Permanganate oxidation of 1,5,9-trienes: Stereoselective synthesis of tetrahydrofuran-containing fragments

Article abstract of DOI:10.1021/jo026295b

Permanganate oxidation of farnesoate esters 12a - d afforded perhydro-2,2′-bifuranyl compounds 16a - d, with control of relative stereochemistry at four new stereocenters. Subsequent oxidative cleavage of 16a - d then provided tetrahydrofuran-containing fragments 17a - d, one of them 17b possessing the same relative stereochemistry present in the C13-C21 portion of the polyether antibiotic semduramycin (1). Control of the absolute stereochemistry was achieved through the use of the Oppolzer sultam chiral auxiliary. The requisite starting trienes were prepared stereoselectively in just three steps from geranyl chloride or neryl chloride, providing a short and versatile route to polyether fragments.

Full text of DOI:10.1021/jo026295b

P er m a n ga n a te Oxid a tion of 1,5,9-Tr ien es: Ster eoselective
Syn th esis of Tetr a h yd r ofu r a n -Con ta in in g F r a gm en ts
Richard C. D. Brown,*,† Carole J . Bataille,† Robert M. Hughes,† Anne Kenney,† and
Tim J . Luker‡
Department of Chemistry, University of Southampton, Highfield,
Southampton SO17 1BJ , UK, and AstraZeneca R&D Charnwood,
Medicinal Chemistry, Bakewell Road, Loughborough, Leics LE11 5RH, UK
rcb1@soton.ac.uk
Received August 7, 2002
Permanganate oxidation of farnesoate esters 12a -d afforded perhydro-2,2′-bifuranyl compounds
16a -d , with control of relative stereochemistry at four new stereocenters. Subsequent oxidative
cleavage of 16a -d then provided tetrahydrofuran-containing fragments 17a -d , one of them 17b
possessing the same relative stereochemistry present in the C13-C21 portion of the polyether
antibiotic semduramycin (1). Control of the absolute stereochemistry was achieved through the
use of the Oppolzer sultam chiral auxiliary. The requisite starting trienes were prepared
stereoselectively in just three steps from geranyl chloride or neryl chloride, providing a short and
versatile route to polyether fragments.
In tr od u ction
cis-2,5-Disubstituted tetrahydrofurans are present in
a large number of biologically active molecules including
many polyether antibiotics and Annonaceous acetogenins
(see Figure 1 for selected examples).1-3 Of the approaches
available for the synthesis of 2,5-disubstituted tetrahy-
drofurans, the oxidative cyclization of 1,5-dienes stands
out as one of the most attractive in terms of level of
structural complexity introduced in a single reaction,4-8
and recently the development of an asymmetric phase-
† Department of Chemistry, University of Southampton.
‡ AstraZeneca R&D Charnwood.
(1) Dutton, C. J .; Banks, B. J .; Cooper, C. B. Nat. Prod. Rep. 1995,
165-181.
(2) Fernandez, J . J .; Souto, M. L.; Norte, M. Nat. Prod. Rep. 2000,
17, 235-246.
(3) Alali, F. Q.; Liu, X. X.; McLaughlin, J . L. J . Nat. Prod. 1999, 62,
504-540.
F IGURE 1. Structures of some biologically active tetrahy-
drofuran-containing compounds.
(4) For reviews on the synthesis of cyclic ethers see: (a) Boivin, T.
L. B. Tetrahedron 1987, 43, 3309-3362. (b) Harmange, J . C.; Figadere,
B. Tetrahedron: Asymmetry 1993, 4, 1711-1754. (c) Elliot, M. C. J .
Chem. Soc., Perkin Trans. 1 1998, 4175-4200.
(5) For studies on the permanganate-mediated oxidative cyclization
of 1,5-dienes see: (a) Ko¨tz, A.; Steche, T. J . Prakt. Chem. 1924, 107,
193. (b) Klein, E.; Rojahn, W. Tetrahedron 1979, 21, 2353-2358. (c)
Walba, D. M.; Wand, M. D.; Wilkes, M. C. J . Am. Chem. Soc. 1979,
101, 4396-4397. (d) Baldwin, J . E.; Crossley, M. J .; Lehtonen, E.-M.
M. J . Chem. Soc., Chem. Commun. 1979, 918-919. (e) Wolfe, S.; Ingold,
C. F. J . Am. Chem. Soc. 1981, 103, 940-941.
transfer-catalyzed variant of the reaction has been real-
ized.7 We have previously reported that the permanga-
nate oxidation of 1,5,9-trienes 3 provided a very short
route to perhydro-2,2′-bifuranyl systems 4 (Scheme 1),8
which are suitable intermediates for further elaboration
to acetogenins or polyether antibiotics.6d-e Here we
provide a full account of some of these earlier studies,
along with further results from the permanganate oxida-
tion of other isomeric farnesoate derivatives.
(6) For earlier applications of the permanganate-promoted oxidative
cyclization of 1,5-dienes to the synthesis of fragments of polyether
antibiotics monensin, ionomycin, and salinomycin see: (a) Walba, D.
M.; Edwards, P. D. Tetrahedron Lett. 1980, 21, 3531-3534. (b) Spino,
C.; Weiler, L. Tetrahedron Lett. 1987, 28, 731-734. (c) Walba, D. M.;
Przybyla, C. A.; Walker, C. B. J . J . Am. Chem. Soc. 1990, 112, 5624-
5625. (d) Brown, R. C. D.; Kocienski, P. J . Syn. Lett. 1994, 415-417.
(e) Kocienski, P. J .; Brown, R. C. D.; Pommier, A.; Procter, M.; Schmidt,
B. J . Chem. Soc., Perkin Trans. 1 1998, 9-39. (f) Cecil, A. R. L.; Brown,
R. C. D. Org. Lett. 2002, 4, 3715-3718.
Resu lts a n d Discu ssion
At first inspection, the oxidative cyclization of a 1,5,9-
triene apparently presents a problem of regioselectivity
(7) For asymmetric oxidative cyclization reactions using KMnO4 see
refs 6c-f and: Brown, R. C. D.; Keily, J . F. Angew. Chem., Int. Ed.
2001, 40, 4496-4498
(8) For a preliminary communication of this work see: Brown, R.
C. D.; Hughes, R. M.; Keily, J .; Kenney, A. Chem. Commun. 2000,
1735-1736.
10.1021/jo026295b CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/22/2002
J . Org. Chem. 2002, 67, 8079-8085
8079

Brown et al.
SCHEME 1. Oxid a tion of 1,5,9-Tr ien es
SCHEME 3. P r op osed Rea ction P a th w a y for th e
Oxid a tion of E,E-Meth yl F a r n esoa te (5) w ith
KMn O4
SCHEME 2a
Careful cleavage of the lactols 7 using Pb(OAc)4 af-
forded the desired lactone 8 in reasonable overall yield
(29% from 5), although it was subsequently found that
cleavage of the crude mixture containing lactols 7 using
the NaIO4/SiO2 reagent provided a milder, more conve-
nient, and higher yielding means of achieving the same
transformation (55% from 5).12 Thus application of the
oxidative cyclization-cleavage sequence to appropriate
trienes provides a short and efficient approach to THF-
diols with control of four new stereocenters. Additionally,
the strategy allows for the selective protection of one of
the two hydroxyl groups flanking the THF ring.
To demonstrate the versatility and convenience of the
triene oxidation method as a stereocontrolled route to
polyether fragments, we decided to prepare and oxidize
the four stereoisomers of ethyl farnesoate 12a -d . The
requisite trienes 12a ,b were synthesized using a slight
modification of methodology developed by Weiler et al.,13
with the central double bond stereochemistry originating
from geraniol or nerol and that of the enoate olefin
secured by stereoselective enol phosphate generation
followed by alkylation using organocuprates (Schemes 4
and 5).
Accordingly, the dianion of ethyl acetoacetate was
alkylated with neryl chloride to afford â-ketoester 10
(Scheme 4).14 It is worth noting that allylic chlorides are
sufficiently reactive to alkylate the dianion when the
olefin is trisubstituted, and are much more stable and
convenient to handle than the corresponding bromides.
The â-ketoester 10 underwent stereoselective enol phos-
phate formation with LiHMDS/(EtO)2POCl to provide the
2-(Z)-enol phosphate from which traces of the minor
2-(E)-stereoisomer were removed by column chromatog-
raphy. Substitution of the enol phosphate occurred ste-
a
Reagents and conditions: (a) KMnO4 (3 equiv), AcOH (4 equiv),
pH 6.2 buffer, acetone-H2O, -20 °C; (b) Pb(OAc)4, Na2CO3,
CH2Cl2; (c) NaIO4/SiO2, CH2Cl2.
in terms of directing the initial site of attack of the metal-
oxo reagent to one of the three double bonds. However,
electronic effects have been shown to significantly affect
the rate of olefin oxidation by permanganate,9 and could
be used to direct the initial oxidation to a particular
double bond. Our first experiments involved the oxidation
of E,E-methyl farnesoate (5) using 3 equiv of KMnO4
(Scheme 2),10 anticipating that the enoate double bond
would be oxidized most rapidly. Gratifyingly, the desired
product 7 was obtained as a mixture of epimers at the
hemiacetal position. Ultimately we were able to confirm
the stereochemical course of the oxidative cyclization
from an X-ray structure of the major epimeric lactol 7
(R-hydroxy), which crystallized from Et2O-hexane.11
The results above are consistent with an initial more
rapid attack of permanganate on the electron-deficient
C2-C3 olefin to give a MnV diester, which has been
proposed to undergo oxidation to a MnVI diester prior to
cyclization onto the C6-C7 double bond and hydrolysis
to afford 6 (Scheme 3).5d The remaining double bond
present in 6 is oxidized more slowly to an R-ketol.
Additional support for this pathway came from the
isolation of the partially oxidized intermediate 6 from
reactions carried out with reduced quantities of perman-
ganate.
(12) Zhong, Y.-L.; Shing, T. K. M. J . Org. Chem. 1997, 62, 2622-
2624.
(9) For studies detailing electronic effects on the rates of oxidation
reactions using MnO4- see: (a) Lee, D. G.; Brown, K. C.; Karaman, H.
Can. J . Chem. 1986, 64, 1054. (b) Lee, D. G.; Brown, K. C. J . Am.
Chem. Soc. 1982, 104, 5076-5081. (c) Henbest, H. B.; J ackson, W. R.;
Robb, B. C. G. J . Chem. Soc. (B) 1966, 803-807.
(13) Sum, F.-W.; Weiler, L. Can. J . Chem. 1979, 57, 1431-1441.
(14) During the course of our investigations the synthesis of all four
isomers of ethyl farnesoate was published using a closely related
strategy: In this work, alkylation of the dianion of ethyl acetoacetate
was achieved using neryl bromide. We found that unless extreme care
was exercised during the preparation of neryl bromide (and related
allylic bromides), significant isomerization of the C6-C7 olefin to the
terminal position occurred. Xie, H.; Shao, Y.; Becker, J . M.; Naider,
F.; Gibbs, R. A. J . Org. Chem. 2000, 65, 8552-8563.
(10) Corey, E. J .; Gilman, N. W.; Ganem, B. E. J . Am. Chem. Soc.
1968, 90, 5616-5617.
(11) For details of the X-ray structure determination see: Light, M.
E.; Hursthouse, M. B. Acta Crystallogr. 2000, C46, e483.
8080 J . Org. Chem., Vol. 67, No. 23, 2002

Permanganate Oxidation of 1,5,9-Trienes
SCHEME 4a
SCHEME 6a
a
Reagents and conditions: (a) ethyl acetoacetate, NaH (1 equiv.),
n-BuLi (1 equiv), THF; (b) LiHMDS, THF then (EtO)2POCl; (c)
Et3N, DMPU, (EtO)2POCl; (d) MeLi in Et2O (2 equiv), CuI, Et2O,
-78 to -50 °C; (e) MeLi in Et2O (1 equiv), CuI then MeMgCl, -30
°C.
SCHEME 5a
a
Reagents and conditions: (a) ethyl acetoacetate, NaH (1 equiv),
n-BuLi (1 equiv); (b) LiHMDS, THF then (EtO)2POCl; (c) Et3N,
DMPU, (EtO)2POCl; (d) MeLi in Et2O (1 equiv), CuI then MeMgCl,
-60 °C.
a
Reagents and conditions: (a) KMnO4 (3 equiv), AcOH (4
equiv.), pH 6.2 buffer, acetone-H2O, -20 °C; (b) Pb(OAc)4, CH2Cl2,
Na2CO3; (c) NaIO4-SiO2, CH2Cl2.
reoselctively either using Me2CuLi in Et2O or MeCu/
MeMgCl to afford (2E)-trienoate 12a (2E:2Z, 65:1 by GC
analysis).13 Surprisingly, when the reaction was con-
ducted using commercial MeLi supplied in THF/cumene
rather than Et2O, the desired product was contaminated
with an inseparable byproduct 13 in a ratio of 4.5:1 (12a :
due to the destruction of the anomeric position in the
subsequent oxidative cleavage reaction. The stereochem-
istry of the products 16/17a -d was assigned on the basis
of literature precedent,5c,d our earlier studies (X-ray
structure of lactol 7),11 and an X-ray structure obtained
from compound 17d .16 One of the lactone products 17b
has the same relative stereochemistry present within
numerous polyether antibiotics including semduramycin
(1), and lactone 17d correlates to the C13-C22 portion
of the antibiotic CP-54883.1
Finally, to demonstrate that the overall approach could
provide enantiomerically enriched polyether fragments,
the camphorsultam auxiliary was introduced into one of
the trienoates (Scheme 7).6c-e Hydrolysis of the unsatur-
ated ester 12c and activation of the resulting acid 18
produced the pentafluorophenyl ester 19, which under-
went substitution with lithiated (2R)-10,2-camphorsul-
tam to afford 20. Oxidation of the resulting triene 20
proceeded with a high level of diastereoselectivity (we
were unable to detect the minor diastereoisomer in the
crude 1H NMR spectrum of 22) returning the THF
lactone 22 in satisfactory yield after cleavage of the lactol
1
13, estimated from the H NMR spectrum).
The synthesis of the corresponding 2(Z),6(Z)-trienoate
12b was carried out along similar lines (Scheme 4), with
the exception that the enolization was performed in
DMPU with Et3N as the base to afford the E-enol
phosphate 11b (crude isomer ratio >49:1 by NMR). The
desired triene 12b was obtained stereoselectively from
11b using the reagent Me2CuLiMgCl, as the analogous
reaction using dimethyllithium cuprate afforded a 1:1
mixture of enoate isomers 12a and 12b in this case.15
The two remaining triene isomers 12c (2Z:2E, >99:1 by
GC) and 12d (2E:2Z, >99:1 by GC) were prepared in
the same way, starting with geranyl chloride and using
Me2CuLiMgCl (Scheme 5).
Permanganate oxidation of the four individual trienes
afforded the expected lactol products 16a -d , which were
converted directly to the corresponding lactones 17a -d
as described above using NaIO4-SiO2 or Pb(OAc)4 (Scheme
6). Single anomers of the lactols 16a -d predominated
in CDCl3 solution, although this was of little consequence
(15) Alderdice, M.; Spino, C.; Weiler, L. Tetrahedron Lett. 1984, 25,
1643-1646.
(16) Coles, S. J .; Hursthouse, M. B. Personal communication.
J . Org. Chem, Vol. 67, No. 23, 2002 8081

Brown et al.
SCHEME 7a
carried out under an inert atmosphere, in oven-dried glass-
ware. The solvents THF (from Na/benzophenone) and CH2Cl2
(from CaH2) were distilled before use,: and where appropriate,
other reagents and solvents were purified by standard tech-
niques.19 TLC was performed on aluminum-precoated plates
of silica gel 60 with an F254 indicator; the chromatograms were
visualized under UV light and/or by staining with phospho-
molybdic acid (20% solution in ethanol). Flash column chro-
matography was performed with 40-63 µm silica gel (Merck).
E t h yl (6Z)-7,11-Dim et h yl-3-oxo-6,10-d od eca d ien oa t e
(10). To an ice-cooled suspension of sodium hydride (2.79 g of
a 60% dispersion in mineral oil, 69.65 mmol) in dry THF (25
mL) was added dropwise ethyl acetoacetate (8.81 mL, 69.55
mmol). After 10 min n-BuLi (27.86 mL of a 2.5 M solution in
hexanes, 69.65 mmol) was added and the mixture was stirred
for a further 10 min. A solution of neryl chloride (9, 12 g, 69.50
mmol) in dry THF (20 mL) was added to the reaction and the
mixture was allowed to warm to room temperature. After 30
min a solution of HCl (70 mL of 3.4 M aq) and Et2O (50 mL)
were added. The organic layer was separated, re-extracting
the aqueous phase with Et2O. The organic layers were
combined, washed with water until neutral, dried (MgSO4),
filtered, and concentrated in vacuo to give an orange oil.
Purification on SiO2 eluting with Et2O:hexane (3:97) gave the
title compound as a pale yellow oil (11.66 g, 43.8 mmol, 63%).
Spectroscopic data were in agreement with the literature.14
E t h yl (6E)-7,11-Dim et h yl-3-oxo-6,10-d od eca d ien oa t e
(15). Following the procedure described for the synthesis of
compound 10, geranyl chloride (14, 4.0 g, 23.15 mmol) was
converted to the title compound 15, which was obtained as a
pale yellow oil (3.12 g, 11.7 mmol, 51%). Spectroscopic data
were in agreement with the literature.19
a
Reagents and conditions: (a) NaOH, NaHCO3, THF-H2O; (b)
DCC, C6F5OH, EtOAc; (c) (2R)-10,2-camphorsultam, NaH, THF;
(d) KMnO4 (3 equiv), AcOH (4 equiv), pH 6.2 buffer, acetone-H2O,
-20 °C; (e) NaIO4-SiO2, CH2Cl2.
Gen er a l P r oced u r e for th e P r ep a r a tion of Z-En ol
P h osp h a tes: Eth yl (2Z,6Z)-3-[(Dieth oxyp h osp h or yl)oxy]-
7,11-d im eth yl-2,6,10-d od eca tr ien oa te (11a ). To an ice-
cooled solution of LiHMDS (7.56 mL of a 1.0 M solution in
THF, 7.56 mmol) in dry Et2O (20 mL) was added a solution of
â-keto ester 10 (2.0 g, 7.51 mmol) in Et2O (40 mL). After 15
min (EtO)2POCl (1.09 mL, 7.56 mmol) was added and the
resulting solution was stirred at room temperature for 3.5 h.
The reaction was quenched with NH4Cl (saturated aq) and the
organic layer was separated then washed with NaHCO3, dried
(MgSO4), filtered, and concentrated in vacuo to give a dark
orange/brown oil. Purification on SiO2 (3 × 12 cm) eluting with
Et2O:hexane (3:97 then 5:95, 1:9) afforded 11a as a yellow oil
21. Oppolzer provided a model to account for the facial
selectivity observed for the dihydroxylation reactions of
enoyl camphor sultams with OsO4,17 and the same model
predicts the observed selectivity for the KMnO4 oxidation
of similar substrates.6c-f Fortuitously, 22 gave crystals
suitable for X-ray structural determination, thus allowing
confirmation of the predicted stereochemical outcome
from the oxidation of 20.18 Chemoselective reduction of
the N-acylsultam group present in a very closely related
lactone has been demonstrated, illustrating the utility
of structures such as 22 in the synthesis of complex
natural products such as polyether ionophores.6e
In summary, we have described a short, efficient, and
stereoselective synthesis of perhydro-2,2′-bifuranyl sys-
tems from readily accessible trienoates 12a -d using
oxidative cyclization methodology. The THF-containing
products 17a -d and 22 represent useful intermediates
for further elaboration toward biologically active natural
products such as polyether antibiotics or novel synthetic
ionophores.
(2.39 g, 5.93 mmol, 79%). IR νmax (neat) 1729, 1661, 1285 cm-1
;
1H NMR (400 MHz) δ 5.32 (1H, s), 5.05 (2H, t, J ) 6.3 Hz),
4.23 (4H, quintet, J ) 7.2 Hz), 4.14 (2H, q, J ) 7.1 Hz), 2.40
(2H, t, J ) 7.4 Hz), 2.24 (2H, q, J ) 7.4 Hz), 2.03-1.96 (4H,
m), 1.65 (6H, s), 1.57 (3H, s), 1.33 (6H, t, J ) 7.0 Hz), 1.23
(3H, t, J ) 7.4 Hz); 13C NMR (100 MHz) 163.9, 161.5, 137.1,
131.8, 124.2, 122.7, 105.4, 64.8 (d, J ) 6.1 Hz), 60.0, 35.5, 32.0,
26.6, 25.8, 24.8, 23.4, 17.7, 16.1 (d, J ) 7.0 Hz), 14.3; 31P NMR
(121 MHz) -8.07 (P(V)).
Gen er a l P r oced u r e for th e P r ep a r a tion of E-En ol
P h osph ates: Eth yl (2E,6Z)-3-[(Dieth oxyph osph or yl)oxy]-
7,11-d im eth yl-2,6,10-d od eca tr ien oa te (11b). To an ice-
cooled solution of DMAP (102 mg, 0.84 mmol) and Et3N (1.2
mL, 8.4 mmol) in DMPU (15 mL) was added a solution of
â-keto ester 10 (2.00 g, 7.5 mmol) in DMPU (9.0 mL). After 50
min the mixture was cooled to -20 °C and (EtO)2POCl (1.3
mL, 8.4 mmol) was added dropwise. The reaction mixture was
allowed to warm to room temperature and stirred for 14 h.
The mixture was diluted with Et2O and acidified with 2 N HCl.
The aqueous layer was extracted with Et2O and the organic
layers combined, washed with saturated CuSO4 solution, dried
(MgSO4), filtered, and concentrated in vacuo. The resulting
rusty orange oil (crude ratio 2E:2Z > 49:1 by 1H NMR) was
purified on SiO2 (250 g) eluting with Et2O:hexane (1:4 then
Exp er im en ta l Section
Gen er a l Meth od s. H NMR and 13C NMR were recorded
1
on 300- or 400-MHz spectrometers (300 or 400 MHz, 1H NMR,
respectively, and 75 or 100 MHz, 13C NMR, respectively) in
deuteriochloroform (CDCl3) with chloroform (δ 7.27 ppm 1H,
δ 77.5 ppm 13C) as the internal standard unless stated
otherwise. Infrared (IR) spectra were reported as wavenum-
bers (cm-1). Melting points were obtained in open capillary
tubes and are uncorrected. All nonaqueous reactions were
(17) Oppolzer, W.; Barras, J .-P. Helv. Chim. Acta 1987, 70, 1666-
1675.
(18) Horton, P. N.; Hursthouse, M. B. Personal communication.
(19) Perrin, D. D.; Armarego, W. L. F. Purification of laboratory
chemicals, 3rd ed; Butterworth-Heinemann Ltd.: Oxford, UK, 1994.
8082 J . Org. Chem., Vol. 67, No. 23, 2002

Permanganate Oxidation of 1,5,9-Trienes
1:1) to give 11b as a pale yellow oil (2.15 g, 5.34 mmol, 71%).
IR νmax (neat) 1716, 1644, 1281, 1030 cm-1; 1H NMR (400 MHz)
δ 5.82 (1H, d, J ) 1.5 Hz), 5.15 (1H, dt, J ) 1.5, 7.0 Hz), 5.12-
5.04 (1H, m), 4.17 (4H, quintet, J ) 7.4 Hz), 4.12 (2H, q, J )
7.1 Hz), 2.79 (2H, dt, J ) 1.5, 7.7 Hz), 2.25 (2H, q, J ) 7.6
Hz), 1.98-2.10 (4H, m), 1.66 (6H, s), 1.58 (3H, s), 1.35 (6H,
dt, J ) 1.5, 7.4 Hz), 1.24 (3H, t, J ) 7.4 Hz); 13C NMR (100
MHz) 166.3, 166.2, 136.7, 131.7, 124.3, 123.4, 105.5, 64.8 (d,
J ) 5.6 Hz), 60.2, 32.2, 32.0, 26.7, 25.8, 25.4, 23.5, 17.7, 16.1
(d, J ) 6.7 Hz), 14.3; MS (ES) m/z (rel intensity) 425.3 (38, [M
+ Na]+), 420.3 (100, [M + NH4]+), 403.3 (32, [M + H]+); HRMS
(ES) Calcd for C20H36PO6 403.2244, found 403.2242 (42, [M +
H]+).
Eth yl (2Z,6E)-3-[(Dieth oxyp h osp h or yl)oxy]-7,11-d i-
m eth yl-2,6,10-d od eca tr ien oa te (11c). Following the general
procedure for the preparation of Z-enol phosphate 11a , â-keto
ester 15 (1 g, 3.75 mmol) afforded 11c as a yellow oil (1.20 g,
2.97 mmol, 79%). Characterization data can be found in the
Supporting Information.
dure described below for the KMnO4 oxidation of trienoate 12a ,
methyl (E,E)farnesoate (5) (500 mg, 2.00 mmol) afforded the
crude title lactol 7 as an oily solid. Purification on SiO2 eluting
with Et2O gave the title lactol 7 as a colorless solid (360 mg,
1.04 mmol, 52%). An X-ray quality crystal of the R-epimer of
hemiacetal 7 was obtained by recrystallization from Et2O-
hexane.11 Signals reported for major epimer: mp 80-83 °C
(Et2O-hexane); IR νmax (neat) 3693, 1738 cm-1; 1H NMR (400
MHz) δ 4.50 (1H, br), 4.01 (1H, s), 3.94 (1H, dd, J ) 5.8, 10.0
Hz), 3.77 (3H, s), 2.28-2.53 (3H, m), 2.00-2.20 (1H, m), 1.89-
1.95 (1H, m), 1.86 (1H, ddd, J ) 1.3, 7.3, 12.3 Hz), 1.79 (1H,
ddd, J ) 8.3, 10.5, 12.3 Hz), 1.63 (1H, ddd, J ) 1.5, 8.0, 12.0
Hz), 1.31 (3H, s), 1.29 (3H, s), 1.23 (3H, s), 1.12 (3H, s); 13C
NMR (100 MHz) 173.9, 109.6, 84.8, 84.1, 83.2, 77.1, 73.1, 52.0,
36.8, 32.3, 31.7, 27.6, 24.3, 24.0, 23.9, 23.7; MS (ES) m/z (rel
intensity) 355.4 (100, [M + Na+]), 350.5 (20, [M + NH4+]), 332.4
(4, [M+]).
Meth yl (2R*)-2-Hydr oxy-2-[(2R*,2′R*,5S*)-2′,5-dim eth yl-
5′-oxoocta h yd r o[2,2′]bifu r a n yl-5-yl)eth a n oa te (8). Fol-
lowing the general procedure described below for the Pb(OAc)4
cleavage of 17a , lactol 7 (210 mg, 0.63 mmol) afforded the title
lactone 8 as a colorless oil (95 mg, 0.347 mmol, 55%). IR νmax
(neat) 3420, 1760, 1737 cm-1; 1H NMR (400 MHz) δ 4.02 (1H,
d, J ) 8.4 Hz), 3.93 (1H, dd, J ) 6.7, 8.6 Hz), 3.78 (3H, s),
2.99 (1H, d, J ) 8.4 Hz), 2.82 (1H, apparent ddd, J ) 8.3, 10.6,
17.8 Hz), 2.38-2.55 (2H, m), 2.33 (1H, ddd, J ) 4.8, 9.0, 17.1
Hz), 1.88-2.11 (3H, m), 1.69 (1H, dt, J ) 8.5, 12.5 Hz), 1.37
(3H, s), 1.25 (3H, s); 13C NMR (100 MHz) 178.0, 172.6, 85.7,
85.1, 84.7, 76.6, 52.4, 35.3, 32.2, 29.6, 27.0, 24.4, 23.0; MS (ES)
m/z (rel intensity) 295.4 (100, [M + Na+]), 273.2 (67, [M + H+]);
HRMS (CI) calcd for C13H20O6Na: 295.1155, found 295.1152
(7, [M + Na]+).
Eth yl (2E,6E)-3-[(Dieth oxyp h osp h or yl)oxy]-7,11-d i-
m eth yl-2,6,10-d od eca tr ien oa te (11d ). Following the general
procedure for the preparation of E-enol phosphates, â-keto
ester 15 (2.00 g, 7.51 mmol) afforded 11d as a very pale yellow
oil (2.30 g, 5.71 mmol, 76%). Characterization data can be
found in the Supporting Information.
Gen er a l P r oced u r e for th e Alk yla tion Su bstitu tion of
En ol P h osp h a tes Usin g Cu Me-MeMgCl: Eth yl (2E,6Z)-
3,7,11-Tr im eth yl-2,6,10-d od eca tr ien oa te (12a ). To a sus-
pension of CuI (211 mg, 1.11 mmol) in THF (10 mL) at 0 °C
was added dropwise MeLi (0.70 mL of a 1.6 M solution in Et2O,
1.11 mmol). The orange mixture was stirred at 0 °C for 10
min, before being cooled to -30 °C. MeMgCl (0.61 mL of a 3
M solution in THF, 1.85 mmol) was added dropwise maintain-
ing the temperature below -25 °C. After 20 min the resulting
light brown suspension was treated with a solution of enol
phosphate 11a (150 mg, 0.373 mmol) in THF (10 mL), and
the mixture was stirred at -30 °C for 3 h, then quenched by
pouring quickly onto ice-cold NH4Cl (saturated aq). The
organic layer was diluted with Et2O and washed with NH4Cl
(saturated aq) until no longer blue. The organic layer was
washed with brine, dried (MgSO4), filtered, and concentrated
in vacuo to give a yellow/orange oil. Purification on SiO2 (2.5
× 8 cm) eluting with Et2O:hexane (2:98 then 3:97) afforded
Alter n a tive P r ep a r a tion of La cton e 8. Following the
general procedure described below for the KMnO4 oxidation
of trienoate 12a , (E,E)-methylfarnesoate (5, 15 mg, 0.060
mmol) afforded the crude lactol 7 as an oily solid (25 mg crude),
which was used without purification in the next reaction.
Following the procedure described below for the NaIO4-SiO2
cleavage of 16b, the crude lactol 7 (25 mg) afforded the title
lactone 8 as a colorless oil (9 mg, 0.033 mmol, 55% from 5).
Spectroscopic data were identical with those reported above.
Gen er a l P r oced u r e for th e KMn O4 Oxid a tion of 1,5,9-
Tr ien oa tes. Eth yl (2R*)-2-Hyd r oxy-2-[(2R*,2′S*,5S*)-5′-
h ydr oxy-5′-(1-h ydr oxy-1-m eth yleth yl)dim eth yloctah ydr o-
[2,2′]bifu r a n yl-5-yl]eth a n oa te (16a ). To a vigorously stirred
mixture of trieneoate 12a (400 mg, 1.51 mmol) and phosphate
buffer (2 mL, pH 6.2) in acetone (25 mL) at -20 °C was added
a solution of KMnO4 (11.35 mL of 0.4 M (aq), 4.54 mmol)
containing AcOH (365 µL). The purple mixture was stirred
rapidly for 30-60 min during which time it became dark
brown. The reaction was then quenched with sufficient ice-
cooled saturated Na2S2O5 (aq) to dissolve all of the manganese
salts and the aqueous layer was saturated with NaCl then
extracted repeatedly using CH2Cl2. The organic extracts were
combined, dried (MgSO4), filtered, and concentrated in vacuo
to give a colorless oily solid. Purification on SiO2 (2 × 15 cm)
eluting with MeOH:CH2Cl2 (4:96) gave the title compound 16a
as a white solid (260 mg, 0.75 mmol, 50%): mp 89-90.5 °C;
IR νmax (neat) 3437, 1716 cm-1; 1H NMR (400 MHz) δ 4.20 (2H,
q, J ) 7.2 Hz), 4.0 (1H, dd, J ) 9.0, 6.5 Hz), 3.95 (1H, s), 2.38-
2.30 (1H, m), 2.20-2.04 (2H, m), 1.84-1.63 (2H, m), 1.54-
1.48 (1H, m), 1.25 (3H, t, J ) 7.5 Hz), 1.20 (3H, s), 1.28 (3H,
s), 1.1 (6H, s); 13C NMR (100 MHz) 172.9, 109.6, 86.9, 85.2,
84.2, 76.7, 74.0, 62.1, 36.0, 33.1, 30.1, 28.3, 25.2, 25.0, 24.5,
23.8, 14.6; MS (ES+) m/z (rel intensity) 369.5 (48, [M + Na]+),
347.4 (5, [M + H]+), 329.4 (20, [M - OH]+), 127.1 (100). Anal.
Calcd for C17H30O7: C, 58.94; H, 8.73. Found: C, 58.47; H,
8.96.
1
12a as a pale yellow oil (80 mg, 0.303 mmol, 81%). H NMR
data were consistent with the literature;14 additional data are
provided. IR νmax (neat) 1718, 1653 cm-1 13C NMR (100 MHz)
;
167.0, 159.9, 136.4, 131.8, 124.3, 123.8, 115.7, 59.6, 41.4, 30.4,
26.7, 26.0, 25.9, 23.5, 19.0, 17.8, 14.5; MS (CI) m/z (rel
intensity) 265 (48 [M + H]+), 191 (100).
Eth yl (2Z,6Z)-3,7,11-Tr im eth yl-2,6,10-d od eca tr ien oa te
(12b). Following the general procedure for the preparation of
12a , enol phosphate 11b (800 mg, 1.99 mmol) afforded 12b as
a pale yellow oil (434 mg, 1.64 mmol, 82%). 1H NMR data were
in agreement with the literature;14 additional data are pro-
vided in the Supporting Information.
Eth yl (2E,6E)-3,7,11-Tr im eth yl-2,6,10-d od eca tr ien oa te
(12c). Following the general procedure for the preparation of
12a , enol phosphate 11c (690 mg, 1.7 mmol) afforded 12c as
a colorless oil (420 mg, 1.59 mmol, 93%). Spectroscopic data
were in agreement with that reported in the literature.19
Eth yl (2Z,6E)-3,7,11-Tr im eth yl-2,6,10-d od eca tr ien oa te
(12d ). Following the general procedure for the preparation of
12a , enol phosphate 11d (660 mg, 1.64 mmol) afforded 12d
as a colorless oil (420 mg, 1.59 mmol, 97%). 1H NMR data were
in agreement with the literature;20 additional data are pro-
vided in the Supporting Information.
Meth yl (2R*)-2-Hyd r oxy-2-[(2R*,2′R*,5S*)-5′-h yd r oxy-
5′-(1-h ydr oxy-1-m eth yleth yl)-5,2′-dim eth yloctah ydr o[2,2′]-
bifu r a n yl-5-yl]eth a n oa te (7). Following the general proce-
Gen er a l P r oced u r e for Glycol Clea va ge Usin g P b-
(OAc)4: Eth yl (2R*)-2-Hyd r oxy-2-[(2R*,2′S*,5S*)-2′,5-d i-
m eth yl-5′-oxooctah ydr o[2,2′]bifu r anyl-5-yl]eth an oate (17a).
To a stirred solution of lactol 16a (30 mg, 0.086 mmol) in dry
(20) Gibbs, R. A.; Krishnan, U.; Dolence, J . M.; Poulter, C. D. J .
Org. Chem. 1995, 60, 7821-7829.
J . Org. Chem, Vol. 67, No. 23, 2002 8083

Brown et al.
CH2Cl2 (5 mL) was added Na2CO3 (9.5 mg, 0.09 mmol) followed
by Pb(OAc)4 (39 mg, 0.088 mmol). After 20 min Celite was
added and the mixture stirred for a further 15 min. The solids
were then removed by filtration through a short plug of SiO2,
washing with EtOAc. The resulting solution was washed with
saturated NaHCO3. The aqueous layer was saturated with
NaCl and re-extracted with CH2Cl2. The combined extracts
were dried (MgSO4) and concentrated in vacuo to give a
colorless oil. Purification on SiO2 (1 × 7 cm) eluting with Et2O
afforded the title compound 17a as a colorless oil (18 mg, 0.063
tural determination.16 Characterization data can be found in
the Supporting Information.
Eth yl (2S*)-2-Hyd r oxy-2-(2R*,2′R*,5S*)-2′,5-d im eth yl-
5′-oxoocta h yd r o[2,2′]bifu r a n yl-5-yl)eth a n oa te (17d ). Fol-
lowing the procedure used for the NaIO4-SiO2 cleavage of 16b,
crude 16d (55 mg, from 0.174 mmol 12d ) afforded the title
lactone 17d (17 mg, 0.059 mmol, 34% from 12d ) as a colorless
oil. Spectroscopic data were identical with those provided in
the Supporting Information.
P en t a flu or op h en yl (2E,6E)-3,7,11-Tr im et h yl-2,6,10-
d od eca tr ien oa te (19). To a solution of the acid 1821 (203 mg,
0.86 mmol) and pentafluorophenol (168 mg, 0.90 mmol) in
EtOAc (8 mL) was added dropwise a solution of DCC (188 mg,
0.91 mmol) in EtOAc (8 mL). After 24 h the mixture was
diluted in hexane and the solids removed by filtration. The
organic layer was washed with NaHCO3 (saturated aq), dried
(Na2SO4), and concentrated in vacuo to give a yellow oil (550
mg). Purification on SiO2 (60 g) eluting with CH2Cl2/hexane
(30:100) gave the title ester 19 as a yellow oil (342 mg, 0.85
1
mmol, 73%). IR νmax (neat) 3411, 1767, 1731 cm-1; H NMR
(400 MHz) δ 4.31 (1H, dq, J ) 7.4, 4.4 Hz), 4.24 (1H, dq, J )
7.4, 4.0 Hz), 4.02 (1H, dd, J ) 9.0, 6.1 Hz), 4.01 (1H, d, J )
6.4 Hz), 3.10 (1H, d, J ) 6.4 Hz), 2.73 (1H, ddd, J ) 8.1, 10.6,
18.2 Hz), 2.52 (1H, ddd, J ) 18.1, 10.5, 5.0 Hz), 2.28-2.45 (2H,
m), 1.80-2.00 (2H, m), 1.63-1.80 (2H, m), 1.39 (3H, s), 1.34
(3H, s), 1.34 (3H, t, J ) 4.0 Hz); 13C NMR (100 MHz) 177.5,
173.1, 87.7, 85.6, 83.7, 76.6, 62.5, 35.8, 29.9, 28.9, 28.5, 24.3,
24.2, 14.6; MS (ES) m/z (rel intensity) 309 (38, [M + Na]+),
304 (100, [M + NH4]+); HRMS (CI) calcd for C14H26NO6
304.1760 and C14H23O6 287.1495, found 304.1753 (62, [M +
NH4]+), 287.1499 (16, [M + H]+).
Eth yl (2S*)-2-Hyd r oxy-2-[(2R*,2′S*,5S*)-5′-h yd r oxy-5′-
(1-h yd r oxy-1-m eth yleth yl)-5,2′-d im eth ylocta h yd r o[2,2′]-
bifu r a n yl-5-yl]eth a n oa te (16b). Following the general pro-
cedure for the KMnO4 oxidation of trienoates, 12b (360 mg,
1.36 mmol) afforded the crude title lactol 16b (510 mg crude)
as a colorless oil that was used in the next reaction without
purification. Selected characterization data for the major
epimer are given in the Supporting Information.
Eth yl (2S*)-2-Hyd r oxy-2-[(2R*,2′S*,5S*)-2′,5-d im eth yl-
5′-oxoocta h yd r o[2,2′]bifu r a n yl-5-yl]eth a n oa te (17b). To
a vigorously stirred suspension of NaIO4-SiO2 reagent (6 g)
in dry CH2Cl2 (20 mL) was added a solution of crude lactol
16b (510 mg) in dry CH2Cl2 (10 mL). The resulting mixture
was stirred for 40 min, then the solids were removed by
filtration washing with CHCl3. The resulting solution was
concentrated under reduced pressure to give a yellow oil (400
mg). Purification on SiO2 (35 g) eluting with CH2Cl2/EtOAc
(85:15) gave the title lactone 17b as a colorless oil (0.63 mmol,
180 mg, 46% from 12b). Characterization data can be found
in the Supporting Information.
Eth yl (2R*)-2-Hyd r oxy-2-[(2R*,2′R*,5S*)-5′-h yd r oxy-5′-
(1-h yd r oxy-1-m eth yleth yl)-5,2′-d im eth ylocta h yd r o[2,2′]-
bifu r a n yl-5-yl]eth a n oa te (16c). Following the general pro-
cedure for the KMnO4 oxidation of trienoates, 12c (97 mg, 0.38
mmol) afforded the crude title lactol 16c (140 mg crude) as a
colorless oil that was used in the next reaction without
purification. Selected characterization data are provided in the
Supporting Information.
Eth yl (2R*)-2-Hyd r oxy-2-[(2R*,2′R*,5S*)-2′,5-d im eth yl-
5′-oxoocta h yd r o[2,2′]bifu r a n yl-5-yl]eth a n oa te (17c). Fol-
lowing the general procedure for the Pb(OAc)4 cleavage of lactol
16a , crude 16c (110 mg, 0.31 mmol) afforded the title lactone
17c as a pale yellow oil (37 mg, 0.14 mmol, 46% from 12c).
Characterization data can be found in the Supporting Infor-
mation.
Eth yl (2S*)-2-Hyd r oxy-2-[(2R*,2′R*,5S*)-5′-h yd r oxy-5′-
(1-h yd r oxy-1-m eth yleth yl)-5,2′-d im eth ylocta h yd r o[2,2′]-
bifu r a n yl-5-yl]eth a n oa te (16d ). Following the general pro-
cedure for the KMnO4 oxidation of trienoates, 12d (200 mg,
0.76 mmol) afforded the crude title lactol 16d (240 mg crude)
as a colorless oil that was used in the next reaction without
purification. Selected characterization data are provided in the
Supporting Information.
Eth yl (2S*)-2-Hyd r oxy-2-(2R*,2′R*,5S*)-2′,5-d im eth yl-
5′-oxoocta h yd r o[2,2′]bifu r a n yl-5-yl)eth a n oa te (17d ). Fol-
lowing the general procedure for the Pb(OAc)4 cleavage of lactol
16a , crude 16d (60 mg, from 0.19 mmol of 12d ) afforded the
title lactone 17d (24 mg, 0.09 mmol, 44% from 12d ) as a
colorless oil that solidified on standing. Recrystallization from
EtOAc/hexane gave colorless needles suitable for X-ray struc-
1
mmol, 99%). IR νmax (neat) 2910, 1763, 1635, 1518 cm-1; H
NMR (400 MHz) δ 5.97 (1H, d, J ) 1.2 Hz), 5.13 (1H, dt, J )
1.2, 6.8 Hz), 5.10 (1H, dt, J ) 1.4, 6.8 Hz), 2.25 (3H, d, J ) 1.3
Hz), 2.31-2.24 (4H, m), 2.08-2.02 (4H, m), 1.69 (3H, s), 1.64
(3H, s), 1.62 (3H, s); 13C NMR (100 MHz) 167.8, 161.7, 136.7,
131.5, 124.1, 122.3, 112.1, 41.3, 39.6, 29.7, 26.6, 25.8 (×2), 17.6,
16.0; MS (ES) m/z (rel intensity) 443.5 (5 [M + CH3CN]+), 153
(100); HRMS (EI) calcd for
402.1617.
C21H23O2F5 402.1618, found
N-((2E,6E)-3,7,11-Tr im eth yldodeca-2,6,10-tr ien oyl)cam -
p h or -10,2-su lta m (20). To a solution of (2R)-10,2-camphor-
sultam (45 mg, 0.20 mmol) in dry THF (3 mL) was added
n-BuLi (0.13 mL of 1.6 M in hexanes, 0.208 mmol) at -78 °C.
The solution was allowed to warm to -20 °C over 1 h
whereupon a solution of the activated ester 19 (80 mg, 0.199
mmol) in dry THF (3 mL) was added dropwise. The solution
was then allowed to warm to room temperature. After 40 min
the reaction was diluted in Et2O and quenched with NH4Cl
(saturated aq). The layers were separated and the organic
phase washed with NaHCO3 (saturated aq), dried (MgSO4),
and concentrated in vacuo to give a yellow oil (200 mg).
Purification was carried out on SiO2 (20 g) eluting with hex-
ane/CH2Cl2 (8:2 then 2:8) to give the title triene 20 as a
colorless oil (55 mg, 0.127 mmol, 64%). [R]20 -11.3 (c 0.3,
D
CDCl3); IR νmax (neat) 1681, 1632, 1329, 1133 cm-1
;
1H
NMR (400 MHz) δ 6.33 (1H, d, J ) 1.2 Hz), 5.09 (1H, tt, J )
1.3, 6.6 Hz), 5.08 (1H, tq, J ) 8.2, 1.4 Hz), 3.93 (1H, dd, J )
5.4, 7.3 Hz), 3.46 (1H, d, J ) 13.7 Hz), 3.43 (1H, d, J ) 13.7
Hz), 2.17 (3H, d, J ) 1.3 Hz), 2.22-1.87 (13H, m), 1.68 (3H, d,
J ) 1.2 Hz), 1.60 (6H, s), 1.43-1.36 (2H, m), 1.18 (3H, s), 0.97
(3H, s); 13C NMR (100 MHz) 164.6, 162.5, 136.1, 131.3, 124.3,
122.8, 115.5, 65.0, 53.1, 48.2, 47.7, 44.7, 38.7, 32.8, 26.6, 26.5,
26.0, 25.7, 20.8, 20.0, 19.9, 17.7, 16.0; MS (ES) m/z (rel
intensity) 456.2 (34, [M + Na]+), 434.3 (40, [M + H]+), 153.0
(100); HRMS (ES) calcd for C25H39NO3SNa 456.2543, found
456.2550.
N -[(2R )-2-H y d r o x y -2-((2R ,2′R ,5S )-2′,5-d im e t h y l-5′-
oxooctah ydr o[2,2′]bifu r an yl-5-yl)eth an oyl]cam ph or -10,2-
su lta m (22). Following the general procedure for the oxidation
of trienoate 12a , oxidation of 20 (30 mg, 0.069 mmol) afforded
the crude lactol 21 as a pale yellow oil (40 mg crude). Selected
data: 13C NMR (100 MHz) δ 174.2, 109.5, 84.8, 83.9, 83.4, 75.7,
73.0, 65.2, 53.1, 48.4, 47.7, 44.6, 38.0, 32.8, 32.2, 31.5, 27.4,
26.4, 24.4, 24.0, 23.9, 23.6, 20.9, 19.8. The crude lactol 21 was
then treated with the NaIO4-SiO2 reagent according to the
procedure described for the preparation of 17b. Following
purification on SiO2 eluting with CH2Cl2/EtOAc (9:1) the title
lactone was obtained as a colorless glass (18 mg, 0.040 mmol,
58%). Crystallization gave colorless needles suitable for X-ray
structural determination.18 Mp 151-154 °C (EtOAc/hexane);
(21) Kulkarni, Y. S.; Niwa, M.; Ron, E.; Snider, B. B. J . Org. Chem.
1987, 52, 1568-1576.
8084 J . Org. Chem., Vol. 67, No. 23, 2002

Permanganate Oxidation of 1,5,9-Trienes
[R]20 -49.5 (c 0.3, CDCl3); IR νmax (neat) 3499, 1763, 1701,
Ack n ow led gm en t. The authors thank AstraZeneca
for a CASE award (C.J .B.) and The Royal Society for a
University Research Fellowship (R.C.D.B.). Pfizer, Mer-
ck Sharp and Dohme and Syngenta are also gratefully
acknowledged for unrestricted support
D
1375, 1134 cm-1; H NMR (400 MHz) δ 4.50 (1H, br s), 4.00
1
(1H, dd, J ) 5.1, 7.8 Hz), 3.93 (1H, dd, J ) 6.2, 9.4 Hz), 3.52
(1H, d, J ) 13.7 Hz), 3.43 (1H, d, J ) 13.7 Hz), 3.15 (1H, br s),
2.85-2.94 (1H, m), 2.51 (1H, dt, J ) 2.8, 4.4 Hz), 2.33 (1H,
ddd, J ) 3.4, 9.1, 12.6 Hz), 1.86-2.30 (8H, m), 1.74 (1H, ddd,
J ) 8.4, 9.3, 12.6 Hz), 1.51-1.45 (3H, m), 1.35 (6H, s), 1.17
(3H, s), 0.96 (3H, s); 13C NMR (100 MHz) δ 178.2, 169.8, 85.4,
84.4, 84.3, 75.0, 65.2, 52.9, 48.6, 47.7, 44.7, 38.1, 34.8, 32.7,
32.1, 29.5, 26.6, 26.3, 24.4, 23.6, 21.0, 19.9; MS (ES) m/z (rel
intensity) 478.2 (5, [M + Na]+), 456.2 (16, [M + H]+), 153 (100);
HRMS calcd for C22H33NO7SNa 478.1870, found: 478.1869 (65,
[M + Na]+).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 7, 8, 11a , 11b, 11d , 12a -d , 17a -d ,
19, 20, and 22 and characterization data for compounds 11c,
11d , 12b, 12d , 16b, 17b, 16c, 17c, 16d , and 17d . This material
is available free of charge via the Internet at http://pubs.acs.org.
J O026295B
J . Org. Chem, Vol. 67, No. 23, 2002 8085