Selective addition of Grignard reagents to 2,3-O-isopropylidene bis-Weinreb tartaric acid amide

Article abstract of DOI:10.1016/S0040-4039(01)01085-1

Controlled addition of Grignard reagents to tartaric acid derived bis-Weinreb amide 3 provides a facile, direct entry to desymmetrized 1,4-functionalized-syn-2,3-diol intermediates 4 and to C₂-symmetrical 1,4-diketones 5. The synthetic versatil

Full text of DOI:10.1016/S0040-4039(01)01085-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5609–5612
Selective addition of Grignard reagents to 2,3-O-isopropylidene
bis-Weinreb tartaric acid amide
James McNulty,* Veronika Grunner and Justin Mao
Institute of Molecular Catalysis, Department of Chemistry, Brock University, St. Catharines, Ontario, Canada L2S 3A1
Received 1 June 2001; revised 18 June 2001; accepted 19 June 2001
Abstract—Controlled addition of Grignard reagents to tartaric acid derived bis-Weinreb amide 3 provides a facile, direct entry to
desymmetrized 1,4-functionalized-syn-2,3-diol intermediates 4 and to C2-symmetrical 1,4-diketones 5. The synthetic versatility of
this method is exemplified by short syntheses of the natural plant growth regulator 10 and the synthetically valuable cyclooctene
derivative 13. © 2001 Elsevier Science Ltd. All rights reserved.
The 1,2-diol subunit occurs in a large number of natu-
ral products of various classes including isoprenoids,
alkaloids, polyketides and carbohydrate derivatives.
Not surprisingly, methods for the asymmetric synthesis
of both syn- and anti-1,2-diols have received much
attention including catalytic asymmetric routes to syn-
1,2-diols via Sharpless asymmetric dihydroxylation1
and more recently anti-1,2-diols via the List proline
catalyzed aldol reaction.2 In order to prepare syn-1,2-
diols through asymmetric dihydroxylation, one first has
to assemble the requisite olefin of defined geometry as
the substrate for the reaction. Tartaric acid 1 is a classic
chiral-pool alternative for the rapid asymmetric synthe-
sis of syn-1,2-diols. It is readily available in either
enantiomeric form and possesses an innate syn-2,3-diol
subunit. Tartaric acid is used extensively as a chiral
precursor in the asymmetric synthesis of natural and
non-natural products3 as well as C2-symmetrical
molecules including chiral ligands.4 Most literature
methods for the differentiation of the 1,4-carboxylate
residues on tartaric acid derivatives involve reaction on
a 2,3-protected derivative (O-benzylidene or acetonide)
via the intermediacy of a reduced 1,4-diol. Selective
mono-protection5 of one alcohol residue and re-oxida-
tion of the remaining alcohol to the aldehyde allows for
subsequent elaboration. The efficiency and versatility of
the tartrate route would be greatly improved if con-
trolled differentiation of the two carboxyl groups at C1
and C4 were possible directly at the oxidation level of
the carboxylic acid leaving valuable functionality at
both ends for subsequent manipulation.
The direct differentiation of the 1,4-carboxylate groups
has been achieved via acylation (esterification, amina-
tion, etc.) of cyclic tartrate–anhydride derivatives.6
Inherent limitations of this method are the necessity for
chemoselective manipulations of the 1,4-carboxylate
residues in the presence of two acetate esters, in addi-
tion to the impossibility of selective organometallic
additions. The 2,3-O-isopropylidene-1,4-bis-Weinreb
amide derivative of tartaric acid 3 has been reported
and converted to C2-symmetrical7 1,4-diketones using
benzyl Grignard reagents as a route to HIV type-1
protease inhibitors. A recent report described one
example of mono addition to this intermediate8 with
benzylmagnesium chloride allowing entry to a non-
symmetrical 4-oxo-Weinreb intermediate, possessing
differential functionality at the two carbonyl positions.
We felt it worthwhile to investigate the generality of
this procedure as a more direct asymmetric route to
syn-2,3-diols retaining useful differentiable 1,4-func-
tionality as well as C2-symmetrical analogs. We now
report that controlled organometallic addition to the
bis-Weinreb amide 3 can provide good to excellent
yields of differentiated non-symmetrical derivatives 4 as
well as valuable C2-symmetrical 1,4-diketone intermedi-
ates 5.
L
-Tartaric acid 1 is readily converted to dimethyl-2,3-
O-isopropylidene tartrate diester 2 in one step on a 100
g scale.9 Conversion of the diester to the bis-Weinreb
amide 3 can be achieved using trimethylaluminum acti-
vation.7 The bis-Weinreb derivative could also be pre-
pared in similar yield directly from the diester using the
method of Williams and co-workers.10 The results of
the addition reaction of various Grignard reagents to
bis-Weinreb amide 3 are summarized in Table 1. For
* Corresponding author. Fax: 905 682 9020; e-mail: jmcnulty@
chemiris.labs.brocku.ca
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01085-1

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J. McNulty et al. / Tetrahedron Letters 42 (2001) 5609–5612
Table 1. Selective addition of Grignard reagents to bis-Weinreb amide 3
Entry
R-Mg-Cl (c equiv.)
Time (min)/Temp (°C)
Product
Yield (%)
1
2
3
4
5
6
7
8
Me (1.10)
Me (2.20)
Et (1.10)
Et (2.20)
iPr (4.00)
iPr (4.00)
Allyl (1.50)
Allyl (3.00)
Bn (1.05)
Bn (3.00)
Ph (1.05)
Ph (3.00)
30/0
70/0
15/0
5/0
135/22
180/22a
15/−78
15/−78
45/−5
135/22
45/−5
135/22
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
4f
73
92
72
98
77
56
52
85
62
73
78
96
9
10
11
12
5f
a Sonication was employed.
simple alkyl groups (entries 1 and 3) monoaddition
occurs with good selectivity when one equivalent of
Grignard is employed with only trace quantities of
diketone detectable. Optimum yields of monoacyl
derivatives were obtained employing 1.1 equivalent of
the Grignard reagent. Monoaddition appears to be
purely kinetically controlled as the reaction intermedi-
ates remain fully in solution. On the other hand, an
excess of the alkyl Grignard (entries 2 and 4) is rapidly
acylated leading to the diketone. Both mono and bis
addition become sluggish as R increases from primary
to secondary. Excess isopropylmagnesium chloride was
slowly added giving 4c (entry 5), while sonication was
necessary to afford reasonable yields of the bis-isopro-
pyl ketone 5c (entry 6). In contrast to this, allylmagne-
sium chloride was acylated rapidly giving mixtures of
4d and 5d even when one equivalent of the Grignard
reagent was employed. Lower temperatures and slightly
more dilute conditions, however, afforded an accept-
able yield of the mono allylketone (entry 7), while the
symmetrical bis-allyl ketone could be obtained in high
yield (entry 8). Both products 4d and 5d could be
isolated using standard flash silica-gel chromatography,
however extended contact with silica promoted the slow
rearrangement to the thermodynamically more stable
a,b-unsaturated mono- or bis-ketone derivatives. Selec-
tive mono- and bis-addition of benzyl and phenyl mag-
nesium chloride to 3 (entries 9–12) could also be
effected in good overall yields. No tertiary alcohols
have been detected in any of the above reactions even
when excess Grignard reagent is used.
The value of this direct de-symmetrization method is
exemplified by a short asymmetric synthesis of the
naturally occurring compound 10 containing a syn-diol
sub-unit, Scheme 1. Compound 10 is the lactone form
of a bacterial metabolite that has been shown to induce
lateral root formation in various infected plant spe-
cies.11 The monophenyl ketone derivative 4f was
reduced with lithium aluminum hydride to give 4-
hydroxyaldehyde 7 as a mixture of lactols, which was
immediately reacted with the Horner–Emmons reagent
to give the unsaturated ester 8 (3:1 mixture of benzylic
alcohols). Reduction of the double bond occurred con-
Scheme 1. Synthesis of growth regulator 10.

J. McNulty et al. / Tetrahedron Letters 42 (2001) 5609–5612
5611
Scheme 2. Synthesis of cyclooctene 13.
In summary, we have shown that the tartaric acid
derived bis-Weinreb amide 3 provides a general entry to
useful desymmetrized keto-Weinreb intermediates 4 as
well as C2-symmetrical diketones 5 through the direct,
selective functionalization of the carboxylate residues.
The utility of this method in the synthesis syn-1,2-diols
is exemplified by the synthesis of the natural butyrolac-
tone 10 as well as a synthetically useful cyclooctene
derivative 13. Further application of this methodology
towards the synthesis of natural products is currently in
progress.
currently with hydrogenolysis of the benzylic secondary
alcohol as expected to furnish the protected diol 9.
Hydrolysis of the O-isopropylidene acetonide under
acidic conditions and concomitant transesterification
provided the desired butyrolactone 10 directly (IR:
1
CꢀO 1768 cm−1). H and 13C NMR spectra as well as
the optical rotation were in complete accord to those
reported.11 Of note here is the rapid assembly of the
desymmetrized intermediate 9† in three steps and 57%
overall yield from 4f.
In addition to the increasing recognition of cyclooctane
derivatives as natural products, cyclooctene derivatives
have proven to be synthetically valuable intermediates
in their own right and are of considerable recent inter-
est. Conversion of cyclooctenes to fused bicyclo
[3.3.0]octanes may be carried out via an epoxidation–
fragmentation strategy.12 In addition, oxidation and
amination protocols can provide stereochemically
defined acyclic fragments as well as O- and N-hetero-
cyclic derivatives.13 It was therefore of interest to inves-
tigate the elaboration of tartaric acid into a chiral,
C2-symmetrical cyclooctene framework, as outlined in
Scheme 2. Reduction of the bis-allyl ketone 5d gave the
C2-symmetrical diol 11 as the major product along with
a minor amount of the non-symmetrical diastereomer
12 (ratio 11:12=84:16). Ring-closing metathesis on 11
proceeded slowly in toluene at 80°C to give the synthet-
ically valuable C2-symmetrical cyclooctene derivative 13
in 59% yield.‡ No protection of the hydroxyl groups14
was necessary using the standard Grubbs catalyst under
these conditions.15
Acknowledgements
We thank the Natural Sciences and Engineering
Research Council of Canada and Research Corpora-
tion (Cottrell Scholar Science Award to J.McN.) for
financial support.
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