Diastereo- and Enantioselective Synthesis of (+)- and (-)-cis-2-Aminocyclobutanols

Article abstract of DOI:10.1002/(sici)1099-0690(199804)1998:4<729::aid-ejoc729>3.0.co;2-b

The hitherto unknown (+)- and (-)-cis-2-aminocyclobutanols 6a,b and 7a,b, as well as the corresponding benzyloxycyclobutanamines 8a,b, have been synthesized by means of asymmetric reductive amination, with de values of 100percent and ee values ranging from 96.9 to 99.8percent. The relative cis configuration has been established by NO experiments, whereas the absolute stereochemistry has been deduced from the CD spectra of the corresponding salicylidene derivatives and confirms the like induction at C-1.

Full text of DOI:10.1002/(sici)1099-0690(199804)1998:4<729::aid-ejoc729>3.0.co;2-b

FULL PAPER
Diastereo- and Enantioselective Synthesis of (؉)- and
(؊)-cis-2-Aminocyclobutanols
Philippe Bisel, Elke Breitling, and August Wilhelm Frahm*
Lehrstuhl für Pharmazeutische Chemie,
Hermann-Herder-Strasse 9, D-79104 Freiburg, Germany
Fax: (internat.) ϩ 49(0)761/203-6351
E-mail: awfrahm@sun2.ruf.uni-freiburg.de
Received November 14, 1997
Keywords: Asymmetric synthesis / Hydrogenation / Hydrogenolysis / α-Amino alcohols
The hitherto unknown (+)- and (Ϫ)-cis-2-aminocyclobutanols
ration has been established by NO experiments, whereas the
6a,b and 7a,b, as well as the corresponding benzyloxycyclo- absolute stereochemistry has been deduced from the CD
butanamines 8a,b, have been synthesized by means of asym- spectra of the corresponding salicylidene derivatives and
metric reductive amination, with de values of 100% and ee
values ranging from 96.9 to 99.8%. The relative cis configu-
confirms the like induction at C-1.
Second-generation asymmetric synthesis[1] remains one Figure 1. The (ϩ)- and (Ϫ)-cis-2-aminocyclobutanols and corre-
sponding benzyloxycyclobutanamines
of the most popular methods for introducing chirality into
potentially bioactive compounds. In pioneering work in this
field, Overberger et al.[2] described the enantioselective syn-
thesis of chiral primary amines by means of asymmetric
reductive amination using (R)-(ϩ)- and (S)-(Ϫ)-1-phenyl-
ethylamine (PEA) as the chiral auxiliaries. In previous com-
munications from this laboratory[3a][3b][3c], we have reported
on both enantio- and diastereoselective syntheses of various
Although multistep syntheses of both the racemic cis-
cyclic amines according to an analogous reaction sequence
(Scheme 1).
and trans-2-aminocyclobutanols have been described pre-
viously[7][8a][8b], to the best of our knowledge, an enantiose-
Scheme 1. Asymmetric reductive amination sequence
lective preparation of 6 has yet to be devised. We reasoned
that the asymmetric reductive amination sequence should
offer a suitable route to the desired optically active α-amino
alcohols. Herein, we describe the first enantioselective
syntheses of the (ϩ)- and (Ϫ)-cis-aminocyclobutanols 6a,b
and 7a,b, and of the corresponding benzyloxycyclobutan-
amines 8a,b (Figure 1).
Racemic 2-benzyloxycyclobutanone 3, the substrate for
the asymmetric reductive amination sequence, was obtained
from dimethyl succinate (1) according to a slightly modified
literature procedure[9]. We improved the initial step, the
condensation of 1 with chlorotrimethylsilane in molten so-
dium, by performing the reaction in an ultrasound bath. In
this way, the intermediate 1,2-bis(trimethylsilyloxy)cyclobu-
tene (2) was obtained in satisfactory yields and could then
be subjected to acid-catalyzed alcoholysis to yield 3
Chiral α-amino alcohols have attracted much interest in (Scheme 2).
recent years as substructures of very potent HIV-I protease
inhibitors[4a][4b]. Furthermore, chiral cyclic cis-α-amino al- either (R)-(ϩ)- or (S)-(Ϫ)-PEA in refluxing benzene[10]
cohols are also of particular interest as effective ligands in containing a catalytic amount of p-toluenesulfonic acid, led
Subsequent imine condensation with one equivalent of
,
asymmetric catalysis[5][6a] and asymmetric synthesis[5][6b]
.
to a mixture of four imines 4a,b. Indeed, for both 4a and
This prompted us to devise a convenient synthesis of the 4b, the complex 13C-NMR spectra exhibited four sets of
optically active (ϩ)- and (Ϫ)-cis-2-aminocyclobutanols signals attributable to the diastereomeric imines, those due
6a,b.
to the two Z isomers indicating that these were present at
Eur. J. Org. Chem. 1998, 729Ϫ733
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0404Ϫ0729 $ 17.50ϩ.50/0
729

P. Bisel, E. Breitling, A. W. Frahm
FULL PAPER
Scheme 2. Synthesis of the optically active 6a, 7a and 8a (the same procedure applies for the synthesis of 6b, 7b and 8b)
(a) Na, THF, TMSCl, ultrasound, under Ar. Ϫ (b) BnOH, HCl/diethyl ether, reflux. Ϫ (c) (S)-PEA [or (R)-PEA, respectively], p-TsOH,
benzene, reflux. Ϫ (d) H2, Raney Ni, 5 bar, 40 h, room temp. Ϫ (e) HCl/diethyl ether. Ϫ (f) 10% Pd/C, 100 mg/mmol substrate, 45°C,
24 h. Ϫ (g) 10% Pd/C, 100 mg/mmol substrate, room temp., 24 h. Ϫ (h) 10% Pd/C, 10 mg/mmol substrate, 45°C, 24 h.
a level of less than 10%. The mixture was subjected to between 1-H and 2-H, strongly indicating a cis arrangement
hydrogenation without further purification. In the opti- of the two substituents on the cyclobutane ring. If we as-
mized hydrogenation procedure, the crude imine 4a,b was sume that, in analogy to our previous studies[3a][3b][3c], the
allowed to react with ethanol-treated Raney nickel in a Parr catalytic hydrogenation proceeds with like induction at C-
hydrogenator at 5 bar and room temperature. The resulting 1, starting with (R)-(ϩ)- or (S)-(Ϫ)-PEA will lead to the
crude secondary amines 5a,b were obtained in 60Ϫ70% enantiomeric αR,1R,2S- and αS,1S,2R-secondary amines
yields, based on the amount of ketone used, and were ana- 5, respectively.
1
lyzed by means of H- and 13C-NMR spectroscopy. The
respective 13C-NMR spectra of materials obtained by fol-
In the final step, the chiral auxiliary was removed along
lowing the optimized procedure showed only one set of sig- with the benzyl protecting group by means of catalytic hy-
nals for the secondary amine, indicating that only one of drogenolysis in the presence of 100 mg of 10% Pd/C per
the four possible diastereomers was formed in a highly dia- mmol substrate at 45°C. In this way, the desired cis-α-
stereo- and enantioselective process[3d]. Since the starting amino alcohol hydrochlorides 6a and 6b were obtained in
ketone 2 is racemic and the chemical yield of the secondary 80% yields. Furthermore, it was possible to selectively de-
amine base > 50%, epimerisation must have occurred at C- protect the amine or the alcohol by adjusting the reaction
2 of the unfavoured diastereomeric imines[3a][3b]
.
conditions of the hydrogenolysis. Thus, by performing the
1
The ranges of the cis and trans H coupling constants in reaction with 10 mg of 10% Pd/C per mmol of substrate
the cyclobutane ring are known to overlap[11]. Therefore the for 24 h at 45°C, we obtained the primary amines 8a and
relative stereochemistry of the substituents could not be un- 8b in yields of up to 70%, whereas when the reaction was
doubtedly deduced from the observed J values. However, carried out with 100 mg of 10% Pd/C per mmol of substrate
this problem could be overcome by performing nuclear for 24 h at room temperature, the secondary amines 7a and
Overhauser experiments. Positive NO effects were observed 7b were obtained in 50% yields.
730
Eur. J. Org. Chem. 1998, 729Ϫ733

Diastereo- and Enantioselective Synthesis of (ϩ)- and (Ϫ)-cis-2-Aminocyclobutanols
FULL PAPER
The ee values, summarized in Table 1, were determined
In summary, starting from the corresponding racemic ke-
by means of MosherЈs derivatization[12] (Scheme 3). For tone, we have synthesized the hitherto unknown optically
this purpose, the primary amines 6a,b were treated with two active title compounds 6a,b and 7a,b, along with 8a,b, by
equivalents, and 8a,b with one equivalent of (S)-(ϩ)-2- means of an asymmetric reductive amination sequence in
methoxy-2-phenyl-2-trifluoromethylethanoyl chloride to af- overall yields of 25, 16 and 22%, respectively. The diastereo-
ford the amido esters 9a,b and the amides 10a,b in quanti- and enantioselective process[14] furnishes products with de
tative yields. 19F-NMR analysis of the diastereomeric mix- values of almost 100% and ee values up to 99.8%.
tures showed ee values ranging from 96.9 to 99.8%. The
The Fonds der Chemischen Industrie, Frankfurt am Main, Ger-
many, is gratefully acknowledged for financial support. We thank
Volker Brecht for careful and skillful NMR measurements.
enantiomeric excesses of 7a,b were not determined, but only
one set of signals in the 13C-NMR spectra of 7a,b indicate
that the steric integrity is unaffected during the hydro-
genolysis step. Therefore the ee values of 7a,b should be of
the same order as those of 6a,b and 8a,b, respectively. The
Experimental Section
General: Column chromatography was performed on Merck sil-
absolute configuration was deduced from the CD spectra
ica gel (70Ϫ230 mesh ASTM). The uncorrected open-capillary
of the corresponding salicylidene derivatives 11a,b accord-
melting points were determined with a Mel-Temp II apparatus (De-
ing to the Smith rule[13]. Indeed, the CD spectrum of 11a
vices Laboratory, USA). Optical rotations were measured with a
Perkin-Elmer 241 polarimeter. NMR spectra were recorded in
CDCl3 or CD3OD with tetramethylsilane as internal standard with
exhibits positive Cotton effects at 314 and 253 nm indicat-
ing the S configuration at C-1, whereas the opposite Cotton
effects were observed for 11b. These findings are in accord-
ance with our previous results[3a][3b][3c] and confirm the like
induction at C-1.
a Varian Unity 300 spectrometer. CD spectra were recorded with
a CD 6 Jobin Yvon Division dЈInstruments spectrometer. Microan-
alyses were carried out at the Chemisches Laboratorium der Uni-
versität Freiburg.
1,2-Bis(trimethylsilyloxy)cyclobutene (2): Sodium (14 g, 0.63
mol) was refluxed with dry toluene (200 ml) in a three-necked
round-bottomed flask for 0.5 h. The flask was then removed from
the heating source and shaken vigorously. The mixture was cooled,
the toluene was decanted, and the residue was suspended in dry
THF (200 ml). The suspension was cooled to 0°C in an ultrasound
bath and a solution of chlorotrimethylsilane (80 ml, 0.63 mol) and
dimethyl succinate (1) (22 g, 0.15 mol) in THF (40 ml) was added
dropwise with stirring over a period of 1.5 h under an inert atmos-
phere. Stirring was continued for a further 2 h, and then dry diethyl
ether (200 ml) was added and the mixture was allowed to stand at
4°C overnight. The resulting precipitate was filtered off and the
filtrate was concentrated in vacuo. Pure 2 (20.56 g, 0.09 mol, 60%)
was obtained as a colourless oil after fractional distillation of the
residue through a Vigreux column; b.p. 73°C/12 Torr (ref.[15] 80°C/
Table 1. Properties of the optically active 2-aminocyclobutanol and
2-benzyloxycyclobutanamine hydrochlorides
Compound
[α]25
ee (%)[a]
Absolute
D
configuration[c]
6a
6b
7a
7b
8a
8b
ϩ4.0
Ϫ6.8
Ϫ64.1
ϩ65.2
Ϫ20.4
ϩ20.9
96.9
99.0
1R,2S
1S,2R
1R,2S
1S,2R
1S,2R
1R,2S
n.d.[b]
n.d.[b]
97.9
99.8
[a] The ee values are corrected to a theoretical 100% ee of the chiral
auxiliaries. Ϫ [b] n.d. ϭ not determined. Ϫ [c] According to IUPAC,
the carbon atom bearing the oxy substituent is labelled C-1 in 6
and 7, while it is C-2 in 8.
1
10 Torr). Ϫ H NMR (CDCl3, 300 MHz): δ ϭ 0.09 (s, 18 H), 2.15
(s, 4 H). Ϫ 13C NMR (CDCl3, 75 MHz): δ ϭ Ϫ0.4, 25.4, 119.4.
2-Benzyloxycyclobutanone (3): A mixture of benzyl alcohol (10
g, 0.09 mol) and HCl-saturated diethyl ether (30 ml) was cooled to
0°C and 2 (18 g, 0.078 mol) was added dropwise with stirring.
After completion of the addition, the mixture was heated to 80°C
for 4 h, concentrated in vacuo, and the residue was distilled under
reduced pressure to give 3 (9.69 g, 0.055 mol, 61%) as a colourless
oil; b.p. 93°C/0.5 Torr (ref.[16] 90°C/0.4 Torr). Ϫ 1H NMR (CDCl3,
300 MHz): δ ϭ 1.93 (dddd, J ϭ 7.8, 7.4, 10.2, 21.3 Hz, 1 H, 3-H),
2.29 (dddd, J ϭ 5.37, 8.06, 9.77, 21.0 Hz, 1 H, 3-H), 2.72 (m, 2 H,
4-H), 4.61 (d, JAB ϭ 11.7 Hz, 1 H, PhCH2), 4.73 (d, JAB ϭ 11.7
Hz, 1 H, PhCH2), 4.75 (m, 1 H, 2-H), 7.25 (m, 5 H, ArH). Ϫ 13C
NMR (CDCl3, 75 MHz): δ ϭ 19.5 (C-3), 39.1 (C-4), 71.9 (C-2),
86.9 (C benzyl), 127.9 (C-4Ј), 127.9 (C-3Ј), 128.3 (C-2Ј), 137.1 (C-
1Ј), 206.5 (C-1).
Scheme 3. Derivatizations
2-Benzyloxy-N-(1-phenylethyl)cyclobutanimine (4a,b): The ke-
tone 3 (8.81 g, 0.05 mol) was taken up in benzene (100 ml) and
(R)-(ϩ)- or (S)-(Ϫ)-PEA (6.06 g, 0.05 mol) was added, along with
a catalytic amount of p-toluenesulfonic acid. The solution was re-
fluxed for 2 h under an inert atmosphere in an apparatus fitted
with a Dean-Stark head. The reaction was monitored by IR and
NMR spectroscopy. After completion, the benzene was evaporated
(a) (S)-(ϩ)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride,
pyridine, 12 h, room temp. Ϫ (b) sodium salicylate, MeOH, reflux.
Eur. J. Org. Chem. 1998, 729Ϫ733
731

P. Bisel, E. Breitling, A. W. Frahm
FULL PAPER
in vacuo and the crude residue was used for the subsequent reac-
tion without further purification.
(1S,2R)- and (1R,2S)-2-Benzyloxycyclobutanamine Hydrochlo-
rides (8a,b): 10% Pd/C (25 mg) was suspended in ethanol (50 ml)
and prehydrogenated at 5 bar and 45°C for 15 min. The amine
hydrochloride 5 (800 mg, 2.5 mmol) in ethanol (75 ml) was then
added and hydrogenolysis was allowed to proceed for 24 h. The
catalyst was then removed by filtration through Celite, and the fil-
trate was concentrated. Recrystallization of the residue from ethyl
acetate afforded 8 (375 mg, 1.75 mmol, 70%) as white crystals. Ϫ
(1S,2R)- and (1R,2S)-2-Benzyloxy-N-(1-phenylethyl)cyclobut-
anamine Hydrochlorides (5a,b): The crude imine 4 (14.0 g, 0.05 mol)
was taken up in absolute ethanol (50 ml) and 2.0 g of ethanol-
treated Raney nickel was added. Hydrogenation was carried out at
5 bar and room temperature for 40 h in a Parr hydrogenator. The
catalyst was then removed by filtration through Celite and the fil-
trate was concentrated. The residue was purified by means of flash
chromatography, with elution by cyclohexane/ethyl acetate, 7.5:2.5.
The crude amine was obtained in 60Ϫ70% yield and was precipi-
tated as its hydrochloride in HCl-saturated diethyl ether. Recrystal-
lization from ethyl acetate afforded 5 (5.08 g, 16 mmol, 32%) as
8a: M.p. 153°C. Ϫ [α]25 ϭ Ϫ20.4. Ϫ C11H16ClNO (197.7): calcd.
D
C 61.8, H 7.55, N 6.55; found C 61.7, H 7.42, N 6.55. Ϫ 8b: M.p.
155°C. Ϫ [α]25 ϭ ϩ20.9. Ϫ C11H16ClNO (197.7): calcd. C 61.8,
D
H 7.55, N 6.55; found C 61.5, H 7.53, N 6.53. Ϫ 1H NMR (CDCl3,
300 MHz): δ ϭ 2.00 (m, 1 H, 4-H), 2.08 (m, 1 H, 4-H), 2.12 (m, 1
H, 3-H), 2.48 (m, 1 H, 3-H), 3.84 (m, 1 H, 1-H), 4.11 (q, J ϭ 6.6
Hz, 1 H, 2-H), 4.49 (d, J ϭ 12.2 Hz, 1 H, PhCH2), 4.69 (d, J ϭ
12.2 Hz, 1 H, PhCH2), 7.25 (m, 3 H, ArH), 7.39 (m, 2 H, ArH),
8.6 (br. s, 3 H, NH3ϩ). Ϫ 13C NMR (CDCl3, 75 MHz): δ ϭ 20.5
(C-4), 26.5 (C-3), 49.9 (C-1), 70.7 (PhCH2), 71.2 (C-2), 127.6 (ArC),
127.8 (ArC), 128.3 (ArC), 137.5 (ArC).
white crystals. Ϫ 5a: M.p. 145°C. Ϫ [α]25 ϭ ϩ115.6.
Ϫ
D
C19H24ClNO (317.8): calcd. C 71.8, H 7.61, N 4.39; found C 71.7,
H 7.57, N 4.41. Ϫ 5b: M.p. 145°C. Ϫ [α]25 ϭ Ϫ114.6. Ϫ
D
C19H24ClNO (317.8): calcd. C 71.8, H 7.61, N 4.39; found C 71.7,
1
H 7.68, N 4.44. Ϫ H NMR (CDCl3, 300 MHz): δ ϭ 1.94 (d, J ϭ
6.8 Hz, 3 H, CH3), 1.97 (m, 1 H, 3-H), 2.12 (m, 1 H, 4-H), 2.58
(m, 1 H, 3-H), 2.77 (m, 1 H, 4-H), 3.38 (m, 1 H, 1-H), 4.40 (d,
JAB ϭ 12 Hz, 1 H, PhCH2), 4.06 (m, 1 H, 2-H), 4.81 (d, JAB ϭ 12
Hz, 1 H, PhCH2), 7.2Ϫ7.6 (m, 10 H, ArH), 10.0 (br. s, 1 H,
NH2ϩ), 10.5 (br. s, 1 H, NH2ϩ). Ϫ 13C NMR (CDCl3, 75 MHz):
δ ϭ 20.8 (CH3), 21.7 (C-4), 24.6 (C-3), 52.3 (C-1), 58.4 (C-α), 69.7
(PhCH2), 72.1 (C-1), 127.7 (ArC), 128.1 (ArC), 128.2 (ArC), 128.4
(ArC), 128.8 (ArC), 129.0 (ArC), 136.7 (ArC), 137.4 (ArC).
General Procedure for Conversion to the Mosher Amides 9a,b (and
10a,b): The primary amine hydrochlorides 6a,b (or 8a,b) (0.15
mmol) were taken up in CHCl3 (1 ml), pyridine (2 ml) was added,
followed by (S)-(ϩ)-2-methoxy-2-phenyl-2-trifluoromethylethanoyl
chloride (0.30 mmol) (0.15 mmol for 8a,b). Stirring was maintained
for 18 h. The solvent was then removed in vacuo, the residue was
taken up in H2O (3 ml) and extracted with diethyl ether (3 ϫ 5
ml). The combined organic extracts were washed with 1  HCl (5
ml), a saturated solution of Na2CO3 (5 ml) and H2O, dried, and
concentrated in vacuo. The crude residue was analyzed by 19F-
NMR spectroscopy.
(1R,2S)- and (1S,2R)-2-Aminocyclobutanol Hydrochlorides
(6a,b): 10% Pd/C (250 mg) was suspended in ethanol (50 ml) and
prehydrogenated at 5 bar and 45°C for 15 min. The amine hydro-
chloride 5 (800 mg, 2.5 mmol) in ethanol (75 ml) was then added
and hydrogenolysis was allowed to proceed for 24 h. The catalyst
was then removed by filtration through Celite, the filtrate was con-
centrated, and the residue was recrystallized from ethyl acetate to
yield 6 (247 mg, 2.0 mmol, 80%) as white crystals. Ϫ 6a: M.p.
General Procedure for the Conversion to the Salicylidene Deriva-
tives 11a,b: The primary amine hydrochlorides 8a,b (0.3 mmol)
were taken up in MeOH (2 ml), and sodium 2-formylphenolate (0.3
mmol) was added. The mixture was refluxed for 15 min and then
allowed to stand at room temperature overnight. The solvent was
removed in vacuo and the residue was submitted to CD spec-
troscopy.
115Ϫ117°C. Ϫ [α]25 ϭ ϩ4.0. Ϫ C4H10ClNO (123.6): calcd. C
D
38.9, H 8.16, N 11.33; found C 38.7, H 7.97, N 11.26. Ϫ 6b: M.p.
116Ϫ118°C. Ϫ [α]25 ϭ Ϫ6.8. Ϫ C4H10ClNO (123.6): calcd. C
D
38.9, H 8.16, N 11.33; found C 38.3, H 8.04, N 11.05. Ϫ 1H NMR
(CD3OD, 300 MHz): δ ϭ 2.05 (m, 1 H, 4-H), 2.10 (m, 1 H, 3-H),
2.20 (m, 1 H, 4-H), 2.30 (m, 1 H, 3-H), 3.78 (m, 1 H, 1-H), 4.45
(m, 1 H, 2-H). Ϫ 13C NMR (CD3OD, 75 MHz): δ ϭ 22.0 (C-4),
29.0 (C-3), 51.6 (C-1), 66.5 (C-2).
[1]
´
R. A. Aitken, S. N. Kilenyi, Asymmetric Synthesis, University
Press, Cambridge, 1992, 83Ϫ142, and references cited therein.
C. G. Overberger, N. P. Marullo, R. G. Hiskey, J. Am. Chem.
Soc. 1961, 83, 1374Ϫ1378.
[2]
[3]
[3a] G. Knupp, A. W. Frahm, Chem. Ber. 1984, 117, 2076. Ϫ
[3b]
[3c]
W. Wiehl, A. W. Frahm, Chem. Ber. 1986, 119, 2668. Ϫ
C.
(1R,2S)- and (1S,2R)-2-[(1-Phenylethyl)amino]cyclobutanol
Hydrochlorides (7a,b): 10% Pd/C (250 mg) was suspended in etha-
nol (50 ml) and prehydrogenated at 5 bar and room temperature
for 15 min. The amine hydrochloride 5 (800 mg, 2.5 mmol) in etha-
nol (75 ml) was then added and hydrogenolysis was allowed to pro-
ceed for 24 h. The catalyst was then removed by filtration through
Celite, and the filtrate was concentrated. Recrystallization of the
residue from ethyl acetate afforded 7 (284 mg, 1.25 mmol, 50%)
M. Nachtsheim, A. W. Frahm, Arch. Pharm. 1989, 322,
199Ϫ206. Ϫ [3d] For the influence of the reducing agent and the
catalyst on the diastereo- and enantioselectivity see: G. Knupp,
A. W. Frahm, Arch. Pharm. 1985, 318, 250Ϫ257.
[4] [4a]
T. A. Lyle, C. M. Wiscount, J. P. Guare, W. J. Thompson,
P. S. Anderson, P. L. Darke, J. A. Zugay, E. A. Emini, W. A.
Schleif, J. C. Quintero, R. A. F. Dixon, I. S. Sigal, J. R. Huff,
J. Med. Chem. 1991, 34, 1230Ϫ1233. Ϫ [4b] B. D. Dorsay, R. B.
Lewin, S. L. McDaniel, J. Vacca, J. P. Guare, P. L. Darke, J. A.
Zugay, E. A. Emini, W. A. Schleif, J. C. Quintero, J. H. Lin, Y.-
W. Chen, M. R. Holloway, P. M. D. Fitzgerald, M. G. Axel, D.
Ostovich, P. Anderson, J. R. Huff, J. Med. Chem. 1994, 37,
3443Ϫ3451.
as white crystals. Ϫ 7a: M.p. 121Ϫ123°C. Ϫ [α]25 ϭ Ϫ64.1. Ϫ
D
C12H18ClNO (227.7): calcd. C 63.3, H 7.97, N 6.15; found C 63.2,
H 7.85, N 6.15. Ϫ 7b: M.p. 122°C. Ϫ [α]25 ϭ ϩ65.2. Ϫ
D
[5]
[6]
C12H18ClNO (227.7) : calcd. C 63.3, H 7.97, N 6.15; found C 63.2,
D. J. Ager, I. Prakash, D.R. Schaad Chem. Rev. 1996, 96,
835Ϫ875.
1
H 8.02, N 6.13. Ϫ H NMR (CDCl3, 300 MHz): δ ϭ 1.90 (d, J ϭ
[6a] R. Hett, Q. K. Fang, Y. Gao, Y. Hong, H. T. Butler, X. Nie,
7.0 Hz, 3 H, CH3), 1.95 (m, 1 H, 4-H), 2.25 (m, 2 H, 3-H), 2.52
(m, 1 H, 4-H), 3.45 (m, 1 H, 1-H), 4.45 [m, 2 H, CH(Ph)CH3, 2-
H], 7.18 (m, 3 H, ArH), 7.62 (m, 2 H, ArH), 9.38 (br. s, 1 H,
NH2ϩ), 9.78 (br. s, 1 H, NH2ϩ). Ϫ 13C NMR (CDCl3, 75 MHz):
[6b]
S. A. Wald, Tetrahedron Lett. 1997, 38, 1125Ϫ1128. Ϫ
M.
H. Kress, C. Yang, N. Yasuda, E. J. J. Grabowski, Tetrahedron
Lett. 1997, 38, 2633Ϫ2636.
[7]
[8]
W. Hartmann, K.-H. Scholz, H.-G. Heine, Chem. Ber. 1980,
113, 1884Ϫ1889.
δ
ϭ 20.5 (CH3), 22.0 (C-4), 27.8 (C-3), 54.2 (C-1), 58.8
[8a] J. G. Cannon, T. Lee, V. Sankaran, J. Med. Chem. 1975, 18,
[8b]
[CH(Ph)CH3], 68.0 (C-2), 128.1 (ArC), 129.3 (ArC), 129.4 (ArC),
136.1 (ArC).
1027Ϫ1028. Ϫ
J. G. Cannon, D. M. Crockatt, J. P. Long,
W. Maixner, J. Med. Chem. 1982, 25, 1091Ϫ1094.
732
Eur. J. Org. Chem. 1998, 729Ϫ733

Diastereo- and Enantioselective Synthesis of (ϩ)- and (Ϫ)-cis-2-Aminocyclobutanols
FULL PAPER
[9]
T. Erker, A. W. Frahm, Sci. Pharm. 1991, 59, 82.
by flash chromatography, the structures of which were estab-
[10]
1
When the imine condensation was attempted by refluxing for 6
h in xylene, the desired imine was not obtained. Instead, we
isolated two diastereomeric amino ketones (Figure 2), separable
lished by means of 13C- and H-NMR spectroscopy.
We assume that these structures are the result of a non-stereose-
lective 1,2-rearrangement, probably via an enamine intermedi-
ate, which is currently being investigated.
F. A. Bovery, Nuclear Magnetic Resonance Spectroscopy, Aca-
demic Press, New York, 1969, p. 138.
J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34,
2543Ϫ2549.
[11]
[12]
[13]
[14]
[15]
[16]
Figure 2. The rearranged α-amino ketones
H. E. Smith, E. P. Burrows, M. J. Marks, R. P. Lynch, F. M.
Chen, J. Am. Chem. Soc. 1977, 99, 707Ϫ703.
Y. Izumi, A. Tai, Stereo-Differentiation Reactions, Academic
Press, New York, London, 1977.
J. J. Bloomfield, J. M. Nelke, Organic Syntheses 1988, Coll. Vol.
VI, 168.
J. M. Conia, J. L. Ripoli, C. R. Acad. Sci. 1961, 252, 423Ϫ427.
[97348]
Eur. J. Org. Chem. 1998, 729Ϫ733
733