General stereoselective synthesis of chemically differentiated α-diamino acids: Synthesis of 2,6-diaminopimelic and 2,7-diaminosuberic acids

Full text of DOI:10.1021/jo0155714

4934
J . Org. Chem. 2001, 66, 4934-4938
Sch em e 1
Gen er a l Ster eoselective Syn th esis of
Ch em ica lly Differ en tia ted r-Dia m in o
Acid s: Syn th esis of 2,6-Dia m in op im elic a n d
2,7-Dia m in osu ber ic Acid s
Nicola´s Herna´ndez and V´ıctor S. Mart´ın*
Instituto Universitario de Bio-Orga´nica “Antonio Gonza´lez”,
Universidad de La Laguna, C/ Astrofı´sico Francisco
Sa´nchez, 2, 38206 La Laguna, Tenerife, Spain
Sch em e 2a
vmartin@ull.es
Received February 14, 2001
In tr od u ction
In recent years, considerable attention has been fo-
cused on R,R′-diamino dicarboxylic acids because of their
presence in living organisms1 or as isosteric analogues
to improve the chemical stability of biologically active
compounds.2 Thus, 2,6-diaminopimelic acid (DAP) (1) is
the key cross-linking amino acid in the cell wall pepti-
doglycan layer in many Gram-negative organisms3 and
a precursor of L-lysine, which is used for this purpose by
many Gram-positive organisms.4 On the other hand, 2,7-
diaminosuberic acid (DAS) (2) has been used as the
constituent amino acid in dicarba cysteine peptide ana-
logues of biologically active peptides.2,5
a
Key: (a) Ph3PdCHCO2Me, benzene, 0 °C; (b) DIBAL-H (2.2
equiv), -78 °C.
in Scheme 1. We envisaged the construction of the new
R-amino acid moiety from a stereochemically controlled
2,3-epoxy alcohol 4 that would be available from the
suitable allylic alcohol 5 obtained from the above-
mentioned aldehydes.
In this paper, we report on a general method for the
synthesis of selectively protected R,R′-diamine dicarboxy-
lic acids with unambiguously defined stereochemistry
based on the regioselective opening with sodium azide
of 2,3-epoxy alcohols 4, reduction with further protection
of the amino group, and oxidative cleavage of the result-
ing diol to the corresponding carboxylic acid.
Our synthesis made use of the known semialdehydes
3, available, respectively, from aspartic and glutamic
acids.8 Wittig homologation with methyl (triphenylphos-
phoranylidene)acetate provided the corresponding E-R,â-
unsaturated esters 6 in very good yields (Scheme 2).
Interestingly, the crucial reduction of the unsaturated
esters, with DIBAL-H at low temperature, provided
exclusively the allylic alcohols 5 without affecting the
esters of the R-amino acid moiety. Regarding this point,
it should be remembered that our methodology for the
synthesis of the ω-aldehydes 3 is based on a selective
reduction of a saturated diester.8
To generate the new R-amino acid moiety with absolute
stereochemical control, Katsuki-Sharpless asymmetric
epoxidation was performed with the suitable choice of
tartrate ester.9 Thus, the use of (+)-(R,R)-dialkyl tar-
trates produced the corresponding (S,S)-2,3-epoxy alco-
hols with excellent diastereoselection. Regioselective
opening with sodium azide provided selectively the
3-azido-1,2-diols 8 contaminated with a small amount of
the C2 isomers.10 Interestingly, under these epoxide
opening reaction conditions an N-Boc group was released
Considerable efforts have been directed to the synthe-
sis of these compounds.6 To extend their applications, for
example, in peptide synthesis, it would be very useful to
develop flexible methods for the unambiguous prepara-
tion of any desired diastereoisomer in differentially
protected forms.7 We have previously reported on the
possibility of obtaining ω-semialdehydes 3 by a selective
reduction of N,N-diBoc-R-amino diesters derived from
natural R-amino acids (glutamic or aspartic acids) or the
homologated compounds.8 With this methodology in our
hands, we considered a possible synthesis of the title
compounds based on the retrosynthetic analysis outlined
(1) (a) Ward, J . B. Pharmac. Ther. 1984, 25, 327 and references cited
therein. (b) Cox, R. J . Nat. Prod. Rep. 1998, 72, 279.
(2) (a) Williams, R. M.; Liu, J . J . Org. Chem. 1998, 63, 2130. (b)
Nutt, R. F.; Strachan, R. G.; Veber, D. F.; Holly, F. W. J . Org. Chem.
1980, 45, 3078. (c) Cox, R. J .; Sherwin, W. A.; Lam, L. K. P.; Vederas,
J . C. J . Am. Chem. Soc. 1996, 118, 7449. (d) Menger, F. M.; Caran, K.
L. J . Am. Chem. Soc. 2000, 122, 11679. (e) Sutherland, A.; Vederas, J .
C. Chem. Commun. 1999, 1739.
(3) Patte, J .-C. In Amino Acids: Biosynthesis and Genetic Regula-
tion; Hermann, K. M., Sommerville, R. L., Eds.; Adison-Wesley:
Reading, MA, 1983; pp 213-218.
(4) (a) Cox, R. J . Nat. Prod. Rep. 1996, 13, 29. (b) Bugg, T. D. H.;
Walsh, C. T. Ibid. 1992, 9, 199.
(5) Veber, D. F.; Holly, F. W.; Nutt, R. F.; Bergstrand, S. J .; Brady,
S. F.; Hirschmann, R.; Glitzer, M. S.; Saperstein, R. Nature 1979, 280,
512.
(6) Davis, F. A.; Srirajan, V. J . Org. Chem. 2000, 65, 3248 and
references cited therein.
(7) (a) J urgens, A. R. Tetrahedron Lett. 1992, 33, 4727. (b) Williams,
R. M.; Yuan, C. J . Org. Chem. 1992, 57, 6519. (c) Williams, R. M.;
Yuan, C. J . Org. Chem. 1994, 59, 6190. (d) Holcomb, R. C.; Show, S.;
Ayral-Kabustian, S.; Powel, D. Tetrahedron Lett. 1994, 35, 7005.
(8) (a) Padro´n, J . M.; Kokotos, G.; Mart´ın, T.; Markidis, T.; Gibbons,
W.; Mart´ın, V. S. Tetrahedron: Asymmetry 1998, 9, 3381. (b) Kokotos,
G.; Padro´n, J . M.; Mart´ın, T.; Gibbons, W.; Mart´ın, V. S. J . Org. Chem.
1998, 63, 3741.
(9) Katsuki, T.; Mart´ın, V. S. In Organic Reactions; Paquette, L.
A., et al., Eds.; Wiley: New York, 1996; Vol. 48, pp 1-299.
10.1021/jo0155714 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/09/2001

Notes
J . Org. Chem., Vol. 66, No. 14, 2001 4935
Sch em e 3a
Sch em e 4a
a
Key: (a) CH2dC(OMe)CH3, PPTS (cat.), CH2Cl2, rt; (b) (i) H2,
Pd/C, EtOAc, rt, (ii) (Cbz)2O, CH2Cl2, rt, (iii) MeOH, TsOH (cat.),
rt; (iv) NaIO4, Na2CO3, KMnO4, dioxane/H2O (3:1), rt; (c) CH2N2,
ether, 0 °C.
fyingly, the reduction of the azide to the desired amino
functionality was performed smoothly under hydrogena-
tion conditions. Amino protection as benzyl carbamate
(Cbz) provided the chemically differentiated diamino
compound that after acetonide cleavage and further
oxidation now provided in a differentially protected
manner the 2,6-diaminopimelic (16a )14 and 2,7-diamino-
suberic acids (16b). Also from the epimeric diol 12, the
synthesis of the remaining diastereoisomers was per-
formed in a straightforward manner.
In summary, in this paper we present an efficient,
albeit simple, protocol for the synthesis of selectively
protected di-R-amino acid. The methodology combines the
possibility of absolute stereochemical control with the
flexibility for obtaining any homologue with additional
methylene units in the carbon chain.
a
Key: (a) Ti(OPr-i)4, (R,R)-(+)-DET, TBHP, CH2Cl2, -20 °C;
(b) NaN3, NH4Cl, MeOH/H2O (8:1), reflux; (c) (i) H2, Pd(OH)2,
(Boc)2O, MeOH, rt, (ii) NaIO4, Na2CO3, KMnO4, dioxane/H2O (3:
1), rt; (d) CH2N2, ether, rt; (e) Ti(OPr-i)4, (S,S)-(-)-DET, TBHP,
CH2Cl2, -20 °C.
without affecting the integrity of the stereogenic center
(Scheme 3).11 At this stage of the synthesis we tried to
perform the necessary conversion of the azide group into
the corresponding amine. However, any attempt to
perform the direct reduction of 8 into the corresponding
free amino diols was fruitless with almost complete
recovery of the starting azido diol.12 Fortunately, we
found that the reduction could be nicely performed with
concomitant protection as the N-Boc-derivative of the
formed amino group.13 Finally, oxidative cleavage of the
diol system provided in excellent yield the corresponding
carboxylic acids 9 that were esterified to the correspond-
ing methyl esters 10 [dimethyl (R,S)-N,N-diBoc-di-
aminopimelic ester (10a ); dimethyl (R,S)-N,N-diBoc-
diaminosuberic ester (10b)]. In a similar manner, we
were also able to obtain the corresponding (S,S)-diaste-
reoisomers (13 and 14) simply choosing the alternative
chiral auxiliary in the asymmetric epoxidation step
(Scheme 3).
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. NMR spectra were measured at
400 or 300 MHz (1H) and 75 MHz (13C), and chemical shifts are
reported relative to internal Me4Si (δ ) 0). Optical rotations were
determined for solutions in chloroform or carbon tetrachloride.
Melting points are reported in degrees Celsius and are uncor-
rected. Column chromatography was performed on Merck silica
gel, 60 Å and 400-500 mesh. Compounds were visualized by
use of UV light and/or 2.5% phosphomolybdic acid in ethanol
and/or ninhydrin both in ethanol stain with heating. All solvents
were purified by standard techniques.15 Reactions requiring
anhydrous conditions were performed under argon. Anhydrous
magnesium sulfate was used for drying solutions.
Although we succeeded in the stereocontrolled synthe-
sis of the diastereoisomers of di-R-amino acid we failed
to obtain the desired compounds with a chemically
differentiated amino group. To overcome this difficulty
we readdressed our attention to the azido diol 8 (Scheme
4). Now, we protected the vicinal diol as the acetonide
15 and attempted the azido reduction once again. Grati-
P r ep a r a tion of Dim eth yl (2E,7S)-7-[Bis(ter t-bu toxyca r -
bon yl)a m in o]-2-octen ed ioa te (6a ). To a stirred solution of
3a 8a (920 mg, 2.57 mmol) in benzene (26 mL) was added
commercially available methyl (triphenylphosphoranylidene)-
acetate (1.03 g, 2.82 mmol) at 0 °C. The mixture was stirred
until TLC showed the end of the reaction. The reaction mixture
was evaporated, and the crude product was purified by silica
gel chromatography to yield 6a (950 mg, 89% yield) as an oil:
1
[R]25 ) -26.8 (c 4.4, CHCl3); H NMR (CDCl3) δ 1.42 (s, 18H),
D
1.40-1.48 (m, 2H), 1.84 (m, 1H), 2.03 (m, 1H), 2.16 (m, 2H), 3.64
(s, 6H), 4.77 (dd, J ) 9.4, 5.2 Hz, 1H), 5.76 (d, J ) 15.6 Hz, 1H),
6.86 (m, 1H); 13C NMR (CDCl3) δ 24.6 (t), 27.9 (q), 29.2 (t), 31.5
(t), 51.2 (q), 52.0 (q), 57.6 (d), 83.0 (s), 121.3 (d), 148.5 (d), 152.1
(s), 166.8 (s), 171.1 (s); IR (CHCl3) (cm-1) 2951, 1794, 1747, 1436,
(10) The regioselectivity of the reaction (C3 vs C2 opening) changes
slightly with the length of the carbon chain (7:1 for the DAP series
and 9:1 for the DAS series). In the next steps, the major isomers were
used after purification.
(11) Herna´ndez, N.; Mart´ın, V. S. Manuscript in preparation. We
speculate about the Lewis acid influence of Na+ promoting the attack
-
of the N3 to one of the carbonyl groups of the N,N-di-Boc system.
(12) Saito, S.; Bunya, N.; Moriwake, T.; Torii, S. Tetrahedron Lett.
1985, 26, 5309.
(13) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron
Lett. 1989, 30, 837.
(14) Gao, Y.; Lane-Bell, P.; Vederas, J . C. J . Org. Chem. 1998, 63,
2133.
(15) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals, 4th ed.; Butterworth-Heinemann: Oxford, 1996.

4936 J . Org. Chem., Vol. 66, No. 14, 2001
Notes
1368, 1141; HRMS calcd for C20H33NO8Na (M + Na)+ 438.2098,
found 438.2093.
δ 1.48 (s, 18H), 1.55-1.42 (m, 6H), 1.85 (m, 1H), 2.09 (m, 1H),
2.89 (m, 2H), 3.63 (dd, J ) 12.3, 3.4 Hz, 1H), 3.69 (s, 3H), 3.86
(d, J ) 12.3 Hz, 1H), 4.81 (dd, J ) 9.4, 5.2 Hz, 1H); 13C NMR
(CDCl3) δ 25.5 (t), 25.9 (t), 27.9 (q), 29.7 (t), 31.3 (t), 52.1 (q),
55.8 (d), 57.9 (d), 58.4 (d), 61.7 (t), 83.1 (s), 152.1 (s), 171.3 (s);
IR (CHCl3) (cm-1) 3499, 2980, 1789, 1731, 1694, 1368; HRMS
calcd for C20H35NO8Na (M + Na - Boc)+ 340.1731, found
340.1736.
P r ep a r a tion of Dim eth yl (2E,8S)-8-[Bis(ter t-bu toxyca r -
bon yl)a m in o]-2-n on en ed ioa te (6b). The procedure used above
to obtain 6a from 3a was applied to 3b8a on a 924 mg (2.48 mmol)
scale, yielding 6b (947 mg, 89% yield) as a colorless oil: [R]25
D
) -29.3 (c 2.2, CHCl3); 1H NMR (CDCl3) δ 1.41 (s, 18H), 1.34-
1.46 (m, 4H), 1.80 (m, 1H), 2.02 (m, 1H), 2.13 (m, 2H) 3.63 (s,
6H), 4.76 (dd, J ) 9.5, 15.7 Hz, 1H), 5.73 (d, J ) 15.7 Hz, 1H),
6.86 (m, 1H); 13C NMR (CDCl3) δ: 25.8 (t), 27.5 (t), 27.9 (q), 29.6
(t), 31.9 (t), 51.2 (q), 52.0 (q), 57.8 (d), 82.9 (s), 121.0 (d), 149.0
(d), 152.2 (s), 166.8 (s), 171.8 (s) IR (CHCl3) (cm-1) 2935, 1794,
1728, 1436, 1368; HRMS calcd for C21H35NO8Na (M + Na)+
452.2260, found 452.2257.
P r ep a r a tion of Meth yl (2S,6R,7R)-6-Azid o-2-ter t-bu toxy-
ca r bon yla m in o-7,8-d ih yd r oxyocta n oa te (8a ). To a stirred
solution of epoxy alcohol 7a (1 g, 2.48 mmol) in methanol-H2O
(8:1) (24.8 mL) were added sodium azide (1.3 g, 20.2 mmol) and
ammonium chloride (780 mg, 14.5 mmol). After the addition,
the mixture was boiled under reflux for 24 h. The reaction
mixture was evaporated, and the residue was extracted with
ethyl acetate. The phases were separated, and the aqueous phase
was extracted with ethyl acetate. The combined organic phases
were washed with a solution of brine, dried, concentrated, and
purified by column chromatography to yield 8a (712 mg, 83%
yield) as an oil: [R]25D ) +13.9 (c 0.36, CHCl3); 1H NMR (CDCl3)
δ 1.41 (s, 9H), 1.40-1.82 (m, 6H), 3.43 (m, 1H), 3.66 (m, 3H),
3.72 (s, 3H), 4.16 (bs, 1H), 5.20 (bs, 1H); 13C NMR (CDCl3) δ
22.0 (t), 28.3 (q), 29.6 (t), 32.5 (t), 52.24 (q), 52.9 (d), 62.5 (t),
63.2 (d), 63.9 (d), 64.0 (d), 73.5 (d), 80.2 (s) 155.5 (s), 173.2 (s),
173.3 (s); IR (CHCl3) (cm-1) 3369, 2930, 1694, 1439, 1367; HRMS
calcd for C14H26N4O6Na (M + Na)+ 369.1745, found 369.1754.
P r ep a r a tion of Meth yl (2S,7R,8R)-7-Azid o-2-ter t-bu toxy-
ca r bon yla m in o-8,9-d ih yd r oxyn on a n oa te (8b). The proce-
dure used above to obtain 8a from 7a was applied to 7b on a
2.39 mmol scale (1 g), yielding 8b (736.5 mg, 86% yield) as an
P r ep a r a tion of Meth yl (2S,6E)-2-[bis(ter t-bu toxyca r bon -
yl)a m in o]-8-h yd r oxy-6-octen oa te (5a ). To a stirred solution
of the R,â-unsaturated dimethyl ester 6a (1 g, 2.4 mmol) in dry
Et2O (24 mL, 0.1 M) was added dropwise DIBAL (3 mL, 1.0 M
in hexane, 5.28 mmol) at -78 °C. The reaction was stirred for 5
min and then quenched with H2O (ca. 0.5 mL). The mixture was
stirred for 30 min, dried, and filtered through a pad of Celite.
The solvent was evaporated and the crude purified by silica gel
column chromatography to afford 5a (790 mg, 85% yield) as an
1
oil: [R]25 ) -30.1 (c 2.36, CHCl3); H NMR (CDCl3) δ 1.47 (s,
D
18H), 1.84 (m, 2H), 2.09 (m, 2H), 3.68 (s, 3H), 4.04 (bs, 1H), 4.83
(m, 1H), 5.61 (m, 2H); 13C NMR (CDCl3) δ 25.6 (t), 27.9 (q), 29.7
(t), 31.7 (t), 52.1 (q), 57.9 (d), 63.6 (t), 83.2 (s), 129.6 (d), 132.3
(d), 152.1 (s), 171.4 (s); IR (CHCl3) (cm-1) 3530, 2980, 1788, 1747,
1458, 1003; HRMS calcd for C14H25NO5Na (M + Na - Boc)+
310.1625, found 310.1629.
P r ep a r a tion of Meth yl (2S,7E)-2-[Bis(ter t-bu toxyca r bon -
yl)a m in o]-9-h yd r oxy-7-n on en oa te (5b). The procedure used
above to obtain 5a from 6a was applied to 6b on a 1 g (2.33
oil: [R]25 ) -3.0 (c 7.0, CH3COCH3): 1H NMR (CDCl3) δ 1.43
D
(s, 9H), 1.80-1.36 (m, 8H), 3.44 (m, 1H), 3.66 (m, 3H), 3.73 (s,
3H), 4.29 (bs, 1H), 5.08 (bs, 1H); 13C NMR (CDCl3) δ 24.5 (t),
24.7 (t), 25.5 (t), 25.5 (t), 27.9 (q), 28.2 (q), 30.0 (t), 32.4 (t), 32.6
(t), 33.3 (t), 52.2 (q), 53.0 (d) 53.2 (d), 62.1 (t), 63.9 (d), 64.0 (d),
66.9 (d), 71.3 (d), 73.5 (d), 73.6 (d), 80.0 (s) 155.5 (s), 155.7 (s),
173.3 (s), 173.4 (s); IR (CHCl3) (cm-1) 3368, 2935, 2098, 1638,
1365, 1049; HRMS calcd for C15H28N4O6Na (M + Na)+ 383.1901,
found 383.1903.
mmol) scale, yielding 5b (811 mg, 87% yield) as an oil: [R]25
)
D
-31.4 (c 4.5, CHCl3); 1H NMR (CDCl3) δ 1.35(m, 2H) 1.47 (s,
18H), 1.68-1.86 (m, 6H), 3.68 (s, 3H), 4.04 (d, J ) 3.7 Hz, 2H),
4.80 (dd, J ) 9.5, 5.1 Hz, 1H), 5.61 (m, 2H); 13C NMR (CDCl3) δ
25.5 (t), 27.9 (q) 28.5 (t), 29.6 (t), 31.8. (t), 52.0 (q), 57.9(d), 63.4
(t), 82.9 (s), 129.4 (d), 132.4 (d), 152.1 (s), 171.3 (s); IR (CHCl3)
(cm-1) 3503, 2981, 1785, 1740, 1437, 972; HRMS calcd for C20H35
-
P r epar ation (6S,2R)-2,6-Bis[(ter t-Bu toxy)car bon ylam in o]-
6-(m eth oxyca r bon yl)h exa n oic Acid (9a ). To a stirred solu-
tion of 8a (386 mg, 1.11 mmol) in dry MeOH (10 mL) were added
Pd(OH)2 (40 mg) and Boc2O (460 mg, 2.1 mmol). The reaction
was stirred under hydrogen atmosphere until TLC showed
complete conversion (ca. 1 h). The mixture was filtered through
a pad of Celite, and the resulting solution was concentrated
yielding an oily residue. This material was dissolved in a
biphasic solvent system (7 mL of dioxane-3 mL of H2O), and
Na2CO3 (54 mg, 0.5 mmol), NaIO4 (856 mg, 4 mmol), and KMnO4
(32 mg, 0.2 mmol) were sequentially added at room temperature
with stirring. The reaction mixture was stirred for 30 min, after
which time TLC showed complete reaction. Then the reaction
mixture was diluted with EtOAc, treated with HCl (5% v/v) until
pH ) 1, washed with brine, dried, and concentrated to yield an
oily residue that was purified by silica gel column chromatog-
raphy to obtain the carboxylic acid 9a as a foamy oil (348 mg,
78% yield): [R]25D ) -3.7 (c 5.93, CHCl3); 1H NMR (CD3COCD3)
δ 1.39 (s, 18H), 1.47-1.84 (m, 4H), 2.1 (m, 2H), 3.66 (s, 3H),
4.14 (bs, 2H), 6.15 (m, 1H); 13C NMR (CD3COCD3) δ: 21.9 (t),
27.7 (q), 31.3 (t), 31.3 (t), 51.2 (q), 53.2 (d), 53.5 (d), 78.3 (s),
155.6 (s), 172.8 (s), 173.2 (s); IR (CHCl3) (cm-1) 3342, 2977, 1713,
1514, 1367, 1164, 1023; HRMS calcd for C13H24N2O6Na (M +
Na - Boc)+ 327.1527, found 327.1529.
NO7Na (M + Na)+ 424.2311, found 424.2282.
P r epar ation of Meth yl (2S)-5-[(3S,2S)-3-(Hydr oxym eth yl)-
o x i r a n -2-y l]-2-[b i s (t er t -b u t o x y c a r b o n y l)a m i n o ]p e n -
ta n oa te (7a ). Crushed, activated 3 Å molecular sieves were
added to stirred CH2Cl2 (7 mL). The flask was cooled to -20 °C,
and Ti(OPr-i)4 (0.35 mL, 1.2 mmol), (R,R)-(+)-diethyl tartrate
(0.24 mL, 1.4 mmol), and the allylic alcohol 5a (387 mg, 1 mmol)
in CH2Cl2 (3 mL) were added sequentially with stirring. The
mixture was stirred at the same temperature for 15 min, and
tert-butyl hydroperoxide (0.4 mL, 4.5 M in isooctane, 1.8 mmol)9
was added slowly. After the addition, the reaction was main-
tained with stirring for 4 h. Tartaric acid aqueous solution (15%
w/v, 10 mL) was added, and the stirring was continued until
clear phases were reached (30min). The phases were separated,
and the aqueous phase was extracted with CH2Cl2. The com-
bined organic phases were concentrated, diluted with ether, and
treated with a precooled (0 °C) 15% (w/v) NaOH aqueous
solution. The two-phase mixture was stirred vigorously for 15
min at 0 C. The organic phase was separated, and the aqueous
phase was extracted with ether. The combined organic phases
were washed with brine, dried, filtered, evaporated, and purified
by silica gel chromatography to yield 7a (330 mg, 82% yield,
>95% de by 1H NMR) as a colorless oil: [R]25 ) -36.3 (c 7.4,
D
CHCl3); 1H NMR (CDCl3) δ 1.47 (m, 4H), 1.48 (s, 18H), 1.91 (m,
1H), 2.14 (m, 1H), 2.91 (m, 2H), 3.60 (dd, J ) 12.5, 3.7 Hz, 1H)
3.73 (s, 3H), 3.87 (d, J ) 12.4 Hz, 1H), 4.84 (dd, J ) 9.4, 5 Hz,
1H): 13C NMR (CDCl3) δ 22.6(s), 22.8 (t), 28.0 (q), 29.6 (t), 31.1
(t), 52.1 (q), 55.5 (d), 57.9 (d), 58.7 (d), 61.2 (t), 83.1 (s), 152.2
(s), 171.2 (s); IR (CHCl3) (cm-1) 3447, 2980, 1789, 1694, 1368,
1126; HRMS calcd for C19H33NO8Na (M + Na)+ 426.2098, found
426.2104.
P r ep a r a t ion of (2R,7S)-2,7-Bis[(ter t-b u t oxy)ca r b on yl-
a m in o]-7-(m eth oxyca r bon yl)h ep ta n oic Acid (9b). The pro-
cedure used above to obtain 9a from 8a was applied to 8b on a
1.11 mmol scale (400 mg), yielding 9b (346 mg, 75% yield) as
an oil: [R]25 ) -2.2 (c 1.9, CHCl3); 1H NMR (CD3COCD3) δ
D
1.39 (s, 18H), 1.35-1.44 (m, 4H), 1.59-1.95 (m, 4H), 3.66 (s,
3H), 4.13 (bs, 2H), 6.1 (bs, 2H); 13C NMR (CD3COCD3) δ 25.2
(t), 25.5 (t) 27.7 (q), 31.5 (t), 31.6 (t), 51.2 (q), 53.3 (d), 53.6 (d),
78.3 (s), 155.6 (s), 173.0 (s), 173.6 (s); IR (CHCl3) (cm-1) 3367,
2978, 1715, 1457, 1368, 1168; HRMS calcd for C19H34N2O8Na
(M + Na)+ 441.2207, found 441.2205.
P r ep a r a tion of Dim eth yl (2S,6R)-2,6-Bis-ter t-bu toxyca r -
bon yla m in oh ep ta n ed ioa te (m eso-10a ). To a solution of 9a
(404 mg, 1 mmol) in ether (45 mL) was added an ethereal
P r ep a r a tion of Meth yl 6-[(2S,3S)-3-(Hyd r oxym eth yl)-
oxir a n -2-yl](2S)-2-[b is(ter t-b u t oxyca r b on yl)a m in o]h ex-
a n oa te (7b). The procedure used above to obtain 7a from 5a
was applied to 5b on a 1 mmol scale (402 mg) using (R,R)-(+)-
diethyl tartrate as the chiral auxiliary, yielding 7b (342 mg, 82%
yield) as an oil: [R]25 ) -33.8 (c 1.3, CHCl3); 1H NMR (CDCl3)
D

Notes
J . Org. Chem., Vol. 66, No. 14, 2001 4937
diazomethane solution until a yellow color persisted. Then
several drops of acetic acid were added until a colorless solution
was obtained. The mixture was concentrated and the residue
purified by column chromatography, yielding 10a (405 mg, 97%)
as an oil: 1H NMR (CDCl3) δ 1.38 (s, 18H), 1.52-1.82 (m, 6H),
3.67 (s, 6H), 4.21 (bs, 2H), 5.11 (bs, 2H); 13C NMR (CDCl3) δ
21.1 (t), 21.3 (t), 27.9 (q), 28.2(q), 32.1 (t), 52.1 (q), 53.0 (d), 79.8
(s), 155.4 (s), 173.0 (s); IR (CHCl3) (cm-1) 3363, 2977, 2933, 1714,
1519, 1366, 1166, 1098, 1061; HRMS calcd for C19H34N2O8Na
(M + Na)+ 441.2207, found 441.2219.
P r ep a r a tion of Dim eth yl (2R,7S)-2,7-Bis-ter t-bu toxyca r -
bon yla m in oocta n ed ioa te (m eso-10b). The procedure used
above to obtain 10a from 9a was applied to 9b on a 1 mmol
scale (418 mg), yielding 10b (411 mg, 95%) as a white solid: mp
144-145 °C; 1H NMR (CDCl3) δ 1.43 (s, 18H), 1.25-1.43 (m,
4H), 1.60 (m, 4H) 3.70 (s, 6H), 4.26 (bs, 2H), 5.00 (bs, 2H); 13C
NMR (CDCl3) δ 24.8 (t), 28.3 (q), 32.5 (t), 52.2 (q), 53.2 (t), 79.9
(s), 155.3 (s), 173.3 (s); IR (CHCl3) (cm-1) 3352, 2932, 1715, 1367,
1166, 1051; HRMS calcd for C20H36N2O8Na (M + Na)+ 455.2364,
found 455.2363.
(s, 18H), 1.55 (m, 2H), 1.75 (m, 4H), 3.66 (s, 3H), 4.07 (bs, 2H),
6.15 (bs, 1H); 13C NMR (CD3COCD3) δ 22 (t), 27.7 (q), 31.2 (t),
31.3 (t), 51.2 (q), 53.4 (d), 78.3 (s), 155.6 (s), 172.9 (s), 173.2 (s);
IR (CHCl3) (cm-1) 3350, 2977, 1715, 1519, 1367, 1163, 1098,
1051, 1024; HRMS calcd for C18H32N2O8Na (M + Na)+ 427.2051,
found 427.2035.
P r ep a r a t ion of (2S,7S)-2,7-Bis[(ter t-b u t oxy)ca r b on yl-
a m in o]-7-(m eth oxyca r bon yl)h ep ta n oic Acid (13b). The pro-
cedure used above to obtain 9a from 8a was applied to 12b on
a 1 mmol scale (400 mg), yielding 13b (350 mg, 83%): [R]25
)
D
+11.0 (c 1.8, CHCl3); 1H NMR (CD3COCD3) δ 1.39 (s, 18H), 1.15-
1.80 (m, 8H), 3.66 (s, 3H), 4.13 (bs, 2H), 6.15 (bs, 1H); 13C NMR
(CD3COCD3) δ: 25.2 (t), 27.7 (q), 31.5 (t), 31.7 (t), 51.2 (q), 53.3
(d), 53.6 (d), 78.3 (s), 78.3 (s), 155.6 (s), 173.0 (s), 173.5 (s); IR
(CHCl3) (cm-1) 3350, 2978, 1714, 1514, 1369, 1167; HRMS calcd
for C19H34N2O8 (M + H)+ 419.2388, found 419.2377.
P r ep a r a tion of Dim eth yl (2S,6S)-2,6-Bis-ter t-bu toxyca r -
bon yla m in o-h ep ta n ed ioa te (14a ). The procedure used above
to obtain 9a from 8a was applied to 13a on a 1 mmol scale (404
mg), yielding 14a (411 mg, 98%) as an oil: [R]25 ) +11.7 (c
D
P r ep a r a t ion of Met h yl (2S)-5-[(2R,3R)-3-(H yd r oxy-
m et h yl)oxir a n -2-yl]-2-[b is(ter t-b u t oxyca r b on yl)a m in o]-
p en ta n oa te (11a ). The procedure used above to obtain 7a from
5a was applied to 5a on a 1 mmol scale (387 mg) using (R,R)-
(-)-diethyl tartrate as the chiral auxiliary, yielding 11a (330
1.8, CHCl3); 1H NMR CDCl3) δ 1.39 (s, 18H), 1.61-1.79 (m, 6H),
3.66 (s, 6H), 4.20 (bs, 2H), 5.11 (bs, 2H); 13C NMR (CDCl3) δ
21.3 (t), 27.9 (q), 28.3 (q), 32.1 (t), 52.2 (q), 52.9 (d), 79.8 (s),
155.5 (s), 173.0 (s), 173.1 (s); IR (CHCl3) (cm-1) 3365, 2977, 1745,
1166, 1097, 1022; HRMS calcd for C19H34N2O8Na (M + Na)+
441.2207, found 441.2203.
mg, 82% yield >95% de by 1H NMR analysis) as an oil: [R]25
)
D
-17.0 (c 6.7, CHCl3); 1H NMR (CDCl3) δ 1.48 (s, 18H), 1.66-
1.58 (m, 4H), 1.91 (m, 1H), 2.14 (m, 1H), 2.91 (m, 2H), 3.61 (dd,
J ) 12.5, 3.7 Hz, 1H) 3.73 (s, 3H), 3.87 (d, J ) 12.4, 1H), 4.84
(dd, J ) 9.4, 5.2 Hz, 1H): 13C NMR (CDCl3) δ 22.6 (t), 27.6 (q),
27.8 (q), 29.5 (t), 31.1 (t), 52.0 (q), 55.6 (d), 57.7 (d), 58.3 (d),
61.7 (t), 83.0 (s), 152.0 (s), 171.1 (s); IR (CHCl3) (cm-1) 3514,
2978, 1744, 1692, 1458, 1126; HRMS calcd for C19H33NO8Na (M
+ Na)+ 426.2098, found 426.2108.
P r ep a r a t ion of Met h yl (2S)-6-[(3R,2R)-3-(H yd r oxy-
m et h yl)oxir a n -2-yl]-2-[b is(ter t-b u t oxyca r b on yl)a m in o]-
h exa n oa te (11b). The procedure used above to obtain 7a from
5a was applied to 5b on a 1 mmol scale (401 mg) using (R,R)-
P r ep a r a tion of Dim eth yl (2S,7S)-2,7-Bis-ter t-bu toxyca r -
bon yla m in oocta n ed ioa te (14b). The procedure used above to
obtain 10a from 9a was applied to 13b on a 1 mmol scale (418
mg), yielding 14b (415 mg, 96% yield) as an oil: [R]25 ) +14.3
D
1
(c 0.7, CHCl3); H NMR (CDCl3) δ 1.43 (s, 18H), 1.63-1.82 (m,
8H), 3.71 (s, 6H), 4.29 (bs, 1H), 5.09 (d, 2H); 13C NMR (CDCl3)
δ 21.3 (t), 28.3 (q), 32.2 (t), 52.3 (q), 53.0 (t), 79.9 (s), 155.5 (s),
173.2 (s); IR (CHCl3) (cm-1) 3364, 2977, 1744, 1513, 1366, 1061;
HRMS calcd for C20H36N2O8Na (M + Na)+ 455.2364, found
455.2374.
P r ep a r a tion of Meth yl (2S,6R)-6-Azid o-2-ter t-bu toxy-
ca r b on yla m in o-6-[(4R)-(2,2-d im et h yl[1,3]d ioxola n -4-yl)]-
h exa n oa te (15a ). To a stirred solution of 8a (346 mg, 1 mmol)
in CH2Cl2 were added 2-methoxypropene (94 mg, 1.3 mmol) and
a catalytic amount of PPTS. The mixture was additionally stirred
at room temperature for 2 h. Then three drops of Et3N were
added to neutralize the catalyst and the stirring was continued
for 2 min. The resulting solution was washed with brine, dried,
concentrated, and purified by column chromatography yielding
15a (329 mg, 85% yield) as an oil: [R]25D ) +24.2 (c 5.0, CHCl3);
1H NMR (CDCl3) δ 1.30 (s, 3H), 1.40 (s, 9H), 1.41 (s, 3H), 1.46-
1.89 (m, 6H), 3.43 (m, 1H), 3.70 (s, 3H), 3.81 (m, 1H), 4.01 (m,
2H), 4.26 (bs, 1H), 5.06 (bs, 1H); 13C NMR (CDCl3) δ 22.0 (t),
25.1 (q), 26.2 (q), 28.2 (q), 30.4 (t), 32.5 (t), 52.2 (q), 53.0 (d),
63.5 (t), 65.8 (d), 77.5 (d) 79.9 (s), 109.6 (s), 155.3 (s), 173.0 (s);
IR (CHCl3) (cm-1) 3370, 2360, 1745, 1715, 1367, 1060; HRMS
calcd for C17H30N4O6Na (M + Na)+ 409.2063, found 409.2097.
P r ep a r a tion of Meth yl (2S,7R)-7-Azid o-2-ter t-bu toxy-
car bon ylam in o-7-[(4R)-2,2-dim eth yl[1,3]dioxolan -4-yl)]h ep-
ta n oa te (15b). The procedure used above to obtain 15a from
8a was applied to 8b on a 1 mmol scale (360 mg), yielding 15b
(-)-diethyl tartrate as the chiral auxiliary, yielding 11b (371
1
mg, 89% yield >95% de by H NMR analysis) as an oil: [R]25
)
D
1
-16.1 (c 8.05, CHCl3); H NMR (CDCl3) δ 1.54 (s, 18H), 1.62-
1.47 (m, 4H), 1.84-2.01 (m, 4H), 2.89 (m, 2H), 3.59 (d, J ) 12.1
Hz, 1H) 3.68 (s, 3H),, 3.87 (d, J ) 13.0 Hz, 1H), 4.81 (dd, J )
9.3, 5.2 Hz, 1H): 13C NMR (CDCl3) δ 25.5 (t), 26.0 (t), 27.9 (q),
29.7 (t), 31.3 (t), 52.1 (q), 55.8 (d), 57.9 (d), 58.7 (d), 61.7 (t), 83.0
(s), 152.1 (s), 171.3 (s); IR (CHCl3) (cm-1) 3499, 2979, 1746, 1697,
1368, 1036; HRMS calcd for C20H35NO8Na (M + Na - Boc)+
340.1731, found 340.1736.
P r ep a r a tion of Meth yl (2S,6S,7S)-6-Azid o-2-ter t-bu toxy-
ca r bon yla m in o-7,8-d ih yd r oxyocta n oa te (12a ). The proce-
dure used above to obtain 8a from 7a was applied to 11a on a
2.48 mmol scale (1 g), yielding 12a (720 mg, 84% yield) as an
oil: [R]25D ) +8.0 (c 0.5, CHCl3); 1H NMR (CDCl3) δ 1.42 (s, 9H),
1.36-1.8 (m, 6H), 3.36 (m, 1H), 3.66 (m, 3H), 3.73 (s, 3H), 4.30
(bs, 1H), 5.18 (d, J ) 8.0 Hz, 1H); 13C NMR (CDCl3) δ 20.8 (s),
21.1 (t), 28.3(q), 29.2 (t), 32.7 (t), 52.4 (q), 52.7 (d), 53.1 (d), 62.4
(t), 63.2 (t), 63.4 (d), 63.9 (d), 66.6 (d), 71.7 (d), 72.6 (d), 80.3 (s)
155.8 (s), 173.2 (s), 173.3 (s); IR (CHCl3) (cm-1) 3369, 2953, 2104,
1694, 1519, 1367, 1167, 1049, 1027; HRMS calcd for C14H26N4O6-
Na (M + Na)+ 369.1745, found 369.1754.
(348 mg, 87% yield) as an oil: [R]25 ) +23.8 (c 3.8, CHCl3); 1H
D
NMR (CDCl3) δ 1.32 (s, 3H), 1.41 (s, 9H), 1.42 (s, 3H), 1.40-
1.79 (m, 8H), 3.43 (m, 1H), 3.71 (s, 3H), 3.82 (m, 1H), 4.01 (m,
2H), 4.26 (bs, 1H), 5.02 (bs, 1H); 13C NMR (CDCl3) δ 25.0 (q),
25.1 (t), 25.7 (t), 26.2 (q), 28.3 (q), 30.7 (t), 32.6 (t), 52.2 (q), 53.3
(d), 63.6 (d), 65.9 (t), 77.7 (d), 79.9 (s), 109.6 (s), 155.3 (s), 173.2
(s) IR (CHCl3) (cm-1) 3356, 2981, 2102, 1745, 1368, 1063; HRMS
calcd for C18H32N4O6Na (M + Na)+ 423.2214, found 423.2224.
P r ep a r a tion of (2R,6S)-6-(ter t-Bu toxyca r bon yla m in o)-
6-(m eth oxyca r bon yl)-2-[(p h en ylm eth oxy)ca r bon yla m in o]-
h exa n oic Acid (16a ). To a stirred solution of 15a (386 mg, 1
mmol) in dry MeOH (10 mL) was added Pd(OH)2 (89 mg). The
reaction was stirred under hydrogen atmosphere until TLC
showed complete conversion (ca. 2 h). The mixture was filtered
through a pad of Celite, and the resulting solution was concen-
trated. The residue was dissolved in dry CH2Cl2 (10 mL) and
treated with dibenzyl dicarbonate (Cbz2O) (350 µL, 1.2 mmol)
at room temperature. The mixture was stirred for 5 min and
then concentrated, yielding a Cbz-protected amine acetonide that
was used without purification in the next step.
P r ep a r a tion of Meth yl (2S,7S,8S)-7-Azid o-2-ter t-bu toxy-
ca r bon yla m in o-8,9-d ih yd r oxyn on a n oa te (12b). The proce-
dure used above to obtain 8a from 7a was applied to 11b on a
2.39 mmol scale (1 g), yielding 12b (732 mg, 85% yield) as an
1
oil: [R]25 ) +14.7 (c 2.72, CHCl3); H NMR (CDCl3) δ 1.42 (s,
D
9H), 1.36-1.8 (m, 8H), 3.36 (m, 1H), 3.66 (m, 3H), 3.72 (s, 3H),
4.27 (bs, 1H), 5.11 (d, J ) 8.3 Hz, 1H); 13C NMR (CDCl3) δ 25.0
(t), 25.6 (t), 27.9 (q), 29.9 (q), 32.2 (t), 33.2 (t), 52.2 (q), 53.3 (d),
62.1 (t), 63.1 (t), 63.9 (d), 67.0 (d), 71.4 (d), 73.6 (d), 79.9 (s) 155.6
(s), 173.4 (s), 173.4 (s); IR (CHCl3) (cm-1) 3369, 2937, 2100, 1692,
1438, 1166; HRMS calcd for C15H28N4O6Na (M + Na)+ 383.1901,
found 383.1913.
P r ep a r a t ion of (2S,6S)-2,6-Bis[(ter t-b u t oxy)ca r b on y-
la m in o]-6-(m eth oxyca r bon yl)h exa n oic Acid (13a ). The pro-
cedure used above to obtain 9a from 8a was applied to 12a on
a 1.11 mmol scale (386 mg), yielding 13a (332 mg, 75%) as an
oil: [R]25D) +7.3 (c 3.1, CHCl3); 1H NMR (CD3COCD3) δ 1.39

4938 J . Org. Chem., Vol. 66, No. 14, 2001
Notes
A solution of the crude acetonide in MeOH (10 mL) and a
catalytic amount of p-toluenesulfonic acid (19 mg) were stirred
at room temperature for 24 h. Then three drops of Et3N were
added to neutralize the catalyst, and the mixture was addition-
ally stirred for 2 min. The resulting solution was washed with
brine, dried, and concentrated, yielding a foamy oil. This residue
was dissolved in a biphasic solvent system (7 mL of dioxane-3
mL of H2O) and treated sequentially with Na2CO3 (53 mg, 0.5
mmol), NaIO4 (856 mg, 4 mmol) and KMnO4 (32 mg, 0.2 mmol)
at room temperature with stirring. The reaction mixture was
stirred for 30 min, after which time TLC showed complete
reaction. Then the reaction mixture was diluted with EtOAc,
treated with HCl (5% v/v) until pH ) 1, washed with brine, dried,
and concentrated. The residue was purified by silica gel column
chromatography to obtain the carboxylic acid 16a as a foamy
oil (263 mg, 60% yield): [R]25D ) +10.0 (c 3.36, CHCl3); 1H NMR
(CD3COCD3) δ 1.39 (s, 9H), 1.38-1.45(m, 2H), 1.55-2.04 (m,
4H), 3.65 (s, 3H), 4.12 (m, 2H), 5.08 (s, 2H), 6.19 (bs, 1H), 6.54
(bs, 1H), 7.31 (m, 5H); 13C NMR (CD3COCD3) δ 21.9 (t), 27.7
(q), 31.3 (t), 51.3 (q), 53.5 (d), 65.9 (t), 78.5 (s), 127.7 (d), 128.3
18b (344 mg, 90%) as an oil: [R]25 ) +2.2 (c 0.5, CHCl3); 1H
D
NMR (CDCl3) δ 1.33 (s, 3H), 1.38 (s, 3H), 1.41 (s, 9H), 1.33-
1.96 (m, 8H), 3.17 (m, 1H), 3.54 (m, 1H) 3.60 (m, 1H), 3.70 (s,
3H), 3.90 (m, 1H), 4.25 (bs, 1H), 4.99 (bs, 1H); 13C NMR (CDCl3)
δ 19.3 (t), 24.4 (q), 24.8 (q), 28.3 (q), 28.4 (q), 32.6 (t), 52.1 (q),
53.3 (d), 58.9 (d), 62.3 (t), 71.9 (d), 79.8 (d), 98.9 (s), 155.3 (s),
173.3 (s); IR (CHCl3) (cm-1) 2954, 2360, 2106, 1714, 1645, 1162;
HRMS calcd for C18H32N4O6Na (M + Na)+ 423.2219, found
423.2162.
P r ep a r a tion of (2S,6S)-6-(ter t-Bu toxy)ca r bon yla m in o)-
6-(m eth oxyca r bon yl)-2-[(p h en ylm eth oxy)ca r bon yla m in o]-
h exa n oic Acid (19a ). The procedure used above to obtain 16a
from 15a was applied to 18a on a 1 mmol scale (386 mg), yielding
1
19a (267 mg, 61%) as an oil: [R]25 ) +7.0 (c 10.5, CHCl3); H
D
NMR (CD3COCD3) δ 1.38 (s, 9H), 1.45-1.86 (m, 6H), 3.65 (s,
3H), 4.18 (m, 2H), 5.08 (s, 2H), 6.18 (bs, 1H), 6.52 (bs, 1H), 7.31
(m, 5H); 13C NMR (CD3COCD3) δ 22.0 (t), 27.7 (q), 31.2 (t), 31.3
(t), 51.3 (q), 53.5 (d), 53.6 (d), 65.9 (t) 78.5 (s), 127.7 (d), 128.3
(d), 137.2 (s), 155.6 (s), 156.3 (s), 172.9 (s), 173.1 (s); IR (CHCl3)
(cm-1) 3338, 2954, 2611, 1715, 1367, 1164, 1064; HRMS calcd
for C21H30N2O8Na (M + Na)+ 461.1894, found 461.1886.
(d), 137.2 (s), 155.6 (s), 156.3 (s), 172.9 (s); IR (CHCl3) (cm-1
)
3360, 2976, 1694, 1367, 1168, 1026; HRMS calcd for C21H30N2O8-
P r ep a r a tion of (2S,7S)-7-(ter t-bu toxyca r bon yla m in o)-7-
(m et h oxyca r b on yl)-2-[(p h en ylm et h oxy)ca r b on yla m in o]-
h ep ta n oic Acid (19b). The procedure used above to obtain 16a
Na (M + 1)+ 439.2080, found 439.2050.
P r ep a r a tion of (2R,7S)-7-(ter t-Bu toxyca r bon yla m in o)-
7-(m eth oxyca r bon yl)-2-[(p h en ylm eth oxy)ca r bon yla m in o]-
h ep ta n oic Acid (16b). The procedure used above to obtain 16a
from 15a was applied to 15b on a 1 mmol scale (400 mg), yielding
from 15a was applied to 18b on a 1 mmol scale (400 mg), yielding
1
19b (280 mg, 62%) as an oil: [R]25 ) +14.5 (c 4.8, CHCl3); H
D
NMR (CD3COCD3) δ 1.39 (s, 18H), 1.70-1.95 (m, 8H), 3.65 (s,
3H), 4.18 (m, 2H), 5.07 (s, 2H), 6.19 (bs, 1H), 6.64 (bs, 1H), 7.32
(m, 5H); 13C NMR (CD3COCD3) δ 25.2 (q), 25.6 (t), 28.8 (q), 31.5
(t), 51.3 (q), 53.6 (d), 53.8 (d), 65.9 (t), 78.4 (s), 127.7 (d), 128.1
(d), 128.3 (d), 137.2 (s), 155.6 (s), 156.2 (s), 173.0 (s), 173.4 (s);
IR (CHCl3) (cm-1) 3336, 2953, 1713, 1455, 1367, 1165, 1050;
HRMS calcd for C22H32N2O8Na (M + Na)+ 475.2051, found
475.2069.
16b (276 mg, 61%) as an oil: [R]25 ) -3.8 (c 3.0, CD3COCD3);
D
1H NMR (CDCl3) δ 1.38 (s, 9H), 1.29-1.45 (m, 4H), 1.50-1.80
(m, 4H), 2.01 (bs, 1H), 3.66 (s, 3H), 4.14 (m, 2H), 5.07 (s, 2H),
6.17 (bs, 1H), 6.53 (d, J ) 8.07 Hz, 1H), 7.31 (m, 5H); 13C NMR
(CD3COCD3) δ 25.2 (t), 25.6 (q), 31.5 (t), 51.2 (q), 53.6 (d), 53.8
(d), 65.8 (t), 78.3 (s), 127.7 (d), 128.3 (d), 137.3 (s), 155.6 (s), 156.2
(s), 173.0 (s), 173.1 (s); IR (CHCl3) (cm-1) 3337, 2952, 1718, 1455,
1367, 1165, 1052; HRMS calcd for C22H32N2O8Na (M + Na)+
475.2051, found 475.2069.
P r ep a r a tion of Dim eth yl (2S,6S)-2-Ben zyloxyca r bon yl-
a m in o-6-(ter t-bu toxyca r bon yla m in o)h ep ta n ed ioa te (20a ).
The procedure used above to obtain 10a from 9a was applied to
19a on a 1 mmol scale (438 mg), yielding 20a (443 mg, 98%) as
P r ep a r a tion of Dim eth yl (2R,6S)-2-Ben zyloxyca r bon yl-
a m in o-6-ter t-bu toxyca r bon yla m in oh ep ta n ed ioa te (17a ).
The procedure used above to obtain 10a from 9a was applied to
an oil: [R]25 ) +3.8 (c 2.3, CHCl3); 1H NMR (CDCl3) δ 1.40 (s,
D
16a on a 1 mmol scale (438 mg), yielding 17a (439 mg, 97%) as
9H), 1.63-1.79 (m, 6H), 3.70 (s, 6H), 4.37 (m, 2H), 5.09 (s, 2H),
5.09 (bs, 1H), 5.42 (bs, 1H), 7.33 (m, 5H); 13C NMR (CDCl3) δ
21.2 (t), 29.7 (q), 31.8 (t), 32.3 (t), 52.3 (q), 52.4 (q), 52.8 (d), 53.5
(d), 67.0 (t), 80.0 (s), 128.2 (d), 128.5 (q), 136.2 (s), 155.6 (s), 156.1
(s), 172.7 (s), 173.1 (s) IR (CHCl3) (cm-1) 3351, 2954, 1747, 1454,
1258, 1213, 1167, 1063, 1027; HRMS calcd for C17H24N2O6 (M
+ Na - Boc)+ 375.1527, found 375.1522.
1
an oil: [R]25 ) +1.7 (c 2.3, CHCl3); H NMR (CDCl3) δ1.41 (s,
D
9H), 1.88-1.64 (m, 6H), 3.70 (s, 6H), 4.29-4.34 (m, 2H), 5.08
(s, 2H), 5.02-5.14 (m, 1H), 5.43 (bs, 1H), 7.33 (m, 5H); 13C NMR
(CDCl3) δ 21.2 (t), 28.3 (q), 31.9 (t), 32.9 (t), 52.3 (q), 52.3 (q),
53.0 (d), 53.5 (d), 67.0 (t), 80.0 (s), 128.1 (d), 128.5 (q), 136.2 (s),
155.4 (s), 155.9 (s), 172.7 (s), 173.0 (s); IR (CHCl3) (cm-1) 3350,
2955, 1522, 1366, 1166, 1063; HRMS calcd for C22H32N2O8Na
(M + Na)+ 475.2051, found 475.2055.
P r ep a r a tion of Dim eth yl (2S,7S)-2-Ben zyloxyca r bon yl-
a m in o-7-ter t-bu toxyca r bon yla m in oocta n ed ioa te (20b). The
procedure used above to obtain 10a from 9a was applied to 19b
on a 1 mmol scale (452 mg), yielding 20b (442 mg, 95%) as an
P r ep a r a tion of Dim eth yl (2R,7S)-2-Ben zyloxyca r bon yl-
a m in o-7-ter t-bu toxyca r bon yla m in oocta n ed ioa te (17b). The
procedure used above to obtain 10a from 9a was applied to 16b
on a 1 mmol (453 mg) scale, yielding 17b (448 mg, 96%) as a
oil: [R]25 ) +17.4 (c 2.2, CHCl3); 1H NMR (CDCl3) δ 1.43 (s,
D
9H), 1.20-1.81 (m, 8H), 3.72 (s, 6H), 4.29-4.36 (m, 2H), 5.10
(s, 2H), 5.08-5.12 (m, 1H), 5.56 (bs, 1H), 7.32 (m, 5H); 13C NMR
(CDCl3) δ 24.8 (t), 25.2 (t), 28.3 (q), 32.4 (t), 32.4 (t), 52.2 (q),
52.3 (q), 53.2 (d), 53.7 (d), 67.0 (t), 79.9 (s), 128.1 (d), 128.1 (d),
128.3 (t), 128.5 (t), 128.6 (d), 136.2 (s), 155.3 (s), 155.9 (s), 172.9
(s), 173.2 (s); IR (CHCl3) (cm-1) 3350, 2952, 1713, 1520, 1366,
1048; HRMS calcd for C23H34N2O8Na (M + Na)+ 489.2207, found
489.2225.
white solid: mp 104-105 °C; [R]25 ) +1.6 (c 2.5, CHCl3); 1H
D
NMR (CDCl3) δ 1.43 (s, 9H), 1.25-1.78 (m, 8H), 3.72 (s, 6H),
4.32 (m, 2H), 5.00 (bs, 1H), 5.10 (s, 2H), 5.30 (bs, 1H), 7.34 (m,
5H); 13C NMR (CDCl3) δ 24.2 (t), 24.8 (t), 28.3 (q), 32.5 (t), 32.5
(t), 52.2 (q), 52.3 (q), 53.2 (d), 53.7 (d), 67.0 (t), 79.9 (s), 128.2
(d), 128.5 (d), 136.2 (s), 155.3 (s), 155.8 (s), 172.8 (s), 173.2 (s);
IR (CHCl3) (cm-1) 2922, 1711, 1513, 1440, 1164, 1024; HRMS
calcd for C23H34N2O8Na (M + Na)+ 489.2207, found 489.2208.
P r ep a r a tion of Meth yl (2S,6S)-6-Azid o-2-ter t-bu toxyca r -
b on yla m in o-6-[(4S)-(2,2-d im et h yl[1,3]d ioxola n -4-yl)]h ex-
a n oa te (18a ). The procedure used above to obtain 15a from 8a
was applied to 12a on a 1 mmol scale (346 mg), yielding 18a
Ack n ow led gm en t. We thank the DGES (PB98-
0443-C02-01) of Spain and FEDER (1FD97-0747-C04-
01) for supporting this research. N.H. thanks the
Consejer´ıa de Educacio´n, Cultura y Deportes del Gobi-
erno de Canarias, and the M.E.C. of Spain for a
fellowship. We also express our appreciation to Dr.
Toma´s Mart´ın for his suggestions and discussions.
(332 mg, 86%) as an oil: [R]25 ) +2.6 (c 0.5, CHCl3);1H NMR
D
(CDCl3) δ 1.34 (s, 3H), 1.44 (s, 9H), 1.59 (s, 3H), 1.45-1.82 (m,
6H), 3.47 (m, 1H), 3.74 (s, 3H), 3.86 (m, 1H), 4.05 (m, 2H), 4.31
(bs, 1H), 5.01 (bs, 1H); 13C NMR (CDCl3) δ 21.9 (t), 25.1 (q), 26.2
(q), 28.3 (q), 30.4 (t), 32.4 (t), 52.3 (q), 53.1 (d), 63.4 (d), 65.9 (t),
77.7 (d), 80.0 (s), 109.7 (s), 155.2 (s), 173.1 (s); IR (CHCl3) (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 all new compounds described in the Experi-
mental Section. This material is available free of charge via
the Internet at http://pubs.acs.org.
2954, 2360, 2106, 1714, 1645, 1162; HRMS calcd for C17H30N4O6-
Na (M + Na)+ 409.2058, found 409.2053.
P r ep a r a tion of Meth yl (2S,7S)-7-Azid o-2-ter t-bu toxyca r -
b on yla m in o-7-[(4S)-(2,2-d im et h yl[1,3]d ioxola n -4-yl)]h ep -
ta n oa te (18b). The procedure used above to obtain 15a from
8a was applied to 12b on a 0.96 mmol scale (346 mg), yielding
J O0155714