz, CDCl3)
d 9.64 (d, J1,2 = 2.3 Hz, 1 H, H-1), 5.79 (ddd, J6,7 =17.4 Hz, J6,7’ =10.3 Hz, J5,6 =7.6
Hz, 1 H, H-6), 5.42 (dt, J6,7 =17.4 Hz, J7,7’ =J7,5 = 1.1 Hz, 1 H, H-7), 5.28 (dt,
J
6,7’ = 10.3 Hz, J7,7’ = J7’,5 =1.1 Hz, 1 H, H-7’), 4.47 (dd, J5,6 = 7.6 Hz, J4,5 = 8.3 Hz, 1 H,
H-5), 4.43 (dd, J1,2 =2.3 Hz, J2,3 =8.4 Hz, 1 H, H-2), 4.33 (dd, J2,3 =8.4 Hz, J3,4 =1.5
Hz, 1 H, H-3), 3.68 (dd, J3,4 =1.5 Hz, J4,5 = 8.3 Hz, 1 H, H-4), 1.60, 1.40, 1.39, 1.36 [4
s, 2Â OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) d 201.5 (C-1), 134.5 (C-6), 119.9 (C-
7), 111.4, 109.7 [2 C, 2 Â OC(CH3)2O], 81.0 (C-4)*, 78.5 (C-5)*, 77.9 (C-3)**, 75.2
(C-2)**, 27.2, 26.6, 26.5, 25.3 [4 C, 2 Â OC(CH3)2O].
Anal. Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C, 60.77; H, 7.80.
1,2-Dideoxy-3,4:5,6-bis-(1-O-methylethylidene)-D/L-glycero-D-gluco-non-1-en-8-yni-
tol (4). Following the GP for Grignard addition, aldehyde 3 (110 mg, 0.43 mmol) was
treated with ethynylmagnesium bromide (3.45 mL, 1.7 mmol, 4 equiv, 0.5 M in THF)
to give 4 (101 mg, 83%), as an unseparable mixture of anti and syn isomers in 6 to 4
ratio, respectively, after chromatography (hexane/ethyl acetate, 3/1): oil; IR (film) n
1
3428 (OH), 2988, 1382, 1219, 1045 cmÀ1; H NMR (300 MHz, CDCl3) (major isomer
anti) d 5.85 (ddd, J1,2 = 17.4 Hz, J1’,2 = 10.4 Hz, J2,3 =8.1 Hz, 1 H, H-2), 5.45 (d,
J1,2 = 17.4 Hz, 1 H, H-1), 5.33 (dd, J1’,2=10.4 Hz, J1,1’ =0.6 Hz, 1 H, H-1’), 4.67 (ddd,
J6,7 = 6.0 Hz, J7,9 =2.2 Hz, J7,OH =8.2 Hz, 1 H, H-7), 4.56 (t, J2,3 =J3,4 = 8.1 Hz, 1 H, H-
3), 4.24 (dd, J5,6 =J6,7 = 6.0 Hz, 1 H, H-6), 4.16 (d, J5,6 = 6.6 Hz, 1 H, H-5), 4.14 (d,
J3,4 = 8.1 Hz, 1 H, H-4), 4.03 (d, J7,OH = 8.2 Hz, 1 H, OH), 2.47 (d, J7,9 = 2.2 Hz, 1 H,
H-9), 1.57, 1.54, 1.48, 1.47 [4 s, 2ÂOC(CH3)2O]; 13C NMR (75 MHz, CDCl3) d 134.2
(C-2), 120.1 (C-1), 109.8, 109.0 [2 C, 2ÂOC(CH3)2O], 82.4 (C-8), 79.3 (C-1), 78.7 (C-
7), 77.2 (C-4), 73.7 (C-6), 73.0 (C-5), 61.3 (C-7), 27.1, 26.7, 26.3, 25.4 [4 C,
2ÂOC(CH3)2O]; MS (70 eV) m/z 282 (M, 8), 149 (30), 105 (22), 91 (100), 57 (38).
Anal. Calcd for C15H22O5: C, 63.81; H, 7.85. Found: C, 63.65; H, 7.81.
[3aR-(3aa,3bb,6ab,7b,10aa,10bb)]-(3a,3b,6a,7,9,10a,10b)-Heptahydro-7-hydroxy-
2,2,5,5,-tetramethylazuleno[4,5-d; 6,7-d]bis[1,3-dioxol]-9-one (5). To a solution of
enyne 4 (100 mg, 0.35 mmol) in dry methylene chloride (14.2 mL, 0.025M), under
argon, at rt, octacarbonyldicobalt (134 mg, 0.39 mmol, 1.1 equiv) was added. After 30
min, the mixture was cooled to 0ꢀC and NMO. H2O (303 mg, 2.2 mmol, 6.3 equiv)
was added, and the mixture was stirred for 6 h. Then, the mixture was filtered over
Celite, the filtrate was concentrated, and the residue was submitted to chromatography

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210
MARCO-CONTELLES AND DE OPAZO
(hexane/ethyl acetate, 65/35) to give 5 (20 mg, 14%): oil; [a]D25 +20 (c 0.17, CHCl3);
1
IR (film) n 3436 (OH), 2932, 1718 (C=O), 1624 (C= C), 1374, 1214, 1051 cm À 1; H
NMR (300 MHz, CDCl3) d 6.18 (s, 1 H, H-8), 5.01 (d, J6a,7 = 2.9 Hz, 1 H, H-7), 4.58
(t, J3a,3b =J3a,10b =8.9 Hz, 1 H, H3a), 4.26 (t, J3a,3b =J6a,3b =8.9 Hz, 1 H, H3b), 4.14
(dd, J6a,7 = 2.9 Hz, J6a,3b =8.9 Hz, 1 H, H-6a), 3.39 (ddd, J10a,10 = 6.4 Hz, J10a,10b =10.1
Hz, J10a,10’ =1.3 Hz, 1 H, H-10a), 3.23 (dd, J10a,10b = 10.1 Hz, J10b,3a =9.0 Hz, 1 H, H-
10b), 2.71 (dd, J10,10’ = 19.4 Hz, J10a,10 =6.4 Hz, 1 H, H-10), 2.73 (s, 1 H, OH), 2.45
(dd, J10,10’ =19.4 Hz, J10a,10’ =1.3 Hz, 1 H, H-10’), 1.59 (s), 1.46 (s), 1.40 (s), 1.39 (s)
[2 Â OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) d 207.3 (C-9), 172.7 (C-7a), 134.5 (C-
8), 110.1, 109.9 [2 C, 2 Â OC(CH3)2O], 80.6 (C-10b), 78.8 (C-3a), 78.0 (C-6a),
77.3 (C-3b), 71.3 (C-7), 42.1 (C-10a), 40.2 (C-10), 29.8, 27.2, 26.5, 23.4 [4 C,
2Â OC(CH3)2O]; MS (70 eV) m/z 310 (M+, 10), 295 (M + À 15, 21), 194 (27), 124
(23), 110 (18), 43 (100).
Anal. Calcd for C16H22O6: C, 61.92; H, 7.15. Found: C, 62.02; H, 7.40.
[3aR-(3aa,3bb,6ab,7b,10aa,10bb)]-7-Acetoxy-(3a,3b,6a,7,9,10a,10b)-heptahydro-
2,2,5,5,-tetramethylazuleno[4,5-d;6,7-d]bis[1,3-dioxol]-9-one (6). Compound 5 (20
mg, 0.064 mmol) was treated with Ac2O/pyridine (1 mL, 1:1) at rt for 24 h. The
solvents were removed and the residue was submitted to chromatography (hexane/ethyl
acetate, 1/1) to give acetate 6 (19 mg, 90%): oil; [a]D25 +21 (c 0.44, CHCl3); IR (film)
1
n 2986, 1748 (O =CCH3O), 1719 (C= O), 1624 (C= C), 1373, 1225, 1073 cm À 1; H
NMR (300 MHz, CDCl3) d 6.26 (s, 1 H, H-8), 6.06 (d, J6a,7 = 2.3 Hz, 1 H, H-7), 4.38
(dd, J3a,3b = 8.0 Hz, J3a,10b’ =9.0 Hz, 1 H, H3a), 4.33 (t, J3a,3b =J6a,3b = 7.7 Hz, 1 H,
H3b), 4.19 (dd, J6a,7 =2.3 Hz, J6a,3b = 7.7 Hz, 1 H, H-6a), 3.32 (dd, J10b,3a = 9.0 Hz,
J10a,10b =10.4 Hz, 1 H, H-10b), 3.11 (ddd, J10a,10b = 10.1 Hz, J10b,10A =6.4 Hz,
J10b,10B =1.7 Hz, 1 H, H-10a), 2.70 (dd, J10A,10B =19.4 Hz, J10a,10A =6.4 Hz, 1 H, H-
10A), 2.45 (dd, J10A,10B = 19.4 Hz, J10a,10B = 1.7 Hz, 1 H, H-10B), 2.17 (s, 3 H,
OCOCH3), 1.49 (2s), 1.42 (s), 1.36 (s) [2 Â-OC(CH3)2O]; 13C NMR (75 MHz, CDCl3)
d 206.5 (C-9), 169.4 (OCOCH3), 169.8 (C-7a), 135.4 (C-8), 110.7 [2 C, 2 Â OC(CH3)2O],
79.9 (C-10b), 79.4 (C-3a), 78.2 (C-3b), 77.4 (C-6a), 72.3 (C-7), 42.9 (C-10a), 40.1 (C-
10), 27.3, 27.1, 26.6, 24.3 [4 C, 2 Â OC(CH3)2O], 21.1 (OCOCH3); MS (70 eV) m/z 337
(M + +1, 18), 310 (7), 177 (19), 149 (14), 43 (100).
Anal. Calcd for C18H24O6: C, 64.27; H, 7.19. Found: C, 64.67; H, 7.05.
7,8-Dideoxy-3,6-bis-O-(phenylmethyl)-D-glycero-D-manno-oct-7-enitol (8) and 7,8-
dideoxy-4,5-O-(1-methylethylidene)-3,6-bis-O-(phenylmethyl)-D-glycero-D-manno-
oct-7-enitol (9). Following the GP for acetal acid hydrolysis compound 7 (27) (1.6 g,
3.4 mmol) afforded compounds 8 (1.0 g, 78%) and 9 (293 mg, 20%), after chro-
25
matography (hexane/ethyl acetate, 7/3). 8: oil; [a]D À 3 (c 3.2, CHCl3); IR (film) n
1
3500 À 3300, 1550, 1460, 1150, 1090 cmÀ1; H NMR (300 MHz, CDCl3) d 7.33 À 7.18
(m, 10 H, aromat.), 5.83 (ddd, J7,8 =18.7 Hz, J7,8’ = 10.7 Hz, J6,7 = 7.9 Hz, 1 H, H-7),
5.34 (dd, J7,8 = 18.7 Hz, J8,8’ =1.7 Hz, 1 H, H-8), 5.30 (dd, J7,8’ =10.7 Hz, J8,8’ = 1.7 Hz,
1 H, H8’), 4.63/4.56 (AB system, J =11.3 Hz, 2 H, OCH2C6H5), 4.60/4.30 (AB system,
J =11.7 Hz, 2 H, OCH2C6H5), 4.02 (dd, J6,7 = 7.8 Hz, J5,6 =3.2 Hz, 1 H, H-6),
3.78 À 3.71 (m, 4 H, H-2, H-3, H-4, H-5), 3.65 (br d, J1,1’ =11.0 Hz, 1 H, H-1), 3.52 (br
dd, J1,1’ = 11.0 Hz, J1’,2 =4.6 Hz, 1 H, H-1’), 3.12 (br s, 3 H, OH), 2.89 (br s, 1 H, OH);
13C NMR (75 MHz, CDCl3) d 137.8 À 127.9 (2 Â OCH2C6H5), 133.9 (C-7), 120.9 (C-8),

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ENANTIOMERICALLY PURE MEDIUM-SIZED CARBOCYCLES
211
81.9 (C-5), 77.4 (C-4), 73.8 (C-6), 72.9 (OCH2C6H5), 71.9 (C-3), 71.3 (C-2), 70.5
(OCH2C6H5), 63.6 (C-1); MS: Calcd for C22H28O6 Na (M + Na) + : 411.5. Found: 411.1.
25
9: oil; [a]D À 9 (c 0.2, CHCl3); IR (film) n 3500 À 3300, 1550, 1460, 1150, 1090 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 7.39 À 7.21 (m, 10 H, aromat.), 5.82 (ddd, J7,8 =17.1 Hz,
J
7,8’ = 10.2 Hz, J6,7 =7.9 Hz, 1 H, H-7), 5.49 (dd, J7,8 = 10.2 Hz, J8,8’ =1.5 Hz, 1 H, H-8),
5.35 (dd, J7,8’ =17.1 Hz, J8,8’ =1.5 Hz, 1 H, H8’), 4.62 (s, 2 H, OCH2C6H5), 4.60/4.13
(AB system, J = 11.0 Hz, 2 H, OCH2C6H5), 4.39 (dd, J3,4 =7.1 Hz, J4,5 =5.1 Hz, 1
H, H-4), 4.17 (dd, J1,1’ =10.0 Hz, J1,2 = 4.7 Hz, 1 H, H-1), 3.97 (br t, J5,6 = J6,7 =7.9
Hz, 1 H, H-6), 3.65 À 3.53 (m, 3 H, H-1’, H-3, H-5), 3.42 À 3.30 (m, 3 H, H-2,
2 Â OH), 1.49, 1.38 [2 s, OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) d 138.3À127.7
(2 Â OCH2C6H5), 135.4 (C-7), 120.7 (C-8), 108.5 [OC(CH3)2O], 80.3 (C-5), 79.0 (C-4),
78.3 (C-6), 74.7 (C-3), 73.1 (OCH2C6H5), 72.9 (C-2), 69.9 (OCH2C6H5), 64.3 (C-1),
27.5, 25.7 [OC(CH3)2O]; MS: Calcd for C25H32O6 Na (M +Na) +: 451.5. Found: 451.2.
Anal. Calcd for C25H32O6: C, 70.07; H, 7.53. Found: C, 69.77; H, 7.45.
7,8-Dideoxy-1-O-[(1,1-dimethylethyl)diphenylsilyl]-3,6-bis-O-(phenylmethyl)-D-gly-
cero-D-manno-oct-7-enitol (10). Following the GP for silylation reactions compound
8 (1.0 g, 2.64 mmol) gave product 10 (1.37 g, 83%) after chromatography (hexane/ethyl
acetate, 7/3): oil; [a]D25 +6 (c 0.11, CHCl3); IR (film) n 3600 À 3200, 3020, 2990, 1530,
1470, 1370, 1200 cm À 1; 1H NMR (300 MHz, CDCl3) d 7.71 À 7.68/ 7.44 À 7.10 (m, 20
H, aromat.), 5.97 (ddd, J7,8 =17.8 Hz, J7,8’ =10.6 Hz, J6,7 = 8.0 Hz, 1 H, H-7), 5.47 (dd,
J7,8 = 10.6 Hz, J8,8’ =1.7 Hz, 1 H, H-8), 5.43 (dd, J7,8’ = 17.8 Hz, J8,8’ = 1.7 Hz, 1 H, H8’),
4.67/4.43 (AB system, J =11.7 Hz, 2 H, OCH2C6H5), 4.62 (s, 2 H, OCH2C6H5), 4.15
(dd, J6,7 = 8.0 Hz, J5,6 =3.8 Hz, 1 H, H-6), 3.99 (st, J1,2 =J1’,2 = J2,3 =J2,OH = 5.1 Hz, 1 H,
H-2), 3.95 À 3.85 (m, 4 H, H-1, H-3, H-4, H-5), 3.76 (dd, J1,1’ =10.2 Hz, J1,2 = 5.4 Hz, 1
H, H-1’), 2.96 (d, J2,OH =5.1 Hz, 1 H, OH), 2.85 (d, J =7.2 Hz, 1 H, OH), 2.53 (d, J =2.9
Hz, 1 H, OH), 1.11 [s, 9 H, Si(C6H5)2C(CH3)3]; 13C NMR (75 MHz, CDCl3) d
138.2 À 127.7 [2 Â OCH2C6H5, Si(C6H5)2C(CH3)3], 133.9 (C-7), 120.5 (C-8), 81.7 (C-
5), 76.4 (C-4), 73.6 (OCH2C6H5), 72.9 (C-6), 71.7 (C-3), 70.7 (C-2), 70.5 (OCH2C6H5),
64.9 (C-1), 26.9 [Si(C6H5)2C(CH3)3], 19.2 [Si(C6H5)2C(CH3)3]; MS: Calcd for
C38H46O6 NaSi (M +Na) +: 649.8. Found: 649.3.
Anal. Calcd for C38H46O6: C, 76.22; H, 7.74. Found: C, 76.58; H, 7.48.
7,8-Dideoxy-1-O-[(1,1-dimethylethyl)diphenylsilyl]-2,4,5-tri-O-methyl-3,6-bis-O-
(phenylmethyl)-D-glycero-D-manno-oct-7-enitol (11). Following the GP for O-meth-
ylation compound 10 (1.3 g, 2.18 mmol) afforded compound 11 (887 g, 60%) after
25
chromatography (hexane/ethyl acetate: 95/5): oil; [a]D À 14 (c 0.36, CHCl3); IR (film)
n 3020, 2900, 1400, 1100 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 7.65 À 7.58/
7.36 À 7.12 (m, 20 H, aromat.), 5.94 (ddd, J7,8 =17.3 Hz, J7,8’ =10.4 Hz, J6,7 =7.6 Hz, 1
H, H-7), 5.32 (dd, J7,8 = 10.4 Hz, J8,8’ = 1.9 Hz, 1 H, H-8), 5.25 (dd, J7,8’ =17.3 Hz,
J
8,8’ = 1.9 Hz, 1 H, H8’), 4.61/4.33 (AB system, J = 11.5 Hz, 2 H, OCH2C6H5), 4.56/4.52
(AB system, J =6.6 Hz, 2 H, OCH2C6H5), 4.05 (dd, J6,7 = 7.8 Hz, J5,6 =2.3 Hz, 1 H, H-
6), 3.90 (dd, J1,1’ =11.5 Hz, J1,2 =1.6 Hz, 1 H, H-1), 3.89 (t, J2,3 =J3,4 = 2.1 Hz, 1 H, H-
3), 3.79 (dd, J1,1’ = 11.5 Hz, J1’,2 = 4.4 Hz, 1 H, H-1’), 3.61 (dd, J4,5’ =8.3 Hz, J5,6 =2.3
Hz, 1 H, H-5), 3.41 (dd, J4,5’ = 8.3 Hz, J3,4 =2.1 Hz, 1 H, H-4), 3.38 (s, 3 H, OCH3),
3.36 À 3.32 (m, 1 H, H-2), 3.31 (s, 3 H, OCH3), 3.20 (s, 3 H, OCH3), 1.00 [s, 9 H,
Si(C6H5)2C(CH3)3]; 13C NMR (75 MHz, CDCl3) d 138.9 À 127.3 [2 Â OCH2C6H5,

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212
MARCO-CONTELLES AND DE OPAZO
Si(C6H5)2C(CH3)3], 133.8 (C-7), 119.1 (C-8), 82.3 (C-5), 81.7 (2 C, C-2, C-4), 79.9 (C-
6), 75.3 (C-3), 74.1 (OCH2C6H5), 70.6 (OCH2C6H5), 65.3 (C-1), 60.0, 59.1, 57.5 (3 C,
3 Â OCH3), 29.7 [Si(C6H5)2C(CH3)3], 19.3 [Si(C6H5)2C(CH3)3]; MS: Calcd for
C41H52O6 NaSi (M +Na) +: 691.9. Found: 691.3.
Anal. Calcd for C41H52O6: C, 76.84; H, 8.18. Found: C, 76.77; H, 8.06.
7,8-Dideoxy-2,4,5-tri-O-methyl-3,6-bis-O-(phenylmethyl)-D-glycero-D-manno-oct-7-
enitol (12). Following the GP for desilylation reactions compound 11 (790 mg, 1.2
mmol) gave product 12 (470 g, 93%) after chromatography (hexane/ethyl acetate, 85/
25
15): oil; [a]D À 2 (c 0.11, CHCl3); IR (film) n 3600À 3200, 3010, 2990, 1460, 1090
cm À 1
;
1H NMR (300 MHz, CDCl3) d 7.30 À 7.17 (m, 10 H, aromat.), 5.89 (ddd,
J7,8 =17.7 Hz, J7,8’ =10.5 Hz, J6,7 =7.6 Hz, 1 H, H-7), 5.32 (dd, J7,8 =10.5 Hz, J8,8’ =1.7
Hz, 1 H, H-8), 5.26 (dd, J7,8’ =17.7 Hz, J8,8’ =1.7 Hz, 1 H, H8’), 4.63/4.59 (AB system,
J =11.5 Hz, 2 H, OCH2C6H5), 4.55/4.32 (AB system, J =11.8 Hz, 2 H, OCH2C6H5), 4.05
(dd, J6,7 = 7.9 Hz, J5,6 =2.8 Hz, 1 H, H-6), 3.85 (dd, J2,3 = 3.1 Hz, J3,4 =6.6 Hz, 1 H, H-3),
3.81 (br d, J1,1’ =4.8 Hz, 1 H, H-1), 3.69 À 3.65 (m, 1 H, H-1’), 3.55 (dd, J4,5’ = 7.8 Hz,
J5,6 =2.8 Hz, 1 H, H-5), 3.37 (s, 3 H, OCH3), 3.36 (s, 3 H, OCH3), 3.35 À 3.27 (m, 2 H, H-
2, H-4), 3.27 (s, 3 H, OCH3), 2.05 (br d, J =5.4 Hz, 1 H, OH); 13C NMR (75 MHz, CDCl3)
d 138.3 À 127.2 (2 Â OCH2C6H5), 134.6 (C-7), 119.1 (C-8), 81.9 (C-5), 81.0, 80.6 (2 C,
C-2, C-4), 79.7 (C-6), 77.1 (C-3), 74.1 (OCH2C6H5), 70.2 (OCH2C6H5), 59.9 (OCH3),
59.0 (C-1), 58.8, 56.3 (2 C, 2 Â OCH3); MS: Calcd for C25H34O6 Na (M +Na) +: 453.6.
Found: 453.5.
Anal. Calcd for C25H34O6: C, 69.74; H, 7.96. Found: C, 69.68; H, 7.85.
1,7,8-Trideoxy-2,4,5-tri-O-methyl-1-[oxido(phenylmethyl)imino]3,6-bis-O-(phenyl-
methyl)-D-glycero-D-manno-oct-7-enitol (14). Following the GP for oxidation via
PCC compound 12 (110 mg, 0.25 mmol) afforded 13 (93 mg, 85%) after chroma-
1
tography (hexane/ethyl acetate, 75/25), H NMR (300 MHz, CDCl3) d 9.63 (d, J1,2 =2.0
Hz, 1 H, H-1), 7.35 À 7.24 (m, 10 H, aromat.), 5.95 (ddd, J7,8 = 17.1 Hz, J7,8’ =10.2 Hz,
J6,7 =7.6 Hz, 1 H, H-7), 5.42 (dd, J7,8 =10.2 Hz, J8,8’ = 1.9 Hz, 1 H, H-8), 5.34 (dd,
J
7,8’ =17.1 Hz, J8,8’ =1.9 Hz, 1 H, H8’), 4.65 (s, 2 H, OCH2C6H5), 4.63/4.38 (AB
system, J =11.7 Hz, 2 H, OCH2C6H5), 4.11 (dd, J6,7 =7.6 Hz, J5,6 = 3.9 Hz, 1 H, H-6),
4.07 (t, J2,3 = J3,4 =4.0 Hz, 1 H, H-3), 3.81 (dd, J2,3 =4.3 Hz, J1,2 =2.0 Hz, 1 H, H-2),
3.63 (dd, J4,5 = 7.0 Hz, J3,4 = 4.0 Hz, H-4), 3.50 (dd, J4,5 =7.0 Hz, J5,6 = 3.9 Hz, H-5),
3.44 (s, 6 H, 2Â OCH3), 3.43 (s, 3 H, OCH3); 13C NMR (75 MHz, CDCl3) d 201.7
(C-1), 138.4 À 127.7 (2 Â OCH2C6H5), 134.9 (C-7), 119.4 (C-8), 86.1 (C-2), 82.3 (C-
3), 80.7 (C-4), 80.5 (C-5), 79.7 (C-6), 74.2 (OCH2C6H5), 70.5 (OCH2C6H5), 60.4
(OCH3), 59.0 (OCH3), 58.1 (OCH3). Following the GP for the synthesis of nitrones this
aldehyde (82 mg, 0.19 mmol) gave nitrone (14) (75 mg, 74%) after chromatography
1
(hexane/ethyl acetate, 6/4): oil; H NMR (300 MHz, CDCl3) d 7.43 À 7.23 (m, 15 H,
aromat.), 6.89 (d, J1,2 = 7.6 Hz, 1 H, H-1), 5.88 (ddd, J7,8 =17.5 Hz, J7,8’ =10.1 Hz,
J6,7 =7.6 Hz, 1 H, H-7), 5.35 (dd, J7,8 =10.1 Hz, J8,8’ = 1.7 Hz, 1 H, H-8), 5.28 (dd,
J
7,8’ =17.5 Hz, J8,8’ = 1.7 Hz, 1 H, H8’), 4.86 À 4.80 (m, 3 H, H-2, N(O)CH2C6H5), 4.73/
4.64 (AB system, J =11.5 Hz, 2 H, OCH2C6H5), 4.58/4.35 (AB system, J =11.6 Hz, 2
H, OCH2C6H5), 4.09 À 4.02 (m, 2 H, H-6, H-3), 3.56 (dd, J3,4 = 3.9 Hz, J4,5 = 6.8 Hz, 1
H, H-4), 3.31 (s, 3 H, OCH3) , 3.30À 3.25 (m, 1 H, H-5), 3.29 (s, 3 H, OCH3), 3.26 (s,
3 H, OCH3).

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ENANTIOMERICALLY PURE MEDIUM-SIZED CARBOCYCLES
213
Anal. Calcd for C32H39NO6: C, 72.02; H, 7.37; N, 2.62. Found: C, 72.24; H, 7.45;
N, 2.77.
7,8-Dideoxy-1-O-[(1,1-dimethylethyl)diphenylsilyl]-4,5-O-(1-methylethylidene)-3,6-
bis-O-(phenylmethyl)-D-glycero-D-manno-oct-7-enitol (15). Following the GP for
silylation reactions compound 9 (167 mg, 0.39 mmol) afforded compound 15 (260 mg,
99%) after chromatography (hexane/ethyl acetate, 4/1): oil; [a]D25 +16 (c 0.11, CHCl3);
IR (film) n 3500 À 3300, 2990, 1450, 1200 cm À 1
;
1H NMR (300 MHz, CDCl3) d
7.79 À 7.71/ 7.48 À 7.26 (m, 20 H, aromat.), 5.85 (ddd, J7,8 =17.2 Hz, J7,8’ =10.3 Hz,
J6,7 = 7.9 Hz, 1 H, H-7), 5.48 (dd, J7,8 = 10.3 Hz, J8,8’ = 1.6 Hz, 1 H, H-8), 5.33 (dd,
J7,8’ = 17.2 Hz, J8,8’ =1.6 Hz, 1 H, H8’), 4.63/4.36 (AB system, J =11.8 Hz, 2 H,
OCH2C6H5), 4.55 (dd, J4,5 =5.7 Hz, J3,4 = 4.6 Hz, 1 H, H-4), 4.56/4.26 (AB system,
J = 11.7 Hz, 2 H, OCH2C6H5), 4.21 (dd, J5,6 = 8.8 Hz, J4,5 =5.7 Hz, 1 H, H-5), 4.11 (t,
J
5,6’ = J6,7 =8.4 Hz, 1 H, H-6), 4.08 À 4.02 (m, 1 H, H-2), 3.92 (dd, J1,1’ = 10.5 Hz,
J1,2 = 4.6 Hz, 1 H, H-1), 3.73 (dd, J1,1’ = 10.5 Hz, J1’,2 =6.2 Hz, 1 H, H-1’), 3.72 (t,
J2,3 = J3,4 = 4.6 Hz, 1 H, H-3), 1.50, 1.38 [2 s, OC(CH3)2O], 1.13 [s, 9 H,
Si(C6H5)2C(CH3)3]; 13C NMR (75 MHz, CDCl3) d 135.7 À 127.0 [2 Â OCH2C6H5,
Si(C6H5)2C(CH3)3], 135.8 (C-7), 119.8 (C-8), 108.2 [OC(CH3)2O], 82.9 (C-5), 78.7
(C-4), 78.1 (C-6), 77.1 (C-3), 72.9 (C-2), 72.0 (OCH2C6H5), 68.7 (OCH2C6H5),
62.5(C-1), 26.6, 26.0, 25.1 [OC(CH3)2O], 25.1 [Si(C6H5)2C(CH3)3], 11.9 [Si(C6H5)2
C(CH3)3]; MS: Calcd for C41H50O6NaSi (M + Na) +: 689.9. Found: 690.1.
Anal. Calcd for C41H50O6: C, 77.08; H, 7.89. Found: C, 77.37; H, 7.76.
7,8-Dideoxy-1-O-[(1,1-dimethylethyl)diphenylsilyl]-2-O-methyl-4,5-O-(1-methy-
lethylidene)-3,6-bis-O-(phenylmethyl)-D-glycero-D-manno-oct-7-enitol (16). Follow-
ing the GP for O-methylations compound 15 (260 mg, 0.39 mmol) afforded compound
25
16 (197 mg, 74%) after chromatography (hexane/ethyl acetate, 93/7): oil; [a]D À 13 (c
1
0.2, CHCl3); IR (film) n 3010, 2900, 1410, 1350, 1200 cm À 1; H NMR (300 MHz,
CDCl3) d 7.76 À 7.69/ 7.47 À 7.21 (m, 20 H, aromat.), 5.89 (ddd, J7,8 = 17.2 Hz,
J
7,8’ = 10.3 Hz, J6,7 = 7.5 Hz, 1 H, H-7), 5.42 (dd, J7,8 =10.3 Hz, J8,8’ =1.5 Hz, 1 H, H-
8), 5.30 (dd, J7,8’ = 17.2 Hz, J8,8’ =1.5 Hz, 1 H, H8’), 4.68/4.29 (AB system, J =11.7 Hz,
2 H, OCH2C6H5), 4.60/4.54 (AB system, J =5.0 Hz, 2 H, OCH2C6H5), 4.42 (d,
J3,4 = 5.6 Hz, 1 H, H-4), 4.22 (dd, J5,6 =6.6 Hz, J6,7 =7.4 Hz, 1 H, H-6), 4.06 (dd,
J
1,1@ = 11.1 Hz, J1,2 =3.2 Hz, 1 H, H-1), 4.05 (d, J5,6 =6.7 Hz, 1 H, H-5), 3.90 (t,
J2,3 = J3,4 =5.6 Hz, 1 H, H-3), 3.81 (dd, J1,1’ =11.1 Hz, J1’,2 =5.1 Hz, 1 H, H-1’), 3.41
(ddd, J1,2 = 3.2 Hz, J1’,2 = 5.1 Hz, J2,3 = 5.6 Hz 1 H, H-2), 3.27 (s, 3 H, OCH3), 1.44,
1.35 [2 s, OC(CH3)2O], 1.08 [s, 9 H, Si(C6H5)2C(CH3)3]; 13C NMR (75 MHz, CDCl3)
d 135.7-127.1 [2 Â OCH2C6H5, Si(C6H5)2C(CH3)3], 135.8 (C-7), 120.0 (C-8), 108.6
[OC(CH3)2O], 83.8 (C-2), 78.9 (C-4), 78.7 (C-5), 78.5 (C-6), 76.9 (C-3), 73.3
(OCH2C6H5), 69.5 (OCH2C6H5), 62.7 (C-1), 57.5 (OCH3), 26.9 [Si(C6H5)2C(CH3)3],
26.5, 25.5 [OC(CH3)2O], 12.3 [Si(C6H5)2C(CH3)3]; MS: Calcd for C42H52O6Na
(M +Na) +: 663.9. Found: 664.9.
Anal. Calcd for C42H52O6: C, 78.71; H, 8.18. Found: C, 78.66; H, 8.42.
7,8-Dideoxy-2-O-methyl-4,5-O-(1-methylethylidene)-3,6-bis-O-(phenylmethyl)-D-gly-
cero-D-manno-oct-7-enitol (17). Following the GP for desilylation reactions com-
pound 16 (187 mg, 0.27 mmol) afforded compound 17 (112 mg, 92%) after

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214
MARCO-CONTELLES AND DE OPAZO
chromatography (hexane/ethyl acetate, 75/25): oil; [a]D25 + 9 (c 0.24, CHCl3); IR (film)
n 3500 À 3100, 2900, 1470, 1360, 1200 cm À 1
;
1H NMR (300 MHz, CDCl3) d
7.71 À 7.21 (m, 10 H, aromat.), 5.80 (ddd, J7,8 =17.4 Hz, J7,8’ = 10.3 Hz, J6,7 = 8.1 Hz, 1
H, H-7), 5.41 (dd, J7,8 =10.3 Hz, J8,8’ =1.0 Hz, 1 H, H-8), 5.25 (dd, J7,8’ = 17.4 Hz,
J
8,8’ =1.0 Hz, 1 H, H8’), 4.71/4.27 (AB system, J =12.2 Hz, 2 H, OCH2C6H5), 4.53/4.20
(AB system, J = 11.6 Hz, 2 H, OCH2C6H5), 4.28 (dd, J3,4 = 3.3 Hz, J4,5 = 6.3 Hz, 1 H,
H-4), 4.17 (dd, J4,5 =6.3 Hz, J5,6 =8.3 Hz, 1 H, H-5), 3.97 (t, J5,6 = J6,7 =8.2 Hz, 1 H,
H-6), 3.89 (dd, J1,1’ = 12.0 Hz, J1,2 =5.1 Hz, 1 H, H-1), 3.85 (t, J2,3 =J3,4 = 3.3 Hz, 1 H,
H-3), 3.69 (dd, J1,1’ =12.0 Hz, J1’,2 = 3.9 Hz, 1 H, H-1’), 3.33 À 3.31 (m, 1 H, H-2), 3.32
(s, 3 H, OCH3), 1.47, 1.33 [2 s, OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) d
138.7 À 127.2 (2 Â OCH2C6H5), 135.8 (C-7), 120.7 (C-8), 109.3 [OC(CH3)2O], 84.4
(C-2), 78.5 (3 C, C-4, C-5, C-6), 67.2 (C-3), 72.9 (OCH2C6H5), 69.4 (OCH2C6H5), 59.9
(C-1), 57.7 (OCH3), 26.5, 25.5 [OC(CH3)2O]; MS (70 eV) m/z 367 (6), 277 (5), 181
(21), 169 (49), 91 (100), 75 (18).
Anal. Calcd for C26H34O6: C, 77.59; H, 8.51. Found: C, 7.44; H, 8.34.
1,7,8-Trideoxy-2-O-methyl-1-[oxido(phenylmethyl)imino]3,6-bis-O-(phenylmethyl)-
D-glycero-D-manno-oct-7-enitol (19). Following the GP for oxidations via PCC
compound 17 (100 mg, 0.22 mmol) afforded compound 18 (93 mg, 93%) after
chromatography (hexane/ethyl acetate, 4/1) {oil; 1H NMR (300 MHz, CDCl3) d 9.82 (d,
J1,2 =0.6 Hz, 1 H, H-1), 7.33 À 7.26 (m, 10 H, aromat.), 5.80 (ddd, J7,8 = 17.8 Hz,
J
7,8’ =10.3 Hz, J6,7 = 8.3 Hz, 1 H, H-7), 5.44 (dd, J7,8 = 10.3 Hz, J8,8’ =1.6 Hz, 1 H, H-8),
5.41 (dd, J7,8’ =17.8 Hz, J8,8’ = 1.6 Hz, 1 H, H8’), 4.70/4.26 (AB system, J = 12.1 Hz, 2 H,
OCH2C6H5), 4.52/4.13 (AB system, J = 11.5 Hz, 2 H, OCH2C6H5), 4.40 (dd, J3,4 =3.7 Hz,
J4,5 =5.9 Hz, 1 H, H-4), 4.19 (dd, J4,5 =5.9 Hz, J5,6 = 9.1 Hz, 1 H, H-5), 3.91 (t,
J5,6 =J6,7 = 8.9 Hz, 1 H, H-6), 3.91 À 3.89 (m, 2 H, H-2, H-3), 3.30 (s, 3 H, OCH3), 1.45,
1.37 [2 s, OC(CH3)2O]; 13C NMR (75 MHz, CDCl3) d 202.0 (CHO), 138.7 À 127.3
(2 Â OCH2C6H5), 135.7 (C-7), 120.8 (C-8), 109.6 [OC(CH3)2O], 88.6 (C-2), 79.6, 78.5,
78.3 (2 C) (4 C, C-3, C-4, C-5, C-6), 67.2 (C-3), 72.5 (OCH2C6H5), 69.4 (OCH2C6H5),
58.5 (OCH3), 26.5, 25.5 [OC(CH3)2O]}. Following the GP for the synthesis of nitrones
this crude aldehyde (50 mg, 0.11 mmol) afforded compound (19) (38 mg, 65%) after
1
chromatography (hexane/ethyl acetate, 1:1) as an oil: H NMR (300 MHz, CDCl3) d
7.38 À 7.26 (m, 15 H, aromat.), 6.89 (d, J1,2 = 7.3 Hz, 1 H, H-1), 5.79 (ddd, J7,8 = 17.2 Hz,
J
7,8’ =10.3 Hz, J6,7 = 7.9 Hz, 1 H, H-7), 5.41 (dd, J7,8 = 10.3 Hz, J8,8’ =1.5 Hz, 1 H, H-8),
5.27 (dd, J7,8’ =17.2 Hz, J8,8’ =1.5 Hz, 1 H, H8’), 4.85 [s, 2 H, N(O)CH2C6H5], 4.84 (dd,
J1,2 =7.3 Hz, J2,3 = 1.9 Hz, 1 H, H-2), 4.80/4.62 (AB system, J = 12.4 Hz, 2 H,
OCH2C6H5), 4.56/4.14 (AB system, J = 11.2 Hz, 2 H, OCH2C6H5), 4.22 (dd, J5,6 =8.8 Hz,
J4,5 =5.4 Hz, 1 H, H-5), 4.11 (dd, J4,5 =5.4 Hz, J3,4 =6.9 Hz, 1 H, H-4), 3.98 (dd, J3,4 =6.9
Hz, J2,3 =1.9 Hz, 1 H, H-3), 3.83 (t, J5,6 = J6,7 =8.6 Hz, 1 H, H-6), 3.02 (s, 3 H, OCH3),
1.41, 1.26 [2 s, OC(CH3)2O].
Anal. Calcd for C33H39NO6: C, 72.64; H, 7.20; N, 2.57. Found: C, 72.54; H, 7.34;
N, 2.64.
(3aS,4R,4aR,7aS,8R,9R,9aS)-Octahydro-9-methoxy-6,6-dimethyl-4,8-bis(phenyl-
methyl)-1H[1,3]-dioxolo[4,5]cyclohept[1,2-c]isoxazole (20) and (3aR,4R,4aR,7-
aS,8R,9R,9aR)-octahydro-9-methoxy-6,6-dimethyl-4,8-bis(phenylmethyl)-1H[1,3]-
dioxolo[4,5]cyclohept[1,2-c]isoxazole (21). Nitrone 19 (38 mg, 0.075 mmol) was
dissolved in chlorobenzene (3 mL), and the solution was warmed at reflux for 20 h.

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215
The solvent was removed, and the residue was submitted to chromatography (hexane/
ethyl acetate, 75/25) to give adducts 20 and 21 (19 mg, 50%) as an unseparable
mixture of isomers in a 6 to 4 ratio, respectively: oil; IR (film) n 2900, 1560, 1480,
1
1120, 1100 cm À 1; H NMR (300 MHz, CDCl3) {(major isomer 20) d 7.33 À 7.16 (m,
15 H, aromat.), 5.03/4.47 (AB system, J =11.7 Hz, 2 H, OCH2C6H5), 4.76/4.52 (AB
system, J = 12.3 Hz, 2 H, OCH2C6H5), 4.60 (t, J8,7a =J4a,7a =8.3 Hz, 1 H, H-7a), 4.51
(d, J4,4a =2.3 Hz, 1 H, H-4), 4.19 (dd, J4,4a =2.3 Hz, J4a,7a = 8.3 Hz, 1 H, H-4a), 3.89
(d, J7a,8 =8.3 Hz, 1 H, H-8), 3.86 (s, 2 H, NCH2C6H5), 3.80 (t, J3,3a =J3,3’ = 7.4 Hz, 1
H, H-3), 3.53 (dd, J3,3’ =7.4 Hz, J3’,3a =10.7 Hz, 1 H, H-3’), 3.50 (s, 3 H, OCH3), 3.44
(br s, 1 H, H-9), 3.05 À 2.70 (m, 1 H, H-9a), 2.69 (dt, J3,3a = 7.4 Hz, J3’,3a = J9a,3a =10.7
Hz, 1 H, H-3a), 1.43, 1.30 [2 s, OC(CH3)2O]} {(minor isomer 21) d 7.33 À 7.16 (m,
15 H, aromat.), 4.89/4.61 (AB system, J =11.5 Hz, 2 H, OCH2C6H5), 4.63/4.42 (AB
system, J =12.0 Hz, 2 H, OCH2C6H5), 4.46 (dd, J8,7a =8.3 Hz, J4a,7a =5.4 Hz, 1 H, H-
7a), 4.14 (d, J7a,4a = 5.4 Hz, 1 H, H-4a), 4.07 (t, J3,3’ =J3a,3’ =7.6 Hz, 1 H, H-3’),
3.90 À 3.87 (m, 2 H, H-4, H-8), 3.84 (s, 2 H, NCH2C6H5), 3.68 (dd, J3,3a = 10.9 Hz,
J
3,3’ = 7.6 Hz, 1 H, H-3), 3.62 (d, J9,9a = 10.1 Hz, 1 H, H-9), 3.46 (s, 3 H, OCH3), 3.14
(br t, J9,9a = J9a,3a = 10.1 Hz, 1 H, H-9a), 3.05 À 2.70 (m, 1 H, H-3a), 1.47, 1.30 [2 s,
OC(CH3)2O]}; 13C NMR (75 MHz, CDCl3) {(major isomer 20) d 138.7 À 127.4
(2 Â OCH2C6H5), 107.5 [OC(CH3)2O], 79.7 (C-4a), 78.7 (C-9), 78.0 (C-7a), 75.8
(OCH2C6H5), 74.7, 74.6 (C-8, C-4),72.8 (OCH2C H5), 67.7 (C-9a), 67.0 (C-3), 62.3
6
(NCH2C6H5), 61.1 (OCH3), 44.5 (C-3a), 26.4, 23.7 [OC(CH3)2O]} {(minor isomer 21)
d 138.5 À 126.9 (2 Â OCH2C6H5), 108.6 [OC(CH3)2O], 82.4 (C-9), 81.1 (C-4), 77.8
(C-4a), 76.1 (C-8), 74.1 (OCH2C6H5), 73.6 (C-7a), 71.7 (OCH2C6H5), 68.4 (C-3), 67.5
(C-9a), 64.7 (NCH2C6H5), 58.1 (OCH3), 42.4 (C-3a), 25.9, 23.3 [OC(CH3)2O]}; MS
m/z 545 (M + , 21), 530 (M + À 15, 5), 284 (64), 188 (8), 91 (100).
Anal. Calcd for C33H39NO6: C, 72.64; H, 7.20; N, 2.57. Found: C, 72.75; H, 7.55;
N, 2.45.
ACKNOWLEDGMENTS
This work was supported by CICYT, CAM and COST Action No. D12 (European
Union). Elsa de Opazo is a fellow of the Consejer´ıa de Educacio´n y Cultura (CAM).
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ENANTIOMERICALLY PURE MEDIUM-SIZED CARBOCYCLES
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218
MARCO-CONTELLES AND DE OPAZO
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Received April 10, 2001
Accepted January 25, 2002