Stereoselective synthesis of functionalised triol units by SnCl4 promoted allylation of α-benzyloxyaldehydes: Crucial role of the stoichiometry of the Lewis acid

Article abstract of DOI:10.1016/j.tet.2004.06.084

Enantiomerically pure syn-anti and syn-syn configured triol units are efficiently synthesized by the SnCl₄ mediated allylation of chiral α-benzyloxyaldehydes with the uniquely functionalised allylstannane 9. Remarkably, the stereochemistry of t

Full text of DOI:10.1016/j.tet.2004.06.084

Tetrahedron 60 (2004) 7693–7704
Stereoselective synthesis of functionalised triol units by SnCl4
promoted allylation of a-benzyloxyaldehydes: crucial role of the
stoichiometry of the Lewis acid
a
Christophe Dubost, Bernard Leroy, Istvan E. Marko, Bernard Tinant, Jean-Paul Declercq
a
a
b
b
,
*
´
and Justin Bryansc
a
´ ´ ´ ´ ˆ
Unite de chimie organique et medicinale, Departement de Chimie, Universite catholique de Louvain, Batiment Lavoisier, Place Louis
Pasteur 1, 1348 Louvain-la Neuve, Belgium
´ ´ ´ ˆ
Unite de chimie structurale, Departement de Chimie, Universite catholique de Louvain, Batiment Lavoisier, Place Louis Pasteur 1,
b
1348 Louvain-la Neuve, Belgium
cPfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
Received 7 April 2004; revised 10 June 2004; accepted 11 June 2004
Available online 2 July 2004
Dedicated with deep respect to Professor Dieter Seebach
Abstract—Enantiomerically pure syn–anti and syn–syn configured triol units are efficiently synthesized by the SnCl4 mediated allylation of
chiral a-benzyloxyaldehydes with the uniquely functionalised allylstannane 9. Remarkably, the stereochemistry of the adducts is solely
governed by the amount of Lewis acid employed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
reaction of allylic organometallic species with aldehydes
has emerged as one of the most synthetically useful
procedures for acyclic stereoselection. Over the past few
years, the allylation of chiral alkoxyaldehydes has been
extensively studied and has become a particularly valuable
tool for the construction of homoallylic alcohols. Numerous
allylic derivatives such as allylborons,4 allylchromiums,5
allyltins,6 etc. were found to be efficient reagent in this
transformation, leading to the desired adducts with high
stereoselectivity for this process (Fig. 2).
Numerous natural products, exhibiting interesting bio-
logical activities, contain a polyhydroxylated subunit in
their structures. These fragments are present, for example,
in molecules such as (þ)-boronolide1 1 or (þ)-aspicilin2 2,
which possess a syn–syn and syn–anti triol sequence,
respectively (Fig. 1).
Figure 1.
In views of the ubiquitousness of these polyol entities, it is
not surprising that numerous synthetic methods have been
developed to assemble these structures with excellent levels
of relative and absolute stereocontrol.3 Among others, the
Figure 2. R1¼Me, Et, nBu; R2¼OR, Me, SR P¼Bn, TBDMS, MOM.
Keywords: Allylation; Allylstannane; Chelation; Triols; Stereocontrol;
Lewis acid.
All four possible diastereoisomers of the triol subunit can be
obtained by varying the nature of the allylic metal, the
*
Corresponding author. Tel.: þ32-10-47-8773; fax: þ32-10-47-2788;
e-mail address: marko@chim.ucl.ac.be
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.084

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C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
Figure 3.
conditions of the reaction (Lewis acid catalysed, high
pressure or thermal), or the geometry of the double bond7
present in the allylating agent. Roush et al.4a–c showed that
b-substituted allylborons provided access to 5, 6 and 7 but
each isomer corresponds to a specific combination of the
double bond geometry of 4 and the nature of the ligand on
the boron. Chromium5 derivatives were found to be less
flexible, giving access only to isomer 8. In sharp contrast,
allyltin species afford isomers 5 and 8, depending upon the
type of transition states involved in the condensation.8 Thus
Lewis acids such as BF3·Et2O give rise to isomer 8 through a
non chelating Felkin–Anh process whilst MgBr2 a chelating
Lewis acid provides access to isomer 5 as described by
Keck.8a–d Furthermore, Marshall8f–g has reported comple-
mentary examples of this transformation by using enantio-
enriched (g-alkoxyallyl) stannanes, which provide well
defined (E) configured alkenes. Therefore, the use of
b-alkoxyallylstannanes has become an efficient method
for the assembly of stereodefined triols by modulating the
experimental parameters.
selectivity can be explained by the preferential pseudo-axial
configuration adopted by the carbamate substitutent in the
chair-like transition state 14b leading to a better chelation of
the titanium (Fig. 5). This preferred configuration is in
agreement with previous observations reported by
Yamamoto.12
Recently, we became interested in the reactivity of the
uniquely functionalised allylstannane 9 and studied its
condensation with various aldehydes. In the presence of
BF3·Et2O, the syn diols9 10a–d were stereoselectively
produced (Fig. 3).
Figure 5. Synthesis of allystannane 9.
Having access to large quantities of 9, we next turned our
attention to its condensation with various aldehydes. In the
presence of BF3·Et2O simple aldehydes reacted smoothly
with 9 to afford selectively the syn diol9 products 10a–d
(Fig. 3). In order to extend the scope of this allylation
protocol, we decided to study the Lewis acid catalysed
addition of 9 to various a-alkoxyaldehydes.
Extension of this methodology to a-alkoxyaldehydes should
increase its scope by giving access to stereodefined,
protected, triols. In this article, we wish to report in full
our results on the successful implementation of this
approach.
The desired aldehydes were prepared from the correspond-
ing racemic or enantiomerically pure a-hydroxy esters
15(b–d), by protection of the alcohol function with a benzyl
substitutent followed by reduction of the ester group (Fig. 6).
The benzyl protection was introduced using
benzyltrichloroacetimidate under acidic catalysis.13 This
protocol suppressed some undesired transesterification
problems we have encountered with the classical
procedure using benzylbromide.14 The a-benzyloxyesters
16(b–d) were then submitted to controlled reduction with
DIBAL-H to afford the expected aldehydes 17(b–d) in good
yields.
Allylic alcohol 12 was prepared in good yield according to
the procedure described by Trost10 and starting from
methallylalcohol 11 (Fig. 4). Allylsilane 12 was then
condensed with isopropylcarbamoylchloride to afford
allylcarbamate 13 in 93% yield. The use of NaH as the
base and of Et2O as the solvent proved essential to obtain
high yields of the desired products. Deprotonation of 13
with secBuLi,11 followed by transmetallation with
Ti(OiPr)4, generated the allyltitanium species 14a, which
subsequently reacted with tributyl tin chloride to give the
allylating agent 9 in high yields.
Figure 4. (i) nBuLi, TMEDA, TMSCl, Et2O/THF, 278 8C; (ii) H2SO4,
THF rt (47% 2 steps); (iii) (iPr)2NCOCl, NaH, Et2O, 0 8C to rt (93%);
(iv) secBuLi, TMEDA, Ti(OiPr)4, Bu3SnCl, Et2O, 278 8C (80%).
This reaction proceeded efficiently at 278 8C and gave only
the (Z)-isomer of allylstannane 9. The observed stereo-
Figure 6. (i) Benzyl-2,2,2-trichloroacetimidate, TfOH cat., Hex/CH2Cl2, rt;
(ii) DIBALH, CH2Cl2, 278 8C.

C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
7695
Figure 7.
Figure 8. proposed allylation mechanism.
The enantiomeric purity of the optically active aldehydes
was controlled by 1H NMR spectroscopy using Eu(hfc)3 as
resolving agent or by HPLC whenever possible. In all cases,
the freshly prepared aldehydes exhibited an enantiomeric
purity greater than 95%.
This methodology takes advantage of the rapid trans-
metallation15 that occurs between an allyltrialkylstannane
and tin tetrachloride, producing an allylic trichlorometal
species 18a that exhibits a higher reactivity and a stronger
coordinating power as compared to the parent allylic
trialkyltin reagent. The a-isomer 18a is in dynamic
equilibrium with its g-form 18b either through an
intramolecular transposition of tin or by reaction of 18a
with tin tetrachloride still available in the reaction
medium. The condensation of intermediate 18a with an
aldehyde then leads to the a-adducts 19a, whilst
reaction with 18b produces the d-addition product 19b
(Fig. 8).
Surprisingly, under these conditions that proved successful
with simple aldehydes, a-alkoxyaldehydes such as 17b did
not give rise to the desired products.
Several Lewis acids were then screened and tin tetrachloride
was found to be the reagent of choice for this transformation
(Fig. 7).
Table 1. Conditions optimisationa
Entry
Eq. of SnCl4
T (8C)
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1,2 dichloropropane
CClF3/CH2Cl2 9/1
Equilibration time
Ratio 20a/20b/20cb
1
2
3
4
5
6
7
8
9
1
1
1
1
2
2
2
2
2
260
276
276
296
260
276
296
2102
(^)-120
1 h 30 min
2 h 30 min
1 h
85/15/0
97/3/0
96/4/0
1 h
97/3/0
1 h 30 min
1 h 30 min
1 h
1 h
1 h
16/31/53
7/57/36
1/83/16
20/80/0
7/45/48
a
The isolated yields were equal to the NMR yields.
1
Determined by integration of the H NMR signal belonging to the vinylic protons.
b

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C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
Figure 9.
To the best of our knowledge, such inversions related to the
stoichiometry of the Lewis acid employed have never been
reported in the literature and this parameter seems, in most
of the cases, to have been largely underestimated. Examples
of allylation by similar g-substituted allyltin compounds,
mediated by magnesium dibromide or titanium tetrachloride
and affording syn–syn alcohols with high stereoselectivity
have already been described.8d–g However, in these cases,
the amount of Lewis acid has never been considered as a key
parameter to influence the stereochemical outcome of the
reaction.
Figure 10. Cyclic transition state.
Such a transmetallation also occurs with allylsilanes, though
it has been shown to proceed more slowly.16
To rationalise these results, we propose the involvement of
two different transition states. When one equivalent of
SnCl4 is used, the transmetallated species 18b would react
with the aldehyde through a bicyclic transition state 21 as
depicted in Figure 10. This transition state has been
postulated for thermal and high pressure reactions of
allyltrialkyltin reagents. In these cases, the tin plays the
role of a weak Lewis acid.17 In contrast the trichlorotin
generated under our conditions, possesses a greater chelat-
ing ability. The carbamate would thus adopt a pseudo-axial
orientation in order to interact with the tin which is already
chelated to the benzyl ether and to the carbonyl of the
aldehyde. Allyl transfer through this rigid, hydrindane-like,
transition state then leads to the observed syn–anti
selectivity.
Since a mixture of a- and d-adducts are produced under
these initial conditions, and taking into account the
proposed transmetallation mechanism, we reasoned that
by changing the temperature of the reaction, it might be
possible to alter the position of the equilibrium and hence
produce either 19a or 19b at will. Our first attempts were
carried out by mixing 9 and SnCl4 at low temperature
followed, after a period of equilibration of one hour, by the
addition of 17b. We were delighted to observe that under
these conditions the g-adduct 19b largely predominated
(Table 1). Lowering the temperature even further resulted in
a significant improvement of the diastereoselectivity and, at
296 8C, a d.r. of 97:3 in favour of the syn–anti isomer 20a
was observed. In order to further improve this procedure,
two equivalents of SnCl4 were added instead of one. Much
to our surprise, an inversion of diastereoselectivity
occurred, leading to the preferential formation of the
previously minor syn–syn diastereoisomer 20b.
In contrast, when 2 equiv. of SnCl4 are used, one equivalent
reacts with the aldehyde to form the chelate 22 whilst the
second equivalent of Lewis acid transmetallates the
allylating agent 9.18,19 The allyl transfer now takes place
through an open transition state such as 23, leading to the
syn–syn diastereoisomer 20b (Fig. 11). Such a reaction
pathway has been proposed by Keck et al.8a–d to rationalize
the selectivities observed during the allylation of aldehydes
with crotyl tin derivatives. In this case, the carbamate will
occupy the less hindered quadrant.
Again, lowering the temperature resulted in the over-
whelming generation of 20b (d.r.¼83:1). Thus, in the
presence of one equivalent of SnCl4, allylstannane 9 reacts
quantitatively with 17b to afford the syn–anti diastereo-
isomer 20a whilst the use of two equivalents of the same
Lewis acid resulted in a complete inversion of selectivity,
leading to the syn–syn isomer 20b (Fig. 9).
The choice of the protecting group present on the
Figure 11. Open transition state.

C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
7697
Table 2. Effect of the order of additiona
Entry
Eq. of SnCl4
T (8C)
Solvent
Equilibration time (h)
Ratio 20a/20b/20cb
1
2
2
2
296
2102
CH2Cl2
1,2 dichloropropane
1
1
1/78/21
15/75/5
a
The isolated yields were equal to the NMR yields.
1
Determined by integration of the H NMR signal belonging to the vinylic protons.
b
Table 3. Allylation of chiral aldehydes
Entry Aldehyde
Product
Yielda (%)
deb (%)
eec
1d
84
90
n.ae
2d
3d
4f
5f
96
81
70
83
81
94
94
91
97
90
.95%
.95%
n.ae
.95%
.95%
6f
a
Isolated yields.
b
c
d
e
f
1
Determined by integration of the H NMR signal belonging to the vinylic protons.
Determined by chiral HPLC.
Using 1 equiv. of SnCl4.
Diol obtained as a racemic mixture.
Using 2 equiv. of SnCl4.

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alkoxyaldehyde is of paramount importance for the success
of this reaction. The use of benzyl ether, exhibiting a high
Lewis basicity on the oxygen, enables the formation of a
strong chelate. In sharp contrast, the use of a silicon-based
protecting group such as a TBDMS which prevents efficient
coordination by the Lewis acid leads to poor selectivities.
racemisation is a slower process than addition of the
allylating agent.
At this stage, it is important to note that each oxygen
function of the triol unit present in adducts 24a–c and
25a–c is differently substituted. Such orthogonal protection
allows subsequent chemoselective transformations to be
readily effected on adducts 20a–b as shown in Figure 12.
In order to lend further support to the postulated open-
transition state pathway, it was decided to effect the
transmetallation first and then to add to the in situ generated
allyltrichlorotin species 18b, one equivalent of the pre-
complexed aldehyde. As can be seen from Table 2, the same
ratios are obtained, at two different temperatures, either
using this ‘inverse’ protocol or the ‘normal’ addition
procedure described previously. (Vide supra). This
observation lends further credit to our proposed transition
states.
The stereochemistry of both syn–anti and syn–syn triol
units was determined by synthesizing the acetonides derived
from each pair of vicinal diols, themselves obtained by
chemoselective deprotection of either the carbamate or the
1
benzylether function. Analysis of the H NMR coupling
constants between the adjacent protons at C2, C3 and C3,
C4 is a reliable method to determine the stereochemistry of
these two stereogenics centres.20
Having demonstrated that the addition of the allylating
agent 9 onto a variety of racemic a-benzyloxyaldehydes
proceeded with excellent levels of diastereocontrol, we
turned our attention to the use of optically pure substrates
with a view to generate enantioenriched triols. Our results
are summarised in Table 3.
Initially, treatment of 20a and 20b by BF3·Et2O removed the
allylic silane which proved to be troublesome at times.
Substrates 26(a–b) were then hydrogenated in order to
cleave the benzyl ether. This reaction occurred with
concomitant reduction of the C–C double bond. Alterna-
tively, reduction of the carbamate moiety with LiAlH4
afforded diols 27b and 27d. Finally, the reaction of the
resulting diols 27(a–d) with acetone under acidic con-
ditions produces the desired acetonides 28(a–d) (Fig. 12).
In all cases, the triols were formed in good to excellent
yields (70–96%) and with high diastereoselectivities.
(90–97%). Gratifyingly, no erosion of the enantiopurity of
the starting a-benzyloxyaldehydes was observed and the
final adducts were isolated in essentially optically pure form
(Table 3, entries 2, 3, 5 and 6). It thus transpires that
1
The H NMR data clearly revealed that in all cases, the
vicinal diols were syn configured (3J.8 Hz) except in the
case of 28b where an anti configuration (3J,7 Hz) was
Figure 12. (i) BF3·Et2O, DCM, 215 8C; (ii) H2, Pd/C cat., AcOEt, 40 8C; (iii) LialH4, THF, reflux; (iv) Acetone, APTS, reflux.

C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
7699
Figure 13. Cross-eyed stereo view of X-ray analysis of acetate derivative 29.
observed. Finally, having access to the enantiomerically
pure, chemoselectively protected compounds 24b and 25b,
we attempted to derivatize the free alcohol function in order
to obtain suitable crystals for an X-ray diffraction analysis.
Gratifyingly, the acetate 29, derived from the syn–anti triol
24b eventually crystallised upon standing. A three-
dimensional view of compound 29 clearly reveals the
syn–anti relationship between the three oxygenated func-
tions, thus fully corroborating our previous assignments
(Fig. 13).
(S)-Methyl 2-hydroxypropanoate 15b is commercially
available from Sigma-Aldrich and was used as received.
2-(Benzyloxy)acetaldehyde 17a is commercially available
from Acros and was used as received.
2.2. Synthesis of allylstannane 9
2.2.1. 2-((Trimethylsilyl)methyl)prop-2-en-1-ol 12. In a
2 l round bottom flask equipped with a mechanical stirrer
were added TMEDA (140 ml, 107.73 g, 0.92 mol,
2.6 equiv.) and freshly distilled Et2O (440 ml). At 0 8C, a
solution of nBuLi (10 M in hexane, 100 ml, 1 mol,
2.8 equiv.) is added via a large diameter canula. Then,
methallylic alcohol 7 (30 ml, 25.71 g, 0.35 mol, 1 equiv.)
was added dropwise to the solution, at 0 8C. (300 ml) Dry
THF was added and the resulting orange solution was
allowed to reach room temperature and was stirred for 24 h
to afford a red gum. The mixture was cooled to 230 8C and
TMSCl (204 ml, 1.60 mol, 4.5 equiv.) was added slowly.
The cooling bath was removed and the white suspension
was stirred 15 min at room temperature to give a brown
suspension. After dilution with Et2O (1.2 l), the mixture was
quenched with a saturated aqueous solution of NaHCO3
(1.2 l). The organic phase was separated and washed with a
saturated aqueous solution of CuSO4 (1.2 l), water (1.2 l)
and dried with MgSO4. The solvent was then removed under
reduced pressure and the resulting viscous oil is distilled
(90–120 8C at 20 mbar) to give 36.51 g (47%) of allylsilane
12. 1H NMR (200 MHz, CDCl3) d: 4.90 (1H, bs), 4.62 (1H,
bs), 3.94 (2H, s), 1.48 (2H, s), 0.13 (9H, s), 0.01 (9H, s); 13C
NMR (50 MHz, CDCl3) d: 145.92, 106.62, 66.49, 22.77,
20.47, 21.37; IR (neat, NaCl) 2957, 1647, 1636, 1251,
1085 cm21; MS (CI) m/z: 216.0 (Mzþ).
In summary, we have developed an efficient methodology
for the rapid assembly of consecutive triols arrays in
good yields (70–96%) and high diastereoselectivities (de.
90–97%). A remarkable and complete inversion of stereo-
chemistry is observed when the amount of Lewis acid is
varied. Thus, 1 equiv. of SnCl4 leads to the syn–anti triol
whilst two equivalents give access to the syn–syn triol. This
stereodivergent behaviour has been rationalized by invoking
the participation of two different transition states. This
convenient procedure allows a ready access to stereo-
complementary, orthogonally protected triol subunits
present in a variety of interesting natural products. The
scope and limitations of this protocol and its application to
the preparation of highly oxygenated natural products are
currently under active investigation. The results of these
studies will be reported in due course.
2. Experimental
2.1. Generalities
Unless otherwise stated all the reactions were carried out
using anhydrous conditions and in an atmosphere of argon.
1H and 13C NMR spectra were recorded on Varian Gemini
200, 300 and 2000 instruments. Chemical shifts are
expressed as parts per million (ppm) down-field from
tetramethylsilane or calibrated from CDCl3. Mass spectra
were obtained using Varian MAT-44 and Finnigan MAT-
TSQ 70 spectrometers with electron impact (70 eV) and
chemical ionisation (100 eV, ionisation gas, isobutane). IR
spectra were taken with a BIO-RAD FTS 135 spectrometer.
2.2.2. 2-((Trimethylsilyl)methyl)allyl diisopropylcarba-
mate 13. Allylsilane 12 (3 g, 13.85 mmol, 1 equiv.) was
dissolved in 50 ml of THF and a 1 N aqueous solution of
sulfuric acid (6 ml, 3 mmol, 0.21 equiv.) was added. The
mixture was stirred for 1 h 30 min and then neutralised with
solid K2CO3 until pH 7 was reached. After dilution with
water (50 ml) and extraction with Et2O, the organics were
combined and dried over MgSO4. Removing of the solvent
under reduced pressure afforded a viscous oil. This oil,
diluted in 12 ml of Et2O, was poured dropwise over a
suspension of NaH (60% in mineral oil, prewashed with
Et2O (833 mg, 20.83 mmol, 1.5 equiv.) in Et2O (12 ml) at
0 8C. A solution of diisopropylcarbamoyl chloride (4.54 g,
27.77 mmol, 2 equiv.) in Et2O (12 ml) was added slowly.
¨
Microanalysis were performed in Professor V. Jager’s
analytical laboratory (Institut fu¨r Organishe Chemie,
¨
Universitat Stuttgart, Germany). High resolution mass
spectra were recorded in Professor R. Flamant’s laboratory
´
(Universite de Mons, Belgium).

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C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
The mixture was then allowed to reach room temperature
and to stir for 18 h. The reaction was quenched by adding
slowly a saturated aqueous solution of NH4Cl (30 ml)
and the aqueous layer was extracted with CH2Cl2
(2£30 ml). The organics were combined, dried over
MgSO4 and evaporated. The residual oil was purified
by column chromatography (PE/EA¼30/1, Et3N 5%) to
give pure allylcarbamate 13 (3.48 g, 93%) as a colourless
oil; 1H NMR (200 MHz, CDCl3) d: 4.85 (1H, q,
J¼1.6 Hz), 4.66 (1H, bs), 4.43 (2H, s), 3.61–4.19
(2H, m), 1.52 (2H, s), 1.18 (12H, d, J¼6.2 Hz), 0.02
(9H, s); 13C NMR (50 MHz, CDCl3) d: 155.93, 143.45,
109.21, 68.64, 46.56, 24.35, 21.70, 20.75; IR (neat,
NaCl) 3084, 2998, 2967, 2894, 1699, 1645, 1439, 1368,
1314, 1296, 1249, 1219, 1158, 1134, 1067, 843,
770 cm21; MS (CI) m/z: 271.2 (Mzþ); Anal. calcd for
C14H29NO2Si C, 61.94; H, 10.77 N, 5.16; found C, 61.97;
H, 10.88; N, 5.10.
1450, 1261, 1220, 1117, 986 cm21; MS (CI) m/z: 172.9
(MþHþ).
2.3. General procedure for the preparation of the
a-benzyloxy esters
The corresponding a-hydroxyester was dissolved in CH2Cl2
(0.5 ml/mmol of ester). At room temperature, were added
sequentially a solution of 2,2,2-trichlorobenzylacetimidate
(2 equiv.) in hexane (1.5 ml/mmol) and triflic acid (5%
mol). The white suspension that formed was stirred for 16 h
at room temperature. The white solid was filtered off and
rinsed with hexane. The filtrate was then washed with a
saturated aqueous solution of NaHCO3, the layers separated
and the aqueous phase extracted with hexane. The combined
organics were dried over MgSO4 and concentrated. The
resulting oil was purified by column chromatography to give
pure a-benzyloxyesters.
2.2.3. (Z)-3-(Tributylstannyl)-2-((trimethylsilyl)methyl)-
prop-1-enyl diisopropylcarbamate 9. In a 100 ml round
bottom flask were introduced TMEDA (1.11 ml, 858 mg,
7.38 mmol, 2 equiv.) and Et2O (15 ml). At 278 8C a
solution of secBuLi (1.3 M in hexanes, 5.67 ml,
7.38 mmol, 2 equiv.) was added dropwise and the mixture
allowed to stir 30 min at 278 8C. A solution of allylcarba-
mate 13 in Et2O (15 ml) was added quickly and the orange-
brown media was stirred 30 min at 278 8C. A solution of
tributyltin chloride (3.00 ml, 3.60 g, 11.07 mmol, 3 equiv.)
in Et2O (15 ml) was added quickly at 278 8C and the dry
ice/acetone cooling bath was replaced immediately with an
Ice/Water cooling bath. The yellow solution was stirred for
15 min at 0 8C, poured over an aqueous solution of HCl
(50 ml, 1 N) and diluted with Et2O (20 ml). The layers were
separated and the organic layer was washed with a saturated
aqueous solution of NaHCO3, dried over MgSO4 and
evaporated. The crude oil was purified by column
chromatography (PE/EA¼30/1) to give pure allylstannane
2.3.1. (S)-Methyl 2-(benzyloxy)propanoate 16c. The title
compound obtained as a colourless oil in 99% yield
following the general procedure; 1H NMR (300 MHz,
CDCl3) d: 7.39–7.23 (5H, m), 4.69 (1H, d, J¼11.7 Hz),
4.44 (1H, d, J¼11.7 Hz), 4.21 (2H, q, J¼7.1 Hz), 4.04 (2H,
q, J¼6.9 Hz), 1.43 (3H, d, J¼6.9 Hz), 1.29 (3H, t,
J¼7.1 Hz); 13C NMR (75 MHz, CDCl3) d: 173.15,
137.49, 128.31, 127.87, 127.73, 79.96, 71.88, 60.75,
18.64, 14.17; IR (neat, NaCl) 3058, 2984, 2937, 2902,
2872, 1751, 1449, 1264, 1133, 1065, 1026, 737 cm21; MS
(EI) m/z: 209.0 (MþHþ).
2.3.2. (R)-Methyl 2-(benzyloxy)-2-cyclohexylacetate 16d.
The title compound as a colourless oil in 49% yield
following the general procedure; 1H NMR (300 MHz,
CDCl3) d: 7.39–7.30 (5H, m), 4.68 (1H, d, J¼11.7 Hz),
4.35 (1H, d, J¼11.7 Hz), 3.74 (H, s), 3.72 (1H, d, J¼6 Hz),
1.85–1.60 (5H, m), 1.35–1.05 (6H, m); 13C NMR (75 MHz,
CDCl3) d: 172.85, 137.52, 128.22, 127.88, 127.66, 82.93,
72.49, 51.65, 41.14, 29.11, 28.30, 26.19, 26.07, 25.97; IR
(neat, NaCl) 3031, 2927, 2854, 2669, 1735, 1452, 1268,
1
9 (1.61 g, 80%) as a colourless oil; H NMR (300 MHz,
CDCl3) d: 6.53 (1H, s), 3.91–3.95 (2H, m), 1.73 (2H, s),
1.17–1.63 (14H, m), 1.24 (12H, d, J¼6.8 Hz), 0.88 (9H, t,
J¼7.2 Hz), 0.74–0.96 (6H, m), 0.04 (9H, s); 13C NMR
(75 MHz, CDCl3) d: 153.05, 126.19, 120.34, 45.91, 29.15,
27.38, 22.94, 21.43, 13.95, 13.69, 9.68, 21.08; IR (neat,
NaCl) 3084, 2956, 2928, 2875, 2857, 1696, 1594, 1461,
1428, 1338, 1302, 1285, 1247, 1152, 1079, 1046, 857,
761 cm21; MS (EI) m/z: 561.4 (Mzþ); Anal. calcd for
C26H55NO2SiSn: C, 55.72; H, 9.89 N, 2.50; found C, 55.98;
H, 9.95; N, 2.45.
1120, 1012, 737 cm21
.
2.4. General procedure for the preparation of the
a-benzyloxy aldehydes
A solution of the corresponding ester in dry CH2Cl2
(5 ml/mmol of ester) was cooled to 278 8C. Cold DIBAL-H
(1.5 M in Tol, 1 equiv.) was added dropwise and the mixture
was allowed to stir at 278 8C for an hour. Then, small portions
of DIBAL-H were added every 15 min until all the starting
material disappeared by TLC (,1 more equiv.). After
completion of the reaction, a saturated aqueous solution of
NH4Cl was poured directly in the cold reaction mixture and
vigorous stirring was maintained until the mixture reached rt.
The layers were separated and the aqueous phase was
extracted with CH2Cl2 (3£50 ml). The combined organic
phase was dried over MgSO4 and concentrated. The residue
was either purified by column chromatography, to give pure
a-alkoxyaldehydes required for analysis, or used directly in
the subsequent step to avoid degradation.
2.2.4. (R)-Methyl 2-cyclohexyl-2-hydroxyacetate 15d.
(R)-hexahydromandelic
acid
(900 mg,
5.68 mmol,
1 equiv.) was dissolved in methanol (50 ml) and SOCl2
(4.14 ml, 6.75 g, 56.8 mmol, 10 equiv.) was added dropwise
at room temperature. After 30 min the mixture was
evaporated to dryness and dissolved in CH2Cl2, washed
with a saturated aqueous solution of NaHCO3, dried over
MgSO4 and concentrated. The crude product was obtained
in 99% yield was essentially pure ester 15c. 1H NMR
(300 MHz, CDCl3) d: 4.03 (1H, d, J¼3.3 Hz), 3.79 (3H, s),
2.70 (1H, bs), 1.9–1 (11H, m); 13C NMR (75 MHz, CDCl3)
d: 175.17, 74.84,52.38, 41.94, 29.10, 26.37, 26.262, 26.02,
25.97; IR (neat, NaCl) 3495, 2998, 2927, 2854, 2665, 1736,
2.4.1. (S)-2-(Benzyloxy)propanal 17c. The title compound
obtained as a colourless oil in 75% yield following the

C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
7701
1
general procedure; H NMR (300 MHz, CDCl3) d: 9.67
J¼6.9 Hz), 3.67 (1H, qd, J¼6.3, 3.0 Hz), 3.56 (1H, td,
J¼7.4, 3.1 Hz), 2.44 (1H, d, J¼7.4 Hz), 1.58 (2H, bs), 1.28
(3H, d, J¼6.3 Hz), 1.19 (12H, m), 0.05 (9H, s); 13C NMR
(50 MHz, CDCl3) d: 153.98, 144.33, 138.34, 128.33,
128.01, 127.61, 111.99, 77.7, 75.06, 73.62, 71.40, 45.92,
22.56, 20.94, 16.76, 21.05; IR (neat, NaCl) 3488, 3067,
3032, 2966, 2928, 2876, 1699, 1636, 1432, 1367, 1298,
1133, 1071, 1048, 848 cm21; MS (EI) m/z: 435.3 (M2Hþ).
[a]D20¼2.7 (c 1.0, CH2Cl2); Anal. calcd for C24H41NO4Si: C,
66.17; H, 9.49; N, 3.21; found: C, 65.48; H, 9.46; N, 3.09.
(1H, d, J¼1.7 Hz), 7.38–7.26 (5H, m), 4.66 (1H, d,
J¼11.7 Hz), 4.60 (1H, d, J¼11.7 Hz), 3.90 (1H, qd,
J¼7.0, 1.7 Hz), 1.34 (3H, d, J¼7.0 Hz); 13C NMR
(75 MHz, CDCl3) d: 203.4, 137.23, 128.51, 128.02,
127.97, 79.35, 71.95, 15.26; IR (neat, NaCl) 3031, 2981,
2869, 1735, 1496, 1454, 1374, 1094, 1047, 737 cm21; MS
(EI) m/z: 165.1 (MþHþ).
2.4.2. (S)-2-(Benzyloxy)-2-cyclohexylacetaldehyde 17d.
The tile compound obtained as a colourless oil in 80%
yield following the general procedure; 1H NMR (300 MHz,
CDCl3) d: 9.66 (1H, d, J¼2.7 Hz), 7.35–7.32 (5H, m), 4.67
(1H, d, J¼11.7 Hz), 4.47 (1H, d, J¼11.7 Hz), 3.49 (1H, dd,
J¼5.7, 2.7 Hz), 1.85–1.6 (5H, m), 1.35–1.05 (6H, m); 13C
NMR (75 MHz, CDCl3) d: 204.43, 137.38, 128.36, 127.83,
87.67, 72.80, 39.57, 28.774, 28.03, 26.17, 26.04, 25.96; IR
(neat, NaCl) 3031, 2928, 2854, 1729, 1497, 1452,
734 cm21; MS (CI) m/z: 231.2 (M2Hþ).
2.5.3. (1R,2S,3R)-1-(Benzyloxy)-1-cyclohexyl-2-hydroxy-
4-((trimethylsilyl)methyl)pent-4-en-3-yl diisopropylcar-
bamate 24c. The tile compound obtained as a colourless oil
1
in 81% yield following the general procedure; H NMR
(300 MHz, CDCl3) d: 7.41–7.26 (5H, m), 5.15 (1H, d,
J¼8.7 Hz), 5.04 (1H, s), 4.89 (1H, d, J¼1 Hz), 4.64 (1H, d,
J¼11 Hz), 4.59 (1H, d, J¼11 Hz), 3.90 (2H, bs), 3.75 (1H,
bd, J¼8.7 Hz), 3.28 (1H, d, J¼7 Hz), 2.52 (1H, bs),1.92–
0.8 (25H, m), 0.06 (6H, s); 13C NMR (75 MHz, CDCl3) d:
153.69, 144.37, 138.22, 128.25, 127.95, 127.58, 112.26,
81.39, 78.01, 74.374, 70.435, 45.92, 40.53, 29.61, 29.35,
26.60, 26.34, 26.30, 22.30, 21.41, 17.58, 13.703, 20.92; IR
(neat, NaCl) 3489, 3031, 2959, 2928, 2854, 1700, 1636,
1436, 1305, 1048, 851 cm21; MS (CI) m/z: 504.5 (M2Hþ);
HRMS (CIþ, MþHþ) calcd for C29H50NO4Si, 504.3509;
found 504.3519. [a]D20¼8.7 (c 1.0, CH2Cl2).
2.5. General procedure for the allylation of a-benzyl-
oxyaldehydes with 1 equiv. of SnCl4
Allylstannane 9 was dissolved in freshly distilled CH2Cl2
(30 ml/mmol of stannane) and cooled to 278 8C with a dry
ice–acetone bath. SnCl4 (1 M in CH2Cl2, 1 equiv.) was
added and the mixture allowed to stir at 278 8C for 1 h. A
solution of aldehyde in CH2Cl2 (10 ml/mmol of aldehyde),
cooled to 278 8C, was added dropwise with a canula over
5 min. The resulting mixture was stirred at 278 8C for 1 h.
The reaction bulk was then diluted with CH2Cl2 (2£volume)
and quenched with a saturated aqueous solution of
NaHCO3. The layers were separated and the aqueous
phase extracted 3£ with CH2Cl2. The combined organic
phase was dried over MgSO4 and concentrated. The
residue was purified by column chromatography to give
pure triols.
2.6. General procedure for the allylation of a-benzyl-
oxyaldehydes with 2 equiv. of SnCl4
Allylstannane 9 was dissolved in freshly distilled CH2Cl2
(30 ml/mmol of stannane) and cooled to 278 8C with a dry
ice–acetone bath. SnCl4 (1 M in CH2Cl2, 2 equiv.) was
added and the mixture allowed to stir at 278 8C for 1 h. The
solution was cooled to 297 8C with a MeOH/N2 bath and a
solution of aldehyde in CH2Cl2 (10 ml/mmol of aldehyde),
cooled to 297 8C, was added dropwise with a canula over
5 min. The resulting mixture was stirred at 297 8C for 1 h.
The reaction bulk was then diluted with CH2Cl2 (2£volume)
and quenched with a saturated aqueous solution of
NaHCO3. The layers were separated and the aqueous
phase extracted 3£ with CH2Cl2. The combined organic
phase was dried over MgSO4 and concentrated. The residue
was purified by column chromatography to give pure triols.
2.5.1. 1-(Benzyloxy)-2-hydroxy-4-((trimethylsilyl)-
methyl)pent-4-en-3-yl diisopropylcarbamate 24a. The
tile compound obtained as a colourless oil in 84% yield
following the general procedure; 1H NMR (300 MHz,
CDCl3) d: 7.24–7.35 (5H, m), 5.16 (1H, d, J¼4.8 Hz),
4.96 (1H, s), 4.82 (1H, s), 4.57 (1H, d, J¼12.0 Hz), 4.53
(1H, d, J¼12.0 Hz), 3.76–4.08 (3H, m), 3.62 (1H, dd
J¼10.0, 2.9 Hz), 3.50 (1H, dd, J¼9.9, 7.7 Hz), 2.99 (1H, d,
J¼5.3 Hz), 1.61 (1H, d, J¼14.4 Hz), 1.50 (1H, d,
J¼14.4 Hz), 1.17 (12H, d, J¼6.7 Hz), 0.06 (9H, s); 13C
NMR (75 MHz, CDCl3) d: 154.39, 143.04, 137.76, 128.12,
127.57, 127.41, 110.25, 78.28, 73.23, 70.69, 70.68, 45.54,
23.31, 20.52–20.94, 21.30; IR (neat, NaCl) 3447, 3029,
2965, 2931, 2875, 1700, 1636, 1435, 1368, 1317, 1248,
1133, 1048, 850 cm21; MS (CIþ) m/z: 422.3 (MþHþ);
HRMS (CIþ, MþHþ) calcd for C23H40NO4Si, 422.2734;
found 422.2726.
2.6.1. 1-(Benzyloxy)-2-hydroxy-4-((trimethylsilyl)-
methyl)pent-4-en-3-yl diisopropylcarbamate 25a. The
tile compound obtained as a colourless oil in 70% yield
following the general procedure; 1H NMR (300 MHz,
CDCl3) d: 7.19–7.31 (5H, m), 5.13 (1H, d, J¼4.3 Hz),
4.89 (1H, s), 4.76 (1H, s), 4.49 (2H, s), 3.91 (1H, dt J¼5.7,
4.3 Hz), 3.76–3.95 (2H, m), 3.50 (1H, dd J¼9.6, 4.8 Hz),
3.45 (1H, dd, J¼9.6, 6.2 Hz), 2.30–2.52 (1H, m), 1.54 (1H,
d, J¼14.4 Hz), 1.43 (1H, d, J¼13.9 Hz), 1.15 (6H, d,
J¼7.2 Hz), 1.14 (6H, d, J¼7.2 Hz), 0.01 (9H, s); 13C NMR
(75 MHz, CDCl3) d: 154.47, 143.60, 137.87, 128.28,
127.72, 127.58, 110.08, 76.99, 73.49, 71.36, 70.93, 45.97,
23.71, 20.70–21.58, 21.18; IR (neat, NaCl): 3457, 3065,
3032, 2965, 2930, 2866, 1699, 1630, 1437, 1368, 1300,
1248, 1126, 1050, 850 cm21; MS (EI) m/z: 421.5 (Mzþ);
HRMS (EIþ, Mþ) calcd for C29H39NO4Si, 421.2650; found
421.2648.
2.5.2. (3S,4R,5S)-5-(Benzyloxy)-4-hydroxy-2-((tri-
methylsilyl)methyl)hex-1-en-3-yl diisopropylcarbamate
24b. The tile compound obtained as a colourless oil in
97% yield following the general procedure; 1H NMR
(200 MHz, CDCl3) d: 7.38–7.27 (5H, m), 5.24 (1H, d,
J¼7.0 Hz), 5.04 (1H, s), 4.88 (1H, d, J¼1.2 Hz), 4.61 (1H,
d, J¼11.1 Hz), 4.46 (1H, d, J¼11.1 Hz), 3.90 (2H, hept,

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C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
2.6.2. (3R,4R,5S)-5-(Benzyloxy)-4-hydroxy-2-((tri-
methylsilyl)methyl)hex-1-en-3-yl diisopropylcarbamate
25b. The tile compound obtained as a colourless oil in
83% yield following the general procedure; 1H NMR
(200 MHz, CDCl3) d: 7.37–7.30 (5H, m), 5.29 (1H, d,
J¼3.3 Hz), 4.98 (1H, s), 4.85 (1H, s), 4.71 (1H, d,
J¼11.4 Hz), 4.48 (1H, d, J¼11.4 Hz), 4.03–3.87 (2H, m),
3.68–3.60 (2H, m), 2.71 (1H, d, J¼3.9 Hz), 1.63 (1H, d,
J¼14.1 Hz), 1.51 (1H, d, J¼14.1 Hz), 1.29 (3H, d,
J¼5.8 Hz), 1.24 (12H, d, J¼6.3 Hz), 0.09 (9H, s); 13C
NMR (50 MHz, CDCl3) d: 154.54, 143.64, 138.17, 128.27,
127.61, 127.49, 110.03, 76.36, 75.51, 75.12, 70.72, 45.58,
23.35, 20.44, 15.52, 21.39; IR (neat, NaCl) 3457, 2967,
(277 mg, 0.63 mmol, 1 equiv.) was dissolved in 10 ml of
CH2Cl2. At 215 8C, BF3.Et2O (79 ml, 91 mg, 0.63 mmol,
1 equiv.) was added and the mixture allowed to stir 18 h at
215 8C. The mixture was diluted with CH2Cl2 (20 ml) and
quenched with a saturated aqueous solution of NaHCO3.
The layers were separated and the aqueous phase was
extracted with CH2Cl2 (2£20 ml). The combined organic
phase was dried over MgSO4 and concentrated. The residue
was purified by column chromatography (PE/EA¼7/1) to
give pure alcohol 26b as colourless oil; 1H NMR (300 MHz,
CDCl3) d: 7.27–7.36 (5H, m), 5.30 (1H, d, J¼5.2 Hz), 4.98
(2H, s), 4.66 (1H, d, J¼11.5 Hz), 4.42 (1H, d, J¼11.5 Hz),
3.74–4.12 (2H, m), 3.55–3.65 (2H, m), 1.79 (3H, s), 1.28
(3H, d, J¼6.0 Hz), 1.21 (12H, d, J¼6.9 Hz); 13C NMR
(75 MHz, CDCl3) d: 155.14, 141.79, 138.17, 128.43,
127.76, 127.67, 114.04, 77.61, 75.57, 74.54, 70.81, 46.34,
21.44, 19.32, 15.73; IR (neat, NaCl) 3474, 2970, 2932,
2872, 1686, 1438, 1297, 1132, 1053, 903, 737 cm21; MS
(EI) m/z: 363.3 (Mzþ); HRMS for C21H33NO4 (CIþ,
MþHþ): Calcd 364.2488; found 364.2492.
2931, 1694, 1635, 1431, 1300, 1248, 1135, 1048, 851 cm21
;
MS (EI) m/z: 435.3 (M2Hþ). [a]2D0¼42.3 (c 1.0, CH2Cl2);
Anal. calcd for C24H41NO4Si: C, 66.17; H, 9.49; N, 3.21;
found: C, 65.62; H, 9.51; N, 3.09.
2.6.3. (1R,2S,3S)-1-(Benzyloxy)-1-cyclohexyl-2-hydroxy-
4-((trimethylsilyl)methyl)pent-4-en-3-yl diisopropyl-
carbamate 25c. The tile compound obtained as a colourless
oil in 81% yield following the general procedure; 1H NMR
(300 MHz, CDCl3) d: 7.41–7.26 (5H, m), 5.20 (1H, d,
J¼4.8 Hz), 4.96 (1H, s), 4.84 (1H, s), 4.66 (2H, s), 3.95 (2H,
bs), 3.90 (H, q, J¼4.8 Hz), 3.30 (1H, t, J¼4.8 Hz), 2.55 (1H,
d, J¼4.8 Hz),1.92–0.8 (25H, m), 0.06 (6H, s); 13C NMR
(75 MHz, CDCl3) d: 154.42, 143.83, 138.57, 128.28,
127.52, 127.45, 110.82, 83.23, 77.69, 74.18, 71.77, 45.97,
40.00, 30.21, 28.01, 27.90, 26.919, 26.576, 26.34, 23.40,
21.52, 20.71, 17.59, 13.688, 21.08; IR (neat, NaCl) 3547,
3032, 2926, 2853, 1698, 1451, 1432, 1311, 1157, 1048,
849 cm21; MS (CI) m/z: 504.4 (M2Hþ); HRMS (CIþ,
MþHþ) calcd for C29H50NO4Si, 504.3509; found 504.3494.
[a]D20¼32.9 (c 1.0, CH2Cl2).
2.7.3. Syn–anti 4,5-dihydroxy-2-methylhexan-3-yl di-
isopropylcarbamate 27a. Carbamate 26a (17 mg,
0.046 mmol, 1 equiv.) was mixed with Pd/C (10 mol%) in
AcOEt (5 ml). The flask was purged 4 times with nitrogen
and 5 times with hydrogen. The mixture was heated to 40 8C
under hydrogen pressure (1 atm) for 48 h. The crude
mixture was filtered through celite, rinsed with CH2Cl2
and the solvent evaporated under reduced pressure. The
resulting oil was purified by column chromatography (PE/
EA¼3/1) to give pure diol 27a as a colourless oil (10 mg,
83%); 1H NMR (300 MHz, CDCl3) d: 4.56 (1H, dd, J¼9.6,
2.4 Hz), 4.03–3.82 (2H, m), 3.66 (1H, qd, J¼6.6, 1.2 Hz),
3.30 (1H, bd, J¼9.9 Hz), 2.30 (1H, hept d, J¼7.2, 2.4 Hz),
1.32–1.22 (15H, m), 1.00 (3H, d, J¼6.9 Hz), 0.98 (3H, d,
J¼7.1 Hz); 13C NMR (75 MHz, CDCl3) d: 156.64, 77.90,
73.22, 65.01, 46.60–45.78, 27.84, 21.28–20.01, 20.65,
18.39, 15.76; IR (neat, NaCl) 3421, 2969, 2937, 2877, 1674,
1443, 1295, 1051, 936, 770 cm21; MS (CIþ) m/z: 276.1
(MþHþ); HRMS (CIþ, MþHþ) calcd for C14H29NO4,
276.2175; found 276.2178.
2.7. Determination of stereochemistry
2.7.1. Syn–anti 5-(benzyloxy)-4-hydroxy-2-methylhex-1-
en-3-yl diisopropylcarbamate 26a. Allylsilane 20a
(822 mg, 1.89 mmol, 1 equiv.) was dissolved in 25 ml of
CH2Cl2. At 215 8C, BF3.Et2O (233 ml, 269 mg, 1.89 mmol,
1 equiv.) was added and the mixture allowed to stir 18 h at
215 8C. The mixture was diluted with CH2Cl2 (20 ml) and
quenched with a saturated aqueous solution of NaHCO3.
The layers were separated and the aqueous phase was
extracted with CH2Cl2 (2£20 ml). The combined organic
phase was dried over MgSO4 and concentrated. The residue
was purified by column chromatography (PE/EA¼6/1) to
give pure alcohol 26a as a colourless oil; 1H NMR
(300 MHz, CDCl3) d: 7.26–7.37 (5H, m), 5.27 (1H, d,
J¼7.7 Hz), 5.08 (1H, s), 5.05 (1H, t, J¼1.8 Hz), 4.62 (1H, d,
J¼11.3 Hz), 4.48 (1H, d, J¼11.3 Hz), 3.72–4.08 (2H, m),
3.65 (1H, qd J¼6.0, 3.0 Hz), 3.57 (1H, bd, J¼7.8 Hz), 2.35
(1H, m), 1.82 (3H, s), 1.29 (3H, d, J¼6.3 Hz), 1.13–1.25
(12H, m); 13C NMR (75 MHz, CDCl3) d: 153.95, 142.14,
137.90, 128.16, 127.82, 127.46, 115.20, 77.02, 74.31, 73.06,
71.06, 46.08, 20.49, 18.62, 16.23; IR (neat, NaCl) 3472, 2971,
2934, 2879, 1695, 1437, 1298, 1136, 1088, 1049, 851,
738 cm21; MS (EI) m/z: 363.3 (Mzþ); HRMS for C21H33NO4
(CIþ, MþHþ): Calcd 364.2488; found 364.2492.
2.7.4. Syn–syn 4,5-dihydroxy-2-methylhexan-3-yl di-
isopropylcarbamate 27c. Carbamate 26c (45 mg,
0.12 mmol, 1 equiv.) was mixed with Pd/C (10 mol%) in
AcOEt (5 ml). The flask was purged 4 times with nitrogen
and 5 times with hydrogen. The mixture was heated to 40 8C
under hydrogen pressure (1 atm) for 48 h. The crude
mixture was filtered through celite, rinsed with CH2Cl2
and the solvent evaporated under reduced pressure. The
resulting oil was purified by column chromatography (PE/
EA¼2/3) to give pure diol 27c as a colourless oil (17 mg,
50%); 1H NMR (300 MHz, CDCl3) d: 4.56 (1H, dd, J¼7.1,
4.1 Hz), 4.03–3.81 (2H, m), 3.71 (1H, qd, J¼6.3, 5.2 Hz),
3.47 (1H, dd, J¼5.2, 4.1 Hz), 2.20 (1H, oct, J¼6.8 Hz),
1.26–1.21 (15H, m), 0.99 (3H, d, J¼6.6 Hz), 0.95 (3H, d,
J¼6.9 Hz); 13C NMR (75 MHz, CDCl3) d: 156.21, 80.49,
75.54, 68.56, 46.43–45.82, 29.12, 21.41, 20.38, 19.35,
18.04; IR (neat, NaCl) 3414, 2968, 2931, 1688, 1440, 1298,
1136, 1050, 768 cm21; MS (EI) m/z: 275.1 (Mzþ).
2.7.2. Syn–syn 5-(benzyloxy)-4-hydroxy-2-methylhex-1-
en-3-yl diisopropylcarbamate 26b. Allylsilane 20b
2.7.5. Syn–anti 5-(benzyloxy)-2-methylhex-1-ene-3,4-
diol 27b. To a solution of carbamate 26b (178 mg,

C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
7703
0.49 mmol, 1 equiv.) in THF (20 ml) was added dropwise a
solution of LiAlH4 (1 M in Et2O, 1.96 ml, 1.96 mmol,
4 equiv.). After completion the mixture was heated at reflux
for 3 h. After cooling to room temperature, the solution was
diluted with 20 ml of Et2O and 30 ml of water. The phases
were separated and the aqueous layer extracted twice with
Et2O. The combined organic phase was dried over MgSO4
and concentrated. The residue was purified by column
chromatography (PE 3/EA 1) to give pure diol 21b as a
colourless oil (75 mg, 65%); 1H NMR (300 MHz, CDCl3) d:
7.38–7.28 (5H, m), 5.03 (1H, bs), 4.98 (1H, bs), 4.64 (1H, d,
J¼11.2 Hz), 4.39 (1H, d, J¼11.2 Hz), 4.17 (1H, d,
J¼5.8 Hz), 3.83 (1H, qd, J¼6.1, 3.1 Hz), 3.53 (1H, dd,
J¼5.8, 3.1 Hz), 1.75 (3H, s), 1.31 (3H, d, J¼6.1 Hz); 13C
NMR (75 MHz, CDCl3) d: 144.72, 137.70, 128.48, 127.93,
112.72, 77.00, 74.64, 73.46, 70.85, 18.48, 15.69; IR (neat,
NaCl) 3439, 3069, 3028, 2975, 2924, 1451, 1131, 1067,
1022, 995, 901, 737 cm21; MS (EI) m/z: 236.3 (Mzþ); Anal.
calcd for C14H20O3: C, 71.16; H, 8.53; found: C, 71.13; H,
8.71.
2.7.8. Syn–syn 2-methyl-1-(2,2,5-trimethyl-1,3-dioxolan-
4-yl)propyl diisopropylcarbamate 28c. Diol 27c (29 mg,
0.10 mmol, 1 equiv.) was mixed with a few crystals of
PTSA in 15 ml of acetone. The mixture was heated at reflux
for 3 h. After cooling, 15 ml of Et2O were added followed
by a saturated aqueous solution of NaHCO3. The phases
were separated and the aqueous layer extracted twice with
Et2O. The combined organic phase was dried over MgSO4
and concentrated to give pure acetonide 28c as a colourless
oil (30 mg, 91%); 1H NMR (300 MHz, CDCl3) d: 4.65 (1H,
dd, J¼8.5, 1.9 Hz), 4.02–3.88 (2H, m), 3.77 (1H, dq, J¼8.5,
5.8 Hz), 3.68 (1H, dd, J¼8.5, 1.9 Hz), 2.08 (1H, hept d,
J¼8.4, 6.6 Hz), 1.39 (3H, s), 1.37 (3H, s), 1.22 (3H, d,
J¼5.8 Hz), 1.22 (12H, m), 0.99 (3H, d, J¼6.9 Hz), 0.95
(3H, d, J¼6.6 Hz); 13C NMR (75 MHz, CDCl3) d: 155.27,
107.69, 81.83, 74.75, 72.93, 46.12–45.55, 30.40, 27.21,
26.91, 29.67–20.56 219.29, 19.16, 17.25; IR (neat, NaCl)
2969, 2933, 2876, 1695, 1435, 1370, 1310, 1221, 1097,
1048, 935, 874, 767 cm21; MS (EI) m/z: 316.3 (MþHþ).
2.7.9. Syn–anti 4-(1-(benzyloxy)ethyl)-2,2-dimethyl-5-
(prop-1-en-2-yl)-1,3-dioxolane 28b. Diol 27b (16 mg,
0.066 mmol, 1 equiv.) was mixed with a few crystals of
PTSA in 5 ml of acetone. The mixture was heated at reflux
for 18 h. After cooling, 20 ml of Et2O were added followed
by a saturated aqueous solution of NaHCO3. The phases
were separated and the aqueous layer extracted twice with
Et2O. The combined organic phase was dried over MgSO4
and concentrated. The residue was purified by column
chromatography (PE/EA¼8/1, Et3N 5%) to give pure
2.7.6. Syn–syn 5-(benzyloxy)-2-methylhex-1-ene-3,4-diol
27d. To a solution of carbamate 26d (84 mg, 0.231 mmol,
1 equiv.) in THF (17 ml) was added dropwise a solution of
LiAlH4 (1 M in Et2O, 0.926 ml, 0.926 mmol, 4 equiv.).
After completion the mixture was heated at reflux for 5 h.
After cooling to room temperature, the solution was diluted
with 20 ml of Et2O and 30 ml of water. The phases were
separated and the aqueous layer extracted twice with
Et2O. The combined organic phase was dried over MgSO4
and concentrated to give pure diol 27d as a colourless oil
1
acetonide 28b as a colourless oil (7 mg, 39%); H NMR
1
(55 mg, 99%); H NMR (300 MHz, CDCl3) d: 7.39–7.27
(300 MHz, CDCl3) d: 7.40–7.23 (5H, m), 4.97 (1H, t,
J¼0.8 Hz), 4.94 (1H, t, J¼1.6 Hz), 4.67 (1H, d, J¼12.1 Hz),
4.62 (1H, d, J¼12.1 Hz), 4.52 (1H, d, J¼6.9 Hz), 4.20 (1H,
dd, J¼8.0, 6.9 Hz), 3.51 (1H, dq, J¼8.0, 6.0 Hz), 1.73 (3H,
s), 1.58 (3H, s), 1.57 (3 h, s), 1.14 (3H, d, J¼6.0 Hz); 13C
NMR (50 MHz, CDCl3) d: 141.94, 139.01, 128.20, 127.67,
127.31, 115.12, 108.63, 82.41, 81.12, 72.99, 71.43, 26.57,
25.12, 19.66, 17.27; IR (neat, NaCl) 2983, 2930, 1451,
1374, 1260, 1212, 1159, 1088, 1045, 874, 735 cm21; MS
(EI) m/z: 276.3 (Mzþ).
(5H, m), 5.00 (1H, bs), 4.96–4.93 (1H, m), 4.68 (1H, d,
J¼11.5 Hz), 4.41 (1H, d, J¼11.5 Hz), 4.08 (1H, d,
J¼3.8 Hz), 3.70 (1H, qd, J¼6.3, 4.1 Hz), 3.46 (1H, bt,
J¼4.1 Hz), 3.11–2.99 (1H, m), 2.69–2.60 (1H, m), 1.74
(3H, s), 1.31 (3H, d, J¼6.3 Hz); 13C NMR (75 MHz,
CDCl3) d: 144.31, 137.75, 128.52, 127.91, 112.73, 75.60,
74.58, 74.84, 70.84, 18.59, 15.79; IR (neat, NaCl) 3428,
3063, 3024, 2975, 2922, 1452, 1137, 1069, 1020, 901,
733 cm21; MS (CI2) m/z: 235.2 (M2H2).
2.7.7. Syn–anti 2-methyl-1-(2,2,5-trimethyl-1,3-dioxo-
lan-4-yl)propyl diisopropylcarbamate 28a. Diol 27a
(54 mg, 0.19 mmol, 1 equiv.) was mixed with a few crystals
of PTSA in 10 ml of acetone. The mixture was heated at
reflux for 5 h. After cooling, 20 ml of Et2O were added
followed by a saturated aqueous solution of NaHCO3. The
phases were separated and the aqueous layer extracted twice
with Et2O. The combined organic phase was dried over
MgSO4 and concentrated. The residue was purified by
column chromatography (PE/EA¼5/1, Et3N 5%) to give
2.7.10. Syn–syn 4-(1-(benzyloxy)ethyl)-2,2-dimethyl-5-
(prop-1-en-2-yl)-1,3-dioxolane 28d. Diol 27d (54 mg,
0.23 mmol, 1 equiv.) was mixed with a few crystals of
PTSA in 20 ml of acetone. The mixture was heated to reflux
for 3 h. After cooling, 10 ml of Et2O were added followed
by a saturated solution of NaHCO3. The phases were
separated and the aqueous layer extracted twice with
Et2O. The combined organic phase was dried over MgSO4
and concentrated. The residue was purified by column
chromatography (PE/EA¼15/1) to give pure acetonide 28d
as a colourless oil (52 mg, 83%); 1H NMR (300 MHz,
CDCl3) d: 7.39–7.24 (5H, m), 4.93–4.91 (2H, m), 4.70 (1H,
d, J¼12.1 Hz), 4.55 (1H, d, J¼12.1 Hz), 4.35 (1H, d,
J¼8.1 Hz), 3.80 (1H, dd, J¼8.3, 4.4 Hz), 3.55 (1H, qd,
J¼6.4, 4.5 Hz), 1.75 (3H, s), 1.45 (3H, s), 1.44 (3 h, s), 1.23
(3H, d, J¼6.4 Hz); 13C NMR (75 MHz, CDCl3) d: 141.97,
139.57, 128.31, 127.85, 127.52, 115.22, 108.91, 82.07,
81.07, 73.33, 71.08, 27.09, 27.03, 17.07, 16.25; IR (neat,
NaCl) 3068, 3033, 2986, 2935, 2871, 1652, 1454, 1372,
1244, 1214, 1154, 1091, 1070, 883, 737 cm21; MS (EI) m/z:
276.2 (Mzþ).
1
pure acetonide 28a as a colourless oil (55 mg, 89%); H
NMR (300 MHz, CDCl3) d: 4.91 (1H, dd, J¼8.5, 3.6 Hz),
4.13 (1H, dq, J¼7.7, 6.0 Hz), 4.02–3.80 (2H, m), 3.61 (1H,
t, J¼8.3 Hz), 2.08 (1H, hept d, J¼6.9, 3.6 Hz),1.40 (3H, s),
1.37 (3H, s), 1.32–1.19 (15H, m), 0.98 (3H, d, J¼6.9 Hz),
0.94 (3H, d, J¼6.9 Hz); 13C NMR (50 MHz, CDCl3) d:
154.60, 108.03, 26.86, 21.48–20.57, 19.28, 18.86, 16.43; IR
(neat, NaCl) 2968, 2936, 2882, 1701, 1430, 1369, 1293,
1215, 1154, 1090, 1048, 985, 858, 766 cm21; MS (CIþ)
m/z: 316.2 (M2Hþ); Anal. calcd for C17H33NO4: C, 64.73;
H, 10.54; N, 4.44; found: C, 64.94; H, 10.51; N, 4.37.

7704
C. Dubost et al. / Tetrahedron 60 (2004) 7693–7704
(d) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A. J.
Synthesis 2000, 7, 990–998.
2.7.11. (3R,4R,5S)-4-Acetoxy-5-(benzyloxy)-2-((tri-
methylsilyl)methyl)hex-1-en-3-yl diisopropylcarbamate
29. Alcohol 24b (1.1 g, 2.52 mmol, 1 equiv.) was dissolved
in 25 ml of pyridine and cooled to 0 8C. Acetic anhydride
(700 ml, 743 mg, 7.58 mmol, 3 equiv.) was added slowly.
Then the mixture was allowed to reach room temperature
within 1 h and was stirred another 12 h. The solution was
poured over a saturated solution of NaHCO3 (50 ml) and
diluted with Et2O (50 ml). The organic phase was washed
with a saturated solution of CuSO4 (50 ml), water (50 ml)
and a saturated solution of NaCl (50 ml). After drying over
MgSO4, the solution was filtered and the solvent removed
under reduced pressure. The resulting oil was purified by
column chromatography (PE/EA¼10/1) to give pure acetate
5. Fronza, G.; Fuganti, C.; Grasselli, P.; Fantoni, G. P. Chem.
Lett. 1984, 335.
6. For a review on Lewis acid mediated reactions of
allylstannanes see: Nishigaishi, Y.; Takuwa, A.; Naruta, Y.;
Maruyama, K. Tetrahedron 1993, 49, 7395–7426.
7. Yamamoto, Y. Acc. Chem. Res. 1987, 20, 243–249.
8. (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25,
1879–1882. (b) Keck, G. E.; Abbott, D. E. Tetrahedron Lett.
1984, 25, 1883–1886. (c) Keck, G. E.; Savin, K. A.; Weglarz,
M. A.; Cressman, E. N. K. Tetrahedron Lett. 1996, 37,
3291–3294. (d) Keck, G. E.; Abott, D. E.; Wiley, M. R.
Tetrahedron Lett. 1987, 28, 139–142. (e) Burgess, K.;
Chaplin, D. A. Tetrahedron Lett. 1992, 33, 6077–6080.
(f) Marshall, J. A.; Luke, G. P. J. Org. Chem. 1991, 56,
483–485. (g) Marshall, J. A.; Luke, G. P. J. Org. Chem. 1993,
58, 6229–6234.
1
29 as a colourless oil (1.02 g, 85%); H NMR (300 MHz,
CDCl3) d: 7.35–7.22 (5H, m), 5.30 (1H, d, J¼3.6 Hz), 5.21
(1H, t, J¼3.6 Hz), 4.89 (1H, s), 4.73 (1H, s), 4.61 (1H, d,
J¼12 Hz), 4.41 (1H, d, J¼12 Hz), 3.99 (2H, bs), 3.70 (1H,
m), 2.03 (3H, s), 1.58 (1H, d, J¼14.4 Hz), 1.47 (1H, d,
J¼14.4 Hz), 1.18 (15H, m), 0.06 (9H, s); 13C NMR
(75 MHz, CDCl3) d: 170.25, 153.77, 142.92, 138.34,
128.16, 127.41, 127.32, 110.38, 75.259, 73.96, 71.00,
45.43, 23.05, 21.56, 20.95, 15.98, 21.14; IR (neat, NaCl)
2966, 2875, 1744, 1701, 1434, 1370, 1306, 1234, 1046,
848 cm21; MS (CI) m/z: 478.4 (MþHþ); Anal. calcd for
C26H43NO5Si: C, 65.43; H, 9.08; N, 2.93; found: C, 65.43;
H, 9.09; N, 2.90. [a]D20¼57.1 (c 1.0, CH2Cl2).
9. Leroy, B.; Marko, I. E. J. Org. Chem. 2002, 67, 8744–8752.
10. Trost, B. M.; King, S. A.; Schmidt, T. J. Am. Chem. Soc. 1989,
111, 5902–5915.
11. Allylic carbanions are well stabilized by the presence of a
¨
carbamate. See (a) Hoppe, D.; Kramer, T. Angew. Chem., Int.
Ed. Engl. 1986, 25, 160. (b) Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1984, 23, 932. (c) Hoppe, D.; Hense, T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2283.
12. Yamamoto, Y.; Saito, Y.; Maruyama, K. Tetrahedron Lett.
1982, 23, 4959–4962.
13. (a) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. I 1985, 2247. (b) Widmer, U. Synthesis 1987,
568.
Acknowledgements
´
Financial support of this work by the Universite catholique
de Louvain and Pfizer Ltd (studentship to C.D.) and Fonds
14. Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247.
15. (a) Naruta, Y.; Nishigaishi, Y.; Maruyama, K. Tetrahedron
1989, 45, 1067–1078. (b) Thomas, E. J.; Carey, J. S. Synlett
1992, 585–586. (c) Thomas, E. J.; Carey, J. S. Tetrahedron
Lett. 1993, 34, 3935–3938.
`
pour la Formation a la Recherche dans l’Industrie et dans
l’Agriculture (FRIA, studentship to B.L.) is gratefully
acknowledged.
16. (a) Dias, L. C.; Meira, P. R. R.; Ferreira, E. Org. Lett. 1999, 1,
1335–1338. (b) Dias, L. C.; Meira, P. R. R.; Ferreira, E.;
Giacominici, R.; Ferreira, A. A.; Diaz, G.; Ribeiro dos Santos,
D.; Steil, L. J. Arkivoc 2003, 240–261. (c) Dias, L. C.;
Giacominici, R. Tetrahedron Lett. 1998, 39, 5343–5346.
(d) Dias, L. C.; Ribeiro dos Santos, D.; Steil, L. J. Tetrahedron
Lett. 2003, 44, 6861–6866.
References and notes
1. (a) Franca, N. C.; Polonsky, J. C. R. Hebd. Seances Acad. Sci.,
Ser. C 1971, 273, 439. (b) Davies-Coleman, M. T.; Rivett,
D. E. A. Phytochemistry 1987, 26, 3047.
2. (a) Hesse, O. J. Prakt. Chem. 1900, 62, 430–480. (b) Hesse, O.
J. Prakt. Chem. 1904, 70, 449–502. (c) Feige, G. B.;
Lumbsch, H. T.; Huneck, S.; Elix, J. A. J. Chromatography
1993, 646, 417–442.
17. Yamamoto, Y.; Maruyama, K.; Matsumoto, K. J. Chem. Soc.,
Chem. Commun. 1983, 489–490.
18. For NMR studies on chelated aldehydes with SnCl4 or TiCl4
see: (a) Keck, G. E.; Castellino, S. J. Am. Chem. Soc. 1986,
108, 3847–3849. (b) Keck, G. E.; Castellino, S. Tetrahedron
Lett. 1987, 28, 281–284.
3. For total synthesis of (þ)-Aspicilin see for example:
Kobayashi, Y.; Nakano, M.; Okui, H. Tetrahedron Lett.
1997, 38(51), 8883–8886, and references cited therein.
4. (a) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Park, J. C.
J. Org. Chem. 1990, 55, 4109–4117. (b) Roush, W. R.; Hoong,
L. K.; Palmer, M. A. J.; Straub, J. A.; Palkowitz, A. D. J. Org.
Chem. 1990, 55, 4117–4126. (c) Roush, W. R.; Palkowitz,
A. D.; Ando, K. J. Am. Chem. Soc 1990, 112, 6348–6359.
19. For X-ray studies on chelated aldehydes with SnCl4 or TiCl4
see Reetz, M. T.; Harms, K.; Reif, W. Tetrahedron Lett. 1988,
29, 5881–5884.
20. Allevi, P.; Tarocco, G.; Longo, A.; Anastasia, M.; Cajone, F.
Tetrahedron: Asymmetry 1997, 8, 1315.