Synthesis of adamantylglycine using a diastereoselective grignard-to-nitrone addition

Article abstract of DOI:10.1055/s-0030-1258235

In contrast to amino acids with a bulky substituent like tert-leucine, adamantylglycine has so far received little attention. Here, a new, practical synthesis of adamantylglycine is described. This is based on a highly diastereoselective addition of adamantyl Grignard reagent to 2,3-O-cyclohexylideneglyceraldehyde N-benzylnitrone, mediated by the Lewis acid diethylaluminum chloride. Adamantylglycine is obtained from the nitrone in 6 steps and 28% yield as a crystalline hydrochloride with 0.5 methanol incorporated.

Full text of DOI:10.1055/s-0030-1258235

PAPER
3693
Synthesis of Adamantylglycine Using a Diastereoselective
Grignard-to-Nitrone Addition
Synthesis of
A
dam
l
antylg
e
Universität Stuttgart, Institut für Organische Chemie, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax +49(711)68564321; E-mail: jager.ioc@uni-stuttgart.de
Received 11 June 2010; revised 13 July 2010
Dedicated to Professor Dr. Franz X. Effenberger on the occasion of his 80th birthday
analyses, were not given.8f However, an interesting
ligand-mediated addition of phenyllithium to the N-ani-
sylimine of 1-adamantane carboxaldehyde, high induc-
tion (89% ee) was achieved, with low overall efficiency.9
Abstract: In contrast to amino acids with a bulky substituent like
tert-leucine, adamantylglycine has so far received little attention.
Here, a new, practical synthesis of adamantylglycine is described.
This is based on a highly diastereoselective addition of adamantyl
Grignard reagent to 2,3-O-cyclohexylideneglyceraldehyde N-ben-
zylnitrone, mediated by the Lewis acid diethylaluminum chloride.
Adamantylglycine is obtained from the nitrone in 6 steps and 28%
yield as a crystalline hydrochloride with 0.5 methanol incorporated.
Amino derivatives with the adamantane framework have
also found attention in medicinal chemistry, for example,
memantine (Alzheimer’s desease),11 amantadine (B),
rimantadine (influenza virus A in adults),12 and tromanta-
dine (herpes simplex).13
Key words: glyceraldehyde, chiral nitrone, Grignard addition,
electrophilic glycine equivalent, crystal structure
In order to elaborate a practical synthesis of adamantyl-
glycine enantiomers, we considered to extend the earlier,
related work in our group concerning approaches to vari-
ous amino acids, amino- and iminopolyols. Thus, addi-
tions of C-nucleophiles to imines derived from optically
active a-oxyaldehydes (e.g., glyceraldehyde, lactalde-
hyde, threose, erythrose) had been used.14–19 Due to the
1,2-asymmetric induction, mostly highly diastereoselec-
tive additions were found. If less so, additional diastereo-
selection was achieved by applying (R)- or (S)-1-phen-
ethylamine-derived imines as match/mismatch-effecting
substrates.17 When the imine approach proved less satis-
factory, recourse to respective nitrones often rectified this
situation.20,21 Now N-derivatives of 1,2-O-alkylidene
glyceraldehyde like C or D were considered: They would
constitute chiral electrophilic equivalents of glycine,22
since the diol part after addition to the C=N bond and
deprotection can then be converted to a carboxy
group14,16,17,19,20b,e,h,23 (see Figure 2). A closely related se-
quence has also been applied with nitrile oxides D such as
glyceronitrile oxide,24 or with respective imines C for
[2+2] cycloadditions towards b-lactams.25
Amino acids, respective amino alcohols, and their deriva-
tives have played a major role in stereoselective organic
chemistry1 as enantiomerically pure building blocks,2
auxiliaries,3 ligands,3a,4 or organocatalysts.5 Of particular
interest in this respect are a-amino acids with bulky sub-
stituents, such as tert-leucine (‘a-tert-butylglycine’) or
the derived tert-leucinol.6,7
In contrast to this, the related adamantylglycine (AdGly,
1, Figure 1) and -glycinol are much less known8,9 and
have rarely been employed in synthesis.8f,10 Notably,
enantiomerically pure adamantylglycine has been secured
by separation of racemic or diastereomeric precursors.8
The seemingly most efficient (6 steps, ‘44%’ overall
yield) approach to N-Boc-adamantylglycine has been de-
veloped in the course of a synthesis of saxagliptin (A), an
efficient dipeptidylpeptidase inhibitior (DPP-IV) applied
for the treatment of type 2 diabetes mellitus.8f This was
based on an asymmetric variant of the Strecker synthesis,
using (R)-phenylglycinol as a chiral adjuvant. In this pa-
per, however, intermediates and adamantylglycine were
The addition of adamantyl Grignard reagent26 was first
1
only characterized by H NMR and low-resolution MS;
studied with N-benzylimines of 2-O-benzyl- and 2,3-O-
other spectroscopic data, optical rotations or elemental
OR2
OR2
CN
O
R1
COOH
NH2
R1
Y
COOH
N
NH2
N
OR3
N
OR3
NH2
NH2
Y
HO
C
1-adamantylglycine
saxagliptin
amantadine
(AdGly) (1)
(A)
(B)
OR2
OR2
Figure 1 Adamantylglycine (1), saxagliptin (A), and amantadine
(B)
C
N
N
OR3
O
OR3
R1
O
SYNTHESIS 2010, No. 21, pp 3693–3699
x
x.
x
x
.
2
0
1
0
D
E
Advanced online publication: 30.08.2010
DOI: 10.1055/s-0030-1258235; Art ID: T12310SS
© Georg Thieme Verlag Stuttgart · New York
Figure 2 Electrophilic glycine equivalents

3694
A. Baskakova et al.
PAPER
isopropylideneglyceraldehyde. Both reactions led to mod- well-known sensitivity of N,N-disubstituted hydroxyl-
erate yields with side-products difficult to remove; it had amines towards aerial oxygen.29 The structure of this un-
been registered earlier that such additions proceeded rath- usual nitrone, which also formed when the hydroxylamine
er sluggishly with voluminous Grignard reagents like tert- 3 was kept in solution (CDCl3, NMR), became evident af-
butylmagnesium chloride, where an aziridine had been ter crystal structure analysis.30
identified as one of the by-products.17 In some cases,
As seen, for example, from the above-mentioned moder-
Grignard additions even had not occurred at room temper-
ate yields, the acetonide group may have caused problems
ature, and high pressure of 12 kbar at 50–54 °C had to be
during workup and chromatographic separations, due to
its lability towards even mildly acidic conditions. Cyclo-
applied.17
We therefore turned to the N-benzylnitrone of glyceralde- hexylidene acetals,24d,31 with diminished water solubility
hyde acetonide 2;20,27 this indeed gave a product from and higher stability,32 were employed therefore, starting
which the required adduct was readily isolated, albeit in from D-mannitol via the 2,3-O-cyclohexylideneglyceral-
51% yield and as a 42:58 mixture of diastereomers 3 and dehyde (7)31a as the new key substrate. Adopting the pro-
4. Similar additions to this nitrone had been reported ear- cedure given by Dondoni et al.,27 the nitrone 8 was
lier by Dondoni et al. and Merino et al., who also had obtained in 74% yield in pure form as the Z-isomer31b,33
shown that distinct variations of diastereoselectivity could (Scheme 2).
be effected by adding Lewis acids.20a,b,d For example, the
reaction of 2 with phenylmagnesium bromide in diethyl
ether alone afforded a 65:35 mixture of threo/erythro iso-
O
O
mers, which then changed to 78:22 (ZnBr2, 1.1 equiv) or
15:85 (Et2AlCl, 1.1 equiv).20b Indeed, upon addition of an
equimolar amount of diethylaluminum chloride in our
case the adamantyl product 3 was obtained as the sole iso-
mer (dr >95:5), in a moderate 42–48% yield (Scheme 1).
(i)
(ii)
O
O
D-mannitol
O
N+
Bn
O–
8
7
Scheme 2 Reagents and conditions: (i) Ref. 31; (ii) BnNHOH,
MgSO4, CH2Cl2, r.t., 17 h, 74%.
O
AdMgBr, Et2AlCl (1.0 equiv)
O
The Grignard addition to yield 9 was carried out as above
and proceeded with better yield, again with erythro/threo
>95:5. Catalytic hydrogenation of the hydroxylamine 9
led to the diol-protected amine 10 and on further acid-
catalyzed acetal cleavage to the free aminodiol hydro-
chloride 11·HCl. This salt crystallized as a monohydrate
suitable for crystal structure determination, which also
permitted to ascertain the relative and absolute configura-
tions (anomalous dispersion method).34
Et2O, –60 °C, 16 h, 42%
(>95:5)
N+
O–
Bn
2
O
O
O
O
+
Ad
Bn
Ad
N
N
OH
OH
Bn
3
4
The diol part of 12, the N-Boc derivative, was converted
to the carboxy function according to standard procedures,
that is, sodium periodate cleavage followed by sodium
chlorite oxidation35 of the intermediate aldehyde. This
furnished the crystalline hydrochloride of 1-adamantyl-
glycine 1·HCl (with 0.5 MeOH) in pure form and some-
what higher optical rotation than reported before (see
experimental section) (Scheme 3).
O
O
H2 (4 bar)
Pd(OH)2/C (4.4 mol% Pd)
O
O
Ad
Ad
3
MeOH, Boc2O, 3 d; 61%
N+
Ph
NHBoc
–O
6
5
Scheme 1
The crystal structure of 1·HCl depicted below (Figure 3)
shows methanol (one half equivalent!) in between two
sheets of organic molecules exhibiting three hydrogen
bonds, while chloride acts to fix the protonated amino
acids with the respective sheet.36,37
The next step of the planned synthesis involved the re-
moval of the N-benzyl and N-hydroxy groups by catalytic
hydrogenation. This also proved a rather slow process;
with Pearlman’s catalyst Pd(OH)2 on carbon,28 ca. 4
mol% of Pd, at a pressure of 4 bar in the presence of di-
tert-butyl dicarbonate (Boc2O) after 3 days the N-Boc-
protected amine 5 was isolated in pure form in 61% yield.
In earlier experiments using less Pd catalyst (1.8 mol%),
the reduction had been incomplete, and after workup and
chromatography on silica gel, the nitrone 6 had also been
obtained (23%). Formation of this nitrone is probably due
to oxidation of the starting compound, in accord with the
In conclusion, we have outlined a convenient route to (S)-
1-adamantylglycine 1·HCl from the known nitrone 8 (6
steps, 28% yield), amenable to access the R-enantiomer
likewise (from L-gulose via the respective L-glyceralde-
hyde). In addition, the intermediate aminodiol 11 and its
N- or O-protected derivatives should be interesting
ligands for applications in metal-catalyzed catalytic pro-
cesses.
Synthesis 2010, No. 21, 3693–3699 © Thieme Stuttgart · New York

PAPER
Synthesis of Adamantylglycine
3695
1H and 13C NMR spectra were recorded on Bruker ARX 300 or
Bruker ARX 500 spectrometers with TMS as internal standard.
Peak assignments are based on DEPT and 2D NMR studies. All dr
values were determined from 13C NMR spectra. IR spectra were re-
corded on a Bruker IFS 28 spectrophotometer. The optical rotations
were measured on a Perkin-Elmer 241 MC polarimeter using the
Drude method to calculate [a]D20 from the values found at 546 and
579 nm. Crystal structure analysis: Nicolet P3 diffractometer with
graphite monochromator, Mo-Ka radiation, calculation of structures
according to programs of Sheldrick.41
(i)
(>95:5)
(ii)
O
O
8
O
O
Ad
Ad
Bn
NH2
10
N
OH
9
OH
(iii)
(iv)
Ad
BocHN
1•HCl
OH
(2S,3RS)-3-(1-Adamantyl)-3-(N-benzylhydroxylamino)-1,2-O-
isopropylidene-1,2-propanediol (3/4)
12
Preparation of the ethereal solution of 1-adamantylmagnesium bro-
mide:26,42 A 50 mL two-necked flask was equipped with a conden-
ser, connected to the vacuum line, and charged with Mg turnings
(23.3 mmol, 0.56 g). The flask was preheated to 150 °C for 10 min
under reduced pressure, cooled under N2, and absolute Et2O (4 mL)
was added followed by the addition of dibromoethane (3 drops). To
this suspension, a solution of 1-bromoadamantane (4.66 mmol,
1.00 g) in absolute Et2O (6 mL) was carefully added within 20–
30 min, keeping the temperature below the boiling point of Et2O.
The suspension was stirred for 30 min at r.t. and heated under reflux
for 1 h. After cooling to r.t., the solution of 1-adamantylmagnesium
bromide was used immediately in the next step.
Scheme 3 Reagents and conditions: (i) AdMgBr, Et2AlCl (1.0
equiv), Et2O, –60 °C, 16 h, 61%; (ii) H2 (4 bar), Pd(OH)2/C (4.1 mol%
Pd), MeOH–THF (4:1), Et3N, 3 d, 87%; (iii) 1. aq 12 N HCl, THF, 16
h, 82% of 11·HCl; 2. Boc2O, Et3N, 16 h, 79%; (iv) 1. NaIO4 (1.2
equiv), MeOH–H2O (1:1), then NaClO2, KH2PO4, 2-methylbut-2-
ene, 82% of N-Boc-AdGly 13; 2. aq 12 N HCl, THF, 21 h, 94% of
1·HCl·(0.5 MeOH).
According to literature procedures,20b,d a well-stirred solution of the
N-benzylnitrone 2 (0.55 g, 2.3 mmol) in absolute Et2O (40 mL) was
cooled to –60 °C, treated with previously prepared AdMgBr, and
stirred for 17 h at this temperature. The reaction was quenched by
the addition of sat. aq NH4Cl (10 mL) and allowed to stir for 20 min.
The aqueous layer was separated and extracted with Et2O
(3 × 15 mL). The combined ethereal layers were washed with brine
(2 × 20 mL), dried (Na2SO4), and concentrated in vacuo (40 °C/15
mbar, then 0.05 mbar) to afford a yellow solid (0.92 g, ‘106%’).
This was purified by flash chromatography on silica gel (60 g, col-
umn 18 cm × 3 cm), eluting first with PE and then with EtOAc–PE
(15:85, v/v) to yield 0.44 g (51%) of a colorless solid consisting of
3/4 with dr = 58:42.
Major Diastereomer (erythro-3)
13C NMR (62.9 MHz, CDCl3): d = 25.7 and 27.00 [2 q, C(CH3)2],
28.8 (d, C-3¢, C-5¢, C-7¢), 37.2 (t, C-4¢, C-6¢, C-9¢), 38.1 (s, C-1¢),
40.4 (t, C-2¢, C-8¢, C-10¢), 64.7 (t, CH2C6H5), 68.2 (t, C-1), 74.9 (d,
C-3), 75.0 (d, C-2), 107.2 [s, C(CH3)2, 127.2 (d, p-C of C6H5), 128.3
and 129.0 (2 d, o-, m-C of C6H5), 139.4 (s, i-C of C6H5).
Minor Diastereomer (threo-4)
13C NMR (62.9 MHz, CDCl3): d = 25.4 and 26.6 [2 q, C(CH3)2],
28.6 (d, C-3¢, C-5¢, C-7¢), 36.7 (t, C-4¢, C-6¢, C-9¢), 36.8 (t, C-2¢, C-
8¢, C-10¢), 39.9 (s, C-1¢), 65.6 (t, CH2C6H5), 70.1 (t, C-1), 75.0 (d,
C-3), 108.0 [s, C(CH3)2], 127.1 (d, p-C of C6H5), 128.2 and 128.2 (2
d, o-, m-C of C6H5), 139.1 (s, i-C of C6H5).
Figure 3 Crystal structure of 1·HCl·(0.5MeOH) as a single species
and orientation in the unit cell36
Benzaldehyde oxime38 and N-benzylhydroxylamine were obtained
in accordance with the literature39 [N-benzylhydroxylamine: 72%
yield; mp 49–52 °C (Lit.39 79%; mp 58–59 °C)]. 1,2:5,6-Diisopro-
pylidene-D-mannitol was prepared according to the literature40 in
49% yield; mp 117–119 °C (Lit.40 54%; mp 121.8–123.4 °C). 2,3-
O-Isopropylidene-D-glyceraldehyde N-benzylnitrone (2) was syn-
thesized according to a known procedure;27 yield: 68%; mp 85–
87 °C; [a]D20 +92 (c = 0.6, CHCl3) {Lit.27 yield: 86%; mp 88 °C;
[a]D20 +96.7 (c = 0.5, CHCl3)}. 2,3-O-Cyclohexylidene-D-glyceral-
dehyde was prepared as described from 1,2:5,6-di-O-cyclohexy-
lidene-D-mannitol by periodate cleavage;31 the crude product (yield
ca. 90%) was used directly. AdBr was purchased from Aldrich and
Et2AlCl (ca. 1 M n-hexane solution) from Fluka. Petroleum ether
(PE) refers to the fraction boiling in the range 40–60 °C.
(2S,3S)-3-(1-Adamantyl)-3-(N-benzylhydroxylamino)-1,2-O-
isopropylidene-1,2-propanediol (3)
1-Adamantylmagnesium bromide was prepared as described above.
In accordance with literature reports,20b,d,e to a well-stirred solution
of the N-benzylnitrone 2 (1.00 g, 4.3 mmol) in absolute Et2O
(50 mL) was added Et2AlCl (ca. 4.3 mmol) in one portion at r.t. The
resulting mixture was stirred for 15 min under N2, cooled to –60 °C,
treated with a solution of 1-adamantylmagnesium bromide (ca. 8.5
mmol), and stirred for 16 h at this temperature. The reaction was
quenched by the addition of 2.5% aq NaOH (20 mL) and allowed to
stir for additional 20 min. The aqueous layer was separated and ex-
tracted with Et2O (3 × 20 mL). The combined ethereal layers were
washed with brine (2 × 30 mL), dried (Na2SO4), and concentrated in
vacuo (40 °C/15 mbar, then 0.05 mbar) to give 1.23 g (89%) of a
Synthesis 2010, No. 21, 3693–3699 © Thieme Stuttgart · New York

3696
A. Baskakova et al.
PAPER
yellow solid. This was purified by flash chromatography on silica
gel (60 g, column 18 cm × 3 cm); elution with EtOAc–PE (20:80,
v/v) yielded 0.67 g (‘42%’) of a spectroscopically pure colorless
solid; mp 131–132 °C. According to the 13C NMR spectra, the ratio
3/4 (erythro/threo) was >95:5; [a]D20 +31 (c = 0.67, CHCl3).
stirred overnight (17 h) at r.t., and the solid was filtered off. The fil-
trate was evaporated and the residue recrystallized from EtOAc–PE
to give the nitrone product 8 as a spectroscopically and analytically
pure solid (1.65 g, 74%); mp 97–100 °C (Lit.31 mp 88–89 °C);
[a]D20 +79 (c = 1.28, EtOH) {Lit.31 [a]D20 +82.5 (c = 1.00, EtOH)}.
IR (neat): 3417 (w, OH), 2899 (s), 2843 (s, NH2), 1447 (m), 1113
(vs, C–O), 1008 (s), 909 (s), 695 cm–1 (s).
IR (neat): 2929 (s), 2852 (m, C = N–O), 1443 (s), 1273 (s, N–O),
1198 (s), 1168 (s), 1102 (vs, C–O), 1024 (s), 927 (vs, N–O), 706
(vs), 664 (s), 589 cm–1 (s).
1H NMR (500.1 MHz, CDCl3): d = 1.39 and 1.48 [2 s, 3 H each,
C(CH3)2], 1.68 (m, 6 H, 4¢-H, 6¢-H, 9-H), 1.78 (m, 6 H, 2¢-H, 8¢-H,
1H NMR (300.1 MHz, CDCl3): d = 1.40 (m, 2 H, 4¢-H), 1.58 (m, 8
3
3
10¢-H), 1.98 (m, 3 H, 3¢-H, 5¢-H, 7¢-H), 2.58 (‘d’, J2,3 = 5.6 Hz,
H, 2¢-H, 3¢-H, 5¢-H, 6¢-H), 3.88 (‘dd’, J2,3a = 5.7 Hz,
1 H, 3-H), 3.96 (A of AB, 2JA,B = 13.7 Hz, 1 H, CHAHBC6H5), 4.20
2J3a,3b = 8.6 Hz, 1 H, 3-Ha), 4.38 (‘dd’, J2,3b = 7.0 Hz,
3
2
3
(‘dd’, J1a,2 = 6.4 Hz, J1b,2 = 8.1 Hz, 2 H, 1-Ha, 1-Hb), 4.24 (B of
2J3a,3b = 8.6 Hz, 1 H, 3-Hb), 4.87 (‘s’, 2 H, A, B of CHAHBC6H5),
5.15 (‘ddd’, 3J1,2 = 4.2 Hz, 3J2,3a = 5.7 Hz, 3J2,3b = 7.0 Hz, 1 H, 2-H),
6.86 (‘d’, 3J1,2 = 4.2 Hz, 1 H, 1-H), 7.39–7.41 (m, 5 H, o-, m-, p-H
of C6H5).
AB, 2J = 13.7 Hz, 1 H, CHAHBC6H5), 4.39 (br s, 1 H, NOH), 4.46
(‘ddd’, J1a,2 = 6.4 Hz, J1b,2 = 8.1 Hz, J2,3 = 5.6 Hz, 1 H, 2-H),
7.24–7.40 (m, 5 H, o-, m-, p-H of C6H5).
2
3
3
13C NMR (125.8 MHz, CDCl3): d = 25.7 and 26.9 [2 q, C(CH3)2],
28.7 (d, C-3¢, C-5¢, C-7¢), 37.1 (t, C-4¢, C-6¢, C-9¢), 40.4 (t, C-2¢, C-
8¢, C-10¢), 38.0 (s, C-1¢), 64.6 (t, CH2C6H5), 68.1 (t, C-1), 74.8 (d,
C-3), 75.0 (d, C-2), 107.1 [s, C(CH3)2], 127.1 (d, p-C of C6H5),
128.3 and 128.9 (2 d, o-, m-C of C6H5), 139.3 (s, i-C of C6H5).
13C NMR (75.5 MHz, CDCl3): d = 23.7 (t, C-4¢), 23.9 and 25.0 (2 t,
C-3¢ and C-5¢), 34.3 and 35.9 (2 t, C-2¢, C-6¢), 67.5 (t, C-3), 69.0 (t,
CH2C6H5), 71.7 (d, C-2), 110.6 (s, C-1¢), 129.2 (d, p-C of C6H5),
129.0 and 129.4 (2 d, o-, m-C of C6H5), 132.1 (s, i-C of C6H5), 139.4
(d, C-1).
Anal. Calcd for C23H33NO3 (371.5): C, 74.36; H, 8.95; N, 3.77.
Found: C, 74.54; H, 8.99; N, 3.63.
Anal. Calcd for C16H21NO3 (275.3): C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.75; H, 7.72; N, 5.05.
(2S,3S)-3-(1-Adamantyl)-3-(tert-butoxycarbonylamino)-1,2-O-
isopropylidene-1,2-propanediol (5)
(2S,3S)-3-(1-Adamantyl)-3-(N-benzylhydroxylamino)-1,2-O-
cyclohexylidene-1,2-propanediol (9)
Diastereomerically pure N-benzylhydroxylamine
3
(320 mg,
1-Adamantylmagnesium bromide was prepared as described above.
In analogy to literature reports,20b,d,e to a well-stirred solution of the
N-benzylnitrone 8 (1.42 g, 5.2 mmol) in absolute Et2O (60 mL) was
added Et2AlCl (ca. 5.2 mmol) in one portion at r.t. The resulting
mixture was stirred for 15 min under N2, cooled to –60 °C, treated
with adamantylmagnesium bromide (ca. 10.4 mmol), and stirred for
17 h at this temperature. The reaction was quenched by the addition
of sat. aq NH4Cl (ca. 40 mL) and allowed to stir for 20 min. The
aqueous layer was then separated and extracted with Et2O
(3 × 20 mL). The combined ethereal layers were washed with brine
(2 × 30 mL), dried (Na2SO4), and concentrated in vacuo (40 °C/15
mbar, then 0.05 mbar) to give the crude product as a yellowish semi-
solid, 2.50 g (‘117%’). Only one diastereomer of 9 was detected ac-
cording to the 13C NMR spectrum, as well as 10–15% of the starting
nitrone 8. The crude material was purified by flash chromatography
on silica gel (40 g, column 14 cm × 3 cm), eluting with PE (ca. 100
mL) followed by PE–EtOAc (80:20, v/v). The product 9 was isolat-
ed as a colorless, analytically pure solid; mp 129–132 °C (1.29 g,
61%); [a]D20 +21 (c = 1.00, CHCl3).
0.86 mmol) was dissolved in anhyd MeOH (10 mL), then di-tert-
butyl dicarbonate (282 mg, 11.5 mmol) was added, and the resulting
solution was transferred into a hydrogenation vessel. This was
flushed with N2 and Pd(OH)2/C (40 mg) was added. The reaction
was carried out under H2 pressure (4.8 bar) for 3 days. The resulting
suspension was filtered through a pad of Celite/silica gel (ca. 1 cm,
Celite on top) and the adsorbent was washed with EtOAc (2 × 10
mL). The filtrate was concentrated in vacuo (40 °C/15 mbar) to give
a colorless semi-solid, which was purified by column chromatogra-
phy on silica gel (10 g, column 1 cm × 4 cm), eluting with EtOAc–
PE–Et3N (50:50:2, v/v/v). From this, 192 mg (61%) of 5 was isolat-
ed as an analytically pure, colorless solid; mp 109–114 °C;
[a]D20 +20 (c = 1.54, MeOH).
IR (neat): 2902 (vs, b), 2849 (vs), 1678 (vs, amide I), 1525 (s, amide
II), 1452 (m), 1365 (s), 1242 (s), 1161 (vs), 1049 (vs, b, C-O), 1011
(vs, C–O), 940 (s), 827 cm–1 (s).
1H NMR (500.2 MHz, CDCl3): d = 1.34 and 1.38 [2 s, 3 H each,
C(CH3)2], 1.44 [s, 9 H, C(CH3)3], 1.51–1.71 (m, 12 H, 2¢-H, 4¢-H,
6¢-H, 8¢-H, 9¢-H, 10¢-H), 1.98 (br s, 3 H, 3¢-H, 5¢-H, 7¢-H), 3.55
IR (neat): 3417 (w, OH), 2899 (s), 2843 (s, NH2), 1447 (m), 1113
(vs, C–O), 1008 (s), 909 (s), 695 cm–1 (s).
3
3
(‘dd’, J2,3 = 6.2 Hz, J2,NH = 10.8 Hz, 1 H, 3-H), 3.67 (‘dd’,
2J1a,1b = 8.4 Hz, J1a,2 = 7.7 Hz, 1 H, 1-Ha), 3.98 (‘dd’, J1a,1b = 8.4
1H NMR (300.1 MHz, CDCl3): d = 1.41 (m, 2 H, 4¢¢), 1.55–1.70 (m,
14 H, 4¢-H, 6¢-H, 9¢-H, 2¢¢-H, 3¢¢-H, 5¢¢-H, 6¢¢-H), 1.80 (br s, 6 H, 2¢-
H, 8¢-H, 10¢-H), 1.99 (br s, 3 H, 3¢-H, 5¢-H 7¢-H), 2.57 (‘d’,
3
2
3
3
Hz, J1b,2 = 6.4 Hz, 1 H, 1-Hb), 4.23 (‘dt’, J1a,2 = 7.5 Hz,
3J1b,2 = 3J2,3 = 6.3 Hz, 1 H, 2-H), 4.45 (d, J3,NH = 10.8 Hz, 1 H,
3
2
NH).
3J2,3 = 6.3 Hz, 1 H, 3-H), 3.95 (A of AB, JA,B = 13.7 Hz, 1 H,
CHAHBC6H5), 4.14 (dd, 2J1a,1b = 8.1 Hz, 3J1a,2 = 8.8 Hz, 1 H, 1-Ha),
13C NMR (125.8 MHz, CDCl3): d = 25.7 and 26.4 [2 q, C(CH3)2],
28.3 [q, C(CH3)3], 28.4 (d, C-3¢, C-5¢, C-7¢), 35.9 (s, C-1¢), 36.9 (t,
C-4¢, C-6¢, C-9¢), 39.1 (t, C-2¢, C-8¢, C-10¢), 58.1 (d, C-3), 66.8 (t,
C-1), 74.7 (d, C-2), 79.2 [s, C(CH3)3], 108.8 [s, C(CH3)2], 156.2
(C=O).
2
4.21 (B of AB, JA,B = 13.8 Hz, 1 H, CHAHBC6H5), 4.22 (‘dd’,
3
2J1a,1b = 8.1 Hz, 3J1b,2 = 5.7 Hz, 1 H, 1-Hb), 4.45 (‘ddd’, J1a,2 = 8.8
Hz, 3J1b,2 = 5.7 Hz, 3J2,3 = 6.3 Hz, 1 H, 2-H), 7.24–7.36 (m, 5 H, o-,
m-, p-H of C6H5).
13C NMR (75.5 MHz, CDCl3): d = 24.1 (t, C-3¢¢, C-5¢¢), 25.3 (t, C-
4¢¢), 28.8 (d, C-3¢, C-5¢, C-7¢), 35.1 and 36.6 (2 t, C-2¢¢, C-6¢¢), 37.2
(t, C-4 ¢, C-6¢, C-9¢), 38.0 (s, C-1¢), 40.4 (t, C-2¢, C-8¢, C-10¢), 64.6
(t, CH2C6H5), 68.1 (t, C-1), 74.4 (d, C-3), 75.0 (d, C-2), 107.8 (s, C-
1¢¢), 127.1 (d, p-C of C6H5), 128.3 and 128.9 (2 d, o-, m-C of C6H5),
139.4 (s, i-C of C6H5).
Anal. Calcd for C21H35NO4 (365.5): C, 69.01; H, 9.65; N, 3.83.
Found: C, 68.77; H, 9.58; N, 3.57.
2,3-O-Cyclohexylidene-D-glyceraldehyde N-Benzylnitrone (8)
According to Dondoni’s procedure,27 2,3-O-cyclohexylidene-D-
glyceraldehyde (7; 1.38 g, 8.1 mmol) and N-benzylhydroxyl-
amine39 (1.00 g, 8.1 mmol) were dissolved in anhyd CH2Cl2
(20 mL), and MgSO4 (ca. 2 g) was added. The suspension was
Anal. Calcd for C26H37NO3 (411.6): C, 75.87; H, 9.06; N, 3.40.
Found: C, 75.41; H, 9.35; N, 3.31.
Synthesis 2010, No. 21, 3693–3699 © Thieme Stuttgart · New York

PAPER
Synthesis of Adamantylglycine
3697
(2S,3S)-3-(1-Adamantyl)-3-amino-1,2-O-cyclohexylidene-1,2-
IR (neat): 2900 (m), 2886 (m) and 2846 (m) (OH, NH), 1694 (s),
1671 (vs, amide I), 1507 (s, NH), 1366 (s), 1158 (s), 1041 (s), 1012
cm–1 (vs) .
propanediol (10)
Diastereomerically pure N-benzylhydroxylamine
9
(1.52 g,
3.7 mmol) was dissolved in THF–MeOH (10 mL:40 mL), and the
resulting solution was transferred into a hydrogenation vessel. This
was flushed with N2, and Pd(OH)2/C (160 mg) was added. The re-
action was carried out under H2 pressure (4.8 bar) for 3 days. Then
the suspension was filtered through a pad of Celite/silica gel
(ca. 1 cm, Celite on top) and the adsorbent was washed with EtOAc
(3 × 30 mL). The filtrate was concentrated in vacuo (40 °C/15
mbar, then 0.05 mbar). The crude product, a colorless semi-solid
(1.13 g, ‘100%’), was chromatographed on silica gel (40 g, column
4 cm × 5 cm), eluting with EtOAc–PE–Et3N (50:50:2, v/v/v). From
this, 0.99 g (87%) of the amine 10 was isolated as an analytically
pure, colorless solid; mp 94–95 °C; [a]D20 +21 (c = 1.2, CHCl3).
1H NMR (500.1 MHz, CDCl3): d = 1.45 [s, 3 H, C(CH3)3], 1.66–
1.72 (br m, 12 H, 2¢-H, 4¢-H, 6¢-H, 8¢-H, 10¢-H), 2.00 (br s, 3 H, 3¢-
H, 5¢-H, 7¢-H), 3.17 (‘dd’, 3J1a,OH = 3.9 Hz, 3J1b,OH = 9.6 Hz, 1 H, 1-
3
3
OH), 3.20 (‘d’, J2,OH = 8.9 Hz, 1 H, 2-OH), 3.27 (‘dd’, J2,3 = 6.7
3
Hz, J3,NH = 9.3 Hz, 1 H, 3-H), 3.58 (m, 1 H, 1-Ha), 3.65 (‘ddd’,
2
3
3J1b,OH = 3.8 Hz, J1a,1b = 11.9 Hz, J1b,2 = 4.2 Hz, 1 H, 1-Hb), 3.72
(m, 1 H, 2-H), 4.69 (d, 3J3,NH = 9.3 Hz, 1 H, NH).
13C NMR (125.8 MHz, CDCl3): d = 28.4 [q, C(CH3)3], 28.4 (d, C-
3¢, C-5¢, C-7¢), 35.5 (s, C-1¢), 36.8 (t, C-4¢, C-6¢, C-9¢), 39.6 (t, C-2¢,
C-8¢, C-10¢), 61.8 (d, C-3), 64.7 (t, C-1), 71.1 (d, C-2), 80.3 [s,
C(CH3)3], 157.8 (s, C=O).
1H NMR (500.1 MHz, DMSO-d6): d = 1.38 [s, 3 H, C(CH3)3], 1.50–
1.69 (br m, 12 H, 2¢-H, 4¢-H, 6¢-H, 8¢-H, 9¢-H, 10¢-H), 1.90 (br s,
IR (neat): 2901 (vs, b, NH2), 2846 (vs, NH2), 1446 (s), 1362 (s),
1165 (s), 1097 (vs, b, C-O), 1032 (vs, C–O), 940 (s,), 827 cm–1 (s).
3
3
3 H, 3¢-H, 5¢-H, 7¢-H), 3.11 (‘dd’, J2,3 = 3.2 Hz, J3,NH = 7.2 Hz,
1 H, 3-H), 3.20 (‘ddd’, J = 1.3, 2.3, 5.0 Hz, 1 H, 1-Ha), 3.42–3.46
(‘ddd’, J = 1.5, 2.8, 3.4 Hz, 1 H, 1-Hb), 3.53–3.58 (m, 1 H, 2-H),
4.38 (m, 2 H, 1-OH and 2-OH), 6.40 (d, 3J3,NH = 10.3 Hz, 1 H, NH).
1H NMR (300.1 MHz, CDCl3): d = 1.15 (br s, 2 H, NH2), 1.40 (br s,
2 H, 4¢¢-H), 1.49–1.74 (m, 20 H, 2¢-H, 4¢-H, 6¢-H, 8¢-H, 9¢-H, 10¢-H,
2¢¢-H, 3¢¢-H, 5¢¢-H, 6¢¢-H),1.98 (br s, 3 H, 3¢-H, 5¢-H, 7¢-H), 2.70 (‘d’,
3J2,3 = 3.6 Hz, 1 H, 3-H), 3.83 (‘dd’, 2J1a,1b = 3J1a,2 = 8.0 Hz, 1 H, 1-
13C NMR (125.8 MHz, DMSO-d6): d = 27.9 [q, C(CH3)3], 28.3 (d,
C-3¢, C-5¢, C-7¢), 36.0 (s, C-1¢), 36.7 (t, C-4¢, C-6¢, C-9¢), 38.5 (t, C-
2¢, C-8¢, C-10¢), 61.0 (d, C-3), 62.5 (t, C-1), 70.5 (d, C-2), 77.2 [s,
C(CH3)3], 156.0 (s, C=O).
2
3
Ha), 3.92 (‘dd’, J1a,1b = 7.9 Hz, J1b,2 = 6.9 Hz, 1 H, 1-Hb), 4.26
(‘ddd’, 3J1a,2 = 7.8 Hz, 3J1b,2 = 6.9 Hz, 3J2,3 = 3.7 Hz, 1 H, 2-H).
13C NMR (75.5 MHz, CDCl3): d = 23.8 and 24.0 (2 t, C-3¢¢, C-5¢¢),
25.2 (t, C-4¢¢), 28.4 (d, C-3¢, C-5¢, C-7¢), 34.7 and 36.2 (2 t, C-2¢¢, C-
6¢¢), 35.1 (s, C-1¢), 37.1 (t, C-4¢, C-6¢, C-9¢), 39.2 (t, C-2¢, C-8¢, C-
10¢), 61.4 (d, C-3), 64.4 (t, C-1), 75.6 (d, C-2), 107.8 (s, C-1¢¢).
Anal. Calcd for C18H31NO4 (325.4): C, 66.43; H, 9.60; N, 4.30.
Found: C, 66.25; H, 9.61; N, 4.13.
Anal. Calcd for C19H31NO2 (305.5): C, 74.71; H, 10.23; N, 4.59.
Found: C, 74.64; H, 10.11; N, 4.57.
(S)-N-(tert-Butoxycarbonylamino)-1-adamantylglycine [(S)-13]
In analogy to the literature,24,35 the diol 12 (370 mg,1.14 mmol) was
dissolved in THF–H2O (60:40, 10 mL) and cooled to 0 °C. NaIO4
(365 mg, 1.71 mmol) was added with vigorous stirring. The react-
ing suspension was left with stirring at 0–5 °C for 45 min, then it
was filtered off and the solid was washed with Et2O (5 mL). The
aqueous layer was extracted with Et2O (3 × 5 mL). The combined
organic layers were washed with brine (15 mL), dried (Na2SO4),
and concentrated in vacuo (cold water bath/200 mbar). The residual
colorless solid was dissolved in a mixture of t-BuOH (3 mL) and
2-methylbut-2-ene (5 mL). To this, an aq solution of NaClO2
(154 mg, 1.71 mmol) and KH2PO4 (236 mg, 1.71 mmol) was added
dropwise within 10 min at 0–10 °C. The resulting suspension was
stirred for 1.5 h, followed by the addition of the same amount of
NaClO2 and KH2PO4 at 0 °C. After stirring overnight (18 h), aq 3 N
NaOH (ca. 5 mL) was added and volatiles were removed in vacuo
(40 °C/15 mbar). The residue was diluted with H2O (ca. 10 mL) and
acidified by the addition of aq 6 N HCl (ca. 3 mL) to reach pH 3–4
(with cooling in an ice-bath). The solid formed was extracted with
EtOAc (5 × 80 mL). The combined organic layers were washed
with sat. aq Na2SO3 (2 × 5 mL) and brine (5 mL), dried (Na2SO4),
and concentrated in vacuo (40 °C/15 mbar) to give 357 mg (quant)
of a colorless solid. Recrystallization from EtOAc–PE gave 291 mg
(82%) of the spectroscopically and analytically pure N-Boc-protect-
ed amino acid (S)-13; mp >300 °C (dec.) (Lit.8f ‘white foam’);
[a]D20 +22.6 (c = 1.13, CHCl3).
(2S,3S)-3-(1-Adamantyl)-3-aminopropane-1,2-diol Hydrochlo-
ride (11·HCl)
According to a known procedure,43 (2S,3S)-3-(1-adamantyl)-3-ami-
no-1,2-O-cyclohexylidene-1,2-propanediol (10; 200 mg, 0.65
mmol) was dissolved in THF (2 mL), treated with concd HCl
(2 mL), and stirred for 16 h at r.t. Then the solvents were removed
in vacuo (40 °C/15 mbar) to give a colorless solid, which after re-
crystallization from MeOH–Et2O gave 606 mg (82%) of the title 3-
aminodiol 11·HCl as a colorless, analytically pure solid; mp 235 °C
(dec.); [a]D20 +13 (c = 0.91, MeOH).
IR (neat): 3052 (bm, OH), 2998 (vs), 2846 (s), 1602 (m), 1505 (s),
1029 cm–1 (s).
1H NMR (300.1 MHz, MeOD): d = 1.70–1.81 (m, 12 H, 2¢-H, 4¢-H,
6¢-H, 8¢-H, 10¢-H), 2.05 (br s, 3 H, 3¢-H, 5¢-H, 7¢-H), 2.98 (‘d’,
3
3J2,3 = 3.9 Hz, 1 H, 3-H), 3.86 (‘d’, J1,2 = 3.5 Hz, 2 H, 1-H), 3.94
(‘dd’, 3J1,2 = 3J2,3 = 3.7 Hz, 1 H, 2-H).
13C NMR (75.5 MHz, MeOD): d = 29.5 (d, C-3¢, C-5¢, C-7¢), 35.5
(s, C-1¢), 37.5 (t, C-4¢, C-6¢, C-9¢), 39.5 (t, C-2¢, C-8¢, C-10¢), 65.2
(t, C-1), 67.2 (d, C-2), 68.5 (d, C-3).
Anal. Calcd for C13H24ClNO2 (261.8): C, 59.64; H, 9.24; N, 5.35;
Cl, 13.54. Found: C, 59.35; H, 9.31; N, 5.22; Cl, 13.38.
(2S,3S)-3-(1-Adamantyl)-3-(tert-butoxycarbonylamino)-1,2-O-
cyclohexylidenepropane-1,2-diol (12)
IR (neat): 2972 (w), 2924 (m), 2901 (s), 2851 (m), 1713 (s, C=O of
Boc), 1686 (s, amide I), 1645(s), 1506 (s, amide II), 1396 (m), 1153
(vs), 1041 (s), 1023 cm–1 (m) .
1H NMR (300.1 MHz, CDCl3): d = 1.45 [s, 9 H, C(CH3)3], 1.60–
1.72 (bm, 12 H, 2¢-H, 4¢-H, 6¢-H, 8¢-H, 9¢-H, 10¢-H), 2.01 (br s, 3 H,
3¢-H, 5¢-H, 7¢-H), 3.99 and 5.08 (2 d, 3J2,NH = 9.3 Hz, together 1 H,
2-H, rotamers). The 1H NMR spectrum corresponds to that of the S-
enantiomer of N-(tert-butoxycarbonylamino)-1-adamantylglycine
reported.8f
In analogy to a literature procedure,44 the amine hydrochloride
11·HCl (100 mg, 0.38 mmol) was suspended in MeCN (3 mL) and
treated with Et3N (ca. 20 mL). After stirring for 1 h, the pH of the so-
lution became ca. 9. Then, di-tert-butyl dicarbonate (83 mg,
0.38 mmol) was added, and the mixture was left with stirring for
21 h. The solvent was removed in vacuo (40 °C/15 mbar), and the
colorless solid was purified by filtration through silica gel (2.5 g,
column 5 cm × 1.5 cm), eluting with EtOAc–PE (50:50, v/v). The
diol 12 was isolated as an analytically pure, colorless solid (98 mg,
79%); mp 147–151 °C; [a]D20 –5.9 (c = 0.56, CHCl3).
13C NMR (75.1 MHz, CDCl3): d = 28.2 [q, C(CH3)3], 28.3 (d, C-3¢,
C-5¢, C-7¢), 36.1 (s, C-1¢), 36.6 (t, C-4¢, C-6¢, C-9¢), 38.5 (t, C-2¢, C-
Synthesis 2010, No. 21, 3693–3699 © Thieme Stuttgart · New York

3698
A. Baskakova et al.
PAPER
8¢, C-10¢), 62.4 (d, C-2), 79.9 [s, C(CH3)3], 155.7 (s, C=O of Boc),
176.3 (s, C=O).
W. In Asymmetric Synthesis, Vol. 4; Morrison, J. D.; Scott,
J. W., Eds.; Academic Press: Orlando, 1984, 1.
(c) Asymmetric Synthesis: Construction of Chiral Molecules
Using Amino Acids; Coppola, G. M.; Schuster, H. F., Eds.;
Wiley: New York, 1987.
At r.t. (295 K) the signals show satellite peaks at 64.5, 81.5 and
156.8 ppm, probably due to the presence of two rotamers. Record-
ing the NMR spectra at 375 K (102 °C) using DMSO-d6 as a solvent
(3) (a) Chiral Auxiliaries and Ligands in Asymmetric Synthesis;
Seyden-Penne, J., Ed.; Wiley: New York, 1995. (b) Evans,
D. A. In Asymmetric Synthesis, Vol. 3B; Morrison, J. D.,
Ed.; Academic Press: Orlando, 1984, 1. (c) Meyers, A. I.;
Lutomski, K. A. In Asymmetric Synthesis, Vol. 3B;
Morrison, J. D., Ed.; Academic Press: Orlando, 1984, 213.
(d) Enders, D. In Asymmetric Synthesis, Vol. 3B; Morrison,
J. D., Ed.; Academic Press: Orlando, 1984, 275. (e) Job, A.;
Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron: Asymmetry 2002, 58, 2253.
led to a coalescence of signals, which resulted in clear 1H and 13
NMR spectra.
C
1H NMR (500.1 MHz, DMSO-d6, 375 K): d = 1.42 [s, 9 H,
C(CH3)3], 1.60–1.71 (br m, 12 H, 2¢-H, 4¢-H, 6¢-H, 8¢-H, 9¢-H, 10¢-
H), 1.98 (br s, 3 H, 3¢-H, 5¢-H, 7¢-H), 3.72 (d, 3J2,NH = 9.2 Hz, 1 H,
2-H), 5.96 (d, 3J2,NH = 8.2 Hz, 1 H, NH).
13C NMR (126 MHz, DMSO-d6, 375 K): d = 28.0 [q, C(CH3)3],
28.2 (d, C-3¢, C-5¢, C-7¢), 35.1 (s, C-1¢), 36.5 (t, C-4¢, C-6¢, C-9¢),
38.5 (t, C-2¢, C-8¢, C-10¢), 63.2 (d, C-2), 78.4 (s, [q, C(CH3)3], 155.4
(s, C=O of Boc), 171.8 (s, CO2H).
(4) (a) Kagan, H. B. In Asymmetric Synthesis, Vol. 5; Morrison,
J. D., Ed.; Academic Press: Orlando, 1985, 1. (b) Wang,
D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J. Q. Science 2010, 327,
315.
Anal. Calcd for C17H27NO4 (309.4): C, 65.99; H, 8.80; N, 4.53.
Found: C, 66.05; H, 8.66; N, 4.51.
(5) See, e.g.: (a) Longbottom, D. A.; Franckevicius, V.; Ley, S.
V. Chimia 2007, 61, 247. (b) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719.
(S)-1-Adamantylglycine Hydrochloride [(S)-1·HCl]
The N-Boc-protected amino acid (S)-13 (50 mg, 0.16 mmol) was
dissolved in THF (1 mL) and treated with aq 12 N HCl (1 mL). Af-
ter stirring for 1 h, a colorless solid was formed. Stirring was con-
tinued for ca. 20 h, and the solvents were removed in vacuo (40 °C/
15 mbar, then 0.05 mbar) to give 40 mg (94%) of the title compound
as an analytically almost pure (vide supra) colorless solid with a
melting/decomposition range of 247–292 °C (Lit.8c mp 236–
240 °C; Lit.9 mp 236–241 °C); [a]D20 +20.9 (c = 0.93, MeOH)
{Lit.8c [a]D +16 (c = 0.50, MeOH); Lit.9 [a]D +18.0 (c = 0.50,
MeOH)}. The hydrochloride of 1 crystallized with 0.5 MeOH.37
(6) For uses of tert-leucine and tert-leucinol, see: (a) Tomioka,
K.; Koga, K. In Asymmetric Synthesis, Vol. 2A; Morrison,
J. D., Ed.; Academic Press: New York, 1983, 201.
(b) Guével, A.-C. In Encyclopedia of Reagents for Organic
Synthesis, Vol. 5; Paquette, L. A., Ed.; Wiley: Chichester,
1995, 2961. (c) Bolm, C.; Kasyan, A.; Drauz, K.; Günther,
K.; Raabe, G. Angew. Chem. Int. Ed. 2000, 39, 2288; Angew.
Chem. 2000, 112, 2374 (including references to tert-sila-
leucine).
IR (neat): 3019 (m, NH2), 2902 (vs, OH), 2848 (s), 2597 (m), 1507
(s, C=O), 1219 (s), 1030 cm–1 (s).
(7) Mahadik, G. S.; Hitchcock, S. R. Tetrahedron: Asymmetry
2010, 21, 33.
(8) (a) Do, K. Q.; Tanei, P.; Gavierel, M.; Schwyzer, R. Helv.
Chim. Acta 1979, 62, 956. (b) Belokon, Y. N.; Maleyev, V.
I.; Vitt, S. V.; Ryzhov, M. G.; Kondrashov, Y. D.; Golubev,
S. N.; Vauchskii, Y. P.; Kazika, A. I.; Novikova, M. I.;
Krasutski, P. A.; Yurchenko, A. G.; Dubchak, I. L.;
Shklover, V. E.; Struchkov, Y. T.; Bakhmutov, V. I.;
Belikov, V. M. J. Chem. Soc., Dalton Trans. 1985, 17.
(c) Gálvez, N.; Moreno-Mañas, M.; Vallribera, A.; Molins,
E.; Cabrero, A. Tetrahedron Lett. 1996, 37, 6197.
(d) Gálvez, N.; Moreno-Mañas, M.; Padros, I.; Sebastian, R.
M.; Serra, N.; Vallribera, A. Polyhedron 1995, 14, 1397.
(e) Clariana, J.; Garsía-Granda, S.; Gotor, V.; Gutiérrez-
Fernández, A.; Luna, A.; Moreno-Mañas, M.; Vallribera, A.
Tetrahedron: Asymmetry 2000, 11, 4549. (f) Augeri, D. J.;
Robl, J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna, A.;
Robertson, J. G.; Wang, A.; Simpkins, L. A.; Taunk, P.;
Huang, Q.; Han, S.-P.; Abboa-Offei, B.; Cap, M.; Xin, L.;
Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.;
1H NMR (300.1 MHz, MeOD): d = 1.63–1.84 (m, 12 H, 2¢-H, 4¢-H,
6¢-H, 8¢-H, 9¢-H, 10¢-H), 2.06 (br s, 3 H, 3¢-H, 5¢-H, 7¢-H), 3.52 (s,
1 H, 2-H).
13C NMR (75.1 MHz, MeOD): d = 29.3 (d, C-3¢, C-5¢, C-7¢), 35.4
(s, C-3), 37.1 (t, C-4¢, C-6¢, C-9¢), 39.0 (t, C-2¢, C-8¢, C-10¢), 63.3 (d,
C-2), 170.2 (C=O).
Anal. Calcd for C12H20ClNO2 (245.7): C, 58.65; H, 8.20; N, 5.70;
Cl, 14.43; Anal. Calcd for C12H20ClNO2·0.5MeOH (261.6): C,
57.35; H, 8.47; N, 5.35; Cl, 13.54. Found: C, 57.91; H, 8.47; N,
5.35; Cl, 13.54.
Acknowledgment
We are grateful to generous support of this project by Prof. Dr. J.
Senn-Bilfinger (Altana Pharma, now Nycomed, Konstanz) and to
Dr. B. Claasen and Dr. P. Fischer for NMR data and discussions.
Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M.
S.; Parker, R. A.; Hamann, L. G. J. Med. Chem. 2005, 48,
5025.
References
(1) For overviews with numerous examples of applications,
see: (a) Risch, N.; Arend, M. In Houben-Weyl, Methoden
der Organischen Chemie, 4th ed., Vol. E21b; Helmchen, G.;
Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme:
Stuttgart, 1995, 1833. (b) Principles and Applications of
Asymmetric Synthesis; Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C.,
Eds.; Wiley-Interscience: New York, 2001. (c) Asymmetric
Synthesis of Natural Products; Koskinen, A., Ed.; Wiley:
Chichester, 1993. (d) Asymmetric Synthesis – The
(9) Yield of 1·HCl 2.3% after 6 steps from 1-adamantane
carboxaldehyde: Hasegawa, M.; Taniyama, D.; Tomioka, K.
Tetrahedron 2000, 56, 10153.
(10) cf.: Use of adamantylglycinol for respective oxazoline
ligands: Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.;
Burkey, B. F.; Dunning, B. E.; Prasad, K.; Mangold, B. L.;
Russell, M. E.; Hughes, T. E. J. Med. Chem. 2003, 46, 2774.
(11) Wanka, L.; Cabrele, C.; Vanejews, M.; Schreiner, P. R. Eur.
J. Org. Chem. 2007, 1474.
Essentials; Christmann, M.; Bräse, S., Eds.; Wiley-VCH:
Weinheim, 2007.
(2) (a) Chemistry and Biochemistry of the Amino Acids; Barrett,
(12) Aldrich, P. E.; Hermann, E. C.; Meier, W. E.; Paulshock, M.;
Prichard, W. W.; Snyder, J. A.; Watts, J. C. J. Med. Chem.
1971, 14, 535.
G. C., Ed.; Chapman and Hall: London, 1985. (b) Scott, J.
Synthesis 2010, No. 21, 3693–3699 © Thieme Stuttgart · New York

PAPER
Synthesis of Adamantylglycine
3699
(13) Rosenthal, K.; Sokol, M. S.; Ingram, R. L.; Subramanian, R.;
Fort, R. C. Antimicrob. Agents Chemother. 1982, 22, 1031.
(14) For pioneering work concerning RM additions to 2,3-O-
isopropylidene gylceraldehyde imines, see: (a) Yoshimura,
J.; Sato, T. J. Am. Chem. Soc. 1964, 86, 3858. (b) Ohgo, Y.;
Yoshimura, J.; Sato, T. Bull. Chem. Soc. Jpn. 1969, 42, 728.
(c) See also: Carcano, M.; Nicotra, F.; Panza, L.; Russo, G.
Chem. Commun. 1989, 297.
Luque, A.; Server-Carrió, J.; Linden, A. J. Org. Chem. 1997,
62, 2070.
(26) Yurchenko, A. G.; Fedorenko, T. V. Zh. Org. Khim. 1987,
23, 970; Chem. Abstr. 1988, 108, 204255y.
(27) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.; Merino,
P.; Tejero, T. Synth. Commun. 1994, 24, 2537.
(28) cf.: Use in isoxazolidine reductions: DeShong, P.; Dicken,
C. M.; Leginus, J. M.; Whittle, R. R. J. Am. Chem. Soc.
1984, 106, 5598.
(15) Bloch, R. Chem. Rev. 1998, 98, 1407.
(16) Franz, T.; Hein, M.; Veith, U.; Jäger, V.; Peters, E.-M.;
Peters, K.; von Schnering, H. G. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1298; Angew. Chem. 1994, 106, 1308.
(17) (a) Veith, U.; Leurs, S.; Jäger, V. Chem. Commun. 1996,
329. (b) Meunier, N.; Veith, U.; Jäger, V. Chem. Commun.
1996, 331.
(18) (a) Veith, U.; Schwardt, O.; Jäger, V. Synlett 1996, 1181.
(b) Schwardt, O.; Veith, U.; Gaspard, C.; Jäger, V. Synthesis
1999, 1473.
(29) Rundel, W. In Houben-Weyl, Methoden der Organischen
Chemie, 4th ed., Vol. X/4; Müller, E., Ed.; Thieme:
Stuttgart, 1968, 309.
(30) Frey, W.; Baskakova, A.; Jäger, V. Z. Kristallogr. - New
Cryst. Struct. 2009, 224, 27.
(31) (a) Yin, H.; Franck, R. W.; Chen, S.-L.; Quigley, G. J.;
Todardo, L. J. Org. Chem. 1992, 57, 644. (b) Menzel, A.
Ph.D. Dissertation; University of Stuttgart: Germany, 2000.
(32) Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994,
95.
(33) Frey, W.; Baskakova, A.; Menzel, A.; Jäger, V. Z.
Kristallogr. - New Cryst. Struct. 2010, 225, 245.
(34) Frey, W.; Baskakova, A.; Jäger, V. Z. Kristallogr. - New
Cryst. Struct. 2010, 225, 247.
(35) (a) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825.
(b) Lindgren, B. O.; Hilsson, T. Acta Chem. Scand. 1973, 27,
888.
(36) Crystallographic data for adamantylglycine
1·HCl·(0.5MeOH) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-770794. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or e-
mail: deposit@ccdc.cam.ac.uk].
(19) Li, F.; Schwardt, O.; Jäger, V. Synthesis 2006, 2173; and
references cited therein.
(20) For basic work on such nitrone additions, see: (a) Dondoni,
A.; Franco, S.; Merchan, F. L.; Merino, P.; Tejero, T.
Tetrahedron Lett. 1993, 34, 5475. (b) Merino, P.; Castillo,
E.; Merchan, F. L.; Tejero, T. Tetrahedron: Asymmetry
1997, 8, 1725. (c) Merino, P.; Anoro, S.; Castillo, E.;
Merchan, F.; Tejero, T. Tetrahedron: Asymmetry 1996, 7,
1887. (d) Merino, P.; Castillo, E.; Franco, S.; Merchan, F.
L.; Tejero, T. Tetrahedron 1998, 54, 12301. (e) Merino, P.;
Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org.
Chem. 1998, 63, 2371. (f) Schade, W.; Reissig, H.-U.
Synlett 1999, 632. (g) Merino, P. C. R. Chim. 2005, 8, 775.
(h) cf.: Portolés, R.; Murga, J.; Falomir, E.; Carda, M.; Uriel,
S.; Marco, J. A. Synlett 2002, 711.
(21) (a) Li, F. Ph.D. Dissertation; University of Stuttgart:
Germany, 2007. (b) cf.: Jäger, V.; Bierer, L.; Dong, H.-Q.;
Palmer, A.; Shaw, D.; Frey, W. J. Heterocycl. Chem. 2000,
37, 455. (c) Palmer, A. M.; Jäger, V. Synlett 2000, 1405.
(d) Palmer, A. M.; Jäger, V. Eur. J. Org. Chem. 2001, 1293.
(e) Palmer, A. M.; Jäger, V. Eur. J. Org. Chem. 2001, 2547.
(22) For ‘asymmetric derivatization of glycines’ and ‘glycine
cations’, see: Williams, R. M. Synthesis of Optically Active
a-Amino Acids; Pergamon Press: Oxford, 1989, 95.
(23) Methods for the Oxidation of Organic Compounds; Haines,
A. H., Ed.; Academic Press: London, 1988.
(24) (a) Zimmermann, P. J.; Blanarikova, I.; Jäger, V. Angew.
Chem. Int. Ed. 2000, 39, 910, Angew. Chem. 2000, 112,
936. (b) Zimmermann, P. J.; Lee, J.-Y.; Blanarikova, I.;
Endermann, R.; Häbich, D.; Jäger, V. Eur. J. Org. Chem.
2005, 3450. (c) Lee, J.-Y.; Schiffer, G.; Jäger, V. Org. Lett.
2005, 7, 2317. (d) Henneböhle, M.; Le Roy, P.-Y.; Hein,
M.; Ehrler, R.; Jäger, V. Z. Naturforsch., B 2004, 59, 451.
(25) (a) Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1993,
66, 2206. (b) Hubschwerlen, C. Synthesis 1986, 962.
(c) Krämer, B.; Franz, T.; Picasso, S.; Pruschek, P.; Jäger, V.
Synlett 1997, 295. (d) Palomo, C.; Aizpurua, J. M.; García,
J. M.; Galarza, R.; Legido, M.; Urchegui, R.; Román, P.;
(37) The presence of MeOH in crystalline 1·HCl has apparently
been overlooked in earlier work.8,9
(38) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980,
45, 3916.
(39) (a) Maskill, H.; Jencks, W. P. J. Am. Chem. Soc. 1987, 109,
2062. (b) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am.
Chem. Soc. 1971, 93, 2897.
(40) (a) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Philips,
J. L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C.
S. J. Org. Chem. 1991, 56, 4056. (b) Chittenden, G. J. F.
Carbohydr. Res. 1980, 84, 350.
(41) (a) Sheldrick, G. M. SHELXS-97. Program for the Solution
of Crystal Structures; University of Göttingen: Germany,
1997. (b) Sheldrick, G. M. SHELXL-97. Program for the
Refinement of Crystal Structures; University of Göttingen:
Germany, 1997. (c) Sheldrick, G. M. SHELXTL-Plus.
Structure Determination Software Suite; Release 4.1.
Siemens Analytical Systems Inc.: Madison, 1991.
(42) cf.: Veith, U. Diploma Thesis; University of Würzburg:
Germany, 1991.
(43) Canas-Rodriguez, A.; Ruiz-Poveda, S. G.; Coronel-Borges,
L. A. Carbohydr. Res. 1987, 159, 217.
(44) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
Synthesis 2010, No. 21, 3693–3699 © Thieme Stuttgart · New York