A practical synthesis of (1S, 2R)-1-amino-2-indanol, a key component of HIV protease inhibitor, indinavir

Article abstract of DOI:10.1055/s-1998-3126

The synthesis of (1S,2R)-1-amino-2-indanol, a key component of HIV protease inhibitor, is accomplished in eight steps from D-phenylalanine. The starting material is converted into 2-acetoxy-1-indanone in four steps involving intramolecular Friedel-Crafts cyclization. The stereochemically labile α-acetoxy ketone is hydrolyzed to 2-hydroxy-1-indanone using a catalytic amount of scandium triflate without any loss of the optical purity. Diastereoselective hydrogenation of α-hydroxy oxime, derived from the α-hydroxy ketone, gives the amino alcohol in 96% cis-selectivity. Optical purity of the starting material is perfectly retained throughout the transformations.

Full text of DOI:10.1055/s-1998-3126

January 1998
SYNLETT
51
A Practical Synthesis of (1S, 2R)-1-Amino-2-indanol, a Key Component of HIV Protease
Inhibitor, Indinavir
Hiroshi Kajiro, Shu-ichi Mitamura, Atsunori Mori, and Tamejiro Hiyama
a, b
a, †
b
b,*
a
Advanced Technology Research Laboratories, Nippon Steel Corporation, 3-35-1 Ida, Nakahara-ku, Kawasaki 211, Japan
b
Research Laboratory of Resources Utilization, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226, Japan
Fax +81(45)9245224; E-mail: thiyamares.titech.ac.jp
Received 13 October 1997
Abstract: The synthesis of (1S,2R)-1-amino-2-indanol,
a key
component of HIV protease inhibitor, is accomplished in eight steps
from D-phenylalanine. The starting material is converted into 2-acetoxy-
1-indanone in four steps involving intramolecular Friedel-Crafts
cyclization. The stereochemically labile α-acetoxy ketone is hydrolyzed
to 2-hydroxy-1-indanone using a catalytic amount of scandium triflate
without any loss of the optical purity. Diastereoselective hydrogenation
of α-hydroxy oxime, derived from the α-hydroxy ketone, gives the
amino alcohol in 96% cis-selectivity. Optical purity of the starting
material is perfectly retained throughout the transformations.
Enantiomerically pure (1S, 2R)-1-amino-2-indanol (1) is currently
receiving considerable attention as the key component of indinavir (2), a
potent inhibitor of the protease of human immunodeficiency virus
1
(HIV). Since indinavir is widely used in medical treatment for AIDS,
inexpensive supply of 1 is strongly desired. In addition, 1 is the
2
precursor of bisoxazoline 3, a ligand for chiral catalysts, and chiral
3
auxiliary 4 is successfully utilized for various asymmetric syntheses.
The intramolecular Friedel-Crafts reaction of the acid chloride using
AlCl in CH Cl at room temperature proceeded smoothly to give 7 in
3
2
2
10,11
quantitative yield without loss of the optical activity.
Our
observation is striking in view that the Friedel-Crafts acylation of acid
chlorides having a chiral center at α-position is often accompanied by
12
racemization.
Hydrolysis of 2-acetoxy-1-indanone (7) was first attempted with
methanolic lithium hydroxide to give acyloin 8 in ca.70% yield with
remarkable racemization: enantiomeric excess of 8 was estimated to be
only 8%. Although the racemization was suppressed under acidic
conditions (MeOH-H SO or trifluoromethanesulfonic acid) at room
2
4
temperature, the reaction took much longer time (21% yield after 48 h).
When the hydrolysis was conducted at 60 °C under acidic conditions
For the efficient synthesis of 1, it is required to prepare the cis-amino
(MeOH-H SO ), the conversion was improved (75% yield after 48 h)
2
4
alcohol moiety with completely controlled regio- and stereochemistry
but by-products formed in considerable amounts and racemization
occurred to a certain extent (86% ee). After screening the catalyst for
4
and with correct absolute configurations. Among various routes to 1,
4c
one of practical methods involves the Ritter reaction of racemic
hydrolysis of 7, we found scandium triflate (Sc(OTf) ) was the supreme
3
indene oxide or indane-1,2-diol and the subsequent resolution. The
catalyst. Hydrolysis of 7 in the presence of 20 mol% of Sc(OTf) in
3
major drawback of optical resolution of racemic 1 or its precursor is that
H O-MeOH (1 : 4) at room temperature attained >95% conversion
2
5
13
it leaves an equal amount of the undesired enantiomer. Although
(>99% ee) in 48 h as determined by HPLC.
Work-up and
asymmetric synthesis of 1 using a variety of chiral catalysts is feasible,
recrystallization gave 8 in 82% yield with >99% ee as a colorless
6
14
the selectivities achieved are not high enough.
solid.
To the best of our knowledge, this is the first example of
15
To establish a practical synthetic route to 1 without optical resolution or
asymmetric synthesis, we focused on i) use of a readily available chiral
pool, ii) transformations without any loss of optical purity, and iii)
induction of (1S, 2R) configuration of 1 from the chiral starting material.
We have chosen D-phenylalanine as the starting material, because D-
phenylalanine is co-produced in the industrial preparation of
Sc(OTf) as a hydrolysis catalyst. Efficiency of the hydrolysis, we
3
consider, is attributed to the coordination ability of Sc(OTf) towards
3
16
the α-acetoxy carbonyl moiety. Indeed, hydrolysis of 2-acetoxyindan
was much slower (30% yield, 48 h) than that of 2-acetoxy-1-indanone.
Details will be described in due course.
Treatment of 8 with HONH ·HCl in pyridine afforded oxime 9 in 96%
2
®
17
Aspartame , an artificial sweetener. Our synthetic route is outlined in
yield as a 65 : 35 mixture of E- and Z-isomers. The ee of each isomer
was >99%. Although the isomers could be easily separated by silica
18
Scheme 1.
7,8
Treatment of D-phenylalanine (5) with NaNO -H SO
4
gave optically
gel column chromatography, each isomer was found to rapidly
isomerize in an acidic solution to reach a ratio of 43 : 57 at room
2
2
pure (R)-2-hydroxy-3-phenylpropanoic acid (6). The hydroxyl group of
9
1
6 was acetylated, and the resulting α-acetoxy carboxylic acid was
temperature as revealed by H NMR. Thus, an isomeric mixture of 9
converted into the corresponding acid chloride with thionyl chloride.
was used for the next reduction.

52
LETTERS
SYNLETT
19
(9) The acetate 6 was also obtained from D-phenylalanine using NaNO2/
AcOH, but the ee was inferior. Kolasa, T.; Miller, M. J. J. Org. Chem.
1987, 52, 4978.
We studied diastereoselective hydrogenation of oxime 9 to our target
molecule 1 using a variety of catalysts, additives, and solvents under
various hydrogen pressures, and found an optimum cis-selectivity and
20
(10) (a) McClure, D. E.; Arison, B. H.; Jones, J. H.; Baldwin, J. J. J. Org.
Chem. 1981, 46, 2431. (b) Dornhege, E. Liebigs Ann. Chem. 1971, 743,
42. (c) Nguy, N. M.; Chiu, I. -C.; Kohn, H. J. Org. Chem. 1987, 52,
1649.
yield were achieved with a Pd black catalyst and HBr. Treatment of 9
(E : Z = 65 : 35) in MeOH-HBr under an atmospheric pressure of
molecular hydrogen at ambient temperature in the presence of Pd black
for 20 h afforded (1S, 2R)-1 along with trans-(1R, 2R) isomer of 1 (cis :
trans=96 : 4), both as hydrobromides. During the hydrogenation, no
epimerization at 2-position was observed. Neutralization with aqueous
21
(11) Ee was determined by HPLC analysis using DAICEL CHIRALCEL
OB analytical column (0.46 mm, 25 cm) with ethanol in hexane (20%)
as an eluent. Mp 80.5-81.5 °C, [α]25D = -19 (c 1.0, MeOH).
NaHCO followed by recrystallization from MeOAc-hexane gave 1 in
3
22
(12) (a) Olah, G. A. Friedel-Crafts and related reactions; Inter Science
Publishers; New York, 1963; Vol I, p 1009. (b) Bleazard, W.;
Rothstein, E. J. Chem. Soc. 1958, 3789. (c) Tsuchihashi, G.; Kitajima,
K.; Mitamura, S. JP Patent 83-10525, Chem. Abstr. 98 : 178945y.
66% yield.
In summary, enantiomerically pure (1S, 2R)-1-amino-2-indanol (1) is
obtained from D-phenylalanine in 8 steps without any chromatographic
purification. This route allows us to produce 1 in a large scale. In
addition, enantiomerically pure 2-hydroxy-1-indanone (8), a useful
structural subunit of natural products and valuable synthetic
(13) Lu(OTf)3 (73%), Dy(OTf)3 (68%), Ho(OTf)3 (65%) exhibit relatively
good yield after 24 h.
23
(14) DAICEL CHIRALCEL OB analytical column (0.46 mm, 25 cm) with
ethanol in hexane (20%) as an eluent was used. Mp 82.4-83.7 °C,
[α]25D = -57 (c 1.0, MeOH) (lit. [α]25D = -62 (c 1.0, CHCl3): See ref 6.
intermediate, is now readily available.
Acknowledgement. We thank N. E. Chemcat Co. and Nikki Chemical
(15) Review on the rare earth triflate (RE(OTf)3), see: (a) Marshman, R. W.
Aldrichimica Acta 1995, 28, 77, and utilization of RE(OTf)3 in aqueous
media is seen in (b) Kobayashi, S. Synlett 1994, 689, and references
cited therein.
Co. for supplying a variety of catalysts.
References and Notes
†
(16) (a) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560. (b) Shull, B. K.; Sakai, T.; Koreeda, M. J. Am.
Chem. Soc. 1996, 118, 11690. (c) Yanada, R.; Negoro, N.; Bessho, K.;
Yanada, K. Synlett, 1995, 1261. (d) Inanaga, J.; Yokoyama, Y.;
Hanamoto, T. J. Chem. Soc., Chem. Commun. 1993, 1090, and
references cited therein.
Current address: Specialty Materials R & D Center, Nippon Steel
Chemical Co., Ltd., 46-80 Nakabaru Sakinohama Tobata-ku, Kitakyushu 804,
Japan.
(1) (a) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel,
S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.;
Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib,
L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.;
Anderson, P. S.; Emini, E. A.; Huff, J. R. Proc. Natl. Acad. Sci. USA,
1994, 91, 4096. (b) Idem., J. Med. Chem. 1994, 37, 3443, and
references cited therein.
(17) The geometry of
9
was determined by NOE experiments after
conversion to 2-acetoxy-1-acetoxyiminoindanone.
(18) DAICEL CHIRALCEL OB analytical column (0.46 mm, 25 cm) with
20% 2-propanol in hexane as an eluent was used for E-9. The tRs
observed at a flow rate of 0.5 mL·min-1 were as follows: 14.7 min (R-
form), 20.2 min (S-form). Analysis of Z-9 was performed by DAICEL
CHIRALPAK AD analytical column (0.46 mm, 25 cm) with 14% 2-
propanol in hexane as an eluent.
(2) (a) Davies, I. W.; Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. Tetrahedron Lett. 1996, 37, 813. (b) Hong, Y.; Gao, Y.;
Nie, X.; Zepp, C. M. Tetrahedron Lett. 1994, 35, 6631. (c) Simone, B.
D.; Savoia, D.; Tagliavini, E.; Umani-Ronchi, A. Tetrahedron:
Asymmetry 1995, 6, 301.
(19) (a) Tillyer, R. D.; Boudreau, C.; Tschaen, D.; Dolling, U. -H.; Reider,
P. J. Tetrahedron Lett. 1995, 36, 4337. (b) Harada, K,; Shiono, S. Bull.
Chem. Soc. Jpn. 1984, 57, 1040. (c) Rimek, H. -J.; Yupraphat, T.;
Zymalkowsky, F. Liebigs Ann. Chem. 1969, 725, 116. (d) Ghosh, A.
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(20) Such catalysts as Pt, Rh, Ru, Re, and Ir also were examined under the
similar conditions. Relatively good cis-selectivity and the yield were
obtained with PtO2, Ir black and Rh black. Catalyst, cis%, and yield are
given in this order: PtO2, 82%, and 28%; Ir black, 89%, and 31%, and
Rh black, 75%, and 33%.
(4) Synthesis of cis-aminoindanol is seen in: (a) Didier, E.; Loubinoux, B.;
Tombo, G. M. R.; Rihs, G. Tetrahedron 1991, 47, 4941. (b) Askin, D.;
Eng, K. K.; Rossen. K.; Purick, R. M.; Wells, K. M.; Volante, R. P.;
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36, 7615. (d) Lakshman, M. K.; Zajc, B. Tetrahedron Lett. 1996, 37,
2529, and references cited therein.
(21) Even when the E- or Z-isomer was used respectively as a substrate, the
ratio of cis and trans did not change, as might be expected on the basis
of the isomerization experiment in an acidic solution.
(5) (a) Takahashi, M.; Ogasawara, K. Synthesis 1996, 954. (b) Matsumoto,
H.; Obara, Y. JP Patent 96-215922, Chem. Abstr. 124 : 175620.
(22) The amino alcohol obtained by this procedure was contaminated with
3% of (1R, 2R)-trans isomer of 1 as determined by HPLC (ODS
column) with 5% methanol in aqueous phosphoric acid (0.2%) as an
eluent. Enantiomeric ratio of the major isomer 1 was determined by
HPLC using DAICEL CROWNPAK CR (+) analytical column (0.46
mm, 15 cm) with HClO4 aq. (pH 2).
(6) Oda, Y.; Yuasa, M. JP Patent 96-228586, Chem. Abstr. 124 : 145646.
(7) Modified procedure of the following reference was used: Urban, F. J.;
Moore, B. S. J. Heterocyclic Chem. 1992, 29, 431.
(8) Ee was determined by HPLC (DAICEL CHIRALCEL OB analytical
column (0.46 mm, 25 cm)) analysis after conversion to the
corresponding methyl ester using trimethylsilyldiazomethane.
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