A convenient synthesis of cis and trans 4-tert-butoxycarbonyl-substituted cyclohexylglycine

Article abstract of DOI:10.1021/jo010512b

A novel synthesis of cis and trans substituted 4-tert-butoxycarbonyl cyclohexylglycines via asymmetric aminohydroxylation of vinyl styrene followed by reduction of the aromatic ring and subsequent oxidation is reported.

Full text of DOI:10.1021/jo010512b

2686
J . Org. Chem. 2002, 67, 2686-2688
Sch em e 1a
A Con ven ien t Syn th esis of Cis a n d Tr a n s
4-ter t-Bu toxyca r bon yl-Su bstitu ted
Cycloh exylglycin e
Srikanth Venkatraman,* F. George Njoroge,
Viyyoor Girijavallabhan, and Andrew T. McPhail†
Schering Plough Research Institute, A301, K-15,
mailstop 3545, 2015 Galloping Hill Road,
Kenilworth New J ersey 07033
Srikanth.Venkatraman@spcorp.com.
Received May 21, 2001
Abstr a ct: A novel synthesis of cis and trans substituted
4-tert-butoxycarbonyl cyclohexylglycines via asymmetric
aminohydroxylation of vinyl styrene followed by reduction
of the aromatic ring and subsequent oxidation is reported.
a
Reagents and conditions: (a) HCNMe2(OtBu)2, benzene reflux
66%; (b) tBuOC(O)NH2, K2OsO4, (DHQ)2Phal, tBuOCl, PrOH-
H2O, 70%; (c) Rh/C, H2, CH3OH, 100%; (d) RuCl3, H5IO6, H2O/
CH3CN, CCl4, 66%.
The nonproteinogenic amino acid cyclohexylglycine is
widely found in various natural products and pharma-
ceutical intermediates.1 The incorporation of these amino
acids into the peptide inhibitors renders resistance from
peptidases and proteinases and thereby imparts phar-
macological stability to molecules.2 In the course of our
ongoing program to identify pharmaceutically active
targets, we required large quantities of cis and trans
substituted 4-tert-butoxycarboxyl substituted cyclohexy-
lglycine. The paucity of methods for asymmetric synthesis
of substituted cyclohexylglycine led us to develop a
general synthesis for this class of compounds.
cessful with the current protecting groups. Thus, 3 was
converted to methyl (S)-4-[1-[[(benzyloxycarbonyl]amino]-
2-hydroxyethyl]benzoate, and the ee of the alcohol was
determined using HPLC with a chiracel-AD column to
be >97% after single recrystallization.5 The aromatic ring
of the amino alcohol 3 was reduced using Rh/C6 and
hydrogen to yield 4 as a single diastereomer.
The stereochemistry of the product 4 was assigned
using H NMR coupling constant analysis. (Figure 1).
1
As outlined in Scheme 1, synthesis of cis-4-tert-butoxy-
carbonyl-substituted cyclohexylglycine was initiated from
4-vinylbenzoic acid 1. The acid 1 was protected as the
tert-butyl ester by refluxing it with dimethylformamide
di-tert-butyl acetal in benzene to form 2 in 66% yield.3
Other methods involving strong acid and isobutene or
tert-butyl alcohol for the formation of the tert-butyl ester
failed or resulted largely in polymeric mixtures with very
low yields of 2. The amino hydroxylation of the styrene
derivative 2 was carried out according to the procedure
reported by Reddy and Sharpless.4 Thus, treatment of
As shown in Figure 1, the coupling constants of the
hydrogen attached to C(R) [indicated as H1] with the
adjacent equatorial and axial hydrogens (indicated as H2
and H3) were identified. If the stereochemistry of the tert-
butoxycarbonyl group was trans with respect to the
amino alcohol, both substituents would occupy equatorial
positions. Then the trans isomer would have J H1,2 ) 5-7
Hz, and J H1,3 ∼ 10-11 Hz, whereas the cis isomer should
generate two small couplings of J H1,2 ∼ 5-7 Hz and J H1,3
∼ 5-7 Hz. Similarly, the coupling constant J C1-H2,3 was
observed in the proton-coupled 13C NMR spectrum. In
the case of the trans isomer, J C1-H2,3 should have a large
5-8 Hz coupling and four small couplings J ∼ 2 Hz and
the cis should have three large J C1-H2,3 couplings in the
order of 5-8 Hz and two small 2 Hz couplings.7 Analysis
t
t
the styrene 2 with BuOC(O)NH2, BuOCl, and catalytic
amounts of (DHQ)2Phal and K2OsO4‚2H2O formed the
alcohol 3 in 50-70%. Various attempts to assess the
enantiomeric purity of 3 using chiral HPLC were unsuc-
† Department Of Chemistry, Duke University, 101, Paul M. Gross
Chemistry Lab, Durham, NC 27708.
(1) (a) Morii, H.; Uedaira, H.; Ogata, K.; Ishii, S.; Sarai, A. J . Mol.
Biol. 1999, 292, 909. (b) Lombardi, A.; De Simone, G.; Nastri, F.;
Galdiero, S.; Della Morte, R.; Staiano, N.; Pedone, C.; Bolognesi, M.;
Pavone, V. Protein Sci. 1999, 8, 91. (c) Tucker, T. J .; Brady, S. F.;
Lumma, W. C.; Lewis, S. D.; Gardell, S. J .; Naylor-Olsen, A. M.; Yan,
Y.; Sisko, J . T.; Stauffer, K. J .; Lucas, B. J .; Lynch, J . J .; Cook, J . J .;
Stranieri, M. T.; Holahan, M. A.; Lyle, E. A.; Baskin, E. P.; Chen, I.-
Wu; Dancheck, K. B.; Krueger, J . A.; Cooper, C. M.; Vacca, J . P. J .
Med. Chem. 1998, 41, 3210. (d) Lomakina, N. N.; Zenkova, V. A.;
Yurina, M. S. Khim. Prir. Soedin. 1969, 5, 43.
(2) Eun Oh, J . Hong, S. Y.; Lee, K.-H. Bioorg. Med. Chem. Lett. 1999,
7, 2509.
(3) (a) Widmer, U. Synthesis 1983, 2, 135. (b) Vorbru¨ggen, H. Angew.
Chem. 1963, 75, 296.
(5) Racemic material for the enantiomeric excess determination was
obtained by epoxidation of methyl 4-vinylbenzoate, followed by acid-
catalyzed opening of the resulting epoxide with azide and subsequent
reduction and N-Cbz protection. Enantiomeric excess was determined
using Chiracel-AD column (hexanes/isopropyl alcohol 4: 1), flow ) 1
mL/min, tR ) 7.26 min (S-isomer) and 12.91 min (R-isomer): 1H NMR
(DMSO-d6, 300 MHz) δ 7.89 (d, 2 H, J ) 8.7 Hz), 7.83 (d, 1 H, J ) 8.4
Hz), 7.44 (d, 2 H, J ) 9.0 Hz), 7.34 (bs, 4 H), 5.04-4.93 (m, 3 H), 4.65
(bq, 1 H, J ) 8.1 Hz), 3.83 (s, 3 H), 3.53-3.50 (m, 2 H).
(6) (a) Kuehn, C.; Lindeberg, G.; Gogoll, A.; Hallberg, A.; Schmidt
B.; Tetrahedron 1997, 53, 12497. (b) Preville, P.; He, J . X.; Tarazi, M.;
Siddiqui, M. A.; Cody, W. L.; Doherty, A. M. Bioorg. Med. Chem. Lett.
1997, 7, 1563. (c) Minnaard, A. J .; Boesten, W. H. J .; Zeegers, H. J . M.
Synth. Commun. 1999, 29, 4327. (d) Stocker, J . H. J . Org. Chem. 1962,
27, 2288.
(4) (a) Reddy, K. L.; Sharpless, K. B. J . Am. Chem. Soc. 1998, 120,
1207. (b) Li, G.; Angert, H. H.; Sharpless K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2813. (c) Berrisford, D. J .; Bolm, C.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1059.
(7) Breitmaier, E.; Voelter, W. In Carbon-13 NMR Spectroscopy;
High-Resolution Methods and Applications in Organic chemistry and
Biochemistry, 3rd ed.; VCH: New York, 1990; p 143.
10.1021/jo010512b CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/22/2002

Notes
J . Org. Chem., Vol. 67, No. 8, 2002 2687
F igu r e 3.
Ta ble 1a
%
yield
trans/cis
ratio
entry
base/conditions
1
2
3
4
5
6
7
K2CO3, CH3OH, 24 h rt.
KtBuO, 4 equiv, reflux 12 h
DBU reflux
80 0:1
0
decomposition
F igu r e 1.
100 0:1
phospazene9 P4 base, -78 °C, 30 min 100 0:1
LDA, 8.0 equiv, -78f 0 °C, 1 h
LDA, 2.5 equiv, -78 °Cf 0 °C, 1 h
LDA, 8.0 equiv, -78 °C, 2 h
40 1:1
33 0:1
81 1:1.2
a
The cis/ trans ratio was determined by integration of H1 in
the 1H NMR spectra. The hydrogen in the cis isomer appears at δ
2.5 ppm whereas the hydrogen in the trans isomer is at δ 1.8 ppm.
and quenching with methanol resulted in the formation
of an inseparable cis/trans mixture in a ratio 1:1.2. All
attempts to separate the mixture using chromatographic
techniques proved futile. Fortunately, the treatment of
the mixture of isomers with hexane resulted in the
preferential precipitation of the cis isomer 4. This method
allowed isolation of the pure cis and trans isomers.
Repetition of the isomerization process followed by
preferential precipitation of the cis isomer from hexane
allowed total conversion of the cis to the trans compound
6. The stereochemistry of the trans isomer 6 was once
again established using coupling constant analysis as
F igu r e 2. Ball and stick representation of X-ray structure of
the reduction product 4.
of the NMR spectra of 4 clearly indicated exclusive
formation of the cis isomer, which had the following
coupling pattern: J H1,2 ∼ 4.5 Hz, J H1,3 ∼ 4.5 Hz, and
J C1-H2,3 ∼ 8 Hz.
described above.7 The observed couplings were J H1,2
)
12 Hz and J C1-H2,3 ) 6.8 Hz (doublet of quartet). The
amino alcohol 6 was oxidized using RuCl3 and HIO4‚2H2O
to produce the trans acid. The crude acid obtained by this
method was used directly for further incorporation into
peptide targets. To enable efficient characterization of
the acid, it was converted to the methyl ester by treat-
ment with TMS-diazomethane,10 and the methyl ester
was further crystallized from hexanes at -30 °C. This
method allowed for routine synthesis of gram quantities
of substituted cyclohexylglycines.
To further confirm our analysis, a single-crystal X-ray
of the reduction product 4 was obtained. As shown in
Figure 2, the ball-and-stick representation of the X-ray
structure of 4 clearly indicated that hydrogenation of 3
exclusively generated the cis product with the cyclohex-
ane ring adopting a chair conformation and the tert-
butylcarboxyl group occupying an axial position. The
completion of the synthesis of protected cis-4-tert-butoxy-
carbonyl-substituted cyclohexylglycine (5) was accom-
plished by oxidation of the alcohol to the corresponding
acid using RuCl3 and HIO5‚2H2O in 66% yield.8
Having synthesized the cis isomer, we now needed an
efficient synthesis of the trans isomer. The isomerization
of the cis isomer to the trans isomer by treatment of base
seemed facile because the tert-butoxycarboxyl group
would prefer an equatorial position (Figure 3). Initial
attempts to epimerize 4 under thermodynamic conditions
using mild bases proved futile. To our surprise, the
epimerization was difficult and only the cis isomer was
isolated under various conditions. The list of the different
bases used and the yields obtained are shown in Table
1.
In summary, the synthesis of nonproteinogenic amino
acid cis-4-tert-butoxycarbonyl-substituted cyclohexylgly-
cines using aminohydroxylation of styrene has been
reported. A method for the isomerization of the cis isomer
using LDA and separation of the cis and trans mixture
by precipitation using hexane has also been established,
which allows for routine synthesis of multigram quanti-
ties of the amino acid. This method is versatile and can
be applied for the synthesis of other analogues of cyclo-
hexylglycine, a very useful nonnatural amino acid.
Exp er im en ta l Section
Gen er a l Meth od s. All glassware were dried in an oven at
150 °C prior to use. Dry solvents were purchased from Aldrich
As shown in the Table 1, the attempted isomerization
of the cis isomer 4 with mild base was unsuccessful.
However, treatment of 4 with 8 equiv of LDA at -78 °C
(9) (a) Schwesinger, R.; Hasenfratz, C.; Schlemper, H.; Walz, L.;
Peters, E. M.; Peters, K.; von Schnering, H. G. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1361 (b) Schwesinger, R.; Schlemper, H. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1167.
(10) (a) Shioiri, T.; Aoyama, T.; Mori, S. Org. Synth. 1990, 68, 1. (b)
Shioiri, T.; Aoyama, T. J . Synth. Org. Chem. J pn. 1986, 44, 149.
(8) (a) Djerassi, C.; Engle, R. R. J . Am. Chem. Soc. 1953, 75, 3838.
(b) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936.

2688 J . Org. Chem., Vol. 67, No. 8, 2002
Notes
or Acros and used without further purification. Other solvents
or reagents were used as acquired except when otherwise noted.
Analytical thin-layer chromatography (TLC) was performed on
precoated silica gel plates available from Analtech. Column
chromatography was performed using Merck silica gel 60
(particle size 0.040-0.055 mm, 230-400 mesh). Visualization
was accomplished with UV light or by staining with a basic
KMnO4 solution, methanolic H2SO4, or Vaughn’s reagent. NMR
spectra were recorded in CDCl3 unless otherwise noted in either
300 or 400 MHz (1H NMR) or 75 or 100 MHz (13C NMR).
1,1-Dim eth yleth yl 4-Eth en ylben zoa te11 (2). A solution of
vinyl benzoic acid 1 (10 g, 68 mmol) in dry benzene (150 mL)
was treated with dimethylformamide di-tert-butyl acetal (69 g,
340 mmol, 5.0 equiv) and heated at reflux for 4 h. The reaction
mixture was concentrated in vacuo and diluted with aq NaOH
(1 M, 300 mL). The aqueous mixture was extracted with diethyl
ether (3 × 100 mL). The combined organic layers were extracted
with aq NaOH (1 M, 100 mL), H2O (2 × 100 mL), brine (1 ×
100 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was distilled under reduced pressure (1 mmHg) to
obtain 2 as a colorless oil: 9.2 g (66%); 1H NMR (CDCl3, 300
MHz) δ 7.96 (d, 2 H, J ) 5.7 Hz), 7.43 (d, 2 H, J ) 8.4 Hz), 6.74
(dd, 1 H, J ) 10.8, 6.6 Hz), 5.85 (d, 1 H, J ) 17 Hz), 5.35 (d, 1
H, J ) 10.2 Hz), 1.60 (s, 9 H); 13C NMR (CDCl3 75 MHz) δ 165.4,
141.3, 136.0, 131.1, 129.8, 125.8, 116.0, 80.8, 28.1.
quenched with CH3OH (20 mL). The reaction mixture was
treated with aq HCl (150 mL, 1 M) and extracted with ether (3
× 100 mL). The combined ether layers were extracted with brine
(50 mL), dried (MgSO4), concentrated in vacuo, and purified by
chromatography (SiO2, Hex/EtOAc 4:1). The isolated mixture
was crystallized from boiling hexanes. The solid separating out
from the mother liquor was predominantly cis stereoisomer,
whereas concentration of the mother liquor gave the enriched
trans isomer. The above sequence was repeated twice to obtain
2.7 g of the trans compound and 600 mg of cis and trans
mixture: [R]D ) -1.48 (c ) 0.68, CHCl3, 25 °C); 1H NMR (CDCl3,
400 MHz) δ 4.76 (d, 1 H, J ) 8.8 Hz), 3.67-3.60 (m, 2 H), 3.42
(bs, 1 H), 2.5 (bs, 1 H), 2.47-2.06 (m, 1 H), 1.99-1.96 (bd, 2 H),
1.83 (bt, 2 H), 1.44 (s, 18 H), 1.44-1.05 (m, 4H) 1.05-1.02 (m,
2 H); 13C NMR (CDCl3, 100 MHz) δ 175.3, 156.6, 79.8, 63.6, 57.0,
44.1, 38.3, 37.7, 28.9, 28.6, 28.4, 28.1, 26.6, 26.1. MS (FAB) m/z
relative intensity: 344 [(M + 1)+,70], 342 (10), 288 (100), 244
(60); HRMS calcd for C18H34NO5 344.2437, found: 344.2444.
cis-4-[(1,1-Dim et h ylet h oxy)ca r b on yl]-(S)-r-[[(1,1-d im e-
th yleth oxy)ca r bon yl]a m in o]cycloh exa n ea cetic Acid (5). A
solution of alcohol 4 (2.6 g, 7.6 mmol) in CH3CN (150 mL) and
CCl4 (150 mL) was treated with H2O (22 mL), cooled to 0 °C,
and treated with periodic acid (7.05 g, 30.92 mmol, 4.0 equiv)
and RuCl3‚3H2O (60 mg, 0.3 mmol, 4 mol %). The reaction
mixture was stirred at 0 °C for 3 h and concentrated in vacuo.
The residue was diluted with water (150 mL) and extracted with
EtOAc (3 × 100 mL). The combined organic layers were filtered
through a plug of Celite and extracted with H2O (100 mL) and
aqueous NaOH (1 M, 3 × 100 mL). The combined aqueous layers
were acidified with HCl (6 M, pH ∼1) and extracted with EtOAc
(3 × 100 mL). The ethyl acetate layers were pooled, extracted
with brine (100 mL), dried (Na2SO4), filtered, and concentrated
in vacuo to yield acid 5 (1.8 g, 66%) used for further couplings
without purification: MS (FAB) m/z relative intensity 380 ([M
+ Na]+, 30) 358 ([M + 1]+, 5), 302 (20), 258(20), 246 (100), 202
(70), 200 (20) The amino acid was characterized as the methyl
ester obtained by the treatment of the acid with TMS-diaz-
omethane in benzene/methanol (5:1 v/v): [R]D ) 17.7 (c ) 1.06,
(S)-1,1-Dim eth yleth yl 4-[1-[[(1,1-Dim eth yleth oxy)ca r bo-
n yl]a m in o]-2-h yd r oxyeth yl]ben zoa te (3). A solution of tert-
butyl carbamate (5.96 g, 50.9 mmol) in 1-PrOH (68 mL) was
treated with aq NaOH (128 mL, 0.41 M) and tert-butyl hypochlo-
rite (5.5 g, 50.9 mmol) and stirred at room temperature for 20
m. The reaction mixture was cooled to 0 °C, and (DHQ)2Phal
(780 mg, 1.00 mmol) in 1-PrOH (64 mL) was added. A solution
of tert-butyl 4-vinylbenzoate 2 in 1-PrOH (119 mL) was added
followed by K2OsO4‚2H2O (248 mg, 0.7 mmol). The reaction
mixture was stirred at 0 °C for 12 h. The green reaction mixture
was concentrated in vacuo, and the residue was diluted with
H2O (300 mL) and extracted with EtOAc (3 × 100 mL). The
combined organic layers were extracted with aq HCl (200 mL)
and brine (100 mL), dried (Na2SO4), filtered, concentrated in
vacuo, and purified by chromatography (SiO2, Hex/EtOAc, 2:1)
to yield 3 as a colorless solid (3.7 g, 70%): [R]D ) 33.4 (c ) 0.68,
1
CHCl3, 25 °C); H NMR (CDCl3, 300 MHz) δ 5.01 (d, 1 H, J )
9.0 Hz), 4.24 (dd, 1 H, J ) 5.7, 3.3 Hz), 3.72 (s, 3 H), 2.50-2.47
(m, 1 H), 2.12-2.08 (bm, 2 H), 1.73 (bs, 1 H), 1.56-1.23 (m, 6
H), 1.45 (s, 9 H), 1.43 (s, 9 H). 13C NMR (75 MHz, CDCl3) δ 174.1,
172.8, 155.4, 85.7, 80.0, 79.7, 57.5, 52.0, 40.2, 39.8, 28.3, 28.1,
26.8, 26.6, 25.7, 24.4; MS (FAB) m/z, relative intensity: 394 [(M
+ Na)+, 93), 372 [(M + 1)+, 38), 316 (25), 260 (100), 216 (84).
Anal. Calcd for C19H33NO6: C 61.43, H 8.95, N 3.77. Found: C
61.32, H 8.73, N 3.64.
tr a n s-4-[(1,1-Dim eth yleth oxy)ca r bon yl] (S)-r-[[(1,1-Dim -
eth yleth oxy)ca r bon yl]a m in o]cycloh exa n ea cetic Acid . The
desired trans acid was prepared from 6 in 55% yield according
to the oxidation procedure mentioned for the synthesis of acid
5. MS (FAB) m/z relative intensity 380 ([M + Na]+, 30) 358 ([M
+ 1]+, 5), 302 (20), 258(20), 246 (100), 202 (70), 200 (20); HRMS
calcd for C18H32NO6 (M + 1)+: 358.2230, found: 358.2237. The
crude mixture was converted to the methyl ester by the treat-
ment of TMS-diazomethane: [R]D ) 12 (c ) 0.39, CHCl3, 25 °C);
1H NMR (CDCl3, 300 MHz) δ: 5.03 (d, 1 H, J ) 9.0 Hz), 4.24
(dd, 1 H, J ) 4.5, 4.5 Hz), 3.74 (s, 3 H), 2.10 (tt, 1 H, J ) 8.4
Hz), 2.06-1.90 (bm, 2 H), 1.77-1.60 (bm, 3 H), 1.40-1.02 (m, 2
H), 1.44 (s, 9 H), 1.43 (s, 9 H); 13C NMR (CDCl3, 75 MHz) δ 175.0,
172.7, 155.5, 79.9, 57.8, 52.2, 43.8, 40.4, 28.4, 28.3, 28.1, 27.1;
MS (FAB) 394 [(M + Na)+, 80], 372 [(M + 1)+, 20], 316 (30), 260
(100), 216 (84), 156 (34); HRMS calcd for C19H34NO6 (M + H)+
372.2386; found 372.2388.
1
CHCl3, 25 °C); H NMR (CD3OD, 300 MHz) δ 7.90 (d, 2 H, J )
6.3 Hz), 7.40 (d, 2 H, J ) 6.0 Hz), 7.14 (bd, 1 H, J ) 5.7 Hz),
4.88 (bm, 1 H), 3.69-3.65 (m, 2 H) 1.58 (s, 9 H), 1.42 (s, 9 Hz);
13C NMR (CD3OD, 75 MHz) δ 169.7, 160.5, 149.8, 134.5, 132.9,
130.4, 84.7, 82.9, 68.7, 60.7, 31.3, 30.9; MS (FAB) m/z relative
intensity 675 ([2M + 1]+, 15), 338 ([M + 1]+, 15), 282 (65), 225
(50), 165 (100); HRMS m/z calcd for C18H28NO5 (M + 1):
338.1967, found 338.1967.
1,1-Dim eth yleth yl 4-[(1S)-1-[[(1,1-Dim eth yleth oxy)ca r -
bon yl]a m in o]-2-h yd r oxyeth yl]cycloh exa n ea ceta te (4). A
solution of the ester 3 (1.0 g, 2.96 mmol) in CH3OH (20 mL)
was treated with Rh/C (10% w/w 100 mg) and hydrogenated (60
psi) for 3 d. The reaction mixture was filtered through a plug of
Celite, and the residue was concentrated in vacuo to yield 4.
The crude product was purified by chromatography (SiO2, Hex/
EtOAc 4:1) to yield the cis compound 4 (830 mg, 83%) which
was further purified by crystallization from hexanes: [R]D
)
-20.0 (c ) 0.87, CHCl3, 25 °C); 1H NMR (CDCl3, 400 MHz) δ
3.59-3.55 (m, 2 H), 3.50-3.46 (m, 1 H), 2.32-2.29 (m, 1 H),
2.13-2.03 (m, 2 H), 1.42 (s, 9 H), 1.36 (s, 9 H), 1.47-1.26 (m, 7
H); 13C NMR (C6H6/CD3OD, 100 MHz) δ 174.4, 157.0, 79.6, 78.9,
63.0, 56.1, 40.9, 37.8, 28.4, 28.0, 26.9, 26.5, 25.5; MS (FAB) m/z
relative intensity 687 ([2M + 1]+, 5), 344 ([M + 1]+, 20), 232
(40), 188 (100), 107 (13); HRMS calcd for C18H34NO5 (M + 1):
343.2437, Found: 344.2444. Anal. Calcd for C18H33NO5: C 64.07,
H 8.07, N 4.15. Found: C 64.32, H 8.21, N 4.32.
Ack n ow led gm en t. We thank Dr. T. M. Chan of
Schering-Plough structural chemistry group for running
the NMR experiments and assisting in assignment of
the structures of intermediates 4 and 6.
1,1-Dim eth yleth yl 4-[(1S)-1-[[(1,1-Dim eth yleth oxy)ca r -
bon yl]a m in o]-2-(h yd r oxyeth yl)cycloh exa n ea ceta te (6). A
solution of amino alcohol 4 (3.3 g, 11.08 mmol) in dry THF (200
mL) was cooled to -78 °C (internal temperature -68 °C) and
was treated with LDA (44 mL, 2 M solution in heptanes, 88
mmol). The reaction mixture was stirred at -78 °C for 2 h and
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for cyclohexylglycines and synthetic intermediates 2,
3, 4, and X-ray stucture data of 4 are available free of charge
via the Internet at http://www.pubs.acs.org.
(11) Shizone, T.; Hirao, A.; Nakahama, S. Macromolecules 1989, 22,
2895.
J O010512B