Total syntheses of (-)-grandinolide and (-)-sapranthin by the sharpless asymmetric dihydroxylation of methyl trans-3-pentenoate: Elucidation of the stereostructure of (-)-sapranthin

Article abstract of DOI:10.1002/(SICI)1521-3765(19981102)4:11<2342::AID-CHEM2342>3.0.CO;2-Q

Methyl trans-3-pentenoate (7) was converted into the cis-substituted γ- lactone 8 in a single step with 78% ee. The derived enolate dilithio-8 was alkylated trans-selectively with primary iodoalkanes with 1-iodobutane dilithio-8 afforded, after esterification with isovaleroyl chloride, the epi- blastmycinone 9. Dilithio-8 gave (-)-grandinolide (II) with 1-iodo-19- phenylnonadecane (20). A third trans-selective alkylation of dilithio-8 was undertaken with 16-iodo-1,5-hexadecadiene-7,9-diyne (21). This gave the γ- 1actone 12, which had the published relative configuration of (-)-sapranthin but different spectroscopic data. When the OH group of lactone 8 was inverted (to hydroxylactone 40) and the derived enolate dilithio-40 alkylated with iodide 21, lactone 41 resulted. Its ¹H and ¹³C NMR spectra and the sign and value of optical rotation coincide with the data of natural sapranthin. These findings establish that (-)-sapranthin possesses the relative and absolute configuration of stereoformula 41. The synthesis of iodide 21 was performed via the dienoic carboxylic ester trans-23 which stemmed from the Claisen-Ireland rearrangement (27 → 28/29)/esterification (28/29 → 26)/Cope rearrangement (26 → 23) sequence shown in Scheme 5.

Full text of DOI:10.1002/(SICI)1521-3765(19981102)4:11<2342::AID-CHEM2342>3.0.CO;2-Q

FULL PAPER
Total Syntheses of ( )-Grandinolide and ( )-Sapranthin by the Sharpless
Asymmetric Dihydroxylation of Methyl trans-3-Pentenoate:
Elucidation of the Stereostructure of ( )-Sapranthin
Christian Harcken, Reinhard Brückner, and Elisabeth Rank*
Dedicated to Professor Reinhard W. Hoffmann on the occasion of his 65th birthday
Abstract: Methyl
trans-3-pentenoate
7,9-diyne (21). This gave the g-lactone
12, which had the published relative
configuration of ( )-sapranthin but dif-
ferent spectroscopic data. When the OH
group of lactone 8 was inverted (to
hydroxylactone 40) and the derived
enolate dilithio-40 alkylated with iodide
NMR spectra and the sign and value of
optical rotation coincide with the data of
natural sapranthin. These findings es-
tablish that ( )-sapranthin possesses the
relative and absolute configuration of
stereoformula 41. The synthesis of
iodide 21 was performed via the dienoic
carboxylic ester trans-23 which stemmed
from the Claisen ± Ireland rearrange-
ment (27 ! 28/29)/esterification (28/29
! 26)/Cope rearrangement (26 ! 23)
sequence shown in Scheme 5.
(7) was converted into the cis-substitut-
ed g-lactone 8 in a single step with
78% ee. The derived enolate dilithio-8
was alkylated trans-selectively with pri-
mary iodoalkanes. with 1-iodobutane
dilithio-8 afforded, after esterification
with isovaleroyl chloride, the epi-blast-
mycinone 9. Dilithio-8 gave ( )-grandi-
nolide (11) with 1-iodo-19-phenylnona-
1
21, lactone 41 resulted. Its H and 13C
Keywords: asymmetric synthesis
´
decane (20).
A third trans-selective
dihydroxylations ´ g-lactones ´ re-
arrangements ´ structure elucidation
alkylation of dilithio-8 was under-
taken with 16-iodo-1,5-hexadecadiene-
Introduction
OH
R
R
Enantiomerically pure or enantiomerically enriched g-chiral
g-lactones[1] and g-chiral butenolides[2] demand syntheses
which are broadly applicable and highly efficient. Recently,
we presented a straightforward and, as we have since
experienced in several projects, versatile novel access to such
compounds.[3] It is based upon the Sharpless asymmetric
dihydroxylation (AD)[4] of b,g-unsaturated esters. This reac-
tion had been almost overlooked previously.[5]
AD mix β
OH
CO2Me
CO2Me
2
1
spontaneously
OH
The principle and first applications of our route in target-
oriented work are summarized in Scheme 1.[3] ADs of a
number of b,g-unsaturated esters 1 initially provided the
enantiopure or enantio-enriched dihydroxylation products 2.
These compounds lactonized spontaneously under the alka-
line reaction conditions. The isolable reaction products were
g-chiral g-lactones 4 of 92 ± 97% ee. The absolute configu-
ration of these lactones only depends on whether the AD is
performed with AD mix b[6] (as in the cases of Scheme 1) or
with AD mix a[6] (where the major isomers would represent
the mirror images of the structures of Scheme 1). In fact, the
lactones 4 were not yet the target molecules of our previous
R
R
1 step
O
O
O
O
4
3
e. g. R = HO-CH2 (92% ee)i)
1 step
1 step
R´
R
R
O
O
O
5
O
6
[*] Prof. Dr. R. Brückner, Dipl.-Chem. C. Harcken, Dipl.-Chem. E. Rank
Institut für Organische Chemie der Universität
Tammannstrasse 2, D-37077 Göttingen (Germany)
Fax: (‡49)551-392944
e. g. R = Oct (95% ee)ii)
e. g. R = Bu, R´ = Me (97% ee)iii)
Scheme 1. i) Equivalent to levorotatory aglycon of ranunculin;[7] ii) equi-
valent to (‡)-dodecanolide;[8] iii) equivalent to ( )-trans quercus lactone.[9]
E-mail: rbrueck@gwdg.de
2342
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2342 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 11

2342±2352
study.[3] Rather, each of them was carried on to a g-chiral
butenolide 3 by a b-elimination induced by mesyl chloride/
triethylamine. For R ˆ HO ± CH2 butenolide 3 constitutes the
aglycon of ranunculin,[7] for R ˆ Oct a precursor of the
pheromone (‡)-dodecanolide (5;[8] available from 3 by
catalytic hydrogenation), and for R ˆ Bu a precursor of the
flavorant ( )-trans quercus lactone (6;[9] available from 3
through the 1,4-addition of Me2CuLi).
OH
a)
O
CO2Me
O
8 (78% ee)
7
b)
Another target reached in our previous study[3] was the epi-
blastmycinone 9 (Scheme 2). To achieve this, the commer-
cially available methyl pentenoate 7 was asymmetrically
dihydroxylated with AD mix a. The resulting lactone 8[10]
exhibited only 78% ee, which is not surprising in view of the
substitution pattern[11] of the substrate. In addition, this
lactone formed in a considerably slower reaction (08C, 5 d
instead of 1 ± 2 d) with distinctly lower yield (40% instead of
81 ± 92%) than the closely related lactones 4 in Scheme 1. This
was because lactone 8 unlike its congeners 4 had to be
prepared in the absence of methanesulfonamide which
accelerates ADs,[4] a modus procedendi required since
methanesulfonamide was inseparable from lactone 8 by flash
chromatography on silica gel.[12] The a-alkylation of dilithi-
ated b-hydroxy-g-lactones occurs in HMPA-containing THF
such that the a-substituent is oriented exclusively trans with
respect to the b-OH group.[13] Conveniently, butylation of the
dilithiated hydroxylactone 8 in 4:1 THF/DMPU[14] also
resulted in an exclusively trans-alkylated hydroxylactone 10
(epi-blastmycinolactol; 53% yield). Treatment of 10 with
isovaleroyl chloride gave the isovalerate 9 in 85% yield.
Compound 9 is an epi-blastmycinone, that is, an epimer of the
antimycin A3 degradation product blastmycinone. Several
other syntheses for 9 are known; however, they are less
O
O
OH
iBu
O
Bu
Bu
O
c)
O
O
10
9
OH
Ph
(
)
18
O
O
11
OH
(
)
4
O
O
12
Scheme 2. a) AD mix a (1.4 gmmol 1 7), tBuOH/H2O (1:1), addition of 7,
08C, 5 d; 40%; b) LDA (3.0 equiv), addition of 8, THF, 788C, 2 h;
358C, 20 h; 53%;
c) isovaleroyl chloride (3.0 equiv), CH2Cl2/pyridine (5:1), 08C to room
1-iodobutane (1.5 equiv) in THF/DMPU (1:1),
temperature, 6 h; 83%.
stereoselective.[15]
.
Our synthesis of the epi-blastmycinolactol 10 was also a
training reaction for synthesizing the natural products ( )-
grandinolide (11)[16] and ( )-sapranthin (12)[17] analogously;
these are constituents of bark from Iryanthera grandis and
Sapranthus palanga, respectively (Scheme 2). The relative
configurations of these compounds had been deduced from
Abstract in German: Methyl-trans-3-pentenoat (7) wurde
durch asymmetrische Sharpless-Dihydroxylierung und eine
sich anschlieûende spontane Lactonisierung in das cis-sub-
stituierte g-Lacton 8 (78% ee) umgewandelt. Dessen Enolat
Dilithio-8 wurde mit primären Iodalkanen trans-selektiv alky-
liert. Mit Iodbutan und nach Veresterung mit Isovaleroylchlo-
rid ergab es das epi-Blastmycinon 9. Mit 1-Iod-19-phenyl-
nonadecan (20) lieferte Dilithio-8 ( )-Grandinolid (11). Eine
analoge trans-Alkylierung mit 16-Iod-1,5-hexadecadien-7,9-
diin (21) führte zu dem Lacton 12. Dieses besaû zwar die für
( )-Sapranthin publizierte Relativkonfiguration, aber abwei-
1
their H NMR spectra. The absolute configuration of gran-
dinolide (11) was established in its first and hitherto only
synthesis,[18] whereas the absolute configuration of sapranthin
(12) was unknown.
Results and Discussion
1
chende H- und 13C-NMR-Daten. Nachdem die OH-Gruppe
The major effort in synthesizing grandinolide (11; Scheme 3)
was achieving the iodoalkane 20. The THP ether 14 of
propargyl alcohol was alkylated[19] with 1-bromohexadecane
giving the chain-elongated THP ether 15 in 76% yield.
Methanolysis[20] provided 92% of the underlying C19 alcohol
des Ausgangslactons 8 invertiert worden war, wurde das Enolat
des erhaltenen Hydroxylactons 40 mit dem Iodid 21 zum
Lacton 41 trans-alkyliert. Die NMR-Spektren und das Vor-
zeichen der spezifischen Drehung dieser Verbindung 41
stimmten mit den Werten von ( )-Sapranthin überein. Dessen
relative und absolute Konfiguration wird folglich durch
Stereoformel 41 angegeben. Das Iodid 21 wurde aus dem
Diencarbonsäureester trans-23 gewonnnen. Letzterer ent-
stammte der Reaktionssequenz Claisen/Ireland-Umlagerung
27 !28/29, Veresterung 28/29 !26 und Cope-Umlagerung
26 !23 von Schema 5.
ꢀ
16. The internal C C bond of this compound was shifted in a
modified[21] alkyne zipper reaction[22] until it became terminal.
The resulting alkynol 18 (84% yield) was coupled with
iodobenzene under standard conditions[23] (5 mol% [PdCl2-
(PPh3)2], 15 mol% CuI, THF/iPr2NH, room temperature) to
ꢀ
give 84% of the unsaturated alcohol 17. Its C C bond was
hydrogenated to saturation (H2, Pd/C; to 82% 19). Subse-
Chem. Eur. J. 1998, 4, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2343 $ 17.50+.25/0
2343

R. Brückner et al.
FULL PAPER
Table 1. 1H NMR comparison in CDCl3 between synthetic and natural grandinolide (11) and between synthetic and natural sapranthin (41); chemical shifts
in ppm, coupling constants in Hz (for the numbering see Table 2 and Scheme 7, respectively).
5-H
4-H
3-H
1'-HA
1'-HB
J5,4
J4,3
J3,1H(A)
J3,1H(B)
Field strength [MHz]
natural 11[16]
synthetic 11
natural 41[17]
synthetic 41
4.54
4.63
4.20
4.20
4.14
4.20
3.86
3.84
2.45
2.53
2.54
2.55
±
±
±
±
5
3
±
±
7.3
7.4
±
±
7.3
5.7
60
300
360
500
5.0
7.1
7.2
3.6
1.5[47]
8.7
1.81 ± 1.87
ca. 1.62
1.81 ± 1.87
1.86
mixture gradually from 788C (1 h) to 408C and main-
taining it at that temperature for 20 h, the diastereopure
lactone 11 was isolated in 53% yield. It was identical to ( )-
grandinolide, as shown by NMR spectroscopy (selected data:
RO
RO
c)
(
)
15
R = H: 13
15: R = THP
16: R = H
Table 1), polarimetry (11: [a]D20
ˆ
23 corrected for an ee of
a)
b)
only 78% ) [a]2D0 of optically pure 11 ˆ 23/0.78 ˆ 30 (c ˆ
R = THP: 14
0.5 in MeOH); ( )-grandinolide: [a]D20
and melting point determination (11: 768C; ( )-grandinolide:
ˆ
34 (MeOH)[16]),
d)
76 788C[16]).
The envisaged synthesis (Scheme 4) of the literature struc-
ture 12 of sapranthin required constructing the side chain 21.
We traced it back retrosynthetically to the terminal alkynol 22
Ph
e)
(
)
16
( )
16
HO
HO
17
18
OH
f)
(
)
4
O
O
g)
Ph
18
Ph
12
(
)
(
)
18
HO
I
19
20
OH
(
)
4
I
8
+
h)
21
O
O
8 (78% ee)
O
OH
(
)
4
HO
Ph
RO
+
(
)
18
R = Me: trans-23
R = H: trans-24
22
O
O
11
Scheme 3. a) Dihydro-2H-pyran (3.0 equiv), pyridinium p-toluenesulfo-
nate (1.0 mol%), CH2Cl2, 16 h; 84%; b) nBuLi (1.2 equiv), 08C, 15 min;
1-bromohexadecane (1.1 equiv), DMSO, room temperature, 14 h; 76%;
c) p-toluenesulfonic acid (0.4 equiv), MeOH, room temperature, 2 h; 92%;
d) Li (6.0 equiv), 1,2-diaminopropane, room temperature to reflux, 30 min;
KOtBu (4.0 equiv), room temperature, 30 min; addition of 16, room
temperature, 1 h; 84%; e) PdCl2(PPh3)2 (5.0 mol%), CuI (15.0 mol%), PhI
(1.2 equiv), (iPr)2NH (10.0 equiv), THF, 08C, 15 min; room temperature,
12 h; 84%; f) Pd (10% on charcoal, 5.0 mol%), H2 (5 bar), EtOAc, room
temperature, 16 h; 82%; g) P(OPh)3 (1.0 equiv), CH2Cl2, room temper-
ature, 10 min; I2 (1.0 equiv), 08C, 1 h; 82%; h) LDA (3.0 equiv), addition of
8, THF, 788C, 2.5 h; addition of 20 (1.0 equiv) in THF/DMPU (1:1),
788C, 1 h; 408C, 20 h; 53%.
O
OSiMe3
MeO
O
25
26
Scheme 4. Retrosynthetic analysis of target structure 12.
(accessible through an alkyne zipper reaction from the penty-
lation product 32 of propargyl alcohol; see Scheme 6) and the
heptadienoic carboxylic ester trans-23.[25] The latter was
thought to arise from a Cope rearrangement[26] of the isomeric
ester 26. This, in turn should be the product of a Claisen ±
Ireland rearrangement [27] of the silylketeneacetal 25.[28]
quent exchange of the OH group for iodine by successive
treatments with P(OPh)3 and I2[24] gave the needed alkylating
agent 20. It was added to the dilithio derivative of hydroxy-
lactone 8 in 1:1 THF/DMPU. After warming the resulting
2344
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2344 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 11

Total Syntheses of ( )-Grandinolide and ( )-Sapranthin
2342±2352
Unlike most Claisen ± Ireland rearrangements, the con-
ceived rearrangement 25 !26 had to start from a conjugated
silylketeneacetal. Such rearrangements are scarce but were
described starting from a,b-unsaturated[29] or b,g-unsaturated
allylesters.[30] Another concern was whether the envisaged
Cope rearrangement 26!23 (Scheme 5) would have a suffi-
OMe
OH
a)
O
30
trans-23
b)
HO
O
OH
OH
R
c)
Br
Br
O
O
O
R = H: 31
a)
+
:
Br
33
R = Pent: 32
27
28
87
13
29
d)
)
e)
b)
(
HO
4
22
34
O
OMe
MeO
MeO
f)
O
c)
+
trans-23
(
)
4
X
O
26
X = OH: 35
X = I: 21
g)
OH
cis-23
Scheme 5. a) LiHMDS (1.0 equiv), THF,
788C, 30 min; Me3SiCl
h)
(1.1 equiv), 10 min, 788C; to room temperature to reflux; quantitative;
b) MeOH (2.0 equiv), p-TsOH (2 mol%), CHCl3, azeotropic removal of
water, 16 h; 63%; c) 2408C, 16 h; 75% trans-23, 8% cis-23.
O
O
8 (78% ee)
cient driving force in the desired direction. However, prece-
dence[28, 31] indicated that if a Cope rearrangement product is
an a,b-unsaturated ester, like ester 23, the conjugation energy
of this substructure makes Cope rearrangements proceed at
least to some extent if not to completion.
OH
(
)
4
O
O
The b,g-unsaturated allylester 27[32] was deprotonated at
788C in THF with LiHMDS (Scheme 5). Addition of
Me3SiCl, warming to reflux temperature, and an aqueous
work-up[33] followed, giving a quantitative yield of crude
carboxylic acids. It comprised a 87:13 mixture of the
deconjugated acid 28 (desired) and the conjugated acid 29
(undesired). Esterification with methanol in CHCl3, with
azeotropic removal of water, turned this mixture into 63% of
a single ester 26[34] as required. Evidently, the conjugated acid
29 was not esterified under these conditions because it is more
stable than the deconjugated acid 28. The ensuing Cope
rearrangement 26 !23 proceeded to completion according to
TLC during 16 h at 2408C. We isolated 75% of the needed
ester trans-23 and 8% of its undesired isomer cis-23 after an
easy-to-perform separation by flash chromatography on silica
gel.[12, 35]
12
Scheme 6. a) DIBAL (1.0 m in toluene, 2.2 equiv), THF, 788C to room
temperature, 30 min; 92%; b) (ClCO)2 (1.1 equiv), DMSO (2.2 equiv),
CH2Cl2, 788C, 3 min; addition of 30, 15 min; NEt3 (5.0 equiv), 30 min;
aqueous work-up; PPh3 (4.0 equiv), CBr4 (2.0 equiv), CH2Cl2, 08C, 10 min;
addition of aldehyde, room temperature, 1 h; 53% for the two steps; c) Li
(3.0 equiv), Fe(NO3)2 (0.2 mol%), liquid NH3, 788C, 30 min; addition of
31, 5 min; 1-bromopentane (0.8 equiv), 1.5 h; to room temperature; 75%;
d) Li (6.0 equiv), 1,2-diaminopropane, room temperature to reflux, 30 min;
KOtBu (4.0 equiv), room temperature, 30 min; addition of 32, room
temperature, 1 h; 82%; e) Bu4NF (1.0 m in THF, 3.0 equiv), THF, 408C,
24 h; 78%; f) Pd(dba)2 (5.0 mol%), CuI (2.5 mol%), LiI (20 mol%),
addition of 34 (1.1 equiv) and 22, degassed DMSO, room temperature,
10 min; pentamethylpiperidine (2.8 equiv), 2 h; 60%; g) PPh3 (1.1 equiv),
imidazole (2.2 equiv), I2 (1.1 equiv), THF, 08C, 1 h; 88%; h) LDA
(2.2 equiv), THF, addition of 8, 788C, 2 h; addition of 21 (1.0 equiv) in
THF/DMPU (1:1), 458C, 20 h; 69%.
The remaining steps of our route to compound 12 are shown
in Scheme 6. The unsaturated ester trans-23 was reduced with
DIBAL in 92% yield giving the allyl alcohol 30.[36] Swern
oxidation[37] gave a crude aldehyde which was combined with
the Corey/Fuchs reagent[38] to provide the dibromotriene 33 in
53% yield over the two steps. A b-elimination of HBr effected
by Bu4NF[39] ensued and gave 78% of the bromodienyne 34.
This compound was C ± C coupled with the alkynol 22 under
the Cadiot ± Chodkievicz conditions developed by Vasella and
Cai,[40] that is, in DMSO solution in the presence of CuI,
Pd(dba)2, LiI, and pentamethylpiperidine; after 2 h at room
temperature the dienediynol 35 had formed in 60% yield. The
Chem. Eur. J. 1998, 4, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2345 $ 17.50+.25/0
2345

R. Brückner et al.
FULL PAPER
alkynol 22 used in this coupling was derived from its isomer 32
by the modified[20] alkyne zipper reaction[22] already men-
tioned in connection with the analogous isomerization 16 !18
of Scheme 3. Compound 32, in turn, was obtained by
pentylating the dianion of propargyl alcohol by using Brands-
maꢁs protocol.[19]
cinolactol 10 (equivalent to cis,trans-36). Consequently, there
was no doubt as to the correctness of the stereostructure of
compound 12. This meant, however, that the published
structure of sapranthin was incorrect. If one excluded that
sapranthin was structurally fundamentally different from 12, it
had to be a diastereomer. A good approximation of the nature
of this diastereomer emerged from comparisons of the NMR
spectra of sapranthin[17] and representatives of all four kinds
of diastereomeric a,g-dialkyl-b-hydroxy-g-lactones (see Ta-
ble 2). The groupwise similarities/discrepancies of the d values
compiled in Table 2 (cf. entries 5 and 6) suggested that
sapranthin was a trans,trans-disubstituted g-lactone (41;
Scheme 7) rather than the cis,trans-disubstituted g-lactone
12. This analysis was confirmed through synthesis (Scheme 7).
En route to compound 41, the OH group of the starting
lactone 8 had to be inverted. Under Mitsunobu conditions,[42]
a b-elimination occurred instead of the desired direct inver-
sion. Therefore, recourse was made to the three-step alter-
native of Scheme 7. Treatment of hydroxylactone 8 with mesyl
chloride and triethylamine effected the same b-elimination
more readily and provided butenolide 37[10] in 81% yield.
From other work in our laboratory[43] we knew that Flemingꢁs
higher order cuprate Li2(Me2PhSi)2Cu(CN)[44] adds to
butenolide 37 trans-selectively giving a lactone enolate which
was alkylated to form trisubstituted lactones 38.[43, 45] Perform-
The Cadiot ± Chodkievicz product 35, an alcohol, was
converted into the analogous iodide 21 through a reaction
‡
with Ph3P ± I
I
(Scheme 6).[41] This was the iodide with
which, according to our retrosynthetic analysis in Scheme 4,
we required to alkylate the enolate of the enantio-enriched
lactone 8. Indeed, in THF/DMPU this alkylation was realized
as smoothly and trans-selectively as the related alkylations 8 ‡
BuI !10 (Scheme 2) or 8 ‡ 20 !11 (Scheme 3). Compound
12 formed as the only stereoisomer in 69% yield.
Astonishingly, the 1H and 13C NMR shifts of the ring protons
and ring 13C nuclei as well as the associated H,H coupling
constants in compound 12 differed from the respective values
of ( )-sapranthin[17] (Table 2, cf. entries 4 and 5). Of course, the
alkylation affording 12 was strictly analogous to the alkylation
which had furnished compound 11 (grandinolide), and the
latterꢁs NMR data (select dH and JH,H values: Table 1, top half)
match exactly the values of the natural product. In addition,
the selected NMR data in Table 2 are almost identical for
compound 12, for grandinolide (11), and for the epi-blastmy-
Table 2. 1H and 13C NMR shifts (cis,cis-36, trans,trans-36, and trans,cis-36 at 270 MHz/67.9 MHz,[15b] cis,trans-36 at 500 MHz/125.7 MHz,[15d] 11 at 60 MHz/
15 MHz,[16] and ( )-sapranthin at 360 MHz/90.5 MHz,[17] respectively, in CDCl3) of differently substituted a,g-dialkyl-b-hydroxy-g-lactones.
Entry
d5-H
d4-H
d3-H
dC-5/dC-4
dC-3
OH
Bu
1
cis,cis-36
4.56
4.33
2.58
71.26/78.63
47.60
4
3
5
O
O
OH
Bu
4
3
2
3
4
cis,trans-36
4.64
4.63
4.64
4.18
4.20
4.21
2.55
2.54
2.54
73.85/78.69
74.0/78.5
49.23
49.2
5
O
O
OH
1´
Ph
(
)
18
4
3
5
O
O
O
11
OH
4
3
73.91/78.41
49.05
(
)
4
5
O
12
(-)-sapranthin
OH
5
6
4.20
4.21
3.86
3.81
2.54
2.57
78.7/80.1
48.4
Bu
4
trans,trans-36
trans,cis-36
79.00/79.91
48.65
5
3
O
O
OH
Bu
O
4
3
7
4.52
4.19
2.59
73.63/82.78
43.74
5
O
2346
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2346 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 11

Total Syntheses of ( )-Grandinolide and ( )-Sapranthin
2342±2352
The stereochemical key reaction 7 !8 of the present study
is just one example of our very general 1 !4 approach to g-
chiral g-lactones.[3] We deem it likely that many more applica-
tions will be found. In the above context this access to lactones
underlines the virtue of synthetic work in verifying or
reassigning the structure of poorly accessible natural products.
OH
a)
O
O
O
O
37
8 (78% ee)
ref. [43]
b)
Experimental Section
SiMe2Ph
SiMe2Ph
R
General methods: All reactions were performed in oven-dried glassware
under N2. THF was freshly distilled from K; toluene from Na; CH2Cl2,
DMPU, DMSO, 1,2-diaminopropane, and pyridine from CaH2. Products
were purified by flash chromatography[12] on Macherey-Nagel silica gel
[230 ± 400 mesh; eluents given in brackets; volume of each collected
fraction (mL)/column diameter (cm): 1.3/1.0, 4/1.5, 8/2.0, 14/2.5, 20/3.0, 30/4,
50/5, 80/6, 125/75; which fractions contained the isolated product is
indicated in each description by product in fractions xx ± yy]. Yields refer to
analytically pure samples. Isomer ratios were derived from suitable
1H NMR integrals. 1H NMR [CHCl3 (d ˆ 7.26) as internal standard in
CDCl3], 13C NMR [CDCl3 (d ˆ 77.00) as internal standard in CDCl3]:
Bruker AMX 300, and Varian VXR 500S; integrals in accord with assign-
ments; coupling constants in Hz. APT 13C NMR spectra: ‡ sign before d
O
O
O
O
39
38
c)
OH
value gives peak orientation of CH or CH3 resonances,
sign before d
O
value gives peak orientation of CH2 or Cquat resonances. The assignments of
1H and 13C NMR resonances refer to the IUPAC nomenclature; primed
numbers belong to the side chain. MS: Dr. G. Remberg, Institut für
Organische Chemie der Universität Göttingen; combustion analyses: F.
Hambloch, Institut für Organische Chemie der Universität Göttingen; IR
spectra: Perkin-Elmer 1600 Series FTIR; optical rotations: Perkin ± Elmer
polarimeter 241 at 589 nm; rotational values are the average of five
measurements of a in a given solution of the respective sample. Melting
O
40
OH
1´
3R
4R
d)
5S
(
)
4
O
O
points were measured on
uncorrected.
a Dr. Tottoli apparatus (Büchi) and are
41
Scheme 7. a) NEt3 (2.1 equiv), methanesulfonyl chloride (1.1 equiv),
CH2Cl2, 08C, 30 min; 81%; b) Li (10.0 equiv), PhMe2SiCl (4.0 equiv),
THF, 08C, 16 h; transferred to CuCN (2.0 equiv), THF, 108C, 30 min;
(4S,5S)-4,5-Dihydro-4-hydroxy-5-methyl-2(3H)-furanone (8): AD mix a
(14.0 g) and ester 7 (1.23 mL, 1.14 g, 10.0 mmol) were added to a 1:1
mixture of tBuOH and H2O (30 mL each) at 08C. After the mixture had
been stirred for four days, the reaction was terminated by adding aqueous
Na2SO3. After extraction with CH2Cl2 (10 Â 50 mL), the organic extracts
were dried over Na2SO4. Evaporation of the solvent gave a residue that was
purified by flash chromatography (3 cm, tBuOMe, fractions 8 ± 20) to
addition of 37,
788C, 15 min; 80%;c) AcOOH (32% in AcOH,
10.0 equiv), KBr (2.0 equiv), NaOAc (12.0 equiv), AcOH, 08C to room
temperature, 16 h; 32%; d) LDA (2.5 equiv), addition of 40, THF, 788C,
2 h; addition of 21 (1.0 equiv) in THF/DMPU (1:1), 408C, 20 h; 45%.
obtain 8 (462 mg, 40%). [a]D25
ˆ
62.2 (c ˆ 0.73 in MeOH); chiral capillary
gas chromatography revealed ee ˆ 78% [20% heptakis-(2,6-di-O-methyl-
3-O-pentyl-b-cyclodextrin) in 80% OV1701 (25 m), 70 kPa H2, 1108C
isothermal; RT 45.4 min, RT of enantiomer 44.3 min]. 1H NMR (300 MHz):
d ˆ 1.45 (d, J1',5 ˆ 6.8, 1'H3), 2.49 (brs, OH), AB signal (dA ˆ 2.58, dB ˆ 2.82,
JAB ˆ 17.8, in addition split by JA,4 ˆ 1.0, JB,4 ˆ 5.7, 3H2), 4.45 (brdd, J4,3-H(B)
ꢁ J4,5 ꢁ 4, 4-H), 4.58 (qd, J5,1' ˆ 6.4, J5,4 ˆ 3.8, 5-H). IR (neat): nÄ ˆ 3420,
2985, 2935, 1775, 1345, 1235, 1205, 1170, 1135, 1060, 995, 945 cm 1. C5H8O3
(116.1): calcd C 51.72, H 6.94; found C 51.64, H 7.24.
ing the same 1,4-addition of Li2(Me2PhSi)2Cu(CN) to bute-
nolide 37 but quenching the resulting enolate with water
rather than with an alkylating agent, we obtained the
silyllactone 39 in 80% yield. Therein, the Cmethine ± Si bond
was oxidized to a Cmethine ± O bond under the conditions
developed by Fleming et al.[46] Hydroxylactone 40 with the
inverted OH group resulted. It was isolated in only 32%
yieldÐa drawback of its high polarity and the associated
difficulty in extracting it from an aqueous solution without
losses. Nonetheless, we obtained enough lactone 40 for
realizing another completely trans-selective alkylation with
iodide 21. It delivered lactone 41 in 45% yield. Juxtaposing
selected NMR data of this compound with the corresponding
data of sapranthin (Table 1, bottom half) proves that the latter
possesses the formerꢁs relative configuration. The specific
[(3S,4S,5S)-3-Butyl-4,5-dihydro-5-methyl-2-oxo-(3H)-4-furyl] 3-methyl-
butanoate (9): Isovaleroyl chloride (96 mL, 94 mg, 0.78 mmol, 3.0 equiv)
was added to a solution of hydroxylactone 10 (45 mg, 0.26 mmol) in
CH2Cl2/pyridine (5:1, 6 mL) at 08C. After the mixture had been stirred for
6 h at room temperature, aqueous HCl (2 m, 1 mL) was added. After
extraction with CH2Cl2 (3 Â 10 mL), the combined organic phases were
dried over MgSO4. After removing the solvents flash chromatography
(2 cm, petroleum ether/tBuOMe 10:1 ! fraction 14, fractions 5 ± 11)
yielded the title compound (55 mg, 83%). [a]D20
ˆ
35.1 (c ˆ 0.9 in
CH2Cl2); the ee of the starting material 10 was 78%, therefore, the
measured specific rotation corresponds to [a]D20
ˆ
35.1/0.78 ˆ 45.0 for
optically pure 9 {ref. [15a] [a]2D0 ˆ 51 for the enantiomer (c ˆ 0.53, MeOH)}.
1H NMR (300 MHz, slightly impure): d ˆ 0.92 (t, J4'',3'' ˆ 7.2, 4''-H3), 0.97 (d,
J3Me,3 ˆ 6.8, 3-Me2), 1.29 ± 1.53 (m, 2''-H2, 3''-H2), partially superimposed by
1.34 (d, J5'-Me,5' ˆ 6.4, 5'-Me), 1.54 ± 1.83 (m, 1''-H2), 2.11 (tqq, central seven
peaks of theoretical nine visible, J3,2 ˆ J3,4 ˆ J3,3-Me ˆ 6.5, 3-H), 2.25 (mc,
which probably can be interpreted as d, J2,3 ˆ 6.4, 2-H2), 2.59 (ddd,
rotation of ( )-sapranthin ([a]D20
ˆ
30 (c ˆ 0.01, CHCl3))
and the specific rotation of 41 ([a]D20
ˆ
22 (c ˆ 0.28, CHCl3)),
after correcting for the latterꢁs ee of only 78% (equivalent to
[a]2D0 of optically pure 41 ˆ 22/ 0.78 ˆ 28) coincide with-
in a reasonable error span. This proves that ( )-sapranthin
possesses also the absolute configuration of compound 41.
J3',1''-H(1) ˆ 8.9, J3',1''-H(2) ˆ 6.4, J3',4' ˆ 3.0, 3'-H), 4.78 (qd, J5',5'-Me ˆ 6.6, J5',4'
ˆ
4.9, 5'-H), 5.18 (dd, J4',5' ˆ 4.9, J4',3' ˆ 2.6, 4'-H). 13C NMR (75 MHz):
Chem. Eur. J. 1998, 4, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2347 $ 17.50+.25/0
2347

R. Brückner et al.
FULL PAPER
d ˆ ‡13.68 and ‡14.24 (5'-Me, C-4''), ‡22.28 and ‡22.31 (C-4, 3-Me),
‡25.55 (C-3), 28.14 and 29.05 (C-1'', C-2'', C-3''), 43.04 (C-2), ‡47.10
(C-3'), ‡75.23 and ‡76.66 (C-4', C-5'), 172.18 and 176.57 (C-2', C-1). IR
material 8 was 78%, therefore, the measured specific rotation corresponds
1
to [a]2D0
ˆ
25/0.78 ˆ 32 for optically pure 12. H NMR (500 MHz): d ˆ
1.32 ± 1.62 (m, 1'-H1, 2'-H2, 3'-H2, 4'-H2, 5'-H2), superimposed by 1.41
(d, J5-Me,5 ˆ 6.6, 5-Me), 1.74 (mc, 1'-H2), 1.83 (brs, OH), 2.12 ± 2.25 (m, 13'-
H2, 14'-H2), 2.31 (t, J6',5' ˆ 7.0, 6'-H2), 2.53 (ddd, J3,1'-H(1) ˆ 7.9*, J3,1'-H(2) ˆ 6.6*,
(neat): nÄ ˆ 2960, 2935, 2870, 1780, 1740, 1465, 1390, 1370, 1340, 1295, 1250,
1
1185, 1120, 1040, 995, 945 cm
.
J3,4 ˆ 3.7, 3-H), 4.21 (brdd, J4,5 ꢁ J4,3 ꢁ 4.1, 4-H), 4.63 (qd, J5,5-Me ˆ 6.5, J5,4
ˆ
(3S,4S,5S)-3-Butyl-4,5-dihydro-4-hydroxy-5-methyl-2(3H)-furanone (10):
BuLi (1.44m in hexane, 4.44 mL, 6.40 mmol, 3.2 equiv) was added to a
solution of diisopropylamine (0.79 mL, 0.61 g, 6.0 mmol, 3.0 equiv) in THF
(20 mL) at 788C. After 30 min, a solution of the b-hydroxylactone 8
(232 mg, 2.00 mmol) in THF (5 mL) was added. After continuous stirring
for 2 h at this temperature, 1-iodobutane (0.34 mL, 0.55 g, 3.0 mmol,
1.5 equiv) in THF/DMPU (1:1, 8 mL) was slowly added. The reaction
mixture was stirred for 20 h at 358C, and then terminated by adding
aqueous HCl (1m, 10 mL). After extracting the aqueous phase with
tBuOMe (3 Â 30 mL), the combined organic extracts were dried over
MgSO4 and the solvent was evaporated. Flash chromatography (3 cm,
petroleum ether/tBuOMe 4:1 ! fraction 10, 2.5:1 ! fraction 26, fractions
15 ± 23) of the residue yielded the title compound (179 mg, 53%) as a
5.1, 5-H), 4.99 (dmc, Jcis ˆ 10.2, 16'-HE), partially superimposed by 5.02 (dtd,
Jtrans ˆ 17.2, J16',14' ˆ Jgem ˆ 1.6, 16'-HZ), 5.51 (dmc, Jtrans ˆ 15.9, 11'-H), 5.77
4
(ddt, Jtrans ˆ 17.1, Jcis ˆ 10.3, J15',14' ˆ 6.4, 15'-H), 6.27 (dt, Jtrans ˆ 15.9, J12',13'
ˆ
7.0, 12'-H); *assignments interchangeable. 13C NMR (75 MHz): d ˆ ‡13.85
(5-Me), 19.41 (C-6')*, 26.98, 28.00, 28.27, 28.40 and 28.72 (C-1',
C-2', C-3', C-4', C-5'), 32.45 and 32.58 (C-13', C-14')*, ‡49.05 (C-3),
65.28, 73.00, 73.88 and 83.55 (C-7', C-8', C-9', C-10'), ‡73.91 (C-4)*,
‡78.41 (C-5)*, ‡109.06 (C-11')*,
115.34 (C-16'), ‡137.23 (C-15')*,
‡147.13 (C-12')*, 177.89 (C-2) (*assignments verified by a C,H-COSY
spectrum (75 MHz/ 300 MHz)). IR (neat): nÄ ˆ 3440, 3075, 2935, 2860, 2235,
2140, 1770, 1640, 1445, 1340, 1190, 1135, 1055, 995, 955, 915 cm 1. C21H28O3
(328.5): calcd C 76.79, H 8.59; found C 74.90, H 8.55. Due to the instability
of 12, no better combustion analysis could be obtained. MS (DCI with
NH3): 348.3 (4%), 347.3 (20%), 346.3 (100%), 330.3 (4%), 329.3 (12%),
328.3 (46%).
colorless liquid. [a]D20
material 8 was 78%, therefore, the measured specific rotation corresponds
ˆ
57.0 (c ˆ 1.46 in MeOH); the ee of the starting
to [a]2D0
ˆ
57.0/0.78 ˆ 73.1 for optically pure 10 (ref. [15a] [a]2D0 ˆ ‡71
for the enantiomer (c ˆ 0.5, MeOH)). 1H NMR (300 MHz): d ˆ 0.92 (t,
J4',3' ˆ 7.2, 4'-H3), 1.30 ± 1.80 (m, 1'-H2, 2'-H2, 3'-H2), partially superimposed
by 1.41 (d, J5-Me,5 ˆ 6.8, 5-Me), 2.21 (mc, OH), 2.55 (ddd, J3,1'-H(1) ˆ 7.8,
J3,1'-H(2) ˆ 6.4, J3,4 ˆ 3.4, 3-H), 4.21 (brddd, J4,5 ꢁ J4,3 ꢁ J4,OH ꢁ 4.5, 4-H), 4.64
(qd, J5,5-Me ˆ 6.4, J5,4 ˆ 4.9, 5-H).
Tetrahydro-2-(2-propinyloxy)pyran (14): 3,4-Dihydro-2H-pyran (23.5 mL,
21.7 g, 258 mmol, 3.0 equiv) and a catalytic amount of pyridinium p-
toluenesulfonate were added to a stirred solution of propargyl alcohol
(5.00 mL, 4.82 g, 85.9 mmol) in CH2Cl2 (100 mL). After 16 h the reaction
mixture was hydrolyzed with aqueous NaCl (50 mL). After extraction with
tBuOMe (2 Â 50 mL) and drying over Na2SO4, the solvent was removed.
The residue was distilled (b.p. 1008C/20 mbar) and the title compound was
obtained as a colorless liquid (10.12 g, 84%). 1H NMR (300 MHz): d ˆ
(3S,4S,5S)-4,5-Dihydro-4-hydroxy-5-methyl-3-(19-phenylnonadecyl)-2(3H)-
furanone (11): BuLi (1.44m in hexane, 1.11 mL, 1.60 mmol, 3.2 equiv) was
added to a solution of diisopropylamine (0.20 mL, 0.15 g, 1.5 mmol,
3.0 equiv) in THF (5 mL) at 788C. After 30 min, a solution of lactone 8
(58 mg, 0.50 mmol) in THF (5 mL) was added. After continuous stirring at
this temperature for 2.5 h the iodide 20 (235 mg, 0.500 mmol, 1.0 equiv) in
THF/DMPU (1:1, 4 mL) was slowly added. The mixture was stirred for 20 h
at 408C. The reaction was terminated by adding aqueous HCl (1m,
5 mL). After extraction of the aqueous phase with tBuOMe (3 Â 20 mL),
the combined organic extracts were dried over MgSO4, and the solvent was
removed. The residue was purified by flash chromatography (2 cm,
petroleum ether/tBuOMe 2:1 ! fraction 6, 1:1 ! fraction 20, fractions
10 ± 18) to obtain the title compound (121 mg, 53%) as a white solid of m.p.
768C (ref. [16] 76 ± 788C). From fractions 1 ± 4 unconverted iodide 20
4
1.48 ± 1.91 (m, 3-H2, 4-H2, 5-H2), 2.42 (t, J3',1' ˆ 2.5, 3'-H), 3.49 ± 3.59 and
3.79 ± 3.89 (2 m each 1H, 6-H2), AB signal (dA ˆ 4.24, dB ˆ 4.29, JAB ˆ 15.8,
4
4
in addition split by JA,3' ˆ 2.3, JB,3' ˆ 2.6, 1'-H2), 4.83 (t, J2,3 ˆ 3.2, 2-H). IR
(neat): nÄ ˆ 3290, 2940, 2870, 2120, 1445, 1390, 1350, 1265, 1205, 1180, 1120,
1025, 975, 950, 900, 870, 815, 665 cm 1. C8H12O2 (140.2): calcd C 68.55, H
8.63; found C 68.69, H 8.61.
1-(Tetrahydropyran-2-yloxy)-2-nonadecyne (15): nBuLi (1.40m, 6.29 mL,
8.81 mmol, 1.2 equiv) was added to a solution of 14 (1.00 g, 7.35 mmol) in
THF (10 mL) at 08C. After 15 min stirring 1-bromohexadecane (2.47 mL,
2.47 g, 8.08 mmol, 1.1 equiv) and DMSO (25 mL) were added. After
stirring at room temperature for 14 h, the reaction was terminated by
adding H2O (30 mL). After extraction with tBuOMe (2 Â 20 mL) and
aqueous NaCl (2 Â 30 mL), then drying over Na2SO4, the solvent was
removed. Flash chromatography (petroleum ether/tBuOMe 30:1, fractions
(102 mg, 43%) was reisolated. [a]D20
starting material 8 was 78 %, therefore, the measured specific rotation
ˆ
23 (c ˆ 0.5 in MeOH); the ee of the
corresponds to [a]D20
ˆ
23/0.78 ˆ 30 for optically pure 11 (ref. [16]
[a]2D0
ˆ
34 (MeOH)). 1H NMR (300 MHz): d ˆ 1.22 ± 1.88 (m, 1'-H2 to
1
4 ± 11) of the residue yielded the title compound (2.05 g, 76%). H NMR
18'-H2, OH), partially superimposed by 1.41 (d, J5-Me,5 ˆ 6.6, 5-Me), 2.53
(ddd, J3,1'-H(1) ˆ 8.2, J3,1'-H(2) ˆ 6.0, J3,4 ˆ 3.6, 3-H), partially superimposed by
2.60 (dd, J19',18'-H(1) ꢁ J19',18'-H(2) ꢁ 7.8, 19'-H2), 4.20 (dd, J4,5 ꢁ J4,3 ꢁ 4.2, 4-H),
4.63 (qd, J5,5-Me ˆ 6.8, J5,4 ˆ 5.0, 5-H), 7.13 ± 7.20 (m, 3Ar-H), 7.24 ± 7.31 (m,
2ArH). 13C NMR (50 MHz): d ˆ 13.84 (5-CH3), 27.21, 28.40, 29.30 (relative
intensity ˆ 2), 29.37 (relative intensity ˆ 2), 29.47 (relative intensity ˆ 2),
29.55 (relative intensity ˆ 3), 29.65 (relative intensity ˆ 7), 31.49 and 35.93
(C-1' to C-19', that is, 9 resonance frequencies for 19 C atoms), 49.26 (C-3),
73.82 and 78.62 (C-4 and C-5), 125.44 (p-C), 128.11 and 128.29 (2 o-C and 2
m-C), 142.84 (ipso-C), 178.28 (C-2). IR (KBr): nÄ ˆ 3130, 2920, 2850, 1745,
1660, 1495, 1470, 1400, 1340, 1235, 1195, 1050, 995, 720, 695 cm 1. C30H50O3
(458.7): calcd C 78.55, H 10.99; found C 78.54, H 10.69.
(300 MHz): d ˆ 0.88 (t, J19,18 ˆ 6.8, 19-H3), 1.26 and approximately 1.30 ±
1.90 (mc and m, relative intensity difficult to estimate, 5-H2 to 18-H2, 3'-H2,
5
4'-H2, 5'-H2), 2.21 (tt, J4,5 ˆ 7.1, J4,1 ˆ 2.1, 4-H2), 3.48 ± 3.58 and 3.80 ± 3.89
(2 m each 1-H, 6'-H2), AB signal (dA ˆ 4.21, dB ˆ 4.29, JAB ˆ 15.4, in
5
5
addition split by JA,4 ˆ 2.1, JB,4 ˆ 2.2, 1-H2), 4.82 (t, J2',3' ˆ 3.4, 2'-H). 13C
NMR (50 MHz): d ˆ ‡14.12 (C-19), 18.84, 19.14, 22.70, 25.40,
28.62, 28.89, 29.14, 29.37, 29.55, 29.68 (fourfold intensity),
30.30 and 31.92 (15 resonances for 18 C atoms: C-4 to C-18, C-3', C-4',
C-5'), 54.63 and 61.96 (C-1, C-6'), 75.67 (C-3), 86.76 (C-2), ‡96.60
(C-2'). IR (neat): nÄ ˆ 2925, 2850, 2225, 1460, 1345, 1265, 1200, 1180, 1120,
1075, 1025, 970, 950, 905, 870, 815, 720 cm 1. C24H44O2 (364.6): calcd C
79.06, H 12.16; found C 79.25, H 12.04.
(3S,4S,5S)-3-(11,15-Hexadecadiene-7,9-diynyl)-4,5-dihydro-4-hydroxy-5-
methyl-2(3H)-furanone (12): nBuLi (2.5m in hexane, 0.44 mL, 1.1 mmol,
2.2 equiv) was added to a solution of diisopropylamine (0.14 mL, 0.11 g,
1.1 mmol, 2.2 equiv) in THF (5 mL) at 788C. After 30 min a solution of
lactone 8 (58.1 mg, 0.500 mmol) in THF (5 mL) was added. After a further
2 h, the iodide 21 (170 mg, 0.500 mmol, 1.0 equiv) in THF/DMPU (1:1,
4 mL) was added within 15 min. Stirring was continued for 20 h at 458C.
The reaction was terminated by adding aqueous HCl (1m, 10 mL). After
extraction of the aqueous phase with tBuOMe (3 Â 30 mL) the combined
organic phases were dried over MgSO4 and the solvent was removed. Flash
chromatography (3 cm, petroleum ether/Et2O 2:1 ! fraction 16, 1.5:1 !
fraction 33, 1:1 ! fraction 60, fractions 42 ± 54) of the residue yielded the
title compound (113 mg, 69%; 79% based on recovered iodide) as a
colorless oil. Unconverted iodide 21 (22.5 mg, 13%) was reisolated from
2-Nonadecyn-1-ol (16): p-Toluenesulfonic acid monohydrate (390 mg,
2.05 mmol, 0.4 equiv) was added to the THP ether 15 (1.87 g, 5.13 mmol)
in MeOH (40 mL) and the reaction mixture was stirred for 2 h. The solvent
was removed after hydrolysis with H2O (30 mL), extraction with tBuOMe
(2 Â 30 mL), and drying over Na2SO4, and the title compound (1.32 g, 92%)
was obtained as a white solid (m.p. 628C). 1H NMR (300 MHz): d ˆ 0.88 (t,
J19,18 ˆ 6.6, 19-H3), 1.26 and approximately 1.30 ± 1.55 (mc and m, relative
intensity difficult to estimate, 5-H2 to 18-H2, OH), 2.21 (tt, J4,5 ˆ 7.0, 5J4,1
ˆ
2.2, 4-H2), 4.25 (mc, 1-H2). 13C NMR (50 MHz): ‡14.15 (C-19), 18.75,
22.71, 28.62, 28.88, 29.15, 29.37, 29.53, 29.70 (fourfold inten-
sity) and 31.93 (12 resonances for 15 C atoms: C-4 to C-18). 51.47 (C-1),
78.22 (C-3), 86.72 (C-2). IR (CDCl3): nÄ ˆ 3155, 2985, 2925, 2855, 2255,
1
1795, 1640, 1560, 1470, 1380, 1295, 1215, 1165, 1095, 915, 740, 650 cm
C19H36O (280.5): calcd C 81.36, H 12.94; found C 81.41, H 12.98.
.
fractions 3 ± 5. [a]D20
ˆ
25 (c ˆ 0.37 in CHCl3); the ee of the starting
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
2348
0947-6539/98/0411-2348 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 11

Total Syntheses of ( )-Grandinolide and ( )-Sapranthin
2342±2352
19-Phenyl-18-nonadecyn-1-ol (17): The following reagents were added to a
solution of the alkynol 18 (1.24 g, 4.42 mmol) in THF (30 mL) at 08C:
PdCl2(PPh3)2 (155 mg, 0.221 mmol, 5.0 mol%), copper iodide (126 mg,
0.663 mmol, 15 mol%), iodobenzene (593 mL, 1.08 g, 5.30 mmol, 1.2 equiv),
and diisopropylamine (5.80 mL, 4.47 g, 44.2 mmol, 10.0 equiv). The reac-
tion mixture was stirred at room temperature for 12 h. Water (10 mL) was
added, the phases were separated, and the aqueous phase was extracted
with tBuOMe (3 Â 50 mL). The combined organic phases were dried over
MgSO4 and the solvent removed. Flash chromatography (5 cm, petroleum
ether/tBuOMe 4:1 ! fraction 12, 1:1 ! fraction 16, fractions 5 ± 12)
yielded 17 (1.33 g, 84%) as a slightly brownish solid (m.p. 558C). 1H NMR
(300 MHz): d ˆ 1.24 ± 1.65 (m, 2-H2 to 16-H2), 2.40 (t, J17,16 ˆ 7.0, 17-H2), 3.64
(t, J1,2 ˆ 6.6, 1-H2), 7.24 ± 7.31 (m, 3Ar-H), 7.36 ± 7.42 (m, 2Ar-H); the
resonance of the OH group was not detected. IR (KBr): nÄ ˆ 3420, 3180,
2915, 2850, 1640, 1615, 1470, 1400, 1075, 755, 690 cm 1. C25H40O (356.6):
calcd C 84.21, H 11.31; found C 84.51, H 11.35.
MgSO4, the solvent was removed. Flash chromatography (3 cm, petroleum
ether/tBuOMe 20:1, fractions 8 ± 15) yielded the iodo compound (449 mg,
88%). 1H NMR (300 MHz): d ˆ 1.37 ± 1.49 (m, 13-H2, 14-H2), 1.49 ± 1.60
(m, 11-H2), 1.83 (tt, J15,14 ˆ J15,16 ˆ 6.9, 15-H2), 2.10 ± 2.27 (m, 3-H2, 4-H2),
2.32 (t, J11,12 ˆ 6.8, 11-H2), 3.19 (t, J16,15 ˆ 7.0, 16-H2), 4.99 (dmc, Jcis ꢁ 10.2, 1-
HE), partially superimposed by 5.02 (dmc, Jtrans ꢁ 17.4, 1-HZ), 5.51 (poorly
7
resolved dd, Jtrans ˆ 16.0, J6,11 ˆ 0.9, 6-H), 5.77 (ddt, Jtrans ˆ 17.2, Jcis ˆ 10.3,
J2,3 ˆ 6.4, 2-H), 6.27 (dt, Jtrans ˆ 15.9, J5,4 ˆ 6.7, 5-H). 13C NMR (50 MHz):
d ˆ 6.95 (C-16), 19.42, 27.65, 27.97, 29.92, 32.45, 32.59 and
33.27 (C-3, C-4, C-11, C-12, C-13, C-14, C-15), 65.35, 72.97, 73.89
and 83.33 (C-7, C-8, C-9, C-10), ‡109.08 (C-6), 115.32 (C-1), ‡137.19
and ‡147.03 (C-2, C-5). IR (neat): nÄ ˆ 3075, 2930, 2855, 2235, 2140, 1640,
1450, 1425, 1360, 1300, 1245, 1200, 1165, 1080, 990, 955, 915 cm 1. C16H21I
(340.2): calcd C 56.48, H 6.22; found C 56.48, H 6.24.
7-Octyn-1-ol (22) was prepared in the same way as 18 using 1,2-
diaminopropane (60 mL), Li (1.00 g, 144 mmol, 6.0 equiv), KOtBu
(10.8 g, 96.2 mmol, 4.0 equiv) and alcohol 32 (3.00 g, 23.8 mmol). Flash
chromatography (3 cm, pentane/Et2O 2:1 ! 1:2, fractions 5 ± 17) yielded
the title compound (2.46 g, 82%). 1H NMR (300 MHz): d ˆ 1.28 ± 1.45 and
18-Nonadecyn-1-ol (18): Li (0.371 g, 53.5 mmol, 6.0 equiv) was added to
dry 1,2-diaminopropane (50 mL) and stirred for 15 min. The resulting blue
solution was refluxed for 15 min, until the blue color disappeared.
Subsequently, KOtBu (4.00 g, 35.7 mmol, 4.0 equiv) was added at room
temperature. After stirring for 30 min, the alkyne 16 (2.00 g, 7.13 mmol)
was added slowly. The reaction mixture was hydrolyzed with ice water
(40 mL) after 1 h. The solvent was removed after extraction with tBuOMe
(3 Â 50 mL), H2O, aqueous HCl (2m), and aqueous NaCl (50 mL each), and
drying over Na2SO4. Flash chromatography (6 cm, petroleum ether/
tBuOMe 7:1 ! tBuOMe, fractions 23 ± 40) yielded the title compound
4
1.46 ± 1.60 (2 m each 4-H, 2-H2, 3-H2, 4-H2 and 5-H2), 1.92 (t, J8,6 ˆ 2.6,
8-H), superimposed by (brs, detectable by the integral only, OH), 2.16 (tt,
J6,5 ˆ 6.9, 4J6,8 ˆ 2.5, 6-H2), 3.60 (t, J1,2 ˆ 6.6, 1-H2). IR (neat): nÄ ˆ 3295, 2935,
2860, 2115, 1460, 1435, 1330, 1055, 1035, 630 cm 1. C8H14O (126.2) calcd C
76.14, H 11.18; found 76.04, H 11.08.
Methyl E-2,6-heptadienoate (trans-23) and methyl Z-2,6-heptadienoate
(cis-23): The unsaturated ester 26 (4.06 g, 29.0 mmol) was heated for 16 h
to 2408C in a pressure-resistant flask in a sand bath. Flash chromatography
(6 cm, pentane/Et2O 30:1 ! fraction 10, 20:1 ! fraction 20) of the
colorless residue yielded cis-23 (fraction 7 ± 10, 325 mg, 8%) and trans-23
(fraction 11 ± 18, 3.055 g, 75%). trans-23: 1H NMR (300 MHz): d ˆ 2.18 ±
2.36 (m, 4-H2, 5-H2), 3.73 (s, OMe), 5.01 (dtd, Jcis ꢁ 10.6, 4J7,5 ꢁ Jgem ꢁ 1.4,
1
(1.67 g, 84%) as a white solid (m.p. 598C). H NMR (300 MHz): d ˆ 1.26
and approximately 1.27 ± 1.63 (mc and m, relative intensity difficult to
estimate, 2-H2 to 16-H2, OH), 1.94 (t, 4J19,17 ˆ 2.9, 19-H), 2.18 (td J17,16 ˆ 7.0,
4J17,19 ˆ 6.8, 5-H2), 3.64 (dt, J1,2 ˆ J1,OH ˆ 5.9, 1-H2). 13C NMR (50 MHz):
18.42, 25.76, 28.51, 28.79, 29.14, 29.45, 29.53, 29.62 (three-
fold intensity), 29.69 (fourfold intensity), 29.84 and 32.83 (11 reso-
nances for 15 C atoms: C-2 to C-16), 63.11 (C-1), ‡68.02 (C-19), 84.83
(C-18). IR (CDCl3): nÄ ˆ 3305, 3155, 2925, 1855, 1155, 1795, 1645, 1560, 1465,
1380, 1295, 1165, 1095, 915, 740, 650 cm 1. C7H12O (112.1): calcd C 81.36, H
12.94; found C 81.30, H 12.93.
4
7-HE), partially superimposed by 5.05 (dtd, Jtrans ꢁ 16.9, J7,5 ꢁ Jgem ꢁ 1.7,
7-HZ), 5.80 (ddt, Jtrans ˆ 17.0, Jcis ˆ 10.2, J6,5 ˆ 6.2, 6-H), severely super-
imposed by 5.84 (dt, Jtrans ˆ 15.8, 4J2,4 ˆ 1.5, 2-H), 6.97 (dt, Jtrans ˆ 15.8, J3,4
ˆ
6.6, 3-H). IR (neat): nÄ ˆ 3080, 2980, 2950, 2845, 1725, 1660, 1645, 1435, 1320,
1270, 1210, 1175, 1040, 990, 915 cm 1. C8H12O2 (140.2): calcd C 68.54, H
8.63; found C 68.71, H 8.83. cis-23: 1H NMR (300 MHz): d ˆ 2.15 (tdt, J5,4
ˆ
19-Phenyl-1-nonadecanol (19): The alkynol 17 (210 mg, 0.590 mmol) was
dissolved in EtOAc (10 mL). Pd (10% on charcoal, 31 mg, 0.029 mmol,
5.0 mol%) was added and the mixture stirred in an H2 atmosphere (5 bar)
in the autoclave for 16 h. After diluting the mixture, filtration through
Celite, and evaporation of the solvent the title compound (173 mg, 82%)
J5,6 ˆ 7.2, 4J5,7 ˆ 1.3, 5-H2), 2.71 (tdd, J4,5 ˆ J4,3 ˆ 7.5, 4J4,2 ˆ 1.7, 4-H2), 3.65 (s,
OMe), 4.94 (dmc, Jcis ꢁ 10, 7-HE), partially superimposed by 4.99 (dtd, Jtrans
ꢁ 17, 4J7,5 ꢁ Jgem ꢁ 1.8, 7-HZ), 5.74 (dt, Jcis ˆ 11.7, 4J2,4 ˆ 1.5, 2-H), completely
superimposed by 5.76 (ddt, Jtrans ˆ 17.0, Jcis ˆ 10.2, J6,5 ˆ 6.6, 6-H), 6.17 (dt,
Jcis ˆ 11.6, J3,4 ˆ 7.6, 3-H). IR (neat): nÄ ˆ 3080, 2950, 1720, 1645, 1440, 1405,
1210, 1175, 995, 910, 820, 735, 650 cm 1. C8H12O2 (140.2): calcd C 68.54, H
8.63; found C 68.42, H 8.49.
1
was isolated as a white solid (m.p. 648C). H NMR (300 MHz): d ˆ 1.24 ±
1.38 (m, 3-H2 to 17-H2), 1.51 ± 1.66 (m, 2-H2, 18-H2), 2.60 (brt, J19,18 ˆ 7.9,
19-H2), 3.64 (t, J1,2 ˆ 6.6, 1-H2), 7.13 ± 7.20 (m, 3Ar-H), 7.24 ± 7.30 (m, 2Ar-
H); the resonance of the OH group was not detected. IR (KBr): nÄ ˆ 3180,
2915, 2850, 1635, 1460, 1400, 1075, 745, 700 cm 1. C25H44O (360.6): calcd C
83.26, H 12.30; found C 83.05, H 12.41.
Methyl (2-ethenyl-4-pentenoate) (26): BuLi (2.5m in hexane, 20.0 mL,
50.0 mmol, 1.0 equiv) was added to a solution of HMDS (10.5 mL, 8.05 g,
50.0 mmol, 1.0 equiv) in THF (200 mL) at 788C. After 30 min, ester 27
(6.31 g, 50.0 mmol) was added and after another 30 min, Me3SiCl (6.94 mL,
5.94 g, 55.0 mmol, 1.1 equiv) was added. The reaction mixture was
gradually warmed to room temperature after continuous stirring for
10 min at 788C and finally refluxed for 30 min. After the mixture had
cooled down, aqueous HCl (1m, 300 mL) was added in one go with
vigorous stirring. After extraction of the aqueous phase with tBuOMe (3 Â
200 mL), the combined organic phases were dried over MgSO4 and the
solvent was evaporated. The 1H NMR spectrum revealed the residue
(6.30 g) to be a 87:13 mixture of 2-vinyl-4-pentenoic acid (28) and a
sterically homogenous 2-ethyliden-4-pentenoic acid (29) of unknown
1-Iodo-19-phenylnonadecane (20): The alcohol 19 (90 mg, 0.25 mmol) and
triphenylphosphite (66 mL, 78 mg, 0.25 mmol, 1.0 equiv) were dissolved in
CH2Cl2 (3 mL). After the mixture had been stirred for 10 min at room
temperature, I2 (64 mg, 0.25 mmol, 1.0 equiv) was added at 08C. Water
(5 mL) was added to the brown solution after 1 h and the colorless organic
phase was removed. After extraction of the aqueous phase with petroleum
ether (2 Â 20 mL), the combined organic extracts were dried over MgSO4.
After the solvent had been removed, flash chromatography (2 cm,
petroleum ether ! fraction 10, fractions 2 ± 4) of the residue yielded the
iodide 20 (91 mg, 82%) as a white solid (m.p. 508C). 1H NMR (300 MHz):
d ˆ 1.23 ± 1.41 (m, 3-H2 to 17-H2), 1.61 (brtt, J18,17 ˆ J18,19 ˆ 7.4, 18-H2), 1.82
(tt, J2,1 ˆ J2,3 ˆ 7.2, 2-H2), 2.60 (brt, J19,18 ˆ 7.7, 19-H2), 3.18 (t, J1,2 ˆ 7.2, 1-H2),
7.13 ± 7.20 (m, 3Ar-H), 7.24 ± 7.32 (m, 2Ar-H). 13C NMR (50 MHz): d ˆ 7.34
(C-1), 28.56, 29.36, 29.44, 29.53, 29.57, 29.61, 29.63, 29.69, 30.52, 31.55, 33.58
and 35.99 (i.e. 12 resonances for 18 C atoms, C-2 to C-19), 125.49 (p-C),
128.16 and 128.34 (2  o-C, 2  m-C), 142.89 (ipso-C). IR (KBr): nÄ ˆ 2915,
2850, 1615, 1470, 1400, 1165, 745, 715, 695, 600 cm 1. C25H43I (470.5): calcd
C 63.82, H 9.21; found C 63.96, H 8.93.
configuration [d
ˆ 7.10 (q, J ꢁ 7)]. The residue was dissolved in
ˆ
CHMe
CHCl3 (60 mL), and MeOH (4.05 mL, 3.20 g, 100 mmol, 2.0 equiv) and p-
TsOH (190 mg, 1.00 mmol, 2.0 mol%) were added. This mixture was
connected to an inverse water trap and refluxed for 16 h. After removal of
most of the solvent at room temperature, the deconjugated ester 26
(4.380 g, 63%) was isolated by flash chromatography (8 cm, pentane/Et2O
40:1 ! fraction 6, 20:1 ! fraction 12, 10:1 ! fraction 16, fractions 8 ± 15).
1H NMR (300 MHz): d ˆ AB signal (dA ˆ 2.33, dB ˆ 2.51, JAB ˆ 14.2, in
addition split by JA,2 ꢁ JA,4 ꢁ 6.8, JB,2 ꢁ JB,4 ꢁ 7.2, signals broadened by
nonresolved Jallyl, 3-H2), 3.12 (ddd, J2,1' ˆ J2,3-H(A) ˆ J2,3-H(B) ˆ 7.7, 2-H), 3.69 (s,
OMe), 5.01 ± 5.18 (m, 5-H2, 2'-H2), 5.74 (dddd, Jtrans ˆ 17.4, Jcis ˆ 10.2,
J4,3-H(A) ˆ J4,3-H(B) ˆ 7.0, 4-H), superimposed by 5.83 (ddd with small extra
peaks indicating transition to higher order splitting, Jtrans ˆ 17.3, Jcis ˆ 9.8,
J1',2 ˆ 8.3, 1'-H). IR (neat): nÄ ˆ 3080, 2980, 2950, 1740, 1640, 1435, 1345,
E-16-Iodo-1,5-hexadecadiene-7,9-diyne (21): A solution of the alcohol 35
(345 mg, 1.50 mmol) in THF (10 mL) was successively treated with PPh3
(432 mg, 1.65 mmol, 1.1 equiv), imidazole (224 mg, 3.30 mmol, 2.2 equiv),
and I2 (419 mg, 1.65 mmol, 1.1 equiv) at 08C. After 1 h a saturated NH4Cl
solution (5 mL) was added to the reaction mixture, followed by extraction
with tBuOMe (2 Â 50 mL). After the organic phase had been dried over
Chem. Eur. J. 1998, 4, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2349 $ 17.50+.25/0
2349

R. Brückner et al.
FULL PAPER
1270, 1240, 1195, 1170, 995, 920 cm 1. C8H12O2 (140.2): calcd C 68.54, H
8.63; found C 68.75, H 8.48.
(100 mL) was added and the organic phase was separated. After extraction
of the aqueous phase with Et2O (2 Â 50 mL) the organic phases were
combined and dried. The solvent was removed at 08C, and the residue was
purified by flash chromatography (5 cm, petroleum ether ! fraction 12,
fractions 5 ± 11) to give the title compound (1.29 g, 78%). 1H NMR
(300 MHz): d ˆ 2.10 ± 2.25 (m, 3-H2, 4-H2), 4.99 (dmc, Jcis ꢁ 10.2, 1-HE),
Allyl 3-butenoate (27): A solution of 3-butenoic acid (8.50 mL, 8.61 g,
0.100 mol), allyl alcohol (6.79 mL, 5.80 g, 0.100 mol, 1.0 equiv) and p-TsOH
(0.19 g, 1.0 mmol, 1 mol%) in CHCl3 (50 mL) was connected to an inverse
water trap and refluxed for 16 h. Distillation (b.p. 738C/15 mbar) yielded
the title ester (12.2 g, 97%). 1H NMR (300 MHz): d ˆ 3.13 (dt, J2,3 ˆ 6.9,
4J2,4 ˆ 1.3, 2-H2), 4.60 (dt, J1',2' ˆ 5.6, 4J1',3' ˆ 1.3, 1'-H2), 5.14 to approximately
partially superimposed by 5.03 (dmc, Jtrans ꢁ 17.0, 1-HZ), 5.46 (dt, Jtrans
ˆ
4
16.2, J6,4 ˆ 1.5, 6-H), 5.78 (ddt, Jtrans ˆ 16.9, Jcis ˆ 10.4, J2,3 ˆ 6.4, 2-H), 6.21
(dt, Jtrans ˆ 15.8, J5,4 ˆ 6.8, 5-H). 13C NMR (50 MHz): d ˆ 32.21 and 32.60
(C-3, C-4), 47.60 (C-8), 78.76 (C-7), 109.52 and 115.31 (C-1, C-6), 137.29 and
145.62 (C-2, C-5). IR (neat): nÄ ˆ 3075, 3025, 3000, 2975, 2925, 2845, 2210,
2165, 1760, 1730, 1640, 1435, 1415, 1300, 990, 960, 915 cm 1. C8H9Br (185.1):
calcd C 51.92, H 4.90; found C 52.03, H 4.77.
5.22 (m, 4-H2), partially superimposed by 5.24 (ddt, Jcis ˆ 10.3, Jgem ˆ 4J3',1'
ˆ
1.3, 3'-HE), 5.32 (ddt, Jtrans ˆ 17.2, Jgem ˆ 4J3',1' ˆ 1.5, 3'-HZ), 5.86 ± 6.01 (m,
3-H, 2'-H).
E-2,6Heptadien-1-ol (30): DIBAL (1.0m in toluene, 66 mL, 66 mmol,
2.2 equiv) was added to a solution of the ester trans-23 (4.20 g, 30.0 mmol)
in THF (100 mL) at 788C. The reaction mixture was slowly warmed to
room temperature. After 30 min, the reaction was terminated by careful
addition of aqueous HCl (2 m, 35 mL). The organic phase was separated
and the aqueous phase extracted with tBuOMe (3 Â 50 mL). After the
combined organic phases had been dried over MgSO4, the solvent was
removed. The residue was purified by flash chromatography (7 cm,
petroleum ether ! fraction 10, petroleum ether/tBuOMe 2:1 ! fraction
24, fractions 14 ± 20) to yield the title compound (3.08 g, 92%) as a colorless
liquid. 1H NMR (300 MHz): d ˆ 1.41 (mc, OH), 2.13 ± 2.17 (m, 4-H2, 5-H2),
4.09 (d, J1,2 ˆ 4.5, 1-H2), 4.97 (dmc, Jcis ꢁ 11, 7-HE), partially superimposed
by 5.02 (dmc, Jtrans ꢁ 17, 7-HZ), 5.61 ± 5.88 (m, 2-H, 3-H, 6-H). IR (neat): nÄ ˆ
3330, 3075, 2980, 2920, 2845, 1670, 1640, 1440, 1415, 1090, 1000, 970,
910 cm 1. C7H12O (112.2): calcd C 74.95, H 10.78; found C 75.11, H 11.02.
E-11,15Hexadecadiene-7,9-diyn-1-ol (35): A mixture of Pd(dba)2 (169 mg,
0.294 mmol, 5 mol%), CuI (28.0 mg, 0.147 mmol, 2.5 mol%), and LiI
(157 mg, 1.18 mmol, 20 mol%) was treated with a solution of bromoalkyne
34 (1.20 g, 6.46 mmol, 1.1 equiv) and alkyne 22 (742 mg, 5.88 mmol) in
degassed DMSO (40 mL). After 10 min 1,2,2,6,6-pentamethylpiperidine
(2.97 mL, 2.55 g, 16.5 mmol, 2.8 equiv) was added. After continued stirring
for 2 h the mixture was diluted with Et2O (50 mL), water (50 mL), and
aqueous HCl (2m, 8 mL). The organic phase was separated and the
aqueous phase extracted with Et2O (2 Â 50 mL). The combined organic
phases were extracted with water (50 mL) and dried over MgSO4. After
removal of the solvent the residue was purified by flash chromatography
(4 cm, petroleum ether/tBuOMe 3:1 ! fraction 30, 2:1 ! fraction 45, 1:1
! fraction 60, fractions 36 ± 58) to yield the title compound (808 mg, 60%).
The homocoupling product of the bromoalkyne 34 (176 mg, 11%) was
obtained from fractions 5 ± 6. 1H NMR (300 MHz): d ˆ 1.30 ± 1.49 (m, 3-H2,
4-H2, OH), 1.50 ± 1.63 (m, 2-H2, 5-H2), 2.10 ± 2.27 (m, 13-H2, 14-H2), 2.32
(brt, J6,5 ˆ 6.8, 6-H2), 3.65 (t, J1,2 ˆ 6.4, 1-H2), 4.99 (dmc, Jcis ꢁ 10.2, 16-HE),
partially superimposed by 5.02 (dtd, Jtrans ꢁ 17.4, 4J16,14 ˆ Jgem ˆ 1.5, 16-HZ),
5.51 (brd, Jtrans ˆ 15.8, 11-H), 5.77 (ddt, Jtrans ˆ 17.0, Jcis ˆ 10.5, J15,14 ˆ 6.3, 15-
H), 6.27 (dt, Jtrans ˆ 15.8, J12,13 ˆ 6.7, 12-H). IR (neat): nÄ ˆ 3330, 3075, 2935,
2860, 2235, 2140, 1640, 1435, 1350, 1300, 1075, 1055, 1030, 995, 955,
915 cm 1. C16H22O (230.4): calcd C 83.43, H 9.63; found C 83.18, H 9.93.
2-Octyn-1-ol (32): A catalytic amount of Fe(NO3)3 (approximately 100 mg)
and Li (4.16 g, 600 mmol, 3.0 equiv) were added to liquid ammonia
(350 mL). After 30 min, 2-propyn-1-ol (14.8 mL, 14.0 g, 250 mmol,
1.25 equiv) was added dropwise. 1-Bromopentane (24.8 mL, 30.2 g,
200 mmol) was slowly added after 5 min. The ammonia was evaporated
after 1.5 h and the residue hydrolyzed with ice water (100 mL). After
extraction with Et2O (6 Â 100 mL) and drying over Na2SO4, the solvent was
removed. Distillation of the residue (b.p. 105oC/30 mbar) yielded the title
compound (19.0 g, 75%). 1H NMR (300 MHz; slightly impure): d ˆ 0.90 (t,
J8,7 ˆ 7.2, CH3), 1.25 ± 1.43 (m, 6-H2, 7-H2), 1.47 ± 1.57 (m, 5-H2), 1.60 (brs,
OH), 2.21 (tt, J4,5 ˆ 7.0, 5J4,1 ˆ 2.1, 4-H2), 4.25 (poorly resolved t, 5J1,4 ˆ 2.1, 1-
H2). IR (neat): nÄ ˆ 3325, 2955, 2930, 2860, 2360, 2290, 2225, 1460, 1430,
1380, 1330, 1135, 1010, 725 cm 1. C8H14O (126.2): calcd C 76.14, H 11.18;
found C 76.27, H 11.05.
(5S)-5-Methyl-2(5H)-furanone (37): Lactone 8 (546 mg, 4.70 mmol) was
dissolved in CH2Cl2 (30 mL). At 08C NEt3 (1.37 mL, 1.00 g, 9.87 mmol,
2.1 equiv) and methanesulfonyl chloride (0.40 mL, 0.59 g, 5.2 mmol,
1.1 equiv) were added. After 1 h the reaction was terminated by adding
saturated NH4Cl solution (10 mL) and water (20 mL). The phases were
separated, and the aqueous phase was extracted with CH2Cl2 (3 Â 50 mL).
After drying the combined organic phases over MgSO4 the solvent was
removed at 08C. Flash chromatography (4 cm, pentane/Et2O 1:2, fractions
10-18) of the residue yielded the butenolide 37 (370 mg, 81%) as a colorless
liquid. [a]2D0 ˆ 80.7 (c ˆ 0.65 in CHCl3); the ee of the starting material 8 was
78%, therefore, the measured specific rotation corresponds to [a]2D0 ˆ 80.7/
E-1,1-Dibromo-1,3,7-octatriene (33): DMSO (4.17 mL, 4.63 g, 59.4 mmol,
2.2 equiv) was slowly added to a solution of oxalyl chloride (2.60 mL,
3.77 g, 29.7 mmol, 1.1 equiv) in CH2Cl2 (60 mL) at 788C. After 3 min, the
allyl alcohol 30 (3.00 g, 27.0 mmol) was added. NEt3 (18.7 mL, 13.6 g,
135 mmol, 5.0 equiv) was added after 15 min followed by water (50 mL)
after another 30 min. The phases were separated, and the aqueous phase
was extracted with CH2Cl2 (2 Â 100 mL). The combined organic phases
were extracted with HCl (2m, 65 mL), dried over MgSO4, and the solvent
was removed at room temperature. The isolated residue was used without
purification to prepare 33: CBr4 (17.9 g, 54.0 mmol, 2.0 equiv) was added to
a solution of PPh3 (28.3 g, 108 mmol, 4.0 equiv) in CH2Cl2 (250 mL) at 08C.
After 10 min, the isolated aldehyde (2.97 g, 27.0 mmol) was added to the
orange solution. Most of the solvent was removed after 1 h at room
temperature. Petroleum ether (500 mL) was added to the residue and the
precipitated solid was filtered off. After thoroughly washing the solid
residue with petroleum ether, the solvent was removed from the filtrate.
Flash chromatography (5 cm, petroleum ether ! fraction 10, fractions 3 ±
5) of the dark brown residue yielded the dibromotriene 33 (3.82 g, 53%
overall yield) as a colorless liquid. 1H NMR (300 MHz): d ˆ 2.19 (mc, 5-H2,
0.78 ˆ 104 for optically pure 37 {ref. [10] [a]D20
ˆ
107 for the enantiomer
(c ˆ 1.61, CHCl3)}. 1H NMR (300 MHz): d ˆ 1.46 (d, J5-Me,5 ˆ 6.8, 5-Me),
4
5.15 (qdd, J5,5-Me ˆ 6.9, J5,4
ꢁ
4J5,3 ˆ 1.7, 5-H), 6.11 (dd, J3,4 ˆ 5.6, J3,5 ˆ 1.9,
3-H), 7.46 (dd, J4,3 ˆ 5.7, J4,5 ˆ 1.5, 4-H).
(4R,5S)-4-[(Dimethylphenyl)silyl]-4,5-dihydro-5-methyl-2(3H)-furanone
(39): A solution of Me2PhSiCl (2.53 mL, 2.58 g, 15.1 mmol, 4.0 equiv) in
THF (30 mL) was stirred for 24 h at 08C with Li (260 mg, 37.8 mmol,
10.0 equiv). The dark red solution was slowly added to a suspension of
CuCN (696 mg, 7.56 mmol, 2.0 equiv) in THF (50 mL) at 108C. After an
additional 30 min the mixture was cooled to 788C and treated dropwise
with a solution of butenolide 37 (370 mg, 3.78 mmol) in THF (10 mL).
Aqueous HCl (1m, 20 mL) was added after 15 min at the same temper-
ature. After extraction of the aqueous phase with tBuOMe (3 Â 30 mL), the
organic phase was dried over MgSO4. After removal of the solvent, the
silane 39 (708 mg, 80%) was obtained by flash chromatography (3 cm,
petroleum ether/tBuOMe 3:1 ! fraction 18, 2:1 ! fraction 24, fractions
4
6-H2), 5.00 (dtd, Jcis ˆ 10.6, J8,6 ˆ Jgem ˆ 1.0, 8-HE), partially superimposed
4
by 5.04 (dtd, Jtrans ˆ 16.9, J8,6 ˆ Jgem ˆ 1.5, 8-HZ), 5.73 ± 5.96 (m, 4-H, 7-H),
6.11 (incompletely resolved ddt, Jtrans ˆ 15.3, J3,2 ˆ 10.0, 4J3,5 ˆ 1.4, 3-H), 6.90
(d, J2,3 ˆ 9.8, 2-H). IR (neat): nÄ ˆ 3075, 2975, 2925, 2850, 2340, 1765, 1725,
1640, 1620, 1445, 1270, 1170, 1075, 995, 970, 915, 810 cm 1. C8H10Br2 (266.0):
calcd C 36.13, H 3.79; found C 34.36, H 3.57. Because of the instability of
this compound no better combustion analysis could be obtained.
10 ± 22) as a colorless oil. [a]D20
starting material 8 was 78%, therefore, the measured specific rotation
ˆ
22 (c ˆ 0.44 in CHCl3); the ee of the
corresponds to [a]D20
ˆ
22/0.78 ˆ 28 for optically pure 39. 1H NMR
(300 MHz): d ˆ 0.38 and 0.39 (2s, SiMe2), 1.29 (d, J5-Me,5 ˆ 6.0, 5-Me), 1.61
(ddd, J4,3-H(A) ˆ 12.0, J4,5 ˆ 10.4, J4,3-H(B) ˆ 9.2, 4-H), AB signal (dA ˆ 2.39,
dB ˆ 2.55, JAB ˆ 17.5, in addition split by JA,4 ˆ 12.8, JB,4 ˆ 9.2, 3-H2), 4.45
(dq, J5,4 ˆ 10.4, J5,5-Me ˆ 6.2, 5-H), 7.36 ± 7.50 (m, 5Ar-H). IR (neat): nÄ ˆ 3070,
3050, 2975, 2935, 2900, 1770, 1430, 1385, 1360, 1345, 1255, 1225, 1190, 1155,
E-8-Bromo-1,5-octadiene-7-yne (34): Bu4NF (1.0m in THF, 27.0 mL,
27.0 mmol, 3.0 equiv) was added to a solution of the dibromotriene 33
(2.39 g, 9.00 mmol) in THF (40 mL) and the mixture was stirred for 24 h at
408C. After dilution of the dark brown solution with Et2O (50 mL), water
2350
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2350 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 11

Total Syntheses of ( )-Grandinolide and ( )-Sapranthin
2342±2352
1115, 1085, 1050, 945, 930, 895, 835, 785, 735, 700, 650 cm 1. C13H18SiO2
(234.4): calcd C 68.62, H 7.74; found C 68.87, H 7.58.
[3] C. Harcken, R. Brückner, Angew. Chem. 1997, 109, 2866 ± 2868;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2750 ± 2752.
[4] Reviews: a) B. B. Lohray, Tetrahedron: Asymmetry 1992, 3, 1317 ±
1349; b) R. A. Johnson, K. B. Sharpless, Asymmetric Catalysis in
Organic Synthesis (Ed.: I. Ojima), VCH, New York, 1993, 227 ± 272;
c) H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483 ± 2547; d) G. Poli, C. Scolastico in Methoden Org. Chem.
(Houben-Weyl) 4th ed. 1952, Vol. E21e (Eds.: G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1995,
pp. 4547 ± 4598.
[5] Z.-M. Wang, X.-L. Zhang, K. B. Sharpless, S. C. Sinha, A. Sinha-
Bagchi, E. Keinan, Tetrahedron Lett. 1992, 33, 6407 ± 6410; Y.
Miyazaki, H. Hotta, F. Sato, Tetrahedron Lett. 1994, 35, 4389 ± 4392.
[6] Preparation of AD mixes: K. B. Sharpless, W. Amberg, Y. L. Bennani,
G. A. Crispino, J. Hartung, K.-S. Jeong, H. L. Kwong, K. Morikawa,
Z. M. Wang, D. Xu, X. L. Zhang, J. Org. Chem. 1992, 57, 2768 ± 2771.
[7] R. Hill, R. van Heyningen, Biochem. J. 1951, 49, 332 ± 335.
[8] J. W. Wheeler, G. M. Happ, J. Araujo, J. M. Pasteels, Tetrahedron Lett.
1972, 4635 ± 4638.
(4R,5S)-4,5-Dihydro-4-hydroxy-5-methyl-2(3H)-furanone (40): A solution
of the silane 39 (234 mg, 1.00 mmol) in diluted HOAc (3 mL) was mixed
with KBr (238 mg, 2.00 mmol, 2.0 equiv), NaOAc (980 mg, 12.0 mmol,
12.0 equiv), and peroxyacetic acid (32% in diluted HOAc, 2.10 mL,
10.0 mmol, 10.0 equiv) at 08C. After stirring the mixture at room temper-
ature for 16 h, aqueous Na2S2O3 solution (10 mL) was added to the brown
solution. K2CO3 solution was added to adjust the pH to 7, followed by
extraction with CH2Cl2 (5 Â 30 mL). After the mixture had been dried over
MgSO4, and the solvent was removed, and the residue was purified by flash
chromatography (3 cm, tBuOMe, fractions 8 ± 16) to yield 40 (37.0 mg,
32%). [a]2D0
ˆ
8.40 (c ˆ 1.20 in CHCl3); the ee of the starting material 8
was 78%, therefore, the measured specific rotation corresponds to [a]D20
ˆ
8.40/0.78 ˆ 10.8 for optically pure 40 {ref. [10] [a]2D0 ˆ ‡10.87 for the
enantiomer (c ˆ 2.42, CHCl3)}. 1H NMR (300 MHz): d ˆ 1.38 (d, J5-Me,5
ˆ
6.7, 5-Me), AB signal (dA ˆ 2.53, dB ˆ 2.85, JAB ˆ 17.9, in addition split by
JA,4 ˆ 3.6, JB,4 ˆ 6.4, 3-H2), superimposed by approximately 2.84 (brs, OH),
4.25 (mc, 4-H), 4.58 (qd, J5,5-Me ˆ 6.6, J5,4 ˆ 2.8, 5-H).
[9] M. Masuda, K. Nishimura, Phytochemistry 1971, 10, 1401 ± 1402; M.
Masuda, K. Nishimura, Chem. Lett. 1981, 1333 ± 1336.
(3R,4R,5S)-3-(11,15Hexadecadiene-7,9-diinyl)-4,5-dihydro-4-hydroxy-5-
methyl-2(3H)-furanone (41) was prepared in the same way as 12 using
diisopropylamine (88 mL, 68 mg, 0.67 mmol, 2.5 equiv), nBuLi (2.5m in
hexane, 0.27 mL, 0.67 mmol, 2.5 equiv), b-hydroxylactone 40 (31.4 mg,
0.270 mmol), and iodo compound 21 (92.0 mg, 0.270 mmol, 1.0 equiv). The
alkylation step was carried out at 408C for 20 h. Flash chromatography
(2 cm, petroleum ether/tBuOMe 2:1 ! fraction 24, 1:1 ! fraction 38,
fractions 27 ± 36) of the residue yielded the title compound (39.8 mg, 45%;
62% based on recovered iodide) as white, light-sensitive crystals melting at
778C (decomp; ref. [17] 888C). From fractions 2 ± 5 unconverted iodide 21
Â
[10] Previous preparation of this compound: S. Y. Chen, M. M. Joullie, J.
Org. Chem. 1984, 49, 2168 ± 2174.
[11] ADs of disubstituted olefins trans-Me-CH CH ± R were reported to
ˆ
show 72% ee in the cases of 2-butene (unpublished results in ref. [4c])
and trans-4,5-diphenyl-2-(trans-3-pentenyl)-1,3-dioxolane (A. Sobti,
G. A. Sulikowski, Tetrahedron Lett. 1995, 36, 4193 ± 4196), 73% ee in
the case of 1-phenylpent-3-en-1-yne (K.-S. Jeong, P. Sjö, K. B.
Sharpless, Tetrahedron Lett. 1992, 33, 3833 ± 3836), and 95% ee in
the cases of 1-chloro-2-butene (K. P. M. Vanhessche, Z.-M. Wang,
K. B. Sharpless, Tetrahedron Lett. 1994, 35, 3469 ± 3472) or 4,4-
dimethyl-2-pentene (unpublished results in ref. [4c]).
(24.5 mg, 27%) was reisolated. [a]D20
ˆ
22 (c ˆ 0.28); the ee of the starting
material 8 was 78%, therefore, the measured specific rotation corresponds
to [a]2D0
ˆ
22/0.78 ˆ 28 for optically pure 41 {ref. [17] [a]D20
ˆ
30 (c ˆ
[12] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem 1978, 43, 2923 ± 2925.
[13] Method: H.-M. Shieh, G. D. Prestwich, J. Org. Chem. 1981, 46, 4319 ±
4321; Tetrahedron Lett. 1982, 23, 4643 ± 4646.
[14] a) D. Seebach, Chimia 1985, 39, 147 ± 148; b) D. Seebach, A. K. Beck,
A. Studer in Modern Synthetic Methods 1995 (Eds.: B. Ernst, C.
Leumann), VCH, Weinheim, 1995, pp. 1 ± 178.
[15] The enantiomer of 9 was synthesized by: a) S. Aburaki, N. Konishi, M.
Kinoshita, Bull. Chem. Soc. Jpn. 1975, 48, 1254 ± 1259; b) J. Mulzer, T.
Schulze, A. Strecker, W. Denzer, J. Org. Chem. 1988, 53, 4098 ± 4103;
and c) M. P. Sibi, J. Lu, C. L. Talbacka, J. Org. Chem. 1996, 61, 7848 ±
7855; and d) racemic 9 by C. Mukai, O. Kataoka, M. Hanaoka, J. Org.
Chem. 1993, 58, 2946 ± 2952.
[16] P. C. Vieira, M. Yoshida, O. R. Gottlieb, H. F. P. Filho, T. G. Nagem,
R. B. Filho, Phytochemistry 1983, 22, 711 ± 713.
[17] J. T. Etse, P. G. Waterman, Phytochemistry 1986, 25, 1903 ± 1905.
[18] R. Zemribo, M. S. Champ, D. Romo, Synlett 1996, 278 ± 280.
[19] Method: L. Brandsma, Preparative Acetylenic Chemistry, Elsevier,
Amsterdam, 1988, pp. 42 ± 43.
1
0.01, CHCl3)}. H NMR (500 MHz): d ˆ 1.32 ± 1.64 (m, 1'-H1, 2'-H2, 3'-H2,
4'-H2, 5'-H2), superimposed by 1.46 (d, J5-Me,5 ˆ 6.3, 5-Me), 1.86 (dddd,
Jgem ˆ 13.4, J1'-H(2),2'-H(1) ˆ 10.8, J1'-H(2),2'-H(2) ˆ J1'-H(2),3 ˆ 5.4, 1'-H2), 2.06 (brd,
JOH,4 ˆ 5.1, OH), 2.12 ± 2.17 and 2.20 ± 2.25 (2 m each 2-H, 13'-H2, 14'-H2),
2.32 (poorly resolved td, J6',5' ˆ 6.9, 7J6',11' ˆ 0.6, 6'-H2), 2.55 (ddd, J3,4 ˆ 8.7*,
J3,1'-H(1) ˆ 7.4*, J3,1'-H(2) ˆ 5.7, 3-H), 3.84 (brddd, J4,5 ꢁ J4,3 ꢁ 8.0, J4,OH ꢁ 4.6,
4-H), 4.20 (dq, J5,4 ˆ 7.2, J5,5-Me ˆ 6.4, 5-H), 4.99 (dmc, Jcis ꢁ 10, 16'-HE),
partially superimposed by 5.02 (dtd, Jtrans ˆ 17.0, 4J16',14' ˆ Jgem ˆ 1.7, 16'-HZ),
5.51 (dmc, Jtrans ˆ 16.0, 11'-H), 5.77 (ddt, Jtrans ˆ 17.0, Jcis ˆ 10.3, J15',14' ˆ 6.4,
15'-H), 6.27 (dt, Jtrans ˆ 16.0, J12',13' ˆ 6.9, 12'-H); *assignments interchange-
able. 13C NMR (75 MHz): d ˆ ‡18.19 (5-Me), 19.43 (C-6')*, 26.49,
28.03, 28.32, 28.45 and 28.90 (C-1', C-2', C-3', C-4', C-5'), 32.46
and 32.59 (C-13', C-14')*, ‡48.51 (C-3), 65.27, 73.04, 73.89 and
83.62 (C-7', C-8', C-9', C-10'), ‡78.95 (C-4)*, ‡79.98 (C-5)*, ‡109.09 (C-
11')*, 115.35 (C-16'), ‡137.24 (C-15')*, ‡147.13 (C-12')*, 176.13 (C-2);
*assignments verified by a C,H-COSY (300 MHz/75 MHz). IR (KBr): nÄ ˆ
3425, 3075, 2935, 2860, 2235, 2140, 1765, 1640, 1460, 1445, 1385, 1335, 1230,
1195, 1135, 1055, 995, 955, 915 cm 1. MS (DCI with NH3): 347.2 (6%), 346.2
(38%), 329.3 (18%), 328.3 (100%).
[20] Procedure: E. J. Corey, H. Niwa, J. Knolle, J. Am. Chem. Soc. 1978,
100, 1942 ± 1943.
[21] E. Rank, Diplomarbeit, Universität Göttingen, 1996. Lithium ap-
peared to dissolve more rapidly in 1,2- than in 1,3-diaminopropane,
which is the first reaction in the preparation of potassium 2-amino-
propane-1-amide (3-aminopropane-1-amide).
Acknowledgments: This work was supported by the Fonds der Chemischen
Industrie, for which we are very grateful. In addition, we thank BASF AG
for donating chemicals.
[22] Method: C. A. Brown, A. Yamashita, J. Am. Chem. Soc. 1975, 97,
891 ± 892; procedure: S. R. Abrams, A. C. Shaw, Org. Syn., Coll. Vol
VIII, Wiley, New York, 1993, pp. 146 ± 148.
Received: January 14, 1998
Revised version: May 28, 1998 [F 962]
[23] Method: K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 4467 ± 4470.
[24] Method: D. G. Coe, S. R. Landauer, H. N. Rydon, J. Chem Soc. 1954,
2281 ± 2288.
[1] Recent syntheses of non-racemic g-chiral g-lactones: W. Y. Yu, C.
Bensimon, H. Alper, Chem. Eur. J. 1997, 3, 417 ± 423; T. Chevtchouk, J.
Ollivier, J. Salaün, Tetrahedron: Asymmetry 1997, 8, 1011 ± 1014; A. M.
Fernandez, J. C. Plaquevent, L. Duhamel, J. Org. Chem. 1997, 62,
4007 ± 4014; S. I. Fukuzawa, K. Seki, M. Tatsuzawa, K. Mutoh, J. Am.
Chem. Soc. 1997, 119, 1482 ± 1483; M. P. Doyle, Aldrichim. Acta 1996,
29, 3 ± 11.
[25] The carboxylic acid trans-24 which underlies ester trans-23 had been
ˆ
ˆ
prepared by the allylation of H2C CH CH C(OCu)2 in excellent
selectivity and yield by J. A. Katzenellenbogen, A. L. Crumrine, J.
Am. Chem. Soc. 1976, 98, 4925 ± 4935. We thank a referee for bringing
this reference to our attention.
Á
[2] Recent syntheses of non-racemic g-chiral butenolides: B. Figadere, J.-F.
Â
[26] R. K. Hill, in Comprehensive Organic Synthesis, Vol. 5 (Eds.: B. M.
Trost, I. Fleming) [Combining C ± C p-Bonds (Ed.: L. A Paquette)],
Pergamon, Oxford, 1991, pp. 785 ± 826; H. Frauenrath, in Methoden
Org. Chem. (Houben-Weyl) 4th ed. 1952, Vol. E21e (Eds.: G.
Peyrat, A. Cave, J. Org. Chem. 1997, 62, 3428 ± 3429; J. A. Marshall,
M. A. Wolf, E. M. Wallace, J. Org. Chem. 1997, 62, 367 ± 371; A. van
Oeveren, B. L. Feringa, J. Org. Chem. 1996, 61, 2920 ± 2921. See also
D. W. Knight, Contemp. Org. Synth. 1994, 1, 287 ± 315.
Chem. Eur. J. 1998, 4, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2351 $ 17.50+.25/0
2351

R. Brückner et al.
FULL PAPER
Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme,
Stuttgart, 1995, pp. 3547 ± 3756.
[27] P. Wipf, in Comprehensive Organic Synthesis, Vol. 5 (Eds.: B. M. Trost,
[35] We did not combine the Claisen ± Ireland and the Cope rearrange-
ments of Scheme 5 in a tandem reaction even if tandem Claisen/Cope
rearrangements are in principle known: F. E. Ziegler, in Comprehen-
I. Fleming) [Combining C ± C p-Bonds (Ed.: L.
A
Paquette)],
sive Organic Synthesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming)
Pergamon, Oxford, 1991, pp. 827 ± 873; S. Pereira, M. Srebnik,
Aldrichimica Acta 1993, 26, 17 ± 29; H. Frauenrath, in Methoden
Org. Chem. (Houben-Weyl) 4th ed. 1952-, Vol. E21e (Eds.: G.
Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme,
Stuttgart, 1995, pp. 3301 ± 3547.
[Combining C ± C p-Bonds (Ed.: L. A Paquette)], Pergamon, Oxford,
1991, pp. 875 ± 898.
[36] Other syntheses of dienol 30: X. Beebe, C. L. Chiappari, M. J. Kurth,
N. E. Schore, J. Org. Chem. 1993, 58, 7320 ± 7321; S. Araki, H. Usui, M.
Kato, Y. Butsugan, J. Am. Chem. Soc. 1996, 118, 4699 ± 4700. A one-
step synthesis from butadienoxide (Y. Naruta, K. Maruyama, Chem.
Lett. 1987, 963 ± 966) gave 82% 30 and 19% 2-vinyl-3-buten-1-ol.
[37] Method: K. Omura, D. Swern, Tetrahedron Lett. 1978, 1651 ± 1660.
[38] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 3769 ± 3772.
[39] Method: J. A. Marshall, B. E. Blough, J. Org. Chem. 1991, 56, 2225±2234.
[40] C. Cai, A. Vasella, Helv. Chim. Acta 1995, 78, 2053 ± 2064.
[41] Method: U. Berlage, J. Schmidt, U. Peters, P. Welzel, Tetrahedron Lett.
1987, 27, 3091 ± 3094.
[28] Directly after submitting our manuscript a report of similar consec-
utive Claisen ± Ireland and Cope rearrangements appeared: S. Gil,
Â
M. A. Lazaro, M. Parra, E. Breitmaier, R. Mestres, Synlett 1998, 70± 72.
[29] For example, S. R. Wilson, R. S. Myers, J. Org. Chem. 1975, 40, 3309 ±
3311.
[30] For example, M. Amaike, K. Mori, Liebigs Ann. Chem. 1995, 1451 ±
1454.
[31] A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441 ± 445; F. E.
Ziegler, J. J. Piwinski, J. Am. Chem. Soc. 1979, 101, 1611 ± 1612.
[32] G. H. Jeffery, A. I. Vogel, J. Chem. Soc. 1948, 658 ± 673.
[33] Procedure: K. Mori, M. Amaike, H. Watanabe, Liebigs Ann. Chem
1993, 1287 ± 1294.
[42] D. L. Hughes, Org. React. 1992, 42, 335 ± 656.
[43] T. Berkenbusch, R. Brückner, Tetrahedron 1998, 54, 11461 ± 11470.
[44] Procedure: B. Lipshutz, in: Organometallics in Synthesis, (Ed.: M.
Schlosser), Wiley, Chichester, 1994, pp. 326 ± 327.
[34] The ethyl analogue of methyl ester 26 was obtained by J. L. Herrmann,
G. R. Kieczykowski, R. H. Schlessinger, Tetrahedron Lett. 1973,
2433 ± 2436 from ethyl crotonate, LDA, and allyl bromide; the
presence of 1.1 equivalents of HMPA (carcinogenic) was required
because otherwise (we confirmed this) only ethyl 3-(diisopropylami-
no)butyrate is obtained. The analogous allylation in the presence of
1.0 equivalents of DMPU still provided ethyl 3-(diisopropylamino)-
butyrate as the major product and no more than 30% of the ethyl ester
analogue of 26. Similar allylations in a 1:1 mixture of THF and DMPU
gave the latter compound not at all, 40% ethyl 2,2-diallyl-3-butenoate
and unreacted ethyl crotonate.
[45] Compound 41 could not be prepared from butenolide 37 via an
ˆ
intermediate of type 38 because the C C bonds in the a-substituent
would not tolerate unchanged the Cmethine-Si !Cmethine-O oxidation
required for reaching the target structure 41.
[46] Method: I. Fleming, R. Henning, D. C. Parker, H. E. Plant, P. E. J.
Sanderson, J. Chem. Soc. Perkin Trans. I 1995, 317 ± 337.
[47] This value was published (ref. [17]) erroneously and interpreted
accidentally (ref. [48]). The 360 MHz 1H NMR spectrum of ( )-
sapranthin shows a 4-H signal which is identical to the 4-H signal of
synthetic 41 (ref. [48]).
[48] P. G. Waterman, personal communication.
2352
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0411-2352 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 11