Total Synthesis of Vancomycin Aglycon -Part 1: Synthesis of Amino Acids 4-7 and Construction of the AB-COD Ring Skeleton

Full text of DOI:10.1002/(SICI)1521-3773(19981016)37:19<2708::AID-ANIE2708>3.0.CO;2-E

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[9] Abbreviations: Tfa: trifluoroacetyl; TFA: trifluoroacetic acid;
DMSO: dimethyl sulfoxide; Boc: tert-butoxycarbonyl; NOE: nuclear
Overhauser effect; Tf: trifluoromethanesulfonyl; Ms: methanesulfon-
OH
O
HO
H2N
HO
O
OH
Ä
yl; Ac:acetyl; Ddm: 4,4Odimethoxydiphenylmethyl; Bn: benzyl;
DCB: 3,4-dichlorobenzyl; Piv: pivaloyl.
O
[10] a) D. A. Evans, C. J. Dinsmore, D. A. Evrard, K. M. DeVries, J. Am.
Chem. Soc. 1993, 115, 6426 ± 6427; b) D. A. Evans, C. J. Dinsmore,
Tetrahedron Lett. 1993, 34, 6029 ± 6032.
O
Cl
O
O
[11] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841 ± 1860.
[12] P. W. Jeffs, G. Chan, L. Mueller, C. DeBrosse, L. Webb, R. Sitrin, J.
Org. Chem. 1986, 51, 4272 ± 4278.
[13] a) A. V. Rama Rao, M. K. Gurjar, K. L. Reddy, A. S. Rao, Chem. Rev.
1995, 95, 2135 ± 2168; b) J. Zhu, Synlett. 1997, 133 ± 144.
[14] The configuration of the M(4 ± 6) and M(2 ± 4) macrocycles could be
ascertained from 1H NOE data for protons on the nitro-containing
aromatic ring; their positions may be established relative to the
benzylic hydroxyl-bearing stereocenters para to the diaryl ether
linkage.
[15] D. A. Evans, P. S. Watson, Tetrahedron Lett. 1996, 37, 3251 ± 3254.
[16] Similar observations have been made in monocyclic model systems.
a) D. L. Boger, R. M. Borzilleri, S. Nukui, Bioorg. Med. Chem. Lett.
1995, 5, 3091 ± 3096; b) D. L. Boger, R. M. Borzilleri, S. Nukui, R. T.
Beresis, J. Org. Chem. 1997, 62, 4721 ± 4736.
[17] A related cyclization (K2CO3/CaCO3, DMF, 458C) proceeding with
negligible atropselectivity has recently been reported: D. L. Boger,
R. T. Beresis, O. Loiseleur, J. H. Wu, S. L. Castle, Bioorg. Med. Chem.
Lett. 1998, 8, 721 ± 724.
[18] The option of thermal atropisomer equilibration of the M(2 ± 4) and
M(4 ± 6) rings is also possible. Boger et al. have begun to explore these
processes: D. L. Boger, O. Loiseleur, S. L. Castle, R. T. Beresis, J. H.
Wu, , Bioorg. Med. Chem. Lett. 1997, 7, 3199 ± 3202. See also ref. [16b].
C
E
D
OH
O
HO
Cl
O
H
N
H
N
O
H
N
H
5
3
1
6
N
O
N
N
Me
Me
4
2
H
H
H
H
H
O
O
HN
HO2C
O
7
B
NH2
Me
H
A
OH
OH
HO
1 Vancomycin
Figure 1. Molecular structure of vancomycin (1). The amino acids are
labeled with numbers, and the aromatic rings with capital letters.
intriguing mode of action[2] coupled with its unusual molec-
ular architecture[3] has fascinated synthetic chemists for some
time.[4] Having established a number of new synthetic
technologies and strategies aimed at this structural type,[5]
we have recently focused our efforts on the total synthesis of
1.[6] In this and the following communication,[7] we wish to
report our progress and findings in the field, beginning with
the stereoselective synthesis of amino acids 4 ± 7 (compounds
8, 22, 27, and 32), the biaryl ring system (35), and the
construction of the AB-COD skeleton (46a) of vancomycin.
Scheme 1 outlines the synthesis of amino acid 6 in its
protected form 8. Thus, benzylation of 4-hydroxybenzalde-
hyde (2) with BnBr under basic conditions (98% yield),
Total Synthesis of Vancomycin AglyconÐ
Part 1: Synthesis of Amino Acids 4 ± 7 and
Construction of the AB-COD Ring Skeleton
OBn
OBn
c
OR
K. C. Nicolaou,* Swaminathan Natarajan, Hui Li,
Nareshkumar F. Jain, Robert Hughes,
HO
H
b
Michael E. Solomon, Joshi M. Ramanjulu,
Christopher N. C. Boddy, and Masaru Takayanagi
EtOOC
NHCbz
O
EtOOC
2, R= H
3, R= Bn
4
5
a
d
Vancomycin (1, Figure 1) is a clinically effective antibiotic
used in cases of severe bacterial infections caused by several
drug resistant pathogens.[1] Its medical importance and
Cl
OH
f
OH
OBn
TBSO
TBSO
TBSO
e
[*] Prof. Dr. K. C. Nicolaou, Dr. S. Natarajan, H. Li, Dr. N. F. Jain,
R. Hughes, Dr. M. E. Solomon, Dr. J. M. Ramanjulu, C. N. C. Boddy,
Dr. M. Takayanagi
EtOOC
NH2
EtOOC
NH2
EtOOC
NHCbz
8
7
6
Department of Chemistry and
Scheme 1. Reagents and conditions: a) K2CO3 (1.5 equiv), BnBr
(1.0 equiv), KI (0.1 equiv), DMF, 258C, 12 h, 98%; b) (EtO)2(O)PCH2-
COOEt (1.1 equiv), KOH (1.5 equiv), THF, 258C, 12 h, 95%; c) NaOH
(3.0 equiv), BnOCONH2 (3.1 equiv), tBuOCl (3.0 equiv), (DHQD)2AQN
(0.05 equiv), K2[OsO2(OH)4] (0.04 equiv), nPrOH:H2O (1:1), 258C, 12 h,
45% (87% ee); d) TBSOTf (1.1 equiv), 2,6-lutidine (1.5 equiv), CH2Cl2,
08C, 0.5 h, 98%; e) H2, Pd(OH)2/C (0.01 equiv), MeOH, 0.5 h, 95%;
f) SO2Cl2 (1.0 equiv), Et2O (3.0 equiv), CH2Cl2, 08C, 1 h, 80%. Bnˆ benzyl;
Cbz ˆ benzyloxycarbonyl; TBS ˆ tert-butyldimethylsilyl. TBSOTf ˆ tert-
butyldimethylsilyltrifluoromethanesulfonate.
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037 (USA)
Fax: (‡1)619-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, California 92093 (USA)
[**] We thank Dr. D. H. Huang and Dr. G. Siuzdak for assistance with the
NMR spectroscopy and mass spectrometry, respectively. Financial
support for this work was provided by the National Institutes of
Health (USA), The Skaggs Institute for Chemical Biology, postdoc-
toral fellowships from the National Institutes of Health (to J.M.R.)
and the George E. Hewitt Foundation (to M.S.), and grants from
Pfizer, Schering Plough, Hoffmann La Roche, Merck, and Dupont
Merck.
followed by olefination with the anion of (EtO)2(O)PCH2-
COOEt, furnished a,b-unsaturated ethyl ester 4 (95% yield)
via compound 3. Asymmetric aminohydroxylation (AA)
according to the Sharpless protocol[8] gave directly the Cbz
derivative (5) of the desired amino alcohol in 45% yield and
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87%ee. The hydroxy group in 5 was then protected by
exposure to TBSOTf and 2,6-lutidine (98% yield), and the
resulting compound 6 was subjected to hydrogenolysis (H2,
10% Pd(OH)2/C), which caused cleavage of both the benzyl
and Cbz groups, affording phenol 7 (95% yield). Finally,
aminobenzoic acid (9) was methylated and thence brominated
to afford dibromide 11 (98% overall yield) via methyl ester
10. The ester group in 11 was reduced with LiAlH4 to afford
alcohol 12 (95% yield) and the amino group of the latter was
diazotized (NaNO2/HCl). The formed diazonium salt was
then intercepted with pyrrolidine to afford triazene 13 in 75%
overall yield. Oxidation of the hydroxy group in 13 with PCC
led to the corresponding aldehyde (14, 88% yield), which was
converted by Wittig reaction into terminal olefin 15 (92%
yield). Asymmetric dihydroxylation (AD) with AD-a accord-
ing to the Sharpless procedure[10] then furnished diol 16 (95%
yield, 95% ee) which was selectively silylated with TBSCl/
imidazole to afford monosilylated compound 17 (88% yield).
Reaction of 17 with DPPA in the presence of Ph3P and DEAD
afforded, with inversion of configuration,[11] azide 18 in 79%
yield, while reduction of the latter with Ph3P and H2O at 658C
led to the desired amine 19 (78% yield). Finally, formation of
the Boc derivative 20 ((Boc)2O, Et3N, 95% yield) followed by
desilylation (TBAF, 93% yield) and oxidation with TEMPO/
NaOCl (75% yield) led to triazene carboxylic acid 22 via
compound 21.
The more challenging AB biaryl system of vancomycin,[4a, 5b,c]
which contains the amino acids 5 and 7, was constructed in the
form of its azide equivalent 35 from its components 27 and 32,
as summarized in Scheme 3. Fragment 27 was synthesized in a
straightforward manner from 4-hydroxyphenylglycine (23) by
esterification (23 !24, 98%), Boc derivative formation
(24 !25, 95%), methylation (25 !26, 93%), and iodination
(26 !27, 90%). The boronic acid derivative 32 corresponding
to amino acid 7 was constructed from 3,5-dimethoxybenzal-
dehyde (28) by a sequence requiring Wittig olefination
(28 !29, 91%), Sharpless asymmetric dihydroxylation
(29 !30, AD-b, 92% yield, 96% ee), selective monobenzyla-
tion with nBu2SnO/BnBr (30 !31, 89%),[12] and boronation
(31 !32, 55%). The latter operation was effected by the
action of nBuLi (2.2 equiv) on benzylic alcohol 31,[13] followed
by quenching with B(OMe)3 and acidic hydrolysis.
[9]
chlorination of 7 with SO2Cl2 resulted in the formation of
the targeted intermediate 8 in 80% yield. This enantiomeri-
cally enriched fragment was coupled with pure fragment 35
and the diastereoisomers were separated (see Scheme 4).
The synthesis of the central amino acid (amino acid 4)
equivalent 22 was carried out as shown in Scheme 2. Thus, 4-
N
N
NH2
NH2
N
Br
Br
Br
Br
d
b
R
COOR
13
OH
11, R= COOMe
12, R= CH2OH
9, R= H
c
a
10, R= Me
e
N
N
N
N
N
N
N
N
R
N
Br
Br
Br
Br
Br
Br
g
TBSO
RO
OH
N3
18
14, R= CHO
16, R= H
h
f
j
15, R= CH=CH2
17, R= TBS
N
N
N
N
Coupling of fragments 27 and 32 proceeded smoothly under
Suzuki conditions[14] ([Pd(Ph3P)4] cat., Na2CO3) furnishing
the two atropisomers 33 and 36 in 84% yield and about 2:1
ratio. The major compound was proven to be the desired
natural atropisomer 33 by incorporating it into the AB-COD
ring system of vancomycin (see compound 46a in Scheme 5)
and establishing its stereochemistry by NOE studies (Table 2).
Both atropisomers 33 and 36 were taken through the sequence
shown in Scheme 3 to the desired biaryl fragments 35 and 38,
respectively. Thus, introduction of an azido group (DPPA,
Ph3P, DEAD)[11] accompanied by inversion of stereochemistry
(33 !34, 95% and 36 !37, 90%) was followed by ester
hydrolysis with LiOH in aqueous THF (34 !35, 99% and
37 !38, 99%).
N
N
N
N
N
Br
Br
Br
Br
Br
Br
m
l
TBSO
HO
HO
NHR
NHBoc
NHBoc
19, R= H
O
k
21
22
20, R= Boc
Scheme 2. Reagents and conditions: a) SOCl2 (1.0 equiv), MeOH, reflux,
2 h, 100%; b) Br2 (2.0 equiv), AcOH, 258C, 0.5 h, 98%; c) LiAlH4
(1.5 equiv), THF, 08C, 2 h, 95%; d) 6m HCl (5.0 equiv), NaNO2 (1.2 equiv),
AcOH:H2O (1:2), 08C, 0.5 h, then KOH (8.0 equiv), pyrrolidine
(1.5 equiv), 08C, 0.5 h, 75%; e) PCC (1.5 equiv), CH2Cl2, 258C, 2 h, 88%;
f) nBuLi (1.4 equiv), CH3PPh3Br (1.5 equiv), THF, 208C, 2 h, 92%;
g) AD-a (1.4 gmmol 1), tBuOH/H2O (1:1), 6 h, 95%, (95% ee); h) TBSCl
(1.1 equiv), imidazole (1.5 equiv), DMF, 08C, 5 h, 88%; i) Ph3P (2.5 equiv),
DEAD (2.5 equiv), DPPA (2.5 equiv), THF, 08C, 2 h, 79%; j) Ph3P
(3.0 equiv), H2O (10.0 equiv), THF, 608C, 3 h, 78%; k) (Boc)2O, Et3N,
CH2Cl2, 258C, 4 h, 95%; l) TBAF (1.2 equiv), THF, 08C, 2 h, 93%;
m) TEMPO (1.0 equiv), 5% aq. NaOCl (3.0 equiv), 5% NaHCO3, KBr
(0.05 equiv), Me2CO, 08C, 1 h, 75%. Boc ˆ tert-butoxycarbonyl; DEAD ˆ
diethyl azodicaboxylate; DPPA ˆ diphenylphosphoryl azide; PCC ˆ pyri-
Having constructed these appropriate functionalized frag-
ments, we were in a position to address their assembly into
more advanced systems. Below, we describe the coupling of
these intermediates and the assembly of the AB-COD
framework of vancomycin with the correct stereochemistry
and functionality for further elaboration, as well as work on
related isomers.[4a, b] These studies also allowed the identifi-
cation of the proper atropisomer of the AB biaryl system and
dinium
chlorochromate;
TBAFˆ tetra-n-butylammonium
fluoride;
TEMPO ˆ 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical.
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Table 1. Selected physical properties of compounds 8, 22, 34, 42a, and 46a.
O
O
O
8: Rf ˆ 0.24 [silica gel, 5% methanol in chloroform]; [a]D25
ˆ
11.5 (c ˆ 0.85
NH2
NHBoc
NHBoc
RO
MeO
MeO
I
CHCl3); IR (film): nÄmax ˆ 3366, 2943, 2849, 2555, 1737, 1602, 1502, 1467,
1
1H NMR (500 MHz, CD3OD): d ˆ 7.19 (d, J ˆ
b
d
1290, 1255, 1079 cm
;
2.0 Hz, 1H), 6.99 (dd, J ˆ 8.5, 2.0 Hz, 1H), 6.78 (d, J ˆ 8.5 Hz, 1H), 4.89
(d, J ˆ 3.5 Hz, 1H), 4.06 (m, 1H), 3.98 (m, 1H), 3.37 (bs, 1H), 1.12 (t, J ˆ
5.0 Hz, 3H), 0.80 (s, 9H), 0.08 (s, 3H), 0.26 (s, 3H); 13C NMR (
125 MHz, CD3OD): d ˆ 173.8, 154.1, 134.5, 129.3, 127.1, 121.5, 117.3, 76.7,
OH
OR
OMe
27
23, R= H
25, R= H
a
62.8, 62.3, 26.2, 19.0, 14.4,
4.4,
5.1; HRMS (FAB): calcd for
c
24, R= Me
26, R= Me
‡
C17H29ClNO4Si [M‡H ]: 374.1554; found: 374.1549.
22: Rf ˆ 0.18 [silica gel, 10% methanol in chloroform]; [a]D25
ˆ
97.4 (c ˆ
OH
O
RO
BnO
MeO
R
0.98 MeOH); IR (film): nÄmax ˆ 3344, 2976, 2872, 1711, 1415, 1367, 1313,
1
1223, 1162, 1052, 1020 cm
;
1H NMR ( 500 MHz, CD3OD): d ˆ 7.53 (s,
B(OH)
OMe
f
h
2H), 4.89 (bs, 1H), 3.81 (bs, 2H), 3.54 (bs, 2H), 1.99 (bs, 2H), 1.95 (bs, 2H),
1.33 (s, 9H); 13C NMR (125 MHz, CD3OD): d ˆ 157.2, 148.7, 139.7, 132.2,
118.7, 112.0, 80.8, 52.3, 47.9, 28.7, 28.6, 24.9, 24.6; HRMS (FAB): calcd for
MeO
MeO
OMe
OMe
‡
28, R= CHO
30, R= H
C17H22Br2N4O4Cs [M‡Cs ]: 636.9062; found: 636.9087.
g
32
e
29, R= CH=CH2
34: Rf ˆ 0.22 [silica gel, 30% ethyl acetate in hexanes]; [a]D25
ˆ
18.1(c ˆ
31, R= Bn
0.25 CHCl3); IR (film): nÄ
ˆ 3359, 2936, 2838, 2092, 1744, 1713, 1603,
max
+
32
27
1
1488, 1459, 1343, 1255, 1201, 1159, 1056 cm
;
1H NMR (500 MHz,
[D6]acetone): d ˆ 7.43 (dd, J ˆ 8.5, 2.0 Hz, 1H), 7.32 ± 7.21 (m, 5H), 7.16
(d, J ˆ 2.0 Hz, 1H), 7.01 (d, J ˆ 8.5 Hz, 1H), 6.67 (d, J ˆ 6.0 Hz, 1H), 6.63
(d, J ˆ 2.5 Hz, 1H), 6.58 (d, J ˆ 2.5 Hz, 1H), 5.29 (d, J ˆ 8.0 Hz, 1H), 4.62
(dd, J ˆ 9.2, 3.0 Hz, 1H), 4.35 (s, 2H), 3.84 (s, 3H), 3.65 (s, 3H), 3.65 (s, 3H),
3.59 (s, 3H), 3.60 ± 3.56 (m, 1H), 3.50 ± 3.49 (m, 1H), 1.39 (s, 9H); 13C NMR
(100 MHz, [D6]acetone): d ˆ 172.5, 161.4, 161.2, 160.8, 159.3, 158.6, 154.9,
131.8, 129.9, 129.1, 128.9, 128.2, 128.2, 125.8, 119.8, 112.0, 103.8, 98.9, 79.1,
74.4, 73.0, 62.9, 58.0, 56.1, 55.6, 55.6, 52.5, 28.5; HRMS (FAB): calcd for
i
O
O
O
O
O
O
NHBoc
OH
NHBoc
MeO
MeO
HO
MeO
OH
MeO
‡
C32H38N4O8Cs [M‡Cs ]: 739.1744; found: 739.1718.
BnO
42a: Rf ˆ 0.58 [silica gel, 50% acetone in hexanes]; [a]2D5 ˆ ‡85.8 (c ˆ 1.94
OMe
OMe
OBn
OMe
CHCl3); IR (film): nÄmax ˆ 3418, 3365, 2955, 2932, 2859, 2099, 1720, 1675,
MeO
MeO
36
1
;
1H NMR
33
1605, 1503, 1409, 1341, 1259, 1201, 1158, 1098, 1027 cm
j
j
(500 MHz, CDCl3): d ˆ 7.47 (br s, 1H), 7.30 (d, J ˆ 2.0 Hz, 1H), 7.28 ± 7.17
(m, 10H), 6.83 (d, J ˆ 8.5 Hz, 1H), 6.71 (m, 2H), 6.66 (d, J ˆ 2.0 Hz, 1H),
6.39 (d, J ˆ 2.0 Hz, 1H), 6.10 (d, J ˆ 8.5 Hz, 1H), 5.18 (m, 1H), 4.91 (m,
1H), 4.72 (d, J ˆ 9.0 Hz, 1H), 4.57 (dd, J ˆ 8.5, 3.0 Hz, 1H), 4.46 ± 4.38 (m,
2H), 4.32 ± 4.26 (m, 1H), 4.16 (m, 1H), 4.09 (m, 1H), 3.96 (br s, 2H), 3.86 (s,
3H), 3.71 (br s, 2H), 3.60 (s, 3H), 3.51 (s, 3H), 3.39 (dd, J ˆ 11.0, 9.0 Hz,
1H), 3.30 (m, 1H), 2.06 (m, 4H), 1.40 (s, 9H), 1.32 (dd, J ˆ 7.5, 7.0 Hz, 3H),
0.75 (s, 9H), 0.06 (s, 3H), 0.23 (s, 3H); 13C NMR (125 MHz, CDCl3):
d ˆ 168.5, 168.4, 168.2, 160.2, 157.8, 157.5, 154.5, 152.1, 141.9, 138.3, 137.5,
136.5, 134.2, 132.2, 129.3, 128.3, 128.1, 127.7, 127.6, 127.5, 127.2, 126.7, 126.6,
125.5, 125.2, 122.5, 119.6, 117.6, 117.5, 111.1, 102.5, 98.6, 80.3, 73.6, 73.3,
71.9, 62.0, 60.3, 59.8, 57.5, 55.6, 55.3, 55.1, 53.3, 51.0, 46.2, 28.2, 25.6, 24.0,
23.6, 17.8, 14.1, 4.4, 5.8; HRMS (FAB): calcd for C60H73BrClN9O12SiCs
NHBoc
NHBoc
MeO
N3
MeO
MeO
BnO
N3
OMe
OMe
OBn
OMe
MeO
37
34
k
k
NHBoc
NHBoc
HO
‡
[M‡Cs ]: 1386.3074; found: 1386.3160.
46a: Rf ˆ 0.11 [silica gel, 50% acetone in hexanes]; [a]D25
ˆ
20.8 (c ˆ 0.48
N3
CHCl3); IR (film): nÄmax ˆ 3273, 2930, 1651, 1488, 1416, 1318, 1249, 1159,
1097, 1058, 1029 cm 1; 1H NMR (600 MHz, [D6]acetone): d ˆ 8.14 (s, 1H),
7.64 (d, J ˆ 1.9 Hz, 1H), 7.49 (dd, J ˆ 8.4, 1.9 Hz, 1H), 7.37 ± 7.32 (m, 6H),
7.26 (m, 1H), 7.14 (d, J ˆ 2.3 Hz, 1H), 7.06 (m, 1H), 7.03 (d, J ˆ 8.4 Hz,
1H), 6.93 (d, J ˆ 8.6 Hz, 1H), 6.88 (d, J ˆ 2.1 Hz, 1H), 6.62 (d, J ˆ 2.1 Hz,
1H), 6.22 (d, J ˆ 10.9 Hz, 1H), 6.06 (d, J ˆ 8.5 Hz, 1H), 5.90 (s, 1H), 5.63 (d,
J ˆ 8.5 Hz, 1H), 5.41 (d, J ˆ 3.8 Hz, 1H), 5.18 (d, J ˆ 4.5 Hz, 1H), 4.75 (d,
J ˆ 5.8 Hz, 1H), 4.57 (m, 2H), 4.40 ± 4.37 (m, 2H), 3.96 ± 3.93 (m, 1H), 3.89
(br s, 2H), 3.83 (s, 3H), 3.82 ± 3.79 (m, 1H), 3.64 (s, 3H), 3.62 (s, 3H), 3.69 ±
3.62 (br s, 2H), 2.06 (m, 4H), 1.38 (s, 9H); 13C NMR (100 MHz,
[D6]acetone): d ˆ 170.8, 170.6, 168.4, 162.7, 161.0, 159.5, 158.1, 156.0,
152.5, 152.2, 142.2,140.5, 139.5, 139.5, 138.7, 136.1, 129.1, 128.7, 128.6, 128.3,
128.0, 127.9, 127.4, 127.0, 125.0, 124.2, 122.3, 119.4, 114.4, 113.2, 106.1, 98.4,
79.6, 73.6, 72.9, 70.2, 63.9, 56.6, 56.0, 55.6, 55.0, 52.7, 51.6, 47.0, 36.1, 28.5,
MeO
MeO
BnO
N3
OMe
OMe
OBn
OMe
38
MeO
35
Scheme 3. Reagents and conditions: a) TMSCl (2.1 equiv), MeOH, 258C,
15 h, 98%; b) (Boc)2O (1.1 equiv), K2CO3 (4.0 equiv), dioxane:H2O (1:1),
258C, 4 h, 95%; c) MeI (2.0 equiv), K2CO3 (4.0 equiv), DMF, 258C, 6 h,
93%; d) I2 (1.2 equiv), CF3COOAg (2.2 equiv), CHCl3, 258C, 12 h, 90%;
e) nBuLi (1.3 equiv), CH3PPh3Br (1.5 equiv), THF, 208C, 10 h, 91%;
f) AD-b (1.4 gmmol 1), tBuOH/H2O (1:1), 258C, 8 h, 92% (96% ee);
g) nBu2SnO (1.0 equiv), toluene, reflux, 1 h, then BnBr (1.5 equiv), nBu4NI
(0.5 equiv), 708C, 2 h, 89%; h) nBuLi (2.2 equiv), benzene, 0 !258C, 2 h,
then B(OMe)3, THF, 788C !258C, 6 h, dilute HCl, 55%, i) [Pd(Ph3P)4]
(0.2 equiv), Na2CO3 (1.2 equiv), PhCH3/MeOH/H2O (10:1:0.5), 908C, 4 h,
about 2:1 (33:36) ratio of atropisomers, 84% combined yield; j) DPPA
(2.5 equiv), DEAD (2.5 equiv), Ph3P (2.5 equiv), THF, 208C, 2 h, 95% of
34, 90% of 37; k) LiOH (1.5 equiv), THF/H2O (1:1), 08C, 0.5 h, 99% of 35,
99% of 38. TMS ˆ trimethylsilyl.
‡
24.5, 24.1; HRMS (FAB): calcd for C52H55BrClN7O11Cs [M‡Cs ]:
1200.1886; found: 1200.1965.
In retrospect, we now know that the major atropisomer of
the biaryl system described above possesses the correct
stereochemical arrangement (35, Scheme 3) for the vanco-
mycin molecule. The coupling of this biaryl fragment with
of the COD ring framework through NMR spectroscopic
techniques (see structures 46a and 46b and Tables 1 and 2).
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Table 2. Diagnostic NOEs for structural determination of selected
atropisomers.[a]
Compound
Solvent
(1H ± 1H) NOE[b]
42a
42b
46a
CDCl3
CDCl3
[D6]acetone
6a $ 6b; 6a $ Cb; 6b $ Cb
6a $ 6b; 6a $ Cf; 6b $ Cf
6a $ 6b; 6a $ Cb; 6b $ Cb;
5a $ Bb; 6a $ 5a
46b
[D6]acetone
6a $ 6b; 6a $ Cf; 6b $ Cf;
5a $ Bb; 6a $ 5a
50a
50b
54a
54b
[D6]acetone
[D6]acetone
[D6]acetone
[D6]acetone
6a $ 6b; 6a $ Cb; 6b $ Cb
6a $ 6b; 6a $ Cf; 6b $ Cf
6a $ Cf; 6b $ Cb; 5a $ Bf
6a $ Cb; 6b $ Cf; 5a $ Bf
[a] 1H-1H NOESY, 600 MHz, 300 K. [b] For the atom labeling in 42a and
42b see formula of compounds 46a and 46b in Scheme 5.
amino acid 6 in the form of derivative 8 (EDC/HOAt, 85%
yield, de ca. 13:1), and the elaboration of the resulting
dipeptide 39 (chromatographically separated from the minor
diastereoisomer) to the desired COD ring system 42a and its
atropisomer 42b is shown in Scheme 4. Thus, cleavage of the
Boc group from 39 by the action of TMSOTf and 2,6-lutidine
(90% yield), followed by EDC/HOAt induced coupling of the
resulting amine 40 with the derivative of the central amino
acid, 22, furnished tripeptide 41 in 76% yield. Exposure of 41
to CuBr´ SMe2, K2CO3, and pyridine in CH3CN at reflux[5a]
resulted in the formation of the two atropisomers of the COD
ring 42a and 42b in 60% combined yield (ca. 1:1 ratio). NMR
(e.g. COSY and NOESY) analysis of 42a and 42b established
the identity of these two atropisomers by revealing the
expected NOE data for each compound (see Scheme 4 and
Tables 1 and 2).
The elaboration of both atropisomers 42a and 42b to the
respective AB-COD ring frameworks (46a and 46b) is shown
in Scheme 5. It was indeed pleasing to observe that the
second ring closure could be effected smoothly by a lactam-
ization protocol as we demonstrated recently in model
systems.[5c] Thus, the correct atropisomer 42a was desilylated
with TBAF, furnishing hydroxy ester 43a (80% yield). This
deprotection was necessary to facilitate, in a subsequent step,
the basic hydrolysis of the ethyl ester which proved, otherwise,
robust. The azido group in 43a was then reduced to an amino
group by the action of Et3P in the presence of H2O at 258C,
furnishing amino ester 44a (71% yield), which was hydro-
lyzed easily with LiOH in THF/H2O (1:1) at 08C to afford
amino acid 45a (68% yield). Finally, exposure of 45a to
FDPP[15] in the presence of iPr2NEt in DMF at 258C resulted
in the formation of the AB-COD ring framework 46a in 71%
yield. A similar sequence allowed the preparation of 46b from
42b via intermediates 43b ± 45b. Again NMR spectroscopy
(COSY and NOESY) proved instrumental in establishing the
stereochemical arrangement within these unusual frameworks
and the arrangement of the AB ring system. Thus, the
observed NOEs (see Scheme 5 and Table 2) for 46a and 46b
were consistent with those observed for 42a and 42b with
regards to the COD ring stereochemistry and also established
the stereochemical identity of the original biaryl system 35 as
being natural.
Scheme 4. Reagents and conditions: a) EDC (3.0 equiv), HOBt (3.3 equiv),
THF, 08C, 12 h, 85%; b) TMSOTf (3.4 equiv), 2,6-lutidine (3.0 equiv),
CH2Cl2, 08C, 3 h, 90%; c) EDC (3.0 equiv), HOAt (3.3 equiv), THF,
58C, 12 h, 76%; d) CuBr´ SMe2 (3.0 equiv), K2CO3 (3.0 equiv), pyridine
(3.0 equiv), MeCN, reflux, 20 min, ca. 1:1 ratio of atropisomers, 60%
combined yield. EDC ˆ 1-ethyl-3-(3-dimethylamino)propylcarbodiimide
hydrochloride; HOAtˆ 1-hydroxy-7-azabenzotriazole; HOBtˆ 1-hydroxy-
benzotriazole.
In order to learn more about the properties of the various
atropisomers of the AB-COD ring systems, we undertook the
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Scheme 6. Reagents and conditions: a) EDC (3.0 equiv), HOAt (3.3 equiv),
THF, 08C, 10 h, 83%; b) TMSOTf (3.4 equiv), 2,6-lutidine (3.0 equiv),
CH2Cl2, 08C, 3 h, 91%; c) EDC (3.0 equiv), HOAt (3.3 equiv), THF, 08C,
10 h, 70%; d) CuBr´ SMe2 (3.0 equiv), K2CO3 (3.0 equiv), pyridine
(3.0 equiv), MeCN, reflux, 20 min, about 1:1 ratio of atropisomers, 60%
combined yield.
Scheme 5. Reagents and conditions: a) TBAF (1.5 equiv), THF, 08C, 2 h,
80% of 43a, 100% of 43b; b) Et3P (2.0 equiv), H2O (10.0 equiv), CH3CN,
258C, 12 h, 71% of 44a, 79% of 44b; c) LiOH (5.0 equiv), THF/H2O (1:1),
08C, 20 min, 68% of 45a, 62% of 45b; d) FDPP (3.0 equiv), iPr2NEt
(5.0 equiv), DMF, 258C, 12 h, 71% of 46a, 52% of 46b. FDPP ˆ penta-
fluorophenyl diphenylphosphinate.
incorporation of the atropisomer of the biaryl system 35,
compound 38, into the AB-COD framework. As outlined in
Scheme 6, the coupling of 38 with fragments 8 and 22 and the
further elaboration proceeded in a similar fashion as for its
isomer 35, furnishing the two atropisomers 50a and 50b via
intermediates 47 ± 49. However, it was interesting to observe
facile epimerization at the indicated positions (see structures
53 and 54, Scheme 7) on attempted elaboration of 50a and
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(10:1) at 08C resulted in essentially complete epimerization of
the adjacent stereocenters to furnish 53a and 53b. Lactam-
ization of the amino acids 53a and 53b in the presence of
HATU[16] and iPr2NEt resulted in the formation of the
respective AB-COD ring frameworks 54a and 54b. The
stereochemical assignments were based on experiments with
both sets of compounds 53a/53b and 54a/54b which revealed
the appropriate coupling constants (J6a,6b ˆ 9.8 Hz for 54a and
54b) and NOEs (see structures 54a and 54b, Scheme 7 and
Table 2). While it was possible to arrest the epimerization
process during the saponification of 52a and 52b by changing
the hydrolysis conditions (THF/H2O, 1:1), the ring-closure
reactions with the non-epimerized amino acids proceeded
with lower yields and, most significantly, with epimerization at
the indicated positions,[4e] leading to the same products 54a
and 54b as before. Thus, it appears that, with the unnatural
AB atropisomers in place, the AB-COD ring frameworks
prefer to reside in the epimeric form shown, irrespective of
the atropisomeric position of the chlorine atom.
Further elaboration of the natural AB-COD framework
(46a) to the vancomycin AB-COD-DOE tricyclic framework
and its conversion into the aglycon of vancomycin are
reported in the following communications.[7]
Received: April 14, 1998
Revised version: June 5, 1998 [Z11733/Z11734IE]
German version: Angew. Chem. 1998, 110, 2872 ± 2878
Keywords: amino acids ´ antibiotics ´ natural products ´
synthetic methods ´ vancomycin
[1] Glycopeptide Antibiotics (Ed.: R. Nagarajan), Dekker, New York,
1994.
[2] D. H. Williams, Nat. Prod. Rep. 1996, 13, 469.
[3] a) G. M. Sheldrick, P. G. Jones, O. Kennard, D. H. Williams, G. A.
Smith, Nature 1978, 271, 223 ± 225; b) P. J. Loll, A. E. Bevivino, B. D.
Korty, P. H. Axelson, J. Am. Chem. Soc. 1997, 119, 1516 ± 1522;
c) M. H. McCormick, W. M. Stark, R. C. Pittenger, G. M. McGuire,
Antibiot. Annu. 1955 ± 1956, 606 ± 611; d) C. M. Harris, T. M. Harris, J.
Am. Chem. Soc. 1982, 104, 4293 ± 4295; e) C. M. Harris, H. Kopecka,
T. M. Harris, J. Am. Chem. Soc. 1983, 105, 6915 ± 6922.
[4] a) D. A. Evans, C. J. Dinsmore, Tetrahedron Lett. 1993, 34, 6029; D. A.
Evans, C. J. Dinsmore, A. M. Ratz, D. A. Evrard, J. C. Barrow, J. Am.
Chem. Soc. 1997, 119, 3417; b) D. A. Evans, J. A. Ellman, K. M.
DeVries, J. Am. Chem. Soc. 1989, 111, 8912; D. A. Evans, C. J.
Dinsmore, D. A. Evrard, K. M. DeVries, J. Am. Chem. Soc. 1993, 115,
6426; D. A. Evans, P. S. Watson, Tetrahedron Lett. 1996, 37, 3251; D. A.
Evans, J. C. Barrow, P. S. Watson, A. M. Ratz, C. J. Dinsmore, D. A.
Evrard, K. M. DeVries, J. A. Ellman, S. D. Rychnovsky, J. J. Lacour, J.
Am. Chem. Soc. 1997, 119, 3419; D. A. Evans, C. J. Dinsmore, A. M.
Ratz, Tetrahedron Lett. 1997, 38, 3189; c) D. L. Boger, O. Loiseleur,
S. L. Castle, R. T. Beresis, J. H. Wu, Bioorg. Med. Chem. Lett. 1997, 7,
3199; D. L. Boger, R. M. Borzilleri, S. Nukui, R. T. Beresis, J. Org.
Chem. 1997, 62, 4721; D. L. Boger, R. M. Borzilleri, S. Nukui, J. Org.
Chem. 1996, 61, 3561; D. L. Boger, R. M. Borzilleri, S. Nukui, Bioorg.
Med. Chem. Lett. 1995, 5, 3091; D. L. Boger, Y. Nomoto, B. R.
Teegarden, J. Org. Chem. 1993, 58, 1425, and references therein; d) R.
Beugelmans, G. P. Singh, M. Bois-Choussy, J. Chastanet, J. Zhu, J. Org.
Chem. 1994, 59, 5535; R. Beugelmans, J. Zhu, N. Husson, M. Bois-
Choussy, G. P. Singh, J. Chem. Soc. Chem. Commun. 1994, 439; R.
Beugelmans, S. Bourdet, J. Zhu, Tetrahedron Lett. 1995, 36, 1279; J.
Zhu, R. Beugelmans, S. Bourdet, J. Chastanet, G. Roussi, J. Org.
Chem. 1995, 60, 6389; M. Bois-Choussy, R. Beugelmans, J.-P. Bouillon,
J. Zhu, Tetrahedron Lett. 1995, 36, 4781; J. Zhu, J.-P. Bouillon, G. P.
Singh, J. Chastanet, R. Beugelmans, Tetrahedron Lett. 1995, 36, 7081;
Scheme 7. Reagents and conditions: a) TBAF (1.5 equiv), THF, 08C, 2 h,
90% of 51a, 95% of 51b; b) Ph3P (3.0 equiv), THF, H2O (10.0 equiv),
608C, 3 h, 82% of 52a, 71% of 52b; c) LiOH (1.5 equiv), MeOH:H2O
(10:1), 08C, 2 h, 92% of 53a, 90% of 53b; d) HATU (1.5 equiv), iPr2NEt
(3.0 equiv), DMF, 258C, 8 h, 50% of 54a, 51% of 54b. HATU ˆ N-
[(dimethylamino)-1H-1,2,3-triazole[4,5-b]-pyridin-1-ylmethylene]-N-me-
thylmethanaminium hexafluorophosphate.
50b to the corresponding AB-COD ring frameworks. Thus,
while desilylation of 50a and 50b and subsequent reduction of
the azido group proceeded smoothly to afford amino esters
52a and 52b via 51a and 51b, respectively, attempted LiOH
saponification of the ethyl ester in aqueous MeOH/H2O
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R. Beugelmans, L. Neuville, M. Bois-Choussy, J. Zhu, Tetrahedron
Lett. 1995, 36, 8787; R. Beugelmans, M. Bois-Choussy, C. Vergne, J.-P.
Bouillon, J. Zhu, Chem. Commun. 1996, 1029; M. Bois-Choussy, L.
Neuville, R. Beugelmans, J. Zhu, J. Org. Chem. 1996, 61, 9309; C.
Vergne, M. Bois-Choussy, R. Beugelmans, J. Zhu, Tetrahedron Lett.
1997, 38, 1403; e) A. J. Pearson, J. G. Park, J. Org. Chem. 1992, 57,
1744; A. J. Pearson, J. G. Park, P. Y. Zhu, J. Org. Chem. 1992, 57, 3583;
A. J. Pearson, H. Shin, Tetrahedron 1992, 48, 7527; A. J. Pearson, K.
Lee, J. Org. Chem. 1994, 59, 2304; A. J. Pearson, H. Shin, Tetrahedron
1994, 59, 2314; A. J. Pearson, K. Lee, Tetrahedron 1995, 60, 7153; A. J.
Pearson, G. Bignan, Tetrahedron Lett. 1996, 37, 735; A. J. Pearson, G.
Bignan, P. Zhang, M. Chelliah, J. Org. Chem. 1996, 61, 3940; A. J.
Pearson, P. Zhang, G. Bignan, J. Org. Chem. 1997, 62, 4536; f) A. V. R.
Rao, T. K. Chakraborty, S. P. Joshi, Tetrahedron Lett. 1992, 33, 4045;
A. V. R. Rao, T. K. Chakraborty, K. L. Reddy, A. S. Rao, Tetrahedron
Lett. 1992, 33, 4799; A. V. R. Rao, M. K. Gurjar, V. Kaiwar, V. B.
Khare, Tetrahedron Lett. 1993, 34, 1661; A. V. R. Rao, K. L. Reddy,
M. M. Reddy, Tetrahedron Lett. 1994, 35, 5039; A. V. R. Rao, T. K.
Chakraborty, K. L. Reddy, A. S. Rao, Tetrahedron Lett. 1994, 35, 5043;
A. V. R. Rao, K. L. Reddy, A. S. Rao, Tetrahedron Lett. 1994, 35, 5047;
A. V. R. Rao, K. L. Reddy, A. S. Rao, Tetrahedron Lett. 1994, 35, 8465;
A. V. R. Rao, K. L. Reddy, A. S. Rao, T. V. S. K. Vittal, M. M. Reddy,
P. L. Pathi, Tetrahedron Lett. 1996, 37, 3023; A. V. R. Rao, M. K.
Gurjar, P. Lakshmipathi, M. M. Reddy, M. Nagarajan, S. Shashwati,
B. V. N. B. S. Sarma, N. K. Tripathy, Tetrahedron Lett. 1997, 38, 7433;
g) N. Pant, A. D. Hamilton, J. Am. Chem. Soc. 1988, 110, 2002; M. J.
Stone, M. S. Van Dyk, P. M. Booth, D. H. Williams, J. Chem. Soc.
Perkin Trans. 1 1991, 1629; K. Nakamura, S. Nishiyama, S. Yamamura,
Tetrahedron Lett. 1996, 37, 191; H. Konishi, T. Okuno, S. Nishiyama, S.
Yamamura, K. Koyasu, Y. Terada, Tetrahedron Lett. 1996, 37, 8791;
A. G. Brown, M. J. Crimmin, P. D. Edwards, J. Chem. Soc. Perkin
Trans. 1 1992, 123; R. B. Lamont, D. G. Allen, I. R. Clemens, C. E.
Newall, M. V. J. Ramsay, M. Rose, S. Fortt, T. Gallagher, J. Chem. Soc.
Chem. Commun. 1992, 1693; R. G. Dushin, S. J. Danishefsky, J. Am.
Chem. Soc. 1992, 114, 3471; D. W. Hobbs, W. C. Still, Tetrahedron Lett.
1987, 28, 2805.
Total Synthesis of Vancomycin AglyconÐ
Part 2: Synthesis of Amino Acids 1 ± 3 and
Construction of the AB-COD-DOE Ring
Skeleton
K. C. Nicolaou,* Nareshkumar F. Jain,
Swaminathan Natarajan, Robert Hughes,
Michael E. Solomon, Hui Li, Joshi M. Ramanjulu,
Masaru Takayanagi, Alexandros E. Koumbis, and
Toshikazu Bando
In the preceding communication,[1] we reported the syn-
thesis of the AB-COD ring system of vancomycin (I, Figure 1).
Herein, we describe conversion of this intermediate (16, see
OH
HO
HO
H2N
O
OH
O
O
O
D
Cl
O
O
C
O
E
OH
O
HO
Cl
O
H
H
H
N
H
5
3
1
N
N
6
N
O
N
N
Me
Me
4
2
H
H
H
H
H
O
O
HN
HO2C
O
7
B
NH2
Me
H
A
OH
OH
HO
I Vancomycin
Figure 1. Molecular structure of vancomycin I.
[5] 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; 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; Angew.
Chem. Int. Ed. Engl. 1997, 36, 1539; c) K. C. Nicolaou, J. M.
Ramanjulu, S. Natarajan, S. Bräse, H. Li, C. N. C. Boddy, F. Rübsam,
Chem. Commun. 1997, 1899; d) K. C. Nicolaou, H. J. Mitchell, F. L.
van Delft, F. Rübsam, R. M. Rodriguez, Angew. Chem. 1998, 110,
1972 ± 1974; Angew. Chem. Int. Ed. 1998, 37, 1871 ± 1874.
[6] For recent reviews, see: a) A. V. R. Rao, M. K. Gurjar, K. L. Reddy,
A. S. Rao, Chem. Rev. 1995, 95, 2135; b) K. Burgess, D. Lim, C. I.
Martinez, Angew. Chem. 1996, 108, 1162; Angew. Chem. Int. Ed. Engl.
1996, 35, 1077; c) J. P. Zhu, Synlett 1997, 133, and references therein.
[7] a) K. C. Nicolaou, N. F. Jain, S. Natarajan, R. Hughes, M. Solomon, H.
Li, J. M. Ramanjulu, M. Takayanagi, A. E. Koumbis, T. Bando,
Angew. Chem. 1998, 110, 2879 ± 2881; Angew. Chem. Int. Ed. 1998, 37,
2714 ± 2716; b) K. C. Nicolaou, M. Takayanagi, N. F. Jain, S. Natarajan,
A. E. Koumbis, T. Bando, J. M. Ramanjulu, Angew. Chem. 1998, 110,
2881 ± 2883; Angew. Chem. Int. Ed. 1998, 37, 2717 ± 2719.
Scheme 3) into the AB-COD-DOE framework (20a, see Sche-
me 3) of vancomycin (I) by assembling and attaching the re-
quired tripeptide 15, followed by triazene-driven ring closure.
Scheme 1 presents the three amino acid derivatives [com-
pounds 8 (amino acid 1), 5 (amino acid 2), and 7 (amino acid
3)] required for the completion of the AB-COD-DOE ring
framework, and their construction from readily available
substrates. Thus, the derivative of amino acid 2, 5, was reached
from aryl ester 1 by the following four-step sequence:[2]
1) Sharpless asymmetric dihyroxylation (AD) to give 2
(79% yield, 92% ee); 2) regioselective nosylation (nosyl ˆ
Nos ˆ 4-nitrobenzenesulfonyl), to give
3 (60% yield);
[*] Prof. Dr. K. C. Nicolaou, Dr. N. F. Jain, Dr. S. Natarajan, R. Hughes,
Dr. M. E. Solomon, H. Li, Dr. J. M. Ramanjulu, Dr. M. Takayanagi,
Dr. A. E. Koumbis, Dr. T. Bando
[8] B. Tao, G. Schlingloff, K. B. Sharpless, Tetrahedron Lett. 1998, 39, 2507.
We thank Professor Sharpless for information on this asymmetric
aminohydroxylation procedure.
[9] D. Masilamani, M. M. Rogic, J. Org. Chem. 1981, 46, 4486.
[10] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994,
94, 2484.
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037 (USA)
Fax: (‡1)619-784-2469
E-mail: kcn@scripps.edu
[11] B. Lal, B. Pramanik, M. S. Manha, A. K. Bose, Tetrahedron Lett. 1977,
1977.
and
Department of Chemistry and Biochemistry, University of California,
San Diego, 9500 Gilman Drive, La Jolla, California 92093 (USA)
[12] S. David, S. Hanessian, Tetrahedron 1985, 41, 643.
[13] For a review on directed orthometalation, see: V. Snieckus, Chem.
Rev. 1990, 90, 879.
[**] We thank Dr. D. H. Huang and Dr. G. Suizdak for assistance with the
NMR spectroscopy and mass spectrometry, respectively. This work
was financially supported by the National Institutes of Health (USA),
The Skaggs Institute for Chemical Biology, postdoctoral fellowships
from the National Institutes of Health (to J. M. R.) and the George E.
Hewitt Foundation (to M. S.), and grants from Pfizer, Schering
Plough, Hoffmann La Roche, Merck, and Dupont Merck.
[14] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2483.
[15] S. Chen, J. Xu, Tetrahedron Lett. 1991, 32, 6711 ± 6714.
[16] A. Ehrlich, H.-U. Heyne, R. Winter, M. Beyermann, H. Haber, L. A.
Carpino, M. Bienert, J. Org. Chem. 1996, 61, 8831 ± 8838.
2714
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