Catalytic asymmetric syntheses of α-amino and α-hydroxyl acid derivatives

Article abstract of DOI:10.1021/jo900368k

(Chemical Equation Presented) Herein we report the first room temperature Heck reaction of aryl bromides and CH₂=C(NHP)CO₂Me (P = Boc or CBz) to form ArCH=C(NHP)CO₂Me, which are then used for the asymmetric syntheses of α-

Full text of DOI:10.1021/jo900368k

Catalytic Asymmetric Syntheses of r-Amino and
r-Hydroxyl Acid Derivatives
Xiaojun Han,* Xiang-Jun Jiang, Rita L. Civiello,
Andrew P. Degnan, Prasad V. Chaturvedula, John E. Macor,
and Gene M. Dubowchik
Neuroscience DiscoVery Chemistry, Research &
DeVelopment, Bristol-Myers Squibb Company, 5 Research
Parkway, Wallingford, Connecticut 06492
xiaojun.han@bms.com
ReceiVed February 18, 2009
asymmetric hydrogenation to give 11 (Scheme 1).4 Jeffery’s
ligandless conditions5 [Pd(OAc)2, TBAC, base (NaHCO3
K2CO3, or Et3N), solvent (THF, DMF, or MeCN), 80-120 °C,
hours] are most commonly used for this Heck reaction in the
literature. To increase functional group tolerance, we needed
to develop milder reaction conditions that would tolerate more
diverse functionality on the phenyl ring (R1-R3) to support our
SAR studies. Moreover, it was desirable to develop conditions
which were compatible with the use of aryl bromides (rather
than aryl iodides) as these are more readily available, both
synthetically and commercially.
Enol esters (10c,d, Scheme 1) have been prepared by
Horner-Wadsworth-Emmons olefination of aldehydes with
R-benzoate phosphonate esters,6 the synthesis of which often
requires the use of diazomethane (vide infra). We believed that
the Heck reaction of aryl bromides 8 with 9c,d7 could serve as
a more practical route to 10c,d, considering the commercial
availability and ease of the syntheses of aryl bromides when
compared with aryl aldehydes. Additionally, it would seem that
the accessibility of 9c,d would be preferable to the preparation
of the R-benzoate phosphonate ester required for the Horner-
Wadsworth-Emmons reaction6,7 and would eliminate the need
to use diazomethane.8b However, there were no literature reports
on this approach (8 + 9c,d f 10c,d). Also, there was very
limited precedent for the asymmetric hydrogenation of 10c,d
forming chiral R-hydroxyl esters,8 probably because of the weak
Herein we report the first room temperature Heck reaction
of aryl bromides and CH2dC(NHP)CO2Me (P ) Boc or
CBz) to form ArCHdC(NHP)CO2Me, which are then used
for the asymmetric syntheses of R-amino acids. We also
report the first syntheses of ArCHdC(OCOAr1)CO2Me (Ar1
) Ph, 4-Cl-Ph) from ArBr and CH2dC(OCOAr1)CO2Me
by the Heck reaction and subsequent successful asymmetric
hydrogenation to afford R-hydroxyl esters in excellent
chemical yields and good-to-excellent enantioselectivities.
In the course of our synthesis of CGRP antagonists for
the treatment of migraines, we found that the 7-methylinda-
zole of 1 imparted excellent potency and an improved
cytochrome P450 (CYP) profile in comparison with earlier
program leads.1 To expand our understanding of the SAR
around the amino acid residue of the above-mentioned
antagonists, we needed a practical asymmetric synthesis of
orthogonally protected amino esters 2-4. We were also
interested in the preparation of the corresponding R-hydroxy
esters 5-7 to form the corresponding carbamates. These
might demonstrate better pharmacokinetic properties by virtue
of their reduced hydrogen-bonding capacity.2
(4) (a) Prasad, C. V. C.; Mercer, S. E.; Dubowchik, G. M.; Macor, J. E.
Tetrahedron Lett. 2007, 48, 2661–2664. (b) Okano, K.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2006, 128, 7136–7137. (c) Li, T.; Tsuda, Y.;
Minoura, K.; In, Y.; Ishida, T.; Lazarus, L. H.; Okada, Y. Chem. Pharm. Bull.
2006, 54, 873–877. (d) Zheng, S.; Chan, C.; Furuuchi, T.; Wright, B. J. D.;
Zhou, B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2006, 45, 1754–1759. (e)
Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky,
S. J. J. Am. Chem. Soc. 2005, 127, 4596–4598. (f) Tullberg, E.; Peters, D.; Freid,
T. J. Organomet. Chem. 2004, 689, 3778–3781. (g) Yamada, K.; Kurokawa, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630–6631. (h)
Willans, C. E.; Mulders, J. M. C. A.; de Vries, J. G.; de Vries, A. H. M. J.
Organomet. Chem. 2003, 687, 494–497. (i) Xu, X.; Fakha, G.; Sinou, D.
Tetrahedron 2002, 58, 7539–7544. (j) Carlstrom, A.; Frejd, T. J. Org. Chem.
1991, 56, 1289–1293.
Previously, R-amino acid derivatives have been prepared by
the coupling of aryl iodides or bromides 8 with enamides 9a,b
to form enamides 10,3 and the latter has been shown to undergo
(1) Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D. A.; Davis,
C. D.; Denton, R.; Han, X.; Macci, R.; Mathias, N. R.; Moench, P.; Pin, S. S.;
Ren, S. X.; Schartman, R.; Signor, L. J.; Thalody, G.; Widmann, K. A.; Xu, C.;
Macor, J. E.; Dubowchik, G. M. J. Med. Chem. 2008, 51, 4858–4861.
(2) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. AdV. Drug
DeliVery ReV. 1997, 23, 3–25.
(3) For an overview of the synthesis methods of enamides, see: Panella, L.;
Aleixandre, A. M.; Kruidhof, G. J.; Robertus, J.; Feringa, B. L.; de Vries, J. G.;
Minnaard, A. J. J. Org. Chem. 2006, 71, 2026–2036.
(5) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287–1289.
(6) Schmidt, U.; Langner, J.; Kirschbaum, B.; Braun, C. Synthesis 1994,
1138–1140.
(7) Herrera, R.; Jime´nez-Va´zquez, H. A.; Modelli, A.; Jones, D.; So¨derberg,
B. C.; Tamariz, J. Eur. J. Org. Chem. 2001, 4657–4669.
10.1021/jo900368k CCC: $40.75
Published on Web 04/20/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3993–3996 3993

SCHEME 1. General Reaction Sequence of the Synthesis of
SCHEME 3. Synthesis of Indazole Amino Ester 2c
2-4 and 5-7
SCHEME 4. Synthesis of Oxazolidinone Amino Ester 3d
SCHEME 2. Asymmetric Syntheses of Aniline Substituted
Alanines 13a-f
SCHEME 5. Synthesis of Benzotriazole Amino Ester 4f
Burk’s rhodium complex of EtDuphos,10 all aryl enamides
12a-f produced amino esters 13a-f in high chemical yields
(90-95%) and excellent enantioselectivities (96.6-100% ee).
Treatment of aniline 13c with i-AmONO in the presence of
acetic acid and potassium acetate in toluene at room temperature
afforded indazole amino ester 2c in 65% yield (Scheme 3).1
During optimization of this reaction, it was found that KOAc
gave higher yields than NaOAc. Similarly, it was found that
toluene was preferred to other solvents such as chloroform and
dichloromethane. Presumably, the reaction proceeds via nu-
-
cleophilic attack of the -CH2 onto the diazonium ion. The
balance between the basicity of the base and the stability of the
diazonium salt was crucial for the reaction.
Acetylation of aniline 13d with acetyl chloride, followed by
removal of the benzyl protection group of 14 by hydrogenolysis,
gave o-hydroxy anilide 15 (Scheme 4). Treatment of 15 with
carbonyldiimidazole afforded oxazolidinone amino ester 3d in
83% yield (three steps from 13d, Scheme 4).11 Benzotriazole
amino ester 4f was synthesized in 85% yield (two steps from
13f) by reduction12 of the nitro group in 13f with iron and
treatment of the resulting aniline (16) with sodium nitrite in
acetic acid/water (Scheme 5).13
coordination power of the enol oxygen in 10c,d to the transition
metal, as well as the difficulties in accessing this class of
substrates by earlier methods.
In this note, we report the first room temperature Heck
reaction of aryl bromides 8 and enamides 9a,b to make aryl
enamides 10a,b, the first Heck reaction of 8 and enol esters
9c,d to make aryl enol esters 10c,d, and the subsequent
asymmetric hydrogenation to synthesize R-hydroxyl esters in
good-to-excellent enantioselectivities.
After much experimentation (vide supra), we found that the
Heck coupling of aryl bromide 8a with 9c afforded enol ester
The Heck reaction of 8a and 9a, under various Jeffery type
conditions (bases, R4NX, solvents, and temperatures) afforded
12a in <20% isolated yield with only 40-60% conversion
(Scheme 2). We were delighted to find that, under Fu and
Littke’s conditions9 [1.5% Pd(P-t-Bu3)2, 1.5% Pd(dba)2, 1.1
equiv Cy2NMe, dioxane, rt, 16 h], the same reaction produced
12a in 77% isolated yield with 100% conversion. To our
knowledge, this is the first room temperature Heck reaction of
aryl bromides 8 and enamides 9a,b. These reaction conditions
have been found to be quite general and have been successfully
applied to a number of other aryl bromides (Scheme 2). The
electronic nature of substituents on the aryl bromide did not
significantly affect this reaction. Electron-rich (8a and 8d),
electron-deficient (8c and 8f), and electron-neutral aryl bromides
(8b and 8e) all produced enamides 12 in good yields (77-93%)
using only 3-5% palladium. Upon hydrogenation, employing
(8) (a) Liu, Y. Sandoval, C. A. Yamaguchi, Y. Zhang, X. Wang, Z. Kato,
K. Ding, K. J. Am. Chem. Soc. 2006, 128, 14212–14213. (b) Burk, M. J. Kalberg,
C. S. Pizzano, A. J. Am. Chem. Soc. 1998, 120, 4345–4353(c) Reference 6.
(9) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989–7000.
(10) (a) Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372. (b) Burk, M. J.;
Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125–
10138. (c) For the mechanistic study of the asymmetric hydrogenation of
enamides employing Burk’s catalyst, see: Armstrong, S. K.; Brown, J. M.; Burk,
M. J. Tetrahedron Lett. 1993, 34, 879–882. (d) For our recent asymmetric
syntheses of tyrosine surrogates using Burk’s rhodium complex of EtDuphos,
see: Han, X.; Civiello, R. L.; Fang, H.; Wu, D.; Gao, Q.; Chaturvedula, P. V.;
Macor, J. E.; Dubowchik, G. M. J. Org. Chem. 2008, 73, 8502–8510.
(11) Davidson, J. P.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486–
13489.
(12) (a) Ramadas, K.; Srinivasan, N. Synth. Commun. 1992, 22, 3189–3195.
(b) Fe/NH4Cl was first reported by Shih to reduce aromatic nitro compounds,
see: Shih, Y.-T. Huaxue Xuebao 1956, 22, 352–355.
(13) (a) Loriga, M.; Paglietti, G.; Sparatore, F.; Pinna, G.; Sisini, A. Il
Farmaco 1992, 47, 439–448. (b) Schmidhammer, H.; Hohenlohe-Oehringen,
K. Sci. Pharm. 1983, 51, 8–16.
3994 J. Org. Chem. Vol. 74, No. 10, 2009

SCHEME 6. Asymmetric Syntheses of r-Hydroxyl Ester 18
which were degassed by bubbling N2 through them for 30 min prior
to use, were added. The resulting suspension was evacuated, filled
with N2 five times, and then stirred at rt for 16 h. The reaction
mixture was diluted with EtOAc (500 mL) and filtered through a
pad of Celite, washing with EtOAc (700 mL). The filtrate was
concentrated and the residue subjected to flash chromatography,
eluting with EtOAc/hexanes (1:5-1:2) containing 1% Et3N to afford
12a as an off-white solid (13.4 g, 77% yield). 1H NMR (500 MHz,
CDCl3) δ ppm 2.11 (s, 3 H), 3.67 (br s, 3H), 3.78 (br s, 3H), 4.06
(br s, 2H), 5.14 (br s, 2H), 6.93 (s, 1H), 6.98 (s, 1H), 7.26-7.40
(m, 5H). 13C NMR (126 MHz, CDCl3) δ ppm 17.2, 52.4, 55.4,
67.4, 109.4, 120.1, 121.4, 122.6, 126.9, 128.3, 128.3, 128.4, 128.6,
135.3, 136.4, 137.0, 146.3, 166.5. HRMS (M + H)+ calcd for
C20H23N2O5 371.1607, found 371.1613.
Representative Procedure for the Asymmetric Hydrogena-
tion of Enamides 12: Amino Ester 13a. To a flame-dried Parr
hydrogenation bottle were added 12a (8.09 g, 21.9 mmol), CH2Cl2
(50 mL), and MeOH (50 mL). The resulting solution was degassed
by bubbling N2 through it for 20 min. After [(R,R)-EtDu-
Phos(COD)]BF4 (0.30 g, 0.45 mmol) was added, the mixture was
immediately transferred to a Parr hydrogenation apparatus and
was agitated at rt under H2 (60 psi) for 16 h. The reaction mixture
was concentrated and the resulting residue subjected to flash
chromatography eluting with EtOAc/hexanes (1:2) to afford 13a
as an off-white solid (7.72 g, 95% yield, and 98.0% ee). The ee
was determined by HPLC analysis (Chiralcel OJ-H column, 4.6 ×
250 mm, 5 µm; 10% MeOH in CO2 at 2.0 mL/min for 15 min; λ
) 220 nm; T ) 35 °C; tR ) 9.15 min for the R- and 11.29 min for
17a in 69% yield using 5% Pd(P-t-Bu3)2 and Cy2NMe in dioxane
at 110 °C over 30 h (Scheme 6).9 As we found with the
enamides, introduction of electron-poor (8f) or electron-neutral
(8b) aryl bromides had very little effect on the reaction,
affording the corresponding enol esters 17f and 17b in good
yields (Scheme 6). Hydrogenation of freshly prepared 17a,b
and f using Burk’s conditions (5.6-8.4% of [(R,R)-Et-Du-
Phos(COD)]BF4, H2 (60 psi), CH2Cl2, rt, 16 h] afforded aryl
R-hydroxyl esters 18a,b and f in excellent chemical yields and
with high levels of enantioselectivity (84.2%, 95.2%, and 97.4%
ee, respectively). Dichloromethane alone gave better results than
a 1:1 mixture of methanol and dichloromethane. The hydroge-
nation of enol esters required a higher catalyst loading in
comparison with the corresponding enamides likely because of
their reduced chemical stability. The aryl aniline esters 18a,b
and f were conveniently converted to the heteroaromatic
R-hydroxyl esters 5-7, employing the same methods used in
the preparation of 2-4 from 13.
In conclusion, we report the first room temperature Heck
reaction of aryl bromides with CH2dC(NHP)CO2Me (P )
Boc or CBz) to form ArCHdC(NHP)CO2Me. The increased
commercial availability of aryl bromides, the more facile
preparation of aryl bromides in comparison with aryl iodides,
and the use of these milder Heck reaction conditions signi-
ficantly expands the range of enamides that can be prepared
by our method. By coupling this method with Burk’s well-
established asymmetric hydrogenation of enamides, we have
developed an efficient, mild, and practical route to unnatural
R-amino acids. We also report the first Heck reaction route
to the synthesis of ArCHdC(OCOAr1)CO2Me (Ar1 ) Ph,
4-Cl-Ph) from aryl bromides and CH2dC(OCOAr1)CO2-
Me. Their subsequent asymmetric hydrogenation afforded
novel R-hydroxyl esters in excellent chemical yields and
good-to-excellent enantioselectivities.
1
the S-enantiomer). H NMR (500 MHz, CDCl3) δ 2.11 (s, 3H),
2.99 (d, J ) 5.49 Hz, 2H), 3.68 (br s, 2H), 3.72 (s, 3H), 3.76 (s,
3H), 4.54-4.63 (m, 1H), 5.04-5.14 (m, 2H), 5.14-5.20 (m, 1H),
6.40 (s, 1H), 6.42 (s, 1H), 7.28-7.38 (m, 5H). 13C NMR (126 MHz,
CDCl3) δ ppm 17.3, 37.9, 52.3, 55.2, 55.7, 67.0, 109.1, 122.6, 123.6,
124.6, 128.2, 128.3, 128.6, 133.4, 136.4, 147.1, 155.8, 172.4. HRMS
(M + H)+ calcd for C20H25N2O5 373.1763, found 373.1768.
r-Amino Ester 2c. i-AmONO (0.40 mL, 2.95 mmol) was added
dropwise to a mixture of 13c (1.0 g, 2.66 mmol), KOAc (2.02 g,
20.6 mmol), HOAc (2.35 mL, 41.2 mmol), and toluene (25 mL).
The resulting suspension was stirred at rt for 16 h. Additional
toluene (75 mL) and i-AmONO (0.18 mL, 1.33 mmol) were added
to the resulting mixture. After stirring at rt for 20 h, H2O (100 mL)
and NaHCO3 (5.0 g) were added, and stirring was continued at rt
for 2 h. The mixture was partitioned between CH2Cl2 and H2O.
The organic layer was separated, washed with brine, dried over
Na2SO4, and filtered. The filtrate was concentrated and the resulting
residue subjected to flash chromatography, eluting with EtOAc/
hexanes (1:1) to afford 2c as an off-white solid (0.66 g, 64% yield).
1H NMR (500 MHz, CDCl3) δ ppm 1.42 (s, 9H), 3.20 (dd, J )
13.89, 5.65 Hz, 1H), 3.27-3.36 (m, 1H), 3.74 (s, 3 H), 4.66 (d, J
) 7.02 Hz, 1H), 5.28 (d, J ) 7.63 Hz, 1H), 7.40 (s, 1H), 7.68 (s,
1H), 8.06 (s, 1H), 10.67 (br s, 1H). 13C NMR (126 MHz, CDCl3)
δ ppm 28.4, 38.1, 52.5, 54.7, 80.3, 112.8 (q, J ) 34.2 Hz), 124.2
(q, J ) 272.6 Hz), 125.2, 125.4, 126.3, 128.8, 134.7, 135.0, 155.2,
172.2. HRMS (M + H)+ calcd for C17H21F3N3O4 388.1484, found
388.1479.
r-Amino Ester 3d. To a mixture of 13d (2.0 g, 4.83 mmol)
and pyridine (50 mL) at 50 °C was added AcCl (0.52 mL, 7.25
mmol), and the mixture was heated at 50 °C for 1 h. A second
portion of AcCl (0.52 mL) was added, and heating was continued
at 50 °C. After 20 min, a final portion of AcCl (0.52 mL) was
added, and heating was continued at 50 °C for 1.5 h. All volatiles
were removed in vacuo, and the resulting residue was partitioned
between EtOAc and 1:1 saturated NaHCO3/brine. The organic layer
was separated and the aqueous layer extracted with more EtOAc.
The combined organic layers were dried over Na2SO4, filtered, and
concentrated. The resulting solid was dissolved in 1:9 2 M
NH3-MeOH/CH2Cl2. All solvents were then removed and the solid
dried under vacuum.
Experimental Section
Representative Procedure for the Room Temperature Heck
Reaction of ArBr (8) and CH2d(NHP)CO2Me (P ) Boc or
CBZ) (9): Enamide 12a. A flame-dried 500 mL Schlenk flask was
charged with 8a (10.0 g, 46.7 mmol), 9a (12.1 g, 51.4 mmol), Pd-
(P-t-Bu3)2 (0.36 g, 0.70 mmol), and Pd(dba)2 (0.40 g, 0.70 mmol).
The flask was alternately evacuated and filled with N2 five times.
Dioxane (100 mL) and Cy2NMe (10.9 mL, 51.4 mmol), both of
J. Org. Chem. Vol. 74, No. 10, 2009 3995

To a flame-dried Parr hydrogenation bottle was added the above
crude solid in EtOH (120 mL). The resulting solution was degassed
by bubbling N2 through it for 20 min. Pearlman’s catalyst (0.88 g)
was added, and the mixture was agitated at rt under H2 (1.2 atm)
for 16 h. The reaction mixture was filtered through a pad of Celite
and the filtrate concentrated to give a solid, which was dried under
vacuum.
In a flame-dried round-bottom flask, the crude solid in THF (100
mL) and i-Pr2NEt (1.7 mL, 9.64 mmol) were cooled to 0 °C. CDI
(1.56 g, 9.64 mmol) was added, and the mixture was stirred at rt
for 16 h. After all volatiles were removed in vacuo, the residue
was subjected to flash chromatography eluting with EtOAc/hexanes
(2:3) to afford 3d (1.41 g, 4.01 mmol, 83% yield for three steps).
1H NMR (500 MHz, CDCl3) δ ppm 1.42 (s, 9H), 2.29 (s, 3H),
3.02 (dd, J ) 13.89, 5.65 Hz, 1H), 3.06-3.17 (m, 1H), 3.74
(s, 3H), 4.57 (d, J ) 7.32 Hz, 1H), 5.11 (d, J ) 7.93 Hz, 1H), 6.73
(s, 1 H), 6.82 (s, 1H), 9.70 (br s, 1H). 13C NMR (126 MHz, CDCl3)
δ ppm 16.2, 28.4, 38.4, 52.5, 54.8, 80.2, 108.4, 120.2, 126.4, 127.8,
130.7, 143.8, 155.3, 156.5, 172.6. HRMS (M + H)+ calcd for
C17H23N2O6 351.1556, found 351.1564.
Representative Procedure for the Heck Reaction of ArBr 8
and Enol Esters 9c,d to Form Enol Esters 17: Enol Ester 17f.
To a flame-dried three-neck flask equipped with a condenser were
added 8f (6.45 g, 28 mmol), 9d (7.4 g, 30.8 mmol), and Pd(P-t-
Bu3)2 (0.50 g, 0.98 mmol). After the system was purged with N2
five times, degassed dioxane (65 mL) and Cy2NMe (6.5 mL, 30.8
mmol) were added. Again, the system was purged with N2 three
times prior to heating the mixture at 110 °C for 24 h. The mixture
was partitioned between CH2Cl2 and saturated NaHCO3. The
organic layer was separated and the aqueous layer extracted with
additional CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated. The residue was subjected to
flash chromatography eluting with straight CH2Cl2 to afford 17f as
a light orange solid (8.3 g, 76% yield). 1H NMR (500 MHz, CDCl3)
δ ppm 2.17 (s, 3H), 3.84 (s, 3H), 6.37 (br s, 2H), 7.29 (s, 1H),
7.49 (s, 1H), 7.52 (d, J ) 8.55 Hz, 2H), 8.17 (d, J ) 8.55 Hz, 2H),
8.46 (s, 1H). 13C NMR (126 MHz, CDCl3) δ ppm 17.8, 52.8, 120.1,
125.6, 126.3, 126.8, 127.0, 129.3, 131.8, 132.1, 136.0, 137.3, 140.9,
144.2, 163.0, 163.5. HRMS (M + H)+ calcd for C18H16ClN2O6
391.0697, found 391.0704.
Amino Ester 4f. Immediately prior to use, both solvents (MeOH
and H2O) were degassed by bubbling N2 through them for 30 min.
A solution of 13f (4.82 g, 12.4 mmol) in MeOH (90 mL) was added
to a mixture of NH4Cl (6.67 g, 124 mmol) and Fe powder (4.17 g,
74.7 mmol) in H2O/MeOH (70 mL/50 mL). The mixture was heated
at 85 °C for 1 h, and then, while still hot, it was filtered through a
pad of Celite, rinsing the filter cake thoroughly with MeOH. The
filtrate was concentrated and dried under high vacuum to afford an
off-white solid.
Representative Procedure for the Asymmetric Hydrogena-
tion of Enol Esters 17 to Form r-Hydroxyl Esters 18: r-Hy-
droxyl Ester 18f. The title compound 18f (3.67 g, 92% yield, and
97.4% ee) was prepared from 17f (4.0 g, 10.2 mmol) according to
the procedure described for the preparation of 13a. The ee was
determined by HPLC analysis (Chiralcel OD-H column, 4.6 × 250
mm, 5 µm; 15% MeOH in CO2 at 2.0 mL/min for 12 min; λ )
220 nm; T ) 35 °C; tR ) 7.51 min for the S- and 8.39 min for the
1
R-enantiomer). H NMR (500 MHz, CDCl3) δ ppm 2.21 (s, 3H),
To a suspension of the crude solid in HOAc/H2O (97 mL/150
mL) was added a solution of NaNO2 (0.86 g, 12.4 mmol) in H2O
(15 mL) at rt. The reaction mixture was stirred at rt for 35 min and
then concentrated in vacuo. The resulting residue was partitioned
between EtOAc and 1:1 saturated NaHCO3/H2O. The organic layer
was separated, and the aqueous layer was extracted with additional
EtOAc. The combined organic layers were dried over Na2SO4,
filtered, and concentrated. The residue was subjected to flash
chromatography eluting with EtOAc/hexanes (2:3) to afford 4f as
3.12-3.24 (m, 2H), 3.76 (s, 3H), 5.39 (dd, J ) 7.63, 4.88 Hz,
1H), 6.11 (br s, 2H), 7.21 (s, 1H), 7.42 (d, J ) 8.55 Hz, 2H), 7.97
(d, J ) 8.55 Hz, 2H), 8.00 (s, 1H). 13C NMR (126 MHz, CDCl3)
δ ppm 17.7, 36.4, 52.7, 73.3, 123.4, 124.9, 125.8, 127.7, 129.0,
131.3, 132.1, 137.4, 140.2, 142.6, 165.0, 169.7. HRMS (M + H)+
calcd for C18H18ClN2O6 393.0853, found 393.0856.
Acknowledgment. We thank Mr. Edward S. Kozlowski for
performing the ee determinations.
1
a light tan solid (4.03 g, 85% yield for two steps). H NMR (500
Supporting Information Available: 1H and 13C NMR
spectra of all new compounds and HPLC traces for all ee
determinations. This material is available free of charge via the
Internet at http://pubs.acs.org.
MHz, CDCl3) δ ppm 2.66 (s, 3H), 3.10-3.23 (m, 1H), 3.24-3.36
(m, 1H), 3.74 (s, 3H), 4.66-4.82 (m, 1H), 4.96-5.19 (m, 2H),
5.37 (d, J ) 7.63 Hz, 1H), 6.94 (s, 1H), 7.28-7.39 (m, 6H). 13C
NMR (126 MHz, DMSO-d6) δ ppm 16.7, 36.5, 51.8, 55.5, 65.3,
127.3, 127.6, 128.2, 136.8, 155.9, 172.1. HRMS (M + H)+ calcd
for C19H21N4O4 369.1563, found 369.1570.
JO900368K
3996 J. Org. Chem. Vol. 74, No. 10, 2009