Highly diastereoselective desymmetrisation of cyclic meso-anhydrides and derivatisation to mono-protected 1,4-diols

Article abstract of DOI:10.1055/s-2005-862393

A new and efficient desymmetrisation of bi- and tricyclic meso-anhydrides is described, providing good yields and diastereoselectivities in all cases (routinely >95% de). Derivatisation of the chiral compounds synthesised is then demonstrated by their conversion into mono-protected 1,4-diols.

Full text of DOI:10.1055/s-2005-862393

646
LETTER
Highly Diastereoselective Desymmetrisation of Cyclic meso-Anhydrides and
Derivatisation to Mono-Protected 1,4-Diols
H
ighlyDiastereose
m
lective
D
esymmetr
a
isationof
C
n
yclic
m
eso-A
d
nhydrides a C. Evans,a Deborah A. Longbottom,a Masato Matsuoka,b Steven V. Ley*a
a
University of Cambridge, Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
b
Nippon Shinyaku Co., Ltd., 3-14-1 Sakura, Tsukuba, Ibaraki 305-0003, Japan
Received 19 November 2004
O
O
O
H
H
H
H
1, CH2Cl2, –78 ºC, 30 min
then TMSCHN2, 16 h
R1
R2
R1
R2
Abstract: A new and efficient desymmetrisation of bi- and tricyclic
meso-anhydrides is described, providing good yields and diastereo-
selectivities in all cases (routinely >95% de). Derivatisation of the
chiral compounds synthesised is then demonstrated by their conver-
sion into mono-protected 1,4-diols.
OMe
O
(+)-Aux
O
Scheme 1 General depiction of desymmetrisation of meso-
anhydride to hemiester using 1.
Key words: chiral auxiliary, diastereoselectivity, desymmetrisa-
tion, stereoselective synthesis, anhydride
Abiko et al. report the effective use of 1 as a chiral auxil-
iary for asymmetric alkylation and also demonstrate its
Weinreb amide-like cleavage to yield alcohols, alde-
hydes, ketones and carboxylic acids.3 However, the use of
1 as a desymmetrisation agent has not been further inves-
tigated; we thus hoped to use 1 as a new reagent for the
asymmetric desymmetrisation of cyclic meso-anhydrides.
Due to the literature precedent,3 auxiliary cleavage was
not envisioned to present difficulties. Additionally, given
the highly crystalline nature of 1 and 2, it was anticipated
that the diastereoselectivity observed within the desym-
metrisation reaction could be further enhanced by stan-
dard recrystallisation methods.
The desymmetrisation of prochiral cyclic anhydrides is a
very useful synthetic process that generates optically-en-
riched chiral hemiesters, containing one or more stereo-
genic centres and two chemically differentiated carbonyl
functionalities.1 These chiral hemiesters, and derivatives
thereof, have proven to be versatile building blocks in
asymmetric synthesis.2
However, existing methods for the desymmetrisation of
meso-anhydrides can suffer from one or more problems:
extended reaction times, low enantio- or diastereoselec-
tivities and limited scope of anhydride substrates.1,2 We
report herein a new, auxiliary-mediated method for anhy-
dride desymmetrisation that combines reduced reaction
times with good to excellent diastereoselectivities and
broad reaction scope.
Initial investigations of the desymmetrisation reaction of
cis-1,2,3,6-tetrahydrophthalic anhydride (Scheme 1,
Entry 1) with (+)-auxiliary 1 [‘(+)-Aux’] at –78 °C in
dichloromethane proved to be problematic, due to the
apparent instability of the amide-acid product. However,
when the desymmetrisation reaction was carried out with
subsequent trapping of the resulting carboxylic acid with
TMS-diazomethane, only one diastereomeric amide-ester
product 3 was isolated, as confirmed by both 1H NMR and
chiral HPLC. Investigation of the scope of 1 as a desym-
metrising reagent proved to be encouraging: the one-pot
desymmetrisation and consequent ester formation pro-
ceeds with high yields and diastereoselectivities on a
broad range of substrates, as shown in Table 1. Both bi-
and tricyclic succinic anhydrides are desymmetrised with
high yields and diastereomeric ratios. All desymmetrised
products are crystalline, as demonstrated by the crystal
structure of the desymmetrized anhydride product 6
(Figure 2); thus recrystallisation could potentially, where
necessary, be used to give diastereomerically pure prod-
ucts.
O
O
HN
HN
O
O
1 (+)-auxiliary: "(+)-Aux"
2 (–)-auxiliary: "(–)-Aux"
Figure 1 Chiral amine auxiliaries 1 and 2 used for meso-anhydride
desymmetrisation.
Work published by Abiko et al. describes the synthesis
and use of a new chiral isoxazolidine auxiliary 1
(Figure 1).3 Synthesis of the auxiliary is straightforward
and scalable, and isolation of both highly crystalline (+)-
and (–)-enantiomers (1 and 2, respectively) from the race-
mic reaction mixture is possible via kinetic resolution
using (+)-CSA.
In order to prove the synthetic utility of our desymmetri-
sation process, it was necessary to demonstrate that the
two carbonyl functionalities can indeed be chemically
differentiated, and that further derivatisation of the de-
symmetrisation products is possible. Conditions were
SYNLETT 2005, No. 4, pp 0646–0648
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-862393; Art ID: D34404ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
3.
2
0
0
5

LETTER
Highly Diastereoselective Desymmetrisation of Cyclic meso-Anhydrides
647
Table 1 Scope of (+)-Aux 1a as a Desymmetrising Chiral Auxiliary
Entry Anhydride
Product
Yield
(%)
de
(%)b
1
96
>95
O
O
H
H
H
H
OCH3
O
(+)-Aux
O
O
3
2
3
4
90
74
99
>95
O
O
H
H
H
H
O
OCH3
(+)-Aux
O
Figure 2 X-ray diffraction analysis of desymmetrised anhydride
product 6.
O
4
5
92
O
O
H
H
H
overall yields. The diastereoselectivity of the original de-
symmetrisation step is maintained throughout the deriva-
OCH3
O
(+)-Aux
O
1
H
tisation process, as monitored by H NMR. Indeed, the
O
diastereoselectivity of the original anhydride desymmetri-
sation ultimately translates into excellent enantioselectiv-
ity upon auxiliary cleavage, as proven by derivatisation
>95
1
via Mosher’s ester formation and subsequent H NMR
O
O
O
analysis.
(+)-Aux
O
O
OCH3
6
O
O
O
H
H
H
H
5
6
7
90
98
98
>95
>95
>95
Cp2Zr(H)Cl
O
O
OMe
OH
OCH3
(+)-Aux
THF, r.t., 30 min
(+)-Aux
(+)-Aux
O
O
O
7
O
O
11
3
O
O
O
O
74%, >95% de
OCH3
(+)-Aux
TBDMSOTf
2,6-lutidine
O
H
OTBS
8
(+)-Aux
O
O
CH2Cl2, 0 °C to r.t., 16 h
H
H
H
H
H
O
OCH3
O
O
O
12
(+)-Aux
O
77%, >95% de
O
H
9
OTBS
OH
LiBH4, EtOH, Et2O
0 °C to r.t., 16 h
a (–)-Aux 2 has been demonstrated to be equally diastereoselective.
b The de (%) was confirmed by 1H NMR and chiral HPLC.
H
13
obtained, after some investigation, whereby 1,4-mono-
protected diols could be formed in good yield and with
retention of the initial chirality induced in the desymme-
trisation process (Scheme 2).
100%, >95%ee
Scheme 2 Derivatisation of chiral products to 1,4-mono-protected
diols; ee (%) of 13 proven by Mosher’s ester formation.
Chemoselective reduction is achieved using Schwartz re-
agent, which selectively reduces the methyl ester moiety
to the alcohol at room temperature in 30 minutes, leaving
the amide portion of the molecule intact.4 Protection of the
alcohol and Weinreb amide-like reductive cleavage of the
auxiliary to the 1,4-mono-protected diol proceeds in good
Further work is ongoing to provide alternative derivatisa-
tion pathways for the desymmetrisation products using
Weinreb amide cleavage conditions. The desymmetrisa-
tion of monocyclic and glutaric anhydrides is also current-
ly being investigated.
Synlett 2005, No. 4, 646–648 © Thieme Stuttgart · New York

648
A. C. Evans et al.
LETTER
General Experimental Protocol
References
A solution of cyclic meso-anhydride (0.55 mmol, 1.1 equiv) in
CH2Cl2 (2 mL) was cooled to –78 °C. A solution of (+)-auxiliary 1
(0.5 mmol, 1.0 equiv) in CH2Cl2 (1 mL) was added dropwise, and
the resulting solution was stirred at –78 °C for 30 min. TMS-diazo-
methane (1.25 mmol, 2.5 equiv, 2.0 M in hexanes) was then added
dropwise. After 16 h at –78 °C, the reaction was quenched with
MeOH (4 mL) and allowed to warm to r.t. Following solvent re-
moval and column chromatography (silica gel, 1% MeOH in
CH2Cl2), the pure desymmetrised anhydrides were isolated in yields
up to 99%.
(1) For some general overviews of enantioselective
desymmetrisation, please see: (a) Willis, M. C. J. Chem.
Soc., Perkin Trans. 1 2001, 1765. (b) Spivey, A. C.;
Andrews, B. I. Angew. Chem. Int. Ed. 2001, 40, 3131.
(c) Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103,
2965. (d) Hoffman, R. W. Angew. Chem. Int. Ed. 2003, 42,
1096.
(2) For some examples of anhydride desymmetrisation as
applied to total synthesis, please see: (a) Hashimato, K.;
Kitaguchi, J.; Mizuno, Y.; Kobayashi, T.; Shirahama, H.
Tetrahedron Lett. 1996, 37, 2275. (b) Hibbs, D. E.;
Hursthouse, M. B.; Jones, I. G.; Jones, W.; Abdul Malik, K.
M.; North, M. Tetrahedron 1997, 53, 17417. (c) Jones, I.
G.; Jones, W.; North, M. Tetrahedron 1999, 55, 279.
(d) Verma, R.; Ghosh, S. K. J. Chem. Soc., Perkin Trans. 1
1999, 265. (e) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am.
Chem. Soc. 2000, 122, 8793. (f) Choi, C.; Tian, S.-K.;
Deng, L. Synthesis 2001, 1737. (g) Mittendorf, J.; Benet-
Buchholz, J.; Fey, P.; Mohrs, K.-H. Synthesis 2003, 1, 136.
(h) Hubbard, R. D.; Miller, B. L. Tetrahedron 2003, 59,
8143. (i) Mans, D. M.; Pearson, W. H. Org. Lett. 2004, 6,
3305.
Acknowledgment
We wish to acknowledge the constructive discussions and useful
advice of Dr. I. R. Baxendale, Dr. A. J. A. Cobb, and D. M. Shaw.
We also wish to thank Dr. J. E. Davies for his assistance with X-ray
diffraction analysis.
(3) (a) Abiko, A. Chem. Lett. 1995, 357. (b)Abiko, A.; Moriya,
O.; Filla, S. A.; Masamune, S. Angew. Chem., Int. Ed. Engl.
1995, 34, 793. (c) Abiko, A.; Davis, W. M.; Masamune, S.
Tetrahedron: Asymmetry 1995, 6, 1295. (d) Abiko, A.;
Masamune, S. Tetrahedron Lett. 1996, 37, 1081. (e) Abiko,
A. Heterogen. Chem. Rev. 1997, 17, 51. (f) Abiko, A.;
Masamune, S. Tetrahedron Lett. 1997, 38, 3261.
(4) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc.
2000, 122, 11995.
Synlett 2005, No. 4, 646–648 © Thieme Stuttgart · New York