Vanadium(V)-catalyzed oxidation of (3R)-linalool - The selective formation of furanoid linalool oxides and their conversion into isocyclocapitelline derivatives

Article abstract of DOI:10.1055/s-2003-36793

Oxidation of (3R)-linalool (2) with tert-butyl hydroperoxide (TBHP) occurs at the 6,7-position to selectively afford linalool oxide cis-1, if catalyzed by vanadium(V) Schiff base complexes 4. Substituted tetrahydrofuran cis-1 and its isomer trans-1 served

Full text of DOI:10.1055/s-2003-36793

LETTER
223
Vanadium(V)-Catalyzed Oxidation of (3R)-Linalool – The Selective
Formation of Furanoid Linalool Oxides and their Conversion into Isocyclo-
capitelline Derivatives
Synthesis
eof Iscoyclo
n
capitelline
D
s
e
rivativesfrom
(
3
R
)-Linalool artung,* Simone Drees, Barbara Geiss, Philipp Schmidt
Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg
Fax +49(931)8884606; E-mail: hartung@chemie.uni-wuerzburg.de
Received 21 October 2002
Dedicated to Professor Dr. Peter Welzel on the occasion of his 65th birthday.
Abstract: Oxidation of (3R)-linalool (2) with tert-butyl hydroper-
oxide (TBHP) occurs at the 6,7-position to selectively afford
linalool oxide cis-1, if catalyzed by vanadium(V) Schiff base com-
plexes 4. Substituted tetrahydrofuran cis-1 and its isomer trans-1
served as starting materials for short concise syntheses of β-car-
bolines cis-3 and trans-3 which are lower homologues of alkaloids
(–)-isocyclocapitelline and (+)-cyclocapitelline.
Key words: tert-butyl hydroperoxide, linalool oxide, oxidation,
Schiff base complex, vanadium
(–)-Isocyclocapitelline (Scheme 1), (+)-cyclocapitelline,
Scheme 1 (3R)-Linalool (2) and derived linalool oxide cis-1 as
building block in synthesis.
and (+)-chrysotricine are tetrahydrofuran-derived β-car-
boline alkaloids, which have been extracted from far east-
ern medicinal plants.1,2 From a biosynthetic point of view
it seems likely that linalool oxides 1 and therefore linalool
2 serve as precursors for the formation of these alka-
loids.1,3 In organic synthesis, however, the abovemen-
tioned β-carbolines are generally obtained in multistep
transformations that use other precursors than terpenol 2
as starting material for the following reasons.4 Conversion
this purpose, since vanadium compound 4a does not
catalyze the epoxidation of allylic alcohols12 but effi-
ciently mediates diastereoselective formation of function-
alized tetrahydrofurans from bishomoallylic alcohols and
TBHP.11,13,14
of substrate 2 into functionalized tetrahydrofurans 1 re- In an initial experiment, terpenol 2 was treated with TBHP
quires selective oxygenation at the 6,7-π-bond which is and 10 mol% of vanadium(V) catalyst 4a in CHCl3 at
attainable by e.g. peracids5 or the combination of 20 °C for 12 hours. Previous optimization studies had
H3CReO3/H2O2.6 Unfortunately, the observed diastereo- shown that these conditions provide high selectivities for
selectivities in these reactions are negligible. If oxidized tetrahydrofuran formation in combination with a satisfac-
with tert-butyl hydroperoxide in the presence of an early tory peroxide efficiency.14 Purification of the reaction
transition metal catalyst such as VO(acac)2,7 a selective mixture furnished furanoid linalool oxides 1 (62%,
conversion of linalool 1 into the corresponding 1,2-epoxy- cis:trans = 61:39), 1,2-epoxylinalool oxides 5 (6%,
alcohol has been reported.8,9 In view of the significance of cis:trans = 56:44), and pyranoid linalool oxides 6 (3%,
linalool oxides 1 as versatile building blocks,10 and the cis:trans = 40:60) (Scheme 2).15–17 No 1,2-epoxides of
contemporary interest in tetrahydrofuran-derived β-car- linalool were detected (1H NMR, GC).8,9 The relative con-
boline alkaloids,1,2,4 we have developed a new stereose- figurations of major isomers of heterocycles 1, 5, and 6
lective access to furanoid linalool oxide cis-1 and disclose were established by NMR experiments (NOE, HMBC,
our latest results in this communication as a part of the HMQC). In a second run, oxidation of substrate 2 with
synthesis of hitherto unknown β-carbolines cis-3 and TBHP was repeated in the presence of (1R,2S)-aminoin-
trans-3.
danol-derived catalyst 4b. The latter reagent had attracted
attention in previous experiments since it generally pro-
vided higher diastereoselectivities for tetrahydrofuran for-
mation compared to 4a. This oxidation, however, only led
to a minor increase in yield of target compound cis-1 with-
out improving its diastereoselectivity. A time dependent
analysis of product formation in the latter run provided
two important results. (i) Formation of epoxide 5 follows
formation of linalool oxide 1. This observation in combi-
nation with the fact that no linalool 1,2-epoxides were
The selected strategy for diastereoselectively oxidizing
substrate 2 at the 6,7-position is based on the use of TBHP
as primary oxidant and vanadium(V) Schiff base com-
plexes 4 as catalysts.11 The latter reagents were chosen for
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2003,0,02,0223,0226,ftx,en;G29902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
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224
J. Hartung et al.
LETTER
formed is indicative of tetrahydrofuran 1 as starting ma-
terial for epoxide 5. (ii) Cis/trans-ratios of tetrahydrofuran
1, epoxide 5, and tetrahydropyran 6 remained constant
throughout the conversion of substrate 2. These findings
point to an absence of kinetic resolution in this experi-
ment.18 Therefore, the origin of the observed fair prefer-
ence for formation of 2,5-cis-configured tetrahydrofuran
cis-1 in this work is not associated with a mismatched ef-
fect using a chiral auxiliary in 4b and the substrate (3R)-
linalool (2). This explanation is supported by the fact that
approximately the same diastereoselectivities were ob-
tained, if the oxidation of 2 was catalyzed by vanadium re-
agent 4a with an achiral Schiff base auxiliary. Still, a cis/
trans-ratio of 61:39 for formation of trisubstituted tetrahy-
drofuran 1 is slightly superior to results, which have been
reported so far for other transition metal catalyzed oxida-
tions of linalool 2.6,19–21
Scheme 3 Ruthenium-catalyzed oxidation of linalool oxides cis-1
and trans-2 into lactol 7 and aldehyde 8.
hot xylenes in order to provide target compound cis-3 as
colorless crystals25 (90%, Scheme 4). In a similar se-
quence, formyl-substituted tetrahydrofuran 8 was treated
at 20 °C with tryptamine and subsequently at –78 °C with
CF3CO2H to yield 88% of a tetrahydro-β-carboline24 (not
shown in Scheme 4) which upon dehydrogenation afford-
ed target compound trans-325 in 51% yield (Scheme 4).
Scheme 2 Vanadium(V)-catalyzed regio- and stereoselective
oxidation of (3R)-linalool (2).
To continue the synthesis of tetrahydrofuran-derived β-
carbolines 3, linalool oxides, cis-1 and trans-1 were sepa-
rated by column chromatography.16 Conversion of vinyl-
Scheme 4 Preparation of β-carbolines cis-3 and trans-3 from lactol
7 and aldehyde 8. Reagents and conditions: (a) Tryptamine, CH2Cl2,
substituted tetrahydrofuran cis-1 into bicyclic lactol 722 20 °C; (b) CF3CO2H, CH2Cl2, –78 °C → 20 °C; (c) Pd/C, xylenes,
was achieved by a RuO4-catalyzed23 oxidation. This reac-
reflux.
tion furnished after chromatographic purification 56% of
analytically pure material (Scheme 3). Alternative re-
agents, such as OsO4/NaIO4 (in 1,4-dioxane/H2O) or
KMnO4 (in acetone/H2O), failed to provide compound 7.
Therefore, the reagent combination of RuCl3 and NaIO4 in
C2H4Cl2/H2O was also applied for the conversion of
trans-configured tetrahydrofuran trans-1 into aldehyde
822 (47%, Scheme 3).
In summary, we have devised a new synthesis of linalool
oxides 1 via a vanadium-catalyzed selective oxygenation
of linalool 2 at the 6,7-position. This oxidation provides
tetrahydrofuran cis-1 as major product. Functionalized
heterocycles 1 served as building blocks for the synthesis
of hitherto unknown 1-substituted β-carbolines cis-3 and
trans-3, which will be subjected to pharmacological test-
ing.
Finally, lactol 7 was treated with tryptamine in a Pictet–
Spengler-type reaction.4c This transformation was per-
formed in CH2Cl2 at room temperature and afforded an
imine (not shown in Scheme 4), which was treated at
–78 °C with CF3CO2H. The reaction time was limited to 1
hour since, according to TLC analysis, formation of addi-
tional products started, if this period was extended. Work
up of the reaction mixture furnished a tetrahydro-β-carbo-
line (27%),24 which was treated with Pd on charcoal in
Acknowledgment
Generous financial support was provided by the Deutsche For-
schungsgemeinschaft (Schwerpunktprogramm Peroxidchemie:
Präparative und mechanistische Aspekte des Sauerstofftransfers,
and SFB 347 ‘Selektive Reaktionen Metall-aktivierter Moleküle’)
and the Fonds der Chemischen Industrie.
Synlett 2003, No. 2, 223–226 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Isocyclocapitelline Derivatives from (3R)-Linalool
225
Hz, 1 H), 4.98 (dd, J = 11, 2 Hz, 1 H), 5.18 (dd, J = 17, 2 Hz,
1 H), 5.85 (dd, J = 17, 11 Hz, 1 H).
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1981, 206, 139. (b) David, L.; Veschambre, H. Tetrahedron
Lett. 1984, 25, 543.
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(18) Control experiments14 indicated that vanadium(V) complex
4b catalyzes oxidation of racemic mixtures of chiral
bishomoallylic alcohols without kinetic resolution.
(19) Tungsten-catalyzed oxidations: (a) Sakaguchi, S.;
Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1996, 61, 5307.
(b) Villa de, O. A. L.; Sels, B. F.; De Vos, D. E.; Jacobs, P.
A. J. Org. Chem. 1999, 64, 7267.
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Org. Chem. 1998, 63, 1408.
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(a) Schofield, L. J.; Kerton, W. J.; McMorn, P.; Bethell, D.;
Ellwood, S.; Hutchings, G. J. J. Chem. Soc., Perkin Trans. 2
2002, 1475. (b) Lattanzi, A.; Della Sala, G.; Russo, M.;
Scettri, A. Synlett 2001, 1479. (c) Corma, A.; Iglesias, M.;
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(6) Villa de, ; De Vos, D. E.; Montes de, C. C.; Jacobs, A.
Tetrahedron Lett. 1998, 39, 8521.
(7) (a) Sams, C. K.; Jørgensen, K. A. Acta Chim. Scand. 1995,
49, 839. (b) Sheldon, R. A. In The Chemistry of Functional
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161–199. (c) Sharpless, K. B.; Verhoeven, T. R.
(23) Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814.
(24) cis-1-[5-(1-Hydroxy-1-methylethyl)-2-methyltetrahydro-
furan-2-yl]-1,2,3,4-tetrahydro-9H-β-carboline: colorless
crystals, mp 119 °C; [α]D25 –22.9 (c 0.82, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 1.08 (s, 3 H), 1.24 (s, 3 H), 1.38 (s,
3 H), 1.80–2.16 (m, 4 H), 2.78 (ddd, J = 12.1, 7.9, 5.5 Hz, 2
H), 3.21 (ddd, J = 12.5, 9.8, 5.5 Hz, 2 H), 4.02 (t, J = 7.0 Hz,
1 H), 4.06 (s, 1 H), 7.00–7.19 (m, 2 H), 7.24–7.36 (m, 1 H),
Aldrichimica Acta 1979, 12, 63.
(8) (a) Ohloff, G.; Giersch, W.; Schulte-Elte, K. H.; Enggist, P.;
Demole, E. Helv. Chim. Acta 1980, 63, 1582. (b) Sharpless,
K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 6136.
(9) Sheldon, R. A. In Aspects of Homogeneous Catalysis, Vol.
4; Ugo, E., Ed.; Reidel Publishing: Dordrecht, 1981, 3–70.
(10) (a) González, I. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000,
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1990, 55, 5088. (c) Corey, E. J.; Ha, D.-C. Tetrahedron Lett.
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7.49 (mc, J = 7.0 Hz, 1 H), 8.75 (s, 1 H), 10.23 (s, 1 H). 13
NMR (63 MHz, CDCl3): δ = 20.5, 22.6, 25.0, 25.8, 27.4,
C
36.0, 43.9, 61.2, 71.2, 83.0, 85.6, 110.9, 112.8, 118.0, 119.0,
121.4, 135.4, 156.7, 175.5. MS (EI, 70 eV,): m/z (%) = 314
+
+
(3) [M+], 171 (100) [C11H11N2 ], 143 (6) [C8H15O2 ], 84 (11)
(11) Hartung, J.; Greb, M. J. Organometal. Chem. 2002, 661, 67.
(12) Mimoun, H.; Mignard, M.; Brechot, P.; Saussine, L. J. Am.
Chem. Soc. 1986, 108, 3711.
[C5H8O+], 43 (10) [C3H6 ]. UV/Vis (EtOH): λmax (lg ε): 232
+
nm (3.76), 282 (3.81), 373 (2.46). C19H26N2O2 (314.4):
Calcd C, 72.58; H, 8.33; N, 8.91. Found: C, 67.25; H, 8.26;
N, 7.99. trans-1-[5-(1-Hydroxy-1-methylethyl)-2-
(13) Hartung, J.; Schmidt, P. Synlett 2000, 367.
(14) Hartung, J.; Drees, S.; Greb, M.; Schmidt, P.; Svoboda, I.;
Fuess, H.; Murso, A.; Stalke, D. Eur. J. Org. Chem.,
submitted.
(15) Weinert, B.; Wüst, M.; Mosandl, A.; Hanssum, H.
Phytochem. Anal. 1998, 9, 10.
(16) A solution of (3R)-linalool (2) (154 mg, 1.00 mmol) in
CHCl3 (5 mL) and vanadium(V) complex 4b (36.3 mg, 0.10
mmol) was stirred for 5 min at 25 °C. Subsequently, TBHP
(273 µL, 5.5 M in nonane, 1.50 mmol) was added and the
deep red reaction mixture was stirred for additional 12 h at
25 °C. Afterwards, the solvent was removed at 250 mbar/
40 °C to afford a dark brown residue which was filtered
through a short pad of Al2O3 in order to remove the catalyst.
The product was washed with Et2O (75 mL) from the
column. Combined filtrate and eluate were concentrated in
vacuo to provide an oil which was distilled under reduced
pressure. The distillate was purified by column
methyltetrahydrofuran-2-yl]-1,2,3,4-tetrahydro-9H-β-
carboline: colorless solid, mp 113 °C. [α]D25 –19.5 (c 0.63,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 1.08 (s, 3 H), 1.22
(s, 3 H), 1.40 (s, 3 H), 1.89–2.22 (m, 4 H), 2.68–2.90 (m, 2
H), 3.22 (ddd, J = 15.0, 9.8, 5.2 Hz, 2 H), 3.99 (dd, J = 8.2,
5.4 Hz, 1 H), 4.08–4.12 (m, 1 H), 7.05–7.20 (m, 2 H), 7.33
(mc, 1 H), 7.50 (mc, 1 H), 8.60 (s, 1 H). 13C NMR (63 MHz,
CDCl3): δ = 21.6, 22.6, 24.6, 26.1, 28.8, 36.8, 43.0, 60.6,
70.4, 77.0, 86.6, 110.1, 110.9, 118.0, 119.0, 121.5, 142.3,
153.4, 174.1. MS (EI, 70 eV): m/z (%) = 314(3) [M+],
+
+
171(100) [C11H11N2 ], 143(6) [C8H15O2 ], 84(11) [C5H8O+],
+
43(10) [C3H6 ]. UV/Vis (EtOH): λmax (lg ε): 242 nm (4.52),
282 (3.85), 371 (2.57). C19H22N2O2 (314.4): Calcd C, 72.58;
H, 8.33; N, 8.91. Found: C, 67.94; H, 8.06; N, 7.78.
(25) cis-1-[5-(1-Hydroxy-1-methylethyl)-2-methyltetrahydro-
furan-2-yl]-9H-β-carboline cis-3: colorless solid, mp
161 °C. [α]D25 –32.9 (c 0.57, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 1.23 (s, 3 H), 1.45 (s, 3 H), 1.78 (s, 3 H), 1.75–
3.08 (m, 4 H), 4.15 (t, J = 7.3 Hz, 1 H), 7.24 (ddd, J = 7.8,
6.1, 1.8 Hz, 1 H), 7.52 (mc, 2 H), 7.86 (d, J = 5.5 Hz, 1 H),
8.13 (d, J = 7.9 Hz, 1 H), 8.39 (d, J = 5.5 Hz, 1 H), 9.53 (s,
1 H). 13C NMR (63 MHz, CDCl3): δ = 24.2, 26.2, 27.6, 27.9,
37.3, 73.3, 88.4, 90.2, 111.5, 113.4, 119.7, 121.6, 121.7,
128.3, 133.2, 136.1, 138.0, 143.2, 148.0. MS (EI, 70 eV):
m/z (%) = 310(17) [M+], 151(24) [C16H15N2O+], 209 (100)
chromatography [SiO2, petroleum ether–Et2O–acetone,
5:2:1 (v/v/v); Rf cis-1 = 0.48; Rf trans-1 = 0.45] to provide
111 mg (65%) linalool oxide 1: colourless liquid, bp 80 °C/
10 mbar (Kugelrohr, Lit. 78 °C/13 Torr), cis:trans = 61:39.
cis-1: [α]D25 +29.1 (c 1.1, CHCl3), ref.17: [α]D25 +11.7
(c = 0.1, CH3OH). 1H NMR (250 MHz, CDCl3): δ = 1.11 (s,
3 H), 1.20 (s, 3 H), 1.29 (s, 3 H), 1.75–1.89 (m, 4 H), 2.05 (s
br, 1 H, OH), 3.84 (dd, J = 8, 7 Hz, 1 H), 4.97 (dd, J = 11, 2
Hz, 1 H), 5.17 (dd, J = 17, 2 Hz, 1 H), 5.96 (dd, J = 17, 11
25
Hz, 1 H). trans-1: [α]D25 –13.1 ( c 1.0, CHCl3), ref.17: [α]D
+
+
[C14H12N2 ], 182 (11) [C10H16NO2 ], 43 (9) [C2H4O+]. UV/
Vis (EtOH): λmax (lg ε): 242 nm (4.52), 288 (4.26), 348
(3.77). C19H22N2O2 (310.4): Calcd C, 73.52; H, 7.14; N,
–10.1 (c 0.1, CH3OH). 1H NMR (250 MHz, CDCl3):
δ = 1.10 (s, 3 H), 1.21 (s, 3 H), 1.29 (s, 3 H), 1.66–1.74 (mc,
1 H), 1.75–1.93 (m, 3 H), 2.05 (s, br., 1 H, OH), 3.78 (t, J = 7
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9.03. Found: C, 72.86; H, 7.11; N, 8.68. trans-1-[5-(1-
Hydroxy-1-methylethyl)-2-methyltetrahydrofuran-2-yl]-
9H-β-carboline trans-3: colorless solid, mp 158 °C. [α]D
CDCl3): δ = 26.2, 26.7, 26.8, 28.4, 38.6, 72.6, 86.0, 88.2,
111.9, 114.1, 119.7, 121.5, 121.9, 128.4, 132.6, 133.0,
25
137.7, 142.9, 148.9. MS (EI, 70 eV): m/z (%) = 310 (17)
+
–50.5 (c 0.5, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 1.25
(s, 3 H), 1.38 (s, 3 H), 1.72 (s, 3 H), 1.75–2.10 (m, 4 H), 4.15
(t, J = 7.6 Hz, 1 H), 7.22 (ddd, J = 7.9, 6.4, 1.5 Hz, 1 H), 7.48
(mc, 2 H), 7.86 (d, J = 5.2 Hz, 1 H), 8.11 (d, J = 7.5 Hz, 1 H),
8.36 (d, J = 5.2 Hz, 1 H), 10.48 (s, 1 H). 13C NMR (63 MHz,
[M+], 151 (24) [C16H15N2O+], 209 (100) [C14H12N2 ], 182
+
(11) [C10H16NO2 ], 43(9) [C2H4O+]. UV/Vis (EtOH): λmax
(lg ε): 227 nm (4.09), 289 (4.03), 340 (3.57). C19H22N2O2
(310.4): Calcd C, 73.52; H, 7.14; N, 9.03. Found: C, 72.86;
H, 7.11; N, 8.68.
Synlett 2003, No. 2, 223–226 ISSN 0936-5214 © Thieme Stuttgart · New York