Synthesis of chiral building blocks for use in drug discovery

Article abstract of DOI:10.3390/90600405

In the past decade there has been a significant growth in the sales of pharmaceutical drugs worldwide, but more importantly there has been a dramatic growth in the sales of single enantiomer drugs. The pharmaceutical industry has a rising demand for chiral intermediates and research reagents because of the continuing imperative to improve drug efficacy. This in turn impacts on researchers involved in preclinical discovery work. Besides traditional chiral pool and resolution of racemates as sources of chiral building blocks, many new synthetic methods including a great variety of catalytic reactions have been developed which facilitate the production of complex chiral drug candidates for clinical trials. The most ambitious technique is to synthesise homochiral compounds from non-chiral starting materials using chiral metal catalysts and related chemistry. Examples of the synthesis of chiral building blocks from achiral materials utilizing asymmetric hydrogenation and asymmetric epoxidation are presented.

Full text of DOI:10.3390/90600405

Molecules 2004, 9, 405–426
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Chiral Building Blocks for Use in Drug Discovery
1
1
1
1
Sharon T. Marino , Danuta Stachurska-Buczek , Daniel A. Huggins , Beata M. Krywult ,
1
1
1
1
1
Craig S. Sheehan , Thao Nguyen , Neil Choi , Jack G. Parsons , Peter G. Griffiths ,
Ian W. James 1, Andrew M. Bray 1,*, Jonathan M. White 2 and Rustum S. Boyce 3
1
Mimotopes Pty Ltd. 11 Duerdin Street, Clayton, Victoria 3168, Australia. Tel. (+61) 3 9565-1111,
Fax (+61) 3 9565-1199.
School of Chemistry, University of Melbourne, Victoria 3010, Australia.
Chiron Corporation, 4560 Horton St, Emeryville, California 94608, USA.
2
3
* Author to whom correspondence should be addressed: e-mail andrew_bray@mimotopes.com
Received: 2 March 2004 / Accepted: 12 March 2004 / Published: 31 May 2004
Abstract: In the past decade there has been a significant growth in the sales of
pharmaceutical drugs worldwide, but more importantly there has been a dramatic growth in
the sales of single enantiomer drugs. The pharmaceutical industry has a rising demand for
chiral intermediates and research reagents because of the continuing imperative to improve
drug efficacy. This in turn impacts on researchers involved in preclinical discovery work.
Besides traditional chiral pool and resolution of racemates as sources of chiral building
blocks, many new synthetic methods including a great variety of catalytic reactions have
been developed which facilitate the production of complex chiral drug candidates for
clinical trials. The most ambitious technique is to synthesise homochiral compounds from
non-chiral starting materials using chiral metal catalysts and related chemistry. Examples of
the synthesis of chiral building blocks from achiral materials utilizing asymmetric
hydrogenation and asymmetric epoxidation are presented.

Molecules 2004, 9
406
Keywords: chiral drugs, chiral building blocks, chiral metal catalysts, asymmetric
hydrogenation, asymmetric epoxidation, DuPHOS, Noyori catalyst, Jacobsen’s catalyst.
Introduction
Chiral chemical synthesis plays an important and growing role in the development of new drugs,
agrochemicals and building blocks. This paper focusses on asymmetric synthesis with chiral catalysts
to provide novel chiral amino acids and amino alcohols. Asymmetric hydrogenation with chiral
DuPHOS Rh-catalyst to provide novel chiral α-amino acids and β-amino alcohols 1 and Noyori's
chiral Ru-catalyst for synthesis of chiral amines 2 via chiral alcohols is discussed. Asymmetric
epoxidation employing Jacobsen’s Mn catalyst to afford α-amino alcohols 3 is also discussed.
Figure 1. Chiral Targets
NH2
S
X
Y
S
S
OH
R
HO
NH2
S
OMe
R
H2N
1
2
3
Results and Discussion
A generic synthesis to access large numbers of diverse chiral α-amino acids 4 and β-amino alcohols
1 has been developed. There are many known methods of preparing the dehydrophenylalanine
intermediate 5 from commercial starting materials (Scheme 1).
Scheme 1
X
CHO
Y
X
CO2R
X
Y
X
Y
CO2R
NHR'
Y
X
CO2R
NH2
5
4
NH2
X
X
Y
Y
I
OH
NH2
1
Y

Molecules 2004, 9
407
This, coupled with selective reduction of the dehydrophenylalanine intermediate 5 using an
asymmetric hydrogenation catalyst, such as DuPHOS, provides a very powerful route. This reaction
synthesis is high yielding overall and provides the final chiral 2-amino-3-phenylpropanol building
blocks 1 in high enantiomeric excess.
The preparation of the dehydro amino acid derivatives was accessed by several routes depending
on the analogue and available starting materials. Dehydrophenylalanine intermediates 5a and 5b
(Figure 2) were prepared from either an Erlenmeyer reaction with benzaldehydes and N-acetyl glycine
or a Horner-Emmons reaction with Cbz-glycine phosphonate respectively. Alternatively, a Heck
reaction between an aryl iodide (where the aldehyde is unavailable) and an acrylate also provides
amidoacrylate 5a.
Figure 2. Dehydrophenylalanine intermediates
X
X
CO2R
NHCbz
CO2R
NHAc
Y
Y
5a
5b
The dehydrophenylalanine intermediate 5 was subjected to selective reduction with a chiral
DuPHOS Rh-catalyst commercially available from Strem. The advantage of this catalyst is that it is
predictable. The relative stereochemistry of the product is determined by the chiral catalyst ie
[(COD)Rh((S,S)-Et-DuPHOS)]+ will always give the (S)-enantiomer and [(COD)Rh((R,R)-Et-
DuPHOS)]+ gives the corresponding (R)-enantiomer [1, 2]. In addition, the double bond geometry of
the starting alkene, whether it be E or Z gives the same absolute configuration in high enantiomeric
excess.
Chiral 2-amino-3-phenylpropanol building blocks 1 were then prepared following several functional
group manipulations. Confirmation of optical purity (stereochemistry obligated by the catalyst
employed) was determined by preparation of either the Mosher amide or Mosher ester derivative. The
diastereomeric excess (de) of the Mosher amide is representative of the enantiomeric excess (ee) of the
precusor. The epimeric compounds were prepared in a similar manner in most cases. In general,
19F-NMR integrals indicated >98% ee. In some cases the minor isomer was not observed at all. The
1
absolute configuration of 2-substituted-1-propanols can be assigned by the H-NMR splitting patterns
of the Mosher’s ester [3]. Reverse phase HPLC was also used to distinguish between Mosher
diastereoisomers.
In the first example, the 2,4-difluoro analogue was best accessed via the Erlenmeyer reaction of
benzaldehyde 6 with N-acetyl glycine. The intermediate azlactone 7 was subsequently ring opened by
reflux in acetone. Asymmetric hydrogenation of acrylic acid 8 with (S,S)-DuPHOS catalyst at 30 psi
then installed the desired S stereochemistry in acetylamino acid 9. The next step in the synthesis was
esterification of acid 9 with methanolic hydrogen chloride. It was observed here, that with longer

Molecules 2004, 9
408
reaction times the acetyl group was also cleaved. Thus, the installation and removal of protecting
groups was achieved in a one pot synthesis in high yield. Reduction of (S)-amino ester 10 to (S)-amino
alcohol 11 was achieved with lithium aluminium hydride. Preparation of the Mosher amide of 11 and
analysis by 19F-NMR (ratio 97:0.065) and HPLC indicated >98% ee.
Scheme 2
CO2H
NHAc
F
F
O
F
aq. Acetone
CO2H
NHAc
CHO
∆
O
77%
N
NaOAc, Ac2O, ∆
F
F
F
69%
8
6
7
[(COD)Rh((S,S)-Et-DuPHOS)]-OTf
30psi, H2, MeOH
93%
F
F
F
LiAlH4
SOCl2, MeOH
THF, 00 C
CO2H
NHAc
CO2Me
NH2
∆
OH
NH2
89%
99%
F
F
F
11
10
9
In a second example, Horner-Emmons reaction of 2,4-dimethylbenzaldehyde 12 with N-Cbz-
glycine phosphonate gave amidoacrylate 13. Catalytic hydrogenation with (S,S)-DuPHOS provided the
(S)-amido ester 14. Hydrogenation of Cbz-amide 14 with Pd/C followed by reduction of ester 15 with
lithium aluminium hydride afforded the desired (S)-amino alcohol 16. LCMS and reverse phase HPLC
of the (R)-Mosher amide derivative estimate the enantiomeric excess to be >98%, as the alternate
(R,R)-diastereoisomer was undetectable.
Scheme 3
O
MeO2C
P(OMe)2
CHO
CO2Me
NHCbz
[(COD)Rh((S,S)-Et-DuPhos)]-OTf
CbzHN
H2, 30psi, MeOH
100%
DBU, DCM
89%
12
14
13
15
1. 10% Pd /C
EtOAc
1. LiAlH4, THF
CO2Me
NHCbz
CO2Me
NH2
OH
NH2.HCl
2. HCl
100%
2. HCl
81%
16

Molecules 2004, 9
409
In a third example, 2-fluoro-4-methylaniline (17) was used as a starting reagent where 2-fluoro-4-
methylbenzaldehyde was not commercially available. The Heck reaction with the diazotized aniline
and methyl acrylate works well, but with methyl 2-acetamidoacrylate this reaction fails completely.
Aniline 17 was thus converted to aryl iodide 18 via the Sandmeyer reaction followed by Heck reaction
with methyl-2-acetamidoacrylate and Pd-acetate to form amidoacrylate 19 [4]. The reaction was done
neat and gave the acrylic ester as a black tar which was purified by chromatography. Catalytic
hydrogenation with (S,S)-DuPHOS provided (S)-amido ester 20. Reduction of ester 20 with lithium
aluminium hydride gave an acetamido alcohol intermediate. Derivatisation of this intermediate as the
1
(R)-Mosher ester indicated, from the H-NMR, that we had obtained 2S stereochemistry [2,3].
Deacetylation of the acetamido alcohol intermediate gave the resulting (S)-amino alcohol 21. Analysis
of the derived (R)-Mosher amide of 21 by LC/LCMS confirmed >98% ee.
Scheme 4
CO2Me
F
F
F
NaNO2, aq HCl
NHAc
NH2
I
CO2Me
NHAc
KI, 0o to ∆
Pd(OAc)2, Bu4NCl,
NaHCO3, N2, 800 C
90%
44%
17
18
19
F
F
1. LiAlH4 , THF, 00C
91%
CO2Me
[(COD)Rh((S,S)-Et-DuPHOS)]-OTf
OH
NHAc
20
NH2
2. aq. NaOH, MeOH
64%
H2, 30psi, MeOH
100%
21
Next we examined the synthesis of chiral amines via chiral alcohols using Noyori's chiral Ru-
catalyst. The Noyori asymmetric hydrogenation catalyst is one of a family of catalysts consisting of a
ruthenium based system with a phosphine and 1,2-diamine ligand. They provide highly efficient
enantio- and diastereoselective hydrogenation of simple ketones. Asymmetric hydrogenation of 2-
substituted cyclohexanone with the Noyori catalyst favors the cis isomer and provides the
cyclohexanol in high ee. This is attributed to the fact that from a racemic mixture, the 2R substituted
cyclohexanone undergoes hydrogenation faster and the slower 2S substrate undergoes epimerisation
under basic conditions faster than it is hydrogenated [5].

Molecules 2004, 9
410
Scheme 5
PPh3, DEAD
(PhO)2P(O)N3
THF, N2, r.t., 18h
Noyori cat
KOH, i-PrOH
H2 (65 psi), 3 d
N3
NH2
O
OH
PPh3, H2O
THF, ∆ , 16h
80%
40%
62%
(1S,2S)-24
(1S,2S)-25
rac-22
(1R,2S)-23
The hydrogenation of 2-methylcyclohexanone 22 with Noyori’s ruthenium catalyst, (S)-Binap-(+)-
(1R, 2R)-diphenylethylenediamine, in the presence of potassium hydroxide at 65 psi affords (1R, 2S)-
2-methyl-1-cyclohexanol 23 as a 40:1 mixture of cis and trans isomers in high yield. Analysis of the
19
Mosher ester of 23 by F-NMR indicated 70% ee. Importantly, the C1 stereochemistry was inverted
by Mitsonobu reaction to afford the corresponding azide 24 in 100% trans form. Reduction of azide 24
with PPh3 gave the desired (1S, 2S)-methyl cyclohexylamine 25 in 70% ee as confirmed by the Mosher
amide of 25. Thus, the enantiomeric excess was maintained throughout the synthesis. This was then
further enhanced by resolution with tartaric acid. Amine 25 was resolved by recrystallisation with (+)-
tartaric acid from methanol to give the hydrogen tartrate salt in 92% ee. The low yields in the synthesis
can be attributed to the volatility of the products compounded by the poor UV absorption
characteristics of these molecules which made the synthesis very difficult. Due to the high volatility of
the free-base 25, the compound was prepared as the hydrogen tartrate salt. When evaporating solutions
of the free-base 25, solvent should be removed at pressures greater than 600 mbar at 60 °C in order to
minimise losses of the free-base through evaporation.
Scheme 6
-
NH2
NH2+
O2C
OH
L-tartaric acid
MeOH
HO
CO2H
(2R, 3R)-(+)-tartaric acid
(1S,2S)-25
(1S,2S)-25
The absolute stereochemistry was confirmed by X-ray analysis of the L-(+)-tartaric acid salt (R, R-
(+)-tartaric acid).

Molecules 2004, 9
411
Figure 3. X-ray structure of (R,R)-(+)-tartaric acid salt of 25 [6].
Finally, the synthesis of (1R, 2S)-cis-amino alcohol 30 is discussed. α-Amino alcohols can be
prepared via asymmetric epoxidation employing Jacobsen’s catalyst. This chiral manganese
epoxidation catalyst gives high ee’s with unactivated alkenes. Single enantiomer amino alcohols are
then efficiently produced from the corresponding chiral epoxide by acid or base catalysed epoxide ring
openings.
Scheme 7
NaBH4, MeOH
TsOH, toluene
∆ / 1 h
r.t., o/n
MeO
MeO
MeO
98%
99%
O
OH
28
27
26
(R,R) Jacobsen's catalyst
4-phenylpyridine N-oxide
NaOCl, 40%
2S
2S
HCl
OH
TfOH, MeCN
2S
OH
-30OC, H2O, ∆
1R
1R
MeO
MeO
MeO
O
1R
NH2.HCl
NH2
31
30
29
The synthesis of aminohydroxyindanes via epoxidation of indenes has been reported in the
literature [7]. Sodium borohydride reduction of indanone 26 to indanol 27 followed by acid catalysed
dehydration gave indene 28 in 50% yield after distillation. Chiral epoxidation of indene 28 with (R,R)-

Molecules 2004, 9
412
Jacobsen’s catalyst, 4-phenylpyridine N-oxide and sodium hypochlorite provides the (1R, 2S)-epoxide
29. Epoxide 29 then underwent a Ritter reaction with acetonitrile under acidic conditions via a cyclic
intermediate which was then hydrolysed to afford the (1R, 2S)-cis-amino alcohol 30 and subsequently
converted to the hydrochloride salt 31. The enantiomeric excess was determined to be >98% by LCMS
and 19F-NMR analysis of the (S)-Mosher amide derivative of 30.
The (1R, 2S) absolute stereochemistry of 30 was confirmed by X-ray analysis of the L-(+)-tartaric
acid salt (R, R-(+)-tartaric acid) of the acetonide 32, prepared in situ by recrystallisation from methanol
and acetone.
Scheme 8
2S
1. NaOH
2S
O
HO
+
OMe
OH
CO2H
2. L-tartaric acid
methanol/ acetone
1R
OMe
NH2
1R
-
H2N
O2C
.HCl
31
32
HO
(2R, 3R)-(+)-tartaric acid
Figure 4. X-ray structure of (R,R)-(+)-tartaric acid salt of 32 [6].

Molecules 2004, 9
413
Conclusions
The demand for chiral intermediates and chiral active ingredients is predicted to grow. Chiral
catalysis has proven an effective means of preparing key chiral intermediates in high ee. Ready access
to these and more advanced intermediates and chiral drugs targets accelerates our collaborative drug
discovery programs.
Experimental
General
Reverse phase HPLC analysis was carried out using a Column Engineering Monitor C18 (5 µm), 50
x 4.6 mm. LCMS were run on a Perkin-Elmer Sciex API-100 instrument. ESMS were run on an API
III LC/MS/MS from Perkin Elmer/Sciex using an electrospray inlet. H-, F- and 13C-NMR spectra
1
19
UNITY
were acquired on a 400 MHz Varian
INOVA spectrometer and were recorded at 400 MHz, 377
MHz and 100 MHz respectively. X-ray crystallography was carried out on a Bruker Smart Apex X-ray
diffractometer. The images were generated using Mercury 1.1 from .pdb files. Chiral catalysts
(DuPHOS, Noyori and Jacobsen’s) were purchased from Strem. Flash chromatography was conducted
on Merck Silica gel type 9385.
Synthesis of azlactone 7.
In a round bottom flask, N-acetylglycine (11.54 g, 98.51 mmol), anhydrous sodium acetate (5.77 g
70.37 mmol), 2,4-difluorobenzaldehyde (6, 20 g, 140.74 mmol) and 95% acetic anhydride (24.43 g,
239.26 mmol) were added and warmed to 40 °C until dissolved (~0.5 h). The resulting solution was
refluxed for 1 h, cooled and placed in the refrigerator overnight. The light brown crystals were
dissolved in ethyl acetate and washed with cold water (3 x 100 mL). The organic layer was collected,
dried over sodium sulfate and the solvent removed under reduced pressure to afford azlactone 7 as a
yellow powder (21.8 g, 69% yield). ECMS m/z 224.2 [M+H]+; LC/MS, tR = 8.30 min. (223.9 [M+H]+,
483.2 [2M+H]+ parent).
Synthesis of 2-acetylamino-3-(2,4-difluorophenyl)acrylic acid (8).
A solution of azlactone 7 (21.8 g, 97.68 mmol) in acetone (210 mL) and water (82 mL) was
refluxed for 4 h. The reaction mixture was then cooled to room temperature and solvent removed under
reduced pressure to yield a yellow solid. The crude product was dissolved in water (100 mL) and
adjusted to pH 10 with potassium carbonate then the aqueous layer was extracted with ethyl acetate (3
x 100 mL). The organic layer was discarded and the aqueous layer adjusted to pH 3-4 with citric acid
then extracted with ethyl acetate (5 x 100 mL). The organic layer was collected then dried over sodium

Molecules 2004, 9
414
sulfate and the solvent removed under reduced pressure to afford as a yellow powder (23.5 g, 88%
yield). This crude material was then purified by recrystalization using boiled water to give acrylic acid
8 as a yellow solid (17.79 g, 75.6% yield). HPLC (214 nm), tR 4.76 min. (92.7%); 1H-NMR (CDCl3) δ:
2.41 (s, 3H), 3.49 (s, 1H), 6.85-6.89 (m,1H), 6.96-7.00 (m, 1H), 7.38 (s,1H), 8.71- 8.77 (m, 1H);
ECMS m/z 483.1 [2M+H]+ ; LC/MS tR = 5.03 min. (242.3 [M+H]+, 483.2 [2M+H]+ parent).
Synthesis of (2S)-2-acetylamino-3-(2,4-difluorophenyl)propionic acid (9).
In an oven dried glass Parr hydrogenation flask, acrylic acid 8 (10.6 g, 41.46 mmol) was dissolved
in anhydrous methanol (270 mL) along with the chiral catalyst (+)-1,2-bis((2S,5S)-2,5-diethyl
phospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate (239 mg, 0.33 mmol). The flask
was then placed in the Parr pressure reactor, which was evacuated and flushed with argon (x 5) before
finally evacuating and flooding with hydrogen (x 5). The reaction was then allowed to proceed
overnight at room temperature with stirring. The reaction mixture was then filtered through Celite™
and the filtrate concentrated under reduced pressure to give (S)-acetylamino acid 9 (10.0 g, 93% yield).
1
This material was used without further purification. HPLC (214 nm), tR 5.42 min. (93.8%); H-NMR
(CDCl3) δ: 1.83 (s, 3H), 2.87 (dd, J = 14.0, 8.8 Hz, 1H), 3.19 (dd, J = 14.0, 5.2 Hz, 1H), 4.61 (dd, J =
8.8, 5.2 Hz, 1H), 6.79-6.84 (m, 2H), 7.18-7.22 (m, 1H); ECMS m/z 244.1 [M+H]+, 285.0
[M+H+MeCN]+, 487.4 [2M+H]+; LC/MS tR = 5.24 min. (244.2 [M+H]+, 487.3 [2M+H]+ parent).
Esterification of the acid 9 to form the amino methyl ester 10.
To a stirred suspension of (S)-acetylamino acid 9 (8.7 g, 33.55 mmol) in anhydrous methanol (160
mL) at 0 °C under nitrogen was added dropwise thionyl chloride (19.5 mL, 268.40 mmol). The
reaction mixture was allowed to reflux overnight then cooled to room temperature and the solvent
removed to give amino methyl ester 10 as a yellow powder (8.1 g, 89% yield). HPLC (214 nm), tR 4.73
min. (78.4%); 1H-NMR (D2O) δ: 3.24 (dd, J = 15.0, 7.2 Hz, 1H), 3.34 (dd, J = 15.0, 6.4 Hz, 1H), 3.79
(s, 3H), 4.40 (appt, J = 6.8 Hz, 1H), 6.95-7.02 (m, 2H), 7.26-7.32 (m,1H); ECMS m/z 216.2 [M+H]+;
LC/MS tR = 3.86 min. (216.3 [M+H]+).
Reduction of the amino methyl ester 10 to form the amino alcohol 11.
In an oven dried round bottom flask under nitrogen, lithium aluminium hydride (2.73 g, 71.81
mmol) was suspended in anhydrous tetrahydrofuran (150 mL) and cooled in an ice bath. To this
stirring solution was added dropwise a solution of methyl ester 10 (4.52 g, 17.95 mmol) in anhydrous
tetrahydrofuran (150 mL). The reaction was stirred at room temperature and monitored via TLC (10%
methanol/dichloromethane/1% ammonia solution was the running solvent and ninhydrin stain) until
completion, approximately 1 h. The reaction was diluted with water and diethyl ether and 15% sodium
hydroxide was added. The reaction was allowed to stir vigorously for a further 0.5 h. The aqueous

Molecules 2004, 9
415
layer was then extracted with ethyl acetate (x 3) and the combined organic extracts dried over sodium
sulfate. The organic layer was then removed under reduced pressure to recover (S)-amino alcohol 11 as
1
a yellow liquid (3.34 g, 99% yield). HPLC (214 nm) tR 4.30 min. (83.1%); H-NMR (CDCl3) δ: 2.62
(dd, J = 13.7, 8.2 Hz, 1H), 2.76 (dd, J = 13.7, 5.6 Hz, 1H), 3.07-3.14 (brm, 1H), 3.38 (dd, J = 10.7, 7.0
Hz, 1H), 3.60 (dd, J = 10.7, 3.7 Hz, 1H), 6.77-6.85 (brm, 3H), 7.14-7.19(brm, 1H); LC/MS tR = 4.00
min. (187.9 [M+H]+, 375.1 [2M+H]+ parent).
Synthesis of the (R)-Mosher amide of (2S)- 2-amino-3-(2,4-difluorophenyl) propan-1-ol (11).
F
F
(R)-(+)-MTPA
OH
Ph
OH
HN
DIEA / EDC / HOBt
THF
OMe
F
NH2
CF3
F
O
To a stirred solution of (S)-amino alcohol 11 (12 mg, 64.11 mmol) in tetrahydrofuran (1 mL) at
room temperature was added (R)-(+)-MTPA [(R)-(+)-α-methoxy-α-trifluoromethylphenyl acetic acid]
(15 mg, 64.11 mmol), EDC (N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride) (12.3
mg, 64.11 mmol), DIEA (diisopropylethylamine) (22.3 µL, 128.2 mmol) and HOBt·H2O (1-hydroxy-
benzotriazole hydrate) (9.8 mg, 66.11 mmol). The reaction was stirred at room temperature overnight
then diluted with water and ethyl acetate. The organic layer was washed with citric acid, 10% sodium
hydrogen carbonate and brine and dried over sodium sulfate. The organic solvent was removed under
1
reduced pressure to yield a yellow oil. H-NMR, LCMS and reverse phase HPLC estimate the
enantiomeric excess to be > 95%. The alternate (R)-enantiomer was also detected (0.65%). HPLC (214
1
nm), tR 8.92 min. (97.0%), 9.10 min. (0.65%, minor-isomer); H-NMR (CDCl3) δ: 2.86-2.97 (brm,
2H), 3.30 (s, 3H), 3.64 (dd, J = 11.3, 5.1 Hz, 1H), 3.69 (dd, J = 11.3, 4.5 Hz, 1H) 4.19-4.26 (brm, 1H),
6.77-6.85 (brm, 2H), 7.08 (d, J = 7.6 Hz, 1H), 7.18-7.23 (brm, 1H), 7.38-7.40 (brm, 3H), 7.49-7.50
(brm, 2H); ECMS m/z 404.1.0 [M+H]+; LC/MS tR = 8.66 min. (404.0 [M+H]+, 807.2 [2M+H]+, parent
ion).
Synthesis of 2-benzyloxycarbonylamino-3-(2,4-dimethylphenyl)acrylic acid methyl ester (13).
To a solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (14.574 g, 44 mmol,
1.1 eq) in dichloromethane (80 mL) was added DBU (6.28 mL, 42 mmol, 1.05 eq). The reaction
mixture was stirred for 0.5 h then 2,4-dimethylbenzaldehyde (12, 6.2 mL, 40 mmol, 1 eq) was added.
The reaction was exothermic after addition of aldehyde 12. The reaction mixture was stirred at room
temperature over the weekend. To this mixture was added aqueous 1N H2SO4 followed by separation
of the dichloromethane layer. The aqueous phase was further extracted with an aliquot of ethyl acetate
and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give an
oil. The crude product was purified by flash chromatography over silica gel with 20% ethyl acetate/

Molecules 2004, 9
416
petroleum ether as eluent followed by 50% dichloromethane/petroleum ether. The fractions containing
the major band were combined and evaporated to dryness to provide amidoacrylate 13 as a colourless
solid (12.19 g, 89% yield). HPLC (214nm), tR = 9.95 min. (80.8%); LC/MS tR = 9.02 min. (340.1
1
[M+H]+, 679.3 [2M+H]+, 696.6 [2M+NH4]+); H-NMR (CDCl3) δ: 2.27 (s, 3H), 2.31 (s, 3H), 3.82 (s,
3H), 5.07 (s, 2H), 6.22 (brs, 1H), 6.93 - 7.02 (m, 2H), 7.26-7.30 (m, 7H).
Synthesis of (2S)-2-benzyloxycarbonylamino-3-(2,4-dimethylphenyl)propionic acid methyl ester (14).
A mixture of amidoacrylate 13 (2.92 g, 8.59 mmol), (+)-1,2-bis((2S,5S)-2,5-diethylphosphonolano)
benzene(cyclooctadiene)rhodium (I) trifluoromethanesulfonate (50 mg) dissolved in deoxygenated
methanol (45 mL) was placed in a bomb. Five vacuum/N2 cycles to purge the gas lines of any oxygen
followed by five vacuum/H2 cycles were carried out before the bomb was pressurised with H2 (30 psi/
2 atm) and reacted at room temperature overnight. The pressure in the vessel was then released and the
reaction mixture was filtered through a pad of Celite™ and concentrated to afford (S)-amido ester 14
as an oil (3.10 g, >100% yield). HPLC (214nm), tR = 9.96 min. (73.5%); LC/MS, tR = 9.06 min. (342.0
[M+H]+, 683.3 [2M+H]+); 1H-NMR (CDCl3) δ: 2.27 (s, 6H), 2.97 (dd, J = 14.0, 7.1 Hz, 1H), 3.12 (dd,
J = 14.0, 6.1 Hz, 1H), 3.70 (s, 3H), 4.57-4.63 (m, 1H), 5.07 (m, 2H), 5.20 (d, J = 9.9 Hz, 1H), 6.91-
6.97 (m, 3H), 7.28-7.36 (m, 5H).
Synthesis of (2S)-2-amino-3-(2,4-dimethylphenyl)propionic acid methyl ester (15).
A mixture of (S)-amido ester 14 (1.81 g, 5.31 mmol), 10% Pd / C (180 mg) in ethyl acetate (35 mL)
was hydrogenated at room temperature overnight. The reaction mixture was filtered and concentrated
to dryness to provide (S)-amino ester 15 as an oil (1.23 g, >100% yield). HPLC (214nm), tR = 5.57
min. (79%); LC/MS tR = 5.03 min. (208.1 [M+H]+, 415.2 [2M+H]+); 1H-NMR (CDCl3) δ: 2.28 (s, 3H),
2.31 (s, 3H), 2.74 (dd, J = 13.9, 8.8 Hz, 1H), 3.10 (dd, J = 13.9, 5.2 Hz, 1H), 3.67-3.71 (m, 4H), 6.93-
7.03 (m, 3H).
(2S)-2-Amino-3-(2,4-dimethylphenyl) propan-1-ol hydrochloride (16).
In a 500 mL 3 necked round bottom flask fitted with a thermometer and flushed with nitrogen,
lithium aluminium hydride (1.71 g, 45.1 mmol, 4eq) was suspended in anhydrous tetrahydrofuran (90
mL) and cooled in an ice bath to 0 °C. (S)-Amino ester 15 (2.75 g, 11.28 mmol) was solubilised in
anhydrous tetrahydrofuran (140 mL) then slowly cannulated into the reaction mixture whilst
maintaining temperature < 3°C. The reaction mixture was allowed to warm to room temperature,
stirred for 1 h, then recooled to 0 °C and very cautiously diluted with water (15 mL), 15% sodium
hydroxide (15 mL) and water (15 mL). The reaction mixture was allowed to stir for a further 0.5 h at
0°C then the aluminium salts were filtered off and the filtrate concentrated. The residue was taken up
in ethyl acetate, washed with brine, extracted with ethyl acetate (x 3) and the combined organic

Molecules 2004, 9
417
extracts dried over sodium sulfate, filtered and concentrated. The crude material was diluted with
dichloromethane, washed with 1N hydrochloric acid (x 5) and the combined aqueous layers were re-
extracted with dichloromethane then basified and re-extracted with dichloromethane (x 5). The organic
layer was dried over sodium sulfate, filtered and concentrated to afford a white solid (2.09 g) which
was then taken up in 3 N hydrochloric acid and lyophilised to provide (S)-amino alcohol 16 as a pale
yellow solid (1.99 g, 81% yield). HPLC (214nm), tR = 5.26 min. (96.4%); LC/MS tR = 4.71 min.
(180.2 [M+H]+, 359.4 [2M+H]+); ESMS m/z 180.4 [M+H]+; 1H-NMR (DMSO-d6) δ: 1.22 (s, 3H), 1.24
(s, 3H), 1.80 (dd, J = 13.7, 9.9 Hz, 1H), 1.89 (dd, J = 13.7, 4.9 Hz, 1H), 2.16-2.26 (brm, 1H), 2.37 (dd,
J = 11.4, 5.9 Hz, 2H), 5.93 (d, J = 7.7 Hz, 1H), 5.97 (s, 1H), 6.07 (d, J = 7.5 Hz, 1H), 7.14 (brs, 2H);
13C-NMR (DMSO-d6) δ: 19.0, 20.6, 31.8, 52.8, 59.5, 126.6, 130.0, 131.1, 131.7, 135.9, 136.2.
Synthesis of (R)-Mosher’s amide of (2S)-2-amino-3-(2,4-dimethylphenyl)propionic acid methyl ester
(15).
CO2Me
NH2
CO2Me
Ph
OMe
CF3
(R)-(+)-MTPA
HN
DIEA / EDC / HOBt
THF
O
Amine 15 (42 mg, 0.2 mmol) was dissoved in tetrahydrofuran (2 mL) under an atmosphere of N2,
DIEA (104 mL, 0.6 mmol, 3 eq), (R)-(+)-MTPA (47 mg, 0.2 mmol), EDC (38 mg, 0.2 mmol) and
HOBt.H2O (31 mg, 0.2 mmol) were added and the reaction stirred overnight. The reaction mixture
was diluted with water and extracted with Et2O (2 x 25 mL). The combined organic layers were
washed with brine (10 mL) then dried over anhydrous sodium sulfate, filtered and concentrated to
afford the (R)-Moshers amide ester of 15 (26 mg, 30% yield) as a colourless oil. 1H-NMR, LCMS and
reverse phase HPLC estimate the enantiomeric excess to be > 98% as the alternate (R, R)-
diastereoisomer was undetectable. HPLC (214nm), tR = 5.76 (15, 13.8%), 10.66 (MA of 15, 60.2%)
min.; LC/MS tR = 5.21 min. (15, 208.3 [M+H]+, 415.1 [2M+H]+), 9.76 min. (MA of 15, 424.2 [M+H]+,
847 [2M+H]+).
Synthesis of 2-fluoro-1-iodo-4-methyl benzene (18) via the Sandmeyer reaction.
In a round bottom flask, 2-fluoro-4-methylaniline (17, 1 g, 7.99 mmol) was suspended in water
(2 mL) and concentrated hydrochloric acid (2 mL). This solution was then cooled in an ice bath with
vigorous stirring. To this stirring solution was added sodium nitrite (662 mg, 9.58 mmol) dissolved in
water (2 mL) dropwise over 0.5 h, keeping the temperature below 10 °C. The reaction was then stirred
for a further 0.5 h. The resulting solution was then added dropwise to a solution of potassium iodide
(1.99 g, 11.98 mmol) dissolved in water (2 mL) stirring in an ice bath. The reaction was then refluxed
for 2 h before being allowed to stir at room temperature over night. The reaction mixture was then
taken up in ethyl acetate and washed with 3N hydrochloric acid and 1M sodium hydroxide containing

Molecules 2004, 9
418
a small portion of sodium metabisulfite. The organic layer was then dried over sodium sulfate and the
solvent removed under reduced pressure to afford a dark brown oil (1.46 g, 77% yield). On scale-up of
this reaction the crude yield increased to 93%. This material was then purified via flash
chromatography using a hexane running solvent and washed with 1M hydrochloric acid (x 2), 2M
sodium hydroxide (x 1), brine (x 1) and dried over sodium sulfate to recover aryl iodide 18 (829 mg,
1
44% yield) as a colourless oil. HPLC (214 nm), tR =10.13 min. (76%); H-NMR (CDCl3) δ: 2.29 (s,
3H), 6.68 - 7.55 (m, 3H).
Synthesis of 2-acetylamino-3-(2-fluoro-4-methylphenyl)acrylic acid methyl ester (19) via the Heck
reaction.
A mixture of aryl iodide 18 (2.00 g, 8.47 mmol), methyl-2-acetamidoacrylate (1.45 g, 10.17 mmol),
Pd(OAc)2 (228 mg, 1.02 mmol), tetrabutylammonium chloride hydrate (2.83 g, 10.17 mmol), and
sodium hydrogen carbonate (1.92 g, 22.88 mmol) was weighed into a thick walled oven dried glass
vial, flushed with nitrogen and sealed. The vial was then heated to 80 °C for 24 h. The reaction was
then cooled to room temperature and dissolved in dichloromethane. The black crude product was then
absorbed onto silica gel. This crude material was then purified via flash chromatography using 45%
ethyl acetate/hexane running solvent to recover amidoacrylate 19 as an off-white solid (average 90%
yield). HPLC (214 nm), tR = 6.78 min. (80%); LC/MS, tR = 6.26 (252.1 [M+H]+, 503.2 [2M+H]+,
parent) min.; 1H-NMR (CDCl3) δ: 2.00 (s, 3H), 2.30 (s, 3H), 3.77 (s, 3H), 6.80-6.89 (m, 2H), 7.32-7.40
(m, 2H).
Synthesis of (2S)-2-acetylamino-3-(2-fluoro-4-methylphenyl)propionic acid methyl ester (20).
In an oven dried Parr hydrogenation vial, amidoacrylate 19 (13.40 g, 53.32 mmol) was dissolved in
anhydrous methanol (100 mL) along with the chiral catalyst; (+)-1,2-Bis((2S,5S)-2,5-diethyl
phospholano)benzene(cyclooctadiene)rhodium (I) trifluoromethanesulfonate (38 mg, 53.32 µmol).
The vial was then placed in the Parr pressure reactor, evacuated and flushed with argon (x 5) before
evacuating and flooding with hydrogen (x 5). The reaction was then allowed to proceed for 48 h at
room temperature with stirring. The reaction mixture was then filtered through cotton wool before
removing the organic solvent under reduced pressure to yield (S)-amido ester 20 (13.80 g, >100%
yield). This material was used without further purification. LC/MS tR = 6.47 min. (254.2 [M+H]+),
507.4 min. ([2M+H]+, parent); 1H-NMR (CDCl3) δ: 1.93 (s, 3H), 2.28 (s, 3H), 3.03 (dd, J = 6.0 Hz, J =
13.9 Hz, 1H), 3.12 (dd, J = 5.7 Hz, J = 13.9 Hz, 1H), 3.69 (s, 3H), 4.73-4.82 (m, 1H), 6.05 (d, J = 6.9
Hz, 1H), 6.78-6.86 (m, 2H), 6.96 (t, J = 7.8 Hz, 1H).

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419
Reduction of methyl ester 20.
In an oven dried round bottom flask under nitrogen, lithium aluminium hydride (6.41 g, 168.88
mmol) was suspended in anhydrous tetrahydrofuran (280 mL) and cooled in an ice bath. To this
stirring solution was added dropwise a solution of (S)-amido ester 20 (13.80 g, 54.47 mmol) in
anhydrous tetrahydrofuran (280 mL). The reaction was then allowed to warm to room temperature and
monitored via TLC (45% ethyl acetate/hexane running solvent) until completion within approximately
2 h. The reaction was then cooled in an ice bath and diluted with water and diethyl ether. To this
vigorously stirring solution was added 2M sodium hydroxide, the reaction was then allowed to stir for
a further 0.5 h. The aqueous layer was then extracted with diethyl ether (x 3) and the combined organic
extracts dried over sodium sulfate. The organic layer was then concentrated under reduced pressure to
recover the intermediate alcohol as a crude yellow solid (11.20 g, 91% yield). HPLC (214 nm), tR =
1
5.66 min. (56%); LC/MS, tR = 5.56 min. (226.2 [M+H]+ parent); H-NMR (CDCl3) δ: 1.91 (s, 3H),
2.28 (s, 3H), 2.80 (d, J = 6.6 Hz, 2H), 3.05 (bs, 1H), 3.54 (dd, J = 11.3, 4.9 Hz, 1H), 3.62 (dd, J = 11.3,
3.7 Hz, 1H), 4.10-4.13 (m, 1H), 6.15 (d, J = 7.3 Hz, 1H), 6.78-6.85 (m, 2H), 7.07 (t, J = 7.87 Hz, 1H).
Hydrolysis of the acetamide to form 2-amino-3-(2-fluoro-4-methylphenyl)-propan-1-ol (21)
In a round bottom flask the intermediate acetamide (11.20 g, 49.71 mmol) was dissolved in
methanol (100 mL) and 2M sodium hydroxide (100 mL) and refluxed. The reaction was then
monitored via TLC using ethyl acetate and ninhydrin stain before it was allowed to cool to room
temperature after 2 d. The reaction was then extracted with ethyl acetate (x 3) and the organic layer
dried over sodium sulfate before being removed under reduced pressure to afford 9.12 g of crude
material. This material was then purified via flash chromatography using 10% methanol/
dichloromethane/1% ammonia solution as running solvent. The material recovered from purification
was then dissolved in 0.2M hydrochloric acid and washed with ethyl acetate (x 3). The aqueous layer
was adjusted to pH 9 with 3M aqueous sodium hydroxide and extracted (x 3) with dichloromethane.
The combined organic layers were then dried over sodium sulfate and the solvent removed under
reduced pressure to recover (S)-amino alcohol 21 (5.861 g, 64% yield). This material was then
converted to the hydrochloric acid salt by dissolving 21 in 90% acetonitrile/water (8 mL) and 4M
hydrochloric acid (5 mL). This solution was then freeze dried to afford the hydrochloride salt of 21
(6.67 g). HPLC (214 nm), tR = 4.72 min. (88%); LC/MS tR = 3.71 min. (184.2 [M+H]+ parent);
1H-NMR (CDCl3) δ: 2.32 (s, 3H), 2.53-2.60 (m, 1H), 2.71-2.80 (m, 1H), 3.09 (bs, 1H), 3.34-3.39 (m,
1H), 3.55-3.67 (m, 1H), 6.83-6.90 (m, 2H), 7.03-7.09 (m, 1H); 13C-NMR (CDCl3) δ: 21.1, 34.2, 53.4,
66.4, 116.1 (d, 2JCF = 22.0 Hz), 122.4 (d, 2JCF = 16.0 Hz), 125.0, 131.4 (d, 3JCF = 5.3 Hz), 138.8 (d, 3JCF
= 7.6 Hz), 161.4 (d, 1JCF = 243.1 Hz).

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Synthesis of the (R)-Mosher ester of the intermediate (S)-acetamido alcohol.
F
OH
O
F
NHAc
DMF / Hexane
Ph
O
NHAc
(R)-(+)-MTPA
(S)-(+)-MTPA-Cl
OMe
Oxalyl chloride
CF3
TEA, DMAP, DCM
Oxalyl chloride (7.14 mL, 81.8 mmol) was added to a stirring solution of (R)-(+)-MTPA (35 mg,
0.195 mmol), DMF (15 µL) and hexane (6.72 mL). This solution was then stirred for 1 h at room
temperature before removing the solvent at reduced pressure to yield (S)-(+)-MTPA-Cl as an oil.
Added to this oil was a solution of the intermediate (S)-acetamido alcohol (44 mg, 0.195 mmol),
triethylamine (42 µL, 0.273 mmol) and DMAP (catalytic quantity) in dichloromethane (7 mL). The
reaction mixture was stirred at room temperature overnight then the solvent concentrated under
reduced pressure. This material was purified via flash chromatography. HPLC (214 nm), tR 9.82 min.
(91%); 1H-NMR (CDCl3) δ: 1.83 (s, 3H), 2.26 (s, 3H), 2.70-2.80 (m, 2H), 3.48 (s, 3H), 4.27 (d, J = 4.4
Hz, 2H), 4.39-4.42 (m, 1H), 5.56 (d, J = 8.2 Hz, 1H), 6.78-6.83 (m, 2H), 6.90-6.94 (m, 1H), 7.36-7.40
(m, 3H), 7.45-7.49 (m, 2H); LC/MS. tR = 9.02 min. (442.3 [M+H]+, 883.2 [2M+H]+, parent).
Synthesis of the (R)-Mosher amide of 2-amino-3-(2-fluoro-4-methylphenyl)propan-1-ol (21).
F
F
(R)-(+)-MTPA
OH
OH
Ph
EDC / HOBt / DIEA
THF
NH2
HN
OMe
CF3
O
To a solution of (S)-amino alcohol 21 (35 mg, 0.191 mmol) in tetrahydrofuran (0.5 mL) stirred at
room temperature was added (R)-(+)-MTPA (45 mg, 0.191 mmol), EDC (37 mg, 0.191 mmol) and
HOBt.H2O (26 mg, 0.171 mmol). The reaction mixture was the stirred at room temperature overnight
then diluted with water and extracted with diethyl ether (x 3). The combined organic layers were then
washed with 0.5M HCl, sodium hydrogen carbonate and brine, dried over sodium sulfate and the
1
solvent removed under reduced pressure to yield a colourless oil. H-NMR, LCMS and reverse phase
HPLC estimate the enantiomeric excess to be greater than 95% as the alternate (R)-enantiomer was
1
undetectable. HPLC (214 nm), tR 9.33 min. (74%); H-NMR (CDCl3) δ: 2.23 (s, 3H), 2.75-2.86 (m,
2H), 2.91 (bs, 1H), 3.20 (s, 3H), 3.48 (dd, J = 11.2, 4.9 Hz, 1H), 3.54 (dd, J = 11.2, 4.0 Hz, 1H), 4.12-
4.18 (m, 1H), 6.74-6.81 (m, 2H), 7.00-7.05 (m, 1H), 7.25-7.30 (m, 3H), 7.40-7.45 (m, 2H); LC/MS tR
= 8.51 min. (400.2 [M+H]+, 799.3 [2M+H]+, parent).

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421
(1R, 2S)-2-Methyl-1-cyclohexanol (23).
A pellet of potassium hydroxide (105 mg, 1.87 mmol) was fused under an atmosphere of argon and
allowed to cool under a stream of argon. Anhydrous 2-propanol (25 mL) was added and the mixture
stirred with heating to dissolve the potassium hydroxide. A solution of 2-methyl-1-cyclohexanone (22,
5.652 g, 50.4 mmol) in anhydrous 2-propanol (25 mL) was prepared under argon. The solution was
sonicated under a stream of argon for 15 min. Dichloro[(S)-2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl][(1R,2R)-1,2-diphenylethylenediamine]ruthenium(II) (50 mg, 50 µmol) was purged with
argon and drawn into a syringe as a suspension in anhydrous 2-propanol (10 mL). The potassium
hydroxide solution was added to the 2-methyl-1-cyclohexanone solution via syringe followed by the
ruthenium catalyst suspension. A hydrogenation flask was heated with a heat gun and allowed to cool
under a stream of argon. The cyclohexanone/catalyst/KOH mixture was added to a hydrogenation flask
via syringe. The argon atmosphere was exchanged with hydrogen with five evacuation/hydrogen purge
cycles. The mixture was stirred at room temperature under an atmosphere of hydrogen (65 psi) for
65 h. Water (250 mL) was added to the reaction mixture and the aqueous phase extracted with ether
(3 × 100 mL). The combined ether extracts were washed with water (250 mL) and brine (250 mL),
dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated to dryness (60 °C,
600 mbar) to give a pale brown oil which was purified by flash chromatography over silica gel with
dichloromethane as eluent. Fractions which contained the cis isomer (Rf 0.46) were combined and
evaporated to dryness (60 °C, 850 mbar) to give (1R, 2S)-2-methyl-1-cyclohexanol (23) as a clear oil
1
(5.40 g, 94%). By comparison of the integrals in the H-NMR spectrum of the resonance due to
dichloromethane and the resonance at δ 3.77, the purity of the sample was 81 mol% or 85 wt%.
1
(Corrected yield after taking dichloromethane into account: 4.58 g, 80% yield). H-NMR (CDCl3) δ:
13
0.94 (d, J = 6.8 Hz, 3H), 1.20-1.78 (m, 10H), 3.77 (br s, 1H); C-NMR (CDCl3) δ: 17.1, 20.9, 24.7,
30.0, 32.7, 36.0, 71.3.
(1S, 2S)-1-Azido-2-methylcyclohexane (24).
Solutions of triphenylphosphine (4.13 g, 15.8 mmol) in anhydrous tetrahydrofuran (60 mL) and (1R,
2S)-2-methyl-1-cyclohexanol (23, 1.50 g, 13.1 mmol) in anhydrous tetrahydrofuran (40 mL) were
prepared under nitrogen. Diethyl azodicarboxylate (2.50 mL, 15.9 mmol) was added dropwise to the
triphenylphosphine solution under nitrogen and the mixture stirred at room temperature for 10 min.
Diphenylphosphoryl azide (3.40 mL, 15.7 mmol) was added dropwise to this mixture under nitrogen.
The (1R, 2S)-2-methyl-1-cyclohexanol solution was transferred via cannula to the mixture. The
mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated to dryness
(60 °C, 285 mbar). The residue was dissolved in a 1:1 dichloromethane/n-hexane mixture (80 mL) and
purified by flash chromatography over gel with 1:1 dichloromethane/n-pentane as eluent. Fractions
eluting prior to the first fraction that could be visualised under a 254 nm lamp (Rf 0.60, eluent:
dichloromethane) were combined and evaporated to dryness (60 °C, 600 mbar) to give a clear oil

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422
1
(647 mg, 35% yield). H-NMR analysis of the first fraction that could be visualised under a 254 nm
lamp showed that it contained (1S,2S)-1-azido-2-methylcyclohexane (24) in addition to triphenyl-
phosphine oxide and tetrahydrofuran. This fraction was dissolved in 1:2 dichloromethane/n-pentane
(20 mL) and purified by flash chromatography over silica gel with 1:2 dichloromethane/n-pentane
(23 × 40 mL), 1:1 dichloromethane/n-pentane (17 × 40 mL), as eluent. The fractions containing the
(1S,2S)-1-azido-2-methylcyclohexane 24 were evaporated to dryness (60 °C, 600 mbar). The samples
of 24 obtained from the two columns were combined and evaporated to dryness (60 °C, 600 mbar) to
give the title compound as a clear oil (865 mg, 47% yield). By comparison of the integrals in the
1H-NMR spectrum of the resonance due to dichloromethane and the resonance at δ 2.78, the purity of
the sample was 78 mol% or 85 wt%. (corrected yield after taking dichloromethane into account:
1
736 mg, 40% yield). HPLC (214 nm), tR = 6.61 min. (9%), 10.28 min. (85%); H-NMR (CDCl3) δ:
1.01 (d, J = 6.8 Hz, 3H), 1.15-1.45 (m, 5H), 1.61-1.68 (m, 1H), 1.71-1.84 (m, 2H), 2.01-2.08 (m, 1H),
2.78 (td, J = 10.6, 4.0 Hz, 1H); 13C-NMR (CDCl3) δ: 19.6, 25.3, 25.5, 31.7, 34.1, 37.9, 67.3; ESMS m/z
No molecular ion observed; LC/MS tR = 5.85 min. (no molecular ion observed), 9.78 min. (no
molecular ion observed).
(1S, 2S)-2-Methyl-1-cyclohexylamine (25).
A mixture of (1S, 2S)-1-azido-2-methylcyclohexane (24, 865 mg, 6.21 mmol), triphenylphosphine
(3.282 g, 12.5 mmol), water (225 µL, 12.5 mmol) and tetrahydrofuran (28 mL) was heated at reflux for
16 h. The reaction mixture was evaporated to dryness (60 °C, 285 mbar).Ether (50 mL) and
hydrochloric acid (0.1 M, 100 mL) were added to the crude product. The phases were separated and
the aqueous phase washed with ether (2 × 50 mL). A 10% sodium carbonate solution (25 mL) was
added and the aqueous phase extracted with dichloromethane (3 × 50 mL). The combined
dichloromethane extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was
evaporated to dryness (60 °C, 500 mbar) to give (1S, 2S)-2-methyl-1-cyclohexylamine (25) as a pale
yellow oil (crude: 680 mg, 97% yield). By comparison of the integrals in the 1H-NMR spectrum of the
resonance due to dichloromethane and the multiplet at δ 2.20, the purity of the sample was 57 mol% or
1
64 wt% (corrected yield after taking dichloromethane into account: 435 mg, 62% yield). H-NMR
(CDCl3) δ: 0.97 (d, J = 6.4 Hz, 3H), 0.99-1.34 (m, 7H), 1.60-1.75 (m, 3H), 1.77-1.84 (m, 1H), 2.20
(ddd, J = 10.9, 9.5, 4.0 Hz, 1H); 13C-NMR (CDCl3) δ: 19.3, 26.0, 26.4, 34.5, 36.6, 41.1, 56.9.
Resolution of 25: (1S, 2S)-2-Methyl-1-cyclohexylammonium hydrogen (+)-tartrate.
(+)-Tartaric acid (790 mg, 5.26 mmol) was dissolved in methanol (2.0 mL) with heating and
allowed to cool. 2-Methyl-1-cyclohexylamine (25, 680 mg, 5.32 mmol) was dissolved in methanol
(3.0 mL). The tartaric acid solution was added to the 2-methyl-1-cyclohexylamine solution. The
volume of the 2-methyl-1-cyclohexylamine / tartaric acid mixture was reduced to ca. 4 mL by heating.
The mixture was allowed to cool to room temperature and then placed in the freezer overnight. The

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mixture was removed from the freezer and allowed to warm to room temperature then filtered and the
residue dried at the pump to give (1S, 2S)-2-methyl-1-cyclohexylammonium hydrogen (+)-tartrate as a
white solid (390 mg, 28% yield). 1H-NMR (D2O) δ: 1.07 (d, J = 6.4 Hz, 3H), 1.11-1.20 (m, 1H), 1.24-
1.48 (m, 3H), 1.52-1.64 (m, 1H), 1.69-1.76 (m, 1H), 1.79-1.88 (m, 2H), 2.02-2.08 (m, 1H), 2.87 (td,
J = 10.7, 3.2 Hz, 1H), 4.58 (s, 2H); 13C-NMR (D2O) δ: δ 17.8, 24.4, 24.9, 30.8, 33.4, 36.0, 56.7, 73.0,
176.4. (n.b. 13C-NMR chemical shifts are relative as there was no internal reference present).
Determination of the enantiomeric excess of 25: preparation of the Mosher amide.
(1S,2S)-2-methyl-1-cyclohexylammonium hydrogen (+)-tartrate (20 mg) was dissolved in
deuterium oxide (0.7 mL). Water (1.0 mL) and a 10% sodium carbonate solution (2.0 mL) were added
to the NMR sample and the aqueous phase extracted with dichloromethane (3 × 2 mL). The organic
extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness
(60 °C, 600 mbar) to give (1S,2S)-2-methyl-1-cyclohexylamine 25 as a white solid. A mixture of EDC
(36.4 mg, 0.19 mmol), (S)-α-methoxy-α-trifluoro-methylphenylacetic acid (35.3 mg, 0.15 mmol),
1-hydroxybenzotriazole hydrate (29.8 mg, 0.19 mmol) and diisopropylethylamine (62 µL, 0.36 mmol)
in tetrahydrofuran (2.0 mL) was stirred at room temperature for 0.5 h. 2-Methyl-1-cyclohexyl-
amine (25) was dissolved in tetrahydrofuran (1.0 mL) and added to the mixture. The mixture was
stirred at room temperature for 15.5 h. Water (10 mL) was added and the mixture extracted with ethyl
acetate (3 × 10 mL). The ethyl acetate extracts were washed with hydrochloric acid (1 M, 2 × 10 mL),
a 10% sodium carbonate solution (2 × 10 mL) and brine (10 mL), dried over anhydrous sodium sulfate
and filtered. The filtrate was evaporated to dryness. The residue was dissolved in dichloromethane and
filtered through a plug of silica gel with dichloromethane as eluent. The filtrate was evaporated to
dryness to give a white solid (crude: 20 mg, 80% yield overall for the neutralisation and Mosher amide
formation). 19F-NMR analysis of the Mosher amide of 25 showed two resonances. The integral of
these two peaks was 96.1:3.9, which is equivalent to an enantiomeric excess of 92%. 19F-NMR
(CDCl3) δ: -70.2 (s, 96.1% of total integral, (1S, 2S, S-MTPA)), -70.5 (s, 3.9% of total integral, (1R,
2R, S-MTPA)). (n.b. 19F-NMR chemical shifts are relative as there was no internal reference present).
Preparation of 6-methoxy -1-indanol (27).
6-Methoxy-1-indanone (26, 92.5 mmol) was dissolved in methanol (150 mL) at room temperature.
Sodium borohydride powder (107.7 mmol) was added portionwise over several minutes with stirring.
After overnight stirring at room temperature, the reaction mixture was diluted with distilled water (100
mL) and acidified with 2M hydrochloric acid (100 mL) then extracted with ether (3 x 150 mL). The
combined ether extracts were washed with brine (150 mL), dried over anhydrous sodium sulfate and
concentrated to give 6-methoxy-1-indanol 27 (15.5 g, 98.6% yield) as a clear oil. HPLC (214 nm), tR =
1
6.13 min. (96.4%); H-NMR (CDCl3) δ: 1.95-1.99 (m, 1H), 2.41-2.57 (m, 1H), 2.65-2.79 (m, 1H),
2.90-3.00 (m, 1H), 3.78 (s, 3H), 5.17 (t, J = 6.0 Hz, 1H), 6.80 (dd, J = 8.4, 2.4 Hz, 1H), 6.93 (d, J =

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2.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H); 13C-NMR (CDCl3) δ: 29.1, 36.8, 55.7, 76.9, 109.0, 115.2, 125.7,
135.3, 146.5, 159.2; LC/MS tR = 5.73 min. (147.3 [M+H-18]+).
Preparation of 5-methoxy-1H-indene (28).
The crude 6-methoxy-1-indanol 27 (92.5 mmol) and 4-toluenesulfonic acid (5.81 mmol) were
dissolved in toluene (200 mL). The mixture was boiled under a Dean-Stark water collector for 5 h
then washed with 5% sodium sulfate (3 x 80 mL) and brine (1 x 50 mL). The organic phase was dried
over anhydrous sodium sulfate, filtered and the solvent evaporated to give crude product as a brown
oil. The crude oil was distilled under vacuum to give pure 5-methoxy-1H-indene 28 as a clear pale oil
(11.2 g, 83.3% yield). HPLC (214 nm), tR = 8.86 min. (98.4%); 1H-NMR (CDCl3) δ: 3.33 (s, 2H), 3.82
(s, 3H), 6.56-6.58 (m, 1H), 6.75 (dd, J = 8.4, 2.4 Hz, 1H), 6.81-6.83 (m, 1H), 6.96 (d, J = 4 Hz, 1H),
13
7.33 (d, J = 8.4 Hz, 1H); C-NMR (CDCl3) δ: 38.5, 55.7, 106.7, 110.9, 124.3, 132.2, 135.8, 136.0,
146.5, 159.1; LC/MS tR = 8.48 min.
Chiral epoxidation of 5-methoxy-1H-indene (28) to produce epoxide 29.
A stirred mixture of 5-methoxy indene (28, 13.9 mmol), (R,R)-Jacobsen’s catalyst (1.39 mmol) and
4-phenylpyridine N-oxide (1.39 mmol) in dichloromethane (1.6 mL) was cooled to 5 °C. A cold
aqueous solution of sodium hypochlorite (10.7 mL) was added in slowly with vigorous stirring while
maintaining the reaction temperature between 0 – 2 °C. Upon complete addition of the bleach, the
reaction mixture was stirred for another one hour at 0 °C. At this point, hexane (11 mL) was added in
one portion with stirring and the reaction mixture was filtered through a pad of Celite™ on a large
buchner funnel. The filtrate brown organic layer was washed with brine (2 x 50 mL), dried over
anhydrous sodium sulfate, filtered and concentrated to give crude epoxide 29 as a brown liquid (990
1
mg, 40% yield). HPLC (214 nm), tR = 4.81 min. (65.4%); H-NMR (CDCl3) δ: 2.91 (dd, J = 17.6,
2.8 Hz, 1H), 3.14 (d, J = 17.6 Hz, 1H), 3.8 (s, 3H), 4.12 (t, J = 2.8 Hz, 1H), 4.21 (m, 1H), 6.80 (dd, J =
13
8.2, 2.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H); C-NMR (CDCl3) δ: 34.0, 55.7,
58.5, 59.3, 111.4, 114.4, 126.8, 135.3, 142.3, 158.6; ESMS m/z 163.2 [M+H]+, 180.9 [M+H+H2O]+,
204.5 [M+H+MeCN]+, 325.5 [2M+H]+; LC/MS tR = 4.51 min. (204.1 [M+H+MeCN]+).
Preparation of (1R, 2S)-1-amino-6-methoxy-indan-2-ol (30).
A three-necked flask under nitrogen atmosphere was charged with indene oxide 29 (4.0 mmol),
acetonitrile (5 mL) then stirred and cooled to –40 °C. To this slurry was added
trifluoromethanesulfonic acid (8.0 mmol) while maintaining the reaction temperature at –30 °C. The
reaction mixture was warmed to room temperature and stirred for 1 h. Water (10 mL) was added and
aged for 15 min. After removal of acetonitrile under reduced pressure, the reaction mixture was heated
at reflux for 5 h. After cooling to room temperature, dichloromethane (5 mL) was added and stirred for

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10 min. The two phases were separated and the aqueous layer containing the amino indanol was
collected. The aqueous solution was basified with 3M sodium hydroxide (5 mL) and extracted with
ethyl acetate (3 x 30 mL). The organic layer was concentrated under reduced pressure to about 10 mL.
To this solution, cold hydrochloric acid in ethyl acetate was added slowly with stirring. The resulting
solid salt was collected and washed with cold petroleum spirit to give the desired (1R, 2S)-cis-amino
1
alcohol as the hydrochloride salt 31. HPLC (214 nm) tR = 4.10 min. (92.4%); H-NMR (CDCl3) δ:
2.86 (dd, J = 16.0, 2.7 Hz, 1H), 3.03 (dd, J = 16.0, 5.6 Hz, 1H), 3.8 (s, 3H), 4.28 (brs,1H), 4.37 (m,
1H), 6.78 (dd, J = 8.4, 2.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H); 13C-NMR
(CDCl3) δ: 38.8, 55.7, 59.0, 73.6, 109.6, 114.1, 126.2, 132.8, 145.61, 159.43; ESMS m/z 180.4
[M+H]+, 221.5 [M+H+MeCN]+; LC/MS tR = 3.80 (180.3 [M+H]+) min.
Determination of the chiral purity via (S)-Mosher amide of (30).
(S)-(-)-MTPA
EDC / HOBt / DIEA
THF / r.t.
OH
MeO
OH
NH
O
MeO
NH2
Ph
CF3
MeO
A mixture of EDC (0.06 mmol, 1 eq), (S)-(-)-MTPA [(S)-α-methoxy-α-trifluoromethylphenylacetic
acid, 0.06 mmol, 1 eq], HOBt·H2O (0.06 mmol, 1 eq) and DIEA (0.12 mmol, 2 eq) in tetrahydrofuran
(300 µL) was stirred at room temperature for 15 min. A solution of (1R, 2S)-cis-amino alcohol 30
(10 mg, 0.06 mmol) in tetrahydrofuran (200 µL) was added and the mixture stirred at room
temperature for two days. Ethyl acetate (20 mL) was added and the solution was washed with 5% citric
acid (2 x 10 mL), 10% sodium hydrogen carbonate solution (2 × 10 mL) and brine (2 x 10 mL), then
dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness to give the
19
(S)-Mosher amide derivative of 30; HPLC (214 nm), tR = 9.01 min. (73.7%); F-NMR (CDCl3) δ: -
69.1; LC/MS tR = 8.53 min. (396.2 [M+H]+). An extracted ion chromatogram (mass = 396.0 – 397.1)
showed only 1 peak corresponding with the (S)-Mosher amide derivative of 30. The chiral purity of the
amide therefore was over 99%. This agreed with 19F NMR data, showing one line for one isomer only.
Thus, the enantiomeric excess of 1-amino-6-methoxy-indan-2-ol (30) was determined to be >98%.
References and Notes
1. Robinson, A. J.; Lim, C.Y.; He, L.; Ma, P.; Li, H-Y. Highly Enantioselective Synthesis of α, β-
Diaminopropanoic Acid Derivatives Using a Catalytic Asymmetric Hydrogenation Approach. J.
Org. Chem. 2001, 66, 4141-4147.

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2. Burk, M.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. Preparation and use of C2-Symmetric
Bis(phospholanes): Production of α-Amino Acid Derivatives via Highly Enantioselective
Hydrogenation reactions. J. Am. Chem. Soc. 1993, 115, 10125-10138.
3. Yasuhara, F.; Yamaguci, S.; Kasai, R.; Tanaka, O. Assignment of Absolute Configuration of 2-
substituted-1-propanols by 1H NMR Spectroscopy. Tetrahedron Lett., 1986, 27, 4033-4034.
4. Gallou-Dagommer, I.; Gastaud, P.; RajanBabu, T. V. Asymmetric Synthesis of Functionalized
1,2,3,4-Tetrahydroquinolines. Org. Lett. 2001, 3, 2053-2056.
5. Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori R. Stereoselective Hydrogenation of
Simple Ketones Catalyzed by Ruthenium(II) Complexes. J. Org. Chem. 1996, 61, 4972-4873.
6. Lists of atomic coordinates, displacement parameters, structure factors and complete geometry of
25 and 32 have been deposited with the CCDC (deposition numbers 239229 and 239230,
respectively). Copies may be obtained through the Managing Editor, Cambridge Crystallographic
Data Centre (CCDC), 12 Union Road, Cambridge, CB2 1EZ, England.
7. Larrow, J. F.; Roberts, E.; Verhoeven, T. R.; Ryan, K. M.; Senanayake, C. H.; Reider, P. J.;
Jacobsen E. N. (1S,2R)-1-aminoindan-2-ol. Org. Syn., 1998, 76, 46.
Sample Availability: Available from the authors.
2004 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.