An approach to chiral amino acids via reductive amination of ketones: Hydride reduction of 1-(S)-phenethyl amine derived Schiff bases of C-protected α-keto acids

Article abstract of DOI:10.1016/j.tetasy.2012.06.017

Various 1-acyl-2,4,10-trioxaadamantanes were prepared from the corresponding 1-methoxycarbonyl derivatives, via conversion to the N-acylpiperidine derivatives followed by reaction with a Grignard reagent in refluxing THF. These α-keto orthoformates were converted to the corresponding imines with 1-(S)-phenethyl amine (TiCl₄/Et ₃N/toluene/reflux), with the Schiff bases being reduced further with NaBH₄ (MeOH/0 °C) into the corresponding 1-(S)-phenethyl amines (diastereomeric excess 91:9 by NMR). Hydrogenolysis of the phenethyl group (Pd-C/MeOH) finally led to the 1-(aminoalkyl)trioxaadamantanes, which are chiral C-protected α-amino acids, in excellent overall yields. 2012 Elsevier Ltd.

Full text of DOI:10.1016/j.tetasy.2012.06.017

Tetrahedron: Asymmetry 23 (2012) 1005–1009
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An approach to chiral amino acids via reductive amination of ketones:
hydride reduction of 1-(S)-phenethyl amine derived Schiff bases
of C-protected
a-keto acids
⇑
Sosale Chandrasekhar , V. Mohana Rao
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2012
Accepted 22 June 2012
Various 1-acyl-2,4,10-trioxaadamantanes were prepared from the corresponding 1-methoxycarbonyl
derivatives, via conversion to the N-acylpiperidine derivatives followed by reaction with a Grignard
reagent in refluxing THF. These a-keto orthoformates were converted to the corresponding imines with
1-(S)-phenethyl amine (TiCl4/Et3N/toluene/reflux), with the Schiff bases being reduced further with
NaBH4 (MeOH/0 °C) into the corresponding 1-(S)-phenethyl amines (diastereomeric excess 91:9 by
NMR). Hydrogenolysis of the phenethyl group (Pd-C/MeOH) finally led to the 1-(aminoalkyl)trioxaada-
mantanes, which are chiral C-protected
a
-amino acids, in excellent overall yields.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
pyrrolidine amide 2 (Scheme 1). The reaction of ester 1 with piper-
idine in THF was promoted by anhydrous MgCl2 and occurred in
excellent yields.12 The resulting amide 2 was reacted with a variety
of Grignard reagents, thus effecting the delivery of the alkyl group
in ketones 3 in very high yields (Table 1).13 These were then con-
densed with a chiral auxiliary, 1-(S)-phenethyl amine, to form
the corresponding imines (Schiff bases) 4. These were not isolated
in purified form, but were reduced further as described below.
The reduction of the chiral Schiff bases 4, with sodium borohy-
dride in MeOH at 0 °C, occurred in excellent yields and diastereose-
lectivity (91:1, Table 1). The like (l) and unlike (u) diastereomeric
products 5 were separated by chromatography,14 and the configu-
ration of the major diastereomer was established as (1S) by X-ray
crystallography (Fig. 1).15 The observed diastereoselectivity can be
best explained by assuming the formation of the Z geometrical iso-
mer of the imines 4; this apparently adopts a conformation around
the N–C single bond with the relatively bulky phenyl ring away
from the trioxaadamantyl moiety (Scheme 2). Hydride delivery to
the C@N group from the less hindered Re face (syn to the H rather
than the Me at the benzylic center) thus leads to the observed (S)-
configuration at the newly created stereogenic center.15
Thus, the observed stereochemistry is predicated on the
preferential formation of the Z imine, which also preferentially
adopts the above conformation around the C–N bond. The forma-
tion of the Z-imine may be driven by the lone pair repulsions be-
tween the N and O centers in the alternative E-isomer; the
conformational preference around C–N is presumably driven by
steric factors as mentioned above. Explanations for the observed
stereoselectivity based on the formation of the E-imine are less
plausible, and would require a U-shaped arrangement in which R
and Ph would clash.
The synthesis of chiral a-amino acids in high enantiomeric purity
is of great interest in chemistry and chemical biology. Currently, chi-
rality at the C2 position may be induced in several ways depending
on the synthetic route employed. Catalytic methods apparently
dominate the scene, with a variety of approaches having been em-
ployed for the selective introduction of groups around the stereo-
genic center.1–6
Resolution of synthetic racemates also remains of continuing
interest as it leads to both enantiomeric forms; note that amino
acids can be transformed into a variety of final products, and that
access to both forms is advantageous to biological activity studies.
Catalytic kinetic resolution strategies, particularly enzymatic ones,
have often been employed; however, conventional derivatization
to diastereomers that are resolved by various chromatographic
methods is also being pursued.7–10
Herein we report an interesting new approach based on the sodium
borohydride reduction of a chiral Schiff base, which was derived from a
carboxyl-protected
a-keto acid. We have previously reported on the
synthetic utility of the 2,4,10-trioxaadamantane unit,11 a tricyclic ortho-
ester proven to be a robust carboxyl protecting group. This has now been
extended to the above synthesis of amino acids.
2. Results and discussion
The carboxyl-protected a-keto acids 3 were prepared from the
known11 trioxaadamantyl carboxylic ester 1 via the corresponding
⇑
Corresponding author. Tel.: +91 80 22932689; fax: +91 80 23600529.
E-mail address: sosale@orgchem.iisc.ernet.in (S. Chandrasekhar).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.017

1006
S. Chandrasekhar, V. Mohana Rao / Tetrahedron: Asymmetry 23 (2012) 1005–1009
O
O
R
O
OMe
O
O
N
Ph
N
O
R
3
4O
O 2
O
(iii)
(i)
O
(ii)
O
O190
O
O
O
5
1
7
6
8
3
2
1
4
(iv)
H
H
N
Ph
N
R
(i) C5H10NH/MgCl2/THF/rt
(ii) RMgX/THF/reflux
Ph
R
H2N
O
R
(iii) 1-(S)-PhCH(Me)NH2/
TiCl4/Et3N/toluene/reflux
(iv) NaBH4/MeOH/0 °C
(v) On l-5: Pd(OH)2/C/MeOH/H2
O
O
O
O
O
(v)
O
O
O
+
u-5
(1S)-6
l-5
(l:u ~ 9:1)
Scheme 1. The conversion of the trioxaadamantyl methyl ester 1 to the diastereomeric phenethyl amine derivatives 5, via amide 2, ketone 3, and imine 4, under the indicated
reaction conditions.
Table 1
Yields (%) of 3, 5, and 6, and the diastereomeric ratio (l:u) of 5 (cf. Scheme 1)
OMe
H
Item
RMgX
3a–3f
5a–5f
Yield (%)
6a–6f
Ph
H
N
R
O
N
Ph
Yield (%)
l:u
Yield (%)
R
H
Me
Me
1
2
3
4
5
6
EtMgBr
92 3a
92 3b
93 3c
89 3d
94 3e
94 3f
84 5a
78 5b
76 5c
71 5d
82 5e
79 5f
91:9
96 6a
94 6b
95 6c
93 6d
93 6e
97 6f
H
H
PrnMgBr
89:11
87:13
83:17
91:9
H-
O
O
O
n-C6H13MgBr
O
O
BuiMgBr
BuiCH2MgBr
PhCH2MgCl
88:12
4
5
Scheme 2. Explanation for the observed stereoselectivity in the reduction of 4 to 5,
based on the formation of the Z-imine 4 and subsequent hydride delivery from the
top Re face as shown, to form 5.
high yields. These are enantiomerically pure, since the hydrogenol-
ysis should occur without disturbing the newly-created stereocen-
ter in 5.
Furthermore, although the reductive amination strategy has
matured in recent decades, its application to amino acid synthesis
is still evolving. The reductive amination of carbonyl compounds
has generally been carried out by hydrogenation or borohydride
reduction of the intermediate imine species.16,17 The reductive
amination of a-keto acids with enzymes or metal catalysts has also
Figure 1. Crystallographic ORTEP diagram of the 1-(S)-phenethyl amine derivative
l-5a, obtained via borohydride reduction of imine 4a. The displayed configuration of
the newly created stereogenic center relative to the known absolute stereochem-
istry of the phenethyl moiety establishes the former as (S).
been reported.18,19 It would thus be useful to extend this strategy
to include relatively inexpensive chiral auxiliaries and reducing
agents, hence the present studies.
It is noteworthy that chiral-auxiliary based approaches lead to
homochiral products upon cleavage of the auxiliary, a level of
enantiopurity rarely achieved with chiral catalysis. These ap-
proaches apparently define a ‘middle ground’ in between the cata-
lytic asymmetric synthesis and the resolution of the racemate. The
auxiliary-based approach thus possesses the advantages of both:
the preferential formation of one of the enantiomers (as in catalytic
synthesis) and access to homochiral products (as in resolution).
The reduction of imines 4 to the amines 5 was investigated un-
der various other conditions and reagents. With NaBH4 in MeOH,
the stereoselectivity was unaltered in the range 0 ? ꢀ78 °C. DI-
BAL-H afforded moderate selectivity (72:28) in CH2Cl2 and negligi-
ble selectivity in THF, both at ꢀ78 °C. Lithium aluminum hydride
also afforded moderate selectivity (80:20) in THF at ꢀ78 °C. The
diastereomer ratios are based on the 1H NMR integration of the
proton at the newly-created stereocenter adjacent to ‘R’ in 5.
The cleavage of the N-phenethyl group in amines 5 was accom-
plished by hydrogenation in the presence of Pd(OH)2/C, in MeOH at
room temperature, to afford the C-protected chiral amino acids 6 in
3. Conclusion
We have developed an auxiliary-based approach to chiral amino
acids by the reductive amination of the chiral imine of carboxyl pro-

S. Chandrasekhar, V. Mohana Rao / Tetrahedron: Asymmetry 23 (2012) 1005–1009
1007
tected
a
-keto acids. The chirality is induced by a 1-(S)-phenethyl
above, and are not assigned again. The other resonances are as-
signed. Similarly, the IR C–H stretch occurs at ꢂ2900 cmꢀ1 and is
not assigned.
unit on the imine nitrogen atom. Our strategy is characterized by
high yields and diastereoselectivity in the reductive amination step.
Chromatographic separation of the diastereomers and cleavage of
the auxiliary in a straightforward fashion give carboxyl-protected
amino acids, which are essentially enantiomerically homogeneous.
It is noteworthy that an auxiliary-based approach generally pos-
sesses certain characteristic advantages, in particular the preferen-
tial formation of an essentially homochiral end-product.
4.4. Ethyl 2,4,10-trioxaadamant-3-yl ketone 3a
White solid, mp 122–123 °C; vmax 2980, 2943, 1747 (C@O),
1318, 1131, 1086, 979, 964; dH 4.51 (3H, br s), 2.74–2.68 (5H, m,
OCCHeq + –CO–CH2), 1.80–1.77 (3H, d, J 12.8), 1.60 (3H, t, J 7.2,
Me); dC 199.89 (C@O), 105.56, 68.83, 32.86, 28.82 (–CO–C), 7.01
(CMe); HRMS: m/z calcd for C10H14O4 + Na 221.0790, found
221.0793.
4. Experimental
4.1. General comments
4.5. n-Propyl 2,4,10-trioxaadamant-3-yl ketone 3b
Instruments employed: JASCO 410 (FTIR); Bruker AV-400
(NMR); Micromass Q-TOF AMPS MAX 10/6A (HRMS); Stuart
SMP10 (melting point); Büchi Rotavapor R-200 (rotary evaporator).
The methyl ester 1 was prepared as reported previously.11 Upon
aqueous work-up and extraction, extracts were generally dried over
MgSO4 prior to evaporation of the solvent in vacuo on a rotary evap-
orator. Melting points (mps) are uncorrected. IR spectra were re-
corded neat and the values are quoted in cmꢀ1. NMR spectra were
recorded in CDCl3 solution with TMS as an internal standard at
either 400 MHz (dH) or 100 MHz (dC); the coupling constants (J)
are in Hz. The NMR assignments indicate atom connectivity only,
with the assigned atom or group in italics; substituents (including
H) are generally now shown and subscripts (C2 etc.) indicate chain
length (not skeletal numbering).
White solid, mp 101–103 °C; vmax 2968, 2940, 1747 (C@O),
1311, 1125, 1117, 1087, 1044, 1007, 983; dH 4.51 (3H, br s),
2.74–2.71 (3H, d, J 12.8), 2.65 (2H, t, J 7.2, –CO–CH2), 1.80–1.77
(3H, d, J 12.8), 1.66–1.57 (2H, m, –CO–C–CH2), 0.92 (3H, t, J 7.2,
Me); dC 199.16 (C@O), 105.49, 68.86, 37.39 (–CO–C), 32.89, 16.37
(–CO–CC), 13.59 (CMe); HRMS: m/z calcd for C11H16O4+Na
235.0946, found 235.0943.
4.6. n-Hexyl 2,4,10-trioxaadamant-3-yl ketone 3c
White solid, mp 94–95 °C; vmax 2962, 2934, 1744 (C@O), 1314,
1127, 1087, 989, 975; dH 4.51 (3H, br s), 2.74–2.71 (3H, d, J 12.8),
2.66 (2H, t, J 7.6, –CO–CH2), 1.80–1.76 (3H, d, J 12.8), 1.61–1.54
(2H, m, –CO–C–CH2), 1.34–1.24 (6H, m, remaining CH2 of the hexyl
moiety), 0.87 (3H, t, J 7.2, Me); dC 199.31 (C@O), 105.52, 68.86,
35.52 (–CO–C), 32.89, 31.50 (–CO–CC), 28.70 (–CO–C2C), 22.83 (–
CO–C3C), 22.44 (–CO–C4C), 13.98 (CMe); HRMS: m/z calcd for
4.2. 2,4,10-Trioxaadamantan-3-carboxylic acid piperidine
amide 212,13
C14H22O4+Na 277.1416, found 277.1415.
Methyl ester 1 (5 mmol) in dry THF (10 mL) was treated with
MgCl2 (5.5 mmol) at 25 °C. The resulting slurry was stirred for
5 min, and treated with piperidine (20 mmol), dropwise over
5 min., with stirring which was continued for 12 h. Water was then
added to the reaction mixture which was extracted with EtOAc
(3 ꢁ 25 mL). The extracts were washed with brine and dried
(Na2SO4). Evaporation of the solvent afforded amide 2 as a pale yel-
4.7. iso-Butyl 2,4,10-trioxaadamant-3-yl ketone 3d
White solid, mp 102–103 °C; vmax 2979, 2958, 2936, 1747
(C@O), 1311, 1124, 1086, 1010, 991; dH 4.51 (3H, br s), 2.74–2.71
(3H, d, J 12.8), 2.56–2.55 (2H, d, J 6.8, –CO–CH2), 2.23–2.13 (1H,
m, Me2CH), 1.79–1.76 (3H, d, J 12.8), 0.93–0.91 (6H, d, J 6.8, 2 x
Me); dC 198.62 (C@O), 105.40, 68.87, 44.30 (–CO–C), 32.90, 23.41
(Me2C), 22.49 (CMe); HRMS: m/z calcd for C12H18O4 + Na
249.1103, found 249.1104.
5
low solid (94%); mp 209–211 °C (lit. 211–212 °C); vmax 2972,
2952, 2936, 2856 (all C–H stretch), 1660 (amide C@O), 1203,
1123, 1030, 990; dH 4.55 (3H, br s, OCH), 3.86–3.84 (2H, m) and
3.56–3.54 (2H, m) (distinct NCH2 due to partial double bond of
CO–N by amide resonance), 2.77–2.74 (3H, d, J 12.8, OCCHeq),
1.78–1.75 (3H, d, J 12.8, OCCHax), 1.63–1.54 (6H, m, NCCH +
NCCCH); dC 161.53 (C@O), 105.60 (OC3), 69.00 (OC1,5,7), 47.57 and
44.22 (distinct NC), 32.64 (OCC6,8,9), 26.37 and 25.60 (distinct
NCC), 24.54 (NCCC); HRMS m/z calcd for C13H19NO4+Na 276.1212,
found 276.1210.
4.8. 3-Methylbutyl 2,4,10-trioxaadamant-3-yl ketone 3e
White solid, mp 100–101 °C; vmax 2963, 2957, 2931, 1745
(C@O), 1310, 1124, 1118, 1086, 1044, 994; dH 4.52 (3H, br s),
2.74–2.71 (3H, d, J 12.8), 2.67 (2H, t, J 7.6, –CO–CH2), 1.80–1.77
(3H, d, J 12.8), 1.61–1.45 (3H, m, –CO–CCH2 + Me2CH), 0.90–0.88
(6H d, J 6.4, 2 ꢁ Me); dC 199.47 (C@O), 105.57, 68.87, 33.54 (–
CO–C), 32.89, 31.64 (–CO–CC), 27.59 (Me2C), 22.32 (CMe); HRMS:
m/z calcd for C13H20O4+Na 263.1259, found 263.1257.
4.3. Ketones 313
The Grignard reagents were generally prepared from Mg turn-
ings (15 mmol) in dry THF (7 ml) under N2, with reaction being ini-
tiated with a speck of I2. This stirred suspension was treated
dropwise with the alkyl halide (10 mmol) over 10 min, thus achiev-
ing gentle reflux, and stirring was continued for a further 30 min.
This was added to amide 2 (0.100 g, 0.4 mmol) in a ratio of
0.6:0.4 in refluxing THF (5 mL) over 5 min., with the reflux being
continued for 3 h. The mixture was cooled to room temperature
and quenched cautiously with saturated NH4Cl. The crude product
was extracted into EtOAc, and finally purified by column chroma-
4.9. Benzyl 2,4,10-trioxaadamant-3-yl ketone 3f
White solid, mp 181–184 °C; vmax 2969, 2939, 1749 (C@O),
1312, 1118, 1084, 1010, 992; dH 7.32–7.18 (5H, m, ArH), 4.54
(3H, br s), 3.99 (2H, s, PhCH2), 2.76–2.73 (3H, d, J 12.8), 1.80–
1.77 (3H, d, J 12.8); dC 196.04 (C@O), 133.63 (CAr), 129.89 (CAr),
128.26 (CAr), 126.71 (CAr), 105.74, 68.98, 41.94 (–CO–C), 32.87;
HRMS: m/z calcd for C15H16O4+Na 283.0946, found 283.0945.
4.10. Reductive amination of ketones 3 to amines 5
tography (SiO2) to afford the C-protected-a-keto acids 3.
The ketone (0.25 mmol) in toluene (5 mL) was treated with (S)-
General spectroscopic features: The dH and dC of the trioxaada-
(ꢀ)-a-methylbenzylamine (39 lL, 0.3 mmol) and triethylamine
mantyl moiety occur at similar values to those in 2 as assigned

1008
S. Chandrasekhar, V. Mohana Rao / Tetrahedron: Asymmetry 23 (2012) 1005–1009
(87
lL, 0.625 mmol) with stirring. The mixture was cooled to 0 °C
(NCPh), 56.83 (NCC6H13), 33.17, 30.08 (NCC), 31.85 (NC2C), 29.27
and treated dropwise with titanium(IV) chloride (15
lL,
(NC3C), 26.09 (NC4C), 24.80 (PhCMe), 22.56 (NC5C), 14.07 (NC6C);
HRMS: m/z calcd for C22H33NO3+H 360.2539, found 360.2538.
0.13 mmol). The stirred reaction mixture was refluxed for 12 h.
Upon cooling to room temperature, the mixture was filtered to re-
move the precipitated TiO2 and Et3NꢃHCl. The filter cake was
washed with toluene and the combined organic layers were con-
centrated under reduced pressure. The resulting crude imine prod-
uct 4 was used for the following step. The crude imine was taken
into dry methanol at 0 °C and treated with NaBH4 (10 mg,
0.25 mmol). The mixture was stirred for 1 h and cautiously
quenched by the addition of water (2 mL). The mixture was ex-
tracted with EtOAc (3 ꢁ 10 mL), and the extracts washed with
brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The
crude residue was purified chromatographically over neutral
Al2O3 to obtain the diastereomerically pure phenethyl amines l-5.
General spectroscopic features: The dH and dC of the trioxaada-
mantyl moiety occur at similar values to those in 2 as assigned
above, and are not assigned again (cf. 3). The other resonances
are assigned. Similarly, the IR C–H stretch occurs at ꢂ2900 cmꢀ1
and is not assigned; the N–H stretch occurs at ꢂ3345 cmꢀ1 and
is assigned.
4.14. N-[(1S)-Phenethyl] (1R)-(2,4,10-trioxaadamant-3-yl)heptyl
amine u-5c
Colorless liquid; ½a D24
¼ ꢀ2:9 (c 0.46, CHCl3); vmax 3343 (N–H),
ꢄ
2955, 2927, 2856, 1601 (C=C), 1450, 1314, 1136, 1006; dH 7.33–
7.26 (4H, m, ArH), 7.22–7.19 (1H, m, ArH), 4.38 (3H, br s), 4.07–
4.02 (1H, q, J 6.4, PhCH), 2.59–2.55 (3H, d, J 13.6), 2.48–2.46 (1H,
dd, J 4.4 and 6.0, NCH), 1.78 (1H, br s, NH), 1.69–1.62 (4H, m, dia-
stereotopic NCCH + OCCHax), 1.45–1.42 (1H, m, diastereotopic
NCCH), 1.33–1.25 [11H, m, PhCMe + (CH2)4], 0.87 (3H, t, J 6.4,
CH2Me); dC 146.49 (CAr), 128.21 (CAr), 126.74 (CAr), 126.45 (CAr),
111.73, 67.86, 60.39 (NCPh), 55.19 (NCC6H13), 33.11, 31.89 (NCC),
29.79 (NC2C), 29.14 (NC3C), 26.60 (NC4C), 23.98 (PhCMe), 22.69
(NC5C), 14.14 (NC6C); HRMS: m/z calcd for C22H33NO3+H
360.2539, found 360.2538.
4.15. N-[(1S)-Phenethyl] (1S)-(2,4,10-trioxaadamant-3-yl)-3-
methylbutylamine 5d
4.11. N-[(1S)-Phenethyl] (1S)-(2,4,10-trioxaadamant-3-yl)propyl
amine 5a
White solid, mp 84–86 °C; ½a D24
¼ ꢀ90:2 (c 1.8, CHCl3); vmax
ꢄ
3346 (N–H), 2955, 2866, 1597 (C@C), 1314, 1135, 1063, 998; dH
7.35–7.33 (2H, m, ArH), 7.28–7.25 (2H, m, ArH), 7.20–7.16 (1H,
m, ArH), 4.40 (3H, br s), 4.32–4.27 (1H, q, J 6.4, PhCH), 2.61–2.58
(3H, d, J 12.8), 2.38–2.34 (1H, dd, J 2.4 and 10.4, NCH), 1.71–1.68
(3H, d, J 12.8), 1.60–1.53 (2H, m, NH + diastereotopic NCCH),
1.32–1.31 (3H, d, J 6.4, PhCMe), 1.27–1.24 (1H, m, diastereotopic
NCCH), 1.14–1.07 (1H, m, Me2CH), 0.79–0.78 (3H, d, J 6.4, diaste-
reotopic MeCMe), 0.31–0.29 (3H, d, J 6.4, diastereotopic MeCMe);
dC 146.51 (CAr), 127.92 (CAr), 127.63 (CAr), 126.48 (CAr), 112.48,
67.78, 58.15 (NCPh), 56.54 (NCBui), 39.43 (NCC), 33.24, 24.76
(PhCMe), 24.18 (Me2C), 23.83 (diastereotopic CMe), 20.87 (diaste-
reotopic CMe); HRMS: m/z calcd for C20H29NO3+H 332.2226, found
332.2226.
White solid, mp 101–103 °C; ½a D24
¼ ꢀ98:1 (c 1, CHCl3); vmax
ꢄ
3358 (N–H), 2963, 2931, 2872, 1598 (C@C), 1315, 1136, 1027,
971; dH 7.36–7.34 (2H, m, ArH), 7.29–7.26 (2H, m, ArH), 7.20–
7.17 (1H, m, ArH), 4.40 (3H, br s), 4.26–4.21 (1H, q, J 6.4, PhCH),
2.60–2.57 (3H, d, J 12.8), 2.27–2.24 (1H, dd, J 3.2 and 9.2, NCH),
1.72–1.68 (3H, d, J 12.8), 1.65–1.55 (2H, m, NH + diastereotopic
MeCH), 1.33–1.32 (3H, d, J 6.4, PhCMe), 1.20–1.11 (1H, m, diaste-
reotopic MeCH), 0.69 (3H, t, J 7.2, CH2Me); dC 146.52 (CAr), 127.86
(CAr), 127.47 (CAr), 126.40 (CAr), 112.19, 67.75, 62.07 (NCPh),
56.80 (NCEt), 33.17, 24.83 (PhCMe), 22.98 (MeC), 10.93 (CMe);
HRMS: m/z calcd for C18H25NO3+H 304.1913, found 304.1912.
4.12. N-[(1S)-Phenethyl] (1S)-(2,4,10-trioxaadamant-3-yl)butyl
amine 5b
4.16. N-[(1S)-Phenethyl] (1S)-(2,4,10-trioxaadamant-3-yl)-4-
methylpentylamine 5e
Colorless liquid; ½a D24
¼ ꢀ110:9 (c 1.38, CHCl3); vmax 3349 (N–
ꢄ
H), 2958, 2931, 2870, 1595 (C@C), 1314, 1135, 988; dH 7.35–7.30
(2H, m, ArH), 7.29–7.25 (2H, m, ArH), 7.21–7.16 (1H, m, ArH),
4.40 (3H, br s), 4.27–4.22 (1H, q, J 6.8, PhCH), 2.61–2.58 (3H, d, J
12.8), 2.33–2.30 (1H, dd, J 3.2 and 9.8, NCH), 1.71–1.68 (3H, d, J
12.8), 1.62 (1H, br s, NH), 1.53–1.45 (1H, m, diastereotopic MeCCH),
1.39–1.25 (4H, m, PhCMe + diastereotopic MeCCH), 1.17–1.07 (1H,
m, diastereotopic MeCH), 0.99–0.88 (1H, m, diastereotopic MeCH),
0.65 (3H, t, J 7.2, CH2Me); dC 146.45 (CAr), 127.90 (CAr), 127.51 (CAr),
126.44 (CAr), 112.26, 67.78, 60.20 (NCPh), 56.74 (NCPr), 33.18,
32.35 (MeCC), 24.84 (PhCMe), 19.34 (MeC), 14.06 (CMe); HRMS:
m/z calcd for C19H27NO3+H 318.2069, found 318.2068.
Colorless liquid; ½a D24
¼ ꢀ72:3 (c 2.15, CHCl3); vmax 3346 (N–H),
ꢄ
2955, 2868, 1601 (C@C), 1314, 1135, 1005; dH 7.34–7.32 (2H, m,
ArH), 7.28–7.25 (2H, m, ArH), 7.20–7.16 (1H, m, ArH), 4.39 (3H,
br s), 4.24–4.19 (1H, q, J 6.8, PhCH), 2.60–2.56 (3H, d, J 12.8),
2.30–2.27 (1H, dd, J 2.8 and 8.8, NCH), 1.70–1.67 (4H, m, NH + OC-
CHax), 1.60–1.52 (1H, m, diastereotopic NCCH), 1.32–1.31 (3H, d, J
6.8, PhCMe), 1.28–1.19 (1H, m, diastereotopic NCCH), 1.17–1.05
(2H, m, NCCCH), 0.88–0.80 (1H, m, Me2CH), 0.76–0.74 (3H, d, J
6.4, diastereotopic Me), 0.73–0.71 (3H, d, J 6.4, diastereotopic
Me); dC 146.51 (CAr), 127.86 (CAr), 127.50 (CAr), 126.40 (CAr),
112.24, 67.75, 60.82 (NCPh), 56.90 (NCCBui), 35.34 (NCC), 33.18,
27.82 (NC2C), 27.79 (Me2C), 24.81 (PhCMe), 22.87 (diastereotopic
CMe), 22.21 (diastereotopic CMe); HRMS: m/z calcd for
4.13. N-[(1S)-Phenethyl] (1S)-(2,4,10-trioxaadamant-3-yl)heptyl
amine l-5c
C21H31NO3 + H 346.2382, found 346.2382.
Colorless liquid; ½a D24
ꢄ
¼ ꢀ73:2 (c 2.2, CHCl3); vmax 3344 (N–H),
4.17. N-[(1S)-Phenethyl] (1S)-(2,4,10-trioxaadamant-3-yl)-2-
phenethylamine 5f
2956, 2928, 2857, 1598 (C@C), 1314, 1136, 1006; dH 7.34–7.32
(2H, m, ArH), 7.28–7.24 (2H, m, ArH), 7.19–7.16 (1H, m, ArH),
4.39 (3H, br s), 4.26–4.21 (1H, q, J 6.4, PhCH), 2.59–2.56 (3H, d, J
12.8), 2.32–2.29 (1H, dd, J 2.8 and 9.2, NCH), 1.70–1.65 (4H, m,
NH + OCCHax), 1.55–1.47 (1H, m, diastereotopic NCCH), 1.32–1.31
(3H, d, J 6.4, PhCMe), 1.28–1.22 (1H, m, diastereotopic NCCH),
1.20–1.06 [5H, m, (CH2)2 + diastereotopic CH], 1.04–0.88 [3H, m,
(CH2) + diastereotopic CH], 0.82 (3H, t, J 7.2, CH2Me); dC 146.48
(CAr), 127.85 (CAr), 127.49 (CAr), 126.41 (CAr), 112.26, 67.75, 60.41
White solid, mp 117–119 °C; ½a D24
¼ ꢀ72:2 (c 0.49, CHCl3); vmax
ꢄ
3344 (N–H), 2956, 2928, 2857, 1598 (C@C), 1314, 1136, 1006, 972;
dH 7.18–7.17 (3H, m, ArH), 7.06–6.98 (5H, m, ArH), 6.68–6.66 (2H,
d, J 7.2, ArH), 4.44 (3H, br s), 4.20–4.15 (1H, q, J 6.8, PhCH), 3.06–
3.02 (1H, dd, J 2.8 and 13.6, NCH), 2.65–2.57 (4H, m, diastereotopic
NCCH + OCCHeq), 2.42–2.36 (1H, dd, J 11.2 and 13.6, diastereotopic
NCCH), 1.74–1.71 (3H, d, J 12.8), 1.55 (NH + H2O), 1.19–1.17 (3H, d,

S. Chandrasekhar, V. Mohana Rao / Tetrahedron: Asymmetry 23 (2012) 1005–1009
1009
J 6.8, diastereotopic PhCMe); dC 145.63 (CAr), 139.72 (CAr), 129.75
(CAr), 128.00 (CAr), 127.79 (CAr), 126.81 (CAr), 125.93 (CAr), 125.68
(CAr), 111.90, 67.91, 61.38 (NCPh), 56.40 (NCBn), 36.13 (PhCH2),
1.25–1.18 (1H, m, Me2CH), 0.94–0.93 (3H, d, J 6.4, diastereotopic
Me), 0.89–0.88 (3H, d, J 6.4, diastereotopic Me); dC 110.89, 68.07,
55.43 (NC), 38.76 (NCC), 33.16, 24.52 (Me2C), 24.11 (diastereotopic
CMe), 21.19 (diastereotopic CMe); HRMS: m/z calcd for C12H21NO3+H
228.1600, found 228.1606.
33.22, 24.77 (PhCMe); HRMS: m/z calcd for
C23H27NO3+H
366.2069, found 366.2069.
4.18. Hydrogenolysis of the phenethyl amines 5 to C-protected
amino acids 6
4.23. (1S)-(2,4,10-Trioxaadamant-3-yl)-4-methylpentylamine 6e
Colorless liquid. ½a D24
¼ ꢀ17:6 (c 1.7, CHCl3); vmax 3383 (N–H),
ꢄ
A solution of 5 (0.15 mmol) in methanol (5 mL) was treated
with Pd(OH)2 (0.01 mmol) under dry argon. The reaction mixture
was hydrogenated for 16 h at 4 atmosphere pressure. The mixture
was then filtered through a pad of celite, which was washed with
methanol. The filtrate was concentrated in vacuo and the residue
column chromatographed on basic Al2O3 to obtain the C-protected
amino acids 6.
General spectroscopic features: The dH and dC of the trioxaada-
mantyl moiety occur at similar values to those in 2 as assigned
above, and are not assigned again (cf. 3 and 5). The other resonances
are assigned. Similarly, the IR C–H stretch occurs at ꢂ2900 cmꢀ1
and is not assigned; the N–H stretch occurs at ꢂ3370–3400 cmꢀ1
and the N–H deformation (‘def.’) at ꢂ1610 cmꢀ1 and are assigned.
2956, 2929, 1607 (N–H def.), 1353, 1131, 1315, 1063, 1013; dH
4.40 (3H, br s), 2.60–2.54 (4H, m, OCHeq + NCH), 1.77–1.69 (4H,
m, OCHax + NCCH), 1.57–1.49 (3H, m, NH2 + diastereotopic NCCH),
1.46–1.36 (1H, m, Me2CH), 1.25–1.12 (2H, m, NC2CH), 0.90–0.89
(3H, d, J 3.2 Hz, diastereotopic Me), 0.885–0.877 (3H, d, J 3.2 Hz,
diastereotopic Me); dC 110.78, 68.03, 57.99 (NC), 36.06 (NCC),
33.13, 28.25 (NC2C), 27.77 (Me2C), 22.89 (diastereotopic CMe),
22.40 (diastereotopic CMe); HRMS: m/z for C13H23NO3+H, calcd for
242.1756; found: 242.1756.
4.24. (1S)-(2,4,10-Trioxaadamant-3-yl)-2-phenethylamine 6f
White solid, mp 118–120 °C; ½a D24
¼ ꢀ23:7 (c 2.8, CHCl3); vmax
ꢄ
3407 (N–H), 2956, 2929, 1607 (N–H def.), 1353, 1316, 1131,
1014; dH 7.30–7.17 (5H, m, ArH), 4.45 (3H, br s), 3.17–3.13 (1H,
dd, J 2.0 and 13.6, NCH), 2.98–2.95 (1H, dd, J 2.0 and 10.8, diaste-
reotopic PhCH), 2.64–2.61 (3H, d, J 12.4), 2.48–2.42 (1H, dd, J
10.8 and 13.6, diastereotopic PhCH), 1.75–1.72 (3H, d, J 12.8),
1.50 (2H, br s, NH2); dC 139.89 (CAr), 129.35 (CAr), 128.26 (CAr),
125.95 (CAr), 110.46, 68.13, 58.81 (NC), 36.56 (NCC), 33.11; HRMS:
m/z calcd for C15H19NO3+H 262.1443, found 262.1445.
4.19. (1S)-(2,4,10-Trioxaadamant-3-yl)propylamine 6a
White solid, mp 98–100 °C; ½a D24
¼ ꢀ14:1 (c 0.8, CHCl3); vmax
ꢄ
3382 (N–H), 2954, 1613 (N–H def.), 1313, 1136, 1062, 1007, 949;
dH 4.40 (3H, br s), 2.59–2.47 (4H, m, OCHeq + NCH), 1.81–1.75
(1H, m, diastereotopic MeCH), 1.72–1.69 (3H, d, J 12.8), 1.41 (2H,
br s, NH2), 1.28–1.17 (1H, m, diastereotopic MeCH), 0.99 (3H, t, J
7.2, Me); dC 110.77, 68.01, 59.14 (NC), 33.14, 22.93 (NCC), 11.25
(CMe); HRMS: m/z calcd for C10H17NO3+H 200.1287, found
200.1289.
Acknowledgement
We are grateful to the Council of Scientific and Industrial Re-
search (New Delhi) for their generous financial support of this
work.
4.20. (1S)-(2,4,10-Trioxaadamant-3-yl)butylamine 6b
Colorless liquid; ½a D24
¼ ꢀ35:7 (c 3.8, CHCl3); vmax 3391 (N–H),
ꢄ
2958, 2929, 2872, 1614 (N–H def.), 1353, 1315, 1133, 1011, 993;
dH 4.40 (3H, br s), 2.63–2.56 (4H, m, OCHeq + NCH), 1.73–1.67
(4H, m, OCHax + diastereotopic NCCH), 1.64 (2H, br s, NH2), 1.60–
1.52 (1H, m, diastereotopic NCCH), 1.40–1.29 (1H, m, diastereotop-
ic MeCH), 1.27–1.16 (1H, m, diastereotopic MeCH), 0.92 (3H, t, J 7.2,
Me); dC 110.76, 68.05, 57.36(NC), 33.14, 32.06 (NCC), 19.84 (MeC),
14.17 (CMe); HRMS: m/z calcd for C11H19NO3+H 214.1443, found
214.1447.
References
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Colorless liquid; ½a D24
¼ ꢀ14:5° (c 1.25, CHCl3); vmax 3390 (N–H),
ꢄ
2954, 2927, 2856, 1612 (N–H def.), 1312, 1136, 1063, 1011, 970; dH
4.40 (3H, br s), 2.59–2.56 (4H, m, OCHeq + NCH), 1.74–1.69 (4H, m,
OCHax + diastereotopic NCCH), 1.59–1.51 (3H, m, NH2 + diastereo-
topic NCCH), 1.34–1.15 [8H, m, Me(CH2)4], 0.87 (3H, t, J 6.4, Me);
dC 110.78, 68.02, 57.68 (NC), 33.13, 31.79 (NCC), 29.96 (NC2C),
29.46 (NC3C), 26.72 (NC4C), 22.61 (NC5C), 14.05 (CMe); HRMS: m/z
calcd for C14H25NO3+H 256.1913, found 256.1913.
4.22. (1S)-(2,4,10-Trioxaadamant-3-yl)-3-methylbutylamine 6d
Colorless liquid. ½a D24
¼ ꢀ17:6 (c 0.64, CHCl3); vmax 3374 (N–H),
ꢄ
17. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.; Shah, R. D. J. Org.
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2.70–2.66 (1H, dd, J 2.4 and 14.8, NCH), 2.59–2.56 (3H, d, J 12.8),
1.86–1.76 (1H, m, diastereotopic NCCH), 1.72–1.69 (3H, d, J 12.8),
1.60 (2H, br s, NH2), 1.48–1.41 (1H, m, diastereotopic NCCH),
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