Studies towards 1,3-diol units starting from syn β-hydroxy acylsilanes

Article abstract of DOI:10.1016/j.tetlet.2013.11.034

Three complementary strategies have been explored to obtain stereodefined 1,3 diols starting from easily accessible syn β-hydroxy acylsilanes: fluoride induced migrations of substituents on silicon, a Grignard addition followed by protodesilylation and Tischenko-type reactions. Preliminary data on scope and limitations of these processes are presented.

Full text of DOI:10.1016/j.tetlet.2013.11.034

Tetrahedron Letters 55 (2014) 365–368
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies towards 1,3-diol units starting from syn b-hydroxy
acylsilanes
Gangireddy PavanKumar Reddy a, Akondi Srirama Murthy a,b, J. Satyanarayana Reddy a,b, Saibal Das b,
Thierry Roisnel a, Jhillu S. Yadav b, Srivari Chandrasekhar b, René Grée a,
⇑
a Université de Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex, France
b CSIR-Indian Institute of Chemical Technology, Natural Product Chemistry Division, Uppal Road, Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Three complementary strategies have been explored to obtain stereodefined 1,3 diols starting from easily
accessible syn b-hydroxy acylsilanes: fluoride induced migrations of substituents on silicon, a Grignard
addition followed by protodesilylation and Tischenko-type reactions. Preliminary data on scope and
limitations of these processes are presented.
Received 16 October 2013
Revised 5 November 2013
Accepted 8 November 2013
Available online 19 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Acyl silanes
1,3 Diols
Aldol
Silicon
Tischenko
The acylsilane is a highly versatile functionality and many ele-
gant applications in organic synthesis have been already reported,
based on the use of this group.1 However only a few studies have
been described, to date, on the synthesis and the applications of
b-hydroxy acylsilanes,2 although such units appear as potentially
very useful building blocks. We have reported recently a new, effi-
cient and stereoselective, synthesis of syn b-hydroxy acylsilanes by
using a tandem isomerization–aldolisation process,3 and their use
for the preparation of several oxygen-containing heterocycles.4
As part of a programme dealing with the total synthesis of bio-
active natural products and structural analogues, we were inter-
ested in the development of methods to access the important
propionate-type 1,3-diol units starting from such syn b-hydroxy
acylsilanes.
The purpose of this Letter is to report our preliminary results
indicating that, by using three complementary approaches, latter
silanes can be used for the synthesis of various 1,3-diols with a
good stereochemical control (Scheme 1). The first route (pathway
1) involves the migration of substituents from silicon onto the vic-
inal carbonyl group. The second (pathway 2) utilizes a Grignard
addition, followed by a protodesilylation pathway. In the third
route (pathway 3), we consider a sequence involving Tischenko-
type reactions.
Ar
R1
OH OH
Ar
R1
OH OH
syn-anti
and/or
syn-syn
(if R1 = small alkyl)
Pathway 1
(if R1 = aryl)
R1
Si
R2
R3
Ar
OH
O
Pathway 2
Pathway 3
syn
R1
Si
R'
OH OH
Ar'
Ar'
R2
Ph
R3
OH
anti-syn
O
O
anti-anti
Scheme 1. Three complementary pathways to stereoisomers of 1,3-diol units.
The alkoxide-induced migrations of alkyl or aryl groups on
simple acylsilanes have been first reported by Brook,5 and this
process has been extended later to fluoride-mediated reactions
by the groups of Ricci and Walton.6 On the other hand, starting
from b-hydroxy acylsilanes, highly stereoselective migrations of
phenyl groups have been reported by Oshima and Utimoto.7 More
recently it has been successfully extended to anti b-alkoxy
⇑
Corresponding author. Tel.: +33 2 23 23 57 15; fax: +33 2 23 23 69 78.
E-mail address: rene.gree@univ-rennes1.fr (R. Grée).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.034

366
G. PavanKumar Reddy et al. / Tetrahedron Letters 55 (2014) 365–368
R1
Si
Ar
R1
OH OH
syn-syn
3a 3d
Ar
R1
OH OH
R2
Ar
TBAF
+
R3
OH
syn
1a-1d
O
THF
0 oC-rt
12h
syn-anti
2a-2d
-
Scheme 2. Fluoride induced migration of alkyl and aryl groups starting from syn
b-hydroxy acylsilanes 1a-1d.
Figure 1. Structure of 1,3-diol 2a by X-ray analysis.
acylsilanes by the group of Honda,8 while some group migrations
OH
were reported during thermal rearrangements of
a-(acyloxy)
O
OH
O
R
R2
F
R2
F
R1
silanes.9
nBu4NF
Ph
1
Si
Ph
Si
R1
We studied first the migratory aptitudes and the stereoselectiv-
ity of fluoride-induced migrations of the syn b-hydroxy acylsilanes
1. The results are indicated in Scheme 2 and Table 1. For the acyl-
silanes bearing three small alkyl groups on silicon (Me to n-Pr), the
migration occurred easily to give, in good to excellent yields and
high stereoselectivities, the syn-anti diols 2a–2c (entries 1–3).
Small amounts (3–10%) of syn–syn derivatives 3a–3c were de-
tected by NMR of the crude reaction mixtures. The major syn-anti
derivatives have been isolated by silica gel chromatography. In the
case of bulkier groups on silicon, such as iPr or tBu, complex reac-
tion mixtures were obtained. In order to study the migration of a
phenyl group, we started from syn aldol 1d obtained by the tandem
isomerization–aldolisation reaction between p-bromobenzalde-
hyde and the allylic alcohol bearing a TBDPS group.3 In agreement
with the literature data,7 the phenyl group migrates preferentially
to tBu and with a syn selectivity. However, this selectivity is tem-
perature dependent since the ratio of 2d to 3d is ranging from
40:60 to 15:85 (Table 1, entries 4–7) and the highest stereoselec-
tivity is obtained at 40 °C. Both isomers 2d and 3d have been iso-
lated after chromatography on SiO2. The syn-anti and syn–syn
stereochemistry of all 1,3-diols 2 and 3 have been established from
the NMR data, by comparison with the literature.10 Further, the
structure of the 1,3-diol 2a was confirmed by X-ray crystallogra-
phy analysis (Fig. 1).11
syn
R
H
H
O
H
H
R
H
H
O
F
F
Si R1
R2
Me
R
Ph
Si
O
H
Ph
R1
O
R2
H
Me
2
syn-anti
3
syn-syn
Scheme 3. Tentative mechanism for the formation of 1,3-diols 2 and 3.
equatorial position affords the syn-anti derivative 2, while the sec-
ond with the phenyl group in equatorial position gives the syn–syn
diols 3. Although the mechanistic details of these reactions need
further experimental and computational studies, it is clear that
the nature of the R group plays a key role in this method and with
R = alkyl, compounds 2 are prefered, while for R = Ph the 1,3-diols 3
are obtained.12
A second route to 1,3-diols (pathway 2) was considered by tak-
ing advantage of the stereoselectivity of both the Grignard addition
to acylsilanes13 and the protodesilylation reaction.13,14 Starting
from 1b, the reaction of methyl Grignard afforded in good yields
and as a single isomer, the tertiary alcohol 5 (Scheme 4).
The stereochemistry of this compound was established by X-ray
crystallography, as indicated in Figure 2.11 It is noteworthy that
this Grignard addition is occurring with complete epimerisation
at the stereocentre bearing the methyl group. Such an epimerisa-
tion has been reported with other aldol derivatives and it is
occurring via retroaldol-aldol processes.15 This pathway is likely
to be occurring here to afford initially anti aldol 4,16 and then the
In agreement with the literature,8 we can propose the tentative
mechanism indicated in Scheme 3. After fluoride addition on sili-
con, the Brook rearrangement gives the corresponding carbanion
which is protonated at the stereoinducing step. The Si–O interac-
tion allows six-membered type transition states but, due to the
syn structure of the starting aldol, two conformers can be in
equilibrium. The protonation of the one with the methyl group in
Table 1
Fluorine-induced diastereofacial migration of aryl or alkyl groups from silicon to carbonyl in b-hydroxy acylsilanes 1
Entry
Aldol
Ar
R1
R2
R3
Temp.
Products
Yielda,b
(%)
Product
diastereoselectivity
(syn-anti, syn-syn)f
1
2
3
1a
1
1c
Ph
Ph
Ph
Me
Et
n-
Pr
Ph
Me
Et
n-
Pr
Ph
Me
Et
n-
Pr
t-
Bu
t-
Bu
t-
rt
rt
rt
2a:3a
2b:3b
2c:3c
90c,d
82d
97.:03
87:13
90:10
83d
4
5
6
7
1d
1d
1d
1d
4Br-
Ph
4Br-
Ph
4Br-
Ph
4Br-
Ph
+40 °C
rt
2d:3d
2d:3d
2d:3d
2d:3d
13a, 70a
86e
15:85
20:80
30:70
40:60
Ph
Ph
Ph
Ph
Ph
Ph
0 °C
80e
Bu
t-
Bu
ꢀ20 °C
85e
a
b
c
d
e
f
Isolated yield.
All products were characterized by 1H NMR, 13C NMR and mass spectral data.
The product was characterized by X-ray.
Isolated yield of major product.
Isolated yield of 2d+3d mixture.
The diastereoselectivities were determined by 1H NMR analysis of the crude reaction mixtures.

G. PavanKumar Reddy et al. / Tetrahedron Letters 55 (2014) 365–368
367
Ph
Me
OH OH
Ph
Me
Ph
SiEt3
TBAF
MeMgBr
SiEt3
OH OH
THF
0 °C-rt
12h
OH
O
THF
rt, 3h
87%
anti-anti
syn
5
6
1b
91%
Me
H
H
H
+TBAF
- HF
SiEt3
Ph
SiEt3
6
5
Ph
1b
O
Me
O
O
O
Me
4
H
H
Scheme 4. Grignard addition on aldol 1b, followed by protodesilylation to anti,anti 1,3-diol 6.
Table 2
Attempts to perform a Tischenko process from b-hydroxy acylsilanes 7d and 7e
Entry
Aldol
R
R0
Products
Yielda,b(%)
1
2
3
4
5
6
7
7d
7d
7d
7d
7d
7d
7e
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
4Br-Ph
4NO2-Ph
Ph
t-Bu
i-Pr
8
9
78c
82
85
40
25
32
81
10
11
12
13
8
4OMe-Ph
4Br-Ph
a
b
c
Isolated yield.
Figure 2. Structure of alcohol 5 by X-ray analysis.
All products were characterized by 1H NMR, 13C NMR and mass spectral data.
The product was characterized by X-ray.
Grignard adduct 5. In a final step, the protodesilylation of 5 occurs
in a fully stereocontrolled fashion to give the anti–anti 1,3-diol 6.
Tentative mechanisms can be proposed in order to explain the
stereochemistry of these reactions (Scheme 4). Taking into account
the intramolecular hydrogen bond in 4, the Grignard addition
should occur anti to the neighbouring methyl group to afford the
adduct 5. On the other hand after fluoride-induced oxygen shift
of the silyl group, the protonation of carbanion intermediate
furnished the anti–anti 1,3-diol 6. Such protodesilylations have
been reported in the literature and their stereoselectivity has been
established.13,14
The next strategy (pathway 3) was to employ a Tischenko-type
process. To the best of our knowledge, it has been reported once
starting from acetyltrimethylsilane,2d but never from b-hydroxy
acylsilanes. On reaction of 7d with p-bromobenzaldehyde under
basic conditions, the expected Tischenko product was not ob-
tained. Instead an unexpected product 8, bearing two p-bromo-
benzaldehyde units, was isolated in good yield together with
benzaldehyde (Scheme 5, Table 2). The structure of 8 was estab-
lished by NMR and MS and the anti-syn stereochemistry of the
1,3-diol 8 was confirmed by X-ray analysis, as indicated in
Figure 3.11
The formation of this compound is very likely due to a
retroaldol process followed by an aldolisation with the added
p-bromobenzaldehyde and completed by a Tischenko-type reac-
tion to give 8 (Scheme 6). In order to study the scope and
limitations of such a method, complementary studies have been
performed. A similar result was obtained with p-nitrobenzalde-
hyde, affording compound 9. In the same way, on reaction of 7d
Figure 3. Structure of alcohol 8 by X-ray analysis.
with benzaldehyde, the 1,3-diol 10 was obtained. However, under
the same conditions and starting from the same b-hydroxysilane
7d but using aldehydes with various alkyl subsituents (R0 = t-Bu,
i-Pr), only the corresponding syn aldol products 11–12 were iso-
lated in low yields, along with the recovered starting material,
without evidence for corresponding Tischenko products. A similar
result was obtained with p-methoxybenzaldehyde, affording syn
aldol 13. The NMR data of derivatives 11–13 were found to be
identical with the compounds obtained by the direct tandem isom-
erization–aldolisation process.3 Therefore, with such aliphatic
aldehydes or less reactive aromatic aldehydes, the reaction
R'
CHO
Ph
Ph
Si
Ph
Si
tBu
Ph
(2.5 equi)
LiHMDS
R'
Si
R
R'
Ph
Ph
tBu
+
R
CHO
+
tBu
O
O
OH
OH
syn
7d-7e
O
OH
syn
11-13
O
THF
-78 oC - 0 o
C
anti-syn
R'
8-10
Scheme 5. Attempts to perform a Tischenko sequence starting from syn b-hydroxy acylsilanes 7d and 7e.

368
G. PavanKumar Reddy et al. / Tetrahedron Letters 55 (2014) 365–368
O
OLi
O
R
R'
TBDPS LiHMDS
H
R'
TBDPS
TBDPS
R
H
OH
O
OLi
O
7
H
11-13
R'
TBDPS
R'
TBDPS
OLi
R
+
TBDPS
'CHO
R'
H
8 10
-
O
O
H
O
O
OLi
O
LiO
R'
R'
Scheme 6. Proposed mechanism for the formation of 1,3 diols 8–10 and syn aldols 11–13.
Johnson, J. S. Product Subclass 4: Silicon compound. In Science of Synthesis;
Fleming, I., Ed.; Stuttgart: Thieme, 2012, Vol. 4; pp 1–85; (d) Zhang, H.-J.;
Priebbenow, D. L.; Bolm, C. Chem. Soc. Rev. 2013, 42, 8540–8571; (e) Boyce, G.
R.; Grezler, S. N.; Johnson, J. S.; Linghu, X.; Malinovski, J. T.; Nicewicz, D. A.;
Satterfield, A. D.; Schmitt, D. C.; Steward, K. M. J. Org. Chem. 2012, 77, 4503–
4515.
stopped at the retroaldol-aldol step and the Tischenko reaction
was not occurring.
In conclusion, these preliminary results demonstrate for the
first time that with b-hydroxy acylsilanes the easily occurring ret-
roaldol processes should be taken care of. However starting from
the same syn b-hydroxy acylsilane and using different reaction
pathways, it was possible to obtain three different sets of 1,3 diols:
2. (a) For syntheses of b-hydroxy acylsilanes via aldol reactions using acyl silane
enolates, see: Schinzer, D. Synthesis 1989, 179–181; (b) Horiuchi, Y.; Taniguchi,
M.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1995, 36, 5353–5356; (c) For
Mukaiyama aldol reactions, see: Honda, M.; Oguchi, W.; Segi, M.; Nakajima, T.
Tetrahedron 2002, 58, 6815–6823; (d) For syntheses through tandem aldol-
Tishchenko reactions, see: Honda, M.; Iwamoto, R.; Nogami, Y.; Segi, M. Chem.
Lett. 2005, 34, 466–467; (e) See also Honda, M.; Segi, M. Yuki Gosei Kagaku
Kyokaishi 2010, 68, 601–613.
3. PavanKumar Reddy, G.; Satyanarayana Reddy, J.; Das, S.; Roisnel, T.; Yadav, J. S.;
Chandrasekhar, S.; Grée, R. Org. Lett. 2013, 15, 1524–1527.
4. Srirama Murthy, Akondi; Roisnel, T.; Chandrasekhar, S.; Grée, R. Synlett 2013.
2216–2220.
1. The first, with the syn,anti (or syn,syn) structures, by
fluoride induced migrations of groups on silicon;
2. The second, with an anti,anti stereochemistry, by
Grignard addition, followed by protodesylilation;
3. The last series, with an anti,syn stereochemistry, by a
retroaldol-aldol-Tischenko sequence. However, the latter
method is more limited since it is occurs only with
reactive aromatic aldehydes.
5. (a) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886–1889; (b) Brook, A. G. Acc.
Chem. Res. 1974, 7, 77–84; (c) Moser, W. H. Tetrahedron 2001, 57, 2065–
2084.
6. Degl’Innocenti, A.; Pike, S.; Walton, D. R. M.; Seconi, G.; Ricci, A.; Fiorenza, M. J.
C. S. Chem. Commun. 1980, 1201–1202.
8. Morihata, K.; Horiuchi, Y.; Taniguchi, M.; Oshima, K.; Utimoto, K. Tetrahedron
Lett. 1995, 36, 5555–5558.
8. Honda, M.; Ohkura, N.; Saisyo, S.; Segi, M.; Nakajima, T. Tetrahedron 2003, 59,
8203–8212.
Thus, these results confirm the potentialities of the b-hydroxy
acylsilanes in synthesis and further studies on the use of these
building blocks are under active development in our groups.
9. Buynak, J. D.; Strickland, J. B.; Lamb, G. W.; Khasnis, D.; Modi, S.; Williams, D.;
Zhang, H. J. Org. Chem. 1991, 56, 7076–7083.
Acknowledgements
10. Abae, A.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Giovenzana, T.; Malpezzi, L.; Serra,
S. J. Org. Chem. 2005, 70, 1281–1290. and references cited therein.
11. CCDC 949455 contain the supplementary crystallographic data for compound
2a. CCDC 949456 contain the supplementary crystallographic data for
compound 5. CCDC 949457 contain the supplementary crystallographic data
for compound 8. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
This research has been performed as part of the Indo-French
‘Joint Laboratory for Sustainable Chemistry at Interfaces’. We thank
CNRS, CSIR, University of Rennes 1 and CEFIPRA/IFCPAR for support
of this research. JSR thanks the UGC, New Delhi for financial assis-
tance. ASM thanks CSIR for financial assistance. We thank Dr. P.
Mosset, Mrs. O. Tasseau and J. Ruiz for fruitful discussions. We
thank a reviewer for useful comments.
12. As pointed out by
a reviewer, the exact structures of the carbanions
(conjugated or not) will be very likely different in the two postulated
transition states. Therefore, they will induce different electronic interactions
with the neighbouring oxygen, as well as different steric effects with the other
alkyl and aryl groups in the molecule.
13. Nakada, M.; Urano, Y.; Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1988, 110,
4826–4827.
Supplementary data
14. (a) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Nanni, C.; Ricci,
A. Tetrahedron Lett. 1998, 39, 6737–6740; (b) Bonini, B. F.; Comes-Franchini,
M.; Fochi, M.; Gawronski, J.; Mazzanti, G.; Nanni, C.; Ricci, A.; Varchi, G. Eur. J.
Org. Chem. 1999, 437–445.
15. (a) Bodnar, P. M.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 1997, 62, 5674–5675;
(b) Simpura, I.; Nevalainen, N. Tetrahedron 2003, 59, 7535–7546; (c) Rohr, K.;
Herrre, R.; Mahrwald, R. Org. Lett. 2005, 7, 4499–4501.
Supplementary data (experimental procedures and compound
characterization) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2013.11.034.
References and notes
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