Highly regioselective homoallyl alcohol protection through ring opening of p-methoxybenzylidene acetal

Article abstract of DOI:10.1016/j.tetlet.2016.10.068

A highly regioselective homoallylic alcohol protection was achieved in the reductive cleavage of anisylidene acetal with DIBAL-H during the selective protection of hydroxyl group in terminal unsaturated diols which was unlikely compare to the diols present adjacent to internal and cyclic double bond. Reductive cleavage of terminal olefenic diols protected as its acetals gave exclusively allyl alcohol product in good to excellent yield. Though the actual reason of such observation is not quite clear, the current reductive protocol can be applied as an efficient solution for indirect protection of less reactive hydroxy group in preference to that of more reactive allylic one as PMB-mono ether.

Full text of DOI:10.1016/j.tetlet.2016.10.068

Accepted Manuscript
Highly regioselective homoallyl alcohol protection through ring opening of p-
methoxybenzylidene acetal
Yada Bharath, Spandana Maduri, Debendra K. Mohapatra
PII:
S0040-4039(16)31389-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.068
TETL 48238
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 August 2016
1 October 2016
18 October 2016
Please cite this article as: Bharath, Y., Maduri, S., Mohapatra, D.K., Highly regioselective homoallyl alcohol
protection through ring opening of p-methoxybenzylidene acetal, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.10.068
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Highly regioselective homoallyl alcohol protection through
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Yada Bharatha,b, Spandana Maduria and Debendra K. Mohapatraa,b,
*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Highly regioselective homoallyl alcohol protection through ring opening of p-
methoxybenzylidene acetal
Yada Bharatha,b, Spandana Maduria and Debendra K. Mohapatraa,b,∗
aNatural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
bAcademy of Scientific and Innovative Research (AcSIR), Mathura Road, New Delhi-110 025, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly regioselective homoallylic alcohol protection was achieved in the reductive cleavage of
anisylidene acetal with DIBAL-H during the selective protection of hydroxyl group in terminal
unsaturated diols which was unlikely compare to the diols present adjacent to internal and cyclic
double bond. Reductive cleavage of terminal olefenic diols protected as its acetals gave
exclusively allyl alcohol product in good to excellent yield. Though the actual reason of such
observation is not quite clear, the current reductive protocol can be applied as an efficient
solution for indirect protection of less reactive hydroxy group in preference to that of more
reactive allylic one as PMB-mono ether.
Available online
Keywords:
Amphidinolactone
Regioselective
Reductive cleavage
Terminal olefinic diols
PMB-acetal.
2009 Elsevier Ltd. All rights reserved.
Protection and deprotection of hydroxyl functional groups
plays a pivotal role in organic synthesis containing more than one
hydroxy group.1 In this aspect, the readily installed and
manipulated benzylidene or p-methoxybenzylidene acetals
gained immense importance and widespread applications in
organic synthesis particularly in carbohydrate chemistry for the
immediate protection of the 1,2- and 1,3-diol derivatives.2 The
most advantageous factor in the use of these benzylidene or p-
methoxybenzylidene acetals is that they can be reductively
opened in a regioselective manner exposing a free hydroxyl
group and a benzyl or p-methoxybenzyl ether enabling the
opportunity for further transformation. The regioselective
opening of cyclic acetals was first performed by Doukas and
Fontaine in 1951 to open the acetal diosgenin by the reagent
combination of LiAlH4 and HCl.3 The HCl was later replaced by
active Lewis acid AlCl3 and was extensively used by Brown et al.
for the regioselective opening of the cyclic acetals.4 Today, a
plethora of reagent combinations are available for regioselective
opening of cyclic acetals.5 For the synthesis of 4-O-benzyl ethers
the reagents include: LiAlH4–AlCl3,6 DIBAL-H,6c,7 BH3.NMe3–
AlCl3,8 BH3.HNMe2–BF3OEt2,9 BH3.NMe3–Me2BBr,10 Et3SiH–
PhBCl2,11 PS-DESTM–PhBCl2,11a polymethyl hydrosiloxane
(PMHS)–AlCl3,12 and BH3.THF alone6c or in combination with
Ph2BBr,13a Bu2BOTf,13b,c lanthanide triflates,13d Cu(OTf)2,13e or
CoCl2.13f Alternatively, for the synthesis of 6-O-benzyl ethers, the
reagents used include: NaCNBH3–HCl,14 NaCNBH3-MsOH,15
BH3NMe3–AlCl3,8a BH3.HNMe2–BF3OEt2,9a or silanes, such as
Et3SiH16 in combination with TFA,16a TfOH,11a or BF3OEt2,9b,16b
and Me2EtSiH–Cu(OTf)2.13e However, the regioselective
reductive opening of benzylidene or p-methoxybenzylidene
acetals of unsymmetrical 1,2-diols is less explored.12
Method A
HO
O
O
Ar
O
(OP)3
O
Ar
1a
O
(OP)3
1
O
O
Ar
HO
Method B
(OP)3
1b
Figure 1: Regioselective reductive ring opening of acetals.
During the selective protection of allyl alcohol over homoalyl
alcohol in diol 2 to obtain 3 (Scheme 1) by selective protection
using PMB-Br towards the total synthesis of amphidinolactone
A,17 the reaction was efficient in milligram scale, but during gram
scale synthesis, it ended up with intractable mixture of products.
OPMB
Intractable
mixture of
OH
TBDPSO
TBDPSO
compounds in
large scale
ref. 5
OH
OH
2
3
Scheme 1: Selective protection of allylic alohol in presence of
homoallylic alcohol.
To circumvent the problem, we thought of improving the yield as
well as selectivity in the protection of hydroxyl group in diol as
its PMB-acetal followed by reductive cleavage using
diisobutylaluminium hydride (DIBAL-H) as reported in the
litertature. As per the earlier literature precedence,18 reductive
———
∗ Corresponding author. Tel.: +91-40-27193128; fax: +91-40-27160512; e-mail: mohapatra@iict.res.in

2
cleavage of p-methoxyphenyl (PMP)-acetal moiety using
DIBAL-H afforded regioisomers depending on the selective co-
ordination of the DIBAL-H to the neighbouring groups present in
the system leading to major product as homoallyl alcohol in case
of diols adjacent to cyclic or internal double bonds. Notably, to
the best of our knowledge this indirect sequence via reductive
cleavage of PMP-acetal for substrate bearing terminal olefinic
bond have not been studied in general. In this communication, we
describe an indirect sequence for the highly regioselective
protection of terminal olefinic diol, based on two easily
manipulating steps, namely an acid catalyzed PMP-acetal
protection and its reductive cleavage.
giving a mixture of PMB mono-ethers 8 and 3 in a ratio of 7:3,
respectively. Similarly, the regioselective ring opening of acetal 7
employing Wei’s reductive cleavage conditions (BH3/Bu2OTf in
THF)25 resulted in the formation of both the alcohols 8 and 3 in a
3:2 ratio. The significantly decreased selectivity of this reductive
cleavage either through chelation or via direct hydride transfer
could not support us to give an exact reason for such
regioselectivity under DIBAL-H reduction conditions.
With the optimized reductive cleavage protocol in hand, next
the study of broad substrate scope in tolerating functionalities
and protecting groups and for the same a number of different
acetals (7a-h) were treated with DIBAL-H to produce the
corresponding allylic alcohols (8a-h, Table 1) in 70-80% yield.
We found this reductive method to be compatible with acetals
carrying a variety of protecting groups such as benzyl (7a),
TBDPS (7b, 7e), and TBS (7c, 7d), providing the required
regioisomeric allylic alcohols (8a-e) in good yield. The
efficiency of substrates bearing a straight aliphatic chain (7f, 7g)
or a aromatic group (7h, 7i) either at the proximal or distant end
of anisylidene acetal, further proved the independent role of the
protecting groups as well as steric bulk of the neighboring
groups. To verify the role of terminal double bond, methyl group
To prepare diol 2, propane-1,3-diol (4) was monosilylated
followed by Swern oxidation gave aldehyde which upon vinyl
Grignard addition furnished 5 in 68% yield over three steps.19
Sharpless enantioselective epoxidation20 using D-(‒)-diisopropyl
tartarate as the chiral source and in the presence of t-BuOOH and
Ti(i-PrO)4, at ‒25 oC furnished (R)-3-(tert-butyldiphenylsilyloxy)
25
-1-((S)-oxiran-2-yl)propan-1-ol (6) {[α]D ‒6.8 (c 1.6, CHCl3)}
in 42% yield. Epoxide 6 was treated with dimethyl sulfonium
o
methylide at ‒20 C in THF to obtain diol 2 in 86% yield. With
good quantities of diol 2 in hand, the p-methoxyphenyl acetal 7
was prepared using p-methoxybenzylidenedimethylacetal21 in
presence of catalytic amount of CSA in CH2Cl2 as a mixture (4:1)
of separable diastereomers in 85% yield. Reductive cleavage of
acetal 7 was achieved in a regioselective manner using DIBAL-
Table 1. Regioselective ring opening of p-methoxybenzylidene
acetalsa,b
H
22 at ‒78 oC in CH2Cl2 to give a mixture (9:1) of silica gel
D-(-)-DIPT
Ti(i-PrO)4
ref. 19 TBDPSO
[d] [%]
Yield
HO
OH
[c]
[h]
Entry
(7)
t
tBuOOH
CH2Cl2, -25 o
24 h, 42%
acetals
allyl alcohols(8)
OH
C
5
4
PMP
OH
a
O
2.0
75
BnO
O
Me3SI
OH
OPMB
OH
BnO
O
n-BuLi
TBDPSO
TBDPSO
PMP
THF, -20 o
1 h, 86%
C
OH
O
OH
O
2
6
b
c
2.0
1.5
73
72
TBDPSO
TBDPSO
TBSO
PMP
O
2
2
3
OPMB
OH
PMP
DIBAL-H, CH2Cl2
-78 oC, 2 h
p-MeO-Ph-
CH(OMe)2
O
O
TBDPSO
O
TBSO
CSA, CH2Cl2
rt, 1 h, 85%
75% (combined yield)
3
PMP = p-Methoxyphenyl
OPMB
OH
7
PMP
OH
OPMB
O
TBDPSO
O
d
e
TBDPSO
+
2.0
2.5
80
TBSO
TBSO
4
4
OPMB
OH
OPMB
O
OH
9 : 1
8
3
PMP
DMP, CH2Cl2
rt, 2 h, 79%
DMP, CH2Cl2
rt, 2 h, 77%
O
O
70
TBDPSO
TBDPSO
OPMB
5
5
OPMB
OH
TBDPSO
TBDPSO
PMP
O
OPMB
O
O
f
10
9
2.0
3.0
75
78
7
OPMB
OH
7
PMP
Scheme 2: Regioselective ring opening of p-methoxybenzylidene
acetal 7.
O
O
g
8
OPMB
8
column separable p-methoxybenzyl (PMB) mono-ethers 8 and 3,
respectively in 75% combined yield (Scheme 2). The existence of
two positional isomers 8 and 3 was further confirmed by
chemical conversion via oxidation approach. Accordingly,
compounds 8 and 3 were converted to their corresponding
ketones 9 and 10, respectively, using Dess-Martin periodonane23
at 0 C in CH2Cl2. From the H NMR spectra, it was observed
that the chemical shift values of olefinic protons in α,β-
unsaturated ketone 9 was deshielded to a higher δ value (6.80
ppm) compared to β,γ-unsaturated ketone 10.
From the above experimental observation, it was quite clear
that the major regioisomer formed on the reductive cleavage of
acetal with DIBAL-H was unmarked allylic alcohol substrate 7.
On the basis of this result, we thought to further improve the
regioselectivity using an external hydride source in presence of
acid. We have observed that, use of a combination of NaCNBH3
and TFA (trifluoro acetic acid)24a as a reducing agent in CH2Cl2
cleaved acetal 7 with a lesser regioselectivity than DIBAL-H
PMP
OH
OPMB
OH
O
O
2.5
2.0
75
72
O
h
PMP
O
O
i
O
o
1
OPMB
OPMB
TBDPSO
TBDPSO
28
PMP
O
OH
8j
O
j
1.5
+
TBDPSO
OH
48
8j'
OPMB
8j:8j'
=
35:65
aReaction conditions: Acetal (1 mmol), DIBAL-H (1.4 M in Hexane, 8
mmol), CH2Cl2, ‒78 oC. bSelected acronyms: Bn = benzyl; PMB = p-
methoxybenzyl; TBS
=
tert-butyldimethylsilyl; TBDPS
=
tert-
butyldiphenylsilyl. cAll acetals were identified by satisfactory NMR and Mass
spectra analyses. dIsolated yields.

3
1-Octene
11
(10 mol%)
OH
p-MeO-Ph-
CH(OMe)2
OH
PMP
O
TBDPSO
TBDPSO
O
CH2Cl2, rt
87%, 8 h
4
OH
CSA, CH2Cl2
rt, 2 h, 80%
OH
12
TBDPSO
4
2
13
DIBAL-H, CH2Cl2
-78 oC, 1 h
OPMB
OH
TBDPSO
+
TBDPSO
4
4
78% (combined yield)
OH
14
OPMB
15
Mes
N
Cl
N
Mes
Ph
DMP, CH2Cl2
0 oC-rt, 2 h
80%
DMP, CH2Cl2
0 oC-rt, 2 h
76%
Ru
Cl
PCy3
11
OPMB
O
TBDPSO
TBDPSO
4
4
O
OPMB
16
17
Scheme 3. Regioselective ring opening of p-methoxybenzylidene acetal in case of internal double bond.
was introduced adjacent to 1,2-diol instead of vinyl group. p-
Methoxybezylidene acetal 7j was prepared following standard
protocol and subjected to regioselective reductive opening of the
cyclic acetal group following DIBAL-H conditions. As expected,
the reaction ended up with a mixture of two regioisomers 8j and
8j’ in a ratio of 35:65 by HPLC.
Supporting Information
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi/xxxxxx.
References and notes
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Further to support for this end result drawn based on the
previous approaches,24 we thought about the protection of
internal allylic diol as acetal with anisaldehyde dimethyl acetal
followed by its reductive cleavage with DIBAL-H. To check the
selectivity in internal alkene system, we have prepared
compound 13 starting from diol 2. Compound 2 was subjected to
cross metathesis with 1-octene using Grubbs’ catalyst II26 to
afford compound 12 in 87% yield with exclusively E-isomer.
PMB-acetal protection of compound 12 with p-
methoxybenzylidene acetal furnished acetal 13 as
a
diastereomeric mixture in 80% yield. Reductive cleavage of
acetal compound 13 with DIBAL-H gave alcohols 14 and 15 as a
separable mixture of regioisomers (31:69 by HPLC analysis) in
78% combined yield (under similar reaction conditions as
described in Table 1). To confirm the regioselectivity, the
alcohols 14 and 15 were subjected to Dess-Martin periodinane
oxidation in CH2Cl2 to obtain ketones 16 and 17 in 76% and 80%
yield, respectively as shown in Scheme 3.
In conclusion, we report an unusual result which was observed
in the reductive cleavage of anisylidene acetal with DIBAL-H
during the selective protection of hydroxyl group in terminal
unsaturated diols. Reductive cleavage of terminal olefenic diols
protected as its acetals gave exclusively allyl alcohol product in
good to excellent yield, where as in case of internal olefinic
acetal, the reductive cleavage proceeds with less selectivity
giving both allyl and homo allyl alcohol. Though the actual
reason of such observation is not quite clear, the current
reductive protocol can be applied as an efficient solution for
indirect protection of less reactive hydroxyl group in preference
to that of more reactive one as PMB-mono ether.
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4
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5
HIGHLIGHTS
1. A highly regioselective homoallylic alcohol
synthesis.
2. Protection of less reactive hydroxy group.
3. Exclusively monoprotection.