Further studies on silatropic carbonyl ene cyclisations: β-crotyl(diphenyl)silyloxy aldehyde substrates; Synthesis of 2-deoxy-2-C-phenylhexoses

Article abstract of DOI:10.1039/b804752a

Silatropic carbonyl ene cyclisations of β-(allylsilyloxy)- and β-(crotylsilyloxy)butyraldehydes are shown to proceed with high stereoselectivity but at a much reduced rate in comparison to the cyclisation of analogous α-substrates. In the second section, olefin cross-metathesis is explored as a route to substituted α-(allylsilyloxy)aldehydes and the method applied to the synthesis of diastereomeric 2-deoxy- and 2-deoxy-2-C-phenyl hexose derivatives from butanediacetal-protected d-glyceraldehyde. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b804752a

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Further studies on silatropic carbonyl ene cyclisations:
b-crotyl(diphenyl)silyloxy aldehyde substrates; synthesis of
2-deoxy-2-C-phenylhexoses†
Jeremy Robertson,*a Stuart P. Green,b Michael J. Hall,a,c Andrew J. Tyrrella and William P. Unswortha
Received 20th March 2008, Accepted 14th April 2008
First published as an Advance Article on the web 19th May 2008
DOI: 10.1039/b804752a
Silatropic carbonyl ene cyclisations of b-(allylsilyloxy)- and b-(crotylsilyloxy)butyraldehydes are shown
to proceed with high stereoselectivity but at a much reduced rate in comparison to the cyclisation of
analogous a-substrates. In the second section, olefin cross-metathesis is explored as a route to
substituted a-(allylsilyloxy)aldehydes and the method applied to the synthesis of diastereomeric
2-deoxy- and 2-deoxy-2-C-phenyl hexose derivatives from butanediacetal-protected D-glyceraldehyde.
Introduction
Results and discussion
Within our programme exploring stereoselective syntheses of non-
natural carbohydrate analogues we discovered that heating a-
dialkyl(allylic)silyloxy aldehydes (1, n = 0) induced intramolecular
transfer of the allylic group to yield syn-1,2-dihydroxypent-4-
enes (3, n = 0) after cleavage of the silyl tether.1 This silatropic
carbonyl ene cyclisation was found to be stereospecific and highly
stereoselective, and we reported its application to the stereocon-
trolled synthesis of carbasugars and hydroxylated piperidines.2
Mechanistically, we view this allylic transfer to occur in concert
with Si–O bond formation as depicted in Scheme 1.
b-Silyloxy substrates
Reetz provided the earliest direct precedent for silicon-tethered
allylation processes in a study of intramolecular allylations of
b-(allylsilyl)oxyaldehydes under Lewis-acidic conditions.3 In that
work the product stereochemistry was shown to depend on the
choice of Lewis acid, and crotyl systems were not examined.
For our study, the unsubstituted allyl substrate 6 (Scheme 2) was
prepared from ( )-ethyl 3-hydroxybutyrate by DIBAL reduction
of ester 5 that was obtained using allyldiphenylsilane4 directly5
or by base-mediated silylation with allyldiphenylchlorosilane6
prepared in situ. In general, the b-systems were much easier
to handle than the a-analogues prepared in our earlier work;
in particular, the DIBAL reductions provided the aldehydes
reproducibly in high yield as stable compounds that could be
purified or stored for prolonged periods without decomposition.
Scheme 1 Alkenyl diols formed by silatropic ene cyclisation.
To conclude our investigations of the silatropic carbonyl ene cy-
clisation, we report the reactions of b-silyloxy aldehyde substrates
(1, n = 1), and the application of our original a-allyl transfer
reaction in the synthesis of C-aryl sugar analogues.
Scheme 2 Reagents and conditions: (i) allyldiphenylsilane, 5% B(C6F5)3,
CH2Cl2, reflux, 2 h (88%); (ii) DIBAL, CH2Cl2, −78 ◦C, 1 h (74%);
(iii) C6H6, 200 ◦C (sealed tube), 5 d (52%); (iv) KF, MeOH, RT, 16 h
(55% from 6).
aDepartment of Chemistry, University of Oxford, Chemistry Research Labo-
ratory, Mansfield Road, Oxford, OX1 3TA, UK. E-mail: jeremy.robertson@
chem.ox.ac.uk; Fax: +44 1865 285002; Tel: +44 1865 275660
bChemical Research & Development Department, Pfizer Global Research
and Development, Sandwich, Kent, CT13 9NJ, UK
Inevitably, the stability of these aldehydes was carried forward
into their behaviour towards heating, there being little tendency
to rearrange to the allyl transfer products under conditions
previously successful for the a-cases. For example, with aldehyde 6,
heating at 200 ◦C in a sealable tube for 5 days was required in order
to effect complete conversion to dioxasilinane 7. The protracted
reaction time for this process led to some decomposition of the
cCurrent address: School of Natural Sciences – Chemistry, Bedson Building,
Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
† Electronic supplementary information (ESI) available: Full experimental
procedures and characterisation data for all compounds 5, 6, 9 (and
intermediates), 11 (and intermediates), 15, 20–24, 31/32 and 43/44,
37/38 and 49/50, 39/40 and 51/52; crystal structure data. See DOI:
10.1039/b804752a
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substrate and the silacycle could be isolated only in moderate
yield. In later work (discussed below), thorough base-washing of
the reaction tubes and replacement of the O-ring with PTFE tape
reduced the amount of decomposition with the consequence that
isolated yields were raised by ca. 10–15%. The isolated silacycle
7 was confirmed as the diastereoisomer depicted in Scheme 2;
1
thus, in the H NMR spectrum the coupling constants (Hz) for
the ring methylene protons supported diequatorial substitution
around the ring (d 1.69: dt, J 14.0, 10.5, CHaxH; d 1.78: dt, J
14.0, 2.5, CHHeq). In a separate experiment, direct desilylation
of the crude silacycle gave syn-1,3-diol 87 in 55% yield from
aldehyde 6.
Extension to the crotyl precursors proceeded very well by
our previously developed methodology (Scheme 3), and single
diastereomers of the methallyl-substituted dioxasilinanes 10 and
12 were obtained in 63% and 68% yields respectively (ca. 45%
overall yield from ethyl 3-hydroxybutyrate). Once more, the
coupling constants for the ring methylene protons in the 1H NMR
spectra of these silacycles supported a diequatorial substitution
pattern (see Experimental section for details). Furthermore, X-
ray-quality crystals of silacycle 12 were grown in order to assign the
allylic stereochemistry in this compound (Fig. 1) and, by analogy,
in diastereomer 10; this also assisted in securing the assignment of
compound 7 by correlation.8
Fig. 1 ORTEP diagram of dioxasilinane 12.
Fig. 2 Pre-transition-state assemblies for cyclisation of b-substrates.
Heating a,a-dimethyl-substituted analogue 1311 (Scheme 4) at
200 ◦C for 5 days resulted in an incomplete reaction (14/13, 3.25 :
1). We assume that any entropic advantage offered by the presence
of the gem-dimethyl group is offset by steric encumbrance at the
carbonyl group. Furthermore, the dioxasilinane (14) was produced
as a 2.5 : 1 ratio of diastereomers as determined by examination
of relative integrations of the newly-formed CHO resonances in
the 1H NMR spectrum of the crude material.
Scheme 3 Reagents and conditions: (i) (Z)-crotyldiphenylsilane, 5%
B(C6F5)3, CH2Cl2, reflux, 2 h (71%); (ii) DIBAL, CH2Cl2, −78 ◦C, 1 h
(96%); (iii) C6H6, 200 ◦C (sealed tube), 5 d (63%); (iv) 3-butenyldiphenylsi-
lane, 5% B(C6F5)3, CH2Cl2, reflux, 2 h (88%); (v) 1% [(COD)Ir(PPh2Me)2]+
PF6
,
(H2), CH2Cl2,–78
→
0
◦C, 20 min., (99%); (vi) DIBAL,
−
CH2Cl2,–78 ◦C, 1 h (79%); (vii) C6H6, 200 ◦C (sealed tube), 5 d (68%).
An attempt to rationalise the stereochemical outcome in these
reactions is presented in Fig. 2. A pre-transition-state assembly
can be considered that consists of a forming bicyclo[3.3.1]nonane
ring in which the ring containing the transferring allylic group
is initially chairlike whilst the forming dioxasilinane adopts a
flattened half-chair conformation (A and B). Although the longer
bonds to silicon9 should allow some relaxation of transannular
interactions in these assemblies, the carbon that bears the Me-
group must adopt an exo-position; in the endo position, the
attached Me substituent or the H atom will suffer an unfavourable
interaction with the central olefinic methine. Of the two possi-
bilities, conformation B appears to be disfavoured because the
pseudoaxial Me substituent is brought into close contact with the
“axial” phenyl group attached to the trigonal bipyramidal silicon
atom.10
Scheme 4 Cyclisation of a gem-dialkyl-substituted substrate.
a-Cinnamyl(diphenyl)silyloxy substrates: application to
2-deoxy-2-C-phenylhexoses
In order to complete our study of the scope and potential
synthetic applications of allylic transfer by silatropic carbonyl
ene cyclisation we sought a flexible synthesis of allylic substrates
bearing a variety of 3-substituents (1, Scheme 1, n = 0, Rꢀꢀ = H).
Given the ease of preparation of allyl substrates (R = H), olefin
cross-metathesis12 was investigated as a means of accessing the
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functionalised allylic variants.13 Most of our work prior to
this point had employed a relatively stable diphenylsilyl tether,
which required the preparation of fresh allyldiphenylchlorosi-
lane; in view of this, and given the commercial availability
of allyldimethylchlorosilane, we decided to explore the cross-
metathesis chemistry on substrate 15 (Scheme 5).
diastereomer after cleavage of the silyl tether (stereochemistry
assumed by analogy to previous work). Cyclisation of the 4-
nitrophenyl derivative 23 was incomplete even after 8 d; regardless,
a single attempt to cleave the small available amount of (nitro-
phenyl)allyl transfer product 26 resulted in fragmentation to give
1-(4-nitrophenyl)propene.16
This exploratory work had shown that the basic synthetic plan
was viable but also that the overall yields were unacceptably low,
largely as a consequence of the DIBAL reduction step; therefore,
subsequent work returned to the more resilient diphenylsilyl-
tethered substrates. With the intention of exploring the potential
of these allyl transfer processes to deliver enantiomerically pure
carbohydrate analogues,17 we initiated studies to outline the
synthetic route and assess the stereochemical aspects in a relatively
simple system.
We envisaged that if the chemistry in Schemes 5 and 6 could be
achieved with an enantiomerically pure masked diol fragment in
place of the tert-butyl group then ozonolysis of the silatropic ene
product and liberation of the diol would yield a variety of 2-deoxy-
2-C-substituted sugars (Scheme 7, e.g. R = phenyl). This class
of carbohydrate analogues has been accessed by organometallic
opening of 2,3-anhydro sugars. In the earlier literature the regio-
and stereochemical features of these reactions were somewhat
vague, and the nature of the products was found to vary depending
on the organometallic reagent.18 More recently, the use of cuprates
was shown to provide reliable results, but only in pyranosides in
which the epoxide and anomeric substituents are present in a cis-
relationship.19 Our study was therefore formulated to provide a
stringent test of the silatropic ene chemistry and to enable a flexible
and complementary route to these useful carbohydrate analogues.
Scheme 5 Reagents and conditions: (i) KCN, NaHSO3, H2O, THF (87%);
(ii) allyldimethylchlorosilane, Et3N, DMAP, DMF, 60 ◦C, 6 h (83%); (iii)
(a) →16: 5 eq. triethoxyvinylsilane, 10% Grubbs II, CH2Cl2, reflux, 21 h
(34%); (b) →17: as (a) but with 1 eq. styrene, 18 h (51%); (c) →18: as (b)
but with 4-nitrostyrene (40%); (d) →19: as (b) but with methyl crotonate
(44%); (iv) DIBAL, CH2Cl2,–78 ◦C, 1 h (19→20, 46%; 16→21, 14%;
17→22, 30%; 18→23, 66%; 15→24, 64%).
Preliminary experiments established that the presence of the
nitrile functionality in this substrate (15) necessitated reasonably
high catalyst loadings in order to drive the cross-metatheses to
completion but, even under the optimised conditions, isolated
yields were moderate at best and in some cases the products could
not be separated from other components in the reaction mixtures.14
Also, the relative fragility of the dimethylsilyl tether was revealed
in the subsequent DIBAL reaction to unmask the aldehyde, and
the isolated yields of the ene substrates 21–24 fell away drastically
in the more electron-rich examples. In the case of substrate 19
reduction took place preferentially at the ester to give the primary
alcohol 20 as the sole isolated product.
Scheme 7 An approach to 2-deoxy-2-C-substituted sugars.
Aldehyde 2820 (Scheme 8) was converted into a 3 : 2 mixture
of cyanohydrins 29 and 30 whose stereochemistry was assigned
retrospectively, as explained below. Ene substrates 33 and 34
were then prepared straightforwardly by the usual silylation and
DIBAL reduction sequence. We were pleased to find that heating
these functionalised substrates in benzene produced protected
tetraols 35 and 36 with complete stereocontrol.21 Ozonolysis of
these dihydroxyaldehydes proceeded poorly; therefore the diol
was benzylated to enable aldehydes 39 and 40 to be obtained
cleanly. Final cleavage of the butanediacetal (BDA) group, under
the standard TFA conditions,22 proved to be problematic as
the products decomposed when concentrated in the presence of
acid. Therefore, intending to minimise potential product isolation
problems associated with an aqueous work-up, we opted for a
90 : 9 : 1 mixture of 1,2-dichloroethane–TFA–water;23 this allowed
selective removal of most of the TFA before the mixture was finally
concentrated, and pyranose products 41 and 42 were isolated,
albeit in rather low yield. In later work we found much improved
conditions for BDA deprotections but did not go back to repeat
this exploratory sequence merely to improve yields. The products
Although these substrates were hydrolytically sensitive, the
neutral, thermal conditions required for silatropic ene reaction
were sufficiently mild to allow the silacycles to form smoothly
1
and the progress of the reactions to be monitored by H NMR
spectroscopy (Scheme 6). The presence of the phenyl group slowed
the cyclisation of substrate 22 relative to that of substrate 24 and
the reaction required 84 h at 80 ◦C to reach completion (vs.
48 h for 24).15 In this example diol 27 was obtained as a single
Scheme 6 Reagents and conditions: (i) C6H6, 80 ◦C, 3.5 d (→25) or 8 d
(→26); (ii) TBAF, THF, 0 ◦C → RT, 2 h (56% from 22).
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Scheme 9 Reagents and conditions: (i) styrene, 7.5% Grubbs II, CH2Cl2,
reflux, 18 h (51%); (ii) DIBAL, CH2Cl2, −78 ◦C, 1 h; (iii) C6D6, 80 ◦C, 5 d
then TBAF, THF, 0 ◦C → RT, 2 h (25% from 43/44); (iv) NaH, TBAI,
benzyl bromide, DMF, 0 ◦C → RT, 16 h (66%); (v) O3, CH2Cl2,–78 ◦C
then Me2S, −78 ◦C → RT, 5 h (81%); (vi) AcOH, H2O, 100 ◦C, 2 h (53,
47%; 54, 27%).
the major product being the D-ido-isomer 53. The minor (D-gluco-
configured) product (54), was isolated as a ca. 1 : 1 mixture of
anomers rather than the 1,6-anhydro-derivative; as expected, the
penalty for placing a phenyl and two benzyloxy substituents in an
axial disposition is clearly too great for this compound to cyclise
under the reaction conditions.
Scheme 8 Reagents and conditions: (i) KCN, NaHSO3, H2O, THF (87%,
3 : 2 ratio); (ii) allyldiphenylchlorosilane, Et3N, DMAP, DMF, 60 ◦C, 6 h
(80%); (iii) DIBAL, CH2Cl2, −78 ◦C, 1 h; (iv) C6D6, 80 ◦C, 16 h then
TBAF, THF, 0 ◦C → RT, 2 h (24% from 31/32); (v) NaH, TBAI, benzyl
bromide, DMF, 0 ◦C → RT, 16 h (65%); (vi) O3, CH2Cl2,–78 ◦C then Me2S,
−78 ◦C → RT, 5 h (89%); (vii) TFA, H2O, 1,2-dichloroethane, RT, 2 min,
(41, 9%; 42, 12%).
Conclusions
These results confirm that the silatropic carbonyl ene cyclisation
proceeds under neutral conditions with high and predictable
stereoselectivity even with b-derivatives and aryl-substituted a-
derivatives. We have shown that the products may be elaborated
in a synthetically useful manner, in this case to a variety of hexose
derivatives, and that the main limitation to the methodology lies
in the inefficiency of the DIBAL reduction used to prepare the
aldehyde ene substrates.
2-deoxy-D-gulo-41 and 2-deoxy-D-gluco-4224 (1 : 1.5 ratio) were
both obtained in the 1,6-anhydro- form, the stereochemistry being
readily assigned in these rigid structures by coupling constant
analysis (see Experimental section).
The stereochemistry of the various intermediates in this se-
quence was assigned as follows: in the reaction to produce diol
mixture 35/36 a small amount of one of the isomers was obtained
as a pure compound. This was then taken through the benzylation,
ozonolysis and deprotection sequence to result in compound 42.
This, in turn, assigned the separated isomer as compound 36
which, based on the isomer ratios, allowed an assignment of NMR
resonances to specific stereoisomers in compounds 29/30 →
39/40.
Experimental
General procedure for allyl transfer reactions of aldehydes
6, 9 and 11
A solution of the aldehyde (0.46–1.08 mmol) in benzene (10 mL)
was placed in a sealed tube and heated at 200 ◦C for 5 days
1
Finally, the sequence was repeated with the inclusion of a cross-
metathesis step with styrene (Scheme 9). This time the 4,6-diol in
aldehydes 51 and 52 was revealed by heating with aqueous acetic
acid25 to generate two pyranose products in good overall yield,
on a Wood’s metal bath with periodic monitoring by H NMR
spectroscopy. The reaction mixture was cooled and the solvent
removed in vacuo. The resulting oil was purified by column
chromatography (petrol–ether, 25 : 1).
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(4R*,6S*)-cis-4-Allyl-6-methyl-2,2-diphenyl[1,3,2]dioxasilinane
(7). From aldehyde 6 (1.0 mmol) the general procedure gave the
title compound (7, 161 mg, 52%) as a colourless oil. Rf 0.53 (petrol–
ether, 10 : 1); mmax/cm−1 (film) 3070m, 3050w, 3003w, 2973m,
2932m, 2902m, 2862m, 1642w, 1592w, 1430s, 1377m, 1348m,
1242w, 1116s, 1024m, 980s, 925m, 910m, 871w, 848w, 786w, 739s,
719s, 699s; dH (400 MHz; CDCl3) 1.36 (3 H, d, J 6.2, CH3), 1.69
(1 H, dt, J 14.0, 10.5) and 1.78 (1 H, dt, J 14.0, 2.5, 5-CH2), 2.31–
with periodic monitoring by 1H NMR spectroscopy. The reaction
mixture was cooled and the solvent removed in vacuo. The resulting
oil was dissolved in a solution of potassium fluoride (80 mg,
1.38 mmol) in methanol (10 mL) then the mixture was stirred for
16 h and poured into water (10 mL). The solution was extracted
with ethyl acetate (2 × 20 mL) and the combined extracts were
washed with brine (10 mL) then dried over magnesium sulfate. The
solvent was removed in vacuo and the resulting oil was purified
by column chromatography (petrol–ether, 3 : 2) to give the title
compound (8, 48 mg, 55%) as a colourless oil. Rf 0.11 (petrol–
ether, 1 : 1); mmax/cm−1 (film) 3351s br, 2968s, 2933s, 1642m, 1433m,
1375m, 1325m, 1262m, 1080s, 1020m, 998m, 916m, 880w, 823w;
dH (400 MHz; CDCl3) 1.21 (3 H, d, J 6.2, CH3), 1.52 (1 H, dt, J
14.5, 9.9) and 1.61 (1 H, dt, J 14.5, 2.5, 3-CH2), 2.18–2.31 (2 H, m,
=
2.38 (1 H, m) and 2.45–2.52 (1 H, m, CH2CH ), 4.20–4.26 (1 H,
=
m, 4-H), 4.29–4.37 (1 H, m, 6-H), 5.10–5.18 (2 H, m, CH2), 5.93
=
(1 H, dddd, 17.2, 10.2, 7.3, 6.7, CH CH2), 7.36–7.53 (6 H, m)
and 7.64–7.77 (4 H, m, 2 × Ph); dC (100 MHz; CDCl3) 24.6 (q),
42.8 (t), 43.5 (t), 70.2 (d), 73.4 (d), 117.2 (t), 127.8 (d), 128.0 (d),
130.4 (d), 130.7 (d), 133.2 (s), 133.4 (s), 134.4 (d), 134.5 (d), 134.8
(d); m/z (CI+) 328 (MNH4 , 78%), 311 (MH+, 100), 269 (74), 250
CH2CH ), 2.94 (1 H, br s) and 3.06 (1 H, br s, 2 × OH), 3.88–3.94
+
=
(9), 216 (35), 198 (14); HRMS (CI+) 311.1473 (MH+. C19H23O3Si
requires 311.1467).
(1 H, m) and 4.02–4.10 (1 H, m, 2 × CH(OH)), 5.11–5.16 (2 H, m,
=
=
CH2), 5.76–5.87 (1 H, m, CH CH2); dC (100 MHz; CDCl3) 24.1
(q), 42.6 (t), 44.1 (t), 68.9 (d), 71.8 (d), 118.4 (t), 134.2 (d); m/z
(4R*,6R*,3ꢀS*)-4-Methyl-6-(but-1-en-3-yl)-2,2-diphenyl[1,3,2]-
dioxasilinane (10). From aldehyde 9 (1.08 mmol) the general
procedure gave the title compound (10, 219 mg, 63%) as a white
crystalline solid, mp 59 ◦C. Rf 0.54 (petrol–ether, 10 : 1); mmax/cm−1
(film) 3070m, 3006m, 2971s, 2930m, 2868m, 1641w, 1592m, 1457w,
1442w, 1430s, 1377s, 1347m, 1259w, 1227w, 1148s, 1116s, 1081s,
1026s, 980s, 913s, 886s, 839w, 813w, 772w, 739s, 719s, 699s; dH
(400 MHz; CDCl3) 1.15 (3 H, d, J 6.9, 3ꢀ-CH3), 1.35 (3 H, d, J
6.1, 4-CH3), 1.63 (1 H, dt, J 14.0, 2.2) and 1.75 (1 H, dt, J 14.0,
11.0, 5-CH2), 2.34–2.42 (1 H, m, 3ꢀ-H), 4.10 (1 H, ddd, J 11.0, 4.0,
2.2, 6-H), 4.26–4.34 (1 H, dqd, J 11.0, 6.1, 2.2, 4-H), 5.06–5.11
+
(CI+) 146 (MNH4 , 6%), 131 (MH+, 100), 113 (6), 95 (8); HRMS
(CI+) 131.1068 (MH+. C7H15O2 requires 131.1072).
General cross-metathesis procedure, used to prepare substituted
allylic derivatives 16–19
To a stirred, degassed solution of silylcyanohydrin 15 (100 mg,
0.48 mmol) and the relevant alkene (see below for relative quan-
tities) in dichloromethane (4.0 mL) was added Grubbs’ second-
generation catalyst (41 mg, 0.048 mmol). The reaction mixture was
heated at reflux for 18 h, cooled to RT, and the solvent removed
in vacuo; the residue was purified by column chromatography
(petrol–ether, 10 : 1) to afford the desired compound.
=
=
(2 H, m, CH2), 5.91–5.99 (1 H, m, CH CH2), 7.37–7.50 (6 H,
m) and 7.61–7.75 (4 H, m, 2 × Ph); dC (100 MHz; CDCl3) 15.5 (q),
24.6 (q), 40.9 (t), 44.2 (d), 70.2 (d), 76.9 (d), 115.0 (t), 127.8 (d),
128.0 (d), 130.3 (d), 130.6 (d), 133.2 (s), 133.3 (s), 134.4 (d), 134.8
2-(E-3-Triethoxysilylprop-2-enyl)dimethylsilanyloxy-3,3-dime-
thylbutyronitrile (16). Prepared as a colourless oil (61 mg, 34%)
using triethoxyvinylsilane (5.0 eq.) as the alkene. Rf 0.11 (petrol–
ether, 10 : 1); mmax/cm−1 (film) 2972m, 2928w, 2882w, 1607w, 1479w,
1466w, 1445w, 1391w, 1366w, 1295w, 1258m, 1166m, 1103s, 1080s,
1035m, 956m, 887w, 957m, 772m; dH (400 MHz; CDCl3) 0.23 (3 H,
s) and 0.25 (3 H, s, Si(CH3)2), 1.02 (9 H, s, C(CH3)3), 1.23 (9 H,
t, J 7.0, 3 × CH2CH3), 1.82–1.97 (2 H, m, SiCH2), 3.82 (6 H, q,
J 7.0, 3 × CH2CH3), 4.03 (1 H, s, CHCN), 5.34 (1 H, dt, J 18.5,
(d), 140.1 (d); m/z (CI+) 342 (MNH4 , 61%), 325 (MH+, 100), 269
+
(64), 216 (22), 198 (10); HRMS (CI+) 325.1637 (MH+. C20H25O2Si
requires 325.1624).
(4R*,6R*,3ꢀR*)-4-Methyl-6-(but-1-en-3-yl)-2,2-diphenyl[1,3,2]-
dioxasilinane (12). From aldehyde 11 (0.46 mmol) the general
procedure gave the title compound (12, 102 mg, 68%) as a white
crystalline solid, mp 48 ◦C. Rf 0.61 (petrol–ether, 10 : 1); mmax/cm−1
(film) 3070m, 3050m, 2970s, 2868m, 1641w, 1592m, 1487w, 1456m,
1430s, 1370s, 1346m, 1217w, 1164s, 1116s br, 1066m, 1035m, 981s,
913s, 885s, 822m, 770w, 739s, 719s, 699s, 679w; dH (400 MHz;
CDCl3) 1.14 (3 H, d, J 6.7, 3ꢀ-CH3), 1.33 (3 H, d, J 6.1, 4-CH3),
1.63 (1 H, ddd, J 14.3, 11.0, 10.6) and 1.76 (1 H, dt, J 14.3, 2.1,
5-CH2), 2.35 (1 H, dquin, J 7.6, 6.7, 3ꢀ-H), 3.94 (1 H, ddd, J 11.0,
6.7, 2.1, 6-H), 4.26 (1 H, dqd, J 10.6, 6.1, 2.1, 4-H), 5.02 (1 H,
=
=
1.5, CHSi), 6.43 (1 H, dt, J 18.5, 8.0, CH2CH ); dC (100 MHz;
CDCl3) −2.6 (q), −2.3 (q), 18.2 (q), 24.9 (q), 28.9 (t), 35.9 (s),
58.4 (t), 71.0 (d), 119.0 (s), 119.4 (d), 148.3 (d); m/z (ESI+) 432
+
(MNH4 ·MeCN, 100%), 396 (MNa+, 3); HRMS (ESI+) 374.2189
(MH+. C17H36NO4Si2 requires 374.2183).
2-(E-Cinnamyl)dimethylsilanyloxy-3,3-dimethylbutyronitrile (17).
Prepared as a colourless oil (70 mg, 51%) using styrene (1.0 eq.) as
the alkene. Rf 0.21 (petrol–ether, 10 : 1); mmax/cm−1 (film) 2964m,
2238w, 1368w, 1255m, 1105s, 1035w, 993m, 860s, 754m, 694m; dH
(400 MHz; CDCl3) 0.28 (3 H, s) and 0.30 (3 H, s, Si(CH3)2), 1.05
(9 H, s, C(CH3)3), 1.87 (1 H, dd, J 18.5, 8.0) and 1.91 (1 H, dd,
J 18.5, 8.0, SiCH2), 4.07 (1 H, s, CHCN), 6.25 (1 H, dt, J 15.5,
=
ddd, J 10.3, 1.8, 1.2) and 5.08 (1 H, ddd, J 17.3, 1.8, 1.1, CH2),
=
5.81 (1 H, ddd, J 17.3, 10.3, 7.6, CH CH2), 7.33–7.48 (6 H, m)
and 7.60–7.71 (4 H, m, 2 × Ph); dC (100 MHz; CDCl3) 15.6 (q),
24.6 (q), 41.5 (t), 45.0 (d), 70.3 (d), 77.1 (d), 114.9 (t), 127.8 (d),
128.0 (d), 130.3 (d), 130.6 (d), 133.4 (s), 133.5 (s), 134.7 (d), 134.8
+
(d), 140.6 (d); m/z (CI+) 342 (MNH4 , 38%), 325 (MH+, 100),
269 (75), 216 (30), 198 (8), 109 (5); HRMS (CI+) 325.1624 (MH+.
C20H25O2Si requires 325.1624).
=
=
8.0, CH2CH ), 6.36 (1 H, d, J 15.5, CHPh), 7.27–7.42 (5 H, m,
Ph); dC (100 MHz; CDCl3) −2.4 (q), −2.2 (q), 23.3 (t), 25.0 (q),
36.0 (s), 71.0 (d), 119.1 (s), 125.1 (d), 125.6 (d), 126.5 (d), 128.7
(d), 130.1 (d), 137.4 (s); m/z (FI+) 287 (M+, 100%); HRMS (FI+)
287.1709 (M+. C17H25NOSi requires 287.1700).
(2R*,4S*)-Hept-6-ene-2,4-diol7 (8). A solution of aldehyde 6
(207 mg, 0.67 mmol) in benzene (10 mL) was placed in a sealed
tube and heated at 200 ◦C for 5 days on a Wood’s metal bath
2632 | Org. Biomol. Chem., 2008, 6, 2628–2635
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+
2-(E-4-Nitrocinnamyl)dimethylsilanyloxy-3,3-dimethylbutyroni-
trile (18). Prepared as a colourless oil (63 mg, 40%) using 4-
nitrostyrene (1.0 eq.) as the alkene. Rf 0.24 (petrol–ether, 5 : 1);
mmax/cm−1 (film) 2965s, 2874m, 2446w, 1639s, 1595s, 1515s, 1478m,
1398m, 1368m, 1341s, 1257s, 1182m, 1108s, 1034m, 986m, 936w,
844s, 799s, 749m, 715m; dH (400 MHz; CDCl3) 0.27 (3 H, s) and
0.29 (3 H, s, Si(CH3)2), 1.02 (9 H, s, C(CH3)3), 1.87–2.01 (2 H, m,
131 (84), 118 (72); HRMS (CI+) 252.1962 (MNH4 . C15H26NO2
requires 252.1964).
(2R)- and (2S)-[(2R,6S)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-
2-yl]-2-hydroxyacetonitrile (29) and (30)
To a stirred solution of aldehyde 2820 (12.7 g, 62.1 mmol) in
THF (25 mL) at 5 ◦C was added a solution of potassium
cyanide (4.86 g, 74.7 mmol) in water (25 mL). A solution of
sodium hydrogen sulfite (saturated, aqueous, 40 mL) was added
dropwise over 10 min and then stirring was continued for 2 h. The
reaction mixture was warmed to RT and extracted with ether (3 ×
50 mL). The combined organic layers were washed successively
with hydrochloric acid (5.0 M, 100 mL) and brine (100 mL) and
then dried over magnesium sulfate and concentrated in vacuo to
afford the title compounds (29 and 30, 3 : 2 ratio, 12.5 g, 87%) as a
colourless, viscous oil that solidified on standing to a white, waxy
solid, mp 74 ◦C. mmax (KBr)/cm−1 3417br, 2951m, 2235w, 1378m,
1146s, 1035m, 946m, 874m; dH (400 MHz; CDCl3) 1.30 (3 H, s,
CH3, 29), 1.31 (3 H, s, CH3, 30), 1.34 (3 H, s, CH3, 30), 1.36 (3 H, s,
CH3, 29), 3.27 (3 H, s, OCH3, 29), 3.28 (3 H, s, OCH3, 30), 3.33
(3 H, s, OCH3, 30), 3.35 (3 H, s, OCH3, 29), 3.52 (1 H, dd, J 11.0,
3.5, CHHꢀ, 29), 3.67 (1 H, dd, J 11.0, 3.5, CHHꢀ, 30), 3.74 (1 H, t,
J 11.0, CHHꢀ, 30), 3.85 (1 H, t, J 11.0, CHHꢀ, 29), 4.11–4.17 (2 H,
m, 2 × CHO, 29/30), 4.38 (1 H, d, J 2.5, CH(OH), 29), 4.45 (1 H,
d, J 6.5, CH(OH), 30); dC (100 MHz; CDCl3) 17.4 (4 × q), 48.2
(2 × q), 48.3 (2 × q), 58.6 (t), 59.8 (t), 61.4 (d), 61.9 (d), 67.5 (d),
68.0 (d), 98.1 and 98.3 (2 × s), 99.8 and 100.0 (2 × s), 117.6 (2 ×
s); m/z (FI+) 231 (M+, 70%), 201 (15), 157 (30), 115 (100), 70 (25);
HRMS (FI+) 231.1111 (M+. C10H17NO5 requires 231.1101).
=
SiCH2), 4.04 (1 H, s, CHCN), 6.38 (1 H, d, J 16.0, CHAr), 6.49
=
(1 H, dt, J 16.0, 8.0, CH2CH ), 7.41 (2 H, d, J 8.5) and 8.13 (2 H,
d, J 8.5, Ar); dC (100 MHz; CDCl3) −2.2 (2 × q), 24.3 (t), 24.8 (q),
35.9 (s), 65.8 (d), 119.0 (s), 124.0 (d), 125.9 (d), 128.1 (d), 131.3
(d), 144.5 (s), 146.1 (s); m/z (FI+) 332 (M+, 100%); HRMS (FI+)
332.1556 (M+. C17H24N2O3Si requires 332.1551).
2-(E-3-Methoxycarbonylprop-2-enyl)dimethylsilanyloxy-3,3-di-
methylbutyronitrile (19). Prepared as an orange oil (56 mg, 44%)
using methyl crotonate (1.0 eq.) as the alkene. Rf 0.17 (petrol–
ether, 5 : 1); mmax/cm−1 (film) 2964m, 2239w, 1720s, 1642m, 1479m,
1436m, 1399m, 1368m, 1323m, 1262m, 1204m, 1103m, 1047m,
953w, 920m, 837m, 758m, 734m, 690m; dH (400 MHz; CDCl3)
0.26 (3 H, s) and 0.29 (3 H, s, Si(CH3)2), 1.02 (9 H, s, C(CH3)3),
1.84–1.97 (2 H, m, SiCH2), 3.72 (3 H, s, OCH3), 4.01 (1 H, s,
=
CHCN), 5.77 (1 H, dt, J 15.5, 1.5, CHCO), 7.02 (1 H, dt, J 15.5,
=
8.5, CH2CH ); dC (100 MHz; CDCl3) −2.4 (q), −2.1 (q), 24.1 (t),
24.9 (q), 35.9 (s), 51.3 (q), 71.0 (d), 118.8 (s), 120.4 (d), 145.3 (d),
166.9 (s); m/z (ESI+) 328 (MNH4 ·MeCN, 100%), 307 (22), 292
+
(MNa+, 4); HRMS (ESI+) 270.1527 (MH+. C13H24NO3Si requires
270.1525).
(3R*,4R*,5R*)-6,6-Dimethyl-3-phenylhept-1-ene-4,5-diol (27).
A solution of aldehyde 22 (120 mg, 0.41 mmol) in benzene (8 mL)
was heated at 80 ◦C for 3.5 d. The mixture was cooled and
the solvent removed in vacuo to yield the dioxasilolane (25). [dH
(200 MHz; C6D6) 0.07 (3 H, s) and 0.22 (3 H, s, Si(CH3)2), 1.07
(9 H, s, C(CH3)3), 3.48 (1 H, dd, J 8.5, 5.0, CHPh), 3.95 (1 H,
d, J 5.0, t-BuCH), 4.51 (1 H, t, J 5.0, CH(O)CHPh), 5.16 (1 H,
Allylchlorodiphenylsilane
Copper(II) chloride was recrystallised from hydrochloric acid
(2.5 M) and then dried under high vacuum for 18 h at 150 ◦C. A
two-necked flask was then charged with a portion of this copper(II)
chloride (0.54 g, 4.0 mmol) and anhydrous copper(I) iodide (20 mg,
0.11 mmol). The flask was equipped with a Schlenk filter attached
to a second flask and all joints were sealed with PTFE tape.
The apparatus was evacuated under high vacuum for 3 h and
purged with argon several times; anhydrous THF (7.5 mL) was
then added followed by allyldiphenylsilane1 (435 mg, 2.0 mmol).
The red/orange suspension was stirred for 20 h at RT, the mixture
becoming light brown in colour after 2 h. At the end of the reaction
the apparatus was inverted through the Schlenk filter and the
inorganic residues filtered off by suction under argon to afford a
solution of allylchlorodiphenylsilane in THF.
=
dd, J 10.0, 2.0) and 5.24 (1 H, ddd, J 17.0, 2.0, CH2), 6.19–
=
6.50 (1 H, m, CH CH2), 7.15–7.55 (5 H, m, Ph)]. The crude
dioxasilolane was dissolved in THF (16 mL), the mixture was
cooled to 0 ◦C and TBAF (1.03 mL, 1.0 M solution in THF,
1.03 mmol) was◦added dropwise. The reaction mixture was stirred
for 30 min at 0 C, warmed to RT and then stirred for a further
1.5 h. The reaction was quenched by the addition of ammonium
chloride solution (saturated, aqueous, 30 mL) and then extracted
with ethyl acetate (3 × 30 mL). The combined organic layers were
washed with brine (80 mL) and dried over magnesium sulfate.
The solvent was removed in vacuo and the residue purified by
column chromatography (petrol–ethyl acetate, 10 : 1) to afford
the title compound (27, 54 mg, 56%) as a colourless oil. Rf 0.32
(petrol–ethyl acetate, 4 : 1); mmax/cm−1 (film) 3399br, 2963s, 2891m,
2232w, 1659w, 1370s, 1257s, 1104m, 843m, 804m; dH (500 MHz;
CDCl3) 0.99 (9 H, s, C(CH3)3), 1.82 (1 H, br s) and 2.31 (1 H,
br s, 2 × OH), 3.44 (1 H, d, J 2.5, t-BuCH), 3.58 (1 H, t, J 9.0,
CHPh), 4.06 (1 H, dd, J 9.0, 2.5, CH(OH)CHPh), 5.20 (1 H,
Typical DIBAL–ene–TBAF sequence, used to prepare 35/36 and
47/48
To a stirred solution of silyloxycyanohydrin (31/32 or 43/44,
1.02 mmol) in dichloromethane (20 mL) at −78 ◦C was added
DIBAL (1.52 mL, 1.0 M solution in dichloromethane, 1.52 mmol)
and the solution was stirred for 1 h. A solution of tartaric acid
in methanol (saturated, 6 mL) was then added and the mixture
stirred for a further 30 min then warmed to RT. The mixture
was partitioned between water (50 mL) and ether (100 mL) and
the aqueous component was extracted with ether (3 × 60 mL).
The combined organic extracts were then washed successively
=
d, J 10.0) and 5.26 (1 H, d, J 17.0, CH2), 6.05 (1 H, ddd,
=
J 17.0, 10.0, 9.0, CH CH2), 7.29–7.37 (3 H, m) and 7.38–7.46
(2 H, m, Ph); dC (125 MHz; CDCl3) 26.3 (q), 35.1 (s), 55.8 (d),
71.4 (d), 76.2 (d), 117.7 (t), 127.3 (d), 128.5 (d), 129.1 (d), 138.3
+
(d), 140.7 (s); m/z (CI+) 252 (MNH4 , 100%), 236 (31), 119 (42),
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with tartaric acid solution (saturated, aqueous, 60 mL) and brine
(60 mL) and dried over magnesium sulfate. The residue was
concentrated in vacuo to afford the crude silyloxyaldehydes (33/34
or 45/46) which were then dissolved in C6D6 and heated at 80 ◦C
Deprotection of compounds 39 and 40
To a stirred solution of aldehydes 39 and 40 (114 mg, 0.249 mmol)
in 1,2-dichloroethane (2.6 mL) at RT was added a solution of
trifluoroacetic acid and water (9 : 1, 0.4 mL). After 2 min the
solvent was removed in vacuo and the residue purified by column
chromatography (petrol–ethyl acetate, 1 : 1) to afford the 1,6-
anhydrosugars 41 [7 mg, 9% (14% based on theoretical quantity
of 39)] and 42 [10 mg, 12% (31% based on theoretical quantity of
40)] as waxy off-white solids.
1
in a sealed tube. Heating was continued until H NMR analysis
indicated disappearance of the aldehyde resonance (16 h to 5 d)
whereupon the solution was cooled and the solvent evaporated
in vacuo. The crude siladioxolanes were then dissolved in THF
(40 mL) and the solution cooled to 0 ◦C. TBAF (2.19 mL, 1.0 M
solution in THF, 2.19 mmol) was added dropwise and the reaction
mixture was stirred at 0 ◦C for 30 min and at RT for a further
1.5 h. The reaction was quenched by the addition of ammonium
chloride solution (saturated, aqueous, 40 mL) and the product
extracted into ethyl acetate (3 × 100 mL). The combined organic
extracts were washed with brine (200 mL), dried over magnesium
sulfate, and concentrated in vacuo. The residue was purified by
column chromatography (petrol–ethyl acetate, 2 : 1) to afforded
the diols 35/36 or 47/48. In the case of diols 35/36 some of
the diol 36 was obtained in a pure form, free of diol 35, and the
subsequent reactions were performed on both the diol mixture and
the separated diol 36. In the 47/48 series all subsequent reactions
were performed on the mixture.
1,6-Anhydro-3,4-di-O-benzyl-2-deoxy-b-D-gulose (41). Rf 0.67
(ethyl acetate); [a]D21 −35 (c 0.75, CHCl3); dH (400 MHz; CDCl3)
1.62 (1 H, ddd, J 13.1, 10.1, 1.2, 2-Hax), 2.33 (1 H, ddd, J 13.1,
6.8, 2.0, 2-Heq), 3.64 (1 H, dd, J 7.5, 4.5, 6-H), 3.72 (1 H, dd, J 8.0,
4.5, 4-H), 3.86 (1 H, ddd, J 10.1, 8.0, 6.8, 3-H), 4.10 (1 H, d, J 7.5,
6-Hꢀ), 4.47 (1 H, t, J 4.5, 5-H), 4.66 (2 H, s, CH2Ph), 4.68 (1 H, d,
J 11.8) and 4.80 (1 H, d, J 11.8, CH2Ph), 5.50 (1 H, app. s, 1-H),
7.28–7.40 (10 H, m, 2 × Ph); dC (100 MHz; CDCl3); 38.2 (t), 65.4
(t), 72.1 (t), 73.0 (t), 73.5 (d), 75.9 (d), 79.4 (d), 100.8 (d), 127.7–
128.6 (overlapping), 138.4 (s), 138.6 (s); m/z (ESI+) 349 (MNa+,
100%), 317 (80); HRMS (ESI+) 349.1402 (MNa+. C27H36NaO6
requires 349.1410).
(1R,2S)- and (1S,2R)-1-[(2R,5R,6R)-5,6-Dimethoxy-5,6-dime-
thyl-1,4-dioxan-2-yl]pent-4-ene-1,2-diol (35) and (36). Colourless
oil (35 and 36, 3 : 2 ratio, 320 mg, 24% on a 4.91 mmol scale). Rf
0.37 (35) and 0.43 (36) (ethyl acetate); mmax (film)/cm−1 3453s br,
3076w, 2949s, 2834w, 1642w, 1449m, 1376s, 1263w, 1211m, 1123s,
1037s, 949m, 879w; dH (400 MHz; CDCl3) 1.28 (12 H, s, 4 × CH3,
1,6-Anhydro-3,4-di-O-benzyl-2-deoxy-b-D-glucose (42)24. Rf
0.65 (ethyl acetate); [a]2D1 −60 (c 0.15, CHCl3), lit.24a [a]2D0 −55.2 (c
0.5, CHCl3), lit.24b [a]D25 −39.3 (c 1, CHCl3); dH (400 MHz; CDCl3)
1.94 (1 H, d, J 14.5, 2-Heq), 2.06 (1 H, ddd, J 14.5, 5.8, 2.0, 2-Hax),
3.43 (1 H, s, 4-H), 3.65 (1 H, d, J 5.8, 3-H), 3.73 (1 H, t, J 6.8,
6-H), 4.20 (1 H, dd, J 6.8, 1.2, 6-Hꢀ), 4.44 (1 H, d, J 12.1) and
4.54 (1 H, d, J 12.1, CH2Ph), 4.57 (1 H, d, J 12.2, CHHPh), 4.58
(1 H, d, J 6.8, 5-H), 4.62 (1 H, d, J 12.2, CHHꢀPh), 5.59 (1 H, s,
1-H), 7.28–7.40 (10 H, m, 2 × Ph); dC (100 MHz; CDCl3) 33.0
(t), 64.7 (t), 71.1 (t), 71.2 (t), 72.3 (d), 73.9 (d), 77.2 (d), 99.9 (d),
127.5–128.5 (overlapping), 138.2 (2 × s); m/z (ESI+) 349 (MNa+,
100%).
=
35/36), 2.31–2.37 (4 H, m, 2 × CH2CH , 35/36), 3.27 (6 H, s, 2 ×
OCH3, 35/36), 3.28 (6 H, s, 2 × OCH3, 35/36), 3.42–3.48 (2 H, m,
2 × CH(O)CH2O, 35/36), 3.67 (2 H, dd, J 11.4, 3.9, 2 × CHHꢀ,
35/36), 3.73 (2 H, t, J 11.4, 2 × CHHꢀ, 35/36), 3.87–3.94 (2 H, m,
2 × CH(OH)CH2, 35/36), 3.97–4.10 (2 H, m, 2 × CH(OH)C(O),
=
35/36), 5.06–5.19 (4 H, m, 2 × CH2, 35/36), 5.80–5.91 (2 H, m,
=
2 × CH CH2, 35/36); dC (100 MHz; CDCl3) 17.5 (q), 17.6 (q),
17.8 (q), 17.8 (q), 37.9 (t), 38.4 (t), 48.1 (q), 48.1 (2 × q), 48.2 (q),
60.1 (t), 61.0 (t), 67.9 (d), 68.5 (d), 69.8 (d), 70.9, (d), 72.7 (d), 73.7
(d), 98.0 (s), 99.2 (s), 99.2 (s), 99.4 (s), 117.9 (t), 118.5 (t), 134.3 (d),
134.5 (d); m/z (ESI+) 299 (MNa+, 100%), 242 (15); HRMS (ESI+)
299.1470 (MNa+. C13H24NaO6 requires 299.1465).
Deprotection of compounds 51 and 52
To a mixture of aldehydes 51 and 52 (10 mg, 0.019 mmol) was
added a solution of acetic acid/water (2 : 1, 1 mL) and the mixture
was stirred at 100 ◦C for 2 h. The mixture was then cooled to
RT, concentrated in vacuo (high vacuum line) for 18 h, and the
residue purified by column chromatography (petrol–ethyl acetate,
3 : 1 → ethyl acetate) to afforded the sugar derivatives 53 [3.5 mg,
47% (78% based on theoretical quantity of 51)] and 54 [2 mg, 27%
(66% based on theoretical quantity of 52), 52(a):48(b) anomeric
mixture] as waxy off-white solids.
(1R,2S,3S)- and (1S,2R,3R)-1-[(2R,5R,6R)-5,6-Dimethoxy-
5,6-dimethyl-1,4-dioxan-2-yl]-3-phenylpent-4-ene-1,2-diol (47) and
(48). Colourless oil (47 and 48, 3 : 2 ratio, 71 mg, 25% on a
0.802 mmol scale). Rf 0.52 (ethyl acetate); mmax (film)/cm−1 3456s
br, 3063w, 2948s, 2833m, 1737m, 1637w, 1601w, 1453m, 1375s,
1131s, 949m, 879s, 765w, 702m, 670m; dH (400 MHz; CDCl3) 1.30
(12 H, s, 4 × CH3, 47/48), 3.26 (3 H, s, OCH3, 47), 3.28 (3 H, s,
OCH3, 48), 3.29 (3 H, s, OCH3, 47), 3.30 (3 H, s, OCH3, 48), 3.48
(1 H, dd, J 11.2, 3.2, CHHꢀ, 48), 3.60 (1 H, app. t, J 9.2, CHHꢀ, 47),
3.65–3.75 (4 H, m), 3.84–3.81 (2 H, m) and 4.02–4.16 (4 H, m, 2 ×
CH(Ph)CH(OH)CH(OH)CH(O)CHHꢀ, 47/48), 5.12–5.23 (4 H,
1,6-Anhydro-3,4-di-O-benzyl-2-deoxy-2-C-phenyl-b-D-idose (53).
Rf 0.81 (ethyl acetate); [a]2D1 −19 (c 0.3, CHCl3); mmax (film)/cm−1
3418m br, 2962s, 1729w, 1496w, 1454m, 1100s, 873w, 800m, 699m;
dH (500 MHz; CDCl3) 2.98 (1 H, d, J 9.8, 2-H), 3.78 (1 H, dd,
J 7.5, 4.5, 6-H), 3.86 (1 H, dd, J 8.0, 4.5, 4-H), 3.94 (1 H, dd, J
9.8, 8.0, 3-H), 4.10 (1 H, d, J 10.8, CHHꢀPh), 4.29 (1 H, d, J 7.5,
6-Hꢀ), 4.49 (1 H, d, J 10.8, CHHꢀPh), 4.56 (1 H, t, J 4.5, 5-H),
4.70 (1 H, d, J 11.7) and 4.79 (1 H, d, J 11.7, CH2Ph), 5.37 (1 H,
d, J 1.2, 1-H), 6.98–7.50 (15 H, m, 3 × Ph); dC (125 MHz; CDCl3)
55.7 (d), 65.7 (t), 73.0 (t), 73.8 (d), 75.0 (t), 80.2 (d), 81.4 (d), 103.5
(d), 127.2–129.3 (overlapping); m/z (ESI+) 425 (MNa+, 100%),
=
=
m, 2 × CH2, 47/48), 5.95–6.06 (2 H, m, 2 × CH CH2, 47/48),
7.22–7.40 (10 H, m, 2 × Ph, 47/48); dC (100 MHz; CDCl3) 17.6–
17.8 (4 × q), 48.1–48.3 (4 × q), 53.4 (t), 53.6 (t), 60.0 (t), 61.6 (t),
67.5 (d), 69.2 (d), 70.5 (d), 71.5 (d), 74.8 (d), 98.0 (2 × s), 99.2
(2 × s), 117.5 (d), 117.6 (d), 126.9–129.1 (overlapping), 137.8 (2 ×
d); m/z (ESI+) 375 (MNa+, 75%), 337 (100), 277 (20), 258 (10);
HRMS (ESI+) 375.1770 (MNa+. C19H28NaO6 requires 375.1778).
2634 | Org. Biomol. Chem., 2008, 6, 2628–2635
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413(50); HRMS (ESI+) 425.1722 (MNa+. C26H26NaO4 requires
425.1723).
˚
˚
˚
9 Approximate bond lengths: Si–C, 1.89 A (C–C, 1.54 A); Si–O, 1.63 A
(C–O, 1.43 A).
˚
10 The timing and degree of association of the carbonyl oxygen with the
silicon is open to speculation but the hybridisation state at the silicon
atom must change from tetrahedral to trigonal bipyramidal (tbp) and
back to tetrahedral as the reaction progresses; in other words, whether
a tbp silicon is an intermediate or transition state is presently an open
question.
11 Prepared from benzaldehyde: (i) ethyl isobutyrate, LDA, THF,
−78 ◦C → RT over 12 h (61%); (ii) allyldiphenylsilane, B(C6F5)3,
CH2Cl2, reflux, 2 h (54%); (iii) DIBAL, CH2Cl2, −78 ◦C, 1 h (84%);
(iv) Swern oxidation (quant.).
12 Leading references: (a) (selectivity) A. K. Chatterjee, T.-L. Choi, D. P.
Sanders and R. H. Grubbs, J. Am. Chem. Soc., 2003, 125, 11360–11370;
(b) (review) S. J. Connon and S. Blechert, Angew. Chem., Int. Ed.,
2003, 42, 1900–1923; (c) (with vinyl silanes) C. Pietraszuk, H. Fischer,
M. Kujawa and B. Marciniec, Tetrahedron Lett., 2001, 42, 1175–
1178.
13 Cross-metathesis to prepare functionalised allyl silanes: (a) W. E.
Crowe, D. R. Goldberg and Z. J. Zhang, Tetrahedron Lett., 1996, 37,
2117–2120. See also: (b) J. D. Huber, N. R. Perl and J. L. Leighton,
Angew. Chem., Int. Ed., 2008, 47, 3037–3039.
3,4-Di-O-benzyl-2-deoxy-2-C-phenyl-D-glucose (54). Rf 0.36–
0.58 (streaks) (ethyl acetate); [a]2D1 +29 (c 0.18, CHCl3); mmax
(film)/cm−1 3453s br, 3079w, 2949s, 2834m, 1642w, 1449m, 1376m,
1263w, 1123s, 1037s, 949w, 879m; dH (500 MHz; CDCl3) 2.84 (1 H,
dd, J 10.8, 8.8, 2-H, b), 3.07 (1 H, dd, J 11.2, 3.0, 2-H, a), 3.68
(1 H, dd, J 9.7, 8.5, 4-H, b), 3.69 (1 H, dd, J 9.8, 8.7, 4-H, a),
3.90 (1 H, dd, J 10.8, 8.5, 3-H, b), 3.95 (1 H, d, J 10.3, CHHꢀPh),
4.06–4.26 (6 H, m, 2 × 5-H and 2 × 6-H2, a/b), 4.18 (1 H, d, J
10.3, CHHꢀPh), 4.36 (1 H, dd, J 11.2, 8.7, 3-H, a), 4.47 (1 H, d,
J 10.3, CHHꢀPh), 4.60 (1 H, d, J 10.3, CHHꢀPh), 4.71 (1 H, d,
J 11.0, CHHꢀPh), 4.72 (1 H, d, J 11.1, CHHꢀPh), 4.91 (1 H, d,
J 11.0, CHHꢀPh), 4.94 (1 H, d, J 11.1, CHHꢀPh), 5.06 (1 H, d, J
8.8, 1-H, b), 5.30 (1 H, d, J 3.0, 1-H, a), 6.76–7.52 (30 H, m, 6 ×
Ph, a/b); dC (125 MHz; CDCl3) 54.2 (d), 57.1 (d), 62.2 (t), 62.3 (t),
71.8 (d), 75.7 (d), 78.5 (d), 79.6 (d), 80.5 (d), 84.5 (d), 75.1–75.4
(4 × t), 94.8 (d), 97.6 (d), 127.4–130.0 (overlapping); m/z (ESI+)
443 (MNa+, 100%), 429 (20), 305 (20), 261 (10), 215 (10); HRMS
(ESI+) 443.1830 (MNa+. C26H28NaO5 requires 443.1829).
14 Under similar conditions, cross-metathesis of the diphenyl ana-
logue of 15 (see ref. 1) with triethoxyvinylsilane proceeded in 52%
yield.
15 The diphenylsilyl analogue (ref. 1) requires as little as 20 h to achieve
complete cyclisation at 80 ◦C (A. J. Tyrrell, Part II Thesis, Oxford
University, 2005).
16 Data for 1-(4-nitrophenyl)propene: dH (400 MHz; acetone-d6) 1.93 (3 H,
References and notes
=
d, J 5.0, CH3), 6.58 (1 H, d, J 16.0, CHAr), 6.64 (1 H, dq, J 16.0,
=
1 J. Robertson, M. J. Hall and S. P. Green, Org. Biomol. Chem., 2003, 1,
3635–3638.
2 J. Robertson, P. M. Stafford and S. J. Bell, J. Org. Chem., 2005, 70,
7133–7148.
5.0, CH3CH ), 7.64 (2 H, d, J 9.0) and 8.18 (2 H, d, J 9.0, Ar); dC
(100 MHz; acetone-d6) 18.6 (q), 124.2 (d), 126.9 (d), 129.8 (d), 131.6
(d), 145.0 (s), 146.9 (s).
17 For leading reviews: (a) H. J. M. Gijsen, L. Qiao, W. Fitz and
C.-H. Wong, Chem. Rev., 1996, 96, 443–473; (b) P. Sears and
C.-H. Wong, Angew. Chem., Int. Ed., 1999, 38, 2300–2324; (c) P.
Compain and O. R. Martin, Bioorg. Med. Chem., 2001, 9, 3077–
3092.
3 (a) M. T. Reetz and A. Jung, J. Am. Chem. Soc., 1983, 105, 4833–4835;
(b) M. T. Reetz, A. Jung and C. Bolm, Tetrahedron, 1988, 44, 3889–
3898; (c) M. T. Reetz, Pure Appl. Chem., 1985, 57, 1781–1788. For allylic
delivery from b-silicate-complexed aldehydes, see: (d) S. R. Chemler and
W. R. Roush, J. Org. Chem., 1998, 63, 3800–3801; (e) S. R. Chemler and
W. R. Roush, Tetrahedron Lett., 1999, 40, 4643–4647; (f) S. R. Chemler
and W. R. Roush, J. Org. Chem., 2003, 68, 1319–1333. For related b-
tethered Sakurai-type allylations, see: (g) J. Beignet and L. R. Cox, Org.
Lett., 2003, 5, 4231–4234; (h) R. Ramalho, J. Beignet, A. C. Humphries
and L. R. Cox, Synthesis, 2005, 3389–3397; (i) P. J. Jervis and L. R.
Cox, Beilstein J. Org. Chem., 2007, 3, No. 6; (j) R. Ramalho, P. J. Jervis,
B. M. Kariuki, A. C. Humphries and L. R. Cox, J. Org. Chem., 2008,
73, 1631–1634. For an early a-tethered example, see: (k) K. Sato, M.
Kira and H. Sakurai, J. Am. Chem. Soc., 1989, 111, 6429–6431.
4 J. Robertson, M. J. Hall, P. M. Stafford and S. P. Green, Org. Biomol.
Chem., 2003, 1, 3758–3767.
5 (a) J. M. Blackwell, K. L. Foster, V. H. Beck and W. E. Piers, J. Org.
Chem., 1999, 64, 4887–4892. See also: (b) V. Gevorgyan, M. Rubin, S.
Benson, J.-X. Liu and Y. Yamamoto, J. Org. Chem., 2000, 65, 6179–
6186.
6 This chlorosilane was prepared from the silane following the method
described in A. Kunai, T. Kawakami, E. Toyoda and M. Ishikawa,
Organometallics, 1992, 11, 2708–2711.
18 See for example: (a) G. N. Richards, J. Chem. Soc., 1955, 2013–2016;
(b) J. B. Lee and B. F. Scanlon, J. Chem. Soc. D, 1969, 955–956.
19 I. Hladezuk, A. Olesker, J. Cle´ophax and G. Lukacs, J. Carbohydr.
Chem., 1998, 17, 869–878.
20 P. Michel and S. V. Ley, Synthesis, 2003, 1598–1602.
21 The low overall yield for the three-step sequences (31/32→35/36 and
43/44→47/48), averaging only ca. 62% per step, was attributed to the
influence of the BDA substituent on the stability of the silyl tether
during the DIBAL reduction, as a-diphenylsilyl-tethered substrates
bearing simple alkyl groups, rather than this BDA group, progressed
through the same sequence in reasonable yield (ref. 1).
22 (a) J.-L. Montchamp, F. Tian, M. E. Hart and J. W. Frost, J. Org. Chem.,
1996, 61, 3897–3899; (b) A. Hense, S. V. Ley, H. M. I. Osborn, D. R.
Owen, J.-F. Poisson, S. L. Warriner and K. E. Wesson, J. Chem. Soc.,
Perkin Trans. 1, 1997, 2023–2031.
23 When evaporating dichloromethane–TFA solutions (dichloromethane,
bp 40 ◦C) we expect that the product spends a significant time as a
concentrated solution in TFA; therefore, we reasoned that switching to
a higher-boiling chlorinated solvent (such as DCE, bp 83 ◦C) would
allow most of the TFA (bp 72 ◦C) to be evaporated off, leaving the
product as a concentrated solution in that solvent.
24 (a) H. Paulsen, D. Schnell and W. Stenzel, Chem. Ber., 1977, 110, 3707–
3713; (b) K. Hatanaka, S. Kanazawa, T. Uryu and K. Matsuzaki,
J. Polym. Sci., Polym. Chem. Ed., 1984, 22, 1987–1996; (c) Y.-Z.
Liang, A. H. Franz, C. Newbury, C. B. Lebrilla and T. E. Patten,
Macromolecules, 2002, 35, 3402–3412.
25 S. V. Ley and H. W. M. Priepke, Angew. Chem., Int. Ed. Engl., 1994,
33, 2292–2294.
7 For comparative data, see: T. Yamazaki, A. Kuboki, H. Ohta, T. M.
Mitzel, L. A. Paquette and T. Sugai, Synth. Commun., 2000, 30, 3061–
3072.
8 Crystal data for 12: C20H24O2Si, M = 324.50, colourless plate, mono-
3
˚
˚
clinic, a = 8.8918(3), b = 15.1623(7), c = 13.7021(5) A, V = 1832.97 A ,
T = 120 K, space group P21/n, Z = 4, 6513 reflections measured, 4136
independent, 2996 used for refinement (Rint = 0.01), final wR = 0.0584.
CCDC reference number 682308. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b804752a.
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