Chiral dihydroxyacetone equivalents in synthesis: Rapid assembly of styryl 1,2-polyols as an entry to the styryllactone family of natural products

Article abstract of DOI:10.1055/s-2002-31905

A rapid entry to the polyol framework of the styryllactone family of natural products is reported. The key steps are two highly diastereoselective boron-mediated aldol reactions of a chiral dihydroxyacetone equivalent followed by a 1,3-anti or 1,3-syn-selective reduction. In addition, Evans-Tishchenko reduction of the cyclic aldol products effected an equilibration to the 1,2-syn aldol product before 1,3-anti selective reduction.

Full text of DOI:10.1055/s-2002-31905

962
LETTER
Chiral Dihydroxyacetone Equivalents in Synthesis: Rapid Assembly of Styryl
1,2-Polyols as an Entry to the Styryllactone Family of Natural Products
C
hira
l
D
ihydroxya
i
cetone
e
Equivalent
t
s
in Sy
e
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 22 February 2002
The retrosynthetic plan for the synthesis of these 1,2-styr-
Abstract: A rapid entry to the polyol framework of the styryllac-
yl polyols hinges on the use of a single auxiliary stereo-
genic centre to build up five contiguous oxygenated
stereocentres (Scheme 2). Our initial disconnections of
tone family of natural products is reported. The key steps are two
highly diastereoselective boron-mediated aldol reactions of a chiral
dihydroxyacetone equivalent followed by a 1,3-anti or 1,3-syn-se-
lective reduction. In addition, Evans–Tishchenko reduction of the gonioheptolide A were to mask the ester as a protected al-
cyclic aldol products effected an equilibration to the 1,2-syn aldol
product before 1,3-anti selective reduction.
cohol and to disconnect the tetrahydrofuran ring. In the
forward sense this would correspond to the attack of an
Key words: -silyldioxanone, aldol reactions, cyclic ketone reduc-
tion, Evans–Tishchenko, styryllactones, asymmetric synthesis
oxyanion at the benzylic position on a tosylate leaving
group, followed by adjustment of the oxidation level.
We considered the thus required linear hexaol to be readi-
ly accessible via a 1,3-anti or 1,3-syn selective reduction
of a suitably protected hydroxyketone. The stereochemis-
try of these hydroxyketones would then be induced
through our recently developed asymmetric bis-aldol
methodology from -silyldioxanone 1, in which the boron
enolates of -chiral dioxanones reacted in a very selective
1,2- and 1,3-anti fashion with a variety of aldehydes.2
Chiral dihydroxyacetone derivatives have proved to be
excellent building blocks for polyhydroxylated natural
product synthesis.1 Recently, we described the application
of bis-aldol methodology to -silyldioxanone 1 resulting
in a diastereo- and enantioselective entry to differentially
protected higher order ketopolyols (Scheme 1).2 Having
established the feasibility of this approach we turned to-
wards natural product synthesis. The styryllactone family
is typified by mono- or bicyclic tetrahydrofuran ring sys-
tems, densely decorated with oxygenated stereocentres,
often exhibiting useful levels of antitumour activity.3–5
Gonioheptolide A (2)6 is an unusual member of this fam-
ily of natural products, in that the usual lactone moiety has
been converted to the corresponding methyl ester. Never-
theless, it displays moderate antitumour activity against a
variety of human tumour cell lines and we decided to ap-
ply our extended methodology to its total synthesis. To-
wards this goal we first investigated the enantio- and
diastereoselective synthesis of an open-chain polyol pre-
cursor as proof of concept.
In this paper we report the development of an efficient
route to the required 1,2-polyol framework of goniohep-
tolide A via two asymmetric aldol reactions and a directed
ketone reduction. A critical factor in this study proved to
be the selection of a suitable diastereoselective reducing
agent.
A challenging aspect of polyol synthesis is to minimise
the number of protecting group manipulations. In this re-
spect the Evans–Tishchenko reduction7 was considered
the perfect choice for the directed reduction as it would in-
troduce a benzoate at the benzylic position. Cleavage of
the ester followed by cyclisation of the resulting anion
onto the tosylate could then be carried out in one synthetic
operation.
-Silyloxyketone 38 was prepared in three steps from the
-silylketone 19 in 65% overall yield (Scheme 3). Reac-
tion of the corresponding boron enolate with benzalde-
hyde gave the diastereopure hydroxyketone 4 in good
yield (84%). Next we turned to introducing the fifth and
final stereocentre. Evans–Tishchenko reduction of 4 un-
der the standard conditions gave hydroxybenzoate 5 in
95% yield (Scheme 3). The relative stereochemistry could
not be proven by NMR due to significant signal overlap.
Subsequent desilylation, however, gave crystalline triol 6
(Figure). Single crystal X-ray analysis (Scheme 3) proved
the structure to be the 1,2-syn-1,3-anti-diastereoisomer
and not the 1,2-anti-1,3-anti-diastereoisomer as re-
quired.10
O
OH
O
OTBS
TDS
ref. 2
R
O
O
O
O
OBn
H3C CH3
H3C CH3
de ≥ 96%; ee = 93%
1
H3C CH3
Si
H3C
H3C
= thexyldimethylsilyl (TDS)
CH3
CH3
Scheme 1
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0962,0966,ftx,en;G05102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Chiral Dihydroxyacetone Equivalents in Synthesis
963
OH
O
O
O
OTBS
O
Ph
TDS
OCH3
gonioheptolide A (2)
a - c
65%
O
O
O
O
OTBDPS
HO
OH
H3C CH3
H3C CH3
anionic ring closure
1
3
d
84%
O
OPG OPG
OH
O
OTBS
OBz OH OTBS
Ph
OPG
OH OTs
e
Ph
Ph
95%
syn-reduction
anti-reduction
OH OPG
O
O
O
O
OTBDPS
OTBDPS
H3C CH3
H3C CH3
O
OPG
O
OH
4
5
Ph
OPG
Ph
OPG
70%
f
O
O
O
O
Ph
H
OBz OH OH
H3C CH3
H3C CH3
H
O
O
CH3
CH3
H
Ph
O
O
diastereoselective aldol
O
O
H
H
OH
TBDPSO
O
OPG
OPG O
H3C CH3
OTBS
conformation of 4 (NMR)
6
OPG
Ph
O
O
O
O
Scheme 3 Reagents and conditions: (a) Cy2BCl, Et3N, Et2O, –78 to
0 ºC, then TBDPSO(CH2)2CHO, Et2O, –78 to –24 ºC. (b) Et3N 3 HF,
THF, –20 ºC. (c) TBSOTf, 2,6-lutidine, CH2Cl2, –78 ºC. (d) Cy2BCl,
Et3N, Et2O, –78 ºC to 0 ºC, then PhCHO, Et2O, –78 to –24 ºC. (e)
SmI2 (0.6 equiv), PhCHO (8 equiv), THF, 0 ºC. (f) TBAF, THF.
(TBDPS = tert-butyldiphenylsilyl; TBS = tert-butyldimethylsilyl).
H3C CH3
H3C CH3
"traceless" silyl auxiliary
mediated aldol reaction
O
TDS
from RAMP hydrazone
O
O
was the phenyl substituted derivative 8 in which methallyl
aldehyde had dissociated and the resulting (postulated)
Sm enolate was trapped with excess PhCHO. The stereo-
chemistry was assigned by derivatisation as the bis-ace-
tal 9.
H3C CH3
1
Scheme 2
O
OH
O
OTBS
TDS
H3C
ref. 2
O
O
O
O
OBn
H3C CH3
H3C CH3
1
7
a
CH3
OBz OH OTBS
H
O
H3C
O
Ph
O
H
H
b, c
Ph
O
21%
(3 steps)
CH3
TBSO
H
O
O
OBn
H
H3C CH3
CH3
BnO
9
8
Figure X-ray structure of 6.
Scheme 4 Reagents and conditions: (a) SmI2, PhCHO, THF, 0 ºC.
(b) K2CO3, MeOH. (c) DMP, CSA (cat.), CH2Cl2.
The diastereomeric result of the Evans–Tishchenko re-
duction is the result of a Sm-catalysed equilibration pro-
cess as previously reported for the Tishchenko reaction of
cyclohexanone and benzaldehyde.11–13 Further proof of
this dissociative mechanism was provided by reduction of
hydroxyketone 72 (Scheme 4). The only observed product
These reduction products are formally derived from a syn-
selective aldol reaction between a cyclic ketone and an al-
dehyde. If this reaction could be generalised for a range of
aldehydes, it offers a route to natural products containing
Synlett 2002, No. 6, 962–966 ISSN 0936-5214 © Thieme Stuttgart · New York

964
D. Enders et al.
LETTER
cyclic substructures previously unattainable by contem-
porary aldol methodology.
O
O
OR
TDS
Ph
ref. 9
To forward the total synthesis it was decided to exploit the
symmetry of the dioxanone system and reverse the order
of the aldol reactions, thus requiring a 1,3-syn reduction to
install the fifth stereocentre. Furthermore, preliminary ex-
periments on 5 had not been successful in deprotecting the
acetal without significant 2º OTBS deprotection as well.14
In view of this the tri-iso-propylsilyl (TIPS) group was
chosen as a more acid stable alternative.
O
O
O
O
H3C CH3
H3C CH3
1
10: R = H
11: R = TIPS
a
TIPSO
Ph
OBn OBn
b
TIPSO
Ph
O
OR
O
O
OTBDPS
c, d
H3C CH3
The second generation synthesis started with hydroxyke-
tone 1015 prepared in 59% yield from -silyldioxanone 1
(Scheme 5). TIPS protection with TIPSOTf and 2,6-luti-
dine returned 11 quantitatively although with a significant
amount of -epimerisation (de = 73%). The resulting syn/
anti mixture could not be separated by HPLC. In an at-
tempt to effect the aldol reaction and reduction in one-pot
Paterson’s conditions were used.16 Thus, the aldol re-
action between the boron enolate of ketone 11 and 3-
(tert-butyl-diphenyl-silanyloxy)-propionaldehyde17 was
quenched at –78 ºC with LiBH4. Subsequent oxidative
(H2O2) work up and chromatography yielded a near 1:1
inseparable mixture of the 1,3-syn diol 14 and its trans
isomer, together with the corresponding minor diastereoi-
somers, in quantitative yield. NMR analysis of this mix-
ture revealed that the aldol reaction itself proceeded with
complete diastereoselection as expected. Upon benzyla-
tion the two major diastereomers could be separated by
chromatography to give 1,3-syn 15 and 1,3-trans 16 in
35% and 33% yield, respectively. A range of boron hy-
dride sources was then screened on both enantiomers of
ketone 13.18 Me4NBH(OAc)3,19 which had shown syn se-
lectivity in the reduction of a 4-(hydroxybenzyl)-1,3-di-
oxan-5-one,20 proved unreactive. L-Selectride®, which
had proven selective in earlier dioxanone work1e,g and
BH3 SMe221 proved only poorly syn selective (yields 67–
78%; 0–17% reduction de). Our breakthrough came with
Zn(BH4)222 which, in a small scale trial experiment, deliv-
ered the syn-diol 1428 in 71% yield and excellent 85% re-
duction de. On scale up (6 mmol) the syn-diol 14 was
afforded in 52% ds (74% reduction de) and excellent yield
(87% over 2 steps from ketone 13). Separation of the dia-
stereoisomers was again possible after benzylation (not
shown). In contrast to the usual Zn(BH4)2 mediated reduc-
tions it was necessary to warm the reaction to room tem-
perature to ensure complete reduction. Furthermore,
simply quenching the reaction with the minimum quantity
of water, filtration of the resulting suspension through
Celite® and a subsequent base wash was found to be the
optimal work up procedure.
15
+
O
O
OTBDPS
H3C CH3
TIPSO
Ph
OBn OBn
12: R = BCy2
13: R = H
O
O
OTBDPS
e
H3C CH3
TIPSO
Ph
OH OH
16
O
O
OTBDPS
H3C CH3
14
Scheme 5 Reagents and conditions: (a) TIPSOTf, 2,6-lutidine,
CH2Cl2, –78 to 0 ºC, quant. (de = 73%). (b) Cy2BCl, Et3N, Et2O, –78
ºC to 0 ºC, then TBDPSO(CH2)2CHO, Et2O, –78 to –24 ºC. (c) LiBH4,
THF/Et2O, –78 ºC, quant. (d) NaHMDS, BnBr, TBAI (cat.), THF, 0
ºC to r.t., 15 35%, 16 33% (from 11 via 12). (e) Zn(BH4)2, Et2O, –78
ºC to r.t., 87% (from 11).
an intermolecular hydride delivery via the corresponding
boron chelate.27 The syn products are the result of pseudo-
axial attack of hydride. It is likely that the increase in se-
lectivity in the case of Zn(BH4)2 is a result of chelation to
one or more of the dioxanone oxygen atoms, especially as
Zn(BH4)2 is well known to favour 5-ring over 6-ring che-
lates. Further work is clearly needed to clarify the exact
nature of reduction in these dioxanone systems.
TIPSO
Ph
O
OH
TIPSO
Ph
OH OH
a
73%
O
O
O
O
OTBDPS
OTBDPS
H3C CH3
H3C CH3
ent-13
17
89%
b
H3C CH3
TIPSO
Ph
O
O
Interestingly, Evans’ catechol borane/Rh(I) system23 re-
turned 73% of the anti diol 17 in 72% reduction de
(Scheme 6). The stereochemistry was proven by derivati-
sation as the bis-acetal 18. The diastereoselectivity of re-
duction of a variety of 4,6-disubstituted 1,3-dioxan-5-
ones has been investigated both theoretically and experi-
O
O
OTBDPS
H3C CH3
18
Scheme
6
Reagents and conditions: (a) Catechol borane,
mentally.24–26 We tentatively assign the anti selectivity to (Ph3P)3RhCl (cat.), THF, –10 ºC. (b) DMP, CSA (cat.), CH2Cl2.
Synlett 2002, No. 6, 962–966 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Chiral Dihydroxyacetone Equivalents in Synthesis
965
M.; Zhao, G.; Yu, Q. S.; Ding, Y. Chin. J. Chem. 2000, 18,
225. (q) Yang, Z. C.; Zhou, W. S. Heterocycles 1997, 45,
367. (r) Ye, J. H.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett.
1993, 34, 8007. (s) Yi, X. H.; Meng, Y.; Hua, X. G.; Li, C.
J. J. Org. Chem. 1998, 63, 7472.
In summary, the combination of diastereoselective aldol
reactions of our chiral dihydroxyacetone equivalent and
diastereoselective reductions offer a competitive route to
the open-chain polyol precursors of styryllactone deriva-
tives. The symmetry of the dioxanone system proved par-
ticularly useful in allowing a reversal of the order of aldol
reactions. By choice of reducing agent either 1,3-syn and
1,3-anti selectivity was attainable. We also discovered
that the Evans–Tishchenko reduction applied to diox-
anone systems gives the formal products of a 1,2-syn se-
lective aldol reaction and a 1,3-anti selective reduction,
proving to be an entry to usually unattainable reaction
products. To conclude, the development of an enantio-
and diastereoselective synthesis of the required 1,2-polyol
framework of gonioheptolide A (2) has opened the way to
a total synthesis which will be reported in due course.
(5) For analogue synthesis see: (a) Bermejo, A.; Léonce, S.;
Cabedo, N.; Andreu, I.; Caignard, D. H.; Atassi, G.; Cortes,
D. J. Nat. Prod. 1999, 62, 1106. (b) Li, H. M.; Yang, M.;
Zhou, G.; Yu, Q. S.; Ding, Y. Chin. J. Chem. 2000, 18, 388.
(c) Mereyala, H. B.; Gadikota, R. R.; Joe, M.; Arora, S. K.;
Dastidar, S. G.; Agarwal, S. Biorg. Med. Chem. Lett. 1999,
7, 2095. (d) Peris, E.; Estornell, E.; Cabedo, N.; Cortes, D.;
Bermejo, A. Phytochemistry 2000, 54, 311. (e) Shing, T. K.
M.; Tai, V. W. F. J. Org. Chem. 1999, 64, 2140.
(6) (a) For isolation see: Fang, X.-P.; Anderson, J. E.; Qiu, X.-
X.; Kozlowski, J. F.; Chang, C.-J.; McLaughlin, J. L.
Tetrahedron 1993, 49, 1563. (b) For semisynthesis and
structure revision see: Mukai, C.; Yamashita, H.; Hirai, S.;
Hanaoka, M.; McLaughlin, J. L. Chem. Pharm. Bull. 1999,
47, 131.
(7) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112,
6447.
(8) All new compounds gave consistent analytical data
including correct elemental analysis and/or HRMS.
(9) Enders, D.; Prokopenko, O. F.; Raabe, G.; Runsink, J.
Synthesis 1996, 1095.
(10) CCDC 179448 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
fax:+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
(11) Lu, L.; Chang, H.-Y.; Fang, J.-M. J. Org. Chem. 1999, 64,
843.
(12) In contrast, the reaction of -silyl ketone 1 with SmI2 and
PhCHO, according to the conditions described for
cyclohexanone in ref.11, was very sluggish and poorly
diastereoselective.
(13) NMR analysis of ketone 4 confirms it to be in a twist-boat
conformation. In this respect a discussion of the reduction
selectivity is complicated, as true axial or equatorial attack is
no longer applicable in a twist-boat system. Pseudoaxial
attack seems possible for both the syn- and anti-aldol
products, the latter case may be disfavoured due to the
proximity of the electron rich aryl ring and the coordinating
Sm species.
Acknowledgement
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.
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acting as a general acid.
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(15) (S,S)-10: See ref.9
(16) Paterson, I.; Perkins, M. V. Tetrahedron 1996, 52, 1811.
(17) Prepared in two steps from propane-1,3-diol (silylation,
Dess–Martin oxidation). Purified by chromatography on
silica gel before use.
(18) Analytical HPLC (chiral stationary phase) showed that the
ee of 1 was carried through to the reduction products with no
depreciation. 1 was prepared in up to 96% ee as judged by
GC (chiral stationary phase).
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Synlett 2002, No. 6, 962–966 ISSN 0936-5214 © Thieme Stuttgart · New York

966
D. Enders et al.
LETTER
27.1 (SiC(CH3)3), 34.6 (CH2), 61.6 (CH2OTBDPS), 68.6
(CHOH), 74.4 (CH(OTIPS)), 76.1 (C-4); 80.0 (C-6), 101.5
(acetal C), 127.7, 127.8, 127.9, 128.0, 129.9, 130.0, (Ar-C),
133.7, 133.8 (Ar-C, ipso), 135.8 (Ar-C), 140.2 (Ar-C, ipso),
209.5 (C=O); MS (CI): m/z (%)= 350(4), 349(16), 313(56),
263(100), 235(62), 175(13); HRMS (EI): m/z calcd for
C19H29O4Si [M+ – C22H31O2Si]: 349.1835. Found: 349.1835.
Anal. Calcd for C40H60O6Si (705.08): C, 69.84; H, 8.85.
Found: C, 69.29; H, 8.60.
(24) For several theoretical models of substituted 1,3-dioxan-5-
ones see: (a) Artau, A.; Ho, Y.; Kenttämaa, H.; Squires, R.
R. J. Am. Chem. Soc. 1999, 121, 7130. (b) Wu, Y.; Houk,
K. N. J. Am. Chem. Soc. 1993, 115, 10993.
(25) For a related examination of substituted 1,3-dioxanes see:
Cieplak, P.; Howard, A. E.; Powers, J. P.; Rychnovsky, S.
D.; Kollman, P. A. J. Org. Chem. 1996, 61, 3662.
(26) For reductions of 4-mono- and 4,6-bis-alkylated 1,3-dioxan-
5-ones see: Enders, D.; Kownatka, D.; Hundertmark, T.;
Prokopenko, O. F.; Runsink, J. Synthesis 1997, 649; and
references 1a–e and 1g.
(27) In this case the much smaller ligands on boron may make
chelate formation much easier. The observed colour change
of the reaction, from red to yellow, is consistent with H2
transfer to the Rh(I) catalyst. On closer examination of a
model there would appear to be more steric crowding on the
lower face of the chelated complex, consistent with the
observed outcome.
(28) Preparation of 1,3-syn diol 14 (over 2 steps from ketone 11):
To a stirred solution of Cy2BCl29 (2.0 mL, 9.0 mmol, 1.5
equiv) in anhyd Et2O (50 mL) at –78 ºC, under an Ar
atmosphere, was sequentially added freshly distilled Et3N
(1.42 mL, 10.2 mmol, 1.7 equiv) and a solution of ketone 11
(2.35 g, 6.0 mmol, 1.0 equiv, de = 73%) in anhyd Et2O (20
mL) dropwise via syringe. Stirring was continued at –78 ºC
for a further 20 min before warming to 0 ºC for 1 h. The
resulting bright yellow suspension was recooled to –78 ºC
and a solution of freshly prepared 3-(tert-butyl-diphenyl-
silanyloxy)-propionaldehyde (3.45 g, 11.0 mmol, 1.8 equiv)
in anhyd Et2O (10 mL) was added dropwise via syringe.
Stirring was continued at –78 ºC for a further 90 min before
the flask was sealed and allowed to stand in a freezer (–24
ºC) for 10 h. The reaction was quenched with phosphate
buffer (pH 7, 120 mL) and extracted. The aq layer was
extracted with Et2O and the combined organic portions were
concentrated in vacuo. The oily residue was resuspended in
phosphate buffer (pH 7, 36 mL) and MeOH (36 mL) and
cooled to 0 ºC. Aq H2O2 solution (30%, 18 mL) was added
dropwise and the mixture stirred vigorously for a further 1 h.
The mixture was poured into phosphate buffer (pH 7, 120
mL) and extracted with CH2Cl2 (4 100 mL). The combined
organic portions were washed with H2O (50 mL), dried
(Na2SO4), filtered and concentrated in vacuo to give a
colourless oil. Purification by chromatography on silica gel
(gradient elution: 19:1 8:1 pentane:Et2O) gave the title
compound 13 (4.94 g, de = 74%) heavily contaminated with
aldehyde. An analytical sample (de = 74%) was afforded by
further chromatography; [ ]25D +58.9 (c 1.0 in CHCl3); IR
(thin film): 3543, 3071, 3050, 3032, 2942, 2891, 2866, 1739,
1472, 1464, 1428, 1383, 1219, 1169, 1112, 1068, 1030 cm–
1; 1H NMR (400 MHz, CDCl3): = 0.96–1.08 (m, 30 H, CH
TIPS, CH3 TIPS and TBDPS), 1.33 (s, 3 H, CH3 acetal), 1.41
(s, 3 H, CH3 acetal), 1.66–1.74 (m, 1 H, CHaHb), 1.75–1.82
(m, 1 H, CHaHb), 3.15 (d, 1 H, J = 3.3 Hz, (CHOH), 3.72 (dd,
1 H, J = 5.9, 1.0 Hz, H-4), 3.74–3.88 (m, 1 H,
To a stirred suspension of NaBH4 (2.70 g, 70 mmol, 2.0
equiv) in anhyd Et2O (210 mL) under an Ar atmosphere, at
r.t., was added a solution of ZnCl2 in Et2O (Aldrich, 1.0 M,
35 mL, 35 mmol, 1.0 equiv) via syringe. The resulting white
suspension was stirred for a further 2 d before allowing the
precipitate to settle. The resulting clear supernatant solution
of Zn(BH4)2 in Et2O (ca. 0.14 M) was cooled to –78 ºC.
To a stirred solution of the crude ketone 13 (4.21 g, ca 5.97
mmol, 1.0 equiv) at –78 ºC, under an Ar atmosphere, was
added the chilled supernatant solution of Zn(BH4)2 in Et2O
(ca 240 mL, ca 34 mmol, 5.6 equiv), via double-ended
needle over 45 min. The reaction mixture was warmed very
slowly to r.t. The reaction mixture was quenched after 24 h
with H2O until effervescence ceased (ca 5 mL) and stirred
vigorously for 1 h. The resulting white suspension was
filtered through Celite® and the filter-cake washed
thoroughly with Et2O (400 mL). The combined filtrates were
washed with sat. aq NaHCO3 solution and the aq portion
back-extracted with Et2O (200 mL). The combined organic
portions were dried (Na2SO4), filtered and concentrated in
vacuo to give a cloudy colourless oil. Purification by
chromatography on silica gel (gradient elution: 6:1 1:1
pentane:Et2O gave the title compound 14 (3.67 g, 87%, 52%
ds, 74% de for reduction). On smaller scales a reduction de
of 85% could be achieved; IR (thin film): 3472, 3071, 3050,
3031, 2943, 2892, 2866, 1471, 1463, 1428, 1380, 1224,
1198, 1172, 1112, 1069, 1029 cm–1; 1H NMR (400 MHz,
CDCl3): = 0.95–1.10 (m, 30 H, CH TIPS, CH3 TIPS and
TBDPS), 1.21 (s, 3 H, CH3 acetal), 1.39 (s, 3 H, CH3 acetal),
1.70–1.81 (m, 2 H, CH2), 3.14 (d, 1 H, J = 2.5 Hz, CHOH),
3.59 (ap t, 1 H, J = 5.5 Hz, H-4), 3.70 (dd, J = 4.7, 3.0 Hz, 1
H, H-6), 3.78–3.90 (m, 2 H, CH2OTBDPS), 3.92–3.97 (m, 1
H, CHOH), 4.09–4.13 (m, 1 H, H-5), 4.45 (d, 1 H, J = 3.6
Hz, 5-OH), 5.16 (d, 1 H, J = 4.7 Hz, CH(OTIPS)), 7.24–7.46
(m, 10 H, Ar-H), 7.63–7.67 (m, 5 H, Ar-H); 13C NMR (100
MHz, CDCl3): = 12.7 (SiCH(CH3)2), 18.2 ( 2)
(SiCH(CH3)2, 19.4 (SiC(CH3)3), 24.1, 25.5 (CH3 acetal),
27.2 (SiC(CH3)3), 34.5 (CH2), 63.2 (CH2OTBDPS), 69.7 (C-
5), 72.4 (CHOH), 73.8 (C-6), 77.7 (CH(OTIPS)), 78.6 (C-4),
101.3 (acetal C), 127.1, 127.9 ( 2), 128.3 ( 2), 130.0 (Ar-
C), 133.2, 133.3 (Ar-C, ipso), 135.7, 135.8 (Ar-C)], 141.3
(Ar-C, ipso); MS (CI): m/z (%) = 709(9) [MH+ + 1], 534(54),
476(41), 458(29), 235(10), 175(100), 163(15); HRMS (EI):
m/z calcd for C38H55O6Si2 [M+ – C3H7]: 663.3537. Found:
663.3534.
(29) Prepared from the hydroboration of freshly distilled
cyclohexene with monochloroborane dimethyl sulfide
complex (Aldrich). For a procedure see: Cowden, C. J.;
Paterson, I. In Organic Reactions, Vol. 51; Paquette, L. A.,
Ed.; Wiley: New York, 1997, 1.
CH2OTBDPS), 4.06–4.12 (m, 1 H, CHOH), 4.46 (dd,
J = 2.8, 1.0 Hz, 1 H, H-6), 5.28 (d, J = 2.8 Hz, 1 H,
(CH(OTIPS)), 7.20–7.67 (m, 15 H, Ar-H); 13C NMR (100
MHz, CDCl3): = 12.5 (SiCH(CH3)2), 18.1, 18.2
(SiCH(CH3)2), 19.4 (SiC(CH3)3), 24.0, 24.3 (CH3 acetal),
Synlett 2002, No. 6, 962–966 ISSN 0936-5214 © Thieme Stuttgart · New York