Scalable synthesis of a new enantiomerically pure π-extended rigid amino indanol

Article abstract of DOI:10.1016/j.tetlet.2011.10.144

A convenient route to a benzo-fused amino indanol chiral controller is disclosed. The synthesis is based on a newly optimized entry to 3H-benz(e)indene that can be performed on decagram scale with no purification of intermediates. Subsequent oxidation, classical resolution, and Ritter steps give the target synthon in >98% ee. The resolution features (S)-naproxen as an inexpensive and highly crystalline resolving agent. Conversion of the amino alcohol to its bis(oxazolinyl)-propane is also reported. A solid state structure of the CuCl₂-box complex shows preservation of the distorted square planar geometry found in the parent CuCl₂(indanyl-box) despite greater steric crowding by the blocking groups.

Full text of DOI:10.1016/j.tetlet.2011.10.144

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Tetrahedron Letters 53 (2012) 15–18
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Scalable synthesis of a new enantiomerically pure
indanol
p-extended rigid amino
⇑
Victor L. Rendina, Samantha A. Goetz, Angelika E. Neitzel, Hilan Z. Kaplan, Jason S. Kingsbury
Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient route to a benzo-fused amino indanol chiral controller is disclosed. The synthesis is based
on a newly optimized entry to 3H-benz(e)indene that can be performed on decagram scale with no
purification of intermediates. Subsequent oxidation, classical resolution, and Ritter steps give the target
synthon in >98% ee. The resolution features (S)-naproxen as an inexpensive and highly crystalline resolv-
ing agent. Conversion of the amino alcohol to its bis(oxazolinyl)-propane is also reported. A solid state
structure of the CuCl2–box complex shows preservation of the distorted square planar geometry found
in the parent CuCl2(indanyl-box) despite greater steric crowding by the blocking groups.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 22 September 2011
Revised 20 October 2011
Accepted 26 October 2011
Available online 31 October 2011
Keywords:
Bis(oxazoline)
Amino indanol
Asymmetric catalysis
Ritter reaction
3H-Benz(e)indene
Chiral vicinal amino alcohols, both natural and fully synthetic,
represent an exceptionally important class of small molecules.
Amino alcohols have long been utilized in asymmetric catalysis
as ligands themselves1 or as precursors to various ligand classes.2
As chemists continue to expand the scope of available catalytic
enantioselective transformations, the need for new and rationally
designed synthetic amino alcohols is justified. The cis-substituted
amino indanol 1 (Chart 1), for instance, was first developed as a
subunit of the orally active HIV protease inhibitor indinavir3 (Crixi-
vanÒ). Davies, Senanayake, and others in process research at Merck
went on to establish the derived oxazolidinone (2) and 2,20-
bis(oxazoline)alkanes4 such as 3 as highly effective and tunable
chiral controllers for catalytic Diels–Alder reactions.5 The superior-
ity of these systems relative to those based on (–)-phenyl-glycinol
draws from the fact that the indane ring prevents free rotation
about the C–Ph bond, enforcing conformational rigidity.6 Herein,
we report a practical synthesis of the p-extended amino indanol
4 and the solid state structure of its corresponding 2,20-bis(oxazoli-
nyl)propane bound to CuCl2.
Scheme 1 shows a retrosynthesis for the new
p-extended box
ligand 5. The required 3H-benz(e)indene (6) is a known material,
but it forms in low yield as a byproduct of the pyrolysis of 20-meth-
ylbiphenyl-2,3-dicarboxylic anhydride.7 As such, it seemed
appropriate to target 6 more efficiently by a simple reduction–
elimination sequence on the known ketone 7. In opening attempts
to prepare 7 in one flask from acryloyl chloride and naphthalene by
tandem AlCl3-mediated Friedel–Crafts acylation and Nazarov cycli-
zation,8 tedious column chromatography was needed and the yield
was only modest. Other literature procedures9 called for expensive
starting materials and did not scale well in our hands. Therefore, an
alternative route was developed from inexpensive 2-methylnaph-
O
H3C CH3
NH2
CH3
NH2
CH3
N
H3C
O
O
O
OH
H
N
O
O
7
6
OH
4
N
N
N
O
2
1
NH2
3
OH
4
Chart 1.
5
⇑
Corresponding author. Tel.: +1 617 552 8543; fax: +1 617 552 2705.
E-mail address: jason.kingsbury@bc.edu (J.S. Kingsbury).
Scheme 1. Synthetic strategy
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.144

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
16
V. L. Rendina et al. / Tetrahedron Letters 53 (2012) 15–18
Br
O
HO
a) NBS, AIBN, PhH, 80 °C
d) No solvent, 160 °C
e) SOCl2, 70 °C
HO2C
CO2H
b)
MeO2C
THF
CO2Me, NaH,
CH3
f) AlCl3, CH2Cl2,
g) LAH, THF;
h) NBS
c) KOH, MeOH, 65 °C
(49%, 3 steps)
–78 °C to 23 °C
1 N HCl, 90 °C
(85%)
THF–H2O
(76%, 3 steps)
(99%)
8
7
6
( )-9
O
H
N
(32% overall, no
chromatography)
i) DMAP,
DCC, CH2Cl2, (34%)
(S)-naproxen
Br
H3C
R
R
11
H3CO
2Cl
NH2 NH2
O
O
O
Br
Br
O
OH
l)
k) H2SO4, CH3CN,
CH2Cl2, 0 °C;
N
N
EtO OEt,
H2N
HO
Et3N, CH2Cl2, 40 °C
j) BH3 DMS,
CH3
m) NaH, CH3I, 0 °C
(58%, 2 steps)
then H2O, 60 °C
(68%)
THF, 70 °C
(91%)
(R = H)
12
5 (R = CH3)
(R,S)-4
(R,R)-9 (>98% ee)
(–)-10 (>98% dr)
Scheme 2.
thalene. As we demonstrate below, a convenient and scalable
seven-step preparation of 6 precedes its conversion to enantiopure
4 by the resolution of a naproxen ester and subsequent Ritter reac-
tion. Conversion to bis(oxazoline) 5 then proceeds via its des(di-
methyl) variant following standard procedures.
The path of synthesis is illustrated in Scheme 2. Radical mono-
bromination, displacement of the crude bromide with the sodium
salt of dimethyl malonate, and basic hydrolysis affords the homo-
benzylic diacid 8 in a 49% yield.10 Cationic cyclization9c to give 7 is
possible in one step using molten H3PO4/P2O5, but the yield is
variable (30–76%) due to competitive oligomerization. In practice,
we found it preferable to accomplish the transformation by the
sequence: (1) thermal decarboxylation, (2) chlorination, and (3)
Friedel–Crafts ring closure (8 ? 7, 76% yield). In just six steps
requiring no purification of intermediates, ketone 7 can be ob-
tained on decagram scale in an overall 37% yield and >95% purity
as judged by 1H NMR analysis. Reduction and acid-mediated
elimination in the same vessel provides the target hydrocarbon
(3H-benz(e)indene, 6) in an 85% yield as a white crystalline solid
after simple filtration through a pad of silica gel.
Figure 1. X-ray crystal structure of naproxen ester (–)-10.
An initial plan to use the Jacobsen epoxidation11 for the control
of absolute stereochemistry was complicated by the propensity for
racemic epoxide (from m-CPBA/NaHCO3 or DMDO) to undergo
spontaneous ring opening/1,2-rearrangement to the homobenzylic
cyclopentanone (not shown). Alternative strategies based on cata-
lytic enantioselective dihydroxylation12 or diboration13 could be
applicable, but experimentation with racemic material quickly
established chiral esters of bromohydrin 9 as highly crystalline.
Thus, indene oxidation with NBS in THF-water (quantitative) and
coupling with (S)-naproxen under standard conditions gives a
mixture of diasteromeric esters from which (–)-10 crystallizes in
a 34% yield as a single diastereomer. Naproxen was selected as a
resolving agent because of the trivial means by which multigram
quantities of enantiopure material can be obtained from over-
the-counter pain relief tablets.14 Absolute configuration in (–)-10
has been unequivocally assigned by X-ray diffraction (Fig. 1).
Among several different hydrolytic conditions tested, cleavage
of the resolving agent was best achieved by borane reduction to
give the desired (R,R) bromohydrin 9 in a 91% yield with >98% ee
by chiral SFC (supercritical fluid chromatography). This material
was then subjected to a Ritter reaction15 to afford (R,S)-4 cleanly
in a 68% yield after an acid/base extraction procedure. The modest
yield is accounted for by the recovery of cis-acetamide 11 (in a >2:1
ratio in favor of amino alcohol 4). Noteworthy is that acetamide
hydrolysis does not occur in the absence of the vicinal hydroxyl
O
H
N
(R,R)-9
Br
OH
H2N
H2SO4
H3C
versus
(1:2 ratio)
H2O
Br
HSO4
11
Br
(R,S)-4
H3C
N
H3C
HN
H2O,
CH3CN
Br
O
O
H
H2O
Scheme 3. Ritter reaction mechanism and co-production of amide 11.
functionality. As illustrated below in Scheme 3, the byproduct
likely forms as a result of non-stereospecific trapping of the ben-
zylic cation by acetonitrile and subsequent failure to undergo
intramolecular closure to the intermediate oxazoline. The added
stability gained by transient bromonium ion formation – a key
feature for stereocontrol in this reaction – is offset by enhanced
delocalization of the cation within the naphthalene ring. Co-pro-
duction of acetamide 11, together with the aforementioned facile
rearrangement of epoxy-6, lends support to this hypothesis.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
V. L. Rendina et al. / Tetrahedron Letters 53 (2012) 15–18
17
10.66°, respectively, from a central plane of reference chosen as
N(2)–Cu–N(1). This likely reflects the modest ability of the two
oxazoline rings to relax into conformations that help to relieve
steric hindrance and situate the benzo(indane) subunits farther
from the metal center. Whether or not these features can translate
into improved enantioselectivities or nonconventional modes of
substrate approach for various copper-catalyzed transformations
is an interesting prospect for future study. The application of box
ligand 5 to our Sc-catalyzed asymmetric
a
-arylation method17 is
currently under investigation and results will be forthcoming.
In summary, we have described an efficient and scalable entry
to the (R,S) enantiomer of p-extended amino indanol 4 and its con-
version to bis(oxazolinyl)propane 5. Such C2-symmetric box
ligands continue to attract interest as mainstream chiral ligands
for asymmetric catalysis.18 Noteworthy features of our strategy
include a minimal use of chromatography, the application of (S)-
naproxen found in commercial pain relief tablets as an inexpensive
and highly crystalline resolving agent, and improved synthetic ac-
cess to the key benzo(indane) intermediate 6, which could be of
use in preparing other ligand constructs. We hope that this new
amino alcohol will find use in asymmetric synthesis or potentially
in other broader areas of chemistry.
Acknowledgments
We thank the ACS Petroleum Research Fund (#5001009) and
Boston College for generous support of our program. B.C. mass
spectrometry and X-ray crystallographic facilities are supported
by grants from the NSF (DBI-0619576 and CHE-0923264,
respectively). Dr. Bo Li is acknowledged for performing X-ray anal-
yses. Samantha A. Goetz is a 2011 John Kozarich Fellow.
Figure 2. ORTEP of the complex between CuCl2 and box ligand 5.
Our experience with the synthesis of bis(oxazolinyl)methanes
shows that the diethoxyimidate methodology of Davies et al.5c
allows expedient access to the unsubstituted box framework. Cou-
pling of amino alcohol 4 with commercially available diethyl malo-
nimidate dihydrochloride furnishes box ligand 12 in a 63% yield as
a white flocculent solid after washing with hexanes and methanol.
Deprotonation with sodium hydride and subsequent trapping with
methyl iodide leads to the target gem-dimethylated ligand 5 in a
92% yield after a hexanes wash.
For further proof of structure and to confirm that 5 can act as a
viable chiral ligand, we turned to copper(II) salts. Suitable single
crystals of CuCl2ꢀ5 were obtained by vapor diffusion of pentane
into a saturated dichloromethane solution. As shown in Figure 2,
X-ray diffraction reveals a four-co-ordinate, 17-electron complex
flanked by sizeable naphthalene units and distorted square planar
geometry. Importantly, there is considerable homology between
this structure and the analogous CuCl2(indanyl-box) catalyst with
regard to the disposition of groups around the copper(II) center.16
Some comparative structural data for each complex are provided in
Table 1. One striking similarity is the extent of distortion from an
ideal square plane, which in the solid state corresponds to a 0°
angle between the Cl(1)–Cu–Cl(2) and bis(oxazoline)–Cu planes.
Jørgensen16 has taken the value [90°–(the C(17)–C(15)–Cu–Cl(1)
dihedral angle)] (or its symmetry equivalent, see final column of
Table 1) as a measure of this distortion; in both structures it lies
between 41° and 46°. It therefore appears that the larger blocking
groups have a negligible effect on the local bonding arrangement at
copper. There is, however, noticeable distortion more proximal to
their site of attachment. In particular, the planes defined by
C(18)–N(2)–C(31) and C(1)–N(1)–C(14) are offset by ꢁ9.65° and
Supplementary data
Crystallographic data (excluding structure factors) for the two
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 844999 and 845000. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.10.144.
References and notes
1. (a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823; (b) Kitamura, M.; Suga,
S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071; (c) Kitamura, M.;
Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028.
2. Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
3. Senanayake, C. H. Aldrichimica Acta 1998, 31, 3.
4. For pioneering studies in this area, see: (a) Lowenthal, R. E.; Abiko, A.;
Masamune, S. Tetrahedron Lett. 1990, 31, 6005; (b) Evans, D. A.; Woerpel, K. A.;
Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726; (c) Corey, E. J.;
Imai, N.; Zhang, H.-Y. J. Am. Chem. Soc. 1991, 113, 728; (d) Müller, D.; Umbricht,
G.; Weber, B.; Pfaltz, A. Helv. Chim. Acta 1991, 74, 232.
5. (a) Davies, I. W.; Senanayake, C. H.; Castonguay, L.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7619; (b) Davies, I. W.; Senanayake, C.
H.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1996, 37, 1725;
(c) Davies, I. W.; Gerena, L.; Castonguay, L.; Senanayake, C. H.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. Chem. Comm. 1996, 1753; (d) Davies, I. W.; Gerena,
L.; Cai, D.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1997, 38,
1145; (e) Davies, I. W.; Deeth, L.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett.
1999, 40, 1233.
Table 1
Select structural data for chiral CuCl2 complexes of 5 and 3
Cu–N1 (Å)
Cu–N2 (Å)
Cu–Cl1 (Å)
Cu–Cl2 (Å)
C17–C15–Cu–Cl1a (°)
C16–C15–Cu–Cl2a (°)
CuCl2ꢀ5
1.977
1.997
1.975
1.992
2.224
2.234
2.235
2.223
41.9
45.9
41.8
41.0
CuCl2(indanyl-box)b
a
Compiled as 90° – dihedral angle to ensure a 0° value in the square planar case.
Reproduced from Ref. 16.
b

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
18
V. L. Rendina et al. / Tetrahedron Letters 53 (2012) 15–18
6. Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800. See also: Refs. 5a,b,d.
12. (a) Hanessian, S.; Meffre, P.; Girard, M.; Beaudoin, S.; Sancéau, J.; Bennani, Y. J.
Org. Chem. 1993, 58, 1991; (b) Reddy, S. M.; Srinivasulu, M.; Reddy, Y. V.;
Narasimhulu, M.; Venkateswarlu, Y. Tetrahedron 2006, 47, 5285.
13. Trudeau, S.; Morgan, J. B.; Shrestha, M.; Morken, J. P. J. Org. Chem. 2005, 70,
9538.
14. Refer to the Supplementary data for experimental details.
15. Davies, I. W.; Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.
Tetrahedron Lett. 1996, 37, 813.
7. Brown, R. F. C.; Eastwood, F. W.; Smith, C. J. Aust. J. Chem. 1992, 45, 1315.
8. Dietrich, U.; Hackmann, M.; Rieger, B.; Klinga, M.; Leskelä, M. J. Am. Chem. Soc.
1999, 121, 4348.
9. (a) Hulin, B.; Koreeda, M. J. Org. Chem. 1984, 49, 207; (b) Kita, Y.; Higuchi, K.;
Yoshida, Y.; Iio, K.; Kitagaki, S.; Ueda, K.-I.; Akai, S.; Fujioka, H. J. Am. Chem. Soc.
2001, 123, 3214; (c) Wu, X.; Nilsson, P.; Larhed, M. J. Org. Chem. 2005, 70,
346.
10. An, Q.; Li, G.; Tao, C.; Li, Y.; Wu, Y.; Zhang, W. Chem. Comm. 2008, 1989.
11. (a) Palucki, M.; Finney, N. S.; Pospisil, P. J.; Güler, M. L.; Ishida, T.; Jacobsen, E. N.
J. Am. Chem. Soc. 1998, 120, 948; (b) Senanayake, C. H.; Jacobsen, E. N. In Process
Chemistry in the Pharmaceutical Industry; Gadamasetti, K. G., Ed.; Dekker: New
York, 1999; p 347.
16. Thorhauge, J.; Roberson, M.; Hazell, R. G.; Jørgenson, K. A. Chem. Eur. J. 2002, 8,
1888.
17. Rendina, V. L.; Moebius, D. C.; Kingsbury, J. S. Org. Lett. 2011, 13, 2004.
18. Reviews: (a) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106,
3561; (b) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339.