Stereoselective synthesis of protected (2R,3R,4S)-4,7-diamino-2,3- dihydroxyheptanoic acid: A novel amino acid of callipeltins A and D

Article abstract of DOI:10.1021/jo052676o

An orthogonally protected derivative 1 of (2R,3R,4S)-4,7-diamino-2,3- dihydroxyheptanoic acid, the unusual amino acid residue of the biologically active marine peptides such as callipeltins A and D and neamphamide A, was efficiently prepared in 10 steps a

Full text of DOI:10.1021/jo052676o

Stereoselective Synthesis of Protected
(2R,3R,4S)-4,7-Diamino-2,3-dihydroxyheptanoic
Acid: A Novel Amino Acid of
Callipeltins A and D
Jongho Jeon, Suk-Koo Hong, Joon Seok Oh, and
Young Gyu Kim*
School of Chemical and Biological Engineering,
Seoul National UniVersity, Seoul 151-744, Korea
ygkim@snu.ac.kr
ReceiVed December 31, 2005
An orthogonally protected derivative 1 of (2R,3R,4S)-4,7-
diamino-2,3-dihydroxyheptanoic acid, the unusual amino acid
residue of the biologically active marine peptides such as
callipeltins A and D and neamphamide A, was efficiently
prepared in 10 steps and 30% overall yield from a com-
mercially available L-ornithine derivative 2. The key step
includes the N-diphenylmethylene-controlled diastereoselec-
tive dihydroxylation of (Z)-ester 3 with >13:1 selectivity
for the desired isomer.
FIGURE 1. Callipeltins A and D and DADHA.
structure is also found in a recently isolated marine natural
product, neamphamide A.7
Although it has a unique structure and is a common
component in some biologically active natural products, there
have been only three synthetic reports to date. The two synthetic
methods using D-ribose and D-glucose as chiral templates have
been published by the same group.5c,j Their syntheses involved
a number of steps with a low yield. Lipton and co-workers
reported the first synthesis of its guanide derivative via the
dihydroxylation reaction of the γ-amino-R,â-unsaturated (Z)-
ester in a respectable yield.5h However, the stereoselectivity of
A novel cyclic depsipeptide callipeltin A was first isolated
from the marine sponge Callipelta sp. by Minale and co-workers
(Figure 1).1 It showed some interesting biological activities such
as antifungal and anti-HIV activities as well as cytotoxicity
against several human carcinoma cell lines.2 It was also shown
to be a selective and powerful inhibitor of the Na+/Ca2+ cardiac
exchanger and a positive inotropic agent in guinea pig atria.3
Later, callipeltin D, a truncated open-chain derivative of
callipeltin A, was also isolated from Latrunculia sp. (Figure
1).4
Callipeltins A and D consist of the novel amino acid and
fatty acid residues whose structures were confirmed by NMR
studies, molecular mechanics calculations, and degradation
studies. Recently, the syntheses of these residues have been
reported in efforts toward the total synthesis of callipeltin A.5,6
Among them, (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic
acid (DADHA) with a vicinal amino diol moiety is a key
component of callipeltins A and D (Figure 1). This unusual
(5) (a) Liang, B.; Carroll, P. J.; Joullie´, M. M. Org. Lett. 2000, 2, 4157-
4160. (b) Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. Tetrahedron:
Asymmetry 2001, 12, 1353-1358. (c) Chandrasekhar, C.; Ramachandar,
T.; Rao, B. V. Tetrahedron: Asymmetry 2001, 12, 2315-2321. (d) Acevedo,
C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron 2001, 57, 6353-6359. (e)
Guerlavais, V.; Carroll, P. J.; Joullie´, M. M. Tetrahedron: Asymmetry 2002,
13, 675-680. (f) Zampella, A.; Sorgente, M.; D’Auria, M. V. Tetrahe-
dron: Asymmetry 2002, 13, 681-685. (g) Zampella, A.; D’Auria, M. V.
Tetrahedron: Asymmetry 2002, 13, 1237-1239. (h) Thoen, J. C.; Morales-
Ramos, AÄ . I.; Lipton, M. A. Org. Lett. 2002, 4, 4455-4458. (i) Okamoto,
N.; Hara, O.; Makino, K.; Hamada, Y. J. Org. Chem. 2002, 67, 9210-
9215. (j) Kumar, A. R.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5645-
5647. (k) Turk, J. A.; Visbal, G. S.; Lipton, M. A. J. Org. Chem. 2003, 68,
7841-7844. (l) Hansen, D. B.; Wan, X.; Carroll, P. J.; Joullie´, M. M. J.
Org. Chem. 2005, 70, 3120-3126. (m) Zampella, A.; D’Orsi, R.; Sepe,
V.; Casapullo, A.; Monti, M. C.; D’Auria, M. V. Org. Lett. 2005, 7, 3585-
3588. (n) C¸ alimsiz, S.; Lipton, M. A. J. Org. Chem. 2005, 70, 6218-6221.
(6) Very recently, a total synthesis of callipeltin D has been reported.
Cranfill, D. C.; Morales-Ramos, AÄ . I.; Lipton, M. A. Org. Lett. 2005, 7,
5881-5883.
(1) Zampella, A.; D’Auria, M. V.; Paloma, L. G.; Casapullo, A.; Minale,
L.; Debitus, C.; Henin, Y. J. Am. Chem. Soc. 1996, 118, 6202-6209.
(2) D’Auria, M. V.; Zampella, A.; Paloma, L. G.; Minale, L.; Debitus,
C.; Roussakis, C.; Le Bert, V. Tetrahedron 1996, 52, 9589-9596.
(3) Trevisi, L.; Bova, S.; Cargnelli, G.; Danieli-Betto, D.; Floreani, M.;
Germinario, E.; D’Auria, M. V.; Lucianni, S. Biochem. Biophys. Res.
Commun. 2000, 279, 219-222.
(7) (a) Oku, N.; Gustafson, K. R.; Cartner, L. K.; Wilson, J. A.;
Shigematsu, N.; Hess, S.; Pannell, L. K.; Boyd, M. R.; McMahon, J. B. J.
Nat. Prod. 2004, 67, 1407-1411. (b) Oku, N.; Krishnamoorthy, R.; Benson,
A. G.; Ferguson, R. L.; Lipton, M. A.; Phillips, L. R.; Gustafson, K. R.;
McMahon, J. B. J. Org. Chem. 2005, 70, 6842-6847.
(4) Zampella, A.; Randazzo, A.; Borbone, N.; Luciani, S.; Trevisi, L.;
Debitus, C.; D’Auria, M. V. Tetrahedron Lett. 2002, 43, 6163-6166.
10.1021/jo052676o CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/16/2006
3310
J. Org. Chem. 2006, 71, 3310-3313

SCHEME 1. Retrosynthetic Analysis of 1
SCHEME 3. Stereoselective Dihydroxylation toward the
Target Compound 1a
SCHEME 2. Preparation of (Z)-Ester 7aa
a Reagents and conditions: (a) (i) AcCl, MeOH, 0 °C to rt, (ii)
benzophenone imine, DCM, rt, 92%; (b) cat. OsO4, NMO, THF-H2O, rt;
90%; (c) Ac2O, TEA, DMAP, DCM, rt, 94%; (d) (i) TFA, aq THF, rt, (ii)
Boc2O, NaHCO3, THF-H2O, 65%.
of Boc2O, 0.1 equiv of DMAP, and 2 equiv of Et3N. Compound
6b was very slow under the Fukuyama conditions, but it can
be recycled to thioester 5 after separation from 6a. Compound
6a was then subjected to the Fukuyama conditions to give
aldehyde 4 as a crude product. The use of 2.0 equiv of MgSO4
and more than 0.5 M of the thioester in acetone was the optimal
condition.10b The crude aldehyde 4 was used without purification
for the next step to minimize the possible racemization of the
unstable R-amino aldehyde.11 The Z-selective olefination under
the Still conditions resulted in the desired γ-amino-R,â-
unsaturated (Z)-ester 7a as a major product in a ratio of more
than 16:1.12
The N-diphenylmethylene group that is necessary for the syn-
selective dihydroxylation reaction of 3 could be easily introduced
by a transimination reaction between benzophenone imine and
the HCl salt of the N-deprotected product of 7a (Scheme 3).13
In the hydrolysis step, the two Boc groups of 7a were selectively
removed with HCl in MeOH at 0 °C in the presence of both
the ester and the Cbz groups. Then, the dihydroxylation of 3
produced diol 8 in 90% yield under the typical OsO4-catalyzed
reaction conditions. It was difficult to determine the correct
diastereomeric ratio of 8 because of the facile isomerism
between ketimine diol 8a and oxazolidine 8b.14 Thus, the two
hydroxyl groups of 8a were acetylated in excellent yield to
afford diacetate 9 of which diastereomeric ratio was determined
to be >13:1 by 1H NMR for the desired syn isomer (see below).
It indicates that the N-diphenylmethylene-controlled dihydrox-
ylation reaction of 3 has resulted in the desired configuration
of 8a with a similar selectivity. For comparison, the same
dihydroxylation reaction of NR-Cbz-protected (Z)-ester 7b
(Scheme 2) resulted in an ∼1:1 mixture of the diastereomeric
diols.15 Compound 7b was prepared from commercially avail-
a Reagents and conditions: (a) (i) isobutyl chloroformate, TEA, DME,
0 °C; (ii) EtSH, TEA, 0 °C, quantitative (from 2); (b) Boc2O, DMAP, TEA,
MeCN, rt, 68% for 6a, 21% for 6b; (c) 10% Pd-C, Et3SiH, MgSO4,
acetone, rt; (d) KHMDS, THF, 18-crown-6, (CF3CH2O)2P(O)CH2CO2Me,
-78 °C, 82% for 7a (from 6a).
the key dihydroxylation reaction of the (Z)-ester was poor for
the desired isomer. We wish to report here an efficient and
stereoselective synthetic route for an orthogonally protected
(2R,3R,4S)-DADHA derivative (1) using the syn-selective
osmium-catalyzed dihydroxylation reaction of γ-amino-R,â-
unsaturated (Z)-esters that has been recently described by us.8
Scheme 1 shows our retrosynthetic analysis for the target
compound 1. The 2,3-dihydroxyl functionality of 1 with the
desired configuration could be established by the syn-selective
OsO4-catalyzed dihydroxylation reaction of R,â-unsaturated (Z)-
ester 3 that would be derived in turn from the corresponding
properly protected R-amino aldehyde 4.8 The fully protected
terminal amino group of 4 seemed necessary for a successful
Z-selective Still olefination reaction.5h,9 We planned to obtain
4 from commercially available Nδ-Cbz-NR-Boc-L-ornithine (2).
The synthetic steps for suitably protected γ-amino-R,â-
unsaturated (Z)-ester 7a are shown in Scheme 2. The required
aldehyde precursor 4 for 7a was made efficiently from 2
according to the Fukuyama’s protocol.10 However, the terminal
amino group of thioester 5 that was obtained in a quantitative
yield from the commercially available L-ornithine derivative 2
should be further protected with a Boc group to prevent
formation of the aminal (Scheme 2) that has been known to be
unreactive toward certain nucleophiles such as an enolate9 or
an ylide.5h In this process, a significant amount of the diBoc-
protected derivative at the internal amino group (6b) was also
produced. The best result for 6a was obtained with 1.5 equiv
(11) (a) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989, 89, 149-164.
(b) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B.
A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359-1362. (c) Yoo, D.; Oh, J.
S.; Lee, D.-W.; Kim, Y. G. J. Org. Chem. 2003, 68, 6979-6982.
(12) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(13) O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663-2666.
(14) (a) Polt, R.; Szabo´, L.; Treiberg, J.; Li, Y.; Hruby, V. J. J. Am.
Chem. Soc. 1992, 114, 10249-10258. (b) Polt, R.; Sames, D.; Chruma, J.
J. Org. Chem. 1999, 64, 6147-6158.
(8) Oh, J. S.; Jeon, J.; Park, D. Y.; Kim, Y. G. Chem. Comm. 2005,
770-771 and references therein.
(9) Salituro, F. G.; Agarwal, N.; Hofmann, T.; Rich, D. H. J. Med. Chem.
1987, 30, 286-295.
(10) (a) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050-7051. (b) Fukuyama, T.; Tokuyama, H. Aldrichim. Acta 2004, 37,
87-96 and references therein.
J. Org. Chem, Vol. 71, No. 8, 2006 3311

SCHEME 4. Assignment of the Relative Stereochemistry
of 8aa
FIGURE 2. Probable transition-state models.
Then, the protection of the R-amino group with a Boc group
gave the desired product 1 in a combined yield of 65% after
purification.
The enhanced stereoselectivity shown by the N-diphenyl-
methylene group could be rationalized by the favorable N-
outside conformation caused by the steric hindrance from the
methoxycarbonyl group as described in the literature (model
A, Figure 2).8 The N-inside conformation of the N-Cbz or N-Boc
derivative would compete with its N-outside conformation
because of the intramolecular hydrogen bonding between the
methoxycarbonyl group and the N-H proton (model B), resulting
in the poor syn or no selectivity.5h The preference of the
N-outside conformation of the N-Boc group in the alkyl-
substituted Z-olefin was proposed to explain the syn dihydrox-
ylation selectivity by Krysan and co-workers (model C).18
In conclusion, we have developed an efficient and stereose-
lective synthetic route for the orthogonally protected derivative
1 of (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid
(DADHA) in 10 steps and 30% overall yield from commercially
available Nδ-Cbz-NR-Boc-L-ornithine (2). DADHA is an unusual
amino acid residue of some biologically active marine peptides
such as callipeltins A and D and neamphamide A and has a
unique structure with a γ-amino-R,â-dihydroxycarboxylic acid
unit. The key intermediate, suitably protected γ-amino-R,â-
unsaturated (Z)-ester 7a, was efficiently obtained using the
Fukuyama’s protocol from 2. The N-diphenylmethylene-
controlled OsO4-catalyzed dihydroxylation of the Z-ester 3
successfully introduced the dihydroxyl functionality of the
desired configuration in the target compound with high selectiv-
ity. The orthogonally protected derivative 1 of DADHA would
be useful for further transformation such as guanylation at the
terminal amine to provide a protected derivative of (2R,3R,4S)-
4-amino-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE).
The higher yield and shorter synthetic steps presented here
would also be valuable for a total synthesis of the natural marine
peptides such as callipeltins A and D and neamphamide A.
a Reagents and conditions: (a) 2,2-DMP, PPTS, PhH, reflux, 75%; (b)
(i) Boc2O, DMAP, MeCN, rt, (ii) 10% Pd-C, HCO2NH4, MeOH, reflux,
89% of 11 cis (from 8a syn).
able NR,Nδ-di-Cbz-L-ornithine using a synthetic sequence similar
to that with 2. The poor selectivity with the similar compound
has been reported.5h Even the Sharpless asymmetric dihydrox-
ylation reactions could not override the inherent selectivity of
the Z-ester. It is quite remarkable that the simple achiral
N-diphenylmethylene group on the γ-amino group shown here
can enhance the syn-diastereofacial selectivity to a great extent.8
The relative configuration of the diol in 8a was confirmed
by comparing the coupling constants of the γ-lactams (Scheme
4). After protection of the diol of 8a into acetonide 10, the
terminal amine of 10 was protected with a Boc group and then
the catalytic hydrogenation removed both the benzophenone and
the Cbz protecting groups, resulting in lactam 11 cis as the only
isomer after purification.8,16 A significant amount of the isomeric
lactam 11 trans was obtained separately using a similar reaction
sequence from the diastereomeric diol that was in turn derived
from the OsO4-catalyzed dihydroxylation of 7b (see above).15
The coupling constant between H-4 and H-5 of the major isomer
(11 cis) was 4.6 Hz, and that of the minor isomer (11 trans)
was 0 Hz. It has been reported that the value of J4,5 of the cis
γ-lactam is larger than that of the trans γ-lactam in a similar
system.7b,8,17 Therefore, the relative configuration of the diol in
the major isomer 8a should be syn to the amino group, which
is the same configuration as that in the target compound 1.
Finally, the dihydroxylation product 8a was converted into
the target compound 1, the orthogonally protected derivative
of DADHA (Scheme 3). Among several acids such as aq HCl,
p-TsOH, PPTS, and TFA, TFA in aqueous THF was the best
for selective removal of the N-diphenylmethylene group of 8a
in the presence of the Cbz group to give the ammonium salt.
Experimental Section
Methyl (2Z,4S)-7-(N-Benzyloxycarbonyl-N-tert-butoxycarbon-
yl)amino-4-(tert-butoxycarbonyl)aminohept-2-enoate (7a). To a
suspension of thioester 6a (0.291 g, 0.570 mmol), 10% Pd/C (0.062
g, 0.057 mmol), and MgSO4 (0.137 g, 1.14 mmol) in dry acetone
(0.8 mL) was added triethylsilane (0.14 mL, 0.855 mmol). The
mixture was stirred for 1 h at room temperature and then filtered
through a Celite pad that was rinsed with Et2O (10 mL × 2). The
filtrate was washed with water (15 mL), and the water layer was
extracted with Et2O (15 mL × 2). The combined organic layers
were dried over MgSO4, filtered, and evaporated under reduced
pressure to give crude aldehyde 4. To a solution of bis(2,2,2-
trifluoroethyl)(methoxycarbonylmethyl)phosphonate (0.191 g, 0.602
mmol) and 18-crown-6 (0.665 g, 2.51 mmol) in dry THF (10 mL)
at -78 °C was slowly added KHMDS (0.5 M in toluene, 1.2 mL,
(15) A ca. 1:1 mixture of the diastereomeric diols obtained from the
same dihydroxylation reaction of 7b was protected to give the acetonide
derivative that was treated under the catalytic hydrogenation conditions to
produce a mixture of the γ-lactams (11 cis and 11 trans). Each isomer was
separated by SiO2 column chromatography. One of the lactams with a
smaller J value (0 Hz) was attributed to 11 trans and the other showed the
same spectroscopic data as those of 11 cis.
(16) Wessjohann, L.; McGaffin, G.; de Meijere, A. Synthesis 1989, 359-
363.
(17) (a) Huang, Y.; Dalton, D. R.; Carroll, P. J. J. Org. Chem. 1997, 62,
372-376. (b) Oba, M.; Koguchi, S. J.; Nishiyama, K. Tetrahedron 2004,
60, 8089-8092.
(18) Krysan, D. J.; Rockway, T. W.; Haight, A. R. Tetrahedron:
Asymmetry 1994, 5, 625-632.
3312 J. Org. Chem., Vol. 71, No. 8, 2006

0.60 mmol). After 15 min at -78 °C, the crude aldehyde 4 in dry
THF (10 mL) was added dropwise to the reaction mixture, and the
resulting mixture was stirred for another 30 min. The reaction was
quenched with a saturated aqueous NH4Cl solution (5 mL), and
the aqueous layer was extracted with EtOAc (15 mL × 3). The
combined organic layers were dried over MgSO4, filtered, and
evaporated under reduced pressure to give the crude alkene. The
crude product was purified by silica gel column chromatography
(hexane/EtOAc ) 8:1) to give 7a (0.235 g, 82%) as colorless oil
over the two steps [(Z)/(E) ) 16.4:1]: [R]21D +18.9 (c 1.10, CHCl3);
IR (film on a silicon wafer) 3386, 1750, 1723, 1717, 1696, 1648
crude diol product was dissolved in dry DCM (10 mL) and treated
with Ac2O (0.10 mL, 1.03 mmol), TEA (0.14 mL, 1.03 mmol),
and DMAP (3 mg, 0.021 mmol). The reaction mixture was stirred
for 24 h at room temperature. The reaction was quenched with a
satd aq NaHCO3 solution (5 mL), and the aqueous layer was
extracted with DCM (10 mL × 3). The combined organic layers
were dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude residue was purified by silica gel column
chromatography (hexane/EtOAc ) 8:1) to give compound 9 as pale
yellow oil (103 mg, 85%): IR (film on a silicon wafer) 3403, 3031,
1
1751, 1724, 1624 cm-1; H NMR δ 1.30-1.55 (m, 2H), 1.60-
1
cm-1; H NMR δ 1.42 (s, 9H), 1.47 (s, 9H), 1.51-1.68 (m, 4H),
1.80 (m, 2H), 2.00 (s, 3H), 2.05 (s, 3H), 3.09 (q, J ) 6.6, 2H),
3.53 (s, 3H), 3.73-3.83 (m, 1H), 4.75 (br s, 1H), 5.08 (s, 2H),
5.24 (d, J ) 4.0, 1H), 5.48 (dd, J ) 7.0, 4.0, 1H), 7.11-7.14 (m,
2H), 7.29-7.45 (m, 11H), 7.55-7.58 (m, 2H); 13C NMR δ 20.5,
20.8, 26.4, 28.9, 40.7, 52.3 60.6, 66.5, 71.2, 73.1, 127.9, 128.0,
128.15, 128.21, 128.4, 128.5, 128.9, 130.0, 132.4, 136.5, 156.3,
167.4, 169.6, 169.8; HRMS (CI) calcd for C33H37N2O8 (M+ + 1)
589.2551, found 589.2557.
3.66 (dt, J ) 7.1, 2.6, 2H), 3.70 (s, 3H), 4.80 (br s, 1H), 5.02-
5.13 (m, 1H), 5.22 (s, 2H), 5.78 (dd, J ) 11.6, 1.0, 1H), 6.05 (br
s, 1H), 7.27-7.41 (m, 5H); 13C NMR δ 25.3, 28.0, 28.4, 31.6, 46.2,
49.0, 51.4, 68.3, 79.5, 82.8, 119.6, 128.28, 128.33, 128.56, 135.8,
150.2, 152.1, 153.9, 155.3, 166.0; HRMS (CI) calcd for C26H39N2O8
(M+ + 1) 507.2707, found 507.2707. Anal. Calcd: C, 61.64; H,
7.56; N, 5.53. Found: C, 61.40; H, 7.79; N, 5.65.
Methyl(2Z,4S)-7-(Benzyloxycarbonyl)amino-4-(diphenylmeth-
ylene)aminohept-2-enoate (3). To a solution of ester 7a (0.400 g,
0.790 mmol) in dry MeOH (15 mL) at 0 °C was added dropwise
AcCl (2 mL, 28.03 mmol). The solution was stirred for 2 h at 0
°C, and then the solvent was evaporated under reduced pressure.
To the crude ammonium salt was added dry DCM (15 mL), and
benzophenonone imine (0.150 g, 0.830 mmol) was added to the
resulting suspension mixture at room temperature. After 12 h, the
reaction was quenched with a satd aq NaHCO3 solution (15 mL).
The aqueous layer was extracted with DCM (20 mL × 3). The
combined organic layers were dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude product was purified
by silica gel column chromatography (hexane/EtOAc ) 8:1) to give
compound 3 as pale yellow oil (0.343 g, 92%) [(Z)/(E) ) 16.4:1]:
Methyl (2R,3R,4S)-7-(Benzyloxycarbonyl)amino-4-(tert-bu-
toxycarbonyl)amino-2,3-dihydroxyheptanoate (1). To a solution
of purified diol 8 (187 mg, 0.371 mmol) in THF (5 mL) were slowly
added TFA (0.4 mL, 5.39 mmol) and H2O (0.2 mL), and the
resulting mixture was stirred for 3.5 h at room temperature. The
solvent was then evaporated under reduced pressure, and the
remaining TFA was removed by addition of toluene and the
following evaporation in vacuo. To the crude ammonium salt were
added H2O (3 mL) and THF (3 mL) followed by addition of Boc2O
(121 mg, 0.557 mmol) and NaHCO3 (93 mg, 1.11 mmol). The
reaction mixture was stirred for 24 h at room temperature. The
reaction was quenched with a satd aq NH4Cl solution (5 mL). Then,
the aqueous layer was extracted with EtOAc (5 mL × 4), and the
combined organic layers were dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude residue was purified
by silica gel column chromatography (hexane/EtOAc ) 1:1) to give
compound 1 as colorless oil (106 mg, 65%): [R]18D -9.01 (c 0.24,
CHCl3); IR (film on a silicon wafer) 3649, 3627, 3386, 3355, 1716,
[R]21 +64.3 (c 0.41, CHCl3); IR (film on a silicon wafer) 3354,
D
1722, 1708, 1648, 1618 cm-1; H NMR δ 1.32-1.72 (m, 3H),
1
1.70-1.75 (m, 1H), 2.96-3.08 (m, 1H), 3.12-3.24 (m, 1H), 3.51
(s, 3H), 4.91-5.06 (m, 2H), 5.07 (s, 2H), 5.72 (d, J ) 11.5, 1H),
6.37 (dd, J ) 11.5, 8.8, 1H), 7.07 (br s, 2H), 7.29-7.41 (m, 11H),
7.59-7.61 (m, 2H); 13C NMR δ 26.0, 33.2, 40.4, 51.1, 60.0, 66.4,
117.9, 127.6, 127.98, 128.02, 128.1, 128.3, 128.4, 128.46, 128.50,
128.57, 128.59, 130.2, 136.8, 137.0, 139.7, 150.2, 156.3, 166.1,
169.5; HRMS (CI) calcd for C29H31N2O4 (M+ + 1) 471.2285, found
471.2284.
1
1702, 1696 cm-1; H NMR (measured at 328 K) δ 1.44 (s, 9H),
1.53-1.67 (m, 4H), 3.18-3.25 (m, 2H), 3.27 (br s, 1H), 3.70 (br
d, J ) 8.4, 1H), 3.81-3.91 (m, 1H), 3.82 (s, 3H), 3.97 (dd, J )
8.5, 5.6, 1H), 4.45 (br s, 1H), 4.80 (br d, J ) 8.8, 2H), 5.10 (s,
2H), 7.29-7.36 (m, 5H); 13C NMR δ 26.9, 28.3, 28.8, 40.7, 50.5,
52.7, 66.7, 71.3, 73.7, 80.6, 128.1, 128.3, 136.5, 156.5, 157.7, 174.1;
HRMS (CI) calcd for C21H33N2O8 (M+ + 1) 441.2238, found
441.2235.
Methyl (2R,3R,4S)-7-(Benzyloxycarbonyl)amino-2,3-diacetoxy-
4-(diphenylmethylene)aminoheptanoate (9). To a mixture of ester
3 (97 mg, 0.206 mmol) and NMO (53 mg, 0.453 mmol) in THF (2
mL) and H2O (2 mL) was added OsO4 (5.2 mg, 0.021 mmol). The
mixture was stirred for 48 h at room temperature. The reaction
was quenched with a satd aq Na2SO3 solution (5 mL), and the
resulting mixture was stirred further for 30 min. The aqueous layer
was extracted by Et2O (10 mL × 4). The combined organic layers
were dried over MgSO4, filtered, and evaporated under reduced
pressure to give crude diol 8 (110 mg, 0.218 mmol). The crude
diol could be purified by silica gel column chromatography (hexane/
EtOAc ) 1:1) to give diol 8 (93 mg, 90%) as colorless oil. The
Acknowledgment. We thank the BK 21 Project and Agency
for Defense Development of Korea for financial support.
Supporting Information Available: Experimental procedures
1
for 5, 6a, 10, 11 cis, and 11 trans. H and 13C NMR spectra for
1, 3, 5, 6a, 7a, 9, 10, 11 cis [11 cis with D2O], and 11 trans.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052676O
J. Org. Chem, Vol. 71, No. 8, 2006 3313