Synthesis of acyclic precursors to (3S,4S)-4-hydroxy-2,3,4,5- tetrahydropyridazine-3-carboxylic acid and incorporation into a luzopeptin/quinoxapeptin dipeptide

Full text of DOI:10.1021/jo980765d

J . Org. Chem. 1998, 63, 6421-6424
6421
Sch em e 1
Syn th esis of Acyclic P r ecu r sor s to
(3S,4S)-4-Hyd r oxy-2,3,4,5-tetr a h yd r o-
p yr id a zin e-3-ca r boxylic Acid a n d
In cor p or a tion in to a Lu zop ep tin /
Qu in oxa p ep tin Dip ep tid e
Dale L. Boger* and Gunter Schu¨le
Department of Chemistry and The Skaggs Institute of
Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
Received April 23, 1998
The luzopeptins (1-3, Figure 1) are potent antitumor
antibiotics that were isolated from Actinomadura luzon-
ensis1 and identified in a single-crystal X-ray structure
determination of 1.2 They constitute the initial members
of a growing class of C2 symmetric cyclic decadepsipep-
tides bearing two pendant chromophores which now
include the quinoxapeptins (4-5),3 quinaldopeptin,4 and
sandramycin (6)5-8 that bind to DNA with bisinter-
calation.6-12 In addition to their potent cytotoxic and
antitumor activity,1,13 which includes members exhibiting
1-100 pM IC50’s,8,14 they are potent inhibitors of HIV
reverse transcriptase (RT)8,15 including single and double
mutants3 responsible for the emerging clinical resistance
to recently introduced RT inhibitors. Moreover, the
cytotoxic potency of the luzopeptins (A > B . C) and their
antiviral potency/HIV RT inhibition (C > B > A) are
reversed, with luzopeptin C exhibiting suppression of
HIV replication in infected MT-4 cells at noncytotoxic
concentrations,15 and similar, albeit structurally distinct,
divergent cytotoxic/HIV RT structure-activity relation-
ships have been described in a more recent series of
sandramycin analogues.8 In an extension of our efforts
which have resulted in the only total synthesis to date
of a member of this class of antitumor antibiotics,
sandramycin (6),6,7 herein we detail the preparation of
the acyclic precursors 8 and 9 to (3S,4S)-4-hydroxy-
2,3,4,5-tetrahydropyridazine-3-carboxylic acid (7, Htp)
and their incorporation into a luzopeptin/quinoxapeptin
dipeptide 10 which complements the studies disclosed to
date.16-18
(1) Konishi, M.; Ohkuma, H.; Sakai, F.; Tsuno, T.; Koshiyama, H.;
Naito, T.; Kawaguchi, H. J . Antibiot. 1981, 34, 148. Ohkuma, H.; Sakai,
F.; Nishiyama, Y.; Ohbayashi, M.; Imanishi, H.; Konishi, M.; Miyaki,
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K.; Hoshino, Y.; Sasahira, T.; Kawaguchi, H. J . Antibiot. 1980, 33,
1098.
(2) Arnold, E.; Clardy, J . J . Am. Chem. Soc. 1981, 103, 1243.
Konishi, M.; Ohkuma, H.; Sakai, F.; Tsuno, T.; Koshiyama, H.; Naito,
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I.; Diez, M. T.; Hirsch, C. F.; Zink, D. L.; Liesch, J . M.; Koch, G. E.;
Gartner, S. E.; Garrity, G. M.; Tsou, N. N.; Salituro, G. M. J . Antibiot.
1996, 49, 253.
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N.; Yamamoto, H.; Konishi, M.; Oki, T. J . Antibiot. 1990, 43, 796.
(5) Matson, J . A.; Bush, J . A. J . Antibiot. 1989, 42, 1763. Matson,
J . A.; Colson, K. L.; Belofsky, G. N.; Bleiberg, B. B. J . Antibiot. 1993,
46, 162.
(6) Boger, D. L.; Chen, J .-H. J . Am. Chem. Soc. 1993, 115, 11624.
Boger, D. L.; Chen, J .-H. J . Org. Chem. 1995, 60, 7369. For an
analogue, see: Olsen, R. K.; Apparao, S.; Bhat, K. L. J . Org. Chem.
1986, 51, 3079.
Condensation of 2-(1,3-dioxan-2-yl)acetaldehyde (11)19
with trimethyl phosphonoacetate (88%) followed by con-
version of 12 to the corresponding benzyl ester 14 (92%,
two steps) provided our starting material (Scheme 1).
Sharpless asymmetric dihydroxylation20 of 14 conducted
with AD mix R (t-BuOH/H2O, 80%) provided the (2R,3S)-
diol 15 in superb enantiomeric excess (>99% ee).21
(7) Boger, D. L.; Chen, J .-H.; Saionz, K. W. J . Am. Chem. Soc. 1996,
118, 1629.
(8) Boger, D. L.; Chen, J .-H.; Saionz, K. W.; J in, Q. Bioorg. Med.
Chem. 1998, 6, 85.
(9) Huang, C.-H.; Mong, S.; Crooke, S. T. Biochemistry 1980, 19,
5537. Huang, C.-H.; Prestayko, A. W.; Crooke, S. T. Biochemistry 1982,
21, 3704. Huang, C.-H.; Mirabelli, C. K.; Mong, S.; Crooke, S. T. Cancer
Res. 1983, 43, 2718.
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J . Nucleic Acids Res. 1988, 16, 2489. Fox, K. R.; Woolley, C. Biochem.
Pharmacol. 1990, 39, 941.
(11) Searle, M. S.; Hall, J . G.; Wakelin, L. P. G. Biochem. J . 1988,
256, 271. Searle, M. S.; Hall, J . G.; Denny, W. A.; Wakelin, L. P. G.
Biochem. J . 1989, 259, 433.
(12) Zhang, X.; Patel, D. J . Biochemistry 1991, 30, 4026. Leroy, J .
L.; Gao, X.; Misra, V.; Gueron, M.; Patel, D. J . Biochemistry 1992, 31,
1407.
(13) Rose, W. C.; Schurig, J . E.; Huftalen, J . B.; Bradner, W. T.
Cancer Res. 1983, 43, 1504.
(14) Boger, D. L.; Chen, J .-H. Bioorg. Med. Chem. Lett. 1997, 7, 919.
(15) Take, Y.; Inouye, Y.; Nakamura, S.; Allaudeen, H. S.; Kubo, A.
J . Antibiot. 1989, 42, 107. Inouye, Y.; Take, Y.; Nakamura, S.;
Nakashima, H.; Yamamoto, N.; Kawaguchi, H. J . Antibiot. 1987, 40,
100.
(16) Hughes, P.; Clardy, J . J . Org. Chem. 1989, 54, 3260.
(17) Ciufolini, M. A.; Swaminathan, S. Tetrahedron Lett. 1989, 30,
3027. Ciufolini, M. A.; Xi, N. J . Chem. Soc., Chem. Commun. 1994,
1867. Ciufolini, M.; Xi, N. J . Org. Chem. 1997, 62, 2320. Xi, N.;
Alemany, L. B.; Ciufolini, M. A. J . Am. Chem. Soc. 1998, 120, 80.
(18) Greck, C.; Bischoff, L.; Genet, J . P. Tetrahedron: Asymmetry
1995, 6, 1989.
(19) Peng, S.; Winterfeld, E. Liebigs Ann. Chem. 1989, 1045.
(20) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa,
K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768.
(21) The ee was established by HPLC on a ChiraCel OD column
(0.46 × 25 cm, 25% i-PrOH/hexane, flow rate ) 1 mL/min) enlisting
racemic 15 as a standard: tR((2R,3S)-15) ) 8.99 min, tR((2S,3R)-15)
) 7.83 min; R ) 1.15.
S0022-3263(98)00765-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/30/1998

6422 J . Org. Chem., Vol. 63, No. 18, 1998
Notes
Sch em e 2
acylating agents including (BOC)2O in the presence of
DMAP (2 equiv, CH2Cl2, 0 °C, 4 h, 53-57%, Scheme 2),
both did not couple with SESNH-Ser-CO2H, SESNH-
Ser(OTBDMS)-CO2H (SES ) 2-trimethylsilylethanesulfo-
nyl) or 25 under a wide variety of conventional coupling
procedures.25 Adopting a protocol introduced by Ciufolini
enlisting an acid chloride,17 the acid 25 prepared from
D-Ser was converted to the corresponding acid chloride
26 ((COCl)2, cat. DMF, CH2Cl2, 25 °C) and in situ coupled
with 8 utilizing K2CO3 as a base26 to provide 27 (85%)
during which little racemization was observed (ca. g 11:
1), Scheme 2. Selective methanolysis (0.3 equiv of Cs2-
CO3, CH3OH, 25 °C, 35 min) of the SES-activated cyclic
carbamate released the dipeptide 28 (64%) suitably
protected for direct incorporation into the synthesis of
1-5. In this regard, the N-sulfonyl versus N-acyl protec-
tion of the D-Ser amine disclosed by Ciufolini17 serves to
activate and direct hydrolysis to the cyclic carbamate and
provides intermediates bearing protecting groups analo-
gous to those enlisted in our synthesis of sandramycin
ensuring their smooth incorporation into ongoing efforts
on 1-5. In efforts which established for us the chemical
behavior of N-acylated Htp derivatives, treatment of 28
with 10% H2O-TFA (25 °C, 2 h) provided 10 (86%) which
proved stable to conventional isolation, purification
(SiO2), and characterization techniques.27 In contrast,
analogous attempts to cyclize 28 with 3 N HCl-EtOAc
provided 10 (20%) in much lower conversions.
F igu r e 1.
Selective sulfonation of the C2 hydroxy group upon
reaction with 4-nitrobenzenesulfonyl chloride as de-
scribed by Fleming and Sharpless22 cleanly provided 16
(68%). Subsequent NaN3 displacement of the nosylate22
provided the azide 17 (87%) with clean inversion of the
C2 stereochemistry and without detection of a second,
minor diastereomer derived from racemization. Stau-
dinger reduction afforded the amine 18 (93%), and
TBDMSOTf protection of the alcohol provided 19 (98%),
a suitably protected substrate for oxaziridine N-amina-
tion. Treatment of 19 with oxaziridine 2023 (1 equiv,
DMF, 23 °C, 24 h) served to transfer the NHBOC and
provided the selectively protected acyclic R-hydrazino
carboxylic acid 8 (72%) along with a small amount of
reisolated 19 (15%). Initial efforts enlisting the condi-
tions disclosed by Collet23 (Et2O or CHCl3) provided only
low yields of N-amination and predominantly recovered
starting material (40-60%) which was substantially
improved in switching to DMF as solvent.24 Treatment
of 8 with Bu4NF (THF, 30 min, 74%) provided the free
alcohol 9.
Efforts on the incorporation of 28 into the total
synthesis of 1-5 are in progress and will be disclosed in
due course.
Preliminary studies conducted with both 8 and 9
indicated that although both may couple with activated
Exp er im en ta l Section
Meth yl 4-(1,3-Dioxa n -2-yl)-(E)-2-bu ten oa te (12). 2-(1,3-
Dioxan-2-yl)acetaldehyde 1119 (4.26 g, 32.6 mmol) in CH3OH (20
mL) was added at 0 °C to a stirred solution of trimethyl
(22) Fleming, P. R.; Sharpless, K. B. J . Org. Chem. 1991, 56, 2869.
(23) Vidal, J .; Guy, L.; Sterin, S.; Collet, A. J . Org. Chem. 1993, 58,
4791. Vidal, J .; Damestoy, S.; Guy, L.; Hannachi, J .-C.; Aubry, A.;
Collet, A. Chem. Eur. J . 1997, 3, 1691.
(24) The corresponding dimethyl acetal was also examined and did
provide the analogous intermediates 11-19 but underwent subsequent
acetal cleavage and condensation reactions under the N-amination
reaction conditions.
(25) This included BOP-Cl/Et3N, EDCI or DCC/HOBt or HOAt,
PyBOP, PyBrOP/i-Pr2NEt, PyBrOP-DMAP, DCC-DMAP, HBTU/
HOBt, and DPPA.
(26) No reaction was observed enlisting collidine17 as the base.
(27) Similar efforts to close 8 or 9 upon treatment with 10% H2O-
TFA failed to provide the benzyl ester of 7.

Notes
J . Org. Chem., Vol. 63, No. 18, 1998 6423
phosphonoacetate (6.88 g, 37.8 mmol) and t-BuOK (4.4 g, 19.6
mmol) in CH3OH (140 mL), allowed to warm to 23 °C, and stirred
for 1 h. The mixture was concentrated and partitioned between
Et2O (100 mL) and saturated aqueous NaHCO3 (50 mL). The
Et2O layer was washed with saturated aqueous NaCl, dried
(MgSO4), and concentrated. Chromatography (SiO2, 10 × 20 cm,
20% EtOAc-hexane) afforded 12 as a clear oil (5.12 g, 88%):
ν
max 3487, 2861, 2102, 1738, 1174, 1138, 733, 692 cm-1; 1H NMR
(250 MHz, CDCl3) δ 7.37-7.24 (m, 5H), 5.22 (s, 2H), 4.78 (t, 1H,
J ) 4.4 Hz), 4.35 (ddd, 1H, J ) 3.0, 5.5, 8.6 Hz), 4.13-4.05 (m,
2H), 4.00 (d, 1H, J ) 5.5 Hz), 3.81-3.69 (m, 2H), 2.15-1.80 (m,
3H), 1.37-1.30 (m, 1H); 13C NMR (62.5 MHz, CDCl3) δ 168.5,
128.6, 128.3, 100.6, 68.9, 67.5, 66.9, 66.8, 65.9, 37.1, 25.5;
FABHRMS (NBA-NaI) m/z 344.1228 (M + Na+, C15H19N3O5
requires 344.1222).
IR (neat) νmax 2954, 2852, 1725, 1660, 1331, 1176, 1027 cm-1
;
1H NMR (250 MHz, CDCl3) δ 6.93 (dt, 1H, J ) 7.2, 15.8 Hz),
5.89 (dt, 1H, J ) 1.4, 15.8 Hz), 4.62 (t, 1H, J ) 5.0 Hz), 4.12-
4.05 (m, 2H), 3.80-3.68 (m, 2H), 3.70 (s, 3H), 2.52-2.14 (m, 2H),
2.16-1.97 (m, 1H), 1.36-1.26 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 166.5, 143.0, 123.3, 100.1, 66.7, 51.2, 37.8, 25.4;
FABHRMS (NBA-NaI) m/z 209.0783 (M + Na+, C9H14O4 re-
quires 209.0790)
Anal. Calcd for C15H19N3O5: C, 56.07; H, 5.96; N, 13.08.
Found: C, 56.20; H, 6.13; N, 13.27.
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-a m in o-3-h yd r oxybu -
ta n oa te (18). A mixture of 17 (1.84 g, 5.7 mmol), Ph3P (3.0 g,
11.4 mmol), THF (20 mL), and H2O (1.03 mL) was stirred
overnight at 50 °C. The solvent was removed in vacuo, and
chromatography (SiO2, 5 × 15 cm, 5% CH3OH-CH2Cl2) afforded
Ben zyl 4-(1,3-Dioxa n -2-yl)-(E)-2-bu ten oa te (14). Lithium
hydroxide monohydrate (942 mg, 22.4 mmol) was added at 4 °C
to a solution of 12 (3.8 g, 20.4 mmol) in THF-H2O (1:1, 100 mL),
and the resulting mixture was stirred for 18 h at 23 °C. The
solvents were removed in vacuo, the residue containing 13 was
dissolved in DMF (40 mL), and benzyl bromide (3.6 mL, 30.2
mmol) was added. The mixture was stirred at 23 °C before ice
water was added, and the product was extracted with CH2Cl2
(4 × 30 mL). The combined organic phases were washed with
1 N aqueous HCl and H2O, dried (MgSO4), and concentrated.
Chromatography (SiO2, 10 × 20 cm, 20% EtOAc-hexane)
afforded 14 (4.9 g, 92%) as a pale yellow oil: IR (neat) νmax 1720,
18 (1.56 g, 93%) as a white solid: [R]23 +6.0 (c 1, CHCl3); IR
D
(neat) νmax 3374, 3292, 2964, 2861, 1733, 1456, 1195, 1143, 753,
697 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.35-7.32 (m, 5H), 5.17
(s, 2H), 4.75 (t, 1H, J ) 4.7 Hz), 4.16 (ddd, 1H, J ) 3.5, 4.7, 8.3
Hz), 4.09-4.04 (m, 2H), 3.80-3.67 (m, 2H), 3.64 (d, 1H, J ) 4.7
Hz), 2.63 (br s, 3H), 2.13-1.98 (m, 1H), 1.88-1.70 (m, 2H), 1.30-
1.29 (m, 1H); 13C NMR (62.5 MHz, CDCl3) δ 168.5, 128.6, 128.3,
100.8, 69.2, 66.9, 58.8, 37.4, 25.6; FABHRMS (NBA-NaI) m/z
296.1489 (M + H+, C15H21NO5 requires 296.1498).
Anal. Calcd for C15H21NO5: C, 61.00; H, 7.17; N, 4.74.
Found: C, 60.82; H, 6.95; N, 4.57.
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-a m in o-3-((ter t-b u -
tyld im eth ylsilyl)oxy)bu ta n oa te (19). A solution of 18 (1.56
g, 5.3 mmol) in CH2Cl2 (100 mL) was treated with 2,6-lutidine
(2.77 mL, 23.8 mmol) and tert-butyldimethylsilyltriflate (4.87
mL, 21.2 mmol) at 0 °C, and the resulting mixture was stirred
for 3.5 h. The mixture was washed with saturated aqueous
NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The
solution was concentrated, and chromatography (SiO2, 5 × 15
cm, 5% CH3OH-CH2Cl2) afforded 19 (2.13 g, 98%) as a colorless
1713, 1660, 1374, 1170, 1129, 1027 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 7.36-7.29 (m, 5H), 6.97 (dt, 1H, J ) 15.7, 7.2 Hz), 5.93
(dt, 1H, J ) 1.3, 15.7 Hz), 5.15 (s, 2H), 4.62 (t, 1H, J ) 5.0 Hz),
4.12-4.04 (m, 2H), 3.79-3.68 (m, 2H), 2.51-2.46 (m, 2H), 2.14-
1.98 (m, 1H), 1.35-1.27 (m, 1H); 13C NMR (62.5 MHz, CDCl3) δ
166.0, 143.5, 136.0, 128.5, 128.2, 128.1, 123.5, 100.2, 66.9, 66.1,
38.1, 25.5; FABHRMS (NBA-NaI) m/z 263.1291 (M + H+,
C15H18O4 requires 263.1283).
Anal. Calcd for C15H18O4: C, 68.69; H, 6.92. Found: C, 68.50;
H, 6.71.
oil: [R]23 +6.0 (c 1, CHCl3); IR (neat) νmax 2951, 2859, 1737,
D
1460, 1245, 1137, 1096, 840 cm-1; 1H NMR (250 MHz, CDCl3) δ
7.36-7.28 (m, 5H), 5.15 (s, 2H), 4.62 (dd, 1H, J ) 4.4, 6.4 Hz),
4.18 (td, 1H, J ) 4.4, 8.5 Hz), 4.08-4.01 (m, 2H), 3.75-3.63 (m,
2H), 3.70 (d, 1H, J ) 4.0 Hz), 2.11-1.81 (m, 4H), 1.73-1.62 (m,
1H), 1.32-1.26 (m, 1H), 0.86 (s, 9H), 0.07 (s, 6H); 13C NMR (62.5
MHz, CDCl3) δ 168.2, 128.5, 128.2, 99.5, 70.4, 66.9, 66.7, 66.6,
59.5, 38.0, 25.7; FABHRMS (NBA-NaI) m/z 410.2374 (M + H+,
Ben zyl (2R,3S)-4-(1,3-Dioxa n -2-yl)-2,3-d ih yd r oxybu ta n -
oa te (15). A cooled mixture of AD mix R (21.4 g), methane
sulfonamide (1.43 g), t-BuOH (90 mL) and H2O (90 mL), was
treated with 14 (4.0 g, 15.2 mmol), and the resulting suspension
was stirred for 24 h at 4 °C. Sodium sulfite (23.0 g) was added,
and the mixture was allowed to warm to 23 °C. The product
was extracted with EtOAc (5 × 50 mL), and the combined
organic phases were washed with 2 N aqueous KOH and H2O,
dried (MgSO4), and concentrated in vacuo. Chromatography
(SiO2, 6 × 20 cm, 50% EtOAc-hexane) afforded 15 (3.6 g, 80%,
C
21H35NO5Si requires 410.2363).
Anal. Calcd for C21H35NO5Si: C, 61.58; H, 8.61; N, 3.42.
Found: C, 61.36; H, 8.71; N, 3.15.
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-(N′-ter t-b u t yloxy-
ca r b on ylh yd r a zin o)-3-((ter t-b u t yld im et h ylsilyl)oxy)b u -
ta n oa te (8). A solution of 19 (922 mg, 2.25 mmol) and 2023 (556
mg, 2.25 mmol) in DMF (15 mL) was stirred for 24 h at 23 °C.
The mixture was concentrated, and chromatography (SiO2, 5 ×
15 cm, 75% EtOAc-hexane gradient) afforded 8 (852 mg, 72%)
>99% ee)21 as a colorless oil: [R]23 -1.1 (c 1, CHCl3); IR (neat)
D
νmax 3436, 2964, 1743, 1210, 1143, 1117, 1066 cm-1
;
1H NMR
(250 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 5.29 (d, 1H, J ) 12.3
Hz), 5.17 (d, 1H, J ) 12.3 Hz), 4.81 (t, 1H, J ) 4.6 Hz), 4.30 (br
dt, 1H, J ) 9.3, 2.2 Hz), 4.13-4.06 (m, 3H), 3.82-3.70 (m, 2H),
3.09 (br s), 2.10-1.98 (m, 2H), 1.87-1.77 (m, 1H), 1.37-1.31
(m, 1H); 13C NMR (62.5 MHz, CDCl3) δ 172.8, 128.6, 128.4, 128.3,
100.7, 73.9, 68.9, 67.4, 66.9, 66.8, 38.1, 25.6; FABHRMS (NBA-
NaI) m/z 319.1151 (M + Na+, C15H20O6 requires 319.1158).
Anal. Calcd for C15H20O6: C, 60.80; H, 6.80. Found: C, 61.02;
H, 7.29.
Ben zyl (2R,3S)-4-(1,3-Dioxa n -2-yl)-3-h yd r oxy-2-((4-n i-
tr oben zen esu lfon yl)oxy)bu ta n oa te (16). A solution of 15
(3.05 g, 10.3 mmol), 4-nitrobenzenesulfonyl chloride (2.28 g, 10.3
mmol), and Et3N (2.08 g, 20.5 mmol) in CH2Cl2 (90 mL) was
stirred for 12 h at 4 °C. The mixture was concentrated, and
the residue was dissolved in Et2O, washed twice with ice-cold 1
N aqueous HCl, saturated aqueous NaHCO3, and saturated
aqueous NaCl, and dried (MgSO4). Chromatography (SiO2, 6 ×
20 cm, 40% EtOAc-hexane) afforded the unstable 16 (3.36 g,
68%) which was used without further characterization in the
next step.
and recovered 19 (138 mg, 15%). For 8: [R]23 -3 (c 1.55,
D
CHCl3); IR (neat) νmax 2926, 2855, 1718, 1457, 1253, 1131, 838
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.34-7.28 (m, 5H), 6.16 (br
m, 1H), 5.19 (d, 1H, J ) 12.5 Hz), 5.13 (d, 1H, J ) 12.5 Hz),
4.59 (dd, 1H, J ) 6.5, 4.0 Hz), 4.25 (dt, 1H, J ) 4.5, 6.5 Hz),
4.03 (dd, 2H, J ) 4.0, 11.5 Hz), 3.77 (br s, 1H), 3.72-3.64 (m,
2H), 2.04-1.95 (m, 2H), 1.78-1.76 (m, 1H), 1.41 (s, 9H), 1.29
(br d, 1H), 0.85 (s, 9H), 0.077 (s, 3H), 0.049 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.5, 155.9, 135.5, 128.5, 128.4, 128.1,
128.0, 99.5, 69.2, 66.8, 66.6, 66.5, 39.2, 28.3, 25.8, -4.5, -5.0;
FABHRMS (NBA-CsI) m/z 657.1985 (M + Cs+, C26H44N2O7Si
requires 657.1972).
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-(N′-ter t-b u t yloxy-
ca r bon ylh yd r a zin o)-3-h yd r oxybu ta n oa te (9). A sample of
8 (78.6 mg, 0.16 mmol) was treated with 1 N Bu4NF in THF
(0.5 mL) at 0 °C for 30 min. EtOAc was added, and the mixture
was washed with H2O and saturated aqueous NaCl. The organic
phase was dried (MgSO4) and concentrated. Chromatography
(SiO2, 1 × 10 cm, 40% CH3OH-CH2Cl2) afforded 9 as a white
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-a zid o-3-h yd r oxybu -
ta n oa te (17). A mixture of 16 (3.36 g, 7.0 mmol) and NaN3
(2.73 g, 42 mmol) in DMF (80 mL) was stirred for 14 h at 50 °C.
Water was added, and the water phase was extracted with Et2O
(5 × 25 mL). The combined organic phases were washed with
H2O and saturated aqueous NaCl and dried (MgSO4). Chro-
matography (SiO2, 6 × 20 cm, 20% EtOAc-hexane) afforded 17
solid (45.6 mg, 74%): mp 98 °C (EtOAc-hexane); [R]23 -16 (c
D
1.1, CHCl3); IR (neat) νmax 2964, 2861, 1723, 1246, 1159, 1150
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 6.28 (s,
1H), 5.19 (d, 1H, J ) 12.5 Hz), 5.16 (d, 1H, J ) 12.5 Hz), 4.72 (t,
1H, J ) 4.8 Hz), 4.25-4.20 (m, 1H), 4.07-4.03 (m, 2H), 3.77-
3.65 (m, 2H), 3.61 (d, 1H, J ) 3.9 Hz), 2.10-1.97 (m, 1H), 1.93-
(1.96 g, 87%) as a yellow oil: [R]23 -8.3 (c 1, CHCl3); IR (neat)
D

6424 J . Org. Chem., Vol. 63, No. 18, 1998
Notes
1.85 (m, 1H), 1.77-1.71 (m, 1H), 1.40 (s, 9H), 1.33-1.29 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 170.9, 156.6, 135.4, 128.7, 128.5,
100.7, 80.8, 68.0, 67.2, 66.8, 38.0, 28.2, 25.7; FABHRMS (NBA-
CsI) m/z 543.1088 (M + Cs+, C20H30N2O7 requires 543.1107).
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-(N,N′-d i(ter t-bu tyl-
oxyca r bon yl)h yd r a zin o)-3-((ter t-bu tyld im eth ylsilyl)oxy)-
bu ta n oa te (21). A solution of 8 (7 mg, 0.013 mmol) and Et3N
(2.7 mg, 0.027 mmol) in CH2Cl2 (50 µL) was treated for 12 h at
0 °C with (BOC)2O (5.8 mg, 0.027 mmol) and DMAP (0.3 mg).
Water was added, and the mixture was washed with dilute
aqueous HCl and saturated aqueous NaCl and dried (MgSO4).
Chromatography (PTLC, 25% EtOAc-hexane) afforded 21 (4.4
mg, 53%) as a colorless oil: [R]23D +26 (c 0.21, CHCl3); IR (neat)
Cl2 (10 mL) was added dropwise at 0 °C to a mixture of 8 (526
mg, 1.00 mmol), K2CO3 (552 mg, 4.0 mmol), and CH2Cl2 (15 mL).
After complete addition a further amount of K2CO3 (440 mg)
was added. The mixture was stirred for 2 h at 0 °C, washed
with dilute aqueous HCl and H2O, and dried (MgSO4). Evapora-
tion of the solvent and chromatography (SiO2, 2.5 × 15 cm, 25%
EtOAc-hexane) afforded 27 (680 mg, 85%): [R]23 +5.3 (c 0.75,
D
CHCl3); IR (neat) νmax 2958, 1792, 1736, 1251, 1153, 839 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.46 (br s, 1H), 7.36-7.29 (m, 5H),
5.38 (br t, 1H, J ) 8.0 Hz), 5.17 (d, 1H, J ) 12.5 Hz), 5.10 (d,
1H, J ) 12.5 Hz), 4.65 (t, 1H, J ) 5.0 Hz), 4.57 (br, 1H), 4.52
(dd, 1H, J ) 5.5, 10.5 Hz), 4.34-4.32 (m, 2H), 4.11-4.00 (m,
2H), 3.73-3.65 (m, 2H), 3.58 (dt, 1H, J ) 4.5, 14 Hz), 3.39 (dt,
1H, J ) 4.5, 14 Hz), 2.08-1.99 (m, 2H), 1.87-1.81 (m, 1H), 1.43
(s, 9H), 1.29 (br d, 1H, J ) 13 Hz), 1.15-1.01 (m, 2H), 0.84 (s,
9H), 0.06 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.0, 167.2, 154.5, 152.6, 135.0, 128.5, 128.3, 100.3,
99.0, 83.0, 68.1, 67.3, 66.8, 66.7, 66.4, 65.9, 57.4, 54.1, 51.0, 50.6,
39.0, 28.0, 25.8, 25.6, 17.9, 8.4, -2.1, -4.7; FABHRMS (NBA-
CsI) m/z 934.2447 (M + Cs+, C35H59N3O12SSi2 requires 934.2412).
Anal. Calcd for C35H59N3O12SSi2: C, 52.41; H, 7.41; N, 5.24;
S, 4.00. Found: C, 52.03; H, 7.89; N, 5.11; S, 3.91.
νmax 2943, 1739, 1369, 1241, 1148 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.36-7.25 (m, 5H), 5.28 (s, 1H), 5.13 (s, 2H), 4.61 (dd,
1H, J ) 6.1, 4.6 Hz), 4.33-4.28 (m, 1H), 4.02 (br dd, 2H, J )
11.9, 4.6 Hz), 3.68 (dt, 2H, J ) 9.6, 3.4 Hz), 2.10-1.88 (m, 2H),
1.46 (s, 18H), 1.29-1.23 (m, 1H), 0.83 (s, 9H), 0.08 (s, 3H), 0.05
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 152.3, 135.6, 128.4,
128.1, 128.0, 99.7, 88.3, 83.0, 70.2, 68.5, 66.8, 66.7, 66.6, 39.9,
28.0, 25.8, 17.9, -4.5, -4.9; FABHRMS (NBA-CsI) m/z 757.2520
(M + Cs+, C31H52N2O9Si requires 757.2496).
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-(N,N′-d i(ter t-bu tyl-
oxyca r bon yl)h yd r a zin o)-3-h yd r oxybu ta n oa te (22). A solu-
tion of 9 (4 mg, 0.0098 mmol) and Et3N (1.97 mg, 0.0195 mmol)
in CH2Cl2 (50 µL) was treated for 12 h at 0 °C with (BOC)2O
(4.25 mg, 0.0195 mmol) and DMAP (0.3 mg). Water was added,
and the mixture was washed with dilute aqueous HCl and
saturated aqueous NaCl and dried (MgSO4). Chromatography
(PTLC, 40% EtOAc-hexane) afforded 22 (2.8 mg, 57%) as a
colorless oil: [R]23D -24 (c 0.1, CHCl3); IR (neat) νmax 2978, 1738,
1369, 1242, 1147 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34-7.27
(m, 5H), 5.20 (d, 1H, J ) 12.4 Hz), 5.15 (d, 1H, J ) 12.4 Hz),
4.77 (dd, 1H, J ) 7.2, 3.2 Hz), 4.09-4.03 (m, 3H), 3.75 (br t, 1H,
J ) 12.1 Hz), 3.53 (d, 1H, J ) 3.5 Hz), 2.10-1.91 (m, 2H), 1.72-
1.61 (m, 2H), 1.46 (s, 18H), 1.35-1.29 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 170.2, 152.7, 135.2, 128.5, 128.3, 128.2, 100.2,
84.1, 68.1, 67.2, 67.0, 66.9, 66.7, 37.8, 27.9, 25.8; FABHRMS
(NBA-CsI) m/z 643.1609 (M + Cs+, C25H38N2O9 requires
643.1632).
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-(N-(N-(2-tr im eth yl-
silyleth a n esu lfon yl)-D-ser in yl)-N′-(ter t-bu tyloxyca r bon yl)-
h yd r a zin o)-3-((ter t-bu tyld im eth ylsilyl)oxy)bu ta n oa te (28).
A solution of 27 (35 mg, 0.044 mmol) in CH3OH (0.5 mL) was
treated for 35 min with Cs2CO3 (4.2 mg, 0.013 mmol). The
mixture was concentrated, and chromatography (PTLC, 50%
EtOAc-hexane) afforded 28 (21.7 mg, 64%) as a colorless oil:
[R]23D -4.4 (c 1.2, CHCl3); IR (neat) νmax 2954, 1736, 1251, 1155,
1104, 838 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.36-
7.27 (m, 5H), 5.44 (d, 1H, J ) 8.8 Hz), 5.20-5.08 (m, 2H), 4.89
(d, 1H, J ) 12.7 Hz), 4.72 (t, 1H, J ) 4.6 Hz), 4.41-4.30 (m,
2H), 4.14-4.04 (m, 2H), 3.84-3.70 (m, 5H), 3.05-2.84 (m, 2H),
2.10-2.01 (m, 2H), 1.92-1.72 (m, 1H), 1.45 (s, 9H), 1.39 (br d,
1H, J ) 14 Hz), 0.74 (s, 9H), 0.04 (s, 3H), -0.04 (s, 9H), -0.08
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6, 167.7, 154.4, 135.3,
128.4, 128.0, 127.8, 99.9, 82.9, 67.1, 67.0, 66.2, 64.9, 60.6, 55.5,
48.4, 39.6, 29.7, 28.0, 25.6, 25.5, 17.9, 10.0, -2.0, -4.4, -5.3;
FABHRMS (NBA-CsI) m/z 908.2603 (M + Cs+, C34H61N3O11SSi2
requires 908.2620).
Ben zyl (4R)-2-Oxo-3-(2-t r im et h ylsilylet h a n esu lfon yl)-
1,3-oxa zolid in e-4-ca r boxyla te (24). A solution of 237 (690 mg,
1.92 mmol) in CH2Cl2 (8 mL) was treated for 1 h with Et3N (1.34
g, 13.2 mmol) and triphosgene (684 mg, 2.3 mmol) at 0 °C. The
mixture was concentrated, and chromatography (SiO2, 2.5 × 15
cm, 20% EtOAc-hexane) afforded 24 (706 mg, 95%) as a
Anal. Calcd for C34H61N3O11SSi2: C, 52.62; H, 7.92; N, 5.41;
S, 4.13. Found: C, 52.52; H, 7.81; N, 5.24; S, 4.35.
Ben zyl (3S,4S)-4-Hyd r oxy-2-(N-(2-tr im eth ylsilyleth a n e-
su lfon yl)-D-ser in yl)-2,3,4,5-tetr a h yd r op yr id a zin e-3-ca r box-
yla te (10). A solution of 28 (15 mg, 0.019 mmol) in 10% H2O-
TFA (0.4 mL) was stirred for 2 h at 23 °C. The mixture was
concentrated and the residue was dissolved in EtOAc, washed
with saturated aqeous NaHCO3, and dried (MgSO4). Chroma-
tography (PTLC, 100% EtOAc) afforded 10 (7.9 mg, 86%) as a
colorless oil: [R]23 +85 (c 0.75, CHCl3); IR (neat) νmax 2956,
D
1788, 1748 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.40-7.31 (m,
5H), 5.28 (m, 2H), 5.20 (d, 1H, J ) 12.0 Hz), 5.98 (dd, 1H, J )
3.5, 9.4 Hz), 4.60 (t, 1H, J ) 9.3 Hz), 4.34 (dd, 1H, J ) 3.5, 9.2
Hz), 3.67 (dt, 1H, J ) 4.7, 13.6 Hz), 3.51 (dt, 1H, J ) 4.7, 13.6
Hz), 1.15-1.07 (m, 2H), 0.05 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 168.6, 152.0, 134.1, 128.9, 128.5, 68.4, 65.6, 56.7, 50.6, 8.5,
colorless oil: [R]23 -26 (c 0.35, CHCl3); IR (neat) νmax 2954,
D
1746, 1678, 1633, 1454, 1403, 1325, 842 cm-1
;
1H NMR (400
MHz, CDCl3) δ 7.37-7.27 (m, 5H), 6.86 (br m, 1H), 6.00 (d, 1H,
J ) 9.5 Hz), 5.23 (t, 1H, J ) 2.7 Hz), 5.19 (d, 1H, J ) 12.1 Hz),
5.11 (dt, 1H, J ) 9.5, 3.4 Hz), 5.06 (d, 1H, J ) 12.1 Hz), 4.53 (br
m, 1H), 3.98 (dd, 1H, J ) 11.6, 3.5 Hz), 3.86 (dd, 1H, J ) 11.6,
3.5 Hz), 2.96-2.83 (m, 2H), 2.28-2.21 (m, 1H), 1.91 (br dd, 1H,
J ) 18.4, 4.0 Hz), 1.11-0.99 (m, 2H), 0.01 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 171.9, 166.6, 141.9, 134.8, 128.7, 128.3, 67.7, 64.9,
59.7, 57.6, 56.5, 49.4, 28.5, 16.1, 10.0, -2.0; FABHRMS (NBA-
CsI) m/z 508.1532 (M + Cs+, C20H31N3O7SSi requires 508.1550).
-2.1; FABHRMS (NBA-NaI) m/z 408.0913 (M + Na+, C16H23
NO6SSi requires 408.0913).
-
(4R)-2-Oxo-3-(2-tr im eth ylsilyleth a n esu lfon yl)-1,3-oxa zo-
lid in e-4-ca r boxylic Acid (25). A mixture of 24 (133 mg, 0.34
mmol), catalytic 10% Pd-C, and CH3OH (2.5 mL) was stirred
under H2 for 2 h at 23 °C. The mixture was concentrated and
filtered through a short column of SiO2 (5% CH3OH-CH2Cl2)
to afford 25 (100 mg, 100%) as a white foam: [R]23 +98 (c 1.0,
D
CHCl3); IR (neat) νmax 3560, 2943, 1394, 1359, 1154 cm-1
;
1H
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA41101), the Skaggs Institute of Chemical Biology,
and Deutsche Forschungsgemeinschaft postdoctoral fel-
lowship (G.S.).
NMR (400 MHz, CDCl3) δ 9.00 (br s, 1H), 5.00 (dd, 1H, J ) 9.6,
3.5 Hz), 4.69 (t, 1H, J ) 9.4 Hz), 4.48 (dd, 1H, J ) 9.3, 3.5 Hz),
3.64 (dt, 1H, J ) 13.8, 4.5 Hz), 3.48 (dt, 1H, J ) 13.8, 4.5 Hz),
1.15-1.05 (m, 2H), 0.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.8, 152.3, 65.7, 56.6, 50.8, 8.7, -2.1; FABHRMS (NBA-NaI)
m/z 318.0456 (M + Na+, C9H17NO6SSi requires 318.0444).
Ben zyl (2S,3S)-4-(1,3-Dioxa n -2-yl)-2-(N-((4R)-2-oxo-3-(2-
tr im eth ylsilyleth a n esu lfon yl)-1,3-oxa zolid in e-4-ca r bon yl)-
N′-(ter t-bu tyloxycar bon yl)h ydr azin o)-3-((ter t-bu tyldim eth -
ylsilyl)oxy)b u t a n oa t e (27). A solution of 25 (592 mg, 2.01
mmol) in CH2Cl2 (20 mL) was stirred for 2 h at 23 °C with 1
drop of DMF and oxalyl chloride (2.00 mL, 2 N solution in CH2-
Cl2). The mixture was concentrated, and crude 26 was used
directly in the next step. A solution of 26 (2.01 mmol) in CH2-
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
8-10, 12, 15, 21, 22, 24, and 25 (9 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 O980765D