Chiral dihydroxyacetone equivalents in synthesis: An expedient diastereo- and enantioselective synthesis of differentially protected ketopolyols

Article abstract of DOI:10.1055/s-2002-23550

A highly diastereo- and enantioselective entry to higher order ketopolyols, employing boron-mediated aldol reactions of a chiral dihydroxyacetone equivalent, is reported. The differentially protected products should prove as useful building blocks for polyhydroxylated natural product synthesis.

Full text of DOI:10.1055/s-2002-23550

PAPER
619
Chiral Dihydroxyacetone Equivalents in Synthesis: An Expedient Diastereo-
and Enantioselective Synthesis of Differentially Protected Ketopolyols
Diastereo- and
E
na
i
ntiosel
e
ective Syn
t
o
e
f
K
etopolyo
r
ls Enders,* Stuart J. Ince
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: Enders@RWTH-Aachen.de
Received 20 February 2002
Abstract: A highly diastereo- and enantioselective entry to higher
order ketopolyols, employing boron-mediated aldol reactions of a
chiral dihydroxyacetone equivalent, is reported. The differentially
protected products should prove as useful building blocks for poly-
hydroxylated natural product synthesis.
O
O
OH OH
*
O
O
+
+
R3
R3
*
R3
*
OR1
OR2
OR1 OR2
OR1 OR2
1,2-polyol
dihydroxyacetone
equivalent
Key words: chiral dihydroxyacetone equivalent -substituted ke-
tones, aldol reactions, polyols, asymmetric synthesis
Scheme 1
An efficient approach to asymmetric 1,2-diol synthesis in-
volves the establishment of the required relative and abso-
lute stereochemistry with concommitant C–C bond
formation. The combination of an aldehyde and a (formal)
carbon-centred nucleophile in which either of the reacting
partners contains -hydroxy substitution fulfills these cri-
terea. An interesting possibility for 1,2-polyol synthesis is
revealed when both the aldehyde and carbon-centred nu-
cleophile are -hydroxylated (Scheme 1). In this context,
the asymmetric aldol reaction involving an -hydroxycar-
bonyl compound has been shown as a reliable method,
with both syn- and anti-diastereoisomers accessible.1
Most of the research has focussed on aldol-type reactions
of suitable glycolic acid derivatives.2 The aldol reaction of
2-(trimethylsilyloxy)furan and -oxygenated aldehydes
has also been utilised with success.3 An alternative route
is presented when the attacking enolate is at the ketone ox-
idation level, thus indicating a directed reduction as the fi-
nal step. This immediately poses the issue of
regioselective enolisation.4 Paterson has employed chiral
propionate- and lactate-derived protected -hydroxy ke-
tones in highly diastereoselective boron-mediated aldol
reactions.1f,5 Recently, Sasaki et al. made elegant use of a
lactate-derived chiral -hydroxy ketone in natural product
synthesis.6 Alternatively, in new developments, the direct
regioselective enolisation of unprotected -hydroxy ke-
tones has been demonstrated with biological catalysts7 as
well as small organic promoters8 and bimetallic complex-
es.9
phate (DHAP) in carbohydrate biosynthesis. It is therefore
not unsurprising that one of the major areas of research on
DHA and its derivatives has been in the area of enzyme-
catalysed aldol reactions.1b,10 In marked contrast, chemi-
cal equivalents of dihydroxyacetone have only been em-
ployed in aldol reactions relatively recently.
Diastereoselectivity has been observed in boron-mediated
aldol reactions of 2,2-dimethyl-1,3-dioxan-5-one11 and in
Mukaiyama aldol reactions of the Z-silyl enol ether of 1,3-
di-O-benzyloxyacetone12 and the corresponding cyclo-
hexylidene derivative.12b The enolisation of a variety of
protected acyclic DHA derivatives with the usually E-se-
lective dicyclohexylboron chloride/triethylamine system
has been reported to give 1,2-syn selectivity.13 In the same
work, regioselective enolisation of an unsymmetrical
DHA derivative was reported in which enolisation to-
wards an O-acyl group but away from a bulky O-silyl
group occurred.
The development of only a few chiral DHAP derivatives
has been reported. In 1988 Hirama showed that the lithi-
um enolate of an -substituted dioxanone (synthesised in
five steps from D-glucose) could participate in a 1,2-anti
selective aldol reaction.14 A conceptually similar bis-ace-
tal erythrulose derivative was employed by Carda and
Marco et al. in boron-mediated aldol reactions.15 By alter-
ing the nature of the protecting groups, 1,2-syn or 1,2-anti
diastereoselectivity could be achieved.
In 1995, a potentially more general approach was pio-
neered by Majewski in which a simple prochiral diox-
anone was deprotonated by a chiral lithium amide base
and the resulting anion trapped with aldehydes to give 1,2-
anti products.16 More recent work has shown that the
combination of prochiral ketone, chiral base and chiral al-
dehyde is essential for high enantioselectivity.11
The problem is simplified when the enolate component
contains both -hydroxy centres thus requiring a dihy-
droxyacetone (DHA) equivalent (Scheme 1). This strate-
gy may be considered biomimetic as nature performs
asymmetric aldol reactions on dihydroxyacetone phos-
In 1993 our group reported a solution to the problem of in-
troducing chirality to a simple DHA system by conversion
of 2,2-dimethyl-1,3-dioxan-5-one to the corresponding
Synthesis 2002, No. 5, 08 04 2002. Article Identifier:
1437-210X,E;2002,0,05,0619,0624,ftx,en;Z03702SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

620
D. Enders, S. J. Ince
PAPER
SAMP or RAMP hydrazone.17 The azaenolate, generated once again no detectable epimerisation was observed. Si-
by deprotonation with t-BuLi at low temperature, reacted lylation of hydroxy ketone 2 with TBSOTf and 2,6-luti-
with aldehydes to give, after cleavage of the auxiliary, the dine as the base gave the required aldol precusor 3 in
1,2-anti diastereomers with de’s up to 79% and ee’s up to excellent yield. Slight epimerisation of the -stereogenic
82%. Interestingly, the reaction with benzyl glyoxylate re- centre (de as low as 82%) was observed in some reactions,
turned the 1,2-syn diastereoisomer. However, the boron the exact origin of which is not clear at present. No silyl
enolate of chiral DHA equivalent (S)-1 (readily available enol ether formation could be detected. Diastereomerical-
from the corresponding SAMP hydrazone) reacted ly pure 3 ( 96% de), however, was obtainable by prepar-
smoothly with a variety of aldehydes to give, after cleav- ative HPLC.
age of the -silyl auxiliary, protected keto triols as single
diastereoisomers in excellent enantiomeric purity
N
(Scheme 2).18 We realised that suitable protection of the
N
O
O
OR
free hydroxyl would offer the possibility of a second aldol
reaction whose stereoselectivity should be controlled in
the same way and thus offer access to higher order polyol
sytems.19
TDS
ref. 17
a, b
72%
O
O
O
O
O
O
OBn
(de ≥96%)
H3C CH3
H3C CH3
H3C CH3
(R)-1
2: R = H
c
(ee = 93%)
3: R = TBS
OBCy2
O
OH
R1
1. R1CHO
2. – TDS
92% (de =82%;
≥96% after
HPLC)
TDS
O
O
ref. 18
O
O
H3C CH3
H3C CH3
Scheme 3 Reagents and conditions: (a) Cy2BCl, Et3N, Et2O, –78 to
0 °C, then BnOCH2CHO, Et2O, –78 to –24 °C, 86%; (b) Et3N 3HF,
THF, –20 °C, 84%; (c) TBSOTf, 2,6-lutidine, CH2Cl2, –78 °C, 92%
boron enolate of (S)-1
OPG OBCy2
OPG
O
OH
R2
R1
R1
We next investigated the reactivity of 3 in the boron-me-
diated aldol reaction with a range of aldehydes
(Scheme 4). Thus, ketone 3 was reacted with a mixture of
Cy2BCl (1.5 equiv) and Et3N (1.7 equiv) in diethyl ether
at low temperature (–78 °C) before warming to 0 °C. The
resulting boron enolate was recooled to –78 °C before a
solution of the corresponding aldehyde (1.3 – 2.5 equiv)
in diethyl ether was added and the reaction was stirred at
–78 °C for 1 hour before warming to –24 °C. Subsequent
oxidative workup (30% aq H2O2, MeOH/pH 7 buffer) af-
forded the crude aldol products that were purified by chro-
matography. In this way, hydroxy ketones 4a–f were
isolated in good yields (60–87%) and with excellent dias-
tereoselectivities ( 96% de) (Scheme 4, Table). It is im-
portant to note that employment of an oxidative workup is
essential to isolate pure products. Crude 4d for example,
could not be separated from the lactol product between
PhCHO and Cy2BOH. The lower yields of the reactions in
some cases may reflect an increased sensitivity towards
this oxidative workup.20
concept
O
O
O
O
H3C CH3
H3C CH3
H3C CH3
Si
H3C
H3C
= thexyldimethylsilyl (TDS)
CH3
CH3
Scheme 2
In this paper we wish to report the extension of this meth-
odology in a practical approach to differentially protected
ketopolyols. The four new oxygenated stereogenic centres
are all induced from the single stereogenic centre in the
simple, RAMP hydrazone derived, -silyldioxanone (R)-
1. To selectively manipulate oxygen functionality, an or-
thogonally cleavable protecting group was required for
the -hydroxyl. In this respect a silyl ether was attractive.
Benzyloxyacetaldehyde was chosen as the first aldehyde,
offering the advantage of a benzyl ether cleavable by hy-
drogenolysis. -Silyldioxanone (R)-1 was prepared in two
steps from the corresponding dioxanone RAMP hydra-
zone in analogy to our previous work (Scheme 3).18 In this
case the ee, as determined by GC (chiral stationary phase),
was 93%. Hydroxy ketone 2 was also prepared in analogy
to the previous work. Furthermore, we have found that the
use of dimethylethylamine as amine base is no longer nec-
essary as triethylamine performs equally well. As expect-
ed the aldol product was isolated in high yield (86%) and
diastereoselectivity ( 96% de). Subsequent desilylation
with triethylamine HF complex was also uneventful and
O
OTBS
OH
O
OTBS
1. Cy2BCl, Et3N, Et2O
2. RCHO, Et2O
R
O
O
OBn
O
O
OBn
60 - 87%
H3C CH3
H3C CH3
3
4 a - f
Scheme 4
In summary the bis-aldol strategy outlined above has al-
lowed rapid access to differentially protected higher order
ketopolyols. The presence of three orthogonal protecting
groups, the possibility of a subsequent directed reduction
Synthesis 2002, No. 5, 619–624 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diastereo- and Enantioselective Synthesis of Ketopolyols
621
Table Cy2BCl-Mediated Diastereoselective Aldol Reactions of Ke-
tone 3 to Form the Protected Ketopolyols 4 (93% ee)
distilled 2,6-lutidine (1.44 mL, 12.4 mmol, 4.0 equiv) and TBSOTf
(2.18 mL, 9.31 mmol, 3.0 equiv) dropwise via syringe. The stirring
was continued for a further 75 min before the reaction was
quenched at –78 °C with aq NaHCO3 solution (10 mL) and warmed
to r.t. The mixture was poured into aq NaHCO3 solution (50 mL)
and extracted with CH2Cl2 (50 mL). The aqueous portion was dilut-
ed with H2O (50 mL) and extracted with CH2Cl2 (2 50 mL). The
combined organic extracts were dried (Na2SO4), filtered and con-
centrated in vacuo to give the crude product as a colourless syrup.
Purification by flash chromatography on silica gel (eluent: 97:3
9:1 pentane–Et2O) gave the title compound 3 (1.13 g, 92%, 82% de)
as a colourless syrup; [ ]D22 +76.8 (c = 1.0, CHCl3).
b
4
a
b
c
d
e
f
R
Yielda (%) [ ]D
dec (%)
96
Pr
64
66
83
87
84
60
+65.8
iPr
+67.7
+60.7
+53.5
+42.1
+66.7
96
CH2=C(Me)
Ph
96
96
(CH2)2OTBDPS
CH2OBn
96
IR (film): 3031, 2987, 2953, 2930, 2886, 2857, 1751, 1497, 1472,
1462, 1375, 1326. 1303, 1252, 1225, 1160, 1100, 1029, 1006 cm–1.
96
1H NMR (400 MHz, CDCl3): = 0.07 (s, 3 H, SiCH3), 0.10 (s, 3 H,
SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 1.43 (s, 3 H, CH3 acetal), 1.44 (s,
3 H, CH3 acetal), 3.51 (dd, J = 9.7, 6.2 Hz, 1 H, CHaHbOBn), 3.72
(dd, J = 9.6, 7.7 Hz, 1 H, CHaHbOBn), 3.86 (d, J = 15.9 Hz, 1 H, H-
6a), 4.18 (dd, J = 15.9, 1.4 Hz, 1 H, H-6b), 4.32–4.36 (m, 2 H, H-4,
CHOTBS), 4.15–4.54 (qAB, 2 H, CH2Ph), 7.25–7.35 (m, 5 H, C6H5).
a Yields after chromatography.
b Measured at 26 1.0 °C, c = 1.0, CHCl3.
c Determined by 1H and 13C NMR spectroscopy.
13C NMR (100 MHz, CDCl3): = –4.4, –4.3 [Si(CH3)2], 18.5
[SiC(CH3)3], 23.4, 25.2 (CH3 acetal), 26.1 [SiC(CH3)3], 67.4
(CH2OBn), 70.8 (C-6), 71.7 (C-4/CHOTBS), 73.6 (CH2Ph), 77.7
(C-4/CHOTBS), 100.5 (acetal C), 127.8, 128.5 (Ar-C), 138.3 (Ar-
C, ipso), 206.9 (C=O).
and the access to both enantiomeric forms makes this ap-
proach attractive and flexible for polyhydroxylated natu-
ral product synthesis with which we are now engaged.
Anhyd CH2Cl2 was distilled from CaH2, MeOH was distilled from
Mg, anhyd Et2O and THF were distilled from Na/Pb alloy (ben-
zophenone indicator). Anhyd Et3N was stored over and distilled
from CaH2. Anhyd 2,6-lutidine was distilled from CaH2 and stored
over activated 4Å molecular sieves. Cy2BCl was prepared using
commercial (Aldrich) H2BCl SMe2 complex.1f (R,R)-4-(2-Benzy-
loxy-1-hydroxyethyl)-2,2-dimethyl[1,3]dioxan-5-one (2) (93% ee,
[ ]D +96.6 (c = 0.73, CHCl3) {Lit.18 [for (S,S)-enantiomer] –107 (c
= 1.0, CHCl3)} was prepared in analogy to our published procedure.
3-(tert-Butyldiphenylsilanyloxy)propionaldehyde was prepared in
two steps (silylation, Dess–Martin oxidation) from propane-1,3-di-
ol.21 Benzyloxyacetaldehyde was prepared in two steps (benzyla-
tion, oxidative cleavage) from (Z)-but-2-ene-1,4-diol.22 All other
reagents were obtained commercially and used without further pu-
rification.
MS (CI): m/z (%) = 396.3 (30, MH+ + 1), 395.3 (100, MH+), 377.3
(13), 338.3 (16), 337.3 (67), 319.3 (10), 287.2 (16), 279.2 (21),
265.2 (11), 205.2 (16), 187.1 (26), 161.2 (10), 155.1 (12), 145.1
(30), 133.2 (10), 91.3 (32).
HRMS (EI): m/z calcd for C14H19O4Si (M+ – C7H15O), 279.1053;
found, 279.1046.
Anal. Calcd for C21H34O5Si (394.6): C, 63.92; H, 8.69. Found C,
63.61; H, 9.21.
Boron-Mediated Aldol Reactions of Ketone 3; General Proce-
dure
To a stirred solution of Cy2BCl (1.5 equiv) in Et2O (20 mL/mmol
ketone), at –78 °C, was added Et3N (1.7 equiv) via syringe fol-
lowed, 10 min later, by a solution of the ketone 3 (1 equiv) in Et2O
(2 mL/mmol), via syringe. Stirring was continued for a further 30
min at –78 °C, before the mixture was warmed to 0 °C for 1 h. The
resulting suspension was recooled to –78 °C before a solution of the
freshly purified aldehyde (1.3–2.5 equiv) in Et2O (3 mL/mmol ke-
tone) was added dropwise via syringe. The stirring was continued
for 1 h at –78 °C before the flask was sealed and placed in a freezer
(–24 °C) for 14–18 h. The mixture was quenched with phosphate
buffer (pH 7, 20 mL/mmol ketone) and extracted with Et2O (2 vol-
umes). The combined organic extracts were concentrated in vacuo,
taken up in phosphate buffer (pH 7, 6 mL/mmol ketone) and MeOH
(6 mL/mmol ketone) and cooled to 0 °C before aq H2O2 (30%, 3
mL/mmol ketone) was added dropwise. The mixture was warmed to
r.t. over 1–2 h, poured into phosphate buffer (pH 7, 20 mL/mmol ke-
tone) and extracted with CH2Cl2 (4 volumes). The combined organ-
ic extracts were dried (Na2SO4), filtered and concentrated in vacuo
to give the crude product as a colourless or yellow syrup. Purifica-
tion by flash chromatography on silica gel (gradients of pentane–
Et2O) gave the hydroxy ketones as a colourless or pale yellow syr-
up.
Reactions were carried out at r.t. under argon in predried glassware
using anhyd solvents unless otherwise stated. Distilled H2O was
used. All aqueous solutions were saturated unless otherwise stated.
Phosphate buffer (pH 7) was a solution of KH2PO4 (34.0 g) and
NaOH (5.82 g) in H2O (500 mL). Distilled solvents were used for
for chromatography and reaction workup. Column chromatography
was carried out under pressure using Merck silica gel (400–630
mesh). Analytical and preparative TLC was performed using pre-
coated, glass backed plates (Merck silica gel 60 F 254) and visual-
ised by ultra violet radiation (254 nm), acidic ammonium
molybdate(IV) or alkaline KMnO4.
Optical rotations were measured with a Perkin-Elmer 241 polarim-
eter. IR spectra were recorded on a Perkin-Elmer 1760 spectropho-
1
tometer. H and 13C NMR spectra were recorded on Gemini 300
MHz, Varian Inova 400 MHz and Unity 500 MHz spectrometers us-
ing TMS as reference. J values are given in Hz. Signals were as-
signed by means of 2D spectra (COSY, HETCOR) and APT. Mass
spectra were obtained on a Finnigan SSQ7000 spectrometer (CI 100
eV; EI 70 eV) and high resolution mass spectra on a Finnigan MAT
95. Microanalyses were determined on a Heraeus CHN-O-RAPID
or an Elementar Vario EL.
(R,R,R,R)-4-[2-Benzyloxy-1-(tert-butyldimethylsilanyloxy)eth-
yl]-6-(1-hydroxybutyl)-2,2-dimethyl[1,3]dioxan-5-one (4a)
The boron enolate of ketone 3 (0.25 g, 0.63 mmol) was generated
and reacted with freshly distilled n-butanal (0.11 mL, 1.27 mmol)
according to the general procedure. Oxidative workup and subse-
(R,R)-4-[2-Benzyloxy-1-(tert-butyldimethylsilanyloxy)ethyl]-
2,2-dimethyl[1,3]dioxan-5-one (3)
To a stirred solution of the hydroxy ketone 218 (0.87 g, 3.10 mmol,
1.0 equiv) in CH2Cl2 (3.8 mL) at –78 °C was added sequentially,
quent flash chromatography on silica gel (eluent: 9:1
7:1 pen-
Synthesis 2002, No. 5, 619–624 ISSN 0039-7881 © Thieme Stuttgart · New York

622
D. Enders, S. J. Ince
PAPER
tane–Et2O) gave the title compound 4a (0.189 g, 64%) as a
colourless syrup; [ ]D26 +65.8 (c = 1.0, CHCl3).
Anal. Calcd for C25H42O6Si (466.7): C, 64.34; H, 9.07. Found C,
64.22; H, 8.82.
IR (film): 3554, 3031, 2987, 2957, 2931, 2859, 1738, 1463, 1409,
1377, 1310, 1254, 1222, 1172, 1104, 1029, 1006 cm–1.
(R,R,R,R)-4-[2-Benzyloxy-1-(tert-butyldimethylsilanyloxy)eth-
yl]-6-(1-hydroxy-2-methylallyl)-2,2-dimethyl[1,3]dioxan-5-one
(4c)
The boron enolate of ketone 3 (0.25 g, 0.63 mmol) was generated
and reacted with freshly distilled 2-methylpropenal (0.10 mL, 1.27
mmol) according to the general procedure. Oxidative workup and
subsequent flash chromatography on silica gel (eluent: 10:1 pen-
tane–Et2O) gave the title compound 4c (0.244 g, 83%) as a colour-
less syrup which upon storage at –24 °C solidified to an amorphous
white solid; [ ]D26 +60.7 (c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): = 0.06 (s, 3 H, SiCH3), 0.09 (s, 3 H,
SiCH3), 0.86 [s, 9 H, SiC(CH3)3], 0.92 (t, J = 7.0 Hz, 3 H,
CH3CH2CH2), 1.30–1.60 (m, 4 H, CH3CH2CH2), 1.39 (s, 3 H, CH3
acetal), 1.43 (s, 3 H, CH3 acetal), 2.92 (d, J = 3.8 Hz, 1 H, CHOH),
3.48 (dd, J = 9.3, 5.9 Hz, 1 H, CHaHbOBn), 3.70 (dd, J = 9.3, 8.2
Hz, 1 H, CHaHbOBn), 3.76–3.82 (m, 1 H, CHOH), 3.94 (dd, J = 7.5,
1.1 Hz, 1 H, H-6), 4.27 (dd, J = 1.9, 1.1 Hz, 1 H, H-4), 4.33 (ddd,
J = 8.0, 6.0, 2.0 Hz, 1 H, CHOTBS), 4.45 (d, J = 11.8 Hz, 1 H, Ph-
CHaHb), 4.51 (d, J = 11.8 Hz, 1 H, PhCHaHb), 7.26–7.36 (m, 5 H,
C6H5).
13C NMR (100 MHz, CDCl3): = –4.9, –4.7 [Si(CH3)2], 14.0
(CH3CH2CH2), 18.1 [SiC(CH3)3], 18.2 (CH3CH2CH2), 23.6, 24.2
(CH3 acetal), 25.7 [SiC(CH3)3], 34.3 (CH3CH2CH2), 69.8 (CHOH),
70.0 (CH2OBn), 71.3 (CHOTBS), 73.3 (PhCH2), 74.6 (C-6), 76.8
(C-4), 101.0 (acetal C), 127.4, 127.5, 127.6, 128.2 (Ar-C), 137.7
(Ar-C, ipso), 209.9 (C=O).
MS (CI): m/z (%) = 468.3 (34, MH+ + 1), 467.3 (100, MH+), 450.3
(20), 449.3 (63), 410.3 (23), 409.2 (86), 396.2 (15), 395.2 (51, MH+
– n-PrCHO), 391.3 (28), 377.2 (13), 337.2 (25), 133.1 (19).
HRMS (EI): m/z calcd for C21H33O6Si (M+ – C4H9), 409.2046;
found, 409.2047; m/z calcd for C21H31O5Si (M+ – C4H11O),
391.1941; found, 391.1940.
IR (KBr): 3547, 3087, 3065, 3030, 2991, 2956, 2927, 2894, 2857,
1735, 1496, 1472, 1460, 1380, 1326, 1312, 1261, 1224, 1173, 1150,
1108, 1056, 1039, 1006 cm–1.
1H NMR (400 MHz, CDCl3): = 0.07 (s, 3 H, SiCH3), 0.10 (s, 3 H,
SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 1.38 (s, 3 H, CH3 acetal), 1.40 (s,
3 H, CH3 acetal), 1.73–1.74 (m, 1 H, CH3C=CH2), 3.20 (d, J = 3.0
Hz, 1 H, CHOH), 3.49 (dd, J = 9.3, 5.8 Hz, 1 H, CHaHbOBn), 3.72
(dd, J = 9.3, 8.2 Hz, 1 H, CHaHbOBn), 4.09 (dd, J = 8.4, 1.2 Hz, 1
H, H-6), 4.21 (dd, J = 8.2, 2.7 Hz, 1 H, CHOH), 4.30 (dd, J = 1.9,
1.1 Hz, 1 H, H-4), 4.34 (ddd, J = 8.0, 5.9, 2.1 Hz, 1 H, CHOTBS),
4.46 (d, J = 12.1 Hz, 1 H, PhCHaHb), 4.52 (d, J = 11.8 Hz, 1 H, Ph-
CHaHb), 4.95–4.96 (m, 1 H, CH3C=CH)), 5.00–5.01 (m, 1 H,
CH3C=CH), 7.26–7.36 (m, 5 H, C6H5).
13C NMR (100 MHz, CDCl3): = –4.5, –4.3 [Si(CH3)2], 18.3
(CH3C=CH2), 18.5 [SiC(CH3)3], 23.9, 24.6 (CH3 acetal), 26.1
[SiC(CH3)3], 70.3 (CH2OBn), 71.7 (CHOTBS), 73.4 (C-6), 73.7
(PhCH2), 74.2 (CHOH), 77.2 (C-4), 101.5 (acetal C), 114.8
(CH3C=CH2)), 127.9, 128.0, 128.6 (Ar-C), 138.0 (Ar-C, ipso),
142.9 (CH3C=CH2), 210.4 (C=O).
Anal. Calcd for C25H42O6Si (466.7): C, 64.34; H, 9.07. Found C,
64.23; H, 9.71.
(R,R,R,R)-4-[2-Benzyloxy-1-(tert-butyldimethylsilanyloxy)eth-
yl]-6-(1-hydroxy-2-methylpropyl)-2,2-dimethyl[1,3]dioxan-5-
one (4b)
The boron enolate of ketone 3 (0.294 g, 0.74 mmol) was generated
and reacted with freshly distilled 2-methylpropionaldehyde (0.10
mL, 1.12 mmol) according to the general procedure. Oxidative
workup and subsequent flash chromatography on silica gel (eluent:
MS (CI): m/z (%) = 466.4 (24, MH+ + 1), 465.4 (83, MH+), 448.4
(20, MH+ + 1 – H2O), 447.4 (66, MH+ – H2O), 407.4 (15), 396.3 [28,
MH+
+
1
–
CH2=C(CH3)CHO], 395.3 [100, MH+
–
CH2=C(CH3)CHO], 378.3 (10), 377.3 (40), 357.3 (31), 337.2 (33),
205.2 (12), 161.2 (28), 127.3 (19), 71.3 (39).
HRMS (EI): m/z calcd for C21H33O5Si (M+ – C4H7O), 393.2097;
98:2
9:1 pentane–Et2O) gave the title compound 4b (0.231 g,
66%) as a colourless syrup; [ ]D26 +67.7 (c = 1.0, CHCl3).
found, 393.2095.
IR (CHCl3): 3556, 3031, 2958, 2931, 2880, 2858, 1736, 1472, 1464,
1456, 1404, 1382, 1375, 1343, 1321, 1252, 1220, 1173, 1108, 1044,
1029, 1006 cm–1.
Anal. Calcd for C25H40O6Si (464.7): C, 64.62; H, 8.68. Found C,
64.70; H, 8.93.
1H NMR (400 MHz, CDCl3): = 0.06 (s, 3 H, SiCH3), 0.10 (s, 3 H,
SiCH3), 0.87–0.89 [m, 12 H, SiC(CH3)3, CHCH3], 0.99 (d, J = 6.9
Hz, 3 H, CHCH3), 1.39 (s, 3 H, CH3 acetal), 1.44 (s, 3 H, CH3 ace-
tal), 1.95–1.99 [m, 1 H, CH(CH3)2], 2.96 (d, J = 3.0 Hz, 1 H,
CHOH), 3.48 (dd, J = 9.2, 5.9 Hz, 1 H, CHaHbOBn), 3.66 (ap dt,
J = 8.5, 3.0 Hz, 1 H, CHOH), 3.71 (dd, J = 9.2, 8.1 Hz, 1 H, CHaH-
bOBn), 4.04 (dd, J = 8.4, 1.0 Hz, 1 H, H-6), 4.29 (ap t, J = 1.8 Hz, 1
H, H-4), 4.34 (ddd, J = 8.0, 6.0, 1.9 Hz, 1 H, CHOTBS), 4.46 (d,
J = 11.8 Hz, 1 H, PhCHaHb), 4.52 (d, J = 11.8 Hz, 1 H, PhCHaHb),
7.26–7.36 (m, 5 H, C6H5).
(R,R,R,R)-4-[2-Benzyloxy-1-(tert-butyldimethylsilanyloxy)eth-
yl]-6-(hydroxyphenylmethyl)-2,2-dimethyl[1,3]dioxan-5-one
(4d)
The boron enolate of ketone 3 (0.30 g, 0.76 mmol) was generated
and reacted with freshly distilled benzaldehyde (0.12 mL, 1.14
mmol) according to the general procedure. Oxidative workup and
subsequent flash chromatography on silica gel (eluent: 8:1
6:1
pentane–Et2O) gave the title compound 4d (0.331 g, 87%) contam-
inated by a trace amount of benzaldehyde as a pale yellow
syrup; [ ]D26 +53.5 (c = 1.0, CHCl3).
13C NMR (100 MHz, CDCl3): = –4.5, –4.3 [Si(CH3)2], 15.4
(CHCH3), 18.5 [SiC(CH3)3], 19.7 (CHCH3), 24.0, 24.8 (CH3 ace-
tal), 26.1 [SiC(CH3)3], 28.7 [CH(CH3)2], 70.3 (CH2OBn), 71.8
(CHOTBS), 72.8 (C-6), 73.7 (PhCH2), 73.9 (CHOH), 77.2 (C-4),
101.3 (acetal C), 127.9, 128.0, 128.6 (Ar-C), 138.1 (Ar-C, ipso),
211.3 (C=O).
MS (CI): m/z (%) = 468.4 (30, MH+ + 1), 467.4 (100, MH+), 450.4
(15, MH+ + 1 – H2O), 449.3 (50, MH+ – H2O), 410.3 (10), 409.3
(34), 395.3 (20, MH+ – i-PrCHO), 391.3 (15), 377.3 (12), 337.3
(16), 205.1 (11).
IR (film): 3533, 3064, 3033, 2987, 2952, 2929, 2895, 2857, 1737,
1496, 1472, 1454, 1406, 1383, 1376, 1363, 1324, 1308, 1252, 1224,
1200, 1170, 1103, 1052, 1029, 1006 cm–1.
1H NMR (400 MHz, CDCl3): = 0.07 (s, 3 H, SiCH3), 0.10 (s, 3 H,
SiCH3), 0.88 [s, 9 H, SiC(CH3)3], 1.14 (s, 3 H, CH3 acetal), 1.32 (s,
3 H, CH3 acetal), 3.49 (dd, J = 9.3, 6.2 Hz, 1 H, CHaHbOBn), 3.57
(d, J = 3.0 Hz, 1 H, CHOH), 3.72 (dd, J = 9.2, 8.4 Hz, 1 H, CHaH-
bOBn), 4.17 (dd, J = 8.2, 1.4 Hz, 1 H, H-6), 4.31 (dd, J = 1.8, 1.2
Hz, 1 H, H-4), 4.36 (ddd, J = 8.0, 5.9, 2.1 Hz, 1 H, CHOTBS), 4.45
(d, J = 12.1 Hz, 1 H, PhCHaHb), 4.52 (d, J = 11.8 Hz, 1 H, Ph-
CHaHb), 4.77 (dd, J = 8.2, 2.7 Hz, 1 H, CHOH), 7.25–7.38 (m, 10
H, 2 C6H5).
HRMS (EI): m/z calcd for C18H27O5Si (M+ – C7H15O), 351.1623;
found, 351.1628.
Synthesis 2002, No. 5, 619–624 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diastereo- and Enantioselective Synthesis of Ketopolyols
623
13C NMR (100 MHz, CDCl3): = –4.4, –4.3 [(Si(CH3)2], 18.5
[SiC(CH3)3], 23.8, 24.2 (CH3 acetal), 26.1 [SiC(CH3)3], 70.3
(CH2OBn), 71.8 (CHOTBS), 72.6 (CHOH), 73.7 (PhCH2), 75.3 (C-
6), 77.4 (C-4), 101.6 (acetal C), 127.2, 127.6, 127.9, 128.0, 128.2,
128.4, 128.6 (Ar-C), 138.0, 139.9 (Ar-C, ipso), 210.1 (C=O).
HRMS: m/z calcd for C17H25O5Si (M+ – C11H15O), 337.1471; found
337.1473.
Hz, 1 H, PhCHaHb), 4.53 (d, J = 11.9 Hz, 1 H, PhCHaHb), 4.59 (d,
J = 11.9 Hz, 1 H, PhCHaHb), 7.27–7.37 (m, 10 H, 2 C6H5).
13C NMR (126 MHz, CDCl3): = –4.9, –4.7 [Si(CH3)2], 18.1
[SiC(CH3)3], 23.6, 24.2 (CH3 acetal), 25.7 [SiC(CH3)3], 69.7
(CHOH), 70.0, 70.1 (CH2OBn), 71.4 (CHOTBS), 72.2 (C-4/6),
73.3, 73.5 (PhCH2), 77.0 (C-4/C-6), 101.3 (acetal C), 127.5, 127.6,
127.7, 127.7, 128.3, 128.3 (Ar-C), 137.9, 138.2 (Ar-C, ipso), 209.2
(C=O).
(R,R,R,R)-4-[2-Benzyloxy-1-(tert-butyldimethylsilanyloxy)eth-
yl]-6-[3-(tert-butyldiphenylsilanyloxy)-1-hydroxypropyl]-2,2-
dimethyl[1,3]dioxan-5-one (4e)
The boron enolate of ketone 3 (0.25 g, 0.63 mmol) was generated
and reacted with freshly prepared 3-(tert-butyldiphenylsilany-
loxy)propionaldehyde (0.26 mL, 0.82 mmol) according to the gen-
eral procedure. Oxidative workup and subsequent flash
MS (CI): m/z (%) = 547.4 (11, MH+ + 2), 546.4 (37, MH+ + 1),
545.4 (100, MH+), 527.3 (15, MH+ – H2O), 437.3 (12), 395.3 (8,
MH+ – BnOCH2CHO), 133.1 (10).
HRMS (EI): m/z calcd for C23H29O6Si (M+ – C7H15O), 429.1733;
found, 429.1733.
Anal. Calcd for C30H44O7Si (544.8): C, 66.14; H, 8.14. Found C,
65.88; H, 8.02.
chromatography on silica gel (eluent: 9:1
7:1 pentane–Et2O)
gave the title compound 4e (0.376 g, 84%) as a colourless syrup;
[ ]D25 +42.1 (c = 1.0, CHCl3).
Acknowledgements
IR (film): 3533, 3070, 3049, 2932, 2886, 2858, 1740, 1472, 1428,
1380, 1254, 1221, 1170, 1109, 1006 cm–1.
1H NMR (400 MHz, CDCl3): = 0.06 (s, 3 H, SiCH3), 0.09 (s, 3 H,
SiCH3), 0.86 [s, 9 H, SiC(CH3)3], 1.05 [s, 9 H, SiC(CH3)3], 1.40 (s,
3 H, CH3 acetal), 1.41 (s, 3 H, CH3 acetal), 3.12 (d, J = 3.3 Hz, 1 H,
CHOH), 3.48 (dd, J = 9.3, 5.8 Hz, 1 H, CHaHbOBn), 3.70 (dd,
This work was supported by an E.C. Marie-Curie Fellowship (to
S.J.I.), the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie. We thank Degussa AG, BASF AG, Bayer
AG, the former Hoechst AG and Wacker Chemie for the donation
of chemicals.
J = 9.3, 8.0 Hz,
1 H, CHaHbOBn), 3.75–3.82 (m, 1 H,
CH2OTBDPS), 3.84–3.93 (m, 1 H, CH2OTBDPS), 4.02 (dd,
J = 6.3, 1.1 Hz, 1 H, H-6), 4.07–4.13 (m, 1 H, CHOH), 4.27 (dd,
J = 1.9, 1.1 Hz, 1 H, H-4), 4.33 (ddd, J = 7.8, 5.8, 2.0 Hz, 1 H,
CHOTBS), 4.43 (d, J = 11.8 Hz, 1 H, PhCHaHb), 4.51 (d, J = 11.8
Hz, 1 H, PhCHaHb), 7.27–7.69 (m, 15 H, 3 C6H5).
13C NMR (100 MHz, CDCl3): = –4.8, –4.7 [Si(CH3)2], 18.1
8SiC(CH3)3], 19.1 [SiC(CH3)3], 23.6, 24.2 (CH3 acetal), 25.7
[SiC(CH3)3], 26.7 [SiC(CH3)3], 61.2 (CH2OTBDPS), 68.0
(CHOH), 70.1 (CH2OBn), 71.2 (CHOTBS), 73.2 (PhCH2), 75.2 (C-
6), 76.9 (C-4), 101.0 (acetal C), 127.5, 127.6, 128.2, 129.4, 129.6
(Ar-C), 133.4, 133.4 (Ar-C, ipso), 135.4 (Ar-C), 137.7 (Ar-C, ipso),
208.7 (C=O).
MS (CI): m/z (%) = 708.6 (1, MH+), 707.7 (2, M+), 395.3 (24),
337.2 (17), 314.3 (11), 313.2 (50), 236.2 (19), 235.2 (100), 205.1
(19).
HRMS (EI): m/z calcd for C33H41O5Si2 (M+ – C7H17O2), 573.2493;
found, 573.2495.
References
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67.73; H, 8.72.
(R,R,R,R)-4-[2-Benzyloxy-1-(tert-butyldimethylsilanyloxy)eth-
yl]-6-(2-benzyloxy-1-hydroxyethyl)-2,2-dimethyl[1,3]dioxan-5-
one (4f)
The boron enolate of ketone 3 (0.265 g, 0.67 mmol) was generated
and reacted with freshly prepared benzyloxyacetaldehyde (0.24 mL,
1.71 mmol) according to the general procedure. Oxidative workup
and subsequent flash chromatography on silica gel (eluent: 4:1
3:1 pentane–Et2O) gave the title compound 4f (0.216 g, 60%) as a
colourless syrup; [ ]D26 +66.7 (c = 1.0, CHCl3).
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IR (film): 3540, 3064, 3031, 2987, 2930, 2858, 1744, 1497, 1456,
1378, 1252, 1223, 1169, 1100, 1029, 1007 cm–1.
(3) See for example: (a) Evans, D. A.; Kozlowski, M. C.;
Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.;
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Bach, J.; Gibson, K. R.; Keown, L. E.; Oballa, R. M.;
Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.; Norcross,
1H NMR (500 MHz, CDCl3): = 0.06 (s, 3 H, SiCH3), 0.09 (s, 3 H,
SiCH3), 0.86 [s, 9 H, SiC(CH3)3], 1.38 (s, 3 H, CH3 acetal), 1.41 (s,
3 H, CH3 acetal), 3.01 (d, J = 3.7 Hz, 1 H, CHOH), 3.47 (dd, J = 9.5,
5.8 Hz, 1 H, CHaHbOBn), 3.57–3.64 (m, 2 H, CH2OBn), 3.69 (dd,
J = 9.2, 7.9 Hz, 1 H, CHaHbOBn), 4.01–4.06 (m, 1 H, CHOH),
4.29–4.30 (m, 2 H, H-4,6), 4.33 (ddd, J = 7.8, 5.9, 1.9 Hz, 1 H,
CHOTBS), 4.45 (d, J = 11.9 Hz, 1 H, PhCHaHb), 4.51 (d, J = 11.9
Synthesis 2002, No. 5, 619–624 ISSN 0039-7881 © Thieme Stuttgart · New York

624
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See Ref.11
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Synthesis 2002, No. 5, 619–624 ISSN 0039-7881 © Thieme Stuttgart · New York