Asymmetric synthesis of cis-aminochromanol

Article abstract of DOI:10.1016/S0040-4039(01)01907-4

An efficient asymmetric synthesis of cis-aminochromanol was achieved in seven steps. The absolute stereochemistry of cis-aminochromanol was derived from (salen)Co(III)-catalyzed phenol opening of methyl glycidate.

Full text of DOI:10.1016/S0040-4039(01)01907-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8743–8745
Asymmetric synthesis of cis-aminochromanol
Karl B. Hansen,* Philippe Rabbat, Shawn A. Springfield, Paul N. Devine, Edward J. J. Grabowski
and Paul J. Reider
Department of Process Research, Merck and Co., PO Box 2000, Rahway, NJ 07765, USA
Received 30 March 2001; revised 5 October 2001; accepted 10 October 2001
Abstract—An efficient asymmetric synthesis of cis-aminochromanol was achieved in seven steps. The absolute stereochemistry of
cis-aminochromanol was derived from (salen)Co(III)-catalyzed phenol opening of methyl glycidate. © 2001 Elsevier Science Ltd.
All rights reserved.
We recently wished to develop a synthesis of cis-
aminochromanol 1 in enantiomerically enriched form.
While 1 has been synthesized as a racemate,1 we wished
to develop an efficient asymmetric synthesis which used
inexpensive and readily available starting materials.
cis-Aminochromanol 1 is structurally similar to cis-
aminoindanol 2, which has been prepared in our labo-
ratories on large scale from indene 3 by asymmetric
epoxidation catalyzed by (salen)Mn(III) complex 4a2
followed by a unique Ritter reaction (Scheme 1).3
Unfortunately, an analogous route from chromene 5 to
1 is not tenable, given the propensity of 5 to oxidize at
the methylene position under asymmetric epoxidation
conditions.4
kinetic resolution of methyl glycidate 8 via asymmetric
ring opening (ARO) with phenol-catalyzed by chiral
(salen)Co(III) complex 4b has been reported to afford
a-hydroxy ester 7b in good chemical and optical yield.6
Herein we describe the elaboration of 7a to cis-
aminochromanol using the (salen)Co(III)-catalyzed
ARO to establish the stereochemistry of 1. The synthe-
sis presented is amenable to large scale since it employs
inexpensive, readily available starting materials and
reagents, requires no chromatography and uses a recy-
clable catalyst to establish the stereochemistry of 1.
Methyl glycidate 8 was prepared in 50–55% yield by
addition of bleach to methyl acrylate, followed by
extraction and distillation (Scheme 3).7 A solution of 8
in methyl-tert-butyl ether (MTBE) was then treated at
−10°C with 0.45 equiv. of phenol in the presence of 6.6
mol% (R,R)-4b.8 Upon complete conversion of phenol
(24 h), the solution was concentrated and the methyl
We recognized that 1 could be accessed by diastereose-
lectively reducing the oxime derived from hydroxy
chromanone 6,1b which in turn, could be constructed
via cyclization of hydroxy acid 7a (Scheme 2).5 The
NH2
NH2
OH
OH
H
N
H
O
2
1
N
M
t-Bu
O
O
t-Bu
1. Asymmetric Epoxidation
2. Ritter Reaction
X
t-Bu
t-Bu
4a M = MnCl
4b M = Co(tosylate)(H2O)
O
3
5
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01907-4

8744
K. B. Hansen et al. / Tetrahedron Letters 42 (2001) 8743–8745
O
NH2
O
O
OH
HO
OH
OR
OMe
O
O
O
O
1
6
7a R = H
8
7b R = Me
Scheme 2.
O
O
O
1. 6.7 mol% (R,R)-4b
2. KOH, H2O
HO
O
NaOCl (aq)
OH
OMe
OMe
+
O
OH
55%
85-90% yield
95% ee
8
7a
O
O
1. Oxalyl chloride, DMF, DCM
2. AlCl3, DCM, -15 ºC
AcCl
MTBE, 50 ºC
AcO
OAc
OH
93% from 7a
O
O
9
10
HO
N
O
(NH3OH)SO4, NaOAc
THF/H2O
H2, Pd/C
HBr, MeOH, 5 ºC
OH
OH
LiOOH, -15 ºC
(S,S)-1
88% yield
94% ee
95%
92% yield
94% ee
O
O
11
6
Scheme 3.
careful quenching of the reaction with dilute hydrochlo-
ric acid, enantiomerically enriched acetoxy chromanone
10 was isolated in 93% yield with no racemization
detected.12 Cleavage of the acetate under both acidic
and basic conditions, also resulted in 6 isolated with
diminished ee. Epimerization could be avoided by using
lithium hydroperoxide at −10°C in THF to afford 6 in
94% yield and <1% racemiziation.13
ester hydrolyzed with 1.2 equiv. of aqueous KOH. The
catalyst was removed and recovered by extracting with
dichloromethane (DCM). Adjusting the aqueous layer
to pH 1 by addition of concentrated HCl afforded
a-hydroxy acid 7a as an off-white crystalline solid in
95% ee and 85–90% yield (based on phenol).9
Attempts to cyclize 7a to 10 directly under acidic
conditions using polyphosphoric acid met with little
success.10 We therefore protected the hydroxyl group of
7a as its acetate 9 and performed an intramolecular
Friedel–Crafts acylation in order to form 10.11 Hydroly-
sis of the acetate provided 6 in good chemical yield,
however, we discovered the ee of 6 had been compro-
mised. Further investigation revealed that racemization
occurred during acylation, cyclization and deacylation,
therefore conditions were developed for each step to
avoid racemization. Use of amine bases, including
dimethylaminopyridine (DMAP), for the acetylation of
7a with either acetyl chloride or acetic anhydride
resulted in diminished ee of the acetoxy acid product.
Acylation of 7a without a loss of optical purity was
achieved by treatment with several equivalents (6–8) of
acetyl chloride in MTBE in the absence of any base at
50°C. Removal of solvent in vacuo followed by treat-
ment with oxalyl chloride and catalytic DMF converted
9 to its corresponding acid chloride. A solution of the
acid chloride was then added to 2 equiv. of AlCl3 at
−15°C in DCM with the reaction temperature con-
trolled by the addition rate of the substrate. Upon
In order to install the nitrogen at C-4, 6 was treated
with 2 equiv. of (NH3OH)2SO4 in aqueous THF
buffered with 4 equiv. NaOAc at room temperature to
give a mixture of E and Z oximes 11.14 This mixture
was then hydrogenated at 5°C and 40 PSIG H2 with
10% palladium on carbon in the presence of 1 equiv.
HBr, affording 1 as its HBr salt with 25:1 cis:trans ratio
and a 94% yield and 94% ee for the desired cis-iso-
mer.15 The material could be crystallized from
methanol/MTBE to afford 1 as a single diastereomer
with >99% ee16 with 77% recovery.17
In summary, we have demonstrated the first asymmet-
ric synthesis of aminochromanol 1 which derives the
absolute stereochemistry of the molecule from an asym-
metric catalytic reaction. Despite the tendency of many
of the intermediates to epimerize, we have developed
conditions which convert hydroxy acid 7a to cis-
aminochromanol in 72% yield with less than 1% racem-
ization. The synthesis described is efficient, requires no
chromatography, uses inexpensive, readily available

K. B. Hansen et al. / Tetrahedron Letters 42 (2001) 8743–8745
8745
starting materials and a recyclable catalyst 4b to install
the stereochemistry of 1.
equiv. of lutidine para-toluenesulfonic acid salt, stirring
for 1 h open to air and concentrating to a dark brown
solid.
9. The ee of 7a was measured by re-esterification in
methanol with catalytic H2SO4 and analysis of 7b by the
procedure described in Ref. 6.
Acknowledgements
10. Kabuto, K.; Kikuchi, Y.; Yamaguchi, S.; Inoue, N. Bull.
Chem. Soc. Jpn. 1973, 46, 1839.
11. Loubinoux, B.; Viriot-Chauveau, C.; Sinnes, J. L. Tetra-
hedron Lett. 1992, 33, 2145.
12. Analysis of acetoxy chromanone was performed by chiral
HPLC: (R,R)-Whelko, 1% EtOH/hexanes, 1.5 ml/min
flow rate.
The authors thank Mr. Robert Reamer for aid in
determining the stereochemistry of 1, Mr. Chris Welch
and Mr. Robert Waters for aid in ee analysis. We also
wish to thank Professor Eric Jacobsen and Mr. Joseph
Ready of Harvard University for helpful discussions.
13. The ee of 6 was measured by chiral supercritical fluid
chromatography (SFC): Chiralpak AD, 300 Bar CO2 at
35°C, 4–40% MeOH at 2% MeOH/min, 1.5 ml/min flow
rate.
References
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14. No epimerization of the a-hydroxyl center was observed
under these reaction conditions. The ee of 9 was mea-
sured by chiral SFC: Chiralpak AS, 300 Bar CO2 at
35°C, 4–40% MeOH at 2% MeOH/min, 1.5 ml/min flow
rate.
1
15. The relative stereochemistry of 3 was determined by H
NMR. For a study on the effect of acid in this
diastereoselective hydrogenation, see: Davies, I; Taylor,
M.; Marcoux, J.; Matty, L.; Wu, J.; Hughes, D.; Reider,
P. J. Tetrahedron Lett. 2000, 41, 8021.
4. Lee, N. H.; Muci, A. R.; Jacobsen, E. N. Tetrahedron
16. 1H NMR (CD3OD): l 7.43 (dd, J=7.9, 1.3 Hz, 1H), 7.30
(m, 1H), 7.02 (m, 1H), 6.89 (dd, J=8.3, 1.1 Hz, 1H), 4.62
(d, J=4.9 Hz, 1H), 4.35 (m, 1H), 4.22 (ddd, J=11.6, 3.4,
1.0 Hz, 1H), 4.07 (dd, J=11.6, 8.2 Hz, 1H). 13C NMR
(CD3OD): l 154.3, 130.4, 129.3, 121.1, 116.9, 116.3, 65.4,
61.7, 48.8. The ee of 3 was measured by chiral HPLC:
DAICEL Crownpak CR analytical column eluted with
pH 2 HClO4.
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5. (a) Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T.
Synlett 1998, 51; (b) Kajiro, H.; Mitamura, S.; Mori, A.;
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8. Catalyst 4b was prepared by treating a solution of com-
mercially available (salen)Co(II) complex in DCM with 1
17. This yield is unoptimized. cis-Aminochromanol can also
be isolated as a mandalate salt. See Ref. 15.