Inositols as chiral templates: 1,4-conjugate addition to tethered cinnamic esters.

Article abstract of DOI:10.1039/b408467e

The 1,4-addition of thio nucleophiles to chiro-inositols containing a cinnamyl Michael acceptor proceeded with excellent diastereochemical induction and good yields. Cleavage of the inositol auxiliary provides beta-thio hydrocinnamic acids in >99% ee's.

Full text of DOI:10.1039/b408467e

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C O M M U N I C A T I O N
Inositols as chiral templates: 1,4-conjugate addition to tethered
cinnamic esters†
Ghislaine Cousins,a Andrew Falshawb and John O. Hoberg*c
a
School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington,
New Zealand
b
Industrial Research Limited, PO Box 31-310, Lower Hutt, New Zealand
Department of Chemistry, University of Wyoming, Laramie, Wyoming, USA
c
Received 4th June 2004, Accepted 1st July 2004
First published as an Advance Article on the web 22nd July 2004
we entertained the possibility that the methoxy group would
The 1,4-addition of thio nucleophiles to chiro-inositols
containing a cinnamyl Michael acceptor proceeded with
excellent diastereochemical induction and good yields. Cleavage
of the inositol auxiliary provides β-thio hydrocinnamic acids
in >99% ee’s.
provide a large enough steric bias to produce facial selectivity
on the unsaturated moiety. This would involve shielding of the
front (Si) face of the acceptor to give attack from the less-hindered
Re-face (back side).8
Methodologies for the efficient asymmetric synthesis of natural
products and other materials are of great importance in organic
synthesis, and in the past decades enormous strides have occurred
in the development of asymmetric synthesis.1,2 A number of asym-
metric catalysts or ‘abiological’ catalysts have now approached
efficiency and selectivity levels comparable to those of enzymes,
and can have the advantage of either enantiomer being available.
In recent years, C2-symmetric chiral molecules have received a
great deal of attention in ligand–metal catalysis and as auxiliaries.3,4
These systems have additional benefits in terms of flexibility in
ligand design and convenient synthesis.
We recently initiated a program to develop inositols as C2-
symmetric molecules for use as auxiliaries in asymmetric
synthesis. Inositols are a family of nine hydroxylated cyclohexanes
that include the enantiomeric pair D- and L-chiro-inositol, Fig. 1.
These are derived from the naturally occurring pinitol and
quebrachitol, which are obtained from pine and rubber trees,
respectively, by simple demethylation.5 Although all four of these
are commercially available, quebrachitol has received the majority
of the attention in asymmetric synthesis.6,7
Scheme 1 Retrosynthetic strategy for inositol auxiliaries.
We began our studies by protection of pinitol as the di-O-
isopropylidene acetal, which produces a single isomer under
literature procedure,9 Scheme 2. Reaction with cinnamoyl chlo-
ride gave ester 3 in a very convenient 85% yield. Treatment of
a thiophenol/THF solution with 10 mol% BuLi at 0 °C or room
temperature followed by 3 gave a myriad of products. However,
reaction at −10 °C gave the single addition adduct 4 in a reasonable
75% yield but a disappointing 1:1 diastereoselectivity. Obviously,
the size of the methoxy moiety was unable to hinder approach from
the front face and a larger group was required.
Scheme 2 Reagents and conditions: a) acetone, (MeO)2CMe2, TsOH,
DMF, 84%; b) PhCHCHCOCl, DMAP, Py, CH2Cl2, 85%; c) PhSH, BuLi,
THF, 75%.
Fig. 1 Chiral inositols.
We therefore converted D-chiro-inositol to di-O-isopropylidene
5 in 93% yield, again according to literature procedure,10 for
subsequent de-symmerization of the C2-symmetric diols. Using
the procedure developed by Clarke et al.,11,12 we recently disclosed
a convenient method for the monoesterification of 5,10 enabling the
placement of a larger protecting group at a single hydroxy moiety.
Thus, treatment of 5 with pivaloyl anhydride in the presence of
catalytic ytterbium chloride gave 6 as a single isomer in high yield,
Scheme 3. This enabled subsequent esterification using cinnamoyl
chloride to provide acceptor 7 with the methoxy group replaced by
the pivoyl ester.
Our initial goal to develop the inositols further was to use
the esters 2 as Michael acceptors, which could subsequently be
hydrolyzed to provide chiral molecules such as acids 1, Scheme 1.
Formation of the required acceptor 2 would be accomplished by
simple protection of the cis-diols of pinitol to give the di-acetals,
followed by esterification of the remaining lone hydroxy moiety.As
this involved a reasonably straightforward synthesis of an acceptor,
† Electronic supplementary information (ESI) available: experimental
details for the preparation and analysis of compounds 3, 4, 6, 7, 8a–e, 10a,
10b, 10e, 11a–11d, 13a, 13b and 13d. See http://www.rsc.org/suppdata/ob/
b4/b408467e/
Gratifyingly, the initial reaction with thiophenol gave a good
yield of the addition product and a single isomer as shown by 13
C
NMR. A range of thiol nucleophiles were subsequently tested as
2 2 7 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 7 2 – 2 2 7 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1 Conjugate addition of thiols
Table 2 Hydrolysis of esters 8 and 10
Entry
Thiol
Product (% yield)a
Product (% yield)a
Entry
R
Product (% yield)a
Product (% yield)a
% ee
dsb
dsb
% eeb
1
2
3
8a (79%)
>99:1
10a (75%)
>99:1
1
2
3
11a (76%)
>95
11b (75%)
>95
11c (59%)
>95
13b (74%)
>95
13b (72%)
>95
8b (74%)
>99:1
10b (72%)
>99:1
8c (68%)
>99:1
—
4
11d (72%)
13d (67%)
33
34
4
5
8d (76%)
>99:1
—
a Isolated yield. b The stereochemistry was determined by comparison of the
optical rotation to the known 3-benzylthio-3-phenylpropanol after LiAlH4
reduction of 8a; and comparison of 11a to literature values (see ESI). All
other compounds were established by comparison of NMR data to 8a or 8c
and 10a or 10c.
0
0
—
—
6
7
The final step in verifying chiro-inositols as useful auxiliaries
involved selective cleavage of the auxiliary to provide acids 11 and
13, Scheme 5. Careful monitoring of the reaction by tlc enabled the
selective cleavage of the thiol ester moiety without cleavage of the
pivalate ester. Upon completion of the reaction, the mixtures were
diluted with water and extracted with CH2Cl2 to provide inositols
12 and 14 in high yields. The crude inositols were filtered through
a silica plug and re-esterified with cinnamoyl chloride to give 7 and
9 in overall 85–91% yields. Thus, an important aspect of a chiral
auxiliary, namely the ability to be recycled, has been realized with
this system.
8e (71%)
3:1
10e (31%)
2.5:1
a Isolated yield. b Determined by 13C NMR on crude mixtures.
Scheme 3 Reagents and conditions: a) (Me3CO)2O, 10% YbCl3·6H2O,
THF, 83%; b) PhCHCHCOCl, DMAP, Py, CH2Cl2, 89%; c) RSH,
BuLi, THF.
shown in Table 1. As seen, entries 1 and 2 gave good yields and
selectivities with the D-chiro-inositol-derived acceptor. The use of
electron donating substituents on the aromatic ring, entries 3 and
4, also gave excellent selectivities but the products proved to be
unstable and began to decompose immediately. As seen in entries
5 and 6, aromatic thiols with electron withdrawing groups failed to
react. Finally, the less hindered methylbutanethiol in entry 7 gave a
comparable yield but disappointing selectivity.
To verify the usefulness of inositols in asymmetric synthesis, the
L-isomer of acceptor 9 was synthesized in an analogous manner
to that of 7 and also subjected to reaction with thiol nucleophiles,
Scheme 4. Again, as seen in entries 1 and 2 of Table 1, excellent
selectivities are observed, and as expected with comparable yields
to the D-chiro-inositol. Given the lack of stability of the amino-
and methoxy-benzenethiols and the lack of reactivity of nitro- and
chloro-benzenethiols, reaction with these was not attempted.
Scheme 5 Cleavage of the inositol auxiliary.
Isolation of the desired enantiomers 11 and 13 was achieved in
typical fashion by acidification of the aqueous layer to give the acids
in good yields as shown in Table 2. Chiral GC analysis of the acids
showed that excellent ee’s are achieved with this system.13 In all
cases, except for the aliphatic thiol, only one isomer was observed
in reactions with both the D- and L-derivatives 7 and 9. Simplifica-
tion of the overall procedure has also been achieved by elimination
of the final hydrolysis step. Workup after addition of the thiol, as in
Schemes 3 and 4, can be modified by simply using aq. KOH/MeOH,
thus achieving the addition and hydrolysis step in one pot.
Given the success with thiol nucleophiles, we next attempted the
addition of an alkyl cuprate, Scheme 6.Although addition did occur,
the yield was a disappointing 43%, and all attempts at modification
of the conditions did not result in any improvements. A possible
rationalization for this low yield is due to the conformation of the
Michael acceptor.8 Presumably, coordination of the metal with the
cinnamoyl carbonyl, and pivoyl carbonyl, causes unfavorable inter-
action between the metal carbonyl and the carbon–carbon double
bond in the s-cis, syn conformation. Typically, this unfavorable
interaction leads to the s-trans, syn conformation, which then under-
goes addition.14,15 However, in our system, formation of the s-trans,
syn conformation presumably leads to unfavorable interactions of
the pivoyl group and a methyl group of the isopropylidene acetal.
Scheme 4 L-chiro-Inositol.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 7 2 – 2 2 7 4
2 2 7 3

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This forces the molecule to adopt the usually unfavoured s-cis,
syn conformation, which is supported by the stereochemical out-
come of the addition reaction. If 7 was adopting the s-trans, syn
conformation, stereochemistry opposite to that observed would be
expected. We therefore used the methoxy-bearing inositol 3, which
as expected gave a 1:1 diastereomeric mixture of the butyl addition
product.
acetal is expected to alleviate the problems associated with the use
of organocuprates.
Acknowledgements
We thank New Zealand Pharmaceuticals and Industrial Research
Limited for funding.
Notes and references
1 M. Nogradi, Stereoselective Synthesis, VCH Publishers, New York,
1995.
2 J. Seyden-Penne, Chiral Auxiliaries and Ligands in Asymmetric
Synthesis, Wiley Interscience, New York, 1995.
3 A. K. Ghosh, P. Mathivanan and J. Cappiello, Tetrahedron: Asymmetry,
1998, 9, 1.
4 J. K. Whitesell, Chem. Rev., 1989, 89, 1581.
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6 T. Akiyama, M. Hara, K. Fuchibe, S. Sakamoto and K. Yamaguchi,
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7 J. J. Kiddle, Chem. Rev., 1995, 95, 2189.
8 K. Totani, T. Nagatsuka, S. Yanaguchi, K. Takao, S. Ohba and J. Tadano,
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9 J. Larner, J. D. Price, D. Heimark, L. Smith, G. Rule, T. Piccariello,
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10 G. Cousins, A. Falshaw and J. O. Hoberg, Carbohydr. Res., 2003, 338,
995.
Scheme 6 Organocopper addition.
11 P. A. Clarke, N. E. Kayaleh, M. A. Smith, J. R. Baker, S. J. Bird and
C. Chan, J. Org. Chem., 2002, 67, 5226.
12 P. A. Clarke, R. A. Holton and N. E. Kayaleh, Tetrahedron Lett., 2000,
41, 2687.
13 The stereochemistry was determined by comparison of the optical
rotation to the known 3-benzylthio-3-phenylpropanol after LiAlH4
reduction of 8a; and comparison of 11a to literature values (see ESI†).
All other compounds were established by comparison of NMR data to
8a or 8c and 10a or 10c.
In conclusion, chiro-inositols appear to be highly effective as
chiral auxiliaries in conjugate 1,4-additions of aromatic thiols and
contain all the requirements of an effective auxiliary, primarily
high diastereoselectivity. Of equal importance is the short, facile,
high-yielding, three-step synthesis and the demonstrated ease with
which the inositol auxiliary can be recycled. Further development
of these inositols in asymmetric synthesis, including the use of
alternative nucleophiles for conjugate addition, is underway and
will address the apparent drawback of the rigid, bulky acetal
protecting groups. The use of alternative groups such as a methylene
14 R. J. Loncharich, T. R. Schwartz and K. N. Houk, J. Am. Chem. Soc.,
1987, 109, 14.
15 W. Oppolzer, Angew. Chem., Int. Ed. Engl., 1984, 23, 876.
2 2 7 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 7 2 – 2 2 7 4