Practical, scalable, enantioselective synthesis of (2R,3R)-N-boc-2-amino-3- cyclohexyl-3-hydroxypropanoic acid

Article abstract of DOI:10.1021/op050076l

An enantioselective synthesis of (2R,3R)-2-(tert-butoxycarbonyl)amino-3- cyclohexyl-3-hydroxypropanoic acid has been described starting from enantiomerically enriched ethyl 3-cyclohexyl-2,3-dihydroxypropanoate, easily available by Sharpless asymmetric dih

Full text of DOI:10.1021/op050076l

Organic Process Research & Development 2005, 9, 690−693
Communications to the Editor
Practical, Scalable, Enantioselective Synthesis of (2R,3R)-N-Boc-2-amino-3-
cyclohexyl-3-hydroxypropanoic Acid
Mo`nica Alonso,† Ferran Santacana,† Llorenc¸ Rafecas,‡ and Antoni Riera*,†
Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB), Parc Cient´ıfic de Barcelona and Departament de Qu´ımica
Orga`nica, UniVersitat de Barcelona, and Enantia, S.L. Parc Cient´ıfic de Barcelona, C/Josep Samitier, 1-5,
08028-Barcelona, Spain
Abstract:
During the past decade we have been involved in a project
devoted to the asymmetric synthesis of biologically active
amino acids.8 In the present case, we envisaged that the
asymmetric Sharpless dihydroxylation of the unsaturated
ester 3 to give the enantiomerically enriched diol 4 would
to be a good procedure to establish the stereochemistry of
both centres, since absolute configuration would be controlled
by the ligand, and the nucleophilic introduction of the amino
function with inversion of configuration would afford the
required erythro relative estereochemistry. For this general
An enantioselective synthesis of (2R,3R)-2-(tert-butoxycarbo-
nyl)amino-3-cyclohexyl-3-hydroxypropanoic acid has been de-
scribed starting from enantiomerically enriched ethyl 3-cyclo-
hexyl-2,3-dihydroxypropanoate, easily available by Sharpless
asymmetric dihydroxylation. The key reaction is the direct
preparation of a sulfate by diol treatment with sulfuryl chloride,
thus avoiding ruthenium-catalyzed sulfite oxidation.
â-Hydroxy-R-amino acids are constituents of many
biologically active natural products and medicinally impor-
tant compounds.1-4 Since both the relative and absolute
stereochemistry of their chiral centres is crucial for their
biological activity, many stereoselective syntheses of this type
of nonproteinogenic amino acids have been reported up to
now.2-5 Among these compounds, (2R,3R)-2-amino-3-hy-
droxy-3-cyclohexylpropanoic acid 1 is particularly relevant
since it is a key component in the antiinflammatory and HIV
antagonist drug ONO-4128 2.6 Although some enantiose-
lective syntheses of this particular amino acid have been
described to date,7 a practical, reliable, and scalable stereo-
selective synthesis of this important amino acid would be
of great interest.
(1) Amino Acids, Peptides and Proteins; Special Periodical Reports; Royal
Society of Chemistry: London, 1968-1995; Vols. 1-28.
(2) Selected synthesis of â-hydroxy amino acids based on aldol reactions: (a)
MacMillan, J. B.; Molinski, T. F. Org. Lett. 2002, 4, 1883-1886. (b) Ooi,
T.; Taniguchi, M.; Kameda, M.; Mauroka, K.; Angew. Chem., Int. Ed. 2002,
41, 4542-4544. (c) Horikawa, M.; Busch-Petersen, J.; Corey, E. J.
Tetrahedron Lett. 1999, 40, 3843-3846. (d) Ito, Y.; Sawamura, M.; Hayashi,
T. J. Am. Chem. Soc. 1986, 108, 6405-6406.
(3) Selected syntheses of â-hydroxy amino acids based on Sharpless epoxida-
tion: (a) Nagamitzu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler,
P. A.; Smith, A. B., III. J. Am. Chem. Soc. 1996, 118, 3584-3590. (b)
Rao, A. V. R.; Dhar, T. G. M.; Bose, D. S.; Chakraborty, T. K.; Gurjar, M.
K. Tetrahedron 1989, 45, 7361-7370.
(4) Selected syntheses of â-hydroxy amino acids based on catalytic non-aldol
reactions: (a) Amador, M.; Ariza, X.; Garcia, J.; Sevilla, S. Org. Lett. 2002,
4, 4511-4514. (b) Shao, H.; Goodman, M. J. Org. Chem. 1996, 61, 2582-
2583. (c) Jung, M. E.; Jung, Y. H. Tetrahedron Lett. 1989, 30, 6637-
6640. (d) Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werner, J.; Fischer,
P. Synthesis 1989, 256-261.
(5) Selected syntheses of â-hydroxy amino acids based on dynamic kinetic
resolution. (a) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew. Chem.,
Int. Ed. 2004, 43, 882-882. (b) Genet, J. P.; Pinel, C.; Mallart, S.; Juge,
S.; Thorimbert, S.; Laffitte, J. A. Tetrahedron: Asymmetry 1991, 2, 555-
567. (c) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi,
H. J. Am. Chem. Soc. 1989, 111, 9134-9135.
(6) (a) Takaoka, Y.; Okamoto, M.; Genba, Y. (Ono Pharmaceutical Co., Japan).
WO 026874, 2004. (b) Takaoka, Y.; Nishizawa, R.; Shibayama, S.; Sagawa,
K.; Matsuo, M. (Ono Pharmaceutical Co., Japan). WO 26873, 2004. (c)
Imawaka, H.; Shibayama, S.; Takaoka, Y. (Ono Pharmaceutical Co., Japan).
WO 035074, 2004. (d) Habashita, H.; Hamano, S.; Shibayama, S.; Takaoka,
Y. (Ono Pharmaceutical Co., Japan). WO 074770, 2002. (e) Mitsuya, H.;
Maeda, K.; Shibayama, S.; Takaoka, Y. (Ono Pharmaceutical Co., Japan).
WO 074769, 2002.
(7) (a) Ikeo, T. (Nippon Kayaku Kabushiki Kaisha, Japan). WO 024934, 2004.
(b) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron 1988, 44, 5553-5562.
(8) See inter alia: (a) Poch, M.; Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera,
A. Tetrahedron Lett. 1993, 34, 7781-7784. (b) Pasto´, M.; Castejo´n, P.;
Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem. 1996, 61, 6033-
6037. (c) Castejo´n, P.; Moyano, A.; Perica`s, M. A.; Riera, A. Chem. Eur.
J. 1996, 2, 1001-1006. (d) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera,
A. J. Org. Chem. 1997, 62, 8425-8431. (e) Medina, E.; Moyano, A.;
Perica`s, M. A.; Riera, A. J. Org. Chem. 1998, 63, 8574-8578. (f) Medina,
E.; Moyano, A.; Perica`s, M. A.; Riera, A. HelV. Chim. Acta 2000, 83, 972-
988. (g) Mart´ın, R.; Islas, G.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron 2001, 57, 6367-6374.
* To whom correspondence should be addressed. E-mail: ariera@pcb.ub.es.
† Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB), Parc Cient´ıfic de
Barcelona and Departament de Qu´ımica Orga`nica, Universitat de Barcelona.
‡ Enantia, S.L. Parc Cient´ıfic de Barcelona.
690
•
Vol. 9, No. 5, 2005 / Organic Process Research & Development
10.1021/op050076l CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/23/2005

Scheme 1a
sequence, Sharpless developed a general methodology9 that
involves the following steps: (a) reaction of a vicinal diol
with thionyl chloride to give a cyclic sulfite, (b) oxidation
to sulfate with periodate and a catalytic amount of Ru-
containing compound, and (c) reaction with a nucleophile,
which in the synthesis of a hydroxy amino acid would be
azide. However, this sequence has the usual drawbacks
associated with the use of ruthenium: difficult workup and
generation of heavy metal residues. Somewhat surprisingly,
the direct transformation of diols into sulfates using sulfuryl
chloride has been scarcely described in the literature,
probably because in most cases the reaction conditions lead
to a complex mixture of compounds. The few reports using
this reagent10,11 claimed that only cyclic or electron-deficient
substrates give good yields. We describe here the preparation
of sulfate 5 from unsaturated amino ester 3 by an advanta-
geous procedure based on Sharpless asymmetric dihydroxy-
lation and sulfuryl chloride treatment, (not involving
sulfite/sulfate oxidation), and the transformation of 5 into
(2R,3R)-2-(tert-butoxycarbonyl)amino-3-hydroxy-3-cyclo-
hexylpropanoic acid, 8, a useful precursor of pharmacologi-
cally important drugs such as ONO-4128, 2.
a Reagents and conditions: (a) K3Fe(CN)6, (DHQD)2PHAL, 0.4% mol
K2OsO2(OH)2, CH3SO2NH2 (76% yield). (b) SO2Cl2, NEt3, AcOEt, 0 °C (93%
yield). (c) NaN3, acetone:H2O (5:1) 0 °C, 2 h. (d) H2SO4, 20% Et2O (1:1) o.n.
(e) Pd/C, AcOEt, H2, Boc2O (77% three steps). (f) KOH, THF (80% yield).
the reaction took place in very low yields. An extensive set
of solvents (toluene, isopropyl acetate, methyl isopropyl
ketone) and temperatures was then tested, but in most cases
the yields were disappointingly low. Attempted purification
of the sulfate by chromatography gave the rearranged ketone
10 as the main product of the reaction. Performing the
reaction in ethyl acetate, at -78 °C, also led to 9 as the
major product. Nevertheless, the slow addition of sulfuryl
chloride into a diluted solution of diol 4 and triethylamine
in ethyl acetate at 0 °C11 afforded a clean reaction crude
that, after work up, gave sulfate 5 in 93% yield. It is worth
noting that, to the best of our knowledge, this is the first
acyclic diol without electron-deficient substituents that has
been converted into sulfate by direct treatment with sulfuryl
chloride.
Submitting the known12 unsaturated ester 3 to the standard
Sharpless asymmetric dihydroxylation13 afforded the enan-
tiomerically enriched diol 4 uneventfully. The preparation
of the sulfate was initially attempted in methylene chloride
in the presence of triethylamine under the typical condi-
tions.10 However at -78 °C the main product was the bis-
chlorosulfate 9. By increasing the temperature up to 0 °C
(9) (a) Sharpless, K. B.; Gao, Y. (Massachusetts Institute of Technology,
U.S.A.). U.S. Patent 5,321,143, 1994. (b) Gao, Y.; Sharpless, K. B. J. Am.
Chem. Soc. 1988, 110, 7538-7539.
(10) (a) Rinner, U.; Siengalewicz, P.; Hudlicky, T. Org. Lett. 2002, 4, 115-
117. (b) Tai, V. W.-F.; Imperiali, B. Tetrahedron Lett. 1998, 39, 7215-
7218, (c) Liu, P.; Vandewalle, M. Tetrahedron Lett. 1993, 34, 3625-3628.
(d) Myers, A. G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000, 39, 2732-
2735. (e) Seimbille, Y.; Ali, H.; van Lieer, J. E. J. Chem. Soc., Perkin Trans.
1 2002, 657-663. (f) Seimbille, Y.; Be´nard, F.; van Lieer, J. E. J. Chem.
Soc., Perkin Trans. 1 2002, 2275-2281. (g) Vanhessche, K. P. M.;
Sharpless, K. B. Chem. Eur. J. 1997, 3, 517-522.
(11) (a) Fuentes, J.; Angulo, M.; Pradera, M. A. J. Org. Chem. 2002, 67, 2577-
2587. (b) Tewson, T. J. J. Org. Chem. 1983, 48, 3507-3510.
(12) (a) Shabtai, J.; Ney-Igner, E.; Pines, H. J. Org. Chem. 1981, 46, 3795-
3802. (b) Borne, R. F.; Forrester, M. L.; Waters, I. W. J. Med. Chem. 1977,
20, 771-776.
With sulfate 5 in hand, the transformation into the N-Boc
derivative 7 took place in 77% yield by regioselective ring-
opening with sodium azide, followed by hydrogenation over
Pd/C and in situ protection with Boc2O. The previously
unknown ethyl N-Boc-2-amino-3-cyclohexyl-3-hydroxy ester
(7) was hydrolyzed under basic conditions to afford the
desired protected amino acid 8. During the entire sequence
all intermediates were either isolated pure from the reaction
or purified by crystallization. Consequently, no chromato-
graphic separations were necessary. The final product was
obtained in very high chemical and optical purity (99% ee
as determined by chiral HPLC). In summary, we have
developed a practical and completely stereoselective syn-
(13) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung,
J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang,
X.-L. J. Org. Chem. 1992, 57, 2768-2771. (b) Sharpless, K. B.; Beller,
M.; Blackburn, B.; Kawanami, Y.; Kwong, H. L.; Ogino, Y.; Shibata, T.;
Ukita, T.; Wang, L. WO 922067, 1992.
Vol. 9, No. 5, 2005 / Organic Process Research & Development
•
691

thesis of (2R,3R)-2-(tert-butoxycarbonyl)-amino-3-hydroxy-
3-cyclohexylpropanoic acid, 8, using the Sharpless asym-
metric dihydroxylation as a source of chirality. The process
has been done on multigram scale without any chromato-
graphic purification. The key step of the synthesis is the
preparation of sulfate 5 from enantiomerically enriched diol
4 using sulfuryl chloride in ethyl acetate, instead of the usual
conditions that involve sulfite/sulfate oxidation with ruthe-
nium reagents.
(CH), 28.2 (CH2), 27.5 (CH2), 25.9 (CH2), 25.5 (CH2), 25.2
(CH2), 14.1 (CH3) ppm. Anal. Calcd for C11H18O6S: C,
47.47; H, 6.52; S, 11.52. Found: C, 47.30; H, 6.56; S, 11.69.
Ethyl (2R, 3R)-2-Azido-3-hydroxy-3-cyclohexylpro-
panoate 6. Cyclic sulfate 5 (5.18 g, 18.6 mmol) was
dissolved in a mixture of acetone:water (5:1, 150 mL) and
cooled to 0 °C. NaN3 (2.42 g, 37.2 mmol) was added, and
the stirring was continued for 3 h. The solvent was
evaporated, and the crude was dissolved in Et2O (90 mL)
and 20% H2SO4 (90 mL). After stirring overnight, excess
NaHCO3 was added to the reaction mixture. The aqueous
layer was extracted with Et2O (3 × 250 mL), and the
combined organic extracts were dried (MgSO4). The solvent
was concentrated, and the solution (ca. 50-100 mL) was
directly used in the next step. A small sample was evaporated
to dryness for characterization to give azide 6 as an oil. IR:
3488 (b), 2927, 2853, 2109, 1737, 1449, 1261, 1192, 1024
Experimental Section
General. Optical rotations were measured at room tem-
perature (concentration in g/100 mL). 1H NMR spectra were
obtained at 400 MHz (s ) singlet, d ) doublet, t ) triplet,
dt ) double triplet, m ) multiplet, and b ) broad) 13C NMR
1
spectra were obtained at 75 MHz. H chemical shifts are
1
cm-1. H NMR (400 MHz, CDCl3): 4.30 (q, 2H), 3.95 (d,
quoted relative to TMS and 13C shifts relative to solvent
signals. 3-Cyclohexylacrylic acid ethyl ester, 2, was prepared
according to the literature procedures.12
1H, J ) 6 Hz), 3.70 (t, 1H, J ) 6 Hz), 2.63 (b, 1H), 1.90-
1.50 (m, 5H), 1.34 (t, 3H), 1.00-1.30 (m, 6H) ppm. 13C
NMR (75 MHz, CDCl3): 169.7 (CO), 76.1 (CH), 63.5 (CH2),
62.2 (CH), 40.1 (CH), 29.6 (CH2), 27.2 (CH2), 26.3 (CH2),
26.2 (CH2), 26.0 (CH2), 14.3 (CH3) ppm.
Ethyl (2S, 3R)-2,3-Dihydroxy-3-cyclohexylpropanoate
4. To a mixture of (DHQD)2PHAL (800 mg, 1.03 mmol),
K3Fe(CN)6 (101.5 g, 308 mmol), K2CO3 (42.6 g, 308 mmol)
t
Ethyl (2R,3R)-2-(tert-Butoxycarbonyl)amino-3-hydroxy-
3-cyclohexylpropanoate 7. A solution of crude azide 6 and
Boc2O (5.3 g, 24.2 mmol) in ethyl acetate (30 mL) was added
to a stirred suspension of 10% Pd/C (448 mg) in ethyl acetate
(60 mL) under hydrogen. The mixture was stirred under
hydrogen until the starting material could not be detected
by TLC (20 h). Then, the suspension was filtered through
Celite, washing with ethyl acetate. Solvent was evaporated
at reduced pressure to give crude 7 as an oil. Crystallization
in heptane gave 4.5 g of 7 as a white solid (77% yield from
sulfate 5). Mp 76-78 °C. [R]D -15.6 (c 1.0, CHCl3). IR:
in H2O: BuOH (1:1, 1000 mL) cooled to 0 °C was added
K2OsO4(OH)4 (158 mg, 0.411 mmol) followed by methane-
sulfonamide (9.8 g, 102.8 mmol). After stirring 10 min at 0
°C, 3-cyclohexylacrylic acid ethyl ester (2) (18.7 g, 102.8
mmol) was added in one portion. The reaction mixture was
stirred at 0 °C for 18 h and then quenched with sodium sulfite
(154 g). Stirring was continued for 1 h at room temperature
and the solution extracted with CH2Cl2 (3 × 300 mL). The
organic layer was washed with KOH 2 N, dried over MgSO4,
and evaporated to give 4. Crystallization in heptane afforded
17.0 g of 4 as a white solid (76% yield). Mp 75.5-76.0 °C.
[R]D +12.5 (c 1.0, CHCl3). IR: 3461(b), 2924, 2851, 1737,
1
3440 (b), 2978, 2925, 2852, 1717, 1502, 1163 cm-1. H
1
1448, 1261 cm-1. H NMR (400 MHz, CDCl3): 4.29 (q,
NMR (400 MHz, CDCl3): 5.50 (bd, 1H, J ) 6.8 Hz), 4.43
(bd, 1H, J ) 4.8 Hz), 4.15-4.27 (m, 2H), 3.50 (bd, 1H, J )
5.2 Hz), 2.56 (b, 1H), 1.93 (bd, 1H, J ) 12 Hz), 1.80-1.60
(m, 4H), 1.45 (s, 9H), 1.28 (t, 3H), 0.9-1.3 (m, 6H) ppm.
13C NMR (75 MHz, CDCl3): 171.4 (CO), 146.9 (CO), 85.3
(CH), 77. 9 (C), 61.6 (CH2), 56.0 (CH), 40.9 (CH), 29.2
(CH2), 29.1 (CH2), 28.4 (CH3), 26.3 (CH2), 26.0 (CH2), 25.9
(CH2), 14.9 (CH3) ppm. Anal. Calcd for C16H29NO5: C,
60.93; H, 9.27; N, 4.44. Found: C, 60.80; H, 9.52; N, 4.42.
(2R,3R)-2-(tert-Butoxycarbonyl)amino-3-hydroxy-3-cy-
clohexylpropanoic Acid 8. To a stirred solution of 7 (2.5
g, 7.9 mmol) in THF, a KOH aqueous solution (0.9 g, 15.8
mmol in 60 mL) was added. After 2 h, no starting material
was detected by TLC. The mixture was concentrated under
vacuum, cooled to 0 °C, acidified with 0.1 M HCl, and
filtered to afford 1.8 g of 8 as a white solid (80% yield).
Mp 142.5-143 °C. [R]D -15.2 (c 1.0, CHCl3). IR: 3442
(b), 3319 (b), 2926, 2852, 1692, 1512, 1366, 1166 cm-1. 1H
NMR (400 MHz, CDCl3): 6.41 (broad, 1H), 5.64 (broad,
1H), 4.47 (s broad, 1H), 3.54 (s broad, 1H), 2.01 (d broad,
1H), 1.80-1.60 (m, 4H), 1.46 (s, 9H), 0.9-1.30 (m, 6H)
ppm. 13C NMR (75 MHz, CDCl3): 174.5 (CO), 156.3 (CO),
2H), 3.55 (t, 1H), 3.05 (s broad, 1H), 2.04 (d broad, 1H),
1.55-1.86 (m, 4H), 1.32 (t, 3H), 0.9-1.27 (m, 6H) ppm.
13C NMR (75 MHz, CDCl3): 174.4 (CO), 77.0 (CH), 71.0
(CH), 62.2 (CH2), 40.5 (CH), 31.3 (CH), 29.4 (CH2), 29.2
(CH2), 26.4 (CH2), 26.0 (CH2), 14.3 (CH3) ppm.
(4S,5R)-4-Ethoxycarbonyl-5-cyclohexyl-1,3,2-dioxathi-
olane-2,2-dioxide 5. To a solution of diol 4 (14.3 g, 66
mmol) in dry AcOEt (2600 mL) was added NEt3 (110.4 mL,
792 mmol). The reaction mixture was cooled to 0 °C under
stirring, and SO2Cl2 (26.5 mL, 330 mmol) was added
dropwise. After 2 h of stirring at this temperature, the reaction
mixture was extracted with water (3 × 800 mL) and NaCl
(2 × 500 mL). The combined organic extracts were dried
(MgSO4) and concentrated to give an oil. The crude was
crystallized in hexane to give 17.1 g of sulfate 5 as a white
solid (93% yield). Mp 84.5-85.0 °C. [R]D +71.07 (c 1.0,
CHCl3). IR: 2933, 2858, 1767, 1745, 1397, 1210 cm-1. 1H
NMR (400 MHz, CDCl3): 4.96 (d, 1H, J ) 6.4 Hz), 4.79
(t, 1H, J ) 6.4 Hz), 4.35 (q, 2H), 1.70-2.00 (m, 5H), 1.36
(t, 3H), 1.00-1.30 (m, 6H) ppm. 13C NMR (75 MHz,
CDCl3): 165.6 (CO), 87.6 (CH), 78.0 (CH), 63.4 (CH2), 40.4
692
•
Vol. 9, No. 5, 2005 / Organic Process Research & Development

80. 8 (C), 78.1 (CH), 55.8 (CH), 40.4 (CH), 29.4 (CH2),
29.0 (CH2), 28.4 (CH3), 26.4 (CH2), 26.0 (CH2), 25.9 (CH2)
ppm. Optical purity: amino acid 8 was converted into its
methyl ester which was analyzed by HPLC (Chiralcel OD,
hexane:2-propanol, 98:2; 0.5 mL/min, λ ) 220 nm; tR (2R,3R
isomer) ) 28.0 min, tR (2S,3S isomer) ) 31.1 min) showing
an enantiomeric purity of 99% ee.
Acknowledgment
Financial support from CIRIT (2001SGR-00050) and
DGICIT (BQU2002-02459) is gratefully acknowledged.
M.A. thanks MCYT (Spain) for a fellowship.
Received for review Received for review May 20, 2005.
OP050076L
Vol. 9, No. 5, 2005 / Organic Process Research & Development
•
693