Synthesis of a model system for the macrocyclic subunit of the oximidines

Article abstract of DOI:10.1055/s-2001-16056

Cross-coupling reaction of aryl triflate 1 and vinyl stannane 13 provided salicylic acid derivative 15. This compound was converted to the dihydroxy acid 16, which provided in a size-selective macrolactonization the two macrolides 17 and 18 in a ratio of 60:40. Compound 17 is a model of the macrocyclic core of the oximidines.

Full text of DOI:10.1055/s-2001-16056

LETTER
1221
Synthesis of a Model System for the Macrocyclic Subunit of the Oximidines
Frank Scheufler, Martin E. Maier*
Universität Tübingen, Institut für Organische Chemie, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax (+49) 7071 29 5137; E-mail: martin.e.maier@uni-tuebingen.de
Received 22 May 2001
To elucidate the important structural features of these
Abstract: Cross-coupling reaction of aryl triflate 1 and vinyl stan-
compounds we initiated a program aimed at the synthesis
of the natural products and analogs thereof. In this paper
we describe initial studies towards the core structure of
nane 13 provided salicylic acid derivative 15. This compound was
converted to the dihydroxy acid 16, which provided in a size-selec-
tive macrolactonization the two macrolides 17 and 18 in a ratio of
60:40. Compound 17 is a model of the macrocyclic core of the oxi- the oximidines. Retrosynthetic cuts can be made at the
enamide,11 the lactone and the styrene single bond (Figure
midines.
2). Initially we targeted a macrocycle lacking the epoxide
and the double bond of oximidine I. According to this ret-
rosynthetic analysis and the structural simplification, the
aryl triflate 1 and a vinyl stannane, such as 2 became pos-
sible starting materials.
Key words: arylations, dihydroxylations, hydrostannations, macro-
cycles, Stille reaction
The screening of extracts from natural sources for cyto-
toxic activity is an essential strategy in the discovery pro-
cess of novel lead structures. An interesting case at hand
is a class of macrolides that embrace the oximidines,1 the
salicylihalamides2-5 and the apicularens.6-8 Related com-
pounds include the lobatamides9 and CJ-12,950 (Figure
1).10 Although these compounds originate from different
sources, they nevertheless share common structural fea-
tures. All of them contain a salicylic acid part, a macrolac-
tone and an enamide side chain. Apicularen differs from
the others in that it contains an additional ring, probably
being formed through a transannular cyclization. More-
over, these natural products show differences in the num-
ber and position of double bonds and the oxidation state
of some of the carbon atoms. Comparing the screening
profiles of the salicylihalamides with that of other known
antitumor compounds indicated that the underlying bio-
logical activity might be due to a novel mode of action.
H
MeO
O
N
OMe
OTf
O
OR
N
O
OH
HO
O
OH
1
Me
O
+
O
HO
Bu3Sn
2
Oximidine I
Figure 2
The synthesis began with methyl 2-hydroxy-6-methoxy-
benzoate 4 which was prepared by esterification12 (1
equiv DBU, 3 equiv MeI, THF, 0 °C to 23 °C, 19 h) from
the commercially available 2-hydroxy-6-methoxybenzoic
acid (3) (Scheme 1). The hydroxy ester 4 was converted
to the triflate in the usual way by treating it with triflic an-
hydride in the presence of pyridine (1.2 equiv Tf2O,
23 °C, 20 h).
H
N
H
N
O
N
O
OH
HO
O
Me
HO
O
O
O
O
MeO
O
MeO
O
OH
Me
Tf2O, pyr
(88%)
O
OMe
OTf
OR
Oximidine I
H
OH
N
Salicylihalamide A
O
3 R = H
4 R = Me
1
DBU
MeI
(94%)
HO
O
O
Apicularen A
Scheme 1
O
OH
The other building block was built form 6-heptynoic acid
(5) (Scheme 2). Reduction of 5 to the alcohol 6, followed
by oxidation13 to the aldehyde and chain elongation by
Figure 1
Synlett 2001, No. 8, 1221–1224 ISSN 0936-5214 © Thieme Stuttgart · New York

1222
F. Scheufler, M. E. Maier
LETTER
Wittig reaction with the stabilized ylide (methoxycarbon- A Stille cross-coupling reaction18 using Pd(PPh3)2Cl2 as a
ylmethylene)-triphenylphosphorane (1 equiv, THF, catalyst combined the two fragments 1 and 13 (Scheme 3)
23 °C, 24 h) gave rise to methyl (2E)-2-nonen-8-ynoate to provide 15 ([ ]25D = -8.19 (c 1.2, CHCl3)) in excellent
(8).14 Reduction of 8 with DIBAH (2.5 equiv, 16 h) gave yield (1 equiv 1, 1.2 equiv 13, 0.05 equiv Pd(PPh3)2Cl2, 8
the allylic alcohol 9. Next, the hydroxyl group of 9 was equiv LiCl, 0.15 equiv 2,6-di-tert-butyl-4-methylphenol,
protected as its p-methoxybenzyl ether 10 (1.5 equiv NaH, DMF, 100 °C, 18 h). In this context we found that the un-
1.0 equiv PMBCl, DMF). The two secondary hydroxy protected diol 2 (R = PMB) gave only low yields in the
functions could easily be established by a Sharpless asym- coupling step. At this stage it was possible to remove the
metric
dihydroxylation
reaction
[0.004
equiv other stereoisomer obtained in the cross-coupling reaction
K2OsO2(OH)4, 3.0 equiv K3Fe(CN)6, 3.0 equiv K2CO3, by flash chromatography (petroleum ether/ethyl acetate,
1.0 equiv MeSO2NH2, tBuOH/H2O (1:1), 0 °C, 24 h] us- 3:1). Liberation of the diol under acidic conditions (80%
ing (DHQ)2PHAL (0.01 equiv) as the chirality inducing AcOH, 23 °C, 18 h) followed by basic hydrolysis of the
ligand (AD-mix ).15 The enantiomeric excess of 11 ester group (10 equiv LiOH, THF/MeOH/H2O (2:2:1),
([ ]D25 = -14.9 (c 1.2, CHCl3)) was determined by chiral 75 °C, 76 h) delivered the dihydroxy acid 16 ([ ]25D = -
HPLC and was found to be 95% [ChiraGrom 2.8 m, 8.75 (c 0.2, CHCl3)). It was our hope that a size-selective
Part-No. GS CH2 0891K0602 (corresponds to CHIRAL- macrolactonization would favor the desired 12-membered
CEL OD), length: 60 mm, nheptane/ipropanol 95:5, flow: lactone. In the event, macrolactonization of 16 under the
0.1 mL/min, 284 nm, retention times: 16.2 min ( ), 24.5 Yamaguchi conditions19 (1 equiv 2,4,6-Cl3(C6H2)COCl,
min ( )]. The next step involved protection of the diol as 1.1 equiv NEt3, 6 equiv DMAP, toluene, 120 °C, 16 h)
an acetonide (1.4 equiv Me2C(OMe)2, 1.5 mol% pTsOH, gave a mixture of two lactones 17 ([ ]22D = +99.4 (c 0.12,
THF, 23 °C, 16 h) to yield compound 12 ([ ]25D = -8.6 (c CHCl3)) and 18 ([ ]23D = -65.8 (c 0.94, CHCl3)) in a ratio
0.7, CHCl3)). This was followed by addition of tributyltin of 60:40. These lactones could be separated by prepara-
hydride to the alkyne under radical conditions,16 which tive HPLC (Grom-SIL 120 Si NP-2, 10 m, length: 250
furnished the vinyl stannane 13 as the major addition mm, nheptane/ethyl acetate, 6:4, 10 mL/min, 254 nm).20
product (1.1 equiv Bu3SnH, 0.1 equiv AIBN, toluene, The yield for the macrolactonization was less at higher
100 °C, 5 h). Based on 1H NMR analysis, these conditions concentrations (44% at 1.6 mmol/L and 33% at 50
provided a 76:24 ratio of the E/Z-isomers 13. This mixture mmol/L).
was taken further in the next step. Performing the reaction
under palladium catalysis (1.7 equiv nBu3SnH, 0.02 equiv
Pd(PPh3)2Cl2, THF, 23 °C, 16 h) gave rise to a mixture of
the external and internal stannanes (13:14 = 62:38). In
this case however, the stannane 13 was isomerically pure
(E only).17
Pd(PPh3)2Cl2, LiCl
1
+ 13
DMF, 100 °C (90%)
MeO
CO2Me
PMBO
1. AcOH, H2O, 23 °C (90%)
2. LiOH (87%)
O
LiAlH4
(100%)
15
X
O
CO2H
MeO
5
6 X = H, OH
7 X = O
Swern
(82%)
CO2H
PMBO
2,4,6-Cl3(C6H2)COCl
NEt3, DMAP (61%)
OH
(Ph)3P=CHCO2Me
THF, 23 °C (86%)
DIBAH
16
OH
+
CO2Me
CH2Cl2, 23 °C
(99%)
8
PMBO
O
HO
OPMB
OH
MeO
MeO
O
OH
4
4
3
3
1
1
O
O
OR
AD-mix α
9
(72%, 95% ee)
9a
11
HO
OR
10a
9 R = H
NaH
PMBCl
(78%)
9
10
17 (60)
18 (40)
10 R = PMB
PMBO
Scheme 3
Me2C(OMe)2
Bu3SnH, AIBN
pTsOH (94%)
toluene, 100 °C
(82%)
O
12
The structures of the two macrolides were easily distin-
guished by 2D-NMR spectroscopy. Thus, in the H/H-
COSY of macrolide 17, H-3 ( = 5.21) shows two cross-
peaks with protons that carry an OR function. Specifical-
ly, crosspeaks are observed with H-4 ( = 4.05) and
CH2OPMB ( = 3.85, 3.77). On the other hand, H-3
( = 5.20) of compound 18 is flanked by the cycloaliphat-
ic C-4 methylene group ( = 1.86, 1.64) and H-1' (exocyc-
O
PMBO
PMBO
Bu3Sn
Bu3Sn
O
O
14
13
O
O
Scheme 2
Synlett 2001, No. 8, 1221–1224 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of a Model System for the Macrocyclic Subunit of the Oximidines
1223
lic CHOH, = 3.80). These assignments were supported a macrolactonization can be exploited to differentiate two
by the H/C-COSY spectra.
functional groups. The stripped down ring system will be
important to clarify the role of the vinyl epoxide of the ox-
imidines. Studies to incorporate the enamide side chain of
salicylihalamide and the oximidines into this model sys-
tem are underway in our laboratory.
The macrolactonization led to a straightforward differen-
tiation of the two secondary hydroxy groups, although
with a moderate selectivity. Therefore, we attempted a
monoprotection prior to the macrolactonization. In this re-
gard, we took recourse to the corresponding tin acetals.21
Thus, diol 19, obtained from 15, was treated with dibutyl-
tin oxide (1.0 equiv nBu2SnO, toluene, 120 °C, 6 h) in tol-
uene followed by the addition of allyl bromide (1.5 equiv
allyl bromide, 2.0 equiv CsF, DMF, 23 °C, 18 h). This re-
action gave a 46:54 ratio of the two monoprotected com-
pounds 20 and 21 (Scheme 4). After chromatographic
separation each of them was converted to the correspond-
ing hydroxy acid (10 equiv LiOH, THF/MeOH/H2O,
75 °C, 76%). These acids were then subjected separately
to the macrolactonization. Again, the Yamaguchi condi-
tions were used. The yields were 34% for the cyclization
of 20 to 22 (1.5 mmol/L) and 12% for 21 to 23 (1.3 mmol/
L), respectively. The structural assignment was possible
at this stage by inspecting the H/H-COSY spectra.
Acknowledgement
Financial support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged.
References and Notes
(1) Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
J. Org. Chem. 1999, 64, 153.
(2) Isolation: Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II;
Boyd, M. R. J. Org. Chem. 1997, 62, 8188.
(3) Model studies: (a) Fürstner, A.; Thiel, O. R.; Blanda, G. Org.
Lett. 2000, 2, 3731; (b) Feutrill, J. T.; Holloway, G. A.; Hilli,
F.; Hügel, H. M.; Rizzacasa, M. A. Tetrahedron Lett. 2000,
41, 8569; (c) Georg, G. I.; Ahn, Y. M.; Blackman, B.; Farokhi,
F.; Flaherty, P. T.; Mossman, C. J.; Roy, S.; Yang, K. J. Chem.
Soc., Chem. Commun. 2001, 255.
(4) First total synthesis and revision of the absolute configuration:
Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem. Int. Ed.
2000, 39, 4308.
(5) Total syntheses: (a) Wu, Y.; Seguil, O.; De Brabander, J. K.
Org. Lett. 2000, 2, 4241; (b) Labrecque, D.; Charron, S.; Rej,
R.; Blais, C.; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645;
(c) Smith, A. B., III; Zheng, J. Synlett 2001, 1019.
(6) Isolation: Kunze, B.; Jansen, R.; Sasse, F.; Höfle, G.;
Reichenbach, H. J. Antibiot. 1998, 51, 1075.
MeO
CO2Me
PMBO
AcOH, H2O, 23 °C (90%)
15
OH
19
OH
MeO
1. nBu2SnO, toluene
CO2Me
PMBO
120 °C
(7) Model studies: Bhattacharjee, A.; De Brabander, J. K.
Tetrahedron Lett. 2000, 41, 8069.
2. allyl bromide, DMF, CsF
OR1
(83%, 20:21 = 46:54)
OR2
(8) First total synthesis: Bhattacharjee, A.; Seguil, O. R.; De
Brabander, J. K. Tetrahedron Lett. 2001, 42, 1217.
(9) (a) McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina, J.
H., II; Laakso, J.; Ireland, C. M.; Murray, L.; Capon, R. J.;
Boyd, M. R. J. Org. Chem. 1998, 63, 7805; (b) Lobatamide A
is identical to the structure of YM-75518, see: Suzumura, K.-
i.; Takahashi, I.; Matsumoto, H.; Nagai, K.; Setiawan, B.;
Rantiatmodjo, R. M.; Suzuki, K.-i.; Nagano, N. Tetrahedron
Lett. 1997, 38, 7573.
(10) Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.; Sakakibara,
T.; Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.; Kojima, N. J.
Antibiot. 1998, 51, 14.
(11) For studies related to the enamide-side chain, see: (a) Snider,
B. B.; Song, F. Org. Lett. 2000, 2, 407; (b) Kuramochi, K.;
Watanabe, H.; Kitahara, T. Synlett 2000, 397; (c) Shen, R.;
Porco, J. A., Jr. Org. Lett. 2000, 2, 1333; (d) Stefanuti, I.;
Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2000, 41,
3737.
R1
R2
allyl
H
20
21
H
allyl
20
21
1. LiOH (76%)
1. LiOH (76%)
2. 2,4,6-Cl3(C6H2)COCl
NEt3, DMAP (12%)
2. 2,4,6-Cl3(C6H2)COCl
NEt3, DMAP (34%)
PMBO
O
OPMB
4
O
4
MeO
O
MeO
O
3
3
1
O
1
9
O
9
9a
10a
10
(12) Mal, D. Synth. Commun. 1986, 16, 331.
23
22
(13) Tidwell, T. T. Org. React. 1990, 39, 297.
(14) Harvey, D. F.; Lund, K. P.; Neil, D. A. J. Am. Chem. Soc.
1992, 114, 8424.
Scheme 4
(15) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
In summary, we have described a synthesis of the model
system for the macrocyclic subunit of the oximidines. Key
reactions are the asymmetric dihydroxylation of the enyne
10, the cross-coupling of the aryl triflate 1 with the vinyl
stannane 13 and finally a size-selective macrolactoniza-
tion of the dihydroxy acid 16. This study also shows that
(16) (a) Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851;
(b) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.;
Prunet, J. J. Org. Chem. 1997, 62, 7768; (c) Yazbak, A.;
Sinha, S. C.; Keinan, E. J. Org. Chem. 1998, 63, 5863.
(17) Zhang, H. X.; Guibé, F.; Balavoine, G. J. Org. Chem. 1990,
55, 1857.
Synlett 2001, No. 8, 1221–1224 ISSN 0936-5214 © Thieme Stuttgart · New York

1224
F. Scheufler, M. E. Maier
LETTER
(18) (a) Scott, W. J.; Crisp, G. T.; Stille, J. K. Org. Synth. 1989, 68,
116; (b) Saá, J. M.; Martorell, G.; Garcia-Raso, A. J. Org.
Chem. 1992, 57, 678; (c) Tsuji, J. Palladium Reagents and
Catalysts - Innovations in Organic Synthesis; John Wiley &
Sons Ltd: Chichester, 1995; (d) Casado, A. L.; Espinet, P. J.
Am. Chem. Soc. 1998, 120, 8978; (e) Han, X.; Stoltz, B. M.;
Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600.
(19) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989; (b) Hikota, M.;
Tone, H.; Horita, K.; Yonemitsu, O. J. Org. Chem. 1990, 55,
7.
(20) Macrolactonization: 2,4,6-Trichlorobenzoyl chloride (0.16
mL, 1.0 mmol) was added to a mixture of the hydroxy acid 16
(0.445 g, 1.0 mmol) and triethylamine (0.15 mL, 1.1 mmol) in
THF (10 mL), after which the reaction was stirred for 1 h at
23 °C. After removal of triethylamine hydrochloride, the
filtrate was diluted with toluene (800 mL) and added to a
refluxing solution of DMAP (0.733 g, 6.0 mmol) in toluene
(190 mL) over a period of 2 h. After being refluxed for further
16 h, the reaction mixture was diluted with Et2O (300 mL),
washed successively with 3% aqueous HCl, an aqueous
NaHCO3 solution, and water, dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification of the
residue by preparative HPLC (Grom-SIL 120 Si NP-2, 10 m,
n-heptane/ethyl acetate, 95:5, 10 mL/min) gave the lactones
17 (157 mg) and 18 (104 mg), combined yield 61%.
17: TLC (petroleum ether/ethyl acetate, 1:1): Rf = 0.51 – 1H
NMR (400 MHz, CDCl3): = 1.27-1.44 (m, 4H, H-5, H-6, H-
7), 1.61-1.75 (m, 1H, H-7), 1.78-1.88 (m, 1H, H-5), 2.10-2.31
(m, 2H, H-8), 2.49 (s, br, 1H, OH), 3.71-3.72 (2 s, 1 m, 7H,
OCH3, CH2OPMB), 3.82 (dd, J = 5.8 Hz, J = 10.7 Hz, 1H,
CH2OPMB), 3.95-4.02 (m, 1H, H-4), 4.41-4.48 (m, 2H,
CH2ArOMe), 5.13-5.20 (m, 1H, H-3), 5.69-5.78 (m, 1H, H-9),
6.40 (d, J = 15.7 Hz, 1H, H-10), 6.70-6.82 (m, 4H, aromatic
H), 7.16-7.23 (m, 3H, aromatic H) – 13C NMR (100 MHz,
CDCl3): = 22.80, 23.82, 30.25, 32.50, 55.22, 55.84, 68.61,
70.00, 73.03, 73.23, 109.24, 113.77, 119.98, 122.44, 128.82,
129.34, 130.22, 135.35, 137.98, 156.03, 159.25, 167.70.
18: TLC (petroleum ether/ethyl acetate, 1:1): Rf = 0.56 – 1H
NMR (400 MHz, CDCl3): = 1.07-1.19 (m, 1H, H-6), 1.30-
1.68 (m, 4H, H-4, H-5, H-6), 1.75-1.89 (m, 2H, H-4, H-7),
2.25-2.34 (m, 1H, H-7), 2.59 (s, br, 1H, OH), 3.44 (dd, J = 6.8
Hz, J = 10.0 Hz, 1H, CH2OPMB), 3.56 (dd, J = 3.5 Hz,
J = 10.0 Hz, 1H, CH2OPMB), 3.72 (s, 6H, OCH3), 3.76-3.85
(m, 1H, H-1'), 4.39, 4.47 (2 d, J = 11.5 Hz, 1H each,
CH2ArOMe), 5.14-5.19 (m, 1H, H-3), 5.59-5.67 (m, 1H, H-8),
6.33 (d, J = 15.9 Hz, 1H, H-9), 6.72-6.82 (m, 4H, aromatic H),
7.16-7.26 (m, 3H, aromatic H) – 13C NMR (100 MHz, CDCl3):
= 18.84, 23.56, 28.36, 32.43, 55.22, 55.87, 71.18, 72.26,
73.09, 73.29, 109.38, 113.77, 120.46, 123.06, 129.33, 129.59,
129.99, 130.25, 134.66, 137.96, 156.51, 168.78.
(21) (a) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643;
(b) Qiao, L.; Hu, Y.; Nan, F.; Powis, G.; Kozikowski, A. P.
Org. Lett. 2000, 2, 115.
Article Identifier:
1437-2096,E;2001,0,08,1221,1224,ftx,en;G09501ST.pdf
Synlett 2001, No. 8, 1221–1224 ISSN 0936-5214 © Thieme Stuttgart · New York