1,1'-Spirobiindane-7,7'-diol: A novel, C2-symmetric chiral ligand

Article abstract of DOI:10.1016/S0957-4166(98)00481-9

A novel, C₂-symmetric chiral diol (16) was prepared in six steps from m-anisaldehyde and resolved via its bis-L-menthoxycarboxylate.

Full text of DOI:10.1016/S0957-4166(98)00481-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 125–131
1,10-Spirobiindane-7,70-diol: a novel, C2-symmetric chiral ligand
Vladimir B. Birman,a,∗ Arnold L. Rheingold b and Kin-Chung Lam b
aDepartment of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
bDepartment of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
Received 5 November 1998; accepted 16 November 1998
Abstract
A novel, C2-symmetric chiral diol (16) was prepared in six steps from m-anisaldehyde and resolved via its
bis-L-menthoxycarboxylate. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Biaryls, most notably 1,10-binaphthalene derivatives (e.g. 11 and 22), occupy a prominent position
among C2-symmetric chiral auxiliaries and ligands for asymmetric synthesis.3 By contrast, spiranes,
another class of molecules with axial chirality,4 have received relatively little attention from the point of
view of ligand design. In fact, only derivatives of cis,cis-spiro[4,4]nonane-1,6-diol 3 appear to have been
employed in asymmetric synthesis.5 Crown ethers incorporating the spirobifluorene moiety (e.g. 4) were
utilized, but only in asymmetric binding studies.6 Despite their limited use, spiranes possess a number of
useful characteristics which make their further exploration worthwhile.
The configurational stability (and therefore, practical utility) of biaryls depends on the restricted
rotation about the central bond and thus, ultimately, on the bulk of the ortho-substituents. By contrast,
spiranes contain a quaternary center, which makes their racemization virtually impossible, regardless of
the substitution pattern. In addition, the spirocyclic framework is considerably more rigid5 than that of
biaryls, since conformational changes involve distortion of the entire molecule, not merely rotation about
∗
Corresponding author. E-mail: vbbirman@rainbow.uchicago.edu
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00481-9

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a single bond. This property may prove useful in designing chiral catalysts, since it can be expected to
minimize the number of possible conformations of the catalytic species.
The structure of 1,10-spirobiindane (5)7a offers a promising combination of chemical robustness and
conformational rigidity. Although a large number of 1,10-spirobiindane derivatives have been prepared7
(e.g. 6,7b 7,7c 87d) and some of them resolved,7c,e,8 their potential in chiral ligand design remains
unexplored. In order to form an efficient chelating agent, 1,10-spirobiindane needs to be substituted with
coordinating groups in positions 7 and 70, i.e. in the ‘bay region’ (cf. 9).
2. Results and discussion
1,10-Spirobiindanes are generally prepared by double cyclization of 1,5-diphenyl-3-pentanone
derivatives.7b–d However, since the condensation tends to occur para, rather than ortho, to the
substituents already present in the aromatic ring, a known literature procedure7c,d was modified in order
to prepare the simplest ‘spiroanalog’ of BINOL, 1,10-spirobiindane-7,70 -diol, 16 (Scheme 1).
Scheme 1.
m-Anisaldehyde was condensed with acetone to produce 1,5-bis-m-anisyl-1,4-pentadien-3-one7c 11,
following a general procedure.9,10 The dienone was hydrogenated (Raney Ni, rt, atmospheric pressure)
to produce virtually pure 1,5-bis-m-anisyl-3-pentanone7c,10 12, which was used directly in the next step

V. B. Birman et al. / Tetrahedron: Asymmetry 10 (1999) 125–131
127
without purification. In order to direct the bis-cyclization ortho- to the methoxy groups, it was necessary
to block the para-positions with removable substituents. This was accomplished by treating crude 12
with bromine in CH2Cl2 in the presence of pyridine. The bis-brominated product 13 was sufficiently pure
for the cyclization step. Cyclization in polyphosphoric acid7d gave crystalline spirobiindane derivative
14.11 Debromination of 14 followed by demethylation afforded racemic 16 in 28% overall yield from
m-anisaldehyde.
Initially, resolution of (ꢀ)-16 was attempted using methods commonly used for BINOL derivatives.
Thus, cyclic phosphoryl chloride (ꢀ)-17 was prepared in quantitative yield by treatment of (ꢀ)-16
with POCl3 and NEt3 (Scheme 2). Addition of lithium (S)-α-phenethylamide produced a mixture of
diastereomeric cyclic α-phenethylphosphamides12 18a and b, inseparable by recrystallization and poorly
separable by chromatography (MPLC). Likewise, attempts to resolve (ꢀ)-16 via the brucine salt of acid
(ꢀ)-19 or via the bis-camphorsulfonate of 16 proved unsuccessful.
Scheme 2.
Gratifyingly, efficient resolution was finally achieved by treating (ꢀ)-16 with L-menthyl chloroformate
and NEt3 (Scheme 3).
Scheme 3.
The resulting diastereomers of 20 were easily separable by flash chromatography: diastereomer 20a
was an oil; 20b was a crystalline compound. The absolute stereochemistry was determined by X-ray
analysis of 20b (S-configuration of the spirobiindane moiety).13,14 Pure enantiomers, (R)-(+)-16 and (S)-
(−)-16, were best obtained by hydrazinolysis of 20a and 20b, respectively. Enantiomerically pure (+)-

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and (−)-16 were efficiently recrystallized from boiling hexanes in which they were less soluble than the
racemate.
Future work concerning the use of 1,10-spirobiindane-7,70 -diol (tentatively named SPINOL) will be
reported in due course.
3. Experimental
3.1. General
Tetrahydrofuran was purified by distillation from potassium/benzophenone ketyl. Dichloromethane
was distilled from calcium hydride. All other reagents were reagent grade and purified where necessary.
Reactions were monitored by thin layer chromatography (TLC) using 250 mm Whatman precoated
silica gel plates. Flash column chromatography was performed over EM Science Laboratories silica
gel (230–400 mesh). Melting points were measured on a Mel-Temp capillary melting point apparatus
1
and are uncorrected. H NMR and 13C NMR spectra were recorded on a Bruker DRX-500 spectrometer
in CDCl3. The chemical shifts are reported as δ values (ppm) relative to TMS. Infrared spectra were
recorded on a Nicolet 20SXB FT-IR spectrophotometer (NaCl plates). Optical rotations were measured
on a Perkin–Elmer 141 polarimeter (Na lamp).
3.2. 1,5-Bis-m-anisyl-1,4-pentadien-3-one7c,9 (11)
A solution of distilled m-anisaldehyde (10.0 g, 73.4 mmol) and acetone (2.70 ml, 36.8 mmol) in 10 ml
of ethanol was added dropwise to a solution of 7.5 g of NaOH in 132 ml of 50% aqueous ethanol, stirring
in a water bath at rt. The mixture was stirred for 2 h, then diluted with CH2Cl2, washed with water, dried
over Na2SO4, and separated by chromatography (hexanes:EtOAc, 5:1) to produce 6.66 g (62% yield) of
slightly contaminated 11 as a yellow oil which solidified on standing.
1H NMR: 3.83 (s, 6H), 6.97 (dd, J=2 Hz, J=8 Hz, 2H), 7.07 (d, J=16 Hz, 2H), 7.14 (m, J=2 Hz, 2H),
7.22 (br d, 8 Hz, 2H), 7.34 (t, 8 Hz, 2H), 7.71 (d, J=16 Hz, 2H); 13C NMR: 55.3, 113.2, 116.3, 121.1,
125.6, 129.9, 136.1, 143.3, 159.9, 188.9; IR (film, cm−1): 1256, 1620, 1652 (dienone).
3.3. 1,5-Bis-m-anisyl-3-pentanone7c,10 (12)
A solution of 11 (1.00 g, 3.4 mmol) in 20 ml of acetone was stirred with Raney Ni (3–4 g) under
an atmosphere of hydrogen at rt, monitoring the reaction progress by TLC and adding more catalyst as
necessary. When the starting material had disappeared (ca. 1 day), the catalyst was filtered off, washed
with acetone, and the filtrate rotary evaporated. The product (0.99 g) was obtained as a colorless oil
containing ca. 2% of the saturated alcohol.
1H NMR: 2.71 (t, J=8 Hz, 4H), 2.86 (t, J=8 Hz, 4H), 3.78 (s, 6H), 6.73 (m, 4H), 7.19 (t, J=8 Hz, 2H);
13C NMR: 29.7, 44.4, 55.1, 111.4, 114.0, 120.6, 129.5, 142.6, 159.7, 209.0; IR (film, cm−1): 1259, 1601,
1713 (C_O).
3.4. 1,5-Bis-(2-bromo-5-methoxyphenyl)-3-pentanone (13)
The crude 12 was dissolved in CH2Cl2, pyridine (1 ml, 12 mmol, 3.5 equiv.) was added, and the
mixture was cooled to −10°C. A solution of bromine in CH2Cl2 (10% v/v, 4.4 ml, 8.6 mmol, 2.5 equiv.)

V. B. Birman et al. / Tetrahedron: Asymmetry 10 (1999) 125–131
129
was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to rt
and stirred until the starting material had disappeared (by NMR, ca. 4 h). The mixture was shaken with
aqueous NaHSO3 to remove excess bromine, washed with dilute HCl and water and dried (Na2SO4).
Evaporation gave 1.48 g of 13 as a light-yellow oil containing ca. 5% impurities by NMR. The product
solidified into a wax on standing.
1H NMR: 2.74 (t, J=8 Hz, 4H), 2.96 (t, J=8 Hz, 4H), 3.81 (s, 6H), 6.63 (dd, J=3 Hz, 9 Hz, 2H), 6.78 (d,
J=3 Hz, 2H), 7.39 (d, J=9 Hz, 2H); 13C NMR: 30.6, 42.5, 55.4, 113.6, 114.6, 116.1, 133.3, 141.2, 159.0,
208.4; IR (film, cm−1): 1241; 1472; 1715 (C_O).
3.5. 4,40-Dibromo-7,70-dimethoxy-1,10-spirobiindane (14)
The crude 13 was stirred with 13 g of polyphosphoric acid at 105°C for 5.5 h. The mixture was poured
into water, extracted with Et2O, then with CH2Cl2. The extract was rotary evaporated with silica gel, and
eluted through a pad of silica gel with hexanes:EtOAc, 9:1. The eluate was evaporated, and the crystalline
residue was recrystallized from hexanes:EtOAc to give 846 mg of 14 (57% for 3 steps). A 65% yield of
1
14 was obtained from chromatographically purified 13. Mp 157–158°C; H NMR: 2.16 (m, 2H), 2.31
(m, 2H), 2.96 (m, 2H), 3.05 (m, 2H), 3.52 (s, 6H), 6.52 (d, J=9 Hz, 2H), 7.26 (d, J=9 Hz, 2H); 13C NMR:
33.1, 37.8, 55.3, 61.8, 110.4, 110.7, 130.3, 138.0, 144.8, 155.5; IR (film, cm−1): 1263, 1471.
3.6. 7,70-Dimethoxy-1,10-spirobiindane (15)
A solution of 14 (1.215 g, 2.773 mmol) in 24 ml of THF in a flame-dried flask, under nitrogen, was
cooled to −78°C and treated with n-BuLi (4.4 ml, 2.5 M solution in hexanes, 4 equiv.). After 1 h, the
reaction mixture was quenched by addition of 1 ml of EtOH, worked up with CH2Cl2 and water, and
dried (Na2SO4). The solution was evaporated, and the residue was recrystallized from hexanes to give
726 mg of the product (93% yield).
Mp 139–140°C; 1H NMR: 2.16 (m, 2H), 2.32 (m, 2H), 2.99 (m, 2H), 3.03 (m, 2H), 3.52 (s, 6H), 6.62
(d, J=8 Hz, 2H), 6.85 (d, J=8 Hz, 2H), 7.12 (t, J=8 Hz, 2H); 13C NMR: 31.6, 38.8, 55.2, 59.2, 108.6,
116.8, 127.5, 136.9, 145.3, 156.5; IR (film, cm−1): 772.
3.7. rac-1,10-Spirobiindane-7,70 -diol (16)
A solution of 15 (759 mg, 2.71 mmol) in 12 ml of CH2Cl2 in a flame-dried flask, under nitrogen,
was cooled to −78°C, treated with 1 M BBr3 in CH2Cl2 (6.2 ml, 2.3 equiv.) and allowed to warm to
rt overnight. The reaction mixture was diluted with CH2Cl2 and washed with water until washings had
neutral reaction. The solution was dried (Na2SO4), evaporated, and the residue was recrystallized from
hexanes to give 582 mg of the product (85% yield).
Mp 115–116°C; 1H NMR: 2.19 (m, 2H), 2.30 (m, 2H), 3.03 (m, 4H), 4.61 (s, 2H), 6.68 (d, J=8 Hz,
2H), 6.89 (d, J=8 Hz, 2H), 7.17 (t, J=8 Hz, 2H); 13C NMR: 31.2, 37.4, 57.4, 114.3, 117.7, 129.9, 130.4,
145.8, 152.9; IR (film, cm−1): 778, 1463, 1586, 3524 (O–H).
3.8. 7,70-Bis-(L-menthyloxy-carbonyloxy)-1,10 -spirobiindane (20a and 20b)
L-Menthyl chloroformate (1.7 ml, 7.93 mmol, 2.43 equiv.) was added to a stirring solution of rac-16
(822 mg, 3.26 mmol), NEt3 (1.7 ml, 12.2 mmol, 3.74 equiv.), and DMAP (40 mg, 0.33 mmol, 0.1 equiv.)
in 33 ml of CH2Cl2 under nitrogen. After stirring for 9 h at rt, the mixture was washed with water, dilute

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HCl, and brine. The solution was dried (Na2SO4), evaporated, and the residue was chromatographed (3%
Et2O in hexanes, 7 inch silica gel column) to give 956 mg of pure 20a as a colorless oil (95% yield), 852
mg of pure crystalline 20b (85% yield), and 168 mg of mixed fractions from which additional 20b could
be obtained by recrystallization from hexanes.
20a: 1H NMR: 0.68 (d, 6H), 0.81 (m, 4H), 0.83 (d, 6H), 0.90 (d, 6H), 0.94 (m, 2H), 1.24 (m, 2H), 1.40
(m, 2H), 1.59 (m, 4H), 1.75 (m, 2H), 1.84 (m, 2H), 2.24 (m, 2H), 2.36 (m, 2H), 3.05 (m, 4H), 4.30 (ddd,
2H), 6.95 (d, J=8 Hz, 2H), 7.07 (d, J=8 Hz), 7.18 (t, J=8 Hz, 2H); 13C NMR: 16.1, 20.8, 22.0, 23.0, 25.5,
31.19, 31.24, 34.0, 38.8, 40.2, 46.5, 59.1, 78.6, 120.0, 122.1, 128.0, 139.0, 145.8, 147.7, 152.7; IR (film,
cm−1): 1231, 1755 (C_O).
20b: mp 185.5–186°C; 1H NMR: 0.67 (d, 6H), 0.81 (m, 4H), 0.82 (d, 6H), 0.88 (d, 6H), 0.90 (m, 2H),
1.21 (m, 2H), 1.37 (m, 2H), 1.51 (m, 2H), 1.58 (m, 4H), 1.87 (m, 2H), 2.96 (m, 2H), 3.01 (m, 2H), 4.35
(ddd, 2H), 6.92 (d, J=8 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 7.19 (t, J=8 Hz, 2H); 13C NMR: 16.0, 20.7, 21.9,
23.0, 25.5, 31.1, 31.3, 34.0, 38.3, 40.4, 46.7, 58.9, 78.6, 120.4, 122.2, 128.0, 139.2, 145.6, 147.5, 153.2;
IR (film, cm−1): 1237, 1268, 1755 (C_O).
3.9. (S)-(−)- and (R)-(+)-1,10-Spirobiindane-7,70 -diol ((S)-(−)-16 and (R)-(+)-16)
A solution of 20b (712 mg, 1.15 mmol) and 0.4 ml of hydrazine hydrate in 7.5 ml of THF was refluxed
under nitrogen for 2 h. The mixture was diluted with CH2Cl2, washed with dilute HCl, water, and dried
(Na2SO4). Chromatography (hexanes:EtOAc, 6:1) followed by recrystallization from boiling hexanes
afforded 266 mg of (S)-(−)-16 as fine needles (91% yield). The opposite enantiomer, (R)-(+)-16, was
obtained analogously from 20a in 86% yield. The enantiomers were less soluble in hexanes than the
racemate. Repeated recrystallization did not raise the melting point.
(S)-(−)-16: mp 155–156°C; [α]D25=−32.7 (c 1.0, CHCl3); (R)-(+)-16: mp 155.5–156°C; [α]D25=+32.5
(c 1.0, CHCl3).
Acknowledgements
VBB is grateful to his Graduate Advisor, Professor V. H. Rawal, for his support and useful discussions
on this project. This work was sponsored in part by a GAANN Fellowship (Department of Education).
References
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8. Kazlauskas, R. J. J. Am. Chem. Soc. 1989, 111, 4953.
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10. Although preparation of 1,5-bis-m-anisyl-3-pentanone via this route has been described,7c difficulties were encountered
in repeating the condensation step according to the published procedure. In addition, reduction with Raney nickel as a
catalyst proved to be more convenient than with Pd/C, causing very little over-reduction to the alcohol and thus obviating
the need for purification.
11. An alternative cyclization method (POCl3, SnCl4, PhH, reflux)7e afforded, at best, 39% yield.
12. Gong, B.-Q.; Chen, W.-Y.; Hu, B.-F. J. Org. Chem. 1991, 56, 423.
13. Although spiranes possess axial symmetry, for purposes of nomenclature they are treated as having a chiral center.4
Configurationally, (S)-(−)-SPINOL corresponds to (R)-(+)-BINOL.
14. Correspondence regarding the X-ray data should be addressed to Professor Arnold L. Rheingold, University of Delaware.