A synthetic approach towards the C1-C9 subunit of zincophorin

Article abstract of DOI:10.1002/1521-3773(20020617)41:12<2144::AID-ANIE2144>3.0.CO;2-E

Antibiotics made from cyclopropylmethanols: The C1-C9 subunit (2) of zincophorin (1) has been synthesized by using three key steps: a hydroboration of an enantiomerically enriched isopropenylcyclopropane, an aldol reaction, and an intramolecular oxymercur

Full text of DOI:10.1002/1521-3773(20020617)41:12<2144::AID-ANIE2144>3.0.CO;2-E

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A Synthetic Approach towards the
C1 C9 Subunit of Zincophorin
Janine Cossy,* Nicolas Blanchard,
Magali Defosseux, and Christophe Meyer*
The useful anti-infectious properties displayed
by many naturally occurring polyoxygenated
ionophores have been explained by their capacity
to form lipophilic complexes with various cations,
which affects proton cation exchange processes
across biological membranes.[1, 2]
In 1984, there were two independent reports on
the isolation of apparently the same antibiotic
from strains of Streptomyces griseus.[3, 4] On the
basis of its exceptional high affinity for divalent
Scheme 1. Retrosynthetic analysis for the C1 C9 subunit of zincophorin. Pg ˆ Protecting
group.
cations and especially zinc, this antibiotic was given the trivial
tion of the cyclopropylmethanol derivative B. According to
the retrosynthetic analysis, the asymmetric carbon atoms C2
and C3 could be installed with the required absolute config-
urations by using a chiral-auxiliary-mediated aldol condensa-
tion between the enolate of ethylketone C and aldehyde D,
which incorporates three contiguous stereocenters (C6 C8).
Based on previous studies,[18] the control of the relative
configuration at the C6 atom could be achieved by performing
a diastereoselective hydroboration of isopropenylcyclopro-
pane E, followed by transformation to aldehyde D. Further-
more, the preparation of isopropenylcyclopropanes of type E,
in an enantiomerically enriched form (ee value > 95%) has
been reported from 3-oxabicylo[3.1.0]hexan-2-one,[19] which is
readily available by a rhodium-catalyzed enantioselective
cyclopropanation of allyl diazoacetate (Scheme 1).[20]
5]
name zincophorin (Figure 1).[3 Zincophorin exhibits strong
in vivo activity against Gram-positive bacteria[3, 4] and its
methyl ester has also been reported to possess antiviral
activity.[6]
Figure 1. Structure of zincophorin.
The C1 C9 subunit of zincophorin was synthesized
(Scheme 2). Hydroboration of the isopropenylcyclopropane 1
with BH3 ¥ THF, followed by a standard oxidative work-up
with alkaline hydrogen peroxide, afforded, with a high
diastereoselectivity (d.r. > 98/2), the corresponding alcohol 2
(91%), with a methyl group syn to the adjacent cyclo-
propane.[18] In order to transform 2 to the aldehyde 5, com-
pound 2 was first oxidized with pyridinium chlorochromate
(PCC) to the corresponding aldehyde,[21] and subsequent
Horner Wadsworth Emmons olefination with triethyl
phosphonoacetate afforded the a,b-unsaturated ester 3
(75%). Compound 3 was then hydrogenated over platinum
oxide in ethyl acetate to give the ethyl ester 4 (98%), which
was reduced with DIBAL-H (DIBAL-H ˆ diisobutylalumi-
num hydride, toluene, À788C) to the aldehyde 5 (97%).
The elaboration of a suitable precursor for the oxymercu-
ration reaction required the installation of the C2 and
C3 stereocenters with an anti relative configuration, by using
a highly diastereoselective anti-aldol condensation between
the E-boron enolate derived from the ethylketone 6[22] and the
aldehyde 5, which afforded 7 in 83% yield (d.r. > 96/4). With
aldol 7 in hand, the feasibility of the intramolecular oxy-
mercuration could then be tested, however treatment of 7
with mercuric trifluoroacetate in CH2Cl2 resulted in a number
of products. As the tert-butyldiphenylsilyl group might
interfere with this reaction,[23] it was removed by treatment
of 7 with HF ¥ pyridine to produce cyclopropylmethanol 8
(86%). Indeed, when 8 was subjected to the oxymercuration
The challenging structure of zincophorin has elicited
considerable synthetic interest and syntheses of advanced
13]
elaborated fragments have been reported,[7
but to date a
single total synthesis has been completed by the Danishefsky
group.[7b] Herein, we report the results of our synthetic studies
concerning a new approach towards the C1 C9 subunit of
zincophorin by using an intramolecular oxymercuration
reaction of an appropriately substituted and enantiomerically
enriched cyclopropylmethanol.
Whereas the intramolecular oxymercuration of alkenes has
often been used to synthesize oxygenated heterocycles, and
especially those encountered in naturally occurring iono-
phores,[14, 15] the corresponding reaction with cyclopropanes
has received much less attention in the context of the total
synthesis of natural products. As the intramolecular oxy-
mercuration of cyclopropanes has been shown to proceed in
some cases with high degrees of regio- and stereocontrol,[16, 17]
a new approach towards the C1 C9 subunit of zincophorin A
was considered, to elaborate the trisubstituted tetrahydropyr-
an (Scheme 1). This approach involved an intramolecular
oxymercuration reaction, followed by reductive demercura-
[*] Prof. J. Cossy, Dr. C. Meyer, Dr. N. Blanchard, M. Defosseux
¬
Laboratoire de Chimie Organique associe au CNRS
ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05 (France)
Fax : (‡33)1-40-79-46-60
E-mail: janine.cossy@espci.fr, christophe.meyer@espci.fr
2144
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butyldiphenylsilyl ether 11 (99%), and reduction with
lithium borohydride, followed by an oxidative cleavage
with sodium periodate, afforded the aldehyde 12,[22]
which was oxidized to the corresponding acid 13 (90%
from 11). Subsequent esterification with trimethylsilyl-
diazomethane and deprotection of the silyl ether lead to
14 (14 ˆ A; 69%),[26] which is the C1 C9 subunit of
zincophorin.
The C1 C9 subunit of zincophorin has been synthe-
sized by an approach that involves three key steps: a
diastereoselective hydroboration of an optically en-
riched isopropenyl-cyclopropane, an anti-aldol conden-
sation, and a diastereoselective intramolecular oxy-
mercuration of a cyclopropylmethanol.
Received: February 25, 2002 [Z18771]
[1] Polyether Antibiotics, Vol. 1 and 2 (Ed.: J. W. Westley), Marcel
Dekker, New York, 1982.
[2] M. Dobler in Ionophores and their Structures, Wiley, New
York, 1981.
[3] H. A. Brooks, D. Gardner, J. P. Poyser, T. J. King, J. Antibiot.
1984, 37, 1501.
[4] U. Gr‰fe, W. Schade, M. Roth, L. Radics, M. Incze, K. Ujszaszy,
J. Antibiot. 1984, 37, 836.
[5] L. Radics, J. Chem. Soc. Chem. Commun. 1984, 599.
[6] U. Gr‰fe (Akademie der Wissenschaften der DDR), Ger.
(East) Patent, DD 231 793, 1986 [Chem. Abstr. 1987, 106,
101970].
[7] a) R. E. Zelle, M. P. DeNinno, H. G. Selnick, S. J. Danishefsky,
J. Org. Chem. 1986, 51, 5032; b) S. J. Danishefsky, H. G.
Selnick, R. E. Zelle, M. P. DeNinno, J. Am. Chem. Soc. 1988,
110, 4368.
[8] a) M. Balestra, M. D. Wittman, J. Kallmerten, Tetrahedron
Lett. 1988, 29, 6905; b) C. L. Cywin, J. Kallmerten, Tetrahedron
Lett. 1993, 34, 1103.
[9] J. A. Marshall, M. R. Palovich, J. Org. Chem. 1998, 63, 3701.
[10] S. R. Chemler, W. R. Roush, J. Org. Chem. 1998, 63, 3800.
[11] J. F. Booysen, C. W. Holzapfel, Synth. Commun. 1995, 25, 1473.
[12] S. D. Burke, R. A. Ng, J. A. Morrison, M. J. Alberti, J. Org.
Chem. 1998, 63, 3160.
Scheme 2. Synthesis of the C1 C9 subunit of zincophorin. a) BH3 ¥ THF/THF,
À308C !RT, then NaOH, H2O2; b) PCC, 4 ä molecular sieves, CH2Cl2, RT;
c) NaH, (EtO)2P(O)-CH2-COOEt, THF; d) H2, cat. PtO2, EtOAc, RT; e) DIBAL-
H, toluene, À788C; f) 6, EtNMe2, cHex2BCl, Et2O, 0 8C; add 5, À788C, 2 h and
À238C, 12 h, then MeOH, H2O2, pH 7buffer; g) HF ¥ pyridine, THF, RT;
h) Hg(OCOCF3)2, CH2Cl2, RT then KBr/H2O; i) nBu3SnH, toluene/THF,
RT !608C then CCl4; j) tBuPh2SiCl, imidazole, DMF, RT; k) LiBH4, THF,
À208C !RT then NaIO4, MeOH, RT; l) NaClO2, NaH2PO4, 2-methylbut-2-ene,
tBuOH/H2O, RT; m) Me3SiCHN2, MeOH/C6H6. R ˆ tBuPh2Si, Bz ˆ benzoyl.
[13] Y. Guindon, L. Murtagh, V. Caron, S. R. Landry, G. Jung, M.
¬
Bencheqroun, A.-M. Faucher, B. Guerin, J. Org. Chem. 2001,
66, 5427.
procedure (Hg(OCOCF3)2, CH2Cl2, RT, aqueous KBr work-
up), an extremely clean conversion to the organomercuric
bromide 9 was observed. The latter was not purified but
immediately subjected to reductive demercuration with
tributyltin hydride;[24] this lead to tetrahydropyran 10 in
85% yield and with a high diastereoselectivity (d.r. ˆ 93/
7).[25] The relative configuration of 10 indicates that the
[14] a) T. L. B. Boivin, Tetrahedron 1987, 43, 3309; b) G. Cardillo, M.
¡
Orena, Tetrahedron 1990, 46, 3321; c) J.-C. Harmange, B. Figadere,
Tetrahedron: Asymmetry 1993, 4, 1711.
[15] a) D. A. Evans, S. L. Bender, J. Morris, J. Am. Chem. Soc. 1988, 110,
2506; b) K. Bratt, A. Garavelas, P. Perlmutter, G. Westman, J. Org.
Chem. 1996, 61, 2109; for a related approach with allenes, see: c) R. D.
Walkup, G. Park, J. Am. Chem. Soc. 1990, 112, 1597; d) R. D. Walkup,
S. W. Kim, J. Org. Chem. 1994, 59, 3433.
[16] a) D. B. Collum, F. Mohamadi, J. S. Hallock, J. Am. Chem. Soc. 1983,
105, 6882; b) A. G. M. Barrett, W. Tam, J. Org. Chem. 1997, 62, 4653.
[17] For the synthesis of stereotriads involving an intramolecular oxy-
mercuration process, see: J. Cossy, N. Blanchard, C. Meyer, Org. Lett.
2001, 3, 2567.
[18] a) J. Cossy, N. Blanchard, C. Hamel, C. Meyer, J. Org. Chem. 1999, 64,
2608; b) J. Cossy, N. Blanchard, C. Meyer, Synthesis 1999, 1063.
[19] J. Cossy, N. Blanchard, C. Meyer, Eur. J. Org. Chem. 2001, 339.
[20] M. P. Doyle, R. E. Austin, A. S. Bailey, M. P. Dwyer, A. B. Dyatkin,
A. V. Kalinin, M. M. Y. Kwan, S. Liras, C. J. Oalmann, R. J. Pieters,
M. N. Protopopova, C. E. Raab, G. H. P. Roos, Q. L. Zhou, S. F.
Martin, J. Am. Chem. Soc. 1995, 117, 5763.
[21] The use of PCC or other oxidation procedures (Swern or Dess
Martin oxidations) afforded similar results and no alteration of the
diastereomeric purity of the aldehyde from 2 was detected.
intramolecular oxymercuration involved, as anticipated, an
[16, 17]
inversion of configuration at the C7atom.
The presence
of the silyl protecting group interferes with the intramolecular
oxymercuration of 7 (R ˆ tBuPh2Si), and implies additional
deprotection and protection steps. The corresponding benzyl
ether derivative was therefore synthesized (R ˆ CH2Ph), but
its intramolecular oxymercuration, followed by reductive
demercuration, proceeded in lower yield (46%) and diaster-
eoselectivity (d.r. ˆ 85/15) than for 8. Therefore, the presence
of the free alcohol at C9 was more appropriate for the
intramolecular oxymercuration step, and the synthesis of the
C1 C9 subunit of zincophorin was pursued from 10
(Scheme 2). The alcohol 10 was transformed to the tert-
Angew. Chem. Int. Ed. 2002, 41, No. 12
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4112-2145 $ 20.00+.50/0
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[22] a) I. Paterson, D. J. Wallace, S. M. Velazquez, Tetrahedron Lett. 1994,
35, 9083; b) I. Paterson, D. J. Wallace, C. J. Cowden, Synthesis 1998,
639; c) C. J. Cowden, I. Paterson, Org. React. 1997, 51, 1.
[23] D. B. Collum, W. C. Still, F. Mohamadi, J. Am. Chem. Soc. 1986, 108,
2094.
[24] G. M. Whitesides, J. San Fillipo, Jr., J. Am. Chem. Soc. 1970, 92, 6611.
[25] Data for 10: [a]2D0 ˆ ‡44.0 (c ˆ 0.04, CHCl3); IR (film): nÄmax ˆ 3440,
1720, 1270, 1120, 720 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 8.08 (m,
2H), 7.59 (m, 1H), 7.48 (m, 2H), 5.60 (q,J ˆ 6.9 Hz, 1H), 4.09 (m, 1H),
3.52 (m, 2H), 3.36 3.24 (m, 2H), 2.28 (br s, 1H, OH), 1.89 (m, 1H),
1.67 1.60 (m, 3H), 1.55 (d, J ˆ 6.9 Hz, 3H), 1.30 1.21 (m, 2H), 1.08
(d, J ˆ 7.0 Hz, 3H), 0.87 (d,J ˆ 7.0 Hz, 3H), 0.84 ppm (d, J ˆ 6.5 Hz,
3H); 13C NMR (75 MHz, CDCl3): d ˆ 210.3 (s), 165.8 (s), 133.3 (d),
129.8 (d, 2C), 129.6 (s), 128.5 (d, 2C), 78.8 (d), 74.7 (d), 73.2 (d), 66.6
(t), 43.9 (d), 35.6 (d), 30.3 (d), 26.4 (t), 24.8 (t), 17.9 (q), 16.1 (q), 13.9
Scheme 1. Possible isomers of a,b-enones that can be generated from the
hydroacylation of alkynes with aldehydes.
Although the intramolecular hydroacylation of alkynals
was developed recently,[3] intermolecular hydroacylation of
alkynes still remains little explored, and only a few non-
selective examples have been reported with limited applica-
tions to internal alkynes[4] or benzaldehydes that bear a
coordination site such as a hydroxy group at the ortho
position.[5] Herein, we report a highly regio- and stereo-
selective intermolecular hydroacylation of terminal alkynes 2
with aldehydes 1 in the presence of a chelation-assisted
catalytic system: [Rh(PPh3)3Cl] (3), 2-amino-3-picoline (4),
and benzoic acid (5). This is the most efficient catalytic system
to date for the synthesis of branched or linear a,b-enones
from 1-alkynes and aldehydes.
The reaction of benzaldehyde (1a) and 1-hexyne (2a) in the
presence of the cocatalyst system consisting of 3 (5 mol%), 4
(40 mol%), and 5 (20 mol%) was performed in toluene at
808C for 12 h to afford the branched a,b-enone 6a in 92%
yield after chromatographic isolation (Table 1, entry 1). No
direct selective synthetic methods for the preparation of
branched a,b-enones have been reported previously, although
syntheses of branched (1,1-disubstituted) vinyl compounds by
hydrosilylation,[6] hydrophosphorylation,[7] and dimerization
of 1-alkynes[8] have been reported. It was found that most
aromatic aldehydes tested underwent smooth hydroacylation
with primary alkyl alkynes to produce branched a,b-enones 6
exclusively in good to excellent yields (Table 1, entries 2 9).[9]
‡
‡
(q), 10.4 ppm (q); MS (CI , CH4): m/z (%): 363 (100) [M‡H ], 241
‡
(20), 207(22), 157(92), 139 (61); HRMS (CI
, CH4): calcd for
‡
C21H31O5 [M‡H ]: 363.2172, found: 363.2169. The relative configu-
ration of compound 10 was confirmed by NMR spectroscopy, by
differential NOE experiments performed on 11.
[26] Data for 14: [a]2D0 ˆ ‡65.6 (c ˆ 1.16, CHCl3); IR (film): nÄmax ˆ 3460,
1740, 1720, 1460, 1435, 1380, 1275, 1255, 1170, 1040, 1020 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 3.92 (ddd, J ˆ 11.0, 5.5, and 1.5 Hz,
1H), 3.73 (s, 3H), 3.52 (dd, J ˆ 9.6 and 2.6 Hz, 1H), 3.46 (m, 2H), 3.15
(dq, J ˆ 11.0 and 7.0 Hz, 1H), 3.02 (br s, 1H, OH), 1.84 (m, 1H), 1.76
1.49 (m, 4H), 1.25 (m, 1H), 1.06 (d, J ˆ 6.6 Hz, 3H), 0.82 (d, J ˆ 7.0 Hz,
3H), 0.81 ppm (d, J ˆ 6.3 Hz, 3H), 13C NMR (75 MHz, CDCl3): d ˆ
176.3 (s), 76.7 (d), 75.1 (d), 65.7 (t), 51.9 (q), 40.0 (d), 35.7 (d), 31.8 (d),
27.2 (t), 25.1 (t), 17.4 (q), 14.2 (q), 8.8 ppm (q); MS (EI):m/z (%): 244
‡
(3) [M ], 185 (100), 157(38), 153 (93), 139 (26), 126 (34), 125 (43), 121
(28), 99 (28), 97(44), 95 (41), 88 (49), 82 (28), 81 (34), 69 (43), 59 (42),
‡
‡
55 (65); HRMS (CI , CH4): calcd for C13H25O4 [M‡H ]: 245.1753,
found: 245.1750.
Efficient and Selective Hydroacylation of
1-Alkynes with Aldehydes by a Chelation-
Assisted Catalytic System**
Table 1. RhI-catalyzed hydroacylation of various aldehydes and
1-alkynes.[a]
Chul-Ho Jun,* Hyuk Lee, Jun-Bae Hong, and
Bong-Il Kwon
Intermolecular hydroacylation is one of the most efficient
methods for preparing ketones from olefins and aldehydes.[1]
Recently, we developed an efficient catalytic system for the
intermolecular hydroacylation of 1-alkenes by using 2-amino-
pyridine derivatives as a chelating auxiliary.[2] Hydroacylation
of alkynes with aldehydes is also very interesting in terms of
regio- and stereoselective synthesis since three possible
isomers of a,b-enones can be generated from this reaction:
branched as well as linear E- and Z-a,b-enones (Scheme 1).
Entry 1 (R1)
2 (R2)[b]
6/7
Yield [%][c]
1
2
a (Ph)
a (n-C4H9)
b (n-C6H13) 100:0 (6b/7b)
c (PhCH2)
a
100:0 (6a/7a)
92 (100)
93 (98)
66 (71)
95 (100)
76(85)
83 (88)
96 (100)
78 (100)
79 (100)
0
3
100:0 (6c/7c)
100:0 (6d/7d)
100:0 (6e/7e)
100:0 (6 f/7f)
100:0 (6g/7g)
100:0 (6 h/7h)
100:0 (6i/7i)
4
5
6
7
b (p-CF3C6H4)
c (p-MeOC6H4)
d (naphthyl)
e (3-thiophenyl)
f (4-pyridyl)
8
9
g (3-pyridyl)
h (2-pyridyl)
i (n-C5H11)
10
11
12
13
14
[*] Prof. Dr. C.-H. Jun, Dr. H. Lee, Dr. J.-B. Hong, B.-I. Kwon
Department of Chemistry, Yonsei University
Seoul, 120-749 (Korea)
a
78:22 (6j/7j)
0:100 (6k/7k)
81:19 (6l/7l)
85
d (t-C4H9)
a
d
7
4
j (cyclohexyl)
98 (100)[d]
Fax : (‡82)2-364-7050
0:100 (6m/7m) 63
E-mail: junch@yonsei.ac.kr
[**] This work was supported by the National Research Laboratory
Program (2000-N-NL-01-C-271) administered by the Ministry of
Science and Technology.
[a] Reagents and conditions: [Rh(PPh3)3Cl] (3; 5 mol%), 2-amino-3-pico-
line (4; 40 mol%), benzoic acid (5; 20 mol%), toluene, 808C, 12 h. [b] Two
equivalents of 2 (based on the aldehyde) were used. [c] GC yields are given
in parentheses, and <1% yields of side products were ignored. [d] Re-
action time: 2 h.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
2146
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4112-2146 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 12