Expeditious routes to evernitrose and vancosamine derivatives and synthesis of a model vancomycin aryl glycoside

Article abstract of DOI:10.1002/(SICI)1521-3773(19980803)37:13/14<1871::AID-ANIE1871>3.0.CO;2-1

Only seven steps are required to synthesize the activated derivatives 2 and 3 of evernitrose and vancosamine from the common intermediate 1 derived from L-lactic acid. The expeditious route to 3 was followed by its efficient incorporation into a vancomyci

Full text of DOI:10.1002/(SICI)1521-3773(19980803)37:13/14<1871::AID-ANIE1871>3.0.CO;2-1

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26.3,
29.3,
31.4 and
34.8 (total of 14B); ESI-MS: (m/z): 268.3
Expeditious Routes to Evernitrose and
Vancosamine Derivatives and Synthesis of a
Model Vancomycin Aryl Glycoside**
[({B20H16(OH)NH3)}‡2H) ].
Received: February 2, 1998 [Z11425IE]
German version: Angew. Chem. 1998, 110, 1969 ± 1972
K. C. Nicolaou,* Helen J. Mitchell, Floris L. van Delft,
Frank Rübsam, and Rosa M. Rodríguez
Keywords: boron ´ clusters ´ isomerizations ´ oxidations
The antibiotics vancomycin[1] (1) and everninomicin 13,384-
1[2] (for the structure, see following contribution)[3] include in
their structures C3-branched 2,6-dideoxy-l-sugars containing
[1] B. L. Chamberland, E. L. Muetterties, Inorg. Chem. 1964, 3, 1450 ±
1456; M. F. Hawthorne, R. L. Pilling, P. F. Stokely, J. Am. Chem. Soc.
1965, 87, 1893 ± 1899.
[2] M. F. Hawthorne, R. L. Pilling, J. Am. Chem. Soc. 1966, 88, 3873.
[3] D. A. Feakes, K. Shelly, C. B. Knobler, M. F. Hawthorne, Proc. Natl.
Acad. Sci. USA 1994, 91, 3029 ± 3033; K. Shelly, D. A. Feakes, M. F.
Hawthorne, P. G. Schmidt, T. A. Krisch, W. F. Bauer, ibid. 1992, 89,
9039 ± 9043.
[4] M. F. Hawthorne, R. L. Pilling, P. F. Stokely, J. Am. Chem. Soc. 1965,
87, 4740 ± 4746.
[5] A. R. Pitochelli, W. N. Lipscomb, M. F. Hawthorne, J. Am. Chem. Soc.
1962, 84, 3026 ± 3027; B. G. DeBoer, A. Zalkin, D. H. Templeton,
Inorg. Chem. 1968, 6, 1085 ± 1090.
[6] a) Crystal structure analysis of [Me4N]2[7]: colorless crystals from
ethanol/acetonitrile: C8H42B20N2, Mr ˆ 382.7; crystal dimensions
3
Å
0.18  0.38  0.5 mm ; Syntex P1 diffractometer, CuKa radiation, l ˆ
1.5418 Š, 298 K; q ± 2q scan mode to 2qmax ˆ 1208. The unit-cell
parameters were determined from 25 accurately centered reflections
(18.98 < 2q < 26.68): orthorhombic, space group Pnam (no. 62), a ˆ
10.279(2), b ˆ 34.000(5), c ˆ 8.310(2) Š, Vˆ 2904 Š3, Z ˆ 4, 1calcd
ˆ
0.97 gcm 3, m ˆ 2.94 cm 1. Of the 2330 unique reflections measured
( ‡ h, ‡ k, ‡ l), 1680 were considered observed (I > 2s(I)), and the
structure was solved by direct methods; 239 refined parameters,
maximum residual electron density 0.13 eŠ 3, least-square refine-
ment against j F2 j ; R ˆ 0.078 for the observed reflections, Rw ˆ 0.113.
b) Crystallographic data (excluding structure factors) for the struc-
tures reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-101302. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK
(fax: ( ‡ 44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
[7] R. L. Pilling, M. F. Hawthorne, E. A. Pier, J. Am. Chem. Soc. 1964, 86,
3568 ± 3569; C. H. Schwalbe, W. N. Lipscomb, Inorg. Chem. 1971, 10,
151 ± 160.
an amino[4] or a nitro group,[5] respectively. Our interest in the
total synthesis of vancomycin[6] and everninomicin 13,384-1[7]
dictated new synthetic routes to these unique sugars and
methods for their attachment onto their respective target
molecules. Here we report the successful attainment of both
goals, culminating in the construction of key intermediates 11
and 16 (see Scheme 1) and the assembly of vancomycin
disaccharide 22 (see Scheme 2). In the following communica-
tion[3] we describe the synthesis of an advanced everninomicin
13,384-1 segment incorporating the nitrosugar.
A key objective of our strategy toward the nitrogen-
containing sugar units of these antibiotics was the construc-
tion of an intermediate (7), from which both compounds 11
and 16 could be generated (Scheme 1). Towards this goal, we
envisioned a stereocontrolled anti addition[8] of an acyl anion
equivalent to an aldehyde derived from l-lactic acid as a
means to install the C4 stereocenter (the numbering is based
on the final carbohydrate), where the functionality at C3 was
projected to arise by nucleophilic chain extension of an
[8] Crystal structure analysis of [Me3NH][9]: colorless crystals from an
aqueous solution, C3H30B20N2, Mr ˆ 310.5, crystal dimensions 0.48 Â
0.05  0.55 mm3, Syntex P1 diffractometer, CuKa radiation, l ˆ
Å
1.5418 Š, 298 K; q ± 2q scan mode to 2qmax ˆ 1158. The unit-cell
parameters were determined from 41 accurately centered reflections
(19.78 < 2q < 40.18): orthorhombic, space group P212121, a ˆ 10.334(7),
3
b ˆ 10.873(8), c ˆ 17.523(12) Š, Vˆ 1969 Š3, Z ˆ 4, 1calcd ˆ 1.05 gcm
,
m ˆ 2.79 cm 1. Of the 1519 unique reflections measured ( ‡ h, ‡ k, ‡
l), 1318 were considered observed (I > 2s(I)), and the structure was
solved by direct methods; 156 refined parameters, maximum residual
electron density 0.1 eŠ 3, least-square refinement against j F2 j ; R ˆ
0.064 for the observed reflections, Rw ˆ 0.082.[6b]
[*] Prof. Dr. K. C. Nicolaou, H. J. Mitchell, Dr. F. L. van Delft,
Dr. F. Rübsam, Dr. R. M. Rodríguez
[9] E. M. Georgiev, K. Shelly, D. A. Feakes, J. Kuniyoshi, S. Romano,
M. F. Hawthorne, Inorg. Chem. 1996, 35, 5412 ± 5416.
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (‡1)619-784-2469
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093
[**] This work was financially supported by the National Institutes of
Health (USA) and The Skaggs Institute for Chemical Biology. We
also thank the Netherlands Organization for Scientific Research
(NWO; F.L.v.D.), the Alexander von Humboldt-Stiftung, Germany
(F.R.), and the M. E. C., Spain (R.M.R., Fullbright) for fellowships.
Angew. Chem. Int. Ed. 1998, 37, No. 13/14
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1871

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ers (ca. 1:1). In contrast, workup with Ph3P led smoothly to
nitrosugar 10 (63% overall yield from 8). The yield of the
latter transformation was significantly improved by carrying
out the ozonolysis in a 2:1 mixture of isooctane and CCl4.
Although the apolar nature of this solvent system dictated two
additional steps (formation of the TMS ether prior to
ozonolysis and removal of TMS prior to treatment with
Ph3P), the targeted nitrosugar 10 was obtained in 82% overall
yield from 8. Finally, exposure to DAST led to rapid
conversion of 10 into a mixture of glycosyl fluorides 11 (83%).
Intermediate 7 also served as a convenient precursor of the
vancomycin derivative 16. Alcohol 7 carries the correct
configurations at C3 and C5 and is readily converted into its
C4 epimer 12 by Swern oxidation followed by chelation-
controlled NaBH4 reduction (90% yield, 92% de; Scheme 1).
After purification of 12, benzylation (96%) and exposure to
LAH resulted in the formation of amino alcohol 13 by
removal of both the benzyloxy and silyl groups.[14] The latter
compound was converted into its Cbz-protected derivative 14
under standard conditions (78% over two steps). Finally,
cleavage of the terminal olefin by ozonolysis followed by
treatment with Ph3P afforded a approximately 1:1 mixture of
lactols 15 in 95% yield. As in the case of 11, conversion of 15
into the glycosyl donor 16 was smoothly effected with DAST
(85%).
With multigram quantities of l-vancosamine and l-ever-
nitrose donors 16 and 11 at hand, strategies for attachment to
their respective natural products were investigated. The
stereoselective construction of a vancomycin disaccharide
model system is shown in Scheme 2, whereas the introduction
of evernitrose into its everninomicin segment is reported in
the following communication.[3]
From the reported techniques for forming b-linked aryl
glycosides,[15-17] the trichloroacetimidate method[18] was found
to be the most suitable for our purpose. Thus, conversion of
glucose derivative 17 into its trichloroacetimidate 18 followed
by coupling with 2,6-dimethoxyphenol in the presence of
Me
O
X
OMe
OMe
O
Me
Me
HO
h, i
j , k
O
MeO
Me NO
Me NH
2 O
RO
Me NO2
OBn
10: X = OH
11: X = F
8
9a: R = H
9b: R = TMS
l
f , g
O
OH
OH
3
5
Me
Me
Me
Me
b, c
e
OEt
OR
Me NH
iPr3SiO
X
iPr3SiO
OBn
3: R = H
4: R = iPr3Si
5: X = O
6: X = NOBn
7
d
a
m, n
Me
BnO
O
X
OH
4
OBn
Me
Me
HO
o, p
r
Me NH
Me NHR
iPr3SiO
Me NHCbz
OBn
13: R = H
14: R = Cbz
12
15: X = OH
16: X = F
s
q
Scheme 1. Synthesis of carbohydrate donors 11 and 16. a) iPr3SiCl
(1.1 equiv), imidazole (2.0 equiv), DMF, 10 h, 99%; b) DIBAL (1.3 equiv),
CH2Cl2, 788C, 45 min; c) EVE-Li (1.3 equiv), THF, 1008C; then 1n
HCl (aq), THF/H2O (80/20), 63% over three steps, de ˆ 85%;
d) BnONH2 ´ HCl (1.1 equiv), py, 0 !258C, 97% (E:Z ꢀ 4:1);
e) C3H5MgBr (2.5 equiv), Et2O, 358C, 95% based on 50% conversion;
f) NaH (1.1 equiv), MeI (1.3 equiv), DMF, 0 !258C, 96%; g) nBu4NF
(1.1 equiv), THF, 92%; h) (Me3Si)2NH (5.0 equiv), Me3SiCl (0.05 equiv),
CH3CN; i) O3, CCl4/iC8H18 (2/1), 78 !258C; j) TFA (2.0 equiv), 5 min;
k) Ph3P (2.0 equiv), 30 min, 82% over four steps; or i) O3, CH2Cl2, 788C;
k) Ph3P (2.0 equiv), 30 min (8 !10), 62% over two steps; l) DAST
(1.3 equiv), CH2Cl2, 08C, 30 min, 83%; m) (COCl)2 (2.0 equiv), DMSO
(2.5 equiv), Et3N (4.0 equiv),
78 !08C, 91%; n) NaBH4 (3.0 equiv),
Et2O/MeOH (5/1), 08C, 2 h, 90%, de ˆ 92%; o) NaH (1.1 equiv), BnBr
(1.2 equiv), nBu4NI (0.2 equiv), DMF, 0 !258C , 2 h, 96%; p) LAH
(1.6 equiv), Et2O, 258C, 24 h; q) CbzCl (3.0 equiv), Na2CO3 (10.0 equiv),
H2O/THF (5/1), 0 !258C, 30 min, 78% over two steps; r) 1. O3, CH2Cl2,
788C, 1 h; 2. Ph3P (2.0 equiv),
78 !258C, 3 h, 95%; s) DAST
(1.4 equiv), CH2Cl2, 1 h, 85%. Bn ˆ benzyl, Cbz ˆ benzyloxycarbonyl,
DASTˆ Et2N ´ SF3, DIBAL ˆ diisobutylaluminum hydride, EVE-Li ˆ
CH2C(OEt)Li, LAH ˆ lithium aluminum hydride, py ˆ pyridine, TFA ˆ
trifluoroacetic acid, TMS ˆ trimethylsilyl.
R1O
RO
OR1
O
OR
OH
oxime.[9] Thus, ethyl l-lactate (3, Scheme 1) was protected
with the bulky iPr3Si group to give 4 in high yield. Sequential
reduction with DIBAL and addition of EVE-Li[10] at 1008C
followed by acidic workup afforded hydroxy ketone 5 as a
mixture of diastereoisomers (85% de, 63% overall yield from
3). After separation from its syn epimer by chromatography
on silica gel, the anti isomer 5 was condensed with O-
benzylhydroxylamine to afford the readily separable oxime
ethers 6 (97%, E:Z ˆ 4:1).[11] Gratifyingly, chain extension of
the E isomer of 6 with allylmagnesium bromide at 358C
afforded hydroxylamine 7 as the sole detectable diaster-
eoisomer (95% based on 50% conversion).[12] Further elab-
oration of 7 to everninomicin carbohydrate 10 involved
methylation of the free hydroxyl group (96%) followed by
desilylation to afford 8 (92%). It was anticipated that
exposure of 8 to ozone would generate simultaneously the
required aldehyde and nitro groups.[13] However, ozonolysis of
8 (CH2Cl2, 788C) followed by workup with Me2S and
chromatography on silica gel afforded, instead of lactol 10, the
remarkably stable ozonide 9a as a mixture of diastereoisom-
BnO
BnO
OR1
MeO
b
OMe
OBz
O
OBn
O
17: R = H
18: R = C(NH)CCl3
a
OMe
c
MeO
Me
R1O
OR1
OR1
19: R = Bz
20: R = H
O
R1O
Me
O
O
Me
O
F
NHR2
MeO
O
d
16
Me NHCbz
BnO
OMe
e
22: R1 = R2 = Bz
21: R1 = Bn, R2 = Cbz
Scheme 2. Synthesis of the vancomycin model disaccharide. a) Cl3CCN
(5.0 equiv), DBU (cat.), CH2Cl2, 08C, 15 min, 100%; b) BF3 ´ Et2O
(0.6 equiv), CH2Cl2, 4-Š molecular sieves, 30 !258C, 24 h, 95%, b:a ꢀ
13:1; c) 1% aq NaOH, MeOH, 258C, 3 h, 90%; d) 16 (1.6 equiv), BF3 ´
Et2O (0.3 equiv), Me3SiOTf (0.3 equiv), CH2Cl2, 4-Š molecular sieves,
30 !258C, 72 h, 89% based on 90% conversion, a:b ꢀ 10:1; e) 1. H2, Pd/
C, EtOAc; 2. BzCl (7.0 equiv), py, 85% over two steps. Bz ˆ benzoyl,
DBU ˆ 1,8-diazobicyclo[5.4.0]undec-7-ene, Tf ˆ trifluoromethylsulfonyl.
1872
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BF3 ´ Et2O afforded the desired aryl glycoside 19 in excellent
yield (95%) and with high stereoselectivity (b:a ꢀ 13:1).
Debenzoylation gave direct access to glycosyl acceptor 20,
setting the stage for coupling with glycosyl fluoride 16. A
combination of BF3 ´ Et2O and Me3SiOTf was found to be
highly effective for activation of 16, furnishing, upon coupling
with 20, the desired a-glycoside 21 in 89% yield (based on
90% conversion) and with a stereoselectivity of about 10:1
(Table 1). Finally, hydrogenation and benzoylation of 21 gave
the protected disaccharide 22 (85% over two steps). The
configuration of the newly formed glycosidic bond was
confirmed by NMR spectroscopy on 21 (J1,2ax ˆ 4.5 Hz)[16, 19]
and 22. The latter compound was also synthesized through
glucal chemistry by Danishefsky and co-workers.[16]
intermediate derived from l-lactic acid. The described
chemistry also provides a plausible scenario for the incorpo-
ration of the carbohydrate domain of vancomycin into its
parent compound.[20]
Received: February 4, 1998 [Z11435IE]
German version: Angew. Chem. 1998, 110, 1972 ± 1974
Keywords: evernitrose ´ glycosides ´ glycosylations ´ van-
comycin ´ vancosamine
[1] a) M. H. McCormick, W. M. Stark, G. F. Pittenger, R. C. Pittenger,
G. M. McGuire, Antibiot. Annu. 1956, 1955 ± 1956, 606 ± 611; b) D. H.
Williams, V. Rajananda, M. P. Williamson, G. Bojesen in Topics in
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Chichester, 1980, pp. 119 ± 158.
[2] A. K. Ganguly, B. Pramanih, T. M. Chan, O. Sarre, Y.-T. Liu, J.
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[3] K. C. Nicolaou, R. M. Rodríguez, H. J. Mitchell, F. L. van Delft,
Angew. Chem. 1998, 110, 1975 ± 1977; Angew. Chem. Int. Ed. 1998, 37,
1874 ± 1876.
In summary, we have synthesized vancosamine derivative
15 (11 steps from 3, ca. 25% overall yield) and evernitrose (10,
9 steps from 3, ca. 30% overall yield) from a common chiral
Table 1. Selected physical properties of compounds 10, 15, and 21.
[4] a) T. T. Thang, F. Winternitz, J. Chem. Soc. Chem. Commun. 1979,
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d) H. I. Ahmad, J. S. Brimacombe, A. S. Mengech, L. C. N. Tucker,
Carbohydr. Res. 1981, 93, 288 ± 293; e) I. Dyong, H. Friege, H.
Luftmann, H. Merten, Chem. Ber. 1981, 114, 2669 ± 2680; f) G. Fronza,
C. Fuganti, P. Grasselli, G. Pedrocchi-Fantoni, Tetrahedron Lett. 1981,
22, 5073 ± 5076; g) J. S. Brimacombe, A. S. Mengech, K. M. M. Rah-
man, L. C. N. Tucker, Carbohydr. Res. 1982, 110, 207 ± 215; h) G.
Fronza, C. Fuganti, P. Grasselli, G. Pedrocchi-Fantoni, J. Carbohydr.
Chem. 1983, 2, 225 ± 248; i) Y. Hamada, A. Kawai, T. Shioiri,
Tetrahedron Lett. 1984, 25, 5413 ± 5414; j) F. M. Hauser, S. R.
Ellenberger, J. Org. Chem. 1986, 51, 50 ± 57; k) I. Dyong, J. Weigand,
J. Thiem, Liebigs Ann. Chem. 1986, 577 ± 599; l) A. Klemer, H.
Wilbers, Liebigs Ann. Chem. 1987, 815 ± 823; m) Y. Hamada, A.
Kawai, T. Matsui, O. Hara, T. Shioiri, Tetrahedron 1990, 46, 4823 ±
4846; n) R. Greven, P. Jütten, H.-D. Scharf, Carbohydr. Res. 1995, 275,
83 ± 93.
[5] a) J. Yoshimura, M. Matsuzawa, K. Sato, M. Funabashi, Chem. Lett.
1977, 1403 ± 1406; b) J. Yoshimura, M. Matsuzawa, M. Funabashi, Bull.
Chem. Soc. Jpn. 1978, 51, 2064 ± 2067; c) J. S. Brimacombe, A. S.
Mengech, M. S. Saeed, Carbohydr. Res. 1979, 75, C5 ± C7; d) J.
Yoshimura, M. Matsuzawa, K. Sato, Y. Nagasawa, Carbohydr. Res.
1979, 76, 67 ± 78; e) J. S. Brimacombe, A. S. Mengech, J. Chem. Soc.
Perkin Trans. 1 1980, 2054 ± 2060; f) J. S. Brimacombe, M. S. Saeed,
T. J. R. Weakley, J. Chem. Soc. Perkin Trans. 1 1980, 2061 ± 2064; g) P.
Jütten, H.-D. Scharf, Carbohydr. Res. 1991, 212, 93 ± 108.
10: Rf ˆ 0.25 (silica gel, 70% Et2O in hexanes); [a]D22
ˆ
31.5 (c ˆ 1.0 in
CHCl3); IR (thin film): nÄmax ˆ 3381, 2987, 2942, 2842, 1548, 1455, 1393, 1354,
1
1285, 1183, 1155, 1102, 1046, 988, 942, 913, 876, 857 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 5.32 (bd, J ˆ 4.0 Hz, 1H, a-H1), 4.88 (dd, J ˆ 8.0,
4.0 Hz, 1H, b-H1), 3.91 (dq, J ˆ 10.0, 6.0 Hz, 1H, a-H5), 3.84 (bs, 1H, OH),
3.76 (d, J ˆ 10.0 Hz, 1H , a-H4), 3.74 (d, J ˆ 10.0 Hz, 1H, b-H4), 3.46 (dq,
J ˆ 10.0, 6.0 Hz, 1H, b-H5), 3.41 (s, 3H, a-OCH3), 3.39 (s, 3H, b-OCH3),
3.15, (bs, 1H, OH), 2.41 (dd, J ˆ 13.5, 4.5 Hz, 1H, a-H2eq), 2.23 (m, 2H, b-
H2eq,ax), 2.17 (dd, J ˆ 13.5, 1.5 Hz, 1H, a-H2ax), 1.81 (s, 3H, a-H3), 1.66 (s,
3H, b-H3), 1.36 (d, J ˆ 6.5 Hz, 3H, a-H6), 1.31 (d, J ˆ 6.0 Hz, 3H, b-H3);
13C NMR (125 MHz, CDCl3) d ˆ 92.4, 90.6, 90.1, 89.6, 84.5, 84.2, 71.2, 66.1,
66.0, 66.0, 60.8, 60.8, 44.2, 40.8, 18.5, 18.4, 18.3, 16.6; HR-MS (FAB) calcd
‡
for C8H15O5NNa [M ‡ Na ]: 228.0848, found: 228.0848.
15: Rf ˆ 0.12 (silica gel, 60% Et2O in hexanes); [a]D22
ˆ
56.8 (c ˆ 0.5 in
CHCl3); IR (thin film): nÄmax ˆ 3410, 3064, 3032, 2930, 1713, 1517, 1453, 1380,
1350, 1280, 1240, 1208, 1160, 1068, 962, 885, 821, 753, 699, 585, 552,
486 cm 1; 1H NMR (500 MHz, CDCl3, mixture of anomers, ca. 1.8:1): d ˆ
7.32 ± 7.27 (m, 10H, ArH), 5.34 (bs, 0.4H, a-H1), 5.03 and 4.99 (AB, J ˆ
12.5 Hz, 2H, CH2Ar), 4.92 (bs, 1H, NH), 4.87 (m, 2.5H, b-H1, NH,
CH2Ar), 4.64 and 4.54 (AB, J ˆ 11.0 Hz, 0.8H, CH2Ar), 4.62 and 4.50 (AB,
J ˆ 11.0 Hz, 1.2H, CH2Ar), 4.29 (bq, J ˆ 6.5 Hz, 0.4H, a-H5), 3.82 (bq, J ˆ
6.5 Hz, 0.6H, b-H5), 3.56 (bs, 0.4H, a-H4), 3.52 (bs, 0.6H, b-H4), 3.15 (d,
J ˆ 8.0 Hz, 0.6H, b-OH), 2.61 (dd, J ˆ 8.0, 1.5 Hz, 0.4H, b-H2ax), 1.96 (dd,
J ˆ 13.0, 4.5 Hz, 0.6H, a-H2eq), 1.81 (bd, J ˆ 11.0 Hz, 0.4H, b-H2ax), 1.78
(bd, J ˆ 13.5 Hz, 0.6H, a-H2ax); 1.73 (s, 1.2H, a-H3), 1.55 (s, 1.8H, b-H3),
1.30 (d, J ˆ 6.5 Hz, 0.8H, a-H6), 1.30 (d, J ˆ 6.5 Hz, 1.2H, b-H6); 13C NMR
(125 MHz, CDCl3): d ˆ 154.8, 154.8, 137.9, 136.6, 136.4, 128.5, 128.4, 128.2,
128.2, 128.1, 128.1, 127.8, 92.7, 91.4, 80.1, 78.8, 75.8, 75.6, 70.1, 66.3, 66.2,
64.8, 55.3, 53.6, 40.5, 36.3, 29.7, 24.0, 22.0, 17.7, 17.5; HR-MS (FAB) calcd
[6] a) K. C. Nicolaou, C. N. C. Boddy, S. Natarajan, T. Y. Yue, H. Li, S.
Bräse, J. M. Ramanjulu, J. Am. Chem. Soc. 1997, 119, 3421 ± 3422;
b) K. C. Nicolaou, X. J. Chu, J. M. Ramanjulu, S. Natarajan, S. Bräse,
F. Rübsam, C. N. C. Boddy, Angew. Chem. 1997, 109, 1518 ± 1519;
Angew. Chem. Int. Ed. Engl. 1997, 36, 1539 ± 1540; c) K. C. Nicolaou,
J. M. Ramanjulu, S. Natarajan, S. Bräse, H. Li, C. N. C. Boddy, F.
Rübsam, Chem. Commun. 1997, 1899 ± 1900.
‡
for C22H27O5NNa [M ‡ Na ]: 408.1787, found: 408.1780.
21: Rf ˆ 0.18 (silica gel, 50% Et2O in hexanes); [a]D22
ˆ
43.8 (c ˆ 0.24 in
CHCl3); IR (thin film): nÄmax ˆ 3409, 3031, 2931, 1723, 1599, 1497, 1478, 1455,
1
1363, 1297, 1256, 1215, 1111, 1062, 735, 699 cm
;
1H NMR (500 MHz,
[7] K. C. Nicolaou, F. L. van Delft, S. C. Conley, H. J. Mitchell, J. Jin,
R. M. Rodríguez, J. Am. Chem. Soc. 1997, 119, 9057 ± 9058.
CDCl3): d ˆ 7.31 ± 7.18 (m, 25H, ArH), 7.02 (t, J ˆ 8.5 Hz, 2H, phenol-H),
6.57 (d, J ˆ 8.5 Hz, 2H, phenol-H), 5.32 (bd, J ˆ 4.5 Hz, 1H, H1'), 5.08 (d,
J ˆ 7.5 Hz, 1H, H1), 4.98 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.90 (s, 1H, NH),
4.83 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.68 (AB, J ˆ 11.0 Hz, 2H, CH2Ar),
4.55 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.50 (m, 1H, H5'), 4.45 (AB, J ˆ
12.0 Hz, 2H, CH2Ar), 3.94 (t, J ˆ 8.0 Hz, 1H, H3), 3.77 (s, 6H, OCH3),
3.72 ± 3.65 (m, 3H, H2, H4, H6a), 3.61 (dd, J ˆ 12.0, 5.5 Hz, 1H, H6b), 3.41
(s, 1H, H4'), 3.37 (m, 1H, H5), 1.84 (s, 3H, H3'), 1.83 (d, J ˆ 13.0 Hz, 1H,
H2'eq), 1.78 (dd, J ˆ 13.0, 4.5 Hz, 1H, H2'ax), 1.09 (d, J ˆ 6.5 Hz, 3H, H6');
13C NMR (125 MHz, CDCl3): d ˆ 154.9, 153.9, 138.6, 138.4, 138.1, 136.6,
134.0, 130.0, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 127.4, 124.0,
105.5, 100.7, 97.7, 86.0, 80.9, 78.2, 75.8, 75.8, 75.7, 75.3, 74.7, 73.6, 68.8, 66.0,
64.3, 56.1, 53.7, 36.6, 29.7, 23.4, 17.4; HRMS (FAB) calcd for C57H63O12NCs
Ã
[8] M. Hirama, I. Nishizaki, T. Shigemoto, S. Ito, J. Chem. Soc. Chem.
Commun. 1986, 393 ± 394.
Â
[9] J. A. Marco, M. Cards, J. Murga, F. Gonzalez, E. Falomir, Tetrahedron
Lett. 1997, 38, 1841 ± 1844.
[10] a) J. E. Baldwin, G. A. Höfle, O. W. Lever, Jr., J. Am. Chem. Soc. 1974,
96, 7125 ± 7127; b) R. K. Boeckman, Jr., K. J. Bruza, J. Org. Chem.
1979, 44, 4781 ± 4788.
[11] The minor Z isomer of 6 was unreactive under these conditions,
whereas prolonged reaction time or higher temperatures led to
desilylation. Regeneration of the E isomer was effected by equilibra-
tion of the Z-oxime (tBuOOH, CCl4, 778C, 70% yield, ca. 4:1): N. B.
Barhate, A. S. Gajare, R. D. Wakharkar, A. Sudalai, Tetrahedron Lett.
1997, 38, 653 ± 656.
‡
[M ‡ Cs ]: 1086.3405, found: 1086.3450.
Angew. Chem. Int. Ed. 1998, 37, No. 13/14
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3713-1873 $ 17.50+.50/0
1873

COMMUNICATIONS
[12] For unclear reasons, condensation fails to go to completion, even upon
use of a large excess of Grignard reagent, at increased dilution or
temperature, or by reverse addition.
OTBS
OH
OTBS
a, b
c, d
O
O
[13] P. S. Bailey, J. E. Keller, J. Org. Chem. 1968, 33, 2680 ± 2684.
[14] E. F. J. de Vries, J. Brussee, A. van der Gen, J. Org. Chem. 1994, 59,
7133 ± 7137.
O
e
2
3
4
[15] D. Kahne, S. Walker, Y. Cheng, D. V. Engen, J. Am. Chem. Soc. 1989,
111, 6881 ± 6882.
[16] R. G. Dushin, S. J. Danishefsky, J. Am. Chem. Soc. 1992, 114, 3471 ±
3475.
[17] B. A. Garcia, J. L. Poole, D. Y. Gin, J. Am. Chem. Soc. 1997, 119,
7597 ± 7598.
[18] R. R. Schmidt, J. Michel, Angew. Chem. 1980, 92, 763 ± 764; Angew.
Chem. Int. Ed. Engl. 1980, 19, 731 ± 732.
[19] A. W. Johnson, R. M. Smith, R. D. Guthrie, J. Chem. Soc. Perkin
Trans. 1 1972, 2153 ± 2159.
O
SPh
OH
O
OAc
OAc
O
X
i, j
g, h
B,C
TBSO
TBSO
TBSO
OH
OAc
7
8
5: X = O
f
6: X = H, OH
Scheme 1. Synthesis of 8. a) l-(‡)-diisopropyl tartrate (0.09 equiv),
Ti(OiPr)4 (0.072 equiv), tBuOOH (2.0 equiv), CH2Cl2, 158C, 9 d;
[20] All new compounds exhibited satisfactory spectral and exact mass
data.
b) TBSCl (1.2 equiv), imidazole (1.5 equiv), CH2Cl2, 0 !258C, 85% over
two steps; c) LiEt3BH (1.0m in THF, 1.1 equiv), CH2Cl2, 408C, 1 h, 91%;
ˆ
d) CH2 CHC(O)Cl (1.1 equiv), Et3N (1.2 equiv), CH2Cl2, 0 !258C, 1 h,
ˆ
90%; e) (PCy3)2Ru( CHPh)Cl2 (0.15 equiv), CH2Cl2, 408C, 72 h, 90%;
f) DIBAL (2.2 equiv), CH2Cl2, 788C, 1 h, 98%; g) OsO4 (0.03 equiv),
NMO (1.5 equiv), acetone/H2O (20/1), 258C, 24 h, 97%; h) Ac2O
(4.0 equiv), Et3N (6.0 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 0 !258C, 2 h,
98%; i) PhSH (1.3 equiv), Me3SiOTf (0.03 equiv), CH2Cl2, 0 !258C, 3 h,
69%; j) K2CO3 (0.2 equiv), MeOH, 258C, 3 h, 100%. Cy ˆ cyclohexyl,
DIBAL ˆ diisobutylaluminum hydride, 4-DMAP ˆ 4-dimethylaminopyri-
dine, NMO ˆ 4-methylmorpholine N-oxide, TBS ˆ tert-butyldimethylsilyl,
Tf ˆ trifluoromethylsulfonyl.
Stereocontrolled Synthesis of the
Everninomicin A1B(A)C Ring Framework**
K. C. Nicolaou,* Rosa M. Rodríguez,
Helen J. Mitchell, and Floris L. van Delft
among these are the formation of A1B(A) and A1BC systems
by Scharf et al.[2h, k±m] and approaches to 2-deoxy-b-glycosides
by Sinay et al.[2i±j] In the preceding contribution[3] we described
a stereoselective synthesis of
Everninomicin[1] (13,384-1, 1), a highly effective antibiotic
against drug-resistant bacterial strains, is a member of the
evernitrose (ring A) in its acti-
vated form (26, see Scheme 5).
Here we report efficient con-
structions of rings B, C, and A1
as well as their assembly to the
A1B(A)C ring system (28, see
Scheme 5) of everninomicin (1).
The reported chemistry fea-
tures a number of interesting
strategies including a) an ap-
proach based on ring-closing olefin metathesis[4] to the
common precursor 8 for carbohydrate systems B and C (see
Scheme 1), b) control of the stereochemistry of the 2-deoxy-b-
anomeric by a 1,2-migration and a sulfur-directed glycosida-
tion,[5] and c) use of an acyl fluoride to effect formation of the
sterically demanding ester bond between rings A1 and B.
An asymmetric synthesis of the common precursor to rings
B and C is shown in Scheme 1. Sharpless epoxidation of
prochiral divinylmethanol (2)[6] followed by silylation (TBSCl,
imidazole, 85% over two steps)[7] furnished epoxide 3.
Regioselective ring opening of 3 with LiEt3BH (ªsuper
hydrideº) followed by esterification with acryloyl chloride
under basic conditions (Et3N) provided diolefin 4 (90%).
orthosomycin family of compounds. Its novel and challenging
structure encompasses, among other structural elements, the
nitrosugar A and the fully substituted aromatic ring A1, and
has stimulated a number of synthetic studies.[2] Notable
[*] Prof. Dr. K. C. Nicolaou, Dr. R. M. Rodríguez, H. J. Mitchell,
Dr. F. L. van Delft
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (‡1)619-784-2469
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093
ˆ
Ring-closing metathesis induced by (PCy3)2Ru( CHPh)Cl2 as
catalyst afforded lactone 5 (90%).[8] Contrary to expectations,
dihydroxylation of 5 under a variety of conditions led to the
wrong diastereomer, with the oxygen atoms cis to the bulky
TBS group. Fortunately, reduction of lactone 5 with DIBAL,
followed by OsO4-catalyzed dihydroxylation of the resulting
[**] This work was financially supported by the National Institutes of
Health (USA) and the Skaggs Institute for Chemical Biology. We also
thank the M. E. C., Spain (R.M.R., Fullbright), and the Netherlands
Organization for Scientific Research (NWO; (F.L.v.D.) for fellow-
ships.
1874
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3713-1874 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 13/14