An efficient synthesis of indane-derived bis(oxazoline) and its application to hetero Diels-Alder reactions on polymer support

Article abstract of DOI:10.1016/j.tetlet.2003.10.097

Indane-derived bis(oxazolines) were synthesized in two steps and 93% overall yield starting from commercially available substrates. This ligand is as effective as tert-butyl bis(oxazoline) in hetero Diels-Alder reaction both in solution and on polymer sup

Full text of DOI:10.1016/j.tetlet.2003.10.097

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 145–148
An efficient synthesis of indane-derived bis(oxazoline) and its
application to hetero Diels–Alder reactions on polymer support
Michio Kurosu,* James R. Porter and Michael A. Foley
Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA
Received 13 August 2003;accepted 20 October 2003
Abstract—Indane-derived bis(oxazolines) were synthesized in two steps and 93% overall yield starting from commercially available
substrates. This ligand is as effective as tert-butyl bis(oxazoline) in hetero Diels–Alder reaction both in solution and on polymer
support.
Ó 2003 Elsevier Ltd. All rights reserved.
Since the introduction of C2-symmetric chiral bis(oxa-
zoline) (Box) ligands in copper-catalyzed asymmetric
cyclopropanations by Masamune in 1990,1 these com-
pounds have been of considerable interest as versatile
bidentate (or tridentate) ligands in asymmetric reac-
tions.2 A variety of Box ligands have been designed and
applied to stoichiometric and catalytic asymmetric re-
actions.3 Evans and co-workers have reported that
(S,S)-tert-butylbis(oxazoline) ((S,S)-t-Bu-Box) (1) de-
rived from (S)-tert-leucine is the optimal ligand for a
number of asymmetric transformations such as Mu-
kaiyama aldol reaction, Mukaiyama–Michael reaction,
Diels–Alder cycloaddition, and cyclopropanation (Fig.
1).4 However, t-Bu-Box ligands are composed of
expensive building blocks5 and their synthesis requires
purification by chromatography.6 The Box ligand
derived from optically pure cis-1-amino-2-indanol
(Inda-Box) (2) has been utilized in a few asymmetric
transformations such as a Diels–Alder reaction7 and
conjugate addition of 1,3-dicarbonyl compounds.8
In an effort to synthesize a large collection of diverse and
complex molecules efficiently, we became interested in
reagent-controlled asymmetric reactions on polymer-
supported molecules. Schreiber and Stavenger have
demonstrated Cu-(S,S)-t-Bu-Box (1) and Cu-ent-1 cat-
alyzed hetero Diels–Alder reactions9 for the construc-
tion of
a 4232-member dihydropyrancarboxamide
library made on 500 lm polystyrene beads.10 We now
wish to report a very practical synthesis of optically pure
Inda-Box ligand 2 in two steps with 93% overall yield
after a single crystallization and its application to
asymmetric hetero Diels–Alder reactions on a polymer
support.
Inda-Box (2) is commonly synthesized via condensation
of ethyl 3-amino-3-ethoxyprop-2-enimidate and 1-amino-
2-indanol (3), followed by double alkylation of 4 under
anhydrous conditions (path a in Scheme 1).2;11 Although
effective on a small scale, these sequences suffer from low
overall yield. Therefore we investigated a more conve-
nient method for this transformation. After acylation of
3 with dimethylmalonyl chloride to give diamide 5, we
investigated a higher yielding method for cyclization of
Me Me
Me Me
O
O
2
O
O
N
N
1
N
N
t
t
Bu
Bu
(1R,2S)-Inda-Box (2)
(S,S)-t-Bu-Box (1)
Figure 1.
1b
12
5 to oxazoline 2. Since Bu2SnCl2 and BF3–OEt2 at
elevated temperature are known to catalyze oxazoline
formation with retention of secondary alcohol stereo-
chemistry, we applied these conditions for the synthe-
sis of Inda-Box 2. Unfortunately, these conditions
resulted in poor conversion of 5 to cyclized product 2
Keywords: bis(oxazoline);hetero Diels–Alder reaction;polymer sup-
port;dihydropyrancarboxylic acid;diversity-orientated synthesis.
* Corresponding author. Tel.: +1-617-4531164;fax: +1-617-4531001;
e-mail: mkurosu@ipi.com
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.097

146
M. Kurosu et al. / Tetrahedron Letters 45 (2004) 145–148
Br
NH NH
Br
2
NH
O
O
2
EtO
OEt
OTBS 5 mol %
2HCl
60%
N
N
4S
6S
ligand (2)-Cu(OTf)2
OH
OTBS
(CH2)
AllylO
MS 3A
1
AllylO
4
path a
O
3
O
O
O
4
°
CH2 Cl2,-20 C
O
O
>19:1 (endo:exo)
90-95%
Dimethylmalonyl chloride
6a: 2-Bromo
7
LDA-TMEDA
then MeI
40-50%
8a: 95% ee for 2-bromo
8b: 97% ee for 4-bromo
6b: 4-bromo
Et N
3
path b
OH
Scheme 3.
Me
O
Me
H
N
H
N
Ti(OiPr)
4
(1R,2S)-Inda-Box (2)
o
145 C
O
OH
93% overall
from 3
the desired allyl dihydropyrancarboxylates 8a and 8b in
>90% yield with >19:1 diastereoselectivity and 95% ee.
These experiments demonstrate that t-Bu-Box ligand
can be replaced with Inda-Box (2 and its enantiomer) in
the hetero Diels–Alder reaction.
5
Scheme 1.
(e.g., 10–15% conversion with Bu2SnCl2 at 140 °C).
Gratifyingly, we found that Ti(OiPr)4 facilitates the
transformation of 5 to 2 at 140–145 °C in very high yield
(path b). To further improve this protocol, we developed
an efficient method to remove Ti(OiPr)4 and other Ti
species from the reaction mixture. Ti species are solu-
bilized and extracted from the organic solution by
complexation with 3-(dimethylamino)-1,2-propane-
diol.13 Crystallization from acetonitrile affords Inda-Box
2 in 93% overall yield from 3. The synthesis of each
enantiomer was performed on a 100 g scale.
In order to investigate the applicability of the (Inda-
Box)–Cu(OTf)2 catalyst to polymer-supported vinyl
ethers, three different vinyl ethers were loaded onto the
LanternTM 15
The polymer-supported vinyl ethers were
.
subjected to hetero Diels–Alder reactions with struc-
turally diverse heterodienes (6a–j) using 100 mol % of
[(1R,2S)-Inda-Box–Cu(OTf)2]. Desired allyl dihydropyr-
ancarboxylates (8a–j) were isolated with good diastereo-
selectivities and 86–97% ee as summarized in Table 1.
These results clearly indicate that [Inda-Box–Cu(OTf)2]
catalyst tolerates a variety of heterodienes and vinyl
ethers as well as solid phase asymmetric synthesis.
As mentioned above, the utility of Box–metal complexes
in solution-phase asymmetric reactions (target-oriented
synthesis) has been demonstrated by a number of
groups. However, its application in diversity-oriented
synthesis,14 which is generally performed on polymer
support is less developed. We have been interested in
dihydropyrancarboxylic acid derivative (Scheme 2) as a
skeleton for small drug-like molecules. Evans and co-
workers have demonstrated that [Cu(S,S)-t-Bu-Box
(1)](OTf)2 catalyzed asymmetric hetero Diels–Alder
reactions (inverse electron demand heterocycloadditions
of vinyl ethers and unsaturated ketoesters) generates a
dihydropyran core with up to three chiral centers in a
single operation (Scheme 2).9
In summary, we have developed an efficient synthetic
method for the preparation of Inda-Box (2) and shown
that the Inda-Box–Cu(OTf)2 complex catalyzes hetero
Diels–Alder reactions with polymer-supported vinyl
ethers to afford dihydropyrancarboxylic acid derivatives
with excellent diastereo- and enantioselectivities. Other
asymmetric reactions on the polymer support promoted
by Inda-Box–metal complex are currently under inves-
tigation.16
Procedure for the synthesis of (1R,2S)-Inda-Box (2). To a
stirred solution of (1R,2S)-1-amino-2-indanol (90 g,
0.604 mol) in CH2Cl2 (1 L) was added triethylamine
(336 mL, 2.56 mol, 4 equiv). At 0 °C, a solution of di-
methylmalonyl chloride (42.4 mL, 0302 mol, 0.5 equiv)
in CH2Cl2 (150 mL) was added slowly via a dropping
funnel. The reaction mixture was stirred at 0 °C for 2 h
and warmed to ambient temperature. After being stirred
for 6 h, the reaction mixture was acidified with 1 N HCl.
The water phase was extracted with CH2Cl2. The com-
bined organic extracts were washed with aq NaHCO3,
brine, dried over Na2SO4, and concentrated in vacuo to
give a crude mixture. Ti(OiPr)4 (97%, 712 mL, 2.42 mol,
4 equiv) was added into the crude dihydroxy malono-
diamide 5 and the reaction mixture was stirred for
Toward the construction of dihydropyrancarboxylic
acid derivatives possessing 4S and 6S stereochemistries,
we examined the hetero Diels–Alder reactions in solu-
tion using (1R,2S)-Inda-Box (2) and Cu(OTf)2. More
than 10 different heterodienes were tested and repre-
sentative examples are summarized in Scheme 3. The
reaction of 6a and 6b with 7 (5 mol % catalyst) afforded
R1
*
R1
O
R2
Chiral Lewis acid
R2
*
i
+
145 °C for 8 h while PrOH was removed via a Dean–
1
PO
*
PO
O
OR3
OR3
Stark trap during the reaction. The reaction was cooled
to ambient temperature and 3-(dimethylamino)-1,2-
propanediol (344 mL, 2.90 mol, 1.2 equiv to Ti) was
added. After 30 min, EtOAc (1 L) and water (1 L) were
added and the reaction mixture was stirred for an ad-
ditional 30–60 min (the white suspension became com-
O
O
Dihydropyrancarboxylic acid
derivative
P: Protecting group
Scheme 2.

M. Kurosu et al. / Tetrahedron Letters 45 (2004) 145–148
Table 1. Hetero Diels–Alder reaction with polymer-supported vinyl ethersa
147
R1
R1
ligand (2)-Cu(OTf) 2
O
R2
AllylO
O
R2
MS 3A
O
CH2Cl2, 0oC
AllylO
O
O
O
O
10a-jd
O
6a-j
9a-c
Entry
1
R1
R2
Endo/exob
12:1
Ee (%)c
95
(CH2)4
9a
Br
6a
Br
(CH2)4
9a
2
3
13:1
12:1
95
90
6b
(CH2)2
Ts
(CH2)2
9b
N
6c
NAlloc
4
15:1
87
6d
NAlloc
9c
(CH2)4
7a
5
6
12:1
14:1
85
98
S
6e
6f
OAlloc
9c
(CH2)2
Ts
7
8
10:1
10:1
86
95
(CH2)2
9b
N
6g
OAlloc
O
O
6h
9c
Ac
N
86
98
9
12:1
10:1
(CH2)4
9a
6i
Ph
O
N
10
(CH2)4
9a
N
Me
6j
Me
a All reactions were carried out using 100 mol % of (1R,2S)-Inda-Box (2) and Cu(OTf)2 for 12 h. De and ee were determined with alcohols after
cleaving from polymer support.
b De was determined by 1H NMR.
c Ee was established by chiral HPLC.
dThe absolute chemistry of the products was assigned by chemical correlation with reported stereochemistry.9
pletely soluble). The water phase was extracted with
EtOAc and the combined extracts were dried over
Na2SO4, and concentrated in vacuo to give crude 2. This
was recrystallized from CH3CN (twice) to give 2 as a
General procedure for hetero Diels–Alder reactions on
polymer-supported vinyl ethers. One lantern (20–30
lmol), heterodiene (1.2 equiv), and MS 3A (50 mg) were
placed in a flask and CH2Cl2 (1 mL) was added. The
reaction mixture was agitated for 30 min at ambient
temperature and then cooled to )78 °C. A 1:1 mixture of
fine white powder (100 g, 93%). ½aŠ +430 (c 0.6, CHCl3,
D
23 °C).

148
M. Kurosu et al. / Tetrahedron Letters 45 (2004) 145–148
6. For an improved procedure;see: Evans, D. A.;Peterson,
G. S.;Johnson, J. S.;Barners, D. A.;Campos, K. R.;
Woerpel, K. A. J. Org. Chem. 1998, 63, 4541.
7. Ghosh, A. K.;Mathivanan, P.;Cappello, J. Tetrahedron
Lett. 1996, 37, 3815–3818;Davies, I. W.;Gerena, L.;Cai,
D.;Lasen, R. D.;Vehoeven, T. R.;Reider, P. J.
Tetrahedron Lett. 1997, 38, 1148.
8. Barners, D. M.;Ji, J.;Fickes, M. G.;Fitzgerald, M. A.;
King, S. A.;Morton, H. E.;Plagge, F. A.;Preskill, M.;
Wagaw, S. H.;Wittenberger, S. J.;Zhang, J. J. Am. Chem.
Soc. 2002, 124, 13097–13105.
(1R,2S)-Inda-Box (2) and Cu(OTf)2 generated in
another flask (0.1 M in CH2Cl2, 0.2–0.3 mL) was added
to the reaction mixture. This mixture was allowed to
cool to 0 °C and shaken for 12 h. The lantern was wa-
shed with THF, THF–water (3:1), THF, and EtOAc.
The dihydropyrancarboxylate was cleaved from the
lantern under a buffered HF–pyridine (70% HF–pyri-
dine/pyridine/THF ¼ 1:1:1, 0.6 mL) for 1.5 h and quen-
ched with TMSOMe (1.2 mL) for 30 min. Diastereo- and
enatioselectivities of the product were determined by 1H
NMR and chiral HPLC (Chiralcel OD and Chiralcel
OJ), respectively (see Table 1).
9. Evans, D. A.;Johnson, J. S.;Olhava, E. J. J. Am. Chem.
Soc. 2000, 122, 1635–1649.
10. Stavenger, R. A.;Schreiber, S. L. Angew. Chem., Int. Ed.
2001, 40, 3417–3421.
}
11. Muller, D.;Umbricht, G.;Weber, B.;Pfaltz, A.
Chim. Acta 1991, 74, 232–241.
Helv.
12. Davies, I. W.;Gerena, L.;Lu, N.;Larsen, R. L.;Reider,
P. J. J. Org. Chem. 1996, 61, 9629–9630.
Acknowledgements
13. 3-(Dimethylamino)-1,2-propanediol is commercially
available from TCI.
Drs. Yun Gao, Lin Yu, and Mr. Nii Koney are grate-
fully acknowledged for the syntheses of the hetero-
dienes. We also thank Dr. John A. Tallarico, Professors
Matthew D. Shair and Stuart L. Schreiber for their
useful discussions.
14. Schreiber, S. L. Science 2000, 287, 1964–1969.
15. (a) LanternTM (trademark of Mimotopes Pty, Ltd) is
cylindrical in appearance and a polystyrene grafted
surface. We utilized L-series lanters (height: 5 mm, dia-
meter: 5 mm, surface area: 1.7 cm2). The general loading
for this type of L-series lantern is 15–20 lmol;for more
information, see http://www.mimotopes.com;(b) Talla-
rico, J. A.;Depew, K. M.;Pelish, H. E.;Westwood, N. J.;
Lindsley, C. W.;Shair, M. D.;Schreiber, S. L.;Foley, M.
A. J. Comb. Chem. 2001, 3, 312–318,
References and Notes
1. (a) Lowenthal, R. E.;Abiko, A.;Masamune, S. Tetra-
hedron Lett. 1990, 31, 6005–6008;(b) Lowenthal, R.;
Masamune, S. Tetrahedron Lett. 1991, 32, 7373–7376.
2. Ghosh, A. K.;Mathivanan, P.;Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1–45.
1) 3-4% TfOH / CH2Cl2
Si
R2
Si
O
O
2)
OH
R2
2,6-lutidine
MeO
15~20 µmol
O
3. Davies, I. W.;Gerena, L.;Castonguay, L.;Senanayake,
C. H.;Larsen, P. D.;Verhoevn, T. R.;Reider, P. J. Chem.
Commun. 1996, 1753–1754.
4. Johnson, J. S.;Evans, D. A. Acc. Chem. Res. 2000, 33,
325–335.
5. The price of D-tert-leucine is approximately $215.00 per
.
16. Inda-Box would be applied to many other asymmetric
reactions as a replacement of t-Bu-Box ligand because of
its conformationally constrained structure, see: Ghosh, A.
K.;Mathivanan, P.;Cappiello, J. Tetrahedron Lett. 1996,
37, 3815.
gram (Fluka).