Synthesis of (+)-manoalide via a copper(I)-mediated 1,2-metalate rearrangement

Article abstract of DOI:10.1021/jo0268097

An enantiospecific synthesis of the phospholipase A₂ inhibitor (+)-(4R)-manoalide is reported in which all 25 carbons of the sesterterpenoid skeleton are constructed from 3-furaldehyde, trimethylalane, oxirane, CO, β-ionone, and propargyl bromide. The overall yield for the longest linear sequence (12 steps) is 12%. Key steps include (a) a zirconium-catalyzed carboalumination reaction to construct the C10-C11 trisubstituted alkene, (b) a Cu(I)-mediated 1,2-metalate rearrangement to construct the C6-C7 trisubstituted alkene, (c) a Sharpless kinetic resolution to secure the (4R)-stereochemistry, (d) generation of a 5-stannyl-2,3-dihydrofuran by Mo-catalyzed cycloisomerization of a homopropargylic alcohol, and (e) construction of the hydroxyfuranone ring by photooxidation of a silylfuran.

Full text of DOI:10.1021/jo0268097

Synthesis of (+)-Manoalide via a Copper(I)-Mediated 1,2-Metalate
Rearrangement
Agne`s Pommier,‡ Viatcheslav Stepanenko,† Krzysztof Jarowicki,† and Philip J. Kocienski*,†
Department of Chemistry, Glasgow University, Glasgow G12 8QQ, Scotland, and Department of
Chemistry, Leeds University, Leeds, LS2 9JT, UK
p.kocienski@chem.leeds.ac.uk
Received December 5, 2002
An enantiospecific synthesis of the phospholipase A2 inhibitor (+)-(4R)-manoalide is reported in
which all 25 carbons of the sesterterpenoid skeleton are constructed from 3-furaldehyde, trimethyl-
alane, oxirane, CO, â-ionone, and propargyl bromide. The overall yield for the longest linear sequence
(12 steps) is 12%. Key steps include (a) a zirconium-catalyzed carboalumination reaction to construct
the C10-C11 trisubstituted alkene, (b) a Cu(I)-mediated 1,2-metalate rearrangement to construct
the C6-C7 trisubstituted alkene, (c) a Sharpless kinetic resolution to secure the (4R)-stereochem-
istry, (d) generation of a 5-stannyl-2,3-dihydrofuran by Mo-catalyzed cycloisomerization of a
homopropargylic alcohol, and (e) construction of the hydroxyfuranone ring by photooxidation of a
silylfuran.
Introduction
Manoalide is a potent and irreversible inhibitor of
phospholipase A2 (PLA2), the hydrolytic enzyme that
catalyses arachidonic acid release from membrane-bound
phosphoglycerides leading to the formation of pro-inflam-
matory mediators such as the leukotrienes and prostag-
landins.15,16 Moreover, it also reduces the expression of
COX-2.17 Current opinion is that irreversible binding of
manoalide to PLA2 is the consequence of Schiff base
formation between the aldehyde tautomer of the hy-
droxyfuranone ring of two manoalide molecules and two
remote lysine residues on the interfacial recognition
surface of the enzyme. Neither lysine is associated with
the active site of the enzyme; hence some residual
catalytic activity of the doubly bound enzyme is ob-
served.18 However, the PLA2 inhibition by cacospongiono-
lide E (3) suggests that Schiff base formation with the
aldehyde tautomer derived from the hydroxypyran ring
(C24) is not essential for biological activity.19 Another
dominant molecular feature that contributes to the
potency and efficacy of manoalide is the presence of a
large hydrophobic chain. Sodano and co-workers have
In 1980 de Silva and Scheuer reported the isolation
and structure determination of manoalide (1), a sester-
terpenoid metabolite from the Pacific sponge Luffariella
variabilis.1 Owing to the presence of two hemiacetal
moieties at C24 and C25, manoalide is a mixture of
diastereoisomers that undergo easy ring-chain tautom-
erism to the dialdehyde 2. The absolute stereochemistry
of the single remaining nonfluxional stereogenic center
at C4 was ascertained by correlation with a synthetic
derivative.2,3 The first total synthesis of racemic manoalide
was reported in 1985 by Katsumura and co-workers,4 and
this was followed by six syntheses of the racemate5-8
(including our own contribution9). However, the first
enantiospecific synthesis of (+)-(4R)-manoalide evaded
conquest until the concise asymmetric aldol approach of
the Sodano group in 1999.10 Syntheses of various pyra-
nofuranone fragments have also been described.11-14
† Leeds University.
‡ Glasgow University. Current address: AstraZeneca Pharmaceu-
ticals, Bakewell Road, Loughborough, LE11 0RH, UK.
(1) de Silva, E. D.; Scheuer, P. J. Tetrahedron Lett. 1980, 21, 1611-
1614.
(11) Katsumura, S.; Inagaki, Y.; Tsujino, K.; Han, Q. Chem. Lett.
1993, 351-352.
(2) Amoo, V. E.; De Bernardo, S.; Weigele, M. Tetrahedron Lett.
1988, 29, 2401-2404.
(3) Kobayashi, M.; Okamoto, T.; Hayashi, K.; Yokoyama, N.; Sasaki,
T.; Kitagawa, I. Chem. Pharm. Bull. 1994, 42, 265-270.
(4) Katsumura, S.; Fujiwara, S.; Isoe, S. Tetrahedron Lett. 1985, 26,
5827-5830.
(12) Lattmann, E.; Coombs, J.; Hoffmann, H. M. R. Synthesis 1996,
171-177.
(13) Soriente, A.; De Rosa, M.; Scettri, A.; Sodano, G. Tetrahedron
Lett. 1996, 37, 8007-8010.
(14) De Rosa, M.; Soriente, A.; Sodano, G.; Scettri, A. Tetrahedron
2000, 56, 2095-2102.
(5) Garst, M. E.; Tallman, E. A.; Bonfiglio, J. N.; Harcourt, D.;
Ljungwe, E. B.; Tran, A. Tetrahedron Lett. 1986, 27, 4533-4536.
(6) Katsumura, S.; Fujiwara, S.; Isoe, S. Tetrahedron Lett. 1988, 29,
1173-1176.
(15) Reynolds, L. J.; Morgan, B. P.; Hite, G. A.; Mihelich, E. D.;
Dennis, E. A. J. Am. Chem. Soc. 1988, 110, 5172-5177.
(16) Glaser, K. B.; de Carvalho, M. S.; Jacobs, R. S.; Kernan, M. R.;
Faulkner, D. J. Mol. Pharmacol. 1989, 36, 782-788.
(17) Glaser, K. B.; Lock, Y. W. Biochem. Pharmacol. 1995, 50, 913-
922.
(7) Bury, P.; Hareau-Vittini, G.; Kocienski, P.; Dhanak, D. Tetra-
hedron 1994, 50, 8793-8808.
(8) Coombs, J.; Lattmann, E.; Hoffmann, H. M. R. Synthesis 1998,
1367-1371.
(18) Bianco, I. D.; Kelley, M. J.; Crowl, R. M.; Dennis, E. A. Biochim.
Biophys. Acta 1995, 1250, 197-203.
(19) De Rosa, M.; Giordano, S.; Scettri, A.; Sodano, G.; Soriente, A.;
Pastor, P. G.; Alcaraz, M. J.; Paya´, M. J. Med. Chem. 1998, 41, 3232-
3238.
(9) Pommier, A.; Kocienski, P. J. J. Chem. Soc., Chem. Commun.
1997, 1139-1140.
(10) Soriente, A.; De Rosa, M.; Apicella, A.; Scettri, A.; Sodano, G.
Tetrahedron: Asymmetry 1999, 10, 4481-4484.
10.1021/jo0268097 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003
4008
J. Org. Chem. 2003, 68, 4008-4013

Synthesis of (+)-Manoalide
SCHEME 2. Synthesis of Iodoalkane 4
aqueous toluene under phase transfer catalysis was
examined in detail because it could be performed on a
large scale.7,21 However, the reaction did not go to
completion despite the use of excess reagents and the
dihydro-â-ionone (7) was invariably contaminated with
5-10% of unreacted starting material, which required
tedious chromatography to separate. Far better is a mild
procedure of Laube and co-workers22 involving Rh-
catalyzed conjugate hydrosilylation of â-ionone with
triethylsilane followed by hydrolysis of the enol silane
intermediate to give the dihydro-â-ionone in 90% yield.
The reaction can be performed on large scale under
solvent-free conditions and only 1 mol % of the com-
mercial [Ph3P]3RhCl catalyst is required. Moreover, the
product is devoid of unreacted starting material.
FIGURE 1.
SCHEME 1. Disconnections and Key Steps
Regioselective dehydration of dihydro-â-ionone via the
enol phosphate derivative gave the terminal alkyne 8 in
73% yield for the 3-step sequence.23 The known conver-
sion of alkyne 8 to the homoallylic alcohol 10 benefited
from two significant improvements. First, the Negishi
carboalumination reaction generating the alkenyl di-
methylalane intermediate 9 was conducted in the pres-
ence of 1 equiv of water as recommended by Wipf and
co-workers24 leading to a faster reaction and a reduction
in the amount of zirconocene dichloride from 1 equiv to
just 10 mol %. The second improvement entailed the
direct reaction of the alkenyl dimethylalane 9 with
oxirane to give the homoallylic alcohol 10 without the
activation of the alane as the ate complex with BuLi as
reported previously.25,26 Although there was no improve-
ment in overall yield in the conversion of 8 to 10 (62%),
the experimental procedure was abbreviated and simpli-
summarized the extensive biochemistry of manoalide and
its many natural and unnatural relatives.20
Results and Discussion
We now report a synthesis of (4R)-manoalide in which
all 25 carbons are derived from 6 simple commercial
fragments: 3-furaldehyde, trimethylalane, oxirane, CO,
â-ionone, and propargyl bromide. The key steps together
with the two principal fragments 4 and 5 encompassing
24 of the 25 carbons of the target are summarized in the
synthetic map depicted in Scheme 1. The synthesis can
be divided into 3 phases as described below.
Phase 1: Synthesis of Iodoalkane 4. Synthesis of
iodoalkane 4 (Scheme 2) began with the conjugate
reduction of â-ionone (6). One attractive and economic
method based on the use of sodium dithionite in hot
(21) Camps, F.; Coll, J.; Guitart, J. Tetrahedron 1986, 42, 4603-
4609.
(22) Laube, T.; Schro¨der, J.; Stehle, R.; Seifert, K. Tetrahedron 2002,
58, 4299-4309.
(23) Negishi, E.; King, A. O.; Klima, W. L. J. Org. Chem. 1980, 45,
2526-2528.
(24) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068-
1071.
(25) Negishi, E. Acc. Chem. Res. 1987, 20, 65-72.
(26) Negishi, E.; Kondakov, D. Y. Chem. Soc. Rev. 1996, 25, 417-
426.
(20) Soriente, A.; De Rosa, M.; Scettri, A.; Sodano, G.; Terencio, M.
C.; Paya´, M.; Alcaraz, M. J. Curr. Med. Chem. 1999, 6, 416-431.
J. Org. Chem, Vol. 68, No. 10, 2003 4009

Pommier et al.
SCHEME 3. Synthesis of Alcohol (R)-13 by
Chromatographic and Kinetic Resolution
SCHEME 4. Mo-Catalyzed CycloIsomerization of
Alkynol (R)-13
(22%). The configurations of the two diastereoisomers
were assigned from the chemical shifts of the propargylic
protons according to the Mosher-Trost model.29,30 In the
case of (S,R)-14, the propargylic protons at δ 2.64 were
shielded by the phenyl group in the conformation de-
picted relative to the corresponding protons in the (S,S)-
diastereoisomer (δ 2.72 and 2.78). Moreover, the man-
delate proton in (S,R)-14 at δ 6.22 was shielded by the
furan ring whereas the corresponding proton in the (S,S)-
diastereoisomer appeared at δ 6.52. Hydrolysis of the
ester (S,R)-14 gave the alcohol (R)-13 in 93% yield with
an er of 98:2. The chromatographic resolution strategy
was able to deliver gram quantities of enantiopure (R)-
13 but the small difference in Rf between the diastereo-
isomeric esters made the chromatographic separation
difficult. A far more practical procedure, and the method
of choice, was the kinetic resolution of rac-13 under
Sharpless asymmetric epoxidation conditions31 where-
upon the desired (R)-alcohol was isolated by an easy
column chromatography in 41% yield.
Five methods for the asymmetric addition of allenyl-
metallic reagents to aldehyde 12 were evaluated. The
yield and enantiomeric ratio (er) of the adducts (R)-13
and (S)-13 are summarized in Table 1. The lowest
enantioselectivities were obtained in the addition of
allenyl-/propargylzinc reagents with chiral ethanol-
amines 16 and 17 as chiral adjuvants (entries 2 and 3).
The allenylboronate derived from the dibenzyl tartrate
15 added in good yield (71%) but the er (80:20) was
unacceptable (entry 1).32 By contrast the allenylboron
reagent derived from 18 gave an acceptable er (91:9) but
the yield was only modest at best (49%, entry 5).33
Potentially the best of the asymmetric methods examined
was that of Keck involving addition of an allenylstannane
to aldehyde 12 under the aegis of an (R)-BINOL-modified
fied. Finally conversion of the alcohol 10 to iodoalkane 4
was accomplished in a single step (92%) with standard
procedures. The overall yield for the 8-step sequence is
37%.
Phase 2: Synthesis of the 2,3-Dihydro-[2,3′]-bi-
furanyl 5. Synthesis of the second key intermediate in
our synthesis, the 2,3-dihydro-[2,3′]-bifuranyl derivative
5, entailed three operations: (1) appendage of the tri-
ethylsilyl group; (2) creation of the C4 (manoalide num-
bering) stereogenic center; and (3) construction of the
5-tributylstannyl-2,3-dihydrofuran ring. The sequence
began with the appendage of a triethylsilyl group at C5
of 3-furaldehyde. The triethylsilyl group, which served
the dual purpose of preventing metalation of the furan
ring and activating the furan during a subsequent
photooxidation, was installed by temporary protection of
the aldehyde in 3-furaldehyde (11, Scheme 3) by nucleo-
philic addition of lithium morpholide to give an adduct
that was then lithiated at the 5-position with s-BuLi.
Addition of triethylsilyl chloride followed by aqueous
workup returned the 5-triethylsilyl-3-furaldehyde 12 in
73% yield for the one-pot sequence.27
The synthesis of enantiomerically pure alcohol (R)-13
by catalytic asymmetric methods (see below) was im-
practical and therefore abandoned in favor of resolution-
based methods. Thus, the racemic alcohol rac-13, pre-
pared by addition of propargylmagnesium bromide to
aldehyde 12, was esterified with (S)-O-acetyl-mandelic
acid with use of DCC28 (Scheme 3) and the mixture of
diastereoisomeric esters was separated by column chro-
matography to give pure (S,R)-14 (41%) and (S,S)-14
(29) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-
519.
(30) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370-2374.
(31) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J. Org. Chem.
1989, 54, 2084-2091.
(32) Ikeda, N.; Arai, I.; Yamamoto, H. J. Am. Chem. Soc. 1986, 108,
483-486.
(33) Corey, E. J.; Yu, C.-M.; Lee, D.-H. J. Am. Chem. Soc. 1990,
112, 878-879.
(27) Lee, G. C. M.; Holmes, J. M.; Harcourt, D. A.; Garst, M. E. J.
Org. Chem. 1992, 57, 3126-3131.
(28) Whitesell, J. K.; Reynolds, D. J. Org. Chem. 1983, 48, 3548-
3551.
4010 J. Org. Chem., Vol. 68, No. 10, 2003

Synthesis of (+)-Manoalide
TABLE 1. Asymmetric Propargylation of 5-(Triethylsilyl)-3-furaldehyde (12)
entry
reagents and conditions
yield (%)
er (R:S)b
1
2
3
4
[a]: H2CdCdCH-B(OH)2 (2.5 equiv), 15 (1.9 equiv), 5 Å MS, CH2Cl2, -78 °C, 3 d
[b]: H2CdCdCH-I/HC≡C-CH2I (2:1, 2.2 equiv), ZnEt2 (2.2 equiv), 16 (20 mol %), PhMe, 0 °C, 4 h
[c]: H2CdCdCH-I/HC≡C-CH2I (2:1, 2.2 equiv), ZnEt2 (2.2 equiv), 17 (20 mol %), PhMe, 0 °C, 4 h
[d]: H2CdCdCHSnBu3 (2.0 equiv), (R)-BINOL (25 mol %), Ti(iPrO)4 (25 mol %), 4 Å MS,
PrS-BEt2 (2.0 equiv), CH2Cl2, -20 °C, 10 d
71
80
80:20
30:70
55:45
96:4
84
87a
5
[e]: 18 (1.1 equiv), BBr3 (1.1 equiv), CH2Cl2, rt, 40 min; add HC≡C-CH2SnPh3, 0 °C, 40 min; add
49
91:9
aldehyde, -78 °C, 4 h
a Yield based on 40% recovered starting material. b The ratio and configuration was determined by 1H NMR spectroscopy of the (S)-
O-acetyl mandelate esters.
SCHEME 5. Transmetalation of
5-Tributylstannyl-2,3-dihydrofuran 5
Lewis acid (entry 4).34,35 The excellent enantiomeric ratio
(96:4) and high yield (87% based on recovered starting
material) was vitiated by the long reaction times (ca 10
days) at the low temperature required to achieve high
er, the capriciousness of the reaction, and the failure of
the reaction to go to completion.
The final hurdle in our synthesis of 2,3-dihydro-[2,3′]-
bifuranyl 5 was the construction of the 5-tributylstannyl-
2,3-dihydrofuran ring (Scheme 4), a task that was easily
lation of R-stannyl enol ethers with BuLi is well-
documented as an easy and efficient reaction,38 but in
the case at hand, the desired lithium reagent 21 under-
went competitive rearrangement to the more thermody-
namically stable furanyllithium 22 under the transmet-
alation conditions with consequent complications in the
next step (see below). However, the problem was mini-
mized by accelerating the transmetalation step by using
s-BuLi at -60 °C instead of n-BuLi and by using a
mixture of Et2O and pentane as the solvent.
A Cu(I)-mediated 1,2-metalate rearrangement that is
the apex of our synthesis (Scheme 6)39,40 was initiated
by halogen-metal exchange of iodoalkane 4 with t-
BuLi41,42 to afford a homoallylic lithium derivative that
was converted to a mixed cuprate 23 by reaction with
1-pentynylcopper. The resultant cuprate was then added
to a solution of the lithiated dihydrofuran 21 at -78 °C
to give a putative higher order cuprate 24 that underwent
1,2-metalate rearrangement on gradual warming to room
temperature. The resultant higher order oxycuprate 25
accomplished in a single step by the Mo-catalyzed cyclo-
isomerization method of McDonald.36 The method en-
tailed the photochemical generation of Et3N‚Mo(CO)5 and
its subsequent reaction with the alkynol (R)-13 and Bu3-
SnOTf in the presence of excess NEt3. After 48 h at room
temperature, the acid-sensitive target 5 was isolated in
65% yield. A plausible mechanism for the transformation
was proposed by McDonald:37 reaction of the terminal
alkyne in (R)-13 with Et3N‚Mo(CO)5 results in formation
of a Fischer-type vinylidenecarbene 19 that cyclizes
under the reaction conditions to the dihydrofuran 20
whence reaction with Bu3SnOTf affords the product and
regenerates the Et3N‚Mo(CO)5.
Phase 3: Construction of the C6-C7 Trisubsti-
tuted Alkene. The principal goals in the third and final
phase of the synthesis were the union of fragments 4 and
5 (as their lithium derivatives) and the construction of
the C6-C7 trisubstituted alkene. The aim in preparing
the stannane 5 was to provide a route to the correspond-
ing lithium reagent 21 (Scheme 5)san essential ingredi-
ent in the 1,2-metalate rearrangement. The transmeta-
(38) Friesen, R. W. J. Chem. Soc., Perkin Trans. 1 2001, 1969-2001.
(39) Kocienski, P.; Wadman, S.; Cooper, K. J. Am. Chem. Soc. 1989,
111, 2363-2365.
(34) Keck, G. E.; Krishnamurthy, D.; Chen, X. Tetrahedron Lett.
1994, 35, 8323-8324.
(40) Fujisawa, T.; Kurita, Y.; Kawashima, M.; Sato, T. Chem. Lett.
1982, 1641-1642.
(35) Yu, C.-M.; Yoon, S.-K.; Choi, H.-S.; Baek, K. J. Chem. Soc.,
Chem. Commun. 1997, 763-764.
(41) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404-
5406.
(36) McDonald, F. E.; Schultz, C. C.; Chatterjee, A. K. Organome-
tallics 1995, 14, 3628-3629.
(42) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990,
55, 5406-5409.
(37) McDonald, F. E. Chem. Eur. J. 1999, 5, 3103-3106.
J. Org. Chem, Vol. 68, No. 10, 2003 4011

Pommier et al.
SCHEME 6. The Key Step: A 1,2-Metalate Rearrangement
SCHEME 7. 1,2-Metalate Rearrangement of
5-Butyl-2-furyllithium
was then quenched with iodine to give the trisubstituted
iodoalkene 26 in 65% overall yield from stannane 5 and
iodoalkane 4. A similar sequence, in which CuCN was
used instead of 1-pentynylcopper, gave the iodoalkene 26
in 58% overall yield. To install the last remaining carbon
of the manoalide skeleton, the iodoalkene was subjected
to a Pd(0)-catalyzed carbonylation43 in which the inter-
mediate acylpalladium(II) species was captured by reac-
tion with the proximate hydroxyl group to give the
lactone 27 in 91% yield. To complete the synthesis, the
lactone was reduced to the corresponding lactol with
DIBALH whereupon photooxidation of the silylfuran44
generated the hydroxyfuranone of manoalide in 60%
yield. The 1H NMR spectrum of the product was identical
with the NMR spectrum of racemic manoalide kindly
provided by Dr. Michael Garst and the sign and magni-
tude of the [R]D (+77.5) was comparable to the value
reported by Kobayashi and co-workers (+80.0).3
2-Furyllithiums Undergo Cu(I)-Mediated 1,2-
Metalate Rearrangment. Above we alluded to compli-
cations arising from the rearrangement of the dihydro-
furyllithium derivative 21 to the 2-furyllithium 22. We
suspected that 22 was participating in the 1,2-metalate
rearrangement with the consequent destruction of the
furan ring. Our suspicions were confirmed by the reaction
of the simpler 5-butyl-2-furyllithium with Bu2CuLi to
give the â,γ-unsaturated ketone 33 in 68% yield in accord
with the mechanism shown in Scheme 7.45
Conclusion
We have accomplished the synthesis of (+)-manoalide
in 12% overall yield for the longest linear sequence of 12
steps from commercial starting materials (3-furaldehyde,
trimethylalane, oxirane, CO, â-ionone, and propargyl
bromide). Noteworthy features include (a) the discovery
of conditions for transmetallating stannyldihydrofuran
5 without competing metalation of the furan, (b) the use
of cyanide and pentyne as nontransferrable ligands in
the key 1,2-metalate rearrangement step used to con-
struct the C6-C7 trisubstituted double bond, and (c) the
discovery that furan rings participate in Cu-mediated 1,2-
metalate rearrangements. The weakest link in the syn-
thesis was the 6-step sequence (18% overall) by which
3-furaldehyde was converted to the stannane 5 because
(43) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318-3326.
(44) Lee, G. C. M.; Syage, E. T.; Harcourt, D. A.; Holmes, J. M.;
Garst, M. E. J. Org. Chem. 1991, 56, 7007-7014.
(45) A related rearrangement involving furylzirconocene derivatives
is known: Erker, G.; Petrenz, R.; Kru¨ger, C.; Lutz, F.; Weiss, A.;
Werner, S. Organometallics 1992, 11, 1646-1655.
4012 J. Org. Chem., Vol. 68, No. 10, 2003

Synthesis of (+)-Manoalide
Supporting Information Available: Experimental de-
tails and characterization data for compounds 1, 4, 5, 7, 10,
(R)-13, (S,R)-14, (S,S)-14, 26, 27, 28, and 33 together with
details of the asymmetric propargylation of 5-triethylsilyl-3-
furaldehyde (12); copies of H spectra for compounds 1, 4, 5,
13, 26, 27, 28, and 33. This material is available free of charge
of the inherent inefficiency in the resolution of the
furylcarbinol rac-13.
Acknowledgment. We thank the Engineering and
Physical Sciences Research Council of Great Britain,
Merck Sharp & Dohme, and Pfizer Central Research
for generous support of our work. We also thank Dr.
Michael Garst for copies of the NMR spectra of
manoalide.
1
via the Internet at http://pubs.acs.org.
JO0268097
J. Org. Chem, Vol. 68, No. 10, 2003 4013