Org. Synth. 2002, 79, 72
DOI: 10.15227/orgsyn.079.0072
ASYMMETRIC SYNTHESIS OF (M)-2-HYDROXYMETHYL-1-(2-HYDROXY-4,6-DIMETHYLPHENYL)NAPHTHALENE
VIA A CONFIGURATIONALLY UNSTABLE BIARYL LACTONE
[
2-Naphthalenemethanol, 1-(2-hydroxy-4,6-dimethylphenyl)-, (R)-
]
Submitted by Gerhard Bringmann
1
, Matthias Breuning, Petra Henschel, and Jürgen Hinrichs.
Checked by Peter M. Greenen and Dennis P. Curran.
1. Procedure
A.
3,5-Dimethylphenyl
1-bromo-2-naphthoate
(
3
)
. Under a nitrogen
atmosphere, a 250-mL, oven-dried, round-bottomed flask containing
anhydrous dichloromethane (100
mL) is charged with
1-bromo-2-naphthoic
acid (1, 2.51 g, 10.0 mmol),
3,5-dimethylphenol (2, 1.23
g, 10.1 mmol),
dicyclohexylcarbodiimide
(DCC, 2.26
g, 11.0 mmol), and
4-(dimethylamino)pyridine
(DMAP, 244
mg, 2.00 mmol)
(Note 1). After
the mixture is stirred for 12 hr at room temperature, the white precipitate that forms
(Note 2) is discarded by filtration through a Buchner
funnel. From the clear filtrate, the solvent is removed by rotary evaporation
(35°C, 720 mbar, 540 mm) to give a colorless solid. Filtration through a short
silica gel column (5 × 40-cm column, silica gel 0.063
- 0.2 mm, 150 g
; eluent:
hexane
/ diethyl ether 5:1) delivers 3.35 g (94%)
of the ester 3, which is recrystallized from
diethyl
ether
/
hexane
to give 3.28 g (92%) of a colorless solid (Note 3).
B.
1,3-Dimethyl-6H-benzo[b]naphtho[1,2-d]pyran-6-one
(
4
)
. Under an argon atmosphere,
a 250-mL, oven-dried, round-bottomed flask, equipped with a
reflux condenser, is charged with freshly distilled
N,N-dimethylacetamide
(DMA, 130 mL),
3,5-dimethylphenyl
1-bromo-2-naphthoate (3, 3.24 g, 9.12 mmol),
palladium(II) acetate
(205 mg, 0.913 mmol),
triphenylphosphine
(481 mg, 1.83 mmol), and
sodium
acetate (1.50 g, 18.3 mmol) (Notes
4 and 5).
The orange suspension is degassed three times, placed in a preheated (130°C)
oil bath
(Note 5), and stirred at 130°C for 12
hr (Note 6). Removal of the solvent at 40°C (0.1 mbar, 0.075
mm) gives a black oily residue, which is chromatographed (5 × 40 cm column,
silica gel 0.063 - 0.2 mm, 170 g
,
1 cm of charcoal at the top of the column; eluent:
hexane
/ diethyl ether 5:1), to yield 2.00 g (80%)
of the lactone 4 as a slightly yellow solid. Recrystallization from
diethyl ether
/
hexane
delivers 1.63 g (65%) of colorless or pale yellow crystals (Note 7).
C.
(M)-2-Hydroxymethyl-1-(2-hydroxy-4,6-dimethylphenyl)naphthalene
[(M)-
6
]
(Note 8). Under an argon atmosphere, an
oven-dried Schlenk tube is charged with the CBS-catalyst
(S)-5 (1.0 M in toluene, 8.39 mL, 8.39
mmol)
(Note 9). The solvent is removed under
high vacuum (0.1 mbar. 0.075 mm) at room temperature and
tetrahydrofuran
(THF, 110 mL)
(Note 9) is added.
After the solution is cooled to 0°C, it is treated with the
borane-THF
complex
(1.0 M in THF, 10.1 mL, 10.1 mmol)
(Note 9) and stirred at room temperature for 30 min. This reagent and
a solution of the lactone 4 (1.84 g,
6.71 mmol) in THF (110
mL) are added simultaneously from two dropping funnels into an
oven-dried, round-bottomed, three-necked flask containing THF (110 mL) at a temperature of 30°C
over a period of 2 hr (Note 10). After the reaction mixture is
stirred for another 30 min, it is adjusted to pH 4 by careful addition of
hydrochloric acid (2.0 M). Water (20
mL) is added, the organic solvent is removed by rotary evaporation (40°C / 350
mbar, 263 mm), and the remaining aqueous phase is extracted with
diethyl
ether (4 × 100 mL)
(Note 11).
The combined organic layers are dried over
magnesium
sulfate (MgSO4). Removal of the solvent by rotary
evaporation and filtration through a short silica gel column (5
× 40-cm column, silica gel 0.063 - 0.2 mm, 100 g
; eluent:
hexane / diethyl ether
1:1) gives 1.83 g (98%) of the biaryl alcohol (M)-6
as a slightly yellow solid with 92% ee (Notes 12
and 13). Crystallization from
diethyl
ether
/
hexane
delivers 1.53 g (82%) of colorless crystals with >99% ee (Notes 14 and 15).
2. Notes
1.
1-Bromo-2-naphthoic acid
(1, 98%, Sigma Chemical Co.),
3,5-dimethylphenol (2, >98%,
Merck-Schuchard),
1,3-dicyclohexylcarbodiimide
(DCC, 99%, Merck-Schuchard), and
4-(dimethylamino)pyridine (DMAP, 99%,
Aldrich Chemical Co., Inc.) were used as received.
Dichloromethane
was distilled
from
phosphorus pentoxide
and stored over activated
molecular sieves (4Å).
2.
The precipitate consists of
1,3-dicyclohexylurea
.
3.
The physical properties of
3 are as follows:
mp 85°C; IR
(KBr) cm
−1:
1594, 1618, 1744,
2916, 3060
;
1H NMR (250 MHz, CDCl
3) δ: 2.38
(s, 6 H), 6.95 (s, 3 H), 7.67 (m
c, 2 H),
7.88 (m
c, 3 H), 8.50 (m
c, 1 H)
;
13C NMR (63 MHz,
CDCl
3) δ: 21.30, 119.1, 123.3,
125.9, 127.9, 128.0, 128.0, 128.2,
128.4, 128.7, 130.7, 132.6, 135.4,
139.5, 150.7, 166.0
; HRMS: m/z 354.0257, calcd. for C
19H
15BrO
2:
354.0255
.
4.
Palladium(II) acetate
(98%, Strem Chemicals Inc.),
triphenylphosphine (99%, Fisher
Scientific Co.), and
sodium
acetate (99%, Fluka Chemika)
were used without further purification.
N,N-Dimethylacetamide
(DMA) was distilled from
calcium hydride
through a 25-cm Vigreux column directly before use.
5.
Freshly distilled DMA, a
preheated oil bath,
and the repeated degassing of the reaction mixture are critical to obtain high yields.
6.
The reaction progress can easily be followed by TLC (
silica,
hexane
/ diethyl ether 5:1) due to the brilliant blue fluorescence
of
4 (R
f = 0.30) upon UV excitation at 366 nm.
7.
The physical properties of
4 are as follows:
mp 158°C; IR
(KBr) cm
−1: 1594, 1614, 1721,
2928, 2985, 3055
;
1H NMR (250 MHz, CDCl
3) δ:
2.25 (s, 3 H), 2.46 (s, 3 H), 7.08 (s, 1 H),
7.15 (s, 1 H), 7.56 (m, 1 H), 7.66 (m, 1 H),
7.96 (d, 3 H, J = 8.5 Hz), 8.27 (d, 1 H, J = 8.5 Hz)
;
13C NMR (63 MHz,
CDCl
3) δ: 21.27, 23.77, 114.7,
116.0, 121.2, 124.0, 125.9, 128.1,
128.3, 128.6, 128.8, 128.9, 135.6,
136.3, 136.3, 140.1, 140.2, 151.9,
161.9
; HRMS: m/z
274.0987, calcd. for C
19H
14O
2: 274.0994
.
8.
For the now recommended M/P denotion for axial chirality, see
Helmchen
2.
9.
The
CBS-catalyst [(S)-2-methyl-CBS-oxazaborolidine]
(S)-5 (1.0 M in toluene) (The CBS catalyst
is named after Corey, Bakshi, and Shibata) and the
borane-THF
complex (1.0 M in THF) were obtained from Aldrich Chemical Co.,
Inc.
and used as received. THF was distilled from
potassium
directly before use.
10.
For optimum stereoselectivity, it is critical to control the
temperature of the reaction vessel to exactly 30°C.
11.
For a recovery of
(S)-α,α-diphenylprolinol
,
which is the hydrolysis product of the
CBS-catalyst (S)-5
(and likewise its synthetic precursor
3),
the aqueous phase is carefully adjusted to pH 10 with
concentrated
ammonia
and extracted with
diethyl
ether (3 × 50 mL). The combined organic
layers are washed with
brine (50 mL)
and dried over
MgSO4
. Removal of the
solvent by rotary evaporation yields
1.68
g (
79%) of crude
(S)-α,α-diphenylprolinol
.
This material is dissolved in
dichloromethane
/ methanol 9:1 (3 mL) and filtered
over Alox B (act. III, 80 g) with
dichloromethane
/ methanol 9:1 as the eluent, to yield
1.64 g (
77%)
of
(S)-α,α-diphenylprolinol
as a white solid.
12.
The ee of
6 was determined by HPLC on a chiral phase [DAICEL
Chiralcel OD-H (4.6 mm × 250 mm), detection at 280 nm, flow rate 1.0 mL/min,
eluent:
hexane / isopropyl
alcohol 95:5, retention times: t
R = 16 min for (M)-
6
and t
R = 22 min for (P)-
6].
13.
The analogous reduction of
4 with a catalytic amount of
the
CBS-catalyst (S)-5 (0.1 equiv) and
1.25 equiv of borane
resulted
in the formation of (M)-
6 in a slightly lower ee of 88% (
94% yield). In several cases, over-stoichiometric amounts
of (S)-
5 and BH
3 · THF had to be used to ensure complete
conversion.
4
5
6 Treatment
of
4 with 3 equiv of (S)-
5 and
4 equiv of
the borane complex gave
97% of (M)-
6 with 90% ee.
14.
The almost racemic alcohol
6 obtained from the concentrated
mother liquor can be recycled by a three-step procedure (1. MnO
2, CH
2Cl
2;
2. NaClO
2, H
2NSO
3H, NaOAc,
dioxane
/
acetic acid
/ water; 3.
N-methyl-2-chloropyridinium iodide
,
(n-Bu)
3N, CH
2Cl
2) to give, in a
49% overall yield, the lactone
4, which can then
be ring-opened atropoenantioselectively once again. Alternatively, the recycling can
be done by just oxidizing to the corresponding hydroxy aldehyde, followed by its atropo-enantioselectively
reduction.
4,
7
15.
The physical properties of
6 are as follows:
mp 140°C;
[α]D
23−41.4°
(CHCl3, c 1.02); IR
(KBr) cm
−1: 1572, 1620, 2923,
2986, 3055, 3376
;
1H NMR (200 MHz, CDCl
3) δ:
1.80 (s, 3 H), 2.38 (s, 3 H), 4.52 (m
c,
2 H), 6.73 (s, 1 H), 6.79 (s, 1 H), 7.32-7.55
(m, 3 H), 7.70 (d, 1 H, J = 8.5), 7.92 (m
c, 2
H)
;
13C
NMR (50 MHz, CDCl
3) δ: 19.73, 21.28, 63.70,
114.0, 121.0, 123.4, 125.4, 126.2,
126.5, 126.8, 128.2, 128.9, 131.2,
132.5, 133.5, 137.4, 138.0, 139.2,
153.1
; HRMS: m/z
278.1304, calcd. for C
19H
18O
2: 278.1307
.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The reaction sequence described here provides a simple and efficient route to the
enantiomerically pure axially chiral biaryl alcohol (M)-
6
8 and illustrates the basic strategy
of the 'lactone concept',
9
in which the two crucial steps, the aryl-aryl bond formation and asymmetric induction
at the newly created axis, are performed
consecutively. This stepwise procedure
is quite generally applicable and offers several advantages over other known methods
10 of stereoselective biaryl coupling: The prefixation
of the aryl moieties as esters of type
3 (Scheme 1), which is easily attainable
by standard procedures, allows an intramolecular cross coupling. This coupling reaction
proceeds regioselectively and in high yields, even against severe steric hindrance
(e.g., with a tert-butyl group ortho to the axis).
11
12 As the catalyst, Pd(OAc)
2 or the more effective,
now likewise commercially available Herrmann-Beller palladacycle
7 can be employed.
11,12 The resulting biaryl lactones
4 are helically distorted and thus chiral,
11
but because of the bridging lactone function, which dramatically lowers the atropoisomerization
barrier, they are still configurationally unstable at the axis (An exception is the
sterically highly hindered lactone
4 (R = tBu), which is configurationally
stable at room temperature.), and thus exist as a racemic mixture of their rapidly
interconverting enantiomers (M)-
4 and (P)-
4.
11,
13 This is the fundamental prerequisite for the subsequent
formation of configurationally stable and stereochemically pure biaryl molecules
6
through
oxazaborolidine-mediated dynamic kinetic resolution
8,12 (see Scheme 1).
Scheme 1
In the stereochemically deciding key step, cleavage of the lactone bridge can also
be performed atropo-diastereo- or -enantioselectively with a wide range of chiral
O-,
14 N-,
15 or other
H-
16 nucleophiles to give the ring-opened,
and now configurationally stable, axially chiral biaryls in high optical and chemical
yields. In each case, the stereochemically pure biaryls can be obtained by crystallization
or, if diastereomers are formed, by chromatographic separation. Two examples are illustrated
in Scheme 2 with
4 (R = Me) as the biaryl lactone.
Scheme 2
Since, for all the chiral ring cleavage reagents [(S)-
5, (R)-
10,
and (S)-
11] used, both enantiomers are commercially available, both atropoisomeric
biaryls are readily accessible from the same lactone precursor
4, which allows
flexible atropo-divergent
9 syntheses.
14,15 Furthermore, for precious material prepared in the course of
multi-step synthesis, even the minor, undesired atropoisomer, if formed at all in
significant quantities, is not lost, but can be recycled, either by acid catalyzed-
(for the ester
8 or the amide
9) or oxidative (for the alcohol
6)
cyclization back to the biaryl lactone
4, and renewed atroposelective cleavage.
14,15 Differing from most of the
existing methods, the decision as to which atropoisomer is to be prepared can be taken
at a very late stage of the synthesis.
The lactone concept is not restricted to the simple model biaryl synthesis presented
here. It has been successfully expanded to a broad series of structurally diverse
biaryl substrates (e.g., lactones with additional stereocenters and functional groups,
9 configurationally stable lactones,
12
seven-membered lactones,
17
and again configurationally unstable biaryl hydroxy aldehydes
7),
to different activation modes in the ring-opening step (e.g., use of metallated nucleophiles,
carbonyl activation by Lewis acids, (η
6-complexation,
etc.),
18 and for various strategies of
stereoselection (e.g., external vs. internal asymmetric induction).
19
The broad applicability of the strategy has been proven in the atroposelective
synthesis of a broad series of structurally different bioactive natural biaryl products
like the naphthylisoquinoline alkaloid dioncopeltine A (
16)
4
(Scheme 3), the dimeric sesquiterpene mastigophorene A,
6
the phenyl anthraquinone knipholone,
20 or even molecules without
O- or (free) C
1-units next to the axis, i.e., dioncophylline C
19 and korupensamine A.
5 Furthermore,
biaryl derivatives resulting from the ring opening of the model lactone
4 were
used successfully as chiral catalysts in asymmetric synthesis, like amino alcohols
for the enantioselective addition of Et
2Zn to aldehydes
21
or a phosphine for the enantioselective hydrosilylation of styrenes.
22
Scheme 3
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(M)-2-Hydroxymethyl-1-(2-hydroxy-4,6-dimethylphenyl)naphthalene:
2-Naphthalenemethanol, 1-(2-hydroxy-4,6-dimethylphenyl)-, (R)-
(13); (140834-52-2)
3,5-Dimethylphenyl-1-bromo-2-naphthoate:
2-Naphthalenecarboxylic
acid, 1-bromo-, 3,5-dimethylphenyl ester (13); (138435-66-2)
1-Bromo-2-naphthoic acid:
2-Naphthoic acid,
1-bromo- (9); (20717-79-7)
3,5-Dimethylphenol:
Phenol, 3,5-dimethyl-
(9); (108-68-9)
Dicyclohexylcarbodiimide: HIGHLY TOXIC:
Carbodiimide,
dicyclohexyl- (8);
Cyclohexanamine, N,N'-methanetetraylbis-
(9); (538-75-0)
4-Dimethylaminopyridine: HIGHLY TOXIC:
Pyridine,
4-(dimethylamino)- (8);
4-Pyridinamine, N,N-dimethyl-
(9); (1122-58-3)
1,3-Dimethyl-6H-benzo[b]naphtho[1,2-d]pyran-6-one:
6H-Benzo[b]naphtho[1,2-d]pyran-6-one, 1,3-dimethyl- (13); (138435-72-0)
N,N-Dimethylacetamide:
Acetamide, N,N-dimethyl-
(8,9); (127-19-5)
Palladium acetate:
Acetic acid, palladium(2+)
salt (8,9); (3375-31-3)
Triphenylphosphine:
Phosphine, triphenyl-
(8,9); (603-35-0)
(S)-2-Methyl-CBS-oxazaborolidine: (CBS named after
Corey, Bakshi, Shibata):
1H, 3H-Pyrrolo[1,2-c][1,3,2]oxazaborole, tetrahydro-1-methyl-3,3-diphenyl-,
(S)- (12); (112022-81-8)
Borane-tetrahydrofuran complex:
Furan, tetrahydro-,
compd. with
borane (1:1) (8,9); (14044-65-6)
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