49
A. Nava et al.
Letter
Synlett
C.; Hiraiwa, N.; Asano, K.; Kondo, S.; Ojima, S.; Yamamoto, G.
Bull. Chem. Soc. Jpn. 1995, 68, 3519. (e) Higuchi, H.; Kiyoto, S.;
Sakon, C.; Hiraiwa, N.; Asano, K.; Kondo, S.; Ojima, S.;
Yamamoto, G. Chem. Lett. 1994, 2291. (f) Okazaki, R.; O-oka, M.;
Tokitoh, N.; Inamoto, N. J. Org. Chem. 1985, 50, 180. (g) Mueller,
P.; Schaller, J.-P. Helv. Chim. Acta 1989, 72, 1608. (h) Vogel, E.;
Puettmann, W.; Duchatsch, W.; Schieb, T.; Schmickler, H.; Lex, J.
Angew. Chem. 1986, 98, 727.
Carboxylic Acid Methyl Ester (1)
Yellow oil; Rf = 0.31 (EtOAc/petroleum ether, 1:5).1H NMR (300
MHz, CDCl3): δ = 7.33–7.27 (m, 1 H, H-10), 7.18–7.13 (m, 1 H, H-
8), 6.93–6.88 (m, 2 H, H-7, H-9), 3.80 (s, 3 H, H-14), 3.01 (s, 2 H,
3
3
H-13), 2.86 (t, JHH= 7.1 Hz, 2 H, H-4), 2.44 (t, JHH= 7.1 Hz, 2 H,
H-2), 1.99 (tt, 3JHH= 7.1 Hz, 2 H, H-3). 13C NMR (75 MHz, CDCl3):
δ = 198.0 (C-5), 178.6 (C-1), 166.0 (C-12), 133.8 (C-9), 133.6 (C-
8), 133.4 (C-6), 133.2 (C-10), 132.0 (C-7), 125.6 (C-11), 52.3 (C-
~
(8) (a) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V.
J. Am. Chem. Soc. 1988, 110, 1539. (b) Brown, H. C.;
Ramachandran, P. V. J. Org. Chem. 1989, 54, 4504.
14), 37.2 (C-4), 32.9 (C-2), 24.7 (C-13), 19.2 (C-3). IR (neat): ν =
3011 (m), 2988 (m), 2947 (w), 1717 (s, br), 1589 (m), 1438 (w),
1276 (s), 1261 (s), 1038 (w), 749 (s), 703 (m), 624 (w) cm–1. MS
(FD, 5 kV/8 mA/min): m/z (%) = 264.4 (100) [M]+, 265.4 (57) [M +
H]+. HRMS (ESI): m/z calcd for C14H16O5Na: 287.0895; found:
287.0887. For further data, see the Supporting Information.
(15) For data of enol ester, see the Supporting Information. Further-
more, cleavage of enol lactone 5 was run under acidic condi-
tions (AcCl, MeOH, 50 °C) delivering 2 in 12%, enol ester of 2 in
42% yield and several isomers.
(16) (a) Hinckley, C. C. J. Am. Chem. Soc. 1969, 91, 5160. (b) McCreary,
M. D.; Lewis, D. W.; Wernick, D. L.; Whitesides, G. M. J. Am.
Chem. Soc. 1974, 96, 1038. (c) Goering, H. L.; Eikenberry, J. N.;
Koermer, G. S.; Lattimer, C. J. J. Am. Chem. Soc. 1974, 96, 1493.
(17) Corey, E. J.; Hashimoto, S.-I. Tetrahedron Lett. 1981, 22, 299.
(18) H. C. Brown Reduction: (1̍S)-6-(5-tert-Butyloxy-5-oxo-1-
hydroxypentyl)-1,3,5-cycloheptatriene 1-carboxylic acid
methyl ester ((S)-7)
(9) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.;
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925. (c) Corey, E. J.;
Helal, C. J. Angew. Chem. 1998, 110, 2092. (d) Jones, D. K.; Liotta,
D. C.; Shinkai, I.; Mathre, D. J. J. Org. Chem. 1993, 58, 799.
(e) Mathre, D. J.; Thompson, A. S.; Douglass, A. W. Hoogsteen K.;
Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993,
58, 2880. (f) Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson,
A. S.; Carroll, J. D.; Corley, E. G.; Desmond, R. Org. Synth. Coll. Vol.
9, 1998, 676.
(10) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(b) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38,
2143. (c) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Prot. 2007, 2,
2451.
(11) Most C6 acylations of methyl-cycloheptatriene-1-carboxylate B
had been stopped after about 50% conversion. Always, remain-
ing B had been recycled. The standard yields presented within
the manuscript based on originally used B. Additionally, yields
based on recovered starting material (brsm) are given in brack-
ets.
Under Ar, to a solution of (–)-diisopinocampheylchloroborane
(0.15 g, 0.47 mmol, 1.5 equiv) in dry THF (2 mL) was added
ketoester 6 (0.10 g, 0.31 mmol, 1.0 equiv) in dry THF (2 mL) at –
25 °C with stirring. After seven days the solvent was removed in
vacuo and replaced by EtOAc (5 mL). Then, diethanolamine
(0.07 g, 0.63 mmol, 2.2 equiv) was added and stirred at room
temperature for 2 h in which a white precipitate formed. The
solid was filtered off and washed with Et2O. The solvent was
removed in vacuo, and α-pinene could be removed in high
vacuum (8 × 10–3 mbar, 5 h). The residual crude product was
purified via column chromatography (EtOAc/petroleum ether,
1:4) affording hydroxyester (S)-7 (0.02 g, 0.06 mmol, 19%) as a
(12) For experimental details and data see the Supporting Informa-
tion.
(13) All cycloheptatriene derivatives suffer from reversible 6п-elec-
trocyclization (norcaradiene intermediates). In the presence of
nucleophiles such as chloride Michael–addition/elimination
cyclopropane ring opening, etc. potentially cause the formation
of regioisomeric norcaradienes and cycloheptatrienes (e.g., 1,3-
diacyl, 2,7-diacyl). Longer reaction times led to the formation of
further isomers.
colorless oil. Rf = 0.20 (EtOAc/petroleum ether, 1:4). [α]D
+11.6° (c 1.0, 25 °C, CH2Cl2, ee 40%). For further analytical data,
see the Supporting Information.
=
(14) Synthesis of Keto Acid 1
Under Ar, in a three-necked flask equipped with a reflux con-
denser aluminum(III) chloride (6.66 g, 49.94 mmol, 1.5 equiv)
was suspended in dry CH2Cl2 (100 mL) and cooled in an ice-
bath. Glutaryl chloride (6.37 mL, 49.94 mmol, 1.5 equiv) was
added, and the mixture was stirred at 0 °C for about 1 h until
complete dissolution of aluminum(III) chloride. Then, the reac-
tion mixture was heated to reflux and methyl ester B (5.00 g,
33.29 mmol, 1.0 equiv) dissolved in dry CH2Cl2 (20 mL) was
added. Refluxing was continued for 4 h. After cooling of the
reaction mixture to –10 °C, acetic acid (15 mL) was added
slowly with stirring. After 30 min, water (100 mL) was added at
–10 °C, and stirring was continued for another 30 min. Then the
layers were separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were
washed (brine) and dried (MgSO4). After removal of the solvent
the residue was purified via column chromatography
(EtOAc/petroleum ether, 1:5 to 1:2). Yields: re-isolated methyl
ester B (2.37 g, 15.78 mmol, 47%), keto carboxylic acid 1 (3.24 g,
12.26 mmol, 37% (70% brsm)), chloro keto carboxylic acid 3
(0.11 g, 0.33 mmol, 1% (2% brsm)), chloro enollactone 4 (1.47 g,
5.20 mmol, 16% (30% brsm)).
(19) CBS Reduction: (1̍R)-6-(5-tert-Butyloxy-5-oxo-1-hydroxy-
pentyl)-1,3,5-cycloheptatriene 1-Carboxylic Acid Methyl
Ester ((R)-7)
Under Ar, (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyr-
rolo[1,2-c][1,3,2]-oxazaborol (0.02 g, 0.07 mmol, 0.1 equiv) was
dissolved in dry toluene (1 mL) and treated with borane
dimethylsulfide (0.05 g, 0.63 mL, 0.84 mmol, 1.2 equiv 2 M) at 0
°C. After 1 h ketoester 6 (0.23 g, 0.70 mmol, 1.0 equiv) was
added to the mixture and stirred for 5 h at 0 °C. Workup started
by quenching with methanol (2 mL) and after 15 min 1 M
hydrochloric acid. The aqueous layer was extracted with
toluene (3 × 5 mL). The combined organic layers were washed
with brine and dried over MgSO4. The solvent was removed, and
the residue was purified via column chromatography
(EtOAc/petroleum ether, 1:9) affording hydroxyester (R)-7 (0.15
mg, 0.42 mmol, 67%) as a colorless oil. Rf = 0.20 (EtOAc/petro-
leum ether, 1:4). [α]D –7.3° (c 1.0, 25 °C, CH2Cl2, ee 71%). For
further analytical data, see the Supporting Information.
(20) 6-(1,5-Dihydroxy-5-oxopentyl)-1,3,5-cycloheptatriene
1-
Carboxylic Acid Methyl Ester (9)
The ketoacid 1 (1.03 g, 3.90 mmol, 1.0 equiv) was dissolved in
6-(1,5-Dioxo-5-hydroxypentyl)-1,3,5-cycloheptatriene
1-
methanol (60 mL) and cooled to 0 °C. Sodium borohydride (0.44
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