Synthesis of hydroxy-and polyhydroxy-substituted 1,3-diaminocyclohexanes

Article abstract of DOI:10.1055/s-0030-1258430

The synthesis of hydroxy-trans-1,3-diaminocyclo-hexanes based on nitroso-Diels-Alder cycloaddition of (cyclohexadienyl)phthalimide is reported. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258430

924
PAPER
Synthesis of Hydroxy- and Polyhydroxy-Substituted 1,3-Diaminocyclohexanes
Hydroxy- and
P
oly
n
hydroxy-1, 3
o
-diaminocyc
b
lohexane
s
ick Sar, Sergey Lindeman, William A. Donaldson*
Department of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA
Fax +1(414)2887066; E-mail: william.donaldson@marquette.edu
Received 22 October 2010; revised 21 December 2010
We have recently reported the synthesis of racemic N-(cy-
Abstract: The synthesis of hydroxy-trans-1,3-diaminocyclo-
hexanes based on nitroso-Diels–Alder cycloaddition of (cyclohexa-
dienyl)phthalimide is reported.
clohexa-2,4-dienyl)phthalimide [( )-6] (Scheme 1) from
+
the (cyclohexadienyl)Fe(CO)3 cation.6 Cycloaddition of
6 with nitrosobenzene7 gave the 2-oxa-3-azaoxabicyc-
lo[2.2.2]oct-5-ene ( )-7. The structure of 7 was tentative-
Key words: cycloaddition, regioselectivity, amino alcohols, enan-
tiomeric resolution
1
ly assigned on the basis of its H NMR spectral data.
Assignment of the signals for the diastereotopic methyl-
ene protons (H3 and H3¢) was facilitated by the magnitude
of their vicinal couplings to H2; the syn-coupling (ca. 0°
dihedral angle) is larger than the anti-coupling (ca. 120°
dihedral angle). The signal for H3¢ appears upfield of the
signal for H3. These relative chemical shifts are due to the
anisotropic effect of the olefin functionality. This tenta-
tive assignment was eventually corroborated on the basis
of single crystal X-ray diffraction analysis.8
Trihydroxy-1,3-diaminocyclohexanes [also known as 2-de-
oxystreptamine (1), Figure 1] are present as key structural
features in aminoglucoside antibiotics, such as kanamycin
A (2), which bind to the bacterial 16S ribosomal RNA.1
While the majority of aminoglucoside antibiotics possess
a cis-1,3-diaminocyclohexane subunit, certain ‘designer’
analogues, containing a trans-1,3-diaminocyclohexane
subunit exhibit interesting differential binding to bacterial
and human rRNA. For example, 3 binds ca. one order of
magnitude more tightly to E. coli 16S rRNA (Kd = 6 0.5
mM) compared to human 18S rRNA (Kd = 68 6.9 mM).2
Additionally, 2,3,4-trihydroxycyclohexane-trans-1,5-di-
amines (e.g., 4) have been prepared as sugar mimics,3 and
2-hydroxycyclohexane-trans-1,5-diamines (e.g., 5) have
been utilized as intermediates in the synthesis of CC
chemokine receptor 2 antagonists.4 We herein report the
synthesis of a series of hydroxydiaminocyclohexanes
from the readily available5 tricarbonyl(cyclohexadi-
enyl)iron(1+) cation.
δ 2.81
1) K+ –NPhth
2) CAN
O
Ph
+
Fe(CO)3
9.6 Hz
H2
PhN=O
NPhth
N
(61%, ref. 5)
H3
NPhth
H3'
( )-7 (67%)
( )-6
–
δ 2.59
BF4
3.6 Hz
Scheme 1
Dihydroxylation of 7 gave a single diol ( )-8. The relative
stereochemistry of 8 was tentatively based on the percep-
tion that reaction would occur on the face of the olefin op-
posite to the sterically bulky phthalimide group. This
tentative assignment was eventually corroborated by fur-
ther derivatization of 8 (vide infra). Reductive N–O bond
cleavage of 8 with molybdenum hexacarbonyl9 gave a sin-
gle allylic alcohol, ( )-9. Hydrogenation of 7 or 8 over
Raney nickel gave ( )-10 or ( )-11, respectively, while di-
hydroxylation of 9 gave the triol ( )-12 (Scheme 2). The
structural assignment for 10 was tentatively assigned
based on the structure of 7; this tentative assignment was
eventually corroborated by single crystal X-ray diffrac-
tion analysis.8 The structures for 11 and 12 were assigned
on the basis of their 1H NMR spectral data. In particular,
the signal for H6ax of each appears as a doublet (J ~ 3–4
Hz) of triplets (J ~ 13 Hz), indicative that the C1 phthal-
imide and the C5 phenylamino substituents are trans.
Similarly, the signal for H1 of each appears as a doublet
of doublet of doublets (J ~ 4.5, 10.8, and 13 Hz) indicative
that the C1 phthalimide and the C2 hydroxy groups are
trans. The relative stereochemistry of the C2 and C3 hy-
droxy groups was assigned on the basis of the H2/H3 cou-
pling (11, J = 2.6 Hz; 12, J = 9.6 Hz).
NH2
OH
OH
NH2
O
HO
HO
O
HO
OH
OH
OH
O
O
H2N
NH2
H2N
NH2
1
H2N
2
NH2
OH NH2
OH
HO
HO
OH
O
H2N
OH
BocHN
HO
N(OH)Boc
CbzHN
O
OH
OH
OH
4
NHBoc
H2N
NH2
3
5
Figure 1
SYNTHESIS 2011, No. 6, pp 0924–0928
Advanced online publication: 10.02.2011
DOI: 10.1055/s-0030-1258430; Art ID: M07110SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

PAPER
Hydroxy- and Polyhydroxy-1,3-diaminocyclohexanes
925
mixture of 14–16 gave a mixture of racemic 17, 18, and
19; separation of this mixture by preparative TLC gave
pure ( )-18, and a mixture of 17 and 19. The structures of
14–19 were tentatively assigned as indicated on the basis
Mo(CO)6
MeCN
H2O
Ph
O
OsO4 (cat.)
NMO
OH
N
HO
HO
PhHN
NPhth
NPhth
1
( )-7
of their H NMR spectral data. Notably, the chemical
( )-9 (45%)
( )-8 (81%)
shifts for signals of the 2-oxa-3-azabicyclo[2.2.2]octane
core of acetate 17 are relatively similar to those for 14.
Similarly, the chemical shifts for 15 or 16 are relatively
similar to those of 18 or 19 respectively. The upfield
chemical shift for H2 of 15 (d = 4.36), relative to that for
H2 of 14 or 16 (d = 4.81 or 4.68, respectively) is due to the
anisotropic effect of the olefin functionality.
H2
Raney-Ni
H2
Raney-Ni
OsO4 (cat.)
NMO
HO
NHPh
HO
OH NHPh
OH NHPh
2
1
2
3
HO
1
NPhth
HO
NPhth
NPhth
3
5
5
6
6
4
4
HO
( )-12 (33%)
( )-10 (76%)
( )-11 (57%)
Scheme 2
The preparation of optically active bicyclooxazines has
been accomplished by the addition of optically active ni-
troso acyls to achiral dienes10 and by the copper-catalyzed
addition of achiral nitroso acyls to achiral dienes in the
presence of a chiral ligand.11 More recently, Jana and
Studer have demonstrated a catalytic, enantioselective,
and regiodivergent addition of 2-nitrosopyridine to race-
mic cyclohexadienes.12 To explore the possibility of gen-
erating optically active oxazines, the reaction of ( )-6
with the nitroso acyl generated from ( )-mandelohydrox-
amic acid [( )-13] was examined (Scheme 3). This gave a
mixture of three diastereomeric cycloadducts 14, 15, and
16 in a ratio of ca. 5:3:2 (76%). Fractional crystallization
of the mixture from acetonitrile gave the racemic diaste-
reomer ( )-14 (25% isolated yield), whose structure was
unambiguously assigned on the basis of single crystal X-ray
diffraction analysis (Figure 2). Similarly, reaction of ( )-
6 with the nitroso acyl generated from (R)-13 gave an op-
tically active mixture of diastereomers 14–16; fractional
crystallization of this mixture gave pure (+)-14 (11%).
Figure 2 ORTEP drawing of ( )-14 with crystallographic numbe-
ring. C22H18N2O5; orthorhombic, ABa2, Z = 8, a = 21.9065(4) Å,
b = 28.3819(6) Å, c = 5.80740(10)Å, V = 3610.74(12) Å3; 30401 re-
flections measured, 3175 unique (Rint = 0.0252). The final wR2 was
0.0701 (all data). CCDC 778912.
The diastereoselectivity may be rationalized by consider-
ation of the possible transition states leading to the prod-
ucts (Scheme 4). It has been proposed that the nitroso
dienophile derived from mandelohydroxamic acid reacts
primarily in a six-membered ring hydrogen-bonded con-
former.10a Approach of the (R)-nitroso dienophile to the
exo-face of (R)-6 (i.e., TS 1) does not involve any steric
hindrance, while approach of the (R)-nitroso dienophile to
the endo-face of (R)-6 (i.e., TS 2) involves steric repulsion
between H4 and the phenyl substituent and between the
nitroso oxygen and the phthalimide substituent. Thus, TS
1 (leading to 14) should be greatly favored over TS 2. In
comparison, approach of the (R)-nitroso dienophile to the
exo-face of (S)-6 (i.e., TS 3) involves repulsion between
the nitroso oxygen and the phthalimide substituent, while
approach of the (R)-nitroso dienophile to the endo-face of
(S)-6 (i.e., TS 4) involves steric repulsion between H4 and
the phenyl substituent. Thus, the energies of TS 3 (leading
to 15) and TS 4 (leading to 16) are more equally matched
in energy.
The mother liquors from the recrystallization of 14, 15,
and 16 could not be further purified by recrystallization or
chromatography. In this case, acylation of the racemic
( )-6
O
( )-13 → 14/15/16 = 5:3:2 (76%)
(R)-13 → 14/15/16 = 5:3:2 (62%)
Ph
NaIO4
NHOH
HO
13
NPhth
H2
δ 4.81
O
O
O
O
Ph
Ph
N
N
H2
NPhth
HO
HO
HO
O
NPhth
H2
N
δ 4.66
Ph
( )-14 (25%a)
(+)-14 (11%a)
( )-15
O
( )-16
δ 4.36
Attempted reduction of bicyclic oxazine ( )-14 with hy-
drogen over Raney nickel gave an intractable mixture of
unidentified products. In comparison, reduction using ti-
tanocene(III) chloride13 proceeded to afford ( )-20, which
upon further catalytic hydrogenation gave the saturated
diaminocyclohexane ( )-21 (Scheme 5). Similar process-
ing of (+)-14 gave (–)-20 and (–)-21, respectively. The
structural assignments for 20 and 21 are based on compar-
ison of their 1H NMR spectral data with that for the previ-
ously prepared 9 and 10, respectively.
Ac2O, pyridine (60%)
O
δ 4.96
NPhth
O
O
H3'
O
O
Ph
AcO
Ph
H2
H2
H3
NPhth
NPhth
N
N
H3
AcO
AcO
H3
H2
H3'
N
ca. δ 4.8
Ph
δ 4.51
H3'
O
( )-17
( )-18 (19%)a
( )-19
Scheme 3 a Isolated yield of pure compound
Synthesis 2011, No. 6, 924–928 © Thieme Stuttgart · New York

926
A. Sar et al.
PAPER
7.6 Hz, 1 H), 7.03 (d, J = 7.6 Hz, 2 H), 7.24 (t, J = 7.6 Hz, 2 H),
7.70–7.84 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 27.6, 48.2, 57.1, 69.4, 117.7,
122.5, 123.3, 128.4, 128.7, 131.7, 132.6, 134.3, 151.8, 168.5.
TS 1
TS 2
H
R
H
O
Ph
R
H
O
NPhth
H4
H
R
N
O
H
O
14
Ph
R
H
O
NPhth
H4
Anal. Calcd for C20H16N2O3: C, 72.28; H, 4.85; N, 8.43. Found: C,
72.11; H, 4.89; N, 8.46.
N
O
NPhth
H
3-Phenyl-7-phthalimido-2-oxa-3-azabicyclo[2.2.2]octane-5,6-
diol [( )-8]
S
H
O
Ph
R
H
O
H4
NPhth
H
N
16
15
A sample of 7 (70 mg, 0.21 mmol) in acetone was treated with cat-
alytic OsO4 (in toluene) and NMO for 10 h at r.t. in a fashion similar
to the typical procedure to give ( )-12. After the standard workup,
the residue was adsorbed onto silica gel using CH2Cl2. This purified
by column chromatography (layered onto silica gel, hexane–
EtOAc, 1:1) to give ( )-8 (63 mg, 81%) as a colorless solid; mp
183–186 °C.
H
O
Ph
R
H
O
O
S
H4
N
O
TS 3
TS 4
Scheme 4
1H NMR (400 MHz, CDCl3): d = 2.29 (ddd, J = 4.8, 11.6, 14.4 Hz,
1 H), 2.72 (ddd, J = 1.2, 7.6, 14.4 Hz, 1 H), 3.44 (d, J = 7.6 Hz, OH,
1 H), 3.71 (d, J = 10.0 Hz, OH, 1 H), 3.98–4.13 (m, 2 H), 4.34 (t,
J = 7.6 Hz, 1 H), 4.58 (dt, J = 3.2, 9.2 Hz, 1 H), 4.88 (ddd, J = 4.0,
8.0, 11.2 Hz, 1 H), 7.04 (t, J = 7.2 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2
H), 7.24 (dd, J = 7.2, 8.8 Hz, 2 H), 7.73–7.86 (m, 4 H).
OH
OH
HN
NPhth
HN
NPhth
OH
OH
O
O
Ph
Ph
13C NMR (100 MHz, CDCl3): d = 19.7, 45.0, 59.5, 64.1, 66.0, 76.6,
116.1, 122.8, 123.8, 129.4, 131.5, 134.7, 149.8, 168.6.
( )-20 (66%)
( )-21 (76%)
( )-14
H2, 10% Pd/C
MeOH
Cp2TiCl2, Zn
THF–MeOH
Anal. Calcd for C20H18N2O5·0.6 H2O: C, 63.69; H, 5.13. Found: C,
63.66; H, 4.93.
(–)-20 (53%)
(–)-21 (80%)
(+)-14
Scheme 5
N-[(1S*,2S*,5S*)-2-Hydroxy-5-(phenylamino)cyclohex-3-
enyl]phthalimide [( )-9]
In summary, the cycloaddition of (cyclohexadien- To a soln of 7 (200 mg, 0.600 mmol) in MeCN (8 mL) and H2O (0.7
mL) was added Mo(CO)6 (158 mg, 0.600 mmol). The mixture was
heated at reflux for 1 h, and then concentrated under reduced pres-
sure. Purification of the residue by column chromatography (silica
gel, hexane–EtOAc, 1:1) gave ( )-9 (90 mg, 45%) as a pale yellow
foamy solid; mp 73–75 °C.
1H NMR (400 MHz, CDCl3): d = 2.05 (br d, J = 13.2 Hz, 1 H), 2.77
(dt, J = 4.8, 13.2 Hz, 1 H), 4.23 (br s, 1 H), 4.39 (ddd, J = 3.4, 9.8,
yl)phthalimide ( )-6 with nitrosobenzene proceeds in a dia-
stereofacial- and regioselective fashion to afford bicyclic
oxazine ( )-7. In contrast, reaction of ( )-6 with the opti-
cally active nitroso acyl derived from mandelohydroxam-
ic acid gave a mixture of three cycloadducts; the structure
of the major product 14 was confirmed by X-ray crystal
structure. The oxazine 7 could be rapidly transformed into
13.2 Hz, 1 H), 4.84 (dd, J = 1.4, 9.8 Hz, 1 H), 5.82–5.95 (m, 2 H),
hydroxy-trans-1,3-diaminocyclohexanes 10–12, while
oxazines (+)-14 was transformed into the optically active
hydroxy-trans-1,3-diaminocyclohexane (–)-21. The
structural assignments are based on their NMR spectral
data and confirmed by X-ray diffraction for 10.
6.64 (d, J = 7.6 Hz, 2 H), 6.71 (d, J = 7.2 Hz, 1 H), 7.17 (dd, J = 7.0,
8.6 Hz, 2 H), 7.65–7.80 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 29.9, 48.0, 51.2, 68.4, 113.3,
117.9, 123.4, 128.4, 129.6, 131.9, 133.8, 134.2, 146.7, 169.0.
HRMS (FAB): m/z [M+] calcd for C20H18N2O3: 334.1317; found:
334.1321.
Elemental analyses were obtained from Midwest Microlabs, Ltd.,
Indianapolis, IN, and HRMS were obtained from the University of
Nebraska Center for mass spectrometry. Anhyd CH2Cl2 and anhyd
DMF were purchased from Aldrich Chemical Company. Reactions
were performed in flame-dried glassware under an atmosphere of
N2 unless otherwise noted. Compounds 6,6 ( )-13, and (R)-1310a
were prepared by literature procedures.
N-[(1S*,2S*,5R*)-2-Hydroxy-5-(phenylamino)cyclohex-
yl]phthalimide [( )-10]; Typical Procedure
In a small hydrogenation vessel, was placed a soln of 7 (0.3 g, 0.9
mmol) in MeOH (30 mL). A slurry of Raney Ni (0.5 mL, 50% in
H2O) was added and the mixture was stirred under H2 (2.76 bar) for
4 h. After releasing the excess H2 pressure, the mixture was filtered
through Celite and the solvent evaporated under reduced pressure.
The residue was dissolved in EtOAc, adsorbed onto silica gel and
purified by column chromatography (silica gel, hexane–EtOAc,
1:1) to give ( )-10 (225 mg, 74%) as a light yellow solid; mp 180–
183 °C.
1H NMR (300 MHz, CD3OD): d = 1.74–2.05 (m, 5 H), 2.51 (dt, J =
3.6, 13.1 Hz, 1 H), 3.80 (br s, 1 H), 4.27–4.40 (m, 2 H), 6.59 (t, J =
7.6 Hz, 1 H), 6.69 (d, J = 7.6 Hz, 2 H), 7.09 (t, J = 7.6 Hz, 2 H),
7.74–7.83 (m, 4 H).
3-Phenyl-7-phthalimido-2-oxa-3-azabicyclo[2.2.2]oct-5-ene
[( )-7]
To a soln of nitrosobenzene (220 mg, 2.04 mmol) in anhyd CH2Cl2
(8 mL), at r.t. under N2, was added in one portion solid 6 (230 mg,
1.02 mmol). The mixture was stirred for 2 h and then concentrated
under reduced pressure. The residue was purified by column chro-
matography (silica gel, hexane–EtOAc, 4:1) to afford ( )-7 (224
mg, 67%) as a colorless solid; mp 148–151 °C.
1H NMR (400 MHz, CDCl3): d = 2.59 (td, J = 3.6, 13.6 Hz, 1 H),
2.81 (ddd, J = 3.2, 9.6, 13.2 Hz, 1 H), 4.63–4.67 (m, 1 H), 4.90 (td,
J = 4.0, 9.6 Hz, 1 H), 5.01 (dt, J = 1.6, 5.2 Hz, 1 H), 6.38 (ddd, J =
1.8, 6.4, 8.2 Hz, 1 H), 6.53 (ddd, J = 1.6, 5.6, 8.4, 1 H), 6.96 (t, J =
13C NMR (100 MHz, CD3OD): d = 29.4, 30.3, 33.4, 54.1, 70.3,
114.6, 118.1, 124.1, 130.2, 133.5, 135.3, 149.2, 170.4; one signal
obscured by solvent.
Synthesis 2011, No. 6, 924–928 © Thieme Stuttgart · New York

PAPER
Hydroxy- and Polyhydroxy-1,3-diaminocyclohexanes
927
Anal. Calcd for C20H20N2O3: C, 71.41; H, 5.99. Found: C, 71.50; H,
6.04.
(m and d, J = 6.6 Hz, 2 H total), 5.79 (t, J = 6.6 Hz, 1 H), 6.57 (t,
J = 6.6 Hz, 1 H), 7.19–7.30 (m, 5 H), 7.65–7.80 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 26.6, 47.6, 48.6, 71.6, 71.8, 123.5,
127.8, 128.08, 128.12, 128.2, 131.4, 134.47, 134.51, 137.5, 168.1,
173.1.
N-[(1S*,2R*,3S*,4S*,5S*)-2,3,4-Trihydroxy-5-(phenylami-
no)cyclohexyl]phthalimide [( )-11]
The reduction of 8 (0.160 g, 0.437 mmol) in MeOH (30 mL) with
H2 (2.76 bar) catalyzed by Raney Ni (0.3 mL, 50% in H2O) was car-
ried out in a fashion similar to the typical procedure for ( )-10. Pu-
rification of the crude product by column chromatography (silica
gel, EtOAc) gave ( )-11 (91 mg, 57%) as a colorless solid; mp 233–
235 °C.
1H NMR (400 MHz, CD3OD): d = 2.03 (td, J = 3.8, 13.2 Hz, 1 H),
2.31 (dt, J = 3.2, 13.2 Hz, 1 H), 3.84 (dd, J = 3.0, 4.3 Hz, 1 H), 3.99–
4.03 (m, 1 H), 4.21 (t, J = 2.6 Hz, 1 H), 4.34 (dd, J = 2.6, 10.8 Hz,
1 H), 4.64 (ddd, J = 3.8, 10.8, 13.2 Hz, 1 H), 6.57 (t, J = 7.6 Hz, 1
H), 6.62 (d, J = 8.0 Hz, 2 H), 7.08 (t, J = 7.6 Hz, 2 H), 7.75–7.83 (m,
4 H).
Anal. Calcd for C22H18N2O5: C, 67.69; H, 4.64. Found: C, 67.48; H,
4.65.
( )-15
1H NMR (partial, CDCl3): d = 2.30–2.50 (m, 2 H), 4.36 (td, J = 4.0,
8.4 Hz, 1 H), 4.97–5.03 (m, 1 H), 5.21 (d, J = 7.2 Hz, 1 H), 6.53 (t,
J = 6.8 Hz, 1 H), 6.88 (t, J = 6.8 Hz, 1 H).
( )-16
1H NMR (partial, CDCl3): d = 4.75–4.80 (m, 1 H), 5.50–5.55 (m, 1
H), 6.15 (t, J = 6.9 Hz, 1 H), 6.39 (t, J = 6.8 Hz, 1 H).
X-ray Structural Analysis of ( )-14
13C NMR (100 MHz, CD3OD): d = 30.1, 48.3, 54.9, 70.2, 70.7, 76.4,
114.2, 117.9, 124.1, 130.3, 133.4, 135.4, 149.4, 170.3.
HRMS (FAB): m/z [M + H]+ calcd for C20H21N2O5: 369.1450;
found: 369.1448.
A crystal suitable for X-ray diffraction analysis was grown from
MeCN. Formula: C22H18N2O5, orthorhombic, space group Aba2,
a = 21.9065(4), b = 28.3819(6), c = 5.80740(10) Å, V =
3610.74(12) Å3, Z = 8, dcalcd = 1.436 mg/m3, u = 0.854 mm–1, 3175
unique reflections, wR2 = 0.0701.
N-[(1S*,2R*,3R*,4R*,5S*)-2,3,4-Trihydroxy-5-(phenylami-
no)cyclohexyl]phthalimide [( )-12]; Typical Procedure
To a soln of 9 (50 mg, 0.15 mmol) in acetone (0.8 mL) was added a
soln of NMO (30.0 mg, 0.230 mmol) in H2O (0.3 mL) followed by
a soln of OsO4 in toluene (0.1 mL, 10 mol%). The mixture was
stirred for 15 h at r.t. and then Na2S2O4 (26 mg) was added and stir-
ring was continued for a further 30 min. The mixture was concen-
trated and the residue purified by column chromatography (silica
gel, hexane–EtOAc, 1:4) to give ( )-12 (18 mg, 33%) as a colorless
solid; mp 253–255 °C.
1H NMR (300 MHz, CD3OD): d = 1.78 (br d, J = 13.3 Hz, 1 H),
3.00 (dt, J = 3.9, 13.3 Hz, 1 H), 3.70–3.78 (m and dd, J = 2.7, 9.3
Hz, 2 H total), 4.11 (narrow t, J = 2.6 Hz, 1 H), 4.43 (ddd, J = 4.2,
10.8, 13.2 Hz, 1 H), 4.55 (d, J = 9.6, 10.2 Hz, 1 H), 6.62 (t, J = 7.2
Hz, 1 H), 6.72 (d, J = 8.4 Hz, 2 H), 7.11 (dd, J = 7.5, 8.4 Hz, 2 H),
7.76–7.83 (m, 4 H).
(7S)-3-[(R)-Mandeloyl]-7-phthalimido-2-oxa-3-azabicyc-
lo[2.2.2]oct-5-ene [(+)-14]
Reaction of ( )-6 (0.300 g, 1.33 mmol) with the nitrosoacyl gener-
ated from (R)-mandelohydroxamic acid (0.212 g, 1.27 mmol) was
carried out in a fashion similar to the typical procedure for 14–16
using ( )-mandelohydroxamic acid. Purification of the residue by
column chromatography (silica gel, hexanes–EtOAc, 1:1) gave a
colorless solid (0.316 g, 62%). Recrystallization (MeCN) gave (+)-
14 (57 mg, 11%); mp 180–183 °C.
[a]D20 +126.5 (c 0.429, CH2Cl2).
1
The H NMR spectrum of this product was identical to that of the
racemic compound.
Reaction of 3-Mandeloyl-7-phthalimido-2-oxa-3-azabicyc-
lo[2.2.2]oct-5-ene with Acetic Anhydride
13C NMR (75 MHz, acetone-d6): d = 28.1, 51.6, 53.3, 69.9, 71.9,
73.7, 113.6, 117.4, 123.7, 129.8, 132.7, 135.1, 148.6, 168.8.
HRMS (FAB): m/z [M + H]+ calcd for C20H21N2O5: 369.1450;
found: 369.1447.
To a mixture of 14, 15, and 16 (80 mg, 0.20 mmol) in CH2Cl2 (1
mL), at r.t. was added dropwise pyridine (0.10 mL, 1.0 mmol) fol-
lowed by Ac2O (0.10 mL, 1.1 mmol). The mixture was stirred for
12 h, diluted with CH2Cl2 and quenched with 1 M HCl. The mixture
was extracted several times with CH2Cl2 and the combined extracts
were washed with brine, dried (Na2SO4), and concentrated. Purifi-
cation of the residue by preparative TLC (hexane–EtOAc = 7:3)
gave ( )-18 (17 mg, 19%) as a colorless oil, followed by a mixture
of ( )-17 and ( )-19 (ca. 8:3 ratio, 39 mg, 41%) as a colorless oil.
3-Mandeloyl-7-phthalimido-2-oxa-3-azabicyclo[2.2.2]oct-5-
enes 14–16; Typical Procedure
To a rapidly stirring soln of ( )-6 (0.600 g, 2.67 mmol) and NaIO4
(0.683 g, 3.19 mmol) in CH2Cl2 (10 mL), DMF (10 mL), and H2O
(5 mL) was added, over a period of 45 min, a soln of ( )-mandelo-
hydroxamic acid (0.441 g, 2.64 mmol) in DMF (10 mL). The mix-
ture was stirred for an additional 3 h, then poured into H2O and
extracted several times with CH2Cl2. The combined extracts were
washed with brine, dried (Na2SO4), and concentrated. The residue
was purified by column chromatography (silica gel, hexanes–
EtOAc, 1:1) to afford a colorless solid (0.795 g, 77%). Analysis of
( )-18
1H NMR (400 MHz, CDCl3): d = 2.16 (s, 3 H), 2.38–2.43 (m, 2 H),
4.47–4.55 (m, 1 H), 5.00–5.05 (m, 1 H), 5.33–5.38 (br s, 1 H), 6.13
(s, 1 H), 6.55 (br t, J = 6.8 Hz, 1 H), 6.89 (br t, J = 7.2 Hz, 1 H),
7.39–7.55 (m, 5 H), 7.70–7.80 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 20.9, 26.9, 47.3, 48.9, 72.2, 73.7,
123.5, 128.4, 128.5, 128.9, 129.2, 131.5, 134.3, 134.5, 135.0, 168.2,
170.7; one CO signal not observed.
1
this product by H NMR spectroscopy indicated it to be a mixture
of 14, 15, and 16 (5:3:2). Recrystallization (MeCN) of two batches
of the above size gave ( )-14 (0.513 g, 25%).
HRMS (ESI): m/z [M + Na]+ calcd for C24H20N2NaO6: 455.1219;
found: 455.1216.
( )-14
Mp 160–162 °C.
( )-17
1H NMR (300 MHz, CDCl3): d = 2.49 (ddd, J = 2.7, 4.5, 13.5 Hz, 1
H), 2.60 (ddd, J = 3.3, 9.0, 13.5 Hz, 1 H), 4.15 (d, J = 7.5 Hz, 1 H),
4.73 (t, J = 3.9 Hz, 1 H), 4.81 (td, J = 4.5, 9.0 Hz, 1 H), 5.25–5.36
1H NMR (partial, CDCl3): d = 2.45 (br d, J = 12.8 Hz, 1 H), 2.67
(ddd, J = 3.2, 9.8, 12.8 Hz, 1 H), 4.80–4.84 (br s, 1 H), 4.96 (dt, J =
4.2, 9.2 Hz, 1 H), 5.28–5.33 (br s, 1 H), 5.94 (br t, J = 6.8 Hz, 1 H),
6.24 (s, 1 H), 6.61 (br t, J = 6.8 Hz, 1 H).
Synthesis 2011, No. 6, 924–928 © Thieme Stuttgart · New York

928
A. Sar et al.
PAPER
( )-19
[a]D20 –84 (c 0.20, MeOH).
1H NMR (partial, CDCl3): d = 2.31 (dd, J = 2.8, 14.0 Hz, 1 H), 2.82
(ddd, J = 3.6, 9.6, 13.6 Hz, 1 H), 4.73–4.77 (br s, 1 H), 5.47–5.51
(br s, 1 H), 6.38 (br t, J = 7.2 Hz, 1 H).
1
The H NMR spectrum of this product was identical to that of the
racemic compound.
(2R*)-2-Hydroxy-N-[(1R*,4R*,5R*)-4-hydroxy-5-phthalimido-
cyclohex-2-enyl)-2-phenylacetamide [( )-20]; Typical Proce-
dure
Acknowledgment
This work was supported by the National Science Foundation
(CHE-0848870) and NSF instrumentation grants (CHE-0521323)
and a Marquette University Research Incentive Grant. High-resolu-
tion mass spectra were obtained at the University of Nebraska-
Center for Mass Spectrometry.
To titanocene dichloride (93 mg, 0.38 mmol) and activated zinc
dust (50 mg, 0.75 mmol), under N2 at r.t. was added freshly distilled
THF (1.2 mL). The mixture was stirred for 45 min during which
time the soln changed in color from red to olive green. The green
mixture was cooled to –30 °C and a soln of ( )-14 (60 mg, 0.15
mmol) in MeOH (1.5 mL) was added. The mixture was stirred for 1
h with the temperature maintained between –15 to –30 °C. The mix-
ture was warmed to r.t. and quenched with sat. aq NH4Cl (5 mL) and
then filtered through filter-aid. The filtrate was extracted several
times with EtOAc, and the combined extracts were washed with
brine, dried (Na2SO4), and concentrated. Purification of the residue
by column chromatography (silica gel, EtOAc) gave ( )-20 (40 mg,
66%) as a colorless solid; mp 223–225 °C.
1H NMR (400 MHz, CD3OD): d = 1.75 (tdd, J = 1.6, 3.2, 14.0 Hz,
1 H), 2.64 (dt, J = 4.8, 14.0 Hz, 1 H), 4.40 (ddd, J = 12.8, 9.4, 3.1
Hz, 1 H), 4.49–4.54 (m, 1 H), 4.98 (s, 1 H), 5.75–5.81 (m, 1 H), 5.94
(br d, J = 10.0 Hz, 1 H), 7.24 (t, J = 7.6 Hz, 1 H), 7.31 (t, J = 8.0 Hz,
2 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.78–7.74 (m, 2 H), 7.84–7.81 (m, 2
H); one signal obscured by solvent.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
References
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13C NMR (100 MHz, CD3OD): d = 32.4, 45.8, 52.1, 67.9, 75.8,
124.2, 127.4, 128.4, 129.4, 129.7, 133.4, 135.6, 136.5, 141.8, 170.1,
175.2.
HRMS (ESI): m/z [M + Na]+ calcd for C22H20N2NaO5: 415.1270;
found: 415.1274.
(2R)-2-Hydroxy-N-[(1R,4R,5R)-4-hydroxy-5-phthalimidocyclo-
hex-2-enyl]-2-phenylacetamide [(–)-20]
The titanium-mediated reduction of (+)-14 (50 mg, 0.13 mmol) was
carried out in a fashion similar to the typical procedure for ( )-20.
Purification of the residue by column chromatography (silica gel,
EtOAc) gave (–)-20 as a colorless solid; mp 193–195 °C.
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D. W.; Siddiquee, T.; Haworth, D. T.; Donaldson, W. A.
J. Heterocycl. Chem. 2007, 44, 719.
[a]D20 –106 (c 0.270, MeOH).
1
The H NMR spectrum of this product was identical to that of the
racemic compound.
(8) The crystallographic data has been deposited with the CCDC
for compounds ( )-7 (CCDC 778910), ( )-10 (CCDC
778911), and ( )-14 (CCDC 778912), respectively. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retreiving.html or from the Cambridge
(2R*)-2-Hydroxy-N-[(1S*,4R*,5R*)-4-hydroxy-5-phthalimi-
docyclohexyl]-2-phenylacetamide [( )-21]
The reduction of ( )-20 (30 mg, 0.077 mmol) in MeOH (6 mL) with
H2 (2.76 bar) catalyzed by 10% Pd/C (2.5 mg) was carried out in a
fashion similar that for the typical procedure for ( )-10. The mix-
ture was filtered through filter-aid and concentrated. Purification of
the residue by column chromatography (EtOAc) gave ( )-21 (23
mg, 76%) as a colorless solid; mp 150–152 °C.
1H NMR (300 MHz, CD3OD): d = 2.05–1.50 (m, 6 H), 2.43 (dt, J =
3.0, 12.3 Hz, 1 H), 4.34–4.04 (m, 3 H), 5.03 (br s, 1 H), 7.51–7.23
(m, 5 H), 7.84–7.71 (m, 4 H); one signal obscured by solvent.
Crystallographic Data Centre, 12 Union Road, Cambridge
CB12 1EZ, UK; fax: +44(1223)336033; e-mail:
deposit@ccdc.ccdc.cam.ac.uk. For the ORTEPs of ( )-7 and
( )-10 see Supporting Information.
(9) (a) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; DeSarlo, F.
Tetrahedron Lett. 1990, 31, 3351. (b) Ritter, A. R.; Miller,
M. J. J. Org. Chem. 1994, 59, 4602.
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13C NMR (75 MHz, CD3OD): d = 29.0, 30.7, 33.3, 46.4, 54.1, 69.7,
75.6, 124.1, 128.4, 129.4, 129.8, 133.4, 135.4, 141.8, 170.2, 175.1.
HRMS (ESI): m/z [M + Na]+ calcd for C24H22N2NaO5: 417.1426;
found: 417.1422.
(2R)-2-Hydroxy-N-[(1S,4R,5S)-4-hydroxy-5-phthalimidocyclo-
hex-1-yl)-2-phenylacetamide [(–)-21]
The reduction of (–)-20 (25 mg, 0.064 mmol) was carried out in a
fashion similar to that for ( )-20. Purification of the residue by col-
umn chromatography (silica gel, EtOAc) gave (–)-21 as a colorless
oil.
Synthesis 2011, No. 6, 924–928 © Thieme Stuttgart · New York