A practical and diastereoselective synthesis of ketomethylene dipeptide isosteres of the type AAψ[COCH2]asp

Full text of DOI:10.1021/jo951988w

J . Org. Chem. 1996, 61, 2901-2903
2901
Sch em e 1a
A P r a ctica l a n d Dia ster eoselective
Syn th esis of Ketom eth ylen e Dip ep tid e
Isoster es of th e Typ e AAΨ[COCH2]Asp
Robert De´ziel,* Raymond Plante, Vale´rie Caron,
Louis Grenier, Montse Llinas-Brunet,
J ean-Simon Duceppe, Eric Malenfant, and Neil Moss
Bio-Me´ga/ Boehringer Ingelheim Research Inc., 2100
Cunard Street, Laval (Que´bec), Canada H7S 2G5
Received November 8, 1995
In recent years much attention has been focused on
the synthesis of ketomethylene isosteres and their use
in biologically active peptides.1 In the course of our
studies on peptidomimetic inhibitors we needed a facile
synthesis of aspartic acid ketomethylene dipeptide iso-
steres (AAΨ[COCH2]Asp). Here we report a practical
synthesis of this type of isostere that features a diaste-
reoselective Michael addition and provides suitably pro-
tected functionalities for subsequent transformations.2
The synthesis, outlined in Scheme 1, began with the
N-Boc protected amino acid methyl esters 1a -e which
were converted into the ketophosphonates 2a -e in good
yield by treatment with 8 equiv of lithium dimethyl
methylphosphonate in THF at -78 °C. The trans-
Michael acceptors 3a ,b were prepared by treating the
ketophosphonates 2a ,b with 1.05 equiv of benzyl glyoxy-
late3 in the presence of 2.0 equiv of triethylamine in
acetonitrile at room temperature. However, we found
that the above reaction conditions were not suitable for
the preparation of Michael acceptors bearing smaller
alkyl groups 3c-e. We observed racemization4 and
formation of the corresponding rearranged products 6.5
We believed that products 6 were formed via a based-
catalyzed 1,5-hydrogen shift as shown in Scheme 2.
a
Reagents and Conditions: (a) LiCH2PO(OMe)2 (8 equiv), THF,
-78 °C; (b) 3a ,b HCOCO2Bn‚0.3H2O, CH3CN, Et3N 23 °C; 3c-e
HCOCO2Bn‚0.3H2O, NMM, CH2Cl2, 0 °C; (c) reaction conditions
of entry 1, Table 1; (d) Pd(PPh3)4 (0.01% mol), pyrrolidine (1.05
equiv), toluene; (e) xylenes, 130 °C.
Sch em e 2
(1) For pertinent references on this topic see: Gonza´lez-Mun˜iz, R.;
Garc´ıa-Lo´pez, M. T.; Go´mez-Monterry, I.; Herranz, R.; J imeno, M. L.;
Sua´rez-Gea, M. L.; J ohansen, N. L.; Madsen, K.; Thogersen, H.;
Suzdak. P. J . Med. Chem. 1995, 38, 1015. Casimir, J . R.; Turetta, C.;
Ettouati, L.; Paris, J . Tetrahedron Lett. 1995, 36, 4797. Groeger, C.;
Wenzel, H. R.; Tschesche, H. Int. J . Protein Res. 1994, 44, 166. Kim,
B. H.; Chung, Y. J .; Ryu, E. J . Tetrahedron Lett. 1993, 34, 8465.
Dominguez, M. J .; Gonza´lez-Mun˜iz, R.; Garc´ıa-Lo´pez, M. T. Tetrahe-
dron 1992, 48, 2761. Hoffman, R. V.; Kim, H-O. Tetrahedron Lett. 1992,
33, 3579. Cheng, L.; Goodwin, C. A.; Shully, M. F.; Kakkar, V. V.;
Claeson, G. J . Med. Chem. 1992, 35, 3364. DiMaio, J .; Gibbs, B.;
Lefebvre, J .; Konishi, Y.; Munn, D.; Yue, S. Y. J . Med. Chem. 1992,
35, 3331. Kaltenbronn, J . S.; Hudspeth, E. A.; Lunney, B. M.;
Michniewicz, E. D.; Nicolaides, J . T.; Repine, J . T.; Roark, W. H.; Stier.
M. A.; Tinner, F. J .; Woo, P. K.W.; Essenburg, A. D. J . Med. Chem.
1990, 33, 838. Harbeson, S. L.; Rich, D. H. J . Med. Chem. 1989, 32,
1378. Garc´ıa-Lo´pez, M. T.; Gonza´lez-Mun˜iz, R.; Harto, J . R. Tetrahe-
dron Lett. 1988, 29, 1577. Garc´ıa-Lo´pez, M. T.; Gonza´lez-Mun˜iz, R.;
Harto, J . R. Tetrahedron Lett. 1988, 44, 5138. Holladay, M. W.;
Salituro, F. G.; Rich, D. H. J . Med. Chem. 1987, 30, 374. McMurray,
J . S.; Dyckes, D. F. J . Org. Chem. 1985, 50, 1112. Holladay, M. W.;
Rich, D. H. Tetrahedron Lett. 1983, 24, 4401. J ennings-White, C.;
Almquist, R. G. Tetrahedron Lett. 1982, 23, 2533.
These problems were overcome by replacing triethyl-
amine by a weaker base, N-methylmorpholine, and by
lowering the reaction temperature to 0 °C. These modi-
fications necessitated longer reaction times and since
these Michael acceptors were somewhat unstable, we
found that the use of dichloromethane and molecular
sieves reduced the quantity of minor byproducts. It
should be noted that the use of N-methylmorpholine in
the Wadsworth-Emmons reaction of phosphonates 2a ,b
gave a substantial amount of the cis isomer. We found
that the cis isomer was not a suitable substrate for the
subsequent reaction.
(2) For the selective removal of a N-Boc protecting group in the
presence of a tert-butyl ester see: Gibson, F. S.; Bergmeier, S. C.;
Rapoport, H. J . Org. Chem. 1994, 59, 3216.
(3) Benzyl glyoxylate (containing 0.3 equiv of H2O) was prepared
by oxidation of benzyl tartrate with periodic acid: Shuda, P. F.; Ebner,
C. B.; Potlock, S. J . Synthesis 1987, 25, 2183.
The first step in the stereoselective introduction of the
tert-butyl acetate side chain involved the conjugate
addition of the sodium salt of allyl tert-butyl malonate6
to 3a -e to give the adducts 4a -e in >90% yields.
However, at this stage the unsymmetrical malonate
moiety made the assessment of the diastereoisomeric
purity of 4a -e difficult. We thus assessed the degree of
(4) The degree of racemization of Michael acceptors 3b-e was
assessed by chiral HPLC. The enantiomers of 3b-e were made from
the corresponding D-amino acids in order to identify the elution time
of both enantiomers. The assessement of optical purity of 3a was made
by proton NMR analysis (400 MHz) of its corresponding Mosher amide.
HPLC conditions: Chiracel OD-H column (0.46 cm × 25 cm, Daicel
Chemical Industries Ltd.); 1.0% ethanol/hexanes (0.5 mL/min, 250 psi),
λ ) 220 nm.
(6) Allyl tert-butylmalonate was prepared by addition of allyl
chloroformate to the lithium salt of tert-butyl acetate generated with
LiHMDS in THF at -78 °C.
(5) Compounds 6 were characterized by 400 MHz proton NMR
analysis.
0022-3263/96/1961-2901$12.00/0 © 1996 American Chemical Society

2902 J . Org. Chem., Vol. 61, No. 8, 1996
Notes
Ta ble 1. Syn th esis of th e Ketom eth ylen e Isoster es 5a -e
fr om 3a -e
important to assess the enantiomeric purity of the final
products. Chiral HPLC analysis of compounds 5b-d
indicated only 2-4% enantiomeric contamination.9 Com-
pound 5e was shown to contain 10% enantiomeric
contamination; however, that contamination was already
present in phosphonate 2e.
In summary, we have developed a diastereoselective
and straightforward synthesis of ketomethylene dipep-
tide isosteres of the type AAΨ[COCH2]Asp bearing
suitably protected functionalities for subsequent trans-
formations. The key feature of this new synthesis
involves a diastereoselective conjugate addition on Michael
acceptors 3a -e. Studies toward expanding the scope of
this reaction and understanding the parameters dictating
facial selectivity are currently in progress.
ratioa
5:(3R)
yieldb
(%) of
electro-
phile
base
T,
entry
solvent (0.25 equiv) °C
epimer 5 from 3
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3b
3b
3b
3b
3b
3b
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
NaH
NaH
NaH
NaH
NaH
NaHMDS -78
KH
LiHMDS
NaH
NaH
-78 >50:1
77
68
62
68
76
74
72
59
70
59
60
-78
-78
-78
-78
10:1
9:1
5:1
5:1
10:1
-78
-78
0
1.5:1
3:1
4:1
10
11
-78
-78
4:1
3.5:1
toluene NaH
a
Ratio assessed by HPLC and 1H NMR (400 MHz) analysis of
b
crude 5. Yields of 5 and 3R epimers obtained after purification
by silica gel column chromatography.
Exp er im en ta l Section
Sch em e 3a
Dim eth yl [(3S)-4,4-Dim eth yl-3-[(ter t-bu tyloxyca r bon yl)-
a m in o]-2-oxop en tyl]p h osp h on a te (2a ). (Gen er a l P r oce-
d u r e for th e Syn th esis of 2 fr om 1). To a solution of dimethyl
methylphosphonate (4.04 g, 32.6 mmol) in THF (30 mL) and
cooled to -78 °C was added 1.6 N n-BuLi (20.4 mL, 32.6 mmol)
dropwise. The solution was stirred at -78 °C for 20 min, and
then a THF (20 mL) solution of 1a (1.00 g, 4.07 mmol) was slowly
added. The mixture was stirred at -78 °C for 1 h and then at
room temperature for 15 min. The solution was acidified with
10% AcOH (20 mL), extracted with EtOAc, washed with 10%
NaHCO3 and brine, and dried over MgSO4. After concentration,
the residue was triturated in hexanes to give 2a (1.05 g, 76%)
as a white solid: mp 82-83 °C; [R]22D ) +20.1° (c, 1.82, CHCl3);
1H NMR (CDCl3) δ 5.23 (d, J ) 9.5 Hz, 1 H), 4.25 (d, J ) 9.5 Hz,
1 H), 3.81 (d, J ) 2 Hz, 3 H), 3.78 (d, J ) 2 Hz, 3 H), 3.32 (dd,
J ) 22 Hz, 14.5 Hz, 1 H), 3.12 (dd, J ) 22 Hz, 14.5 Hz, 1 H),
1.44 (s, 9 H), 1.00 (s, 9 H); HRMS m/ z calcd for C14H29NO6P
a
Reagents and Conditions: (a) HCl, EtOAc, (b) H2, Pd/C,
solvent (c) (i) TBTU, N-methylmorpholine, (ii) separation.
diastereoselectivity after deallylation7 and decarboxyla-
tion. The desired aspartic acid ketomethylene isosteres
5a -e were obtained in 62-77% yields from the Michael
acceptors 3a -e. As shown in Table 1 (entry 1), conjugate
addition to the Michael acceptor bearing the bulkiest
alkyl group can occur with remarkably high diastereo-
selectivity (>50:1). Conjugate addition to Michael ac-
ceptors bearing smaller alkyl groups proceeded with
selectivities ranging from 5-10:1. Surprisingly, the
addition to the Michael acceptor bearing a methyl group
occurred with a respectable 5:1 selectivity.
Several reaction conditions for the Michael addition
were investigated, and the use of sodium hydride and
THF at -78 °C gave the highest selectivity. Results from
entries 6-11 show that the diastereoselectivity of the
conjugate addition greatly depends on the base counter-
ion, solvent, and temperature. The sodium counterion
proved superior to either potassium and lithium (cf.
entries 2, 6-8). So far THF appears to be the solvent of
choice in this particular reaction (cf. entries 2, 10, and
11). Not surprisingly, better selectivity was obtained at
lower temperature (cf. entries 2 and 9).
The assessment of the relative configuration of the two
asymmetric centers in 5b and 5e was made by analyzing
the corresponding lactams 7b and 7e prepared as shown
in Scheme 3. For the lactam 7b we obtained crystals and
the stereochemistry assigned was confirmed by X-ray
analysis.8 NOE analysis of lactam 7e showed a 4.5%
enhancement between Ha and Hb whereas none was
observed with the minor isomer 8e. On the basis of these
results, we assume the same relative stereochemistry for
compounds 5a ,c,d . Since we found that the Michael
acceptors 3c-e were susceptible to base-catalyzed eno-
lization during the Wadsworth-Emmons reaction, it was
(MH+) 338.1732, found 338.1721. Anal. Calcd for C14H28
-
NO6P: C, 49.85; H, 8.37; N, 4.15. Found: C, 49.77; H, 8.56; N,
4.09.
Dim eth yl [(3S)-4-m eth yl-3-[(ter t-bu tyloxyca r bon yl)a m i-
n o]-2-oxop en tyl]p h osp h on a te (2b): colorless oil; [R]22
)
D
+16.8° (c, 1.35, CHCl3); 1H NMR (CDCl3) δ 5.30 (d, 8.5 Hz, 1
H), 4.32 (dd, J ) 8.5 Hz, 4 Hz, 1 H), 3.81 (d, J ) 2 Hz, 3 H), 3.78
(d, J ) 2 Hz, 3 H), 3.29 (dd, J ) 22 Hz, 14.5 Hz, 1 H), 3.09 (dd,
J ) 22 Hz, 14.5 Hz, 1 H), 2.32-2.28 (m, 1 H), 1.45 (s, 9 H), 1.00
(d, J ) 7 Hz, 3 H), 0.82 (d, J ) 7 Hz, 3 H); HRMS m/ z calcd for
C
C
13H27NO6P (MH+) 324.1576, found 324.1554. Anal. Calcd for
13H26NO6P: C, 48.29; H, 8.11; N, 4.33. Found: C, 47.83; H,
8.36; N, 4.21.
Dim eth yl [(3S)-5-m eth yl-3-[(ter t-bu tyloxyca r bon yl)a m i-
n o]-2-oxoh exyl]ph osph on ate (2c): colorless oil; [R]22D ) -15.7°
(c, 2.06, CHCl3); 1H NMR (CDCl3) δ 5.19 (d, J ) 7.5 Hz, 1 H),
4.36-4.32 (m, 1 H), 3.81 (d, J ) 4 Hz, 3 H), 3.78 (d, J ) 4 Hz,
3 H), 3.33 (dd, J ) 22 Hz, 14 Hz, 1 H), 3.10 (dd, J ) 22 Hz, 14
Hz, 1 H), 1.68-1.60 (m, 2 H), 1.45 (s, 9 H), 1.41-1.37 (m, 1 H),
0.95 (d, J ) 6 Hz, 3 H), 0.94 (d, J ) 6 Hz, 3 H); HRMS m/ z
calcd for C14H29NO6P (MH+) 338.1732, found 338.1721. Anal.
Calcd for C14H28NO6P: C, 49.85; H, 8.37; N, 4.15. Found: C,
48.87; H, 8.50; N, 4.08.
Dim eth yl [(3S)-4-p h en yl-3-[(ter t-bu tyloxyca r bon yl)a m i-
n o]-2-oxobu tyl]p h osp h on a te (2d ): white solid, mp 76-78 °C;
1
[R]22 ) -5.94° (c, 1.80, CHCl3); H NMR (CDCl3) δ 7.31-7.17
D
(m, 5 H), 5.28 (d, J ) 7 Hz, 1 H), 4.54-4.57 (m, 1 H), 3.77 (d, J
) 11.5 Hz, 3 H), 3.76 (d, J ) 11.5 Hz, 3 H), 3.29-2.92 (m, 4 H),
1.39 (s, 9 H); HRMS m/ z calcd for C17H27NO6P (MH+) 372.1576,
found 372.1587. Anal. Calcd for C17H26NO6P: C, 54.98; H, 7.06;
N, 3.77. Found: C, 54.60; H, 7.09; N, 3.75.
Dim eth yl [(3S)-3-[(ter t-bu tyloxyca r bon yl)a m in o]-2-oxo-
bu tyl]p h osp h on a te (2e): colorless oil; [R]22D ) -1.18° (c, 2.62,
CHCl3); 1H NMR (CDCl3) δ 5.36 (broad s, 1 H), 4.39-4.35 (m, 1
(7) De´ziel, R. Tetrahedron Lett. 1987, 28, 4371
(8) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(9) In order to make sure that we were indeed measuring ratios of
enantiomers and not diastereoisomers, we made the enantiomers of
5b-e from the corresponding D-amino acids and compared their elution
time with 5b-e. See footnote 4 for HPLC conditions.

Notes
J . Org. Chem., Vol. 61, No. 8, 1996 2903
H), 3.81 (d, J ) 2.5 Hz, 3 H), 3.78 (d, J ) 2.5 Hz, 3 H), 3.31 (dd,
J ) 22.5 Hz, 14 Hz, 1 H), 3.12 (dd, J ) 22.5 Hz, 14 Hz, 1 H),
EtOAc (75 mL), and the organic layer was washed with water
and brine, dried over MgSO4, and concentrated to give 4b (512
mg, 91%) as a colorless oil.
1.45 (s, 9 H), 1.36 (d, J ) 7 Hz, 3 H); HRMS m/ z calcd for C11H23
-
NO6P (MH+) 296.1263, found 296.1269. Anal. Calcd for
11H22NO6P: C, 44.75; H, 7.51; N, 4.74. Found: C, 44.47; H,
(b) To a solution of Pd(PPh3)4 (11 mg, 0.01 eq) and pyrrolidine
(1.10 mmol, 92 µL) in toluene (6 mL) was added a toluene
solution (6 mL) of crude 4b (0.90 mmol, 505 mg). The mixture
was stirred at room temperature for 2 h, diluted with EtOAc,
successively washed with 0.10 M HCl, water, and brine, dried
over MgSO4, and concentrated. The crude carboxylic acid
derivative was heated in 10 mL of xylenes at 130 °C for 4 h.
After concentration the residue was flash chromatographed
(hexane-EtOAc, 4:1) to give 5b and its 3R epimer (322 mg, 68%
from 3b) as a colorless oil: 1H NMR (CDCl3) δ 7.37-7.29 (m, 5
H), 5.11 (s, 2 H), 5.05 (d, J ) 8 Hz, 1 H), 4.23 (dd, J ) 8 Hz, 4
Hz, 1 H), 3.34-3.28 (m, 1 H), 3.12 (dd, J ) 18.5 Hz, 7.5 Hz, 1 H
× 10/11), 3.01 (dd, J ) 18.5 Hz, 6.5 Hz, 1 H × 1/11), 2.81 (dd, J
) 17.5 Hz, 5.5 Hz, 1 H × 1/11), 2.71 (dd, J ) 18.5 Hz, 5.5 Hz, 1
H × 10/11), 2.63-2.50 (m, 2 H), 2.21-2.18 (m, 1 H), 1.43 (s, 9
H), 1.40 (s, 9 H), 0.99 (d, J ) 7 Hz, 3 H), 0.77 (d, J ) 7 Hz, 3 H);
HRMS m/ z calcd for C26H40NO7 (MH+) 478.2805, found 478.2819.
Anal. Calcd for C26H39NO7: C, 65.39; H, 8.23; N, 2.93. Found:
C, 65.45; H, 8.11; N, 3.38.
C
7.65; N, 4.62.
Ben zyl (E)-(5S)-6-Meth yl-5-[(ter t-bu tyloxyca r bon yl)a m i-
n o]-4-oxo-2-h ep ten oa te (3b) (Gen er a l P r oced u r e for th e
Syn th esis of 3a ,b). To a solution of phosphonate 2b (24.7
mmol, 8.00 g) in acetonitrile (120 mL) were added triethylamine
(49.4 mmol, 6.88 mL) and a solution of benzyl glyoxylate3 (24.7
mmol, 4.05 g) in acetonitrile (30 mL). The solution was stirred
at room temperature for 1 h, poured into hexane-EtOAc,
washed with 0.1 M aqueous HCl and brine, and dried over
MgSO4. After concentration, the residue was purified by flash
chromatography (hexane-EtOAc 7:1, trans-isomer elutes faster
than the cis) to give 3b (6.43 g, 72%) as a light yellow oil: [R]22
D
) +53° (c, 2.64, CHCl3); 1H NMR (CDCl3) δ 7.39-7.35 (m, 5 H),
7.23 (d, J ) 16 Hz, 1 H), 6.83 (d, J ) 16 Hz, 1 H), 5.28-5.21 (m,
2 H), 5.13 (d, J ) 8.5 Hz, 1 H), 4.51 (dd, J ) 8.5 Hz, 4 Hz, 1 H),
2.19-2.16 (m, 1 H), 1.43 (s, 9 H), 1.02 (d, J ) 7 Hz, 3 H), 0.79
(d, J ) 7 Hz, 3 H); HRMS m/ z calcd for C20H28NO5 (MH+)
362.1967, found 362.1979. Anal. Calcd for C20H27NO5: C, 66.46;
H, 7.53; N, 3.88. Found: C, 66.60; H, 7.39; N, 4.33.
ter t-Bu tyl (3S,6S)-7,7-d im eth yl-6-[(ter t-bu tyloxyca r bo-
n yl)a m in o]-5-oxo-3-(b en zyloxyca r b on yl)oct a n oa t e (5a ):
1
white solid, mp 59-61 °C; H NMR (CDCl3) δ 7.30-7.35 (m, 5
Ben zyl (E)-(5S)-6,6-d im eth yl-5-[(ter t-bu tyloxyca r bon yl)-
a m in o]-4-oxo-2-h ep ten oa te (3a ): yellow oil; [R]22 ) +50° (c,
H), 5.12 (s, 2 H), 5.06 (d, J ) 9 Hz, 1 H), 4.10 (d, J ) 9 Hz, 1 H),
3.25-3.31 (m, 1 H), 3.15 (dd, J ) 19 Hz, J ) 7.5 Hz, 1 H), 2.82
(dd, J ) 19 Hz, 5 Hz, 1 H), 2.49-2.63 (m, 1 H), 1.42 (s, 9 H),
1.40 (s, 9 H), 0.96 (s, 9 H); HRMS m/ z calcd for C27H42NO7
(MH+) 492.2961, found 492.2975. Anal. Calcd for C27H41NO7:
C, 65.96; H, 8.41; N, 2.85. Found: C, 65.75; H, 8.49; N, 2.81.
ter t-Bu tyl (3S,6S)-8-m eth yl-6-[(ter t-bu tyloxyca r bon yl)-
a m in o]-5-oxo-3-(ben zyloxyca r bon yl)n on a n oa te (5c) a n d
D
1.29, CHCl3); 1H NMR (CDCl3) δ 7.39-7.33 (m, 5 H), 7.22 (d, J
) 16 Hz, 1 H), 6.79 (d, J ) 16 Hz, 1 H), 5.27-5.21 (m, 2 H), 5.20
(d, J ) 9 Hz, 1 H), 4.41 (d, J ) 9 Hz, 1 H), 1.42 (s, 9 H), 0.97 (s,
9 H); HRMS m/ z calcd for C21H30NO5 (MH+) 376.2124, found
376.2142. Anal. Calcd for C21H29NO5: C, 67.18; H, 7.79; N, 3.73.
Found: C, 66.82; H, 7.92; N, 3.61.
Ben zyl (E)-(5S)-5-[(ter t-bu tyloxyca r bon yl)a m in o]-4-oxo-
2-h exen oa te (3e) (Gen er a l P r oced u r e for th e Syn th esis of
3c-e). To a solution of 2e (3.40 mmol, 1.00 g) in dichlo-
romethane (5 mL) were added a dichloromethane (4 mL) solution
of benzyl glyoxylate (3.40 mmol, 560 mg) and 4 Å molecular
sieves (1 g). The mixture was stirred at room temperature for
1 h, cooled to 0 °C, and N-methylmorpholine (3.40 mmol, 354
µL) was added. After 16 h of stirring at 0 °C, the reaction
mixture was worked-up as above and purified by flash chroma-
tography (hexane-EtOAc 5:1) to give 3e (684 mg, 60%) as a light
1
(3R) ep im er : colorless oil; H NMR (CDCl3) δ 7.37-7.28 (m, 5
H), 5.13 (d, J ) 12.5 Hz, 1 H), 5.09 (d, J ) 12.5 Hz, 1 H), 4.89
(d, J ) 8 Hz, 1 H), 4.30-4.22 (m, 1 H), 3.34-3.30 (m, 1 H), 3.10
(dd, J ) 18 Hz, 7.5 Hz, 1 H × 11/12), 3.03 (dd, J ) 18.5 Hz, 7
Hz, 1 H × 1/12), 2.72 (dd, J ) 18.5 Hz, 5.5 Hz, 1 H), 2.64-2.52
(m, 2 H), 1.73-1.63 (m, 1 H), 1.57-1.48 (m, 1 H), 1.42 (s, 9 H),
1.40 (s, 9 H), 1.31-1.24 (m, 1 H), 0.94 (d, J ) 6.5 Hz, 3 H), 0.91
(d, J ) 6.5 Hz, 3 H); HRMS m/ z calcd for C27H42NO7 (MH+)
492.2961, found 492.2940. Anal. Calcd for C27H41NO7: C, 65.96;
H, 8.41; N, 2.85. Found: C, 65.95; H, 8.47; N, 2.84.
yellow oil: [R]22 ) +6.0° (c, 1.20, CHCl3); 1H NMR (CDCl3) δ
D
ter t-Bu tyl (3S,6S)-7-p h en yl-6-[(ter t-bu tyloxyca r bon yl)-
a m in o]-5-oxo-3-(ben zyloxyca r bon yl)h ep ta n oa te (5d ) a n d
(3R) ep im er : colorless oil; 1H NMR (CDCl3) δ 7.37-7.12 (m, 10
H), 5.14 (s, 2 H), 4.97 (d, J ) 7.5 Hz, 1 H), 4.49-4.43 (m, 1 H),
3.33-3.27 (m, 1 H), 3.10 (dd, J ) 14.5 Hz, 5.5 Hz, 1 H), 3.01
(dd, J ) 18 Hz, 7 Hz, 1 H), 2.84 (dd, J ) 14 Hz, 7.5 Hz, 1 H),
2.71 (dd, J ) 18.5 Hz, 6 Hz, 1 H), 2.62-2.48 (m, 2 H), 1.40 (s, 9
H), 1.39 (s, 9 H × 1/6), 1.38 (s, 9 H × 5/6); HRMS m/ z calcd for
7.39-7.34 (m, 5 H), 7.24 (d, J ) 16 Hz, 1 H), 6.86 (d, J ) 16 Hz,
1 H), 5.28-5.22 (m, 2 H), 5.21 (d, J ) 6 Hz, 1 H), 4.57-4.54 (m,
1 H), 1.43 (s, 9 H), 1.35 (d, J ) 7.5 Hz, 3 H); HRMS m/ z calcd
for C18H24NO5 (MH+) 334.1654, found 334.1664. Anal. Calcd
for C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C, 64.36; H,
7.01; N, 4.19.
Ben zyl (E)-(5S)-7-m eth yl-5-[(ter t-bu tyloxyca r bon yl)a m i-
n o]-4-oxo-2-octen oa te (3c): yellow oil; [R]22 ) -0.3° (c 2.3,
D
C
C
30H40NO7 (MH+) 526.2805, found 526.2791. Anal. Calcd for
30H39NO7: C, 68.55; H, 7.48; N, 2.66. Found: C, 68.51; H, 7.58;
1
CHCl3); H NMR (CDCl3) δ 7.39-7.34 (m, 5 H), 7.24 (d, J ) 16
Hz, 1 H), 6.85 (d, J ) 16 Hz, 1 H), 5.28-5.21 (m, 2 H), 4.98 (d,
J ) 7.5 Hz, 1 H), 4.60-4.52 (m, 1 H), 1.78-1.68 (m, 1 H), 1.58-
1.50 (m, 1 H), 1.43 (s, 9 H), 1.39-1.32 (m, 1 H), 0.98 (d, J ) 6.5
N, 2.66.
ter t-Bu tyl (3S,6S)-6-[(ter t-bu tyloxyca r bon yl)a m in o]-5-
oxo-3-(ben zyloxycar bon yl)h eptan oate (5e) an d (3R) epim er :
Hz, 3 H), 0.93 (d, J ) 6.5 Hz, 3 H); HRMS m/ z calcd for C21H30
-
-
1
NO5 (MH+) 376.2124, found 376.2111. Anal. Calcd for C21H29
colorless oil; H NMR (CDCl3) δ 7.37-7.29 (m, 5 H), 5.13-5.10
(m, 3 H), 4.32-4.25 (m, 1 H), 3.37-3.30 (m, 1 H), 3.11 (dd, J )
18 Hz, 7.5 Hz, 1 H × 5/6), 3.01 (dd, J ) 18 Hz, 7 Hz, 1 H × 1/6),
2.78-2.52 (m, 3 H), 1.44 (s, 9 H × 1/6), 1.43 (s, 9 H × 5/6), 1.40
(s, 9 H), 1.29 (d, J ) 7 Hz, 3 H × 5/6), 1.28 (d, J ) 7 Hz, 3 H ×
1/6); HRMS m/ z calcd for C24H36NO7 (MH+) 450.2492, found
450.2484. Anal. Calcd for C24H35NO7: C, 64.12; H, 7.85; N, 3.12.
Found: C, 64.20; H, 8.04; N, 3.09.
NO5: C, 67.18; H, 7.79; N, 3.73. Found: C, 67.29; H, 7.89; N,
3.73.
Ben zyl (E)-(5S)-6-p h en yl-5-[(ter t-bu tyloxyca r bon yl)a m i-
n o]-4-oxo-2-h exen oa te (3d ): white solid, mp 113-114 °C; [R]22
D
1
) +12.6° (c 1.15, CHCl3); H NMR (CDCl3) δ 7.39-7.09 (m, 10
H), 7.16 (d, J ) 16 Hz, 1 H), 6.78 (d, J ) 16 Hz, 1 H), 5.23 (s, 2
H), 5.10 (d, J ) 7.5 Hz, 1 H), 4.79-4.75 (m, 1 H), 3.13 (dd, J )
14 Hz, 6.5 Hz, 1 H), 3.00 (dd, J ) 14 Hz, 6.5 Hz, 1 H), 1.40 (s,
9 H); HRMS m/ z calcd for C24H28NO5 (MH+) 410.1967, found
410.1975. Anal. Calcd for C24H27NO5: C, 70.40; H, 6.65; N, 3.42.
Found: C, 70.38; H, 6.67; N, 3.37.
ter t-Bu t yl (3S/R,6S)-7-Met h yl-6-[(ter t-b u t yloxyca r b o-
n yl)a m in o]-5-oxo-3-(b en zyloxyca r b on yl)oct a n oa t e (5b )
(Gen er a l P r oced u r e for th e Syn th esis of 5 fr om 3). (a ) To
a solution of allyl tert-butylmalonate (1.00 mmol, 200 mg) in THF
(10 mL) was added sodium hydride (60% in mineral oil, 0.25
mmol, 10 mg). After gas evolution ceased, the mixture was
cooled to -78 °C and a THF solution (3 mL) of 3b (1.00 mmol,
361 mg) was added over a period of 5 min. The mixture was
stirred at -78 °C for 2 h and quenched with 0.1 M HCl (4 mL).
The resulting solution was extracted with a 2:1 mixture hexane-
Ack n ow led gm en t. We thank N. Aubry for the NOE
experiments, N. Shore for the HPLC analysis, and M.
Simard from the department of chemistry at Universite´
de Montre´al for the X-ray analysis. We are also grateful
to Dr. Paul C. Anderson for his encouragement and
support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR of 2b, 2c,
and 3e (3 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 O951988W