Erythrulose derivatives as functionalized chiral d3 and d4 synthons

Article abstract of DOI:10.1016/S0957-4166(02)00638-9

Protected erythrulose derivatives have been shown to undergo highly stereoselective dicyclohexylboron chloride-mediated aldol reactions. After suitable synthetic manipulation of the resulting aldol adducts, chiral polyoxygenated molecules can be obtained in which either three or all four carbon atoms of the starting erythrulose molecule have been incorporated. Erythrulose derivatives may therefore behave, according to convenience, as chiral, functionalized d³ or d⁴ synthons. As an example, this methodology has been applied to a stereoselective synthesis of the naturally occurring, pharmacologically active lactone (+)-boronolide.

Full text of DOI:10.1016/S0957-4166(02)00638-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2317–2327
Erythrulose derivatives as functionalized chiral d3 and d4
synthons†
Juan Murga,a Eva Falomir,a Miguel Cardaa,* and J. Alberto Marcob,*
aDepartamento de Qu´ımica Inorga´nica y Orga´nica, Univ. Jaume I, E-12080 Castello´n, Spain
bDepartamento de Qu´ımica Orga´nica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
Received 5 August 2002; accepted 27 September 2002
Abstract—Protected erythrulose derivatives have been shown to undergo highly stereoselective dicyclohexylboron chloride-medi-
ated aldol reactions. After suitable synthetic manipulation of the resulting aldol adducts, chiral polyoxygenated molecules can be
obtained in which either three or all four carbon atoms of the starting erythrulose molecule have been incorporated. Erythrulose
derivatives may therefore behave, according to convenience, as chiral, functionalized d3 or d4 synthons. As an example, this
methodology has been applied to a stereoselective synthesis of the naturally occurring, pharmacologically active lactone
(+)-boronolide. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
is performed, derivatives 1 can also act as an a,b,g-tri-
hydroxy butanal bishomoenolate equivalent (cf. 5), also
lacks any literature precedent. This possibility is partic-
ularly interesting as 1 would then function as a hitherto
unprecedented chiral d4 synthon type with no loss of
carbon, thus maximizing atom economy.4 All afore-
mentioned chirons, most particularly the d3 and d4
types, may be extremely useful for the stereoselective
synthesis of natural, polyhydroxylated compounds such
as long-chain sugars, macrolide and polyether polyke-
tides,5 etc. Furthermore, a combination of these aldol
reactions with appropriate nucleophilic substitution
reactions should open a way to aza analogues of the
aforementioned compounds, including the biologically
significant amino polyols and amino sugars.
Over the last few years we have investigated the eno-
lization of protected
general formula
L
-erythrulose derivatives having
1
(Scheme 1, P1–P3=protecting
groups) and the subsequent addition of the resulting
enolates to aldehydes.1 As shown in Scheme 1, further
manipulation of the key aldol adduct 2 through car-
bonyl reduction and oxidative cleavage of C−C bonds a
or b should yield protected a,b-dihydroxy aldehydes 3
(X=H) or a,b,g-trihydroxy aldehydes (X=H),
respectively, with high selectivity. The corresponding
acid derivatives (X=heteroatom) should be similarly
obtained through oxidative cleavage of the same bonds
without prior carbonyl reduction. Compounds 1 should
thus be potential equivalents of the d2 and d3 chiral
synthons depicted in Scheme 1. We have recently con-
firmed this1 in the case of the hydroxyacetic acid eno-
late, a well-precedented d2 type chiron.2 However,
counterparts for the functionalized d3 synthon a,b-
dihydroxy propanal homoenolate (Scheme 1) are yet to
be reported in the literature.3 Furthermore, the interest-
ing possibility that, if no oxidative C−C bond cleavage
6
6
4
2. Results and discussion
As alluded to above, some of the aforementioned ideas
have recently been brought into practice. For practical
reasons (mainly the ease of preparation),6 the most
convenient derivatives 1 are those having an acetal
moiety joining the hydroxyl groups at C-3 and C-4
(Scheme 1, P1, P2=CR2) and a silylated hydroxyl func-
tion at C-1. As a matter of fact, ketone 6 has been
shown to undergo dicyclohexylboron chloride
(Chx2BCl)-mediated aldol reactions with achiral alde-
hydes to yield aldol condensation products 7 with very
high diastereoselectivity (Scheme 2).1,7 Oxidative cleav-
age of bond C2ꢀC3 in the latter compounds (which
* Correspondence authors. Tel.: +34-96-3864337; fax: +34-96-
3864328; e-mail: alberto.marco@uv.es
Dedicated to Professor Emanuel Vogel, former Director of the
Institute of Organic Chemistry at the University of Cologne, on the
occasion of his 75th birthday.
†
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00638-9

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J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
Scheme 1. Erythrulose derivatives as chiral, functionalized synthons of various types.
Scheme 2. Reaction conditions: (a) Chx2BCl, base; RCHO; LiBH4, 0°C (75–80%). (b) Ac2O, pyridine, cat. DMAP, rt (83–87%).
(c) H5IO6, EtOAc, rt (79–81%). For abbreviations, see Section 3.
corresponds to bond a
6
in 2, Scheme 1) furnishes pro-
this one-pot aldolization/reduction procedure8 yields
syn 1,3-diols 9 with very high stereoselectivity (2-
methylpropanal and benzaldehyde were used here as
standard achiral aldehydes). Suitable protection of the
two free hydroxyl groups, for example as acetate
esters,9 gives compounds 10, amenable to oxidative
cleavage of the C1ꢀC2 bond. In fact, treatment of 10
with periodic acid hydrate in ethyl acetate10 provides
a,b,g-trioxygenated aldehydes 11 with good yields
(Scheme 2). Compounds 11 contain three differently
protected hydroxyl groups and a carbonyl function,
structural features which permit many additional syn-
tected a,b-dihydroxy esters 8 (loss of two of the erythru-
lose carbon atoms) in good yields,1a thus showing the
ability of ketone 6 to behave as a chiral, functionalized
d2 synthon. In order to unveil the potential nature of 6
as a d3 synthon (loss of one of the erythrulose carbon
atoms), it is necessary to oxidatively cleave the bond
connecting C1 and C2 (bond b6 in 2, Scheme 1). It is not
possible to do this in 7 until the carbonyl function has
been reduced and protected. It is possible to perform
direct in situ reduction of the ketone function in the
boron aldolate formed after the aldolization step and

J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
2319
thetic manipulations to give various polyfunctionalized,
chiral molecules. Ketone 6 therefore behaves as an
equivalent of the depicted chiral d3 synthon.
can be exploited synthetically in a number of ways. We
now show one of these possibilities in a stereoselective
synthesis of the naturally occurring, pharmacologically
active lactone (+)-boronolide 16. This compound was
first found in extracts of bark and branches of Tetra-
denia fruticosa Benth., a shrub which grows in Mada-
gascar and is widely used there for various medicinal
purposes.14 Total syntheses of 16 have been reported in
the literature in recent years.15 In the synthesis planned
here (Scheme 4), we make use of the d4 synthon hidden
in erythrulose derivative 6. Retrosynthetic disconnec-
tion of the target molecule through an olefin ring-clos-
ing metathesis and an epoxide opening leads to
compound 18 (ꢁ15, R=n-C4H11) via acrylate ester 17.
Thus, the synthesis was carried out as depicted in
Scheme 3. Erythrulose 6 was subjected to aldol addition
with n-pentanal followed by in situ reduction with
LiBH4 to yield syn-1,3-diol 19. Protection of the latter
as its bis-MOM derivative 20 followed by conversion
into epoxide 18 was performed as described above in
Scheme 3. Epoxide opening with a vinyl copper
reagent16 afforded alcohol 22, subsequently acylated to
ester 17. Ring-closing metathesis of the latter com-
pound was performed with Grubbs’s catalyst17
PhCHꢂRuCl2(PCy3)2 and furnished conjugated lactone
23 with a good yield. Cleavage of all protecting groups
and peracetylation (six steps altogether, 46% overall
yield) provided synthetic boronolide 16, with physical
and spectroscopic properties identical to literature
data.15a,c
The previous reaction sequence furnishes all-syn a,b,g-
trioxygenated aldehydes 11 because LiBH4 was used as
an in situ aldol reducing agent. We also tried to obtain
compounds with different relative configurations
through anti reduction of the isolated aldol 7. However,
we have not been successful thus far: using tetra-
methylammonium triacetoxyborohydride,
a reagent
which usually reduces b-hydroxy ketones to anti-1,3-
diols with high stereoselectivity,11 afforded only a 3:7
mixture of 9 (minor) and its desired anti diastereoiso-
mer. A great deal of other reagents, including reductive
Tishchenko procedures, were investigated but no suc-
cess was met with.12
Synthetic applications of erythrulose derivative 6 as a
chiral d4 synthon demand a hydrolytic, non-oxidative
cleavage of the acetal ring in protected derivatives of 9.
We have found that the success of this hydrolytic
cleavage is closely related to the nature of the hydroxyl
protecting groups. For instance, we were not able to
find suitable reaction conditions when only silyl protect-
ing groups were present.9 In contrast, when one or two
of the hydroxyl groups were protected, for example, as
their MOM derivatives 12,13 hydrolytic cleavage of the
acetal occurred smoothly (Scheme 3). Compounds 12
were then transformed in a straightforward manner
into epoxides 14 through diols 13. The diastereoiso-
meric epoxides 15 were also readily obtained through a
minor variation in the reaction sequence (Scheme 3),
where closure of the epoxide ring takes place via inter-
nal nucleophilic substitution in a secondary mesylate.
These reaction sequences show therefore that ketone 6
is equivalent to the depicted chiral d4 synthon—a spe-
cific case of the general d4 synthon shown in Scheme 1.
In summary, we have described various synthetic proto-
cols according to which erythrulose derivatives can be
manipulated to act as chiral, functionalized d3 or d4
synthons. As a demonstration of the practical applica-
tion of the latter synthon type, we have described a
stereoselective synthesis of a pharmacologically active,
naturally occurring product. Further applications of
this methodology are currently being investigated
within our group and will be reported in the near
future.
The potential reactivity of the epoxide ring in molecules
14 and 15 offers many additional possibilities, which
Scheme 3. Reaction conditions: (a) MOMCl, DIPEA, CH2Cl2, D (78–80%). (b) PPTS, MeOH, rt (83–85%). (c) p-TsCl, Et3N, cat.
Bu2SnO, rt, then K2CO3, MeOH, rt (65–66%). (d) PivCl, NEt3, cat. DMAP, rt, then MsCl, Et3N, DMAP, rt, then K2CO3, MeOH,
rt (60–61%). For abbreviations, see Section 3.

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J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
Scheme 4. Retrosynthetic scheme and actual synthetic path for (+)-boronolide 16. Reaction conditions: (a) Chx2BCl, base;
n-C4H9CHO; LiBH4, 0°C (83%). (b) MOM chloride, DIPEA, CH2Cl2, D (82%). (c) PPTS, MeOH, rt (81%). (d) PivCl, Et3N, cat.
DMAP, CH2Cl2, rt, then MsCl, Et3N, cat. DMAP, CH2Cl2, rt, then K2CO3, MeOH, rt (60%). (e) VinylMgBr, CuI, THF, −30°C
(89%). (f) Acryloyl chloride, Et3N, cat. DMAP, CH2Cl2, rt (84%). (g) 10% PhCHꢂRuCl2(PCy3)2, CH2Cl2, D (83%). (h) BF3, SMe2,
−30°C, then aq HF, MeCN, rt, then Ac2O, Et3N, cat. DMAP, CH2Cl2, rt (46% overall). For abbreviations, see Section 3.
3. Experimental
freshly distilled from sodium wire. Methylene chloride
was freshly distilled from CaH2. Tertiary amines were
freshly distilled from KOH. Commercially available
reagents were used as received. Chx2BCl was prepared
according to the described procedure,18 distilled and
used as the neat liquid. If not detailed otherwise, the
work-up of the reactions was consistently performed in
the following manner: the reaction mixture was poured
into brine and extracted twice with solvent (Et2O or
CH2Cl2), the organic layer was washed with diluted aq
NH4Cl and then washed again with brine, the organic
layer was dried over anhydrous MgSO4 or Na2SO4, and
the solvent was eliminated with a rotary evaporator at
aspirator pressure. Abbreviations used throughout the
text: TBS, t-butyldimethylsilyl; MOM, methoxymethyl;
DMAP, 4-dimethylaminopyridine; DIPEA, N,N-diiso-
propyl ethylamine; PPTS, pyridinium p-toluene-
sulphonate; PivCl, pivaloyl chloride.
3.1. General methods
1H NMR spectra (400 or 500 MHz) and 13C NMR
spectra (100 or 125 MHz) were measured at 22°C. The
signals of the deuterated solvent (CDCl3) were taken as
1
the reference (the singlet at l 7.25 for H NMR and the
triplet centered at 77.00 ppm for 13C NMR data).
Multiplicity assignments of 13C NMR signals were
made with the DEPT pulse sequence. Mass spectra
were run in a VG AutoSpec mass spectrometer using
either the electron impact (EIMS, 70 eV), the chemical
ionization (CIMS, CH4) or the fast atom bombardment
mode (FAB MS, m-nitrobenzyl alcohol matrix). Sam-
ples for IR spectroscopic measurements were prepared
as oily films on NaCl plates (oils) or KBr pellets
(solids). Optical rotations were measured at 25°C.
Column chromatography (CC) was performed on silica
gel Su¨d-Chemie AG (60–200 mm). Experiments which
required an inert atmosphere were carried out under
dry argon (Ar) in a flame-dried glassware. THF and
Et2O were freshly distilled from sodium/benzophenone
ketyl and were transferred via syringe. Toluene was
3.2. General experimental procedure for the one-pot
aldolization–reduction protocol
Ketone 6 (1 mmol) dissolved in anhydrous ether (5 mL)
was added at 0°C to a stirred solution prepared by
dissolving Chx2BCl (neat, 395 mL, ca. 1.8 mmol) and

J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
2321
Et3N (280 mL, 2 mmol) in anhydrous Et2O (5 mL).
After stirring for 30 min at this temperature, a solution
of the appropriate aldehyde (1.5 mmol) in anhydrous
ether (6 mL) was added, and the reaction mixture was
stirred at the same temperature for 4 h. A solution of
LiBH4 in THF (2 M, 1.5 mL, 3 mmol) was then added
via syringe and stirring was continued at 0°C for 2 h.
The reaction was quenched with aqueous phosphate
buffer (pH 7 6 mL) and MeOH (6 mL), followed by a
30% aq H2O2 solution (3 mL). After stirring for 1 h at
room temperature, the mixture was poured into satd.
aq NaHCO3 and extracted with Et2O. The organic
layer was washed with brine and dried on anhydrous
Na2SO4. Solvent removal in vacuo afforded an oily
residue which was chromatographed on silica gel (hex-
anes–EtOAc, 9:1 and 4:1) to yield syn-1,3-diols of
general formula 9. Overall chemical yields of the
aldolization–reduction sequence were: 9a, 75%; 9b,
80%.
mmol) in dry CH2Cl2 (4 mL) was stirred overnight at
room temperature. After this time, the reaction mixture
was worked-up and washed with aqueous 1 M HCl
(extraction with CH2Cl2). Column chromatography on
silica gel was made with hexanes–EtOAc, 9:1. Chemical
yields: 10a, 87%; 10b, 83%.
3.6. (1R,2R,3S)-3-Acetoxy-2-(tert-butyldimethylsilyl-
oxy)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-
methylpentyl acetate, 10a
Oil: [h]2D2 −4.8 (c 2, CHCl3). 1H NMR (500 MHz) l 4.95
(1H, dd, J=6, 4.2 Hz), 4.85 (1H, t, J=6 Hz), 4.40 (1H,
ddd, J=6.6, 6, 4.2), 4.03 (1H, dd, J=8.6, 6.6 Hz), 4.00
(1H, t, J=6 Hz), 3.80 (1H, dd, J=8.6, 5.9 Hz), 2.13
(1H, m), 2.12 (3H, s), 2.08 (3H, s), 1.41 (3H, s), 1.35
(3H, s), 0.96 (3H, d, J=6.5 Hz), 0.89 (9H, s), 0.87 (3H,
d, J=6.5 Hz), 0.13 (3H, s), 0.12 (3H, s). 13C NMR (125
MHz) l 170.5, 170.4, 109.3, 18.0 (C), 77.8, 73.9, 73.7,
70.3, 28.4 (CH), 66.0 (CH2), 26.1, 25.7, 25.6, 21.1, 20.0,
17.8, −4.6, −4.8 (CH3). IR wmax 2961, 2930, 2859, 1743,
1473, 1372, 1200, 1104, 1069, 916, 839, 778, 735 cm−1.
HR EIMS m/z (% rel. int.) 417.2316 (M+−Me, 15), 317
(32), 259 (28), 197 (60), 117 (89), 101 (100). Calcd for
C21H40O7Si−Me, 417.2308. Anal. calcd for C21H40O7Si:
C, 58.30; H, 9.32. Found C, 58.15; H, 9.50%.
3.3. (4S)-2,2-Dimethyl-4-[(1R,2R,3S)-2-(tert-
butyldimethylsilyloxy)-1,3-dihydroxy-4-methylpentyl]-
1,3-dioxolane, 9a
1
Oil: [h]2D2 −23.7 (c 6.8, CHCl3). H NMR (400 MHz) l
4.30 (1H, dt, J=5.5, 6.5 Hz), 4.02 (1H, dd, J=8.4, 6.5
Hz), 3.84 (1H, dd, J=8.4, 6.5 Hz), 3.82 (1H, dd, J=4.5,
1.5 Hz), 3.55 (1H, dt, J=4.5, 5.5 Hz), 3.22 (1H, td,
J=9, 1.5 Hz), 2.40 (1H, d, J=5.5 Hz, OH), 2.20 (1H, d,
J=9 Hz, OH), 1.65 (1H, br m), 1.42 (3H, s), 1.34 (3H,
s), 0.99 (3H, d, J=6.5 Hz), 0.90 (9H, s), 0.88 (3H, d,
J=6.5 Hz), 0.14 (3H, s), 0.11 (3H, s). 13C NMR (100
MHz) l 109.0, 18.3 (C), 76.1, 75.0, 73.4, 73.0, 31.1
(CH), 66.4 (CH2), 26.7, 26.0, 25.3, 19.4, 18.8, −3.9, −4.7
(CH3). IR wmax 3400 (br), 1215, 1066, 756, 700 cm−1.
HR CIMS m/z 349.2398 (M+H+). Calcd for
C17H37O5Si, 349.2410. Anal. calcd for C17H36O5Si: C,
58.58; H, 10.41. Found C, 58.79; H, 10.50%.
3.7. (1R,2R,3S)-3-Acetoxy-2-(tert-butyldimethylsilyl-
oxy)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-phenyl-
propyl acetate, 10b
1
Oil: [h]2D2 −31.5 (c 1, CHCl3). H NMR (500 MHz) l
7.35–7.20 (5H, m), 5.95 (1H, d, J=5.8 Hz), 4.80 (1H, t,
J=5 Hz), 4.40 (1H, ddd, J=6.6, 6.3, 5 Hz), 4.18 (1H, t,
J=5.5 Hz), 4.03 (1H, dd, J=8.6, 6.6 Hz), 3.78 (1H, dd,
J=8.6, 6.3 Hz), 2.10 (3H, s), 1.83 (3H, s), 1.38 (3H, s),
1.36 (3H, s), 0.89 (9H, s), 0.10 (3H, s), −0.16 (3H, s).
13C NMR (125 MHz) l 170.3, 169.7, 138.0, 109.4, 18.0
(C), 128.2, 128.0, 127.4, 75.2, 73.7, 73.6, 72.8 (CH), 66.0
(CH2), 26.2, 25.7, 25.6, 21.2, 20.6, −4.7, −5.3 (CH3). IR
wmax 2950, 2932, 2858, 1744, 1473, 1372, 1210, 1069,
952, 838, 779 cm−1. HR EIMS m/z (% rel. int.)
451.2146 (M+−Me, 8), 351 (88), 317 (34), 231 (56), 156
(37), 117 (98), 101 (100). Calcd for C24H38O7Si−Me,
451.2152. Anal. calcd for C24H38O7Si: C, 61.77; H, 8.21.
Found C, 61.88; H, 8.40%.
3.4. (4S)-2,2-Dimethyl-4-[(1R,2R,3S)-2-(tert-
butyldimethylsilyloxy)-1,3-dihydroxy-3-phenylpropyl]-
1,3-dioxolane, 9b
1
Oil: [h]2D2 −26.3 (c 3.1, CHCl3). H NMR (400 MHz) l
7.35–7.25 (5H, m), 4.90 (1H, dd, J=7, 3.3 Hz), 4.36
(1H, ddd, J=7, 6.5, 5.5 Hz), 4.02 (1H, dd, J=8, 6.5
Hz), 3.84 (1H, dd, J=3.6, 3.3 Hz), 3.76 (1H, dd, J=8,
7 Hz), 3.50 (1H, ddd, J=7, 5.5, 3.6 Hz), 2.95 (1H, d,
J=7 Hz, OH), 2.53 (1H, d, J=7 Hz, OH), 1.40 (3H, s),
1.37 (3H, s), 0.84 (9H, s), −0.03 (3H, s), −0.36 (3H, s).
13C NMR (100 MHz) l 142.1, 109.3, 18.1 (C), 128.2,
128.1, 127.4, 77.9, 76.0, 72.5, 71.8 (CH), 66.4 (CH2),
26.6, 25.9, 25.5, −4.6, −5.2 (CH3). IR wmax 3400 (br),
3020, 1215, 1066, 756 cm−1. HR FAB MS m/z 405.2065
(M+Na)+. Calcd for C20H34O5NaSi, 405.2073. Anal.
calcd for C20H34O5Si: C, 62.79; H, 8.96. Found C,
62.62; H, 9.00%.
3.8. Oxidative cleavage of acetals 10a–b with periodic
acid hydrate
Acetal 10 (1 mmol) was dissolved in dry EtOAc (10
mL) and treated with H5IO6 (410 mg, 1.8 mmol). The
mixture was then stirred at room temperature until
consumption of the starting material (ca. 2–3 h, TLC
monitoring!). After this, solid sodium thiosulfate pen-
tahydrate (250 mg, ca. 1 mmol) was added to the
reaction mixture, which was then stirred for 15 min,
filtered through Celite (the Celite pad was additionally
washed with 10 mL of EtOAc) and evaporated under
reduced pressure. The oily residue was then subjected to
column chromatography on silica gel (hexanes–EtOAc,
4:1). Chemical yields: 11a, 79%; 11b, 81%.
3.5. Acetylation of diols 9a–b to diacetates 10a–b
A solution of diol 9 (1 mmol), Et3N (700 mL, 5 mmol),
DMAP (12 mg, 0.1 mmol) and Ac2O (380 mL, ca. 4

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J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
3.9. (2S,3R,4S)-2,4-Diacetoxy-3-(tert-butyldiphenylsilyl-
wmax 2956, 2931, 2894, 2859, 1471, 1379, 1369, 1254,
1215, 1154, 1100, 1035, 919, 863, 837, 777 cm−1. HR
EIMS m/z (% rel. int.) 421.2635 (M+−Me, 1), 303 (21),
261 (26), 187 (24), 159 (40), 143 (87), 101 (100). Calcd
for C21H44O7Si−Me, 421.2622. Anal. calcd for
C21H44O7Si: C, 57.76; H, 10.16. Found C, 57.69; H,
10.40%.
oxy)-5-methylhexanal, 11a
1
Oil: [h]2D2 +33.9 (c 0.85, CHCl3). H NMR (500 MHz) l
9.71 (1H, s), 5.14 (1H, d, J=5.7 Hz), 4.78 (1H, dd,
J=8.5, 3.5 Hz), 4.26 (1H, dd, J=5.7, 3.5 Hz), 2.17 (3H,
s), 2.01 (1H, m), 2.00 (3H, s), 0.96 (3H, d, J=6.5 Hz),
0.93 (9H, s), 0.89 (3H, d, J=6.5 Hz), 0.16 (3H, s), 0.15
(3H, s). 13C NMR (125 MHz) l 170.1, 169.9, 18.0 (C),
195.9, 77.3, 76.8, 71.5, 28.4 (CH), 25.7, 20.8, 20.5, 19.4,
18.4, −4.4, −4.8 (CH3). IR wmax 2950, 2932, 2860, 1748
(br), 1473, 1372, 1222, 1095, 1035, 839, 779, 734 cm−1.
HR EIMS m/z (% rel. int.) 361.2050 (M+H+, 2), 301
(14), 259 (37), 201 (36), 183 (47), 127 (63), 117 (100), 75
(57). Calcd for C17H33O6Si, 361.2046. Anal. calcd for
C17H32O6Si: C, 56.64; H, 8.95. Found C, 56.49; H,
8.80%.
3.13. (4S)-2,2-Dimethyl-4-[(1R,2R,3S)-2-(tert-
butyldimethylsilyloxy)-1,3-bis(methoxymethoxy)-3-
phenylpropyl]-1,3-dioxolane, 12b
1
Oil: [h]2D2 +19.8 (c 4.5, CHCl3). H NMR (500 MHz) l
7.40–7.20 (5H, m), 4.87 (1H, d, J=3.1 Hz), 4.77 (1H, d,
J=6.7 Hz), 4.71 (1H, d, J=6.7 Hz), 4.59 (1H, d, J=6.3
Hz), 4.53 (1H, d, J=6.3 Hz), 4.53 (1H, overl. m), 4.12
(1H, dd, J=8.3, 6.3 Hz), 4.00 (1H, dd, J=8.3, 7.2 Hz),
3.88 (1H, dd, J=4.5, 3.1 Hz), 3.60 (1H, dd, J=8, 4.5
Hz), 3.42 (3H, s), 3.36 (3H, s), 1.39 (3H, s), 1.38 (3H,
s), 0.88 (9H, s), −0.03 (3H, s), −0.49 (3H, s). 13C NMR
(125 MHz) l 139.5, 108.2, 18.0 (C), 128.0, 127.8, 127.5,
80.2, 76.7, 76.5 (CH), 97.5, 95.1, 66.3 (CH2), 56.5, 55.7,
26.7, 26.0, 25.8, −4.6, −6.0 (CH3). IR wmax 3087, 3064,
3030, 2931, 2857, 2823, 1494, 1472, 1460, 1375, 1369,
1254, 1214, 1150, 1100, 1085, 1030, 964, 937, 811, 776,
703 cm−1. HR EIMS m/z (% rel. int.) 455.2463 (M+−
Me, 3), 409 (5), 319 (44), 243 (48), 207 (27), 101 (100).
Calcd for C24H42O7Si−Me, 455.2465. Anal. calcd for
C24H42O7Si: C, 61.24; H, 8.99. Found C, 61.10; H,
8.79%.
3.10. (2S,3R,4S)-2,4-Diacetoxy-3-(tert-butyldiphenyl-
silyloxy)-4-phenylbutanal, 11b
1
Oil: [h]2D2 +58.4 (c 3.1, CHCl3). H NMR (500 MHz) l
9.67 (1H, s), 7.40–7.25 (5H, m, aromatic), 5.85 (1H, d,
J=5 Hz), 4.88 (1H, d, J=4.4 Hz), 4.40 (1H, dd, J=5,
4.4 Hz), 2.18 (3H, s), 2.06 (3H, s), 0.87 (9H, s), 0.03
(3H, s), −0.24 (3H, s). 13C NMR (125 MHz) l 169.8,
169.4, 136.7, 18.0 (C), 196.3, 77.6, 75.4, 74.2 (CH), 25.7,
20.9, 20.4, −5.1, −5.4 (CH3). IR wmax 2958, 2932, 2858,
1747 (br), 1473, 1372, 1225, 1142, 1093, 951, 838, 780,
702 cm−1. HR EIMS m/z (% rel. int.) 335.1671 (M+H+−
HOAc, 3), 277 (45), 245 (62), 235 (54), 217 (55), 203
(63), 159 (46), 117 (100), 91 (60), 75 (90). Calcd for
C20H31O6Si−HOAc, 335.1678. Anal. calcd for
C20H30O6Si: C, 60.89; H, 7.66. Found C, 60.60; H,
7.79%.
3.14. Hydrolytic cleavage of acetonides, 12
A solution of compound 12 (2 mmol) in MeOH (20
mL) containing a catalytic amount of water (0.2 mL)
was treated with PPTS (25 mg, 0.1 mmol) and stirred
for about 48 h at room temperature (TLC monitoring!).
After this, solid NaHCO3 (25 mg) was added to the
reaction mixture, which was then stirred for 10 min and
filtered through Celite (the Celite pad was additionally
washed with EtOAc). Solvent removal under reduced
pressure was followed by column chromatography of
the residue on silica gel (hexanes–EtOAc, 1:1) to afford
1,2-diols 13. Chemical yields: 13a, 83%; 13b, 85%.
3.11. Formation of MOM derivatives of diols 9
A solution of 1,3-diol 9 (2 mmol) and DIPEA (1.75
mL, 10 mmol) in dry CH2Cl2 (40 mL) was treated
under Ar with MOM chloride (608 mL, 8 mmol) and
heated at reflux for 48 h. After cooling, the mixture was
worked-up (extraction with CH2Cl2). Column chro-
matography on silica gel (hexanes–EtOAc, 9:1)
afforded the protected derivatives. Chemical yields: 12a,
78%; 12b, 80%.
3.15. (2S,3R,4R,5S)-4-(tert-Butyldimethylsilyloxy)-3,5-
bis(methoxymethoxy)-6-methylheptane-1,2-diol, 13a
3.12. (4S)-2,2-Dimethyl-4-[(1R,2R,3S)-2-(tert-
butyldimethylsilyloxy)-1,3-bis(methoxymethoxy)-4-
methylpentyl]-1,3-dioxolane, 12a
1
Oil: [h]2D2 +36.3 (c 0.85, CHCl3). H NMR (500 MHz) l
4.84 (1H, d, J=6.5 Hz), 4.75 (1H, d, J=6.3 Hz), 4.66
(1H, d, J=6.5 Hz), 4.62 (1H, d, J=6.3 Hz), 4.10 (1H,
dd, J=7.7, 4.4 Hz), 4.02 (1H, m), 3.70 (3H, br m), 3.44
(3H, s), 3.41 (3H, s), 3.32 (1H, dd, J=7.2, 4.4 Hz), 3.00
(1H, d, J=6.5 Hz, OH), 2.90 (1H, t, J=7 Hz, OH),
1.98 (1H, octup, J=6.8 Hz), 1.03 (3H, d, J=6.8 Hz),
0.96 (3H, d, J=6.8 Hz), 0.91 (9H, s), 0.13 (3H, s), 0.10
(3H, s). 13C NMR (125 MHz) l 18.0 (C), 85.4, 79.7,
73.9, 70.0, 29.0 (CH), 99.2, 98.2, 63.6 (CH2), 56.4, 55.9,
26.0, 20.8, 19.4, −4.7 (CH3). IR wmax 3450 (br), 2958,
2931, 2858, 1472, 1388, 1253, 1152, 1040, 919, 836, 776
cm−1. HR EIMS m/z (% rel. int.) 365.2372 (M+−OMe,
1), 333 (8), 275 (16), 231 (59), 187 (100), 147 (380), 73
White solid: mp 58.5–59°C; [h]2D2 −36.6 (c 2, CHCl3). 1H
NMR (500 MHz) l 4.75 (1H, d, J=6.8 Hz), 4.74 (2H,
s), 4.58 (1H, d, J=6.8 Hz), 4.27 (1H, q, J=6.6 Hz),
4.03 (1H, dd, J=8.4, 6.6 Hz), 3.95 (1H, dd, J=8.4, 6.6
Hz), 3.88 (1H, dd, J=8, 4 Hz), 3.58 (1H, dd, J=6.6, 4
Hz), 3.42 (3H, s), 3.40 (3H, s), 3.33 (1H, dd, J=8, 3.2
Hz), 1.40 (3H, s), 1.35 (3H, s), 1.00 (3H, d, J=7 Hz),
0.91 (9H, s), 0.90 (3H, d, J=7 Hz), 0.12 (3H, s), 0.10
(3H, s). 13C NMR (125 MHz) l 108.7, 18.0 (C), 83.6,
79.6, 75.6, 73.5, 28.2 (CH), 98.5, 97.1, 66.3 (CH2), 55.9,
55.8, 26.5, 26.0, 25.8, 20.8, 16.7, −4.6, −4.8 (CH3). IR

J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
2323
(63). Calcd for C18H40O7Si−OMe, 365.2359. Anal. calcd
for C18H40O7Si: C, 54.51; H, 10.17. Found C, 54.49; H,
10.29%.
3.19. (2S)-2-[(1R,2R,3S)-2-(tert-Butyldimethylsilyloxy)-
1,3-bis(methoxymethoxy)3-phenylpropyl]oxirane, 14b
1
Oil: [h]2D2 +57.8 (c 2, CHCl3). H NMR (500 MHz) l
7.40–7.25 (5H, m), 4.87 (1H, d, J=5.3 Hz), 4.78 (1H, d,
J=6.6 Hz), 4.63 (1H, d, J=6.6 Hz), 4.62 (1H, d, J=6.6
Hz), 4.56 (1H, d, J=6.6 Hz), 3.94 (1H, dd, J=5.3, 4.2
Hz), 3.41 (3H, s), 3.40 (1H, m), 3.28 (3H, s), 2.97 (1H,
dd, J=7.2, 4.2 Hz), 2.80 (1H, t, J=4.7 Hz), 2.50 (1H,
dd, J=4.7, 2.8 Hz), 0.91 (9H, s), 0.01 (3H, s), −0.22
(3H, s). 13C NMR (125 MHz) l 139.2, 18.3 (C), 128.2,
128.0, 127.8, 80.5, 78.5, 77.1, 53.1 (CH), 96.5, 95.3, 44.6
(CH2), 56.2, 55.9, 26.1, −4.7, −5.0 (CH3). IR wmax 3071,
3032, 2930, 2891, 2857, 1494, 1472, 1403, 1361, 1254,
1214, 1151, 1103, 1036, 939, 920, 867, 811, 777, 703
cm−1. HR EIMS m/z (% rel. int.) 381.2101 (M+−OMe,
1), 221 (35), 193 (33), 177 (36), 143 (52), 119 (42), 89
(100), 73 (66). Calcd for C21H36O6Si−OMe, 381.2097.
Anal. calcd for C21H36O6Si: C, 61.13; H, 8.79. Found
C, 61.28; H, 8.79%.
3.16. (2S,3R,4R,5S)-4-(tert-Butyldimethylsilyloxy)-3,5-
bis(methoxymethoxy)-5-phenylpentane-1,2-diol, 13b
1
Oil: [h]2D2 +79.4 (c 1.25, CHCl3). H NMR (500 MHz) l
7.40–7.20 (5H, m), 4.85 (1H, d, J=4.2 Hz), 4.64 (1H, d,
J=6.3 Hz), 4.63 (1H, d, J=6.5 Hz), 4.57 (1H, d, J=6.3
Hz), 4.56 (1H, d, J=6.5 Hz), 4.10 (1H, dd, J=5.8, 4.2
Hz), 4.05 (1H, m), 3.66 (2H, m), 3.42 (1H, dd, J=5.8,
3.8 Hz), 3.39 (3H, s), 3.34 (3H, s), 2.60 (1H, br s, OH),
1.70 (1H, br s, OH), 0.91 (9H, s), 0.04 (3H, s), −0.23
(3H, s). 13C NMR (125 MHz) l 138.5, 18.2 (C), 128.2,
127.9, 127.8, 80.8, 78.9, 75.6, 70.3 (CH), 98.7, 95.2, 64.0
(CH2), 56.3, 56.1, 26.1, −4.6, −5.1 (CH3). IR wmax 3400
(br), 2927, 2890, 2858, 1457, 1253, 1205, 1144, 1115,
1014, 942, 835, 772 cm−1. HR CIMS m/z (% rel. int.)
431.2450 (M+H+, 40), 399 (16), 369 (26), 337 (100), 279
(36), 205 (39), 157 (46), 146 (46). Calcd for C21H39O7Si,
431.2465. Anal. calcd for C21H38O7Si: C, 58.57; H, 8.89.
Found C, 58.60; H, 8.79%.
3.20. Conversion of 1,2-diols 13 into epoxides 15
Diol 13 (1 mmol) was dissolved under Ar in dry
CH2Cl2 (10 mL) and treated with PivCl (136 mL, 1.1
mmol), Et3N (170 mL, ca. 1.2 mmol) and DMAP (6 mg,
0.05 mmol). The mixture was stirred at room tempera-
ture for 2 h, then worked-up (extraction with CH2Cl2).
Removal of volatiles under reduced pressure gave an
oily crude monopivalate. The crude compound was
then dissolved under Ar in dry CH2Cl2 (5 mL) and
treated with MsCl (78 mL, 1 mmol), Et3N (170 mL, ca.
1.2 mmol) and DMAP (6 mg, 0.05 mmol). The mixture
was stirred at room temperature for 1 h, then worked-
up (extraction with CH2Cl2). Removal of volatiles
under reduced pressure gave a crude product which was
dissolved in MeOH (8 mL) and treated with K2CO3
(140 mg, ca. 1 mmol). The reaction mixture was then
stirred overnight at room temperature and filtered
through Celite (the Celite pad was additionally washed
with EtOAc). Removal of volatiles under reduced pres-
sure and column chromatography on silica gel (hex-
anes–EtOAc, 9:1) gave epoxides 15. Overall chemical
yields: 15a, 60%; 15b, 61%.
3.17. Conversion of 1,2-diols 13 into epoxides 14
Diol 13 (1 mmol) was dissolved under Ar in dry
CH2Cl2 (10 mL) and treated with n-Bu2SnO (5 mg, 0.02
mmol), p-TsCl (210 mg, 1.1 mmol) and Et3N (170 mL,
ca. 1.2 mmol).19 The mixture was stirred overnight at
room temperature, then filtered through Celite (the
Celite pad was additionally washed with EtOAc) and
evaporated under reduced pressure. The crude tosylate
was then dissolved in MeOH (8 mL) and treated with
K2CO3 (140 mg, ca. 1 mmol). The reaction mixture was
then stirred at room temperature for 1 h (TLC monitor-
ing!), filtered through Celite (the Celite pad was addi-
tionally washed with EtOAc) and evaporated under
reduced pressure. Column chromatography on silica gel
(hexanes–EtOAc, 9:1) gave epoxides 14. Overall chemi-
cal yields: 14a, 65%; 14b, 66%.
3.18. (2S)-2-[(1R,2R,3S)-2-(tert-Butyldimethylsilyloxy)-
1,3-bis(methoxymethoxy)-4-methylbutyl]oxirane, 14a
3.21. (2R)-2-[(1R,2R,3S)-2-(tert-Butyldimethylsilyloxy)-
1,3-bis(methoxymethoxy)-4-methylbutyl]oxirane, 15a
1
Oil: [h]2D2 −47.1 (c 2, CHCl3). H NMR (500 MHz) l
4.80 (1H, d, J=6.6 Hz), 4.78 (1H, d, J=6.8 Hz), 4.70
(1H, d, J=6.6 Hz), 4.61 (1H, d, J=6.8 Hz), 3.87 (1H,
dd, J=7.4, 4 Hz), 3.47 (1H, dd, J=7.4, 3.8 Hz), 3.41
(3H, s), 3.40 (3H, s), 3.36 (1H, dd, J=6.2, 4 Hz), 3.15
(1H, m), 2.80 (1H, t, J=4.8 Hz), 2.70 (1H, dd, J=4.8,
3 Hz), 2.00 (1H, m), 1.03 (3H, d, J=6.8 Hz), 0.92 (3H,
d, J=6.8 Hz), 0.91 (9H, s), 0.11 (3H, s), 0.09 (3H, s).
13C NMR (125 MHz) l 18.0 (C), 83.6, 79.3, 74.6, 52.2,
28.8 (CH), 98.5, 96.2, 43.9 (CH2), 55.9, 26.0, 20.8, 17.0,
−4.4, −4.8 (CH3). IR wmax 2957, 2934, 2860, 1472, 1254,
1154, 1100, 1032, 836, 776 cm−1. HR EIMS m/z (% rel.
int.) 347.2217 (M+−OMe, 9), 231 (26), 159 (57), 89 (45),
75 (100). Calcd for C18H38O6Si−OMe, 347.2254. Anal.
calcd for C18H38O6Si: C, 57.11; H, 10.12. Found C,
57.30; H, 10.00%.
1
Oil: [h]2D2 −34 (c 0.5, CHCl3). H NMR (500 MHz) l
4.78 (1H, d, J=6.7 Hz), 4.66 (1H, d, J=6.7 Hz), 4.61
(1H, d, J=6.7 Hz), 4.60 (1H, d, J=6.7 Hz), 3.91 (1H,
dd, J=6.7, 4 Hz), 3.60 (1H, t, J=4 Hz), 3.40 (1H, dd,
J=6.8, 4.4 Hz), 3.39 (3H, s), 3.37 (3H, s), 3.20 (1H, dt,
J=4, 3.5 Hz), 2.80 (2H, m), 1.96 (1H, m), 1.02 (3H, d,
J=7 Hz), 0.93 (3H, d, J=7 Hz), 0.93 (9H, s), 0.14 (3H,
s), 0.13 (3H, s). 13C NMR (125 MHz) l 18.1 (C), 83.5,
76.7, 74.2, 50.7, 29.2 (CH), 98.5, 96.9, 45.5 (CH2), 55.9,
55.7, 26.0, 20.8, 17.4, −4.3, −4.9 (CH3). IR wmax 2957,
2930, 2860, 1463, 1033, 836, 776 cm−1. HR FABMS
m/z 379.2508 (M+H+). Calcd for C18H39O6Si, 379.2516.
Anal. calcd for C18H38O6Si: C, 57.11; H, 10.12. Found
C, 57.33; H, 10.30%.

2324
J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
3.22. (2R)-2-[(1R,2R,3S)-2-(tert-Butyldimethylsilyloxy)-
25.9, 25.7, 14.1, −4.6, −4.8 (CH3). IR wmax 2960, 2934,
2860, 1471, 1378, 1369, 1254, 1214, 1154, 1098, 1028,
918, 901, 837, 777 cm−1. HR EIMS m/z (% rel. int.)
435.2792 (M+−Me, 4), 317 (26), 259 (26), 231 (32), 187
(36), 173 (46), 143 (74), 101 (100), 89 (47), 73 (56).
Calcd for C22H46O7Si−Me, 435.2778. Anal. calcd for
C22H46O7Si: C, 58.63; H, 10.29. Found C, 58.49; H,
10.20%.
1,3-bis(methoxymethoxy)3-phenylpropyl]oxirane, 15b
1
Oil: [h]2D2 +56.8 (c 1.6, CHCl3). H NMR (500 MHz) l
7.35–7.25 (5H, m), 4.73 (1H, d, J=6.6 Hz), 4.62 (2H, d,
J=6.6 Hz), 4.55 (1H, d, J=6.3 Hz), 4.37 (1H, d, J=6.6
Hz), 4.07 (1H, dd, J=6.5, 3.3 Hz), 3.35 (3H, s), 3.28
(1H, m), 3.22 (3H, s), 2.97 (1H, dd, J=5.5, 3.3 Hz),
2.80 (1H, dd, J=5.3, 4.2 Hz), 2.62 (1H, dd, J=5.3, 2.6
Hz), 0.94 (9H, s), 0.12 (3H, s), 0.00 (3H, s). 13C NMR
(125 MHz) l 139.4, 18.4 (C), 128.3, 128.0, 127.9, 79.6,
78.8, 76.5, 51.0 (CH), 97.4, 95.6, 47.1 (CH2), 55.9, 55.6,
26.2, −4.3, −5.0 (CH3). IR wmax 3019, 2933, 2857, 1472,
1215, 1035, 759 cm−1. HR EIMS m/z (% rel. int.)
381.2087 (M+−OMe, 1), 261 (35), 231 (39), 219 (42),
193 (43), 177 (44), 161 (43), 143 (34), 119 (52), 89 (83),
73 (100). Calcd for C21H36O6Si−OMe, 381.2097. Anal.
calcd for C21H36O6Si: C, 61.13; H, 8.79. Found C,
61.06; H, 8.98%.
3.26. (2S,3R,4R,5S)-4-(tert-Butyldimethylsilyloxy)-3,5-
bis(methoxymethoxy)nonane-1,2-diol, 21
1
Oil: [h]2D2 +17.6 (c 0.7, CHCl3). H NMR (500 MHz) l
4.82 (1H, d, J=6.6 Hz), 4.74 (1H, d, J=6.3 Hz), 4.65
(1H, d, J=6.6 Hz), 4.61 (1H, d, J=6.3 Hz), 4.02 (2H,
m), 3.70 (2H, m), 3.62 (1H, dd, J=8, 2 Hz), 3.55 (1H,
m), 3.44 (3H, s), 3.39 (3H, s), 1.75 (1H, m), 1.50–1.25
(5H, br m), 0.91 (3H, d, J=7 Hz), 0.90 (9H, br s), 0.11
(3H, s), 0.10 (3H, s). 13C NMR (125 MHz) l 17.9 (C),
81.2, 80.0, 73.6, 70.1 (CH), 99.4, 97.4, 63.2, 29.0, 28.9,
22.6 (CH2), 56.3, 55.6, 25.8, 14.0, −4.6, −5.0 (CH3). IR
wmax 3400 (br), 2934, 2862, 1473, 1367, 1215, 1179,
1028, 929, 873, 838, 758 cm−1. HR EIMS m/z (% rel.
int.) 347.2247 (M+−OMe−MeOH, 7), 289 (35), 259 (30),
231 (63), 187 (100), 147 (48), 73 (52). Calcd for
C19H42O7Si−OMe−MeOH, 347.2253. Anal. calcd for
C19H42O7Si: C, 55.58; H, 10.31. Found C, 55.59; H,
10.41%.
3.23. Conversion of 1,2-diol 19 into epoxide 18
Compound 19 was prepared in 83% yield from ketone
6 as described in the general aldolization–reduction
procedure. It was subsequently transformed into epox-
ide 18 according to the same procedures described
above for the sequence 9“15. Chemical yields of the
intermediate products: 20 (82%); 21 (81%); 18 (60%).
3.27. (2R)-2-[(1R,2R,3S)-2-(tert-Butyldimethylsilyloxy)-
1,3-bis(methoxymethoxy)heptyl]oxirane, 18
3.24. (4S)-2,2-Dimethyl-4-[(1R,2R,3S)-2-(tert-butyl-
dimethylsilyloxy)-1,3-dihydroxyheptyl]-1,3-dioxolane, 19
1
Oil: [h]2D2 +3.2 (c 2.2, CHCl3). H NMR (500 MHz) l
1
4.71 (1H, d, J=6.7 Hz), 4.66 (1H, d, J=6.5 Hz), 4.61
(1H, d, J=6.5 Hz), 4.60 (1H, d, J=6.7 Hz), 3.89 (1H,
dd, J=5, 4.7 Hz), 3.59 (1H, m), 3.53 (1H, t, J=4.7 Hz),
3.37 (3H, s), 3.36 (3H, s), 3.20 (1H, dt, J=4.7, 3.5 Hz),
2.80 (2H, m), 1.76 (1H, m), 1.60–1.30 (5H, br m), 0.91
(9H, s), 0.90 (3H, d, J=7 Hz), 0.11 (3H, s), 0.10 (3H,
s). 13C NMR (125 MHz) l 18.1 (C), 80.0, 77.1, 74.1,
50.7 (CH), 97.5, 96.9, 45.9, 30.2, 28.4, 22.8 (CH2), 55.6,
55.5, 25.9, 14.1, −4.6, −4.8 (CH3). IR wmax 2956, 2931,
2893, 2859, 1472, 1379, 1361, 1253, 1215, 152, 1102,
1042, 918, 838, 776, 759 cm−1. HR EIMS m/z (% rel.
int.) 361.2405 (M+−OMe, 1), 275 (16), 243 (18), 229
(45), 199 (46), 173 (100), 143 (77), 131 (36), 89 (58), 75
(70). Calcd for C19H40O6Si−OMe, 361.2410. Anal. calcd
for C19H40O6Si: C, 58.13; H, 10.27. Found C, 58.33; H,
10.30%.
Oil: [h]2D2 −2.1 (c 1.5, CHCl3). H NMR (400 MHz) l
4.30 (1H, ddd, J=6.7, 6.4, 5.5 Hz), 4.01 (1H, dd,
J=8.2, 6.4 Hz), 3.84 (1H, dd, J=8.2, 6.7 Hz), 3.67 (1H,
m), 3.60 (1H, dd, J=4.4, 2.2 Hz), 3.57 (1H, m), 2.50
(1H, br s, OH), 2.15 (1H, br s, OH), 1.88 (1H, m), 1.70
(1H, m), 1.60–1.20 (4H, br m), 1.42 (3H, s), 1.35 (3H,
s), 0.91 (9H, br s), 0.90 (3H, t, J=7 Hz), 0.12 (3H, s),
0.10 (3H, s). 13C NMR (100 MHz) l 109.2, 18.3 (C),
76.2, 75.5, 72.7, 70.3 (CH), 66.4, 34.5, 28.2, 22.7 (CH2),
26.7, 26.0, 25.4, 14.1, −4.1, −4.5 (CH3). IR wmax 3480
(br), 1463, 1380, 1339, 1255, 1217, 1067, 838. 1615
cm−1. HR EIMS m/z (% rel. int.) 347.2243 (M+−Me,
23), 247 (60), 215 (98), 187 (62), 173 (65), 161 (83), 143
(100), 101 (77), 75 (88). Calcd for C18H38O5Si−Me,
347.2253. Anal. calcd for C18H38O5Si: C, 59.63; H,
10.56. Found C, 59.41; H, 10.73%.
3.28. Conversion of epoxide 18 into acrylate 17
3.25. (4S)-2,2-Dimethyl-4-[(1R,2R,3S)-2-(tert-
butyldimethylsilyloxy)-1,3-bis(methoxymethoxy)heptyl]-
1,3-dioxolane, 20
CuI (67 mg, 0.35 mmol) was gently heated in vacuo
until the solid turned light yellow. The flask was then
filled with Ar and cooled to −30°C, followed by addi-
tion of dry THF (5 mL). A 1 M solution of vinylmag-
nesium bromide in THF (3.5 mL, 3.5 mmol) was then
added dropwise via syringe. The mixture was then
stirred for 15 min at −30°C. Epoxide 18 (295 mg, 0.75
mmol) was dissolved in dry THF (5 mL) and added
dropwise to the solution of the organocopper reagent.
The reaction mixture was then stirred for 3 h at the
same temperature. The reaction was then quenched
1
Oil: [h]2D2 −10.2 (c 1.7, CHCl3). H NMR (500 MHz) l
4.72 (3H, m), 4.60 (1H, d, J=6.6 Hz), 4.32 (1H, q,
J=6.3 Hz), 3.98 (2H, m), 3.85 (1H, t, J=5.3 Hz), 3.55
(2H, m), 3.40 (3H, s), 3.38 (3H, s), 1.75 (1H, m),
1.50–1.30 (5H, br m), 1.40 (3H, s), 1.33 (3H, s), 0.90
(12H, br s), 0.11 (3H, s), 0.10 (3H, s). 13C NMR (125
MHz) l 108.6, 18.0 (C), 79.3, 78.7, 76.1, 73.5 (CH),
97.7, 96.8, 66.1, 30.2, 28.2, 22.7 (CH2), 55.9, 55.8, 26.6,

J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
2325
with satd. aq. ammonium chloride (15 mL) and
3.31. Ring-closing metathesis of acrylate, 17
worked-up (extraction with CH2Cl2). Column chro-
matography on silica gel (hexanes–EtOAc, 9:1)
afforded alcohol 22 (280 mg, 89%).
A solution of acrylate 17 (237 mg, 0.5 mmol) and
Grubbs catalyst PhCHꢂRuCl2(PCy3)2 (41 mg, 0.05
mmol) in dry, degassed CH2Cl2 (50 mL) was heated
under Ar at reflux for 2 h. After removal of all
volatiles in vacuo, the crude residue was chro-
matographed on silica gel (hexanes–EtOAc, 4:1) to
furnish lactone 23 (185 mg, 83%).
Alcohol 22 (252 mg, 0.6 mmol) was dissolved under
Ar in dry CH2Cl2 (10 mL), cooled to 0°C and treated
at this temperature with Et3N (155 mL, 1.1 mmol),
acryloyl chloride (81 mL, 1 mmol) and DMAP (6 mg,
ca. 0.05 mmol). The mixture was then stirred
overnight at room temperature, poured onto satd. aq
NH4Cl and worked-up (extraction with CH2Cl2).
Column chromatography on silica gel (hexanes–
EtOAc, 19:1) furnished acrylate 17 (239 mg, 84%).
3.32. (5R)-6-[(1R,2R,3S)-2-(tert-Butyldimethylsilyloxy)-
1,3-bis(methoxymethoxy)heptyl]-5,6-dihydropyran-2-one,
23
White solid: mp 72–73°C; [h]2D2 +43.8 (c 1.25, CHCl3).
1H NMR (500 MHz) l 6.88 (1H, dt, J=9.7, Hz),
5.98 (1H, dd, J=9.7, 2.5 Hz), 4.80 (2H, m), 4.69 (1H,
d, J=6.2 Hz), 4.65 (1H, d, J=6.5 Hz), 4.51 (1H, d,
J=6.2 Hz), 3.90 (1H, br dd, J=7.9, 2.5 Hz), 3.76
(1H, br dd, J=7.9, 4 Hz), 3.50 (1H, dt, J=9.5, 3.3
Hz), 3.38 (3H, s), 3.35 (3H, s), 2.73 (1H, ddt, J=18,
12, 2.5 Hz), 2.30 (1H, br dt, J=18, 5 Hz), 1.77 (1H,
m), 1.50–1.25 (5H, br m), 0.90 (3H, d, J=7 Hz), 0.88
(9H, s), 0.09 (3H, s), 0.08 (3H, s). 13C NMR (125
MHz) l 164.0, 18.0 (C), 145.5, 121.0, 80.6, 78.4, 77.1,
72.9 (CH), 98.3, 97.1, 29.1, 28.9, 24.0, 22.7 (CH2),
56.1, 55.8, 25.9, 14.1, −4.5, −4.9 (CH3). IR wmax 2955,
2934, 2858, 1712, 1469, 1385, 1252, 1149, 1123, 1102,
1042, 1018, 923, 838, 779 cm−1. HR EIMS m/z (%
rel. int.) 415.2509 (M+−OMe, 3), 313 (26), 283 (100),
231 (16), 197 (11), 173 (10), 129 (12), 97 (16), 73 (20).
Calcd for C22H42O7Si−OMe, 415.2516. Anal. calcd for
C22H42O7Si: C, 59.16; H, 9.48. Found C, 59.29; H,
9.50%.
3.29. (4R,5R,6R,7S)-6-(tert-Butyldimethylsilyloxy)-5,7-
bis(methoxymethoxy)undec-1-en-4-ol, 22
1
Oil: [h]2D2 +26.3 (c 0.9, CHCl3). H NMR (500 MHz)
l 5.95 (1H, m), 5.10–5.05 (2H, m), 4.68 (2H, d, J=
6.5 Hz), 4.64 (1H, d, J=6.5 Hz), 4.60 (1H, d, J=6.5
Hz), 3.90 (1H, m), 3.77 (1H, dd, J=7.2, 3.8 Hz), 3.60
(1H, dt, J=8.5, 3.8 Hz), 3.53 (1H, dd, J=7.2, 4.5
Hz), 3.42 (3H, s), 3.38 (3H, s), 2.30 (1H, br dd, J=
14, 6 Hz), 2.20 (1H, m), 1.75 (1H, m), 1.55–1.25 (5H,
br m), 0.91 (3H, d, J=7 Hz), 0.89 (9H, s), 0.09 (6H,
s). 13C NMR (125 MHz) l 18.0 (C), 136.1, 85.8,
79.3, 73.6, 70.1 (CH), 116.3, 99.0, 96.5, 37.4, 29.4,
28.6, 22.7 (CH2), 55.9, 25.8, 14.0, −4.4, −4.9 (CH3).
IR wmax 3450 (br), 3030, 2956, 2932, 2859, 1642, 1464,
1255, 1102, 1035, 918, 873, 837, 777 cm−1. HR EIMS
m/z (% rel. int.) 389.2700 (M+−OMe, 1), 357 (1), 317
(32), 231 (80), 187 (100), 173 (57), 89 45), 73 (80).
Calcd for C21H44O6Si−OMe, 389.2723. Anal. calcd for
C21H44O6Si: C, 59.96; H, 10.54. Found C, 60.03; H,
10.59%.
3.33. Conversion of lactone 23 into boronolide 16
A solution of lactone 23 (90 mg, 0.2 mmol) in dry
SMe2 (2 mL) was cooled under Ar to −10°C and
treated with freshly distilled BF3·Et2O (500 mL, ca. 4
mmol). The resulting solution was stirred for 30 min
at the same temperature, then poured into satd. aq
NaHCO3 and worked-up (extraction with CH2Cl2).
After removal of all volatiles in vacuo, the crude
residue was used directly in the next step.
3.30. (4R,5R,6R,7S)-6-(tert-Butyldimethylsilyloxy)-5,7-
bis(methoxymethoxy)undec-1-en-4-yl acrylate, 17
White solid: mp 50–51°C; [h]2D2 +43.4 (c 1, CHCl3).
1H NMR (500 MHz) l 6.40 (1H, d, J=17.2 Hz),
6.12 (1H, dd, J=17.2, 10.3 Hz), 5.80 (2H, m), 5.32
(1H, br d, J=10.2 Hz), 5.06 (1H, br d, J=17.2 Hz),
5.00 (1H, br d, J=10.2 Hz), 4.75 (1H, d, J=6.6 Hz),
4.68 (1H, d, J=6.6 Hz), 4.58 (1H, d, J=6.6 Hz), 4.56
(1H, d, J=6.6 Hz), 3.81 (1H, br d, J=8.6 Hz), 3.76
(1H, br dd, J=8.6, 3.3 Hz), 3.53 (1H, dt, J=9.2, 3.3
Hz), 3.38 (6H, s), 2.58 (1H, m), 2.33 (1H, dd, J=15,
6 Hz), 1.77 (2H, m), 1.55–1.25 (4H, br m), 0.90 (3H,
d, J=7 Hz), 0.88 (9H, s), 0.10 (3H, s), 0.08 (3H, s).
13C NMR (125 MHz) l 165.8, 18.0 (C), 134.9, 128.8,
80.1, 79.7, 73.9, 73.5 (CH), 130.2, 116.8, 98.3, 96.4,
33.0, 29.1, 28.3, 22.7 (CH2), 55.9, 55.8, 25.9, 14.1,
−4.5, −4.9 (CH3). IR wmax 2958, 2929, 2862, 1722,
1641, 1463, 1405, 1256, 1197, 1090, 1028, 976, 873,
835, 810, 776 cm−1. HR EIMS m/z (% rel. int.)
443.2837 (M+−OMe, 1), 341 (18), 271 (34), 239 (100),
173 (36), 129 (60). Calcd for C24H46O7Si−OMe,
443.2829. Anal. calcd for C24H46O7Si: C, 60.72; H,
9.77. Found C, 60.89; H, 9.62%.
The crude product from above was dissolved in ace-
tonitrile (3 mL) and treated with 48% aq HF (50 mL,
1.2 mmol). The resulting solution was stirred for 3 h
at room temperature, then neutralized with solid
NaHCO3, filtered and evaporated to dryness under
reduced pressure. The oily residue was dissolved
under Ar in dry CH2Cl2 (5 mL) and treated with
Et3N (170 mL, 1.2 mmol), acetic anhydride (96 mL, 1
mmol) and DMAP (12 mg, ca. 0.1 mmol). The mix-
ture was then stirred for 3 h at room temperature,
poured onto satd. aq NH4Cl and worked-up (extrac-
tion with CH2Cl2). Column chromatography on silica
gel (hexanes–EtOAc, 1:1) furnished 16 (34 mg, 46%
overall), which showed physical and spectral proper-
ties identical to those published:15a,c colourless crys-
tals, mp 88–90°C, lit.1 mp 90°C; [h]2D2 +25.1 (c 0.1,
EtOH), lit.1 [h]D22 +25 (c 0.2, EtOH). 1H NMR (500

2326
J. Murga et al. / Tetrahedron: Asymmetry 13 (2002) 2317–2327
MHz) l 6.86 (1H, ddd, J=9.7, 6.2, 2.5 Hz), 6.02 (1H,
dd, 9.7, 2.5 Hz), 5.33 (2H, m), 5.00 (1H, q, J=6 Hz),
4.52 (1H, dt, J=12, 4.5 Hz), 2.52 (1H, ddt, J=18, 11.8,
2.5 Hz), 2.30 (1H, m), 2.12 (3H, s), 2.08 (3H, s), 2.06
(3H, s), 1.55 (2H, m), 1.25 (4H, m), 0.87 (3H, t, J=6.5
Hz). 13C NMR (125 MHz) l 170.5, 169.9, 169.7, 162.5,
144.1, 121.5, 75.2, 71.7, 70.8, 70.7, 30.3, 27.1, 25.2, 22.4,
21.0, 20.7, 20.6, 13.9. IR wmax 1736 (br), 1374, 1220,
1030, 816 cm−1. HR EIMS m/z (% rel. int.) 371.1699
(M+H+, 1), 273 (16), 242 (86), 182 (69), 140 (100), 97
(37). Calcd for C18H27O8, 371.1706.
conceptually related synthon based on a dihydroxyacetone
derivative, see: Enders, D.; Jegelka, U. Tetrahedron Lett.
1993, 34, 2453–2456.
4. Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259–281.
5. (a) Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G.; Ohno, M., Eds.; Springer, Berlin, 1990; (b)
Tatsuta, K. in Ref. 2a, pp. 1–38; (c) Blizzard, T.; Fisher,
M.; Mrozik, H.; Shih, T. in Ref. 2a, pp. 65–102; (d) Isobe,
M. in Ref. 2a, pp. 103–134; (e) Beau, J.-M. in Ref. 2a, pp.
135–182; (f) Yonemitsu, O.; Horita, K. in Ref. 2a, pp.
447–466; (g) Norcross, R. D.; Paterson, I. Chem. Rev. 1995,
95, 2041–2114.
6. Carda, M.; Rodr´ıguez, S.; Murga, J.; Falomir, E.; Marco,
J. A.; Ro¨per, H. Synth. Commun. 1999, 29, 2601–2610.
7. We have shown1a that other silyl groups (TES, TPS) on the
hydroxyl group at C-1 are also suitable for boron aldol
reactions with ketones 1. Since these protecting groups
differ in their stability to various reaction conditions, the
projected synthetic sequence will dictate which one is the
most convenient in each case.
8. This reduction is done in situ by addition of LiBH4 to the
boron aldolate mixture prior to work-up: Paterson, I.;
Channon, J. A. Tetrahedron Lett. 1992, 33, 797–800.
9. Silyl groups proved less convenient here. Substrates 9 with
R=TBS were sensitive to acidic conditions, such as those
of the oxidative cleavage with periodic acid.
Acknowledgements
The authors acknowledge financial support by the
DGI-MCYT (project BQU2002-00468) and by BAN-
CAJA (project P1B99-18). The authors further thank
Dr. H. Ro¨per, Eridania Be´ghin-Say, Vilvoorde, Bel-
gium, for a very generous supply of L-erythrulose, and
the S.C.S.I.E. of the University of Valencia, for mass
spectrometry measurements. One of the authors (J.M.)
thanks the Spanish Ministry of Science and Technology
for a Ramo´n y Cajal fellowship.
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