Preparation of (S)-3-carbethoxy-3-benzypiperidine and the growth hormone secretagogue L-163,540

Full text of DOI:10.1021/jo980990v

9548
J . Org. Chem. 1998, 63, 9548-9551
Sch em e 1
P r ep a r a tion of
(S)-3-Ca r beth oxy-3-ben zylp ip er id in e a n d
th e Gr ow th Hor m on e Secr eta gogu e
L-163,540
Peter E. Maligres,* Michel M. Chartrain,†
Veena Upadhyay, Deborah Cohen,† Robert A. Reamer,
David Askin, R. P. Volante, and Paul J . Reider
Department of Process Research and Department of
Bioprocess Research, Merck Research Laboratories,
Merck & Co. Inc., P.O. Box 2000,
Rahway, New J ersey 07065
Received May 26, 1998
Human growth hormone (GH) is valuable for the
treatment of GH-deficient children and has potential uses
in burn victims, hip fracture cases, and the improvement
of the quality of life in the frail elderly. The relatively
high expense of natural GH has spurred the search for
less complex molecules which could act as orally effica-
cious peptidomimetic GH secretagogues.1 These agents
act by inducing the endogenous release of GH and include
MK-677.2 Recently, L-163,540 has been introduced as a
potential new GH secretagogue candidate.3
Sch em e 2
The preparation of L-163,540 requires the optically
active piperidine 1 (Scheme 1). Initially, 1 was prepared
by selective C-benzylation of ethyl nipecotate with benzyl
chloride4 followed by resolution of the racemate.5 How-
ever, an asymmetric synthesis of 1 was desired. It was
envisaged (Scheme 2) that a precursor to 1 could be chiral
disubstituted malonic acid monoester 4 or 6 potentially
available from enzymatic hydrolysis of the desired enan-
tiotopic ester of the corresponding prochiral diesters 3
or 5. Diester 5 was prepared (Scheme 3) from diethyl
benzylmalonate by Michael reaction with acrylonitrile in
the presence of catalytic NaOEt in tert-butyl methyl ether
(MTBE) to give nitrile 3 in nearly quantitative yield.
Enzymatic hydrolysis of 3 gave only low yields of 4 with
Sch em e 3
low enantioselectivity. Catalytic hydrogenation of 3 with
Pearlman’s catalyst in the presence of HCl followed by
protection of the resulting amine with Boc2O and DIEA
gave the Boc derivative 5 in 62% yield after crystalliza-
tion. Enzymatic hydrolysis of 5 (Scheme 4) with porcine
liver esterase (PLE) gave the optically active mono acid
6 in 99% ee and 86% yield. Boc removal with TFA
followed by cyclization with DCC and HOBT gave the
piperidone 7 in 70% yield.
Chemoselective reduction of the lactam 7 was neces-
sary to provide 1. Attempts to selectively reduce the
lactam in the presence of the ester with LiBH4 or DIBAL
gave no reaction, while BH3‚Me2S gave overreduction.
Thionation of 7 (Scheme 5) with Lawesson’s reagent
followed by treatment of the thiolactam 8 with Raney
nickel gave mixtures of 1 and imine 9. Further reduction
of the crude mixture with NaBH4 gave 1 in 30% yield
and 99% ee. In an improved protocol, 7 was activated
as its Boc derivative 10 in 90% yield and reduced with
lithium triethylborohydride to a diastereomeric mixture
of the N-Boc aminals 11. Further reduction with tri-
ethylsilane and BF3‚OEt2 followed by acidic workup gave
1 in 85% overall yield from 10 and 99% ee.
† Department of Bioprocess Research, Merck Research Laboratories,
Merck & Co. Inc.; P.O. Box 2000; Rahway, NJ 07065.
(1) (a) Aloi, J . A.; Gertz, B. J .; Hartman, M. L.; Huhn, W. C.; Pezzoli,
S. S.; Wittreich, J . M.; Krupa, D. A.; Thorner, M. O. J . Clin. Endocrinol.
Metab. 1993, 79, 943-949. (b) Gertz, B. J .; Sciberas, D. G.; Yogendran,
L.; Christie, K.; Bador, K.; Wittreich, J . M.; Krupa, D. A.; J ames, I. J .
Clin. Endocrinol. Metab. 1993, 79, 745-749. (c) Gertz, B. J .; Barrett,
J . S.; Eisenhandler, R.; Krupa, D. A.; Wittreich, J . M.; Seibold, J . R.;
Schneider, S. H. J . Clin. Endocrinol. Metab. 1993, 78, 1393-1397. (d)
Smith, R. G.; Cheng, K.; Schoen, W. R.; Pong, S.-S.; Hickey, G.; J acks,
T.; Butler, B.; Chan, W. W-S.; Chaung, L.-Y. P.; J udith, F.; Taylor,
J .; Wyvratt, M. J .; Fisher, M. H. Science 1993, 260, 1640-1643.
(2) Patchett, A. A.; Nargund, R. P.; Tata, J . R.; Chen, M.-H.; Barakat,
K. J .; J ohnston, D. B. R.; Cheng, K.; Chan, W. W.-S.; Butler, B.; Hickey,
G.; J acks, T.; Schleim, K.; Pong, S. S.; Chuang, L.-Y. P.; Chen, H. Y.;
Frazier, E.; Leung, K. H.; Chiu, S.-H. L.; Smith, R. G. Proc. Natl. Acad.
Sci. U.S.A. 1995, 92, 7001-7005.
(3) Yang, L.; Morriello, G.; Patchett, A. A.; Leung, K.; J acks, T.;
Cheng, K.; Schleim, K. D.; Feeney, W.; Chan, W. W.-S.; Chiu, S.-H.
L.; Smith, R. G. J . Med. Chem. 1998, 41, 2439-2441.
(4) Unpublished results, Brands, J .; Maligres, P. E.; Upadhyay, V.,
Department of Process Research, Merck Research Laboratories, Merck
& Co. Inc., P.O. Box 2000, Rahway, NJ 07065. Ethyl nipecotate 1 can
be directly alkylated with BnCl in the presence of KHMDS in THF
without nitrogen protection/deprotection. Thus, direct benzylation of
1 in toluene at e -25 °C (1.3 equiv of KHMDS in THF, 1.05 equiv of
BnCl) gave racemic 2 in 81% HPLC assay yield as a solution in toluene
after extractive workup.
Installation of the dipeptide side chain on 1 provided
L-163,540 (Scheme 1). Both peptide couplings were
readily effected with DCC and HOBT and were followed
by deprotection with HCl to provide 2 and L-163,540 as
(5) Racemic 1 could be resolved as its tartaric acid salt by crystal-
lization from 3:1 acetone/water (37% yield, 99% ee).
10.1021/jo980990v CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/17/1998

Notes
J . Org. Chem., Vol. 63, No. 25, 1998 9549
Sch em e 4
g, 1.10 mol), and methyl tert-butyl ether (MTBE) (100 mL) in a
500 mL flask equipped with a coldfinger condenser filled with
dry ice/acetone. Within 5-10 min an exotherm set in and the
mixture began to reflux (10-15 min). The mixture was aged at
40 °C for 1 h, diluted 9:1 v/v MTBE-hexane (100 mL), and
filtered through a pad of silica (15 g), washing the pad with 9:1
v/v MTBE-hexane (100 mL). The filtrate was evaporated to
give malonate 3 (300.3 g, 99%) as a colorless oil. 3: HPLC
retention time ) 19.7 min; Rf ) 0.55 (1:1 hexane-MTBE); 1H
NMR (250.1 MHz, CDCl3) δ 7.26 (m, 3 H), 7.07 (m, 2 H), 4.23
(q, J ) 7.1, 4 H), 3.26 (s, 2 H), 2.44 (t, J ) 8.3, 2 H), 2.10 (t, J
) 8.3, 2 H), 1.27 (t, J ) 7.1, 6 H); 13C NMR (62.9 MHz, CDCl3)
δ 170.5, 135.4, 130.3, 129.0, 127.9, 119.6, 62.3, 58.1, 40.0, 29.2,
Sch em e 5
14.4, 13.6; FTIR (thin film) νmax 2983, 1730, 1200, 1185 cm-1
;
HRMS (EI) m/z calcd for C17H21NO4 (M+) 303.1471, found
303.1492.
Dieth yl Ben zyl(3-N-Boc-a m in op r op yl)m a lon a te (5). The
crude malonate 3 from above (300.3 g, 0.99 mol) was dissolved
in a mixture of EtOH (1750 mL) and 5 M aqueous HCl (250 mL,
1.25 mol). Pearlman’s catalyst containing 20% palladium
hydroxide (40 g) was added, and the mixture was hydrogenated
in a 1 gallon Hastalloy vessel on a Parr shaker at 50 °C under
40 psi H2 for 22 h. The slurry was filtered through a pad of
solkafloc (100 g), and the pad was washed with EtOH (2.0 L).
The filtrates were evaporated (25 in. Hg, bath at 100 °C), and
the oily residue was dissolved in water (3.5 L). The aqueous
solution was washed with 2:1 v/v hexane-MTBE (1.0 L), and
the organic phase was extracted with water (500 mL). The
combined aqueous phases were extracted with CH2Cl2 (3 × 500
mL). The organic extracts were dried over Na2SO4 and evapo-
rated (100 °C at 10 Torr) to an oily residue which crystallized
upon cooling to afford crude diethyl benzyl(3-aminopropyl)-
malonate HCl salt (240.0 g, 70%): HPLC retention time ) 5.2
crystalline HCl salts. The well-known problem of the
slow separation of the DCU byproduct from the reaction
mixture was remedied by an oxalic acid quench which
rapidly and quantitatively converts all remaining DCC
to DCU with the formation of CO2 and CO under mild
conditions.6 L-163,540 was isolated in 23% overall yield
from benzyl diethylmalonate as a crystalline HCl salt
monohydrate with >99.4% purity by HPLC analysis. In
summary, we have demonstrated the synthesis of chiral
quaternary piperidine 1 via enantioselective hydrolysis
of a prochiral diester derived from malonate.
min; FTIR (thin film) νmax 2980, 2930, 1729, 1221, 1137 cm-1
;
HRMS (EI) m/z calcd for C17H25NO4 (M+) 307.1784, found
307.1775. To a solution of the crude HCl salt (100.0 g, 0.291
mol) in CH2Cl2 (600 mL) cooled to 10 °C was added Et3N (6.6
mL, 4.8 g, 0.047 mol) followed by a solution of Boc2O (65.5 g,
0.30 mol) and Et3N (38 mL, 27.6 g, 0.27 mol) in CH2Cl2 (20 mL)
added over 15 min. The temperature rose to 30 °C and was
accompanied by gas evolution (CO2). The mixture was aged for
2 h at 25 °C and was evaporated to a semisolid/oil. The residue
was diluted with MTBE (600 mL) and hexane (200 mL) and
washed with saturated aqueous NaH2PO4 (200 mL), 20% aque-
ous NaH2PO4 (300 mL), water (500 mL), and saturated aqueous
NaCl (200 mL). The organic phase was dried over MgSO4 and
filtered through a pad of silica (40 g), washing with 2:1 MTBE-
hexane (200 mL). The filtrates were concentrated to an oil and
redissolved in hexane (200 mL). Once crystallization had begun,
hexane (600 mL) was added over 1 h. The mixture was
gradually cooled to -20 °C over 26 h and filtered cold (-20 °C)
to give Boc carbamate 5 (105.0 g, 89%) as a white crystalline
solid. 5: HPLC retention time ) 23.0 min; Rf ) 0.20 (4:1
hexane-MTBE); mp ) 53-55 °C; 1H NMR (250.1 MHz, CDCl3)
δ 7.23 (m, 3 H), 7.05 (m, 2 H), 4.57 (br t, J ) 6, 1 H), 4.17 (q, J
) 7.0, 4 H), 3.22 (s, 2 H), 3.09 (q, J ) 6.1, 2 H), 1.76 (m, 2 H),
Exp er im en ta l Section
Gen er a l. Reagents were used as received unless otherwise
stated; 3 Å molecular sieves were used to dry solvents for
anhydrous reactions. Unless otherwise noted, all manipulations
were carried out under an inert atmosphere of nitrogen gas.
High-pressure liquid chromatography (HPLC) was performed
using a B-03-5 YMC Basic (S-5 micron) 250 × 4.6 mm column
with isocratic elution over 10 min (42/58 MeCN/0.025% H3PO4),
then gradient elution over 5 min (42/58 f 62/38 MeCN/0.025%
H3PO4), and then isocratic elution over 15 min (62/38 MeCN/
0.025% H3PO4, 1.0 mL/min flow at 25 °C with detection at 220
nm). Analytical TLC and flash column chromatography was
performed using silica gel (Merck). Elemental analyses were
obtained from Quantitative Technologies Inc, Whitehouse, NJ .
Dieth yl Ben zyl(2-cya n oeth yl)m a lon a te (3). A solution of
21% NaOEt in EtOH (3 mL) was added to a solution of diethyl
benzylmalonate (250.3 g, 1.00 mol), acrylonitrile (72.4 mL, 58.4
(6) Despite the insolubility of DCU in common reaction solvents,
small quantities of this urea tend to come out of solution even after
repeated filtrations. This problem is presumably due to the slow
hydrolysis of the remaining DCC in the reaction product solution. Since
carbodiimides are far more easily hydrolyzed in acidic media, addition
of an acid to the reaction mixture prior to filtration would eliminate
any remaining DCC. In the case of acid-stable peptides, the addition
of aqueous HCl at the end of the reaction rapidly hydrolyzed the DCC,
but a milder quench would be required for more sensitive peptides. A
simple carboxylic acid could rapidly react with DCC but can introduce
new byproducts. Oxalic acid was found to circumvent this problem by
rapidly reacting with DCC to give DCU and the gaseous byproducts
CO2 and CO. Furthermore, oxalic acid reacts with DCC under a wide
range of pH values.
1.50 (overlapped m, 2 H), 1.43 (s, 9 H), 1.23 (t, J ) 7.0, 6 H); 13
C
NMR (62.9 MHz, CDCl3) δ 171.1, 155.8, 136.0, 129.8, 128.3,
127.0, 79.1, 61.3, 58.5, 40.5, 38.1, 29.1, 28.4, 24.8, 14.0; FTIR
(thin film) νmax 3401, 2983, 1712, 1502 cm-1. Anal. Calcd for
C22H33NO6: C, 64.84; H, 8.16; N, 3.44; O, 23.56. Found: C,
65.17; H, 8.18; N, 3.37; O, 23.44.
(S)-2-Ca r b et h oxy-2-b en zyl-2-(N-Boc-a m in o)p en t a n oic
Acid (6). A 14 L bioreactor (New Brunswick Scientific, Edison,
NJ ) was charged with 10 mM phosphate buffer (pH 7.0, 10 L),
diester 5 (10.0 g, 24.5 mmol), and porcine liver esterase (20 000

9550 J . Org. Chem., Vol. 63, No. 25, 1998
Notes
units, Sigma, St. Louis, MO). The mixture was agitated (220
rpm) at 37 °C. After 7 h a second portion of porcine liver esterase
(20 000 units) was added, and after 27 h HPLC analysis
indicated completion of reaction. Quantitative HPLC analysis
indicated 8.30 g of monoacid 6 present in the mixture, and HPLC
analysis of the (R)-(+)-1-(naphthyl)ethylamide derivative (vide
infra) of 6 indicated >99.5% ee. The mixture was extracted with
EtOAc (2 × 5 L), and the organic extracts were concentrated to
on oil. The crude residue was dissolved in EtOAc (10 mL) and
treated with MgSO4 (0.4 g) and Darco G60 carbon (0.1 g) for 15
min at 25 °C. The mixture was filtered through a pad of silica
(3 g), washing with EtOAc (40 mL). The filtrates were evapo-
rated to give 6 (9.6 g) as a pale yellow gum. Quantitative HPLC
analysis indicated that this matarial contained 8.00 g (86%) of
6. A 2.00 g portion of the crude gum was dissolved in toluene
(4 mL) at 60 °C. Crystallization was completed by the slow
addition of hexane (20 mL) over 2 h at 20 °C. The slurry was
filtered to provide 6‚0.5 toluene (1.27 g, 58%) as a white
crystalline solid. Prolonged drying under vacuum removed the
remaining toluene from a 100 mg sample. HPLC analysis of
the (R)-(+)-1-(naphthyl)ethylamide derivative of 6 indicated
>99.5% ee. Sample preparation for (R)-(+)-1-(naphthyl)ethyl-
amide derivatization: a mixture of 0.5 mg of monoacid 6, 0.5
mg of (R)-(+)-1-(naphthyl)ethylamine, 0.5 mg of EDC‚HCl, 0.5
mg of HOBT, and 0.1 mL of MeCN was heated at 55 °C (4-5
min) and made up to 1 mL with 1:1 MeCN and H2O. HPLC
retention times: (R)-(+)-1-(naphthyl)ethylamide derivative of
(S)-6 ) 25.6 min, (R)-(+)-1-(naphthyl)ethylamide derivative of
(R)-6 ) 26.2 min. 6: HPLC retention time ) 16.7 min; Rf )
0.30 (1:1 hexane-MTBE); mp ) 110-112 °C. 13C NMR indi-
cated 6 to be a ca. 3:2 mixture of carbamate rotamers, major
rotamer: 1H NMR (250.1 MHz, CDCl3) δ 7.26 (m, 3 H), 7.10 (m,
2 H), 4.62 (br t, 1H), 4.23 (m, 2 H), 3.34 (d, J ) 13.9, 1 H), 3.16
(d, J ) 13.9, 1 H), 3.10 (m, 2 H), 2.90 (m, 2 H), 1.50 (overlapped
m, 2 H), 1.44 (s, 9 H), 1.24 (br t, J ) 7.4, 3 H); 13C NMR (62.9
MHz, CDCl3) δ 174.6, 172.4, 156.1, 135.8, 129.7, 128.4, 127.1,
79.4, 61.9, 58.6, 41.5, 40.4, 30.5, 28.4, 25.1, 14.0; FTIR (thin film)
νmax 2979, 1706, 1510, 1250 cm-1. Anal. Calcd for C20H29NO6:
C, 63.31; H, 7.70; N, 3.69; O, 25.30. Found: C, 63.53; H, 7.77;
N, 3.58; O, 24.94.
was stirred for 2 h and was found to be complete by HPLC
analysis. The volatiles were evaporated, and the crude HCl salt
was redissolved in 50 mL of CH2Cl2. DIEA (5.05 mL, 28.99
mmol) and 2-chloro-1-methylpyridinium iodide (5.05 g, 19.77
mmol) were added, and the mixture was aged for 30 min. EtOAc
(150 mL) and water (50 mL) were added to the mixture. The
aqueous phase was separated, and the organic phase was
washed with 0.4 N HCl (75 mL), saturated NaHCO3 (50 mL),
and 10% brine (50 mL) and dried over Na2SO4. The mixture
was concentrated, and the residue was purified by chromatog-
raphy (silica, gradient elution, 10% MTBE in hexane then
MTBE) to give lactam 7 (2.76 g, 80%). Chiral SFC indicated 7
to be in >99.5% ee.
(S)-3-Ca r beth oxy-3-ben zyl-p ip er id in e (1) via Th iola c-
ta m 8. A mixture of piperidone 7 (349 mg, 1.34 mmol),
Lawesson’s reagent (594 mg, 1.47 mmol), and toluene (1.5 mL)
was heated to 110 °C for 2 h. The mixture was cooled to 25 °C,
aged for 15 min, and filtered through a cotton plug, washing
with toluene (3.5 mL). The filtrate was evaporated, and the
residue containing thiolactam 8 was dissolved in THF (2 mL)
and EtOH (2 mL). A 50% aqueous slurry of Raney nickel (1
mL) was added.7 After a 5 min age, another portion of the Raney
nickel (1 mL) was added followed by NaBH4 (25 mg). After 15
min the mixture was filtered through a pad of solkafloc, washing
the pad with THF (5 mL) and EtOH (5 mL). The filtrates were
evaporated to 4 mL and diluted with MTBE (20 mL). The
mixture was extracted with 0.5 M aqueous HCl (2 × 3 mL), and
the aqueous extract was basified with 5 M aqueous NaOH (0.7
mL). The aqueous mixture was extracted with CH2Cl2 (2 × 3
mL). The organic extracts were dried over Na2SO4 and evapo-
rated to give piperidine 1 (100 mg, 30%) as a colorless oil. HPLC
analysis of the Marfey’s derivative of 1 indicated >99.5% ee.
Sample preparation for Marfey’s derivatization: a mixture of
0.5 mg of piperidine 1, 0.5 mg of Marfey’s reagent {N-(2,4-
dinitro-5-fluorophenyl)-L-alaninamide}, 50 µL of 6 M NaHCO3,
and 0.5 mL of acetone was heated at 55 °C (4-5 min) and made
up to 1 mL with 1:1 MeCN-H2O. HPLC retention times:
Marfey’s derivatized (S)-1 ) 19.5 min, Marfey’s derivatized (R)-1
) 19.9 min. 1: HPLC retention time ) 4.0 min; Rf ) 0.20 (9:1
1
MTBE-MeOH); H NMR (250.1 MHz, CDCl3) δ 7.23 (m, 3 H),
7.05 (m, 2 H), 4.11 (m, 2 H), 3.36 (dd, J ) 13.0, 2.3, 1 H), 2.95
(m, 1 H), 2.80 (d, J ) 13.4, 1 H), 2.75 (d, J ) 13.4, 1 H), 2.58 (m,
1 H), 2.54 (d, J ) 13.0, 1 H), 2.19 (m, 1 H), 2.10 (br s, 1 H), 1.59
(m, 1 H), 1.51-1.35 (overlapping m, 2 H), 1.19 (t, J ) 6.9, 3 H);
13C NMR (62.9 MHz, CDCl3) δ 175.1, 136.5, 129.6, 127.8, 126.4,
60.2, 53.1, 47.8, 46.1, 44.3, 32.8, 24.3, 13.9; FTIR (thin film) νmax
(S)-3-Ca r beth oxy-3-ben zyl-2-p ip er id on e (7). Meth od A.
A solution of Boc carbamate 6 (759 mg, 2.0 mmol) and TFA (764
mg, 6.70 mmol) in CH2Cl2 (3 g) was aged at 40 °C for 1.5 h. The
mixture was evaporated, and the residue containing the crude
amine (HPLC retention time ) 3.5 min) was dissolved in CH2Cl2
(3 g). DIEA (491 mg, 3.80 mmol), HOBT (41 mg, 0.30 mmol),
DCC (516 mg, 2.5 mmol), and DMAP (12 mg, 0.10 mmol) were
added sequentially, and the mixture was aged for 20 h at 25 °C.
Oxalic acid dihydrate (250 mg) and MTBE (5 mL) were added,
and the mixture was aged for 1 h. The mixture was filtered
from the DCU, and the filter cake was washed with a mixture
of CH2Cl2 (2 mL) and MTBE (15 mL). The filtrate was washed
with saturated aqueous NaH2PO4 (2 × 10 mL), water (10 mL),
saturated aqueous NaHCO3 (10 mL), water (10 mL), and
saturated aqueous NaCl (10 mL). The organic phase was dried
over MgSO4 and evaporated. The residue was purified by
chromatography (silica, gradient elution, 10% MTBE in hexane
then MTBE) to provide piperidone 7 (366 mg, 70%) as a white
crystalline solid. Chiral supercritical phase chromatography
(SFC) indicated 7 to be in >99.5% ee. SFC conditions: Sumi-
chiral AG OA3200 250 × 4.6 mm column, isocratic elution, 16%
MeOH in supercritical CO2 at 300 bar, 2.0 mL/min flow at 35
°C with detection at 210 nm. SFC retention times: (R)-7 ) 2.35
min, (S)-7 ) 2.87 min. 7: HPLC retention time ) 7.35 min; Rf
) 0.38 (MTBE); 1H NMR (250.1 MHz, CDCl3) δ 7.24 (br s, 5 H),
6.10 (br s, 1 H), 4.24 (m, 2 H), 3.60 (d, J ) 13.5, 1 H), 3.22 (m,
1 H), 3.06 (d, J ) 13.5, 1 H), 2.98 (m, 1 H), 2.10 (m, 1 H), 1.79
(m, 2 H), 1.55 (m, 1 H), 1.29 (t, J ) 7.2, 3 H); 13C NMR (62.9
MHz, CDCl3) δ 172.8, 170.5, 136.6, 130.6, 128.1, 126.6, 61.5, 54.8,
42.0, 40.5, 28.9, 19.5, 14.0; FTIR (thin film) νmax 2939, 1732,
2938, 1723, 1454, 1222 cm-1; HRMS (EI) m/z calcd for C15H21
-
NO2 (M+) 247.1572, found 247.1582.
(S)-3-Ca r beth oxy-3-ben zyl-N-Boc-2-p ip er id on e (10). To
a solution of lactam 7 (2.30 g, 8.80 mmol) in toluene (25 mL)
was added DMAP (1.61 g, 13.2 mmol) followed by Boc2O (2.31
g, 10.56 mmol). The resulting mixture was heated to 60 °C for
1 h, diluted with toluene (50 mL), and washed with saturated
NaH2PO4 (2 × 50 mL) and brine (50 mL). The mixture was dried
over Na2SO4 and concentrated; the residue was purified by flash
chromatography (silica, 3:1 hexane-MTBE), affording 10 (2.96
g, 93%, >95 A% purity by HPLC analysis). 3: HPLC retention
time ) 21.5 min; Rf ) 0.23 (4:1 hexane-MTBE); 1H NMR (250.1
MHz, CDCl3) δ 7.3-7.1 (overlapping m, 5 H), 4.21 (m, 2 H), 3.55,
(m, 1 H), 3.48 (d, J ) 13.6, 1 H), 3.30 (m, 1 H), 3.16 (d, J ) 13.6,
1 H), 2.16 (m, 1 H), 1.9-1.6 (overlapping m, 3 H), 1.54 (s, 9 H),
1.27 (t, J ) 7.1, 3 H); 13C NMR (62.9 MHz, CDCl3) δ 172.0, 170.3,
152.8, 136.1, 130.7, 128.1, 126.9, 82.9, 61.7, 57.7, 45.6, 41.6, 29.0,
28.0, 20.0, 14.0; FTIR (thin film) νmax 3030, 2987, 1740, 1453,
1385 cm-1. Anal. Calcd for C20H27NO5: C, 66.46; H, 7.53; N,
3.88. Found: C, 66.81; H, 7.61; N, 3.60.
(S )-3-Ca r b e t h oxy-3-b e n zyl-2-h yd r oxy-N -Boc-p ip e r i-
d in e (11). A solution 1.0 M Superhydride (4.1 mL, 4.05 mmol)
(7) In a similar experiment the mixture was filtered at this stage.
Evaporation followed by extractive workup provided a ca. 1:1 mixture
of piperidine 1 and cyclic imine 9. The mixture was subjected to
preparative TLC (silica, EtOAc) to provide 1 and 9. 9: 1H NMR (250.1
MHz, CDCl3) δ 7.89 (s, 1 H), 7.27 (m, 3 H), 7.13 (m, 2 H), 4.15 (q, J )
7.1, 2 H), 3.65 (m, 1 H), 3.40 (m, 1 H), 3.02 (q, J ) 13.4, 2 H), 2.13 (m,
1 H), 1.55 (m, 3 H), 1.23 (t, J ) 7.1, 3 H); 13C NMR (62.9 MHz, CDCl3)
δ 172.6, 162.2, 135.8, 129.9, 128.3, 127.0, 61.2, 49.7, 49.4, 43.4, 27.2,
19.6, 14.1.
1668, 1515, 1236, 1155 cm-1
. Anal. Calcd for C15H19NO3: C,
68.94; H, 7.33; N, 5.36; O, 18.37. Found: C, 69.15; H, 7.39; N,
5.28; O, 18.67.
(S)-3-Ca r beth oxy-3-ben zyl-2-p ip er id on e (7). Meth od B.
HCl gas was passed into a solution of carboxylic acid monoester
6 (5.0 g, 13.2 mmol) in CH2Cl2 (50 mL) in a 250 mL flask was
cooled to 0 °C until 50 mmol was absorbed. The reaction mixture

Notes
J . Org. Chem., Vol. 63, No. 25, 1998 9551
was added over 30 min to a solution of 10 (1.22 g, 3.37 mmol) in
THF (5 mL) cooled to -10.0 °C. After 2 h at 0 °C the reaction
mixture was quenched with water (15 mL) and extracted with
EtOAc (40 mL). The organic phase was evaporated, and the
residue was purified by flash chromatography (silica, 1:1 MTBE-
hexane) to afford 11 (1.10 g, 90%). 11: HPLC retention time )
20.0 min. 13C NMR indicated 11 to be a ca. 3:2 mixture of
isomers: 13C NMR (62.9 MHz, CDCl3) δ 173.1, 171.4, 154.9,
136.8, 136.7, 129.9, 129.8, 128.3, 128.1, 126.8, 126.7, 80.8, 80.2,
60.7, 60.4, 52.8, 51.8, 43.2, 38.0, 28.5, 28.4, 26.8, 22.3, 21.2, 20.1,
14.3, 14.1, 14.0; FTIR (thin film) νmax 3360, 2976, 1700, 1158
175.3, 169.1, 138.2, 137.5, 131.1, 129.2, 128.4, 127.9, 125.7, 123.0,
120.5, 119.0, 112.8, 108.0, 61.8, 51.6, 49.4, 49.3, 47.0, 42.8, 32.2,
29.0, 22.9, 14.3; FTIR (thin film) νmax 3400, 3227, 2932, 1715,
1644, 1458 cm-1; HRMS (EI) m/z calcd for C26H31N3O3 (M+)
433.2365, found 433.2341.
L-163,540‚HCl‚H2O. A solution of DCC (1.61 kg, 7.80 mol)
in EtOAc (1.61 kg) was added to a mixture of 2 (3.33 kg, 7.09
mol), HOBt (1.11 kg, 7.26 mol), and N-Boc-Me alanine (1.48 kg,
7.26 mol), DIEA (962 g, 7.442 mol) was added to a mixture of
HCl salt (3.33 kg, 7.088 mol) and EtOAc (21.3 kg) over 30 min,
and the mixture was aged for 1 h at 26 °C. Oxalic acid (134 g,
1.06 mol) was added to quench any remaining DCC. The
mixture was heated to 50 °C for 1 h and then cooled over 1 h to
-5 °C and stirred for 20 min. The slurry was filtered, and the
DCU cake was washed with EtOAc (4 × 4 L). The combined
filtrates were washed with 7% NaHSO4 (14 L), 10% brine (10
L), 6% aqueous NaHCO3 (2 × 14 L), and 20% brine (14 L).
L-163,540 N-Boc derivative: HRMS (EI) m/z 618.3417, found
618.3429. The organic phase containing N-Boc-protected
L-163,540 (HPLC retention time ) 20.4 min; Rf ) 0.50 (MTBE);
FTIR (thin film) νmax 3318, 2980, 2934, 1716, 1632, 1496, 1456
cm-1) was concentrated to ca. 9 L. A solution of HCl (2.44 kg,
66.9 mol) in EtOH (7.3 kg) was added, and the mixture was aged
at 25 °C for 2 h. The mixture was concentrated, and the residue
was dissolved in EtOAc (20 L). The mixture was extracted with
water (2 × 14 L). The combined aqueous extracts were basified
(pH ) 10.5) with 5 M NaOH (2.2 L) and extracted with EtOAc
(2 × 14 L). The organic extracts were concentrated to ca. 9 L
and diluted with EtOH (3.6 L). The solution containing L-163,540
free base (3.30, 6.34 mol by quantitative HPLC assay) was cooled
to 5 °C, and 6.0 M HCl (1.04 L, 6.34 mol) was added over 5 h.
The mixture was aged at 20 °C for 16 h. The slurry was filtered,
and the filter cake washed with EtOAc containing 15% EtOH
and 1% H2O by wt (2 × 8 kg) to provide L-163,540‚HCl‚H2O
(3.01 kg, 83%, >99.4 A% purity by HPLC).
cm-1
.
(S)-3-Ca r beth oxy-3-ben zylp ip er id in e (1). A solution of
N-Boc-aminal 11 (580 mg, 1.59 mmol) and triethylsilane (255
µL, 1.59 mmol) in CH2Cl2 (8 mL) was cooled to -78 °C, and BF3‚
OEt2 (197 µL, 1.59 mmol) was then added dropwise under a
nitrogen atmosphere. After 30 min, more triethylsilane (255 µL,
1.59 mmol) and BF3‚OEt2 (197 µL, 1.59 mmol) were added. The
resulting mixture was stirred for 2 h at -78 °C, and reaction
was found to be complete by HPLC analysis (retention time of
N-Boc derivative of 1 ) 25.4 min). The N-Boc piperidine was
deprotected by passing HCl gas through the reaction mixture
until 87 mg had been absorbed. The amine HCl salt was
extracted into water (50 mL), and the aqueous phase was washed
with MTBE (50 mL) and basified with 5 N NaOH (7 mL) (pH )
11.5). The mixture was extracted with EtOAc (2 × 40 mL). The
organic extracts were dried over Na2SO4 and evaporated to afford
1 as a colorless oil (363 mg, 85%). HPLC analysis of the Marfey’s
derivative of 1 indicated >99.5% ee (vide supra).
Mon op ep tid e 2. A solution of DCC (1.79 kg, 8.68 mol) in
EtOAc (1.79 Kg) was added to a mixture of (S)-1 (1.95 kg, 8.09
mol), N-Boc-D-tryptophan (2.46 kg, 8.09 mol), HOBt (1.07 kg,
7.89 mol), and EtOAc (10.8 kg) over 30 min, and the mixture
was aged for 16 h at 22 °C. Oxalic acid (314 g, 2.49 mol) was
added to quench any remaining DCC. The mixture was heated
to 55 °C and aged for 1 h and then cooled over 3 h to -8 °C and
stirred for 45 min. The slurry was filtered, and the DCU cake
was washed with EtOAc (4 × 4 L). The combined filtrates were
washed with 2 M HCl (8 L), 10% brine (8 L), 7% aqueous
NaHCO3 (16 L), and 20% brine (8 L). 2 N-Boc derivative: Rf )
0.15 (1:1 hexane-MTBE); HRMS (EI) m/z calcd for C31H39N3O5
(M+) 533.2890, found 533.2905. The organic phase containing
the N-Boc-protected monopeptide (HPLC retention time ) 21.6
min; FTIR (thin film) νmax 3316, 2978, 2932, 1713, 1634, 1456
cm-1) was concentrated, and the residue was dissolved in EtOH
(8 L). A solution of HCl (604 g, 16.5 mol) in EtOH (4 L) was
added, and the mixture was aged at 60 °C for 1 h. EtOAc (41
L) was added to the mixture over 20 min, and the slurry was
aged for 16 h at 20 °C. The slurry was filtered, and the filter
cake was washed with EtOAc (2 × 8 L) to provide 3.41 kg of
HCl salt 2 (3.41 kg, 92%, >98 A% purity by HPLC). 2: HPLC
retention time ) 6.3 min; Rf ) 0.10 (9:1 MTBE-MeOH); mp )
229-231 °C dec; major rotamer 13C NMR (62.9 MHz, CD3OD) δ
L-163,540‚HCl‚H2O: HPLC retention time ) 6.9 min; [R]25
365
) -200° (c 2%, CH3OH/H2O, 50/50); Rf ) 0.20 (9:1 MTBE-
MeOH); mp ) 165-185 °C dec; major rotamer 13C NMR (100.5
MHz, CD3OH) δ 175.3, 172.6, 172.1, 138.1, 137.6, 130.9, 129.0,
128.5, 127.6, 125.0, 122.5, 120.0, 119.0, 112.5, 110.3, 61.6, 58.2,
51.3, 49.1, 48.7, 47.1, 42.4, 32.2, 29.3, 24.2, 24.1, 22.9, 14.2; FTIR
(thin film) νmax 3307, 2963, 2929, 1723, 1634, 1456 cm-1
.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compound 1 in CDCl3 and CD3OD and 1H
NMR and 13C NMR spectra for L-163,540 in CD3OH. Mass
spectra for compound 1 and L163,540 (8 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O980990V