An Improved Enantiospecific Synthesis of Statine and Statine Analogs via 4-(N,N-Dibenzylamino)-3-keto Esters

Full text of DOI:10.1021/jo961836g

2292
J . Org. Chem. 1997, 62, 2292-2297
Sch em e 1
An Im p r oved En a n tiosp ecific Syn th esis of
Sta tin e a n d Sta tin e An a logs via
4-(N,N-Diben zyla m in o)-3-k eto Ester s
Robert V. Hoffman* and J unhua Tao
Department of Chemistry and Biochemistry, New Mexico
State University, Las Cruces, New Mexico 88003-0001
agents (NaBH4,6,9 NaBH3CN,10 KBH4,8 and K-Selec-
tride6), the diastereoselectivities are usually modest (0-
65% de), and the major diastereomer is the incorrect
3R,4S diastereomer which must be inverted at C-3.
The best success using carbamate protecting groups
has come in the synthesis of isostatine (R ) sec-butyl).
Chain branching at the point of attachment of the
R-group improves the diastereoselectivity to >90%, but
an inversion of configuration at C-3 is still required.8,11
Catalytic hydrogenation of the ketone function of 2 (P )
Boc) using chiral ruthenium catalysts gives high de’s and
produces the correct 3S,4S stereochemistry, but the
hydrogenation requires 100 atm of hydrogen and 6 days
of reaction time.12
Received September 25, 1996
In tr od u ction
Statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic
acid, 1, is a critical component of pepstatin, a naturally
occurring peptidic aspartate protease inhibitor.1 The
4-amino-3-hydroxy ester functional grouping of statine
is thought to mimic the tetrahedral intermediate of
peptide hydrolysis, and a syn diastereotopic relationship
between the amine and hydroxyl groups is required.2
Replacement of the terminal isobutyl group with other
groups has led to derivatives with greatly improved
activities.3
The most successful reductive method was that of
Reetz, who reported that N,N-dibenzyl protection of the
amino group of the 4-amino-3-keto ester, eg. 3, led to
products with high de’s and which had the correct 3S,4S
stereochemistry (eq 1).13 The improved diastereoselection
Because of their inhibitory activity toward aspartate
proteases, particularly renin,1 much effort has been
directed toward the enantioselective synthesis of statine
and statine analogs. In spite of these considerable
efforts, there has not emerged a general and reliable
strategy for their preparation.4 Even though they are
relatively simple compounds, current methods are com-
promised by several recurring problems. Often syntheses
are overly long (often 7-10 steps from commercial
starting materials), in many cases the diastereoselectivi-
ties are low (30-70% de), and it is very common for the
wrong diastereomer to be formed and an inversion of
stereochemistry to be required at C-3. These difficulties
have resulted in a continuing search for new methodolo-
gies for the synthesis of statine analogs.4,5
One of the simplest conceptual approaches to the
statine family is the reduction of 4-amino-3-keto esters
2 which are available from R-amino acids (Scheme 1).
While a majority of the early work focused on this
approach, the reduction step has proven to be somewhat
disappointing. In spite of a number of different protect-
ing groups (P ) t-Boc,6 Cbz,7 and Fmoc8 ) and reducing
was attributed an open Fekin-Ahn transition state for
the bulky N,N-dibenzyl-protected compounds compared
to a chelated transition state for the carbamate-protected
compounds. The N,N-dibenzylamino group has been
found to give excellent diastereoselectivities in a variety
of other reactions as well.14 Good results were reported
for statine and two analogs (R ) i-Bu, CH2C6H11, CH2-
Ph).
In connection with the synthesis of a series of hy-
droxyethylene peptide isosteres by chiral alkylation,15
we found it necessary to prepare a series of scalemic
4-(N,N-dibenzylamino)-3-keto esters, 3. To do so requires
the saponification of an R-(N,N-dibenzylamino) ester, as
had been described by Reetz in the synthesis of statine
(7) Dufour, M.-N.; J ouin, P.; Poncet, J .; Pantaloni, A.; Castro, B. J .
Chem. Soc. Perkins Trans. I 1986, 1895.
(8) Kessler, H.; Schudok, M. Synthesis 1990, 457.
(9) Harris, B. D.; Bhat, K. L.; J ouille´, M. M. Tetrahedron Lett. 1987,
25, 2837.
(10) Schuda, P. F.; Greenlee, W. J .; Chakravarty, P. K.; Eskola, P.
J . Org. Chem. 1988, 53, 873.
(1) Umezawa, H.; Aoyagi, T.; Morishima, H.; Matsuzaki, M.; Ha-
mada, M.; Takeuchi, T., J . Antibiot. 1970, 23, 259.
(2) Rich, D. H., J . Med. Chem. 1985, 28, 263.
(3) (a) Boger, J . L.; Payne, L. S.; Perlow, D. S.; Lohr, N. S.; Poe, M.;
Blaine, E. H.; Ulm, E. H.; Schorn, T. W.; LaMont, B. I.; Lin, T.-Y.;
Kawai, M.; Rich, D. H.; Veber, D. F., J . Med. Chem. 1985, 28, 1779.
(b) Rich, D. H.; Bernatowicz, M. S.; Agarwal, N. S.; Kawai, M.; Salituro,
F. G.; Schmidt, P. G. Biochemistry 1985, 24, 3165.
(4) An excellent discussion of the strategies that have been used
for the synthesis of statine analogs exists: Castejo´n, P.; Moyano, A.;
Perica`s, M. A.; Riera, A. Tetrahedron 1996, 52, 7063.
(5) Recent synthetic efforts include: (a) Nebois, P.; Greene, A. G. J .
Org. Chem. 1996, 61, 5210. (b) Gennari, C.; Pain, G.; Moresca, D. J .
Org. Chem. 1995, 60, 6248. (c) Kang, S. H.; Rhu, D. H. Biorg. Med.
Chem. Lett. 1995, 5, 2959. (d) Williams, R. M.; Colson, P. J .; Zhai, W.
X. Tetrahedron Lett. 1995, 35, 9371 and references therein. (e)
Yamamoto, T.; Ishibuchi, S.; Ishizuka, T.; Haratake, M.; Kunieda, T.
J . Org. Chem. 1993, 58, 1997.
(11) (a) Harris, B. D.; J ouille´, M. M., Tetrahedron 1988, 44, 3489.
(b) J ouin, P.; Poncet, J .; Dufour, M.-N.; Maugras, I.; Pantaloni, A.;
Castro, B. Tetrahedron Lett. 1988, 29, 2661. c. Hamada, Y.; Kondo,
Y.; Shibata, M.; Shioiri, T. J . Am. Chem. Soc. 1989, 111, 669.
(12) Nishi, T.; Kitamura, M.; Ohkuma, T.; Noyori, R. Tetrahedron
Lett. 1988, 29, 6327.
(13) (a) Reetz, M. T.; Drewes, M. W.; Matthews, B. R.; Lennick, K.
Chem. Commun. 1989, 1474. (b) It is not possible to make the N,N-
dibenzylamino acid directly from the amino acid by benzylation. The
nitrogen is monobenzylated and a second benzyl group then reacts with
the carboxylate group. N,N-Dibenzylation ocurrs in the third benzy-
lation step.
(14) (a) Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1991, 30, 1531.
(b) Lagu, B. R.; Liotta, D. C. Tetrahedron Lett. 1994, 35, 547.
(15) (a) Hoffman, R. V.; Kim, H. -O. Tetrahedron Lett. 1993, 34, 2051.
(b) Hoffman, R. V.; Kim, H.-O. J . Org. Chem. 1995, 60, 5107.
(6) Maibaum, J .; Rich, D. H. J . Org. Chem. 1988, 53, 869.
S0022-3263(96)01836-1 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 7, 1997 2293
derivatives.13 To our great surprise we were unable to
duplicate this hydrolysis under a variety of experimental
conditions. A reexamination of the reaction sequence has
led to an improved synthesis of 4-(N,N-dibenzylamino)-
3-keto esters, 3, and hence statine derivatives, starting
from R-hydroxy esters.
Ta ble 1. Rea ctivity of Am in o Ester s 5 u n d er Va r iou s
Hyd r olysis Con d ition s
compound
conditions
yield (%)a
5h
5a
5a
5g
5g
6a
LiOH, THF/H2O,reflux, 24 h
LiOH, THF/H2O, reflux, 4 days
KOH, THF/H2O, reflux 6 days
LiOH, THF/H2O, reflux, 7 days
KOH, THF/H2O. reflux, 7 days
KOH, dioxane/H2O, reflux,
6 days
92 (45% ee)
86
79
0
0
Resu lts
10 (90% ee)
6b
KOH, dioxane/H2O, reflux,
7 days
0
A series of scalemic R-hydroxy methyl esters was
converted to R-triflyloxy esters and then to R-(N,N-
dibenzylamino) esters by reaction with dibenzylamine (eq
2).16 It is known that R-triflyloxy esters react with amine
nificant racemization of 5h suggests this would be a
serious complication for other members of the series as
well.
These results were disappointing in light of the work
of Reetz, who reported that benzyl ester 6a was saponi-
fied by KOH in aqueous dioxane.13 While no experimen-
tal details were given, the hydrolysis was reported to
occur without significant racemization. Attempts to
reproduce these previous results were unsuccessful (Table
1). After refluxing for 6 days with KOH (5 equiv) in
aqueous dioxane, less than 10% hydrolysis was found for
6a and the starting material had degraded to 90% ee.
The â-branched compound 6b gave no detectable hy-
drolysis after 7 days under the same conditions.
Because nucleophilic attack at the carbonyl group of 5
by either enolates or hydroxide seemed to be sterically
retarded, particularly in the â-branched systems, we
turned to an iodide-based hydrolysis. Treatment of keto
esters 5a -h with a mixture of lithium iodide/sodium
cyanide in refluxing pyridine for 24 h18 gave N,N-
dibenzylamino acids 7a -h in good yields (64-82%) and
without detectable racemization of the chiral center.
Neither the yields nor the optical purities seemed to be
affected by branching at the â-position (eq 3).
nucleophiles with clean inversion of configuration,16a and
this was confirmed for 5a and 5b by a chiral shift reagent
study using Eu(hfc)3. By comparison to racemic samples,
both 5a and 5b were enantiomerically pure within the
limits of detection (>97% ee) and it is thus reasonable
to assume that 5c-h are also enantiomerically pure. The
choice of configuration at C-2 of the starting hydroxy
esters 4 was made on the basis of price, commercial
availability, and demonstrating the methodology. To
obtain any particular configuration at C-2 of 5 and
ultimately at C-4 of the statine product, the opposite
configuration would be chosen for the starting hydroxy
ester 4.
Reaction of amino esters 5a -d ,h with the lithium
enolate of tert-butyl acetate gave â-keto esters 3a -d ,h
in high yields (80-90%). The N,N-dibenzylamino group
introduces significant steric congestion around the car-
bonyl group. Reaction of 5a -d ,h with lithio tert-butyl
acetate requires 6 h at room temperature for comple-
tion.17 Amino esters 5e-g, which are even more steri-
cally hindered due to chain branching at the â-position,
failed to react. Because of the longer reaction times, it
was found that keto esters 3a -d ,h were racemized to
the extent of 78-90% ee. To avoid these structural and
stereochemical limitations, hydrolysis of 5 and conversion
to a more reactive acylating agent was required.
Saponification of amino esters 5a ,g,h with a variety
of reagents demonstrated the remarkable inertness of the
ester function in these compounds toward nucleophilic
addition (Table 1). This is certainly a direct result of
steric shielding of the ester group; as the steric bulk of
the R-group goes up (Me < i-Bu < s-Bu), the reaction
time increases and the yield decreases. â-Branching (R
) s-Bu) prevents hydrolysis altogether. Moreover, sig-
Amino acids 7a -h were converted to the corresponding
â-keto esters 3a -h by the carbonyldiimidazole (CDI)-
mediated coupling of the amino acid with lithio tert-butyl
acetate in excellent yields (eq 4).11a Determination of the
optical purity of 3 was done by a chiral LIS study using
Eu(hfc)3 and nearly all the analogs were found to have
g97% ee, with the exception of 3h , which had an optical
purity of 70% ee.
(16) (a) Effenberger, F.; Burkard, U. Willfahrt, J . Angew. Chem. Int.
Ed. Engl. 1983, 22, 65. (b) Urbach, H.; Henning, R. Tetrahedron Lett.
1984 25, 1143. c. Review: Hoffman, R. V. Tetrahedron 1991, 47, 1109.
(17) Normal methyl and ethyl esters react with lithio tert-butyl
acetate in 1-2 h. Kim, H.-O.; Saenz, J . unpublished results in these
laboratories.
(18) McMurry, J . E. Org. React. 1976, 24, 187 and references therein.

2294 J . Org. Chem., Vol. 62, No. 7, 1997
Notes
Sch em e 2
at the â-position and impossible when the R-group is
â-branched. Moreover, significant amounts of racemiza-
tion accompany the hydrolysis under these conditions.
In our hands N,N-dibenzyl benzyl esters were virtually
inert toward saponification probably because the bulky
N,N-dibenzylamino group at the R-position inhibits at-
tack of hydroxide at the neighboring ester group. The
methyl ester cleavage of 5 using an iodide nucleophile is
successful because nucleophilic displacement on the
methyl group is removed from the steric congestion at
the R-position. The ester cleavage works well even for
â-branched substrates, and the conditions do not result
in any detectable racemization. Thus the ester cleavage
is also tolerant of a wide range of R-groups. This
procedure is not suitable for benzyl esters.18
The CDI-mediated coupling to produce 3 takes place
normally. Evidently the carbonyl imidazole intermediate
is sufficiently reactive, in spite of the steric congestion
around the carbonyl carbon, that it reacts with enolates.
Stereoselective reduction to protected statine analogs 8
proceeds in high yield and with high diastereoselectivity
as described in the literature.13
The high optical purities of 3 confirm that neither the
hydrolysis nor the CDI coupling causes detectable race-
mization. Keto esters 3a -g were reduced with NaBH4
in absolute methanol to give protected statine analogs
8a -g in excellent yields and diastereoselectivities.13 The
syn diastereomer is presumed to be the major product in
all cases on the basis of the known stereochemistry of
reduction of (N,N-dibenzylamino)carbonyl compounds,14
and it was readily separable by flash chromatography.
Debenzylation of 8 can be accomplished by catalytic
hydrogenation.19
In summary, a diverse set of statine analogs, 8a -g,
with both natural and unnatural configurations, and both
branched and unbranched R-groups, can be prepared by
a four-step sequence from scalemic R-hydroxy esters in
excellent overall yields (35-50% for four steps). The
sequence is highly syn-diastereoselective (>90% de) and
produces optically pure products (>97% ee).
Discu ssion
The best reductive procedure for the enantioselective
preparation of statine analogs was that of Reetz,13 who
converted amino acids to tribenzylated esters 6 and then
saponified the benzyl ester to the N,N-dibenzylamino
acids 7.13b Subsequent conversion to a â-keto ester and
borohydride reduction gave statines with the correct
relative and absolute stereochemistry (Scheme 2). The
advantages of the Reetz approach are that the reduction
proceeds with high diastereoselectivity and gives the
correct syn diastereomer.14
On the other hand, that method requires the amine
group of an amino acid be converted to the N,N-diben-
zylamino group, thus the R-group and the chirality of the
product are restricted to those available in amino acid
precursors. The present methodology utilizes scalemic
R-hydroxy methyl esters as starting materials, which are
readily available either commercially or from amino
acids20 or from a variety of other sources.21 A large
selection of R-groups may be used since triflate substitu-
tion by dibenzylamine to produce the N,N-dibenzylamino
ester is fairly insensitive to the nature or size of the
R-group.
Exp er im en ta l Section
Infrared spectra were recorded as neat liquids or as KBr
pellets. 1H NMR and 13C NMR spectra were recorded at 200
and 50 MHz, respectively. Thin-layer chromatography was
performed on silica gel 60 F254 plates from EM reagents and
visualized by UV irridiation and/or iodine. Preparative thin-
layer chromatography was performed on silica gel 60 F254 plates
from EM reagents and visualized by UV irridiation. Flash
chromatography was performed using silica gel 60 (230-400
mesh). Radial chromatography was performed on 2 mm layer
plates of silica gel 60 PF254 containing gypsum. Tetrahydrofuran
was distilled from benzophenone ketyl. Other solvents were
HPLC grade and were used without further purification. Start-
ing materials were purchased from Aldrich or Sigma and used
as received. Elemental analyses were carried out by M-H-W
Laboratories, Phoenix, AZ.
(S)-Meth yl 2-Hyd r oxy-4-m eth ylp en ta n oa te (4a ).22 Gen -
er a l P r oced u r e. A solution of NaNO2 (5.04 g, 73.0 mmol) in
H2O (20mL) was added dropwise to a stirred, ice-cooled (0 °C)
solution of L-leucine (6.56 g, 50.0 mmol) in 1 N H2SO4 (80.0 mL,
80.0 mmol). The resulting mixture was stirred at the same
temperature for 1 h and then at room temperature for 12 h. After
extraction with ethyl ether (5 × 100 mL), the etheral extracts
were combined and concentrated by rotary evaporator. Then
the residue was dried by refluxing in benzene (200 mL). After
concentration, the (S)-2-hydroxy-4-methylpentanoic acid was
dissolved in acetone (100 mL), and K2CO3 (7.60 g, 55.0 mmol)
A more serious limitation lies in the saponification of
the dibenzylamino esters. The basic hydrolysis of N,N-
dibenzylamino methyl esters 5 by several standard
procedures is difficult when the R-group is unbranched
(19) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem. Int.
Ed. Engl. 1984, 26, 1141.
(20) Hoffman, R. V.; Kim, H.-O. Tetrahedron 1992, 48, 3007 and
references therein.
(21) Xiang, Y. B.; Snow, K.; Belley, M. J . Org. Chem. 1993, 58, 993
and references therein.
(22) Miller, M. J .; Kolasa, T. J . Org. Chem. 1987, 52, 4978. See also
Kim, H.-O., Ph.D. Dissertation, New Mexico State University, 1990.

Notes
J . Org. Chem., Vol. 62, No. 7, 1997 2295
was added. The suspension was stirred at room temperature
for 1 h. Iodomethane (4.00 mL, 64.0 mmol) was added, and the
milky solution was refluxed overnight, filtered, concentrated, and
purified by Kugelrohr distillation (bath temperature 60-65 °C/
0.07 mmHg) to provide 4a as a colorless oil (5.12 g, 70% based
on L-leucine): [R]25D +2.2 (c 2.2, CHCl3); 1H NMR (CDCl3) δ 0.92
(d, 3H, J ) 2.2 Hz), 0.96 (d, 3H, J ) 6.5 Hz), 1.54 (t, 2H, J ) 6.5
Hz), 1.89 (m, 1H), 2.91 (d, 1H, J ) 6.1 Hz), 3.78 (s, 3H), 4.22 (m,
(m, 1H), 3.38 (d, 2H, J ) 13.9 Hz), 3.95 (d, 2H, J ) 13.9 Hz),
3.74 (s, 3H), 7.29 (m, 15H).
(R)-Met h yl 2-(N,N-d ib en zyla m in o)-3-cycloh exylp r o-
p a n oa te (5d ): yield 100% (based on 4d );
1H NMR (CDCl3) δ
0.55-1.80 (set of m, 13H), 3.38 (dd, 1H, J ) 4.5, 9.0 Hz), 3.50
(d, 2H, J ) 13.7 Hz), 3.91 (d, 2H, J ) 13.7 Hz), 3.75 (s, 3H),
7.31 (m, 10H).
(S)-Meth yl 2-(N,N-d iben zyla m in o)-2-cycloh exyla ceta te
(5e): yield 65% (based on 4e); 1H NMR (CDCl3) δ 1.00-2.35 (set
of m, 11H), 3.02 (d, 1H, J ) 11.1 Hz), 3.30 (d, 2H, J ) 14.0 Hz),
3.99 (d, 2H, J ) 14.0 Hz), 3.76 (s, 3H), 7.30 (m, 10H).
(R)-Met h yl 2-(N,N-d ib en zyla m in o)-3-m et h ylb u t a n oa t e
(5f): yield 75% (based on 4f ); 1H NMR (CDCl3) δ 0.78 (d, 3H, J
) 6.5 Hz), 1.02 (d, 3H, J ) 6.6 Hz), 2.15 (m, 1H), 2.87 (d, 1H, J
) 11.0 Hz), 3.28 (d, 2H, J ) 14.0 Hz), 4.00 (d, 2H, J ) 14.0 Hz),
3.77 (s, 3H), 7.33 (m, 10H).
1H); FTIR (neat) 3478 (br), 2958, 1739, 1213, 1143 cm-1
.
(R)-Meth yl 2-h yd r oxy-4-p h en ylp r op a n oa te (4b):22 yield
95% (based on commercially available D-3-phenyllactic acid) as
a white solid after purification by Kugelrohr distillation (bath
temperature 120 °C /0.07 mmHg); mp 45.5-46.5 °C; [R]25D +11.2
(c 2.8, CHCl3); 1H NMR (CDCl3) δ 2.74 (d, 1H, J ) 9.0 Hz), 3.05
(m, 2H), 3.77 (s, 3H), 4.45 (m, 1H), 7.27 (m, 5H).
(R)-Meth yl 2-h yd r oxy-4-p h en ylbu ta n oa te (4c): yield 89%
(based on commmercially available (R)-(-)-2-hydroxy-4-phenyl-
butyric acid) as a colorless oil after purification by Kugelrohr
distillation (bath temperature 130-150 °C/0.07 mmHg); 1H NMR
(CDCl3) δ 2.20 (m, 2H), 2.74 (d, 1H, J ) 6.4 Hz), 2.82 (m, 2H),
3.75 (s, 3H), 4.20 (m, 1H), 7.22 (m, 5H).
(2R,3S)-Met h yl 2-(N,N-d ib en zyla m in o)-3-m et h ylp en -
ta n oa te (5g): yield 80% (based on 4g); [R]25 +72.8 (c 2.2,
D
CHCl3); 1H NMR (CDCl3) δ 0.79-1.04 (m, 3H), 1.00 (d, 3H, J )
6.6 Hz), 1.21 (m, 2H), 2.01 (m, 1H), 3.00 (d, 1H, J ) 10.9 Hz),
3.27 (d, 2H, J ) 14.1 Hz), 3.99 (d, 2H, J ) 14.1 Hz), 3.77 (s,
3H), 7.36 (m, 10H).
(S)-Meth yl 2-h yd r oxy-3-cycloh exylp r op a n oa te (4d ): yield
70% (based on commercially available cyclohexylalanine) as a
colorless oil after purification by Kugelrohr distillation (bath
(R)-Meth yl 2-(N,N-d iben zyla m in o)p r op a n oa te (5h ): yield
100% (based on commercially available (S)-(-)-methyl lactate
temperature 150-180 °C/0.07 mmHg); [R]25 -0.24 (c 2.1,
(4h )); [R]25 +88.5 (c 2.2, CHCl3); 1H NMR (CDCl3) δ 1.32 (d,
D
D
CHCl3); 1H NMR (CDCl3) δ 0.78-1.92 (set of m, 13H), 2.68 (br,
3H, J ) 6.5 Hz), 3.51 (q, 1H, J ) 6.5 Hz), 3.59 (d, 2H, J ) 13.9
Hz), 3.84 (d, 2H, J ) 13.9 Hz), 3.73 (s, 3H), 7.33 (m, 10H).
(R)-2-(N,N-d iben zyla m in o)-4-m eth ylp en ta n oic Acid (7a ).
Gen er a l P r oced u r e. Dibenzylamino ester 5a (1.62 g, 5.00
mmol) was refluxed with lithium iodide (3.34 g, 25.0 mmol) and
sodium cyanide (1.23 g, 25.0 mmol) in pyridine (25 mL) under a
N2 atmosphere. The reaction was monitored by TLC. After 24
h, the resulting mixture was dissolved in ethyl acetate (150 mL)
and then washed with aqueous NH4Cl (2 × 75 mL), H2O (100
mL), and brine (100 mL). After concentration, the residue was
extracted with pentane (3 × 50 mL), dried (MgSO4), filtered,
and concentrated to afford 7a as a pale yellow oil (1.17 g, 75%
based on 5a ), which was virtually pure by NMR analysis and
was carried on without further purification: 1H NMR (CDCl3)
δ 0.69 (d, 3H, J ) 6.4 Hz), 0.85 (d, 3H, J ) 6.6 Hz), 1.65 (dd,
2H, J ) 6.7, 9.0 Hz), 1.86 (m, 1H), 3.42 (t, 1H, J ) 6.7 Hz), 3.70
(d, 2H, J ) 13.5 Hz), 3.86 (d, 2H, J ) 13.5 Hz), 7.32 (m, 10H).
(S)-2-(N,N-d iben zyla m in o)-3-p h en ylp r op a n oic a cid (7b):
1H), 3.78 (s, 3H), 4.24 (dd, 1H, J ) 4.5, 9.2 Hz).
(R)-Meth yl 2-h yd r oxy-2-cycloh exyla ceta te (4e): yield 98%
(based on commercially available (R)-(-)-2-hydroxy-2-cyclohexyl-
acetic acid as a colorless oil after purification by Kugelrohr
distillation (bath temperature 100-120 °C /0.07 mmHg); 1H
NMR (CDCl3) δ 1.00-1.78 (set of m, 11H), 2.68 (d, 1H, J ) 6.3
Hz), 3.79 (s, 3H), 4.38 (dd, 1H, J ) 4.4, 6.3 Hz).
(S)-Meth yl 2-h yd r oxy-3-m eth ylbu ta n oa te (4f):22 yield 93%
(based on commercially available (S)-(+)-2-hydroxy-3-methyl-
butyric acid) as a colorless oil after purification by Kugelrohr
distillation (bath temperature 50-70 °C /0.07 mmHg); [R]25
D
+23.1 (c 2.5, CHCl3); 1H NMR (CDCl3) δ 0.87 (d, 3H, J ) 6.8
Hz), 1.02 (d, 3H, J ) 7.0 Hz), 2.07 (m, 1H), 2.78 (d, 1H, J ) 6.1
Hz), 3.80 (s, 3H), 4.05 (dd, 1H, J ) 3.7, 6.1Hz).
(2S,3S)-Meth yl 2-h yd r oxy-3-m eth ylp en ta n oa te (4g): yield
70% (based on isoleucine) as a colorless oil after purification by
Kugelrohr distillation (bath temperature 50 °C/0.07 mmHg);
1
1
[R]25 +25.5 (c 2.0, CHCl3); H NMR (CDCl3) δ 0.90 (t, 3H, J )
yield 72% (based on 5b); H NMR (CDCl3) δ 3.15 (m, 2H), 3.74
D
(dd, 1H, J ) 5.1, 7.5Hz), 3.73 (d, 2H, J ) 14.0 Hz), 3.90 (d, 2H,
J ) 14.0 Hz), 7.21 (m, 15 Hz).
7.3 Hz), 0.98 (d, 3H, J ) 7.1 Hz), 1.30 (m, 2H), 1.82 (m, 1H),
2.70 (br, 1H), 3.79 (s, 3H), 4.09 (d, 1H, J ) 3.8 Hz).
(R)-2-(N,N-d iben zyla m in o)-4-p h en ylbu ta n oic a cid (7c):
(R)-Meth yl 2-(N,N-Diben zyla m in o)-4-m eth ylp en ta n oa te
(5a ). Gen er a l P r oced u r e. To a stirred solution of (S)-methyl
2-hydroxy-4-methylpentanoate (4a ) (1.46 g, 10.0 mmol) in
dichloromethane (20 mL) at 0 °C under a nitrogen was added
triflic anhydride (1.90 mL, 11.0 mmol), followed by 2,6-lutidine
(1.28 mL, 11.0 mmol). After stirring for 15 min, dibenzylamine
(6.00 mL, 31.0 mmol) in dichloromethane (10 mL) was added
dropwise to the pink solution. The resulting mixture was stirred
for 2 h at room temperature and then concentrated by evapora-
tion under vacuum. The residue was dissolved in pentane (150
mL), passed through a short pad of silica gel, and concentrated
again to provide dibenzylamino ester 5a as a pale yellow oil.
This material was carried on to the next step without further
1
yield 75% (based on 5c); H NMR (CDCl3) δ 2.08 (m, 2H), 2.70
(m, 2H), 3.44 (m, 1H), 3.64 (d, 2H, J ) 13.9 Hz), 3.79 (d, 2H, J
) 13.9 Hz), 7.32 (m, 15H).
(R)-2-(N,N-d iben zyla m in o)-3-cycloh exylp r op a n oic a cid
(7d ): yield 78% (based on 5d ); 1H NMR (CDCl3) δ 0.62-1.80 (set
of m, 13H), 3.44 (dd, 1H, J ) 6.7, 9.0 Hz), 3.70 (d, 2H, J ) 14.0
Hz), 3.82 (d, 2H, J ) 14.0 Hz), 7.34 (m, 10H).
(S)-2-(N,N-d iben zyla m in o)-2-cycloh exyla cetic a cid (7e):
yield 82% (based on 5e); 1H NMR (CDCl3) δ 0.72-2.38 (set of
m, 11H), 3.04 (d, 1H, J ) 10.0 Hz), 3.47 (d, 2H, J ) 14.1 Hz),
4.04 (d, 2H, J ) 14.1 Hz), 7.26 (m, 10 H).
(R)-2-(N,N-d iben zyla m in o)-3-m eth ylbu ta n oic a cid (7f):
yield 79% (based on 5f); 1H NMR (CDCl3) δ 0.90 (d, 3H, J ) 7.8
Hz), 1.05 (d, 3H, J ) 8.0 Hz), 2.18 (m, 1H), 2.91 (d, 1H, J ) 11.3
Hz), 3.46 (d, 2H, J ) 13.9 Hz), 4.02 (d, 2H, J ) 13.9 Hz), 7.32
(m, 10 Hz).
(2R,3S)-2-(N,N-d iben zyla m in o)-3-m eth ylp en ta n oic a cid
(7g): yield 74% (based on 5g); 1H NMR (CDCl3) δ 0.86 (m, 3H),
1.03 (d, 3H, J ) 6.7 Hz), 1.27 (m, 2H), 2.00 (m, 1H), 3.05 (d, 1H,
J ) 11.1 Hz), 3.44 (d, 2H, J ) 14.1 Hz), 4.02 (d, 2H, J ) 14.1
Hz), 7.35 (m, 10H).
(R)-2-(N,N-d iben zyla m in o)p r op a n oic a cid (7h ): yield 64%
(based on 5h ); 1H NMR (CDCl3) δ 1.41 (d, 3H, J ) 7.0 Hz), 3.56
(q, 1H, J ) 7.0 Hz), 3.57 (d, 2H, J ) 11.9 Hz), 3.87 (d, 2H, J
)11.9 Hz), 7.34 (m, 10 Hz).
P r ep a r a tion of Am in o Acid s by Sa p on ifica tion w ith
LiOH or KOH. Gen er a l P r oced u r e. (R)-Methyl 2-(N,N-
dibenzylamino)-4-methylpentanoate (5a ) (650 mg, 2.00 mmol)
was refluxed with LiOH‚H2O (416 mg, 10.0 mmol) in THF (20
mL) and H2O (10 mL). The reaction was monitored by TLC.
After four days the starting material was consumed. The
purification (3.15 g, 97% based on 4a ): [R]25 +89.8 (c 3.2,
D
CHCl3); 1H NMR (CDCl3) δ 0.59 (d, 3H, J ) 6.5 Hz), 0.82 (d,
3H, J ) 6.6 Hz), 1.50 (m, 1H), 1.72 (m, 2H), 3.38 (dd, 1H, J )
4.5, 10.0 Hz), 3.50 (d, 2H, J ) 13.9 Hz), 3.92 (d, 2H, J ) 13.9
Hz), 3.75 (s, 3H), 7.30 (m, 10H).
An LIS study was carried out on 5a using Eu(hfc)3 (1 equiv)
in chloroform-d. A racemic sample was first used to monitor
the lanthanide-induced shifts, and then scalemic 5a prepared
above was used. Only a single enantiomer could be detected,
and thus the sample is >97% ee.
(S)-Meth yl 2-(N,N-d iben zyla m in o)-3-p h en ylp r op a n oa te
1
(5b): yield 100% (based on 4b); [R]20 -77.8 (c 2.2, CHCl3); H
D
NMR (CDCl3) δ 3.05 (m, 2H), 3.54 (d, 2H, J ) 14.0 Hz), 3.67
(dd, 1H, J ) 6.7, 8.9 Hz), 3.95 (d, 2H, J ) 14.0 Hz), 3.73 (s, 3H),
7.22 (m, 15H). Only a single enantiomer was detected in an
LIS study; thus, the sample is >97% ee.
(S)-Met h yl 2-(N,N-d ib en zyla m in o)-4-p h en ylb u t a n oa t e
1
(5c): yield 100% (based on 4c); [R]25 -82.8 (c 0.5, CHCl3); H
D
NMR (CDCl3) δ 2.04 (m, 2H), 2.46 (m, 1H), 2.78 (m, 1H), 3.39

2296 J . Org. Chem., Vol. 62, No. 7, 1997
Notes
solution was diluted with ethyl acetate (100 mL), washed with
aqueous NH4Cl (2 × 50 mL), H2O (100 mL), and brine (100 mL),
and then dried (MgSO4), filtered, and concentrated to afford 7a
(535 mg, 86%), which was virtually pure by NMR analysis.
Using KOH (560 mg, 10.0 mmol), the saponification took a total
of 6 days (yield 79%).
Other N,N-dibenzylamino esters (5b-d ,h ) gave similar re-
sults; however, this procedure failed to give hydrolysis products
7e-g from 5e-g, which are â-branched.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-m et h ylh ex-
a n oa te (3f): yield 75% (based on 7f) and >97% ee as a colorless
oil after purification by flash chromatography (hexane:ethyl
acetate ) 95:5 to 90:10); [R]25 +201.7 (c 0.60, CHCl3); 1H NMR
D
(CDCl3) δ 0.80 (enol) (d, 3H, J ) 6.4 Hz), 0.82 (d, 3H, J ) 6.5
Hz), 1.08 (enol) (d, 3H, J ) 6.5 Hz), 1.12 (d, 3H, J ) 6.6 Hz),
1.46 (s, 9H), 1.54 (enol) (s, 9H), 2.28 (m, 1H), 3.07 (d, 1H, J )
10.4 Hz), 3.21 (d, 1H, J ) 15.0 Hz), 3.30 (d, 1H, J ) 15.0 Hz),
3.38 (enol) (d, 2H, J ) 14.0 Hz), 3.60 (d, 2H, J ) 13.9 Hz), 3.94
(d, 2H, J ) 13.9 Hz), 3.98 (enol) (d, 2H, J ) 14.0 Hz), 4.73 (enol)
(s, 1H), 7.31 (m, 10H); 13 C NMR (CDCl3) (keto and enol) δ 20.4,
20.7, 26.5, 27.6, 28.4, 28.9, 52.4, 54.7, 68.6, 71.4, 81.4, 82.0, 94.7,
127.2, 127.6, 128.6, 129.3, 139.8, 140.7, 174.2, 204.8; FTIR (neat)
2977, 1751, 1721, 1646 (br) cm-1. Anal. Calcd for C25H33O3N:
C, 75.91; H, 8.41; N, 3.54. Found: C, 76.07; H, 8.18; N, 3.56.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-m et h ylh ep -
ta n oa te (3g): yield 74% (based on7g) and > 97% ee as a
colorless oil after purification by flash chromatography (hexane:
ter t-Bu t yl 4-(N,N-Dib en zyla m in o)-3-oxo-6-m et h ylh ep -
ta n oa te (3a ). Gen er a l P r oced u r e. To a stirred solution of
N,N-dibenzylamino acid 7a (1.34 g, 4.30 mmol) in THF (20 mL)
was added CDI (767 mg, 4.70 mmol) at room temperature under
a N2 atmosphere. The resulting solution was stirred at room
temperture for 1 h. Meanwhile, a solution of lithium (tert-
butoxycarbonyl)methanide was made from BuLi (2.50 M, 3.60
mL, 9.00 mmol), diisopropylamine (1.30 mL, 9.00 mmol), and
tert-butyl acetate (1.22 mL, 9.00 mmol). The imidazole solution
was added dropwise to the pale yellow solution of the lithium
enloate at -78 °C under a N2 atmosphere. The resulting
mixture was stirred at -78 °C for 50 min, quenched with 1 N
HCl (50 mL), and extracted with ethyl acetate (3 × 50 mL). The
organic extracts were combined, washed with brine (100 mL),
dried (MgSO4), passed through a short pad of silica gel, and
concentrated to provide 3a as a colorless oil (1.32 g, 80% based
on 7a ) after purification by flash chromatography (hexane:ether
) 95:5 to 85:10): 97% ee by a chiral LIS study using Eu(hfc)3 in
comparison with a racemic sample); [R]25D +93.8 (c 0.45, CHCl3);
1H NMR (CDCl3) δ 0.79 (d, 3H, J ) 5.8 Hz), 0.88 (d, 3H, J ) 6.0
Hz), 1.37 (s, 9H), 1.38 (m, 2H), 1.81 (m, 1H), 3.34 (dd, 1H, J )
3.3, 9.5 Hz), 3.44 (d, 2H, J ) 13.7 Hz), 3.70 (d, 2H, J ) 13.7 Hz),
3.53 (s, 2H), 7.32 (m, 10H); 13C NMR (CDCl3) δ 22.7, 23.5, 25.8,
31.3, 48.1, 54.9, 64.8, 82.0, 127.2, 127.7, 128.9, 129.5, 139.7,
ethyl acetate ) 95:5 to 90:10); [R]25 +197.3 (c 0.55, CHCl3); 1H
D
NMR (CDCl3) δ 0.83 (t, 3H, J ) 6.9 Hz), 1.08 (d, 3H, J ) 6.8
Hz), 1.25 (m, 1H), 1.46 (s, 9H), 1.54 (enol) (s, 9H), 2.08 (m, 2H),
3.17 (d, 1H, J ) 6.4 Hz), 3.19 (d, 1H, J ) 15.6 Hz), 3.31 (d, 1H,
J ) 15.6 Hz), 3.37 (enol) (d, 2H, J ) 14.0 Hz), 3.59 (d, 2H, J )
13.9 Hz), 3.93 (d, 2H, J ) 13.9 Hz), 3.99 (enol) (d, 2H, J ) 14.0
Hz), 4.70 (enol) (s, 1H), 7.31 (m, 10H), 12.16 (enol) (s, 1H); 13C
NMR (CDCl3) (keto and enol) δ 11.8, 16.2, 16.6, 27.1, 28.5, 28.8,
32.8, 34.2, 52.4, 54.6, 67.2, 70.1, 82.0, 94.8, 127.2, 127.6, 128.6,
128.9, 139.8, 140.7, 166.8, 173.0, 174.2, 204.7; FTIR (neat) 2957,
1751, 1711, 1646 (enol) (br) cm-1. Anal. Calcd for C26H35O3N:
C, 76.25; H, 8.61; N, 3.42. Found: C, 76.48; H, 8.42; N, 3.50.
ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-oxo-p en ta n oa te (3h ):
yield 78% (based on 7h ) and 70% ee as a colorless oil after
purification by flash chromatography (hexane: ether ) 85:5 to
80:10); 1H NMR (CDCl3) δ 1.18 (d, 3H, J ) 6.7 Hz), 1.37 (s, 9H),
3.41 (d, 2H, J ) 13.6 Hz), 3.46 (q, 1H, J ) 6.7 Hz), 3.54 (d, 1H,
J ) 15.6 Hz), 3.68 (d, 1H, J ) 15.6 Hz), 3.72 (d, 2H, J ) 13.6
Hz), 7.34 (m, 10H); 13C NMR (CDCl3) 6.9, 28.4, 47.3, 55.0, 62.6,
81.9, 127.9, 129.0, 129.3, 139.4, 167.6, 205.7; FTIR (neat) 2996,
167.4, 204.3; FTIR (neat) 2955, 1730, 1710 cm-1
.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-p h en ylp en -
ta n oa te (3b): yield 76% (based on 7b) and >97% ee as a
colorless oil after purification by flash chromatography (hexane:
ether ) 95:5 to 85:10); [R]25 -69.4 (c 0.85, CHCl3); 1H NMR
D
1741, 1716 cm-1
.
(CDCl3) δ 1.24 (s, 9H), 3.02 (m, 2H), 3.37 (d, 1H, J ) 15.4 Hz),
3.54 (d, 2H, J ) 13.2 Hz), 3.57 (d, 1H, J ) 15.4 Hz), 3.60 (dd,
1H, J ) 3.7, 7.5 Hz), 3.82 (d, 2H, J ) 13.2 Hz), 7.30 (m, 15H);
13C NMR (CDCl3) δ 28.2, 28.9, 48.2, 55.1, 68.8, 82.0, 126.6, 127.9,
129.0, 129.5, 130.1, 139.2, 140.0, 166.9, 203.0; FTIR (neat) 2976,
P r ep a r a tion of 3-Oxo Ester s Dir ectly fr om Ester s 5a -
d ,h . ter t-Bu tyl 4-(N,N-Diben zyla m in o)-3-oxo-6-m eth ylh ep -
ta n oa te (3a ). Gen er a l P r oced u r e. A solution of lithium (tert-
butylcarbonyl)methanide was prepared using BuLi (2.50 M, 2.10
mL, 5.25 mmol), diisopropylamine (531 mg, 5.25 mmol), and tert-
butyl acetate (609 mg, 5.25 mmol). To this pale yellow solution
at -78 °C was added dropwise (S)-methyl 2-(N,N-dibenzyl-
amino)-4-methylpentanoate (5a ) (812 mg, 2.50 mmol). The
resulting mixture was stirred at -78 °C for 5 min and then
warmed to room temperature. The reaction was monitord by
TLC. Six hours later, the yellow solution was quenched with 1
N HCl (50 mL) and extracted with ethyl acetate (3 × 50 mL).
The organic extracts were combined, washed with brine (100
mL), dried (MgSO4), passed through a short pad of silica gel,
and concentrated by evaporation in vacuum to provide 3a as a
colorless oil (870 mg, 85% based on 5a ; 87% ee by chiral LIS
study using Eu(hfc)3 in comparison with a racemic sample).
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-p h en ylp en -
ta n oa te (3b): yield 84% (based on 5b) and 92% ee as a colorless
oil after purification by radial chromatography (hexane:ether )
85:10).
1745, 1730 cm-1
.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-6-p h en ylh ex-
a n oa te (3c): yield 78% (based on 7c) and 94% ee as a colorless
oil after purification by radial chromatography (hexane:ethyl
acetate ) 95:5); [R]25 -35.9 (c 1.0, CHCl3); 1H NMR (CDCl3) δ
D
1.38 (s, 9H), 1.88 (m, 1H), 2.19 (m, 1H), 2.33 (m, 1H), 2.70 (m,
1H), 3.28 (dd, 1H, J ) 2.8, 9.6 Hz), 3.35 (d, 2H, J ) 13.4 Hz),
3.44 (d, 1H, J ) 15.8 Hz), 3.54 (d, 1H, J ) 15.8 Hz), 3.67 (d, 2H,
J ) 13.4 Hz), 7.28 (m, 15H); 13C NMR (CDCl3) δ 24.6, 28.4, 28.8,
33.5, 47.9, 55.0, 65.7, 82.0, 126.5, 127.8, 128.1, 129.6, 139.4,
142.4, 167.5, 203.5; FTIR (neat) 2987, 1741, 1716 cm-1
.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-cycloh exyl-
p en ta n oa te (3d ): yield 77% (based on 7d ) and > 97% ee as a
colorless oil after purification by flash chromatography (hexane:
1
ether ) 85:10); [R]25 +113.0 (c 0.50, CHCl3); H NMR (CDCl3)
D
δ 1.37 (s, 9H), 0.70-1.85 (set of m, 13H), 1.53 (enol) (s, 9H), 3.38
(dd, 1H, J ) 4.5, 9.4 Hz), 3.44 (d, 2H, J ) 13.5 Hz), 3.47 (d, 1H,
J ) 15.5 Hz), 3.58 (d, 1H, J ) 15.5 Hz), 3.69 (d, 2H, J ) 13.5
Hz), 4.80 (enol) (s, 1H), 7.31 (m, 10H); 13C NMR (CDCl3) δ 26.7,
28.4, 30.0, 33.5, 34.4, 35.3, 48.2, 54.9, 64.2, 82.0, 127.7, 128.9,
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-6-p h en ylh ex-
a n oa te (3c): yield 88% (based on 5c) and 88% ee as a colorless
oil after purification by radial chromatography (hexane:ether )
95:5).
129.5, 140.0, 167.4, 204.5; FTIR (neat) 2937, 1745, 1720 cm-1
.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-cycloh exyl-
p en ta n oa te (3d ): yield 85% (based on 5d ) and 90% ee as a
colorless oil after purification by radial chromatography (hexane:
ethyl acetate ) 95:5).
ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-oxop en ta n oa te (3h ):
yield 80% (based on 5h ) and 78% ee as a colorless oil after
purification by radial chromatography (hexane:ether ) 85:5 to
80:10).
This procedure failed for the synthesis of 3e-g from 5e-g,
which are â-branched.
(3R,4R)-ter t-Bu tyl 4-(N,N-Diben zyla m in o)-3-h yd r oxy-6-
m eth ylh ep ta n oa te, (8a ). Gen er a l P r oced u r e. 3-Oxo ester
3a (372 mg, 0.910 mmol) was dissolved in methanol (17.0 mL),
which was dried using Mg turnings and iodine. The resulting
ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-oxo-4-cycloh exylbu -
ta n oa te (3e): yield 73% (based on 7e) and >97% ee as a colorless
oil after purification by flash chromatography (hexane:ethyl
acetate ) 95:5 to 90:10); [R]25 -200.5 (c 0.40, CHCl3); 1H NMR
D
(CDCl3) δ 0.70-2.24 (set of m, 11H), 1.46 (s, 9H), 1.53 (enol) (s,
9H), 3.17 (d, 1H, J ) 10.4 Hz), 3.18 (d, 1H, J ) 15.8 Hz), 3.28
(d, 1H, J ) 15.8 Hz), 3.39 (enol) (d, 2H, J ) 14.1 Hz), 3.59 (d,
2H, J )14.0 Hz), 3.96 (d, 2H, J ) 14.0 Hz), 3.99 (enol) (d, 2H, J
) 14.1 Hz), 4.70 (enol) (s, 1H),7.31 (m, 10H); 13C NMR (CDCl3)
(keto and enol) δ 26.2, 26.5, 27.1, 28.4, 28.8, 30.5, 30.9, 35.7,
37.3, 52.7, 54.7, 67.3, 70.2, 81.4, 82.0, 94.8, 127.2, 127.6, 128.6,
129.0, 140.0, 140.7, 172.9, 174.0, 205.1; FTIR (neat) 2937, 1745,
1715, 1646 (br) cm-1. Anal. Calcd for C28H37O3N: C, 77.20; H,
8.56; N, 3.22. Found: C, 77.30; H, 8.33; N, 3.15.

Notes
J . Org. Chem., Vol. 62, No. 7, 1997 2297
solution was then cooled to -22 °C and treated with NaBH4 (70.0
mg, 1.84 mmol). The reaction was monitored by TLC. After
3.5 h, the solution was quenched with H2O (100 mL) at pH )
5-6 (adjusted by 1 N HCl), extracted with ether (3 × 100 mL),
washed by brine (100 mL), dried (MgSO4), and concentrated to
provide 8a as a colorless oil (325 mg, 87% based on 3a ); 88% de
based on 1H NMR. The diastereomers were separated by flash
chromatography (hexane:ether ) 85:15) in the ratio of 94:6. The
(3S,4S)-ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-h yd r oxy-4-
cycloh exylbu ta n oa te (8e): yield 89% (based on 3e) and 98%
de by 1H NMR of a colorless oil. The diastereomers were
separated by flash chromatography (hexane:ether ) 85:15) in
the ratio of 99:1. The major diastereomer: [R]25D +2.25 (c 0.40,
1
CHCl3); H NMR (CDCl3) δ 1.05-1.95 (set of m, 11H), 1.44 (s,
9H), 2.18 (m, 2H), 2.26 (m, 1H), 3.52 (d, 2H, J ) 13.1 Hz), 3.96
(d, 2H, J )13.1 Hz), 4.19 (dd, 1H, J ) 2.5, 7.5 Hz), 4.25 (br,
1H), 7.27 (m, 10H); 13C NMR (CDCl3) δ 26.8, 27.3, 28.6, 30.7,
major diastereomer: [R]25 -2.5 (c 0.20, CHCl3); 1H NMR
D
(CDCl3) δ 0.90 (d, 6H, J ) 6.4 Hz), 1.43 (s, 9H), 1.24 (m, 2H),
1.60 (m, 1H), 2.31 (m, 2H), 2.52 (m, 1H), 3.43 (d, 2H, J ) 13.4
34.2, 36.7, 42.2, 54.9, 65.8, 81.1, 127.6, 128.7, 129.8, 139.7, 172.3;
-1
FTIR (neat) 3525 (br), 2947, 1730 cm
. Anal. Calcd for
Hz), 3.92 (d, 2H, J ) 13.4 Hz), 3.68 (m, 1H), 7.28 (m, 10H); 13
C
C
28H39O3N: C, 76.85; H, 8.98; N, 3.20. Found: C, 76.89; H, 8.95;
NMR (CDCl3) δ 23.3, 23.8, 26.6, 28.6, 35.2, 41.1, 54.6, 60.1, 69.3,
81.3, 127.6, 128.9, 129.5, 140.0, 172.5; FTIR (neat) 3483 (br),
2955, 1728 cm-1. Anal. Calcd for C26H37O3N: C, 75.87; H, 9.06;
N, 3.40. Found: C, 76.04; H, 8.86; N, 3.34.
N, 3.20.
(3R,4R)-ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-h yd r oxy-5-
m eth ylh exa n oa te (8f): yield 91% (based on 3f) and 96% de by
1H NMR of a colorless oil. The diastereomers were separated
by flash chromatography (hexane:ethyl acetate ) 90:10) in the
(3S,4S)-ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-h yd r oxy-5-
p h en ylp en ta n oa te (8b): yield 90% (based on 3b) and 92% de
based on 1H NMR of a colorless oil. The diastereomers were
separated by flash chromatography (hexane:ether ) 90:10) in
the ratio of 96:4. The major diastereomer: [R]25D +11.5 (c 1.35,
ratio of 98:2. The major diastereomer: [R]25 +4.4 (c 0.75,
D
CHCl3); 1H NMR (CDCl3) δ 1.02 (d, 3H, J ) 4.1 Hz), 1.06 (d,
3H, J ) 6.8 Hz), 1.44 (s, 9H), 2.25 (m, 2H), 2.27 (m, 1H), 2.33
(m, 1H), 3.54 (d, 2H, J ) 13.2 Hz), 3.98 (d, 2H, J ) 13.2 Hz),
4.09 (br, 1H), 4.20 (dd, 1H, J ) 3.4, 6.9 Hz), 7.27 (m, 10H); 13C
NMR (CDCl3) δ 20.4, 23.8, 26.4, 28.6, 41.9, 55.0, 65.7, 66.7, 81.1,
127.6, 128.8, 129.4, 129.8, 172.5; FTIR (neat) 3515 (br), 2937,
1726 cm -1. Anal. Calcd for C25H35O3N: C, 75.53; H, 8.87; N,
3.52. Found: C, 75.61; H, 8.80; N, 3.54.
1
CHCl3); H NMR (CDCl3) δ 1.39 (s, 9H), 2.23 (m, 2H), 2.84 (m,
2H), 2.92 (m, 1H), 3.42 (d, 2H, J ) 13.3 Hz), 4.07 (d, 2H, J )
13.3 Hz), 3.90 (m, 1H), 7.28 (m, 15H); 13C NMR (CDCl3) δ 28.6,
31.3, 41.1, 55.0, 63.5, 68.5, 81.3, 126.6, 127.6, 128.9, 139.8, 140.7,
172.9; FTIR (neat) 3525 (br), 2986, 1736 cm-1. Anal. Calcd for
C
29H35O3N: C, 78.17; H, 7.92; N, 3.14. Found: C, 77.79; H, 7.69;
N, 3.06.
(3S,4S)-ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-h yd r oxy-6-
(3R,4R,5S)-ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-h yd r oxy-
5-m eth ylh ep ta n oa te (8g): yield 90% (based on 3g) and 97%
de by 1H NMR as a colorless oil. The diastereomers were
separated by flash chromatography (hexane:ethyl acetate ) 85:
15) in the ratio of 98.5:1.5. The major diastereomer: [R]25D +5.0
(c 0.30, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, 3H, J ) 7.2 Hz),
1.03 (d, 3H, J ) 7.2 Hz), 1.08 (m, 1H), 1.44(s, 9H), 1.85 (m, 2H),
2.28 (m, 2H), 2.44 (m, 1H), 3.52 (d, 2H, J ) 13.1 Hz), 3.88 (d,
2H, J ) 13.1 Hz), 4.09 (br) (s, 1H), 4.26 (m, 1H), 7.28 (m, 10H);
13C NMR (CDCl3) δ 12.6, 19.4, 26.7, 28.6, 33.6, 41.8, 55.2, 65.4,
66.4, 81.3, 127.5, 128.8, 129.8, 140.0, 172.3; FTIR (neat) 3495
p h en ylh exa n oa te (8c): yield 92% (based on 3c) and 92% de
based on 1H NMR of a colorless oil. The diastereomers were
separated by flash chromatography (hexane:ether ) 85:5 to 90:
10) in the ratio of 96:4. The major diastereomer: [R]25 +77.2
D
(c 0.40, CHCl3); 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.79 (m, 1H),
2.05 (m, 1H), 2.40 (m, 2H), 2.50 (m, 1H), 2.71 (m, 1H), 3.42 (d,
2H, J ) 13.4 Hz), 3.94 (d, 2H, J ) 13.4 Hz), 4.06 (m, 1H), 7.27
(m, 15H); 13C NMR (CDCl3) δ 27.8, 28.6, 35.0, 41.1, 54.8, 61.6,
69.0, 81.4, 126.6, 127.6, 128.9, 129.6, 139.8, 142.4, 172.5; FTIR
(neat) 3505 (br), 2947, 1736 cm-1. Anal. Calcd for C30H37O3N:
C, 78.40; H, 8.11; N, 3.05. Found: C, 78.69; H, 8.06; N, 3.02.
(3R,4R)-ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-h yd r oxy-5-
cycloh exylp en ta n oa te (8d ): yield 91% (based on 3d ) and 94%
de by 1H NMR of a colorless oil. The diastereomers were
separated by flash chromatography (hexane:ether ) 80:20) in
the ratio of 97:3. The major diastereomer: [R]25D -15.7 (c 0.65,
(br), 2957, 1721 cm-1
. Anal. Calcd for C26H37O3N: C, 75.87;
H, 9.06; N, 3.40. Found: C, 76.04; H, 8.91; N, 3.39.
Ack n ow led gm en t. This work was supported by a
grant from the National Science Foundation (9520431).
Su p p or tin g In for m a tion Ava ila ble: The 13C NMR spec-
1
1
CHCl3); H NMR (CDCl3) δ 0.75-1.82 (set of m, 13H), 1.44 (s,
tra of 3a -d , h and the H NMR spectra of 4c-e, g and 5a -h
9H), 2.28 (m, 2H), 2.52 (m, 1H), 3.44 (d, 2H, J ) 13.6 Hz), 3.92
(d, 2H, J )13.6 Hz), 3.94 (m, 1H), 4.12 (br) (s, 1H), 7.28 (m,
10H); 13C NMR (CDCl3) δ 26.9, 28.6, 33.8, 34.0, 34.5, 36.0, 41.4,
54.6, 59.2, 69.4, 81.3, 127.5, 128.8, 129.5, 140.1, 172.5; FTIR
(neat) 3495 (br), 2947, 1736 cm-1. Anal. Calcd for C29H41O3N:
C, 77.12; H, 9.15; N, 3.10. Found: C, 77.20; H, 8.94; N, 3.12.
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