An organocatalyzed enantioselective synthesis of (2S,3R,4S)-4- hydroxyisoleucine and its stereoisomers

Article abstract of DOI:10.1021/jo100233u

A concise enantioselective total synthesis of (2S,3R,4S)-4- hydroxyisoleucine and its stereoisomers is described. A key feature of this protocol is a catalytic enantioselective mannich reaction that is either anti- or syn-selective as genesis of chirality.

Full text of DOI:10.1021/jo100233u

pubs.acs.org/joc
An Organocatalyzed Enantioselective Synthesis of
(2S,3R,4S)-4-Hydroxyisoleucine and Its
Stereoisomers
Gullapalli Kumaraswamy,*,† Neerasa Jayaprakash,† and
Balasubramanian Sridhar‡
†Organic Division-III, Indian Institute of Chemical
Technology, Hyderabad, 500 007, India, and ‡Laboratory of
X-ray crystallography, Indian Institute of Chemical
Technology, Hyderabad, 500 007, India
FIGURE 1. Stereoisomers of 4-hydroxyisoleucine.
gkswamy_iict@yahoo.co.in
Received February 11, 2010
molecules, impressive synthetic strategies have been re-
ported. To date, most strategies rely on asymmetric induc-
tion resulting from either chiral auxiliaries6 resident chirality
or enzymatic kinetic resolution of racemic mixtures.7
Herein, we report a highly practical and organocatalyzed
enantioselective synthesis of (2S,3R,4S)-4-hydroxyisoleu-
cine and its stereoisomers. In principle, the stereogenic
centers 2 and 3 in (2S,3R,4S)-4-hydroxyisoleucine 2 could
be accessed through a catalytic enantioselective Mannich
reaction that are either anti-8 or syn-selective9 and by using
N-Boc-furylimine 7 with 1-propanal 8. We chose furyl
moiety as a masked carboxylic acid as well as to enhance
its solubility in water.10 To obtain high selectivities (i.e., de)
of the main product, we considered using water as the solvent
in the Mannich reaction. Further, the stereogenic center 4
could be realized through a chelation-controlled nucleophilic
addition of one carbon Grignard. Additionally, Mitsunobu
inversion of stereogenic center 4 in 1, ent-1, 3, and ent-3
would generate a set of four diastereomers. Our retro-
synthetic approach is shown in Scheme 1.
A concise enantioselective total synthesis of (2S,3R,4S)-
4-hydroxyisoleucine and its stereoisomers is described.
A key feature of this protocol is a catalytic enantioselec-
tive mannich reaction that is either anti- or syn-selective as
genesis of chirality.
The nonproteinogenic aminoacid (2S,3R,4S)-4-hydroxy-
isoleucine 2 has received renewed attention due to its broad
range of pharmaceutical activities as insulinotropic, antidys-
lipidemic, and antihyperglycemic agent.1 This unusual amino-
acid was first isolated as free acid from fenugreek (Trigonella
foenum-graecum) seeds2 and the structure was validated by
X-ray crystallography,3 establishing the absolute stereo-
chemistry as 2S,3S,4R. Further, the SAR studies indicated
that the absolute configuration of 2S,3R,4S stereogenic
centers has considerable influence on their pharmaceutical
activity (Figure 1).4
Accordingly, readily available furfural derived N-Boc-
imine 7 was treated with 8 in the presence of a catalytic
(6) (a) Kassem, T.; Wehbe, J.; Rolland-Fulcrand, V.; Rolland, M.;
Roumestant, M. L.; Martinez, J. Tetrahedron: Asymmetry 2001, 12, 2657.
(b) Gull, R.; Schollkopf, U. Synthesis 1985, 1052. (c) Inghardt, T.; Frejd, T.;
Svensson, G. Tetrahedron 1991, 47, 6469. (d) Jamieson, A. G.; Sutherland,
A.; Willis, C. L. Org. Biomol. Chem. 2004, 2, 808–809. (e) Sergent, D.;
wang, Q.; Sasaki, N. A.; Ouazzani, J. Bioorg. Med. Chem. Lett. 2008, 18,
4332–4335.
(7) Wang, Q.; Ouazzani, J.; Sasaki, N. A.; Potier, P. Eur. J. Org. Chem.
2002, 834.
In fenugreek (2R,3R,4S)-4-hydroxyisoleucine ent-3 was
also found as a minor component. Later on, the (2S,3S,4R)-
4-hydroxyisoleucine 3, which is a component of the natural
product funebrine 4, was isolated from Quararibea fune-
bris (Figure 1).5 Owing to the significant activity of these
(8) (a) Ibrahem, I.; Cordova, A. Chem. Commun 2006, 1760. (b) Trost,
B. M.; Jaratjaroong, J. J. Am. Chem. Soc. 2006, 128, 2778. (c) Kano, T.;
Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005, 127,
16408. (d) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.;
Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 1040. (e) Gianelli,
C.; Sambri, L.; Carlone, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int.
Ed. 2008, 47, 8700–8702.
(9) (a) Yang, J. W.; Stadler, M.; List, B. Angew. Chem. Int. Ed 2007, 46,
609. (b) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.;
Sakai, K. Angew. Chem., Int. Ed 2003, 42, 3677. (c) Fustero, S.; Jimenez, D.;
Sanz-Cervera, J. F.; Sanchez-Rosello, M.; Esteban, E.; Simon-Fuentes, A.
Org. Lett. 2005, 7, 3433. (d) Cardova, A.; Barbas, C. F., III Tetrahedron Lett.
2002, 43, 7749. (e) Liao, W. W.; Ibrahem, I.; Cardova, A. Chem. Commun.
2006, 674. (f) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew.
Chem., Int. Ed. 2005, 44, 4079. (g) Cardova, A.; Watanabe, S. I.; Tanaka, F.;
Notz, W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1866.
(10) The PMP-protected iminoesters have been used in organocatalyzed
Mannich reactions. The protecting group PMP poses potential problems
while deprotecting. The Boc-protected iminoesters were not suitable in our
case. Hence, N-Boc-furylimine was employed in our study, which is easy to
prepare and also hydrophilic in nature.
*To whom correspondence should be addressed. Phone: þ 91-40-
27193154. Fax: þ 91-40-27193275.
(1) (a) Sauvaire, Y.; Petit, P.; Broca, C.; Manteghetti, M.; Baissac, Y.;
Fernandez-Alavarez, J.; Gross, R.; Roye, M.; Leconte, A.; Gomis, R.; Ribes,
G. Diabetes 1998, 47, 206. (b) Narender, T.; Puri, A.; Shweta; Khaliq, T.;
Saxena, R.; Bhatia, G.; Chandra, R. Bioorg. Med. Chem. Lett. 2006, 16, 293.
(2) Fowden, L.; Pratt, H. M.; Smith, A. Phytochemistry 1973, 12, 1707.
(3) Alcock, N. W.; Crout, D. H. G.; Gregorio, M. V. M.; Lee, E.; Pike, G.;
Samuel, C. J. Phytochemistry 1989, 20, 1835.
(4) Broca, C.; Manteghetti, M.; Gross, R.; Baissac, Y.; Jacob, M.; Petit,
P.; Sauvaire, Y.; Ribes, G. Eur. J. Pharmacol. 2000, 390, 339.
(5) Raffauf, R. F.; Zennie, T. M.; Onan, K. D.; Le Quesne, P. W. J. Org.
Chem. 1984, 49, 2714.
DOI: 10.1021/jo100233u
r
Published on Web 03/22/2010
J. Org. Chem. 2010, 75, 2745–2747 2745
2010 American Chemical Society

Kumaraswamy et al.
SCHEME 3. Synthesis of syn-Varient β-Aminoaldehydes
JOCNote
SCHEME 1. Retrosynthesis of (2S,3R,4S)-4-Hydroxy-
isoleucine
SCHEME 2. TMS-Protected r,r-Diphenyl-2-pyrrolidine-
methanol-Catalyzed Synthesis of β-Aminoaldehyde
SCHEME 4. Synthesis of (2S,3R,4R)-4-Hydroxyisoleucine and
Its Stereoisomers
amount of TMS-protected R,R-diphenyl-2-pyrrolidine-
methanol 9 (10 mol %) in water at 4 °C for 16 h. The desired
β-aminoaldehyde 6 was isolated in 75% yield with 93:7
diastereoselectivity and 99% ee (Scheme 2).8a,11
As anticipated, 10 mol % of ent-9 under otherwise identical
conditions resulted in ent-6 in 73% yield with the same dr and
ee. The diastereoselectivity was determined by integration of
one set of 1H NMR signals of the corresponding aldehyde (δ
major 9.68 ppm as doublet and minor 9.75 ppm as singlet).11
The ee value was analyzed by HPLC on the chiral staionary
phase (Daicel Chiralpak OD-H column: 99/1 n-hexane/
i-PrOH, flow rate 0.8 mL/min, major=15.77 min).
In a similar vein, L-proline-catalyzed syn-selective Man-
nich reaction9a was evaluated employing 7 and 8 in water.
To our surprise, no trace of the desired product 11 was iso-
lated. When a similar reaction was conducted with 10 mol %
of 4-tert-butyldiphenylsilyloxy L-proline, the required Man-
nich adduct 11 was isolated in 89% yield with a dr value of
99:111 and 99% ee.
However, the syn-variant ent-11 was generated with a
catalytic amount of (R)-proline 12 (10 mol %) in acetonitrile
at 4 °C. The resulting product ent-11 was isolated in good
yield (92%) with high diastereo-enantioselectivity (dr 99:1,
ee >99%) (Scheme 3).11 With anti-syn-varients of β-ami-
noaldehydes in hand, we examined the addition of one
carbon Grignard for the synthesis of β-aminoalcohols. The
exposure of 6 to 1.5 equiv of methylmagnesium iodide at 0 °C
to rt for 3 h furnished 5 in 89% yield as the only isolable
diastereomer. In the same way, ent-6 subjected to identical
conditions (vide infra) resulted in ent-5 in 85% yield with the
same optical purity. The diastereoselectivity could be ratio-
nalized on the basis of a chelation-controlled mechanism
wherein the nucleophile is approaching from the re-face of
the pro-carbonyl group leading to the observed product 5,
while the adjacent methyl-substituted stereogenic center
does not play any significant role.
Oxidative cleavage of the furyl moiety of 5 (O3, 10 min)
followed by Boc deprotection under acidic conditions
(6 M HCl in dioxane) and subsequent purification (Dowex
50WX8-400) led to (2S,3R,4R)-4-hydroxyisoleucine 1 in
65% yield. Inversion of stereogenic center 4 in 5 under
Mitsunobu conditions (p-NO2C6H4CO2H, DIAD, THF,
rt, 3 h/K2CO3, MeOH) afforded 13 in 86% yield.
Compound 13 was subjected to oxidation, followed by
deprotection of the Boc group and purification resulting in
the title compound 2 with 59% isolated yield. The chemical
data of 2 are identical with those reported for the naturally
occurring molecule ([R]24 þ31.2 (c 0.9, H2O), lit.2 [R]24
D
D
þ31 (c 1, H2O)) (Scheme 4). As a result, the absolute stereo-
chemistry of 2 was assigned as 2S,3R,4S, which inturn
conformed with the absolute configuration of 1 as 2S,3R,4R.
The above-mentioned addition of Grignard/oxidation/
Boc-deprotection was repeated with compound 14 and ent-
14 to give 3 and ent-3 in 60% and 62% yields, respectively.
The relative stereochemistry of 3 was assigned as 2S,3S,4R
based on single X-ray crystallography (CCDC reference no.
764863;12 the crystal was obtained from 5% EtOAc in hex-
ane (see the Supporting Information)). The optical rotation
(11) The dr values of 6, ent-6, 11, and ent-11 have been determined after
chromatography of the corresponding reaction mixture (see the Supporting
Information).
2746 J. Org. Chem. Vol. 75, No. 8, 2010

Kumaraswamy et al.
JOCNote
SCHEME 5. Synthesis of (2S,3R,4R)-4-Hydroxyisoleucine and
Its Stereoisomer
9.1; MS (ESIMS) m/z 254 (M þ H)þ, 276 (M þ Na)þ; HRMS
(ESI) m/z 276.1215 (calcd for C13H19NO4Na 276.1211).
tert-Butyl (1S,2R,3R)-1-(Furan-2-yl)-3-hydroxy-2-methyl-
butylcarbamate (5). An ether solution of aldehyde 6 (450 mg,
1.78 mmol, 20 mL) was added dropwise to a cooled (0 °C)
solution of methylmagnesium iodide prepared from magnesium
(64 mg, 2.67 mmol) and methyl iodide (336 mg, 2.67 mmol) in dry
ether (15 mL). After addition, the resulting solution was stirred at
room temperature for 3 h . The solution was then slowly poured
into crushed ice, and the precipitated magnesium hydroxide was
quenched by the addition of saturated ammonium chloride (30
mL). Theorganic layer was separated, and the aqueous phase was
saturated with sodium chloride (20 mL) and extracted with
chloroform (3 ꢀ 15 mL). The combined organic layers were dried
over Na2SO4 and filtered. The solvent was removed under
reduced pressure. The crude residue was subjected to column
chromatography eluting with hexane/EtOAc (90/10) to furnish 5
as a colorless liquid (425 mg, 89%). [R]24D þ25.8 (c 0.9, CHCl3).
IR (KBr) 3424, 2278, 2972, 2931, 1675, 1542, 1504, 1365, 1267,
1168, 1092, 1009, 935, 748, 695 cm-1 1H NMR (300 MHz,
;
of ent-14 was found to be approximately equal in magnitude
to that of 14 but opposite in sign, indicating an enantiomeric
relationship, hence stereochemistry of ent-3 was assigned as
2R,3R,4S (Scheme 5).
CDCl3) δ7.34-7.33 (1H, m), 6.31-6.29 (1H, m), 6.16(1H, d, J =
3.2 Hz), 4.91-4.85 (2H, m), 3.82-3.72 (1H, m), 1.97-1.88 (1H,
m), 1.46 (9H, s), 1.21 (3H, d, J = 6.2 Hz), 0.95 (3H, t, J = 6.8 Hz);
13C NMR (150 MHz, CDCl3) δ 141.2, 109.9, 106.8, 69.2, 50.3,
45.5, 28.1, 20.2, 11.8; MS (ESIMS) m/z 270 (M þ H)þ, 292 (M þ
Na)þ; HRMS (ESI) m/z 292.1533 (calcd for C14H23NO4Na
292.1524).
In conclusion, we have accomplished a concise enantio-
selective total synthesis of (2S,3R,4S)-4-hydroxyisoleucine
2 and its stereoisomers. Strategic transformation includes
a catalytic enantioselective Mannich reaction that is either
syn- or anti-selective as genesis of chirality, methyl Grig-
nard addition, and Mitsunobu inversion to generate eight
stereoisomers with perfect stereocontrol. To our knowledge,
no catalytic diastereo-enantioselective variant reaction has
been explored before for the synthesis of (2S,3R,4S)-4-
hydroxyisoleucine. Moreover, flexibility was built into the
synthesis to generate a library of analogues. This protocol is
also amenable to large-scale synthesis of nonproteinogenic
aminoacid.
tert-Butyl (1S,2R,3S)-1-(Furan-2-yl)-3-hydroxy-2-methyl-
butylcarbamate (13). Triphenylphosphine (780 g, 2.98 mmol),
p-nitrobenzoicacid (279 g, 1.48 mmol), andcompound5 (400 mg,
1.48 mmol) were dissolved in THF (10 mL). To this mixture was
added a solution of diisopropylazodicarboxylate (601 mg, 2.97 mmol)
in THF (5 mL) at 0 °C via a syring. The reaction contents were
stirred at room temperature. After 3 h, the reaction mixture was
concentrated under vacuum. The crude residue was dissolved in
methanol (20 mL) and cooled to 0 °C. To this was added potas-
sium carbonate (410 mg, 2.97 mmol) portionwise. The mixture
was warmed to room temperature over a period of 1 h. Then the
solvent was removed under vacuum and the residue was dissolved
in CH2Cl2 (20 mL). The organic layer was washed with brine
(20 mL) and then separated. The aqueous layer was ex-
tracted with CH2Cl2 (2 ꢀ 10 mL), and the combined organic
layers were dried over Na2SO4 and concentrated. The crude re-
sidue was subjected to silica gel column chromatography (100-
200 mesh), using hexane and ethyl acetate (90:10) as solvents,
yielding the pure product 13 as a colorless liquid (344 mg, 86%).
Experimental Section
tert-Butyl (1S,2R)-1-(Furan-2-yl)-2-methyl-3-oxopropylcar-
bamate (6). 1-Propanal 8 (594 mg, 10.25 mmol) and N-Boc-
protected imine 7 (1.0 g, 5.12 mmol) were added to a round-
bottomed flask charged with catalyst 9 (167 mg, 10 mol %) and
2 mL of H2O at 4 °C. The reaction mixture was stirred for 16 h at
this temperature, then the reaction was quenched by addition of
EtOAc (15 mL) and the mixture was extracted with EtOAc (3 ꢀ
10 mL). The organic layer was separated and dried over
Na2SO4, concentrated, and evaporated to give crude product.
The crude residue was subjected to column chromatography
eluting with hexane/EtOAc (95/5) furnishing 6 as a colorless
liquid (973 mg, 75%) with dr 93:7 and 99% ee [dr 93:7,
determined by integration of one set of 1H NMR signals
(δmajor 9.65 ppm, d; δminor 9.73 ppm, s)]. HPLC analysis on a
DaicelChiralpak OD-H column: 99/1 n-hexane/i-PrOH, flow
rate 0.8 mL/min, λ = 215 nm; τmajor =15.77 min; [R]24D þ19.8 (c
0.9, CHCl3, 99% ee). IR (KBr) 3365, 2979, 2932, 1728, 1681,
[R]24 þ28.8 (c 0.9, CHCl3). IR (KBr) 3414, 2281, 2977, 2932,
D
1678, 1547, 1517, 1366, 1270, 1173, 1092, 1012, 965, 745, 689 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.32-7.31(m, 1H), 6.29-6.31 (m,
1H), 6.19 (1H, m), 5.14-5.12 (1H, m), 4.96-4.84 (1H, m),
3.64-3.62 (1H, m), 1.20-1.98 (1H, m), 1.46 (9H, s), 1.98 (3H,
d, J = 6.3 Hz), 0.80 (3H, t, J = 6.9 Hz); 13C NMR (150 MHz,
CDCl3) δ 142.0, 110.7, 106.3, 69.0, 51.9, 43.5, 28.5, 21.1, 8.8; MS
(ESIMS) m/z 270 (M þ H)þ, 292 (M þ Na)þ; HRMS (ESI) m/z
292.1529 (calcd for C14H23NO4Na 292.1524).
Acknowledgment. We are grateful to Dr. J. S. Yadav,
Director, IICT, for his constant encouragement. Financial
support was provided by the DST, New Delhi, India (Grant
No. SR/SI/OC-12/2007), and CSIR (New Delhi) is also
gratefully acknowledged for awarding a fellowship to N.J.
Thanks are also due to Dr. G. V. M. Sharma for his support.
1527, 1451, 1372, 1276, 1169, 1051, 919, 753, 612 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 9.73 (1H, s), 7.34-7.31 (1H, m),
6.30-6.28 (1H, m), 6.20-6.18 (1H, m), 5.21-5.01 (2H, m),
2.97-2.84 (1H, m), 1.44 (9H, s), 1.09 (3H, t, J = 7.5 Hz); 13C
NMR (150 MHz, CDCl3) δ 202.2, 141.6, 109.8, 106.8, 49.4, 27.7,
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds along
with copies of 1H and 13C NMR spectra, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) The crystallographic coordinates have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. 764863. These
data can be obtained free of charge from the Cambridge Crystallographic
Data Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.cam.
ac.uk/conts/retrieving.html.
J. Org. Chem. Vol. 75, No. 8, 2010 2747